Note: Descriptions are shown in the official language in which they were submitted.
~3~3~3
This is a divisional application of Serial No. 386,091 filed
September 17, 1981.
The parent application re]ates to certain novel 3-[2-hydroxy-4-
(substituted)phenyl]-4 (or --5)-substituted cyc]oalkanols useful as analgesic
agents and as anti-emetic agents and processes for their preparation.
This invention relates to novel 3-[2-hydroxy-4-(substituted)phenyl~
-4 (or-5)-hydroxyalkyl cycloalkanone derivatives useful as analgesic agents
and as anti-emetic agents as well as intermediatesfor preparingthe cyclo-
alkanol compoundsof ~he parent application, and processes for their preparation.
Despite the current availability of a number of analgesic agents,
the search for new and improved agents useful for~he control of broad levels
of pain and accompanied by a minimum of side-effec~s continues. The most
commonly used agent, aspirin, is of no practical value for the control cf
severe pain and is kno~n to exhibit various undesirable side-effects. Other
analgesic agents, such as meperidine, codeine, and morphine, possess addietive
liability. The need for improved and potent analgesic agents is, thereere,
evident.
Compounds having utility as analgesics, tranquilizers, sedatives,
antianxiety agents and/or as anticonvulsants, diuretics and antidiarrheal
agents are described in Belgian Patents 870,404 and 870,402, both granted
~arch 12, 1979. Belgian Patent 870,404 describes 3-[2-hydroxy-4-~sllbst:itutecl)
phenyl]cycloalkanones and cycloalkanols which may ~have at the 4-position oE
the cycloalkanone or cycloalkanol residue, an alkyl, alkenyl, phenyl or
phenylalkyl substituent; or, at the 5-position, an alkyl substituent, and
Belgian Patent 870,402 discloses certain 2-(acyclic substituted)phenols;
namely, 2-(hydroxyalkyl)-4-(substituted)phenols and 2-(oxoalkyl)-4-
(substituted)phenols.
3353~
IJnited Sta-tes Patent 3,576,887, issued April 27, 1971, discloses a
series of l-~l'-hydroxy)alkyl-2-(o-hydroxyphenyl)cyclohexanes which exhibit
central nervous system depressant properties.
Our concurrently filed Canadian application, Serial No. 386,121,
entitled "Pharmacologically Active 4-[2-Hydroxy-4-(Substi~uted)phenyl]
Naphthalen-2~1H)-ones and 2-ols~ Derivatives Thereof and Intermediates
Therefore," describes a series of 4-[2-hydroxy-4-(substituted)-phenyl]
naphthalen-2~lH)-ones and 2-ols useful as CNS agentsandasanti-emetic agents.
United States Paten~ 3,974,157 describes 2-phenylcyclohexanones which
can be substituted in the phenyl ring with up to two alkyl, hydroxy or alkoxy
groups as intermediates for preparation of l-(aminoalkyl)-2-phenylcyclohexanols
useful as analgesics, local anesthetics and antiarrhythmics.
Chemical Abstracts 85, 176952f (1976) disc].oses a number of 3-phenyl-
and 3-phenylalkylcyclohexanones as intermediates for 2-aminomethyl-3-phenyl
(or phenylalkyl)cyclohexanones which exhibit analgesic, sedative, antidepres-
sant and anticonvulsant activities.
The present invention provides a process for making a compound having
the formula
( ~ ~ 2 ORl
~Y ~ ,l _ z W ~II)
wherein Rl is hydrogen, alkanoyl having from one to five carbon atoms,
or a hydroxy-protecting group selected from the group consisting of a lower
alkyl, tetrahydropyranyl, benzyl and a substituted benzyl having as the substi-
i38
tuent alkyl having from one to four carbon a~oms, halo or alkoxy having from
one to four carbon atoms;
s i.s an integer of 1 or 2;
W is hydrogen, pyridyl or- ~ Wl wherein Wl is hydrogen, chloro or
fluoroy provided that
when W is hydrogen, Z is
(a~ alkylene havimg from five to thirteen carbon atoms; or
(b) -~alkl)m-0-(alk2)n- wherein each of (alkl) and(alk2) is alkylene
having from one to thirteen carbon atoms; each of m and n is 0 or 1; wi.th the
provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less
than five or greater than thirteen; and at least one of m and n is l; or
(c) -Z-W is 1,1-dimethyl-2-hep~enyl;
when W is other than hydrogen, Z is
(a) alkylene having from three to eight carbon atoms; or
(b) -talkl)m-0--(alk2)n- wherein each of (alkl) and (alk2) is alkylene
having from one to eight carbon atoms; each of m and n is 0 or 1 with the
provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less
than three or greater than eight; and at least one of m and n is l;
Y' is CH(R2") CH(R2)- or -CH(R3)CH2- wherein R2" is hydrogen or
methyl; R2 is a hydroxy alkyl with up to six carbon atoms; R3 is a hydroxy
alkyl with up to three carbon atoms; and R2 is a ~-position substituent and R3
is a 5-position substitLIent; which process comprises:
(A) hydrating a].kenyl R2 or R3 in a ~- or 5-alkenyl-3-phenyl-
cycloalkan-l-one derivative having the formula (II-B), or a ketal thereof;
~l
(~5 1
Y' ~ ~ (II-B)
~ Z-W
3~i3~
wherein s, Rl, Z and W are as defined above; and Y" is -CH(R2")
CH(R2)- or -CH(R3)CH2- wherein R2" is asdefined abova, R2 is a 4-position
substituent and is alkenyl with up to six carbon atoms and R3 is a 5-position
substituent and is an alkenyl with up to three carbon atoms, or
(B) reducing oxo-alkyl R2 or R3 in a 4- or 5- oxo-alkyl-3-phenyl~
cycloalkan-l-one derivative having the formula ~II-C), or a C-l ketal thereof,
o
~S
~ ~ Z - W (II-C)
wherein s, Rl, Z and W are as defined above; and Y"' is -CH(R2")CH
(R2)- or -CH(R3)CH2- wherein R2" is as defined above, R2 is a ~-position
substituent and is oxo-alkyl with up to six carbon atoms, R3 is a 5-position
substituent and is oxo-alkyl with up to three carbon atoms, to hydroxy alkyl or
(C~ subjecting oxo-alkyl R2 or R3 in the compound of ~ormula (II-C)
as defined above or a C-l ketal thereof to the Grignard reaction, and
(D) when required, converting the ketal into the corresponding ketone,
and/or removing the hydroxy-protecting group, and/or acylating the hydroxy
group.
The present invention also provides a compound of formula (II) as
described above, prepared by the process defined above.
Also included in this invention as noted above are the pharmaceuti-
cally acceptable acid addition salts of those compounds of formulae II which
contain pyridyl as the W variable.
Representative of such pharmaceutically acceptable acid addition
-- 4 --
salts are the mineral acid salts such as the hydrocllloride, hydrobromide,
sulfate, phosphate, nitrate; organic acid salts suchas the citrate, acetate,
sulfosalicylate, tartrate, glycolate, malate, malonate, maleate, pamoate,
salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate,
lactate, mandelate and methanesulfonate.
Compounds of formula II wherein Rl is hydrogen exist, in solution, in
equilibrium with their hemiketal forms. The keto and hemiketal forms of said
compounds of formula II are included in this invention.
Compounds of formula II contain asymmetric cent~rs at the 3-, ~he 4-
and the 5-positions in the cycloalkyl moiety and may, of course, contain
additional asymmetric centers in ~-Z-W) of the phenyl ring. Trans-relationship
between the 3- and ~- substituents and the 3- and 5-substituents on the cyclo-
alkyl moiety are favored because of the greater ~quantitatively) biological
activity.
For convenience, the above formula depicts the racemic compounds.
However, the above formula is considered to be generic to anu embracive of the
racemic modifications of the compounds of ~his invention, the diastereomeric
mixtures, the pure enant:iomers and diastereomers thereo-~. The utility of the
racemic mixture, the diastereomeric mixture as well as of the pure enantiomers
and diastereomers is determined by the biological evaluation procedures
described belo~.
Favoréd because o:E their greater biological activity relative to that
of other compounds described herein are compounds of formula II wherein Rl is
hydrogen; R2" is hydrogen or methyl; and Z alld W have the values shown below:
-- 5 --
13~53~
z m n w
.
C7_11 alkylene --- _ H
C4 7 al~ylene ~ _ W1, pyridyl
-(alkl)m-O-(alk2)n- 0,1 1 _<~ Wl~ pyridyl
each of (alkl) and (alk2) is Cl 7 alkylelle with theproVisO tha-t the
summa~ion of carbon atoms in (alkl~ plus (alk2) is not less ~han four or greater
than seven;
-(alkl)m-0-(alk2)n- 0~1 1 H
each of (alkl) and ~alk2) is Cl 11 alkylene with ~he proviso that
the summation of carbon atoms in (alkl) plus (alk2) is not less than seven or
greater than eleven.
Preferred compounds of formula II are those ~avored compounds wherein:
each of R2" and Rl is hydrogen;
Z is C(CH3)2(CH2)6 and W is hydrogen;
Z is C4 7 alkylene and W is phenyl;
Z is -0-alkylene having 7 to 9 carbon a-toms and W is hydrogen;
Z is -0-alkylene having from 4 to 5 carbon atoms and W is phenyl;
R2 = ~-hydroxy(C2_4)alkyl.
Especially preferred are compounds of formula II wherein Rl, Z and W
are as defined for the preferred compounds; R2 is 3-hydroxypropyl; and R3 is
hydroxymethyl. The l-form of a given compound is preferred over the d-form
thereof.
The compounds having formula (II-B) or (II-C) wherein Y" is
-CH(R2")CH(R2)- or Y"' is -CH(R2")CH(R2 ) are prepared from the appropriate
2-bromo-5-(Z-W substituted)phenol by a series of reactions which comprises as
the first step protection of the phenolic group. Suitable protecting groups are
-- 6 --
~13~
those which do not interfere with the subsequent reactions and which can be
removed under condi~ions which do not cause undesired reactions at other sites
of said compounds or of products produced therefrom. Representative of such
protective groups are those phenolic protecting groups described by ~laslam in
Chapter ~ of "Protective Groups in Organic Chemistry," Edited by J~F.W. McOmie,
Plenum Press, London and New York (1973). Favored groups are lower alkyl
(particularly methyl and ethyl), tetrahydropyranyl, benzyl or substituted
benzyl wherein the substituent is 3 for example, alkyl having from one to four
carbon atoms, halo (Cl, ~r, F, I) and alkoxy having from one to four carbon
atoms. The ether protecting, or blocking, groups can be removed through the
use of hydrobromic acid in acetic acid or hydrobromic acid, 48% aqueous. The
reaction is conducted at elevated temperatures and desirably at the reflux
temperature. However, when Z is -(alkl)m-0-(alk2)n-, acids such as polyphos-
phoric acid or trifluoroacetic acid must be used to avoid cleavage of the ether
linkage, Other reagents such as hydriodic acid, pyridine hydrochloride or
hydrobromide can be used to remove protecting ether groups such as methyl or
ethyl groups. When the protecting groups are benzyl or substituted benzyl groups,
they can be removed by catalytic hydrogenolysis. ~uitable catalysts are
palladium or platinum, especially when suppor-ted on carbon. Alternatively, they
can be removed by solvolysis using tri~luoroacetic acid. A further proced~lre
comprises treatment with n-butyl-lithium in a reaction-inert solvent at
room temperature.
The exact chemical structure of the protecting group is not critical
to this invention since its importance resides inits ability to perform in the
manner described above. The selection and identification of appropriate pro-
tecting groups can easily and readily be madeby one skilled in the art. The
- 7 -
~1 33~3~
suitability and effectiveness of a group as a hydroxy protecting group are
determined by employing such a group in the herein-illustrated reaction se-
quences. It should, therefore, be a group which is easily removed to reg0nerate
the hydroxy groups. Methyl, tetrahydropyranyl and benzyl are preferred pro-
tecting groups since they are readily removed.
The protected 2-bromo-5-~Z-W substituted)phenol is then reacted with
magnesium in a reaction-inert solvent and generally in the presence of a
promoter, e.g.~ cuprous salts such as the chloride, bromide and iodide (to
promote 1,4-addition) with the appropriate 4-R2 (or R2)-2-cycloalken-1-one
(e.g., ~-R2-2-cyclohexen-1-one) wherein R2 is alkenyl with up to six carbon
atoms and R2 is oxo-alkyl with up to six carbon atoms or a precursor therefor,
e.g., -CH(OCH3)2 or -HCOCH2CH20 as precursor for -CH0. Suitable reaction-
inert solvents are cyclic and acyclic ethers such as, for example, tetrahydro-
furan, dioxane and dimethyl ether of ethylene glycol (diglyme). The Grignard
reagent is formed in known manner, as, for example, by refluxing a mixture of
one molar proportion of the bromo reactant and two molar proportions of magnesium
in a reaction-inert solvent, .e.g., tetrahydrofuran. 'I`he resulting mixture is
then cooled to about 0C. to -20C. The amountof cuprous iodide used is not
critical, but can vary widely. Molar proportions ranging from about 0.2 to
about 0.02 moles per mole of bromo reactant afford satisfactory yields of the
cycloalkanone wherein the phenolic hydroxy group is protectcd (formula Il-B
or II-C, Rl = a hydroxy protecting group).
Alternatively, compounds of formulae II~B and II-C are prepared by
reaction of the copper deriva~ive of an appropriate 3-(Z-W-substituted)phenol,
the hydroxy group of which is suitably protected, with an appropriate ~- or 5-
substituted cycloalk-2-en-1-one in a reaction-inert solvent at a low temperature,
~335i3~
e.g., below -20C. Suitable protec-ting groups are those enumerated above
except, of course, benzyl or substituted benzyl which would be removed during
preparation of the precursor lithio derivative of the copper 3-(Z-W)phenol.
An especially useful protecting group for this alternative methodology is the
tetrahydropyranyl group. Said protecting group is easily introduced into the
phenol reactant, is stable to the conditions of subsequent reactions in which
said protected compound serves as intermediate, and is conveniently removed by
hydrolysis.
The copper derivative of the 3-(Z-W-substituted) -phenol is prepared
from the lithio derivative of said phenol by treatment of said lithio derivative
with l-hexyne copper. It undergoes 1,4-addition tothe conjuga~ed C=C-C=o
system of the cycloalk-2-en-1-one reactant, in contrast to the characteristic
1,2-addition of the corresponding lithio derivative.
This alternative 1,4-addition step, of course, gives rise to the same
compounds as does theabov;e-described Grignard reaction. It generally affords
better yields of the formula II-B and II-C compounds.
It will be noted that in a preparation o a compound of formula II
herein wherei.n Rl is hydroxy, Y' is -CH2CHR2-, R2 is (C~12)30~l and Z-W is 1J1-
dimethylheptyl, the particular sequence exemplified utilizes intermediates
wherein the Z-W group is 1,1-dimethyl-2-heptenyl and which is hydrogenated in
the last step of the sequence to l,l-dimethylheptyl. Reduction of said 1,1-
dimethyl-2~heptenyl group can, oE course, be accompl:ished at any stage oE the
sequence if desired, i.e., it need not be delayed wltil the final step.
The protected cycloal~anone is then treated with an appropriate
reagent to remove the protecting group, if desired. The benzyl group is con-
venientlv removed by the method described above. If the protecting group is an
alkyl group (methyl or ethyl), it is removed by the above-mentioned methods or
by treatment with, for example, pyridine hydrochloride. The tetrahydropyranyl
_ g _
~3~3~
group is removed by means of an acidic reagent.
Compounds of formula II-~ wherein R2 is oxo-substitu-ted (Cl 6) alkyl,
and especially those wherein R2 is formyl~ serve as intermediates for other
compounds.
When R2 is an alkenyl group, the cycloalkanones (:Eormula II-B) thus
produced serve as intermediates for preparation of the corresponding cycloalk-
anones wherein R2 is hydroxy substituted alkyl as defined above.
Compounds of formula (II-B) wherein R2 is alkenyl are hydrated to
corresponding hydroxyalkyl derivatives of formula II, via, for example,hydro-
boration-oxidation using borane, preferably in tetrahydrofuran or diethylene-
glycol dimethyl ether ~diglyme) at 0 to 50C. The intermedia-te borane product
is not isolated but is directly oxidized with alkaline hydrogen peroxide to
the alcohol. The alcohols of formula (II) thus produced correspond to anti-
Markovnikov addition of the elements of water tothe double bond.
Further, hydro.cyalkyl derivatives of formula (II) can also be
produced from the compound of formula (II-B) by oxymercuration-demercuration
using mercuric acetate in water followed by reduction (sodium borohydride) of
the intermediate hydro~y mercurial derivative. The reaction is carried out at
ambient temperature using an aqueous mercuric acetate/tetrahydrofuran medium.
The intermediate is not separated, but is reduced in situ to the alcohol.
Addition occurs opposite to that of the hydroboration-oxidation reaction; namely,
Markovnikov addition, the elements oE water being added to the double bond in a
manner opposite to that of the hydroboration-oxidation reaction to produce
secondary alcohols.
The alcohols may be used as intermediates for production of corres-
ponding aldehydes and ketones (oxoalkyl compounds) by oxidation ~ith a sui~able
- 10 -
i3~3
oxidizing agent such as pyridinium chlorochromate. The resulting oxo
compounds in turn serve as intermediates for increasing the chain length of
the alkyl groups having oxo functionality and, of course, for introducing
branching into said alkyl group. lhe Wi~tig reaction, using the appropriate
ylide, serves admirably for this purpose. For example, reaction of an oxo-
alkyl group with triphenylphosphonium methylide converts the oxo group to a
methylene ~= CH2) group. Hydroboration-oxidation, affords a primary or
secondary alcohol, itself a useful intermediate.
Formula II-C compounds wherein R2 or R3 is oxo substituted alkyl
are conveniently prepared by oxidation of corresponding compounds of formula
II-B wherein R2 or R3 is an alkenyl group having one more carbon atom than
R2 or R3. Sodium metaperiodate and a catalytic amount of osmium tetroxide in
aqueous tetrahydrofuran or dioxane at ambient temperature is favored as oxidizing
agent since it tends to minimize oxidation beyond the aldehyde stage. ~lowever,
despite its relative mildness as an oxidant compared to, for example, sodium
metaperiodate/potassium permanganate, some oxidation to the corresponding acid
and the corresponding hydroxy ketone does occur.
The compounds of formula (II-C) can also be prepared by Grignard
reaction of the appropriate 4-(acetal or ketal substituted alkyl)-2-cycloalken-
l-one with the appropriate 2-bromo-5-~Z-W substituted)phenol according to the
procedure described above. The acetal or ketal group is then transformecl by
treatment with acidJ e.g., a mineral acid such as llCl, to -the oxo group.
A favored procedure for preparation of compounds of formula II wherein
Z-W is -0-(alk2)n-W comprises selective alkylation of the appropriate 3-(2,4-
dihydroxyphenyl)-4-(~2'-substituted)-cyclo-alkan-1-one ketal in a reaction-
inert solvent according to the procedure described below. The 3-(2,4-dibenzy-
loxyphenyl)-4-~R2'-substituted)-cycloalkanone is, if no transformations are to
~33~3~
be carried out on the R2'-group, debenzylated via hydrogerl over palladium-on-
charcoal to the corresponding 3-(2,4-dihydroxy?-4-(R2'-substituted)cycloalkane
and then converted ~o a ketal.
Ketal formation is accomplished according to well-known procedures
for ketalization, such as reaction of said 3-(2,4-dihydroxyphenyl)cycloalkanone
with an alcohol, especially an alcohol having from one to four carbon atoms, in
the presence of an acid, such as sulfuric acid, p-toluenesulfonic acid,
hydrogen chloride, under conditions which remove the by-product water. A
favored procedure comprises reaction of said 3-(2,~-dihydroxyphenyl)cycloal-
kanone with an orthoformic ester in solution in an alcohol corresponding to the
alcohol moiety of the orthoformic ester. Trimethyl orthoformate and methanol
are favored reactants along with concentrated sulfuric acid, anhydrous hydrogen
chloride, or ammonium chloride as catalyst.
The ketal thus produced is then alkylated by reaction with an approp-
Tiate alkylating agent such as W-Z-X " wherein W andZ are as defined above, and
X " is selected from the group consisting of chloro, bromo, mesyloxy (CH3-SO2-0)
and tosyloxy (p-CH3-C6H~-SO2-O) in the presence of an acid acceptor, e.g.,
sodium or potassium carbonate. The alkylated ketal is then deketalized by
treatment with aqueous acid according to known procedures.
3-[2-Hydroxy-4-(-0-(alk2) -W-substituted)phenyl]-~-(R2'-substituted~
cycloalkanones are thus produced.
When trans~ormations are to bc conducted ongrDup R2' as precursor
to group R2, e.g., alkenyl to hydroxyalkyl, the desired transformations are
carried out prior to removal of the protective, i.e., benzyl groups. For
exampleJ when R2' is alkenyl, said group is hydrated viathe hydroboration-
oxidation procedure described above, by first converting the ketone to a ketal,
- 12 -
Eollowed by hydration of the alkenyl group and then deketalization.
Formula II-C compounds wherein R2~ is oxo substituted alkyl serve
as intermediates for preparation of oxo substituted alkyl derivatives having
increased chain length via the Wittig reaction. A representative procedure
comprises, for example, reacting an appropriate 2-(1,3-dioxolan-2-yl)alkyl
triphenylphosphonium bromide at about 10C. to about 80C. with sodium dimeisylate
in dimethyl sulfoxide to generate the corresponding ylide in situ. To the
thus produced ylide is then added an appropriate reactant such as 3-~2-
benzyloxy-4-(Z-W substituted)ph~nyl-4-(2-oxoethyl)-cycloalkanone ethylene ketal
in a suitable solvent such as dimethyl sulfoxideat a temperature of from about
10C. to about 80C. The product, a 3-(2-benzyloxy-4-(Z-W substituted)phenyl
-4-(~-oxoalk-2-enyl)cycloalkanone bis ethylene ketal, is recovered by known
methods such as extraction and column chromatography on silica gel. In this
Wittig reaction, the oxo group of the cycloalkanone moiety is protected by
conversion to a ketal. If desired, the product is subjected to acid hydrolysis
to regenerate the oxo groups. However, when theproduct is to be subjected to
further reactions, it is advantageous to retain the bis ethylene ketal pro-
tecting groups on the product.
Reduction o the protected ~-oxoalkenyl) group (R2 ) of the thus
produced compounds using catalytic hydrogenationover a noble metal catalyst,
e.g., Pd/C, affords the corresponding protected (~-oxoalkyl~ compound. Treatment
of the reduced product with aqueous acid (~ICl) as described herein provides the
~-oxoalkyl derivative oE formula II-C wherein R2 is ~-oxoalkyl. Sodium
borohydride reduction affords a formula II compound wherein R2 is ~-hydroxyalkyl.
Formation of a secondary alcohol group in ~2 is readi]y achie~ed by
Grignard reaction on an appropriate compound of formula II-C, the l-oxo group of
- 13 -
33~3~3
which is protected as an alkylene ketal, and in which R2 is oxoalkyl.
Compounds of formula II wherein Y is ~CH(R3)CH2- are prepared via the
previously described Grignard reaction from the appropriate 5-[2-benzyloxy-4-
(Z-W substituted)phenyl]-2-cycloalken-1-ones, the preparation of which are
described in Belgian Patent 870,404, published March 12a 1979. Nucleophilic
addition of the elements of HCN to said 2-cycloalken-1-one compounds by reaction
thereof with aqueous sodium or potassium cyanide affords the corresponding
trans-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyano cycloalkanones which
are valuable intermediates. Reduction of the oxo group of the cycloalkanone
moiety by means of sodium borohydride yields the corresponding trans-cis hydroxy
compound. It is converted to the corresponding trans-trans compound by reflux-
ing in t-butanol solution in the presence of potassium t-butoxide.
The stereoisomeric cis-3[2-benzyloxy-4-(Z-W substituted)phenyl~-cis-
5-cyanocycloalkanols are prepared by oxidation of ~he trans-trans stereoisomers
using, for example, Jones' reagent followed by sodium borahydride reduction
of the thus-produced cis-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyano-
cycloalkanone.
Each of the above-mentioned 5-cyanocycloalkanol and -alkanone
derivatives is also a valuable intermediate. The cyano group is readily con-
verted by reduction with diisobutyl aluminum hydride (DIBAL-H) to the corres-
ponding formyl derivative. The procedure comprises reacting the cyflno
derivative with DIBAL-H, two equivalents, in toluene at a low temperature, e.g.,
0C. to -65 C., followed by treating the reaction with dilute acid, e.g., a
mineral acid such as sulfuric acid. The formyl derivative is recovered by
standard procedures such as extraction with ether and evaporation of the solvent.
Reduction of the formyl derivative, e.g., by sodium borohydride, affords the
- 14 -
35~
corresponding hydroxymethyl derivative. In the above reactions the ben~yl
ether derivative of the 3-(2-hydroxy-4-(Z-W substituted)phenyl)-5-cyanocyclo-
alkanol is used as reactant in order to avoid reactions at the phenolic hydroxy
group. The protecting benzyl group is removed by me~hods described above.
The 5-formyl derivative serves as intermedia~es to the 5-hydroxymethyl
compound by means of the reactions described above as regards ccnversion of
oxoalkyl value of R2 ~.
Acyl derivatives of formula II compoundswherein Rl is hydrogen are
prepared by acylation with the appropriate alkanoic acid in the presence of a
condensing agent such as dicyclohexylcarbodiimide, or by reaction with the
appropriate alkanoic acid chloride or anhydride in the presence of a base such
as pyridine. The order of reactivity of the acylatable Rl, R2 and R3 groups
which are or which contain a hydroxy group is primary alcoholic OH, phenolic
Oll, secondary OH.
The analgesic properties of the compounds of this invention and of
the parent application are determined by tests using nociceptive stimuli. It
is noted that compounds of formula II wherein Rl is a hydroxy protecting group
are not pharmacologically active for the purposes described herein but are
useful as intermediates for said compounds wherein Rl is hydrogen.
Tests Using Thermal Nociceptive Stimuli
a) Mouse Hot Plate Anal~esic Testing
The method used is modified after Woolfe and Macnonald, J. armacol.
Exp. Ther., 80, 300-307 ~1944). A controlled heat stimulus is applied to the
feet of mice on a l/8-inch thick aluminum plate. A 250 watt reflector infrared
heat lamp is placed under the bottom of ~he aluminum plate. A thermal regulator,
connected to thermistors on the plate surface, programs the heat lamp to main-
tain a constant temperature of 57C. Each mouse is dropped into a glass cylinder
(6 1/2-inch diameter) resting on the hot plate, and
- 15 _
353~3
_16_
~iming is begun when the animal's feet touch the
pla~e. The mouse is observed at 0.5 and 2 hours after
treatment with the test compound for the first "flicking"
movements of one or both hind feet, or until 10 seconds
elapse without such movements. Morphine has an MPE50 a
~-5.6 mg./kg. (s.c.).
b) Mouse Tall Flick Analqesic Testing
Tail flick testing in mice is modified a~ter
D'Amour and Smith, J. Pharmacol. ~. Ther., 72, 74-79
(1941) using controlled high intensity heat applied
to the tail. Each mouse i.s placed in a snug-fitting
metal cylinder, with the tail protruding through one
end. This cylinder is arranged so that the tail lies
~lat over a concealed heat lamp. At the onset of
~esting, an aluminum flag ovex the lamp is drawn back,
allowing the light beam to pass through the slit and
focus onto the end of the tail. A timer is simultaneously
activated. The latency of a sudden flick of the tail
is ascertained. Untreated mice usually react within
3-4 seconds after exposure to the lampq The end point
for protection is 10 seconds. Eacn mouse is tested at
0.5 and 2 hours after treatment with morphine and the
~es~ compound~ Morphine has an MPR50 o~ 3O~-5~6 mg./kg~
( s . c . ) .
c) Tail Immersion Procedure
.. . .
The method is a modificatio~ of the receptacle
procedure deve~oped by Benbasset, e al., Arch. int
., 122, 434 (1~59). Male albino mice (19-~1 g.)
of the Charles River CD-l strain are weighed and marked
~or identification. Five animals are normally used in
each drug treatment group with each animal ser~ing as
its own control. For general screening purpuses, new
test agents are first administered at a dose of 56 mg.~kg.
intraperitoneally or subcutaneously, delivered in a volume
of lO ml.~g. Preceding drug treatment and at 0.5 and
( ',~' ~
335;3~
-17-
2 hours post drug, each animal is placed in the cylinder.
Each cylinder is provided with holes to allow for
adequate ventilation and is closed by a round nylon plug
through which the animal's tail protrudes. The cylinder
is held in an upright position and the tail is completely
immersed in the constant temperature waterbath (56 C.).
The endpoint for each trial is an energetic jerk or
twitch of the tail coupled with a motor response. In
some cases, the endpoint may be less vigorous post drugO
To prevent undue tissue damage, the trial is terminated
and the tail removed from the waterbath within lO seconds.
The response latenc~ is recorded in seconds to the
nearest 0.5 second. A vehicle control and a standard of
known potency are tested concurrently with screening
candidates. If the activity of a test agent has not
returned to baseline values at the 2-hour testing point,
response latencies are determined at 4 and 6 hours. A
final measurement is made at 24 hours if activity is
sti11 observed at the end of the test day.
Test Us;in~_Chemical N ciceptive Stimuli
... .
Suppression of Phenylbenzoquinone
_ Ir~ 5-I~d~d Writhing
Groups of 5 Carworth Farms CF-l mice are pretreated
su~cutaneously or orally with saline, morphine, codei~e
25 or tha tes~ compound. Twenty minutes (if treated sub-
cutan~ousl~) ox ~ifty minutes (if treated orally) later,
each group is treated wi~h intraperitoneal i~jection of
pheny1benzoquinone, an irritant known to produce abdominal
contractions, The mice are observed for 5 minutes for
the presence or absence of writhing starting 5 minutes
after the in~ection of the irritant. MPE50's of the
drug pretreatments in blocking writhing are ascertained.
Tests Using Pressure Noc1ceptive Stimuli
Effect on the Haffner
Tail_Pinch Procedure
A modification of the procedure of Haffner,
Ex~erimentelle Prufung Schmerzstillender. Deutch Med
. __ _ _ _ . _ ~ . __ _ . . _ . . . _ . _--A _ _ __ __._ --_-- _
~3353~
-18-
Wschx.0 55, 731-732 (1923) is used to aSGertain the
effec~ of the test compound on aggressive attac~ing
responses elicited by a stimulus pinching the tail~
Male albino rats (50-60 g.) of the Charles River
(Sprague-Dawley) CD strain are used. Prior to drug
treatment, and again at 0.5, 1, 2 and 3 hours after
treatment, a Johns Hopkins 2.5-inch "bulldog'~ clamp
is clamped onto the root of the rat's tail~ The end-
point at each trial is clear attacking and biting
behavior directed toward the offending stimulus, with
the latency for attack recorded in seconds. Th~ clamp
is removed in 30 seconds if attacking has not yet
occurred, and the latency of response is recorded as
30 seconds. Morphine is active at 17.8 mg./Xg. (i.p.).
The "Flinch-Jum~" Test
A modification of the 1inch-jump procedure of
Tenen, ~ harmacolo~, 12, 278-285 tl968) is used
for determining pain thresholds. Male albino rats
(175-200 g.) oE the Charles River (Sprague-Dawley) CD
strain are used. Prior to receiving the drug, the feet -
of each rat are dipped into a 20% glycerol/saline
solution. The animals are then placed in a chamber and
presented with a series of l-second shocks to the feet
¦ 25 which are delivered in increasing intensity at 30-second
I intervals. These intensities are 0~2~, 0.3~, 0.52, 0.7B,
l.OS, 1.31, 1.~8, 1.86, 2.13, 2.42, 2.72 and 3.04 mA.
Each animal's behavior is rated for the presence o
(a) flinch, (b) squeak and (c) jump or rapid forward
movement at shock onset. Single upward series of shock
intensities are presented to each rat just prior to,
and at 0.5, 2, 4 and 24 hours subsequent to drug
~, tr eatment.
!
~ ` ~
3353~
--19--
Resul~s of the a~ove tests are recorded as percent
maximum possible effect (~MPE~. The %MPE of each group
is statis tically compared to the ~MPE of the standard
and the predrug control values. The %MPE is calculatad
5 as follows~
cutof~-~tlme co,n,ttrol time 10
The compounds of this invention, when used as
analgesics via oral or parenteral administration, are
convenientl~ administered in composition form. Such
compositions include a pharmaceutical carrier selected
on the basis of the chosen route of administration and
standard pharmaceutical practices. For example, they
can be administered in the form of tablets, pills,
powders or granules containing such excipients as starch,
mil~ sugar, certain types of clay, etc. They can be
administered in capsules, in admixtures with the same or
equivalent excipients. They can also be administered in
the form of oral. suspensions, solutions, emulsions,
syrups and Plixi.rs which may contain flavoring and
coloring agents. For oral administration of the thera-
pautic agents of this invention, tablets or capsules
containing from about 0.01 to about lU0 mg. are ~uitable
for most applications.
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35i3~
-- 23--
A, ~B
~~~(~ (C~3) 2C6H13
Table II
MPE50 (mg./kg, ~
R3 A B PBQ RTC
HOD-- ~ OH5. 6
HOI~ EI OH13 o 9 39. 2
HOI~ OH H50 8 >56
NCS~I_ }I OH7 0 20
HOCH2~_ H OH1. 21 . 3 . 34
l Q NC a~_ ~ O -- ~ 2, 8 7
__ _ _ ~
The antiemetic properties of the compounds of
~ormula II are determined in uhanesthetized unre-
strained cats according to the procedure described in
Proc. Soc. ExptL. Biol. and Med., 160, 437-440 (1979).
The compounds of the present invention are
active antiemetLcs via oral and parenteral administra-
tion and are con~eniently administered in composition
form. Such ~ompositions include a pharmaceutical
carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice~
For example, they may be administered in the foxm of
tablets, pills, powders or granules containing such
excipients as starch, milk sugar, certain types of
clay, etc. They may be administered in capsules, in
admixt~lres with the same or equivalent excipients.
They may also ~e administexed in the form of oral
suspensions, dispersions, solutions~ emulsions,
syrups and elixirs which may contain flavoring and
coloring agents. For oral administration of the
~3~
-24
therapeutic agents of this invention, tablets or
capsules containing from about 0.01 to about 100 mgO
are suitable or most applications.
The physician will determine the dosage which will
ba most suitable for an individual patient and it will
vary with the a~e, weight and response of the particular
patient and the route of administration. Generally,
however, the initial analgesic dosage in adults may range
from about 0.1 to about 750 mg. per day in single or
divided doses. In many instances, it is not necessary
to exceed 100 mg. daily. The favored oral dosage range
is from about 1.0 to about 300 mg./day; the preferred
dose is from about 1.0 to about 50 mg./day. The favored
parenteral dose is Erom about 0.1 to about 100 mg./day;
the preferred range from about 0.1 to about 20 mg./day~
This invention also provides pharmaceutical
compositions, including unit dosage forms~ ~aluable ~or
the use of the herein described compounds as analgesics
and other utilities disclosed herein. The dosage form
can be given in si~gle or multiple doses, as previously
noted, to achieve the daily dosage effective for a
particular u-tility.
The compounds (drugs) described herein can be
formulated for administration in solid or liquid form
~5 for ~ral or parentaral administration. Capsules con-
~aining drugs of this invention are prepared by mixing
one part by weight of drus with nine parts of excipient
such as starch or milk. sugar and then loading the mixture
into telescoping gelatin capsules such that each capsule
contains 100 parts of the mixture~ Table~s containing
said compounds are prepared by compounding suitable
mixtures of drug and standard ingredients used in prepar-
ing tablets, such as starch, binders and lubricants,
such that each tablet contains from 0.10 to 100 mg. of
drug per tablet.
The following samples indicate those of the present inven~ion as
well as the parent application.
35~
E~MPLE 1
Trans-3-[2-Benzyloxy-lL-(l,l-dLmethylheptyl)-
phenyl]~ (2-propenyl)cyclohexanone_
~ solution of 73.0 g. (0.188 mole) of 1-bromo-2-
benzyloxy-4-(l,l~dimethylheptyl)benzene (BrZ') in 350 ml.
of tetrahydrofuran was slowly added to 9.0 g. (0.375 mole)
of 70-80 mesh magnesium metal. After a 5 minute initia-
~ion period the rate of addition was adjusted so as to
just maintain re1ux. The reaction was stirred 1.5 hours
longer ~ollowing completion of addition while cooling
to 25 C~ The reaction was cooled to -20 C. and 1.78 gO
(9.38 mmoles) o~ cuprous iodide added. The resultant
mixture was stirred 5 minutes and ~hen a solution of
25.5 g. ~0.188 mole) of 4-(2-propenyl)-2-cyclohexen-1-one
(enone) in 30 ml. of tetrahydrofuran added dropwise while
the reaction temperature was maintained at about 18 C.
Additional 1.78 g. (9.33 mmoles) portions of cuprous
i~dide were added ~ollowing addition of 1/3 and ~/3 of
the enone reactant. The reaction was stirred 5 minutes
longPr at -20 C. and then added to 1000 ml. of ice cold
saturated ~mmon:ium chloride~ The quenched mixture was
extracted with :L000 ml. of ether and the organic ex-
tract washed tw:ice with 500 ml. of saturated ammonium
chloride, once with 500 ml. of saturated sodium chloride,
dried over magnesium sulfate and evaporated (aspirator)
to an oil. The crude oil was purified via column chroma-
tograpny on 1 k5. of silica gel eluted with 20% ether-
hexane to yield 58.3 g. (70~ of the title compo~md as
an oil.
IR (CHC13~ 1712, 1645, 1613 and 1575 cm 1
~S (m/e) 446 (M+), 360, 354 and 91.
PMR 5TM~1 0.82 (m, terminal methyl), 1.23 (s, gem
dimethyl), ~o7~5~1 (m, vinyl H), 5.02 (s, benzylic
methine), 5.3-6.1 (m, vinyl H), 6~79 (d, J=2Hz, ArH),
6.82 (dd, J=8 and 2Hz, ArH) and 7.0 (d, J=8Hz, ArH).
(~
353
-~6-
In like manner the following compounds were
prep~red from the appropriate 4-(R2-substituted-2-
cycloalken-l-one (enone) in place of the enone used
above and proportionate amounts of magnesium metal,
cuprous iodide and 1-bromo-Z-benzyloxy-4-(1,1-dimethyl
hept~ enzene (BrR): ~
(~ I
R ~ ~C(CH3)z(C~2)5~H3
~ ~ ~ . I ra _ cn ~ ~ ~318353~
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-29-
EXAMPLE 2
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans~4-(2-propenyl)cyclohexanol and the trans, Ci5 i~omer
~o a 0 C~ solution of 14.3 g. ~32.1 mmoles) of
trans-3-t2-benzyloxy-4-(1,1-dimethylheptyl~phenyl]-4-
(2-propenyl)cyclohexanone in 50 ml. of methanol was
added L.22 g. ~32.1 mmoles~ of sodium borohydride. The
reaction was stirred 30 minutes at 0 C. and then added
to 500 ml. saturated sodium chloride and 300 ml. ether.
The organic extract was washed twice with 500 ml. satu-
; rated sodium chloride, dried over magnesium sulfate and
evapora~ed (aspirator) ~o an oil. The crude oil was
purified via column chromatography on 200 g. of silica
geL eluted with 2 1 pentane:ether to yield in order of
elution 1.9 g. (13%) of the trans, c1s-isomer of the
title compound as an oil, 2.7 g. (19%) of a mixture of
isomers and 7.3 g. (51~) of the title compound as an
oil.
Cis-3, trans-~ isomer:
.
IR (C~C13) 8571, 3401, 1639, 1610 and 1572 cm 1.
MS (m/e) 44~ (~+), 406, 363 and 91.
PMR ~c~sl 0.82 (m, terminal me~hyl), 1.22 (s, gem
dimethyl), 2.90 (m, benzylic methine), 3.73 (m, carbinol
methine), 4.6~-5.1 (m~ vinyl H), 5.02 (s, benæylic
methylen~), 5.3~6.3 (m, vi~yl H~, 6.75 (d, J=2H~, ArH),
6.75 (dd, J-8 and 2Hz, ArH), 6.99 (d, J=8Hz, ArH) and
7.25 (bs, Ph).
Trans-3, cis~4 isomer:
IR (CHC13) 3559, 3401, 1639, 1608 and 1567 cm 1.
MS ~m/e) 448 (M ), 433, 430, 363, 406 and 91.
PMR ~cMSl 0.82 (m, terminal methyl), 1.25 (s, gem
dimeth~l), 3.30 (m, benzylic methine), 4.12 (m, carbinol
methine), 4.6-5.0 (m, vinyl H), 5.06 (s, benzylic
methylenel, 5.2-6.1 (m, vinyl H), 6.82 (d, J=2Hz, ArH),
~.82 ~dd, J=3 and 2Hz, ArH), 7.07 (d, J=8Hz, ArH) and
7.38 (bs, Phl.
5;~
-30-
Followin~ the above procedure, the compounds tabulated
below were prepaxed from appropriate 3-[2~benzyloxy-4-
(l,l-dimethylheptyl)phenyl]-4-t2-R2-substituted)cyclo-
alkanones and stoichiometric amounts of sodium boro-
S hydride, i.e., one gram atom/oxo group present:
.~
~ O
(~
~2 ~C(C~3)2(CH2)5cH3
In the table, R represents the 3-[2-b nzyloxy~4-
(l,l-dimethylheptyl)phenyl] moiety.
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_37_
EXAMPLE 3
Cis-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)-
ph~nyl] trans-4-hydroxymethylcyclohexanol
.. . . . _
Using the procedure of Example 2, 1.0 g. ~2.2g mmole)
S of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl]phenyl)-
trans-4-oxome-thylcyclohexanol is reduced to give a
quantitative yield of the title compound as an oil.
IR (CHC13) 3400, 1605 and 1562 cm 1.
MS (m/e~ 438 (M+), 420, 353, 330, 312, 299 and 91.
PMR ~CDCl 0.82 lm, terminal methyl), 1.23 (s, gem
dimethyl), 3.25 (m, hydroxymethylene), 3.65 (m, carbinol
methine), 5.08 (s, benzylic methylene), 6.90 (m, Ar~),
7.12 (d, J=8Hz, ArH) and 7.39 (s, Ph).
EXAMPLE ~
Trans-3-[2-Benzyloxy 4-(1,1-dimethylheptyl)phenyl~-
4-(2-hYdroxyethyl)cyclohexanone ethvlene ketal
- Using the procedure o~ Example 2, 1.00 g. (2.03 mmole)
of trans-3-[2-ben2yloxy-4-(l,l-dimethylheptyl)phenyl]-4-
(2~oxoethyl)cyclohexanone ethylene ketal is reduced to
give a quantitative yield of the title compound as an
oil.
PMR ~cDsl 0.82 (m, terminal methylj, 1.11 (s, gem
dimethyl~, 3.50 (bt, J=6Hz, alcohol methylene~, 3u9l
~s, ethylene), 5.02 (s, benzylic methylene), 6.8-7.1
(m, ArH) and 7.33 (m, PhH).
~3~;i3~
~38_
EXAMPLE 5
Cis-3-~2-Benæyloxy-4-(1,1-dimethylheptyl)~
phenyl]-trans-4-(3-hydroxypropyl~cyclohexanol
To a mechanically stirred~ 0C. solution of 2.0 g.
(4.46 mmoles) of cls-3-[2-benzyloxy-4-(1,1-dimethylheptyl~-
phenyl]-trans-4-(2 propenyl)cyclohexanol in 20 ml. of
tetrahydrofurall was added 9 ml. (8.92 mmoles) of boran
tetrahydrofuran complex (lM in tetrahydrofuran). The
reaction was allowed to warm to 25 C. and was then
stirred for 30 minutes at 25 C~ The reaction was cooled
to 0 C. and oxidi~ed by the addition of 1 ml. water,
2.66 ml. (5.34 mmoles) of 2N sodium hydroxide and 0.92 ml.
(10~7 mmoles) of 30~ hydrogen peroxide. The reaction
was allowed to warm to 25 C., stirred ~or 35 minutes,
and added to 200 ml. saturated sodium chloride and 200 ml.
ether. The ether extract was washed twice with 100 ml.
of saturated sodium chloride, dried over magnesium sulfate
and evaporated (aspirator) to an oil. The crude oil was
p~rified via column chromatography on 40 g. of silica
gel, eluted with ether to yield 2.0 g. (96%) of t~e
title compound as an oil.
IR (CHC13) 3623, 3425, 1623 and 1580 cm 1.
MS (m/e) 466 (M ), 448, 381, 363, 358, 357 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1~24 (s, gem
dimethyl), 2.93 (m, benzylic methine), 3.2-3.9 (m, carbinol
methine and methylene), 5.08 (s, benzylic methylene),
6.86 (d, J=2Hz, ArH), 6.86 (dd, J=8 and 2Hz, ArH) and
7.05 (d, J=8Hz, ArH).
~r~
353
-- 39--
In like manner the following compounds are prepared
from appropriate reactants.
A B O
~~C (CH3) 2 (C~2) 5CH3
`` ~ 3~
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EX~M LE 6
Cis-3-[4-(1,1-Dimethylheptyl)~2-hydroxyphenyl]-
trans-4-(3-hydroxypropyl)cyclohexanol
,
A mixture of 2.0 g. (4.29 mmole) of CiS-3- [2-
benzyloxy-4-~1,1-dimethylheptyl3phenyl]-trans-4-(3
hydroxypropyl)cyclohexanol and 300 mg. of 5~ Pd/C/50~
water in 10 ml. of ethanol was stirred under 1 atmssphere
of hydrogen gas for 45 minutes at room temperature.
The reaction was filtered through diatomaceous earth
and the filtrate evaporated under reduced pressure to
a solid. RecrystallizatiQn of the crude solid product
from diisopropyl ether gave 1.41 g. (94%) of the title
compound.
m.p~: 132-3 C. (diisopropyl ether).
~R (KBr) 3448, 3226, 1626 an~ 1592 cm 1.
MS (m/e) 376 (M+), 358, 304, 291 and 273.
PMR (CDC13, D2O, D6-DMSO) ~ 0.83 (m, terminal methyl),
1.23 (s, gem dimethyl), 3.39 (t, J=6Hz, carbinol
methylene), 3.64 (m, carbinol methine), 6.85 (m, ArH) and
6.91 (d, J=8~z, Ar~).
Calc'd. for C24H4003
C, 76.55; H, 10~71.
Found: C, 76.55; H, 10.44.
Similarly, the ~ollowing compounds are prepared
from appropriate benzyl ether reactants:
,
A B
( ~ OH
~ ~ ~ C(cH3)2(cH2)scH3
(The value of R2 is the same in reactant and product).
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~:~8353~3
-~2-
EXAMPLE 7
Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-
phenyl_-4-(2 propenyl)cyclohexanone ethylen_ ketal
~ mixture of 17.0 g. (38.1 m~loles) of trans-3-
[2-benzyloxy-4-~1,1-dimethylheptyl)phenyl]-4~ propenyl)-
cyclohexanone~ 47.2 g. (0.762 mole) ethylene g~ycol and
250 mg. o~ ~-toluenesulfonic acid monohydrate in 200 ml.
of benzene was heated at reflux for 3 hours with a Dean-
Stark trap. The reaction was cooled and added to 200 ml.
1~ sodium hydroxide, 100 ml. ether and 100 ml. pentane.
The organic extract was washed twice with 200 mL. portions
of water, ~wice with 200 ml. portions of saturated sodium
chloride, dried over magnesium sulfate and evaporated
(aspirator) giving a quantitative yield of the titl~
compound.
IR (CHC13) 1656, 1626 and 1587 cm 1.
~ S (m/e) 490 (M+), 475, 450, 449, 448, 446, 407,
405, 399, 383 and 91.
PMR ~cDMcl 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 3.1 (m, benzylic methine), 3.90 (s, ethylene
ketal), 4.6-5.0 and 5.2-6.0 (m, vinyl H), 5.07 (s,
benzylic methyl~ne), ~.81 (d, J-2Hz, ArH~, 6.81 (dd,
J=8 and 2~z, Ar~) and 7.02 (d, J=8Hz, ArH).
In like manner, 4.S g. (9~8 mmole) of trans-3 ~2-
2S benzyloxy~ dimethylheptyl)phenyl]-4-(2-propenyl)
cycloheptanone is converted in ~uantitative yield to
trans-3-E2-benzyloxy-4-(1,1-dimethylheptyl)phen~1]-4-
(2-propenyl)cyl.oheptanone ethylene ketal, an oiL.
IR (CIIC13) 1650, 1613, 1550, 1504 and 1460 cm 1.
MS (m~e) 504 (M+)
PMR ~CDCl 0.80 (m, terminal methyl), 1.22 (s, gem
dimethyl~, 3.20 (m, benzylic methine), 3.80 (bs, ethylene),
4.6-6~0 (m, ole~inic), 5.07 (s, benzylic methylene),
6.85 (m~ ArH), 7.02 (d, J=8Hz, ArH) and 7.38 (m, PhH).
33~
-~53
The following compounds are prepared from ap-
propriate cycloalkanone reactants in like manner:
(~ r~
R2 ~ Z-W
.. .. W.._
1 -CH2-CH=CH2 CH3 C(CH3)2(CH2)5cH3
2 -CH2~C~=C~I2 H ocH(cH3)(cH2)3c6H5
2 -C32- ~=CH2 E C~C33)z~C~2 SC~3
~; ~
33~3~
54
EXAMPLE 8
Trans-3-[4-tl,l-Dimethylheptyl)-2-hydroxyphenyl]-
4-~3-hydro~ypropyl~cyclohexanone
A mixture of 4.0 g. (9.56 mmoles) of trans~3-[4-
(l,l-dimethylheptyl) 2-hydroxyphenyl]-4~(3-hydroxypropylj-
cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric
acid and 100 ml. of tetrahydrofuran was heated at reflux
for 2 hours. The reaction was cooled and added to 500 ml.
saturated sodium chloride and 250 ml. ether. The ether
extract was separated and washed once with 500 ml.
saturated sodium chloride, once with 500 ml. satura ed
sodium ~icarbonate, dried over magnesium sulfate and
evaporated (aspirator) to an oil. The crude oiL was
purifled via column chromatography on 200 g. of silica
gel eluted with 80% ether-hexane to yield 2.93 g. ~82%)
of the title compound as an oil.
IR (CHC13) 3521, 3333, 1709, 1616 and 1567 cm 1.
MS (m/e) 374 (M ), 356, 289, 273, 247, 203 and 161.
PMR ~CDCl 0.82 (m, terminal methyl), 1.28 (s, gem
dimethyl), 3.76 (m, alcohol methylene), 6.8 (m, ArH) and
6 . 99 (d, J-8Hz, ArH).
In like manner the following compounds are prepared
from appropriate ketals:
tp~ IORl
~ C~CH3)2tCH2)scH3
('~' -- ~- . . "~a~ ~ ',
c~ . ~ o . . r~
o I o I
_ tY
C) O ._ U O ~ ~ ` N ~ ~1
O ~ O O~ Q) ~ ~1 ` a) ~ .
t~ r l ~\ C ;~ .C ~ ~ S ~ _i O ~D
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o u~ ~ o ul ~ a) ~ o 1~ _ a~
11o~O 11 0~ ~ E~ ~ ~ ~ .c ~ --L: .
k ~ ~ ~ 9 Q, ~ a~ S ~ G rl O E3 ~ 1:~
~ ~ ~\-- . 41 E3 a
~ O E~ 'S S -
)~ 5-1 k O ~ ~ ~
~ $ ~ ~ ~ ~ ~ V
tl~ t) ~ ` N.~ ` ` O U 'a
a ~ 0 c 5
__
t`~ ~ ~` N N _
U~ O ~i ~--7~ -- O ~ ~ ~ ~ ~
O _ -_ ,. _ ~ - .... ._- -_
1:4
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C~ ~ o ~ ~ co t~
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. ___ . _ _
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~33S3~3
3~3
-~6-
EXAMPLE 9
.
Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-4-(2-oxoethyl)cyclohexanone eth~lene ketal
A mixture o 17~0 g. (34.7 mmoles) of trans-3-~2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-~2-propenyl)-
cyclohexanone ethylene ketal, 44.5 g. (0.208 mmole) of
sodium metaperiodate and 176 mg. (0.69 mmole) of osmium
tetroxide in 340 ml. tetrahydrofur~n and 100 ml. of water
was stirred at room temperature for 3.5 hours. The
reaction mixture was then added to 1000 ml. 15% sodium
su3.fite-1000 ml. ether. The organic phase was separated,
washed twice with 500 ml. of saturated sodium bicarbonate,
dried o~ler magnesium sulfate and evaporated (aspirator).
The residue was purified by column chromatography on
~00 g. of silica gel eluted with 33-7~ ether-petxoleum
ether to yield lO.O g. t59%) of the title compound as an
oil.
IR (CHC13) :L730, 1621 and 1577 cm 1
MS (m/e) 492 (M~ 64, 448, 407, 401, 357, 339, 337
319, 317, 271 and 91.
P~R ~CDCl 0.83 (m, terminal methyl), 1.23 (s, gem
dime~hyl), 3.2 (m, benzylic methine)~ 3.94 (s, ethylene
ketal), S.10 (s, benzylic methylene), 6.85 (dd, J-8 and
2Hz, ArH), 6.85 ~d, J=2Hz, ~rH), 7.07 (d, J=8Hz, ArH) a~d
9.57 (t, J=1.5Hz, CHO).
Further elution gave 5.53 g. of a mixture of two
compounds. ~his mixture was dissolved in 500 ml. of
ether and washed with four 250 ml. portions of lN s~dium
hydroxide. The ether phase was dried over magnesium
sulfate and ~vaporated (aspirator) to yield 2.7 g. of
oil~ This oil was further purified via column chroma-
tography on 100 g. of silica gel eluted with 50% ether-
pentane to yield 2.16 g. (12~) of trans-3-~2-benzyloxy-
4-(1,1-dime~hylheptyl)phenyl]-4-(3-hydro.Yy-2 oxopropvl)=
cyclohexanone ethylene ketal as an oil. The basic extract
~353~ ~
~!57--
from above was acidified with ice cold 6N hydrochloric
acid and then extxacted with 500 ml. of ether The
ether extract was washed twice with 200 ml. water, once
with 100 ml. saturated sodium chloride, dried over
magnesium sulfate and evaporated to give 2~4 g. of oil
which was purified by column chromatography on 100 g.
of silica gel eluted with 33~ ethyl acetate-pentane to
yield 1.51 g. (9%~ of _rans-3-[2-benzyloxy-4-(1,1-
dimethylheptyl)phenyl]-4 (2-car~oxymethyl)cyclohexanone
ethvLene ketal.
Trans-3-[2-benzyloxy 4-(1,1-dimethylhep-tyl)phenyl3
4-(3-hydroxy-2-oxopropyl)cyclohexanone ethylene ketal:
IR (CHC13) 3484, 1724, 1613 and 1575 cm 1.
MS (m/e~ 522 (M ), 491~ 448, 432, 407, 358, 99,
91 and 860
CDC13 0.82-(texminal methy]), 1 22 (s g
dimethyl~, 2.17 (m, methylene a to ketone), 2.88 (t, J=5Hz,
OH), 3.82 (d, overlaps 3.90), 3.90 (s, ethylene), 5.08
(s, benzylic mel:hylene), 6.83 (m, ArH), 7.02 (d, J=8Hz,
ArH) and 7.40 (m, PhH).
T~rans-3-[2--benzyloxy-4-(1,1-dimethylheptyl~phenyl3-
4-(2-carbox~methyl)cyclohexanon0 ethylene ketal:
IR (CHC13) 3636-2273 (broad), 1724, 1621 and 1582
cm
MS (m/e) 5()8 (M ), 449~ 424, 418, 408, 402, 99, 91
and 86.
PMR ~CDCl 82 (m, terminal methyl), 1.22 (5, yem
dimethyl), 3.2 (m, benzylic methine), 3.93 (s, e~hylene),
S.L0 (s, benzylic methylene), 6.85 (m, ArH), 7.10 (d,
J=8Hz, ArH) and 7.41 (m, PhH)o
SLmilarly, oxidation of 2.60 g. (5.80 mmole) of
ClS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-
4-(2-propenyl~cyclohexanol gave 1.4 g. (54%) of
ClS-3- [2-DenZyloxy-4~ dimethylheptyl)phenyl]-trans-4-
3 5 (2-o~oethyl)cyclohexanol; 409 mg. ( 1 5 % ) 0 f
~3~3~il
- 5~ -
ClS-3- [2-benzy]oxy-4-(1,1-dlmethylheptyl)phenyl]-trans-
4-(3-hydroxy-2-oxopropyl?cyclohexanol and 120 mg. (4.9~) of
cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4~
... .
(carboxymethyLjcyclohexanol.
2-Oxoethyl compound:
IR (C~C13) 3610, 3425, 1623 and 1582 cm 1.
MS (m/e) 450 (M ), 422, 405f 365, 359, 342 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.23 (sy gem
dimethyl), 3.00 (m, benzylic methine), 3.70 (m, carbinol
methine), 5.09 (s, benzylic methylen`e), 6.88 (d, J=2Hz,
ArH), 6.88 ~dd, J=8 and 2Hz, ArH), 7.10 (d, J=8Hæ, ArH),
7~40 (s, PhH) and 9.53 (t, J=1.5Hz, CHO).
~-Hydroxy ~etone:
IR (CHC13) 3448, 1721, 161~ and 1580 cm 1.
MS (m/e) 480 (M ), 466, 450, 449, 406 and 91.
PMR ~CD~l 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 3~75 (m, carbinol methine), 3.86 (bs, hydroxy-
methylene), 5.08 (s, ~enzylic methylene), 6~95 (m, ArH),
7.05 (d, J=8Hz, ArH) and 7.38 (s, PhH).
Acid:
Rf - 0.32 (0.25 mm, silica gel ether).
In li~e manner, 3,4-trans, 4j5-trans-3-[2-benzyl-
oxy-4-tl,l-dimethylkeptyl)phenyl]-5-methyl-4 (2-pro-
penyl)cyclohexanone ethylene ketal i5 oxidized to ~he
corresponding 4-(2-oxoethyl)cyclohexanone derivative.
Also produced are the corresponding 4-(3-hydroxy-2
oxopropyl)- and the 4-(2-carboxymethyl)cyclohexanone
derivatives.
( ~ ~ L 1`i
~L83~3~
-59-
EX~MP1E 10
- Trans-3-[2-Benzyloxy-4-(1l1-dimethylheptyl)phenyl]-
4-(5-oxopent-2-enyl)cyclohexanone bis ethylene ketal
~_ . . ~ . v . . . . . .. . .
To a 15 C. solution of 4.05 mmole of sodium
dimsylate in 6 ml. o~ dimethyl sulfoxide is added 1.61 gO
(4.05 mmole) of 2-(1,3-dioxolan-2-yl)ethyltriphenylphos-
phonium bromide. The reaction mixture was stirred for
15 minutes and then a solution of l.0 g. (2.03 mmole) of
trans-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl] 4-
(2-oxoethyl)cyclohexanone ethylene ketal in one ml~ of
dimethyl sulfoxide was added. The raaction was stirred
for lO minutes and then added to a mixture of 200 ml.
saturated sodium chloride and 200 ml. ether with stirring.
The ether phase was separated and washed twice with 200 ml.
of saturated sodium chloride, dried over magnesium sulfate
and evaporat~d to an oil. The crude product was purified
via column chromatography on 60 g. of silica gel eluted
with 30~ e~her-pentane to yield 359 mg. (31~) of the title
compound as an oil.
IR (CHC13) 1600 and 1563 cm ~.
MS (m~e) 576 (M ).
PMR ~cMcl 0.82 (m, terminal methylj, 1.24 (s, gem
dimethyl~, 2.25 (m, methylene), 3.2 (m, benzylic methine),
3.85 tm~ ethylenes), 4.80 ~t, J=5Hz, dioxolane methine)~
5.08 (s, benzylic methylene), 5~42 (m, olefinic H), 6.8S
(m, ArH), 7.09 (dt J=8Hz, ArH) and 7.4 (m, PhH).
In like manner, 3,4-trans, 4,5-trans-3-[2-benzy].-
oxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-(2-
oxoethyl)cyclohexanone ethylene ketal and cis-3-[2w
benzyloxy-4-(R)~ methyl-4-phenylbutoxy)phenyl]-4-
trans-(2-oxoethyl)cycloheptanone ethylene ketal are
converted to the corresponding 4-(5-oxopent-2-enyl)-
bis ethylene ketals.
118353B
_60_
EXAMPLE 11
Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenylJ-4-
(S-oxopentyl)cyclohexanone bis ethylene ketal
A mixture o~ 520 mg. (0.902 mmole) of trans-3-[2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5 oxopent-2-
enyl)cyclohe~anone bis ethylene ketal and 100 mg. of
5% Pd/C/50~ water in 15 ml. of ethanol was stirred under
one atmosphere of hydrogen gas until one equivalent of
hydrogen was absorbed. The reaction was filtered through
diatomaceous earth and evaporated to give a quantitative
yield of thé title compound as an oil
CDC13 0.80 (m, terminal methyl) 1 32 (s
d~methyl), 3.9 (m, ethylenes), 4~78 (m~ dioxolane methine~,
5.08 (s, benzylic methylene~, 6.85 (m, ArH), 7.08 (d,
3=8Hz, ArH) and 7.42 (m, PhH).
Deketalization according to the procedure of Example
8 affords the corresponding (5-oxopentyl)cycloalkanone
as an oil.
CDCL3 0.82 (m, terminal methyl), 1 23 ~s
dimethyl), 5.06 (s, ben7ylic methylene), 6.88 (m, ArX),
7.03 (d, J=8Hz, ArH), 7.36 (bs, PhH) and 9.S8 (t, J-2Hz,
CHO)~
The remaini.ng products of Example 10 are reduced
and deketalized in like manner to the corresponding 5-
oxopentyl ketones.
i3~
-61-
EXAMPLE 12
Trans-3-t2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl3-
4-~2-hydroxypropyl)cyclohexanone ethylene ketal
Diastereomers A and B
S To a 0 C. solution of 1.72 ml. (5.00 mmole) of
methyl magnesium iodide (2.9M in 5 ml. of ether) was
added a solution of 2.0 g. (4.06 mmole) of rans-3-
[2-benzyloxy-4-(l,l-dimethylheptyl)phenyl]-4-(2-oxoethyl)-
cyclohexanone ethylene ketal in 5 ml. of ether. The
reaction was stirred 30 minutes and then added to 250 ml.
saturated arnmonium ch~oride and 250 ml. ether. The
organic extract was washed with 250 ml. of saturated
sodium chloride, dried over magnesium sulfate and evapo-
rated to an oil. The crude oil was purified via high
pressure liquid chromatography on four 60 cm x 9.5 mm
Porasil B (a form of silica gel available from Waters
Associates, Milford, Mass., U.S.A.) columns eluted with
~0~ ether-hexane to yield in order of elution 746 mg.
(36%) of diastereomer A of the title compound and 935 mg.
(45%) of diastereomer B of the title compound.
Diastereomer A-
. ..~
IR (CHCl3) 3571, 3472, 1613 and 1575 cm ~.
MS (m/e) 508 (M~).
PMR ~TMcl 0085 (m, sidechain methyl), 1.06 (d,
J=6Hz, methyl), 1.26 (s, geTn dimethyl), 3.0 ~m, benzylic
methine), 3.7 (m, carbinol methine), 3.98 (s, ethylene),
5.02 (s, benzylic methylene), 6~81 (d, J=2Hz, ArH), 6.81
(dd, J=8 and 2Hz, ArH), 7.08 (d, J--8Hz, ArH) and 7.37
(m, PhH).
Diastereomer B:
.. .. .
IR (CHCl3) 3610, 3460, 1618 and 1575 cm l.
MS (m/e) 508 (M+).
PMR ~CDCl 0.85 (m, sidechain rnethyl), 0.99 (d J=6Hz
methyl), 1.27 (s, gem dimethyl), 3.1 (m, benzylic me~hine),
3.55 (m, carbinol methine), 6.82 (m, ArH), 7.04 (d, J=8Hz,
~rH) and 7.35 (m, PhH).
~353l~
-- 62--
EXAMI?LE 13
Trans-3-C2-Benzylo~y-4~ dimethyllleptyl)phenyl]-
cis~ ( 2-propenyl)cycloheptanol
To a re1uxing solution of 3.0 g. (0.0789 mole) of
sodium borohydride in 50 ml. of isopropanol was added
a solution of 5.0 g~ (0.011 mole) of trans-3-[2-benzyloxy-
4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cycloheptanone
in 50 ml..of isopropanol over a 1.5 hour period. The
reaction was heated one hour longer, cooled and then added
to 500 ml. saturated sodium chloride. The quench was
extracted twice with 800 ml. saturated ether, the extracts
combined, dried o~er magnesium sulfate and evaporated
(aspirator3 to an oil. The crude oil was puri~ied via
column chromatography on 500 g. of silica gel eluted with
15~ ether-hexane to yield in order of elution 1~78 g.
(36~) o the title compound, 0.55 g. (11%) of mixture and
1.24 g. (36~) of the cis 3-trans~4 lsomer of the title
compound as oils.
Cis, trans isomer:
IR (CHC13) :3333, 1626, 1600 and 1563 cm 1.
MS (m/e) 46;2 (M+) and 91.
PMR ~DCl 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 2.70 (m, benzylic methine), 3.70 (m, carbinol
methine), 4.5-5.0 and 5.1-6.0 (m, olefinic), 5.03 (s,
~5 benzylic methylene), 6.75 ~m, ArH), 7.02 (d, J=8Hz) and
7.34 (s, PhH).
Title com~ und:
IR (CHC13) 3571, 1642, 1613 and 1575 cm 1.
MS (m/e) 462 (M+) and 91.
PMR ~cDMsl 0.80 (m, terminal met.hyl), 1.22 (s, gem
dimeth~l), 4.6-S.0 and 5.2-6.0 (m, ole~inic H), 5.02 (s,
benzylic meth~lene), 6O88 (m, ArH), 7.03 (d, J=8Hz, ArH)
and 7.30 (bs, PhH).
33~3~3 ~
_63~
E.YAMPLE 14
Cis-3~[2-benzyloxy-4 (l,l-dimethylheptyl)phenyl~-
trans-4-(2-propenyl)cycloheptyl d-mandelate
Diastereomer A & B
A mixture of 2.2 g. (4.76 mmole~ of cis-3- ~2-
benzyloxy~4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-
propenyl~cycloheptanol, 869 mg. (5.72 mmole) of d-mandelic
acid and 110 mg. (0.579 mmole) of p-toluenesulfonic acid
monohydrate in 40 ml. of benzene was heated at reflux
for 7 hours. Water was removed via a soxhlet extractor
filled with a synthetic crystalline aluminosilicate
(molecular sieve) such as those distributed by the Linde
Company or the Davison Chemical Company. The reaction was
stirred at 25 C. for 9 hours and then added to 300 ml.
of saturated sodium bicarbonate and 300 ml. ether. The
ether phase was separated and washed once with 300 mlO
of saturated sodium bicarbonate, dxied over magnesium
sulfate and evapor~ted (aspirator) to an oil. The crude
oil was purified via column chromatography on si~ica gel
eluted with 15% ether-hexane to yield in order of elution
1.08 g. (38%) of diastereomer A of the title compound,
0.233 g. (8~) of mixture and 1.12 g. of diastereomer B
of the title compound as an oil~
Diastereomer A:
m.p.: 86-90 C. (Methanol)
~RMS (m/e) 596.3883 tM+, calc'd. for C40H5204:
596~3852~, 444, 359, 354, 313, 269 and 91.
PMR ~cMS~ 0.82 (m, terminal methyl), 1.22 ~s, gem
dimet~yl), 2.90 (m, benzylic methine), 3.4S ~m, ester
methine), 4.5-6vO (m, olefinic and mandelate H), 5.06
(s, benzyl ether methylene), 6.90 (m, ArH) and 7.38
tm, PhEI).
CH3OH, 25C. ~4 42
83~3~
_6~_
Diastereomer ~:
HRMS ~m/e) 596.3855 ~M , calc'd~ for C40H52O4:
596.3852), 354, 269, 107 and 91.
PMR ~CDCl 0.82 ~m, terminal methyl) t 1.21 (s, gem
dimethyl), 2.80 (m, benzylic methine), 3.40 (m, ester
methine), 4.5-6.0 (m, ole~inic and mandelate H), 6.80
(m, ArH) and 7.25 (m, PhH).
~a3 C~30H, 25 C- = +53 34O
33~3~
65~
EX~MPI.E l5
Cis-3-~2-Benzyloxy-4-(l,l-dimethylheptyl)phenyl]-
trans-4-(2-propenyl)cycloheptanol Enantiomer A
A mixture of 1.25 g. (2.09 mmole) of c -3-[2-
benzyLoxy-4-(l,l-dimethYlheptyl)phenyl]-trans-4-(2-
pxopenyl3cycloheptyl d-mandelate~ diastereomer A, and
577 mg. (4.18 mmole) o~ potassium carbonate in 20 ml.
methanol, 5 ml. tetrahydrofuran and 2 ml. of water was
stirred at 25 C. for 20 hours. The reaction was added
to 300 ml. water-250 ml. ether. The ether extract was
washed once with 300 ml. saturated sodium chloride, dried
over magnesium sulfate and evapoxated. The crude product
was purified via column chromatography on 75 g. of silica
gel eluted with 33~ ether-hexane to yield 650 mg. (67~)
of the title compound as an oil..
HRMS (m/e) 462.3482 (M+, calcld. or C32H~602:
462.3490), 377, 313, 269, 233, 227 and 91.
[ ]CH30}1, 25 C. = -20.18
In like manner l.25 g. (2.09 mmole) of ClS-3- [2-
~0 benzyloxy-4 (l,l-dimethylheptyl)phenylj-trans= 4-(2-pro-
penyl~cyclohepty1 d-mandelate, diastereomer B, was
converted to 3)33 mg. (40%) of cis-3-[2-benzyloxy-4-(l,l-
_ _
dimethylheptyl)phenyl]-trans-4-(2-propenyl)cycloheptanol
.
enantiomer B as an oil
HRMS (m/e) 462.3543 (M+, calc'd. for C32H~602:
462.3490), 377, 313, 269, 233, 227 and 9l.
~ ]CH30H/ 25 C. = +16.06
1','~ ~
~3~3~
-66_
EXAMPLE 16
~ . _
Cis-3-[2-Hydroxy-4~ dimethylheptyl)phenyl]-
trans-4 (2-aminoethyl)cyclohexanol hydrochloride
~ . _ . , _ . . . .
A mixture of 1.00 g. (2.~7 mmole) of cis-3- [2-
S hydroxy-4-(1,1-dimethylheptyl)phenyl]- rans-4-~2-oxo-
eth~l)cyclohexanol, 2.31 g. (30. 0 mmole) of ammonium
acetate and 177 mg. (2.77 mmole) o~ sodium cyanoboro-
hydride in 10 ml. of methanol was stirred for 16 hours
at 25 C. The pH of the reaction was made <2 with con-
centrated hydrochloric acid and the methanol evaporatedon a rotovapor. The residue was dissolved in 200 ml.
of water and 20 ml. of methanol and the solution washed
twice with 200 ml. of ether. The aqueous pha e was
separated and made basic (pH>10) with concentrated sodium
hydroxide, saturated with sodium chloride and ex~racted
with 200 ml. of ether. This ether phase was removed,
dried over magnesium sulfate and evaporated (aspirator~
to an oil. The oil was dissolved in dichloromethane
and excess ethereal hydrogen chloride added forming an
oily precipitate which crystallized from ether-ethyl
acetate-ethanol (1-1-1) solution upon cooiing to yield
136 mg. (12%) of the title compound.
m.p.: 218-220 C. (ether, ethyl acetate, ethanol)
HRMS (m/e) 361~2993 (M , calc'd. for C23H39N02:
361.2971), 2760 259 and 241.
!'` ..1~
~335i3~
-67~
EX~MPLE 17
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl~-
trans-4-oxomethylcyclohexanol
A mixture o~ 14.4 g. (29.9 mmole) o~ CiS-3- ~2
benzyloxy-4-(1,1-dimethylheptyl~phenyl]-trans-4~di-
methox~methylcyclohexanol, 150 ml. of 1,4-diox~ne and
150 ml. of 2N hydrochloric acid was refluxed for one
hour. The reaction was cooled and added to 2 liter~ of
saturated sodium chloride. The aqueous quench was ex-
tracted twice wi-th 300 ml. of ether and the combined
ether extract washed once with saturated sodium bica~-
bonate, dried over magnesium sulfate and evaporated
on a rotovac to give a quantitative yield of the title
compound as an oil.
IR (CHC13) 3546, 3401, 1715, 1607 and 1572 cm 1.
MS ~m/e) 436 (M ), 352, 345, 328, 310, 299, 259 and
91 .
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 2.75 (m, benzylic methine~, 3.65 (m, carbinol
methine), 5.01 (s, ben2ylic methylene), 6.83 (m, ~rH),
7.06 (d, J=8~z, ArH) and 7.36-(s, PhH).
Similarly, 6.3 g. (13 . 07 mmole) of trans-3-[2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-4-dimethoxy
methylcyclohexanol (contains some of the Ci5-3, trans-4
isomer) was converted to 2.05 g. (36%) of trans-3-[2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl~-cis-4-oxomethyl-
cyclohexanol an~ 2.2 g. (39~) of the cis-3, trans-4 isomer.
Separation was achieved via column chromatography on
120 g. o~ silica gel eluted with 66% ether-hexane.
Trans, cis isomer:
IR (CHC13) 1715, 1607 and 1557 cm 1.
MS (m/e) 436 (M ), 418, 351 328 and 91.
PMR ~CDCl 0.86 (m, terminal methyl3, 1.28 (s, gem
dimethyl), 2.7 (m, benzylic methine), 4.22 (m, carbinol
methine), 5.13 (s, benzylic methylene), 6.9 (m, ~rH), 7.15
~d, J=8Hz, ArH), 7.42 (bs, PhH) and 9.42 ~d, J=3~z, C.-IO).
~-? `:~
3~3~
--6~
EX~MPLE 18
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-4-oxomethylcyclohexanol oxime
A mixture of 1.5 g. (3.44 mmole) of ClS-3- [2
S benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-oxo-
methylcyclohexanol and 358 mg. (5.15 mmole) of hydroxyl~
amine hydrochloride in 10 ml. of pyridine was stirred
at 25 C. for 24 hours~ The reaction was added to one
liter of 10~ hydrochloric acid and extracted with 250 ml.
ether. The ether extract was washed with 200 ml~ saturate~
sodium bicarbonate, 200 ml. saturated sodium chlorider
dried over magnesium sulfate and evaporated to yield
1.40 g. (90%) of the title compound as an oil.
IR (CHC13) 3533, 33G0, 1612 and 1572 cm 1.
lS MS (m/e) 451 (M+3, 433 and 91.
PMR ~cMcl 0.86 (m, terminal methyl)~ 1.28 (s, gem
dimethyl), 2.5-4.0 (m, 3H~, 5.08 (s, benzylic methylene~,
6.39 (m, lH), 6.7-702 (m, ArH) and 7.40 (s, PhH).
I~ like manner trans~3-l2-benzylo~v-4-~l,l di w thyl-
heptyl)phenyl]-cis~4 oxomethylcyclohexanol oxime was
_ _ . _ _ _ _
prepared in 89~ (i.84 g.) yield as an oil from 2.00 g.
(4.59 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyl~-cis-4-oxomethylcyc~ohexanol.
IR (CHC13) 3497, 3225, 1600 and 1562 cm 1.
MS (m/e) 451 (M~), 433, 416, 362, 348 and 91.
PMR ~cMcl 0.82 (mr terminal methyl), 1~22 (s, gem
dimethyl), 4.13 (m, carbinol methine), 5.08 (s, benzylic
methylene), 6.85 (m, ArH), 7.08 (d, J-8H~, ArH) and
7.40 (bs, PhH)~
6~
EXAMPLE 19
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-4-(2-carbomethoxyethenyl)cyclohexanol
_ .
To a 25 C. slurry of 242 mg. (10.1 mmole) of
sodium hydride in 20 ml. tetxahydrofuran and 10 ml.
dimethylformamide ~as added dropwise a solution o.f 1.83 g.
(10 mmole) of me-thyl dimethylphosphonoacetate in 5 ml.
of tetrahydrofuran. The reaction was stirred 5 minutes
and then a solution of 2.0 g. (4n 58 mmole~ of Ci5-3
[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-
oxomethylcyclohexanol in 5 ml. of tetrahydrofuran was
added dropwise~ The reaction was stirred 15 minutes
longer and then added to 700 ml. o~ saturated sodium
chloride. The quenched reaction was extracted with 250 ml.
of ether, the extract dried over magnesium sulfate and
evaporated to an oil. The crude oil was puxified via
column chromatography on 50 g. of silica gel eluted with
50~ ether-pentane to yield 1.28 g. ~58%) of the title
compound as an oil.
IR (CHC13) 3389, 1709, 1650, 1610 and 1557 cm 1,
MS (m/e) 492 (M+~, 407, 383, 323 an~ 91.
PMR ~cMcl 0.83 (m~ terminal methyl), 1.25 (s, gem
dimethyl), 3.10 (m, benzylic methine) 3.62 (s, methyl
ester), 3.62 (m, carbinol methine), 5.05 ~e ~ benzylic
methylene), 5.57 (d, J=16Hz, olefinic H), 6.85 (m, Ar~),
7.05 ~d, J=8Hz, ArH) and 7.40 (s, PhH).
38
-7~-
EXAMPLE 20
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl~
trans-4-(2-carbamoylethenyl)cyclohe~anol
.
A mixture oE 3.0 g. (6.88 mmolej of CiS-3- ~2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]~trans-4 oxo-
methylcyclohexanol and 2.43 g. (7.58 mmole) of carbamoyl-
methylenetriphenylphosphorane in 40 ml. of dichloromethane
was heated at reflux or 24 hours. The reaction was
concentrated and ether added to cause crystallization o~
triphenylphosphine oxide. The residue was purified first
via column chromatography on 120 ~. of silica gel eluted
with ether and khen on lll g. of neu~ral alumina eluted
with 0-100% ethyl acetate-ether to yield 2.0 g. (61%) of
the title compound as an oil.
IR ~CHC13) 3533, 1678, 1612 and 1587 cm 1.
MS ~m/e) 477 (M ), 460, 386, 368 and 307.
PMR ~CDCl 0.84 (m, terminal methyl), 1.22 (s, gem
dimethyl), 3.05 (m, benzylic methine), 3~70 (m, carbinol
methine), 5.08 (s, ben ylic methylene), 5.55 (d, J=16Hz,
oleEinic), 6.95 (m, ArH~, 7.07 (d, J=8Hz, Ar~) and 7.42
(bs, Ph~).
( :`~
71
EXAMPLE 21
Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-
trans-~-(2~carbomethoxyethyl)cyclohexanol
A mixture of 1.28 g. (2.60 mmole) of cis-3-[2-
benzyloxy-4-(l,l~dimethylheptyl)phenyl~-trans-4-(2-
carbomethoxyethenyl)cyclohexanol and 640 mg. of 5~
Pd/C/50~ H2O in 20 ml. of methanol was stirred under
one atmosphere of hydrogen ~or 75 minutes. The reaction
was ~iltered through diatomaceous earth and the filtrate
evaporated. The residue was again mixed with 640 mg.
of fresh 5% Pd/C/50% ~2 in 20 ml. of methanol and
stirred undex one atmosphere of hydrogen for 30 minutes,
then filtered and evaporated as before. The residual oil
was crystallized in ether-pentane to yield 540 mg. (51%)
of ~he title compound.
m.p.: 81-83 C. (ether-pentane)
IR tCHC13) 3521, 3289, 1724, 1612 and 1574 cm 1.
MS (m/e) 404 tM ), 3867 355, 332 and 319.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (sl gem
dimethyl), 2.65 (m, benzylic methine)~ 3.46 (s, methyl
estex~, 3.6 (m, carbinol methine), 5.7 tbroad, OH), 6.75
(m, Ar~ and 7.03 (d, J=8Hz, ArH).
: Calc'd. fox C H O :
C, 74.22; H, 9.97.
Found: C, 73.85; H, 9.64.
Similarly, cis-3-[2-hydrox ~ l-dimethylheptyl)
phenyl]-trans-4-(2-carbamoylethyl)cyclohexanol was pre-
pared in 39% (630 mg.) yield from 2.00 g~ (4.19 mmole)
of cis-3-~2-benzyloxy-4-~1,1-dimethylheptyl)phenyl]-
rans-4-(2-carbamoylethenyl)cyclohexanol.
m.p.: 152-153 C. (ethyl acetate)
IR (KBr) 3267, 3095, 1661, 1618 and 1575 cm 1.
MS tm/e) 389 (M ), 372, 371, 354, 353, 286, 287
and 269.
A
~ 33~3~3
-~2.-
PMR (CDC13 + D6-DMSO)~ 0.83 (m, terminal methyl
1.25 (s, gem dimethyl), 3.0 (m, benzylic methine), 3.70
(m, carbinol methine), 6.75 ~m, ArH~ and 7.03 (d, J=8H7.
ArH).
5 Analysis: Calc'd. or C24H39NO3:
C, 73.99; H, 10.09; N, 3.60.
Found: C, 74.10; H, 10.11; N, 3.52.-
-
3~3~ ~
_73-
EXAMPLE 22
Cis-3-~2-Hydroxy-4~ 1-dimethylheptyl)phenyl]-
trans-4-(2-carboxyethyl)cyclohexanol
... .. . _ . . _
A mixture of 1.01 g~ (2.50 mmole) of cis-3- [2-
hydroxy-4-(1,1-dimethylheptyl)phPnyl]-trans-4-(2~
carbomethoxyethyl)cyclohexanol, 25 ml. 6N sodium hydroxide
and 25 ml. dioxane was heated at reflux for 40 minutes
and then cooled to 0 C. and acidified with 6N hydro-
chloric acid. The quPnched reaction was diluted with
saturated sodium chloride and e~tracted several times
with ether and then dichloromethane. The.combined organic
extract was evaporated and the residue recrystallized
from ethyl acetate to yield 314 mg. (32%) of the title
comFound O
m O p.: 194-195 C. (ethyl acetate)
IR (KBr) 3367, 3125, 1694, 1612 and 1575 cm 1.
HRMS (m/e~ 390.2758 (M , calc'd. for C24H38O~:
390.2760), 305, 287, 269.
PMR (CDC13, D6-DMSO) ~TMS 0.82 (m, terminal methyl),
1.23 (s, gem dimethyl), 3.50 (m, carbinol methine), 6.78
. (m, ArH) and 7.04 (d, J-8Hz, ArH).
~ ~ ~3~38
j7~_
) EX~MPLE 23
Cis-3- [2-Hydroxy-4-(1,1-dimethylheptyl)phenyl~-
trans-4-(3-aminopropyl)cyclohexanol
To a 0 C. slurry of 500 mg~ (13.1 mmole) of lithi~n
aluminum ~ydride in 15 ml. of tetrahydrofuran was added a
solution of 460 mg. (1.18 mmole) of C15-3- [2-hydroxy-
4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-carbamoyle~hyl~-
cyclohexanol in 14 ml. of tetrahydrofuran. The reaction
was stirred at 25 C. for one hour and at reflux for
10 20 hours. ~he reaction was cooled to 0 CO and ~uenched
by the addition of a 30% solution of sodium potassium
tartrate. The quenched reaction was extracted with ethyl
acetate, the extra~t dried over magnesium sulfate and
evaporated to an oil. Crystallization o~ the residue in
15 ether-ethyl acetate gave 390 mg. (88%) of the title
compound.
m.p.: 137~138 C.
MS (m/e) 375 (M~1, 358 and 340.
PMR (CDC13 ~ D6DMSO)~TMS 0.80 (m, terminal methyl),
20 1.22 ts, gem dimethyl), 3.3~ (bs, excAangeable OH), 3.75
(m, carbinol methine~, 6.75 ~m, ArH~ and 7.00 (d, J=8~z,
ArH).
The following compounds were similarly prepared:
ClS-3- t2-hYdroxY-4- (1, l-dimethylheptyl)phenyl]-
~ . . ~ . .
25 trans-4-aminomethylcyclohexanol in 43% (819 mg.~ yield
~ . . .
from 1.99 g. (5.~1 mmole) of ClS-3- [2-hydroxy-4-(1,1-
dimethylheptyl)phenyl]-trans-4-oxomethylcyclohexanol
o~ime.
m.p.: 104-106 C. (ethyl acetate-pentane)
IR (KBr) 3205, 1602 and 1572 cm l
HRMS (m/e) 347 . 2853 (M , calc'd. for C22H37NO2:
347.2815), ~45, 227.
~ 35i3~3
trans-3- [2-hydroxy-4- (1, 1-dimethylheptyl) phenyl]
cis-4-aminomethylcyclohexanol in 44~ (427 mg.) yield
from l.01 g. (2.80 mmole) of trans-3-[2-hydroxy-4~
(l ,1-dimethylheptyl) phenyl] -cis-4-oxomethylcyclohexanol
S oxime.
m.p.: 121-124 C. (ether-hexane)
MS (m/e) 347 ~M+), 330, 312, 245 and 227.
y
353~
-76-
EXAMPLE 24
,
Cis-3-[2-Hydroxy~4-(1,1-dimethylheptyl)phenyl]-
trans-4-(3-dimethylaminopropyl)cyclohexanol hydrochloride
_ _ f . ,~
A mixture of 340 mg. (0.906 mmole) of CiS~3-[2
hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-amino
propyl)cyclohexanol, 268 ~1. of 37~ formaldehyde and
137 ~1. of formic acid was heated at 100 C. for 30
min~tes~ The reaction was cooled and added to ether and
saturated sodium bicarbonate. The ether extract was
dried over magnesium sulfate and evaporated to yield an
oil which was purified via column chromatography on
8 g. of silica gel eluted with 50% methanol-dichloro-
me~hane to yield 78 mg. (21~) of the free base of the
title compound as a glass.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 2.19 (s, N-methyls), 3.7 (m, carbinol methine),
5.55 (broad, O~), 6.75 (m, ArH) and 6.98 (d, J=8Hz, ArH).
HRMS (m/e) 403.3447 (M , 100~, calc'd. for C26H45N02:
403.3439).
The above free base was dissolved in ether-ethanol and
excess ethereal hydrogen chloride added. The solution
was then evaporated and the residue crystallized from
ether-dichlorom~ethane to yield 71.8 mg. (18%) of the
title compound.
m.p.: 170-175 C. (ether-dichloromethane~
The following compounds were prepared by the above
procedure:
CiS~3- [2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-
. _ . . _
~rans-4~N,N~dimethylaminomethylcyclohexanol hydrochloride
in 25~ (30mg.) yield from 100 mg. (0.288 mmole) of
cis-3~[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-
aminomethylcyclohexanol.
m.p.: 202-203 C. (ether-dichloromethane)
MS (m/e) 375 (M )
~` ~:
~3~3~
-77 -
Free Base:
PMR (CDCl3)~ 0.82 (m, terminal methyl), 1.30 (s,
gem dimethyl), 2.28 (s, N,N-dimethyl), 3.75 (m, carhinol
methine), 6.9 (m, ArH) and 7.12 (d, J=8Hz, ArH).
5H~MS (m/e) 375.3140 (M , calc'd. for C24H4lNO2:
37S.3127).
trans-3-[2 hydroxy-4-(1,1-dimethylheptyl)phenyl]-
cis-4-N,N-dimethylaminomethylcyclohexanol hydrochloride
in 25~ (198 mg.) yield from 672 mg. (1.94 mmole) of
rans-3-[~-hydroxy-4-(l,l-dimethylheptyl)phenyl]-cis-4-
aminomethylcyclohexanol.
m.p.: 176 178 C.
PMR ~CDC13) ~C~Cl 0.82 (m, terminal methyl), 1~25
(m, gem dimethyl and methylenes), 4.26 (m, carbinol
methine) and 6.6 7.2 (m, ArH).
Free Base~ -
IR (CHC13) 3333, 1607 and 1563 cm 1
MS (m/e) 375 (M ), 330 and 245.
33~
_ 7~
EXAMPLE 25
Trans-l [2-~ydroxy-4-(1,1-dimethylheptyl)phenyl]-2-
(3-hydroxy~ropyl)cyclohexane
~ mixture of 1.9 g. (5.08 mmoles) of rans-3-~2-
hydro~y-4-(1,1-dimethylheptyl)phenyl]-2-(3-hydroxypropyl)-
cyclohexanone and 10.2 ml. of hydrazine hydrate i~ 20 ml.
of ethylene glycol is heated at 100 C. for an hour.
The reaction was cooled to 60 C. and 4.05 g. (72.3 mmoles)
of solid potassium hydroxide added. The resultant mixture
was heated for 2 hours at 200 C., then cooled and added
to 500 ml. lN hydrochloric acid and 300 ml. ether. The
ether extract was washed with 300 ml. saturated sodium
chloride, 300 ml. saturated sodium bicarbonate, dried
over magnesium sulfate and evaporated under reduced pressure
~aspirator) to an oil. The crude oil was purified via
column chromatography on 100 g. of silica gel eluted with
70~ ether~hexane to yield 406 mg. (22~) of the title
compound as an oil.
IR (CHC13) 3509t 3279, 1605, 1595 and 1570 cm 1
MS ~m/e) 360 (M ), 345, 342, 275, 257, 233, 215,
147 and 141.
PMR ~DCl 0.82 (m, terminal methyl~, 1.25 (s, gem
dimethyl), 2.58 (m, benzylic methine), 3.46 (bt, J=6EI2,
hydroxy methylene), 5.0 (broad, OH), 6.67 (d, J=2Hz,
ArH), 6.79 (d, J=8 and 2Hz) and 7.02 (d, J=8Hæ, ArH).
~ ~33~3~
-79-
EXAMPLE 26
Cis-3 [2-Benzyloxy-4-(1,1~-dimethylheptyl)phenyl)-
trans-4-(2-propenyl)-1-benzyloxycyclohexane
To a slurry of 214 mg. (8.92 mmole) of sodium
hydride in 10 ml. dimethylformamide was added a solution
of 2.0 g. (4.46 mmole) of cis-3~[2-benzyloxy-4-(1,1-di-
methylheptyl)phenyl]-trans-4-(2-pro~enyl)cyclohexanol
in 10 ml. of dimethylformamide. The reac~ion was stirred
5 hours and then 0~6 ml. (4.9 mmole) or benzyl bromide
was added. The reaction mixture was stirred 18 hours
longer and added to 500 ml. saturated sodium chloride
and 500 ml. ether. The organic extract was dried over
magnesium sulfate and evaporated to yield an oil which
was purified via column chromatography on 100 g. of silica
gel eLuted with 5% ether-hexane to yield 2.0 g. (83%) of
the title compound as an oil.
IR (CHC13) 1539, 1600 and 1567 cm 1,
HRMS (m/e) 538.3823 (M , calc'd. for C38H5002:
538.3798), 453, 299, 255 and 91.
PMR ~CDCl 0.83 (m, terminal methyl), 1024 (s, gem
dimethyl), 2~85 and 3.40 (m, ether methines), 4.50 and
5.05 (s, benzylic methylenes), 4.6-5.0 and 5.2-6.1 (n,
vinyl H), 6.9 (m, ArH), 7.28 and 7.34 (bs, PhH).
3538
~ 8~
EXAMPLE 27
Cis-3-[4-11,1-Dimethylheptyl)-2-hydroxyphenyl]-
trans-4-(3-methoxypropyl)~yclohexanol
To a slurr~ of 172 mg. (7 mmole) of sodium hydride
in 15 mL. dimethylformamide was added 2.0 g. (3.60 mmole)
of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-
trans= 4-(3-hydroxypropyl)-1-benzyloxycyclohexane in 15 ml.
dimethylformamide. The reaction mixture was ~hen heated
at 40-50 C. for 3 hours, then cooled to 25 C. and
0.663 ml. (7.0 mmole) of dLmethylsulfate was added. The
resultant mixture was stirred 18 hours at 0 C. and then
added to 250 ml. saturated sodium chloride and 250 ml.
ether. The organic extract was dried over magnesium
sulfate and evaporated to an oil. The crude oil was
puriied via coLumn chromatography on 75 g. of silica
gel eluted with 20~ ether-hexane to yield 500 mg. (24%)
of cis-3-[4-tl,l-dimethylheptyl)-2 hydroxyphenyl]-trans-
4-(3-methoxypropyl)cyclohexanol as an oil.
PMR ~cDSl 0.83 (m, terminal methyl), 1.23 (s, gem
dimethyl), 3.20 (s, OCH3), 2.6 4.0 (m), 4.54 and 5.06 (s,
benzylic methylenes), 6.85 (m, ArH) and 7.28 (m, PhH).
Debenzylation of 500 mg. (0.874 mmole) of the product
according to the procedure of Example 6 gives the titla
compound .
m.p.: 72-74 C. (pentane)
MS (m/~) 390.3100 (M , calc'd. for C25H42O3; 390.3123),
372, 286, 272 and 147.
PMR (CDC13) ~ 0.85 (m), 1.22 (s, gem dimethyl), 3.20
(OCH3), 2.4-4~2 (several m), 5.05 (bs, OH), 6.8 (m, ArH)
and 7.02 (d, J=8Hz, ArH).
353~3
- ~ 1
EXAMPLE 2 8
Trans-3-[2-Benzyloxy-4-(R)-(l-methyl-4-phenylbutoxy~-
phenyl]-4-(2-prop~nyl)cycloheptanone
Using the procedure of Example 1, 23 g. (54.1 mmole)
of (R)-l-bromo-2-benzyloxy-4~ methyl-4-phenylbutoxy)-
benzene and 7O5 g. (50.0 mmole) of 4-(2-propenyl)~2-
cyclohepten-l-one ga~e 8.14 g. (30~) of the title compound
as an oil.
[~]D = -10.61 (C = 1.077, CHC13)
HRMS (m/e) 496.2954 (~ , calcld. for C34a40O3:
496.29673, 405, 259, 241 and 91.
CDC13 1.22 (d, J-6Hz, methyl), 4.33 (m side
chain methine~, 4.6~5.0 and 5 . 2-6. 0 (m, vinyl H), 5.00
(s, benz~lic methylene), 6.45 (m, ArH), 7.00 (d, J=8Hz,
ArH), 7.24 (s, PhH) and 7.42 (s, PhH).
33~3~
-- 82~
EXA~qPLE 29
Ci s 3 - [ 2 -Benzyloxy- 4 - ( R) ~ methyl-4-phenylbutoxy)phenyl]-
4-trans-(2-propenyl)cycloheptanol and Isomeric Alcohol
Using the procedure of Example 2, 8.14 g. (16.5 mmole)
o trans-3-~2-benzyloxy-4-(R)-(l-methyl-4 phenylbutoxy)-
phenyl]-4-(2-propenyl)cycloheptanone gives in ordar of
elution 3.14 g. (39%) of the trans-3, Cl5-4 isomer and
3.23 g. (40%3 o the title compound.
Trans-3, Cis-4 Isomer:
[]D = -10.40 (C = 1.058, CEC13)
IR (CHC13) 3508, 3448, 1626 and 1600 cm 1.
HRMS (m/e) 498.3120 (M , calc'd. for C34H4203:
498.3123) and 91.
PMR ~cMcl 1.22 (d, J=6Hz, methyl), 2.6 (m, benæylic
methylene), 3.2 (m, ~enzylic methine), 4.0 (m, car~inol
methine), 4.25 (m, sidechain methine), 4O6-5.0 and 5.2-
6.0 (m, ~inyl H), 5.02 (s, benzylic methylene), 6.4 (m,
ArH), 7.20 and 7.38 (s, PhH).
Cis-3, Trans-4 Isomer:
ta~D = -9.97 ( = 1.471, CHC13)
IR (C~C13) 3508, 3448, 1626 and 1600 cm 1.
~RMS (m~e~ 498.3104 (M+, calc'd. for C34H42O3:
498.3123), 261, 243 and 91.
PMR ~c~sl 1.22 (d, J=6Hz, methyl), 2.55 ~m, benzylic
methyl~ne and methine), 3.65 (m, car~inol methine), 4.20
(m, sidechain methine), 4.6-5.0 and 5.2-6.0 (m, vinyl H),
5.02 (s, benzylic methylene), 6.4 (m, ArH), 7.00 (d,
~8Hz, ArH3, 7.2 and 7.38 (s, PhH)~
353~
_~3_
EXAMPLE 30
Cis-3-[2-Benzyloxy-4-(R)~ methyl-4~phenylbu~oxy)-
phenyl ] -4 -trans-(3-hydroxypropyl)cycloheptanol
Using the procedure of Example 5, 1O03 g. (2.07
mmole) of cis-3- ~2-benzyloxy-4-(R)-51-m~thyl-4-phenyl-
butoxy)phenyl]-4-trans-(2~propenyl)cycloheptanol gave
l.08 g. (100%~ of the title compound as an oil.
1 ]25o _ _9 83 (C = 1.051, CHC13)
IR (CHC13) 3571, 3389, 1600 and 1574 cm 1.
HRMS (m/e~ 516.3216 (M , calc'd. for C34H4404:
516.32283.
PMR ~cMcl 1.22 (d, J=6Hz, methyl), 2.7 (m, benzylic
methylene~, 3.42 (bt, C~O~), 3.85 (m, carbinol methine),
4.35 (m, sidechain methine), 5.00 (s, benzylic methylene),
6.45 (m, ArH), 7.02 (d, J=8Hz, ArH), 7.25 and 7.42 (s,
PhH).
( ~ (~
~ 33~
_84_
EXAMPLE 31
Cis-3-E2-Hydroxy-4-(R)-(l-methyl-4-phenylbutoxy)~
phenyl]-4-tran~ (3-hydroxypropyl)cycloheptanol
. _ ~ _ . . . _ _
Using the procedure of Example 6~ 1.0 g. (1.93 mmole)
of cis-3- [2-benzyloxy-4-(R) (l-methyl-4-phenylbutoxy)-
phenyl]-4~ rans-(3-hydroxypropyl)cycloheptanol gave
500 mg. (61~) of the title compound as an oil.
~]D5 = ~7 53 (C = 0.68, CHC13)
IR (CHC13) 3508, 3333, 1600 and 1587 cm 1.
HRMS (m/e) 426.2758 (M , calc'd. for C~7H3804
426.2760), 280, 262, 123 and 91.
PMR ~CDCl 1.22 (d, J=6Hz, methyl), 2.58 ~m, benzylic
methylene), 3.40 (t, J=7Hz, CH20H), 3.8 (m, carbin~l
methine), 4.15 ~m, sidechain methine), 6.35 (m, ArH), 6~g5
lS (d, J=8Hz, ArH) and 7.19 (s, PhH)o
3~ ~
EXAMPLE 32
Cis-3-[2-Benzyloxy-4-(1,1-dimeth~lheptyl)phenyl]-
trans-4-(2-propenyl)-1-phthalimidocyc.loheptane
. . _ . . _ ~ .
To a 25 CO mixture Qf 1.00 g. (2.16 mmole) of
trans 3-[2-benzyloxy~~-(1,1-dimethylheptyl)phenyl~ -Ci5-
4-(2-propenyl)cycloheptanol, 476 mg. (3.24 mmole) of
phthalimide and 846 mg. (3.24 mmole) of triphenylphosphine
in 1.0 ml acetonitrile was 510wly added 0.51 ml. (3.24
mmole) of diethyl azodicarboxylate. The reaction mixture
was stirred 5 hours and then dissolved in Z50 ml. ether.
The ether phase was washed once with 250 ml. water, once
with 250 ml. saturated sodium chloride, dried over
magnesium sulfate and evaporated to an oil. The crude
oil was purified via column chromatography on 200 g. of
lS silica gel eluted with 10~ ether-hexane to yield 820 mg.
(64~) of the title compound as an oil.
IR (CHC13) 1761, 1695, 1625, 16Q3 and 1563.
~RMS (m/e) 591.3i99 (M+, calc'd. for C40H49N03:
591.3700), 506, 353 and 91.
CDC13 0.8 (m, terminal methyl), 1.20 (s gem
dimethyl), 2.98 tm, benzylic methine), 4.4 (bm, methine),
4.5-5.0 (m, vinyl H), 5.03 (s, benzylic methylene), 5.2-
6.0 (m, vinyl H), 6.78 (m, ArH), 7~02 (d, J=8Hz, ArR),
7.33 and 7.65 (m, ArH and PhH).
' , 1'.
3~3~
EXAMPLE 33
_
Cis-3 [2-Benzyloxy-4~(1,1-dimethylheptyl)phenyl]-
trans-4-(2-propenyl)-1-aminocycloheptane
A solution of 1.0 g. (1.68 mmole) of CiS-3- [2~
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-
propenyl)-l-phthalimidocycloheptane and 0.834 ml.
(1.68 mmole) of hydrazine hydrate in 2 ml. ethanol was
heated at reflux for 20 minutes forming a precipitate.
The reaction was cooled, filtered and the solid washed
with 200 ml. ether. The filtrate was washed once with
100 ml. saturated sodium chloride, once with 100 ml.
50% 2N sodium hydroxide, dried over magnesium sulfate
and evaporated to yield 770 mg. (99%) of ~he title
compound as an oil.
IR ~CHC13) 3125, 1695, 1632, 1600 and 1562 cm 1.
HRMS (m/e) 461~3607 (M , calc'd. for C32H47NO:
461.3646), 420, 370, 354 and 91.
PMR ~CDCl 0.8 (m, terminal methyl), 1.24 (s, gem
dimethyl), 2.9 (m, 2H), 4.6-S.0 (m, vinyl H~, 5.04 (s~
benzylic mathylene), 5.2-6.1 (m, vinyl H), 6.85 (m,
ArH), 7.07 (d, J=8Hz, ArH) and 7O4 (m, PhH).
Following the procedures of Example 32 and of
this example~ cis-3~~2-benzyloxy-4-(1,1-dimethylheptyl)-
phen~l]-trans-4-(2-propenyl)-1-aminocyclohexane is
prepared from trans-3~[2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyl]-cis-4-(2-propenyl)cyclohexanol.
,i` ~
3~ `
-87-
EXAMPLE 34
Cis-3-[2-Benzylo~y-4-(1,1-dimethylheptyl)phenyl]-
trans-4-(2-propenyl)-1-acetamidocycloheptane.
A mixture of 500 mg. ~1.08 mmole) of CiS-3- ~2-
benzylo~y-4-(1,1-dimethylheptyl)phenyl]-trans=4 (2
propenyl)-l-aminocycloheptane, 131 mg. ~1.08 mmole)
4-N,N-dimethylaminopyridine and O.iOl ml. (1~08 mmole)
of acetic anhydride in 5 ml. dichloromethane was stirred
for one hour. The reaction was added to 100 ml. ether
and washed twice with 100 ml. lN hydrochloric acid and
twice with 100 ml. saturated sodium bicarbonate. The
organic phase was dried over magnesium sulfate and
evaporated t~ give 485 mg. ~89~) of the title compound
as an oil.
lS IR (CHC13) 3389/ 1652, 1602 and 1562 cm 1
HRMS (m/e) 503.3793 (M , calc'd. for C3~H49N02
503.3751), 418, 412, 353 and 91.
PMR ~Tc~cl 0.82 (m, terminal methyl), 1.22 (s, gem
dimethyl), 1.86 (s, COCH3), 2.95 (m, benzylic methine) f
4.02 (bm, CHN), 4.6-5.0 (m, vinyl H), 5.08 ~s, benzylic
methylene), 5.3-6.0 (m, vinyl H), 6.85 (m, ArH), 7.03
(d, J=8Hz, Ar~) and 7.38 (m, ArH).
35i3~
-88-
EXAMPLE 35
Cis-3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-
trans-4-(3-hydroxypropyl)-1-acetamidocycloheptane
Using the procedure of Example 5, 1.7 g. ~3.37 mmole)
of cis-3-[2-benzyloxy-4 (l,l-dimethylheptyl)phenyl~-
trans-4-(2-propenyl)-1-acetamidocycloheptane gave 962 mg.
(55%) of the title compound as an oil.
IR (C~C13) 3448, 1652, 1600 and 1562 cm 1.
H~MS (m~e~ 521.38L3 (M+, calc'd. for C34H51NO3:
521.3856), 430, 371 and 91.
CDC13 0.8 (m~ terminal methyl), 1 20 (5 ge
dimethyl), 2.85 (m, benzylic methinel, 3.35 (m, C~2OH),
4.0 (m, C~N), 5~05 (s, benzylic methylene), 5.38 (bd,
NH), 6.8 (m, ArH), 7.00 (d, J=8Hz, ArH) and 7.39 (bs,
PhH).
EXAMPLE 36
Cis 3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-
trans-4-(3-hydroxypropyl) l-acetamidocycloheptan~
Using the procedure of Example 6, 960 mg. (1.84 mmole)
of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-4-(3-hydroxypropyl)-1-acetamidocycloheptane gave
630 mg. (79~ of the title compound as an oil.
IR (CHC13) 3649, 3389, 3279, 1652, 1600 and 1562 cm 1,
HRMS (m/e) 431.3420 (M+, calc'd. for C27H45N03:
431.3388), 346J 287, 257, 161, 147 and 133.
PMR ~cMcl 0.8 (m, terminal methyl), 1.20 (s, gem
dimethyl), 1.85 (s, COCH3), 2.82 (m, benzyli~ methine),
3.4~ (m, CH2OH), 4.0 (m, CHN), 5~6 (bd, NH), 6~75 (m,
ArH) and 6.98 ~d, 3=8Hz, ArH).
By means of the procedures of Examples 34, 35 and
this example, cis-3-[4-(1,1-dimethylheptyl) 2-hydroxy-
phenyl~-trans-(3-hydroxypropyl)-1-acetamidocyclohexane
is prepared from cis-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl1phenyl]-txans-(2-propenyl)-1-aminocyclohexane.
-`,,Ç~
-89-
EXAMPLE 37
-
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
t_ans-4-(3~hydroxypropyl)cyclohexanol bis-d-mandelate
A mixture of 31.3 g. (67.2 mmole~ of Ci5-3-[2-
benzyloxy-4-(1,1-dimethylheptyl)phanyl]-trans-4-
(3~hydroxypropyl)cyclohexanol, 25.5 g. (168 mmole3 of
d-mandelic acid and 1.0 g. ~5.26 mmole~ of ~toluene-
sulfonic acid monohydrate in 500 ml. of benzene was
heated at reflux for ll hours. Water was removed by
use of a sbxhlet extractor filled with 209 g. of 3A
molecular sieves. The reaction is cooled, added to one
liter saturated sodium bicarbonate and extracted with
four 500 ml. portions of ether. The combined organic
extract was dried over magnesium sulfate and evaporated
to an oil. The crude oil was purified via column chroma-
tography on 2 kg. of silica gel eluted with 40-50~ ether-
hexane to yield in order of elution 18 g. (37~) of
diastereomer A and 21 g. (43~) of diastereomer B of the
title compound.
Diastereomer A
m.p~ 112.5 C. ~methanol)
[a]25 = +20.19 (C = 1.107, 5~ chloroform-methanol)
PMR (CDC13)~ Q.84 (m, terminal methyl), 1.25 (s, gem
dimethyl), 2.8 Im, benzylic methine), 3.45 (m), 4.0 (m),
4.6-5.2 (m), ~05 (s, benzylic methylene), 6.88 (m, ArH),
7.27 and 7.34 (s, PhH).
Analysis: Calc'd. for C47H5~07-
C, 76.81; H, 7.95.
Founcd: C, 76.49; Hl 7.76.
In like manner, but using the same relative
stoichiome~ric proportion of d-mandelic acid and
p-toluenesulfonic acid monohydrate, 9.0 g. ~16 mmole)
of ClS-3~ [ 2-Benzyloxy-4~ dimethylheptyl)phenyl]-
trans-4-(3-benzyloxypropyl)cyclohexanol gave, in order
~ 3~3~
--. 90.--
of elution, 4.1 g. (37%) of diastereomer A and 4.2 g.
(38~) of diastereomer B of cis-3-[2-benzyloxy-4 (1,1-
dimethylheptyl)phenyl]-trans-4-(3-benzyloxypropyl~ 1-
d-mandeloyloxycyclohexane as solids.
~ _ .
Diastereomer A:
-
m.p.: 56-58 C.
[a]25 = 0.232 (C = 1.25, CH3OH)
PMR ~CDCl 0.80 (m, terminal methyl), 1.20 (s, gem
dLmethyl), 2.9 (m), 3.0-3.6 (m), 4.30 (~, benzylic
methylene), 4.5-5.1 (m), 5.00 (s, benzylic methylene),
6.78 (m, ArH), 6.98 (d, J=8Hz, ArH), 7.17 (s, PhH) and
7.30 (s, PhH).
Diastereomer B:
m.p.: 65-69 C.
lS []25 = ~40.. 95 (C = 1.21, CH3OH)
PMR ~TcDSl 0.80 (m, terminal methyl), 1.20 (s, gem
dimethyl), 2.8 (m), 3.0-3.5 (m), 4.26 (s, benzylic
methylene), 4.4-S.1 (m), 4.95 (sl benzylic methylene),
6.70 (mj ArH), 6.87 (d, J=8Hz), 7.12 (s, PhH) and 7.20
(s, PhH).
335~1~
--91, --
EXAMPLE 38
.
Enantiom~r A of Cis-3-[2-Ben~yloxy-4-(1~1-dimethylheptyl)~
phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol
A mixture of 18 g. (24.5 mmole) of diastereomer A
of cis 3 [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-4-(3-hydroxypropyl)cyclohexanol bis-d-mandelate
and 13.5 g. (98.1 mmole) of potassium carbonate in 250 ml.
methanol, 175 ml. tetrahydrofuran and 35 ml. water was
stirred for 24 hours. The reaction was added to one
liter saturated sodium chloride and extracted twice
with 500 ml. portions of ether. The comhined or~anic
extract was dried over magnesium sulfate and evaporated
to a quantitative yield of the title compound as an oil.
[~D ~ -34.51 ~C = 1.083, methanol)
PMR ~CDCl 0.82 (m, terminal methanol), 1.25 (s,
gem dimethyl), 2.90 (m, benzylic methine), 3.4Q (bt,
CH20H), 3.7 (m, carbinol methine), S. 06 (5, benzylic
methylene), 6.82 (d, J=2Hz, ArH), 6.8Z (dd, J=8 and 2Hz,
Ar~), 7.00 (d, J=8Hz, ArH) and 7.32 (s, PhH).
Using the above procedure, 4.00 g. (5.79 mmole)
of CiS-3- [2-benxyloxy-4~ dimethylheptyl)phenyl~
trans-4-(3-benzyloxypropyl)-1-d-mandeloyloxycyclohexane,
~iastereomer A, gave a quantitative yield of c -3-[2-
benzyloxy-4-(1,1-dLmethylheptyl)phenyl]~trans-4-(3-
. . .
benzyloxyproPyl)cyclohexanol~ enantiomex ~, as an oil.
[]D ~ -24.92 (C = 1.23, C~30H)
PMR ~CDcl 0.82 (m, terminal methyl), 1~22 (s, gem
dimethyl~, 2.9 (m, benzylic methine), 3.23 (bt, J=6Hz,
methylene), 3.7 (m, carbinol methine), 4.35 and 5.00
~s, ~enzylic methylenes), 6.82 (m, ArH), 7.02 (d, J=8Hæ,
ArH), 7.19 and 7.35 (s, PhH).
33~ii3~
- 92 -
EXA~PLE 39
Enantiomer B of Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-trans~4- (3 hydroxypropyl)cyclohexa~ol
a. Using the procedure of Example 3~, 21 g~
(28.6 mmole) of diastereomer B of cis-3- [2-benzyloxy
4-(1,1-dimethylheptyl~phenyl]~trans-4-(3-hydroxypropyl)
cyclohexanol bis-d-mandelate gave 13 g. ~98~ of the
title compound as on oi~.
~ ~25 = ~26 30 (C = 1.051, CH3OH)
b. Using the procedure of Example 37, 13 g. (27.8
mmole) of the title compound and 10.6 g. (69.7 mmole)
of l-mandelic acid gave 8 g. (39~) of diastereomer A of
CiS 3-[2~benzyloxy-4-tl,l-dimethylheptyl)phenyl]-trans-
4-(3-hydroxypropyl)cyclohexanol bis-l-mandelate.
m.p. 106-107.5 C. (methanol)
PMR ~CDCl 0.83. (terminal methyl), 1.25 (s, gem
dimethyl), 2.85 ~mr benzylic methine), 3.40 (m), 4.0
(m), 4.7 S.l (m), 5.07 (s, benzylic methylene).
Anal~s_s: Calc'd. for C47H58O7
C, 76.81; H, 7.95~
Found C, 76,69; H, 7~86.
c. Using t:he procedure of Example 38, 8.~ g.
(1~.9 mmole) of diastereomer A o~ CiS-3- 12-benzyloxy-
4-(1,1 dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl~
Z5 cyclohexanol bis-l-mandelate gives 4.7 g. (93~) of the
title compound.
~]25 = +34.17 ~C - l.lS, CH30H)
PM~ ~CDCl 0.86 (m, terminal methyl), 1.28 (s, gem
dimethyl), 2.82 (m, benzylic methine), 3.42 (bt, CH2OH),
3.7 ~m, car~inol methine), 5.10 (s, benzylic methylene),
6.9 (m, ArH), 7.10 (d, J=8Hz, ArH) and 7.40 (s, PhH).
" ~83S3~
-l93 _
EXAMPLE 40
Cis-3 [4-~1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-
4-(3-hydroxypropyl)cyclohexanol, Enantiomer A
. . _ ~
Using the procedure of Example 6, 17.4 g. ~24.5
mmole) of enantiomer A of cis-3- [ 2-benzyloxy~4~
dimethylheptyl)phenyl]-trans~4 (3-hydroxypropyl)cyclo-
hexanol gave 8.5 g. (93%) of the title compo~nd.
m.p. 65-72 C. (hexane-dichloromethane3
[~3D = -39.24 (C = 1.00, CH30H)
HRMS (m/e) 376.2938 (M , calc'd. for C24H4003:
376.2967), 304, 273, 255, 199, 147 and 121.
PMR ~CDCl 0 83 (m~ terminal methyl), 1.23 (s, gem
dimethyl), 2.83 (m, benzylic methine), 3.58 (bt, CH20H~,
3.7 (m, carbinol methine), 6.9 (m, ArH) and 7.00 (d,
Ja8Hz, Ar~).
EXAMPLE 41
Cis-3-~4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-
4-(3-hydroxyprQpyl)cyclohexanol, Enantiomer B
Using the procedure of Example 6, 4.7 g. (10.1 mmole)
~0 of enantiomer B of CiS-3- [ 2-benzyloxy-4-(1,1-dimethyl
heptyl)phenyl]-t:rans-4-(3-hydroxypropyl)cyclohexanol
gave 3.5 g. (92%) o~ the title compound as an oil.
,~0
~]D' = +36.47 (C = ~.947, CH30H)
HRMS (m/e) 376.2942 (M , calc'd. for C24H4003:
Z5 376.2967), 358, 291, ~73 and 147.
PMR (~DC13) ~ 0.82 (s, terminal methyl), 1.2 (s, gem
dimethyl) 2.7 (m, benzylic met~ine), 3.41 (bt, ~-7Hz,
carbinol methylene), 3.78 ~m, carbinol methine), 6.77 (m,
Ar~) and 7.00 (d, J=8Hz~ ArH).
~3L 51~353~
9'~1,
EX~MPLE 42
Trans-3-[2-Benzyloxy-4-(1~1-dimethylheptyl)phenyl]-
5 cyanocyclohexanone
To a reXluxing solution of 3.99 g. (9.87 mmole)
of 5 ~2-benzyloxy-4~ dimethylheptyl)phenyl]-2-cyclo
hexen-l-one in 6.65 ml. of ethyl acetate was added a hot
solution of 800 mg. ~11.9 mmole) of potassium cyanide
in 2 ml. wat~r and 2.3 ml. ethanol. The reaction wzs
refluxed 2 hours and then another 2.74 mmole of potassium
cyanide added. The reaction was refluxed one hour longer
and then cooled and added to 400 ml. saturated sodium
chloride-400 mlO ether. The ether extract was dried
over magnesium sulfate and evaporated to yield an oil.
The crude oil was purified via column chromatography on
160 g. of silica gel eluted with 10~ acetone-hexane to
yield 3.02 g. (71%) of the title compound.
m.p~ 79 C. (petroleum ether)
IR (CHC13) 2202, 1706, 1600 and 1552 cm 1.
MR (m/e) 431 (M ), 414, 403, 346, 340 and 91o
E ~4PLE 43
Trans-3-[2-BenzylGxy-4-(l,l~dimethylheptyl)phenyl]-
cis-5-cyanocyclohexanol
Using the procedure of Example 2, 3.02 g. (7.00
mmole) of trans-3-[2-benæyloxy-4-(1,1 dimethylheptyl~-
phenyl~-5-cyanocyclohexanone was reduced to 2.66 g.
(88%~ of the title compound.
m.p. 94-102 C. (pentane)
IR (C~C13) 3413, 2222, 1612 and 1575 cm 1,
MS (m~e) 433 (M+).
~3353~
~ 95
_X~MPLE 44
Trans-3-[2-Benzyloxy-4-(1,1 dimethylheptyl)phenyl~- -
trans~5-cyanocyclohexanol
. ~
A mixture of 3.12 g. ~7.20 mmole) o~ trans-3-~2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cls-5-cyano-
cyclohexanol and 808 mg. ~7~20 mmole) of potassium
t~butoxide in 70 ml. of t-bu~anol was refluxed for 2.5
hours~ The - t-butanol was evaporated on a rotovapor and
the residue diluted with saturated sodium chloride. The
quenched residue was extracted with ether, the extract
dried over magnesium sulfate and evapoxated to yield
an oil. The crude oil was purified via column chroma~
tography on 124 g. o~ silica gel eluted with 10% acetone-
hexane to yield 1.53 g. (44~) of the title compound.
m.p. 62-64 C. (petroleum ether)
IR (CHC13) 2247, 1597 and 1579 cm 1.
MS (m/e) 433 ~M ), 348, 342, 305 and 91.
~DC13 0.83 (m, terminal methyl), 2 8-3 9
(two methines), 4.25 (m, carbinol methine), 5.12 (s,
benzylic methylene), 6.9 ~m, ArH), 7.06 (d, J=8Hz, ArH)
and 7.4 (s, PhH).
~ 35~3
_ 96 _
EX~MPLE 45
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
S-cyanocyclohexanone
.
To a 0 C. solution of 1.43 g. (3~30 ~mole~ of
trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans 5-cyanocyclohexanol in 25 ml. of acetone was added
__
2.37 ml. (6~6 mmole) of Jones's Reagent. The reaction
was stirred 20 minutes at 0 C. and then quenched by
the addition of 1 ml. o~ isopropanol. The quenched
reaction was added to 70Q ml. saturated sodium chloxide
and extracted with 300 ml. of ether. The ether extract
was dried over magnesium sulfate and e~aporated to yield
1.31 g. (92%) of th~ title compound as an oil.
IR (C~C13) 2247, 1733, 1623 and 1584 cm 1.
MS (m/e) 431 (M ), 416, 404, 362, 347, 340 and 91.
PMR ~cMcl 0.83 (m, terminal methyl), 1.24 (~, gem
dimethyl), 200-3.7 (m), 5.10 (s, benzylic methylene),
6.95 (m, ArH), 7.02 (d, J-8Hz) and 7.38 (s, ArH).
35i~
_ 97 -
EXAMPLE 46
_ .
Cis-3-~2-Benzylo~y 4-(1,1-dimethylheptyl)phenyl]-
cls-S-cyanocyclohexanol
Using the procedure of Example 2, 1.11 g. (2.58
mmole) of cis-3-[2-benz~loxy-4-(1,1-dimethylheptyl)-
phenyl] S-cyanocyclohexanone gave 949 mg. (84%) of the
title compound as an oil.
IR ~CHC13) 3571, 3389, 2232, 1612 and 1574 cm 1.
CDC13 0~83 (m, terminal methyl) 1 25 (s
gem dimethyl), 3.70 (m, carbinol methine), 5.10 (s,
benzylic methylene), 6.9 (m, ArH), 7.09 (d, J=8Hz, ArH)
and 7.41 (s, Ph~).
EXAMPLE 47
Cis-3-[4~(1,1-Dimethylheptyl)~2-hydroxyphenyl]-
5-cyanocyclohexanone
_ _ . _ . . .... . _ . ... .. . . . _ _
Using the procedure of Example 6, 200 mg. (0.462
mmole) o cis-3 [2-benzyloxy-4-(1,1-dimethylhep~yl)-
phenyl]-5-cyanocyclohexanone was converted to 133 mg.
(84%) of the title compound.
m p~ 111-112 C. (ether-petroleum ether)
IR (CHC13) 3571, 3300, 2237, 1724, 1626 and 1577 cm ~.
MS (m/e) 341 ~M+), 256, 239 and 229.
Analy__s: Calc'd. for C22H31NO~:
C, 77.38; H, 9.15; ~, 4~10.
Found: C, 76.89; H~ 9.0S; N, 4.14.
~353~3
- 98-
EXAMPLE 48
Cis-3-~4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]~
cis-5-cyanocyclohexanol
.
Using the procedure o Example 6, 235 mg. 10.542
mmole) of cis-3-[2-benzyloxy 4-(1,1-dimethylheptyl)-
phenyl] -CiS-5 ~ cyanocyclohexanol ga~e 74.5 mg. (40%) of
the title compound.
m.p. 165 C. (dichloromethane-petroleum ether)
IR (XBr) 3225, 2232, 1618 and 1582 cm 1.
lQ MS ~m/e) 343 (M ), 299, 258, 241 and 213 cm 1
PMR (CDC13, D6-DMSO)~ 0.83 (m, terminal me hyl)~
1.22 (s, gem dimethyl), 3.65 (m, carbinol methine),
6.77 (m, ~rH) and 7.00 td, J-8Hz, ArH).
nalysis: CalC~d for C22~33N2
C, 76.92; H, 9.68; N, 4.08.
Found~ C3 76.51; H, 9.23; X, 3.~5.
__
X~MPLE 49
Cis-3-[2-Benzyloxy-4-(1,1 dimethylheptyl~phen
5-cis hydroxycyclohexane carboxaldehyde
,,~,_ . . _. .
To a -65~ C:. solution o~ 704 mg. (1.62 mmole) of
_s-3-[2-benzylc)xy-4-(1,1-dimethylhep~yl?phe~yl] -cis-
5-cyanocyclohexanol in 30 ml~ toluene was added 3.40 ml.
(3.4 mmole) of diisobutylaluminum hydride ~lM in toluene).
The reaction wa~ allowed to warm to -5 C. and was ~hen
poured onto dilute sulfuric acid and ice. The quenched
reaction was extracted with ether, the extract dried over
magnesium sulate and evaporated to give a quantitative
yield of the title compound as an oil.
IR ~CHC13) 316S, 1730, 1612 and 1574 cm 1.
MS (m/e) 436 (M~), 408 and 350.
PMR ~CDCl 0.83 (m, terminal methyl), 1.23 (5 gem
dimethyl), 3.7 (m, carbinol methine), 5~11 (s, ben~ylic
methylene), 6~85 (m, ArH), 7.35 (m, PhH) and 9.60 (bs, CHO).
.:
3353~
_ ~9
EXAMPLE 50
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
cls-5-hydroxymethylcyclohexanol
Using the procedure of Example 2, 700 mg. ~1.60 mmole)
of cis-3--[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-
cis-hydroxycyclohexane carboxaldehyde was converted to
208 m~. (30%~ of the title compound as an oil.
MS (m/e) 438 (M+)
PMR ~CDC13 0.83 (mf terminal methyl), 1 23 ~s gem
dimethyl), 2.7-4.0 (m, 4H), 5.09 (s, benzylic methylene),
6.90 (m,-ArH), 7.10 (d, J=8Hz, ArH) and 7.38 (s, PhH).
XAMPLE 51
Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-
cis-5-hydroxymethylcyclohexanol
Using the procedure of Example 6, 208 mg. (0.475 mmolej
of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-
5-hydroxymethylcycLohexanol was hydrogenolyzed to 127 mg.
(77~) of the title compound.
m.p. 126-127 C. (ether-petroleum ether)
IR (CHC13) 3597, 3333, 1623 and 1587 cm 1.
HRMS (m/e) 348.2662 (M , calc'd. for C22H3603-
3~8. 2655), 330, 299, 287, 263 and 245.
PMR (CDC13, D6-DMS0~ 0.85 5m, terminal methyl),.
1.25 ~s,. gem dimethyl), 3.5 (m, carbinol methylene), 3.8
(m, carbinol methine), 6.8 (m, ArH) and 7.07 5d, J=8Hz,
ArH).
35~
--i00 -
E~AMPLE 52
7-Oxabicyc1O[4.1.0]-4-~2-berlzyloxy-4-(1,1-
dimethylheptyl)phenyll-2-heptanone
To a 0 C. solution of 3.24 g. (8.01 mmole3 of
5-[2 benzyloxy-4~ dimethylheptyl)phenyl]-2-c~clo-
hexen-l-one and 2.3 ml. (24 mmole) of 30~ hydrogen
peroxide in 80 ml. methanol was added dropwise 0.66 ml.
(3.96 mmole) of 6~ sodium hydroxide. The reaction was
stirred one hour longer at 0 C. and then added to
1000 ml. saturated sodium chloride. The que~ched reaction
was extracted with 500 ml. of ether, the extract dried
over magnesium sulfate and evaporated to yield 3.02 g. o~
crude product. The crude product was purified via column
chromatography on 200 g. of silica gel eluted with 20%
ether-petroleum ether to yield in srder of elution 237 mg.
(7~) of the cls isomer, 1.72 g. (51%~ of a mixture and
1.01 g. t30%) of the trans isomer of title compound.
Column chromatography o~ the mixed fraction on 300 g.
of silica gel eluted wi~h 10~ ether-petroleum-ether yielded
34 mg. ~1~) o cis isomer and 1.56 g. (46%) of the trans
isomer of title compound, both as oils~
Cis Isomer:
IR (C~C13) 1718, 1626 and 1582 cm 1
MS (m/e) 420 (M ), 404, 335, 312, 206 and 91.
PMR ~CDC1 0083 (m, terminal methyl), 1027 ~s, gem
dimethyl), 2.0-2.5 (m), 2~9-3.7 (m), 5.15 (s, benzylic
methylene), 6.9 (m, ArH), 7.10 (d, J-8Hz, ArH) and
7.41 (s, Ph~l).
Tran Isomer:
IR (CHC13) 1718, 1623 and 1577 cm 1.
MS (mje) 420 (~), 404, 33S, 329, 316, 257 and 91.
PMR ~cDMsl 0~83 (m, terminal methyl), 1.26 (s, gem
dimethyl), 2.0-2~8 (m), 3.3 (m), 3.4-4.0 (m), 5.13 (s
benzylic methyle~e), 6.9 (m, Ar~), 7.07 (d, J-8Hz, ArH~
and 7.41 (s, PhH)~
3~
--101
In like manner, the cis- and trans-isomers of
[5.1.03-4-[2~benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
2-cyclooctanone are prepared from 6-~2-benzyloxy-4 (1,1-
dLmethylheptyl)phenyl]cyclohept-3-en-1-one.
3~3~
10~
EXAMPLE 53
3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-
cis-5-hydroxycyclohexanone
To a solution of 267 mg. (0.635 mmole) of the cis-
isomer of 7-oxabicyclo[4.1.0]-4-~2 benzyloxy-4-(1,1-
dimethylheptyl)phenyl]-2-heptanone in 20 ml. of 10~
aqueous tetrahydrofuraIl was added 220 m~. of aluminum
amalgam (prepared by washing 1 cm. strips of aluminum
foil 15 seconds each in 2N sodium hydroxide, water,
0.5% mercuric chloride, watert 2N sodium hydroxide, waterS
0.5% mercuric chlorider water, ethanol and ether). The
reaction was stirred 3 hours at 25 C. and then ~iltered
through diatomaceous earth. The filtrate was e~aporated
on a rotovapor and the residue dissolved in ether, dried
over magnesium sulfate and evaporated. The residue was
purified via p~eparative layer chromatography on two
20 cm. x 20 cm. x 2mm. silica gel plates eluted with
ether to yield 156 mg. (58%) of the title compound as
an oil.
IR (CHC13) 3597, 3546, 1718, 1612 and 1577 cm 1
MS (m/e) 422, 404, 337, 331~ 319, 313 and 310.
PMR CcDcl 0.81 (m, terminal methyl~, 1.22 (s, gem
dimethyl), 3.2 (m, benzylic methine), 3.95 (m, carbinol
methine), 5.02 (s, benzylic methylene), 6.9 (m, ALH),
7.03 ~d, J-8Hzl ArH) and 7,38 (s, PhH~.
~3~3~3
~103 -
EXAMPLE 54
. .
3-[2~Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-5~hydroxycyclohexanone
....
Using the procedure of Example 53, 1.47 g.
(3.5 mmole) of the trans isomer of 7-oxabicyclo[4.1.0]-
4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2 heptanone
gave 1.25 g. (8~) of the title compound.
m~p. 95 C. (pentane)
IR (CHC13) 3636, 3448, 1724, 1626 and 1587 cm 1.
MS ~m/e) 422 (M~), 404, 337, 331, 319, 313 and 91.
PMR ~cDsl 0 85 (m, terminal methyl), 1.25 (s, gem
dLmethyl), 2.15 (m), 2.3-2.8 (m)~ 3.9 (m, benzylic
methine), 4.5 (m, carbinol methine), 5.12 (s, benzylic
methylene~, ~.9 (m~ ArH), 7.08 (d, J-8Hz, Ar~) and 7.40
(bs, PhH~.
In like manner, reduction of the cis- and trans-
isomers of 8-oxabicyclb[5.1.0]-4-[2-benzyloxy-4-(1,1-
dimethylheptyl)E)henyl~ 2-cyclooctanone affords the
corresponding cis- and -trans 5-hydroxy derivatives.
~L~83~3~
-lD4-
EXAMPLE 55
Cis-3-~2-BenzyloYy-4-(l,l-dimethylheptyl)phenyl]-
txans-5-cyclohexan-1,5-diol, and the trans-3-cis-5 Isomer
Using the procedure of Example 2, 629 mg. (1.49
mmole) of 3-[2-benzyloxy-4-(l,l-dime~hylheptyl)phenyl]-
trans-5-hydroxycyclohexanone (Example 54) ga~e 237 mg.
(38%) of the trans-3 ClS-5 isomer and 385 mg. ~61~) of
the trans-5 isomer of title compound.
Cis-5 Isomer:
_ . 1
HRMS (m/e) 424.3002 (M , calc7d. for C28H4003:
424.2~27)
PMR ~CDCl 0.83 (m, terminal methyl), 1.26 (s, gem
dimethyl), 4.25 (m, carbinol methine), 5.13 (s, benzylic
methylene), ~.9 (m, ArH), 7.17 ~d, J=8Hz) and 7.41 (m,
lS PhEI~.
Tr_ns-5 Isomer:
HRMS (m~e) 424.2992 (M~, calc'd for C28~4003:
424.2927~, 339, 231, 2~3 and 91.
CDC13 0.83 (m, terminal methyl), 1 25 (s
gem dimethyl), 3.0 4.4 (m, 3H), 5.~0 (s, benzylic
methylene), 6.88 (d/ J=2Hz, ArH), 6.88 ~dd, J=8 and 2~z,
ArH), 7.10 (d, J=8Hz, ArH) and 7.40 (m, PhH~.
,
3~313
-~105-
EXAMPLE 56
Cis-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]~
cis-5-cyclohexan-1,5-diol, and the cis-3-trans-5 Isomer
Using the procedure of Example 2, 203 mg. (0.481
5 mmole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]~
cis-5-hydroxycyclohexanone (Example 54) was reduced to
25 mg. (12%) of the cis-3 trans-5 isomer of title com-
- pound and 132 mg. (65~) of the title compound.
Cis-3-cis-5 Isomer:
HRMS 424.2974 (M , calc'd. for C28H40O3: 424.2927),
339, 298, 231, 213 and 91.
The remaining compounds of Example 54 are reduced
to corresponding cycloheptandiols in like manner.
EXAMPLE 57
Cis-3-t4~ dimethylheptyl)-2-hydroxyphen
cis- _cyclohexan-1,5-diol
Using the procedure of Example 6, 132 mg.
(0.311 mmole) of cls-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-cis-5-cyclohexan~1,5-diol was converted to 72 mg.
(69%) o~ the title compound.
m.pO lZ3 C. (ether~pentane)
HRMS (m/e) 334.2517 (M~, calc'd~ for C21H3403:
334.2483), 298, :249, 231 and 213.
PMR ~CDC13 0 83 (t, terminal methyl), 1.24 (s gem
~5 dLmethyl), 2.94 (m, benzylic methine), 3.35, 3.11 (bs,
OH), 3~47-3~97 (m, carbinol methines), 6.72 tm, ArH) and
7.00 (d, J=8Hz, ArH).
- ~8353~
-106-
EXAMPLE 58
Cis-3-[4 (1,1-Dimethylheptyl)-2-hydroxyphenyl)-
trans-5-cyclohexan-1,5-diol
Using the procedure of Example 6, 385 mg. (0.908
S mmole) of ClS-3- ~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
trans-5-cyclohexan-1,5-diol gave 162 mg~ (53~) of the
title compound.
m.p. 170 C. (dichloromethane)
~RMS (m/e) 334O2513 (M+, calc'd. for C21H34O3:
334.2483), 298, 249, 2~1 and 213.
PMR (100 MHz, CDC13, D6-DMSO)~ 0.81 (m, terminal
methyL), 1.23 (s, gem dimethyl), 3.38 (m, benzylic
methine), 3~9-4.3 (m, carbinol methines), 6~74 ~m, ArH)
and 7.00 (d~ J=8Hz~ ArH)O
EXAMPLE 59
Trans-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-
_ _ _cis-5-cyclohexan-1,5-diol
Using the procedure of Example 6, 237 mg. ~0.558
mmole) of trans--3-~2-benzyloxy-4-(1,1-dimethylheptyl)-
.
phen~l]-cis-5-cyclohexan-1,5-diol gave 107 mg. (57%)
of the title compound.
m.p. 126-127 CO (ether-pentane) .
HRMS (m/e) 334O2503 (M , calcld. for C21H34O3:
334.2483), 316, 298, 24g and 231.
PMR (100 M~Iz, CDCI3, D6-DMSO)C 0.83 (m, terminal
methyl), 1.24 (s, gem dimethyl), 3.82 (m, benzylic
methine), 4.29 (m,.carbinol methines), 6.88 (m, ArH) and
7.~6 (d, J=8Hz, ArH).
In like manner, the cyclohepta.ndiols of Example
3~ 56 are debenzylated.
:
5~
- 107-
EXAMPLE 60
The Eollowing compounds are prepared according to
the procedure of Example 1 from the appropriate l-
bromo-2-ben~yloxy-4-(Z-W)benzenes and the appropriate
4-(and 5)-2~cycloalken-l-one~
( ~
Y ~Z-W
s RX Ry Z W
l CH2-CH=CH2 H (CH2)7 H
. L CH2-CH=CH2 (C 2)11 H
1 CH~-CH=CH2 H [CH(C~3)]2(CH2)5
1 (CH2)2CX=C~H2 H C(CH3)2(CH2)4 H
l (CH2)2CH=C'H2 H (C~2)8
1 (CH2)3CH=C'H2 H C(CH3)2(CH2)6 H
(C~2)4CH CH2 H C(CH3)2(C~2)6 H
1 CH2CH=CH2 H (CH2)3 C6H5
~ 2)4CH CH2 H [CH(C~3)]2(CH2)5 H
l CH2CH=CH2 H (CH2)4 4~FC6H4
(CH2)2c~ CH2 H CH(CH3)(CH2)3 4-ClC6H4
( 2)3 H CH2 H CH(C~3)(CH2)3 C6HS
1 CH2CH=CH2 H CH(CH3)(CH2)3 C6H5
1 (C 2)3CH CH2 ( 2H5)(CH~)4 4-FC~H~
( 2)3CH CH2 H C(CH3)2(CH2)4 c6~s
l CH2CH=CH2 H (CH2)4 4-pyridyl
l CH2CH-CH2 H (CH2)8 C6H5
1 CH2CH=CH~ H CH(CH3)(CH2)3 2-pyridyl
35~3
- 108-
s RY Ry Z W
( 2)3CH CH2 (CH2)11 H
2 CH2CH=CH2 H ~(C~3)]~CH2)5 H
2 CH2CH=CH2 ~ ( 237
2 (CH2)2CH=CH2 H C(C~3)2(CH2)6 H
2 ( 2)3CH CH2 H ~CH(CH3)]2(CH2)5 H
1 CH2CEI=CH2 H (CH2)4 C6H5
1 CH2CH=CH2 ( 3)~CH2)5 C6H5
1 CH2CH=CH2 H C~(CH3)(CH2)3 C6H5
1 CH2CEI=CH2 H CH(C~3)(CH2)3 4-FC6H4
1 CHzCH=CH2 (CH3)(CH2)3 C6H5
(C 2)4CH CH2 H OCH(CH3)(CH2~3 4-pyridyl
1 (CH2)2cH=c~2 H O(CH2~7 4-ClC6H4
1 CH2CH=CH2 ~ ( 2)4OCH2 C6H5
1 (C~2)3CH C~2 H (CH2)6O C6H5
1 CH2CH=CH2 H (CH2)5 H
1 CH2CH=CH2 H (CH2)13 H
1 CH2CH=CH2 H O~CH2)3 C6H5
(C~2)4CH CH2 H [CH(CH3)]2CH2 4-pyridyl
2 CEI2CH=CH2 H CH(CH3)(CH2)~ 4-pyridyl
2 (CH2)3CH=C~2 H (CH2)7 4-pyridyl
1 CN2CH=CH2 H O(CH2)7 EI
1 CH2CH=CH2 H O(CH2)11 H
( 2)3CH CH2 H OC(CH3)2(CH2)5 H
1 CH2C~H=CH2 H (CH2)O~CH2)7 H
( 2)~CH CH2 H (CH2)11 H
( 2)2CH CH2 ( 2) 3 (CH2) 4 H
1 CH2C~=CH2 ~ O(CH2)4 C6H5
~835~
109
s RX Ry Z W
2 H CH2CH=CH;~ C(C~3) 2 (CH2) 6 H
2 H CH;2CH=CH;~ (CH2) 11 H
2 H CH2CH=CH2 [CH (CH33 ] 2 (CH;2) 3 H
2 H CH2CH=CH;~ ( 2) 11 H
2 H CH2CH=CH2 (CH2) 5 El
2 H CH2CH=CH2 (CH2)13 H
2 H CH2CH=CH2 ~CH2) 0 ~CH2) 7 4ClC6H4
(CH2) 2CH C~2 H (CH2) 30CH (CH3) 2-pyridyl
1 CH2CH=CH2 H O (CH2 ) 5 3-pyridyl
2 CH2CH=CH2 H OCH(CH3) (C~2) 5 H
2 CH2CH=CH2 ~ ( 2 ) 7 H
2) 3CH CH2 ( 2) 3 (CH2) 4 H
2) 3CH CH2 (CH2) 11 H
2 CH2CH=CH2 H OC~I (CH3) (CH2) 3 4-FC6H4
2 CH2CH=CH2 ~CH2) 6 C6H5
2 tCH2)3CH=CE[2 H OCH(CH3) (CH2)3 2-pyridyl
2) 3CH C}I2 H (~H2) 30CH (CH3) 4--ClC6H4
CH(OCH3)2 H [CH(CH3) 3 tCH2)5 H
1 CH (OC1~3) 2 H ~CH2) ll H
CH(OCH3) ;2 H CH(C~3) (CH2) 3 C6H5
CH(OCH3)2 EI CH(C~3) (CH2)3 4-FC6H4
CH (OCH3) ~ H (CH2) 5 H
2 H CH2CH=CH2 (CH23 30 (CH2) 4 H
2 H CH2cH=cH2 0 tCH2 ) 7 H
2 H CH2CH=CH2 OCH (C1~3) (CH2) 3 C6H5
2 H CH2CH=CH2 0 (CH2 ) 7 4_C1C6H4
2 H CH2CH=CH2 OCH(CH3) (CH2)3 py
2 H CH2CH=CH2 CH (CH3 ) (C~I2 ) 3 C6~I5
2 H CH2CH=CH2 CH(C2H5) (CH2)4 4-FC6H4
~3353~
~110--
s ~Y Ry Z W
2 H CH2CH=CH2 oC~tCH3)~C~2)~ H
1 CH(OCH3)2 H CH(CH3)(CH2)3 4-pyridyl
CEI(OCH3)2 ~ 0CH(CH3) (CH2)3 C6H5
1 CH(OC~3)2 H OCH(CH3)(~2)3 4-pyrid~l
1 CH(OCH3)2 H OCH(CH3)(CH2)5 H
1 CH(OCH3)2 H (H2)40CH2 C6H5
1 CH(OCH3)2 H O(CH2)13 H
1 CH(OCH3)2 H (CH2)3 C6~5
(CH2)2cH CH2 CH3 C(CH3)2(c~2)6 H
1 C~2CH=CH2 C~3 OCH(CH3)(CH2)3 C6H5
~C 2)3CH CH2 CH3 O(CH2)7
1 CH2CH=CH2 CH3 CH(CH3)(CH2)3 C6H5
1 CH2CH=CH2 C~3 OCH(CH3)(CH~3 4-FC6H4
lS 1 CH2CEI-CH2 CH3 (CH~)30CH(CH3) 4-ClC6X4
L CH2CH=CH2 CH3 ( 2)13 H
( 2)2CH CH2 CH3 (C~2)3 C6~H5
(C 2)3CH CH2 CH3 (CH2)8 C6H5
tCH2)~CH CH,~ CH3 CH(CH3)(C~2)3 2-pyridyl
C~2C~ CH2 c~3 (C~2)11 H
1 CH2CH=CH2 CH3 (CH2)30(CH2)4 H
2 C~2CH=CH2 CH3 OCH(CH3)(CH2)3 C6H5
2)3CH=CH2 ~H3 C(CH3)2(
2 CH2CH=CH2 CH3 CH(CH3)(CH2)3 4-pyridyl
2 CH2CH CH2 CH3 O(CH~)7 H
2 CH2CH=CH2 CH3 CH(CH3)(CH2)3 4-FC~H4
The products are converted to the corresponding
ethylene ketals according to the procedure of Example 7.
3~
EXAMPLE 61
The cycloalkanone compounds of Example 60 are reduced
according to the procedure of Example 2 to provide the
corresponding 3-[2-benzyloxy-4-(Z W)phenyl]-4-(and 5)~
substituted-cycloalkanols.
EXAMPLE 62
The cycloalkanols of Example 61 wherein Rx or Ry
is alkenyl are hydrated according to the method of
Example 5 to give the corresponding 3-~2~benzyloxy-4-
(Z-W)phenyl~~4-(and 5)-~-hydroxyalkylcycloalkanols.
Debenzylation of said compounds according to the
catalytic hydrogenation procedure of Example 6 provides
the corresponding phenols.
EXAMPLE 63
The cycloalkanone compounds of Example 60 wherein
RY or Ry is alkenyl are ketalized to their corres-
ponding e~hylene ketals by the procedure of Example 7
and then hydrated according to the procedure of
ExampLe 5 to produce the corresponding 3-[2-benzyl-
o~y-4-(Z-W)phenyl]-4-(or 5)-(~-hydroxyalkyl)cyclo-
alkanone ethyl~lle ketals. Catalytic hydrogenation
according to the procedure of Example 6, followed by
deketalization according to Example 8, affords the
corresponding 3--[2-h~droxy-4 (Z-W)phenyl~-4-(or 5)-
~-(hydroxyalkyl)cycloalkanones.
~33~38
-112
E~AMPLE 6
Following the procedure of Example 9, the 3-[2~
benz~loxy-4-(Z-W)phenyl]-4-(or 5)-alkenylcycloalkanones
and cycloalkanols of Examples 60 and 61 are oxidized
to give the corresponding compounds of the formula
A B
/~ Z -W
wh~rein ~ B is -OCH2CH2O- or H, OH; s, Z and W are as
defined in Examples 60 and 61; Rx or Ry represents
the ~ oxoalkyl moiety having one less carbon in the
al~yl group -than does Rx or Ry of Examples 60 and 61.
Of course~ in this example, the cycloalkanones are
f.irst ketalized according to the procedure of Example 7.
Also produced in this Example are coxresponding
compounds, wherein Rx or Ry is carboxyalkyl having
two less carbon atoms in the alkyl group than does Rx or
Ry; ~nd the corresponding ~-hydroxyketones in which
the unsaturated carbon atoms of the alkenyl moiety
are converted to -CO-CH2OH.
Deberlzylation of the thus-produced oxygenated
products by the procedure of Example 6 provides the
corresponding phenols. Deketalization of the ketals
according to the method of Example 8 gives the cor-
r~sponding cycloalkanones.
~353~
_ 113_
EXAMPLE 65
The procedure of Example 12 is used to convert the
3~[2-benzyloxy-~-(Z-W)phenyl]-4 (or 5)-1-(oxoalkyl~cyclo-
al~anone ethylene Xetals of Example 64 to the corre
sponding compounds wherein the 4-(or S)~substituen~ is
a secondary alcohol group. Deketalization of the
products gives the cycloal~anones.
EXAMPLE 66
- ~he ethylene ketal compounds of Example 60 wherein
Rx or Ry is al.'ce.nyl and of Example 99 are converted
to correspondin~ compounds wherein Rx or Ry is 4-(or
5)-~-(1,3-diox~lan~2-yl)alk-2-enyl by the procedure
of Example 10~ Catalytic hydrogenation of said
compounds according to the procedure of Example 11,
followed by deketalization as per ~xample 8, affords
3-[2-benzyloxy-4-(Z-W?phenyl~-4-(or 5)-~-(oxoalkyl)-
cycloalkanones wherein the oxoalk~l group contains 3
more carbon atoms than did group Rx or Ry.
EXAMPLE 67
~ . _
2 0 ~rhe 3 - [ 2-hyclroxy-4 - ( Z -W ) phenyl~-4-(and 5)-~-toxo-
alkyl)cycloalkanone ethylene ketals and cycloalkanols
of Example 64 ancl 66 are converted to corresponding
4-(and 5)-~-(aminoalkyi) derivatives by the procedure
of Example 16. The products are isolated as their
hydrochloride saltsO
EXAMPLE 68
. ~
The compounds o~ Examples 60 and 61 wherein R2'
is dimethoxymethyl ~CH(OCH3)2] are converted to the
corresponding ~ormyl (CHO) compounds by the procedl1re
of Example 17.
3~
~~114~
EXAMPLE 69
Th~ procedures of Examples 19 and 21 are used to
produce the following compounds from appropriate 3
~2-benzt~loxy-4-(Z-W)phenyl]-4-(and 5)-~-(oxoalkyl~
S cycloal~anols o~ Examples 17, 64, 68 and 104 and the
~ppropriate dial~ylphosphonoalkanoic acid esters.
0~
( ~ OH
~\Z-W
. _ _ . .. . _ _ . _ . _
s Rx Ry Z W
.. __ ~. _ . _ . ... __ _
1 (CH2)3cOocH3 H (C~2)7 H
(CH2)3cOocH3 H [CH(CH3)~2(CH2)5 H
(C~2)3COOCH3 ( 3)2(CH2~6 H
(CH2)3COOC2H5 C( H3~2(C~2~6 H
(CH2~5COOCH3 ( 3~2(CH2)6 H
1 (CH2~3COOC2H5 [ ( ~3~]2(CH2~5 H
1 (CE~2~2COOCH3 H (C82)5
~ ~2)2COOC2H5 H (CH2)5 H
2 H ~CH2)2COOcH3 (CH2)O(CH2)7 4-ClC6H~
(CH2)3cOocH3 ( 2)11 H
( H2)5COOCH3 H ( 3)2(CH2~6 H
( 2~3COOCH3 (CH2)11 H
(CH2)5cOocH3 H C(CH3~2(CH2~6 H
( 2)5COOCH3 H (CH2)11 H
( 2)2COOCH3 H CH(CH3)(CH2)3 C6H5
( 2)2COOCH3 H (CH2)13 H
( 2)2COOCH3 H (CH2)3 C6H5
( 2)2COOCH3 H OlCH2)3 C6~5
, . .
~35i3~3
_ 115_
_ _
s RY Ry Z W
(C 2)5COOCH3 . H CH(CH3)(CH2)3 4-FC6H4
( 2)4 H3. H (CH2)40CH2 C6H5
1 (c~)4cOOcH3 H C(CH3)2(CH2)6 H
( 2)3COOCH3 H ( ~3)(CH2)5 H
( 2)4COOC2H5 H OCH(CH3)(CH2)3 C6H5
1 H (CH2)3COOCH3 O~H(CH3)(C 2)3 C6H5
1 H (CH2)3COOCH3 OCH(CH3)(CH~3 4-ClC6H4
1 H (CH~)2COOC~3 OCH(CH3)(CH2)5 H
1 H (CH2)3COOC2HS (CH2)11 H
1 H (CH2)2COOCH3 C(C~3)2(CH2)6 H
2 H (CH2)3COOCH3 C(CH3)2(CH2)6
2 H (CH2)3COOCH3 (CH2)11 H
2 X (CH2)3COOC2Hs (CH2)30(cH2)4 H
2 EI (CH2~3COOCH3 OCH(CH3)(CH2)3 4-pyridyl
2 H tCH2)3cooCH3 CH(CH3)(CH2)3 C6H5
t 2)2COOC2H5 H OCH(CH3)(CH2)3 C6H5
1 (C~I2)3CooCH3 H OCH(CH3)(CH2)3 4-pyridyl
1 (CH2)3COOC2H,; H C(CH3)2(CH2)6
(C 2)5COOCH3 H OCH(CH3)(CH2)5 H
1 H (CH2)3COOCH3 OCH(CH3)CH3 C6H5
1 H tCH2)2CooCH3 OCH(CEI3)(CH2)3 4-pyridyl
1, H (CH2)3COOCH3 CH(CH3)(CH2)3 C6H5
1 H (CH2)3COOCH3 (CH2)30(0CH2)~ H
1 H ( 2)3COOCH3 ~CH(CH3)]2(CH2)5 H
1 H (CH2)3COOC2Hs C(C~3)2(CH2)6 H
2 H (CH2)3COOC2H5 tCH(CH3)]2( 2)5 H
2 H (CH2)3COOCH3 (CH2)11 EI
2 H ( ~2)3COOCH3 OCH(CH3)(CH2)5 H
2 H (CH2)3COOC2H5 OCH(CH3)(CH2)3 C6H5
1 (C~I2~2coocH3 H (CH2)3 C6H5
3S3~3
-116-
s Rx Ry Z W
. .~
l (CH2)2COOC2EI5 CH3 C(cH3)2(c~2)6 H
( 2)3 3 CH3 ( 3)( 2)3C6H5
1 (C~2)5COOCH3 CH3 O(CH2)7 H
l (CH~)~COOCH3 CH3 CH(CH3)(c~2)3C6H5
(~2)~c~n C3~7~ CH3 0CH~CH3)(CH2)3 ~-FC6H4
l ~H~33COo(n-c6Hl3) C 3 (CH2)30CH(CH3) 4-ClC6H4
(CH2)3COOCH3 CH3 O(C 2)13 H
( 2)~C 3 CH3 (CH2)3 C6~I5
lOl (CH~)6COO(n-C6~l3) CH3 (CH2)8 C6H5
l (CH2)4COO(n-C4H9) CH3 C(CH3)2(CH2)6 H
l (CH2)~COOC2H5 C~3 (CH2)30(CH2)4 H
2 (CH2)3cc2H5 CH3 OCH(CH3)(CH2)3 C6HS
( 2)5 3 CH3 ( 3)2( 2)6 H
2 (CH2)4cooti C3~7) CH3 C~lCH3)(CH2)3 4-py~idyl
2 (CH2)~COOC2H5 C~3 O(CH2)7 H
~ (CH2)COOCH3 CH3 CH(CH3)(CH2)34-FC6H4
3~3~3
- 117-
EXAMPLE 70
The 3-~2-benzyloxy-4-(Z-W)phenyl]-4-(and S)-~-
(oxoal~syl)cycloalkanols of Examplas 17, 64~ 68 and 104
are converted to corresponding 3 [2-hydroxy-4-(Z-W)-
phenyl]-4-~and S)-~-(carbamoylalkyl)cycloalkanols by the
proc~dures o~ Examples 20 and 21 using, of course, the
appropriate carbamoylalkylene triphenylphosphorane as
the Wittig reagent.
OH
(~ O
R / ~ ~ Z-W
s RX Ry Z W
. _ . .. .
(CH2)2cNEI2 H ~CH2)7
1 (CH2)2CONH(C2H5~ H ( 3)~(CH2)6 H
(CH2)3CONEt2 H ~CH(CH3)]2(CH2)5H
1 (CH2)3c~[2 ~ (CH2)11 H
lS 1 (CE~2)scONtcEI3)2 H ( 3)2~CH2)6 H
1 (CH2)2CON(CH3)2 H C(CH3)2(CH2)6 H
1 ~CE~2)3CONEI2 H C(CH3)2(CH2)6 H
(CH2)2cNEI2 H (CH2~11 EI
1 (CE~2)~CONH2 .H C(CEI3)2(CH2)6 H
1 (CH2)~CONH(C2H5) H (CH2~8 H
1 (C~2)6CoNH2 H [CH(CH3)2]2(CH2)5 H
1 (C~2)2C0NH2 H (CEI2)4 C6H
1 (CH2)2CONH(C2H5) H (CH2)4 C6H
1 (CEI2)2CON(CH3)2 H CH(CH3)(CH2)3 C6H
3~
, . . . .
RX Ry 2 W
(C~:[2) 2CNH2 H CH (CH3) (C~I2) 3 4-F6H4
(CH;~ CONH2 H CH (CH3) tCH2) 4 4-pyridyl
2 (CH2) 2CONH2 H C~ (CH3) (CH2) 3 C6}I5
2 ( 2) 3CONH2 C (C2Hs) (CH2) 4 4-FC6H4
2) 6 2 ~ C [CH3) 2 (CH2) 6 H
2 (CH2) d~CON(CH3) 2 H ~CH2) 7 H
2 (CH2~ 3CON(CH3) 2 H ( 3) (CH2) 3 C6H5
2 (CH2) 3CONH (C2HS) H OCH (CH3) (CH2) 3 4-FC6H4
2 (CH2) ~iCNH2 H (CH2) 30CH(CH3) 4-ClC6Ei4
2 (CH2) 4CON(CH3) 2 H ( 2) 7 Ei
2) 3CONH2 H O (CH2) 4 C6H5
2) 6C N 2 ~ OCH (CH3) (CH2) 34-pyridyl
(C~I2) 5CON (CH3) 2 H [CH (C~3~ ] 2 (CH2) 5 H
1 (CH2) 2CON(CE~3) 2 H (CH2) 4 C6H5
(CH2) 2CNH2 ( 3) (CH2) 3 C6H5
(CH2) 6CONH2 H CH (CH3) (CH2) 3 C6H5
(CH2)2CONH2 H CH(CH3) (CH2)3 2-pyridyl
L (CH2) 2CON(CH3) 2 H [CH(CH3) ] 2CH2 4-pyridyl
2 (CH2)5CON(CH3)z H CH(c~3) (C~)3 C6H5
( H2) 3CONH2 H C (CH3) 2 (CH2) 6 H
2 (CH2) 3CONH (C2H5) H ( 3) 2 (CH2) 6 H
2)3CONH2 H OCH(CH3) (C~I2)3 C6H5
2) 4CONH2 H OCH (CH3) (CH~) 3 C6H5
(C~2) 4CONH2 H (CH2) 6 C6H5
2) 3CONH2 H OC~I (CH3) (CH2) 5 H
2 (C~I2) 6CONH2 (CH2) 11 H
(C~12 ) 3CON~I ~C~H5 ) H ( 3 ) (CH2 ) 3 C6H5
2)4CONH2 H (CH2)30CH(CH3) 2-pyridyl
1 (CH2)3CON(cEI3)2 O(CH2)5 3-pyridyl
~L8353~
119_
s Rx R~ ~ W
... . . . . _ _
1 ~ ( 2)2CON(C~3)2 C(CH3)2(CH2)6 H
1 H ( 2)3 ( 2H5) C(CH3)2(CH2)6 H
2 H ( 2)3CONH2 (CH2)3O(CH2)4 H
2 H ( 2)3 2 ( 3)2(CH2~6 H
~ ~ (CH2)3CON(CH3)2 OCH(CH3)(CH2) C6H5
1 - H (C 2)2CN~2 C(CH3)2(CH2~6 H
2 H ( 2)3CONH2 (CH2)S H
- 2 ( 2)3CONH2 (CH2)11 H
2 H (CH2)3CON(CH3)2 OCH(C~3)(CH2)5 H
2 EI ( 2)3CONH2 CH(CH3)(CH2)3 C6H5
2 H ( 2)3CONH2 . CH(C2H5)(CH2)4 4 FC6H4
1 (CH2)2coNH2 CH3 C(CH3)2(CH2)6
1 (CH~)~CON-
(CH3~2 C 3 ( 3)2(CH2)6 H
(CH233CONH2 CH~3 OCH(CH3)(CH2)3 C6EI5
( 2)2CONH
(C2H5) CH3 OcH(cH3)(cH2)3 C6H5
.1 (C~2) 2CON-
(CH3)(n-C,tH9) CH3 OcH(cH3)(cH2)3 C6~5
1 (C~2~4CONH2 CH3 O(CH2)7 H
1 (CE~2)3Co~-
( 3H7)2 C~23 ( 2)13 H
~CH2~ 2CONEI-
( 6Hl3~ CH3 CH(CH3)(CH2)3 4 FC6H4
1 (CH2)2CO~I~
(n C4H9)2 CH3 CH(CH3)(CH2)3 4-pyridyl
(CH2)2cNF22 CH3 OC~2(C~I3)(CH2)3 C6H5
2 (CH2)3CON-
(CH3)(n-C4E29) CH3 , OCH(CH3)(CH2)3 C6H5
2 (C~22)5CON-
(C2H5)2 CH3 (CH3)2(cH2)6 H
~ ~3538
-- 1~0--
s Rx Ry 2 W
2 (CH2~2cON(cH3)2 C~3 C(CH3)(CH2)3 4-pyridyl
2 ~C~2)4CONH(C2H5) CX3 O(CH2)7 H
2 (CH2~3CoNH-
S ~i-C3H7) CH3 CH(C~3)(C~2)34-FC~H4
( 2)3CO~H
. CH3 ( 3)2(C 2)6 H
R~duction o~ the above~ ted amides according to
1~ the procedure of Example 23 affords the corresponding
amines.
. .
3353~
~121~
EXAMPL~ 71
The 3-[2-hydroxy-4~(Z-W)phenyl]-4-(or 5)-substi-
tuted-cycloalkanones and the 3-[2-benzyloxy-4-(Z-W)-
phenyll-4-~or 5)-substituted-cycloalkanones wherein
s the substituent is other than ~-sxoalkyl of Examples
6, ~, 28, 53, 54, 60, 63 and 65 are converted to
corresponding cycloalkanes by the procedure o~
Example 25. The compounds have the formula shown
- below wherein R is hydrogen or benzyl; s, Z, W and
10 the ~- (or 5) substituents are as defined in said examples.
o~
Ry ~ ~
Rx z W
EXAMPLE 72
Following the procedures of Examples 26 and 5, the
3-[2-benæyloxy-4-(Z-~)phenyl]-4-(or 5)-alkenyl cyclo-
alkanols of Examples 2, 13, 15, 29, 50 ar.d 61 are con-
verted to the corresponding benzyloxycycloalkanols
according to th.e procedure of Example 26 and the ethers
then hydrated by the procedure of Example S to give the
corresponding 3-~2-bcnzyloxy-4-~Z~W)phenyl]-4- (or 5) -0 ~-hydroxyalkyl)~l-be~zyloxycycloalkanes.
EXAMPLE 73
The 3-~ en2yloxy-4-(Z-W)phenyl]-4-(or 5)~
hydroxyalkyl~ benzyloxycycloalkanes o~ Exa.mple 72 are
converted to corresponding ~-(Cl_6alkoxy)alkyl ethers
by ~he procedures of Examples 26 or 27.
353~
_~22
EXAMP~E ? 4
The 3-[2-benzyloxy-4-(Z-W)phenyl]-4 (or 5)-
~(al~oxyalkyl) l~benzyloxycycloalkanes of Examples 27
and 73 are debenzylated to the corresponding 3 12-hydroxy-
4-(Z-W)phenyll-4-(or S)-~-(alkoxyalkyl)cycloalkanols by
the procedure of Example 6.
EXAMPLE 75
Using the procedures of Examples 32 and 33, the
cycloalkanol compounds of Examples 61, 67 and 70 are
converted to corresponding 3-~2-benzyloxy-4-(Z-W)phenyl~-
4-(or 5)-substituted-1-aminocycloalkanes,
Acetylation of the amino compounds thus produced
provides the corresponding l-acetamidocycloalkanes. Of
course, when more than one amino group is present, as
in ~he 3-[2-benzyloxy-4-(Z-W)phenyl~4-tor 5)-~-(amino
alkyl)-l-aminocycloalkanes, 2 molar propoxtions of each
of acetic anhydride and 4-N/N dimethylaminopyridine are
used.
The compounds are de~enzylated to corresponding
phenols by the procedure of Example 6.
EX~MPL~ 76
Using the procedure of Example 5, the 3-[2-benzyloxy-
~-(Z W)phenyl]-4 (or 5)-alkenyl-1-acetamidocycloalkanes
o~ Example 75 are hydrated to corresponding ~hydroxy-
alkyl-L-acetamidocycloalkane~.
Debenzylation via the procedure of Example 6 a~fords
the corxesponding phenol d~rivatives.
~3~i3~
_ 123_
EX~PLE 77
Trans-3-(2,4-Dib~nzyloxyphenyl)-
4-(2-propenyl)cyclohexanone
Using the procedure of Example 1, 23 g. (62.3 mmole)
of 2,4-dibenz~loxybromobenzene and 7.2 g. (53 mmole) of
4-(2-propenyl)-2-cyclohexanone gave 8O56 g. (38%~ of the
title compound.
m.p. 104-106 C. (diisopropyl ether)
H~MS (m/e) 426.2203 (M , calc'd. for C29H3003:
425.2187), 335, 181 and 91.
Analysis: Calc'd. for C29H30o3
C, 81.66; ~, 7.09.
Found: C, 31.53; H, 6.85.
EXAMPLE 78
Trans-3 ( 2, 4-Dibenzyloxyphenyl ) -4 -
~2-pr penyl)cyclohexane ethylene Ketal
A muxture of 5.0 g. (ll.73 mmole) of trans-3- (2, 4-
dibenzyloxyphen~fl)-4-(2-propenyl)cyclohexanone, 6.5 m7.
(117 mmole~ of ethylene glycol and 223 mg. (1.17 mmole)
20 of p-toluenesulfonic acid in 50 ml. of benzene was
heated at reflux for -1. 5 hours. Water was removed via
a soxhlet extrac:tor filled with molecular sieves. The
reaction was cooled and added to 500 ml. saturated sodium
bicarbonate and 300 ml. ether. The ether phase was
25 separated, dried over magnesium sul~ate and evaporatedO
Tri turation with diisopropyl ether-hexane gave 5.31 g.
~9~ of the title compound.
m~p. 112-113 CO
HRMS tm/e) ~70.2520 (M~, calc'd. for C31H34O4:
470.2448), 387, 379, 303, 181 and 91.
A ~ : Calc'd. for C31H34O4
~ C, 79.12; H, 7.28.
Found: C, 79.13; H, 7.02.
~1~3~3~ .
_ 12~.
EXAMPLE 79
Trans~3-~2,4-Dibenzyloxyphenyl)-4-
(3-hy*roxypropyl~cyclohexanone ethylene Ketal
= _
Using the procedure of Exampl 5, 5.00 g. (10.6
S mmole~ of trans-3-(2,4-dibenzyloxyphenyl~-4-~2-propenyl)-
cyclohexanune e-thylene ketal afforded a quantita~ive
yield of the title compound as an oil. The product was
used in the procedure of Example 80 without purification~
EXAMPLE 80
10Trans-3-(2,4-Dibenzyloxyphenyl)-4
(3-h~droxy ~
A mixture of 5.17 g. (10.6 mmole) of trans-3-~2,4-
dibenzyloxyphen~l)-4-(3-hydroxypropyl)cyclohexanone
ethylene Xetal, 50 ml. lN hydrochloric acid and 100 ml.
tetrahydrofuran was heated at reflux for one hour. The
reaction was cooled, partially evaporated on a rotovapor
and the residue diluted with 300 ml. saturated sodium
chloride-300 mlO ether. The ether extract was washed
with 300 ml. saturated sodium bicarbonate, dried o~er
magnesium sulfate and evaporated. The residue was
crystallize~ from diisopropyl ~ther to yield 4.32 g.
(92~) of the ti~le compound.
m.p. llO-:L17 C.
~ :Calc'd. for C2~H32O~:
C, 78~35; ~, 7.26.
Found:C, 78017; H, 7.15.
EXAMPLE 81
Trans-3-t2,4-~ihydroxyphenyl)-4-
(3-h~droxypropyl)cyclohexanone
Following the proc~dure of Example 6, 3.9 g.
(8.78 mmole~ of trans-3-(2,4-di~enzyloxyphenyl)-4-
(3-hydroxyphenyl)cyclohexanone provided 2.12 g~ (91~)
of the title compound as an oil.
HRMS (m/e) .264.1345 (M , calc'd. for C15H200~:
264.1356)~ 178, 163, 161, 155, 136 and ].23.
3353~
_125_
EXAMPLE 82
3,~-Dihydro-2-methoxy-7-hydroxy-2,4
propano-2H-l-benzopyran-9-propanol
A solution of 1O5 g. ~5.68 mmole) of trans-3-
S (2,~l dihydroxyphenyl)-4-(3-hydroxypropyl)cyclohexanone
in 40 ml. methanol, 6 ml. trimethylorthoformate and
7 drops of concentrated sulfuric acid was stirred at
0 C. for 45 minutes. The reaction was quenched by the
addition of excess solid sodium bicarbonate and then
evaporated on a rotovapor. The residue was diluted with
300 ml. saturated sodium bicar~onate-300 ml~ ether.
The ether extract was dried over magnesium sulfate and
evaporated. T~e crude product was purified via column
chromatography on 150 g. of silica gel eluted in 15 ml.
lS fractions with ether to yield 1.29 g. (82~ of t~e title
compound as an oil.
PMR (CDC13 ~ D6-DMSO) ~ 1.88 (m~, 2.85 (m), 3.35
(s, methoxy), 3.45 (m, methylene), 6.22 (d, J-2Hz, ArH),
6.22 ~dd, J=~ & 2Hz, Ar~) and 6.75 (d, J=8Hz, ArH).
HRMS (m/e) 278.1514 (M+, calc'd. for C16H2~04:
278.1512), 246, 192, 177 and 161.
- 1~6
E2~MPLE 8 3
d-3, ~-Di.hydro-2-methoxy-7- [ ( 2-octyl ~ oxy] -
2,4-propano-2H-l-benzopyran~9~propanol
~ mixture o~ 700 mg. (2.52 mmole) of 3,4-dihydro-
S 2-methoxy-7-hydroxy-2,4 propano-2H-l-benzopyran-9~propanol
786 mg. (3.78 mmole) of 1-2-octylmethanesulfonate and
1.33 g. (10 mmole) o~ anhydrous potassium carbonate in
5 ml. of dimethylformamide was heated at 80 C. for
8 hours and then stirxed at room temperature for 10 hours.
The reaction mixture was added to 300 ml. saturated
sodium chloride-300 ml. e~her. The ether extxact was
dried over magnesium sul~ate and evaporated. The crude
product was purified via column chromatography on 100-y.
o~ silica gel eluted in 10 ml. fractions with ether to
yi~ld 711 mg. (72~) of the title compound as an oil.
PMR (CDC13) ~ 0.88 (m, t~rminal methyl), 1.28 (dt
J=SHz, methyl), 2.95 (m), 3.40 (5, methoxy), 3.7G (m,
methylene), 4.22 (m, methine~, 6.35 (m, ArH) and 6 . 82
(d, J=8Hz, Ar~).
~0 HRMS tm/e) 390.2769 (M , calc'd. for C2~H3~O4:
390.2760), 304, 289, 273, 192, 191, 177 and 161.
ta~ 20 C- = +3.17 (c = 1.29 methanol)
EXAMP1E 8 4
,
d-Trans-3-[2-hydroxy-4-(2-octyloxy)phenyl]-4-
2$ (3-h~_roxvpropx~)cyclohexanone
~ .
A mixture of 711 mg~ (1.82 mmole) of d 3,4-dihydro-
2-methoxy-7-[(2~octyl)oxy]-2,4-propano-2~ benzo~
pyran-9-propanol, 25 ml. tetrahydrofuran and 15 ml. lN
hydrochl~ric acid was heated 1.5 hours A`t reflux. The
reaction was cooled and diluted with 200 ml. saturated
sodium chloride-200 ml. ether. The ether e~tract was
washed wlth 200 ml. ~aturated sodium bicarbonate, dried
over magnesium sulfate and evaporated to give a quanti-
tative yield of the title compound as an oil.
HRMS (m/e) 376.2592 (M , calc'd. for C23H36O4:
376.2604), 290, 275, 264, 179, 178, 177, 164, 163 and 161.
~3~
~127-
EXAMPLE 85
d-Cis-3-[2-hydroxy-4-(2-octyloxy)phenyl]-trans-4-
(3-hydroxypropyL)c~clohexanol and the rans-3, cis-4 isomPr
_ _
Using the procedure of Example 2, 684 mg. (1.82 mmole)
of d-trans 3-[2-hydroxy-4-(2 octyloxy)phenyl]-4-(3-
hydroxypropyl)c~clohexanone yielded in order of elution
with 50~ ether-dichloromethane, 420 mg. (61~ of the
titLe compound and 75 mg~ (11%j of the trans-3, C15-4
isomer as oilsu
10 . Cls-3, trans~
= ~4.26 (c = 1.01, methanol)
HR~S (m/e) 378.2762 (M , calc' do for C23H38O4:
378.2760), 266, 248, 147 and 123.
Trans-3, CiS-'~
~5 HRMS (m/e) 378.2789 (M , calc'd. for C23H3804:
37~.27~0), ~6~, 248 and 123.
The compounds tabulated ~elow are prepared according
to the procedures of Examples 83 and 84 from the appro-
priate reactant CH3-SO2-O-Z~Wo
OH
?~o (alk2~-w
~I2
CH2H
(alX2 ) W
.
(CH2)4 C6H5
CH(CH3)(CH2)3 C6H5
CH~CH3~(CH2)5 C6H5
35~
.- ,~1~
(c~lk~ ) W
C~ ( CH3 ) ( C~I2 ) 3 4--ClC 6H4
CEI~CH3) (CH2) 34-FC6H4
CE~(CH33 (CH2) 5 H
(CH2) 11
CH(CH3) (CH2) 34-pyridyl
( CH 2 ) 42-pyxidyl
(CH2) 7 2-pyridyl
(C~2) 13 H
- (CEI2) 3 C6H5
~3~315
_ 129-
EXAMPLE 86
1-3,4-Dihydro-2~methoxy-7-[(2~octyl)oxy]-
2,4-propano-2H-l-benzopyran-9~propanol
Using the procedure of Example 83, 700 mg. (2.52
S mmole) of 3,4-dihydro-2-methoxy-7-hydroxy~2,4-propano-
2H-l-benzopyran-9-propanol and 786 mg. ~3.78 mmole~ of
d-2-octylme~hanesulfonate gave 742 mg. (75~j of the
ti-tle compound a~ an oil.
PMR (CDC13) ~ 0.88 ~m, methyl), 1.29 (d, J=6Hz,
lQ methyl), 2.92 (m, methine), 3,38 (s; methoxy), 3.7
(m, methylene), 4.25 (m, methine), 6.3 (m, ArH) and
6080 (d~ 3=8~Izt ALH).
~n]20 = -1.76 (c = 1.33, methanol)
H~MS (m~e~ 390.2763 (M , calc'd. for C24H3804:
lS 390.2769~, 304, 289,.278, 273, 246, 192, 191, 177 znd
175.
EXAMPLE 87
l-Trans-3-[2-hydroxy-4-(2-octyloxy)phenyl]-4-
(3-hydroxypropYl)cyclohexano~e
Using the procedure of Example 84, 742 mg. (l.gO
mmole) of 1-3,~-di~ydro-2-methoxy-7~C(2-octyl)oxy]-
2,~-propano-2~I-L-benzopyran-9-propanol gave a quantitative
~ield of title compound as an oil.
H~MS (m/e) 376.2624 (M , calc'd. for C23H3604:
376~2592), 264, 179, 178 and 177.
:~83533~
-.130-
EXAMPLE 88
~ .
l-Cis 3-r2-hydroxy-4-(2-octyloxy)phenyl3-txans-4-
(3-hydroxypropyl)cyclohexanol and the trans~3, CiS-4 isom~r
Using the procedure of Example 5, 714 mg. (1.90
mn~ole) of 1-trans-3-[2-hydroxy-4-(2-octyloxy)phenyl]-4-
t3-hydrox~prop~l)cyclohexano~e afforded 483 mg. ~67%)
of the title compound and 101 mg~ ~14~ of ~he tr~ns-3;
cis-4 isomer as oils.
Cis 3, trans 4
t~]20 C- = -5.21 (c = 1.13, methanol~
HRMS (m/e) 378.2775 (M~, calc'd. for C23~38O4:
378.2760), 266, 249, 248, 147 and 123.
Trans-3, c~s-4
_
HRMS (m/e) 378.2767 (M , calc'd. for C23H38O4:
378.2760), 266, 248, 189, 149, 147 and 1230
EXAMPLE 89
Following the procedures of Examples 77 - 81,
4-(2-propenyl)-2-cycloheptenone is converted to trans-
3 (2,4-dihydxoxyphenyl)-4-(3-hydroxypropyl)cyclo-
heptanone.
~ .8~3~
-131-
EXAMPLE 9O
~ , . _ .
Repetition of the procedures of Examples 82 - 88,
but using trans-3-(2,4-dihydroxyphenyl)-4-(3-hydroxy-
propyl)cycloheptanone as reactant in Example 82 procedure,
and the appropriate CH3502-0-Z-W alkylating agent affords
the following compounds:
~H
(p~ fH
~0- ( alk2 ) -~
CH2
CH20H
(alk2 ) W
C~l(C~I3)(CH2)6 H
CH(CH3)(CH2)5 H
tCH2)11 H
~tC~3)(CH2)3 C6H5
(C~2)4 C6HS
CH(C~3)(CH2)34-FC6H4
(CH2)4 4-pyridyl
~ ~3~3~
-132-
EXAMPLE 91
.
Trans-4-(2-Propenyl)-3-[2-(tetrahydropyranyl-2-oxy)-
4-(1,1-dimethyl)-cis-2-hept~nyl)phenyl]cyclohexanone
, . . ~
To a 0C. solution of 2.0 g. (6.62 mmole) of 1,1
~imethyl-1-[3-(tetrahydropyranyl-2-oxy)phenyl] cis 2-
heptane and 844 mg. (7.28 mmole~ of tetramethylethylene
diamine in 10 ml. o~ ether was slowly added 3.17 ml.
(7.28 mmole) of n-butyllithium (in hexane). The
resultant solution was stirred 5 minutes at 0C. and
then refluxed ~or 70 minutes. The resultant was then
cooled to -78Co
To a 0C~ solution of 597 mg. (7.28 mmole) of 1-
hexyne in 10 ml. of tetrahydrofuran is slowly added
3.17 ml. ~7.28 mmole) of _-butyllithium (in hexane).
The resultant solution was stirred 10 minutes at 0C.
and then slowl~ added to a 0 QC . slurry of 1.38 g.
(7.28 mmole~ of cuprous iodide in 10 ml. of tetra-
hydrofuran. The resultan~ yellow slurry was stirred
30 minutes at 0C. and then slowly added to the above
prepared -78C~ solution of aryl lithium reagent. The
resultant yellow mixture was stirred 10 minutes at
-78C. and then 300 mg. (6.62 mmole) of 4-(2-propenyL)-
cyclohex-2-en-1-one is added dropwise. Stirring was
continued for 10 minutes and then the reaction was
placed in a -~0C. ~ooling bath and allowed to war~
to -20C. over 20 minutes. The reaction was quenched
by addition ~o 200 ml. of cold saturated ammonium
chloride brought to pH 10 with saturated ammonium hy-
droxide. The quenched reaction mixtuxe was extracted
with 300 ml. o~ ether. The ether extract was dried
over magnesium sulfate and evaporated to an oil which
- was purified via column chromatography on 200 g. of
silica gel eluted in 15 ml. fractions with 20Po ether-
hexane to yield from fractions 40-63, 2.36 g. (32%) of
the title compound as an oil.
~3L83~ii3~
_133_
EXAMPLE 91 ~Cont.)
IR (CHC13) 1709, 1641, 1610 and 1571 cm ~.
HRMS (m~e) 354.2569 ~P. -C5H80: Calcd. for C24H3202:
354.25S0)~ 272, 271, 161, 137 and 85 (100%~.
PMR ~CDCl~) ~ 0.69 (m, terminal C~3~, 1.41 (s, gem
dimethyl), 0.8-4.2 (series of m), 4.7-5.6 (m,
olefinic H and T~P methine), S.62 (d, J=12H~
vinyl H) and 6.7-7.3 (m, ArH)O
~L8353~3
-13~_
EX~MPLE 92
rans 4-(?.-Propenyl)-cis-3~[2~(tetrahydropyranyl-2-
oxy)-4-(1,1-dimethyl-cis-2-heptenyl)phenyl]-
cyclohexanol and the cls-~,trans-3 isomer
l'o a -7~C. sclution of 20.0 g. (45.7 mmole3 of
trans-4-(2-propenyl)-3-l2-(te~ahydr~yran~ .y)-~-
(l,L-dimethyl-c i S- 2-heptenyl)phenyl]cyclohexanol in
200 ml. of methanol wa~ added in one portion 5.20 g.
(L37 mmole~ o sodium borohydride. The reaction was
stirxed overniyht at -78C. and then allowed to warm
to 0C. The reaction was quenched with 10 ml. satu-
rated sodium chloride and then concentrated on a
rotovapor. The residue was diluted with S00 ml.
saturated sodium chloride and 500 ml~ ether. The
lS ether e~tract was washed once with 250 ml. saturated
sodium bicarbonate/ dried over magnesium sulfate and
evaporated to an oil. The crude oil was purified via
coLumn chromatography on 1 kg. of silica gel eluted
with 30% ether-hexane to yield in order of elution
~o 2.20 g. (11~) of the cis-4, rans-3 isomer, 0.74 g.
(4%) of mixture and 17.0 g. (85%) of the title compound
as oils.
Title Compound:
IR (CHC13) 3593, 3464, 1640, 1610 and 1571 cm 1.
HRMS (m/e) 356.2709 (P. -C5H8O, Calcd. for C24H36O~:
35~.2706), 297, 273, 255, 124 and 85 (100~).
P~IR (CDC13) C 0.70 (m, terminal C~3), 1.42 (s, gem
dLmethyl), 2.8 (bm, benzylic methine), 3.4-
4.1 (m, carbinol methine and OCH2), 4.6-
S.5 (m, vinyl H and THP methine), 5.60 (d, J=ll
Hz, vinyl H) and 6.8-7.2 (m, Ar~).
35i~
-.135-
EX~MPLE 93
........ .
Trans-4-(3~Hydroxypropyl)-cis-3- [ 2-(tetrahydro-
pyranyl-2-oxy)-4~ dimethy.l cis 2 heptenyl~-
phenyl]cyclohexanol
To a -S~C~ solution of 13O3 g. (0.0302 mole) o~
trans-4-(2-propen~ ClS-3- [2-(tetrahydropyranyl-2-
oxy)-4-(1~1-dimethyl~c_s-2-heptenyl)p~e~yi3~clonexanoi
in 100 ml. of ~etrahydrofuran was slowly added 35.1 ml.
(0.035L mole) of ~oran-tetrahydrofuran (lM in tetra-
hydrofuran), with stirring. After 30 minutes another
50 ml. of tetrahydrofuran was added and the reaction
stirred 30 min~ltes longer, then quenched by addition o~
40 ml~ (0.1~ mole) of 3N sodium hydroxide and oxidized
by addition o~ 10 ml. (0.112 mole) of 30~ hydrogen
peroxide. After s~irring 20 minutes the reaction was
added to 500 ml~ saturated sodium chloride - 500 ml.
ether~ The aqueous phase was extracted with another
250 ml. portion o~ ether and the combined ether
extract dried over magnesium sulfate and evaporated ~o
an oiL. The crude oil was purified via column chroma-
tography on 1 kg. of silica gel eluted with 80% ether-
hexane to 3~ methanol-ether to yield in order of elution .
600 mg. t5~) o~ unreacted starting material, 7.45 g.
(54~) of the title compound as an oil, 1.32 g. (12~) o~
trans-~-(3-hydroxypropyl)-cis-3-[2-hydrDxy-4-~1,1-di-
methyl-cis-2-heptenyl)phenyl]cyclohexanol (phenolic
product) and 1.7~ g. ~13~) of trans-4-(3-hydroxy-
propyl)-cis~3-12-(tetrah~dropyranyl-2-oxy)-4-(1,1
dimethyl-3-hydroxyheptyl)phenyl]cyclohexanol (Triol-
T~P).
3~ii3 !3
-~36-
Example 93 (Cont. ?
Title Compound:
~RMS (m~e) 374.2831 (P~ -C5H8O, Calcd. for c24H38O3:
374.2811), 356, 242, 151 and 85.
PMR (CDC13) ~ 0.72 (m, terminal CH3~, 1.40 ~s, gem
dimethyl)~ 2.8 (m, benzylic methin~), 3.47 (m,
CH20H), 3.2-4.2 (m, carbinol methine and
-CH~O-), 4~9-5 5 (vinyl H and THP methine),
5.62 ~d, J=llHz, vinyl H) and 6.9-7.2 (m, ArH~.
Phenotic Product:
~R~S (m/e) 374.2839 (M. , Calcd. for C24H38O3:
374.2811), 356, 341, 299, 273 and 270.
Triol-TXP:
HRMS (m/e) 392.2949 (P. -C5H80, Calcd. for C24~0040
392~2916), 374, 292, 274, 165 and 85 (100~).
~83~3~
_ 137_
EXAMPLE 94
.
Trans-4-(3-d-Mandeloyloxy)-ciS-3-[2~hydroxy-4-
(l,l-dLmethyl~cis-2-heptenyl)phenyl]-1-d-mandeloyloxy-
_ _ _ cyclohexane
- ~
A mixture of 6.00 g. (13.1 mmole) of trans~4-(3-
hydroxypropyl~-cis-3~2-(tetrahydropyranyl-2-oxy)-4-
(l,l-dimethyl-cis-2-heptenyl)phenyl]cyclohexanol,
9.96 g. (65.5 mmole) d-mandelic acid and 498 mg.
2.62 mmole) ~-toluenesulfonic acid monohydrate in 250 ml.
- 10 of benzene ~as heated at reflux. Water was removed via
a 3A molecular sieve illed soxhlet extractor~ The
reac~ion was heated a-t re~lux for 160 minutes with
additional por-tions of p-toluenesulfonic acid mono-
hydrate added at 40, 80 and 120 minutes. The reaction
was cooled and added to 500 ml~ saturated sodi~m bi-
carbonate - 500 ml. ether. The aqueous phase was ex-.
tracted with a second 250 ml. portion of eth~r and the
combined ether extract dried over magnesium sulfate
and evaporated to an oil. The crude product was purified
via column chromatography on 800 g. of silica gel eluted
with 55% ether-hPxane to yield order of elu~ion 2.25 g.
(~7~) of diasterPomer A of the title compound, 2.0 g.
~24~) of a mixture and 4.0 g. (48~) of slightly Lmpux~
dia~tereomer B o the ~itle compound as ~ils.
25 Diastereomer A:
20~]CE13O~ = ~ 31.62 (C=1.85)
P.~R (CDC13) ~ 0.68 (m, terminal CH3), 1~37 (s, gem
dLmethyl), 3.4 (bd, J=6Hz, OH), 3.93 (~t, J=
6E~z, -CH2O-), 4.75 (m, OH~, 5.02 (m, CHOH),
5.0 5.7 (m, vinyl H), 6.6-6.9 (m, ArH), 7.23
and 7.26 (s, PhH),
~1353~3
_138_
EXAMPLE 95
Trans~ (3-hydroxypropyl)-cls-3-~2~hydroxy-4-
(l,l-dimethyl-cls-2-heptenyl)phenyl]cyclohexanol
A mixture of 3.10 gO (4.82 mmol~) of diastereomer
A of trans 4~(3-d-mandeloyloxy) -ClS-3- [2-hydroxy-4-
(l,l-dimethyl-cls-2-heptenyl)phenyl]-1 d-mandeloyloxy-
cyclohe~ane, 5.32 g. (38.6 mmole) potassi~m carbonate,
40 ml. me-thanol, 40 mlO ketrahydrofuran and 10 ml. water
was s~irred at 25C. for 24 hours. The reaction was
evaporated on a .rotovapor and the residue dissolved in
250 ml. ether - 250 ml. saturated sodium chloride. The
2queous phase was extracted with two additional 150 ml.
portions of ether, the combined ether extract dried over
magnesium sulfa~e and evaporated to an oilO The crude
product was purified via column chromatography on 150 g.
of silica gel eluted with ether to yield 1.3 g. ~72~)
of khe title compound~
~P: 95-97C. (Diisopropyl ether-hexane)
~ 20[~]CH3~ = -56 32
HRMS (m/e) 374.2819 (M. , Calcd. for C24H3803:
374.2811), 356, 213, 187, 161, 147, 124, 121,
~nd 93.
PMR (250 mHz, CDC13) ~ 0.73 (m, terminal methyl),
1.39 (s, gem dimethyl~, 2.03 (m, CH2~vinylic),
2.72 ~m, b~nzylic met~ine), 3.47 (m, CH20H),
3.7~1 (m, CHOM), 5.07 (bs, OH), S.22 and 5.27
(dk, J=11.51 and 7.31 Hz, vin~l H), 5.61 (dt,
J=11.51 and 1.6 Hz, vinyl H), 6.73 (d, J=1.64
Hz , ArH), 6.91 (dd, J=8.22 and 1.82 Hz, ArH)
and 7.02 (d, J=8.04 Hz, Ar}I)
83531~
~ 9
~X~MPLE 96
(w)-Trans-4-(3-hydroxypropyl)-cls-3- [ 2-hydrQxy-4 -
(l,l~dimethylheptyl)phenyl]cyclohexanol
~ mixture of 50.0 mg. (0.134 mmole) of (-)-trans=
4~(3-hydroxypropyl) -cis-3- ~2-hydroxy-4-(l,l~dimethyl~
cis-2-heptenyl)phenyl]cyclohexanol and 50 mg. of 10%
palladium on carbon in S ml. of dry tetrahyd-r~f~ n W7~
stirred under one abmospher~ of hydrogen for 30 minutes.
The react.ion wa~ filtered through diatvmaceous earth
with ~etrahydrofuran and the filtra~e evaporated to
yield 47.9 mg. ~g5%~ of the title compound as an oil.
20~[~]CH30H = -36 12
.
EXAMPLE 97
_
Trans-3,4,trans-~,5-3-~2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyl~-5-methyl-4-(2-~ropenyl) ~
Using the procedure of Example 1, 7.S g. ~S0 mmole)
of trans-5-methyl-4 (2-propenyl)cyclohex-2-en-1-one and
2~.3 g. (62.5 mmole) of l-benzyloxy 2-bromo-5-(1,1-di-
meth~lheptyl~benzene ~ave 13.0 g. fs7~ of the title
compound as an oil.
IR (C~C13) 1709, 1639, 1609 and 1568 cm 1.
~RMS (m/e) 460.3353 (M~ , Calcd. for C32H44O2:
460.3330), 375, 370, 369 and 91 (100~).
PMR (CDC13) ~ 0.82 ~m, terminal CH3) J 1.26 (s, gem,
dimethyl), 4.5-5.1 (m, vinyl H), 5.00 (s,
benzylmethylane), 5.3-5.8 (vinyl H), 6.6-7.1
lS (m, ArH) and 7.25 (bs, PhH)o
In like manner, trans-3,4-trans-4,5-3-~2-benzyloxy-
4-(1,1-dimethylheptyl)phenylJ-5-methyl~4-(2-propenyl)-
cycloheptanone is prepared from trans-5-methyl-4-(2-
propenyl)cyclohept-2-en-1-one.
~L835;~
EXAMPLE 98
Cis-3-[2-benzylox~-4-(1,1-dimethylheptyl)phenyl] -CiS 5-
methyl-trans-4-(2-propenyl)cyclohexanol
Using the procedure of Example 2, 6.0 g. ~13.0
mmole) of trans-3,4-trans, 4,5-3-[2-benzyloxy-4-(1,1-
dimethylheptyl)phenyl]-S-methyl-4-(2-propenyl)cyclohex r
anone gave 1.1 g. (18~) o~ the cis-~,trans-3,trans-~
isomer of the title compound, 1.077 g. (17~) of a mi~-
~ure and 2.79 (46~) of the title compound as an oil.
Cis-~,Trans-3,Trans-5 Isomer^
HRMS (m/e) 462.3501 (M. , Calcd. for C32H46O2:
362.3486)~ 377, 269, 227 and 91 (100~).
PMR (CDC13) ~ 0.82 (m, terminal methyl~, 0.95 (d~
J=5Hz, methyl), 1.23 (s, gem dimethyl), 3.5
(m, benzylic methine)~ 4.13 (m, carbinol
. methine), 4.6-5.0 (m, Yinyl H), 5.05 (s,
benzylic methylene), 5.2-6.1 (m, vinyl H),
6.85 (m, ArH), 7.05 (d, J=8Hz, ArH~ and 7.38
(bs, PhH).
Title Compound:
IR (CHC13) 3596, 3463, 1639, 1609 and 1570 cm 1.
HRMS (m/e) 462.3499 (M. , Calcd. for C3~H46O2:
462.3501), 377, 353, 269, 227 and 91 (100%).
PMR (CDC13) ~ 0.83~ (m, terminal CH3), 1.25 ts,
gem dimethyl), 3.2 (m, ben~ylic methine),
3.62 (b~n, carbinol methine), 4.5-5.0 (m,
vinyl H), 5.02 (s, benzylic methylene), 5.3-
6.1 ~m, vinyl H), 6.82 (m, ArH)~ 7.00 (d, J=
8Hz, ArH) and 7.35 (bs, PhH).
Following the above procedure trans-3,4-trans-4,5-
3-~2~benz~10xy-4-(l,l-dimethylheptyl)phenyl]-5-methyl-
trans-4-(2-propenyl)cycloheptanone is prepared from the
correspondingly substituted cyclohept-2-en-1-one.
~3~
-1~2 -
EX~MPLE 99
Trans-3,4-Trans,4,5-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyl]-5-methyl-4~(2--propenyl)cyclo-
hexanone ethylene ketal
.. . . ..
S A mixture of 7.0 g. (lS.2 mmole) of trans-3,4~
trans,4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
~-methyl-4-~2-propenyl)cyclohexanone, 8.47 ml. (152
mmole) of ethylene glycol and 289 mg. (-1.52 mmole) of
p-toluenesul~onic acid monohydrate was heated at reflux
for 2.5 hoursO Water was removed via a soxhlet extractor
filled with 3A si~ves. The reaction was cooled and added
to 250 ml. saturated sodium bicarbonate - 250 ml. etherO
The ether extract was dried over magnesium sulfate and
evaporated to an oil. The crude product was puri~ied
L5 via column chromatography on 300 g. of silica gel eluted
with 20~ ether-hexane to yield 5.2 g. (68~) of the title
compoun~ as an oil.
IR (CHCl3) 1638, 1608 and 1569 cm l
HRMS (m/e) 504.3579 ~M. , Calcd. for C34H48O3:
504.3S91~, 419, 413, 407 and 91 (lO0~).
PMR (CDCl3) ~ 0.82 (mr terminal methyl), 0.99 (d,
J-6Hzl, CH3), 1.25 (s, gem dimethyl), 3.4 (m,
benæy:Lic me~hine), 3.90 (s, ethylene ketal~,
4.4-5~0 (m~ vinyl H), 5.03 (s, benzylic
methylene), 5.3-6.2 ~m, vinyl H), 6.80 (m,
ArH), 7.00 (d, J=8Hz, ArH) and 7.35 (bs, PhH).
The ethylene ketal of trans 3,4-trans-4,5-3~[2-
benzyloxy-4-(l,l-dimethylheptyl)phenyl] 5-methyl-4-(2-
propenyl)cycloheptanone is prepared in like manner from
the corresponding cycloheptanone.
3353~3
~-~ 3ff
EXAMPLE 100
Cls-3~[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-
cis-5-methylcyclohexanol
. . . ~
To a 0C. solution of 900 mg. (1.95 mmole) of ClS-
3-~2-benzyloxy~4-(1,1-dimethylheptyl)phenyl]-cls-5-
methyl-trans-4-(2-propenyl~cyclohexanol in 2 mlO of ether
was added 5.1 ml. ~11.7 mmole~ of _-butyllithium (in
hexane). The reaction was stirred 10 hours at 25C. and
then added to 200 ml. ether - 200 ml. saturated ammoni~m
chloride. The ether extract was dried over magnesium
sulfate and evaporated to an oil. This oil was crystal-
lized in h~xane to yield 495 mg. (68~) of the ti~le
compound.
MP 149-150C. (hexane)
~R (CHC13) 3455, 3Z53, 1643, 1617 and 1583 cm 1.
~RMS (m/e) 372.3050 (M~ , Calcd. for C25~40O2:
372.3018), 312, 288, 287 (100~, 272, 269,
227, 187, 161, 147 and 135.
Analysis:
Analysis G~lcd. For C~5H40O2: C, 80.59; H, 10.82
Found : C, 80.35; ~, 10.81
Debenzylation of cis-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyl]~cls-5-met.hyl-trans-4-(2-propenyl)cyclo-
heptanol is carried out in like manner.
~L8~5~
EXAMPLE 101
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl~-
trans-4-(3-hydroxypropyl)-cis-5-methylcyclohexanol
. _ . . .
Using ~he procedure of Example 5, 900 mgO (1.95
mmole) of eis-3-~2-benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-cis-5-methyl-trans-4-~2-propenyl)cyclohexanol
was converted in quantitative yieLd to the title com-
pound, an oil.
HRMS (m/e) ~80.3574 (M. , Calcd. for C32H4803
480.3591), 462, 395, 377, 287 and 91 (100%)o
By means of this procedure, CiS-3- [2-benzyloxy-4-
(l,l-dimethylheptyl)phenyl]-cis-5-methyl-trans-4-(2-
propenyl!cycloheptanol is converted to the corresponding
3-hydroxypropyl derivative.
~Lb}3~3~
-145
EXAMPLE 102
.
C-s-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-
trans-4-(3-hydroxypropyl)-cls-5-methylcyclohexanol
Using the procedure o~ Example 6, 936 mg. (1.95
mmole) of cls-3-~2-benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-trans-4-~3-hydroxypropyl3-~is-5-methylcyclo-
hexanol afforded 602 mg. (79%) of the title compound.
MP 159-150C. (diisopropyl ether - ethyl acetate~
IR (KB.r~ 3533~ 33G7, 3211, 1617 and 1585 cm 1.
L0 HRMS (m/e) 390.3100 (M~ , Calcd. for C25H~2O3,
390.3123), 372, 304, 288, 287, 272, 257, 227,
219 and 187.
Analysis:
C2sH423: C, 76.87; H, 10.8~.
Found : C, 76.60; H, 10.66.
Similarly, cis-3-~2-ben2yloxy-4-~ dimethyl-
heptyl)phenyl]-~rans-4~(3-hydroxypropyl~-cls-5-methyl-
cycloheptanol is debenzylated to the corresponding phenol.
~353~3
-14~-
EXAMPLE 103
. .
Trans~3,4,Trans-4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]-4-(2-hydroxypropyl)-S-methylcyclohexanone
ethylene ketal
S To a 25C. mixture of 3028 g. ~10.3 mmole) of
mercuric acetate in 50 ml. of 50~ aqueous tetrahydro-
f~ran was adde~ 5.2 ~ C.3 ~ole) ~f '.-1ans-3,4,tran~-
4,5-3-[-2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-S-
methyl-4-(2-propenyl)cyclohexanone ethylene ketal in
25 ml. tetrahydrofuran. Another 25 ml. of water was
added to aid solution and stirring. Additional 1.5 g.
(4.7 mmole) portions of mercuric acetate were added
after 2 hours and 24 hours. The reaction was stirred
a total of 64 hours at 25C. and then reduced by addition
lS of 20 ml. 3N sodium hydroxide and 20 ~1. of 0.5M sodium
bor~ahydride in 3N sodium hydroxide. The reaction was
stirred 30 minutes longer and then added to 250 ml~
ether - 300 ml. saturated sodium chloride. The ethes
extract was dried over magnesium sul ate and evaporated
to an oil. The crude product was purified via column
chromatography on 300 g. of silica gel eluted with 50%
ether-hexane to gi~e 1.5 g. (30%) o the title compound
as an oil.
~RMS (m/e) 522.3712 (M+ , Calcd. for C34H5004:
522.3696), 431, 407, 372, 113 and 91 (100~).
PMR (CDC13) ~ 0.75 (m, terminal methyl), 0.92 (d,
J=6Hz, C-S methyl), 1~24 (s, gem dimethyl),
3.35 (bm, caxbinol and benzylic methines),
3.90 (bs, ethylene ketal), 5.03 (s, benzylic
methylene) and 6.6-7.5 (m, ArH).
Trans-3,4-trans-4,5-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl) phenyl] -4-(2-hydroxypropyl)-5-methylcyclohepta-
none ethylene ~etal is also prepared via this procedure
from the corresponding 4-(2-propenyl)cycloheptanone ethylene
- 35 ketal.
3~83~3~
1~ --
EXAMPLE 104
.
Trans-3J4,Trans-~,5-3-~2-3enzyloxy-4-(l,l~dimethyl-
.
heptyl)phenyl]-5~methyl-4-~2-oxopropyl)cyclo-
hexanone ethylene ketal
, .. _ _ . . ..
To a 25C. mixture of 1.5 g. (2.87 mmole) of trans-
3,~,trans-4,5-3-[2-benzyloxy~4~(1,1-dimethylheptyl)-
pnenyl~-4-(2-nydroxyprop~i3-5-met~ylcy~lo~x~non~
ethylene ketal.and 2.35 g. (28.7 mmole) of sodium acetate
in 20 ml. of dichloromethane was added 1.93 g. (9 ~moLe)
of pyridinium chlorochromate. The reaction mixture was
stirred 3 hours at 25C~ and then added to 250 ml. lN
NaOH-250 ml. ether. The organic extract was dried over
magnesium sulfate and evaporated to give a quan~itative
yield of the title compound as an oil.
PMR (CDC13) ~ 0.85 (m, methyls), 1.23 (s; gem
dimethyl), 1.80 (bs, CH3CO-), 2.23 ~bs,
-CH2CO-), 3.3 (m, benzylic methine), 3.93
(s, ethylene ketal), 5~05 ~s, benzylic
methylene) and 6.7-7.6 (m, ArH).
In like manner, oxidation of trans-3,4-trans-4,5-
3-[2-benzyloxy-4-(1,1-dimethylhep~yl)phenyl~-4-(2- -
hydroxypropyl)cycloheptanone ethylene ketal affords .the
corresponding 4-(2-oxopropyl)cycloheptanone ethylene
katal.
~ 3~38
EXAMPLE 105
Trans-3,4-Trans-~,5-3-~2-Benzyloxy-4-(1,1 dimethyl-
heptyl)phenyl~-5-methyl-4-(2-methyl-2-propenyl~-
cYclohexanone ethylene ketal
. _ . . ~
To a 15C. mixture of 5.74 mmole of triphenyl phos-
phoni~methylide in 6 ml. of dimethyl sulfoxide was added
~olu~ion of 1.5 g. ~2.~7 mmole) of t~n~-3,~ trans-~
3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-
(2-oxopropyl)cyclohexanone ethylene ketal in 6 ml. of
~etrahydrofuran and the reaction stirred 1.5 hours at
15-25~C. It was then added to 200 ml. saturated sodium
chloride - 200 ml. ether. The ether extrac~ was washed
once with 200 ml. saturated sodium chloride, dried over
magnesium sulfate and evaporated to give an oil. Puri-
fication via column chromatography on 50 g. of silica
gel eluted with 20~ eth~r-hexane gave 1.17 g. (79~) of
the title compound as an oil.
HRMS (m/e) 518.3706 (M. , Calcd. for C35H50O3:
518.3747), 462, 427, 407, 372, 371, 285 and
~0 91 (100%).
PMR (CDC13) 6 1.25 (s, gem dimethyl), 1.48 (bs,
vinyl methyl), 3.3 (m, benzylic methine),
3~89 (s, ethylene ketal), 4.40 (m, vinyl H),
5~02 (s, ~enzylic methy~ene), 6.85 (m, ArH),
7.10 (d, J=8Hz, ArH) and 7.4 (m, PhH)~
Trans-3,4-trans-4,5-3-[2-benzyloxy-4-(1,1-dimethyl-
heptyl)phenyL]-5-methyl-4-(2-oxopropyl)cycloheptanone
ethylene ketal is converted in like manner to the corres-
ponding 4-(2-methyl-2-propenyl)cycloheptanone ethylene
ketal.
353~
--1~9 _
EXAMPLE 106
Trans-3,4~trans-4,5-3-[2~Benæyloxy-4-(l,l-dimethyl-
heptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)-
_ cyclohexanone
....
mi~ture of l.l g. (2.12 mmole) of ~he ethylene
Xetal of the title compound, 20 ml. tetrahydrofuran and
20 ml. lN hydrochloric acid was heated at reflux for 5
hours and stirred at 25C. for 16 hours. The reaction
was added to 250 ml. saturated sodium chloride - 250 ml.
ether. The ether extract was washed with 250 ml.
sa~urated sodium bicarbonate, dried over magnesium sulfate
and e~aporated to give a quantitative yield of the title
compound as an oil.
HRMS (m/e~ 474.3524 (M~ , Calcd. for C33H4602~o
lS 474.3486), 418, 383, 327, 273 and 91 ~100%).
Deketalization of trans-3,4~trans-4,5-3-[2-benzyloxy-
4-(l,L~dimethylheptyl)phenyl]-5-methyl-4-t2-methyl-2-
propenyl)cycloheptanone ethylene ketal is accomplished
in li~e manner.
353~
-150-
EXAMPLE 107
Cis~3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]~
cls-5-methyl-trans-4 ~2-methyl-2-propenyl)-
cyclohexanol and its axial Isomer
.. . . _ ~ _
S Using the procedure of Example 13, 1.00 g. (2.12
mmole) of trans-3,4-txans-4,5-3-[2-benzyloxy-4-(1,1-
m~thylhep~yl)~h~nyl~-Gis-5-me~h~ rans~ -m.~Qthyl-
2-propenyl)cyclohexanone gave 24 8 mg. (2S%) of the
trans-3, ClS-4, trans-5 isomer of the title compound and
720 g. (71~ of the title compound as oils.
Trans-3,c]s-4,trans-5 Isomer:
HRMS (m/e) 476.3664 (M+ , Calcd. for C33H4~O2:
476.3642), 420, 335, 330, 329 (100%), 312, 311,
and 283.
Title Compound:
HRMS (m/e) 476.3646 (M. , Calcd. for C33H48O2:
476.:3642), ~20, 330, 329 and 91 (100%).
Similarly trans-3,4-trans~4,5-3-[2-benzyloxy-4-tl,1-
dimethylheptyl~phenyl]-cis-5-methyl-trans-4-(2-methyl-
2 propenyl)cycloheptanone is transformed to ClS-3- [2-
benzyloxy-4~(1,1-dimethylheptyl)phenyl]-cis-5-methyl-
trans=4-(2-methyl-2-propenyl)cycloheptanol and the corres-
ponding axial derivative.
~L~83~3~
-`151-
EXAMPLE lO8
Cis-3-[2-Benzyloxy-4-(l,l-dimethylheptyl)phenyl]-
trans-~-(3-hydroxy-2-methylpropyl) -ClS-5-
methylcyclohexanol
... . . . .
Using the procedure of Example 5, 710 mg. (1.49
mmole) of cls-3-[2-benzyloxy-4-(l,l-dimethylheptyl)
-~h~n~l]-c~ me~yl-~ra~-~-(2-metnyl-~-propenyl~-
cyclohexanol (compound of Example 107) gave 322 mg.
(44~) of diastereomer A and 356 mg~ (48~) of dia-
stereomer B of title compound as oils.
Diastereomer A:
~RMS (m/e) 494.3769 (M. , Calcd. for C33H5~03:
494.3747), 386, 301 and 9l (lO0~)~
Diastereomer B:
HRMS (m/e) 494.3790 (M. , Calcd. for C33H5003:
494.3747) and 9l (lO0~).
In like manner, the remaining alkenyl derivatives of
Example 107 are hydrated to the corresponding alcohols.
~8~53~3
-152-
EXAMPLE 109
Cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-
4-(3-hydroxy-2-methylpropyl)-cis-5-methylcyclohexanol
Diastereomer A
~ _ . . . _ .
S Usiny the procedure of Example 6, 320 mg. (0.648
~-ol~ G ~ ~lia~; ~e~ ~3n~~ 2--~ellzy~
dimethylheptyl)phenyl]-trans-4 ~3-hydroxy-2~methyl-
propyl)-cls-5 methylcyclohexanol (product of Example
108) provided 221 mg. (84%) of the title compound.
MP 139-141C. (diisopropyl ether-hexane)
IR (CHC13) 3588, 3407, 1616 and 1579 cm 1.
HRMS (m/e) 404.3247 (M. , Calcd. for C26H~4O3:
404.3279), 386, 301, 233, 187, 161 and 147
(100~) .
~nalysis:
26 443: C, 77.17; H, 10~96.
Found : C, 77.41; H, 10.77.
Diastereomer B
Using the procedure of ~xample 6, 350 mg. (0.709
mmole) of diastereomer B of cis-3~[2-benzyloxy-4-(1,1
dimethylheptyl)phenyl]-trans-4-~3-hydroxy-2-methyl-
propyl)-cls-5-methylcyclohexanol (product of Example
108) gave 255 mg. (89%) of the title compound.
MP 118-120C. (diisopropyl ether-hexane).
~lS (m/e) 404.3237 (~. , Calcd. for C26H44O3:
~04.3279), 386, 318, 301 (100%), 233~ 187,
167 and 147.
~3S3~
_1~3_
EXAMPLE 109 (Cont.)
. _ . .
AnaL~sis:
Anal. Calcd. for C26H44O3: C, 77-17; H~ 10-96-
Found : C, 77.40; H, 10.76.
By means of this procedure, the remaining benzyl
S ethers of Example 108 are converted to the corresponding
phenols.
353~
~15~-
EXAMPLE 110
7-Oxabicyclo[4.1.0]-1-[2-benzyloxy-4-(1,1-dimethyl-
he~tyl)phenvl]-3-heptanone ethylene ketal
~rO a 0C. solution of 5.0 g. (11.2 mmole) of 3-~2-
S benzyloxy-4-(l,l-dimethylheptyl)phenyl]cyclohex-3-en-l-
one ethylene ~etal in 15 ml. of dichloromethane is
added 1.26 g. (lS mmole) of sodium bicarbonate and
2.58 g. (15 mmole) of m-chloxoperbenzoic acid. The
reaction is stirred overnight at 0~C. and then filteredO
The filtrate is diluted with 200 ml. of ether and washed
with two 100 ml. portions of saturated sodium bicarbonate.
The organic extract is dried over magnesium sulfate and
evaporated to yield the title compound.
L 5}3~38
_ 1~5_
EXAMPLE 111
3-[2-Hydroxy-~-(1,1-dimethylheptyl)phenyl]-4-
hydroxycyclohexanone ethylene ketal_ _
Following the pxocedure of Example 6, 7-oxabi-
cyclo~l.l.O]-1-[2-ben~yloxy-4-(1,1-dimethylheptyl)-
phenyl3-3-heptanon~ ethylene ketal is hydrogenate~ to
qive the title compound.
Deketali~ation according to the procedure of Example
~ affords the corresponding ketone.
Following the procedures of Example 1101 3-~2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohept-3-en-1-
one is converted to 3-~2-hydroxy-4-(1,1-dimethylheptyl)-
phenyl~ hydroxycycloheptanone.
3~3~
-156_
EXAMPLE 112
Cis-3-~2-Hydroxy-4-(1,1-dimethylheptyl)-
phenyl]-trans-4-hydroxycyclohexanol
. . .
Sodium borohydride reduction of 3~[2-hydroxy-~-
S (l,l-dimethyLheptyl)ph~nyl]-4-hydroxycyclohexanone
according to the procedure o Example 2 afords the
title compound.
Similarly, reduction of 3-[2-hydroxy-4-(1,1-
dimethylheptyl)phenyl]~4~hydroxycycloheptanone afords
the corresponding alcohol.
~ 335~3
- ls?-
PREPARATION A
... _ . . . .
6-(3-Butenyl)-3- thoxy-2-cyclohexen-1-one
A solution of 25 g. (0.178 moLe) of 3-etho~y-2~
cyclohexen-l-one in 25 ml. of te-trahydrofuran was added
S dropwise over a 30 minute period to a 78 C. solution
of 0.196 mole of lithium diisopropylamide (from 27.4 ml.,
0.196 mo]e, of diisopropylamine and 85 ml., 0.187 moles
of 2.ZM n butyllithium in hexane) in 125 ml. of tetra-
hydrofuran. The reaction was then stirred for 30 minutes
and 65 ml. (0.374 mole) of hexamethylphosphoramide added
followed by 38.9 ml. (0.383 mole) of 4-bromo-1-butene.
The reaction was then allowed to warm to room temperature,
stirred for 1.5 hours and then quenched by addition of
5 ml. (0.277 mole) of water. Most of the solvent was
removed on a rotovapor and the residue diluted with 1000 ml.
ice water and 500 ml. ether. The ether phase was separated
washed with two 300 ml. portions of water, dried over
magnesium sulfate and evaporated on a rotovapor. Dis~
lation of the resulting crude oil gave 10.1 g. (29%) of
the title productO
b.p.: 83 C. (0002 ~orr)
PMR ~CDCl 1.34 (t, J=7Hz, methyl), 1.3-2.6 (m),
3.B6 q, ~=7~Iz, methylene), 4.75-5.2 and 5~45-6.2 (m,
terminal olefin~ and 5.26 ~s, vinyl H)~
In like manner, 6-(3-benzyloxypropyl)-3-ethoxy ~
cyclohexen-l-one was prepared from 12.9 g. (91.9 ~nole)
of 3-ethoxy-2-cyclohexen-l~one and ~8.0 g. (101 ~nole) of
l-benzyloxy-3-iodopropane. Yield: 17.0 g. (67~).
Purification was achieved via column chromatography on
~35~3~
-158--
500 ~. of 5~ sodium bicarbonate sillca gel eluted with
75% ether-hexane.
IR (CHCl3) 1632 and 1600 cm l.
MS (m/e) 288 (M )
~CDC13 1.34 (t, J=7Hz, methyl), l.4-2 6 ~m)
3.50 (bt, J=6Hz, methylene), 3.85 (q, J=7H~, methylene)~
~49 (s~ benzylic methylene), 5.27 (s, vinyl H) ~d
7.27 (s, PhH).
~33538
-15~ -
PREPARATION B
. .
4-(3-Butenyl)-2-cyclohexen-1-one
. _ _
To a 0 C. slurry of 1.06 g. (26 mmoles) of lithium
aluminum hydride in 75 ml. of ether was added a solution
S of 10 g. (51 mmoles) of 6 (3-butenyl)-3-ethoxy-2-cyclo~
hexen-l-one in 25 ml. of ether. After stirring for one
hour, the reaction was quenched by addition of 100 ml.
o~ 2N hydrochloric acid. The quenched mixture was stirred
for 30 minutes and then extracted with 300 ml~ of ether.
The ether extract was washed with 250 ml. saturated sodium
~icarbonate, dried over magnesium sulfate and evaporated
on a rotovapor. Distillation o~ the crude oil gave 5.98 g.
(7B%) of the title product.
b~p.: 133-136 Cn (22 torr)
PMR ~CDCl 1.3-2.7 (m), 4~9-5.4 (m, terminal olefin),
5.S-G.2 (m, terminal olefin~, 6.02 (bd, J=lOHz, C-2 vinyl H)
and 6.91 (bd, J=lOHz, C-3 vinyl H)~
Similarly, 4-(3-benzyloxypropyl)-2-cyclohexen-1-one
was prepared in 74~ (11.1 g.) yield from 17~0 g. (61.6
~0 mmole) of 6-(3-benzyloxypropyl)-3-ethoxy-2-cyclohexen-1-one.
The product was an oil.
IR (CHC13) 1680 and 1459 cm 1.
PMR ~CDCl 1.2-2.8 (m), 3.55 (bt, J=6Hz, methylene),
4.50 (s, benzylic methylene), 5.92 (dd, J=10 and 2Hz,
~inyl H), 6.82 (bd, J=lOHz, vinyl H) and 7.33 (s, PhH).
3S~I~
-160_
PREPARATION C
... . _ ..
2-(1,3-Dioxolan-2-yl)ethyltriphenylphosphonium bromide
A so1u-tion of 25 g. ~0.138 mmole3 of 2-(2-bromoethyl)-
1,3-dioxolane and 36.2 g. (0~138 mmole) of triphenyl-
5 phosphine in 30 ml~ of toluene was heated at 100 C. for18 hours. The reaction was cooled to yield two phases.
The toluene phase was decanted and the oil remaining
crystallize~ at -7B'~ C. in ethyl acetate. Decantation
of the ethyl acetate and warming of the crystals to room
temperature gave an oil. The oil was dried under vacuum
(0.05 torr) at 100 C. for 16 hours to yield 15 g. (27%)
o~ the title compound as a solid glass which was ground
~o a powder.
3~3~3
- 161-
PREPARATION D
8-Oxabicyclo[5.1.0]octan-2-one
. .
To a 0 C. solu-tion of 50.0 g. (0.454 mmolel of
cyclohept-2-en-1-one in 800 ml~ of methanol was added
85 ml. of 30% hydrogen peroxide (0.75 mole) followed by
the dropwise addition of lS ml. of 6N sodium hydroxide
(0.09 mole). The reaction was stirred for on~ hour and
then added to ~l00 ml. ether-500 mlO petroleum ether.
The ether extract was rPmoved and the aqueous methanol
phase extracted with ~our 500 ml. portions of petroleum
ether and three 300 ml. portions of dichloromethane.
The combined organic extracts were washed with three
800 ml. portions of saturated sodium chloride, dried
over magnesium sulfate and evaporated under reduced
lS pr~ssure to an oil (53 g.). The crude oil was purified
via vacuum distillation to yield 45.9 g. (80~) of the
title compound as an oil. Caution: several forceful
detonations have occurred during distillation of the
crude product. (In general, however, the crude product
is pure enough for further synthetic manipulations and
distillation can be avoided.)
b.p~: 89-90 C. ~14 torr)
IR (C~Ci3) 1695 and 1600 cm 1.
MS (m~e) 126 (M ), g9~ 98, 97 and 84.
PMR ~CDCl 0.7-1.5 (m), 1.5-3.0 (m) and 3.48 (d,
J=3E~z, C-lH). 3
3~3~3
_`162
PREPARATION E
3-HYdroxycycloheptanone
r' ~
To a 25 C. solution of 45.9 g. (0.364 mole~ of
8-oxabicyclo[5.1~0]octan~2-one in 950 ml. of 10%
aqueous tetrahydrofuran was added 39~7 g. (1.47 mmoles)
o alumin~n amalgam. (The al~minum amalgam was prepared
by 15-30 second successive washing of small pieces of
aLuminum foil with 2N sodium hydroxide, distilled water,
~ 0.5% mercuric chloride, distilled water, 2N sodium
hydroxide, distilled water, 0.5% mercuric chloride,
distilled water, ethanol and ether.) The mixture was
stirred for 2 hours, then filtered through diatomaceous
earth. The filtrate was evaporated on a rotovapor, the
residue sat~lrated with solid sodium chloride and extracted
with three 50Q ml. portions of ether. The ether extract
was dried over magnesium sulfate and evaporated to yield
45 g. t97~) of the title compound as an oil.
IR (CHC13) 3390, 1695 and 1610 cm 1
MS ~m/e) 128 (M ), 110, 100 and 85.
PMR ~CDCl 1.80 (m), 2.42 (m, C-7 methylene), 2.89
(d, J=6Hz, C-2 methylene3) 3.40 (bs, OH) and 4.02 (m,
C-3 methine).
~8353~3
-1~3-
PREPARATION F
Cycloheptan-1,3-dione
To a 10 - 20 C. solution of 20 g. (0.156 mole~
of 3-hydroxycycloheptanone in 700 ml. of acetone was
s slowly added 54.9 ml. of 2.67 M Jone's reagent (0.146
mole). The mixture was stirred 15 minutes and the~
quenched by addition of 12 ml. of isopropanol. The
reaction was Eiltered through diatomaceous earth and
the filtrate concentrated on a rotovapor to about 100 ml.
The residue was diluted with 300 ml. of saturated sodium
chloride and ~hen extracted with six 250 ml. portions of
ether. The combined organic extract was washed with
two 100 ml. portions of saturated sodium bicarbonate,
dried over magnesium sulfate and evaporated under reduced
lS pressure (aspirator) to yield an oil. Dis~illation of
the crude oil gave 11.5 g. ~58~) of the title compound
as an oil.
b.p.: 117-121 C. (14 torr)
IR (CHC13) ~509 (weak), 1733, 170~ and 1621 cm 1.
2~) M5 tm/e) 126 ~M ), 98, 83 and 70.
PMR ~CDC13 2.0 (m, C-5,6 methylenesj, 2.58 (m, C-4,7
methylene) and 3.60 (s, C-2 methylene).
3~3~
-il6~-
PREPARATION G
3-Ethoxycyclohept-2-en-1-one
:
A soLution o~ 22.3 g. (0.177 mole) of cycloheptan-
1,3-dione and 600 mg. (3.16 mmoles~ of p-toluenesulfonic
acid monohydrate in 86 ml. of ethanol and 250 ml. of
toluene was heated at reflux for 18 hours. A soxhlet
extractor filled with molecular sieves (3A) was used
to remove water from the reaction. The reaction was
cooled, added to 800 ml. saturated sodium chloride and
extracted with four 800 ml. portions of ether. The
combined organic extract was dried over magnesium sulfate
and e~aporated to an oil. Distillation of the crude
oil gave 25.3 g. (93%) of the title compound as an oil.
b.p.: 74~78 C. (0.10-0.15 torr)
IR (Neat~ 1645 and 1613 cm 1.
MS (m/e) 154 (M )~ 135, 109, 98 and 97.
CDC13 1.34 (t, J=7Hz, methyl), 1.8 (m C 5 6
methylenes), ~.6 (m, C-4,7 methylene~, 3.80 (q, J=7Hz,
ether methylene) and 5.37 (s, olefinic H).
PREPARATION H
3-Ethoxy-7-(2-propenyl)cvclohept-~-en-1-one
Following Preparation A, 15 g. (97~4 mmole) of
3-ethoxycyclohept-2-en-1-one and 23.5 g. (0.195 mole)~
of allyl bromide gave 11.4 g. (60~) of the title compound
as an oil.
.p.: 80-87 C. (0.05-0.1 torr)
IR (Neat) 1650 and 1608 cm 1.
MS (m/e) 194 (M+)
PMR ~CDCl 1.38 (t, J=7Hz, methyl), 1.4-3.1 (m),
3.87 (q, J-7Hz~ ether methylene), 4.9-5.3 and 5.4-6.3
(M, olefinic) and 5.42 (s, C-2 vinyl H).
3~3~il
-165 ~
PREPARATION I
4-(2-Propenyl)cyclohept-2-en-1-one
.
Following Preparation B, 12.0 g. (61.8 mmole~ of
3-etho~y-7-(2-propenyl)cyclohept-2-en-1-one ga~e 3~0 g.
(33%) of -the title compound as an oil.
b.p.: 71-72 C. (0.1 torr)
IR ~Neat~ 1678 ~hroad~ cm 1,
MS (m/e) 150 (M ~
PMR CcDcl 1.2-300 (m), 4.8-6.1 (m, terminal olefin),
5.96 (dd, J=12 and 2Hz, C-2H) and 6.42 (dd, J=12 and 3Hz,
C-3H).
PREPARATION J
(R)-l-Bromo-2-benzyloxy-4-(1-me~hyl-4-phenyl-
_ _ _ butoxy)benzene
~ mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4
bromopheno1, 20.0 g. (82.6 mmole) of (S)-l-methyl-4-
phenylbutyl methane sulfonate and 25.2 g. (200 mmole) of
potassijm carbonate in 100 ml. dimethylformamide was
heated at 85 C. for 13.5 hours. The reaction was cooled
and ~dded to 500 ml. water-500 ml. ether. The organic
extract was washed with two 250 ml. portions of water,
dried over magn;esium sulfate and evaporated to an oil.
The crude oil was purified via column chromatography on
750 y. of silica gel eluted with 10% ether-hexane to
~ield 23.9 g. (72%) of the title compound as an oil.
~~25 = -:Ll.39 (C = 1.137, CH3Cl)
IR (CHC13) 1574 cm 1.
HRMS (m/e) 426.1011 (M~, calc'd. for C2~2502Br:
426.1012), 424, 280, 278, 104 and 91.
PMR (CDC13)~ 1.22 (d, J=6Hz/ methyl), 1.4-2.0 (m),
2~60 (m, benzylic methylene), 4.24 (m, methine), 5.07
(s, benzylic methylene), 6~30 (d, J=2Hz and 8Hz, ArH),
6.46 (d, Ja2Hz~ ArH), 7.17 (s, PhH) and 7.35 (m, PhH).
3538
-1~6-
PREPARATION K
l-Benzyloxy-3-iodopropane
To a sol~1tion of 83.3 g. (0.318 mole) triphenyl-
phosphine in 200 ml. benzene was added, in four portions,
80 g. (0.318 mole) of iodine~ The resultant mixture was
stirred 3 hours and then 50 mlO ~0. 618 mole) of pyridine
was added followed by the slow addition of 32 g. ~0.l92
mole) of 3-benzyloxypropanol in 250 ml. of benzene.
The reaction was stirred 15 hours longer and then diluted
with 40 ml. of methanol. The mixture was flltered through
diatomaceous earth and the filtrate evaporated to an oil.
Distillation of the crude oil yielded 28 g. (53~) of
the title compound as an oil.
b.p.: 94-97 C. (0.45 torr)
lS PMR (CDCl3)~ 2.00 (quintet, J=6Hz, methylene), 3.20
(t, J=6Hz, methylene), 3.43 (t, J=6Hz, methylene), 4.42
(s, ~enæylic methylene) and 7.20 (s, PhH).
3~i38
- 167-
PREPARATION L
.. .
(R)-l-Bromo-2-benzyloxy-4-
(l-me thyl-4-phenylbutoxy) benzene
A mixture o 21.8 g~ 578 mmole) o 3-benzyloxy-4-
bromophenol, 20.0 g. (82.6 mmole) of (S)-1-methyl-4-
phenylbutylmethane sulfonate and 25.2 g. (200 mmole)
of potassium carbonate in 100 ml. dimethylformamide
was heated at 85 C. for 13.5 hours. The reastion waæ
cooled and added to 500 ml. water-500 ml. ether. The
organic extract was washed with two 250 ml. portions of
water, dried over magnesium sulfate and evaporated to
an oil~ The crude oil was purified via column chroma-
tography on 750 g. of silica gel eluted with 10~ ether-
hexane to yield 23.9 g. (72%) of the title compound as
~n oil.
ta] 25 _ --11.39 (C = 1.1.37, CH3Cl)
IR (CHC13) 1574 cm 1,
HRMS (m/e) 426.1011 (M , Calc'd for C24H2502Br,
426.1012), 424, 280, 278, 104 and 91.
CDC13 1.22 (d, J=6Hz, methyl), 1.4-2 0 (m~
.60 (m, benzyJ.ic methylene), 4.24 (m, methine)~ 5.07
(s, benzylic methylene), 6. 30 (d, J=2Hz and 8H2, ArH),
6.~6 (d, J=2Hx, ~rH), 7.17 (S, PhH) and 7.35 (m, PhH)_
~3~
168-
RÆPARATION M
2-(3-Hydroxyphenyl)-2-methylpropanal
A mixture of 38.9 g. (0.153 mole) of 2-(3-benzyloxy-
phenyl)-2-methylpropanal, 20 g. 5% Pd/C/50% water, l.0
S sodium bicarbonate and 150 ml. ethanol was shaken over-
~iSht under SS psi o~ h~dro~en. The reaction was filtere~
through diatomaceous earth, the filter cake washed with
ethanol and -tha combined filtrate evaporated. The residue
was reduced as above ~or another 8 hours. Another l0 g.
portion of catalyst was added and the reaction continued
overnight. The reaction was work~d-up as above and
the residue purified via column chromatography on
500 g. of silica gel eluted with 25% ether-hexane to
yield l4 g. (56%~ of the title compound as an oil.
lS PMR (CDCl33 ~ l.42 (s, gem dimethyl), 6.36 (bs,
OH), 6.7-6.9 (m, ArH), 7.05-7.2 (m, ArH) and
9.62 (s, CHO).
3~3~
-169 -
PREPARATION N
~ .
2-13-(Tetrahydropyranyl-~-oxy)phenyl]-2-methylpropanal
To a 0C. solution cf 11.3 g. (0.0688 mole~ of 2-
(3-hydro~yphenyl)-2-methylpropanal and 11.1 ml. (0.122
S mole) of dihydropyran in 113 ml. dichloromethane was
added several crystals of p-toluenesulfonic acid mono-
nydrate. ~Fne reaction was stirred one hour at 0C.
and then added to 60 ml. saturated sodium bicarbonate -
460 ml. ether. The ether extract was washed once with
100 ml. saturated sodium chloride, dried over mag~esium
sulfate and evaporated to yield 15.3 g. (89%) of the
title compound as an oil.
IR (CHC13) 1727, 1603 and 1582 cm 1~
PMR (CDC13) ~ 1.48 (s, gem dimethyl), 1.5-2.1 (m),
lS 3.~ .2 (m), 5.37 tm, methine), 6.7-7.4 (m,
ArH) and 9.53 (s, CHO).
3~
-1~70
PREPARA~ION O
_
1,1-Dimethyl-1-[3-(tetrahydropyranyl-2-oxy)
phenyl]-cis-2-heptene
To a 15C. solution of 75.5 mmole of dimsyl
sodium (from sodium hydride and dimethyl sulfoxide) in
94 ml~ dimethyl sul~id~ ~as added por~ionwise~
31.2 g. (75,5 mmole) of n-pentyltriphenylphosphonium
bromide~ The resultant slurry was stirred 30 minutes
and the 15.3 gq (61.6 mmole) of ~-~3-(tetrahydro-
pyranyl-2-oxy)phenyl]-2-methylpropanal was added o~er
15 minutes. The reaction mixture was stirred 50
minutes at 15C. and then added t~ 803 ml. ice -
800 mlO ether. The aqueous phase was extracted twice
with 400 ml. of ether. The combined ether extract was
~a~hed once with 250 ml.,water and once with 250 mlq
saturated sodium chloride, dried over magnesium sul-
fate and evaporated ~o yield an oil. Triph nylphos-
phine oxide was remov~d by crystalli7ation from
pentane. The remaining oily residue was purified via
-column chromatography on 1 kg. of silica gel eluted
with Oq7S~ ether-hPxane to yield 17.7 g. (95~) o~ the
title compound as an oil.
~R (CHC13) 1603 and 1581 cm lq
PMR (CDC13~ ~ 0.76 (m, terminal CH3), 1.20 (s, gem
dimethyl)~ 3.3~4.1 (m), 4.9-5.4 (m, 2H), 5.56
(d, Jal2Hz) and 6.6-7.3 (m, ArH).
3538
- 171-
P~EPAR~TION P
Trans-3-methyl-4-(2-propenyl)cyclohexanone
q'o a 0C. solution of 0.282 mole of dimethyl
copper lithium in 200 ml. of tetrahydrofuran was
slowly added a solution of 25.6 g. (0.188 mole) of 4-
~2~propenyl)cyclohe,Y ~-en-l-one in ~0 ml. ~f tetr~-
~ydrofuran~ The reaction was stirred 15 minutes and
then ~uenched by addi~ion to a 0C~ saturated soLution
(500 ml.) o ammonium ~hloride. The quenched reac-tion
was ex~racted with 500 ml. ether. The ether extract
was washed with 500 ml. saturated ammonium chloride,
dried over magnesium sulfate and evaporated to an oil
which was purified v.ia distillation to yield 15.5 g.
(55%~ of the title compound.
BP 110-113C. (15 torr)
~R (CHC13) 1710 and 1640 rm 1.
MS (m/e) 152 (M ), 136, 110.
Analysis:
~alcd. for CloH16O: C, 78.89; H, 10.5g.
Found : C~ 78.76; H, 10.24.
P~R (CDC13) ~ 1.05 (d, J=6Hz, methyl), 1.0-3.0 (m),
4,8-5.3 (m, vinyl H) and 5.4-6.1 (m, vinyl H).
SimiliarLy, trans-3-methyl-4-(2-propenyl)cyclo-
heptanone is produced ~rom 4-(2-propenyl)cyclohept-2-
25 en-L-one.
33~31~
_172 _
PREPARATION Q
5-Methyl-4-~2-propenyl)-2-phenylsulfenyl
cyclohexanone
, . . .. . _
To a 0C. mixture of 16.9 g. (0.109 mole) of
methyl benzen~sulfinate and 8.68 g. (0.217 mole~ of
potassium hydride in 100 ml. of dimethoxyethane was
slowly added a solution of 15.0 g. (0.0987 mole) of
trans-3-methyl-4~(2-propenyl)cyclohexanone in 50 ml.
of dimethoxyethaneO The reaction was stirred 30
minutes longer at 0C. and then cautiously added to
500 ml. of ice-satuxated sodium chloride and 45 mlO 6N
hydrochloric acid. The quenched xeaction mixture was
extracted once with 300 ml. ether and once with
200 ml. dichloromethane. The organic extract was
LS dried over magnesium sulfate and evaporated to give a
quantitative yield of the title compound as a semisolid
mix~ure of axial and equatorial sulfenates. Crystal-
liæation from ether yields 7.8 g. of pure axial sul-
fenate~
Axial Sulfenate~
PMR (CDCl3) C 1.05 (d, J=5Xz, methyl), 1~0-
1~
2.7 (m), 3.39 (dd, J=ll and 6Hz, CHS),
4.7-5.2 (m, vinyl H), 5.3-6.1 (m, vinyl
H) and 7.4 (m, PhH).
In like manner, 3-methyl-4-(Z-propenyl)cyclohept
2~en-1-one is converted to 5 methyl-4-(Z-propenyl) 2-
phen~lsulfenylcycloheptanone.
35i3~
- 173-
PREPARATION R
1'rans-5-methyl-4-(2-propenyl)cyclohex-2-en~l-one
_ _ _ _ ~ _
~ mi,Yture of 96.7 mmole of 5-methyl-4-~2-propenyl)-
2-phenylsulfenylcyclohexanone and lO g. (lOO mmole) of
calci~un carbonate in 300 ml. o~ t~luene was heated at
llOC_ F4r 40 ~in~l~es. The reaction ~ _oo'.~,
magnesium sulfate added and filtered. The filtrate
was evaporated and the residue purified via column
chromatography on 300 g. of silica gel eluted with 20
ether-hexane and then distillation to yield 7.61 g.
(52%) of the title compound.
BP 50C. (0.03 torr).
PMR (CDCl3) ~ l.ll (d, J=6Hz, CH3), 1.3-2.9 (m),
4.g-5.3 (m, vinyl H), 5.3-6.2 (m, v.inyl H),
5.95 (bd, J=lOHz, C 2 H) and 6.80 (bd, J-lOHz,
C~3 H).
By means of this procedure~ 5-methyl-~-(2-propenyl)-
2-phenylsulfenylcyclohep~anone is converted to tra_s-
5-meth~yl-4-(2-pr.openyl)cyclohept-2-en-l-one.
~353~
-~4 -
PREPARATION S
3-~2-Benzyloxy~ dimethylheptyl)phenyl]-
cyclohex-3-en-1-on~ ethylene ketal
A solution of 500 mg. of 3-[2-benzyloxy~4~(1,1-
dimethylheptyl)phenyl~cyclohex-2-en-1-one, 7.8 g. of
ethylene glycol, 375 mg. of hydroquinone and 50 m~. of
p-toluenesulfonic acid monohydrate in 50 ml. of
benzene is heated at rerlux for 12 hours using a Dean-
Star.~ condensor filled with 3A molecular sieves. The
reaction is cooled, added to 500 ml. saturated sodium
bicarbonate and the quenched mixture extracted with
three 150 ml. portions of ether, dried over magnesium
sulfate and evaporated to a solid. This solid is
puxi~ied via column chromatography on 50 g. of silica
gel eluted with 50% ether-petroleum ether to yield the
title product~
Similarly, 3-[2-benzyloxy-4-(1,1-dimethylheptyl)-
phenyl]cyclohept:-3-en-1-one ethylene ketal is prepared
~rom 3-[2-benzyloxy=~-(1,1-dimethylheptyl)phenyl]-
cy_lohept-2-en-1-one.
3~ii3~
- 175-
PREPARATION T
3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
- cyclohex-2-enone
A solution of 3.89 g~ (10 mmoles) of 2-(3-henzyl-
oxy-4-~romophenyl)-2-methyloctane in 10 ~1. of tetra-
hydrofuran was slowly added to 360 mg~ ~14.4 mmoles)
of 70-80 mesh magnesium metal. The resulting mixture
was refluxed for 30 minutes and then cooled to 0C.
To this solution was slowly added a solution of 1.~0 ~O
(10 mmoles~ of 3-ethoxy-2-cyclohexen-1-one in 3 ml. of
tetrahydro~uran. The reaction mixture was stirred for
30 minutes at 0C. and then quenched by the addition
of 20 ml. of lN sulfuric acid and heating on the steam
bath ~or 30 minutesO It was then cooled and added to
200 mL. of ether - 200 ml. of water. The organic
extract was washed successively with 200 ml. of satu-
rated sodium bicarbonate and 200 ml. o~ satuxated
sodium chloride, dried over magnesium sulfate and
evaporated to an oil. The crude product was purified
~ia column chromatography on 170 g. of silica gel
eluted with 1 1 ether:pentane to yield 2.5 g. (54%) of
the title compound as an oil.
IR (CHC13) 1667, 1610 and 1558 cm 1
MS (m/e) 404 tM ), 319, 313 and 91.
In liXe manner, 3-~2-~enzyloxy-4-(1,1-dimethyl-
heptyl)pllenyl]cyclohepten-2-enone is prepared from 3-
ethoxy-2-cyclohepten-1-one.
33~
_ 176_
PREPARATION U
~-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl~-
cYclohept-3-en-1-one
.... , _ . ..................... . ~
To a 0CO slurry of 2.19 g. (0.055 mole) of
potassium hydride in 20 ml. of dimethoxyethane is
added 4.32 g. ~0.02~ -rl~ie3 ~ m~i~yi pnenyisuirinate.
To the resultant mixture is added~ dropwise over a 30
minute period, a solution of 9~82 g. (0.024 mole) of
3-[2-benzyloxy-~-(1,1-d~methylheptyl)phenyl]cyclo-
hep~anone in 20 ml. of dimethoxyethane. The reactionis stirred one hour at 0C. and then quenched by
dropwise addition of 1 ml. of water. The quenched
reaction mixture is added to 15 ml ether - 15 ml.
dichloromethane - 12O5 ml. 6N HCl-40 ml. saturated
lS sodium chloride. The aqueous phase is extracted with
another 15 ml. portion of dichloromethane. The com-
bined organic e~tract is dried over magnesium sulfa~e
and evaporated to a semisolid. It is used as is in
the next step.
The crude product thus obtai~ed i5 mixed with
2.68 g. (0.0268 mole) of calcium carbonate in 100 ml.
of toluene and heated at 110C. for 30 minutes. The
xeaction mixture is cooled, filtered through magnesium
sulfate and the filtrate evaporated on a rotovapor to
yield an oil which was purified via column chroma-
tography on 500 g. of silica gel eluted with 39%
ether-hexane to yield the title compound.
