Note: Descriptions are shown in the official language in which they were submitted.
PF 0000056345/Wa CA 02596998 2007-08-06
as originally filed
Selective splitting of substituted bisbenzylamides and bisbenzylamines
Description
The present invention relates to a process for the regioselective cleavage of
secondary
amines or amides to give primary amines.
1n prim~ni nmin'+r~ are important 'n~por~ aan~ a s~d<<i~~y ar...a=.__ cvt
.. ,,,,,.u~y u~~~~~~~~ iipuunds or intermediates for industrial
chemistry. A number of reactions are available for producing amines. Examples
are the
Hofmann alkylation, the reductive amination of carbonyl compounds, the
reduction of
nitro compounds and the Gabriel synthesis.
Chiral amines in optically active form are of particular interest, since they
can be used
as intermediates in many processes for producing drugs or crop protection
agents.
There is therefore great interest in the preparation of, in particular,
optically active
amines.
E. Lee-Ruff, F. J. Ablenos, Can. J. Chem., 1989, pages 699 to 702, disclose
the
selective oxidation of electron-rich aromatics according to the following
reaction
scheme. Here, a charge transfer complex between the electron-poor 2,3-dichloro-
5,6-cyano-1,4-benzoquinone (DDQ) and the electron-rich substrate is formed in
a first
reaction step, with the resulting cationic species being able to be reacted
with a
nucleophile:
H O OH
I\ + NC CI \ C\ NC CI
Donor / NCI ICI Donor I~ +NC CI
O
Nu-
Nu
Donor
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2
R. Daniel Little, Kevin D. Moeller, The Electrochemical Society Interface,
Winter 2002,
pages 36 to 41, disclose the electrochemical anodic oxidation of uncharged
compounds of the general formula (I)
R1 -1 lr~ R
X
Y /~ R 2
(I).
Here, a reactive cation radical (ll) is firstly formed as intermediate and is
converted by
further elimination into a second cationic intermediate (III). The cationic
intermediale
(III) is subsequenily reacted with a nucleophile, for example methanol. The
n2t result is
that this substituent Y in the compound (I) is replaced by a nucleophilic
radical:
3 R R 3 , 3
R
RX~ R anodic oxidation X/ ~ RX+
Y~ Rz -e' Y R2 -e Ra
(III)
(lI)
NucH -H-F
r
3
RX4, R
Nuc" \R2
Examples of compounds which can be oxidized by the process described above are
imI-acetylated arnides of the general formula (IV), which are converted by
anodic
oxidation and subsequent reaction with the nucleophile methanol into N-
acetylated
aminals of the general formula (V):
0 H 0 O
RNR R4)t' N'JI-, R
PS
(!V) (V)
The preparation of amines by regioselective cleavage of N-acetylated amides by
means of electrochemical oxidation or wet chemical oxidation by 2,3-dichloro-
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5,6-dicyano-1,4-benzoquinone and subsequent further reaction, for example with
a
nucleophile, is not known.
The present invention therefore preferably has the object of providing a
process for
preparing primary amines from secondary amines or amides by electrochemical
anodic
oxidation. The process of the invention should preferably proceed with
retention of the
optical activity when optically active starting materials are used, so that
the
diastereomeric purity of the starting material can be carried over to the
product.
The achievement of this object starts out from a process for the
regioselective cleavage
of secondar y an-iiiies or dr-iides.
The process of the invention then comprises, in a first embodiment, the
following
process steps:
(a') provision of at least one secondary bisbenzylamine or bisbenzylamide
having at
least one benzylic hydrogen atom in a solvent;
(b') electrochemical oxidation of the secondary amine or amide in the presence
of an
electrolyte salt and reaction of the electrolysis intermediate with a
nucleophile,
giving an electrolysis product mixture;
(c') work-up of the electrolysis product mixture;
(d') hydrolysis of the workup electrolysis product mixture.
Primary amines can be prepared in an efficient manner by means of the process
of the
invention.
In the first process step of the process of the invention, at least one
bisbenzylamine or
bisbenzylamide having at least one benzylic hydrogen atom in a solvent is
provided.
The amine or amide used in the process of the invention is, for example, a
bisbenzylamine of the general formula (VI) or a bisbenzylamide of the general
formula (VII):
R 8 R 10
R~ R11
Ar 1 N ~< Ar 2
R9
VII
where R', R8, RiO, R11 are identical or different and are each H or C1-C5-
alkyl and
R9 = H (VI) or R9 = acyl (VII), with the bisbenzylamine or bisbenzylamide
having at
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least one benzylic hydrogen atom so that at least R' or R8 or R10 or R" is
hydrogen.
As secondary amine, preference is given to using a bisberrzylamine in which
the
unsubstituted nitrogen function of the bisbenzylamine is provided with a
protective
group. The protective group is preferably selected from the group consisting
of acyl
groups, sulfone groups, phosphoryl groups and silyl groups. If an acyl group
is used as
protective group, the abovementioned bisbenzylamides of the general formula
(VII) are
used as starting materials.
In addition, preference is given to at least one of the benzy! rings of the
bisr~Jei ~ylai i iineS or blSbei ~zylai t iides beirig substituted, with
further preference being
given to the at least one substituted benzyl ring being substituted by an
electron-
pushing substituent. For the purposes of the present invention, an electron-
pushing
substituent is a substituent which exerts a+I effect and/or a +M Effect on the
benzyl
ring.
The electron-pushing substituent is preferably selected from the group
consisting of
alkoxy groups, alkyl groups, thiolalkyl groups and halogens, with the alkyl
groups
preferably being selected from the group consisting of C,-C5-alkyls.
If an alkoxy group is used as electron-pushing substituent, it is preferably
selected from
the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-
butoxy
groups.
The second benzyl radical of the bisbenzylamines or bisbenzylamides is
preferably
either unsubstituted or substituted by an electron-pulling group. For the
purposes of the
present invention, an electron-pulling substituent is a substituent which
exerts a
-I effect and/or -M effect on the phenyl ring. Examples of suitable electron-
pulling
substituents are selected from the group consisting of cyano groups, nitro
groups, ester
groups and the halides fluorine, chlorine, bromine and iodine.
The classification of aromatic substituents into substituents having a+I and -
1 effect or
a +M effect and -M effect is known per se to those skilled in the art. Further
details may
be found in Beyer/Walter, "Lehrbuch der Organischen Chemie", 1998, 23rd
revised and
updated edition, pages 515-518, whose disclosure on the subject is
incorporated by
reference into the present invention.
In process step (a'), the secondary amine or amide is provided in a solvent.
In a
particularly preferred embodiment, the solvent is an organic solvent,
preferably an
organic nucleophilic solvent. Further preference is given to the solvent being
selected
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from the group consisting of protic polar solvents such as alcohols, aliphatic
carboxylic
acids such as acetic acid and water.
If an alcohol is used as solverit, it is, for example, methanol, ethanol, n-
or i-propanol or
butanols. Preference is given to methanol.
5
In a further embodiment of the present invention, mixtures of the
abovementioned
solvents can also be used.
If appropriate, customary cosolvents are added to the electrolysis solution.
These are
the inert solvents having a high oxidation potential which are generally
customary in
organic chemistry. Examples which may be mentioned are dimethyl carbonate,
propylene carbonate, ethylene carbonate, tetrahydrofuran, dimethoxyethane,
dichloromethane, trichioromethane, tetrachloromethane and acetonitrile.
In process step (b'), an electrochemical oxidation of the secondary amine or
amide and
a reaction of the electrolysis intermediate with a nucleophile take place,
giving an
electrolysis product mixture.
An electrolyte salt is necessary as depolarizer for the electrochemical
oxidation, and
this is added to the solution provided in process step (a').
Electrolyte salts present in the electrolysis solution are generally alkali
metal salts,
alkaline earth metal salts, tetra(C,-C6-alkyl)ammonium salts, preferably
tri(C,-C6-alkyl)-
methylammonium salts. Possible counterions are sulfate, hydrogensulfate, alkyl
sulfates, aryl sulfates, halides, phosphates, carbonates, alkyl phosphates,
alkyl
carbonates, nitrate, alkoxides, tetraflLjoroboratP, ..r.~ ~.,.~r~ ~uw v hexa
fI~õi~rnnhncnh~+., ~., N. ......~ci ~a 4.nlv.....+..i aic
...
Furthermore, the acids derived from the abovementioned anions are also
possible as
electrolyte salts.
In addition, ionic liquids are also suitable as electrolyte salts. Suitable
ionic liquids are
described in "Ionic Liquids in Synthesis", edited by Peter Wasserscheid, Tom
Welton,
Verlag Wiley VCH, 2003, chapters 1 to 3, and in DE-A-10 2004 011427.
In particular, strong mineral acids and sulfonic acids are suitable as
electrolyte salts for
the purposes of the present invention. Examples are H2SO4, H3PO4.
methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid. For the purposes of the
present
invention, the use of H2SO4 is particularly preferred.
The concentration of the electrolyte salt is generally 0.0001 - 5 mol/l,
preferably 0.001 -
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1 mol/l, particularly preferably 0.001 - 0.1 mol/l, very particularly
preferably 0.005 -
0.05 mol/l.
The process conditions for electrochemical oxidation in respect of
temperature,
electrolysis time, current and concentration of the secondary amines or amides
are
dependent on the starting material used, in particular bisbenzylamine or
bisbenzylamide, and on the solvent used.
The electrolysis is carried out in customary electrolysis cells known to those
skilled in
i u the art. Suitable electrolysis cells are known to those skilled in the
art. The electrolysis
is preferably carried out continuously using undivided flow cells or batchwise
in glass
beaker cells at reaction volumes of < 100 ml.
Very particularly useful cells are bipolar capillary cells or plate stack
cells in which the
electrodes are configured as plates and are arranged parallel to one another
(cf. Ullmann's Encyclopedia of Industrial Chemistry, 1999 electronic release,
sixth
edition, VCH-Verlag Weinheim, Volume Electrochemistry, chapter 3.5. special
cell
designs and chapter 5, Organic Electrochemistry, subchapter 5.4.3.2 Cell
Design).
The current densities at which the process is carried out are generally from 1
to
1000 mA/cm2, preferably from 10 to 100 mA/cm2. The temperatures are usually
from
-20 to 60 C, preferably from 10 to 60 C. The process is generally carried out
at
atmospheric pressure. Higher pressures are preferably employed when the
process is
to be carried out at relatively high temperatures, so as to avoid boiling of
the starting
compounds or cosolvents.
Suitable anode materials are, for example, graphite, carbon, noble metals such
as
platinum, metal oxides such as ruthenium oxide or chromium oxide, mixed oxides
of
the type RuOxTiOX and diamond electrodes. Preference is given to graphite or
carbon
electrodes.
Possible cathode materials are, for example, iron, steel, stainless steel,
nickel, noble
metals such as platinum, graphite, carbon materials and diamond electrodes.
Preference is given to the systems graphite as anode and cathode, graphite as
anode
and nickel, stainless steel or steel as cathode and platinum as anode and
cathode.
Furthermore, the electrochemical oxidation is carried out until the
benzylamide used as
starting material has completely reacted or most of it has reacted. For the
purposes of
the present invention, the term "mostly reacted" means a conversion of
preferably more
than 90%. The progress of the reaction is monitored by means of customary
laboratory
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methods (e.g. gas chromatography or thin layer chromatography). A multiple of
the
theoretical amount of charge of 2 F/mol of amide can often be necessary to
achieve
complete conversion.
Furthermore, the concentration of the starting material to be oxidized in the
solution to
be electrolyzed is preferably from 0.00001 to 5 mol/l, particularly preferably
from
0.0001 to 3 mol/l, in particular from 0.001 to 2 mol/l.
The electrochemical oxidation provided in process step (b') results in
oxidation of the
nitrogen function of the secondary amine or amide and formation of a radical
cation.
The electrochemical oxidatiori preferably occurs on the side of the amine or
amide on
which the more stable radical is formed. This is the side of the secondary
amine or
amide at which the benzyl ring having the electron-pushing substituent is
located. The
regioselectivity is achieved, in particular, in the case of substrates having
alkoxy,
thioalkyl or alkyl groups.
In process step (b'), a reaction of the electrolysis intermediate with a
nucleophile
occurs immediately after the electrochemical oxidation.
The electrolysis product mixture is preferably reacted with a nucleophile
selected from
the group consisting of methanol, acetic acid and water.
The nucleophile used is preferably the solvent used in process step (a'), so
that
addition of a further nucleophile can be dispensed with.
The process of the invention in a first embodiment is preferably suitable for
the
electrochemical oxidation of optically active, i.e. diastereomeric,
bisbenzylamines or
bisbenzylamides, since the stereochemical purity of the resulting product is
not
significantly changed by the electrochemical oxidation. For the purposes of
the present
invention, "not significantly changed" means that the optical purity of the
product differs
from the optical purity of the starting material by not more than 10%,
particularly
preferably not more than 5%, in particular not more than 3%.
A work-up of the electrolysis product mixture is carried out in process step
(c').
Here, the electrolysis product mixture resulting from process step (b') is
preferably
worked up by means of the following process steps:
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(c'1) removal of the solvent and addition of water, an organic solvent
selected from the
group consisting of dichloromethane; chloroform; ethers such as diethyl ether,
tert-butyl methyl ether; esters such as ethyl acetate; hydrocarbons such as
toluene, xylene or cyclohexane and an acid;
(c'2) extraction of the mixture resulting from process step (c'l) with an
organic solvent
selected from the group consisting of dichloromethane; chloroform; ethers such
as diethyl ether, tert-butyl methyl ether; esters such as ethyl acetate;
hydrocarbons such as toluene, xylene or cyclohexane;
(c'3) drying of the resulting organic phases;
(c'4) removal of the oraanic solvent.
Any suitable acid can be used in process step (c'1). Suitable acids are known
to those
skilled in the art. Examples are hydrochloric acid, sulfuric acid, phosphoric
acid and
nitric acid. Preference is given to using 10% strength hydrochloric acid.
Drying of the organic phases in process step (c'3) is carried out, for
example, over
sodium carbonate or sodium sulfate. As an alternative, it is also possible to
use all
further customary desiccants.
In process step (c'4), the organic solvent is preferably removed by
distillation.
In process step (d'), the electrolysis product mixture which has been worked
up is
hydrolyzed.
The hydrolysis of the electrolysis product mixture which has been worked up is
preferably effected using a mixture of sodium hydroxide solution or potassium
hydroxide solution and triethanolamine. The use of 50% strength sodium or
potassium
hydroxide solution is preferred. Here, the content of 50% strength sodium
hydroxide
solution in the mixture is preferably from 10 to 50% by weight, particularly
preferably
from 20 to 40% by weight, in particular from 25 to 35% by weight. The content
of
triethanolamine in the mixture is preferably from 10 to 50% by weight,
particularly
preferably from 20 to 40% by weight, in particular from 25 to 35% by weight.
The
primary amine is formed in the hydrolysis.
In a second embodiment, the present invention provides a "wet chemical"
process for
the regioselective cleavage of secondary amines or amides.
The process of'the invention in this second embodiment then comprises the
following
process steps:
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(a") provision of at least one secondary bisbenzylamine or bisbenzylamide
having at
least one benzylic hydrogen atom in a solvent, with the solvent optionally
comprising a nucleophile; I
(b") oxidation of the secondary amine or amide by means of 2,3-dichloro-5,6-
dicyano-
1,4-benzoquinone (DDQ), giving an oxidation product mixture;
(c") reaction of the oxidation product mixture with a nucleophile.
In process step (a"), at least one secondary amine or amide in a solvent is
provided,
with the solvent optionally comprising a nucleophile.
As regards the starting materials to be used, viz. secondary amine or amide,
reference
is made to what has been said above in respect of the first embodiment of the
process
of the invention. However, preference is given to at least one benzyl ring of
the
bisbenzylamines or bisbenzylamides which are preferably used as starting
materials
bearing an alkoxy substituent. Particular preference is given to the aikoxy
substituent
being selected from the group consisting of methoxy, ethoxy, propoxy,
isopropoxy,
butoxy and tert-butoxy.
The solvent used in process step (a") is preferably selected from the group
consisting
of dichloromethane, chloroform; 1,2-dichloroethane, tert-butyl methyl ether,
acetonitrile,
toluene and xylene.
Preference is also given to the solvent being used in admixture with a
nucleophile such
as water, for example distilled water, an alcohol, for example methanol,
ethanol,
n-propanol, i-propanol or butanol. Suitable mixtures are, for example,
mixtures of
1,2-dichloroethane with water in a ratio of from 100:1 to 1:1, particufarly
preferablv from
20:1 to 5:1, in particular from 12:1 to 8:1.
Process step (b") comprises the oxidation of the secondary amine or amide by
means
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), giving an oxidation
product
mixture. The oxidation provided in process step (b") of the secondary amine or
amide
is preferably carried out by adding DDQ to the starting material to be
oxidized, which is
present in the above-described solvent, if appropriate in the presence of a
nucleophile.
The oxidation is preferably carried out with stirring at a temperature of from
-10 C to
150 C, particularly preferably from 20 to 100 C, in particular from 60 to 90
C. The
reaction time under these preferred conditions is preferably from 0.2 to 24
hours,
particularly preferably from 1 to 12 hours, in particutar from 5 to 10 hours.
In process step (c"), the oxidation product mixture is reacted with a
nucleophile. This is
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effected by addition of the optionally dissolved nucleophile to the oxidation
product
mixture.
Suitable nucleophiles are, for example, water, alcohols such as methanol,
ethanol or
5 propanol.
As mentioned above, the amine or amide to be oxidized can be provided in a
solvent in
admixture with a nucleophile in process step (a"). As a result, the oxidized
amine or
amide reacts immediately with the nucleophile present after it has been
oxidized in
10 process step (b"), so that further addition of the nucleophile can be
dispensed with.
The product resulting from process step (c") can, for example, be worked up by
washing with saturated sodium carbonate solution and/or saturated sodium
chloride
solution, extraction of the resulting aqueous phases with an organic solvent,
drying of
the combined organic phases, for example over sodium sulfate, and
concentration, for
example under reduced pressure.
The second embodiment of the process of the invention also leads to
regioselective
cleavage of the secondary amines or amides used as starting materials. Thus,
the
regioselective oxidation in the second embodiment of the process of the
invention
occurs on the more electron-rich benzyl ring.
This second embodiment of the process of the invention is therefore likewise
suitable
for the electrochemical oxidation of optically active, i.e. diastereomeric,
bisbenzylamines or bisbenzylamides, since the stereochemical purity of the
resulting
products is not siqnificantlv chanqed bv the oxidation bv means of DDQ. For
the
purposes of the present invention, "not significantly changed" means that the
optical
purity of the product differs from the optical purity of the starting material
by not more
than 10%, particularly preferably not more than 5%, in particular not more
than 2%.
The present invention further provides for the use of 2,3-dichloro-5,6-
benzoquinone for
the regioselective oxidation of secondary bisbenzylamines or bisbenzylamides
having
at least one benzylic hydrogen atom.
The secondary bisbenzylamides used as starting material in the process of the
invention in its first and second embodiments can, for example, be prepared by
reacting secondary bisbenzylamines with acetic anhydride.
Here, particular mention may be made of the following process steps:
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(1) addition of acetic anhydride to the secondary amine or addition of the
secondary
amine to acetic anhydride, resulting in a reaction mixture I;
(2) stirring of the resulting reaction mixture I for a period of preferably
from 0.5 to
24 hours, particularly preferably from 1 to 15 hours, in particular from 1 to
2 hours, resulting in a reaction mixture II;
(3) hydrolysis of the reaction mixture II resulting from process step (2) and
extraction
of the resulting aqueous solution with an organic solvent, resulting in an
organic
phase;
(4) if appropriate, removal of acetic anhydride present in the organic phase.
The addition of acetic anhydride to the secondary amine can be carried out at
a
temperature of preferably from 0 to 100 C; particularly preferably from 10 to
50 C, in
particular from 20 to 30 C.
The resulting reaction mixture I is stirred at a temperature of preferably
from 0 to
150 C, particularly preferably from 50 to 120 C, in particular from 80 to 100
C.
The removal of acetic anhydride present in the organic phase can, for example,
be
effected by addition of a base, with the base preferably being present in an
aqueous
solution. The base can be, for example, sodium carbonate.
If appropriate, the process step (3) or, if appropriate, the process step (4)
can be
followed by the following process steps (5) and (6):
(5) treatment of the organic phase while stirring with a mixture of an organic
solvent
selected from the group consistinq of ethers and optionallv halonenatPd
hydrocarbons and water for a period of preferably from 0.1 to 24 hours,
particularly preferably from 0.5 to 4 hours, in particular from 0.5 to 2
hours, and
(6) separation of the organic and aqueous phases, if appropriate multiple
shaking of
the aqueous phase with an organic solvent, drying of the combined organic
phases and removal of the organic solvent.
The present invention further provides for the use of 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone for the regioselective oxidation of secondary bisbenzylamines
or
bisbenzylamides having at least one benzylic hydrogen atom.
The present invention is illustrated by the following examples which do not,
however,
restrict the scope of the present invention.
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Examples:
1. General procedure for the preparation of secondary amides
5.5 ml of acetic anhydride are added dropwise to 23.5 mmol of the amine at
room
temperature. 20 minutes after the addition is complete, the temperature is
increased to
90 C for a period of 30 minutes while stirring. The solution is poured into 20
ml of cold
water, admixed with 20 ml of ether and the resulting phases are separated. The
combined extracts are dried over Na2SO4 and concentrated under reduced
pressure.
To remove the unreacted acetic anhydride, 10 ml of a saturated aqueous
solution of
Na2CO3 are added to the unpurified reaction product. The resulting mixture is
then
admixed with 15 ml of ether and 10 ml of water, stirred for 30 minutes and the
resulting
aqueous phase is extracted a number of times with ether (3 = 15 ml). The
combined
extracts are dried over Na2SO4 and concentrated under reduced pressure.
The diastereomeric purity is determined by means of gas chromatography.
a) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide
R,R isomer: 92.7% R,S isomer: 7.3%
b) N-[1-(2-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide
R,R isomer: 96.0% R,S isomer: 4.0%
'H-NMR (400 MHz, CDCI3):
S= 1.6 (3H, m); 1.8 (3H, m); 2.4 (3H, s); 3.7 (3H, s); 4.2 (1 H, q); 5.4 (1 H,
q); 6.4 - 7.4
(9H, aromatic).
c) N-[1-Phenylethyl]-N-(1-o-tolylethyl)acetamide
R,R isomer: 87.0% R,S isomer: 13.0%
'H-NMR (400 MHz, CDCI3):
8= 1.4 - 1.6 (6H, m); 1.8 (3H, m); 2.4 (3H, s); 4.1 (1 H, q); 4.2 (1 H, q);
6.5 - 7.5 (9H,
aromatic).
d) N-[1-(2,4-Dimethoxyphenyl)ethyl](1-phenylethyl)acetamide
R,R isomer: 96.6% R,S isomer: 3.4%
'H-NMR (400 MHz, CDC13):
S= 1.6 (3H, m); 1.8 (3H, m); 2.3 (3H, s); 3.6 (3H, s); 4.3 (1 H, q); 5.3 (1 H,
q); 6.3 - 7.4
(8H, aromatic).
e) N-[1-(4-Chlorophenyl)ethyl](1-phenylethyl)acetamide
Rt (silica gel): 0.44 (ethyl acetate : cyclohexane = 1:1)
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f) N-[1-Phenylethyl]-N-(1-p-tolylethyl)acetamide
S,S isomer: 87.5% S,R isomer: 12.5%
'H-NMR (400 MHz, CDCI3):
8= 1.6 - 1.7 (6H, d); 1.9 (3H, s); 2.3 (3H, s); 4.8 (1 H, br); 5.8 (1 H, br);
6.8 - 7.5 (9H,
aromatic).
g) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-pyridin-3-yl-ethyl)acetamide
R,R isomer: 88.0% R,S isomer: 12.0%
2. Electrochemical oxidation
8.4 mmol of the amide prepared under 1.) are dissolved in 47 g of methanol,
admixed
with 0.5 g of concentrated sulfuric acid (96%) and transferred to an undivided
glass
beaker cell provided with two graphite electrodes (20 x 70 mm, immersion
depth:
50 mm, type: MKUS F04, manufactured by SGL Carbon, Meitingen, Germany) at a
spacing of 10 mm. The mixture is heated to 40 C while stirring and
electrolyzed at a
current density of 34 mA/cm2 until most of the amide has reacted (1.0-4.5
hours
corresponding to from about 2 F/mol of amide to about 16 F/mol of amide,
corresponding to from about 100% to 800% of the theoretical amount of charge
required). The methanol is removed under reduced pressure and the residue is
admixed with 25 ml of water, 50 ml of dichloromethane and 10 ml of 10%
strength
hydrochloric acid. The aqueous phase is extracted a number of times with
dichloromethane (3 = 20 ml). The combined extracts are dried over Na2SO4 and
the
solvent is removed. The crude yield of amide is 80%.
12 mmol of triethanolamine and 22.5 mmol of 50% strength NaOH are added to
6.7 mmol of the amide mixture and the resulting mixture is stirred at 120 C
for 3 hours.
20 ml of ether and 15 ml of water are added to the mixture. The aqueous phase
is
extracted with ether (3 = 15 ml). The combined extracts are dried over Na2SO4,
the
solvent is removed under reduced pressure and the residue is examined by GC
and
'H-NMR.
a) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr = 93:7)
77.5% of N-1-phenylethylacetamide
10.9% of p-methoxyacetophenone
11.6% of 1-methoxy-4-(1-methoxyethyl)benzene
1H-NMR (400 MHz, CDCI3):
S= 1.4 (3H, d); 1.5 (3H, d); 2.0 (3H, s); 2.6 (3H, s); 3.8 (3H, s); 3.9 (3H,
s); 4.2 (1 H, q);
5.2 (1 H, q); 5.7 (1 H, br); 6.9 - 8.0 (13H, aromatic).
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14
Optical purity:
92% of R-1-phenylethylamine
8% of S-1-phenylethylamine
b) N-[1-(2-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr = 87:13)
100% of N-1-phenylethylacetamide
'H-NMR (400 MHz, CDCI3):
8= 1.35 (3H, m); 2.0 (3H, s); 5.1 (1 H, q); 5.8 (1 H, br); 7.2 - 7.3 (5H,
aromatic).
c) N-[1-Phenylethyl]-N-(1-o-tolylethyl)acetamide (dr: 87:13)
65% of 1 -phenylethylamine
35% of 1-p-tolyiethylamine
'H-NMR (400 MHz, CDCI3):
8= 1.3 (6H, m); 1.6 (4H, br); 2.3 (3H, s); 4.2 (1 H, q); 4.4 (1 H, q); 7.1 -
7.5 (9H,
aromatic).
Optical purity:
89.3% of R-1-phenylethylamine
10.7% of S-1-phenylethylamine
d) N-[1-(2,4-Dimethoxyphenyl)ethyl](1-phenylethyl)acetamide
100% of 1-phenylethylamine
e) N-[1-(4-Chlorophenyl)ethyl](1-phenylethyl)acetamide
74.8% of 1-phenylethylamine
25.2% of 1-(4-chlorophenyl)ethylamine
'H-NMR (400 MHz, CDCI3):
8= 1.4 - 1.5 (6H, m); 1.6 (4H, br); 4.1 (2H, m); 7.2 - 7.4 (9H, aromatic).
f) N-[1-Phenylethyl]-N-(1-p-tolylethyl)acetamide (dr: 87.5:12.5)
90% of 1-phenylethylamine
10% of 1-p-tolylethylamine
'H-NMR (400 MHz, CDCI3):
8= 1.5 (3H, d); 2.0 (3H, s); 5.2 (1 H, q); 5.7 (1 H, br); 7.3 - 7.4 (5H,
aromatic).
Optical purity:
89.3% of R-1-phenylethylamine
10.7% of S-1-Phenylethylamine
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3. Oxidation by means of DDQ
1.8 g (6 mmol) of N-[1-(4-methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr:
82:18)
are dissolved in 20 ml of 1,2-dichloroethane : water/10:1 (v/v). 2.1 g (9
mmol) of
5 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resulting
mixture is
refluxed for 7 hours. The mixture is washed with 20 ml of a saturated Na2CO3
solution
and 15 ml of a saturated NaCI solution. The combined aqueous phases are
extracted a
number of times with 1,2-dichloroethane (3 x 15 ml). The combined organic
phases are
dried over Na2SO4 and concentrated under reduced pressure.
The residue consists of a mixture of N-1-phenylethylacetamide (37 GC-% by
area) and
4-methoxyacetophenone (63 GC-% by area). The optical purity of the N-1-
phenylethyl-
acetamide is:
R-N-1-phenylethylacetamide: 81.8%
S-N-1-phenylethylacetamide: 18.2%
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