SYNTHESIS OF VINYL ETHERS, METHODS AND REAGENTS RELATED THERETO

SYNTHESE D'ETHERS D'ARYLE, PROCEDES ET REACTIFS AFFERENTS

English Abstract

A method for preparing a vinyl ether compound is provided in which an alcohol
is
reacted with an alkene in the presence of a base, and a catalyst to form a
vinyl ether.

Claims

-60-
CLAIMS:
1. A method of preparing a vinyl ether, comprising: reacting an alcohol with
an
alkene comprising an activated substituent, X, in an aromatic hydrocarbon
solvent, in the
presence of a base and a catalyst selected from the group consisting of
complexes of
nickel, palladium and platinum; wherein X is bonded to a carbon of a carbon-
carbon
double bond comprised by the alkene; wherein X is a moiety whose conjugate
acid, HX,
has a pKa of less than 5.0; wherein said catalyst catalyzes the reaction; and
whereby a
vinyl ether is produced.
2. A method of preparing a vinyl ether, comprising: reacting an alkoxide salt
with an
alkene comprising an activated substituent, X, in an aromatic hydrocarbon
solvent, in the
presence of a catalyst selected from the group consisting of complexes of
nickel,
palladium, and platinum; wherein X is bonded to a carbon of a carbon-carbon
double bond
comprised by the alkene; wherein X is a moiety whose conjugate acid, HX, has a
pKa of
less than 5.0; wherein said catalyst catalyzes the reaction; and whereby a
vinyl ether is
produced.
3. A method of preparing a vinyl ether, comprising: reacting an alcohol with
an
alkene comprising an activated substituent, X, in the presence of a base and a
catalyst
comprising palladium and a chelating ligand; wherein X is bonded to a carbon
of a carbon-
carbon double bond comprised by the alkene; wherein X is a moiety whose
conjugate acid,
HX, has a pKa of less than 5.0; wherein said catalyst catalyzes the reaction;
and whereby a
vinyl ether is produced.
4. A method of preparing a vinyl ether, comprising: reacting an alkoxide salt
with an
alkene comprising an activated substituent, X, in the presence of a catalyst
comprising
palladium and a chelating ligand; wherein X is bonded to a carbon of a carbon-
carbon
double bond comprised by the alkene; wherein X is a moiety whose conjugate
acid, HX,
has a pKa of less than 5.0; wherein said catalyst catalyzes the reaction; and
whereby vinyl
ether is produced.

-61-
5. The method of claim 1 or 3, wherein a thiol or selenol is used in place of
the
alcohol.
6. The method of claim 2 or 4, wherein a salt of a thiol or a salt of a
selenol is used in
place of the alkoxide salt.

Description

... _1_,
Synthesis of Vinyl Ethers, Methods and Reagents Related Thereto
This application is a division of PCT International Application No.
PCT/L1S97/18719
bearing Canadian Application Serial No. 2,267,153 with the international
filing date of
October 10, 1997.
Iiackt=_round of the invention
The present invention relates to improved methods for preparing aryl ethers
which ..
are useful intermediates and end products in pharmaceutical and agricultural
applications. .
It has been recently reported that aryl bromides react with simple primary and
secondary amines in the presence of a palladium catalyst, supporting ligands
and
Na(O~Bu) (base) to form the corresponding arylamine in good yields. See, Guram
et al.
Angew. Chem. 34(12):1348 (1995).
Despite the recent successes with palladium-catalyzed cross-coupling reactions
of
Ar-X with amines, comparable coupling of aryl halides with alcohols remains
elusive, and
this in spite of its obvious utility in organic synthesis. Aryl ethers,
including oxygen
heterocycles, are prominent in a large number of pharmacologically important
molecules
and are found in numerous secondary metabolites.
I S Existing methods for the conversion of Ar-X to aryl ethers often require
harsh or
restrictive reaction conditions and/or the presence of activating groups on
the arene ring.
For example, the Cu(I)-catalyzed syntheses of aryl and vinyl ethers commonly
require
large amounts of freshly prepared sodium alkoxides and/or large excess of the
corresponding alcohol in order to achieve reasonable yields from the
corresponding aryl
halides and vinyl halides. See, Keegstra et al. Tetrahedron 48(17):3633
(1992).
Cramer and Coulson also reported limited success with the Ni(1I)-catalyzed
synthesis of diphenyl ether using sodium phenolate at reaction temperatures
greater than
200 'C. See, J. Org. Chem. 40(16):2267 (1975). Christau and Desmurs describe
the
nickel-catalyzed reactions of alcohols with aryl bromides in the presence of a
base. Good
yields (ca. 80%) were reported only for reactions with primary alcohols with 7
mol%
nickel catalyst at 125 'C. See, Ind. Chem Libr. 7:240 ( 1995). Christau and
Desmurs also
_ reported that synthesis of aryl ethers was possible only for primary and
secondary
alcohols. Houghton and Voyle reported the Rh(III)-catalyzed cyclization of 3-
(2
fluorophenyl)propanols to chromans activated by n-bonding to the metal center;
however,
the reaction required very high rhodium catalyst loading (17 mol%). See, J.
Chem. Soc.
Perkin Tra~zs. !, 925 (1984).
Ether formation has been reported as a minor side product in the palladium-
CA 02467977 2004-06-08

-2-
catalyzed carbonylation reactions of highly activated aromatic compound such
as a-
substituted quinolines. Because of the highly reactive nature of the a-site,
it is possible
that the reaction proceeds by direct nucleophilic substitution, without
promotion or
catalysis by the palladium metal center. See, Cacchi et al. Tetrahedron Lett.
27(33):3931
( 1986).
Thus there remains a need for an effective method of preparing a wide range of
aryl ethers under mild conditions and in high yields. There is a further need
for an efficient
catalytic system with high efficiencies and turnover number for the synthesis
of aryl
ethers. In addition, there still remains a need for an effective method for
the arylation of
tertiary alkoxides.
Summary of the Invention
The present invention provides general and attractive routes to a wide range
of aryl
ethers. The methods provide several improvements over methods known
heretofore,
namely, the efficient synthesis of aryl ethers under mild conditions and in
high yields. In
particular, the method of the invention may be used in coupling reactions
using tertiary
alcohols. In other aspects of the invention, the invention provides a class of
transition
metal complexes useful in the catalytic reactions of the invention which were
heretofore
not known to be useful in the preparation of aryl ethers.
In one embodiment of the invention, there is provided a method of preparing an
aryl ether, comprising: reacting an alcohol with an aromatic compound, ArX,
comprising
an activated substituent, X, in an aromatic hydrocarbon solvent, in the
presence of a base
and a catalyst selected from the group consisting of complexes of nickel,
palladium, and
platinum; wherein X is a moiety whose conjugate acid, HX, has a pKa of less
than 5.0;
wherein said catalyst catalyzes the reaction; and whereby an aryl ether is
produced.
In a preferred embodiment, the alcohol has a formula R'OH, wherein R' is
selected
from the group consisting of alkyl, aryl, heteroaryl, cyclic, heterocyclic,
and polycyclic
groups. In another preferred embodiment, the aromatic compound has the formula
(Z)nC6H(5_~}X, wherein each occurrence of Z is selected independently from the
group
consisting of alkyl, aryl, acyl, heteroaryl, amino, carboxylic ester,
carboxylic acid,
hydroxyl, alkoxyl, ether, thioether, amide, carboxamide, nitro, phosphonic
acid, sulfonic
acid, and halide groups; and n is in the range of 0 to 5.
CA 02467977 2004-06-08

-2a-
In a further embodiment of the invention, there is provided a method of
preparing
an aryl ether, comprising: reacting an alkoxide salt with an aromatic
compound, ArX,
comprising an activated substituent, X, in an aromatic hydrocarbon solvent, in
the
presence of a catalyst selected from the group consisting of complexes of
nickel,
palladium, and platinum; wherein X is a moiety whose conjugate acid, HX, has a
pKa of
less than 5.0; wherein said catalyst catalyzes the reaction; and whereby an
aryl ether is
produced.
In a preferred embodiment, the alkoxide salt has a formula R'O(counter ion),
wherein R' is selected from the group consisting of alkyl, aryl, heteroaryl,
cyclic,
heterocyclic, and polycyclic groups.
In a further embodiment, there is provided a method of preparing a vinyl
ether,
comprising: reacting an alcohol with an alkene comprising an activated
substituent, X, in
an aromatic hydrocarbon solvent, in the presence of a base and a catalyst
selected from the
group consisting of complexes of nickel, palladium and platinum; wherein X is
bonded to
a carbon of a carbon-carbon double bond comprised by the alkene; wherein X is
a moiety
whose conjugate acid, HX, has a pKa of less than 5.0; wherein said catalyst
catalyzes the
reaction; and whereby a vinyl ether is produced.
In a further embodiment, there is provided a method of preparing a vinyl
ether,
comprising: reacting an alkoxide salt with an alkene comprising an activated
substituent,
X, in an aromatic hydrocarbon solvent, in the presence of a catalyst selected
from the
group consisting of complexes of nickel, palladium, and platinum; wherein X is
bonded to
a carbon of a carbon-carbon double bond comprised by the alkene; wherein X is
a moiety
whose conjugate acid, HX, has a pKa of less than 5.0; wherein said catalyst
catalyzes the
reaction; and whereby a vinyl ether is produced.
In a further embodiment, there is provided a method of preparing a vinyl
ether,
comprising: reacting an alcohol with an alkene comprising an activated
substituent, X, in
the presence of a base and a catalyst comprising palladium and a chelating
ligand; wherein
X is bonded to a carbon of a carbon-carbon double bond comprised by the
alkene; wherein
X is a moiety whose conjugate acid, HX, has a pKa of less than 5.0; wherein
said catalyst
catalyzes the reaction; and whereby a vinyl ether is produced.
In a further embodiment, there is provided a method of preparing a vinyl
ether,
comprising: reacting an alkoxide salt with an alkene comprising an activated
substituent,
CA 02467977 2004-06-08

-,
-2b-
X, in the presence of a catalyst comprising palladium and a chelating ligand;
wherein X is
bonded to a carbon of a carbon-carbon double bond comprised by the alkene;
wherein X is
a moiety whose conjugate acid, HX, has a pKa of less than 5.0; wherein said
catalyst
catalyzes the reaction; and whereby vinyl ether is produced
S
Brief Description of the Drawings
Figure 1. Scheme illustrating possible reaction steps in the synthesis of aryl
ethers
according to the method of the invention.
Figure 2. Representative first-order plots for disappearance of 4 in THF-d8 at
23
(~, 37 (O), 47 (O), and 55 °C (x), where [KOCHZCMe3] 2 0.002 M. Error
bars correspond
to t 5% integration error in the corresponding 1H NMR spectra.
Figure 3. Second-order plot for disappearance of 4 in THF-dg at 47
°C.
Figure 4. Eyring plot for the thermolysis of 4 in THF-dg over the temperature
range 23-57 °C.
Figure 5. Potassium neopentoxide concentration dependence of the rate of
reductive elimination of 4 in THF-d8 at 47 °C.
CA 02467977 2004-06-08

.. _3 _
Figure 6. Potassium neopentoxide concentration dependence of the rate of
alkoxide exchange with 4 in THF-dg at 47 °C.
Detailed Description of the Invention
Overview
in one aspect of the invention, an aryl ether compound is prepared by reacting
an
alcohol or its corresponding alkoxide salt with an aromatic compound in the
presence of a
base and a metal catalyst including a metal atom of Group Vlll metals such as
iron, cobalt,
nickel, rhodium, palladium and platinum, though platinum, palladium and nickel
(group
10) are most preferred. The aromatic compound comprises an activated
substituent, X,
which generally is a moiety such that its conjugate acid HX has a pKa of less
than 5Ø
When the reaction takes place using an alkoxide salt, a base may not be
required.
In preferred embodiments, the subject synthetic reaction can be characterized
by
the general reaction schemes (Scheme 1 a):
catalytic
etherification
R-YH + ArX ~ Ar-Y-R
2 1 metal catalyst
base -
Scheme 1 a:
wherein: Ar represents an aryl group (which may be furthered substituted
beyond
X); X represents a leaving group (such as a halide or a sulfonate), which can
be displaced
by a nucleophilic alcohol oxygen, such as in a metal-dependent etherification
reaction; Y
represents O, S or Se; R represents, as valence and stability permit, a
subsitituted or
unsubstituted alkyl or alkenyl group, or -(CH2)m-Rg, wherein Rg represents a
substituted
or unsubstitute~d aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle,
and rn is zero or
an integer in the range of 1 to 8.
According to scheme la, an alcohol 1 (e.g., Yes) is reacted with an aromatic
compound 2 having an activated substituent, X, to form an aryl ether 3_. The
reaction is run
in the presence of at least a catalytic.amount of a transition metal catalyst
which promotes
the cross-coupling of the alcohol and activated aryl nucleus to form the
resulting ether
product, 3. The reaction, in general, proceeds in the presence of a transition
metal
complex (with or without a supporting ligand) and a suitable base.
CA 02467977 2004-06-08

The reaction may be either an intermolecular or intramolecular reaction. In
the
instance of the latter, it will be relined that, with reference to scheme la,
RYH is a
subsituent of Ar, and the reaction scheme can be represented by the formula:
catalytic
etherification
+HY-R-ArX
metal catalyst Ar-R
base
wherein R-YH represents a substituent of Ar, e.g., a hydroxy-subsitituted
alkyl or alkenyl
group, which disposes Y from 2 to 10 bond lengths away from the substituted
position on
Ar, more preferably from 2 to 5 bond lengths. Thus, upon intramolecular
etherification, Y
is bonded to R and the X-substituted site on Ar. Preferably, Y, R and the
bridging portion
of Ar form a fused ring with Ar having from 4 to 8 atoms in the ring, more
preferably 5, 6
or 7 atoms. Recast slightly, the intermolecular and intramolecular reaction
involving an
aryl substrate can be represented in the two schemes:
X OR'
R R
Ar + R' OH -~ Ar
X O
R R
Ar --~ Ar
R'OH R
While not intending to be bound by any particular theory, the reaction most
likely
proceeds via oxidative-addition of the aromatic compound 2 to a zero-valent
catalyst metal
center; substitution of X by the alcohol 1 at the metal center, followed by
reductive-
elimination to generate the aryl ether 3. The base presumably promotes
formation of an
oxygen-metal bond, in which the metal is the metal center of the catalyst,
presumably by
facilitating proton abstraction from the alcohol hydrogen.
While not being bound by any particular mode of operation, it is hypothesized
that
the mechanism of the preferred Pd-catalyzed synthesis of aryl ethers and vinyl
ethers may
proceed via a pathway similar to depicted in Figure 1. Figure 1 presents a
proposed
reaction pathway for the synthesis of an aryl ether via an intermolecular
reaction. Any
ligands that may be present on the palladium atom during this process have
been omitted
CA 02467977 2004-06-08

-5
for clarity. With reference to the Figure, oxidative addition of the Pd(0)
complex to the
aryl halide affords the Pd(11) organometallic complex intermediate A. In the
presence of a
suitable base, reaction of the alcohol (or alkoxide) moiety with A could,
after ~a
dcprotonation event to generate I3, afford intermediate C, which would then
undergo
reductive elimination to yield the product aryl ether and regenerate the
active catalyst. The
reaction sequence is likely to be similar for intramolecular reactions.
Alternatively, and'
particularly for nickel catalysts, the active transition metal species in the
oxidative addition
step rnay involve the metal in the +1 oxidation state.
In preferred embodiments of the invention, there is no need to use large
excesses of
either reactant - alcohol or aromatic compound. The reaction proceeds quickly
and in high
yield to the product aryl ether using substantially stoichiometric amount of
reagents.
Thus, the alcohol may be present in as little as a two-fold excess and
preferably in no
greater than a 20% excess relative to the aromatic compound. Alternatively,
the aromatic
compound may be present in as little as a two-fold excess and preferably in no
greater than
a 20% excess relative to the alcohol.
In another embodiment, the alcohol of the above reaction can be replaced with
a
thiol or selenol, e.g., having a formula HS-R or HSe-R, respectively, R being
defined
above. In such embodiments, the thiol or selenol is activated as the
nucleophile to form an
adduct with an aryl group of the general formula Ar-S-R and Ar-Se-R.
Accordingly,
throughout the application, it will be apparent that most recitation of
embodiments
involving an alcohol can also be carried out with a thiol or selenol.
-In still another embodiment, the subject method can be used to generate vinyl
ethers. In similar fashion to the reaction scheme set above, the
etherification of a vinyl-
aetivated hydrocarbon can be carried out according to the general reaction
scheme:
catalytic
X R~ etherification RY R'
+ RYH
R' R~ R~ R~
Scheme 1 b
wherein: X represents a leaving group (such as a halide or a sulfonate), which
can be
displaced by the nucleophilic ether oxygen, such as in a metal-dependent
etherification
reaction; Y represents O, S or Se; R, represents, as valence and stability
permit, a
subsitituted or unsubstituted alkyl or alkenyl group, or -(CH2)m-Rg, wherein
Rg
CA 02467977 2004-06-08

=6 -
represents a substituted or unsubstituted aryl. cycloalkyl, cycloalkenyl.
heterocycle or
polycycle, and m is zero or an integer in the range of I to 8; and each R' is
independently
selected, as valence and stability permit, to be a hydrogen, a halogen, a
lower alkyl, a
lower alkenyl, a lower alkynyl, a carbonyl (e.g., an ester, a carboxylate, or
a formate), a
thiocarbonyl (e.g., a thiolester, a thiolcarboxylate.- or a thiolformate), a
ketone, an
aldehyde, an amino, an acylamino, an amido, an amidino, a eyano, a vitro, an
azido, a
sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
phosphoryl, a
phosphonate, a phosphinate, -(CH2)m-R,, -(CH2)m-OH, -(CH2)m-O-lower alkyl, -
(CH2)m-O-lower alkenyl, -(CH2)m-O-(CH2)n-R,, -(CH2)m-SH, -(CH2)m-Slower alkyl,
-(CH2)m-S-lower alkenyl, -(CH2)m-S-(CH2)n-R,, or protecting groups of the
above or a
solid or polymeric support; Rg represents a substituted or unsubstituted aryl,
aralkyl,
cycloalkyl, cycloalkenyl, or heterocycle; and n and m are independently for
each
occurrence zxro or an integer in the range of I to 6. P is preferably in the
range of 0 to 5.
As above, the alcohol can be provided in the form of a precursor which
activated in situ to
provide the reactive alcohol.
The reaction can proceed at mild temperatures and pressures to give high
yields of
the product aryl ether. Thus, yields of greater than 45%. preferably greater
than 75% and
even more preferably greater than 80% may be obtained by reaction at mild
temperatures
according to the invention. The reaction may be carried out at temperature
less than
120°C, and preferably in the range of 50-120°C. In one preferred
embodiment, the
reaction is carried out at a temperature in the range of 65°-
100°C and in a further preferred
embodiment, in the range of 80-100°C.
The reaction can be run in a wide range of solvent systems, including polar
aprotic
solvents.
The ability to provide an ether synthesis scheme which can be carried out
under
mild conditions and/or with non-polar solvents has broad application,
especially in the
agricultural and pharmaceutical industries, as well as in the polymer
industry. In this
regard, the subject reaction is more amenable to use of reactants or products
which include
sensitive functionalities, e.g., which would otherwise be labile under harsh
reaction
conditions.
The subject etherification reactions can be used as part of a combinatorial
synthesis
scheme to yield aryl ethers. Accordingly, another aspect of the present
invention relates to
use of the subject method to generate variegated libraries of aryl ethers of
the general
CA 02467977 2004-06-08

formula Ar-OR, and to the libraries themselves. The libraries can be soluble
or linked to
insoluble supports, e.g., either through substituents of the aryl Group or
through R.
Dc tnilions
For convenience, before further description of the present invention, certain
terms'
employed in the specification, examples, and appended claims are collected
here.
The term "substrate aryl group" refers to an aryl group containing an
electrophilic
atom which is susceptible to the subject cross-coupling reaction, e.g., the
electrophilic
atom bears a leaving group. In reaction scheme 1, the substrate aryl is
represented by
ArX, and X is the leaving group. The aryl group, Ar, is said to be substituted
if, in
addition to X, it is substituted at yet other positions. The substrate aryl
group can be a
single ring molecule, or can be a substituent of a larger molecule.
1'he term "reactive alcohol group" refers to an alcohol group which can attack
the
eleetrophilic atom of the substrate aryl group and displace the leaving group
in the subject
I S cross-coupling reaction. In reaction schemes la and Ib, the nucleophilic
aryl group is
represented by ROH. The reactive alcohol group can be a component of a
molecule
separate from the substrate aryl group, or a substituent of the same molecule
(e.g., for
intramolecular condensation). A "reactive thiol" and a "reactive selenol" have
similar
meanings.
The term "nucleophile" is recognized in the art. and as used herein means a
chemical moiety having a reactive pair of electrons.
The term "electrophile" is art-recognized and refers to chemical moieties
which can
accept a pair of electrons from a nucleophile as defined above. Electrophilic
moieties
useful in the method of the present invention include halides and sulfonates.
The terms "electrophilic atom", "electrophilic center" and "reactive center"
as used
herein refer to the atom of the substrate aryl moiety which is attacked by,
and forms a new
bond to, the alcohol oxygen. In most (but not all) cases, this will also be
the aryl ring atom
from which the leaving group departs.
The term "electron-withdrawing group" is recognized in the art, and denotes
the
tendency of a substituent to attract valence electrons from neighboring atoms,
i.e., the
substituent is electronegative with respect to neighboring atoms. A
quantification of the
level of electron-withdrawing capability is given by the Hammett sigma (s)
constant. This
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_g -
well known constant is described in many references, for instance. J. March,
Advanced
Qrttanic Chemistry, McGraw Hill Book Company, New York, ( 1977 edition) pp.
251-259.
The Hammett constant values are generally negative for electron donating
groups (s[P] = -
0.66 for NH2) and positive for electron withdrawing groups (s[P] = 0.78 for a
vitro group),
s[P] indicating para substitution. Exemplary electron-withdrawing groups
include vitro,
ketone, aldehyde, sulfonyl, trifluoromethyl, -CN. chloride, and the like,
Exemplary
electron-donating groups include amino, methoxy, and the like.
The term "reaction product" means a compound which results from the reaction
of
the alcohol and the substrate aryl group. In general. the term "reaction
product" wilt be
used herein to refer to a stable, isolable aryl ether adduct, and not to
unstable intermediates
or transition states.
The term "catalytic amount" is recognized in the art and means a
substoichiometric
amount of reagent relative to a reactant. As used herein, a catalytic amount
means from
0.0001 to 90 mole percent reagent relative to a reactant, more preferably from
0.001 to SO
i S mole percent. still more preferably from 0.01 to 10 mole percent, and even
more
preferably from 0.1 to 5 mole percent reagent to reactant.
The term "alkyl" refers to the radical of saturated aliphatic groups,
including
straight-chain alkyl groups, branched-chain alkyl groups, eycloalkyl
(alicyclic) groups,
alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
In preferred
embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon
atoms in its
backbone (e.g., Cl-C30 for straight chain, C3-C30 for branched chain), and
more
preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon
atoms in
their ring structure, and more preferably have 5, 6 or 7 carbons in the ring
structure.
Moreover, the term "alkyl" (or "lower alkyl") as used throughout the
specification
and claims is intended to include -both "unsubstituted alkyls" and
"substituted alkyls", the
latter of which refers to alkyl moieties having substituents replacing a
hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can include, for
example, a
halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, a formyl, or a
ketone), a
thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an
alkoxyl, a phosphoryl,
a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a
eyano, a vitro,
an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
sulfonamido, a
sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
It will be
understood by those skilled in the art that the moieties substituted on the
hydrocarbon
CA 02467977 2004-06-08

-9 -
chain can themselves be substituted, if appropriate. For instance, the
substituents of a
substituted alkyl may include substituted and unsubstituted forms of amino,
azido, imino,
amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including
sulfate,.
sulfonamido, sulfamoyl and sulfonatc), and silyl groups, as well as ethers.
alkylthios,
carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN
and the like.
Exemplary substituted alkyls are described below. Cycloalkyls can be further
substituted '
with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted
alkyls, -CF3, -
CN, and the like.
The term "aralkyl", as used herein, refers to an alkyl group substituted with
an aryl
group (e.g., an aromatic or heteroaromatic group).
The terms "atkenyl" and "alkynyl" refer to unsaturated aliphatic groups
analogous
in length and possible substitution to the alkyls described above, but that
contain at least
one double or triple bond respectively.
Unless the number of carbons is otherwise specified, "lower alkyl" as used
herein
means an alkyl group, as defined above, but having from one to ten carbons,
more
preferably from one to six carbon atoms in its backbone structure. Likewise,
"lower
alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl
groups are lower
alkyls. In preferred embodiments, a substituent designated herein as alkyl is
a lower alkyl.
The terns "aryl" as used herein includes 5-, 6- and 7-membered single-ring
aromatic groups that may include from zero to four heteroatoms, for example,
benzene,
pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,
pyridine,
pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having
heteroatorns
in the ring structure may also be referred to as "aryl heterocycles" or
"heteroaromatics".
The aromatic ring can be substituted at one or more ring positions with such
substituents
as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl,
cycloalkyl, hydroxyl, amino, vitro, sulfhydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heteroeyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The
term "aryl"
also includes polycyclic ring systems having two or more cyclic rings in which
two or
more carbons are common to two adjoining rings (the rings are "fused rings")
wherein at
least one of the rings is aromatic, e.g., the other cyclic rings can be
cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
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-tt7 _
The terns "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered
ring
structures, more preferably 3- to 7-membered rings, whose ring structures
include one to
Tour heteroatoms. Heterocycles can also be polycycies. Heterocyclyl groups
include, for
example, thiophene, thianthrcnc, furan, pyran, isobcnzofuran, chromene,
xanthene,
phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine,
pyrazine,
pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,
quinolizine, ;.
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaiine, quinazoline,
cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,
phenanthroline,
phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane,
thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such
as
azetidinones and pyrrolidinones, sultams, sultones, and the ~ike. The
heterocyclic ring can
be substituted at one or more positions with such substituents as described
above, as for
example, halogen, alkyl, aralkyl, alkenyl, alkynyl. cycloalkyl, hydroxyl,
amino, vitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic
moiety, -CF3, -CN, or the tike.
The teens "polycyclyl" or "polycyclic group" refer to two or more rings (e.g.,
cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in
which two or
more carbons are common to two adjoining rings, e.g., the rings are "fused
rings". Rings
that are joined through non-adjacent atoms are termed "bridged" rings. Each of
the rings
of the polycycle can be substituted with such substituents as described above,
as for
example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,
amino, vitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, ketone, atdehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic
moiety, -CF3, -CN, or the like. .
The term "carbocycle", as used herein, refers to an aromatic or non-aromatic
ring in
which each atom of the ring is carbon.
The term "heteroatom" as used herein means an atom of any element other than
carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and
phosphorous.
As used herein, the term "vitro" means -N02; the term "halogen" designates -F,
-
Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH;
and the
term "sulfonyl" means -S02-.
CA 02467977 2004-06-08

., -11 -
The terms "amine" and "amino" are art reco6nized and refer to both
unsubstitutcd
and substituted amines, e.g.. a moiety that can be represented by the general
formula:
R ~ ~o
Rio (+
-N~ or - i -Rio
R9 R
9
wherein Rg, Rl0 and R'Ip each independently represent a hydrogen, an alkyl, an
alkenyl,
-(CH2)n~-Rg, or Rg and R 10 taken together with the N atom to which they are
attached
complete a heterocycle having from 4 to 8 atoms in the ring structure; Rg
represents an
aryl, a cycloalkyl, a cycfoalkenyf, a heterocycle or a polycycle; and m is
zero or an integer
in the range of 1 to 8. In preferred embodiments, only one of Rg or R10 can be
a carbonyl,
e.b., Rg, R10 and the nitrogen together do not form an imide. In even more
preferred
embodiments. Rg and Rl0 (and optionally R' l0) each independently represent a
hydrogen,
an alkyl, an alkenyl, or -(CH2)m-Rg. Thus. the term "alkylamine" as used
herein means
an amine group, as defined above, having a substituted or unsubstituted alkyl
attached
thereto, i.e., at least one of Rg and R 10 is an alkyl group.
The term "acylamino" is art-recognized and refers to a moiety that can be
represented by the general formula:
O
Ry
wherein R9 is as defined above, and R'l l represents a hydrogen, an alkyl, an
alkenyl or
-(CH2),n-Rg, where m and Rg are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl and
includes
a moiety that can be represented by the general formula:
O
~ R9
N
R
wherein Rg, R10 are as defined above. Preferred embodiments of the amide will
not
include imides which may be unstable.
CA 02467977 2004-06-08

The term "alkylthio" refers to an alkyl broup, as defined above, having a
sulfur
radical attached thereto. In preferred embodiments, the "alkylthio" moiety is
represented
by one of -S-alkyl, -S-atkenyl, -S-alkynyl, and -S-(CH2)m-Rg, wherein m and Rg
arc
defined above. Representative alkylthio groups include methylthio. ethyl thio,
and the
like.
The term "carbonyl" is art recognized and includes such moieties as can be
represented by the general fotinula:
O O
~X-Ri, ~ or-X~ R,
m
wherein X is a bond or represents an oxygen or a sulfur, and RI I represents a
hydrogen,
an alkyl, an alkenyl, -(CH2jm-Rg or a pharmaceutically acceptable salt, R'I l
represents a
hydrogen, an alkyl, an alkenyl or -(CH2)m-Rg. where rn and Rg are as defined
above.
Where X is an oxygen and R11 or R'1 l is not hydrogen, the formula represents
an "ester".
Where X is an oxygen, and RI 1 is as defined above. the moiety is referred to
herein as a
carboxyl group, and particularly when Rll is a hydrogen, the formula
represents a
"carboxylic acid". Where X is an oxygen, and R'l l is hydrogen, the formula
represents a
"formate". In general, where the oxygen atom of the above formula is replaced
by sulfur,
the formula represents a "ihiolcarbonyl" group. Where X is a sulfur and R1 l
or R'l l is not
hydrogen, the formula represents a "thio(ester." Where X is a sulfur and Rl l
is hydrogen,
the formula represents a "thiolcarboxylic acid." Where X is a sulfur and R1 I'
is hydrogen,
the formula represents a "thiolformate." On the other hand, where X is a bond,
and Rl l is
not hydrogen, the above formula represents a "ketone" group. Where X is a
bond, and
R l l is hydrogen, the above formula represents an "aldehyde" group.
The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as
defined
above, having an oxygen radical attached thereto. Representative alkoxyl
groups include
methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two
hydrocarbons
covalently linked by an oxygen. Accordingly, the substituent of an alkyl that
renders that
alkyl an ether is or resembles an alkoxyl, such as can be represented by one
of -O-alkyl,
0-alkenyl, -O-alkynyl, -O-(CH2)m-Rg, where m and Rg are described above.
The term "sulfonate" is art recogrtized and includes a moiety that can be
represented by the general formula:
CA 02467977 2004-06-08

-l3 -
o
I I
-~ -ORm
O '
in which R4l is an electron pair, hydrogen. alkyl,_cycloalkyl, or aryl.
The term "sulfate" is art recognized and includes a moiety that can be
represented ~,
by the general formula:
O
I I
-o-~ -OR4i
O
in which R~ l is as defined above.
The term "sulfonamido" is art recognized and includes a moiety that can be
represented by the general formula:
O
I I
R9 O
in which R9 and R' l 1 are as defined above.
The term "sulfamoyl" is art-recognized and includes a moiety that can be
represented by the general formula:
O Rio
-S-N
ll ~R
0 9
in which Rg and Rlp are as defined above.
The terms "sulfoxido" or "sulfinyl", as used herein, refers to a moiety that
can be
represented by the general formula:
o
I I
-S-R49
- - . 9
in which IZ,44 is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl,
cyeloalkyl, heterocyclyl, aralkyl, or aryl.
A "phosphoryl" can in general be represented by the formula:
CA 02467977 2004-06-08

Qt
II
-p-
I
OR,6
wherein Ql represented S or O, and R46 represents hydrobcn. a lower alkyl or
an aryl.
When used to substitute, e.g., an alkyl, the phosphoryl group of the
phosphorylalkyl can be
represented by the general formula:
Qt Qt
II I)
-Q2 ; -O- -Qz p-OR,6
or I
OR, 6 OR, 6
wherein QI represented S or O, and each R46 independently represents hydrogen,
a lower
alkyl or an aryl, Q2 represents O, S or N. When Q l is an S, the phosphoryl
moiety is a
"phosphorothioate".
A "phosphoramidite" can be represented in the general formula:
O O
-.Q-p-O- -Q-p-OR4s
or Z I
N (R9) Rto N (R9) Rto
wherein R9 and R10 are as defined above, and Q2 represents O, S or N.
A "phosphonamidite" can be represented in the general formula:
R4e Rye
I I
-..Q2 ~ ~~'_' O~ Q2 ~ _-" ~R46
N (R9) Rio N (R9) Rto
wherein R9 and R10 are as defined above, Q2 represents O, S or N, and R4g
represents a
lower alkyl or an aryl, Q2 represents O, S or N.
A "selenoalkyl" refers to an alkyl group having a substituted seleno group
attached
thereto. Exemplary "selenoethers" which may be substituted on the alkyl are
selected from
one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2)m-R~, m and R~ being
defined
above.
Analogous substitutions can be made to alkenyl and alkynyl groups to produce,
for
example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls,
iminoalkenyls,
iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or
alkynyls.
CA 02467977 2004-06-08

-I s
The phrase "proteetinb group" as used herein means substituents which protect
the
reactive functional group from undesirable chemical reactions. Examples of
such
protecting groups include esters of carboxylic acids, ethers of alcohols and
acetals and
ketals of aldehydes and ketones.
s It will be understood that "substitution" or "substituted with" includes the
implicit
proviso that such substitution is in accordance with permitted valence of the
substituted
atom and the substituent, and that the substitution results in a stable
compound, e.g., which
does not spontaneously undergo transformation such as by rearrangement,
cyclization,
elimination, etc.
l0 As used herein, the term "substituted" is contemplated to include all
permissible
substituents of organic compounds. in a broad aspect. the permissible
substituents include
acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and
nonaromatic substituents of organic compounds. Illustrative substituents
include, for
example, those described hereinabove. The permissible substituents can be one
or more
1 s and the same or different for appropriate organic compounds. For purposes
of this
invention, the heteroatoms such as nitrogen may have hydrogen substituents
andJor any
permissible substituents of organic compounds described herein which satisfy
the
valencies of the heteroatoms. This invention is not intended to be limited in
any manner by
the permissible substituents of organic compounds.
20 A "polar solvent" means a solvent which has a dipole moment (s) of 2.9 or
greater,
such as DMF, THF, ethylene gylcol dimethyl ether, DMSO, acetone, acetonitrile,
methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether.
Preferred
solvents are DMF, diglyme, and acetonitrile.
A "polar, aprotic solvent" means a polar solvent as defined above which has no
2s available hydrogens to exchange with the compounds of this invention during
reaction, for
example DMF, acetonitrile, diglyme, DMSO, or THF.
An "aprotic solvent" means a non-nucleophilic solvent having a boiling point
range
above ambient temperature, preferably from about 25°C to about
190°C, more preferably
from about 80°C to about 160°C, most preferably from about
80°C to 150°C, at
30 atmospheric pressure. Examples of such solvents are acetonitrile, toluene,
DMF, diglyme,
THF or DMSO.
For purposes of this invention, the chemical elements are identified in
accordance
with the Periodic Table of the Elements, CAS version, Handbook of Chemistry
and
CA 02467977 2004-06-08

Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention,
the term
"hydrocarbon" is contemplated to include all permissible compounds having at
least one
hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons
include
acyclic and cyclic, branched and unbranched, carbocyclic and heteroeyclic,
aromatic and
nonaromatic organic compounds which can be substituted or unsubstituted.
~xemnIarYCa~alYZed Reactions
As described above, one invention of the Applicants' features a general cross-
coupling reaction which comprises combining a alcohol with an aryl group (a
"substrate
aryl") having an electrophilic center susceptible to attack by the alcohol
oxygen. In
embodiments where the cross-coupling is catalyzed by a transition metal, the
reaction will
also include at least a catalytic amount of a transition metal catalyst and
the combination is
maintained under conditions appropriate for the metal catalyst to catalyze the
nucleophilic
addition of the reactive alcohol to the electrophilic atom of the substrate
aryl.
In one embodiment, the subect method can be used to bring about formation of
an
intramolecular ether linkage, e.g., to form oxygen, thin or seleno
heterocycles. In an
exemplary embodiment, the subject method can be used to effect the
intrarnolecular Pd-
catalyzed ipso substitution of an activated aryl:
Pd(OAc)2 (3-Smol%)
BINAP (4-6mo1%)
/ R K2C03, toluene, 80-1000 ~ ~ ~ R
R ~ / R
n OH n
As illustrated in the appended examples, five, six and seven-membered
heterocyles were
obtained in good yields from the corresponding halides. In addition, a variety
of
functional groups were found to be compatible with the reaction conditions,
including
acetals, sityl ethers, and amides.
The subject method can also be used for the intermolecular formation of carbon-
oxygen bonds. As an exemplary embodiment, the subject method can be used to
catalyze
such reactions as:
.Pd2ldba)3 (l.Smo1%)
Tol-BINAP (3.6mo1%) \ 0R'
\ X toluene, 80-100C
R + 1.2 R'OH + 2.0 + NaH R
/ /
CA 02467977 2004-06-08

_17 _
To further illustrate, the examples describe, in«r alia, that reaction of 3-
propanol, 4-
bromobenzonitrile and NaH in the presence of 1.5 mol% Pd2(dba)3 and 3 mol% (S~-
(-)-
2,2'-bis(di p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) at 50 °C
afforded 4-
isopropoxy-benzonitrile in 80% isolated yield.
The subject reaction can also be used in the synthesis of diary! selenoethers
and,
diary! thioethers. For instance, the subject method can be used to generate
the 6-pyridyl.
substituted pyrimidines of U.S, patent 5,278,167. Such compounds are useful in
the
treatment of retroviral infections. In an illustrated embodiment, 6-bromo-5-
ethyl-I -
(phenoxymethyl)-uracil and 3-pyridineselenol can be reacted according to the
conditions
of the subject reaction to yield a S-ethyl-1-(phenoxymethy!)-6-(3-
pyridylselanyl)-uracil.
o O
HN CH2CH3 HSe ~ HN CHZCH3
I
O N Br N O N Se
/O~ ~.0~ N
Ph Ph
Likewise, 6-bromo-S-ethyl-I-(phenoxymethyl)-uracil and 3-pyridinethiol can be
reacted
according to the present method in order to yield a 5-ethyl-I-(phenoxymethyl)-
6-(3
pyridylsulfanyl~uracil.
The substrate aryl compounds include compounds derived from simple aromatic
rings (single or polycylic) such as benzene, naphthalene, anthraeene and
phenanthrene; or
heteroaromatic rings (single or polycylic), such as pyrrole, thiophene,
thianthrene, furan,
pyran, isobenzofuran, chmmene, ~ xanthene, phenoxathiin, pyrtole, irnidazole,
pyrazole,
thiazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine,
isoindole, indole, indazole, purine, quinotizine, isoquinoline, quinoline,
phthalazine,
naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline,
phenanthridine, acridine, perimidine, phenanthroline, phenazine, phenarsazine,
phenothiazine, furazan, phenoxazine, pyaolidine, oxolane, thiolane, oxazole,
piperidine,
piperazine, morpholine and the like. Itt preferred embodiment, the reactive
group, X, is
substituted on a five, six or seven membered ring (though it can be part of a
larger
polycyle).
CA 02467977 2004-06-08

-l,g _
In preferred embodiments, aryl substrate may be selected from the group
consisting
of phenyl and phenyl derivatives, heteroaromatic compounds, polycyclic
aromatic and
heteroaromatic compounds, and functionalized derivatives thereof. Suitable
aromatic
compounds derived from simple aromatic rings and heteroaromatic rings, include
but are
not limited to, pyridine, imidizole, quinoline, furan, pyrrole, thiophene, and
the like.
Suitable aromatic compounds derived from fused ring systems, include but are
not limited ~..
to naphthalene, anthracene, tetralin, indole and the like.
Suitable aromatic compounds may have the formula ZpArX, where X is an
activated substituent. An activated substituent, X, is characterized as being
a good leaving
group. In general, the leaving group is a group such as a halide or sulfonate.
For the
purposes of the present invention. an activated substituent is that moiety
whose conjugate
acid, HX, has a pKa of less than 5Ø Suitable activated substituents include,
by way of
example only, halides such as chloride, bromide and iodide, triflate, mesylate
and tosylate.
In certain embodiments, the leaving group is a halide selected from iodine and
bromine.
Chlorine and fluorine can also be used as leaving groups, though other
electronegative
substitution on the aryl group may be required to activate those halogens as
leaving groups
in the subject metal cross-coupling reactions.
Z represents one or more optional substituents on the aromatic ring, though
each
occurence of Z (p> I ) is independently selected. By way of example only, each
incidence
of substitution independently can be, as valence and stability permit, a
halogen, a lower
alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (e.g., an ester, a
carboxylate, or a
formate), a thiocarbonyi (e.g.. a thiolester, a thiolcarboxyiate, or a
thioiformate), a ketyi,
an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a vitro,
an azido, a
sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
phosphoryl, a
phosphonate, a phosphinate, -(CH2)nt-R,, -(CH2)m-OH, -(CH2),n-O-lower alkyl, -
(CH2)m-O-lower alkenyl, -(CH2)m-O-(CH2)n-Ra, -(CH2)m-SH, .~(CH2)m-S-lower
alkyl,
-(CH2)m-S-lower alkenyl, -(CH2)m-S-(CH2)n-R,, or protecting groups of the
above or a
solid or polymeric support; Rg represents a substituted or unsubstituted aryl,
aralkyl,
eycloalkyl, cycloalkenyl, or heterocycle; and n and m are independently for
each
occurrence zero or an integer in the range of 1 to 6. P is preferably in the
range of 0 to 5.
For fused rings, where the number of substitution sites on the aryl group
increases, p may
be adjusted appropriately.
In certain embodiments, suitable substitients Z include alkyl, aryl, acyl,
heteroaryi,
amino, carboxylic ester, carboxylic acid, hydrogen group, ether, thioether,
amide,
CA 02467977 2004-06-08

r -1 7 -
carboxamide, vitro, phosphonic acid, hydroxyl, sulfonic acid, halide.
pseudohalide groups,
and substituted derivatives thereof, and n is in the range of 0 to 5. In
particular, the
reaction has been found compatible with acetals. amides and silyl ethers as
functional
groups. For fused rings, where the number of substitution sites on the
aromatic ring
increases, n may be adjusted appropriately. In~addition, the above mentioned
moieties
may be covalently linked to an alcohol moiety in intramolecular reactions.
In preferred embodiments, the resonance structure of the aryl group Ar, or at
least
one substituent Z, is electron-withdrawing from the substituted position of X.
A wide variety of substrate aryl groups are useful in the methods of the
present
l0 invention. The choice of substrate wilt depend on factors such as the
alcohol to be
employed and the desired product, and an appropriate aryl substrate will be
apparent to the
skilled artisan. It will be understood that the aryl substrate preferably wiU
not contain any
interfering functionalities. It will further be understood that not all
activated aryl
substrates will react with every alcohol.
The reactive alcohol group can be a molecule separate from the substrate aryl
group, or a substituent of the same molecule (e.g., for intramolecular
condensation).
The alcohol is selected to provide the desired reaction product. In general,
the
alcohol may be any alcohol such as, but not limited to, alkyl alcohols,
including primary,
secondary and tertiary alcohols, and phenols. The alcohol may be
functionalized. The
alcohol may be selected from a wide variety of structural types, including but
not limited
to, acyclic, cyclic or heterocyclic compounds, fused ring compounds or phenol
derivatives.
The aromatic compound and the alcohol may be included as moieties of a single
molecule, whereby the arylation reaction proceeds as an intramolecular
reaction.
In certain embodiments, the reactive alcohol group which is used in the
subject
coupling reaction can be represented by general formula ROH (or RSH or RSeH as
the
case may be). R represents, as valence and stability permit, a subsitituted or
unsubstituted
alkyl or alkeny) group, or -(CH2)m-Rg, wherein Rg represents a substituted or
unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, and m
is zero or an
integer in the range of 1 to 8. In other embodiments, R is linker to a solid
support. Where
R is substituted, it is preferably substituted with an electron withdrawing
group in a
manner which would substantially reduce the nucleophilicity of the hydroxyl
group. For
instance, R will not include any electron withdrawing groups bonds less than
two bonds
from the hyroxyl-substituted carbon.
CA 02467977 2004-06-08

20 -
In certain embodiments, the alcohol is generated in sim, e.g., by conversion
of a
precursor under the reaction conditions.
Alternatively, the corresponding alkoxide salt, e.g., NaOR, LiOR, KOR, etc.,
may
be prepared and used in place of the alcohol. When the corresponding alkoxide
is used in
S the reaction, an additional base may not be required.
The active form of the transition metal catalyst is not well characterized.
Therefore, it is contemplated that the "transition metal catalyst" of the
present invention, as
that term is used herein, shall include any transition metal catalyst and/or
catalyst
precursor as it is introduced into the reaction vessel and which is, if
necessary, converted
l0 in situ into the active phase, as well as the active form of the catalyst
which participates in
the reaction.
In preferred embodiments, the transition metal catalyst complex is provided in
the
reaction mixture is a catalytic amount. In certain embodiments, that amount is
in the range
of 0.0001 to 20 mol%, and preferably O.OS to S mot%, and most preferably 1-3
mol%,
1 S with respect to the limiting reagent, which may be either the aromatic
compound or the
alcohol (or alkoxide) or both, depending upon which reagent is in
stvichiornetric excess.
In the instance where the molecular formula of the catalyst complex includes
more than
one metal, the amount of the catalyst complex used in the reaction may be
adjusted
accordingly. By way of example, Pd~(dba)3 has two metal centers; and thus the
molar
20 amount of Pd~(dba), used in the reaction may be halved without sacrifice to
catalytic
activity.
Additivnaliy, heterogeneous catalysts containing forms of these elements are
also
suitable catalysts for any of the transition metal catalyzed reactions of the
present
invention. Catalysts containing palladium and nickel are preferred. It is
expected that
2S these catalysts will perform similarly because they are known to undergo
similar reactions,
namely oxidative-addition reactions and reductive-elimination reactions, which
are
thought to be involved in the formation of the aryl ethers of the present
invention.
However, the different ligands are thought to modify the catalyst performance
by, for
example, modifying reactivity and preventing undesirable side reactions.
30 As suitable, the catalysts employed in the subject method involve the use
of metals
which can mediate cross-coupling of the aryl groups ArX and the alcohol as
defined
above. In general, any transition metal (e.g., having d electrons) may be used
to form the
catalyst, e.g., a metal selected from one of Groups 3-IZ of the periodic table
or from the
CA 02467977 2004-06-08

-21 -
lanthanide series. llowever. in preferred embodiments, the metal will be
selected from the
group of late transition metals, c.g. preferably from Groups 5-12 and even
more preferably
Groups 7-I1. For example, suitable metals include platinum, palladium, iron,
nickel,
ruthenium and rhodium. The particular form of the metal to be used in the
reaction is
S selected to provide, under the reaction conditions, metal centers which arc
coordinately.
unsaturated and not in their highest oxidation state. The metal core of the
catalyst should.
be a zero valent transition metal, such as Pd or Ni with ability to undergo
oxidative
addition to Ar-X bond. The zerovalent state, M0, may be generated in situ from
M+2.
To further illustrate, suitable transition metal catalysts include soluble
complexes
of platinum, palladium and nickel. Nickel and palladium are particularly
preferred and
palladium is most preferred. A zero-valent metal center is presumed to
participate in the
catalytic carbon-oxygen bond forming sequence. Thus, the metal center is
desirably in the
zero-valent state or is capable of being reduced to metal(0). Suitable soluble
palladium
complexes include, but are not limited 10, tris(dibenzylideneacetone)
dipalladium
[Pd,(dba),], bis(dibenzylideneacetone) palladium [Pd(dba)1] and palladium
acetate.
Alternatively, particularly for nickel catalysts, the active species for the
oxidative-addition
step may be in the metal (~-1 ) oxidative-addition state.
Catalysts containing palladium and nickel are preferred. It is expected that
these
catalysts will perform comparably because they are known to undergo similar
reactions,
namely cross-coupling reactions, which may be involved in the formation of the
aryl
ethers of the present invention.
The coupling can be catalyzed by a palladium catalyst which may take the form
of,
to illustrate, PdCl2, Pd(OAc~, (CH3CN)2PdCl2, Pd[P(C6H5),]4, and polymer
supported
Pd(0). In other embodiments, the reaction can be catalyzed by a nickel
catalyst, such as
Ni(acac)2, NiCl2(P(C6H5)]2, Raney nickel and the like, wherein "acac"
represents
acetylacetonate.
The catalyst wil( preferably be provided in the reaction mixture as metal-
ligand
complex comprising a bound supporting ligand, that is, a metal-supporting
(igand
complex. The ligand effects can be key to favoring, inter alia, the reductive
elimination
pathway or the like which produces 'the ether, over such side reactions as (3-
hydride
elimination. In particular, the use of bulky and less electron-donating
ligands (but
probably still chelating ligands) should favor the reductive elimination
process. In
preferred embodiments, the subject reaction employs bulky bidentate ligands
such as
CA 02467977 2004-06-08

-~2
bisphosphines.
The ligand, as described in greater detail below, may include chelating
ligands,
such as by way of example only, alkyl and aryl derivatives of phosphines and
bisphosphines, imines, arsines, and hybrids thereof, including hybrids of
phosphines with
amines. Weakly or non-nucleophilic stabilizing ions are preferred to avoid
complicating
side reaction of the counter ion attacking or adding to the eleetrophilic
center of the
substrate aryl. This catalyst complex may include additional ligands as is
necessary to
obtain a stable complex. Moreover, the ligand can be added to the reaction
mixture in the
form of a metal complex, or added as a separate reagent relative to the
addition of the
metal. E3y way of example, PdCh(BINAP) may be prepared in a separate step and
used as
the catalyst complex set forth in scheme l a.
The ligand, if chiral can be provided as a racemic mixture or a purified
stereoisomer.
The supporting ligand may be added to the reaction solution as a separate
compound or it may be complexed to the metal center to form a metal-supporting
ligand
complex prior to its introduction into the reaction solution. Supporting
ligands are
compounds added to the reaction solution which are capable of binding to the
catalyst
metal center, although an actual metal-supporting ligand complex has not been
identified
in each and every synthesis. In some preferred embodiments, the supporting
ligand is a
chelating ligand. Although not bound by any theory of operation, it is
hypothesized that
the supporting ligands prevent unwanted side reactions as well as enhancing
the rate and
efficiency of the desired process. Additionally, they often aid in keeping the
metal catalyst
soluble. Although the present invention does not require the formation of a
metal-
supporting ligand complex, such complexes have been shown to be consistent
with the
postulate that they ace intermediates in these reactions and it has been
observed the
selection of the supporting ligand has an affect on the course of the
reaction.
The supporting ligand is present in the range of 0.0001 to 40 mol% relative to
the
limiting reagent, i.e., alcohol or aromatic compound. The ratio of the
supporting ligand to
catalyst complex is typically in the range of about I to 20, and preferably in
the range of
about 1 to 4 and most preferably about 2.4.. These ratios are based upon a
single metal
complex and a single binding site ligand. In instances where the ligand
contains additional
binding sites (i.e., a chelating ligand) or the catalyst contains more than
one metal, the
ratio is adjusted accordingly. By way of example, the supporting ligand BINAP
contains
CA 02467977 2004-06-08

_23 _
two coordinating phosphorus atoms and thus the ratio of I3INAP to catalyst is
adjusted
downward to about 1 to 10, preferably about 1 to 2 and most preferably about
1.2.
Conversely, Pd~(dba), contains two palladium metal centers and the ratio of
ligand 'to
Pd,(dba), is adjusted upward to 1 to 40, preferably l to 8 and most preferably
about 4.8. -
S In certain embodiments of the subject method, the transition metal catalyst
includes
one or more phosphine ligands, e.g., as a Gewis basic co-catalyst that
controls the stability
and electron transfer properties of the transition metal catalyst, and/or
stabilizes the metal
intermediates. Phosphine ligands are commercially available or can be prepared
by
methods similar to processes known per se. The phosphines can be monodentate
i 0 phosphine ligands, such as trimethylphosphine, triethylphosphine,
tripropylphosphine,
triisopropylphosphine, tributylphosphine, tricyclohexylphosphine, trimethyl
phosphate,
methyl phosphate, tripropyl phosphate, triisopropyl phosphate, tributyl
phosphate and
tricyclohexyl phosphate, in particular triphenylphosphine, trio-
tolyl)phosphine,
triisopropylphosphine or tricyclohexylphosphine; or a bidentate phosphine
ligand such as
1 S 2,2'-bas(diphenylphosphino)-I,1'-binaphthy) (BINAP), 1,2-
bis(dimethylphosphino~thane,
1,2-bis(diethylphosphino)ethane, 1,2-bis(dipropylphosphinokthane, 1,2
bis(diisopropylphosphino)ethane, 1.2-bis(dibutyl-phosphino)ethane_ 1,2
bis(dicyclohexyiphosphino)ethane, 1,3-bis(dicyclohexylphosphino) propane, 1,3-
bis(diiso
propylphosphino)propane, 1,4-bas(diisopropylphvsphino)-butane and 2,4
20 bas(dicyclohexylphosphino)pentane.
In preferred embodiments, the phosphine ligand is one (or a mix of) of P(o-
tolyl),.
Bis(phosphine) ligands are particularly preferred chelating supporting
ligands. Suitable
bis(phosphine) compounds include but are in no way limited to (t)-Z,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (and separate enantiomers), (t)-2,2'-
bis(di-p-
25 tolylphosphino)-1,1'-binaphthyl (and separate enantiomers), I-I'-
bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane; 1,2-
bis(diphenylphosphino)benzene, and 1,2-bis(diphenylphosphino~thane. Hybrid
chelating
ligands such as (t)-N,N-dimethyl-i-[2-(diphenylphosphino)
ferrocenylJethylamine (and
separate enantiomers), and (t)-(R)-1-[(S)-2-(diphenylphosphino)-
ferrocenylJethyl methyl
30 ether (and separate enantiomers) are also within the scope of the
invention.
tn some instances, it may be necessary to include additional reagents in the
reaction to promote reactivity of either the transition metal catalyst or
activated aryl
nucleus. In particular, it may be advantageous to include a suitable base. In
general, a
variety of bases may be used in practice of the present invention. The base is
desirably
CA 02467977 2004-06-08

-~a _
capable of extraction of a proton to promote metal-alkoxide formation. It has
not been
determined if deprotonation occurs prior to or after oxygen coordination. The
base may
optionally be slerically hindered to discourage metal coordination of the base
in those
circumstances where such coordination is possible, i.e., alkali metal
alkoxides. Exemplary
bases include such as, for example: an alkoxides such as sodium tert-butoxide,
an alkali
metal amide such as sodium amide, lithium diisopropylamide or an alkali metal
bis(trialkyl-silyl)amides, c.g., such as lithium bis-(trimethyl-silyl)amide or
sodium bis-
(trimethyl- silyl) amide, a tertiary amine (e.g. triethylamine,
trimethylamine, N,N-
dimethylaminopyridine, l,S-diazabicycl(4.3.OJnonene-S (DBN), l,S-diazabicycl
(5.4.0]undecene-5 (DBU), alkali, alkaline earth carbonate, bicarbonate or
hydroxide (e.g.
sodium, magnesium, calcium, barium, potassium carbonate, hydroxide and
bicarbonate).
By way of example only, suitable bases include NaH, LiH, KH, KiCO,, NalCO,,
ThCO,,
Cs:CO,, K(OtBu), Li(OrBu), Na(O~Bu) K(OPh), Na(OPh), triethylamine or mixtures
thereof. NaH, Na(OtBu) and KiCO, have been found useful in a wide variety of
aryl ether
I S bond forming reactions. Preferred bases include Cs2C03, DBU, NaH, KOt-Bu,
KN(SiMe3~, NaN(SiMe3)2, and LiN(SiMe3)2.
Base is used in approximately stoichiometric proportions in reaction using
alcohol.
The present invention has demonstrated that there is no need for large
excesses of base in
order to obtain good yields of aryl ether under mild reaction conditions. No
more than
four equivalents and preferably no more than two equivalents are needed.
Further, in
reactions using the corresponding aikoxide as the reagent, there may be no
need for
additional base.
In this way a wide range of aryl ethers, thioethers and selenoethers may be
prepared from available alcohols, thiols and selenols. The reaction can be
accomplished
using a wide range of alcohols, which are either commercially available or
obtainable from
conventional syntheses using a variety of methods known in the art.
As is clear from the above discussion, the products which may be produced by
the
etherification reaction of this invention can undergo further reactions) to
afford desired
derivatives thereof. Such permissible derivatization reactions can be carried
out in
accordance with conventional procedures known in the art. For example,
potential
derivatization reactions include esterificafion, oxidation of alcohols to
aldehydes and
acids, N-alkylation of amides, nitrite reduction, acylation of ketones by
esters, acylation of
amines and the like.
CA 02467977 2004-06-08

. -2S -.
I!!. Reaction Conditions
The etherification reactions of the present invention may be performed under a
wide range of conditions, though it will be understood that the solvents and
temperature
ranges recited herein are not limitative and only correspond to a preferred
mode of the
process of the invention.
In general, it will be desirable that reactions are run using mild conditions
which
will not adversely af~'ect the reactants, the catalyst, or the product. For
example, the
reaction temperature influences the speed of the reaction, as well as the
stability of the
reactants and catalyst. The reactions will usually be run at temperatures in
the range of
25°C to 300°C, more preferably in the range ZS°C to
150°C.
In general, the subject reactions are carried out in a liquid reaction medium.
The
reactions may be run without addition of solvent. Alternatively, the reactions
may be run
in an inert solvent, preferably one in which the reaction ingredients,
including the catalyst,
Z S are substantially soluble. Suitable solvents include ethers such as
diethyl ether, 1,2-
dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like;
halogenated
solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzxne,
and the
like; aliphatic or aromatic hydrocarbon solvents such as benzene, xylene,
toluene, hexane,
pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-
butanone;
polar aprotic solvents such as acetonitrile, dimethylsulfoxide,
dimethylformamide and the
like; or combinations of two or more solvents.
The invention also contemplates reaction in a biphasic mixture of solvents, in
an
emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain
embodiments, it
may be preferred to perform the catalyzed reactions in the solid phase with
one of the
reactants anchored to a solid support.
In certain embodiments it is preferable to perform the reactions under an
inert
atmosphere of a gas such as nitrogen or argon.
The reaction processes of the pt~esent invention can be conducted in
continuous,
semi-continuous or batch fashion and- may involve a liquid recycle operation
as desired.
The processes of this invention are preferably conducted in batch fashion.
Likewise, the
manner or order of addition of the reaction ingredients, catalyst and solvent
are also not
generally critical and may be accomplished in any conventional fashion.
CA 02467977 2004-06-08

The reaction can be conducted in a single reaction zone or in a plurality of
reaction
zones, in series or in parallel or it may be conducted batchwise or
continuously in an
elongated tubular zone or series of such zones. The materials of construction
employed
should be inert to the starting materials during the reaction and the
fabrication of the
equipment should be able to withstand the reaction temperatures and pressures.
Means to
introduce and/or adjust the quantity of starting materials or ingredients
introduced
batchwise or continuously into the reaction zone during the course of the
reaction can be
conveniently utilized in the processes especially to maintain the desired
molar ratio of the
starting materials. The reaction steps may be effected by the incremental
addition of one
of the starting materials to the other. Also, the reaction steps can be
combined by the joint
addition of the starting materials to the metal catalyst. When complete
conversion is not
desired or not obtainable, the starting materials can be separated from the
product and then
recycled back into the reaction zone.
The processes may be conducted in either glass lined, stainless steel or
similar type
reaction equipment. The reaction zone may be fitted with one or more internal
and/or
external heat exchangers) in order to control undue temperature fluctuations,
or to prevent
any possible "runaway" reaction temperatures.
Furthermore, one or more of the reactants can be immobilized or incorporated
into
a polymer or other insoluble matrix by, for example, derivativation with one
or more of
substituents of the aryl group.
IV. Combinatorial Libraries
The subject etherification reaction readily lends itself to the creation of
combinatorial libraries of aryl ethers for the screening of pharmaceutical,
agrochemical or
other biological or medically-related activity or material-related qualities:
A combinatorial
library for the purposes of the present invention is a mixture of chemically
related
compounds which may be screened together for a desired property. The
preparation of
many related compounds in a single reaction greatly reduces and simplifies the
number of
screening processes which need to be carried out. Screening for the
appropriate biological,
pharmaceutical, agrochemical or physical property is done by conventional
methods.
Diversity in the library can be created at a vareity of different levels. For
instance,
the substrate aryl groups used in the combinatorial reactions can be diverse
in terms of the
CA 02467977 2004-06-08

-27 -
core aryl moiety, e.g., a vareigation in terms of the ring structure, and/or
can be varied
with respect to the other substituents.
A variety of techniques are available in the art for generating
combinatoriallv
libraries of small organic molecules such as the subject arylamines. See, for
example,
Blondelle et al. ( 1995) Trends Anal. Chem. 14:83; the AfFymax U.S. Patents
5,359, I l 5
and 5,362,899: the Ellman U.S. Patent 5,288,514: the Still et al. PCT
publication WO
94/08051; Chen et al. ( 1994) IACS 116:2661: Kerr et al. ( 1993) JACS 115:252;
PCT
publications W092/10092, W093/09668 and W091/07087; and the L,erner et al. PCT
publication W093/20242). Accordingly, a variety of libraries on the order of
about 100 to
1,000,000 or more diversomers of the subject aryl ethers can be synthesized
and screened
for particular activity or property.
In an exemplary embodiment, a library of substituted diversomers can be
synthesized using the subject alcohol cross-coupling reaction adapted to the
techniques
described in the Still et al. PCT publication WO 94/08451, e.g., being linked
to a polymer
I S bead by a hydrotyzable or photolyzable group e.g., located at one of the
positions of the
aryl group or a substituent of the alcohol. According to the Still et al.
technique, the
library is synthesized on a set of beads, each bead including a set of tags
identifying the
particular diversomer on that bead. In one embodiment, which is particularly
suitable for
discovering enzyme inhibitors, the beads can be dispersed on the surface of a
permeable
membrane, and the diversorners released from the beads by lysis of the bead
linker. The
diversomer from each bead will diffuse across the membrane to an assay zone.
where it
will interact with an enzyme assay.
Exemplification
The invention may be understood with reference to the following examples,
which
are presented for illustrative purposes only and which are non-limiting.
Alcohols and
aromatic compounds for intermolecular reactions were all commercially
available.
Substrates used in intramolecuiar reactions were prepared using standard
synthetic organic
methods in about 3-5 synthetic steps. Palladium catalysts were all
commercially available.
Example 1-11. Examples 1-11 demonstrate the versatility of the aryl ether
synthetic route of the invention. A variety of substituted aromatic compounds
with
attached alcohol moieties were subjected to palladium-catalyzed cross coupling
to afford
variously substituted heterocyclic ethers. The starting aromatic compounds and
alcohols
CA 02467977 2004-06-08

-28
are reported in Table I . The reactions were carried out as described in the
legend.
As shown in Table l, five, six and seven-membered heterocycles were obtained
in
good yields from the corresponding aryl halide. In addition, a number of
functional
groups were found compatible with the reaction conditions including acetals
(Example 3),
silyl ethers (Example 4), and amides (Example 7). Reactions performed using
method A
were significantly slower (24-36 h) than reactions performed using method B (l-
6 h), :-
however, the reactions using method A were somewhat cleaner. Cyclization of
the aryl
iodide substrate (Example 2) was extremely slow in toluene, but in 1,4-
dioxane, complete
conversion occurred in 24-36 h. Two equivalents of ligand relative to
palladium (P:Pd =
4) and two equivalents of base relative to substrate were used to achieve
reasonable yields
in the cyclization reactions of Example 1 l containing a secondary alcohol.
Observed side
products included dehalogenation of the aryl halides and in the case of
substrates
containing secondary alcohols, along with the oxidation of the alcohol to a
ketone.
CA 02467977 2004-06-08

. -29 -
Tabte 1. Pd-Catalyzed Synthesis of Cyclic Aryl Ethers
~w suhsua~e Method' P~oclucc llieia ~~flb
A bte 89
~IMe Me ~I
a. _ o M.
/ ~ / Me .
\ ( Me Me A ~s~~Me ~
1
IAOMO MOMO
Me /
3 Me A \ Me 93
Br M.
?BOMSO OH T60M9O
Me
Me
\ & A \ I Me
Me
HO Me
~ I A \ ( 65
Me
hi~ Me H
/ /
6 \ I A ~,, I 73
OH
Me
/ Me /
I _ Me I
7 Ep \ ~ A EyIV \ O~ Me 66
Me
O 0~.~ O
Me /
8 \ ( M D \ ( Me 69
Br Me
Me
9 / I Mo B ~ I
6~i
\ & OH \ Q~ Me
HO Mo Ms
' I D \ I 73
O Me
aH
s
/ /
1 \ ( C \ I 0,~ 66
H
OH
. t2 ~ ( Me C \ I o 32
g Me
Method A: 5 mol 9'o Pd(OAc)Z, 6 mol % Tol-BINAP, 1? equiv
of K~CO~ in toluene at 100 °C. Method B: 3 mol % Pd(OAc)2, 3.6
:~ol 9c DPPF, 1.2 equiv of NaOt-Bu in toluene at 80 °C. Method C:
mol ~'o Pd(OAc)2, 10 mol °!o DPPF, 2.0 equiv of NaOc-Bu in toluene
a~ 90 °C. b Yields refer to average isolated yields of two or more
rugs.
Reaction was performed in 1,4-dioxane.
CA 02467977 2004-06-08

-3U -
Example ~2. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 4-t-butoxybenzonitrile.
A Schlenk tube was charged with Na(OtBu) (97 mg, 1.00 mmol), Pd(OAc)~ (5.6
mg, 0.025 mmol), (R)-(+)-2,2'-bis(di-p-tolylphosphino}-1,1'-binaphthyl (Tol-
B1NAP)
(20.4 mg, 0.030 mmol), 4-bromobenzonitrile (9l mg, 0.50 mrnoi), and toluene (3
mL).The
mixture was heated at 100 'C for 30 h under an atmosphere of argon. The
mixture was
cooled to room temperature and diethyl ether (20 mL) and water (20 mL) were
added. The
organic layer was separated, washed with brine (20 mL), dried over anhydrous
MgSO,,
and concentrated in vacuo. The crude product was purified by flash
chromatography on
silica gel (19l1 hexanelethyl acetate) to afford 4-t-butoxybenzonitrile as a
yellow oii (39
mg, 45°/a yield).
Example 13. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 4-~-butylphenyl t-butyl ether.
An oven dried Schlenk equipped with a teflon coated stir bar was charged with
Na(Ut-Bu) (97 mg, 1.00 mmol), Pd(OAc)~ (5.6 mg. 0.025 mmol), and Tol-BINAP
(20.4
mg, 0.030 mmol). The Schtenk was evacuated, back-filled with argon, and
charged with
toluene (3 mL) and 4-t-butyl bromobenzene (87 ItL, 0.50 mmo!). The mixture was
heated
at 104 'C for 40 h at which time the mixture was cooled to room temperature
and diethyl
ether (20 mL) and water (20 mL) were added. The organic layer was separated,
washed
with brine (20 mL), dried over anhydrous MgSO,, and concentrated in vacuo. The
crude
product was purified by flash chromatography on silica gel (99lI hexanelethyl
acetate) to
afford 4-t-butylphenyl t-butyl ether as a yellow oil (59 mg. 53% yield).
Example 14. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 4-benzonitriie cyclopentyl ether.
A Schienk tube was charged with NaH (80.0 mg, 60% dispersion in mineral oil,
2.00 mmol), cyctopentanol { 182 ~tL, 2.00 mmvl), and toluene (2.5 mL). The
mixture was
heated at 70 'C for 30 minutes under an atmosphere of argon followed by the
addition of
Pd(OAc)Z (6.7 mg, 0.030 mmol), (R)~(+)-2,2'-bis(di-p-tolylphosphina)-l,l'-
binaphthy!
(Tol-BINAP) (27.2 mg, 0.040 mmol), 4-bromvbenzonitrile (182 mg, 1.00 mmol),
and
toluene (2.5 mL). The mixture was heated at 100 'C for 1.5 h at which time
diethyl ether
(30 mL) and water (30 mL) were added at room temperature. The organic layer
was
separated, washed with brine (20 mL), dried over anhydrous MgSO,, and
concentrated in
vacuo. The crude product was purified by flash chromatography on silica gel
{1911
CA 02467977 2004-06-08

-3 t -.
hexanelethyl acetate) to afford 4-benzonitriie cyclopentyl ether as a
colorless oil (140 mg,
?5% yield).
Example I 5. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 4-benzonitrile isopropyl ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
.
with NaH (60% dispersion in mineral oil, 40 mg, 1.00 mrnol), placed under
vacuum, and .
back-filled with argon. To this was added 2-propanol (46 pL, 0.60 mmol) and
toluene (2
mL). The mixture was heated at 50 'C for 1 S min at which time the 4-
bromabenzonitrile
(91 mg, 0.50 mmol), Fd,(dba), (6.9 mg, 0.0075 rnmot), (R)-(+)-2,2'-bis(di-p-
tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) ( 12.2 mg, 0.018 mmol), and 1 mL
of
toluene were added. The mixture was heated to 50 'C white under an atmosphere
of
argon. After 22 h, water (50 mL) and diethyl ether (50 mL) were added and the
aqueous
layer separated and extracted with diethyl ether (50 mL). The organics were
combined,
washed with brine (50 rnL) and dried over anhydrous MgSO,. The crude product
was
i S purified by flash chromatography on silica gel ( 19:1 hexane/ethyl
acetate) to afford 4-
benzonitrile isopropyl ether (65 mg, 80% yield) as a white solid.
Example 16. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 1-naphthyl cyclohexyl ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
with NaH (40 mg, 1.50 mmol), toluene (2 mL) and cyclohexanol (94 pL, 0.90
mmol).
The mixture was heated to 70 'C for 10 min under an atmosphere of argon. To
this was
added -1-bromonaphthalene (104 pL, 0.75 mmol), Pd,(dba)~ (10.3 mg, 0.0113
mmol), {R)-
(+)-2,2'-bis(di-p-tolytphosphino)-I,l'-binaphthyl (Tol-BINAP) (18.3 mg, 0.02?
mmol),
and 2 mL of toluene. The mixture was heated to TO 'C for 20 h at which time
water (60
mL) and diethyl ether (60 mL) were added. The aqueous layer was separated and
extracted with diethyl ether (60 mL). The organics were combined, washed with
brine (60
mL) and dried over anhydrous MgSO,. The drying agent was removed by filtration
and
the mother liquor concentrated in vacua. The crude product was purified by
flash
chromatography on silica gel (50:1 hexanes:ethyl acetate) to afford 1-naphthyl
cyclohexyl
ether ( 101 mg, 60% yield) as a colorless oil.
Example 17. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 3-pentyl-(4-trifluoromethylphcnyl) ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
CA 02467977 2004-06-08

-f2
with NaH {60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under
vacuum and
back-filled with argon. To this was added toluene (2 mL) and 3-pentanol (98
IrL, 0.90
mmol). The mixture was heated at 70 'C for l0 min at which time 4-
bromobenzotrifluoride (105 NL, 0.75 mmol), Pdz(dba), (10.3 mg, 0.01 l3 mmol),
(R)-(+)-
S 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyt (Tol-BINAP) (18.3 mg, 0.02?
mmol), and 1
mL of toluene were added. The mixture was heated to 70 'C for 18 h at which
time
diethy! ether (60 mL) and water (60 mL) were added. The aqueous layer was
separated
and extracted with diethyl ether (60 mL). The organics were combined, washed
with brine
(60 mL) snd dried over MgSO,. The drying agent was removed by filtration and
the
mother liquor concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel ( 19:1 hcxanes:ethyt acetate) to afford 3-pentyl-
(4-
trifluoromethylphenyl) ether ( 114 mg, 54% yield) as a colorless oil.
Example 18. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 9-anthryl cyclopentyl ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under
vacuum and
back-filled with argon. To this was added toluene {2 mL) and cyclopentanol
(109 pL, 0.90
rnrnol). The mixture was heated at 70 'C for 15 min at which time 9-
bromoanthracene
(193 ~tL, 0.75 mmol), Pd,(dba), (10.3 mg, 0.0113 mmol), (R)-(+)-2,2'-bis(di-p-
tolylphosphino)-I,l'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of
toluene were added. The mixture was heated at 100 'C under an atmosphere of
argon.
After 20 hours diethyl ether (30 mL) and brine (30 mL) were added. The organic
layer
was separated and dried over anhydrous MgSO,. The drying agent was removed by
Fltration and the mother liquor concentrated in vacuo. The crude product was
purified by
flash chromatography on silica gel (99:1 hexanes:ethyl acetate) to afford 9-
anthryl
cyclopentyl ether (135 mg, 68% yield) as a yellow solid
example 19. This example demonstrates the palladium-catalyzed interrnalecular
synthesis of the aryl ether, 4-benzonitrile benzyt ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
with NaH {b0% dispersion in mineral oil, 60_mg, I.50 mmol), placed under
vacuum and
back-filled with argon. To this was added toluene (2 mL) and benzyl alcohol
(93 ~tL, 0.90
mmol). The mixture was heated at ?0 'C for i0 min at which time 4-
bromobenzanitrile
(136 p.L, 0.75 mmol), Pd,(dba), (10.3 mg, 0.0113 mrnol), (R)-(+)-2,2'-bis(di-p-
CA 02467977 2004-06-08

.33 -
tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 1 mL of
toluene were added. The mixture was heated at 70 'C under an atmasphere of
argon.
After 14 hours diethyl ether (SO mL} and water (SO mL) were added. The aqueous
layer.
was separated and extracted with diethyl ether (SO mL). The organics were
combined;
S washed with brine (SO mL), and dried over MgSO,. The drying agent was
removed by
filtration and the mother liquor concentrated in vacuo. The crude product was
purified by '
hash chromatography on silica gel (19:1 hexanes:ethyl acetate) to afford 4-
benzonitrile
benzyl ether (I 13 mg, 72°lo yield) as a white solid.
Example 20. This example demonstrates the palladium-catalyzed intermolecular
synthesis of the aryl ether, 4-benzonitrile methyl ether.
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged
with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under
vacuum and
back-filled with argon. To this was added toluene (2 mL) and methyl alcohol
(87 p,L, 0.90
tnmol). The mixture was heated at 70 'C for 10 min at which time 4-
bromobenzonitrile
1S (136 pL, 0.75 mrnol), Pd3(dba)~ (10.3 mg, 0.0113 mmol), (R)-(+)-2,2'-bis(di-
p-
tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol}, and 1 mL of
toluene were added. The mixture was heated at 70 'C under an atmosphere of
argon.
After 20 hours diethyl ether (SO mL) and water (SO mL) were added. The aqueous
layer
was separated and extracted with diethyl ether (SO mL). The organics were
combined,
washed with brine (SO mL}, and dried over MgSO,. The drying agent was removed
by
filtration and the mother liquor concentrated in vacuo. The crude product was
purified by
flash chromatography vn silica get { 19:1 hexanes:ethyl acetate) to afford a-
benzonitrile
methyl ether (77 mg, 77% yield) as a white solid.
Exac~ple 21: Direct Observation of C-O Reductive Elimination From
2S Palladium(Aryl)Alkoxide Complexes to Form Aryl Ethers
Reaction of KOCHZCMe3 with [(R)-Tol-BINAPJPd(~n-G6H4CN)Br (1) or
(dppf)Pd(p-CbHqCN)Br (2} formed the palladium(p-cyanophenyl)neopentoxide
complexes [P-P]Pd{p-C6H4CN)(OCH~CMe3) [P-P = Toi-BINAP (4), dppf {6)] as the
exclusive products. Thetmolysis of 4 in THF-dg at SS °C formed p-
neopentoxybenzonitrile (5) in 85 % yield {tt.~ = 2.7 min). Thermolysis of 6 in
THF-ds
at SS °C formed 5 in 60 % yield and pivaidehyde in 23 % yield (tt~ =
8.8 min).
Kinetic analysis of the decomposition of 4 in the presence of excess alkoxide
established the two-term rate law: Rate = k[4] + k'[4)[KOCH2CMe3]. The
alkoxide
CA 02467977 2004-06-08

-
independent pathway is consistent with direct reductive elimination from 4 to
generate
S and [(R}-Tol-BINAP]Pd (t). The alkoxide dependent pathway is consistent with
either alkoxide attack at palladium followed by reductive elimination from a
five-
coordinate palladium bis(alkoxide) complex or is consistent with attack of
alkoxide at
the ipso carbon atom of the palladium-bound aryl group followed by elimination
of
{ [(R)-Tol-BINAPJPd(OCH2CMe3)?- (la).
Reductive elimination from a low valent group 10 metal center to fairn an aryl
C-C bond represents the key bond forming step in a variety of synthetically
relevant
catalytic cross-coupling protocols. i As a result, the mechanisms of C-C
reductive
elimination from well defined Pd, Ni, and Pt complexes have been intensely
investigated.' Similarly, C-X [X = N, S] reductive elimination presumably
serves as
the key bond-forming step in the corresponding palladium-catalyzed cross-
coupling
protocols,3~~ and both C NS and C-S6 reductive elimination from well
characterized
group 10 metal complexes has been directly observed. Despite numerous examples
of
group 10 metal(aryl~lkoxide complexes, direct thermal reductive elimination to
foam
an aryl C-0 bond has not been observed 8~9 We have recently developed a
palladium-
catalyzed procedure fvr the formation of aryl ethers from aryl bromides and-
sodium
alkoxides which employed mixtures of Pd(OAc)~ and bulky chelating
bis(phosphine)
ligands such as 1,1'-bis(diphenylphosphino)ferrocene (dppfj or (R)-(+)-2,2'-
bis(di p-
tolylphosphino)-1,1'-binaphthyl [(R)-Tol-BINAP].tfl Significantly, this system
appeared to provide an opportunity to observe (aryl)C-0 reductive elimination
from a
group 10 metal center. Here we report the generation of thermally unstable
palladium(aryl)-alkoxide complexes which undergo reductive elimination to form
aryl
ethers.
Our approach to generate pailadium(aryl)alkoxide complexes with chelating
bis(phosphine) ligands involved direct displacement of the bromide ligand of a
palladium (p-cyanophenyi)bromide complex with potassium neopentoxide.
Neopentoxide was employed due to its diagnostic signals in the ~ H NMR
spectrum and
because neopentanol coupled efficiently with aryl bromides under catalytic
conditions. t ~ The requisite palladium ehelating bis(phosphineXp-
cyanophenyl)bromide complexes Pd[(R~ToI-BINAP](p-C6HaCNXBr} (I} and
Pd(dppf)(p-C~H~CN)(Br) (2} were prepared in good yield (>75 %) from reaction
of the
palladium trio-tolylphosphine} dimer {Pd[P(o-tolyl)3](p-C6H~CN)(p-Br)}2 (3)
with
CA 02467977 2004-06-08

-35 -
(R)-Tol-B1NAP or dppf, respectively. Complexes 1 - 3 were characteriud by
standard
spectroscopic techniques and elemental analysis (Scheme 21.1 ).
CN CH
/ P~ ~ (o-tol}~P.~ - fgr ~p\
Pd ~(R1-Tol-BINAP pd~ dpi ~
...".p/ \t3r . ~ i 6r ~ p/ d\6r
Ar: ~'' ~ph=
1 (Ar~ P-tolyll Nc
2
S Treatment of a pale yellow solution of 1 in THF-dg with a slight excess (--
1.!
equiv.) potassium neopentoxide formed an orange solution of the palladium
neopentoxide complex [(R)-Tal-BINAP]Pd(p-C6H4CNXOCH2CMe3) (4) in
quantitative yield (tH NMR; PhSiMe3 internal standard). Solutions of 4
darkened
within minutes at room temperature and attempts to isolate d from the
corresponding
preparative scale reaction were unsuccessful. As a result, alkoxide complex 4
was
characteriud by i H and 3 ~ P NMR spectroscopy without isolation. The ~ H NMR
spectrum of 4 in THF-dg displayed a l :I:1:1 ratio ofp-toIyl peaks at 8 2.38,
2.19, 1.98,
and 1.93 and a single tent-butyl resonance at 0.17; the ratio of these
resonances
established the 1:1 ratio of neopentoxide ligands to [(R)-Tol-BINAP]PdAr
groups. A
I 5 pair of doublets at 2.76 and 2.62 (J = 8.8 Hz) assigned to the
diastereotopic methylene
protons of the alkoxide ligand confirmed binding of the alkoxide to the chiral
metal
fragment. The ~ t P NMR spectrum of 4 displayed two doublets at 25.1 and 12. I
(Jpp =
~36 Hz), which established bidentate coordination of the phosphine ligand to
the
palladium alkoxide fragment.
CN CN
/
P~ ~ P~ O ~t-8u O
pd KO t~u ~ 55'C '
/ \ THF_ d~ C / \ /'~ ,J 5
H~-8u
P 8r P O t-Bu NG
~P = Tot-Binap (1~ ~P = Tot-t3lnap (1) 85~/. < 2Y.
p dppf (2) p dppf (6j 6Q'/. 2~'/.
Thermolysis of a freshly prepared solution of 4 in THF-dg at 55 °C led
to rapid
decomposition (tin A 2.7 min).i2 tH NMR and GCMS analysis of the resulting
black
CA 02467977 2004-06-08

r
-36
solution revealed the formation of p-neapentoxybenxonitrilc (5, 85 %), 4,4'-
dimethylbiphenyl (--10 %}, and traces of benzonitrile (<5 %).t3 Products
resulting
from Fd/F aryl exchanget4.ts such as p-neopentoxytoluene or 4-methyl-4'-cyano-
biphenyl were not observed. Thermolysis of 4 in the presence of PPh3 led to no
w
increase in yield of 5 but lowered the yield of 4,4'-dimethylbiphenyl (< 2 %).
This
behavior is in contrast to C-S reductive elimination froEn related
palladium(aryl)tert-
butylsulfide complexes which required the presence of a trapping agent to
benerate
high yields of thioether.s In addition, these observations suggest that the P-
C bond
cleavage reaction which forms 4,4'-dimethylbiphenyl occurs subsequent to C-0
reductive elimination from the reactive bis(phosphine) Pd(0) species ((R)-Tol-
BINAP]Pd (I); PPh3 presumably traps I prior to P--C oxidative addition.
Thermolysis
of 4 in the presence of '0.04 M KOCH~CMe3 led to nearly quantitative formation
of 5
('94 t 5 %).
Addition of 1.1 eq KOCH2CMe3 to a suspension of 2 in THF-dg formed
Pd(dppf)(p-CbH4CNXOCH2CMe3) (6) as the exclusive palladium species as
indicated
by ~ H and 3 ~ P NMR spectroscopy; 6 was characterized by t H and 3 ~ F NMR
without
isolation. Decomposition of neopentoxide complex 6 at 55 °C was ~ 4
times slower
(hn_ = 8-8 ruin) than decomposition of 4. tH NMR and GC analysis of the
resulting
black solution revealed the presence of 5 (60 %), pivaldehyde (23 %),
benzonitrile (30
%), and biphenyl (-10 %) (Table 2I.1, Scheme 21.2). Presumably, the lower rate
of
reductive elimination from 6 relative to 4 leads to competitive (i-hydrogen
elimination
in the case of 6 with formation of pivaldehyde.t6
CA 02467977 2004-06-08

. -37 -
Table 21.1. First-order rate constants and yields of 5 for the decomposition
of 4 ([Pd]
A 1. x 10-Z M) in THF-dg.
ArOR
Temp (1d'~"s yield (t 5to)
[KOCt-~Ct-l~J '
23 0.0017 1.42 t 76
0.01
23 0.0017 1.43 t -
0.09
23 0.0017 1.45 t 72 a
0.02
35 0.0017 5.2 t 0.2
37 0.0017 6.3 t 0.2 -
47 0.0017 15.7 t 84
0.2
47 0.0017 14.9 t 86
0.5
47 0.0017 16.1 t - b
0.3
47 0.043 11.8 t 97
0.6
47 0.11 20.9 t 97
0.6
47 0.12 23.0 t -
0.9
47 0.17 23.2 t 94
0.3
47 0.20 25.5 t -
0.9
47 0.26 33 f 1
47 0.28 33 t 1 -
52 0.0017 30 t 1 85
55 0.0017 43 t 2 -
55 0.0017 45 t 3 87 a
57 0.0017 58 t 2 86
aContained FPh3 (0.15 M). bContained excess KBr
CA 02467977 2004-06-08

-38 =
The kinetics of the reductive elimination of 4 were investigated in greater
detail
in an e~'ort to probe the mechanism of palladium mediated C-0 bond formation.
Thermotysis of a freshly prepared solution of 4 t[4jp = 17 mM} in THF-dg at 4?
°C
led to first-order decay of 4 over > 3 half lives with an observed rate
constant of tcobs =
1.52 f O.OS x l0-3 sv.~2~~~~~g The rate of decomposition of 4 in THF-dg was
not
significantly altered (<10%) by the presence of PPh3 (0.15 M) or KBr
(saturated) but
was accelerated by addition of excess KOCHZCMe3. In order to determine the
dependence of the rate on alkoxide concentration, observed rate constants for
decomposition of 4 were measured as a function of KOCHZCMe3 concentration from
0.0017 to 0.30 M at 4? °C in THF-dg. A plot of kobs versus alkoxide
concentration
was linear with a significant positive intercept of the ordinate which
established the
two-term rate law shown in eq 1, where k = 1.50 f 0.0'7 x 10-3 s'~ [OG: = 22.9
f 0.1
kcal mol-~J and k~ = 6.2 t 0.4 x i0-3 s-~ M-~ [AG~ = 22.0 t 0.1 kcal mol-~].~~
In
addition, observed rate constants for disappearance of 4 in the absence of
added
I 5 KOCH2CMe3 ~'- were measured at temperatures between 23 and S7 °C in
THF-dg. An
Eyring plot of the data provided the activation parameters for the alkoxide
independent
pathway: OIY~ = 19.8 t 0.8 kcal mol-~; ASS _ -g f eu. ~~~19
rate = - d4 = k[4j + k'[4j[KOCHZCMegJ
. (I)
The neopentoxide ligand of 4 underwent facile associative exchange with free
KOCH2CMeg at 47 °C in THF-dg. At low KOCHZCMeg concentration (<2
mM), the
tH NMR spectrum of 4 at 47 °C displayed a sharp tort-butyl resonance
(c~utn < 2 Hz)
2S with no loss of coupling between the diastereotopic benzyl protons.
However, in the
ptrsence of excess KOCHZCMe3, the tert-butyl peak broadened considerably.
Observed rate constants for alkoxide exchange were determined from excess line
broadening (twin = k!n)2p as a function of aikoxide concentration from 0.0017
to 0.3
M KOCH2CMe3 at 4? °C. A plot of ko~ versus [KOCH~CMe3] established a
first-
order dependence of the rate of exchange on alkoxide concentration and the
second-
order rate law shown in eq 2, where ke,; = 1.0 t 0.1 x 102 s-~ M-~ [dG~ = 1
S.8 t 0.1
kcal mol-~ j. ~ ~
CA 02467977 2004-06-08

_3g _
rate of alkoxide exchange = k~X [4][KOCH~CMe3] (2)
CN~ "
,,,OR
..
CN P Pd.~
OR
P p a
p ~ P CN
Pd-X t
Pd
P / RO
P d OR k O~ Rt t ~ x . ~ ~~ (p 5
W ~ OR tta)
~ P = Tol-81NAP P~ ~CN
P ~ Pd
R = CH=CIYIa~ /
P OR
pl
Reductive elimination from square planar dg metals to form C-C bonds has
been proposed to occur from three-, four-, or five-coordinate complexes. ~ The
experimental rate law for decomposition of 4 (eq 1 ) is consistent with C-O
reductive
elimination via competing alkoxide dependent and alkoxide independent
pathways.
The activation parameters for the alkoxide independent pathway are consistent
with
unimolecular reductive elimination directly from 4 to form 5 and presumably
the Pd(0)
species t (Scheme 2I.3), where the empirical rate constant k = k~ (Scheme
21.3).5
We can not strictly rule out a mechanism initiated by rapid and reversible
dissociation
of a single phosphorus center. However, the rate of C-S reductive elimination
from
palladium(aryl)tert-butylsulfide complexes was not effected by the rigidity of
the
chelating phosphine ligand, which suggested that ligand dissociation did not
precede
reductive elimination.5
The alkoxide dependent pathway could occur via rapid and reversible attack of
alkoxide at palladium to generate the five-coordinate bis(alkoxide)
intermediate
{Pd[(R)--Tol-BINAPJ(p-C6H4CN)(OCH2CMe3)2}- (tt) or a related isomer.2~ Rate
limiting reductive elimination from tt could then generate 5 and presumably
the three-
coordinate palladium alkoxide fragment {[(R)-Tol-I3INAPJPd{OCH2CMe3)}~- (Ia).
CA 02467977 2004-06-08

=ao -
.
Tht intermediacy of II is supported by the facile associative alkoxide
exchange
observed for 4 in the presence of KQCHICMeg. The steady-state rate law for
this
pathway (eq 3) is of the same form as the second term of the experimental rate
law (eq
I ), where k' = k2k31(k_2 + k;). Alternatively, the alkoxide dependent pathway
could
occur via direct attack of atkoxide at the ipso carbon atom of the palladium-
bound aryl
group to form the Meisenheimer complex III. Collapse of III would then
generate 5
and Ia. The steady-state rate law for this pathway (eq 4) is also of the same
form as
the second term in the experimental rate law (eq 1 ) where k' = k4k5/(~ +
ks).22
14 rate _ - d4] =k- k2k k [4][KOCH2CMe3] (3)
rate = - ~ =-~-[4J(KOCH2CMe3] (4)
dt k~+k5
In conclusion, we have presented the first examples of C-0 reductive
1 S elimination from group 10 metal(aryl)alkoxide complexes to form aryl
ethers. Kinetic
analysis of the decomposition of 4 in the presence of excess alkoxide
established a
two-term rate taw consistent with the presence of both an alkoxide independent
and
alkoxide dependent pathway for C-0 reductive elimination. We continue to
investigate the mechanism of this important transformation. ~b In particular,
we are
20 probing the electronic and steric effects of both the palladium-bound aryl
gmup and
the chelating phosphine ligand on the rate and efficiency of C-0 reductive
elimination.
Experimental Protocol jor Example 20
General Methods. All manipulations and reactions were performed under an
25 atmosphere of nitrogen or argon in a glavebox or by standard Schlenk
techniques.
Preparative scale reactions were performed in flame or oven dried Schlenk
tubes
equipped with a stir bar, side arm joint, and a septum. NMR spectra were
obtained in
oven dried 5 mm thin-walled NMR tubes capped with a rubber septum an a Varian*
XL-300 spectrometer at 22 °C unless otherwise noted. Gas
chromatography was
30 performed on a Hewlett-Packard* model 5890 gas chromatograph using a 25 m
* Trade-mark
CA 02467977 2004-06-08

-41 -
polymethylsiloxane capillary column. GC response factors were determined from
mixtures of pure compounds. Elemental analyses were performed by E+R
Microanalytical Laboratories (Corona, NY). Diethyl ether, hexane, and THF-dg
were
distilled from solutions of sodiumlbenzophenone ketyl under argon or nitrogen.
Pdz(DBA)3, P(o-tol)3, {R)-Tol-BINAP, dppf (Strem), 4-bromobenzonitrile,
pivaldehyde, biphenyl, 4,4'-dimethylbiphenyi, and benzonitrile (Aldrich) were
used as
received. KOCH2CMe3, was synthesized from reaction of anhydrous neopentanol
(Aldrich) and I equiv KH in THF.
Kinetic Measurements. Samples for kinetic analysis were prepared from
f 0 stock solutions of the appropriate palladium aryl halide complex and were
performed
in oven dried 5 mm thin-walled NMR tubes capped with rubber septa. Solvent
volume
in the NMR tubes was calculated from the solvent height measured at 25
°C according
to the relationship V (mL) = H (mm) X 0.013$4 - 0.006754 and from the
temperature
dependence of the ,density of benzene.'-3 Kinetic data was obtained by iH NMR
1 S spectroscopy in the heated probe of a Varian XL-300 spectrometer. Probe
temperatures were measured with an ethylene glycol thermometer and were
maintained
at t 0.5 °C throughout data acquisition. Syringes employed in measuring
liquids for
kinetic measurements were calibrated by mercury displacement and were accurate
to >
95 °to. Error limits for rate constants refer to the standard deviation
of the
20 corresponding least-squares-fct line.
(Pd[P(o-tolyl)3[(p-C6HdCN)(p-Br)}~ (3). A purple solution of Pd~(DBA)3
( 1.0 g, i . i mmol), P(o-tal)3 ( 1.3 g, 4.3 mmol) and p-bromobenzonitrile
{2.0 g, 11
mmol) in benzene (60 mL) was stirred at room temperature for 1 h. The
resulting
greenlbrown solution was filtered through Celite and benzene was evaporated
under
25 vacuum. The oily residue was dissolved in Et20 (25 mL) and allowed to stand
at room
temperature overnight. The resulting yellow precipitate was filtered, washed
with
Et20 and dried under vacuum to give 3 (0.95 g, 75 %) as a yellow powder. tH
NMR
(CHC13, 55 °C): 8 7.33, 7.13, 6.90, 6.73, 2.10. 3 ~ P { ~ H ~ NMR
(CDCI3, 55 °C): &
22.5 {br s). IR (THF): vl~N1 2222 cmat. Anal: calcd. (found) far
30 CS6H~oBr2N2P2Pd2: C, 56.73 (56.57); H, 4.25 (4.51 ).
Pd[(R)--To1-BINAPy(p-C,~H4CN)(Br) (1). A solution of 3 (200 mg, 0.17
mmol), and (R)-Tol-BINAP (240 mg, 0.35 moral) in CH2Cl2 {10 mL) was stirred at
room temperature far 5 h and then evaporated under vacuum. The oily residue
was
dissolved in Et~O (IO mL) and allowed to stand at room temperature far 4 h.
The
CA 02467977 2004-06-08

-42 -
resulting precipitate was filtered, washed with Et20 and dried under vacuum to
give 1
(308 mg, 94 °lo) as a yellow solid which contained traces of ether (<5
%) by tH NMR
analysis. ~ H NMR (THF-dg): b 8.26 (dd, J = 8.73, 10.5), 8.04, (t, J = 8.2
Hz), 7.98 (t,
J = 9.3 Hz), 7.91 (q, J = 7.7 Hz), 7.77 - 7.60 (m, 7 H), ?.38 (m, 4 H), 7.28 -
7.14 (m, 5
l~), 6,90 (d, J = 8.4 Hz, I H). 6.7? (d, J = 6.8 Hz, 2 H, CbN~CN), 6.67 (d, J
= 7.0 Hz, 2
H, C~H4CN), 2.?6 (s, 3 H, p-toiyl), 2.56, (s, 3 H, p-tolyl), 2.31, (s, 3 H, p-
tolyl), 2.29
(s, 3 H ,p-tolyl). 3 ~ P { t H } NMR: b 26.? (d, J = 38.1 Hz), 11.4 (d, J =
37.9 Hz). 1R
(1'HF): vl~~Nl 2219 cm-t. Anal: calcd. (found) for CSSH44BrNP2Pd: C, 68.30
(68.36); H, 4.59 (4.8?).
! 0 Pd(dppt)(p-C6H~CN)(Br) (2). A solution of 3 (200 mg, 0.1 ? mmol), and dppf
(258 mg, 0.4T mmol) in CH2CI2 (10 mL) was stirred at room temperature for 12
h.
The resulting solution was concentrated under vacuum. Addition of Et~O ( 10
mL)
formed a precipitate which was filtered, washed with Et20 and dried under
vacuum to
give 2 (280 mg, 79 %) as a bright yellow solid which contained traces of ether
(<5 %)
by iH NMR analysis. tH NMR (CDCl3): S 8.0! (dt, J= 2.7, 9.7 Hz), ?.47 (m. 6
H),
7.33 (t, J = 1 t .2 Hz, 6 H), 7.12 (dt, J = 1.7, 15.4 Hz, 6 H), 6.76 (d, J =
7.54 Hz, 2 H),
4.68 (d, J = 1.95 Hz, 2 H, Cp). 4.51 (s, 2 H, Cp), 4,14 (d, J = 2.23 Hz, 2 H,
Cp), 3.59
(d, J = 1.74 Hz, 2 H, Cp). 3 t P { t H } NMR (CDC13): b 30.0 (d, J = 29.2 Hz),
10.8 (d, J
- 31.6 Hz). IR (CH2Cl2): vlc~N1 2220 cm-~. Anal: calcd. (found) far
C4 ~ H32BrFeNP2Pd: C, 58.43 (58.4 ! ); H, 3.83 (3.98).
Pd((R}-Tot-BINAP](p-C6H4CN)(OCH2CMe3) (4). A 0.54 M solution of
KOCH2Me3 in THF-dg (25 pL, 1.35 x l0-2 mmol) was added via syringe to a
colorless solution of 2 ( 12 mg, 1.25 x 10-2 mmol) and PhSiMe3 ( 1.75 mg, 1.16
x 10-2
mmol) in THF-dg (0.70 mL). The tube was shaken briefly at room temperature and
centrifuged to form an orange solution of 4 in quantitative (98 t S %) yield
by t H
NMR spectroscopy versus PhSiMe~ internal standard. 4 was thermally unstable
and
was analyzed without isolation by ~ H and 3 ~ F NMR spectroscopy. i H NMR (THF-
dg): in addition to a small resonance corresponding to free alkoxide (8 0.85),
resonances were observed at 8 7.83 (t, J = 8.4 Hz), 7.78 - ?.59 (m), 7.51 -
7.25 (m),
7.12 (t, J = 7.4 Hz), 7.04-6.93 (rn), 6.81 (d, J = 7.0 Hz), 6.44 (d, J = 7.4
Hz), 6.29 (d, J
= 7.4 Hz) 2.?6 (d, J = 9.0 Nz, 1 H, -OCHZCMe~), 2.62 (d, J = 8.8 Hz, 1 H, -
OCH2CMe3), 2.38 (s, 3 H, p-tolyl), 2.19 (s, 3 H, p-tolyl), 1.98 (s, 3 H, p-
tolyl), 1.93 (s,
3 H, p-tolyl), 0.17 (s, 9 H, CMc3). 3 ~ P { i H } NMR (THF-dg): & 29.3 (d, J =
36.6 Hz),
14.1 (d,J= 36.7 Hz). IR (THF): v~~aN~ 2218 cm-~.
CA 02467977 2004-06-08

-43 -
Pd(dpplNp-C6H,tCN)(UCH=CMe3) (6}. A yellow suspension of 2 ( I I mg.
1.3 x 10-~ mmol) in THF-d8 (0.70 mL) was treated with aliquots of KOCH2Me3 in
THF-dg. Addition of 1.1 equiv alkoxide formed an orange solution of 6 and a
small
amount of free KOCH2Me3 as the exclusive products by ~ H NMR spectroscopy.
Despite the relatively slow decomposition of 6' at room temperature (t ~n A 4
h}
attempts to isolate b from the corresponding preparative scale reaction gave
only
impure brown solids. ~ H NMR (22 °C, THF-d8): 8 8.21 (m, 4 H), ?.4b
{m), 7.40 (d J
= 1 I .5 Hz), 7.37 (dd, J = 1.2, I 1.6 Hz), 7.31 (t, J = 7.3 Hz), ?.09 (dt, J
= 2.1, 8.0 Hz),
6.75 (dd, J = 2.2, 8.2 Hz, 2 H), 4.82 (q, J = 2.0 Hz, 2 H, Cp), 4.58 (br s, 2
H, Cp), 4.20
(t, J = 1.6 Hz, 2 H, Cp), 3.55 {q, J = 1.8 Hz, 2 H, Cp). 2.68 (s, 2 H,
OCH2CMe3), 0.23
(s, 9 H, OCH2CMe3 ). ~ t P { t H } NMR (22 °C, THF-dg): 8 30.9 (d, J =
32 Hz), 1 I .9
(d, J= 31.7 Hz). IR (THF): vIcENI 2218 cm-t.
Kinetics of Thermalysis of 4. An NMR tube containing a freshly prepared
solution of 4 ( 12 mg, I .2 x 10-~ mmol) and PhSiMe3 ( 1.75 mg, 1.16 x 10-2
mmol) in
THF-dg (0.70 mL) {[KOCH~CMe3] A 1.7 mM} was placed in the probe of an NMR
spectrometer heated at 47 °C. The concentrations of 4, and p-
neopentoxybenzonitrile,
were determined by integrating the tert-butyl resonances for 4 (b 0.17) and p-
neopentoxybenzonitrile (8 1.06) versus the trimethylsilyl resonance of PhSiMe3
(8
0.25) in the ~H NMR spectrum. The concentration of 4,4'-dimethylbiphenyl and
benzonitrile were determined by integration of the peaks for 4,4'-
dimethylbiphenyl,
benzanitrile, and PhSiMe3 in the GC spectnrm. The first-order rate constant
for
disappearance of 4 was determined from a plot of In [4] versus time (Figure 2,
Table
21.1 ). The corresponding plot of reciprocal concentration versus time (Figure
3)
deviated considerably from linearity.
First-order rate constants for disappearance of 4 in the absence of added and
KOCH~CMe3 (Q mM) were also obtained at 23, 35, 37, 52, and 57 °C
(Figure 2,
Table 21.1 ); activation parameters were obtained from a plot In [k/T] versus
1/T
(Figure 4). First-order rate constants for disappearance of 4 were also
measured as a
function of [KOCH2CMe3] from 0.043 to 0.30 M at 47 °C in THF-dg (Table
21.1).
Solutions of 4 with KOCHZCMe~ concentrations ranging from 0.43 to 0.12 M were
obtained by a procedure analogous to that described above. Solutions of 4 with
KOCHZCMe3 concentrations > 0.12 M were prepared by adding (via syringe) a THF-
dg solution of 4 (17 mM) to an NMR tube containing solid KOCH~CMe3. The first-
order rate constant k was obtained as the intercept of a plot of kobs versus
CA 02467977 2004-06-08

[KOCH~CMe3] (Figure 5). The second-order rate constant k' was obtained from
the
slope of this plot.
Kinetics of Alkoxide Exchange with 4. An NMR tube containing a freshly
prepared solution of 4 ( 12 mg, I .2 x 10-2 mmol, 19 mM), PhSiMe3 ( I .75 mg,
1. I6 x
10-'- mmol), and KOCHZCMe3 (3.4 mg, 0.0271 mmol, 0.043 mM) in THF-dg (0.63
mL) was placed in the probe of an NMR spectrometer heated at 47 °C. The
excess line
broadening (Aw gin) of the tart-butyl resonance of 4 was determined by
measuring the
peak width at half height (w p) for the tart-butyl resonance of 4 (8 0.17)
relative to
w p for the trimethylsilyl resonance of PhSiMe3 (S 0.25) in the ~ H NMR
specicum
[Aw tn (4) = w p (4) - w tn (PhTMS)]. Because the separation of the tart-butyl
peaks
for PdOCH~CMe3 and KOCH~CMe; (Av > 200 Hz) was much larger than the excess
broadening of the tern-butyl resonance of 4 (tn~~ = 5.5 Hz), the slow-exchange
approximation (Awin = k~sin) was employed to convert Awt~ to Jcobs.z~ Observed
rate constants for alkoxide exchange were also determined at K.OCH~CMe3
concentrations ranging from 0.001? to 0.30 M. The second-order rate constant
Ac~x for
exchange of alkoxide with 4 was determined from the slope of a plot of kobs
versus
[KOCH~CMe3] (Figure b, Table 21.2).
Table 21.2. First-order rate constants for alkoxide exchange 4 at 4? °C
in THF-dg.
[KOCt-lzCH3]k~ s [KOCt-t~Cti3]IBS
t s'~
0.0017 0.62 0.12 16
0.0082 1.6 0.17 18
0.019 3.0 0.20 22
0.030 4.2 0.26 26
0.043 6.1 0.28 29
0.11 17
CA 02467977 2004-06-08

;45 -
Kinetics of Thermolysis of 6. An NMR tube containing a freshly prcparcd
solution of 6 ( I I mg, 1.2 x 10-2 mmol, 18 mM) in THF-dg {0.70 mL) and
mesityfene
(1.72 mg, 1.14 x 10-2 mmol) was placed in the probe of an NMR spectrometer pre-
heated to 55 °C. The concentrations of 6, and p-neopentoxybenu~nitrile,
and
pivaldehyde were determined by integrating the tort-butyl resonances for 6 (8
0.23), p-
neopentoxybenzonitrile (S 1.06), and pivaldehyde (b 1.04) versus the methyl
resonance
of mesitylene (8 2.12) in the iH NMR spectrum. The concentration of biphenyl
and
benz~onitrile were determined by integration of the peaks for biphenyl,
benzonitriie,
and mesitylene in the GC spectrum. The first-order rate constant for
disappearance of
6 (k~,s = 1.33 t 0.04 x 10-3 s-t ) was determined from a plot of In [6] versus
time.
References for Example 20
1) (a) Stifle, J. K. Angew. Chem. Int. Ed Engl. 1986, 25, 508. (b) Miyaura,
N.;
Suzuki, A. Chem. Rev 1995, 9S, 2457. (c) de Meijere, A.; Meyer, F. E. Angew.
Chem. Int. Ed. Engl. 1994, 33, 2379.
2) (a) Collman, J. F.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and
Applications of Organotransition Metal Chemistry; University Science: Mill
Valley,
CA, 1987: p 322.
3) (a) Kosugi, M.; Ogata, T.; Terada. M.; Sano, H.; Migita, T. Bull Chem. Soc.
Jpn.
1985, 58, 3657. (b) Dickens, M. J.; Gilday,1. P.; Mowlem T. J.; Widdowson, D.
A.
Tetrahedron,1991, 47, 8621 and references therein.
4) (a} Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
7215
and references therein. (b) Louie, J.; Hartwig, 1. F. Tetrahedron Lett. 1995,
36,
3609.
5) Bilranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, I 17, 293?.
6) (a) Driver, M. S.; Hartwig, J. F. J. Am. Cheer. Soc. 1996, 118, 7217. (b)
Villanueva, L. A.; Abboud, K. A.; Bancella, J. M. Organometallics, 1994,13,
3921.
7} Bryndza, H. E.; Tam, W. Chem. Rev.1988, 88, 1163.
8) Oxidation of nickel oxametallacycIes has been demonstrated to form C(sp3}-O
bonds. Koo, K.; Hillhouse, G. L.; Rheingold, A. L. Organometallics, 1995, I ~,
456.
CA 02467977 2004-06-08

-46 -
9) Reductive elimination from Pd and Ni to form an ester C(Ol~-O bond has been
observed: Komiya, S.; Akai, Y.; Tanaka, K.; Yamamoto, T.; Yamamoto, A.
Organametattics 1985, 4, 1130. ,
10) (a) Pafueki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chern. Sac. 1996, t
t8,
10333. (b) Palucki, M.; Buchwald, S. L. submitted. '
11 ) (a) Palucki, M.; Buchwald, S. L. unpublished results. (b) We investigated
a
range of alkoxides and will report the results of these studies in a full
paper.
12) The solution contained a small amount (< 2 mM) of free KOCHZCMe~.
13) (a) The ultimate fate of the palladium is unclear. The t H NMR spectrum of
the
reaction mixture revealod a broad resonance at b 2.1 possibly corresponding to
(R)-
Tol-BINAP palladium complexes while the 3 ~ P NMR spectrum displayed a small
resonance for free (RrTol-BINAP (8 -l 6.1 ) and a broad resonance at b ~-2. No
resonances in the region expected for Pd[(R)-Tol-BINAPj2 {& --25 for Pd[(R)
gpfppj2 [ t 3b ire observed. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lets.
1992, 2177.
14) Motile, D. K.; Stille, J. K.; Norton, J. R. J. ~Im. Chem. Soc. 1995, 11 ?,
8576.
15) Braterman, P. S.; Cross, R. J.; Young, G. B. J. Chem. Sac., Datton Trans.
197?,
1892.
16) (a) Bryndza, H. E.; Calabrese, J. C.; Marsi, M.; Roe, D. C.; Tam, W.;
Bercaw,
J. E. d. Am. Chem. Soc. 1986, 108, 4805. (b) Hoffman, D. M.; Lappas, D.;
Wierda,
D. A. J. Am. Chem. Sac. 1993, ll~, 10538. (c) Blum, O.; Milstein, D. Angew.
Chem., Int. Ed Engl. 1995, 3~, 229.
17) See experimental protocol above.
18) The corresponding second-order plots (see Supporting Information) deviated
significantly from linearity. Rate measurements employing different batches of
4 and
KOCHzCMe3 provided values for k~,s which differed by < 7.5°fo.
19) Under these conditions {[KOCH2CMe3j< 2 mM}, k » k'[KOCH2CMe3j, and
~bS A k.
20) Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy, 2nd Ed. Academic
Press: San Diego, CA, 19$8.
CA 02467977 2004-06-08

-4? -
21) The proposed structure of II assumes the Tot-BINAP ligand will span an
equatorial-axial sites (90°) rather than equatorial-equatorial sites (
120°) in the trigonal
bipyramid due to the preferred bite angle of ~92°; Hayashi, T.;
Konishi, M.; Kobori,
Y.; Kurnada, M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Sac. 1984, 106, 158.
22) This rate law assumes rate limiting collapse of II1. The rate law for rate
limitins
formation of III, followed by rapid collapse to form 5 (rate =
k4[4][KOCH?CMe3]) is
also of the same form as the second term of the experimental rate law.
23) International Critical Tables of Numerical Data, Physic, Chemistry, and
Technology, Volume Ill, Washburn, E. W., Ed.; McGraw-Hill: London, 1928; pp
29,
39, 221.
24) Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy, 2"d Ed. Academic
Press: San Diego, CA, 1988)
~xamnle 22: Palladium-Catalyzed lntermolecuiar Carbon-Oxygen Bond Formation: A
New Synthesis of Aryi Ethers
The synthesis of aryl ethers by the intermolecular formation of a carbon-
oxygen
bond can be catalyzed by a combination of Pd2(dba)3 or Pd(OAc)~ and Tol-BINAP
in
toluene. This process yields aryl ethers in moderate to good yields. While
tittle or no
conversion is seen in control reactions run in toluene, it was found for some
electron-poor
aryl bromides that nucleophilic aromatic substitution could be carried out in
DMF is the
absence of metal catalyst under mild conditions.
Aryl ethers are ubiquitous structural constituents in pharmacologically
important
molecules, and, consequently, much research has been focused on their
synthesis.'
Available methods for the synthesis of aryl ethers via direct nucleophilic or
Cu(I)-
catalyzed substitution of an aryl halide with an alcohol typically require
high reaction
temperatures andlar a large excess of the alcohol and are limited in substrate
scope i~~~'
The need to employ HMPA, DMSO or DMF as solvent further diminishes the
applicability of these methods, particularly for large-scale processes.
Recently we reported the first example of palladium-catalyzed aromatic carbon-
oxygen bond formation; the intramolecular Pd-catalyzed ipso substitution of an
aryl
halide with an alcohol to afford oxygen heterocycles.s~6 This method was used
to
synthesize five-, six- and seven-membered oxygen heterocycles in moderate to
good
CA 02467977 2004-06-08

-48' _
yields.' We sought to determine whether a related catalyst system could be
used for the
synthesis of aryl ethers by the intermolecular coupling of alcohols and aryl
bromides {eq
1 )." Herein we report our initial results which demonstrate the viability of
using
palladium catalysis for the intermolecular formation of carbon-oxygen bonds in
a process
which takes place under mild conditions.
Pd2(dba)3 (l.5mo1%)
Tol-BINAP (3.6% moll) OR'
R + 1.2 R'OH + 2.0 NaH Toluene, heat R
/ /
The conditions employed for the intramoiecular process (vide supra) were not
immediately applicable to the intermolecular version. We found, however, that
reaction of
2-propanol, 4-bromobenzonitrile and NaH in the presence of 1.5 mo!% Pd~(dba)3
and 3
mol% (S)-(-)-2,2'-bis(di p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) at 50
°C afforded
4-isopropoxy-benzonitrile in 80% isolated yield.' Although Pd(OAc)2 was an
effective
catalyst precursor, use of Pd2(dba)3 afforded superior ratios of product to
reduced side-
product (benzonitrile) as determined by GC analyses.'° Aryl bromides
containing
electron-withdrawing substituents (Table l, entries I-S) coupled effectively
with a wide
variety of alcohols including 2-propanol, 3-pentanol, ( I R, 2S, SR)-(-)-
menthol," benzyl
alcohol and methanol within 24 hours using 1.5 mol% Pd~(dba)3 and 3.6 mol% Tol-
BINAP at 70 °C." The Pd-catalyzed coupling of methanol with 4-
bromobenzonitrile is of
interest since it has previously been demonstrated that methanol in
combination with
catalytic amounts of Pd(PPh~)4 is effective in reducing aryl halides to the
dehalogenated
arene products with concomitant formation of HCHO." Application of this
methodology
using electron-rich or -neutral aryl bromides and various alcohols affords the
desired
coupling products in good yields only when alkoxides from tertiary alcohols or
cycloalkanols are employed. For example, reaction of 4-bromo-t-butylbenzene
with 2-
propano! or cyclopentanol afforded predominantly the reduction product t-
butylbenzene.
However, reaction with Na4t-Bu afforded the aryl ether product in 53% isolated
yield
(entry 6)." A similar reaction of 1-bromonaphthalene with 2-propanol afforded
naphthalene as the major product, while, employing cyclohexanol afForded the
aryl ether
product in 65% yield (entry 7). Higher ratios of aryl ether to anthracene were
observed for
the reaction of 9-bromoanthracene with tetrahydro-4H-pyran-4-of than with
cyclopentano!
(entries 8 and 9). ''
CA 02467977 2004-06-08

-49 -
'fable 22.1 Synthesis of Aryl Ethers via Pd-catalyzed and t)irect Nucleophilic
Substitution Reactions
Entry Aryl T~ (C) ~~~ne rx~~ pf,~~Frt'~) Y~eM.
Hslide
OH t6 55'C
1 i 1 er ~ 50 _ 80 t )
Me Me
70
i I Or Me Me ..
50 48
2
F ~C
er 70 77 73
3 ~ .~ 1 OH
Br
,t ~ /~~ 70 71 78
NC
Br
Meoti 7o s1 s5 ass ~c)
Nc
1 Na0 f-8u 100 53 <10
t-8u
Br
TO 65 <5
7
1 i
Br
8 / W w 100 48 < 10
i i
sr
w ~ 100 84 No Rxn
w. 1 i i o
Fa entries t-5 arW 7-8, roadion conditions: 1.5 moH6 Pd =(dba) ~. 3.6 mol%
Tot-BtNAP, t equiv of aryl txorrride.l.2 equlv of alcohol and 2.0 eqtriv of
NaH. For entry
ti: 5 rrat% Pd(QAc) Z. 8 mal% Tot-BIIVAP.1 equiv of aryl Mnrtade and 2.o equiv
of
Na0 f-Hu. a Yields rofer 1o the sveraQe of isolated Yields to two nms.
While only preliminary studies of the mechanism of this process have been
carried
out, it most likely proceeds via a pathway similar to the Pd-catalyzed
intramolecular C-O
bond-forming reactions and the related aryl amination process (Scheme
22.1a).tb
Oxidative addition of the Pd(0)Ln complex to the aryl bromide affords A.
Substitution of
the bromide with the alkoxide affords palladium(aryl)alkoxide B. Reductive
elimination
of B gives the aryl ether wish regeneration of the active catalyst." In cases
which proceed
in lower yields, a fi-hydride elimination/reductive elimination sequence which
produces
the reduced arene side product is competitive with reductive elimination
(Scheme
22.1 b).13~ As was observed in the aryl amination procedure, ligand effects
are key to
favoring the reductive-elimination process over the p-hydride elimination
pathway. We
CA 02467977 2004-06-08

.so -
feel that the use of sterically bulky and less electron-donating ligands (but
probably still
chelating ligands) should favor the reductive cfimination proc~ss.t~~"~
Schemt IZ.1
la) R-,~' oa. Papa a w ~ (b) _
h'HY~ R
Phosphine ~ ne~~ Pa"" ~ R' Elimination ! R
OmIttEd tOf R OR' p"~ R O R-
da~isy.
g ~ A R- O H~
N~Bt
Under the conditions employed, aryl ether formation was not observed in
toluene
in the absence of catalyst for any of the substrates examined in Table 22.1.
Since rates of
nucleophilic aromatic substitution processes are enhanced in polar aprotic
solvents we
chose to further investigate the uncatalyzed reactions employing DMF as
solvent for the
substrates shown in Table 22.1.'9 In fact under those conditions, aryl
bromides containing
electron-withdrawing substituents could be effectively converted to aryl
ethers (entries 1-
5). In previous reports of the nucleophilic substitution reactions of aryl
bromides with
alcohols, either higher temperatures or the use of 4 or more equivalents of
the alcohol were
generally employed. For the substrates studied, we found that 1.2 equivalents
of the
I S alcohol was suWcient to achieve good yields of aryl ethers at 55-70
°C.~° In contrast, in
reactions of electron-neutral or -rich aryl bromides with alcohols in DMF only
small
amounts (<10%) of aryl ether products were observed. In addition, under these
conditions,
both mete and para isomers were observed in the reaction of 4-bromo-t-
butylbenzene with
NaOt-Bu suggesting that a benzyne pathway is operative?'
In order to further contrast the catalyzed and uncatatyzed processes and to
extend
the synthetic utility of the Pd-catalyzed transformation, the reaction of 4-
bromo-2-
chlorobenzonitrile was examined under both- the Pd-catalyzed conditions in
toluene and
the urtcatalyzed conditions in DMF (Table 22.2). The Pd-catalyzed reaction of
4-bromo-2-
chlorobenzonitrile with cyclohexanol, NaO~-Bu or sec-phenethyl alcohol in
toluene
afforded the aryl ether product resulting from~exclusive substitution of the
bromide. in the
absence of a Pd-catalyst, slow substitution of chloride was observed in
toluene for
cyclohexanol and sec-phenethyl alcohol, whereas reaction with NaOt-Bu did not
afford
CA 02467977 2004-06-08

°
-51 _ .
aryl ether products. In DMF. the uncatalyzed reaction with either cyclohexanol
or sec-
phenethyl alcohol in DMF afforded a mixture of aryl ether products while no
aryl ether
products were observed with NaOt-Bu.
Table 22.2. Comparison of the Pd-catalyzed and Uncatalyzed Substitution of 4-
Bromo-2- -
chlorobenzonitrite.
CN , CN
CN Pd-catalyzed
+ ROH °r t~atalyzed R - R
8r ~ CI 70 'C O Ct + tar ~ O'
C
Entry ROH Catalyzed Yield C (%)' Uncatalyzed Yield (%) ' CID
(toluene) (OMF) (u~atalyzed)
OH
~ ° 80 54 1:1
2' ~ 73 79 1:1.2
Ph Me
3 Na0 t-t3u 82 No rxn
' Yields refer to the average of isolated yield of C for finro runs. °
Isolated produd from the
catalyzed reaction contains 5% 4-cydohexylo~ryhenzonitrile. Isolated yield for
the uncatalyzed
readion refers to a mixture of C and D. 9sotated yield for the uncatalyzed
readion refers to
the sum of the isolated yield fa C and D.
The results presented above provide proof of concept that our palladium-
catalyzed
methodology is applicable for the formation aryl ethers by the intermolecular
coupling of
an aryl bromide and an alkoxide. Furthermore, our study of the uncatalyzed
substitutions
in both toluene (under conditions of the catalyzed process) and DMF are
instructive. They
indicate that the accurate comparison of the efficacies of catalyzed and
uncatalyzed
reactions requires the use of favorable reaction conditions for each.
Experimental Protocol jor Example 21
General Considerations. All reactions were performed in oven-dried or flame-
dried glassware. All manipulations involving air-sensitive materials were
conducted in a
CA 02467977 2004-06-08

-52
Vacuum Atmospheres glovebox under purified nitrogen or using standard Schlenk
techniques under an atmosphere of argon. Al) reactions were carried out under
an argon
atmosphere and were stirred using a magnetic stirrer. Toluene was distilled
under nitrogen
from molten sodium. Sodium-tern-butoxide and sodium hydride (95%) were
purchased
from Aldrich chemical company and stored in a Vacuum Atmospheres glovebox.
(S')-(-)-
2,2'-bis{di P-tolylphosphino)-l,l'-binaphthyl) (Tot-BINAP), Pd2(dba)3,
Pd(OAc)2, were
purchased from Strem Chemical Company and used without further purification.
Sodium
hydride (60% dispersion in mineral oil), anhydrous methyl alcohol,
cyclopentanol, 3-
pentanol, ( 1 R, 2S, 5R)-(-)-menthol, 9-bromoanthracene, sec-phenethyl
alcohol, anhydrous
2-propanol, anhydrous benzyl alcohol, tetrahydro-4N pyran-4-ol, menthol, 4-
bromobenzonitrile, and 1-bromonaphthalene were purchased from Aldrich Chemical
Company and used without further purification. 4-bromobenzotrifluoride and 4-
bromo-2-
chiorobenzonitrile were purchased from Lancaster Inc. and used without further
purification. Cyclohexanol was purchased from Mallinckrodt Inc. and distilled
over CaH2
under reduced pressure. Anhydrous DMF was purchased from Aldrich Chemical
Company or was distilled over CaH2. Silica gel chromatographic pucifications
were
performed by flash chromatography using E. M. Science Kieselgel 60 (230-400
mesh)
silica packed in columns. Yields refer to isolated yields of compounds of
greater than
95% purity as determined by capillary gas chromatography (GC) and proton
Nuclear
Magnetic Resonance spectroscopy ( ~ H NMR) analysis. New compounds were also
characterizxd by elemental analysis (E & R Analytical Laboratory, Inc). Yields
reported
in this section refer to a single experiment whereas those reported in Table 1
are an
average of two experiments.
General Procedures for the Pd-Catalyzed Aryi Ether Formation. A 25 mL
Schlenk flask equipped with a teflon coated stir bar was charged with NaH (1.0
mmol,
60% dispersion in mineral oil), toluene (2 mL) and the alcohol {0.50 mmol).
The mixture
was stit~ed at 70 °C for 15 min under an atmosphere of argon, cooled to
room temperature,
and Pd2(dba)3 (0.0075 mmol), Tol-BINAP (0.018 mmol), aryl bromide (0.50 mmol)
and
toluene (1 mL) were added. The mixture was stirred at the indicated
temperature until the
starting material had been consumed as judged by GC analysis. At this point,
the solution
was cooled to room temperature and diethyl~ether {50 mL} and water {50 mL)
were added.
The aqueous layer was separated, and extracted with diethyl ether (50 mL). The
organic
fractions were combined, washed with brine (50 mL), dried over anhydrous
MgSO~,
filtered, and concentrated in vacuo. The crude product was purified by flash
CA 02467977 2004-06-08

-'S 3 -
chromatography on silica gel.
4-isopropoxybenzonitrile (Table 1, entry 1). The general procedure was
followed
on a 0.50 mmo) scale to afford 65 m6 (80% yield) of a colorless oil. IR (neat,
cm-i) vmax:. .
2981. 2225, ! 605, 150b, ! 299, 1259; t H NMR (CDCI3) & 7.55 (d, .l = 8.7 liz,
2H), 6.91
(d, J = 8.8 Hz, 2H), 4.61 (septet, J = 6.0, I H), 1.34 (d, J = 6.0 Hz, 6H); t
3C NMR (CDCI3)
161.4, 133.9, 126.3, 11 b.0, ?0.4, 21.7; Anal Calcd. for C ~ off t t NO: C,
74.5 I ; H, 6.88.
Found: C, 74.35; H, 7.08.
4-trifluoromethylphenyl 3-pentyl ether (Table 1, entry 2). The general
procedure was followed on a 0.75 mmol scale to afford 114 mg (54% yield) of a
colorless
oil. IR (neat, cm-t) vmax: 2970, 1615, 1518, 1329, 125?, 1161, 1116, 1068; iH
NMR
(CDC13) b ?.53 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 4.19 (quintet, J
= 5.8 Hz,
1 H), 1.65-I .7? (m, 4H) 0.97 (t, J = 7.4 Hz, 6H); t 3C NMR (CDC13) 8 161.4, !
26.9, 126.8,
126.7, 1 l 5.6, 80.5, 26.0, 9.5; Anal Calcd. for C t 2H t sF34: C, 62.31; H,
6.11. Found: C,
62.04; H, 6.30.
4-((1R, 2S, SR)-menthyloxy)benzonitrile (Table 1, entry 3). The general
procedure was followed on a 0.5 mmol scale to afford 96 mfi (74% yield) as a
white solid,
mp 73 °C; IR (neat, cm-~ ) v,nax~ 2959. 2220, 1602, ! 504, 1252, 988; t
H NMR (CDCIg) b
7.55 (d, J = 8.5 Hz, 2H), 9.92 (d, .l = 8.5 Hz, 2H), 4.10 (dt, 1 H, J = 3.8,
10.4 Hz), 2.08-
2.1 S (m. 2H), 1.68-1.79 (m. ZH), 1.40-1.60 (m, 2H), 0.90-1.97 (m, 9H), 0.74
(d, J = 7.0
Hz, 3H); t3C NMR (CDC13) 161.8, 134.0, 119.4, 115.8, 103.2, 77.8, 47.7, 39.8,
34.3,
31.3, 26.1, 23.2, 22.0, 20.6. 16.5; Anal Calcd. for C»H2~N0: C, 70.33; H,
9.01. Found:
C, 79.50; H, 8.91.
4-Benzyloxybenzonitrile2'- (Table i, entry 4). The general procedure was
followed on a 0.75 mmol scale to afford 113 mg (72% yield) of a white solid.
tnp 89-90
°C (lit mp 91-93 °Cr IR (KBR, cm-t) vm~: 2220, 1606, 1508, 1462,
1263, 1170, 1027,
837; ~ H NMR (CDCi3) 8 7.57 (dd, J = 6.8, 1.9 Hz, 2H), 7.37-7.42 (m, SH), 7.02
(dd, J =
6.8, 1.9 Hz, 2H), 5.11 (s, 2H); t 3C NMR (CDCl3) b 161.8, 135.6, 133.9, 128.6,
128.3,
127.3, 119.0, I 15.5, 104.1, 70.2; Anal Calcd. for CtQHI iNO: C, 80.35; H,
5.30. Found: C,
80.60; H, 5.27.
4-tnethoxybenzonitrile (Table 1, entry S). The general procedure was followed
on
a 0.75 mmol scale to afford 77 mg (77% yield) of a white solid, mp 56.0-56.8
°C (1it23 mp
57-59 °C); ~ H NMR (CDCI;) b 7.57 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.8
Hz, 2I-I), 3.84 (s,
3H); ~ 3C NMR (CDCI3) b 162.7, 133.8, 119.0, 114.6, 103.8, 55.4.
CA 02467977 2004-06-08

_S4 _
4-I-Butylphcnyl t-butyl ether (Table I, entry 6). A 25 mL Schlenk flask with a
teflon coated stir bar was charged with NaOt-Bu (97 mg, I.00 mmol), Pd(OAc)2
(5.6 mg,
0.025 mmol) and Tol-BINAP (20.4 mg, 0.030 mmol). The flask was evacuated, back-
filled with argon, and charged with toluene {3 mL) and 4-t-butyl bromobenzene
(87 trL,
0.50 mmol). The mixture was heated at 100 °C for 40 h, cooled to room
temperature and
then diethyl ether (20 mL) and water (20 mL) were added. The organic layer was
separated, washed with brine (20 mL), dried over anhydrous MgS04, and
conecntrated in
vacuo. The crude product was purified by flash chromatography on silica gel
(9911
hexanelethyl acetate) to afford 4-t-butylphenyl t-butyl ether as a colorless
oil (S9 mg, 53%
yield). 1R (neat, cm-t) vmax: 2964, 1605, 1506, 1364, 1245, I 169; tH NMR
{CDGl3) &
7.25 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 1.33 (s, 9H), 1.30 (s,
9H); ~3C NMR
(CDCI3) 8 153.0, 145.9, ?7.9, 34.2, 31.5, 28.9; Anal Calcd. for CtqH220: C,
81.50; H.
10.75. Found: C, 81.59; H, 10.53.
1-Naphthyl cyclohexyi ether (Table 1, entry ?). A 25 mL Schlenk flask with a
teflon coated stir bar was charged with NaH {40 mg, 1.50 mmol), toluene (2
mL), and
cyclohexanol (94 pL. 0.90 mmol). The mixture was heated to ?0 °C for 10
min under an
atmosphere of argon and then cooled to room temperature. To this was added 1-
bromonaphthalene (104 uL, 0.75 mmol), Pd~(dba)3 (10.3 mg, 0.0125 mmol), (R}-
(+)-2,2'-
(di p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2
mL of
toluene. The mixture was heated to ?0 °C for 20 h at which time water
(60 mL) and
diethyl ether (60 mL) were added. The aqueous layer separated and extracted
with diethyl
ether (60 mL). The organic fractions were combined, washed with brine (60 mL),
and
dried over anhydrous Mg2SOq. The drying agent was removed by filtration and
the
mother liquor concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (50:1 hexanes:ethyl acetate) to afford 1-naphthy)
cyclohexyl
ether ( 101 mg, 60 % yield) as a colorless oil. IR (neat, crn-I ) vmax: 3051,
2934, 2857,
I 579, 1401, 1268, 1236, 1094; ~ H NMR (CDC13) b 8.25-8.29 (m, 1 H), 7.69-7.36
(m, 1 H),
7.28-7.43 (m, 3H), 6.77 (dd, J = 7.1, 1.3 Hz, 1 H), 4.41 (quintet, J = 4.4 Hz,
1 H), 1.93-1.97
(m, 2H), 1.32-r.80 (m SH); t3C NMR (CDCl3) b 153.5, 134.8, 127.4, 126.7,
126.2, 125.8,
I 24.9, 122.4, 119.9, 75.3, 31.6, 25.8, 23.6; Anal Calcd. for C ~ 6H ~ g0: C,
84.9 I ; H, 8.02.
Found: C, 85.04; H, 7.88.
9-Anthryl cyclopentyl ether ('Table 1, entry 8). The general procedure was
followed on a 0.5 mmol scale with a reaction temperature of 100 °C to
afford 58 mg (49%
yield) of a white solid. mp 60-62 °C; IR (neat, cm-1 ) vmax: 2960,
1337, 1084; tH NMR
CA 02467977 2004-06-08

-SS -
(CDCI;} & 8.29-8.32 (m, 2H), 8.19 (s, lH), 7.95-?.99 (m, 2H), 7.41-7.48 (m,
4H). 4.90-
4.96 (m, 1H), 2.00-2.20 (m. 4H), 1.65-1.85 (m, 4H); t3C NMR {CDCl3) S 150.9,
132.4.
130.9, 128.3, 125.3, 124.7, 123.1, 121.7, 88.3, 33.1. 23.1; Anai Calcd. for
C~9H~g0: C;.
86.99; H, 6.92. Found: C, 87.2; H, 6.92
9-Anthryl 4-tctrs~hydro-4H pyrs~n ether (Table l, entry 9). The general
procedure was followed on a 0.50 mrnol scale with a reaction temperature of
100 °C to
afford 125 mg (90% yield) of a yellow solid, mp 99.9-100.8 °C; IR (KBr,
cm-t) vm~:
3048, 2951, 2839, 1409, 1343, 11b8, 1092, 1003, 737; iH NMR {CDCl3) 8 8.27-
8.30 (m,
2H). 8.18 (s, lH), 7.92-7.97 (m, 2H), ?.39-7.48 (m, 4H), 4.38-4.46 (m, 1H),
3.98-4.06 (m,
2H), 3.27-3.37 (m, 2H), 1.95-2.17 (m, 4H); ~3C NMR (CDC13) & 149.4, 132.3,
128.3,
125.4, 125.3, 125.0, 122.8, 122.1, 106.5, 80.5, 66.2, 33.6; Anal Calcd. for
C~gH~g02: C.
81.99; H, 6.52. Found: C, 81.75; H, 6.66.
4-Cyclohexyfoxy-2-chlorobenzonitrite (Table 2, entry 1 ). The general
procedure
was followed on a 0.50 mmol scale to afford 96 mg {81% yield) of a white
solid, mp 30-
1 S 32 °C. The isolated product contained a 5% impurity as determined
by GC analysis which
was identified by GC/MS as 4-cyclohexyloxybenzonitrile (GCaMS, m/z = 201 ) and
NMR
analysis. IR (neat, cm-t} vm~: 2935, 2228, 1599, 1491, 1044; ~H NMR (CDCl3) b
7.52-
7.57 (m, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 6.80-6.85 (m, 1 H), 4.31 {quintet, J
= 3.8 Nz, 1 H).
1.90-2.01 (m, 2H), 1.74-1.89 (m, 2H), 1.50-1.62 (m, 3H), 1.30-1.43 (m, 3H);
~3C NMR
(CDCl3) 8 161.8, 138.1, 134.9, 116.9, I 16.4, 114.6, 104.3, 76.3, 31.3, 25.3,
23.4; GC/MS
(mlz) 235, 237.
Z-Chloro-4-sec-phenethyloxybenzonitrile (Table 2, entry 2). The general
procedure was followed on a 0.50 mmol scale to afford 107 mg (83% yield) of a
colorless
oil. IR (neat, cm-1) vm~: 3032, 2982, 2932, 2228, 1598, 1489, 1454, 1297,
1277, 1239,
1067; t H NMR (CDCl3) b 7.24-7.46 (m, 6H); 6:97 {d, J= 2.4 Hz, 1 H), 5.33 (q,
J = 6.4 Hz,
1 H), 1.6S (d, J = 6.4 Hz, 3H); t 3C NMR (CDCl3) & 161.8, 141.2, 137.9, 134.8,
128.9,
128.1, 125.3, 117.5, 1 I6.2, 114.7, 104.8, 77.5, 24.1; Anal Calcd. for C ~ gH
i2C1N0: C,
70.02; H, 4.70. Found: C, 70.14; H, 4.68.
4-1-Butyloxy-2-chlorobenzonitrite (Table 2, entry 3). The general procedure
was
followed on a O.SO mmol scale to afford 87 mg (83% yield) of a colorless oil.
(Table 2,
entry 3) IR (neat, cm-t ) vmax= 2'80, 2228, 1595, 1484, 1238, 1160, 1041; ~ H
NMR
(CDC13 ) 8 7.54-7.56 (m, 1 H), 7.09-7.10 (m, 1I-1), 6.93-6.97 (m 1 H), 1.44
(s, 9I-I}; ~ 3C
NMR (CDCl3) b 160.6, 137.4, 134.4, 123.1, 120.5, I 16.1, 106.4, 81.0, 28.7;
Anal Caicd.
CA 02467977 2004-06-08

-SG -
for C ~ ~ H ~ ~C1N0: C, 63.01; H, 5.?7. Found: C, 62.09; H, S.56.
Genera! Procedure for the uncatalyzed coupling reaction in DMIi. A 25 mL
resealable Schlenk flask was charged with NaH (0.60 mmol, 60% dispersion in
mineral
oil), anhydrous DMF (2 mL), alcohol (0.60 mmol), and aryl halide (0.50 mmol)
under an
argon atmosphere. The flask was sealed and heated to the temperature indicated
until the
starting material had been consumed as judged by GC analysis. At this point,
the solution
was cooled to room temperature and diethyl ether (50 mL) and water (50 mL)
were added.
The aqueous layer was separated, and extracted with diethyl other (50 mL). The
organic
layers were combined, washed with brine (50 mL), dried over anhydrous MgS04,
filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography on
silica gel.
4-Bro~no-Z sec-phenethyloxybenzonitrile (Table 2. entry 2). The general
procedure for the uncatalyzed coupling reaction in DMF was followed on a 0.50
mmoi
scale to afford 61 mg (40% yield) of the title compound as a white solid and 2-
chloro-4-
sec-phenethyloxybenzonitrile (44 mg, 34% yield) as a colorless oil. mp 101-102
°C; IR
(KHr, cm-~) vmax: 2226, 1590, 1482, 1408, 1253, 1063, 943; iH NMR (CDCl3) 8
7.29-
7.39 (m, 6H), ?.07 (dd, J = 8.3, I .6 Hz, 1 H), 6.99 (d, 1.6 Hz, I H), 5.39
(q, J = 6.4 Hz, 1 H),
1.71 (d, J = 6.4 Hz, I H); ~ 3C NMR (CDCl3) b 159.4, 140.4, 133.7, 128.3,
127.8, 127.6,
124.9, 123.7, 11 ?.4, 115.2, 76.0, 23.6; Anal Calcd. for C t SH ~ 2BrN0: C,
59.62; H, 4.00.
Found: C, 59.41; H, 3.84.
References for Example 21
(I) For a review of alkenyl and aryl C-0 bond forming reactions, see: (a}
Chiuy, C. K.-F.
In Comprehensive Organic Functional Group Transforma~iur~s; Katritzky, A. R.;
Meth-
Cohn, O.; Rees, C. W., Ed; Pergamon Press: New York, 1995; Vol. 2, Ch. 2.13.
(b)
Paradisi, C. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, L;
Semmelhack,
M. F., Ed; Pergamon Press: New York, 1991; Vol 4, Ch 2.1.
(2) (a) Lu, T.; Hyunsook, K. S.; Zhang. H.; Bott, S.; Atwood, J. L.;
Echegoyen, L.; Gokel,
G. W. J. 4rg. Chem. 199U, SS, 2269. (b) Pluta, K. J. Neterocyctic Chem. 1984,
31, 557
(c) Testaferri, L.; Tiecco, M.; Tingoli, M.; Baitoli, C.; Massoli, A.
Tetrahedron 1985, 4l ,
1373. (d) Testaferri, L.; Tiecco, M.; Tingoli, D.; Chianelli, D.; Montanucci,
M.
Tetrahedron 1983, 39, 193. (e) Shaw, J. E.; Kunerth, D. C.; Swanson, S. B. J.
4rg.
Chem. 1976, d l , 732. (f) Bradshaw, J. S.; Hales, R. I3. J. Org. Chem. 1971,
36, 318
CA 02467977 2004-06-08

:57 -
(3) (a) Lee, S.; Frescas, S.; Nichols, D. C. Synthetic Comm. 1995, 2.i, 2775.
(b)
Capdevielle, P.; Maumy, M. Tetrahedron Gett. 1993, 3d, 1007. (c) Keegstra, M.
A.;
Peters, T. H.; Brandsma, L. Tetrahedron 1992, :I~i, 3633. (d) Yeager, G. W.;
Schissel, D:
N. Synthesis 1991, 63. (e) Aalten, H. L.; Van Koten, G.; Grove, D. M.:
Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, a~, 5565.
Pentavalent
organobismuth reagents have been used in the synthesis of aryl ethers in the
presence and
absence of Cu salts, see: (d) Barton, D. H. R.; Finet, J.-P.; Khamsi. J.;
Pichon, C.
Tetrahedron Gett. 1986, 27, 3619. (e) Barton, D. H. R.; Finet, J.-P.;
Motherwell, W. B.;
Pichon, C. J. Chem. Soc., Perkin Trans. I 1987, 251.
(4) A variety of electron-deficient transition metal complexes have been used
as activators
for the synthesis of aryl ethers from the reaction of aryl fluorides and ary!
chlorides with
alcohols see: (a) Pearson, A. J.; Bruhn, P. R.; Gouz~oules, F.; Lee, S-H. J.
Chem. Soc.,
Chem. Cummun. 1989, 659. Pearson, A. J.; Gelormini, A. M. J. Org. Chenz 1994,
59,
4561. (c) Moriarty, R. M.; Ku, Y-Y.; Gill, U. S. Organumetallics 1988, 7, 660.
(d)
Baldoli, C.; Buttero, P. D.; Maiorana, S.; Papagni, A. J. Chem. Soc., Chem.
Common.
1985, 1181. (e) Percec, V.; Okita, S. J. Polym. Sci. Parl A: Polym. Chenr.
1993, 31. 923.
(5) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
10333.
(6) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(7) For examples of nickel-catalyzed synthesis of aryl ethers, see: (a)
Cramer, R.;
Coulson, D. R. J. Org. Chcm. 1975, 40, 2267. (b) Cristau, H.-J.; Desrnurs, 1.-
R. Ind
Chem. Libr. 1995, 7, 249.
(8) It has been reported that treatment of truns-[PdBr(G6HSxPPh3}2j with a
solution of
NaOMe in toluene at 35 °C afforded benzene (80% yield), HCHO (20%
yield) and anisole
(trace) see: Yoshida, T.; Okano, T.; Otsuka, S. J. Chem. Soc., Dalton Trans.
1976, 993.
(9) Either enantiomer of Tol-BINAP can be used as can BINAP. However BINAP is
approximately 2.6 times more expensive (Strem Chemicals) than Tol-BINAP.
(10) Reactions performed at 100 °C using Pd(OAc}2 as precatalyst
afforded an aryl ether
to benzonitrile ratio of 6:1, whereas the benzonitrile side-product was net
observed using
Pd2(dba)3 as precatalyst.
(11) Since only one product was detected by GC and TLC analyses, and the
stereochemistry of the carbinol carbon was preserved in the Pd-catalyzed
intramolecular
CA 02467977 2004-06-08

-58 -
coupling reaction (see reference 5), it is assumed that the stereochemistry of
( 1 R, 2S, SR)-
(-)-menthol is preserved during the course of the reaction.
( 12) The following is a representative procedure: An-oven dried 25 mL Schlenk
flask was
charged with Nali (60% dispersion in mineral oil, 40 mg, 1.00 mmol), 2-
propano) (46 NL,
0.60 mmol) and toluene (2 mL) under an argon atmospfiere. The mixture was
heated at 50
°C for 15 min, cooled to room temperature, and 4-bromobenzonitrile (91
mg, 0.50 mmol),
Pd2(dba)3 (6.9 mg, 0.0075 mmol), (R)-(+)-2,2'-(di n-tolylphosphino)-1,1'-
binaphthyl (Tol-
BINAP) (12.2 mg, 0.018 mmol), and 1 mL of toluene were added. The mixture was
heated at 50 °C under argon for 22 h and then cooled to room
temperature. Water (50
mL) and diethyl ether (50 mL) were added, and the aqueous layer separated and
extracted
with diethyl ether (50 mL). The organic layers were combined. washed with
brine (50
mL), and dried over anhydrous Mg2S04. The drying agent was removed by
filtration and
the mother liquor concentrated in vacuo. The crude product was purified by
flash
chromatography on silica gel ( 19:1 hexanes:ethyl acetate) to afford 4-
isopropoxybenzonitrile (65 mg, 80% yield) as a colorless oil.
(13) Zask, A.; Helquist, P. J. Org. Chem. 1978, 4.J, 1619.
(14) (a) With Pd(OAc)2 as precatalyst a ratio of 9.2:1 aryl ethera-
butylbenzene was
obtained; using Pd2(dba)3 this ratio was 4:1 (GC analyses-uncorrected for
response
factors). This trend is the opposite of that observed in the Pd-catalyzed
coupling of 4-
bromobenzonitrile with 2-propanol. (b) No meta product, as would be expected
from
benzyne formation, was observed in this process. (c) Both t-butylbenzene and
4,4'-di-t-
butylbiphenyl were side products of the palladium-catalyzed reaction of 4-~-
butylbromobenzene with NaOtBu. We are uncertain about the mechanism of
formation of
t-butylbenzene in this reaction. (d) In contrast to the other substrates
examined (Table 1 ),
use of t-BuOH and NaH in place of NaOtBu afforded large amounts of arene side
products
and only traces of the desired aryl ether product.
(IS) GC analysis of the crude reaction mixture of 9-brornoanthracene with
tetrahydro-4H
pyran-4-of gave a 10:1 ratio of aryl ether to anthracene, whereas, GC analysis
of the crude
reaction mixture of 9-bromoanthracene with cyclopentanol gave a 2.4:1 ratio of
aryl ether
to anthracene. Note: these ratios are not corrected for response factors.
(16) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L..l. Am. Chem. Soc. 1996, 118,
7215. (b)
Hartwig, J. F.; Richards, S.; Barariano, D.; Paul, F J. Am. Chem. Sac. 1996,
18, 3626. (c)
Dover, M.S.; Hartwig, J. F. .I. Am. Clrem.Soc. 1996, 118, 7217. (d)
Widenhoefer, R. A.;
CA 02467977 2004-06-08

-59 -
,1
Buchwald, S. L. Oyanometallics 199b, l,i, 2755. (e) Louie, J.; Paul, F.;
Hartwig, J. F.
Organometallics 1996, l5, 2794. (f) Paul, F.; Patt, J.; Hartwig, J. F
OrRanometallics
1995, l -l, 3030.
(17) Direct reductive elimination from [(R)-Tol-I~INAPjPd(p-C6H4CNxOCH2CMe3)
to
afford the aryl ether product in 84% yield has been recently demonstrated in
this
laboratory.
( 18) (a) Stifle, J. K. The Chemistry o~ the Metal-Carhan Bond, Vol 2,
Hartley, F. R.;
Patai, S. F.ds., Wiley, New York, 1985, 625. (b) Gillie, A.; Stifle, J. K. J.
Am. Cheer. Soc.
1980, 101, 4933. (c) The steric effect of ligands on the rate of a reductive-
elimination
process was first reported by Jones: Jones, W. D.; Kuykendall, Y. L, laorg.
Chem. 1991,
30, 2615.
(19) Nucleophilic substitution reaction conditions typically require 4.0
equivalents of
alkoxide relative to aryl bromide at 80-120 °C. See reference 2.
(20) Uncatalyzxd reactions performed in DMF that was not strictly anhydrous
did not
afford aryl ether products.
(21 ) (a) Cram, D. J.; Rickborn, R.; Knox, G. R. J. Am_ Chem. .Soc. 1964, 81,
64 I2. (b)
Hales, R. H.; Bradshaw, J. S.; Pratt, D. R.; J. Orb Chem. 1971, 3G, 314.
(22) Mauleon, D.; Granados, R.; Minguillon J. Org. Chem. Suc. 1983, .18, 31
O5.
(23) Aldrich Chemical Company
Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following
claims.
CA 02467977 2004-06-08

Representative Drawing