Dimethylmalonyltrialkylphosphoranes: New general reagents for esterification reactions allowing controlled inversion or retention of configuration on chiral alcohols

Article abstract of DOI:10.1021/jo026639y

A new class of trialkylphosphorane has been prepared through reaction of a trialkylphosphine with 2-chlorodimethylmalonate in the presence of triethylamine. These new reagents promote the condensation reaction of carboxylic acids with alcohols to provide esters along with trialkylphosphine oxide and dimethylmalonate. The condensation reaction of chiral secondary alcohols can be controlled to give either high levels of inversion or retention through a subtle interplay involving basicity of the reaction media, solvent, and tuning the electronic and steric nature of the carboxylic acid and steric nature of the phosphorane employed. A coherent mechanism is postulated to explain these observations involving reaction via an initial acyloxyphosphonium ion.

Full text of DOI:10.1021/jo026639y

SCHEME 1. Mech a n ism s for th e Mitsu n obu
Ester ifica tion Rea ction
Dim eth ylm a lon yltr ia lk ylp h osp h or a n es:
New Gen er a l Rea gen ts for Ester ifica tion
Rea ction s Allow in g Con tr olled In ver sion or
Reten tion of Con figu r a tion on Ch ir a l
Alcoh ols
J ames McNulty,*,† Alfredo Capretta,†
Vladimir Laritchev,† J eff Dyck,† and Al J . Robertson‡
Institute of Molecular Catalysis, Department of Chemistry,
Brock University, St. Catharines, Ontario L2S 3A1 Canada,
Cytec Canada Inc., P.O. Box 240, Niagara Falls,
Ontario L2E 6T4, Canada
trialkylphosphoranes,6,7 have been developed which also
result in inversion of stereochemistry on esterification
of chiral alcohols.6a These new phosphoranes have also
be employed in carbon-carbon5,7b and amination7a reac-
tions with alcohols.
jmcnulty@chemiris.labs.brocku.ca
Received October 31, 2002
The initial step of the DIAD/triphenylphosphine medi-
ated esterification reaction3,4 is understood to involve
nucleophilic addition of triphenylphosphine to the azodi-
carboxylate followed by proton transfer from a carboxylic
acid to give 3 (Scheme 1). The subsequent steps involve
nucleophilic attack of the alcohol 2 on 3 to form an
activated alkoxyphosphonium salt 42a (Scheme 1, Path
1). Finally, SN2-type displacement by the carboxylate
anion on 4 with loss of triphenylphosphine oxide produces
the ester with inversion of stereochemistry. Evidence for
the existence of an alternative pathway for this reaction
proceeding via an acyloxyphosphonium salt (such as 5,
Scheme 1) has been described by J enkins8a and Kunz.8b
More recently, DeShong3b,9 demonstrated clear evidence
for the involvement of an acyloxyphosphonium salt when
hindered alcohols are involved and a further example of
a Mitsunobu macrolactonization likely proceeding via the
acyloxyphosphonium ion has also recently been described
by Smith.10 In these cases, lactone products were ob-
tained exclusively with retention of stereochemistry. The
competitive pathway leading to retention of stereochem-
istry with hindered alcohols via the acyloxyphosphonium
ion 5 is outlined in Scheme 1, Path 2. This scheme also
illustrates a competing view of the Mitsunobu reaction
involving initial reaction along Path 2. The formation of
the basic hydrazide anion leads to subsequent alkoxide
formation and “crossover” to the alkoxyphosphonium salt
4,3b,11 perhaps proceeding via a mixed alkoxy/acyloxy
phosphorane-type intermediate,4g,8a,12 ultimately yielding
the ester with inversion of configuration as the normal
outcome. The formation of a basic anion capable of
alkoxide formation during the Mitsunobu processes
Abstr a ct: A new class of trialkylphosphorane has been
prepared through reaction of a trialkylphosphine with
2-chlorodimethylmalonate in the presence of triethylamine.
These new reagents promote the condensation reaction of
carboxylic acids with alcohols to provide esters along with
trialkylphosphine oxide and dimethylmalonate. The con-
densation reaction of chiral secondary alcohols can be
controlled to give either high levels of inversion or retention
through a subtle interplay involving basicity of the reaction
media, solvent, and tuning the electronic and steric nature
of the carboxylic acid and steric nature of the phosphorane
employed. A coherent mechanism is postulated to explain
these observations involving reaction via an initial acyloxy-
phosphonium ion.
The Mitsunobu reaction1-4 is widely employed in both
condensation and displacement reactions of alcohols with
various nucleophiles, normally proceeding with inversion
of stereochemistry when chiral alcohols are utilized. The
original process employed carboxylic acids 1 (or carboxyl-
ates 1a ) as the nucleophile producing ester or lactone
products2a but has since been extended considerably to
include a variety of both heteroatom and carbon-based
nucleophiles.2,5 The most commonly employed promoters
for this reaction are dialkyl azodicarboxylates, such as
diethyl azodicarboxylate (DEAD) or diisopropyl azodi-
carboxylate (DIAD), used in conjunction with triphen-
ylphosphine. New reagents, such as the (cyanomethyl)-
* Corresponding author.
† Brock University.
‡ Cytec Canada Inc.
(1) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. J pn. 1967, 40,
2380.
(2) For comprehensive reviews see: (a) Mitsunobu, O. Synthesis
1981, 1. (b) Hughes, D. L. Org. React. 1992, 42, 335.
(3) (a) Hughes, D. L.; Reamer, R. A.; Bergan, J . J .; Grabowski, E. J .
J . J . Am. Chem. Soc. 1988, 110, 6487. (b) Ahn, C.; Correia, R.; DeShong,
P. J . Org. Chem. 2002, 67, 1751.
(4) For further mechanistic discussions see: (a) Varasi, M.; Walker,
K. A. M.; Maddox, M. L. J . Org Chem. 1987, 52, 4235. (b) Camp, D.
D.; J enkins, I. D. Aust. J . Chem. 1988, 41, 1835. (c) Crich, D.; Dyker,
H.; Harris, R. J . J . Org. Chem. 1989, 54, 257. (d) Camp, D.; J enkins,
I. D. J . Org. Chem. 1989, 54, 3045. (e) Dodge, J . A.; Trujillo, J . I.;
Presnell, M. J . Org. Chem. 1994, 59, 234. (f) Hughes, D. L. Org. Prep.
Proced. Int. 1996, 28, 127. (g) Adam, W.; Narita, N.; Nishizawa, Y. J .
Am. Chem. Soc. 1984, 106, 1843.
(6) (a) Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett. 1994, 35,
5081. (b) Uemoto, K.; Kawahito, A.; Matsushita, N.; Sakamoto, I.;
Kaku, H.; Tsunoda, T. Tetrahedron Lett. 2001, 42, 905.
(7) (a) Zaragoza, F.; Stephensen, H. J . Org. Chem. 2001, 66, 2518.
(b) Zaragoza, F. J . Org. Chem. 2002, 67, 4963.
(8) (a) Camp, D.; J enkins, I. D. J . Org. Chem. 1989, 54, 3049. (b)
Kunz, H.; Schmidt, P. Chem. Ber. 1979, 112, 3886.
(9) Ahn, C.; DeShong, P. J . Org. Chem. 2002, 67, 1754.
(10) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J . Am. Chem.
Soc. 2002, 124, 11102.
(11) Hughes, D. L.; Reamer, R. A. J . Org. Chem. 1996, 61, 2967.
(12) Harvey, P. J .; von Itzstein, M.; J enkins, I. D. Tetrahedron 1997,
53, 3933.
(5) Ito, S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053.
10.1021/jo026639y CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003
J . Org. Chem. 2003, 68, 1597-1600
1597

TABLE 1. Ester ifica tion Rea ction s P r om oted by
P h osp h or a n e 6a
SCHEME 2. Syn th esis of P h osp h or a n es 6 a n d
Gen er a l Ester ifica tion Rea ction
described makes it difficult to differentiate between the
direct reaction along Path 1 or initial reaction along Path
2 followed by the crossover leading to the necessary
alkoxyphosphonium salt 4.
We have developed a new class of trialkylphosphorane
reagent designed to allow for esterification under mild
conditions that also helps delineate the competitive
pathways described above. These reagents, exemplified
by dimethylmalonyltributylphosphorane 6a (DMTP), are
readily prepared by the reaction of a trialkyl phosphine
with R-chlorodimethylmalonate in the presence of Et3N,
Scheme 2.
The tributylphosphorane 6a is a colorless, viscous oil
stable under argon at room temperature for at least six
months. When exposed to air, the oil slowly solidifies over
a period of several days yielding the products of its
hydrolysis, tributylphosphine oxide and dimethylma-
lonate (DMM). The DMTP reagent has been shown to
effect the general condensation reaction of a wide variety
of carboxylic acids 1 with simple alcohols 2 (Scheme 2)
efficiently at neutral pH. The reactions were conducted
in dry toluene under argon providing the ester product
along with tributylphosphine oxide and DMM. Repre-
sentative results are summarized in Table 1.
Yields are high with methanol and drop slightly as the
bulk of the alcohol increases (Table 1, entries 1-3) while
no reaction occurred with the tertiary alcohol tert-butanol
(Table 1, entry 4). The â-aryl alcohol 2-phenyl-1-propanol
reacted cleanly without styrene formation (Table, entry
5), indicating that â-elimination does not occur. Electron-
deficient benzoic acids gave slightly better yields (Table
1, entries 1 and 7) with the same alcohol (compare to
entries 6 and 8-10). The reaction may also be carried
out successfully in the presence of a free phenol (Table
1, entry 8). Finally, cinnamic and aliphatic acids appear
to react without difficulty (Table 1, entries 11-13).
A clear advantage gained when using DMTP is that
the side products tributylphosphine oxide and DMM can
be largely removed by aqueous base partition (0.2 M Na2-
CO3) thereby simplifying purification. The yields reported
in Table 1 pertain to the isolated mass of the purified
esters obtained by silica gel chromatography.
toluene provided the ester with 95% retention of config-
uration (Table 2, entry 1). The degree of inversion
increased as the electron donating ability of the 4-sub-
stituent increased (Table 2, entries 1-3) while conversion
was higher when electron-deficient 4-substituted benzoic
acids were employed. We next investigated the steric
nature of the acid with remarkable results. Even a single
ortho substituent was seen to have a considerable effect
on the outcome of the reaction now delivering the product
of inversion with high selectivity (Table 2, entries 4-7).
The conversions were lower when mono-ortho-substituted
benzoic acids were employed due to competitive formation
of the acid anhydride. The reaction of L-menthol with
2,4,6-trimethylbenzoic acid promoted by 6a gave the ester
with greater than 99.5% inversion (Table 2, entry 7).
When we returned to the use of 4-nitrobenzoic acid, but
performed the reaction in DMF, the ester was obtained
in good yield but with 99.2% retention (Table 2, entry 8)
in sharp contrast with entry 7. The general results
observed with L-menthol were shown to also hold for the
other chiral alcohols investigated. Thus, (1R)-1-phenyl-
1-propanol 9 reacted slowly in DMF with 4-nitrobenzoic
acid in the presence of 6a to give the ester with 64%
retention and 36% inversion of configuration at the
alcohol center (Table 2, entry 9) while bulky phosphorane
6b provided 95% retention (Table 2, entry 10). The same
reaction conducted in toluene and employing 2,4,6-
trimethylbenzoic acid proceeded faster and delivered the
ester with 95% inversion of configuration (Table 2, entry
11).
The stereochemical implications of the reaction were
then investigated utilizing chiral alcohols L-menthol 7,
the secondary aliphatic (2S)-hexanol 8, and the benzylic
(1R)-1-phenyl-1-propanol 9 under a variety of conditions.
The reaction could be carried out successfully in toluene,
THF, 1,2-dichloroethane, ethyl acetate, or DMF, however,
we determined that toluene and DMF gave slightly
higher yields and often complementary results in terms
of inversion and retention ratios. The overall results are
summarized in Table 2. The reaction of L-menthol 7 with
4-nitrobenzoic acid promoted by phosphorane 6a in
1598 J . Org. Chem., Vol. 68, No. 4, 2003

TABLE 2. Ester ifica tion Rea ction s P r om oted by
P h osp h or a n e 6a
SCHEME 3. P ostu la ted Mech a n ism s for th e
Ester ifica tion w ith 6a
derived analogue of 6 was not very effective in promoting
the esterification reaction.
The mechanistic underpinnings of the reaction were
then investigated. In control experiments we determined
that alcohols do not enter into reaction with DMPT 6a
in the absence of any carboxylic acid or proton source.
However, carboxylic acids react slowly with 6a in the
absence of alcohol to produce the acid anhydride. The
reaction of 2,4,6-trimethylbenzoic acid with 6a (1:1 molar
1
ratio) conducted at 70 °C in CDCl3 was followed by H
NMR. After 4 h the anhydride was formed in over 90%
yield. Isolation of the anhydride in the absence of an
alcohol13 and formation of the ester with retention of
configuration3b,9 are strongly indicative of the interme-
diacy of an acyloxyphosphonium ion. We also determined
that chiral alcohols do not react with the anhydride that
is formed under the conditions of the esterification
reaction, indicating that products of retention do not arise
by simple alcohol acylation; clearly two competing path-
ways leading to the products of inversion or retention are
operative.
To explain the results obtained in our studies, the
mechanism outlined in Scheme 3 is postulated. Initial
protonation of 6a provides the activated intermediate 3′,
analogous to 3, Scheme 1. However, since esters with
retention of stereochemistry are formed as well as
anhydride in certain cases, the major reaction appears
to follow Path 2, proceeding via the acyloxyphosphonium
ion intermediate 5′. In contrast to hydrazide ion forma-
tion in the Mitsunobu reaction3b the only basic anions
that can be formed in the above process are the dimeth-
ylmalonyl anion (DMM pKa approximately 10) or the
carboxylate anion, formed by proton transfer to DMM.
Under these circumstances, base-mediated crossover to
Path 1 (5′ to 4′) becomes less favorable and a higher
degree of retention is expected.
a
Conversions are unoptimized results based on the isolated
mass of purified ester after the standard 24 h reaction period.
Retention:inversion ratios measured by 1H NMR (menthol) and
b
chiral GC or HPLC in comparison with authentic standards.
Similarly, (2S)-2-hexanol 8 could be esterified yielding
the products of inversion or retention in a controlled
fashion (Table 2, entries 12-15). The reaction in DMF
using the tributylphosphorane 6a and 4-nitrobenzoic acid
for the esterification of nonhindered alcohols 8 and 9 gave
ester with 80% retention maximum, while bulky tri-
isobutyl phosphorane 6b gave up to 97% retention (Table
2, entries 10 and 13) although the reaction conversion
was lower than when 6a was employed.
The substituent effect on the reaction conversion with
4-substituted benzoic acids (Table 2, entries 1-3) indi-
cates that 4-nitrobenzoic acid forms the acyloxyphospho-
nium salt (corresponding to 5′, Scheme 3) with 6a faster
likely due to its greater acidity. High degrees of retention
were also observed with the electron-deficient acids. For
more electron-rich carboxylic acids (Table 2, entries 2 and
3) the corresponding carboxylate ions are expected to be
stronger bases compared to the 4-nitrobenzoate anion.
This would lead to increasing conversion of 5′ to 4′
allowing for higher degrees of inversion as the acid
becomes more electron rich.
Overall, the product of inversion is favored with use
of phosphorane 6a when the reaction is performed in
toluene, using a carboxylic acid with one or more ortho-
substituents and preferably these being electron releas-
ing groups (i.e. 2,4,6-trimethyl- or 2,6-dimethoxybenzoic
acid). The product of retention is favored when the
reaction is performed in DMF with 4-nitrobenzoic acid
and is increased as the steric bulk of the trialkyl
substituents on the phosphorane increases. In most cases,
DMTP 6a was the reagent of choice in effecting rapid
esterification. Interestingly, the triphenylphosphine-
(13) Greenbaum, M. A.; Denney, D. B.; Hoffman, A. K. J . Am. Chem.
Soc. 1956, 78, 2563.
J . Org. Chem, Vol. 68, No. 4, 2003 1599

In addition to the importance of the basicity of the
reaction media, steric factors on the alcohol, carboxylic
acid, and phosphorane, as well as solvent, play important
roles on the balance between the competing pathways
leading to retention or inversion. In the case involving
the 4-nitrobenzoate anion and a hindered alcohol such
as menthol, the crossover path is less likely and the
reaction proceeds with high retention (99%) in DMF
(Table 2, entry 8) and 95% in toluene (Table 2, entry 1).
For 4-nitrobenzoic acid and less hindered alcohols 8 and
9 intermediate ratios of retention and inversion are
observed (Table 2, entries 9 and 12). As the steric nature
of the acid is increased (Table 2, entries 4-7, 11, 14, and
15) the acyloxyphosphonium salt 5′ becomes more hin-
dered and the attack of alcohol on the acyl center becomes
slower allowing more alkoxyphosphonium ion 4′ forma-
tion leading to higher degrees of inversion and essentially
complete inversion when 2,4,6-trimethylbenzoic acid is
used (Table 2, entries 7, 11, and 15).
of stereochemistry in a predictable manner. The reagents
also promote the esterification of achiral substrates with
a wide range of carboxylic acid and alcohol partners
under neutral conditions. The major advantage of these
new reagents is the controlled levels of inversion or
retention that can be achieved through choice of reagents
and solvent. These results appear to be manifest because
no strongly basic species is generated during the reaction
allowing clean separation of the two competing pathways
available for the reaction. The side products of this
reaction, DMM and tributylphosphine oxide, are largely
removed by using a basic extraction protocol, simplifying
purification. Strong evidence in favor of the reaction
proceeding via an acyloxyphosphonium salt has been
uncovered in accord with the mechanism proposed. The
question of inversion vs retention in the esterification
reaction of chiral alcohols promoted by phosphorane 6a
is rationalized as competition between direct alcohol
acylation by the acyloxyphosphonium ion 5′, leading to
retention, and base-mediated crossover from 5′ to the
alkoxyphosphonium ion 4′, resulting in the product of
inversion. The implications of these results for the
current view of the standard Mitsunobu esterification are
such that the basic hydrazide anion may indeed play a
very significant role.3b,11 Basic anions are also implicated
during the esterification reaction carried out with (cya-
nomethyl)trialkylphosphoranes, such as the elimination
of the anion of acetonitrile,6,7 resulting in inversion of
stereochemistry also. By analogy with our results, such
basic species may provide a crossover path, via alkoxide
anion formation, from an initial acyloxyphosphonium salt
to an alkoxyphosphonium salt leading ultimately to
esters with inversion of stereochemistry. The results
described with the new phosphoranes 6a and 6b, along
with the recent reports by DeShong9 and Smith,10 con-
cerning standard Mitsunobu reagents providing esters
(lactones) with retention of stereochemistry draw atten-
tion to the fine line between the divergent mechanisms
operative in the reaction. While inversion of stereochem-
istry is the normal outcome for the standard Mitsunobu
reaction on chiral secondary alcohols, this should no
longer be assumed to be the case, particularly in cases
where hindered secondary alcohols are involved. A
detailed study concerning the independent generation
and trapping of acyloxyphosphonium ions is in progress
and will be reported in due course.
In the cases where the hindered phosphorane 6b (Table
2, entries 10 and 13) was employed in conjunction with
a nonhindered acid, alkoxide or alcohol attack on the acyl
carbon (as opposed to phosphorus) of the acyloxyphos-
phonium salt 5′ is expected to become dominant, result-
ing in higher degrees of retention.
Further evidence in accord with the postulated mech-
anism, including base-mediated crossover, was obtained
from the following experiments. The independent genera-
tion and trapping of acyloxyphosphonium ions can be
accomplished oxidatively through the treatment of a
tertiary phosphine with benzoyl peroxide.13 Thus, a
solution of benzoyl peroxide (BPO) in THF was added
dropwise to a mixture of L-menthol and tributylphos-
phine,13 under our standard esterification conditions (70
°C), and separately with added diisopropylamine. The
menthyl ester of benzoic acid was formed in good yield
in both cases with retention:inversion ratios of 80:20 and
40:60. This first result is very similar to that obtained
with phosphorane 6a and benzoic acid (ratio 81:19). This
provides strong evidence for the acyloxyphosphonium3b
intermediate 5′ and that Path 1 in Scheme 3 may not be
operative under our conditions. The result with diiso-
propylamine is direct independent evidence for the base-
mediated competitive crossover path in the esterification
reaction promoted by phosphorane 6a leading to more
inversion. The use of triphenylphosphine and BPO was
recently shown to generate anhydrides via the acyloxy-
phosphonium ion even when the reaction was performed
in ethanol as solvent.3b Only traces of ethyl ester were
produced in this process. In contrast to these results, the
trialkylacyloxyphosphonium ion allows esterification to
proceed efficiently even when a stoichiometric amount
of a hindered alcohol is present.
Ack n ow led gm en t. Financial support of this work
by NSERC and Materials and Manufacturing Ontario
is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have prepared a new class of trialkyl-
phosphorane that promotes the esterification reaction of
chiral alcohols allowing controlled inversion or retention
J O026639Y
1600 J . Org. Chem., Vol. 68, No. 4, 2003