The role of acyloxyphosphonium ions and the stereochemical influence of base in the phosphorane-mediated esterification of alcohols

Article abstract of DOI:10.1002/anie.200351209

Intimate details of the Mitsunobu mechanism: The trapping of an acyloxytributylphosphonium ion with a chiral secondary alcohol leads to either retention or inversion of stereochemistry in the resulting ester depending on the exclusion or inclusion of a base (see scheme). Insight into the mechanism of phosphorane-mediated esterification processes is presented.

Full text of DOI:10.1002/anie.200351209

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Angewandte
Chemie
Acyloxyphosphonium Ion Trapping
The Role of Acyloxyphosphonium Ions and the
Stereochemical Influence of Base in the
Phosphorane-Mediated Esterification of
Alcohols**
James McNulty,* Alfredo Capretta, Vladimir Laritchev,
Jeff Dyck, and Al J. Robertson
The Mitsunobu reaction[1–4] is widely employed in both
condensation and displacement reactions of alcohols with
various nucleophiles and normally proceeds with inversion of
stereochemistry when chiral secondary alcohols are used. The
mechanism of the reaction continues to receive attention and
the present view is summarized in Scheme 1. Although the
[*] Dr. J. McNulty, Dr. A. Capretta, Dr. V. Laritchev
Department of Chemistry, McMaster University
1280 Main Street West, Hamilton, Ontario, L8S 4M1 (Canada)
Fax: (+1)905-522-2509
E-mail: mcnulty@chemistry.mcmaster.ca
J. Dyck
Department of Chemistry, Brock University
St. Catharines, Ontario, L2S 3A1(Canada)
A. J. Robertson
Cytec Canada Inc.
P.O. Box 240, Niagara Falls, Ontario, L2E 6T4 (Canada)
[**] Financial support was provided by the Natural Sciences and
Engineering Research Council of Canada.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 4051 –4054
DOI: 10.1002/anie.200351209
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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described in Equation (1). We now report
the independent generation of the benzoy-
loxytributylphosphonium ion, which could
be trapped with chiral secondary alcohols
under both neutral and basic conditions in
the synthesis of esters with either retention
or inversion of configuration. Clear evidence
was thus obtained for both direct acylation
and the postulated base-mediated crossover
step.
Acyloxyphosphonium ions have been
generated through the addition of a perox-
ide to a tertiary phosphane, for example, the
addition of benzoyl peroxide (BPO) to a
solution of triphenylphosphane.[11] When a
solution of BPO in N,N-dimethylformamide
Scheme 1. Mechanism of the Mitsunobu esterification.
initiation and termination steps of the reac-
tion seem clear cut, there is still debate
concerningthe exact details involved in the
intermediate stages of the reaction. The
reaction proceeds through the rapid addi-
tion[3a] of triphenylphosphane to an azodi-
carboxylate such as diethyl azodicarboxylate (DEAD), fol-
lowed by proton transfer from the carboxylic acid to give 1a
and 3 as shown. As the esters obtained are the product of
inversion of stereochemistry in the vast majority of cases, it
appears that the reaction normally terminates through
nucleophilic displacement by 1a of triphenylphosphane
oxide from the activated alkoxyphosphonium ion 4.
Recent evidence from several laboratories has challenged
the original mechanistic hypothesis put forward by Mitsunobu
and Yamada,[1,2a] wherein the reaction proceeds directly to the
alkoxyphosphonium salt 4 (Scheme 1, path 1). Evidence for
the involvement of acyloxyphosphonium ion intermediates 5
has been obtained indirectly over a number of years.[5]
Hughes et al.[3b] and Jenkins and co-workers[6] independently
reported the isolation of anhydrides from the reaction of acids
with DEAD and attributed this to the intermediacy of
acyloxyphosphonium ions 5 that Jenkins[6] postulated were
in equilibrium with 4. More recently, DeShongand co-
workers,[7] Smith et al.,[8] and De Brabander and co-workers[9]
have reported the isolation of products of retention of
configuration from the reactions of certain sterically hindered
chiral secondary alcohols under standard Mitsunobu condi-
tions.
Retention of stereochemistry is thought to arise through
the direct attack of the alcohol at the carbonyl carbon atom of
an intermediate acyloxyphosphonium salt. It has been
postulated that the normal product obtained from the
Mitsunobu reaction may be the result of a competitive
crossover reaction mediated by basic species present or
generated (such as the hydrazide anion 6) duringthe
reaction.[7a,10] Accordingto this hypothesis (Scheme 1,
path 2), an initial acyloxyphosphonium ion 5 is generated by
the attack of the more nucleophilic carboxylate anion 1a,
rather than the alcohol, at the phosphorus center in 3. The
details of the postulated base-mediated crossover to 4 are
(DMF) was added dropwise to a mixture of l-menthol and
tributylphosphane at 708C under argon, menthol benzoate
was isolated from the reaction mixture in 50% yield. Spectral
analysis of the product showed 97% retention of stereo-
chemistry, which indicates that direct attack of menthol at the
carbonyl carbon of the benzoyloxyphosphonium intermediate
had occurred predominantly. These results concur with the
postulated intermediacy of acyloxytrialkylphosphonium ions
in esterification reactions, generated alternatively by using
our recently described phosphorane method.[10] When this
method was used, l-menthol reacted with 4-nitrobenzoic acid
in DMF to give the corresponding menthol ester with 99.2%
retention of configuration (76% yield). Recently, Burke and
co-workers reported a further independent route to acylox-
yphosphonium ions, from trihaloethyl esters. These species
also reacted in DMF with l-menthol under nonbasic con-
ditions to provide the correspondingesters with retention of
configuration.[12]
Havingdemonstrated that the benzoyloxytributylphos-
phonium ion can be trapped with menthol to yield the desired
ester with retention of configuration, we now focused on
developinga more synthetically useful process that could
provide access to esters with inversion of stereochemistry. We
screened a large variety of bases for their ability to effect the
postulated crossover step that might lead to inversion.
Although essentially any amine added increased the amount
of the product of inversion obtained, we quickly determined
that bulky primary amines, such as tert-butylamine or 1,1,3,3-
tetramethylbutylamine, were superior both in terms of the
product of inversion/product of retention ratio observed and
in terms of the yield of the desired product. The results with l-
menthol show that high selectivity in favor of the product of
inversion might be anticipated when such hindered bases are
present (Table 1, entries 1 and 2), whereas retention of
configuration is favored in the absence of a base (Table 1,
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Table 1: Esterification reactions of chiral alcohols promoted by BPO/Bu3P alone and in the presence of
bulky primary amines.
facilitate the crossover step, or to remove a
proton with formation of the phosphorane
intermediate 7 [Eq. (1)], followed by disso-
ciation to give the required alkoxyphospho-
nium ion 4. In either case, the function of the
base is to shift the equilibrium shown in
Equation (1) to the right and promote the
formation of 4.[12]
In conclusion, we have demonstrated the
independent generation of the benzoyloxy-
tributylphosphonium ion and shown that it
can be directly trapped with chiral alcohols
to yield esters with retention of configura-
tion, or can be converted into an alkoxy-
phosphonium ion through the addition of a
base to yield esters predominantly with
inversion of configuration. These studies
confirm the existence of a base-induced
crossover step and highlight the significance
Entry
Alcohol
Base
Method[a]
Ret./inv.[b]
Conv.[c]
1
2
3
4
5
6
7
8
9
l-menthol
l-menthol
l-menthol
(2S)-hexanol
Me3CNH2
Me3CCH2CMe2NH2
–
Me3CCH2CMe2NH2
–
Me3CCH2CMe2NH2
–
A
A
B
A
B
A
B
A
B
0.7:99.3
1.1:98.9
97.0:3.0
1.9:98.1
55.0:45.0
2.7:97.3
43.7:56.3
5.6:94.4
72.3:27.7
57%
55%
50%
73%
67%
54%
56%
73%
70%
(2S)-hexanol
(1R)-1-phenyl propanol
(1R)-1-phenyl propanol
ethyl (S)-(À)-lactate
ethyl (S)-(À)-lactate
Me3CCH2CMe2NH2
–
[a] BPO (1.5 equiv) was dissolved in 1.5 mL of benzene (protocol A) or DMF (protocol B) and added
dropwise over 70 min to a stirred solution of tributylphosphane (1.5 equiv), the alcohol (1.0 equiv), and
the appropriate base (2.5 equiv) in 0.5 mL of benzene or DMF at 708C. [b] Product of retention/product
of inversion ratio determined by NMR spectroscopy and GC on a chiral phase in comparison with
authentic samples. [c] Unoptimized conversion based on mass of purified ester product obtained under
standard conditions described.
entry 3). These results are evidence for the base-mediated
crossover step proposed in Equation (1). To the best of our
knowledge, this is the first report of clear independent
evidence for the involvement of a base in such a redox
condensation leadingto esters with inversion of configura-
tion. These results proved to be general for the chiral
secondary alcohols investigated: (2S)-2-hexanol (98.1%
inversion), (1R)-1-phenyl-1-propanol (97.3% inversion),
and (2S)-ethyl lactate (94.4% inversion).
A relatively clear mechanism can now be proposed to
explain the dichotomous results obtained. In contrast with
standard Mitsunobu[1] and phosphorane-mediated esterifica-
tion processes,[11] in the new esterification protocol with
inversion of stereochemistry in the presence of BPO/Bu3P,
direct formation of the alkoxyphosphonium ion 4a is not
possible, and the reaction must proceed via 5a (Scheme 2).
of basic species with regard to the stereochemical outcome of
an esterification when such a redox condensation reaction
that proceeds via an acyloxytrialkylphosphonium intermedi-
ate is used. Attention has often been drawn to the subtle
interplay of factors that contribute to the stereochemical
outcome in a given case.[6,7a,9,13] The results presented here
show that the nature of any basic species present or generated
duringthe reaction can have a profound effect on the
stereochemistry of the esterification and thus requires due
consideration.
Received: February 18, 2003 [Z51209]
Keywords: acylation · amines · peroxides · phosphanes ·
.
synthetic methods
[1] O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn.
1967, 40, 2380.
[2] For comprehensive reviews, see: a) O. Mitsunobu,
Synthesis 1981, 1; b) D. L. Hughes, Org. React.
1992, 42, 335.
[3] a) D. L. Hughes, R. A. Reamer, J. J. Bergan, E. J. J.
Grabowski, J. Am. Chem. Soc. 1988, 110, 6487;
b) D. L. Hughes, R. A. Reamer, J. Org. Chem.
1996, 61, 2967.
[4] For further mechanistic discussions, see: a) M.
Varasi, K. A. M. Walker, M. L. Maddox, J. Org.
Chem. 1987, 52, 4235; b) D. Camp, I. D. Jenkins,
Aust. J. Chem. 1988, 41, 1835; c) D. Crich, H.
Dyker, R. J. Harris, J. Org. Chem. 1989, 54, 257;
d) D. Camp, I. D. Jenkins, J. Org. Chem. 1989, 54,
3045; e) J. A. Dodge, J. I. Trujillo, M. Presnell, J.
Org. Chem. 1994, 59, 234; f) D. L. Hughes, Org. Prep. Proced.
Int. 1996, 28, 127.
Scheme 2. Generation and trapping of the benzoyloxytributylphosphonium ion 5a
with l-menthol.
When an alcohol is present and in the absence of base, direct
acylation of the alcohol predominates, which leads to esters
[5] For early reports on the involvement of acyloxyphosphonium
ions in Mitsunobu-type processes, see: a) H. Kunz, P. Schmidt,
Chem. Ber. 1979, 112, 3886; b) W. Adam, N. Narita, Y.
Nishizawa, J. Am. Chem. Soc. 1984, 106, 1843; c) D. Camp,
I. D. Jenkins, J. Org. Chem. 1989, 54, 3049.
with retention of configuration. This process is also facilitated
by the use of DMFas the solvent. In the presence of a base the
crossover path becomes dominant, thus leadingto the
alkoxyphosphonium ion 4a, and then to esters with inversion
of configuration. The function of the base must be either to
generate a continuous low concentration of alkoxide to
[6] P. J. Harvey, M. von Itzstein, I. D. Jenkins, Tetrahedron 1997, 53,
3933.
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[7] a) C. Ahn, R. Correia, P. DeShong, J. Org. Chem. 2002, 67, 1751;
addendum: C. Ahn, R. Correia, P. DeShong, J. Org. Chem. 2003,
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[9] X. Liao, Y. Wu, J. K. De Brabander, Angew. Chem. 2003, 115,
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[10] J. McNulty, A. Capretta, V. Laritchev, J. Dyck, A. J. Robertson, J.
Org. Chem. 2003, 68, 1597.
[11] a) A. M. Pautard, S. A. Evans Jr. , J. Org. Chem. 1988, 53, 2300;
b) M. A. Greenbaum, D. B. Denney, A. K. Hoffman, J. Am.
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[12] J. J. Hans, R. W. Driver, S. D. Burke, J. Org. Chem. 2000, 65,
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4054
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Angew. Chem. Int. Ed. 2003, 42, 4051 –4054