J . Org. Chem. 2002, 67, 1751-1753
1751
Mech a n istic Stu d y of th e Mitsu n obu Rea ction
Chuljin Ahn,† Reuben Correia, and Philip DeShong*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742
pd10@umail.umd.edu
Received November 8, 2000 (Revised Manuscript Received J anuary 10, 2002)
The Mitsunobu reaction occurs typically with inversion of configuration in secondary alcohol
derivatives. In this paper, a mechanistic explanation for lactonizations of hindered alcohols under
Mitsunobu conditions with retention is proposed. This involves the intermediacy of an acyloxy-
phosphonium salt followed by acyl transfer to the alcohol.
In tr od u ction
benzoic acid to give benzoate and phosphonium ion 10.9
However, at this juncture, it is unlikely that benzoate
would serve as a base to assist in proton removal from
alcohol 11 as indicated in Scheme 2. Hughes proposed
that benzoate would displace hydrazide anion 15 to afford
acyloxyphosphonium ion 14 instead.7 Deprotonation of
alcohol 11 by hydrazide anion 15 followed by phosphorus
transfer would lead to formation of phosphonium salt 12
and, subsequently, the inverted product 13. With unhin-
dered alcohols, it is expected that conversion of 14 to 12
occurs readily and that attack at phosphorus is preferred
to acyl transfer. Under these circumstances, the inverted
product 13 is observed exclusively. However, in systems
in which the alcohol is hindered (i.e., 5, Scheme 1), we
proposed that attack onto phosphorus by alkoxide to give
the Mitsunobu intermediate 12 was precluded and that
lactonization with retention was observed instead.6 The
central question posed by these results was whether acyl
transfer was observed only because of the intramolecular
nature of the reaction. In an effort to determine whether
acyl transfer would be observed in intermolecular reac-
tions, we investigated unambiguous methods for prepa-
ration of acyloxyphosphonium salts and determined their
fate in esterification reactions.
The Mitsunobu reaction is widely employed for the
inversion of configuration in secondary alcohol deriva-
tives.1-5 Recently, we reported lactonizations under Mit-
sunobu conditions that afforded bicyclic lactones in which
either inversion or retention of configuration was ob-
served depending on the steric accessibility of the alcohol
moiety as summarized in Scheme 1.6 In that paper, it
was proposed that the retention product, lactone 8,
resulted from direct acyl transfer from phosphonium ion
6. The lactonization with retention proceeded in prefer-
ence to formation of phosphonium salt 7, the classical
Mitsunobu intermediate (see Scheme 1). In this system,
the hindered nature of the alcohol precluded formation
of the Mitsunobu intermediate 7. Previously, Hughes had
proposed formation of acyloxyphosphonium ions (i.e., 2
and 6) as intermediates in the Mitsunobu process.7
However, direct evidence for their formation in the
Mitsunobu reaction was not reported. In this paper, we
report studies designed to prepare acyloxyphosphonium
salts such as 2 and 6 by alternative methods and
investigate the stereochemical consequences of their
reactions with alcohols.
From the outset, the standard mechanism proposed for
the Mitsunobu reaction (9-13, Scheme 2) was deemed
incomplete.7-14 For example, as noted by Hughes, anion
9 should preferentially undergo proton transfer with
Resu lts a n d Discu ssion
As summarized in Scheme 3, treatment of benzoic acid
under Mitsunobu conditions (PPh3, DEAD)15,16 in the
absence of an alcohol gave benzoic anhydride (19) in high
yield. The formation of the anhydride 19 was consistent
with the intermediacy of acyloxyphosphonium salt 14,17,18
followed by benzoate attack on the acyl function. Also,
benzoic anhydride (19) was obtained from the reaction
of benzoyl peroxide (18) and triphenylphosphine (Scheme
3), presumably via intermediate 14. Under these condi-
tions, benzoate anion reacted with the in situ generated
phosphonium salt 14 by acyl transfer to provide the
anhydride 19.
* To whom correspondence should be addressed. Phone: 301-405-
1892. Fax: 301-314-9121.
† Current address: Department of Chemistry, Changwon National
University, Changwon, Korea 641-773.
(1) Dodge, J . A.; J ones, S. A. Recent Res. Dev. Org. Chem. 1997, 1,
301-336.
(2) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164.
(3) Hughes, D. L. Org. React. 1992, 42, 335-656.
(4) Castro, B. R. Org. React. 1983, 29, 1-162.
(5) Mitsunobu, O. Synthesis 1981, 1-28.
(6) DeShong, P.; Ahn, C. J . Org. Chem., in press.
(7) Hughes, D. L.; Reamer, R. A. J . Org. Chem. 1996, 61, 2967-
2971.
(8) Pautard-Cooper, A.; Evans, J . S. A. J . Org. Chem. 1989, 54,
2485-2488.
(9) Hughes, D. L.; Reamer, R. A.; Bergan, J . J .; Grabowski, E. J .
Am. Chem. Soc. 1988, 110, 6487-6491.
(15) Overman, L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc. 1984,
106, 6, 4192-4201.
(10) Bajwa, J . S.; Anderson, R. C. Tetrahedron Lett. 1990, 31, 6973-
6976.
(16) Smith, A. B.; Sulikowski, G. A.; Sulikowski, M. M.; Fujomoto,
K. J . Am. Chem. Soc. 1992, 114, 2567-2576.
(11) Crich, D.; Dyker, H.; Harris, R. J . Org. Chem. 1989, 54, 257-
259.
(17) Burke, S. D.; Hans, J . J .; Driver, R. W. J . Org. Chem. 2000,
65, 2114-2121.
(12) Grochowski, E.; Hitton, B. D.; Kupper, R. J .; Michaejda, C. J .
Am. Chem. Soc. 1982, 104, 6876-6877.
(18) Burke and co-workers have also proposed that an acyloxyphos-
phonium salt intermediate is produced from the reaction of tribromo-
and trichloroethyl esters with phosphines.17 They demonstrated that
amines and alcohols react rapidly with the acyloxyphosphonium salt
with acyl transfer to afford amides and esters, respectively.
(13) Guthrie, R. D.; J enkins, I. D. Aust. J . Chem. 1982, 35, 767-
774.
(14) Varasi, M.; Walker, K. A.; Maddox, M. L. J . Org. Chem. 1987,
52, 4235-4238.
10.1021/jo001590m CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/19/2002