ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Cyclopropenone Catalyzed Substitution
of Alcohols with Mesylate Ion
Eric D. Nacsa and Tristan H. Lambert*
Department of Chemistry, Columbia University, New York, New York 10027,
United States
Received October 30, 2012
ABSTRACT
The cyclopropenone catalyzed nucleophilic substitution of alcohols by methanesulfonate ion with inversion of configuration is described. This
work provides an alternative to the Mitsunobu reaction that avoids the use of azodicarboxylates and generation of hydrazine and phosphine oxide
byproducts. This transformation is shown to be compatible with a range of functionality. A cyclopropenone scavenge strategy is demonstrated to
aid purification.
Chemical transformations involving the nucleophilic
substitution of alcohols are a crucial component of the
synthetic toolbox. One of the most widely used approaches
is the Mitsunobu reaction,1 a process in which a diazodi-
carboxylate and triphenylphosphine conspire to effect the
nucleophilic substitution of hydroxyl groups, typically
with inversion of stereochemistry. Due to the importance
of this type of transformation, the Mitsunobu reaction has
become a key technology for the preparation of complex
molecules.1d Unfortunately, a number ofmajor drawbacks
plague the Mitsunobu reaction, including the toxic and
explosive nature of diazodicarboxylates and the proble-
matic purification of products from triphenylphosphine
oxide and dicarboxyhydrazine byproducts.2 Despite sig-
nificant advances,3 alternative strategies are very much in
demand.4,5
We recently disclosed a catalytic strategy for the pro-
motion of dehydrative reactions6 using simple cyclopro-
penones7,8 as catalysts. This strategy, which relies on the
facile formation of cyclopropenium cations for substrate
activation,9 was first demonstrated in the context of
alcohol chlorodehydration using oxalyl chloride as the
activating agent and source of nucleophile. Here, we
advance this concept to the context of cyclopropenone
catalyzed alcohol substitution with an acid anhydride.10,11
(4) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman,
B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green. Chem. 2007, 9, 411.
(5) For other recent alternative approaches to catalytic alcohol
substitution, see: (a) Denton, R. M.; Jie, A.; Adeniran, B. Chem.
Commun. 2010, 46, 3025. (b) Dai, C.; Narayanam, J. M. R.; Stephenson,
C. R. J. Nature Chem. 2011, 3, 140.
(1) (a) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967,
40, 2380. For reviews, see: (b) Mitsunobu, O. Synthesis 1981, 1–28.
(c) Hughes, D. L. Org. React. 1992, 42, 335. (d) Kumara Swamy, K. C.;
Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem.
Rev. 2009, 109, 2551. (e) But, T. Y. S.; Toy, P. H. Chem.;Asian. J. 2007,
2, 1340.
(6) Vanos, C. M.; Lambert, T. H. Angew. Chem., Int. Ed. 2011, 50,
12222.
(7) (a) Breslow, R.; Haynie, R. R.; Mirra, J. J. Am. Chem. Soc. 1959,
81, 247. (b) Breslow, R.; Peterson, R. J. Am. Chem. Soc 1960, 82, 4426.
(c) Kursanov, D. N.; Volpin, M. E.; Koreshkov, Y. D. Izu. Acad. Nauk
SSSR, Otd. Khim. Nauk. 1959, 560.
(8) (a) Potts, K. T.; Baum, J. S. Chem. Rev. 1973, 73, 189. (b) Komatsu,
K.; Kitagawa, T. Chem. Rev. 2003, 103, 1371.
(9) (a) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131,
13930. (b) Hardee, D. J.; Kovalchuke, L.; Lambert, T. H. J. Am. Chem.
Soc. 2010, 132, 5002. (c) Vanos, C. M.; Lambert, T. H. Chemical Science
2010, 1, 705. (d) Kelly, B. D.; Lambert, T. H. Org. Lett. 2011, 13, 740.
(2) (a) Dandapani, S.; Curran, D. P. Chem.;Eur. J. 2004, 10, 3130.
(b) Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
(3) For examples, see: (a) Pelletier, J. C.; Kincaid, S. Tetrahedron
Lett. 2000, 41, 797. (b) Lipshutz, B. H.; Chung, D. W.; Rich., B.; Corral,
^
R. Org. Lett. 2006, 8, 5069. (c) Tsunoda, T.; Nagino, C.; Oguri, M.; Ito,
S. Tetrahedron Lett. 1996, 37, 2459. (d) Kiankarimi, M.; Lowe, R.;
McCarthy, J. R.; Whitten, J. P. Tetrahedron Lett. 1999, 24, 4497.
(e) Starkey, G. W.; Parlow, J. J.; Flynn, D. L. Bioorg. Med. Chem. Lett.
1998, 8, 2385. (f) Amos, R. A.; Emblidge, R. W.; Havens, N. J. Org.
Chem. 1983, 48, 3598. (g) Tunoori, A. R.; Dutta, D.; Georg, G. I.
^
Tetrahedron Lett. 1998, 39, 8751. (h) Tsunoda, T.; Ozaki, F.; Ito, S.
Tetrahedron Lett. 1994, 35, 5081.
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10.1021/ol302970c
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