ORGANIC LETTERS
Cyclopropenone Catalyzed Substitution of Alcohols with Mesylate Ion
XXXX Vol. XX, No. XX 000–000
Eric D. Nacsa and Tristan H. Lambert* Department of Chemistry, Columbia University, New York, New York 10027, United States
[email protected] 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 diazodicarboxylate 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 of major drawbacks plague the Mitsunobu reaction, including the toxic and explosive nature of diazodicarboxylates and the problematic purification of products from triphenylphosphine (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. (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.; It^ o, 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.; It^ o, S. Tetrahedron Lett. 1994, 35, 5081.
oxide and dicarboxyhydrazine byproducts.2 Despite significant advances,3 alternative strategies are very much in demand.4,5 We recently disclosed a catalytic strategy for the promotion of dehydrative reactions6 using simple cyclopropenones7,8 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. (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. 10.1021/ol302970c
r XXXX American Chemical Society
Scheme 1. Design of a Cyclopropenone Catalyzed Alcohol Inversion with Mesylate Ion
product was isolated with 100% retention of stereochemistry, demonstrating that the proposed activation mode is essential to the desired outcome.
Scheme 2. Demonstration of Alcohol Inversion with Mesylate Ion via Cyclopropenium Activation
Our design of a cyclopropenone catalyzed alcohol inversion is shown in Scheme 1. In previous work by our group9d and others,12 it has been demonstrated that a cyclopropenone 1 can undergo conversion to a cyclopropenium salt (2) by the action of acid anhydrides including methanesulfonic anhydride (Ms2O). Alkylation of an alcohol substrate 3 by cyclopropenium ion, followed by reionization, leads to formation of the cyclopropenium activated intermediate 5. We reasoned that nucleophilic displacement of the cyclopropenium alkoxide fragment of such intermediates by either the mesylate counterion or mesylate ion generated by the addition of base would produce the desired substitution product 6 with concomitant regeneration of the cyclopropenone catalyst. Of crucial importance to the proposed catalytic cycle is the successful competition of the desired pathway in preference to the direct mesylation of 3, which would produce mesylate product epi-6 with retention of stereochemistry. To test this proposal, enantioenriched alcohol 7 was treated with 1.3 equiv of diphenylcyclopropenone13 (8) and Ms2O at 23 °C in CDCl3 (Scheme 2). After 2 h, quantitative formation of cyclopropenium ether 9 was observed by 1 H NMR (see Supporting Information), as diagnosed by the significantly downfield shift of the methine proton. Extended monitoring of the reaction revealed minimal (
