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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Chem Soc. Author manuscript; available in PMC 2010 December 23.
Published in final edited form as:
PMCID: PMC2801057
NIHMSID: NIHMS161433

Rhodium-Catalyzed Enantioselective Cyclopropanation of Olefins with N-Sulfonyl 1,2,3-Triazoles

Abstract

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N-Sulfonyl 1,2,3-triazoles readily form rhodium(II) azavinyl carbenes, which react with olefins to produce cyclopropanes with excellent diastereo- and enantioselectivity and in high yield.

Diazocarbonyl compounds 1 are well known precursors to metal carbenes 2 (eq 1).1 The versatile reactivity of the latter is recognized by numerous synthetic applications.2 In contrast, related azavinyl carbenes 3 have not been employed in synthesis,3 primarily due to the limited availability of corresponding α-diazoimines.4 These reactive intermediates can be viewed as synthetic equivalents of formyl carbenes, in which both amine and aldehyde functions can be revealed by simple transformations, thus significantly expanding the repertoire of chiral molecules that may be accessed via carbene-based synthetic methods. Herein we wish to report a first example of highly diastereo- and enantioselective Rh(II)-catalyzed cyclopropanation employing azavinyl carbenes 3 derived from 1-sulfonyl 1,2,3-triazoles 4. The latter can be obtained using the copper-catalyzed cycloaddition reaction of alkynes with sulfonyl azides.5

equation image
(1)

Our recent success in the Rh-catalyzed transannulation of N-sulfonyl 1,2,3-triazoles had proven that these easily available, reasonably stable and seemingly unreactive compounds are reliable precursors of azavinyl carbenes.6 Accordingly, we further explored the Rh(II) catalysis with 1,2,3-triazoles targeting enantioselective transformations. To this end, we examined the cyclopropanation of styrene with 1-sulfonyl-4-phenyl-1,2,3-triazoles 4 in the presence of various chiral Rh(II) complexes7 (Figure 1) in 1,2-dichloroethane at 80 °C (Table 1). The resulting sulfonyl imine 5 was smoothly converted into the corresponding aldehyde 6a by treatment with K2CO3 in wet methanol.

Figure 1
Rh(II) carboxylates for asymmetric cyclopropanation.
Table 1
Optimization of the Enantioselective Cyclopropanation of styrene with N-sulfonyl 1,2,3-triazolesa

First, we found that the use of 1-toluenesulfonyl derivative 4a with Rh2(S-DOSP)48 catalyst afforded cyclopropane-carboxaldehyde 6a in high yield and excellent trans-diastereoselectivity. However, enantioselectivity of the reaction was low (Table 1, entry 1). Next, Rh2(S-PTAD)49 and Rh2(S-PTTL)410 catalysts were examined, providing 6a with over 70% ee (entries 2 and 3). Increased steric demand of the ligands on rhodium resulted not only in very sluggish reaction, but also in drastic erosion of the diastereoselectivity (entry 4). We hypothesized that switching to a less sterically encumbered carbene precursor might improve the overall performance of the reaction. Indeed, 1-mesyl triazole 4b reacted smoothly in the presence of Rh2(S-PTTL)4 catalyst furnishing the cyclopropane product with 88% ee (entry 5). To our great delight, Rh2(S-NTTL)4,11 in combination with sulfonyl triazole 4b allowed for excellent enantioselectivity (96% ee) and yield, 95% (entry 6). Remarkably, n-octylsulfonyl and isopropylsulfonyl triazoles 4c and 4d provided similar results with Rh2(S-NTTL)4 catalyst (entries 7 and 8). Interestingly, cyclopropanation of 4d in the presence of Rh2(S-DOSP)4 complex provided the opposite enantiomer,9a albeit with very low ee (entry 9).

Further optimization revealed that this cyclopropanation reaction performed well at lower temperature (65 °C) with reduced catalyst loading (entry 10). Notably, only slight excess of olefin (1.2 equiv) was required, and no slow addition techniques (eg. syringe pump) were needed.12

With the optimized conditions for the cyclopropanation with 1,2,3-triazoles in hand, we examined the scope with respect to the olefin (Scheme 1). As illustrated in Scheme 1, a broad range of substituted styrenes participated in the reaction, affording cyclopropanecarbaldehydes13 6b-f in good to excellent yields and high enantioselectivity. Significantly less reactive 1-hexene afforded the corresponding n-butyl-substituted cyclopropane 6g in 70% yield and 96% ee. Interestingly, trans-methylstyrene produced tetrasubstututed cyclopropane 6h with excellent enantioselectivity, while the cyclopropanation of the cis analog delivered almost racemic product 6i. It is worth mentioning that in the last three cases, reaction proceeded with complete chemoselectivity, and the commonly observed insertion into allylic C-H bond8c,14 did not occur.

Scheme 1
Enantioselective Cyclopropanation with 1,2,3-Triazoles: Scope of Olefinsa

Examination of the scope of the process with respect to 1-sulfonyl 1,2,3-triazoles revealed (Scheme 2) that substrates possessing both electron-rich and electron-deficient aryl groups at C-4 reacted smoothly to produce cyclopropanes 6j-m with excellent enantioselectivity. Moreover, heteroaryl- and alkenyl-substituted triazoles were competent substrates for this reaction (Scheme 2, 6n, 6o), further demonstrating the utility of this methodology.

Scheme 2
Enantioselective Cyclopropanation of Styrene with N-Methanesulfonyl 1,2,3-Triazoles

While the instability of sulfonyl imines 5 towards hydrolysis precluded their isolation in pure form, we recognized that a reduction of 5 immediately after they are synthesized could provide an easy access to chiral homo-aminocyclopropanes. Indeed, cyclopropanation of a series of styrenes, followed by the treatment of the crude imine product with LiAlH4, furnished N-(cyclopropylmethyl) sulfonamides 7a-c in good yields and excellent enantioselectivity (eq 2).

equation image
(2)

In summary, a novel and very efficient Rh(II)-catalyzed asymmetric cyclopropanation methodology that utilizes stable and readily available N-sulfonyl 1,2,3-triazoles as azavinyl carbene precursors is now available. The azavinyl carbenes readily react with olefins under experimentally simple conditions, providing cyclopropane carboxaldehydes and N-sulfonyl homo-amino cyclopropanes in generally excellent yields and with high enantioselectivity. Further studies on the scope, origins of high selectivity, and the mechanism of the reaction are underway in our laboratories.

Supplementary Material

1_si_001

2_si_002

Acknowledgements

Financial support of this work by the National Institute of General Medical Sciences, National Institutes of Health (GM087620) and the Skaggs Institute for Chemical Biology is gratefully acknowledged.

Footnotes

Supporting Information Available: Experimental details, characterization data and NMR spectral charts. This material is available free of charge via the Internet at http://pubs.acs.org.

References

1. Doyle MP, McKervey MA, Ye T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides. New York: Wiley; 1998.
2. For recent reviews, see: (a) Davies HML, Manning JR. Nature. 2008;451:417. [PubMed] (b) Doyle MP. In: Modern Rhodium-Catalyzed Organic Reactions. Evans PA, editor. NY: Wiley; 2005. pp. 341–355. (c) Davies HML, Beckwith REJ. Chem. Rev. 2003;103:2861. [PubMed] (d) Lebel H, Marcoux J-F, Molinaro C, Charette AB. Chem. Rev. 2003;103:977. [PubMed]
3. For related transformations involving (2-pyrydyl)-carbenoids, see: (a) Davies HML, Townsend RJ. J. Org. Chem. 2001;66:6595. [PubMed] (b) Chuprakov S, Gevorgyan V. Org. Lett. 2007;9:4463. [PubMed]
4. α-Diazoimines are known to exist in cyclic 1,2,3-triazole form, except for those bearing strong electron-withdrawing group at N-1: (a) Dimroth O. Ann. 1909;364:183. (b) Gilchrist TL, Gymer GE. Adv. Heterocycl. Chem. 1974;16:33.
5. Raushel J. Ph.D. Dissertation (The Scripps Research Intitute). Diss. Abstr. Int., B. 8. Vol. 69. 2009. p. 4763. (b) Cassidy MP, Raushel J, Fokin VV. Angew. Chem. Int. Ed. 2006;45:3154. [PubMed] See also ref. 6a
6. (a) Horneff T, Chuprakov S, Chernyak N, Gevorgyan V, Fokin VV. J. Am. Chem. Soc. 2008;130:14972. [PubMed] For transannulation of related pyridotriazoles, see: (b) Chuprakov S, Hwang FW, Gevorgyan V. Angew. Chem., Int. Ed. 2007;46:4757. [PMC free article] [PubMed]
7. Rh(II) carboxamidates were incompetent in this transformation. See Supporting Information for the full catalyst screening data.
8. For recent application examples, see: (a) Davies HML, Nagashima T, Klino JL., III Org. Lett. 2000;2:823. [PubMed] (b) Davies HML, Lee GH. Org. Lett. 2004;6:1233. [PubMed] (c) Davies HML, Coleman MG, Ventura DL. Org. Lett. 2007;9:4971. [PubMed] See also ref. 5
9. (a) Reddy RP, Lee GH, Davies HML. Org. Lett. 2006;8:3437. [PubMed] (b) Denton JR, Sukumaran D, Davies HML. Org. Lett. 2007;9:2625. [PubMed] (c) Denton JR, Davies HML. Org. Lett. 2009;11:787. [PubMed]
10. For cyclopropanation, see: (a) DeAngelis A, Dmitrenko O, Yap GPA, Fox JM. J. Am Chem. Soc. 2009;131:7230. [PubMed] For C-H insertions, see: (b) Minami K, Saito H, Tsutsui H, Nambu H, Anada M, Hashimoto S. Adv. Synth. Catal. 2005;347:1483. (c) Tsutsui H, Yamaguchi Y, Kitagaki S, Nakamura S, Anada M, Hashimoto S. Tetrahedron:Asymmetry. 2003;14:817. (d) Saito H, Oishi H, Kitagaki S, Nakamura S, Anada M, Hashimoto S. Org. Lett. 2002;4:3887. [PubMed]
11. (a) Müller P, Allenbach YF, Robert E. Tetrahedron: Asymmetry. 2003;14:779. (b) Müller P, Bernardinelli G, Allenbach YF, Ferry M, Flack HD. Org. Lett. 2004;6:1725. [PubMed] (c) Marcoux D, Charette AB. Angew. Chem., Int. Ed. 2008;47:10155. [PubMed] (d) Marcoux D, Azzi S, Charette AB. J. Am. Chem. Soc. 2009;131:6970. [PubMed]
12. Generally, to avoid carbene dimerization side process a dilute solution of diazocompound is added over several hours to a mixture of rhodium catalyst and large excess (3–10 equiv) of olefin.
13. For a recently reported synthesis of chiral cyclopropyl aldehydes via a highly efficient rhodium-catalyzed hydroformylation of cyclopropenes, see: Sherrill WM, Rubin M. J. Am. Chem. Soc. 2008;130:13804. [PubMed]
14. Thompson JL, Davies HML. J. Am. Chem. Soc. 2007;129:6090. [PubMed]