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

Abstract

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

(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-triazoles^a

				dr = >20:1b
entry	triazole	catalyst	yield, %c	ee, %d
1	4a (R = p-Tol)	Rh2(S-DOSP)4	92	28
2	4a	Rh2(S-PTAD)4	91	74
3	4a	Rh2(S-PTTL)4	87	76
4	4a	Rh2(S-NTTL)4	42e,f	78
5	4b (R = Me)	Rh2(S-PTTL)4	91	88
6	4b	Rh2(S-NTTL)4	95	96
7	4c (R = n-C8H17)	Rh2(S-NTTL)4	99	96
8	4d (R = i-Pr)	Rh2(S-NTTL)4	83	97
9	4d	Rh2(S-DOSP)4	75	−16
10g	4c	Rh2(S-NTTL)4	90	96

^aTriazole 4 (0.2 mmol), styrene (1.0 mmol), Rh(II) catalyst (0.002 mmol), 1,2-dichloroethane (0.5 mL).

^bDetermined by ¹H NMR of the crude reaction mixture.

^cNMR yield of 6a after hydrolysis.

^dDetermined by chiral HPLC.

^eReaction did not proceed at temperatures below 100 °C.

^fdr = 3:1.

^g1.2 equiv of styrene, 0.5 mol % of catalyst, 65 °C.

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 bond^8c,14 did not occur.

Scheme 1.

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

^aUnless specified otherwise, all reactions were carried out on 0.5 mmol scale with 1.2 equiv of olefin and under ambient atmosphere; ^bdetermined by ¹H NMR of the crude reaction mixture; ^c2.0 equiv. of alkene were used.

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

^a All reactions were carried out in 0.5 mmol scale with 1.2 equiv of olefin, and under ambient atmosphere. ^b Determined by ¹H NMR of the crude reaction mixture.

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).

(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.