Rh₂ (S-biTISP)₂-Catalyzed Asymmetric Functionalization of Indoles and Pyrroles with Vinylcarbenoids

Abstract

Asymmetric functionalization of N-heterocycles by vinylcarbenoids in the presence of catalytic amounts of Rh₂ (S-biTISP)₂ has been successfully developed. This bridged dirhodium catalyst not only selectively enforces the reaction to occur at the vinylogous position of the carbenoid, but also, affords high levels of asymmetric induction.

Asymmetric methods for the selective functionalization of indoles or pyrroles are in great demand¹ because these electron-rich heterocycles are constituents of many natural products and pharmaceutical agents.² The most widely used approach has been the conjugate addition of heterocycles to α,β-unsaturated carbonyl compounds using chiral transition-metal catalysts³ or organocatalysts.⁴ An alternative approach has been to use carbenoid intermediates.⁵ We have demonstrated that chiral 4-substituted indoles can be generated in a cascade sequence involving a combined C—H functionalization/Cope rearrangement.^5a Fox^5b and Hashimoto^5g have shown that the electrophilic substitution reactions of methyl 2-diazoalkanoate generate chiral 3-substituted indoles with high levels of asymmetric induction. In this paper we describe an alternative carbenoid approach for the asymmetric synthesis of 3-substituted indoles by exploiting the vinylogous electrophilic character of vinylcarbenoids (Scheme 1). This transformation occurs with substrates that are too sterically crowded to react with the carbenoid site of the vinylcarbenoid

Scheme 1.

We have recently described the functionalization of electron rich heterocycles using 2-diazo-3-pentenoates as the carbenoid source.⁶ These reactions proceed by attack of the heterocycles at the vinylogous position of the vinylcarbenoid.^6,7 Vinylogous reactivity of the carbenoid is more pronounced in Z-vinylcarbenoids than E-vinylcarbenoids.⁶ For example, the reaction of Z-2-diazopentenoate 1a with 1,2,5-trimethylpyrrole (2) gave the vinylogous alkylation product 3 in 78% yield exclusively (Scheme 2), whereas the major product from the reaction with the E-2-diazopentenoate 1b with 2 was 4, derived from electrophilic attack at the carbenoid center.⁶ The objective of the current study was to identify suitable chiral catalysts that enable the application of this unusual vinylogous reactivity to the asymmetric functionalization of electron rich heterocycles.

Scheme 2.

We initiated this study by exploring the enantioinduction by some of the standard chiral dirhodium catalysts that have been developed for the reactions of vinyldiazoacetates (Figure 1).⁸ The alkylation of indole 5 with Z-vinyldiazoacetate 1a was used as the standard screening reaction and the results are summarized in Table 1. All the catalysts in our study produced the alkylation product 6 in excellent yields (up to 93%). The two most versatile chiral catalysts for the asymmetric transformations of donor/acceptor carbenoids, Rh₂(S-PTAD)₄ (7) and Rh₂(S-DOSP)₄ (8), failed to give high levels of asymmetric induction in the test reaction. The more bulky catalysts Rh₂(S-TISP)₄ (9) gave slightly higher enantioselectvity than Rh₂(S-DOSP)₄ (26% ee vs 10% ee) but the bulky and conformationally constrained catalyst Rh₂(S-biTISP)₂ (10)⁹ gave 0% ee.

Figure 1.

Chiral dirhodium catalysts

Table 1.

Asymmetric alkylation of indole 5 by Z-vinyldiazoacetate 1a

entry	catalyst	yield (%)	ee (%)a
1	Rh2(S-PTAD)4	88	48
2	Rh2(S-DOSP)4	93	−10
3	Rh2(S-TISP)4	84	−26
4	Rh2(S-biTISP)2	90	0

^aNegative value indicates opposite asymmetric induction.

Having failed to achieve high levels of asymmetric induction with the Z-vinyldiazoacetate 1a, we decided to re-explore the possibility of using E-vinyldiazoacetate 1b as an effective reagent for vinylogous reactivity. Recently, we calculated that the s-cis configuration (conformer B) of Z-vinyldiazoacetates is sterically unfavorable.¹⁰ In contrast E-vinyldiazoacetates exist as equilibrating mixture of s-trans and s-cis conformers (conformers C and D) (Figure 2). On the basis of the reactivity patterns we have observed to date,^6,10 we propose that carbenoids in s-trans configurations (conformers A and C) are more likely to display vinylogous reactivity than carbenoids in s-cis configurations (conformers B and D). The double bond geometry of the products derived from vinylogous reactivity is indicative of the reacting conformation of the carbenoid.⁶ Thus, the reaction of Z-vinyldiazoacetate with indole 5 proceeds through the s-trans conformer, leading to the formation of Z-6. Donor/acceptor carbenoids are known to be sensitive to steric effects, and if the nucleophile is sterically demanding, reactions at the vinylogous position of the carbenoid are enhanced.^7c We, therefore, hypothesized that it would be possible to enhance the vinylogous reactivity of E-vinyldiazoacetates by re-enforcing the s-trans conformation of the carbenoid through the use of highly bulky catalysts.

Figure 2.

Steric influence on the conformation and reactivity of vinylcarbenoids

In order to explore this hypothesis, three standard achiral catalysts and four chiral catalysts were screened in the rhodium(II)-catalyzed decomposition of the (E)-vinyldiazoacetate 1b with 1,2-dimethylindole 5 (Table 2). These reactions afforded variable mixtures of three products (6, 11 and 12). Products 6 and 11 arise from the vinylogous reactivity of the s-trans and s-cis conformers of the vinylcarbenoid, respectively. Product 12 is derived from attack of the heterocycle at the carbenoid center and could, in principle, be derived from reaction with either conformer of the vinylcarbenoid. The product ratio is dependent on the catalyst structure. While the sterically less crowded catalysts Rh₂(OAc)₄ and Rh₂(OAc)₄ give considerable amounts of 11 and 12 (entries 1,2), the bulkier catalysts Rh₂(esp)₄, Rh₂(S-PTAD)₄, Rh₂(S-TISP)₄ and Rh₂(S-biTISP)₂ show a strong preference for the formation of 6 (entries 3,4,6,7). Most notable is the comparison between Rh₂(S-DOSP)₄, which gives near equimolar amounts of the three compounds (entry 5), and Rh₂(S-TISP)₄, which gives about a 8:1 preference for 6 over the two other products (entry 6). Furthermore, in the Rh₂(S-biTISP)₂ catalyzed reaction, 6 is isolated in 66% yield (after purification) and in 89% ee (entry 7).

Table 2.

Asymmetric alkylation of indole 5 with E-vinyldiazoacetate 1b

entry	catalyst	ratioa of 6/11/12	yieldb of 6 (%)	ee of 6 (%)
1	Rh2(OAc)4	62/33/5	57	---
2	Rh2(TFA)4	49/44/7	43	---
3	Rh2(esp)2	74/26/0	52	---
4	Rh2(S-PTAD)4	76/16/8	55	−8
5	Rh2(S-DOSP)4	26/38/36	22	17
6	Rh2(S-TISP)4	89/6/5	66	39
7	Rh2(S-biTISP)2	88/9/3	66	89

^aratio was the average of two runs and determined from the ¹H NMR of the crude reaction mixture.

^bisolated yield

The Rh₂(S-biTISP)₂-catalyzed asymmetric vinylogous alkylation is applicable to a range of substituted indoles as illustrated in Figure 3. The desired transformation was observed for all substrates tested and the (Z)-pent-2-enoates 13–24 were produced in 48–86% yields with good levels of enantioselectivity (82–95% ee). Protected and unprotected 2-methylindoles are both effective in producing the vinylogous alkylation products, although increasing the size of the protecting group enhanced the asymmetric induction slightly (compare 13, 6, 14–16). This transformation was also successful with 2-methylindoles bearing different functionalities on the 5-position. However, 3-substituted indoles did not results in an efficient transformation. Good yields and excellent enantioselectivities were achieved with indoles containing bulky groups at the 2-position, such as TMS and pinacol boronate ester (23 and 24). The generation of 23 and 24 may offer the opportunity for further functionalization. The absolute configuration of 17 was unambiguously assigned by X-ray crystallography¹¹ and the other products were assigned by analogy.

Figure 3.

Substrate scope of asymmetric vinylogous reactivity

^areactions were conducted at −20 °C

This reaction can be extended to pyrrole derivatives as shown in Figure 4. Due to the decreased reactivity of pyrroles, the reaction was conducted at −20 °C instead of −45 °C.¹² Even so, the alkylation products 25–27 were obtained in good yield with high levels of enantioselectivity (87–91% ee). The absolute configuration of these products was assigned by analogy to the absolute configuration of 17.

Figure 4.

Scope of asymmetric vinylogous reactivity with pyrroles

In conclusion, the Rh₂(S-biTISP)₂-catalyzed asymmetric vinylogous alkylation between N-heterocycles and methyl E-2-diazo-3pentenoate is an effective method for C-3 functionalization of indoles and pyrroles. This work illustrates the subtle controlling elements of dirhodium catalysts on the chemistry of donor/acceptor carbenoids.