Rhodium Carbenoid Approach for Introduction of 4-Substituted (Z)-Pent-2-enoates into Sterically Encumbered Pyrroles and Indoles

Abstract

An unusual rhodium-carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles is described. These studies show that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids to react at the vinylogous position of the carbenoid rather than at the carbenoid center.

Highly functionalized indoles and pyrroles are constituents of a variety of natural products and pharmaceutical targets.¹ The development of novel strategies to these targets is still an active field of organic synthesis.² In particular, the selective introduction of functionalized alkyl groups into the heterocycles has drawn considerable attention.³ In this paper we describe a rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles.

For some time, we have explored the reactions of rhodium-stabilized donor/acceptor carbenoids with pyrroles and indoles.⁴ The rhodium-catalyzed reaction of vinyldiazoacetates with N-Boc-pyrroles offers a direct entry into tropanes by means of a tandem cyclopropanation/Cope rearrangement.⁵ When N-methylpyrroles are used as substrates, alkylation occurs rather than cyclopropanation.^5a The reaction of aryldiazoacetates with N-Boc-pyrrole results in double cyclopropanation of the pyrrole rings.⁶ Similarly, reaction of N-Boc-indole with aryldiazoacetates causes double cyclopropanation of the benzene ring to occur.⁶ However, if the indole is 6-substituted, C–H functionalization of a side-chain becomes the preferred reaction.⁶ Francis has shown that vinyldiazoacetates will alkylate 3-alkylindoles and that this can be used to selectively derivatize proteins.⁷ Rainier has reported an unusual reaction between vinylcarbenoids and thioindoles, which generates indolinethiones by means of ylide formation, followed by proton transfer and a [3,3]-sigmatropic rearrangement.⁸

One of the more unusual features of the chemistry of vinylcarbenoids is the occurrence of vinylogous reactivity when the vinyl group is unsubstituted.^5a,9 The reaction with pyrroles leads to 4-pyrrolylbutenoates,^5a and this reactivity can be enhanced by using either polar solvents,^5a bulky esters on the carbenoid⁹ or diruthenium catalysis.¹⁰ In this paper we describe a new approach to enhance vinylogous reactivity, which led to a practical method to functionalize indoles and pyrroles.

The impetus for this investigation was an unexpected result observed during studies on the reaction of N-methylpyrroles with vinyldiazoacetates (Scheme 1). The Rh₂(esp)₂-catalyzed¹¹ decomposition of (E)-vinyldiazoacetate 2 with N-methylpyrrole 1 (6 equiv) afforded the expected aromatic substitution product 3. This is a well-precedented type of product from the reaction of carbenoids with electron rich heterocycles.¹² When the reaction was repeated with the more bulky substrate 1,2,5-trimethylpyrrole 4, an unexpected product 5 was formed (28% yield) in addition to the expected aromatic substitution product 6. Two features of this reaction were intriguing. Firstly, 5 was formed exclusively as the Z isomer. Secondly, 5 is the type of product that would be generated from attack at the vinylogous position of the vinylcarbenoid.⁹ This type of reactivity profile had not been seen previously in rhodium-catalyzed reactions of vinylcarbenoids with a substituent at the vinyl terminus.¹³ Therefore, we decided to explore further this unusual reactivity.

Scheme 1.

Rhodium-stablized vinylcarbenoids could in principle exist in two possible conformations, s-cis (conformer A) and s-trans (conformer B) (Figure 1). The catalyst face is considered to be a steric wall, but neither conformer A nor conformer B would be expected to have significant interference with this wall. Very little studies have been carried out to determine which of the two conformers is likely to be the most reactive form in rhodium vinylcarbenoid chemistry.¹⁴ The formation of 5 as the (Z)-isomer is indicative that the vinylogous reactivity occurs through conformer B. This leads us to propose that the highly substituted pyrrole 4 is sterically too crowded for an effective reaction at the carbenoid center and leads to competing vinylogous reactivity, occurring through conformer B. We then became intrigued with the concept that the vinylogous reactivity could be enhanced if the (Z)-vinylcarbenoid was used as substrate. In this case, the s-cis conformation of the carbenoid (conformer C) would be expected to interfere with the catalyst wall, and so, the (Z)-vinylcarbenoid would be expected to preferentially exist in the s-trans conformation (conformer D).

Figure 1.

Conformations of vinylcarbenoids

In order to probe the role of the vinylcarbenoid geometry, the reactions of N-methylpyrrole (1) and 1,2,5-trimethylpyrrole (4) were repeated using the (Z)-vinyldiazoacetate 7 as the carbenoid source (Scheme 2). The reaction with N-methylpyrrole still preferentially formed the normal alkylation product 8, but a trace of the vinylogous substitution product 9 was also formed. In contrast, the reaction with 1,2,5-trimethylpyrrole 4 lead to the formation of the vinylogous substitution product 5 in 78% yield, exclusively as the Z isomer without any detectable amount of the product derived from reaction at the carbenoid center. The reaction could also be conducted with some of the more standard catalysts such as rhodium acetate and rhodium trifluoroacetate, but the highest yield of 5 was obtained using Du Bois’ Rh₂(esp)₂.¹¹

Scheme 2.

Normally, the reaction of vinylcarbenoids at the carbenoid site is very sensitive to steric crowding,¹⁵ and this may explain why vinylogous reactivity is more favored in a crowded substrate. Consequently, we explored if a double alkylation process was feasible. The Rh₂(esp)₂-catalyzed reaction using 5 equiv of the (Z)-vinyldiazoacetate 7 with 1,2,5-trimethylpyrrole (4) generated the bis-alkylated product 10 in 86% yield (Scheme 3). 10 was formed as a mixture of diastereomers, as would be expected for this type of reaction conducted with an achiral catalyst,.

Scheme 3.

The vinylogous reactions of diazoacetate 7 is applicable to other sterically crowded pyrroles, forming the alkylated pyrroles 11–13 in 59–87% yield (Figure 2). Not only N-protected indoles undergo the alkylation with vinyldiazoacetate 7, but also, an N-unprotected pyrrole was able to furnish the vinylogous product 11. The regiochemistry in the formation of 12 and 13 reveals that N-TIPS is acting as a bulky protecting group,¹⁶ blocking the reactivity at the 2-position and forcing the reaction to occur at the 3-position to form 13.

Figure 2.

Vinylogous reaction of 7 with pyrroles

When this reaction was extended to N-methylindole 14 the standard substitution product 15 was isolated in 78% yield (Scheme 4). This result is consistent with the data obtained from the pyrrole derivatives that a sterically crowded aromatic systems is essential to achieve highly selective vinylogous reactivity.

Scheme 4.

The vinylogous reaction can be applied to indoles as long as they are sufficiently crowded. Representative examples are shown in Figure 3. The reactions could be conducted at temperatures as low as −45 °C, presumably because of the greater nucleophilicity of indoles over pyrroles.¹⁷ Both unprotected and protected (methyl or benzyl) 2-methylindoles afforded the vinylogous products in good yields. Typically, substitution at the 2-position of the indole is necessary for the vinylogous reactivity to occur. However, a similar effect can be achieved when a bulky substituent is introduced at the 4-position of the indole, as illustrated in the formation of 18.

Figure 3.

Vinylogous reaction of 7 with indoles

In order to further extend this transformation to less crowded indoles, the use of a (Z)-vinyldiazoacetate approach combined with a complementary strategy for enhancing vinylogous reactivity was examined. Increasing the size of the ester group enhances vinylogous reactivity⁸ and so, tert-butyl (Z)-vinyldiazoacetate 22 was prepared and tested (Scheme 5). The Rh₂(esp)₂-catalyzed reaction of 22 with 6.0 equiv of N-methylpyrrole 1 caused a major change in the reaction outcome. No evidence of the regular alkylation product was observed and the vinylogous product 23 could be isolated in 50% yield.

Scheme 5.

In summary, these studies demonstrate that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids for reaction at the vinylogous position of the carbenoid rather than at the carbenoid center. This type of reactivity leads to an effective method for the functionalization of pyrroles and indoles.