Synthesis of furans and pyrroles via migratory and double migratory cycloisomerization reactions of homopropargylic aldehydes and imines

Abstract

A novel gold-catalyzed divergent sysnthesis of furans and pyrroles employing readily available homopropargylic aldehydes and imines have been developed. The regiochemical outcome of this reaction is dependent on the substituent on the terminal alkyne of substrate. Thus, substrates possessing alkyl and aryl substituent at the alkyne moiety produce 2,3,5-substituted furans and pyrroles via a migratory cycloisomerizaton reaction. Whereas, their silicon analogues are capable to undergo a double migratory process leading to 2,3,4-substituted heterocycles.

Furans and pyrroles are highly important motifs exist in a broad range of biologically active natural products¹ and drugs.² They also have broad applications as synthetic intermediates³ and are widely used in material science.⁴ Accordingly, a vast number of efficient methodologies toward these important scaffolds have been developed.^1a,5 Among these methods, the transition metal-catalyzed migratory cycloisomerization reaction is one of the powerful approaches, which offers mild and selective assembly of furans and pyrroles with a diverse substitution pattern.⁶ Readily available homopropargylic ketones and imines have been employed in migratory cascade reactions ^5a,6a giving access to a variety of heterocycles (Scheme 1). For instance, Kirsch reported⁷ a platinum-catalyzed cascade reaction of 1 toward 3(2H)-furanones and 3-pyrrolones 2 proceeding via a pinacol-type 1,2-alkyl migration⁸ (eq. 1). Moreover, Tang and Shi reported synthesis of densely-substituted pyrroles 4 from the rhodium-catalyzed reaction of propargylic imines 3, where one of the substituents of the heterocyclic core is formed via a 1,2-alkyl migration from the adjacent carbon (eq. 2).⁹ Recently, Zhang disclosed a divergent reactivity of ketones 5 in the presence of gold catalysts, where a selective 1,2-alkyl migration to the neighboring carbon affords dihydrofurans 6 or furans 7 (eq. 3).¹⁰ Herein, we report a mild and regiodivergent reaction of homopropargylic aldehydes and imines 8 in the presence of gold catalysts towards heterocycles 9 and 10. Thus, a gold-catalyzed migratory cycloisomerization of 8 (R¹= Alk/Ar) produces 2,3,5-substituted heterocycles 9. Whereas, employment of silylated 8 (R¹=SiR₃) affords 2,3,4-substituted furans and pyrroles 10 proceeding via a double migratory cycloisomerization reaction (eq. 4).

Scheme 1.

Cycloisomerization of homopropargylic systems involving a 1,2-migration

In continuation of our interest in development of cycloisomerization reactions toward synthesis of densely substituted heterocycles,¹¹ we aimed at employing aldehyde 8 possessing a cyclopentyl group (Scheme 1, X=O, R¹=Ph, R²=R³= (CH₂)₄) in the transition metal-catalyzed migratory cascade reaction. It was hypothesized that cyclization of the latter in the presence of a metal catalyst would be accompanied with a five-to-six-membered ring expansion¹² and therefore producing the bicyclic fused furan 9 (Scheme 1, X=O, R¹=Ph, R²=R³= (CH₂)₄). Our optimization study indicated that the use of the cationic gold catalyst,¹³ such as triphenylphosphine gold with hexafluoroantimonate counter ion, was the best choice. Thus, we explored the scope of this migratory cycloisomerization. Hence, aldehydes 8a-c possessing phenyl, electron poor aryl, as well as alkyl substituents at the terminal alkyne position underwent a five-to-six-membered ring expansion during the cycloisomerization process to afford furans 9a-c in good to excellent yields (entry 1-3). Importantly, this reaction is not limited to cyclic substrates only. Thus, by employing 2,2-diphenyl homopropargyl aldehyde 8d, a phenyl group migration occurs smoothly to afford the triarylated furan 9d in an excellent yield (entry 4). Expectedly,¹² a phenyl migration took place over the methyl- and benzyl group migration in cycloisomerization of 8e and 8f to furnish 9e and 9f in moderate yields (entries 5 and 6). Moreover, tetrasubstituted pyrrols can also be synthesized using 2,2-substituted homopropargylic imines under these reaction conditions. Therefore, the five-to-six-membered ring expansion of imines 8g and 8h proceeded smoothly during cyclization to provide pyrroles 9g and 9h in good yields (entry 7 and 8). Expectedly, a phenyl group migration occurred preferably over the methyl- and benzyl group migrations to produce pyrroles 9i and 9j selectively in good yields (entry 9 and 10).

Next, we hypothesized that employing homopropargylic aldehyde 8 possessing a silicon terminus (Scheme 1, X=O, R¹=SiMe₃, R²=R³= (CH₂)₄) would enable a 1,2-migration of silicon group during the cyclization process.¹⁴ This 1,2-alkyl-/Si-double migratory cascade¹⁵ would allow synthesis of 2,3,4-trisubstituted fused furan 10. Indeed, it was found that cationic (C₆F₅)₃PAuSbF₆ catalyst¹⁶ efficiently catalyzes this reaction (Table 2).¹⁷ Thus, homopropargylic aldehyde 8k-m underwent a facile ring expansion/trimethyl-, triethyl-, and t-butyldimethylsilyl migration-cycloisomerization cascade to efficiently produce furans 10k-m, respectively. Aldehyde 8n possessing a strained four-membered ring produced bicyclic furan 10n in a reasonable yield (entry 4). Notably, employment of t-Bu- and Ph-protected imines 8o and 8p in this double migratory process afforded silylated fused pyrroles 10o and 10p.

Table 1.

Scope of double migratory reaction

We propose the following plausible mechanism for these cascade reactions (Scheme 2). First, the π-philic gold catalyst activates substrate 8, which upon the following nucleophilic attack of carbonyl at the activated alkyne moiety of A in a 5-endo-dig fashion produces cyclic oxonium intermediate B. A 1,2-R² migration in the latter takes place to generate an allylic cation C, which upon proton loss furnishes the key furyl gold intermediate D. In the case of G=Alk or Ar, a protiodematallation (α-protonation) of D takes place to produce 2,3,5-trisubstituted furan 9. Whereas, the β-protonation of the furyl gold species D occurs¹⁴ when G=SiR₃ to furnish E, in which the positive charge at the carbene carbon is stabilized by the silicon atom.¹⁸ A 1,2-silicon- over hydrogen 1,2-migration in the latter takes place¹⁴ to form F, which upon aromatization affords 2,3,4-trisusbstituted furan 10.

Scheme 2.

Proposed Mechanism for the migratory and double migratory cascade reactions

In summary, two complementary gold-catalyzed cycloisomerization reaction protocols of homopropargylic aldehydes and imines toward differently substituted furans and pyrrols have been developed. The regiochemical outcome depends on the substituent at the terminal alkyne moiety of the substrates. Thus, employment of homopropargylic aldehydes and imines possessing alkyl and aryl substituent at the alkyne moiety produces 2,3,5-substituted heterocycles via a migratory cycloisomerizaton reaction. Whereas, substrates possessing a silicon atom at the terminal position of alkyne undergo a double migratory cascade to afford 2,3,4-substituted furans and pyrrols.¹⁹

Table 1.

Scope of the migratory cycloisomerization reaction