Gold-catalysed rearrangement of O-vinyl oximes for the synthesis of highly substituted pyrroles

Abstract

O-Vinyl oximes were synthesised from the reaction of oximes with activated alkynes and subsequently rearranged using gold catalysis to afford highly substituted pyrroles in an efficient and regiocontrolled process. Additionally, pyrroles were formed directly from oximes and activated alkynes in a multifaceted catalysis process.

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The mild and selective synthesis of pyrroles using metal catalysis has received considerable research interest in recent years due to the prevalence of nitrogen-containing heterocycles in pharmaceuticals, agro-chemicals and biologically active natural products.¹ One procedure for the convergent synthesis of pyrroles is the reaction of oximes² with alkynes under thermal superbasic conditions (DMSO/LiOH), the Trofimov reaction (Fig. 1).^3,4 Importantly, this reaction allows for the direct formation of both a C–C and C–N bond from unactivated alkynes. This powerful transformation is underutilised due to the harsh reaction conditions that result in poor yields and low levels of product chemo-/regioselectivity.⁵ However, due to the potential of the Trofimov reaction in synthesis, catalytic variants seeking to improve the yield and selectivity whilst removing the need for strongly basic conditions have been developed. For example, earlier this year Anderson et al. described an iridium-catalysed isomerisation of O-allyl oximes under reductive conditions that afforded 4-methyl-5-unsubstituted pyrroles.⁶ Recently, we reported a nucleophilic catalysis method for the regioselective synthesis of pyrroles from oximes and activated alkynes.⁷ This one-pot procedure relies on a two-stage microwave process to initially form the O-vinyl oximein situ, followed by thermal rearrangement.⁸ In an effort to lower the reaction temperature, improve the yield and increase the substrate scope of the nucleophilic catalysis/thermal rearrangement protocol, we examined a novel method using noble metal catalysis. A number of synthetically useful reactions involving oximes have employed gold catalysis,⁹ though not for their intermolecular addition to alkynes.¹⁰ This communication describes the unprecedented gold-catalysed rearrangement of vinyl oximes to pyrroles as well as a one-pot procedure for the direct formation of pyrroles from oximes and activated alkynes.

Fig. 1 Synthesis of pyrrolesvia the Trofimov reaction and viarearrangement of substituted oximes.

Our initial investigations were aimed at the synthesis of the requisite O-vinyl oximes using nucleophilic catalysis. Thus, O-vinyl oximes 4a–5e were synthesised by the reaction of oximes 1 with electron deficient alkynes 2 or 3 using the nucleophilic catalyst DABCO under our previously reported conditions (Scheme 1).^7,11 The oximes were used as diastereomeric mixtures in the subsequent transformations.

Scheme 1 Synthesis of O-vinyl oximesvia nucleophilic catalysis.

The second phase of the work was directed towards the catalytic rearrangement of O-vinyl oxime 5a to pyrrole 6a. Noble metals are known to catalyse related [3,3]-sigmatropic rearrangements,¹² including the Overman¹³ and Claisen reactions.¹⁴Toluene was found to be the best solvent for the clean formation of pyrrole 6a from O-vinyl oxime 5a. A variety of noble metal catalysts were screened under microwave irradiation conditions, and the catalytic system derived from Ph₃PAuCl and AgBF₄ was optimal (for selected examples, see Table 1). Thus, rearrangement of 5a in the microwave at 100 °C afforded the desired pyrrole 6a in 68% yield. Experiments involving prolonged heating, inclusion of PPh₃ or AgBF₄ and the use of other gold(I) catalysts indicated that the specific gold-complex is necessary for the reaction to proceed at 100 °C. To the best of our knowledge this is the first example of noble metal catalysis of both the rearrangement of O-vinyl oximes to pyrroles and of N–O bond cleavage.

Table 1 Optimisation of the noble metal-catalysed rearrangement of O-vinyl oximes

Entry	Catalyst	Time/min	Yield (%)
a Percent conversion to product based on ^1H NMR analysis. b Au(I) = (acetonitrile)[(2-biphenyl)-di-tert-butylphosphine] gold(I).
1	Ph3PAuCl, AgOTf	10	10^a
2	Ph3PAuCl, AgOTf	40	52
3	Ph3PAuCl, AgBF4	10	13^a
4	Ph3PAuCl, AgBF4	40	68
5	PtCl4	10	NR
6	AuCl3	10	NR
7	Au(I) ^b	10	NR
8	None	40	NR
9	PPh3	40	NR
10	AgBF4	40	NR

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We next developed a more practical method for the gold-catalysed rearrangement of O-vinyl oximes under thermal conditions that eliminated the need for microwave irradiation. For example, stirring O-vinyl oxime 4a in the presence of PPh₃AuCl and AgBF₄ in toluene at 100 °C for 12 h gave the desired pyrrole 7a in good yield (Scheme 2). Several features of the gold-catalysed method are noteworthy. Microwave irradiation was not required to rearrange and dehydrate the O-vinyl oxime to form the pyrrole. The reaction proceeded at 100 °C in contrast to the 170 °C required for a thermal rearrangement. This method proved particularly amenable to α-methyl-α-aromatic ketoxime substrates. Interestingly, substituents at the R¹-position and non-aromatic groups at the R-position, substrates that are incompatible with our thermal nucleophilic catalysis conditions,⁷ also gave good yields of the corresponding pyrroles 7e, 7g–h. Additionally, the pyrroles were isolated as the unsubstituted free NH compounds with little to no polymerisation observed. The O-vinyl oximes that did not rearrange to give the desired pyrroles afforded significant amounts of the oximes precursor indicating the predominance of the known retro-Michael reaction (vide infra).

Scheme 2 Gold-catalysed rearrangement of O-vinyl oximes to form pyrroles.

Finally, a gold-catalysed one-pot synthesis of pyrroles from activated alkynes and oximes was investigated. The gold should act as a multifaceted catalyst (MFC)¹⁵ and promote the two mechanistically distinct steps of the reaction; the addition of the oxime to the alkyne and the subsequent rearrangement to the pyrrole. The acetylene moiety is a strong σ-donor and weak π-acceptor¹⁶ towards the highly Lewis-acidic gold catalysts¹⁷ making attack of the oxime oxygen onto the intrinsically electrophilic gold–alkyne complex highly favorable. Thus, reaction of acetophenone oxime 1a with 2 in the presence of PPh₃AuCl and AgOTF afforded the desired pyrrole 7a in good yield (Scheme 3). Experiments involving prolonged heating of 1a and 2 and the addition of AgOTf only gave starting material. Similar to the rearrangement of O-vinyl oximes 5 to pyrroles 6, the reaction of 1a with mono-ester 3 gave a lower yield of pyrrole 6a. This is possibly due to the competing retro-Michael reaction followed by insertion of the catalyst into the alkynyl CH bond to form a gold–alkyne compound.¹⁸ The overall process may follow a pathway that is similar to the Trofimov reaction. Initial gold-catalysed addition of oxime 1a to the alkyne gives O-vinyl oxime 8, which could then undergo a 1,3-hydrogen shift to afford diene 9. A gold-catalysed cyclisation induced rearrangement¹⁵ to give 1,4-iminoaldehyde 10, followed by cyclodehydration would give the pyrrole, in a manner analogous to the Paal–Knorr pyrrole synthesis. The gold-complex catalyses both the formation of the O-vinyl oxime and its rearrangement to the pyrrole, but the precise role of the catalyst in each of these proposed steps is unclear and future efforts will be directed towards characterising intermediates to elucidate the reaction mechanism.¹⁹

Scheme 3 Gold multifaceted catalysis reaction for the synthesis of pyrroles.

In summary, we have developed a simple and effective gold-catalysed synthesis of pyrroles from O-vinyl oximes. In particular, we note the amenability of this novel method to the regioselective generation of di-, tri- and tetra-substituted pyrroles. A functional group handle at C3/C4 of the pyrrole is also incorporated, whilst the need for strongly basic conditions or high temperatures was eliminated. A mild gold-catalysed one-pot synthesis of pyrrole from activated alkynes and oximes was also developed. Importantly, the formation of pyrroles and other heterocycles should be accessible from the intermolecular addition of oximes to unactivated alkynes.²⁰ On going work is concerned with the further development of the one-pot gold-catalysed pyrrole formation reaction of both activated and unactivated alkynes as well as application of this method towards the synthesis of biologically active natural products. The results of these studies will be reported in due course.

We gratefully acknowledge the School of Chemistry at the University of Nottingham for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and full spectroscopic data for all novel compounds. See DOI: 10.1039/c0cc04372a

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