Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed isomerisation of alkynediols and in situ cyclisation

doi:10.1016/j.tet.2009.06.108

Tetrahedron

Volume 65, Issue 44, 31 October 2009, Pages 8981-8986

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Abstract

Alkyne-1,4-diols are readily available substrates which are isomerised to 1,4-diketones using Ru(PPh₃)₃(CO)H₂/xantphos as a catalyst. In situ cyclisation into furans, pyrroles and pyridazines has been achieved under suitable conditions.

Graphical abstract

Introduction

In 1884 Paal and Knorr simultaneously reported that treatment of 1,4-diketones with strong mineral acids or with concentrated ammonia or ammonium acetate produced 2,5-disubstituted furans and pyrroles respectively.1, 2 Similarly, the use of a source of nucleophilic sulfur will result in thiophene derivatives,³ whilst pyridazines can be formed in the presence of hydrazine (Scheme 1).⁴

For furan synthesis,5, 5(a), 5(b), 5(c) various acid catalysts may be used, including strong mineral acids such as HCl as well as organic acids such as acetic acid, TFA and p-TsOH.6, 7 Lewis acids, including zinc halides and BF₃·Et₂O have been used for furan synthesis from 1,4-dicarbonyls.⁸ The availability of 1,4-dicarbonyl compounds can be a limiting factor, and a number of transition metal catalysed approaches to furans have been developed using alternative starting materials.⁹

Of particular relevance to our work are the reports of Lu et al. who used a palladium catalyst to isomerise 2-butyne-1,4-diol derivatives to 1,4-dicarbonyl surrogates in the presence of acidic resin to afford the corresponding 2,5-disubstituted furans.10, 10(a), 10(b) However, the high catalyst loading and temperature required as well as the requirement for a strong acid to be present to facilitate the cyclisation reaction were limitations. Similarly, 2-butyne-1,4-diones have been used as precursors to furans. Reduction of the alkyne functionality using palladium on carbon with formic acid as the reductant was combined with sulfuric acid co-catalyst for the cyclisation under microwave conditions.¹¹

A variety of other alkyne substrates have also been successfully used for furan synthesis, catalysed by palladium,12, 13 silver,14, 14(a), 14(b) gold,¹⁵ ruthenium¹⁶ and copper complexes.¹⁷ Mortreux has reported a one-pot route to furans and pyrroles using a rhodium catalysed 1,4-carbonylative addition of arylboronic acids to vinylketones to synthesise 1,4-dicarbonyls. The dicarbonyls are then cyclised in situ to afford the corresponding furan and pyrrole derivatives.¹⁸ In addition, the isomerisation of propargylic alcohols into enals and enones with ruthenium catalysts is a known transformation.19, 20

We have recently used a variety of ruthenium-based catalysts for oxidative reactions of alcohols²¹ and for redox-neutral borrowing hydrogen reactions.22, 22(a), 22(b), 22(c), 22(d), 22(e), 22(f), 22(g), 22(h) In particular, the use of xantphos²³ with Ru(PPh₃)₃(CO)H₂ was found to be effective for catalysing the formation of C–C bonds from alcohols,24, 24(a), 24(b) the conversion of alcohols into methyl esters,25, 25(a), 25(b) and the conversion of alcohols into alkenes.²⁶ We therefore chose to examine this catalyst combination for reactions involving the isomerisation of alkyne-1,4-diols and report our results herein. Preliminary results indicated that Ru(PPh₃)₃(CO)H₂/xantphos was a more effective catalyst than other Ru and Ir complexes that we had screened.²⁷

Section snippets

Synthesis of 2,5-disubstituted furans

We chose the reaction of alkynediol 1 as a model substrate, and in the presence of 5 mol % Ru(PPh₃)₃(CO)H₂/xantphos we obtained a mixture of dicarbonyl compound 2a (56%) and the desired furan 3a (12%) after heating at 80 °C in toluene for 24 h. In the presence of 5 mol % acetic acid, the selectivity towards furan formation was more favourable, providing diketone 2a (18%) and furan 3a (63%). A comparison of acetic acid with propanoic acid and benzoic acid revealed that all three acids provided an

Conclusion

In summary, alkynediols undergo a ruthenium-catalysed isomerisation reaction which leads to 1,4-diketones. In situ cyclisation in the presence of acid generates furans, whilst in the presence of amines or hydrazine, the corresponding pyrroles or pyridazines are formed.

General

General experimental details, along with the synthesis of alkynediols 5a–5v and furans and pyrroles which were analysed by GC–MS are provided in Supplementary data.

2-Methyl-5-phenylfuran (3a)

To an oven dried, argon purged Young's tap carousel tube was added 1-phenylpent-2-yne-1,4-diol 5a (352 mg, 2 mmol), Ru(PPh₃)₃(CO)H₂ (18.3 mg, 0.01 mmol), xantphos (11.5 mg, 0.01 mmol) and acid co-catalyst (acetic, propanoic or benzoic 5.7 μL, 7.4 μL, 12.2 mg respectively, 0.05 mmol). Degassed anhydrous toluene (1 mL) was added and the reaction

Acknowledgements

We thank the EPSRC and the University of Bath for funding.

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Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed isomerisation of alkynediols and in situ cyclisation

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis of 2,5-disubstituted furans

Conclusion

General

2-Methyl-5-phenylfuran (3a)

Acknowledgements

Tetrahedron

Angew. Chem., Int. Ed.

Org. Biomol. Chem.

J. Org. Chem.

Tetrahedron

Chem. Commun.

Tetrahedron Lett.

Chem. Commun.

Tetrahedron Lett.

J. Am. Chem. Soc.

Adv. Synth. Catal.

Dalton Trans.

J. Am. Chem. Soc.

Tetrahedron Lett.

J. Am. Chem. Soc.

Chem. Ber.

Chem. Ber.

Chem. Ber.

J. Org. Chem.

Org. Lett.

Strategic Applications of Named Reactions in Organic Synthesis

J. Org. Chem.

Arkivoc

J. Org. Chem.

J. Chem. Soc., Chem. Commun.

J. Org. Chem.

J. Org. Chem.