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Synthesis 2010(14): 2367-2378  
DOI: 10.1055/s-0029-1218766
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Selective Base-Promoted Synthesis of Dihydroisobenzofurans by Domino Addition/Annulation Reactions of ortho-Alkynylbenzaldehydes

Monica Dell’Acqua, Diego Facoetti, Giorgio Abbiati*, Elisabetta Rossi
Dipartimento di Scienze Molecolari Applicate ai Biosistemi (DISMAB) - Sezione di Chimica Organica ‘A. Marchesini’, Università degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
Fax: +39(02)50314476; e-Mail: giorgio.abbiati@unimi.it;
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Publication History

Received 11 March 2010
Publication Date:
05 May 2010 (online)

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Abstract

Synthesis of the dihydroisobenzofuran nucleus was achieved by the base-promoted tandem nucleophilic addition/annulation reaction of ortho-alkynylbenzaldehydes in the presence of methanol. The reactions of aryl-, trimethylsilyl- and diethoxymethyl-substituted alkynylbenzaldehydes occurred with complete regio­selectivity in good to excellent yields under microwave irradiation. The reactions of alkyl-substituted alkynylbenzaldehydes took place with good yields and high regioselectivity only when performed at room temperature and in the presence of a catalytic amount of a gold(III) salt. Plausible reaction mechanisms involved are discussed. The effect of the substituent at the alkynyl terminus on the cyclisation mode was tentatively rationalised.

Key words

alkynes - heterocycles - domino reaction - microwave-promoted synthesis - gold

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The Z-stereochemistry was determined by comparison with literature data, and confirmed by NOE experiments on compounds 2d, 2i and 2j; the assignment was extended by analogy to the entire series.

21

These compounds are acid-sensitive. Their stability also depends on the nature of the substituent on the exocyclic double bond. In general, they can be optimally stored for several weeks in a sealed tube, under a nitrogen atmosphere at -20 ˚C.

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The same behaviour was observed by Belmont and co-workers for the related compound 2-[(trimethylsilyl)ethyn-yl]quinoline-3-carbaldehyde (see ref. 10a). In that paper, the authors also demonstrated that, under basic conditions, the desilylation occurred before the cyclisation step.

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Other metal catalysts such as Au(I)/Ag(I), Ag(I) and Cu(I) either failed or gave very poor results.

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Belmont and co-workers have recently observed in a related silver-catalysed process that the presence of electron-donating or electron-withdrawing groups on the phenyl substituent made no difference to the selectivity (see ref. 12e).