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Synlett 2008(8): 1159-1164  
DOI: 10.1055/s-2008-1072723
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Isoquinoline-3-Carboxylates and Benzocyclobutanes via Reaction of 2-Amidoacrylate Esters with Arynes

Tom Blackburn, Yeeman K. Ramtohul*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Inc., P.O. Box 1005, 16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada
Fax: +1(514)4284900; e-Mail: yeeman_ramtohul@merck.com;
Further Information

Publication History

Received 1 January 2008
Publication Date:
16 April 2008 (online)

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Abstract

A mild and general method for the synthesis of a variety of 2-substituted isoquinoline 3-carboxylates and benzocyclobutanes from the reaction of 2-amidoacrylate esters with arynes has been developed.

Key words

arynes - isoquinoline heterocycles - benzocyclobutanes - annulations - 2-amidoacrylate esters

    References and Notes

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15

Representative Experimental Procedure
To a mixture of methyl 2-acetamidoacrylate (11j, 57.3 mg, 0.4 mmol, 1 equiv) and CsF (152 mg, 1 mmol, 2.5 equiv) in dry MeCN (2 mL, 0.2 M) was added o-silyl aryltriflate (1) (121 µL, 0.5 mmol, 1.25 equiv) in an oven-dried 4 mL glass vial. The vial was capped under nitrogen and the mixture was stirred at r.t. overnight (ca. 18 h). The reaction mixture was quenched with HCl (1 N) or TFA (154 µL, 2 mmol, 5 equiv) and the solvent was evaporated. The residue was diluted with NaHCO3 (2 mL, 5%) and extracted with EtOAc (3 × 1 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by CombiFlash chromatography (ISCO) on silica gel column using a gradient elution of 30-80% EtOAc-hexanes to afford methyl 1-methylisoquinoline-3-carboxylate (12j) and methyl 7-(acetylamino)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (13j).
Methyl 1-methylisoquinoline-3-carboxylate (12j): solid (53 mg, 66%). 1H NMR (500 MHz, acetone-d 6): δ = 8.38 (s, 1 H), 8.23 (d, J = 8.23 Hz, 1 H), 8.07 (d, J = 8.03 Hz, 1 H), 7.84-7.74 (m, 2 H), 3.93 (s, 3 H), 2.94 (s, 3 H). 13C NMR (126 MHz, acetone-d 6): δ = 22.4, 52.4, 123.0, 126.5, 129.4, 129.5, 130.2, 131.5, 136.3, 141.6, 159.6, 166.7. HRMS (ESI, MH+): m/z calcd for C12H12NO2: 202.0862; found: 202.0863.
Methyl 7-(acetylamino)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (13j): solid (19 mg, 22%). 1H NMR (500 MHz, acetone-d 6): δ = 8.38 (s, 1 H), 7.33-7.28 (m, 1 H), 7.25-7.14 (m, 3 H), 3.91 (d, J = 14.18 Hz, 1 H), 3.62 (s, 3 H), 3.24 (d, J = 14.18 Hz, 1 H), 1.92 (s, 3 H). 13C NMR (126 MHz, acetone-d 6): δ = 22.2, 43.2, 52.5, 64.1, 123.3, 124.2, 128.2, 130.4, 144.1, 144.9, 170.9, 171.9. 1H-1H COSY (500 MHz, acetone-d 6): correlation of the cyclobutane methylene protons at δ = 3.62 and 3.24. 1H-13C HMQC (500 MHz, acetone-d 6): correlation of the cyclobutane methylene protons at δ = 3.62 and 3.24 with the methylene carbon at
δ = 43.2. HRMS (ESI, MH+): m/z calcd for C12H14NO3: 220.0968; found: 220.0971.