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

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

• For reviews on the use of arynes in organic synthesis, see:
• 1a Peña D. Pérez D. Guitián E. Angew. Chem. Int. Ed.  2006,  45:  3579 
• 1b Kessar SV. Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.483-515  
• 2a For the application of arynes in total synthesis, see: Tambar UK. Ebner DC. Stoltz BM. J. Am. Chem. Soc.  2006,  128:  11752 
• 2b Sato Y. Tamura T. Mori M. Angew. Chem. Int. Ed.  2004,  43:  2436 
• 3 Himeshima Y. Sonoda T. Kobayashi H. Chem. Lett.  1983,  1211 
• 4 Liu ZJ. Larock RC. J. Org. Chem.  2006,  71:  3198 ; and references therein
• 5 Tambar UK. Stoltz BM. J. Am. Chem. Soc.  2005,  127:  5340 
• 6 Yoshida H. Watanabe M. Ohshita J. Kunai A. Chem. Commun.  2005,  3292 
• 7 Yoshida H. Watanabe M. Ohshita J. Kunai A. Tetrahedron Lett.  2005,  46:  6729 
• 8 Ramtohul YK. Chartrand A. Org. Lett.  2007,  9:  1029 
• 9 During the preparation of this manuscript, Stoltz reported a similar transformation whereby only the isoquinoline-3-carboxylates were obtained using Bu₄NPh₃SiF₂ (TBAT) as the fluoride source in THF, see: Gilmore CD. Allan KM. Stoltz BM. J. Am. Chem. Soc.  2008,  130:  1558 
• 10 Jeganmohan M. Cheng C.-H. Chem. Commun.  2006,  2454 
• 11 Yoshida H. Watanabe M. Ohshita J. Kunai A. Chem. Commun.  2005,  3292 
• 12 Avenoza A. Cativiela C. Busto JH. Fernández-Recio MA. Peregrina JM. Rodríguez F. Tetrahedron  2001,  57:  548 
• 13a Yoshida H. Shirakawa E. Honda Y. Hiyama T. Angew. Chem. Int. Ed.  2002,  41:  3247 
• 13b Yoshida H. Fukushima H. Ohshita J. Kunai A. J. Am. Chem. Soc.  2006,  128:  11040 
• 14a Zhu Y.-F. Wilcoxen K. Gross T. Connors P. Strack N. Gross R. Huang CQ. McCarthy JR. Xie Q. Ling N. Chen C. Bioorg. Med. Chem. Lett.  2003,  13:  1927 
• 14b Chen C. Zhu Y.-F. Liu X.-J. Lu Z.-X. Xie Q. Ling N. J. Med. Chem.  2001,  44:  4001 

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.