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Synlett 2008(15): 2334-2338  
DOI: 10.1055/s-2008-1078022
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Highly Efficient Catalyst-Free Cycloisomerization Approach to Indolizinones

Ikyon Kim*, Jihyun Choi, Sunkyung Lee, Ge Hyeong Lee
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
Fax: +82(42)8607160; e-Mail: ikyon@krict.re.kr;
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Publication History

Received 13 May 2008
Publication Date:
31 July 2008 (online)

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Abstract

A highly efficient catalyst-free synthetic route to indoli­zinones was established from readily available tertiary propargylic alcohols via a facile thermally induced cycloisomerization. In addition, this transformation was found to be further expedited by microwave irradiation.

Key words

indolizinones - catalyst-free - cyclization - 1,2-migration - microwave

    References and Notes

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  • Indolizinone skeleton was known to be accessed by the similar type of cyclization-1,2-shift sequence using either PtCl2 or CuI:
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5

No examples on the generation of zwitterions such as 8 from intramolecular cyclization have been disclosed in the literature.

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Spectral data of 10a: ¹H NMR (300 MHz, CDCl3): δ = 7.18-7.37 (m, 5 H), 6.84 (d, J = 7.2 Hz, 1 H), 6.39 (d, J = 9.0 Hz, 1 H), 6.03 (dd, J = 5.3, 9.2 Hz, 1 H), 5.39-5.43 (m, 1 H), 4.98 (s, 1 H), 1.46 (s, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 201.0, 184.5, 140.1, 128.6, 127.9, 125.5, 124.8, 124.6, 123.3, 110.0, 97.1, 72.2, 34.4, 29.0. HRMS (EI): m/z [M+] calcd for C18H19NO: 265.1467; found: 265.1469.

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Heating a solution of 1a in ethanol in the presence of cesium carbonate was also carried out but did not shorten the reaction time.

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Alcoholic solvents seemed crucial for effective conversion. Propanol also gave similar efficiency as ethanol. Reaction under refluxing toluene gave very low conversion whereas no reaction took place in DMF or acetonitrile.

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In most cases, the desired indolizinones were the only isolable product so that the evaporation of the reaction solvent was enough for the characterization of compounds.

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10b: ¹H NMR (300 MHz, CDCl3): δ = 7.52 (s, 5 H), 6.53 (d, J = 7.2 Hz, 1 H), 5.89-5.97 (m, 2 H), 5.36-5.40 (m, 1 H), 5.18 (s, 1 H), 1.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.2, 172.7, 131.2, 129.8, 129.2, 128.3, 124.0, 123.3, 122.1, 109.0, 99.0, 68.8, 25.2. HRMS (EI): m/z [M+] calcd for C15H13NO: 223.0997; found: 223.0995. 10c: ¹H NMR (300 MHz, CDCl3): δ = 7.68-7.70 (m, 1 H), 7.47-7.50 (m, 1 H), 7.27-7.30 (m, 1 H), 6.67 (d, J = 6.9 Hz, 1 H), 5.90-5.98 (m, 2 H), 5.46 (m, 1 H), 5.20 (s, 1 H), 1.42 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 202.9, 166.6, 130.6, 128.0, 127.4, 127.3, 124.4, 123.3, 122.0, 109.4, 98.3, 68.7, 24.9. HRMS (EI): m/z [M+] calcd for C13H11NOS: 229.0561; found: 229.0566. 10d: ¹H NMR (300 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.83 (t, J = 9.3 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.22-7.27 (m, 1 H), 7.19 (s, 1 H), 6.64 (d, J = 7.5 Hz, 1 H), 5.90-5.99 (m, 2 H), 5.39 (t, J = 5.9 Hz, 1 H), 5.27 (s, 1 H), 3.96 (s, 3 H), 1.49 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.1, 173.0, 159.4, 136.0, 130.3, 128.4, 128.3, 127.8, 125.4, 124.8, 124.1, 123.6, 122.0, 120.4, 108.9, 106.0, 99.0, 68.9, 55.7, 25.2. HRMS (EI): m/z [M+] calcd for C20H17NO2: 303.1259; found: 303.1255. 10e: ¹H NMR (300 MHz, CDCl3): δ = 7.49 (s, 5 H), 6.50 (d, J = 7.2 Hz, 1 H), 5.84-5.93 (m, 2 H), 5.27-5.32 (m, 1 H), 5.18 (s, 1 H), 1.85 (q, J = 7.5 Hz, 2 H), 0.89 (t, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 202.7, 174.5, 131.2, 129.8, 129.3, 128.1, 124.1, 123.8, 122.3, 109.2, 100.8, 72.2, 32.8, 7.1. HRMS (EI): m/z [M+] calcd for C16H15NO: 237.1154; found: 237.1155. 10f: ¹H NMR (300 MHz, CDCl3): δ = 6.54 (d, J = 7.2 Hz, 1 H), 6.14-6.22 (m, 1 H), 5.87-5.88 (m, 2 H), 5.32-5.42 (m, 1 H), 4.96 (s, 1 H), 2.00-2.40 (m, 4 H), 1.68-1.78 (m, 4 H), 1.34 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.4, 174.4, 133.5, 128.6, 124.0, 123.7, 121.9, 108.3, 96.8, 68.2, 27.6, 25.5, 25.0, 22.3, 21.7. HRMS (EI): m/z [M+] calcd for C15H17NO: 227.1310; found: 227.1315. 10g: ¹H NMR (300 MHz, CDCl3): δ = 6.68 (d, J = 7.2 Hz, 1 H), 5.86-5.96 (m, 2 H), 5.41-5.46 (m, 1 H), 4.98 (s, 1 H), 1.36 (s, 9 H), 1.29 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.4, 182.2, 125.4, 124.3, 122.0, 108.9, 96.5, 68.7, 34.0, 28.8, 24.2. HRMS (EI): m/z [M+] calcd for C13H17NO: 203.1310; found: 203.1312. 10h: ¹H NMR (300 MHz, CDCl3): δ = 6.44 (d, J = 6.9 Hz, 1 H), 5.90 (d, J = 3.3 Hz, 2 H), 5.43-5.48 (m, 1 H), 4.93 (s, 1 H), 2.48 (t, J = 7.7 Hz, 2 H), 1.64 (quint, J = 7.5 Hz, 2 H), 1.38-1.50 (m, 2 H), 1.30 (s, 3 H), 0.97 (t, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.3, 175.4, 124.6, 122.0, 121.8, 109.1, 97.0, 68.0, 28.9, 27.1, 24.5, 22.7, 13.9. HRMS (EI): m/z [M+] calcd for C13H17NO: 203.1310; found: 203.1313. 10i: ¹H NMR (300 MHz, CDCl3): δ = 6.48 (dd, J = 0.6, 7.2 Hz, 1 H), 5.89 (d, J = 3.3 Hz, 2 H), 5.42-5.47 (m, 1 H), 4.94 (s, 1 H), 2.86-2.96 (m, 1 H), 1.95-2.16 (m, 2 H), 1.63-1.79 (m, 6 H), 1.30 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 203.5, 179.7, 124.6, 122.2, 122.1, 109.0, 94.6, 68.1, 37.3, 31.8, 31.5, 25.8, 25.6, 24.5. HRMS (EI): m/z [M+] calcd for C14H17NO: 215.1310; found: 215.1309. 10j: ¹H NMR (300 MHz, CDCl3): δ = 8.55 (d, J = 4.8 Hz, 1 H), 7.60 (dt, J = 1.8, 7.8 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.13 (ddd, J = 1.2, 4.8, 7.5 Hz, 1 H), 6.85 (d, J = 7.2 Hz, 1 H), 6.49 (d, J = 6.3 Hz, 1 H), 6.09 (dd, J = 5.6, 9.2 Hz, 1 H), 5.39 (dd,
J = 6.3, 7.2 Hz, 1 H), 5.00 (s, 1 H), 1.47 (s, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 199.4, 185.1, 158.6, 149.7, 136.7, 125.8, 124.2, 123.5, 122.7, 120.0, 109.3, 97.2, 73.7, 34.3, 29.0. HRMS (EI): m/z [M+] calcd for C17H18N2O: 266.1419; found: 266.1423. 10k: ¹H NMR (300 MHz, CDCl3): δ = 7.37-7.40 (m, 2 H), 7.23-7.33 (m, 3 H), 6.94 (d, J = 7.2 Hz, 1 H), 6.31 (d, J = 9.0 Hz, 1 H), 6.00 (dd, J = 5.4, 9.0 Hz, 1 H), 5.42 (t, J = 6.3 Hz, 1 H), 5.05 (s, 1 H), 3.79 (t, J = 4.5 Hz, 4 H), 3.58 (d, J = 14.4 Hz, 1 H), 3.42 (d, J = 14.4 Hz, 1 H), 2.53-2.67 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 201.3, 172.5, 140.5, 128.8, 128.1, 124.5, 124.3, 123.6, 123.1, 109.8, 99.8, 72.1, 67.1, 55.1, 54.2. HRMS (EI): m/z [M+] calcd for C19H20N2O2: 308.1525; found: 308.1523. 10l: ¹H NMR (300 MHz, CDCl3): δ = 7.41-7.42 (m, 2 H), 7.22-7.39 (m, 5 H), 6.89-6.93 (m, 2 H), 6.69 (d, J = 7.2 Hz, 1 H), 6.31 (dd, J = 0.9, 9.3 Hz, 1 H), 5.96-6.01 (m, 1 H), 5.39 (t, J = 7.2 Hz, 1 H), 5.08 (s, 1 H), 4.46-4.64 (m, 4 H), 3.78 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 201.4, 172.4, 160.0, 140.2, 130.0, 129.0, 128.8, 128.1, 124.7, 124.0, 123.4, 123.2, 114.3, 110.1, 98.5, 73.1, 72.0, 63.5, 55.6. HRMS (EI): m/z [M+] calcd for C23H21NO3: 359.1521; found: 359.1523.

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The slightly lower product yields under conventional heating conditions as compared to those under microwave conditions are ascribed to the small amount of remaining starting material under the former conditions.