A Highly Efficient Catalyst-Free Cycloisomerization Approach to Indolizinones

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

• 1a Kim I. Lee GH. No ZS. Bull. Korean Chem. Soc.  2007,  28:  685 
• 1b Kim I. Choi J. Won HK. Lee GH. Tetrahedron Lett.  2007,  48:  6863 
• 1c Kim I. Won HK. Choi J. Lee GH. Tetrahedron  2007,  63:  12954 
• 1d Kim I. Kim SG. Kim JY. Lee GH. Tetrahedron Lett.  2007,  48:  8976 
• 1e Choi J. Lee GH. Kim I. Synlett  2008,  1243 
• For recent synthetic approaches involving 1,2-shift, see:
• 2a Kirsch SF. Binder JT. Liébert C. Menz H. Angew. Chem. Int. Ed.  2006,  45:  5878 
• 2b Crone B. Kirsch SF. Chem. Eur. J.  2008,  14:  3514 ; and references therein
• 3 Baldwin JE. J. Chem. Soc., Chem. Commun.  1976,  734 
• 4 For recent examples on the chemistry of zwitterions (1,4-dipoles) generated from the reaction of pyridines or quinolines with dimethyl acetylenedicarboxylate (DMAD), see: Nair V. Devipriya S. Suresh E. Tetrahedron  2008,  64:  3567 ; and references therein
• Indolizinone skeleton was known to be accessed by the similar type of cyclization-1,2-shift sequence using either PtCl₂ or CuI:
• 6a Smith CR. Bunnelle EM. Rhodes AJ. Sarpong R. Org. Lett.  2007,  9:  1169 
• 6b Yan B. Zhou Y. Zhang H. Chen J. Liu Y. J. Org. Chem.  2007,  72:  7783 
• For books and reviews on microwave in organic synthesis, see:
• 10a Lidström P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
• 10b Loupy A. Microwaves in Organic Synthesis   Wiley-VCH; Weinheim: 2002. 
• 10c Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
• 10d Kappe CO. Stadler A. Microwaves in Organic and Medicinal Chemistry   Wiley-VCH; Weinheim: 2005. 
• 10e Roberts BA. Strauss CR. Acc. Chem. Res.  2005,  38:  653 

5

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

7

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.

8

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

9

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.

11

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.

12

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.

13

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.