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DOI: 10.1055/s-2008-1078022
A Highly Efficient Catalyst-Free Cycloisomerization Approach to Indolizinones
Publication History
Publication Date:
31 July 2008 (online)
![](https://www.thieme-connect.de/media/synlett/200815/lookinside/thumbnails/10.1055-s-2008-1078022-1.jpg)
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
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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:
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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:
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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:
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10a
Lidström P.Tierney J.Wathey B.Westman J. Tetrahedron 2001, 57: 9225 -
10b
Loupy A. Microwaves in Organic Synthesis Wiley-VCH; Weinheim: 2002. -
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Roberts BA.Strauss CR. Acc. Chem. Res. 2005, 38: 653
References and Notes
No examples on the generation of zwitterions such as 8 from intramolecular cyclization have been disclosed in the literature.
7Spectral 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.
8Heating a solution of 1a in ethanol in the presence of cesium carbonate was also carried out but did not shorten the reaction time.
9Alcoholic 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.
11In 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.
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.