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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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72
7 CATEGORY Mac CYCLIZATIONS
О
NC| ch3sch2cr
H ^
SCH3
- ca-
H
nh2
(7,18)
When longer chain а-methylthio substituents or a-methylthiocycloalkanones are used, 3-methylthio-3ff-indole intermediates are isolated. These can be converted to 2,3-disubstituted indoles by reduction with LiAlH4[4],
(7.19)
The Gassman method has proven to be adaptable to complex structures, such as the intermediate 7.20B used in the synthesis of the indole diterpenes paspalicine and pasalinine[5]. Table 7.5 gives some other examples.
Table 7.5
Indoles from anilinosulfonium salts
Yield (%)
Entry Substituents Cycl. Desulf. Ref.
1 2-F.thyl-3-methyl 81 [4]
2 5-(Fthoxycarbonyl)-2-methyl 50 -70 [6]
3 5-Chloro-2-mcthyl 72 74 [la]
4 5-Cyano-2-mcthyl 85 83 [3]
5 7-Methoxy-2-mcthyl 45 87 [lb]
6 4.5-Difluoro-2-methyl 93 86 [7]
7 2-Methylbenzo[e] 76 88 [2]
8 2-Methyl-3-(methylthio)-l,7-trimethylene“ 39 [8]
aSystcmahc name: l-(Mcthylthio)-2-methyl-5,6-dihydro-4f/-pyrrolo[3,2,l-ij]quinoline.
7.3 THE GASSMAN SYNTHESIS
73
CH3S
PhNHCI
1) Et3N (93%)
2) Ni (71%)
3) TsOH
7.20B
(7.20)
The Gassman synthesis has been a particularly useful method for the synthesis of oxindoles[lb,8]. Use of methylthioacetate esters in the reactions leads to 3-(methylthio)oxindoles which can be desulfurized with Raney nickel. Desulfurization can also be done by reduction with zinc or tin[10,ll].
NHCI
1) CH3CH2CO2C2H5 x
2) Et3N
SCH3
CHC02C2H5 N H2
SCH3
Ra Ni xfiTVО (7.21)
or Sn
H
There are two sequences in which the reaction can be carried out. For most anilines the first step is N-ehlorination which can be done with i-butyl hypochlorite[9]. However, for anilines with ER substituents it may be preferable to halogenate the thioester. The halogenation can be done with Cl2[lb] or S02C12[12], For some anilines simply adding f-butyl hypochlorite to a mixture of the aniline and thioester is satisfactory (Entries 1, 4, Table 7.6).
Procedure
7-Benzoyl-3-methyloxindole[ 15]
Chlorination, rearrangement and cyclization
A solution of 2-aminobenzophenone (98 g, 0.50 mol) and methyl 2-(methyl-thio)propanoate (74 g, 0,50 mol) in CH2C12 (21) was cooled to — 70CC and 95% i-butyl hypochlorite (56 g, 0.5 mol) was added dropwise at such a rate that the temperature did not rise above — 655C. One hour after the addition was complete, Et3N was added and the mixture was allowed to come to room temperature. The solution was mixed with 3 N HCl (800 ml) and stirred for 1 h. The organic layer was separated, dried (Na2S04) and filtered. The solution was evaporated in vacuo and the residue triturated with ether. Filtration gave the
3-(methylthio)oxindole intermediate (92 g) in 62% yield.
Table 7.6
Oxindoles by the Gassman method
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4: Xylene, 120 C
5-(2-Chloro-l-oxopropyl)-3-spiro[thiolane-2,3'- 1: 4-(2-Chloro-l-oxopiopyl)aniline, t-BuOCl
2: Methyl thiolane-2-carboxylate 3: Et,N
7.4 THE SUGASAWA SYNTHESIS
75
Desulfurization
The above intermediate (8 g, 0.03 mol) in THF (80 ml) was stirred with Raney nickel (40g) for 2h and then carefully filtered. [CAUTION. Raney nickel can ignite during filtration.'] Cone. HCI (2 drops) was added to the filtrate and it was evaporated in vacuo. Recrystallization of the residue from 2-propanol gave the product (6.0 g) in 89% yield.
References
1. (a) P. G. Gassman, T. J. van Bergen, D. P. Gilbert and B. W. Cue, Jr, J. Am. Chem. Soc. 96, 5495 (1974); (b) P. G. Gassman, G. Gruetzmacher and T. J. van Bergen, J. Am. Chem. Soc. 96, 5512 (1974).
2. P. G. Gassman and W. N. Schenk, J. Org. Chem. 42, 3240 (1977).
3. P, Hamel, N. Zajac, J. G. Atkinson and Y. Girard, J. Org. Chem. 59, 6372 (1994).
4. P. G. Gassman, D. P. Gilbert and T. J. van Bergen, J. Chem. Soc., Chem. Commun. 201 (1974).
5. A. B. Smith, 111, J. Kingery-Wood, T. L. Leenay, E. G. Nolen and T. Sunazuka, J. Am. Chem. Soc. 114, 1438 (1992); R. E. Mewshaw, M, D. Taylor and A. B. Smith, III, J. Org. Chem. 54, 3449 (1989).
6. P, G. Gassman and T. J. van Bergen, Org. Synth., Co!!. Vol. 6, 601 (1988).
7. H. Ishikavva, T. Uno, H. Miyamoto, H. Ueda. H. Tamaoka, M. Tominaga and K. Nakagawa, Chem. Pharm. Bull. 38, 2459 (1990).
8. P G. Gassman, J. J. Roos and S. J. Lee, J. Org. Chem.. 49, 717 (1984).
9. P G. Gassman and T. J. van Bergen, J. Am. Chem. Soc. 96. 5508 (1974).
10. M. An-naka, K. Yasuda, M. Yamada, A. Kavvai, N. Takamura, S. Sugasavva, Y. Matsuoka, H. Ivvata and T. Fukushima, Heterocycles, 39, 251 (1994).
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