A rapid conversion of 3-oxothiolanes into 3-aminothiophenes

Article abstract of DOI:10.1081/SCC-120005940

3-Oxotetrahydrothiophenes can be rapidly converted into 3-aminothiophenes by refluxing with hydroxylamine hydrochloride in a polar solvent, usually acetonitrile.

Full text of DOI:10.1081/SCC-120005940

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A RAPID CONVERSION OF 3-OXOTHIOLANES INTO 3-
AMINOTHIOPHENES
John M. Barker a , Patrick R. Huddleston b & Michael L. Wood a
a Dept. of Chemistry and Physics, The Nottingham Trent University, Clifton Lane,
Nottingham, NG11 8NS, UK
b Dept. of Chemistry and Physics, The Nottingham Trent University, Clifton Lane,
Nottingham, NG11 8NS, UK
Published online: 16 Aug 2006.
To cite this article: John M. Barker , Patrick R. Huddleston & Michael L. Wood (2002): A RAPID CONVERSION OF 3-
OXOTHIOLANES INTO 3-AMINOTHIOPHENES, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:16, 2565-2568
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2565–2568, 2002
A RAPID CONVERSION OF
3-OXOTHIOLANES INTO
3-AMINOTHIOPHENES
*
John M. Barker, Patrick R. Huddleston,
and Michael L. Wood
Dept. of Chemistry and Physics, The Nottingham Trent
University, Clifton Lane, Nottingham NG11 8NS, UK
ABSTRACT
3-Oxotetrahydrothiophenes can be rapidly converted into
3-aminothiophenes by refluxing with hydroxylamine hydro-
chloride in a polar solvent, usually acetonitrile.
The conversion of 3-oxotetrahydrothiophenes into 3-aminothiophenes
by the Semmler–Wolff aromatisation[1] was first described by Cheney
and Piening[2] and involved the conversion of the ketone into its oxime
followed by its rearrangement with HCl in ether into the amine hydrochlor-
ide, each step typically requiring one or more days for completion. We
have found that the conversion can be rapidly accomplished in one step
by refluxing the ketone with hydroxylamine hydrochloride in a polar
solvent, usually acetonitrile[3] (Scheme 1).
*Corresponding author.
2565
DOI: 10.1081/SCC-120005940
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2566
BARKER, HUDDLESTON, AND WOOD
Scheme 1.
Table 1.
Time
(h)
Yielda
(%)
M.p.ꢀC
HCl Salt
Lit.
M.p.ꢀC
R1
R2
R3
Ref.
H
H
Me
Me
H
CO2Me
CO2Me
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
Me
H
H
Me
H
Me
H
Me
CO2Me
H
H
CO2Me
Ph
Me
1
1b
4
77
49
66
70
203–204
183–185d
189–191c
64–70d
203–205d
179–181
191–192
4
5
6
–
7
8
9
10
11
12
e
4
–
1f
1½
5
52
186–188dg
62–63d
60–61d,g
63–64d
73d
64d
82
82–83d
80–81d
168–169.5d
189–192d
84–85d
1
3/4
2
81–82d
H
H
82
72
168–170d
189–193d
b
c
d
e
aof HCl salt unless otherwise stated; in ethanol; see Ref. 13; free base; an analy-
tical sample crystallized from cyclohexane had m.p. 75–76ꢀC (Found: C, 51.7; H, 6.1;
N, 7.3. Calc. for C8H11NO2S: C, 51.9; H, 6.0; N, 7.6%) dH (270 MHz; CDCl3) 2.12
and 2.56 (2s, 2 Â ArCH3) 3.85 (s, CO2CH3) 4.48 (br s, NH2) dC 10.67 and 16.77
(2 Â ArCH3) 51.02 (CO2CH3) 105.14 (C5) 118.45 (C3) 142.06 (C4) 144.37 (C2)
f
g
164.98 (CO2Me); in methanol; see Experimental.
The process requires only a few hours and generally results in good
yields. Presumably the reaction occurs by HCl liberated from the oxime
formation inducing the rearrangement and trapping the product as its
hydrochloride (Table 1).
EXPERIMENTAL
Yields (not optimised) and melting points refer to crude product in
each case.
4-Amino-3-methoxycarbonylthiophene hydrochloride: 4-Oxo-3-methoxy-
carbonyltetrahydrothiophene[14] (3.9 g), hydroxylamine hydrochloride (1 g)
and acetonitrile (10 mL) were boiled together under reflux for 1 h. The

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CONVERSION OF 3-OXOTHIOLANES
2567
mixture was then cooled and the solid which separated was filtered off
and washed with dry ether to afford the title compound (3.65 g, 77%)
m.p. 203–204ꢀC (lit.[4] 203–205dꢀC).
Dimethyl 4-amino-2,3-bismethoxycarbonylthiophene hydrochloride: 2,3-
Bismethoxycarbonyl-4-oxotetrahydrothiophene[7] (1.32 g), hydroxylamine
hydrochloride (0.5 g) and methanol (2.5 mL) were boiled together under
reflux for 1 h. At the end of this time the mixture was cooled whereupon
it solidified and was diluted with ethyl acetate. The compound was filtered
off and washed with ethyl acetate to give a white solid (0.79 g, 52%) m.p.
186–188dꢀC. A sample of this material afforded the yellow free base, m.p.
61.5–63.5ꢀC (lit.[7] m.p. 60–61ꢀC) on treatment with aqueous ammonia. An
analytical sample of the hydrochloride, crystallized from methanol/ether,
had m.p. 193–195dꢀC (Found: C, 38.1; H, 3.9; N, 5.6. C8H10ClNO4S
requires C, 38.2; H, 4.0; N, 5.6%).
4-Amino-3-methoxycarbonyl-2-methylthiophene
hydrochloride:
3-
Methoxycarbonyl-2-methyl-4-oxotetrahydrothiophene[5] (1.11 g), hydroxyl-
amine hydrochloride (0.5 g) and ethanol (2.5 mL) were stirred and boiled
under reflux in an oil bath at 100–105ꢀC for 1 h. The mixture solidified on
cooling; it was diluted with ethyl acetate and chilled in ice water before the
pale pink solid was filtered off and dried at the pump, the product weighted
0.65 g (49%) and had m.p. 183–185dꢀC (lit.[5] m.p. 179–181ꢀC).
REFERENCES
1. (a) For a General Review of this Reaction see Conley, R.T.; Ghosh, S.
In Mechanisms of Molecular Migrations, Volume 4; Thyagarajan, B.S.,
Ed.; Wiley-Interscience, 1971; p. 251; (b) The Application of this
Reaction to the Preparation of Thiophenes is Reviewed by Norris,
R.K. In Thiophene and its Derivatives, Part 2, Gronowitz, S., Ed.;
Wiley: New York and Chichester, 1986; 638.
2. Cheney, L.C.; Piening, J.R. J. Am Chem. Soc. 1945, 67, 729.
3. This Procedure has been Published as a Patent: Huddleston, P.R.;
Barker, J.M. Eur. Pat. Appl. EP 298,542; Chem. Abstr. 1989, 111,
P7216u.
4. Baker, B.R.; Schaub, R.E.; Joseph, J.P.; McEvoy, F.J.; Williams, J.H.
J. Org. Chem. 1953, 18, 138.
5. Binder, D.; Noe, C.R.; Zahora, M. Arch. Pharm. (Weinheim) 1981,
314, 557.
6. Confalone, P.; Pizzolato, G.; Rouge, M.; Uskokovic, M.R. Ger. Offen.,
2, 737, 738; Chem. Abstr. 1978, 88, P190582d.
7. Binder, D.; Stanetty, P. Synthesis 1977, 200.

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2568
BARKER, HUDDLESTON, AND WOOD
8. Huddleston, P.R.; Barker, J.M. Synth. Commun. 1979, 9, 731.
9. Hoechst, Brit. Patent, 837,086; Chem. Abstr. 1960, 54, 24798e.
10. Arcamone, F.M.; Animati, F.; Barbieri, B.; Configliacchi, E.;
D’Alessio, R.; Geroni, C.; Giuliani, F.; Lazzari, E.; Menozzi, M.;
Mongelli, N.; Penco, S.; Verini, M.A. J. Med. Chem. 1989, 32, 774.
11. Reinhoudt, D.N.; Geevers, J.; Trompenaars, W.P.; Harkema, S.; van
Hummel, G.J. J. Org. Chem. 1981, 46, 424.
12. Davies, R.E.; Fraser, J. Eur. Pat. Appl. EP 209,977; Chem. Abstr.
1987, 107, P70809x.
13. Data taken from: Woodland, E.D. PhD thesis, Nottingham
Polytechnic, 1992.
14. Rossy, P.A.; Hoffmann, W.; Muller, M. J. Org. Chem. 1980, 45, 617.
¨
Received in the UK July 31, 2001