The synthesis of 5-alkoxy and 5-amino substituted thiophenes

Article abstract of DOI:10.1016/S0040-4039(99)02338-2

5-Alkoxythiophenes have been prepared by an extension of the Gewald thiophene synthesis and a novel four component condensation reaction uncovered by which 5-aminothiophenes have been prepared. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02338-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1597–1600
The synthesis of 5-alkoxy and 5-amino substituted thiophenes
Ivan L. Pinto,∗ Richard L. Jarvest and Halina T. Serafinowska
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 18 October 1999; accepted 16 December 1999
Abstract
5-Alkoxythiophenes have been prepared by an extension of the Gewald thiophene synthesis and a novel four
component condensation reaction uncovered by which 5-aminothiophenes have been prepared. © 2000 Elsevier
Science Ltd. All rights reserved.
The synthesis of highly substituted thiophenes has attracted a great deal of interest over the years due
to their presence in natural products,1 as novel conducting polymers2 and as isosteric replacements for
phenyl groups in medicinal chemistry.3 Our interest in this class of compound was founded on their
use as precursors to a series of novel serine protease inhibitors such as 1.3 Of particular interest was
the preparation of analogues of 1 in which R1 was an alkoxy substituent with a view to stabilising
the oxazinone ring to hydrolytic cleavage. For this work we required intermediate 2 where R1 was an
alkoxy substituent. The synthesis of highly substituted thiophenes is restricted by the relative paucity
of methods available to construct the ring bearing functionality in a controlled fashion. In particular, the
introduction of alkoxy groups is very limited relying on substitution of halothiophenes with alkoxide4,5 or
oxygenation of metallothiophenes6 or directly7 and is generally low yielding. We therefore investigated
a more versatile method for preparing oxygenated thiophenes.
The most convenient method for preparing thiophenes with a high degree of functionality as in 2
is by the Gewald method in which elemental sulfur is reacted with an activated acetonitrile and an
aldehyde, ketone or 1,3-dicarbonyl compound in the presence of base (equimolar quantities of each).8
However, there are no examples, to our knowledge, in which this methodology has been used to prepare
2-alkoxythiophenes, presumably due to the potential for mixtures of 4- and 5-regioisomers being formed
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02338-2
tetl 16266

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(Scheme 1).9 We surmised that the presence of the heteroatom would render the methylene more acidic
than the methyl group and would therefore direct the condensation reaction predominantly towards the
5-regioisomer. We tested this hypothesis with the reaction of methoxyacetone and ethyl cyanoacetate.
The only product isolated from the reaction was 5-methoxythiophene 5a (R=Me) in 61% yield (Table
1). Indeed when tert-butyl cyanoacetate was used in the same reaction the yield of 5a (tert-butyl ester)
was near quantitative. The reaction was found to be general for a range of alkoxymethylketones with
yields from moderate to good (Table 1). Of particular note was the silyl derivative 5e which could be
desilylated10 to the 5-hydroxythiophene 5f which existed exclusively in the keto form.5
Scheme 1.
Table 1
Non-trivial ketones 4 were readily prepared from the alcohol and chloroether 7 in a one-pot process
using the method described by Okahara (Scheme 2).11
Scheme 2.
Attempts to introduce a 5-aryloxy substituent into the thiophene ring led to the discovery of an unex-
pected transformation. Reaction of phenoxyacetone 8 with ethyl cyanoacetate and sulfur in the presence
of morpholine as described above, resulted not in the 5-phenoxythiophene but in 5-morpholinothiophene
9 in 21% yield (Scheme 3). Clearly the morpholine displaces the phenoxy group but it is not apparent at
what stage in the reaction sequence this occurs. It is known that the initial condensation product (e.g. 10)
can react further with sulfur and morpholine to provide the thiophene9,12 suggesting that displacement
occurs after this stage but before insertion of sulfur. We speculate that the reaction proceeds as shown

1599
in Scheme 4 but further studies are required to delineate the exact mechanism. In any event the reaction
constitutes a novel four component condensation reaction.
Scheme 3.
Scheme 4.
The morpholine can be replaced by a variety of cyclic secondary amines all of which provided the 5-
aminothiophene as the sole thiophene product in modest yields (Table 2). A variety of functional groups
are tolerated under these mild reaction conditions as demonstrated in Table 2. When the amine was
replaced by pyrrolidine or homopiperidine the condensation failed, as it did if an acyclic secondary amine
was used. The requirement for a cyclic six-membered ring secondary amine is difficult to rationalise but
may be related to the stability of the intermediate 12 and whether it cyclises or eliminates the amine to
give a thioaldehyde which would be unstable under the reaction conditions.
In conclusion, we have extended the Gewald synthesis of thiophenes to the preparation of a variety
of 5-alkoxythiophenes and provided a convenient method for the preparation of 5-hydroxythiophenes.
A novel four component condensation reaction in which 5-aminothiophenes are formed has also been
disclosed which could have potential in combinatorial chemistry for the preparation of diverse libraries.13
Preparation of 5a: To ethyl cyanoacetate (26.6 mmol) in 6 ml ethanol was added methoxyacetone (26.6
mmol) followed by powdered sulfur (26.6 mmol) and morpholine (3.5 ml). The solution was stirred for
18 h, concentrated and chromatographed over silica (CH2Cl2/5% diethyl ether) to yield 61% of 5a (mp
61–63°C). 1H NMR (CDCl3): 5.86 (br, 2H); 4.26 (q, J=7 Hz, 2H); 3.73 (s, 3H); 2.13 (s, 3H); 1.33 (t, J=7
Hz, 3H). 13C NMR (CDCl3): 166.2, 155.4, 142.7, 118.1, 103.3, 63.5, 59.5, 14.4, 12.5.
Preparation of 9: To phenoxyacetone (13.3 mmol) in 4 ml ethanol was added ethyl cyanoacetate (13.3
mmol) followed by sulfur (13.3 mmol) and morpholine (1.5 ml). The solution was stirred for 18 h,
concentrated and chromatographed over silica (CH2Cl2/5% diethyl ether) to yield 21% of 9 (mp 137°C).
1H NMR (CDCl3): 6.0 (br, 2H); 4.26 (q, J=7 Hz, 2H); 3.78 (br t, J=5 Hz, 4H); 2.75 (br t, J=5 Hz, 4H);
2.22 (s,3H); 1.34 (t, J=7 Hz, 3H). 13C NMR (CDCl3): 166.4, 159.4, 134.9, 127.0, 104.2, 67.1, 59.5, 54.6,
14.5, 14.3.

1600
Table 2
Acknowledgements
We thank Jean-Michel Poncelet for technical assistance.
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