Synthesis of novel 2-aminothiophene-3-carboxylates by variations of the Gewald reaction

Article abstract of DOI:10.1007/s007060170137

The synthesis of the title compounds through variations of the Gewald reaction is presented. Knoevenagel condensation of methylketone derivatives with methyl cyanoacetate and subsequent treatment of the α,β-unsaturated nitriles with sulfur and amine resul

Full text of DOI:10.1007/s007060170137

Monatshefte fuÈr Chemie 132, 279±293 (2001)
Synthesis of Novel 2-Aminothiophene-3-
carboxylates by Variations of the Gewald
Reaction
Hans-Peter Buchstaller1;2;Ã, Carsten D. Siebert2, Ralf H. Lyssy2, Ina Frank2,
Adil Duran2, Rudolf Gottschlich1, and Christian R. Noe2;3
1
Merck KGaA, D-64271 Darmstadt, Germany
2
Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, D-60439 Frankfurt,
Germany
3
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria
Summary. The synthesis of the title compounds through variations of the Gewald reaction is
presented. Knoevenagel condensation of methylketone derivatives with methyl cyanoacetate and
subsequent treatment of the ꢀ,ꢁ-unsaturated nitriles with sulfur and amine resulted in the
corresponding 2-aminothiophenes 5 or isomers 9 and 10. Reaction of methylketone derivatives
bearing a leaving group at the methyl group under modi®ed Gewald conditions selectively led to the
formation of 4-substituted 2-aminothiophenes 9a and 12. The introduction of the sulfur atom occurs
through nucleophilic displacement with sodium sul®de.
Keywords. 2-Aminothiophenes; Gewald reaction; Heterocycles; Methylketones.
Introduction
The couple benzene±thiophene represents one of the most prominent examples of
bioisosterism. Whereas the replacement of a benzene ring by a thiophene ring in a
pharmacologically active compound has been frequently regarded as a mere case of
`me-too strategy' in drug research, the advent in the market of an increasing number
of thiophene containing drugs having no benzene ring predecessor points to the fact
that in many cases the speci®c placement of a thiophene moiety has become the ®rst
choice in drug design and is superior to the use of benzene. During the last years our
interest in this class of compounds has been focused on their use as precursors to a
series of novel inhibitors at the glycine binding-site of the NMDA-receptor such as
1 [1, 2]. For this work we required intermediate 2. Of particular interest has been the
preparation of analogues of 2 bearing various substituents at position 4 (R2) of the
ring system.
The Gewald synthesis is probably the most versatile and important reaction for
the preparation of biological active compounds and intermediates containing a
thiophene moiety. Three major modi®cations of this method are well known in
Ã
Corresponding author

280
H.-P. Buchstaller et al.
Scheme 1
literature which offer access to various 2-aminothiophenes in a simple fashion [3].
In the ®rst, an ꢀ-mercaptoaldehyde or an ꢀ-mercaptoketone is treated with an
activated nitrile bearing an electron withdrawing group. However, this particular
version is less attractive due to a few drawbacks such as utilization of starting
compounds which are unstable and dif®cult to prepare [4±7]. Much more elegant
and simple is the one-pot procedure, which includes the condensation of aldehydes,
ketones, or 1,3-dicarbonyl compounds with activated nitriles and sulfur in the
presence of amines [8±10]. In the third version, a two-step procedure is preferred.
It involves the isolation of ꢀ,ꢁ-unsaturated nitriles from Knoevenagel condensation
and subsequent conversion of these ole®ns to the corresponding 2-aminothiophenes
by treatment with sulfur and amine. This variation not only gives higher yields, but
also allows the conversion of alkyl aryl ketones to thiophenes which is not possible
with the one-pot procedure [8, 11±12]. Some time ago, we published a further
modi®cation of the Gewald reaction which renders 4-n-alkyl substituted 2-
aminothiophene derivatives accessible not obtainable via the classical methods
[13]. Herein, we wish to report the results of further investigations on this
modi®cation. At the same time we include results on the synthesis of novel methyl
2-aminothiophene-3-carboxylates using the two-step variation of the Gewald
reaction, particularly of compounds exhibiting a functionalized alkyl group at
position 4.
Results and Discussion
The ꢀ,ꢁ-unsaturated nitriles 4a±e, in all cases isolated as E/Z-isomeric mixtures,
were obtained by heating of the respective ketones 3a±e with methyl cyanoacetate
in benzene under a constant water separator in the presence of glacial acetic acid
and catalytic amounts of ammonium acetate [14, 15]. However, the low reactivity of
pinacolone 3c, due to sterical hindrance by the adjacent methyl groups, required the
addition of equimolar amounts of ammonium acetate and extended reaction times
to obtain 4c in at least poor yield [16]. The condensation products 4a±e were
subsequently cyclized with sulfur and diethylamine in methanol to yield 5a±e. In
contrast to Gewald, who described the synthesis of 5a at room temperature
but without a yield given [11], we observed that for complete conversion of
4a±e extended reaction times at 35±40ꢀC were necessary. This indicates that
isomerization from E to Z occurs at elevated temperature and enables the reaction of
the E-isomer, which is the major condensation product. Depending on the applied
amount of sulfur and the course of the reaction the mixtures were worked up
according to three different variations, and the ®nal compounds 5a±d were isolated

Novel 2-Aminothiophene-3-carboxylates
281
Scheme 2. Reagents and conditions: i) NH4OAc, AcOH, benzene, re¯ux;
ii) S, Et2NH, abs. MeOH, 35±40ꢀC
Scheme 3
in moderate to good yields. When compound 4e was treated as described above, the
formation of 5e along with one byproduct was observed. On the basis of
spectroscopic studies, we assigned structure 5f to this byproduct. Moreover, we
assume that the formation of 5f proceeds via the mechanism depicted in Scheme 3.
The ®rst step of the formation of both products is an ꢀ-thiolation. On the one hand
this intermediate cyclizes to the desired thiophene 5e; on the other hand it is likely
that a dithiolation reaction takes place to a certain extent. It is worth mentioning that
such dithiolated species have already been decribed as reaction intermediates by

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H.-P. Buchstaller et al.
Scheme 4. Reagents and conditions: i) 5 M HCl, re¯ux; ii) (Boc)2O, Et3N, CH2Cl2, 0ꢀC; iii) MtsCl,
Et3N, CH2Cl2, 0ꢀC; iv) NH4OAc or piperidine, AcOH, benzene, re¯ux;
v) S, Et2NH, abs. MeOH, 40ꢀC
Asinger [17] as well as Gewald [8]. Finally, 5f is formed by cycloaddition and
concurrent nucleophilic opening of the cyclopropyl moiety. It is interesting to note
that this side reaction has not been observed during the preparation of the respective
ethyl ester [18].
Apart from the described 4-alkyl substituted thiophene derivatives we were
interested in 2-aminothiophenes with alkyl groups at position 4 bearing functional
groups such as cyano, carboxylic ester, protected amino, and hydroxy groups which
allow further synthetic transformations. Thus, we investigated the availability of
such compounds via Gewald synthesis. Therefore, appropriately substituted methyl-
ketones and the corresponding Knoevenagel condensation products were required as
precursors.
Michael addition of phthalimide to methylvinylketone yielded the ketone 7a
[19], which upon treatment with hydrochloric acid afforded 6, the key intermediate
for the preparation of further protected aminoketones. Thus, the Boc and 2,4,6-
Trimethylbenzenesulfonyl (Mts) protected derivatives 7b and 7c were obtained from
6 using standard reaction conditions. Subsequent condensation of 7a±c with methyl
cyanoacetate resulted in E/Z-mixtures of 8a±c. In general, the thiolation-
heterocyclization reactions of such intermediates to the corresponding aminothio-
phenes furnish 4-methyl derivatives, because thiolation occurs preferentially at the
methylene group and not at the methyl group [11]. However, some reactions have
been reported in literature by which thiolation and incorporation of the methyl
group led to unexpected aminothiophene derivatives [20]. For this reason, a
regioselective thiolation and subsequent formation of the 4-substituted thiophenes
could not be expected. Indeed, when compounds 8a±c were treated with sulfur and
diethylamine in methanol at 40ꢀC, mixtures of 4- and 5-substituted isomers 9 and 10
were obtained, which were separated by either chromatography or recrystallization.
Unfortunately, in all cases the desired 4-substituted thiophene was the minor
reaction product. Nevertheless, this approach gives access to highly substituted
thiophenes which could have potential as building blocks in combinatorial
chemistry. In order to circumvent the observed selectivity problems we further

Novel 2-Aminothiophene-3-carboxylates
283
Scheme 5. Reagents and conditions: i) Na2S nonahydrate, Et3N, abs. MeOH or EtOH
investigated a modi®cation of the Gewald reaction [13] which requires the
introduction of a leaving group at the methyl group of methylketone derivatives.
This was accomplished by either bromination or total synthesis of the appropriate
ketones. Treatment of such ketones under the modi®ed Gewald conditions avoids
the formation of product mixtures, since the introduction of the sulfur atom occurs
through nucleophilic displacement with sodium sul®de. However, reaction of 11e,
which was readily prepared from 7a through bromination using the conditions
described by Elz [21], with sodium sul®de in methanol at elevated temperature gave
9a in a yield similar to that achieved by the foregoing procedure. Despite this
unpleasant result, the following examples emphasize the usefulness of this method
for the conversion of functionalized alkylmethylketones to 4-substituted thiophenes,
particularly in the case of heteroatoms or electron-withdrawing substituents being
present, thus rendering the methylene group more acidic than the methyl group.
Recent investigations have shown that for such ketones, e.g. methoxyacetone, the
thiolation-heterocyclization reaction is directed exclusively towards the 5-isomer
and generates 5-alkoxy-thiophenes [22]. In contrast to these ®ndings, our
modi®cation of the Gewald reaction gives acess to the respective 4-isomers.
Monotosylation of 3-methoxypropane-1,2-diol followed by oxidation of the
secondary hydroxy group resulted in ketone 11a, which upon treatment according to
the one-pot procedure described above yielded 12a. Introduction of a cyanomethyl or
(ethoxycarbonyl)-methyl residue was achieved in a similar manner using 4-bromo-3-
oxo-butanenitrile [23] (11c) or commercially available ethyl chloroacetoacetate
(11b). The precursor 11d for the synthesis of derivative 12d was obtained by
oxidation of (R/S)-2-hydroxy-3-(((4-methylbenzene)-sulfonyl)-oxy)-propyl benzoate
[24]. Treatment of 11d under the conditions described above yielded the thiophene
12d. The deprotected derivative 12e was isolated in small amounts as well.
Experimental
Melting points were determined on a Ko¯er apparatus and are uncorrected. Column chromatography
and vacuum ¯ash chromatography (VFC) were performed on silica gel 60 (Merck). Thin layer

284
H.-P. Buchstaller et al.
chromatography was performed on aluminum sheets, coated with silica gel 60 F254 (Merck).
Microanalyses were within Æ0.4% of theoretical values and were performed by the Institute of
Organic Chemistry, University of Frankfurt/Main (CHN-Rapid, Heraeus). 300MHz 1H NMR spectra
1
were recorded on a Bruker AC 300, 200 MHz H NMR and 50 MHz 13C NMR spectra on a Bruker
AC 200 spectrometer; chemical shifts are reported in ppm relative to internal TMS. IR spectra were
obtained on a Bruker IFS-48 instrument. UV spectra were recorded on a Varian 300 Bio
spectrophotometer. Petroleum ether, diethylether, and CH2Cl2 were distilled before use. Other
chemicals and solvents were used in standard commerical quality. Abbreviations: bz, benzoyl; chxl,
cyclohexyl; D, CH2Cl2; PE, petroleum ether; tos, tosyl; VFC, vacuum ¯ash chromatography.
Compounds 7a [19] and 11c [23] were prepared as described in the literature. The synthesis of
compound 7b has also been previously described [25], but an alternative route was used.
Methyl (E/Z)-2-cyano-3-cyclohexyl-2-butenoate (4a; C12H17NO2)
Methyl cyanoacetate (15.7 g, 0.16 mol) and 20 g 3a (0.16 mol) were dissolved in 35 cm3 dry benzene
to which 2.4 g ammonium acetate (31 mmol) and 7.6 g glacial acetic acid (0.13 mol) were added. The
mixture was re¯uxed under a constant water separator until the formation of H2O ceased. The mixture
was cooled, diluted with benzene, and washed with H2O. The organic layer was dried (Na2SO4),
®ltered, and concentrated in vacuo. The residue was puri®ed by VFC (300 g silica gel, eluent:
PE/Et2O ˆ 20/1) to yield 28.4 g (86.5%) of colourless crystals.
M.p.: 97±101ꢀC (Ref. [11]: m.p.: 96±100ꢀC); Rf (PE/Et2O ˆ 5/1) ˆ 0.27; 1H NMR (200 MHz, ꢂ,
CDCl3): 3.87±3.59/3.03±2.81 (2m, 4H, therein: 3.78 (s, 3H, OCH3); 1H, CH, chxl, Z/E), 2.26/2.18 (s,
CH3, E/Z), 1.92±1.0 (m, 10H, chxl) ppm.
Methyl (E/Z)-2-cyano-3,4-dimethyl-2-pentenoate (4b; C9H13NO2)
Methyl cyanoacetate (31.4 g, 0.32 mol), 30 g 3b (0.35 mol), 4.85 g ammonium acetate (63 mmol), and
15.6 g glacial acetic acid (0.26 mol) were dissolved in 60 cm3 dry benzene and treated for 22 h as
described for 4a. The isolated residue was distilled in vacuo to yield 42.7 g (80%) of a colourless
liquid.
1
B.p.: 105±107ꢀC (9±10 mbar) (Ref. [26]: b.p.: 107±108ꢀC (8 mbar)); H NMR (200 MHz, ꢂ,
CDCl3): 4.06/3.31 (2sept, J ˆ 6:7 Hz, CH(CH3)2, Z/E), 3.79 (s, OCH3), 2.25/2.17 (2s, 3-CH3, E/Z),
1.12/1.06 (2d, J ˆ 6:7 Hz, CH(CH3)2, E/Z) ppm.
Methyl (E/Z)-2-cyano-3,4,4-trimethyl-2-pentenoate (4c; C10H15NO2)
Methyl cyanoacetate (159.3 g, 1.6 mol), 80.5 g 3c (0.8 mol), 62 g ammonium acetate (0.8 mol), and
77.2 g glacial acetic acid (1.29 mol) were dissolved in 350 cm3 dry benzene and treated according to
a modi®ed Knoevenagel procedure previously described [16]. The residue was distilled in vacuo to
yield 6.38 g (4.5%) of a colourless liquid.
B.p.: 137±139ꢀC (21 mbar) (Ref. [16]: b.p.: 127±130ꢀC (16 mbar)); Rf (PE/Et2O ˆ 5/1) ˆ 0.36; 1H
NMR (200 MHz, ꢂ, CDCl3): 3.80 (s, OCH3), 2.26/2.18 (2s, CH3, E/Z), 1.36/1.18 (s, C(CH3)3), E/Z)
ppm.
Methyl (E/Z,R/S)-2-cyano-3,4-dimethyl-2-hexenoate (4d; C10H15NO2)
Methyl cyanoacetate (23.7 g, 0.24 mol), 24 g 3d (0.24 mol), 3.32 g ammonium acetate (43 mmol),
and 10.79 g glacial acetic acid (0.18 mol) were dissolved in 40 cm3 dry benzene and treated for 17 h
as described for 4a. The isolated residue was distilled in vacuo to yield 38.5 g (89%) of a colourless
liquid.

Novel 2-Aminothiophene-3-carboxylates
285
B.p.: 115±118ꢀC (12 mbar); 1H NMR (200MHz, ꢂ, CDCl3): 4.0±3.82/3.17±2.96 (2m, 4-CH, Z/E),
3.78 (s, OCH3), 2.21/2.13 (2s, 3-CH3, E/Z), 1.58±1.33 (m, 5-CH2), 1.09/1.04 (2d, J ˆ 6:7 Hz, 4-CH3,
E/Z), 0.92±0.75 (m, 6-CH3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 180.97 (s, 3-C), 162.08/161.66 (2s,
COOMe), 115.39/115.03 (2s, CN), 104.64/103.87 (2s, 2-C), 52.0 (q, OCH3), 44.11/37.38 (2d, 4-C),
27.46/27.22 (2t, 5-C), 18.39/17.75 (2q, 3-CH3), 15.01 (q, 4-CH3), 11.52 (q, 6-C) ppm.
Methyl (E/Z)-2-cyano-3-cyclopropyl-2-butenoate (4e; C9H11NO2)
Methyl cyanoacetate (23.56g, 0.24 mol), 20 g 3e (0.24 mol), 3.59 g ammonium acetate (46.5 mmol),
and 11.4 g glacial acetic acid (0.19 mol) were dissolved in 50 cm3 dry benzene and treated for 6 h as
described for 4a. The isolated residue was puri®ed by VFC (330 g silica gel, eluent: PE/Et2O ˆ 9/1) to
yield 28.6 g (73%) of colourless crystals.
M.p.: 74±78ꢀC; Rf (D) ˆ 0.38; 1H NMR (300 MHz, ꢂ, CDCl3): 3.82/3.80 (2s, OCH3, Z/E), 3.53±
3.41/2.46±2.34 (2m, CH, Z/E), 1.96/1.87 (2s, CH3, E/Z), 1.21±1.09 (m, CH2), 1.07±0.97 (m, CH2)
ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 178.87 (s, 3-C), 163.05/162.48 (2s, COOMe), 116.35 (s, CN),
103.58/102.57 (2s, 2-C), 52.25/52.17 (2q, OCH3), 20.33/16.20 (2d, CH), 17.78/14.01 (2q, 4-C), 10.43/
9.36 (2t, CH2) ppm.
Syntheses of 5a±e; general procedure
A stirred solution of 0.1 mol 4a±e in 20±40 cm3 dry methanol was treated with 0.12±0.2 mol sulfur
and 0.07±0.12 mol diethylamine at room temperature and subsequently warmed to 35±40ꢀC.
Depending on the applied amount of sulfur and the course of the reaction, the mixtures were worked
up according to the following methods:
Method A: The reaction mixture was ®ltered, diluted with diethyl ether, washed with H2O, dried
(Na2SO4), ®ltered, and concentrated in vacuo. The residue was puri®ed by VFC and crystallized by
digesting in cold PE.
Method B: The reaction mixture was concentrated in vacuo. The residue was dissolved in diethyl
ether and extracted several times with 6 M HCl. The aqueous layer was rendered basic and extracted
with diethyl ether. The combined organic layers were dried (Na2SO4), ®ltered, and concentrated in
vacuo. The residue was crystallized by digesting in cold PE and recrystallized.
Method C: The reaction mixture was concentrated in vacuo, and the residue was puri®ed by VFC
and crystallized by digesting in cold PE.
Methyl 2-amino-4-cyclohexylthiophene-3-carboxylate (5a; C12H17NO2S)
Compound 5a was prepared from 14.4 g 4a (69.5 mmol), 2.7 g sulfur (84.2 mmol), and 8.75 cm3
diethylamine (84.2 mmol) in 35 cm3 dry MeOH as described above. After being stirred for 23 h at
35ꢀC, the reaction mixture was worked up according to method C (VFC: 500 g silica gel, eluent: D/
PE ˆ 2/1) to yield 10.6 g (64%) of yellow crystals.
M.p.: 89±90.5ꢀC (Ref. [11]: m.p.: 88±92ꢀC); Rf (D) ˆ 0.5; 1H NMR (300 MHz, ꢂ, CDCl3): 6.0 (s,
br, NH2), 5.86 (s, 5-H), 3.82 (s, OCH3), 3.1±2.92 (m, CH, chxl), 2.01±1.64 (m, 5H, CH2, chxl), 1.48±
1.12 (m, 5H, CH2, chxl) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 166.26 (s, COOMe), 161.35 (s, 2-C),
147.41 (s, 4-C), 105.70 (s, 3-C), 100.65 (d, 5-C), 50.70 (q, OCH3), 39.34 (d, CH, chxl), 34.08 (t, CH2,
chxl), 26.98 (t, CH2, chxl), 26.48 (t, CH2, chxl) ppm; IR (KBr): ꢃ~ ˆ 3421, 3317, 2947, 2921, 2847,
1651, 1602, 1525, 1476, 1459, 1442, 1287, 1267, 1195, 1119, 1065, 989, 682 cm 1; UV (MeOH):
ꢄmaxꢁ"† ˆ 227 (24293), 300.5 (5340) nm.
Methyl 2-amino-4-isopropylthiophene-3-carboxylate (5b; C9H13NO2S)
Compound 5b was prepared from 37 g 4b (0.22 mol), 14.2 g sulfur (0.44 mol), and 17 cm3
diethylamine (0.16 mol) in 45 cm3 dry MeOH as described above. After being stirred for 17 h at 40ꢀC,

286
H.-P. Buchstaller et al.
the reaction mixture was worked up according to method A (VFC: 500g silica gel, eluent: D/PE ˆ
1/1) to yield 30.9 g (70%) of yellow crystals.
1
M.p.: 31±32ꢀC; Rf (D) ˆ 0.29; H NMR (200 MHz, ꢂ, CDCl3): 6.05 (s, br, NH2), 5.88 (s, 5-H),
3.81 (s, OCH3), 3.38 (sept, J ˆ 6:8 Hz, CH(CH3)2), 1.16 (d, J ˆ 6:8 Hz, CH(CH3)2) ppm; 13C NMR
(50 MHz, ꢂ, CDCl3): 166.23 (s, COOMe), 164.56 (s, 2-C), 148.19 (s, 4-C), 105.63 (s, 3-C), 100.27
(d, 5-C), 50.59 (q, OCH3), 29.0 (d, CH), 23.16 (q, CH3) ppm; IR (KBr): ꢃ~ ˆ 3441, 3333, 2963, 1674,
1584, 1527, 1475, 1439, 1285, 1260, 1105, 1010, 787, 672 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 227
(24205), 303 (5148) nm.
Methyl 2-amino-4-tert-butylthiophene-3-carboxylate (5c; C10H15NO2S)
Compound 5c was prepared from 5.66 g 4c (31.23 mmol), 1.5 g sulfur (46.85 mmol), and 2.43 cm3
diethylamine (23.42 mmol) in 12 cm3 dry MeOH as described above. After being stirred for 25 h at
40ꢀC, the reaction mixture was worked up according to method C (VFC: 140 g silica gel, eluent: PE/
Et2O ˆ 5/1) to yield 1.64 g (25%) of colourless crystals.
1
M.p.: 56±58ꢀC; Rf (D) ˆ 0.44; H NMR (200 MHz, ꢂ, CDCl3): 5.97 (s, 5-H), 5.89 (s, br, NH2),
3.83 (s, OCH3), 1.33 (s, C(CH3)3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 166.21 (s, COOMe), 164.48
(s, 2-C), 149.84 (s, 4-C), 106.80 (s, 3-C), 102.14 (d, 5-C), 50.57 (q, OCH3), 35.15 (s, C(CH3)3), 30.46
(q, C(CH3)3) ppm; IR (KBr): ꢃ~ ˆ 3413, 3311, 2950, 1655, 1595, 1513, 1469, 1437, 1293, 1268, 1192,
1119, 998, 782, 728, 675 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 227:5 (22083), 300.5 (5269) nm.
Methyl (R/S)-2-amino-4-(1-methylpropyl)thiophene-3-carboxylate (5d; C10H15NO2S)
Compound 5d was prepared from 35 g 4d (0.19 mol), 11.15 g sulfur (0.35 mol), and 15 cm3
diethylamine (0.15 mol) in 40 cm3 dry MeOH as described above. After being stirred for 23 h at 40ꢀC,
the reaction mixture was worked up according to method B to yield 25.75 g (65%) of yellow crystals.
M.p.: 54.5±55.5ꢀC (PE); Rf (D) ˆ 0.52; 1H NMR (200 MHz, ꢂ, CDCl3): 6.02 (s, br, NH2), 5.85 (s,
5-H), 3.80 (s, OCH3), 3.32±3.11 (m, 10-H), 1.77±1.52 (m, 1H, 20-CH2), 1.49±1.22 (m, 1H, 20-CH2),
1.15 (d, J ˆ 6:9 Hz, CH-CH3), 0.88 (t, J ˆ 7:4 Hz, 30-CH3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3):
166.32 (s, COOMe), 164.37 (s, 2-C), 147.12 (s, 4-C), 105.90 (s, 3-C), 100.81 (d, 5-C), 50.61 (q,
OCH3), 35.41 (d, 10-C), 30.27 (t, 20-C), 20.07 (q, CH-CH3), 11.81 (q, 30-C) ppm; IR (KBr): ꢃ~ ˆ 3413,
3311, 2960, 1651, 1605, 1525, 1475, 1459, 1442, 1283, 1194, 671 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ
227:5 (26009), 303 (5614) nm.
Methyl 2-amino-4-cyclopropylthiophene-3-carboxylate (5e; C9H11NO2S) and Methyl
2-amino-5,6-dihydro-4H-thieno[2,3-b]thiopyran-3-carboxylate (5f; C9H11NO2S2)
Compound 4e (28.1 g, 0.17 mol) was treated with 6.5 g sulfur (0.2 mol) and 21.3 cm3 diethylamine
(0.2 mol) in 70 cm3 dry MeOH as described above. After being stirred for 42 h at 35ꢀC, the reaction
mixture was worked up according to method C (VFC: 500 g silica gel, eluent: D/PE ˆ 1/1). The
obtained product mixture was digested in diethylether and ®ltered. The residue was recrystallized
from CHCl3 and identi®ed as 5f. The ®ltrate was extracted with 6 M HCl, the aqueous layer was
washed with diethyl ether, rendered basic, and extracted with diethyl ether. The combined organic
layers were dried (Na2SO4), ®ltered, concentrated in vacuo, and crystallized by digesting in PE.
5e: 18.4 g (55%) of beige crystals; m.p.: 72±74ꢀC; Rf (D) ˆ 0.37; 1H NMR (200 MHz, ꢂ, CDCl3):
6.0 (s, br, NH2), 5.69 (s, 5-H), 3.82 (s, OCH3), 2.25±2.06 (m, CH), 0.87±0.65 (m, CH2), 0.63±0.44
(m, CH2) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 166.51 (s, COOMe), 164.17 (s, 2-C), 142.75 (s, 4-C),
106.75 (s, 3-C), 100.73 (d, 5-C), 50.72 (q, OCH3), 12.35 (d, CH), 6.87 (t, CH2) ppm; IR (KBr):
ꢃ~ ˆ 3425, 3314, 1650, 1596, 1529, 1480, 1441, 1293, 1268, 1013, 784, 664 cm 1; UV (MeOH):
ꢄmaxꢁ"† ˆ 229 (25206), 300.5 (5318) nm.

Novel 2-Aminothiophene-3-carboxylates
287
5f: 2.35 g (6%) of colourless crystals; m.p.: 208.5±209.5ꢀC; Rf (D) ˆ 0.33; 1H NMR (200 MHz, ꢂ,
DMSO-d6): 7.29 (s, NH2), 3.67 (s, OCH3), 3.03±2.86 (m, 6-CH2), 2.71 (t, J ˆ 6:4 Hz, 4-CH2), 2.12±
1.90 (m, 5-CH2) ppm; 13C NMR (50 MHz, ꢂ, DMSO-d6): 164.63 (s, COOMe), 161.76 (s, 2-C), 128.05
(s, 3a-C), 106.27 (s, 3-C), 103.38 (s, 7a-C), 50.29 (q, OCH3), 27.0 (t, 6-C), 25.54 (t, 4-C), 23.26 (t, 5-
C) ppm; IR (KBr): ꢃ~ ˆ 3413, 3298, 2941, 2915, 1635, 1582, 1536, 1482, 1442, 1293, 1263, 981,
779 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 232 (23276), 283 (5724), 318.5 (4769) nm.
4-Aminobutan-2-one hydrochloride (6; C4H10ClNO)
Compound 7a [19] (50.30 g, 0.23 mol) was suspended in 200 cm3 5 M HCl and re¯uxed for 24 h. The
reaction mixture was ®ltered, the ®ltrate was evaporated to dryness, and the residue was dried in
vacuo to give 28.1 g (99%) of a yellow hygroscopic solid.
1
‡
H NMR (300 MHz, ꢂ, DMSO-d6): 8.09 (s, br, H3N ), 2.93±2.81 (m, 4H, 4-CH2/3-CH2), 2.12 (s,
1-CH3) ppm; 13C NMR (50 MHz, ꢂ, DMSO-d6): 205.87 (s, 2-C), 39.97 (t, 4-C), 33.54 (t, 3-C), 29.85
(q, 1-C) ppm.
tert-Butyl (3-oxobutyl)-carbamate (7b; C9H17NO3)
Di-tert-butyldicarbonate (8.83 g, 40.48 mmol) and 12.30 g triethylamine (121.44 mmol) were
dissolved in 70 cm3 CH2Cl2 and cooled to 0ꢀC. 5.0 g 6 (40.48 mmol), dissolved in 20 cm3 DMSO,
were added dropwise, and the solution was stirred at 0ꢀC until the evolution of gas ceased. The
reaction mixture was washed with H2O (3x). The organic layer was dried (Na2SO4), ®ltered, and
evaporated to dryness. The residue was puri®ed by VFC (155 g silica gel, eluent: PE/Et2O ˆ 3/1, then
1/1) to give 6.46 g (85%) of a yellowish oil.
1
Rf (PE/Et2O ˆ 1/2) ˆ 0.26; H NMR (300 MHz, ꢂ, CDCl3): 4.92 (t, J ˆ 5:9 Hz, NH), 3.25 (q,
J ˆ 5:9 Hz, 1-CH2), 2.58 (t, J ˆ 5:9 Hz, 2-CH2), 2.09 (s, 4-CH3), 1.34 (s, C(CH3)3) ppm.
2,4,6-Trimethyl-N-(3-oxobutyl)-benzenesulfonamide (7c; C13H19NO3S)
2,4,6-Trimethylbenzenesulfonyl chloride (8.80 g, 40.48 mmol) and 12.30 g triethylamine
(121.44 mmol) were dissolved in 70 cm3 CH2Cl2 and cooled to 0ꢀC. 5.0 g 6 (40.48 mmol), dissolved
in 20 cm3 DMF, were added dropwise, and the solution was stirred at 0ꢀC for 6 h. The reaction
mixture was washed with H2O several times; the organic layer was dried (Na2SO4), ®ltered, and
concentrated in vacuo. The residue was puri®ed by VFC (280 g silica gel, eluent: PE/ethyl acetate ˆ
10/1, then 2/1) to yield 9.59 g (88%) of a yellowish solid.
1
M.p.: 57±58ꢀC; Rf (PE/ethyl acetate ˆ 1/1) ˆ 0.29; H NMR (300 MHz, ꢂ, CDCl3): 6.97 (s, 2H,
Harom), 5.27 (t, J ˆ 6:0 Hz, NH), 3.09 (m, 10-CH2), 2.68 (t, J ˆ 5:4 Hz, 20-CH2), 2.65 (s, 6H, 2 o-
CH3), 2.31 (s, p-CH3), 2.11 (s, 40-CH3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 208.0 (s, 30-C); 142.13
(s, 1-C), 138.94 (s, 4-C), 133.83 (s, 2-C/6-C), 131.96 (d, 3-C/5-C), 42.58 (t, 10-CH2), 37.44 (t, 20-
CH2), 29.97 (q, 40-CH3), 22.73 (q, 2 o-CH3), 20.87 (q, p-CH3) ppm.
Methyl (E/Z)-2-cyano-5-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-methyl-2-pentenoate
(8a; C16H14N2O4)
Methyl cyanoacetate (7.53 g, 75.5 mmol), 15 g 7a [19] (69 mmol), 100 mg ammonium acetate
(1.3 mmol), and 825 mg glacial acetic acid (13.81 mmol) were dissolved in 80 cm3 dry benzene and
treated for 12 h as described for 4a. The obtained residue was recrystallized from MeOH to yield
15.5 g (75%) of yellow crystals.
M.p.: 90±92ꢀC; Rf (CHCl3/acetone ˆ 40/1) ˆ 0.16; 1H NMR (300 MHz, ꢂ, CDCl3): 7.87±7.83 (m,
2H, Harom), 7.76±7.72 (m, 2H, Harom), 4.03±3.91 (m, 5-CH2), 3.77/3.66 (2s, OCH3, E/Z), 3.16/2.96

288
H.-P. Buchstaller et al.
(2t, J ˆ 6:6 Hz, 4-CH2, Z/E), 2.50/2.39 (2s, CH3, E/Z) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 172.84/
172.24 (2s, 3-C), 167.84 (s, 10-C/30-C), 161.76/161.65 (2s, COOMe), 134.15/134.06 (2d, 50-C/60-C),
131.85/131.79 (2s, 3a0-C/7a0-C), 123.45/123.32 (2d, 40-C/70-C), 115.09/114.85 (2s, CN), 107.03/
106.39 (2s, 2-C), 52.81/52.59 (2q, OCH3), 39.54/35.40 (2t, 5-CH2), 35.05/34.31 (2t, 4-CH2), 25.35/
21.16 (2q, CH3) ppm.
Methyl (E/Z)-5-((tert-butoxycarbonyl)-amino)-2-cyano-3-methyl-2-pentenoate (8b; C13H20N2O4)
Methyl cyanoacetate (3.42 g, 34.51 mmol), 6.46 g 7b (34.51 mmol), 59 mg piperidine (0.69 mmol),
and 1.04 g glacial acetic acid (17.25 mmol) were dissolved in 30 cm3 dry benzene and treated for 12 h
as described for 4a. The obtained residue was puri®ed by VFC (170 g silica gel, eluent: PE/Et2O ˆ 2/
1) to give 7.86 g (85%) of a yellow oil.
Rf (PE/Et2O ˆ 1/2) ˆ 0.29; 1H NMR (300 MHz, ꢂ, CDCl3): 4.80/4.71 (2s, br, NH, Z/E), 3.83/3.82
(2s, OCH3, Z/E), 3.43±3.37 (m, 5-CH2), 3.01/2.77 (2t, J ˆ 6:75 Hz, 4-CH2, Z/E), 2.45/2.35 (2s, CH3,
E/Z), 1.43 (s, C(CH3)3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 174.64 (s, 3-C), 162.31/162.03 (2s,
COOMe), 155.84 (s, COOC(CH3)3), 115.53/115.27 (2s, CN), 106.22/105.96 (2s, 2-C), 79.76 (s,
C(CH3)3), 52.62/52.46 (2q, OCH3), 41.57/38.89 (2t, 5-CH2), 38.40/35.79 (2t, 4-CH2), 28.30 (q,
C(CH3)3), 25.59/21.36 (2q, CH3) ppm.
Methyl (E/Z)-2-cyano-3-methyl-5-(((2,4,6-trimethylphenyl)-sulfonyl)-amino)-2-pentenoate
(8c; C17H22N2O4S)
Methyl cyanoacetate (2.94 g, 29.7 mmol), 8 g 7c (29.7 mmol), 50 mg piperidine (0.59 mmol), and
891 mg glacial acetic acid (14.84 mmol) were dissolved in 40 cm3 dry benzene and treated for 12 h as
described for 4a. The obtained residue was puri®ed by VFC (220 g silica gel, eluent: PE/ethyl
acetate ˆ 2/1) to yield 7.87 g (76%) of yellow crystals.
1
M.p.: 159±160ꢀC; Rf (PE/ethyl acetate ˆ 1/1)ˆ 0.37; H NMR (300 MHz, ꢂ, CDCl3): 7.01/7.0
(2s, 2H, Harom, Z/E), 5.13/4.74 (2s, br, NH, Z/E), 3.87/3.86 (2s, OCH3, Z/E), 3.28±3.18 (m, 5-CH2),
2.96/2.78 (2t, J ˆ 6:75 Hz, 4-CH2, Z/E), 2.67/2.66 (2s, 6H, 2 o-CH3, E/Z), 2.35 (s, p-CH3), 2.33/2.20
(2s, CH3, E/Z) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 173.19/172.99 (2s, 3-C), 162.59/161.70 (2s,
COOMe), 142.57/142.46 (2s, 10-C), 139.09/139.03 (2s, 40-C), 133.34 (s, 20-C/60-C), 132.05 (d, 30-C/
50-C), 115.33/114.82 (2s, CN), 106.99/106.59 (2s, 2-C), 52.93/52.59 (2q, OCH3), 40.66/40.54 (2t, 5-
C), 40.23/34.87 (2t, 4-C), 24.93/22.92 (2q, CH3), 22.89 (q, 2 o-CH3), 20.90 (q, p-CH3) ppm.
Methyl 2-amino-4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl)-thiophene-3-carboxylate
(9a; C16H14N2O4S) and Methyl 2-amino-5-((1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl)-
4-methylthiophene-3-carboxylate (10a; C16H14N2O4S)
A solution of 4.88 g 8a (16 mmol), 513 mg sulfur (16 mmol), and 836 mg diethylamine (11 mmol) in
50 cm3 dry MeOH was stirred at 40ꢀC for 12 h. The reaction mixture was ®ltered and the ®ltrate
concentrated in vacuo. The obtained product mixture was separated by repeated recrystallization from
MeOH.
1
9a: 710 mg (14%) of yellow needles; m.p.: 160±163ꢀC; Rf (Et2O) ˆ 0.6; H NMR (300 MHz, ꢂ,
CDCl3): 7.86±7.81 (m, 2H, Harom), 7.74±7.69 (m, 2H, Harom), 6.11 (s, br, NH2), 5.93 (s, 5-H), 3.97±
3.80 (m, 5H, N-CH2-CH2, OCH3), 3.06 (t, J ˆ 7:3 Hz, C-CH2-CH2) ppm; 13C NMR (50 MHz, ꢂ,
CDCl3): 168.18 (s, 10-C/30-C), 166.09 (s, COOMe), 164.60 (s, 2-C), 136.60 (s, 3-C), 133.80 (d, 50-C/
60-C), 132.14 (s, 3a0-C/7a0-C), 123.10 (d, 40-C/70-C), 105.66 (s, 4-C), 104.73 (d, 5-C), 50.93 (q,
OCH3), 38.28 (t, N-CH2-CH2), 30.72 (t, C-CH2-CH2) ppm; IR (KBr): ꢃ~ ˆ 3448, 3318, 2934, 1770,
1700, 1672, 1575, 1482, 1447, 1393, 1365, 1274, 1111, 1067, 1010, 870, 736, 720 cm 1; UV
(MeOH): ꢄmaxꢁ"† ˆ 221 (60703), 300 (7392) nm.

Novel 2-Aminothiophene-3-carboxylates
289
10a: 1.87 g (37%) of colourless crystals; m.p.: 211±215ꢀC; Rf (Et2O) ˆ 0.6; 1H NMR (300 MHz,
ꢂ, DMSO-d6): 7.88±7.81 (m, 4H, Harom), 7.30 (s, br, NH2), 4.65 (s, CH2), 3.67 (s, OCH3), 2.29 (s,
CH3) ppm; 13C NMR (50 MHz, ꢂ, DMSO-d6): 167.31 (s, 10-C/30-C), 165.20 (s, COOMe), 163.89 (s,
2-C), 134.56 (d, 50-C/60-C), 133.27 (s, 3-C), 131.37 (s, 3a0-C/7a0-C), 123.14 (d, 40-C/70-C), 112.43 (s,
4-C), 103.12 (s, 5-C), 50.34 (q, OCH3), 33.46 (t, CH2), 14.55 (q, CH3) ppm; IR (KBr): ꢃ~ ˆ 3432,
3320, 2924, 2853, 1767, 1698, 1660, 1577, 1481, 1438, 1400, 1269, 1128, 728 cm 1; UV (MeOH):
ꢄmaxꢁ"† ˆ 225:5 (36580), 267.5 (4832), 296 (4815) nm.
Methyl 2-amino-4-((2-(tert-butoxycarbonyl)-amino)-ethyl)-thiophene-3-carboxylate
(9b; C13H20N2O4S) and Methyl 2-amino-5-(((tert-butoxycarbonyl)-amino)-methyl)-
4-methylthiophene-3-carboxylate (10b; C13H20N2O4S)
A solution of 5.0 g 8b (18.6 mmol), 775 mg sulfur (24.18 mmol), and 935 mg diethylamine
(12.78 mmol) in 40 cm3 dry MeOH was stirred at 40ꢀC for 12 h. The reaction mixture was ®ltered and
the ®ltrate concentrated in vacuo. The obtained product mixture was separated by VFC (70 g silica
gel, eluent: PE/Et2O ˆ 2/1).
1
9b: 890 mg (16%) of yellowish crystals; m.p.: 117±118ꢀC; Rf (PE/Et2O ˆ 1/2) ˆ 0.33; H NMR
(300 MHz, ꢂ, CDCl3): 6.15 (s, br, NH2), 6.0 (s, 5-H), 4.52 (s, br, NH), 3.75 (s, OCH3), 3.27 (m, N-
CH2-CH2), 2.80 (t, J ˆ 6:5 Hz, C-CH2-CH2), 1.36 (s, C(CH3)3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3):
166.0 (s, COOMe), 164.65 (s, 2-C), 155.91 (s, COOC(CH3)3), 137.62 (s, 4-C), 105.57 (s, 3-C), 104.17
(d, 5-C), 79.08 (s, C(CH3)3); 50.84 (q, OCH3), 40.34 (t, N-CH2-CH2), 32.15 (t, C-CH2-CH2), 28.42
(q, C(CH3)3) ppm; IR (KBr): ꢃ~ ˆ 3401, 3304, 2977, 1693, 1649, 1596, 1531, 1486, 1447, 1270, 1167,
1139, 1063, 960, 794, 698cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 227 (25077), 300 (5707) nm.
1
10b: 1.84 g (33%) of colourless crystals; m.p.: 133±134ꢀC; Rf (PE/Et2O ˆ 1/2) ˆ 0.4; H NMR
(300 MHz, ꢂ, CDCl3): 6.08 (s, br, NH2), 4.70 (s, br, NH), 4.28 (d, J ˆ 5:3 Hz, CH2), 3.85 (s, OCH3),
2.26 (s, CH3), 1.49 (s, C(CH3)3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 166.39 (s, COOMe), 162.59 (s,
2-C), 155.48 (s, COOC(CH3)3), 132.96 (s, 5-C), 116.17 (s, 4-C), 106.61 (s, 3-C), 79.64 (s, C(CH3)3),
50.71 (q, OCH3), 36.96 (t, CH2), 28.37 (q, C(CH3)3), 14.80 (q, CH3) ppm; IR (KBr): ꢃ~ ˆ 3435, 3325,
2970, 2946, 1666, 1583, 1522, 1485, 1271, 1165, 1120, 1052, 783 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 228
(29081), 262.5 (4670), 305.5 (5089) nm.
Methyl 2-amino-4-(2-(((2,4,6-trimethylphenyl)-sulfonyl)-amino)-ethyl)-thiophene-3-carboxylate
(9c; C17H22N2O4S2) and Methyl 2-amino-4-methyl-5-((((2,4,6-trimethyl-phenyl)-sulfonyl)-
amino)-methyl)-thiophene-3-carboxylate (10c; C17H22N2O4S2)
A solution of 5.0 g 8c (14.26 mmol), 457 mg sulfur (14.26 mmol), and 706 mg diethylamine
(9.66 mmol) in 40 cm3 dry MeOH was stirred at 40ꢀC for 12 h. The reaction mixture was ®ltered and
the ®ltrate concentrated in vacuo. The obtained product mixture was separated by column
chromatography (75 g silica gel, eluent: PE/Et2O ˆ 2/1).
1
9c: 709mg (13%) of colourless crystals; m.p.: 115±117ꢀC; Rf (PE/Et2O ˆ 1/2)ˆ 0.21; H NMR
(300 MHz, ꢂ, CDCl3): 6.89 (s, 2H, Harom), 6.34 (s, 5-H), 6.12 (s, br, NH2), 4.49 (s, br, NH), 3.72 (s,
OCH3), 3.13 (m, N-CH2-CH2), 2.92 (t, J ˆ 6:4 Hz, C-CH2-CH2), 2.55 (s, 6H, 2 o-CH3), 2.28 (s, p-
13
CH3) ppm; C NMR (50 MHz, ꢂ, CDCl3): 165.22 (s, COOMe), 162.99 (s, 2-C), 142.42 (s, 10-C),
139.34 (s, 40-C), 139.06 (s, 20-C/60-C), 134.46 (s, 4-C), 131.88 (d, 30-C/50-C), 115.23 (d, 5-C), 113.17
(s, 3-C), 50.78 (q, OCH3), 39.08 (t, N-CH2-CH2), 22.90 (q, 2 o-CH3), 22.83 (t, C-CH2-CH2), 20.93 (q,
p-CH3) ppm; IR (KBr): ꢃ~ ˆ 3414, 3320, 3312, 2943, 1652, 1608, 1536, 1482, 1444, 1323, 1276,
1158, 1082, 784, 658cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 205 (51409), 226.5 (30634), 301.5 (5623) nm.
1
10c: 2.13g (39%) of colourless needles; m.p.: 151±152ꢀC; Rf (PE/Et2O ˆ 1/2) ˆ 0.26; H NMR
(300 MHz, ꢂ, CDCl3): 6.98 (s, 2H, Harom), 6.06 (s, br, NH2), 4.52 (s, br, NH), 4.03 (d, J ˆ 5:7 Hz,
CH2), 3.80 (s, OCH3), 2.65 (s, 6H, 2 o-CH3), 2.32 (s, p-CH3), 2.09 (s, CH3) ppm; 13C NMR (50 MHz,

290
H.-P. Buchstaller et al.
ꢂ, CDCl3): 165.24 (s, COOMe), 162.89 (s, 2-C), 142.32 (s, 10-C), 139.33 (s, 40-C), 139.08 (s, 20-C/60-
C), 131.98 (s, 5-C), 131.87 (d, 30-C/50-C), 128.12 (s, 4-C), 113.17 (s, 3-C), 50.78 (q, OCH3), 39.06 (t,
CH2), 22.90 (q, 2 o-CH3), 20.93 (q, p-CH3), 14.75 (q, CH3) ppm; IR (KBr): ꢃ~ ˆ 3424, 3374, 3309,
3201, 2937, 1641, 1575, 1485, 1443, 1334, 1276, 1151, 1033, 1021, 675 cm 1; UV (MeOH):
ꢄmaxꢁ"† ˆ 206:5 (41884), 229.5 (34261), 269.5 (6014), 303 (4708) nm.
1-Methoxy-3-(((4-methylbenzene)-sulfony)-oxy)-2-propanone (11a; C11H14O5S)
a) 3-Methoxypropane-1,2-diol (11.04 g, 103.8 mmol) and 16.78 cm3 pyridine (207.6 mmol) were
dissolved in 55 cm3 dry CH2Cl2 at room temperature. The solution was cooled to 10ꢀC, and 19.82 g
p-toluenesulfonyl chloride (103.8 mmol) were added. After stirring for 8 h at 10ꢀC, the reaction
mixture was washed with 5% NaHCO3 solution (3x) and 2 M HCl (2x). The organic layer was dried
(Na2SO4), ®ltered, and concentrated in vacuo. The obtained product mixture was separated by VFC
(300 g silica gel, eluent: Et2O/PE ˆ 1/1, then Et2O/PE ˆ 3/1) to yield 16.35 g (60%) 1-tosylate.
1
Colourless oil; Rf (MeOH/D ˆ 1=5) ˆ 0.5; H NMR (300 MHz, ꢂ, CDCl3): 7.79 (d, J ˆ 8:2 Hz,
2H, Harom), 7.30 (d, J ˆ 8:2 Hz, 2H, Harom), 4.15±3.92 (m, 3H, 10-CH2, 20-H), 3.39 (m, 30-CH2), 3.30
(s, OCH3), 2.56 (d, J ˆ 5:3 Hz, OH), 2.42 (s, CH3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 145.02 (s, 1-
C), 132.64 (s, 4-C), 129.90 (d, 3-C/5-C), 127.97 (d, 2-C/6-C), 72.48 (t, 10-C), 70.62 (t, 30-C), 68.19 (d,
20-C), 59.19 (q, OCH3), 21.61 (q, CH3) ppm.
The second VFC fraction consisted of 9.47 g (22%) 1,2-bis-tosylate (colourless oil).
b) To a stirred solution of 16.29 g 1-tosylate (62.6 mmol) in 26 cm3 diethyl ether, 31.4 cm3
Na2Cr2O7 solution [27] were added dropwise such that the reaction temperature was kept between
20±30ꢀC. After stirring for 3 h, further 15.6 cm3 of Na2Cr2O7 solution were added, and the reaction
mixture was stirred for additional 7.5 h at 20±30ꢀC. The phases were separated, and the aqueous layer
was extracted twice with diethyl ether. The combined organic layers were washed with saturated
NaHCO3 silution, dried (Na2SO4), ®ltered, and concentrated in vacuo. The residue was puri®ed by
VFC (150g silica gel, eluent: D, then Et2O/PE ˆ 2/1) to give 7 g (43%) of colourless crystals.
M.p.: 35±37ꢀC; 1H NMR (300 MHz, ꢂ, CDCl3): 8.84 (d, J ˆ 8:2 Hz, 2H, Harom), 7.35 (d,
J ˆ 8:2 Hz, 2H, Harom), 4.76 (s, 1-CH2), 4.16 (s, 3-CH2), 3.41 (s, OCH3), 2.47 (s, CH3) ppm; 13C
NMR (50 MHz, ꢂ, CDCl3): 200.07 (s, 2-C), 145.47 (s, 10-C), 132.36 (s, 40-C), 130.0 (d, 30-C/50-C),
128.06 (d, 20-C/60-C), 75.97 (t, 1-C), 70.79 (t, 3-C), 59.55 (q, OCH3), 21.66 (q, CH3) ppm.
3-(((4-Methylbenzene)-sulfonyl)-oxy)-2-oxopropyl benzoate (11d; C17H16O6S)
To a stirred solution of 10 g (R/S)-2-hydroxy-3-(((4-methylbenzene)-sulfonyl)-oxy)-propyl benzoate
[24] (28.54 mmol) in 100 cm3 diethyl ether, 61 cm3 Na2Cr2O7 solution [27] were added dropwise in
four portions every 6 h, and the solution was stirred for additional 6 h after the last addition. The
phases were separated, and the aqueous layer was extracted twice with diethyl ether. The combined
organic layers were washed with NaHCO3 solution, dried (Na2SO4), and concentrated in vacuo. The
crude product was puri®ed by VFC (200 g silica gel, eluent: D/n-hexane ˆ 50/1) to give 5.0 g (50%)
of a colourless solid.
M.p.: 83±85ꢀC; Rf (D) ˆ 0.25; 1H NMR (300 MHz, ꢂ, CDCl3): 8.05 (d, J ˆ 7:4 Hz, 2H, Harom, bz),
7.83 (d, J ˆ 8:15 Hz, 2H, Harom, tos), 7.60 (t, J ˆ 7:4 Hz, 1H, Harom, bz), 7.46 (t, J ˆ 7:4 Hz, 2H,
Harom, bz), 7.38 (d, J ˆ 8:15 Hz, 2H, Harom, tos), 5.08 (s, 10-CH2), 4.69 (s, 30-CH2), 2.46 (s, CH3) ppm;
13C NMR (50 MHz, ꢂ, CDCl3): 196.74 (s, 20-C), 165.65 (s, COOCH2), 145.83 (s, 4-C, tos), 133.63 (d, 4-
C, bz), 131.85 (s, 1-C, tos), 130.17 (d, 2-C/6-C, tos), 129.93 (d, 2-C/6-C, bz), 128.77 (s, 1-C, bz), 128.53
(d, 3-C/5-C, bz), 128.14 (d, 3-C/5-C, tos), 70.69 (t, 10-CH2), 66.76 (t, 30-CH2), 21.71 (q, CH3) ppm.
2-(4-Bromo-3-oxobutyl)-1,3-dihydro-2H-isoindol-1,3-dione (11e; C12H10BrNO3)
7a (13.72 g, 63.19 mmol) was dissolved in 120 cm3 dry MeOH/n-butanol ˆ 1/1 to which a solution of
10.19 g bromine (63.19 mmol) in 120 cm3 dry MeOH/dioxane ˆ 1/1 was added at 50ꢀC. The solution

Novel 2-Aminothiophene-3-carboxylates
291
was stirred at 50ꢀC until complete decolourization, poured onto water, and kept at 4ꢀC overnight. The
precipitate was collected by ®ltration and puri®ed by repeated recrystallization to yield 7.81 g (42%)
of colourless needles.
1
M.p.: 120ꢀC; Rf (PE/Et2O ˆ 2/1) ˆ 0.05; H NMR (300 MHz, ꢂ, CDCl3): 7.88±7.82 (m, 2H,
Harom), 7.76±7.70 (m, 2H, Harom), 3.96 (t, J ˆ 7:1 Hz, 10-CH2), 3.95 (s, 40-CH2), 3.12 (t, J ˆ 7:1 Hz,
20-CH2) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 199.56 (s, 30-C), 167.93 (s, 1-C/3-C), 134.09 (d, 5-C/6-
C), 131.95 (s, 3a-C/7a-C), 123.35 (d, 4-C/7-C), 37.99 (t, 10-C), 33.70 (t, 40-C), 33.09 (t, 20-C) ppm.
Methyl 2-amino-4-(methoxymethyl)-thiophene-3-carboxylate (12a; C8H11NO3S)
Methyl cyanoacetate (0.355 g, 3.6 mmol) and 861 mg Na2S nonahydrate (3.6 mmol) were dissolved in
5 cm3 dry methanol to which 926 mg 11a (3.6 mmol) dissolved in 5 cm3 dry MeOH were added at
0ꢀC. The cooling bath was removed, and 0.5 cm3 triethylamine (3.6mmol) were added. After stirring
for 2.5 h at room temperature the reaction mixture was evaporated to dryness, and the residue was
partitioned between H2O and diethyl ether. The combined organic layers were dried (Na2SO4),
®ltered, and concentrated in vacuo. The crude product was puri®ed by VFC (7 g silica gel, eluent: PE/
Et2O ˆ 6/1) to yield 310 mg (43%) of colourless crystals.
M.p.: 82±83ꢀC; Rf (PE/Et2O ˆ 3/1) ˆ 0.14; 1H NMR (300 MHz, ꢂ, CDCl3): 6.21 (s, 5-H), 6.06 (s,
br, NH2), 4.52 (s, CH2), 3.83 (s, COOCH3), 3.46 (s, OCH3) ppm; 13C NMR (50 MHz, ꢂ, CDCl3):
165.87 (s, COOMe), 164.48 (s, 2-C), 137.52 (s, 3-C), 104.57 (s, 4-C), 103.82 (d, 5-C), 71.42 (t, CH2),
58.62 (q, COOCH3), 50.89 (q, OCH3) ppm; IR (KBr): ꢃ~ ˆ 3422, 3320, 1653, 1606, 1544, 1483, 1440,
1114, 1051, 967, 780, 737cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 224:5 (24468), 298.5 (5804) nm.
Ethyl 2-amino-4-((ethoxycarbonyl)-methyl)-thiophene-3-carboxylate (12b; C11H15NO4S)
Ethyl cyanoacetate (7.44 g, 66 mmol) and 15.8 g Na2S nonahydrate (66 mmol) were dissolved in
54 cm3 dry EtOH to which 10.8g ethyl chloroacetoacetate (66 mmol) dissolved in 22 cm3 EtOH were
added at 0ꢀC. The cooling bath was removed, and 9.2 cm3 triethylamine (66 mmol) were added. The
solution was stirred for 1 h at room temperature and for additional 3 h at 40ꢀC. The reaction mixture
was evaporated to dryness, and the residue was treated with H2O and extracted with diethyl ether. The
combined organic layers were extracted with 6 M HCl. The aqueous layer was rendered basic and
extracted with diethyl ether. The combined organic layers were dried (Na2SO4), ®ltered, and
concentrated in vacuo. The crude product was puri®ed by VFC (170 g silica gel, eluent: PE/Et2O ˆ 5/
1) to yield 3.45 g (20%) of colourless crystals.
1
M.p.: 63±65ꢀC; Rf (D) ˆ 0.16; H NMR (300 MHz, ꢂ, CDCl3): 6.10 (s, br, NH2), 6.03 (s, 5-H),
4.30±4.12 (m, 4H, 2 OCH2CH3), 3.70 (s, CH2), 1.35±1.20 (m, 6H, 2 OCH2CH3) ppm; 13C NMR
(50 MHz, ꢂ, CDCl3): 171.45 (s, 2-C), 165.37 (s, COOEt), 164.19 (s, COOEt), 132.46 (s, 4-C), 106.04 (d,
5-C), 105.88 (s, 3-C), 60.51 (t, OCH2), 59.65 (t, OCH2), 37.53 (t, CH2), 14.22 (q, OCH2CH3), 14.17 (q,
OCH2CH3) ppm; IR (KBr): ꢃ~ ˆ 3401, 3302, 3099, 2976, 1725, 1667, 1598, 1541, 1491, 1440, 1279,
1187, 1071, 1025, 721cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 225 (24541), 266 (3642), 299.5 (5985) nm.
Methyl 2-amino-4-(cyanomethyl)-thiophene-3-carboxylate (12c; C8H8N2O2S)
Methyl cyanoacetate (1.24 g, 12.52 mmol) and 3.03 g Na2S nonahydrate (12.6 mmol) were dissolved
in 10 cm3 dry MeOH to which 2.03 g 4-bromo-3-oxo-butyronitrile [23] (12.5 mmol) dissolved in
20 cm3 MeOH were added within 1 h at 20ꢀC. The cooling bath was removed, and 1.74 cm3 triethyl
amine (12.52 mmol) were added. After stirring for 16 h at room temperature the reaction mixture was
concentrated in vacuo, diluted with H2O, and extracted with CH2Cl2 (4x). The combined organic
layers were dried (Na2SO4), ®ltered, and evaporated to dryness. The residue was puri®ed by VFC
(35 g silica gel, eluent: D) to give 320 mg (13%) of colourless crystals.

292
H.-P. Buchstaller et al.
1
M.p.: 139±140ꢀC; Rf (D) ˆ 0.5; H NMR (300 MHz, ꢂ, CDCl3): 6.27 (s, 5-H), 6.10 (s, br, NH2),
3.85 (s, OCH3), 3.79 (s, CH2) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 165.2 (s, COOMe), 164.8 (s, 2-C),
128.0 (s, 3-C), 117.7 (s, CN), 105.9 (d, 5-C), 104.5 (s, 4-C), 51.1 (q, OCH3), 20.9 (t, CH2) ppm; IR
(KBr): ꢃ~ ˆ 3429, 3410, 3305, 3084, 2946, 2242, 1674, 1600, 1539, 1488, 1442, 1331, 1276, 1040,
778, 744, 696cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 223 (26971), 296 (6962) nm.
Methyl 2-amino-4-((benzoyloxy)-methyl)-thiophene-3-carboxylate (12d; C14H13NO4S) and Methyl
2-amino-4-(hydroxymethyl)-thiophene-3-carboxylate (12e; C7H9NO3S)
Methyl cyanoacetate (569 mg, 5.74 mmol) and 1.4 g Na2S nonahydrate (5.74 mmol) were dissolved in
20 cm3 dry MeOH to which 2 g 11b (5.74 mmol) dissolved in 20 cm3 dry MeOH were added at 0ꢀC.
The cooling bath was removed, and 581 mg triethylamine (5.74 mmol) were added. After stirring for
3 h at room temperature the reaction mixture was evaporated to dryness. The residue was partitioned
between H2O and diethyl ether. The combined organic layers were dried (Na2SO4), ®ltered, and
concentrated in vacuo. The obtained product mixture was separated by VFC (20 g silica gel, eluent:
Et2O/PE ˆ 1/2).
12d: 237mg (14%) of colourless crystals; m.p.: 130±132ꢀC; Rf (Et2O/PE ˆ 1/1) ˆ 0.53; 1H NMR
(300 MHz, ꢂ, CDCl3): 8.05 (d, J ˆ 7:4 Hz, 2H, Harom, bz), 7.54 (t, J ˆ 7:4 Hz, 1H, Harom, bz), 7.42 (t,
J ˆ 7:4 Hz, 2H, Harom, bz), 6.24 (s, 5-H), 6.11 (s, br, NH2), 5.39 (s, CH2), 3.77 (s, OCH3) ppm; 13
C
NMR (50 MHz, ꢂ, CDCl3): 166.24 (s, 2-C), 165.82 (s, COOCH2), 164.68 (s, COOMe), 134.69 (s, 4-
C), 132.97 (d, 40-C, bz), 130.21 (s, 10-C, bz), 129.60 (d, 20-C/60-C, bz), 128.38 (d, 30-C/50-C, bz),
105.24 (d, 5-C), 104.56 (s, 3-C), 63.40 (t, CH2), 51.05 (q, OCH3) ppm; IR (KBr): ꢃ~ ˆ 3454, 3335,
2958, 2929, 2872, 1716, 1673, 1618, 1511, 1460, 1445, 1273, 1124, 1066, 704 cm 1; UV (MeOH):
ꢄmaxꢁ"† ˆ 224 (29507), 297.5 (5220) nm.
12e: 63 mg (6%) of yellow crystals; m.p.: 117±119ꢀC; Rf (Et2O/PE ˆ 1/1) ˆ 0.15; 1H NMR
(300 MHz, ꢂ, CDCl3): 6.24 (s, 5-H), 6.11 (s, br, NH2), 4.52 (d, J ˆ 5:5 Hz, CH2), 3.85 (s, OCH3), 3.33
(s, br, OH) ppm; 13C NMR (50 MHz, ꢂ, CDCl3): 165.67 (s, 2-C), 164.72 (s, COOMe), 140.52 (s, 4-C),
105.68 (d, 5-C), 104.82 (s, 3-C), 61.47 (t, CH2), 51.38 (q, OCH3) ppm; IR (KBr): ꢃ~ ˆ 3416, 3304,
1650, 1597, 1528, 1482, 1455, 1281, 1068, 999, 972, 782, 685 cm 1; UV (MeOH): ꢄmaxꢁ"† ˆ 225:5
(21315), 297.5 (5219) nm.
Methyl 2-amino-4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl)-thiophene-3-carboxylate
(9a; C16H14N2O4S)
Methyl cyanoacetate (321 mg, 3.24 mmol) and 778mg Na2S nonahydrate (3.24 mmol) were dissolved
in 30 cm3 dry MeOH to which 960 mg 11e (3.24 mmol) were added in small portions at 0ꢀC. After
complete addition the cooling bath was removed, and 328 mg triethylamine (3.24 mmol) were added.
After stirring for 12 h at 50ꢀC the reaction mixture was evaporated to dryness. The residue was
partitioned between H2O and diethyl ether. The combined organic layers were dried (Na2SO4),
®ltered, and concentrated in vacuo. The residue was puri®ed by VFC (10 g silica gel, eluent: Et2O/
PE ˆ 1/1) to yield 120mg (11%) of yellow needles.
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Received July 5, 2000. Accepted (revised) August 23, 2000