Synthesis of novel 5-chlorinated 2-aminothiophenes using 2,5-dimethylpyrrole as an amine protecting group

Article abstract of DOI:10.1002/jhet.5570450124

(Chemical Equation Presented) A new synthetic methodology towards substituted 2-amino-5-chlorothiophenes is described. Compounds of this type are important as building blocks for oligomers used in polymer research. Easily available 2-aminothiophenes underwent Paal-Knorr reaction to protect the free amino group before electrophilic substitution. Although the chlorination was predicted to proceed at the thiophene ring, only free positions of 2,5-dimethylpyrrole were substituted. To direct chlorination to the thiophene ring acetamido derivative was prepared first and then chlorinated. Transamination with hexane-2,5-dione created a 2,5-dimethyl pyrrole ring from the acetamido group. In the final step, after treatment with hydroxylamine dihydrochloride, the pyrrole ring is removed and a free amino group is regenerated.

Full text of DOI:10.1002/jhet.5570450124

Jan-Feb 2008
201
Synthesis of Novel 5-Chlorinated 2-Aminothiophenes Using 2,5-
Dimethylpyrrole as an Amine Protecting Group
Zita Puterová, Tomáꢀ Bobula and Daniel Végh
Slovak University of Technology, Faculty of Chemical and Food Technology, Radlinského 9, Bratislava,
Slovakia
Received May 29, 2007
R
R
R
X
X
X
4
4
4
3
3
3
Paal-Knorr
reaction
Chlorination
5
2´
5
2
2
5
2
2´
S
N
S
NH2
S
N
3´
3´
Cl
5´
4´
5´ 4´
2-aminothiophene
2-(2,5-dimethyl-1H-pyrrol-1-yl)thiophene
2-(3(3,4)-chloro (dichloro)
2,5-dimethyl- 1H-pyrrol-1-yl)
thiophene
1) Acetylation
2)Chlorination
R
R
R
Transamination
Deprotection
X
X
X
4
4
4
3
3
3
5
5
5
2
2
2
2´
Cl
Cl
Cl
S
N
S
NH2
S
NHCOCH3
3´
5´ 4´
2-acetamido-5-chlorothiophene
5-chloro-2-aminothiophene
5-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)
thiophene
R = CH3 or H
X = CO2CH3 or CN
A new synthetic methodology towards substituted 2-amino-5-chlorothiophenes is described. Compounds
of this type are important as building blocks for oligomers used in polymer research. Easily available 2-
aminothiophenes underwent Paal-Knorr reaction to protect the free amino group before electrophilic
substitution. Although the chlorination was predicted to proceed at the thiophene ring, only free positions
of 2,5-dimethylpyrrole were substituted. To direct chlorination to the thiophene ring acetamido derivative
was prepared first and then chlorinated. Transamination with hexane-2,5-dione created a 2,5-dimethyl
pyrrole ring from the acetamido group. In the final step, after treatment with hydroxylamine
dihydrochloride, the pyrrole ring is removed and a free amino group is regenerated.
J. Heterocyclic Chem., 45, 201 (2008).
INTRODUCTION
can produce thiophene trimers and oligomers with
potential to vary the existing hydrophilic and
hydrophobic substituents.
2-Aminothiophenes are widely used in syntheses of
pharmaceuticals [1], dyes [2] and agrochemicals [3].
Our interest is aimed at creating good and easily
available building blocks for the preparation of
designer oligothiophene derivatives. Design of such
compounds is important as they form components in
molecular devices for polymer research, electronic
semiconducting materials, non-linear optical materials
and highly ordered molecular assemblies [4,5]. The key
criteria among such design process are the yield
achievable in each synthetic step and the nature of the
terminal groups. Towards this goal, we have prepared a
series of substituted 2-amino-5-chloro thiophenes. Such
monomers can be used in homocoupling reactions to
create thiophene dimers and polyazomethines. In
heterocoupling reactions 2-amino-5-chlorothiophenes
R
R
R
X
X
X
4
4
4
3
3
3
5
5
5
2
2
2
2´
Cl
Cl
S
NH2
S
N
S
NH2
3´
5´
4´
1a-c
3a-c
4a-c
see Tables 1 and 3 for R, X
Figure 1. Synthetic approach towards 2-amino-5-chlorothiophenes.
Since Gewald and coworkers [6] presented in 1965 a
simple synthesis towards 2-aminothiophenes many new
methods were published to widen the compound library
of such compounds with various substituents [7].

202
Z. Puterová, T. Bobula and D. Végh
Vol 45
Table 1
However, recently there has been a revival of interest in
the synthesis of 2-aminothiophenes [8,9], and none of
published methods has pointed to synthesis of 5-
halogenated-2-aminothiophenes. Our focus was centred
on the use of 2,5-dimethylpyrrole as an amine protecting
group in route to 5-chloro-2-aminothiophenes (4a-c)
(Figure 1). Intermediates 2a-c and 3a-c are isosteric
analogues of N-aryl and N-heteroarylpyrroles, which
display a manifold of pharmacologically interesting
properties [10].
Application of the Paal-Knorr reaction on 2-aminothiophenes.
Pyrrole yield %
Method Method Method
Amine
R
X
A
B
C
1a
1b
1c
CH3
H
H
CO2CH3
CO2CH3
CN
2a, 38
2b, 45
2c, 53
2a, 42
2b, 47
2c, 50
2a, 40
2b, 43
2c, 50
Method A: toluene, p-TsOH, temperature: 110-111°C, Method B:
Bi(NO3)2.5H2O, dichloromethane, room temperature, Method C: I2,
THF, room temperature.
Based upon our theoretical knowledge on synthesis of
N-aryl and N-heteroaryl-pyrroles the yields were higher
than 70% in almost all cases [17-20]. Only in one study it
is pointed out that the difference between the reactivity of
six-membered amino derivatives versus five-membered
amines in the Paal-Knorr reaction. Bruekelman [21,22] in
his paper showed that when the protection with hexane-
2,5-dione is performed for substituted pyridyl amines, the
yield of the corresponding N-pyridyl-2,5-dimethylpyrroles
was more than 90%, whilst when the amino group in
substituted 1,3-thiazoles is converted to 2,5-dimethyl-
pyrrole the yield is only about 60%. This experimental
founding was not disclosed. In our opinion, the lower
yield of the pyrrole synthesis for 5-membered rings is
caused by twisting of the pyrrole ring from the plane of
existing thiophene, during its formation. This causes the
decreasing effect on the yield of final N-thiophenyl
pyrroles.
RESULTS AND DISCUSSION
Three types of 2-aminothiophenes (1a-c) used in our
study were prepared by the Gewald reaction according to
the published procedures [2,11,12].
Paal-Knorr Reaction. Paal-Knorr reaction [13]
remains one of the most attractive methods for prepar-
ation of 2a-c and similar N-aryl and N-hetero-
arylpyrroles. The reaction involves mixing of amino-
derivative with hexane-2,5-dione (Figure 2). There are
three different reaction conditions published for
converting primary amines into N-substituted 2,5-
dimethylpyrroles. The classical method uses toluene
as solvent and p-toluenesulphonic acid as catalyst
(Method A) [14]. Recently, two new alternatives were
published by Banik and coworkers [15,16]. Method B
involves the bismuth nitrate-catalyzed procedure of the
pyrrole formation [15] and method C makes use of
iodine as catalyst [16].
Chlorination. Electrophilic substitution at the free ꢀ-
position in substituted 2-aminothiophenes (1a-c) is
possible only when the amino group is protected. Because
of the suitable behaviour, we have chosen 2,5-dimethyl-
pyrrole as the protecting group. 2,5-Dimethylpyrroles are
stable to strong bases, to reducting agents, show weakly
nucleophilic properties – in terms of low reactivity to acid
chlorides and the 3-and 4-positions can be left
unsubstituted [19,22]. The last mentioned characteristics
with the fact-that the pyrrole group is easily removable
and after treatment with hydroxylamine hydrochlorides
under basic conditions while amino group is being re-
created, 2,5-dimethylpyrrole seemed to fit our purpose.
Although chlorination was assumed to proceed to the free
5-position on the thiophene in 2a-c, only pyrrole ring
underwent monosubstitution or disubstitution (Figure 3).
Chlorination of 2a-c was investigated under two different
sets of reaction conditions, using N-chlorosuccinimide
(NCS) as the source of chloronium species in 1.5 equiv.
and 3.0 equivalent excess. Following the procedure
published independently by two different research groups
[23,24], the chlorination was done in acetonitrile. The
second approach involved a two-phase catalytic method in
n-hexane with 70% HClO4 as catalyst [25] (Figure 3).
R
X
O
A: p-TsOH, Toluene,
110-111°C
R
X
4
3
4
3
2´
2
2
5
5
B: Bi(NO3)2.5H2O, CH2Cl2
room temp.
C: I2, THF, room temp.
N
3´
NH2
S
S
O
4´
5´
1a-c
2a-c
Figure 2. Paal-Knorr reaction of substituted 2-aminothiophenes.
All three methods mentioned above were tested for the
conversion of primary amino group of the starting 2-
aminothiophenes (1a-c) into 2,5-dimethylpyrrole
derivatives (2a-c). The reason why we have tried all
possible methods was based on our observation that the
conversion of starting compound into protected
derivatives never proceeded to completion. The yields of
products were only about 50% and unreacted starting
material was isolated from the reaction. The modifications
using bismuth nitrate or iodine-catalyzed reaction also
failed our expectations to increase the yield of N-
substituted pyrroles (Table 1). Hexane-2,5-dione was used
in 1.2 equiv excess in all cases.

Jan-Feb 2008
Synthesis of Novel 5-Chlorinated 2-Aminthiophenes
using 2,5-Dimethylpyrrole as an Amine protecting group
203
R
X
R
X
2-aminothiophenes were first protected with acetyl group
(6a-c), then chlorinated (7a-c) in high yields. To remove
the acetyl group we have tried deprotection under basic as
well as under acidic conditions. In both cases we failed to
get the 2-amino-5-chlorothiophenes 4a-c. Other types of
deprotection of the amino group are rather limited [28].
We have explored a new method where 2,5-dimethyl-
pyrrole was re-used in the transamination reaction. The
treatment of the 2,5-dimethylpyrrole group in 3a-c with
hydroxylamine hydrochloride in alcohols (i-propanol, n-
butanol) under basic conditions caused deprotection of the
amino group (4a-c) [27]. Acetylation of amino group was
performed using acetic anhydride as both reagent and
solvent. Reaction catalysed by Mg(ClO4)2.2H2O led to
acetylated derivatives 6a-c in almost quantitative yields.
There are many reports delineating the ability of N-
chlorosuccinimide to chlorinate reactive anilines in
benzene and tetrachloromethane [29]. Unfortunately, the
reaction of N-acetyl-2-aminothiophenes in these solvents
gives products in low yields. This problem is easily
obviated using N-chlorosuccinimide in a dipolar-aprotic
solvent such as acetonitrile [23] or i-propanol at reflux
[24]. We report herein the use of acetic acid to chlorinate
the N-acetylated derivatives with N-chlorosuccinimide.
The mixture of starting compounds 6a-c with NCS in
acetic acid was heated to reflux for one hour. The reaction
is clean and generally uncomplicated. Products 7a-c are
easily isolated in high yields. We have applied the Paal-
Knorr reaction for the deprotection of acetamido group to
free amino group. Whereas such type of deacetylation
have never been used, we tried two approaches. First, by
the standard technique only 1.2 equiv. of hexane-2,5-
dione was mixed with the starting compound in boiling
toluene (1 mol % amount of p-toluenesulphonic acid,
Dean-Stark apparatus). No conversion of the starting
material was observed even if the amount of hexane-2,5-
dione was increased to 3.0 equiv. and reaction left to run
8-12 hours. We assumed that the reaction in toluene will
not proceed because the reaction temperature (110-111°C)
is too low.
A: NCS, CH3CN, room temp.
4
3
4
3
2´
2´
5
2
2
5
Cl
N
3´
N
3´
S
S
B: NCS, 70%HClO4, n-hexane
room temp.
4´
4´
5´
5´
3a-c
2a-c
A: NCS, CH3CN, room temp.
B: NCS, 70%HClO4, n-hexane
room temp.
R
X
R
X
4
3
4
3
2´
2´
2
2
5
5
Cl
3´
4´
N
N
or
S
S
3´
4´
5´
5´
Cl
Cl
5c
5a,b
Figure 3. Chlorination of 2-(2,5-dimethyl-1H-pyrrol-1- yl)thiophenes
Final products 5a-c were isolated from the dark slurry
after purification by column chromatography in yields not
exceeding 30% (Table 2) by both techniques used. The
heterolysis of a N-Cl bond releases positive chloronium
ions which besides the electrophilic substitution at the
pyrrole ring also causes a decrease in pH resulting in an
acidic reaction mixture. Under these conditions, pyrroles
undergoe uncontrollable polymerization without any
chance to identify the by products after halogenation.
Table 2
Chlorination of 2a-c by use of N-chlorosuccinimide.
Yield % / equiv. of NCS
Entry
2a
R
CH3
X
Method A
5a, 21%,
1.5 equiv
5a, 20%,
3.0 equiv
5b, 23%,
1.5 equiv
5b, 20%,
3.0 equiv
5c, 18%,
1.5 equiv
5c, 14%,
3.0 equiv
Method B
5a, 28%,
1.5 equiv
5a, 25%,
3.0 equiv
5b, 27%,
1.5 equiv
5b, 22%,
3.0 equiv
5c, 20%,
1.5 equiv
5c, 16%,
3.0 equiv
CO2CH3
2a
2b
2b
2c
2c
CH3
H
CO2CH3
CO2CH3
CO2CH3
CN
H
H
H
CN
Method A: 1.5 or 3.0 equiv of NCS, CH3CN, room temperature, Method
B: 1.5 or 3.0 equiv of NCS, n-hexane, 70% HClO4 (0.5 mol %), room
temperature.
Thus, by the use of xylenes as solvent, which boil at
138-144°C, we found that the reaction with 1.2 equiv of
hexane-2,5-dione utillizing Dean-Stark trap for removal
of water and acetic acid was completed after 6-8 hours
(with additional of 1 mol% p-TsOH and 1 mol% HCl to
catalyse the reaction). During the reaction with aceta-
mides 7a-c not only water eliminates but also acetic acid
from the N-acetyl group. Once activation energy is
achieved, acetic acid leaves the molecule and catalyses
the reaction in equimolar quantities. That means that not
only sufficiently high reaction temperature is required for
reaction to proceed successfully, but autocatalysis by
acetic acid as well. The yields of N-(5-chlorothiophene-2-
yl)-2,5-dimethylpyrroles (3a-c) were only about 40%. The
Substitution of the pyrrole hydrogens at positions 3 and
4 by chlorine have not been described in the literature. We
have found similar product only in one case, when the
chlorination was directed to free positions of 2-acetyl-
pyrrole by using sulphuryl chloride [26].
General Synthesis of 5-Chlorinated 2-Amino-
thiophenes. The five-step procedure was employed in the
context of synthesis of 5-chlorinated 2-aminothiophenes
3a-c. As discussed above, our primary plan of synthesis
involved using 2,5-dimethylpyrrole as an amine masking
group in the key step. This strategy failed to produce the
desired compounds. In the second approach, the starting

204
Z. Puterová, T. Bobula and D. Végh
Vol 45
methods: 2-amino-4-methylthiophene-3-carboxylic acid methyl
ester (1a) according to [11], 2-aminothiophene-3-carboxylic
acid methyl ester (1b) and 2-aminothiophene-3-carbonitrile
(1c) according to [2, 12].
Thin Layer Chromatography. Thin Layer Chromatography
(TLC) was performed on F365, 20x20 cm, silica gel sheets
(Merck). Plates were spotted with substrates and were eluted
bulky ortho-substituents in our substrates inhibit the
formation of 2,5-dimethylpyrrole ring at the same site as
the substituent and causes the skewed position of the
forming pyrrole ring. This decreases the yields in
transamination reaction in 3a-c derivatives, as was the
case in the Paal-Knorr reaction in 2a-c.
Step I: Acetylation
Step II: Chlorination
O
R
X
R
X
R
X
AcOH, NCS
4
3
4
3
4
3
Ac2O, Mg(ClO4)2.2H2O
140°C, 3 hours
5
2
2
2
5
5
118°C, 1 hour
O
NH2
NHCOCH3
Cl
NHCOCH3
S
S
S
1a-c
6a-c
7a-c
Cl
R
R
X
X
4
3
NH2OH.2HCl, Et3N
4
3
p-TsOH, HCl, xylene
5
5
2
2
2´
Cl
n-BuOH-H2O, 80°C, 60 hours
138-144°C, 6-8 hours
S
NH2
S
N
3´
5´
4´
3a-c
4a-c
Step III: Transamination
Step IV: Deprotection
Figure 4. General synthesis of 5-chlorinated 2-aminothiophenes.
with appropriate solvent system. The developed plates were
analyzed under UV 365 nm or stained with iodine.
The removal of the 2,5-dimethylpyrrole masking group
with hydroxylamine dihydrochloride (3.0 equiv) and
triethylamine (2.0 equiv) in the mixture n-butanol: water
(6:1) proceeded smoothly with all substrates. Table 3
summarizes the results from synthesis of substituted 5-
chloro 2-aminothiophene derivatives (4a-c) shown on
Figure 4.
Column Chromatography. Column chromatography was
performed using silica gel Kiesegel 60 with particle size 40-63
μm (230-400 mesh, Merck) by preparing the slurry with the
eluent mixture and packing it into the chromatography column.
The collected fraction samples were analyzed by TLC.
Nuclear Magnetic Resonance Spectroscopy (NMR). 1H and
13C spectra were acquired with the Varian VXR 300 spectro-
1
meter at 293 K, at 300 MHz for H and 75 MHz for 13C. The
Table 3.
samples were prepared in CDCl3 (deuterated chloroform) using
TMS (tetramethylsilane) as internal standard. Chemical shifts (ꢀ
scale) are quoted in parts per million (ppm) and the following
abbreviations are used: s (singlet), d (doublet), br s (broad
singlet) some combinations of these were made by DEPT editing
of the spectra. Coupling constants (J) were measured in Hertz
(Hz).
Synthesis of Substituted-5-chloro-2-aminothiophenes.
Starting
material
1a
R
X
R.Temp./ °C R.Time/
hours
Yield /
%
CH3
H
CO2CH3
CO2CH3
CN
140
140
3
3
6a, 95
6b, 91
6c, 93
7a, 72
7b, 69
7c, 74
3a, 51
3b, 48
3c, 46
4a, 30
4b, 34
4c, 28
1b
1c
H
140
118
3
6a
6b
CH3
H
CO2CH3
CO2CH3
CN
1
Melting Point Determination. Melting points (mp) were
determined with the Kofler hot stage and are uncorrected.
Elemental analyses were performed on CarloErba CHNS-
OEA 1108-Elementar Analyser.
118
118
1
6c
7a
7b
7c
H
1
CH3
H
CO2CH3
CO2CH3
CN
138-144
138-144
138-144
80
80
80
6
8
Compounds are numbered according to Figure 1-4.
H
8
3a
3b
CH3
H
CO2CH3
CO2CH3
CN
60
60
60
Step I. Paal-Knorr reaction.
3c
H
Method A. Hexane-2,5-dione (1.2 mmol) was added to a
mixture of starting 2-aminothiophene 1a-c (1 mmol) and p-
TsOH (0.5-1 mol%) in toluene (30 mL/mmol of amine 1).
Reaction was stirred in refluxing toluene for 2 hours utilizing
Dean-Stark trap for removal of water. After cooling down to
room temperature, the mixture was washed with saturated
aqueous solution of NaHCO3 (2x20mL), water (2x20mL) and
aqueous NaCl. The toluene phase was dried over Na2SO4. The
products 2 were purified by column chromatography, eluent
hexane-ethyl acetate (9:1).
EXPERIMENTAL
Chemicals and reagents. The chemicals and reagents
were purchased from Sigma-Aldrich, Merck or ACROS. All
solvents were of analytical or laboratory grade; for their
purification standard methods were used. Starting 2-
aminothiophenes were prepared according to published

Jan-Feb 2008
Synthesis of Novel 5-Chlorinated 2-Aminthiophenes
using 2,5-Dimethylpyrrole as an Amine protecting group
205
Method B. To a solution of amine 1 (1 mmol) and hexane-
2,5-dione (1.2 mmol) in dichloromethane (2 mL) at room
temperature, bismuth nitrate pentahydrate (0.5–1 mmol) was
added. The mixture was allowed to stir at this temperature for 24
hours. The resulting mixture was washed with saturated
NaHCO3 solution (2 mL) and brine (2 mL). The organic layer
was collected and dried with sodium sulfate and concentrated.
The residue was purified through a column on silica gel using
hexane-ethyl acetate (9:1).
(10 mL) at room temperature N-chlorosuccinimide was added in
small portions (1.5 equiv and 3.0 equiv, see Table 2) to avoid
harsh exothermic reaction. The mixture was stirred at room
temperature for 3 hours. When the reaction was complete (the
colour of reaction mixture changes from light to dark during
reaction) formed N-succinimide was filtered off and the residue
was concentrated to get the crude products 5a-c. Black slurry
was purified by column chromatography on silica gel using
hexane-ethyl acetate (9:1).
Method C. To a solution of amine 1 (1 mmol) and hexane-2,5-
dione (1.1 mmol) in THF (5 mL) at room temperature, iodine was
added (0.1 mmol). The mixture was stirred at this temperature for
24 hours. Dichloromethane (20 mL) was added to this mixture.
The resulting mixture was washed successively with 5% Na2S2O3
solution (2 mL), saturated NaHCO3 solution (2 mL)and brine (2
mL). The organic layer was dried with sodium sulfate and
concentrated. The slurry was purified using column chroma-
tography on silica gel, eluent hexane-ethyl acetate (9:1).
Method B. To a suspension of NCS (1.5 equiv. and 3 equiv.)
in hexane (5 mL) were added 2-(2,5-dimethyl-1H-pyrrol-1-
yl)thiophene derivtive 2a-c (2 mmol) and 70% HClO4 (1 mol %)
and the reaction mixture was stirred overnight at room
temperature. Potassium carbonate (ca. 10 mg) was added and the
solids were filtered off. The solvent was evaporated to get crude
5a-c. Purification on column using silica gel, eluent hexane-ethyl
acetate (9:1).
Methyl 2-(3,4-dichloro-2,5-dimethyl-1H-pyrrol-1-yl)-4-
methylthiophene-3-carboxylate (5a). Reaction run using 2a
(500 mg, 2 mmol) and N-chlorosuccinimide (400 mg, 3 mmol
and 800 mg, 6 mmol) to provide 5a as yellow solid in yields
listed in Table 2 (133 mg and 180 mg by method A, 127 mg and
160 mg by method B), mp = 74-76°C. 1H NMR (CDCl3): ꢀ 6.95
(s, 1H, 5-H), 3.58 (s, 3H, CO2CH3), 2.21 (s, 3H, CH3), 2.15 (s,
6H, 2xCH3). 13C (CDCl3,): ꢀ 158.0 (CO), 145.2 (C-2), 138.6 (C-
4), 136.6 (C-3), 129.8 (C-2´, C-5´), 123.2 (C-5), 108.9 (C-3´, C-
4´), 51.2 (CO2CH3), 11.7 (CH3), 11.9 (2xCH3). Anal. calcd. For
C13H13Cl2NO2S (318.2): C, 49.07; H, 4.12; N, 4.40. Found: C,
49.22; H, 4.15; N, 4.45.
Methyl 2-(3,4-dichloro-2,5-dimethyl-1H-pyrrol-1-yl)thio-
phene-3-carboxylate (5b). Reaction run using 2b (470 mg, 2
mmol) and N-chlorosuccinimide (400 mg, 3 mmol and 800 mg,
6 mmol) to provide 5b as light yellow solid in yields given in
Table 2 (140 mg and 164 mg by method A, 122 mg and 134 mg
by method B), mp = 80-83°C. 1H NMR (CDCl3,): ꢀ 7.48 (d, 1H,
J = 5.6 Hz, H-4), 7.28 (d, 1H, J = 5.6 Hz, H-3), 3.72 (s, 3H,
CO2CH3), 1.96 (s, 6H, 2xCH3). 13C (CDCl3,): ꢀ 159.7 (CO),
144.5 (C-2), 132.6 (C-3), 129.7 (C-2´, C-5´), 126.8 (C-5), 124.1
(C-4), 108.1 (C-3´, C-4´), 50.9 (CO2CH3), 11.7 (CH3), 11.5
(CH3). Anal. Calcd. For C12H11Cl2NO2S (304.19): C, 47.38; H,
3.64; N, 4.60. Found: C, 47.45; H, 3.75; N, 4.75.
Methyl 4-methyl-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiophene-
3-carboxylate (2a). Reaction run using methyl 2-amino-4-
methylthiophene-3-carboxylate (170 mg, 1 mmol) and hexane-
2,5-dione (137 mg, 0.14 mL, 1.2 mmol) in all three methods.
Reactions provided 2a as a pale yellow crystalline product in
yields given in Table 1 (95 mg by method A, 104 mg by
1
method B, 100 mg by method C), mp = 81-84°C. H NMR
(CDCl3,):ꢀ 6.88 (s, 1H, 5-H), 5.86 (s, 2H, 3´-H, 4´-H), 3.64 (s,
3H, CO2CH3), 2.43 (s, 3H, CH3), 2.01 (s, 6H, 2xCH3). 13C
(CDCl3): ꢀ 160.0 (CO), 145.0 (C-2), 139.0 (C-4), 137.2 (C-3),
127.6 (C-2´, C-5´), 123.0 (C-5), 107.0 (C-3´), 106.9 (C-4´), 52.0
(CO2CH3), 11.7 (CH3), 11.5 (CH3), 11.1 (CH3). Anal. Calcd. for
C13H15NO2S (249.3): C, 62.62; H, 6.06; N, 5.62. Found: C,
62.99; H, 5.93; N, 6.08.
Methyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)thiophene-3-carbox-
ylate (2b). Reaction run using methyl-2-aminothiophene-3-
carboxylate (157 mg, 1 mmol) and hexane-2,5-dione (137 mg,
0.14 mL, 1.2 mmol) in all three methods. Reactions provided 2b
as yellowish crystalline product in yields given in Table 1 (106
mg by method A, 113 mg by method B, 101 mg by method C),
mp = 101-103 °C. 1H NMR (CDCl3): ꢀ 7.46 (d, 1H, J = 5.6 Hz,
4-H), 7.22 (d, 1H, J = 5.6 Hz, 5-H), 5.91 (s, 2H, 3´-H, 4´-H),
3.72 (s, 3H, CO2CH3), 2.01 (s, 6H, 2xCH3). 13C (CDCl3,): ꢀ
161.0 (CO), 144.0 (C-2), 135.2 (C-3), 128.1 (C-2´), 127.3 (C-
5´), 126.5 (C-5), 123.0 (C-4), 107.2 (C-3´, C-4´), 51.3
(CO2CH3), 11.7 (CH3), 11.3 (CH3). Anal. Calcd. For
C12H13NO2S (235.3): C, 61.25; H, 5.57; N, 5.95. Found: C,
61.44; H, 5.85; N, 5.88.
2-(3-Chloro-2,5-dimethyl-1H-pyrrol-1-yl)-3-carbonitrile
(5c). Reaction run using 2c (405 mg, 2 mmol) and N-
chlorosuccinimide (400 mg, 3 mmol and 800 mg, 6 mmol) to
provide 5c as yellowish solid in yields given in Table 2 (85 mg
and 95 mg by method A, 66 mg and 76 mg by method B), mp =
1
2-(2,5-Dimethyl-1H-pyrrol-1-yl)thiophene-3-carbonitrile
(2c). Reaction run using 2-aminothiophene-3-carbonitril (124 mg,
1 mmol) and hexane-2,5-dione (137 mg, 0.14 mL, 1.2 mmol) in
all three methods. Reactions provided 2c as a light brown oily
product in yields given in Table 1 (107 mg by method A, 101 mg
68-70°C, H NMR (CDCl3,): ꢀ 7.38 (d, 1H, J = 5.7 Hz, 3-H),
7.27 (d, 1H, J = 5.7 Hz, 4-H), 5.98 (s, 1H, 4´-H), 2.08 (s, 3H,
CH3), 2.07 (s, 3H, CH3). 13C (CDCl3): ꢀ 136.7 (C-2), 129.6 (C-
2´), 129.3 (C-5), 129.2 (C-4), 127.0 (C-5´), 116.1 (CN), 111.6
(C-3), 108.7 (C-3), 108 (C-4), 12.3 (CH3), 10.1 (CH3). Anal.
Calcd. For C11H9ClNO2S (236.7): C, 55.81; H, 3.83; N, 11.83.
Found: C, 56.01; H, 3.95; N, 11.60.
1
by method B, 101 mg by method C), mp = 90-92°C. H NMR
(CDCl3): ꢀ 7.36 (d, 1H, J = 5.7 Hz, 3-H), 7.22 (d, 1H, J = 5.7 Hz,
4-H), 5.95 (s, 2H, 3´-H, 4´-H), 2.11 (s, 6H, 2xCH3). 13C (CDCl3):
ꢀ137.0 (C-2), 130.4 (C-5), 129.5 (C-4), 127.3 (C-2´, C-5´), 115.3
(CN), 111.8 (C-3), 106.5 (C-3´, C-4´), 12.8 (CH3), 11.9 (CH3).
Anal. calcd. For C11H10NO2S (202.3): C, 65.32; H, 4.98; N, 13.85.
Found: C, 65.74; H, 4.85; N, 14.08.
Step III. Acetylation
Procedure. Acetic anhydride (180 mg, 0.185 mL, 2 mmol),
starting aminothiophene 1a-c (2 mmol) and 1 mol% of
Mg(ClO4)2.2H2O were heated at reflux for 3 hours. After cooling
down to room temperature the precipitated crude product was
collected by filtration and washed with water. After
recrystallization from aqueous methanol (1:1) acetylated
derivatives 6a-c were obtained.
Step II. Chlorination.
Method A. To a mixture of starting 2-(2,5-dimethyl-1H-
pyrrol-1-yl)thiophene derivtive 2a-c (2 mmol) in dry acetonitrile

206
Z. Puterová, T. Bobula and D. Végh
Vol 45
Methyl-2-acetamido-4-methylthiophene-3-carboxylate (6a).
Step V. Transamination.
Reaction run using methyl-2-aminothiophene-3-carboxylate (1a)
(340 mg, 2 mmol) and provided 405 mg of acetylated derivative
6a (95%). C9H11NO3S (213.25), mp = 100-101°C, 1H NMR
(CDCl3): ꢀ 11.26 (br s, 1H, NH), 6.38 (s,1H, 5-H), 3.87 (s, 3H,
CO2CH3), 2.34 (s, 3H, COCH3), 2.26 (s, 3H, CH3). 13C (CDCl3,):
ꢀ 180.1 (C-2), 168.0 (COCH3), 161.0 (CO2CH3), 139.1 (C-4),
111.8 (C-5), 98.6 (C-3), 52.4 (CO2CH3), 22.6 (COCH3), 11.4
(CH3).
Procedure. Hexane-2,5-dione (1.2 mmol) was added to a
mixture of 2-acetamido-5-chloro-thiophene derivative 7a-c (1
mmol) and p-TsOH (1 mol%) and conc. HCl (1 mol%) in
xylene (30 mL/mmol of acetamide 7). Reaction was stirred in
refluxing xylene for 8 hours utilizing Dean-Stark trap for
removal of forming acetic acid and water. After cooling down to
room temperature the mixture was washed with saturated
solution of NaHCO3 (2x20mL), water (2x20mL) and aqueous
NaCl. The toluene phase was dried over Na2SO4. The products
3a-c were purified by column chromatography, eluent hexane-
ethyl acetate (9:1).
Methyl-2-acetamidothiophene-3-carboxylate (6b). Reaction
run using methyl-2-aminothiophene-3-carboxylate (1b) (314
mg, 2 mmol) and provided 362 mg of acetylated derivative 6b
(91%). C8H9NO3S (199.23), mp
=
196-201°C, 1H NMR
Methyl 5-chloro-4-methyl-2-(2,5-dimethyl-1H-pyrrol-1-yl)-
thiophene-3-carboxylate (3a). Reaction run using 248 mg of 7a
to give 145 mg (51%) of light yellow crystalline product 3a, mp
(CDCl3): ꢀ 10.97 (br s, 1H, NH), 7.24 (d, 1H, J4,5 = 5.6 Hz, 4-H),
6.73 (d, 1H, J4,5 = 5.6 Hz, 5-H), 3.87 (s, 3H, CO2CH3), 2.26 (s,
3H, COCH3). 13C (CDCl3,): ꢀ 178.3 (C-2), 168.8 (COCH3),
161.0 (CO2CH3), 122.4 (C-4), 118.6 (C-3), 114.5 (C-5), 50.7
(CO2CH3), 23.8 (COCH3).
1
= 70-72°C. H NMR (CDCl3): ꢀ 5.90 (s, 2H, 3´-H, 4´-H), 3.91
(s, 3H, CO2CH3), 2.80 (s, 6H, 2xCH3), 2.32 (s, 3H, CH3). 13C
(CDCl3): ꢀ 160.0 (CO2CH3), 146.5 (C-2), 136.5 (C-4), 135.2 (C-
3), 128.0 (C-2´, C-5´), 124.6 (C-5), 107.1 (C-3´, C-4´), 48.9
(CO2CH3), 11.2 (CH3) 12.6 (2xCH3). Anal. Calcd. For
C13H14ClNO2S (283.77): C, 55.02; H, 4.97; N, 4.94. Found: C,
55.40; H, 4.63; N, 4.39.
N-(3-Cyanothiophen-2-yl)acetamide (6c). Reaction run
using 2-aminothiophene-3-carbonitril (1c) (248 mg, 2 mmol)
and provided 309 mg of acetylated derivative 6c (93%).
1
C7H6N20S (166.2), mp = 167-170°C, H NMR (CDCl3,): ꢀ11.2
(br s, 1H, NH), 7.06 (d, 1H, J = 6.0 Hz, 4-H), 6.87 (d, 1H, J =
6.0 Hz, 5-H), 2.32 (s, 3H, CH3). 13C (CDCl3,): ꢀ 167.2 (COCH3),
151.0 (C-2), 128.2 (C-4), 117.1 (C-5), 114.9 (CN), 97.3 (C-3),
22.9 (CH3).
Methyl 5-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiophene-
3-carboxylate (3b). Reaction run using 234 mg of 7b to give
130 mg (48%) of pale yellow crystalline product 3b., mp = 82-
84°C. 1H NMR (CDCl3,): ꢀ 7.27 (s, 1H, 4-H), 5.90 (s, 2H, 3´-H,
4´-H), 3.70 (s, 3H, CO2CH3), 2.04 (s, 6H, 2xCH3). 13C (CDCl3,):
ꢀ 162.0 (CO2CH3), 146.2 (C-2), 133.2 (C-4), 131.3 (C-3), 129.0
(C-5), 127.1 (C-3´, C-5´), 106.4 (C-3´, C-4´), 49.8 (CO2CH3),
12.2 (2xCH3). Anal. Calcd. For C12H12ClNO2S (269.75): C,
53.43; H, 4.48; N, 5.19. Found: C, 53.30; H, 4.32; N, 4.54.
5-Chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiophene-3-carbo-
nitrile (3c). Reaction run using 201 mg of 7c to give 109 mg (46%)
Step IV. Chlorination of acetylated derivatives.
Procedure. To
a solution of 2-acetylaminothiophene
derivative 6a-c (1.5 mmol) in 5 mL of glacial acetic acid N-
chlorosuccinimide (214 mg, 1.6 mmol) was added. Mixture was
refluxed for 2 hours and after cooling down to room temperature
the solution was poured into water (15 mL) and after standing 2-
4 hours the crystals formed were collected by filtration and
crystallized from methanol.
1
of light brown crystalline product 3c, mp = 79-81°C. H NMR
(CDCl3,): ꢀ 6.87 (s, 1H, 4-H), 5.78 (s, 2H, 3´-H, 4´-H), 2.12 (s, 6H,
2xCH3). 13C (CDCl3,): ꢀ 138.3 (C-2), 131.2 (C-5), 127.5 (C-2´, C-
5´), 124.6 (C-4), 115.7 (CN), 110.8 (C-3), 106.7 (C-3´, C-4´), 12.0
(2xCH3). Anal. Calcd. For C11H9ClN2S (236.72): C, 55.81; H, 3.83;
N, 11.83. Found: C, 55.70; H, 3.64; N, 11.96.
Methyl 2-acetamido-5-chloro-4-methylthiophene-3-carb-
oxylate (7a). Reaction run using 6a (320 mg) and yielded 268
1
mg (72%) of 7a as brownish powder, mp = 142-145 °C. H
NMR (CDCl3, ꢀ): ꢀ 11.5 (br s, 1H, NH), 3.90 (s, 3H, CO2CH3),
2.34 (s, 3H, CH3), 2.25 (s, 3H, COCH3). 13C (CDCl3) ꢀ 180.0 (C-
2), 168.7 (COCH3), 158.9 (CO2CH3), 135.6 (C-4), 114.2 (C-5),
96.8 (C-3), 49.7 (CO2CH3), 21.6 (CH3). Anal. Calcd. For
C9H10ClNO3S (247.7): C, 40.88; H, 3.92; N, 6.81. Found: C,
49.01; H, 3.97; N, 6.60.
Step VI. Deprotection.
A round-bottomed flask was charged with 5-chloro-2-(2,5-
dimethyl-1H-pyrrol-1-yl)thiophene derivative 4a-c (0.5 mmol),
hydroxylamine dihydrochloride (1.5 g, 30 equiv.,15 mmol) and
triethylamine (4.0 mL, 20 equiv., 10 mmol), n-butanol (6 mL)
and water (1 mL), then warmed to 80°C and stirred at this
temperature for 60 hours. After cooling down to room
temperature saturated solution of NaHCO3 was added slowly to
a mixture to increase the pH to basic (10-12) - caution, during
the addition of NaHCO3 the mixture foams heavily. The mixture
was stirred for another 30 minutes. The formed solid was filtered
off, washed with dichloromethane. The aqueous phase was then
separated from organic phase and extracted with dichloro-
methane (2x10 mL). Combined organic extracts were
concentrated to provide an oily solid. Crude mixture of the
product and acetonylacetone related by-products of the
deprotection were separated using column chromatography,
eluent: dichloromethane.
Methyl 2-acetamido-5-chloro-3-carboxylate (7b). Reaction
run using 6b (299 mg) and yielded 242 mg (69%) of 7b as pale
brown powder, mp = 109-111°C. 1H NMR (CDCl3): ꢀ 10.92 (br
s, 1H, NH), 7.15 (s, 1H, 4-H), 3.88 (s, 3H, CO2CH3), 2.29 (s,
3H, COCH3). 13C (CDCl3,): ꢀ 177.6 (C-2), 167.9 (COCH3),
158.7 (CO2CH3), 130.1 (C-4), 117.4 (C-3), 116.8 (C-5), 50.0
(CO2CH3), 22.8 (COCH3). Anal. Calcd. For C8H8ClNO3S
(233.67): C, 37.60; H, 3.16; N, 7.31. Found: C, 37.36; H, 3.27;
N, 7.45.
N-(5-Chloro-3-cyanothiophen-2-yl)acetamide (7c).
Reaction run using 6c (249 mg) and yielded 222 mg (74%) of 7c
1
as ash-grey powder., mp = 121-125°C, H NMR (CDCl3,): ꢀ
10.95 (br s, 1H, NH), 7.02 (s, 1H, 4-H), 2.22 (s, 3H, COCH3).
13C (CDCl3): ꢀ 168.5 (COCH3), 150.0 (C-2), 124.4 (C-4), 120.0
(C-5), 115.5 (CN), 95.4 (C-3), 21.9 (COCH3). Anal. Calcd. For
C7H5ClN2OS (200.65): C, 37.86; H, 1.91; N, 17.66. Found: C,
37.51; H, 1.85; N, 17.42.
Methyl 5-chloro-2-amino-4-methylthiophene-2-carboxyl-
ate (2a). Reaction run using 142 mg of 3a to yield 31 mg (30%)
1
of 2a as an orange solid, mp = 59-63°C. H NMR (CDCl3,): ꢀ

Jan-Feb 2008
Synthesis of Novel 5-Chlorinated 2-Aminthiophenes
using 2,5-Dimethylpyrrole as an Amine protecting group
207
[6] Gewald, K.; Schnike, E.; Bottcher, H. Chem. Ber. 1966, 99,
8.75 (br s, 2H, NH2), 3.70 (s, 3H, CO2CH3), 2.75 (s, 3H, CH3).
13C (CDCl3,): ꢀ 163.7 (C-2), 158.2 (CO2CH3), 135.9 (C-4), 124.6
(C-5), 112.0 (C-), 54.3 (CO2CH3), 2.7 (CH3). Anal. Calcd. For
C7H8ClNO2S (205.66): C, 40.88; H, 3.92; N, 6.81. Found: C,
40.70; H, 3.75; N, 6.88.
Methyl 2-amino-5-chlorothiophene-2-carboxylate (2b).
Reaction run using 117 mg of 3a to yield 29 mg (34%) of 2b as
an yellow solid, mp = 65-67°C. 1H NMR (CDCl3,): ꢀ 8.50 (br s,
2H, NH2), 7.36 (s, 1H, 4-H), 3.43 (s, 3H, CO2CH3). 13C
(CDCl3,): ꢀ 160.9 (C-2), 158.9 (CO2CH3), 134.1 (C-3), 131.0
(C-4), 128.3 (C-5), 50.3 (COCH3). Anal. Calcd. For
C6H6ClNO2S (191.64): C, 37.60; H, 3.16; N, 7.31. Found: C,
37.72; H, 3.20; N, 7.40.
94.
[7] Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J.
Heterocyclic. Chem. 1999, 36, 333.
[8] Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Y.;
Mikhalina, T. V.; Troitskaya, T. I.; Flinn, A. SYNLETT 2006, 16, 2559.
[9] Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M.
A.; Mei, J.; Tedrow, J. S.; Riva Toma, J. D. Tetrahedron 2006, 62,
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Knop, J. V. J. Chem. Soc. Perkin Trans. 2, 1997, 2597.
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2-Amino-5-chlorothiophene-3-carbonitrile (3c). Reaction
run using 118 mg of 3c to yield 22 mg (28 %) of 2c as a light
brown solid, mp = 75-77°C. 1H NMR (CDCl3,): ꢀ 8.20 (br s, 2H,
NH2), 6.83 (s, 1H) ppm. 13C (CDCl3,): ꢀ 138.6 (C-2), 131.1 (C-
5), 126.0 (C-4), 115.7 (CN), 108.2 (C-3). Anal. Calcd. For
C5H3ClN2S (158.61): C, 37.60; H, 3.16; N, 7.31. Found: C,
37.72; H, 3.20; N, 7.40.
Acknowledgements. This work was supported by the Slovak
Ministry of Education Grants No: 1/4453/07 and by Science and
Technology Assistance Agency under the contract No. APVT-
20-007304. Z.P appreciates Dr. Peter Zálupskꢀ for correcting the
manuscript.
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