Regioselective acylation of methyl 2-methyl-4H-thieno[3,2-b]pyrrole-5- carboxylate

Article abstract of DOI:10.1023/A:1023435605723

The influence of catalysts, acid chlorides, and solvents on the acylation of methyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate was studied. The use of AlCl₃ allows the regioselective introduction of the acyl group into position 3 to be performed, whereas the acyl group is regioselectively introduced into position 6 of thienopyrrole when SnCl₄ is used.

Full text of DOI:10.1023/A:1023435605723

Russian Chemical Bulletin, International Edition, Vol. 52, No. 2, pp. 451—456, February, 2003
451
Regioselective acylation of methyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylate
ꢀ
V. N. Yarovenko, S. L. Semenov, I. V. Zavarzin, A. V. Ignatenko, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: yarov@mail.ioc.ac.ru
The influence of catalysts, acid chlorides, and solvents on the acylation of methyl 2ꢀmethylꢀ
4
Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate was studied. The use of AlCl allows the regioselective
3
introduction of the acyl group into position 3 to be performed, whereas the acyl group is
regioselectively introduced into position 6 of thienopyrrole when SnCl is used.
4
Key words: thienopyrroles, regioselective acylation, ionic liquid.
Thienopyrroles are thio analogs of indoles and, hence,
are of great interest for syntheses of various biologically
active compounds. Considerable attention is presently
given to the synthesis of physiologically active compounds
from esters of 4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylic
acid.1
acylation of methyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ
5ꢀcarboxylate (3а) (Scheme 2). Compounds 3b,c were
synthesized for unambiguous interpretation of NMR specꢀ
tra of the isomers formed upon acylation of ester 3а.
Thienopyrrole 3а can exist as two rotamers (3а´ and
3а″) stabilized by the intramolecular hydrogen bond.
—3
Taking into account the electronꢀexcessive nature of
thienopyrroles, they are modified, as a rule, using electroꢀ
philic processes. However, regioselective reactions with
thienopyrroles bearing free positions in both the thiophene
and pyrrole cycles are a serious and yet poorly studied
problem.
4
In this work, using a described method, we carried
out condensations of thiophenecarbaldehydes 1 with meꢀ
thyl azidoacetate to form esters of 2ꢀazidoꢀ3ꢀ(2ꢀthiꢀ
enyl)acrylic acids, which produced thienopyrrolecarbꢀ
oxylates 3 (Scheme 1) and studied the regioselectivity of
The IR spectrum of thienopyrrole 3а exhibits one band
with the frequency ν(NH) = 3466 cm . Since the IR
spectrum of ethyl 1Hꢀpyrroleꢀ2ꢀcarboxylate is known to
–
1
have two absorption bands with the frequencies ν(NH) =
Scheme 1
–1
3
465 and 3482 cm , which are assigned to rotamers with
the intramolecular hydrogen bond of the pyrrole nitrogen
5
atom with the keto or ester group, respectively, we can
conclude that thienopyrrole 3a exists in the form of 3a´.*
Also note that, according to the Xꢀray diffraction data,
the pyrrole nitrogen atom in ethyl 4Hꢀfuran[3,2ꢀb]pyrroleꢀ
5
ꢀcarboxylate is bound to the carbonyl group of the ester
6
fragment.
Since a molecule of thienopyrrole 3a has several reacꢀ
tion centers, we studied the influence of the nature
of catalysts, reactants, and solvents on the acylation
process.
*
The authors thank E. D. Lubuzh for help in recording and
1
2
1
2
R = Me, R = H (a), Br (b); R = R = H (c)
interpretation of the IR spectra of thienopyrrole 3a.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 431—435, February, 2003.
066ꢀ5285/03/5202ꢀ451 $25.00 © 2003 Plenum Publishing Corporation
1

452
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Yarovenko et al.
Scheme 2
i
R = Me (a), Et (b), ClCH (c), Cl CH (d), Cl C (e), Pr (f)
2
2
3
The results of acylation in dichloroethane, nitroꢀ
when two or three equivalents of AlCl and acyl halide are
3
methane, and ionic liquid, viz., 1ꢀbutylꢀ3ꢀmethylimidꢀ
used (entries 1—7). The AlCl complexes formed at the
3
azolium heptachloroaluminate(III) [bmim][Al Cl ], at difꢀ
ester and acyl groups prevent, most likely, the interaction
of acid chloride with the pyrrole ring of the initial ester 3a
and acylation products 4a—f.
2
7
ferent ratios of acyl halide, AlCl , SnCl , and thienoꢀ
3
4
pyrrole 3a are presented in Table 1.
It is seen from the data in Table 1 that acylation in
dichloroethane is regioselective to the thiophene cycle
When equimolar amounts of the reactants are used in
both nitromethane and dichloroethane, the formation of
Table 1. Acylation of thienopyrrole 3a
Entry
Acyl
halide
Molar
ratioa
Solvent
Composition of acylation
products (%)
4
a—f : 6a : 5
1
2
3
4
5
6
7
8
9
MeCOCl
MeCOCl
EtCOCl
1 : 1 : 2.1 b
2.1 : 1 : 3.1
Cl(CH ) Cl
100 (4a) : 0 : 0
100 (4a) : 0 : 0
100 (4b) : 0 : 0
100 (4c) : 0 : 0
100 (4d) : 0 : 0
100 (4e) : 0 : 0
100 (4f) : 0 : 0
25 (4a) : 0 : 75
10 (4a) : 0 : 90
40 (4a) : 60 : 0
35 (4a) : 0 : 60
100 (4a) : 0 : 0
100 (4c) : 0 : 0
35 (4a) : 0 : 65
0 (4a) : 20 : 80
0 (4a) : 100 : 0
0 (4a) : 0 : 100
2
2
b
Cl(CH ) Cl
2
2
1 : 1 : 2.1 b
Cl(CH ) Cl
2 2
b
ClCH COCl 1 : 1 : 2.1
Cl(CH ) Cl
2
2 2
Cl CHCOCl 1 : 1 : 2.1 b
Cl(CH ) Cl
2
2 2
Cl CCOCl
1 : 1 : 2.1 b
Cl(CH ) Cl
3
2 2
i
b
Pr COCl
1 : 1 : 2.1
Cl(CH ) Cl
2
2
MeCOCl
MeCOCl
MeCOCl
MeCOCl
MeCOCl
1 : 1 : 1.1 b
Cl(CH ) Cl
2
2
b
1 : 1 : 1.1
MeNO2
10
11
12
13
14
15
16
17
3.1 : 1 : 5 b
1.1 : 1 : 1.1
Cl(CH ) Cl
2 2
c
Cl(CH ) Cl
2
2
b,d
1.1 : 1 : 2
[bmim][Al Cl ]
2 7
b,d
ClCH COCl 1.1 : 1 : 2
[bmim][Al Cl ]
2
2
7
e
e
e
MeCOCl
MeCOCl
MeCOCl
MeCOCl
1.1 : 1 : 1.1
2.1 : 1 : 2.1
2.1 : 1 : 4.1
Cl(CH ) Cl
2
2
Cl(CH ) Cl
2
2
Cl(CH ) Cl
2
2
e
1 : 1 : 2.1
Cl(CH ) Cl
2 2
a
b
c
Acyl halide : thienopyrrole 3a : Lewis acid.
Lewis acid is AlCl3.
Lewis acid is AlBr3.
d
e
No AlCl was added in excess of the amount contained in the Al Cl anion.
3
2
7
Lewis acid is SnCl4.

Regioselective acylation of thieno[3,2ꢀb]pyrrole
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
453
product 5 becomes predominant because thienopyrrole,
which is not bound to the catalyst, enters into the reacꢀ
tion under these conditions (entries 8 and 9). It is of
thiophene cycle of thienopyrrole 3a in the presence of
AlCl in dichloroethane (products 4b—e) and then anꢀ
3
other introduction into the pyrrole ring in the presence of
interest that the use of a significant excess of AlCl and
SnCl in nitromethane. The latter reaction does not occur
3
4
acetyl chloride also results in the acylation of the pyrrole
cycle to form diacylation product 6a (entry 10). This is
in dichloroethane, which poorly dissolve complexes of
compounds 4b—e with the catalyst.
possibly reasoned by the formation of the AlCl complex
Acetylation at the pyrrole nitrogen atom of thienoꢀ
pyrrole 3a was successful in the presence of potassium
tertꢀbutoxide (product 7).
3
at the thiophene cycle, which also decreases the relative
reactivity of the latter. Diketone 6a is not formed by the
acetylation of 3ꢀacetylthienopyrroleꢀ5ꢀcarboxylate 4a in
the presence of AlCl3 but can be synthesized from
keto ester 5. This indicates that the reaction leadꢀ
ing to the diacetylꢀsubstituted compound 6a begins
from the introduction of the acetyl group into the pyrrole
cycle.
The structures of the synthesized compounds were
1
13
proved by the data of H and C spectroscopy, elemental
analysis, and chemical transformations.
The ratios of ketones resulting from acylation were
determined from the ratio of intensities of signals from
1
the pyrrole, thiophene, and ester protons. The H NMR
The use of a stronger Lewis acid (AlBr ) in equimolar
amounts with acetyl chloride and thienopyrrole decreases
the formation of the product of acylation at the pyrrole
spectrum of thienopyrrole 7 acylated at the nitrogen
atom contains signals from both rings of the diheteroꢀ
cycle, and the signal of the proton at the nitrogen atom is
absent.
3
cycle compared to that formed when AlCl is used. This is
3
likely related to an increase in the volume of the acylating
complex and an enhancement of its reactivity (entry 11).
The acylation of thienopyrrole 3a with acyl halides
in 1ꢀbutylꢀ3ꢀmethylimidazolium heptachlorodialumiꢀ
nate(III) affords in high yields only products of substituꢀ
tion at the thiophene cycle (entries 12 and 13). When
The signals in the 13С NMR spectrum of thienopyrrole
3с were completely assigned from their multiplicity in the
gated regime. This assignment exactly coincided with the
1
13
data of the { H and C} correlation spectrum by farꢀ
range spinꢀspin coupling constants. The signals in comꢀ
pounds 3а, 4a, and 5 were assigned based on the data for
ester 3с using the additive scheme taking into account the
1
equiv. of SnCl , which is a weaker Lewis acid than
4
13
AlCl , and 1 equiv. of acetyl chloride in dichloroethane
influence of substituents on the chemical shifts of С in
3
7
8
are used, a smaller amount of keto ester 5 and, correꢀ
spondingly, more keto ester 4a (entry 14) are formed than
in experiments with AlCl . The use of 2 equiv. of SnCl
thiophenes and pyrroles (Table 2).
The structure of keto ester 5 was chemically confirmed
by its transformation into pyridazinone 8 under the action
of hydrazine.
3
4
and 2 equiv. of acetyl chloride makes it possible to inꢀ
crease the yield of keto ester 5 with the additional formaꢀ
tion, however, of diacylation product 6a (entry 15). Only
diacetylꢀsubstituted ester 6a forms in the presence of
4
equiv. and more of SnCl and 2 equiv. of acetyl chloride
4
(
entry 16). We succeeded to selectively synthesize monoꢀ
keto ester 5 when using 2 equiv. of SnCl and 1 equiv. of
4
acetyl chloride (entry 17).
Thus, the use of SnCl allows the regioselective acetyꢀ
4
lation of the pyrrole cycle to be performed with the forꢀ
mation of diacetylꢀsubstituted ester 6a in one step.
The target synthesis of various mixed diacylꢀsubstiꢀ
tuted derivatives 6b—e was performed by the successive
regioselective introduction of one acyl group into the
Thus, we developed the methods for regioselective
introduction of acyl groups into different positions of
thienopyrrole 3а. It was shown that the position of acyl
groups in the reaction products can unambiguously be
determined from the NMR spectroscopic data.
Table 2. 13C NMR spectra (δ) of thienopyrroles 3a,c, 4a, and 5
Comꢀ С(2)
pound
С(3)
С(5)
С(6)
С(7)
С(8)
С(O)O OMe
2ꢀMe
3ꢀMeC(O)
6ꢀMeC(O)
Me C(O)
Me
C(O)
3
3
4
5
a
c
a
143.8
129.7
153.2
145.6
110.3
111.8
126.0
109.7
124.7
126.2
123.5
124.8
107.4
107.2
107.5
123.4
121.9
123.3
119.3
121.4
142.1
142.4
140.1
138.7
161.4
161.3
160.9
160.3
51.2
51.4
51.5
51.3
16.6
—
17.6
16.4
—
—
30.8
—
—
—
192.7
—
—
—
—
—
—
—
30.2
193.2

454
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Yarovenko et al.
Experimental
Methyl 4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylates (3а—c)
general procedure). A solution of methyl 2ꢀazidoꢀ3ꢀ(2ꢀthiꢀ
(
enyl)acrylate 2a—c (30 mmol) in toluene (10—15 mL) was reꢀ
fluxed for 3 h. A precipitate that formed was filtered off, and the
mother liquor was concentrated in vacuo and recrystallized from
toluene. The residues were combined.
1H NMR spectra were recorded on Bruker WMꢀ200
(
200 MHz) and Bruker WMꢀ250 (250 MHz) instruments in
1
13
DMSOꢀd and СDCl relatively to HMDS. { H and C} correꢀ
6
3
lation spectra by longꢀrange spinꢀspin coupling constants were
obtained on a Bruker DRXꢀ500 instrument. Mass spectra were
recorded on a Varian MAT CHꢀ6 instrument with direct injecꢀ
tion of a sample into the ion source, an ionization energy of
Methyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate
(3а). The yield was 95%, m.p. 189—190 °С (from toluene). MS,
+
1
m/z: 195 [M] . Н NMR (CDCl ), δ: 2.54 (s, 3 Н, Me); 3.82 (s,
3
3 Н, MeО); 6.65 (s, 1 Н, СНarom); 7.06 (s, 1 Н, СНarom);
9.25 (br.s, 1 Н, NH). Found (%): С, 55.40; H, 4.65; N, 7.23;
S, 16.53. C H NO S. Calculated (%): С, 55.37; H, 4.65; N, 7.17;
7
0 eV, and an accelerating voltage of 1.75 kV. Melting points
were measured on a Boetius heating stage and were not corꢀ
rected. Reaction mixtures were analyzed and purity of isoꢀ
lated products was monitored by TLC on Silufol UVꢀ254
plates using an AcOEt—hexane (1 : 3, vol/vol) mixture as
eluent.c
9
9
2
S, 16.42.
Methyl 3ꢀbromoꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarbꢀ
oxylate (3b). The yield was 93%, m.p. 163—165 °С (from toluꢀ
+
1
ene). MS, m/z: 195 [M] . Н NMR (CDCl ), δ: 2.54 (s, 3 Н,
3
IR spectra were recorded on a Specord Mꢀ80 instrument in
Me); 3.82 (s, 3 Н, MeО); 6.65 (s, 1 Н, СНarom); 7.06 (s, 1 Н,
СНarom); 9.25 (br.s, 1 Н, NH). Found (%): С, 39.53; H, 2.93;
Br, 29.15; N, 5.19; S, 11.82. C H BrNO S. Calculated (%):
–
1
the 3600—3000 and 1800—1600 cm frequency regions (с =
–
1
0
.01 mol L in dichloroethane) in cells with windows of fluoꢀ
9
8
2
rite CaF and d = 0.165 and 3.10 cm, respectively.
С, 39.43; H, 2.94; Br, 29.15; N, 5.11; S, 11.70.
2
In order to synthesize complexes, anhydrous AlCl (SnCl )
Methyl 4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (3с). The
yield was 93%, m.p. 143—145 °С (from toluene). MS, m/z: 181
3
4
was weighted guarding against air moisture and added by reꢀ
quired amounts of thienopyrrole and anhydrous dichloroethane
with slight heating until a suspension formed. The resulting
complexes were rapidly transferred into cells.
+
1
[M] . Н NMR (DMSOꢀd ), δ: 3.81 (s, 3 Н, MeО); 6.99 (dd, 1
6
3
4
Н, СНarom, J = 5.3 Hz, J = 0.73 Hz); 7.11 (s, 1 Н, СНarom);
3
7.52 (d, 1 Н, СНarom
, J = 5.3 Hz); 12.09 (br.s, 1 Н, NH).
Anhydrous dichloroethane was prepared by distillation above
Р О . Commercially available 2ꢀthiophenecarbaldehyde and
Found (%): С, 53.12; Н, 3.90; N, 7.82; S, 17.68. C H NO S.
Calculated (%): С, 53.02; H, 3.89; N, 7.73; S, 17.70.
8
7
2
2
5
5
ꢀmethylꢀ2ꢀthiophenecarbaldehyde were used as initial subꢀ
3ꢀAcyl derivatives of methyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrꢀ
roleꢀ5ꢀcarboxylate (4a—f) (general procedure). Acyl chloride
(0.52 mmol) was added with stirring to a suspension of meꢀ
thyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (0.1 g,
stances in the syntheses of compounds 2a—c. 4ꢀBromoꢀ5ꢀ
methylthiopheneꢀ2ꢀcarbaldehyde and methyl azidoacetate were
synthesized using described procedures.
9
,10
1ꢀButylꢀ3ꢀmethylꢀ
imidazolium heptachlorodialuminate(III) was synthesized acꢀ
cording to a known procedure.11
Methyl 2ꢀazidoꢀ3ꢀ(2ꢀthienyl)acrylates (2a—c) (general proꢀ
cedure). A mixture of sodium methoxide, prepared from Na
0.51 mmol) and AlCl (0.14 g, 1.02 mmol) in dichloroethane
3
(5 mL). The mixture was stirred for 5 h (TLC monitoring),
poured into water, extracted with AcOEt, washed with water
and a saturated aqueous solution of NaCl, and dried with MgSO4.
The solvent was distilled off in vacuo. The product was recrystalꢀ
lized from EtOH.
(1.8 g, 78.3 mmol) and dehydrated MeOH (30 mL), and methyl
azidoacetate (22.8 g, 0.2 mol) was added by the corresponding
thiophenecarbaldehyde (25—45 mmol) with stirring at –5—0 °С.
The mixture was stirred for 30 min at 0 °С and for 2 h at ∼ 20 °C.
Methyl 3ꢀacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarbꢀ
oxylate (4а). The yield was 95%, m.p. 168—170 °С (from EtOH).
+
1
An aqueous solution of saturated NH Cl was added, and the
MS, m/z: 237 [M] . Н NMR (CDCl ), δ: 2.58 (s, 3 Н, Me);
4
3
resulting mixture was stirred for 10 min. The precipitated that
formed was filtered off and dried.
2.82 (s, 3 Н, MeС(О)); 3.90 (s, 3 Н, MeО); 7.02 (s, 1 Н, СН);
9.84 (br.s, 1 Н, NH). Found (%): С, 55.72; H, 4.65; N, 6.05;
S, 13.71. C H NO S. Calculated (%): С, 55.68; H, 4.67;
Methyl 2ꢀazidoꢀ3ꢀ(5ꢀmethylꢀ2ꢀthienyl)acrylate (2a). The
1
3
13
4
+
yield was 76%, m.p. 51 °С (with decomp.). MS, m/z: 223 [M] .
N, 5.90; S, 13.51.
1
H NMR (CDCl ), δ: 2.55 (s, 3 H, Me); 3.80 (s, 3 H, MeО);
Methyl 2ꢀmethylꢀ3ꢀpropionylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylate (4b). The yield was 67%, m.p. 134—136 °С (from
3
6
.74 (s, 1 H, CH); 7.10 (s, 1 H, CHarom); 7.15 (s, 1 H, CHarom).
–
1
+ 1
IR (KBr), ν/cm : 2120 v.s (N ). Found (%): С, 48.52; H, 4.20;
EtOH). MS, m/z: 251 [M] . Н NMR (CDCl ), δ: 1.10 (t, 3 Н,
3
3
N, 19.02; S, 14.81. C H N O S. Calculated (%): С, 48.42;
Me, J = 7 Hz); 2.72 (s, 3 Н, Me); 3.05 (q, 2 Н, CH , J = 7 Hz);
9
9
3
2
2
H, 4.06; N, 18.82; S, 14.36.
3.83 (s, 3 Н, MeО); 7.12 (s, 1 Н, СН); 11.17 (br.s, 1 Н, NH).
Found (%): С, 57.55; H, 5.19; N, 5.77; S, 12.87. C H NO S.
Methyl 2ꢀazidoꢀ3ꢀ(4ꢀbromoꢀ5ꢀmethylꢀ2ꢀthienyl)acrylate
12
13
3
(
3
2b). The yield was 52%, m.p. 91 °С (with decomp.). MS, m/z:
Calculated (%): С, 57.35; H, 5.21; N, 5.57; S, 12.76.
+
1
01 and 303 [M] . Н NMR (CDCl ), δ: 2.45 (s, 3 Н, Me); 3.90
Methyl 3ꢀchloroacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylate (4c). The yield was 77%, m.p. 158—160 °С (from
3
(
(
s, 3 Н, MeО); 6.98 (s, 1 Н, СН); 7.14 (s, 1 Н, СНarom). IR
KBr), ν/cm : 2128 v.s (N ). Found (%): С, 36.00; Н, 2.79;
–
1
+ 1
EtOH). MS, m/z: 271 [M] . Н NMR (DMSOꢀd ), δ: 2.74 (s,
3
6
Br, 26.52; N, 14.05; S, 10.81. C H BrN O S. Calculated (%):
3 Н, Me); 3.84 (s, 3 Н, MeО); 5.16 (s, СН С(О)); 7.14 (s, 1 Н,
9
8
3
2
2
С, 35.78; H, 2.67; Br, 26.45; N, 13.91; S, 10.61.
СН); 11.44 (s, 1 Н, NH). Found (%): С, 48.72; H, 3.70;
Cl, 13.10; N, 5.23; S, 11.92. C H ClNO S. Calculated (%):
С, 48.62; H, 3.71; Cl, 13.05; N, 5.15; S, 11.80.
Methyl 2ꢀazidoꢀ3ꢀ(2ꢀthienyl)acrylate (2с). The yield was
1
1
10
3
+
4
9%, m.p. 43 °С (with decomp.). MS, m/z: 209 [M] .
Found (%): С, 46.12; Н, 3.36; N, 19.02; S, 15.41. C H N O S.
Calculated (%): С, 45.92; H, 3.37; N, 19.11; S, 15.33.
Methyl 3ꢀdichloroacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ
5ꢀcarboxylate (4d). The yield was 67%, m.p. 163—165 °С (from
8
7
3
2

Regioselective acylation of thieno[3,2ꢀb]pyrrole
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
455
+
1
EtOH). MS, m/z: 306 [M] . Н NMR (DMSOꢀd ), δ: 2.74 (s,
3
Methyl 3,6ꢀdiacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylates (6b—e) (general procedure). Methyl 3ꢀacylꢀ2ꢀmeꢀ
thylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate 4b—e (0.3 mmol)
6
Н, Me); 3.84 (s, 3 Н, MeО); 7.20 (s, 1 Н, СН); 7.88 (s, 1 Н,
Cl CH); 11.98 (s, 1 Н, NH). Found (%): С, 43.22; H, 2.95;
2
Cl, 23.24; N, 4.64; S, 10.62. C H Cl NO S. Calculated (%):
and SnCl (0.14 mL, 1.23 mmol) in nitromethane (2 mL) were
1
1
9
2
3
4
С, 43.15; H, 2.96; Cl, 23.16; N, 4.57; S, 10.47.
added by the corresponding acyl halide (0.35 mmol). The mixꢀ
ture was stirred for 3 h (TLC monitoring). The reaction mixture
was poured into water and extracted with AcOEt. The extract
was washed with water and a saturated aqueous solution of NaCl
Methyl 2ꢀmethylꢀ3ꢀtrichloroacetylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ
5
ꢀcarboxylate (4e). The yield was 66%, m.p. 147—149 °С (from
+
1
EtOH). MS, m/z: 341 [M] . Н NMR (DMSOꢀd ), δ: 2.62 (s,
6
3
Н, Me); 3.72 (s, 3 Н, MeО); 7.14 (s, 1 Н, СН); 11.54 (s, 1 Н,
and dried with MgSO . The solvent was distilled off.
4
NH). Found (%): С, 38.92; H, 2.37; Cl, 31.28; N, 4.20; S, 9.61.
C H Cl NO S. Calculated (%): С, 38.79; H, 2.37; Cl, 31.23;
N, 4.11; S, 9.41.
Methyl 6ꢀacetylꢀ2ꢀmethylꢀ3ꢀpropionylꢀ4Hꢀthieno[3,2ꢀb]pyrꢀ
roleꢀ5ꢀcarboxylate (6b). The yield was 62%, m.p. 123—125 °С
1
1
8
3
3
+
1
(from EtOH). MS, m/z: 293 [M] . Н NMR (DMSOꢀd ), δ:
6
Methyl 3ꢀisobutyrylꢀ2ꢀmethylꢀ4Нꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylate (4f). The yield was 63%, m.p. 107—109 °С (from
1.10 (t, 3 Н, Me, J = 6.86 Hz); 2.61 (s, 3 Н, Me); 2.74 (s, 3 Н,
MeС(О)); 3.01 (q, 2 Н, CH , J = 6.82 Hz); 3.92 (s, 3 Н, MeО);
2
+
1
EtOH). MS, m/z: 265 [M] . Н NMR (DMSOꢀd ), δ: 1.08 (s,
11.66 (br.s, 1 Н, NH). Found (%): С, 57.41; H, 5.14; N, 4.88;
S, 11.05. C H NO S. Calculated (%): С, 57.32; H, 5.15;
6
3
Н, Me); 1.11 (s, 3 Н, Me); 2.66 (s, 3 Н, Me); 3.55 (t, 1 Н, CH,
J = 6.68 Hz); 3.83 (s, 3 Н, MeО); 7.13 (s, 3 Н, СНarom); 11.51
s, 1 Н, NH). Found (%): С, 58.90; Н, 5.71; N, 5.31; S, 12.14.
1
4
15
4
N, 4.77; S, 10.93.
(
Methyl
6ꢀacetylꢀ3ꢀchloroacetylꢀ2ꢀmethylꢀ4Hꢀthieꢀ
C13H NO S. Calculated (%): С, 58.85; H, 5.70; N, 5.28;
S, 12.09.
no[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (6c). The yield was 62%, m.p.
145—147 °С (from EtOH). MS, m/z: 382 [M] . Н NMR
15
3
+
1
The influence of the amount of reactants and nature of the
catalyst and solvent on the direction of acylation of thienopyrrole
(DMSOꢀd ), δ: 2.60 (s, 3 Н, Me); 2.75 (s, 3 Н, MeС(О)); 3.94
6
(s, 3 Н, MeО); 5.13 (s, 2 Н, СlСН ); 11.90 (s, 1 Н, NH).
2
3
a was studied under similar conditions.
Acylation of thienopyrrole 3a in the ionic liquid, 1ꢀbutylꢀ3ꢀ
Found (%): С, 49.80; H, 3.86; Cl, 11.32; N, 4.51; S, 10.34.
C H ClNO S. Calculated (%): С, 49.76; H, 3.85; Cl, 11.30;
13
12
4
methylimidazolium heptachlorodialuminate(III). 1ꢀButylꢀ3ꢀ
N, 4.46; S, 10.22.
methylimidazolium heptachlorodialuminate(III) (0.132 g,
Methyl
6ꢀacetylꢀ3ꢀdichloroacetylꢀ2ꢀmethylꢀ4Hꢀthieꢀ
0
.75 mmol) was added by AlCl (0.202 g, 1.52 mmol) with gentle
no[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (6d). The yield was 65%, m.p.
143—145 °С (from EtOH). MS, m/z: 348 [M] . Н NMR
3
+
1
stirring in an argon atmosphere until a homogeneous mixture
formed (the mixture warmed). Acyl chloride (0.77 mmol) was
added to the resulting ionic liquid with stirring under argon. The
mixture was stirred for 15 min, and thienopyrrole 3a (0.146 g,
(DMSOꢀd ), δ: 2.62 (s, 3 Н, Me); 2.72 (s, 3 Н, MeС(О)); 3.95
6
(s, 3 Н, MeО); 7.74 (s, 1 Н, Сl СН); 12.28 (s, 1 Н, NH).
2
Found (%): С, 44.93; H, 3.17; Cl, 20.40; N, 4.12; S, 9.41.
C H Cl NO S. Calculated (%): С, 44.84; H, 3.18; Cl, 20.36;
0
.75 mmol) was added. The mixture was stirred for 2 h, poured
13
11
2
4
into water, and filtered off. Keto esters 4a and 4b were obtained
in 92 and 90% yields, respectively.
N, 4.02; S, 9.21.
Methyl
6ꢀacetylꢀ2ꢀmethylꢀ3ꢀtrichloroacetylꢀ4Hꢀthieꢀ
Methyl 6ꢀacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarbꢀ
oxylate (5). Ester 3a (0.1 g, 0.51 mmol) was added to SnCl4
no[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (6e). The yield was 69%, m.p.
166—168 °С (from EtOH). MS, m/z: 382 [M] . Н NMR
+
1
(
0.063 mL, 0.54 mmol) and acetyl chloride (0.04 mL, 0.57 mmol)
(DMSOꢀd ), δ: 2.60 (s, 3 Н, Me); 2.75 (s, 3 Н, MeС(О)); 3.93
6
in dichloroethane (5 mL). The mixture was stirred for 3 h (TLC
monitoring). The reaction mixture was poured into water, exꢀ
tracted with AcOEt, washed with water and a saturated aqueous
(s, 3 Н, MeО); 11.68 (s, 1 Н, NH). Found (%): С, 44.92;
H, 3.18; Cl, 20.40; N, 4.15; S, 9.30. C H Cl NO S. Calcuꢀ
13
10
3
4
lated (%): С, 44.84; H, 3.18; Cl, 20.36; N, 4.02; S, 9.21.
Methyl 4ꢀacetylꢀ2ꢀmethylꢀ4Нꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarbꢀ
oxylate (7). Thienopyrrole 3a (0.5 g, 2.56 mmol) in anhydrous
solution of NaCl, and dried with MgSO . The solvent was disꢀ
4
tilled off in vacuo. The yield was 93%, m.p. 139—141 °С (from
+
1
t
EtOH). MS, m/z: 237 [M] . Н NMR (CDCl ), δ: 2.58 (s, 3 Н,
dioxane (7 mL) was added by Bu OK (0.345 g, 3.07 mmol), and
3
Me); 2.82 (s, 3 Н, MeС(О)); 3.90 (s, 3 Н, MeО); 7.02 (s, 1 Н,
СН); 9.84 (br.s, 1 Н, NH). Found (%): С, 55.73; H, 4.65;
N, 5.95; S, 13.62. C H NO S. Calculated (%): С, 55.68;
the mixture was stirred for 15 min. Then AcCl (0.22 mL,
3.11 mmol) was added. The reaction mixture was stirred for 2 h
(TLC monitoring), poured into water, extracted with AcOEt,
washed with a saturated aqueous solution of NaCl, and dried
1
1
11
3
H, 4.67; N, 5.90; S, 13.51.
Methyl 3,6ꢀdiacetylꢀ2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀ
carboxylate (6a). Acetyl chloride (0.23 mL, 3.23 mmol) was
added to methyl 2ꢀmethylꢀ4Hꢀthieno[3,2ꢀb]pyrroleꢀ5ꢀcarboxyꢀ
late (0.3 g, 1.54 mmol) and SnCl4 (0.74 mL, 6.31 mmol) in
dichloroethane (10 mL). The mixture was stirred for 3 h (TLC
monitoring). The reaction mixture was poured into water, exꢀ
with MgSO . The solvent was distilled off in vacuo. The yield
4
+
was 89%, m.p. 94—96 °С (from EtOH). MS, m/z: 237 [M] .
1
Н NMR (DMSOꢀd ), δ: 2.55 (s, 3 Н, Me); 2.62 (s, 3 Н, Me);
6
3.82 (s, 3 Н, MeO); 7.14 (s, 3 Н, CHarom); 7.33 (s, 1 Н, СНarom).
Found (%): С, 55.72; Н, 4.67; N, 5.95; S, 13.59. C H NO S.
1
1
11
3
Calculated (%): С, 55.68; H, 4.67; N, 5.90; S, 13.51.
tracted with AcOEt, and dried with MgSO . The solvent was
2,8ꢀDimethylꢀ4,6ꢀdihydroꢀ5Нꢀthieno[2´,3´:4,5]pyrroꢀ
le[2,3ꢀd]pyridazinꢀ5ꢀone (8). Thienopyrrole 4a (0.1 g,
0.42 mmol) in EtOH (10 mL) was added by 85% hydrazine
hydrate (0.1 g, 1.7 mmol). The reaction mixture was heated with
stirring until the precipitate dissolved and stored for 48 h (TLC
monitoring). The resulting mixture was poured into water, and
the precipitate was filtered off and washed with water. The yield
4
distilled off in vacuo. The residue was recrystallized from EtOH.
The yield was 78%, m.p. 141—144 °С (from EtOH). MS, m/z:
+
1
2
79 [M] . Н NMR (CDCl ), δ: 2.60 (s, 3 Н, Me); 2.82 (s, 3 Н,
3
MeС(О)); 2.86 (s, 3 Н, MeС(О)); 4.00 (s, 3 Н, MeО); 10.12
br.s, 1 Н, NH). Found (%): С, 56.12; Н, 4.75; N, 5.12; S, 11.68.
(
C13H NO S. Calculated (%): С, 55.90; H, 4.69; N, 5.01;
13
4
+
S, 11.48.
was 69%, m.p. >250 °С (from EtOH). MS, m/z: 219 [M] .

456
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Yarovenko et al.
1
Н NMR (DMSOꢀd ), δ: 2.48 (s, 3 Н, Me); 2.61 (s, 3 Н, Me);
5. R. A. Jones and A. G. Moritz, Spectrochim. Acta, 1965,
21, 295.
6. P. Sivy, B. Koren, F. Valach, and A. Krutosikova, Acta
Crystallogr., Sect. C (Cr. Str. Comm.), 1988, 44, 2032.
7. S. Gronowitz, I. Johnson, and A. B. Hörnfeldt, Chem.
Scripta, 1975, 7, 211.
6
6
.98 (s, 1 Н, СНarom); 12.18 (s, 1 Н, NH); 12.61 (br.s, 1 Н,
NH). Found (%): С, 54.83; Н, 4.15; N, 19.24; S, 14.70.
C H N OS. Calculated (%): С, 54.78; H, 4.14; N, 19.16;
1
0
9
3
S, 14.62.
8
. R. Abraham, R. Lapper, K. Smith, and J. Unsworth, J. Chem.
Soc., Perkin Trans. 2, 1974, 1004.
References
9
. R. Lantz and A. Hörnfeldt, Chem. Scripta, 1972, 2, 9.
1
1
0. M. O. Foster and H. E. Fierz, J. Chem. Soc., 1908, 93, 72.
1. J. Surette, L. Green, and R Singer, J. Chem. Soc., Chem.
Commun., 1996, 24, 2753.
1
2
3
4
. EP Pat. 252809; Chem. Abstrs., 1985, 110, 135070.
. WO Pat. 9940914; Chem. Abstrs., 1999, 131, 170342.
. WO Pat. 9946268; Chem. Abstrs., 1999, 131, 214301.
. H. Hemetsberger and D. Knittel, Monatsh. Chem., 1972,
Received July 18, 2002;
1
03, 194.
in revised form September 16, 2002