Three-component condensation of 3-aminothiophene-2-carboxylic acid derivatives with aldehydes and Meldrum's acid

Article abstract of DOI:10.1007/s11172-010-0020-8

A convenient method was developed for the synthesis of the previously unknown substituted 6,7-dihydro-4H-thieno[3,2-b]pyridin-5-ones based on the three-component condensation of 3-aminothiophenes, Meldrum's acid, and aromatic aldehydes. 3-Aminothiophenes

Full text of DOI:10.1007/s11172-010-0020-8

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 387—391, February, 2009
387
Threeꢀcomponent condensation of 3ꢀaminothiopheneꢀ2ꢀcarboxylic
acid derivatives with aldehydes and Meldrum´s acid*
B. V. Lichitsky, R. M. Belyi, A. N. Komogortsev, A. A. Dudinov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: mkray@ioc.ac.ru
A convenient method was developed for the synthesis of the previously unknown substiꢀ
tuted 6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]pyridinꢀ5ꢀones based on the threeꢀcomponent condensꢀ
ation of 3ꢀaminothiophenes, Meldrum’s acid, and aromatic aldehydes. 3ꢀAminothiophenes
are easily formed in situ by decarboxylation of 3ꢀaminothiopheneꢀ2ꢀcarboxylic acids in an
acidic medium. Sodium salts of the latter acids were prepared by alkaline hydrolysis of the
corresponding available esters.
Key words: 3ꢀaminothiopheneꢀ2ꢀcarboxylic acids, threeꢀcomponent condensation,
Meldrum’s acid, 3ꢀaminothiophenes, decarboxylation, 6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]pyridinꢀ
5ꢀones.
Earlier, we have developed a procedure for the synꢀ
thesis of fused dihydropyridinones based on the threeꢀ
component condensation of labile 2ꢀaminothiophenes or
2,4ꢀdiaminothiazoles with aldehydes and Meldrum’s
acid.1,2 The obvious advantage of this approach is that it
allows the generation of unstable aminoheterocycles
directly in the reaction medium from 2ꢀaminocarboxylic
acids, which are produced from the corresponding readily
available esters by alkaline hydrolysis.
The aim of the present study was to apply the preꢀ
viously developed approach to the synthesis of unꢀ
known 6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]pyridinꢀ5ꢀones 1
(Scheme 1). Acids 2 containing various substituents
at positions 4 and 5 of the thiophene ring, which are
required for the synthesis of products 1 and which readily
undergo decarboxylation,3—5 were prepared as sodium
salts by alkaline hydrolysis4,6 of readily available corresꢀ
ponding esters 3.
Aminothiophenes are rather labile compounds,7
3ꢀaminothiophene derivatives being more stable than the
corresponding 2ꢀisomers. This allowed us to generalize
the conditions for the synthesis of fused systems based on
these compounds. Thus, the alkaline hydrolysis of all startꢀ
ing esters 3a—d afforded the corresponding sodium salts
4a—d, which were directly used in the reaction. The use
of acetic acid as the solvent resulted in the formation of
acids, their decarboxylation, and the in situ generation
of 3ꢀaminothiophenes 5. It should be noted that in the
reaction of diester 3a, the carboxy group in the α position
with respect to the amino group undergoes regiospecific
decarboxylation. The condensation of aminothiophenes
5 with arylmethylene derivatives 6, which were formed
directly in the reaction mixture from aldehydes and
Meldrum’s acid, afforded the target 6,7ꢀdihydroꢀ4Hꢀ
thieno[3,2ꢀb]pyridinꢀ5ꢀones 1. The proposed scheme of
the reaction involves the Michael addition of 3ꢀaminoꢀ
thiophene 5 to arylmethylene derivative of Meldrum’s
acid 6 followed by the intramolecular cyclization accomꢀ
panied by elimination of CO2 and acetone molecules
(Scheme 2).
The reaction products were obtained as crystalline
compounds. Their structures were confirmed by elemenꢀ
1
1
tal analysis and H NMR spectroscopy. The H NMR
spectra of the products show characteristic signals for the
methine protons at δ 4.28—4.88 and for the nonequivalent
protons of the methylene group at δ 2.76—3.02, which is
in good agreement with the published data1,2 for analoꢀ
gous compounds.
To sum up, we developed a new convenient procedure
for the synthesis of the previously unknown substituted
6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]pyridinꢀ5ꢀones based on the
threeꢀcomponent condensation of 3ꢀaminothiophenes,
Meldrum’s acid, and aromatic aldehydes. 3ꢀAminothioꢀ
phenes are easily formed in situ by decarboxylation of
3ꢀaminothiopheneꢀ2ꢀcarboxylic acids in an acidic
medium. The sodium salts of the latter acids were preꢀ
pared by alkaline hydrolysis of the corresponding readily
available esters.
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 382—386, February, 2009.
1066ꢀ5285/09/5802ꢀ0387 © 2009 Springer Science+Business Media, Inc.

388
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Lichitsky et al.
Scheme 1
Comꢀ
pound
R1
R2
Ar
Comꢀ
pound
2a
R1
R2
Comꢀ
pound
4a
R1
R2
Ph
Ph
SO2Ph
H
CO2H
CO2Me
Ph
Ph
SO2Ph
H
COONa
CO2H
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
SO2Ph
SO2Ph
SO2Ph
H
H
H
H
H
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
2ꢀOEtꢀC6H4
4ꢀ(COOCH3)ꢀC6H4
3ꢀMeOꢀ4ꢀHOꢀC6H3
2ꢀMeOꢀC6H4
Thiophenꢀ3ꢀyl
Thiophenꢀ2ꢀyl
4ꢀOHꢀ3ꢀMeOꢀC6H3
3,4,5ꢀ(MeO)3C6H2
Ph
3a
5a
2b, 3b
2c, 3c
2d, 3d
H
H
H
4b, 5b
4c, 5c
4d, 5d
H
H
H
Ph
Ph
Comꢀ
pound
1a
1b
1c
1d
1e
1g
R1
R2
Ar
Ph
Ph
Ph
Ph
Ph
COOH
COOH
COOH
COOH
COOH
H
2ꢀClꢀC6H4
Pyridinꢀ3ꢀyl
2ꢀOEtꢀC6H4
2ꢀCH3ꢀC6H4
2,5ꢀ(CH3)2ꢀC6H4
2ꢀCH3ꢀC6H4
3,4ꢀOCH2OꢀC6H3
4ꢀClC6H4
4ꢀMeOC6H4
Ph
Ph
Ph
3ꢀMeOC6H4
SO2Ph
Scheme 2
Experimental
The 1H NMR spectra were recorded on a Bruker AMꢀ300
(300 MHz) instrument in DMSOꢀd6. The melting points were
measured on a Boetius hotꢀstage apparatus and are uncorrected.
The course of the reactions was monitored and the purity of the
reaction products was checked by TLC on Merck Silica gel 60
F254 plates using an ethyl acetate—hexane mixture as the
eluent.
Ester 3c was a commercially available reagent. Esters 3b8
and 3d9 were synthesized according to known methods. Ester 3a
was synthesized from ethyl cyanophenylpyruvate10 according to
a procedure used for the synthesis of 3d.9
Ethyl 3ꢀcyanoꢀ3ꢀphenylꢀ2ꢀ(4ꢀtolylsulfonyloxy)acrylate
(mixture of E and Z isomers). Triethylamine (1.01 g, 0.01 mol)
and 4ꢀtoluenesulfonyl chloride (1.90 g, 0.01 mol) were added to
a solution of ethyl 3ꢀcyanoꢀ2ꢀoxoꢀ3ꢀphenylpropionate (2.17 g,
0.01 mol) in benzene (30 mL). The solution was refluxed for 2 h
and poured into water (30 mL). The organic phase was sepaꢀ
rated, and the aqueous layer was extracted with benzene. The
combined organic extracts were washed with water and a
NaHCO3 solution and then dried over Na2SO4. The solvent was
removed in vacuo. The product was recrystallized from ethanol.
The yield was 3.19 g (86%), m.p. 87—88 °C. 1H NMR (DMSOꢀd6),
δ: 1.27 and 1.33 (both t, 3 H, CH3, J = 7 Hz); 2.29 and 2.34

3ꢀAminothiopheneꢀ2ꢀcarboxylic acid derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
389
Table 1. Yields, melting points, and elemental analysis data for compounds 1a—t
Comꢀ
pound
Substituents
R2
M.p.
/°С
Yield
Found
Calculated
Molecular
formula
(%)
R1
Ar
С
H
N
S
Cl
1a
1b
1c
1d
1e
1f
Ph COOH
2ꢀClC6H4
Pyridinꢀ3ꢀyl
2ꢀEtOC6H4
2ꢀMeC6H4
2,5ꢀ(Me)2C6H3
Ph
270—273
293—294
285—287
284—285
274—275
164—165
238—239
176—177
63
52
40
37
50
56
65
71
63
77
63
62
51
66
58
34
69
65
68
40
62.71
3.60
3.68
4.15
4.03
4.94
4.87
4.83
4.71
4.91
5.07
5.21
4.09
4.52
4.47
4.61
4.63
4.03
4.01
4.25
4.12
5.13
5.05
3.73
3.85
3.94
3.85
4.63
4.76
5.23
5.37
5.03
4.95
4.46
4.33
4.12
4.15
5.26
5.11
5.34
5.11
3.74 8.28 9.31
3.65 8.35 9.24
C20H14ClNO3S
C19H14N2O3S
C22H19NO4S
C21H17NO3S
C22H19NO3S
C19H15NO3S2
C20H17NO3S2
C21H19NO4S2
C21H17NO5S2
C20H17NO5S2
C14H13NO2S
C11H9NOS2
62.58
75.28
65.13
67.29
67.16
69.52
69.40
70.15
70.01
61.85
61.77
62.53
62.64
61.19
61.00
60.19
59.00
57.73
57.82
64.73
64.84
56.23
56.14
55.97
56.14
60.95
61.07
60.23
60.17
74.56
74.73
68.58
68.75
67.34
67.15
71.53
71.62
71.84
71.62
8.08 9.16
7.99 9.15
3.48 8.06
3.56 8.15
3.76 8.95
3.85 8.82
3.84 8.41
3.71 8.49
4.65 10.23
3.79 17.36
3.45 16.54
3.65 16.72
3.21 15.41
3.39 15.51
3.06 15.11
3.28 15.00
3.45 15.31
3.37 15.43
5.45 12.21
5.40 12.36
5.83 27.21
5.95 27.25
6.03 27.03
5.95 27.25
5.05 17.38
5.09 17.43
4.23 10.19
4.39 10.04
4.64 10.45
4.59 10.50
3.87 9.26
4.01 9.18
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
SO2Ph
H
H
H
1g
1h
1i
2ꢀMeC6H4
2ꢀEtOC6H4
4ꢀ(COOCH3)C6H4 177—178
4ꢀHOꢀ3ꢀMeOꢀC6H3 180—181
1j
1k
1l
H
2ꢀMeOC6H4
Thiophenꢀ3ꢀyl
Thiophenꢀ2ꢀyl
163—164
175—177
146—147
1m
1n
1o
1p
1q
1r
1s
1t
C11H9NOS2
4ꢀHOꢀ3ꢀMeOC6H3 205—208
3,4,5ꢀ(MeO)3C6H2 155—156
C14H13NO3S
C16H17NO4S
C19H15NOS
Ph
Ph
138—139
152—153
190—191
140—141
93—94
3,4ꢀOCH2OC6H3
4ꢀClC6H4
C20H15NO3S
C19H14ClNOS
C20H17NO2S
C20H17NO2S
4.02 9.56 10.34
4.12 9.43 10.43
4ꢀMeOC6H4
3ꢀMeOC6H4
4.23 9.41
4.18 9.54
4.12 9.67
4.18 9.54
—
—
(both s, 3 H, CH3); 4.32 and 4.36 (both q, 2 H, CH2, J = 7 Hz);
7.07—7.75 (m, 9 H, HAr). Found (%): C, 61.62; H, 4.72; N,
3.61; S, 8.72. C19H17NO5S. Calculated (%): C, 61.44; H, 4.61;
N, 3.77; S, 8.63.
Dimethyl 3ꢀaminoꢀ4ꢀphenylthiopheneꢀ2,5ꢀdicarboxylate (3a).
Ethyl 3ꢀcyanoꢀ3ꢀphenylꢀ2ꢀ(4ꢀtolylsulfonyloxy)acrylate (3.72 g,
0.01 mol) was added to a solution of sodium (0.46 g, 0.02 mol)
and methyl mercaptoacetate (1.17 g, 0.011 mol) in methanol
(30 mL). The reaction mixture was refluxed with stirring for 1 h
and cooled. Then water (30 mL) was added. The precipitate was
filtered off and recrystallized from 50% aqueous methanol. The
yield was 1.83 g (63%), m.p. 137—138 °C. 1H NMR (DMSOꢀd6),
δ: 3.6 (s, 3 H, CH3); 3.8 (s, 3 H, CH3); 5.9 (s, 2 H, NH2);
7.2—7.5 (m, 5 H, HAr). Found (%): C, 57.57; H, 4.64; N, 4.63;
S, 11.51. C14H13NO4S. Calculated (%): C, 57.72; H, 4.5; N, 4.81;
S, 11.01.
4,7ꢀDihydroꢀ5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀones 1a—t (general
procedure). A mixture of ester 3 (2 mmol) and NaOH (0.16 g,
4 mmol; 0.24 g, 6 mmol in the case of 3a) in ethanol (5 mL)
and water (5 mL) was refluxed for 4 h and then concentrated to
dryness. Meldrum’s acid (0.32 g, 2.3 mmol), the corresponding
aldehyde (2.15 mmol), and acetic acid (7 mL) were added to the
residue. The reaction mixture was refluxed for 2 h and concenꢀ
trated in vacuo. The precipitate was recrystallized from ethanol
(for the recrystallization of 1a—e, concentrated hydrochloric
acid (0.7 g) was added to the ethanolic solution after cooling),

390
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Lichitsky et al.
Table 2. 1H NMR spectra (DMSOꢀd6, δ, J/Hz) of compounds 1a—t
Comꢀ
pound
R1
R2
H—C—H
(dd, 1 H)
H—C—H
(dd, 1 H)
CH
(dd, 1 H)
Ar
NH
(br.s, 1 H)
1a
1b
7.6—7.2
(m, 5 H, Ph)
7.2—7.5
12.4—13.2
(br.s, 1 H)
12.4—13.2
(br.s, 1 H)
2.83
(J = 16; 7)
2.95
3.02
(J = 16; 7)
2.95
4.88
(J = 7; 7)
4.70
7.6—7.2
(m, 5 H)
7.56 (m, 1 H, Py);
7.91 (m, 1 H, Py);
8.63 (m, 2 H, Py)
9.27
9.29
(m, 5 H, Ph)
(J = 0; 7)
(J = 0; 7)
(J = 7; 7)
1c
6.9—7.4
(m, 5 H, Ph)
12.4—13.0
(br.s, 1 H)
2.79
(J = 16; 7)
2.96
(J = 16; 7)
4.72
(J = 7; 7)
6.9—7.4 (m, 4 H, Ph);
1.39 (t, 3 H, EtO, J = 7);
4.12 (dq, 2 H, EtO,
J1 = 2.94, J2 = 7)
9.09
1d
1e
7.1—7.5
(m, 5 H, Ph)
12.4—13.0
(br.s, 1 H)
2.78
(J = 16; 8)
2.87
(J = 16; 7)
4.72
(J = 7; 8)
7.1—7.5 (m, 4 H);
2.41 (s, 3 H, Me)
9.19
9.17
6.95—7.5
(m, 5 H, Ph)
12.4—13.0
(br.s, 1 H)
2.77
(J = 16; 7)
2.85
(J = 16; 9)
4.68
(J = 7; 9)
6.95—7.5 (m, 3 H);
2.23 (s, 3 H, Me);
2.35 (s, 3 H, Me)
1f
7.2—8.2
(m, 5 H, Ph)
6.95—8.2
(m, 5 H, Ph)
6.8—8.2
8.4
(s, 1 H)
8.4
(s, 1 H)
8.39
(s, 1 H)
2.85
(J = 16; 8)
2.75
(J = 16; 8)
2.99
2.93
(J = 16; 8)
2.91
(J = 16; 7)
2.76
4.52
(J = 8; 8)
4.73
(J = 7; 8)
4.66
7.2—8.2 (m, 5 H, Ph)
8.85
8.87
8.74
1g
1h
6.95—8.2 (m, 4 H, Ph);
2.34 (s, 3 H, Me)
6.8—8.2 (m, 4 H, Ph);
1.24 (t, 3 H, EtO, J = 7);
4.02 (dq, 2 H, EtO,
(m, 5 H, Ph)
(J = 16; 8)
(J = 16; 6)
(J = 6; 8)
J1 = 7, J2 = 7)
1i
1j
7.3—8.2
(m, 5 H, Ph)
7.6—8.2
8.43
(s, 1 H)
8.39
2.87
(J = 16; 8)
2.79
2.97
(J = 16; 6)
2.91
4.65
(J = 6; 8)
4.39
7.3—8.2 (m, 4 H, Ph);
3.83 (s, 3 H, MeO)
8.88
8.81
7.6—8.2 (m, 3 H, Ph);
3.69 (s, 3 H, MeO);
8.8—9.2 (br.s, 1 H, OH)
7.2—7.3 (m, 1 H, Ph);
6.7—6.9 (m, 3 H, Ph);
3.72 (s, 3 H, MeO)
7.0—7.1 (m, 1 H, Th);
7.18—7.25 (m, 1 H, Th);
7.46—7.56 (m, 1 H, Th)
6.86—7.0 (m, 2 H, Th);
7.32—7.47 (m, 1 H, Th)
6.65—6.9 (m, 3 H, Ph);
3.72 (s, 3 H, MeO);
8.8—9.1 (br.s, 1 H, OH)
6.58 (s, 2 H, Ph);
(m, 5 H, Ph)
(s, 1 H)
(J = 16; 6)
(J = 16; 9)
(J = 6; 9)
1k
1l
6.7 (d, 1 Н,
7.34 (d, 1 Н,
2.71
(J = 16; 8)
2.86
(J = 16; 7)
4.38
(J = 7; 8)
10.25
10.22
J = 5)
J = 5)
6.68 (d, 1 Н,
7.33 (d, 1 Н,
2.76
(J = 16; 8)
2.84
(J = 16; 7)
4.50
(J = 7; 8)
J = 5)
J = 5)
1m
1n
6.68 (d, 1 Н,
J = 5)
6.68 (d, 1 Н,
J = 5)
7.37 (d, 1 Н,
J = 5)
7.32 (d, 1 Н,
J = 5)
2.72
(J = 16; 7)
2.71
2.97
(J = 16; 7)
2.77
4.74
(J = 7; 7)
4.28
10.27
10.20
(J = 16; 9)
(J = 16; 8)
(J = 8; 9)
1o
6.71 (d, 1 Н,
7.34 (d, 1 Н,
2.78
2.80
4.35
10.21
J = 5)
J = 5)
(J = 16; 8)
(J = 16; 8)
(J = 8; 8)
3.72 (s, 6 H, 2 MeO);
3.64 (s, 3 H, MeO)
1p
1q
7.2—7.5
(m, 5 H, Ph)
7.3—7.5
7.2—7.5
(m, 1 H)
7.3—7.5
(m, 1 H)
2.81
(J = 16; 8)
2.78
2.93
(J = 16; 7)
2.87
4.47
(J = 7; 8)
4.39
7.2—7.5 (m, 5 H, Ph)
9.58
9.54
6.7—6.8 (m, 1 H, Ph);
6.83—6.94 (m, 2 H, Ph);
6.00 (d, 2 H, OCH2O, J = 1)
7.25—7.54 (m, 4 H, Ph)
(m, 5 H, Ph)
(J = 16; 8)
(J = 16; 7)
(J = 7; 8)
1r
1s
7.25—7.54
(m, 5 H, Ph)
7.3—7.5
7.25—7.54
(m, 1 H)
7.3—7.5
2.79
(J = 16; 8)
2.78
2.93
(J = 16; 6)
2.86
4.51
(J = 6; 8)
4.40
9.60
9.54
6.91 (d, 2 H, C6H4, J = 8);
7.21 (d, 2 H, C6H4, J = 8);
3.74 (s, 3 H, OCH3)
(m, 5 H, Ph)
(m, 1 H)
(J = 16; 9)
(J = 16; 7)
(J = 7; 9)
1t
7.3—7.56
(m, 5 H, Ph)
7.3—7.56
(m, 1 H)
2.81
(J = 16; 8)
2.92
(J = 16; 7)
4.43
(J = 7; 8)
6.8—6.92 (m, 3 H, C6H4);
7.3—7.56 (m, 1 H, C6H4);
3.73 (s, 3 H, OCH3)
9.57

3ꢀAminothiopheneꢀ2ꢀcarboxylic acid derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
391
filtered off, and washed on a filter with ethanol and water. The
yields, melting points, and elemental analysis data are given in
Table 1. The spectroscopic data are presented in Table 2.
6. R. L. Elliot, P. J. O´Hanlon, N. H. Norman, Tetrahedron,
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1963, pp. 1—124.
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Received November 20, 2008