Synthesis and reactivity of thieno[2,3-b]pyridine-2,3-diamines

Article abstract of DOI:10.1007/s10593-007-0182-y

It has been established that the interaction of N¹-(2- hydroxyphenylmethylthieno[2,3-b]pyrid-3-yl)arylamides with hydrazine hydrate leads to thieno[2,3-b]pyridine-2,3-diamines. It was shown that the reaction of the latter with acetylacetone and

Full text of DOI:10.1007/s10593-007-0182-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 9, 2007
SYNTHESIS AND REACTIVITY
OF THIENO[2,3-b]PYRIDINE-
2,3-DIAMINES
M. M. Lipunov1, E. A. Kaigorodova2, L. D. Konyushkin3,
S. I. Firgang3, and G. D. Krapivin1
It has been established that the interaction of N1-(2-hydroxyphenylmethylthieno[2,3-b]pyrid-
3-yl)arylamides with hydrazine hydrate leads to thieno[2,3-b]pyridine-2,3-diamines. It was shown that
the reaction of the latter with acetylacetone and acetoacetic ester occurs regioselectively at the amino
group in position 3 of the thiophene ring.
Keywords: (Z)-3-(2-aminothieno[2,3-b]pyrid-3-ylamino)-1-R-2-buten-1-one, N3-[(E)-1-arylmethylidene-
imino]thieno[2,3-b]pyrid-2-ylamine, 2,3-dihydro-1H-imidazo[4′,5′:4,5]thieno[2,3-b]pyridine, thieno[2,3-b]-
pyridine-2,3-diamine, ring-chain tautomerism.
The sole method described in the literature for obtaining 4,6-dimethylthieno[2,3-b]pyridine-2,3-diamine
(1a) is the interaction of 4,6-dimethyl-2-thioxo-1,2-dihydro-3-pyridinecarbonitrile with ethyl 2-chloro-
2-fluoroacetate [1]. In spite of the good yield of diamine this method is hardly acceptable in connection with the
commercial unavailability of ethyl 2-chloro-2-fluoroacetate. Possibly for this reason the authors of [1], obtaining
this compound for the first time, did not investigate its properties practically. At the same time, thieno[2,3-b]-
pyridine-2,3-diamines are of interest as a subject for investigating the reactivity of the amino groups located in
positions α and β of the thiophene ring.
Scheme 1
H
R
N
R
R
N
NH2
NH2
N
NH2
N
.
O
NH2NH2 H2O
+
Ph
S
S
DMSO
S
Ph
N
2a,b
3a,b
1-3 a R = Me; b R = CH2OMe
1a,b
__________________________________________________________________________________________
2
1Kuban State Technological University, Krasnodar 350072, Russia; e-mail: organics@kubstu.ru. Kuban
3
State Agricultural University, Krasnodar 350044, Russia; e-mail: e_kaigorodova@mail.ru. N. D. Zelinsky
Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail: LeonidK@chemical-
block.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1400-1408, September, 2007.
Original article submitted December 4, 2006.
0009-3122/07/4309-1189©2007 Springer Science+Business Media, Inc.
1189

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp °C
Yield, %
C
H
N
1a
C9H11N3S
55.87
55.93
53.88
53.79
68.90
68.79
66.06
66.00
68.40
68.30
65.61
65.57
65.45
65.36
61.16
61.06
59.07
58.99
59.10
58.99
57.35
57.29
64.69
64.62
69.03
69.12
58.81
58.88
65.66
65.57
62.45
62.37
5.70
5.74
5.89
5.87
4.71
4.69
4.88
4.89
5.38
5.37
5.48
5.50
5.18
5.16
6.20
6.22
6.27
6.27
6.25
6.27
6.33
6.31
5.05
5.08
5.83
5.80
4.30
4.32
5.51
5.50
5.21
5.23
21.79
21.74
18.79
18.82
15.00
15.04
13.61
13.58
14.90
14.93
13.52
13.49
9.00
8.97
15.23
15.26
13.72
13.76
13.74
13.76
12.50
12.53
14.09
14.13
14.25
14.22
17.22
17.17
13.45
13.49
12.85
12.83
177-178
166-167
>300
63
61
42
52
5.6
2.4
9
1b
C10H13N3OS
C16H13N3S
3a
3b
C17H15N3OS
C16H15N3S
260-261
284-285
155-156
175-176
170-171
156-157
138-139
148-149
239-240
196-197
229-230
158-159
203-204
203-204
173-174
211-212
5a
5b
C17H17N3OS
C17H16N2O2S
C14H17N3OS
C15H19N3O2S
C15H19N3O2S
C16H21N3O3S
C16H15N3OS
6b
8a
72
77
64
73
88
78
75
85
68
72
65
73
8b
8c
8d
9a, 10a
9b, 10b C17H17N3S
9c, 10c C16H14N4O2S
9d, 10d C17H17N3OS
9e, 10e
9f, 10f
9g, 10g
C17H17N3O2S
C17H16N4O3S
C18H19N3O2S
57.20
57.29
63.41
63.32
42.20
42.08
4.52
4.53
5.59
5.61
3.11
3.12
15.76
15.72
12.34
12.31
8.61
8.66
9h, 10h C17H15Br2N3O2S
It is known that the interaction of 1-(3-aminothieno[2,3-b]pyrid-2-yl)-1-ethanol with hydrazine hydrate
leads to the tricyclic system 1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridine [2]. On investigating the interaction of
compounds 2a,b [3, 4] with hydrazine hydrate in DMSO we isolated 2,3-diaminothieno[2,3-b]pyridines 1a,b
together with 1H-pyrazolo[3',4':4,4]thieno[2,3-b]pyridines 3a,b (Scheme 1, Table 1). The yields of compounds
1a,b were only 12 and 1% respectively.
The structures of compounds 1a,b, 3a,b were confirmed by IR and 1H NMR spectroscopy (Table 2), and
of diamines 1a,b in addition by mass spectroscopy (see Experimental). In the IR spectra of products 1a,b there
1
were two absorption bands at 3360-3370 and 3190-3195 cm-1. In the H NMR spectra of compounds 1a,b the
signals of the amino groups were found at 3.97-3.98 (2-NH2) and 6.53-6.57 ppm (3-NH2) respectively
(assignment of signals was made on the basis of [5]).
Assuming that compounds 1a,b may also prove to be products of the reaction of alcohols of the type of
4a,b [6] with hydrazine hydrate, we investigated this interaction (Scheme 2).
1190

The reaction takes place on boiling for 5 h and the optimal molar ratio of reactants of the initial alcohol 4
with hydrazine hydrate was 1:30 (without solvent).
Scheme 2
Ph
H
R
N
O
.
NH2NH2 H2O
OH
S
Ph
N
Ph
H
H
R
N
4a,b
R
N
N
NH
Ph
O
+
1a,b
+
S
S
N
5a,b
6b
4a, 5a R = Me; 4-6 b R = CH2OMe
It was established that the main products of this reaction were thieno[2,3-b]pyridine-2,3-diamines 1a,b
(yields over 60%), and also 2,3-dihydro-1H-pyrazolo[3',4':4,5]thieno[2,3-b]pyridines 5a,b (in yields ≤5.5%). On
using compound 4b 3-benzoylaminothieno[2,3-b]pyridine 6b was also isolated in small yield (9%). Compounds
3a,b were not detected among the reaction products. Products 1, 5, and 6 were separated by fractionation and
fractional crystallization.
The presumed reaction routes are illustrated in Scheme 3.
Scheme 3
Route 1
Route 2
4a,b
NH2NH2
R
– NH2COPh
NH2NH2
– H2O
Ph
NHNH2
O
OH
Ph
R
N
NH
NHNH2
S
N
S
Ph
C
A
Route 1a
– H2O
– NH2COPh
Route 1b
R
– PhHC=NH
5a,b
Ph
H
Route 1с
N
O
– PhHC=NNH2
NH2
S
6b
N
B
NH2NH2 – PhCONHNH2
1a,b
1191

Route 1, the nucleophilic replacement of the OH group by a hydrazine group, leads to intermediate A.
Then 1a) intramolecular nucleophilic substitution of the benzamide group at atom C(3) leads to compounds 5a,b;
1b) cleavage of the N–N and C–C bonds accompanying migration of an NH2 group to the C(2) atom and
elimination of phenylmethylamine leads to intermediate B (the latter gives diamines 1a,b under the action of
hydrazine); 1c) migration of a hydrogen atom to atom C(2) of the thiophene ring, cleavage of a C–C bond, and
elimination of benzhydrazone leads to substance 6b.
Route 2 is the nucleophilic substitution of the benzamide group by a hydrazine group (structure C) with
subsequent intramolecular dehydration (compounds 5a,b).
The reactivity of the amino groups in positions 2 and 3 of the thiophene ring of compounds 1a,b were
investigated in reactions with 1,3-dicarbonyl compounds and aromatic aldehydes.
The chemical nonequivalence of the amino groups in positions 2 and 3 of thieno[2,3-b]pyridines was
displayed on interaction of thieno[2,3-b]pyridine-2,3-diamines 1a,b with acetylacetone 7a and with acetoacetic
ester 7b, and led to monocondensation products 8a-d (Scheme 4).
Scheme 4
R1
O
H
R1
R
N
O
AcOH
1a,b
+
NH2
EtOH
O
S
N
7a,b
8a–d
8 a,c R = Me, b,d R = CH2OMe; 7a, 8 a,b R1 = Me; 7b, 8 c,d R1 = OEt
The structures of (Z)-3-(2-aminothieno[2,3-b]pyrid-3-ylamino)-R1-2-buten-1-ones 8a-d were proved by
1
IR and H NMR spectroscopic methods (Table 2). The signal of the amino group proton in position 3 of the
thiophene ring of compounds 8a-d was registered at low field for 8a,b at 13.27 and 13.24 ppm and for 8c,d at
11.36 and 11.34 ppm, which is explained by the formation of a hydrogen bond with the oxygen atom (Scheme 4).
The signal of the amino group protons at position 2 of the thiophene ring of compounds 8a-d is displaced towards
low field by approximately 0.20 ppm in comparison with the spectra of the initial diamines 1a,b.
Thieno[2,3-b]pyridine-2,3-diamines 1a,b interact readily with aromatic aldehydes with the formation of
an equilibrium mixture of tautomers 9a-h and 10a-h (Scheme 5).
Scheme 5
Ar
R
H
Ar
R
N
N
N
O
H
NH
Ar
1a,b
NH2
+
S
S
N
9a–h
10a–h
9, 10 a–d R = Me, e–h R = CH2OMe; a, e Ar = 2-НOC6H4, b Ar = 4-MeC6H4;
c, f Ar = 4-O2NC6H4, d, g Ar = 4-MeОС6H4, h Ar = 3,5-Br2-2-НOC6H2
1192

TABLE 2. IR and 1H NMR Spectra of the Synthesized Compounds
IR spectrum,
Com-
pound
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
ν, cm-1
1a
1b
3360 (N–H);
3190 (N–H)
3370 (N–H);
3195 (N–H);
1130 (C–O–C)
2.34, 2.42 (both 3Н, both s, 4-CH3, 6-CH3);
3.98 (2Н, s, 2-NH2); 6.53 (2Н, br. s, 3-NH2); 6.77 (1H, s, HPy)
2.41 (3Н, s, 6-CH3); 3.40 (3H, s, OCH3); 3.97 (2Н, s, 2-NH2);
4.68 (2H, s, CH2O); 6.57 (2Н, br. s, 3-NH2); 7.03 (1H, s, HPy)
3a
3445 (N–H)
1-H form (34%): 2.57, 2.75 (both 3Н, both s, 4-CH3, 6-CH3);
7.24 (1H, s, HPy); 7.39-7.45 (1Н, m, Н-4 arom.);
7.53-7.57 (2Н, m, Н-3 and Н-5 arom.);
7.88 (2Н, d, J = 8.0, Н-2 and Н-6 arom.); 14.01 (1Н, br. s, NH)
2-H form (66%): 2.56, 2.77 (both 3Н, both s, 4-CH3, 6-CH3);
7.21 (1H, s, HPy); 7.39-7.45 (1Н, m, Н-4 arom.);
7.58-7.62 (2Н, m, Н-3 and Н-5 arom.);
7.78 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 14.08 (1Н, br. s, NH)
3b
3486 (N–H);
1123 (C–O–C)
1-H form (34%): 2.59 (3Н, s, 6-CH3); 3.43 (3H, s, OCH3);
4.91 (2H, s, CH2O); 7.37 (1H, s, HPy); 7.40-7.47 (1Н, m, Н-4 arom.);
7.53-7.64 (2Н, m, Н-3 and Н-5 arom.);
7.85 (2Н, d, J = 7.9, Н-2 and Н-6 arom.); 13.71 (1Н, br. s, NH)
2-Н form (66%): 2.60 (3Н, s, 6-CH3); 3.46 (3H, s, OCH3);
4.99 (2H, s, CH2O); 7.37 (1H, s, HPy); 7.40-7.47 (1Н, m, Н-4 arom.);
7.53-7.64 (2Н, m, Н-3 and Н-5 arom.);
7.76 (2Н, d, J = 7.9, Н-2 and Н-6 arom.); 14.08 (1Н, br. s, NH)
5a
5b
3425 (N–H);
3158 (N–H)
2.03, 2.32 (both 3Н, both s, 4-CH3, 6-CH3); 6.57 (1Н, d, J = 6.1, СН);
6.60 (1H, s, HPy); 7.26-7.33 (1Н, m, Н-4 arom.);
7.38-7.45 (2Н, m, Н-3 and Н-5 arom.);
7.84 (2Н, d, J = 8.0, Н-2 and Н-6 arom.);
12.81, 13.41 (both 1Н, both br. s, NH and NH)
3418 (N–H);
3120 (N–H)
2.41 (3Н, s, 6-CH3); 3.26 (3H, s, OCH3); 4.11 (2H, s, CH2O);
6.64 (1Н, d, J = 5.8, СН); 6.76 (1H, s, HPy);
7.26-7.37 (1Н, m, Н-4 arom.);
7.39-7.48 (2Н, m, Н-3 and Н-5 arom.);
7.82 (2Н, d, J = 8.0, Н-2 and Н-6 arom.);
12.83, 13.57 (both 1Н, both br. s, NH and NH)
6b
8a
—
2.61 (3Н, s, 6-CH3); 3.33 (3H, s, OCH3); 4.43 (2H, s, CH2O);
7.33 (1H, s, HPy); 7.56-7.61 (2Н, m, Н-3 and Н-5 arom.);
7.62-7.66 (1Н, m, J = 8.2, Н-4 arom.);
7.97 (2Н, d, J = 8.0, Н-2 and Н-6 arom.);
8.08 (1H, s, HHet); 10.62 (1Н, br. s, NH)
3455 (N–H);
3385 (N–H);
1625 (C=O);
1610 (С=О)
2.05 (3H, s, CH3); 2.19 (3H, s, CH3CO);
2.41, 2.50 (both 3Н, both s, 4-CH3, 6-CH3); 4.17 (2Н, s, 2-NH2);
5.36 (1H, s, CH); 6.92 (1H, s, HPy); 13.27 (1Н, br. s, NH)
8b
8c
3371 (N–H);
1615 (C=O);
1115 (C–O–C)
2.06 (3H, s, CH3); 2.22 (3H, s, CH3CO); 2.48 (3Н, s, 6-CH3);
3.19 (3H, s, OCH3); 4.17 (2Н, s, 2-NH2); 4.73 (2H, s, CH2O);
5.37 (1H, s, CH); 7.13 (1H, s, HPy); 13.24 (1Н, br. s, NH)
1.23 (3Н, t, J = 6.8, CH3); 2.02 (3H, s, CH3);
2.43, 2.51 (both 3Н, both s, 4-CH3, 6-CH3); 4.09 (2H, q, J = 6.8,
OCH2);
4.18 (2Н, s, 2-NH2); 4.82 (1H, s, CH); 6.91 (1H, s, HPy);
11.36 (1Н, br. s, NH)
3205 (N–H);
1650 (C=O);
1620 (C=O);
1280 (CO–O–C)
8d
1650 (C=O);
1615 (C=O);
1280 (CO–O–C);
1.23 (3Н, t, J = 6.9, CH3); 2.22 (3H, s, CH3); 2.46 (3Н, s, 6-CH3);
3.45 (3H, s, OCH3); 4.11 (2H, q, J = 6.9, OCH2); 4.17 (2Н, s, 2-NH2);
4.73 (2H, s, CH2O); 4.82 (1H, s, CH); 7.13 (1H, s, HPy);
The overall yields of products 9a-h and 10a-h were ~ 70% (Table 1).
The existence of two tautomeric forms and the possibility of transition of one form into the other was
1
proved by H NMR spectroscopy (Table 3). The ratios of the tautomeric forms are given in Table 4. It was
established that donating substituents in the aromatic fragment were capable of displacing the tautomeric
1193

TABLE 3. 1H NMR Spectra of the Synthesized Compounds 9a-h and 10a-c,e-h
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
9a
2.44, 2.75 (both 3Н, both s, 4-CH3, 6-CH3); 4.48 (2Н, s, 2-NH2);
6.94-7.00 (3H, m, Н-3 and Н-5 arom, НPy); 7.37–7.42 (1Н, m, H-4 arom.);
7.72 (1Н, d, J = 8.0, H-6 arom.); 8.86 (1H, s, CH); 11.08 (1H, s, OH)
[2.52, 2.68 (both 3Н, both s, 4-CH3, 6-CH3); 4.34 (2Н, s, 2-NH2); 6.78 (1H, s, HPy);
6.95-6.99 (1H, m, H-5 arom.); 7.04 (1Н, d, J = 8.1, H-3 arom.);
7.35-7.41 (2Н, m, H-4 and Н-6 arom.); 8.71 (1H, s, CH); 11.57 (1H, s, OH)]
9b
9c
2.36, 2.43, 2.62 (both 3Н, all s, 4-CH3, 6-CH3, CH3–C6H5); 4.43 (2Н, s, 2-NH2);
6.92 (1H, s, HPy); 7.30 (2H, d, J = 8.0, H-3 and Н-5 arom.);
7.78 (2Н, d, J = 8.0, H-2 and Н-6 arom.); 8.50 (1H, s, CH)
2.53, 2.68 (both 3Н, both s, 4-CH3, 6-CH3); 4.43 (2Н, s, 2-NH2); 6.78 (1H, s, HPy);
8.00 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.30 (2Н, d, J = 8.1, Н-3 and Н-5 arom.);
8.54 (1H, s, CH)
[2.44, 2.62 (both 3Н, both s, 4-CH3, 6-CH3); 4.48 (2Н, s, 2-NH2); 6.97 (1H, s, HPy);
8.15 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.34 (2Н, d, J = 8.1, Н-3 and Н-5 arom.);
8.69 (1H, s, CH)]
9d
9e
2.43, 2.62 (both 3Н, both s, 4-CH3, 6-CH3); .3.38 (3Н, s, OCH3); 4.47 (2Н, s, 2-NH2);
6.94 (1H, s, HPy); 7.06 (2Н, d, J = 8.0, Н-3 and Н-5 arom.);
7.85 (2Н, d, J = 8.0, Н-2 and Н-6 arom.); 8.52 (1H, s, CH)
2.48 (3Н, s, 6-CH3); 3.45 (3Н, s, OCH3); 4.45 (2Н, s, 2-NH2); 4.88 (2H, s, OCH2);
6.93-6.98 (2H, m, Н-3 and H-5 arom.); 7.19 (1H, s, HPy); 7.36-7.40 (1Н, m, H-4 arom.);
7.72 (1Н, d, J = 7.9, H-6 arom.); 8.84 (1H, s, CH); 11.03 (1H, s, OH)
[2.58 (3Н, s, 6-CH3); 3.59 (3Н, s, OCH3); 4.33 (2Н, s, 2-NH2); 4.98 (2H, s, OCH2);
7.25 (1H, s, HPy); 6.96–7.07 (2H, m, Н-3 and H-5 arom.);
7.38-7.43 (2Н, m, H-4 and Н-6 arom.); 8.73 (1H, s, CH); 11.52 (1H, s, OH)]
9f
2.51 (3Н, s, 6-CH3); 3.46 (3Н, s, OCH3); 4.47 (2Н, s, 2-NH2); 4.89 (2H, s, OCH2);
7.21 (1H, s, HPy); 8.15 (2Н, d, J = 8.2, Н-2 and Н-6 arom.);
8.33 (2Н, d, J = 8.2, Н-3 and Н-5 arom.); 8.69 (1H, s, CH)]
9g
9h
2.49 (3Н, s, 6-CH3); 3.47, 3.84 (both 3Н, both s, OCH3, OCH3); 4.43 (2Н, s, 2-NH2);
4.88 (2H, s, OCH2); 7.05 (2Н, d, J = 8.1, Н-3 and Н-5 arom.); 7.18 (1H, s, HPy);
7.85 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.52 (1H, s, CH)
2.52 (3Н, s, 6-CH3); 3.44 (3Н, s, OCH3); 4.52 (2Н, s, 2-NH2); 4.91 (2H, s, OCH2);
7.28 (1H, s, HPy); 7.92 (1Н, s, Н-4 arom.); 7.94 (1Н, s, Н-6 arom.);
8.84 (1H, s, CH); 12.19 (1H, s, OH)
[2.59 (3Н, s, 6-CH3); 3.57 (3Н, s, OCH3); 4.32 (2Н, s, 2-NH2); 4.93 (2H, s, OCH2);
7.24 (1H, s, HPy); 7.48 (1Н, s, Н-4 arom.); 7.76 (1Н, s, Н-6 arom.); 8.61 (1H, s, CH);
12.42 (1H, s, OH)]
10a
10b
10c
2.52, 2.63 (both 3Н, both s, 4-CH3, 6-CH3); 6.86-6.91 (3H, m, CH, H-3 and H-5 arom.);
7.06 (1Н, s, НPy); 7.18 (1H, m, Н-4 arom.); 7.57 (1Н, d, J = 8.1, Н-6 arom.);
8.41 (1Н, br. s, NH); 9.57 (1Н, br. s, NH); 10.58 (1H, s, OH)
2.33, 2.51, 2.75 (both 3Н, all s, 4-CH3, 6-CH3, CH3–C6H5); 6.91 (1H, s, CH);
7.03 (1H, s, HPy); 7.22 (2H, d, J = 8.0, H-3 and Н-5 arom.);
7.57 (2Н, d, J = 8.0, H-2 and Н-6 arom.); 8.10 (1Н, br. s, NH); 9.37 (1Н, br. s, NH)
2.51, 2.75 (both 3Н, both s, 4-CH3, 6-CH3); 7.07 (1H, s, HPy); 7.12 (1H, s, CH);
7.92 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.22 (1Н, br. s, NH);
8.25 (2Н, d, J = 8.1, Н-3 and Н-5 arom.); 10.07 (1Н, br. s, NH)
[2.63, 2.77 (both 3Н, both s, 4-CH3, 6-CH3); 6.94 (1H, s, HPy); 7.03 (1H, s, CH);
7.79 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.16 (1Н, br. s, NH);
8.24 (2Н, d, J = 8.1, Н-3 and Н-5 arom.); 9.98 (1Н, br. s, NH)]
10e
2.56 (3Н, s, 6-CH3); 3.42 (3Н, s, OCH3); 4.92 (2H, s, OCH2);
6.82-6.88 (3H, m, Н-3 and H-5 arom., СН); 7.17–7.21 (1Н, m, H-4 arom.);
7.26 (1H, s, HPy); 7.58 (1Н, d, J = 8.0, H-6 arom.); 8.29 (1Н, br. s, NH);
9.62 (1Н, br. s, NH); 10.48 (1H, s, OH)
[2.68 (3Н, s, 6-CH3); 3.45 (3Н, s, OCH3); 4.81 (2H, s, OCH2); 6.75 (1H, s, CH);
6.90-6.94 (1H, m, H-5 arom.); 7.01 (1H, s, HPy); 7.02 (1Н, d, J = 8.0, H-3 arom.);
7.19 (1Н, d, J = 8.0, H-6 arom.); 7.24–7.29 (1Н, m, H-4 arom.); 7.98 (1Н, br. s, NH);
9.67 (1Н, br. s, NH); 11.06 (1H, s, OH)]
10f
2.58 (3Н, s, 6-CH3); 3.43 (3Н, s, OCH3); 4.91 (2H, s, OCH2); 7.13 (1H, s, CH);
7.28 (1H, s, HPy); 7.94 (2Н, d, J = 8.1, Н-2 and Н-6 arom.); 8.12 (1Н, br. s, NH);
8.24 (2Н, d, J = 8.1, Н-3 and Н-5 arom.); 10.10 (1Н, br. s, NH)
1194

TABLE 3. (continued)
1
2
10g
2.53 (3Н, s, 6-CH3); 3.54, 3.79 (both 3Н, both s, OCH3, OCH3); 4.91 (2H, s, OCH2);
6.93 (1H, s, CH); 6.98 (2Н, d, J = 8.2, Н-3 and Н-5 arom.); 7.25 (1H, s, HPy);
7.66 (2Н, d, J = 8.2, Н-2 and Н-6 arom.); 7.99 (1Н, br. s, NH); 9.76 (1Н, br. s, NH)
10h
2.57 (3Н, s, 6-CH3); 3.42 (3Н, s, OCH3); 4.87 (2H, s, OCH2); 7.02 (1H, s, CH);
7.20 (1H, s, HPy); 7.71 (1Н, s, Н-4 arom.); 7.73 (1Н, s, Н-6 arom.); 8.22 (1Н, br. s, NH);
9.98 (1Н, br. s, NH); 11.93 (1H, s, OH)
[2.68 (3Н, s, 6-CH3); 3.44 (3Н, s, OCH3); 4.80 (2H, s, OCH2); 6.78 (1H, s, CH);
7.00 (1Н, s, Н-4 arom.); 7.24 (1H, s, HPy); 7.59 (1Н, s, Н-6 arom.); 7.83 (1Н, br. s, NH);
9.97 (1Н, br. s, NH); 11.87 (1H, s, OH)]
_______
*The 1H NMR spectra were taken in DMSO-d6, spectra taken in CDCl3 are
given in square brackets.
TABLE 4. Ratio of Tautomeric Forms 9a-h (open) and 10a-h (closed) in
1H NMR Spectra
Ratio
of tautomers
Ratio
of tautomers
Tautomers
Solvent
Tautomers
Solvent
9a : 10a
9a : 10a
9b : 10b
9c : 10c
9c : 10c
9d : 10d
50: 50
100 : 0
89 : 11
21 : 79
82 : 18
100 : 0
DMSO-d6
CDCl3
9e : 10e
9e : 10e
9f : 10f
38 : 62
81 : 19
59 : 41
93 : 7
DMSO-d6
CDCl3
DMSO-d6
DMSO-d6
CDCl3
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
9g : 10g
9h : 10h
9h : 10h
17 : 83
40 : 60
DMSO-d6
equilibrium towards the azomethine form 9, and electron-withdrawing substituents, on the other hand, towards the
imidazole form 10. At the same time replacement of DMSO-d6 by CDCl3 aided an increase in the mass part of the
open form 9.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker DRX-500 (500 MHz) instrument in DMSO-d6 and
CDCl3, internal standard was TMS. The IR spectra were measured on a Specord IR-75 instrument with NaCl
prisms, in KBr or as a suspension in nujol. The mass spectra were taken on a Finnigan MAT INCO S50
instrument with direct insertion of samples into the ion source (energy of ionizing electrons 70 eV, temperature of
ionizing chamber 50-180°C).
8-Methoxymethyl-6-methyl-3-phenylpyrazolo[3',4':4,5]thieno[2,3-b]pyridine (3b) and 4-Methoxy-
methyl-6-methylthieno[2,3-b]pyridine-2,3-diamine (1b). Compound 2b (3.12 g, 10 mmol) was dissolved in
DMSO (20 ml), hydrazine hydrate (24.5 ml, 500 mmol) was added, and the mixture boiled for 36 h. The reaction
mixture was cooled, the precipitated crystals were filtered off, washed with ethanol (10 ml), and dried. Using
fractional crystallization from ethanol the mixture obtained was separated into substances 1b and 3b. Yield of
compound 3b was 1.57 g (51%) and of compound 1b 0.02 g (1%).
Compounds 1a and 3a were obtained analogously.
1195

4-Methoxymethyl-6-methylthieno[2,3-b]pyridine-2,3-diamine (1b), 8-Methoxymethyl-6-methyl-
3-phenyl-2,3-dihydro-1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridine (5b), and 3-Benzoylamino-4-methoxy-
methyl-6-methylthieno[2,3-b]pyridine (6b). Hydrazine hydrate (14.5 ml, 300 mmol) was added to
3-benzoylamino-2-hydroxy(phenyl)methyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridine (4b) (4.19 g, 10 mmol)
and the mixture was boiled with vigorous stirring for 5 h. The reaction mixture was cooled, the solid filtered off
(filtrate 1), washed with EtOH (100 ml) (filtrate 2), and air-dried to give compound 1b. Filtrate 1 was poured into
water (150 ml), the precipitated crystals were filtered off, to give compound 5b. Filtrate 2 was cooled
additionally, the resulting crystals were filtered off, and recrystallized from ethanol until isolation of a single
substance (check by TLC, eluent acetone–hexane, 1:1). Compound 6b was obtained.
Compounds 1a, 5a were obtained analogously.
4,6-Dimethylthieno[2,3-b]pyridine-2,3-diamine (1a). Mass spectrum, m/z (Irel, %): 193 [M]+ (13), 178
[M–CH3]+ (6), 176 [M–NH3]+ (6), 163 [M–N2H2]+ (70).
4-Methoxymethyl-6-methylthieno[2,3-b]pyridine-2,3-diamine (1b). Mass spectrum, m/z (Irel, %): 223
[M]+ (38), 208 [M-CH3]+ (68), 191 [M–CH3–NH3]+ (53), 178 (12) [M–CH3–N2H2]+, 163 [M–CH3–NH3–CO]+ (100).
(Z)-4-(2-Amino-4-methoxymethyl-6-methylthieno[2,3-b]pyrid-3-ylamino)-3-penten-2-one
(8b).
Acetylacetone (0.52 ml, 5 mmol) and glacial acetic acid (1.72 ml, 30 mmol) were added sequentially to a solution
of diamine 1b (1.12 g, 5 mmol) in EtOH (15 ml). The reaction mixture was brought to boiling, then slowly
cooled. The solid which precipitated was filtered off, washed with EtOH (10 ml), and air-dried. The product was
recrystallized from EtOH.
Compound 8a was obtained analogously.
Ethyl (Z)-3-(2-Amino-4-methoxymethyl-6-methylthieno[2,3-b]pyrid-3-ylamino)crotonoate (8d).
Acetoacetic ester (0.63 ml, 5 mmol) and glacial acetic acid (1.72 ml, 30 mmol) were added sequentially to a
solution of diamine 1b (1.12 g, 5 mmol) in EtOH (15 ml). The reaction mixture was boiled for 5 min, the EtOH
(one third) evaporated, and the mixture cooled in an ice bath. The precipitated solid was filtered off, washed with
EtOH (10 ml), and air-dried.
Compound 8c was obtained analogously.
4-Methoxymethyl-3-[(E)-1-(4-methoxyphenyl)methylideneimino]-6-methylthieno[2,3-b]pyrid-2-yl-
amine (9g) and 4-Methoxymethyl-2-(4-methoxyphenyl)-6-methyl-2,3-dihydro-1H-imidazo[4',5':4,5]-
thieno[2,3-b]pyridine (10g). 4-Methoxybenzaldehyde (0.6 ml, 5 mmol) was added to a solution of diamine 1b
(1.12 g, 5 mmol) in toluene (15 ml). The mixture was boiled for 5 min, cooled in an ice bath, the precipitated
crystals were filtered off, washed with EtOH (10 ml), air-dried, and recrystallized from EtOH.
Compounds 9a-f,h and 10a-f,h were obtained analogously.
REFERENCES
1.
2.
A. W. Erian and F. A. Abu-Shanab, Bull. Chem. Soc. Jpn., 71, 2387 (1998).
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(1999).
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4.
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6.
M. Negm Abdalla, Abd El-Aal Fatma, Abd El-Maksoud, Hafez Ebtisam, H. Elnagdi Mohamed, and M.
N. Mostafa Yasser, Phosphorus, Sulfur, Silicon Relat. Elem., 106, 1 (1995).
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