Synthesis and properties of substituted isoxazolo[3′,4′:4,5]- thieno[2,3-b]pyridines

Article abstract of DOI:10.1023/B:COHC.0000028636.31350.c0

We synthesized derivatives of a novel heterocyclic system, isoxazolo[3′,4′:4,5]thieno[2,3-b]pyridine by sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by α-halomethyl ketones in alkaline medium, to form 3-aminothieno[2,3-b] pyridines; diazotization of the amino group followed by nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the diazonium salts; and thermolysis of the azides formed.

Full text of DOI:10.1023/B:COHC.0000028636.31350.c0

Chemistry of Heterocyclic Compounds, Vol. 40, No. 3, 2004
SYNTHESIS AND PROPERTIES OF
SUBSTITUTED ISOXAZOLO[3',4':4,5]-
THIENO[2,3-b]PYRIDINES
V. K. Vasilin1, E. A. Kaigorodova1, S. I. Firgang2, and G. D. Krapivin1
We synthesized derivatives of a novel heterocyclic system, isoxazolo[3',4':4,5]thieno[2,3-b]pyridine by
sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides
obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by α-halomethyl ketones in
alkaline medium, to form 3-aminothieno[2,3-b]pyridines; diazotization of the amino group followed by
nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the
diazonium salts; and thermolysis of the azides formed.
Keywords: 3-aminothieno[2,3-b]pyridines, 3-azidothieno[2,3-b]pyridines, isoxazolo[3',4':4,5]thieno-
[2,3-b]pyridines, 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides, 3-cyano-2(1H)pyridinethiones.
3-Cyano-2(1H)-pyridinethiones are widely used for synthesis of polycondensed heteroaromatic systems
[1-4]. We previously obtained compounds containing pyridine, thiophene, and oxazole rings in their structure
[5]. The aim of this work was directed synthesis of isoxazolo[3',4':4,5]thieno[2,3-b]pyridines and a study of their
physicochemical characteristics.
As the starting materials for constructing the tricyclic system, we used substituted 3-cyano-2(1H)-
pyridinethiones 1-3 and α-halomethyl ketones 4a-g.
The reaction of pyridinethiones 1-3 with ketones 4a-g was carried out in the presence of a two-fold
amount of KOH to bind the evolved hydrogen halide and to ensure Thorpe–Ziegler cyclization of intermediates
5 to form thienopyridines 6. The alkylation products 5, as shown in our papers [6, 7], can be isolated in pure
form and characterized, but in this case they were not the object of our investigation.
3-Aminothieno[2,3-b]pyridines 6 are bright yellow crystals which are quite soluble in polar solvents, and
insoluble in water and alkanes; their physicochemical characteristics are given in Table 1. The characteristics of
compounds 6a,d,g, which we synthesized earlier, are given in [6-8].
1
The IR and H NMR spectral data were the most informative for establishing the structure of
thienopyridines 6 (Table 1). Thus in the IR spectra of compounds 6, there are no absorption bands for the nitrile
group in the 2240-2215 cm-1 region or from the C=S group of the thioamide at 1215-1220 cm-1, typical of
compounds 1-3, and two absorption bands appear for the stretching vibrations of the N–H bond of the amino
group at 3520-3340 cm-1 and 3315-3230 cm-1, and also an absorption band for the conjugated carbonyl group at
1
1605-1590 cm-1. In the H NMR spectra there are signals from all the protons, and a broadened singlet for the
protons of the amino group is observed in the 7.32-8.17 ppm region.
__________________________________________________________________________________________
1
Kuban State Technological University, Krasnodar 350072, Russia; e-mail: organics@kubstu.ru.
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 462-472, March 2004. Original article submitted
August 5, 2001.
0009-3122/04/4003-0377©2004 Plenum Publishing Corporation
377

R2
R2
N
N
N
O
X
+
R3
R3
1
R
1
R
N
S
S
4a–g
H
O
5
1–3
R2
N
NH2
O
R3
R1
S
6a–g
1, 6a, 6d-g R1 = Me, R2 = CH2OMe; 2, 6b R1 = CH2OMe, R2 = Me; 3, 6c R1 = R2 = Me;
4а-c, 6а-c R3 = Ph; 4d, 6d R3 = C6H4Br-4; 4e, 6e R3 = C6H3Cl2-2,4; 4f, 6f R3 = C6H3F2-2,4;
4g, 6g R3 = Ad1
Diazotization of 3-aminothienopyridines 6 was carried out in acetic acid medium in the presence of
conc. H2SO4, which ensured good solubility of the starting components at sufficiently low temperatures (5-7°C).
The low basicity of 2-acyl-substituted aminothienopyridines in the diazotization reaction enables a sufficiently
large amount of free amine to exist in the equilibrium mixture, as needed for efficient reaction. The diazonium
salts 7a-g obtained in the solutions, immediately after removal of the excess nitrous acid, underwent a
nucleophilic substitution reaction with a concentrated aqueous solution of sodium azide.
_
R2
R2
NH2
N
HSO4
+
2
NaNO2
H2SO4
O
NaN3
O
R3
1
R
R1
S
S
R3
N
6a–g
N
7
R2
N3
O
R1
R3
S
N
8a–g
8a, 8d–g R1 = Me, R2 = CH2OMe; 8b R1 = CH2OMe, R2 = Me; 8с R1 = R2 = Me; 8а–c R3 = Ph;
8d R3 = C6H4Br-4; 8e R3 = C6H4Cl2-2,4; 7f, 8f R3 = C6H4F2-2,4; 8g R3 = Ad1
The 2-acyl-3-azidothieno[2,3-b]pyridines (8) obtained are crystalline compounds ranging from pale
cream to light yellow in color and darkening in air, with decomposition temperatures in the range 114-128°C
(Table 2).
The structure of pyridines 8 is supported by the IR, 1H NMR, and mass spectral data (Tables 2, 3, 6). In
the IR spectra of products 8, we see the typical very intense absorption band for the azide group at
2105-2125 cm-1. Replacing the amino group with an azide group leads to a shift of the absorption bands for the
carbonyl group toward the higher frequency region by 40 cm-1 on the average, to 1625-1660 cm-1 (Table 4). In
1
the H NMR spectra, compared with the spectra for the starting aminothienopyridines 6, the signal from the
protons of the amino group are missing; the signal from the proton of the pyridine cycle is shifted downfield
(∆δ = 0.25-0.35 ppm).
378

TABLE 1. Physicochemical Characteristics of Substituted 3-Aminothieno[2,3-b]pyridines 6a-g
Found, %
Calculated, %
H
IR spectrum,
Com-
pound
Empirical
formula
1Н NMR spectrum, δ, ppm (J, Hz)
Yield,
%
——————
ν, cm-1
mp, °С
С
N
NH2
C=O CH3, s OCH3, s CH2O, s HPy, s NH2, s
Other protons
6а
6b
6c
6d
C17H16N2O2S
C17H16N2O2S
C16H14N2OS
C17H15BrN2O2S
65.25
65.36
5.15
5.16
8.94
8.97
137-138
126-127
203-204
135-136
3465
3260
1595
1590
1590
1605
2.66
2.84
3.45
3.41
—
4.80
4.53
—
7.01
7.22
7.05
7.00
8.10
7.98
7.96
8.17
7.27-7.90 (5H, m, HPh)
92
90
89
93
65.20
65.36
5.14
5.16
9.05
8.97
3480
3305
7.50-7.76 (5H, m, HPh)
7.50-7.75 (5H, m, HPh)
68.20
68.06
5.01
5.00
9.94
9.92
3520
3310
2.53
2.78
52.01
52.18
3.81
3.86
7.12
7.16
3340
3230
2.66
2.57
2.58
3.45
4.80
7.62 (2H, d, 3J = 8.1,
2,6-HAr); 7.82 (2H, d,
3J = 8.1, 3,5-HAr)
7.50-7.55 (2H, m,
5,6-HAr); 7.71 (1H, d,
4J = 2.2, 3-HAr)
7.20 (1H, d. d, 4J = 2.7,
3-HAr); 7.33 (1H, d,
3J = 8.6, 4J = 2.7, 5-HAr);
7.63 (1H, d, 3J = 8.6,
6-HAr)
6e
6f
C17H14Cl2N2O2S
C17H14F2N2O2S
53.64
53.55
3.69
3.70
7.37
7.35
185-186
169-170
3400
3298
1595
1595
3.42
3.43
4.86
4.87
7.28
7.28
8.11
8.07
90
92
58.72
58.61
4.05
4.05
8.05
8.04
3410
3310
6g
C21H26N2O2S
68.22
68.08
7.11
7.07
7.50
7.56
176-177
3370
3250
1600
2.80
3.48
4.63
7.13
7.32
1.79-1.90 (6H, m, HAd);
96
2.06-2.20 (9H, m, HAd
)

TABLE 2. Some Physicochemical Characteristics of 2-Acyl-3-azidothieno-
[2,3-b]pyridines 8a-g
IR spectrum,
Found, %
Calculated, %
H
——————
Т. decomp.,
°C
Com-
pound
Empirical
formula
Yield,
%
ν, cm-1
C
N
N3
C=O
1625
1625
1630
1625
1640
1640
1635
8a
8b
8c
8d
8e
8f
C17H14N4O2S
C17H14N4O2S
C16H12N4OS
60.55
60.34
4.19
4.17
4.18
4.17
3.93
3.92
3.16
3.14
2.98
2.97
3.25
3.23
6.13
6.10
16.50
16.56
115-117
114-115
118-119
126-128
122-124
118-119
120-122
2110
2110
2115
2105
2125
2125
2125
74
79
78
75
83
73
82
60.39
60.34
16.52
16.56
62.39
62.32
18.10
18.17
C17H13BrN4O2S
C17H12Cl2N4O2S
C17H12F2N4O2S
C21H24N4O2S
49.00
48.93
13.36
13.43
50.32
50.13
13.60
13.69
54.70
54.54
14.91
14.97
8g
63.81
63.61
14.06
14.13
The carbonyl group located adjacent to the azide group accelerates the process of decomposition of the
azide in the presence of π-conjugation, due to formation of a transition state in which nucleophilic attack by the
unshared electron pair of the oxygen atom occurs at the nitrogen atom in the plane of the molecule, which
promotes formation of oxazoles [9, 10]. A similar pattern is observed in the case of thermolysis of 2-acyl-3-
azidothienopyridines 8a-g, leading to formation of derivatives of a novel heteroaromatic system:
isoxazolo[3',4':4,5]thieno[2,3-b]pyridine 9.
R2
R2
N3
N
O
O
∆
R3
R1
S
R1
N
S
N
R3
9a–g
8a–g
8а, 8d-g, 9a, 9d-g R1 = Me, R2 = CH2OMe; 8b, 9b R1 = CH2OMe, R2 = Me; 8c, 9c R1 = R2 = Me;
8a-c, 9a-c R3 = Ph; 8d, 9d R3 = C6H4Br-4; 8e, 9e R3 = C6H3Cl2-2,4; 8f, 9f R3 = C6H3F2-2,4; 8g, 9g R3 = Ad1
1
TABLE 3. H NMR Spectra of Some of the Synthesized 2-Acyl-3-
azidothieno[2,3-b]pyridines 8
1Н NMR spectrum, δ, ppm (J, Hz)
Com-
pound
CH3, s CH3O, s CH2O, s
НPy, s
Other protons
8a
8d
2.50
2.64
3.38
3.51
4.76
5.05
7.26
7.46
7.07-7.62 (5H, m, HPh)
7.80 (2H, d, 3J = 8.1, 2,6-HAr);
7.87 (2H, d, 3J = 8.1, 3,5-HAr)
8e
2.63
3.50
5.03
7.46
7.63 (1H, d, 3J = 8.3, 6-HAr);
7.74 (1H, dd, 3J = 8.3, 4J = 2.2, 5-HAr);
7.79 (1H, d, 4J = 2.2, 3-HAr)
8f
8g
2.62
2.62
3.49
3.47
5.03
4.98
7.45
7.40
7.24-7.90 (3H, m, HAr)
1.70-1.82 (6H, m, HAd), 2.00-2.15 (9H, m, HAd)
380

TABLE 4. Physicochemical Characteristics of Compounds 9
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
9a
9b
9c
9d
9e
9f
C17H14N2O2S
C17H14N2O2S
C16H12N2OS
65.93
65.79
65.95
65.79
68.66
68.55
52.29
52.45
53.72
53.84
59.00
58.95
68.30
68.45
4.50
4.55
4.52
4.55
4.29
4.31
3.36
3.37
3.18
3.19
3.50
3.49
6.55
6.56
9.07
9.03
9.05
9.03
10.02
9.99
7.18
7.20
7.39
7.39
8.11
8.09
7.58
7.60
183-184
176-177
202-203
259-260
242-243
233-234
191-192
81
77
84
83
72
78
83
C17H13BrN2O2S
C17H12Cl2N2O2S
C17H12F2N2O2S
C21H24N2O2S
9g
The reaction of decomposition of azides 8a-g was carried out in m-xylene at the boiling point of the
solvent. The process was completed with approximately 30 min of boiling (according to TLC data). The
isoxazolothienopyridines 9a-g were isolated from the reaction mixture in 72 to 83% yields.
Products 9 are colorless crystalline compounds that are insoluble in water, alkanes, and ether and are
soluble in haloalkanes. Some physicochemical characteristics of compounds 9 are given in Tables 4 and 5.
We note that the sets of major lines in the mass spectra of isoxazolothienopyridines 9 and the
corresponding azides 8 are identical (Table 6). This allows us to say that extrusion of the nitrogen molecule from
the molecular ion of the azides is accompanied by rearrangement to the corresponding isoxazole radical ion (Φ1).
Further ΦM+ fragmentation processes do not depend on the route by which this species is obtained: directly from
the isoxazolothienopyridine molecule, or as a result of decomposition of the azide molecular ion. The major
directions of fragmentation of the molecular ion for compounds 8 and 9 are given in Fig. 1.
Some of the priority directions for decomposition of isoxazolo[3',4':4,5]thieno[2,3-b]pyridines
containing a methoxymethyl fragment is ejection of a formaldehyde molecule, accompanied by formation of an
Φ2 radical cation (M+ for the compound 9c). Upon abstraction of a methoxymethyl group, the cations Φ3
(CH2=O+–CH3) and Φ4 are formed. Further fragmentation of the Φ2 radical cation can occur along two routes: a)
cleavage of a methyl radical to form the Φ4 cation; b) dissociation, leading to the cation Φ5, the decomposition
products of which (the cations Φ6, Φ7, Φ8) give the most intense signals in the mass spectrum.
Another direction for fragmentation of M+ (Φ1) includes cleavage of a methyl radical, rearrangement of
the cation Φ9 formed with transfer of a portion to the pyridine nitrogen atom (the rearranged ion Φ9a) followed
by extrusion of a carbon monoxide molecule. Fragmentation of the Φ10 cation leads to formation of
methylnicotinonitrile and the unstable cation Φ5.
Thus the mass spectral fragmentation of 2-acyl-3-azidothieno[2,3-b]pyridines
8
and
isoxazolo[3',4':4,5]thieno[2,3-b]pyridines 9 occurs according to a common scheme. In the initial fragmentation
step, the methoxymethyl group of the molecule undergoes decomposition.
According to a quantum chemical study of the structure of 6-methyl-8-methoxymethyl-3-
phenylisoxazolo[3',4':4,5]thieno[2,3-b]pyridine (9a) (AM1 method), combining three different types of
heterocycles in the same molecule leads to significant changes in the interatomic distances in the aromatic
system compared with the corresponding bonds of the isolated rings. An interesting feature is the fact that the
common bonds for the heterocycles become longer than in the isolated systems (Fig. 2, Table 7).
381

TABLE 5. Spectral Characteristics of 3-R-Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines 9
IR spectrum,
ν, cm-1,
1Н NMR spectrum, δ, ppm (J, Hz)
Com-
pound
UV spectrum, λmax, nm (log ε)
–CH3, s
2.65
–O–CH3, s –CH2–O–, s
HPy, s
Other protons
С=С, С=N
9a
9b
212(4.33), 221(4.26)
245(4.19), 254(4.18)
288(4.53), 335(3.90)
1600
1605
3.54
3.46
4.87
4.60
7.41
7.45-7.83 (5Н, m, НPh)
7.51-7.84 (5Н, m, НPh)
7.52-7.83 (5Н, m, НPh)
212(4.32), 222(4.26)
245(4.13), 257(4.07)
287(4.43), 337(3.87)
2.81
7.46
9c
—
1600
1605
2.60
2.75
2.72
—
—
7.30
7.28
9d
210(4.12), 227(3.96)
247(3.90), 256(3.93)
292(4.34), 336(4.14)
3.61
5.01
7.42 (2H, d, 3J = 8.1, 3,5-HAr); 7.71 (2H, d, 3J = 8.1, 2,6-HAr)
9e
9f
—
1600
1605
2.64
2.66
3.50
3.52
4.91
4.91
7.46
7.46
7.67 (1H. dd, 3J = 8.3, 4J = 2.2, 5-HAr);
7.89 (1H, d, 3J = 8.3, 6-HAr); 7.95 (1H, d, 4J = 2.2, 3-HAr)
207(4.54), 225(4.24)
242(4.16), 253(4.03)
287(4.56), 388(3.89)
7.33 (1H, d, 4J = 2.7, 3-HAr); 7.48 (1H, dd, 3J = 8.6,
4J = 2.7, 5-HAr); 8.08 (1H, d, 3J = 8.6, 6-HAr)
9g
212(4.02), 221(4.10)
238(4.00), 244(4.06)
275(4.39), 322(3.57)
1603
2.67
3.58
4.93
7.38
1.83 (6H, m, HAd); 2.24 (9H, m, HAd)

TABLE 6. Values of m/z (Irel, %) and Basic Characteristics of Ions in Mass Spectra of 3-Azidothieno[2,3-b]pyridines (8)
and Isoxazolothienopyridines (9)
Compound
M+
Ф1
Ф2
Ф3
Ф4
Ф5
Ф6
Ф7
Ф8
Ф9
Ф10
(azide)
8a
338
310
280
45
265
149
105
121
77
295
267
(1.4)
(5.1)
(9.8)
(13.0)
(—)
(1.0)
(78.0)
(18.5)
(100)
(36.6)
(—)
8d*
417
388
359
45
344
228
183
199
155
373
342
(—)
(5.5)
(8.0)
(37.8)
(—)
(—)
(100)
(28.7)
(54.5)
(17.8)
(—)
8f
374
(5.4)
346
(8.0)
316
(14.1)
45
(13.6)
301
(—)
185
(—)
141
(100)
157
(16.6)
179
113
(34.4)
331
(51.3)
303
(10.2)
8g
396
368
338
45
323
207
163
135
353
325
(4.0)
(30.6)
(22.0)
(14.9)
(—)
(—)
(—)
(100)
(16.6)
(9.7)
(—)
9a
9b
9c
—
—
—
—
—
—
310
(22.1)
310
(31.5)
280
(16.5)
280
(100)
45
(11.5)
45
(5.4)
265
(—)
265
(3.0)
149
(—)
149
(0.4)
105
(81.9)
105
(24.4)
121
(17.3)
121
(6.8)
77
(100)
77
(24.1)
295
(51.2)
—
—
267
(5.1)
—
—
280
(100)
280
(100)
—
265
(2.2)
149
(0.4)
105
(18.5)
121
(7.4)
77
(25.8)
9d*
9f
388
(35.5)
359
(18.0)
45
(7.0)
344
(—)
228
(—)
183
(100)
199
(20.4)
155
(70.0)
373
(29.0)
342
(—)
346
(54.4)
316
(38.1)
45
(7.0)
301
(7.0)
185
(—)
141
(100)
157
(17.6)
113
(29.8)
331
(97.0)
303
(19.8)
9g
368
338
45
323
207
163
179
135
353
325
(64.6)
(49.0)
(13.0)
(3.9)
(—)
(6.7)
(—)
(100)
(27.8)
(17.5)
_______
* The m/z values are given for fragments containing the lighter bromine isotope.

+
_
.
N
O
+
N
O
N
HO
H
+
N
O
R
S
N
O
H
R
+
S
M (for 8f,d,f,g)
N
N
O
.
Φ9
–N2
–CH3
R
+
S
N
–CH2O
+
.
O
Φ9a
H
+
N
O
O
Φ3
N
+
O
R
.
–CO
S
N
–H2C–O–
R
+
S
Φ1
N
M
(for 9f,d,f,g)
Φ4
–CH2O
.
–CH3
N
O
+
.
N
O
R
S
N
R
+
S
N
N
H
+
Φ10
Φ2
(for 9c)
_
M
N
R
O
–CH2O
+
S
+
.
Φ5
N
O
R
–CS
+
–CO
O
S
N
+
+
S
(for 9b)
M
R
O
R
Φ6
Φ7
–CS
+
–CO
R
Φ8
Fig. 1. Major fragmentation routes for 3-azidothieno[2,3-b]pyridines 8 and isoxazolothienopyridines 9.
TABLE 7. Interatomic Distances (d, Å) in the Isoxazolothienopyridine 9a Molecule
Heterocyclic
system
Isolated
heterocycle
Heterocyclic
system
Isolated
heterocycle
Bond
Bond
N(1)–C(1)
1.357
1.347
C(6)–C(7)
1.490
1.377 (Tf)
1.462 (Isox)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
1.416
1.398
1.398
1.435
1.407
1.396
1.396
C(7)–S
S–C(5)
1.667
1.736
1.341
1.320
1.672
1.672
1.342
1.320
C(6)–N(2)
N(2)–O(1)
1.407 (Py)
1.377 (Tf)
C(5)–N(1)
C(4)–C(6)
1.343
1.438
1.347
1.342
O(1)–C(8)
C(8)–C(7)
1.428
1.381
1.411
1.379
384

N(2)
O(1)
C(8)
C(3)
C(4)
C(6)
C(2)
C(1)
C(5)
C(7)
N(1)
S
Fig. 2. Projection of the spatial structure of compound 8a, obtained by the AM1 method.
EXPERIMENTAL
The UV spectra were recorded on a Specord UV-vis and a Specord M-40 in the 200-700 nm range in
quartz cuvets of thickness 10 mm in ethanol; the IR spectra were recorded on a Specord 71 IR-20 in the
3600-650 cm-1 range, NaCl prisms, KBr. The crystalline substances were recorded as a suspension in vaseline
1
oil. The H NMR spectra were recorded on a Bruker WM-250 (250 MHz) in DMSO-d6, internal standard
HMDS. The mass spectra were obtained on a Varian CH-6 with ionizing potential 70 eV and temperatures
50-180°C.
3-Amino-2-benzoyl-6-methoxymethyl-4-methylthieno[2,3-b]pyridine (6b). An 10% aqueous solution
of KOH (5.6 ml, 0.01 mol) was added to a suspension of 3-cyano-2(1H)-pyridinethione 2 (1.94 g, 0.01 mol) in
DMF (20 ml). Then phenacyl bromide (1.99 g, 0.01 mol) was added with stirring; the mixture was held for
10-15 min at room temperature. Then another 5.6 ml of a 10% aqueous KOH solution was added, and the
reaction mixture was stirred for 20 min; then the precipitate formed was separated, washed successively with
water and a 1:1 ethanol–water mixture, and dried in air. The filtrate was diluted with a two-fold amount of water,
the flocculent precipitate was separated and washed with water and then recrystallized from ethanol. Compounds
6a,c-g were obtained similarly.
3-Azido-2-benzoyl-4-methoxymethyl-6-methylthieno[2,3-b]pyridine (8a). Conc. H2SO4 (0.6 ml) was
added to a solution of compound 6a (1.69 g, 0.005 mol) in glacial acetic acid (12 ml). The reaction mixture was
cooled in an ice bath down to +5 to +8°C and a solution of sodium azide (0.48 g, 0.007 mol) in water (2 ml) was
slowly added in small portions. The mixture was stirred for 20 min and then the excess nitrous acid was
neutralized with urea (monitored using starch/iodide indicator paper), and a solution of sodium azide (0.46 g,
0.007 mol) in water (2 ml) was added dropwise over a 10 min period. Stirring was continued for one hour. Then
the reaction mass was slowly poured into water with finely shaved ice. The precipitate of azide 6a was separated,
washed on the filter with cold water until the wash water tested neutral, and then it was dried over concentrated
sulfuric acid. The 2-acyl-3-azidothieno[2,3-b]pyridines 8b-g was obtained similarly.
8-Methoxymethyl-6-methyl-3-phenylisoxazolo[3',4':4,5]thieno[2,3-b]pyridine (9a). Compound 8a
(1.69 g, 0.005 mol) was boiled for 30 min in m-xylene (30 ml). Then the solution was cooled down to room
temperature, diluted with hexane (40 ml) (petroleum ether). The precipitated crystals of isoxazolothienopyridine
were separated, washed with hexane, and dried in air. They were purified by recrystallization from DMF.
Compounds 9b-g were obtained by a similar procedure.
385

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