Synthesis of 1H-1,2,3-triazole derivatives by the cyclization of aryl azides with 2-benzothiazolylacetonone, 1,3-benzo-thiazol-2-ylacetonitrile, and (4-aryl-1,3-thiazol-2-yl)acetonitriles

Article abstract of DOI:10.1007/s10593-009-0287-6

The cyclization of aryl azides with 2-benzothiazolylacetone, 1,3-benzothiazol-2-ylacetonitrile, and (4-aryl-1,3-thiazol-2-yl)acetonitriles in methanol in the presence of sodium methylate gives high yields of new products, 2-(5-methyl(amino)-1-aryl-1H-1,2,

Full text of DOI:10.1007/s10593-009-0287-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 4, 2009
SYNTHESIS OF 1H-1,2,3-TRIAZOLE DERIVATIVES
BY THE CYCLIZATION OF ARYL AZIDES WITH
2-BENZOTHIAZOLYLACETONONE, 1,3-BENZO-
THIAZOL-2-YLACETONITRILE, AND (4-ARYL-
1,3-THIAZOL-2-YL)ACETONITRILES
N. T. Pokhodylo1, V. S. Matiychuk1, and N. B. Obushak1*
The cyclization of aryl azides with 2-benzothiazolylacetone, 1,3-benzothiazol-2-ylacetonitrile, and
(4-aryl-1,3-thiazol-2-yl)acetonitriles in methanol in the presence of sodium methylate gives high yields
of new products, 2-(5-methyl(amino)-1-aryl-1H-1,2,3-triazol-4-yl)-1,3-benzothiazoles and 1-aryl-
(4-aryl-1,3-thiazol-2-yl)-1H-1,2,3-triazole-5-amines. 1,3-Benzothiazol-2-ylacetonitrile undergoes an
anionic domino reaction with methyl 2-azidobenzoate or 2-azidobenzonitrile to give
[1,2,3]triazolo[1,5-a]quinazoline derivatives.
Keywords: 1,3-benzothiazole derivatives, 1,3-thiazole derivatives, tetrazole, 1H-1,2,3-triazole,
[1,2,3]triazolo[1,5-a]quinazoline, heterocyclization, domino reaction.
Functionalized 1,2,3-triazoles have a broad range of biological activity although these compounds are not
encountered in natural products. The cephalosporin antibiotic cefatricin is an efficient drug for countering agents
leading to diseases in the respiratory tract, connective tissue, and skin [2, 3]. Difluoride I is an anticonvulsive agent,
compounds II displays anti-HIV activity [5], while compounds III play an important role in the treatment of
Alzheimer's disease as well as type-1 and type-2 diabetes [6]. Some 1,2,3-triazoles act as antagonists of the
GABA receptor [7, 8], agonists of muscarine receptors [9], neuroleptics [11], antihistaminics [12], and
antiproliferative agents [13].
R
N
R
t-Bu
Me
R
N
N
O
N
N
N
R
N
Si
N
O
N
Me
R
N
O
O
H
O
N
NH2
N
F
F
Me
H2N
Me
N
Si
O
O
N
O
Bu-t
S
Me
O
O
III
I
II
_______
* To whom correspondence should be addressed, e-mail: obushak@lviv.ua.
1Ivan Franko Lviv National University, Lviv 79005, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 612-618, April, 2009. Original
article submitted December 11, 2007.
0009-3122/09/4504-0483©2009 Springer Science+Business Media, Inc.
483

A good method for the synthesis of 1H-1,2,3-triazole derivatives involves the reaction of aryl azides with
CH-active compounds containing a COR or C≡N group [14]. However, the scope for the preparative application
of this method has not been elucidated due, in part, to competing reactions. For example, the partial reduction of
the azido group to an amino group occurs in some cases under the conditions of this reaction [14]. The reaction
of azides with α-methylene ketones and acetonitriles activated by an aryl or hetaryl substituent holds promise as
a synthetic method. Only a few examples have been reported for the reaction of aryl azides with arylacetonitriles
and phenylacetone [14, 15] leading to 5-aminomethyl-1,4-diaryl-1H-1,2,3-triazoles. The introduction of a
heterocyclic substituent at C-4 of the triazole ring might be expected to expand the biological activity of these
compounds.
We investigated the reaction of aryl azides 1a-i with 1,3-benzothiazol-2-ylacetone (2),
1,3-benzothiazol-2-ylacetonitrile (3), and 4-R1-thiazolylacetonitriles 4a-e obtained according to reported
procedures [16-18].
We found that compound 2-4 react with aryl azides to give triazole derivatives 5-7 (Tables 1 and 2) with
a heterocyclic substituent at C-4.
N
N
S
N
N
R
Me
5 a–e
O
N
R1
S
Me
2
R1
N
S
N
N
N
S
N
N
N
N
S
S
N3
N
NH2
4 a–e
3
N
N
NH2
R
N
1 a–g
R
R
7 a–h
6 a–e
1 a R = Н, b R= 2-Ме, c R = 3-Ме, d R = 4-Ме, e R = 4-F, f R = 4-NO2, g R = 4-СООН;
5 a R = Н, b R = 2-Ме, c R = 4-Ме, d R = 4-NO2, e R = 4-СООН; 6 a R = H, b R = 3-Me,
c R = 4-Me, d R = 4-F, e R = 4-NO2; 4 a R1 = Ph, b R1 = 4-МеС6Н4, c R1 = 4-FС6Н4,
d R1 = 4-СlС6Н4, e R1 = 2-naphthyl; 7 a–e R = H, a R1 = Ph, b R1 = 4-MeC6H4, c R1 = 4-FC6H4,
d R1 = 4-ClC6H4, e R1 = 2-naphthyl, f R = Ме, g R = F, h R = 4-NO2, f–h R1 = Ph
The reaction of aryl azide 1 with 2-benzothiazolylacetone 2 is complete in a few minutes upon heating or
after 1 h at room temperature. Triazole derivatives 6a-e were obtained in the reaction of aryl azides with
1,3-benzothiazol-2-ylacetonitrile 3 after 1 min at room temperature. Products of the Dimroth rearrangement and
reduction of the azide group from the reaction mixture were not isolated from the reaction mixture. Thus, these
reactions are a good method for the synthesis of triazole derivatives with a benzothiazole substituent at C-4.
(4-R1-1,3-thiazol-2-yl)acetonitriles 4a-e also react with aryl azides without complications; the yields of
cyclization products 7 ranged from 66 to 93%.
484

The use of aryl azides 1h,i containing a nitrile or ester group in the ortho position to the azido group in
the abovementioned reactions permits anionic domino reaction [19] of these azides with 1,3-benzothiazol-
2-ylacetonitrile 3. In both cases, the amino group at C-5 in the triazole ring formed in the first step reacts with
N
N
S
S
NaN3
N3
O
N
N
MeONa
MeOH
POCl3
3
N
+
N
OMe
N
N
NH
N
N
MeCN
N
O
N
1 h
9
8
TABLE 1. Characteristics of Products 5-10
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
C16H12N4S
65.80
65.73
66.50
66.64
66.72
66.64
56.84
56.96
60.35
60.70
61.26
61.42
62.69
62.52
62.37
62.52
57.93
57.87
53.21
53.25
63.76
63.93
64.95
64.84
60.63
60.52
57.43
57.71
68.39
68.27
64.72
64.84
4.05
4.14
4.52
4.61
4.70
4.61
3.19
3.29
3.68
3.60
3.85
3.78
4.15
4.26
4.18
4.26
3.06
3.24
3.08
2.98
4.07
4.10
4.45
4.53
3.50
3.59
3.33
3.42
4.01
4.09
4.58
4.53
19.07
19.16
18.19
18.29
18.17
18.29
20.67
20.76
16.72
16.66
23.75
23.87
22.93
22.78
22.66
22.78
22.59
22.49
24.72
24.84
21.80
21.93
20.88
21.01
20.84
20.76
19.72
19.79
19.02
18.96
20.93
21.01
147-148
145-146
171-172
223-224
>300
81
74
88
94
72
82
77
85
93
91
65
80
71
82
76
66
87
73
84
93
91
C17H14N4S
C17H14N4S
C16H11N5O2S
C17H12N4O2S
C15H11N5S
C16H13N5S
C16H13N5S
C15H10FN5S
C15H10N6O2S
C17H13N5S
C18H15N5S
C17H12FN5S
C17H12ClN5S
C21H15N5S
C18H15N5S
C17H12FN5S
C17H12N6O2S
C16H9N5OS
C16H8N8S
227-228
188-189
231-232
247-248
259-260
151-152
199-200
167-168
206-205
174-175
196-197
194-195
291-292
>300
7g
7h
8
60.40
60.52
56.10
56.04
60.27
60.18
55.67
55.81
3.45
3.59
3.20
3.32
2.78
2.84
2.41
2.34
20.42
20.76
22.94
23.06
21.82
21.93
32.36
32.54
9
221-222
>300
10
C16H10N6S
60.08
60.36
3.27
3.17
26.25
26.40
485

TABLE 2. 1H NMR spectra of Compounds 5-10
Com-
pound
Chemical shifts, δ, ppm (J,Hz)
1
2
5a
2.82 (3Н, s, СН3); 7.43 (1Н, m, benzothiazole Н-5); 7.49 (1Н, m, benzothiazole Н-6);
7.60-7.68 (5Н, m, C6H5); 7.99 (1Н, d, 3J = 8.0, benzothiazole Н-4);
8.06 (1Н, d, 3J = 7.6, benzothiazole Н-7)
5b
5c
2.10 (3Н, s, СН3); 2.61 (3Н, s, СН3); 7.39-7.57 (6Н, m, Ar);
7.97 (1Н, d, 3J = 8.0, benzothiazole Н-4); 8.05 (1Н, d, 3J = 8.0, benzothiazole Н-7)
2.48 (3Н, s, СН3); 2.78 (3Н, s, СН3); 7.42 (1Н, m, benzothiazole Н-5);
7.43 (2Н, d, 3J = 8.0, НAr-3,5); 7.49 (1Н, m, benzothiazole Н-6);
7.51 (2Н, d, 3J = 8.0, НAr-2,6); 7.97 (1Н, d, 3J = 8.0, benzothiazole Н-4);
8.04 (1Н, d, 3J = 8.0, benzothiazole Н-7)
5d
5e
2.90 (3Н, s, СН3); 7.44 (1Н, m, benzothiazole Н-5); 7.52 (1Н, m, benzothiazole Н-6);
8.01 (1Н, d, 3J = 8.4, benzothiazole Н-4); 8.05 (1Н, d, 3J = 8.4, benzothiazole Н-7);
8.07 (2Н, d, 3J = 8.8, НAr-2,6); 8.50 (2Н, d, 3J = 8.8, НAr-3,5)
2.86 (3Н, s, СН3); 7.44 (1Н, m, benzothiazole Н-5); 7.52 (1Н, m, benzothiazole Н-6);
7.81 (2Н, d, 3J = 8.8, НAr-2,6); 8.01 (1Н, d, 3J = 8.0, benzothiazole Н-4);
8.07 (1Н, d, 3J = 7.6, benzothiazole Н-7); 8.22 (2Н, d, 3J = 8.8, НAr-3,5);
13.07 (1Н, br. s, СООН)
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
6.78 (2Н, s, NH2); 7.34 (1Н, m, benzothiazole Н-6); 7.45 (1Н, m, benzothiazole Н-5);
7.54 (1Н, m, НPh-4); 7.63 (2Н, m, НPh-3,5); 7.68 (2Н, d, 3J = 7.6, НPh-2,6);
7.93 (1Н, d, 3J = 8.4, benzothiazole Н-7); 7.99 (1Н, d, 3J = 8.0, benzothiazole Н-4)
2.49 (3Н, s, СН3); 6.78 (2Н, s, NH2); 7.33-7.38 (2Н, m, benzothiazole Н-6 + НAr);
7.41-7.54 (4Н, m, benzothiazole Н-5 + НAr); 7.93 (1Н, d, 3J = 8.0, benzothiazole Н-7);
8.00 (1Н, d, 3J = 8.0, benzothiazole Н-4)
2.46 (3Н, s, СН3); 6.70 (2Н, s, NH2); 7.34 (1Н, m, benzothiazole Н-6);
7.39-7.47 (3Н, m, benzothiazole Н-5 + НAr-3,5); 7.53 (2Н, d, 3J = 8.0, НAr-2,6);
7.92 (1Н, d, 3J = 8.4, benzothiazole Н-7); 7.98 (1Н, d, 3J = 8.0, benzothiazole Н-4)
6.79 (2Н, s, NH2); 7.35 (1Н, m, benzothiazole Н-6); 7.41 (2Н, m, НAr-3,5);
7.46 (1Н, m, benzothiazole Н-5); 7.70 (2Н, dd, JH,H = 8.8, JH,F = 4.8, НAr-2,6);
7.93 (1Н, d, 3J = 8.0, benzothiazole Н-7); 8.00 (1Н, d, 3J = 8.0, benzothiazole Н-4)
7.08 (2Н, s, NH2); 7.36 (1Н, m, benzothiazole Н-6); 7.47 (1Н, m, benzothiazole Н-5);
7.95 (1Н, d, 3J = 8.0, benzothiazole Н-7); 7.99 (1Н, d, 3J = 7.6, benzothiazole Н-4);
8.02 (2Н, d, 3J = 8.8, НAr-2,6); 8.46 (2Н, d, 3J = 8.8, НAr-3,5)
6.56 (2Н, s, NH2); 7.32 (1Н, m, НPh-4); 7.43 (2Н, t, 3J = 7.6, НPh-3,5);
7.54 (1Н, m, НPhN-4); 7.63 (2Н, m, НPhN-3,5); 7.69 (2Н, d, 3J = 8.0, НPhN-2,6);
7.77 (1Н, s, thiazole); 7.99 (2Н, d, 3J = 7.2, НPh-2,6)
2.38 (3Н, s, СН3); 6.55 (2Н, s, NH2); 7.22 (2Н, d, 3J = 8.0, НAr-3,5); 7.53 (1Н, m, НPh-4);
7.63 (2Н, m, НPh-3,5); 7.68 (2Н, d, 3J = 8.0, НAr-2,6); 7.70 (1Н, s, thiazole);
7.86 (2Н, d, 3J = 8.0, НPh-2,6)
6.55 (2Н, s, NH2); 7.18 (2Н, t, 3J = 8.8, НAr-3,5); 7.53 (1Н, m, НPh-4);
7.63 (2Н, m, НPh-3,5); 7.68 (2Н, d, 3J = 7.6, НPh-2,6); 7.77 (1Н, s, thiazole);
8.04 (2Н, dd, JH,F = 5.2, JH,H = 8.8, НAr-2,6)
6.55 (2Н, s, NH2); 7.43 (2Н, d, 3J = 8.8, НAr-3,5); 7.53 (1Н, m, НPh-4);
7.63 (2Н, m, НPh-3,5); 7.67 (2Н, d, 3J = 7.6, НPh-2,6); 7.86 (1Н, s, thiazole);
8.02 (2Н, d, 3J = 8.8, НAr-2,6)
6.64 (2Н, s, NH2); 7.45-7.51 (2Н, m, naphthyl); 7.54 (1Н, m, НPh-4);
7.64 (2Н, m, НPh-3,5); 7.70 (2Н, d, 3J = 7.2, НPh-2,6); 7.86 (1Н, d, 3J = 6.8, naphthyl);
7.92 (1Н, d, 3J = 8.8, naphthyl); 7.95 (1Н, s, thiazole); 7.97 (1Н, d, 3J = 8.8, naphthyl);
8.12 (1Н, dd, 3J = 8.8, 4J = 1.6, naphthyl); 8.56 (1Н, s, naphthyl)
7f
2.47 (3Н, s, СН3); 6.47 (2Н, s, NH2); 7.32 (1Н, m, НPh-4);
7.40-7.46 (4Н, m, НPh-3,5 + НAr-3,5); 7.55 (2Н, d, 3J = 7.6, НAr-2,6);
7.76 (1Н, s, thiazole); 7.99 (2Н, d, 3J = 8.0, НPh-2,6)
7g
7h
6.56 (2Н, s, NH2); 7.33 (1Н, m, НPh-4); 7.38-7.46 (4Н, m, НPh-3,5 + НAr-3,5);
7.71 (2Н, dd, JH,H = 8.0, JH,F = 4.8, НAr-2,6); 7.80 (1Н, s, thiazole);
8.00 (2Н, d, 3J = 7.6, НPh-3,5)
6.85 (2Н, s, NH2); 7.33 (1Н, m, НPh-4); 7.44 (2Н, m, НPh-3,5); 7.81 (1Н, s, thiazole);
7.98-8.04 (4Н, m, НPh-2,6 + НAr-2,6); 8.46 (2Н, d, 3J = 8.8, НAr-3,5)
486

TABLE 2 (continued)
1
2
8
7.27 (1Н, m, quinozaline); 7.41 (1Н, m, benzothiazole Н-6);
7.49 (1Н, m, benzothiazole Н-5); 7.74 (1Н, m, quinozaline);
7.90-7.99 (2Н, m, quinozaline + benzothiazole Н-4);
8.17-8.25 (2Н, m, quinozaline + benzothiazole Н-7)
9
7.44 (1Н, m, benzothiazole Н-6); 7.54 (1Н, m, benzothiazole Н-5); 7.96 (1Н, m, НAr-4);
8.08 (1Н, d, 3J = 8.0, benzothiazole Н-7); 8.13 (1Н, d, 3J = 8.0, benzothiazole Н-4);
8.26 (1Н, m, НAr-5); 8.44 (1Н, d, 3J = 8.4, НAr-6); 8.75 (1Н, d, 3J = 8.0, НAr-3)
10
7.35 (1Н, m, benzothiazole Н-6); 7.45 (1Н, m, benzothiazole Н-5); 7.70 (1Н, m, НAr-4);
7.95 (1Н, d, 3J = 7.6, benzothiazole Н-7); 7.97-8.02 (2Н, m, benzothiazole Н-4 + НAr-5);
8.35 (2H, br. s, NH2); 8.45 (1Н, d, 3J = 8.0, С6Н4 НAr-3); 8.50 (1Н, d, 3J = 7.6, НAr-6)
N
N
N
N3
N
MeONa
MeOH
3
+
S
N
N
1i
10
NH2
the ortho substituent (C≡N or CO2Me) to give the [1,2,3]triazolo[1,5-a]quinazoline system (compounds 8 and 10,
Tables 1 and 2). The domino reaction takes place in a few minutes with a good yield of the reaction products
when there is an ester or nitrile group in the starting azide.
Benzothiazole derivative 8 is transformed by the action of POCl3 and sodium azide in acetonitrile in one
step to give 5-(1,3-benzothiazol-2-yl)tetrazolo[1,5-c][1,2,3]triazolo[1,5-a]quinazoline (9) (Tables 1 and 2).
Thus, we have shown that 2-benzothiazolylacetone 2, 1,3-benzothiazol-2-ylacetonitrile 3, and (4-aryl-
1,3-thiazol-2-yl)acetonitriles 4 are convenient reagents for the synthesis of 1H-1,2,3-triazole derivatives.
EXPERIMENTAL
The 1H NMR spectra were taken on a Mercury 400 spectrometer at 400 MHz in DMSO-d6. The chemical
shifts are given relative to TMS.
Azides 1a-i were obtained by a method similar to a reported procedure [20]. Samples of
2-benzothiazolylacetone 2 [16], 1,3-benzothiazol-2-ylacetonitrile 3 [17], and 4-R-thiazolylacetonitriles 4a-e [18]
were obtained according to reported procedures.
2-[5-Methyl-1-(R-phenyl)-1H-1,2,3-triazol-4-yl]-1,3-benzothiazoles 5a-e (General Method). A
solution of sodium (0.3 g, 13 mmol) in methanol (20 ml) was added with cooling to a solution of the
corresponding aryl azide 1 (10 mmol). Then, 2-benzothiazolylacetone 2 (1.9 g, 10 mmol) was added with
vigorous stirring. The mixture was heated for 30 min and cooled to room temperature. The precipitate formed
was filtered off and purified by recrystallization from ethanol.
Synthesis of Compounds 6-8 and 10 (General Method). Hetarylacetonitrile 3 or 4 (10 mmol) and aryl
azide 1 (10 mmol) were added with vigorous stirring to a solution of sodium methylate obtained from 0.3 g
sodium and 20 ml methanol. The mixture was stirred at room temperature until formation of a precipitate, which
was filtered off and purified by recrystallization from ethanol–DMF.
5-(1,3-Benzothiazol-2-yl)tetrazolo[1,5-c][1,2,3]triazolo[1,5-a]quinazoline (9). A mixture of compound 8
(0.64 g, 2 mmol), NaN3 (0.26 g, 4 mmol), and POCl3 (1.54 g, 10 mmol) in acetonitrile (20 ml) was heated at
reflux with stirring for 10 h. The solvent and excess POCl3 were distilled off at reduced pressure. The residue
was cooled and neutralized by adding saturated aqueous NaHCO3. The precipitate formed was filtered off and
crystallized from ethanol–DMF.
487

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