Microwave assisted synthesis of thiazolo[3,2-b][1,2,4]-triazoles containing 1,8-naphthyridine moiety

Article abstract of DOI:10.1002/jhet.5570440530

(Chemical Equation Presented) A simple and efficient protocol for the synthesis of 5-aryl-2-(2-substituted-1,8-naphthyridin-3-yl)-thiazolo[3,2-b][1,2, 4]triazoles (4) is achieved by cyclocondensation of 3-(2-substituted-1,8- naphthyridin-3-yl)-1,2,4-triaz

Full text of DOI:10.1002/jhet.5570440530

Sep-Oct 2007
1161
Microwave Assisted Synthesis of Thiazolo[3,2-b][1,2,4]-triazoles
Containing 1,8-Naphthyridine Moiety
K. Mogilaiah*, M. Prashanthi, S. Kavitha, and H. Sharath Babu
Department of Chemistry, Kakatiya University
Warangal – 506 009, India
E-mail: mogilaiah_k@yahoo.co.in
Received June 6, 2006
Ar
N
R
N
N
R
N
O
C
Ar
CH2Br
N
SH
N
S
H
anhyd. MeOH
MW
N
N
N
N
4
3
A simple and efficient protocol for the synthesis of 5-aryl-2-(2-substituted-1,8-naphthyridin-3-yl)-
thiazolo[3,2-b][1,2,4]triazoles (4) is achieved by cyclocondensation of 3-(2-substituted-1,8-naphthyridin-3-
yl)-1,2,4-triazoles (3) with ꢀ-halogenoketones in anhyd. methanol under microwave irradiation. The
products are obtained in good yields and in a state of high purity.
J. Heterocyclic Chem., 44, 1161 (2007).
INTRODUCTION
yielded the corresponding 3-(2-substituted-1,8-naphthyr-
idin-3-yl)-5-mercapto-1,2,4-triazoles (3).
1,8-Naphthyridine derivatives represent one of the
most active class of compounds possessing a wide
spectrum of biological activity [1-4]. Various 1,2,4-
triazoles [5-7] and thiazole derivatives [8,9] occupy an
important place in medicinal chemistry as they show a
variety of pharmacological and microbiological activities.
Microwave (MW) activation as a non-conventional
energy source has become a very popular and useful
technology in organic chemistry [10-12]. Many reactions
proceeded must faster under microwave irradiation and
with higher yields compared to conventional heating.
Microwave irradiation has also been applied to organic
synthesis in open vessels using organic solvents such as
methanol, ethanol, N,N-dimethylformamide (DMF), 1,2-
dichloroethane (DCE), o-dichlorobenzene, etc. as energy
transfer media which absorb microwave energy
efficiently through dipole rotation. In view of this and in
continuation of our interest in microwave-assisted
organic transformations on 1,8-naphthyridine derivatives
[13-17], we report herein, a convenient, practical and
efficient method for the synthesis of thiazolo[3,2-
b][1,2,4]triazoles containing 1,8-naphthyridine moiety
under microwave irradiation.
Scheme 1
O
O
S
NHNH2
NHNH
C NH2
KSCN, HCl
MW
N
N
R
N
N
R
(1)
(2a-c)
8% KOH
MW
Ar
N
N
N
N
O
N
S
N
SH
Ar
C
CH2Br
H
anhyd. MeOH
MW
N
N
R
N
N
R
(4a-l)
(3a-c)
Cyclocondensation of 3 with ꢀ-halogenoketones in
anhyd. methanol under microwave irradiation furnished
the respective 5-aryl-2-(2-substituted-1,8-naphthyridin-3-
yl)thiazolo[3,2-b][1,2,4]triazoles (4). The reaction
proceeds efficiently in good yields at ambient pressure
within a few minutes. The transformation is facile, clean
and efficient and is devoid of any by-products. The
experimental procedure is very simple. Furthermore, it is
to be noted that highly pure products were obtained using
this simple procedure and in most cases no further
purification was needed. Interestingly, this reaction
proceeds only to a minor extent (5-8% in 2.5 – 5.0 min)
when conducted under conventional conditions in an oil-
bath preheated to 110°C (temperature measured at the end
RESULTS AND DISCUSSION
The reaction of 2-substituted-1,8-naphthyridine-3-
carboxylic acid hydrazides (1) with potassium thio-
cyanate in conc. HCl under microwave irradiation
resulted in the formation of 1-(2-substituted-1,8-naph-
thyridine-3-carbonyl)-3-thiosemicarbazides (2), which on
base catalyzed cyclization under microwave irradiation

1162
K. Mogilaiah, M. Prashanthi, S. Kavitha, and H. Sharath Babu
Vol 44
Table 1
Physical and analytical data of 1-(2-substituted-1,8-naphthyridine-3-carbonyl)-
3-thiosemicarbazides (2) and 3-(2-substituted-1,8-naphthyridin-3-yl)-
5-mercapto-1,2,4-triazoles (3).
Reaction
time
(min)
Elemental analysis
Found / (Calcd)
H
M.P.
(°C)
Yield
(%)
Compd
R
Mol. formula
C
N
2a
2b
2c
3a
3b
3c
CH3
CF3
3.0
3.5
4.5
3.0
4.0
5.0
252-254
240-242
230-231
>320
92
90
88
90
89
92
C11H11N5OS
C11H8F3N5OS
C16H13N5OS
C11H9N5S
50.74
(50.57)
41.78
(41.90
59.62
(59.44)
54.50
(54.32)
44.59
4.25
(4.21)
2.59
(2.54)
4.07
(4.02)
3.74
(3.70)
2.08
26.89
(26.82)
22.30
(22.22)
21.60
(21.67)
28.89
(28.81)
23.57
C6H5
CH3
CF3
300-302
306-308
C11H6F3N5S
C16H11N5S
(44.44)
62.78
(2.02)
3.56
(23.66)
22.95
C6H5
(62.95)
(3.61)
(22.87)
Table 2
Physical and analytical data of 5-aryl-2-(2-substituted-1,8-naphthyridin-
3-yl)thiazolo[3,2-b][1,2,4]triazoles 4.
Reaction
time
(min)
Microanalysis calculated [Found]
%
M.P.
(°C)
Yield
(%)
Compd
R
Ar
Mol. Formula
C
H
N
4a
4b
4c
4d
4e
4f
CH3 C6H5
2.5
3.0
3.5
4.5
3.0
4.0
3.5
4.5
3.5
4.0
4.5
5.0
230-232
240-241
250-252
140-143
160-162
150-151
180-182
192-194
140-141
180-183
200-202
124-125
86
90
88
89
85
88
85
86
84
87
86
88
C19H13N5S
66.62
(66.47)
60.58
(60.40
54.19
(54.03)
71.74
(71.60)
57.59
(57.43)
52.98
(52.84)
47.75
(47.90)
64.60
(64.42)
71.30
3.83
(3.79)
3.23
(3.18)
2.89
(2.84)
3.42
(3.47)
2.56
(2.52)
2.04
(2.09)
1.85
(1.89)
2.92
(2.96)
3.75
20.47
(20.41)
18.60
(18.54)
16.65
(16.58)
16.79
(16.71)
17.68
(17.63)
16.16
(16.22)
14.79
(14.71)
14.88
(14.80)
17.35
CH3 p-ClC6H4
CH3 p-BrC6H4
CH3 p-C6H5C6H4
CF3 C6H5
C19H12ClN5S
C19H12BrN5S
C25H17N5S
C19H10F3N5S
C19H9ClF3N5S
C19H9BrF3N5S
C25H14F3N5S
C24H15N5S
CF3 p-ClC6H4
CF3 p-BrC6H4
CF3 p-C6H5C6H4
C6H5 C6H5
4g
4h
4i
(71.11)
65.69
(65.53)
59.68
(59.50)
74.68
(3.70)
3.14
(3.19)
2.85
(2.89)
3.91
(17.28)
15.85
(15.93)
14.41
(14.46)
14.63
4j
C6H5 p-ClC6H4
C6H5 p-BrC6H4
C6H5 p-C6H5C6H4
C24H14ClN5S
C24H14BrN5S
C30H19N5S
4k
4l
(74.84)
(3.95)
(14.55)
of exposure during microwave experiment) which
confirms the rate increase during microwave heating.
The structural assignments of compounds 2-4 were
yield, short reaction time, simple operation and pure
products are advantages of this procedure.
1
based on their elemental analyses and spectral (IR and H
EXPERIMENTAL
NMR) data. To the best of our knowledge this is the first
report on rapid synthesis of thiazolo[3,2-b][1,2,4]triazoles
under microwave irradiation.
Melting points were determined on a Cintex melting point
apparatus and are uncorrected. The purity of the compounds
was checked using precoated TLC plates (Merk, 60F-254). IR
spectra (KBr) (ꢀmax: cm-1) were recorded on a Perkin-Elmer BX
series FT-IR spectrophotometer H NMR spectra were recorded
on a Varian Gemini 200 MHz spectrometer (chemical shifts in ꢁ,
In conclusion, we have demonstrated a convenient and
highly efficient protocol for the synthesis of thiazolo[3,2-
b][1,2,4]triazoles under microwave irradiation. High
1

Sep-Oct 2007
Thiazolo[3,2-b][1,2,4]triazoles Containing 1,8-Naphthyridine Moiety
1163
ppm) using TMS as internal standard. Microanalyses were
performed on a Perkin-Elmer 240 CHN elemental analyser.
Irradiation was carried out in a domestic microwave oven (LG
MG 556 P, 2450 MHz). The starting compounds 1 were
prepared according to the reported procedures [18-21].
General procedure for the synthesis of 1-(2-substituted-1,8-
naphthyridine-3-carbonyl)-3-thiosemicarbazides (2). A mixture
of 1 (20.0 mmol), potassium thiocyanate (20.0 mmol), conc.
HCl (10 ml) and water (30 ml) was subjected to microwave
irradiation at 400 watts intermittently at 30 sec intervals for the
specified time (Table 1). On completion of the reaction, as
monitored by TLC, the reaction mixture was cooled, the solid
thus obtained was filtered and washed with water and
recrystallized from methanol to give 2.
9.28 (m, 1H, C7'-H), 7.36–7.68 (m, 6H, C6-H, 5Ar-H).
1
4f: IR: 1603 (C=C), 1589 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 8.45 (m, 1H, C5'-H), 8.04 (m, 2H, C4'-H, C6'-H),
9.28 (m, 1H, C7'-H), 7.48 – 7.76 (m, 5H, C6-H, 4Ar-H).
1
4g: IR: 1605 (C=C), 1591 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 8.42 (m, 1H, C5'-H), 7.95 (m, 2H, C4'-H, C6'-H),
9.28 (m, 1H, C7'-H), 7.44–7.74 (m, 5H, C6-H, 4Ar-H).
1
4h: IR; 1608 (C=C), 1595 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 8.44 (m, 1H, C5'-H), 8.02 (m, 2H, C4'-H, C6'-H),
9.15 (m, 1H, C7'-H), 7.46–7.83 (m, 10H, C6-H, 9Ar-H).
1
4i: IR: 1605 (C=C), 1592 cm-1 (C=N); H NMR (CDCl3): ꢀ
8.24 (m, 1H, C5'-H), 8.00 (m, 2H, C4'-H, C6'-H), 9.05 (m, 1H,
C7'-H), 7.38 – 7.61 (m, 6H, C6-H, 5Ar-H).
1
4j: IR: 1610 (C=C), 1589 cm-1 (C=N): H NMR (CDCl3): ꢀ
2a: IR: 3320, 3287, 3110 (NHNHCSNH2), 1686 (CONH),
1601 (C=N), 1136 cm-1 (C=S).
2b: IR: 3509, 3274, 3160 (NHNHCSNH2), 1712 (CONH),
1626 (C=N), 1130 cm-1 (C=S).
2c: IR: 3474, 3296, 3088 (NHNHCSNH2), 1680 (CONH),
1600 (C=N), 1138 cm-1 (C=S).
8.25 (m, 1H, C5'-H), 7.95 (m, 2H, C4'-H, C6'-H), 9.06 (m, 1H,
C7'-H), 7.38 – 7.55 (m, 5H, C6-H, 4Ar-H).
1
4k: IR: 1610 (C=C), 1585 cm-1 (C=N); H NMR (CDCl3): ꢀ
8.27 (m, C5'-H), 7.89 (m, 2H, C4'-H, C6'-H), 9.12 (m, 1H, C7'-H),
7.42 – 7.65 (m, 5H, C6-H, 4Ar-H).
1
4l: IR: 1605 (C=C), 1590 cm-1 (C=N); H NMR (CDCl3): ꢀ
General procedure for the synthesis of 3-(2-substituted-
1,8-naphthyridin-3-yl)-5-mercapto-1,2,4-traizoles (3). Compound
2 (20.0 mmol) in 8% KOH (50 ml) was exposed to microwaves
at 400 watts intermittently at 30 sec intervals for the specified
time (Table 1). On completion of reaction, as monitored by
TLC, the reaction mixture was cooled to room temperature,
diluted with cold water and neutralized with dilute acetic acid.
The solid thus obtained was collected by filtration, washed with
water and recrystallized from methanol to give 3.
8.32 (m, 1H, C5'-H), 8.08 (m, 2H, C4'-H, C6'-H), 9.10 (m, 1H,
C7'-H), 7.44 – 7.84 (m, 10H, C6-H, 9Ar-H).
Acknowledgements. The authors are thankful to the
Directors, IICT, Hyderabad and IIT, Madras for providing
spectral and analytical data.
REFERENCES AND NOTES
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1
3a: IR: 3385 (NH), 2574 (SH), 1618 cm-1 (C=N); H NMR
(CDCl3 + DMSO-d6): ꢀ 3.03 (s, 3H, CH3), 8.62 (s, 1H, C4'-H),
8.25 (m, 1H, C5'-H), 7.54 (m, C6'-H), 9.14 (m, 1H, C7'-H), 13.40
(brs, 1H, SH), 13.72 (brs, 1H, NH).
3b: IR: 3347 (NH), 2553 (SH), 1615 cm-1 (C=N)
3c: IR: 3325 (NH), 2565 (SH), 1610 cm-1 (C=N)
General procedure for the synthesis of 5-aryl-2-(2-substi-
tuted-1,8-naphthyridin-3-yl)-thiazolo[3,2-b][1,2,4]triazoles
(4). A mixture of 3 (20.0 mmol), ꢁ-halogenoketone (20.0 mmol)
and anhyd. methanol (40 ml) was subjected to microwave
irradiation at 200 watts intermittently at 30 sec intervals for
specified time (Table 2). On completion of reaction, as monitored
by TLC, the reaction mixture was cooled and treated with chilled
water. The precipitate thus obtained was collected by filtration,
washed with water and recrystallized from ethanol to afford 4.
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1
4a: IR: 1608 (C=C), 1595 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 3.04 (s, 3H, CH3), 8.20 (m, 1H, C5'-H), 8.09 (m,
2H, C4'-H, C6'-H), 9.18 (m, 1H, C7'-H), 7.40 – 7.62 (m, 6H, C6-
H, 5Ar-H).
1
4b: IR: 1605 (C=N), 1591 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 3.01 (s, 3H, CH3), 8.26 (m, 1H, C5'-H), 8.00 (m,
2H, C4'-H, C6'-H), 9.08 (m, 1H, C7'-H), 7.42 – 7.63 (m, 5H, C6-
H, 4Ar-H).
1
4c: IR: 1610 (C=C), 1586 cm-1 (C=N); H NMR (CDCl3 +
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DMSO-d6): ꢀ 3.04 (s, 3H, CH3), 8.26 (m, 1H, C5'-H), 7.99 (m,
2H, C4'-H, C6'-H), 9.09 (m, C7'-H), 7.55 – 7.70 (m, 5H, C6-H,
4Ar-H).
1
4d: IR; 1602 (C=C), 1592 cm-1 (C=N), H NMR (CDCl3 +
DMSO-d6): ꢀ 3.02 (s, 3H, CH3), 8.12 (m, 1H, C5'-H), 7.71 (m,
2H, C4'-H, C6'-H), 9.09 (m, 1H, C7'-H), 7.45 – 7.67 (m, 10H, C6-
H, 9Ar-H).
1
4e: IR: 1609 (C=C), 1598 cm-1 (C=N); H NMR (CDCl3 +
DMSO-d6): ꢀ 8.74 (m, 1H, C5'-H), 8.06 (m, 2H, C4'-H, C6'-H),