Microwave-assisted synthesis of spiro(cycloalkane thiazolo-s-tetrazine)

Article abstract of DOI:10.1080/10426500802590038

Microwave irradiation of cyclic ketones with thiocarbohydrazide furnish the corresponding s-tetrazine derivatives 1a-d, which upon irradiation with chloroacetic acid and sodium acetate in acetic acid, give the corresponding thiazolidinone derivatives 2a-d

Full text of DOI:10.1080/10426500802590038

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Microwave-Assisted Synthesis
of Spiro(cycloalkane thiazolo-s-
tetrazine)
Rajani K. Behera a , Anita Pati b , Manabendra Patra
a & Ajay K. Behera a
a Organic Synthesis Laboratory, Department of
Chemistry , Sambalpur University , Burla, Orissa,
India
b National Institute of Science & Technology ,
Berhampur, Orissa, India
Published online: 03 Nov 2009.
To cite this article: Rajani K. Behera , Anita Pati , Manabendra Patra & Ajay K.
Behera (2009) Microwave-Assisted Synthesis of Spiro(cycloalkane thiazolo-s-tetrazine),
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:11, 2827-2834, DOI:
10.1080/10426500802590038
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Phosphorus, Sulfur, and Silicon, 184:2827–2834, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802590038
Microwave-Assisted Synthesis of Spiro(cycloalkane
thiazolo-s-tetrazine)
Rajani K. Behera,1 Anita Pati,2 Manabendra Patra,1 and
Ajay K. Behera1
1Organic Synthesis Laboratory, Department of Chemistry, Sambalpur
University, Burla, Orissa, India
2National Institute of Science & Technology, Berhampur, Orissa, India
Microwave irradiation of cyclic ketones with thiocarbohydrazide furnish the corre-
sponding s-tetrazine derivatives 1a–d, which upon irradiation with chloroacetic
acid and sodium acetate in acetic acid, give the corresponding thiazolidinone
derivatives 2a–d. These derivatives 2a–d upon condensation with benzaldehyde
afford the benzylidine derivatives 3a–d. The s-tetrazine derivatives 1a–d and 1,2-
dibromoethane upon irradiation gives the thiazolo-s-tetrazine derivatives 4a–d.
The structures of 1–4 were established by IR, 1H NMR, and 13C NMR data.
Keywords Irradiation; microwave assisted; spiro; tetrazine
INTRODUCTION
Sometimes, in a chemical reaction, starting materials as well as prod-
ucts decompose or unwanted products are formed because of a long
reaction time and high temperature, which invariably reduce the per-
centage of yield. Thus the production of a large amount of waste from a
reaction is undesirable both from economic and an environmental point
of view. Green technologies form an alternative method to allow a more
clean and efficient chemical syntheses. Microwave energy is fast be-
coming the method of choice for both industrial and academic chemists
for driving reactions to completion, as it offers the safest, most effective
way to increase reaction rates and improve product yields, while pro-
moting green chemistry ideas. Reactions that previously took hours, or
Received 12 June 2008; accepted 20 October 2008.
The authors thank to the Department of Science & Technology, Govt. of India, and
University Grant Commission, New Delhi, for FIST and DRS support. One of the authors
(A.P.) thanks Sambalpur University for the Sir J.J. Ghandy fellowship.
Address correspondence to Rajani K. Behera, Organic Synthesis Laboratory, Depart-
ment of Chemistry, Sambalpur University, Jyoti Vihar, Burla 768 019, Orissa, India.
E-mail: rajanibehera@yahoo.co.in
2827

2828
R. K. Behera et al.
even days, to complete can now be performed in minutes.1–8 In the last
decade, some of the first examples yielded interesting results, which led
to much research in this novel technique.9–19 Dandia et al.20 reported a
one-pot synthesis of novel spiro[pyrazolo[4,3-c][1, 5]benzothiazepines]
with a 71% yield within 6–8 min using microwave irradiation. They also
reported the synthesis of novel spiro[indole-pyrido[2,3-d]pyrimidines]
by the reaction of in situ generated spiro[indole-dihydropyridine] and
urea/CS2 using basic alumina as a solid support or a few drops of DMF
as a homogenizer under microwave irradiation for 3–4 min in 85–89%
yield.21 Spiro-(indoline-isoxazolidines) were prepared in modest yields,
by the cycloaddition reaction between ethyl(3-indolylidene)-acetate and
various substituted α, N-diphenylnitrones under solvent-free condi-
tions using a microwave method.22 The reaction conducted under con-
ventional heating in an oil bath did not proceed even after 20 h, espe-
cially when it was carried out without solvent. The 4ꢀ-(2-butyl-4-oxo-1,3-
diaza-spiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-carbonitrile was syn-
thesized by irradiating methyl 1-amino-1-cyclopentanecarboxylate and
valeric acid in anhydrous pyridine, with triphenyl phosphate (neat).23
In our ongoing research program on the development of spirohete-
rocycles, we became interested in the efficient and microwave-assisted
syntheses of the spirotetrazines into which thiazole and thiazolidinone
moieties were incorporated. Pujari and colleagues24–27 reported the syn-
theses of spirotetrazines derivatives (1–4) by conventional methods
that required long reaction times and only moderate yields. Therefore,
we have investigated the syntheses of these compounds (1–4) in mi-
crowave conditions.
RESULTS AND DISCUSSION
Cycloalkanones of different sizes undergo condensation with thiocabo-
hydrazide under microwave condition to yield corresponding s-tetrazine
derivatives 1a–d. Thiazolidinone derivatives 2a–d are obtained upon
irradiation of a mixture of s-tetrazine derivatives 1a–d and chloroacetic
acid in acetic acid in the presence of sodium acetate. These thiazolidi-
none derivatives 2a–d containing active methylene groups are sub-
jected to condensation with benzaldehyde to form respective benzyli-
dine compounds 3a–d. Thiazolo-s-tetrazine derivatives 4a–d are also
obtained by the reaction of the s-tetrazine derivatives 1a–d with dibro-
moethane. These reactions are depicted in Scheme 1.
The IR spectral data of the compounds synthesized by microwave ir-
1
radiation were identical to those reported earlier.24–27 The H NMR

Synthesis of Spiro(cycloalkanethiazolo-s-tetrazine)
2829
SCHEME 1
spectral data of compounds 2–4 revealed some interesting results,
which were not observed by Pujari and colleagues.24–27 It was reported
that the methylene protons of cycloalkane ring adjacent to the spiro
carbon in compounds 2 appeared as one multiplet at δ 2.46–2.62 in
1
their H NMR spectra. In the case of these compounds synthesized by
1
microwave irradiation, two clear multiplets were observed in the H

2830
R. K. Behera et al.
NMR spectra at δ 2.54–2.57 and at δ 2.68–2.71. This is because these
compounds have a thiazolidinone moiety on one side of the spirote-
trazine structure, which makes the methylene proton of cycloalkane
ring adjacent to spiro carbon slightly different. The downfield shift ex-
perienced by one of the methylene protons is due to the carbonyl group
of thiazolidinone ring in 2, which is evident from the fact that in case of
compound 4, where there is no carbonyl group, only one multiplet has
been observed at δ 2.42–2.52.
1
The H NMR data of compounds 3c and 4c and the 13C NMR data
of compounds 1c–4c are also given in the appropriate places in the
Experimental section, which were not reported earlier.25 The 13C NMR
spectral data provides strong evidence in favor of the formation of the
products as mentioned and also confirm the proposed structures.
We have synthesized 16 novel spiro compounds. The IR and 1H NMR
data of all the compounds synthesized by microwave irradiation were
found to be almost identical with those reported earlier.24–27 The analyt-
ical and spectral data of compounds 3b, 3d, 4a, 4c, and 4d synthesized
by the microwave method are given in the Experimental section, as
these were not reported earlier. The reaction times, yields of the prod-
ucts (1–4) under microwave condition and from the classical heating
method, and also the melting points of these compounds are given in
the Table I.
EXPERIMENTAL
The melting points were determined on a Zenith apparatus and are
uncorrected. IR spectra were recorded on a Perkins Elmer FT-IR spec-
trophotometer using KBr disc. 1H and 13C NMR spectra were recorded
on a 400 MHz FT NMR spectrometer and were recorded in CDCl3.
Purity of the products was checked by TLC, using silica gel G (BDH)
and toluene:ethyl acetate (1:1) as eluent. The reactions were done in a
domestic microwave oven (LG make) operated at 700 Watt generating
2450 MHz frequency. Thiocarbohydrazide was prepared according to
the reported procedure.28
1,2,4,5-Tetraazaspiro[5.6]dodecane-3-thione (1c)
A mixture of thiocarbohydrazide (1.06 g, 0.01 mol) and cycloheptanone
(1.18 mL, 0.01 mol) in water:ethanol (1:1, 2 mL) was taken in a beaker
(25 mL). Then the mixture was irradiated in a microwave oven for 50
sec. The cream-colored precipitate obtained was washed well with hot
water (25 mL) and finally crystallized from ethanol to obtain needle-
shaped crystals. Mp 155◦C, Yield 95%, (Found S, 15.89, C8H16N4S

Synthesis of Spiro(cycloalkanethiazolo-s-tetrazine)
2831
TABLE I Physical and Analytical Data
Microwave method Conventional method
Comp.
No.
Molecular
formula
Mp Yield Time Mp
Yield Time
S% Cal.
(Found)
n
(◦C)
(%) (Sec) (◦C)
(%)
(h)
1a
1b
1c
1d
2a
2b
2c
2d
3a
3c
4b
0
1
2
3
0
1
2
3
0
2
1
C6H12N4S
C7H14N4S
C8H16N4S
C9H18N4S
C8H12N4SO
C9H14N4SO
167
168
155
175
140
129
92
93
95
90
70
75
77
75
62
70
60
50
40
50
45
40
40
40
40
40
40
35
179a
169b
150c
180d
144e
130b
135c
120d
177e
240c
179b
89a
81b
85c
84d
59e
53b
66c
63d
40e
50c
44b
24a
24b
24c
24d
6e
21.62 (21.55)
17.20 (17.16)
16.00 (15.89)
14.95 (14.90)
15.09 (14.96)
14.16 (13.99)
13.33 (13.18)
12.60 (12.54)
10.67 (10.61)
9.76 (9.68)
5b
C10H16N4SO 133
5c
C11H18N4SO 125
C15H16N4SO 180
C17H20N4SO 235
5d
3e
3c
C9H16N4S
176
6b
15.09 (14.95)
aRef.29
bRef.24
cRef.26
dRef.27
eRef.25
requires S, 16.0%). IR (KBr) in cm−1: 1231 (C S), 3155–3205 (N H).
1H NMR (CDCl3): δ1.64 (m, 8H, 4 × CH2), 2.35 (m, 4H, 2 × CH2), 4.35
(bs, 2H, 2 × NH), 8.44, 8.50 (bs, 2H, 2 × NHCS). 13C NMR (CDCl3): δ
24.23, 27.50, 30.10, 36.88, 179.72 (C S).
6ꢀ(7ꢀH)-Oxospiro[cycloheptane-1,3ꢀ(4ꢀH)-[2H]thiazolo[3,2-b]-s-
tetrazine] (2c)
To a mixture of 1c (2.00 g, 0.01 mol), chloroacetic acid (0.95 g, 0.01 mol),
and fused sodium acetate (0.82 g, 0.01 mol), a few drops of glacial acetic
acid were added and the mixture was irradiated in a microwave oven
for 40 sec. Then the reaction mixture was poured into ice cold water,
and the precipitate obtained was filtered, washed well with water (50
mL), and crystallized from ethanol. Mp 133◦C, Yield 77%, (Found S,
13.18, C10H16N4SO requires S, 13.33%). IR (KBr) in cm−1: 1613(C N),
1
1738(C O), 3209–3318 (N H). H NMR (CDCl3): δ 1.64 (m, 8H, 4 ×
CH2), 2.56 (m, 2H, CH2), 2.71 (m, 2H, CH2), 3.74 (s, 2H, S-CH2), 4.59
(bs, 2H, 2 × NH). 13C NMR (CDCl3): δ 24.24, 27.50, 30.12, 32.49 (Thia-
zolidinone CH2), 36.88, 149.5 (N = C S), 171.3 (C O).

2832
R. K. Behera et al.
7ꢀ-Benzylidine-6ꢀ(7ꢀH)-oxospiro[cycloheptane-1,3ꢀ(4ꢀH)-
[2H]thiazolo[3,2-b]-s-tetrazine] (3c)
To a mixture of 2c (0.24 g, 0.001 mol), benzaldehyde (0.1 mL, 0.001
mol), and sodium acetate (0.16 g, 0.002 mol), a few drops of glacial
acetic acid were added and the mixture was irradiated in a microwave
oven for 40 sec. The yellow-colored precipitate obtained was washed
well with water (50 mL) and then crystallized from glacial acetic acid.
Mp 235◦C, Yield 70%, (Found S, 9.68, C17H20N4SO requires S, 9.76%).
IR (KBr) in cm−1: 1615 (C N), 1705 (C O), 3201–3315 (N H). 1H NMR
(CDCl3): δ1.64 (m, 8H, 4 × CH2), 2.54 (m, 2H, CH2), 2.73 (m, 2H, CH2),
4.57 (bs, 2H, 2 × NH), 7.71 (m, 6H, Ar-H & = CH). 13C NMR (CDCl3): δ
24.22, 27.49, 30.12, 36.88, 122.2 (Thiazolidinone C = CH), 127.1, 128.6,
129.4, 132.5 ( CH), 136.8, 149.4 (N = C S), 166.22 (C O).
7ꢀ-Benzylidene-6ꢀ(7ꢀH)-oxospiro[cyclohexane-1,3ꢀ(4ꢀ)H-
[2H]thiazole[3,2-b]-s-tetrazine] (3b)
It was prepared from 2b by the same method as above in 40 sec. Mp
215◦C, Yield 65%, (Found S, 10.19, C16H18N4SO requires S, 9.99%). IR
1
(KBr) in cm−1: 1565, 1630, 1705, 3240, 3300. H NMR (CDCl3): 1.55
(m, 6H, 3 × CH2), 2.52 (m, 4H, 2 × CH2), 4.59 (bs, 2H, 2 × NH), 7.74
(m, 6H, Ar-H & = CH). 13C NMR (CDCl3): 24.22, 27.49, 30.12, 36.88,
122.2, 127.1, 128.6, 129.4, 132.5, 136.8, 149.4, 166.2.
7ꢀ-Benzylidene-6ꢀ(7ꢀH)-oxospiro[cyclooctane-1,3ꢀ(4ꢀ)H-
[2H]thiazole[3,2-b]-s-tetrazine] (3d)
It was prepared from 2d by the same method as above in 60 sec. Mp
225◦C, Yield 64%, (Found S, 9.36, C18H22N4SO requires S, 9.24%). IR
1
(KBr) in cm−1: 1570, 1635, 1708, 3245, 3310. H NMR (CDCl3): 1.58
(m, 10H, 5 × CH2), 2.46 (m, 4H, 2 × CH2), 4.60 (bs, 2H, 2 × NH), 7.69
(m, 6H, Ar-H & = CH). 13C NMR (CDCl3): 23.60, 24.34, 27.55, 30.28,
37.10, 122.8, 127.4, 128.8, 130.2, 133.0, 137.4, 150.6, 167.1.
6ꢀ,7ꢀ-Dihydrospiro[cycloheptane-1,3ꢀ(4ꢀH)-[2H]thiazolo[3,2-b]-s-
tetrazine] (4c)
To a mixture of 1c (2.00 g, 0.01 mol) and 1,2-dibromoethane (1.88 g, 0.01
mol), a few drops of glacial acetic acid were added and the mixture was
irradiated in a microwave oven for 35 sec. Then the reaction mixture
was cooled, ice cold water was added, and the precipitate obtained was
filtered, dried, and crystallized from ethanol. Mp 170◦C, Yield 74%,

Synthesis of Spiro(cycloalkanethiazolo-s-tetrazine)
2833
(Found S, 14.09, C10H18N4S requires S, 14.16%). IR (KBr) in cm−1
:
1
1610 (C N), 3160–3250 (N H). H NMR (CDCl3): δ1.67 (m, 8H, 4 ×
CH2), 2.50 (m, 4H, 2 × CH2), 3.16 (t, 2H, S-CH2), 3.85 (t, 2H, -N-CH2),
4.45 (bs, 2H, 2 × NH). 13C NMR (CDCl3): δ 24.24, 27.48, 30.12, 36.12
(S- CH2), 36.88, 55.64 (N-CH2), 149.4 (N C-S).
6ꢀ,7ꢀ-Dihydrospiro[cyclopentane-1,3ꢀ(4ꢀH)-[2H]thiazolo[3,2-b]-s-
tetrazine] (4a)
It was prepared from 1a by the same method as above in 35 secs. Mp
175◦C, Yield 62%, (Found S, 16.02, C8H14N4S requires S, 16.16%). IR
1
(KBr) in cm−1: 1530, 1600, 3080, 3160. H NMR (CDCl3): δ 1.72 (m,
4H, 2 × CH2), 2.55 (m, 4H, 2 × CH2), 3.20 (t, 2H, S-CH2), 3.88 (t, 2H,
-N-CH2), 4.52 (bs, 2H, 2 × NH). 13C NMR (CDCl3): δ 27.60, 30.38, 36.44,
37.15, 55.74, 150.10.
6ꢀ,7ꢀ-Dihydrospiro[cyclooctane-1,3ꢀ(4ꢀH)-[2H]thiazolo[3,2-b]-s-
tetrazine] (4d)
It was prepared from 1d by the same method as above in 35 sec. Mp
171◦C, Yield 69%, (Found S, 13.33, C11H20N4S requires S, 13.14%). IR
(KBr) in cm−1: 1560, 1610, 3160–3250. 1H NMR (CDCl3): δ1.58 (m, 10H,
5 × CH2), 2.52 (m, 4H, 2 × CH2), 3.18 (t, 2H, S-CH2), 3.86 (t, 2H, -N-
CH2), 4.64 (bs, 2H, 2 × NH). 13C NMR (CDCl3): δ 23.58, 24.44, 27.56,
30.32, 36.12, 36.90, 55.70, 149.8.
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