Novel and expedient regioselective synthesis of 2-imino-3-methyl-2,3- dihydrothiazoles

Article abstract of DOI:10.1080/00397910802029356

Cyclization of α-tosyloxyacetophenones 1 and N-methylthiourea 2 in acidic medium affords a novel and expedient method to synthesize 2-imino-3-methyl-2,3-dihydrothiazoles 3 with excellent level of regiocontrol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802029356

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Novel and Expedient
Regioselective Synthesis
of 2-Imino-3-methyl-2,3-
dihydrothiazoles
Ranjana Aggarwal a & Rajiv Kumar a
a Department of Chemistry, Kurukshetra University,
Kurukshetra, Haryana, India
Published online: 18 Aug 2008.
To cite this article: Ranjana Aggarwal & Rajiv Kumar (2008): Novel and Expedient
Regioselective Synthesis of 2-Imino-3-methyl-2,3-dihydrothiazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:13, 2096-2102
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Synthetic Communications1, 38: 2096–2102, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802029356
Novel and Expedient Regioselective Synthesis of
2-Imino-3-methyl-2,3-dihydrothiazoles
Ranjana Aggarwal and Rajiv Kumar
Department of Chemistry, Kurukshetra University,
Kurukshetra, Haryana, India
Abstract: Cyclization of a-tosyloxyacetophenones 1 and N-methylthiourea 2 in
acidic medium affords a novel and expedient method to synthesize 2-imino-3-
methyl-2,3-dihydrothiazoles 3 with excellent level of regiocontrol.
Keywords: Acidic medium; 2-imino-3-methyl-2,3-dihydrothiazoles; N-methylthi-
ourea; Regioselective synthesis; a-tosyloxyacetophenones
INTRODUCTION
Recently, while studying the reaction of heteroarylhydrazines with
fluorinated b-diketones,[1] we observed that regiochemistry of the
products was altered when the reaction medium was changed from neutral
to acid. Whereas 5-hydroxy-5-trifluoromethyl-D2-pyrazolines (hydrated
form of 5-trifluoromethylpyrazoles) were the major product in a neutral
medium, formation of 3-trifluoromethylpyrazoles occurred in the acidic
medium. This observation prompted us to explore the possibility of
synthesis of 2-imino-3-methyl-2,3-dihydrothiazole 3, a regioisomer of
2-methylaminothiazole 4, by modifying the conditions of Hantzsch
thiazole synthesis. In contrast to several methods available for the
synthesis of 2-aminothiazoles,[2–6] there are only a few reports that
describe the synthesis of 2-imino-2,3-dihydrothiazole derivatives,[7–10]
Received October 11, 2007.
Address correspondence to Ranjana Aggarwal, Department of Chemistry,
Kurukshetra University, Kurukshetra 136119, Haryana, India. E-mail:
ranjana67in@yahoo.com
2096

2-Imino-3-methyl-2,3-dihydrothiazoles
2097
despite the clear opportunity to introduce an additional handle for
chemical diversity. The most commonly reported routes to 2-imino-2,3-
dihydrothiazole derivatives involve reaction of a-thiocyanatoketones
with anilines,[7] reaction of bis-methylformamidine disulphide dihy-
drochloride with ketones,[8] reaction of 2-aminothiazoles with alkyl
halides,[9] and reaction of a-haloketones with substituted thioureas.[10]
However, these methods involve a multistep synthesis, prolonged reac-
tion time, use of lachrymatory substrates, and finally yields of the
products are moderate at best. Consequently, there is need for an alter-
native procedure involving milder conditions and simpler substrates.
We describe here a novel and expedient method for regioselective syn-
thesis of 2-imino-3-methyl-2,3-dihydrothiazoles 3 involving reaction of
a-tosyloxyacetophenones 1 and N-methylthiourea 2 in an acidic medium.
RESULTS AND DISCUSSION
Hantzsch thiazole synthesis involves reaction of a-haloketones with
thioamides and thioureas, and it provides a useful method for the syn-
thesis of a wide variety of 2-alkyl=arylamino-4-substituted thiazoles.[6,11]
A large variety of different thiazoles have been synthesized by us using
an efficient modification utilizing a-tosyloxyketones, obtained by the
oxidation of enolizable ketones with [hydroxy(tosyloxy)iodo]benzene
(HTIB) in place of highly lachrymatory a-haloketones.[12,13] In the
present study, initially, the reaction between a-tosyloxyacetophenones 1
Scheme 1. Reaction of a-tosyloxacetophenones 1 and N-methylthiourea 2 with or
without HCl.

2098
R. Aggarwal and R. Kumar
and N-methylthiourea 2 was carried out with or without adding HCl to
refluxing ethanol. Although the reaction in neutral conditions afforded
the exclusive formation of 2-methylaminothiazole 4, the thin-layer
1
chromatography (TLC) and H NMR of the crude reaction mixture of
the acidic medium indicated the formation of an additional compound,
2-imino-3-methyl-2,3-dihydrothiazole 3, along with 4 (Scheme 1).
Encouraged by this preliminary result, we attempted to optimize the
reaction conditions for the formation of 3 as the major product. We
envisaged accomplishing a set of experiments by varying the concen-
tration of HCl in ethanol and the temperature of the reaction taking
a-tosyloxy-p-methoxyacetophenone 1a as a typical compound.
As evident in Table 1, the optimum condition of concentration of
HCl and temperature for the formation of 3a in 88% proportion was
established as 10 M HCl– EtOH (3:5) at 80 ꢀC for 45 min. To check the
scope of this method, other a-tosyloxyacetophenones 1b–f were made
to react with 2 under similar conditions of concentration and tempera-
ture. The ratios of 3 and 4 were calculated on the basis of an analysis
of 1H NMR of the crude reaction mixture. The results summarized
in Table 2 indicate the generality of this reaction with respect to vari-
ous a-tosyloxyacetophenones 1. The method is mild, and except for
a-tosyloxy-p-nitroacetophenone 1e, tolerates several substituted aryl
and thienyl groups at 4-position and affords the desired products in
isolated yields ranging from 67 to 79%.
Hydrochloride salts of two isomers 3 and 4 were purified by frac-
tional crystallization. 3-HCl, being less soluble in ethanol, crystallized
out first, was neutralized with aq. NaOH, and recrystallized from ethanol
to give 3. The mother liquor, on basification followed by extraction
with ethyl acetate and recrystallization from ethanol, provided 4 as a free
base. 2-Imino-3-methyl-4-(p-nitrophenyl)-2,3-dihydrothiazole 3e could
not be completely purified because of its low yield. Finally, the known
products were identified by comparison of mp’s with those reported in
Table 1. Ratio of 3a at different temperatures and concentrations of
HCl in ethanol
Temperature (ꢀC)
10M HCl–EtOH
Ratio of 3a
95
95
80
60
30
1:2
3:5
3:5
3:5
3:5
75
80
88
84
68
aRatio calculated from the 1H NMR of the crude reaction mixture.

2-Imino-3-methyl-2,3-dihydrothiazoles
2099
Table 2. 1H NMR data, proportion, and physical data of 3 and 4 in 10M
HCl–EtOH (3:5) at 80 ꢀC for 45 min
d (5-H)
(CDCl3)
d (CH3)
(CDCl3)
Proportion (%)
in mixturesa
Mp (ꢀC)
(lit.)
Yieldsb
(%)
Compound
3a
3b
3c
3d
3e
5.65
5.70
5.89
5.85
5.92
3.20
3.22
3.29
3.27
3.27
88
85
80
71
4
76–78
72–74
78–80[10]
70–71[10]
Cannot be
isolated
79
78
73
67
—
3f
5.76
6.58
6.66
6.63
6.64
6.95
6.57
3.21
3.00
3.02
2.94
2.96
3.06
2.96
79
12
15
20
29
96
21
76–78
76
9
4a
4b
4c
4d
4e
4f
120–12215
126–12816
132–13410
136–13810
184–18610
120–122
12
13
14
88
10
1
aRatio calculated from the H NMR of the crude reaction mixture.
bIsolated yields.
the literature. The structures of other unknown compounds were
1
confirmed on the basis of their IR, H NMR, and elemental analyses.
1H NMR proved to be an important tool in distinguishing the
structure of the isomers 3 and 4 on the basis of two sharp singlets due
to 5-H of thiazole ring and N-CH3 of methyl protons. The difference
in the chemical shift of the proton at 5-position of the two isomers is
about d 0.9 units. In the case of 3, the 5-H proton resonated upfield at
about d 5.7, whereas in 4 it resonated at about d 6.6. Such a shielding
in 3 can be attributed to the less aromatic character of the 2,3-
dihydrothiazole ring. Similarly, the proton signal of N-CH3 of the two
isomers exhibited the difference of around d 0.2 units. This deshielding
is because in case of 3, CH3 is attached to a sp3 hybridized nitrogen,
which is the part of ring (Table 2). In IR, N-H stretch of these two
isomers 3 and 4 appears at about 3050 and 3350 cmꢁ1, respectively.
Murav’eva and Shchukina[14] have reported that in an acidic
medium, 3 rearranges to 4. However, when 3b and 4b were separately
subjected to these conditions of temperature and concentration, no such
isomerization was observed.
In summary, we have developed an efficient and high-yielding
protocol for the regioselective synthesis of 3 from readily available
a-tosyloxyacetophenones 1 and N-methylthiourea 2 under acidic

2100
R. Aggarwal and R. Kumar
conditions. These results are from our preliminary experiments, further
studies concerning the full scope of this reaction and its mechanism are
in progress.
EXPERIMENTAL
The IR spectra of the compounds were recorded on a Buck Scientific
IR M-500 spectrophotometer using KBr pellets (nmax in cmꢁ1): 1H
NMR spectra were recorded on a Bruker instrument at 300 MHz; and
chemical shifts are expressed in d-scale downfield from TMS as an
internal standard.
General Procedure
(a)Reaction between a-tosyloxyacetophenones 1 and N-methylthiourea
2: a-tosyloxyacetophenones 1 (2 m mol) was added to the solution of
N-methylthiourea 2 (0.18 g, 2 m mol) in 10 M HCl (6 ml)-EtOH (10 ml).
The resulting solution was stirred for 45 min. at a temperature of 80 ꢀC.
On cooling slowly, a solid separated out, which was filtered, washed with
aq. NaOH, and recrystallized from ethanol to afford 2-imino-3-methyl-
2,3-dihydrothiazole 3. The filtrate was neutralized using aq. NaOH and
extracted with ethyl acetate (3 ꢂ 20 ml). The combined organic extracts
were dried over anhydrous sodium sulphate, filtered, and concentrated.
The solid thus obtained was recrystallized from ethanol to give 2-
methylaminothiazole 4.
(b)
A
solution of 2-imino-3-methyl-4-(p-methylphenyl)-2,3-
dihydrothiazole (3b) (0.5 g) in 10 M HCl (6 ml)–EtOH (10 ml) was
stirred 45 min. at 80 ꢀC. Workup of the reaction as in the previous
experiment gave unreacted 3b (0.46 g), identified by comparison with
an authentic sample. Similarly, the 2-methylamino-4-(p-methylphenyl)-
thiazole (4b) was recovered unchanged when subjected to the previous
conditions.
Data
Compound 3a (found N, 12.63;C11H12N2OS required N, 12.73). IR
(cmꢁ1) 3045 (N-H); 1H NMR (CDCl3): 3.20 (s, 3H, N-CH3), 3.86
(s, 3H, OCH3), 5.65 (s, 1H, 5-H), 6.94 (d, J ¼ 8.4 Hz, 2H, 30, 50-H),
7.26 (d, J ¼ 8.4 Hz, 2H, 20, 60-H).

2-Imino-3-methyl-2,3-dihydrothiazoles
2101
Compound 3b (found N, 13.65; C11H12N2S required N, 13.72) IR
1
(cmꢁ1) 3047 (N-H); H NMR (CDCl3): 2.41 (s, 3H, CH3), 3.22 (s, 3H,
N-CH3), 5.70 (s, 1H, 5-H), 7.24–7.29 (m, 4H, 20, 30, 50, 60-H).
Compound 3f (found N, 14.25; C8H8N2S2 required N, 14.29) IR
(cmꢁ1) 3055 (N-H); 1H NMR (CDCl3): 3.21 (s, 3H, N-CH3), 5.76
(s, 1H, 5-H), 6.99–7.03 (m, 2H, 30, 40-H), 7.29 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz,
Hz, 1H, 50-H).
Compound 4f (found N, 14.22; C8H8N2S2 required N, 14.29) IR
(cmꢁ1) 3550 (N-H); 1H NMR (CDCl3): 2.96 (s, 3H, NH-CH3), 6.57
(s, 1H, 5-H), 6.94–7.35 (m, 3H, 30, 40, 50-H).
ACKNOWLEDGMENTS
We thank the Council of Scientific and Industrial Research, New Delhi,
for financial assistance and a junior research fellowship to Rajiv Kumar.
Thanks are also due to Sophisticated Analytical Instrumentation Facility,
Central Drug Research Institute (RSIC, CDRI), Lucknow, India, for
providing elemental analysis. We also thank Professor S. P. Singh for
helpful suggestions.
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