An efficient one-pot synthesis of functionally diverse 2-aminothiazoles from isothiocyanates, amidines/guanidines and halomethylenes

Article abstract of DOI:10.1016/j.tetlet.2013.07.122

An efficient one-pot method for the synthesis of 2-aminothiazoles using simple starting materials like isothiocyanates, amidines/guanidines and various halomethylenes is reported. The synthesis of 2-aminothiazoles involves reactions such as nucleophilic a

Full text of DOI:10.1016/j.tetlet.2013.07.122

Accepted Manuscript
An efficient one-pot synthesis of functionally diverse 2-aminothiazoles from
isothiocyanates, amidines/guanidines and halomethylenes
Hitesh B. Jalani, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, V.
Sudarsanam, Kamala K. Vasu
PII:
S0040-4039(13)01290-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.122
TETL 43320
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 June 2013
19 July 2013
23 July 2013
Please cite this article as: Jalani, H.B., Pandya, A.N., Pandya, D.H., Sharma, J.A., Sudarsanam, V., Vasu, K.K., An
efficient one-pot synthesis of functionally diverse 2-aminothiazoles from isothiocyanates, amidines/guanidines and
halomethylenes, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.122
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An efficient one-pot synthesis of functionally diverse 2-aminothiazoles
from isothiocyanates, amidines/guanidines and halomethylenes†
Hitesh B. Jalani, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma,
V. Sudarsanam, Kamala K. Vasu*
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and
Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej,
Ahmedabad-380 054, Gujarat, India.
† Communication Ref. No.: PERD-130613
*Corresponding author. Tel.: +91 79 27439375; Fax: +91 79 27450449;
e-mail: kamkva@gmail.com,
Abstract: An efficient one-pot method for the synthesis of 2-aminothiazoles using simple
starting materials like isothiocyanates, amidines/guanidines and various halomethylenes is
reported. The synthesis of 2-aminothiazoles involves reactions such as nucleophilic
addition, S-alkylation and intramolecular nucleophilic substitution in which amines
departs as the leaving group.
Keywords: 2-aminothiazoles, isothiocyanates, amidines, guanidines, one-pot reaction.
2-Aminothiazole is an important and classic heterocyclic scaffold used in the drug
discovery programs. The broad spectrum biological activities exhibited by this structure
include anticancer,1 antiviral,2 antibacterial,3 antiprion,4 and psychotropic activities5 that
assign it as an indispensible heterocyclic feature in drug design. In addition to this,
recently, our group has successfully employed 2-aminothiazole scaffolds in the design of
anti-inflammatory agents6 as well as adenosine receptor antagonist.7 Recently, 2-
aminothiazole analogues have been identified as druglike candidates in the treatment of
diabetes8 and mycobacterium tuberculosis.9 Apart from biological properties, films of
conjugated polyaminothioazole have recently been demonstrated to have electrochemical
properties with high thermal stability.10 All the above described biological and physico-
chemical properties of aminothioazole are probably due to its small ring structure with π
excessive and π deficient properties, due to nitrogen atom behaving as hydrogen bond
acceptor site.
In view of diverse biological and physico-chemical properties by 2-aminothiazoles
scaffold, many synthetic protocols have been reported for their synthesis, which includes
Hantzsch’s cyclocondensation of thiourea with α-haloketones/α-tosylketone11 and the
reactions of α-thiocyanate carbonyl compounds with aromatic or aliphatic amine
hydrochlorides.12 2-aminothiazoles are also synthesized by one-pot reaction of enolizable
ketones with a mixture of N-bromosuccinimide, thiourea, and benzoyl peroxide,13 as well
as through the reaction of amidinothioureas with halomethylenes6 in multistep synthesis.

In continuation of our work on the development of efficient protocols for the synthesis of
various biologically interesting heterocyclic compounds from simple starting materials
like isothiocyanates and amidines/guanidines,14,15 we have been working on the reaction
of various isothiocyanates with amidines/guanidines to produce functionally diverse
adducts, known as amidinothioureas and guanidinothioureas. These amidinothioureas
and guanidinothioureas adducts were further explored for the synthesis of thiazole,16
imidazole,17 triazine,18 triazole19 and recently 1,2,4-oxadiazole20 using either multistep or
one-pot synthesis. Earlier, we reported multistep process for the preparation of substituted
thiazoles and their use as potential anti-inflammatory agents.6,21 Despite of some methods
published which are mild and high yielding,22 the present protocol describes one-pot
synthesis with structural diversity. In order to simplify the process and to obtain new
derivatives of 2-aminothiazoles, we wish to demonstrate the extended development of
highly functionalized 2-aminothiazoles in a one-pot, multicomponent process from
simple starting materials which proceeds in good to excellent yields.
We report herein, a sequential multicomponent reaction leading to diverse 2-
aminothiazoles 4, by reacting different isothiocyanates 1 with amidines/guanidines 2 and
halomethylene compounds 3 in one-pot to furnish 4 with good to excellent yields
(Scheme 1).
In order to check the feasibility of thiazole formation in one-pot manner, we carried out
the sequential reaction of phenyl isothiocyanate 1a and benzamidine 2a in DMF at
ambient temperature, which resulted in the intermediate amidinothiourea 5. This
intermediate was further reacted with phenacyl bromide 3a to give the desired 2-
aminothiazole 4a, which has different Rf value from starting materials as well as
characteristic yellow spot on thin layer chromatography. Further work-up of this reaction
gave the yellow solid23. The structure of this compound was confirmed by 1H-NMR, and
mass spectroscopy (Table 1). The present protocol, useful for the synthesis of various
trisubstituted thiazoles bearing amino group at the 2nd position, is quite efficient (high
yield) and concise (one-pot, as compared to our earlier reported protocol6,7) to furnish the
functionally diverse 2-aminothiazoles compounds library.

2
2
2
2
3
1
1
1
1
3
2
2
1
2
3
2
1
3
1
3
The plausible reaction mechanism for the formation of these trisubstituted thiazoles are
described in Scheme 2. The synthesis of various isothiocyanates and amidine/guanidines
2 are well documented in the literature.20 Nucleophilic addition of amidines 2 to the
isothiocyanate results into the formation of adduct known as amidinothioureas 5 (in the
case of guanidine it is referred to as guanidinothioureas). The intermediate 5 being a
thiourea derivative, has one dominant nucleophilic (C=S) site and one electrophilic (C-
NEt2) site. The highly polar C-Br bond of phenacyl bromide is facile towards the
nucleophilic attack of sulfur resulted into S-alkylation to give species 6. Now the
methylene group being acidic in nature attacks the electron deficient imine carbon (to
which electron pulling quaternary nitrogen is attached and thus this carbon a strong
electrophile) to give the intermediate 7. This intermediate further undergoes cyclization
to 8 in a 5-exo-trig manner. This intermediate now could be stabilized by gaining the
aromatic property through the removal of diethyl amine and hydrogen bromide resulting
into the desired 2-aminothiazoles 4. During the course of study, it was observed that the
reaction of bromomethylenes furnished good yield (4b, c, d, l, t).
INSERT TABLE-1 HERE
In conclusion, we have demonstrated an efficient one-pot method for the synthesis of
disubstituted-2-aminothiazoles from simple starting materials like aryl and alkoxyl
isothiocyanate, amidine/guanidine and various halomethylenes to produce the tri-
substituted thiazoles in good to excellent yields. The present method is attractive due to
its facile conditions suggesting this protocol could be an alternative to other protocols.
The product can be isolated very easily with or without the use of chromatography. Being
characterized by three points of diversity, the novel chemotypes are rapidly assembled in
just one operationally friendly step and the methodology proved to be general and
tolerates a wide range of functional groups.
Acknowledgements

We gratefully acknowledge the financial support for this work from B.V. Patel PERD
centre. H. B. J thanks the Industrial Commissioner (IC) of Gujarat for the grant provided
to carry out research work. We thank Dr. Manish Nivsarkar and Prof. C.J. Shishoo
Directors of B.V. Patel PERD centre, for their constant encouragement and support.
References and Notes
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23. General experimental procedure for the preparation of 2-aminothiazoles: To a hot
air dried round bottom flask, containing solution of isothiocyanate (2.0 mmol) and
0
DMF (5 mL), amidine/guanidine (2.0 mmol) was added at 20-25 C temperature
and the solution was stirred for 2-3 h. To the above solution, halomethylene
compound (2.0 mmol) in DMF (5 mL) was added at ambient temperature and it was
further maintained for 8-24 h with stirring. (in the case of chloro compounds,
reaction was warmed to 40-45 0C). Progress of the reaction was monitored by TLC
using ethyl acetate/hexane (2:8). After the completion of reaction, the reaction
mixture was poured into ice. Upon stirring, precipitate was observed (in the case of
no precipitation, reaction mass was extracted with either dichloromethane or ethyl
acetate) which were collected through Buchner funnel. These precipitates were then
dissolved in either dichloromethane or ethyl acetate and dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The residues were
further subjected to purification either by chromatography or by treating with
hexane and/or ether to give the pure compounds (4a-t).

Table-1: One-pot synthesis of 2-aminothiazoles from isothiocyanates, amidines/guanidines and halomethylenes
Entr Isothiocyanate
Amidine/
Guanidine(2
)
Halomethylen
e (3)
2-aminothiazole (4)
Yield (%)a
& Melting
range (oC)
1H-NMR & LC-MS Spectrum datab
y
(1)
1H NMR (CDCl3) = 6.91-6.93 (d, 2H),
1
68
6.99-7.10 (m, 3H), 7.15-7.17 (d, 2H),
(192-194) 7.20-7.29 (m, 3H), 7.34-7.36 (d, 2H),
7.39-7.48 (m, 3H), 8.69 (s, 1H).
Mol. Wt. = 356.44, Found = 357.0.
1H NMR (CDCl3) 3.81 (s, 3H), 6.81-
6.86 (d, 4H), 7.02-7.11 (m, 3H), 7.14-
2
3
4
5
89
(187-189) 7.16 (d, 2H), 7.26-7.28 (d, 2H), 7.36-
7.38 (d, 2H), 8.96 (s, 1H). Mol. Wt. =
420.91, Found = 422.0.
1H NMR (CDCl3) = 2.24 (s, 3H,), 3.81
79
(s, 3H), 6.85-6.91 (d, 4H), 7.04-7.14 (m,
(154-157) 3H), 7.18-7.20 (d, 2H), 7.31-7.33 (d,
2H), 7.39-7.41 (d, 2H), 8.49 (s, 1H).
Mol. Wt. = 400.49, Found = 401.0.
1H NMR (CDCl3) = 3.10 (s, 3H,), 7.02-
76
7.11 (m, 3H), 7.20-7.30 (m, 3H), 7.40-
(214-216) 7.44 (m, 2H), 7.51-7.60 (m, 6H), 11.06
(s, 1H).
Mol. Wt. = 434.53, Found = 436.0.
1H NMR (CDCl3) = 1.22-1.28 (t, 3H,),
68
1.84 (s, 3H), 4.21-4.32 (q, 2H), 7.39-
(224-226) 7.56 (m, 5H), 11.81 (s, 1H), 11.83 (s,
1H).
Mol. Wt. = 305.35, Found = 357.40.

1H NMR (CDCl3) = 1.32-1.46 (m, 9H,),
2.73 (s, 3H), 4.30-4.49 (m, 6H), 10.90
(153-156) (s, 1H).
6
7
71
Mol. Wt. = 357.38, Found = 358.0.
1H NMR (DMS0-d6) = 1.23-1.27 (t,
70
3H,), 1.31-1.36 (t, 3H), 2.59 (s, 3H),
(249-251) 4.26-4.38 (m, 4H), 7.38-7.40 (d, 2H),
7.61-7.63 (d, 2H), 11.09 (s, 1H).
Mol. Wt. = 395.86, Found = 396.0.
1H NMR (CDCl3) = 2.47 (s, 3H,), 2.50
(s, 3H), 7.43-7.45 (d, 2H), 7.65-7.67 (d,
2H), 11.20 (s, 1H), 11.81 (s, 1H).
Mol. Wt. = 353.78, Found = 354.50.
8
9
70
(>270°C)
1H NMR (DMS0-d6) = 2.14 (s, 3H,),
7.21-7.27 (m, 1H), 7.39-7.41 (d, 2H),
78
(249-251) 7.49-7.51 (d, 2H), 11.46 (s, 1H), 12.48
(s, 1H).
Mol. Wt. = 262.28, Found = 263.0.
1H NMR (DMS0-d6) = 6.59-6.61 (d,
2H), 7.07-7.84 (m, 15H), 8.33-8.35 (d,
10
61
1H), 9.39 (s, 1H).
Mol. Wt. = 507.00, Found = 507.0.
(>270°C)
1H NMR (DMS0-d6) = 1.25-1.32 (t,
3H), 2.36 (s, 3H,), 4.21-4.29 (q, 2H),
7.22-7.84 (m, 8H), 8.33-8.35 (d, 1H),
11
59
(249-252) 10.75 (s, 1H).
Mol. Wt. = 406.45, Found = 407.0.

1H NMR (DMS0-d6) = 6.76-6.78 (d,
1H), 7.34-7.62 (m, 6H), 7.69-8.10 (m,
5H), 12.19 (s, 1H), 13.09 (s, 1H).
12
76
Mol. Wt. = 414.43, Found = 415.0.
(>270°C)
1H NMR (DMS0-d6) = 3.90 (s, 3H),
6.79 (s, 1H), 6.90-6.92 (d, 2H), 7.10-
7.13 (d, 2H), 7.25-8.11 (m, 9H).
13
14
72
(179-182) Mol. Wt. = 453.51, Found = 454.0.
1H NMR (CDCl3) = 2.20 (s, 3H,), 2.40
64
(s, 3H,), 2.45 (s, 3H,), 3.90 (s, 3H),
(178-181) 7.30-7.50 (m, 6H), 8.30 (s, 1H).
Mol. Wt. = 325.42, Found = 326.0.
1H NMR (CDCl3) = 1.15-1.20 (t, 3H,),
1.82 (s, 3H), 4.12-4.18 (q, 2H), 4.38-
4.46 (q, 2H), 6.73-6.75, (d, 1H,), 7.22-
15
16
73
(169-171) 7.28 (m, 3H), 7.37-7.42 (m, 2H), 8.50-
8.52 (d, 1H), 9.58 (s, 1H). Mol. Wt. =
437.43, Found = 338.0.
1H NMR (CDCl3) = 2.60 & 2.93 (s,
6H,), 6.94 (s, 2H), 7.31-8.13 (m, 10H),
69
(>270°C)
9.50 (s, 1H).
Found = 418.0.
Mol. Wt. = 417.48,

1H NMR (CDCl3) = 2.42 (s, 3H,), 2.46
(s, 3H,), 2.52 (s, 3H,), 6.85 (s, 2H),
7.33-7.87 (m, 9H), 9.62 (s, 1H).
2
17
18
19
62
Mol. Wt. = 371.59, Found = 472.0.
(>270°C)
1H NMR (CDCl3) = 3.07 (s, 6H), 3.88
(s, 3H), 4.04 (s, 3H), 7.13-7.51 (m, 5H),
7.88 (s, 1H).
68
(180-182) Mol. Wt. = 362.40, Found = 363.00.
1H NMR (CDCl3) = 1.25-1.37 (t, 3H,),
3.13 (s, 6H), 3.88 (s, 3H), 4.12 (s, 3H),
65
4.28-4.35 (q, 2H), 8.49 (s, 1H).
(158-160) Mol. Wt. = 358.37, Found = 358.40.
1H NMR (CDCl3) = 2.39 (s, 3H), 3.09
(s, 6H), 4.40-4.41 (d, 2H), 5.86-5.88 (t,
20
76
(164-167) 1H), 7.18-7.20 (d, 2H), 7.31-7.35 (m,
5H), 7.63-7.65 (d, 2H).
Mol. Wt. = 351.46, Found = 352.50.
a Yields refer to isolated products. Melting points are uncorrected. b LC-MS analysis M+1 at m/z.