A simple, three-component synthesis of 2-aminothiazoles using trimethylsilyl isothiocyanate

Article abstract of DOI:10.1016/j.tetlet.2013.06.102

The first multicomponent, solution-phase protocol to prepare privileged 2-aminothiazoles from α-bromocarbonyl compounds and amines (aromatic and aliphatic) using commercially available trimethylsilyl isothiocyanate is described.

Full text of DOI:10.1016/j.tetlet.2013.06.102

Accepted Manuscript
A simple, three-component synthesis of 2-aminothiazoles using trimethylsilyl
isothiocyanate
Viktor Golubev, Fedor Zubkov, Mikhail Krasavin
PII:
S0040-4039(13)01078-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.102
TETL 43155
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 May 2013
9 June 2013
21 June 2013
Please cite this article as: Golubev, V., Zubkov, F., Krasavin, M., A simple, three-component synthesis of 2-
aminothiazoles using trimethylsilyl isothiocyanate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.06.102
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A simple, three-component synthesis of 2-aminothiazoles using trimethylsilyl
isothiocyanate
Viktor Golubev, Fedor Zubkov, Mikhail Krasavin*

A simple, three-component synthesis of 2-aminothiazoles using trimethylsilyl
isothiocyanate
Viktor Golubev,a Fedor Zubkov,a Mikhail Krasavin*b
a Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, Russia
b Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
*Corresponding author, e-mail: m.krasavin@griffith.edu.au, phone: +61 7 3735 6041, fax: +61 7
3735 6001.
Abstract: The first multicomponent, solution-phase protocol to prepare privileged 2-aminothiazoles
from -bromocarbonyl compounds and amines (aromatic and aliphatic) using commercially
available trimethylsilyl isothiocyanate is described.
Keywords: 2-aminothioazoles, multicomponent reactions, combinatorial chemistry, privileged
structures, parallel solution-phase synthesis.
Despite the fact that 2-aminothiazoles have been recently flagged as undesired structural elements
for screening library design (arguably, due to their thiourea-like character and tendency to modulate
promiscuously multiple biological targets),1, 2 this heterocyclic core was key in the design of kinase
inhibitors (e.g., the marketed cancer drug, dasatinib3) and continues to prove its worth in medicinal
chemistry practice. Its privileged character is evidenced by 2-aminothiazoles being reported as
antiviral,4 antiprion,5 anti-inflammatory,6 antimicrobial,7 antitubercular8 and anticancer9 agents.
Numerous methods to access 4-substituted 2-aminothiazoles 1 have been reported in the literature,
with most based on the Hantzsch-type10 condensation of -halocarbonyl compounds 2 with various
thioureas 3. The latter can, in turn, be generated from primary and secondary amines using
isothiocyanate sources such as (a) benzoyl isothiocyanate (4) (with subsequent alkaline
hydrolysis),4 (b) Fmoc-isothiocyanate (5) (followed by Fmoc group removal with piperidine),11 or
(c) tert-butyl isothiocyanate (6), requiring subsequent tert-butyl group cleavage under strongly
acidic conditions (Scheme 1).12 However, despite recent developments in the Hantzsch thiazole
synthesis (including syntheses under microwave irradiation,13 in aqueous medium,14 on solid
support,11 as well as in a flow reactor15), there appears to be no convenient protocol that allows
conversion of a wide range of -halocarbonyl compounds and amines (aliphatic and aromatic) into
2-aminothiazoles, in a truly multicomponent format. In this Letter, we report on the development of
the first multicomponent solution-phase protocol16 for the synthesis of 2-aminothioazoles using

commercially available trimethylsilyl isothiocyanate (TMSNCS) along with readily available amine
and -halocarbonyl components.
A few isolated examples of the preparation of 2-aminothiazoles using TMSNCS are available in the
patent literature.17 These typically include stepwise transformation of a secondary aliphatic amine
into its N-thiocarbamoyl derivative, which in turn is exposed to an -haloketone to give, upon
several hours of reflux in EtOH, the desired 2-aminothiazoles (Scheme 2). This literature precedent
prompted us to use TMSNCS to prepare the same heterocycles in a multicomponent format.
Initially, we investigated the possibility of transforming a set of substituted anilines into the
respective 2-aminothiazoles. To our delight, simple mixing of the anilines with the respective -
bromocarbonyl compounds 2, followed by addition of TMSNCS and heating the reaction mixture at
70 °C afforded the target 2-aminothiazoles 1a-n (Scheme 3, equation 1) in good to excellent yields
(Table 1). The latter were isolated as hydrobromide salts by simple filtration.
When we attempted to extend the same approach to primary aliphatic amines, we realized that in
order for the desired product to be formed, an equivalent of triethylamine18 had to be added. This
observation appeared to be consistent with the following mechanistic considerations (Scheme 4).
When exposed to ethanol, TMSNCS rapidly releases isothiocyanic acid,19 which could react with
the -bromocarbonyl compound 2 to form the respective thiocyanate 7.20 While anilines are
certainly capable of scavenging the HBr released when 7 is formed, they are not as basic as
aliphatic amines and the amount of unprotonated aniline in the reaction mixture is sufficient to drive
the reaction forward, while the 2-aminothiazole product formed becomes a competent scavenger of
HBr, thus leading to the complete conversions (vide supra). With aliphatic amines, due to their
higher basicity, all of the amine present in the reaction mixture is likely to be protonated (as the
result of the formation of 7), and the use of an added organic base is necessary for the reaction to
proceed. Apart from this aspect, the general protocol applied to primary aliphatic amines was
identical to that used for anilines, leading to the formation of free-base 2-aminothiazoles 1o-s in
good to excellent yields (Scheme 3, equation 2). The same methodology was found to be applicable
to secondary aliphatic amines as well, except that the amine (and not TMSNCS) was added last
(Scheme 3, equation 3), in order to avoid the formation of -aminocarbonyl compound 8. Without
such a precaution, 8 was found to form quite rapidly (due to the high nucleophilicity of the
secondary amine) which led to a lower yield of the target 2-aminothiazole 1.
In summary, we developed a convenient multicomponent synthesis of privileged 2-
aminothiazoles.21 The protocol is applicable to a range of aromatic and aliphatic amines, as well as
various -bromocarbonyl substrates. The simplicity of this new ‘mix-it-all’ methodology is

expected to aid early drug discovery lead generation based on this popular core,22 possibly leading
to thiazole-based biologically active compounds.
2-Aminothiazoles 1 General Procedure: To a solution of -bromocabonyl compound 2 (1 mmol)
in EtOH (2 mL) were added equimolar amounts of the following reagents in the order indicated:
Equation 1 (aromatic amines): amine followed by TMSNCS;
Equation 2 (primary aliphatic amines): amine followed by Et3N and TMSNCS;
Equation 3(secondary aliphatic amines): TMSNCS followed by Et3N and amine.
°
The reaction mixture was heated at 70 C for 2-4 h and then allowed to cool. The target 2-
aminothiazole was filtered off, washed with ice-cold EtOH and air-dried (Equation 1). Alternatively
(Equations 2 and 3), the mixture was concentrated in vacuo and the target product was isolated by
chromatography on silica gel using an appropriate gradient of EtOAc in hexanes.
Acknowledgements
Mikhail Krasavin acknowledges support from Griffith University.
References and notes
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10. Metzger, J. V. Thiazole and its Derivatives, Part 1, John Wiley & Sons, New York, 1979, pp.
166–310.

11. Dadiboyena, S.; Nefzi, A. Synthesis 2012, 44, 215–218.
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13. Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2006, 47, 5171-5172.
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15. Thompson, C. M.; Poole, J. L.; Cross, J. L.; Akritopoulou-Zanze, I.; Djuric, S. W. Molecules
2011, 16, 9161-9177.
16. A formal multicomponent synthesis of 2-(alkylamino)thiazole using SiO2-supported KNCS and
Al2O3-supported alkylammonium acetates has been reported, see: Aoyama, T.; Murata, S.;
Arai, I.; Araki, N.; Takido, T.; Suzuki, Y.; Kodomari, M. Tetrahedron 2006, 62, 3201-3213.
The scope of this methodology, however, appears to be limited and the preparation of the solid-
supported reagents is required in advance.
17. (a) Cao, G.-Q.; Chen, J. J.; Dominguez, C.; Reed, A.; Sham, K. K. C.; Thaman, M. C.; Zhang,
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18. Using other bases such as DIPEA or polymer-supported morpholine provided the target 2-
aminothiazoles, albeit in somewhat lower yields.
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1
21. Characterization data for representative compounds: 1b – white solid, mp = 243-245 °C; H
NMR (500 MHz, DMSO-d6)  9.67 (br s, 2H), 8.27 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.55 (d,
13
J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.16 (d, J = 8.0 Hz, 2H); C NMR (125 MHz, DMSO-d6) 
169.3, 138.2, 135.6, 134.7, 131.6 (q, JC-F = 50 Hz), 131.1, 131.0, 130.2 (unresolved q), 127.0,
125.2 (unresolved q), 123.0, 122.9, 120.8, 105.7. Anal. Calcd for C16H10Br3F3N2S: C, 34.38; H,
1.80; N, 5.01. Found: C, 34.42; H, 1.88; N, 5.12. 1e – beige solid, mp = 247-249 °C; 1H NMR
(500 MHz, DMSO-d6)  9.61 (br s, 2H), 8.28 (t, J = 1.5 Hz, 1H), 8.11 (d, J = 9.0 Hz, 2H), 8.07
(d, J = 7.5 Hz, 1H), 7.74 (m, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.44 (s,
1H), 2.58 (s, 3H); 13C NMR (125 MHz, DMSO-d6)  196.3, 169.2, 147.1, 138.0, 137.6, 134.2,
133.1, 132.4, 130.3, 130.2, 129.7, 128.2, 122.9, 107.5, 26.3; Anal. Calcd for C17H14BrN3O3S:
C, 48.58; H, 3.36; N, 10.00. Found: C, 48.68; H, 3.42; N, 9.89. 1g – off-white solid, mp = 239-

241 °C; 1H NMR (500 MHz, DMSO-d6)  9.53 (br s, 2H), 7.62 (dd, J = 8.0, 2.0 Hz, 1H), 7.59
(s, 1H), 7.31-7.33 (m, 3H), 7.29 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 7.24-7.26 (m, 2H), 2.28 (s, 3H),
2.17 (s, 3H); 13C NMR (125 MHz, DMSO-d6)  166.5, 142.7, 133.4, 130.5, 129.8, 129.5,
129.3, 129.2, 127.9, 126.6, 121.0, 115.1, 19.8, 11.2; Anal. Calcd for C17H16Br2N2S: C, 46.38;
1
H, 3.66; N, 6.36. Found: C, 46.51; H, 3.73; N, 6.29. 1v – yellow oil; H NMR (500 MHz,
DMSO-d6)  7.89 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 6.70 (s,
13
1H). 3.57 (t, J = 7.0 Hz, 4H), 2.08 (quin, J = 7.0 Hz, 4H); C NMR (125 MHz, DMSO-d6) 
167.4, 152.0, 128.4, 127.4, 126.1, 100.1, 49.5, 25.7; Anal. Calcd for C13H14N2S: C, 67.79; H,
1
6.13; N, 12.16. Found: C, 67.88; H, 6.22; N, 12.08. 1w – white solid, mp = 143-145 °C; H
NMR (500 MHz, DMSO-d6)  7.84 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.34 (s, 1H),
7.28-7.29 (m, 1H), 7.21-7.24 (m, 3H), 4.68 (s, 2H), 3.77 (t, J = 5.5 Hz, 2H), 2.97 (t, J = 5.5 Hz,
2H); 13C NMR (125 MHz, DMSO-d6)  169.1, 148.9, 133.7, 133.4, 132.2, 130.9, 127.9, 127.2,
126.0, 125.9, 125.6, 119.9, 102.4, 48.8, 45.1, 27.2. Anal. Calcd for C18H15BrN2S: C, 58.23; H,
4.07; N, 7.54. Found: C, 58.12; H, 3.96; N, 7.61.
22. Of the 23 compounds reported in this Letter, 19 had not been described in the literature, clearly
attesting to the existing room for library expansion around the 2-aminothiazole chemotype. All
of the compounds synthesized in this work have been deposited with the Queensland
Compound Library (Griffith University) and are available for collaborative discovery projects.
Scheme 1. Various isothiocyanate sources for 4-substituted 2-aminothiazole synthesis reported in
the literature.

Scheme 2. Examples of the use of TMSNCS to prepare 2-aminothiazoles.17
Scheme 3. Multicomponent approach to 2-aminothiazoles developed in this work (see the general
procedure for the order of addition of the reagents).
Scheme 4. A plausible mechanism for the multicomponent synthesis of 2-aminothiazoles.
Table 1. 2-Aminothiazoles 1a-w prepared in this work.
Entry
1a
R1
Ph
R2
H
R3
R4
H
Yield (%) a
92
4-BrC6H4
H
H
78
1b
1c
4-BrC6H4
H
H
69

4-BrC6H4
H
H
H
H
73
66
1d
1e
4-O2NC6H4
4-O2NC6H4
Ph
H
Me
Me
Me
H
H
H
H
H
H
H
70
95
93
82
66
83
1f
1g
1h
1i
Ph
Ph
COOEt
COOEt
1j
H
1k
COOEt
H
H
77
1l
COOEt
Ph
H
H
H
H
78
64
1m
1n
Ph
4-PhC6H4
H
H
Bn
H
H
58
67
1o
1p
Ph
H
H
H
H
H
H
83
76
67
1q
1r
1s
4-BrC6H4
4-BrC6H4
Ph
Ph
Ph
H
H
H
H
-CH2CH2OCH2CH2-
-CH2CH2N(Et)CH2CH2-
-CH2CH2CH2CH2-
83
68
79
91
1t
1u
1v
1w
4-BrC6H4
a
Compounds 1a-n were isolated as hydrobromide salts; compounds 1o-w were isolated as free
bases.