A one-step, multi-component reaction for the synthesis of fully substituted 5-amino-4-carboxamidthiazoles

Article abstract of DOI:10.1016/j.tetlet.2013.03.014

A novel multi-component reaction has been developed for the synthesis of fully substituted 5-amino-4-carboxamidthiazoles. Condensation of an aldehyde with commercially available 2-amino-2-cyanoacetamide in the presence of elemental sulfur and base affords these heterocycles in a one-pot reaction sequence. A variety of aryl, heteroaryl, and aliphatic aldehydes were successfully utilized, thus providing rapid access to functionalized thiazoles that are valuable intermediates in the synthesis of pharmacologically active compounds.

Full text of DOI:10.1016/j.tetlet.2013.03.014

Tetrahedron Letters 54 (2013) 2506–2510
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Tetrahedron Letters
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A one-step, multi-component reaction for the synthesis of fully substituted
5-amino-4-carboxamidthiazoles
⇑
Kaleen K. Childers , Andrew M. Haidle, Michelle R. Machacek, J. Patrick Rogers, Eric Romeo
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel multi-component reaction has been developed for the synthesis of fully substituted
Received 19 December 2012
Revised 4 March 2013
Accepted 5 March 2013
Available online 14 March 2013
5-amino-4-carboxamidthiazoles. Condensation of an aldehyde with commercially available 2-amino-2-
cyanoacetamide in the presence of elemental sulfur and base affords these heterocycles in a one-pot
reaction sequence. A variety of aryl, heteroaryl, and aliphatic aldehydes were successfully utilized, thus
providing rapid access to functionalized thiazoles that are valuable intermediates in the synthesis of
pharmacologically active compounds.
Keywords:
Thiazole
Ó 2013 Elsevier Ltd. All rights reserved.
Gewald reaction
Multi-component reaction
Thiophenes and thiazoles are frequently found in biologically
active compounds and are used by medicinal chemists to explore
structure–activity relationships (SAR) in drug discovery. During
the course of a recent medicinal chemistry program aimed at ki-
nase inhibitors, substituted 2-amino-3-carboxamidthiophenes
were extensively explored.1 These were readily accessed through
the Gewald reaction,2–4 which allowed for facile determination of
SAR (Scheme 1).
with ethyl 2-amino-2-cyanoacetate, which means one of the diver-
sification steps has to occur at the start of the synthesis rather than
at the end.
NH2
R2
O
O
S8
N
O
R1
R1
NH2
R2
S
Base
H2N
The Gewald reaction cascade begins by condensation of an
1
2
3
a
-methylene ketone or aldehyde (2) with a-cyanoacetamide (1)
(Scheme 2).5 Following the deprotonation of 4 and nucleophilic at-
tack on elemental sulfur, the proposed mechanism proceeds
through cyclization and tautomerization steps to produce a substi-
tuted 2-amino-3-carboxamidthiophene (3) (note: C-3 esters can
Scheme 1. The Gewald reaction.
also be formed by using an a
-cyanoacetate instead of 1).6
O
O
N
O
N
N
S
To expand the scope of SAR exploration beyond thiophenes, ac-
cess to the corresponding thiazole core was desired. It was envi-
sioned that a sequence of mechanistic steps very similar to those
found in the Gewald reaction could be used to provide these
compounds (Scheme 3). A literature search revealed no analogous
methods for the synthesis of 5-amino-4-carboxamidthiazoles;
instead reported syntheses require additional steps where the sul-
fur needs to be incorporated into a reactant such as a thioester7 or
a dithioic acid.8 Alternatively, an ethyl 2-acylamido-2-cyanoace-
tate can be reacted with elemental sulfur followed by ester ammo-
nolysis to afford compounds of structure 3.9 This approach
requires the substituent at the 2-position be brought in during
the initial step of a two-step procedure through amide formation
NH2
S8
NH2
NH2
1
2
R2
R2
Sx
- H2O
Base
R1
O
R1
5
4
R1
R2
NH2
R2
NH2
R2
O
HN
O
R1
R1
S
H
S
H2N
Base
3
6
⇑
Corresponding author. Tel.: +1 617 992 3081; fax: +1 617 992 2406.
E-mail address: kaleen.childers@merck.com (K.K. Childers).
Scheme 2. Reported Gewald mechanism.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.014

K. K. Childers et al. / Tetrahedron Letters 54 (2013) 2506–2510
2507
O
O
O
O
N
N
N
N
NH2
NH2
base
NH2
NH2
NH2
N
N
N
- H2O
7
R
R
9
10
11
R
O
S8
H
R
O
NH2
NH2
8
N
S
N
S
N
S
NH2
O
H2N
O
HN
R
R
N
Sx
H
R
Base
14
12
13
Scheme 3. Proposed mechanism for thiazole formation.
The proposed one-pot reaction begins by condensation of
commercially available 2-amino-2-cyanoacetamide (7) with an
aldehyde (8), which would initially provide aldimine (9) that could
tautomerize to ketimine (10). Either intermediate 9 or 10 could be-
with a base and elemental sulfur, undergoing cyclization and
tautomerization steps to produce a fully substituted 5-aminothia-
zole (14).
To examine the viability of the proposed reaction, both 4-chlo-
robenzaldehyde and p-tolualdehyde were used as model
have similarly to unsaturated a-cyanoacetamide (4) when treated
Table 1
Synthesis of 5-amino-4-carobxamidothiazoles
NH2
O
O
S8
N
N
O
NH2
H
R
R
Δ
Base,
NH2
S
H2N
Entry
1
Aldehyde
Product
Isolated yield (%)
O
NH2
N
S
H
O
O
O
32b
H2N
15
O
H
NH2
N
S
2
3
15b
H2N
16
17
NH2
O
H
N
S
20b
H2N
O
H
NH2
N
S
O
O
O
4
5
6
44b
H2N
18
19
20
O
H
NH2
N
S
30a
H2N
O
H
NH2
N
S
11b
OMe
OMe
H2N
(continued on next page)

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K. K. Childers et al. / Tetrahedron Letters 54 (2013) 2506–2510
Table 1 (continued)
Entry
Aldehyde
Product
Isolated yield (%)
O
NH2
N
S
O
H
7
8
9
40b
CH3
Cl
CH3
Cl
H2N
NH2
21
O
H
N
S
O
28b
H2N
NH2
22
23
O
H
N
S
O
23b
Br
N
Br
N
H2N
O
H
NH2
N
S
O
10
11
12
O
18b
H2N
NH2
24
25
O
O
H
N
S
O
8c
OH
H2N
HO
O
H
NH2
O
O
N
S
O
11c
O
H2N
NH2
26
O
O
H
F
F
F
N
S
O
O
O
13
14
24b
OH
F
H2N
F
HO
27
NH2
O
H
F
N
S
17b
Br
F
Br
H2N
F
28
O
H
NH2
N
N
S
N
15
16
17
Br
21b
14b
17b
Br
H2N
29
30
O
H
NH2
S
N
S
S
O
O
H2N
O
H
NH2
N
S
H2N
Cl
31
Cl

K. K. Childers et al. / Tetrahedron Letters 54 (2013) 2506–2510
2509
Table 1 (continued)
Entry
Aldehyde
Product
Isolated yield (%)
O
NH2
N
S
O
H
18
14b
H2N
CH3
32
33
CH3
O
H
NH2
N
S
O
19
0b
H2N
a
1 equiv aldehyde, 1 equiv 2-amino-2-cyanoacetamide, 1 equiv S8, 1 equiv 1-methyl morpholine, 0.5 M DMF, 72 h at 100 °C.
1 equiv aldehyde, 1 equiv 2-amino-2-cyanoacetamide, 1–1.2 equiv S8, 1 equiv 1-methyl imidazole, 0.5 M 1:1 toluene/NMP, overnight at 80–130 °C.
1 equiv aldehyde, 1 equiv 2-amino-2-cyanoacetamide, 1 equiv S8, 1 equiv 1-methyl imidazole, 0.5 M DMF, 24 h at 100 °C.
b
c
we found the thiazole synthesis of 34 and 35 afforded comparable
yields to 22 and 25 (Fig. 1).13
NH2
NH2
N
S
In summary, we have developed a novel and convenient multi-
component reaction for the synthesis of fully substituted thiazoles.
A key difference between this reaction and the Gewald reaction in
terms of practical application is the commercial availability of the
starting materials: the Gewald aldehyde needs to have a methy-
lene group adjacent to the carbonyl, thus limiting the number of
building blocks readily available for the synthesis of thiophenes,
while any aldehyde can in theory be used for the synthesis of thi-
azoles. Commercially available starting materials and a one-pot
procedure allow for rapid incorporation of alkyl, aryl, and hetero-
aryl functionality into a scaffold of both synthetic and medicinal
chemistry interest.
O
O
Cl
Cl
S
H2N
H2N
22
34
44% yield
28% yield
NH2
NH2
N
S
O
O
S
OH
OH
H2N
H2N
35
25
8% yield
11% yield
Typical experimental procedure: A solution of p-tolualdehyde
Figure 1. Comparison of Gewald and thiazole-forming reaction.
(0.24 mL,
2.0 mmol),
2-amido-2-cyanoacetamide
(200 mg,
2.0 mmol), sulfur (65 mg, 2.0 mmol), 1-methylimidazole (0.16 mL,
2.0 mmol) and a 1:1 mixture of toluene:N-methyl-2-pyrrolidinone
(4 mL, 0.5 M) were stirred at 130 °C for 25 h and then cooled to room
temperature. The reaction mixture was diluted with ethyl acetate
(30 mL), washed with water (2 Â 10 mL) and brine, dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica (20–70% ethyl acetate/hexanes) to afford 5-amino-2-(p-
tolyl)thiazole-4-carboxamide (190 mg, 0.81 mmol, 40% yield) as a
dark yellow solid.
aldehydes. The aldehyde was combined with an equimolar amount
of 2-amino-2-cyanoacetamide and sulfur, and a variety of bases
were screened for their efficacy in promoting the desired transfor-
mation.10 1-Methylimidazole provided the cleanest conversion to
product while stronger bases (pKa >8) were noticeably worse. A
variety of solvents were also investigated11 with a 1:1 mixture of
toluene/NMP affording the best yields, presumably due to the rea-
sonable solubility of elemental sulfur under these conditions.
A number of other factors were examined to further enhance
starting material conversion and reaction yields, although to lim-
ited effect. For example, since the first step in the reaction se-
quence is a condensation, sodium sulfate was introduced into the
reaction mixture as a dehydrating agent; this modification did
not change the yield. Varying the concentration of each reactant
individually as well as in combination with other reactants simi-
larly did not lead to any improvements. Due to the fast paced nat-
ure of a medicinal chemistry program, limited studies were
completed to understand the low yields and any possible byprod-
uct pathways. Further studies could be warranted. In the end, the
best conditions were identified as equimolar concentrations of
aldehyde, 2-amino-2-cyanoacetamide, S8, and 1-methylimidazole
in 1:1 toluene/NMP overnight at a concentration of 0.5 M and a
temperature of 80–130 °C.
Acknowledgments
The authors would like to thank Maria Emilia DiFrancesco for
helpful discussions.
Supplementary data
Supplementary data (NMR data for compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.03.014.
References and notes
1. Wilson, K.; De Almeida, G.; Haidle, A.; Konrad, K.; Machacek, M.; Zabierek, A.
Preparation of thiophenecarboxamides as inhibitors of Janus kinases (JAK)
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2. Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94–100.
3. Feroci, M.; Chiarotto, I.; Rossi, L.; Insei, A. Adv. Synth. Catal. 2008, 350, 2740–
2746.
4. Huang, Y.; Doemling, A. Mol. Divers. 2011, 15, 3–33.
5. Tinsely, J. M. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J.,
Eds.; Wiley: New York, 2005; pp 193–198.
With these conditions in hand,12 the scope of the methodology
was explored. As seen in Table 1, aryl (entries 5–14, 17–18) and
heteroaryl aldehydes (entries 15–16) provided the best yields.
Alkyl aldehydes (entries 1 and 2) gave similar yields while a reac-
tion with an
a,b-unsaturated aldehyde (entry 19) afforded no
desired product. In direct comparisons to the Gewald reaction,

2510
K. K. Childers et al. / Tetrahedron Letters 54 (2013) 2506–2510
6. Peet, N. P.; Sunder, S.; Barbuch, R. J.; Vinogradoff, A. P. J. Heterocycl. Chem. 1986,
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1985, 50, 1741–1746.
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9. Inami, H.; Mizutani, T.; Maeda, J.; Usuda, H.; Nagashima, S.; Ito, T.; Aoyama, N.;
Kontani, T.; Hayashida, H.; Terasawa, T.; Seo, R.; Akamatsu, M.; Ishikawa, T.;
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inhibitors, WO 2011043371A1, April 14, 2011.
11. Toluene, xylenes, dimethylformamide, dimethylacetamide, N-methyl-2-
pyrrolidone, dimethyl sulfoxide, 2-ethoxyethanol and an array of mixtures
were investigated as reaction solvents.
12. A handful of substrates were prepared with modified conditions and were not
repeated with our preferred conditions due to the nature of an industrial
medicinal chemistry program.
13. Gewald conditions: Equimolar amounts of substrates and morpholine in 0.5 M
EtOH, 75 °C, overnight.
10. The following bases were screened: 1,8-Diazabicyclo[5.4.0]undec-7-ene,
i-Pr2NEt, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, N-methyl
morpholine, 1-methylimidazole, diethylaniline and pyridine.