Synthesis of substituted esters of imidazoles, oxazoles, thiazoles, and diethyl pyrazine-2,5-dicarboxylate from a common acyclic precursor employing C-formylation strategy

Article abstract of DOI:10.1016/j.tetlet.2014.03.039

A novel synthetic route to substituted esters of imidazoles, oxazoles, thiazoles, and diethyl pyrazine-2,5-dicarboxylates via C-formylation of glycine ethyl ester hydrochloride is reported. This methodology is simple, robust, and gives good yields of different heterocyclic esters in one or two steps from a common acyclic precursor and is amenable to large scale synthesis.

Full text of DOI:10.1016/j.tetlet.2014.03.039

Tetrahedron Letters 55 (2014) 2671–2674
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Tetrahedron Letters
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Synthesis of substituted esters of imidazoles, oxazoles, thiazoles,
and diethyl pyrazine-2,5-dicarboxylate from a common acyclic
precursor employing C-formylation strategy
Goraksha Khose, Shailesh Shinde, Anil Panmand, Ravibhushan Kulkarni, Yogesh Munot,
⇑
Anish Bandyopadhyay, Dinesh Barawkar, Santoshkumar N. Patil
Drug Discovery Facility, Advinus Therapeutics Ltd, Quantum Towers, Plot-9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune 411057, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic route to substituted esters of imidazoles, oxazoles, thiazoles, and diethyl pyrazine-2,
5-dicarboxylates via C-formylation of glycine ethyl ester hydrochloride is reported. This methodology
is simple, robust, and gives good yields of different heterocyclic esters in one or two steps from a common
acyclic precursor and is amenable to large scale synthesis.
Received 5 December 2013
Revised 5 March 2014
Accepted 6 March 2014
Available online 17 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C-formylation of glycine ethyl ester
Substituted esters of imidazoles
Substituted esters of oxazoles
Substituted esters of thiazoles
Diethyl pyrazine-2,5-dicarboxylate
synthesis
Common acyclic precursor
Introduction
timelines. For instance, expedited synthesis of substituted oxazoles
and thiazole esters has been reported.10,11
Many heterocycles for example imidazole, oxazole, thiazole,
and pyrazine are bioactive moieties that are ubiquitously present
in nature and have been adopted in numerous pharmaceutical
products.1 Vitamin B1,2 Histidine,3 and alkaloids such as disoraz-
oles,4 halfordinol,5 and texamine6 are a few examples of natural
products containing these heterocycles. Anti-diabetic drug glipiz-
ide7 (a 2,5 substituted pyrazine), antiviral ritonavir8 (a 2,4 substi-
tuted thiazole), and antihypertensive losartan9 (N-substituted
imidazoles) stand as examples to show the importance of these
heterocycles in the pharmaceutical research. (Fig. 1). These hetero-
cycles with ester functionality are useful building blocks in natural
product synthesis for example disorazole F1 could be synthesized
from highlighted 2-substitued 4-oxazole ester and losartan, glipiz-
ide, and ritonavir could be obtained from corresponding 2-substi-
tuted carboxyl heterocyclic systems (Fig. 1).
Common reported synthetic methods for preparing these substi-
tuted heterocycles are cyclization, oxidation, and functionalization
of pre-formed heterocycles.12–14 Among these methods, cyclization
of acyclic precursors is a widely used route. For example, oxazole
synthesis involves cyclization of 2-acylaminoketones (Robinson-
Gabriel synthesis)15,16 and cyanohydrin aldehydes (Fischer oxazole
synthesis).16 Likewise, a much preferred route to imidazoles and
thiazole involves cyclization of substituted isothiocyanate and thio-
amides respectively.17a–18a Synthesis of substituted imidazoles,
thiazoles, oxazoles, and pyrazines has been reported in recent liter-
ature.13–20
However, as a part of in-house high throughput synthetic ef-
forts, we wanted to prepare these different heterocycles from a
common acyclic precursor. To the best of our knowledge, there is
no reported strategy to prepare these heterocycles from a common
acyclic precursor. Herein, we report a novel route for the synthesis
of substituted esters of imidazoles, oxazoles, thiazoles, and diethyl
pyrazine-2,5-dicarboxylate from glycine ethyl ester hydrochloride.
We demonstrated that intra-molecular cyclization of C-formylated
glycine ethyl ester would provide us a variety of diversely substi-
tuted heterocycles with ester functionality (Scheme 1).
Access to these heterocyclic cores with ester functionality as
handle is much sought for synthetic manipulations and is helpful
particularly to expedite drug discovery efforts with aggressive
⇑
Corresponding author. Tel.: +91 20 66539637; fax: +91 20 66539620.
E-mail address: santosh.patil@advinus.com (S.N. Patil).
http://dx.doi.org/10.1016/j.tetlet.2014.03.039
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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G. Khose et al. / Tetrahedron Letters 55 (2014) 2671–2674
N
N
N
N
O
N
O
O
O
N
O
O
O
O
HO
Cl
N
OMe
N
losartan
disorazole F1
O
O
O
O
S
S
N
N
N
O
N
N
N
N
O
O
O
O
S
N
N
N
N
glipizide
ritonavir
Figure 1. Examples of pharmaceuticals and natural products with heterocycle core highlighted.
H
N
KSCN
Lawesson's reagent
S
S
COOEt
N
O
R1
COOEt
COOEt
O
N
R2
N
4
R1
COOEt
formylation
3
2
6
HClH2N
CO2Et
1
EtOOC
N
glycine ethyl ester
hydrochloride
O
R1
N
N
COOEt
2N HCl
TPP/Et3N/I
2
5
Scheme 1.
The main challenge was to develop a robust way to install a
C-formyl functional group on differently substituted glycine ethyl
ester hydrochloride. In the pursuit to access the C-formyl group
in one step, we tried different formylation conditions on N-(4-fluo-
rophenyl) glycine ethyl ester (a) using ethylformate. A variety of
bases and solvents under varied conditions were tried; inorganic
bases (K2CO3, and Cs2CO3), alkoxide bases (NaOEt and NaOMe),
and lithium bases (LiHMDS, LDA and n-BuLi) did not yield the de-
sired product (structure b) and only resulted in N-formylated prod-
uct (Scheme 2). The reported C-formylation using sodium ethoxide
also failed.21,22 Nonetheless, when we used sodium hydride as a
base, the reaction progressed smoothly to provide C- and
N-diformylated product (structure b). Quantitative yields were ob-
tained by changing the solvent from acetonitrile to toluene
(scheme 2).
Having established C-formylation strategy, one pot synthesis of
imidazole was achieved by selectively deprotecting the N-formyl
group and treating the reaction mixture with potassium thiocya-
nate (Table 1).
We then investigated the scope and substrate effect of this one
pot conversion of N-substituted glycine ethylester to ethyl
N-substituted 2-mercapto imidazole 5-carboxylate (Table 1). The
products 2a–2j, were obtained in good to excellent yields
(68–98%). Both aliphatic 2d, aromatic functionalities (2a–2b and
2e–2j), and benzylic functionality 2c were tolerated. Derivatives
with electron rich substituent 2f and electron deficient carboxylic,
nitro, and fluoro substituents (2g–2i) were obtained in good to
excellent yields. It is noteworthy that one of the key intermediates
2h was synthesized in 50 g scale with excellent yield (98%) con-
firming the amenability of this methodology to scale up operations.
Hetero-aromatic substitution was also tolerated and 2j was ob-
tained with 79% yield (please, see SI for procedure).
O
N
H
H
O
COOEt
conditions a*
H
N
COOEt
b
i
F
The above methodology developed for the synthesis of imida-
zoles was extended for preparing thiazole and oxazole using appro-
priate reagents. However, unlike imidazole, thiazole, and oxazole
synthesis could not be furnished in one pot. Nonetheless, formyla-
tion and cyclization of 3a–3g, using Lawesson’s reagent (condition
a)23 and triphenylphosphine (TPP) (condition b)23 gave thiazole
(4a–4f) and oxazole (5b–5g) respectively in good to excellent yield
(Table 2) (please see SI for procedure). It is noteworthy that the
labile 2-chloro pyridine group was well tolerated and oxazole 5g
was obtained in good yield from 3g. However, thiazole formation
failed and starting material 3g was recovered. This could be due
conditions b #
F
a
x
Scheme 2. Optimization of C-formylation reaction condition. Reagents and condi-
tions: (i) ethyl formate (2 equiv); 18-crown 6-ether (0.1 equiv), conditions a⁄ = NaH
(2.5 equiv), ACN, 0–60 °C, 2 h, 60% yield; NaH (2.5 equiv), toluene, 0–60 °C, 20 min,
99% yield. Conditions b# = K2CO3 (3.0 equiv), DMF, rt to 90 °C, 12 h; Cs2CO3
(3.0 equiv), DMF, rt to 90 °C, 12 h; NaOEt (2.0 equiv), toluene, rt to 70 °C, 12 h;
NaOMe (2.0 equiv), toluene, rt to 70 °C, 12 h; LiHMDS (2.0 equiv), THF, À78 °C to rt,
12 h; LDA (2.0 equiv), THF, À78 °C to rt, 12 h; n-BuLi (2.0 equiv), THF, À78 °C to
rt,12 h and desired product, b, not obtained. Instead N-mono formylated product
isolated.

G. Khose et al. / Tetrahedron Letters 55 (2014) 2671–2674
2673
Table 1
Synthesis of substituted imidazole-5-carboxylate derivatives
H
N
H
N
i
COOEt
S
R2
N
COOEt
R2
ii
1a-1j
2a-2j
i) ethyl formate (2 eq.), NaH (2 eq.), 18-Crown 6-ether (0.1 eq.), toluene, rt to 60 oC, 20 min
ii) ethanol, conc. HCl, H2O, KSCN (5 eq.), reflux 3 h
Substrate
Product
R2
Yielda (%)
68
Substrate
Product
R2
Yielda (%)
MeO
OMe
1a
2a
1f
2f
85
HOOC
1b
1c
2b
2c
84
92
1g
1h
2g
2h
88
98
F
1d
2d
2e
94
83
1i
1j
2i
2j
71
79
O2N
1e
N
a
= isolated yield.
Table 2
Synthesis of oxazole and thiazole
S
conditions a*
R1
COOEt
N
4a-4g
O
O
H
O
i
R1
N
H
COOEt
R1
N
H
COOEt
O
R1
COOEt
conditions b#
N
3a-3g
7a-g
5a-5g
i) ethyl formate (2 eq.), NaH (2 eq.), 18-Crown 6-ether (0.1 eq.), toluene, heating (60°C)
conditions a* = Lawesson's reagent (2 eq.); 1, 4 dioxane, reflux, 12 h
conditions b # = TEA (4 eq.), TPP (2 eq.), I2 (2 eq.), DCM, rt, 3-12 h
Entry
1
Substrate
Product
R1
Yielda (%)
53
Entry
8⁄
Substrate
Product
R1
Yielda (%)
NR#
3a
4a
Me
3a
5a
5b
Me
2
3b
4b
81
9⁄
3b
86
3
3c
4c
98
10⁄
3c
5c
71
4
3d
4d
88
11⁄
3d
5d
90
F C
3
F C
3
12⁄
13
3e
3f
5e
5f
93
73
Cl
Cl
5
6
3e
3f
4e
4f
91
88
7
3g
4g
NR#
14
3g
5g
76
N
N
Cl
Cl
#
Starting material recovered.
*
Except for reaction entries 7–11, which were stirred for 3 h, all reactions were stirred for 12 h.
a
Isolated yields.
NR = no reaction.
#
to harsher heating condition used in the synthesis of thiazole.
Nonetheless, thiazole with isopropyl substituent was obtained with
excellent yield (98%), when 3c was subjected to oxazole formation
yield was relatively lower (71%). Both thiazole and oxazole
formation was robust as diverse substituents were tolerated.
All attempts to synthesize 5a failed possibly due to N-deacyla-
tion under harsher basic reaction conditions. This observation was
verified by one pot synthesis of pyrazine-2,5-dicarboxylate 6 (72%
yield, see SI for procedure) by subjecting 3a to formylation,
N-deacylation followed by cyclization (Scheme 3).

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G. Khose et al. / Tetrahedron Letters 55 (2014) 2671–2674
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O
O
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i
HN
EtOOC
O
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Crown 6-ether (0.1 equiv), toluene, heating (60 °C); (ii) 2 N HCl, 65 °C, 2 h.
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In summary, a novel route involving C-formylation and subse-
quent cyclization of readily available glycine ester derivatives pro-
vided a highly efficient one or two-step synthetic routes for
imidazoles, oxazoles, thiazoles, and diethyl pyrazine-2,5-dicarbox-
ylate. The amenability for large scale synthesis has also been dem-
onstrated. Further studies on exploring scope and limitation of this
methodology and detailed reaction mechanisms are under investi-
gation and will be reported in near future.
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Acknowledgments
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We are grateful to Drs. Rashmi Barbhaiya, Kasim Mookhtiar,
and B. Kulkarni for their support and encouragement. We thank
Drs. Anil Deshpande and Anup Ranade for proof reading this
article.
17. (a) Recent literature of Imidazole synthesis: Bollu, V.; Boren, B. C.; Dalgard, J. E.;
Flatt, B. T.; Haq, N.; Hudson, S.; Mohan, R.; Morrissey, M.; Pratt, B.; Wang, Tie-
Lin. Patent WO 2010 093845.; (b) Pavlenko, N. V.; Oos, T. I.; Kirij, N. V.;
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Advinus Publication no. ADV–A–024.
Supplementary data
Supplementary data (complete experimental procedures and
full characterization data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.03.039.
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obtained involving multiple protection and de-protection sequence tailored
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