Facile synthesis of 2-(2-ethoxy-1,2-dioxoethyl)azoles

Article abstract of DOI:10.1055/s-0030-1260003

C-Acylation of N-substituted imidazoles with ethyl oxalyl chloride in the presence of N,N-diisopropylethylamine as a base afforded 2-(2-ethoxy-1,2- dioxoethyl)imidazoles in 83-95% yield. Application of this synthetic protocol to thiazoles and triazoles le

Full text of DOI:10.1055/s-0030-1260003

PAPER
1633
Facile Synthesis of 2-(2-Ethoxy-1,2-dioxoethyl)azoles
S
ynthesis of 2-(2-E
l
thoxy-
e
1,2-dioxoe
k
thyl)azoles sandr V. Geraschenko,a,b Pavel V. Khodakovskiy,a Oleg V. Shishkin,c Pavel K. Mykhailiuk,*a,b
Olga A. Zaporozhets,a Andrey A. Tolmacheva,b
a
Enamine Ltd., Oleksandra Matrosova Street 23, Kyiv 01103, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine
b
Fax +380(44)2351273; E-mail: Pavel.Mykhailiuk@gmail.com
STC, ‘Institute for Single Crystals’, National Academy of Science of Ukraine, 60 Lenina Ave, Kharkiv 61001, Ukraine
c
Received 6 February 2011; revised 22 February 2011
oxalic acid derivatives.8 A systematic study of this trans-
formation, has, however, not been performed.
Abstract: C-Acylation of N-substituted imidazoles with ethyl ox-
alyl chloride in the presence of N,N-diisopropylethylamine as a base
afforded 2-(2-ethoxy-1,2-dioxoethyl)imidazoles in 83–95% yield.
Application of this synthetic protocol to thiazoles and triazoles led
to the corresponding 2-ethoxy-1,2-dioxoethyl derivatives in 40–
51% yield.
N-methylimidazole (1) was chosen as the model com-
pound in this study (Scheme 1). Addition of ethyl oxalyl
chloride to a solution of compound 1 in anhydrous dichlo-
romethane at –20 °C led to the formation of a precipitate,
which presumably had the structure of ionic compound A.
Subsequent addition of the base N,N-diisopropylethyl-
amine to the reaction mixture resulted in dissolution of the
precipitate and formation of a transparent solution. After
12 hours of stirring at room temperature, standard workup
of the reaction mixture afforded the target product 1a in an
excellent yield of 95% (Scheme 1, Table 1). Deprotona-
tion of intermediate A by N,N-diisopropylethylamine
Key words: azoles, acylations, glyoxylates, keto esters, heterocy-
cles
a-Keto acids and their derivatives are very abundant with-
in drug discovery programs.1 The antineoplastics
indibulin2 and rosabulin,3 the antithrombotic tiplasinin,4
the septic shock agent varespladib,5 and the anti-
Alzheimer’s disease agent aleplasinin6 are representative
examples of pharmacologically relevant heterocyclic de-
rivatives of a-keto acids (Figure 1). In this context, the de-
velopment of novel synthetic methodologies for the
practical preparation of functionalized a-keto acid precur-
sors is of particular interest. Herein, we report a facile
one-step procedure for the synthesis of 2-(2-ethoxy-1,2-
dioxoethyl)azoles.
O
O
O
F3CO
O
N
N
OH
H
N
N
Cl
indubulin
tiplasinin
(Asta Medica)
(Wyeth Pharmaceuticals)
Despite the great potential of the imidazole motif in me-
dicinal chemistry,7 there are only a few isolated examples
reported in the literature on the preparation of 2-(imida-
zolyl)-2-oxoacetates from N-substituted imidazoles and
O
O
O
O
HO2C
O
NH2
OH
OEt
OEt
O
O
O
OEt
O
N
N
O
O
N
N+
N+
C–
DIPEA
Cl
Cl–
t-Bu
H
N
H
N
varespladib
(Eli Lilly)
aleplasinin
N
Me
(Wyeth Pharmaceuticals)
Me
Me
1
A
B
O
O
O
N
N
N
acyl transfer
95%
OEt
S
H
N
O
N
Me
1a
CN
Scheme 1 Acylation of N-methylimidazole (1) with ethyl oxalyl
chloride in the presence of N,N-diisopropylethylamine as a base
rosabulin
(Synta Pharmaceuticals)
Figure 1 Examples of pharmacologically relevant heterocyclic a-
keto acid derivatives: antineoplastics indibulin and rosabulin, anti-
thrombotic tiplasinin, septic shock agent varespladib, and anti-
Alzheimer’s disease agent aleplasinin
SYNTHESIS 2011, No. 10, pp 1633–1637
Advanced online publication: 15.04.2011
DOI: 10.1055/s-0030-1260003; Art ID: Z17811SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

1634
O. V. Geraschenko et al.
PAPER
Table 1 Synthesis of 2-(2-Ethoxy-1,2-dioxoethyl)azoles 1a–12a
(continued)
most probably gave the zwitterionic structure B, which
underwent acyl transfer to afford the corresponding prod-
uct 1a. The structure of compound 1a was proven by an
X-ray diffraction study (Figure 2).
Azole
Product
Yield (%)
O
N
N
To demonstrate the applicability of the given transforma-
tion to form a wide variety of imidazoles, we performed
several syntheses with diverse substrates 2–9 (Table 1).
By following the elaborated protocol, the corresponding
products 2a–9a could be obtained in good to excellent
yields of 85–95%.
N
OEt
N
O
90
5
5a
N
With a practical procedure available for preparing 2-(2-
ethoxy-1,2-dioxoethyl)imidazoles, we next carried out
several experiments to find out whether this strategy could
be applied to the synthesis of other 2-(2-ethoxy-1,2-di-
oxoethyl)azoles. The reaction of triazole 10 with ethyl ox-
alyl chloride under the standard reaction conditions
resulted in the formation of a complex mixture. According
to the LC-MS data, the mixture consisted mainly of com-
pounds 10a, 10b, and 10c (Scheme 2). The target product
10a was isolated from the reaction mixture in 40% yield
by distillation. Acidic hydrolysis of the residue obtained
after distillation, i.e. crude compounds 10b and 10c, in
aqueous hydrochloric acid provided the pure alcohol 10d
(Scheme 2).
O
N
N
OEt
OEt
N
85
92
O
6
6a
N
O
N
N
N
O
N
N
CF3
CF3
7
7a
O
O
N
The two thiazoles 11 and 12 were also tested (Table 1).
The reactions of compounds 11 and 12 with ethyl oxalyl
chloride by the standard protocol proceeded similarly to
that of imidazole 10, providing the corresponding prod-
ucts 11a and 12a in the moderate yields of 45% and 51%,
respectively. Nevertheless, the formation of the side prod-
ucts was also observed.
N
OEt
N
N
O2N
O2N
85
CF3
CF3
N
8
8a
Table 1 Synthesis of 2-(2-Ethoxy-1,2-dioxoethyl)azoles 1a–12a
O
O
N
OEt
91
40
N
N
Azole
Product
Yield (%)
95
Me
Me
O
N
9
9a
N
OEt
O
N
Me
1
N
N
Me
1a
N
O
N
N
N
N
OEt
O
Me
Me
O
O
N
10
N
10a
Cl
OEt
Cl
N
O
N
95
85
N
S
N
Me
Me
OEt
45
51
2
2a
S
O
11
O
N
11a
N
OEt
OEt
O
O
N
Bu
3
N
N
N
O
Bu
OEt
S
S
3a
12
O
12a
N
N
N
N
83
O
4
4a
Synthesis 2011, No. 10, 1633–1637 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-(2-Ethoxy-1,2-dioxoethyl)azoles
1635
CH2Cl2 (100 mL) at –20 °C. Then DIPEA (1.29 g, 0.01 mol) was
added and the mixture was allowed to warm to r.t. The reaction mix-
ture was stirred for an additional 12 h and then washed with H2O
(3 × 50 mL). The organic layer was dried (Na2SO4) and evaporated
under vacuum to give the crude product.
Ethyl 2-(1-Methyl-1H-imidazol-2-yl)-2-oxoacetate (1a)
The crude product was purified by crystallization (i-PrOH–H2O,
1:1).
Yield: 95%; colorless crystals; mp 48 °C.
1H NMR (500 MHz, CDCl3): d = 0.55 (t, J = 7.0 Hz, 3 H), 3.19 (s,
3 H), 3.53 (q, J = 7.0 Hz, 2 H), 6.35 (s, 1 H), 6.73 (s, 1 H).
Figure 2 X-ray crystal structure of 1a
13C NMR (125 MHz, CDCl3): d = 14.01, 35.64, 62.39, 128.55,
O
OEt
O
131.88, 140.08, 163.75, 177.25.
O
N
N
N
N
MS (CI): m/z = 201 [M + 1 + H2O].
Cl
DIPEA
N
N
N
OEt
N
+
N
N
N
N
Ethyl 2-(5-Chloro-1-methyl-1H-imidazol-2-yl)-2-oxoacetate
(2a)
The crude product was purified by crystallization (i-PrOH).
O
XO
Me
Me
CO2Et
Me
10
Me
10a
10b X = H
10c X = COCO2Et
Yield 95%; yellow powder; mp 45 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.31 (t, J = 7.1 Hz, 3 H), 3.93
(s, 3 H), 4.37 (q, J = 7.1 Hz, 3 H), 7.50 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.02, 32.60, 62.55, 127.15,
129.22, 139.48, 163.31, 176.75.
N
N
N
N
N
aq HCl
10b + 10c
N
Me
Me
OH
10d
MS (CI): m/z = 217 [M + 1].
Scheme 2 Synthesis of alcohol 10d
Ethyl 2-(1-Butyl-1H-imidazol-2-yl)-2-oxoacetate (3a)
The crude product was purified by flash column chromatography
(silica gel, hexane–EtOAc, 4:1).
Obviously, the activity of the carbonyl group in 1a–12a
and steric effects both influence the reaction yield signif-
icantly. The carbonyl groups in 10a, 11a, and 12a are
more active toward nucleophiles than those of compounds
1a–9a, due to the strong electron-withdrawing nature of
the triazole and thiazole moieties. Therefore, the products
10a, 11a, and 12a can react with the corresponding inter-
mediate B (Scheme 1), which results in the formation of
the side products, thereby decreasing the yields of 10a,
11a, and 12a, in contrast to the imidazole derivatives 1a–
9a.
Yield 85%; brown liquid.
1H NMR (500 MHz, CDCl3): d = 0.95 (t, J = 7.1 Hz, 3 H), 1.34–1.43
(m, 5 H), 1.76–1.82 (m, 2 H), 4.40 (t, J = 7.3 Hz, 2 H), 4.46 (q,
J = 7.1 Hz, 2 H), 7.21 (s, 1 H), 7.30 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.51, 14.03, 19.62, 32.89, 48.30,
62.40, 127.46, 131.98, 139.62, 163.89, 177.35.
MS (CI): m/z = 225 [M + 1].
Ethyl 2-(1-Allyl-1H-imidazol-2-yl)-2-oxoacetate (4a)
The crude product was purified by flash column chromatography
(silica gel, hexane–EtOAc, 4:1).
In summary, we have shown that C-acylation of imida-
zoles with ethyl oxalyl chloride in the presence of N,N-di-
isopropylethylamine as a base is a facile and practical
method for the preparation of 2-(2-ethoxy-1,2-dioxoeth-
yl)imidazoles. To demonstrate the applicability of this
strategy for the synthesis of other 2-(2-ethoxy-1,2-dioxo-
ethyl)azoles, various model 2-(2-ethoxy-1,2-dioxoeth-
yl)triazoles and 2-(2-ethoxy-1,2-dioxoethyl)thiazoles
were prepared in 40–90% (non-optimized) yield. A sys-
tematic study on the C-acylation of various azoles with
ethyl oxalyl chloride is ongoing.
Yield 83%; brown liquid.
1H NMR (500 MHz, CDCl3): d = 1.41 (t, J = 7.1 Hz, 3 H), 4.45 (q,
J = 7.1 Hz, 2 H), 5.04 (m, 2 H), 5.17 (d, J = 16.9 Hz, 1 H), 5.28 (d,
J = 10.7 Hz, 1 H), 5.96 (m, 1 H), 7.24 (s, 1 H), 7.33 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.03, 50.49, 62.47, 119.17,
120.88, 127.12, 130.89, 132.14, 136.02, 163.71, 177.35.
MS (CI): m/z = 227 [M + 1 + H2O].
Ethyl 2-(1-Benzyl-1H-imidazol-2-yl)-2-oxoacetate (5a)
The crude product was purified by crystallization (i-PrOH).
Yield 90%; brown powder; mp 45 °C.
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruk-
er Avance 500 spectrometer at 499.9, 124.9 and 470 MHz, respec-
tively. Chemical shifts are reported in ppm downfield from TMS
(1H, 13C) and C6F6 (19F) as internal standard. Mass spectra (CI) were
recorded on an Agilent 1100 LCMSD SL instrument.
1H NMR (500 MHz, DMSO-d6): d = 1.29 (t, J = 7.1 Hz, 3 H), 4.35
(q, J = 7.1 Hz, 2 H), 5.64 (s, 2 H), 7.23 (d, J = 7.1 Hz, 2 H), 7.30–
7.33 (m, 1 H), 7.36–7.40 (m, 3 H), 7.95 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.07, 51.66, 62.50, 127.34,
127.78, 127.95, 128.54, 129.07, 129.27, 132.32, 135.26, 139.75,
163.71, 177.56.
Ethyl 2-Azolyl-2-oxoacetates 1a–13a; General Procedure
Ethyl oxalyl chloride (1.08 g, 0.01 mol) was added dropwise over
20 min to a stirred soln of the appropriate azole (0.01 mol) in
MS (CI): m/z = 259 [M + 1].
Synthesis 2011, No. 10, 1633–1637 © Thieme Stuttgart · New York

1636
O. V. Geraschenko et al.
PAPER
Ethyl 2-Oxo-2-(1-vinyl-1H-imidazol-2-yl)acetate (6a)
The crude product was purified by flash column chromatography
(silica gel, hexane–EtOAc, 4:1).
(15 mL). The reaction mixture was heated at reflux for 1 h. The sol-
vent was removed under vacuum. The residue was triturated with
acetone (30 mL), filtered, washed with acetone (30 mL), and dried
under vacuum.
Yield 85%; brown liquid.
Yield 25%; white powder; mp 148 °C.
1H NMR (500 MHz H2O): d = 3.8 (s, 6 H), 6.65 (s, 1 H), 8.20 (s, 2
H).
1H NMR (500 MHz, DMSO-d6): d = 1.31 (t, J = 7.1 Hz, 3 H), 4.38
(q, J = 7.1 Hz, 2 H), 5.27 (d, J = 8.6 Hz, 1 H), 5.81 (d, J = 15.6 Hz,
1 H), 7.45 (s, 1 H), 7.77 (dd, J = 15.6, 8.6 Hz, 1 H), 8.29 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.36, 61.26, 103.57, 117.33,
127.52, 130.10, 136.56, 163.13, 176.30.
13C NMR (125 MHz, CDCl3): d = 36.92, 59.73, 146.68, 150.63.
MS (CI): m/z = 195 [M + 1].
MS (CI): m/z = 213 [M + 1 + H2O].
Ethyl 2-(4-Methyl-1,3-thiazol-2-yl)-2-oxoacetate (11a)
The crude product was purified by distillation (117–121 °C/3 Torr).
Ethyl 2-Oxo-2-{1-[5-(trifluoromethyl)-2-pyridyl]-1H-imidazol-
2-yl}acetate (7a)
The crude product was purified by crystallization (i-PrOH).
Yield 45%; yellow liquid.
1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H), 2.44 (s,
3 H), 4.34 (q, J = 7.1 Hz, 2 H), 6.94 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.04, 17.14, 62.91, 123.64,
157.02, 160.41, 162.48, 177.55.
Yield 92%; brown powder; mp 65 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.20 (t, J = 7.1 Hz, 3 H), 4.26
(q, J = 7.1 Hz, 2 H), 7.53 (s, 1 H), 8.11 (d, J = 8.6 Hz, 1 H), 8.26 (s,
1 H), 8.59 (d, J = 8.6 Hz, 1 H), 8.98 (s 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.04, 62.78, 118.81, 126.13,
132.33, 138.10, 138.12, 140.79, 146.21, 146.24, 151.87, 162.38,
176.31.
MS (CI): m/z = 200 [M + 1].
Ethyl 2-(1,3-Benzothiazol-2-yl)-2-oxoacetate (12a)
The crude product was purified by flash column chromatography
(silica gel, hexane–EtOAc, 4:1).
19F NMR (470 MHz, DMSO-d6): d = –60.33.
MS (CI): m/z = 314 [M + 1].
Yield 51%; yellow liquid.
1H NMR (500 MHz, CDCl3): d = 1.48 (t, J = 7.2 Hz, 3 H), 4.56 (q,
J = 7.2 Hz, 2 H), 7.62 (m, 2 H), 8.03 (d, J = 7.6 Hz, 1 H), 8.29 (d,
J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.09, 63.09, 122.42, 126.39,
127.54, 128.78, 137.26, 153.59, 161.40, 162.44, 180.03.
Ethyl 2-{1-[2-Nitro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-
yl}-2-oxoacetate (8a)
The crude product was purified by crystallization (i-PrOH).
Yield 85%; brown powder; mp 116 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.32 (t, J = 7.1 Hz, 3 H), 4.40
(q, J = 7.1 Hz, 2 H), 7.63 (s, 1 H), 8.08 (s, 1 H), 8.11 (d, J = 8.1 Hz,
1 H), 8.41 (d, J = 8.1 Hz, 1 H), 8.69 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.34, 62.89, 123.38, 123.41,
130.23, 132.06, 132.08, 132.15, 133.36, 134.12, 139.81, 145.35,
163.36, 176.91.
MS (CI): m/z = 236 [M + 1].
X-ray Diffraction Structure of 1a
The crystals of 1a (C8H10N2O3) are monoclinic. At 293 K,
a = 8.0576(6), b = 13.8255(8), c = 8.3947(4) Å, b = 98.247(6)°,
V = 925.5(1) Å3, Mr = 182.18, Z = 4, space group P21/c,
dcalc = 1.307 g/cm3, m(Mo Ka) = 0.102 mm–1, F(000) = 384. Inten-
sities of 8966 reflections (2703 independent, Rint = 0.029) were
measured on an Xcalibur-3 diffractometer (graphite monochromat-
ed Mo Ka radiation, CCD detector, w scanning, 2Qmax = 60°). The
structure was solved by direct methods using the SHELXTL pack-
age.9 The positions of the hydrogen atoms were located from elec-
tron density difference maps and refined by a riding model with
Uiso = nUeq (n = 1.5 for methyl groups and n = 1.2 for other hydro-
gen atoms) of the carrier atom. Restraints on the bond lengths of the
ethyl group (1.54 Å) are used in the refinement of the structure.
Full-matrix least-squares refinement against F2 in the anisotropic
approximation for non-hydrogen atoms using 2640 reflections was
converged to wR2 = 0.099 (R1 = 0.042 for 1131 reflections with F >
4s(F), S = 0.753). CCDC 784044 contains the supplementary crys-
tallographic data for 1a. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
19F NMR (470 MHz, DMSO-d6): d = –61.76.
MS (CI): m/z = 358 [M + 1].
Ethyl 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-oxoacetate (9a)
The crude product was purified by crystallization (i-PrOH).
Yield 91%; white powder; mp 103 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.35 (t, J = 7.1 Hz, 3 H), 4.15
(s, 3 H), 4.46 (q, J = 7.1 Hz, 2 H), 7.43 (t, J = 8.3 Hz, 1 H), 7.56 (t,
J = 8.3 Hz, 1 H), 7.82 (d, J = 8.3 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.07, 31.89, 62.75, 110.61,
122.85, 124.38, 127.34, 137.07, 142.62, 142.97, 163.43, 180.45.
MS (CI): m/z = 251 [M + 1 + H2O].
Ethyl 2-(1-Methyl-1H-1,2,4-triazol-5-yl)-2-oxoacetate (10a)
The crude product was purified by distillation (154–156 °C/3 Torr).
Yield 40%; colorless liquid.
1H NMR (500 MHz, CDCl3): d = 1.32 (t, J = 7.1 Hz, 3 H), 4.16 (s,
3 H), 4.38 (q, J = 7.1 Hz, 2 H), 7.96 (s, 1 H).
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Synthesis 2011, No. 10, 1633–1637 © Thieme Stuttgart · New York

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Synthesis 2011, No. 10, 1633–1637 © Thieme Stuttgart · New York