Imidazo[1,2]hetarylglyoxylates: Synthesis and reactivity toward nucleophiles

Article abstract of DOI:10.1055/s-0029-1218739

A practical approach to imidazo[1,2]hetarylglyoxylates via Friedel-Crafts acylation of the parent fused imidazoles with ethyl oxalyl chloride is reported. The reaction is strongly influenced by the electron-donating properties of the starting heterocycle. The generated imidazo[1,2]hetarylglyoxylates undergo standard transformations typical of -keto esters upon reaction with various nucleophiles. All the products contain an imidazoheterocyclic scaffold which is considered a privileged structure for drug discovery. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218739

1692
PAPER
Imidazo[1,2]hetarylglyoxylates: Synthesis and Reactivity toward
Nucleophiles
S
ynthesi
r
s
and Re
i
activity
n
of Imidazo[
a
1,2]hetarylglyoxy
A
lates . Zamkova,a Oleksiy O. Chekotylo,a Oleksandr V. Geraschenko,a,b Oleksandr O. Grygorenko,*a,b
Pavel K. Mykhailiuk,*a,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Alexandra 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: gregor@univ.kiev.ua; E-mail: pashamk@gmx.de
Received 3 February 2010
mations depend strongly on the electron-donating
properties of the heterocyclic substrate. Taking this into
consideration, we selected a range of imidazoles 8a–h
possessing different electronic properties as model com-
Abstract: A practical approach to imidazo[1,2]hetarylglyoxylates
via Friedel–Crafts acylation of the parent fused imidazoles with eth-
yl oxalyl chloride is reported. The reaction is strongly influenced by
the electron-donating properties of the starting heterocycle. The
generated imidazo[1,2]hetarylglyoxylates undergo standard trans- pounds for this study (Figure 2).
formations typical of a-keto esters upon reaction with various nu-
cleophiles. All the products contain an imidazoheterocyclic scaffold
which is considered a privileged structure for drug discovery.
The reactions of heterocyclic compounds 8 with ethyl ox-
alyl chloride were performed by heating the substrates in
1,4-dioxane or xylene. The following results were ob-
tained: acylation of imidazo[1,2-a]pyridines 8a,b oc-
curred in 1,4-dioxane at reflux, however, due to their low
basicity the products 6a,b formed slowly as their free
bases. The acylation of imidazo[1,2-a]pyrimidines 8c,d
was accomplished by prolonged heating of the substrates
in xylene at reflux temperature to give compounds 6c,d as
the free bases. Acylation of imidazo[2,1-b][1,3]thiazoles
Key words: imidazoheterocycles, acylation, glyoxylates, privi-
leged scaffolds
The concept of privileged scaffolds, introduced to drug
discovery by Evans et al. in 1988,1 has attracted signifi-
cant attention.2 Having the ability to bind to multiple re-
ceptors, these compounds represent very useful building
blocks for the synthesis of potential lead compounds.
Imidazoheterocycles can be considered as privileged
structures for drug discovery. In particular, they are repre-
sented by several marketed drugs including the sedatives
zolpidem (1), alpidem (2) and necopidem (3),3 olprinone
(4) for the treatment of heart failure,4 and zolimidine (5)5
which is used to treat peptic ulcers and gastroesophageal
reflux disease (Figure 1). Furthermore, several other ex-
amples are undergoing biological testing and preclinical
evaluation.
N
N
R2
N
N
R2
Me
N
O
R1
N
O
R1
1 R1 = Me, R2 = Me
2 R1 = n-Pr, R2 = Cl
3
In order to expand the range of compounds comprising the
imidazo[1,2]heterocyclic scaffold, we turned our atten-
tion to the preparation of glyoxylate derivatives of general
formula 6. Compounds of this type are highly reactive
1,2-bis-electrophiles toward various nucleophiles.6 To the
best of our knowledge, the only literature approach for the
synthesis of hetarylglyoxylates 6 involves metalation of
halides 7 followed by quenching the resulting carbanions
with a dialkyl oxalate.7 Herein, we report an alternative
method for the synthesis of compounds 6 via Friedel–
Crafts acylation of the parent imidazo[1,2]heterocycles 8
with ethyl oxalyl chloride (Scheme 1).8
N
N
N
N
NH
NC
O
S
O
O
Me
4
5
Figure 1 Marketed drugs containing the imidazo[1,2]heterocyclic
scaffold
It should be noted that Friedel–Crafts acylation of fused
imidazoles of type 8 is not well documented in the litera-
ture.9 The conditions used to achieve analogous transfor-
N
N
N
R
R
EtOOCCOCl
1. R'Li or R'MgX
2. (CO2Et)2
R
N
N
N
X
CO2Et
O
SYNTHESIS 2010, No. 10, pp 1692–1696
x
x.
x
x
.
2
0
1
0
Advanced online publication: 15.04.2010
7 X = Cl, Br
6
8
DOI: 10.1055/s-0029-1218739; Art ID: P01310SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Syntheses of imidazo[1,2]hetarylglyoxylates

PAPER
Synthesis and Reactivity of Imidazo[1,2]hetarylglyoxylates
1693
N
Table 1 Acylation of Fused Imidazoles 8a–h
N
N
N
Ph
N
N
N
N
Imidazole
Product
Solvent
Yield
76
8a
8b
8c
N
N
N
N
8a
6a
6b
6c
1,4-dioxane
N
N
S
S
Ph
Ph
N
N
CO2Et
Ph
O
8d
8e
8f
N
N
Pr
Pr
N
8b
8c
1,4-dioxane
xylene
71
73
N
N
N
N
CO2Et
N
N
O
Ph
N
N
8g
8h
N
N
Figure 2 Structures of the imidazo[1,2]heterocycles 8a–h used in
this study
CO2Et
O
N
8e,f proceeded smoothly in 1,4-dioxane at reflux temper-
ature to afford the corresponding products 6e,f as their hy-
drochloride salts. Finally, the acylation of imidazo[1,2-
a]benzimidazoles 8g,h in 1,4-dioxane resulted in only 40–
50% yields of the products 6g,h. Higher yields of 6g,h
(75–85%) were obtained by performing the reaction in xy-
lene at reflux temperature; the products were again
formed as their hydrochloride salts (Table 1).
Ph
8d
xylene
68
6d
CO2Et
O
S
N
N
8e
8f
1,4-dioxane
1,4-dioxane
79
82
6e
6f
CO2Et
O
From the results listed in Table 1, the following order of
reactivity was observed in the acylation reaction: imid-
azo[2,1-b]thiazoles > imidazo[1,2-a]benzimidazoles >
imidazo[1,2-a]pyridines > imidazo[1,2-a]pyrimidines.
Moreover, the reactivities of the heterocycles possessing
an electron-withdrawing phenyl substituent (8b,d,f,h)
were similar or lower than those of the corresponding
methyl analogues (8a,c,e,g). These results correlate well
S
N
Ph
N
CO2Et
O
N
Pr
N
8g
8h
xylene
xylene
85
75
6g
6h
N
N
CO2Et
O
N
R
Pr
N
N
N
N
N
R
Ph
CO2Et
N
R
HO
O
N
9
CO2Et
N
NH
H2N
NH2
O
NaBH4
(0.35 equiv)
HO
OH
10
NaBH4
with reported data on the electron-donating properties of
the starting heterocycles.10
(1.2 equiv)
N
14
R
N
O
Next, various standard reactions of hetarylglyoxylates 6
(see experimental section for selected examples) with H-,
O- and N-nucleophiles were explored (Scheme 2). Reduc-
tion of 6 with sodium borohydride resulted in the forma-
tion of hydroxy esters 9 or diols 10 depending on the
number of equivalents of the reducing reagent used for the
reaction. Alkaline hydrolysis of 6 afforded glyoxylic acids
11 whilst reaction of 6 with hydroxylamine hydrochloride
yielded the corresponding oximes 12. Finally, 5,6-dihy-
dropyrazin-2-ones 13 and quinoxalin-2-ones 14 were
obtained when glyoxylates 6 were reacted with ethylene-
diamine and o-phenylenediamine, respectively.
CO2Et
NaOH
N
N
H2N
H2N
R
6
R
O
N
N
CO2H
NH2OH⋅HCl
O
N
11
NH
N
13
R
N
N
CO2Et
HO
12
In conclusion, a simple and practical one-step procedure
for the synthesis of imidazo[1,2]hetarylglyoxylates 6 has
Scheme 2 Reactions of imidazo[1,2]hetarylglyoxylates 6 with va-
rious nucleophiles
Synthesis 2010, No. 10, 1692–1696 © Thieme Stuttgart · New York

1694
I. A. Zamkova et al.
PAPER
1H NMR (DMSO-d6): d = 9.78 (1 H, d, J = 6.8 Hz), 8.93 (1 H, d,
J = 4.2 Hz), 7.49 (1 H, dd, J = 6.8, 4.2 Hz), 7.60–7.50 (5 H, m), 3.62
(2 H, q, J = 7.0 Hz), 0.88 (3 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d = 176.9, 163.2, 159.0, 156.4, 150.8, 137.8,
130.5, 130.0, 129.0, 116.2, 113.2, 62.5, 13.6.
been developed. The products were shown to undergo
standard transformations characteristic of a-keto esters
upon reaction with various H-, O- and N-nucleophiles.
Fused imidazoles 8a,11 8b,12 8c,d,g,h,9b 8e13 and 8f14 were synthe-
sized according to the literature. Solvents were purified using stan-
dard procedures. Starting materials were purchased from Acros,
Merck and Fluka. Analytical TLC was performed using Polychrom
SI F254 plates. 1H and 13C NMR spectra were recorded on a Bruker
170 Avance 500 spectrometer at 499.9 MHz (1H) and 124.9 MHz
(13C), respectively, in DMSO-d6 as solvent. Chemical shifts are re-
ported in ppm downfield with respect to TMS as the internal stan-
dard. Mass spectra were recorded on an Agilent 1100 LCMSD SL
instrument using atmospheric pressure chemical ionization (APCI).
Elemental analysis (C, H, N and S) data was obtained using an Ele-
mentar Vario MICRO Cube CHNS/O analyzer.
MS (APCI): m/z = 266 [M + H+].
Hetarylglyoxylates 6e–h; General Procedure
To a soln of 8e–f (0.1 mol) in anhyd 1,4-dioxane or xylene (40 mL,
see Table 1) was added ethyl oxalyl chloride (16.8 mL, 0.15 mol)
dropwise. The resulting mixture was heated at reflux for 7–8 h, then
allowed to cool and evaporated. The residue was treated with H2O
(100 mL) and neutralized with 20% aq Na2CO3 (100 mL) soln. The
product was either filtered and washed with H2O (20 mL) (6f,h) or
extracted with CH2Cl2 (3 × 60 mL) (6e,g). In the latter case, the
combined organic extracts were dried over Na2SO4 and evaporated.
Ethyl (6-Methylimidazo[2,1-b][1,3]thiazol-5-yl)(oxo)acetate
(6e)
Colorless solid; yield: 79%; mp 63–65 °C.
1H NMR (DMSO-d6): d = 8.30 (1 H, d, J = 4.5 Hz), 7.58 (1 H, d,
J = 4.5 Hz), 4.41 (2 H, q, J = 7.0 Hz), 2.40 (3 H, s), 1.32 (3 H, t,
J = 7.0 Hz).
13C NMR (DMSO-d6): d = 173.8, 164.5, 156.5, 156.4, 122.0, 121.2,
117.4, 61.6, 16.1, 14.2.
Hetarylglyoxylates 6a–d; General Procedure
To a soln of 8a–d (0.1 mol) in anhyd 1,4-dioxane or xylene (40 mL,
see Table 1) was added ethyl oxalyl chloride (16.8 mL, 0.15 mol)
dropwise. The mixture was heated at reflux for 7–8 h, then allowed
to cool and evaporated. The residue was triturated with H2O (80
mL) and the resulting precipitate was either removed by filtration
and washed with H2O (20 mL) (6a,c,d) or extracted with CH2Cl2
(3 × 60 mL) (6b). In the latter case, the combined organic extracts
were dried over Na2SO4 and evaporated to afford the product.
MS (APCI): m/z = 239 [M + H+].
Ethyl (2-Methylimidazo[1,2-a]pyridin-3-yl)(oxo)acetate (6a)
Colorless solid; yield: 76%; mp 74 °C.
Anal. Calcd for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46.
Found: C, 50.08; H, 3.99; N, 11.62; S, 13.31.
1H NMR (DMSO-d6): d = 9.42 (1 H, t, J = 6.8 Hz), 7.71 (2 H, m),
7.13 (1 H, t, J = 6.8 Hz), 4.47 (2 H, q, J = 7.0 Hz), 2.48 (3 H, s), 1.32
(3 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d = 175.2, 164.8, 156.4, 148.4, 132.3, 129.2,
117.6, 117.1, 116.8, 62.9, 16.0, 14.2.
Ethyl (6-Phenylimidazo[2,1-b][1,3]thiazol-5-yl)(oxo)acetate (6f)
Colorless solid; yield: 82%; mp 90–92 °C.
1H NMR (DMSO-d6): d = 8.50 (1 H, d, J = 4.5 Hz), 8.15 (2 H, d,
J = 7.3 Hz), 7.87 (1 H, d, J = 4.5 Hz), 7.68 (2 H, t, J = 7.3 Hz), 7.45
(1 H, t, J = 7.3 Hz), 4.52 (2 H, q, J = 7.0 Hz), 0.92 (3 H, t,
J = 7.0 Hz).
MS (APCI): m/z = 233 [M + H+].
Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C,
62.31; H, 4.98; N, 12.17.
13C NMR (DMSO-d6): d = 173.2, 153.9, 159.2, 147.9, 133.5, 128.7,
127.3, 121.2, 122.6, 117.4, 61.7, 15.8.
MS (APCI): m/z = 301 [M + H+].
Ethyl (2-Phenylimidazo[1,2-a]pyridin-3-yl)(oxo)acetate (6b)
Colourless oil; yield: 71%.
Ethyl (2-Methyl-9-propyl-9H-imidazo[1,2-a]benzimidazol-3-
yl)(oxo)acetate (6g)
Colorless solid; yield: 85%; mp 121 °C.
1H NMR (DMSO-d6): d = 8.44 (1 H, d, J = 7.8 Hz), 7.70 (1 H, d,
J = 8.0 Hz), 7.41 (1 H, dd, J = 8.0, 7.0 Hz), 7.28 (1 H, dd, J = 8.0,
7.0 Hz), 4.22 (4 H, m), 2.40 (3 H, s), 1.84 (2 H, m), 1.32 (3 H, t,
J = 7.0 Hz), 0.85 (3 H, t, J = 7.8 Hz).
13C NMR (DMSO-d6): d = 172.7, 165.8, 157.8, 151.0, 135.1, 125.2,
124.7, 121.7, 119.7, 115.6, 111.6, 62.8, 44.9, 21.9, 16.5, 14.2, 11.4.
MS (APCI): m/z = 314 [M + H+].
1H NMR (DMSO-d6): d = 9.61 (1 H, d, J = 6.9 Hz), 7.95 (1 H, d,
J = 8.8 Hz), 7.81 (1 H, dd, J = 8.8, 6.9 Hz), 7.54–7.60 (5 H, m),
7.41 (1 H, t, J = 6.9 Hz), 3.46 (2 H, d, J = 7.0 Hz), 0.92 (3 H, t,
J = 7.0 Hz).
13C NMR (DMSO-d6): d = 176.5, 163.6, 158.1, 148.2, 133.8, 132.5,
130.1, 130.0, 129.2, 128.8, 117.8, 117.7, 117.2, 62.3, 13.6.
MS (APCI): m/z = 295 [M + H+].
Ethyl (2-Methylimidazo[1,2-a]pyrimidin-3-yl)(oxo)acetate (6c)
Colorless solid; yield: 73%; mp 108 °C.
1H NMR (DMSO-d6): d = 9.72 (1 H, d, J = 6.8 Hz), 8.88 (1 H, d,
J = 4.2 Hz), 7.45 (1 H, dd, J = 6.8, 4.2 Hz), 4.42 (2 H, q,
J = 7.0 Hz), 2.51 (3 H, s), 1.35 (3 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d = 175.7, 164.4, 157.9, 155.9, 151.1, 137.6,
116.3, 112.9, 63.2, 16.7, 14.2.
Ethyl (2-Phenyl-9-propyl-9H-imidazo[1,2-a]benzimidazol-3-
yl)(oxo)acetate (6h)
Colorless solid; yield: 75%; mp 142–144 °C.
1H NMR (DMSO-d6): d = 8.55 (1 H, d, J = 7.5 Hz), 7.80 (1 H, d,
J = 7.5 Hz), 7.6–7.5 (5 H, m), 7.49 (1 H, t, J = 7.5 Hz), 7.35 (1 H, t,
J = 7.5 Hz), 4.30 (2 H, t, J = 7.0 Hz), 3.65 (2 H, q, J = 7.4 Hz), 1.94
(2 H, m), 0.90 (6 H, 2 × t, J = 7.2 Hz).
13C NMR (DMSO-d6): d = 173.5, 164.6, 159.2, 159.1, 150.9, 135.3,
134.3, 130.0, 129.9, 128.7, 125.0, 121.8, 119.6, 115.8, 111.6, 62.1,
45.0, 22.0, 13.7, 11.5.
MS (APCI): m/z = 234 [M + H+].
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.29; H, 4.70; N, 17.73.
Ethyl (2-Phenylimidazo[1,2-a]pyrimidin-3-yl)(oxo)acetate (6d)
Colorless solid; yield: 68%; mp 124–126 °C.
MS (APCI): m/z = 376 [M + H+].
Synthesis 2010, No. 10, 1692–1696 © Thieme Stuttgart · New York

PAPER
Synthesis and Reactivity of Imidazo[1,2]hetarylglyoxylates
1695
Anal. Calcd for C22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C,
70.07; H, 5.63; N, 11.03.
13C NMR (DMSO-d6): d = 149.1, 140.9, 136.0, 128.6, 125.0, 123.4,
120.2, 114.7, 110.1, 66.4, 64.7, 44.5, 21.8, 14.9, 11.7.
MS (APCI): m/z = 274 [M + H+].
Hydroxy Esters 9; General Procedure
Hetarylglyoxylate 6 (0.01 mol) was dissolved in anhyd THF
(25 mL), cooled to –78 °C, and NaBH4 (0.13 g, 0.0035 mol) was
added with stirring. The cooling bath was removed and the mixture
was stirred for 2–3 h and then quenched with H2O (25 mL). The
mixture was stirred for 1 h and extracted with CH2Cl2 (3 × 15 mL).
The combined organic phase was dried over Na2SO4 and evaporat-
ed. The residue was dissolved in acetone (2–3 mL) and allowed to
stand at –4 °C for 10–12 h. The precipitate that formed was removed
by filtration and washed with acetone (1 mL).
Glyoxylic Acids 11; General Procedure
Hetarylglyoxylate 6 (0.1 mol) was dissolved in 30% aq NaOH (50
mL) soln and the resulting mixture was stirred at ambient tempera-
ture for 30 h, and then at 70–75 °C for 30–50 min. After cooling, the
mixture was neutralized with 6 M HCl until pH 7. The precipitate
formed (if any) was filtered and washed with cold H2O (10 mL). If
the precipitate did not form, the solution was evaporated to 80–100
mL and left at 4 °C for 10–12 h, then worked up as described above.
(2-Methylimidazo[1,2-a]pyridin-3-yl)(oxo)acetic Acid (11a)
Colorless solid; yield: 82%; mp >220 °C.
1H NMR (DMSO-d6): d = 9.54 (1 H, d, J = 6.8 Hz), 7.82 (1 H, d,
J = 8.7 Hz), 7.70 (1 H, dd, J = 8.7, 6.8 Hz), 7.35 (1 H, t, J = 6.8 Hz),
2.55 (3 H, s). COOH proton is exchangeable with deuterium pro-
tium oxide (HDO).
13C NMR (DMSO-d6): d = 178.1, 167.1, 155.6, 147.9, 131.9, 129.1,
117.5, 117.0, 116.6, 15.8.
MS (APCI): m/z = 205 [M + H+].
Ethyl hydroxy(2-methylimidazo[1,2-a]pyridin-3-yl)acetate (9a)
Colorless solid; yield: 52%; mp 132 °C (acetone).
1H NMR (DMSO-d6): d = 8.42 (1 H, d, J = 6.9 Hz), 7.45 (1 H, d,
J = 8.8 Hz), 7.22 (1 H, dd, J = 8.8, 6.9 Hz), 6.87 (1 H, t, J = 6.9 Hz),
6.21 (1 H, d, J = 5.2 Hz), 5.15 (1 H, d, J = 5.2 Hz), 4.17–4.02 (2 H,
m), 2.31 (3 H, s), 1.08 (3 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d = 171.5, 144.2, 141.4, 126.0, 124.9, 118.0,
116.6, 112.1, 64.6, 61.4, 14.5, 13.7.
MS (APCI): m/z = 235 [M + H+].
(6-Methylimidazo[2,1-b][1,3]thiazol-5-yl)(oxo)acetic Acid (11e)
Colorless solid; yield: 89%; mp >220 °C.
1H NMR (DMSO-d6): d = 8.63 (1 H, d, J = 4.4 Hz), 7.62 (1 H, d,
J = 4.4 Hz), 2.41 (3 H, s). COOH proton is exchangeable with
HDO.
13C NMR (DMSO-d6): d = 176.1, 166.8, 155.8, 153.1, 121.9, 121.0,
117.2, 15.9.
MS (APCI): m/z = 211 [M + H+].
Ethyl Hydroxy(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)ace-
tate (9e)
Colorless solid; yield: 53%; mp 134 °C (acetone).
1H NMR (DMSO-d6): d = 7.70 (1 H, d, J = 4.5 Hz), 7.18 (1 H, d,
J = 4.5 Hz), 6.25 (1 H, s), 5.45 (1 H, s), 4.16–4.02 (2 H, m), 2.20 (3
H, s), 1.11 (3 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d = 171.4, 148.2, 141.6, 120.3, 120.0, 112.4,
64.9, 61.3, 14.4, 13.8.
MS (APCI): m/z = 241 [M + H+].
Oximes 12; General Procedure
Anal. Calcd for C10H12N2O3S: C, 49.99; H, 5.03; N, 11.66; S, 13.34.
Found: C, 50.31; H, 5.07; N, 11.81; S, 13.69.
To a soln of hetarylglyoxylate 6 (0.0125 mol) in EtOH (50 mL) was
added a soln of hydroxylamine hydrochloride (6.3 g, 0.09 mol) and
sodium acetate trihydrate (13 g, 0.09 mol) in H2O (50 mL). The re-
sulting mixture was heated at reflux for 2 d, then cooled, evaporated
to 20–30 mL of the original volume, and diluted with H2O (80 mL).
The obtained precipitate was filtered and washed with H2O (20
mL).
Diols 10; General Procedure
Hetarylglyoxylate 6 (0.01 mol) was dissolved in anhyd THF (25
mL), cooled to 5–10 °C, and NaBH4 (0.45 g, 0.012 mol) was added
with stirring. The mixture was stirred for 2–3 h, quenched with H2O
(25 mL) and stirred for 1 h. The product was extracted with CH2Cl2
(3 × 15 mL) and the combined organic phase dried over Na2SO4 and
evaporated.
Ethyl (2E/Z)-(Hydroxyimino)(2-methylimidazo[1,2-a]pyridin-
3-yl)acetate (12a)
Colorless solid; yield: 91%; mp 176 °C.
1-(2-Phenylimidazo[1,2-a]pyrimidin-3-yl)ethane-1,2-diol (10d)
Colorless oil; yield: 63%.
1H NMR (DMSO-d6): d (1:1 mixture of E/Z isomers) = 12.72 (0.5
H, s), 11.69 (0.5 H, s), 9.09 (0.5 H, d, J = 6.9 Hz), 7.77 (0.5 H, d,
J = 6.9 Hz), 7.64 (0.5 H, d, J = 8.7 Hz), 7.53 (0.5 H, d, J = 8.7 Hz),
7.42 (0.5 H, dd, J = 8.7, 6.9 Hz), 7.30 (0.5 H, dd, J = 8.7, 6.9 Hz),
7.12 (0.5 H, t, J = 6.9 Hz), 6.93 (0.5 H, t, J = 6.9 Hz), 4.36 (2 × 0.5
H, q, J = 7.1 Hz), 4.25 (2 × 0.5 H, q, J = 7.1 Hz), 2.30 (3 × 0.5 H, s),
2.18 (3 × 0.5 H, s), 1.30 (3 × 0.5 H, t, J = 7.1 Hz), 1.32 (3 × 0.5 H,
t, J = 7.1 Hz).
13C NMR (DMSO-d6): d (1:1 mixture of E/Z isomers) = 163.2,
163.1, 145.8, 145.7, 145.1, 144.5, 144.2, 140.0, 128.0, 127.3, 127.2,
125.7, 116.9, 116.4, 114.2, 112.3, 112.2, 111.9, 62.3, 62.0, 15.0,
14.8, 14.5, 14.3.
1H NMR (DMSO-d6): d = 9.10 (1 H, dd, J = 6.8, 2.0 Hz), 8.53 (1 H,
dd, J = 4.3, 2.0 Hz), 7.82 (2 H, d, J = 7.2 Hz), 7.48 (2 H, t,
J = 7.2 Hz), 7.41 (1 H, t, J = 7.2 Hz), 7.02 (1 H, dd, J = 6.8, 4.3 Hz),
5.83 (1 H, d, J = 6.3 Hz), 5.22 (1 H, q, J = 6.3 Hz), 5.11 (1 H, t,
J = 6.1 Hz), 3.98–3.82 (2 H, m).
13C NMR (DMSO-d6): d = 150.4, 147.8, 144.0, 136.3, 134.6, 129.3,
128.9, 128.4, 120.3, 108.3, 66.9, 64.3.
MS (APCI): m/z = 256 [M + H+].
1-(2-Methyl-9-propyl-9H-imidazo[1,2-a]benzimidazol-3-
yl)ethane-1,2-diol (10g)
MS (APCI): m/z = 248 [M + H+].
Colorless oil; yield: 58%.
Ethyl (2E/Z)-(Hydroxyimino)(6-methylimidazo[2,1-b][1,3]thia-
zol-5-yl)acetate (12e)
Colorless solid; yield: 94%; mp 180 °C.
1H NMR (DMSO-d6): d (1:1 mixture of E/Z isomers) = 13.08 (0.5
H, s), 11.77 (0.5 H, s), 7.98 (0.5 H, d, J = 4.5 Hz), 7.61 (0.5 H, d,
1H NMR (DMSO-d6): d = 8.07 (1 H, d, J = 8.1 Hz), 7.70 (1 H, d,
J = 8.1 Hz), 7.42 (1 H, dd, J = 8.1, 7.0 Hz), 7.30 (1 H, dd, J = 8.1,
7.0 Hz), 5.95 (1 H, d, J = 6.1 Hz), 4.97 (1 H, m), 4.87 (1 H, m), 4.63
(1 H, m), 3.75 (1 H, m), 3.45–3.35 (2 H, m), 2.33 (3 H, s), 1.9–1.75
(2 H, m), 0.87 (3 H, t, J = 7.8 Hz).
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I. A. Zamkova et al.
PAPER
J = 4.5 Hz), 7.38 (0.5 H, d, J = 4.5 Hz), 7.20 (0.5 H, d, J = 4.5 Hz),
4.35 (2 × 0.5 H, q, J = 7.0 Hz), 4.26 (2 × 0.5 H, q, J = 7.0 Hz), 2.23
(3 × 0.5 H, s), 2.12 (3 × 0.5 H, s), 1.30 (3 × 0.5 H, t, J = 7.0 Hz), 1.21
(3 × 0.5 H, t, J = 7.0 Hz).
13C NMR (DMSO-d6): d (1:1 mixture of E/Z isomers) = 163.3,
163.2, 151.2, 149.2, 145.2, 145.0, 143.1, 143.0, 121.7, 121.4, 114.6,
114.5, 112.1, 112.1, 62.3, 61.8, 15.5, 14.6, 14.4, 14.2.
F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D.
J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(2) (a) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. Mini-Rev.
Med. Chem. 2007, 7, 1108. (b) DeSimone, R. W.; Currie, K.
S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Comb.
Chem. High Throughput Screening 2004, 7, 473.
(c) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13,
65.
MS (APCI): m/z = 254 [M + H+].
(3) (a) Langer, S. Z.; Arbilla, S.; Benavides, J.; Scatton, B. Adv.
Biochem. Psychopharmacol. 1990, 46, 61. (b) George, P.;
Rossey, G.; Depoortere, H.; Mompon, B.; Allen, J.; Wick, A.
Farmaco 1991, 46, 277.
(4) Mizushige, K.; Ueda, T.; Yukiiri, K.; Suzuki, H.
Cardiovasc. Drug. Rev. 2002, 20, 163.
(5) Carminati, G. M. Farmaco Prat. 1978, 33, 68.
(6) For selected examples, see: (a) Primofiore, G.; Da Settimo,
F.; Taliani, S.; Marini, A. M.; La Motta, C.; Novellino, E.;
Greco, G.; Gesi, M.; Trincavelli, L.; Martini, C. J. Med.
Chem. 2000, 43, 96. (b) Tse, B.; Jones, A. B. Tetrahedron
Lett. 2001, 42, 6429. (c) Zhu, G.; Conner, S.; Zhou, X.;
Shih, C.; Brooks, H. B.; Considine, E.; Dempsey, J. A.; Ogg,
C.; Patel, B.; Schultz, R. M.; Spencer, C. D.; Teicher, B.;
Watkins, S. A. Bioorg. Med. Chem. Lett. 2003, 13, 1231.
(d) Willardsen, J. A.; Dudley, D. A.; Cody, W. L.; Chi, L.;
McClanahan, T. B.; Mertz, T. E.; Potoczak, R. E.;
Narasimhan, L. S.; Holland, D. R.; Rapundalo, S. T.;
Edmunds, J. J. J. Med. Chem. 2004, 47, 4089.
5,6-Dihydropyrazin-2-ones 13 and Quinoxalin-2-ones 14; Gen-
eral Procedure
A soln of 1,2-ethylenediamine (0.85 mL, 0.013 mol) or o-phe-
nylenediamine (1.38 g, 0.013 mol) was added to a soln of hetaryl-
glyoxylate 6 (0.0125 mol) in anhyd MeCN (25 mL). The reaction
mixture was heated at reflux for 2 d, then allowed to cool and left to
stand at –4 °C for 10–12 h. The resulting precipitate was filtered and
washed with MeCN (5–10 mL).
3-(6-Methylimidazo[2,1-b][1,3]thiazol-5-yl)-5,6-dihydropy-
razin-2(1H)-one (13e)
Colorless solid; yield: 67%; mp >220 °C (MeCN).
1H NMR (DMSO-d6): d = 8.65 (1 H, s), 7.96 (1 H, d, J = 4.5 Hz),
7.23 (1 H, d, J = 4.5 Hz), 3.82 (2 H, t, J = 6.1 Hz), 3.31 (2 H, t,
J = 6.1 Hz), 2.32 (3 H, s).
13C NMR (DMSO-d6): d = 155.9, 155.6, 150.4, 148.6, 122.1, 120.6,
112.6, 48.6, 38.4, 16.8.
MS (APCI): m/z = 235 [M + H+].
(e) Kishorebabu, N.; Periasamy, M. Tetrahedron Lett. 2006,
47, 2107.
Anal. Calcd for C10H10N4OS: C, 51.27; H, 4.30; N, 23.91; S, 13.69.
Found: C, 51.02; H, 4.68; N, 23.90; S, 14.02.
(7) Clayton, J. R.; Diefenbacher, C. G.; Engler, T. A.; Furness,
K. W.; Henry, J. R.; Malhotra, S.; Marquart, A. L.; McLean,
J. A.; Mendel, D.; Burkholder, T. P.; Li, Y.; Reel, J. K.
WO03076442, 2003; Chem. Abstr. 2003, 139, 261331.
(8) Recently, the Friedel–Crafts acylation of benzene
derivatives with ethyl oxalyl chloride was applied to the
synthesis of ethyl arylglyoxylates, see: Xiang, J. M.; Li, B.
L. Chin. Chem. Lett. 2009, 20, 55.
(9) (a) Anisimova, V. A.; Simonov, A. M. Chem. Heterocycl.
Compd. 1976, 12, 110. (b) Anisimova, V. A.; Korochina, T.
B.; Avdyunina, N. I.; Simonov, A. M. Chem. Heterocycl.
Compd. 1986, 22, 275. (c) Anisimova, V. A.; Avdyunina, N.
I.; Simonov, A. M.; Kovalev, G. V.; Gofman, S. M. Chem.
Heterocycl. Compd. 1976, 12, 1365. (d) Kawamoto, T.;
Tomimatsu, K.; Ikemoto, T.; Abe, H.; Hamamura, K.;
Takatani, M. Tetrahedron Lett. 2000, 41, 3447. (e) Daly,
M.; Hopkinson, C. J. Chem. Soc., Perkin Trans. 1 1991, 855.
(10) (a) Montgomery, J. A.; Sechrist, J. A. In Comprehensive
Heterocyclic Chemistry, Vol. 5; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984, 608–668.
(b) Anisimova, V. A.; Avdyunina, N. I.; Pozharskii, A. F.;
Simonov, A. M.; Talanova, L. N. Chem. Heterocycl. Compd.
1980, 16, 409.
3-(2-Methylimidazo[1,2-a]pyridin-3-yl)quinoxalin-2(1H)-one
(14a)
Colorless solid; yield: 84%; mp >220 °C (MeCN).
1H NMR (DMSO-d6): d = 12.63 (1 H, s), 8.73 (1 H, d, J = 6.7 Hz),
7.82 (1 H, d, J = 8.8 Hz), 7.62–7.52 (2 H, m), 7.37 (1 H, d,
J = 8.1 Hz), 7.41–7.33 (2 H, m), 6.97 (1 H, d, J = 8.4 Hz), 2.50 (3
H, s).
13C NMR (DMSO-d6): d = 154.4, 149.6, 147.2, 145.6, 132.6, 132.2,
130.6, 128.9, 128.0, 126.4, 123.9, 118.2, 116.4, 115.7, 112.5, 16.2.
MS (APCI): m/z = 277 [M + H+].
Anal. Calcd for C16H12N4: C, 69.55; H, 4.38; N, 20.28. Found: C,
69.31; H, 4.25; N 20.33.
3-(6-Methylimidazo[2,1-b][1,3]thiazol-5-yl)quinoxalin-2(1H)-
one (14e)
Colorless solid; yield: 81%; mp >220 °C (MeCN).
1H NMR (DMSO-d6): d = 8.13 (1 H, d, J = 4.5 Hz), 7.80 (1 H, d,
J = 4.5 Hz), 7.54 (1 H, t, J = 8.3 Hz), 7.37–7.28 (2 H, m), 7.27 (1 H,
d, J = 8.1 Hz), 2.42 (3 H, s). NH proton is exchangeable with HDO.
(11) Tschitschibabin, A. E. Chem. Ber. 1926, 59, 2048.
(12) Djerassi, C.; Pettit, G. R. J. Am. Chem. Soc. 1954, 76, 4470.
(13) Meakins, G. D.; Musk, S. R. R.; Robertson, C. A.;
Woodhouse, L. S. J. Chem. Soc., Perkin Trans. 1 1989, 643.
(14) Palagiano, F.; Arenare, L.; Luraschi, E.; de Caprariis, P.;
Abignente, E.; D’Amico, M.; Filippelli, W.; Rossi, F. Eur. J.
Med. Chem. 1995, 30, 901.
13C NMR (DMSO-d6): d = 154.2, 150.7, 149.0, 148.8, 132.6, 131.9,
130.1, 128.7, 123.9, 123.0, 120.9, 115.6, 112.3, 17.1.
MS (APCI): m/z = 283 [M + H+].
References
(1) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D.
Synthesis 2010, No. 10, 1692–1696 © Thieme Stuttgart · New York