Reaction of quinoxalin-2-ones with TosMIC reagent: Synthesis of imidazo[1,5-a]quinoxalin-4-ones

Article abstract of DOI:10.1016/S0040-4039(01)00697-9

Imidazo[1,5-a]quinoxalin-4-ones were prepared in four steps starting from 1,2-phenylenediamines using a new strategy for the construction of the ring system. A key step in this new method involves the reaction of quinoxalin-2-ones with TosMIC (tosylmethyl isocyanide).

Full text of DOI:10.1016/S0040-4039(01)00697-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4293–4295
Reaction of quinoxalin-2-ones with TosMIC reagent: synthesis of
imidazo[1,5-a]quinoxalin-4-ones
Ping Chen,* Joel C. Barrish, Edwin Iwanowicz, James Lin, Mark S. Bednarz and Bang-Chi Chen
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 15 December 2000; revised 24 April 2001; accepted 27 April 2001
Abstract—Imidazo[1,5-a]quinoxalin-4-ones were prepared in four steps starting from 1,2-phenylenediamines using a new strategy
for the construction of the ring system. A key step in this new method involves the reaction of quinoxalin-2-ones with TosMIC
(tosylmethyl isocyanide). © 2001 Elsevier Science Ltd. All rights reserved.
Imidazo[1,5-a]quinoxalin-4-ones are common structural
arrays that are found in a variety of biologically impor-
tant and medicinally useful agents and therefore often
serve as important intermediates for their synthesis. For
example, they have been used as templates for the
synthesis of GABA/benzodiazepine receptor agonists/
antagonists,1 cAMP and cGMP phosphodiesterase
inhibitors,2 A1- and A2a-adenosine receptor agonists3 in
addition to many other pharmacologically active com-
pounds.4–7 Three methods have been previously devel-
oped for the preparation of imidazo[1,5-a]-
quinoxalin-4-ones. The first method involved the cou-
pling of 2-fluoronitrobenzenes 2 with imidazoles (3,
X"H, Z=H) via nucleophilic aromatic substitution to
give 1-(2-nitrophenyl)imidazoles (4, X"H, Z=H).2–4,8
Reduction of 4 (X"H, Z=H) afforded the correspond-
ing 2-imidazolylanilines 5 (X"H, Z=H), which upon
reaction with carbonyldiimidazole gave rise to imi-
dazo[1,5-a]-quinoxalin-4-ones. While this approach is
quite useful for the synthesis of 1-substituted imi-
dazo[1,5-a]-quinoxalin-4-ones (1, X"H),2–4 it is not
adaptable to the preparation of 1-unsubstituted imi-
dazo[1,5-a]quinoxalin-4-ones (1, X=H) since the use of
2-unsubstituted imidazoles (3, X=H) in this sequence
will ultimately lead to exclusive formation of the iso-
meric imidazo[1,2-a]quinoxalin-6-ones 6.2–4,8 The second
approach involves the reaction of ethyl imidazole-4,5-
dicarboxylate (3, Y=Z=COOEt) with 2-fluronitroben-
zene to give 1-(2-nitrophenyl)imidazole-4,5-dicarb-
oxylate (4, Y=Z=COOEt).7 Subsequent reduction
and spontaneous cyclization of the corresponding ani-
line (5, Y=Z=COOEt) afforded ethoxycarbonyl-imi-
dazo[1,5-a]quinoxalin-4-ones 1 (Y=COOEt).7 In the
third method, 1,2-phenylenediamines 7 were condensed
with ethyl oxalyl chloride to give 2,3-dioxoquinoxalines
8, which, after transformation to enol phosphates 9 and
subsequent reaction with aryl isocyanides, afforded
3-aryl-imidazo[1,5-a]quinoxalin-4-ones (1, X=H, Y=
X
X
X
N
N
X
R
N
R
R
N
R
F
N
N
Y
Y
N
Y
HN
Y
Z
Z
NO2
NH2
NO2
Z
N
H
O
2
4
3
5
1
Y
Z
R
H
N
R
R
OPO(OEt)2
O
R
N
O
NH2
N
O
N
N
R'
N
R'
NHR'
O
N
H
7
9
8
6
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00697-9

4294
P. Chen et al. / Tetrahedron Letters 42 (2001) 4293–4295
Ar).1,5,6 A variety of 1- and/or 3-substituted imi-
dazo[1,5-a]-quinoxalin-4-ones have been prepared by
appropriate choice of the above methods. These
approaches, however, could not be used for the synthe-
sis of both 1- and 3-unsubstituted imidazo[1,5-a]-
quinoxalin-4-ones (1, X=Y=H). Recently, in one of
our drug discovery programs, we required easy access
to various 1- and 3-unsubstituted imidazo[1,5-a]-
quinoxalin-4-ones (1, X=Y=H). We report herein a
novel method for the preparation of these compounds.
Table 1. Preparation of imidazo[1,5-a]quinoxalin-4-ones 15
Entry
R1
R2
R3
R4
Yield (%)c
12
13
14
15
a
1
2
3
4
5
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
63
61
54
97
90
96
97
90
99
b
OMe
OMe
CO2Me
H
86
93d 67d 88d 94d
NO2
37e 70
68
91
a Commercially available materials.
b For details, see Ref. 14.
Our approach to both 1- and 3-unsubstituted imi-
dazo[1,5-a]quinoxalin-4-ones began with the condensa-
tion of 1,2-phenylenediamines 10 with ethyl glyoxalate
11 (Scheme 1). Thus, refluxing 1,2-phenylenediamine
10a and ethyl glyoxalate 11 in ethanol gave quinoxalin-
2(1H)-one 12a in 88% yield.9,10 Treatment of 12a with
sodium hydride in DMF followed by addition of p-
methoxybenzyl chloride afforded a mixture of N-(p-
methoxybenzyl)-quinoxlin-2-one 13a and 2-(p-methoxy-
benzyloxy)quinoxline 13%a. The major isomer 13a can
be isolated by chromatography in 74% yield.10,11 Reac-
tion of 13a with TosMIC (tosylmethyl isocyanide) in
THF in the presence of a base such as NaH provided
5-(p-methoxybenzyl)-imidazo[1,5-a]-quinoxalin-4-one
14a in 97% yield.10,12 It should be noted that the minor
isomer 13%a reacts very sluggishly with TosMIC to give
the corresponding imidazole derivative under similar
reaction conditions. Finally, deprotection of the N-(p-
methoxybenzyl) group of 14a afforded imidazo[1,5-
a]quinoxalin-4-one 15a in 97% yield.10,13 Other
imidazo[1,5-a]quinoxalin-4-ones were prepared in an
analogous manner; these results are summarized in
Table 1.
c Isolated by chromatography unless otherwise indicated.
d Isolated as a mixture of regioisomers.
e Isolated by crystallization.
either electron-donating or electron-withdrawing
groups on the phenyl ring (Table 1, entries 2 and 3 and
entries 4 and 5, respectively). One drawback with this
method is the formation of a mixture of quinoxalin-2-
one regioisomers when an unsymmetrical phenylenedi-
amine is used, thereby significantly reducing the overall
yield (Table 1, entries 4 and 5). However, the desired
isomer of intermediate 12 can be prepared regiospecifi-
cally via an alternative route if needed (Table 1, entry
2).14
In summary, a novel method has been developed for
the preparation of both 1- and 3-unsubstituted imi-
dazo[1,5-a]quinoxalin-4-ones. A key step in this newly
developed method involves an efficient imidazole ring
formation by reaction of quinoxalin-2-ones with
TosMIC. The application of this new synthetic
sequence to the preparation of novel protein tyrosine
kinase (PTK) inhibitors will be reported in due
course.15
As can been seen from Table 1, this newly developed
method is general for the preparation of 1- and 3-
unsubstituted imidazo[1,5-a]quinoxalin-4-ones with
O
O
H
11
R1
R1
R4
R1
OEt
R2
R3
R2
R3
R2
PMB-Cl
DMF/NaH
N
NH2
NH2
N
EtOH, reflux
(Step 1)
R3
N
H
O
N
R4 PMB
13
O
(Step 2)
R4
TosMIC
12
10
NaH/THF
+
(Step 3)
R1
R1
R1
N
N
R2
R3
R2
R3
R2
R3
N
N
N
N
TFA/anisole/TfOH
(Step 4)
N
H
O
O
N
OPMB
R4
R4 PMB
R4
15
14
13'
a, R1=R2=R3=R4=H; b, R1=R2=R4=H, R3=OMe; c, R1=R4=H, R2=R3=OMe
d, R1=R2=R4=H, R3=CO2Me; e, R1=NO2, R2=R3=R4=H
Scheme 1.

P. Chen et al. / Tetrahedron Letters 42 (2001) 4293–4295
4295
References
mmol) was added and the mixture was stirred at ambient
temperature for 12 h. The mixture was poured into a
mixture of water and EtOAc. The organic phase was
dried (Na2SO4) and evaporated under reduced pressure.
Flash chromatography then yielded 13a as a white solid.
(b) 14a: To a 0°C suspension of NaH (1.0 mmol) in dry
THF was added a mixture of 13a (0.5 mmol) and
TosMIC (0.5 mmol) in dry THF. The mixture was stirred
at room temperature for 4 h and poured into ice water.
The white precipitate was collected by filtration, washed
with water and dried under high vacuum to give 14a as a
white solid. (c) 15a: To a mixture of 14a (1.0 mmol) in 5
mL of TFA and 2 mL of anisole was added 1 mL of
triflic acid. The mixture was stirred at room temperature
for 6–8 h. After concentration under reduced pressure,
the residue was poured into a mixture of ice/saturated
NaHCO3–ether with vigorous stirring (final pH >7.0).
The white precipitate was collected by filtration, rinsed
with water, and triturated with ether to give 15a as a
white solid.
1. Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter, D.
B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigt-
lander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820.
2. Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg,
S. S.; Ingebretsen, W. R.; Wiggins, J. J. Med. Chem.
1991, 34, 2671.
3. Colltta, V.; Cecchi, L.; Catarzi, D.; Filacchioni, G.; Mar-
tini, C.; Tacchi, P.; Lucacchini, A. Eur. J. Med. Chem.
1995, 30, 133.
4. Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.;
Sakamoto, S. J. Med. Chem. 1997, 40, 2053.
5. TenBrink, R. E.; Jacobsen, E. J.; Gammill, R. B. US
Patent 5541324, July 30, 1996; Chem. Abstr. 1996, 125,
195687.
6. Hansen, H. C.; Watjen, F. EP 344943 A1, December 6,
1989; Chem. Abstr. 1990, 112, 216962.
7. Lee, T. D.; Brown, R. E. US 4440929, April 3, 1984;
Chem. Abstr. 1984, 101, 7202.
8. Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini,
S.; Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.;
Goegan, M.; Cervo, L.; Valle, D. F.; Fracasso, C.; Cac-
cia, S.; Mennini, T. J. Med. Chem. 1999, 42, 4362.
9. (a) Gowenlock, A. H.; Newbold, G. T.; Spring, F. S. J.
Chem. Soc. 1945, 622; (b) Collins, P. A.; McFarlane, M.
D.; Mackie, R. K.; Smith, D. M. Tetrahedron 1992, 48,
7887; (c) Epperson, J. R.; Hewawasam, P.; Meanwell, N.
A.; Boissard, C. G.; Gribkoff, V. K.; Post-Munson, D.
Bioorg. Med. Chem. Lett. 1993, 3, 2801.
10. The structures of new intermediates and final products
referred to in this work were determined by a combina-
tion of spectroscopic techniques (1H and 13C NMR, EI
MS) and microanalysis. In particular, the structures of
compounds 12d, 13d and 14d were inferred by NOE
studies on 15d (i.e. irradiation of H2% and H8, respectively,
generated NOE signals for corresponding H5 and N–H
and vice versa).
11. For a recent reference on N-alkylations of quinoxalin-2-
ones, see: Katoh, A.; Yoshida, T.; Ohkanda, J.; Nishio,
T. Heterocycles 1997, 44, 357.
12. For a recent reference on the preparation of imidazoles
using TosMIC reagent, see: Chen, B.-C.; Bednarz, M. S.;
Zhao, R.; Sundeen, J. E.; Chen, P.; Shen, Z.; Skoum-
bourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41,
5453.
13. For a recent reference related to deprotection of PMP
group on nitrogen using TFA/anisole, see: Couture, A.;
Deniau, E.; Grandclaudon, P.; Hoarau, C. J. Org. Chem.
1998, 63, 3128.
14. Compound 12b was regiospecifically prepared as shown
below:
H
N
CO2H
H2/Pd-C
MeOH/HOAc
MeO
MeO
NO2
"nOE"
H
2'
H
N
N
N
H
H2O2
NaOH
5
8
N
6
MeO
N
H
O
N
H
O
MeO2C
N
H
O
12b
77% for two steps
H
"nOE"
15d
For an alternative approach, see: Sakata, G.; Makino,
K.; Morimoto, K. Heterocycles 1985, 23, 143.
15. Barrish, J.; Chen, P.; Das, J.; Iwanowicz, E.; Norris, D.;
Padmanabha, R.; Roberge, J.; Schieven, G. Imidazo-
quinoxaline Protein Tyrosine Kinase Inhibitors, PCT Int.
Appl. (1999), WO 9909845.
Typical reaction conditions: (a) 13a: To a 0°C suspension
of NaH (11.0 mmol) in 5 mL of dry DMF was added a
solution of 2-hydroxyquinoline (10.0 mmol) in 10 mL of
dry DMF. After 20 min, p-methoxybenzyl bromide (11.0
.