Highly efficient synthesis of quinoxalinone-N-oxide via tandem nitrosation/aerobic oxidative C-N bond formation

Article abstract of DOI:10.1021/ol202760c

An efficient method for constructing quinoxalinone-N-oxides from cyanoacetanilides has been developed. This transformation can be achieved using inexpensive reagents and molecular oxygen under mild conditions, thus offering a practical pathway to quinoxalinone-containing pharmaceuticals such as ataquimast and opaviraline.

Full text of DOI:10.1021/ol202760c

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6280–6283
Highly Efficient Synthesis of
Quinoxalinone-N-oxide via Tandem
Nitrosation/Aerobic Oxidative CÀN
Bond Formation
Yusuke Kobayashi,* Mami Kuroda, Natsuki Toba, Mari Okada, Rie Tanaka, and
Tetsutaro Kimachi*
Faculty of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien
Kyubancho, Nishinomiya 663-8179, Hyogo, Japan
ykoba@mukogawa-u.ac.jp; tkimachi@mukogawa-u.ac.jp
Received October 14, 2011
ABSTRACT
An efficient method for constructing quinoxalinone-N-oxides from cyanoacetanilides has been developed. This transformation can be achieved
using inexpensive reagents and molecular oxygen under mild conditions, thus offering a practical pathway to quinoxalinone-containing
pharmaceuticals such as ataquimast and opaviraline.
One of the goals of synthetic organic chemistry is to
construct complex and valuable molecules from simple
starting materials with inexpensive and readily available
reagents. Nitrogen-containing heterocycles constitute me-
dicinally important molecules, and therefore continuous
efforts have been made to develop novel efficient methods
for their preparation.1 Transition-metal-catalyzed intra-
molecular aromatic CÀN bond formation, generally by
the reaction of a preinstalled amino (or amide) group with
(pseudo)haloarene, has been developed as a fundamental
reaction for constructing N-containing heterocyclic
compounds.2 Recent progress on processes for direct aro-
matic CÀH functionalization/CÀN bond formation has
enabled more efficient access to N-heterocycles from
nonprefunctionalized simple arenes.3À6 After the pioneer-
ing work of Buchwald,4 various oxidative aromatic CÀN
bond-forming reactions have been devised to synthesize
heterocycles,5,6 for example, utilizing an inexpensive catalyst
(3) For transition-metal-catalyzed nitrene insertion into aromatic
CÀH bonds, see: (a) Smitrovitch, J. H.; Davies, I. W. Org. Lett. 2004,
6, 533. (b) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006,
128, 9048. (c) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.;
Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
(4) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Tsang, W. C. P.; Munday, R. H.; Brasche, G.;
Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603.
(5) For recent examples, see: (a) Inamoto, K.; Saito, T.; Katsuno, M.;
Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (b) Yamamoto, M.;
Matsubara, S. Chem. Lett. 2007, 36, 172. (c) Li, B.-J.; Tian, S.-L.; Fang,
Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (d) Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 14058. (e) Jordan-Hore, J. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 16184. (f) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen,
J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15, 7292. (g) Mei, T.-S.;
Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.
(6) For recent examples using copper catalysts, see: (a) Brasche, G.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (b) Wang, H.;
Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132,
13217. For an iron-mediated reaction, see:(c) Zheng, Z.; Tang, L.; Fan,
Y.; Qi, X.; Du, Y.; Zhang-Negrerie, D. Org. Biomol. Chem. 2011, 9,
3714. For metal-free reactions, see:(d) Cho, S. H.; Yoon, J.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 5996. (e) Antonchick, A. P.; Samanta, R.;
Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605.
(1) (a) Li, J.-J., Corey, E. J., Eds. Name Reactions in Heterocyclic
Chemistry; Wiley-Intersciences: Hoboken, NJ, 2005. (b) For reviews on
CÀH functionalization for the synthesis of heterocycles, see: (b) Zhang, M.
Adv. Synth. Catal. 2009, 351, 2243. (c) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874.
(2) For reviews, see: (a) Jiang, L.; Buchwald, S. L. Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004; Vol. 2, p
699. (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; p
1051. (c) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338.
r
10.1021/ol202760c
Published on Web 11/08/2011
2011 American Chemical Society

or oxidant.6 We hypothesized that oxidative aromatic
CÀN bond-forming strategies together with introduction
of a nitrogen-containing functional group should enable a
more straightforward synthesis of N-heterocycles. We also
envisioned a greener process for the oxidative CÀN bond
formation by utilizing molecular oxygen as the oxidant.
Herein, we report introduction of a nitroso group into
cyanoacetanilides and simultaneous aerobic oxidative
CÀN bond formation to construct quinoxalinone-N-oxide
under transition-metal-free conditions.
We first examined nitrosation of cyanoacetanilide 1a7
using NaNO2 and a variety of acids (Table 1). After
screening various conditions, we found nitrosation of the
active methylene of 1a was best mediated when H2SO4 was
employed, and aci-nitrosocyanoacetanilide 2a was ob-
tained in 48% yield (entry 1). Interestingly, when the
solvent was changed to AcOH, quinoxalinone-N-oxide
3a,8 presumably derived from 2a via oxidation, was ob-
tained in 62% yield (entry 2). The yield of 3a was improved
to 78% when the process was carried out in MeCN (entry 3).
Although 5 equiv of H2SO4 and NaNO2 were required to
obtain 3a in a decent yield (entry 4), the reaction was
readily and successfully scaled up as both reagents are
inexpensively available (entry 5). It should be noted that
the formation of 3a was greatly inhibited under an argon
flow, and 2a was obtained in 67% yield (entry 6). This
result strongly suggests that the tandem reaction pro-
ceeded via 2a and that molecular oxygen was involved in
the oxidation of 2a. H2SO4 seemed to play a crucial role in
the tandem reaction since AcOH and TFA were ineffective
(entries 7 and 8).
To gain mechanistic insight into the tandem reaction, we
investigated the reactivity of the isolated 2a (eqs 1 and 2).
Oxidative cyclization of 2a proceeded smoothly to furnish
3a in 85% yield,9 substantially under the same conditions
as those given in Table 1 (eq 1).10 In contrast to this result,
the reaction of 2a did not proceed at all in the presence of
2,6-di-tert-butyl-4-hydroxytoluene (BHT) as a radical sca-
venger, suggesting that a single electron transfer process
was involved in the present aerobic oxidation.
Taking these results into consideration, a plausible
mechanism for the tandem reaction of 1 is shown in
Scheme 1. Initially, the active methylene of 1 reacts with
a nitrosyl cation to generate aci-nitroso species 2 via iso-
merization. The subsequent aerobic oxidative cyclization
would occur through electron transfer from 2 to molecular
oxygen by the mediation of NO2:11 (1) stepwise single
electron transfer would afford the reactive N-oxonitre-
nium intermediate B12 via N-oxyl A, and (2) intramolecu-
lar electrophilic aromatic substitution of B would furnish
N-oxide 3.13
Scheme 1. Hypothesized Mechanism
Table 1. Survey of the Reaction Conditions of 1aa
yieldb (%)
time
entry
acid (equiv)
solvent
(h)
2a
48
n.d.c
n.d.c
n.d.c
n.d.c
67
3a
1
H2SO4 (5.0)
H2SO4 (5.0)
H2SO4 (5.0)
H2SO4 (1.5)
H2SO4 (5.0)
H2SO4 (5.0)
AcOH (5.0)
TFA (5.0)
CH2Cl2
AcOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
12
3
0
62
78
48
79
12
0
2
3
5
4d
5e
6f
7
24
5
5
5
4
(7) For our previous work using cyanoacetanilides, see: (a) Kobayashi,
Y.; Harayama, T. Org. Lett. 2009, 11, 1603. (b) Kobayashi, Y.;
Harayama, T. Tetrahedron Lett. 2009, 50, 6665. (c) Kobayashi, Y.;
Katagiri, K.; Azumaya, I.; Harayama, T. J. Org. Chem. 2010, 75, 2741.
(d) Kobayashi, Y.; Nakatani, T.; Tanaka, R.; Okada, M.; Torii, E.;
Harayama, T.; Kimachi, T. Tetrahedron 2011, 67, 3457. (e) Kobayashi,
Y. Yakugaku Zasshi 2011, 131, 1037.
8
7
0
0
a Unless otherwise stated, the reactions were carried out with 1.0
mmol of 1a under air (open flask). b Isolated yields. c Not determined.
d 1.5 equiv of NaNO2 was used. e 30 mmol of 1a was employed. f The
reaction was carried out under an argon flow.
(8) Ahmad, Y.; Habib, M. S.; Ziauddin Tetrahedron 1964, 20, 1107.
Org. Lett., Vol. 13, No. 23, 2011
6281

With an optimized set of reaction conditions, we next
investigated the scope and limitation of the tandem reac-
tion (Table 2). The reaction of secondary anilide 1b
afforded 2b exclusively in 31% yield, whose cyclization
to 3b seemed to be prohibited presumably due to confor-
mational reasons14 (entry 1). However, the tandem reac-
tion of cyanoacetanilides 1c,d substituted at amide
nitrogen with ethyl and benzyl groups took place smoothly
to afford the desired quinoxalinone-N-oxides 3c,d in 70%
and 98% yields, respectively (entries 2 and 3). Notably, the
N-oxides 3e,f were obtained in high yields (entries 4, 5)
since the halogenated products could in principle be
further functionalized by way of transition-metal-
catalyzed coupling reactions. Importantly, the tandem reac-
tions successfully proceeded with arenes bearing strong
electron-withdrawing substituents 1gÀj (entries 6À9). The
prolonged reaction time and decreased chemical yield
(entry 9) support the mechanism proposed above via
intramolecular electrophilic substitution. The following
results indicate that the cyclization step is sensitive to the
steric hindrance: (1) the cyclization of meta-substituted
cyanoacetanilide 1l,m occurred almost exclusively para
to the methyl and bromo group to afford 6-substituted
qunoxalinone-N-oxide 3l,m in 75% and 50% yields, re-
spectively (entries 11 and 12); and (2) ortho-substituted
cyanoacetanilide 1n was ineffective in the tandem reaction
(entry 13). It should be worth noting that the isolation of all
products 3cÀl could be readily accomplished by precipita-
tion and filtration.15
Table 2. Scope and Limitation of Tandem Nitrosation/Aerobic
Oxidative Cyclization of Cyanoacetanilides 1bÀna
(9) Although the aerobic oxidative cyclization of aci-nitroso species 2
has not been reported to our knowledge, a few cyclization reactions of
the related R-arylimino oximes have been reported; see: (a) Maroulis,
A. J.; Domzaridou, K. C.; Hadjiantoniou-Maroulis, C. P. Synthesis
1998, 1769. (b) Xekoukoulotakis, N. P.; Hadjiantoniou-Maroulis, C. P.;
Maroulis, A. J. Tetrahedron Lett. 2000, 41, 10299. (c) Aggarwal, R.;
Sumran, G.; Saini, A.; Singh, S. P. Tetrahedron Lett. 2006, 47, 4969.
(10) No cyclization of 2a was observed in the absence of NaNO2 or
H2SO4.
(11) For a gaseous NO2-mediated oxidative cyclization, see: (a)
ꢀ
Pasinszki, T.; Havasi, B.; Hajgato, B.; Westwood, N. P. C. J. Phys.
a All reactions were carried out with 1.0 mmol of 1 under air (open
Chem. A 2009, 113, 170. For selected recent examples for aerobic alcohol
oxidation utilizing NO2, see: (b) Liu, R.; Liang, X.; Dong, C.; Hu, X.
J. Am. Chem. Soc. 2004, 126, 4112. (c) Uyanik, M; Fukatsu, R.; Ishihara, K.
Chem.;Asian J. 2010, 5, 456. (d) Shibuya, M.; Osada, Y.; Sasano, Y.;
Tomizawa, M.; Iwabuchi, Y. J. Am. Chem. Soc. 2011, 133, 6497.
(12) Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009,
11, 1015.
(13) In the strongly acidic reaction media, an alternative mechanism
via an electrocyclic reaction of the dicationic intermediate C cannot be
ruled out.
flask). b Isolated yields.
Quinoxalinone derivatives, including 3,4-dihydroqui-
noxalinone, show important biological and pharmacological
properties and are widely used in material sciences.16,17
Therefore a number of synthetic methods have been reported
to date.18,19 We hypothesized that quinoxalinone-N-oxides20
could be used as intermediates for their preparation.21 In
particular, the CN group at the C2 position of 3 could be
(18) For selected recent examples for quinoxalinones, see: (a) Bi,
F. C.; Aspnes, G. E.; Guzman-Perez, A.; Walker, D. P. Tetrahedron
Lett. 2008, 49, 1832. (b) Chen, D.; Wang, Z.-J.; Bao, W. J. Org. Chem.
2010, 75, 5768.
(19) For selected recent examples for 3,4-dihydroquinoxalinones,
see: (a) Luo, X.; Chenard, E.; Martens, P.; Cheng, Y.-X.; Tomaszewski,
M. J. Org. Lett. 2010, 12, 3574. (b) Rueping, M.; Tato, F.; Schoepke,
F. R. Chem.;Eur. J. 2010, 16, 2688. (c) Chen, D.; Bao, W. Adv. Synth.
Catal. 2010, 352, 955. (d) Xue, Z.-Y.; Jiang, Y.; Peng, X.-Z.; Yuan, W.-C.;
Zhang, X.-M. Adv. Synth. Catal. 2010, 352, 2132. (e) Tanimori, S.;
Kashiwagi, H.; Nishimura, T.; Kirihata, M. Adv. Synth. Catal. 2010,
352, 2531.
(14) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177 and references cited therein.
(15) For experimental details, see the Supporting Information.
(16) For recent examples of quinoxalinone derivatives, see: (a) Saoudi,
N.; Bellaouchou, A.; Guenbour, A.; Bachir, A. B.; Essassi, E.; Achouri,
M. E. Bull. Mater. Sci. 2010, 33, 313. (b) Galal, S. A.; Abdelsamie, A. S.;
Tokuda, H.; Suzuki, N.; Lida, A.; ElHefnawi, M. M.; Ramadan, R. A.;
Atta, M. H. E.; El Diwani, H. I. Eur. J. Med. Chem. 2011, 46, 327.
(17) For recent reviews on quinoxalinone scaffolds, see: (a) Li, X.;
Yang, K.; Li, W.; Xu, W. Drugs Future 2006, 31, 979. (b) Carta, A.; Piras,
S.; Loriga, G.; Paglietti, G. Mini-Rev. Med. Chem. 2006, 6, 1179.
6282
Org. Lett., Vol. 13, No. 23, 2011

substituted by a variety of nucleophiles, readily enabling
the derivatization.
Scheme 3. Synthesis of Opaviraline
Scheme 2. Synthesis of Ataquimast
of the amino group, cleavage of the N-benzyl group
furnished opaviraline.19e
In this context, we investigated the rapid synthesis of
ataquimast22 which is useful in the treatment of chronic
obstructive bronchopneumopathies such as asthma
(Scheme 2). To our delight, introduction of the nitrogen-
containing functional group at the C2 position of 3c could
be achieved by substitution of the CN group with HNMe-
Boc under basic conditions, giving the corresponding
carbamate 4 in 69% yield. Reduction of N-oxide 4 with
Na2S2O4 followed by deprotection of the Boc group of 5
furnished ataquimast in good yield.
We also hypothesized that substitution of CN groups
of 3 with carbon nucleophiles allows rapid entry into
the anti-HIV-1 reverse transcriptase inhibitor23 such
as opaviraline (GW-420867X). To this end, the treat-
ment of 3h with a Grignard reagent was examined
(Scheme 3). As a result, EtMgBr could be successfully
substituted for the CN group to give 2-ethyl-quinox-
alinone-N-oxide 6 in 51% yield, which was then re-
duced with zinc powder in acetic acid to provide 3,4-
dihydroquinoxalinone 7. After carbamate protection
In conclusion, we have developed a highly efficient me-
thod for constructing quinoxalinone-N-oxide through the
tandem nitrosation/aerobic oxidative cyclization of cyano-
acetanilides with inexpensive reagents. The CN groups
of 3 were successfully substituted with not only a carbon
nucleophile but also a nitrogen nucleophile. This strategy
enables rapid access to various substituted quinoxalinone
derivatives. In addition, we proposed a mechanistically novel
oxidative aromatic CÀN bond-forming reaction of aci-
nitroso species 2 utilizing molecular oxygen as the sole
oxidant. More detailed mechanistic studies as well as exten-
sion of the present chemistry to the synthesis of other quin-
oxalinone-containing pharmaceuticals are under investigation.
Acknowledgment. We thank Instrument Analysis Cen-
ter of Mukogawa Women’s University for the NMR and
MS measurements.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) For selected recent examples, see: (a) Meyer, C.; Zapol’skii,
V. A.; Adam, A. E. W.; Kaufmann, D. E. Synthesis 2008, 2575. (b)
€
Ozpınar, G. A.; Erdem, S. S.; Meyer, C.; Kaufmann, D. E. J. Org. Chem.
2009, 74, 4727 and references cited therein.
(21) Only a few reactions of quinoxalinone-N-oxides have been
reported; see: (a) Reference 8. (b) Ahmad, Y.; Habib, M. S.; Iqbal,
M.; Ziauddin Bull. Chem. Soc. Jpn. 1965, 38, 562. (c) Ahmad, Y.; Habib,
M. S.; Ziauddin, Bashir, N. Bull. Chem. Soc. Jpn. 1965, 38, 1654.
(22) Patoisear, J.-F.; Tarayre, J.-P.; Autin, J.-M. PCT Int. Appl. WO
9626928 A1 19960906, 1996.
(23) (a) Roesner, M.; Billhardt-Troughton, U.-M.; Kirsch, R.;
Kleim, J.-P.; Meichsner, C.; Riess, G.; Winkler, I. Eur. Pat. Appl. EP
708093 A1 19960424, 1996. (b) Balzarini, J.; De Clercq, E.; Carbonez, A.;
Burt, V.; Kleim, J.-P. AIDS Res. Hum. Retroviruses 2000, 16, 517. (c) Cass,
L. M.; Moore, K. H. P.; Dallow, N. S.; Jones, A. E.; Sisson, J. R.; Prince,
W. T. J. Clin. Pharmacol. 2001, 41, 528.
Org. Lett., Vol. 13, No. 23, 2011
6283