Photoinduced and N-bromosuccinimide-mediated cyclization of 2-azido-N-phenylacetamides

Article abstract of DOI:10.1021/ol401338e

An efficient synthesis of quinoxalin-2(1H)-ones or spiro[cyclohexene-1, 2′-imidazol]-4′-ones has been achieved in moderate to high yields by the visible light-induced and N-bromosuccinimide-mediated cyclization reaction of 2-azido-N-phenylacetamides at ambient temperature. Both the regioselectivity and the speed of cyclization are affected by the substituents attached to the phenyl ring. For example, quinoxalin-2-ones are produced as the main products when the substrates bear electron-withdrawing groups at the para-position of the phenyl ring; in contrast, spiro[cyclohexene-1,2′-imidazol]-4′-ones are obtained as the main products when the substrates bear electron-donating groups at the para-position.

Full text of DOI:10.1021/ol401338e

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3820–3823
Photoinduced and N‑Bromosuccinimide-
Mediated Cyclization of
2‑Azido‑N‑phenylacetamides
Zhan-Shan Li, Wei-Xia Wang, Ji-Dong Yang, Yue-Wei Wu, and Wei Zhang*
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China
zhangwei6275@lzu.edu.cn
Received May 14, 2013
ABSTRACT
An efficient synthesis of quinoxalin-2(1H)-ones or spiro[cyclohexene-1,20-imidazol]-40-ones has been achieved in moderate to high yields by the
visible light-induced and N-bromosuccinimide-mediated cyclization reaction of 2-azido-N-phenylacetamides at ambient temperature. Both the
regioselectivity and the speed of cyclization are affected by the substituents attached to the phenyl ring. For example, quinoxalin-2-ones are
produced as the main products when the substrates bear electron-withdrawing groups at the para-position of the phenyl ring; in contrast,
spiro[cyclohexene-1,20-imidazol]-40-ones are obtained as the main products when the substrates bear electron-donating groups at the para-position.
Organic azides have been long known as versatile and
valuable intermediates in the construction of nitrogen-
containing heterocycles. They can be used as progenitors
of nitrenes and nitrenium ions in cycloadditions with
various dipolarophiles or used as 1,3-dipolar ions to
[3 þ 2] reaction with alkenes, alkynes, and nitriles for
the preparation of heterocycles such as triazoles and
tetrazoles.1 In recent years, great attention has also been
devoted to the radical reactions of organic azides.2 Numer-
ous studies have clearly established that azides, including
aliphatic, aromatic, and sulfonyl derivatives, can be trans-
formed to nitrogen-centered radicals.3 Among these
nitrogen-centered radicals, iminyl radicals are of signifi-
cant interest in synthetic chemistry because they display
ability to perform cyclizations onto aromatic rings4 and
double bonds.5 Iminyl radicals are generally produced by
the photolysis or thermolysis of N-substituted imine
derivatives4ꢀ6 and intramolecular addition of carbon and
nitrogen radicals to nitriles.7 As a complement to these
protocols, iminyl radicals can be generated from aliphatic
azides via the abstraction of R-hydrogen by carbon
radicals4c or via the addition of carbon radicals to vinyl
azides, followed by nitrogen extrusion.8 There are studies
showing that iminyl radicals are involved in the photo-
reaction of β-glycosyl azides with N-bromosuccinimide
(NBS).9 However, no report has been found to apply
this reaction to the synthesis of heterocyclic compounds.
€
(1) (a) Brase, S.; Banert, Klaus. Organic Azides: Syntheses and
€
Applications; John Wiley & Sons: New York, 2010. (b) Brase, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188. (c)
Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (d) Scriven,
E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297. (e) Lang, S.; Murphy,
J. A. Chem. Soc. Rev. 2006, 35, 146.
(2) (a) Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. IUPAC
Commission. Pure Appl. Chem. 2012, 84, 1633. (b) Chiba, S. Synlett
2012, 23, 21.
(3) Minozzi, M.; Nanni, D.; Spagnolo, P. Chem.;Eur. J. 2009, 15, 7830.
(4) (a) McBurney, R. T.; Portela-Cubillo, F.; Walton, J. C. RSC Adv.
2012, 2, 1264. (b) McBurney, R. T.; Slawin, A. M. Z.; Smart, L. A.; Yu,
Y.; Walton, J. C. Chem. Commun. 2011, 47, 7974. (c) Bencivenni, G.;
Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi,
G. J. Org. Chem. 2008, 73, 4721. (d) PorteIa-Cubillo, F.; Scott, J. S.;
Walton, J. C. J. Org. Chem. 2008, 73, 5558. (e) Alonso, R.; Caballero, A.;
Campos, P. J.; Rodrıguez, M. A. Tetrahedron 2010, 66, 8828.
(5) (a) Alonso, R.; Campos, P. J.; Rodrıguez, M. A.; Sampedro, D.
J. Org. Chem . 2008, 73, 2234. (b) Alonso, R.; Campos, P. J.; Garcia, B.;
Rodriguez, M. A. Org. Lett. 2006, 8, 3521.
(6) (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Kitamura, M.;
Narasaka, K. Bull. Chem. Soc. Jpn. 2008, 81, 539. (c) Fallis, A. G.;
Brinza, I. M. Terrahedron 1997, 53, 17543. (d) Xu, H.; Wan, X.; Geng, Y.
Chin. J. Org. Chem 2011, 31, 453.
^
(7) (a) Larraufie, M. H.; Courillon, C.; Ollivier, C.; Lacote, E.; Malacria,
M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381. (b) Leardini, R.;
Nanni, D.; Tundo, A.; Zanardi, G. Tetrahedron Lett. 1998, 39, 2441.
(8) (a) Wang, Y. F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett.
2008, 10, 5019. (b) Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.;
Stein, T. Org. Biomol. Chem. 2005, 3, 1460.
r
10.1021/ol401338e
Published on Web 07/22/2013
2013 American Chemical Society

As part of our ongoing venture to develop new synthetic
methodologies based on the photochemical reactions of
azides,10 we report herein a new cyclization reaction of
iminyl radicals generated by the visible light induced and
NBS-mediated reaction of 2-azido-N-phenylacetamides
(1) (Scheme 1). The reactions afforded two kinds of
products, quinoxalin-2-ones (2) and spiro[cyclohexen-
1,20-imidazol]-40-ones (3 or 4), in different proportions.
Quinoxalin-2(1H)-ones and spiro[cyclohexene-1,20-
imidazol]-40-ones are important heterocycles displaying
a wide range of biological and medicinal activities, and
are scaffolds for drug-related molecules. For example,
compounds I and II show antithrombotic and antitumor
activity;11 compounds III are glycine transporter inhibi-
tors;12a IV are antagonists of CGRP receptors12b (Figure 1).
Many reports have been found for the synthesis of
quinoxalin-2-ones. The traditional methods for assem-
bling quinoxalin-2-ones are based on the condensation of
a substituted o-phenylenediamine with an R-ketone acid
ester or R-aldehyde acid ester.13a,b In recent years, a num-
ber of new methods have been developed. For example,
Bao reportedthesynthesis of quinoxalin-2-onesbycopper-
catalyzed cascade reaction of 2-halo-N-(2-halophenyl)-
acetamides with TsNH2;13c Leardini and Spagnolo re-
ported the synthesis of quinoxalin-2-ones by tributyltin
hydride mediated radical cyclization reaction of o-iodo-N-
methylanilides.13d Compared with the synthesis of quinoxalin-
2-ones, few reports are avaliable concerning the synthe-
sis of spiro[cyclohexene-1,20-imidazol]-40-ones and similar
compounds. Recently, Chiba and co-workers described a
copper-catalyzed synthesis of spiro[cyclohexadiene-1,20-
imidazol]-4,40-diones by the cyclization of R-azido-N-
arylamides under an oxygen atmosphere.14 The new
method reported here is an efficient and simple proce-
dure for the synthesis of both quinoxalin-2-ones and
spiro[cyclohexadiene-1,20-imidazol]-40-ones.
Scheme 1. Photoreaction of 2-Azido-N-phenylacetamides with
NBS
The initial pilot efforts were focused on the optimization
of light-induced and NBS-mediated cyclization of 2-azido-
N-phenylacetamide (1a). Previous NBS-related articles
suggested the formation of radicals from NBS could be
achieved under both UV irradiation15 and visible light
irradiation.16 It was found, however, that only visible light
irradiation was suitable for the cyclization of 1a to afford
2a and 3a in dichloromethane (DCM) at room tempera-
ture (Table 1). Under UV irradiation, the reaction resulted
in formation of complex products. Control experiment
showed that no reaction was detected under reflux in dark
in DCM, indicating that irradiation was essential to this
reaction. Under visible light irradiation, complete conver-
sion of 1a could be achieved when 2.0 equiv of NBS was
used (entry 3, Table 1). It was noticed that the product 3a
was always detected no matter how much NBS was used
(entries 1ꢀ3), and the proportion of 2a and 3a did not vary
greatly, suggesting that 2a and 3a were formed at the same
time.
Moreover, various solvents were also examined, and
DCM proved to be the best choice (entries 3ꢀ6, Table 1).
Under the optimal reactionconditions(entry 3, Table1),
the photoreactions of a group of 2-azido-N-phenylacet-
amides (1bꢀh) bearing different substituents on both phenyl
ring and nitrogen atom withNBS wereexamined(Table2).
All photoreactions of 1aꢀh could afford the cycliza-
tion products, but both the proportion and the yields of
Figure 1. Some pharmaceutically important quinoxalin-2-one
and spiro[cyclohexene-1,20-imidazol]-40-one derivatives.
(9) (a) Praly, J.-P.; Di Stefano, C.; Somsak, L.; Descotes, G. J. Chem.
Soc., Chem. Commun. 1992, 200. (b) Praly, J.-P.; Senni, D.; Faure, R.;
Descotes, G. S. Tetrahedron 1995, 51, 1697.
(10) (a) Shi, Z.; Ren, Y.; Li, B.; Lu, S.; Zhang, W. Chem. Commun.
2010, 46, 3973. (b) Ren, Y.; Wang, X.; Wang, W.; Li, B.; Shi, Z.; Zhang,
W. Tetrahedron Lett. 2011, 52, 192. (c) Li, Z.; Wang, W.; Zhang, X.; Hu,
C.; Zhang, W. Synlett 2013, 24, 73.
(11) (a) Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.; Belonga, K. L.;
Carter, D. B.; Im, H. K.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Zhong, W. Z.;
Mickelson, J. W. J. Med. Chem. 1999, 42, 1123. (b) Ries, U. J.; Priepke,
H. W. M.; Hauel, N. H.; Haaksma, E. E. J.; Stassen, J. M.; Wienen, W.; Nar,
H. Bioorg. Med. Chem. Lett. 2003, 13, 2297. (c) Lawrence, D. S.; Copper,
J. E.; Smith, C. D. J. Med. Chem. 2001, 44, 594. (d) Carta, A.; Sanna, P.;
Gherardini, L.; Usai, D.; Zanetti, S. Farmaco 2001, 56, 933.
ꢀ
(13) (a) Gris, J.; Glisoni, R.; Fabian, L.; Fernandez, B.; Moglioni,
A. G. Tetrahedron Lett. 2008, 49, 1053. (b) Ballini, R.; Gabrielli, S.;
Palmieri, A. Synlett 2009, 965. (c) Chen, D.; Wang, Z.; Bao, W. J. Org.
Chem. 2010, 75, 5768. (d) Bencivenni, G.; Lanza, T.; Leardini, R.;
Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. J. Org. Chem.
2008, 73, 4721.
(14) Chiba, S.; Zhang, L.; Lee, J. Y. J. Am. Chem. Soc. 2010, 132,
7266.
(15) (a) Chow, Y. L.; Zhao, D. C. J. Org. Chem. 1989, 54, 530–534.
(b) Lu, F. L.; Naguib, Y. M. A.; Kitadani, M.; Chow, Y. L. Can. J.
Chem. 1979, 57, 1967.
(12) (a) Willam, D. A.; Alan, P. R. PCT Int. Appl. 2007, WO
2007014762 A2 20070208. (b) Selnick, H. G.; Wood, M. R.; McWherter,
M.; Hills, I. D.; Stump, C. A. PCT Int. Appl. 2010, WO 2010077752 A1
20100708.
(16) Kim, S. S.; Choi, S. Y.; Kang, C. H. J. Am. Chem. Soc. 1985, 107,
4234.
Org. Lett., Vol. 15, No. 15, 2013
3821

Table 1. Optimization of Photoreaction Conditions of 1a with
NBSa
Table 2. NBS-Mediated Photoreactions of Substituted
2-Azido-N-phenylacetamides 1aꢀha
substrate
yieldc (%)
entry
R1
R2
time (h) convb (%)
yieldc (%)
entry equiv (NBS)
solvent
CH2Cl2
time (h) convb (%) 2a
3a
1
2
3
4
5
6
7
8
1a CH3
1b Ph
H
H
3
99
98
99
99
80
99
99
99
2a 85 3a
2b 77 3b
2c 78 4c
2d 76 4d
9
9
9
8
1
2
3
4
5
6
1
6
6
60
83
99
80
50
30
82
83
85
70
50
40
11
12
9
4
1.5
2
CH2Cl2
CH2Cl2
CCl4
1c CH3 Br
1d CH3 Cl
2
3
2
2
10
15
20
8
1e CH3 CH3
1f CH3 NO2
1g CH3 CN
8
4e 50
2
CH3COCH3
CH3CN
6
1
2f 90
2g 90
2h 88
2
5
1
a Reaction conditions: compound 1a (95 mg, 0.5 mmol) and NBS
1h CH3 CO2Me
1.5
were dissolved in anhyd solvent (20 mL). The solution was irradiated
with a household fluorescent lamp (45 W, λ > 400 nm) at ambient
temperature under aerobic atmosphere. b Conversion based on 1a.
c Isolated yields based on consumed substrate.
a Reaction conditions: compound 1 (0.5 mmol) and NBS (2.0 equiv)
were dissolved in anhydrous DCM (20 mL). The solution was irradiated
with a household fluorescent lamp (45 W, λ > 400 nm) at ambient tem-
perature. b Conversions calculated on the basis of substrate. c Isolated
yields based on the consumed substrate.
products 2 and 3 were influenced by the substitutents. The
photoreaction of 1b gave products 2b and 3b in the similar
proportion and yield to 1a (entry 2), while for compounds
1c,d bearing a halogen atom at the para-position of the
phenyl ring, the reaction gave isomerized spirocycles 4c,d
besides main products 2c,d (entries 3 and 4). When the
para-substituent was changed to methyl group, as in the
case of 1e, a spirocyclic product 4e was separated as the
main product from the complex mixture after the reaction
(entry 5). In contrast to 1aꢀd, only the annulated products
2fꢀh were produced from 1fꢀh where a strong electron-
attraction group like the nitro, cyano, or ethoxycarbonyl
group was attached to the para-position (entries 6ꢀ8).
Moreover, the photoreaction rate of 1fꢀh increased
greatly as compared with that of 1a.
Unexpectedly, when compounds 1i,j which bear an o-Cl
or CO2Me at the phenyl ring were subjected to the reaction
conditions, spiro[cyclohexadien-1,20-imidazol]-4,40-diones
(5i,j) were separated as the main products in moderate
yields after reaction (Table 3, entries 1 and 2). Obviously,
this group of products derived from an oxygen-mediated
reaction. Similar products 5k and 5k-1 were also obtained
from the photoreaction of 1k where a methoxy group was
present at the para-position (Table 3, entry 3). All products
2ꢀ5 were fully identifiedby 1H, 13C NMR and HRMS, IR,
and the stereochemistry of spirocyclic compounds was
evaluated by means of NOESY. The structures of 3b and
5j were further confirmed by X-ray crystallography (see
Supporting Information).
Table 3. NBS-Mediated Photoreactions of Substituted
2-Azido-N-phenylacetamides 1iꢀk
substrate
entry
R2
R3
time (h) conv (%)
yielda (%)
1
2
3
1i
1j
H
Cl
3
91
92
99
3i 10 5i
5j
48
60
H
CO2Me
H
2.5
1
1k OMe
5k 45 5k-1 25
a Isolated yields based on the consumed substrate.
photoreaction of 1m. The structures of 2l and 3l were also
confirmed by X-ray crystallography (see the Supporting
Information).
On the basis of the results described above and the
discussion about the photoreaction of NBS by Chow15
and Kim,16 a plausible mechanistic rationale for the for-
mation of methylquinoxalin-2-ones (2aꢀh) and the spi-
rocyclic compounds (3a,b, 4cꢀe, and 5iꢀk) is given in
Scheme 2. Initially, the iminyl radical 8 is produced via the
abstraction of R-hydrogen by bromine radical followed by
nitrogen extrusion. Compound 8 then undergoes cycliza-
tion following either route a or route b to afford 9 or
10. 9 is converted to 2 after aromatization. From 10 com-
pounds 3, 4, and 5 are generated. The formation of 3 and 4
apparently involves the bromine atom abstraction from
For further extension, the photoreactions of two azido-
N-naphthalenylacetamides (1l,m) were tested under the
same conditions. As shown in Table 4, these two substrates
behaved differently: for 1l, both the annulated product (2l)
and the spirocyclic product (3l) were produced; whereas
only spirocyclization products were obtained after the
3822
Org. Lett., Vol. 15, No. 15, 2013

Table 4. NBS-Mediated Photoreactions of Substituted
2-Azido-N-naphthylacetamides 1lꢀm
Scheme 2. Proposed Mechanism for the Formation of 2ꢀ5
entry sub time (h) conv (%)
yielda (%)
1
2
1l
7
85
80
2l
70 3l
15
1m
15
3m 40 3m-1 30 5m 10
a Isolated yields based on the consumed substrate.
NBS or Br2 followed by the addition of bromine molecule,
while 5i and 5j are produced probably through intermedi-
ates 12, 13, and 14. The oxygen atom in 5i and 5j is believed
to come from oxygen, as the reactions were performed
under the aerobic atomosphere.17
In summary, a simple and efficient synthesis of quinoxalin-
2-ones or spiro[cyclohexene-1,20-imidazol]-40-ones has
been developed by employing the reaction of 2-azido-N-
phenylacetamides with NBS under visible light irradiation
atambient temperature. Thesetwo kindsofproductsresult
from a free radical process involving the formation and
cyclization of iminyl radicals. Notably, both the regio-
selectivity and the speed of the photocyclization are affected
by the substituents attached to the phenyl ring. Detailed
mechanism investigations and NBS-mediated photcycliza-
tion for the synthesis of other heterocycles are ongoing in
our laboratory.
Acknowledgment. We are grateful to the National Na-
ture Science Foundation of China (Grant No. 20872056
and J0730425) for financial support.
Supporting Information Available. Experimental pro-
1
cedures, solubility data, spectroscopic data, H and 13C
NMR spectra for all new compounds, and X-ray crystal-
lographic data (CIF file) of 3b, 5j, 2l, and 3l. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(17) For a detailed mechanistic discussion, see the Supporting
Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
3823