Synthesis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones through copper-catalyzed tandem reactions of N-(2-haloaryl)propiolamides with sodium azide

Article abstract of DOI:10.1021/ol300114w

A simple and efficient approach for the synthesis of [1,2,3]triazolo[1,5-a] quinoxalin-4(5H)-ones is described. The methodology is based on a tandem reaction of 1-(2-haloaryl)propiolamides with sodium azide through a [3 + 2] azide-alkyne cycloaddition and

Full text of DOI:10.1021/ol300114w

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1262–1265
Synthesis of [1,2,3]Triazolo-
[1,5-a]quinoxalin-4(5H)-ones through
Copper-Catalyzed Tandem Reactions
of N-(2-Haloaryl)propiolamides with
Sodium Azide
Jiajie Yan,† Fengtao Zhou,† Dongguang Qin,†,‡ Tong Cai,† Ke Ding,*,† and Qian Cai*,†
Key Laboratory of Regenerative Biology and Institute of Chemical Biology,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, 510530,
China and ABA Chemicals Corporation, Suite 18, Ningxia Road, Shanghai, China
ding_ke@gibh.ac.cn; cai_qian@gibh.ac.cn
Received January 17, 2012
ABSTRACT
A simple and efficient approach for the synthesis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones is described. The methodology is based on a
tandem reaction of 1-(2-haloaryl)propiolamides with sodium azide through a [3 þ 2] azideꢀalkyne cycloaddition and intramolecular Ullmann-type
CꢀN coupling process.
Structurally novel and diverse heterocycles are very
useful in drug discovery and related fields. However,
modern drug discoveries have also stimulated the rapid
development of innovative synthetic strategies for the
synthesis of such compounds.1 The [1,2,3]triazolo[1,5-a]-
quinoxalin-4(5H)-one and its analogue tricyclic systems
have been found to possess important biological activities
such as agonists for the G-protein-coupled Niacin receptor
109A2 and inhibitors for the benzodiazepine receptor and
adenosine receptors.3 The broad potential biological activ-
ities for these kinds of compounds, however, have not
yet been fully explored, which is perhaps due to the lack
of general methods for the synthesis of the unique tricyclic
core. The reported methods for synthesizing such com-
pounds often involve multiple reaction steps, with low
efficiency, and difficulties in introducing different func-
tional groups.2ꢀ4
Our continued efforts to develop efficient and practical
methodologies for the synthesis of novel N-containing
heterocyclic compounds have led to the development of
tandem copper-catalzyed [3 þ 2] cycloadditionꢀcoupling
reactions for the synthesis of 4-oxo-indeno[1,2-b]-
pyrroles and pyrrolo[3,2-c]quinoline-4-ones.5 The [3 þ 2]
† Guangzhou Institutes of Biomedicine and Health.
‡ ABA Chemicals Corporation.
(1) (a) Quin, L. D.; Tyrell, J. Fundamentals of Heterocyclic Chemis-
try: Importance in Nature and in the Synthesis of Pharmaceuticals; Wiley:
2010; ISBN:978-0-470-56669-5. (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 5th ed.; Wiley: 2010; ISBN: 978-1-4051-9365-8.
(2) Shen, H. C.; Ding, F.-X.; Deng, Q. L.; Wilsie, L. C.; Krsmanovic,
M. L.; Taggart, A. K.; Carballo-Jane, E.; Ren, N.; Cai, T.-Q.; Wu, T.-J.;
Wu, K. K.; Cheng, K.; Chen, Q.; Wolff, M. S.; Tong, X. C.; Holt, T. G.;
Waters, M. G.; Hammond, M. L.; Tata, J. R.; Colletti, S. L. J. Med.
Chem. 2009, 52, 2587.
(3) (a) Biagi, G.;Giorgi, I.;Livi, O.;Scartoni, V.;Betti, L.;Giannaccini,
G.; Trincavelli, M. L. Eur. J. Med. Chem. 2002, 37, 565. (b) Bertelli, L.;
Biagi, G.; Giorgi, I.; Manera, C.; Livi, O.; Scarton, V.; Betti, L.;
Giannaccini, G.; Trincavelli, L.; Barili, P. L. Eur. J. Med. Chem. 1998,
33, 113.
(4) (a) Toman, J.; Mindl, J.; Lycha, A.; Klicnar, J.; Srovnalova, I.;
Konicek, M. Collect. Czech. Chem. Commun. 1994, 59, 2493. (b) Vogel,
M.; Lippmann, E. J. Prakt. Chem. 1989, 331, 69. (c) Vogel, M.;
Lippmann, E. J. Prakt. Chem. 1989, 331, 75. (d) Vogel, M.; Lippmann, E.
J. Prakt. Chem. 1987, 329, 101.
(5) (a) Cai, Q.; Zhou, F.; Xu., T.; Fu, L.; Ding, K. Org. Lett. 2011, 13,
340. (b) Zhou, F.; Liu, J.; Ding, K.; Liu, J.; Cai, Q. J. Org. Chem. 2011,
76, 5346.
r
10.1021/ol300114w
Published on Web 02/15/2012
2012 American Chemical Society

cycloaddition of ethyl isocyanoacetate with carbonꢀ
carbon triple bonds produced highly reactive organocopper
intermediates, which were then trapped intramolecularly
by arylhalides and formedarylCꢀC bonds. Based on these
results, we envisoned that the intermediate produced in the
[3 þ 2] azideꢀalkyne cycloaddition (AAC)6,7 may also be
trapped intramolecularly with aryl halides under copper-
catalyzed conditions, which may lead to the formation of
aryl CꢀN bonds8,9 (Scheme 1).
was formed through the [3 þ 2] cycloaddition reaction
of sodium azide to 1a (Table 1, entry 1). The same result
was observed upon reaction in different solvents, such as
DMF, MeCN, and 1,4-dioxane. We speculated that it was
caused by the hydrogen of the amide group, which may
transfer to the nitrogen atom of triazole and make the
NꢀCu intermediate hard to form, impeding proceeding to
the coupling reaction.11 When N-methylated substrate 1b
wastested, the desiredproduct2bwasisolatedin10%yield
even without a copper catalyst (Table 1, entry 2). A much
better result was obtained when 10 mol % CuI was used as
the catalyst and the desired tandem reaction product 2b
was isolated in 88% yield, accompanied with a small
amount of byproduct 3b. Compared to other screened
solvents such as DMF, 1,4-dioxane, and toluene, DMSO
appeared to be the best solvent for our tandem reaction
(Table 1, entries 3ꢀ6). The product yield decreased upon
lowering the reaction temperature to 70 °C or ambient,
with most of the starting material 1b remaining unreacted
(Table 1, entries 7 and 8). Furthermore, when 3b was
subjected to the copper-catalzyed conditions with K2CO3
as the base,12 the desired product 2b was obtained in 60%
yield in 24 h at 90 °C. However, 3a was not converted into
2a under the same reaction conditions.
In this paper, we would like to disclose our discoveries
on the copper-catalyzed tandem reaction of N-(2-haloaryl)-
propiolamides with sodium azide for the synthesis of
[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones.
Scheme 1. Design of Copper-Catalyzed Tandem Reaction
of N-(2-Haloaryl)propiolamides with Sodium Azide for the
Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones
Table 1. Condition Screeninga
The investigation was initiated by exploring the copper-
catalyzed reaction of N-(2-iodophenyl)-3-phenylpropiola-
mide 1a with sodium azide. As shown in Table 1, with
CuI as the catalyst and DMSO as the solvent, no desired
tandem reaction product 2a or aryl azide product10 was
detected at 90 °C. The only isolated product was 3a, which
temp
yield of
entry
substrate
solvent
(°C)
2(%)b
1
2
3
4
5
6
7
8
1a
1b
1b
1b
1b
1b
1b
1b
DMSO
DMSO
DMSO
DMF
90
90
90
90
90
90
70
rt
n.d.c,d
10e,f
88
72
dioxane
toluene
DMSO
DMSO
n.d.c
n.d.c
60g
(6) (a) Huisgen, R. In 1,3-Dipolar Cyloaddtion Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; pp 1ꢀ176. (b) Padwa, A. In Comprehensive
Organic Synthesis, Vol. 4; Trost, B. M., Ed.; Pergamon: Oxford, 1991; pp
1069ꢀ1109. (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (d) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
<10g
a Reagents and reaction conditions: 1 (0.5 mmol, 1.0 equiv), CuI
(10 mol %), solvent (1 mL), 24 h. b Isolated yields. c No desired product
was detected. d The [3 þ 2] product 3a was isolated in >90% yield.
e No copper catalyst was added. f The [3 þ 2] product 3b was isolated in
>80% yield. g With recovery of 1b.
(7) For some important reviews about AAC reactions, see: (a)
Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem.;Asian J. 2011, 6,
2696. (b) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7. (c) Lutz,
€
J. F. Angew. Chem., Int. Ed. 2007, 46, 1018. (d) Brase, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
(8) For some recent important reviews about copper-catalyzed
Ullmann-type coupling reactions, see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. Rev. 2004, 248, 2337. (c) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054. (d) Monnier, F.; Taillefer, M.
Angew. Chem., Int. Ed. 2009, 48, 6954. (e) Ma, D.; Cai, Q. Acc. Chem.
Soc. 2008, 41, 1450.
(9) For copper-catalyzed triazole formation and post-triazole aryla-
tion in one pot, see: (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org.
Lett. 2004, 6, 3897. (b) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng, X.;
Zhao, M.; Chen, B. Org. Lett. 2012, 14, 26.
Withthe optimizedconditions in hand, wethenexplored
the scope of the new methodology. As displayed in Table 2,
in most cases, the desired tandem reaction products were
obtainedin good toexcellent yields. Both the alkyl and aryl
substituents on the alkyne moietieswerewelltolerated, and
(11) A similar result was observed in the copper-catalyzed tandem
reaction of N-(2-haloaryl)propiolamides with ethyl isocyanoacetate; see
ref 5b.
(10) Aryl azides could be synthesized through amino acid promoted
copper-catalzyed coupling reactions of aryl halides with sodium azide.
See: Zhu, W.; Ma, D. Chem. Commun. 2004, 7, 888.
(12) No 2b was detected without the necessary base.
Org. Lett., Vol. 14, No. 5, 2012
1263

Table 2. Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones through Copper-Catalyzed Tandem Reactiona
a Reagents and reaction conditions:arylhalides1 (0.5mmol), sodiumazide(0.6mmol), CuI(0.05mmol), DMSO, 90°C, 24h. b iIsolated yields. c 120 °C.
the corresponding tandem reaction products were delivered
in high yields. Furthermore, both the electron-donating
and -withdrawing substituents on the 1-(2-iodoaryl) ring
were well tolerated and the corresponding reaction prod-
ucts were obtained in high yields (Table 2, entries 9ꢀ14).
Excellent yields of the desired products were also
achieved for other N-substituted-(2-haloaryl)propiolamides
(Table 2, entries 15ꢀ17). In addition, aryl bromides were
explored under the same reaction conditions and exhibited
similar reactivity to aryl iodides, with generally high reaction
yields (Table 2, entries 18ꢀ20). As for less reactive aryl
chlorides, the desired products were obtained in rather
moderate yields even at an elevated temperature of 120 °C
(Table 2, entries 21 and 22).
1264
Org. Lett., Vol. 14, No. 5, 2012

Based on the literature reports and our experimental
observations, a plausible reaction process is proposed as
shown in Scheme 2. First, the NꢀCu species A was formed
through an azideꢀalkyne [3 þ 2] cycloaddition in the
presence of CuI, which was then quickly inserted into the
aryl C-halo bond and eventually led to the Ullmann CꢀN
coupling product.
on the copper-promoted reaction of 1-(2-haloaryl)-
propamides with sodium azide through a tandem azideꢀ
alkyne cycloaddition/Ullmann CꢀN coupling process,
which is applicable to a variety of 1-(2-haloaryl) propiola-
mides. Further, the reaction displayed wide functional
group compatibility. It should find further application in
organic synthesis and medicinal chemistry.
Acknowledgment. The authors are grateful to National
Natural Science Foundation of China (Grant 21002102),
National S&T Major Special Project on Major New Drug
Innovation (Grant No. 2011ZX09102-010) and State Key
Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry (Grant 10184),
Chinese Academy of Sciences for their financial support.
We also thank Prof. Fayang Qiu in Guangzhou Institutes
of Biomedicine and Health, Chinese Academy of Sciences
for helpful discussions.
Scheme 2. A Plausible Reaction Process
Supporting Information Available. Full experimental
procedures, characterization data for all the compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have successfully developed a novel,
simple, and efficient method for the synthesis of [1,2,3]-
triazolo[1,5-a]quinoxalin-4(5H)-ones. The method is based
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
1265