Copper(I)-catalyzed synthesis of novel 4-(trifluoromethyl)-[1,2,3] triazolo[1,5-a]quinoxalines via cascade reactions of N-(o-haloaryl)alkynylimine with sodium azide

Article abstract of DOI:10.1002/adsc.200900875

Novel tricyclic 4-(trifluoromethyl)[1, 2, 3]triazolo[1,5-a]quinoxalines were readily prepared from N-(o-haloaryl)alkynylimines and sodium azide via copper(I)-catalyzed tandem reactions. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.

Full text of DOI:10.1002/adsc.200900875

COMMUNICATIONS
DOI: 10.1002/adsc.200900875
Copper(I)-Catalyzed Synthesis of Novel 4-(Trifluoromethyl)-
[1,2,3]triazolo[1,5-a]quinoxalines via Cascade Reactions of
G
N-(o-Haloaryl)alkynylimine with Sodium Azide
Zixian Chen,a,b Jiangtao Zhu,b Haibo Xie,b Shan Li,b Yongming Wu,b,*
and Yuefa Gonga,*
a
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074,
Peopleꢀs Republic of China
E-mail: gongyf@mail.hust.edu.cn
Key laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5192; e-mail: ymwu@mail.sioc.ac.cn
Received: December 17, 2009; Published online: May 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900875.
Abstract: Novel tricyclic 4-(trifluoromethyl)-
[1,2,3]triazolo[1,5-a]quinoxalines were readily pre-
pared from N-(o-haloaryl)alkynylimines and
sodium azide via copper(I)-catalyzed tandem reac-
tions. This synthetic strategy provides an efficient
way to access a library of novel heterocyclic com-
pounds that are of interest in drug discovery.
tivity for GPR109A[1a] and C was designed as a novel
antitumor agent (Figure 1).[1b] In this context, we
became interested in the preparation of potentially
biologically active tricyclic fluorine-containing 1,2,3-
ACHTUNGTRENNUNG
triazoloACTHNUTRGENUG[N 1,5-a]quinoxaline derivatives. Traditionally,
the synthesis of such skeletons, rationalized by Kundu
et al.,[3] was realized using alkynes, o-nitroaryl halides,
azide, and aryl aldehydes via several steps. Herein we
report a highly efficient and convenient approach to
construct these molecules via a Cu(I)-catalyzed cas-
À
Keywords: cascade reactions; C N cross-coupling;
copper; quinoxalines; trifluoromethyl substituents
À
cade cyclization/C N bond formation process.
À
The formation of aryl C N bonds via copper-cata-
lyzed Ullmann coupling between aryl halides and N-
centered nucleophiles has received considerable at-
Due to the need for generating new chemical entities tention in the past few years.[4] The high stability and
with a useful biological activity profile, methodologies low cost of the copper catalysts enable these transfor-
for the rapid generation of structural complexity and mations to be a useful complement to the more exten-
diversity are much sought after. Recently, 1,2,3-triazo-
lo polycyclic compounds have been widely studied be-
cause of their interesting pharmacological activities.[1]
It is well known that introduction of fluorine atoms
into biologically active substances may lead to im-
provements in pharmacological properties. In particu-
lar, the trifluoromethyl group, which is highly hydro-
phobic, electron-rich, and sterically demanding, occu-
pies a prominent position in medicinal chemistry as a
substituent with peculiar properties. Moreover, it can
provide high in vivo stability and features good mimi-
cry of several naturally occurring residues such as
methyl, isopropyl, isobutyl, phenyl, and so on.[2]
Biologically active 1,2,3-triazolo polycyclic com-
pounds have previously been reported. For instance,
A has a good affinity towards the benzodiazepine re-
Figure 1. Examples of biologically active 1,2,3-triazolo poly-
ceptors,[1d] B possesses remarkable affinity and selec- cyclic compounds.
1296
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1296 – 1300

Copper(I)-Catalyzed Synthesis of Novel 4-(Trifluoromethyl)-[1,2,3]triazoloACTHNUTRGENUGN[1,5-a]quinoxalines
Using cascade reactions to construct complex mo-
lecular skeletons starting from simple, inexpensive
starting materials with high efficiency is an appealing
strategy in organic synthesis. In recent years, various
types of cascade reactions which involve a copper-cat-
À
alyzed C N formation process have been developed
and employed in the synthesis of heterocyclic com-
pounds.[5] We envisaged that treatment of sodium
azide and N-(o-haloaryl)alkynylimine (Scheme 1)
which is activated by a fluorinated imino group,[6]
with a copper(I) catalyst would initiate a cascade cyc-
À
lization/C N coupling process to give the target mole-
cule.
We began our investigations into the feasibility of
this cascade process using N-(o-haloaryl)alkynylimine
1a (Table 1) with sodium azide in DMSO at 608C as a
model reaction, it was found that a single product 3a
Scheme 1. Conceptual cascade approach to tricyclic rings.
sively investigated Pd(0)-catalyzed processes. By the was obtained in quantitative yields after purification
appropriate choice of copper source, ligand, base, and (Table 1, entry 1). Then various catalysts and ligands
reaction temperature, these coupling reactions have were attempted. Using 10 mol% of CuI and 20 mol%
been developed to include a wide range of substrates tetramethylethylenediamine (TMEDA) as the ligand,
under mild conditions.
2a was obtained in 70% yield (Table 1, entry 2),
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst/Ligand[b]
Solvent
Temp.[8C]
Time [h]
Yield [%][c]
3a
2a
1
2
3
4
5
6
7
8
–
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
CH3CN
toluene
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
60
60
60
60
60
60
60
60
60
r.t.
r.t.
r.t.
r.t.
r.t.
1 min
8 h
8 h
5 min
5 min
2 h
2 h
2 h
1 h
2 h
>98 (91)
–
CuI/L1
CuI
10
>98
–
–
–
30
–
7
>98
–
–
70 (66)
–
98 (90)
98
–
–
–
73
–
98
87
91
98[d]
7[e]
CuI/L2
CuI/L3
CuI/L3
CuI/L3
CuI/L3
CuI/L3
9
10
11
12
13
14
15
Cu
(OAc)2/L3
CuI/L3
CuBr/L3
CuCl/L3
CuI/L3
CuI/L3
5 min
15 min
15 min
2 h
–
–
88
2 h
[a]
Reactions were carried out on a 0.2 mmol scale in DMSO (2 mL) under nitrogen with sodium azide (1.1 equiv.), catalyst
(10 mol%) and ligand (20 mol%) unless otherwise stated.
L1: tetramethylethylenediamine. L2: N,N’-dimethylethylenediamine. L3: l-proline.
Reported yields were based on 1a as determined by 19F NMR. Values in parentheses are the isolated yields.
5 mol% of CuI were used.
[b]
[c]
[d]
[e]
2 mol% of CuI were used.
Adv. Synth. Catal. 2010, 352, 1296 – 1300
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1297

Zixian Chen et al.
Table 2. Studies on the N-o-haloaryl moiety.[a]
COMMUNICATIONS
Entry
Product
Time Temp. Yield
[h]
[8C]
[%][b]
1
2
2a
10
10
60
130
95[c,d,e]
65[c,d,f]
Figure 2. X-ray structure of 2a.
which was confirmed by X-ray crystal diffraction stud-
ies (Figure 2).[7] Product 2a was not formed in the ab-
sence of the ligand (Table 1, entry 3), indicating that
the ligand effect is essential for this coupling reaction.
Encouraged by this result, we next examined different
ligands, such as N,N’-dimethylethylenediamine
(DMEDA) and l-proline, which were used in classical
copper-catalyzed Ullmann reactions. Surprisingly,
both gave excellent yields (Table 1, entries 4 and 5).
Then the solvent effect was investigated using l-pro-
line as the ligand. The product was also obtained
when DMF was used, although the yield (73%) was
decreased (Table 1, entry 9). Other solvents such as
water, acetonitrile, toluene, which were not suitable
for the first step transformation,[6] could not provide
the target compound (Table 1, entries 6–8). Employ-
3
4
5
6
7
2b
2c
2d
2e
2f
2g
1.5
4
r.t.
60
60
60
80
60
90
87
80
75
70
70
10
24
10
10
ment of Cu
(OAc)2 as the catalyst also failed to form
À
the C N bond (Table 1, entry 10). Other Cu(I) salts,
such as CuBr and CuCl, were also tested, all of them
worked well even at room temperature (Table 1, en-
tries 12 and 13), and CuI proved to be the best
copper source with the highest efficiency (Table 1,
entry 11). The attempt to reduce the catalyst loading
led to longer reaction time and lower yields (Table 1,
entries 14 and 15). After optimization, the best reac-
tion conditions were ascertained as 10 mol% CuI,
20 mol% of l-proline, and 1.1 equivalents of sodium
azide in DMSO at room temperature.
8
[a]
Reactions were carried out on a 0.3 mmol (X=I) scale in
DMSO (2 mL) under nitrogen with sodium azide
(1.1 equiv.) ,catalyst (10 mol%) and ligand (20 mol%)
unless otherwise stated.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
Yield determined by 19F NMR.
CuI (20 mol%) and ligand (40 mol%) were used.
X=Br.
To investigate the scope of the proposed synthetic
strategy, a number of fluorine-containing N-(o-halo-
X=Cl.
ACHTUNGTRENNUNG
kynes with fluoroalkylimidoyl chlorides in high Table 2, entries 3 and 4). In contrast, electron-with-
yields.[8] As Table 2 shows, N-(o-bromoaryl)alkynyl- drawing groups such as fluorine, trifluoromethyl or
ACHTUNGTRENNUNGimine could also give a good yield at 608C (Table 2, nitro led to decreased yields with longer reaction
entry 1). Even the N-phenyl group with a chlorine times (Table 2, entries 5–7). Other fluoroalkyl groups
atom provided the product in moderate yield, al- were attempted, the CF2Cl was also a suitable sub-
though with a higher temperature (1308C) and a stituent (Table 2, entry 8) for this process compared
longer reaction time (Table 2, entry 2).[9] The o-iodo- with the CF2Br group, which led to decompose of the
phenyl rings substituted by electron-donating substitu- starting material.
ents such as Me and OMe afforded the desired prod-
Good functional group tolerance of this methodolo-
ucts in good yields within several hours (87–90%, gy also allows for the modification of the alkyne
1298
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1296 – 1300

Copper(I)-Catalyzed Synthesis of Novel 4-(Trifluoromethyl)-[1,2,3]triazoloACTHNUTRGENUGN[1,5-a]quinoxalines
moiety. Yields for all substrates were moderate to fluorine-containing 1,2,3-triazolo tricyclic compounds.
good (56–97%, Table 3). The electron-rich alkynes This tandem process involves copper-catalyzed forma-
À
gave good yields under mild conditions (Table 3, en- tion of a C N bond by intramolecular cyclization
tries 1, 3–6), while electron-deficient alkynes needed under base free conditions, which is also suitable for
raised temperature with lower yields (Table 3, en- aryl bromides and aryl chlorides. A variety of func-
tries 2 and 7). The alkyne with a tert-butyl group also tional groups can be employed, rendering this method
formed the product in 91% yield, which indicated particularly attractive for the efficient preparation of
that steric bulk did not significantly affect the reactiv- biologically and medicinally interesting molecules.
ity (Table 3, entry 5). A substrate containing a CF2Cl
group still gave a favourable yield (Table 3, entry 8).
In conclusion, we have designed a new cascade Experimental Section
À
cyclization/C N coupling reaction to provide novel
Typical Experimental Procedure for CuI-Catalyzed
Cascade Reactions of N-(o-Haloaryl)alkynylimine
with Sodium Azide
Table 3. Studies on the alkyne moiety.[a]
Compound 1 (0.3 mmol) was added to a solution of CuI
(10 mol%), l-proline (20 mol%), sodium azide (0.33 mmol,
1.1 equiv.) in DMSO (2.0 mL), The reaction mixture was
then stirred under a nitrogen atmosphere until completion
of the reaction as indicated by TLC. The mixture was parti-
tioned between ethyl acetate and water, the organic layer
was washed with brine, dried over MgSO4, and concentrated
under vacuum. The residue was purified by column chroma-
tography on silica gel to provide 2.
Entry
Product
Time Temp. Yield
[h]
[8C]
[%][b]
1
2
3
4
5
6
7
2h
2i
30 min r.t.
94
Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Science Foundation of China (Nos. 20532040 and
20772145).
10 h
10 h
80
60
87
92
97
91
65
56
70
2j
References
[1] a) H. C. Shen, F. Ding, Q. Deng, L. C. Wilsie, M. L.
Krsmanovic, A. K. Taggart, E. Carballo-Jane, N. Ren, T.
Cai, T. Wu, K. K. Wu, K. Cheng, Q. Chen, M. S. Wolff,
X. Tong, T. G. Holt, M. G. Waters, M. L. Hammond,
J. R. Tata, S. L. Colletti, J. Med. Chem. 2009, 52, 2587–
2602; b) A. Lauria, C. Patella, G. Dattolo, A. M. Almeri-
co, J. Med. Chem. 2008, 51, 2037–2046; c) F. Da Settimo,
G. Primofiore, S. Taliani, A. M. Marini, C. La Motta, F.
Simorini, S. Salerno, V. Sergianni, T. Tuccinardi, A. Mar-
tinelli, B. Cosimelli, G. Greco, E. Novellino, O. Ciampi,
M. L. Trincavelli, C. Martini, J. Med. Chem. 2007, 50,
5676–5684; d) G. Biagi, I. Giorgi, O. Livi, V. Scartoni,
L. Betti, G. Giannaccini, M. L. Trincavelli, Eur. J. Med.
Chem. 2002, 37, 565–571; e) A. W. Thomas, Bioorg.
Med. Chem. Lett. 2002, 12, 1881–1884; f) L. Bertelli, G.
Biagi, I. Giorgi, C. Manera, O. Livi, V. Scartoni, L.
Betti, G. Giannaccini, L. Trincavelli, P. L. Barili, Eur. J.
Med. Chem. 1998, 33, 113–122; g) L. Betti, G. Biagi, G.
Giannaccini, I. Giorgi, O. Livi, A. Lucacchini, C.
Manera, V. Scartoni, J. Med. Chem. 1998, 41, 668–673;
h) J. L. Kelley, C. S. Koble, R. G. Davis, E. W. McLean,
F. E. Soroko, B. R. Cooper, J. Med. Chem. 1995, 38,
4131–4134; i) I. R. Ager, A. C. Barnes, G. W. Danswan,
P. W. Hairsine, D. P. Kay, P. D. Kennewell, S. S. Matharu,
2k
2l
30 min r.t.
1 h
r.t.
r.t.
60
2m
2n
2o
10 h
10 h
2 h
8
60
[a]
Reactions were carried out on a 0.3 mmol scale in
DMSO (2 mL) under nitrogen with sodium azide
(1.1 equiv.) , catalyst (10 mol%) and ligand (20 mol%)
unless otherwise stated.
[b]
Isolated yield.
Adv. Synth. Catal. 2010, 352, 1296 – 1300
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1299

Zixian Chen et al.
COMMUNICATIONS
P. Miller, P. Robson, J. Med. Chem. 1988, 31, 1098–
1115; j) E. J. Trybulski, L. Benjamin, S. Vitone, A.
Walser, R. I. Fryer, J. Med. Chem. 1983, 26, 367–372.
[2] I. Ojima, Fluorine in Medicinal Chemistry and Chemical
Biology, Wiley-Blackwell, 2009.
2007, 72, 1510–1513; b) C. P. Jones, K. W. Anderson,
S. L. Buchwald, J. Org. Chem. 2007, 72, 7968–7973;
c) B. L. Zou, O. L. Yuan, D. W. Ma, Org. Lett. 2007, 9,
4291–4294; d) B. L. Zou, Q. L. Yuan, D. W. Ma, Angew.
Chem. 2007, 119, 2652–2655; Angew. Chem. Int. Ed.
2007, 46, 2598–2601; e) F. S. Melkonyan, A. V. Karcha-
va, M. A. Yurovskaya, J. Org. Chem. 2008, 73, 4275–
4278; f) D. S. Yang, H. Fu, L. M. Hu, Y. Y. Jiang, Y. F.
Zhao, J. Org. Chem. 2008, 73, 7841–7844; g) K. Hasega-
wa, N. Kimura, S. Arai, A. Nishida, J. Org. Chem. 2008,
73, 6363–6368; h) A. Minatti, S. L. Buchwald, Org. Lett.
2008, 10, 2721–2724; i) L. Guo, B. Li, W. L. Huang, G.
Pei, D. W. Ma, Synlett 2008, 1833–1836; j) J. T. Zhu,
H. B. Xie, Z. X. Chen, S. Li, Y. M. Wu, Chem. Commun.
2009, 2338–2340.
[3] B. Saha, S. Sharma, D. Sawant, B. Kundu, Tetrahedron
2008, 64, 8676–8684.
[4] For copper-catalyzed C N bond formation reactions,
À
see: a) D. W. Ma, Y. D. Zhang, J. C. Yao, S. H. Wu, F. G.
Tao, J. Am. Chem. Soc. 1998, 120, 12459–12467; b) A.
Klapars, X. H. Huang, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 7421–7428; c) J. C. Antilla, A. Klapars,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 11684–
11688; d) F. Y. Kwong, A. Klapars, S. L. Buchwald, Org.
Lett. 2002, 4, 581–584; e) D. W. Ma, Q. Cai, H. Zhang,
Org. Lett. 2003, 5, 2453–2455; f) H. J. Cristau, P. P. Celli-
er, J. F. Spindler, M. Taillefer, Chem. Eur. J. 2004, 10,
5607–5622; g) H. H. Rao, H. Fu, Y. Y. Jiang, Y. F. Zhao,
J. Org. Chem. 2005, 70, 8107–8109; h) H. Zhang, Q. Cai,
D. W. Ma, J. Org. Chem. 2005, 70, 5164–5173; i) Z. Lu,
R. J. Twieg, Tetrahedron Lett. 2005, 46, 2997–3001; j) A.
Shafir, S. L. Buchwald, J. Am. Chem. Soc. 2006, 128,
8742–8743; k) B. De Lange, M. H. Lambers-Verstappen,
L. Schmieder-van de Vondervoort, N. Sereinig, R.
de Rijk, A. de Vries, Synlett 2006, 3105–3109; l) L.
Rout, S. Jammi, T. Punniyamurthy, Org. Lett. 2007, 9,
3397–3399; m) R. A. Altman, E. D. Koval, S. L. Buch-
wald, J. Org. Chem. 2007, 72, 6190–6199; n) R. A.
Altman, A. Shafir, A. Choi, P. A. Lichtor, S. L. Buch-
wald, J. Org. Chem. 2008, 73, 284–286.
[6] Y. Tanaka, S. R. Velen, S. I. Miller, Tetrahedron 1973, 29,
3271–3283.
[7] CCDC 755240 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] Fluorine-containing N-(o-haloaryl)alkynylimines were
synthesized using a new method created by our group
recently (in press), which is detailed in the Supporting
Information.
À
[9] For copper-catalyzed C N bond formation with aryl
chlorides, see: a) A. Klapars, X. H. Huang, S. L. Buch-
wald, J. Am. Chem. Soc. 2002, 124, 7421–7428; b) S. U.
Son, I. K. Park, J. Park, T. Hyeon, Chem. Commun.
2004, 778–779; c) H. C. Ma, X. Z. Jiang, J. Org. Chem.
2007, 72, 8943–8946; d) H. H. Xu, C. Wolf, Chem.
Commun. 2009, 1715–1717; e) H. H. Xu, C. Wolf, Chem.
Commun. 2009, 3035–3037.
À
[5] For cascade processes involving a copper-catalyzed C N
coupling reaction, see: a) X. Y. Yuan, X. B. Xu, X. B.
Zhou, J. W. Yuan, L. G. Mai, Y. Z. Li, J. Org. Chem.
1300
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1296 – 1300