Copper-catalyzed tandem azide-alkyne cycloaddition, Ullmann type C-N coupling, and intramolecular direct arylation

Article abstract of DOI:10.1021/ol401655r

A ligand-free copper-catalyzed tandem azide-alkyne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation has been described. The designed strategy resulted in the synthesis of a novel trazole-fused azaheterocycle framework.

Full text of DOI:10.1021/ol401655r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Copper-Catalyzed Tandem AzideꢀAlkyne
Cycloaddition, Ullmann Type CꢀN
Coupling, and Intramolecular Direct Arylation
Kasiviswanadharaju Pericherla,†,‡ Amitabh Jha,‡ Bharti Khungar,† and Anil Kumar*,†
Department of Chemistry, Birla Institute of Technology and Science, Pilani, 333031,
India, and Department of Chemistry, Acadia University, Wolfville, NS, B4P 2R6,
Canada
anilkumar@pilani.bits-pilani.ac.in
Received June 12, 2013
ABSTRACT
A ligand-free copper-catalyzed tandem azideꢀalkyne cycloaddition (CuAAC), Ullmann-type CꢀN coupling, and intramolecular direct arylation has
been described. The designed strategy resulted in the synthesis of a novel trazole-fused azaheterocycle framework. The reaction gave good yields
(59ꢀ77%) of 1,2,3-triazole-fused imidazo[1,2-a]pyridines in a single step.
Transition metal-catalyzed coupling reactions play a
vital role in organic and medicinal chemistry allowing
construction of novel and biologically relevant molecules.1
In particular, significant attention has been focused on
copper catalysts over other expensive transition metals
such as palladium, ruthenium, and rhodium for the for-
mation of CꢀC and C-heteroatom bonds mainly because
of their efficiency, good functional group tolerance, and
economical attractiveness.2 Tandem or cascade reactions
catalyzed by copper salts serve as an efficient tool for the
assembly of complex biologically active heterocyclic
molecules.3 1,2,3-Triazoles are found to have broad range
of applications in the field of synthetic, medicinal, and
material chemistry.4 Since the pioneering work by
Sharpless5 and Meldel6 groups, copper-catalyzed azideꢀ
alkyne cycloaddition (CuAAC) has become the finest way
to generate 1,4-substituted-1,2,3-triazoles. Another impor-
tant copper-catalyzed reaction is Ullmann coupling.7 The
scope of Ullmann-type reactions was actively developed
after the discovery of organic ligands and applied in
various fields to synthesize potentially important mole-
cules via CꢀC and C-heteroatom bond formation.8 Tran-
sition metal-catalyzed direct CꢀH functionalization has
become an alternative to traditional cross-coupling reac-
tions that results in fabrication of complex molecular
skeleton where prefunctionalization of precursors can be
obviated.9 Moreover, inexpensive copper salts have also
proved to be efficient catalysts in the area of CꢀH activa-
tion and functionalization to assemble vital organic
frameworks.10 Recently, Ackermann et al. demonstrated
† Birla Institute of Technology and Science
‡ Acadia University
(1) For transition metal-catalyzed coupling reactions: (a) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998. (b) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S.
Chem. Soc. Rev. 2011, 40, 5068. (d) Shi, W.; Liu, C.; Lei, A. Chem. Soc.
Rev. 2011, 40, 2761. (e) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev.
2011, 111, 1780 and references cited therein.
(2) Selected examples: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337. (b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 15185.
(6) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
(7) Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174.
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D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13. (c) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(3) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873.
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2011, 6, 2696. (b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(c) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7.
(5) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(9) (a) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
111, 1215.
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J. Am. Chem. Soc. 2011, 133, 2160. (b) Bernini, R.; Fabrizi, G.;
Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078.
r
10.1021/ol401655r
XXXX American Chemical Society

the synthesis of decorated 1,2,3-triazoles via Cu/Pd-catalyzed
click reaction, direct arylation sequence.11 Lauten et al. have
described interesting results on fused 1,2,3-triazole through
cycloaddition followed by direct arylations.12 Cai et al.
trapped CꢀCu formed in CuAAC for intramolecular
Ullmann coupling to synthesize novel fused-1,2,3-
triazoles.13 However, the combination of copper-catalyzed
CuAAC, Ullmann-type coupling and CꢀH functionaliza-
tion is rare in the literature.
Scheme 1. Tandem Reaction of 1a, 2a, and 3 in the Presence of
Copper Catalyst
There are several drugs that contain imidazo[1,2-a]-
pyridine as the core structure such as zolpidem and
alpidem (used for the treatment of anxiety and insomnia),
zolimidine (used for peptic ulcers), and saripidem and
necopidem (for sedative and anxiolytic effects). The deri-
vatives of imidazo[1,2-a]pyridine have shown impressive
biological activities such as antiinflammatory, antibacter-
ial, antiviral, antiulcer, anti-HIV, and immunomodulatory
effects.14 On the basis of the significance of imidazo[1,2-a]-
pyridine nucleus, we believe that further functionalization
leading to fused novel heterocycles will have new and
interesting properties. As a part of our continuous efforts
for the synthesis of novel heterocycles containing imidazo-
[1,2-a]pyridines,15 herein we wish to report a ligand-free
inexpensive copper-catalyzed tandem CuAAC, Ullmann
type CꢀN coupling, and intramolecular direct arylation
for the regioselective synthesis of novel 1,2,3-triazole-fused
imidazo[1,2-a]pyridines.
failed to furnish tandem product, and starting materials
were recovered (entry 3), whereas an inseparable mix-
ture of compounds was observed in the absence of base
(entry 4).
To improve the yield of desired pentacyclic product 5a,
various copper salts, bases, and solvents were screened
(Table 1). Use of CuI and CuO resulted in poor yields,
Cu(OAc)2 gave relatively better yield of desired product
(entries 5, 6, and 7). At the same time CuBr2, Cu(OTf)2,
and Cu2O gave moderate yields of desired product 5a
(entries 9, 10, and 11), whereas CuSO4 resulted in forma-
tion of 4a (entry 8). Among all the screened catalysts,
3-Bromo-2-(2-bromophenyl)imidazo[1,2-a]pyridine (1a),
phenylacetylene (2a) and sodium azide (3) were chosen as
model substrates for the initial investigation, and the results
are summarized in Table 1. In a typical experiment, com-
pound 1a (1 mmol) was treated with 2a (1.2 mmol) and 3
CuCl2 2H2O was found to give the best yield of 5a. Next,
we screened various bases such as KOtBu, Cs2CO3,
K2CO3, Na2CO3, and NaOAc (entries 12ꢀ15) with
3
CuCl2 2H2O as the catalyst. Among these, K2CO3 turned
3
out to be the most effective base to give 5a (entry 2),
whereas use of NaOAc resulted in formation of 4a
(entry 15). Finally, the effect of solvents was also in-
vestigated for this tandem process yielding 5a. Aprotic
polar solvents such as DMF and DMSO were found
to be effective (entries 2 and 16) for this conversion.
1,4-Dioxane and toluene (entries 17 and 18) did not give
any reaction. Use of acetonitrile resulted in formation of
4a (entry 19). Moreover, use of external ligands like N,
N0-dimethylethylenediamine, 1,10-phenonthroline and
L-proline (40 mol %) failed to improve the yield of 5a
(entries 20, 21 and 22).
Having optimized the reaction conditions (Table 1,
entry 2), we investigated the scope of this tandem reaction,
and the results are summarized in Scheme 2. Various
substituted phenylacetylenes smoothly reacted under the
optimized conditions to give desired 1,2,3-triazole-fused
imidazo[1,2-a]pyridines(5aꢀo) inmoderatetogoodyields.
For example, phenylacetylenes with electron-donating
substituents such as 4-methoxy, 4-butyl, 4-pentyl, 4-tert-
butyl, and 3-methyl produced the corresponding 1,2,3-
triazole-fused imidazo[1,2-a]pyridines (5bꢀe and 5n) in
good yields (59ꢀ68%), and 4-fluorophenylacetylene with
electron-withdrawing fluoro group underwent smooth
conversion to afford 62% of 1,2,3-triazole-fused imidazo-
[1,2-a]pyridines (5f). Aliphatic alkynes also efficiently par-
ticipated in tandem reaction to give the corresponding
(1.2 mmol) in the presence of CuCl2 2H2O (20 mol %) and
3
K2CO3 (2.5 mmol) in DMF at 80 °C for 24 h. 3-Bromo-
2-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)imidazo[1,2-a]-
pyridine (4a) (Table 1, entry 1) was obtained in 66% yield
(Scheme 1). It was realized that direct Cu-catalyzed arylation
product of 4a can be achieved in one pot at higher tempera-
ture; thus, the reaction temperature was increased to 150 °C
with other conditions keeping similar to entry 1. To our
delight, target compound (5a) was obtained in 65% yield
(entry 2). In the absence of copper catalyst, reaction
(11) (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente,
R. Org. Lett. 2008, 10, 3081. (b) Ackermann, L.; Potukuchi, H. K. Org.
Biomol. Chem. 2010, 8, 4503.
(12) (a) Panteleev, J.; Geyer, K.; Aguilar-Aguilar, A.; Wang, L.;
Lautens, M. Org. Lett. 2010, 12, 5092. (b) Schulman, J. M.; Friedman,
A. A.; Panteleev, J.; Lautens, M. Chem. Commun. 2012, 48, 55.
(13) Cai, Q.; Yan, J.; Ding, K. Org. Lett. 2012, 14, 3332.
(14) (a) Rival, Y.; Grassy, G.; Taudou, A.; Ecalle, R. Eur. J. Med.
Chem. 1991, 26, 13. (b) Hamdouchi, C.; de Blas, J.; del Prado, M.;
Gruber, J.; Heinz, B. A.; Vance, L. J. Med. Chem. 1998, 42, 50. (c)
ꢁ
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Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic, M.; Suman, L.; Pavelic, K.;
Zamola, G. K. J. Med. Chem. 2007, 50, 5696. (d) Lhassani, M.;
Chavignon, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J.-P.; Snoeck,
R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med.
Chem. 1999, 34, 271. (e) Fisher, M. H.; Lusi, A. J. Med. Chem. 1972, 15,
982. (f) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli,
P.; Biancotti, A.; Gamba, A.; Murmann, W. J. Med. Chem. 1965, 8, 305.
(g) Couty, F.; Evano, G. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F.V., Taylor, R. J. K., Eds.;
Elsevier: Oxford, 2008; p 409.
(15) Pericherla, K.; Khedar, P.; Khungar, B.; Kumar, A. Chem.
Commun. 2013, 49, 2924.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditions for the Synthesis
of 5a via Tandem Reactiona
Scheme 2. Tandem Synthesis of 1,2,3-Triazole-Fused Imidazo-
[1,2-a]pyridines (5)
temp
yield of 5a
entry
catalyst
base
solvent
(°C)
(%)b
c
1
2
3
4
5
6
7
8
9
CuCl2 2H2O K2CO3 DMF
80
ꢀ
3
CuCl2 2H2O K2CO3 DMF
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
65
3
d
ꢀ
K2CO3 DMF
NRe
f
g
CuCl2 2H2O
ꢀ
DMF
ꢀ
3
CuI
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
18h
22
CuO
Cu(OAc)2
CuSO4
CuBr2
38
h
ꢀ
48
54
45
22
50
46
10 Cu(OTf)2
11 Cu2O
12 CuCl2 2H2O Na2CO3 DMF
3
3
3
3
3
3
3
3
13 CuCl2 2H2O KOtBu DMF
14 CuCl2 2H2O Cs2CO3 DMF
h
15 CuCl2 2H2O NaOAc DMF
ꢀ
16 CuCl2 2H2O K2CO3 DMSO
51
17 CuCl2 2H2O K2CO3 1,4-dioxane 150
NRe
NRe
18 CuCl2 2H2O K2CO3 toluene
150
150
150
150
150
h
19 CuCl2 2H2O K2CO3 MeCN
ꢀ
20 CuCl2 2H2Oi K2CO3 DMF
56
3
3
3
21 CuCl2 2H2Oj K2CO3 DMF
62
tracesg
22 CuCl2 2H2Ok K2CO3 DMF
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), NaN3 (1.2 mmol),
catalyst (0.2 mmol), base (2.5 mmol), solvent (4 mL), 24 h. b Isolated yields.
c 4a was isolated in 66% yield. d No copper catalyst. e No conversion. f No
base was used. g A mixture of products was observed. h The major product
i
was 4a. N,N0-Dimethylethylenediamine was used (40 mol %). j 1,10-
Phenonthroline was used (40 mol %). k L-Proline was used (40 mol %).
1,2,3-triazole-fused imidazo[1,2-a]pyridines in compara-
tively better yields (72%, 5g and 76%, 5h). Similarly,
different substituted imidazo[1,2-a]pyridines also produced
1,2,3-triazole-fused imidazo[1,2-a]pyridines in good yields
(74%, 5i; 68%, 5j and 78%, 5k; 76%, 5l; 71%, 5m; 73%,
5o). Unfortunately, reation of 3-bromo-2-(2-bromophenyl)-
5-methyl imidazo[1,2-a]pyridine (1d) with 2a and 3 failed
to give the corresponding 1,2,3-triazole-fused imidazo[1,2-a]-
pyridine (5p). This may be due to the steric hindrance
caused by 5-methyl in imidazo[1,2-a]pyridine nucleus.
Since two bromo groups are present in the starting
material (1aꢀe), two regioisomers can be visualized for
the compounds 5aꢀo from the tandem process (explained
for compound 5i in Figure 1). To understand the reactivity
of each of the bromo groups, two individual experiments
were performed using the optimized reaction conditions.
In the first experiment, 2-(2-bromophenyl) imidazo[1,2-a]-
pyridine (6) was treated with 2a and 3, and the anticipated
product, 2-(2-(4-phenyl-1H-1,2,3-triazol-1-yl) phenyl)-
imidazo[1,2-a]pyridine (7), was obtained via CuAAC
followed by Ullmann-type coupling reaction in good
yield (78%, Scheme 3). In the second experiment, 3-bromo-
2-phenylimidazo[1,2-a]pyridine (8) was treated with 2a and
3. A mixture of products was observed in this reaction,
from which two major products isolated were found to
be dehalogenated starting material, i.e., 2-phenylimidazo-
[1,2-a]pyridine (9), and Sonagashira-type coupling product,
i.e., 2-phenyl-3-(phenylethynyl)imidazo[1,2-a]pyridine (10)
(Scheme 3). In addition to these two products, formation of
azideꢀalkyne condensation (AAC) product between 2a and
3 was also observed in the reaction mixture. The outcome
from these experiments indicates that the bromo substituent
at the 2-aryl ring undergoes Ullmann-type coupling. This is
due to the ortho-directing effect of the nitrogen atom in the
imidazole moiety of imidazo[1,2-a]pyridine that chelates
with copper and favors the CꢀN coupling.15 On the other
hand, the bromo on compound 8 appears to be more prone
toward CꢀC bond formation.
On the basis of these two independent experimental
results, regioisomer A appears to be a more logical product
than the regioisomer B (Figure 1). But to conclusively
ascertain the correct structure of the product, compound 5i
was selected for NOE studies. Compound 5i was strategi-
cally chosen, as the CH3 group on the pyridine ring would
enable assignment of aromatic proton resonances indi-
cated by blue and red dotsinFigure1 requiredtoverifyany
NOE enhancement on the phenyl substituent on triazole
ring of regioisomer A. For the regioisomer B, with phenyl
group on the other side, no NOE would be expected.
Focusing on the methyl group in the HMBC, the proton
indicated by the blue dot was assigned to the resonance at
6.5 ppm (13C shift 115 ppm from HSQC). Subsequently,
from the COSY, the proton indicated by the red dot was
assigned to the resonance at 7.4 ppm (13C shift 127.2 ppm
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Reactivity of Bromo Group on Imidazo[1,a]pyridine
Figure 1. Possible regioisomers of compound 5i.
There are two possible pathways for the transformation of
intermediate 4a into fused triazole 5a: (a) direct arylation of
intermediate 4a, as reported by Ackermann group,11a and
(b) by CꢀCu trapping as reported by Cai group.13 To
clarify the mechanism of this step, isolated compound 4a
was subjected under the optimized reaction conditions
(Scheme 1), which led to formation of 5a in excellent yield
(73%). This indicates that this step proceeds via direct
arylation instead of CꢀCu trapping.
from HSQC). The 13C NMR spectrum of 5i helped in
identifying symmetrical phenyl ring carbons (128.4 and
131.3 ppm), which in turn helped to (through HSQC
experiment) identify the chemical shifts of proton they
harbored (7.6 and 7.7 ppm; shown in black dots in Figure 1).
After having identified the chemical shifts of the protons of
interest, 1D NOESY experiment was run. Irradiation at
frequency of the signal at δ 7.4 ppm (proton shown in red
dot in Figure 1) enhanced the signal at δ 6.5 ppm (proton
shown in blue dot in Figure 1), which was expected.
However, there is also a significant response at a resonance
involving δ 7.7 ppm, which is assigned for two of the 4
protons (shown in black dot in Figure 1) on the benzene
ring substituent. If the benzene ring is on the other side
(isomer B), then no enhancement would be expected on
benzene ring substituent. Thus, on the basis of the two
experiments with 6 and 8 and the NOE results, the struc-
ture of 1,2,3-triazole-fused imidazo[1,2-a]pyridines were
conclusively established ascorresponding toregioisomerA
(Figure 1).
In conclusion, we have successfully developed an effi-
cient and simple tandem protocol for the synthesis of struc-
turally complex and novel 1,2,3-triazole-fused imidazo-
[1,2-a]pyridines via CuAAC, Ullmann-type CꢀN coupling,
followed by intramolecular CꢀC bond formation by CꢀH
functionalization. The reaction shows high generality and
functional group tolerance. It provides a straightforward
means for the preparation of fused triazoles derivatives.
Attempts to understand the mechanism of the tandem
reaction and its application for the synthesis of fused
heterocycles are in progress in our laboratory.
Acknowledgment. The authors sincerely thank Natural
Sciences and Engineering Research Council (NSERC) of
Canada and University Grant Commission (UGC) of
India for research funding. K.P. thanks the Canadian
Bureau for International Education for awarding Canadian
Commonwealth Scholarship and University Grants Com-
mission (India) for providing research fellowship.
Although mechanistic details are not clear at this point,
on the basis of experimental observations, intermediates
isolated, and the literature precedent, it has been proposed
that Cu(II) can initially oxidize alkynes to result in reactive
Cu(I) along with diyne.16 Subsequently, Cu(I)-catalyzed
CuAAC reaction followed by ortho-directed Ullman-type
CꢀN coupling with phenyl triazole leads to intermediate
4a (Scheme 1).
Supporting Information Available. General experimen-
1
tal details, copy of H and 13C NMR of the synthesized
Intramolecular direct arylation of intermediate 4a affords
the desired 1,2,3-triazole-fused imidazo[1,2-a]pyridine (5a).
compounds 1aꢀe, 5aꢀo, 7, 9, and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Hu, Y. Y.; Hu, J.; Wang, X. C.; Guo, L. N.; Shu, X. Z.; Niu,
Y. N.; Liang, Y. M. Tetrahedron 2010, 66, 80.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX