A facile synthesis of 5-amino-[1,2,3]triazolo[5,1-a]isoquinoline derivatives through copper-catalyzed cascade reactions

Article abstract of DOI:10.1039/c3ob41774c

A copper-catalyzed cascade method was developed for the synthesis of [1,2,3]triazolo[5,1-a]isoquinoline derivatives. The N-fused heterocycles were obtained in good to excellent yields under mild conditions, which provided a new strategy for the preparation of this highly functionalized building block.

Full text of DOI:10.1039/c3ob41774c

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A Facile Synthesis of 5-Amino-[1,2,3]triazolo[5,1-a]isoquinoline
Derivatives through Copper-Catalyzed Cascade Reactions
Yunfeng Chena,*, Shilei Zhoua, Shan Maa, Wenqian Liua, Zhiquan Pana, Xiaodong Shib,*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
hydrazine condensation with pyridylketone followed by
A copper-catalyzed cascade method was developed for the
synthesis of [1,2,3]triazolo[5,1-a]isoquinoline derivatives. The
N-fused hetereocycles were obtained in good to excellent
yields under mild conditions, which provided a new strategy
10 for the preparation of this highly functionalized building
block.
the base mediated cyclization.5 The overall process
involved harsh condition and the reaction substrate was
limited. With the recent successes in the syntheses of
35 various 1,2,3-triazole-fused heterocyclic derivatives,6 we
were interested in whether these fused N-hetereocycles
could be achieved from 1,2,3-triazoles, which were readily
available starting materials from “click chemistry”.7
Herein, we report the copper catalyzed intermolecular
40 condensation between o-halo-phenyl-triazole and activated
nitrile for one-pot synthesis of the TAIQ under mild
conditions with large substrate scope.
Structurally novel and diverse fused heterocycles are
important building blocks for chemical, biological,
medicinal and material research.1 The [1,2,3]-triazolo-
15 [5,1-a]-isoquinoline (TAIQ) (Scheme 1A) is one
interesting class of N-hetereocycles for biological and
material research.2 With the recent discovery of Rh, Cu
and Ni catalyzed 1,2,3-triazoles denitrogenation reactions,3
these fused structures became potential new synthons for
20 complex molecule synthesis. In addition, our recent
studies on triazole-metal coordination and new
fluorescence active 1,2,3-triazole derivatives suggested
potential interesting metal coordination ability and photo
activity with these compounds. 4
Since the 1,2,3-triazoles are readily available from “click
chemistry”, there have been more and more studies
45 regarding the 1,2,3-triazole-metal coordination.
One
interesting reported strategy was to use 1,2,3-triazole as the
directing group for the metal catalyzed aryl (ortho
position) functionalization. Ackermann and co-workers
have done comprehensive investigations on 1,2,3-triazole
50 directed C-H activation of the conjugated triazole-phenyl
compounds.8 One potential issue of this transformation
was the competition of C-cyclization (acidic C-H proton at
triazole C-4 or C-5 position) over N-cyclization. Although
that synthesis gave good substrate scope and good to
55 excellent yields, the starting materials, vinyl azides, were
not readily available. Thus, effective synthesis of TAIQ
from 1,2,3-triazoles has not been reported so far.
25
Scheme 1.
biological, medicinal and
(A)
material applications
[1,2,3]-triazolo-
[5,1-a]-isoquinoline
N
N
N
synthon: metal catalyzed
denitrogenation
Recently, Fu and coworkers reported several
transformations involving copper catalyzed heterocycle
60 condensation with nitrile for the synthesis of fused N-
hetereocycles.9 Sparked by this work, we decided to
investigate the condensation between triazole aryl halides
and activated nitriles as a new effective path for the
preparation of TAIQ compounds. The o-bromo-phenyl-
65 triazole 1a and ethyl cyanoacetate 2a were selected for the
initial condition screening. The results are summarized in
Table 1.
(B) Typical synthetic route
R
R
R
NH2NHTs
Base
O
N
NNHTs
N
reflux
N
N
N
Limitation: Harsh conditions; Low overall yield; limited scope
(C) A new cascade strategy: This work
R
R
one step synthesis;
> 25 examples;
up to 97% yield
10% CuI, Ligand
DMSO, 80 o
N
N
X
HN
N
N
N
C
N
EWG
EWG
NH2
Readily available SM
70
As shown in Scheme 1B, the traditional synthesis of
30 triazole-isoquinoline (TAIQ) was achieved through the
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[journal], [year], [vol], 00–00 | 1

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DOI: 10.1039/C3OB41774C
Table 1. Reaction condition screeninga
coupling10 was obtained exclusively (over the triazole
Ullmann coupling, 3t and 3u). Overall, the extensive
40 substrate scope at various positions greatly highlighted the
utility of this method for the preparation of TAIQ
derivatives over the literature reported methods.
N
N
N
N
[Cu] 10%, ligand 12%
N
N
+
NC
CO2Et
H
base, solvent, Ar
NH2
CO2Et
3a
Br
1a
2a
Table 2. Reaction substrate scopea, b
N
N
R2
COOH
R2
N
N
N
H
N
COOH
N
N
N
N
N
N
10% CuI, 12% L4
N
L1
L2
L3
L4
L5
N
NC
EWG
R1
+
R1
H
K2CO3, DMSO, 80 oC, Ar
NH2
yield
(%)b
56
81
70
85
90
78
92
87
trace
0
62
75
90
74
67
52
solvent temp (oC)time (h)
X
entry cat.
ligand
base
1
2
EWG
EWG = CN, CO2R (R = Me, Et, t-Bu)
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
None
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
80
80
80
80
80
80
80
80
80
rt
60
110
80
80
80
80
80
80
4
2
4
4
2
4
2
2
10
10
6
2
2
2
2
4
4
45
N
N
3a: EWG = COOEt, 92%
3b: EWG = COOMe, 80%
3c: EWG = COOtBu, 94%
3d: EWG = CN, 72%
N
N
N
N
H
Br
1a
NH2
EWG
N
N
N
N
3d: EWG = CN, 28%
N
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
N
H
3c: EWG = COOtBu, 41%
Cl
1b
NH2
EWG
Ar
N
3e: Ar = Ph, EWG = COOMe, 88%;
3f: Ar = Ph, EWG = COOEt, 92%;
3g: Ar = Ph, EWG = COOtBu, 97%
3h: Ar = Ph, EWG = CN, 86%
N
N
K3PO4
K2CO3
K2CO3
K2CO3
NH2
3i: Ar = p-NO2-Ph, EWG = COOtBu, 97%
16 CuCl
17 CuBr
18 Cu2O
EWG
80
41
H3C
N
N
4
N
aReaction condition: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (0.05 mmol), ligand
5 (0.06 mmol), base (0.75 mmol), solvent (2 mL), under argon atmosphere, b Isolated
yields.
N
3l: EWG = COOtBu, 78%;
3m: EWG = COOEt, 60%;
3n: EWG = CN, 45%
3j: EWG = COOEt, 78%;
3k: EWG = COOtBu, 90%
N
EWG
N
N
F
F
NH2
NH2
EWG
H3C
N
N
Initially we proposed that the 1,2,3-triazole might act as
a directing group to promote coupling reaction, so the
10 reaction was carried out using CuI as catalyst and K2CO3
as base under Ar in the absence of a ligand. However,
only modest yield (56%) was obtained (entry 1). Some N-
containing ligands were then evaluated (entries 2-6).
Improved yields were obtained with the presence of these
15 ligands and 1,10-phenanthroline gave the best results
(entry 6). Screening of solvents revealed DMSO as the
optimal solvent, giving the desired TAIQ 3a in 92%
isolated yield (entry 7). Further lowering the reaction
F
3o: EWG = COOMe, 65%;
3p: EWG = COOEt, 78%;
3q: EWG = COOtBu, 84%
N
N
3r: EWG = COOEt, 70%;
3s: EWG = COOtBu, 81%
N
NH2
NH2
EWG
N
N
N
EWG
Br
X-ray crystal structure of
3c. (see crystal structure
of 3d in ESI)
3t: EWG = CN, 54%;
3u: EWG = COOtBu, 82%
NH2
EWG
a
General reaction conditions: compound 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.05
mmol), 1,10-phenanthroline(0.06 mmol), K2CO3 (0.75 mmol), DMSO (2 mL), 3-8h,
b Isolated yield.
o
50
temperature to 60 C (entry 11) significantly decrease the
20 reaction rate while higher temperature (110 C, entry 12)
Some control experiments were conducted to uncover
the reaction mechanism. The results are shown in Scheme
Initially, the reaction of N-substituted 5-(2-
bromophenyl)-1H-1,2,3-triazole (4) with the ethyl
o
caused product decomposition. Screening of different
Cu(I) catalysts (entries 16-18) revealed CuI as the optimal
choice. The K2CO3 was also identified as the practical
choice of base (cheaper and better performance).
With the optimized conditions in hand, we then explored
the substrate scope. The results are summarized in Table
2. The aryl bromide substrates generally gave good to
excellent yields. The aryl chloride substrate (1b) has also
been tested and lower yields were observed, likely caused
30 by the decreased reactivity of the C-Cl bond. Both ester
and CN could serve as the effective EWG to promote this
reaction. The t-Bu esters gave overall better results over
ethyl and methyl esters, presumably due to the improved
stability (slow product decomposition). Good substitute
35 group tolerance at the triazole C-5 position was observed
(H, allyl or alkyl). Impressively, with the C-5-bromo-
triazole substrate, the desired aryl-halide Ullmann
2.
55 cyanoacetate under identical reaction condition was
performed. The coupling product 5 was observed with
20% conversion and 18% yield in 10 h (Scheme 2A).
First, it is highly unlikely that the Ullmann coupling can be
reversible (C-C bond dissociation) under the reaction
60 conditions. Thus, considering the fact that the reaction of
NH-triazole substrate 1a finished in 1h (up to 86% yield)
under identical condition, it is likely that the triazolate was
a much better directing group (compared with the neutral
triazole) for the copper catalyzed Ullmann coupling.13
65 This result suggested further extensions of this copper
catalyzed coupling approach with the 1,2,3-triazole
directing group. Meanwhile, it has been reported in
literature that proper Pd catalysts can activate the C-Br
25
2 | Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C3OB41774C
bond on the triazole ring.6h,11 Thus, to evaluate the
chemoselectivity of this copper catalyzed reaction, excess
amounts of nitrile nucleophiles (5 equiv.) were applied. As
extracted with EtOAc. The solvent was removed in vacuo
and the residue was purified by column chromatography
on silica gel using petroleum ether/ethyl acetate (3:1) as
shown in Scheme 2B, no bromotriazole coupling products 50 eluent to provide 3a as white solid (92% yield).
were obtained. The designated Ullmann aryl coupling
5
product 3u was obtained exclusively. Notably, the triazole
C-Br bond can be potentially converted into other
functional groups through C-Br activation. Thus, the
excellent chemoselectivity observed in these copper
10 coupling conditions provided a highly effective and
practical approach to diverse TAIQ derivatives.
Notes and references
a Key Laboratory for Green Chemical Process of Ministry of Education,
55 Wuhan Institute of Technology, Wuhan 430073, P. R. China, E-mail:
chyfch@hotmail.com
b
C. Eugene Bennett Department of Chemistry, West Virginia University,
Morgantown, WV 26506, USA. Fax: 1-304-293-4904; Tel:1-304-293-
3435 x6438; E-mail: Xiaodong.Shi@mail.wvu.edu
Scheme 2.
(A)
Ph
Ph
60 † Electronic Supplementary Information (ESI) available: experimental
1
details, X-ray measurement and HNMR, 13NMR for all compounds. See
N
N
N
CuI, 1,10-phenanthroline
N
http://dx.doi.org/10.1039/b000000x/
N
N
t-BuO2C
CN
+
K2CO3, DMSO, 80 oC, Ar
10h
CN
Br
1. (a) L. D. Quin, J. Tyrell, Fundamentals of Heterocyclic Chemistry:
1.2 eq
CO2Bu-t
4
5
10 h, 20% conversion,18% yield
65
70
Importance in Nature and in the Synthesis of Pharmaceuticals;
Wiley: 2010; ISBN:978-0-470-56669-5; (b) P. J. Crowley, in:
Comprehensive Heterocyclic Chemistry, (Eds.: A. R. Katritzky, C.
W. Rees), Pergamon, New York, 1984. (c) J. K. Landquist, in:
Comprehensive Heterocyclic Chemistry (Eds.: A. R. Katritzky, C. W.
Rees), Pergamon, New York, 1984.
In comparison: 1a, identical conditions, 1h, 90% convn, 78% yield
Br
(B)
Br
N
NH
N
N
CuI, 1,10-phenanthroline
N
N
t-BuO2C
CN
+
K2CO3, DMSO, 80 oC, Ar
1h
NH2
Br
2. (a) S. G. Agalave, S. R. Maujan, V. S. Pore. Chem. Asian J. 2011, 6,
2696; (b) A. Carta, M. Palomba, G. Paglietti, P. Molicotti, B.
Paglietti, S. Cannas, S. Zanetti. Bioorg. Med. Chem. Lett. 2007, 17,
4791; (c) X. Su, M. D. Liptak, I. Aprahamian, Chem. Commun. 2013,
49, 4160; (c)
CO2Bu-t
3u
5.0 eq
1a
100% convn, 92% yield
15
75
In conclusion, we report herein a simple and efficient
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cascade process for the synthesis of 5-amino-
[1,2,3]triazolo[5,1-a]isoquinoline (TAIQ) derivatives in
good to excellent yields under mild conditions. To the best
80
20 of our knowledge, this is the first example of the TAIQ
synthesis using the readily available 1,2,3-triazoles as
starting materials. The NH-triazole directed-annulation
approach allowed further modification for synthesis of
other N-fused hetereocycles. The fluorescence activities
25 along with the metal coordination ability of these new
TAIQ derivatives are currently under investigation and will
be reported in due course.
85
90
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The authors are grateful to National Natural Science
30 Foundation of China (21000276), the Scientific Research
Foundation for the Returned Overseas Chinese Scholars,
and Wuhan Youth Chenguang Program of Science and
Technology (201271031374) for financial support.
95
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Experimental
100
105
110
35 General Information
Procedure for Synthesis of Compounds 3a
Substituted 5-(2-bromophenyl)-1H-1,2,3-triazole 1a (0.5
mmol) and CuI (0.05 mmol, 10 mg), K2CO3 (0.75 mmol,
104 mg), 1,10-phenanthroline (0.1 mmol, 18 mg) were
40 added to a pear-shaped Schlenk tube charged with a
magnetic stirrer. The tube was evacuated and backfilled
with argon and then DMSO (2.0 mL) and ethyl 2-
cyanoacetate (0.6 mmol) were added to the tube under a
stream of argon. The tube was sealed and the mixture was
45 stirred at 80 °C under argon atmosphere. After completion
of the reaction, the mixture was washed with water and
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30 11. (a) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan, Org.
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12. CCDC 938028 and 938029 contain the supplementary
35
crystallographic 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.
13. Another plausible reason for the observed poor conversion of 4 is the
coordination of compound 5 and Cu cation that traps the catalysts.
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