Four-component, three-step cascade reaction: an effective synthesis of indazole-fused triazolo[5,1-c]quinoxalines

Article abstract of DOI:10.1039/C8NJ06299D

An efficient four-component, three-step cascade reaction was developed for the synthesis of indazole-fused triazolo[5,1-c]quinoxalines from o-azido aldehyde, o-iodoaniline, phenylacetylene, and sodium azide. The methodology involves the sequential formation of 2H-indazole, then azide-alkyne cycloaddition, followed by C-N coupling, and finally intramolecular cross-dehydrogenative C-C coupling. Notable features of this protocol include simple starting materials, reduced synthetic steps, and good yields.

Full text of DOI:10.1039/C8NJ06299D

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DOI: 10.1039/C8NJ06299D
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Four-component, three-stepcascade reaction: An effective
synthesis of indazole fused triazolo[5,1-c]quinoxalines
a
a
a
Received 00th January 20xx,
Accepted 00th January 20xx
K. Shiva Kumar,* Praveen Kumar Naikawadi, Bandari Rajesham, D.
b
Rambabu
DOI: 10.1039/x0xx00000x
www.rsc.org/
privileged structures in the area of drug discovery.9-10 A series
An efficient four component,three-step cascade reaction
has been developed for the synthesis of indazole fused
triazolo[5,1-c]quinoxalines from o-azido aldehyde,
iodoaniline, phenylacetylene, and sodium azide. The
methodology involves sequential formation of 2H-indazole
then azide−alkyne cycloaddition followed by C−N coupling,
and finally intramolecular cross dehydrogenative C−C
coupling. Notable features of this protocol include simple
starting materials, reduced synthetic steps and good yields.
of 1,2,3-triazolo[l,5a]quinoxaline-4-ones (D) have shown good
o-
affinity toward the benzodiazepine receptor10 (K
i
53-314 nM)
whereas 1,2,4-triazolo[1,5-a]quinoxaline (E) is known to be
useful as selective hA3 AR antagonists.9a
Thus combination of structural features of both 2H-indazole
and triazolo quinoxaline in
a single molecular entity
represented by F (Fig. 1) was expected to provide a new
hybrid chemical structure i.e. indazole fused triazolo[5,1-
c]quinoxalines that might lead to the identification of novel
molecules possessing pharmacological and photophysical
properties.
In modern organic synthesis, chemical reaction sequencing by
combining two or more distinct steps into
transformation, thereby producing sequential multi-
a
single
a
CH3
component reaction which is one of the most important and
H3CHN
O
NH2
O
1
economicstrategys. Fused heterocyclic framework systems are
N
CH3
CH3
H3C
N
N
N
one of the abundantly motifs in organic chemistry and have
vast applications in medicinal2 and material3 chemistry.
Among them, nitrogen-fused polycyclic compounds are widely
distributed in pharmaceutical agents and natural products.4
Therefore, continuing efforts have been devoted to explore
efficient approaches for accessing nitrogen-heterocycles.5
N
F
N
N
HN
S
N
NH
O
NH2
N
N
S
3
H C
O
H
O
O
Pazopanib vEGF inhibitor (A)
Niraparib (B)
Viral polymerase inhibitor (C)
O
N
N
N
N
N
HN
R1
N
OCH3
N
N
R
N
N
R2
O
2
H-Indazoles are the integral part of several bioactive
Ph
N
N
6
compounds for example, Pazopanib (A) is a selective multi-
Human A3 adenosine receptor
antagonist (E)
1
,2,3-Triazolo[l,5a]quinoxaline-4-
New designed molecule (F)
one (D)
targeted receptor tyrosine kinase inhibitor that blocks tumour
Fig. 1 Representative bio-active molecules (A-E) and our
designed molecule (F).
growth,
Niraparib7
(B),
that
inhibits
poly(ADP-
ribose)polymerase is useful for the potential treatment ovarian
cancer and compound C is a viral polymerase inhibitor.8
Triazoloquinoxalines, on the other hand, are considered as
One of the major goals and aim of the present work was to
develop a one-pot and robust methodology for the consturction
of fused heterocyclic framework as represented by F (Fig. 1).
CHO
R1
aDepartment of Chemistry, Osmania University, Hyderabad-500
R1
N
R1
N
N3
I
N
N
0
07, India.
N
1
N
bDepartment of Industrial and Engineering Chemistry, Institute
N
3
I
R2
N
N
of Chemical Technology, IOC-Bhubaneswar Campus,
Samantpuri, Bhubaneswar-751013, India
E-mail: shivakumarkota@yahoo.co.in; Tel: +91 40 27682337
N
R2
R2
N
NaN3
+
R1
NH2
N
F/7
6
5
4
2
Scheme 1 Strategy for the synthesis of indazole fused
triazolo[5,1-c]quinoxalines.
†
Electronic Supplementary Information (ESI) available: Experimental
procedures, spectral data for all new compounds, and copies of spectra.
CCDC 1863988. For ESI and crystallographic data in CIF and other
electronic format see DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry 20xx
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In continuation of our interest in the synthesis of fused
heterocyclic compounds,11 we envisioned that the sequential
one-pot cascade synthesis of indazole fused triazolo[5,1-
c]quinoxaline based on
iodoaniline is resulting to form 2-(2-iodophenyl)-2H-indazole,
followed by azide−alkyne cycloaddition would provide the
intermediate 2-(2-(4-phenyl-1H-1,2,3-triazol-1-yVl)iepwhAernticylel)O-2nlHine-
DOI: 10.1039/C8NJ06299D
indazole (6) with respect to catalyst, base, solvents and
temperatures. After optimization of the conditions (see the
Supporting Information for details), we found that the
combination of CuI and K CO in DMF at 120 °C under air for
2 3
2 h (see Table S1, entry 1, in the Supporting Information) is
the the best condition for the synthesis of 6a.
With these results in hand, we moved forward to study a three
1-phenylindazolo[2,3-
a][1,2,3]triazolo[5,1-c]quinoxaline (7a). Thus, the mixture of
1a and o-iodoaniline (2a) was heated at 110 °C for 40 min.
F via a o-azidoaldehyde and
1
,2,3-triazole. Later, C−N coupling between 1,2,3-triazole and
aryl iodide, finally intramolecular cross dehydrogenative C−C
coupling between 1,2,3-triazole and imidazo[1,2-a]pyridine
would afford indazole fused with triazolo[5,1-c]quinoxaline
0
1
2
3
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1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
step,
one-pot
synthesis
of
(
Scheme 1). This cascade approach would involve the
formation of three new bonds i.e. C−N, N−N and C−C,
resulting in the formation of three heterocyclic rings.
Metal-catalyzed reactions play a vital role in the synthesis of
polycyclic aromatic and heteroaromatic compounds.12
Then, 4a, 5, CuI and K
mixture was heated at 120 °C under air for 2 h to provide the
intermediate 2H-indazole (3a). To this was added Pd(OAc)
and Cu(OAc) and the resulting mixture was stirred at 120 °C
2 3
CO in DMF was added and the
2
2
Azide−alkyne
cycloaddition
(CuAAC)
followed
by
for 16 h, to afford the targeted intramolecular cross
dehydrogenative C−C coupling product 7a in 21% yield. An
improvement in the yield of 7a was observed when AcOH (2
equiv.) was used as an additive (Table 1, entry 2).
Interestingly, further increase in the amount of AcOH to 3
equiv. improved the yield of 7a to 65% (Table 1, entry 3).
However, the further increase of the AcOH (4 equiv.), did not
improve the yield of 7a (Table 1, entry 4) further. Increasing
intramolecular cyclisation has become the most efficient
method to generate the fused triazoles and is used extensively
by different groups.13-17 Kumar et al. reported copper-
catalysed tandem synthesis of 1,2,3-triazole/quinoline-fused
imidazo-[1,2-a]pyridines via azide-alkyne cycloaddition,
Ullmann-type C-N coupling, and intramolecular direct
arylation (Scheme 2a).18 Recently, Fan at al. reported the one-
pot construction of 1,2,3-triazole/quinoline-fused imidazo[1,2-
a]pyridines through azide−alkyne cycloaddition followed by
C−N coupling between 1,2,3-triazole and aryl bromide,
finally, intramolecular cross-dehydrogenative C−C coupling
between 1,2,3-triazole and imidazo[1,2-a]pyridine (Scheme
the loading of Cu(OAc)
in the yield of 7a (Table 1, entry 5) though further increase in
Cu(OAc) loading did not increase product yield (Table 1,
entry 6). When the reaction was performed under O in the
presence of 1.5 equiv of Cu(OAc) , 7a was obtained in highest
yield (71%) (Table 1, entry 7). Notably, ommission of
Cu(OAc) decreased the yield of 7a to 10% (Table 1, entry 8)
whereas use of other oxidants e.g. Cu(OTf) , CuO or Ag CO
was less effective (Table 1, entry 9–11). The use of other
additive e.g. Ac O, PivOH and PhCOOH (Table 1, entry 12-
14) was also examined but found to be less effective.
Furthermore, the use of other catalysts, e.g. PdCl (PPh and
Pd (dba) afforded the product 7a but in low yield (Table 1,
2
up to 1.5 equiv provided an increase
2
2
2
2
b).19 While the above methods are effective, but they require
synthetically challenging starting meterials. Moreover, this
strategy has not been explored for the synthesis of indazole
fused triazolo[5,1-c]quinoxalines. We, therefore, decided to
develop a practical and one-pot method for the synthesis of
indazole fused triazolo[5,1-c]quinoxaline derivatives starting
2
2
2
3
2
from commercially available simple materials.
2
3 2
)
Previous work
2
3
(
a) Ref 15
N
N
CuCl2.2H2O,
K CO
entries 15–16). The use of a lower quantity of Pd-catalyst
decreased the product yield (Table 1, entry 17). The lowering
or increasing the reaction temperature or time was also found
to be less effective (Table 1, entry 18–20).
N
N
N
2
3
N
R
NaN3
N
DMF, 150 o
N
N
C
Br
N
Br Br
N
N
R
N
R
i) CuI, K2CO3
(b) Ref 16
N
o
N
DMF, 120 C
a
N
N
Table 1 Optimization of the reaction conditions.
Air, 6 h
N
R
NaN3
ii) Pd(OAc)2
Cu(OAc)2
N
CHO
N
N
Br
N
110 oC,
40 min
NaN3 5
Ph
N
N
AcOH, 120 o
C
R
N
N3
I
R
N
N
1
2
N
N
4
Air, 7 h
N
Pd Catalyst
This work
N
CuI, DMF
120 oC, 2 h
N
Oxidant
additive
120 oC, 16 h
CHO
N3
I
Ph
N
Ph
N
R1
N
N
NH2
3a
10 oC,
0 min
N
R1
4
6a
1
7a
N
1
2
4
N
1.
R2 NaN3
5
N
N
I
2. Pd catalyst
R1
I
R2
N
Oxidant
(equiv)
Additive
(equiv)
%
Yieldb
N
7
NH2
3
Entry
Catalyst
one-pot four component reaction
1
2
3
4
5
6
7
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
(1)
(1)
(1)
(1)
(1.5)
(2.0)
(1.5),
-
21
AcOH (2)
AcOH (3)
AcOH (4)
AcOH (3)
AcOH (3)
AcOH (3)
48
65
62
68
65
71
Scheme 2 Synthetic strategies towards the fused heterocycles
via cascade azide−alkyne cycloaddition, C−N Coupling
followed by intramolecular cyclisation.
2
2
2
Initially, we heated the o-azido aldehyde (1a) at 110 °C with o-
iodoaniline (2a) to provide the intermediate 2H-indazole (3a)
with satisfactory yields.20 We next screened the synthesis of
Cu(OAc)
2
O
2
2
| J. Name., 2012, 00, 1-3
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Pd(OAc)
Pd(OAc)
2
2
O
2
AcOH (3)
AcOH (3)
10
56
terminal alkyne 4 afforded intermediate C via B.VieFwolAlroticwleeOdnlbinye
DOI: 10.1039/C8NJ06299D
C−N coupling between the triazole (C) and 2H-
Cu(OTf)
2
(1.5),
O
2
Table 2 One-pot synthesis of indazole fused triazolo[5,1-
c]quinoxalines (7) via sequential cascade reactions
1
1
1
0
1
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
CuO (1.5), O
Ag CO (1.5), O
Cu(OAc)
2
AcOH (3)
AcOH (3)
Ac O (3)
2
57
55
28
2
3
2
CHO
R1
2
2
2
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
(1.5),
NaN3 5
N
R1
10 o
R1
1
C
N
N3
I
N
O
2
1
40 min
N
R2
4
Pd(OAc)2
Cu(OAc)2
N
N
N
1
1
1
1
3
4
5
6
Pd(OAc)
Pd(OAc)
2
2
Cu(OAc)
PivOH
(3)
PhCOOH
(3)
55
38
48
45
37
62
68
62
67
CuI, DMF
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
AcOH, O2
120 oC, 16 h
I
20 oC, 2 h
R2
N
1
R2
N
N
N
O
2
R1
NH2
N
2
3
6
7
Cu(OAc)
O
2
N
N
N
N
N
PdCl
2
(PP
Cu(OAc)
2
AcOH (3)
h
3
)
2
O
2
N
N
N
N
N
N
N
N
3
H CO
N
Pd
2
(dba)
3
Cu(OAc)
2
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
H C
3
O
2
7b (68%)
7c (68%)
7a (71%)
1
1
1
7c
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
Cu(OAc)
2
2
2
2
2
N
N
N
N
N
N
O
2
N
N
N
N
8d
Cu(OAc)
N
H C(H C)
H C(H C)
4
N
3
2
3
3
2
N
N
N
N
O
2
7
e (62%)
7f (68%)
9e
7d (65%)
Cu(OAc)
O
2
N
N
N
N
N
N
9f
0g
Cu(OAc)
CH3
CH3
1
N
N
O
2
N
H3C(H2C)5
N
N
N
N
N
N
2
Cu(OAc)
CH3
7
g (67%)
O
2
7h (70%)
7i (66%)
aReaction conditions: 1a (0.67 mmol) and 2a (0.67 mmol) was
heated at 110 °C, 40 min, and then added 4a (0.67 mmol), 5 (0.67
mmol), CuI (10 mol%), K CO (0.81 mmol), DMF (3 mL) and
2 3
heated for , air, 2 h under air followed by addition of Pd catalyst
N
N
N
N
N
N
CH3
CH3
CH3
N
N
N
N
N
H3C(H2C)3
N
N
N
H3C(H2C)4
N
N
7
k (65%)
7
l (68%)
o
(
10 mol %), oxidant, additive and heating at 120 C for 16 h.
Isolated yields. 5 mol % of Pd(OAc)
7j (65%)
b
c
d
N
H3C
H3C
N
N
2
was used. The reaction
N
CH3
N
N
o
e
o
CH3
CH3
was carried out at 100 C. The reaction was carried out at 140 C.
N
N
f
g
N
N
The reaction was stirred for 12 h. The reaction was stirred for 18
H3C(H2C)5
N
N
N
N
N
h.
7m (68%)
3
H C
The substrate scope and generality of the present three step,
one–pot cascade reaction was assessed by synthesizing a large
number of indazole fused triazolo[5,1-c]quinoxaline
derivatives (7) (Table 2). Variously substituted terminal
acetylenes (3a–g) smoothly reacted under the optimized
conditions to give desired indazole fused triazolo[5,1-
c]quinoxalines in good yields. For example, aryl (4a–c) and
heteroaryl (4d) substituents on the triple bond participated well
in the reaction. Aliphatic alkynes (4e–4g) also efficiently
participated in cascade reaction to give the corresponding
indazole fused triazolo[5,1-c]quinoxalines. Similarly, various
substituted iodoanilines (2b-d) containing a methyl and fluro
on the aryl ring gave the corresponding indazole fused
triazolo[5,1-c]quinoxalines (7h–7v) in good yields. The
7o (60%)
7n (65%)
H3C
N
N
H3C
H3C
N
N
CH3
N
CH3
N
CH3
N
N
N
N
N
N
N
H3C(H2C)3
H3C(H2C)4
H3CO
N
N
7
q (65%)
7r (62%)
7p (65%)
H3C
N
N
N
N
F
F
N
N
CH3
N
N
N
N
N
N
N
N
3
H C
H3C(H2C)5
N
7u (62%)
7
t (61%)
7
s (60%)
N
N
N
N
F
F
N
N
N
H3C(H2C)3
N
H3C(H2C)4
N
N
molecular structures of 7q was confirmed by the single-crystal
X-ray data analysis (Fig. 2).21
7v (62%)
7w (65%)
aReaction conditions: 1a (0.67 mmol) and 2a (0.67 mmol) was
heated at 110 °C, 40 min, and then added 4a (0.67 mmol), 5 (0.67
On the basis of these results and the literature precedents,19-20
a
tentative mechanism is proposed in Scheme 3. First, the o-azido
aldehyde 1 reacts with amine 2 to give an imine intermediate A,
followed by a subsequent intramolecular cyclization in
the formation of 2H-indazole 3. In the first catalytic cycle, Cu(I)
catalyzed azide−alkyne cycloaddition between the azide 5 and
mmol), CuI (10 mol%), K
heated for 2 h under air followed by addition of Pd catalyst (10
mol %), Cu(OAc) (1.01 mmol), AcOH (2.03 mmol) and heated at
120 C for 16 hunder O
. bIsolated yields.
2 3
CO (0.81 mmol), DMF (3 mL) and
2
o
2
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[
02(0234)/15/EMR-II], New Delhi and OU-DST-VPieEwRASrtiEcle-IOInflioner
funding this project. B. R. thanks UGDCOI,: 1N0.e1w039D/Ce8lNhJi,06f2o9r9Da
Senior Research Fellowship.
Conflicts of interest
The authors confirm that this article content has no conflict of
interest.
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Notes and references
1
.
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Fig. 2 X-ray crystal structure of 7q (ORTEP diagram). Thermal
ellipsoids are drawn at the 50% probability level.
Indazole 3 results in the formation of the key intermediate triazol-
2
.
1
-yl)phenyl)-2H-indazole (6). In the second catalytic cycle,
electrophilic palladiation occurs at C3-position of indazole that
results in the formation of intermediate D. Further electrophilic
palladation of trizole occurs to form seven-membered palladacycle
intermediate E, which on reductive elimination generates the
indazole fused triazolo[5,1-c]quinoxalines (7) together with Pd(0).
Finally, palladium acetate was regenerated from Pd(0) under
oxidant to complete the catalytic cycle.
3. (a) A. R. Katritzky, D. O. Tymoshenko, D. Monteux, V.
Vvedensky, G. Nikonov, C. B. Cooper, and M.
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O
H
N3
H
Cu
Cu
N
1
I
N
N
N
B
N
Ph
NH2
N
C
2
Ph
I
I
R
4
Cu(I)
+
N
NaN3 5
N
N
N
N
N
N
Pd(OAc)2
3
N
A
N
Pd(II)
Oxidant
5. (a) A. H. Bansode, A. C. Shaikh, R. D. Kavthe, S.
Thorat, R. G. Gonnade and N. T. Patil, Chem. – Eur. J.,
Ph
N
N
6
2
015, 21, 2319; (b) N. T. Patil, V. S. Shinde and B.
Sridhar, Angew. Chem., Int. Ed., 2013, 52, 2251.
S. V. Keisner and S. R. Shah, Drugs 2011, 71, 443.
N
Pd(0
)
N
6
.
(
II)Pd
N
7
Ph
D
N
N
N
7. P. Jones, S. Altamura, J. Boueres, F. Ferrigno, M. Fonsi,
C. Giomini, S. Lamartina, E. Monteagudo, J. M.
Ontoria, M. V. Orsale, M. C. Palumbi, S. Pesci, G.
Roscilli, R. Scarpelli, C. Schultz-Fademrecht, C.
Toniatti and M. Rowley, J. Med. Chem., 2009, 52, 7170.
8. R. Halim, M. Harding, R. Hufton, C. J. Morton, S.
Jahangiri, B. R. Pool, T. P. Jeynes, A. G. Draffan,M. J.
N
Pd
Ph
N
N
N
E
Scheme 3 Plausible mechanism.
Lilly
and
B.
Frey,
PCT
Int.
In conclusion, we have demonstrated a facile and efficient route
for the synthesis of diverse indazole fused triazolo[5,1-
c]quinoxalines through one-pot sequential cascade reaction of o-
azido aldehyde, o-iodoaniline, phenylacetylene and sodium azide.
The reaction proceeds via 2H-indazole formation, azide–alkyne
cycloaddition followed by C−N coupling and intramolecular cross
dehydrogenative C−C coupling. Overall, we have reported
synthesis of privileged fused heterocyclic compounds from simple
starting meterials.
Appl,WO2012051659A120120426, 2012.
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Alessi, B. Tarus, S. Quideau, B. Riteau and A. S. -
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A. K. Taggart, E. Carballo-Jane, N. Ren, T.-Q. Cai, T. -
J. Wu, K. K. Wu, K. Cheng, Q. Chen, M. S. Wolff, X.
Tong, T. G. Holt, M. G. Waters, M. L. Hammond, J. R.
KSK thanks the University Grants Commission (UGC), New
Delhi, for a faculty position under FRP. We also thank CSIR
4
| J. Name., 2012, 00, 1-3
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Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Journal Name
COMMUNICATION
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1. Crystal data of (7q): CCDC 1863988, Single crystals
suitable for X-ray diffraction of 7q DCM: EtOAc (1:1).
Molecular formula = C21
43.43, Crystal system = Monoclinic, space group = 2/c,
a = 12.2671(5)Å, b = 18.1570(8)Å, c = 15.9123(7)Å, V
3523.8(3)Å3, T = 100(2) K, Z = 8, Dc = 1.295
21 5
H N , Formula weight =
3
=
Mg/m3, 54074 Reflections collected, 4570 unique
reflections (R(int) = 0.0669).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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New Journal of Chemistry
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View Article Online
DOI: 10.1039/C8NJ06299D
GRAPHICAL ABSTRACT
An efficient four component, three-step cascade synthesis of indazole fused triazolo[5,1-
c]quinoxalines has been described. Notable features of this protocol include simple starting
materials, reduced synthetic steps and good yields.
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CHO
o
1
. 110 C, 40 min
R1
N
R2 NaN3
2
.
N3
N
o
CuI, DMF, 120 C, 2 h
I
N
3
. Pd(OAc) Cu(OAc)
2,
2
R2
N
o
AcOH, O , 120 C, 16 h
N
2
R1
NH2
one-pot four component reaction