Convenient synthesis of quinoline-fused triazolo-azepine/oxepine derivatives through Pd-catalyzed C-H functionalisation of triazoles

Article abstract of DOI:10.1039/c9nj05254b

The efficient and convenient synthesis of a new fused heterocyclic scaffold comprising three different heterocycles, viz., quinolines, azepines/oxepines and triazoles is reported from quinoline-tethered triazoles. The quinoline-tethered triazoles were eas

Full text of DOI:10.1039/c9nj05254b

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A convenient synthesis of quinoline fused triazolo-azepine/oxepine derivatives
‡
through Pd-catalyzed C-H functionalisation of triazoles
Kukkamudi Mahesh, Kanakaraju Ravi, Praveen Kumar Rathod and Panaganti Leelavathi*
a
a
a
,a
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and convenient synthesis of new fused heterocyclic scaffold comprising three different heterocycles viz.
quinoline,azepine/oxepine and triazoleis reported from quinoline tethered triazoles. The quinoline tethered triazoles were
easily obtained in three steps from 2-chloro-3-formylquinolines,that is, reductive amination with benzyl amines, N-
propargylation followed by ‘click’ reaction under standard conditions. For the first time, we present quinoline fused
triazolo-azepines in good to high yields by palladium-catalysed C-H functionalisation at C-5position of triazole moiety. The
protocol readily extended even to the construction of quinoline fused triazolo-oxepines from (2-chloroquinolin-3-
yl)methanol through the similar sequence,that is, O-propargylation,click reaction and palladium catalysedC-H
functionalisation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
motif constitute an privileged class of compounds for new
drug development. Therefore, development of new and
efficient methodologies to access these molecules of medicinal
Introduction
Fused heterocycles are structurally important motifs and
represent one of the abundant classes in organic chemistry
which have extensive applications in medicinal and material
chemistry. Especially, nitrogen-fused polycyclic compounds
utility have attracted much of the attention. In view of this it
was planned to synthesise some new chemical entities
incorporating the three active pharmacophores, that is,
quinoline, azepine/oxepine and triazole in a single molecular
framework. To the best of our knowledge, quinoline fused
triazolo-azepine/oxepine scaffolds have not been reported.
Hence an attempt was made towards the synthesis of
quinoline fused triazolo-azepine/oxepines via palladium-
catalysed C-H functionalisation of triazoles.
1
2
are widely distributed in natural products and pharmaceutical
agents. Among nitrogen heterocycles, quinoline moiety is a
3
privileged scaffold that appears in numerous natural products
and widely exploited heterocyclic ring for the development of
bioactive molecules. Recent reports are enriched with
progressive findings about the synthesis and pharmacological
actions of quinoline and its derivatives. Triazoles are another
4
5
6
N
important five-member nitrogen heterocycles, which have
N
N
R1
N
N
N
N
attracted much of the attention due to their excellent stability,
ready accessibility and variety of applications in organic
R2
R3
H
N
N
N
O
7
8
9
OH
chemistry, medicinal chemistry and functional materials.
R4
C4H9
O
10
11
Antidepressant
HIV protease inhibitor
Bronchodilator
Azepines and oxepines represent yet another class of
heterocycles that have vast applications in medicinal chemistry
and their activities are generally imparted when they are fused
R1
R2
O
O
12
F
with other molecular scaffolds.
Cl
R3
Synthesis of fused heterocyclic compounds through the
combination of different pharmacophores in a molecular
framework is of considerable interest due to a wide variety of
such molecules showing promising biological activities (Figure
N
O
R4
N
H
Steroidal mineralocorticoid receptor
(MR) antagonist
Antifungal
13
Figure 1. Representative bioactive azepine/oxepine fused heterocycles.
1
). Particularly, the hybrid compounds containing quinoline
According to the retrosynthetic analysis as shown in Scheme 1,
we envisioned that the target compounds (I) could be easily
obtained through C-H functionalisation of corresponding
triazoles (II), which can be constructed from N/O-propargyl
derivatives (III) by click reaction with azides. The propargyl
derivatives (III) are disconnected to anticipated analogues (IV),
a
Department of Chemistry, University College of Science, Osmania University,
Hyderabad 500 007, India. E-mail: leelaou@gmail.com
Electronic Supplementary Information (ESI) available: General experimental
procedures, spectroscopic data and NMR spectra for all compounds See
DOI: 10.1039/x0xx00000x
‡
This journal is © The Royal Society of Chemistry 20xx
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which are obtained in turn from 2-chloro-3-formyl quinolines As a model reaction, we attempted the synthesis of trazolo-
View Article Online
DOI: 10.1039/C9NJ05254B
azepino quinoline (6a). The intramolecular cyclisation of
10 mol% Pd(OAc) ,
2
triphenylphosphine (20 mol%) and potassium carbonate (2
(V) via reduction/reductive amination.
1
9a
quinoline tethered triazole (4a) with
X
Pd(OAc)2
X
'click' reaction
X
C-H activation
o
R1
N
R1
N
Cl
N
equiv.) in DMF at 130 C under nitrogen atmosphere for 35 h
R1
N
III
Cl
I
N
N
II
N
R2
N
N
R2
furnished the quinoline fused heterocyclic system (6a) as
shown in Scheme 3. The reaction is found to be clean and
afforded the desired product in 73% yield and was confirmed
by the disappearance of characteristic singlet for triazole
X = O, NR3
propargylation
O
XH
0
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H
reduction/
reductive amination
R1
N
Cl
R1
N
Cl
IV
V
1
proton at δ 7.79 ppm in the H-NMR spectrum of cyclised
Scheme 1. Retrosynthetic analysis of quinoline fused triazolo-azepine/oxepines.
product (6a).
Interestingly, C-H functionalisation14 is one of the most
powerful tools in the C-C or C-heteroatom (C-O, N, S, etc.)
bond formation and considered as viable strategy for the
synthesis of complex targets. Transition metal mediated C–H
functionalisation15 represents a paradigm shift from the
regular methods of organic synthesis as metal-catalysed C-H
functionalisation allows the step-economical and unusual
construction of C-C as well as C-O and C-N bonds without the
need of prior non catalytic oxidation steps. Following our
interest16 in synthesis of heterocyclic compounds containing
quinoline moiety, we herein report an efficient approach
towards the synthesis of quinolines containing fused 1,2,3-
triazolo-azepine/oxepine motifs via C-H functionalisation at C-
N
Ph
N
Ph
N
Pd(OAc) , PPh
3
2
N
Cl
N
K2CO3, DMF, 130 o
73%
C
4a
N
N
N
N
N
6a
Cl
Cl
Scheme 3. Synthesis of[1,2,3]triazolo[4',5':5,6]azepino[4,3-b]quinoline (6a)
Encouraged by the result, our next attempt was to establish the
best reaction conditions for the synthesis of title compound 6a.
Several reaction conditions were performed as summarized in Table
1. By changing the solvent from DMF to toluene, the yield of the
desired product decreased drastically, but changing to DMSO
resulted in marginal increase in the product (entries 1-3). The
product 6a yield (86%) was substantially improved by the use of
5
position of triazole moiety.
Cs
2
CO
3
instead of K
2 3
CO (entry 4). Decreasing the catalytic load of
10% to 5%, lowered the yield of the product (entry 5).
Results and discussion
The required triazole precursors (4) for the synthesis of
trazolo-azepino quinolines were prepared as shown in Scheme
Pd(OAc)
2
Table 1. Optimisation of the reaction conditions for the synthesis of 6a.
Ph
1
7
N
Ph
N
N
2
. Readily available 2-chloro-3-formyl quinoline (1) was
subjected to reductive amination with N-arylalkyl amine in the
presence of NaBH
by adapting literature procedure.18 The
resulting secondary amine was treated with propargyl
bromide/K CO in DMF at room temperature for 15 h to afford
the desired N-propargyl product (2) in 90 % yield. The 2 was Entry
N
Cl
Reaction Conditions
N
N
4a
N
N
N
6a
N
4
Cl
Cl
2
3
Reaction conditions
Time(h)
35
Yield(%)
73
subjected to CuACC reaction with aryl/benzyl azides under the
standard procedure, which afforded the corresponding triazole
1
2
3
4
5
6
7
8
9
Pd(OAc)
(
2
(10 mol%), PPh
3
(20 mol%), K
3
(20 mol%), K
3
(20 mol%), K
2
2
2
CO
CO
CO
3
3
3
2 eq), DMF, 130 oC
Pd(OAc)
2
(10 mol%), PPh
40
35
30
35
30
30
30
35
30
45
77
86
65
60
70
54
48
76
(
4) in 87% yield. Similarly the triazole precursors (5) were
prepared by reduction of (1) with NaBH and then
propargylation under PTC conditions to yield the O-
(2 eq), Toluene, reflux
4
2
Pd(OAc) (10 mol%), PPh
2 eq), DMSO, 130 oC
(
propargylated derivatives (3) followed by CuACC reaction. The
click products 4 and 5 were taken directly for the next
investigation without any further purification.
Pd(OAc)
Cs CO
(2 eq), DMF, 130oC
Pd(OAc)
2
(10mol%), PPh
3
(20 mol%),
CO
(20 mol%),
2
3
2
(5 mol%), PPh
3
(10 mol%), Cs
2
3
o
O
( 2 eq), DMF, 130 C
2
NR2
Pd(OAc)
NaOAc ( 2 eq), DMF, 130 C
2
(10 mol%), PPh
3
H
i. R -NH , NaBH4
2
o
ii. Propargyl bromide
R1
N
Cl
R1
N
Cl
DMF, K2CO3, rt
2
Pd(OAc)
(2 eq), DMF, 130
2
(10 mol%), PPh
3
(20 mol%), KOAc
CO (2 eq), DMF,
(10 mol%), CuI (20 mol%), K CO
1
CuSO4.5H2O
R -N3 Na-ascorbate
DMF, rt
0
C
i. NaBH4/MeOH
ii. Propargyl bromide
NaH, TEAB, DMF, rt
3
Pd(OAc)
1
2
(10 mol%), Cs
2
3
30 oC
3
X
Pd(OAc)
2
2
3
O
R -N3
o
CuSO4.5H2O
Na-ascorbate
DMF, rt
( 2 eq), DMF, 130 C
Pd(OAc) (10 mol%), 1, 10-phen(20 mol%),
R1
N
Cl
N
R1
N
Cl
: X = NR2
N
10
4
2
3
N
5: X= O
Cs CO (2 eq), DMF, 130 C
o
R3
2
3
a
Scheme 2. Synthesis of quinoline tethered triazoles.
All reactions were performed on 0.25 mmol in 3 mL of solvent and isolated
yields are after purification.
2
| J. Name., 2012, 00, 1-3
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reaction under Ackermann19b and Kumaraswamy20 procedures,
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DOI: 10.1039/C9NJ05254B
The use of bases like NaOAc and KOAc has not much effect on the
but unfortunately we could not succeed in getting the final
yield of final product (entries 6,7). Carrying the reaction without product (6a) and ended up only with click product (4a). Thus,
triphenyl phosphine or using CuI in place of it, reduced the product we decided to continue with the conventional method of
yield(entries 8,9). Changing the ligand triphenyl phosphine to 1,10 synthesising target compounds via the triazole intermediate.
phenanthroline (entry 10) did not increase the efficiency of the With the required click products (4a-m) for cyclisation in hand,
reaction.
we proceeded for the intramolecular Pd-catalyzed C-H
functionalisation under the optimised conditions (Table 1;
entry 4).
0
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Table 2. Scope of Pd-catalysed synthesis of triazolo azepine fused quinolines
a,b
(6a-m).
Inspired by the above results, we examined the scope of the
method by using a diverse range of substrates (Table 2). The
substrates with substituents like methyl and methoxy on the
quinoline moiety, fluoro and methoxy in amine part reacted
smoothly to give the products in good yields. The presence of
electron releasing groups like methyl, methoxy and electron
withdrawing groups like fluorine and chlorine in azide did not
affect the yields under the optimised conditions. Interestingly
the reaction was found to be clean and proceeded well with all
the range of substituents without much effect on reaction rate
of the transformation.
Ar
N
Ar
N
N
Pd(OAc)2, Cs2CO3
N
Cl
PPh , DMF, 130 oC, 30h
3
N
4
N
6
N
N
N
R
N
R
________________________________________________
N
N
N
Cl
N
N
N
R
N
N
N
R
N
6a: R= 4-ClC6H4;86%
b: R= 4-MeC6H4;83%
c: R= 4-OMeC6H4;85%
4
4
4
a: R= 4-ClC6H4; 87%
b: R= 4-MeC6H4; 85%
c: R= 4-OMeC6H4; 84%
6
6
Table 3. Pd catalysed synthesis of triazolo-oxepine fused quinolines (7a-h).a,b
O
O
F
N
Pd(OAc)2, Cs2CO3
PPh3, DMF, 130 oC, 30 h
N
N
N
Cl
N
N
N
Cl
N
F
N
5
N
N
7
N
N
N
R
N
N
R
N
R
N
R
________________________________________
6
6
d: R= C6H5; 80%
4d: R= C6H5; 82%
O
e: R= 4--FC6H4;90%
6f: R= 2-ClC6H4; 78%
N
O
4
4
e: R= 4--FC6H4;85%
f: R= 2-ClC6H4; 80%
N
N
N
N
Cl
Me
R
N
N
O
R
N
N
N
Me
5
5
a: R= 2-ClC H ; 81%
7a: R= 2-ClC6H4; 75%
7b: R=4-ClC6H4; 84%
N
Cl
N
O
N
6 4
b: R=4-ClC H ; 85%
N
N
N
6 4
7
c: R=4-MeC H ; 86%
N
R
N
5c: R=4-MeC6H4; 88%
6
4
R
4
4
g: R= 4-ClC6H4;86%
h: R= 4-MeC6H4; 86%
6 4
6g: R= 4-ClC H ; 85%
6h: R= 4-MeC H ; 84%
Me
N
Me
O
O
6
4
N
N
N
Cl
N
R
Me
Me
N
N
N
N
N
R
N
Cl
N
N
5
d: R=C H CH ; 76%
7d: R=C H CH ; 80%
6 5 2
6
5
2
N
N
N
N
R
N
O
R
N
O
6
i: R= 2-MeC6H4; 82%
6j: R= 3-MeC6H4; 82%
k; R= 4-ClC6H4: 88%
N
4
4
4
i: R= 2-MeC6H4; 83%
j: R= 3-MeC6H4; 84%
k: R= 4-ClC6H4: 86%
N
Me
N
Cl
Me
N
6
R
N
N
Me
R
N
Me
N
O
5e: R= C H ; 82%
6 5
Me
N
7e: R= C H ; 80%
6 5
5f: R=2-MeC H ; 80%
6
4
Me
7f: R=2-MeC6H4; 80%
7g: R=4-ClC H ; 85%
N
Cl
N
O
N
5g: R=4-ClC H ; 86%
6 4
N
N
6
4
N
R
N
N
O
O
O
N
Me
R
Me
O
N
4
4
l: R= 3-MeC6H4; 84%
m: R= 4-ClC6H4: 88 %
6
l: R= 3-MeC6H4; 81%
6m : R= 4-ClC6H4: 82%
N
N
N
Cl
N
R
N
R
N
5
h: R=4-MeC H ; 80%
7h: R=4-MeC6H4; 82%
6
4
a
Reaction conditions: All reactions are carried out for 4 (0.25 mmol), Pd(OAc)
2
(10
b
a
mol%), PPh
3
(20 mol%), Cs
2
CO
3
(2 equiv.), DMF (3 mL). Isolated yields are after
Reaction conditions: All reactions are carried out for 5 ( 0.25 mmol), Pd(OAc)
2
b
purification by column chromatography.
(10 mol%), PPh (20 mol%), Cs CO ( 2 equiv.), DMF (3 mL). Isolated yields are
3
2
3
after purification by column chromatography.
Our next effort was to explore the possibility of getting the
target compound (6a) from N-propargyl derivative (2a)
involving click reaction and C-H activation in on one pot or
Having prepared the triazolo azepino-quinolines (6a-m)
successfully, our next efforts was to generate oxepine analogues.
sequential one-pot synthesis. For which we performed the The method was extended successfully to the synthesis of triazolo-
This journal is © The Royal Society of Chemistry 20xx
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oxepine fused quinolines (7a-h) via the Pd-catalysed cyclisation of and extracted with EtOAc (2 x20 mL).The combined organic
View Article Online
5
a-h under the optimised conditions. The anticipated triazolo- layer was dried over anhydrous Na2S
D
O
OI
4
,
: 1
f
0
i
.
l
1
t
0
e
3
r
9
e
/
d
C9NanJ0
d
52
the
5
4B
oxepine fused quinolines (7a-h) afforded in 75-86% yields. The solvent was removed under reduced pressure. The crude
formation of these products is confirmed from H-NMR spectra by product was purified by silica gel column chromatography
the absence of triazole proton signal at δ ~8.0 ppm.
1
(
eluted with 10% hexane/EtOAc) to afford the title
compounds.
-Benzyl-1-(4-chlorophenyl)-1,4,5,6-tetrahydro[1,2,3]triazolo
4',5':5,6]azepino[4,3-b]quinoline (6a): Light brownsolid, yield:
4 mg, 86%; m.p. 118-120 C; H NMR (400 MHz, CDCl ): δ
3
.70 – 7.62 (m, 2H), 7.60 (dd, J = 8.2, 7.0 Hz, 1H 7.51-7.46 (m,
H), 7.44 – 7.37 (m, 3H), 7.30 -7.26 (m, 3H), 7.24-7.22 (m,
H).4.53 (s, 2H), 4.12 (s, 2H), 3.77(s, 2H); C NMR (101 MHz,
): δ 146.2, 146.0, 145.9, 138.1, 138.1, 136.6, 134.7,
32.3, 131.6, 129.9, 129.0, 128.9 (2C), 128.7 (2C), 128.5 (2C),
28.1 (2C), 127.5( 2C), 127.2, 127.0, 59.1, 56.7, 54.1; HRMS
Based on the literature precedents,19a,21 we proposed a plausible
mechanism as shown in Scheme 4. The suggested mechanism
consists of initial oxidative addition of 4/5 to a palladium(0) catalyst
to form the intermediate, aryl palladium species (A). In next step
may involves electrophilic aromatic substitution of the intermediate
A with triazole ring to generate a cationic intermediate (B).
Subsequent deprotonation gives (C) and final reductive elimination
results in desired product 6/7 and regeneration of the active
5
[
9
7
3
2
CDCl
1
1
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
o
1
1
3
3
palladium(0) catalyst.
+
(ESI) calculated for C26
H
20ClN
5
[M+H] m/z 438.1485; found
4
38.1485.
Pd(OAc)2 + Ph3P
X
X
5-Benzyl-1-(p-tolyl)-1,4,5,6-tetrahydro[1,2,3]triazolo[4',5':5,6]
N
N
6/7
Pd(0)Ln
N
Cl
azepino[4,3-b]quinoline(6b):
N
N
N
4/5
R
N
(L = Ph3P)
N
Light orange solid, yield: 86 mg, 83% ; m.p. 110-112oC; 1H
R
oxidative
addition
NMR (400 MHz, CDCl
1H), 7.51-7.48 (m, 1H), 7.45–7.31 (m,3H), 7.33 – 7.17 (m, 7H),
.52 (s, 2H), 4.11 (s, 2H), 3.78 (s, 2H), 2.50(s, 3H); (101 MHz,
3
): δ 7.70- 7.67 (m, 2H), 7.59–7.52 (m,
Reductive
elimination
4
X
L
X
N
N
CDCl3): δ 146.4, 146.3, 145.8, 138.8, 138.3, 137.1, 136.5,
132.2, 131.6, 129.6, 129.2, 129.1(2C), 129.0(2C), 128.5 (2C),
27.5, 127.3, 127.1, 127.0, 126.5 (2C), 59.2, 56.7, 54.0, 21.5;
N
Pd-Cl
L
N
(A)
N
N
N
Pd
(
C)
N
R
1
R
+
HRMS (ESI) calculated for C27
4
H
23
N
5
[M+H] m/z 418.2032; found
Cs2CO3 H+ Br-
18.2021.
X
H
N
5-Benzyl-1-(4-methoxyphenyl)-1,4,5,6-tetrahydro-
Cs2CO3
N
N
Pd
N
[1,2,3]triazolo[4',5':5,6]azepino[4,3-b] quinoline (6c): Light
(B)
HCl
R
o
1
brown solid, yield: 92 mg, 85% ; m.p. 121-123 C; H NMR
400 MHz, CDCl ): δ 7.69 – 7.64 (m, 1H), 7.64 (s, 1H), 7.60 –
.53 (m, 1H), 7.51 – 7.44 (m, 1H), 7.44 – 7.37 (m, 3H), δ 7.31 –
.26 (m, 3H), 7.24-7.22 (m, 2H), 7.00 (d, J = 9.0 Hz, 2H), 4.52 (s,
Scheme 4. Proposed reaction mechanism.
(
3
7
7
2
CDCl
1
1
Conclusions
1
3
H), 4.10 (s, 2H), 3.91 (s, 3H), 3.77 (s, 2H); C NMR (101 MHz,
): δ 160.0, 146.4, 146.3, 145.8, 138.3, 136.5, 132.6,
32.3, 131.6, 129.7, 129.3, 129.0(2C), 128.5(2C), 128.0(2C),
We disclose hitherto unreported polycyclic fused system
containing quinoline, azepine/oxepine and triazole moieties. A
simple and efficient methodology from 2-chloro-3-formyl
quinolines via reductive amination/reduction followed by N/O-
propargylation, click reaction and finally intramolecular
cyclisation via Pd catalysed C-H functionalisation. The
operational simplicity of the method, high purity of the
products, and isolation of products up to triazoles without
chromatographic purification, and in high yields, makes this
approach attractive for the preparation of a new scaffold that
is quinoline annulated triazolo-azepine/oxepine.
3
27.5, 127.3, 127.1, 127.0, 113.7 (2C), 59.2, 56.7, 55.8, 54.1;
+
HRMS (ESI) calculated for C27
found 434.1981.
5
[
H
23
N
5
O[M+H] m/z 434.1981;
-(4-Fluorobenzyl)-1-phenyl-1,4,5,6-tetrahydro-[1,2,3]triazolo
4',5':5,6]azepino[4,3-b] quinoline (6d): Light orange solid,
o
1
yield: 84 mg, 80% ; m.p. 117-118 C; H NMR (400 MHz,
CDCl ): δ 7.66 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.55 – 7.43 (m,
H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.7, 5.5 Hz, 2H), 6.98
3
7
(
1
3
t, J = 8.7 Hz, 2H), 4.52 (s, 2H), 4.11 (s, 2H), 3.72 (s, 2H);
C
3
NMR (101 MHz, CDCl ): δ 162.2 (d, J = 245.3 Hz)146.31, 146.1,
45.7, 139.6, 136.5, 134.0(d, J = 3.1Hz, ) , 132.3, 131.4, 130.4
d, J = 7.9 Hz, 2C) 129.7, 129.1, 128.9, 128.6 (2C), 127.4, 127.1,
26.9, 126.8 (2C), 115.3 (d, J = 21.3 Hz, 2C)., 58.2, 56.6, 54.0;
[M+H] m/z422.1781; found
22.1781.
-(4-Fluorobenzyl)-1-(4-fluorophenyl)-1,4,5,6-tetrahydro-
Experimental
General procedure for the preparation of 5-arylalkyl-1-aryl-
1,4,5,6-tetrahydro[1,2,3] triazolo [4',5':5,6] azepino[4,3-
b]quinolines (6a-m): To
chloroquinolin-3-yl)-N-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-
methanamines (4a, 0.25 mmol) in DMF (3mL) was added
2
Pd(OAc) (5.6 mg, 0.025 mmol, 10 mol%), triphenylphosphine
(13.0 mg, 0.05 mmol, 20 mol%), and then cesium carbonate
(162.0 mg, 0.5 mmol) were added. The reaction mixture was
heated with stirring at 130 C for 25h. After completion of the
1
(
1
the
solution N-aralkyl-1-(2-
+
HRMS (ESI) calculated forC26
4
5
[
H20FN
5
1,2,3] triazolo[4',5':5,6] azepino [4,3-b]quinoline (6e): Light
o
1
brown solid, yield: 99 mg, 90% ; m.p. 145-147 C; H NMR
o
(400 MHz, CDCl ): δ 7.67 (dd, J = 8.1, 1.0 Hz, 1H), 7.63 (s, 1H),
.61 – 7.53 (m, 1H), 7.52-7.47 (m, 1H), 7.47-7.43 (m, 2H), 7.38
3
7
reaction monitored by TLC , the reaction mixture was cooled
4
| J. Name., 2012, 00, 1-3
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Please do not adjust margins

Page 5 of 8
Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(d, J = 8.4 Hz, 1H), 7.22 – 7.16 (m 4H), 6.98 (t, J = 8.7 Hz, 2H), CDCl
3
) : δ 7.59 (s, 1H), 7.43 (s, 1H), 7.38-7.36 (m, 3H), 7.34 –
View Article Online
1
3
DOI: 10.1039/C9NJ05254B
4
.52 (s, 2H), 4.10 (s, 2H), 3.73 (s, 2H); C NMR (101 MHz, 7.26 (m, 7H), 7.20 (s, 1H), 4.51 (s, 2H), 4.11 (s, 2H), 3.77 (s,
1
3
3 3
CDCl ): δ 162.8 (d, J = 248.5 Hz), 162.3 (d, J = 245.4 Hz) 146.3, 2H), 2.49 (s, 3H), 2.42 (s, 3H); C NMR (101 MHz, CDCl )
1
1
46.0, 145.8, 136.5, 135.7 (d, J = 3.3 Hz), 133.9 (d, J = 3.1 Hz), δ145.6, 145.3, 145.0, 139.4, 138.6, 138.3, 137.4, 135.9, 132.3,
31.5, 130.4 (d, J = 8.0 Hz, 2C) , 129.9, 129.1, 128.7 (d, J = 8.8 132.0, 131.5, 129.5, 129.0(2C), 128.8, 128.5 (2C), 128.2, 127.5,
Hz, 2C), 127.6, 127.1, 126.9, 115.5 (d, J = 23.1 Hz, 2C), 115.3 (d, 127.2, 127.0, 126.0, 123.8, 59.0, 56.7, 53.9, 21.89, 21.4; HRMS
J = 21.3 Hz, 2C), 77.2, 58.2, 56.7, 54.1; HRMS (ESI) calculated (ESI) calculated for C28
+
H N
25 5
[M+H] m/z 432.2188; found
+
for C26
H
19
F
2
N
5
[M+H] m/z 422.1687; found 440.1687.
432.2188.
5-Benzyl-1-(4-chlorophenyl)-9-methyl-1,4,5,6-tetrahydro-
1,2,3] triazolo[4',5':5,6] azepino [4,3-b] quinoline (6f): Light [1,2,3] triazolo[4',5':5,6]azepino[4,3-b]quinoline (6k): Light
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
1
-(2-Bhlorophenyl)-5-(4-fluorobenzyl)-1,4,5,6-tetrahydro-
[
o
1
o
1
brown solid, yield: 89 mg, 78% ; m.p. 117-119 C; H NMR brown solid, yield: 99 mg, 88%; m.p. 123-125 C; H NMR
400 MHz, CDCl ): δ 7.65 (dd, J = 8.1, 1.0 Hz, 1H), 7.62-7.60 (m, (400 MHz, CDCl ): δ 7.56 (s, 1H), 7.48 – 7.44 (m, 2H), 7.44 –
H), 7.55 – 7.48 (m, 4H), 7.45 (ddd, J = 8.1, 7.0, 1.3 Hz, 1H), 7.39 (m, 4H), 7.31 – 7.26 (m, 4H), 7.22 (dd, J = 7.3, 2.0 Hz, 2H),
(
3
3
2
7
2
2
=
1
=
C
1
1
3
.21-7.18 (m, 3H), 7.03 – 6.93 (m, 2H), 4.56 (s, 2H), 4.14 (s, 4.51 (s, 2H), 4.09 (s, 2H), 3.76 (s, 2H), 2.50 (s, 3H); C NMR
H), 3.75 (s, 2H); 13C NMR (101 MHz, CDCl
): δ 162.2 (d, J = (101 MHz, CDCl ): δ 145.8, 145.0, 144.9, 138.2, 138.2, 137.7,
45.3 Hz), 146.28, 145.82, 145.21, 138.16, 136.34, 133.94 (d, J 136.0, 134.7, 132.4, 132.2, 131.5, 129.0(2C), 128.7, 128.7(2C),
3.1Hz), 133.3, 132.0, 131.0, 130.5, 130.4(2C), 129.6, 129.6, 128.5(2C), 128.1 (2C), 127.5, 127.1, 126.0, 59.1, 56.7, 54.0,
29.1, 129.1, 127.4 (d, J = 4.8 Hz, 2C), 127.1, 126.9, 115.3 (d, J 21.8; HRMS (ESI) calculated for
3
3
+
C
27
H
22ClN
5
[M+H] m/z
21.3 Hz, 2C) 8.84, 57.0, 54.2; HRMS (ESI) calculated for 452.1642; found 452.1642.
+
26
H19ClFN
5
[M+H] m/z 456.1391; found 456.1391.
5-(4-Methoxybenzyl)-9-methyl-1-(m-tolyl)-1,4,5,6-tetrahydro-
[1,2,3]triazolo [4',5':5,6] azepino[4,3-b]quinoline (6l): Light
-(4-Chlorophenyl)-5-(4-methoxybenzyl)-1,4,5,6-tetrahydro-
o
1
[
1,2,3] triazolo[4',5':5,6]azepino [4,3-b]quinoline (6g): Brown brown solid, yield: 93 mg, 81% ; m.p. 107-109 C; H NMR (400
o
1
solid, yield: 99 mg, 85% ; m.p. 116-118 C; H NMR (400 MHz, CDCl
MHz, CDCl ) : δ 7.67 (d & s, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50- 7.34 – 7.30 (m, 2H), 7.23-7.16 (m, 2H), 7.13 (d, J = 8.6 Hz, 2H),
.45 (m, 3H), 7.44–7.34 (m, 3H), 7.13 (d, J = 8.7 Hz, 2H), 6.83 6.83 (d, J = 8.7 Hz, 2H), 4.50 (s, 2H), 4.08 (s, 2H), 3.81 (s, 3H),
3
): δ 7.56 (s, 1H), 7.43 (s, 1H), 7.38- 7.34 (m, 2H),
3
7
1
3
(
(
d, J = 8.7 Hz, 2H), 4.50 (s, 2H), 4.10 (s, 2H), 3.81 (s, 3H), 3.70 3.69 (s, 2H), 2.49 (s, 3H), 2.42 (s, 3H); C NMR (101 MHz,
s, 2H); 13C NMR ( 101 MHz, CDCl
) : δ 159.0, 151.2, 146.9, CDCl ) : δ 159.0, 145.6, 145.3, 144.9, 139.4, 138.6, 137.4,
45.9, 138.6 135.62, 134.6, 131.1, 130.5, 130.2, 130.2(2C) , 135.9, 132.3, 132.0, 131.5, 130.3, 130.2(2C), 129.5, 128.8,
30.0(2C) , 128.3, 127.6, 127.5, 127.2, 121.8(2C) , 120.8, 128.2, 127.2, 127.0, 126.0, 123.8, 113.(2C),
14.0(2C) , 58.1, 55.4, 55.1, 48.1; HRMS (ESI) calculated for 58.3, 56.5, 55.4, 53.8, 21.8, 21.4; HRMS (ESI) calculated for
3
3
1
1
1
C
5
+
+
27 5
H22ClN O[M+H] m/z 468.1591; found 468.1591.
C
29
H
27
N
5
O[M+H] m/z 462.2294; found 462.2292.
-(4-Methoxybenzyl)-1-(p-tolyl)-1,4,5,6-tetrahydro-
1-(4-Chlorophenyl)-5-(4-methoxybenzyl)-9-methyl-1,4,5,6-
[
1,2,3]triazolo [4',5':5,6]azepino[4,3-b] quinoline (6h): Light tetrahydro-[1,2,3]triazolo[4',5':5,6]azepino[4,3-b]quinoline
o
1
o
1
brown solid, yield: 94 mg, 84% ; m.p. 118-120 C; H NMR (6m): Brown solid, yield: 98 mg, 82% ; m.p. 118-120 C; H
400 MHz, CDCl ): δ 7.66 (d & s, 2H), 7.56 (t, J = 8.4 Hz, 1H), NMR (400 MHz, CDCl ): δ 7.57 (s, 1H), 7.48 – 7.38 (m, 6H), 7.29
.46 (t, J = 7.5 Hz, 1H), 7.41 – 7.32 (m, 3H), 7.28 (d, J = 8.1 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.7 Hz,
Hz,2H), 7.14 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.50 2H), 4.49 (s, 2H), 4.08 (s, 2H), 3.81 (s, 3H), 3.69 (s, 2H), 2.50 (s,
(
7
3
3
1
3
13
(s, 2H), 4.09 (s, 2H), 3.81 (s, 3H), 3.70 (s, 2H), 2.49 (s, 3H);
C
3H); C NMR (101 MHz, CDCl
3
): δ 159.1, 145.7, 145.0, 144.9,
): δ 159.0, 151.2, 146.9, 145.3, 138.9, 138.1, 137.7, 136.1, 134.7, 132.5, 132.2, 131.5, 130.2(2C),
NMR (101 MHz, CDCl
3
1
1
5
C
5
38.6, 134.9, 131.1, 130.6, 130.3(2C), 130.1(2C), 128.2, 127.6, 130.1, 128.7, 128.7(2C), 128.1 (2C), 127.1, 126.0, 113.9(2C),
27.5, 127.1, 120.9, 120.6(2C), 114.0 (2C), 77.2, 57.8, 55.3, 58.4, 56.5, 55.4, 53.7, 21.8; HRMS (ESI) calculated for
+
4.9,
48.0,
O[M+H] m/z 448.2137; found 448.2139.
-Benzyl-9-methyl-1-(o-tolyl)-1,4,5,6-tetrahydro-
21.2;
HRMS
(ESI)
calculated
for
C
28
H
24ClN
5
O[M+] m/z 481.1669; found 481.1650.
+
H N
28 25 5
General procedure for the preparation of 1-aryl/aralkyl-4,6-
dihydro-1H-[1,2,3] triazolo [4',5':5,6]oxepino[4,3-b]quinolines
[
1,2,3]triazolo [4',5':5,6]azepino[4,3-b] quinoline (6i): Pale (7a-h):To the solution of 2-chloro-3-(((1-aryl/aralkyl-1H-
o
1
yellowsolid, yield: 88 mg, 82% ; m.p. 101-103 C; H NMR (400 1,2,3-triazol-4-yl) methoxy) methyl) quinolines(5a, 0.3 mmol)
MHz, CDCl ): δ 7.50 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.39 – 7.33 in DMF (3mL) was added Pd(OAc) (6.7 mg,0.03 mmol, 10
m 3H), 7.33 – 7.27 (m, 5H), 7.25-7.23 (m, 2H), 7.11 (d, J = 8.5 mol%), triphenylphosphine (15.6 mg, 0.06 mmol, 20 mol%),
3
2
(
Hz, 1H), 4.56 (s, 2H), 4.09 (s, 2H), 3.80 (s, 2H), 2.46 (s, 3H), 1.98 and then cesium carbonate (194 mg, 0.6 mmol) were added.
s, 3H); 13C NMR (101 MHz, CDCl
): δ 145.2, 145.1, 145.1, 139.5 The reaction mixture was heated with stirring at 130 C for
o
(
3
1
1
5
C
5
38.3, 137.4, 135.9, 135.5, 133.0, 131.8, 131.3, 130.2, 129.3, 25h. After completion of the reaction monitored by TLC , the
29.0, 128.9(2C), 128.5(2C), 127.5, 127.4, 126.9, 126.2, 125.8, reaction mixture was cooled and extracted with EtOAc (2 x20
9.1, 57.0, 54.5, 21.8, 17.8 ); HRMS (ESI) calculated for mL).The combined organic layer was dried over anhydrous
+
28 25 5
H N [M+H] m/z 432.2188; found 432.2188.
Na
2 4
SO , filtered and the solvent was removed under reduced
pressure. The crude product was purified by silica gel column
-Benzyl-9-methyl-1-(m-tolyl)-1,4,5,6-tetrahydro-[1,2,3]-
triazolo [4',5':5,6]azepino[4,3-b] quinoline (6j): Light brown chromatography (eluted with 10% hexane/EtOAc) to afford the
solid, yield: 88 mg, 82% ; m.p. 89-91 C; H NMR (400 MHz, title compounds.
o
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Page 6 of 8
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
-(2-Chlorophenyl)-4,6-dihydro-1H-[1,2,3]triazolo
130.3, 129.9, 129.6, 128.3, 127.4, 127.00, 126.3, 124.6, 72.2,
View Article Online
DOI: 10.1039/C9NJ05254B
[
4',5':5,6]oxepino[4,3-b]quinoline(7a):Light brown
solid, 69.4, 22.0, 17.9.
o
1
yield: 78 mg, 75% ; m.p. 113-115 C; H NMR (400 MHz, 1-(4-Chlorophenyl)-10-methyl-4,6-dihydro-1H-[1,2,3]triazolo
CDCl ):δ 7.96 (s, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, [4',5':5,6] oxepino[4,3-b] quinoline (7g): Light yellow solid,
3
o
1
1
4
1
1
H), 7.58 – 7.43 (m, 5H), 7.24 (d, J = 8.3 Hz, 1H), 5.41 (s, 2H), yield: 92 mg, 85% ; m.p. 161-163 C; H NMR (400 MHz, CDCl
.94 (d, J = 10.5 Hz, 2H); C NMR (101 MHz, CDCl
46.1, 145.5, 137.6, 135.2, 133.1, 132.2, 131.3, 130.6, 130.0, 7.42 (d, J=8.8 Hz, 2H), 7.36 (d, J =9.7 Hz, 1H), 7.21 (s, 1H), 5.37
29.7, 129.3, 129.3, 127.6, 127.4, 127.4, 126.7, 72.2, 69.34; (s, 2H), 4.90 (s, 2H), 2.49 (s, 3H); C NMR (101 MHz, CDCl
3
):
1
3
3
): δ 146.7, δ 7.94 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H),
3
3
): δ
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
+
HRMS (ESI) calculated for C19
found 371.0761.
H
13ClN
4
O[M+Na] m/z 371.0676; 147.0, 146.5,145.4, 140.8, 137.7, 135.3, 135.0, 132.1, 130.8,
130.2, 128.8(2C), 128.2 (2C), 128.1, 127.1, 124.8, 71.7, 69.1,
+
1
-(4-Chlorophenyl)-4,6-dihydro-1H-[1,2,3] triazolo [4',5':5,6] 22.0; HRMS (ESI) calculated for
20
C H
15ClN
4
O[M+H] m/z
oxepino[4,3-b]quinoline (7b): Colourless solid, yield: 86 mg, 363.1013; found 363.1012.
o
1
8
7
3% ; m.p. 138-140 C; H NMR (400 MHz, CDCl
.77 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.0 Hz, 1H), 7.54 (d, J = 7.3 [4',5':5,6] oxepino[4,3-b]quinoline: (7h): Light brown solid,
3
):δ 7.99 (s, 1H), 9-Methoxy-1-(p-tolyl)-4,6-dihydro-1H-[1,2,3]triazolo
o
1
Hz, 1H), 7.51–7.44 (m, 3H), 7.42 (d, J = 8.7 Hz, 2H), 5.38 (s, 2H), yield: 88 mg, 82% ; m.p. 180-182 C; H NMR (400 MHz, CDCl
3
):
): δ 146.7, 146.6, 145.4, δ 7.86 (s, 1H), 7.39-7.31 (m, 5H), 7.23 (dd, J = 9.2, 2.7 Hz, 1H),
37.7, 135.6, 135.1, 132.0, 131.7, 130.3, 129.2, 128.7(2C), 7.01 (d, J = 2.6 Hz, 1H), 5.37 (s, 2H), 4.89 (s, 2H), 3.91 (s, 3H),
1
3
4
1
1
.93 (s, 2H); C NMR (101 MHz, CDCl
3
1
3
28.3 (2C), 127.8, 127.5, 126.8, 71.8, 69.2; HRMS (ESI) 2.48 (s 3H); C NMR (101 MHz, CDCl
3
): δ 158.9, 145.9, 143.4,
371.0676; found 143.0, 139.1, 136.7, 134.2(2C), 132.1, 130.9, 129.1 (2C), 128.0,
+
calculated for C19
H
13ClN
4
O[M+Na] m/z
3
71.0712..
126.8 (2C), 123.0, 105.0, 71.9, 69.2, 55.8, 21.5; HRMS (ESI)
+
1
-(p-Tolyl)-4,6-dihydro-1H-[1,2,3] triazolo [4',5':5,6] oxepino calculated for C21
H18ClN
4
O[M+H] m/z
359.1508.; found
[
4,3-b] quinoline(7c): Light brown solid, yield: 78 mg, 80% ; 359.1521.
o
1
m.p. 123-125 C; H NMR (400 MHz, CDCl
3
): δ 7.98 (s, 1H), 7.76
(d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.50 (t, J = 7.5 Hz,
Conflicts of interest
There are no conflicts to declare.
1
8
H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 (d, J =
.1 Hz, 2H), 5.38 (s, 2H), 4.91 (s, 2H), 2.49 (s, 3H); C NMR
): δ 146.8, 146.4, 145.8, 139.1, 136.6, 135.4,
1
3
(101 MHz, CDCl
3
1
1
C
1
31.9, 131.7, 130.1, 129.3, 129.1(2C), 127.6, 127.4, 127.2,
26.7 (2C), 71.7, 69.2, 21.5; HRMS (ESI) calculated for
Acknowledgments
We thank UPE-FAR and OU DST-PURSE program for the
financial assistance.KR and KM thank UGC, New Delhi for their
fellowship. We also thank Department of Chemistry, OU for
laboratory infrastructure under UGC-SAP (DRS-II) and DST-FIST
programmes.
+
H N
20 16 4
O[M+H] m/z 329.1402; found 329.1407.
-Benzyl-9-methyl-4,6-dihydro-1H-[1,2,3]triazolo[4',5':5,6]
oxepino[4,3-b]quinoline (7d): Colourless solid, yield: 82 mg,
o
1
8
8
1
5
3
0% ; m.p. 133-135 C; H NMR (400 MHz, CDCl ):δ 7.98 (d, J =
.6 Hz, 1H), 7.84 (s, 1H), 7.58 (dd, J = 8.6, 1.8 Hz, 1H), 7.54 (s,
H), 7.33 (d, J = 8.2 Hz, 2H), 7.25 – 7.15 (m, 3H), 6.47 (s, 2H),
References
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.30 (s, 2H), 4.77 (s, 2H), 2.55 (s, 3H); C NMR (101 MHz,
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30.6, 128.7, 128.6(2C), 127.9 (2C), 127.8, 126.8, 126.5, 71.9,
9.4, 54.4, 21.8; HRMS (ESI) calculated for
O[M+H] m/z 343.1559; found 343.1554.
0-Methyl-1-phenyl-4,6-dihydro-1H-[1,2,3]triazolo [4',5':5,6]
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8
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H), 7.65 (d, J = 8.3 Hz, 1H), 7.55-7.45 (m, 5H), 7.33 (d, J = 9.7
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35.2, 132.1, 130.9, 130.0, 129.1, 128.6 (2C), 128.2, 127.1,
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+
H N
20 16 4
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oxepino[4,3-b]quinoline(7f):Colourless solid, yield: 82 mg,
o
1
8
1
7
3
0% ; m.p. 108-109 C; H NMR (400 MHz, CDCl ): δ 7.89 (s,
H), 7.62 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.40 (d, J =
.6 Hz, 1H), 7.33 – 7.27 (m, 3H), 7.02 (s, 1H), 5.40 (s, 2H), 4.91
1
3
(s, 2H), 2.44 (s, 3H), 2.02 (s, 3H); C NMR (101 MHz, CDCl
3
): δ
1
47.2, 146.1,145.5, 140.4, 138.9, 136.2, 134.9, 132.7, 130.6,
6
| J. Name., 2012, 00, 1-3
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New Journal of Chemistry
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View Article Online
DOI: 10.1039/C9NJ05254B
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Table of Content
A convenient synthesis of quinoline fused triazolo-azepine/oxepine derivatives
through Pd-catalyzed C-H functionalisation of triazoles
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Kukkamudi Mahesh, Kanakaraju Ravi, Praveen Kumar Rathod and Panaganti Leelavathi*
A convenient synthesis of novel polycyclic fused system comprising three different heterocycles viz.
quinoline, azepine/oxepine and triazole is presented in high yields.