An effective BINAP and microwave accelerated palladium-catalyzed amination of 1-chloroisoquinolines in the synthesis of new 1,3-disubstituted isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2010.06.045

A facile and microwave accelerated reaction of 1-chloro-3-(4-chlorophenyl) isoquinoline with various heterocyclic amines, catalyzed by Pd, in the presence of BINAP additive and sodium carbonate as the base, leads to the formation of 3-(4-chlorophenyl)-1-(1H-1,2,3-triazol-1-yl)isoquinoline, 3-(4-chlorophenyl)-1- (1H-imidazol-1-yl)isoquinoline and 3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl) isoquinoline via Buchwald protocol in good yields. Similarly pyrazolylisoquinolines are also reported.

Full text of DOI:10.1016/j.tetlet.2010.06.045

Tetrahedron Letters 51 (2010) 4340–4343
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Tetrahedron Letters
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An effective BINAP and microwave accelerated palladium-catalyzed
amination of 1-chloroisoquinolines in the synthesis of new
1,3-disubstituted isoquinolines
K. Prabakaran a,b, P. Manivel a,b, F. Nawaz Khan a,
*
a Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
b Syngene International Limited, Bangalore, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and microwave accelerated reaction of 1-chloro-3-(4-chlorophenyl)isoquinoline with various
heterocyclic amines, catalyzed by Pd, in the presence of BINAP additive and sodium carbonate as the base,
leads to the formation of 3-(4-chlorophenyl)-1-(1H-1,2,3-triazol-1-yl)isoquinoline, 3-(4-chlorophenyl)-
1-(1H-imidazol-1-yl)isoquinoline and 3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)isoquinoline via
Buchwald protocol in good yields. Similarly pyrazolylisoquinolines are also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 April 2010
Revised 8 June 2010
Accepted 9 June 2010
Available online 16 June 2010
Keywords:
Microwave
Buchwald
BINAP
Isoquinoline
1. Introduction
A number of methods have been developed for the synthesis of
disubstituted isoquinolines including palladium-catalyzed cross-
The Pd-catalyzed cross-coupling methods have been utilised
exponentially over the years for the construction of C–C, C–N,
and C–O bonds.1 As coupling protocols of mild and chemoselective
conditions are very desirable for the preparation of compounds
with highly functionalized and complex molecular structures, this
methodology was applied for preparing new drug candidates on a
small scale as well as for manufacturing on a commercial scale by
pharmaceutical companies.2 Similarly, a widely used and preferred
tool for accelerating reactions namely microwave irradiation
(MWI) has been applied to organic reactions,3 in the absence of a
solvent or in the presence of a solid support, such as clays, alumina
and silica, resulting in shorter reaction times and higher product
yields than those obtained by using conventional heating. Disubsti-
tuted isoquinolines are endowed with an extensive range of bio-
logical activities.4 They have emerged as potent non-nucleoside
inhibitors of HIV-1 reverse transcriptase,5 and specific inhibitors
of the NS5B polymerase of the hepatitis C virus (HCV).6 Appropri-
ately functionalized disubstituted isoquinolines are used as ago-
nists against gamma amino butyric acid A receptor (GABAA).7
Moreover, they display potent thrombin inhibitory activity and
antibacterial activity against Gram-positive bacteria.8
coupling of N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl,
allylic, benzylic, alkynyl halides, as well as a vinylic halide,9 Disub-
stituted isoquinolines were prepared under mild conditions from
allylbenzenes and nitriles using silver trifluoromethanesulfonate
and iodine.10 Silver-assisted reaction of b-arylvinyl bromides and
the photolysis in nitriles gave isoquinoline derivatives, indicating
that the Ritter reaction involving a vinyl cation took place.11 3-aryl
4-(1-alkenyl)isoquinolines have been prepared by the Pd(II)-cata-
lyzed cyclization of 2-(1-alkynyl)benzaldimines, followed by alke-
nylation (Heck reaction) in good to excellent yields. But one of the
major limitations of these methodologies is that they gave poor
yields.
These applications of Pd catalysis, microwave enhancement and
disubstituted isoquinolines and continued interest of our research
on Pd catalysis, microwave-assisted reactions, C–C and C–N bond
formations,12–19 prompted us to develop a simple and facile MW
accelerated synthesis of 1,3-disubstituted isoquinolines using bis-
(dibenzylideneacetone)palladium(0) catalyst by Buchwald cou-
pling of 1-chloroisoquinoline and heterocyclic amines.
2. Results and discussion
In this Letter, we report the reaction of 1-chloroisoquinoline
derivative, 1 with various nitrogenous heterocyclic amine, 2 in
1,4-dioxane and in the presence of bis-(dibenzylidene acetone)
* Corresponding author. Tel.: +91 416 220 2334, mobile: +91 094442 34609; fax:
+91 416 224 3092.
E-mail address: nawaz_f@yahoo.co.in (F.N. Khan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.045

K. Prabakaran et al. / Tetrahedron Letters 51 (2010) 4340–4343
4341
Het
Het
2
NH
Cl
N
Pd2(dba)3/BINAP
Na2CO3/ Dioxane
N
N
Heating at 110°C/ MW/ 45 min
Cl
Cl
3
1
NH
NH
N
HN
NH
N
NH
N
N
CN
N
N
N
2d
2e
2c
2b
2a
Scheme 1. Synthesis of 1,3-disubstituted isoquinolines.
R1
R1
N
R2
Cl
N
Pd2(dba)3/BINAP
Na2CO3 / Dioxane
+
N
N
R2
N
N
H
Heating at 110°C/ MW/ 45 min
R
R
(f-m)
3
1 (a,b)
2 (f-i)
Scheme 2. Synthesis of pyrazolylisoquinolines compounds.
Table 1
reaction. Initially, several bases were screened for the reaction in
the presence of a catalytic amount of bis-(dibenzylideneace-
tone)palladium(0) catalyst. As shown in Table 2, the reaction is sig-
nificantly influenced by the nature of the base employed. The
reaction works very well in most common inexpensive bases such
as alkali carbonate (Table 2, entries 2–4), with best results being in
the case of sodium carbonate (Table 2, entry 2). However the most
common Pd/phosphine reaction bases like Cs2CO3, KF were found
to be least effective.
The influence of the amounts of chelating ligand BINAP, and the
catalyst were investigated using the reactions of compound 1 with
2a. The results are shown in Table 3. Increasing the amount of the
palladium catalyst could shorten the reaction time but does not in-
crease the yield (entries 10 and 11). Low palladium concentration
often prolonged the reaction time and decreased the yield (entry
1). The use of BINAP is also critical for the success of the reaction,
without which, the yield dropped from 90% to 30% (Table 3, com-
Amination of 1-chloro-3-(4-chlorophenyl)isoquinoline, 1 with various heterocyclic
aminesa
Entry
Amines, 2
Time in min
Yield%
1
2
3
4
5
2a
2b
2c
2e
2d
45
45
45
45
65
90
85
83
95
80
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), base (3 mmol), Pd (0.05 equiv),
BINAP (0.5 equiv) at MW watts 155–160 W, 110 °C.
palladium(0) catalyst, rac-BINAP, and sodium carbonate at
110 °C.20 The 1,3-disubstituted isoquinolines 3a–m was obtained
in moderate to high yields (Schemes 1 and 2, Tables 1 and 4).
The reactions were carried out under argon atmosphere.
Optimization of the reaction conditions was done by choosing
the reaction of 1-chloroisoquinoline, 1 with imidazole, 2a as model
Table 3
Effect of BINAP and Pd catalyst on coupling of compound, 1 with imidazole, 2a
Table 2
Entry
Additive/catalyst
Time in min
Yield%
Effect of base on coupling of compound, 1 with imidazole, 2a
1
2
3
4
5
6
7
8
9
Nil
60
60
60
60
60
60
60
60
60
60
45
NR
NR
30
54
73
90
25
38
52
65
66
Entry
Base
Time in min
Yield%
BINAP (0.5 equiv)
Pd (0.05 equiv)
1
2
3
4
5
6
7
8
9
KOH
60
60
60
60
60
60
60
60
60
20
90
62
68
25
38
27
23
52
Na2CO3
K2CO3
CS2CO3
Et3N
BINAP (0.1 equiv)/Pd (0.05 equiv)
BINAP (0.3 equiv)/Pd (0.05 equiv)
BINAP (0.5 equiv)/Pd (0.05 equiv)
BINAP (0.7 equiv)/Pd (0.05 equiv)
BINAP (0.5 equiv)/Pd (0.01 equiv)
BINAP (0.5 equiv)/Pd (0.03 equiv)
BINAP (0.5 equiv)/Pd (0.07 equiv)
BINAP (0.5 equiv)/Pd (0.07 equiv)
DIEA
Pyrrolidine
Piperidine
KF
10
11
Reaction conditions: 1 (1 mmol), 2 (1 mmol), base (3 mmol), Pd (0.05 equiv), BINAP
(0.5 equiv) at MW watts 155–160 W, 110 °C.
Reaction conditions: 1 (1 mmol), 2 (1 mmol), base (3 mmol), at MW watts 155–
160 W, 110 °C.

4342
K. Prabakaran et al. / Tetrahedron Letters 51 (2010) 4340–4343
Table 4
Pyrazolylisoquinolines, 3f–m
Acknowledgements
Sl. No.
Substrate 1, 2 and product 3
Yielda
%
The authors wish to express their gratitude to the Indian Insti-
tute of Science, SAIF, Bangalore and Syngene International Limited
for their support of NMR, LC–MS and IR facilities.
Entry
R
R1
R2
1
2
3
4
5
6
7
8
3f
H
H
CH3
Ph
CH3
Ph
Ph
C2H5
CH3
Ph
80
82
85
76
83
87
85
83
3g
3h
3i
3j
3k
3l
H
H
Cl
Cl
Cl
Cl
CH3
C2H5
CH3
Ph
CH3
C2H5
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.045.
Ph
C2H5
3m
a
Isolated product yield, characterized by spectral techniques.
References and notes
R1
1. Anthony, O. K.; Nobuyoshi, Y. Topics Organomet. Chem. 2004, 6, 205.
2. Ioannis, N. H.; Didier, S.; Ulrike, N.; Anita, S.; Erhart, B.; Weerts, K.; Martine, C.;
Wim, V. Org. Process Res. Dev. 2009, 13, 596.
3. Antonio de la, H.; Angel, D.; Andres, M. Chem. Soc. Rev. 2005, 34, 164.
4. Xin-Hua, L.; Jing, Z.; An-na, Z.; Bao-An, S.; Hai-Liang, Z.; Shan, B.; Pinaki, B.;
Chun-Xiu, P. Bioorg. Med. Chem. 2009, 17, 1207.
Cl
N
R2
N
N
N
R
Pd(dba)2
5. Véronique, J.; Patrick, Y. AIDS Rev. 1999, 1, 37.
6. Robert, T. H.; Stacey, R. S.; James, F. N.; Jay, B. F.; John, P. D.; Peter, J. S.; Vincent,
J. P. L.; Sophie, L.; Sonal, R.; Isabel, N.; John, A. J.; Steven, S. Bioorg. Med. Chem.
Lett. 2009, 19, 410.
R
7. Johnston, G. A. R. Pharmacol. Ther. 1996, 69, 173.
8. Heike, B.; Julia, W.; Christian, A.; Jorg, A.; Matthias, L. Develop. Comp. Immun.
2006, 30, 597.
9. Tadashi, S.; Kunio, T.; Kazuo, N. Chem. Lett. 1983, 12, 791.
R
Cl
10. Tsugio, K.; Shinjiro, K.; Hiroshi, T. Chem. Lett. 1984, 13, 1351.
11. Qinhua, H.; Richard, C. L. Tetrahedron Lett. 2002, 43, 3557.
12. Khan, F. N.; Jayakumar, R.; Pillai, C. N. J. Mol. Catal. A, Chem. 2003, 195, 139.
13. Khan, F. N.; Jayakumar, R.; Pillai, C. N. Tetrahedron Lett. 2002, 43, 6807.
14. Tajudeen, S. S.; Khan, F. N. Synth. Commun. 2007, 37, 3649.
15. Manivel, P.; Roopan, S. M.; Khan, F. N. J. Chil. Chem. Soc. 2008, 53, 1609.
16. Patil, N. T.; Khan, F. N.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 8497.
17. Roopan, S. M.; Maiyalagan, T.; Khan, F. N. Can. J. Chem. 2008, 86, 1019.
18. Roopan, S. M.; Khan, F. N. Indian J. Heterocyl. Chem. 2008, 18, 183.
19. Roopan, S. M.; Hathwar, V. R.; Kumar, A. S.; Malathi, N.; Khan, F. N. Acta
Crystallogr., Sect. E 2009, 65, o571.
Pd(dba)2
N
N
Pd(dba)2
R2
N
R
N
R1
20. General procedure for the synthesis of 1,3-disubstituted isoquinolines: A mixture
of the 1-chloroisoquinoline (1 mmol), Pd catalyst (0.05 equiv), BINAP
(0.5 equiv), and sodium carbonate (3 mmol) was stirred in dioxane (5 mL) at
60 °C for 2 min under argon atmosphere. Different heterocyclic amines were
then added, and the mixture was microwave irradiated at 110 °C for 1 h. After
completion of the reaction, the resulting solution was concentrated in vacuo,
and the crude product was subjected to silica-gel column chromatography
using CHCl3–CH3OH (95:5) as eluent to afford the pure product (Table 1). The
compounds were conformed by FT-IR, 1H NMR, 13C NMR and MS techniques.21
21. The analysis data of 3a, 3b, 3f and 3g are given below and for the data of the
3c–e, 3h–m see Supplementary data.
R1
HCl
N
R2
N
H
Scheme 3. Mechanism of the reaction.
pare entries 3 and 6). The addition of chelating ligand racemic-BIN-
AP is significant in modification of yields, moreover, addition of
0.5 equiv for 0.05 equiv Pd catalyst is essential for the reaction
and any excess of BINAP did not modify the yields under our exper-
imental conditions. An investigation of the influence of solvents on
coupling reaction was carried out with a range of solvent systems
and it was observed that dioxane gave near quantitative yield
within 1 h. It is worth to mention the Buchwald coupling reaction
when carried out under conventional method under same opti-
mized condition required 6–7 h however with a low yield 57%.
Subsequently, the reaction of a variety of heterocyclic amines,
2a–e and 1-chloroisoquinoline derivative, 1 were studied under
optimised conditions (Table 1). Similarly under optimised condi-
tions, various pyrazoles were reacted with the 1-chloroisoquino-
line derivative to give the pyrazolylisoquinolines 3f–m (Table 4).
The plausible mechanism for the reaction is depicted below
(Scheme 3).
3-(4-Chlorophenyl)-1-(1H-imidazol-1-yl)isoquinoline (3a): Yellow solid, mp
138.5–138.8 °C, 1H NMR (400 MHz, CDCl3): d 8.49 (br s, 1H), 8.19 (br s, 1H),
8.12–8.09 (d, J = 8.6 Hz, 2H), 8.01–8.05 (m, 2H), 7.83–7.85 (t, J = 7.6 Hz, 1H),
7.51–7.48 (d, J = 8.6 Hz, 2H), 7.48 (br s, 1H), 13C NMR (100 MHz, CDCl3): d
140.0, 135.9, 135.0, 131.6, 129.1, 128.9, 128.0, 127.8, 123.7, 117.2, IR (m
cmÀ1),
3069, 2921, 2852, 2186, 2118, 1662, 1624, 1593, 1567, 1488, 1437, 1400, 1350,
1322, 1290, 1245, 1145, 1109, 1101, 1091, 1034, 1012, 954, 905, 858, 822, 737,
677, 652, 520, 454, LC–MS: m/e 306.2, C18H12ClN3.
3-(4-Chlorophenyl)-1-(1H-1,2,3-triazol-1-yl)isoquinoline (3b): Yellow solid, mp
120–121 °C, 1H NMR (400 MHz, CDCl3): d 8.44–8.42 (d, J = 8.5 Hz, 1H), 8.20 (br
s, 1H), 8.16–8.14 (d, J = 8.4 Hz, 2H), 8.075 (br s, 2H), 8.00–7.98 (d, J = 8.2 Hz,
1H), 7.80–7.76 (t, J = 7.2 Hz, 1H), 7.68–7.64 (t, J = 7.7 Hz, 1H), 7.49–7.47 (d,
J = 8.4 Hz, 2H), 13C NMR (100 MHz, CDCl3): d 148.2, 139.6, 136.6, 136.2, 135.1,
131.2, 129.0, 128.5, 128.3, 127.3, 125.9, 121.4, 117.9.; IR (m
cmÀ1), 3131, 3121,
3058, 2955, 2919, 2851, 1624, 1591, 1569, 1495, 1443, 1404, 1346, 1259, 1146,
1089, 1003, 959, 946, 881, 836, 808, 744, 716, 674, 650, 590, 516, 476, 453, LC–
MS: m/e 307.2, C17H11ClN4.
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-phenylisoquinoline (3f): Colorless solid, mp
170 °C, 1H NMR (400 MHz, DMSO-d6) 8.52 (s, 1H), 8.19–8.17 (m, 2H), 8.11–8.06
(m, 2H), 7.83–7.79 (m, 1H), 7.66–7.62 (m, 1H), 7.52–7.49 (m, 2H), 7.44–7.40
(m, 1H), 6.21 (s, 1H), 2.35 (s, 3H, -CH3), 2.24 (s, 3H, -CH3), 13C NMR (100 MHz,
DMSO-d6) 150.07 (–C@N, isoquinoline ring), 149.0 (C@C–C6H5), 148.0 (–N–
N@C–CH3), 141.9 (–C@C–CH3), 139.6, 138.3, 131.6, 129.4, 2 Â 129.4, 2 Â 128.5,
127.8, 126.8, 126.8, 122.9, 117.0, 107.7 (–C@C–CH3), 13.9 (–CH3), 13.55 (–CH3),
3. Conclusion
IR (m
cmÀ1) 3050, 2922, 1623, 1589, 1566, 1488, 1463, 1439, 956, 883, 764, 695,
LC–MS: m/e 300.0; C20H17N3; Mol. Wt.: 299.37; Calculated: C, 80.24; H, 5.72; N,
14.04. Found: C, 79.98; H, 5.30; N, 14.01.
3-Phenyl-1-(3,5-diphenyl-1H-pyrazol-1-yl)isoquinoline (3g): Colorless solid, mp
120 °C, 1H NMR (400 MHz, DMSO-d6): 8.57 (s, 1H), 8.18–8.16 (d, J = 8.3 Hz, 1H),
8.08–8.08 (d, J = 8.4 Hz, 1H), 7.99–7.97 (t, 2H), 7.89–7.85 (t, 1H), 7.80–7.77 (m,
2H), 7.73–7.69 (t, 1H), 7.50–7.46 (m, 2H), 7.40–7.37 (m, 5H), 7.27–7.24 (m, 5H).
In conclusion, we have developed a successful microwave irra-
diated palladium-catalyzed reaction for the synthesis of various
1,3-disubstituted isoquinolines in the presence of BINAP and
sodium carbonate as the base in 1,4-dioxane.

K. Prabakaran et al. / Tetrahedron Letters 51 (2010) 4340–4343
4343
13C NMR (100 MHz, DMSO-d6): 152.2 (–C@N, isoquinoline ring), 150.2 (C@C–
C6H5), 148.3 (–N–N@C–C6H5), 147.2 (–C@C–C6H5), 139.6, 138.0, 132.9, 131.9,
130.7, 2 Â 129.4, 2 Â 129.3, 2 Â 129.2, 2 Â 128.9, 2 Â 128.8, 2 Â 128.7,
2 Â 128.3, 2 Â 128.1, 126.8, 126.1, 125.7, 123.3, 117.9, 105.3 (–C@C–CH3), IR
(m
cmÀ1) 3057, 2922, 1624, 1572, 1492, 1405, 980, 884, 775, 692; LC–MS: m/e
424.2; C30H21N3, Mol. Wt.: 423.51; Calculated: C, 85.08; H, 5.00; N, 9.92.
Found: C, 85.02; H, 4.93; N, 9.84.