An efficient copper-free Pd(OAc)2/Ruphos-catalyzed Sonogashira coupling of 1-chloroisoquinolines in the formation of 1-alkynyl-3-substituted isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2011.03.040

An efficient, copper-free Sonogashira coupling reaction of 1-chloroisoquinolines and terminal alkynes, catalyzed by Pd(OAc) ₂/Ruphos, in the presence of Et₃N and tetrahydrofuran leads to the formation of 1-alkynyl-3-substituted isoqu

Full text of DOI:10.1016/j.tetlet.2011.03.040

Tetrahedron Letters 52 (2011) 2566–2570
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An efficient copper-free Pd(OAc)2/Ruphos-catalyzed Sonogashira coupling of
1-chloroisoquinolines in the formation of 1-alkynyl-3-substituted isoquinolines
K. Prabakaran a, F. Nawaz Khan a,b, , Jong Sung Jin b,
⇑
⇑
a Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 01, Tamil Nadu, India
b Division of High Technology Materials Research, Busan Center, Korea Basic Science Institute (KBSI), Busan 618 230, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, copper-free Sonogashira coupling reaction of 1-chloroisoquinolines and terminal alkynes,
catalyzed by Pd(OAc)2/Ruphos, in the presence of Et3N and tetrahydrofuran leads to the formation of
1-alkynyl-3-substituted isoquinolines in good yields.
Received 28 September 2010
Revised 3 March 2011
Accepted 8 March 2011
Available online 15 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1-Alkynyl-3-substituted isoquinolines
Copper-free
Sonogashira coupling
Ruphos
Sonogashira coupling represents the most straightforward and
an easy method for the synthesis of internal acetylenic compounds
involving Pd-catalysis.1 Since its discovery by Sonogashira2–6 in
1975, several modifications7–14 have been made including ligand
variation, palladium sources, solvents, amines, the amount of cata-
lyst loading, and use of microwave in order to promote the C–C
bond formation.15–17 The most important modification is the elim-
ination of copper salt and hence diacetylenes are formed in situ
during the reaction of copper acetylide and oxygen or oxidant.18–22
Based on the above facts, we decided to explore an efficient cat-
alytic system for the synthesis of 1-alkynyl-3-substituted isoquin-
olines (Schemes 1 and 2) by replacing triphenylphosphine with
other phosphines to enhance the catalyst efficiency.
2a
Cl
Ph
H
Ligand/catalyst
N
N
base,THF/H2O
reflux
Cl
Cl
1a
3a
Scheme 1. Sonogashira coupling of 1-chloro-3-(4-chlorophenyl)isoquinoline, 1a
with phenyl acetylene, 2a. Catalyst = Pd(OAc)2, bases = Et3N, pyrrolidine, piperidine,
(i-Pr)2NH, K2CO3, KOAc.
In continuation of our work on isoquinolines,23–29 we report the
synthesis of, 1,3-disubstituted isoquinolines through copper-free
Sonogashira coupling. The reaction of 1-chloroisoquinolines, 1
with various terminal acetylenes, 2 in tetrahydrofuran and in the
presence of palladium acetate catalyst, Ruphos ligand and triethyl-
amine in aqueous medium at 70 °C afforded 1,3-disubstituted iso-
quinolines 3 in good yields (Scheme 2, Table 4).
Optimization of the reaction conditions was achieved by choos-
ing Sonogashira coupling of 1-chloro-3-(4-chlorophenyl)isoquino-
line, 1a and phenylacetylene, 2a as model reaction (Scheme 1)
and screening of various ligands (Fig. 1) in the presence of palla-
dium acetate catalyst as shown in Table 1. The reaction proceeds
1
R
R1
2 (1.2 eq)
Cl
Pd(OAc)2 (2.5 mol%)
Ruphos (10 mol%)
Et3N (2.0 eq)
N
N
THF/H2O
reflux at 70 o
45 min
R
R
C
1
(70-93%)
3
R = 4-chlorophenyl, phenyl, 2-thiophenyl
R1= phenyl, 2-aminophenyl, p-tolyl, cyclopropyl,
cyclopentyl, cyclohexyl, 4-fluorophenyl
⇑
Corresponding authors. Tel.: +91 416 220 2334; fax: +91 416 224 3092 (F.N.K.).
E-mail addresses: nawaz_f@yahoo.co.in (F. Nawaz Khan), jsjin@kbsi.re.kr (J.S.
Jin).
Scheme 2. Synthesis of 1-alkynyl-3-substituted isoquinolines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.040

K. Prabakaran et al. / Tetrahedron Letters 52 (2011) 2566–2570
2567
Ph
Ph Ph
O
Ph
H
P
P
P(Cy)2
i-Pr
-
P(Cy)2
Oi-Pr
BF4
i-Pr
P+
i-PrO
C(CH3)3
C(CH3)3
(H3C)3C
i-Pr
Tri-tert-butylphosphonium
tetrafluoroborate
XPhos
Ruphos
Oxydiphos
PPh2
PPh2
O
PPh2
PPh2
P
P
Xantphos
(R)-BINAP
Triphenylphosphine
Tricyclohexylphosphine (Cy3P)
PPh2
PPh2
(CH2)4
Fe
PPh2
PPh2
1,4-Bis(diphenylphosphino)butane
(dppb)
1,1'-Bis(diphenylphosphino)ferrocene
(dppf)
Figure 1. Ligands.
Table 3
Table 1
Effect of base on the Sonogashira couplinga of 1a and 2a
Effect of ligands on the Sonogashira couplinga of 1a and
2a
Entry
Base
Base equivalents
Yield (%)
Entry
Ligand
Yield (%)
1
2
3
4
5
6
7
8
9
10
Et3N
2.0
2.0
2.0
2.0
2.0
2.0
0.5
1.0
1.5
3.0
93
67
59
75
40
35
65
70
81
92
Pyrrolidine
Piperidine
(i-Pr)2NH
K2CO3
KOAc
Et3N
Et3N
Et3N
Et3N
1
2
3
4
5
6
7
8
9
10
PPh3
45
35
NR
23
25
20
47
76
73
93
BINAP
Xantphos
Dppb
Dppf
Cy3P
(n-Bu)3P
Oxydiphos
XPhos
a
Ruphos
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), base, Pd (OAc)2 (2.5 mol %),
Ruphos (10 mol %), degassed water (0.5 mL) at 70 °C for 45 min.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol),
Et3N (2 equiv), Pd (OAc)2 (2.5 mol %), ligand (10 mol %),
degassed water (0.5 mL) at 70 °C for 45 min.
moderate yields (Table 1, entries 8 and 9), and the effect of the rest
of the ligands was found to be poor.
Table 2
Effect of catalyst loading on the Sonogashira couplinga of 1a and 2a
The influence of the amount of ligand, and the catalyst was fur-
ther investigated using the reaction of 1a with 2a (Scheme 1, Table
2). The results indicated that increase in the amount of both ligand
and palladium catalyst could bring about dechlorination of 1a, and
resulted in low yield of the desired product 3a (Table 2, entries 1–
3). Low catalyst and ligand loading and prolonged reaction time
decreased the yield (Table 2, entry 7).
The influence of bases in the reaction of 1a and 2a was also
explored as shown in Table 3. Among the bases tested, triethyl-
amine (Table 3, entry 1) proved to be an excellent base at 70 °C
in tetrahydrofuran-water mixture. Pyrrolidine and dialkylamine
were found to be moderately efficient bases (Table 3, entries 2
and 4) and the rest of the bases (piperidine, K2CO3, KOAc) were less
effective (Table 3, entries 3, 5 and 6). While smaller quantity of
base resulted in lower yield of product 3a, (Table 3, entries 7–9)
the amount of base by more than 2.0 equiv did not make any
difference in the yield (Table 3, entry 10).
Entry
Additive/catalyst
Yield (%)
1
2
3
4
5
6
7
8
Ruphos (50 mol %)/Pd(OAc)2 (25 mol %)
Ruphos (40 mol %)/Pd(OAc)2 (20 mol %)
Ruphos (30 mol %)/Pd(OAc)2 (15 mol %)
Ruphos (20 mol %)/Pd(OAc)2 (10 mol %)
Ruphos (10 mol %)/Pd(OAc)2 (05 mol %)
Ruphos (5 mol %)/Pd(OAc)2 (2.5 mol %)
Ruphos (2.5 mol %)/Pd(OAc)2 (1.25 mol %)
Ruphos (10 mol %)/Pd(OAc)2 (2.5 mol %)
20
23
36
55
70
60
45
93
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Et3N (2 equiv), degassed water
(0.5 mL) at 70 °C for 45 min.
well in the presence of Ruphos ligand (Table 1, entry 10) with over
90% yield. Other ligands, such as oxydiphos and XPhos produced

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K. Prabakaran et al. / Tetrahedron Letters 52 (2011) 2566–2570
Table 4
Sonogashira coupling of 1-chloroisoquinolines, 1 in the synthesis of internal alkynes (1-alkynyl-3-substituted isoquinolines, 2)a
Entry
1-Chloroisoquinolines 1
Alkynes 2
Product
Yieldb (%)
R
R1
3
Cl
N
2a
N
N
N
N
1
93
1a
3a
Cl
Cl
Cl
Cl
Cl
H2N
2
3
4
1a
1a
1a
70
82
87
2b
H2N
3b
CH3
2c
CH3
3c
2d
3d
2e
N
3e
5
1a
72
Cl
Cl
2f
N
6
1a
65
3f
Cl
N
7
8
2a
2f
92
57
N
N
1b
3g
3h
1b

K. Prabakaran et al. / Tetrahedron Letters 52 (2011) 2566–2570
2569
Table 4 (continued)
Entry
1-Chloroisoquinolines 1
Alkynes 2
Product
Yieldb (%)
R
R1
3
F
F
2g
9
1b
71
70
N
3i
Cl
N
10
2a
N
3j
1c
S
S
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), triethylamine (2 equiv), Pd (OAc)2 (2.5 mol %), Ruphos (10 mol %), degassed water (0.5 mL) at 70 °C for 45 min.
Isolated yield.
b
Pd(OAc)2
Ligand
Cl
R1
N
-AC2O
-ligand oxide
R
N
Pd0
L2
R
1
5
R1
L
Cl
Pd
L
AcO
Pd
L
N
N
4
2
R
R
3
L
Et3NH + Cl -
H
R1
Pd
Cl
N
L
R
H
Et3N + L
R1
L=
P(Cy)2
Oi-Pr
and Base or solvent
i-PrO
R = 4-chloro phenyl, phenyl, 2-thiophenyl; R1= phenyl, 2-amino phenyl, p-tolyl, cyclopropyl,
cyclopentyl, cyclohexyl, 4-fluorophenyl
Scheme 3. Mechanism of the reaction.
With the optimized conditions, various 1-alkynyl-3-substituted
isoquinolines were synthesized and the results are reported in
Scheme 2, Table 4. The desired products 3a–j were obtained in high
yields (70–93%) and purity.

2570
K. Prabakaran et al. / Tetrahedron Letters 52 (2011) 2566–2570
17. He, H.; Wu, Y. J. Tetrahedron Lett. 2004, 45, 3237.
The proposed mechanism of the reaction is depicted in Scheme
18. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.
3. The catalytically active Pd0species I is stabilized by the ligands
present. The catalytic cycle is initiated by oxidative addition of aryl
halide to species I, forming the adduct II as a homogeneous-PdII
species followed by a reversible coordination of the alkyne to II
producing an alkyne–PdII complex III. The base then abstracts a
proton from the coordinated alkyne, forming the palladium–acety-
lide complex IV, from which the cross-coupled product V is ob-
tained by reductive elimination regenerating the catalyst species I.
Our method presents a direct route for the sp–sp2 bond forma-
tion and eliminates the oxidative dimerization of the alkyne which
occurs as a side reaction in copper catalysis. The ready availability
of catalyst, high catalytic activity and water as the co-solvent make
the present methodology very attractive for the exploitation of
substituted isoquinolines which possess extensive range of biolog-
ical activities.30,31 The typical procedure of the reaction and analy-
sis data are presented.32,33
19. Arques, A.; Auñon, D.; Molina, P. Tetrahedron Lett. 2004, 45, 4337.
20. Komáromi, A.; Tolnai, G. L.; Novák, Z. Tetrahedron Lett. 2008, 49, 7294.
21. Wang, X.; Qin, W.; Kakusawa, N.; Yasuike, S.; Kurita, J. Tetrahedron Lett. 2009,
50, 6293.
22. Leadbeater, N. E.; Tominacka, B. J. Tetrahedron Lett. 2003, 44, 8653.
23. Tajudeen, S. S.; Khan, F. N. Synth. Commun. 2007, 37, 3649.
24. Manivel, P.; Roopan, S. M.; Khan, F. N. J. Chil. Chem. Soc. 2008, 53, 1609.
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27. Khan, F. N.; Manivel, P.; Prabakaran, K.; Hathwar, V. R.; Seik Weng, N. Acta
Crystallogr., Sect. E 2010, 66, o370.
28. Khan, F. N.; Manivel, P.; Prabakaran, K.; Hathwar, V. R.; Seik Weng, N. Acta
Crystallogr., Sect. E 2010, 66, o488.
29. Khan, F. N.; Manivel, P.; Prabakaran, K.; Hathwar, V. R.; Mehmet, A. Acta
Crystallogr., Sect. E 2010, 66, o1056.
30. 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.
31. Heike, B.; Julia, W.; Christain, A.; Matthias, L. Dev. Comp. Immunol. 2006, 30,
410.
32. General procedure for the synthesis:
A mixture of 1-chloroisoquinoline, 1
(0.5 mmol), acetylenes, (0.6 mmol), Ruphos (10 mol %), triethylamine
2
(2.0 equiv), water (0.5 mL) and tetrahydrofuran (5 mL) was degassed twice
using nitrogen gas. Then Pd(OAc)2 (2.5 mol %) was added, again degassed twice
and heated at 70 °C in a sealed tube under nitrogen atmosphere for 45 min.
After completion of the reaction, the resulting solution was filtered off using
Celite pad (to remove catalyst) and the filtrate was concentrated in vacuo. The
crude products were subjected to silica-gel (230–400 mesh) flash column
chromatography using hexane/ethyl acetate (90:10) eluent to afford the pure
products (Table 4). The compounds were confirmed by 1H NMR, 13C NMR, FTIR
LC–MS and elemental analysis techniques.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.040.
References and notes
33. The analysis data of 3a, 3b are given below, remaining data are presented in
Supplementary data attached with this manuscript.
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3-(4-Chlorophenyl)-1-(phenylethynyl)isoquinoline, 3a.
Yellow solid, mp 110–112.5 °C, 1H NMR (400 MHz, CDCl3, ppm): d 8.53–8.51 (d,
J = 8.4 Hz, 1H), 8.13–8.10 (d, J = 13.6 Hz, 2H), 8.02 (s, 1H), 7.90–7.88 (d,
J = 8.0 Hz, 1H), 7.77–7.71 (m, 3H), 7.69–7.65 (t, J = 8.4 Hz, 1H), 7.49–7.42 (m,
5H); 13C NMR (100 MHz, CDCl3, ppm): d 150.1, 144.4, 137.6, 136.7, 134.8,
132.3, 130.9, 129.3, 128.9, 128.6, 128.5, 128.4, 128.0, 127.3, 127.0, 122.2,
116.7; IR (
1391, 1334, 1261, 1148, 1092, 1017, 831, 753, 527; LC–MS: m/e 340.2,
23H14ClN requires Mol. Wt.: 339.08. Elemental analysis, calculated: C, 81.29;
m
cmÀ1) 3058, 2924, 2850, 2211, 2164, 1999, 1961, 1557, 1494, 1439,
C
H, 4.15; Cl, 10.43; N, 4.12%. Found: C, 81.22; H, 4.12; N, 4.14%.
3-[((4-Chlorophenyl)isoquinolin-1-yl)ethynyl]aniline, 3b.
Yellow solid, mp 153–154 °C, 1H NMR (400 MHz, CDCl3, ppm): d 8.53 (s, 1H),
8.44–8.42 (d, J = 8.0 Hz, 1H), 8.27–8.25 (d, J = 8.4 Hz, 2H), 8.11–8.09 (d,
J = 8.0 Hz, 1H), 7.89–7.86 (t, J = 7.4 Hz, 1H), 7.82–7.78 (t, J = 7.6 Hz, 1H), 7.62–
7.60 (d, J = 8.4 Hz, 2H), 7.18–7.14 (t, J = 7.8 Hz, 1H), 6.97–6.92 (t, J = 9.8 Hz, 2H),
6.73–6.71 (d, J = 8.0 Hz, 1H), 5.4 (bs, 2H); 13C NMR (100 MHz, CDCl3, ppm): d
149.5, 149.0, 143.8, 137.5, 136.8, 134.1, 131.8, 129.9, 129.3, 129.3, 128.8, 128.3,
126.5, 121.7, 119.8, 117.2, 117.1, 116.1, 95.1, 86.0; IR (m
cmÀ1) 3850, 3727,
3605, 3347, 3054, 2924, 2853, 2234, 2210, 2151, 2132, 2049, 2026, 2017, 1998,
1973, 1928, 1619, 1597, 1556, 1493, 1439, 1391, 1305, 1091, 1012, 751, 520;
LC–MS: m/e 355.2, C23H15ClN2 requires Mol. Wt.: 354.09. Elemental analysis,
calculated: C, 77.85; H, 4.26; Cl, 9.99; N, 7.89%. Found: C, 77.77; H, 4.21; N,
7.84%.
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