Facile synthesis of isoquinolines by imination and subsequent palladacycle-catalyzed iminoannulation of internal alkynes

Article abstract of DOI:10.1016/j.tet.2011.02.044

An efficient and facile synthesis of isoquinolines has been described via a tandem reaction of imination of o-halobenzaldehydes with tert-butyl amine and subsequent palladacycle-catalyzed iminoannulation of internal alkynes. This tandem reaction could be carried out successively in one pot without any special operation, and the annulation step could afford isoquinolines derivatives in moderate to good yields with high regioselectivity. In addition, the simple synthesis of indoles was realized by palladacycle-catalyzed annulation of o-iodoaniline or o-bromoanilines with internal alkynes.

Full text of DOI:10.1016/j.tet.2011.02.044

Tetrahedron 67 (2011) 2969e2973
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Facile synthesis of isoquinolines by imination and subsequent
palladacycle-catalyzed iminoannulation of internal alkynes
,
b
,
,
b
,
,b,c,
Fan Yang a c, Junli Zhang a c, Yangjie Wu a
*
a Department of Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
b Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou 450052, PR China
c Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and facile synthesis of isoquinolines has been described via a tandem reaction of imination of
o-halobenzaldehydes with tert-butyl amine and subsequent palladacycle-catalyzed iminoannulation of
internal alkynes. This tandem reaction could be carried out successively in one pot without any special
operation, and the annulation step could afford isoquinolines derivatives in moderate to good yields with
high regioselectivity. In addition, the simple synthesis of indoles was realized by palladacycle-catalyzed
annulation of o-iodoaniline or o-bromoanilines with internal alkynes.
Received 21 December 2010
Received in revised form 25 January 2011
Accepted 15 February 2011
Available online 22 February 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Tandem reaction
Internal alkynes
Annulation
Palladium catalysis
1. Introduction
fascinating and desirable to utilize a tandem reaction, which con-
sists of two steps: imination of o-halobenzaldehydes with tert-
The palladium-catalyzed annulation of internal alkynes has
become a reliable and versatile tool for the convenient synthesis of
heterocycles derivatives, such as isoquinolines and indoles.1 Iso-
quinolines as important alkaloids are abundantly found in nu-
merous natural products and pharmaceutically active compounds,
and a substantial number of their applications have been developed
at the laboratory and industrial scale.2 In the last decades, much
effort has been devoted to developing transition-metal-catalyzed
reactions for the facile construction of the skeleton of heterocycles,
and particularly palladium-catalyzed processes have received
much attention.3 Initially, Widdowson,4 Pfeffer,5 and Heck6 repor-
ted three palladium-assisted stoichiometric versions of the annu-
lation, respectively. Subsequently, Larock et al. realized the catalytic
and simple synthesis of isoquinolines via palladium-catalyzed
iminoannulation of internal alkynes with imines.7 Recently, Konno
et al. described an efficient and convenient protocol of this imi-
noannulation affording fluoroalkylated isoquinolines as the prod-
ucts in a single isomer.8 Generally, the tert-butylimines and internal
alkynes were used as the starting materials in the above-men-
tioned literatures, and the tert-butylimines should be prepared in
advance. To overcome this limitation, we consider it highly
butyl amine and palladium-catalyzed iminoannulation of internal
alkynes.
Cyclopalladated ferrocenylimines as a family of versatile palla-
dacyclic catalysts, which were described by our research group,
have been applied to various reactions (Fig. 1).9 Inspired by these
pioneering reports and our own works, we would like to report for
the first time the facile synthesis of isoquinolines by a tandem
reaction of imination and following palladacycle-catalyzed imi-
noannulation of internal alkynes.
2. Results and discussion
In our initial study, effects of bases and additives on the syn-
thesis of 3,4-diphenylisoquinoline were explored and the results
are summarized in Table 1. Firstly, the imination of 2-bromo-
benzaldehyde (1a) with tert-butyl amine and subsequent
N
Fe Pd
Cl
PPh3
* Corresponding author. Tel./fax: þ86 371 67766667; e-mail address: wyj@
zzu.edu.cn (Y. Wu).
Fig. 1. Palladacycle.
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doi:10.1016/j.tet.2011.02.044

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F. Yang et al. / Tetrahedron 67 (2011) 2969e2973
Table 1
Effects of bases and additives on the catalytic synthesis of 3,4-diphenylisoquinolinea
O
Br
i) rt, 12 h or 100 oC, 4 h
N
+
H2N
Ph
+
ii) diphenylacetylene (2a), base
Ph
CHO
palladacycle, additive, DMF
Ph
Ph
3a
1a
4a
Entry
Base
Additive
Yieldb [%]
3a
4a
1
2
3
4
5
6
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
d
61
81
20
43
53
65
13
9
35
29
24
23
LiCl
n-Bu4NCl
n-Bu4NBr
LiCl
NaOAc
LiCl
Bold values in entry 2 represent the optimal conditions.
a
Reaction conditions: under nitrogen atmosphere, after the mixture of 2-bromobenzaldehyde (0.25 mmol) and tert-butyl amine (0.75 mmol) in DMF (1 mL) was stirred at
room temperature for 12 h (or 100 ꢀC for 4 h), diphenylacetylene (0.50 mmol), base (0.50 mmol), additive (0.25 mmol), and palladacycle (1 mol %) in DMF (1 mL) were added
under stirring at 100 ꢀC for 24 h.
b
Isolated yields.
palladacycle-catalyzed iminoannulation of diphenylacetylene (2a)
were carried out using Na2CO3 as the base under the additive-free
conditions, affording the desired product in a moderate yield of 61%
and 2,3-diphenyl-1H-inden-1-one (4a) as the byproduct (Table 1,
entry 1). Interestingly, with the addition of LiCl as the additive, the
yield of the product could increase to as high as 81% and the yield of
byproduct was decreased to 9% (Table 1, entry 2). However, other
additives, such as n-Bu4NCl and n-Bu4NBr did not do good to the
reaction process and only relatively low yields were obtained (Table
1, entries 3 and 4). From this point of view, the additive plays
a crucial role for the successful reaction. Finally, some other bases,
such as K2CO3 and NaOAc were also screened and the reactions only
gave the corresponding product in moderate yields of 53% and 65%,
respectively (Table 1, entries 5 and 6).
Under the optimized conditions, the scope of this tandem re-
action was explored (Table 2). For symmetrical internal alkynes,
such as diphenylacetylene (2a), the reactions proceeded well to
afford the desired products in moderate to good yields (Table 2,
entries 1e3). For the asymmetrical internal alkynes, this reactions
exhibited high regioselectivity with the more sterically hindered
group in the 3-position of the isoquinolines as the major isomer
(Table 2, entries 4e8). Particularly, if asymmetrical internal alkynes
Table 2
The palladacycle-catalyzed formation of isoquinolinesa
O
X
i) rt, 12 h or 100 oC, 4 h
N
R1
+
R3
R1
+ R1
H2N
2
ii) internal alkyne ( ),Na2CO3
R3
CHO
palladacycle, LiCl, DMF
R2
4
R2
1
3
Entry
o-Halobenzaldehyde
Alkyne
Product
Yieldb [%]
3
4
N
Br
Ph
Ph
1
81 (3a)
11 (4a)
Ph
Ph
2a
CHO
Ph
1a
3a
N
I
2
3
2a
91 (3a)
3 (4a)
CHO
Ph
1b
3a
N
Br
2a
67 (3b)
d
Ph
CHO
Ph
3b
1c

F. Yang et al. / Tetrahedron 67 (2011) 2969e2973
2971
Table 2 (continued )
Entry
o-Halobenzaldehyde
Alkyne
Product
Yieldb [%]
3
4
N
N
Ph
CH3
4
5
1b
1b
83 (3c)
92 (3d)
5 (4c)
Ph
Ph
2b
3c
Ph
CH2OH
d
2c
CH2OH
3d
6
7
1a
1a
2b
2c
3c
3d
54 (3c)
80 (3d)
15 (4c)
d
N
8
1c
2b
73 (3e)
d
Ph
3e
N
N
:
Ph
9c
1a
85 (3f/3g)
d
2d
3f
(1:1)
3g
O
O
N
Br
O
10
2a
12 (3h)
68 (4h)
Ph
O
CHO
Ph
3h
1d
a
Reaction conditions: under nitrogen atmosphere, after the mixture of o-halobenzaldehyde (0.25 mmol) and tert-butyl amine (0.75 mmol) in DMF (1 mL) was stirred at
room temperature for 12 h (or 100 ꢀC for 4 h), internal alkyne (0.50 mmol), Na2CO3 (0.50 mmol), LiCl (0.25 mmol), and palladacycle (1 mol %) in DMF (1 mL) were added under
stirring at 100 ꢀC for 24 h.
b
Isolated yields.
A colon (:) indicates that the products were inseparable.
c
contain a phenyl group, the phenyl group tends to attach to the
carbon atom near to the nitrogen atom in the major isoquinoline
products (Table 2, entries 4e8). When the sterical hindrance of two
substituents on asymmetrical internal alkynes was almost the
same, an inseparable 1:1 mixture of isomers (e.g., 3f and 3g) was
obtained (Table 2, entry 9). For the o-halobenzaldehydes, when the
substrate contains two electron-donating groups (1d), the side
reaction would occur to afford the byproduct as the major product
(Table 2, entry 10).
In addition, the facile synthesis of indoles via palladium-
catalyzed annulation of o-haloanilines with internal alkynes was
also investigated, since construction of the indole skeleton
would have great importance in heterocyclic chemistry (Scheme 1).
The reactions of o-iodoaniline and o-bromoaniline with
diphenylacetylene (2a) proceeded smoothly to afford the desired
product of 2,3-disubstituted indole (6a) in yields of 83% and 91%,
respectively.
H
X
NH2
N
palladacycle (1 mol%)
+
Ph
Ph
Ph
K2CO3, additive
100 oC, 24 h
Ph
2a
5
6a
Yield
X =I; additive = LiCl
X =Br; additive = dppf
83%
91%
Scheme 1.

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F. Yang et al. / Tetrahedron 67 (2011) 2969e2973
3. Conclusion
4.2.4. (3-Phenylisoquinolin-4-yl)methanol (3d)7b. White solid, mp
177e178 ꢀC (lit. 175e176 ꢀC); 1H NMR (400 MHz, CDCl3):
5.08
d
In summary, we have accomplished the convenient and efficient
synthesis of isoquinolines by a tandem reaction of imination and
palladacycle-catalyzed iminoannulation of internal alkynes with
high regioselectivity. On the other hand, we also offered a facile
protocol for the synthesis of indoles via the catalytic annulation of
o-iodoaniline or o-bromoaniline with internal alkynes. Further in-
vestigations on the application of these synthetic methodologies
are currently underway in our laboratory.
(s, 2H), 7.43 (m, 1H), 7.48 (t, J¼6.8 Hz, 2H), 7.66 (m, 3H), 7.82
(t, J¼7.7 Hz, 2H), 8.03 (d, J¼8.1 Hz, 1H), 8.31 (d, J¼8.5 Hz, 1H), 9.26
(s, 1H); 13C NMR (100 MHz, CDCl3):
d 59.4, 123.9, 125.7, 127.0, 127.7,
128.1, 128.2, 128.3, 129.7, 131.1, 135.8, 140.1, 152.3, 152.8.
4.2.5. 4,6-Dimethyl-3-phenylisoquinoline (3e). White solid, mp
95e96 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.61 (s, 3H), 2.63 (s, 3H),
7.26 (s, 1H), 7.40e7.49 (m, 3H), 7.57e7.59 (d, 2H), 7.82 (s, 1H), 7.90
(d, J¼8.2 Hz, 1H), 9.14 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 15.5,
22.5, 122.6, 123.4, 125.6, 127.4, 128.0, 128.8, 129.8, 136.4, 140.7, 141.4,
149.7, 151.8; HRMS (positive ESI) calcd for C17H16N: 234.1283
(MþþH), found: 234.1279.
4. Experimental
4.1. General methods
4.2.6. 4-Phenyl-3-(p-tolyl)isoquinoline (3f) with 3-phenyl-4-(p-tolyl)
isoquinoline (3g) (1:1)3a. White solid, mp 93e100 ꢀC (3g lit.129 ꢀC);
All commercial materials were used without further purifica-
tion. 1H and 13C NMR spectra were recorded in CDCl3 solution on
a Bruker DPX-400 spectrometer. Melting points were measured
using a WC-1 microscopic apparatus and were uncorrected. GC
analysis was performed on Agilent 4890D gas chromatograph.
Mass spectra were measured on an LC-MSD-Trap-XCT instrument.
High-resolution mass spectra were obtained on a Waters Q-Tof
MicroTM spectrometer. Ethyl acetate and hexane (analytical grade)
were used for column chromatography without purification. The
other chemicals were obtained from commercial sources and used
as received unless otherwise noted.
1H NMR (400 MHz, CDCl3):
d
2.28 (s, 3H), 2.39 (s, 3H), 7.00e7.02 (m,
2H), 7.14e7.28 (m, 16H), 7.36e7.39 (m, 4H), 7.58e7.60 (m, 2H),
8.02e8.04 (m, 1H), 9.36 (s, 2H); 13C NMR (100 MHz, CDCl3):
21.1,
d
21.3, 125.5, 125.6, 126.7, 126.8, 126.9, 127.2, 127.5, 127.6, 128.3, 128.4,
130.1,130.2,130.4, 131.0, 131.2, 136.7, 137.4,150.5, 151.5,151.7; HRMS
(positive ESI) calcd for C22H18N: 296.1439 (MþþH), found: 296.1437.
4.2.7. 7,8-Diphenyl-[1,3]dioxolo[4,5-g]isoquinoline
solid, mp 231e233 ꢀC (lit. 234e235 ꢀC); 1H NMR (400 MHz, CDCl3):
6.04 (s, 2H), 7.00 (s, 1H), 7.17e7.34 (m, 1H); 13C NMR (100 MHz,
CDCl3): 101.8, 102.1, 103.0, 124.9, 127.1, 127.5, 128.2, 130.1, 131.1,
(3h)7b. White
d
d
4.2. General procedure for synthesis of isoquinolines
134.5, 137.9, 140.9, 148.3, 149.5, 150.2, 151.4.
To a solution of o-halobenzaldehyde (0.25 mmol) in DMF (1 mL),
tert-butyl amine (0.75 mmol) was added. The resulting mixture was
stirred under a nitrogen atmosphere at room temperature for 12 h
(or 100 ꢀC for 4 h). After the haloaldehyde was consumed com-
pletely (monitored by TLC), alkynes (0.50 mmol), Na2CO3
(0.50 mmol), LiCl (0.25 mmol), palladacycle (1 mol %), and DMF
(1 mL) were added to the mixture. Then the vial was placed in
a preheated oil bath and heated at 100 ꢀC under stirring for 24 h.
After the reaction was complete (monitored by TLC), the mixture
was diluted with CH2Cl2 (10 mL), filtered through a pad of Celite,
and extracted with CH2Cl2. The combined organic phase was dried
over anhydrous Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (ethyl acetate/hexane) to afford the pure product.
4.2.8. 2,3-Diphenyl-1H-inden-1-one (4a)10. Red solid, mp 147e
149 ꢀC (lit. 152e153 ꢀC); 1H NMR (400 MHz, CDCl3):
d 7.15 (d,
J¼7.3 Hz, 1H), 7.25e7.28 (m, 6H), 7.37e7.42 (m, 6H), 7.59 (d,
J¼7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 121.2, 122.9, 127.7,
128.0, 128.5, 128.7, 128.9, 129.2, 129.9, 130.7, 132.3, 132.7, 133.4,
145.1, 155.2, 196.5.
4.2.9. 2-Methyl-3-phenyl-1H-inden-1-one (4c)11. Orange solid, mp
80e82 ꢀC (lit. 83e84 ꢀC); 1H NMR (400 MHz, CDCl3):
d
1.93 (s, 3H,
C-2 methyl), 7.07 (d, J¼7.2 Hz, 1H), 7.17e7.54 (m, 3H), 7.49 (s, 5H);
13C NMR (100 MHz, CDCl3):
8.6, 120.4, 122.5, 128.0, 128.1, 128.7,
d
129.1, 131.0, 131.1, 132.7, 133.1, 145.7, 154.7, 198.3.
4.2.10. 6,7-Diphenyl-5H-indeno[5,6-d][1,3]dioxol-5-one
(4h). Purple solid, mp 157e158 ꢀC; 1H NMR (400 MHz, CDCl3):
4.2.1. 3,4-Diphenylisoquinoline (3a)7a. White solid, mp 168e169 ꢀC
d
6.02 (s, 2H), 6.65 (s, 1H), 7.09 (s, 1H), 7.22e7.26 (s, 5H), 7.32e7.35
(lit. 170 ꢀC); 1H NMR (400 MHz, CDCl3):
d
7.19e7.21 (m, 3H),
(m, 2H), 7.40 (m, 3H); 13C NMR (100 MHz, CDCl3):
d
102.1, 104.0,
7.24e7.26 (m, 2H), 7.35e7.38(m, 5H), 7.59e7.62 (m, 2H), 7.67 (dd,
J¼4.2 and 5.3 Hz, 1H), 8.04 (dd, J¼5.1 and 4.2 Hz, 1H), 9.37 (s, 1H);
105.3, 124.7, 127.5, 128.0, 128.4, 128.9, 129.3, 129.8, 130.8, 131.4,
132.7, 141.8, 147.7, 151.6, 153.7, 195.2; HRMS (positive ESI) calcd for
C22H14O3Na: 349.0841 [MþNa]þ, found: 349.0840.
13C NMR (100 MHz, CDCl3):
d 125.6, 126.9, 127.1, 127.3, 127.6, 127.6,
128.3, 130.2, 130.5, 130.6, 131.2, 135.9, 137.2, 140.8, 150.6, 151.7.
4.3. General procedure for synthesis of indole
4.2.2. 6-Methyl-3,4-diphenylisoquinoline (3b). White solid, mp
178e179 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.45 (s, 3H), 7.18e7.20 (m,
o-Halobenzaldehyde (0.25 mmol), diphenylacetylene (0.50 mmol),
palladacycle (1 mol %), additive (0.25 mmol), and K2CO3 (0.50 mmol)
were dissolved in DMF (1.50 mL) in a 10 mL vial under air and heated at
100 ꢀC for 24 h. After the reaction was complete (monitored by TLC),
the mixture was diluted with CH2Cl2 (10 mL), filtered through a pad of
Celite, and washed multiple times with CH2Cl2. The combined organic
layerwasdried overanhydrous Na2SO4, filtered, and evaporated under
reduced pressure and the residue was purified by flash chromatogra-
phy on silica gel (ethyl acetate/hexane) to afford the pure product.
3H), 7.23e7.25 (m, 3H), 7.34e7.37 (m, 5H), 7.42e7.45 (m, 2H), 7.96
(d, J¼8.2 Hz, 1H), 9.30 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 22.4,
124.4,125.8, 126.9,127.2,127.4,127.6, 128.2, 129.1,130.1, 130.2, 131.2,
136.1, 137.4, 140.9, 150.7, 151.3; HRMS (positive ESI) calcd for
C22H18N: 296.1439 (MþþH), found: 296.1440.
4.2.3. 4-Methyl-3-phenylisoquinoline (3c)7a. White solid, mp
101e102 ꢀC (lit. 103e104 ꢀC); 1H NMR (400 MHz, CDCl3):
d 2.66 (s,
3H), 7.24e7.26 (m, 2H), 7.35e7.38(m, 5H), 7.59e7.62 (m, 2H), 7.67
(dd, J¼4.2 and 5.3 Hz, 1H), 8.04 (dd, J¼5.1 and 4.2 Hz, 1H), 9.21 (s,
4.3.1. 2,3-Diphenyl-1H-indole (6a)12. White solid, mp 113e114 ꢀC
1H); 13C NMR (100 MHz, CDCl3):
d
15.5, 123.6, 124.0, 126.6, 127.2,
(lit. 120e121 ꢀC); 1H NMR (400 MHz, CDCl3):
d 7.44e7.15(m, 13H),
127.5, 128.1, 129.8, 130.4, 136.2, 141.3, 150.1, 151.8.
7.67 (d, J¼7.9 Hz, 1H), 8.21 (s, 1H); 13C NMR (100 MHz, CDCl3):

F. Yang et al. / Tetrahedron 67 (2011) 2969e2973
2973
3. For nickel-catalyzed and cobalt-catalyzed annulation of 2-iodobenzaldimines
with alkynes, see: (a) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5149; (b) Liu,
C.-C.; Korivi, R. P.; Cheng, C.-H. Chem.dEur. J. 2008, 14, 9503.
4. Girling, I.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
5. Maassarani, F.; Pfeffer, M.; Le Borgne, G. J. Chem. Soc., Chem. Commun. 1987,
565.
d
110.9, 115.0, 119.7, 120.4, 122.7, 126.2, 127.7, 128.2, 128.5, 128.7,
130.1, 132.7, 134.1, 135.0, 135.9.
Acknowledgements
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We are grateful to the National Natural Science Foundation of
China (No. 20772114) and the Innovation Fund for Outstanding
Scholar of Henan Province (No. 621001100) for financial support to
this research.
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€
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