Efficient copper(I)-catalyzed, microwave-assisted, one-pot synthesis of 3,4-diaryl isoquinolines

Article abstract of DOI:10.1007/s11164-013-1462-z

An efficient copper-catalyzed, microwave-assisted, one-pot reaction has been developed for synthesis of 3,4-diaryl isoquinolines. The reaction was performed in two steps via a CuI/2,2′-biimidazole-catalyzed tandem process from N-tert-butyl-o-iodobenzaldim

Full text of DOI:10.1007/s11164-013-1462-z

Res Chem Intermed
DOI 10.1007/s11164-013-1462-z
Efficient copper(I)-catalyzed, microwave-assisted,
one-pot synthesis of 3,4-diaryl isoquinolines
•
Zhang Hu Li-Li Ou Si-Dong Li Lei Yang
•
•
Received: 17 August 2013 / Accepted: 16 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract An efficient copper-catalyzed, microwave-assisted, one-pot reaction has
been developed for synthesis of 3,4-diaryl isoquinolines. The reaction was per-
formed in two steps via a CuI/2,20-biimidazole-catalyzed tandem process from N-
tert-butyl-o-iodobenzaldimine and a terminal aryl alkyne, followed by addition of
an aryl iodide. A variety of 3,4-diaryl isoquinolines have been obtained in moderate
to good yields.
Keywords Isoquinolines ꢀ Copper-catalyzed ꢀ One-pot synthesis ꢀ
Microwave irradiation
Introduction
The isoquinoline nucleus frequently occurs in natural products and pharmaceuti-
cally active compounds with remarkable biological activity, for example antifertility
[1], antitumor [2], anti-HIV [3, 4], analgesic [5], anti-inflammatory [6], among
others. As a consequence of their substantial biological importance, much attention
has recently been devoted to the synthesis of isoquinoline derivatives. Some
valuable approaches to isoquinolines have been developed via transition metal-
catalyzed synthesis, including use of palladium [7–10], nickel [11], cobalt [12], and
copper [13]; palladium-catalyzed processes, in particular, have received much
attention. Unfortunately, palladium-catalyzed methodology is difficult to apply
Z. Hu (&) ꢀ S.-D. Li ꢀ L. Yang
Department of Chemistry, College of Science, Guangdong Ocean University,
Zhanjiang 524088, China
e-mail: huzhangqyx@126.com
L.-L. Ou
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China
e-mail: liliouzju@163.com
123

Z. Hu et al.
because of high cost and the difficulty of removing of palladium. To the best of our
knowledge, copper-catalyzed, one-pot synthetic strategies to obtain isoquinolines
are still scarce.
It is noteworthy that microwave irradiation (MWI) is a widely applied and
powerful tool in organic synthesis; its advantages, including enormous acceleration
of the rate of reaction, and improved yields and selectivity, have been well
demonstrated [14–16]. As a continuation of our long-term interest in developing
new methods for synthesis of functionalized heterocyclic compounds [17–19], we
describe herein a copper(I)-catalyzed, one-pot, microwave-assisted procedure for
synthesis of 3,4-diaryl isoquinolines.
Experimental
General procedures
All microwave reactions were conducted in sealed, oven-dried microwave vials. An
LWMC-201 microwave reactor was used for all experiments; the conditions used
are described below. Unless otherwise indicated, all reactions were conducted under
a dry nitrogen atmosphere. The chemicals were obtained from commercial sources
and used as received unless otherwise noted. Melting points (mp) were obtained on
1
a Bu¨chi B-540 melting-point apparatus and are uncorrected. H NMR (400 MHz)
and 13C NMR (100 MHz) data were recorded on a DPX-400 instrument with CDCl3
as solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts are
given in ppm and spin–spin coupling constants, J, are given in Hz. Mass spectra
(MS) were recorded on an HP5989A mass spectrometer.
Synthesis of N-tert-butyl-o-iodobenzaldimine (1) [8]
tert-Butylamine (25.8 mmol) was added to a solution of o-iodobenzaldehyde
(2.00 g, 8.6 mmol) in CH2Cl2 (30 mL). The resulting mixture was stirred under a
nitrogen atmosphere at room temperature for 12 h. After the o-iodobenzaldehyde
had been consumed completely (monitored by TLC), the solution was concentrated
under reduced pressure, and the resulting residue was extracted with ether. The
organic phases were combined, dried with Na2SO4, and filtered. The filtrate was
evaporated under reduced pressure and N-tert-butyl-o-iodobenzaldimine was
1
afforded in 87 % yield as a pale yellow oil. H NMR (CDCl3) d: 1.30 (s, 9H),
7.02–7.06 (m, 1H), 7.28–7.35 (m, 1H), 7.78–7.89 (m, 2H), 8.37 (s, 1H). ESI–MS:
[M ? 1]? m/z 288.1.
General procedure for copper-catalyzed one-pot synthesis of isoquinolines (4)
In an oven-dried 5-mL microwave vial, N-tert-butyl-o-iodobenzaldimine (0.14 g,
0.5 mmol) was dissolved in freshly distilled dioxane (3 mL), then CuI (9.5 mg,
0.05 mmol, 10 mol%), 2,20-biimidazole (13.4 mg, 0.1 mmol, 20 mol%), Cs2CO3
(0.49 g, 1.5 mmol), and aryl alkyne (0.55 mmol) were added. The vial was purged
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Efficient copper(I)-catalyzed one-pot synthesis
with nitrogen, sealed, and placed in the microwave reactor for 20 min at 550 W. An
aryl iodide (0.55 mmol) in dry dioxane (1 mL) was added to the vial and the
resulting mixture was heated in the microwave reactor (550 W) for 20 min. After
cooling, the reaction mixture was diluted with diethyl ether and washed with brine
(10 mL). The aqueous phase was extracted with diethyl ether (2 9 5 mL). The
organic phases were combined and dried over anhydrous MgSO4. The solvent was
removed under vacuum and the residue was purified by flash column chromatog-
raphy on silica gel with ethyl acetate–hexanes (1:8 to 1:2) as eluent. The desired
products 4 were afforded.
3,4-Diphenylisoquinoline (4a)
White solid, mp 166–168 °C (lit. [7] 168–169 °C), yield 56 %; 1H NMR (CDCl3) d:
7.12–7.18 (m, 3H), 7.21–7.26 (m, 2H), 7.29–7.37 (m, 5H), 7.56–7.62 (m, 2H), 7.68
(dd, J = 4.8 and 4.2 Hz, 1H), 8.06 (dd, J = 6.0 and 4.2 Hz, 1H), 9.36 (s, 1H). 13C
NMR (CDCl3) d: 125.2, 126.7, 126.9, 127.0, 127.3, 127.4, 127.5, 128.4, 130.0,
130.3, 130.6, 131.3, 135.6, 137.3, 140.5, 150.6, 151.8. ESI–MS: [M ? 1]?
m/z 282.1.
3-Phenyl-4-p-tolylisoquinoline (4b)
White solid, mp 126–128 °C (lit. [7] 129 °C), yield 51 %; 1H NMR (CDCl3) d: 2.35
(s, 3H), 7.12–7.25 (m, 7H), 7.34–7.36 (m, 2H), 7.57–7.61 (m, 2H), 7.65–7.69 (m,
1H), 8.03–8.05 (m, 1H), 9.35 (s, 1H). 13C NMR (CDCl3) d: 21.7, 126.1, 126.9,
127.1, 127.3, 127.5, 127.6, 128.8, 130.3, 130.7, 130.9, 131.4, 134.5, 136.1, 137.2,
140.4, 150.7, 151.9. ESI–MS: [M ? 1]? m/z 296.2.
4-(4-Methoxyphenyl)-3-phenylisoquinoline (4c)
White solid, mp 143–145 °C (lit. [10] 141–142 °C), yield 57 %; 1H NMR (CDCl3)
d: 3.83 (s, 3H), 7.00 (d, J = 7.2 Hz, 2H), 7.13–7.25 (m, 5H), 7.36 (d, J = 7.2 Hz,
2H), 7.58–7.62 (m, 2H), 7.68–7.70 (m, 1H), 8.01–8.03 (m, 1H), 9.34 (s, 1H). 13C
NMR (CDCl3) d: 55.1, 114.2, 126.1, 127.0, 127.3, 127.5, 127.8, 128.5, 129.3, 130.3,
130.5, 131.1, 133.0, 136.5, 140.5, 150.9, 151.8, 159.2. ESI–MS: [M ? 1]?
m/z 312.1.
4-(4-Nitrophenyl)-3-phenylisoquinoline (4d)
1
Yellow white solid, mp 134–136 °C, (lit. [10] 133–134 °C), yield 63 %; H NMR
(CDCl3) d: 7.21–7.25 (m, 3H), 7.29–7.32 (m, 2H), 7.39–7.45 (m, 2H), 7.52–7.55
(m, 1H), 7.63–7.68 (m, 2H), 8.05–8.09 (m, 1H), 8.21–8.24 (m, 2H), 9.40 (s, 1H).
13C NMR (CDCl3) d: 125.1, 125.8, 127.0, 127.5, 127.9, 128.3, 128.5, 128.7, 130.5,
131.3, 131.9, 133.2, 140.5, 145.8, 147.0, 150.6, 152.0. ESI–MS: [M ? 1]?
m/z 327.2.
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Z. Hu et al.
3-(4-Methoxyphenyl)-4-p-tolylisoquinoline (4e)
White solid, mp 156–158 °C, yield 65 %; 1H NMR (CDCl3) d: 2.33 (s, 3H), 3.84 (s,
3H), 7.02 (d, J = 7.2 Hz, 2H), 7.13–7.25 (m, 4H), 7.35–7.37 (m, 2H), 7.59–7.63
(m, 2H), 7.66–7.70 (m, 1H), 8.02–8.05 (m, 1H), 9.35 (s, 1H). 13C NMR (CDCl3) d:
21.8, 55.2, 114.3, 126.2, 127.0, 127.2, 127.5, 127.7, 128.5, 129.1, 130.0, 130.2,
130.6, 131.0, 133.2, 140.4, 150.8, 151.7, 159.1. ESI–MS: [M ? 1]? m/z 326.3.
3,4-Bis(4-methoxyphenyl)isoquinoline (4f)
White solid, mp 149–151 °C, yield 62 %; 1H NMR (CDCl3) d: 3.84 (s, 6H), 7.01 (d,
J = 7.2 Hz, 2H), 7.08 (d, J = 7.2 Hz, 2H), 7.33–7.37 (m, 2H), 7.58–7.63 (m, 3H),
7.64–7.71 (m, 2H), 8.02–8.06 (m, 1H), 9.34 (s, 1H). 13C NMR (CDCl3) d: 55.1,
114.2, 114.3, 126.1, 126.8, 127.2, 127.6, 127.9, 128.4, 128.6, 129.1, 130.5, 131.0,
140.5, 150.7, 151.6, 159.1, 160.2. ESI–MS: [M ? 1]? m/z 342.1.
3-(4-Methoxyphenyl)-4-(4-nitrophenyl)isoquinoline (4g)
1
Yellow white solid, mp 179–181 °C, (lit. [10] 181–182 °C), yield 71 %; H NMR
(CDCl3) d: 3.81 (s, 3H), 6.99 (d, J = 7.2 Hz, 2H), 7.26–7.32 (m, 2H), 7.48–7.54 (m,
Table 1 Optimization of copper-catalyzed one-pot synthesis of isoquinolines
N
I
N
2a
3a
CuI, base
2,2'-biimidazole
I
MWI
N
MWI
1
4a
Entry Catalyst/L
Amount of catalyst (L) Solvent
Base
MWI
Yield (%)a
1
CuI/L
CuI/L
CuI/L
CuI/L
CuI/L
CuI/L
CuI/L
10 (20) mol%
10 (20) mol%
10 (20) mol%
10 (20) mol%
10 (20) mol%
10 (20) mol%
10 (20) mol%
Toluene
DMF
Cs2CO3 550 W, 20 min 25
Cs2CO3 550 W, 20 min 34
2
3
Dioxane Cs2CO3 550 W, 20 min 56
THF Cs2CO3 550 W, 20 min 22
Dioxane K2CO3 550 W, 20 min 37
4
5
6
Dioxane Cs2CO3 600 W, 20 min 52
Dioxane Cs2CO3 450 W, 20 min 39
7
8
Cu(OAc)2/L 10 (20) mol%
Dioxane Cs2CO3 550 W, 20 min
7
9
CuCl/L
CuI/L
CuI/L
10 (20) mol%
5 (10) mol%
20 (40) mol%
Dioxane Cs2CO3 550 W, 20 min 15
Dioxane Cs2CO3 550 W, 20 min 31
Dioxane Cs2CO3 550 W, 20 min 58
10
11
Reaction conditions: after mixing of 1 (1.0 equiv), 2a (1.1 equiv), CuI (10 mol%), 2,20-biimidazole
(20 mol%), and base (3.0 equiv), the mixture was microwaved in microwave-resistant vials for 20 min,
then 3a (1.1 equiv) was added and the mixture was again treated with microwaves for 20 min
a
Isolated yields
123

Efficient copper(I)-catalyzed one-pot synthesis
3H), 7.65–7.70 (m, 2H), 8.04–8.06 (m, 1H), 8.21–8.25 (m, 2H), 9.37 (s, 1H). 13C
NMR (CDCl3) d: 55.2, 114.2, 124.6, 125.1, 126.9, 127.2, 128.0, 128.4, 131.0, 131.5,
132.5, 134.6, 145.4, 147.0, 150.8, 152.7, 159.2. ESI–MS: [M ? 1]? m/z 357.1.
4-(4-(4-Methoxyphenyl)isoquinolin-3-yl)benzonitrile (4h)
White solid, mp 136–138 °C, yield 33 %; 1H NMR (CDCl3) d: 3.83 (s, 3H), 7.02 (d,
J = 7.2 Hz, 2H), 7.36–7.39 (m, 2H), 7.58–7.61 (m, 3H), 7.65–7.70 (m, 3H),
7.78–7.80 (m, 1H), 8.06–8.09 (m, 1H), 9.38 (s, 1H). 13C NMR (CDCl3) d: 55.4,
111.5, 114.2, 117.6, 126.3, 126.9, 127.3, 128.2, 128.3, 128.6, 128.7, 129.2, 130.7,
131.2, 140.6, 146.2, 150.8, 151.9, 159.2. ESI–MS: [M ? 1]? m/z 337.2.
4-(4-(4-Nitrophenyl)isoquinolin-3-yl)benzonitrile (4i)
1
Yellow white solid, mp 152–153 °C, yield 36 %; H NMR (CDCl3) d: 7.38–7.44
(m, 2H), 7.53–7.56 (m, 1H), 7.62–7.70 (m, 5H), 7.78–7.81 (m, 1H), 8.09–8.11 (m,
1H), 8.22–8.26 (m, 2H), 9.43 (s, 1H). 13C NMR (CDCl3) d: 111.5, 117.7, 125.7,
126.4, 127.1, 127.4, 128.3, 128.6, 128.9, 129.0, 129.4, 131.5, 132.2, 141.8, 147.1,
152.6, 154.8, 159.3. ESI–MS: [M ? 1]? m/z 352.1.
Results and discussion
N-tert-butyl-o-iodobenzaldimine (1), phenylacetylene (2a), and iodobenzene (3a)
were used as the starting materials to develop a procedure for one-pot, microwave-
assisted synthesis of isoquinoline 4a. Initially, one-pot, three-component reactions in
the presence of CuI–2,20-biimidazole (L) and Cs2CO3 in dioxane under different
reaction conditions with MWI were investigated; LC–MS analysis revealed the
desired products were obtained in low yields (\5 %). After more tests, we found that
better yields could be achieved by stepwise MWI. Thus, the one-pot, two-step
procedure for synthesis of isoquinolines was developed. A study of the effect of
different solvents (toluene, DMF, dioxane, and THF) on the reactions was performed
and dioxane seemed to be the best solvent for the processes (Table 1, entries 1–4).
Comparison of the efficiency of different bases in the reaction revealed Cs2CO3 was
more effective than K2CO3 (Table 1, entries 3 and 5). Different levels of irradiation
were also investigated. It was observed that microwave power at 550 W gave better
results (Table 1, entries 3, 6 and 7). A brief study of several copper compounds as
catalyst was conducted. CuI furnished acceptable results, whereas Cu(OAc)2 and
CuCl performed poorly in the reactions (Table 1, entries 3, 8, and 9). In an effort to
determine the optimum amount of CuI (L) we found that 10 (20) mol% was the best
choice. When the amount of CuI (L) was decreased to 5 (10) mol%, the yield was
dramatically reduced. It should be noted that no significant effect on reactivity was
observed when the amount of CuI (L) was raised from 10 (20) to 20 (40) mol% whereas
product yield improved slightly from 56 to 58 % (Table 1, entries 3, 10, and 11).
Encouraged by these results, we started to investigate the scope of this one-pot
synthesis under the optimized conditions (CuI (10 mol%), 2,20-biimidazole
123

Z. Hu et al.
Table 2 Copper-catalyzed one-pot synthesis of isoquinolines 4 under microwave irradiation
CuI, Cs2CO3
Ar
2,2'-biimidazole
dioxane
N
N
R1
ArI
R1
N
I
MWI (550W)
20 min
MWI (550W)
20 min
R1
1
4
Entry
1
R1
Ar
Product
Yield (%)a
56
N
4a
CH3
2
51
CH3
N
4b
OCH3
3
57
OCH3
N
4c
NO2
4
63
NO2
N
4d
CH3
OCH3
5
65
CH3
OCH3
N
4e
123

Efficient copper(I)-catalyzed one-pot synthesis
Table 2 continued
Entry
R1
Ar
Product
Yield (%)a
OCH3
OCH3
6
62
OCH3
OCH3
N
4f
NO2
OCH3
7
71
OCH3
NO2
N
4g
OCH3
CN
8
33
OCH3
CN
N
4h
NO2
CN
9
36
NO2
CN
N
4i
a
Isolated yields after column chromatography
(20 mol%), Cs2CO3 (3.0 equiv), dioxane, MWI 550 W, 20 min). The 3,4-diaryl
1
isoquinolines were characterized by electrospray LC–MS, and H NMR and 13C
NMR spectroscopy. The results are summarized in Table 2. These results show that
yields of the isoquinolines depended on the nature of substituents on the aryl
acetylenes. When aryl acetylenes bearing electron-donating groups were used, the
corresponding isoquinoline derivatives were obtained in moderate to good yields
(Table 2, entries 5, 6, and 7). When the strongly electron-withdrawing cyano group
was present on the aryl acetylene, yields decreased drastically, and isoquinolines 4h
and 4i were isolated in 33 and 36 % yields, respectively (Table 2, entries 8 and 9).
When different aryl iodides were used, no significant electronic effect was observed.
When the reaction was conducted using aryl iodides with electron-withdrawing
123

Z. Hu et al.
N
N
CuI/L
R1
N
R1
I
Ar
R1
2
1
4
A
reductive
elimination
N
L: 2,2'-biimidazole
N
D
B
L
electrophilic
cyclization
R1
I
R1
Cu
I
L
N
I
L
Cu
Ar
SN2 displacement
I
CuI
ArI
Ar
R1
I
oxidative
addition
C
3
Cu
L
Ar
Scheme 1 A proposed mechanism for the copper-catalyzed synthesis of 3,4-diaryl isoquinolines
groups, good results were obtained (Table 2, entries 4 and 7). Surprisingly, aryl
iodides bearing electron-donating groups were well tolerated and afforded the
desired isoquinolines in satisfactory yields (Table 2, entries 2, 3, 5, and 6). These
results can be rationalized as a consequence of the high nucleophilicity of the tert-
butylimine moiety.
Mechanistically, we believe that the overall process involves two steps
(Scheme 1). First, CuI/2,20-biimidazole can catalyze the coupling of N-tert-butyl-
o-iodobenzaldimine (1) with aryl alkynes (2) to form N-tert-butyl-o-(1-alky-
nyl)benzaldimine (A). Oxidative addition of aryl iodide (3) to CuI with 2,20-
biimidazole affords an electrophilic species, which activates the alkyne triple bond
of (A) by coordination to form a p-copper complex (B), which subsequently
undergoes electrophilic cyclization leading to (C), tert-butyl group removal via SN2
displacement leading to (D), and reductive elimination affording the corresponding
3,4-diaryl isoquinoline (4).
Conclusions
In summary, we have developed an experimentally simple procedure for synthesis
of 3,4-diaryl isoquinolines. The most important aspect of the method was use of a
copper-catalyzed system. Although product yields were sometimes restricted if the
aryl acetylenes bore electron-withdrawing groups, the inexpensive CuI, the
convenient availability of the ligand, and experimental ease are still attractive for
isoquinoline preparation in many cases.
Acknowledgments This work was supported by the Program for Excellent Talents in Guangdong
Ocean University (Grant No. 0912118).
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