A novel three-component reaction for the synthesis of 1,2-dihydroisoquinolines via the reaction of isoquinoline and isocyanides with strong CH-acids in water

Article abstract of DOI:10.1016/j.tetlet.2007.11.079

A straightforward and efficient method for the synthesis of 1,2-dihydroisoquinolines via the one-pot, three-component reaction of an isocyanide, isoquinoline and a strong CH-acid in water without using any catalyst at 70 °C is reported. The method offers

Full text of DOI:10.1016/j.tetlet.2007.11.079

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Tetrahedron Letters 49 (2008) 1277–1281
A novel three-component reaction for the synthesis of
1,2-dihydroisoquinolines via the reaction of isoquinoline
and isocyanides with strong CH-acids in water
Ahmad Shaabani,* Ebrahim Soleimani and Jafar Moghimi-Rad
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Received 2 October 2007; revised 2 November 2007; accepted 14 November 2007
Available online 19 November 2007
Abstract—A straightforward and efficient method for the synthesis of 1,2-dihydroisoquinolines via the one-pot, three-component
reaction of an isocyanide, isoquinoline and a strong CH-acid in water without using any catalyst at 70 ꢀC is reported. The method
offers several advantages including high yields of products and an easy work-up procedure.
ꢁ 2007 Published by Elsevier Ltd.
1. Introduction
blood–brain barrier.8–11 These compounds also exhibit
sedative,12 antidepressant,13,14 antitumour and antimi-
crobial activity.15–17 For the functionalization of quino-
line, isoquinoline and related aromatic amines, the
Reissert reaction has remained one of the most powerful
tools.18–20 The reaction can be considered as a multi-
component reaction, where adducts are formed from
an azine, an acyl chloride and sodium cyanide via an
N-acyliminium intermediate.
Water is an ideal solvent and reagent for biochemical
transformations. In the past, water was not used as a
solvent for synthetic organic chemistry due to the poor
solubility and, in some cases, the instability of organic
reagents in aqueous solutions. Now, it has been recog-
nized that chemical reactions in mixed aqueous solu-
tions or two-phase systems often give better results
than in organic solvents and often the insolubility of
the final products facilitates their isolation.1,2
As part of our continuing interest in the development of
new synthetic methods in heterocyclic chemistry and our
interest in isocyanide-based multi-component reac-
tions,21–28 herein we describe an efficient synthesis of
1,2-dihydroisoquinolines 4 via the reaction of CH-acids
1 with isoquinoline 2 and isocyanide 3 in water at 70 ꢀC
(Scheme 1).
The isoquinoline skeleton is found in a large number of
naturally occurring and synthetic biologically active
heterocyclic compounds.3–7 In particular, 1,2-dihydro-
isoquinolines act as delivery systems that transport
drugs through the otherwise highly impermeable
OH
N
N
R
H2O
70 oC, 12 h
+
H
O
R
N
C
+
N
O
OH
O
O
2
1
3
4a-f
Scheme 1. Synthesis of 1,2-dihydroisoquinolines via the one-pot, three-component reaction of isocyanides, isoquinoline and CH-acids.
Keywords: 1,2-Dihydroisoquinoline; Isoquinoline; Isocyanide; Multi-component reactions.
*
Corresponding author. Fax: +98 21 22431663; e-mail: a-shaabani@cc.sbu.ac.ir
0040-4039/$ - see front matter ꢁ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.079

1278
A. Shaabani et al. / Tetrahedron Letters 49 (2008) 1277–1281
1
As indicated in Table 1, CH-acids, isoquinoline and iso-
cyanides undergo a smooth 1:1:1 addition reaction in
water at 70 ꢀC to produce 1,2-dihydroisoquinolines.
The structures of the products were deduced from their
The H NMR spectrum of 4a consisted of a multiplet
for the cyclohexyl ring (d = 1.12–1.89 ppm), a multiplet
for the N–CH cyclohexyl proton (d = 2.98 ppm), two
doublets for the N–CH@CH (d = 6.15 ppm, JHH
7.4 Hz) and N–CH@CH (d = 6.85 ppm, JHH = 7.4 Hz)
protons, a singlet for the N–CH@N (d = 6.61 ppm)
proton, a multiplet for the aromatic protons (d = 6.89–
3
=
1
3
IR, mass, H NMR and 13C NMR spectra. The mass
spectra of these compounds displayed molecular ion
peaks at the appropriate m/z values.
Table 1. Synthesis of 1,2-dihydroisoquinoline derivatives in water
Entry
CH-acid
R
Product
Yield (%)
Product
N
OH
O
N
H
O
1
Cyclohexyl
99
O
OH
O
4a
N
N
OH
O
H
O
O
OH
2
3
4
5
6
tert-Butyl
95
78
62
62
59
O
4b
N
N
OH
O
H
O
O
OH
1,1,3,3-Tetramethyl-butyl
O
4c
N
N
OH
H
O
O
OH
Cyclohexyl
Me
Me
Me
O
O
Me
4d
N
N
OH
O
H
O
O
OH
tert-Butyl
O
Me
4e
N
N
OH
O
H
O
O
OH
1,1,3,3-Tetramethyl-butyl
O
Me
4f

A. Shaabani et al. / Tetrahedron Letters 49 (2008) 1277–1281
1279
N
OH
O
O
O
+
+
R
N
C
R
N CH
+
N
O
O
O
C
N R
5
H
O
6
O
1
3
4
Scheme 2. Proposed mechanism.
8.15 ppm), and two broad singlets for the N–CH
isoquinoline ring and OH of the enolic tautomer
(d = 8.00 ppm and 11.96 ppm) protons. The 1H
decoupled 13C NMR spectrum of 4a showed 25 distinct
resonances, partial assignment of these resonances is
given in Section 2.
6.89–8.15 (8H, m, H-Ar), 8.00 (1H, br s, N–CH),
11.96 (1H, br s, OH). 13C NMR (75 MHz, CDCl3): dC
(ppm) 24.23, 24.31, 24.62, 31.99, 33.41 (C-cyclohexyl),
53.02 (CH–N of cyclohexyl), 57.53 (N–CH), 101.56
(CO–C@COH), 112.21, 116.09, 121.51, 123.03, 124.96,
125.64, 126.00, 126.90, 126.93, 127.35, 129.36, 131.25,
132.61, 153.07 (C-Ar, N–CH@CH), 154.15, 164.31,
174.18 (CO–C@COH, 1C@N). Anal. Calcd for
C25H24N2O3: C, 74.98; H, 6.04; N, 7.00. Found: C,
74.82; H, 5.95; N, 7.05.
The rationale for the formation of the products is shown
in Scheme 2. It is conceivable that the initial event is the
formation of acid–base complex 5 from the isocyanide
and the activated CH-acid. Complex 5 activates the iso-
cyanide functional group sufficiently for further nucleo-
philic attack by isoquinoline to produce intermediate 6.
Finally, nucleophilic attack of the conjugated base of
the CH-acid on 6 affords product 4.29
2.2. 3-(2-((tert-Butylimino)methyl)-1,2-dihydroisoquino-
lin-1-yl)chroman-2,4-dione (4b)
Colourless crystals (0.35 g, yield 95%); mp 176–178 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2966, 1657, 1649, 1507,
1451. MS, m/z (%): 374 (M+, 3), 344 (15), 288 (15),
209 (10), 183 (20), 155 (70), 121 (70), 92 (50), 64 (25),
In conclusion, we have described a new and successful
strategy for the convenient synthesis of 1,2-dihydroiso-
quinolines via a one-pot, three-component condensation
reaction of a CH-acid, isoquinoline and an isocyanide in
water at 70 ꢀC. The method offers several advantages
including high yields of products and an easy experi-
mental work-up procedure.
1
44 (100). H NMR (300 MHz, CDCl3): dH (ppm) 1.22
3
(9H, s, C(CH3)3), 6.21 (1H, d, JHH = 8.0 Hz,
N–CH@CH), 6.62 (1H, s, N–CH@N), 6.71–5.15 (9H,
m, N–CH@CH, H-Ar), 7.93 (1H, br s, N–CH), 11.86
(1H, br s, OH). 13C NMR (75 MHz, CDCl3): dC
(ppm) 28.92 (C(CH3)3), 53.01 (C(CH3)3), 55.81
(N–CH), 101.79 (CO–C@COH), 112.55, 116.15,
121.49, 123.00, 125.10, 125.58, 125.96, 126.92, 127.26,
127.57, 129.60, 131.19, 132.50, 150.51 (C-Ar, N–
CH@CH), 154.24, 164.41, 173.98 (CO–C@COH,
1C@N). Anal. Calcd for C23H22N2O3: C, 73.78; H,
5.92; N, 7.48. Found: C, 73.70; H, 5.96; N, 7.53.
2. Experimental
2.1. Typical procedure for the preparation of 3-(2-
((cyclohexylimino)methyl)-1,2-dihydroisoquinolin-1-yl)
chroman-2,4-dione (4a)
To a magnetically stirred solution of isoquinoline
(0.13 g, 1 mmol) and 4-hydroxycoumarin (1 mmol) in
H2O (3 mL) was added cyclohexyl isocyanide (1 mmol)
and the reaction heated for 12 h at 70 ꢀC. After comple-
tion of the reaction, as indicated by TLC (ethyl acetate/
n-hexane, 2:1), the reaction mixture was filtered and
washed with water (2 · 10 mL) and the solid residue
was crystallized from ethyl acetate to afford 4a as
colourless crystals (0.39 g, yield 99%); mp 194–196 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2929, 2856, 1682, 1657,
1603, 1508, 1453. MS, m/z (%): 401 (M++1, 5), 329
(15), 287 (20), 265 (99), 243 (25), 222 (45), 183 (98),
155 (100), 128 (100), 67 (30), 39 (50). 1H NMR
(300 MHz, CDCl3): dH (ppm) 1.12–1.89 (10H, m,
5CH2 of cyclohexyl), 2.98 (1H, m, CH–N of cyclohexyl),
2.3. 3-(2-((2,4,4-Trimethylpentan-2-ylimino)methyl)-1,2-
dihydroisoquinolin-1-yl)chroman-2,4-dione (4c)
Colourless crystals (0.33 g, yield 78%); mp 149–151 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2952, 1669, 1601, 1509,
1451. MS, m/z (%): 430 (M+, 3), 155 (75), 121 (78), 92
1
(60), 64 (30), 44 (100). H NMR (300 MHz, CDCl3):
dH (ppm) 0.92 (9H, s, C(CH3)3), 1.30 (3H, s,
3
C(CH3)2), 1.39 (3H, s, C(CH3)2), 1.65 (1H, d, JHH
=
3
14.2 Hz, CH2), 1.77 (1H, d, JHH = 14.2 Hz, CH2),
6.18–7.74 (11H, m, N–CH@CH, N–CH@N,H-Ar),
8.15 (1H, br s, N–CH), 12.16 (1H, br s, OH). 13C
NMR (75 MHz, CDCl3): dC (ppm) 28.45 (C(CH3)2),
19.35 (C(CH3)2), 31.22 (C(CH3)3), 31.63 (CH2), 53.56
(N–CH), 54.15 (C(CH3)3), 59.41 (C(CH3)2), 101.66
(CO–C@COH), 113.21, 116.21, 121.49, 122.78, 125.08,
125.46, 126.13, 126.40, 127.13, 127.79, 129.38, 131.08,
3
6.15 (1H, d, JHH = 7.4 Hz, N–CH@CH), 6.61 (1H, s,
N–CH@N), 6.85 (1H, d,3JHH = 7.4 Hz, N–CH@CH),

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A. Shaabani et al. / Tetrahedron Letters 49 (2008) 1277–1281
132.47, 149.86 (C-Ar, N–CH@CH), 154.26, 163.86,
173.74 (CO–C@COH, 1C@N). Anal. Calcd for
C27H30N2O3: C, 75.32; H, 7.02; N, 6.51. Found: C,
75.21; H, 7.14; N, 6.38.
6.66–7.11 (5H, m, N–CH@CH, H-Ar), 7.66 (1H, br s,
N–CH), 12.45 (1H, br s, OH). 13C NMR (75 MHz,
CDCl3): dC (ppm) 19.84 (CH3–C@CH), 28.18
(C(CH3)2), 29.82 (C(CH3)2), 31.31 (C(CH3)3), 31.69
(CH2), 53.16 (N–CH), 54.19 (C(CH3)3), 59.28
(C(CH3)2), 101.03 (CO–C@COH), 106.49, 113.02,
124.91, 126.20, 126.37, 127.02, 127.65, 129.44, 132.52,
149.78 (CH3–C@CH, C-Ar, N–CH), 160.57, 165.00,
177.93 (CO–C@COH, 1C@N). Anal. Calcd for
C24H30N2O3: C, 73.07; H, 7.66; N, 7.10. Found: C,
72.56; H, 7.60; N, 7.00.
2.4. 3-(2-((Cyclohexylimino)methyl)-1,2-dihydroisoquino-
lin-1-yl)-6-methyl-3H-pyran-2,4-dione (4d)
Colourless crystals (0.22 g, yield 62%); mp 181–191 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2927, 2856, 1688, 1633,
1488, 1451. MS, m/z (%): 365 (M++1, 2), 284 (5), 257
(5), 129 (100), 101 (30), 98 (35), 67 (50), 55 (25), 43
1
(35), 39 (35). H NMR (300 MHz, CDCl3): dH (ppm)
1.17–1.96 (10H, m, 5CH2 of cyclohexyl), 2.10 (3H, s,
Acknowledgement
CH3–C@CH), 2.92 (1H, m, CH–N of cyclohexyl), 5.76
3
(1H, s, CH3–C@CH), 6.08 (1H, d, JHH = 7.4 Hz,
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University.
N–CH@CH), 6.38 (1H, s, N–CH@N), 6.83 (1H, d,
3
3JHH = 7.2 Hz, H-Ar), 6.88 (1H, d, JHH = 7.4 Hz,
N–CH@CH), 6.95–7.08 (3H, m, H-Ar), 7.99 (1H, br s,
N–CH), 11.96 (1H, br s, OH). 13C NMR (75 MHz,
CDCl3): dC (ppm) 19.85 (3H, s, CH3), 24.40, 24.47,
24.64, 32.31, 33.14 (C-cyclohexyl), 52.49 (CH–N of
cyclohexyl), 57.50 (N–CH), 101.12 (CO–C@COH),
106.79, 112.03, 124.87, 126.07, 126.80, 126.87, 127.23,
References and notes
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132.62,
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Colourless crystals (0.20 g, yield 62%); mp 188–190 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2971, 1678, 1642, 1492,
1448. MS, m/z (%): 339 (M++1, 100), 240 (15), 170
(10), 129 (100), 130 (100), 129 (100), 102 (25), 57 (50),
1
41 (20). H NMR (300 MHz, CDCl3): dH (ppm) 1.25
(9H, s, C(CH3)3), 2.09 (3H, s, CH3–C@CH), 5.76 (1H,
3
s, CH3–C@CH), 6.13 (1H, d, JHH = 6.8 Hz, N–
CH@CH), 6.39 (1H, s, N–CH@N), 6.91–7.03 (5H, m,
N–CH@CH, H-Ar), 7.85 (1H, br s, N–CH), 12.04
(1H, br s, OH). 13C NMR (75 MHz, CDCl3): dC
(ppm) 19.83 (CH3–C@CH), 28.88 (C(CH3)3), 52.43
(C(CH3)3), 55.66 (N–CH), 101.33 (CO–C@COH),
106.79, 112.25, 125.05, 125.94, 126.75, 126.38, 127.49,
129.69, 132.54, 153.64 (C-Ar, CH3–C@CH, N–
CH@CH), 160.44, 165.84, 178.15 (CO–C@COH,
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Colourless crystals (0.23 g, yield 59%); mp 127–130 ꢀC
(dec). IR (KBr) (mmax/cmÀ1): 2961, 1668, 1605, 1509.
MS, m/z (%): 395 (M++1, 80), 129 (100), 130 (90), 129
´
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3
1.42 (3H, s, C(CH3)2), 1.66 (1H, d, JHH = 14.7 Hz,
3
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