Facile benzannulation of isocoumarins in the efficient synthesis of diversified 1,3-disubstituted isoquinolines

Article abstract of DOI:10.1007/s11164-011-0351-6

An efficient and facile one-pot synthesis of 1,3-disubstituted isoquinolines 3 was accomplished from 3-substituted isocoumarins 1 through diketones, formed in situ via the Grignard reaction, in the presence of ammonium acetate, montmorillonite K-10 catalyst, and ethanol solvent. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0351-6

Res Chem Intermed (2012) 38:347–357
DOI 10.1007/s11164-011-0351-6
Facile benzannulation of isocoumarins in the efficient
synthesis of diversified 1,3-disubstituted isoquinolines
•
•
•
P. Manivel K. Prabakaran F. Nawaz Khan
Jong Sung Jin
Received: 20 April 2011 / Accepted: 16 July 2011 / Published online: 30 July 2011
Ó Springer Science+Business Media B.V. 2011
Abstract An efficient and facile one-pot synthesis of 1,3-disubstituted isoquinolines 3
was accomplished from 3-substituted isocoumarins 1 through diketones, formed in situ
via the Grignard reaction, in the presence of ammonium acetate, montmorillonite K-10
catalyst, and ethanol solvent.
Keywords Annulations Á 1,3-disubstituted isoquinolines Á Ammonium acetate Á
MK-10 clay Á Grignard reaction Á Diketones
Introduction
Isocoumarins have been useful intermediates in the synthesis of a variety of
important carbocyclics and heterocyclics [1, 2]. Recently, much attention has been
directed towards palladium catalyzed annulations and electrophilic cyclization of
alkynes as powerful methods for the construction of various heterocycles, such as
isochromenes [3], isoquinolines [4] and benzfurans [5], under mild conditions. The
1,3-disubstituted isoquinolines skeleton forms an integral part of many naturally
occurring substances, including pharmaceutically important compounds [6–10], as
chiral ligands for the transition metal catalysts [11], and their iridium complexes in
organic light-emitting diodes (OLEDs) [12].
P. Manivel Á K. Prabakaran Á F. Nawaz Khan (&)
Organic & Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F. Nawaz Khan Á J. S. Jin (&)
Division of High Technology Materials Research, Busan Center, Korea Basic Science Institute
(KBSI), Busan 618 230, Korea
e-mail: jsjin@kbsi.re.kr
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A number of methods have been developed for the synthesis of 1,3-disubstituted
isoquinolines including palladium-catalyzed cross-coupling of iodine-mediated electro-
philic cyclization of 2-alkynylbenzaldoximes [13], copper-catalyzed tandem synthesis
of [1–3] triazolo[5,1-a]isoquinolines [14], irradiation of 1-methoxy-2-azabuta-1,
3-dienes in neutral medium [15], isobenzofuran-nitrile Diels–Alder reaction [16],
light-induced iminyl radical cyclization of acyloximes [17], and silver- [18] and gold
[19]-catalyzed cyclization of 2-alkynyl benzyl azides. Disubstituted isoquinolines were
prepared under mild conditions from allylbenzenes and nitriles using silver triflurom-
ethanesulfonate and iodine [20]. The disubstituted isoquinolines are endowed with an
extensive range of biological activities [21–23]. Moreover, they display potent thrombin
inhibitory activity and antibacterial activity against Gram-positive bacteria [22].
Although the above-mentioned classical methods have been employed in the synthesis
of isoquinolines, these approaches have considerable drawbacks, including the use of
strong acids and elevated temperatures, many transition metal catalysts, use of trimethyl
aluminium in asymmetric synthesis methods and copper catalysts, which are not suitable
for sensitive substrates. Recently, we have reported the synthesis of diketones by the
Grignard reaction of 3-substituted isocoumarin [24, 25]. As an extension of this study,
here we report the intramolecular cyclization of diketones (formed from isocoumarins via
the Grignard reaction and without isolating the product from the reaction mixture) using
ammonium acetate and Montmorillonite K-10 acidic catalyst.
This provides an efficient economically and environmentally friendly methodology
which is in progress in our laboratory for the synthesis of diversified 1,3-disubstituted
tetrahydroisoquinolines, TIQ, specifically analogues of (-)-norcriptostiline,
(?)-cryptostiline II, alkaloid (-)-salsolidine, laudanozine and (-)-carnegine, and
also other isoquinoline system which pave their way to berberine alkaloids.
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Facile benzannulation of isocoumarins
349
As a continuation of our research interest in isoquinolines and other heterocyclics
[24–41], the synthesis of a series of 1,3-disubstituted isoquinolines is reported. The
reaction of isocoumarin 1 with various Grignard reagents, 2 in tetrahydrofuran at
-30 to 25 °C for 1h (RT) afforded diketones, which without isolating from the
reaction mixture, further treated with ammonium acetate and in the presence of
Montmorillonite K-10 catalyst, and ethanol solvent at 70 °C afforded 1,3-
disubstituted isoquinolines 4 in good yields (Scheme 1).
In our preliminary attempt, the reaction between 3-phenylisocoumarin 1a and
phenyl magnesium bromide afforded the corresponding diketone which, when
further reacted with ammonium acetate in the presence of ethanol and Montmo-
rillonite K-10 catalyst under reflux condition, produced the cyclised product in good
yields (Scheme 2). In attaining the optimized condition, screening of various
catalysts in the presence of ammonium acetate and ethanol solvent was investigated
as shown in Table 1. The reaction in the presence of Montmorillonite K-10 catalyst
produced the desired product in an excellent yield in comparison to other catalysts.
The effect of solvent in the benzannulation reaction was also investigated using
the diketones obtained from 3-phenylisocoumarin 1a and 2a (Scheme 2; Table 2).
Among all the solvents tested, ethanol proved to be excellent at 70 °C (entry 2),
while isopropanol, xylene, toluene and 1,4-dioxane were found to be moderately
effective in the reaction. With the optimized solvent and catalyst system, the effect
of the amount of ammonium acetate in the reaction was explored (Scheme 2;
O
R'
MK-10
NH4OAc
R'MgBr
(1.1 eq) 2a-j
O
N
THF
-78 to 25 oC
Ethanol
reflux
R
R
1
3 (a-l)
R= Phenyl, 4-chlorophenyl, 4-methylphenyl
R’= phenyl, methyl, isopropyl, cyclopentyl, cyclohexyl, 3-methoxyphenyl, 2,4-
dichlorphenyl,benzyl, biphenyl, 4-pyridyl
Scheme 1 Synthesis of 1,3-disubstituted isoquinolines
O
MK-10
NH4OAc
PhMgBr
(1.1 eq) 2a
O
N
THF
Ethanol
reflux
-78 to 25 oC
1a
3a
Scheme 2 Synthesis of 1,3-diphenylisoquinoline 3a from 3-phenylisocoumarin 1a
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P. Manivel et al.
Yielda(%)
Table 1 Effect of catalysts in
the benzannulation reaction
Entry
Catalyst
1
2
3
4
5
6
7
Nil
No reaction
No reaction
85
Con. HCl
MK-10
Amberlyst
Acetic acid
Trifluoroacetic acid
Perchloric acid
No reaction
No reaction
No reaction
No reaction
Ammonium acetate (5.0 eq),
catalyst (10 mol %), ethanol
(10 volume), reflux at 70 °C,
12 h
a
Isolated yields
Table 2 Effect of solvents in
the benzannulation reaction
Entry
Solvent
Yielda (%)
1
2
3
4
5
6
7
THF
50
85
52
67
68
74
72
Ethanol
Acetonitrile
1,4-dioxane
Toluene
Ammonium acetate (5.0 eq),
Montmorillonite K-10 (10 mol
%), solvent (10 volume), reflux
at 70 °C, 12 h
Isopropanol
Xylene
a
Isolated yields
Table 3 Optimization of the
amount of ammonium acetate in
the benzannulation reaction
Entry
Ammonium acetate
equivalents
Yielda (%)
1
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
20
28
35
46
57
63
72
79
85
85
85
85
2
3
4
5
6
7
8
9
Montmorillonite K 10 (10 mol
%), ethanol (10 volume), reflux
at 70 °C, 12 h
10
11
12
a
Isolated yields
Table 3). The results indicated that increasing amounts of ammonium acetate
steadily increased the yield up to 85% with 5 equivalents of ammonium acetate, but
beyond that excess ammonia is liberated and further increases do not provide any
satisfactory advantages.
With the optimized result to hand, various 1,3-disubstituted isoquinolines were
synthesized and the results are reported (Scheme 1; Table 4). The desired products
3a–l were obtained in high yield and purity and were characterized by different
spectral techniques.
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Facile benzannulation of isocoumarins
351
The role of montmorillonite K10 in the formation of isoquinolines 3 is well
understood as shown below. The first step may involve the Grignard reaction to
form the diketone derivatives, which undergo condensation to produce the
isoquinolines; the ammonium acetate was used as the source of ammonia. The
condensation is promoted by the montmorrillonite K10 catalyst. The imine
intermediate, formed in the reaction of diketone and ammonia, was activated by
the montmorillonite K10 resulting in enolic intermediate, which later, with the
elimination of water and catalyst, produced the corresponding isoquinolines in high
yield and purity.
Experimental section
Solvents and reagents were purchased from Sigma Aldrich, India, and used without
further purification or preparation. Montmorillonite K-10 catalyst having the surface
area of 250 m2/g was purchased from Sigma-Aldrich. Thin-layered chromatography
(TLC) was performed on preparative plates of silica gel (S.D. fine, India). Column
chromatography was performed by using silica gel (60–120 mesh). Melting points
were taken on Elchem microprocessor-based DT apparatus in open capillary tubes.
IR spectra were obtained on a Nucon infrared spectrophotometer using KBr pellets.
The NMR spectra were recorded on a Bruker-500 MHz spectrometer including 1H,
13C and LC–MS.
General procedure
A mixture of isocoumarin 1 (2.25 mmol), and THF solvent (10 mL) was cooled to
-30 °C using dry ice and acetone. We then added Grignard reagent 2 (1.1 eq) and
slowly warmed the reaction to 22–25 °C over a period of 45 min. The reaction was
monitored by TLC. After completion of the reaction, the mixture was quenched
using aq.NH4Cl solution and then extracted with DCM (50 mL). The DCM layer
was dried over sodium sulphate, filtered in 250-mL single neck RB flask to which
was then added ammonium acetate (5.0 eq), MK-10 catalyst (10 mol%) and
concentrated solution to 1–2 volume stage. The mixture was heated to reflux in the
presence of ethanol solvent at 90 °C for 12 h. The reaction was monitored by TLC.
After completion of the reaction, the mixture was filtered off using a funnel and the
filtrate concentrated and purified by column chromatography using ethyl acetate/
petether as eluent to produce the pure products 3 (Table 4). The compounds were
1
confirmed by H NMR, 13C NMR, FTIR and MS techniques.
The analysis data of 3a–j are given below
3a White solid: mp 165.8 °C; IR (m cm-1), 3,056, 2,920, 2,850, 1,722, 1,620,
1,566, 1,494, 1,443, 1,384, 1,332, 1,266, 1,138, 1,070, 1,025, 963, 878, 848, 742,
1
687, 581, 557, 511; H NMR (400 MHz, CDCl3): d 7.85–7.82 (2H, d, J = 8.31),
7.40–7.11 (11H, m), 6.68–6.66 (1H, d, J = 7.59), 6.51 (1H, s); 13C NMR (100
MHz, CDCl3): d 151.1, 143.8, 134.4, 133.2, 131.8, 128.6, 128.5, 128.3, 128.28,
128.22, 127.8, 127.7,127.6, 127.2, 126.0, 124.9, 124.0; LC–MS: m/e 282.2,
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P. Manivel et al.
Table 4 Synthesis of 1,3-disubstituted isoquinolines
Entry
1
Isocoumarin, 1
Grignard reagent,
Product, 3
Yielda (%)
R’MgBr, 2
O
O
MgBr
85
N
2a
3a
3b
1a
O
O
CH3
N
H3C MgBr
2
3
72
77
2b
1a
O
H3C
CH3
N
O
BrMg
3c
2c
1a
O
O
BrMg
4
5
74
3d
N
N
2d
1a
O
O
MgBr
3e
2e
80
84
1a
O
O
OCH3
MgBr
2f
OCH3
6
7
3f
N
1a
O
O
Cl
MgBr
Cl
Cl
76
70
2g
1a
3g
N
Cl
O
O
BrMg
8
3h
N
2h
1a
123

Facile benzannulation of isocoumarins
353
Table 4 continued
Entry
Isocoumarin, 1
Grignard reagent,
Product, 3
Yielda (%)
R’MgBr, 2
O
O
9
87
MgBr
N
1a
2i
3i
O
O
N
10
11
74
N
MgBr
3j
N
1a
2j
O
MgBr
O
2a
86
89
N
3k
1b
CH3
CH3
O
MgBr
O
3l
2a
12
N
1c
Cl
Cl
Grignard reagent 2 (1.1 eq), THF, -30 to 25 °C (1 h), ammonium acetate (5.0 eq), Montmorillonite
K-10 (10 mol %), ethanol (10 volume), reffux at 70 °C, 12 h
a
Isolated yields
C21H15N requires Mol. Wt.: 281.12. Elemental analysis, calculated for C21H15N: C,
89.65; H, 5.37; N, 4.98%. Found: C, 89.59; H, 5.31; N, 4.89%.
3b White solid: mp, 147.8 °C, IR (m cm-1), m3,053, 3,025, 2,920, 2,853, 1,568,
1,488, 1,444, 1,379, 1,283, 1,232, 1,141, 1,099, 1,073, 1,051, 1,021, 962, 915, 875,
1
851, 790, 757, 698, 626, 609, 556, 504; H NMR (400 MHz, CDCl3) d 7.77–7.74
(2H, d, J = 9.63), 7.40–7.36 (3H, m), 7.21–7.11 (5H, m), 6.4 (1H, s), 3.05 (1H, s);
13C NMR (100 MHz, CDCl3): d 150.9, 136.2, 135.0, 130.3, 128.5, 128.1, 127.4,
126.6, 124.9, 124.0, 122.3, 100.1, 78.4, 26.9; LC–MS: m/e 220.2, C16H13N requires
Mol. Wt.: 219.1. Elemental analysis, calculated for C16H13N: C, 87.64; H, 5.98; N,
6.39%. Found: C, 87.58; H, 5.90; N, 6.32%.
3c White solid, mp, 167.5 °C, IR (m cm-1), 3,056, 3,023, 2,955, 2,924, 2,867,
2,361, 1,618, 1,600, 1,564, 1,485, 1,465, 1,450, 1,382, 1,366, 1,277, 1,205, 1,076,
1,052, 1,026, 972, 936, 907, 811, 757, 684; 1H NMR (400 MHz, CDCl3)
123

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P. Manivel et al.
d:7.81–7.78 (2H, d, J = 8.46), 7.43–7.34 (3H, m), 7.24–7.02 (4H, m); 13C NMR
(100 MHz, CDCl3): d 151.7, 134.6, 131.2, 130.1, 128.6, 128.3, 127.7, 125.9, 125.1,
124.8, 123.8, 100.0, 83.5, 31.3, 19.3, 17.9; LC–MS: m/e 248.2, C18H17N requires
Mol. Wt.: 247.14. Elemental analysis, calculated for C18H17N: C, 87.41; H, 6.93; N,
5.66%. Found: C, 87.36; H, 6.85; N, 5.59%.
3d White solid, mp, 78.8 °C, IR (m cm-1), 3,053, 3,017, 2,942, 2,862, 1,619,
1,599, 1,564, 1,490, 1,451, 1,365, 1,298, 1,275, 1,153, 1,048, 1,023, 908, 809, 758,
751, 686, 617; 1H NMR (400 MHz, CDCl3) d: 7.80–7.78 (2H, d, J = 6.93),
7.43–7.35 (3H, m), 7.26–7.06 (4H, m), 6.45 (1H, s), 1.93–1.90 (1H, m), 1.71–1.43
(8H, m); 13C NMR (100 MHz, CDCl3): d 151.6, 134.6, 131.1, 128.6, 128.3, 127.7,
126.0, 125.0, 124.7, 123.7, 100.3, 82.3, 42.3, 29.4, 29.2, 25.3; LC–MS: m/e 273.7,
C20H19N requires Mol. Wt.: 273.15. Elemental analysis, calculated for C20H19N: C,
87.87; H, 7.01; N, 5.12%. Found: C, 87.84; H, 6.95; N, 5.06%.
3e White solid, mp, 59.7 °C, IR (m cm-1), 3,058, 2,923, 2,844, 1,968, 1813, 1,618,
1,591, 1,561, 1,496, 1,444, 1,404, 1,372, 1,325, 1,268, 1,196, 1,141, 1,072, 1,028,
991, 917, 884, 849, 800, 770,750, 687, 571; 1H NMR (400 MHz, CDCl3) d:
8.27–8.24 (2H, d, J = 8.58), 8.21 (1H, s), 7.93 (1H, s), 7.88–7.85 (1H, d, J = 8.01),
7.67–7.62, (1H, t, J = 7.86), 7.58–7.49 (3H, m), 7.43–7.41 (1H, d, J = 7.14), 3.60
(1H, m), 2.09–1.84 (7H, m), 1.61–1.44 (3H, m); 13C NMR (100 MHz, CDCl3): d
165.2, 149.3, 140.0, 137.2, 129.4, 128.6, 128.2, 128.0, 126.8,126.4,125.3, 124.7,
114.2, 41.8, 32.6, 26.9, 26.3; LC–MS: m/e 288.2, C21H21N requires Mol. Wt.:
287.17. Elemental analysis, calculated for C21H21N: C, 87.76; H, 7.36; N, 4.87%.
Found: C, 87.67; H, 7.27; N, 4.78%.
3f White solid, mp, 110.2 °C; IR (m cm-1), 3,063, 3,032, 2,992, 2,960, 2,918,
2,851, 2,829, 2,361, 1,951, 1,923, 1,662, 1,617,1606, 1,578, 1,559, 1,484, 1,446,
1,431, 1,378, 1,363, 1,337, 1,284, 1,178, 1,244, 1,170, 1,141, 1,086, 1,057, 1,044,
1
983, 921, 894, 865, 858, 806, 799, 780, 765, 758, 690, 564; H NMR (400 MHz,
CDCl3) d: 8.21–8.14 (m, 3H), 8.09 (1H, s), 7.96–7.94 (1H, d, J = 8.13), 7.74–7.69
(1H, t, J = 8.1), 7.53–7.36 (m, 1H), 7.12–7.10 (1H, d, J = 8.10), 3.91 (3H, s); 13C
NMR (100 MHz, CDCl3): d 160.1, 159.5, 149.9, 139.1, 137.8, 130.4, 129.2, 128.7,
128.6, 127.7, 127.4, 127.2, 127.1, 125.8, 122.7, 116.2, 115.6, 114.6, 55.4; LC–MS:
m/e 312.2, C22H17NO requires Mol. Wt.: 311.13. Elemental analysis, calculated for
C22H17NO: C, 84.86; H, 5.50; N, 4.50; O, 5.14%. Found: C, 84.79; H, 5.42; N,
4.44%.
3g White solid, mp, 108.4 °C, IR (m cm-1), 3,058, 3,033, 2,924, 2,361, 1954,
1,896, 1,619, 1,588, 1,576, 1,563, 1,545, 1,496, 1,468, 1,451, 1,438, 1,398, 1,370,
1,332, 1,251, 1,207, 1,177, 1,126, 1,072, 1,022, 985, 876, 850, 827,764, 745, 722,
1
674, 607, 569; H NMR (400 MHz, CDCl3) d: 8.21–8.18 (2H, d, J = 8.58), 8.11
(1H, s), 8.07–8,04(1H, d, J = 8.49), 7.97–7.93 (2H, m), 7.74–7.69 (1H, t,
J = 7.95), 7.65 (2H, s), 7.58–7.43 (4H, m); 13C NMR (100 MHz, CDCl3): d
157.6, 150.3, 139.1, 137.8, 132.9, 132.6, 132.0, 130.3, 130.2, 129.4, 128.6, 127.3,
127.0, 126.7, 125.4, 116.2; LC–MS: m/e 350.2, C21H13Cl2N requires Mol. Wt.:
349.04. Elemental analysis, calculated for C21H13Cl2N: C, 72.01; H, 3.74; Cl, 20.24;
N, 4.00%. Found: C, 72.13; H, 3.67; N, 3.94%.
123

Facile benzannulation of isocoumarins
355
3h White solid, mp, 168.4 °C, IR (m cm-1), 3,052.7, 3,021.8, 2,920.9, 1,628.9,
1,594.4, 1,483.8, 1,443.8, 1,338.6, 1,283.1, 1,230.4, 1,203.4, 1,178.8, 1,155.0,
1
1,047.7, 1,023.1, 963.3, 923.2, 866.8, 812.3, 750.9, 692.1, 629.0, 557.4, 537.6; H
NMR (400 MHz, CDCl3) d: 8.35–8.25 (1H, m), 7.91–7.84 (1H, m), 7.56–7.52 (3H,
m), 7.37–7.31 (3H, m), 7.25–7.23 (2H, m), 7.18 (5H, bs), 5.72 (2H s); 13C NMR
(100 MHz, CDCl3): d 148.2, 141.2, 139.6, 135.2, 133.5, 131.1, 129.7, 129.1, 127.7,
127.5, 127.4, 126.8, 126.3, 125.4, 123.1, 122.4, 120.9, 29.6; LC–MS: m/e 297.2,
C22H17N requires Mol. Wt.: 295.14. Elemental analysis, calculated for C22H17N: C,
89.46; H, 5.80; N, 4.74%. Found: C, 89.44; H, 5.75; N, 4.65%.
3i White solid, mp, 189.6 °C, IR (m cm-1), 3,056, 3,302, 2,921, 2,851, 1,635,
1,597, 1,567, 1,481, 1,451, 1,444, 1,342, 1,303, 1,204, 1,180, 1,157, 1,077, 1,051,
1
1,025, 964, 924, 815, 776, 752, 709, 693, 631; H NMR (400 MHz, DMSO d6) d:
8.47 (1H, s), 8.30–8.28 (2H, d, J = 7.2), 8.15–8.12 (2H, d, J = 8.0), 7.90–7.85 (m
4H), 7.82–7.80 (d, J = 7.2, 3H), 7.68–7.64 (t, J = 7.6, 1H), 7.56–7.52 (t, J = 7.6,
4H), 7.47–7.42 (m, 2 H); 13C NMR (100 MHz, DMSO d6): d 159.5, 149.3, 140.9,
140.1, 139.2, 138.8, 138.0, 131.0, 129.5, 129.2, 129.1, 128.2, 127.3, 127.1, 127.0,
125.0, 125.5, 116.0; LC–MS: m/e 358.2, C27H19N requires Mol. Wt.: 357.15.
Elemental analysis, calculated for C27H19N: C, 90.72; H, 5.36; N, 3.92%. Found: C,
90.64; H, 5.29; N, 3.83%.
3j White solid, mp, 108.4 °C, IR (m cm-1), 3,029, 2,918, 2,850, 2,167, 2,027,
1,988, 1,951, 1,588, 1,562, 1,539, 1,492, 1,447, 1,408, 1,379, 1,333, 1,211, 1,176,
1,137, 1,067, 1,026, 977, 881, 856, 828, 761, 680, 643, 621, 594, 564, 516; 1H NMR
(400 MHz, CDCl3) d: 8.83–8.82 (2H, d, J = 5.60), 8.21–8.18 (2H, d, J = 8.40),
8.14 (1H, s), 8.07–8.05 (1H, d, J = 8.40), 7.98–7.96 (1H, d, J = 8.40), 7.74–7.71
(3H m), 7.58–7.41 (3H, m); 13C NMR (100 MHz, CDCl3): d 157.5, 150.4, 149.9,
147.3, 139.1, 137.8, 130.4, 128.8, 128.7, 127.7, 127.5, 127.0, 126.5, 125.3, 124.8,
116.6; LC–MS: m/e 283.2, C20H14N2 requires Mol. Wt.: 282.12. Elemental
analysis, calculated for C20H14N2: C, 85.08; H, 5.00; N, 9.92%. Found: C, 85.11; H,
5.12; N, 9.85%.
3k White solid, mp, 112.6 °C, IR (m cm-1), 3,051, 2,916, 2,854, 2,729, 2,360,
1,904, 1,872, 1,616, 1,588, 1,561, 1,515, 1,488, 1,441, 1,385, 1,335, 1,308, 1,185,
1
1,022, 975, 829, 823, 813, 766, 744, 698, 678, 643, 616; H NMR (400 MHz,
CDCl3) d: 8.14–8.11(3H, d, J = 8.16), 8.06 (1H, s), 7.94–7.91 (1H, d, J = 8.10),
7.83–7.81 (2H, d, J = 7.95), 7.68 (1H, m), 7.57–7.50 (4H, m), 7.32–7.30 (2H, d,
J = 7.89), 2.43 (3H, s); 13C NMR (100 MHz, CDCl3): d 160.2, 150.1, 139.8, 138.3,
137.8, 136.7, 130.2, 130.0, 129.4, 128.5, 128.2, 125.5, 127.3, 126,9, 126.7, 125.6,
115.2, 21.28 LC–MS: m/e 296.2, C22H17N requires Mol. Wt.: 294.14. Elemental
analysis, calculated for C22H17N: C, 89.46; H, 5.80; N, 4.74%. Found: C, 89.37; H,
5.74; N, 4.66%.
3l White solid, mp, 127.4 °C, IR (m cm-1), 3,052, 2,923, 1,899, 1,728, 1,621,
1,593, 1,560, 1,492, 1,439, 1,413, 1,385, 1,334, 1,210, 1,180, 1,143, 1,099, 1,089,
1,018, 1,008, 976, 881, 858, 826, 806, 769, 743, 701, 677, 632; 1H NMR (400 MHz,
CDCl3): d 8.19–8.12 (3H, m), 8.06 (1H, s), 7.95–7.92 (1H, d, J = 8.25), 7.82–7.79
(2H, dd, J = 1.77, 7.98), 7.67–7.73 (1H, t, J = 8.25), 7.58–7.45 (6H, m); 13C NMR
123

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P. Manivel et al.
(100 MHz, CDCl3): d 160.5, 148.8, 139.6.138.0, 137.7, 134.5, 130.2, 130.1, 128.8,
128.6, 128.3, 128.2, 127.6, 127.4, 127.1, 125.8, 115.5; LC–MS: m/e 316.0,
C21H14ClN requires Mol. Wt.: 315.08. Elemental analysis, calculated for
C21H14ClN: C, 79.87; H, 4.47; Cl, 11.23; N, 4.44%. Found: C, 79.78; H, 4.39; N,
4.37%.
In short, an efficient and facile benzannulation methodology has been established
for the one pot synthesis of diversified 1,3-disubstituted isoquinolines from
isocoumarins. The methodology demonstrates an environmentally and ecofriendly
technique in achieving biologically active compounds. The methodology may be
extended in achieving target isoquinolines such as diversified 1,3-disubstituted
tetrahydroisoquinolines, TIQ, specifically for analogues of (-)-norcriptostiline,
(?)-cryptostiline II, alkaloid (-)-salsolidine, laudanozine and (-)-carnegine, and
also other isoquinoline system which pave their way to berberine alkaloids, active
pharmaceutical compounds, which are in progress in our laboratory.
Acknowledgments This study was supported by Department of Science & Technology Government of
India (Grant No. SR/FTP/CS-99/2006). The authors are grateful to the VIT University management for
their generous support and facilities.
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