A facile route to pyrrolo[2,1-a]-and 1,2,3-triazolo[5,1-a]- dihydroisoquinolines

Article abstract of DOI:10.3987/COM-08-11452

Treatment of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline 1 with α-bromoketones 2a-c in benzene in presence of triethylamine afforded the corresponding pyrrolo[2,1-a]isoquinoline 4. Also treatment of 3,4-dihydro-6,7-diethoxyisoquinoline-1-carbonitrile 1

Full text of DOI:10.3987/COM-08-11452

HETEROCYCLES, Vol. 75, No. 11, 2008
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HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2779 - 2789. © The Japan Institute of Heterocyclic Chemistry
Received, 27th May, 2008, Accepted, 27th June, 2008, Published online, 3rd July, 2008. COM-08-11452
A FACILE ROUTE TO PYRROLO[2,1-a]- AND 1,2,3-TRIAZOLO[5,1-a]-
DIHYDROISOQUINOLINES
Tayseer A. Abdallah
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613,
Egypt
Fax: +202 35727556; e-mail: tiseersu@yahoo.com
Abstract- Treatment of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline 1 with
α-bromoketones 2a-c in benzene in presence of triethylamine afforded the
corresponding pyrrolo[2,1-a]isoquinoline 4. Also treatment of 3,4-dihydro-
6,7-diethoxyisoquinoline-1-carbonitrile 10 with α-bromo ketones 2a,b,d under
the same reaction condition afforded the corresponding pyrroloisoquinoline 12.
While treatment of isoquinolinium salt 11 with p-tolyldiazonium chloride in
ethanol afforded triazoloisoquinoline derivative 16.
INTRODUCTION
The chemistry of tetrahydroisoquinoline alkaloids has recently attracted great interest due to their
fascinating range of biological activities.1-3 Tetrahydroisoquinoline moiety was found in many marine
natural products and has been demonstrated to be potent antitumor agents.4 In addition, 1,2,3-triazoles are
highly versatile chemicals which exhibit a wide spectrum of utilities in pharmaceutical and industrial
areas.5 As a continuation of our previous studies on the chemistry of 1-substituted tetrahydro-
isoquinoline in construction of tetrahydroisoquinoline-based heterocycles,6-13 our present aim is to
synthesis pyrrolo and 1,2,3-triazolo-tetrahydroisoquinoline heterocycles.
RESULTS AND DISCUSSION
3,4-Dihydro-6,7-dimethoxy-1-methylisoquinoline 1 was prepared following literature procedure.14 When
compound 1 was treated with phenacyl bromide 2a in dry benzene at refluxing temperature it gave the
corresponding isoquinolinium bromide 3a. Heating the latter salt in presence of triethylamine in dry
benzene resulted in the formation of a single product as examined by TLC. The molecular formula of the
reaction product was established as C20H19NO2 on the basis of its elemental analyses and mass spectrum.
1
Spectral data (IR, H NMR) of the reaction product were in consistent with structure 4a, named as

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HETEROCYCLES, Vol. 75, No. 11, 2008
5,6-dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]isoquinoline, as shown in Scheme 1. Similarly,
treatment of 1-methylisoquinoline 1 with the α-bromoketones 2b,c furnished the corresponding
isoquinolinium bromide salts 3b,c which on treatment with triethylamine in refluxing benzene underwent
intramolecular cyclization via elimination of water and hydrogen bromide to give
2-arylpyrrolo[2,1-a]isoquinoline derivatives 4b,c. In addition, reaction of compound 4a with
aryldiazonium chlorides in cold pyridine afforded 3-arylazo-2-phenylpyrrolo[2,1-a]isoquinoline
derivatives 6a,b (Scheme 1). The latter structures were substantiated from their elemental analyses and
1
13
spectral data (MS, IR, H and C NMR) of the reaction products as well as their alternative synthesis
from reaction of 3a with aryldiazonium chlorides. Thus, treatment of the isoquinolinium bromide salt 3a
in cold ethanol with aryldiazonium chlorides resulted in the formation of compounds identical in all
aspects with compounds 6a,b that obtained above. Compounds 6a,b could be directly obtained during the
arylazo coupling of 3a without separation of the hydrazones 5a,b as outlined in Scheme 1.
MeO
N
MeO
Me
1
O
Ar
Br
2a-c
benzene, reflux
Br-
O
MeO
MeO
MeO
MeO
Et3N,
N+
2-4 Ar
N
benzene, reflux
-H2O, -HBr
Ar
Me
Ph
a
b
c
Ar
4a-c
3a-c
S
N
Ar´N2 Cl- / EtOH
+
Ar´N2 Cl- / pyridine
MeO
+
3a
4a
O O
Br-
MeO
MeO
-H2O
H
N+ N N Ar´
N
N N Ar´
Ph
-HBr
MeO
Me
O
Ph
6a,b
5a,b
5a,6a: Ar´ = Ph
5b,6b: Ar´ = 4-MeC6H4
Scheme 1
Prompted by the foregoing results, compound 1 was treated with ethyl bromoacetate in dry benzene at
refluxing temperature to give quantitatively the corresponding isoquinolinium bromide salt 7. Treatment
of the latter salt with triethylamine in refluxing benzene gave a single reaction product identified as
5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinolin-2(3H)-one 8 based on elemental and spectral
analyses of the reaction product (Scheme 2).

HETEROCYCLES, Vol. 75, No. 11, 2008
2781
MeO
MeO
MeO
MeO
Et3N,
Br-
CO2Et
N+
N
benzene, reflux
-EtOH, -HBr
Me
O
8
7
BrCH2CO2Et
9
benzene, reflux
MeO
MeO
N
Me
1
Scheme 2
Next, reaction of 6,7-diethoxy-3,4-dihydroisoquinolin-1-acetonitrile 10 with α-bromoketones 2a,b,d gave
the corresponding isoquinolinium bromide salts 11a,b,d in almost quantitative yields (Scheme 3).
Compounds 11a,b,d underwent intramolecular cyclization when treated with triethylamine in refluxing
benzene to afford the corresponding 2-arylpyrrolo[2,1-a]isoquinoline-1-carbonitrile derivatives 12a,b,d
and not the other structures 13a,b,d that are depicted in Scheme 3. Compound 12a smoothly coupled with
p-tolyldiazonium chloride in cold pyridine to afford a product identified as 3-(p-tolylazo)-5,6-dihydro-
8,9-diethoxy-2-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile 14 (Scheme 3) on the basis of its
elemental analyses and spectral data (MS, IR, 1H and 13C NMR).
O
Br
Br -
N+
EtO
EtO
Ar
2a,b,d
EtO
EtO
O
N
Ar
benzene, reflux
NC
NC
10
11a,b,d
Et3N
benzene, reflux
-H2O
-HBr
EtO
EtO
-HBr
N
N
N N
Ph
EtO
EtO
EtO
4-MeC6H4N2+Cl-
O
N
NC
EtO
Ar
pyridine
12a
14
Ar
NC
12a,b,d
NH2
13a,b,d
11-13
Ar
a
b
d
Scheme 3
S
N
Ph
O
Treatment of compounds 11a with p-tolyldiazonium chloride in ethanol under neutral conditions afforded
a single product as tested by TLC. The product was analyzed correctly for C22H24N4O2 with mass
spectrum having a molecular ion peak at m/e 376. In addition, the spectral data (IR, 1H and 13C NMR) of

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HETEROCYCLES, Vol. 75, No. 11, 2008
the reaction product provided a firm support for the formation of the triazole structure 16; named as
2,3,5,6-tetrahydro-8,9-diethoxy-3-p-tolyl[1,2,3]triazolo[5,1-a]isoquinoline-1-carbonitrile as shown in
Scheme 4. This finding shows that the hydrazones 15 or 17 are not isolable. Formation of the triazole
structure 16 can be discussed via intramolecular cyclization of the salt 15 via phenacyl bromide
elimination under the base-free coupling condition. Interestingly, coupling of either bromide salts 11b or
11d with p-tolyldiazonium chloride under similar reaction conditions furnished one and the same product
that was found to be identical with compound 16. This finding excludes the formation of the hydrazone
17 and consequently the pyrrolo[2,1-a]isoquinoline structure 14 and rationales the elimination of the
α-bromoketones 2b or 2d from the intermediate hydrazone 15 followed by an intramolecular N-N bond
formation to give 16.
EtO
Br-
O
N+
EtO
Ar
CN
11a,b,d
+
4-MeC6H4N2 Cl-
EtO
EtO
EtO
EtO
Br-
Br-
O
H
N+
N+
O
N N Ar´
Ar
H
NC
N N Ar´
NC
Ar
15
17
O
Br
Ar
2,a,b,d
EtO
EtO
EtO
N
N N Ar´
Ar
EtO
N
Ar´
N
N
NC
14
NC
14-17: Ar´ = 4-MeC6H4
H
16
Scheme 4
EXPERIMENTAL
Melting points were measured on a Gallenkamp apparatus. IR spectra were recorded on Shimadzu FT-IR
8101 PC infrared spectrophotometer. NMR spectra were determined in CDCl3 or DMSO-d6 at 300 MHz
(1H NMR) and at 75 MHz. 13C NMR on a Varian Mercury VX 300 NMR spectrometer using TMS as an
internal standard. Mass spectra were measured on a GCMS-QP1000 EX spectrometers at 70 e.V.
Elemental analyses were carried out at the Microanalytical center of Cairo University.
1-Methylisoquinoline 1,14 isoquinoline-1-acetonitrile 10,15 α-bromoketones 2a,16 2b,17 2c18 and 2d19 were
prepared according to the procedures reported in literature.

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Synthesis of the Isoquinolinium Salts 3a-c
To a solution of the appropriate α-bromoketone derivatives 2a-c (2 mmol) in dry benzene (20 mL),
3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline 1 (0.41g, 2 mmol) was added. The mixture was
refluxed for 3 h, then left to cool. The solid product was filtered off, washed with Et2O, and dried to
afford the isoquinolinium bromides 3a-c, respectively.
1
Isoquinolinium salt 3a: Yield (67%); mp138-140 oC (MeOH); IR (KBr) υ 1651 (C=O) cm-1; H NMR
(DMSO-d6) δ 2.50 (s, 3H, Isoquinoline-CH3), 3.24 (s, 2H, CH2CO), 3.45 (m, 2H, Isoquinoline-CH2), 3.56
(s, 3H, OCH3), 3.61(s, 3H, OCH3), 4.49 (m, 2H, Isoquinoline-CH2), 7.62 (s, 1H, Isoquinoline-CH), 7.74 (s,
1H, Isoquinoline-CH),7.71 (m, 2H, Ar H), 7.80 (d, 1H, J = 9 Hz, Ar H), 8.18 (d, 1H, J = 9 Hz, Ar H),
8.36 (s, 1H, Ar H). Anal. Calcd for C20H22BrNO3: C, 59.42; H, 5.48; N, 3.46. Found: C, 59.34; H, 5.25; N,
3.63 %.
o
1
Isoquinolinium salt 3b: Yield (70%); mp 217-219 C (AcOH); IR (KBr) υ 1649 (C=O) cm-1; H NMR
(DMSO-d6) δ 2.48 (s, 3H, Isoquinoline-CH3), 3.07 (m, 2H, Isoquinoline-CH2), 3.78 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 3.90 (s, 2H, CH2CO), 4.13 (m, 2H, Isoquinoline-CH2), 6.92 (s, 1H, Isoquinoline-CH),
7.35 (s, 1H, Isoquinoline-CH), 7.42-8.10 (m, Ar H). Anal. Calcd for C21H21BrN2O3S: C, 54.67; H, 4.59;
N, 6.07; S, 6.95. Found: C, 54.59; H, 4.67; N, 6.32; S, 6.75 %.
o
Isoquinolinium salt 3c: Yield (72%); mp 227-229 C (AcOH); IR (KBr) υ 1720 (C=O), 1689 (C=O)
1
cm-1; H NMR (DMSO-d6) δ 2.49 (s, 3H, Isoquinoline-CH3), 2.98 (t, 2H, J = 6 Hz, Isoquinoline-CH2),
3.8 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.1 (t, 2H, J= 6 Hz, Isoquinoline-CH2), 4.70 (s, 2H, CH2CO), 6.89
(s, 1H, Isoquinoline-CH), 7.17 (s, 1H, Isoquinoline-CH), 7.32-8.22 (m, Ar H). Anal. Calcd for
C23H22BrNO5: C, 58.49; H, 4.69; N, 2.97. Found: C, 58.36; H, 4.51; N, 2.75 %.
Synthesis of 5,6-dihydro-8,9-dimethoxy-2-arylpyrrolo[2,1-a]isoquinoline 4
To a solution of isoquinolinium bromide salt 3a-c (2 mmol) in dry benzene (30 mL), triethylamine (0.4
mL) was added and the reaction mixture was refluxed for 3~5 h, then left to cool to rt. The triethylamine
hydrobromide was removed by filtration and the filtrate was evaporated under vacuum. The residue was
triturated with MeOH where a brown precipitate was formed that was filtered off, washed with MeOH
and dried. Recrystallization from the proper solvent afforded the corresponding 5,6-dihydro-
8,9-dimethoxy-2-arylpyrrolo[2,1-a]isoquinoline 4.
5,6-Dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]isoquinoline 4a
o
1
Yield (65%); mp 242-244 C (EtOH); IR (KBr) υ 1604 (C=C) cm-1; H NMR (DMSO-d6) δ 2.95 (t, 2H,

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HETEROCYCLES, Vol. 75, No. 11, 2008
J = 9Hz, Isoquinoline-CH2), 3.76 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.03 (t, 2H, J = 9 Hz,
Isoquinoline-CH2), 6.87-7.56 (m, Ar H); MS m/z (%) 305 (M+, 40), 290 (30.9), 205 (90.3), 190 (80.9).
Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.69; H, 6.15; N, 4.35 %.
5,6-Dihydro-8,9-dimethoxy-2-(benzothiazol-2-yl)pyrrolo[2,1-a]isoquinoline 4b
o
1
Yield (69%); mp 207-208 C (MeOH); IR (KBr) υ 1658 (C=C) cm-1; H NMR (CDCl3) δ 2.95 (t, 2H,
J = 6.6 Hz, Isoquinoline-CH2), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.07 (t, 2H, J = 6.6 Hz,
Isoquinoline-CH2), 6.65 (s, 1H, Isoquinoline-CH), 6.87 (s, 1H, Isoquinoline-CH), 7.21-7.35 (m, 4H, Ar
H), 7.73 (d, 1H, J = 8.1Hz, Ar H), 7.86 (d, 1H, J = 8.1Hz, Ar H); 13C NMR (CDCl3) δ 28.46, 44.35, 46.0,
55.85, 101.34, 105.88, 111.18, 118.98, 121.06, 121.15, 122.89, 123.83, 125.66, 128.03, 131.24, 133.83,
147.78, 148.23, 153.84, 163.66; MS m/z (%) 362 (M+,100), 347 (42.6), 275 (12.0), 181 (14.9). Anal.
Calcd for C21H18N2O2S: C, 69.59; H, 5.01; N, 7.73; S, 8.85. Found: C, 69.65; H, 5.27; N, 7.72; S, 8.96 %.
5,6-Dihydro-8,9-dimethoxy-2-(2-oxo-2H-chromen-3-yl)pyrrolo[2,1-a]isoquinoline 4c
Yield (68%); mp 245-247 oC (MeOH); IR (KBr) υ 1719 (C=O) cm-1; 1H NMR (CDCl3) δ 3.03 (t, 2H, J =
6.6 Hz, Isoquinoline-CH2), 3.91 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.13 (t, 2H, J = 6.6 Hz,
Isoquinoline-CH2), 6.69 (s, 1H, Isoquinoline-CH), 6.73 (s, 1H, Isoquinoline-CH), 6.81 (s, 1H,
Pyrrole-CH), 7.26-7.52 (m, 5H, Ar H), 7.85 (s, 1H, Oxochromon-CH); 13C NMR (CDCl3) δ 28.83, 44.28,
56.02, 56.07, 99.87, 106.08, 111.40, 116.09, 117.31, 120.19, 121.61, 122.69, 122.89, 123.25, 124.20,
126.87, 129.56, 130.59, 132.17, 147.77, 148.36, 152.04, 160.31; MS m/z (%) 373 (M+,100), 358 (39.4),
330 (17.4), 187 (12.3). Anal. Calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75. Found: C, 73.76; H, 5.36;
N, 3.58 %.
Synthesis of 3-arylazo-5,6-dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]isoquinoline 6
To a cold solution of 2-phenylpyrrolo[2,1-a]isoquinoline 4a (0.61g, 2 mmol) in pyridine (20 mL), the
appropriate aryldiazonium salt (2 mmol) was added portionwise over 1 h at 0-5 oC. After the addition was
completed, the reaction mixture was left to stir at rt overnight then diluted with water (10 mL). The
precipitate was filtered off, washed with EtOH and dried. Recrystallization from the proper solvent
afforded the corresponding 3-arylazo-2-phenylpyrrolo[2,1-a]isoquinoline derivatives 6a,b.
3-Phenylazo-5,6-dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]isoquinoline 6a
o
1
Yield (67%); mp 159-161 C (dioxane-EtOH); IR (KBr) υ 1604 (C=C), 1375 (N=N) cm-1; H NMR
(CDCl3) δ 3.03 (t, 2H, J = 6.9 Hz, Isoquinoline-CH2), 3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.80 (t, 2H,
J = 6.9 Hz, Isoquinoline-CH2), 6.75 (s, 1H, Isoquinoline-CH), 6.86 (s, 1H, Isoquinoline-CH), 7.35-7.51(m,

HETEROCYCLES, Vol. 75, No. 11, 2008
2785
13
7H, Ar H), 7.82 (d, 2H, J = 8.0 Hz, Ar H), 7.92 (d, 2H, J = 8.0 Hz, Ar H); C NMR (CDCl3) δ 28.56,
43.57, 56.01, 56.15, 105.14, 107.16, 111.03, 120.31, 121.82, 125.69, 126.87, 128.06, 128.33, 128.51,
128.95, 129.54, 132.08, 134.95, 138.92, 148.42, 149.37, 154.10; MS m/z (%) 409 (M+, 100), 317 (56.1),
301 (19.0). Anal. Calcd for C26H23N3O2: C, 76.26; H, 5.66; N, 10.26. Found: C, 76.53; H, 5.46; N,
10.32 %.
3-(p-Tolylazo)-5,6-dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]isoquinoline 6b
Yield (68%); mp 195-196 oC (AcOH); IR (KBr) υ 1602 (C=C), 1356 (N=N) cm-1; 1H NMR (DMSO-d6) δ
2.50 (s, 3H, CH3), 3.45 (m, 2H, Isoquinoline-CH2), 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.70 (m, 2H,
Isoquinoline-CH2), 6.95 (s, 1H, Isoquinoline-CH), 7.05 (s, 1H, Isoquinoline-CH), 7.23-7.43 (m, Ar
13
H),7.60 (d, 2H, J = 8.1 Hz, Ar H), 7.86 (d, 2H, J = 8.1 Hz, Ar H), 8.0 (s, 1H, Pyrrole-CH); C NMR
(DMSO-d6) δ 20.88, 27.62, 43.36, 55.63, 55.89, 105.94, 107.96, 111.90, 119.38, 121.44, 125.60, 126.83,
127.49, 128.09, 129.00, 129.74, 130.88, 134.52, 135.12, 138.47, 148.14, 149.31, 151.50; MS m/z (%) 423
(M+, 100), 317 (31.2), 218 (12.2). Anal. Calcd for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92. Found: C,
76.43; H, 5.68; N, 9.85 %.
Synthesis of the Isoquinolinium Salt 7
To a solution of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline 1 (0.82 g, 4 mmol) in dry benzene (20
mL), ethyl α-bromoacetate 9 (0.67 g, 4 mmol) was added. The mixture was refluxed for 6h, then left to
cool. The solid product was filtered off, washed with ether, and dried to afford the isoquinolinium
o
bromide 7 as brown powder ( 0.98 g), Yield (76%); mp 200-202 C (MeOH); IR (KBr) υ 1745 (C=O)
cm-1; 1H NMR (CDCl3) δ 2.96 (s, 3H, Isoquinoline-CH3), 3.0 (t, 3H, J = 7.5 Hz, Ester-CH3), 3.07 (m, 2H,
Isoquinoline-CH2), 3.86 (q, 2H, J = 7.5 Hz, Ester-CH2), 3.9 (s, 3H, OCH3), 4.0 (s, 3H, OCH3), 4.1(m, 2H,
Isoquinoline-CH2), 4.68 (s, 2H, CH2COO), 6.8 (s, 1H, Isoquinoline-CH), 7.17 (s, 1H, Isoquinoline-CH).
Anal. Calcd for C16H22BrNO4: C, 51.62; H, 5.96; N, 3.76. Found: C, 51.35; H, 5.74; N, 3.62 %.
Synthesis of 5,6- dihydro-8,9-dimethoxy- 2-oxopyrrolo[2,1-a]isoquinoline 8
To a solution of isoquinolinium bromide salt 7 (0.74 g, 2 mmol) in dry benzene (30 mL), triethylamine
(0.4 mL) was added and the reaction mixture was refluxed for 8 h, then left to cool to rt. The
triethylamine hydrobromide salt was removed by filtration and the filtrate was evaporated under vacuum.
The residue was triturated with methanol where a precipitate was formed that was filtered off, washed
with MeOH and dried. Recrystallization from MeOH afforded 2,3,5,6-tetrahydro-8,9-dimethoxy-
o
2-oxopyrrolo[2,1-a]isoquinoline 8 as dark brown powder (0.31 g). Yield (64%); mp 243-244 C, IR
1
(KBr) υ 1742 (C=O) cm-1; H NMR (CDCl3) δ 2.88 (s, 2H, Oxopyrrolo-CH2), 3.03 (m, 2H,

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Isoquinoline-CH2), 3.83 (m, 2H, Isoquinoline-CH2), 3.90 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.95 (s, 1H,
Oxopyrrolo-CH), 6.82 (s, 1H, Isoquinoline-CH), 7.15 (s, 1H, Isoquinoline-CH); MS m/z (%) 245
(M+,100), 219 (27.5), 205 (47.5), 160 (21.2). Anal. Calcd for C14H15NO3: C, 57.14; H, 6.12; N, 5.71.
Found: C, 57.34; H, 6.25; N, 5.63 %.
Synthesis of the Isoquinolinium Salt 11
These compounds were prepared by the same method described for the synthesis of 3 via reaction of
α-bromoketone derivatives 2a,b,d with 3,4-dihydro-6,7-diethoxyisoquinolin-1-acetonitrile 10. The
compounds prepared with their data are listed below.
o
Isoquinolinium salt 11a: Yield (71%); mp 130-132 C (MeOH); IR (KBr) υ 2205 (C≡N), 1688 (C=O)
1
cm-1; H NMR (CDCl3): δ 1.37 (m, 6H, Isoquinoline-2CH3 ), 2.84 (s, 2H, CH2CO), 2.95 (m, 2H,
Isoquinoline-CH2), 4.07 (m, 2H, Isoquinoline-CH2), 4.19 (m, 4H, Isoquinoline-2CH2O), 5.58 (s, 2H,
CH2CN), 6.49 (s, 1H, Isoquinoline-CH), 6.75 (s,1H, Isoquinoline-CH ), 7.27-7.76 (m, 5H, Ar H). Anal.
Calcd for C23H25BrN2O3: C, 60.40; H, 5.51; N, 6.13. Found: C, 60.12; H, 5.56; N, 6.28%.
o
Isoquinolinium salt 11b: Yield (63%); mp 219-220 C (DMF-EtOH); IR (KBr) υ 2209 (C≡N),1677
1
(C=O) cm-1; H NMR (DMSO-d6) δ 1.38 (m, 6H, Isoquinoline-2CH3), 2.51 (s, 4H, CH2CO, CH2CN),
3.05 (t, 2H, J = 9 Hz, Isoquinoline-CH2), 4.09 (m, 4H, Isoquinoline-2CH2O), 4.20 (t, 2H, J = 9 Hz,
Isoquinoline-CH2), 7.03 (s, 1H, Isoquinoline-CH), 7.41-7.46 (m, 2H, Ar H), 7.63 (s, 1H, Isoquinoline-CH),
7.95 (d, 1H, J = 7.2 Hz, Ar H), 8.09 (d, 1H, J = 7.2 Hz, Ar H). Anal. Calcd for C24H24BrN3O3S: C, 56.03;
H, 4.70; N, 8.17; S, 6.23; Found: C, 56.17; H, 4.52; N, 7.95; S, 6.48 %.
o
Isoquinolinium salt 11d: Yield (63%); mp 204-206 C (AcOH); IR (KBr) υ 2211 (C≡N), 1646 (C=O),
1
cm-1; H NMR (DMSO-d6) δ 1.35 (m, 6H, Isoquinoline-2CH3), 2.48 (s, 2H, CH2CO), 2.76 (t, 2H, J = 6
Hz, Isoquinoline-CH2), 3.25 (t, 2H, J = 6 Hz, Isoquinoline-CH2), 4.11 (m, 4H, Isoquinoline-2CH2O), 4.94
(s, 2H, CH2CN), 6.92 (s, 1H, Isoquinoline-CH), 6.96 (s, 1H, Isoquinoline-CH), 7.09 (s, 1H, Ar H), 7.26 (s,
1H, Ar H), 7.36 (s, 1H, Ar H), 7.46 (s, 1H, Ar H), 7.59 (s, 1H, Benzofuryl-CH). Anal. Calcd for
C25H25BrN2O4: C, 60.37; H, 5.07; N, 5.63. Found: C, 60.55; H, 5.13; N, 5.69 %.
Synthesis of 5,6-dihydro-8,9-diethoxy -2-arylpyrrolo[2,1-a]isoquinoline-1-carbonitrile 12
These compounds were prepared by the same method described for the synthesis of 4a-c using
isoquinolinium salt derivatives 11a,b,d instead of 3a-c. The compounds prepared with their data are listed
below.

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2787
5,6-Dihydro-8,9-diethoxy-2-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile 12a
o
1
Yield (73%); mp 158-160 C (MeOH); IR (KBr) υ 2178 (C≡N) cm-1; H NMR (DMSO-d6): δ 1.37 (m,
6H, Isoquinoline-2CH3), 2.96 (m, 2H, Isoquinoline-CH2), 3.45 (m, 2H, Isoquinoline-CH2), 4.07 (m, 4H,
Isoquinoline-2CH2O), 6.68 (s, 1H, Isoquinoline-CH), 7.01 (s, 1H, Isoquinoline-CH), 7.40-7.49 (m, 5H,
Ar H), 7.58 (s, 1H, Pyrrole-CH); 13C NMR (DMSO-d6): δ 14.60, 27.96, 54.06, 63.80, 64.09, 85.60,
108.22, 110.23, 112.20, 113.10, 120.13, 121.38, 125.87, 128.62, 130.33, 133.93, 135.78, 147.01, 148.51,
150.55, 156.70; MS m/z (%) 358 (M+, 25), 301(14.6), 101(16.0). Anal. Calcd for C23H22N2O2: C, 77.07;
H, 6.19; N, 7.82. Found: C, 77.26; H, 6.39; N, 7.64 %.
5,6-Dihydro-8,9-diethoxy-2-(benzothiazol-2-yl)pyrrolo[2,1-a]isoquinoline-1-carbonitrile 12b
o
1
Yield (67%); mp 243-244 C (EtOH) IR (KBr) υ 2202 (C≡N) cm-1; H NMR (CDCl3) δ 1.50 (m, 6H,
Isoquinoline-2CH3), 3.09 (t, 2H, J = 6.9 Hz, Isoquinoline-CH2), 4.20 (m, 4H, Isoquinoline-2CH2O), 4.91
(t, 2H , J = 6.9 Hz, Isoquinoline-CH2), 6.80 (s, 1H, Isoquinoline-CH), 7.08 (s, 1H, Isoquinoline-CH), 7.38
(m, 1H, Ar H ), 7.48 (m, 1H, Ar H), 7.85 (s, 1H, Pyrrole-CH), 7.88 (d, 1H, J = 6 Hz, Ar H), 7.97 (d, 1H, J
= 6 Hz, Ar H); MS m/z (%) 415 (M+, 50), 358 (72.7), 181 (28.8). Anal. Calcd for C24H21N3O2S: C, 69.37;
H, 5.09; N, 10.11; S, 7.72. Found: C, 69.42; H, 5.33; N, 10.26; S, 7.51%.
5,6-Dihydro-8,9-diethoxy-2-(2-benzofuryl)pyrrolo[2,1-a]isoquinoline-1-carbonitrile 12d
o
1
Yield (66%); mp 164-165 C (EtOH) IR (KBr) υ 2212 (C≡N) cm-1; H NMR (CDCl3): δ 1.26 (m, 6H,
Isoquinoline-2CH3), 3.17 (t, 2H, J = 7.2 Hz, Isoquinoline-CH2), 3.79 (m, 4H, Isoquinoline-2CH2O), 4.25
(t, 2H, J = 7.2 Hz, Isoquinoline-CH2), 5.32 (s, 1H, Benzofuryl-CH), 6.66 (s, 1H, Isoquinoline-CH), 6.89
(s, 1H, Isoquinoline-CH), 7.18-7.63 (m, 4H, Ar H), 8.58 (s, 1H, Pyrrole-CH); 13C NMR (CDCl3): δ 14.69,
46.23, 55.19, 58.99, 64.64, 104.0, 112.21, 119.43, 124.30, 124.36, 126.55, 129.77, 148.92, 156.12,
180.65; MS m/z (%) 398 (M+, 20), 217 (6.4), 86 (100). Anal. Calcd for C25H22N2O3: C, 75.36; H, 5.57; N,
7.03. Found: C, 75.51; H, 5.42; N, 7.19 %.
Synthesis of 3-(p-tolylazo)-5,6-dihydro-8,9-diethoxy-2-phenylpyrrolo[2,1-a]isoquinoline-1-carbnitrile
14
To a cold solution of 5,6-dihydro-8,9-diethoxy-2-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile 12a
(0.71g, 2 mmol) in pyridine (20 mL), p-tolyldiazonium salt (0.21g, 2 mmol) was added portionwise over
o
1 h at 0-5 C. After the addition was completed, the reaction mixture was left to stir at rt overnight then
diluted with water (10 mL). The precipitate was filtered off, washed with MeOH and dried.
o
Recrystallization from EtOH afforded 14 Yield (69%); mp 197-198 C (EtOH) IR (KBr) υ 2183 (C≡N),
1
1390 (N=N) cm-1; H NMR (DMSO-d6): δ 1.37 (m, 6H, Isoquinoline-2CH3), 2.34 (s, 3H, CH3), 2.96 (t,

2788
HETEROCYCLES, Vol. 75, No. 11, 2008
2H, J = 12 Hz, Isoquinoline-CH2), 3.47 (t, 2H, J = 12 Hz, Isoquinoline-CH2), 4.09 (m, 4H,
Isoquinoline-2CH2O), 6.68 (s,1H, Isoquinoline-CH), 7.0 (s,1H, Isoquinoline-CH), 7.22-7.25 (d, 2H, J =
7.8 Hz, Ar H), 7.48-7.58 (m, Ar H), 7.66-7.69 (d, 2H, J = 7.8 Hz, Ar H), 7.87 (s,1H, Ar H). 13C NMR (75
MHz, DMSO-d6): δ 14.54, 14.65, 20.80, 27.85, 42.09, 63.90, 64.07, 108.24, 111.21, 112.43, 113.14,
117.49, 118.03, 121.53, 123.88, 125.90, 127.93, 128.66, 129.44, 130.36, 133.97, 137.53, 145.97, 149.54,
150.81, 151.74. Anal. Calcd for C30H28N4O2: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.49; H, 5.93; N,
11.58 %.
2,3,5,6-Tetrahydro-8,9-diethoxy-3-(p-tolyl)-[1,2,3]triazolo[5,1-a]isoquinoline-1-carbonitrile 16
To a cold solution of the appropriate isoquinolinium bromide salts 11a,b,d (2 mmol) in base-free absolute
o
EtOH (20 mL), p-tolyldiazonium salt (2 mmol) was added portionwise over 1 h at 0-5 C. After the
addition was completed, the reaction mixture was left to stir at rt overnight then diluted with 10 mL water.
The precipitate so formed was filtered off, washed with MeOH and dried. Recrystallization from EtOH
afforded the corresponding 1,2,3-triazolo[5,1-a]isoquinoline-1-carbonitrile 16 Yield (65%); mp 193-195
1
oC (DMF-EtOH); IR (KBr) υ 3380 (NH), 2205 (C≡N) cm-1; H NMR (DMSO-d6): δ 1.38 (m, 6H,
Isoquinoline-2CH3), 2.17 (s, 3H, CH3), 2.34 (t, 2H, J = 6.9 Hz, Isoquinoline-CH2), 3.52 (t, 2H, J = 6.9 Hz,
Isoquinoline-CH2), 4.10 (m, 4H, Isoquinoline-2CH2O), 5.13 (s, 1H, Triazole-NH), 6.66 (s, 1H,
Isoquinoline-CH), 6.90 (s, 1H, Isoquinoline-CH), 7.25 (d, 1H, J = 8.7 Hz, Ar H), 7.47-7.65 (m, 1H, Ar H),
7.86 (s, 1H, Ar H), 8.0 (d, 1H, J = 8.7 Hz, Ar H); 13C NMR (75 MHz, DMSO-d6): δ 14.52, 14.61, 20.79,
27.81, 42.09, 45.33, 64.07, 112.48, 113.20, 117.48, 120.68, 121.57, 128.66, 129.41, 133.26, 137.50,
145.95, 151.73; MS m/z (%) 376 (M+, 78), 301 (37.4), 258 (19.9), 91 (78). Anal. Calcd for C22H24N4O2: C,
70.19; H, 6.43; N, 14.88. Found: C, 70.34; H, 6.29; N, 14.69 %.
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