Synthesis of annulated dihydroisoquinoline heterocycles via their nitrogen ylides

Article abstract of DOI:10.1016/j.tet.2008.06.043

3,4-Dihydro-6,7-dimethoxyisoquinoline-1-acetonitrile reacts with some α-bromoketones in dry benzene to give the corresponding isoquinolinium salts, which undergo intramolecular cyclization to give pyrrolo[2,1-a]isoquinolines. Cross-coupling of the latter compounds with some aryldiazonium chlorides resulted in the formation of 3-arylhydrazonopyrrolo[2,1-a]isoquinolines, 3-arylazopyrrolo[2,1-a]isoquinolines and 3-aryl-1,2,3-triazolo[5,1-a]isoquinolines, respectively. The structures of the products were established on the basis of their elemental and spectral analyses as well as X-ray single crystal studies.

Full text of DOI:10.1016/j.tet.2008.06.043

Tetrahedron 64 (2008) 7890–7895
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of annulated dihydroisoquinoline heterocycles via their
nitrogen ylides
*
Tayseer A. Abdallah , Kamal M. Dawood
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2008
Received in revised form 27 May 2008
Accepted 12 June 2008
Available online 14 June 2008
3,4-Dihydro-6,7-dimethoxyisoquinoline-1-acetonitrile reacts with some a-bromoketones in dry benzene
to give the corresponding isoquinolinium salts, which undergo intramolecular cyclization to give pyr-
rolo[2,1-a]isoquinolines. Cross-coupling of the latter compounds with some aryldiazonium chlorides
resulted in the formation of 3-arylhydrazonopyrrolo[2,1-a]isoquinolines, 3-arylazopyrrolo[2,1-a]iso-
quinolines and 3-aryl-1,2,3-triazolo[5,1-a]isoquinolines, respectively. The structures of the products were
established on the basis of their elemental and spectral analyses as well as X-ray single crystal studies.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
cyclization through elimination of hydrogen bromide and ethanol
from the bromide salt 2 (Scheme 1). Coupling of compound 3 with
Isoquinoline alkaloids have been an interesting structural class
of compounds, which have found important medicinal and phar-
macological applications.1,2 On the other hand, substituted tetra-
hydroisoquinolines have been found to exhibit a broad spectrum of
biological activities3 and furthermore being relevant to pathogen-
esis of Parkinson’s disease.4 In addition, 1,2,3-triazoles are highly
versatile chemicals, which exhibit a wide spectrum of utilities in
pharmaceutical and industrial areas.5 Synthesis of 1,2,3-tri-
azolo[5,1-a]isoquinolines was also reported.6 As part of our re-
search interest towards developing new routes for the synthesis of
isoquinoline heterocycles,7–9 we conduct here a novel route to
some new bridgehead-nitrogen heterocycles utilizing some versa-
tile isoquinolinium N-ylides.
benzenediazonium chloride in pyridine solution afforded the cor-
responding 3-phenylhydrazono-2-oxopyrrolo[2,1-a]isoquinoline-
1-carbonitrile derivative 4a in a good yield, as shown in Scheme 1.
Similar results were obtained on coupling of 3 with p-tolyl and
p-chlorophenyldiazonium chlorides to give the corresponding
arylhydrazones 4b and 4c, respectively. Compounds 4a–c were
found to be regioisomers of 2-arylhydrazono-3-oxopyrro-
lo[2,1-a]isoquinoline-1-carbonitriles 5 that were reported earlier
by our group.7a
The annulation reaction was also extended to salts derived from
isoquinoline derivative 1 as shown in Scheme 2. Thus, treatment
of isoquinoline-1-acetonitrile 1 with phenacyl bromide 6a in dry
benzene at refluxing temperature gave the corresponding iso-
quinolinium bromide 7a. The latter salt when heated at reflux in dry
benzene and in the presence of triethylamine furnished a single
product as examined by TLC. Elemental analyses and mass spectrum
of the reaction product established its molecular formula as
2. Results and discussion
3,4-Dihydro-6,7-dimethoxyisoquinoline-1-acetonitrile
1 was
C
21H18N2O2. Spectroscopic data (IR, 1H and 13C NMR) of the reaction
prepared according to a literature procedure.10 Treatment of 1 with
ethyl bromoacetate in dry benzene at refluxing temperature gave
quantitatively the corresponding isoquinolinium bromide salt 2.
Treatment of the bromide salt 2 with triethylamine in refluxing
benzene gave a single annulated reaction product identified as
2,3,5,6-tetrahydro-8,9-dimethoxy-2-oxopyrrolo[2,1-a]isoquinoline-
1-carbonitrile 3 based on elemental and spectral analyses of the
reaction product as well as its further chemical transformation.
The formation of 3 is assumed to proceed via intramolecular
product were in complete agreement with the assigned 2-phenyl-
pyrrolo[2,1-a]isoquinoline-1-carbonitrile structure 9a and not with
structure 8a, as depicted in Scheme 2. Similar treatment of iso-
quinoline-1-acetonitrile 1 with other a-bromoketones 6b–e gave the
corresponding isoquinolinium bromide salts 7b–e, which underwent
intramolecular cyclization via elimination of water and hydrogen
bromide molecules to give the angularly fused 2-arylpyrrolo[2,1-
a]isoquinoline-1-carbonitrile derivatives 9b–e. Furthermore, re-
action of compound 9awith aryldiazonium chlorides in cold pyridine
afforded, in each case, only one product identified as 3-arylazo-
2-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile structures 10a,b
(Scheme 2) on the basis of elemental analyses and spectroscopic data
* Corresponding author. Fax: þ202 35727556.
E-mail address: tiseersu@yahoo.com (T.A. Abdallah).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.043

T.A. Abdallah, K.M. Dawood / Tetrahedron 64 (2008) 7890–7895
7891
MeO
MeO
MeO
MeO
O
O
EtO
Br
Br
Et3N,
N
N
OEt
PhH, reflux
PhH, reflux
-EtOH, -HBr
NC
1
NC
2
MeO
MeO
MeO
MeO
ArN2+Cl-
H
N
N
N
N
Ar
N
O
MeO
MeO
H
O
NC
O
N N
NC
NC
Ar
4
5
3, 72%
4a: Ar = C6H5,
68%
4b: Ar = 4-CH3C6H4, 75%
4c: Ar = 4-ClC6H4,
70%
Scheme 1.
O
MeO
MeO
MeO
Ar
Br
O
6a-e
Br
N
N
PhH, reflux
MeO
Ar
NC
NC
7a-e
1
PhH, reflux
-H2O
Et3N
-HBr
MeO
MeO
-HBr
MeO
MeO
MeO
N
N
N Ar´
Ar´N2+Cl-
9a
O
N
N
Ar
MeO
NC
Ph
10a,b
NC
NH2
Ar
10a: Ar´ = C6H5
10b: Ar´ = 4-CH3C6H4
8a-e
9a-e
MeO
MeO
6-9
a
b
c
d
e
S
N
N
Ph
Ar
Br
O
O
O
Ar
N N
NC
11
Scheme 2.
(MS, IR, 1H and 13C NMR) of the reaction products. Compounds 10a,b
were proved to be regioisomers of our early published7b 2-arylazo-
3-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile structures 11
(Scheme 2).
alternatively obtained from the reaction of the bromide salt 7b
(Ar¼p-BrC6H4) with benzenediazonium chloride, which rationales
the elimination of p-bromophenacyl bromide from the in-
termediate 12 followed by an intramolecular N–N bond formation
to give 13a.
Furthermore, treatment of either compound 7a or 7b with
p-tolyldiazonium chloride under similar reaction conditions gave
only one and the same product identified as 2,3,5,6-tetrahydro-
8,9-dimethoxy-3-p-tolyl-[1,2,3]triazolo[5,1-a]isoquinoline-1-carbo-
nitrile 13b (Scheme 3).
Reaction of isoquinolinium bromide salt 7a with benzenedia-
zonium chloride in ethanol under neutral conditions afforded
a single product as tested by TLC. The product should be the
hydrazone structure 12 as shown in Scheme 3. However, mass
spectrum of the reaction product gave a molecular ion peak at m/z
334, which is consistent with the elemental analyses of the mo-
lecular formula C19H18N4O2. These data indicate that the bromide
salt 12 is not isolable and support the formation of the triazole
structure 13a, which is obtained from intramolecular cyclization of
the salt 12 via phenacyl bromide elimination under the base-free
coupling condition. Spectroscopic data (IR, 1H and 13C NMR) of the
reaction product provided a further evidence for the formation of
the triazole structure 13a. In addition, single crystal X-ray analysis
of the reaction product (Fig. 1) provided an unequivocal evidence
for the formation of 3-phenyl-1,2,3-triazolo[5,1-a]isoquinoline-1-
carbonitrile 13a and ruled out the other possible structure 14 as
outlined in Scheme 3. Interestingly, compound 13a was
3. Experimental
3.1. General
Melting points were measured on a Gallenkamp apparatus. IR
spectra were recorded on Shimadzu FT-IR 8101 PC infrared spec-
trophotometer. 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

7892
T.A. Abdallah, K.M. Dawood / Tetrahedron 64 (2008) 7890–7895
MeO
MeO
MeO
O
O
Ar´N2+Cl-
Br
Br
N
N
MeO
Ar
Ar
H
NC
CN
N
N Ar´
7a,b
O
Ar
6a,b
12
Br
MeO
MeO
MeO
MeO
O
N
Ar
N
Ar´
N
N
´Ar N N
NH2
NC
H
14
13a,b
13a: Ar´ = C6H5,
72%
13b: Ar´ = 4-CH3C6H4, 67%
Scheme 3.
Figure 1. X-ray structure of compound 13a.
spectrometer at 70 eV. Elemental analyses were carried out at the
Microanalytical center of Cairo University. Isoquinoline-1-acetoni-
temperature. The triethylamine–hydrobromide salt was removed
by filtration and the filtrate was evaporated under vacuum. The
residue was triturated with methanol where a black-coloured
precipitate was formed that was filtered off, washed with methanol
and dried. Recrystallization from DMF afforded 2,3,5,6-tetrahydro-
8,9-dimethoxy-2-oxopyrrolo[2,1-a]isoquinoline-1-carbonitrile 3 as
trile 1,10 -haloketones 6a,b,11 6c,12 6d13 and 6e14 were prepared
a
according to the procedures reported in the literature.
3.2. Synthesis of the isoquinolinium salt 2
grey powder (0.39 g, 72%), mp >300 ꢀC; IR (KBr)
n
1693 (C]O),
2205 (C^N) cmꢁ1; 1H NMR (DMSO-d6)
d
2.94 (t, 2H, J¼6.9 Hz), 3.55
To a solution of isoquinoline-1-acetonitrile derivative 1 (0.92 g,
(s, 2H), 3.6 (t, 2H, J¼6.9 Hz), 3.78 (s, 3H), 3.8 (s, 3H), 7.0 (s, 1H), 7.69
(s, 1H); MS (m/z) (%), 270 (Mþ, 79), 241 (52), 225 (91), 182 (40), 166
(19), 127 (30.7), 76 (21.7), 51 (30.7). Anal. Calcd for C15H14N2O3: C,
66.66; H, 5.22; N, 10.36. Found: C, 66.72; H, 5.49; N, 10.61%.
4 mmol) in dry benzene (20 mL), ethyl
a-bromoacetate (0.67 g,
4 mmol) was added. The mixture was refluxed for 2 h, then left to
cool. The solid product was filtered off, washed with ether and
dried to afford the isoquinolinium bromide 2 as green powder
(1.24 g, 78%), mp 258–260 ꢀC; IR (KBr)
n
1726 (C]O), 2194
(C^N) cmꢁ1 1H NMR (DMSO-d6)
;
d 2.49 (s, 2H), 2.74 (t, 3H,
3.4. Synthesis of 3-arylhydrazono-2-oxopyrrolo[2,1-a]-
J¼7.2 Hz), 2.94 (t, 2H, J¼6.3 Hz), 3.77 (q, 2H, J¼7.2 Hz), 3.55 (s, 2H),
3.78 (t, 2H, J¼6.3 Hz), 3.78 (s, 3H), 3.84 (s, 3H), 7.0 (s, 1H), 7.6 (s, 1H).
Anal. Calcd for C17H21Br N2O4: C, 51.40; H, 5.33; N, 7.05. Found: C,
51.35; H, 5.19; N, 7.28%.
isoquinoline-1-carbonitrile 4
To a cold solution of 2-oxopyrrolo[2,1-a]isoquinoline-1-car-
bonitrile 3 (0.54 g, 2 mmol) in pyridine (20 mL), the appropriate
aryldiazonium 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 room temperature for further 3 h, then diluted with
10 mL water and the precipitate was filtered, washed with ethanol
and dried. Recrystallization from DMF afforded the correspond-
ing 3-arylhydrazono-2-oxopyrrolo[2,1-a]isoquinoline-1-carbonitrile
derivatives 4a–c.
3.3. Synthesis of 2-oxopyrrolo[2,1-a]isoquinoline-1-
carbonitrile 3
To a solution of isoquinolinium bromide salt 2 (0.794 g, 2 mmol)
in dry benzene (30 mL), triethylamine (0.4 mL) was added and the
reaction mixture was refluxed 3–5 h, then left to cool to room

T.A. Abdallah, K.M. Dawood / Tetrahedron 64 (2008) 7890–7895
7893
3.4.1. 3-(Phenylhydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-2-
oxopyrrolo[2,1-a]-isoquinoline-1-carbonitrile (4a)
1H). Anal. Calcd for C23H21BrN2O4: C, 58.86; H, 4.51; N, 5.97. Found:
C, 58.64; H, 4.59; N, 5.81%.
Brownish red crystals (0.51 g, 68%); mp 294–296 ꢀC; IR (KBr)
n
1727 (C]O), 2197 (C^N) cmꢁ1
;
1H NMR (DMSO-d6)
d
3.03 (t, 2H,
3.5.5. Isoquinolinium salt 7e
J¼6.9 Hz), 3.82 (s, 3H), 3.84 (s, 3H), 3.7 (t, 2H, J¼6.9 Hz), 7.0 (s, 1H),
7.4 (s, 1H), 7.6–7.7 (m, 5H), 12.5 (s, 1H, NH); MS (m/z) (%), 374 (Mþ,
100), 269 (2.3), 241 (48.5), 227 (25.2), 211 (45.8), 197 (9.3), 167 (8.6),
128 (8.3), 77 (9.7), 51 (12.5). Anal. Calcd for C21H18N4O3: C, 67.37; H,
4.85; N, 14.96. Found: C, 67.60; H, 4.63; N, 14.77%.
Yellowish-white crystals (0.75 g, 76%); mp>300 ꢀC (dioxane); IR
(KBr)
n ; d 3.05 (t,
1715 (C]O), 2212 (C^N) cmꢁ1 1H NMR (CDCl3)
2H, J¼6.3 Hz), 3.93 (s, 3H), 3.98 (s, 3H), 4.05 (t, 2H, J¼6.3 Hz), 4.76 (s,
4H), 6.64 (s, 1H), 6.76 (s, 1H), 7.38–7.43 (m, 2H), 7.69–7.82 (m, 2H),
8.64 (s, 1H). Anal. Calcd for C24H21BrN2O5: C, 57.96; H, 4.26; N, 5.63.
Found: C, 57.80; H, 4.34; N, 5.42%.
3.4.2. 3-(p-Tolylhydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-2-
oxopyrrolo[2,1-a]-isoquinoline-1-carbonitrile (4b)
3.6. Synthesis of 2-arylpyrrolo[2,1-a]isoquinoline-1-
carbonitriles 9a–e
Intense red powder (0.58 g, 75%); mp 261–263 ꢀC; IR (KBr)
n
1724 (C]O), 2203 (C^N) cmꢁ1; 1H NMR (DMSO-d6)
d 2.26 (s, 3H),
3.03 (t, 2H, J¼6.3 Hz), 3.78 (t, 2H, J¼6.3 Hz), 3.80 (s, 3H), 3.81 (s, 3H),
7.0 (s, 1H), 7.15 (d, 2H, J¼8.4 Hz), 7.29 (d, 2H, J¼8.4 Hz), 7.6 (s, 1H),
12.51 (s, 1H, NH); MS (m/z) (%), 388 (Mþ, 100), 373 (3.5), 268 (2.4),
255 (6), 223 (2.9), 194 (5), 106 (9.3). Anal. Calcd for C22H20N4O3: C,
68.03; H, 5.19; N, 14.42. Found: C, 68.28; H, 5.47; N, 14.25%.
To a solution of the appropriate isoquinolinium bromides 7a–e
(2 mmol) in dry benzene (30 mL), triethylamine (0.4 mL) was
added and the reaction mixture was refluxed 2–4 h, then left to cool
to room temperature. The triethylamine–hydrobromide salt was
removed by filtration and the filtrate was evaporated under vac-
uum. The residue was triturated with methanol and the solid
formed was filtered off, washed with methanol and dried. Re-
crystallization from proper solvent afforded the corresponding
pyrrolo[2,1-a]isoquinoline-1-carbonitrile derivatives 9a–e.
3.4.3. 3-(p-Chlorophenylhydrazono)-2,3,5,6-tetrahydro-8,9-
dimethoxy-2-oxopyrrolo[2,1-a]-isoquinoline-1-carbonitrile (4c)
Orange red powder (0.57 g, 70%); mp 278–280 ꢀC; IR (KBr)
n
1679 (C]O), 2204 (C^N) cmꢁ1; MS (m/z) (%), 408 (Mþ, 100), 225
(9.2), 127 (15.1), 101 (6), 90 (16.1), 63 (10.2). Anal. Calcd for
3.6.1. 5,6-Dihydro-8,9-dimethoxy-2-phenylpyrrolo[2,1-a]-
isoquinoline-1-carbonitrile (9a)
C
21H17ClN4O3: C, 61.69; H, 4.19; N, 13.70. Found: C, 61.78; H, 4.33;
N, 13.49%.
Yellow crystals (0.45 g, 69%); mp 208–210 ꢀC (ethanol); IR (KBr)
n
2212 (C^N) cmꢁ1; 1H NMR (CDCl3)
d
3.0 (t, 2H, J¼6.6 Hz), 3.91 (s,
3H), 3.96 (s, 3H), 4.09 (t, 2H, J¼6.6 Hz), 6.48 (s, 1H), 6.75 (s, 1H),
7.34–7.44 (m, 5H), 7.75 (s, 1H); 13C NMR
28.8, 42.3, 55.9, 56.1, 86.9,
3.5. Synthesis of the isoquinolinium salts 7a–e
d
To a solution of the appropriate
a
-bromoketone derivatives
107.0, 110.9, 111.7, 118.3, 119.9, 124.7, 128.1, 128.7, 128.8, 130.8, 134.1,
136.3, 148.4, 148.9; MS (m/z) (%), 330 (Mþ, 100), 243 (17.6), 230
(27.8), 165 (12.1), 86 (8.5). Anal. Calcd for C21H18N2O2: C, 76.36; H,
5.46; N, 8.48. Found: C, 76.15; H, 5.32; N, 8.71%.
6a–e (2 mmol) in dry benzene (20 mL), isoquinoline-1-acetonitrile
1 (0.46 g, 2 mmol) was added. The mixturewas refluxed for 2 h, then
left to cool. The solid product was filtered off, washed with ether
and dried to afford the isoquinolinium bromides 7a–e, respectively.
3.6.2. 2-(4-Bromophenyl)-5,6-dihydro-8,9-dimethoxypyrrolo-
[2,1-a]isoquinoline-1-carbonitrile (9b)
3.5.1. Isoquinolinium salt 7a
Yellowish-brown crystals (0.59 g, 69%); mp 184–186 ꢀC (meth-
Yellowish-brown powder (0.59 g, 73%); mp 174–176 ꢀC (meth-
anol); IR (KBr)
d6)
n
1644 (C]O), 2253 (C^N) cmꢁ1
;
1H NMR (DMSO-
anol); IR (KBr) n ; d 2.87 (t, 2H,
2177 (C^N) cmꢁ1 1H NMR (CDCl3)
d
2.50 (s, 2H), 2.75 (t, 2H, J¼6.3 Hz), 3.24 (t, 2H, J¼6.3 Hz), 3.77
J¼6.3 Hz), 3.43 (t, 2H, J¼6.3 Hz), 3.90 (s, 3H), 3.92 (s, 3H), 5.57 (s,
1H), 6.67 (s, 1H), 6.99 (s, 1H), 7.61 (d, 2H, J¼6.9 Hz), 7.78 (d, 2H,
J¼6.9 Hz); MS (m/z) (%), 409 (Mþ, 13.6), 230 (6.8), 101 (19.9), 86
(100), 79 (12.7), 58 (37.2). Anal. Calcd for C21H17BrN2O2: C, 61.63; H,
4.16; N, 6.84. Found: C, 61.38; H, 3.92; N, 6.95%.
(s, 3H), 3.79 (s, 2H), 3.82 (s, 3H), 6.98 (s, 1H), 7.16–7.49 (m, 5H), 7.62
(s, 1H). Anal. Calcd for C21H21BrN2O3: C, 58.75; H, 4.93; N, 6.53.
Found: C, 58.94; H, 5.03; N, 6.77%.
3.5.2. Isoquinolinium salt 7b
Brown crystals (0.72 g, 71%); mp 152–154 ꢀC (methanol); IR
(KBr)
(t, 2H, J¼6.3 Hz), 3.44 (t, 2H, J¼6.3 Hz), 3.88 (s, 3H), 3.91 (s, 3H), 4.24
(s, 2H), 4.40 (s, 2H), 6.67 (s, 1H), 6.98 (s, 1H), 7.65 (d, 2H, J¼6.9 Hz),
7.86 (d, 2H, J¼6.9 Hz). Anal. Calcd for C21H20Br2N2O3: C, 49.63; H,
3.97; N, 5.51. Found: C, 49.46; H, 3.68; N, 5.22%.
3.6.3. 2-(Benzothiazol-2-yl)-5,6-dihydro-8,9-dimethoxy-
pyrrolo[2,1-a]isoquinoline-1-carbonitrile (9c)
n d 2.83
1649 (C]O), 2253 (C^N) cmꢁ1; 1H NMR (DMSO-d6)
Pale brown crystals (0.55 g, 72%); mp 264–266 ꢀC (acetic acid);
IR (KBr)
n ; d 3.03 (t, 2H,
2215 (C^N) cmꢁ1 1H NMR (CDCl3)
J¼6.9 Hz), 3.87 (s, 3H), 3.91 (s, 3H), 4.84 (t, 2H, J¼6.9 Hz), 6.72 (s,
1H), 7.01 (s, 1H), 7.30–7.41 (m, 2H), 7.74 (s, 1H), 7.79 (d, 1H,
J¼7.2 Hz), 7.92 (d, 1H, J¼7.2 Hz); MS (m/z) (%), 387 (Mþ, 100), 345
(6.7), 328 (8.1), 300 (7.3), 156 (12), 69 (8.1). Anal. Calcd for
C22H17N3O2S: C, 68.22; H, 4.42; N, 10.85; S, 8.28. Found: C, 68.05; H,
4.37; N, 10.72; S, 8.43%.
3.5.3. Isoquinolinium salt 7c
Brown powder (0.71 g, 74%); mp 233–235 ꢀC (DMF); IR (KBr)
n
1649 (C]O), 2214 (C^N) cmꢁ1
;
1H NMR (CDCl3)
d
3.03 (t, 2H,
J¼6.9 Hz), 3.86 (s, 3H), 3.92 (s, 3H), 3.94 (s, 2H), 4.83 (t, 2H,
J¼6.9 Hz), 4.89 (s, 2H), 6.72 (s, 1H), 7.27–7.40 (m, 2H), 7.77 (s, 1H),
7.79 (d, 1H, J¼7.8 Hz), 7.93 (d, 1H, J¼7.8 Hz). Anal. Calcd for
3.6.4. 2-(2-Benzofuryl)-5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]-
isoquinoline-1-carbonitrile (9d)
C
22H20BrN3O3S: C, 54.32; H, 4.14; N, 8.62; S, 6.58. Found: C, 54.15; H,
Pale yellow crystals (0.49 g, 67%); mp 218–220 ꢀC (DMF); IR
3.95; N, 8.74; S, 6.46%.
(KBr)
n
2214 (C^N) cmꢁ1; 1H NMR (CDCl3)
d
3.09 (t, 2H, J¼6.9 Hz),
3.95 (s, 3H), 3.99 (s, 3H), 4.42 (t, 2H, J¼6.9 Hz), 6.79 (s, 1H), 6.81 (s,
1H), 6.89 (s, 1H), 7.28–7.35 (m, 2H), 7.79 (d, 1H, J¼8.4 Hz), 7.92 (d,
3.5.4. Isoquinolinium salt 7d
Yellow crystals (0.62 g, 67%); mp 201–203 ꢀC (ethanol); IR (KBr)
1H, J¼8.4 Hz), 7.80 (s, 1H); 13C NMR
d 28.5, 42.7, 56.0, 56.1, 87.7,
n
1651 (C]O), 2217 (C^N) cmꢁ1
;
1H NMR (CDCl3)
d
3.01 (t, 2H,
104.0, 107.2, 110.8, 111.0, 113.6, 117.7, 119.3, 120.8, 123.2, 124.0,
124.5, 124.6, 128.3, 137.4, 147.2, 148.5, 149.4, 154.5; MS (m/z) (%),
370 (Mþ, 100), 355 (23.3), 327 (22.5), 185 (12.8), 89 (2.4). Anal.
J¼6.9 Hz), 3.94 (s, 3H), 3.96 (s, 3H), 3.99 (s, 2H), 4.05 (s, 2H), 4.38 (t,
2H, J¼6.9 Hz), 6.79 (s, 1H), 6.89 (s, 1H), 7.29–7.59 (m, 4H), 7.80 (s,

7894
T.A. Abdallah, K.M. Dawood / Tetrahedron 64 (2008) 7890–7895
Calcd for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.49; H,
4.75; N, 7.25%.
2H, J¼6.6 Hz), 3.81 (s, 3H), 3.83 (s, 3H), 4.10 (t, 2H, J¼6.9 Hz), 6.67 (s,
1H), 7.02 (s, 1H), 7.41–7.50 (m, 5H), 7.61 (s, 1H); 13C NMR
27.7, 41.9,
d
55.6, 85.6, 106.8, 111.9, 117.7, 118.9, 121.2, 125.7, 127.7, 130.2, 133.8,
135.6, 147.8, 148.9; MS (m/z) (%), 334 (Mþ, 3.7), 315 (42.4), 287
(43.2), 243 (20.5), 165 (9.6), 51 (6.8). Anal. Calcd for C19H18N4O2: C,
68.25; H, 5.43; N, 16.76. Found: C, 68.36; H, 5.47; N, 16.82%.
3.6.5. 5,6-Dihydro-8,9-dimethoxy-2-(2-oxo-2H-chromen-3-
yl)pyrrolo[2,1-a]-isoquinoline-1-carbonitrile (9e)
Pale yellow crystals (0.61 g, 77%); mp 296–297 ꢀC (DMF); IR
(KBr)
n ; d 3.03 (t,
1715 (C]O), 2212 (C^N) cmꢁ1 1H NMR (CDCl3)
2H, J¼6.9 Hz), 3.92 (s, 3H), 3.98 (s, 3H), 4.06 (t, 2H, J¼6.9 Hz), 6.64
(s, 1H), 6.76 (s, 1H), 7.35–7.42 (m, 2H), 7.56–7.60 (m, 2H), 7.78 (s,
1H), 7.82 (s, 1H); MS (m/z) (%), 398 (Mþ, 100), 384 (18.8), 355 (23.9),
312 (12.5), 299 (32.9), 199 (12.7), 156 (10.1), 127 (15.1), 87 (10.1).
Anal. Calcd for C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.57; H, 4.71; N, 6.95%.
3.8.2. 2,3,5,6-Tetrahydro-8,9-dimethoxy-3-p-tolyl-[1,2,3]-
triazolo[5,1-a]isoquinoline-1-carbonitrile (13b)
Orange-yellow crystals (0.46 g, 67%); mp 207–209 ꢀC (metha-
nol); IR (KBr)
n ;
2207 (C^N), 3358 (NH) cmꢁ1 1H NMR (CDCl3)
d
2.21 (s, 3H), 3.15 (t, 2H, J¼6.9 Hz), 3.91 (s, 3H), 4.02 (s, 3H), 4.08 (t,
2H, J¼6.9 Hz), 6.85 (s,1H), 7.07 (d, 2H, J¼7.8 Hz), 7.62 (s, 1H), 7.95 (d,
2H, J¼7.8 Hz), 9.55 (s, 1H); MS (m/z) (%), 348 (Mþ, 77.6), 230 (10.7),
187 (4.2), 157 (4.6), 91 (100), 51 (18.5). Anal. Calcd for C20H20N4O2:
C, 68.95; H, 5.76; N, 16.08. Found: C, 68.91; H, 5.63; N, 16.24%.
3.7. Synthesis of 3-arylazo-2-phenylpyrrolo[2,1-a]-
isoquinoline-1-carbonitriles 10a,b
To a cold solution of 2-phenylpyrrolo[2,1-a]isoquinoline-1-car-
bonitrile 9a (2 mmol) in pyridine (20 mL), the appropriate aryl-
diazonium 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 room temperature overnight, then diluted with 10 mL water.
The precipitate was filtered off, washed with ethanol and dried.
Recrystallization from proper solvent afforded the corresponding
3-arylazo-2-phenylpyrrolo[2,1-a]isoquinoline-1-carbonitrile de-
rivatives 10a,b.
3.9. X-ray structure determination of compound 13a
The X-ray diffraction measurement was made on using maXus
(Bruker Nonius, Delft & MacScience, Japan) at temperature 300(2) K
and wavelength 0.71073 Å; radiation: Mo Ka. Crystal data for
compound 13a: C19H18N4O2, M¼334.37, crystal system, space
group: triclinic, P21/n; unit cell dimensions: a¼7.1322(6) Å,
b¼9.1238(6) Å, c¼13.3906(13) Å,
a
¼102.942(3)ꢀ,
b
¼90.099(3)ꢀ,
g
¼91.293(7)ꢀ; volume: 848.99(12) Å3; Z¼2; calculated density:
1.435 Mg/m3; absorption coefficient:
m
¼0.25 mmꢁ1
; reflection
3.7.1. 3-Phenylazo-5,6-dihydro-8,9-dimethoxy-2-phenyl-
pyrrolo[2,1-a]isoquinoline-1-carbonitrile (10a)
3562 measured, qmax¼22.37ꢀ;
R factor¼0.135.
u
Crystallographic data for the structural analysis of compound
13a has been deposited with the Cambridge Crystallographic Data
Centre (CCDC) under the number 684888. Copies of the information
may be obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: þ44 01223 336033; e-mail:
deposit@ccdc.cam.ac.uk or www:http://www.ccdc.cam.ac.uk).
Yellowish-orange crystals (0.60 g, 70%); mp 286–288 ꢀC (DMF);
IR (KBr)
n ; d 3.04 (t, 2H,
2206 (C^N) cmꢁ1 1H NMR (CDCl3)
J¼6.6 Hz), 3.94 (s, 3H), 4.0 (s, 3H), 4.17 (t, 2H, J¼6.6 Hz), 6.76 (s, 1H),
7.37–7.58 (m, 8H), 7.82 (m, 2H), 8.0 (s, 1H); MS (m/z) (%), 434 (Mþ,
100), 329 (61.9), 313 (19.8), 298 (60.3), 255 (27.7), 210 (13.3), 77
(99.5). Anal. Calcd for C27H22N4O2: C, 74.64; H, 5.10; N, 12.89.
Found: C, 74.56; H, 5.34; N, 12.67%.
Supplementary data
3.7.2. 3-(p-Tolylazo)-5,6-dihydro-8,9-dimethoxy-2-phenyl-
pyrrolo[2,1-a]isoquinoline-1-carbonitrile (10b)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.043.
Yellowish-white crystal (0.67 g, 75%); mp 176–178 ꢀC (ethanol);
IR (KBr) n d 2.38 (s, 3H), 3.58 (t,
2212 (C^N) cmꢁ1; 1H NMR (CDCl3)
2H, J¼6.9 Hz), 3.96 (s, 3H), 3.97 (s, 3H), 3.98 (t, 2H, J¼6.9 Hz), 6.75 (s,
References and notes
1H), 7.19 (d, 2H, J¼8.1 Hz), 7.38–7.43 (m, 5H), 7.55 (d, 2H, J¼8.1 Hz),
8.06 (s, 1H); 13C NMR
d 21.2, 28.6, 42.4, 56.1, 56.3, 107.1, 110.7, 110.9,
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111.8, 118.2, 118.3, 121.1, 124.6, 128.0, 128.7, 128.8, 129.5, 131.9, 138.3,
147.6, 152.2; MS (m/z) (%), 448 (Mþ, 70), 330 (55.2), 316 (4.4), 287
(28.1), 199 (10.8), 91 (100), 64 (4). Anal. Calcd for C28H24N4O2: C,
74.98; H, 5.36; N, 12.49. Found: C, 75.26; H, 5.19; N, 12.57%.
3.8. 3-Aryl-[1,2,3]triazolo[5,1-a]isoquinoline-1-carbonitriles
13a,b
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To a cold solution of the appropriate isoquinolinium bromide
salts 7a,b (2 mmol) in base-free absolute ethanol (20 mL), the ap-
propriate phenyl or p-tolyldiazonium salts (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 room temperature overnight,
then diluted with 10 mL water. The precipitate so formed was fil-
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proper solvent afforded the corresponding 1,2,3-triazolo[5,1-a]-
isoquinoline-1-carbonitrile derivatives 13a,b.
3.8.1. 2,3,5,6-Tetrahydro-8,9-dimethoxy-3-phenyl-[1,2,3]-
triazolo[5,1-a]isoquinoline-1-carbonitrile (13a)
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Yellow crystal (0.48 g, 72%); mp 225–227 ꢀC (acetonitrile); IR
(KBr) n d 2.99 (t,
2211 (C^N), 3327 (NH) cmꢁ1; 1H NMR (DMSO-d6)

T.A. Abdallah, K.M. Dawood / Tetrahedron 64 (2008) 7890–7895
7895
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