Michael reactions of arylidenesulfonylacetonitriles. A new route to polyfunctional benzo[a]quinolizines

Article abstract of DOI:10.3390/70700540

Arylidenesulfonylacetonitriles react in acetonitrile with 1-methylisoquinoline and isoquinolin-1-yl-acetonitrile in the presence of piperidine to give benzo[a]quinolizines 6,9 and 7,10, respectively. The structures of the products were established on the basis of elemental and spectral analyses and their chemical reactivity.

Full text of DOI:10.3390/70700540

Molecules 2002, 7, 540-548
molecules
ISSN 1420-3049
http://www.mdpi.org
Michael Reactions of Arylidenesulfonylacetonitriles. A New
Route to Polyfunctional Benzo[a]quinolizines
Tayseer. A. Abdallah, Hyam. A. Abdelhadi, Huwida M. Hassaneen and Hamdi M. Hassaneen*.
Department of Chemistry, Faculty of Science, Cairo University, Giza, 1263, Egypt.
*Author to whom correspondence should be addressed; e-mail: tiseer123@hotmail.com
Received: 29 January 2002; in revised form: 10 July 2002 / Accepted: 11 July 2002/ Published: 31
July 2002
Abstract: Arylidenesulfonylacetonitriles react in acetonitrile with 1-methylisoquinoline
and isoquinolin-1-yl-acetonitrile in the presence of piperidine to give benzo[a]quinolizines
6,9 and 7,10, respectively. The structures of the products were established on the basis of
elemental and spectral analyses and their chemical reactivity.
Keywords: Arylidenesulfonylacetonitriles, 1-methylisoquinoline, isoquinolin-1-yl-
acetonitrile, benzo[a]quinolizines.
Introduction
High yielding syntheses of polyfunctional benzo[a]quinolizines are well documented [1-9]. As a
continuation of our work on the use of isoquinoline and its derivatives for the synthesis of fused
heterocyclic compounds [10,11], we now report a new and general one step route affording
polyfunctional substituted benzo[a]quinolizines in good yield from readily available inexpensive
starting materials, which competes favorably with the methods previously reported for the preparation
of the title compounds.

Molecules 2002, 7
541
Results and Discussion
Treatment of 1-methylisoquinoline (1) [12] with arylidenesulfonylacetonitriles 3a-c [13] in boiling
acetonitrile in the presence of an equimolar amount of piperidine leads, in each case, to the formation
of only one product 6a-c, as indicated by TLC and 1H-NMR analyses (Scheme 1).
Scheme 1
CN
acetonitrile/ piperidine (1 mol)
CH3O
CH3O
ArCH=C
+
N
SO2Ph
1
3
CH3
CH3O
CH3O
CH3O
CH3O
N
NH
CN
CN
H
SO2Ph
H
SO2Ph
H
H
H
Ar
H
Ar
H
4
CH3O
CH3O
CH3O
-H2
N
NH
SO2Ph
N
NH
CH3O
piperidine (1 mol)
H
SO2Ph
H
Ar
Ar
6
5
CH3O
CH3O
-PhSO2H
piperidine (2 moles)
N
NH
Ar
7
3a, 6a,7a: Ar = C6H5
3b, 6b, 7b: Ar = 4-ClC6H4
3c, 6c, 7c: Ar = 4-NO2C6H4

Molecules 2002, 7
542
The structures of the products 6a-c were established on the basis of their elemental analyses and
1
spectral data (IR, H-NMR, MS). For example, the IR spectrum of compound 6a shows a stretching
frequency at 3350 cm-1 (NH) in addition to characteristic bands at 1315 and 1155 cm-1 (asymmetric
and symmetric stretching vibrations of a SO2 group). Its 1H-NMR spectrum reveals a singlet at δ = 6.9
assignable to the C-1 proton and a singlet at δ = 8.8, which disappears upon deuterium exchange,
assignable to the NH proton, in addition to the typical signals of the isoquinoline moiety. The
formation of 6 may be explained by cyclization of the initially formed Michael addition product 4 to
the unisolated product 5. Subsequent autoxidation of the latter leads to the final product 6 (cf. Scheme
1). When the reaction of 1 with 3a-c was carried out in the presence of excess piperidine (2 moles)
then the products 7a-c were formed directly. The structures of the products 7 were also inferred from
their elemental analyses and spectral data. For example, the IR spectra show a characteristic peak near
3320 cm-1 due to a NH group. The mass spectra of the products also show a molecular ion peak of high
1
intensity, and the H-NMR and chemical reactivity also support the proposed structures of the
products. In light of the previous results, it may be suggested that the unisolated products 5 afford the
end products 7 via loss of benzenesulfinic acid (Scheme 1). Similarly, isoquinolin-1-yl-acetonitrile (2)
[14] reacts with 3a,b to give 9a,b (cf. Scheme 2). The structures of the latter products were confirmed
by elemental analysis and spectroscopic data. Upon treatment of p-nitrobenzylidene
phenylsulfonylacetonitrile 3c in this fashion a product 10c was formed directly due to elimination of
benzenesulfinic acid from the intermediate 8 (Scheme 2). The structure of the product 10c was
confirmed by its independent synthesis via reaction of 2 with 11 (Scheme 3).
Scheme 2
CH3O
CH3O
piperidine (1 mol)
acetonitrile /
+
3
N
2
CH2CN
CH3O
CH3O
CH3O
-H2
N
NH
SO2Ph
N
NH
CH O
piperidine (1 mol)
3
NC
NC
H
SO2Ph
H
Ar
Ar
9
8
CH3O
CH3O
-PhSO2H
3a, 9a, 10a: Ar = C6H5
N
NH
3b, 9b, 10b: Ar = 4-ClC6H4
3c, 10c: Ar = 4-NO2C6H4
piperidine (2 moles)
NC
Ar
10

Molecules 2002, 7
543
Scheme 3
CH3O
CH3O
CN
4 -
NO2C6H4-CH=C
2
N
+
NH
SO2C6H4CH3 -4
11
NC
Ar
10
The structures of 10b,c were also confirmed by their chemical reactions as described in Scheme 4.
For example, acylation of 10b,c with acetic anhydride or benzoylation with benzoyl chloride in
pyridine affords the corresponding N-acetylimino or N-benzoylimino compounds 12b,c and 13b,c,
respectively. Nitrosation of 10c with sodium nitrite in acetic acid gives the corresponding N-nitroso
compound 14c. Thermolysis of 14c in xylene gives the carbonyl compound 15c. The structure of 15c
was confirmed by its alternative synthesis by hydrolysis of 10c with dilute hydrochloric acid. Also,
hydrolysis of 10b with dilute hydrochloric acid leads to the formation of 15b. Their elemental analyses
and spectral data (cf. Table 1 and 2) confirmed the structures of 12, 13, 14 and 15.
Scheme 4
CH3O
CH3O
CH3O
CH3O
- N2
, xylene
N
N
N-N=O
O
NC
14c
NC
Ar
Ar
15b,c
NaNO2
AcOH
HCl
NH
CH3O
CH3O
N
NC
PhCOCl
pyridine
Ar
(CH3CO)2O
10b,c
CH3O
CH3O
CH3O
CH3O
N
N-COCH3
N
N-COPh
NC
NC
13b,c
Ar
Ar
12b,c

Molecules 2002, 7
544
Experimental
General
All melting points were determined on an Electrothermal melting point apparatus and are
uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer.
1H NMR spectra were recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini 200 MHz
spectrometer and chemical shifts are expressed in δ units using TMS as internal reference. Mass
spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer, operating at 70 eV.
Elemental analyses were carried out at the Microanalytical Center of the University of Cairo, Giza,
Egypt. The analytical and spectral data of the compounds prepared is summarized in Tables 1 and 2.
Synthesis of 2-aryl-6,7-dihydro-9,10-dimethoxy-4-imino-2-phenylsulphonyl-benzo[a]quinolizines 6
and 9.
Piperidine (0.5 mL, 0.005 mol) was added at room temperature to a solution of arylidene-
sulfonylacetonitriles 3 (0.005 mol) and 1-methylisoquinoline (1) (1.02 g, 0.005 mol) or isoquinolin-1-
yl-acetonitrile (2) (1.15 g, 0.005 mol) in acetonitrile (40 mL). The reaction mixture was refluxed for 8
h. The solvent was evaporated under reduced pressure and the residue was triturated with methanol (10
mL) whereupon it solidified. The crude product was collected and crystallized from DMF.
Synthesis of 2-aryl-6,7-dihydro-9,10-dimethoxy-4-iminobenzo[a]-quinolizines 7 and 10
These compounds were prepared by the same procedure described for the synthesis of compounds
6 and 9 using (1mL, 0.01 mol) of piperidine. The precipitated compounds were crystallized from
DMF.
Nitrosation of 10c.
Cold sodium nitrite solution (0.7 g in 10 mL water) was added dropwise to a stirred solution of 10c
(2.01 g, 0.005 mol) in acetic acid (30 mL). The mixture was left in an ice bath for 4 h., then the reddish
solid that precipitated was collected. Crystallization of the crude product from DMF gave the
corresponding N-nitroso derivative 14c.
Thermolysis of 14c.
The N-nitroso compound 14c (2.16 g, 0.005 mol) was refluxed in xylene (20 mL) until its red color
disappeared (ca. 20 min). The reaction mixture was then cooled, the crude product was collected,
washed with water and crystallized from DMF.

Molecules 2002, 7
Acylations of 10b,c.
545
A solution of 10b,c (0.005 mol) in acetic anhydride (25 mL) was refluxed for 1 h. The solvent was
removed under reduced pressure and the residue was triturated with water. The solid formed was
collected, washed with water and crystallized from ethanol to give N-acetylimino derivatives 12b,c.
Treatment of 10b,c (0.005 mol) with benzoyl chloride (0.58 mL, 0.005 mol) in pyridine (30 mL) at
reflux for 30 min. and workup of the reaction mixture in usual way gave the corresponding N-benzoyl-
imino derivatives 13b,c.
Hydrolysis of 10 b,c.
A suspension of 10 b,c (2.01g, 0.005 mol) in 10% hydrochloric acid (20 mL) was refluxed for 30
min. The reaction mixture was cooled and the solid that precipitated out was collected and crystallized
from DMF to give 15b,c.
Table 1. Analytical data of the synthesized compounds
Compd.
no.
Yield
%
m.p.°C
solvent
225-226
DMF
Mol. formula
Mol. Wt.
C27H24N2O4S
472.23
% Analysis Calcd. (Found)
Color
C
H
N
S
yellow
80
68.64
5.08
5.93
6.78
6a
(68.72)
63.96
(5.02)
4.54
(5.83)
5.53
(6.66)
dark
82
78
84
77
81
85
88
86
79
264-266
DMF
C27H23N2O4SCl
506.72
6.32
6b
6c
yellow
orange
(64.23)
62.67
(4.44)
4.45
(5.52)
8.12
(6.38)
276-277
DMF
C27H23N3O6S
517.23
6.19
(62.52)
67.61
(4.24)
4.63
(8.03)
8.45
(6.08)
dark
258-259
DMF
C28H23N3O4S
497.23
6.44
9a
yellow
bright
brown
yellow
(67.43)
63.22
(4.52)
4.14
(8.62)
7.90
(6.27)
320-322
DMF
C28H22N3O4SCl
531..72
6.02
9b
7a
(63.04)
75.90
(4.03)
6.02
(7.84)
8.43
(6.14)
329-331
DMF
C21H20N2O2
332.19
-
-
-
-
-
-
-
-
-
-
(75.63)
68.76
(6.14)
5.18
(8.63)
7.64
yellow
yellow
206-207
DMF
C21H19N2O2Cl
366.68
7b
7c
(68.64)
66.84
(5.02)
5.04
(7.83)
11.14
(11.24)
11.76
(11.54)
10.73
(10.94)
214-215
DMF
C21H19N3O4
377.19
(66.90)
73.95
(5.13)
5.32
dark
214-216
DMF
C22H19N3O2
357.19
10a
10b
yellow
bright
brown
(73.63)
67.43
(5.21)
4.60
223-224
DMF
C22H18N3O2Cl
391.68
(67.13)
(4.73)

Molecules 2002, 7
546
dark
yellow
dark
89
84
78
77
79
81
78
83
275-277
DMF
C22H18N4O4
402.19
65.67
(65.51)
66.44
4.48
(4.32)
4.61
13.93
(13.83)
9.69
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
10c
12b
12c
13b
13c
14c
15b
15c
153-155
EtOH
C24H20N3O3Cl
433..70
yellow
dark
(66.12)
64.86
(4.51)
4.50
(9.82)
12.61
(12.41)
8.48
150-151
EtOH
C24H20N4O5
444.21
yellow
dark
(64.84)
70.23
(4.32)
4.44
241-242
DMF
C29H22N3O3Cl
495.72
yellow
brown
(70.13)
68.77
(4.24)
4.35
(8.21)
11.07
(10.90)
16.24
(16.42)
7.13
260-262
DMF
C29H22N4O5
506.23
(68.63)
61.25
(4.11)
3.94
red
250-251
DMF
C22H17N5O5
431.19
(61.21)
67.26
(3.67)
4.33
yellow
yellow
294-295
DMF
C22H17N2O3Cl
392.67
(67.13)
65.51
(4.12)
4.22
(7.34)
10.42
(10.35)
244-246
DMF
C22H17N3O5
403.17
(65.23)
(4.12)
Table 2. IR and 1H-NMR spectroscopic data
1H NMR (δ ppm)
Compd.
no.
IR (cm-1)
M+
3350
(NH)
3380
(NH)
3446
(NH)
2.6 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.9 (s, 1H); 7.0-
7.7 (m, 10H); 7.8 (s, 1H);7.9 (s, 1H), 8.8 (s, 1H)
3.0 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 7.0 (s, 1H);
7.2-7.6 (m, 10H); 7.9 (s, 2H).
472
507
517
497
532
332
367
377
357
6a
6b
6c
3.1 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 6.9 (s, 1H); 7.1-8.5 (m,
12H).
2216 (CN), 3.0 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 6.9 (s, 1H); 7.0-7.6 (m,
3417 (NH) 11H); 7.7 (s, 1H)
9a
9b
7a
7b
7c
2219 (CN), 2.8 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 7.2 (s, 1H); 7.3-
3415 (NH) 7.7 (m, 10H); 7.9 (s, 1H)
3386
(NH)
3252
(NH)
3323
(NH)
2.9 (m, 2H); 3.3 (s, 3H); 3.4 (s, 3H); 3.8 (m, 2H); 6.7 (s, 1H); 6.8
(s, 1H); 6.9 (s, 1H), 7.1 (s, 1H) 7.2-7.6 (m, 6H)
2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.3 (s, 1H); 6.4
(s, 1H); 6.7 (s,1H); 7.1 (s, 1H); 7.4-7.8 (m, 5H)
2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.2 (m, 2H); 6.4 (s, 1H); 6.5
(s, 1H); 6.7 (s, 1H), 6.9 (s, 1H) 7.1-7.6 (m, 5H)
2221 (CN), 2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.3 (s, 1H); 6.4
3316 (NH) (s, 1H); 6.7 (s, 1H); 7.2-7.6 (m, 5H)
10a

Molecules 2002, 7
2225 (CN), 2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.8 (s, 1H); 6.9
547
392
402
434
444
496
506
431
393
403
10b
10c
12b
12c
13b
13c
14c
15b
15c
3420(NH) (s, 1H); 7.1 (s, 1H); 7.4-8.2 (m, 5H)
2200 (CN), 2.8 (m, 2H); 3.6 (s, 3H); 3.7 (s, 3H); 4.0 (m, 2H); 6.4 (s, 1H); 6.9
3307(NH) (s, 1H); 7.1 (s, 1H); 7.4-8.2 (m, 5H)
1656(CO), 2.8 (m, 2H); 3.7 (s, 3H); 3.9 (s, 6H); 4.0 (m, 2H); 6.7 (s, 1H); 7.0
2217 (CN) (s, 1H); 7.4-8.2 (m, 5H)
1658(CO), 2.0 (s, 3H); 2.9 (m, 2H); 3.9 (s, 6H); 4.0 (m, 2H);
2210(CN)
1654(CO), 2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.7 (s, 1H); 7.3-
2211(CN) 8.2 (m, 11H)
1672 (CO), 3.0 (m, 2H); 3.9 (s, 6H); 4.6 (m, 2H); 6.8 (s, 1H), 7.3 (s, 1H); 7.4-
6,5 (s, 1H); 6.8 (s, 1H); 7.4-7.6 (m, 4H); 7.9 (s, 1H)
2210(CN)
2218(CN)
8.2 (m, 10H)
2.7 (m, 2H); 3.8 (s, 6H); 4.0 (m, 2H); 6.7 (s, 1H); 6.8 (s, 1H); 7.4-
8.2 (m, 5H)
1659 (CO), 2.8 (m, 2H); 3.7 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.7 (s, 1H); 6.8
2216 (CN) (s, 1H); 7.4-8.2 (m, 5H)
1666(CO), 2.7 (m, 2H); 3.8 (s ,3H); 4.0 (s, 3H); 4.1 (m, 2H); 6.7 (s, 1H); 6.9
2218 (CN) (s, 1H); 7.4-8.2 (m, 5H)
Compound 10c: 13C-NMR 27.54, 41.51, 56.78, 56.92, 100.73, 112.06, 113.92, 118.62,
119.82, 120.05, 123.40, 124.31, 130.70, 133.72, 135.31, 139.32, 142.12, 147.82, 148.65,
157.69.
Compound 9a: 13C-NMR 28.95, 47.44, 58.31, 58.39, 95.67, 108.45, 112.09, 114.03,
115.60, 119.22, 119.72, 126.32, 130.29, 130.79, 130.96, 132.51, 133.62, 136.76, 150.08,
152.21, 155.38, 155.94, 157.48, 158.58.
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Sample Availability: Available from the authors.
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