Synthesis and cyclizations of 1-azapolyene derivatives

Article abstract of DOI:10.1016/j.tet.2011.03.058

Imminium salts of enaminonitriles with polyenals gave stable 1-azapolyenes, which could be readily transformed to benzo- and indoloquinolizines in 1,6-electrocyclizations. Azatrienes and azatetraenes with formaldehyde and primary amines afforded pyrimido[

Full text of DOI:10.1016/j.tet.2011.03.058

Tetrahedron 67 (2011) 3380e3387
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Synthesis and cyclizations of 1-azapolyene derivatives
y
*
ꢀ
ꢀ
Zoltan Vincze , Peter Nemes
ꢀ
Department of Chemistry, Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest, P.O. Box 2, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Imminium salts of enaminonitriles with polyenals gave stable 1-azapolyenes, which could be readily
transformed to benzo- and indoloquinolizines in 1,6-electrocyclizations. Azatrienes and azatetraenes
with formaldehyde and primary amines afforded pyrimido[6,1-a]isoquinolines.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 November 2010
Received in revised form 28 February 2011
Accepted 21 March 2011
Available online 12 April 2011
Keywords:
b-Enaminonitriles
1-Azapolyenes
1,6-Electrocyclizations
Mannich reaction
Benzo- and indoloquinolizines
1. Introduction
2.1. Synthesis of 1-azatetraenes and 1-azapentaenes
The benzoquinolizine framework is a common constituent of
various naturally occurring alkaloids and biologically active com-
pounds. Due to the great significance of these heterocycles both
from chemical and biological point of view, several methods are
The aromatic polyenals 5aef were prepared easily in good yields
by Wittig-type oxopropenylation of the properly substituted un-
saturated aldehyde with 1,3-dioxan-2-yl methyltributyl phos-
phorane.5 Azapolyenes 6aef were obtained in an acid catalyzed
Knoevenagel condensation from the mesylate salt 1 and the cor-
responding polyenals 5aef. The reactions were carried out in gla-
cial acetic acid at room temperature (Scheme 2).
The mesylate salts of 1-azatetraenes 6a,c,e and 1-azapentaenes
6b,d,f, formed under mild reaction conditions (Table 1), proved to
be stable for extended time at room temperature.
known for their preparation.1 Pushepull enamines, e.g.,
b-enami-
nonitriles or esters have also proved to be valuable precursors for
the construction of benzoquinolizines, and other bridgehead het-
erocycles, such as pyrrolizidines, indolizidines, and quinolizidines.2
We have reported previously, that 1-cyanomethylene-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline mesylate (1) readily re-
acts with a,b-unsaturated aldehydes 2, resulting in 1-azatrienes 3,
which could be cyclized to 6,7-dihydro-4H-benzo[a]quinolizines 4
in good yields (Scheme 1).3 It is noteworthy, that only few examples
can be found in the literature for such 1,6-electrocyclizations of 1-
azatrienes providing different dihydropiridines.4 These results
prompted us to investigate the possible extension of the azaelec-
trocyclization process for 1-azatetraenes and 1-azapentaenes, and
to study the synthetic potential of 1-azapolyenes.
2.2. Cyclizations of azapolyenes
Similarly to the azatrienes the cyclizations of 1-azatetraenes
6a,c,e and 1-azapentaenes 6b,d,f took place by adding Et3N in
excess, in CH3CN at reflux to give 4-styryl-6,7-dihydro-4H-pyrido
[2,1-a]isoquinoline 7a,c,e and 4-(buta-1,3-dienyl)-6,7-dihydro-4H-
pyrido[2,1-a]isoquinoline 7b,d,f derivatives with acceptable yields
(Table 2). In contrast to the 1,6-electrocyclizations of 1-azatrienes,
no significant difference was observed in reactivity of the differ-
ently substituted azapolyene derivatives 6aef. If the reactions were
carried out at lower temperature, in different solvents (CH3CN,
toluene, and ethanol), low conversion and decomposition of the
starting material was observed during the prolonged reaction time
(2e3 days).
2. Results and discussion
We report herein the synthesis, electrocyclizations, and Man-
nich reactions of 1-azapolyenes 6aef.
* Corresponding author. Tel.: þ36 1 478 4176; fax: þ36 1 478 4268; e-mail
As we described in our earlier study,3 the computation revealed,
address: Nemes.Peter@aotk.szie.hu (P. Nemes).
y
Fax: þ36 1 478 4268.
that the
6
p-cyclization was promoted by
a
nucleophilic
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.058

Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
3381
H3CO
CH3SO3
O
NH
H3CO
H3CO
R2
H3CO
H3CO
H3CO
CH3SO3
NH
R1
Et3N, CH3CN
NC
N
CH3COOH
+
R1
CN
NC
R1
R2
1
2
3
4
R2
Scheme 1.
O
non-bonding
electron pair
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
CH3SO3
NH
2
1
N
N
n
1'
+
1. CH3COOH
2. Et3N, CH3CN
2'
NC
n
CN
NC
R1
n
R1
5a-f
1
6a-f 79-91 %
R1
A
R1
H3CO
H3CO
R1
H3CO
H3CO
N
N
n-1
n-1
NC
7a-f 49-62 %
NC
B
Scheme 2.
2.3. Cyclization of azapolyenes to indoloquinolizines
1-Cyanomethylene-1,2,3,4-tetrahydro- -carboline 8, a valuable
Table 1
Yields for the 1-azatetraenes and 1-azapentaenes
R1
n
Reaction time (h)
Yield %
b
Entry
starting material in the synthesis of numerous biologically active
compounds, was prepared according to literature procedure start-
ing from N-(indol-3-yl-ethyl)-cyanoacetamide.6,7 The reactions of
polyenals (9, 5c,d) with the mesylate salt of 8 gave the required 1-
azapolyenes 10aec in good yields (Table 1, Scheme 3).
After deprotonation of 10aec the 1-azapolyene bases cyclized
readily at room temperature in 5e6 h to afford 11aec indoloqui-
nolizine derivatives. The progress of the cyclization could be fol-
lowed by 1H NMR in CDCl3 solution (Fig. 1). The appearance of the
new methine H-4 proton of the formed dihydropyridine ring at
4.72 ppm indicates the ring closure unequivocally (Fig. 1).
6a
6b
6c
6d
6e
H
H
2
3
2
3
2
3
1
2
3
4
4
3
4
4
4
3
3
4
85
89
91
85
82
79
92
85
82
NO2
NO2
NMe2
NMe2
NO2
NO2
NO2
6f
10a
10b
10c
Table 2
Yields for the cyclization products
Entry
R1
n
Reaction time (h)
Yield %
7a
7b
7c
7d
7e
H
H
1
2
1
2
1
2
0
1
2
5
6
6
6
5
6
5
6
6
56
50
62
53
60
49
75
56
48
2.4. C-Acylation of b-enaminonitrile
NO2
NO2
NMe2
NMe2
NO2
NO2
NO2
As we and others published earlier, enaminonitriles, enami-
noesters, and nitroenamines are able to undergo regioselective
7f
[3þ3] cyclizations with
a,b
-unsaturated carboxylic acid chlorides.8
These results inspired us to examine the ring closure of the C-ac-
ylated product (14).
11a
11b
11c
1-Cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (12) was acylated with 5-phenyl-penta-2,4-dienoic acid chlo-
ride (13). The reaction took place smoothly at room temperature in
acetonitrile in the presence of excess base (K2CO3), affording the
C-acylated product 14 exclusively (Scheme 4). Under the standard
reaction conditions (acetonitrile, reflux) however, the formation of
the cyclized product could not be observed.
intramolecular attack of the nitrogen atom on the electron-poor C20
atom. The formation of the dihydroazete intermediate A decrease
the activation energy of the rate determining (E)/(Z) isomeriza-
tion step affording B trough ring opening (Scheme 2). Although, no
computations were carried out to date, a similar mechanism could
be assumed for these azaelectrocyclizations as well.

3382
Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
O
CH3SO3
NO2
NH
CH3SO3
N
n
H
CH3COOH
NH
Et3N, CH3CN
N
N
H
N
H
+
NC
n-1
CN
NC
n
NO2
8
10a: n = 1 92 %
10b: n = 2 85 %
11c: n = 3 82 %
11a: n = 0 75 %
11b: n = 1 56 %
11c: n = 2 48 %
9: n = 1
5c: n = 2
5d: n = 3
NO2
Scheme 3.
Applying high temperature (reflux in xylene) and using different
bases as catalysts (Cs2CO3, La(OH)3), only the decomposition of the
14 was detected.
N
N
H
NC
0 hr
2.5. Aza-annulations of azatrienes
10b
According to earlier publications the aza-annulation reactions of
various pushepull enaminones (15a,b), nitroenamine (15c), and
enaminonitrile (15d) with formaldehyde/amine result in func-
tionalized pyrimido[6,1-a]isoquinoline derivatives (16aec),
(Scheme 5).9
NO
H3CO
H3CO
NH
R
NH2, CH2O
H3CO
N
H3CO
3 hr
CH3OH, rt
H
X
N
R
X
16a: X = COMe; R = PhCH2
16b: X = COPh; R = Ph
16c: X = NO2; R = PhCH2
16d: X = CN; R = PhCH2
15a: X = COMe
15b: X = COPh
15c: X = NO2
15d: X = CN
Scheme 5.
These results led us to examine the Mannich reactions of
enaminonitrile 15d and the new azapolyenes. According to the de-
scribed examples the reaction of enaminonitrile with 2 mol of
formaldehyde and 1 mol of primary amine afforded tetrahydropyr-
imido[6,1-a]isoquinole 16d in a double Mannich reaction. Aza-
trienes 17aed under similar reaction conditions consumed only
1 mol of formaldehyde to give 2-styryl-3,4,6,7-tetrahydro-2H-pyr-
imido[6,1-a]isoquinolines 18aed (Scheme 6, Table 3). The products
proved to be stable in contrast to 2-(buta-1,3-dienyl)-3,4,6,7-tetra-
hydro-2H-pyrimido[6,1-a]isoquinoline (18e), formed in the reaction
of the 1-azatatraene (17e) under similar conditions. Compound 18e
could be isolated, identified but rapid decomposition was observed
at room temperature.
NO
N
6 hr
N
H
NC
11b
H3CO
H3CO
Fig. 1. The progress of the cyclization of 10b followed by NMR (25 ꢀC, CDCl3).
N
N
R2
CH3OH, rt
H3CO
NH ,
H3CO
CH2O
2
R2
N
Cl
O
NC
NC
H3CO
H3CO
n
n
Ph(p-R1)
Ph(p-R1)
NH
17a: R1 = H, n = 1
17b: R1 = H, n = 1
17c: R1 = H, n = 1
17d: R1 = NO2, n = 1
17e: R1 = H, n = 2
13
O
H3CO
H3CO
18a: R1 = H, n = 1, R2 = CH3
79 %
NC
18b: R1 = H, n = 1, R2 = CH2Ph
65 %
83 %
NH
CN
K2CO3, acetonitrile
18c: R1 = H, n = 1, R =
2
OMe
OMe
CH CH2
2
14 67 %
12
18d: R1 = NO2, n =1, R2 = CH2Ph
18e: R1 = H, n = 2, R2 = CH2Ph
65 %
60 %
Scheme 4.
Scheme 6.

Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
3383
Table 3
NMR Spectra were recorded on a Varian Unity 300 (300 MHz)
spectrometer, in CDCl3 solutions. Chemical shifts are
expressed in parts per million relative to the internal standard
TMS. IR spectra were recorded on a Perkin Elmer 1600 FT IR
spectrometer. The microanalysis was carried out on a Heraeus
Yields for the cyclization products
(d)
Entry
n
R1
R2
Reaction time (h)
Yield %
18a
18b
18c
18d
18e
1
1
1
1
2
H
H
H
NO2
H
CH3
CH2Ph
CH2CH2Ph(OMe)2
CH2Ph
CH2Ph
16
18
18
18
18
79
65
83
65
60
€
Micro Rapid CHN. All melting points were measured with a Buchi
SMP-20 apparatus and are uncorrected. Column chromatography
was conducted with Merck Kieselgel 60 (0.063e0.200 mm). An-
alytical TLC was carried out on precoated plates (Merck silica gel
60, F254). Solvents were dried and freshly distilled according to
the common practice.
To explain the interesting aza-annulation of azatrienes 17aed we
made some mechanistic considerations. In earlier publications it
was already described that enaminones gave anellated pyrimidine
derivatives in Mannich reactions.10 Surprisingly, the reaction path-
way was suggested via first N- rather than C-aminomethylation.
For the reactions of azatrienes two different mechanisms can be
considered (Scheme 7). Route I involves the nucleophilic attack of
the amine nitrogen resulting in the addition product, which can
exist either in the imine (A) or the enamine (B) form. Subsequent
condensation of the enamine with formaldehyde can afford 18aed.
4.2. General procedure for the synthesis of 1-azatetraenes
and 1-azapentaenes (6aef, 10aec)
To the solution of b-enaminonitrile-mesylate (1, 8) (2.0 mmol)
in glacial acetic acid (6 mL), the polyenal (5aef, 9) (3.0 mmol) was
added. The mixture was stirred at room temperature for 3e4 h until
the reaction was complete. The solution was then poured into dii-
Route I
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
N
N
NH
CH2O
NH
H2N R2
Ph(p-R1)
R2
NC
R2
NH
NC
NC
A
B
H3CO
H3CO
Ph(p-R1)
Ph(p-R1)
17a-d
N
Route II
R2
N
NC
H3CO
H3CO
H3CO
H3CO
18a-d
Ph(p-R1)
CH2
N
R2
N
N
NC
N
NC
R2
C
Ph(p-R1)
Ph(p-R1)
17a-d
Scheme 7.
Route II follows the mechanism of the double Mannich conden-
sation. The N-aminomethylation giving intermediate C however is
followed by a cyclization/prototropic rearrangement sequence.
To validate either of the two mechanisms depicted in Scheme 7,
we attempted the reaction of 17a with benzyl amine, but no trace of
the addition product A could be detected. This result may support
the formation of the pyrimidine ring according to the Route II.
sopropyl ether (30 mL), the formed precipitate was filtered, and
washed with diethyl ether.
4.2.1. 2-(6,7-Dimethoxy-3,4-dihydro-isoquinolin-1-yl)-7-phenyl-
hepta-2,4,6-trienenitrile mesylate (6a). Recrystallization (EtOAc)
gave 6a (630 mg, 85%) orange solid, mp 145 ꢀC; Rf (EtOAc) 0.72.
[Found: C, 77.62; H, 6.00; N, 7.66. C24H22N2O2 requires C, 77.81; H,
5.99; N, 7.56%]; nmax (KBr) 2935, 2178, 1600, 1563, 1516, 1280 cmꢁ1
;
dH 7.74 (1H, dd, J 14.3, 3.5 Hz, CHCHCHCHCHPh), 7.53e7.50 (2H, m,
Ph), 7.46 (1H, s, H-11), 7.38e7.35 (3H, m, Ph), 7.24e7.17 (2H, m,
CHCHCHCHCHPh), 7.11e6.95 (2H, m, CHCHCHCHCHPh), 6.83 (1H, s,
H-8), 3.92 (3H, s, OMe), 3.88 (3H, s, OMe), 3.73 (2H, t, J 7.3 Hz, H-6),
2.64 (2H, t, J 7.3 Hz, H-7); dC (75 MHz, CDCl3) 161.0, 151.7, 147.6,
144.3, 139.5, 136.4, 132.8, 129.1, 128.5, 128.0, 127.4, 119.8, 117.3, 111.6,
110.8, 110.3, 56.5, 56.3, 48.0, 26.0.
3. Conclusion
In summary, this work demonstrates the synthetic usefulness of
azapolyenes, that are able to undergo 6p-electrocyclization to af-
ford 6,7-dihydro-4H-pyrido[2,1-a]isoquinolines and indoloquino-
lizine derivatives. Azatrienes and azatetraenes with formaldehyde
and primary amines afford pyrimido[6,1-a]isoquinolines. Further
investigation of these interesting and novel azaelectrocyclizations
and aza-annulations with other azapolyenes is in progress.
4.2.2. 2-(6,7-Dimethoxy-3,4-dihydro-isoquinolin-1-yl)-9-phenyl-
nona-2,4,6,8-tetraenenitrile mesylate (6b). Recrystallization (EtOAc)
gave 6b (705 mg, 89%) dark red solid, mp 105 ꢀC; Rf (EtOAc) 0.74.
[Found: C, 78.60; H, 6.23; N, 6.95. C26H24N2O2 requires C, 78.76; H,
4. Experimental section
4.1. General
6.10; N, 7.07%]; nmax (KBr) 2934, 2178, 1596, 1560, 1518, 1279 cmꢁ1
;
dH 7.55 (1H, dd, J 14.2, 3.9 Hz, CHCHCHCHCHCHCHPh), 7.42e7.26
(5H, m, Ph), 7.05 (1H, s, H-11), 6.96e6.49 (6H, m,
CHCHCHCHCHCHCHPh), 6.74 (1H, s, H-8), 3.93 (3H, s, OMe), 3.78
The structures and the purity of the final products as free
bases were confirmed by 1H, 13C NMR, IR, and microanalysis.

3384
Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
(3H, s, OMe), 3.73 (2H, t, J 7.1 Hz, H-6), 2.65 (2H, t, J 7.1 Hz, H-7); dC
(75 MHz, CDCl3) 161.1, 151.7, 149.1, 147.6, 144.2, 140.1, 136.9, 136.8,
132.8, 132.1, 128.9, 128.7, 128.6, 128.4, 127.1, 119.9, 117.4, 111.2, 110.8,
110.3, 56.5, 56.3, 48.0, 26.1.
[Found: C, 72.87; H, 4.51; N, 14.01. C24H18N4O2 requires C, 73.08; H,
4.60; N, 14.20%]; nmax (KBr) 3432, 2931, 2180, 1592, 1522, 1341, 1084,
866 cmꢁ1
; dH 8.87 (1H, br s, NH), 8.19 (2H, d, J 8.8 Hz, Ph(p-NO2)),
7.83 (1H, d, J 11.4 Hz, CHCHCHCHPh(p-NO2)), 7.61 (1H, d, J 8.0 Hz, H-
5), 7.54 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.43 (1H, d, J 8.1 Hz, H-8), 7.32
(1H, dd, J 8.0, 7.0 Hz, H-7), 7.18 (1H, dd, J 8.1, 7.0 Hz, H-6), 7.06 (1H,
m, CHCHCHCHCHPh(p-NO2)), 6.98e6.84 (2H, m, CHCHCHCHCHPh
(p-NO2)), 6.80 (1H, d, J 15.5 Hz, CHCHCHCHCHPh(p-NO2)), 4.00 (2H,
t, J 8.9 Hz, H-3), 2.90 (2H, t, J 8.9 Hz, H-4); dC (75 MHz, CDCl3) 147.8,
143.9, 142.5, 137.1, 136.7, 131.9, 130.7, 127.7, 127.6, 125.6, 125.2, 124.4,
124.2, 121.0, 120.2, 119.5, 115.3, 112.6, 82.3, 49.3, 19.4.
4.2.3. 2-(6,7-Dimethoxy-3,4-dihydro-isoquinolin-1-yl)-7-(4-nitro-
phenyl)-hepta-2,4,6-trienenitrile mesylate (6c). Recrystallization
(EtOAc) gave 6c (756 mg, 91%) red solid, mp 164 ꢀC; Rf (EtOAc) 0.66.
[Found: C, 69.56; H, 5.04; N, 10.02. C24H21N3O4 requires C, 69.39; H,
5.10; N, 10.11%]; nmax (KBr) 2938, 2176, 1597, 1514, 1342, 1199,
861 cmꢁ1
; dH 8.22 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.59 (2H, d, J 8.8 Hz,
Ph(p-NO2)), 7.53 (1H, dd, J 11.0, 2.9 Hz, CHCHCHCHCHPh(p-NO2)),
7.28e7.10 (2H, m, CHCHCHCHCHPh(p-NO2)), 7.05 (1H, s, H-11),
6.94e6.84 (2H, m, CHCHCHCHCHPh(p-NO2)), 6.78 (1H, s, H-8), 3.95
(3H, s, OMe), 3.91 (3H, s, OMe), 3.76 (2H, t, J 7.5 Hz, H-6), 2.67 (2H, t, J
7.5 Hz, H-7); dC (75 MHz, CDCl3) 161.0, 151.9, 148.4, 147.8, 142.9,
142.8, 136.3, 132.9, 132.2, 131.3, 127.9, 127.8, 124.6, 119.8, 117.1, 113.7,
111.0, 110.2, 56.7, 56.5, 48.2, 26.1.
4.2.8. 2-(4,9-Dihydro-3H-b-carbolin-1-yl)-9-(4-nitro-phenyl)-nona-
2,4,6,8-tetraenenitrile mesylate (10c). Recrystallization (EtOAc) gave
10c (689 mg, 82%) dark red solid, mp 124 ꢀC; Rf (EtOAc) 0.75.
[Found: C, 74.37; H, 4.55; N, 13.10. C26H20N4O2 requires C, 74.27; H,
4.79; N, 13.33%]; nmax (KBr) 3433, 2930, 2179, 1587, 1540, 1338,
1084 cmꢁ1
; dH 8.89 (1H, br s, NH), 8.17 (2H, d, J 8.8 Hz, Ph(p-NO2)),
7.82 (1H, d, J 11.5 Hz, CHCHCHCHCHCHCHPh(p-NO2)), 7.61 (1H, d, J
7.6 Hz, H-5), 7.52 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.44 (1H, d, J 8.1 Hz, H-
8), 7.30 (1H, dd, J 7.6, 7.0 Hz, H-7), 7.16 (1H, dd, J 8.1, 7.0 Hz, H-6),
7.05e6.49 (6H, m, CHCHCHCHCHCHCHPh(p-NO2)), 3.99 (2H, t, J
8.8 Hz, H-3), 2.95 (2H, t, J 8.8 Hz, H-4); dC (75 MHz, CDCl3) 147.7,
143.8, 142.6, 139.1, 137.1, 136.7, 132.6, 131.9, 130.7, 127.8, 127.6, 127.4,
125.6, 125.4, 124.4, 124.3, 121.0, 120.2, 117.5, 115.3, 112.6, 82.0, 49.3,
19.5.
4.2.4. 2-(6,7-Dimethoxy-3,4-dihydro-isoquinolin-1-yl)-9-(4-nitro-
phenyl)-nona-2,4,6,8-tetraenenitrile mesylate (6d). Recrystallization
(EtOAc) gave 6d (750 mg, 85%) dark red solid, mp 157 ꢀC; Rf (EtOAc)
0.65. [Found: C, 70.50; H, 5.39; N, 9.36. C26H23N3O4 requires C, 70.73;
H, 5.25; N, 9.52%]; nmax (KBr) 2934, 2200,1534,1517,1393,1218,1023,
864 cmꢁ1
; dH 8.17 (2H, d, J 8.1 Hz, Ph(p-NO2)), 7.54 (2H, d, J 8.1 Hz, Ph
(p-NO2)), 7.55 (1H, dd, J 14.2, 3.9 Hz, CHCHCHCHCHCHCHPh(p-
NO2)), 7.06 (1H, s, H-11), 6.96e6.52 (6H, m, CHCHCHCHCHCHCHPh
(p-NO2)), 6.75 (1H, s, H-8), 3.94 (3H, s, OMe), 3.89 (3H, s, OMe), 3.77
(2H, t, J 7.0 Hz, H-6), 2.67 (2H, t, J 7.0 Hz, H-7); dC (75 MHz, CDCl3)
161.0, 157.4, 151.8, 148.6, 147.7, 147.3, 143.3, 138.6, 134.8, 133.6, 132.8,
129.9, 127.3, 124.4, 121.4, 119.7, 117.2, 110.9, 110.3, 107.9, 56.5, 56.2,
40.0, 26.1.
4.3. General procedure for the cyclization (7aef, 11aec)
To the solution of 1-azapolyenes (6aef, 10aec) (1 mmol) in
acetonitrile (10 mL), Et3N (2 mmol) was added. The solution was
stirred for 6e8 h at reflux or at room temperature (6aef and 10aec,
respectively). The solvent was removed under reduced pressure,
and the residue dissolved in CH2Cl2 (10 mL). The CH2Cl2 solution
was washed with water (2ꢂ5 mL), dried over Na2SO4, and then
evaporated under reduced pressure to give the crude product,
which was purified by column chromatography on silica gel using
EtOAc/hexane as eluent.
4.2.5. 2-(6,7-Dimethoxy-3,4-dihydro-isoquinolin-1-yl)-7-(4-dime-
thylamino-phenyl)-hepta-2,4,6-trienenitrile mesylate (6e). Recrysta
llization (EtOAc) gave 6e (678 mg, 82%) dark blue solid, mp 127 ꢀC;
Rf (EtOAc) 0.55. [Found: C, 75.59; H, 6.44; N, 9.98. C26H27N3O2 re-
quires C, 75.52; H, 6.58; N, 10.16%]; nmax (KBr) 2915, 2178, 1536,
1366,1160, 808 cmꢁ1
; dH 7.51 (1H, dd, J 7.4, 3.4 Hz, CHCHCHCHCHPh
(p-NMe2)), 7.37 (2H, d, J 8.9 Hz, Ph(p-NMe2)), 7.09 (1H, s, H-11),
6.91e6.86 (2H, m, CHCHCHCHCHPh(p-NMe2)), 6.81e6.79 (2H, m,
CHCHCHCHCHPh(p-NMe2)), 6.75 (1H, s, H-8), 6.68 (2H, d, J 8.9 Hz,
Ph(p-NMe2)), 3.94 (3H, s, OMe), 3.91 (3H, s, OMe), 3.74 (2H, t, J
8.5 Hz, H-6), 3.02 (6H, s, NMe2), 2.66 (2H, t, J 8.5 Hz, H-7); dC
(75 MHz, CDCl3) 161.3, 151.6, 151.2, 149.8, 147.6, 145.8, 140.6, 132.8,
129.0, 126.1, 124.6, 123.6, 120.1, 117.8, 112.3, 110.7, 110.4, 109.2, 56.5,
56.3, 48.0, 40.4, 26.1.
4.3.1. 9,10-Dimethoxy-4-styryl-6,7-dihydro-4H-pyrido[2,1-a]iso-
quinoline-1-carbonitrile (7a). Purification by column chromatog-
raphy (EtOAc/hexane 1:1) gave the title compound 7a (207 mg,
56%) yellow solid, mp 145 ꢀC; Rf (EtOAc/hexane 1:1) 0.50. [Found: C,
77.85; H, 6.03; N, 7.96. C24H22N2O2 requires C, 77.81; H, 5.99; N,
7.56%]; nmax (KBr) 2924, 2180, 1636, 1609, 1529, 1288, 1031 cmꢁ1
; dH
7.91 (1H, s, H-11), 7.28e7.12 (5H, m, Ph), 6.64 (1H, s, H-8), 6.46 (1H,
d, J 15.7 Hz, H-2), 6.27 (1H, dd, J 15.7, 8.1 Hz, H-3), 6.12 (1H, d, J
9.5 Hz, CHCHPh), 5.17 (1H, dd, J 9.5, 5.4 Hz, CHCHPh), 4.65 (1H, dd, J
8.1, 5.4 Hz, H-4), 3.83 (3H, s, OMe), 3.88 (3H, s, OMe), 3.44e3.17 (2H,
m, H-6), 3.00e2.69 (2H, m, H-7); dC (75 MHz, CDCl3) 151.1, 150.8,
147.6, 136.2, 130.8, 129.7, 128.8, 128.4, 127.0, 126.3, 124.6, 124.0,
121.2, 112.3, 111.1, 110.3, 74.7, 64.2, 56.5, 56.2, 47.4, 29.7.
4.2.6. 2-(4,9-Dihydro-3H-b-carbolin-1-yl)-5-(4-nitro-phenyl)-
penta-2,4-dienenitrile mesylate (10a). Recrystallization (EtOAc)
gave 10a (678 mg, 92%) yellow solid, mp 158 ꢀC; Rf (50% EtOAc/
hexane) 0.47. [Found: C, 71.88; H, 4.30; N, 15.45. C22H16N4O2 re-
quires C, 71.73; H, 4.38; N, 15.21%]; nmax (KBr) 3439, 2932, 2176,
1594, 1522, 1344, 1084, 855 cmꢁ1
;
dH 8.97 (1H, br s, NH), 8.09 (2H, d,
4.3.2. 9,10-Dimethoxy-4-(4-phenyl-buta-1,3-dienyl)-6,7-dihydro-
4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (7b). Purification by
column chromatography (EtOAc/hexane 1:1) gave the title com-
pound 7b (198 mg, 50%) yellow solid, mp 154 ꢀC; Rf (EtOAc/hexane
1:1) 0.67. [Found: C, 78.97; H, 5.89; N, 7.00. C26H24N2O2 requires C,
78.76; H, 6.10; N, 7.07%]; nmax (KBr) 2937, 2180, 1632, 1465, 1289,
J 8.8 Hz, Ph(p-NO2)), 7.83 (1H, d, J 11.5 Hz, CHCHCHPh(p-NO2)), 7.57
(1H, d, J 14.0 Hz, CHCHCHPh(p-NO2)), 7.54 (2H, d, J 8.8 Hz, Ph(p-
NO2)), 7.47 (1H, dd, J 11.5, 14.0 Hz, CHCHCHPh(p-NO2)), 7.40 (1H, d, J
8.0 Hz, H-5), 7.42 (1H, d, J 8.3 Hz, H-8), 7.28 (1H, dd, J 8.0, 6.9 Hz, H-
7), 7.12 (1H, dd, J 8.3, 6.9 Hz, H-6), 3.99 (2H, t, J 8.7 Hz, H-3), 2.88
(2H, t, J 8.7 Hz, H-4); dC (75 MHz, CDCl3) 149.3, 148.1, 145.5, 137.8,
127.5, 125.8, 124.8, 124.6, 123.7, 122.2, 121.0, 119.7, 116.4, 114.9, 112.4,
64.8, 48.6, 21.1.
1030 cmꢁ1
; dH 7.89 (1H, s, H-11), 7.35e7.25 (5H, m, Ph), 6.70 (1H,
dd, J 15.7, 10.3 Hz, CHCHCHCHPh), 6.65 (1H, s, H-8), 6.61 (1H, d, J
15.7 Hz, H-2), 6.30 (1H, dd, J 15.2, 10.3 Hz, CHCHCHCHPh), 6.03 (1H,
d, J 9.6 Hz, CHCHCHCHPh), 5.85 (1H, dd, J 15.1, 7.7 Hz, H-3), 5.14 (1H,
dd, J 9.6, 5.0 Hz, CHCHCHCHPh), 4.57 (1H, dd, J 7.7, 5.0 Hz, H-4), 3.93
(3H, s, OMe), 3.89 (3H, s, OMe), 3.35e3.20 (2H, m, H-6), 2.92e2.50
(2H, m, H-7); dC (75 MHz, CDCl3) 151.0, 150.8, 147.5, 137.0, 134.6,
4.2.7. 2-(4,9-Dihydro-3H-b-carbolin-1-yl)-7-(4-nitro-phenyl)-
hepta-2,4,6-trienenitrile mesylate (10b). Recrystallization (EtOAc)
gave 10b (670 mg, 85%) orange solid, mp 160 ꢀC; Rf (EtOAc) 0.77.

Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
3385
131.2,130.3, 129.8, 128.9, 128.1,127.8,126.6, 124.5,124.1, 121.2,112.2,
111.1, 110.3, 74.6, 63.7, 56.5, 56.2, 47.5, 29.7.
132.0, 129.8, 129.0, 128.5, 127.8, 125.4, 124.2, 123.5, 121.4, 112.6,
112.5, 111.2, 110.3, 75.3, 64.0, 56.5, 56.2, 47.3, 40.5, 29.9.
4.3.3. 9,10-Dimethoxy-4-[2-(4-nitro-phenyl)-vinyl]-6,7-dihydro-4H-
pyrido[2,1-a]isoquinoline-1-carbonitrile (7c). Purification by col-
umn chromatography (EtOAc/hexane 1:1) gave the title compound
7c (257 mg, 62%) yellow solid, mp 138 ꢀC; Rf (EtOAc/hexane 1:1)
0.61. [Found: C, 69.17; H, 5.11; N, 10.32. C24H21N3O4 requires C,
69.39; H, 5.10; N, 10.11%]; nmax (KBr) 2933, 2176, 1639, 1488, 1285,
4.3.7. 4-(4-Nitro-phenyl)-4,6,7,12-tetrahydro-indolo[2,3-a]quinoli-
zine-1-carbonitrile (11a). Purification by column chromatography
(EtOAc/hexane 1:1) gave the title compound 11a (276 mg, 75%)
yellow solid, mp 129 ꢀC; Rf (EtOAc/hexane 1:1) 0.70. [Found: C,
71.92; H, 4.43; N, 14.99. C22H16N4O2 requires C, 71.73; H, 4.38; N,
15.21%]; nmax (KBr) 3441, 2930, 2181, 1599, 1513, 1340, 748 cmꢁ1
; dH
855 cmꢁ1
;
dH 8.07 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.83 (1H, s, H-11),
9.46 (1H, br s, NH), 8.17 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.56 (2H, d, J
8.8 Hz, Ph(p-NO2)), 7.50 (1H, d, J 8.0 Hz, H-8), 7.42 (1H, d, J 8.3 Hz,
H-11), 7.27 (1H, dd, J 8.0, 7.0 Hz, H-10), 7.13 (1H, dd, J 8.3, 7.0 Hz, H-
9), 6.05 (1H, d, J 9.6 Hz, H-2), 5.31 (1H, d, J 4.7 Hz, H-4), 5.22 (1H, dd,
J 9.6, 4.7 Hz, H-3), 3.56e3.49 (1H, m, H-6), 3.19e3.12 (1H, m, H-6),
2.98e2.93 (2H, m, H-7); dC (75 MHz, CDCl3) 149.3, 148.1, 145.5,
137.8,129.2,127.5,125.8, 124.8,124.6,123.7,122.2, 121.0,119.7,116.4,
114.9, 112.4, 82.3, 64.8, 48.6, 21.1.
7.43 (2H, d, J 8.8 Hz, Ph(p-NO2)), 6.64 (1H, s, H-8), 6.48 (1H, d, J
15.5 Hz, H-2), 6.40 (1H, dd, J 15.5, 7.9 Hz, H-3), 6.09 (1H, d, J 9.5 Hz,
CHCHPh(p-NO2)), 5.13 (1H, dd, J 9.5, 5.3 Hz, CHCHPh(p-NO2)), 4.65
(1H, dd, J 7.9, 5.3 Hz, H-4), 3.87 (3H, s, OMe), 3.83 (3H, s, OMe),
3.32e3.18 (2H, m, H-6), 2.87e2.56 (2H, m, H-7); dC (75 MHz, CDCl3)
151.3, 151.1, 147.7, 147.6, 142.9, 130.9, 129.8, 128.7, 127.7, 125.5, 124.4,
123.9, 121.1, 111.4, 111.1, 110.4, 75.3, 63.8, 56.6, 56.4, 47.9, 29.9.
4.3.4. 9,10-Dimethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-6,7-
dihy dro -4H-p yr ido[ 2,1 -a]isoq uinol in e-1-car bonitrile
(7d). Purification by column chromatography (EtOAc/hexane 1:1)
gave the title compound 7d (234 mg, 53%) yellow solid, mp 135 ꢀC;
Rf (EtOAc) 0.64. [Found: C, 70.95; H, 5.06; N, 9.51. C26H23N3O4 re-
quires C, 70.73; H, 5.25; N, 9.52%]; nmax (KBr) 2930, 2176,1643,1492,
4.3.8. 4-[2-(4-Nitro-phenyl)-vinyl]-4,6,7,7a,12,12a-hexahydro-indolo
[2,3-a]quinolizine-1-carbonitrile (11b). Purification by column
chromatography (EtOAc/hexane 1:1) gave the title compound 11b
(221 mg, 56%) yellow solid, mp 123 ꢀC; Rf (EtOAc/hexane 1:1) 0.68.
[Found: C, 73.06; H, 4.85; N, 14.25. C24H18N4O2 requires C, 73.08; H,
4.60; N, 14.20%]; nmax (KBr) 3440, 2928, 2181, 1595, 1515, 1342,
1280, 860 cmꢁ1
;
dH 8.17 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.91 (1H, s, H-
747 cmꢁ1
; dH 9.43 (1H, br s, NH), 8.15 (2H, d, J 8.9 Hz, Ph(p-NO2)),
11), 7.48 (2H, d, J 8.8 Hz, Ph(p-NO2)), 6.86 (1H, dd, J 15.7, 10.3 Hz,
CHCHCHCHPh(p-NO2)), 6.67 (1H, s, H-8), 6.61 (1H, d, J 15.7 Hz, H-2),
6.31 (1H, dd, J 15.2, 10.3 Hz, CHCHCHCHPh(p-NO2)), 6.15 (1H, d, J
9.5 Hz, CHCHCHCHPh(p-NO2)), 6.01 (1H, dd, J 15.1, 7.7 Hz, H-3), 5.16
(1H, dd, J 9.5, 5.5 Hz, CHCHCHCHPh(p-NO2)), 4.62 (1H, dd, J 7.7,
5.5 Hz, H-4), 3.87 (3H, s, OMe), 3.83 (3H, s, OMe), 3.32e3.18 (2H, m,
H-6), 2.87e2.56 (2H, m, H-7); dC (75 MHz, CDCl3) 151.2, 151.1, 147.8,
143.7,133.5,132.5,132.1,130.4,129.8,127.1,126.6,125.2,124.5,121.3,
120.1, 111.76, 111.3, 110.4, 75.2, 63.5, 56.7, 56.4, 47.9, 29.9.
7.51 (2H, d, J 8.9 Hz, Ph(p-NO2)), 7.49 (1H, d, J 7.8 Hz, H-8), 7.42 (1H,
d, J 8.3 Hz, H-11), 7.29 (1H, dd, J 7.8, 7.0 Hz, H-10), 7.14 (1H, dd, J 8.3,
7.0 Hz, H-9), 6.59 (1H, d, J 16.0 Hz, H-2), 6.48 (1H, dd, J 16.0, 7.3 Hz,
H-3), 6.11 (1H, d, J 9.6 Hz, CHCHPh(p-NO2)), 5.21 (1H, dd, J 9.6,
5.4 Hz, CHCHPh(p-NO2)), 4.72 (1H, dd, J 7.3, 5.4 Hz, H-4), 3.63e3.44
(2H, m, H-6), 3.18e2.95 (2H, m, H-7); dC (75 MHz, CDCl3) 147.5,
145.5, 142.6, 137.7, 131.2, 128.8, 127.5, 126.3, 125.6, 124.9, 124.2,
123.8, 123.4, 120.9, 119.6, 116.3, 112.8, 112.3, 82.3, 63.0, 48.4, 21.2.
4.3.9. 4-[4-(4-Nitro-phenyl)-buta-1,3-dienyl]-4,6,7,12-tetrahydro-in-
dolo[2,3-a]quinolizine-1-carbonitrile (11c). Purification by column
chromatography (EtOAc/hexane 1:1) gave the title compound 11c
(202 mg, 48%) yellow solid, mp 122 ꢀC; Rf (EtOAc/hexane 1:1) 0.65.
[Found: C, 74.43; H, 4.94; N, 13.15. C26H20N4O2 requires C, 74.27; H,
4.79; N, 13.33%]; nmax (KBr) 3441, 2927, 2180, 1590, 1510, 1342,
4.3.5. 4-[2-(4-Dimethylamino-phenyl)-vinyl]-9,10-dimethoxy-6,7-
dihy dro -4H-p yr ido[ 2,1 -a]isoq uinol in e-1-car bonitrile
(7e). Purification by column chromatography (EtOAc/hexane 1:1)
gave the title compound 7e (248 mg, 60%) orange solid, mp 153 ꢀC;
Rf (EtOAc/hexane 1:1) 0.48. [Found: C, 75.73; H, 6.60; N, 10.05.
C26H27N3O2 requires C, 75.52; H, 6.58; N, 10.16%]; nmax (KBr) 2930,
750 cmꢁ1
; dH 9.43 (1H, br s, NH), 8.14 (2H, d, J 8.8 Hz, Ph(p-NO2)), 7.50
2177, 1601, 1530, 1290, 860 cmꢁ1
;
dH 7.91 (1H, s, H-11), 7.26 (2H, d, J
(2H, d, J 8.8 Hz, Ph(p-NO2)), 7.47 (1H, d, J 7.9 Hz, H-8), 7.43 (1H, d, J
8.3 Hz, H-11), 7.27 (1H, dd, J 7.9, 7.0 Hz, H-10), 7.13 (1H, dd, J 8.3,
7.0 Hz, H-9), 6.84 (1H, dd, J 15.2, 9.6 Hz, CHCHCHCHPh(p-NO2)), 6.56
(1H, d, J 15.8 Hz, H-2), 6.15 (1H, dd, J 15.2, 9.5 Hz, CHCHCHCHPh(p-
NO2)), 6.12 (1H, d, J 9.5 Hz, CHCHCHCHPh(p-NO2)), 6.03 (1H, dd, J
15.1, 7.7 Hz, H-3), 5.16 (1H, dd, J 9.5, 5.4 Hz, CHCHCHCHPh(p-NO2)),
4.72 (1H, dd, J 7.7, 5.4 Hz, H-4), 3.55e3.49 (2H, m, H-6), 3.10e2.97
(2H, m, H-7); dC (75 MHz, CDCl3) 147.6, 145.4, 142.6, 137.7, 133.8,
132.2,131.9,128.8,127.5,126.9,125.6,124.3,124.2,123.4,120.9,119.6,
116.3, 115.33, 112.81, 112.3, 82.30, 63.0, 48.5, 21.3.
6.0 Hz, Ph(p-NMe2)), 6.65 (2H, d, J 6.0 Hz, Ph(p-NMe2)), 6.70 (1H,
dd, J 16.5, 7.9 Hz, H-3), 6.62 (1H, s, H-8), 6.39 (1H, d, J 16.5 Hz, H-2),
6.10 (1H, d, J 9.3 Hz, CHCHPh(p-NMe2)), 5.18 (1H, dd, J 9.3, 4.3 Hz,
CHCHPh(p-NMe2)), 4.61 (1H, dd, J 7.9, 4.3 Hz, H-4), 3.96 (3H, s,
OMe), 3.90 (3H, s, OMe), 3.35e3.23 (2H, m, H-6), 3.02 (6H, s, NMe2),
2.90e2.56 (2H, m, H-7); dC (75 MHz, CDCl3) 151.2, 150.7, 147.5,
130.9, 129.8, 128.0, 125.7, 124.4, 124.3, 124.1, 122.0, 121.4, 112.9,
112.5, 111.2, 110.3, 75.2, 64.7, 56.5, 56.2, 47.2, 40.6, 27.1.
4.3.6. 4-[4-(4-Dimethylamino-phenyl)-buta-1,3-dienyl]-9,10-dime-
thoxy-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile
(7f). Purification by column chromatography (EtOAc/hexane 1:1)
gave the title compound 7f (215 mg, 49%) orange solid, mp 146 ꢀC;
Rf (EtOAc/hexane 1:1) 0.43. [Found: C, 76.48; H, 6.60; N, 9.39.
C28H29N3O2 requires C, 76.51; H, 6.65; N, 9.56%]; nmax (KBr) 2924,
4.4. 2-(6,7-Dimethoxy-3,4-dihydro-2H-isoquinolin-1-
ylidene)-3-oxo-7-phenyl-hepta-4,6-dienenitrile (14)
Enaminonitrile (12) (691 mg, 3 mmol), potassium carbonate
(1.66 g, 12 mmol), and carboxylic acid chloride (13) (693 mg,
3.6 mmol) were heated to reflux in acetonitrile (50 mL) for 4 h. Po-
tassium carbonate was filtered, and the solvent was removed in
vacuo. Purification by column chromatography (EtOAc/hexane 1:1)
gave the title compound 14 (777 mg, 67%) yellowsolid, mp 210 ꢀC; Rf
(EtOAc) 0.67. [Found: C, 74.69; H, 5.32; N, 7.01. C24H22N2O3 requires
C, 74.59; H, 5.74; N, 7.25%]; nmax (KBr) 3450, 2964, 2199, 1692, 1618,
2179,1603,1527,1290, 859 cmꢁ1
; dH, 8.03 (1H, s, H-11), 7.46 (2H, d, J
8.7 Hz, Ph(p-NMe2)), 6.65 (2H, d, J 8.7 Hz, Ph(p-NMe2)), 6.58 (1H,
dd, J 15.2, 10.3 Hz, CHCHCHCHPh(p-NMe2)), 6.55 (1H, d, J 15.2 Hz,
H-2), 6.50 (1H, s, H-8), 6.28 (1H, dd, J 14.9, 9.5 Hz, CHCHCHCHPh(p-
NMe2)), 6.11 (1H, d, J 9.5 Hz, CHCHCHCHPh(p-NMe2)), 5.79 (1H, dd,
J 14.9, 8.3 Hz, H-3), 5.15 (1H, dd, J 9.5, 5.4 Hz, CHCHCHCHPh(p-
NMe2)), 4.57 (1H, dd, J 8.3, 5.4 Hz, H-4), 3.99 (3H, s, OMe), 3.90 (3H,
s, OMe), 3.35e3.19 (2H, m, H-6), 2.96 (6H, s, Ph(p-NMe2)), 2.88e2.70
(2H, m, H-7); dC (75 MHz, CDCl3) 151.0, 150.8, 150.5, 147.6, 135.0,
1573, 1265 cmꢁ1
; dH 8.00 (1H, s, H-8), 7.53e7.43 (3H, m, Ph),
7.38e7.33 (2H, m, Ph), 7.29 (1H, dd, J 14.6, 6.7 Hz, CHCHCHCHPh),
7.12 (1H, d, J 14.7 Hz, CHCHCHCHPh), 6.99 (1H, d, J 14.6 Hz,

3386
Z. Vincze, P. Nemes / Tetrahedron 67 (2011) 3380e3387
CHCHCHCHPh), 6.97e6.88 (1H, m, CHCHCHCHPh), 6.72 (1H, s, H-5),
3.98 (3H, s, OMe), 3.93 (3H, s, OMe), 3.49 (2H, td, J 6.7, 3.8 Hz, H-3),
2.85 (2H, t, J 6.7 Hz, H-4), 1.66 (1H, br s, NH); dC (75 MHz, CDCl3)
188.0,164.2,152.8,147.8,141.7,140.4,136.6,132.2,129.0,129.0,128.0,
127.5, 127.3, 123.1, 118.9, 112.2, 110.7, 79.1, 56.6, 56.3, 39.1, 28.2.
(18c). Recrystallization (EtOAc) gave 18c (714 mg, 83%) pale yellow
solid, mp 97 ꢀC; Rf (EtOAc) 0.55. [Found: C, 73.88; H, 6.60; N, 7.99.
C33H35N3O4 requires C, 73.72; H, 6.56; N, 7.82%]; nmax (KBr) 2936,
2168, 1590, 1552, 1514, 1028 cmꢁ1
; dH (300 MHz CDC13) 8.06 (1H, s,
H-11), 7.44e7.23 (5H, m, Ph), 6.80e6.75 (3H, m, Ph(OMe)2), 6.66
(1H, s, H-8), 6.57 (1H, d, J 16.2 Hz, CHCHPh), 6.30 (1H, dd, J 4.8,
16.2 Hz, CHCHPh) 4.49 (1H, d, J 12.8 Hz, Ha-4), 4.18 (1H, d, J 4.8 Hz,
H-2), 3.98 (3H, s, OMe), 3.91 (s, 3H, OMe), 3.87 (3H, s, OMe), 3.96
(3H, s, OMe), 3.77 (1H, d, J 12.8 Hz, Hb-4), 3.26e3.14 (2H, m, H-6),
2.90e2.76 (6H, m, H-7, CH2CH2Ph(OMe)2); dC (75 MHz, CDCl3)
150.6,149.9,149.2,147.8,147.7,137.0,133.4,132.7,130.5,129.5, 128.7,
127.9, 126.9, 124.6, 121.1, 120.8, 112.4, 111.6, 111.1, 110.6, 82.3, 67.4,
65.7, 61.7, 56.6, 56.2, 56.1, 55.0, 46.7, 34.9, 29.5.
4.5. 3-Benzyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-
pyrimido[6,1-a]isoquinoline-1-carbonitrile (16d)
A solution of formaldehyde (37% w/w aqueous solution, 0.2 mL,
3.2 mmol), benzyl amine (0.15 mL, 171 mg, 1.6 mmol), and enami-
nonitrile (12) (368 mg, 1.6 mmol) in MeOH (5 mL) was stirred at
room temperature for 12 h. The reaction mixture was concentrated
under reduced pressure and the oily residue was dissolved in
CH2Cl2 (20 mL). The solution was washed with H2O (3ꢂ10 mL),
dried over Na2SO4, and then evaporated to give the crude product.
Recrystallization (EtOAc) gave 16d (422 mg, 73%) white solid, mp
172 ꢀC; Rf (EtOAc/hexane 1:1) 0.64. [Found: C, 73.25; H, 6.35; N,
11.60. C22H23N3O2 requires C, 73.11; H, 6.41; N, 11,63%]; nmax (KBr)
4.6.4. 3-Benzyl-9,10-dimethoxy-2-[2-(4-nitro-phenyl)-vinyl]-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
(18d). Recrystallization (EtOAc) gave 18d (528 mg, 65%) white
solid, mp 114 ꢀC; Rf (EtOAc/hexane 1:1) 0.47. [Found: C, 70.67; H,
5.53; N, 10.89. C30H28N4O4 requires C, 70.85; H, 5.55; N, 11.02%];
2935, 2175, 1600, 1539, 1525, 1265 cmꢁ1
;
dH (300 MHz CDC13) 7.99
nmax (KBr) 2938, 2169, 1593, 1551, 1483, 1342, 1290 cmꢁ1
; dH
(1H, s, H-11), 7.35e7.29 (5H, m, CH2Ph), 6.65 (1H, s, H-8), 4.10 (2H, s,
H-4), 3.95 (3H, s, OMe), 3.90 (s, 3H, OMe), 3.77 (2H, s, NCH2Ph), 3.69
(2H, s, H-2), 3.16 (2H, t, J 5.8 Hz, H-6), 2.82 (2H, t, J 5.8 Hz, H-7); dC
(75 MHz, CDCl3) 150.5, 150.1, 147.7, 138.0, 129.4, 129.3, 128.8, 127.8,
124.3, 121.0, 110.9, 110.6, 69.0, 65.8, 56.9, 56.5, 56.2, 52.4, 46.5, 29.6.
(300 MHz CDC13) 8.15 (2H, d, J 8.7 Hz, PhNO2), 8.09 (1H, s, H-11),
7.55 (2H, d, J 8.7 Hz, PhNO2), 7.58e7.34 (5H, m, Ph), 6.70 (1H, s, H-8),
6.66 (1H, d, J 15.5 Hz, CHCHPhNO2), 6.49 (1H, dd, J 4.4, 15.5 Hz,
CHCHPh) 4.45 (1H, d, J 12.5 Hz, Ha-4), 4.15 (1H, d, J 4.4 Hz, H-2), 3.99
(3H, s, OMe), 3.93 (s, 3H, OMe), 3.85 (1H, d, J 13.0 Hz, CH2Ph), 3.78
(1H, d, J 13.0 Hz, CH2Ph), 3.73 (1H, d, J 12.5 Hz, Hb-4), 3.22e3.20
(2H, m, H-6), 2.90e2.83 (2H, m, H-7); dC (75 MHz, CDCl3) 150.8,
150.2, 147.8, 147.2, 143.5, 137.8, 135.7, 131.0, 129.7, 129.2, 128.9, 127.9,
127.4, 124.4, 124.1, 120.8, 111.1, 110.7, 66.5, 64.5, 61.3, 57.2, 56.6, 56.3,
46.7, 29.5.
4.6. General procedure for cyclocondensation of
1-azapolyenes (17aee) with formaldehyde/amine
A solution of formaldehyde (37% w/w aqueous solution, 0.1 mL,
1.6 mmol), amine (1.6 mmol), and 1-azapolyene (17aee) (1.6 mmol)
in MeOH (5 mL) was stirred at room temperature for 16e18 h. The
reaction mixture was concentrated under reduced pressure and the
oily residue was dissolved in CH2Cl2 (20 mL). The solution was
washed with H2O (3ꢂ10 mL), dried over Na2SO4, and then evapo-
rated to give the crude product.
4.6.5. 3-Benzyl-9,10-dimethoxy-2-(4-phenyl-buta-1,3-dienyl)-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
(18e). Purification by column chromatography (EtOAc/hexane 1:1)
gave the title compound 18e (470 mg, 60%) yellow oil, Rf (EtOAc)
0.63. [Found: C, 78.43; H, 6.30; N, 8.59. C32H31N3O2 requires C,
78.50; H, 6.38; N, 8.58%]; nmax (KBr) 2935, 2174, 1598, 1522, 1466,
4.6.1. 9,10-Dimethoxy-3-methyl-2-styryl-3,4,6,7-tetrahydro-2H-pyr-
1344, 1277 cmꢁ1
; dH (300 MHz CDC13) 8.10 (1H, s, H-11), 7.39e7.18
imido[6,1-a]isoquinoline-1-carbonitrile
(18a). Recrystallization
(10H, m, Ph), 6.84 (1H, dd, J 10.6, 15.6 Hz, CHCHCHCHPh), 6.68 (1H,
s, H-8), 6.58 (1H, d, J 15.6 Hz, CHCHCHCHPh), 6.44 (1H, dd, J 10.6,
15.3 Hz, CHCHCHCHPh), 5.94 (1H, dd, J 4.6, 15.3 Hz, CHCHCHCHPh),
4.42 (1H, d, J 12.3 Hz, Ha-4), 4.07 (1H, d, J 4.6 Hz, H-2), 4.00 (3H, s,
OMe), 3.92 (s, 3H, OMe), 3.85 (1H, d, J 12.3 Hz, Hb-4), 3.79 (1H, d, J
13.3 Hz, CH2Ph), 3.73 (1H, d, J 13.3 Hz, CH2Ph), 3.22e3.13 (2H, m, H-
6), 2.92e2.77 (2H, m, H-7); dC (75 MHz, CDCl3) 150.6, 149.8, 147.7,
138.1, 137.5, 135.0, 133.7, 133.2, 129.6, 129.2, 129.1, 128.8, 128.7,
128.5, 128.4, 127.8, 127.7, 126.6, 124.6, 121.1, 111.2, 110.6, 68.5, 67.2,
64.3, 61.3, 57.1, 26.6, 26.2, 46.6, 29.6.
(EtOAc) gave 18a (490 mg, 79%) white solid, mp 140 ꢀC; Rf (EtOAc)
0.48. [Found: C, 74.25; H, 6.59; N,10.58. C24H25N3O2 requires C, 74.39;
H, 6.50;N,10.84%];nmax (KBr)2943,2162,1588,1551,1525,1289 cmꢁ1
;
dH (300 MHz CDC13) 8.03 (1H, s, H-11), 7.41e7.16 (5H, m, Ph), 6.65 (1H,
s, H-8), 6.57 (1H, d, J 16.0 Hz, CHCHPh), 6.26 (1H, dd, J 5.1, 16.0 Hz,
CHCHPh) 4.43 (1H, d, J 12.1 Hz, Ha-4), 3.97 (3H, s, OMe), 3.88 (s, 3H,
OMe), 3.80 (1H, d, J 5.1 Hz, H-2) 3.68 (1H, d, J 12.1 Hz, Hb-4), 3.27e3.22
(2H, m, H-6), 2.82e2.78 (2H, m, H-7), 2.50 (3H, s, NCH3); dC (75 MHz,
CDCl3) 150.6,149.5,147.6, 136.9,133.6,130.2, 129.7, 128.7,127.9, 126.9,
124.6, 121.0, 111.2, 110.6, 67.1, 63.5, 56.6, 56.2, 46.7, 41.3, 29.4.
Acknowledgements
4.6.2. 3-Benzyl-9,10-dimethoxy-2-styryl-3,4,6,7-tetrahydro-2H-pyr-
imido[6,1-a]isoquinoline-1-carbonitrile
(18b). Recrystallization
The authors are grateful to Mrs. Vali Sz. Marjay for her technical
help.
(EtOAc) gave 18b (482 mg, 65%) paleyellowsolid, mp133 ꢀC; Rf (EtOAc/
hexane 1:1) 0.50. [Found: C, 77.59; H, 6.44; N, 9.00. C30H29N3O2 re-
quires C, 77.73; H, 6.31; N, 9.06%]; nmax (KBr) 2937, 2172, 1591, 1553,
1290 cmꢁ1
; dH (300 MHz CDC13) 8.13 (1H, s, H-11), 7.46e7.23 (10H, m,
Supplementary data
Ph), 6.70 (1H, s, H-8), 6.62 (1H, d, J 15.0 Hz, CHCHPhNO2), 6.33 (1H, dd, J
4.6, 15.0 Hz, CHCHPh) 4.47 (1H, d, J 12.4 Hz, Ha-4), 4.15 (1H, d, J 4.6 Hz,
H-2), 4.02 (3H, s, OMe), 3.94 (s, 3H, OMe), 3.82 (1H, d, J 13.2 Hz, CH2Ph),
3.73 (1H, d, J 13.2 Hz, CH2Ph), 3.66 (1H, d, J 12.4 Hz, Hb-4), 3.23e3.18
(2H, m, H-6), 2.92e2.82 (2H, m, H-7); dC (75 MHz, CDCl3) 150.6, 149.9,
147.8, 138.2, 137.0, 133.3, 130.8, 129.6, 129.2, 128.8, 128.7, 127.8, 127.8,
126.9,124.6,121.1,111.2,110.7, 67.2, 64.3, 61.4, 57.1, 56.6, 56.3, 46.6, 29.6.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.03.058.
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