A novel strategy for the synthesis of 2,6-diaryl-1,2-dihydropyridines via 6π-electrocyclization

Article abstract of DOI:10.1016/j.tet.2013.05.013

Enaminonitriles with α,β-unsaturated aldehydes in a BF ₃·OEt₂ catalyzed reaction gave stable 1-azatrienes, which could be readily transformed to 1,2-dihydropyridines via 1,6-electrocyclizations.

Full text of DOI:10.1016/j.tet.2013.05.013

Tetrahedron 69 (2013) 6269e6274
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel strategy for the synthesis of 2,6-diaryl-1,2-dihydropyridines
via 6p
-electrocyclization
*
ꢀ
ꢀ
Zoltan Vincze, Peter Nemes
ꢀ
Department of Chemistry, Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest, PO Box 2, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Enaminonitriles with
a,b-unsaturated aldehydes in a BF3$OEt2 catalyzed reaction gave stable 1-
Received 12 February 2013
Received in revised form 23 April 2013
Accepted 9 May 2013
azatrienes, which could be readily transformed to 1,2-dihydropyridines via 1,6-electrocyclizations.
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 14 May 2013
Keywords:
b
-Enaminonitriles
1-Azatrienes
1,6-electrocyclizations
Pyridines
Boron trifluoride diethyl etherate
1. Introduction
We have reported previously a new strategy to 1-azatrienes and
1-azapolyenes. The mesylate salts of
b-enaminonitriles 1 were
Polysubstituted pyridines and dihydropyridines occupy a cen-
tral position in heterocyclic chemistry. Many naturally occurring
and synthetic products containing the pyridine scaffold are valu-
able pharmaceuticals or agrochemicals, and they are also useful
intermediates in preparing a large variety of interesting heterocy-
clic compounds.1 Although a huge number of various approaches
are known from the literature, new and efficient methods for the
construction of this type of molecule attract continuous interest in
contemporary organic chemistry.2,3
reacted with -unsaturated aldehydes 2 to afford the iminium salts
a,b
of the target compounds 3, which underwent electrocyclization after
adding TEAtothe MeCN solution to afford pyrido[2,1-a]isoquinolines
and indoloquinolizines 4. We investigated the mechanism of the
cyclization process by computational methods, and established
unequivocally that the presence of the electron-withdrawing group
plays a crucial role in the required (E)/(Z) isomerization step.7
Moreover we showed that azatrienes and azatetraenes resulted in
pyrimido[6,1-a]isoquinolines 5 with formaldehyde and primary
amines in aza-annulation reactions (Scheme 1).8
While 6p-azaelectrocyclizations are well established in the lit-
erature, few research groups apply them to the synthesis of pyri-
dines.4 It is envisaged that a new 1,6-electrocyclization approach to
multifunctional 1,2-dihydropyridines would carry significant syn-
These results prompted us to investigate the possible extension
of these earlier results to the synthesis of polysubstituted pyridines
and pyrimidines.
thetic interest. The traditional, but not widely used, thermal 6p-
electrocyclizations of 1-azatrienes likely involve a classical con-
certed mechanism, which proceeds in a disrotatory mode. Never-
theless, because of the low reactivity of the azatrienes and the
difficulties in the preparation of the 3-cis-azatriene precursors, the
applicability of these electrocyclizations to the synthesis of N-het-
erocycles is very limited.5 Recently, some research groups pub-
lished azaelectrocyclization approaches to 1,2-dihydropyridines
starting from 1-azatrienes.6 The reactivity of the azatrienes and the
applicability in natural product synthesis were also discussed.
2. Results and discussion
We report hereinthe BF3$OEt2 catalyzed formation of 1-azatrienes
10aej, starting from b-aminocrotonitriles 7aed, and their electro-
cyclizations to give 2,6-diaryl-3-cyano-1,2-dihydropyridines.
2.1. Synthesis and cyclization of 1-azatrienes
Compounds 7aed were prepared according to literature
methods from phenylpropargyl nitrile (6) and primary amines in
refluxing ethanol with good yields (Scheme 2).9
* Corresponding author. Tel.: þ36 1 478 4176; fax: þ36 1 478 4268; e-mail ad-
dress: Nemes.Peter@aotk.szie.hu (P. Nemes).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.013

6270
Z. Vincze, P. Nemes / Tetrahedron 69 (2013) 6269e6274
R1
N
Et3N, CH3CN
O
n-1
CH3SO3
NH
NC
CH3SO3
4
n
CH3COOH
NH
+
NC
CN
R2
NH ,
CH2O
n
2
1
2
3
R1
N
CH3OH, rt
R2
N
n = 1-3
NC
R1
n
Ph(p-R1)
5
Scheme 1.
R1
NH
O
R1
NH
BF4
CN
8a-c
R1
EtOH, reflux
CN
R1
NH
NH2
CN
BF3.OEt2
AcOH
R2
CN
6
7a-d 79-91 %
9a-j
R2
7a-d
75-92 %
7a R1 = 2-(2-bromo-4,5-dimethoxy-phenyl)-ethyl
7b R1 = cyclohexyl
8a R2 = H
8b R2 = NO2
8c R2 = NMe2
7c R1 = tert-Bu
7d R1 = adamantyl
Scheme 2.
Scheme 3.
In order to prepare 1-azatrienes, first we tried to transform
7aed into the corresponding mesylate salts, according to our ear-
lier method. These attempts, however, were unsuccessful because
of the formation of a complex mixture of decomposition products.
No conversion of the starting materials could be observed when we
attempted to carry out the reaction of the enaminonitriles 7aed
with unsaturated aldehydes in acetic acid without salt formation.
It is well known that BF3 can activate carbonyl compounds in
spectra prove the tetrafluoroborate salt formation unequivocally. It
can be assumed that BF3 and water, rising from the condensation
step, result in HF, which forms tetrafluoroboric acid with the excess
of BF3. The synthesis worked smoothly with enaminonitriles
bearing bulky alkyl and cycloalkyl R1 groups. Unfortunately, be-
cause of the fast polymerization of the azatrienes, the method was
non utilizable for simple methyl- or ethyl-substituted enaminoni-
triles. In our earlier study we proved the (E,E) configurations of the
double bonds for similar azatrienes by NMR (J-HMBC, J-INEPT)
methods.10 Although no such examinations were carried out to date
the favored (E,E) configurations can be assumed for 9aej as well.
After deprotonation of the azatrienes with TEA the free bases
(10aej) cyclized readily to give 11aej 1,2-dihydropyridine de-
rivatives in acceptable yields (Scheme 4). The first step of the
process is the rate determining (E)/(Z) isomerization, which is
facilitated by the electron-withdrawing CN group. The cyclizations
could be followed by 1H NMR spectroscopy. The appearance of the
H-6 methine proton of the formed dihydropyridine ring
(5.01e5.33 ppm) indicates the progress of the ring closure.
carbonecarbon bond forming reactions. We found that b-enami-
nonitriles 7aed with unsaturated aldehydes 8aec in glacial acetic
acid afforded the stable tetrafluoroborate salts of 1-azatrienes 9aej
in the presence BF3$OEt2 at room temperature (Table 1, Scheme 3).
The salts precipitated from the reaction mixtures by adding diiso-
propyl ether. Although the structure elucidation of the new aza-
trienes was carried out in base form (10aej) the 1H NMR spectra of
some salts were also registered. The presence of an NeH proton at
8.5 ppm and the strong absorption band at 1070 cmꢀ1 in the IR
Table 1
Yields for the 1-azatrienes
Entry R1
R2
Reaction Yield %
time (h)
R1
N
R2
9a
9b
9c
9d
9e
9f
2-(2-Bromo-4,5-dimethoxy-phenyl)-ethyl NO2
4
4
4
3
4
4
4
3
3
4
78
85
89
82
85
82
75
92
77
82
R1
N
CN
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Bu
H
heat or rt
NO2
NMe2
H
NO2
NMe2
H
NC
tert-Bu
70-92 %
9g
9h
9i
tert-Bu
R2
Adamantyl
Adamantyl
Adamantyl
10a-j
11a-j
NO2
NMe2
9j
Scheme 4.

Z. Vincze, P. Nemes / Tetrahedron 69 (2013) 6269e6274
6271
Significant reactivity differences could be observed in the cy-
4. Experimental section
4.1. General
clization processes depending on the substituent at the nitrogen
atom. Compound 10a bearing a phenethyl group cyclized at room
temperature in 2 h, while the electrocyclization of the N-cyclohexyl
derivatives 10bed required longer reaction times. The decrease of
the reactivity was more striking for 10eeg and 10hej with the
bulky tert-butyl and adamantyl substituents, respectively, which
gave the dihydropyridine derivatives only at elevated temperatures
up to 80 ꢁC. Moreover, a considerable effect of the C(6)-phenyl
substituents on the reaction rate could also be detected. It was
found that the electron donating dimethylamino group accelerated
the cyclization, while the electron-withdrawing nitro group in-
creased the reaction time (Table 2).
The structure and the purity of the final products as free bases
were confirmed by 1H, 13C NMR, IR, and microanalysis. NMR spectra
were recorded on a Varian Unity 300 (300 MHz) spectrometer, in
CDCl3 solutions. Chemical shifts (d) are expressed in parts per
million (ppm) relative to the internal standard TMS. IR spectra were
recorded on a Perkin Elmer 1600 FT IR spectrometer. The micro-
analysis was carried out on a Heraeus Micro Rapid CHN. 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). Analytical TLC was carried out on
precoated plates (Merck silica gel 60, F254). Solvents were dried and
freshly distilled according to the common practice.
Table 2
Yields for the cyclization products
Entry R1
R2
Temperature Reaction Yield %
4.2. General Procedure for the synthesis of 1-azatrienes
(10aej)
(ꢁC)
time (h)
11a
2-(2-Bromo-4,
NO2
25
1
82
5-dimethoxy-phenyl)-ethyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Bu
tert-Bu
tert-Bu
Adamantyl
Adamantyl
Adamantyl
The
a
,
b
-unsaturated aldehydes (8aec) (3.0 mmol) and BF3$OEt2
-enam-
11b
11c
11d
11e
11f
11g
11h
11i
H
NO2
NMe2 25
H
NO2
NMe2 60
H
NO2
25
25
36
48
12
5
7
4
14
24
8
88
92
90
84
79
84
78
70
71
(6 mmol, 852 mg, 0.740 mL) were added to a solution of
b
inonitriles (7aed) (2.0 mmol) in glacial acetic acid (6 mL). The
mixture was stirred at room temperature for 3e4 h until the re-
action was complete. The solution was then poured into diisopropyl
ether (30 mL), the precipitated tetrafluoroborate salt was filtered,
and washed with diethyl ether. The solid was dissolved in CH2Cl2
(10 mL) and the solution was washed with saturated NaHCO3
(2ꢂ10 mL) with water (1ꢂ10 mL), dried over Na2SO4 and then
evaporated. After evaporation the crude base was obtained.
60
60
80
80
11j
NMe2 80
2.2. Aza-annulations of b-aminocrotonitrile derivatives
4.2.1. 2-{[2-(2-Bromo-4,5-dimethoxy-phenyl)-ethylimino]-phenyl-
methyl}-5-(4-nitro-phenyl)-penta-2,4-dienenitrile (10a). Recrystalli
zation of the crude product (EtOAc) gave 10a (989 mg, 78%) as
a yellow solid, mp 79 ꢁC; Rf (hexane/EtOAc 5:1) 0.51. Found: C,
61.77; H, 4.53; N, 7.65. C28H24BrN3O4 requires C, 61.55; H, 4.43; N,
According to earlier publications, various pushepull alkenes
such as enaminones, nitroenamines or enaminonitriles with 2 mol
of formaldehyde and primary amines give condensed pyrimidine
derivatives in ‘double’ Mannich reactions.8,11
7.69%; nmax (KBr) 3429, 2938, 1561, 1298, 1005 cmꢀ1
; dH (300 MHz
Although a wide scope of reaction conditions were tested, in
contrast to the 1-cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahyd
roisoquinoline, the reactivity of b-aminocrotonitriles proved to be
poor. Compound 7c and dimethoxy-phenethylamine (12) gave 13
tetrahydropyrimidine derivative in very low yield, but the synthesis
could not be applied to other amines (Scheme 5).
CDC13) 8.19 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.59 (2H, d, J 8.7 Hz, Ph(p-
NO2)), 7.41e7.24 (5H, m, Ph), 6.91 (1H, s, H-30), 6.85 (1H, d, J 15.3 Hz,
H-3), 6.80 (1H, s, H-60), 6.76 (1H, dd, J 11.4, 15.3 Hz, H-4), 6.55 (1H, d,
J 11.4 Hz, H-5), 3.86 (3H, s, OMe), 3.82 (3H, s, OMe), 3.58 (2H, t, J
6.6 Hz, NeCH2eCH2-Ph(OMe)2), 3.04 (2H, t,
J
6.6 Hz,
NeCH2eCH2ePh(OMe)2); dC (75 MHz, CDCl3) 165.4, 148.3, 148.0,
141.5,140.7,133.4,131.3,129.5,129.1,128.6,128.4,128.3, 127.7,124.4,
120.6, 115.6, 115.4, 114.7, 114.4, 56.4, 56.3, 54.0, 37.0.
OMe
OMe
4.2.2. 2-(Cyclohexylimino-phenyl-methyl)-5-phenyl-penta-2,4-
dienenitrile (10b). Recrystallization of the crude product (EtOAc-
hexane) gave 10b (727 mg, 85%) as a yellow solid, mp 108 ꢁC; Rf
(hexane/EtOAc 5:1) 0.56. Found: C, 84.55; H, 7.00; N, 8.37. C24H24N2
requires C, 84.67; H, 7.11; N, 8.23%; nmax (KBr) 3432, 2937, 1561,
H2N
NH
12
CN
OMe
N
OMe
CH2O, C2H5OH
N
NC
1294, 1014 cmꢀ1
; dH (300 MHz CDC13) 7.48e7.38 (5H, m, Ph),
7c
13
7.35e7.32 (3H, m, Ph), 7.24 (1H, dd, J 11.9, 16.0 Hz, H-4), 7.12e7.11
(2H, m, Ph), 6.83 (1H, d, J 16.0 Hz, H-3), 6.60 (1H, d, J 11.9, H-5),
3.14e3.08 (1H, m, C6H11), 1.72e0.98 (10H, m, C6H11); dC (75 MHz,
CDCl3) 162.2, 148.7, 143.6, 135.7, 134.7, 130.1, 129.2, 129.1, 129.0,
127.9, 127.7, 124.8, 118.5, 116.1, 61.9, 33.9, 25.8, 24.3.
25 %
Scheme 5.
3. Conclusions
4.2.3. 2-(Cyclohexylimino-phenyl-methyl)-5-(4-nitro-phenyl)-penta-
2,4-dienenitrile (10c). Recrystallization of the crude product
(EtOAc) gave 10c (686 mg, 89%) as an orange solid, mp 170 ꢁC; Rf
(hexane/EtOAc 5:1) 0.45. Found: C, 74.69; H, 5.90; N, 11.02.
C24H23N3O2 requires C, 74.78; H, 6.01; N, 10.90%; nmax (KBr) 3441,
It was demonstrated that simple aryl substituted
b-aminocroto
nitriles with -unsaturated aldehydes afforded 1-azatrienes
a,b
at room temperature in BF3$OEt2 catalyzed reactions. The prod-
ucts could be transformed into N-alkyl-2,6-diaryl-3-cyano-1,2-
2937,1593, 1519, 1342, 1014 cmꢀ1
; dH (300 MHz CDC13) 8.18 (2H, d, J
dihydropyridine derivatives in a 6
The new strategy can serve as an attractive synthetic route to 1,2-
dihydropyridines.
p
-electrocyclization sequence.
8.4 Hz, Ph(p-NO2)), 7.60 (2H, d, J 8.4 Hz, Ph(p-NO2)), 7.52e7.48 (3H,
m, Ph), 7.35 (1H, dd, J 11.2, 15.4 Hz, H-4), 7.15e7.11 (2H, m, Ph), 6.85
(1H, d, J 15.3 Hz, H-3), 6.75 (1H, d, J 11.2, H-5), 3.13e3.07 (1H, m,

6272
Z. Vincze, P. Nemes / Tetrahedron 69 (2013) 6269e6274
C6H11), 1.68e0.94 (10H, m, C6H11); dC (75 MHz, CDCl3) 161.9, 148.2,
147.2, 141.7, 140.1, 134.2, 129.4, 129.2, 128.6, 128.3, 127.7, 124.4, 121.3,
115.6, 62,1, 33.8, 25.7, 24.3.
product (EtOAc) gave 10i (674 mg, 77%) as an orange solid, mp
173 ꢁC; Rf (hexane/EtOAc 5:1) 0.28. Found: C, 76.99; H, 6.40; N, 9.73.
C28H27N3O2 requires C, 76.86; H, 6.22; N, 9.60%; nmax (KBr) 3428,
2923, 1656, 1512 cmꢀ1
; dH (300 MHz CDC13) 8.18 (2H, d, J 8.7 Hz,
4.2.4. 2-(Cyclohexylimino-phenyl-methyl)-5-(4-dimethylamino-phe-
nyl)-penta-2,4-dienenitrile (10d). Recrystallization of the crude
product (EtOAc) gave 10d (628 mg, 82%) as a red solid, mp 124 ꢁC; Rf
(hexane/EtOAc 5:1) 0.41. Found: C, 81.35; H, 7.60; N,11.05. C26H29N3
requires C, 81.42; H, 7.62; N, 10.96%; nmax (KBr) 3439, 2926, 1591,
Ph(p-NO2)), 7.58 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.47e7.38 (5H, m, Ph),
7.14 (1H, dd, J 11.2, 15.4 Hz, H-4), 6.77 (1H, d, J 15.4 Hz, H-3), 6.54
(1H, d, J 11.2 Hz, H-5), 1.94 (3H, br s, C10H15), 1.66e1.60 (6H, m,
C10H15), 1.57e1.47 (6H, m, C10H15); dC (75 MHz, CDCl3) 159.4, 148.2,
146.1,146.0,141.8,139.7,137.2,129.1,128.8,128.5,128.4,128.3,124.4,
115.8, 59.6, 44.1, 36.5, 29.8.
1565, 1165 cmꢀ1
; dH (300 MHz CDC13) 7.56e7.45 (3H, m, Ph), 7.36
(2H, d, J 8.6 Hz, Ph(p-NMe2)), 7.29 (1H, dd, J 11.1, 15.3 Hz, H-4),
7.13e7.05 (2H, m, Ph), 6.74 (1H, d, J 15.3 Hz, H-3), 6.71 (1H, d, J 11.1,
H-5), 6.63 (2H, d, J 8.7 Hz, Ph(p-NMe2)), 3.03 (6H, s, Ph(p-NMe2)),
2.95e2.93 (1H, m, C6H11), 1.65e0.93 (10H, m, C6H11); dC (75 MHz,
CDCl3) 162.6, 151.7, 150.2, 144.7, 135.2, 129.8, 128.9, 127.8, 123.7,
120.2, 117.0, 114.5, 112.1, 61.7, 40.3, 33.9, 25.8, 24.5.
4. 2.10. 2-[(Adamantan-1-ylimino)-phenyl-methyl]-5-
(4-dimethylamino-phenyl)-penta-2,4-dienenitrile (10j). Recrystalliz
ation of the crude product (EtOAc) gave 10j (714 mg, 82%) as a red
solid, mp 158 ꢁC; Rf (hexane/EtOAc 5:1) 0.23. Found: C, 82.66; H,
7.68; N, 9.77. C30H33N3 requires C, 82.72; H, 7.64; N, 9.65%; nmax
(KBr) 3442, 2902, 1592, 1561 cmꢀ1
; dH (300 MHz CDC13) 7.42e7.35
4.2.5. 2-(tert-Butylimino-phenyl-methyl)-5-phenyl-penta-2,4-
dienenitrile (10e). Recrystallization of the crude product (EtOAc/
hexane) gave 10e (534 mg, 85%) as a yellow solid, mp 125 ꢁC; Rf
(hexane/EtOAc 5:1) 0.45. Found: C, 84.00; H, 6.95; N, 9.02. C22H22N2
requires C, 84.04; H, 7.05; N, 8.91%; nmax (KBr) 3442, 2969, 1605,
(3H, m, Ph), 7.32 (2H, d, J 8.9 Hz, Ph(p-NMe2)), 7.15e7.14 (2H, m, Ph),
7.08 (1H, dd, J 11.4, 15.6 Hz, H-4), 6.68 (1H, d, J 15.6 Hz, H-3), 6.62
(2H, d, J 8.9 Hz, Ph(p-NMe2)), 6.52 (1H, d, J 11.4 Hz, H-5), 3.01 (6H, s,
Ph(p-NMe2)), 1.94 (3H, br s, C10H15), 1.78e1.65 (6H, m, C10H15),
1.58e1.48 (6H, m, C10H15); dC (75 MHz, CDCl3) 160.2, 151.7, 149.0,
144.2, 138.1, 129.7, 128.7, 128.5, 128.2, 123.9, 120.4, 117.6, 117.1, 112.2,
58.9, 44.3, 40.3, 36.6, 29.9.
1576 cmꢀ1
; dH (300 MHz CDC13) 7.50e7.40 (5H, m, Ph), 7.37e7.32
(3H, m, Ph), 7.26 (1H, dd, J 11.3, 15.5 Hz, H-4), 7.17e7.13 (2H, m, Ph),
6.75 (1H, d, J 15.5 Hz, H-3), 6.54 (1H, d, J 11.3, H-5), 1.12 (9H, s,
tBueN); dC (75 MHz, CDCl3) 160.4, 147.8, 143.3, 137.1, 135.7, 130.0,
129.1, 129.0, 128.5, 128.4, 127.9, 121.0, 116.2, 58.1, 31.5.
4.3. General procedure for the cyclization (11aej)
The free base of the 1-azatriene (10aej) was dissolved (1 mmol)
in acetonitrile (10 mL), and stirred at the appropriate temperature
(Table 2) until the starting material consumed. 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.
4.2.6. 2-(tert-Butylimino-phenyl-methyl)-5-(4-nitro-phenyl)-penta-
2,4-dienenitrile (10f). Recrystallization of the crude product
(EtOAc) gave 10f (510 mg, 71%) as an orange solid, mp 128 ꢁC; Rf
(hexane/EtOAc 5:1) 0.39. Found: C, 73.33; H, 5.99; N, 11.42.
C22H21N3O2 requires C, 73.52; H, 5.89; N, 11.69%; nmax (KBr) 3424,
2930, 1595, 1513, 1346 cmꢀ1
; dH (300 MHz CDC13) 8.19 (2H, d, J
8.3 Hz, Ph(p-NO2)), 7.60 (2H, d, J 8.3 Hz, Ph(p-NO2)), 7.59e7.47 (3H,
m, Ph), 7.35 (1H, dd, J 11.4, 15.5 Hz, H-4), 7.16e7.11 (2H, m, Ph), 6.80
(1H, d, J 15.4 Hz, H-3), 6.56 (1H, d, J 11.4, H-5), 1.19 (9H, s, tBueN); dC
(75 MHz, CDCl3) 160.1, 148.2, 146.2, 141.8, 139.8, 136.7, 129.2, 128.8,
128.6, 128.5, 128.3, 124.4, 123.8, 115.7, 58.4, 31.4.
4.3.1. 1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-ethyl]-6-(4-nitro-phe-
n y l ) - 2 - p h e n y l - 1, 6 - d i h y d r o p y r i d i n e - 3 - c a r b o n i t r i l e
(11a). Recrystallization of the crude product (EtOAc) gave 11a
(520 mg, 82%) as a pale yellow solid, mp 123 ꢁC; Rf (hexane/EtOAc 5:1)
0.67. Found: C, 61.43; H, 4.42; N, 7.89. C28H24BrN3O4 requires C, 61.55;
4.2.7. 2-(tert-Butylimino-phenyl-methyl)-5-(4-dimethylamino-phe-
nyl)-penta-2,4-dienenitrile (10g). Recrystallization of the crude
product (EtOAc) gave 10g (536 mg, 75%) as a red solid, mp 97 ꢁC; Rf
(hexane/EtOAc 5:1) 0.54. Found: C, 80.60; H, 7.69; N,11.80. C24H27N3
requires C, 80.63; H, 7.61; N, 11.75%; nmax (KBr) 3424, 2928, 1600,
H, 4.43; N, 7.69%; nmax (KBr) 3450, 2203, 1629, 1513, 1340 cmꢀ1
; dH
(300 MHz CDC13) 8.27 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.63 (2H, d, J 8.7 Hz,
Ph(p-NO2)), 7.46e7.30 (3H, m, Ph), 7.14e7.09 (2H, m, Ph), 6.89 (1H, s,
H-30), 6.34 (1H, s, H-60), 6.15 (1H, d, J 8.1 Hz, H-4), 5.28 (1H, dd, J 5.9,
8.1 Hz, H-5), 5.23 (1H, d, J 5.9 Hz, H-6), 3.82 (s, 3H, OMe), 3.73 (3H, s,
OMe), 3.50e3.44 (1H, m, NeCH2aeCH2ePhðOMeÞ2), 3.08e3.03 (1H,
m, NeCHbeCH2ePhðOMeÞ2), 2.72e2.68 (2H, m, NeCH2eCH2e
Ph(OMe)2)2; dC (75 MHz, CDCl3) 157.7, 149.3, 148.9, 148.7, 148.2, 132.9,
130.5, 129.2, 128.6, 127.5, 124.7, 123.2, 120.9, 115.7, 114.5, 114.0, 113.6,
82.0, 62.0, 56.4, 56.2, 35.5.
1559, 1350 cmꢀ1
; dH (300 MHz CDC13) 7.45e7.39 (3H, m, Ph), 7.35
(2H, d, J 8.8 Hz, Ph(p-NMe2)), 7.15e7.11 (2H, m, Ph), 7.08 (1H, dd, J 11.4,
15.2 Hz, H-4), 6.65 (1H, d, J 15.2 Hz, H-3), 6.60 (2H, d, J 8.8 Hz, Ph(p-
NMe2)), 6.52 (1H, d, J 11.4 Hz, H-5), 3.00 (6H, s, Ph(p-NMe2)),1.11 (9H,
s, tBueN); dC (75 MHz, CDCl3) 160.8, 151.7, 149.2, 144.3, 137.6, 129.7,
128.7, 128.6, 128.3, 123.8, 120.3, 117.4, 117.0, 112.1, 57.7, 40.3, 31.6.
4.2.8. 2-[(Adamantan-1-ylimino)-phenyl-methyl]-5-phenyl-penta-
2,4-dienenitrile (10h). Recrystallization of the crude product
(EtOAc) gave 10h (721 mg, 92%) as a yellow solid, mp 155 ꢁC; Rf
(hexane/EtOAc 5:1) 0.52. Found: C, 85.65; H, 6.99; N, 7.33. C28H28N2
requires C, 85.67; H, 7.19; N, 7.14%; nmax (KBr) 3440, 2900, 1685,
4.3.2. 1-Cyclohexyl-2,6-diphenyl-1,6-dihydropyridine-3-carbonitrile
(11b). Recrystallization of the crude product (EtOAc/hexane) gave
11b (299 mg, 88%) as a pale yellow solid, mp 141 ꢁC; Rf (hexane/
EtOAc 5:1) 0.72. Found: C, 84.39; H, 6.99; N, 8.22. C24H24N2 requires
C, 84.67; H, 7.11; N, 8.23%; nmax (KBr) 3428, 2925, 2193, 1525,
1576 cmꢀ1
;
dH (300 MHz CDC13) 7.49e7.40 (5H, m, Ph), 7.36e7.30
1500 cmꢀ1
; dH (300 MHz CDC13) 7.55e7.15 (10H, m, Ph), 6.10 (1H, d,
(3H, m, Ph), 7.26 (1H, dd, J 11.4, 15.4 Hz, H-4), 7.15e7.13 (2H, m, Ph),
6.73 (1H, d, J 15.4 Hz, H-3), 6.53 (1H, d, J 11.4 Hz, H-5), 2.03 (3H, br s,
C10H15), 1.68e1.60 (6H, m, C10H15), 1.55e1.48 (6H, m, C10H15); dC
(75 MHz, CDCl3) 159.7, 147.7, 143.2, 137.6, 135.8, 130.0, 129.1, 128.9,
128.5, 128.3, 127.9, 121.3, 116.3, 59.3, 44.2, 36.5, 29.8.
J 9.0 Hz, H-4), 5.40 (1H, dd, J 6.4, 9.0 Hz, H-5), 5.33 (1H, d, J 6.4 Hz, H-
6), 3.56e3.28 (1H, m, C6H11),1.62e0.91 (10H, m, C6H11); dC (75 MHz,
CDCl3) 157.9, 145.0, 134.6, 130.5, 129.1, 129.0, 128.9, 127.9, 125.6,
122.3, 121.8, 115.4, 84.4, 61.7, 55.9, 33.5, 32.4, 25.9, 25.3.
4. 3. 3. 1-Cyclohexyl-6-(4-nitro-phenyl)-2-phenyl-1,6-
dihydropyridine-3-carbonitrile (11c). Recrystallization of the crude
product (EtOAc) gave 11c (354 mg, 92%) as a yellow solid, mp
4.2.9. 2-[(Adamantan-1-ylimino)-phenyl-methyl]-5-(4-nitro-phe-
nyl)-penta-2,4-dienenitrile (10i). Recrystallization of the crude

Z. Vincze, P. Nemes / Tetrahedron 69 (2013) 6269e6274
6273
209 ꢁC; Rf (hexane/EtOAc 5:1) 0.76. Found: C, 74.85; H, 5.93; N,
10.99. C24H23N3O2 requires C, 74.78; H, 6.01; N, 10.90%; nmax (KBr)
m, C10H15); dC (75 MHz, CDCl3) 155.1,140.9,138.7,129.9,129.7,128.4,
128.1, 127.8, 127.8, 124.7, 120.9, 120.0, 96.2, 63.1, 53.0, 44.9, 36.1,
30.3.
3424, 2930, 2194, 1519, 1490, 1344 cmꢀ1
; dH (300 MHz CDC13) 8.22
(2H, d, J 8.8 Hz, Ph(p-NO2)), 7.61 (2H, d, J 8.8 Hz, Ph(p-NO2)),
7.56e7.39 (5H, m, Ph), 6.17 (1H, d, J 8.7 Hz, H-4), 5.41 (1H, dd, J 6.5,
8.7 Hz, H-5), 5.33 (1H, d, J 6.5 Hz, H-6), 3.38e3.30 (1H, m, C6H11),
1.68e0.94 (10H, m, C6H11); dC (75 MHz, CDCl3) 157.8, 151.3, 147.6,
133.9, 130.9, 129.3, 128.9, 126.5, 124.4, 123.8, 121.0, 113.8, 85.4, 61.8,
55.2, 33.3, 32.6, 25.8, 25.2.
4.3.9. 1-Adamantan-1-yl-6-(4-nitro-phenyl)-2-phenyl-1,6-
dihydropyridine-3-carbonitrile (11i). Recrystallization of the crude
product (EtOAc) gave 11i (306 mg, 70%) as a yellow solid, mp
208 ꢁC; Rf (hexane/EtOAc 5:1) 0.46. Found: C, 76.75; H, 6.41; N, 9.70.
C28H27N3O2 requires C, 76.86; H, 6.22; N, 9.60%; nmax (KBr) 3440,
2908, 1617, 1518 cmꢀ1
; dH (300 MHz CDC13) 8.16 (2H, d, J 8.5 Hz,
4.3.4. 1-Cyclohexyl-6-(4-dimethylamino-phenyl)-2-phenyl-1,6-
dihydropyridine-3-carbonitrile (11d). Recrystallization of the crude
product (EtOAc) gave 11d (345 mg, 90%) as an orange solid, mp
158 ꢁC; Rf (hexane/EtOAc 5:1) 0.54. Found: C, 81.45; H, 7.51; N,
11.04. C26H29N3 requires C, 81.42; H, 7.62; N, 10.96%; nmax (KBr)
Ph(p-NO2)), 7.64 (2H, d, J 8.5 Hz, Ph(p-NO2)), 7.42e7.32 (5H, m, Ph),
6.49 (1H, d, J 8.6 Hz, H-4), 5.74 (1H, dd, J 6.8, 8.6 Hz, H-5), 5.44 (1H,
d, J 6.3 Hz, H-6), 2.00 (3H, br s, C10H15), 1.73e1.65 (6H, m, C10H15),
1.50e1.48 (6H, m, C10H15); dC (75 MHz, CDCl3) 155.1, 148.8, 147.6,
137.9, 130.4, 129.5, 128.7, 128.3, 125.8, 123.6, 120.1, 118.8, 96.4, 63.6,
52.6, 44.9, 36.0, 30.3.
3428, 2930, 2192, 1611, 1519, 1435 cmꢀ1
; dH (300 MHz CDC13)
7.55e7.40 (5H, m, Ph), 7.30 (2H, d, J 8.7 Hz, Ph(p-NMe2)), 6.72 (2H, d,
J 8.7 Hz, Ph(p-NMe2)), 6.09 (1H, d, J 9.1 Hz, H-4), 5.35 (1H, dd, J 6.4,
9.1 Hz, H-5), 5.08 (1H, d, J 6.4 Hz, H-6), 3.28e3.11 (1H, m, C6H11),
2.96 (6H, s, Ph(p-NMe2)), 1.70e0.98 (10H, m, C6H11); dC (75 MHz,
CDCl3) 157.7, 150.4, 134.9, 133.1, 130.2, 129.0, 126.8, 122.1, 121.6,
120.2, 116.0, 112.8, 84.0, 61.7, 55.5, 40.7, 33.7, 32.4, 25.9, 25.4.
4.3.10. 1-Adamantan-1-yl-6-(4-dimethylamino-phenyl)-2-phenyl-
1,6-dihydropyridine-3-carbonitrile (11j). Recrystallization of the
crude product (EtOAc) gave 11j (309 mg, 71%) as an orange solid,
mp 200 ꢁC; Rf (hexane/EtOAc 5:1) 0.45. Found: C, 82.50; H, 7.58; N,
9.41. C30H33N3 requires C, 82.72; H, 7.64; N, 9.65%; nmax (KBr) 3447,
2902, 1611, 1521 cmꢀ1
; dH (300 MHz CDC13) 7.52e7.38 (5H, m, Ph),
4.3.5. 1-tert-Butyl-2,6-diphenyl-1,6-dihydropyridine-3-carbonitrile
(11e). Recrystallization of the crude product (EtOAc/hexane) gave
11e (264 mg, 84%) as a pale yellow solid, mp 128 ꢁC; Rf (hexane/
EtOAc 5:1) 0.59. Found: C, 83.87; H, 6.89; N, 9.24. C22H22N2 requires
C, 84.04; H, 7.05; N, 8.91%; nmax (KBr) 3429, 2963, 1511, 1488,
7.29 (2H, d, J 8.7 Hz, Ph(p-NMe2)), 6.70 (2H, d, J 8.7 Hz, Ph(p-NMe2)),
6.38 (1H, d, J 8.6 Hz, H-4), 5.67 (1H, dd, J 6.5, 8.6 Hz, H-5), 5.30 (1H,
d, J 6.5 Hz, H-6), 2.99 (6H, s, Ph(p-NMe2)), 1.99 (3H, br s, C10H15),
1.75e1.68 (6H, m, C10H15), 1.59e1.48 (6H, m, C10H15); dC (75 MHz,
CDCl3) 155.0, 150.3, 139.0, 129.5, 128.5, 128.2, 127.9, 123.8, 121.2,
120.5, 112.6, 112.1, 95.8, 62.8, 52.6, 44.3, 40.7, 36.1, 30.3.
1184 cmꢀ1
; dH (300 MHz CDC13) 7.62e7.30 (10H, m, Ph), 6.41 (1H, d,
J 8.4 Hz, H-4), 5.70 (1H, dd, J 6.6, 8.4 Hz, H-5), 5.33 (1H, d, J 6.6 Hz, H-
6), 1.12 (9H, s, tBueN); dC (75 MHz, CDCl3) 155.6, 141.1, 138.2, 129.7,
129.1, 128.4, 128.0, 127.7, 127.4, 124.4, 120.9, 119.5, 95.4, 61.9, 55.3,
32.4.
4.4. 3-tert-Butyl-1-(3,4-dimethoxy-benzyl)-5-phenyl-1,2,3,6-
tetrahydropyrimidine-4-carbonitrile (13)
A solution of formaldehyde (37% w/w aq solution, 0.2 mL,
3.2 mmol), 3,4-dimethoxy-benzylamine (12) (0.17 mL, 117 mg,
1.6 mmol), and enaminonitrile (7e) (320 mg, 1.6 mmol) in MeOH
(5 mL) was stirred at room temperature for 10 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. The
crude product was purified by column chromatography on silica gel
using EtOAc/hexane as eluent to give 13 (156 mg, 25%) as a white
solid, mp 139 ꢁC; Rf (hexane/EtOAc 5:1) 0.18. Found: C, 73.76; H,
7.40; N, 10.65. C24H29N3O2 requires C, 73.63; H, 7.47; N, 10.73%; nmax
4.3.6. 1-tert-Butyl-6-(4-nitro-phenyl)-2-phenyl-1,6-dihydropyridine-
3-carbonitrile (11f). Recrystallization of the crude product (EtOAc)
gave 11f (284 mg, 79%) as a yellow solid, mp 145 ꢁC; Rf (hexane/
EtOAc 5:1) 0.62. Found: C, 73.65; H, 6.00; N, 11.52. C22H21N3O2 re-
quires C, 73.52; H, 5.89; N, 11.69%; nmax (KBr) 3448, 2204, 1636,
1513, 1341 cmꢀ1
; dH (300 MHz CDC13) 8.20 (2H, d, J 8.7 Hz, Ph(p-
NO2)), 7.66 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.45e7.31 (5H, m, Ph), 6.50
(1H, d, J 8.6 Hz, H-4), 5.76 (1H, dd, J 6.5, 8.6 Hz, H-5), 5.41 (1H, d, J
t
6.5 Hz, H-6), 1.20 (9H, s, BueN); dC (75 MHz, CDCl3) 160.8, 151.7,
149.2,144.3,137.6,129.7,128.7,128.6, 128.3,123.8,120.3,117.2,117.0,
112.1, 57.7, 40.3, 31.6.
(KBr) 3438, 2965, 2192, 1513 cmꢀ1
; dH (300 MHz CDC13) 7.38e7.30
(5H, m, Ph), 6.92 (3H, m, Ph(OMe)2), 3.86 (6H, s, OMe), 3.75 (2H, s,
CH2ePh(OMe)2), 3.52 (2H, s, H-2), 3.30 (2H, s, H-6), 0.95 (9H, s,
tBueN); dC (75 MHz, CDCl3) 160.0, 149.2, 148.8, 138.6, 130.1, 129.7,
129.6, 128.2, 121.6, 120.9, 112.6, 111.1, 90.0, 66.6, 59.6, 59.1, 56.2,
54.0, 31.2.
4.3.7. 1-tert-Butyl-6-(4-dimethylamino-phenyl)-2-phenyl-1,6-
dihydropyridine-3-carbonitrile (11g). Recrystallization of the crude
product (EtOAc) gave 11g (300 mg, 84%) as an orange solid, mp
135 ꢁC; Rf (hexane/EtOAc 5:1) 0.49. Found: C, 80.69; H, 7.49; N,
11.76. C24H27N3 requires C, 80.63; H, 7.61; N, 11.75%; nmax (KBr)
3444, 2970, 1612, 1521 cmꢀ1
; dH (300 MHz CDC13) 7.49e7.35 (5H,
Acknowledgements
m, Ph), 7.25 (2H, d, J 8.6 Hz, Ph(p-NMe2)), 6.40 (2H, d, J 8.6 Hz, Ph(p-
NMe2)), 6.50 (1H, d, J 8.7 Hz, H-4), 5.66 (1H, dd, J 6.4, 8.7 Hz, H-5),
5.24 (1H, d, J 6.4 Hz, H-6), 2.94 (6H, s, Ph(p-NMe2)), 1.17 (9H, s,
tBueN); dC (75 MHz, CDCl3) 155.6, 149.5, 134.9, 130.8, 130.1, 129.0,
126.7, 123.2, 121.3, 120.0, 112.9, 112.2, 94.9, 61.6, 54.9, 40.7, 32.4.
The authors are grateful to Mrs. Vali Sz. Marjay for her technical
help.
References and notes
4.3.8. 1-Adamantan-1-yl-2,6-diphenyl-1,6-dihydropyridine-3-
carbonitrile (11h). Recrystallization of the crude product (EtOAc)
gave 11h (306 mg, 78%) as a pale yellow solid, mp 169 ꢁC; Rf
(hexane/EtOAc 5:1) 0.70. Found: C, 85.80; H, 7.09; N, 7.10. C28H28N2
requires C, 85.67; H, 7.19; N, 7.14%; nmax (KBr) 3432, 2908, 1617,
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