Effect of the nature of substituents on aromatic aldehydes in microwave induced N-cyclohexylamidine-aldehyde condensation reactions

Article abstract of DOI:10.1139/V06-014

A simple, environmentally friendly protocol for the selective synthesis of the 4-aryl substituted acyclic 1,3-dienes and the medicinally potent triazines has been developed using a domestic microwave oven with excellent yields and reproducibility.

Full text of DOI:10.1139/V06-014

453
Effect of the nature of substituents on
aromatic aldehydes in microwave induced
N-cyclohexylamidine–aldehyde condensation
reactions
Vipan Kumar, Manish Gupta, and M.P. Mahajan
Abstract: A simple, environmentally friendly protocol for the selective synthesis of the 4-aryl substituted acyclic 1,3-
dienes and the medicinally potent triazines has been developed using a domestic microwave oven with excellent yields
and reproducibility.
Key words: microwave, dihydrotriazine, triazine, imine metathesis.
Résumé : Utilisant un four microonde domestique, on a développé un protocole soucieux de l’environnement et repro-
ductible pour la synthèse sélective, avec d’excellents rendements, de 1,3-diènes acycliques substitués par un groupe
aryle en position 4 et de triazines efficaces d’un point de vue médicinal.
Mots clés : microonde, dihydrotriazine, triazine, métathèse d’imines.
[Traduit par la Rédaction] Kumar et al. 457
Introduction
electrocyclization of initially formed 1,3-diazabuta-1,3-
dienes as intermediates (5). Recent work from our laboratory
has shown a simple and convenient version of the aza-Wittig
reaction between N-imidoyliminophosphoranes and alde-
hydes using a domestic microwave oven (6). The strategy
was further simplified by employing the condensation reac-
tions of N-arylamidines with aldehydes (7). This simplified
version to quinazolines is of significance because of the lack
of reports on the condensation reactions of N-
arylbenzamidines with aldehydes. Even the reported reac-
tions of N-alkylamidines with aldehydes involve the use of
Lewis acid catalysts (8), have longer reaction periods, suffer
from the irreproducibility of the results, and have lower re-
action yields (9). It was felt that the problem of spontaneous
electrocyclization experienced with N-aryl-4-phenyl-1,3-
diazabuta-1,3-dienes could be circumvented by the conden-
sation reactions of N-alkylamidines with aldehydes.
Azadienes have proved to be of great synthetic potential
in heterocyclic synthesis, acting as 4π components in hetero
Diels Alder cycloaddition reactions with various dienophiles
(1). They have been explored in the synthesis of pyrimi-
dines, pyrimidinones, thioxopyrimidines, and other aza-
heterocyclic compounds. One of the crucial and common
steps in most synthetic approaches for such heterocycles in-
volves the formation of a new carbon–nitrogen double bond.
The reaction of iminophosphoranes with carbonyl com-
pounds is an excellent method for the construction of
carbon–nitrogen double bonds under mild and neutral condi-
tions (2). On the other hand, aza-Wittig type reactions with
heterocumulenes like carbon dioxide, carbon disulphide,
isocyanates, isothiocyanates, and ketenes, provide access to
functionalized heterocumulenes, which are highly reactive
intermediates able to undergo a plethora of heterocyclization
reactions (3). It has been observed that 1-aryl-2-phenyl-5-
alkyl/aryl-1,3-diazapenta-1,3,4-triene, generated in situ via
aza-Wittig reactions of N′-aryl-N-(triphenylphosphoranili-
dene)carboximidamides, selectively undergo [4+2] cyclo-
addition and electrocyclization reactions leading to the
formation of novel pyrimidinones and quinazolines with
monosubstituted ketenes and diphenyl ketenes, respectively
(4). A conceptually similar annulation involved the aza-
Wittig reaction of N-imidoyliminophosphoranes with alde-
hydes to give 3,4-dihydroquinazolines and quinazolines via
Results and discussion
Thus, in continuation of our pursuits towards the synthesis
and reactivity of azadienes (10), we report herein the results
of a few condensation reactions of N-cyclohexylbenzami-
dines with various aldehydes using microwave irradiation.
Interestingly, the reaction of N-cyclohexylbenzamidine with
aromatic aldehydes containing p-electron-donating (-OCH3)
substituent under microwave irradiation resulted in a good
yield of 1-(4-methoxy-benzyl)-2-(4-methoxy-phenyl)-4,6-
Received 1 May 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 7 April 2006.
V. Kumar, M. Gupta, and M.P. Mahajan.1 Department of Applied Chemistry, Guru Nanak Dev University, Amritsar-143005,
Punjab, India.
1Corresponding author (e-mail: mahajanmohinderp@yahoo.co.in).
Can. J. Chem. 84: 453–457 (2006)
doi:10.1139/V06-014
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
Scheme 1.
Ph
N
Ph
R
O
H
microwave
N
N
+
N
NH2
R
R
2
3
1
a: R = -OCH3
b: R = -N(CH3)2
O
H
N
+
1
N
H
R1
R1
4
a: R1 = -H
b: R1 = -Cl
c: R1 = -NO2
:
d R = -o-hydroxy
diphenyl-1,2-dihydro-[1,3,5]triazine (3), while other alde-
hydes led to the formation of N-cyclohexyl-1,3-diazabuta-
1,3-dienes (4) (Scheme 1).
Experimental
Melting points were determined by open capillary using a
Veego Precision digital melting point apparatus (MP-D) and
are uncorrected. IR spectra were recorded on a Shimadzu D-
The structure of the dihydrotriazine (3a) was confirmed
1
with the help of its spectral data. H NMR spectrum of the
1
8001 spectrophotometer. H NMR spectra were recorded in
compound showed the presence of a pair of doublets corre-
sponding to methylene protons with a coupling constant of
14.8 Hz at δ 4.12 and 4.90 and a sharp singlet for a methine
proton at δ 5.95. Its mass spectrum exhibited the molecular
ion peak at 461.5. The structure of the product was further
deuterochloroform with Bruker AC-E 200 (200 MHz) spec-
trometers using TMS as an internal standard. Chemical shift
values are expressed as ppm downfield from TMS and J val-
ues are in Hz. Splitting patterns are indicated as singlet (s),
doublet (d), triplet (t), multiplet (m), quartet (q), and broad
peak (br). 13C NMR spectra were also recorded with Bruker
AC-200E (50.4 MHz) spectrometers, in deuterochloroform,
and using TMS as an internal standard. Mass spectra were
recorded on a Shimadzu GCMS-QP-2000 mass spectrome-
ter. Elemental analyses were performed on a Heraus CHN-
O-Rapid elemental analyzer.
1
confirmed using H–1H correlation spectroscopic data.
In an attempt to generalize the previous observation, the
reaction was repeated with another readily available alde-
hyde having a strong electron-donating substituent at its p-
position (p-dimethylamino benzaldehyde), which also
resulted in a good yield of the desired dihydrotriazine (3b).
The probable mechanistic pathway leading to the formation
of dihydrotriazines (3a and 3b) is outlined in Scheme 2. In
this scheme it is assumed that the initially formed 1,3-
diazabuta-1,3-diene (5) and its tautomer (6) undergoes imine
metathesis (imine exchange between the cyclohexylidene-
amine group of 6 and the cyclohexylimine group of 5, form-
ing N-cyclohexylcyclohexylideneamine and the 1,3,5-triaza-
1,3,5-hexatriene derivative (7)). The 1,3,5-triaza-1,3,5-hexa-
triene thus formed underwent electrocyclization to yield
dihydrotriazines (3). These dihydrotriazines were easily con-
verted to the corresponding triazines (8) by their exposure to
microwave irradiation (oxidative debenzylation) (11) at a
power of 200 W for a period of 10 min (5 cycles of 2 min
each) (Scheme 2).
General procedure
The typical procedure involved the irradiation of N-
cyclohexylbenzamidine with 1.5 equiv. of aldehydes at a
power of 100 W for a period of 20 min (10 cycles of 2 min
each). The progress of the reaction was monitored using
TLC. The product was then isolated by trituration using hex-
ane and was recrystallized using an ethyl acetate – hexane
mixture (1:10).
1-(4-Methoxy-benzyl)-2-(4-methoxy-phenyl)-4,6-
diphenyl-1,2-dihydro-[1,3,5]triazine (3a)
Melting point: 166 to 167 °C. H NMR (200 MHz) ␦:
1
© 2006 NRC Canada

Kumar et al.
455
Scheme 2.
R
H
H
N
N
N
+
N
H
N
NH2
H
O
H
R
R
5
6
N
H
imine
metathesis
N
N
+
N
N
N
N
H
H
+
N
H
H
7
R
R
6
5
N
Ph
Ph
N
R
Ph
Ph
N
N
N
N
microwave
R
R
8
3
a: R = -OCH3
b: R = -N(CH3)2
3.80 (s, 3H, -OCH3), 3.84 (s, 3H, -OCH3), 4.08–4.15 (d, 1H,
J = 14.6 Hz, CH of CH2), 4.86–4.93 (d, 1H, J = 15.0 Hz,
CH of CH2), 5.95 (s, 1H, -CH), 6.84–6.88 (d, 2H, J =
8.4 Hz, ArH), 6.92–6.96 (d, 2H, J = 8.6 Hz, ArH), 7.13–7.17
(d, 2H, J = 8.4 Hz, ArH), 7.41–7.51 (m, 8H, ArH), 7.63–
7.67 (m, 2H, ArH), 8.27–8.32 (m, 2H, ArH). 13C NMR
(50.4 MHz) δ: 52.3 (CH2), 55.2 (-OCH3), 73.2 (-CH),
114.2, 114.3, 127.4, 127.8, 127.9, 128.0, 128.7, 128.8,
130.1, 130.6, 133.8, 134.9, 137.0, 156.5, 159.4, 159.9
(C=N), 163.6 (C=N). MS m/z: 461.5 (M+). Anal. calcd. for
C30H27N3O2 (%): C 78.07, H 5.90, N 9.10; found: C 77.36,
H 5.74, N 9.02.
2H, ArH), 8.24–8.29 (m, 2H, ArH). 13C NMR (50.4 MHz) δ:
40.1 (-N(CH3)2), 40.3 (-N(CH3)2), 52.6 (CH2), 73.2 (-CH),
114.1, 114.5, 127.5, 127.7, 127.9, 128.0, 128.5, 128.7,
130.5, 130.8, 133.8, 134.2, 137.2, 156.2, 159.3, 159.5
(C=N), 163.2 (C=N). MS m/z: 487 (M+). Anal. calcd. for
C32H33N5 (%): C 78.82, H 6.82, N 14.36; found: C 78.91, H
6.64, N 14.45.
N-Benzylidene-N′-cyclohexylbenzamidine (4a)
1
Melting point: 148 to 149 °C. H NMR (200 MHz) δ:
1.40–1.78 (m, 10H, cyclohexyl), 3.12 (m, 1H, cyclohexyl),
7.19–7.34 (m, 3H, ArH), 7.38–7.49 (m, 6H, ArH + olefinic),
7.77–7.80 (m, 2H, ArH). 13C NMR (50.4 MHz) δ: 24.5,
27.2, 33.2, 54.5, 123.3, 127.1, 127.4, 129.1, 129.6, 129.8,
131.8, 137.4, 166.3 (C=N-), 174.1 (C=N). MS m/z: 290 (M+).
1-(4-N,N-Dimethylamino-benzyl)-2-(4-dimethylamino-
phenyl)-4,6-diphenyl-1,2-dihydro-[1,3,5]triazine (3b)
Melting point: 176 to 177 °C. 1H NMR (200 MHz) ␦: 3.11
(s, 6H, -N(CH3)2), 3.13 (s, 6H, -N(CH3)2), 4.06–4.13 (d, 1H,
J = 14.4 Hz, CH of CH2), 4.83–4.90 (d, 1H, J = 14.6 Hz,
CH of CH2), 5.92 (s, 1H, CH), 6.82–6.86 (d, 2H, J = 8.4 Hz,
ArH), 6.90–6.94 (d, 2H, J = 8.6 Hz, ArH), 7.11–7.15 (d, 2H,
J = 8.4 Hz, ArH), 7.36–7.46 (m, 8H, ArH), 7.60–7.64 (m,
N-(4-Chloro-benzylidene)-N′-cyclohexylbenzamidine (4b)
1
Melting point: 157 to 158 °C. H NMR (200 MHz) ␦:
1.32–1.68 (m, 10H, cyclohexyl), 3.13 (m, 1H, cyclohexyl),
7.20–7.24 (d, 2H, J = 8.4 Hz, ArH), 7.34–7.38 (d, 2H, J =
8.4 Hz, ArH), 7.40–7.48 (m, 3H, ArH), 8.02–8.06 (m, 2H,
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
ArH). 13C NMR (50.4 MHz) δ: 24.3, 27.8, 34.0, 54.7, 123.2,
127.2, 127.6, 129.2, 130.0, 130.8, 131.6, 134.9, 161.8,
172.7. MS m/z: 324.5 (M+).
Acknowledgements
Vipan Kumar is grateful to the Council of Scientific and
Industrial Research (CSIR, New Delhi) for a Junior Re-
search Fellowship under grant No. 01(1590)/99/EMR-II. The
authors also gratefully acknowledge the support of Professor
Takao Saito and Dr. Takashi Otani of the Tokyo University
of Science (Japan) for providing high resolution NMR and
1H–1H correlation spectra.
N-Cyclohexyl-N′-(4-nitro-benzylidene)benzamidine (4c)
1
Melting point: 140 to 141 °C. H NMR (200 MHz) δ:
1.42–1.88 (m, 10H, cyclohexyl), 3.29 (m, 1H, cyclohexyl),
7.16–7.20 (d, 2H, J = 8.2 Hz, ArH), 7.34–7.38 (d, 2H, J =
8.2 Hz, ArH), 7.40–7.46 (m, 3H, ArH), 8.00–8.04 (m, 2H,
ArH). 13C NMR (50.4 MHz) δ: 24.7, 28.0, 33.8, 54.5, 123.7,
126.8, 127.7, 129.4, 130.1, 131.0, 131.5, 135.0, 162.1,
171.9. MS m/z: 335 (M+).
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1
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1
Melting point: 211 to 212 °C. H NMR (200 MHz) δ:
3.11 (s, 6H, -N(CH3)2), 6.87–6.91 (d, 2H, J = 8.8 Hz, ArH),
7.54–7.60 (m, 6H, ArH), 8.62–8.66 (d, 2H, J = 8.8 Hz,
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