Electrophilic substitution as a convenient approach to functionalized N-benzyl-1,4-dihydropyridines

Article abstract of DOI:10.1016/S0040-4039(02)01083-3

The reactivity of 1-benzyl-3-cyano-1,4-dihydropyridine was studied in reactions with electrophilic reagents based on structural analogy of 1,4-dihydropyridines with enamines. Different 5-functionalized derivatives were obtained by direct electrophilic substitution.

Full text of DOI:10.1016/S0040-4039(02)01083-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5423–5425
Electrophilic substitution as a convenient approach to
functionalized N-benzyl-1,4-dihydropyridines
Aleksandr N. Kostyuk,* Dmitriy M. Volochnyuk, Larisa N. Lupiha, Aleksandr M. Pinchuk and
Andrei A. Tolmachev
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya 5, 02094 Kyiv-94, Ukraine
Received 5 April 2002; accepted 7 June 2002
Abstract—The reactivity of 1-benzyl-3-cyano-1,4-dihydropyridine was studied in reactions with electrophilic reagents based on
structural analogy of 1,4-dihydropyridines with enamines. Different 5-functionalized derivatives were obtained by direct elec-
trophilic substitution. © 2002 Elsevier Science Ltd. All rights reserved.
1,4-Dihydropyridines play a key role in biological Red–
Ox systems,1 in treatment and prophylaxis of cardiovas-
cular diseases2 and are also convenient building blocks
in the synthesis of alkaloids.3 Thus the search for new
methods of synthesizing functionalized derivatives of
1,4-dihydropyridines is a useful exercise. Electrophilic
substitution is a promising method for functionalization
of 1,4-dihydropyridines as they are cyclic enamines.
The results of several investigations reported recently
support this.4
In this paper we report the results of a study of the
reactions of N-benzyl-3-cyano-1,4-dihydropyridine 15
with various types of electrophilic reagent (Scheme 1).
1-Benzyl-3-cyano-1,4-dihydropyridine 1 was regioselec-
tively acylated with ethyl oxalyl chloride and tosyl
isocyanate affording the corresponding acyl derivatives
2 and 3.6,7 Also, 1 was sulfenylated with 2-nitrophenyl-
sulphenyl chloride giving 4.8
Scheme 1.
Keywords: 1,4-dihydropyridine; electrophilic substitution.
* Corresponding author. Fax: 380 44 269 67 94; e-mail: dov@fosfor.kiev.ua
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01083-3

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A. N. Kostyuk et al. / Tetrahedron Letters 43 (2002) 5423–5425
Scheme 2.
Vilsmeier–Haak formylation of dihydropyridine 1 also
occurred easily affording 5.9
The structures of compounds 2–5, 8 and 9 were confir-
1
med by H NMR spectroscopy, and the structures of
compounds 5, 8 and 9 were also confirmed by 13C
There are reports of unsuccessful attempts to phospho-
rylate 1,4-dihydropyridines with phosphorous halides
(III and V).4a,10 However, we have found that 1-benzyl-
3-cyano-1,4-dihydropyridine 1 can be phosphorylated
with PBr3, like other enamines with phosphorus
halides.11 Dibromophosphine 6 was not obtained in a
pure state because of its low stability and high reactiv-
ity (Scheme 2). However, its formation was proved by
31P NMR spectroscopy and its further transformation
into stable thiophosphonamide 8.12 In an attempt to
obtain the analogous phosphonate by oxidation of 7
with H2O2, oxygenation of the dihydropyridine ring
occurred and the bismorpholide of 1-benzyl-2-oxo-3-
cyano-1,2-dihydro-5-pyridinylphosphonic acid 9 was
obtained.13
NMR spectroscopy.14
References
1. Lyle, R. E. In Pyridine and its Derivatives Supplement;
Abramovich, R. A., Ed.; Wiley: New York, 1974; Vol. 1,
p. 137.
2. (a) Goldman, S.; Stoltefuss, J. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1559–1578; (b) Sunkel, C.-E.; Fau de
Casa-Juana, M.; Santos, L.; Gomes, M.-M.; Villarroya,
M.; Gonzalez-Morales, M.-A.; Priego, J.-G.; Ortega, M.-
P. J. Med. Chem. 1990, 33, 3205–3210; (c) Jaing, J. L.; Li,
A.-H.; Jang, S.-Y.; Chang, L.; Melman, N.; Moro, S.; Ji,
X.; Lobkovsky, E.; Clardy, J.; Jacobson, K. A. J. Med.
Chem. 1999, 42, 3055–3060.
As is known, the introduction of the second electron-
withdrawing substituent leads to an increase in stability
of dihydropyridines. In fact, unlike the starting dihy-
dropyridine 1 bearing one electron-acceptor group, sub-
stances 2–5 and 8, with two electron-acceptor groups
are quite stable substances with a long shelf-life in air
(Table 1).
3. (a) Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: London,
1996; Vol. 2, pp. 251–294; (b) Comins, D. L.; LaMunyon,
D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182–8187; (c)
Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.
J. Org. Chem. 1999, 64, 2184–2185; (d) Kuethe, J. T.;
Comins, D. L. Org. Lett. 2000, 2, 855–857; (e) Pays, C.;
Mangeney, P. Tetrahedron Lett. 2001, 42, 589–592.
4. (a) Lavilla, F.; Kumar, R.; Coll, O.; Masdeu, C.; Spada,
A.; Bosch, J.; Espinosa, E.; Molins, E. Chem. Eur. J.
2000, 6, 1763–1772; (b) Bennasar, M.-L.; Juan, C.; Bosch,
J. Tetrahedron Lett. 2001, 42, 585–588.
Table 1. Yields and melting points of compounds 2–5 and
8
Product
Electrophile
Yield (%)a
Mp (°C)b
5. The starting material, 1-benzyl-3-cyano-1,4-dihydropy-
ridine was obtained by reduction of N-benzyl-3-cyanopy-
ridinium chloride with Na2S2O4. See: Dittmer, D. C.;
Lombardo, A.; Batzold, F. H.; Greene, C. S. J. Org.
Chem. 1976, 41, 2976–2981.
6. To a stirred solution of 10 mmol of 1 in 40 ml of dry
toluene, 10 mmol of triethylamine was added. Then a
solution of 10 mmol of ethyl oxalyl chloride in 10 ml of
2
3
4
5
8
EtO2CCOCl
TosNꢀCꢀO
2-NO2-C6H4-SCl
DMF, POCl3
PBr3
60
78
61
52
47
105–108
184–186
125–127
122–124
145–147
a Yields refer to pure isolated products.
b Melting points are uncorrected.

A. N. Kostyuk et al. / Tetrahedron Letters 43 (2002) 5423–5425
5425
toluene was added. After 5 h, triethylamine hydrochlo-
ride was removed by filtration and the toluene was evap-
orated in vacuo. The residue was triturated with
petroleum and crystallized from 2-propyl alcohol to give
11. Kostyuk, A. N.; Lysenko, N. V.; Marchenko, A. P.;
Koidan, G. N.; Pinchuk, A. N.; Tolmachev, A. A. Phos-
phorus Sulfur Silicon Relat. Elem. 1998, 139, 209–229.
12. To a stirred solution of 2.5 mmol of 1 and 30 mmol of
triethylamine in 20 ml of dry benzene, a solution of 2.5
mmol of phosphorus tribromide in 5 ml of dry benzene
was added. A solution of 10 mmol of morpholine in 5 ml
of dry benzene was then added. After 2 h, 2.5 mmol of
finely ground elemental sulfur was added. After the sulfur
had dissolved, the precipitated solid was filtered and
benzene was evaporated in vacuo. The residue was tritu-
rated with octane and crystallized from ethanol to give 8.
1H NMR (300 MHz, CDCl3): 3.07 (8H, t, 3J=4.5 Hz,
-N(CH2-CH2)2O), 3.17 (2H, d, 3JPH=3.5 Hz, -CH2-),
3.65 (8H, t, 3J=4.5 Hz, -N(CH2-CH2)2O), 4.39 (2H, s,
1
3
2. H NMR (300 MHz, CDCl3): 1.34 (3H, t, J=7.1 Hz,
-CH3), 3.25 (2H, s, -CH2-), 4.29 (2H, q, 3J=7.1 Hz,
4
-O-CH2-), 4.48 (2H, s, N-CH2-), 6.51 (1H, d, J=1.5 Hz,
3
4
N-C6Hꢀ), 7.23 (2H, dd, J=7.8 Hz, J=2.1 Hz, CHo-Ph),
7.38–7.47 (3H, m, CHm,p-Ph), 7.63 (1H, d, 4J=1.5 Hz,
N-C2Hꢀ).
7. To a stirred solution of 10 mmol of 1 in 15 ml of dry
benzene a solution of 10 mmol of tosyl isocyanate in 15
ml of dry benzene was added. The precipitated solid was
crystallized from acetonitrile to give 3. 1H NMR (300
MHz, DMSO-d6): 2.39 (3H, s, -CH3), 2.97 (2H, s, -CH2-),
4.49 (2H, s, N-CH2-), 7.14 (1H, s, N-C6Hꢀ), 7.28–7.48
3
N-CH2-), 6.55 (1H, s, N-C2Hꢀ), 6.85 (1H, d, JPH=15.6
Hz, N-C6Hꢀ), 7.22 (2H, dd, 3J=7.8 Hz, 4J=2.1 Hz,
CHo-Ph), 7.35–7.45 (3H, m, CHm,p-Ph).
3
(8H, m, CH), 7.79 (2H, d, J=7.9 Hz, C2%H), 11.55 (1H,
s, -NH-).
13. The product was prepared according to the procedure
applied to the substance 8,12 but instead of sulfur, 0.35 ml
50% H2O2 was added. The precipitated solid was filtered
and the benzene was evaporated in vacuo. The residue
was crystallized from ethanol to give 9. Compound 9:
8. To a stirred solution of 10 mmol of 1 in 15 ml of dry
benzene a solution of 10 mmol of 2-nitrophenylsulphenyl
chloride in 15 ml of dry benzene was added. After 24 h,
triethylamine hydrochloride was removed by filtration
and the toluene was evaporated in vacuo to give 4. The
residue was crystallized from a mixture of methanol–ace-
1
yield 12%; mp 228–229°C; H NMR (300 MHz, CDCl3):
3
1
3.00–3.12 (8H, m, -N(CH2-CH2)2O), 3.64 (8H, t, J=4.2
tonitrile (1:1). H NMR (300 MHz, CDCl3): 3.14 (2H, s,
-CH2-), 4.40 (2H, s, N-CH2-), 6.48 (1H, s, N-C6Hꢀ), 6.62
(1H, s N-C2Hꢀ), 7.23–7.49 (7H, m, CH), 7.60 (1H, t,
Hz, -N(CH2-CH2)2O), 5.19 (2H, s, N-CH2-), 7.37–7.42
(5H, m, CHPh), 7.81 (1H, dd, 3JPH=8.7 Hz, 4JHH=1.8
Hz, C4H), 8.18 (1H, dd, 3JPH=9.3 Hz, 4JHH=1.8 Hz,
C6H).
3
3J=7.6 Hz, C5%H), 8.21 (1H, d, J=8.1 Hz, C3%H).
9. To a solution of 6 mmol of 1 in 5 ml of dry DMF, 2 ml
of POCl3 was added at 0°C. The mixture was maintained
at 50°C for 90 min, then cooled and poured onto ice and
neutralized with a solution of NaHCO3. The precipitated
solid was crystallized from a mixture of ethanol–water
(2:1) to give 5. 1H NMR (300 MHz, DMSO-d6): 3.02
(2H, s, -CH2-), 4.59 (2H, s, N-CH2-), 7.25 (1H, s, N-
C6Hꢀ), 7.32–7.47 (6H, m, CH), 9.21 (1H, s, CHO).
2,4-Dinitrophenylhydrazone derivative: mp 210–212°C;
1H NMR (300 MHz, DMSO-d6): 3.23 (2H, s, -CH2-),
4.58 (2H, s, N-CH2-), 6.79 (1H, s, N-C6Hꢀ), 7.28 (1H, s,
N-C2Hꢀ), 7.32–7.47 (5H, m, CHPh), 7.88 (1H, d, 3J=10.2
Hz, C6%H), 8.24 (1H, s, CHꢀN), 8.29 (1H, dd, 3J=10.2
Hz, 4J=2.3 Hz, C5%H), 8.83 (1H, d, 4J=2.3 Hz, C3%H),
11.48 (1H, s, -NH-).
14. Compound 5: 13C NMR (75 MHz, DMSO-d6): 24.3 C(4),
60.3 N-CH2-, 89.6 C(3)-CN, 117.7 CN, 123.3 C(5)-CHO,
131.4 C(o-Ph), 131.9 C(p-Ph), 132.7 C(m-Ph), 140.5
C(ipso-Ph), 146.6 C(2), 152.5 C(6), 192.8 CHO. Com-
pound 8: 13C NMR (75 MHz, CDCl3): 24.2 (2JPC=8.0
Hz) C(4), 45.1 -N(CH2-CH2)2O, 57.97 N-CH2-, 66.8
(3JPC=7.2 Hz) -N(CH2-CH2)2O, 82.3 (3JPC=11.8 Hz)
C(3)-CN, 102.0 (1JPC=129.0 Hz) C(5)-P, 119.6 CN,
127.4 C(o-Ph), 128.7 C(p-Ph), 129.2 C(m-Ph), 135.3
C(ipso-Ph), 141.2 (2JPC=21.6 Hz) C(6), 142.0 C(2).
Compound 9: 13C NMR (75 MHz, CDCl3): 44.5
-N(CH2-CH2)2O, 53.8 N-CH2-, 66.9 (3JPC=3.5 Hz)
-N(CH2-CH2)2O, 106.1 (3JPC=20.3 Hz) C(3)-CN, 107.3
(1JPC=130.6 Hz) C(5)-P, 114.8 CN, 128.7 C(o-Ph), 129.1
C(p-Ph), 129.4 C(m-Ph), 134.3 C(ipso-Ph), 147.1 C(4),
149.3 (2JPC=16.4 Hz) C(6), 159.0 C(2)ꢀO.
10. Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1997,
62, 3597–3609.