Synthesis of new 1,4-dihydropyridine derivatives containing thiazolyl substituents

Article abstract of DOI:10.1080/10426500802239529

A series of 4-[2-methyl (or aryl) thiazole-4-yl]-2,6-dimethyl-3,5-diacetyl (or dibenzoyl) 1,4-dihydropyridines were synthesized using a modified Hantzsch reaction involving the condensation of the corresponding aldehyde with acetyl acetone or benzoyl acetone. The preparation of the corresponding aldehydes (2-methylthiazole-4-carboxaldehyde and some 2-arylthiazole-4-carboxaldehydes) was achieved by a simplified protocol of the published synthesis.

Full text of DOI:10.1080/10426500802239529

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Phosphorus, Sulfur, and Silicon
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Synthesis of New 1,4-
Dihydropyridine Derivatives
Containing Thiazolyl
Substituents
Leila Bazargan a , Abbas Shafiee b , Mohsen Amini b ,
Ebrahim Bakhshi Dezfouli b , Ebrahim Azizi c & Seyed
Mahmood Ghaffari a
a Institute of Biochemistry and Biophysics, Tehran
University , Tehran, Iran
b Department of Medicinal Chemistry, Faculty of
Pharmacy and Pharmaceutical Sciences Research
Center , Tehran University of Medical Sciences ,
Tehran, Iran
c Department of Toxicology and Pharmacology,
Faculty of Pharmacy and Pharmaceutical Sciences
Research Center , Tehran University of Medical
Sciences , Tehran, Iran
Published online: 18 Feb 2009.
To cite this article: Leila Bazargan , Abbas Shafiee , Mohsen Amini , Ebrahim Bakhshi
Dezfouli , Ebrahim Azizi & Seyed Mahmood Ghaffari (2009) Synthesis of New 1,4-
Dihydropyridine Derivatives Containing Thiazolyl Substituents, Phosphorus, Sulfur, and
Silicon and the Related Elements, 184:3, 602-609, DOI: 10.1080/10426500802239529
To link to this article: http://dx.doi.org/10.1080/10426500802239529
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Phosphorus, Sulfur, and Silicon, 184:602–609, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802239529
Synthesis of New 1,4-Dihydropyridine Derivatives
Containing Thiazolyl Substituents
Leila Bazargan,1 Abbas Shafiee,2 Mohsen Amini,2
Ebrahim Bakhshi Dezfouli,2 Ebrahim Azizi,3
and Seyed Mahmood Ghaffari4
1Institute of Biochemistry and Biophysics, Tehran University,
Tehran, Iran
2Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
3Department of Toxicology and Pharmacology, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
4Institute of Biochemistry and Biophysics, Tehran University,
Tehran, Iran
A series of 4-[2-methyl (or aryl) thiazole-4-yl]-2,6-dimethyl-3,5-diacetyl (or diben-
zoyl) 1,4-dihydropyridines were synthesized using a modified Hantzsch reaction
involving the condensation of the corresponding aldehyde with acetyl acetone or
benzoyl acetone. The preparation of the corresponding aldehydes (2-methylthiazole-
4-carboxaldehyde and some 2-arylthiazole-4-carboxaldehydes) was achieved by a
simplified protocol of the published synthesis.
Keywords 1,4-Dihydropyridines; β-diketones; thiazoles
INTRODUCTION
Development of multidrug-resistance (MDR) in tumor cells remains
one of the major clinical obstacles during antitumor chemotherapy
against many malignancies.1 The introduction of potent MDR rever-
sal agents such as NIK-250, N276-9, nicardipine (Figure 1) and other
Received 14 May 2008; accepted 1 June 2008.
This research was supported by grants from the Research Council of Tehran Univer-
sity of Medical Sciences and INSF (Iran National Science Foundation), Tehran, Iran.
Address correspondence to Abbas Shafiee, Department of Medicinal Chemistry, Fac-
ulty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran 14174, Iran. E-mail: ashafiee@ams.ac.ir
602

Thiazolyl-Substituted 1,4-Dihydropyridines
603
FIGURE 1 Structures of nicardipine, NIK-250, and N276-9.
1,4-dihydropyridines (DHP) stimulated the synthesis of novel dihy-
dropyridine (DHP) derivatives.2
1,4-Dihydropyridines were classically prepared by the Hantzsch
reaction3 (Scheme 1), in which the mixture of an aldehyde, a β-
dicarbonyl compound, and ammonia (or ammonium acetate) was re-
fluxed in an alcohol for 12 to 36 h.
A one-pot condensation of an aldehyde with alkyl acetoacetate and
ammonia either in acetic acid or refluxing in an alcohol was later
developed.4 The synthesis of dihydropyridines under solvent free con-
ditions also has been recently reported.5 In all of the reported methods
for the preparation of DHPs, an aldehyde was used as source of the
substituents in the 4-position.
As a part of our ongoing program to design new DHPs,6–12 we report
the synthesis of 1,4-dihydropyridines having a substituted thiazolyl
moiety in the 4-position from the corresponding substituted thiazolyl
aldehydes. The latter were prepared by a simplified protocol as shown
in Scheme 1.
RESULTS AND DISCUSSION
It has been reported13,14 that the reaction of substituted thioamides
1 and 1,3-dichloroacetone in acetone provides the intermediates
3. The latter under acidic conditions gives the 2-substituted 4-
chloromethylthiazoles 4. We found that refluxing compounds 1 and 2

604
L. Bazargan et al.
SCHEME 1
in toluene gives compounds 4 in one step and in good yields. This syn-
thesis could serve as a valuable method to prepare other 2-substituted
thiazoles. The hydrolysis of compounds 4 in 50% aqueous sulfuric acid
gave the 2-substituted 4-hydroxymethylthiazoles 5. Oxidation of the
latter with activated manganese(IV) oxide gave the corresponding 2-
substituted 4-formylthiazoles 6 in excellent yields.
Several syntheses of 1,4-dihydropyridines have been reported. Most
of the symmetrical 1,4-dihydropyridine 3,5-diesters were prepared by
the well known Hantzsch reaction.3 For asymmetrical analogues, a
modified method was developed by Meyer et al.15 in which first an
aldehyde was condensed with a β-dicarbonyl compound, and then the
ring was closed by reaction with alkyl 3-aminocrotonate. Recently,
the preparation of 1,4-dihydropyridines under solvent free conditions

Thiazolyl-Substituted 1,4-Dihydropyridines
605
was reported.5 In this case, alkyl acetoacetate and a series of aldehy-
des were converted to 1,4-dihydropyridines in the presence of ammo-
nium acetate under solvent-free conditions at 80◦C. Good to excellent
yields were obtained by this method in the case of some aliphatic, aro-
matic, and heteroaromatic aldehydes. However, condensation of the
aldehyde 6 with acetyl and benzoyl acetone under the same condi-
tions gave only low yields of the corresponding dihydropyridines. The
condensation reaction between aldehydes and 1,3-cyclohexanedione
in the solid state by grinding at room temperature has also been
reported.16 In our case, however, this procedure was also unsuccess-
ful. We could prepare the compounds 7 and 8 through the modified
method of Hantzsch reaction. Thus, the reaction of aldehydes 6 with
acetyl acetone or benzyl acetone and ammonium acetate in ethanol in
darkness and under nitrogen afforded the dihydropyridines 7 and 8
(Table I).
EXPERIMENTAL
Melting points were determined with a Kofler hot stage apparatus and
are uncorrected. 1H NMR spectra were obtained with a 400 Varian
Unity Plus spectrometer. TMS was used as the internal standard. The
IR spectra were recorded with a Nicolet-550 FT-IR spectrophotome-
ter. 4-Chlorothiobenzamide and 2-chlorothiobenzamide were prepared
from the corresponding nitrile derivatives as reported.17 Column chro-
matography was carried out using silica gel (230–400 mesh). The com-
pounds 5a–d and 6a–d were prepared as reported.13
Preparation of 4-Chloromethyl-2-methyl (or Aryl) Thiazoles 4:
General Procedure
To a magnetically stirred solution of 1,3-dichloroacetone (0.1 mol) in 100
mL of toluene, thioacetamide or the respective 4-substituted thioben-
zamide (0.1 mol) was added, and the reaction mixture was refluxed at
110◦C for 2–3 h. The course of the reaction was monitored by TLC. Af-
ter completion of the reaction, the solvent was removed under reduced
pressure. To the residue, 200 mL of water was added, and the pre-
cipitate formed was filtered. The crude product was crystallized from
methanol (10 mL). In the case of thioacetamide, after the addition of wa-
ter, the mixture was extracted with dichloromethane (2 × 50 mL). The
organic phase was dried (sodium sulfate), and the solvent was removed
under reduced pressure. Purification was achieved by distillation at
65◦C (5 mm Hg) to give pure 4a.

606

Thiazolyl-Substituted 1,4-Dihydropyridines
607
4-Chloromethyl-2-methylthiazole (4a)
Yield 70%, 1H NMR (CDCl3): δ = 7.13 (s, 1H, 5-H), 4.60 (s, 2H,
CH2Cl), 2.66 (s, 3H, CH3). Anal. Calcd. for C5H6ClNS (147.63): C 40.68,
H 4.10, N 9.49%; Found: C 40.36, H 4.44, N 9.29%.
4-Chloromethyl-2-(4-chlorophenyl)thiazole (4b)
1
Yield 75%, mp 79–80◦C, H NMR (CDCl3): δ = 4.80 (s, 2H, CH2),
7.23 (s, 1H, 5-H), 7.40 (d, J = 8 Hz, 2H, arom-H), 7. 68 (d, J = 8 Hz,
2H, arom-H). Anal. Calcd. for C10H7Cl2NS (244.14): C 49.20, H 2.89, N
5.74%; Found: C 49.44, H 2.59, N 5.91%.
2-Chlormethyl-2-(2-chlorophenyl)thiazole (4c)
Yield 68%, mp 61–63◦C, 1H NMR (CDCl3): δ = 4.75 (s, 2H, CH2), 7.20
(s, 1H, 5-H), 7.37–7.80 (m, 4H, arom-H). Anal. Calcd. for C10H7Cl2NS
(244.14): C 49.20, H 2.89, N 5.74%; Found: C 49.55, H 2.68, N 5.48%.
2-Chlormethyl-2-(2,4-dichlorophenyl)thiazole (4d)
1
Yield 76%, mp 69–71◦C, H NMR (CDCl3): δ = 4.75 (s, 2H, CH2),
7.15–7.60 (m, 3H, arom-H), 8.20 (d, J = 8.2 Hz, 1H, arom-H). Anal.
Calcd. for C10H6Cl3NS (278.59): C 43.11, H 2.17, N 5.03%; Found: C
43.29, H 2.34, N 5.34%.
Preparation of Diacetyl 1,4-Dihydropyridines 7 and Dibenzoyl
1,4-Dihydropyrines 8: General Procedure
To a solution of 6a–d (2 mmol) and acetyl acetone or benzoyl acetone
(4 mmol) in 20 mL of ethanol, ammonium acetate (2 g) was added.
The mixture was refluxed in the dark and under nitrogen atmosphere
overnight. After cooling, the solvent was removed under reduced pres-
sure. The mixture was extracted with ethyl acetate (3 × 20 mL). The
organic phase was dried (sodium sulfate), the solvent was removed in
vacuo, and the crude product was purified by column chromatography
using CH2Cl2:ethyl acetate (80:20) as eluent. Compounds 7 and 8 were
recrystallized from methanol-water (Table I).
4-(2-Methylthiazole-4-yl)-2,6-dimethyl-3,5-diacetyl-1,4-
dihydropyridine (7a)
1
IR (KBr, cm−1): 1665, 3316. H NMR (CDCl3): δ = 2.30 (s, 6H, 2,6-
CH3), 2.37 (s, 6H, COCH3), 2.61 (s, 3H, CH3-thiazole), 5.20 (s, 1H, 4-H),
6.37 (bs, 1H, NH ), 6.57 (s, 1H, H-thiazole).
4-[2-(4-Chlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-diacetyl-
1,4-dihydropyridine (7b)
1
IR (KBr, cm−1): 1669 (CO). H NMR (CDCl3): δ = 2.33 (s, 6H, 2,6-
CH3), 2.48 (s, 6H, COCH3), 5.38 (s, 1H, 4-H), 6.90 (bs, 1H, NH), 7.22 (s,

608
L. Bazargan et al.
1H, H-thiazole), 7.38 (d, J = 8.1 Hz, 2H, arom-H), 7.70 (d, J = 8.1 Hz,
2H, arom-H).
4-[2-(2-Chlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-diacethyl-
1,4-dihydropyridine (7c)
1
IR (KBr, cm−1): 1669 (CO). H NMR (CDCl3): δ = 2.34 (s, 6H, 2,6-
CH3), 2.44 (s, 6H, COCH3), 5.36 (s, 1H, 4-H), 6.40 (bs, 1H, NH), 7.05–
7.35 (m, 5H, arom-H).
4-[2-(2,4-Dichlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-
diacethyl-1,4-dihydropyridine (7d)
1
IR (KBr, cm−1): 1675 (CO). H NMR (CDCl3): δ = 2.36 (s, 6H, 2,6-
CH3), 2.47 (s, 6H, COCH3), 5.36 (s, 1H, 4-H), 6.93 (bs, 1H, NH), 7.21
(s, 1H, H-thiazole), 7.32 (dd, J = 8 Hz, J = 2 Hz, 1H, arom-H), 7.48 (d,
J = 2 Hz, 1H, arom-H), 8.14 (d, J = 8 Hz, 1H, arom-H).
4-(2-Methylthiazole-4-yl)-2,6-dimethyl-3,5-dibenzoyl-1,4-
dihydropyridine (8a)
1
IR (KBr, cm−1): 1665 (CO). H NMR (CDCl3): δ = 1.97 (s, 6H, 2,6-
CH3), 2.53 (s, 3H, CH3-thiazole), 5.35 (s, 1H, 4-H), 6.25 (bs, 1H, NH),
6.43 (s, 1H, H-thiazole), 7.29–7.70 (m, 10H, arom-H).
4-[2-(4-Chlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-dibenzoyl-
1,4-dihydropyridine (8b)
1
IR (KBr, cm−1): 1669 (CO). H NMR (CDCl3): δ = 2.30 (s, 6H, 2,6-
CH3), 5.72 (s, 1H, 4-H), 6.05 (bs, 1H, NH), 6.75 (s, 1H, H-thiazole),
7.20–7.85 (m, 14H, arom-H).
4-[2-(2-Chlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-dibenzoyl-
1,4-dihydropyridine (8c)
1
IR (KBr, cm−1): 1670 (CO). H NMR (CDCl3): δ = 2.03 (s, 6H, 2,6-
CH3), 5.43 (s, 1H, 4-H), 5.60 (bs, 1H, NH), 6.92 (s, 1H, H-thiazole),
7.20–7.90 (m, 14H, arom-H).
4-[2-(2,4-Dichlorophenylthiazole)-4-yl]-2,6-dimethyl-3,5-
dibenzoyl-1,4-dihydropyridine (8d)
1
IR (KBr, cm−1): 1674 (CO). H NMR (CDCl3): δ = 2.03 (s, 6H, 2,6-
CH3), 5.35 (s, 1H, 4-H), 5.80 (bs, 1H, NH), 6.93 (s, 1H, H-thiazole),
7.15–7.98 (m, 13H, arom-H).

Thiazolyl-Substituted 1,4-Dihydropyridines
609
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