Iodobenzene diacetate (IBD) catalyzed an quick oxidative aromatization of Hantzsch-1,4-dihydropyridines to pyridines under ultrasonic irradiation

Article abstract of DOI:10.1016/j.ultsonch.2011.12.021

This project was undertaken to demonstrate the potential of iodobenzene diacetate for the oxidative aromatization of Hantzch-1,4-dihydropyridines under ultrasonic irradiation. All reactions were carried out under ultrasonic irradiation and results were co

Full text of DOI:10.1016/j.ultsonch.2011.12.021

Ultrasonics Sonochemistry 19 (2012) 729–735
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Short Communication
Iodobenzene diacetate (IBD) catalyzed an quick oxidative aromatization
of Hantzsch-1,4-dihydropyridines to pyridines under ultrasonic irradiation
Parvin Kumar a, , Ashwani Kumar b, Khalid Hussain c
⇑
a Department of Chemistry, Kururkshetra University, Kurukshetra, Haryana 136119, India
b Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science & Technology, Hissar, Haryana 125001, India
c Department of Chemistry, Guru Nanak Khalsa P.G. College, Yamuna Nagar, Haryana 135001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 October 2011
Received in revised form 15 December 2011
Accepted 26 December 2011
Available online 12 January 2012
This project was undertaken to demonstrate the potential of iodobenzene diacetate for the oxidative aro-
matization of Hantzch-1,4-dihydropyridines under ultrasonic irradiation. All reactions were carried out
under ultrasonic irradiation and results were compared with traditional method. Sonochemical switching
was observed in case of oxidative aromatization of 4-n-alkyl substituted 1,4-DHP. Without sonication,
dealkylation occurred in case of n-alkyl substituted 1,4-DHP (ionic mechanism) but under ultrasonic irra-
diation, n-alkyl group was not expelled (radical mechanism). However, secondary alkyl (isopropyl) and
benzyl group were expelled under both conditions.
Keywords:
Oxidative aromatization
IBD
Ó 2012 Elsevier B.V. All rights reserved.
1,4-DHP
Dealkylation
Sonication
1. Introduction
Ultrasound irradiation has been considered as a clean and use-
ful protocol in organic synthesis in the recent years [49–54]. Com-
Hantzsch 1,4-dihydropyridines have attracted growing interest
from both organic and medicinal chemists owing to their diverse
range of biologic and pharmacological activities such as antihyper-
tensive and calcium channels blocker [1–10]. These compounds
generally undergo oxidative metabolism in the liver by the action
of cytochrome p-450 to form the corresponding pyridine deriva-
tives [6]. With this increasing repertoire of applications, develop-
ing efficient methods for the oxidation of 1,4-dihydropyridines
has drawn much attention in recent years [11–45]. Despite these
intensive efforts, the majority of them have several drawbacks
such as the use of toxic and corrosive reagents, drastic reaction
conditions, tedious workup, long reaction times, and poor selectiv-
ity. To overcome these difficulties, development of a convenient
protocol for oxidation of 1,4-DHP is still of high importance.
Hypervalent iodine(III) reagents have become increasingly
important reagents for the oxidation of organic molecules com-
bined with their benign environmental character and easy com-
mercial availability [39–47]. It is of great interest to explore their
ability as extremely discriminating oxidants, their electrophilic
properties and to develop novel reaction using hypervalent iodine
compounds [48].
pared with traditional methods, this method is more convenient
and can be easily controlled. The prominent features of the ultra-
sound approach are improved reaction rates, high yields, and eas-
ier manipulation and considered a processing aid in terms of
energy conservation and waste minimization, which compared
with traditional methods, this technique is more convenient taking
green chemistry concepts into account [55].
2. Results and discussion
As a continuing interest in the development of new methodolo-
gies for oxidative aromatization of 1,4-DHP [23,41,42], herein,
oxidation of 1,4-DHP to corresponding pyridine derivative using
iodobenzene diacetate (IBD) under ultrasonic irradiation (Scheme 1)
is reported. Results are summarized in Table 1.
The reaction of diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyri-
dine-3,5-dicarboxylate with IBD was screened to optimize reaction
conditions. Our initial attempts to oxidize diethyl 2,6-dimethyl-4-
phenyl-1,4-dihydropyridine-3,5-dicarboxylate with IBD (1.2 equiv-
alent) in dichloromethane at room temperature yielded diethyl 2,
6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (2j) (78%) in
60 min under mechanical agitation (Table 1, entry 13). When the
reaction mixture was irradiated with ultrasound, almost quantita-
tive conversion was observed (TLC) within 10 min (Table 1, entry
13) and 2j was isolated in 95% yield. Thus the role of irradiation
was definitely identified.
⇑
Corresponding author. Tel.: +91 9416955143.
E-mail addresses: drpkawasthignkc@rediffmail.com, parvinjangra@gmail.com
(P. Kumar).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.12.021

730
P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
Table 1
Oxidative aromatization of 1,4-DHPs derivatives with IBD (1.2 equivalent) under ultrasonic irradiation.
Entry
Substrate R
Product
Reaction time t (min)
Yielda (%)
Mpb (°C)
Under sonication
Without sonication
Under sonication
Without sonication
1.
2.
3.
4.
5.
H
CH3
C2H5
(CH3)2CH
n-C6H13
3
5
6
6
5
8
6
25
40
40
35
60
50
96
90 + 5c
89 + 5c
90
90
10c+75
10c+77
78
70–71
Oil
Oil
70–71
Oil
2a + 3
2b + 3
3
2c + 3
3
85 + 7c
95
8c+70
75
70–71
6.
2d
2e
9
9
70
80
91
92
78
79
112–113
61–62
7.
8.
2f
9
7
5
80
42
30
95
95
94
78
84
80
73–75
51–52
9.
10.
11.
2g
2h
100–101
2i
5
60
93
80
71–72
12.
2j
10
7
60
70
95
95
78
83
62–63
69–71
13.
14.
2k
2l
10
9
75
65
91
90
79
76
112–113
70–72
15.
16.
2m
2n
2o
10
10
85
90
92
96
78
75
Oil
17.
18.
84–86
2p
10
90
90
70
114–116
116–118
19.
2q
10
90
91
71
20.

P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
731
Table 1 (continued)
Entry
Substrate R
Product
Reaction time t (min)
Under sonication
10
Yielda (%)
Mpb (°C)
Without sonication
90
Under sonication
92
Without sonication
72
2r
101–102
21.
a
b
c
Yields are isolated.
Melting points are uncorrected and compared with literature reports [42,59,60].
Yields are noted on GC.
Table 2
To understand the effect of ultrasonic radiation and sonochemi-
cal switching, the oxidative aromatization of diethyl 4-n-hexyl-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was carried
out with IBD in CH2Cl2 at different temperature under mechanical
agitation. At higher temperature the radical pathway was favored
and became predominant at 90 °C. For ultrasound mediated reac-
tion, the temperature of reaction mixture was determined before
and after the reaction, the former being lower than the later by about
6.5 °C. Then the reaction was carried out at lower temperature
(10–15 °C) under ultrasonic irradiation and radical pathway being
predominant gave diethyl 2,6-dimethyl-4-n-hexylpyridine-3,5-
dicarboxylate (2c) as major product. This may be due to hot spot the-
ory of ultrasonic cavitation [49b,55]. Literature survey also revealed
that sonochemical switching occurred with variation of tempera-
ture [56]. Under sonochemical condition, the reproducibility of the
results was good when the reaction conditions were kept constant.
The results of Table 1 clearly indicate the advantage of ultra-
sonic irradiation method over conventional method, i.e. (a) time
required for oxidative aromatization of 1,4-DHPs under ultrasonic
irradiation is shorter, (b) aromatization takes place at room tem-
perature, and (c) yields are higher.
Effect of solvent on oxidative aromatization of diethyl-2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate by IBD under sonication at room temperature.
Entry
Solvent
Reaction condition
Reaction time t (min)
Yielda (%)
1.
2.
3.
4.
CH2Cl2
CHCl3
CH3CN
THF
Sonication
Sonication
Sonication
Sonication
10
20
20
20
95
88
80
82
a
Yields are isolated.
IBD is sparingly soluble in CH2Cl2 at room temperature and gen-
erates heterogeneous reaction conditions. Upon application of
ultrasound, IBD was dispersed in CH2Cl2 and reacted with dis-
solved 1,4-DHP to give dark colored solutions, afforded the
pyridine derivatives in short reaction times with very good yields.
The influence of various solvents was also investigated using
CH2Cl2, CHCl3, CH3CN, and THF. The ultrasound promoted reaction
in CH2Cl2 gave better yields than in other solvents (Table 2). Using
the optimized reaction conditions, we oxidized a series of 1,4-DHP’s
to corresponding pyridine derivatives under ultrasonic irradiation.
4-Substituted-1,4-dihydropyridines were oxidized in excellent
yield bearing substituents at the 4-position such as hydrogen,
methyl, n-alkyl, aryl and heterocyclic groups, with a number of
electron donating as well as electron withdrawing group on aro-
matic ring. However, in the case of oxidation of the 1,4-DHP with
isopropyl/benzyl group at 4-position gave exclusively dealkylat-
ed/debenzylated pyridine derivative (3) (entry 4 and 6, Table 1).
Literature survey showed that oxidative aromatization of 4-n-al-
kyl/isopropyl/benzyl-1,4-DHP by IBD–CH2Cl2 [40], dealkylated
product was major while in case of hydroxy-tosyloxy-iodobenzene
(HTIB) [43] only isopropyl or benzyl group was debarred. Results of
this protocol are in accordance to results of HTIB. Thus, for this pro-
tocol, the reactivity of IBD under ultrasonic irradiation was found
similar to HTIB. This may be due to sonochemical switching, i.e.
changes of product distribution by ultrasound [55,56]. Literature
survey reveals that IBD in CH2Cl2 under stirring at room tempera-
ture react via ionic mechanism but under ultrasonic irradiation
[57] an alternative SET pathway exists in this reaction leading to
the formation of n-alkyl substituted pyridine derivatives
(Scheme 2). Moreover, the radical pathway was almost inhibited
after the addition of 4-tert-butylcatechol (radical scavenger).
In conclusion, we have demonstrated how to increase the oxi-
dative potential of IBD under ultrasonic irradiation and this poten-
tial is utilized for oxidative aromatization of 1,4-DHPs. The mild
experimental conditions, operational simplicity, rapid conversions,
and high yields of the product are the attractive feature of the pres-
ent protocol. These reaction conditions are contributing to the
development of sustainable techniques in organic synthesis and
to the simplicity of reactions with hypervalent iodine compounds.
3. Experimental procedure
All chemicals used in this study were of the highest purity avail-
able and purchased from local vendors. Melting points were deter-
mined on a Buchi oil heated melting apparatus and are uncorrected.
1H NMR spectra were recorded in CDCl3 on a Bruker-300 MHz spec-
trometer using TMS as an internal standard (chemical shift in d). IR
spectra were taken on a Perkin–Elmer 1600 FT-IR spectrophotome-
ter using KBr pellets and peaks are reported in cmÀ1. Sonication was
performed in a PCI made ultrasound cleaner with a frequency of 25
and 40 kHz through manual adjustment and an output power of
R
H
iodobenzene
R
H
EtO2C
CO2Et
diacetate(1.2 equiv)
EtO2C
CO Et EtO2C
CO2Et
2
CH2Cl2
sonication OR stirring
or
N
H
N
3
N
2
1
Scheme 1. Oxidative aromatization of 1,4-DHP.

732
P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
Path A, Ionic
R
H
mechanism
room temp
R
H
EtO2C
CO2Et
+
EtO2C
CO2Et
AcO
AcOH
+
I
stirring
N
I
N
H
OAc
AcO
Path B, Radical
mechanism
SET
R
)))
OAc
H
I
I
H
EtO2C
CO2Et
EtO2C
CO2Et
ROAc
+
OAc
R
+
+
+
N
3
N
H
Iodobenzene
OAc
R
H
EtO2C
EtO2C
CO2Et
N
R
N
R
R
I
I
OAc
EtO2C
CO2Et
+ AcOH
CO2Et
EtO2C
CO2Et
+
SET
+
OAc
+
N
H
N
H
Iodobenzene
R = CH3, C2H5, n-C6H13
Scheme 2. Proposed mechanism for oxidative aromatization of 4-n-alkyl-1,4-DHP.
250 W. The reaction flask was located at the center of the cleaner,
and the surface of the reactants was placed slightly lower than
the level of the water. The addition or removal of water controlled
the temperature of the water bath. The temperature of the water
bath was controlled at 25–30 °C.
3.3. Diethyl 1,4-dihydro-2,6-dimethyl-4-(3-p-chlorophenyl-1-phenyl-
4-pyrazolyl) pyridine-3,5-dicarboxylates
M.p. 166–168 °C.
IR (KBr): 3344, 3074, 2979, 1697, 1682, 1603, 1470, 1222, 837.
1H NMR (CDCl3, d, ppm): 1.096 (t, J = 7.2 Hz, 6H), 2.278 (s, 6H),
3.766–3.837 (m,2H); 3.997–4.104 (m, 2H), 5.285 (s, 1H), 5.558 (s,
1H), 7.235–7.260 (d, J = 7.5 Hz, 1H), 7.406–7.454 (t, J = 7.2 Hz, 4H)
7.668–7.75 (m, 2H), 7.814 (s, 1H), 7.863–7.891 (d, J = 8.4 Hz, 2H).
Anal. Calcd. for C28H28N3O4Cl: C, 66.47; H, 5.54; N, 8.31. Found:
C, 66.47; H, 5.55; N, 8.31.
1,4-Dihydropyridine was prepared according to the literature
[10,41,42,58].
3.1. General procedure for the synthesis of pyrazole substituted-1,4-
dihydropyridines 2a–g
A mixture of pyrazole aldehyde (5 mmol), ethylacetoacetate
(10 mmol), and ammonium acetate (10 mmol) in ethanol (20 mL)
was heated at 90 °C for 3 h. Progress of reaction was monitored
on TLC. The reaction mixture was cooled to room temperature
and solid, thus separated, was filtered. A yellowish colored solid
mass was obtained and it was recrystallized with ethanol to get
pure diethyl 1,4-dihydro-2,6-dimethyl-4-(3-aryl-1-phenyl-4-pyr-
azolyl) pyridine-3,5-dicarboxylates.
3.4. Diethyl 1,4-dihydro-2,6-dimethyl-4-(3-p-bromophenyl-1-phenyl-
4-pyrazolyl) pyridine-3,5-dicarboxylates
M.p. 181–182 °C.
IR (KBr): 3399, 3063, 2981, 1695, 1683, 1612, 1466, 1208, 842.
1H NMR (CDCl3, d, ppm): 1.096 (t, J = 7.2 Hz, 6H), 2.277 (s, 6H),
3.763–3.870 (m, 2H), 3.998–4.103 (m, 2H), 5.281 (s, 1H), 5.584 (s,
1H), 7.257 (t, J = 7.2 Hz, 1H), 7.400–7.451 (m, 2H); 7.575 (d,
J = 8.1 Hz, 2H), 7.678 (d, J = 7.8 Hz, 2H) 7.753 (s, 1H), 7.820 (d,
J = 8.4 Hz, 2H).
3.2. Diethyl 1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-4-pyrazolyl)
pyridine-3,5-dicarboxylates
Anal. Calcd. for C28H28BrN3O4: C, 61.10; H, 5.13; N, 7.63. Found:
C, 61.22; H, 5.27; N, 7.72.
M.p. 167–169 °C.
IR (KBr): 3355, 3035, 2986, 1697, 1689, 1602, 1465, 1213, 750.
1H NMR (CDCl3, d, ppm): 1.092 (t, J = 6.9 Hz, 6H), 2.234 (s, 6H),
3.744–3.848 (m, 2H), 3.986–4.068 (m, 2H), 5.307 (s, 1H), 5.537 (s,
1H), 7.221–7.279 (m, J = 6.9 Hz, J = 7.5 Hz, 2H), 7.353–7.377 (d,
J = 7.2 Hz, 2H), 7.424–7.447 (d, J = 6.9 Hz, 2H) 7.760 (s, 1H),
7.681–7.706 (d, J = 7.5 Hz, 2H); 7.844–7.868 (d, J = 7.2 Hz, 2H).
Anal. Calcd. for C28H29N3O4: C, 71.32; H, 6.20; N, 8.91. Found: C,
71.45; H, 6.26; N, 9.03.
3.5. General procedure for the oxidative aromatization of 1,4-DHP
under ultrasonic irradiation
In a 25 mL round bottom flask, 1,4-dihydropyridine (1.0 mmol)
and IBD (1.2 mmol) in 10 mL CH2Cl2 was taken. The reaction mix-
ture was irradiated (25 kHz, 280 W) in the water bath of an ultra-
sonic cleaner for a period as indicated in Table 1. Sonication was

P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
733
continued until the 1,4-DHP disappeared, as indicated by TLC. After
completion of reaction, the organic layer was concentrated to give
crude product. The pure product was obtained by column chroma-
tography using ethyl acetate–hexane (1:6). All compounds were
fully characterized by mp, IR, 1H NMR and elemental analysis.
These data are in full agreement with those previously reported
in literature [42,59–60].
Anal. Calcd. for C20H23NO5: C, 67.21; H, 6.49; N, 3.92. Found: C,
67.34; H, 6.54; N, 4.02.
3.12. Diethyl-4-(4-methylphenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2i
IR (KBr): 3022, 2978, 1725, 1582, 1444, 1228, 1013, 822, 857,
776 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.234 (t, J = 7.11 Hz, 6H, CH3), 2.35
(s, 3H, CH3), 2.66 (s, 6H, CH3), 4.28 (q, J = 7.11 Hz, 4H, OCH2), 7.12
(d, J = 6.79 Hz, 2H), 7.23 (d, J = 6.79 Hz, 2H).
3.6. Diethyl 2,6-dimethyl-4-methylpyridine-3,5-dicarboxylate 2a
IR (KBr): 2979, 2869, 1722, 1586, 1464, 1268, 1222, 1116, 1054,
873, 769 cmÀ1
.
Anal. Calcd. for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.44; H, 6.84; N, 4.28.
1H NMR (CDCl3, d, ppm): d = 1.25 (t, J = 7.11 Hz, 6H, CH3), 2.20 (s,
3H, CH3), 2.49 (s, 6H, CH3), 4.26 (q, J = 7.11 Hz, 4H, OCH3).
Anal. Calcd. for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.19; H, 7.28; N, 5.11.
3.13. Diethyl-4-phenyl-2,6-dimethylpyridine-3,5-dicarboxylate 2j
IR (KBr): 3026, 2978, 1729, 1592, 1477, 1301, 1212, 1171, 792,
3.7. Diethyl 2,6-dimethyl-4-ethylpyridine-3,5-dicarboxylate 2b
761 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.22 (t, J = 7.11 Hz, 6H, CH3), 4.27
(q, J = 7.11 Hz, 4H, OCH2), 2.67 (s, 6H, CH3), 7.18-7.23 (m, 2H),
7.30-7.32 (m, 3H).
IR (KBr): 2989, 1729, 1577, 1441, 1276, 1111, 1045, 923, 846,
751 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.09 (t, J = 7.40 Hz, 3H, CH3), 1.25 (t,
J = 7.11 Hz, 6H, CH3), 2.49 (s, 6H, CH3), 2.80 (q, J = 7.40Hz, 2H, CH2),
4.26 (q, J = 7.11 Hz, 4H, OCH3).
Anal. Calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.88; H, 6.55; N, 4.19.
Anal. Calcd. for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.38; H, 7.69; N, 4.96.
3.14. Diethyl-4-(4-chlorophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2k
3.8. Diethyl-4-(4-nitrophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2d
IR (KBr): 3028, 2991, 1728, 1588, 1232, 1106, 1045, 857, 657
cmÀ1
.
IR (KBr): 3023, 2988, 1726, 1555, 1504, 1351, 1106, 866, 843,
1HNMR (CDCl3, d, ppm): d = 1.22 (t, J = 7.11 Hz, 6H, CH3), 4.27 (q,
J=7.11 Hz, 4H, OCH2), 2.70 (s, 6H, CH3), 7.12 (d, J = 8.99 Hz, 2H),
7.32 (d, J = 8.99 Hz, 2H).
745 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.23 (t, J = 7.12 Hz, 6H, CH3), 2.63
(s, 6H, CH3), 4.25 (q, J = 7.12 Hz, 4H, OCH2), 7.41 (d, J = 8.23 Hz,
2H), 8.22 (d, J = 8.23 Hz, 2H).
Anal. Calcd. for C19H20ClNO4: C, 63.07; H, 5.57; N, 3.87. Found:
C, 62.92; H, 5.66; N, 3.66.
Anal. Calcd. for C19H20N2O6: C, 61.29; H, 5.41; N, 7.53. Found: C,
61.44; H, 5.32; N, 7.65.
3.15. Diethyl-4-(2, 4-dichlorophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2l
3.9. Diethyl-4-(3-nitrophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2e
IR (KBr): 3041, 2977, 1732, 1587, 1466, 1281, 1231, 1100, 857,
775, 701 cmÀ1
.
1HNMR (CDCl3, d, ppm): d = 1.23 (t, J = 7.12 Hz, 6H, CH3), 4.29 (q,
J = 7.12 Hz, 4H, OCH2), 2.68 (s, 6H, CH3), 7.15–7.42 (m, 3H).
Anal. Calcd. for C19H19Cl2NO4: C, 57.59; H, 4.83; N, 3.53. Found:
C, 57.44; H, 5.02; N, 3.66.
IR (KBr): 3033, 2991, 1724, 1579, 1549, 1508, 1351, 1281, 1178,
872, 783, 717 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.24 (t, J = 7.11 Hz, 6H, CH3), 2.69
(s, 6H, CH3), 4.26 (q, J = 7.11 Hz, 4H, OCH2), 7.57–8.28 (m, 4H).
Anal. Calcd. for C19H20N2O6: C, 61.29; H, 5.41; N, 7.53. Found: C,
61.36; H, 5.36; N, 7.48.
3.16. Diethyl-4-(3-bromophenyl)-2, 6-dimethylpyridine-3, 5-
dicarboxylate 2m
3.10. Diethyl-4-(2-nitrophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2f
IR (KBr): 3055, 2988, 1727, 1562, 1280, 1102, 1035, 866, 777,
697 cmÀ1
.
IR (KBr): 3029, 2991, 1725, 1608, 1548, 1511, 1353, 1278, 1192,
1HNMR (CDCl3, d, ppm): d = 1.24 (t, J=7.13 Hz, 6H, CH3), 4.30 (q,
J=7.13 Hz, 4H, OCH2), 2.66 (s, 6H, CH3), 7.20–7.44 (m, 4H).
Anal. Calcd. for C19H20BrNO4 C, 56.17; H, 4.96; N, 3.45. Found: C,
56.32; H, 4.88; N, 3.28.
762, 701 cmÀ1
.
1H NMR (CDCl3, d, ppm): d 1.23 (t, J = 7.11 Hz, 6H, CH3), 2.69 (s,
6H, CH3), 4.27 (q, J = 7.11 Hz, 4H, OCH2), 7.48–8.25 (m, 4H).
Anal. Calcd. for C19H20N2O6: C, 61.29; H, 5.41; N, 7.53. Found: C,
61.46; H, 5.38; N, 7.48.
3.17. Diethyl 4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethylpyridine-
3,5-dicarboxylate 2p
3.11. Diethyl-4-(4-methoxyphenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate 2g
IR (KBr): 3055, 3033, 2989, 1737, 1618, 1591, 1470, 1212, 747.
1H NMR (CDCl3, d, ppm): 0.910–0.996 (t, J = 7.2 Hz, 6H), 2.618 (s,
6H), 3.909–4.072 (m, 4H), 7.110–7.313 (m, 4H), 7.819 (s, 1H),
7.581–7.690 (m, 6H).
Anal. Calcd. for C28H27N3O4: C, 71.62; H, 5.80; N, 8.95. Found: C,
71.77; H, 5.98; N, 9.09.
IR (KBr): 3034, 2987, 1731, 1599, 1523, 1288, 1107, 856, 834,
772 cmÀ1
.
1H NMR (CDCl3, d, ppm): d = 1.22 (t, J = 7.12 Hz, 6H, CH3), 4.27
(q, J = 7.12 Hz, 4H, OCH2), 2.69 (s, 6H, CH3), 3.86 (s, 3H, OCH3),
6.91 (d, J = 8.57 Hz, 2H), 7.11 (d, J = 8.57 Hz, 2H).

734
P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
[13] L. Chai, Y. Zhao, Q. Sheng, Z.Q. Liu, Aromatization of Hantzsch 1,4-
dihydropyridines and 1,3,5-trisubstituted pyrazolines with HIO3 and I2O5 in
water, Tetrahedron Lett. 47 (2006) 9283–9285.
3.18. Diethyl 4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-
dimethylpyridine-3,5-dicarboxylate 2q
[14] J.M. Chen, X.-M. Zeng, b-Cyclodextrin-catalyzed mild aromatization of
Hantzsch 1,4-dihydropyridines with o-iodoxybenzoic acid in water/acetone,
Synth. Commun. 39 (2009) 3521–3526.
[15] J.J.V. Eynde, F. Delfosse, A. Mayence, Y. Van Haverbeke, Old reagents, new
results: aromatization of Hantzsch 1,4-dihydropyridines with manganese
dioxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Tetrahedron 51
(1995) 6511–6516.
[16] M. Filipan-Litvic, M. Litvic, V. Vinkovic, An efficient, metal-free, room
temperature aromatization of Hantzsch-1,4-dihydropyridines with urea–
hydrogen peroxide adduct, catalyzed by molecular iodine, Tetrahedron 64
(2008) 5649–5656.
IR (KBr): 3042, 2988, 1743, 1611, 1598, 1559, 1452, 1338, 1241,
1208, 1089, 1017, 867, 757, 732, 693 cmÀ1
.
1H NMR (CDCl3, d, ppm): 0.932 (t, J = 7.2 Hz, 6H), 2.612 (s, 6H),
3.909–4.098 (m, 4H), 7.310–7.371 (m, 2H); 7.470–7.522 (m, 5H),
7.745 (d, J = 7.7 Hz, 2H), 7.920 (s, 1H).
Anal. Calcd. for C28H26N3O4Br: C, 61.42; H, 4.75; N, 7.68. Found:
C, 61.55; H, 4.87; N, 7.86.
[17] B. Han, Z. Liu, Q. Liu, L. Yang, Z. Liu, W. Yu, An efficient aerobic oxidative
aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted
pyrazolines, Tetrahedron 62 (2006) 2492–2496.
[18] M.M. Hashemi, Y. Ahmadibeni, H. Ghafuri, Aromatization of Hantzsch 1,4-
dihydropyridines by hydrogen peroxide in the presence of cobalt(II) acetate,
Monatsh. Chem. 134 (2003) 107–110.
[19] M.M. Heravi, F.K. Behbahani, H.A. Oskooie, R.H. Shoar, Catalytic aromatization
of Hantzsch 1,4-dihydropyridines by ferric perchlorate in acetic acid,
Tetrahedron Lett. 46 (2005) 2775–2777.
[20] M.M. Heravi, F. Derikvand, S. Hassan-Pour, K. Bakhtiari, F.F. Bamoharram, H.A.
Oskooie, Oxidative aromatization of Hantzsch 1,4-dihydropyridines in the
presence of mixed-addenda vanadomolybdophosphate heteropolyacid
H6PMo9V3O40, Biol. Med. Chem. Lett. 17 (2007) 3305–3309.
3.19. Diethyl 4-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-
dimethylpyridine-3,5-dicarboxylate 2r
IR(KBr): 3055, 2989, 1747, 1620, 1597, 1461, 1322, 1087, 1002,
952, 850, 836, 698 cmÀ1
.
1H NMR (CDCl3, d, ppm): 0.935 (t, J = 7.2 Hz, 6H), 2.618 (s, 6H),
3.898–4.118 (m, 4H), 7.310–7.370 (m, 2H); 7.487–7.513 (m, 5H),
7.746 (d, J = 7.8 Hz, 2H), 7.923 (s, 1H).
Anal. Calcd. for C28H26ClN3O4: C, 66.73; H, 5.20; N, 8.34. Found:
C, 61.66; H, 5.29; N, 8.26.
[21] J.S. Yadav, B.V.S. Reddy, A.K. Basak, G. Baishya, A. Venkat Narsaiah,
Iodoxybenzoic acid (IBX): an efficient and novel oxidizing agent for the
aromatization of 1,4-dihydropyridines, Synthesis 3 (2006) 451–454.
[22] B. Khadilkar, S. Borkar, Silica gel-supported ferric nitrate:
oxidizing reagent, Synth. Commun. 28 (1998) 207–212.
a convenient
3.20. Diethyl 2,6-dimethylpyridine-3,5-dicarboxylate 3
[23] P. Kumar, A. Kumar, An expeditious oxidative aromatization of Hantzsch 1,4-
dihydropyridines to pyridines using cetyltrimethylammonium
IR (KBr): 2988, 1727, 1597, 1512, 1302, 1246, 1122, 1023, 776
cmÀ1
.
peroxodisulfate: a phase transferring oxidant, Bull. Korean Chem. Soc. 31
(2010) 2299.
1H NMR (CDCl3, d, ppm): d = 1.31 (t, J = 7.12 Hz, 6H, CH3), 2.75
(s, 6H, CH3), 4.29 (q, J = 7.12 Hz, 4H, OCH3).
[24] M. Litvic, I. Cepanec, M. Filipan, K. Kos, A. Bartolincic, V. Druskovic, M.M. Tibi,
V. Vinkovic, Mild, selective, and high-yield oxidation of Hantzsch 1,4-
dihydropyridines with lead(IV) acetate, Heterocycles 65 (2005) 23.
[25] D. Liu, J. Gui, C. Wang, F. Lu, Y. Yang, Z. Sun, Oxidative aromatization of
Hantzsch 1,4-dihydropyridines catalyzed by ferric perchlorate in ionic liquids
with air, Synth. Commun. 40 (2010) 1004–1008.
Anal. Calcd. for C13H17NO4:C, 62.14; H, 6.82; N, 5.57. Found: C,
62.23; H, 7.01; N, 5.45.
[26] Z. Liu, W. Yu, L. Yang, Z.-L. Liu, A novel oxidation-ring contraction of Hantzsch
1,4-dihydropyridines to polysubstituted furans, Tetrahedron Lett. 48 (2007)
5321.
Acknowledgment
[27] H.R. Memarian, M. Abdoli-Senejani, Ultrasound-assisted photochemical
oxidation of unsymmetrically substituted 1,4-dihydropyridines, Ultrason.
Sonochem. 15 (2008) 110.
The author (P. Kumar) is thankful to authorities of BRL Mokhra
for providing chemicals and ultrasonicator.
[28] H.R. Memarian, M. Abdoli-Senejani, S. Tangestaninejad, Photosensitized
oxidation of unsymmetrical 1,4-dihydropyridines, J. Iran Chem. Soc. 3 (2006)
285.
[29] M. Moghadam, M. Nasr-Esfahani, S. Tangestaninejad, V. Mirkhani, Mild and
efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate
catalyzed by a new polystyrene-bound Mn(TPP)Cl, Bioorg. Med. Chem. Lett. 16
(2006) 2026.
[30] M. Nasr-Esfahani, M. Moghadam, S. Tangestaninejad, V. Mirkhani, A.R.
Momeni, Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridines
with sodium periodate catalyzed by manganese(III) Schiff base complexes,
Bioorg. Med. Chem. 14 (2006) 2720.
[31] J.R. Pfister, Rapid, high-yield oxidation of Hantzsch-type 1,4-dihydropyridines
with ceric ammonium nitrate, Synthesis (1990) 689–690.
[32] A. Saini, S. Kumar, J.S. Sandhu, New strategy for the oxidation of Hantzsch 1,4-
dihydropyridines and dihydropyrido[2,3-d]pyrimidines catalyzed by DMSO
under aerobic conditions, Synth. Commun. 37 (2007) 2317–2324.
[33] S.D. Sharma, P. Hazarika, D. Konwar, A simple, green, and one-pot, four-
component synthesis of 1,4-dihydropyridines and their aromatization, Catal.
Commun. 9 (2008) 709–714.
[34] F. Tamaddon, Z. Razmi, Oxidation of 1,4-dihydropyrimidines and 3,4-
dihydropyrimidin-2(1H)-ones to substituted pyridines and pyrimidinones
using Ca(OCl)2 in aqueous media, Synth. Commun. 41 (2011) 485–492.
[35] J. Vanden Eynde, R. Dorazio, Y. Van Haverbeke, Potassium permanganate, a
versatile reagent for the aromatization of Hantzsch 1,4-dihydropyridines,
Tetrahedron 50 (1994) 2479–2484.
[36] R.S. Varma, D. Kumar, Manganese triacetate-mediated oxidation of Hantzsch
1,4-dihydropyridines to pyridines, Tetrahedron Lett. 40 (1999) 21–24.
[37] J.J. Xia, G.W. Wang, One-pot synthesis and aromatization of 1,4-
dihydropyridines in refluxing water, Synthesis (2005) 2379–2383.
[38] B. Zeynizadeh, K.A. Dilmaghani, M. Mirzaei, Mild and convenient method for
aromatization of Hantzsch esters of 1,4-dihydropyridines with Ag2O, Acta
Chim. Slov. 54 (2007) 366.
[39] N.N. Karade, S.V. Gampawar, J.M. Kondre, S.V. Shinde, An efficient combination
of Dess–Martin periodinane with molecular iodine or KBr for the facile oxidative
aromatization of Hantzsch 1,4-dihydropyridines, ARKIVOC xii (2008) 9–16.
[40] D.P. Cheng, Z.C. Chen, Hypervalent iodine in synthesis 76. An efficient
oxidation of 1,4-dihydropyridines to pyridines using iodobenzene diacetate,
Synth. Commun. 32 (5) (2002) 793–798.
References
[1] D.M. Stout, A.I. Meyers, Recent advances in the chemistry of dihydropyridines,
Chem. Rev. 82 (1982) 323.
[2] A. Hilgeroth, Dimeric 4-aryl-1,4-dihydropyridines: development of a third
class of nonpeptidic HIV-1 protease inhibitors, Min. Rev. Med. Chem. 2 (2002)
235–247.
[3] M. Suarez, Y. Verdecia, B. Illescas, R. Matinenz-Alvarez, A. Alvarez, E. Ochoa, C.
Seoane, N. Kayali, N. Martin, Synthesis and study of novel fulleropyrrolidines
bearing biologically active 1,4-dihydropyridines, Tetrahedron 59 (2003) 9179–
9186.
[4] T. Chennot, U. Eisner, A new synthesis of 1,4-dihydropyridines, J. Chem. Soc.
Perkin Trans. 1 (1975) 926–929.
[5] G.T. Babcock, M. Wikstrom, Oxygen activation and the conservation of energy
in cell respiration, Nature 356 (1992) 301.
[6] F.P. Guengerich, M.V. Martin, P.H. Beaune, P. Kremers, T. Wolf, D.J. Waxman,
Characterization of rat and human liver microsomal cytochrome P-450 forms
involved in nifedipine oxidation, a prototype for genetic polymorphism in
oxidative drug metabolism, J. Biol. Chem. 261 (1986) 5051–5060.
[7] M.M. Cox, D.L. Nelson, Lehninger Principles of Biochemistry, Oxford, 2005.
[8] U. Eisner, J. Kuthan, The chemistry of dihydropyridines, Chem. Rev. 72 (1972)
1.
[9] B. Bulbul, G.S. Ozturk, M. Vural, R. Simsek, Y. Sarioqlu, A. Linden, M. Ulqen, C.
Safak, Condensed 1,4-dihydropyridines with various esters and their calcium
channel antagonist activities, Eur. J. Med. Chem. 44 (2009) 2052–2058.
[10] Z.A. Moshtaghi, H.S. Baradaran, Montmorillonite K10 clay: an efficient catalyst
for Hantzsch synthesis of 1,4-dihydropyridine derivatives, Synth. Commun. 38
(2008) 290–296.
[11] H. Adibia, A.R. Hajipour, A convenient and efficient protocol for oxidative
aromatization of Hantzsch 1,4-dihydropyridines using benzyltriphenyl
phosphonium peroxymonosulfate under almost neutral reaction conditions,
Biol. Med. Chem. Lett. 17 (2007) 1008–1012.
[12] M. Anniyappan, D. Muralidharan, P.T. Perumal, A novel application of the
oxidizing properties of urea nitrate and peroxydisulfate–cobalt(II):
aromatization of NAD(P)H model Hantzsch 1,4-dihydropyridines, Tetrahedron
58 (2002) 5069–5073.

P. Kumar et al. / Ultrasonics Sonochemistry 19 (2012) 729–735
735
[41] P. Kumar, Solid state oxidative aromatization of Hantzsch 1,4-
dihydropyridines to pyridines using iodobenzene diacetate or hydroxy
(tosyloxy)iodobenzene, Chin. J. Chem. 27 (2009) 1487–1491.
[42] P. Kumar, A novel, facile, simple and convenient oxidative aromatization of
Hantzsch 1,4-dihydropyridines to pyridines using polymeric iodosobenzene
with KBr, J. Heterocycl. Chem. 47 (6) (2010) 1429–1433.
[51] J.-T. Li, Z.-P. Lin, An efficient and practical synthesis of 2-((1H-indol-3-
yl)(aryl)methyl)malononitriles under ultrasound irradiation, Ultrason.
Sonochem. 15 (2008) 265–268.
[52] J.-T. Li, M.-X. Sun, Y. Yin, Ultrasound promoted efficient method for the
cleavage of 3-aryl-2,3-epoxyl-1-phenyl-1-propanone with indole, Ultrason.
Sonochem. 17 (2010) 359–362.
[43] K.H. Lee, K.Y. Ko, Aromatization of Hantzsch 1,4-dihydropyridines with
[hydroxy(tosyloxy)iodo]benzene, Bull. Korean Chem. Soc. 23 (2002) 1505–
1506.
[53] J. Noei, A.R. Khosropour, Ultrasound-promoted a green protocol for the
synthesis of 2,4-diarylthiazoles under ambient temperature in [bmim]BF4,
Ultrason. Sonochem. 16 (2009) 711–717.
[44] J.W. Lee, K.Y. Ko, Aromatization of Hantzsch 1,4-dihydropyridines with a
polymer-supported hypervalent iodine reagent, Bull. Korean Chem. Soc. 25 (1)
(2004) 19–20.
[45] R.S. Varma, D. Kumar, Solid state oxidation of 1,4-dihydropyridines to
pyridines using phenyliodine(III) bis(trifluoroacetate) or elemental sulfur, J.
Chem. Soc. Perkin Trans. 1 (1999) 1755–1757.
[54] Y. Zou, H. Wu, Y. Hu, H. Liu, X. Zhao, H. Ji, D. Shi, A novel and environment-
friendly method for preparing dihydropyrano[2,3-c]pyrazoles in water under
ultrasound irradiation, Ultrason. Sonochem. 18 (2011) 708–712.
[55] T.J. Mason, Ultrasound in synthetic organic chemistry, Chem. Soc. Rev. 26
(1997) 443–451.
[56] V.A. Chebanov, Y.I. Sakhno, S.M. Desenko, High regioselective ultrasonic-
assisted synthesis of 2,7-diaryl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-
carboxylic acids, Ultrason. Sonochem. 19 (2012) 707–709.
[46] A. Varvoglis, Chemical transformations induced by hypervalent iodine
reagents, Tetrahedron 53 (1997) 1179–1255.
[47] T. Wirth, M. Chiai, V.V. Zhdankin, G.F. Koser, H. Tohma, Y. Kita, Hypervalent
iodine chemistry-modern developments in organic synthesis, Topics in
Current Chemistry, vol. 224, Springer, Berlin, 2003.
[57] M. Katohgi, H. Togo, Oxidatively sonochemical dealkylation of various N-
alkylsulfonamides to free sulfonamides and aldehydes, Tetrahedron 57 (2001)
7481–7486.
[48] V.V. Zhdankin, P.J. Stang, Chemistry of polyvalent iodine, Chem. Rev. 108 (12)
(2008) 5299–5358.
[49] (a) S. Puri, B. Kaur, A. Parmar, H. Kumar, Ultrasound-promoted greener
synthesis of 2H-chromen-2-ones catalyzed by copper perchlorate in
solventless media, Ultrason. Sonochem. 16 (2009) 705–707;
[58] J. Li, J. Qiu, H. Li, G. Zhang, An efficient, three-component one-pot preparation
of 1,4-dihydropyridines containing novel substituted pyrazole under sulfamic
acid catalysis, Chin. J. Chem. 29 (2011) 511–514.
[59] R. Murugan, K. Ramamoorthy, S. Sundarrajan, S. Ramakrishna, Simple and
efficient synthesis of 2,6-dialkyl-3,5-dialkoxycarbonyl-4-(3-aryl-1-phenyl-
pyrazol-4-yl)pyridines using TPAP/NMO as a catalyst under mild conditions,
Tetrahedron 67 (2011) 2998–3002.
(b) T.J. Mason, J.P. Lorimer, Applied Sonochemistry: The Uses of Power
Ultrasound in Chemistry and Processing, Wiley-VCH, Weinheim, 2002.
[50] Y. Hu, Y. Zou, H. Wu, D. Shi,
A
facile and efficient ultrasound-assisted
[60] O. Prakash, K. Hussain, R. Kumar, D. Wadhwa, C. Sharma, K.R. Aneja, Synthesis
and antimicrobial evaluation of new 1,4-dihydro-4-pyrazolylpyridines and 4-
pyrazolylpyridines, Org. Med. Chem. Lett. (2011), doi:10.1186/2191-2858-1-5.
synthesis of novel dispiroheterocycles, Ultrason. Sonochem. 19 (2012) 264–
269.