Facile aromatisation of Hantzsch 1,4-dihydropyridines by autoxidation in the presence of p-toluenesulfonic acid in acetic acid

Article abstract of DOI:10.3184/174751918X15208600846791

A simple protocol to achieve the aromatisation of Hantzsch dihydropyridines in high yield was established using p-toluenesulfonic acid in acetic acid and yields of 90% were obtained at room temperature. With regards to the Hantzsch 1,4-dihydropyridines derived from alkyl aldehydes bearing one or more á-hydrogens, dealkylation products were obtained through a proposed autoxidation mechanism.

Full text of DOI:10.3184/174751918X15208600846791

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 MARCH, 141–144
RESEARCH PAPER 141
Facile aromatisation of Hantzsch 1,4-dihydropyridines by autoxidation in the
presence of p-toluenesulfonic acid in acetic acid
Ding Zhanga and Min Shab*
aSchool of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, P.R. China
bSchool of Management Science and Engineering, Nanjing University of Finance and Economics, Nanjing, Jiangsu 210046, P.R. China
A simple protocol to achieve the aromatisation of Hantzsch dihydropyridines in high yield was established using p-toluenesulfonic acid in
acetic acid and yields of 90% were obtained at room temperature. With regards to the Hantzsch 1,4-dihydropyridines derived from alkyl
aldehydes bearing one or more á-hydrogens, dealkylation products were obtained through a proposed autoxidation mechanism.
Keywords: autoxidation, dehydrogenation, free radicals, heterocycles, catalysis
Table 1 Optimisation of conditions for aromatisation of 1a
1,4-Dihydropyridine-3,5-dicarboxylates, also known as
Hantzsch dihydropyridines, can be easily synthesised by the
reaction of aldehydes, â-ketoesters and ammonia (Hantzsch
reaction).1 The functionality of 1,4-dihydropyridine (DHP) can
be widely found in numerous biologically active compounds
including vasodilators, such as calcium channel blocker drugs.2
A DHP derivative serves as an essential co-enzyme in the
respiratory chain to donate electrons in redox reactions.3 These
important observations triggered the interest of chemists to
explore the aromatisation of Hantzsch dihydropyridines and the
relevant biological processes.4
To date, various approaches have been established for the
transformation of Hantzsch dihydropyridines. The general
methodologyistouseanexcessstrongoxidants, includingnitric
acid,5 ceric ammonium nitrate (CAN),6 2,3-dichorochromate
(PCC),7 sodium nitrite8 and 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ).9 Alternatively, RuCl3/O2,10 Pd/C,11
activated carbon/O2,12 Fe(ClO4)3,13 N-hydroxyphthalimide
(NHPI) and Co(OAc)2/O2,14 and 9-phenyl-10-methy-
lacridinium perchlorate15 have also emerged as photocatalysts
for catalytic aerobic oxidation. Both microwave irradiation
and a variety of reagents have been used to permit oxidations
in good yield.16 Moreover, hypervalent iodine reagents and
electrochemical and ultrasound approaches have likewise
been developed to promote these reactions.17 p-Toluenesulfonic
acid (p-TSA) is widely used in synthetic chemistry due to its
high reactivity with cheap and easy access.18 In this study,
we describe for the first time an extremely simple procedure
for the aromatisation of 1,4-DHPs. With oxygen as the
autoxidation reagent, aromatisation is easily performed in the
presence of p-TSA in acetic acid, accompanied by high yields
for most selected model molecules.
R
R
catalyst,
solvent
EtO2C
Et
CO2
EtO2C
CO2
Et
conditions
N
H
N
2a
1a
Entry Catalyst
Solvent Conditions
Yield (%)a
1
2
3
4
5
6
7
8
p-TSA 1.0 equiv.
p-TSA 0.5 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
p-TSA 1.0 equiv.
AcOH
AcOH
CH3CN r.t., 9 h
EtOH r.t., 9 h
CH2Cl2 r.t., 9 h
EtOAc r.t., 9 h
AcOH
AcOH
AcOH
r.t., 1 h
r.t., 9 h
95
93
0
0
0
0
25
0
0
80
32
r.t., dark, 9 h
r.t., N2 protection
r.t., 9 h, phenol
9
10
11
p-TSA 1.0 equiv., AIBN cat. CH2Cl2 30 °C, 10 h
p-TSA 1.0 equiv. CH2Cl2 30 °C, 10 h
aIsolated yield.
reaction time was longer (9 h) giving a 93% yield of 2a (Table
1, entry 2). This interesting phenomenon indicates that p-TSA
might play a catalytic role in the reaction. By controlling the
performance of such reactions, we note that the real oxidant is
probably molecular oxygen from the air. Furthermore, natural
light is also indispensable for the success of this transformation
(Table 1, entries 7 and 8). We assume that the reaction is
initiated by the autoxidation of 1,4-dihydropyridines to the
corresponding hydroperoxides 3, which react with p-TSA to
form 1,4-dihydropyridin-4-yl-4-methylbenzenesulfonates (4).
The elimination of p-TSA from 4 gives the final product 2
(Scheme 1).
Results and discussion
By screening the catalytic systems for the aromatisation of
1,4-DHPs, we note that the combination of p-TSA and acetic
acid has unexpected power towards this transformation based
on a control experiment. We selected diethyl 2,6-dimethyl-1,4
dihydropyridine-3,5-dicarboxylate (1a) as a model compound
to optimise the reaction conditions, as shown in Table 1.
In terms of the mixture of 1a (1 mmol), p-TSA (1 mmol) in
acetic acid (2 mL), simple stirring under aerobic conditions
at room temperature (r.t.) for 1 h achieved the full conversion
of 1a. An isolated yield of 95% was observed for the desired
aromatisation product (Table 1, entry 1). However, the use
of acetonitrile, ethanol, dichloromethane or ethyl acetate as
solvent led to no target products (Table 1, entries 3–6). When
the amount of p-TSA was decreased from 1.0 to 0.5 equiv., the
The autoxidation of 1 to the corresponding hydroperoxides
can be ascribed to a free radical mechanism. The autoxidation of
organic compounds in the presence of oxygen is reported to be
possible.19 Recently, Klussmann and co-workers demonstrated
an interesting oxidative coupling reaction of xanthene
and acridanes with ketones in the presence of oxygen and
methanesulfonic acid.20 The authors declared that the reaction
was initiated by autoxidation of xanthene or acridanes to the
corresponding hydroperoxides. The addition of an autoxidation
inhibitor such as phenol terminates the aromatisation reaction
of 1,4-dihydropyridines (Table 1, entry 9). Acetic acid is a
common medium used for autoxidation processes.21 No obvious
aromatisation takes place when the reaction is carried out in
dichloromethane (Table 1, entry 5). Interestingly, when the
* Correspondent. E-mail: shaminjingjing@163.com

142 JOURNAL OF CHEMICAL RESEARCH 2018
R
H
R
O-OH
Et
CO2
Et
CO2
EtO2C
EtO2C
O2/AcOH
autoxidation
N
N
H
H
1
3
H
2O2
TsOH
R
R
Et
CO2
Et
CO2
EtO2C
EtO2C
OTs
N
N
H
2
4
Scheme 1 Plausible mechanism for aromatisation.
OH
O
CR2
CHR2
CO2
EtO
Et
CO2
2C
EtO
Et
2C
O2/AcOH
autoxidation
N
H
N
H
1
TsOH
OH2
O
CR2
EtO
Et
CO2
2C
EtO
Et
CO2
2C
N
N
H
5
Scheme 2 Plausible mechanism for the formation of dealkylation products.
Table 2 Aromatisation of Hantzsch 1,4-dihydropyridinesa
free radical initiator, 2,2′-azo-bis-isobutyronitrile (AIBN)
is added to the reaction system, 80% of the aromatisation
product is obtained, even though the reaction was carried out
in dichloromethane (Table 1, entries 10 and 11). These results
provide reliable experimental evidence for the autoxidation
mechanism.
R
R
EtO2C
CO2
Et
O2/TsOH
AcOH,rt
EtO2C
CO2
Et
EtO2C
CO2
Et
N
H
N
N
1
5
2
Entry
1
2
R
H
CH3
Product
5
2b
Time(h)
2
2
Yield (%)B
98
With the optimised conditions in hand, we synthesised a
variety of 1,4-DHPs to examine the generality and scope of
this protocol. The 1,4-DHPs bearing aliphatic, aromatic or
heteroaromatic substituents in the C4 position were all smoothly
and quickly oxidised to the corresponding pyridines, in high
yields (Table 2). However, for 1,4-DHPs with a strong electron-
withdrawing group on the benzene ring, the aromatisation was
greatly hindered by the nitro group (Table 2, entry 11). This
is in accordance with the proposed mechanism that a strong
electron-withdrawing group at the C4 position would make the
intermediate 4 unstable (Scheme 1). For Hantzsch 1,4-DHPs
derived from alkyl aldehydes bearing one or more á-hydrogens,
dealkylation products are also obtained (Table 2, entries 3–6).
This result may be explained by the autoxidation of the side
chains (Scheme 2). In the case of the 2-furyl group, a large
amount of the dearylation product is formed simultaneously
(Table 2, entry 13).
96
91
66 + 30
92
80 + 15
95
95
92
98
<5
3
4
5
6
(CH3)2CH
n-C3H7
CH3(CH3CH2)CH
n-C7H17
5
1.5
2.5
3
7
1
2c + 5
5
2d + 5
2a
7
Ph
8
9
10
11
12
13
4-MeOC6H4
4-ClC6H4
4-HOC6H4
4-NO2C6H4
C6H4CH=CH
2-Furyl
2e
2f
2g
2h
2i
2j + 5
2.5
4
4
12
2
2.5
93
45 + 53
aReaction performed with 1,4-dihydropyridines (1 mmol), p-TSA (1 mmol) in acetic acid
(2 mL) at r.t.
bIsolated yield.

JOURNAL OF CHEMICAL RESEARCH 2018 143
CH2CH3), 2.62 (s, 6H, CH3), 4.02 (q, 4H, J = 7.0, CH2CH3), 7.26–7.28 (m,
3H, Ph), 7.38 (d, 2H, J = 3.0, Ph).
Diethyl 2,4,6-dimethylpyridine-3,5-dicarboxylate (2b): Oil (lit.18 oil);
1H NMR (500 MHz, CDCl3): 1.15 (t, 6H, J = 7.3, CH2CH3), 2.06 (s, 3H,
CH3), 2.30 (s, 6H, CH3), 4.18 (q, 4H, J = 7.3, CH2CH3).
O
O2/TsOH
H
O
H
AcOH,rt,2h
O
97%
Diethyl 2,6-dimethyl-4-propylpyridine-3,5-dicarboxylate (2c): Oil (lit.24
oil); 1H NMR (500 MHz, CDCl3): 0.80 (t, 3H, J = 7.5, CH2CH2CH3), 1.25
(t, 6H, J = 7.3, CH2CH3), 1.46 (sext, 2H, J = 7.5, CH2CH2CH3), 2.38 (s, 6H,
CH3), 2.44 (t, 2H, J = 7.5, CH2CH2CH3), 4.27 (q, 4H, J = 7.3, CH2CH3).
Diethyl 4-heptyl-2,6-dimethylpyridine-3,5-dicarboxylate (2d): Oil (lit.25
oil); 1H NMR (500 MHz, CDCl3): 0.80 (t, 3H, J = 6.8, CH2(CH2)5CH3),
1.19–1.26 (m, 8H, CH2CH2(CH2)4CH3), 1.32 (t, 6H, J = 7.3, CH2CH3),
1.45–1.51 (m, 2H, CH2CH2(CH2)4CH3), 2.44 (s, 6H, CH3), 2.51 (t, 2H,
J = 8.3, CH2(CH2)5CH3), 4.34 (q, 4H, J = 7.3, CH2CH3).
Diethyl 4-(4-methoxyphenyl)-2,6-dimethylpyridine-3,5-dicarboxylate
(2e): M.p. 50–51 °C (lit.18 51–52 °C); 1H NMR (500 MHz, CDCl3): 0.89 (t,
6H, J = 7.0, CH2CH3), 2.58 (s, 6H, CH3), 3.82 (s, 3H, OCH3), 4.05 (q, 4H,
J = 7.0, CH2CH3), 6.89 (d, 2H, J = 8.8, Ph), 7.19 (d, 2H, J = 8.8, Ph).
Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate
(2f): M.p. 68–69 °C (lit.18 69–71 °C); 1H NMR (500 MHz, CDCl3): 1.00 (t,
6H, J = 7.3, CH2CH3), 2.62 (s, 6H, CH3), 4.06 (q, 4H, J = 7.3, CH2CH3), 7.22
(d, 2H, J = 8.5, Ph), 7.37 (d, 2H, J = 8.5, Ph).
O
O
O2/TsOH
O
AcOH,rt,2h
85%
Scheme 3
The Baeyer–Villiger oxidation is
a
reaction using
peroxyacids as an oxidant that convert ketones to esters.22 In
our postulated mechanism, we assume the production of a
peroxide intermediate and H2O2, so we further speculate that
the combination of AcOH or p-TSA with in situ-generated H2O2
may catalyse Baeyer–Villiger oxidation.23 Two substrates were
chosen to test the ability of the p-TSA–AcOH system. 1-Butanal
was smoothly converted to propyl formate in 97% yield. Cyclic
ketones such as cyclohexanone also underwent the reaction
to form 6-hexanolactone. These two reactions support our
postulated mechanism and show more possibilities of further
application of the p-TSA–AcOH system (Scheme 3).
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl- 3,5-pyridine dicarboxylate
1
(2g): M.p. 174–176 °C (lit.11 174–176 °C); H NMR (500 MHz, CDCl3):
1.02 (t, 6H, J = 7.3, CH2CH3), 2.61 (s, 6H, CH3), 4.09 (q, 4H, J = 7.3,
CH2CH3), 6.79 (d, 2H, J = 9.0, Ph), 7.13 (d, 2H, J = 9.0, Ph), 7.18 (brs, 1H).
Diethyl 2,6-dimethyl-4-styrylpyridine-3,5-dicarboxylate (2i): M.p.
161–162 °C (lit.18 161–162 °C); 1H NMR (500 MHz, CDCl3): 1.19 (t, 6H, J =
7.3, CH2CH3), 2.51 (s, 6H, CH3), 4.25 (q, 4H, J = 7.3, CH2CH3), 6.77 (d, 1H,
J = 16.3, CH=CH), 7.10 (d, 1H, J = 16.3, CH=CH), 7.19 (t, 1H, J = 7.5, Ph),
7.25 (t, 2H, J = 7.5, Ph), 7.35 (t, 2H, J = 7.5, Ph).
Conclusion
Diethyl 4-(furan-2-yl)-2,6-dimethylpyridine-3,5-dicarboxylate (2j): Oil
(lit.18 oil); 1H NMR (500 MHz, CDCl3): 1.25 (t, 6H, J = 7.3, CH2CH3), 2.61
(s, 6H, CH3), 4.30 (q, 4H, J = 7.3, CH2CH3), 6.51 (dd, 1H, J = 3, furan), 6.65
(d, 1H, J= 3, J= 1.8, furan), 7.53 (brs, 1H, furan).
We developed an aerobic oxidative aromatisation procedure to
convert 1,4-dihydropyridines to their corresponding pyridine
derivatives. The reaction proceeds smoothly under mild
conditions without metal reagents and is based on commercially
availablep-toluenesulfonicacidandoxygen.Thereactionprocess
is easy to handle without column chromatography purification
for most cases. The elucidation of an autoxidation mechanism
may be helpful for the understanding of the metabolism process
for the drugs containing the 1,4-dihydropyridine functionality.
Acknowledgements
This research was financially supported by Natural Science
Foundation of Jiangsu University (17KJD550001) and the
National Natural Science Foundation of China (61602217). We
are grateful to Nanjing University of Science and Technology
for help with all the measurements.
Experimental
Electronic Supplementary Information
The ESI (copies of 1H NMR spectra of all products) is
available through:
The Hantzsch 1,4-dihydropyridine derivatives were prepared
according to literature procedures.15 1H NMR spectra were recorded on
a Bruker 500 spectrometer in CDCl3 solution, wherein shifts are given
in ppm downfield from TMS as an internal standard. All reagents
were purchased from commercial suppliers and used without further
purification.
http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000003/art00006
Received 12 December 2017; accepted 1 March 2018
Paper 1705145
https://doi.org/10.3184/174751918X15208600846791
Published online: 28 January 2018
Oxidative aromatisation of 1,4-DHPs; general procedure
Diethyl 2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (329 mg,
1 mmol) and p-TSA (170 mg, 1 mmol) were dissolved in acetic acid
(2 mL). The mixture was stirred at room temperature until the
starting material was completely consumed. Then, 10% Na2CO3
solution (25 mL) was added to precipitate the crude product, which
was collected by filtration and recrystallised from ethanol. Likewise,
the product was extracted with ethyl acetate (3 × 15 mL) and washed
with water (2 × 10 mL). The crude product was purified by column
chromatography on silica gel (petroleum ether:EtOAc = 7:1) to yield
the pure product as a pale yellow solid (312 mg, 95% yield).
Diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (5): M.p 69–70 °C
(lit.18 70–71 °C); H NMR (500 MHz, CDCl3): 1.44 (t, 6H, J = 7.3,
CH2CH3), 2.87 (s, 6H, CH3), 4.42 (q, 4H, J = 7.3, CH2CH3), 8.70 (s, 1H,
pyridine).
Diethyl 2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (2a): M.p.
61–62 °C (lit.18 62–63 °C); 1H NMR (500 MHz, CDCl3): 0.92 (t, 6H, J = 7.0,
References
1
2
A. Hantzsch, Eur. J. Org. Chem., 1882, 215, 1.
A.K. Ogawa, C.A. Willoughby, R. Bergeron, K.P. Ellsworth, W. M. Geissler,
R.W. Myers, J. Yao, G. Harris and K.T. Chapman, Bioorg. Med. Chem. Lett.,
2003, 13, 3405.
3
4
P. Mitchell, Science, 1979, 206, 1148.
S. Fukuzumi, S. Koumitsu, K. Hironaka and T. Tanaka, J. Am. Chem. Soc.,
1987, 109, 305.
5
6
7
8
9
A. Singer and S.M. McElvain, Org. Synth., 1934, 14, 30.
P. Fister and R. Jürg, Synthesis, 1990, 8, 689.
J.J.V. Eynde, A. Mayence and A. Maquestiau, Tetrahedron, 1992, 48, 463.
B. Love and K.M. Snader, J. Org. Chem., 1965, 30, 1914.
J.J.V. Eynde, F. Delfosse, A. Mayence and Y.V. Haverbeke, Tetrahedron, 1995,
51, 6511.
1
10 S.H. Mashraqui and M.A. Karnik, Tetrahedron Lett., 1998, 39, 4895.
11 N. Nakamichi, Y. Kawashita and M. Hayashi, Org. Lett, 2002, 4, 3955.

144 JOURNAL OF CHEMICAL RESEARCH 2018
12 N. Nakamichi, H. Kawabata and M. Hayashi, J. Org. Chem., 2003, 68,
8272.
13 M.M. Heravi, F.K. Behbahani, H.A. Oskooie and R.H. Shoar, Tetrahedron
Lett, 2005, 46, 2775.
14 B. Han, Z. Liu, Q. Liu, L. Yang, Z.L. Liu and W. Yu, Tetrahedron, 2006,
62, 2492.
15 X. Fang, Y.-C. Liu and C. Li, J. Org. Chem., 2007, 72, 8608.
16 A. Saini, S. Kumar and J.S. Sandhu, J. Sci. Ind. Res. India, 2008, 67, 95.
17 P. Kumar, J. Heterocyclic. Chem., 2010, 47, 1429.
18 V. Anuradha, P.V. Srinivas, P. Aparna and J.M. Rao, Tetrahedron Lett.,
2006, 47, 4933.
19 N.A. Milas, Chem. Rev., 1932, 10, 295.
20 A. Pintér, A. Sud, D. Sureshkumar and M. Klussmann, Angew. Chem. Int.
Ed., 2010, 49, 5004.
21 W. Partenheimer, Adv. Synth. Catal., 2005, 347, 580.
22 K. Hayakawa, M. Yodo, S. Ohsuki and K. Kanemats, J. Am. Chem. Soc.,
1984, 106, 6735.
23 M. Goverdhan and P.N. Paras, Synthesis, 1975, 6, 404.
24 Z.Y. Chen and W. Zhang, Chin. Chem. Lett., 2007, 18, 1443.
25 O.D. Paolis, J. Baffoe, S.M. Landge and B. Török, Synthesis, 2008, 21,
3423.