An efficient transition-metal-chloride/sodium-nitrite/TEMPO catalytic system for aerobic oxidative aromatisation of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.3184/174751913X13701832537930

A facile and efficient transition-metal-chloride/sodium-nitrite/TEMPO catalytic system for aerobic oxidative aromatisation of Hantzsch 1,4-dihydropyridines in high yields under mild conditions is described.

Full text of DOI:10.3184/174751913X13701832537930

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 409
JULY, 409–412
An efficient transition-metal-chloride/sodium-nitrite/TEMPO
catalytic system for aerobic oxidative aromatisation of Hantzsch
1,4-dihydropyridines
Bin-Hui Lou, Shu-Bin Chen, Jian Wang, Ying Chen and Jing-Hua Li*
College of Pharmaceutical Sciences, Zhejiang University ofTechnology, 310032, Hangzhou, P. R. China
A facile and efficient transition-metal-chloride/sodium-nitrite/TEMPO catalytic system for aerobic oxidative aromati-
sation of Hantzsch 1,4-dihydropyridines in high yields under mild conditions is described.
Keywords: Hantzsch 1,4-dihydropyridines, aerobic oxidative aromatisation, transition metal chloride, sodium nitrite, TEMPO
Hantzsch ester 1,4-dihydropyridines (1,4-DHPs) as NADPH
coenzyme analogues have been used for the study of the
mechanism of the in vivo redox reaction.1 The oxidation
of 1,4-DHPs provided a facile access to their corresponding
pyridine derivatives, some of which show anti-hyperlipidemic,
anti-hyperglyacemic and anti-cancer activities.2,3
The methodology of oxidative aromatisation of 1,4-DHPs
had been investigated using different oxidants. Recently, syn-
thetic chemists have paid more attention to developing more
environmentally friendly syntheses, such as using graphite
oxide,4 9-phenyl-10-methylacridinium/O2,5 Fe(ClO4)3/O2,6
Co(OAc)2/O2,7 and activated charcoal/O2.8 In spite of the
potential utility of these reagents, most methods for the syn-
thesis of 1,4-DHPs and their subsequent aromatisation suffer
from drawbacks such as long reaction time,5 use of toxic
reagents7 and high temperature.4,8 Therefore, the development
of more effective methods for aromatisation of DHPs is still
required.
Reactions of DHPs with TEMPO or other N-oxides alone
need long reaction times and afford low yields.9–11 However,
there have been reports that the combination of TEMPO
and some metallic and non-metallic elements with variable
valency,12–14 suchasCu(I)/Cu(II), N(II)/N(V)andCl(I)/Cl(VII),
was a good catalytic system for many oxidations. A similar
system has been reported using FeCl3/NaNO2/TEMPO as a
catalyst for the aerobic oxidation of alcohols to aldehydes and
ketones.15 According to the facts mentioned above, we thought
that the Cu(I or II)/N(III orVI)/TEMPO catalytic system might
be effective in the oxidative aromatisation of 1,4-DHPs.
A preliminary experiment was carried out using diethyl 2,6-
dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate
(1a) as a model substrate with Cu(NO3)2/TEMPO as catalyst in
CH3CN/CH3COOH under an oxygen atmosphere (balloon).
A very low conversion rate was observed (Table 1, entry 1).
Then the oxidative aromatisation of 1a was carried out using
Cu(NO3)2/NaNO2/TEMPO and CuCl2/NaNO2/TEMPO instead
of Cu(NO3)2/TEMPO as a catalytic system (Table 1, entries 2
and 3). We were pleased to find that the reaction took place
smoothly. The success of this reaction prompted us to study
the catalytic system of multivalent metallic salt/NaNO2/
TEMPO. So, various multivalent inorganic metallic salts and
solvents were scanned in order to find a desired catalytic
system. During the screening of a variety of reaction solvents,
we found that CH3CN/CH3COOH or AcOEt/CH3COOH were
suitable for efficient conversion of 1,4-DHPs under an oxygen
atmosphere at ambient pressure and temperature. The results
are summarised in Table 1 and show that 1a is readily converted
into 2a (Scheme 1) in the presence of FeCl3, MnCl2, NiCl2,
CuCl2 and other copper salts (Table 1, entries 2–7, 9 and 15),
and addition of CH3COOH significantly accelerates the speed
of the reaction (Table 1, entries 15,16, 23 and 24). Apart from
copper salts, transition metal chlorides proved to be superior to
the corresponding nitrates and sulfates (Table 1, entries 7–10
and 13–15). Interestingly, the catalytic oxidation system runs
ineffectively in the absence of any one component of the
catalytic system (Table 1, entries 1, 2 and 25–27).
FeCl3 seems to be the superior metal salt as it is safe, cheap
and environmentally friendly, and CH3CN/CH3COOH are
preferred solvents because CH3CN dissolves some 1,4-DHPs
more easily than EtOAc. Therefore, a model aerobic oxidation
of Hantzsch 1,4-DHPs with FeCl3/NaNO2/TEMPO as the
catalytic system and CH3CN/CH3COOH as the solvent is
established.
In order to evaluate the scope and limitations of this reaction
system, different substrates were tested. The results are
summarised in Table 2 (Scheme 2).
As shown in Table 2, in most cases, many 1,4-DHPs can be
converted efficiently into the corresponding pyridine deriva-
tives with high yields at room temperature using oxygen as the
terminal oxidant. In some cases, replacement of FeCl3 by
CuCl2 significantly enhances the oxidation reactions (Table 2,
entries 2 and 7).
A possible mechanism for this catalytic system is presented
in Scheme 3, which is a sequential cascade of double-cycle
redox reactions.13,15 In the presence of a weak acid (HOAc),
TEMPO could convert 1,4-DHPs to its corresponding pyridines
and itself be reduced to TEMPOH.9 Then TEMPOH is oxidised
to TEMPO by M[ox.] (high-valent metal)/NO2−, and M[ox.]/
NO2− is reduced to M[red.] (low-valent metal)/NO, and
M[red.]/NO is re-oxidised to M[ox.]/NO2− by O2, wherein
NO2− is formed via rapid oxidation of NO with O2 in the
presence of a weak acid.
In conclusion, the oxidative aromatisation of substituted
Hantzsch 1,4-DHPs was achieved efficiently by using molecu-
lar oxygen as the terminal oxidant source with FeCl3/NaNO2/
TEMPO (in some cases, with CuCl2/NaNO2/TEMPO) as the
catalysts at room temperature. The addition of acetic acid can
greatly accelerate the speed of the reaction. In short, it is a
facile, convenient and high-yielding catalytic system.
Experimental
Commercially available reagents were used without further purifica-
tion unless mentioned. All reactions were monitored by TLC.
Visualisation of TLC plates was accomplished with an UV lamp.
The column chromatography was performed using silica gel (200–
300 mesh) with ethyl acetate/hexane as eluent. Melting points were
1
recorded on a X-4 micro melting point apparatus. H and 13C NMR
spectra were obtained in CDCl3 on a Bruker Spectrospin 500 MHz
spectrometer using tetramethylsilane (TMS) as internal standard.
All 1,4-dihydropyridines were synthesised according to literature
methods.5,16–18 All products were known and their physical and
spectroscopic data were compared with the literature.
Synthesis of compounds 2a-t; general procedure
1,4-DHPs (1 mmol, dissolved in 10 mL acetonitrile), TEMPO
(0.05 mmol), FeCl3·6H2O (0.05 mmol), NaNO2 (0.05 mmol) and
* Correspondent. E-mail: lijh@zjut.edu.cn

410 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Aromatisation of Hantzsch 1,4-dihydropyridines under different conditionsa
Entry
Metal salt
TEMPO/mol%
NaNO2/mol%
Solvent
Yield/%b
1
2
Cu(NO3)2
Cu(NO3)2
CuCl2
CuSO4
CuBr
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
/
/
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN
Trace
96
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
/
3
96
4
95
5
95
6
CuCl
97
7
MnCl2
MnSO4
NiCl2
Ni(SO4)2
CoCl2
CrCl3
97
8
19
9
95
10
11
12
13
14
15
16c
17
18
19
20
21
22
23
24
25
26
27
28d
29e
15
50
20
Fe2(SO4)3
Fe(NO3)3
FeCl3
26
40
97
FeCl3
92
FeCl3
CH2Cl2/CH3COOH (5:1)
EtOAc/CH3COOH (5:1)
CH3COOH
30
FeCl3
96
FeCl3
19
FeCl3
EtOAc/H2O/CH3COOH (2.5:2.5:1)
AcOH/H2O (1:1)
15
FeCl3
Trace
20
FeCl3
CH3CN/H2O/CH3COOH (2.5:2.5:1)
CH3CN/conc. HCl (5:1)
CH3CN/HCOOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (5:1)
CH3CN/CH3COOH (10:1)
FeCl3
36
40
FeCl3
FeCl3
Trace
Trace
Trace
85
FeCl3
5
5
5
5
/
5
5
5
FeCl3
FeCl3
97
a General procedure: 1a (0.5 mmol), metal salt (0.025 mmol), TEMPO (0.025 mmol), NaNO2 (0.025 mmol), solvent (6 mL) at room
temperature with an oxygen balloon for 1 h.
b Isolated yield.
c The reaction was completed in 10 h.
d 0.005 mmol FeCl3 was used.
e CH3CN (5ml) and CH3COOH (0.5 mL) were used.
Scheme 1 The oxidative aromatisation of 1a.
CH3COOH (1 mL) were added successively to a 25 mL three-necked
round-bottom flask equipped with a magnetic stirrer and a thermom-
eter. The resulting mixture was stirred at room temperature and ambi-
ent pressure with an oxygen balloon until the reaction was completed
as monitored by TLC (5:1 ethyl acetate/petroleum ether as eluent).
Saturated aqueous NaHCO3 solution was added to make it neutral.
The mixture was extracted with ethyl acetate three times. The
combined organic extracts were washed with saturated aqueous
NaCl solution, dried over MgSO4 and filtered. After removal of the
solvent under reduced pressure, the residue was purified by column
chromatography (10:1 ethyl acetate/petroleum ether as eluent).
Diethyl 4-phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate (2a): Pale
Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
1
(2d): Pale yellow solid, m.p. 64–65 °C (lit.7 65–66 °C). H NMR
(500 MHz, CDCl3): δ 7.36 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H),
4.04 (q, J = 7 Hz, 2H), 2.60 (s, 3H), 0.98 (t, J = 7 Hz, 3H).
Diethyl 4-(4-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
(2e): Pale yellow solid, m.p. 113–114 °C (lit.20 114–115 °C). 1H NMR
(500 MHz, CDCl3): δ 8.26 (d, J = 9 Hz, 2H), 7.46 (d, J = 9 Hz, 2H),
4.04 (q, J = 7 Hz, 4H), 2.63 (s, 6H), 0.98 (t, J = 7 Hz, 6H).
Diethyl 4-(3-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
1
(2f): Pale yellow oil (lit.20 62–63 °C). H NMR (500 MHz, CDCl3):
δ 8.27–8.25 (m, 1H), 8.19–8.18 (m, 1H), 7.62–7.58 (m, 2H), 4.05 (q,
J = 7 Hz, 4H), 2.63 (s, 6H), 1.00 (t, J = 7 Hz, 6H).
Dimethyl 2,6-dimethyl-3,5-pyridinedicarboxylate (2g): Pale yellow
solid, m.p. 99–100 °C (lit.21 99–100 °C). 1H NMR (500 MHz, CDCl3):
δ 8.71 (s, 1H), 3.94 (s, 6H), 2.86 (s, 6H).
1
yellow solid, m.p. 60–61 °C (lit.7 61–62 °C). H NMR (500 MHz,
CDCl3): δ 7.38–7.36 (m, 3H), 7.27–7.25 (m, 2H), 4.01 (q, J = 7 Hz,
4H), 2.62 (s, 6H), 0.91 (t, J = 7 Hz, 6H).
Diethyl 2,6-dimethyl-3,5-pyridinedicarboxylate (2b): Pale yellow
Dimethyl 2,4,6-trimethyl-3,5-pyridinedicarboxylate (2h): Pale
1
1
solid, m.p. 69–70 °C (lit.19 69–70 °C). H NMR (500 MHz, CDCl3):
yellow solid, m.p. 76–77 °C (lit.22 78–80 °C). H NMR (500 MHz,
δ 8.68 (s, 1H), 4.41 (q, J = 7 Hz, 4H), 2.86 (s, 6H), 1.42 (t, J = 7 Hz,
6H).
Diethyl 4-(2-furyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (2c):
Pale yellow oil (lit.20 oil). 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J =
2 Hz, 1H), 6.62 (d, J = 3 Hz, 1H), 6.48 (dd, J = 3 Hz, 2 Hz, 1H), 4.28
(q, J = 7 Hz, 4H), 2.58 (s, 6H), 1.23 (t, J = 7 Hz, 6H).
CDCl3): δ 3.94 (s, 6H), 2.52 (s, 6H), 2.26 (s, 3H).
Dimethyl 4-propyl-2,6-dimethyl-3,5-pyridinedicarboxylate (2i):
Pale yellow oil (lit.23 oil). 1H NMR (500 MHz, CDCl3): δ 3.91 (s, 6H),
2.53–2.48 (m, 8H), 1.55–1.50 (m, 2H), 0.91 (t, J = 7 Hz, 3H).
Dimethyl 4-phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate (2j):
White solid, m.p. 133–134 °C (lit.21 134–136 °C). 1H NMR (500 MHz,

JOURNAL OF CHEMICAL RESEARCH 2013 411
Table 2 Aromatisation of Hantzsch 1,4-dihydropyridines by transition metal chloride/sodium nitrite/TEMPO systema
Entry
Substrate
R1
R2
R3
Time/min
Product
Yield/%b
1
2c
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
OEt
OEt
OEt
OEt
Ph
H
30
30
30
30
50
40
30
30
40
30
30
30
30
50
40
30
40
30
50
45
60
60
60
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
97
97(40)
96
3
OEt
OEt
2-Furyl
4
OEt
OEt
p-ClC6H4
p-NO2C6H4
m-NO2C6H4
H
98
5
OEt
OEt
95
98
6
OEt
OEt
7c
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
98(35)
98
8
9
Me
n-Pr
96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
96
2-Furyl
94
p-ClC6H4
p-NO2C6H4
m-NO2C6H4
p-PhC4H6
3,4-(OCH3)2C6H4
3,4-(CH2O2)C6H3
Ph
98
98
98
97
97
93
98
1s
1t
3a
3b
3c
OEt
OEt
p-NO2C6H4
m-NO2C6H4
Ph
p-ClC6H4
m-NO2C6H4
2s
2t
4a
4b
4c
96
97
92
OEt
OEt
95
90
a The reaction conditions were as follows: substrate (1 mmol), FeCl3 (0.05 mmol), TEMPO (0.05mmol), NaNO2 (0.05 mmol), CH3CN
(10 mL), CH3COOH (1 mL) at Room temperature with an oxygen balloon for appropriate time.
b Isolated yield.
c The number on the outside of the parentheses is the isolated yield of the product with CuCl2 as catalyst, and the one on the inside
of the parentheses with FeCl3 as catalyst.
Scheme 2 The oxidative aromatisation of many 1,4-DHPs.
Scheme 3 Proposed reaction mechanism.
CDCl3): δ 7.39–7.37 (m, 3H), 7.25–7.23 (m, 2H), 3.54 (s, 6H), 2.61 (s,
6H).
Dimethyl 4-(2-furyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (2k):
Pale yellow solid, m.p. 60–61 °C (lit.21 60–62 °C). 1H NMR
(500 MHz, CDCl3): δ 7.51 (d, J = 2 Hz, 1H), 6.61 (d, J = 3 Hz, 1H),
6.49 (dd, J = 3Hz, 2 Hz, 1H), 3.82 (s, 6H), 2.57 (s, 6H).
Dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
(2l): Pale yellow solid, m.p. 138–140 °C (lit.24 137–139 °C). 1H NMR
(500 MHz, CDCl3): δ 7.37 (d, J = 8 Hz, 2H), 7.19 (d, J = 8 Hz, 2H),
3.58 (s, 3H), 2.60 (s, 3H).
Dimethyl 4-(4-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
(2m): Yellow solid, m.p. 147–148 °C (lit.24 148 °C). 1H NMR

412 JOURNAL OF CHEMICAL RESEARCH 2013
(500 MHz, CDCl3): δ 8.27 (d, J = 9 Hz, 2H), 7.44 (d, J = 9 Hz, 2H),
3.57 (s, 6H), 2.64 (s, 6H).
151–152 °C). 1H NMR (500 MHz, CDCl3): δ 7.35 (d, J = 8 Hz, 2H),
7.08 (d, J = 8 Hz, 2H), 4.01 (q, J = 7 Hz, 2H), 3.21 (t, J = 6 Hz, 2H),
2.63–2.60 (m, 5H), 2.21–2.16 (m, 2H), 0.99 (t, J = 7 Hz, 3H).
Ethyl 4-(3-nitrophenyl)-2-methyl-5-oxo-5,6,7,8-tetrahydroquino-
line-3-carboxylate (4c): Pale yellow solid, m.p. 134–135 °C (lit.5
123–124 °C). 1H NMR (500 MHz, CDCl3): δ 8.26–8.24 (m,1H), 8.03
(t, J = 2 Hz, 1H), 7.58–7.47 (m, 2H), 4.00 (q, J = 7 Hz, 2H), 3.24 (m,
2H), 2.64–2.61 (m, 5H), 2.23–2.18 (m, 2H), 0.97 (t, J = 7 Hz, 3H).
Dimethyl 4-(3-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
1
(2n): Pale yellow solid, m.p. 121–122 °C (lit.25 121 °C). H NMR
(500 MHz, CDCl3): δ 8.28–8.26 (m, 1H), 8.17–8.16 (m, 1H),
7.60–7.59 (m, 2H), 3.60 (s, 6H), 2.63 (s, 6H).
Dimethyl 4-(4-biphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate
1
(2o): Yellow solid, m.p. 143–145 °C (lit.26 143–145 °C). H NMR
(500 MHz, CDCl3): δ 7.65–7.63 (m, 4H), 7.49–7.32 (m, 5H), 3.58
(s, 6H), 2.62 (s, 6H).
Received 20 February 2013; accepted 13 April 2013
Paper 1301803 doi: 10.3184/174751913X13701832537930
Published online: 18 July 2013
Dimethyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-3,5-pyridinedicar-
boxylate (2p): Pale yellow solid, m.p. 124–125 °C (lit.27 129–130 °C).
1H NMR (500 MHz, CDCl3): δ 6.88 (d, J = 8 Hz, 1H), 6.84–6.81
(m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.61 (s, 6H), 2.59 (s, 6H).
Dimethyl 4-(3,4-methylenedioxyphenyl)-2,6-dimethyl-3,5-pyridin-
edicarboxylate (2q): Pale yellow solid, m.p. 122–123 °C (lit.27 121–
122 °C), 1H NMR (500 MHz, CDCl3): δ 6.82 (d, J = 8 Hz, 1H), 6.75
(d, J = 2 Hz, 1H), 6.71 (dd, J = 8 Hz, 2 Hz, 1H), 6.01 (s, 2H), 3.64
(s, 6H), 2.58 (s, 6H).
References
1
2
3
4
F.P. Guengerich, W.R. Brian, M. Iwasaki, M.A. Sari, et al. J. Med. Chem.,
1991, 34, 1838.
W. Wang, P. Devasthale, A.Y. Wang, et al. Bioorg. Med. Chem. Lett., 2011,
21, 6646.
L. Vincent, C. Soria, F. Mirshahi, P. et al. Arterioscl. Throm. Vas., 2002, 22,
623.
M. Mirza-Aghayan, R. Boukherroub, M. Nemati and M. Rahimifard,
Tetrahedron Lett., 2012, 53, 2473.
3-Ethyl 5-methyl 4-phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate
1
(2r): Yellow solid, m.p. 64–65 °C. (lit.28 63.5–64.5 °C), H NMR
(500 MHz, CDCl3): δ 7.38–7.37 (m, 3H), 7.26–7.24 (m, 2H), 4.01
(q, J = 7 Hz, 2H), 3.53 (s, 3H), 2.62 (s, 3H), 2.60 (s, 3H), 0.91 (t,
J = 7 Hz, 3H).
5
6
X.Q. Fang, Y.C. Liu and C.Z. Li, J. Org. Chem., 2007, 72, 8608.
M.M. Heravi, F.K. Behbahani, H.A. Oskooie and R.H. Shoar, Tetrahedron
Lett., 2005, 46, 2775.
3-Ethyl 5-methyl 4-(4-nitrophenyl)-2,6-dimethyl-3,5-pyridinedi-
carboxylate (2s):29 Pale yellow solid, m.p. 98–99 °C. 1H NMR
(500 MHz, CDCl3): δ 8.27–8.26 (m, 2H), 7.46–7.44 (m, 2H), 4.04 (q,
J = 7 Hz, 2H), 3.57 (s, 3H), 2.64 (s, 3H), 2.63 (s, 3H), 0.99 (t, J =
7 Hz, 3H). 13C NMR (500 MHz, CDCl3): δ 167.66, 167.13, 156.32,
156.20, 147.86, 144.05, 143.27, 129.29, 126.22, 126.05, 123.28,
61.67, 52.40, 23.13, 13.70. HRMS m/z calcd for C18H18N2O6: 358.1165,
found 358.1183.
3-Ethyl 5-methyl 4-(3-nitrophenyl)-2,6-dimethyl-3,5-pyridinedi-
carboxylate (2t): Pale yellow oil (lit.30 59–61 °C). 1H NMR (500 MHz,
CDCl3): δ 8.26–8.15 (m, 2H), 7.59–7.58 (m, 2H), 4.05 (q, J = 7 Hz,
2H), 3.58 (s, 3H), 2.62 (s, 3H), 2.61 (s, 3H), 0.99 (t, J = 7 Hz, 3H).
7
B. Han, Z.G. Liu, Q. Liu, L. Yang, Z.L. Liu and W. Yu, Tetrahedron, 2006,
62, 2492.
8
9
N. Nakamichi, Y. Kawashita and M. Hayashi, Synthesis, 2004, 7, 1015.
M. Lu, J.G. Fang, Z.L. Liu and L.M. Wu, Chinese Chem. Lett., 2002, 13,
923.
10 Y.Z. Mao, M.Z. Jin, Z.L. Liu and L.M. Wu, Org. Lett., 2000, 2, 741.
11 L.J. Peng, J.T. Wan, Z. Lu, Z.Q. Liu and L.M. Wu, Tetrahedron Lett., 2008,
49, 1586.
12 M.J. Schultz and M.S. Sigman, Tetrahedron, 2006, 62, 8227.
13 S.M. Ma, J.X. Liu, S.H. Li, et al. Chem. Eur. J., 2008, 14, 2679.
15 N.W. Wang, R.H. Liu, J.P. Chen and X.M. Liang, Chem. Commun., 2005,
41, 5322.
16 S.K. Ko, M.N.V. Sastry, C.C. Lin and C.F.Yao, Tetrahedron Lett., 2005, 46,
5771.
Synthesis of compounds 4a-c; general procedure
17 M. Suarez, M. Armas, O. Ramírez, et al. New J. Chem., 2005, 29, 1567.
1,4-DHPs (1 mmol, dissolved in 10 mL acetonitrile), TEMPO
(0.05 mmol), FeCl3·6H2O (0.05 mmol), NaNO2 (0.05 mmol) and
CH3COOH (1 mL) were successively added to a 25 mL three-necked
round-bottom flask equipped with a magnetic stirrer and a thermom-
eter The resulting mixture was stirred at room temperature and ambi-
ent pressure with an oxygen balloon until the reaction was completed
as monitored by TLC (3:1 ethyl acetate/petroleum ether as eluent).
Saturated aqueous NaHCO3 solution was added to make it neutral.
The mixture was extracted with ethyl acetate three times. The com-
bined organic extracts were washed with saturated aqueous NaCl
solution, dried over MgSO4 and filtered. After removal of the solvent
under reduced pressure, the crude product was recrystallised with
alcohol.
18 A. Ghorbani-Choghamarani, M.A. Zolfigol, P. et al. Acta Chim. Slov.,
2008, 55, 644.
19 A. Kumar, R.A. Maurya and S. Sharma, Bioorg. Med. Chem. Lett., 2009,
19, 4432.
20 J. Lu, Y.J. Bai, Z.J. Wang, B.Q. Yang and W.H. Li, Synth. Commun., 2001,
31, 2625.
21 M. Filipan-Litvic, M. Litvic, I. Cepanec and V. Vinkovic, ARKIVOC, 2008,
xi, 96.
22 A. Ghorbani-Choghamarani and J. Zeinivand, Synth. Commun., 2010, 40,
2457.
23 J.J. Xia and G.W. Wang, Synthesis, 2005, 14, 2379.
24 S.P. Chavan, R.K. Kharul, U.R. Kalkote, et al, Synth. Commun., 2003, 33,
1333.
25 M.M. Awachat, A.C. Shaikh, N.V. Ganjave, et al. J. Chem. Res., 2007, 4,
193.
Ethyl 4-phenyl-2-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-car-
boxylate (4a): Pale yellow solid, m.p. 95–96 °C (lit.5 93–94 °C).
1H NMR (500 MHz, CDCl3): δ 7.37–7.36 (m, 3H), 7.15–7.13 (m, 2H),
3.96 (q, J = 7 Hz, 2H), 3.21 (t, J = 6 Hz, 2H), 2.63–2.60 (m, 5H),
2.21–2.16 (m, 2H), 0.93 (t, J = 7 Hz, 3H).
26 M. Filipan-Litvić, M. Litvić and V. Vinković, Tetrahedron, 2008, 64,
5649.
27 H. Iwamoto, M. Satoh, N. Nagano, T. Kolde and H. Lkadai, Eur. Pat. Appl.
1988, EP 0285267(A2).
28 F.P. Guengerich, J. Biol. Chem.,1987, 262, 8459.
29 E. Baloglu and G. Ertan, Pharm. Sci., 1995, 1, 115.
30 J.R. Pfister, Synthesis, 1990, 8, 689.
Ethyl 4-(4-chlorophenyl)-2-methyl-5-oxo-5,6,7,8-tetrahydroquino-
line-3-carboxylate (4b): Pale yellow solid, m.p. 149–150 °C (lit.4