Microwave-assisted four-component, one-pot condensation reaction: An efficient synthesis of annulated pyridines

Article abstract of DOI:10.1039/b617256c

A one-pot, effective synthesis of pyridines by a modified Kroehnke procedure is described. Polysubstituted annulated pyridines were synthesized in high yields by four-component, one-pot cyclocondensation reactions of N-phenacylpyridinium bromide, aromatic

Full text of DOI:10.1039/b617256c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Microwave-assisted four-component, one-pot condensation reaction: an
efficient synthesis of annulated pyridines
Chao-Guo Yan,* Xi-Mei Cai, Qi-Fang Wang, Ting-Yu Wang and Ming Zheng
Received 27th November 2006, Accepted 8th January 2007
First published as an Advance Article on the web 30th January 2007
DOI: 10.1039/b617256c
A one-pot, effective synthesis of pyridines by a modified Kro¨hnke procedure is described.
Polysubstituted annulated pyridines were synthesized in high yields by four-component, one-pot
cyclocondensation reactions of N-phenacylpyridinium bromide, aromatic aldehydes, acetophenones or
cyclic ketones in the presence of ammonium acetate and acetic acid, assisted by microwave irradiation.
In this procedure, cyclic ketones with two a-CH2 groups yield annulated pyridines with additional
a-benzylidene groups, which are derived in situ from double aldol condensation of cyclic ketones with
two moles of aromatic aldehydes.
(MCRs), which offer significant advantages and are increasingly
important in organic and medicinal chemistry. Herein we wish to
describe a simple but effective modification of the Kro¨hnke syn-
thesis of pyridines in one-pot reactions of N-phenacylpyridinium
Introduction
The pyridyl heterocyclic core is a widespread sub-unit in numerous
natural products1,2 and a versatile ligand in coordination and
supramolecular structures,3,4 which consequently provides a strong
bromide with aromatic aldehydes and cyclic ketones under
incentive for their synthesis. For a number of years polysubstituted
microwave irradiation to give annulated pyridine derivatives.
pyridines (or Kro¨hnke pyridines) have been synthesized using
an enormous number of preparative approaches such as: [5 +
Results and discussion
1]-type Hantzsch synthesis from a 1,5-diketone and a nitrogen
derivative;5,6 [2 + 2 + 2]-type cobalt-catalyzed cyclization of
The typical Kro¨hnke synthesis of pyridines is readily achieved
substituted acetylenes and nitriles;7 [3 + 3]-type cyclization of chal-
by heating a,b-unsaturated ketones and pyridinium salts in the
cones and iminophosphoranes8; [4 + 2] reactions of unsaturated
presences of a mixture of ammonium acetate and acetic acid
imines with enolates;9 and [3 + 2 + 1]-type cyclization of a,b-
unsaturated compounds with a-substituted ketones and a nitrogen
source.10 Among these approaches, the [3 + 2 + 1]-type is that
most frequently employed.11 The efficiency of such pyridine ring
closures depends on the nature of the a-substituted group in the
ketone moiety, which acts as a leaving group in the aromatization
process. The two-step Kro¨hnke synthesis12–14 via condensation of
a,b-unsaturated ketones with pyridinium salts in the presence of
a mixture of ammonium acetate and acetic acid gives a variety
of polysubstituted pyridines and has distinct advantages over the
other routes.
Due to the aromatic character of the pyridine heterocycle, its
basicity, and the electron-attracting influence of the nitrogen atom,
pyridinium cations can behave as nucleophiles and 1,3-dipoles and
show a great variety of synthetic uses, such as in the reaction
with alkenes substituted with electron-withdrawing groups.15–18
Pyridinium cations with stronger electron-withdrawing carbonyl,
cyano and nitro groups increase the activity of the methylene group
and have much more versatile applications. N-Phenacylpyridinium
bromide in the presence of a base is known to undergo, for
example, Knoevenagel condensation with aldehydes,19,20 Michael
addition to a, b-unsaturated carbonyl compounds21,22 and dipolar
cycloaddition with activated alkenes.23 Therefore, it is worthwhile
investigating new types of reactions and synthetic applications
of this kind of salt with emphasis on multicomponent reactions
for several hours.14,24–26 However, the pyridinium salts and the
unsaturated ketones have to be synthesized first, so this method is
relatively expensive. It is generally recognized that chalcones are
easily formed from the condensation of aromatic aldehydes with
acetophenone under mild basic conditions, and in fact there have
been several studies27–30 reporting the aldol condensation under
microwave irradiation with little or no solvent in the presence
of either an acidic or basic catalyst. Microwave irradiation is
very attractive for chemical applications and has become a
widely accepted non-conventional energy source for performing
organic synthesis.31,32 Compared with classical heating, microwave-
assisted organic synthesis is characterized by spectacular acceler-
ation, higher yields, milder reaction conditions and shorter reac-
tion times as well as allowing syntheses to become environmentally
benign, improving many processes.33–35 We hypothesized that
aromatic aldehydes could react with acetophenone to give chal-
cones in situ by the microwave irradiation procedure described
above, and then react with pyridinium salts to accomplish
the Kro¨hnke synthesis of 2,4,6-triarylpyridines. So, N-phenacyl-
pyridinium bromide 1 was used in the reaction with an equivalent
molar ratio of aromatic aldehydes 2 and acetophenones 3 in a
mixture of ammonium acetate and acetic acid (Scheme 1).
Under microwave irradiation, the five-component mixture re-
acted smoothly to give 2,4,6-triarylpyridines 4a–d in high yield
(84–92%).31 Here, the formation of 2,4,6-triarylpyridine is a typical
multicomponent domino reaction. The aromatic aldehyde first
reacts with acetophenone to form an a,b-unsaturated ketone,
which in turn reacts with N-phenacylpyridinium bromide to give a
College of Chemistry & Chemical Engineering, Yangzhou University,
Yangzhou, 225002, China. E-mail: cgyan@yzu.edu.cn
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Scheme 1 One-pot synthesis of 2,4,6-triarylpyridines.
1,5-diketone derivative, which is cyclized with ammonia and finally
eliminates the pyridinium cation to form the triarylpyridine. So,
a two-step Kro¨hnke synthesis of pyridines can be combined in
a one-pot reaction, and this method allows the introduction of
various substituted aryl groups into the 2-, 4- and 6-positions of
pyridine.
With the initial success of this reaction, we set out to determine
the scope and variability of the procedure. A variety of cyclic
ketones was used to replace the acetophenone in order to
prepare the annulated pyridine derivatives. Under the above-
mentioned microwave irradiation conditions, cyclohexanone
reacted smoothly and gave the 5,6,7,8-tetrahydroquinolines
with an additional 8-benzylidene group as the products 6a–f
(Scheme 2). Compounds 6a–f clearly result from the reaction of
the initially formed 2,6-bis(benzylidene)cyclohexanone, which is
derived in situ from a double aldol condensation of cyclohexanone
with two moles of aromatic aldehyde. Using a 1 : 1 molar ratio
of aromatic aldehyde to cyclohexanone still gives these products
but in lower yields. Cyclopentanone and cycloheptanone react
similarly to give the five- and seven- membered alicyclic fused
pyridines with an additional benzylidene group 6g–j and 6k,
respectively. It is worth mentioning that under microwave irradia-
tion, all aromatic aldehydes, even those bearing electron-donating
methyl or methoxy groups, form pyridine derivatives in high
yields. 1-Tetralone reacted with one mole of aromatic aldehyde to
form 2-benzylidene-1-tetralone. When this compound is used in
the above reaction, the expected 5,6-dihydrobenzo[h]quinolines
7a–f (Fig. 1) were formed in 75–90% yield.
Fig. 1 1,2-Diaryl-5,6-dihydrobenzo[h]quinolines 7a–f.
1
be obtained with high purity, which give very good H and 13C
NMR spectra. Because there are at least three substituted phenyl
groups in each compound and these show very complicated mixed
signals in the aromatic region, it is very difficult to elucidate each
proton and carbon atom. In order to compare the results of the
classical heating with that of microwave heating, we also conducted
some reactions using classical heating methods. For example,
triarylpyridine 4b and fused pyridine 6a were prepared in 78%
and 84% yields by heating a mixture of five reaction components
at 90 ◦C for three hours. Similar yields were obtained by the
two heating methods, but the microwave heating needs shorter
reaction times and is therefore more convenient. The structures
of the fused pyridines were further confirmed by X-ray crystal
analysis of two representative compounds, 6b and 7b (Fig. 2,
Fig. 3 and Table 1). In 6b, the phenyl and 4-methylphenyl groups
at the 2- and 4-positions of the pyridine ring are twisted out of
the plane of the pyridine ring. In the fused cyclic six-membered
ring, which also has a 4-methylbenzyl group attached, there are
Scheme 2 One-pot synthesis of annulated pyridines.
The structures of the polysubstituted and annulated pyridines
1
were characterized by IR, H and 13C NMR spectroscopy, and
HPLC-MS analysis. It should be mentioned that the reaction
under microwave irradiation is very clean, and very small amounts
of by-products were detected. Therefore, the work-up procedure
involves only a simple filtration of the precipitate followed by
crystallization with alcohol. In all instances the products can
Fig. 2 Molecular structure of compound 6b. Hydrogen atoms are omitted
for clarity.
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Table 1 Crystal data of compounds 6b and 7b. CCDC reference numbers 618866 (6b) and 628794 (7b). For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b617256c
6b
7b
Empirical formula
Formula weight
C30H27N
401.53
Triclinic, P1
10.0240(17)
10.7729(18)
11.1615(19)
89.328(2)
1117.1(3)
C52H42N2
694.88
Triclinic, P1
10.7313(14)
10.8332(14)
17.189(2)
101.774(2)
1925.0(4)
¯
¯
Crystal system, space group
˚
a/A
˚
b/A
˚
c/A
b/◦
Volume/A
3
˚
Z
2
2
Calculated density/g cm−3
Absorption coefficient/mm−1
F(000)
1.194
0.068
428
1.199
0.069
736
Crystal size/mm
0.32 × 0.20 × 0.08
0.40 × 0.20 × 0.20
h Range for data collection/◦
Limiting indices
2.02–25.00
2.20 to 25.00
−11 ≤ h ≤ 11, −12 ≤ k ≤ 11, −13 ≤ l ≤ 12
5834/3867 [Rint = 0.0183]
98.4
−7 ≤ h ≤ 12, −12 ≤ k ≤ 12, −20 ≤ l ≤ 20
10008/6674 [Rint = 0.0193]
98.2
Reflections collected/unique
Completeness (%)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2rI]
R indices (all data)
Full-matrix least-squares on F2
3867/0/282
Full-matrix least-squares on F2
6674/0/494
1.050
1.001
R1 = 0.0487, wR2 = 0.1207
R1 = 0.0761, wR2 = 0.1358
0.181 and −0.177
R1 = 0.0619, wR2 = 0.1548
R1 = 0.1110, wR2 = 0.1796
0.621 and −0.142
−3
˚
Largest difference peak and hole/e A
membered ring in the 5,6-dihydrobenzo[h]quinoline core is also in
a screw-boat conformation.
With the assistance of microwave irradiation, a two-step
Kro¨hnke synthesis of pyridines is performed in a one-pot re-
action. The reaction proceeds as follows: aromatic aldehydes
react firstly with cyclic ketones to form doubly a,b-unsaturated
ketones (2-methylcyclohexanone and 1-tetralone could only give
mono-a,b-unsaturated ketones), which in turn react with N-
phenacylpyridinium bromide to give 1,5-diketone derivatives.
The latter is then cyclized with ammonia and finally eliminates
pyridinium cations to form annulated pyridines (Scheme 3).
Fig. 3 Molecular structure of compound 7b.
Scheme 3 The mechanism of formation of annulated pyridines.
three carbon atoms with sp3 hybridization and three carbon atoms
having sp2 hybridization, and so the whole ring is best described
as having a screw-boat conformation. The asymmetric unit of
compound 7b contains two independent molecules with slightly
different conformations (Fig. 3). In each molecule of 7b, the
5,6-dihydrobenzo[h]quinoline core has a phenyl group at the 2-
position, which has come from N-phenacylpyridinium chloride,
and a 4-methyphenyl group at the 4-position, which has clearly
come from 4-methylbenzaldehyde. The central fused cyclic six-
Conclusion
In conclusion, we have described a simple and efficient one-pot
procedure for the generation of polysubstituted or annulated
pyridines with microwave assistance. The advantages of this
approach are as follows: the reaction procedure is convenient,
involves simple experimental procedures and product isolation,
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and thus dispenses with extensive recrystallization or chromato-
graphic purification steps. Hence it is a useful modification and
addition to the existing methods. It is a four-component reaction
which allows the construction of relatively complicated nitrogen-
containing heterocyclic systems using simple starting materials.
The introduction of various substituted alkyl and aryl groups into
the 2-, 4- and 6-positions of pyridine is very easy. Further studies
aiming to extend the synthetic scope of this reaction, especially
using other N-substituted pyridinium salts, are currently under
way.
2H, 2C6H5), 7.63–7.53 (m, 6H, 2C6H5), 7.16–7.14(d, J = 8.4 Hz,
2H, 2C6H5), 3.98 (s, 3H, CH3). 13C NMR (600 MHz, CDCl3)
d 160.6, 157.4, 149.8, 139.6, 131.2, 129.0, 128.7, 128.4, 127.2,
116.7, 114.6, 55.4. IR (KBr) t 3016(w), 2957(w), 2931(w), 1596(s),
1514(s), 1291(s), 1257(s), 1178(s), 1030(s), 840(s) cm−1. Anal. calc.
for C24H19NO: C 85.43, H 5.68, N 4.15; found. C 85.22, H 5.33, N
3.81.
4d: 2-Phenyl-4-p-chlorophenyl-6-m-nitrophenylpyridine. 63%.
Mp 168–170 ◦C. 1H NMR (600 MHz, CDCl3) d 9.00, 8.55,
8.29 (s, br, s br, 3H, m-NO2C6H4), 8.17 (d, 2H, J = 7.8 Hz,
p-ClC6H4), 7.90, 7.87 (s, s, 2H, 3,5-PyH), 7.67–7.69 (m, 3H,
m-NO2C6H4, p-ClC6H4), 7.64–7.55 (m, 5H, C6H5). 13C NMR
(600 MHz, CDCl3) d 158.1, 154.9, 149.7, 148.8, 140.8, 140.8, 138.5,
136.8, 135.7, 133.1, 129.9, 129.7, 129.6, 129.5, 129.4, 128.9, 128.5,
127.2, 123.9, 122.0, 118.0, 117.0. IR (KBr) t 3074(w), 1659(w),
1601(s), 1521(s), 1493(m), 1087(m), 828(m), 770(m) cm−1. Anal.
calc. for C23H15ClN2O2: C 71.41, H 3.91, N 7.24; found. C 71.36,
H 4.17, N 7.11.
Experimental
Material and apparatus
Melting points were recorded on a hot-plate microscope appara-
tus. IR spectra were obtained on a Bruker Tensor 27 spectrometer
(KBr disc). 1H NMR spectra were recorded with a Bruker AV-600
spectrometer with CDCl3 as solvent and TMS as internal standard.
HPLC-MS spectra were measured using a Fennigan LCQ Deca
XPMAXinstrument. Pyridine, aromaticaldehydes, cyclicketones,
1-tetralone and other reagents are commercial reagents and were
used as received. Solvents were purified by standard techniques.
N-Phenacylpyridinium bromide was prepared according to the
published method.23 The progress of reaction was monitored by
TLC.
General procedure for the preparation of annulated pyridines
To a 50 mL flask was added N-phenacylpyridinium bromide
(1.2 mmol, 0.280 g), aromatic aldehyde (2.0 mmol), cyclic ketone
(1.0 mmol), ammonium acetate (3.0 g) and acetic acid (2.0 mL).
The mixture was heated in a microwave for about 2–4 minutes
(130 W). After cooling, the reaction mixture was diluted with water
(50 mL) and the resulting precipitate was collected by filtration.
The crude product was recrystallized from ethanol to give the pure
solid sample for analysis.
General procedure for the preparation of 2,4,6-triarylpyridines
To a 50 mL flask was added N-phenacylpyridinium bromide
(1.2 mmol, 0.280 g), aromatic aldehyde (1.0 mmol), aromatic
ketone (1.0 mmol), ammonium acetate (3.0 g) and acetic acid
(2.0 mL). The mixture was heated in a microwave for about 3–
4 minutes (130 W). After cooling, the reaction mixture was diluted
with water (50 mL) and the resulting precipitate was collected by
filtration. The crude product was recrystallized from ethanol to
give the pure solid sample for analysis.
◦
1
6a. 74%. Mp 140.0–142.0 C. H NMR (600 MHz, CDCl3)
d 8.14 (d, J = 7.2 Hz, 1H, PhH), 7.74 (s, 1H, PyH), 7.60 (s, 3H,
PhH), 7.56 (d, 2H, J = 7.2 Hz, PhH), 7.50 (s, 3H, PhH), 7.45–7.41
(m, 5H, PhH, CH ), 3.21 (s, 4H, CH2). 13C NMR (600 MHz,
=
CDCl3) d 161.5, 157.2, 146.9, 141.6, 139.8, 138.8, 138.0, 137.9,
136.9, 135.2, 129.2, 129.1, 128.8, 128.6, 128.5, 128.5, 128.4, 128.2,
128.0, 127.1, 126.9, 126.7, 122.8, 122.0, 119.3, 29.4, 29.2, 28.2,
27.73. IR (KBr) t 3053(w), 2942(w), 1950(w), 1577(m), 1535(m),
1373(m), 1149(w), 920(w), 763(s) cm−1; MS: 359.67. Anal. calc. for
C27H21N: C 90.22, H 5.89, N 3.89; found. C 89.79, H 5.71, N 3.75.
4a: 2,6-Diphenyl-4-p-methylphenylpyridine. 53%. Mp 116–
118 ◦C. 1H NMR (600 MHz, CDCl3) d 8.31 (d, J = 7.2 Hz, 4H,
MeC6H4), 7.98 (s, 2H, 3,5-PyH), 7.76 (d, J = 8.4 Hz, 2H, ArH),
7.42–7.63 (m, 8H, ArH), 2.54 (s, 3H, CH3). 13C NMR (600 MHz,
CDCl3) d 157.5, 150.2, 139.6, 139.1, 136.1, 129.8, 129.0, 128.7,
127.2, 127.0, 117.0, 21.2. IR (KBr) t 3033(w), 2916(w), 1579(s),
1544(s), 1390(m), 1026(w), 814(s), 770(s) cm−1. Anal. calc. for
C24H19N: C 89.68, H 5.96, N 4.36; found. C 89.50, H 5.62, N 4.28.
◦
1
6b. 75%. Mp 114.5–146.0 C. H NMR (600 MHz, CDCl3)
d 8.15 (d, 2H, J = 7.8 Hz, PhH), 7.74 (s, 1H, PyH), 7.60 (s, 1H,
ArH), 7.53–7.49 (m, 5H, ArH), 7.46–7.43 (t, 1H, PhH), 7.33 (d,
=
2H, J = 7.8 Hz, PhH), 7.28 (s, 1H, CH ), 7.24 (d, 2H, J = 7.8 Hz,
ArH), 3.22 (s, 4H, CH2), 2.46 (s, 3H, CH3), 2.41 (s, 3H, CH3). 13
C
4b: 2-Phenyl-4-p-chlorophenyl-6-p-methylphenylpyridine. 58%.
◦
1
NMR (600 MHz, CDCl3) d 139.3, 133.5, 133.2, 132.0, 130.2, 129.7,
129.5, 129.4, 129.2, 129.2, 128.8, 128.7, 128.5, 128.3, 128.2, 128.1,
128.0, 127.2, 127.1, 126.9, 126.1, 29.2, 28.3, 21.3, 21.3. IR (KBr) t
2926(w), 1628(w), 1528(s), 1435(w), 1349(s), 1092(w), 904(w), 807
(w), 735(w) cm−1; MS: 387.73. Anal. calc. for C29H25N: C 89.88,
H 6.50, N 3.62; found. C 89.56, H 6.62, N 3.29.
Mp 122–124 C. H NMR (600 MHz, CDCl3) d 8.28, 7.76 (d,
d, J = 7.8, 4H, p-ClC6H4), 8.19 (d, J = 7.2 Hz, 2H, MeC6H4), 7.90
(s, 2H, 3,5-PyH), 7.54–7.62 (m, 7H, C6H5, MeC6H4), 2.53 (s, 3H,
CH3). 13C NMR (600 MHz, CDCl3) d 157.7, 157.6, 148.8, 139.5,
139.2, 137.6, 136.6, 135.1, 129.5, 129.3, 129.1, 128.7, 128.4, 127.1,
127.0, 116.5, 116.4. IR (KBr) t 3033(w), 1600(s), 1542(s), 1493(s),
1383(m), 1093(m), 1014(m), 816(s), 772(s) cm−1. Anal. calc. for
C24H18ClN: C 80.00, H 5.10, N 3.94; found. C 79.77, H 5.34, N
4.15.
6c. 80%. Mp 160.0–161.5 ◦C. 1H NMR (600 MHz, CDCl3) d
8.12 (d, J = 7.8 Hz, 1H, PhH), 7.68 (s, 1H, ArH), 7.57 (s, 1H,
PyH), 7.52–7.47 (m, 7H, ArH), 7.47–7.43 (m, 4H, ArH), 7.38–
=
4c: 2,6-Diphenyl-4-p-methoxyphenylpyridine. 82%. Mp 96–
98 ◦C. 1H NMR (600 MHz, CDCl3) d 8.31, 7.80 (d, d, J = 7.8 Hz,
4H, MeOC6H4), 7.96 (s, 2H, 3,5-PyH), 7.81–7.80 (d, J = 7.8 Hz,
7.36 (m, 3H, ArH), 7.30 (d, J = 8.4 Hz, 1H, CH ), 3.18 (s, 2H,
CH2); 13C NMR (600 MHz, CDCl3) d 161.3, 157.4, 145.8, 141.9,
139.4, 137.1, 136.2, 135.0, 134.6, 132.6, 130.3, 130.2, 129.5, 129.0,
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128.8, 128.7, 127.1, 121.7, 119.1, 29.1, 28.1. IR (KBr) t 2916(w),
1634(m) 1597(m), 1491(s), 1359(w), 1239(w), 1091(m), 896(w),
824(m) cm−1; MS: 428.67. Anal. calc. for C27H19Cl2N: C 75.71,
H 4.47, N 3.27; found. C 75.45, H 4.81, N 3.23.
2.73 (s, 2H, CH2), 2.55 (t, J = 6.0 Hz, 2H, CH2), 2.22 (s, 3H,
CH3), 2.17 (s, 3H, CH3), 1.56 (t, 3H, J = 6.0 Hz, CH2); 13C NMR
(600 MHz, CDCl3) d 153.2, 152.8, 150.5, 138.7, 137.7, 136.8, 136.5,
135.5, 135.4, 132.9, 129.7, 129.1, 128.8, 128.6, 127.7, 126.8, 28.2,
28.0, 23.1, 21.2; IR (KBr) t 3022(w), 2947(m), 2869(w), 1905(w),
1577(m), 1507(m), 1426(m), 1373(m), 1116(w), 912(w), 817(s),
768(m) cm−1; MS: 401.80. Anal. calc. for C30H27N: C 89.73, H
6.78, N 3.49; found. C 89.55, H 6.60, N 3.58.
◦
1
6d. 70%. Mp 167.0–168.0 C. H NMR (600 MHz, CDCl3)
d 8.13 (d, J = 7.8 Hz, 1H, PhH), 7.68 (s, 1H, PyH), 7.63 (s, 1H,
ArH), 7.55–7.49 (m, 6H, ArH, PhH), 7.42 (d, J = 7.2 Hz, 1H,
=
PhH), 7.30 (d, J = 7.8 Hz, 1H, CH ), 7.03–6.98 (m, 2H, ArH),
6i. 70%. Mp 164.0–166.0 ◦C. 1H NMR (600 MHz, CDCl3) d
8.30 (s, 1H, pyH), 8.14 (d, J = 7.8 Hz, 2H, ArH), 7.53 (s, 1H, ArH),
7.50–7.47 (m, 5H, ArH), 7.43–7.37 (m, 5H, PhH), 7.28–7.24 (m,
6.95 (s, 2H, PhH), 3.88–3.84 (m, 6H, OCH3), 3.18–3.11(m, 4H,
CH2). 13C NMR (600 MHz, CDCl3) d 161.7, 161.0, 159.8, 159.2,
158.6, 158.4, 151.0, 146.4, 140.0, 139.4, 136.2, 134.6, 131.2, 131.0,
130.8, 130.5, 129.6, 129.5, 129.4, 128.7, 127.1, 122.2, 121.3, 118.3,
118.7, 114.1, 114.0, 113.9, 55.4, 55.3, 29.3, 29.1, 28.3, 27.8. IR
(KBr) t 3053(w), 2919(w), 1582(w), 1543(w), 1491(w), 1435(w),
1238(w), 1189(w), 1075(w), 1026(w), 917(w), 762(m) cm−1; MS:
419.67. Anal. calc. for C29H25NO2: C 83.03, H 6.01, N 3.34; found.
C 83.45, H 5.69, N 3.57.
=
1H, CH), 2.95 (s, 2H, CH2), 2.76 (t, J = 6.0 Hz, 2H, CH2), 1.78 (t,
J = 5.4 Hz, 2H, CH2). 13C NMR (600 MHz, CDCl3) d 153.8, 152.7,
139.6, 138.1, 129.7, 128.8, 128.7, 128.6, 128.4, 127.9, 126.9, 126.7,
119.8, 28.1, 27.9, 23.0. IR (KBr) t 2946(w), 1636(w), 1582(w),
1532(m), 1485(w), 1372(w), 1181(w), 1088(m), 1010(w), 911(w),
827(m), 769(w) cm−1; MS: 443.67. Anal. calc. for C28H21Cl2N: C
76.02, H 4.78, N 3.17; found. C 76.24, H 5.17, N 3.42.
◦
1
6e. 71%. Mp 150.0–152.0 C. H NMR (600 MHz, CDCl3)
d 8.46 (s, 2H, ArH), 8.34 (d, J = 6.6 Hz, 1H, ArH), 8.16–8.12
(m, 3H, ArH), 7.92–7.88 (m, 2H, ArH), 7.81–7.79 (m, 1H, PhH),
7.74–7.73 (d, J = 7.2 Hz, 1H, PhH), 7.67 (s, 1H, PyH), 7.59–7.54
6j. 75%. Mp 130.0–131.5 ◦C. 1H NMR (600 MHz, CDCl3) d
8.23 (s, 1H, ArH), 8.14 (d, J = 7.2 Hz, 2H, PhH), 7.50–7.45 (m,
4H, ArH), 7.40 (t, J = 7.2 Hz, 1H, PyH), 7.32 (d, J = 7.8 Hz,
=
=
2H, PhH), 7.04–6.92 (m, 5H, ArH, PhH, CH ), 3.87–3.82 (m,
(m, 3H, PhH), 7.48 (d, J = 6.0 Hz, 1H, CH ), 3.30–3.27 (d, 4H,
CH2). 13C NMR (600 MHz, CDCl3) d 161.1, 161.1, 160.8, 157.9,
148.6, 144.7, 144.1, 143.9, 139.2, 135.3, 134.9, 134.0, 130.0, 129.5,
129.35, 128.9, 127.1, 123.4, 123.1, 123.1, 121.6, 121.0, 119.5, 29.3,
29.1, 28.0, 27.6. IR (KBr) t 2926(w), 2834(w), 1603(m), 1509(m),
1456(w), 1364(w), 1243(s), 1176(m), 1029(m), 1029(m), 896(w),
823(m), 765(w) cm−1; MS: 449.40. Anal. calc. for C27H19N3O4: C
72.15, H 4.26, N 9.35; found. C 72.09, H 4.68, N 9.10.
6H, OCH3), 2.94 (s, 2H, CH2), 2.78 (s, 4H, CH2), 1.78 (s, 2H,
CH2). 13C NMR (600 MHz, CDCl3) d 159.4, 158.4, 153.8, 152.9,
150.0, 139.7, 134.6, 132.0, 131.1, 130.8, 130.0, 128.9, 128.6, 127.3,
126.8, 119.5, 113.8, 113.6, 55.4, 55.3, 28.3, 28.0, 23.1. IR (KBr) t
2930(w), 2930(w), 2833(w), 1607(m), 1508(m), 1438(w), 1381(w),
1381(w), 1291(w), 1347(s), 1174(m), 1111(w), 1032(m), 885(w),
834(w), 766(w) cm−1; MS: 433.53. Anal. calc. for C30H27NO2: C
83.11, H 6.28, N 3.23; found. C 82.87, H 5.91, N 3.02.
6f. 73%. Mp 175–176 ◦C. 1H NMR (600 MHz, CDCl3) d 8.15
(d, J = 7.2 Hz, 2H, PhH), 7.68 (s, 1H, PyH), 7.56 (s, 1H, ArH),
7.53–7.51 (m, 2H, PhH), 7.46–7.43 (m, 1H, ArH), 7.18 (d, J =
8.4 Hz, 1H, ArH), 7.13–7.12 (m, 2H, ArH), 7.07–7.06 (m, 2H,
ArH), 6.99 (d, J = 8.4 Hz, 1H, ArH), 5.79 (s, 1H, OH), 5.71 (s,
6k. 73%. Mp 153.5–155.5 ◦C. 1H NMR (600 MHz, CDCl3) d
8.03 (d, 2H, J = 7.2 Hz, PhH), 7.47 (s, 1H, PyH), 7.45–7.41 (m,
=
6H, ArH), 7.37 (t, J = 7.2 Hz, 1H, CH2), 7.32 (d, J = 8.4 Hz,
2H, ArH), 7.26 (d, J = 7.8 Hz, 2H, ArH), 7.10 (s, 1H, PhH), 2.76–
2.67 (m, 4H, CH2), 1.86–1.75 (m, 4H, CH2). 13C NMR (600 MHz,
CDCl3) d 160.6, 153.2, 148.0, 143.2, 138.3, 137.4, 135.2, 133.0,
131.6, 129.8, 129.6, 129.5, 129.2, 129.1, 127.8, 127.7, 127.7, 127.6,
127.0, 125.9, 119.1, 28.6, 26.9, 25.7. IR (KBr) t 3447(m), 3044(m),
2931(m), 2858(w), 1573(m), 1538(m), 1488(s), 1452(m), 1418(m),
1376(m), 1223(w), 1087(s), 1011(m), 877(m), 764(m) cm−1; MS:
455.80. Anal. calc. for C29H23Cl2N: C 76.32, H 5.08, N 3.07; found.
C 76.14, H 5.28, N 3.51.
1H, OH), 3.98 (d, J = 6.64 Hz, 6H, OCH3), 3.22 (s, 4H, CH2); 13
C
NMR (600 MHz, CDCl3) d 146.7, 146.4, 146.1, 145.0, 130.6, 128.7,
128.7, 127.1, 122.4, 121.5, 118.8, 114.7, 114.5, 112.0, 110.7, 56.1,
55.9, 29.1, 28.4; IR (KBr) t 2932(w), 2843(w), 1595(w), 1513(s),
1458(w), 1429(w), 1376(w), 1272(m), 1209(m), 1129(w), 901(w),
818(w), 774(w) cm−1; MS: 451.53. Anal. calc. for C29H25NO4: C
77.14, H 5.58, N 3.30. found. C 76.75, H 5.69, N 3.22.
◦
1
6g. 75%. Mp 137.0–139.0 C. H NMR (600 MHz, CDCl3)
d 8.30 (s, 1H, ArH), 8.14 (d, J = 7.8 Hz, 2H, PhH), 7.53 (s, 1H,
PyH), 7.50–7.47 (m, 6H, PhH), 7.43–7.37 (m, 6H, PhH), 7.28–7.24
General procedure for the preparation of
5,6-dihydrobenzo[h]quinolines
=
(m, 1H, CH ), 2.95 (s, 2H, CH2), 2.76 (t, J = 6.0 Hz, 2H, CH2),
1.78 (t, J = 5.4 Hz, 2H, CH2). 13C NMR (600 MHz, CDCl3) d
151.8, 150.6, 148.4, 137.6, 137.5, 136.1, 134.0, 127.7, 126.9, 126.6,
126.6, 126.3, 126.0, 125.8, 125.7, 124.8, 124.6, 117.6, 26.1, 25.9,
21.0. IR (KBr) t 3053(w), 2942(w), 1577(m), 1535(m), 1373(m),
763(s) cm−1; MS: 373.67. Anal. calc. for C28H23N: C 90.04, H 6.21,
N 3.75; found. C 89.64, H 5.89, N 3.62.
To a 50 mL flask was added N-phenacylpyridinium bromide
(1.2 mmol, 0.280 g), aromatic aldehyde (1.0 mmol), 1-tetralone
(1.0 mmol), ammonium acetate (3.0 g) and acetic acid (2.0 mL).
The mixture was placed in a microwave and heated for about 2–
4 minutes (130 W). After cooling, the reaction mixture was diluted
with water (50 mL) and the resulting precipitate was collected by
filtration. The crude product was recrystallized with ethanol to
give the pure solid sample for analysis.
◦
1
6h. 78%. Mp 156.5–157.5 C. H NMR (600 MHz, CDCl3)
d 8.05 (s, 1H, PyH), 7.92 (d, J = 7.8 Hz, 2H, PhH), 7.30 (s, 1H,
PhH), 7.26 (t, J = 7.8 Hz, 2H, PhH), 7.19 (d, 3H, J = 7.8 Hz,
7a. 81%, Mp 123.0–124.0 ◦C. 1H NMR (600 MHz, CDCl3) d
8.58 (d, J = 7.8 Hz, 1H, ArH), 8.17 (d, 2H, J = 7.2 Hz, PhH), 7.59
=
ArH, CH ), 7.06 (s, 4H, ArH), 7.00 (d, 2H, J = 7.8 Hz, ArH),
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(s, 1H, PyH), 7.48 (t, J = 7.8 Hz, 4H, ArH), 7.44–7.39 (m, 5H,
ArH, PhH), 7.32 (t, J = 7.2 Hz, 1H, ArH), 7.21 (d, J = 7.2 Hz, 1H,
PhH), 2.95 (t, J = 7.8 Hz, 2H, CH2), 2.90 (s, 2H, CH2). 13C NMR
(600 MHz, CDCl3) d 154.4, 152.6, 149.3, 139.6, 139.4, 138.2, 135.3,
129.1, 128.9, 128.8, 128.7, 128.5, 128.0, 127.5, 127.1, 126.9, 125.8,
112.0, 28.2, 25.3. IR (KBr) t 3060(w), 3030(w), 2941(w), 2841(w),
1957(w), 1544(m), 1418(m), 1377(m), 1227(m), 1028(w), 834(w),
760(s) cm−1; MS: 333.73. Anal. calc. for C25H19N: C 90.06, H 5.74,
N 4.20; found. C 89.71, H 5.88, N 4.17.
7f. 81%. Mp 178.3–178.9 ◦C. 1H NMR (600 MHz, CDCl3) d
8.56 (d, J = 7.8 Hz, 1H, ArH), 8.17 (d, J = 8.4 Hz, 2H, PhH), 7.58
(s, 1H, PyH), 7.48 (t, J = 7.8 Hz, 2H, PhH), 7.40 (d, J = 7.8 Hz, 2H,
ArH), 7.32 (t, J = 7.8 Hz, 1H, ArH), 7.22 (d, J = 7.8 Hz, 1H, ArH),
7.03 (d, J = 7.8 Hz, 1H, ArH), 6.90 (t, J = 7.8 Hz, 2H, ArH), 5.77
(s, 1H, OH), 3.91 (s, 3H, OCH3), 2.95 (t, J = 7.2 Hz, 2H, CH2), 2.85
(t, J = 7.2 Hz, 2H, CH2). 13C NMR (600 MHz, CDCl3) d 153.3,
151.5, 148.1, 145.4, 144.6, 138.6, 137.1, 134.2, 130.3, 127.9, 127.6,
127.5, 126.9, 126.32, 126.0, 125.7, 124.7, 121.0, 118.9, 113.3, 110.4,
55.0, 27.1, 24.3. IR (KBr) t 2931(w), 1601(w), 1538(w), 1513(s),
1466(w), 1416(m), 1384(s), 1267(w), 1242(w), 1197(m), 1121(w),
1079(w), 1030(m), 887(w), 821(w), 745(m) cm−1. MS: 379.67. Anal.
calc. for C26H21NO2: C 82.30, H 5.58, N 3.69; found. C 81.89, H
5.75, N 3.47.
7b. 85%. Mp 153.8–155.4 ◦C. 1H NMR (600 MHz, CDCl3) d
8.63 (s, 1H, ArH), 8.23 (s, 2H, PhH), 7.64 (br s, 1H, PyH), 7.53 (d,
J = 4.2 Hz, 2H, PhH), 7.46 (s, 2H, ArH), 7.35 (s, 5H, ArH), 7.28
(s, 1H, PhH), 2.99 (s, 2H, CH2), 2.90 (s, 2H, CH2), 2.49 (s, 3H,
CH3). 13C NMR (600 MHz, CDCl3) d 154.4, 152.3, 149.3, 139.7,
138.3, 137.9, 136.4, 136.3, 129.3, 129.2, 129.1, 128.8, 128.1, 127.5,
127.1, 126.9, 125.8, 120.1, 28.2, 25.4, 21.4. IR (KBr) t 3032(w),
2928(w), 1906(w), 1581(m), 1542(m), 1506(m), 1419(m), 1376(s),
1225(w), 1029(m), 821(m), 748(vs) cm−1; MS: 347.67. Anal. calc.
for C26H21N: C 89.88, H 6.09, N 4.03; found. C 89.80, H 6.35, N
3.81.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (grant no. 20672091), China. We
are grateful to Ms Min Shao for assistance with measuring the
X-ray single crystal structures.
7c. 82%. Mp 137.2–138.0 ◦C. 1H NMR (600 MHz, CDCl3) d
8.57 (d, J = 7.2 Hz, 1H, ArH), 8.16 (d, J = 7.8 Hz, PhH), 7.54 (s,
1H, PyH), 7.50–7.45 (m, 4H, ArH), 7.41 (t, J = 7.2 Hz, 2H, PhH),
7.34 (d, J = 7.2 Hz, 3H, ArH), 7.22 (d, J = 7.2 Hz, 1H, ArH),
2.90–2.86 (m, 4H, CH2) 13C NMR (600 MHz, CDCl3) d 154.6,
152.8, 148.1, 139.4, 138.1, 137.7, 135.1, 134.2, 130.2, 129.2, 128.9,
128.7 127.8, 127.5, 127.2, 126.8, 125.8, 119.7, 28.1, 25.3. IR (KBr)
t 3032(w), 2936(w), 2846(w), 1906(w), 1597(m), 1542(m), 1488(s),
1419(m), 1376(m), 1272(w), 1088(m), 830(s), 748(vs) cm−1; MS:
367.67. Anal. calc. for C25H18ClN: C 81.62, H 4.93, N 3.81; found.
C 81.47, H 5.15, N 3.62.
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7d. 80%, Mp 104.5–105 C. H NMR (600 MHz, CDCl3) d
8.57 (d, J = 7.8 Hz, 1H, ArH), 8.18 (d, J = 8.4 Hz, 2H, PhH), 7.58
(s, 1H, PyH), 7.48 (t, J = 7.8 Hz, 2H, PhH), 7.40 (t, J = 7.8 Hz, 2H,
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2H, CH2), 2.90 (s, 2H, CH2) 13C NMR (600 MHz, CDCl3) d 159.5,
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128.0, 127.5, 127.0, 126.8, 125.8, 120.1, 114.0, 55.4, 28.2, 25.4. IR
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1542(m), 1507(vs) 1418(m), 1375(m), 1243(vs), 1030(m), 834(m),
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8.57 (d, 1H, J = 7.8 Hz, ArH), 8.30 (s, 2H, ArH), 8.17 (d, J =
7.8 Hz, 2H, PhH), 7.74 (d, J = 7.8 Hz, 1H, ArH), 7.68 (t, J =
7.8 Hz, 1H, ArH), 7.57 (s, 1H, PyH), 7.50 (t, J = 7.8 Hz, 2H,
PhH), 7.43 (m, 2H, ArH), 7.35 (t, J = 7.2 Hz, 1H, ArH), 7.23 (d,
1H, J = 7.8 Hz, ArH), 2.89 (s, 4H, CH2). 13C NMR (600 MHz,
CDCl3) d 154.9, 153.1, 148.4, 146.7, 141.0, 139.1, 137.9, 134.8,
129.6, 129.4, 129.0, 128.7, 127.5, 127.5, 127.2, 126.8, 125.9, 123.8,
123.0, 119.4, 28.0, 25.2. IR (KBr) t 3067 (w), 2942(w), 1604(w),
1572(w), 1525(vs), 1432(w), 1416(w), 1383(m), 1347(s), 1282(w),
1090(w), 902(w), 774(m). MS: 378.67. Anal. calc. for C26H21NO:
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