Iodine-catalyzed aerobic oxidative formal [4+2] annulation for the construction of polyfunctionalized pyridines

Article abstract of DOI:10.1016/j.tet.2015.10.040

An iodine-catalyzed aerobic oxidative formal [4+2] annulation for the construction of polyfunctionalized pyridines in one step has been developed through the green reaction system of catalytic amounts of molecular iodine and amine in combination with oxyg

Full text of DOI:10.1016/j.tet.2015.10.040

Accepted Manuscript
Iodine-catalyzed aerobic oxidative formal [4+2] annulation for the construction of
polyfunctionalized pyridines
Chunyin Zhu, Benwei Bi, Ya Ding, Te Zhang, Qiu-Yun Chen
PII:
S0040-4020(15)30140-X
10.1016/j.tet.2015.10.040
TET 27212
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 July 2015
Revised Date: 14 October 2015
Accepted Date: 15 October 2015
Please cite this article as: Zhu C, Bi B, Ding Y, Zhang T, Chen Q-Y, Iodine-catalyzed aerobic oxidative
formal [4+2] annulation for the construction of polyfunctionalized pyridines, Tetrahedron (2015), doi:
10.1016/j.tet.2015.10.040.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Iodine-Catalyzed Aerobic Oxidative Formal
[4+2] Annulation for the Construction of
Polyfunctionalized Pyridines
Leave this area blank for abstract info.
Chunyin Zhu*, Benwei Bi, Ya Ding, Te Zhang and Qiu-Yun Chen
School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Iodine-catalyzed aerobic oxidative formal [4+2] annulation for the construction of
polyfunctionalized pyridines
Chunyin Zhu*, Benwei Bi, Ya Ding, Te Zhang and Qiu-Yun Chen
School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An iodine-catalyzed aerobic oxidative formal [4+2] annulation for the construction of
polyfunctionalized pyridines in one step has been developed through the green reaction system
of catalytic amounts of molecular iodine and amine in combination with oxygen. Various
ketones and aldehydes were able to react with different chalcones and β, γ-unsaturated
α‑ketoesters through this reaction strategy. Synthetically, this iodine catalytic system could be
scaled up with good efficiency.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Iodine
[4+2] annulation
Pyridine
Aerobic
1. Introduction
construction of 1,2,3-triazoles under metal-free and azide-free
conditions.12 Lei group reported an iodine-catalyzed oxidative
annulation of β-keto esters or 2-pyridinyl-β-esters with alkenes
providing a simple and selective way for the synthesis of
dihydrofurans and indolizines in one step.13 These emblematic
examples have proved iodine-catalyzed oxidative annulation to
be an effective approach for the synthesis of heterocycles, but the
same strategy has rarely been applied in the synthesis of
pyridines from simple starting materials.
The direct construction of substituted pyridines has continued
to capture the attention of the synthetic community due to their
major applications in coordination chemistry1, material sciences2,
super-molecular chemistry3, catalysis4, organo-catalysis5,
medicinal chemistry6 and natural product synthesis7. Of all the
investigations into the synthesis of pyridines8, most of the efforts
have been devoted to multicomponent reactions (MCRs) which
usually involves the condensation of carbonyl compounds with
ammonia under harsh conditions like high temperature and
microwave irradiation9. Given the increasing demand for more
environmentally acceptable processes, synthetic methods for
polysubstituted pyridines employing mild and cheap conditions
are still desirable.
Recently iodine-mediated organic transformations have
undergone rapid advances10, because iodine is inexpensive, low
toxicity, and readily available. Moreover, iodine catalysis has
evident advantages over acid catalysis and transition-metal
catalysis, such as less health and safety problems; greater atom
economy; and greener, milder reaction conditions. While
understanding of the exact role of iodine species in those types of
transformations has not been fully established, iodine can serve
as both an alternative catalyst for Lewis acid, and a mediator for
oxidation simultaneously, thus making it possible to promote an
oxidative coupling/annulation. For example, Wang group has
developed an iodine-catalyzed oxidative amination of N-
alkylamides, ethers, and alcohols with orthocarbonyl-substituted
anilines for the synthesis of quinazolines.11 Wang and Ji et al.
described an efficient I2/TBPB mediated oxidative formal [4+1]
cycloaddition of N-tosylhydrazones with anilines for the
Scheme 1. Proposed aerobic oxidative formal [4+2] annulation
With continuous interest in the mild synthesis of
heterocycles14, we proposed an iodine -catalyzed aerobic
oxidative formal [4+2] annulation of NH4OAc, α, β-unsaturated
carbonyls, and ketones/aldehydes to form polyfunctionalized
pyridines. Iodine was expected to catalyze the formal [4+2]
annulation of in situ generated 1-azadiene with
a
ketone/aldehyde, as well as the aromatization of dihydropyridines
through aerobic oxidation to furnish the polyfunctionalized
pyridines. (Scheme 1).
2. Results and discussion.
To test the idea, we commenced our study by the reaction of
chalcone 1a, cyclohexanone and ammonium acetate with 20

2
Tetrahedron
ACCEPTED MANUSCRIPT
mol% I2 under oxygen atmosphere (balloon). The reaction
corresponding product 3u was furnished in a 92% yield. Notably
resulted in desired pyridine 3a with 14% yield after stirring for
12 hours at 30 C, and the pyridine structure was confirmed by
the scalability and preparative utility of the developed
methodology was exemplified by the fact that the desired product
3a was obtained with even a slightly better yield when the
reaction was scaled up to 20 mmol.
o
single-crystal X-ray diffraction analysis (entry 1, table 1). We
envisaged that the inferior yield could be caused by the poor
activity of enol serving as the dienophile in the [4+2] annulation.
Given that enamine was proven to be better dienophile in similar
transformation15, various amines were tested to enhance the
enamine formation. As a result, significant improvement in yields
were observed for most of the reactions with 20 mol% amines
added (entries 2-6, table 1), and pyrrolidine was found to be the
best among all amines examined (entry 6, table 1). Subsequently,
the evaluation of solvents reveals that alcoholic solvents were
superior to DCM, THF and MeCN, while DMSO and DMF were
found to be ineffective.
Scheme 2. Substrate scope of enonesa
Table 1. Optimization of Reaction Conditionsa
yieldb
(%)
entry
solvent
additive
time (h)
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
none
12
12
12
12
12
12
12
12
12
12
8
14
2
Me2NH•HCl
L-proline
45
3
51
4
piperidine
morpholine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
32
5
15
6
59
7
22
8
THF
35
9
DMSO
DMF
trace
trace
78
a0.5 mmol of 1, 0.6 mmol of 2a, 0.6 mmol of NH4OAc, 0.1 mmol of
o
I2, 0.1 mmol of pyrrolidine, 1.5 mL of MeOH, 30 C, O2 ballon. b20
10
11
12
mmol of 1.
EtOH
MeOH
Scheme 3. Substrate scope of aldehydes/ketonesa
8
82
a0.5 mmol of 1a, 0.6 mmol of 2, 0.6 mmol of NH4OAc, 0.1
o
mmol of I2, 0.1 mmol of additive, 1.5 mL of MeOH, 30 C, O2
ballon. bisolated yield.
With the identification of optimized conditions for aerobic
oxidative formal [4+2] annulation, the scope of α, β-unsaturated
carbonyls was evaluated (Scheme 2). It was determined that most
of the tested chalcones provided good to excellent yields. To our
delight, diverse β, γ-unsaturated α ketoesters were also found to
be suitable for the transformation. The generality was
investigated using 21 different enones to reflect differing
electronic and steric factors. Substrates with both electron-
donating and -withdrawing groups on the para-position of the
benzene ring reacted smoothly in good to excellent yields, and
strong electron-withdrawing group –NO2 can be tolerated (3q).
The substrates with a meta-substituent (3e, 3k, 3l, 3o and 3t) also
worked very well leading to desired products in yield comparable
to that of para-substitution. Notably, the reaction was found to be
tolerant with steric hindrance, since ortho-substituted and 2,4-
disubstituted substrates (3f, 3m, 3p) can be transformed to
desired products in up to 85% yield. Moreover, substrates with
ortho-, meta- and para-fluorine group on the aromatic ring could
afford fluorine-contained pyridine derivatives in good yield,
which should be of interest to medical chemistry (3c-3f). For
other substituent, substrate 1u containing a cinnamyl-group on
the aromatic ring could also undergo the reaction and the
a0.5 mmol of 1, 0.6 mmol of 2, 0.6 mmol of NH4OAc, 0.1 mmol
of I2, 0.1 mmol of pyrrolidine, 1.5 mL of MeOH, 30 oC, O2 ballon.

3
The scope of carbonyl compounds was explored for this
reaction and a wide range of ketones were chosen to react with
chalcones or β, γ-unsaturated α ketoesters (Scheme 3). As a
result, cyclic ketones of different ring-size (4a-4c), and various
substituted cyclohexanones (4d-4g) were transformed into the
corresponding pyridines in good yield (65–86%), while acyclic
ketones can give 52-85% yield (4h-4m, 4p, and 4q). Notably, for
the unsymmetrical ketonesꢀreactions occurred exclusively to
the α-carbons of less steric hindrance leading to exclusive
regioselectivitiy (4d, 4e, 4j and 4q). Moreover, the methodology
was also applicable to aldehydes, including various simple
aldehydes (4n-4o) and citronellal (4r), a naturally occurred
aldehyde, which could also be converted to corresponding
pyridine in moderate yield.
ketones and aldehydes were able to react with different
ACCEPTED MANUSCRIPT
chalcones and β, γ-unsaturated α‑ketoesters through this reaction
strategy. Synthetically, this iodine catalytic system could be
scaled up to 20 mmol with good efficiency.
4. Experimental section
4.1. General
Unless otherwise indicated, all commercial reagents and
solvents were used without additional purification. Chemical
1
shifts (in parts per million) of H NMR spectra were referenced
to tetramethylsilane (δ 0) in CDCl3 as an internal standard. 13C
NMR spectra were calibrated with CDCl3 (δ 77.00).
4.2 General procedures for pyridines
Scheme 4. Control experiment
To a solution of α, β-unsaturated carbonyl (0.5 mmol) in 1.5
mL methanol was added ketone or aldehyde (0.6 mmol), iodine
(0.1 mmol), pyrrolidine (0.1 mmol) and ammonium acetate (0.6
mmol). The reaction mixture was stirred at 30 ꢁ under oxygen
atmosphere (balloon). The reaction was monitored by thin layer
chromatography (TLC). When the reaction was completed, it was
diluted with water and extracted with ethyl acetate 3 times.
Removal of solvent followed by column chromatography
afforded desired products.
To understand the role of iodine in this aerobic oxidative
formal [4+2] annulation, we reacted chalcone 1a, cyclohexanone
and ammonium acetate under our standard reaction protocol with
additional TEMPO (2.0 equiv.) as a radical scavenger. In this
experiment, we observed the formation of 3a in 78% yield and no
TEMPO-bound intermediate was detected (scheme 4). Therefore,
we think that a radical-based reaction mechanism can be
excluded. A plausible mechanism was proposed in scheme 5.
Initially, the reaction of ketone with amine gives an enamine
which can undergo [4+2] annulation with chalcone in the
4.2.1. 2,4-diphenyl-5,6,7,8-tetrahydroquinoline (3a). 82% yield
1
(215 mg), white solid, M.p. 107-108 ꢁ. H NMR (400 MHz,
CDCl3) δ 7.98 (s, 1H), 7.96 (s, 1H), 7.33-7.47 (m, 9H), 3.09 (t, J
= 6.4 Hz, 2H), 2.65 (t, J = 6.4 Hz, 2H), 1.91-1.97 (m, 2H), 1.72-
1.78 (m, 2H). 13C NMR (100 MHz, CDCl3)δ 157.5, 154.2, 150.1,
139.6, 128.5, 128.4, 128.3, 128.2, 127.6, 126.7, 118.9, 33.3, 27.2,
23.0, 22.9. MS (ESI, m/z) 286.3 (M + H+), 308.3 (M + Na+). IR
(film) v/cm-1 3066(m), 2950(s), 1593(vs), 1387(vs), 1221(m),
773(vs). Anal. calcd for C21H19N: C, 88.38; H, 6.71; N, 4.91.
Found: C, 88.29; H, 6.60; N, 5.11.
presence of I2. The resulting intermediate
A generates
intermediate B by removing one molecular amine. Subsequently
intermediate B reacts with I2 to form C which can give D by
elimination of one molecular HI. Finally 3 is obtained through
elimination of another molecular HI. Notably, two molecular HI
generated in situ are oxidized by oxygen to regenerate iodine to
complete the I2/I− catalytic cycle.
4.2.2. Methyl 4-phenyl-5,6,7,8-tetrahydroquinoline-2-carboxylate
1
(3b). 76% yield (215 mg), white solid, M.p. 119-120 ꢁ. H
NMR (400 MHz, CDCl3)δ 7.77 (s, 1H), 7.35-7.41 (m, 3H), 7.23-
7.26 (m, 2H), 3.93 (s, 3H), 3.05 (t, J = 6.4 Hz, 2H), 2.64 (t, J =
6.4 Hz, 2H), 1.84-1.90 (m, 2H), 1.64-1.72 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 166.0, 158.3, 150.2, 144.6, 138.3, 134.1,
128.3, 127.9, 123.4, 52.6, 33.1, 27.6, 22.5, 22.4. MS (ESI, m/z)
268.3 (M + H+), 290.3 (M + Na+). IR (film) v/cm-1 2947(s),
1711(vs), 1583(m), 1454(m), 1248(vs), 1130(s), 702(s). Anal.
calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.31; H, 6.34; N, 5.32.
Scheme 5. A plausible mechanism
I2
O
HN
NH4OAc
R1
R2
R1
R2
H
N
N
1
R4
R3
R2
[4+2]
O
R1
N
R3
A
R4
R3
H
N
R4
4.2.3. Methyl 4-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline-2-
2
I
I
carboxylate (3c). 75% yield (270 mg),white solid, M.p. 103-104
H
N
1
I2: Lewis acid
I2: oxidation mediator
R4
R3
R2
ꢁ. H NMR (400 MHz, CDCl3)δ 7.75 (s, 1H), 7.22-7.24 (m,
I2 + H2O
2H), 7.08 (t, J = 8.0 Hz, 2H), 3.93 (s, 3H), 3.05 (t, J = 8.0 Hz,
2H), 2.62 (t, J = 6.0 Hz, 2H), 1.84-1.90 (m, 2H), 1.67-1.73 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 166.0, 162.5 (d, J = 247.3
Hz), 158.6, 149.4, 144.8, 134.3(4) (d, J = 2.4 Hz), 134.2(8),
130.2 (d, J = 7.9 Hz), 123.5, 115.5 (d, J = 21.2 Hz), 52.8, 33.2,
27.8, 22.6, 22.5. MS (ESI, m/z) 286.3 (M + H+), 308.3 (M +
Na+). IR (film) v/cm-1 2948(s), 1731(vs), 1609(m), 1508(s),
1254(vs), 1130(m), 846(s). Anal. calcd for C17H16FNO2: C,
71.56; H, 5.65; N, 4.91. Found: C, 71.64; H, 5.43; N, 4.99.
2 HI + 1/2 O2
R1
I
B
I
H
I
R4
R3
N
R2
R4
R3
N
R2
R4
R3
N
R2
H
R1
R1
R1
3
C
D
3. Conclusion.
We have developed an iodine-catalyzed aerobic oxidative
4.2.4. 4-(4-fluorophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
1
(3d). 69% yield (105 mg), yellow solid, M.p. 131-132 ꢁ. H
formal [4+2] annulation for the construction of
NMR (400 MHz, CDCl3)δ 7.96-7.98 (m, 2H), 7.30-7.46 (m, 6H),
7.12-7.16 (m, 2H), 3.09 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 6.4 Hz,
2H), 1.91-1.97 (m, 2H), 1.74-1.79 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 163.6, 161.1, 156.0 (d, J = 340 Hz), 149.2, 139.6, 135.6
(d, J = 2.6 Hz), 130.2 (d, J = 8.1 Hz), 128.6, 128.5, 128.4, 126.8,
polyfunctionalized pyridines in one step. Catalytic amounts of
molecular iodine and amine in combination with oxygen was
proven to be an effective alternative reaction system for
traditional harsh conditions in these transformations. Various

4
Tetrahedron
119.0, 115.3 (d, J = 21.5 Hz), 33.3, 27.2, 23.0(4), 22.9(9). MS
C1 H16BrNO2: C, 58.97; H, 4.66; N, 4.05. Found: C, 59.12; H,
ACCEPTED MANUSCRIPT
7
(ESI, m/z) 304.3 (M + H+), 326.3 (M + Na+). IR (film) v/cm-1
3040(m), 2965(s), 1605(s), 1515(vs), 1221(vs), 849(vs). Anal.
calcd for C21H18FN: C, 83.14; H, 5.98; N, 4.62. Found: C, 83.05;
H, 5.94; N, 4.69.
4.54; N, 4.23.
4.2.10. 4-(4-bromophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
(3j). 77% yield (198 mg), yellow solid, M.p. 138-139 ꢁ. H
1
NMR (400 MHz, CDCl3)δ 7.96-7.98 (m, 2H), 7.21-7.61 (m, 8H),
3.09 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H), 1.91-1.97 (m,
2H), 1.75-1.80 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.8,
154.4, 148.9, 139.5, 138.5, 131.5, 130.2, 128.6, 128.5, 128.2,
126.8, 122.0, 118.7, 33.3, 27.2, 23.0, 22.9. MS (ESI, m/z) 364.2
(M + H+), 386.2 (M + Na+). IR (film) v/cm-1 2939(vs), 1605(vs),
1439(vs), 1081(s), 1017(s), 773(s). Anal. calcd for C21H18BrN: C,
69.24; H, 4.98; N, 3.85. Found: C, 69.26; H, 4.97; N, 3.88.
4.2.5. Methyl 4-(3-fluorophenyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3e). 68% yield (164 mg), white solid, M.p. 76-77 ꢁ
1
. H NMR (400 MHz, CDCl3)δ 7.83 (s, 1H), 7.42-7.47 (m,1H),
7.02-7.16ꢂmꢀ3Hꢃ, 4.01 (s, 3H), 3.13 (t, J = 6.4 Hz, 2H), 2.71
(t, J = 6.4 Hz, 2H), 1.94-1.97 (m, 2H), 1.77-1.79 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 166.0, 162.5 (d, J = 245.2 Hz), 158.7,
149.1 (d, J = 2.6 Hz), 144.8, 140.5 (d, J = 6.8 Hz), 134.1, 130.1
(d, J = 8.1 Hz), 124.2 (d, J = 2.8 Hz), 123.3, 115.6 (d, J = 21.8
Hz), 115.1 (d, J = 20.7 Hz), 52.8, 33.2, 27.7, 22.6, 22.5. MS
(ESI, m/z) 286.2 (M + H+), 308.2 (M + Na+). IR (film) v/cm-1
2961(vs), 1723(vs), 1445(s), 1264(s), 1117(m), 788(s). Anal.
calcd for C17H16FNO2: C, 71.56; H, 5.65; N, 4.91. Found: C,
71.43; H, 5.57; N, 5.11.
4.2.11. Methyl 4-(3-bromophenyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3k). 72% yield (150 mg),white solid, M.p. 1086-107
ꢁ. 1H NMR (400 MHz, CDCl3)δ 7.73 (s, 1H), 7.47-7.50 (m,1H),
7.40 (t, J = 1.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.16-7.18
(m,1H), 3.93 (s, 3H), 3.05 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz,
2H), 1.85-1.88 (m, 2H), 1.68-1.71 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 165.7, 158.5, 148.6, 144.7, 140.3, 133.9, 131.2, 131.0,
129.9, 126.9, 123.1, 122.3, 52.7, 33.0, 27.5, 22.5, 22.3. MS (ESI,
m/z) 346.1 (M + H+), 368.1 (M + Na+). IR (film) v/cm-1 3055(m),
2948(s), 1731(vs), 1577(s), 1423(vs), 1355(s), 1231(vs), 1130(s),
1008(m), 793(s). Anal. calcd for C17H16BrNO2: C, 58.97; H, 4.66;
N, 4.05. Found: C, 58.88; H, 4.73; N, 3.92.
4.2.6. Methyl 4-(2-fluorophenyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3f). 66% yield (144 mg), white solid, M.p. 75-76 ꢁ
1
. H NMR (400 MHz, CDCl3)δ 7.85 (s, 1H), 7.41-7.46 (m,1H),
7.16-7.26ꢂmꢀ3Hꢃ, 4.00 (s, 3H), 3.13 (t, J = 6.4 Hz, 2H),
2.56-2.70 (m, 2H) 1.92-1.96 (m, 2H), 1.70-1.78 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 165.9, 158.9 (d, J = 246.0 Hz), 158.3,
144.7 (d, J = 14.5 Hz), 135.4, 130.5 (d, J = 2.8 Hz), 130.3 (d, J =
7.9 Hz), 125.8 (d, J = 15.8 Hz), 124.3 (d, J = 3.0 Hz), 123.9,
115.7 (d, J = 22.2 Hz), 52.7, 33.1, 26.8 (d, J = 2.9 Hz), 22.6,
22.2. MS (ESI, m/z) 286.2 (M + H+), 308.2 (M + Na+). IR (film)
v/cm-1 2934(vs), 1706(vs), 1584(m), 1264(s), 762(s), 615(w).
Anal. calcd for C17H16FNO2: C, 71.56; H, 5.65; N, 4.91. Found:
C, 71.48; H, 5.33; N, 4.76.
4.2.12. 4-(3-bromophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
(3l). 88% yield (277 mg), yellow solid, M.p. 139-140 ꢁ. H
1
NMR (400 MHz, CDCl3)δ 7.98-8.00 (m, 2H), 7.29-7.58 (m, 8H),
3.11 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 1.94-2.00 (m,
2H), 1.77-1.82 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.8,
154.4, 148.6, 141.7, 139.4, 131.4, 130.7, 129.8, 128.6, 128.5,
128.1, 127.2, 126.8, 122.4, 118.7, 33.3, 27.1, 23.0, 22.9. MS
(ESI, m/z) 346.2 (M + H+), 368.2 (M + Na+). IR (film) v/cm-1
3066(w), 2951(s), 2834(w), 1593(s), 1451(vs), 1067(w). Anal.
calcd for C21H18BrN: C, 69.24; H, 4.98; N, 3.85. Found: C,
69.27; H, 4.97; N, 3.89.
4.2.7. Methyl 4-(4-chlorophenyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3g). 85% yield (235 mg), white solid, M.p. 128-129
ꢁ. H NMR (400 MHz, CDCl3)δ 7.74 (s, 1H), 7.36-7.38 (m,
1
2H), 7.17-7.20 (m, 2H), 3.93 (s, 3H), 3.05 (t, J = 6.4 Hz, 2H),
2.61 (t, J = 6.4 Hz, 2H), 1.85-1.88 (m, 2H), 1.68-1.71 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 166.0, 158.6, 149.1, 144.8, 136.8,
134.3, 134.1, 129.8, 128.7, 123.3, 52.8, 33.2, 27.7, 22.6, 22.5.
MS (ESI, m/z) 302.2 (M + H+), 324.2 (M + Na+). IR (film) v/cm-1
2931(s), 1716(vs), 1609(m), 1500(s), 1446(s), 1354(s), 1246(vs),
1124(s), 839(s). Anal. calcd for C17H16ClNO2: C, 67.66; H, 5.34;
N, 4.64. Found: C, 67.87; H, 5.44; N, 4.85.
4.2.13. 4-(2-bromophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
(3m). 85% yield (257 mg), yellow solid, M.p. 87-88 ꢁ. 1H NMR
(400 MHz, CDCl3)δ 7.97-7.99 (m, 2H), 7.66-7.68 (m, 1H), 7.19-
7.45 (m, 7H), 3.06-3.11 (m, 2H), 2.36-2.56 (m, 2H), 1.90-1.98
(m, 2H), 1.74-1.81 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
157.6, 154.1, 149.3, 140.4, 139.5, 132.7, 129.9, 129.3, 128.8,
128.5, 128.4, 127.3, 126.8, 122.4, 118.5, 33.3, 26.4, 23.0, 22.7.
MS (ESI, m/z) 346.2 (M + H+), 368.2 (M + Na+). IR (film) v/cm-1
3052(w), 2939(s), 2848(w), 1567(s), 1439(vs), 1017(s). Anal.
calcd for C21H18BrN: C, 69.24; H, 4.98; N, 3.85. Found: C,
69.28; H, 4.99; N, 3.84.
4.2.8. 4-(4-chlorophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
(3h). 78% yield (210 mg), yellow solid, M.p. 136-137 ꢁ. H
1
NMR (400 MHz, CDCl3)δ 7.95-7.97 (m, 2H), 7.26-7.46 (m, 8H),
3.08 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 1.91-1.95 (m,
2H), 1.74-1.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.8,
154.4, 149.0, 139.6, 138.1, 133.8, 129.9, 128.7, 128.6, 128.5,
128.3, 126.8, 118.9, 33.3, 27.2, 23.1, 23.0. MS (ESI, m/z) 320.3
(M + H+), 342.3 (M + Na+) . IR (film) v/cm-1 2939(vs), 2835(m),
1581(s), 1363(m), 1105(vs), 823(s). Anal. calcd for C21H18ClN:
C, 78.86; H, 5.67; N, 4.38. Found: C, 78.92; H, 5.63; N, 4.41.
4.2.14. Methyl 4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-
2-carboxylate (3n). 66% yield (336 mg),white solid, M.p. 99-100
1
ꢁ. H NMR (400 MHz, CDCl3)δ 7.76 (s, 1H), 7.17(5)-7.18(0)
(m, 2H), 6.90-6.92 (m, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.04 (t, J =
6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 1.84-1.87 (m, 2H), 1.66-
1.69 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 166.2, 159.4,
158.3, 150.0, 144.6, 134.4, 130.6, 129.7, 123.7, 113.8, 55.2, 52.7,
33.2, 27.9, 22.7, 22.6. MS (ESI, m/z) 298.2 (M + H+), 320.2 (M +
Na+). IR (film) v/cm-1 2940(s), 1716(vs), 1615(s), 1508(vs),
1239(vs), 1130(s), 1031(s), 831(m). Anal. calcd for C18H19NO3:
C, 72.71; H, 6.44; N, 4.71. Found: C, 72.68; H, 6.58; N, 4.67.
4.2.9. Methyl 4-(4-bromophenyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3i). Petroleum ether/ethyl acetate = 2:1, 69% yield
(168 mg), white solid, M.p. 163-164 ꢁ. H NMR (400 MHz,
CDCl3)δ 7.74 (s, 1H), 7.51-7.55 (m,2H), 7.11-7.14 (m,2H), 3.93
(s, 3H), 3.05 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 1.85-
1.89 (m, 2H), 1.68-1.71 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
166.0, 158.7, 149.2, 144.9, 137.3, 134.1, 131.7, 130.1, 123.3,
122.5, 52.8, 33.2, 27.7, 22.6, 22.5. MS (ESI, m/z) 346.2 (M +
H+), 368.2 (M + Na+). IR (film) v/cm-1 2955(m), 1709(vs),
1585(m), 1455(m), 1239(vs), 1130(s), 823(s). Anal. calcd for
1
4.2.15. Methyl 4-(3-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-
2-carboxylate (3o). 75% yield (188 mg),white solid, M.p. 58-59
1
ꢁ. H NMR (400 MHz, CDCl3)δ 7.84 (s, 1H), 7.37 (t, J = 8.0
Hz, 1H),6.94-6.97 (m,1H), 6.86-6.89 (m,1H),6.82-6.83
(m,1H),3.99 (s, 3H), 3.85 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 2.71
(t, J = 6.4 Hz, 2H), 1.92-1.94 (m, 2H), 1.74-1.77 (m, 2H). 13C

5
NMR (100 MHz, CDCl3) δ 166.2, 159.5, 158.5, 150.3, 144.7,
139.9, 134.3, 129.6, 123.5, 120.8, 114.2, 113.5, 55.3, 52.8, 33.3,
27.8, 22.7, 22.6. MS (ESI, m/z) 298.2 (M + H+), 320.2 (M +
Na+). IR (film) v/cm-1 3055(w), 2944(s), 1731(vs), 1584(s),
1255(s), 1038(s), 788(m). Anal. calcd for C18H19NO3: C, 72.71;
H, 6.44; N, 4.71. Found: C, 72.92; H, 6.36; N, 4.87.
4.2.21. (E)-Methyl 4-styryl-5,6,7,8-tetrahydroquinoline-2-
ACCEPTED MANUSCRIPT
carboxylate (3u). 71% yield (217 mg), white solid, M.p. 123-124
ꢁ. H NMR (400 MHz, CDCl3)δ 8.11 (s, 1H), 7.50 (d, J = 7.2
1
Hz, 2H), 7.19-7.36 (m, 5H), 3.95 (s, 3H), 2.82-3.02 (m, 4H),
1.57-1.59 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 166.3, 158.5,
144.7, 144.6, 136.3, 134.7, 133.3, 128.8, 128.7, 127.0, 122.7,
118.7, 52.8, 33.4, 26.2, 22.4(1), 22.3(6). MS (ESI, m/z) 294.3 (M
+ H+), 316.3 (M + Na+). IR (film) v/cm-1 2940(s), 1709(vs),
1585(m), 1455(s), 1224(vs), 970(m), 761(m). Anal. calcd for
C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.54; H, 6.45;
N, 4.89.
4.2.16.
4-(2,4-dichlorophenyl)-2-phenyl-5,6,7,8-
tetrahydroquinoline (3p). 83% yield (208 mg), yellow solid, M.p.
1
140-141 ꢁ. H NMR (400 MHz, CDCl3)δ 7.96-7.98 (m, 2H),
7.30-7.52 (m, 6H), 7.15-7.17 (m, 1H), 3.06-3.11 (m, 2H), 2.37-
2.55 (m, 2H), 1.91-1.96 (m, 2H), 1.75-1.81 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 157.8, 154.3, 146.7, 139.4, 137.0, 134.4,
133.4, 131.0, 129.5, 129.0, 128.6(1), 128.5(6), 127.2, 126.8,
118.6, 33.3, 26.4, 23.0, 22.7. MS (ESI, m/z) 354.2 (M + H+),
376.2 (M + Na+). IR (film) v/cm-1 2939(s), 1605(s), 1541(m),
1491(vs), 1094(m), 837(vs). Anal. calcd for C21H17Cl2N: C,
71.20; H, 4.84; N, 3.95. Found: C, 71.22; H, 4.86; N, 3.94.
4.2.22. Methyl 4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-
2-carboxylate (4a). 86% yield (125 mg), white solid, M.p. 108-
109 ꢁ. 1H NMR (400 MHz, CDCl3)δ 7.97 (s, 1H), 7.38-7.47 (m,
5H), 3.96 (s, 3H), 3.12 (t, J = 7.6 Hz, 2H), 3.04 (t, J = 7.6 Hz,
2H), 2.07-2.14 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.3,
166.2, 146.4, 145.8, 138.8, 137.6, 128.6, 128.1, 122.8, 52.7, 34.5,
31.0, 23.5. MS (ESI, m/z) 254.2 (M + H+), 276.2 (M + Na+). IR
(film) v/cm-1 2948(s), 1731(vs), 1585(s), 1361(m), 1239(vs),
993(m), 769(s). Anal. calcd for C16H15NO2: C, 75.87; H,5.97; N,
5.53. Found: C, 75.69; H, 6.11; N, 5.65.
4.2.17. 4-(4-nitrophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline
1
(3q). 71% yield (190 mg), yellow solid, M.p. 188-189 ꢁ. H
NMR (400 MHz, CDCl3)δ 8.31-8.34 (m, 2H), 7.96-7.98 (m, 2H),
7.37-7.54 (m, 6H), 3.11 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 6.4 Hz,
2H), 1.94-1.97 (m, 2H), 1.77-1.80 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 158.2, 154.6, 147.9, 147.4, 146.4, 139.2, 129.6, 128.8,
128.7, 127.8, 126.8, 123.6, 118.3, 33.3, 27.2, 22.9(1), 22.8(5).
MS (ESI, m/z) 331.2 (M + H+), 353.2 (M + Na+). IR (film) v/cm-1
3066(s), 2950(s), 2835(s), 1529(vs), 1337(vs), 823(vs). Anal.
calcd for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C,
76.36; H, 5.48; N, 8.49.
4.2.23. 2,4-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyridine (4b).
86% yield (313 mg), white solidꢀ M.p. 145-146 ꢁ. H NMR
1
(400 MHz, CDCl3)δ 7.98-8.00 (m, 2H), 7.39-7.55 (m, 9H), 3.17
(t, J = 7.6 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H), 2.12-2.19 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 166.6, 156.4, 145.8, 139.9, 139.0,
133.0, 128.5, 128.3, 128.1(3), 128.0(6), 126.9, 117.9, 34.7, 30.5,
23.4. MS (ESI, m/z) 272.2 (M + H+), 294.2 (M + Na+). IR (film)
v/cm-1 3052(w), 2938(vs), 1605(vs), 1375(vs), 1017(s), 695(vs).
Anal. calcd for C20H17N: C, 88.52; H, 6.31; N, 5.16. Found: C,
88.55; H, 6.33; N, 5.15.
4.2.18.
Methyl
4-(p-tolyl)-5,6,7,8-tetrahydroquinoline-2-
carboxylate (3r). 66% yield (280 mg),white solid,M.p. 107-108
1
ꢁ. H NMR (400 MHz, CDCl3)δ 7.76 (s, 1H), 7.19-7.21 (m,
2H), 7.13-7.15 (m, 2H), 3.93 (s, 3H), 3.05 (t, J = 6.4 Hz, 2H),
2.65 (t, J = 6.4 Hz, 2H), 2.36 (s, 3H), 1.85-1.88 (m, 2H), 1.67-
1.70 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 166.2, 158.3,
150.4, 144.7, 137.9, 135.5, 134.3, 129.0, 128.3, 123.6, 52.7, 33.2,
27.8, 22.7, 22.6, 21.2. MS (ESI, m/z) 282.2 (M + H+), 304.2 (M +
Na+). IR (film) v/cm-1 2940(vs), 1709(vs), 1594(s), 1517(s),
1446(vs), 1246(vs), 1124(vs), 808(vs). Anal. calcd for
C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.74; H, 6.76;
N, 5.11.
4.2.24. 2,4-diphenyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
(4c). 72% yield (167 mg), white solid, M.p. 141-142 ꢁ. 1H NMR
(400 MHz, CDCl3)δ 7.99-8.01 (m, 2H), 7.30-7.46 (m, 9H), 3.13
(t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 1.88-1.91 (m, 2H),
1.46-1.51 (m, 4H), 1.36-1.41 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 161.8, 153.9, 150.3, 140.6, 139.7, 131.7, 128.6, 128.5,
128.3, 128.1, 127.5, 126.8, 119.7, 35.6, 31.3, 30.9, 27.1, 26.6,
25.8. MS (ESI, m/z) 314.2 (M + H+), 336.2 (M + Na+). IR (film)
v/cm-1 3052(w), 2912(vs), 1605(s), 1427(s), 1169(m), 773(vs).
Anal. calcd for C23H23N: C, 88.13; H, 7.40; N, 4.47. Found: C,
88.15; H, 7.44; N, 4.45.
4.2.19. 2-phenyl-4-(p-tolyl)-5,6,7,8-tetrahydroquinoline (3s).
1
87% yield (197 mg), yellow solid, M.p. 105-106 ꢁ. H NMR
(400 MHz, CDCl3)δ 7.96-7.98 (m, 2H), 7.25-7.46 (m, 8H), 3.09
(t, J = 6.4 Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H), 1.92-
1.95 (m, 2H), 1.74-1.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
157.5, 154.2, 150.2, 139.8, 137.5, 136.7, 128.9, 128.6, 128.4(4),
128.4(1), 128.3, 126.8, 119.1, 33.3, 27.3, 23.1, 23.0, 21.2. MS
(ESI, m/z) 300.2 (M + H+), 322.2 (M + Na+). IR (film) v/cm-1
3052(w), 2965(s), 2860(m), 1581(vs), 1427(vs), 811(s). Anal.
calcd for C22H21N: C, 88.25; H, 7.07; N, 4.68. Found: C, 88.28;
H, 7.09; N, 4.65.
4.2.25. Methyl 7-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline-2-
carboxylate (4d). 72% yield (205 mg),yellow solid, M.p. 65-66
ꢁ. H NMR (400 MHz, CDCl3)δ 7.85 (s, 1H), 7.41-7.47 (m,
1
3H), 7.30-7.32 (m, 2H), 4.00 (s, 3H), 3.26 (q, J = 4.4 Hz, 1H),
2.65-2.76 (m, 2H), 1.86-2.05 (m, 2H), 1.27-1.33 (m, 2H), 1.12 (d,
J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.0, 158.2,
150.2, 144.8, 138.4, 133.6, 128.3, 128.2, 128.0, 123.5, 52.7, 41.7,
30.6, 28.9, 27.2, 21.5. MS (ESI, m/z) 282.2 (M + H+), 304.2 (M +
Na+). IR (film) v/cm-1 3446(m), 2944(vs), 2216(s), 1740(vs),
1445(m), 1134(m), 926(m). Anal. calcd for C18H19NO2: C, 76.84;
H, 6.81; N, 4.98. Found: C, 77.01; H, 7.02; N, 4.87.
4.2.20. 2-phenyl-4-(m-tolyl)-5,6,7,8-tetrahydroquinoline (3t).
1
84% yield (154 mg), yellow oil. H NMR (400 MHz, CDCl3)δ
7.96-7.98 (m, 2H), 7.32-7.46 (m, 5H), 7.13-7.22 (m, 3H), 3.09 (t,
J = 6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H), 1.91-1.95
(m, 2H), 1.74-1.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
157.3, 154.0, 150.2, 139.6, 139.5, 137.7, 129.0, 128.4, 128.2,
128.0, 126.6, 125.4, 118.8, 33.2, 27.1, 23.0, 22.9, 21.3. MS (ESI,
m/z) 300.2 (M + H+), 322.2 (M + Na+). IR (film) v/cm-1 3052(w),
1605(vs), 1375(s), 1055(w), 887(m), 747(vs). Anal. calcd for
C22H21N: C, 88.25; H, 7.07; N, 4.68. Found: C, 88.27; H, 7.08; N,
4.66.
4.2.26. 7-methyl-2,4-diphenyl-5,6,7,8-tetrahydroquinoline (4e).
1
65% yield (198 mg), white solidꢀ M.p. 102-103 ꢁ. H NMR
(400 MHz, CDCl3)δ 7.97-7.99 (m, 2H), 7.33-7.48 (m, 9H), 3.19-
3.24 (m, 1H), 2.66-2.71 (m, 2H), 1.85-2.05 (m, 2H), 1.26-1.39
(m, 2H), 1.13 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
157.5, 154.3, 150.0, 139.8, 139.7, 128.6, 128.5, 128.4, 128.3,
127.8, 127.7, 126.8, 119.0, 41.9, 31.2, 29.3, 26.9, 21.8. MS (ESI,
m/z) 300.2 (M + H+), 322.2 (M + Na+). IR (film) v/cm-1 3041(w),
2924(vs), 1567(vs), 1247(vs), 1067(vs), 823(vs). Anal. calcd for

6
Tetrahedron
C22H21N: C, 88.25; H, 7.07; N, 4.68. Found: C, 88.28; H, 7.09;
4.2.33. 2-ethyl-3-methyl-4,6-diphenylpyridine (4l). 68% yield
ACCEPTED MANUSCRIPT
N, 4.66.
(145 mg), yellow oil. 1H NMR (400 MHz, CDCl3)δ 8.02-8.04 (m,
2H), 7.31-7.45 (m, 9H), 2.95 (q, J = 7.6 Hz, 2H), 2.22 (s, 3H),
1.41 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 161.7,
153.4, 150.3, 140.4, 139.7, 128.7, 128.5, 128.4, 128.3, 128.2,
127.9, 127.5, 126.6, 126.5, 118.9, 29.2, 15.3, 12.8.MS (ESI, m/z)
274.2 (M + H+), 296.2 (M + Na+). IR (film) v/cm-1 2976(vs),
1939(m), 1683(vs), 1427(vs), 1209(s), 875(s). Anal. calcd for
C20H19N: C, 87.87; H, 7.01; N, 5.12. Found: C, 87.82; H, 6.96; N,
5.14.
4.2.27. Methyl 6-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline-2-
carboxylate (4f). 74% yield (211 mg), yellow solid, M.p. 56-57
1
ꢁ. H NMR (400 MHz, CDCl3)δ 7.84 (s, 1H), 7.43-7.49 (m,
3H), 7.29-7.32 (m, 2H), 3.99 (s, 3H), 3.20-3.27 (m, 1H), 3.04-
3.13 (m, 1H), 2.71-2.76 (m, 1H), 2.32-2.39 (m, 1H), 2.00-2.05
(m, 1H), 1.77-1.84 (m, 1H), 1.53-1.60(m, 1H), 1.01 (d, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1, 158.2, 150.3,
144.7, 138.4, 133.8, 128.4(2), 128.4(0), 128.1, 123.6, 52.8, 36.1,
32.9, 30.9, 28.9, 21.5. MS (ESI, m/z) 282.2 (M + H+), 304.2 (M +
Na+). IR (film) v/cm-1 3420(w), 2961(s), 1723(vs), 1454(m),
1238(vs), 779(m), 692(m). Anal. calcd for C18H19NO2: C, 76.84;
H, 6.81; N, 4.98. Found: C, 76.69; H, 7.08; N, 5.21.
4.2.34. 2-ethyl 6-methyl 4-phenylpyridine-2,6-dicarboxylate
1
(4m). 74% yield (184 mg), white solid, M.p. 42-43 ꢁ. H NMR
(400 MHz, CDCl3)δ 8.48-8.50 (m, 2H), 7.70-7.73 (m, 2H), 7.46-
7.50 (m, 3H), 4.48 (q, J = 6.8 Hz, 2H), 4.01 (s, 3H), 1.44 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.3, 164.8, 151.1,
149.2, 148.9, 136.2, 130.1, 129.4, 127.2, 125.6(4), 125.5(7), 62.5,
53.2, 14.3. MS (ESI, m/z) 286.1 (M + H+). IR (film) v/cm-1
2987(s), 2239 (m), 1716(vs), 1438(s), 1245(s), 1032(s), 908(s).
Anal. calcd for C16H15NO4: C, 67.36; H,5.30; N, 4.91. Found: C,
67.49; H, 5.54; N, 5.12.
4.2.28. 6-methyl-2,4-diphenyl-5,6,7,8-tetrahydroquinoline (4g).
77% yield (213 mg), white solid, M.p. 109-110 ꢁ. 1H NMR (400
MHz, CDCl3)δ 7.96-7.99 (m, 2H), 7.33-7.49 (m, 9H), 3.04-3.22
(m, 2H), 2.66-2.71 (m, 1H), 2.28-2.35 (m, 1H), 1.79-2.03 (m,
2H), 1.51-1.61 (m, 1H), 1.02 (d, J = 6.4 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 157.2, 154.1, 150.0, 139.5(3), 139.5(0), 128.4(1),
128.3(8), 128.3, 128.2, 127.7, 127.5, 126.7, 118.9, 35.5, 33.0,
31.2, 29.1, 21.6. MS (ESI, m/z) 300.2 (M + H+), 322.2 (M +
Na+). IR (film) v/cm-1 2938(vs), 1721(s), 1555(vs), 1427(vs),
1081(m), 773(vs). Anal. calcd for C22H21N: C, 88.25; H, 7.07; N,
4.68. Found: C, 88.27; H, 7.08; N, 4.66.
4.2.35. Methyl 4-phenylpicolinate (4n). 62% yield (347 mg),
brown oil. 1H NMR (400 MHz, CDCl3)δ 8.80-8.81 (m, 1H), 8.41
(d, J = 1.6 Hz, 1H) 7.50-7.73 (m, 6H), 4.07 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 165.7, 150.1, 149.5, 148.3, 136.9, 129.5,
129.1, 126.9, 124.5, 122.9, 52.8. MS (ESI, m/z) 214.1 (M + H+),
236.1 (M + Na+). IR (film) v/cm-1 3064(w), 3032(w), 2948(m),
2239(w), 1739(vs), 1608(s), 1438(s), 1316(s), 961(m), 754(s).
Anal. calcd for C13H11NO2: C, 73.23; H, 5.20; N, 6.57. Found: C,
73.10; H, 5.45; N, 6.30.
4.2.29. Methyl 6-methyl-4-phenylpicolinate (4h). 84% yield (169
1
mg), yellow oil. H NMR (400 MHz, CDCl3)δ 8.15 (d, J = 1.2
Hz, 1H), 7.61-7.63 (m, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.40-7.46
(m, 3H), 3.97 (s, 3H), 2.66 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 166.0, 159.4, 149.7, 148.0, 137.3, 129.3, 129.1, 127.0, 124.4,
120.6, 52.9, 24.7. MS (ESI, m/z) 228.1 (M + H+), 250.1 (M +
Na+). IR (film) v/cm-1 2940(vs), 1724(vs), 1438(s), 1085(s),
1015(m), 769(vs), 692(s). calcd for C14H13NO2: C, 73.99; H,
5.77; N, 6.16. Found: C, 74.25; H, 5.47; N, 6.43.
4.2.36. Methyl 5-butyl-4-phenylpicolinate (4o). 81% yield (317
1
mg), brown oil. H NMR (400 MHz, CDCl3)δ 8.65 (s, 1H), 8.01
(s, 1H), 7.45-7.50 (m, 3H), 7.30-7.34 (m, 2H),4.02 (s, 3H), 2.71
(t, J = 8.0 Hz, 2H), 1.43-1.49 (m, 2H), 1.22-1.29 (m, 2H), 0.81 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.4, 150.7,
149.8, 145.0, 139.3, 137.9, 128.2, 128.1, 127.9, 125.6, 52.3, 32.6,
29.7, 21.9, 13.3. MS (ESI, m/z) 270.2 (M + H+), 292.2 (M +
Na+). IR (film) v/cm-1 2961(vs), 1731(vs), 1454(m), 1108(m),
969(w), 701(w). Anal. calcd for C17H19NO2: C, 75.81; H, 7.11;
N, 5.20. Found: C, 75.70; H, 6.86; N, 5.44.
4.2.30. 2-methyl-4,6-diphenylpyridine (4i). 56% yield (112 mg),
1
white solid, M.p. 72-73 ꢁ. H NMR (400 MHz, CDCl3)δ 8.02-
8.04 (m, 2H), 7.67-7.69 (m, 3H), 7.41-7.52 (m, 6H), 7.32-7.33
(m, 1H), 2.70 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.7,
157.6, 149.4, 139.8, 138.7, 128.9, 128.8, 128.7, 128.6, 127.1,
127.0(5), 126.9(9), 119.7, 116.0, 24.8. MS (ESI, m/z) 246.1 (M +
H+), 268.1 (M + Na+). IR (film) v/cm-1 3040(m), 1593(vs),
1387(s), 1209(w), 1041(m), 759(vs). Anal. calcd for C18H15N: C,
88.13; H, 6.16; N, 5.71. Found: C, 88.15; H, 6.17; N, 5.68.
4.2.37. 2,4,6-triphenylpyridine (4p). 83% yield (171 mg), yellow
1
solid, M.p. 138-139 ꢁ. H NMR (400 MHz, CDCl3)δ 8.20-8.22
(m, 4H), 7.90 (s, 2H), 7.75-7.77 (m, 2H), 7.43-7.56 (m, 9H). 13C
NMR (100 MHz, CDCl3) δ 157.5, 150.2, 139.6, 139.1, 129.1,
129.0(1), 128.9(5), 128.7, 127.2, 127.1, 117.1. MS (ESI, m/z)
308.2 (M + H+), 330.2 (M + Na+). IR (film) v/cm-1 3052(m),
1605(vs), 1401(s), 1055(m), 849(m), 683(vs). Anal. calcd for
C23H17N: C, 89.87; H, 5.57; N, 4.56. Found: C, 89.89; H, 5.58; N,
4.55.
4.2.31. Methyl 6-isopropyl-5-methyl-4-phenylpicolinate (4j). 85%
yield (313 mg), yellow solid,M.p. 44-45 ꢁ. 1H NMR (400 MHz,
CDCl3)δ 8.22 (d, J = 1.6 Hz, 1H), 7.69-7.71 (m, 2H), 7.47-7.54
(m, 3H), 4.03 (s, 3H), 2.17-2.25 (m, 1H), 1.58 (s, 3H), 0.97 (d, J
= 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 166.3, 162.7,
149.4, 148.3, 137.6, 129.3, 129.2, 127.1, 124.5, 120.8, 53.0, 47.5,
29.2, 22.4. MS (ESI, m/z) 270.2 (M + H+). IR (film) v/cm-1
2963(vs), 1716(vs), 1594(s), 1446(s), 1254(s), 769(m), 684(m).
Anal. calcd for C17H19NO2: C, 75.81; H,7.11; N, 5.20. Found: C,
75.77; H, 6.86; N, 5.33.
4.2.38. 2-isobutyl-4,6-diphenylpyridine (4q). 77% yield (155
mg), yellow oil. 1H NMR (400 MHz, CDCl3)δ 8.04-8.06 (m, 2H),
7.68-7.74 (m, 3H), 7.40-7.51 (m, 6H), 7.24-7.27 (m, 1H), 2.80 (d,
J = 7.2 Hz, 2H), 2.24-2.33(m, 1H), 1.01 (d, J = 6.8 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ 162.0, 157.5, 149.2, 140.0, 139.0,
129.0, 128.8, 128.6(9), 128.6(5), 127.1, 120.0, 116.1, 47.8, 29.1,
22.6.MS (ESI, m/z) 288.3 (M + H+), 310.3 (M + Na+). IR (film)
v/cm-1 3028(vs), 1965(m), 1709(m), 1541(vs), 1093(vs), 875(vs).
Anal. calcd for C21H21N: C, 87.76; H, 7.36; N, 4.87. Found: C,
87.79; H, 7.38; N, 4.86.
4.2.32. Methyl 6-ethyl-5-methyl-4-phenylpicolinate (4k). 65%
yield (305 mg), yellow oil. 1H NMR (400 MHz, CDCl3)δ 7.88 (s,
1H), 7.43-7.49 (m, 3H), 7.31-7.33 (m, 2H), 4.00 (s, 3H), 3.02 (q,
J = 7.6 Hz, 2H), 2.32 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 166.2, 163.0, 150.7, 144.5, 139.1, 132.4,
128.6, 128.4, 128.0, 124.0, 52.7, 29.5, 16.0, 13.1. MS (ESI, m/z)
256.2 (M + H+), 278.2 (M + Na+). IR (film) v/cm-1 2963(vs),
2239(w), 1747(vs), 1594(m), 1231(m), 778(s). Anal. calcd for
C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.10; H, 6.63;
N, 5.61.
4.2.39. Methyl 5-(6-methylhept-5-en-2-yl)-4-phenylpicolinate
(4r). 92% yield (453 mg), yellow oil. 1H NMR (400 MHz,
CDCl3)δ 8.74 (s, 1H), 7.99 (s, 1H), 7.45-7.51 (m, 3H), 7.28-7.30
(m, 2H), 4.88 (t, J = 6.8 Hz, 1H), 4.03 (s, 3H), 3.02 (q, J = 7.2
Hz, 1H), 1.77-1.83 (m, 2H), 1.63-1.74 (m, 2H), 1.60 (s, 3H), 1.46

7
(s, 3H), 1.27 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
165.5, 149.8, 148.6, 144.6, 144.1, 137.9, 131.7, 128.3, 128.2,
127.9, 125.7, 123.3, 52.4, 37.5, 32.5, 25.6, 25.3, 21.7, 17.3. MS
(ESI, m/z) 324.3 (M + H+), 346.3 (M + Na+). IR (film) v/cm-1
2935(vs), 2233(m), 1740(vs), 1573(m), 1428(s), 1307(w),
1247(w), 1125(m), 909(w), 709(m). Anal. calcd for C21H25NO2:
C, 77.98; H, 7.79; N, 4.33. Found: C, 78.16; H, 7.87; N, 4.19.
2011, 41, 3448. (h) Tenti, G.; Ramos, M. T.; Menéndez, J. C.
ACS Comb. Sci. 2012, 14, 551.
ACCEPTED MANUSCRIPT
10. For recent reviews: (a) Liu, D.; Lei, A. Chem. Asian J. 2015, 10,
806. (b) Ren, Y.-M.; Cai, C.; Yang, R.-C. RSC Adv., 2013, 3,
7182. (c) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G.
Chem. Eur. J. 2012, 18, 5460. For recent selected examples: (d)
Guo, S.; Wan, G.; Sun, S.; Jiang, Y.; Yua, J.-T.; Cheng, J. Chem.
Commun. 2015, 51, 5085. (e) Zhu, T.-H.; Wang, S.-Y.; Tao, Y.-
Q.; Ji, S.-J. Org. Lett. 2015, 17, 1974. (f) Liu, S.; Gao, Q.; Wu, X.;
Zhang, J.; Ding, K.; Wu, A. Org. Biomol. Chem. 2015, 13, 2239.
(g) Saba, S.; Rafique, J.; Braga, A. L. Adv. Synth. Catal. 2015,
357, 1446. (h) Goswami, P.; Borah, A. J.; Phukan, P. J. Org.
Chem. 2015, 80, 438. (i) C. Zhu, Y. Zhang, H. Zhao, S. Huang, M.
Zhang, W. Su, Adv. Synth. Catal. 2015 357, 331. (j) Xiao, F.; Xie,
H.; Liu, S.; Geng, G.-J. Adv. Synth. Catal. 2014, 356, 364 (k) Wu,
X.; Gao, Q.; Liu, S.; Wu, A. Org. Lett. 2014, 16, 2888. (l) Zi, Y.;
Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2014, 16, 3094. (m)
Jiang, Q.; Xu, B.; Zhao, A.; Jia, J.; Liu, T.; Guo, C. J. Org. Chem.
2014, 79, 8750. (n) Huang, H.-M.; Li, Y.-J.; Ye, Q.; Yu, W.-B.;
Han, L.; Jia, J.-H.; Gao, J.-R. J. Org. Chem. 2014, 79, 1084. (o) C
Zhu, W Wei, P Du, X Wan, Tetrahedron. 2014, 70, 9615. (p)
Zhang, J.; Shao, Y.; Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X.
Org. Lett. 2014, 16, 3312. (q) Dhineshkumar, J.; Lamani, M.;
Alagiri, K.; Prabhu, K. R. Org. Lett. 2013, 15, 1092. (r) Nobuta,
T.; Tada, N.; Fujiya, A.; Kariya, A.; Miura, T.; Itoh, A. Org. Lett.
2013, 15, 574. (s) Xu, W.; Kloeckner, U.; Nachtsheim, B. J. J.
Org. Chem., 2013, 78, 6065. (t) Wei, W.; Shao, Y.; Hu, H.;
Zhang, F.; Zhang, C.; Xu, Y.; Wan, X. J. Org. Chem. 2012, 77,
7157. (u) Ge, W.; Wei, Y. Green Chem., 2012, 14, 2066.
Acknowledgements
We acknowledge the Natural Science Foundation of China (No.
1601310045 and 21271090) and Jiangsu University Foundation
(No. 1281310043).
Supplementary data
Copies of 1H and/or 13C spectra for isolated products.
Supplementary data associated with this article can be found
online.
References and notes
1. (a) Bora, D.; Deb, B.; Fuller, A. L.; Slawin, A. M. Z.; Derek
Woollins, J.; Dutta, D. K. Inorg. Chim. Acta 2010, 363, 1539. (b)
Zhou, M.-D.; Jain, K. R.; Günyar, A.; Baxter, P. N. W.;
Herdtweck, E.; Kühn, F. E. Eur. J. Inorg. Chem. 2009, 2907. (c)
Chan, Y.-T.; Moorefield, C. N.; Soler, M.; Newkome, G. R.
Chem. Eur. J. 2010, 16, 1768. (d) Belhadj, E.; El-Ghayoury, A.;
Mazari, M.; Sallé, M. Tetrahedron Lett. 2013, 54, 3051.
2. (a) Functional Organic Materials; Müller, T. J. J., Bunz, U. H. F.,
Eds.; Wiley-VCH: Weinheim, 2007. (b) Makiura, R.; Motoyama,
S.; Umemura, Y.; Yamanaka, H.; Sakata, O.; Kitagawa, H. Nat.
Mater. 2010, 9, 565.
11. (a) Yan, Y. Z.; Zhang, Y. H.; Feng, C. T.; Zha, Z. G.; Wang, Z. Y.
Angew. Chem., Int. Ed. 2012, 51, 8077. (b) Yan, Y. Z.; Zhang, Y.
H.; Zha, Z. G.; Wang, Z. Y. Org. Lett. 2013, 15, 2274
12. Cai, Z.-J.; Lu, X.-M.; Zi, Y.; Yang, C.; Shen, L.-J.; Li, J.; Wang,
S.-Y.; Ji, S.-J. Org. Lett. 2014, 16, 5108.
13. Tang, S.; Liu, K.; Long, Y.; Gao, X.; Gao, M.; Lei, A. Org. Lett.
2015, 17, 2404.
14. (a) Zhu, C.; Bi, B.; Ding, Y.; Zhang, T.; Chen, Q.-Y. Org. Biomol.
Chem., 2015, 13, 6278. (b) Zhu, C.; Bi, B.; Yao, D.; Chen, Q.-Y.;
Luo, Z.-B. Synthesis, 2015, 47, 1877.
15. (a) Xu, Z.; Liu, L.; Wheeler, K.; Wang, H. Angew. Chem. 2011,
123, 3546; Angew. Chem. Int. Ed. 2011, 50, 3484. (b) Deng, Y.;
Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z. Angew.
Chem., Int. Ed. 2013, 52, 3663. (c) Liu, L.; Sarkisian, R.; Deng,
Y.; Wang H. J. Org. Chem. 2013, 78, 5751.
3. (a) Lehn, J.-M. Supramolecular Chemistry Concepts and
Perspectives; VCH: Weinheim, 1995. (b) Schubert, U. S.;
Eschbaumer, C. Angew. Chem., Int. Ed. 2002, 41, 2892. (c)
Hofmeier, H.; Schubert, U. S. Chem. Commun. 2005, 2423. (d)
Šmejkal, T.; Breit, B. Angew. Chem. Int. Ed. 2008, 47, 311.
4. (a) Jarusiewicz, J.; Yoo, K.; Jung, K. Synlett 2009, 482. (b)
Shibatomi, K.; Muto, T.; Sumikawa, Y.; Narayama, A.; Iwasa, S.
Synlett 2009, 241. (c) Lin, S.; Lu, X. Org. Lett. 2010, 12, 2536.
5. (a) Zheng, H.; Deng, J.; Lin, W.; Zhang, X. Tetrahedron Lett.
2007, 48, 7934; (b) Guizzetti, S.; Benaglia, M.; Rossi, S.; Org.
Lett. 2009, 11, 2928; (c) Coeffard, V.; Müller-Bunz, H.; Guiry, P.
J. Org. Biomol. Chem. 2009, 7, 1723. (d) Felten, A.; Zhu, G.;
Aron, Z. D. Org. Lett. 2010, 12, 1916. (e) Fang, P.; Chaulagain,
M. R.; Aron, Z. D. Org. Lett. 2012, 14, 2130.
6. (a) Fuks, L.; Gniazdowska, E.; Mieczkowski, J.; Sadlej-
Sosnowska, N. Polyhedron 2008, 27, 1353; (b) Betts, H. M.;
Barnard, P. J.; Bayly, S. R.; Dilworth, J. R.; Gee, A. D.; Holland,
J. P. Angew. Chem. 2008, 120, 8544; Angew. Chem. Int. Ed. 2008,
47, 8416.
7. Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
8. For recent selected examples: (a) Shen, Y., Chen, J., Liu, M.,
Ding, J., Gao, W., Huang, X., Wu, H. Chem. Commun. 2014, 50,
593. (b) Jiang, Y.; Park, C.-M.; Loh T.-P. Org. Lett. 2014, 16,
3432. (c) Satoh, Y.; Obora, Y. J. Org. Chem. 2013, 78, 7771. (d)
Onodera, G.; Shimizu, Y.; Kimura, J.; Kobayashi, J.; Ebihara, Y.;
Kondo, K.; Sakata, K.; Takeuchi, R. J. Am. Chem. Soc. 2012, 134,
10515. (e) Souza, B. R. D.; Lane, T. K.; Louie, J. Org. Lett. 2011,
13, 2936. (f) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew. Chem. Int.
Ed. 2011, 50, 7162. (g) Kumar, P.; Prescher, S.; Louie, J. Angew.
Chem., Int. Ed. 2011, 50, 10694. (h) Kral, K.; Hapke, M. Angew.
Chem., Int. Ed. 2011, 50, 2434. (i) Hapke, M.; Kral, K.; Fischer,
C.; Spannenberg, A.; Gutnov, A.; Redkin, D.; Heller, B. J. Org.
Chem. 2010, 75, 3993. (j) Komine, Y.; Tanaka, K. Org. Lett.
2010, 12, 1312 (k) Hill, M. D. Chem. Eur. J. 2010, 16, 12052.
9. For recent selected reviews on MCRs applied to the synthesis of
pyridines: (a) Brauch, S.; Berkel, S. S.; van Westermann, B.
Chem. Soc. Rev. 2013, 42, 4948. (b) Allais, C.; Grassot, J.-M.;
Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114, 10829. For
selected examples: (c) Allais, C.; Constantieux, T.; Rodriguez, J.
Chem. Eur. J. 2009, 15, 12945. (d) Sanchez Duque, M. M.; Allais,
C.; Isambert, N.; Constantieux, T.; Rodriguez, J. Top. Heterocycl.
Chem. 2010, 23, 227. (e) Geng, L.-J.; Feng, G.-L.; Yu, J.-G. J.
Chem. Res. 2010, 34, 565. (f) Geng, L.-J.; Feng, G.-L.; Yu, J.-G.;
Zhang, H.-L. J. Chem. Res. 2011, 35, 74. (g) Geng, L.-J.; Feng,
G.-L.; Yu, J.-G.; Zhang, H.-L.; Zhang, Y.-M. Synth. Commun.