The first example of glucose-containing carbene Br?nsted acid synthesis and catalysis: Efficient synthesis of five substituted tetrahydropyridines

Article abstract of DOI:10.1016/j.tet.2015.06.062

β-1-Imidazole-2,3,4,6-tetrasulfonic-D-glucopyranosyl bisulfate ([Bmim-G-(SO₃H)₄]⁺[HSO₄]^-, I) was synthesized for the first time and used as an efficient catalyst to prepare five-substituted tetrahydropyridines via the three-component condensation of aromatic aldehyde, aromatic aniline and ethyl acetoacetate in ethanol at 40 °C. Six bonds were cleaved while five new bonds and one new ring were formed in one-pot with water as the only one by-product in this highly atom-economic reaction. The work opens up a new and efficient synthesis and application of sugar-containing carbene Br?nsted acid.

Full text of DOI:10.1016/j.tet.2015.06.062

Accepted Manuscript
The First Example of Glucose-containing Carbene Brønsted Acid Synthesis and
Catalysis: Efficient Synthesis of Five Substituted Tetrahydropyridines
Qiu-ju Zhou, Yu Wan, Xiao-xiao Zhang, Li-zhuo Zhang, Huan Zou, Hao Cui, Sheng-
liang Zhou, Hai-ying Wang, Hui Wu
PII:
S0040-4020(15)00959-X
10.1016/j.tet.2015.06.062
TET 26898
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 December 2014
Revised Date: 14 June 2015
Accepted Date: 16 June 2015
Please cite this article as: Zhou Q-j, Wan Y, Zhang X-x, Zhang L-z, Zou H, Cui H, Zhou S-l, Wang H-
y, Wu H, The First Example of Glucose-containing Carbene Brønsted Acid Synthesis and Catalysis:
Efficient Synthesis of Five Substituted Tetrahydropyridines, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.06.062.
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β-1-Imidazole-2,3,4,6-tetrasulfonic-D-
The First Example of Glucose-containing Carbene
Brønsted Acid Synthesis and Catalysis: Efficient
Synthesis of Five Substituted Tetrahydropyridines
glucopyranosyl bisulfate ([Bmim-G-
(SO3H)4]+[HSO4]-, I) was synthesized
for the first time and used as an
efficient catalyst to prepare five-
substituted tetrahydropyridines via the
three-component condensation of
aromatic aldehyde, aromatic aniline
and ethyl acetoacetate in ethanol at
40°C. Six bonds were cleaved while
five new bonds and one new ring were
formed in one-pot with water as the
only one by-product in this highly
atom-economic reaction. The work
opens up a new and efficient synthesis
and application of sugar-containing
carbene Brønsted acid.
Qiu-ju Zhoua, Yu Wanb*, Xiao-xiao Zhanga, Li-zhuo Zhanga,
Huan Zoua, Hao Cuia, Sheng-liang Zhoub, Hai-ying Wanga,
Hui Wua,b*
a School of Chemistry and Chemical Engineering, Jiangsu
Normal University, Xuzhou 221116, P. R. China
b State Key Laboratory Cultivation Construction Base of
Biotechnology on Med-edible Plant of Jiangsu Province,
Jiangsu Normal University, Xuzhou, 221116, P. R.

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
The First Example of Glucose-containing Carbene Brønsted Acid Synthesis and
Catalysis: Efficient Synthesis of Five Substituted Tetrahydropyridines
Qiu-ju Zhoua‡, Yu Wanb‡, Xiao-xiao Zhanga, Li-zhuo Zhanga, Huan Zoua, Hao Cuia, Sheng-liang Zhoub,
Hai-ying Wanga, Hui Wua,b*
a School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, P. R. China
b State Key Laboratory Cultivation Construction Base of Biotechnology on Med-edible Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou, 221116,
P. R. China
ARTICLE INFO
ABSTRACT
β-1-Imidazole-2,3,4,6-tetrasulfonic-D-glucopyranosyl bisulfate ([Bmim-G-(SO3H)4]+[HSO4]-,
I) was synthesized for the first time and used as an efficient catalyst to prepare five-substituted
tetrahydropyridines via the three-component condensation of aromatic aldehyde, aromatic
aniline and ethyl acetoacetate in ethanol at 40°C. Six bonds were cleaved while five new bonds
and one new ring were formed in one-pot with water as the only one by-product in this highly
atom-economic reaction. The work opens up a new and efficient synthesis and application of
sugar-containing carbene Brønsted acid.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Glucose sulfonic acid
Catalysis
Five-substituted tetrahydropyridines
2014 Elsevier Ltd. All rights reserved
.
1. Introduction
The five-substituted tetrahydropyridines are widely distributed
in many natural products, biologically active molecules and
organic Finechemicals.16 They are also the key structural units of
many important synthetic bioactive molecules or drugs such as
antibacterial,17 anti-inflammation agent,18 antineoplastic19-20 and
mental disorder drugs.21
Glucose is an important nature product bearing five hydroxyl
groups. As a cheap and readily available substance, its
physiological and pharmacological activity has been widely
investigated.1 However, its application in synthetic chemistry,
especially as a catalyst, is relatively rare concerned. By far, it is
mainly used as surfactant,2 carrier to extract and separate protein
from complex system3 and substrate in asymmetric organic
synthesis.4 Although possessing five hydroxyl groups in its
framework, glucose is not active enough to be an organocatalyst.
Therefore, it should be functionalized and introduced active sites
into its framework if we want to use it as catalyst or enhance its
catalysis.
Recently the researches on MCRs in which more than four
components were used are of great important in organic
chemistry due to their higher efficiency and atom economy and
have already become a trend of organic chemistry. However,
related researches are still not full enough to meet the demand of
researches. Only several groups investigated these kind of MCRs.
Bonfield et al. reported a six-compound to prepare isoindoline
via tandem double A3-coupling and [2+2+2]-cyclo-addition
reaction.22 Brauch et al. have extended MCRs to seven
components by taking advantage of the different
chemoselectivities of the Ugi-Mumm and the Ugi-Smiles
reaction.23 Orru group developed a one-pot reaction of up to eight
components that involves nine new bond formation and eleven
points of diversity.24 A key factor of a successful MCR is to
choose an efficient and appropriate.
N-heterocyclic carbenes (NHCs) have become versatile
neutral ligands for catalysis since 1991.5 They also play
important roles in catalysis6 and biomedical applications7 as well
as other fields such as luminescent and functional materials
applications.8 Carbohydrate-containing metal NHC complexes
such as Ag(I),9-10 Ni(II),11 Pd(II),5 Pt(II),12 Ru(III),13 Ir(III)11,14
and Rh(III)14 have ever been synthesized and used as the efficient
catalyst of organic reaction.5,13,15
*
———
* Corresponding author. Tel.: +86051683536977; fax: +86051683536977; e-mail: wuhui72@aliyun.com

2
Tetrahedron
Glucose sulfonic acid (GSA), a sulfonic group functional
reaction. It was also realized that the process was efficiently
ACCEPTED MANUSCRIPT
glucose which is synthesized in our lab, is proved to be an
efficient, inexpensive, non-toxic, non-metallic, readily available
and
facilitated at 40°C (Table 1, Entry 13). However, elevating the
temperature did not enhance the yields of products (Table 1,
Entry 12).
environmentally
benign
catalyst
to
afford
tetrahydrobenzo[α]xanthens and tetrahydrobenzo[α]acridines in
To explore the application of this method, the scope of the
substrates was evaluated with a variety of aromatic aldehydes
and aromatic anilines (Table 2). It showed that aromatic
aldehydes and aromatic amine can afford moderate to high yield
of product 4 and the product can be separated easily. The electric
and effect and steric hindrance had no regular influence on the
yields.
water firstly in our previous work.25
To obtain these potential units in high the type and
application of sugar-containing Brønsted acid, we herein
introduced a carbene unit into the GSA framework to give a
novel and efficient functional catalyst β-1-imidazole-2,3,4,6-
tetrasulfonic-D-gluco-pyranosyl
bisulfate
([Bmim-G-
(SO3H)4]+[HSO4]-, I) firstly. It’s catalytic activity was then
evaluated based on the three-component condensation of
aromatic aldehyde (2 eq.), aromatic aniline (2 eq.), ethyl
acetoacetate (1 eq.) in ethanol at 40oC to afford a series of five-
substituted tetrahydropyridines efficiently (Scheme 1).
Table 2 Synthesis of 4 under optimum conditionsa
Yield
Comp.
Ar
Ar1
Mp/°C
/ % b
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
C6H5
3-FC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
83
60
76
83
65
53
55
71
70
80
77
71
64
54
80
76
55
60
63
70
198-199
150-153
193-195
233-236
184-185
218-220
220-222
166-168
222-224
171-172
196-197
187-189
229-232
186-186
208-209
230-231
193-194
195-200
199-202
250-252
4-ClC6H4
4-CNC6H4
4-OHC6H4
4-CH3C6H4
2-CH3OC6H4
2,3-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
C6H5
4-ClC6H4
C6H5
3-FC6H4
4-FC6H4
C6H5
3-FC6H4
4-FC6H4
4-ClC6H4
C6H5
Scheme 1. Synthesis of five-substituted tetrahydropyridines
2. Results and discussion
Firstly, the optimal reaction condition was tested based on the
synthesis of 4a (Table 1). From Table 1, this transformation
could not run smoothly in the presence of catalysts such as
TsOH, L-proline and Cl-SO3H (Table 1, Entries 1-3). SSA could
catalyze this reaction but with lower yield against I (Table 1,
Entries 4 and 5, respectively), which indicated that strong acid
condition was the key factor of this reaction. While increasing
loading of I to 10 mol%, 4a was afforded in 75% yield (Table 1,
Entry 5), which showed the important role of catalyst
concentration in the reaction. However, the yield decreased
unexpectedly when the molar amount of catalyst was over 15
mol% (Table 1, Entry 7). A possible reason is that the starting
4t
a All reactions were carried out in the scale of 10 mol% of I in 2 mL ethanol
o
at 40 C, and starting materials (1:2:3=2.0:2.0:1.0 mmol) were completely
consumed. b Isolated yield.
Alkyl aldehyde, alkyl amine or different beta-ketone esters
(ethyl 3-oxo-3-phenylpropanoate) were used as substrates
subsequently. However, the results indicated that alkyl-
substituted aldehyde or amine could not react with other
reactants to afford product 4. Another aryl-substituted beta-
ketone ester ethyl 3-oxo-3-phenylpropanoate could also not
obtain the product like the result of most of literatures.26
Table 1 Synthesis of 4 under different conditions
Entry
Cat.
X /
mol%
Solvent
T
/ °C
t
/ h
Yield
/ %b
It is regret that no chiral product was detected which may be
due to that chiral center of catalyst I was tightly wrapped by
circumjacent sulfo groups. It also mentioned the necessity of
further modification on sugar ring if we want to get an efficient
asymmetric catalyst based on it.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
L-proline
TsOH
Cl-SO3H
SSAd
10
10
10
10
10
5
15
---
10
10
10
10
10
10
10
10
10
EtOH
EtOH
EtOH
EtOH
EtOH
60
60
60
15
15
15
Nrc
<5
20
60
60
60
60
60
60
60
60
60
40
30
r.t
15
15
15
15
15
15
15
15
15
15
15
15
10
5
62
75
70
65
16
24
Nrb
Nrb
70
85
30
25
85
83
I
I
I
---
I
I
I
I
I
I
I
I
I
EtOH
EtOH
The possible reaction mechanism was proposed in Scheme 4.
The reaction proceeds via initial formation of enamine 5 through
condensation of aromatic aldehyde 1 and aromatic aniline 2.
Meanwhile, ethyl acetoacetate 3 condense with another aromatic
aniline 2 to give enamine ester 6. Subsequently, 6 react with
another aromatic aldehyde 1 to give intermediate 7 by the
[BMIM][BF4]
[BMIM][BF4]
H2O
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Knoevenagel reaction. Intermediate
7
provide
8
via
tautomerization, then 8 cyclize with 5 to give the expected 4 by
an [4+2]-aza-Diels–Alder reaction. We supposed that the
40
40
-
important role of ([Bmim-G']+HSO4 ) in this reaction is to
aAll reactions were carried out in the scale of 2.0 mmol and in 2.0 mL of
solvent. bIsolated yields. cnot reacted. d Silica sulfuric acid.
provide an apropos acidity and supporting function.
3. Conclusion
material or the products had been destroyed when excess amount
of I was added. Ethanol is the best solvent (Table 1, Entries 7-
11) maybe due to its appropriate solubility and basicity. It seems
that [BmIm][BF4] (pKa[BF4]-=0.5) is too alkaline to meet this
-
In summary, we have developed a [Bmim-G']+HSO4 -
catalyzed three-component condensation for the construction of
five-substituted tetrahydropyridines from commercially available

-
materials. ([Bmim-G']+HSO4 ) showed its important role in this
Rev. 2012, 41(21), 7032-7060.
ACCEPTED MANUSCRIPT
interesting reaction. One ring of the fused-ring framework was
constructed in one-pot. This method offers several advantages
including cheap starting materials, low catalyst loading and no
formation of by-products. In addition, there are several
modifiable and coordinate sites in this framework, so the
subsequent structural optimization should be possible.
7. (a) Oehninger, L.; Rubbiani, R.; Ott, I. Dalton Trans.
2013, 42(10), 3269-3284. (b) Liu, W.; Gust, R. Chem.
Soc. Rev. 2013, 42(2), 755−773. (c) Gautier, A.;
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1903−1912.
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Organomet. Chem. 2007, 692(21), 4593-4602.
H
H
+
Ar'NH2
Ar'
O
Ar
O
Ar
N
10. Nishioka,
T.;
Shibata,
T.;
Kinoshita,
I.
5
1
2
Organometallics. 2007, 26(5), 1126-1128.
Ar'
-H2O
H+
NH
O
O
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H.; Kinoshita, I.; Yanod, S.; Nishioka, T. Dalton Trans.
2011, 40(25), 6778-6784.
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2146–2154.
+
Ar'NH2
OEt
OEt
6
3
2
Ar'
Ar'
H
N
O
N
O
Ar CHO
H+
13. Keitz, B. K.; Grubbs, R. H. Organometallics. 2010,
29(2), 403–408.
OEt
OEt
Knoevenagel reaction
Ar
Ar
14. Shibata, T.; Hashimoto, H.; Kinoshita, I.; Yanod, S.;
Nishioka, T. Dalton Trans. 2011, 40(18), 4826-4829.
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18. Lin, S. Y; Cox, H J.; Rhodes, P G.; Cai Z W.
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8
7
Ar'
NH
O
Ar'
Ar
N
OEt
5
Ar
N
Ar
[4+2]
aza-Diels-Alder reaction
Ar'
4
Scheme 4. Proposed mechanisms
Acknowledgements
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We are grateful to the foundation of the “National Natural
Sciences Foundation of China” (No. 31300067), "Major Project
of Natural Science Research of University in Jiangsu" (No.
14KJA430003, 13KJA430002), “Priority Academic Program
Development of Jiangsu Higher Education Institutions”,
“Natural Sciences Foundation of Jiangsu Normal University"
(No. 13XLA01)” for financial support.
References and notes
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
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Supporting information
A mixture of aromatic aldehyde 1 (2.0 mmol), aniline 2 (2.0
ACCEPTED MANUSCRIPT
-
mmol), ethyl acetoacetate 3 (1.0 mmol), ([Bmim-G']+HSO4 )
General remarks
(10mol%) and EtOH (2.0 mL) was stirred at 40 °C for 10 hours
until complete consumption of the starting material as monitored
by TLC. After completion of the reaction, the mixture was
diluted with water and the crude solid was filtered and washed
with 95% EtOH. The solid residue was then recrystallized by
95% EtOH/DMF (1:4) to provide the pure product 4.
IR spectra were recorded with a Varian FTIR-Tensor-27
spectrophotometer using KBr optics. 1H NMR spectra were
recorded at 400 MHz on a Bruker DPX 400 spectrometer using
TMS as an internal standard and DMSO-d6 as solvent. Mass was
determined by using a Bruker TOF-MS high resolution mass
spectrometer. All reagents were obtained from commercial
suppliers and used without further purification unless otherwise
stated. Organic solvents were dried and distilled prior to use.
The spectral data of new products are given below:
Ethyl4-(4-tolylamino)-1,2,5,6-tetrahydro-2,6-diphenyl-1-(4-
tolylpyridine)-3-carboxylate (4a):
-
The synthesis of ([Bmim-G']+HSO4 )
White solid. 83% yield. IR (KBr, ν, cm-1): 3245, 3025, 2920,
1
A
mixture of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl
1650, 1594, 1517, 1250; H NMR (400 MHz, DMSO-d6) δ 1.39
bromide (10 mmol) and N-methylimidazole (20 mmol) were
dissolved in 1.0 mL of acetonitrile and then stirred at room
temperature for 2h to give a white powder of β-1-imidazole-
2,3,4,6-tetraacetyl-D-glucopyranoyl bromide which was
collected by filtration and washed with cold acetone. After that,
chlorosulfonic acid (20 mmol) was dropped into (5 mmol) at 0-5
°C under N2 atmosphere, generated gas was absorbed by
saturated NaOH solution. The mixture was stirred for 12 h at the
same temperature to afford 2.5g of β-1-imidazole-2,3,4,6-
tetrasulfonic-D-glucopyranosyl bisulfate (1) as yellow oil (78%).
Because there was only two reactants β-1-imidazole-2,3,4,6-
tetraacetyl-D-glucopyranoyl bromide and chlorosulfonic acid in
the reaction system whose amount were calculated accurately,
when these two reactants reacted completely there only the
(t, J=7.0 Hz, 3H), 2.06 (s, 3H), 2.22 (s, 3H), 2.75 (dd, J=14.8 and
2.0 Hz, 1H), 2.88 (dd, J=15.6 and 8.4 Hz, 1H), 4.25-4.42 (m, 2H),
5.32 (brs, 1H), 6.24-6.33 (m, 5H), 6.81 (d, J=8.8 Hz, 2H), 6.96
(d, J=8.0 Hz, 2H), 7.15 (d, J=7.2 Hz, 2H), 7.28-7.31 (m, 8H),
10.18 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 168.3, 156.4,
144.9, 144.4, 143.1, 135.5, 135.2, 129.5, 129.4, 128.6, 128.2,
127.0, 126.7, 126.5, 126.2, 125.9, 125.0, 112.9, 97.7, 59.6, 58.2,
55.2, 33.6, 20.9, 20.1, 14.8; HRMS (ESI) m/z: calc. for
C34H34N2O2Na [M+Na]+, found (expected): 525.2513 (525.2518).
Ethyl4-(4-tolylamino)-2,6-bis(3-fluorophenyl)-1,2,5,6-tetrah-
ydro-1-4-tolylpyridine)-3-carboxylate (4b):
White solid. 60% yield. IR (KBr, ν, cm-1): 3242, 2985,
2911, 2855, 1651, 1591, 1517, 1250; 1H NMR (400 MHz,
DMSO-d6) δ 1.37 (t, J=7.0 Hz, 3H), 2.07 (s, 3H), 2.23 (s, 3H),
2.75 (dd, J= 15.6 and 1.2 Hz, 1H), 2.93 (dd, J=15.6 and 5.6 Hz,
1H), 4.26-4.41 (m, 2H), 5.38 (brs, 1H), 6.25 (s, 1H), 6.31 (d,
J=8.4 Hz, 2H), 6.38 (d, J=8.0 Hz, 2H), 6.84-6.88 (m, 3H), 6.95-
7.06 (m, 6H), 7.17 (d, J=8.0 Hz, 1H), 7.30-7.39 (m, 2H), 10.20
(s, 1H);13C NMR (100 MHz, CDCl3): δ 168.0, 161.9, 161.8,
156.1, 144.3, 135.9, 135.0, 130.2, 130.1, 129.7, 129.5, 125.9,
125.7, 122.1, 122.0, 114.2, 114.0, 113.8, 113.6, 113.3, 113.1,
112.9, 97.0, 59.7, 57.6, 55.0, 33.4, 20.9, 20.1, 14.8; HRMS (ESI)
m/z: calc. for C34H32F2N2O2Na [M+Na]+, found (expected):
561.2347 (561.2330).
-
product [Bmim-G']+HSO4 itself in the system (HBr was
removed out of the system by absorption via NaOH) and no
further purification was necessary.
β-1-imidazole-2,3,4,6-tetraacetyl-D-glucopyranosyl bromide:
White solid; mp: 229-231 °C; IR (KBr) ν: 3077, 3046,
1
1750, 1539, 1264, 1224, 1210, 1103, 1047, 756, 617 cm-1; H
NMR (400 MHz, DMSO-d6) (δ, ppm): 1.91 (s, 3H), 1.98 (s, 3H),
2.02 (s, 3H), 2.04 (s, 3H), 3.88 (s, 3H), 4.13 (d, J =3.5 Hz, 2H),
4.31-4.41 (m, 1H), 5.25 (t, J=9.6 Hz), 5.55 (dd, J=6.3 and 2.2
Hz, 2H), 6.05 (d, J =8.4 Hz, 1H), 7.80 (s, 1H), 8.08 (s, 1H), 9.47
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 170.0, 169.5, 169.4,
169.0, 137.0, 124.5, 120.2, 83.2, 73.5, 71.5, 70.5, 67.2, 61.7,
36.3, 20.5, 20.4, 20.2, 20.1; HRMS (ESI) m/z: calc. for
C18H25N2O9 [M-Br]+, found (expected): 413.1573 (413.1560).
Ethyl4-(4-tolylamino)-2,6-bis(4-fluorophenyl)-1,2,5,6-tetrah-
ydro-1-(4-tolylpyridine)-3-carboxylate (4c):
White solid. 76% yield. IR (KBr, ν, cm-1): 3236, 2987,
2922, 1650, 1596, 1517, 1250; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.07 (s, 3H), 2.23 (s, 3H), 2.72 (dd,
J=15.2 and 1.2 Hz, 1H), 2.87 (dd, J=15.2 and 4.8 Hz, 1H), 4.24-
4.40 (m, 2H), 5.33 (brs, 1H), 6.23 (s, 1H), 6.30 (d, J=8.8 Hz,
2H), 6.37 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 7.01 (d,
J=8.0 Hz, 2H), 7.11-7.14 (m, 6H), 7.31-7.33 (m, 2H), 10.21 (s,
1H); 13C NMR (100 MHz, CDCl 3): δ 169.1, 156.2, 144.5, 139.8,
138.4, 135.8, 135.1, 129.5, 128.2, 128.1, 128.0, 127.9, 125.8,
125.6, 115.5, 115.3,115.0, 114.8, 113.0, 97.5, 59.7, 57.3, 54.7,
β-1-imidazole-2,3,4,6-tetrasulfonic-D-glucopyranosyl
bisulfate (I):
Yellow oil; IR (KBr) ν: 3423, 2960, 1232, 1061, 1004, 885,
1
855; H NMR (400 MHz, DMSO-d6) (δ, ppm): 3.03 (d, J=2.0
Hz, 1H), 3.09-3.18 (m, 1H), 3.24-3.28 (m, 1H), 3.34-3.39 (m,
1H), 3.57 (s, 1H), 3.75 (s, 3H), 4.01-4.12 (m, 1H), 5.25-5.53 (m,
1H), 7.55 (s, 1H), 7.71 (s, 1H), 9.14 (s, 1H), 9.77 (s, 5H). 13C
NMR (100 MHz, DMSO-d6): δ 170.0, 169.5, 169.4, 169.0,
137.0, 124.5, 120.2, 83.2, 73.5, 71.5, 70.5, 67.2, 61.7, 36.3, 20.5,
20.4, 20.2, 20.1; IR (KBr) ν: 3423, 2960, 1232, 1061, 1004, 885,
855.
33.7, 20.9, 20.1, 14.8; HRMS (ESI) m/
z : calc. for
C34H32F2N2O2Na [M+Na]+, found (expected): 561.2(561.2330).
Ethyl4-(4-tolylamino)-2,6-bis(4-chlorophenyl)-1,2,5,6-tetrah-
ydro-1-(4-tolylpyridine)-3-carboxylate (4d):
White solid. 83% yield. IR (KBr, ν, cm-1): 3247, 2978,
1
2919, 1655, 1491, 1255; HNMR (400 MHz, DMSO-d6) δ 1.35
(t, J=7.0 Hz, 3H), 2.05 (s, 3H), 2.22 (s, 3H), 2.74 (dd, J=15.6 and
5.6 Hz, 1H), 2.90, 4.22-4.38 (m, 2H), 5.33 (brs, 1H), 6.19 (s,
1H), 6.27 (d, J=8.8 Hz, 2H), 6.38 (d, J=8.0 Hz, 2H), 6.82 (d,
J=8.4 Hz, 2H), 7.00 (d, J =8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H),
7.31-7.36 (m, 6H), 10.19 (s, 1H); 13C NMR (100 MHz, CDCl 3):
General procedure for the Synthesis of five-substituted
tetrahydropyridines derivatives 4

2
Tetrahedron
δ 168.0, 156.2, 144.4, 142.8, 141.3, 135.9, 135.0, 132.8, 132.0,
Ethyl4-(4-tolylamino)-1,2,5,6-tetrahydro-2-(2,3,4-trimethox-
ACCEPTED MANUSCRIPT
129.6, 128.8, 128.4, 128.2, 128.1, 127.9, 125.9, 125.8, 113.0,
97.3, 59.3, 57.4, 54.9, 33.6, 21.0, 20.2, 14.8; HRMS (ESI) m/z:
calc. for C34H32Cl2N2O2Na [M+Na]+, found (expected): 593.1716
(593.1739).
yphenyl)-6-(2,3-dimethoxypheny-1-(4-tolylpyridine)-3-carbo-
xylate (4i):
White solid. 70% yield. IR (KBr, ν, cm-1): 3245, 2940,
2829, 1646, 1597, 1517, 1477, 1233; 1H NMR (400 MHz,
CHCl3) δ 1.37 (t, J=7.0 Hz, 3H), 2.10 (s, 3H), 2.31 (s, 3H), 2.33
(s, 3H), 3.01 (dd, J=30.8 and 14.0 Hz, 1H), 3.21 (d, J=4.0 Hz,
1H), 3.63 (s, 3H), 3.89 (s, 3H), 3.98 (s, 3H), 4.20 (dd, J=14.0 and
6.8 Hz, 2H), 4.60 (brs, 1H), 5.23 (s, 1H), 6.39 (d, J=8.0 Hz, 2H),
6.61-6.67 (m, 4H), 6.80-7.00 (m, 4H), 7.05 (d, J=8.4 Hz, 2H),
7.12 (d, J=8.4 Hz, 2H), 10.22 (s, 1H); 13CNMR (100 MHz,
CDCl3): δ 170.2, 164.6, 159.0, 152.8, 152.5146.9, 146.2, 141.8,
136.7, 136.0, 135.0, 134.8, 133.8, 129.6, 128.6, 125.9, 125.8,
123.3,123.2, 119.8, 111.4, 110.7, 93.3, 60.1, 59.1, 58.8, 56.4,
55.6, 43.2, 28.8, 28.4, 20.9, 20.7, 14.7; HRMS (ESI) m/z: calc.
for C38H42N2O6Na [M+Na]+, found (expected): 645.2886
(645.2941).
Ethyl4-(4-tolylamino)-2,6-bis(4-cyanophenyl)-1,2,5,6-tetrahy-
dro-1-(4-tolylpyridine)-3-carboxylate (4e):
White solid. 65% yield. IR (KBr, ν, cm-1): 3357, 2979,
2923, 2227, 1653, 1602, 1517, 1250; 1H NMR (400 MHz,
DMSO-d6) δ 1.45 (t, J=7.2 Hz, 3H), 2.17 (s, 3H), 2.29 (s, 3H),
2.77 (s, 2H), 4.29-4.48 (m, 2H), 5.14(brs, 1H), 6.27-6.30 (m,
4H), 6.38 (s, 1H), 6.89 (d, J=8.0 Hz, 2H), 6.96 (d, J=7.6 Hz, 2H),
7.22 (d, J=7.6 Hz, 2H), 7.43 (d, J=7.6 Hz, 2H), 7.55-7.59 (m,
4H), 10.19 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 167.7, 155.7,
143.8, 136.3, 132.5, 132.2, 132.0, 129.8, 129.7, 128.1, 127.7,
127.4, 127.3, 125.6, 119.1, 119.0, 118.7, 112.9, 111.2, 110.4,
96.5, 60.0, 57.6, 55.3, 33.4, 20.9, 20.1, 14.8; HRMS (ESI) m/z:
calc. For C36H32N4O2Na [M+Na]+, found (expected):
553.2414(575.2423).
Ethyl4-(4-tolylamino)-1-(4-tolyl)-2,6-bis(3,4,5-trimethoxyph-
enyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4j):
Ethyl4-(p-tolylamino)-1,2,5,6-tetrahydro-2,6-bis(4-hydroxy-
phenyl)-1-(4-tolylpyridine)-3-carboxylate (4f):
White solid. 80% yield. IR (KBr, ν, cm-1): 3245, 2934,
2835, 1649, 1593, 1516, 1233; 1H NMR (400 MHz, DMSO-d6) δ
1.36 (t, J=7.0 Hz, 3H), 2.08 (s, 3H), 2.24 (s, 3H), 2.72 (dd,
J=14.4 and 4.4Hz, 1H), 2.94 (dd, J=15.6 and 5.6 Hz, 1H), 3.59
(s, 6H), 3.63 (s, 3H), 3.64 (s, 3H), 3.67 (s, 6H), 4.21-4.44 (m,
1H), 5.28 (brs, 1H), 6.19 (s, 1H), 6.30 (d, J=8.0 Hz 2H), 6.38 (d,
J=8.8 Hz 2H), 6.43 (s, 2H), 6.56 (s, 2H), 6.86 (d, J=8.4 Hz, 2H),
6.98 (d, J=8.0 Hz, 2H), 10.19 (s, 1H); 13CNMR (100 MHz, CDCl
3): δ 167.2, 155.9, 152.8, 152.7, 144.2, 140.3, 138.9, 136.2,
135.8, 135.1, 135.0, 129.3, 129.2, 125.5, 124.2, 112.3, 103.4,
103.1, 96.6, 60.0, 59.9, 56.5, 55.6, 55.5, 33.3, 20.4, 19.8, 14.8;
HRMS (ESI) m/z: calc. for C40H46N2O8Na [M+Na]+, found
(expected): 705.3188 (705.3152).
Yellow solid. 53% yield. IR (KBr, ν, cm-1): 3026, 2917,
2860, 1607, 1577, 1505, 1287; 1H NMR (400 MHz, DMSO-d6) δ
2.07 (s, 6H), 2.10 (s, 3H), 2.29 (s, 4H), 4.76 (brs, 1H), 6.46 (m,
1H), 6.80 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.92 (d,
J=8.4 Hz 2H), 7.10 (d, J=8.8 Hz 3H), 7.17 (d, J=8.4 Hz 3H),
7.75 (dd, J=8.4 and 2.4 Hz, 4H), 8.43 (s,1H), 9.77 (s,1H), 10.23
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 163.3, 160.4, 159.2,
149.2, 145.8, 134.6, 132.1, 130.5, 129.6, 129.2, 128. 4, 127.5,
124.2, 120.7, 115.8, 115.6, 114.9, 114.1, 113.2, 52.6, 51.4, 30.6,
30.1, 20.5, 20.1, 19.9; HRMS (ESI) m/z: calc. for C34H34N2O4Na
[M+Na]+, found (expected): 557.2413 (557.2416).
Ethyl4-(4-methoxyphenylamino)-1,2,5,6-tetrahydro-1-(4-
methoxyphenyl)-2,6-diphenylpyridine-3-carboxylate (4k):
Ethyl4-(4-tolylamino)-1,2,5,6-tetrahydro-1,2,6-trip-tolylpyr-
idine-3-carboxylate (4g):
White solid. 77% yield. IR (KBr, ν, cm-1): 3231, 2990,
2902, 1647, 1597, 1510, 1244; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.65 (dd, J=15.2 and 1.6 Hz, 1H), 2.83
(dd, J=15.6 and 5.6 Hz, 1H), 3.55 (s, 3H ), 3.69 (s, 3H), 4.26-
4.36 (m, 2H), 5.26 (brs, 1H), 6.21 (s, 1H), 6.28-6.34 (dd, J=17.6
and 9.2 Hz, 4H), 6.63 (d, J=8.8 Hz, 2H), 6.70 (d, J=8.8 Hz, 2H),
7.13-7.30 (m, 10H), 10.09 (s, 1H); 13C NMR (100 MHz, DMSO-
d6): δ 168.3, 157.8, 156.8, 144.4, 143.6, 143.3, 141.6, 136.9,
128.6, 128.1, 127.9, 127.1, 126.8, 126.5, 126.2, 114.5, 114.1,
113.9, 97.3, 59.5, 58.3, 55.7, 55.6, 55.4, 33.6, 14.8; HRMS (ESI)
m/z: calc. for C34H34N2O4Na [M+Na]+, found (expected):
557.2413 (557.2416).
White solid. 55% yield. IR (KBr, ν, cm-1): 3236, 2979,
2919, 1651, 1596, 1515, 1254; 1H NMR (400 MHz, DMSO-d6) δ
1.46 (t, J=7.2 Hz, 3H), 2.17 (s, 3H), 2.28 (s, 3H), 2.33 (s, 3H),
2.35 (s, 3H), 2.74 (dd, J=15.2 and 2.4 Hz, 1H), 2.83 (dd, J=15.2
and 5.6 Hz, 1H), 4.32-4.47 (m, 2H), 5.10 (brs, 1H), 6.19 (d,
J=8.0 Hz, 2H), 6.38 (s, 1H), 6.45 (d, J=8.4 Hz, 2H), 6.89 (t,
J=7.2 Hz, 4H), 7.09 (t, J=6.8 Hz, 6H), 7.24 (t, J=6.8 Hz, 2H),
10.23 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 168.4, 156.5,
145.0, 141.5, 140.0, 13 6.5, 135.7, 135.4, 129.5, 129.4, 129.3,
128.9, 126.6, 126.4, 125.9, 124.9, 112.9, 97.9, 59.5, 58.0, 55.0,
33.6, 21.2, 21.1, 20.9, 20.2, 14.9; HRMS (ESI) m/z: calc. for
C36H38N2O2Na [M+Na]+, found (expected): 553.2826
(553.2831).
Ethyl4-(4-methoxyphenylamino)-2,6-bis(4-chlorophenyl)-
1,2,5,6–tetrahydro-1-(4-methoxyphenyl)pyridine-3-carboxy-
late (4l):
Ethyl4-(4-tolylamino)-1,2,5,6-tetrahydro-2,6-bis(2-methoxyp-
henyl)-1-(4-tolylpyridine)-3-carboxylate (4h):
White solid. 71% yield. IR (KBr, ν, cm-1): 3230, 2907,
2832, 1660, 1611, 1511, 1247; 1H NMR (400 MHz, DMSO-d6) δ
1.34 (t, J=7.0 Hz, 3H), 2.65 (dd, J= 15.6 and 2.0 Hz, 1H), 2.85
(dd, J=16.0 and 5.6 Hz, 1H), 3.55 (s, 3H), 3.71 (s, 3H), 4.21-4.36
(m, 2H), 5.25 (brs, 1H), 6. 11 (s, 1H), 6.31 (d, J=9.2 Hz, 2H),
6.45 (d, J=8.8 Hz, 2H), 6.65 (d, J=9.2 Hz, 2H), 6.77 (d, J=8.8
Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.29-7.36 (m, 6H), 10.12 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 168.1, 158.0, 156.5, 151.5,
142.8, 141.5, 141.0, 132.8, 132.0, 130.5, 128.7, 128.3, 128.0,
127.7, 114.7, 114.6, 114.1, 113.2, 96.7, 59.7, 57.4, 55.6, 55.4,
33.7, 14.8; HRMS (ESI) m/z: calc. for C34H32Cl2N2O4Na
[M+Na]+, found (expected): 625.1626 (625.1637).
White solid. 71% yield. IR (KBr, ν, cm-1): 3265, 2918,
2836, 1664, 1619, 1604, 1517, 1244;1H NMR (400 MHz,
CHCl3) δ 1.41 (t, J= 7.2 Hz, 3H), 2.13 (s, 3H), 2.24 (s, 3H), 2.79
(dd, J = 15.6 and 5.6 Hz, 1H), 2.96 (dd, J=15.6 and 2.0 Hz, 1H),
3.60 (s, 3H), 3.82 (s, 3H), 4.23-4.44 (m, 2H), 5.38 (brs, 1H), 6.15
(d, J=8.4 Hz, 2H), 6.32 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 6.79-6.90
(m, 8H), 7.03 (d, J=6.8 Hz, 1H), 7.14-7.23 (m, 3H), 9.70 (s, 1H);
13C NMR (100 MHz, CDCl3): δ 168.9, 157.5, 156.1, 155.1,
144.8, 136.0, 134.7, 130.9, 129.8, 129.4, 129.1, 128.3, 127.9,
127.4, 126.0, 124.6, 120.7, 119.6, 112.6, 111.1, 109.8, 97.6,
59.3, 55.3, 54.8, 53.3, 53.2, 29.3, 20.8, 20.2, 14.9; HRMS (ESI)
m/z: calc. for C36H38N2O4Na [M+Na]+, found (expected):
585.2716 (585.2729).

Ethyl4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-
tetrahydro-2,6-diphenylpyridine-3-carboxylate (4m):
6.23 (s, 1H), 6.35 (d, J=9.2 Hz, 2H), 6.50 (d, J=8.4 Hz, 2H), 6.88
(d, J=8.4 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.05-7.09 (m, 3H),
7.18-7.22 (m, 3H), 7.30-7.43 (m, 4H),10.18 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 167.8, 161.9, 161.8, 154.9, 145.4, 144.8,
136.7, 132.2, 131.8, 130.5, 130.0, 127.2, 122.0, 121.9, 119.4,
114.6, 113.8, 113.7, 113.6, 113.5, 113.3, 109.1, 98.2, 60.2, 57.6,
55.0, 33.4, 14.7; HRMS (ESI) m/z: calc. for C32H26Br2F2N2O2Na
[M+Na]+, found (expected): 698.0229 (698.0227).
ACCEPTED MANUSCRIPT
White solid. 64% yield. IR (KBr, ν, cm-1): 3242, 2972,
2857, 1646, 1604, 1585, 1494, 1258; 1H NMR (400 MHz,
DMSO-d6) δ 1.38 (t, J=7.0 Hz, 3H), 2.76 (dd, J=15.2 and 4.0
Hz, 1H), 2.96 (dd, J=16.0 and 6.0 Hz, 1H), 4.24-4.44 (m, 2H),
5.39 (brs, 1H), 6.28 (s, 1H), 6.38-6.42 (m, 4H), 7.05 (d, J=9.2
Hz, 2H), 7.13 (d, J=6.8 Hz, 2H), 7.18-7.33 (m, 10H), 10.16 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 168.2, 115.4, 145.5, 143.3,
142.3, 136.4, 131.4, 129.0, 128.8, 128.7, 128.4, 127.5, 127.0,
126.6, 126.5, 126.3, 121.3, 114.1, 98.7, 60.0, 58.3, 55.3, 33.5,
14.8; HRMS (ESI) m/z: calc. for C32H28Cl2N2O2Na [M+Na]+,
found (expected): 565.1420 (565.1426).
Ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis(4-
fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4r):
White solid. 60% yield. IR (KBr, ν, cm-1): 3237, 2928,
2862, 1673, 1656, 1504, 1253; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.77 (dd, J=14.4 and 4.0 Hz, 1H), 2.98
(dd, J=15.6 and 5.6 Hz, 1H), 4.21-4.42 (m, 2H), 5.40 (brs, 1H),
6.21 (s, 1H), 6.33 (d, J=9.2 Hz, 2H), 6.51 (d, J=8.8 Hz, 2H),
7.13-7.20 (m, 8H), 7.31-7.38 (m, 4H), 10.19 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 167.9, 160.9, 160.4, 155.1, 145.6, 136.8,
132.1, 131.7, 128.1, 128.0, 127.9, 127.8, 127.1, 119.3, 115.8,
115.6, 115.3, 115.1, 114.7, 108.9, 98.7, 60.1, 57.4, 54.8, 33.7,
14.8; HRMS (ESI) m/z: calc. for C32H27Br2F2N2O2 [M+H]+,
found (expected): 667.0154 (667.0407).
Ethyl4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,6-bis(3-
fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4n):
Yellow solid. 54% yield. IR (KBr, ν, cm-1): 3241, 2981,
2858, 1647, 1607, 1494, 1260; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.76 (dd, J= 15.6 and 1.6 Hz, 1H), 3.02
(dd, J=16.0 and 6.0 Hz, 1H), 4.26-4.44 (m, 2H), 5.44 (brs, 1H),
6.24 (s, 1H), 6.41 (d, J=8.8 Hz, 2H), 6.56 (d, J=8.8 Hz, 2H), 6.85
(d, J=8.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.05-7.10 (m, 5H),
7.18 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.31-7.41 (m,
2H), 10.19 (s, 1H); 13C NMR(100 MHz, CDCl3): δ 167.9, 161.9,
161.8, 155.1, 146.1, 145.0, 136.2, 131.7, 130.5, 130.4, 129.9,
129.8, 129.2, 128.9, 126.9, 121.9, 114.6, 114.4, 114.1, 113.8,
113.5, 113.3, 98.0, 60.1, 57.7, 55.1, 33.4, 14.7; HRMS (ESI)
m/z: calc. for C32H26Cl2F2N2O2Na [M+Na]+, found (expected):
601.1189 (601.1237).
Ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis(4-
chlorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4s):
White crystal. 63% yield. IR (KBr, ν, cm-1): 3243, 2928,
1665, 1647, 1586, 1491, 1252; 1HNMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.2 Hz, 3H), 2.78 (dd, J= 14.4 and 4.0 Hz, 1H), 3.00
(dd, J=16.0 and 5.6 Hz, 1H), 4.25- 4.40 (m, 2H), 5.38 (brs, 1H),
6.21 (s, 1H), 6.31 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 7.11
(d, J=8.4 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.32-7.40 (m, 8H),
10.18 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 167.8, 155.0,
145.4, 141.6, 140.3, 136.7, 133.2, 132.5, 132.2, 131.8, 129.0,
128.6, 127.9, 127.7, 127.1, 119.4, 114.6, 109.1, 98.4, 60.1, 57.4,
54.9, 33.6, 14.8; HRMS (ESI) m/z: calc. for
C32H26Br2Cl2N2O2Na [M+Na]+, found (expected): 698.9504
(698.9816).
Ethyl4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,6-bis(4-
fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4o):
White solid. 80% yield. IR (KBr, ν, cm-1): 3237, 3069,
1
2978, 1650, 1495, 1227; H NMR (400 MHz, DMSO-d6) δ 1.37
(t, J=7.0 Hz, 3H), 2.76 (dd, J=15.6 and 4.0 Hz, 1H), 2.96 (dd,
J=16.0 and 5.6 Hz, 1H), 4.25-4.41 (m, 2H), 5.39 (brs, 1H), 6.22
(s, 1H), 6.37 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 7.06-7.17
(m, 8H), 7.24 (d, J=8.8 Hz, 2H), 7.32-7.36 (m, 2H), 10.19 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 168.0, 160.9, 160.4, 155.2,
145.2, 13 8.8, 137.6, 136.3, 131.6, 129.2, 128.9, 128.1, 128.0,
127.9, 127.8, 126.8, 121.7, 115.8, 115.6, 115.3, 115.1, 114.2,
98.6, 60.1, 57.4, 54.8, 33.7, 14.8; HRMS (ESI) m/z: calc. for
C32H26Cl2F2N2O2Na [M+Na]+, found (expected): 601.1228
(601.1237).
Ethyl4-(4-nitrophenylamino)-1,2,5,6-tetrahydro-1-(4-nitrop-
henyl)-2,6-diphenylpyridine-3-carboxylate (4t):
Yellow solid. 70% yield. IR (KBr, ν , cm-1): 3289, 2985,
1
1680, 1596, 1501, 1246; H NMR (400 MHz, DMSO-d6) δ 1.37
(t, J=7.0 Hz, 3H), 2.87 (dd, J=14.4 and 4.0 Hz, 1H), 3.39 (dd,
J=16.0 and 5.6 Hz, 1H), 4.10-4.23 (m, 2H), 4.48 (brs, 1H), 6.03
(dd, J=18.8 and 7.6 Hz, 3H), 6.61 (t, J=7.4 Hz, 2H), 6.67-6.70
(m, 1H), 6.74-6.78 (m, 1H), 6.83-6.89 (m, 4H), 7.03-7.07 (m,
2H), 7.42 (d, J=8.8 Hz, 2H), 8.15 (d, J=9.2 Hz, 2H), 8.42 (d,
J=8.8 Hz, 2H), 10.80 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
169.2, 157.0, 152.1, 146.9, 143.6, 141.4, 139.3, 136.7, 127.4,
126.9, 126.4, 126.2, 125.8, 125.2, 123.5, 115.8, 115.3, 103.5,
60.3, 52.3, 45.6, 38.5, 13.6; HRMS (ESI) m/z: calc. for
C32H28N4O6Na [M+Na]+, found (expected): 587.1923
(587.1907).
Ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-
tetrahydro-2,6-diphenylpyridine-3-carboxylate (4p):
White solid. 76% yield. IR (KBr, ν, cm-1): 3241, 2973,
2834, 1646, 1602, 1491, 1225; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.74 (dd, J=15.6 and 4.0 Hz, 1H), 2.96
(dd, J=16.0 and 5.6 Hz, 1H), 4.25-4.41 (m, 2H), 5.39 (brs, 1H),
6.22 (s, 1H), 6.37 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H),
7.06-7.17 (m, 10H), 7.25 (d, J=8.8 Hz, 2H), 7.32-7.36 (m, 2H),
10.19 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 168.1, 155.2,
145.9, 143.1, 142.1, 136.9, 132.0, 131.6, 128.8, 128.4, 127.5,
127.2, 126.6, 126.4, 126.3, 119.1, 114.6, 108.4, 98.8, 59.9, 58.3,
55.2, 33.4, 14.8; HRMS (ESI) m/z: calc. for C32H28Br2N2O2Na
[M+Na]+, found (expected): 653.0405 (653.0415).
Ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis(3-
fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4q):
Yellow solid. 55% yield. IR (KBr, ν , cm-1): 3242, 2977,
2859, 1647, 1590, 1488, 1260; 1H NMR (400 MHz, DMSO-d6) δ
1.37 (t, J=7.0 Hz, 3H), 2.77 (dd, J=16.4 and 2.0 Hz, 1H), 3.04
(dd, J=16.0 and 5.6 Hz, 1H), 4.27-4.42 (m, 2H), 5.43 (brs, 1H),