Lewis acid-catalyzed cyclization of enaminones with propargylic alcohols: Regioselective synthesis of multisubstituted 1,2-dihydropyridines

Article abstract of DOI:10.1021/jo4005553

A highly efficient BF₃·Et₂O-catalyzed cascade reaction of enaminones with propargylic alcohols under mild reaction conditions has been developed. This methodology offers regioselective access to multisubstituted 1,2-dihydropyridines in good to excellent yields.

Full text of DOI:10.1021/jo4005553

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Note
Lewis Acid-Catalyzed Cyclization of Enaminones with Propargylic alcohols:
Regioselective Synthesis of Multi-substituted 1, 2-Dihydropyridines
Yushang Shao, Kai Zhu, Zhengchen Qin, Ende Li, and Yanzhong Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4005553 • Publication Date (Web): 07 May 2013
Downloaded from http://pubs.acs.org on May 7, 2013
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Lewis Acid-Catalyzed Cyclization of Enaminones with Propargylic alcohols:
Regioselective Synthesis of Multi-substituted 1, 2-Dihydropyridines
Yushang Shao, Kai Zhu, Zhengchen Qin, Ende Li, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, 500 Dongchuan Road, Shanghai, 200241,
People’s Republic of China
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Fax: (+86) 021-54340096, E-mail: yzli@chem.ecnu.edu.cn
R5
O
R4 OH
R3
O
NHR2
R1
cat. BF3 Et2O
R4
R3
+
R1
N
R2
CH3NO2, 80 oC
R5
R1= aryl, heteroaryl,
R2, R3, R4 = alkyl, aryl
R5 = alkyl, aryl
35-94%
19 examples
Abstract: A highly efficient BF3ꢀEt2Oꢁcatalyzed cascade reaction of enaminones with
propargylic alcohols under mild reaction conditions has been developed. This methodology
offers regioselective access to multiꢁsubstituted 1,2ꢁdihydropyridines in good to excellent
yields.
Dihydropyridines are of great value as core structures in biologically active
molecules.1,2 They are also versatile building blocks that provide ready access to a variety
of nitrogenꢁcontaining heterocycles such as piperidines3 or pyridines.4
1,4ꢁ
Dihydropyridines have been the most studied,5 whereas 1,2ꢁdihydropyridines have received
relatively little attention. There are several synthetic approaches to 1,2ꢁdihydropyridines
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reported in the literature, such as nucleophilic addition onto Nꢁalkyl or Nꢁacylpyridinium
salts,3,6 6πꢁelectrocyclization of 1ꢁazatrienes,7 and others.8 Although these methods are
effective for certain substrates, the development of general procedures for the
regioselective synthesis of highly functionalized dihydropyridines from readily available
starting materials still remains an important task in organic chemistry. As a part of our
ongoing studies on the development of heterocycle forming protocols starting from
enaminone derivatives,9 we recently reported a facile acidꢁcatalyzed approach to the
synthesis of 1,4ꢁdihydropyridines from the reactions of readily available aldehydes with
enaminones (Scheme 1, eq 1).10 Next, we became interested in the development of new
methodologies for the construction of 1,2ꢁdihydropyridines from enaminones. We
envisioned that this might be realized by the proper choice of electrophiles and acid
catalysts. It was found when propargylic alcohols were used as electrophiles, an efficient
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Scheme 1
Previous work
O
O
O
R3
O
cat. TsOH H2O
or NaAuCl4 2H2O
H
R1
R1
R1
+ R3CHO
(1)
(2)
cyclization
R2HN
N
R2
This work
R5
R3 R4
O
O
R1
R1
R1
OH
R4
R3
R4
catalyst
R5
+
R5
N
R2
R3
N
R2HN
R2
not detected
synthesis of 1,2ꢁdihydropyridines could be achieved by a Lewis acidꢁcatalyzed cyclization
reaction. Herein, we describe this new synthetic route for the synthesis of functionalized
1,2ꢁdihydropyridines. In addition, these reactions could proceed smoothly without the
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requirement of inert atmospheres (Scheme 1, eq 2).
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We began our investigation with (Z)ꢁ1ꢁphenylꢁ3ꢁ(phenylamino)propꢁ2ꢁenꢁ1ꢁone (1a)，
which was readily prepared through conjugate addition of aniline with terminal alkynone.10
The reaction of 1a with propargyl alcohol 2a was selected as the prototypical case to screen
the experimental conditions. Firstly, the reaction of 1a with 2,4ꢁdiphenylbutꢁ3ꢁynꢁ2ꢁol (2a)
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o
was carried out using CuI (10 mol%) as the catalyst in nitromethane at 80 C, however,
only trace amounts of the desired dihydropyridine were detected (Table 1, entry 1). Similar
results were observed for CuCl (Table 1, entry 2). To our delight, when Cu(OTf)2 was
used, the desired dihydropyridine 3a was produced in 47% yield after 4 h (Table 1, entry 3).
Brønsted acids gave good yields of the desired dihydropyridine (Table 1, entries 4ꢁ6). It is
interesting that BF3ꢀEt2O in nitromethane afforded 3a in 88% yield within 1 h (Table 1,
entry 9). Other solvents such as 1,4ꢁdioxane, toluene and DCE also produced the desired
dihydropyridine in good yields (Table 1, entries 12, 20, 21). However, DMF or DMSO
gave only a trace amount of the product (Table 1, entries 10ꢁ11). CH3CN gave similar
result as that of nitromethane (Table 1, entry 22). When the reaction was carried out at 50oC
in nitromethane, the desired product was obtained in 69% yield and required much longer
reaction time (Table 1, entry 13). Reactions conducted at room temperature resulted in
much lower yield (Table 1, entry 14). Lowering the catalyst loading to 5 mol% gave 89%
yield in 1h (Table 1, entry 17). Even 3 mol% of BF3ꢀEt2O resulted in a high yield of the
desired dihydropyridine, however, prolonged reaction time was required (Table 1, entry 18).
Other Lewis acids such as FeCl3, FeCl2, FeBr3 also gave good yields of 3a (Table 1, entries
8, 24, 25). A controll experiment showed that no desired product was formed in the absence
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Table 1. Optimization of reaction conditions for the formation of 3a
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Ph
O
OH
O
NHPh
Ph
catalyst
solvent, 80 oC
Ph
+
Ph
Ph
N
Ph
3a
Ph
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1a
2a
entry catalyst (mol%)
time(h)
yield(%)a, b
solvent
1
2
3
4
CuI (10)
7
7
4
3
trace
trace
47
CH3NO2
CH3NO2
CuCl (10)
Cu(OTf)2 (10)
TsOH.H2O (10)
CF3COOH (10)
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
75
74
2
2
3
5
6
CF3SO3H (10)
80
.
7
67
FeCl3 6H2O (10)
FeCl3 (10)
8
CH3NO2
CH3NO2
DMF
3
77
88
.
9
1
BF3 Et2O (10)
.
10
trace
12
BF3 Et2O (10)
.
11
DMSO
trace
82
12
2
BF3 Et2O (10)
.
1,4-dioxane
CH3NO2
12
13
BF3 Et2O (10)
8
69c
.
BF3 Et2O (10)
.
18
1
14
15
CH3NO2
CH3NO2
23d
88e
BF3 Et2O (10)
.
BF3 Et2O (10)
.
83f
89
16
1
CH3NO2
CH3NO2
BF3 Et2O (10)
.
1
17
18
19
20
21
22
23
BF3 Et2O (5)
.
BF3 Et2O (3)
89g
--
4
4
2
CH3NO2
CH3NO2
Toluene
DCE
--
.
81
80
BF3 Et2O (5)
.
2
1
3
BF3 Et2O (5)
.
CH3CN
THF
BF3 Et2O (5)
89
52
.
BF3 Et2O (5)
4
3
24
25
CH3NO2
CH3NO2
CH3NO2
75
80
23
FeCl2 (5)
FeBr3 (5)
5
AlCl3 (5)
26
a Unless otherwise noted, all reactions were carried out under air in 0.25 mmol
scale with the ratio of 1a : 2a = 1: 1.2. b Isolated yield. c The reaction was
carried out at 50oC. d The reaction was carried out at room temperature. e The
ratio of 1a : 2a = 1: 1.3. f The ratio of 1a : 2a = 1.2: 1. g 0.5 mmol scale.
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of BF3ꢀEt2O (Table 1, entry 19). The optimized reaction conditions were to use 5 mol % of
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BF3ꢀEt2O as the catalyst, and nitromethane as the solvent at 80 C. One of the advantages
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of this method to prepare dihydropyridines is that the substituents on the pyridine ring were
introduced in a regioselective manner.
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With the optimized reaction conditions in hand, we next examined the substrate scope
of this catalytic method for the synthesis of 1,2ꢁdihydropyridines using a variety of
(Z)ꢁenaminones and propargyl alcohols with the results shown in Table 2. We first
investigated the electronic effects of the aromatic substituents on carbonyl carbon of
enaminones. It was found that an electronꢁdonating (ꢁOMe) aryl group afforded the
corresponding product 3b in 85% yield (Table 2, entry 2). Electronꢁwithdrawing (ꢁCl, ꢁBr)
aryl groups also gave high yields of 3c and 3d, respectively (Table 2, entries 3, 4). A
heteroaryl enaminone such as 2ꢁthienylenaminone was also compatible under the reaction
conditions, furnishing 3e in 98% yield (Table 2, entry 5). The substituents on the carbonyl
carbon could also be alkyl groups, such as cyclohexyl (1f), with the corresponding 3f
obtained in 85% yield (Table 2, entry 6). The electronic effects of the aromatic substituents
on nitrogen of enaminones were then examined. An electronꢁdonating (ꢁOMe) aryl group
gave much higher yield than that of an electronꢁwithdrawing (ꢁNO2) one (Table 2, entries 7,
8). The reaction also proceeded smoothly with other electronꢁwithdrawing aryl groups,
such as mꢁCl (1i), oꢁCN (1j), furnishing the desired dihydropyridines 3i, 3j in 88% and
73% yields, respectively (Table 2, entries 9, 10). Enaminone 1k with an alkyl substituent
on nitrogen led to the formation of 3k in moderate yield (Table 2, entry 11). The cyclization
reaction has been successfully extended to other propargyl alcohols. Triphenyl substituted
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Table 2. Synthesis of various of 1,2-dihydropyridines
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8
R5
O
R4 OH
R1
O
NHR2
Cat. BF3 Et2O
CH3NO2, 80oC
R3
R4
R3
+
R1
N
R2
3
R5
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1
2
1 (R1, R2)
1a (Ph, Ph)
2 (R3/R4/R5)
entry
time(h)
yield(%)a
product
1
2
3
4
5
6
7
1
2
1
1
3a
3b
3c
3d
3e
3f
2a (Ph/Me/Ph)
89
85
94
77
98
85
90
1b (p-MeOC6H4, Ph)
1c (p-ClC6H4, Ph)
1d (o-BrC6H4, Ph)
1e (2-thienyl, Ph)
1f (cyclohexyl, Ph)
1g (Ph, p-MeOC6H4)
2a
2a
2a
2a
2a
2a
1
1
1
3g
1h (Ph, p-NO2C6H4)
1i (Ph, m-ClC6H4)
1j (Ph, o-CNC6H4)
1k (Ph, benzyl)
8
2a
2a
2a
2a
1
1
1
3h
3i
67
88
9
3j
73
35
10
11
3k
5
3l
2b (Ph/Ph/Ph)
4
2
12
13
82
89
1a
1a
3m
2c (p-ClC6H4/Me/Ph)
2
1
2
14
15
2d (Ph/cyclopropyl/Ph)
2e (Ph/Me/p-FC6H4)
3n
3o
1a
1a
67
92
16
17
2f (Ph/Me/p-MeC6H4)
2g (Ph/Ph/H)
1a
1a
3p
72
-
4
a Isolated yields.
alcohol 2b reacted smoothly with 1a to give 3l in 82% yield (Table 2, entry 12). The
structure of 3l was further confirmed by Xꢁray crystallographic analysis. Compound 2c
with a pꢁCl aryl group on the propargylic carbon gave the dihydropyridine 3m in 89% yield
(Table 2, entry 13). Incorporation of a cyclopropyl group on the propargylic alcohol in the
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reaction provided 3n in a good yield, with the cyclopropyl group well tolerated during the
reaction (Table 2, entry14). Both aryl and alkyl groups are tolerated at the alkynyl position.
The pꢁF aryl group resulted in 92% of 3o, while pꢁMe group gave 72% of the
corresponding 3p (Table 2, entries 15, 16). Unfortunately, the terminal propargylic alcohol
2g provided no product (Table 2, entry 17). It is worthy to note that substrates with alkyl
groups on the triple bond resulted in not only the desired 1,2ꢁdihydropyridines 3, but also
its isomers 4 derived from a 1,3ꢁhydrogen shift. In the case of 4c, the structure was
confirmed by Xꢁray crystallography (eq. 3).
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R6
R6
O
O
Ph OH
.
O
NHR2
5 mol% BF3 Et2O
Ph
Ph
(3)
+
+
R6
CH3NO2, 80 oC, air
Ph
N
R2
3
N
R2
4
Ph
Ph
1a
2
R2= Ph, R6 =(CH2)2CH3
R2= Ph, R6=CH2Ph
3r (21%)
3s (35%)
3t (21%)
4a (39%)
4b (31%)
4c (33%)
R2= p-NO2C6H4, R6=CH2Ph
On the basis of the above results and the reported work concerning the reaction of
propyargyl alochols,11 a possible reaction mechanism is proposed in Scheme 2. Initially,
propargyl cation 5 or allenyl cation 6 12, 13 is generated in the presence of BF3ꢀEt2O, which
is trapped by enaminone 1 to give intermediate 7. Deprotonation of 7 forms 8, which then
undergoes protonation followed by double bond E/Z isomerization to produce allylic cation
9. Intramolecular cyclization leads to product 3. Alternatively, a formal 1,3ꢁhydrogen
migration to allenic moiety might occur after deprotonation at imine nitrogen of 7 to afford
a conjugated azatriene, and the final dihydropyridine 3 is formed through a
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6πꢁelectrocyclization. To understand the reaction mechanism, the reaction was carried out
at lower temperature in order to ‘observe’ intermediate 8. However, no information about
such intermediate could be obtained at the current stage. It seems that the transformation of
8 to the final dihydropyridine is not the rate determining step.
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In conclusion, we have shown that multiꢁsubstituted 1,2ꢁdihydropyridines are
efficiently prepared by the BF3ꢀEt2Oꢁcatalyzed cascade reactions using enaminones and
propargyl alcohols. Aryl and alkyl substituents on both enaminones and propargyl alcohols
are compatible in the cascade reactions, furnishing the desired 1,2ꢁdihydropyridines in
good to excellent yields. In this procedure, the regioselective introduction of substituents
on the pyridine is determined by the appropriate choice of the enaminone and propargyl
alcohol, thereby allowing for considerable versatility.
Scheme 2. A proposed reaction pathway
R4
R3 + R4
R5
O
R3
OH
BF3 Et2O
R5
O
H
R3
R1
N+HR2
+
R1
R3
R4
NHR2
R4
R5
R5
F3BOH
2
5
6
1
7
R5
O
R5
O
R5
O
R1
R1
H+
R3
R4
R1
NHR2
R4
R3
+
N
R2
R3
H+
H+
NHR2
R4
8
9
3
Experimental Section
Highꢁresolution mass spectra were performed on a mass spectrometer with a TOF (for
EI or ESI) or FTꢁICR (for MALDI) analyzer.
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.
A
typical
procedure
for
the
BF3 Et2O-catalyzed
synthesis
of
5
6
7
(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3a). To
a
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solution of (Z)ꢁenaminones 1a (0.25 mmol, 56 mg) and propargyl alcohol 2a (0.3 mmol, 67
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.
mg) in CH3NO2 (2 mL) was added BF3 Et2O (1.6 uL, 5 mol %). The resulting solution was
o
stirred at 80 C under air until the reaction was complete as monitored by thinꢁlayer
chromatography. The solvent was evaporated under reduced pressure and the residue was
purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to
afford the 1,2ꢁdihydropyridine derivatives 3a in 89% (95 mg) isolated yield as a yellow
solid; mp 139ꢁ140 oC. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.60 (d, J = 6.4 Hz, 2H), 7.47
(d, J = 7.2 Hz, 2H), 7.31ꢁ7.27 (m, 4H), 7.25ꢁ7.20 (m, 3H), 7.13ꢁ7.08 (m, 8H), 6.80ꢁ6.78 (m,
2H), 5.11 (s, 1H), 1.74 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 191.5, 149.8,
146.1, 143.5, 140.2, 140.1, 133.7, 130.8, 129.1, 128.9, 128.6, 128.0, 127.8, 127.7, 127.2,
127.0, 126.7, 126.4, 124.4, 110.6, 64.5, 26.6. HRMS (EI) calcd for C31H26NO (M+H)+ :
428.2014, found 428.2020.
(4-methoxyphenyl)(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)methanone (3b)
(the reaction time was 2 h). Column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 5:1) afforded the title product in 85% (97 mg) isolated yield as a
o
1
yellow solid; mp 127ꢁ128 C. H NMR (400 MHz, CDCl3, Me4Si) δ 7.60 (d, J = 8.4 Hz,
2H), 7.48 (d, J = 7.4, 2H), 7.31ꢁ7.26 (m, 4H), 7.15ꢁ7.08 (m, 8H), 6.81 (d, J = 7.0 Hz, 2H),
6.73 (d, J = 8.4, 2H), 5.10 (s, 1H), 3.69 (s, 3H), 1.75 (s, 3H). 13C NMR (100.6 MHz, CDCl3,
Me4Si) δ 190.8, 161.9, 148.7, 146.3, 143.6, 140.1, 133.9, 132.6, 131.2, 128.8, 128.6, 127.7,
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127.2, 126.8, 126.7, 126.4, 124.2, 113.2, 110.8, 64.4, 55.2, 26.6. HRMS (EI) calcd for
C32H28NO2(M+H)+: 458.2120, found 458.2125.
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(4-chlorophenyl)(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)methanone
(3c).
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Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1)
afforded the title product in 94% (108 mg) isolated yield as a yellow solid; mp 143ꢁ144oC.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.51ꢁ7.46 (m, 4H), 7.32ꢁ7.28 (m, 3H), 7.25ꢁ7.22 (m,
1H), 7.18ꢁ7.16 (m, 2H), 7.14ꢁ7.06 (m, 8H), 6.81 (s, 2H), 5.11 (s, 1H), 1.74 (s, 3H); 13C
NMR (100.6 MHz, CDCl3, Me4Si) δ 190.2, 149.7, 146.0, 143.4, 140.0, 138.6, 136.8, 133.6,
130.4, 128.96, 128.6, 128.2, 127.9, 127.8, 127.2, 126.9, 126.4, 124.3, 110.4, 64.7, 26.7.
HRMS (ESI) calcd for C31H25ClNO (M+H)+: 462.1625, found 462.1619.
(2-bromophenyl)(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)methanone (3d).
Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 8:1) afforded
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the title product in 77% (97 mg) isolated yield as a yellow solid; mp 162ꢁ163oC. H NMR
(300 MHz, CDCl3, Me4Si) δ 7.54ꢁ7.52 (m, 2H), 7.47ꢁ7.44 (m, 1H), 7.38ꢁ7.33 (m, 5H),
7.30ꢁ7.15 (m, 9H), 7.12ꢁ7.07 (m, 1H), 6.88ꢁ6.85 (m, 2H), 5.18 (s, 1H), 1.79 (s, 3H). 13C
NMR (75 MHz, CDCl3, Me4Si) δ 189.0, 152.3, 145.5, 143.0, 141.9, 139.9, 132.9, 132.7,
130.0, 129.7, 128.8, 128.5, 127.8, 127.5, 127.4, 127.3, 127.1, 126.6, 126.3, 125.1, 120.0,
110.1, 64.8, 26.8. HRMS (ESI) calcd for C31H24BrNO : 505.1041, found 505.1031.
(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)(thiophen-2-yl)methanone
(3e).
Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 15:1)
afforded the title product in 98% (106 mg) isolated yield as a yellow liquid. 1H NMR (400
MHz, CDCl3, Me4Si) δ 7.50ꢁ7.47 (m, 3H), 7.38 (d, J = 2.8Hz, 1H), 7.34ꢁ7.27 (m, 3H),
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7.24ꢁ7.20 (m, 1H), 7.14ꢁ7.11 (m, 8H), 6.89ꢁ6.87 (m, 1H), 6.84ꢁ6.82 (m, 2H), 5.10 (s, 1H),
1.74 (s, 3H). 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 182.9, 148.4, 146.2, 145.3, 143.5,
139.2, 133.4, 131.0, 130.9, 128.9, 128.6, 127.7, 127.1, 127.0, 126.8, 126.4, 124.4, 110.8,
64.5, 26.6. HRMS (ESI) calcd for C29H23NOS : 433.1500, found 433.1504.
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cyclohexyl(6-methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)methanone (3f). Column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 25:1) afforded the
title product in 85% (92 mg) isolated yield as a yellow liquid. 1H NMR (400 MHz, CDCl3,
Me4Si) δ 7.51 (s, 1H), 7.43ꢁ7.41 (m, 2H), 7.30ꢁ7.11 (m, 11H), 6.89ꢁ6.87 (m, 2H), 4.99 (s,
1H), 2.35 (t, J = 11.2 Hz, 1H), 1.71 (s, 3H), 1.66ꢁ1.47 (m, 5H), 1.35ꢁ1.26 (m, 2H),
1.07ꢁ0.93(m, 3H). 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 199.9, 146.1, 146.1, 143.7,
141.3, 134.0, 128.9, 128.5, 127.8, 127.6, 127.1, 126.8, 126.8, 126.3, 124.2, 111.1, 64.1,
45.8, 29.9, 29.2, 26.5, 26.0, 25.8, 25.7. HRMS (ESI) calcd for C31H32NO (M+H)+:
434.2484, found 434.2494.
(1-(4-methoxyphenyl)-6-methyl-4,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methan
one (3g). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 5:1)
afforded the title product in 90% (103 mg) isolated yield as a yellow solid; mp 132ꢁ133 oC.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.58 (d, J = 7.2 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H),
7.31ꢁ7.08 (m, 12H), 6.69ꢁ6.59 (m, 4H), 5.09 (s, 1H), 3.64 (s, 3H), 1.70 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, Me4Si) δ 191.3, 158.6, 150.6, 146.0, 140.3, 140.3, 136.2, 133.9, 130.6,
129.1, 128.6, 128.6, 128.0, 127.8, 127.7, 127.2, 126.7, 126.7, 124.0, 113.9, 109.6, 64.6,
55.3, 26.6. HRMS (MALDI/DHB) calcd for C32H28NO2 (M+H)+: 458.2120, found
458.2115.
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(6-methyl-1-(4-nitrophenyl)-4,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone
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(3h). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 8:1)
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afforded the title product in 67% (79 mg) isolated yield as a yellow solid; mp 225ꢁ226 C.
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1H NMR (400 MHz, CDCl3, Me4Si) δ 7.97ꢁ7.95 (m, 2H), 7.65ꢁ7.63 (m, 2H), 7.47ꢁ7.45 (m,
2H), 7.33ꢁ7.25 (m, 7H), 7.14ꢁ7.05 (m, 5H), 6.99ꢁ6.96 (m, 2H), 5.19 (s, 1H), 1.90 (s, 3H);
13C NMR (100.6 MHz, CDCl3, Me4Si) δ 192.3, 149.3, 145.5, 145.2, 144.6, 139.3, 139.1,
133.0, 131.6, 129.1, 129.1, 128.2, 128.1, 127.9, 127.2, 127.1, 126.0, 124.5, 124.4, 114.9,
65.1, 25.8. HRMS (ESI) calcd for C31H25N2O3 (M+H)+: 473.1865, found 473.1860.
(1-(2-chlorophenyl)-6-methyl-4,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanon
e (3i). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1)
afforded the title product in 88% (101 mg) isolated yield as a yellow solid; mp 185ꢁ186 oC.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.60ꢁ7.50 (m, 2H), 7.46ꢁ7.40 (m, 2H), 7.32ꢁ7.22 (m,
7H), 7.14ꢁ6.99 (m, 7H), 6.82 (s, 1H), 6.68ꢁ6.66 (m, 1H), 5.12 (s, 1H), 1.76 (s, 3H); 13C
NMR (100.6 MHz, CDCl3, Me4Si) δ 191.7, 148.3, 145.7, 144.6, 139.8, 139.8, 134.4, 133.7,
131.0, 129.8, 129.1, 128.7, 128.0, 128.0, 127.7, 127.2, 127.0, 126.8, 126.4, 124.7, 124.6,
111.6, 64.6, 26.4. HRMS (ESI) calcd for C31H24ClNO: 461.1546, found 461.1537.
2-(5-benzoyl-2-methyl-2,4-diphenylpyridin-1(2H)-yl)benzonitrile
(3j).
Column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) afforded the
title product in 73% (83 mg) isolated yield as a yellow liquid. 1H NMR (400 MHz, CDCl3,
Me4Si) δ 7.92ꢁ7.90 (m, 2H), 7.64ꢁ7.62 (m, 1H), 7.58ꢁ7.56 (m, 2H), 7.44ꢁ7.35 (m, 5H),
7.33ꢁ7.31 (m, 1H), 7.29ꢁ7.17 (m, 7H), 7.10ꢁ7.06 (m, 1H), 6.64 (s, 1H), 5.31 (s, 1H), 1.86 (s,
3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 191.8, 148.0, 145.7, 145.2, 139.6, 139.3,
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133.9, 133.7, 132.8, 131.1, 129.3, 128.7, 128.4, 128.1, 128.1, 128.1, 127.7, 127.7, 127.1,
126.8, 126.7, 125.3, 116.5, 112.8, 112.4, 65.1, 26.2. HRMS (ESI) calcd for C32H24N2O:
452.1889, found 452.1881.
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benzyl-6-methyl-4,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3k) (the
reaction time was 5 h). Column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1) afforded the title product in 35% (39 mg) isolated yield as a yellow liquid.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.54 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H),
7.33ꢁ7.36 (m, 2H), 7.26ꢁ7.07 (m, 13H), 6.99ꢁ6.97 (m, 2H), 4.97 (s, 1H), 3.98 (d, J = 14.8
Hz, 1H), 4.07 (d, J = 14.8 Hz, 1H), 1.77 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ
190.5, 151.4, 145.3, 140.5, 140.2, 136.7, 133.9, 130.3, 129.0, 128.9, 128.6, 128.0, 128.0,
127.9, 127.8, 127.6, 127.2, 127.1, 126.6, 123.7, 108.0, 64.5, 53.3, 25.4. HRMS (ESI) calcd
for C32H28NO (M+H)+: 442.2171, found 442.2173.
phenyl(1,4,6,6-tetraphenyl-1,6-dihydropyridin-3-yl)methanone (3l) (the reaction time
was 4 h). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
10:1) afforded the title product in 82% (100 mg) isolated yield as a yellow solid; mp
o
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145ꢁ146 C. H NMR (400 MHz, CDCl3, Me4Si) δ 7.59 (s, 1H), 7.38ꢁ7.36 (m, 5H),
7.22ꢁ76.99 (m, 15H), 6.97ꢁ6.86 (m, 5H), 5.55 (s, 1H); 13C NMR (100.6 MHz, CDCl3,
Me4Si) δ 192.4, 146.5, 144.2, 143.1, 140.1, 139.5, 134.6, 130.9, 128.9, 128.8, 128.3, 127.9,
127.8, 127.7, 127.6, 127.4, 126.9, 125.7, 125.6, 124.1, 114.0, 72.6. HRMS (MALDI/DHB)
calcd for C36H28NO (M+H)+: 490.2171, found 490.2165.
(6-(4-chlorophenyl)-6-methyl-1,4-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanon
e (3m) (the reaction time was 2 h). Column chromatography on silica gel (eluent:
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petroleum ether/ethyl acetate = 15:1) afforded the title product in 89% (103 mg) isolated
yield as a yellow solid; mp 176ꢁ177 oC. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.59 (d, J =
7.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.27ꢁ7.21 (m, 6H), 7.16ꢁ7.12 (m, 8H), 6.81ꢁ6.79 (m,
2H), 5.06 (s, 1H), 1.72 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 191.6, 149.5,
144.7, 143.2, 140.0, 139.9, 134.2, 133.8, 130.9, 129.1, 129.0, 128.8, 128.1, 127.9, 127.8,
127.3, 127.2, 126.9, 126.8, 123.8, 110.7, 64.1, 26.7. HRMS (ESI) calcd for C31H25ClNO
(M+H)+: 462.1625, found 462.1633.
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(6-cyclopropyl-1,4,6-triphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3n) (the
reaction time was 2 h). Column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1) afforded the title product in 67% (76 mg) isolated yield as a yellow solid;
o
mp 241ꢁ242 C. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.71ꢁ7.67 (m, 4H), 7.39ꢁ7.27 (m,
7H), 7.21ꢁ7.12 (m, 8H), 6.91ꢁ6.89 (m, 2H), 4.68 (s, 1H), 1.43ꢁ1.38 (m, 1H), 0.95ꢁ0.89 (m,
1H), 0.78 ꢁ0.70 (m, 2H), 0.59ꢁ0.55 (m, 1H); 13C NMR (100.6 MHz, CDCl3, Me4Si) ) δ
191.2, 150.4, 147.2, 143.7, 140.4, 140.1, 135.9, 130.7, 129.1, 128.7, 128.4, 127.9, 127.7,
127.6, 127.3, 127.28, 127.1, 127.0, 126.6, 117.2, 108.9, 69.1, 18.4, 2.5, 1.7. HRMS (ESI)
calcd for C33H27NO: 453.2093, found 453.2084.
(4-(4-fluorophenyl)-1,6,6-triphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3o).
Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1)
afforded the title product in 92% (103 mg) isolated yield as a yellow solid; mp 144ꢁ145 oC.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.69ꢁ7.67 (m, 2H), 7.55ꢁ7.53 (m, 2H), 7.38 ꢁ7.29 (m,
7H), 7.20ꢁ7.14 (m, 5H), 6.91ꢁ6.85 (m, 4H), 5.15 (s, 1H), 1.81 (s, 3H); 13C NMR (100.6
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MHz, CDCl3, Me4Si) δ 191.2, 161.7 (d, JCꢁF = 245.1 Hz ), 150.0, 145.9, 143.2, 139.9,
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136.0 (d, JCꢁF = 3.5 Hz ), 132.6, 130.8, 128.9, 128.8, 128.6 (d, JCꢁF = 8.0 Hz ), 128.6,
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128.0, 127.8, 127.0, 126.6, 126.2, 124.4, 114.4 (d, JCꢁF = 21.4 Hz ), 110.1, 64.5, 26.7.
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HRMS (ESI) calcd for C31H24FNO: 445.1842, found 445.1833.
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(6-methyl-1,6-diphenyl-4-(p-tolyl)-1,6-dihydropyridin-3-yl)(phenyl)methanone
(3p)
(the reaction time was 2 h). Column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1) afforded the title product in 72% (80 mg) isolated yield as a
yellow liquid. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.71ꢁ7.69 (m, 2H), 7.55ꢁ7.52 (m, 2H),
7.37ꢁ7.28 (m, 8H), 7.16ꢁ7.11 (m, 4H), 7.03ꢁ7.01 (m, 2H), 6.87ꢁ6.84 (m, 2H), 5.18 (s, 1H),
2.26 (s, 3H), 1.81 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 191.4, 149.8, 146.0,
143.3, 139.9, 137.0, 136.2, 133.4, 130.7, 129.0, 128.8, 128.5, 128.3, 127.9, 127.6, 126.9,
126.9, 126.6, 126.3, 124.1, 110.6, 64.5, 26.7, 21.1. HRMS (ESI) calcd for C32H27NO:
441.2093, found 441.2081.
(4-butyl-6-methyl-1,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3r) (the
reaction time was 3 h). Column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 30:1) afforded the title product in 21% (22 mg) isolated yield as a yellow liquid.
1H NMR (400 MHz, CDCl3, Me4Si) δ 7.65ꢁ7.63 (m, 2H), 7.49ꢁ7.47 (m, 2H), 7.39ꢁ 7.34 (m,
5H), 7.31ꢁ7.27 (m, 1H), 7.14ꢁ7.11 (m, 3H), 7.08 (s, 1H), 6.75ꢁ6.72 (m, 2H), 4.94 (s, 1H),
2.67ꢁ2.56 (m, 2H), 1.71 (s, 3H), 1.47ꢁ1.34 (m, 4H), 0.90 (t, J = 7.2Hz, 3H); 13C NMR
(100.6 MHz, CDCl3, Me4Si) δ 192.9, 151.2, 146.7, 143.5, 141.1, 132.3, 130.3, 128.9, 128.7,
128.4, 128.0, 127.6, 126.9, 126.7, 126.4, 121.9, 110.0, 64.2, 33.0, 31.7, 26.8, 22.6, 14.1.
HRMS (ESI) calcd for C29H29NO: 407.2249, found 407.2243.
(E)-(4-butylidene-6-methyl-1,6-diphenyl-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)meth
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anone (4a) (the reaction time was 3 h). Column chromatography on silica gel (eluent:
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yield as a yellow liquid. H NMR (400 MHz, CDCl3, Me4Si) δ 7.63ꢁ7.61 (m, 2H),
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7.41ꢁ7.30 (m, 8H), 7.26ꢁ7.23 (m, 1H), 7.17ꢁ7.13 (m, 2H), 7.09ꢁ7.05 (m, 1H), 6.92ꢁ6.89 (m,
2H), 6.20 (t, J = 7.6 Hz, 1H), 2.98 (d, J = 14.0 Hz, 1H), 2.57 (d, J = 14.0 Hz, 1H),
1.96ꢁ1.90 (m, 1H), 1.85ꢁ1.77 (m, 1H), 1.69 (s, 3H), 1.15ꢁ1.08 (m, 1H), 0.99ꢁ0.94 (m, 1H),
0.68 (t, J = 7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 194.3, 149.1, 144.2,
144.0, 141.3, 130.1, 128.8, 128.7, 128.3, 128.1, 127.9, 127.0, 125.6, 125.5, 124.7, 124.6,
113.2, 63.2, 41.9, 29.6, 26.4, 22.8, 13.7. HRMS (ESI) calcd for C29H29NO: 407.2249,
found 407.2243.
(6-methyl-4-phenethyl-1,6-diphenyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (3s)
(the reaction time was 2 h). Column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 15:1) afforded the title product in 35% (40 mg) isolated yield as a
yellow liquid. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.67ꢁ7.64 (m, 2H), 7.41ꢁ7.31 (m, 7H),
7.29ꢁ7.23 (m, 5H), 7.18ꢁ7.14 (m, 1H), 7.12ꢁ7.07 (m, 4H), 6.72ꢁ7.69 (m, 2H), 4.82 (s, 1H),
2.98ꢁ2.92 (m, 2H), 2.84ꢁ2.80 (m, 2H), 1.61 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si)
δ 192.8, 151.7, 146.2, 143.3, 142.4, 141.1, 131.0, 130.2, 128.9, 128.8, 128.7, 128.4, 128.1,
128.0, 127.5, 127.0, 126.8, 126.6, 125.4, 123.0, 109.6, 64.2, 35.9, 35.6, 26.5. HRMS (ESI)
calcd for C33H29NO: 455.2249, found 455.2239.
(E)-(6-methyl-1,6-diphenyl-4-(2-phenylethylidene)-1,4,5,6-tetrahydropyridin-3-yl)(phe
nyl)methanone (4b) (the reaction time was 2 h). Column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 15:1) afforded the title product in 31% (35 mg)
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isolated yield as a yellow liquid. 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.62ꢁ7.59 (m, 2H),
7.46 (s, 1H), 7.35ꢁ7.28 (m, 8H), 7.17ꢁ7.03 (m, 6H), 6.93ꢁ6.91 (m, 2H), 6.70ꢁ6.68 (m, 2H),
6.37 (t, J = 7.6 Hz, 1H), 3.26 (d, J = 8.0 Hz, 2H), 3.12 (d, J = 13.6 Hz, 1H), 2.66 (d, J =
14.0 Hz, 1H), 1.70 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si) δ 194.0, 149.4, 143.9,
143.8, 141.1, 140.6, 130.0, 128.7, 128.6, 128.5, 128.24, 127.9, 127.8, 127.0, 125.8, 125.6,
125.5, 125.3, 125.1, 124.6, 112.7, 63.0, 41.7, 33.5, 26.6. HRMS (ESI) calcd for C33H29NO:
455.2249, found 455.2239.
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(6-methyl-1-(4-nitrophenyl)-4-phenethyl-6-phenyl-1,6-dihydropyridin-3-yl)(phenyl)m
ethanone (3t) (the reaction time was 2 h). Column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1) afforded the title product in 21% (26 mg) isolated
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yield as a yellow liquid. H NMR (400 MHz, CDCl3, Me4Si) δ 7.97ꢁ7.95 (m, 2H),
7.74ꢁ7.71 (m, 2H), 7.50ꢁ7.43 (m, 3H), 7.34ꢁ7.10 (m, 11H), 6.88ꢁ6.85 (m, 2H), 4.88 (s, 1H),
2.87ꢁ2.85 (m, 2H), 2.77ꢁ2.75 (m, 2H), 1.75 (s, 3H); 13C NMR (100.6 MHz, CDCl3, Me4Si)
δ 193.4, 149.2, 147.4, 145.4, 144.5, 141.9, 140.2, 131.2, 130.2, 128.9, 128.8, 128.8, 128.3,
128.1, 127.9, 126.1, 125.6, 125.1, 124.5, 124.4, 113.7, 64.7, 35.6, 34.8, 25.7. HRMS (ESI)
calcd for C33H28N2O3: 500.2100, found 500.2091.
(E)-(6-methyl-1-(4-nitrophenyl)-6-phenyl-4-(2-phenylethylidene)-1,4,5,6-tetrahydropy
ridin-3-yl)(phenyl)methanone (4c) (the reaction time was 2 h). Column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) afforded the title product in 33%
o
(42 mg) isolated yield as a yellow solid; mp 152ꢁ153 C. 1H NMR (400 MHz, CDCl3,
Me4Si) δ 8.00ꢁ7.99 (m, 2H), 7.66ꢁ7.64 (m, 2H), 7.45ꢁ7.30 (m, 9H), 7.15ꢁ7.09 (m, 3H),
6.96ꢁ6.94 (m, 2H), 6.76ꢁ6.74 (m, 2H), 6.25 (t, J = 7.6 Hz, 1H), 3.29 (d, J = 7.6 Hz, 2H),
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3.06 (d, J = 14.0 Hz, 1H), 2.78 (d, J = 13.6 Hz, 1H), 1.82 (s, 3H); 13C NMR (100.6 MHz,
CDCl3, Me4Si) δ 194.7, 149.3, 145.0, 143.6, 142.9, 140.3, 140.2, 131.1, 129.0, 128.9, 128.3,
128.2, 128.1, 127.6, 127.4, 125.7, 125.5, 125.2, 124.5, 122.9, 116.1, 63.4, 42.6, 33.6, 25.5.
HRMS (ESI) calcd for C33H28N2O3: 500.2100, found 500.2091.
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Acknowledgment. We thank the National Natural Science Foundation of China (Grant No.
21272074) for financial support.
Supporting Information Available: Experimental details, spectroscopic characterization
of all new compounds and Xꢁray crystallography of compound 3l and 4c. This material is
available free of charge via the Internet at http://pubs.acs.org.
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