Cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of 3-aza-1,5-enynes to synthesize 1,2-dihydropyridines and 3-iodo-1,2- dihydropyridines

Article abstract of DOI:10.1021/jo400387b

Metal-free cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of readily available 3-aza-1,5-enynes have been developed. The reactions selectively give 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines involving an aza-Claisen rearrangement and a 6π-electrocyclization step. Furthermore, the reaction could be carried out in 10 g scale for the synthesis of 1,2-dihydropyridines.

Full text of DOI:10.1021/jo400387b

Article
pubs.acs.org/joc
Cyclization and N‑Iodosuccinimide-Induced Electrophilic
Iodocyclization of 3‑Aza-1,5-enynes To Synthesize 1,2-
Dihydropyridines and 3‑Iodo-1,2-dihydropyridines
Xiaoyi Xin, Dongping Wang, Fan Wu, Xincheng Li, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: Metal-free cyclization and N-iodosuccinimide-induced
electrophilic iodocyclization of readily available 3-aza-1,5-enynes have
been developed. The reactions selectively give 1,2-dihydropyridines and 3-
iodo-1,2-dihydropyridines involving an aza-Claisen rearrangement and a
6π-electrocyclization step. Furthermore, the reaction could be carried out
in 10 g scale for the synthesis of 1,2-dihydropyridines.
Dihydropyridines (three examples) were also obtained as a
dominant product or accompanied with pyrroles by changing
the reaction conditions or the structure of starting materials.7d
Recently, in a short communication, we reported that 3-aza-1,5-
enyne 1 was selectvely trasformed into two kinds of
functionalized pyrroles via regioselective sulfonyl group
migration under thermal or base conditions (Scheme 1, eq 3,
left).7e As a continuation of this work, we found that 1,2-
dihydropyridines 2 and 3-iodo-1,2-dihydropyridines 3 were
selectively synthesized by changing the reaction conditions via
cyclization or N-iodosuccinimide (NIS)-induced electrophilic
iodocyclization8 of 3-aza-1,5-enynes 1 (Scheme 1, eq 3, right).
Herein, we report the detailed results for selective synthesis of
1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines via cycli-
zation or NIS-induced electrophilic iodocyclization of 3-aza-1,5-
enynes.
INTRODUCTION
■
Dihydropyridines (DHPs)1 are an important class of
heterocyclic compounds that have found widespread applica-
tions in therapeutically active compounds2 and have been
recognized as versatile synthetic intermediates for a broad
variety of nitrogen-containing heterocycles such as piperidines3
and pyridines.4 Moreover, iodinated dihydropyridines are useful
building blocks for allowing further structural elaboration via
cross-coupling reactions.5 Historically, 1,4-dihydropyridines
(1,4-DHPs) have been extensively studied, whereas 1,2-
dihydropyridines (1,2-DHPs) have received limited attention.
Although 1,2-dihydropyridines are accessible via several
routes,1,6 the most popular approaches to 1,2-dihydropyridine
synthesis is nucleophilic addition of a variety of nucleophiles to
N-acyl, N-alkyl, or N-heteroatom pyridinium salts, and these
processes usually require harsh reaction conditions and often
yield regioisomeric products. The development of alternative
methods for the synthesis of 1,2-dihydropyridines and iodo-1,2-
dihydropyridines from readily available starting materials under
mild conditions continues to be of intense interest.
RESULTS AND DISCUSSION
■
Synthesis of 1,2-Dihydropyridines. In the course of our
continuing investigation on the transformation of aza-enyne 1
to N-heterocycles, we found that treatment of the model
substrate 1a (R1 = R2 = Ph, R3 = p-tolyl) in methanol at 60 °C
for 48 h, a different type of heterocycle, 1,2-dihydropyridine 2a,
was obtained in 95% yield (Table 1, entry 1). The structure of
2a was unambiguously confirmed by X-ray crystallography (see
Supporting Information).
3-Aza-1,5-enyne substrate is a versatile framework for the
synthesis of a broad variety of heterocyclic compounds.7 Cacchi
and co-workers reported that N-propargylic β-enaminones
could be selectively transformed into pyrroles or pyridines via
5-exo-dig or 6-endo-dig cyclization (Scheme 1, eq 1, left).7a
Recently, the electrophilic cyclizations of N-propargylic β-
enaminones with molecular iodine leading to iodo-substituted
pyridines were studied by the Zora research group (Scheme 1,
eq 1, right),7b and the resulting iodo-substituted pyridines were
successfully elaborated to more complex molecules via
palladium-catalyzed reactions.7c Saito and co-workers described
that the similar structure, N-tosyl, N-propargylic β-enaminones,
underwent Au(I)-catalyzed amino-Claisen rearrangement and
heterocyclization to yield pyrroles (Scheme 1, eq 2).7d 1,2-
We directly explored the scope and generality of this
reaction, and the results are given in Table 1. Aryl R1 groups
bearing different substituents, including electron-neutral groups
(entry 1), electron-donating groups (entries 2−4), electron-
withdrawing groups (entry 5), and halogen groups (entries 6−
Received: February 22, 2013
Published: March 8, 2013
© 2013 American Chemical Society
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Scheme 1. Synthetic Variability of 3-Aza-1,5-enynes
a
8), were well-tolerated, and the desired products were isolated
with moderate to high yields (78−95%). A fused ring was also
suitable for this process, although a relatively lower yield was
obtained (72%, entry 9). Alkyl R1 substituents were also
tolerated (entries 10 and 11) but only at elevated temperature
(140 and 100 °C). Both aryl- and alkyl-substituted alkyne (R2)
units in the substrate were well-tolerated (entries 12−17). It is
worthwhile to note that alkyl-substituted alknyl substrates also
reacted in high yield (entries 16 and 17). The electronic
properties of the sulfonyl group (R3) had a relatively small
impact on the yield (entries 1, 18, and 19).
Deuterium-labeling experiments were performed to explore
the reaction mechanism. Substrate deuterated at the C4
position (1a-D) was subjected to the standard reaction
conditions (Scheme 2a), where no deuterium scrambling was
detected based on 1H NMR spectroscopy, indicating that C−H
cleavage is not involved at this position. When substrate 1a was
allowed to react in deuterium/methanol, 95% of the D atom
was incorporated in the olefinic position of product 2a-D′
(Scheme 2b). A control experiment was also performed. 1,2-
DHP 2a was heated in deuterium/methanol, and no deuterated
product was detected (Scheme 2c). This result ruled out a
postreaction H/D exchange.
A plausible reaction mechanism is depicted in Scheme 3.
Aza-Claisen rearrangement7d,e of 1 leads to A. Enamine B is the
equilibrium form of imine A via 1,3-H-shift. H-shift (Hb) of A
results in azatriene C. Subsequent 6π-electrocyclization6d−f of
C generates 1,2- dihydropyridine 2. The H atom (N−C−H,
Ha) of the reactant connects to the same carbon atom in
product 2. This goes well with the deuterium-labeling
experiment (Scheme 2a). The olefinic H atom (Hb) of 1
appears in the olefinic position of product 2. When the reaction
was performed in CD3OD, H/D exchange takes place between
Table 1. Scope of the Synthesis of 1,2-Dihydropyridines
entry
1
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
95 (2a)
91 (2b)
92 (2c)
78 (2d)
81 (2e)
88 (2f)
87 (2g)
86 (2h)
72 (2i)
97 (2j)
69 (2k)
95 (2l)
93 (2m)
95 (2n)
97 (2o)
96 (2p)
97 (2q)
92 (2r)
95 (2s)
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-CF3C6H4
4-FC6H4
2-ClC6H4
2-BrC6H4
1-naphthyl
iPr
1g
1h
1i
b
10
1j
c
11
1k
1l
cPr
12
13
14
15
16
17
18
19
Ph
3-MeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
nPr
1m
1n
1o
1p
1q
1r
1s
Ph
Ph
Ph
Ph
Ph
nBu
Ph
Ph
Ph
Ph
2-ClC6H4
a
Reaction conditions: in sealed tube, 0.2 mmol of 1 in 2.0 mL of
methanol was heated at 60 °C under an argon atmosphere until the
consumption of the starting material unless otherwise noted. At 140
b
c
°C. At 100 °C.
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Scheme 2. Mechanistic Studies
Scheme 4. Synthesis of 1,2-DHP in 10 Gram Scale via
Simple Operation
a
Table 2. Solvent Screening for 3-Iodo-1,2-dihydropyridines
entry
solvent
yield (%)
1
2
3
4
5
THF
66
64
70
87
93
1,2-dichloroethane
1,4-dioxane
CH3CN
intermediate B (Hb) and CD3OD, thus the D atom appears in
the olefinic position of the product 2. This illustrates the D-
incorporated experiment (Scheme 2b).
DMF
a
Reaction conditions: 1 (0.2 mmol), NIS (0.24 mmol) in 1 mL of
solvent was heated at 80 °C under an argon atmosphere for 5 h.
This reaction could also be carried out under air atmosphere
and in 10 g scale (Scheme 4). The product 2a was obtained in
96% yield after simple precipitation and recrystallization.
Reactant 1a was readily prepared from commercially available
starting materials.7e,9 This method provided a highly efficient,
operationally convenient approach to access polysubstituted
1,2-dihydropyridines.
Synthesis of 3-Iodo-1,2-dihydropyridines. After suc-
cessful transformation of aza-enyne 1 to 1,2-dihydropyridines,
we attempted to synthesize 3-iodo-1,2-dihydropyridines
through a simple NIS-induced electrophilic cyclization. When
model substrate 1a (R1 = R2 = Ph, R3 = p-tolyl) was treated
with NIS (1.2 equiv) in THF at 80 °C under argon atmosphere,
to our delight, the desired product 3a was obtained in 66%
yield (Table 2, entry 1). The structure of 3a was also
unambiguously confirmed by X-ray crystallography (see
Supporting Information). The solvent effect was then
investigated. The use of 1,2-dichloroethane or 1,4-dioxane as
solvent did not greatly improve the product yield (Table 2,
entries 2 and 3). Gratifyingly, the yield was improved to 87%
when the reaction was performed in acetonitrile (Table 2, entry
4). Fortunately, 3a was obtained in 93% yield when using DMF
as solvent. Therefore, we performed the reaction in DMF at 80
°C under argon atmosphere.
Following the optimization of the reaction conditions, we
explored the reaction scope, and the results are given in Table
3. Aryl R1 and R2 groups bearing different substituents were
well-tolerated, and the desired products were isolated with
moderate to high yields. A fused ring was also suitable for this
process (entry 9). When R1 was changed to an isopropyl or
cyclopropyl group, the products were very complicated and the
desired compounds were not obtained. Alkyl-substituted alkyne
(R2) units in the substrate were also tolerated (entries 16 and
17), but the yields were very low. The electronic properties of
the sulfonyl group (R3) had a relatively small impact on the
yields (entries 1, 18, and 19).
A plausible reaction mechanism is depicted in Scheme 5. An
initial attack of iodonium ion to the alkyne moiety leads to
cation D and succinimide anion. Subsequent cyclization of
cation D generates cation E. The succinimide anion traps a
proton of E to furnish 3-iodo-1,2-dihydropyridine product 3
and succinimide.
Scheme 3. Proposed Mechanism
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a
Table 3. Scope of Synthesis of 3-Iodo-1,2-dihydropyridines
Scheme 6. Further Structural Elaboration of the Iodide
Product
entry
1
R1
R2
R3
yield (%)
1
2
3
4
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
93 (3a)
89 (3b)
88 (3c)
71 (3d)
69 (3e)
92 (3f)
85 (3g)
80 (3h)
63 (3i)
d
operation. 3-Iodo-1,2-dihydropyridines are obtained via NIS-
induced electrophilic iodocyclization of 3-aza-1,5-enyne, which
makes it possible to allow further structural derivatization using
palladium-catalyzed cross-coupling reactions. Studies to explore
more versatile reactions of the aza-enyne building block by
changing the substituent patterns or altering reaction
conditions are currently in process.
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-CF3C6H4
4-FC6H4
2-ClC6H4
2-BrC6H4
1-naphthyl
iPr
b
5
6
b
7
1g
1h
1i
b
8
9
EXPERIMENTAL SECTION
c
■
10
1j
c
cPr
d
General. All reactions were carried out under an atmosphere of
argon using standard Schlenk techniques unless otherwise noted.
Column chromatography was carried out on silica gel (300−400
mesh) using a forced flow of eluent at 0.3−0.5 bar pressure. For TLC,
silica gel GF254 was used and visualized by fluorescence quenching
under UV light. Solvents were dried according to the standard
procedure and were distilled prior to use. Starting materials 1 were
prepared according to literature procedures.7e,9
11
1k
1l
12
13
14
15
Ph
3-MeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
nPr
89 (3l)
83 (3m)
80 (3n)
93 (3o)
23 (3p)
33 (3q)
90 (3r)
91 (3s)
1m
1n
1o
1p
1q
1r
1s
Ph
Ph
Ph
b
16
Ph
b
17
Ph
nBu
1H NMR, 13C NMR, 19F NMR spectra were recorded with 400 or
500 MHz spectrometers. The 1H NMR spectra of 1, 2, 3p−3q, and 4
18
19
Ph
Ph
Ph
Ph
2-ClC6H4
1
were recorded at room temperature. The H NMR spectra of 3a−3i,
a
Reaction conditions: 1 (0.2 mmol), NIS (0.24 mmol) in DMF (1
mL) was heated at 80 °C under an argon atmosphere for 5 h unless
otherwise noted. For 10 h. At 140 °C, 20 h. The products were
3l−3o, and 3r−3s were recorded in (CD3)2SO at 60 °C. The chemical
1
shifts for H NMR were recorded in parts per million downfield from
b
c
d
tetramethylsilane (TMS) with the solvent resonance as the internal
standard (7.26 ppm for CDCl3, 2.05 ppm for CD3COCD3, or 2.50
ppm for (CD3)2SO). The chemical shifts for 13C NMR were recorded
in parts per million downfield using the central peak of CDCl3 (77.16
ppm) or CD3COCD3 (29.84 ppm) as the internal standard. Coupling
constants (J) are reported in hertz and refer to apparent peak
multiplications. The abbreviations s, d, t, q, and m stand for singlet,
doublet, triplet, quartet, and multiplet in that order. All 13C NMR
spectra were proton decoupled.
very complicated, and the desired compounds were not obtained.
Scheme 5. Proposed Mechanism of NIS-Induced Cyclization
of 3-Aza-1,5-enynes
General Procedure To Prepare the Starting Materials 3-Aza-
1,5-enynes 1. The 3-aza-1,5-enynes were prepared following the
procedure described in the literature:7e,9 the corresponding propargyl
amines and dimethyl acetylenedicarboxylate (1.2 equiv) were placed in
a dried flask under argon atmosphere, and CH2Cl2 was added until the
dissolution of the solid. Subsequently, 10−20 mol % of Cs2CO3 was
added. The resulting mixture was stirred at 0 °C or room temperature
until the consumption of propargyl amines was detected by TLC. The
solvent was evaporated, and the crude product was directly purified by
silica gel flash column chromatography (eluent: 10:1 petroleum ether/
ethyl acetate) to give the desired complex 1.
Dimethyl 2-(N-(1,3-Diphenylprop-2-ynyl)-4-methylphenyl-
sulfonamido)maleate (1a) (ref 7e): white solid; 31% yield; 1H
NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 7.7
Hz, 2H), 7.40−7.27 (m, 8H), 7.16 (dd, J = 8.1, 1.4 Hz, 2H), 6.54 (s,
1H), 6.10 (s, 1H), 3.76 (s, 3H), 3.60 (s, 3H), 2.31 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.9, 164.2, 144.9, 139.7, 135.3, 133.9, 131.7,
129.8, 129.1, 128.8, 128.7, 128.5, 128.4, 128.0, 121.7, 117.4, 89.7, 82.8,
55.0, 53.0, 52.0, 21.7.
The presence of iodine at the product allows further
structural elaboration for increasing molecular complexity via
palladium-catalyzed reactions. For example, when compound
3a was exposed to Sonogashira coupling conditions10 with
phenylacetylene, the corresponding coupling product 4 was
obtained in 62% yield (Scheme 6).
Dimethyl 2-(N-(1,3-Diphenylprop-2-ynyl)-4-methylphenyl-
sulfonamido)-maleate-d6 (1a-D): white solid; 59% yield; mp 100−
101 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.30
(m, 5H), 7.15 (m, 2H), 6.10 (s, 1H), 3.76 (s, 3H), 3.59 (s, 3H), 2.31
(s, 3H); HRMS (Q-TOF, m/z) calcd for C28H19D6NO6NaS [M +
Na]+ 532.1677, found 532.1671.
Dimethyl 2-(4-Methyl-N-(3-phenyl-1-o-tolylprop-2-ynyl)phenyl-
sulfonamido)maleate (1b): white solid; 66% yield; mp 117−118
°C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 2H), 7.57 (d, J
CONCLUSIONS
■
In summary, we have developed highly efficient cyclization and
iodocyclization of 3-aza-1,5-enynes for the synthesis of 1,2-
dihydropyridines and 3-iodo-1,2-dihydropyridines. The metal-
free approach to 1,2-dihydropyridines involves an aza-Claisen
rearrangement and a 6π-electrocyclization step. This reaction
can be carried out under air atmosphere in 10 g scale via simple
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= 7.7 Hz, 1H), 7.28 (m, 7H), 7.13 (m, 3H), 6.65 (s, 1H), 6.38 (s, 1H),
3.66 (s, 3H), 3.61 (s, 3H), 2.63 (s, 3H), 2.31 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.8, 163.9, 144.6, 138.6, 137.7, 135.1, 131.6, 131.4,
131.2, 130.3, 129.6, 129.4, 129.0, 128.7, 128.4, 125.6, 124.1, 121.8,
89.4, 84.2, 53.9, 52.7, 52.3, 21.6, 19.5; HRMS (Q-TOF, m/z) calcd for
C29H27NO6NaS [M + Na]+ 540.1457, found 540.1448.
Dimethyl 2-(4-Methyl-N-(3-phenyl-1-m-tolylprop-2-ynyl)phenyl-
sulfonamido)maleate (1c) (ref 7e): white solid; 25% yield; 1H
NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 7.5
Hz, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.24 (m, 2H), 7.15 (m, 2H),
7.11 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 6.10 (s, 1H), 3.77 (s, 3H), 3.60
(s, 3H), 2.35 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.0, 164.2, 144.9, 139.7, 138.4, 135.3, 133.7, 131.7, 129.8, 129.5,
129.4, 129.0, 128.6, 128.5, 128.4, 125.0, 121.8, 117.1, 89.5, 82.9, 54.9,
53.0, 52.0, 21.6, 21.5.
Dimethyl 2-(4-Methyl-N-(3-phenyl-1-p-tolylprop-2-ynyl)phenyl-
sulfonamido)maleate (1d) (ref 7e): white solid; 51% yield; 1H
NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.0
Hz, 2H), 7.31 (m, 5H), 7.15 (m, 4H), 6.50 (s, 1H), 6.10 (s, 1H), 3.77
(s, 3H), 3.61 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.0, 164.3, 144.8, 139.8, 138.6, 135.3, 131.7, 130.8, 129.8,
129.4, 129.0, 128.5, 128.4, 127.9, 121.8, 117.1, 89.5, 83.0, 54.8, 53.0,
52.1, 21.7, 21.3.
7.18 (m, 5H), 7.03 (dd, J = 8.1, 1.4 Hz, 2H), 6.49 (s, 1H), 4.70 (d, J =
10.4 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 2.30 (s, 3H), 2.27−2.18 (m,
1H), 1.14 (d, J = 0.6 Hz, 3H), 1.13 (d, J = 1.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.3, 164.6, 144.7, 141.4, 135.2, 131.5, 129.6,
128.7, 128.5, 128.3, 122.0, 117.1, 87.6, 84.8, 58.5, 53.1, 52.2, 30.5, 21.6,
20.4, 19.5; HRMS (Q-TOF, m/z) calcd for C25H27NO6NaS [M +
Na]+ 492.1457, found 492.1453.
Dimethyl 2-(N-(1-Cyclopropyl-3-phenylprop-2-ynyl)-4-methyl-
phenylsulfonamido)maleate (1k): white solid; 45% yield; mp 79−
80 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 2H), 7.25
(m, 5H), 7.08 (d, J = 6.3 Hz, 2H), 6.46 (s, 1H), 4.77 (d, J = 6.6 Hz,
1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.33 (s, 3H), 1.40 (d, J = 3.5 Hz, 1H),
0.74−0.43 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 165.1, 164.5,
144.4, 139.5, 135.5, 131.6, 129.6, 128.8, 128.4, 128.3, 122.5, 121.8,
86.7, 83.7, 56.3, 53.0, 52.3, 21.6, 14.2, 5.3, 3.6; HRMS (Q-TOF, m/z)
calcd for C25H25NO6NaS [M + Na]+ 490.1300, found 490.1314.
Dimethyl 2-(4-Methyl-N-(1-phenyl-3-m-tolylprop-2-ynyl)phenyl-
sulfonamido)maleate (1l): white solid; 53% yield; mp 102−103 °C;
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 2H), 7.64 (d, J =
7.6 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.31 (m, 3H), 7.21−7.13 (m,
2H), 6.97 (d, J = 9.4 Hz, 2H), 6.54 (s, 1H), 6.11 (s, 1H), 3.76 (s, 3H),
3.60 (s, 3H), 2.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.0,
164.2, 144.8, 139.7, 138.1, 135.3, 134.0, 132.2, 129.9, 129.8, 128.8,
128.7, 128.6, 128.5, 128.3, 128.0, 121.5, 117.4, 89.9, 82.4, 55.0, 53.0,
52.0, 21.7, 21.3; HRMS (Q-TOF, m/z) calcd for C29H27NO6NaS [M
+ Na]+ 540.1457, found 540.1439.
Dimethyl 2-(4-Methyl-N-(3-phenyl-1-(2-(trifluoromethyl)phenyl)-
prop-2-ynyl)phenylsulfonamido)maleate (1e) (ref 7e): white solid;
1
53% yield; mp 89−90 °C; H NMR (400 MHz, CDCl3) δ 7.82 (m,
3H), 7.72 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5
Hz, 1H), 7.32 (m, 3H), 7.22 (m, 4H), 6.89 (s, 1H), 6.52 (s, 1H), 3.74
(s, 3H), 3.39 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.8, 163.4, 144.5, 135.5, 135.2, 133.2, 132.2, 131.8, 131.6, 131.4,
129.4, 129.3, 129.19, 128.90 (q, J = 31.0 Hz), 128.89, 128.4, 126.7 (q, J
= 5.6 Hz), 124.0 (q, J = 274.4 Hz), 121.5, 89.4, 84.3, 52.5, 52.4, 52.0
(q, J = 2.5 Hz), 21.6.
Dimethyl 2-(4-Methyl-N-(1-phenyl-3-p-tolylprop-2-ynyl)phenyl-
sulfonamido)maleate (1m) (ref 7e): white solid; 29% yield; mp
107−108 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H),
7.64 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.32 (d, J = 7.1 Hz,
1H), 7.28 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.1
Hz, 2H), 6.53 (s, 1H), 6.10 (s, 1H), 3.76 (s, 3H), 3.60 (s, 3H), 2.36 (s,
3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 164.2,
144.8, 139.7, 139.3, 135.3, 134.0, 131.6, 129.8, 129.1, 128.7, 128.6,
128.5, 128.0, 118.7, 117.4, 89.9, 82.1, 55.0, 53.0, 52.1, 21.7, 21.6.
Dimethyl 2-(N-(3-(4-Fluorophenyl)-1-phenylprop-2-ynyl)-4-
methylphenylsulfonamido)maleate (1n): white solid; 18% yield;
mp 104−105 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz,
2H), 7.62 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 7.1
Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.16 (m, 2H), 6.99 (t, J = 8.3 Hz,
2H), 6.52 (s, 1H), 6.08 (s, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 164.2, 162.9 (d, J = 245.5
Hz), 144.8, 139.6, 135.4, 133.8, 133.7, 133.6, 129.8, 128.8, 128.7,
128.6, 127.9, 117.6, 115.8 (d, J = 22.1 Hz), 88.6, 82.7, 54.9, 53.0, 52.1,
21.7.
Dimethyl 2-(N-(1-(4-Fluorophenyl)-3-phenylprop-2-ynyl)-4-
methylphenylsulfonamido)maleate (1f) (ref 7e): white solid; 40%
1
yield; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2H), 7.63
(m, 2H), 7.32 (m, 5H), 7.15 (d, J = 7.4 Hz, 2H), 7.06 (t, J = 8.2 Hz,
2H), 6.50 (s, 1H), 6.12 (s, 1H), 3.77 (s, 3H), 3.63 (s, 3H), 2.32 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 164.2, 162.9 (d, J = 244.7
Hz), 145.0, 139.5, 135.2, 131.7, 130.0, 129.9, 129.8, 129.2, 128.5,
128.4, 121.5, 118.1, 115.7 (d, J = 21.9 Hz), 89.8, 82.7, 54.4, 53.1, 52.2,
21.7.
Dimethyl 2-(N-(1-(2-Chlorophenyl)-3-phenylprop-2-ynyl)-4-
methylphenylsulfonamido)maleate (1g) (ref 7e): white solid; 63%
1
yield; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.66
(dd, J = 7.5, 1.6 Hz, 1H), 7.41 (dd, J = 7.8, 1.2 Hz, 1H), 7.27 (m, 9H),
6.81 (s, 1H), 6.44 (s, 1H), 3.69 (s, 3H), 3.53 (s, 3H), 2.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.8, 163.7, 144.4, 137.3, 135.5, 135.2,
131.9, 131.69, 131.67, 130.6, 130.2, 129.4, 129.2, 128.8, 128.5, 126.7,
126.5, 121.7, 89.3, 83.8, 53.5, 52.6, 52.4, 21.7.
Dimethyl 2-(N-(3-(4-Chlorophenyl)-1-phenylprop-2-ynyl)-4-
methylphenylsulfonamido)maleate (1o): white solid; 31% yield;
1
mp 85−86 °C; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz,
2H), 7.60 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.34−7.24 (m,
5H), 7.09 (d, J = 7.6 Hz, 2H), 6.52 (s, 1H), 6.06 (s, 1H), 3.74 (s, 3H),
3.60 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9,
164.1, 144.9, 139.6, 135.4, 135.2, 133.7, 132.9, 129.8, 128.9, 128.8,
128.7, 128.6, 127.9, 120.2, 117.7, 88.5, 84.0, 54.9, 53.0, 52.1, 21.7;
HRMS (Q-TOF, m/z) calcd for C28H24NO6NaSCl [M + Na]+
560.0911, found 560.0923.
Dimethyl 2-(N-(1-(2-Bromophenyl)-3-phenylprop-2-ynyl)-4-
methylphenylsulfonamido)maleate (1h) (ref 7e): white solid; 64%
1
yield; H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.67
(dd, J = 7.7, 1.6 Hz, 1H), 7.60 (dd, J = 7.9, 1.2 Hz, 1H), 7.31 (m, 4H),
7.20 (m, 5H), 6.77 (s, 1H), 6.45 (s, 1H), 3.69 (s, 3H), 3.53 (s, 3H),
2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 163.6, 144.4,
137.2, 135.3, 133.6, 133.3, 132.3, 131.7, 130.8, 129.4, 129.2, 128.8,
128.5, 127.1, 126.9, 125.4, 121.7, 89.4, 83.9, 55.8, 52.5, 52.4, 21.7.
Dimethyl 2-(4-Methyl-N-(1-(naphthalen-1-yl)-3-phenylprop-2-
ynyl)phenylsulfonamido)maleate (1i) (ref 7e): white solid; 38%
Dimethyl 2-(4-Methyl-N-(1-phenylhex-2-ynyl)phenyl-
sulfonamido)maleate (1p): white solid; 63% yield; mp 86−87 °C;
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 2H), 7.56 (d, J =
1
6.8 Hz, 2H), 7.38−7.24 (m, 5H), 6.30 (s, 1H), 6.04 (s, 1H), 3.76 (s,
3H), 3.59 (s, 3H), 2.45 (s, 3H), 2.00 (s, 2H), 1.44−1.29 (m, 2H), 0.87
(t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.0, 164.2,
144.6, 139.8, 135.5, 134.4, 129.1, 128.54, 128.49, 127.9, 116.5, 90.6,
74.1, 54.8, 52.9, 51.9, 21.7, 20.7, 13.6; inverse gated decoupling 13C
NMR (125 MHz, CDCl3) δ 165.0 (1C), 164.2 (1C), 144.6 (1C),
139.8 (1C), 135.5 (1C), 134.4 (1C), 129.6 (2C), 128.54 (2C), 128.49
(3C), 127.9 (2C), 116.4 (1C), 90.6 (1C), 74.0 (1C), 54.8 (1C), 52.9
(1C), 51.9 (1C), 21.72 (2C), 20.7 (1C), 13.6 (1C); Note: as shown in
inverse gated decoupling 13C NMR (integrate carbon singles), two sp2
carbon peaks overlap at δ 128.49 ppm; two sp3 carbon peaks overlap at δ
yield; H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.6 Hz, 1H), 7.91
(d, J = 8.2 Hz, 2H), 7.84 (t, J = 8.5 Hz, 3H), 7.68 (t, J = 7.7 Hz, 1H),
7.54 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.32 (m, 3H), 7.23
(m, 3H), 7.17 (m, 2H), 6.42 (s, 1H), 3.64 (s, 3H), 3.12 (s, 3H), 2.30
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 163.5, 144.5, 137.0,
135.3, 133.9, 131.6, 131.4, 130.5, 129.5, 129.2, 129.0, 128.9, 128.8,
128.6, 128.4, 127.1, 126.9, 126.2, 124.7, 124.2, 121.9, 89.6, 84.2, 53.6,
52.3, 52.1, 21.6.
Dimethyl 2-(4-Methyl-N-(4-methyl-1-phenylpent-1-yn-3-yl)-
phenylsulfonamido)maleate (1j): white solid; 52% yield; mp 85−
86 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.35−
4069
dx.doi.org/10.1021/jo400387b | J. Org. Chem. 2013, 78, 4065−4074

The Journal of Organic Chemistry
Article
21.72 ppm. HRMS (Q-TOF, m/z) calcd for C25H27NO6NaS [M +
Na]+ 492.1457, found 492.1450.
2H), 6.10 (d, J = 6.0 Hz, 1H), 5.61 (d, J = 6.0 Hz, 1H), 3.76 (s, 3H),
3.53 (s, 3H), 2.67 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.7, 164.4, 144.7, 137.0, 136.3, 135.1, 135.0, 133.6, 132.8, 131.5,
129.7, 128.8, 128.2, 128.1, 127.8, 127.7, 127.6, 126.3, 54.8, 53.0, 52.5,
21.6, 20.1; HRMS (Q-TOF, m/z) calcd for C29H27NO6NaS [M +
Na]+ 540.1457, found 540.1451.
Dimethyl 2-(4-Methyl-N-(1-phenylhept-2-ynyl)phenyl-
sulfonamido)maleate (1q) (ref 7e): white solid; 63% yield; mp 97−
98 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.56
(d, J = 7.8 Hz, 2H), 7.34 (t, J = 8.3 Hz, 4H), 7.28 (m, 1H), 6.30 (s,
1H), 6.04 (s, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 2.45 (s, 3H), 2.03 (m,
2H), 1.28 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.0, 164.2, 144.6, 139.9, 135.5, 134.4, 129.6, 128.6, 128.5,
127.9, 116.3, 90.8, 73.9, 54.8, 53.0, 52.0, 30.3, 22.1, 21.8, 18.4, 13.6.
Dimethyl 2-(N-(1,3-Diphenylprop-2-ynyl)phenylsulfonamido)-
Dimethyl 4-Phenyl-6-m-tolyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2c): following general procedure A, 60 °C, 48 h; white
1
solid; 95.0 mg; 92% yield; mp 136−137 °C; H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.29−7.18
(m, 6H), 7.13 (s, 1H), 6.79 (d, J = 7.6 Hz, 2H), 5.82 (d, J = 6.2 Hz,
1H), 5.66 (d, J = 6.2 Hz, 1H), 3.81 (s, 3H), 3.50 (s, 3H), 2.42 (s, 3H),
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 164.4, 144.7,
138.4, 136.9, 136.7, 135.8, 134.9, 130.9, 129.9, 129.5, 129.4, 128.6,
128.1, 128.0, 127.9, 127.9, 127.8, 127.3, 124.1, 56.6, 53.1, 52.4, 21.7,
21.6; HRMS (Q-TOF, m/z) calcd for C29H27NO6NaS [M + Na]+
540.1457, found 540.1458.
1
maleate (1r): white solid; 35% yield; mp 105−106 °C; H NMR
(400 MHz, CDCl3) δ 8.05 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 6.8 Hz,
2H), 7.54 (m, 3H), 7.34 (m, 6H), 7.18 (d, J = 6.6 Hz, 2H), 6.57 (s,
1H), 6.13 (s, 1H), 3.73 (s, 3H), 3.60 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 164.1, 139.2, 138.3, 133.9, 133.7, 131.7, 129.1, 128.8,
128.7, 128.4, 128.3, 128.0, 121.5, 118.6, 89.7, 82.7, 55.1, 53.0, 52.1;
HRMS (Q-TOF, m/z) calcd for C27H23NO6NaS [M + Na]+ 512.1144,
found 512.1148.
Dimethyl 4-Phenyl-6-p-tolyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2d): following general procedure A, 60 °C, 72 h; white
1
Dimethyl 2-(2-Chloro-N-(1,3-diphenylprop-2-ynyl)phenyl-
sulfonamido)maleate (1s): white solid; 41% yield; mp 116−117
°C; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 1H), 7.70 (d, J
= 6.1 Hz, 2H), 7.38 (m, 11H), 6.53 (s, 1H), 6.26 (s, 1H), 3.62 (6H,
two CH3); 13C NMR (100 MHz, CDCl3) δ 164.8, 163.7, 138.2, 136.6,
134.6, 134.2, 133.8, 132.7, 132.2, 131.8, 129.2, 129.0, 128.7, 128.5,
128.4, 127.2, 124.3, 121.8, 89.2, 83.0, 55.6, 52.8, 52.2; HRMS (Q-
TOF, m/z) calcd for C27H22NO6NaSCl [M + Na]+ 546.0754, found
546.0747.
General Procedure A for the Synthesis of 1,2-Dihydropyr-
idine 2. In a glass pressure tube (15 mL) equipped with a magnetic
stir bar, starting material 1 (0.2 mmol) and methanol (2 mL) were
added. The pressure tube was closed with a Teflon cap, and the
resulting mixture was stirred at 60 °C under argon protection until the
consumption of the starting material monitored by HPLC. After
cooling to room temperature, the solvent was removed under vacuum.
The residue was directly purified by flash chromatography (eluent:
10:1 petroleum ether/ethyl acetate) to give the desired 1,2-
dihydropyridine 2.
Dimethyl 4,6-Diphenyl-1-tosyl-1,6-dihydropyridine-2,3-dicarbox-
ylate (2a): following general procedure A, 60 °C, 48 h; white solid;
95.3 mg; 95% yield; mp 130−131 °C; 1H NMR (400 MHz, CDCl3) δ
7.80 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 7.4 Hz, 2H), 7.34 (m, 5H), 7.24
(m, 3H), 6.80 (d, J = 7.1 Hz, 2H), 5.86 (d, J = 6.2 Hz, 1H), 5.67 (d, J
= 6.2 Hz, 1H), 3.80 (s, 3H), 3.49 (s, 3H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.6, 164.3, 144.8, 137.0, 136.6, 135.8, 135.1,
130.9, 129.9, 128.8, 128.6, 128.2, 128.1, 128.0, 127.9, 127.8, 127.2,
127.1, 56.6, 53.1, 52.5, 21.7; HRMS (Q-TOF, m/z) calcd for
C28H25NO6NaS [M + Na]+ 526.1300, found 526.1308.
solid; 80.8 mg; 78% yield; mp 169−170 °C; H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.32 (m, 4H), 7.22 (m, 3H), 7.16
(d, J = 8.0 Hz, 2H), 6.80 (dd, J = 7.9, 1.4 Hz, 2H), 5.82 (d, J = 6.2 Hz,
1H), 5.65 (d, J = 6.2 Hz, 1H), 3.79 (s, 3H), 3.49 (s, 3H), 2.42 (s, 3H),
2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 164.4, 144.7,
138.4, 136.7, 135.9, 134.9, 133.9, 130.9, 129.9, 129.5, 128.1, 127.9,
127.7, 127.3, 127.2, 56.5, 53.1, 52.4, 21.7, 21.3; HRMS (Q-TOF, m/z)
calcd for C29H27NO6NaS [M + Na]+ 540.1457, found 540.1454.
Dimethyl 4-Phenyl-1-tosyl-6-(2-(trifluoromethyl)phenyl)-1,6-
dihydropyridine-2,3-dicarboxylate (2e): following general procedure
A, 60 °C, 48 h; white solid; 92.2 mg; 81% yield; mp 154−155 °C; 1H
NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.2
Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.42 (dd, J
= 17.1, 9.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.23−7.15 (m, 3H), 6.79
(d, J = 6.9 Hz, 2H), 6.22 (d, J = 6.3 Hz, 1H), 5.61 (d, J = 6.3 Hz, 1H),
3.93 (s, 3H), 3.54 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.7, 164.6, 145.1, 138.1, 136.6, 135.0, 133.5, 132.7, 130.0, 129.9,
128.5, 128.4, 128.1, 128.0, 127.9, 127.1, 127.0, 126.3 (q, J = 5.9 Hz),
125.8, 125.2, 54.7, 53.3, 52.5, 21.7; 19F NMR (377 MHz, CDCl3) δ
−58.64; HRMS (Q-TOF, m/z) calcd for C29H24NO6F3NaS [M +
Na]+ 594.1174, found 594.1168.
Dimethyl 6-(4-Fluorophenyl)-4-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2f): following general procedure A, 60
°C, 48 h; white solid; 91.9 mg; 88% yield; mp 163−164 °C; 1H NMR
(500 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.44 (m, 2H), 7.32 (d,
J = 8.0 Hz, 2H), 7.24 (m, 3H), 7.05 (m, 2H), 6.80 (m, 2H), 5.82 (d, J
= 6.2 Hz, 1H), 5.64 (d, J = 6.2 Hz, 1H), 3.81 (s, 3H), 3.50 (s, 3H),
2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.5, 164.2, 163.0 (d, J
= 247.3 Hz), 144.9, 136.5, 135.9, 135.4, 132.8, 130.7, 130.0, 129.1,
129.0, 128.3, 128.1, 128.0, 127.8, 126.6, 115.8 (d, J = 21.6 Hz), 55.9,
53.1, 52.5, 21.7; 19F NMR (471 MHz, CDCl3) δ −114.4; HRMS (Q-
TOF, m/z) calcd for C28H24NO6FNaS [M + Na]+ 544.1206, found
544.1210.
Dimethyl 6-(2-Chlorophenyl)-4-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2g): following general procedure A, 60
°C, 48 h; white solid; 93.6 mg; 87% yield; mp 138−139 °C; 1H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 7.0 Hz, 2H), 7.67 (d, J = 7.4 Hz,
1H), 7.36 (d, J = 7.3 Hz, 1H), 7.25 (m, 7H), 6.77 (d, J = 7.0 Hz, 2H),
6.23 (d, J = 6.1 Hz, 1H), 5.84 (d, J = 6.3 Hz, 1H), 3.93 (s, 3H), 3.52
(s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 164.6,
144.9, 136.7, 136.3, 135.7, 135.4, 135.2, 133.5, 130.7, 130.0, 129.9,
129.5, 128.16, 128.12, 128.09, 128.0, 127.9, 127.8, 125.9, 55.3, 53.3,
52.41, 21.7; HRMS (Q-TOF, m/z) calcd for C28H24NO6NaSCl [M +
Na]+ 560.0911, found 560.0905.
Dimethyl 4,6-Diphenyl-1-tosyl-1,6-dihydropyridine-2,3-dicarbox-
ylate-d6 (2a-D): following general procedure A, 60 °C, 48 h; white
1
solid; mp 133−134 °C; H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.27−7.19 (m, 3H), 6.88−6.73
(m, 2H), 5.67 (s, 1H), 3.81 (s, 3H), 3.50 (s, 3H), 2.43 (s, 3H); HRMS
(Q-TOF, m/z) calcd for C28H19D6NO6NaS [M + Na]+ 532.1677,
found 532.1686.
Dimethyl 4,6-Diphenyl-1-tosyl-1,6-dihydropyridine-2,3-dicarbox-
ylate-d1 (2a-D′) (partly deuterated product): Following general
procedure A, 1a (0.1 mmol, 50.4 mg) in CD3OD (1 mL) was heated
at 60 °C under argon protection for 48 h. After cooling to room
temperature, the solvent was removed under vacuum. The residue was
directly purified by flash chromatography (eluent: 10:1 petroleum
ether/ethyl acetate) to give the desired 2a-D′: white solid, mp 130−
131 °C; mp 137−138 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
8.3 Hz, 2H), 7.47 (d, J = 7.3 Hz, 2H), 7.35 (m, 5H), 7.27−7.19 (m,
3H), 6.83−6.76 (m, 2H), 5.85 (s, 0.95H), 5.67 (d, J = 6.3 Hz, 0.05H),
3.81 (s, 3H), 3.50 (s, 3H), 2.42 (s, 3H); HRMS (Q-TOF, m/z) calcd
for C28H24DNO6NaS [M + Na]+ 527.1363, found 527.1351.
Dimethyl 4-Phenyl-6-o-tolyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2b): following general procedure A, 60 °C, 72 h; white
Dimethyl 6-(2-Bromophenyl)-4-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2h): following general procedure A, 60
°C, 48 h; white solid; 100.3 mg; 86% yield; mp 137−138 °C; 1H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 7.8 Hz,
1H), 7.52 (d, J = 7.9 Hz, 1H), 7.31 (m, 3H), 7.23−7.11 (m, 4H), 6.78
(d, J = 6.6 Hz, 2H), 6.21 (d, J = 6.4 Hz, 1H), 5.87 (d, J = 6.4 Hz, 1H),
3.93 (s, 3H), 3.52 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
1
solid; 93.9 mg; 91% yield; mp 146−147 °C; H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.22 (m, 9H), 6.73 (d, J = 7.3 Hz,
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δ 165.6, 164.6, 144.9, 138.2, 136.7, 135.2, 133.1, 129.8, 129.7, 129.6,
128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 125.9, 120.3,
57.3, 53.3, 52.4, 21.7; HRMS (Q-TOF, m/z) calcd for
C28H24NO6NaSBr [M + Na]+ 604.0405, found 604.0408.
Dimethyl 4-(4-Chlorophenyl)-6-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2o): following general procedure A, 60
°C, 48 h; white solid; 104.7 mg; 97% yield; mp 165−166 °C; 1H NMR
(500 MHz, CDCl3) δ 7.83−7.76 (m, 2H), 7.44 (dd, J = 5.1, 3.8 Hz,
2H), 7.39−7.29 (m, 5H), 7.23−7.18 (m, 2H), 6.80−6.71 (m, 2H),
5.87 (d, J = 6.3 Hz, 1H), 5.67 (d, J = 6.3 Hz, 1H), 3.81 (s, 3H), 3.52
(s, 3H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.4, 164.2,
144.8, 136.9, 135.9, 135.1, 134.3, 134.1, 129.9, 129.8, 129.6, 128.9,
128.8, 128.7, 128.1, 127.8, 127.3, 127.1, 56.6, 53.2, 52.6, 21.7; HRMS
(Q-TOF, m/z) calcd for C28H24NO6NaSCl [M + Na]+ 560.0911,
found 560.0904.
Dimethyl 6-(Naphthalen-1-yl)-4-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2i): following general procedure A, 60
°C, 66 h; white solid; 80.1 mg; 72% yield; mp 172−173 °C; 1H NMR
(400 MHz, CDCl3) δ 8.71 (d, J = 8.3 Hz, 1H), 7.86 (m, 4H), 7.66 (t, J
= 7.3 Hz, 1H), 7.54 (m, 2H), 7.42 (m, 1H), 7.31 (d, J = 7.3 Hz, 2H),
7.22 (m, 3H), 6.75 (d, J = 8.1 Hz, 3H), 5.72 (d, J = 4.6 Hz, 1H), 3.68
(s, 3H), 3.54 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.8, 164.5, 148.6, 146.1, 144.8, 136.4, 135.2, 135.1, 134.4, 130.9,
130.7, 129.8, 129.7, 129.0, 128.3, 128.2, 128.1, 128.0, 127.9, 127.1,
126.2, 126.0, 125.5, 123.7, 54.4, 53.0, 52.5, 21.7; HRMS (Q-TOF, m/
z) calcd for C32H27NO6NaS [M + Na]+ 576.1457, found 576.1465.
Dimethyl 6-Isopropyl-4-phenyl-1-tosyl-1,6-dihydropyridine-2,3-
dicarboxylate (2j): following general procedure A, 140 °C, 96 h;
Dimethyl 6-Phenyl-4-propyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2p): following general procedure A, 60 °C, 96 h; white
1
solid; 90.2 mg; 96% yield; mp 101−102 °C; H NMR (500 MHz,
CDCl3) δ 7.74−7.70 (m, 2H), 7.38−7.34 (m, 2H), 7.29 (m, 5H), 5.64
(d, J = 6.3 Hz, 1H), 5.47 (dt, J = 6.3, 1.3 Hz, 1H), 3.78 (s, 3H), 3.71
(s, 3H), 2.40 (s, 3H), 1.95−1.89 (m, 2H), 1.23−1.13 (m, 1H), 1.04−
0.97 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 166.2, 164.6, 144.6, 137.6, 135.9, 132.8, 131.0, 129.7, 128.6, 128.3,
128.2, 127.6, 127.0, 123.5, 56.3, 53.0, 52.6, 33.6, 22.0, 21.6, 13.8;
HRMS (Q-TOF, m/z) calcd for C25H27NO6NaS [M + Na]+ 492.1457,
found 492.1442.
1
white solid; 90.8 mg; 97% yield; mp 101−102 °C; H NMR (400
MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H),
7.23−7.13 (m, 3H), 6.67 (d, J = 7.7 Hz, 2H), 5.44 (d, J = 6.0 Hz, 1H),
4.23 (dd, J = 8.9, 6.0 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H), 2.40 (s, 3H),
1.95−1.80 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 165.9, 164.7, 144.5, 136.8, 136.0,
Dimethyl 4-Butyl-6-phenyl-1-tosyl-1,6-dihydropyridine-2,3-dicar-
boxylate (2q): following general procedure A, 60 °C, 66 h; colorless
133.7, 131.1, 129.7, 128.8, 128.1, 128.0, 127.9, 127.8, 127.6, 60.6, 53.1,
52.4, 31.8, 21.6, 18.6, 18.3; HRMS (Q-TOF, m/z) calcd for
C25H27NO6NaS [M + Na]+ 492.1457, found 492.1460.
1
oil; 93.9 mg; 97% yield; H NMR (400 MHz, CDCl3) δ 7.72 (d, J =
8.2 Hz, 2H), 7.37 (d, J = 7.3 Hz, 2H), 7.28 (m, 5H), 5.65 (d, J = 6.2
Hz, 1H), 5.47 (d, J = 6.3 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.40 (s,
3H), 1.93 (t, J = 7.1 Hz, 2H), 1.13 (m, 3H), 0.88 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 166.1, 164.5, 144.5, 137.6, 135.9, 133.0, 131.1,
129.7, 128.5, 128.3, 128.2, 127.6, 127.0, 123.4, 56.2, 52.9, 52.6, 31.4,
31.2, 22.4, 21.6, 14.0; HRMS (Q-TOF, m/z) calcd for C26H29NO6NaS
[M + Na]+ 506.1613, found 506.1610.
Dimethyl 6-Cyclopropyl-4-phenyl-1-tosyl-1,6-dihydropyridine-
2,3-dicarboxylate (2k): following general procedure A, 100 °C, 48
1
h; white solid; 64.6 mg; 69% yield; mp 137−138 °C; H NMR (500
MHz, CDCl3) δ 7.76−7.67 (m, 2H), 7.28 (m, 2H), 7.24−7.16 (m,
3H), 6.82−6.63 (m, 2H), 5.41 (d, J = 6.0 Hz, 1H), 4.08 (dd, J = 8.1,
6.0 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H), 2.40 (s, 3H), 1.11 (m, 1H),
0.64−0.52 (m, 2H), 0.44 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
166.0, 164.7, 144.5, 136.8, 136.1, 134.1, 130.4, 129.8, 128.4, 128.1,
128.0, 127.8, 127.7, 127.2, 58.9, 53.1, 52.4, 21.7, 14.0, 2.8, 2.4; HRMS
(Q-TOF, m/z) calcd for C25H25NO6NaS [M + Na]+ 490.1300, found
490.1296.
Dimethyl 4,6-Diphenyl-1-(phenylsulfonyl)-1,6-dihydropyridine-
2,3-dicarboxylate (2r): following general procedure A, 60 °C, 96 h;
1
white solid; 90.2 mg; 92% yield; mp 121−122 °C; H NMR (500
MHz, CDCl3) δ 7.94 (m, 2H), 7.63 (m, 1H), 7.54 (m, 2H), 7.47 (m,
2H), 7.36 (m, 3H), 7.23 (m, 3H), 6.82 (m, 2H), 5.86 (d, J = 6.3 Hz,
1H), 5.69 (d, J = 6.3 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 165.6, 164.3, 139.0, 137.0, 136.6, 135.3, 133.7,
130.9, 129.4, 128.9, 128.7, 128.2, 128.1, 128.0, 127.7, 127.2, 127.0,
125.6, 56.7, 53.1, 52.5; HRMS (Q-TOF, m/z) calcd for
C27H23NO6NaS [M + Na]+ 512.1144, found 512.1143.
Dimethyl 6-Phenyl-4-m-tolyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2l): following general procedure A, 60 °C, 66 h; white
1
solid; 98.4 mg; 95% yield; mp 158−159 °C; H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 7.7 Hz, 2H), 7.47 (d, J = 7.3 Hz, 2H), 7.41−7.29
(m, 5H), 7.15−7.04 (m, 2H), 6.72−6.48 (m, 2H), 5.85 (d, J = 6.1 Hz,
1H), 5.66 (d, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 2.43 (s, 3H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 164.4, 144.6,
137.5, 137.1, 136.6, 135.9, 135.2, 131.2, 129.9, 128.9, 128.8, 128.6,
127.8, 127.2, 126.9, 125.2, 56.6, 53.1, 52.4, 21.7, 21.5; HRMS (Q-
TOF, m/z) calcd for C29H27NO6NaS [M + Na]+ 540.1457, found
540.1448.
Dimethyl 1-(2-Chlorophenylsulfonyl)-4,6-diphenyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2s): following general procedure A, 60
°C, 66 h; white solid; 99.9 mg; 95% yield; mp 131−132 °C; 1H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 1H), 7.57−7.48 (m, 4H),
7.46−7.33 (m, 4H), 7.29−7.22 (m, 3H), 6.95 (d, J = 6.5 Hz, 2H), 5.98
(d, J = 6.2 Hz, 1H), 5.93 (d, J = 6.3 Hz, 1H), 3.78 (s, 3H), 3.47 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 163.9, 136.9, 136.8,
136.6, 135.8, 134.6, 132.8, 132.6, 132.3, 130.6, 128.8, 128.7, 128.3,
128.2, 128.1, 128.0, 127.2, 127.1, 127.0, 56.5, 53.1, 52.4; HRMS (Q-
TOF, m/z) calcd for C27H22NO6NaSCl [M + Na]+ 546.0754, found
546.0758.
Procedure for the Syntheses 1,2-DHP 2a in 10 Gram Scale.
In a Schlenk tube (500 mL) equipped with a condenser and a
magnetic stir bar, starting material 1a (10.78 g, 0.0214 mol) and
methanol (215 mL) were added. The resulting mixture was stirred
under air atmosphere in reflux condition for 16 h. After cooling to room
temperature, the resulting mixture was kept undisturbed for 3 h and
8.83 g product 2a precipitated from the solution. After removal of the
residual solvent, the solid was washed with the solution of ethyl
acetate/petroleum ether = 10:1 (50 mL) to give the second batch of
product (1.52 g). Yield 10.35 g, 96% yield.
Dimethyl 6-Phenyl-4-p-tolyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (2m): following general procedure A, 60 °C, 48 h;
1
white solid; 96.4 mg; 93% yield; mp 141−142 °C; H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H),
7.34 (m, 5H), 7.02 (d, J = 7.3 Hz, 2H), 6.69 (d, J = 7.3 Hz, 2H), 5.84
(d, J = 5.8 Hz, 1H), 5.64 (d, J = 6.1 Hz, 1H), 3.79 (s, 3H), 3.51 (s,
3H), 2.42 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.7, 164.4, 144.7, 138.0, 137.2, 136.0, 135.9, 135.0, 133.7, 131.2,
129.9, 128.8, 128.6, 128.5, 128.1, 127.8, 127.2, 126.8, 56.6, 53.0, 52.4,
21.7, 21.3; HRMS (Q-TOF, m/z) calcd for C29H27NO6NaS [M +
Na]+ 540.1457, found 540.1450.
Dimethyl 4-(4-Fluorophenyl)-6-phenyl-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (2n): following general procedure A, 60
°C, 48 h; white solid; 99.1 mg; 95% yield; mp 135−136 °C; 1H NMR
(500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.45 (m, 2H), 7.35 (m,
5H), 6.91 (m, 2H), 6.80 (m, 2H), 5.86 (d, J = 6.3 Hz, 1H), 5.67 (d, J =
6.3 Hz, 1H), 3.81 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 165.5, 164.3, 162.7 (d, J = 247.8 Hz), 144.8, 137.0,
135.9, 134.2, 132.6, 130.4, 130.1 (d, J = 8.2 Hz), 129.9, 128.9, 128.7,
128.6, 127.8, 127.2, 127.1, 114.9 (d, J = 21.6 Hz), 56.6, 53.1, 52.5,
21.7; 19F NMR (471 MHz, CDCl3) δ −114.6; HRMS (Q-TOF, m/z)
calcd for C28H24NO6FNaS [M + Na]+ 544.1206, found 544.1213.
General Procedure for the Syntheses of 3-Iodo-1,2-dihydro-
pyridines 3. In a glass pressure tube (10 mL) equipped with a
magnetic stir bar, starting material 1 (0.2 mmol), NIS (0.24 mmol,
54.0 mg), and DMF (1 mL) were added. The resulting mixture was
stirred at 80 °C under argon protection until the consumption of the
starting material monitored by HPLC. After cooling to room
temperature, the solvent was removed under vacuum. The residue
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was directly purified by flash chromatography (eluent: 20:1 petroleum
ether/ethyl acetate) to give the desired 3-iodo-1,2-dihydropyridine 3.
Dimethyl 5-Iodo-4,6-diphenyl-1-tosyl-1,6-dihydropyridine-2,3-di-
carboxylate (3a): white solid; 117.0 mg; 93% yield; mp 110−111 °C;
1H NMR (500 MHz, DMSO, 60 °C) δ 7.84−7.77 (m, 2H), 7.56 (d, J
= 7.9 Hz, 2H), 7.47−7.40 (m, 5H), 7.34−7.28 (m, 3H), 6.59 (s, 2H),
5.97 (s, 1H), 3.64 (s, 3H), 3.30 (s, 3H), 2.50 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 164.6, 164.1, 145.1, 140.2, 138.9, 135.4, 134.1, 130.4,
130.2, 129.2, 129.0, 128.6, 128.5, 128.2, 128.0, 127.9, 126.6, 99.6, 67.3,
53.1, 52.5, 21.8; HRMS (Q-TOF, m/z) calcd for C28H24NO6NaSI [M
+ Na]+ 652.0267, found 652.0264.
Dimethyl 5-Iodo-4-phenyl-6-(o-tolyl)-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (3b): white solid; 114.9 mg; 89% yield;
mp 142−143 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.79 (d, J =
8.3 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.37−7.29 (m, 5H), 7.24 (m,
2H), 6.48 (s, 2H), 6.23 (s, 1H), 3.63 (s, 3H), 3.35 (s, 3H), 2.65 (s,
3H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.7, 164.3,
145.0, 140.0, 138.8, 138.4, 134.6, 132.7, 131.8, 130.5, 130.0, 129.4,
128.6, 128.5, 128.3, 128.1, 127.4, 126.5, 125.8, 102.7, 65.3, 53.0, 52.5,
21.8, 20.2; HRMS (Q-TOF, m/z) calcd for C29H26NO6NaSI [M +
Na]+ 666.0423, found 666.0431.
131.8, 131.4, 130.9, 130.8, 130.0, 128.9, 128.7, 128.5, 128.3, 128.2,
127.7, 126.3, 101.8, 64.5, 53.1, 52.6, 21.8.; HRMS (Q-TOF, m/z) calcd
for C28H23NO6NaSClI [M + Na]+ 685.9877, found 685.9880.
Dimethyl 6-(2-Bromophenyl)-5-iodo-4-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3h): white solid; 113.0 mg; 80%
1
yield; mp 149−150 °C; H NMR (500 MHz, DMSO, 60 °C) δ 7.79
(dd, J = 10.9, 8.2 Hz, 3H), 7.58 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 11.0,
4.0 Hz, 1H), 7.39 (dd, J = 10.9, 4.5 Hz, 2H), 7.36−7.26 (m, 3H), 6.53
(d, J = 1.5 Hz, 3H), 3.66 (s, 3H), 3.38 (s, 3H), 2.53 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.8, 164.2, 145.0, 139.3, 138.2, 134.6, 134.2,
133.4, 131.8, 131.1, 130.0, 128.9, 128.7, 128.5, 128.3, 128.2, 126.2,
124.6, 102.6, 66.5, 53.1, 52.6, 21.8; HRMS (Q-TOF, m/z) calcd for
C28H23NO6NaSBrI [M + Na]+ 729.9372, found 729.9376.
Dimethyl 5-Iodo-6-(naphthalen-1-yl)-4-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3i): white solid; 85.3 mg; 63%
1
yield; mp 210−211 °C; H NMR (500 MHz, DMSO, 60 °C) δ 8.80
(d, J = 8.5 Hz, 1H), 8.12−7.99 (m, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.75
(ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.67−7.63 (m, 1H), 7.61 (d, J = 8.0 Hz,
2H), 7.59−7.53 (m, 1H), 7.48−7.44 (m, 1H), 7.41−7.26 (m, 3H),
6.86 (s, 1H), 6.54 (s, 2H), 3.50 (s, 3H), 3.37 (s, 3H), 2.56 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 164.7, 164.2, 145.1, 140.7, 138.4, 134.6,
134.6, 133.0, 132.0, 130.6, 130.1, 128.9, 128.7, 128.6, 128.5, 128.2,
127.3, 127.1, 126.3, 126.2, 125.7, 125.2, 124.1, 102.2, 64.8, 52.9, 52.6,
21.8; HRMS (Q-TOF, m/z) calcd for C32H26NO6NaSI [M + Na]+
702.0423, found 702.0397.
Dimethyl 5-Iodo-4-phenyl-6-(m-tolyl)-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (3c): white solid; 113.5 mg; 88% yield;
1
mp 169−170 °C; H NMR (500 MHz, DMSO, 60 °C) δ 7.86−7.78
(m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.38−7.30 (m, 4H), 7.28−7.19 (m,
3H), 6.60 (s, 2H), 5.93 (s, 1H), 3.66 (s, 3H), 3.32 (s, 3H), 2.52 (s,
3H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.6, 164.2,
145.0, 140.0, 138.9, 138.7, 135.3, 133.9, 130.5, 130.2, 130.0, 128.9,
128.8, 128.6, 128.5, 128.2, 127.9, 126.5, 124.7, 99.8, 67.3, 53.1, 52.5,
21.8, 21.7; HRMS (Q-TOF, m/z) calcd for C29H26NO6NaSI [M +
Na]+ 666.0423, found 666.0406.
Dimethyl 5-Iodo-6-phenyl-4-m-tolyl-1-tosyl-1,6-dihydropyridine-
2,3-dicarboxylate (3l): white solid; 114.4 mg; 89% yield; mp 153−154
1
°C; H NMR (500 MHz, DMSO, 60 °C) δ 7.89−7.78 (m, 2H), 7.59
(d, J = 8.0 Hz, 2H), 7.51−7.40 (m, 5H), 7.21 (t, J = 7.6 Hz, 1H), 7.13
(d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 6.35 (s, 1H), 5.98 (s, 1H), 3.65 (s,
3H), 3.33 (s, 3H), 2.52 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.6, 164.1, 144.9, 140.2, 138.6, 135.3, 134.0, 130.6, 130.2,
129.3, 129.1, 129.0, 128.8, 127.9, 127.8, 127.2, 126.3, 125.4, 110.1,
99.4, 67.2, 53.1, 52.5, 31.7, 22.8, 21.8, 21.5, 14.2; HRMS (Q-TOF, m/
z) calcd for C29H26NO6NaSI [M + Na]+ 666.0423, found 666.0416.
Dimethyl 5-Iodo-6-phenyl-4-(p-tolyl)-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (3m): white solid; 107.4 mg; 83% yield;
mp 191−192 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.81 (d, J =
8.3 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.50−7.39 (m, 5H), 7.13 (d, J =
7.9 Hz, 2H), 6.48 (s, 2H), 5.96 (s, 1H), 3.65 (s, 3H), 3.34 (s, 3H),
2.51 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6,
164.1, 145.0, 140.1, 138.4, 135.7, 135.2, 134.0, 130.7, 130.1, 129.1,
129.0, 128.9, 128.3, 127.9, 127.8, 126.3, 99.8, 67.2, 53.1, 52.5, 21.8,
21.5; HRMS (Q-TOF, m/z) calcd for C29H26NO6NaSI [M + Na]+
666.0423, found 666.0422.
Dimethyl 5-Iodo-4-phenyl-6-(p-tolyl)-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (3d): white solid; 91.5 mg; 71% yield;
1
mp 183−184 °C; H NMR (500 MHz, DMSO, 60 °C) δ 7.84−7.77
(m, 2H), 7.62−7.54 (m, 2H), 7.33 (m, 5H), 7.26 (d, J = 8.0 Hz, 2H),
6.59 (s, 2H), 5.93 (s, 1H), 3.66 (s, 3H), 3.32 (s, 3H), 2.51 (s, 3H),
2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 164.2, 145.0,
140.0, 139.1, 138.9, 135.3, 130.8, 130.5, 130.2, 129.8, 128.6, 128.5,
128.2, 128.1, 127.8, 126.4, 100.0, 67.1, 53.1, 52.5, 21.8, 21.4; HRMS
(Q-TOF, m/z) calcd for C29H26NO6NaSI [M + Na]+ 666.0423, found
666.0413.
Dimethyl 5-Iodo-4-phenyl-1-tosyl-6-(2-(trifluoromethyl)phenyl)-
1,6-dihydropyridine-2,3-dicarboxylate (3e): white solid; 96.0 mg;
1
69% yield; mp 136−137 °C; H NMR (500 MHz, DMSO, 60 °C) δ
7.92 (d, J = 7.8 Hz, 1H), 7.81−7.67 (m, 4H), 7.56 (m, 3H), 7.38−7.25
(m, 3H), 6.54 (s, 1H), 6.45 (s, 2H), 3.62 (s, 3H), 3.38 (s, 3H), 2.54 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 164.9, 164.3, 145.1, 140.2,
138.2, 134.4, 132.9, 132.8, 131.6, 129.9, 129.8, 129.5, 129.4 (d, J = 30.7
Hz), 128.7, 128.6, 128.5, 128.2, 127.5 (q, J = 6.0 Hz), 126.1, 123.9 (d, J
= 274.8 Hz), 103.0, 63.2, 53.1, 52.6, 21.8; 19F NMR (471 MHz,
CDCl3) δ −58.08; HRMS (Q-TOF, m/z) calcd for C29H23NO6F3NaSI
[M + Na]+ 720.0141, found 720.0123.
Dimethyl 4-(4-Fluorophenyl)-5-iodo-6-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3n): white solid; 103.9 mg; 80%
1
yield; mp 183−184 °C; H NMR (500 MHz, DMSO, 60 °C) δ 7.82
(d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.50−7.39 (m, 5H),
7.21−7.11 (m, 2H), 6.65 (s, 2H), 5.99 (s, 1H), 3.66 (s, 3H), 3.36 (s,
3H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.525, 164.0,
162.7 (d, J = 248.8 Hz), 145.1, 139.3, 135.3, 134.7, 133.9, 130.5 (d, J =
8.2 Hz, 1H), 130.1, 130.0, 129.2, 129.0, 127.9, 127.8, 127.0, 115.4 (d, J
= 21.4 Hz), 100.1, 67.3, 53.2, 52.6, 21.8; 19F NMR (471 MHz, CDCl3)
δ −113.33; HRMS (Q-TOF, m/z) calcd for C28H23NO6FNaSI [M +
Na]+ 670.0173, found 670.0190.
Dimethyl 6-(4-Fluorophenyl)-5-iodo-4-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3f): white solid; 118.8 mg; 92%
yield; mp 173−174 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.86−
7.78 (m, 2H), 7.58 (dd, J = 8.5, 0.5 Hz, 2H), 7.51−7.45 (m, 2H),
7.36−7.26 (m, 5H), 6.60 (s, 2H), 5.98 (s, 1H), 3.66 (s, 3H), 3.32 (s,
3H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.5, 164.0, 163.2
(d, J = 248.2 Hz), 145.2, 140.3, 138.7, 135.2, 130.3, 130.2, 129.8,
129.7, 128.7, 128.4, 128.3, 127.8, 126.5, 116.1 (d, J = 21.8 Hz), 99.1,
66.7, 53.2, 52.5, 21.8; 19F NMR (471 MHz, CDCl3) δ −113.47;
HRMS (Q-TOF, m/z) calcd for C28H23NO6FNaSI [M + Na]+
670.0173, found 670.0190.
Dimethyl 6-(2-Chlorophenyl)-5-iodo-4-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3g): white solid; 113.2 mg; 85%
yield; mp 143−144 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.83−
7.76 (m, 2H), 7.66−7.53 (m, 3H), 7.49 (td, J = 7.6, 1.8 Hz, 1H), 7.43
(td, J = 7.6, 1.4 Hz, 1H), 7.37 (dd, J = 7.8, 1.7 Hz, 1H), 7.35−7.28 (m,
3H), 6.53 (s, 3H), 3.65 (s, 3H), 3.37 (s, 3H), 2.53 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.8, 164.2, 145.0, 139.8, 138.3, 134.7, 134.7,
Dimethyl 4-(4-Chlorophenyl)-5-iodo-6-phenyl-1-tosyl-1,6-
dihydropyridine-2,3-dicarboxylate (3o): white solid; 123.0 mg; 93%
yield; mp 157−158 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.89−
7.74 (m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.50−7.42 (m, 5H), 7.41 (dd, J
= 7.3, 1.4 Hz, 2H), 6.63 (s, 2H), 5.99 (s, 1H), 3.67 (s, 3H), 3.37 (s,
3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 164.1,
145.1, 139.2, 137.2, 135.2, 134.7, 133.9, 130.2, 130.1, 129.7, 129.3,
129.1, 128.6, 128.5, 127.9, 127.8, 99.8, 67.3, 53.2, 52.7, 21.8; HRMS
(Q-TOF, m/z) calcd for C28H23NO6NaSClI [M + Na]+ 685.9877,
found 685.9885.
Dimethyl 5-Iodo-6-phenyl-4-propyl-1-tosyl-1,6-dihydropyridine-
2,3-dicarboxylate (3p): white solid; 27.6 mg; 23% yield; mp 158−
1
159 °C; H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H),
7.46−7.29 (m, 7H), 5.89 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.44 (s,
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3H), 2.32−2.19 (m, 1H), 1.99−1.88 (m, 1H), 1.20−1.03 (m, 1H),
0.83 (t, J = 7.1 Hz, 3H), 0.78−0.64 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 165.1, 164.0, 144.6, 137.3, 134.8, 133.9, 130.4, 129.7, 129.2,
128.7, 128.5, 127.6, 127.2, 96.5, 66.9, 52.8, 52.6, 37.9, 21.4, 14.0;
HRMS (Q-TOF, m/z) calcd for C25H26NO6NaSI [M + Na]+
618.0423, found 618.0422.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21172218) is gratefully acknowledged.
Dimethyl 4-Butyl-5-iodo-6-phenyl-1-tosyl-1,6-dihydropyridine-
2,3-dicarboxylate (3q): white solid; 40.0 mg; 33% yield; mp 149−
1
150 °C; H NMR (500 MHz, CDCl3) δ 7.78−7.72 (m, 2H), 7.41−
REFERENCES
■
7.37 (m, 2H), 7.35 (m, 5H), 5.89 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H),
2.43 (s, 3H), 2.26 (td, J = 12.5, 4.9 Hz, 1H), 2.02−1.91 (m, 1H),
1.28−1.19 (m, 2H), 1.08 (tdd, J = 8.2, 5.8, 3.3 Hz, 1H), 0.87 (t, J = 7.3
Hz, 3H), 0.66−0.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 165.4,
164.3, 144.8, 137.7, 135.3, 134.3, 130.1, 129.5, 129.0, 128.8, 128.1,
127.9, 127.6, 96.6, 67.2, 53.1, 52.9, 36.2, 30.3, 22.9, 21.8, 14.0; HRMS
(Q-TOF, m/z) calcd for C26H28NO6NaSI [M + Na]+ 632.0580, found
632.0583.
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dihydropyridines, see: (a) Oshima, K.; Ohmura, T.; Suginome, M. J.
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Dimethyl 5-Iodo-4,6-diphenyl-1-(phenylsulfonyl)-1,6-dihydro-
pyridine-2,3-dicarboxylate (3r): white solid; 113.3 mg; 90% yield;
mp 162−163 °C; 1H NMR (500 MHz, DMSO, 60 °C) δ 7.96 (dt, J =
8.5, 1.6 Hz, 2H), 7.93−7.88 (m, 1H), 7.82−7.76 (m, 2H), 7.50−7.42
(m, 5H), 7.36−7.30 (m, 3H), 6.64 (s, 2H), 5.99 (s, 1H), 3.66 (s, 3H),
3.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.5, 164.0, 140.3,
138.7, 138.4, 134.0, 133.9, 130.4, 129.6, 129.2, 129.0, 128.6, 128.5,
128.2, 127.9, 127.7, 126.4, 99.4, 67.2, 53.1, 52.5; HRMS (Q-TOF, m/
z) calcd for C27H22NO6NaSI [M + Na]+ 638.0110, found 638.0098.
Dimethyl 1-((2-Chlorophenyl)sulfonyl)-5-iodo-4,6-diphenyl-1,6-
dihydropyridine-2,3-dicarboxylate (3s): white solid; 117.7 mg; 91%
1
yield; mp 129−130 °C; H NMR (500 MHz, DMSO, 60 °C) δ 8.21
(dd, J = 8.0, 1.5 Hz, 1H), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 7.82 (td, J =
7.7, 1.6 Hz, 1H), 7.67 (ddd, J = 8.0, 7.5, 1.3 Hz, 1H), 7.56−7.52 (m,
2H), 7.50−7.44 (m, 3H), 7.42−7.34 (m, 3H), 6.89 (d, J = 6.7 Hz,
2H), 5.91 (s, 1H), 3.64 (s, 3H), 3.32 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.6, 163.5, 141.0, 139.0, 137.7, 134.8, 134.0, 133.1, 132.8,
132.7, 129.3, 129.2, 129.0, 128.7, 128.6, 128.4, 127.9, 127.4, 127.2,
98.5, 66.9, 53.1, 52.4; HRMS (Q-TOF, m/z) calcd for
C27H21NO6NaSClI [M + Na]+ 671.9721, found 671.9703.
́
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Procedure for the Synthesis of Sonogashira Product 4.
Dimethyl 4,6-Diphenyl-5-(phenylethynyl)-1-tosyl-1,6-dihydro-
pyridine-2,3-dicarboxylate (4). To a solution of 3a (125.9 mg, 0.2
mmol) in anhydrous DMF (1 mL) were added PdCl2(PPh3)2 (3.5 mg,
2.5 mol %), CuI (1.9 mg, 5 mol %), and Et3N (40.5 mg, 2.0 equiv).
The reaction mixture was stirred for 5 min under argon protection at
room temperature. Phenylacetylene (30.6 mg, 0.3 mmol) was then
added. The resulting solution was stirred at 60 °C for 16 h. After
cooling to room temperature, the solvent was removed under vacuum.
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20:1 petroleum ether/ethyl acetate) to give the desired product 4:
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1
yellow solid; 74.6 mg; 62% yield; mp 150−151 °C; H NMR (400
MHz, acetone) δ 7.90 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H),
7.50 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.41−7.28 (m, 7H),
7.16 (d, J = 7.2 Hz, 2H), 6.87 (s, 2H), 6.00 (s, 1H), 3.77 (s, 3H), 3.42
(s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, acetone) δ165.4, 164.4,
146.2, 138.7, 137.3, 136.4, 136.0, 132.4, 132.3, 130.9, 130.2, 129.7,
129.6, 129.5, 129.4, 129.0, 128.5, 128.4, 127.9, 127.7, 123.0, 120.4,
100.0, 88.7, 60.6, 53.2, 52.6, 21.5; HRMS (Q-TOF, m/z) calcd for
C36H29NO6NaS [M + Na]+ 626.1613, found 626.1614.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra, HRMS spectra, and crystallo-
graphic information files (CIF) for compounds 2a and 3a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bswan@dicp.ac.cn.
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