Palladium-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen: Stereoselective assembly of (Z)-enamines

Article abstract of DOI:10.1021/jo402117r

An efficient Pd-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen is disclosed. Under mild reaction conditions, it provides a rapid access to (Z)-enamine compounds with exceptional functional group tolerance and ex

Full text of DOI:10.1021/jo402117r

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pubs.acs.org/joc
Palladium-Catalyzed Oxidative Coupling of Aromatic Primary Amines
and Alkenes under Molecular Oxygen: Stereoselective Assembly of
(Z)‑Enamines
Xiaochen Ji, Huawen Huang, Wanqing Wu, Xianwei Li, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
S
* Supporting Information
ABSTRACT: An efficient Pd-catalyzed oxidative coupling of
aromatic primary amines and alkenes under molecular oxygen
is disclosed. Under mild reaction conditions, it provides a rapid
access to (Z)-enamine compounds with exceptional functional
group tolerance and excellent regio- and stereoselectivity. This
attractive route is of great significance due to its applicability to
a wide range of aromatic primary amines, most of which could
not be efficiently converted into enamines previously.
Moreover, this protocol is scalable, and the resultant enamines could be conveniently transformed into a series of N-containing
heterocyclics, thus illustrating its potential applications in synthetic and medicinal chemistry.
successful precedents have been developed by employment of
nonbasic nitrogen nucleophiles such as carboxamides, carba-
mates, sulfoneamides, or diaryl amines.41−46 Despite these
advances, oxidative coupling reactions utilizing simple amines
have been relatively less explored so far, and there are few
reported examples dedicated to oxidative coupling of alkenes
with aromatic primary amines to the best of our knowledge.47,48
Very recently, Obora and co-workers reported a palladium-
catalyzed oxidative amination reaction of alkenes with ortho-
substituted primary anilines.47 However, the indispensable
ortho substituents of anilines and the use of excess amine
partner (3 equiv) limited the practical application of this
synthetic method. Clearly, such a transformation will only be
widely accepted and further used in organic synthesis when a
broad spectrum of aromatic primary amines can be utilized as
coupling partners with high efficiency.
An inherent challenge in transition-metal-catalyzed reactions
involving aromatic primary amines arises from the strong
coordination of nitrogen nucleophiles to the metal catalyst
center, thus leading to catalyst’s inhibition or deactivation. Until
now, the only method was to increase the steric hindrance of
amines to hamper this coordination, taking introduction of
substituents in the ortho position of anilines for example.47 We
hypothesized that it would be preferable to develop an efficient
catalytic system to completely eliminate this coordination
problem. In this article, we disclose the first general catalytic
system capable of the oxidative coupling of a wide range of
aromatic primary amines and alkenes, in which the appropriate
additive played an important role on the efficiency.
INTRODUCTION
■
Oxidative coupling reaction has become a powerful tool in
synthetic chemistry over the years, due to its high efficiency in
construction of carbon−carbon and carbon-heteroatom
bonds.1−5 Alongside the atom economy advantage, it is a
fundamentally fascinating approach to provide complex
products from simple starting materials, especially for the
dehydrogenative coupling reactions, without the need for
prefunctionalized reagents. Under oxidative conditions, two C−
H or heteroatom−H bonds could be coupled directly to
construct a new bond via mono- or cross-coupling reactions.
Transition metal catalysts have been widely used in varieties of
oxidative coupling reactions. Notably, palladium-catalyzed
processes have attracted considerable attention over the past
decades and continue to be an active research topic in chemical
synthesis, because of the outstanding superiorities such as the
diversity of chemical bond-forming processes available,
excellent chemo-, regio-, and stereoselectivity, as well as the
great functional-group tolerance generally achieved.6,7 Among
the oxidants commonly used in these reactions, molecular
oxygen is undoubtedly an environmentally friendly and
inexpensive oxidant, generally producing water as the by-
product only, which is in line with the principle of “green
chemistry”.8,9
Enamine derivatives, employed as valuable and highly
versatile intermediates in synthetic and medicinal chemistry,
have been widely utilized in the formation of numerous
heterocycles10−20 and in the asymmetric synthesis of secondary
or tertiary chiral amines.21−25 Therefore, a variety of methods
have been developed to construct the enamine scaffold.26−39
The transition-metal-catalyzed oxidative coupling between
amines and alkenes would be an attractive strategy to give
direct access to enamines, which features cost-effective and high
stereoselectivity usually observed.40 In recent years, some
We recently reported a novel and efficient palladium-
catalyzed dehydrogenative aminohalogenation of alkenes with
Received: September 24, 2013
Published: October 27, 2013
© 2013 American Chemical Society
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a
molecular oxygen as the sole oxidant, with unprecedented
stereoselectivity and great functional group tolerance (Scheme
1a).49 The protocol directly employs simple aromatic amines as
Table 1. Optimization of the Reaction Conditions
Scheme 1. Palladium-Catalyzed Transformations under
Molecular Oxygen
b
entry
catalyst
Pd(OAc)2
additive
solvent
yield (%)
1
2
3
4
5
6
LiBr
TBAB
NaBr
KBr
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
DMSO
toluene
CH3CN
THF
THF
97 (91)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
38
8
10
7
NaI
LiCl
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
6
c
d
7
21
8
86
84
89
35
trace
91
13
0
9
Pd(TFA)2
Pd(CH3CN)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10
11
12
13
14
15
16
the nitrogen sources, and provides highly convenient access to a
wide range of brominated enamines under mild conditions,
which were difficult to prepare by traditional methodologies.
The reactions were performed under 5 atm O2 to give the
desired products in good to excellent yields and great
stereoselectivity. However, trace of the product was detected
by GC−MS with an O2 balloon; instead, the oxidative coupling
of aniline and methyl acrylate was achieved to afford exclusive
(Z)-enamine compound. Herein, we disclose a highly regio-
and stereoselective Pd-catalyzed oxidative coupling of aromatic
primary amines and alkenes under molecular oxygen,49−52 in
which varieties of aromatic primary amines could be
successfully transformed into the corresponding enamines in
excellent Z-selectivity (Scheme 1b).
56
e
f
17
g
9
18
85
a
Reaction conditions: aniline 1a (0.5 mmol), methyl acrylate 2a (0.6
mmol), additive (4 equiv), catalyst (5 mol %), solvent (2 mL), with an
O2 balloon, 50 °C for 8 h. GC yield based on 1a with tridecane as an
internal standard, and isolated yield is given in parentheses. Reaction
mixtures analyzed by GC−MS and/or H NMR to determine Z/E
ratio. Z/E > 99:1 unless otherwise noted. 2 equiv of LiBr were used.
A heavy yellow precipitate was observed. Under N2 atmosphere.
With 87% of aniline recovered. With Pd(OAc)2 (1 equiv), under N2
b
1
c
d
e
f
g
atmosphere.
RESULTS AND DISCUSSION
■
We commenced our study by investigating the Pd-catalyzed
oxidative cross-coupling of aniline (1a) and methyl acrylate
(2a) under 1 atm of molecular oxygen (Table 1). Several
additives were screened, such as LiBr, TBAB, NaBr, KBr, NaI,
LiCl, and LiBr was found to be the best one (entries 1−6). To
our delight, the desired enamine (Z)-3a was obtained in 91%
isolated yield with LiBr (4 equiv) as additive and Pd(OAc)2 as
catalyst in THF (entry 1). Further optimization study indicated
that the use of 4 equiv of LiBr as additive was important to
maintain the efficiency, since only 21% GC yield was acquired
when 2 equiv of LiBr was employed (entries 1 and 7).
Compared with the red-brown reaction solution obtained with
4 equiv of LiBr (Figure 1b), a heavy yellow precipitate,
presumably the metal complex formed from the strong
coordination of aniline to palladium catalyst, was observed
with 2 equiv of LiBr, thus leading to the deactivation of the
catalyst, which was confirmed to contain Pd on the basis of
atomic absorption spectroscopy (AAS) analysis (Figure 1a).53
This was probably due to the competitive coordination of more
excess bromide anion to palladium catalyst with that of aniline
in the solvent when 4 equiv of LiBr was employed, thus
decreasing the chance for the binding of a heterocycle or basic
amine, therefore preventing deactivation of the catalyst. The
investigation of other palladium catalysts and other solvents
resulted in no further improvement of the yield (entries 8−16).
The reaction hardly proceeded to yield product 3a under N2
atmosphere, with only 9% yield of 3a obtained and 87% yield of
Figure 1. The comparation of solutions after the reactions performed
with different amount of LiBr. (a) The same conditions with that in
Table 1, entry 7. (b) The same conditions with that in Table 1, entry
1.
aniline 1a recovered, probably because of the failure of catalyst
regeneration without O2 (entry 17).54 Moreover, the reaction
using a stroichiometric amount of Pd(OAc)2 under N2
atmosphere was conducted to probe the mechanism, and
good result was obtained, thus suggesting a Pd(0)/Pd(II)
process in the reaction (entry 18).
A plausible reaction mechanism for this transformation is
shown in Scheme 2. The reaction is initiated by the
coordination of a Pd(II) catalyst to the olefin 2a to give
complex I, which undergoes nucleophilic attack by aniline 1a to
generate the σ-alkylpalladium complex II. Subsequent β-H
elimination from the complex II results in (Z)-enamine 3a
exclusively and releases Pd(0), which could be oxidized by O2
to recover the Pd(II) catalyst. The excellent stereoselectivity
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affording 3f in a relatively low yield (41%). Notably, most of
these substrates were not reactive enough or even unreactive in
previous reports concerning the oxidative coupling of aromatic
primary amines with alkenes, releasing the corresponding
enamines in low yields generally (<38%).47,48 Intriguingly, 3-
ethynylaniline and 4-vinylaniline could also successfully under-
go oxidative coupling reactions with methyl acrylate, providing
3q and 3r in 85 and 87% yield, respectively, thus providing
ample opportunity for further derivatization of the products. In
addition, α-naphthylamine proceeded smoothly to give the
product 3s in excellent yield (92%). It is noteworthy that
coumarin 151 was also productive, leading to product 3t in 86%
yield, hence illustrating the potential applications of this
protocol in the synthesis of biologically active substances.
As for the alkene partner, other acrylates with various
functional groups, such as tetrahydrofuran, cyclohexyl and
trifluoromethyl, showed good reactivities in the oxidative
coupling reactions with aniline to give the desired products
(3u−3y) in good to excellent yields as illustrated in Scheme 4.
Scheme 2. Plausible Mechanism for Pd-Catalyzed Oxidative
Coupling Reaction of Aromatic Primary Amines and Alkenes
observed in this transformation is mainly attributed to the
favorable formation of the σ-alkylpalladium intermediate II,
which bears an intramolecular hydrogen bond. In addition, the
role of excess bromide anion in the reaction system is to
prevent Pd(II) catalyst from deactivation by strong coordina-
tion to aromatic primary amines, thus facilitating the catalytic
cycle.
Scheme 4. Pd-Catalyzed Oxidative Coupling of Aniline with
a
Various Alkenes for the Synthesis of Z-Enamines
We next investigated the substrate scope of this trans-
formation (Scheme 3). The present catalytic systems were
Scheme 3. Pd-Catalyzed Oxidative Coupling of Various
Aromatic Primary Amines with Methyl Acrylate for the
a
Synthesis of Z-Enamines
a
Reaction conditions: aniline 1a (0.5 mmol), alkene 2 (0.6 mmol),
Pd(OAc)2 (5 mol %), LiBr (4 equiv), in THF (2 mL), with an O2
balloon, 50 °C for 8 h.
N,N-Dimethylacrylamide was also smoothly transformed into
the enamine product 3z in 92% yield. Gratifyingly, pent-1-en-3-
one, a more electron-deficient alkene, could be converted to the
desired product 3aa in 51% yield, accompanied by some aza-
Michael addition product generated. Unfortunately, the
disubstituted olefin, such as methyl methacrylate and methyl
but-2-enoate, could not undergo this transformation in the
current reaction system, with no desired corresponding
products obtained and aniline almost completely recovered.
Moreover, this oxidative cross-coupling reaction could be
scaled up to 20 mmol without significant decrease in the yield
and stereoselectivity of the product even with 3 mol %
Pd(OAc)2 and 2 equiv of LiBr under oxygen atmosphere
(Scheme 5), illustrating its potential industrial applications in
the future.
a
Reaction conditions: amine 1 (0.5 mmol), methyl acrylate 2a (0.6
mmol), Pd(OAc)2 (5 mol %), LiBr (4 equiv), in THF (2 mL), with an
O2 balloon, 50 °C for 8 h.
applicable to the oxidative coupling of methyl acrylate with a
variety of aromatic primary amines. A series of functional
groups, such as methyl, methoxyl, fluoro, chloro, bromo, ester,
mesyl, cyanide, trifluoromethyl, and even nitro, were well
tolerated at the ortho, meta, and para positon on the phenyl ring
of amines, and the desired products were isolated in excellent
yields. 4-Iodoaniline was also an effective substrate, albeit
As mentioned above, enamines are versatile intermediates
and building blocks in organic synthesis. Enaminoesters,
especially with both the nucleophilicity of an enamine and
the electrophilicity of an enone in one molecule, are an
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a
Scheme 5. Large Scale Experiment
Scheme 7. Synthesis of Various N-Heterocycles from
a
Enamines
a
Reaction conditions: amine 1 (20 mmol), alkene 2 (24 mmol),
Pd(OAc)2 (3 mol %), LiBr (2 equiv), in THF (40 mL), with an O2
balloon, 50 °C for 8 h.
important class of them. Thus, to further demonstrate the
synthetic utility of this protocol, we investigated trans-
formations of enamines 3 to prepare a series of functionalized
molecules. The intramolecular oxidative cyclization of the
enamines could be successfully accomplished to deliver 3-
substituted indoles (Scheme 6).55 It was found that enamines
Scheme 6. Indole Synthesis from Enamines via Pd-Catalyzed
a
Intramolecular Oxidative Cyclizaiton
a
Reagents and conditions: (1) enamine 3 (0.3 mmol), Cu(OAc)2 (0.9
mmol), PhCN (1 mL), 120 °C for 20 h; (2) enamine 3 (0.3 mmol), β-
nitrostyrene (0.2 mmol), in CH3OH (1.5 mL), 120 °C for 12 h; (3)
enamine 3 (0.3 mmol), cinnamaldehyde (0.3 mmol), PdCl2 (0.03
mmol), TBAB (0.15 mmol), in MeCN (1.5 mL), with an O2 balloon,
70 °C for 10 h.
CONCLUSION
■
In conclusion, we have developed an efficient Pd-catalyzed
oxidative cross-coupling of aromatic primary amines and
alkenes under molecular oxygen, providing highly regio- and
stereoselective approach to (Z)-enamines. The resultant
enamines were demonstrated to be versatile building blocks
for the synthesis of N-containing heterocyclics such as indoles,
pyrazoles, pyrroles, and 1,4-dihydropyridines. The addition of
LiBr was crucial to the success of the transformation, because of
its important role in avoiding the deactivation of palladium
catalyst arising from the strong coordination of aromatic
primary amines to it. This catalytic system is applicable to a
variety of aromatic primary amines, most of which are not
efficiently converted into enamines in previous reports. The
process is scalable and environmentally benign, with O2
employed as the terminal oxidant and H2O formed as the
only byproduct. Moreover, the use of inexpensive and readily
available starting materials as well as the exceptional functional
group tolerance makes this atom-economical approach
particularly attractive.
a
Reaction conditions: enamine 3 (0.3 mmol), PdCl2 (10 mol %),
Cu(OAc)2 (3 equiv), K2CO3 (2 equiv), in DMF (3 mL), 120 °C for
10 h.
with electron-donating groups on the phenyl ring showed
better reactivity than those with electron-withdrawing groups.
In the case of meta-substituted enamines, excellent selectivity to
the C−H bond with less steric hindrance was observed,
regardless of the electronic character of the substituents in the
meta position (4c−4e).
In addition, the enamine products could also be utilized to
construct various N-containing heterocyclic compounds. When
treated with benzonitrile, enamines could be converted into
pyrazoles in moderate yields (Scheme 7, eq 1).16 The pyrrole 6
could be easily obtained from the cyclization of enamine
product and β-nitrostyrene in 81% yield (Scheme 7, eq 2).19
Notably, 1,4-conjugated addition of 3 and cinnamaldehyde,
followed by intramolecular cyclization and dehydration,
afforded unsymmetric 1,4-dihydropyridines 7 in excellent yields
(Scheme 7, eq 3). The structure of 7b was further characterized
by X-ray crystal diffraction measurement.56
EXPERIMENTAL SECTION
■
Typical Procedure for Pd-Catalyzed Oxidative Cross-Cou-
pling Reactions. A 25 mL Schlenk tube was charged with a solution
of Pd(OAc)2 (0.025 mmol), LiBr (2 mmol), amine 1 (0.5 mmol), and
alkene 2 (0.6 mmol) in THF (2 mL) with an O2 balloon, and the
mixture was heated at 50 °C under magnetic stirring for 8 h. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc/Et3N) to afford the corresponding products 3.
Procedure for Large Scale Reaction. A 100 mL round-bottom
flask was charged with a solution of Pd(OAc)2 (0.6 mmol), LiBr (40
mmol), aniline 1a (20 mmol), and methyl acylate 2a (24 mmol) in
THF (40 mL) with a O2 balloon, and the mixture was heated at 50 °C
under magnetic stirring for 8 h. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc/Et3N) to
afford 3.08 g (87%) of product 3a.
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(Z)-Methyl 3-(phenylamino)acrylate (3a).57 Light yellow solid
(80.5 mg, 91%): 1H NMR (CDCl3, 400 MHz) δ 9.87 (d, J = 10.4 Hz,
1H), 7.30−7.21 (m, 3H), 7.00−6.94 (m, 3H), 4.84 (d, J = 8.4 Hz,
1H), 3.70 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.6, 143.1,
140.6, 129.6, 122.5, 115.3, 86.9, 50.6 ppm; MS (EI) m/z 77, 91, 117,
145, 177.
(Z)-Methyl 3-((4-methoxyphenyl)amino)acrylate (3b). Light
yellow oil (93.1 mg, 90%): 1H NMR (CDCl3, 400 MHz) δ 9.78 (d, J =
12.0 Hz, 1H), 7.15 (dd, J = 12.8, 8.4 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H),
6.85 (d, J = 9.2 Hz, 2H), 4.78 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.71
(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.8, 155.6, 144.3,
134.4, 117.0, 114.9, 85.6, 55.6, 50.5 ppm; HRMS-ESI (m/z) calcd for
C11H13NO3, [M + H]+ 208.0968, found 208.0960.
(Z)-Methyl 3-((3-fluorophenyl)amino)acrylate (3k). Light
yellow solid (90.6 mg, 93%): mp 54−56 °C; H NMR (CDCl3, 400
MHz) δ 9.91 (d, J = 10.8 Hz, 1H), 7.26−7.15 (m, 2H), 6.73−6.65 (m,
3H), 4.89 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 170.5, 163.7, 142.4, 142.3, 130.9, 111.1, 109.1, 102.3,
88.2, 50.7 ppm; HRMS-ESI (m/z) calcd for C10H10FNO2, [M + H]+
196.0768, found 196.0771.
1
(Z)-Methyl 3-((3-(trifluoromethyl)phenyl)amino)acrylate (3l).
Light yellow solid (109.0 mg, 89%): mp 41−43 °C; 1H NMR (CDCl3,
400 MHz) δ 10.02 (d, J = 11.2 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H),
7.28−7.23 (m, 2H), 7.20 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.94 (d, J =
8.4 Hz, 1H), 3.74 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.5,
142.2, 141.2, 132.2, 130.2, 123.8, 118.9, 118.5, 111.7, 88.8, 50.8 ppm;
HRMS-ESI (m/z) calcd for C11H10F3NO2, [M − H]− 244.0591, found
244.0585.
(Z)-Methyl 3-((4-fluorophenyl)amino)acrylate (3c). Light
1
yellow solid (84.8 mg, 87%): mp 61−63 °C; H NMR (CDCl3, 400
(Z)-Methyl 3-(o-tolylamino)acrylate (3m).47 Light yellow oil
(80.2 mg, 84%): 1H NMR (CDCl3, 400 MHz) δ 10.00 (d, J = 10.4 Hz,
1H), 7.32 (dd, J = 12.6, 8.2 Hz, 1H), 7.19 (t, J = 8.6 Hz, 2H), 7.04 (d,
J = 7.6 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 4.90 (d, J = 8.0 Hz, 1H), 3.74
(s, 3H), 2.34 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.9,
143.4, 139.1, 131.0, 127.1, 125.3, 122.4, 112.9, 87.1, 50.7, 17.4 ppm;
MS (EI) m/z 77, 91, 118, 130, 159, 191.
MHz) δ 9.84 (d, J = 10.0 Hz, 1H), 7.15 (dd, J = 12.8, 8.4 Hz, 1H),
7.00 (t, J = 8.6 Hz, 2H), 6.92−6.89 (m, 2H), 4.84 (d, J = 8.0 Hz, 1H),
3.71 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.7, 158.6, 143.6,
137.0, 116.8, 116.3, 86.9, 50.6 ppm; HRMS-ESI (m/z) calcd for
C10H10FNO2, [M + H]+ 196.0768, found 196.0764.
(Z)-Methyl 3-((4-chlorophenyl)amino)acrylate (3d). Light
1
yellow solid (98.3 mg, 93%): mp 57−58 °C; H NMR (CDCl3, 400
(Z)-Methyl 3-((2-methoxyphenyl)amino)acrylate (3n). Light
yellow oil (92.1 mg, 89%): 1H NMR (CDCl3, 400 MHz) δ 10.14 (d, J
= 12.4 Hz, 1H), 7.26 (dd, J = 13.2, 8.4 Hz, 1H), 7.02 (dd, J = 7.4, 1.8
Hz, 1H), 6.94−6.86 (m, 3H), 4.87 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H),
3.72 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.4, 147.7, 141.9,
130.2, 122.1, 120.9, 112.0, 110.8, 87.2, 55.7, 50.5 ppm; HRMS-ESI
(m/z) calcd for C11H13NO3, [M + H]+ 208.0968, found 208.0973.
(Z)-Methyl 3-((2-bromophenyl)amino)acrylate (3o).48 Light
yellow oil (117.7 mg, 92%): 1H NMR (CDCl3, 400 MHz) δ 10.32 (d,
J = 11.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.28−7.21 (m, 2H), 7.06
(d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 4.97 (d, J = 8.4 Hz, 1H),
3.76 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.3, 141.4, 137.5,
130.1, 127.8, 122.5, 121.9, 113.3, 89.3, 50.9 ppm; MS (EI) m/z 77, 89,
116, 145, 195, 223, 255.
MHz) δ 9.87 (d, J = 11.2 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.17 (dd, J
= 12.4, 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 4.87 (d, J = 8.4 Hz, 1H),
3.72 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.6, 142.7, 139.3,
129.6, 127.5, 116.5, 87.7, 50.7 ppm; HRMS-ESI (m/z) calcd for
C10H10ClNO2, [M + H]+ 212.0473, found 212.0478.
(Z)-Methyl 3-((4-bromophenyl)amino)acrylate (3e). Light
1
yellow solid (108.8 mg, 85%): mp 130−132 °C; H NMR (CDCl3,
400 MHz) δ 9.88 (d, J = 11.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.18
(dd, J = 12.6, 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 4.88 (d, J = 8.0
Hz, 1H), 3.72 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.6,
142.6, 139.8, 132.6, 116.9, 114.8, 87.9, 50.7 ppm; HRMS-ESI (m/z)
calcd for C10H10BrNO2, [M + H]+ 255.9968, found 255.9966.
(Z)-Methyl 3-((4-iodophenyl)amino)acrylate (3f). Light yellow
1
oil (62.1 mg, 41%): H NMR (CDCl3, 400 MHz) δ 9.87 (d, J = 11.6
(Z)-Methyl 3-((2-chlorophenyl)amino)acrylate (3p). Light
Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 12.8, 8.4 Hz, 1H), 6.73
(d, J = 8.8 Hz, 2H), 4.88 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 170.6, 142.4, 140.4, 138.4, 117.2, 88.0,
84.7, 50.7 ppm; HRMS-ESI (m/z) calcd for C10H10INO2, [M + H]+
303.9829, found 303.9830.
(Z)-Methyl 3-((4-nitrophenyl)amino)acrylate (3g). Light yel-
low oil (91.0 mg, 82%): 1H NMR (CDCl3, 400 MHz) δ 10.26 (d, J =
10.8 Hz, 1H), 8.20 (d, J = 8.0 Hz, 2H), 7.29−7.24 (m, 1H), 7.00 (d, J
= 8.0 Hz, 2H), 5.07 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 170.2, 146.0, 142.2, 140.7, 126.1, 114.3, 91.8,
51.1 ppm; HRMS-ESI (m/z) calcd for C10H10N2O4, [M − H]−
221.0568, found 221.0566.
(Z)-Methyl 4-((3-methoxy-3-oxoprop-1-en-1-yl)amino)-
benzoate (3h).58 Light yellow solid (102.2 mg, 87%): 1H NMR
(CDCl3, 400 MHz) δ 10.05 (d, J = 12.0 Hz, 1H), 7.97 (d, J = 8.8 Hz,
2H), 7.27 (dd, J = 12.6, 8.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 4.95 (d,
J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 170.4, 166.5, 144.4, 141.6, 131.6, 123.8, 114.3, 89.5, 51.9,
50.8 ppm; MS (EI) m/z 59, 89, 144, 172, 203, 235.
1
yellow oil (93.1 mg, 88%): H NMR (CDCl3, 400 MHz) δ 10.36
(d, J = 10.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz,
1H), 7.22 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.92 (t, J = 8.4
Hz, 1H), 4.97 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 170.3, 141.4, 137.5, 130.1, 127.8, 122.5, 121.9,
113.3, 89.3, 50.9 ppm; HRMS-ESI (m/z) calcd for C10H10ClNO2, [M
+ H]+ 212.0473, found 212.0475.
(Z)-Methyl 3-((3-ethynylphenyl)amino)acrylate (3q). Light
1
yellow oil (85.4 mg, 85%): H NMR (CDCl3, 400 MHz) δ 9.87 (d,
J = 11.6 Hz, 1H), 7.21 (dd, J = 13.2, 8.0 Hz, 2H), 7.13−7.09 (m, 2H),
6.93 (dd, J = 8.0, 1.6 Hz, 1H), 4.88 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H),
3.08 (s, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.5, 142.6, 140.7,
129.6, 126.2, 123.5, 118.4, 116.1, 87.9, 83.1, 77.6, 50.7 ppm; HRMS-
ESI (m/z) calcd for C12H11NO2, [M + H]+ 202.0863, found 202.0856.
(Z)-Methyl 3-((4-vinylphenyl)amino)acrylate (3r). Light yellow
solid (88.3 mg, 87%): mp 176−177 °C; 1H NMR (CDCl3, 400 MHz)
δ 9.91 (d, J = 12.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.25 (dd, J =
12.6, 8.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.65 (dd, J = 17.6, 10.8 Hz,
1H), 5.64 (d, J = 17.6 Hz, 1H), 5.16 (d, J = 10.8 Hz, 1H), 4.86 (d, J =
8.4 Hz, 1H), 3.72 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.6,
142.8, 140.1, 135.9, 132.2, 127.5, 115.3, 112.3, 87.2, 50.6 ppm; HRMS-
ESI (m/z) calcd for C12H13NO2, [M + H]+ 204.1019, found 204.1009.
(Z)-Methyl 3-(naphthalen-1-ylamino)acrylate (3s). Light
(Z)-Methyl 3-((4-(methylsulfonyl)phenyl)amino)acrylate (3i).
1
Light yellow oil (102.0 mg, 80%): H NMR (CDCl3, 400 MHz) δ
10.16 (d, J = 12.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.29 (dd, J = 11.8,
9.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 5.03 (d, J = 8.8 Hz, 1H), 3.75 (s,
3H), 3.05 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.2, 145.1,
141.0, 133.2, 129.5, 114.8, 90.8, 51.0, 44.7 ppm; HRMS-ESI (m/z)
calcd for C11H13NO4S, [M + H]+ 256.0638, found 256.0636.
1
yellow oil (104.4 mg, 92%): H NMR (CDCl3, 400 MHz) δ 10.73
(d, J = 11.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz,
1H), 7.54−7.46 (m, 3H), 7.37 (t, J = 8.0 Hz, 2H), 7.07 (d, J = 7.6 Hz,
1H), 4.97 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 171.1, 144.2, 136.5, 134.3, 128.4, 126.4, 126.2, 125.8,
124.5, 122.9, 120.5, 109.6, 87.9, 50.7 ppm; HRMS-ESI (m/z) calcd for
C14H13NO2, [M + H]+ 228.1019, found 228.1010.
(Z)-Methyl 3-((4-cyanophenyl)amino)acrylate (3j). Light yel-
1
low solid (95.9 mg, 95%): mp 156−158 °C; H NMR (CDCl3, 400
MHz) δ 10.10 (d, J = 11.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.22 (d, J
= 12.4, 8.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.00 (d, J = 8.4 Hz, 1H),
3.73 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 170.2, 144.1, 140.9,
133.9, 119.0, 115.0, 104.8, 90.7, 51.0 ppm; HRMS-ESI (m/z) calcd for
C11H10N2O2, [M − H]− 201.0670, found 201.0666.
(Z)-Methyl 3-((2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)-
amino)acrylate (3t). Light yellow solid (134.6 mg, 86%): mp
1
177−178 °C; H NMR (CDCl3, 400 MHz) δ 10.22 (d, J = 12.0 Hz,
11159
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Featured Article
1H), 7.62 (dd, J = 8.6, 1.4 Hz, 1H), 7.26−7.21 (m, 1H), 6.92−6.89
(m, 2H), 6.61 (s, 1H), 5.07 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 170.2, 159.2, 156.3, 144.8, 141.3, 140.6,
126.9, 115.0, 112.8, 112.4, 108.0, 101.7, 91.7, 51.1 ppm; HRMS-ESI
(m/z) calcd for C14H10F3NO4, [M + H]+ 314.0635, found 314.0627.
(Z)-Butyl 3-(phenylamino)acrylate (3u).47 Light yellow oil (99.6
mg, 91%): 1H NMR (CDCl3, 400 MHz) δ 9.89 (d, J = 12.0 Hz, 1H),
7.28 (t, J = 8.0 Hz, 2H), 7.25−7.21 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H),
6.95 (d, J = 8.0 Hz, 2H), 4.83 (d, J = 8.4 Hz, 1H), 4.12 (t, J = 6.8 Hz,
2H), 1.69−1.61 (m, 2H), 1.46−1.37 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 170.4, 142.9, 140.7, 129.6,
122.4, 115.3, 87.4, 63.2, 30.9, 19.2, 13.7 ppm; MS (EI) m/z 77, 91,
117, 145, 163, 201, 219.
(Z)-2-Ethylhexyl 3-(phenylamino)acrylate (3v). Light yellow oil
(122.4 mg, 89%): 1H NMR (CDCl3, 400 MHz) δ 9.89 (d, J = 12.4 Hz,
1H), 7.31−7.22 (m, 3H), 7.00 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz,
2H), 4.85 (d, J = 8.4 Hz, 1H), 4.04 (dd, J = 5.8, 3.4 Hz, 2H), 1.64−
1.59 (m, 1H), 1.39−1.31 (m, 8H), 0.94−0.90 (m, 6H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 170.6, 142.8, 140.7, 129.6, 122.4, 115.3,
87.5, 65.8, 38.9, 30.4, 29.0, 23.8, 23.0, 14.0, 11.0 ppm; HRMS-ESI (m/
z) calcd for C17H25NO2, [M + H]+ 276.1958, found 276.1949.
(Z)-Cyclohexyl 3-(phenylamino)acrylate (3w). Light yellow oil
(113.9 mg, 93%): 1H NMR (CDCl3, 400 MHz) δ 9.95 (d, J = 12.0 Hz,
1H), 7.33−7.24 (m, 3H), 7.03−6.97 (m, 3H), 4.86−4.79 (m, 2H),
1.95−1.77 (m, 4H), 1.61−1.58 (m, 1H), 1.50−1.40 (m, 4H), 1.34−
1.27 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 169.9, 142.7,
140.7, 129.6, 122.4, 115.2, 88.0, 71.6, 31.9, 25.4, 23.9 ppm; HRMS-ESI
(m/z) calcd for C15H19NO2, [M + H]+ 246.1489, found 246.1482.
(Z)-(Tetrahydrofuran-2-yl)methyl 3-(phenylamino)acrylate
(3x). Light yellow oil (116.1 mg, 94%): 1H NMR (CDCl3, 400
MHz) δ 9.84 (d, J = 12.0 Hz, 1H), 7.31−7.23 (m, 3H), 7.01−6.95 (m,
3H), 4.89 (d, J = 8.4 Hz, 1H), 4.24−4.08 (m, 2H), 3.90 (t, J = 7.4 Hz,
1H), 3.82 (t, J = 6.8 Hz, 1H), 2.05−1.86 (m, 4H), 1.67−1.60 (m, 1H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 170.0, 143.3, 140.6, 129.6,
122.6, 115.3, 87.1, 76.8, 68.4, 65.3, 28.0, 25.6 ppm; HRMS-ESI (m/z)
calcd for C14H17NO3, [M + H]+ 248.1281, found 248.1271.
131.2, 125.7, 123.2, 122.0, 121.4, 111.6, 108.6, 51.1 ppm; MS (EI) m/z
63, 89, 116, 144, 175.
Methyl 7-methyl-1H-indole-3-carboxylate (4b). Off-white
solid (47.1 mg, 83%): mp 163−165 °C; 1H NMR (CDCl3, 400
MHz) δ 8.94 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 2.8 Hz,
1H), 7.20 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 3.94 (s, 3H),
2.50 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 166.0, 135.7, 130.9,
125.4, 123.7, 122.2, 120.8, 119.0, 108.9, 51.1, 16.5 ppm; HRMS-ESI
(m/z) calcd for C11H11NO2, [M + H]+ 190.0863, found 190.0856.
Methyl 6-methoxy-1H-indole-3-carboxylate (4c).60 Off-white
solid (52.3 mg, 85%): 1H NMR (CDCl3, 400 MHz) δ 8.95 (d, J = 12.8
Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 6.92 (dd, J
= 8.8, 1.6 Hz, 1H), 6.85 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 166.0, 157.0, 137.0, 130.2, 122.0, 119.9,
111.8, 108.4, 95.0, 55.5, 51.1 ppm; MS (EI) m/z 76, 103, 146, 162,
174, 190, 205.
Methyl 5,6-dimethyl-1H-indole-3-carboxylate (4d). Off-white
solid (48.7 mg, 80%): mp 202−205 °C; 1H NMR (CDCl3, 400 MHz)
δ 8.60 (s, 1H), 7.93 (s, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.17 (s, 1H),
3.92 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H) ppm; 13C NMR (CDCl3, 100
MHz) δ 165.9, 135.0, 132.3, 130.9, 130.3, 124.1, 121.4, 111.8, 108.1,
51.0, 20.4, 20.1 ppm; HRMS-ESI (m/z) calcd for C12H13NO2, [M +
H]+ 204.1019, found 204.1011.
Methyl 6-(trifluoromethyl)-1H-indole-3-carboxylate (4e).
1
Off-white oil (38.6 mg, 53%): H NMR (DMSO-d6, 400 MHz) δ
12.30 (s, 1H), 8.31 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.49
(d, J = 8.4 Hz, 1H), 3.83 (s, 3H) ppm; 13C NMR (DMSO-d6, 100
MHz) δ 164.5, 135.4, 135.4, 128.4, 125.2, 123.0, 121.4, 117.7, 110.0,
106.9, 51.0 ppm; HRMS-ESI (m/z) calcd for C11H8F3NO2, [M − H]−
242.0434, found 242.0439.
Methyl 5-fluoro-1H-indole-3-carboxylate (4f).61 Off-white
1
solid (37.0 mg, 64%): H NMR (DMSO-d6, 400 MHz) δ 12.04 (s,
1H), 8.14 (d, J = 3.2 Hz, 1H), 7.65 (dd, J = 9.6, 2.4 Hz, 1H), 7.49 (dd,
J = 8.8, 4.4 Hz, 1H), 7.06 (td, J = 9.2, 2.4 Hz, 1H), 3.80 (s, 3H) ppm;
13C NMR (DMSO-d6, 100 MHz) δ 164.5, 158.3, 134.0, 133.0, 126.2,
113.7 110.7, 106.6, 105.2, 50.7 ppm; MS (EI) m/z 81, 107, 134, 162,
193.
(Z)-2,2,2-Trifluoroethyl 3-(phenylamino)acrylate (3y). Light
yellow oil (91.9 mg, 75%): 1H NMR (CDCl3, 400 MHz) δ 9.77 (d, J =
11.6 Hz, 1H), 7.38−7.31 (m, 3H), 7.06 (t, J = 7.4 Hz, 1H), 7.00 (d, J =
8.0 Hz, 2H), 4.92 (d, J = 8.0 Hz, 1H), 4.52 (q, J = 8.4 Hz, 2H) ppm;
13C NMR (CDCl3, 100 MHz) δ 168.1, 145.0, 140.1, 129.7, 123.3,
Methyl 5-chloro-1H-indole-3-carboxylate (4g).62 Off-white
1
solid (44.6 mg, 71%): H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H),
8.16 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22
(dd, J = 8.6, 1.8 Hz, 1H), 3.93 (s, 3H) ppm; 13C NMR (CDCl3, 100
MHz) δ 165.2, 134.4, 132.0, 128.0, 126.8, 123.7, 121.2, 112.5, 108.7,
51.2 ppm; MS (EI) m/z 75, 89, 114, 150, 178, 209.
123.3, 115.8, 85.1, 59.3 ppm; HRMS-ESI (m/z) calcd for
C11H10F3NO2, [M + H]+ 246.0736, found 246.0729.
Methyl 5-bromo-1H-indole-3-carboxylate (4h).63 Off-white
(Z)-N,N-Dimethyl-3-(phenylamino)acrylamide (3z). Light yel-
low oil (87.4 mg, 92%): 1H NMR (CDCl3, 400 MHz) δ 10.86 (d, J =
11.2 Hz, 1H), 7.26 (t, J = 8.0 Hz, 2H), 7.17 (dd, J = 12.0, 8.4 Hz, 1H),
6.95−6.91 (m, 3H), 5.00 (d, J = 8.4 Hz, 1H), 3.00 (s, 6H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 170.5, 141.2, 140.7, 129.5, 121.6, 115.0,
86.3, 37.3, 34.9 ppm; HRMS-ESI (m/z) calcd for C11H14N2O, [M +
H]+ 191.1179, found 191.1175.
1
solid (52.6 mg, 69%): H NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H),
8.32 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29
(d, J = 8.8 Hz, 1H), 3.93 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz)
δ 165.1, 134.7, 131.8, 127.4, 126.3, 124.2, 115.7, 112.9, 108.6, 51.2
ppm; MS (EI) m/z 71, 115, 143, 194, 222, 253.
Dimethyl 1H-indole-3,5-dicarboxylate (4i).64 Off-white solid
1
(42.6 mg, 61%): H NMR (DMSO-d6, 400 MHz) δ 12.26 (s, 1H),
(Z)-1-(Phenylamino)pent-1-en-3-one (3aa). Light yellow solid
8.69 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.57
(d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H) ppm; 13C NMR
(DMSO-d6, 100 MHz) δ 167.0, 164.4, 139.0, 134.3, 125.2, 123.3,
122.7, 112.5, 107.4, 51.9, 50.9 ppm; MS (EI) m/z 71, 114, 142, 174,
202, 233.
Typical Procedure for the Enamine Products’ Transforma-
tion into Pyrazoles.16 To a mixture of enamine (0.3 mmol) and
Cu(OAc)2 (0.9 mmol) was added 1 mL of PhCN. The reaction
mixture was stirred vigorously at room temperature to suspend the
solids well and then stirred at 120 °C for 20 h. After cooling to room
temperature, EtOAc (5 mL) was added, and the mixture was shortly
stirred at room temperature to suspend the metallic precipitates,
followed by filtration and subsequent concentration in vacuo. The
residue was purified by column chromatography on silica gel to afford
the corresponding products 5.
1
(44.6 mg, 51%): mp 109−111 °C; H NMR (CDCl3, 400 MHz) δ
7.27 (t, J = 7.6 Hz, 2H), 7.19−7.15 (m, 3H), 6.82 (d, J = 6.4 Hz, 1H),
4.91 (d, J = 6.4 Hz, 1H), 1.82 (q, J = 7.6 Hz, 2H), 0.49 (t, J = 7.6 Hz,
3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 182.6, 155.5, 150.7, 128.0,
125.4, 125.0, 93.3, 31.6, 10.5 ppm; HRMS-ESI (m/z) calcd for
C11H13NO, [M + H]+ 176.1070, found 176.1064.
Typical Procedure for the Enamine Products’ Transforma-
tion into Indoles.18 The enamine product 3 (0.3 mmol) was stirred
with PdCl2 (0.03 mmol), Cu(OAc)2 (0.9 mmol) and K2CO3 (0.6
mmol) in DMF (3 mL) at 120 °C for 10 h. Then the mixture is cooled
to room temperature and diluted with ethyl acetate, washed with brine
and dried with MgSO4. The solvent was removed under reduced
pressure and the residue was purified by column chromatography on
silica gel to afford the corresponding products 4.
Methyl 1H-indole-3-carboxylate (4a).59 Off-white solid (42.5
Methyl 1-(4-chlorophenyl)-3-phenyl-1H-pyrazole-4-carbox-
1
1
mg, 81%): H NMR (CDCl3, 400 MHz) δ 8.94 (s, 1H), 8.19−8.17
ylate (5a). Light yellow solid (49.6 mg, 53%): mp 142−143 °C; H
(m, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.42−7.38 (m, 1H), 7.29−7.23 (m,
NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 7.86 (dd, J = 7.8, 1.4 Hz,
2H), 7.73 (d, J = 8.8 Hz, 2H), 7.48−7.42 (m, 5H), 3.82 (s, 3H) ppm;
2H), 3.92 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.9, 136.1,
11160
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Featured Article
13C NMR (CDCl3, 100 MHz) δ 163.2, 154.3, 137.7, 133.1, 132.2,
ASSOCIATED CONTENT
■
131.8, 129.7, 129.3, 128.9, 128.0, 120.6, 113.7, 51.5 ppm; HRMS-ESI
(m/z) calcd for C17H13ClN2O2, [M + H]+ 313.0738, found 313.0730.
Methyl 1-(3,4-dimethylphenyl)-3-phenyl-1H-pyrazole-4-car-
boxylate (5b). Light yellow solid (56.9 mg, 62%): mp 149−150 °C;
1H NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H),
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds and
crystallographic information (CIF) for compound 7b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7.58 (s, 1H), 7.47−7.40 (m, 4H), 7.23 (d, J = 8.0 Hz, 1H), 3.82 (s,
3H), 2.34 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
163.4, 153.8, 138.1, 137.2, 136.1, 132.2, 130.5, 129.3, 128.6, 127.9,
123.5, 120.8, 116.8, 112.9, 51.4, 19.9, 19.3 ppm; HRMS-ESI (m/z)
calcd for C19H18N2O2, [M + H]+ 307.1441, found 307.1436.
Typical Procedure for the Enamine Products’ Transforma-
tion into Pyrrole.19 A pressure tube (15 mL) was charged with β-
nitrostyrene (0.2 mmol), enamine (0.3 mmol), and CH3OH (1.5 mL).
The mixture was stirred at 120 °C for 12 h. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography on silica gel to afford the corresponding product 6.
Methyl 1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-3-carboxy-
late (6). Light yellow solid (50.4 mg, 81%): mp 94−96 °C; 1H
NMR (CDCl3, 400 MHz) δ 7.72 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 7.2
Hz, 2H), 7.46−7.43 (m, 2H), 7.40−7.37 (m, 4H), 7.31 (t, J = 7.4 Hz,
1H), 7.03 (d, J = 2.4 Hz, 1H), 3.77 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 164.7, 138.1, 134.0, 132.6, 129.9, 129.2, 128.8, 127.9,
126.9, 125.9, 122.0, 119.6, 115.5, 51.1 ppm; HRMS-ESI (m/z) calcd
for C18H14ClNO2, [M + H]+ 312.0786, found 312.0776.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (973 Program) (2011CB808600), the
National Nature Science Foundation of China (20932002,
21172076, and 21202046), the Changjiang Scholars and
Innovation Team Project of Ministry of Education, and the
Guangdong Natural Science Foundation (10351064101000000
and S2012040007088).
Typical Procedure for the Enamine Products’ Transforma-
tion into 1,4-Dihydropyridines. A 25 mL Schlenk tube was charged
with PdCl2 (0.03 mmol), TBAB (0.15 mmol), cinnamaldehyde (0.3
mmol), and enamine (0.3 mmol) in MeCN (1.5 mL) with an O2
balloon, and the mixture was heated at 70 °C under magnetic stirring
for 10 h. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography on silica gel to afford
the corresponding products 7.
Methyl 1,4-diphenyl-1,4-dihydropyridine-3-carboxylate
(7a). Light yellow oil (77.7 mg, 89%): 1H NMR (CDCl3, 400
MHz) δ 7.75 (d, J = 1.2 Hz, 1H), 7.42−7.30 (m, 6H), 7.23−7.18 (m,
4H), 6.48 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 8.0, 4.8 Hz, 1H), 4.60 (d, J
= 4.8 Hz, 1H), 3.62 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
168.1, 147.2, 143.7, 137.3, 129.7, 128.4, 127.8, 126.4, 125.2, 124.9,
119.6, 110.4, 105.3, 51.1, 38.6 ppm; HRMS-ESI (m/z) calcd for
C19H17NO2, [M + Na]+ 314.1152, found 314.1162.
Methyl 1-(4-fluorophenyl)-4-phenyl-1,4-dihydropyridine-3-
carboxylate (7b). Light yellow oil (76.0 mg, 82%): 1H NMR
(CDCl3, 400 MHz) δ 7.64 (s, 1H), 7.36−7.30 (m, 4H), 7.22−7.16 (m,
3H), 7.09 (t, J = 8.6 Hz, 2H), 6.37 (d, J = 8.0 Hz, 1H), 5.10 (dd, J =
8.0, 4.8 Hz, 1H), 4.59 (d, J = 4.8 Hz, 1H), 3.61 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 168.1, 160.1, 147.2, 140.2, 137.5, 128.4,
127.8, 126.5, 125.4, 121.7, 116.4, 110.3, 105.2, 51.1, 38.5 ppm; HRMS-
ESI (m/z) calcd for C19H16FNO2, [M + Na]+ 332.1057, found
332.1058.
Methyl 1-(4-chlorophenyl)-4-phenyl-1,4-dihydropyridine-3-
carboxylate (7c). Light yellow oil (88.8 mg, 91%): 1H NMR (CDCl3,
400 MHz) δ 7.60 (d, J = 2.0 Hz, 1H), 7.29−7.21 (m, 6H), 7.14−7.10
(m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 7.2 Hz, 1H), 5.05 (dd, J
= 7.6, 4.8 Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H) 3.54 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 167.9, 146.9, 142.2, 136.8, 130.2, 129.7,
128.4, 127.8, 126.5, 124.8, 120.7, 110.8, 106.0, 51.1, 38.5 ppm; HRMS-
ESI (m/z) calcd for C19H16ClNO2, [M + Na]+ 348.0762, found
348.0752.
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