IBX-Promoted Oxidative Cyclization of N-Hydroxyalkyl Enamines: A Metal-Free Approach toward 2,3-Disubstituted Pyrroles and Pyridines

Article abstract of DOI:10.1021/acs.joc.0c00625

An iodoxybenzoic acid-mediated selected oxidative cyclization of N-hydroxyalkyl enamines was developed. Through this strategy, a variety of 2,3-disubstituted pyrroles and pyridines were produced in good selectivity involving oxidation of alcohol, followed by condensation of aldehyde and α-C of enamines. Furthermore, this metal-free method has several advantages, including the use of environmentally friendly reagents, broad substrate scope, mild reaction conditions, and high efficiency.

Full text of DOI:10.1021/acs.joc.0c00625

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Article
IBX-Promoted Oxidative Cyclization of N-Hydroxyalkyl Enamines: A
Metal-free Approach towards 2,3-Disubstituted Pyrroles and Pyridines
Peng Gao, Huai-Juan Chen, Zi-Jing Bai, Mi-Na Zhao, Desuo
Yang, Juan Wang, Ning Wang, Lele Du, and Zheng-Hui Guan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00625 • Publication Date (Web): 22 May 2020
Downloaded from pubs.acs.org on May 22, 2020
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IBX-Promoted Oxidative Cyclization of N-Hydroxyalkyl Enamines:
A Metal-free Approach towards 2,3-Disubstituted Pyrroles and
Pyridines
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Peng Gao,*,†,‡ Huai-Juan Chen,† Zi-Jing Bai,† Mi-Na Zhao,† Desuo Yang,† Juan Wang,*,† Ning
Wang,† Lele Du,† Zheng-Hui Guan*,‡
†Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering,
Baoji University of Arts and Sciences, Baoji, Shaanxi 721013, P. R. China
‡Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of
Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710127, P.
R. China
E-mail: gaopeng_hx@bjwlxy.edu.cn; 313967158@qq.com; guanzhh@nwu.edu.cn
ABSTRACT: An IBX-mediated selected oxidative cyclization of N-hydroxyalkyl enamines was
developed. Through this strategy, a variety of 2,3-disubstituted pyrroles and pyridines were
produced in good selectivity involving oxidation of alcohol, followed by condensation of aldehyde
and α-C of enamines. Furthermore, this metal-free method has several advantages, including the
use of environment-friendly reagents, broad substrate scope, mild reaction conditions and high
efficiency.
INTRODUCTION
Nitrogen-containing heterocycles are core structural unit that exist in many bioactive
compounds, natural products and functional organic materials.1 Among them, 2,3-disubstituted
pyrroles and pyridines have been attracted considerable attention, owing to their versatile
applications in many vibrant research fields.2,3 Examples are in Figure 1: (a) vitepyrroloids A,2a
containing a 2-cyano substituted pyrrole ring, isolated from the leaves of Vitex trifolia; (b)
Roseophilin, isolated from Streptomyces griseoviridis and identified as a novel protein tyrosine
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phosphatase inhibitor; (c) a pyrrole fused benzosultam skeleton organic lightemitting diodes
material,2c which exhibits good photoelectric performance; (d) a synthesized 2,3-disubstituted
pyridine,3a showing high PDE4 inhibitory activity; (e) and omeprazole,3b a successful proton
pump inhibitor for the treatment of gastric ulcers. The common methods for the synthesis of these
valuable targets rely on multistep synthesis,4-6 Hantzsch reactions,7,8 Parr-Knorr pyrrole
synthesis,9 and Krohnke pyridine synthesis.10 However, these methods usually are associated with
problems such as requirement of toxic additives and catalysis, harsh reaction conditions or low
atom-economy. Therefore, given their importance, simple and practical procedures for the facile
construction of 2,3-disubstituted pyrroles and pyridines remain significant issue in organic
synthesis.
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Figure 1. Selected examples of useful 2,3-disubstituted pyrroles and pyridines
Hypervalent iodines have been traditionally served as powerful oxidants with the properties
of low toxicity, easy handling and high stability.11 Today, their applications have been
successfully expanded in the fields of fluoroalkylation, heterocyclization, C-H bond
functionalization, rearrangement reactions and stereoselective synthesis.12 As a versatile
hypervalent iodine (V) reagent, iodoxybenzoic acid (IBX) has been used for the oxidation of
alcohols for decades, and some of the methods have been widely applied in the organic
synthesis.13 Furthermore, IBX could also be used in some domino transformations for the
synthesis of complex compounds.14,15 Zhu and co-workers reported a IBX-mediated oxidative
Ugi-type multicomponent reactions giving 1,2-diacylated tetrahydroisoquinolines (Scheme 1,
a).14a Luo et.al developed an asymmetric β-C−H functionalization of ketones including a key IBX-
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mediated enamine oxidation procedure.14b Compared to amines, only activated alcohols could be
involved in the IBX-mediated domino reactions (Scheme 1, b). For example, Pal and co-workers
presented an important method for the synthesis of pyridines via IBX-promoted oxidation of
allylic alcohols to allylic aldehydes or ketones, followed by cyclization with enamines.15a
However, oxidation of non-activated alcohols to aldehydes, sequentially, reaction with
nucleophiles to furnish heterocycles, is seldom reported, especially, existing other competitive
nucleophilic sites on the substrates. Therefore, focusing on these challenges and in continuation of
our efforts on the transition-metal-free oxidative cyclization reactions,16 we herein reported an
IBX-mediated intramolecular oxidative cyclization of N-hydroxyalkyl enamines, providing 2,3-
disubstituted pyrroles and pyridines as the products (Scheme 1, c).
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Scheme 1. IBX-Mediated Oxidative Domino Reactions
RESULTS AND DISCUSSION
In the initial study, we selected 1a as the model substrate because such an N-hydroxyethyl
enamine can be readily prepared from condensation of β-ketoester and ethanolamine. To our
delight, the desired product 2a was obtained in 51% yield by using IBX as an oxidant in DMSO
(Table 1, entry 1). The structure of 2a was confirmed by single-crystal X-ray diffraction analysis.
Further solvent screening revealed that THF was more competent among the tested solvents such
as DMSO, DME, CH3CN, DCE and toluene, giving 2a in 84% yield (Table 1, entries 2-6). No
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improvement in yield was observed when the temperature was changed to 100 or 130 oC (Table 1,
entries 7, 8). Tuning the amounts of IBX to 0.8 or 1.0 equiv declined the yield of 2a (Table 1,
entries 9, 10). Oxidants such as DMP, HTIB, PIDA or NaIO4 entirely suppressed the desired
product formation (Table 1, entries 11-14), in which methyl benzoylacetate was obtained as the
main byproduct. Therefore, the optimal conditions were to react using 1.2 equiv of IBX at 120 oC
for 12 h, providing the product 2a in 84% yield.
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Table 1. Optimization of the Reaction Conditionsa
entry
oxidant
solvent
T/oC
yield (%)b
1
2
IBX
IBX
DMSO
DME
CH3CN
THF
DCE
toluene
THF
120
120
120
120
120
120
100
130
120
120
120
120
120
120
51
70
21
84
0
3
IBX
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IBX
5
IBX
6
IBX
0
7
IBX
68
77
67
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0
8
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THF
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10d
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14
IBX
THF
IBX
THF
DMP
HTIB
PIDA
NaIO4
THF
THF
0
THF
0
THF
0
aConditions: 1a (0.5 mmol), oxidant (0.6 mmol) and 2 mL solvent in a sealed tube at 120 °C for
12 h. bIsolated yields. cIBX (0.4 mmol). d IBX (0.5 mmol).
Having the optimized conditions in hand, the substrate scope and generality with respect to
N-hydroxyethyl enamines were first investigated, and the results were summarized in Scheme 2.
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In general, a host of N-hydroxyethyl phenyl enaminoesters could be applicable and afford the
corresponding 2,3-disubstituted pyrroles up to 89% yields (2a-n). Phenyl enaminoesters having
methyl group substitution at the ortho-, meta-, and para-positions of the phenyl ring gave the
corresponding products in good yields (2b-d). 2,4-Dimethyl and 3,5-dimethyl substituted phenyl
enaminosters were well tolerated, furnishing the target products 2e and 2f in 53% and 77% yields,
respectively. Likewise, phenyl enaminoesters tethered to methoxyl group substitution provided the
desired pyrrole 2g-i in 74-78% yields. For substrates with halo substituents such as fluoro, chloro
and bromo, the desired cyclization was found to proceed smoothly and produced the substituted
pyrroles in yields arranging from 80% to 85% (2j-m). Notably, biaryl, fused aryl and heteroaryl
enaminoesters were tolerable to give the corresponding products in good yields as well (2n-p).
Moreover, further explorations of other electron-withdrawing group instead of -CO2Me
demonstrated that several functional groups such as -CO2Et, -CN and -COPh well suited for this
transformation (2q-s).
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Scheme 2. Substrate Scope of N-Hydroxyethyl Enaminesa,b
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aReaction Conditions: 1 (0.5 mmol), IBX (0.6 mmol) and THF (2 mL)
in a sealed tube at 120 °C for 12 h. bIsolated yields.
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To illustrate the applicability of this transformation, several enaminoesters containing
different hydroxyethyl groups on the N-substituted moiety were examined. To our delight, a
number of substrates bearing substitutions adjacent the nitrogen atom or hydroxyl group,
including alkyl, phenyl and cycloalkyl, also underwent the reaction giving the desired products in
17-82% yields (Scheme 3, 4a-i). Notably, the steric effect of the substituents has little influence on
the cyclization procedure. For example, substrates bearing the substitutions adjacent the nitrogen
atom (R3) afforded the 2,3,5-trisubstituted pyrroles in moderate to good yields (4a and 4b).
However, only 17% yield of desired product 4g was obtained when 2-aminocyclopentanol derived
enaminoester 3g was employed in the reaction. The lower yield of the corresponding product
might be due to the combination of steric effecting and the strain of cyclopentane. Additionally,
the -CN, and -COPh substituted enamines also worked well, to provide the pyrrole compounds in
moderate yields (4h, 4i).
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Scheme 3. Substrate Scope of N-Hydroxyethyl Enaminesa,b
aReaction Conditions: 3 (0.5 mmol), IBX (0.6 mmol) and THF (2 mL)
in a sealed tube at 120 °C for 12 h. bIsolated yields.
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Furthermore, the substrate substitution on the N-substituted moiety was exchanged as N-
hydroxypropyls. Only increasing the loading of IBX from 1.2 to 1.6 equiv led to moderate to good
yields of 2,3-disubstituted pyridines (Scheme 4, 6a-m). In the case of substrates bearing various
substitutions on the phenyl ring, including methyl, methoxyl, chlolo and phenyl, afforded the
desired products 6b-6g in 65-88% yields. Heterocyclic substrate was also applicable in the
reaction. For example, thiophene derived substrate was smoothly transferred to corresponding
pyridine 6h in 53% yield. Beside –CO2Me group, substrate containing -CO2Et, -CN and -COPh as
the electron-withdrawing group also showed good reactivity and furnished the products in 67%,
53% and 77% yields (6i-k), respectively. Moreover, when enaminoesters 5l and 5m bearing
hydroxypropyl derivatives on the N-substituted moiety were subjected into the reaction,
polysubstituted pyridines could be obtained in 67% and 65% yields, respectively.
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Scheme 4. Substrate Scope of N-Hydroxypropyl Enaminesa,b
aReaction Conditions: 5 (0.5 mmol), IBX (0.8 mmol) and THF (2 mL)
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in a sealed tube at 120 °C for 12 h. bIsolated yields.
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Gram-scale reaction of 1a was also performed and desired product was isolated in 52% yield
(48% yield in an open flask, Scheme 5, a). Further synthetic manipulations were conducted to
explore the reactivity of the 2.3-disubstituted pyrrole and pyridine products according to the
literatures. Delightedly, the products could be further transformed into other useful molecules. For
example, the ester moiety of 2a could be effectively converted to methyl via reductive reaction
with LiAlH4 (Scheme 5, b).16b Bromination of 2a with NBS, followed by Pd-catalyzed Suzuki
coupling resulted in substituted pyrrole 8 in 85% yield (Scheme 5, c).17 Furthermore, a two-step
sequential reduction of ester group and oxidative acylation furnished a heterocyclic fluorenone
product 9 in 32% yield (Scheme 5, d),18 which is a useful building block in further
transformation.19
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Scheme 5. Scaled-up Reaction and Product Modifications
To clarify the possible reaction mechanism, several control experiments were conducted.
When 1 equiv of bases such as Et3N, NaCO3 were added into the standard reaction, the cyclization
reaction was suppressed completely (Scheme 6, a). When 1 equiv of AcOH was employed, the
reaction outcome also decreased to 55 % and 28% yield of methyl benzoylacetate was isolated.
These results suggested that weak acidic system might enhance the product yields. 2a was
obtained in 71% yield by using fresh prepared IBX instead of the commercial one which
contained benzoic acid and isophthalic acid as stabilizers (Scheme 6, b). Further addition of 20 wt%
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of the stabilizers to the mixture increased the yield of 2a to 78%. These observations also
demonstrated that the acidity played a key role in this transformation. Particularly, the
transformation of 3g to 4g gave a cyclic α-enamone 4g′ in 11% yield (Scheme 6, c). The results
might suggest that the oxidation of hydroxyl groups is the initial procedure to form B-I and B-II.
Sequentially, the desired 4g is produced by a condensation of carbonyl with enamine α-C from B-
I. The acidic system might enhance the outcomes of this nucleophilic cyclization procedure. 4g′
can be easily generated from oxidation of the key intermediate B-II.14,20 Due to the special cyclic
structure, intramolecular hydrogen bond and conjugated effects, 4g′ hardly forms a pyrrole
compound via a condensation procedure.
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Scheme 6. Control Experiments and Possible Mechanism
CONCLUSIONS
In conclusion, an IBX-mediated oxidative cyclization of readily available N-hydroxyalkyl
enamines was developed. A wide range of enamines with different substitutions could be
smoothly converted to desired 2,3-disubstituted pyrroles and pyridines, which are highly valued
chemicals and useful building blocks for further derivativations. Notably, IBX, a known
environmentally friendly oxidant, was employed in the reaction without any transition-metal
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catalysts. Further studies to discover the synthetic applications of this practical method are now
under investigation in our laboratory.
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EXPERIMENTAL SECTION
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General Methods. All reactions were carried out in sealed tubes. Column chromatography was
1
carried out on silica gel. H NMR spectra were obtained with tetramethylsilane (TMS, δ = 0 ppm)
as internal standard in CDCl3 using an Agilent DD2 400-MR spectrometer (400 MHz). Data were
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, b = broad), coupling constant (J) and integration. 13C NMR spectra were recorded on
an Agilent DD2 400-MR spectrometer (100 MHz). The chemical shifts were determined in the δ-
scale relative to CDCl3 (δ = 77.0 ppm). HR MS were recorded on an AB SCIEX TOFTM 4600
MS equipped with an electrospray ionization (ESI-TOF) probe operating in positive ion mode.
IBX was were purchased from Aladdin Reagent, Ltd in Shanghai, China, which was stabilized
with benzoic acid and isophthalic acid (20 wt%). All of the commercially available compounds
were used without further purification.
Enamine compounds were prepared according to our previous work16a,b and the detail
procedure and characterization data were given in as follows:
General Procedure for the Synthesis of 1, 3 and 5: A mixture of 1,3-dicarbonyl compound (5
mmol), amine (10 mmol) and acetic acid (10 mmol) was stirred at 80 °C in an oil bath under
nitrogen atmosphere until TLC indicated the total consumption of the 1,3-dicarbonyl compound.
Then, the reaction mixture was purified by column chromatography using a mixture of PE and EA
as eluent to afford substrate 1, 3 and 5 (PE : EA = 3 : 1).
1
(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-phenylacrylate (1a). H NMR (400 MHz, CDCl3): δ
8.64 (b, 1H), 7.36-7.40 (m, 5H), 4.67 (s, 1H), 3.68 (s, 3H), 3.63 (t, J = 5.4 Hz, 2H), 3.21-3.25 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 165.2, 136.1, 129.5, 128.6, 128.1, 86.2, 62.5,
50.5, 46.8.
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(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(o-tolyl)acrylate (1b). H NMR (400 MHz, CDCl3): δ
8.77 (b, 1H), 7.24-7.28 (m, 1H), 7.16-7.20 (m, 2H), 7.12-7.13 (m, 1H), 4.48 (s, 1H), 3.65 (s, 3H),
3.55-3.59 (m, 2H), 2.97-3.04 (m, 2H), 2.28 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.0,
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164.2, 135.5, 135.2, 130.1, 128.9, 128.0, 125.8, 84.1, 62.2, 50.2, 45.9, 19.1.
(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(m-tolyl)acrylate (1c). 1H NMR (400 MHz, CDCl3): δ
8.62 (b, 1H), 7.25-7.29 (m, 1H), 7.19-7.21 (m, 1H), 7.14-7.16 (m, 2H), 4.65 (s, 1H), 3.67 (s, 3H),
3.60-3.63 (m, 2H), 3.21-3.25 (m, 2H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.0,
166.5, 138.4, 136.0, 130.2, 128.7, 128.4, 125.1, 85.8, 62.5, 50.5, 46.9, 21.5.
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1
(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(p-tolyl)acrylate (1d). H NMR (400 MHz, CDCl3): δ
8.59 (b, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.63 (s, 1H), 3.64 (s, 3H), 3.58-
3.61 (m, 2H), 3.19-3.23 (m, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 165.3,
139.4, 133.0, 129.1, 127.8, 85.6, 62.3, 50.3, 46.7, 21.3.
(Z)-Methyl 3-(2,4-dimethylphenyl)-3-((2-hydroxyethyl)amino)acrylate (1e). 1H NMR (400 MHz,
CDCl3): δ 8.77 (b, 1H), 6.98-7.03 (m, 3H), 4.48 (s, 1H), 3.65 (s, 3H), 3.56-3.57 (m, 2H), 2.98-3.06
(m, 2H), 2.31 (s, 3H), 2.24 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.0, 164.4, 138.7,
135.0, 132.6, 130.9, 128.0, 126.5, 84.2, 62.3, 50.2, 45.9, 21.1, 19.0.
1
(Z)-Methyl 3-(3,4-dimethylphenyl)-3-((2-hydroxyethyl)amino)acrylate (1f). H NMR (400 MHz,
CDCl3): δ 8.61 (b, 1H), 7.08-7.15 (m, 3H), 4.65 (s, 1H), 3.67 (s, 3H), 3.60-3.63 (m, 2H), 3.23-3.27
(m, 2H), 2.28 (s, 3H), 2.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.0, 165.6, 138.3,
136.9, 133.6, 129.8, 129.2, 125.5, 85.8, 62.6, 50.4, 46.9, 19.9, 19.8.
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(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(3-methoxyphenyl)acrylate (1g). H NMR (400 MHz,
CDCl3): δ 8.61 (b, 1H), 7.27-7.31 (m, 1H), 6.89-6.94 (m, 3H), 4.67 (s, 1H), 3.81 (s, 3H), 3.67 (s,
3H), 3.61-3.64 (m, 2H), 3.21-3.26 (m, 2H), 2.30 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
170.9, 165.0, 159.7, 137.4, 129.7, 120.4, 115.1, 113.6, 85.9, 62.5, 55.5, 50.5, 46.8.
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(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(4-methoxyphenyl)acrylate (1h). H NMR (400 MHz,
CDCl3): δ 8.57 (b, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.62-4.63 (m, 1H), 3.80
(s, 3H), 3.64 (s, 3H), 3.59-3.61 (m, 2H), 3.21-3.25 (m, 2H), 2.72-2.84 (m, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ 170.9, 165.1, 160.5, 129.4, 128.3, 113.9, 85.6, 62.3, 55.4, 50.4, 46.9.
(Z)-Methyl 3-(3,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate (1i). 1H NMR (400
MHz, CDCl3): δ 8.65 (b, 1H), 6.94-6.96 (m, 1H), 6.89-6.90 (m, 1H), 6.85-6.87 (m, 1H), 4.68 (s,
1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.67 (s, 3H), 3.62-3.64 (m, 2H), 3.24-3.29 (m, 2H), 2.22 (b, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 165.2, 150.1, 148.9, 128.3, 120.9, 111.3, 111.0, 86.0,
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(Z)-Methyl 3-(4-fluorophenyl)-3-((2-hydroxyethyl)amino)acrylate (1j). 1H NMR (400 MHz,
CDCl3): δ 8.57 (b, 1H), 7.29-7.34 (m, 2H), 7.01-7.06 (m, 2H), 4.57 (s, 1H), 3.61 (s, 3H), 3.58 (t, J
= 5.4 Hz, 2H), 3.23 (s, 1H), 3.16 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 164.5,
163.2 (d, JC-F = 249.2 Hz), 132.0 (d, JC-F = 3.4 Hz), 129.9 (d, JC-F = 8.3 Hz), 115.5 (d, JC-F = 21.7
Hz), 85.9, 62.1, 50.4, 46.7.
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(Z)-Methyl 3-(3-chlorophenyl)-3-((2-hydroxyethyl)amino)acrylate (1k). H NMR (400 MHz,
CDCl3): δ 8.57 (b, 1H), 7.31-7.39 (m, 3H), 7.24-7.26 (m, 1H), 4.65 (s, 1H), 3.68 (s, 3H), 3.62-3.65
(m, 2H), 3.18-3.23 (m, 2H), 2.16 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 163.4,
137.9, 134.6, 129.9, 129.6, 128.2, 126.3, 86.7, 62.4, 50.6, 46.9.
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(Z)-Methyl 3-(4-chlorophenyl)-3-((2-hydroxyethyl)amino)acrylate (1l). H NMR (400 MHz,
CDCl3): δ 8.57 (b, 1H), 7.35-7.37 (m, 2H), 7.29-7.32 (m, 2H), 4.63 (s, 1H), 3.66 (s, 3H), 3.60-3.63
(m, 2H), 3.17-3.21 (m, 2H), 2.42 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 163.8,
135.6, 134.5, 129.5, 128.9, 86.5, 62.4, 50.5, 46.8.
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(Z)-Methyl 3-(4-bromophenyl)-3-((2-hydroxyethyl)amino)acrylate (1m). H NMR (400 MHz,
CDCl3): δ 8.58 (b, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 4.65 (s, 1H), 3.68 (s,
3H), 3.62-3.64 (m, 2H), 3.19-3.23 (m, 2H), 2.08 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
170.8, 163.9, 135.0, 131.9, 129.8, 123.8, 86.7, 62.5, 50.6, 46.8.
(Z)-Methyl 3-([1,1'-biphenyl]-4-yl)-3-((2-hydroxyethyl)amino)acrylate (1n). 1H NMR (400 MHz,
CDCl3): δ 8.65 (b, 1H), 7.59-7.63 (m, 4H), 7.44-7.48 (m, 4H), 7.36-7.40 (m, 1H), 4.75 (s, 1H),
3.70 (s, 3H), 3.65-3.68 (m, 2H), 3.28-3.33 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.9,
164.9, 142.5, 140.4, 134.9, 129.0, 128.6, 127.9, 127.3, 127.3, 86.5, 62.6, 50.6, 47.0.
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(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(naphthalen-2-yl)acrylate (1o). H NMR (400 MHz,
CDCl3): δ 8.99 (b, 1H), 7.97-8.01 (m, 1H), 7.85-7.89 (m, 2H), 7.46-7.55 (m, 3H), 7.40-7.42 (m,
1H), 4.71 (s, 1H), 3.70 (s, 3H), 3.52-3.55 (m, 2H), 3.89-3.04 (m, 2H), 2.06 (b, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ 171.1, 163.3, 133.6, 133.4, 130.7, 129.4, 128.5, 127.1, 126.5, 126.2, 125.3,
125.2, 85.8, 62.4, 50.5, 46.4.
(Z)-Methyl 3-((2-hydroxyethyl)amino)-3-(thiophen-2-yl)acrylate (1p). 1H NMR (400 MHz,
CDCl3): δ 8.56 (b, 1H), 7.34-7.35 (m, 1H), 7.19-7.20 (m, 1H), 7.01-7.03 (m, 1H), 4.85 (s, 1H),
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3.63-3.67 (m, 2H), 3.63 (s, 3H), 3.38-3.42 (m, 2H), 3.07 (b, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 170.6, 157.4, 136.8, 128.4, 127.4, 127.3, 86.9, 62.2, 50.5, 47.1.
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(Z)-Ethyl 3-((2-hydroxyethyl)amino)-3-phenylacrylate (1q). 1H NMR (400 MHz, CDCl3): δ 8.63
(b, 1H), 7.35-7.40 (m, 5H), 4.67 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.61-3.64 (m, 2H), 3.21-3.25 (m,
2H), 1.28 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.6, 165.1, 136.2, 129.5,
128.6, 128.1, 86.8, 62.6, 59.0, 46.8, 14.7.
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(Z)-3-((2-Hydroxyethyl)amino)-3-phenylacrylonitrile (1r). H NMR (400 MHz, CDCl3): δ 7.54-
7.56 (m, 2H), 7.40-7.46 (m, 3H), 4.88 (b, 1H), 4.03 (s, 1H), 3.84-3.86 (m, 2H), 3.20-3.24 (m, 2H),
2.08 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.9, 135.9, 130.6, 128.9, 128.0, 121.8, 61.5,
60.0, 45.8.
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(Z)-3-((2-Hydroxyethyl)amino)-1,3-diphenylprop-2-en-1-one (1s). H NMR (400 MHz, CDCl3):
δ 11.46 (b, 1H), 7.87-7.89 (m, 2H), 7.37-7.44 (m, 8H), 5.78 (s, 1H), 3.72-3.76 (m, 2H), 3.36-3.41
(m, 2H), 2.89 (b, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 188.7, 167.3, 140.3, 135.6, 130.9,
129.7, 128.7, 128.4, 128.0, 127.2, 94.1, 62.1, 47.1.
(Z)-Methyl 3-((1-hydroxypropan-2-yl)amino)-3-phenylacrylate (3a). 1H NMR (400 MHz,
CDCl3): δ 8.36 (b, 1H), 7.37-7.41 (m, 5H), 4.67 (s, 1H), 3.68 (s, 3H), 3.45-3.52 (m, 3H), 2.04 (b,
1H), 1.10-1.12 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 165.1, 136.4, 129.5, 128.6,
128.0, 86.9, 67.3, 51.9, 50.5, 18.7.
(Z)-Methyl 3-((1-hydroxybutan-2-yl)amino)-3-phenylacrylate (3b). 1H NMR (400 MHz, CDCl3):
δ 8.36 (d, J = 10.1 Hz, 1H), 7.36-7.40 (m, 5H), 4.66 (s, 1H), 3.68 (s, 3H), 3.47-3.56 (m, 2H), 3.25-
3.31 (m, 1H), 2.16 (b, 1H), 1.41-1.56 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 171.0, 165.9, 136.5, 129.4, 128.5, 128.2, 86.6, 65.9, 57.5, 50.5, 26.0, 10.5.
(Z)-Methyl 3-((1-hydroxy-3-methylbutan-2-yl)amino)-3-phenylacrylate (3c). 1H NMR (400 MHz,
CDCl3): δ 8.48 (b, 1H), 7.33-7.40 (m, 5H), 4.67 (s, 1H), 3.69 (s, 3H), 3.58-3.60 (m, 2H), 3.15-3.22
(m, 1H), 2.17 (b, 1H), 1.74-1.83 (m, 1H), 0.92-0.94 (m, 3H), 0.83-0.85 (m, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 171.0, 166.3, 136.4, 129.4, 128.5, 128.4, 86.6, 64.5, 61.2, 50.5, 30.7, 19.8,
18.2.
(Z)-Methyl 3-((1-hydroxy-4-methylpentan-2-yl)amino)-3-phenylacrylate (3d). 1H NMR (400
MHz, CDCl3): 8.30 (d, J = 10.3 Hz, 1H), 7.36-7.39 (m, 5H), 4.65 (s, 1H), 3.70 (d, J = 7.4 Hz, 1H),
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3.67 (s, 3H), 3.47-3.33 (m, 2H), 1.41-1.33 (m, 1H), 1.24 (s, 2H), 0.79 (d, J = 6.6 Hz, 3H), 0.66 (d,
J = 6.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.4, 165.3,129.3, 128.4, 128.1, 86.4, 66.4,
54.2, 50.3, 42.2, 24.4, 23.1, 22.2.
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CDCl3): δ 9.08 (d, J = 10.0 Hz, 1H), 7.24-7.37 (m, 6H), 7.18-7.22 (m, 2H), 7.11-7.14 (m, 2H),
4.73 (s, 1H), 4.41-4.47 (m, 1H), 3.74-3.78 (m, 2H), 3.71 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 170.8, 164.8, 139.9, 135.8, 129.3, 128.7, 128.3, 127.9, 127.6, 126.4, 87.5, 67.3, 60.2,
50.5.
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(Z)-Methyl 3-((2-hydroxypropyl)amino)-3-phenylacrylate (3f). H NMR (400 MHz, CDCl3): δ
8.66 (b, 1H), 7.36-7.39 (m, 3H), 7.33-7.35 (m, 2H), 4.64 (s, 1H), 3.77-3.85 (m, 1H), 3.66 (s, 3H),
2.98-3.13 (m, 2H), 2.52 (b, 1H), 1.10 (d, J = 6.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
170.9, 165.2, 136.1, 129.4, 128.5, 128.1, 85.8, 67.5, 51.9, 50.4, 20.6.
(Z)-Methyl 3-((2-hydroxycyclopentyl)amino)-3-phenylacrylate (3g). 1H NMR (400 MHz, CDCl3):
δ 8.50-8.52 (m, 1H), 7.37-7.41 (m, 5H), 4.62 (s, 1H), 3.97-4.01 (m, 1H), 3.67 (s, 3H), 3.44-3.52
(m, 1H), 1.88-2.01 (m, 3H), 1.61-1.72 (m, 2H), 1.45-1.55 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 171.0, 164.9, 136.4, 129.5, 128.6, 128.1, 85.8, 79.2, 62.7, 50.4, 31.9, 31.5, 20.2.
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(Z)-3-((2-Hydroxypropyl)amino)-3-phenylacrylonitrile (3h). H NMR (400 MHz, CDCl3): δ
7.52-.55 (m, 2H), 7.38-7.45 (m, 3H), 4.84 (s, 1H), 4.04-4.08 (m, 1H), 4.01 (s, 1H), 3.11-3.16 (m,
1H), 2.93-2.99 (m, 1H), 1.27 (d, J=6.29 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.6,
135.8, 130.4, 128.8, 127.8, 121.6, 65.6, 61.4, 50.6, 21.5.
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(Z)-3-((1-Hydroxypropan-2-yl)amino)-1,3-diphenylprop-2-en-1-one (3i). H NMR (400 MHz,
CDCl3): δ 11.26 (b, 1H), 7.84-7.86 (m, 2H), 7.35-7.41 (m, 8H), 5.71 (s, 1H), 3.55-3.58 (m, 2H),
3.84-3.87 (m, 1H), 1.18 (b, J=6.48 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 188.5, 166.9,
140.1, 135.8, 130.8, 129.4, 128.5, 128.2, 127.7, 127.1, 94.0, 67.0, 52.1, 18.6.
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(Z)-Methyl 3-((3-hydroxypropyl)amino)-3-phenylacrylate (5a). H NMR (400 MHz, CDCl3): δ
8.54 (b, 1H), 7.31-7.38 (m, 5H), 4.57 (s, 1H), 3.64 (s, 3H), 3.61-3.64 (m, 2H), 3.16 (q, J = 6.6 Hz,
2H), 2.45 (b, 1H), 1.64-1.70 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 165.2, 136.1,
129.3, 128.4, 137.8, 84.9, 59.8, 50.3, 41.5, 33.5.
(Z)-Methyl 3-((3-hydroxypropyl)amino)-3-(p-tolyl)acrylate (5b). 1H NMR (400 MHz, CDCl3): δ
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8.54 (b, 1H), 7.16-7.24 (m, 4H), 4.58 (s, 1H), 3.68 (d, J = 6.1 Hz, 2H), 3.65 (s, 3H), 3.19 (q, J =
6.5 Hz, 2H), 2.36 (s, 3H), 1.64-1.73 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 165.3,
139.3, 133.2, 129.1, 127.7, 84.8, 60.1, 50.2, 41.4, 33.5, 21.3.
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MHz, CDCl3): δ 8.53 (b, 1H), 7.09-7.16 (m, 2H), 7.05-7.07 (m, 1H), 4.57 (s, 1H), 3.67 (t, J = 6.1
Hz, 2H), 3.65 (s, 3H), 3.20 (q, J = 6.5 Hz, 2H), 2.26 (m, 6H), 1.62-1.73 (m, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 170.8, 165.5, 138.0, 136.7, 133.6, 129.6, 128.9, 125.2, 84.7, 60.0, 50.2, 41.4,
33.5, 19.7, 19.6.
(Z)-Methyl 3-((3-hydroxypropyl)amino)-3-(4-methoxyphenyl)acrylate (5d). 1H NMR (400 MHz,
CDCl3): δ 8.52 (b, 1H), 7.25-7.31 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.58 (s, 1H), 3.81 (s, 3H),
3.68 (d, J = 6.1 Hz, 2H), 3.65 (s, 3H), 3.21 (q, J = 6.5 Hz, 2H), 1.63-1.74 (m, 2H).13C{1H} NMR
(100 MHz, CDCl3): δ 170.8, 165.0, 160.4, 129.2, 128.3, 113.8, 84.9 , 60.0, 55.3, 50.2, 41.5, 33.5.
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(Z)-Methyl 3-(3,4-dimethoxyphenyl)-3-((3-hydroxypropyl)amino)acrylate (5e). H NMR (400
MHz, CDCl3): δ 8.48 (t, J = 6.2 Hz, 1H), 6.89-6.91 (m, 1H), 6.82-6.85 (m, 2H), 4.58 (s, 1H), 3.86
(s, 3H), 3.84 (s, 3H), 3.65 (t, J = 6.1 Hz, 2H), 3.63 (s, 3H), 3.20 (q, J = 6.5 Hz, 2H), 1.68 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 165.1, 149.9, 148.8, 128.6, 120.5, 111.0, 110.8, 84.8,
59.9, 56.0, 55.9, 50.2, 41.6, 33.5.
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(Z)-Methyl 3-(4-chlorophenyl)-3-((3-hydroxypropyl)amino)acrylate (5f). H NMR (400 MHz,
CDCl3): δ 8.50 (b, 1H), 7.33-7.37 (m, 2H), 7.25-7.30 (m, 2H), 4.56 (s, 1H), 3.67 (t, J = 6.0 Hz,
2H), 3.65 (s, 3H), 3.16 (q, J = 6.5 Hz, 2H), 1.67-1.72 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ 170.6, 163.7, 135.3, 134.5, 129.2, 128.7, 85.5, 59.9, 50.3, 41.6, 33.3.
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(Z)-Methyl 3-([1,1'-biphenyl]-4-yl)-3-((3-hydroxypropyl)amino)acrylate (5g). H NMR (400
MHz, CDCl3): δ 8.57 (b, 1H), 7.58-7.61 (m, 4H), 7.40-7.46 (m, 4H), 7.33-7.38 (m, 1H), 4.65 (s,
1H) 3.70 (t, J = 6.1 Hz, 2H), 3.67 (s, 3H), 3.25 (q, J = 6.5 Hz, 2H), 1.70-1.76 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 170.8, 164.8, 142.2, 140.2, 134.9, 128.9, 128.3, 127.7, 127.1, 85.2,
60.0, 50.3, 41.6, 33.5.
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(Z)-Methyl 3-((3-hydroxypropyl)amino)-3-(thiophen-2-yl)acrylate (5h). H NMR (400 MHz,
CDCl3): δ 8.52 (b, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.19 (dd, J = 3.6, 1.2 Hz, 1H), 7.03-7.05 (m,
1H), 4.81 (s, 1H), 3.68-3.75 (m, 2H), 3.66 (s, 3H), 3.40 (q, J = 6.5 Hz, 2H), 1.71-1.82 (m, 2H).
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13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 157.3, 136.8, 128.1, 127.1, 86.2, 60.1, 50.3, 41.8, 33.4.
(Z)-Ethyl 3-((3-hydroxypropyl)amino)-3-phenylacrylate (5i). 1H NMR (400 MHz, CDCl3): δ 8.55
(b, 1H), 7.31-7.39 (m, 5H), 4.58 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.66 (t, J = 6.1 Hz, 2H), 3.17 (q,
J = 6.5 Hz, 2H), 1.66-1.72 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
170.5, 165.0, 136.1, 129.2, 128.4, 127.8, 85.5, 60.0, 58.7, 41.4, 33.5, 14.6.
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(Z)-3-((3-Hydroxypropyl)amino)-3-phenylacrylonitrile(5j). H NMR (400 MHz, CDCl3): δ 7.53-
7.55 (m, 2H), 7.38-7.42 (m, 2H), 5.05 (b, 1H), 4.01 (s, 1H), 3.81-3.85 (2H), 3.22-3.26 (m, 2H),
1.86-1.94 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 136.0, 130.3, 128.8, 127.7, 126.9, 121.7,
61.6, 60.7, 42.4, 30.2.
(Z)-3-((3-Hydroxypropyl)amino)-1,3-diphenylprop-2-en-1-one (5k). 1H NMR (400 MHz, CDCl3):
δ 11.41 (b, 1H), 7.85-7.88 (m, 2H), 7.37-7.43 (m, 8H), 5.75 (s, 1H), 3.72 (t, J = 6.0 Hz, 2H), 3.35
(q, J = 6.6 Hz, 2H), 1.77-1.83 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 167.0, 140.2,
135.6, 130.7, 129.5, 128.6, 128.2, 127.7, 127.0, 93.5, 59.8, 41.5, 33.2.
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(Z)-Methyl 3-((3-hydroxy-1-phenylpropyl)amino)-3-phenylacrylate (5l). H NMR (400 MHz,
CDCl3): δ 8.99 (d, J = 9.8 Hz, 1H) (b, 1H), 7.25-7.35 (m, 4H), 7.16-7.24 (m, 2H), 7.12-7.16 (m,
2H), 7.03-7.06 (m, 2H), 4.63 (s, 1H), 4.45-4.51 (m, 1H), 3.60-3.74 (m, 2H), 3.70 (s, 3H), 1.94-
2.03 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 164.8, 143.2, 136.1, 129.2, 128.6, 128.2,
127.8, 127.0, 126.0, 86.6, 59.5, 55.6, 50.3, 41.1.
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(Z)-Methyl 3-((3-hydroxybutyl)amino)-3-phenylacrylate (5m). H NMR (400 MHz, CDCl3): δ
8.33 (d, J = 10.4 Hz, 1H), 7.28-7.43 (m, 5H), 4.58 (s, 1H), 3.66-3.69 (m, 1H), 3.66 (s, 3H), 3.51
(m, 2H), 1.66 (m, 2H), 1.11 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 164.8,
136.4, 129.3, 128.4, 127.7, 85.6, 59.6, 50.2, 47.2, 40.7, 22.8.
General Procedure for the Synthesis of 2 or 4. A sealed tube was charged with enamine 1 or 3
(0.5 mmol), THF (2 mL), and then IBX (0.6 mmol) was added. The reaction mixture was stirred at
120 °C in an oil bath for 12 h. Then, the mixture was cooled to room temperature and 20 mL
water was added to the mixture, which was extracted with ethyl acetate (3 × 10 mL). The organic
layer was combined and dried with anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the residue was separated by flash column chromatography to afford the pure
product 2 or 4 (PE : EA = 3 : 1).
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Methyl 2-phenyl-1H-pyrrole-3-carboxylate (2a).4b Light yellow solid (84 mg, 84% yield), mp 89-
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91 C. H NMR (400 MHz, CDCl3): δ 8.60 (b, 1H), 7.55-7.58 (m, 2H), 7.33-7.41 (m, 3H), 6.71-
6.73 (m, 2H), 3.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.6, 137.3, 132.1, 129.0, 128.4,
128.3, 117.9, 112.2, 111.9, 51.1. HRMS (ESI-TOF): m/z calcd for C12H11NNaO2 [M + Na]+
224.0682, found: 224.0682.
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Methyl 2-(o-tolyl)-1H-pyrrole-3-carboxylate (2b). Light yellow solid (80 mg, 74% yield), mp
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138-140 C. H NMR (400 MHz, CDCl3): δ 8.23 (b, 1H), 7.22-7.31 (m, 4H), 6.77-6.78 (m, 1H),
6.72-6.74 (m, 1H), 3.67 (s, 3H), 2.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.2, 138.0,
132.4, 130.4, 130.1, 128.9, 125.5, 117.4, 111.0, 51.0, 20.0. HRMS (ESI-TOF): m/z calcd for
C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0839.
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Methyl 2-(m-tolyl)-1H-pyrrole-3-carboxylate (2c).4b Light yellow oil (94 mg, 87% yield). H
NMR (400 MHz, CDCl3): δ 8.43 (b, 1H), 7.38-7.40 (m, 2H), 7.28-7.32 (m, 1H), 7.17-7.19 (m, 1H),
6.72-6.75 (m, 2H), 3.74 (s, 3H), 2.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 138.0,
137.5, 132.1, 129.5, 129.2, 128.2, 126.3, 117.7, 112.3, 111.9, 51.1, 21.6. HRMS (ESI-TOF): m/z
calcd for C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0834.
Methyl 2-(p-tolyl)-1H-pyrrole-3-carboxylate (2d). Light yellow solid (96 mg, 89% yield), mp 80-
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81 C. H NMR (400 MHz, CDCl3): δ 8.38 (b, 1H), 7.47-7.49 (m, 2H), 7.21-7.24 (m, 2H), 6.72-
6.75 (m, 2H), 3.75 (s, 3H), 2.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 138.4, 137.5,
129.3, 129.1, 128.9, 117.6, 112.3, 111.8, 51.1, 21.5. HRMS (ESI-TOF): m/z calcd for
C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0837.
Methyl 2-(2,4-dimethylphenyl)-1H-pyrrole-3-carboxylate (2e). Light yellow solid (61 mg, 53%
yield), mp 76-77 oC. 1H NMR (400 MHz, CDCl3): δ 8.19 (b, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.09 (s,
1H), 7.04 (d, J = 7.7 Hz, 1H), 6.75-6.76 (m, 1H), 6.71-6.72 (m, 1H), 3.68 (s, 3H), 2.36 (s, 3H),
2.16 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.2, 138.6, 137.8, 130.9, 130.2, 129.5, 126.2,
117.2, 113.4, 111.0, 110.2, 51.0, 21.4, 19.9. HRMS (ESI-TOF): m/z calcd for C14H15NNaO2 [M +
Na]+ 252.0995, found: 252.0994.
Methyl 2-(3,4-dimethylphenyl)-1H-pyrrole-3-carboxylate (2f). Light yellow solid (88 mg, 77%
yield), mp 44-46 oC, 1H NMR (400 MHz, CDCl3): δ 8.52 (b, 1H), 7.31-7.33 (m, 2H), 7.15-7.16 (m,
1H), 6.68-6.71 (m, 2H), 3.73 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
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δ 165.6, 137.6, 137.0, 136.4, 130.0, 129.7, 129.6, 126.6, 117.5, 112.1, 111.5, 51.0, 19.9, 19.7.
HRMS (ESI-TOF): m/z calcd for C14H15NNaO2 [M + Na]+ 252.0995, found: 252.0992.
Methyl 2-(3-methoxyphenyl)-1H-pyrrole-3-carboxylate (2g).4c Light yellow solid (91 mg, 78%
yield), mp 145-146 oC. 1H NMR (400 MHz, CDCl3): δ 8.51 (b, 1H), 7.29-7.33 (m, 1H), 7.13-7.14
(m, 2H), 6.89-6.92 (m, 1H), 6.72-6.75 (m, 2H), 3.83 (s, 3H), 3.75 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 165.4, 159.5, 137.0, 133.4, 129.3, 121.3, 117.8, 114.7, 114.2, 112.4, 112.1, 55.5,
51.1. HRMS (ESI-TOF): m/z calcd for C13H13NNaO3 [M + Na]+ 254.0788, found: 254.0788.
Methyl 2-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (2h).4c Yellow oil (87 mg, 75% yield). 1H
NMR (400 MHz, CDCl3): δ 8.65 (b, 1H), 7.48 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.66-
6.70 (m, 2H), 3.81 (s, 3H), 3.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.7, 159.7, 137.4,
130.3, 124.6, 117.5, 113.7, 112.0, 111.2, 55.4, 51.0. HRMS (ESI-TOF): m/z calcd for
C13H13NNaO3 [M + Na]+ 254.0788, found: 254.0781.
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Methyl 2-(3,4-dimethoxyphenyl)-1H-pyrrole-3-carboxylate (2i). Yellow oil (97 mg, 74% yield).
1H NMR (400 MHz, CDCl3): δ 8.92 (b, 1H), 7.17-7.18 (m, 1H), 7.06-7.08 (m, 1H), 6.82 (d, J =
8.4 Hz, 1H), 6.66-6.68 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.71 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 165.7, 149.1, 148.4, 137.2, 124.9, 121.4, 117.3, 112.8, 112.1, 111.3, 110.9, 55.9, 51.0.
HRMS (ESI-TOF): m/z calcd for C14H15NNaO4 [M + Na]+ 284.0893, found: 284.0890.
Methyl 2-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (2j). Light yellow solid (90 mg, 82% yield),
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mp 96-97. H NMR (400 MHz, CDCl3): δ 8.38 (b, 1H), 7.55-7.58 (m, 2H), 7.08-7.26 (m, 2H),
6.77 (t, J = 2.8 Hz, 1H), 6.73 (t, J = 2.9 Hz, 1H), 3.75 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 165.4, 162.9 (d, JC-F = 249 Hz), 136.4, 130.9 (d, JC-F = 8.3 Hz), 117.8, 115.4 (d, JC-F = 21 Hz),
112.4, 51.2. HRMS (ESI-TOF): m/z calcd for C12H10 FNNaO2 [M + Na]+ 242.0588, found:
242.0587.
Methyl 2-(3-chlorophenyl)-1H-pyrrole-3-carboxylate (2k).4c Light yellow oil (99 mg, 84% yield).
1H NMR (400 MHz, CDCl3): δ 8.58 (b, 1H), 7.55-7.56 (m, 1H), 7.46-7.49 (m, 1H), 7.31-7.33 (m,
2H), 6.72-6.77 (m, 2H), 3.75(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.1, 135.3, 134.0,
133.6, 129.4, 128.8, 128.2, 127.2, 118.1, 112.4, 51.1. HRMS (ESI-TOF): m/z calcd for
C12H10ClNNaO2 [M + Na]+ 258.0292, found: 258.0292.
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Methyl 2-(4-chlorophenyl)-1H-pyrrole-3-carboxylate (2l).4b Light yellow solid (100 mg, 85%
yield), mp 107-109 oC. 1H NMR (400 MHz, CDCl3): δ 8.53 (b, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.37
(d, J = 8.5 Hz, 2H), 6.73-6.76 (m, 2H), 3.74 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.4,
137.0, 134.4, 130.6, 130.3, 128.5, 118.2, 112.5, 112.4, 51.2. HRMS (ESI-TOF): m/z calcd for
C12H10ClNNaO2 [M + Na]+ 258.0292, found: 258.0287.
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Methyl 2-(4-bromophenyl)-1H-pyrrole-3-carboxylate (2m). Light yellow solid (112 mg, 80%
yield), mp 124-125 oC. 1H NMR (400 MHz, CDCl3): δ 8.56 (b, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.44
(d, J = 8.6 Hz, 2H), 6.72-6.75 (m, 2H), 3.74 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.4,
136.0, 131.5, 131.0, 130.6, 122.6, 118.2, 112.5, 112.3, 51.2. HRMS (ESI-TOF): m/z calcd for
C12H11BrNO2 [M + H]+ 279.9968, found: 279.9969.
Methyl 2-([1,1'-biphenyl]-4-yl)-1H-pyrrole-3-carboxylate (2n). Light yellow solid (119 mg, 86%
yield), mp 165-166 oC. 1H NMR (400 MHz, CDCl3): δ 8.55 (b, 1H), 7.60-7.68 (m, 6H), 7.44-7.48
(m, 2H), 7.35-7.39 (m, 1H), 6.75-6.78 (m, 2H), 3.77 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
165.6, 141.1, 140.7, 137.0, 131.0, 129.3, 129.0, 127.6, 127.2, 127.0, 118.0, 112.5, 112.1, 51.2.
HRMS (ESI-TOF): m/z calcd for C18H16NO2 [M +H]+ 278.1181, found: 278.1173.
Methyl 2-(naphthalen-2-yl)-1H-pyrrole-3-carboxylate (2o).4d Light yellow solid (89 mg, 71%
yield), mp 173-175 oC. 1H NMR (400 MHz, CDCl3): δ 8.45 (b, 1H), 7.88-7.92 (m, 2H), 7.65-7.67
(m, 1H), 7.46-7.54 (m, 3H), 7.40-7.44 (m, 1H), 6.83-6.85 (m, 2H), 3.53 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 165.2, 135.3, 133.6, 132.7, 130.5, 129.2, 128.4, 128.4, 126.5, 126.1, 125.8,
125.1, 117.9, 114.5, 111.4, 51.0. HRMS (ESI-TOF): m/z calcd for C16H14NO2 [M + H]+ 252.1019,
found: 252.1023.
Methyl 2-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (2p). Light yellow solid (82 mg, 79% yield),
mp 73-74 oC. 1H NMR (400 MHz, CDCl3): δ 8.50 (b, 1H), 7.52-7.53 (m, 1H), 7.34-7.35 (m, 1H),
7.07-7.10 (m, 1H), 6.72-6.75 (m, 2H), 3.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.2,
133.2, 130.5, 127.4, 127.4, 126.1, 118.0, 112.6, 112.4, 51.2. HRMS (ESI-TOF): m/z calcd for
C10H9NNaO2S [M + Na]+ 230.0246, found: 230.0248.
Ethyl 2-phenyl-1H-pyrrole-3-carboxylate (2q).4d Light yellow solid (80 mg, 74% yield), mp 62-
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63 C. H NMR (400 MHz, CDCl3): δ 8.39 (b, 1H), 7.58-7.60 (m, 2H), 7.36-7.43 (m, 3H), 6.75-
6.78 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
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δ 165.0, 137.2, 132.3, 129.1, 128.4, 128.3, 117.7, 112.4, 59.8, 14.4. HRMS (ESI-TOF): m/z calcd
for C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0832.
2-Phenyl-1H-pyrrole-3-carbonitrile (2r).5a Light yellow solid (36 mg, 47% yield), mp 159-160 oC.
1H NMR (400 MHz, CDCl3): δ 8.74 (b, 1H), 7.68-7.71 (m, 2H), 7.45-7.49 (m, 2H), 7.37-7.40 (m,
1H), 6.82-6.84 (m, 1H), 6.56-6.57 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.1, 129.9,
129.4, 129.9, 125.9, 119.2, 117.6, 114.0, 90.5. HRMS (ESI-TOF): m/z calcd for C11H8N2Na [M +
Na]+ 191.0580, found: 191.0576.
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Phenyl(2-phenyl-1H-pyrrol-3-yl)methanone (2s).4d Light yellow solid (56 mg, 45% yield), mp
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124-125 C. H NMR (400 MHz, CDCl3): δ 8.87 (b, 1H), 7.76-7.78 (m, 2H), 7.40-7.43 (m, 3H),
7.29-7.33 (m, 2H), 7.23-7.27 (m, 3H), 6.76-6.77 (m, 1H), 6.58-6.59 (m, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 192.8, 139.7, 137.3, 132.2, 131.1, 129.8, 128.6, 128.5, 128.1, 128.0, 120.5, 117.9,
113.8. HRMS (ESI-TOF): m/z calcd for C17H13NNaO [M + Na]+ 270.0889, found: 270.0885.
Methyl 5-methyl-2-phenyl-1H-pyrrole-3-carboxylate (4a). Light yellow solid (58 mg, 54% yield),
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mp 100-101 C. H NMR (400 MHz, CDCl3): δ 8.24 (b, 1H), 7.55-7.57 (m, 2H), 7.32-7.38 (m,
3H), 6.36-6.38 (m, 1H), 3.71 (s, 3H), 2.25 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.4,
136.1, 132.2, 128.8, 128.7, 128.1, 127.9, 111.7, 109.5, 50.8, 12.7. HRMS (ESI-TOF): m/z calcd
for C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0841.
Methyl 5-ethyl-2-phenyl-1H-pyrrole-3-carboxylate (4b).5b Light yellow solid (84 mg, 73% yield),
mp 84-87 oC. 1H NMR (400 MHz, CDCl3): δ 8.20 (b, 1H), 7.56-7.59 (m, 2H), 7.33-7.41 (m, 3H),
6.41-6.42 (m, 1H), 3.72 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 165.6, 136.1, 134.3, 132.4, 128.9, 128.3, 128.1, 111.7, 108.0, 51.0, 20.7,
13.3. HRMS (ESI-TOF): m/z calcd for C14H15NNaO2 [M + Na]+ 252.0995, found: 252.0990.
Methyl 5-isopropyl-2-phenyl-1H-pyrrole-3-carboxylate (4c). Light yellow oil (81 mg, 67% yield).
1H NMR (400 MHz, CDCl3): δ 8.13 (b, 1H), 7.58-7.60 (m, 2H), 7.34-7.42 (m, 3H), 6.42-6.43 (m,
1H), 3.74 (s, 3H), 2.88-2.95 (m, 1H), 1.29 (d, J = 6.89 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):
δ 165.6, 139.0, 136.0, 132.4, 128.9, 128.3, 128.2, 111.6, 106.9, 51.0, 27.0, 22.5. HRMS (ESI-
TOF): m/z calcd for C15H17NNaO2 [M + Na]+ 266.1151, found: 266.1146.
Methyl 5-isobutyl-2-phenyl-1H-pyrrole-3-carboxylate (4d). Light yellow oil (105 mg, 82% yield).
1H NMR (400 MHz, CDCl3): δ 8.54 (b, 1H), 7.53-7.56 (m, 2H), 7.28-7.37 (m, 3H), 6.39-6.40 (m,
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1H), 3.69 (s, 3H), 2.42-2.44 (m, 2H), 1.84-1.91 (m, 1H), 0.95 (d, J = 6.60 Hz, 6H). 13C{1H} NMR
(100 MHz, CDCl3): δ 165.8, 136.0, 132.3, 132.0, 128.8, 128.1, 127.9, 111.4, 109.6, 50.9, 36.7,
28.9, 22.4. HRMS (ESI-TOF): m/z calcd for C16H19NNaO2 [M + Na]+ 280.1308, found: 280.1303.
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NMR (400 MHz, CDCl3): δ 8.56 (b, 1H), 7.63-7.65 (m, 2H), 7.49-7.51 (m, 2H), 7.37-7.43(m, 5H),
7.24-7.26 (m, 1H), 6.99-7.00 (m, 1H), 3.76 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.1,
137.8, 131.8, 131.7, 131.4, 129.0, 128.9, 128.5, 128.3, 127.1, 124.0, 113.4, 109.1, 51.0. HRMS
(ESI-TOF): m/z calcd for C18H16NO2[M + H]+ 278.1183, found: 278.1176.
Methyl 4-methyl-2-phenyl-1H-pyrrole-3-carboxylate (4f). Light yellow solid (77 mg, 72% yield),
mp 94-95 oC. 1H NMR (400 MHz, CDCl3): δ 8.11 (b, 1H), 7.46-7.49 (m, 2H), 7.33-7.41 (m, 3H),
6.57 (d, J = 1.1 Hz, 1H), 3.69 (s, 3H), 2.29-2.30 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
166.1, 137.6, 133.0, 128.8, 128.1, 128.0, 122.7, 116.6, 50.5, 12.5. HRMS (ESI-TOF): m/z calcd
for C13H13NNaO2 [M + Na]+ 238.0838, found: 238.0840.
Methyl 2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate (4g). Light yellow solid
(20 mg, 17% yield), mp 50-52 oC. 1H NMR (400 MHz, CDCl3): δ 8.10 (b, 1H), 7.54-7.58 (m, 2H),
7.36-7.40 (m, 2H), 7.30-7.34 (m, 1H), 3.71 (s, 3H), 2.81-2.85 (m, 2H), 2.70-2.74 (m, 2H), 2.41-
2.47 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.8, 139.8, 136.1, 132.8, 130.4, 128.7, 128.1,
127.8, 107.8, 50.7, 28.6, 26.7, 25.4. HRMS (ESI-TOF): m/z calcd for C15H16NO2 [M + H]+
242.1175, found: 242.1181.
4-methyl-2-phenyl-1H-pyrrole-3-carbonitrile (4h).5d Brown solid (45 mg, 49% yield), mp 143-
145 oC. 1H NMR (400 MHz, CDCl3): δ 8.49 (b, 1H), 7.64-7.67 (m, 2H), 7.41-7.45 (m, 2H), 7.32-
7.36 (m, 1H), 6.59-6.59 (m, 1H), 2.22 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.4, 130.0,
129.2, 128.5, 125.4, 124.3, 117.2, 116.6, 91.8, 10.6. HRMS (ESI-TOF): m/z calcd for C12H11N2
[M + H]+ 183.0922, found: 183.0926.
(5-methyl-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone(4i).5e White solid (52 mg, 40%), mp 128-
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129 C. H NMR (400 MHz, CDCl3): δ 8.39 (b,1H), 7.72-7.75 (m, 2H), 7.36-7.38 (m, 3H), 7.19-
7.29 (m, 5H), 6.24-6.25 (m, 1H), 2.28 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 192.4, 139.7,
136.1, 132.2, 131.4, 129.6, 128.3, 128.2, 127.7, 127.6, 120.6, 111.2, 12.7. HRMS (ESI-TOF): m/z
calcd for C18H16NO [M + H]+ 262.1232, found: 262.1239.
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General Procedure for the Synthesis of 6. A sealed tube was charged with enamine 5 (0.5
mmol), THF (2 mL), and then IBX (0.8 mmol) was added. The reaction mixture was stirred at
120 °C in an oil bath for 12 h. Then the mixture was cooled to room temperature and 20 mL water
was added to the mixture, which was extracted with ethyl acetate (3 × 10 mL). The organic layer
was combined and dried with anhydrous Na2SO4. After removal of the solvent under reduced
pressure, the residue was separated by flash column chromatography to afford the pure product 6
(PE : EA = 10 : 1).
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Methyl 2-phenylnicotinate (6a).6c Yellow oil (87 mg, 82% yield). 1H NMR (400 MHz, CDCl3): δ
8.77-8.79 (m, 1H), 8.08-8.10 (m, 1H), 7.53-7.55 (m, 2H), 7.42-7.43 (m, 3H), 7.31-7.34 (m, 1H),
3.68 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.6, 158.9, 151.3, 140.0, 138.0, 128.8, 128.6,
128.2, 127.1, 121.7, 52.4. HRMS (ESI-TOF): m/z calcd for C13H12NO2 [M + H]+ 214.0868, found:
214.0871.
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Methyl 2-(p-tolyl)nicotinate (6b).6c Yellow oil (79 mg, 70% yield). H NMR (400 MHz, CDCl3):
δ 8.73 (dd, J = 4.8, 1.8 Hz, 1H), 8.05 (dd, J = 7.8, 1.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.27-7.30
(m, 1H), 7.20-7.24 (m, 2H), 3.70 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.7,
158.7, 151.2, 138.7, 137.7, 137.1, 128.9, 128.4, 126.8, 121.2, 52.3, 21.3. HRMS (ESI-TOF): m/z
calcd for C14H14NO2 [M + H]+ 228.1025, found: 228.1029.
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Methyl 2-(3,4-dimethylphenyl)nicotinate (6c). Yellow oil (78 mg, 65% yield). H NMR (400
MHz, CDCl3): δ 8.74 (dd, J = 4.8, 1.8 Hz, 1H), 8.03 (dd, J = 7.8, 1.8 Hz, 1H), 7.36-7.38 (m, 1H),
7.26-7.29 (m, 1H), 7.20-7.22 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 3.70 (s, 3H), 2.30 (s, 3H), 2.29 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.9, 158.7, 151.1, 137.7, 137.4, 136.5, 129.6, 129.4,
126.9, 126.0, 121.1, 52.3, 19.8, 19.6. HRMS (ESI-TOF): m/z calcd for C15H16NO2 [M + H]+
242.1181, found: 242.1181.
Methyl 2-(4-methoxyphenyl)nicotinate (6d).6c Yellow oil (85mg, 70% yield). 1H NMR (400 MHz,
CDCl3): δ 8.72 (dd, J = 4.8, 1.8 Hz, 1H), 8.03 (dd, J = 7.8, 1.8 Hz, 1H), 7.43-7.54 (m, 2H), 7.25-
7.28 (m, 1H), 6.92-6.98 (m, 2H), 3.84 (s, 3H), 3.71 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
168.9, 160.2, 158.2, 151.2, 137.8, 132.3, 129.9, 126.6, 121.0, 113.7, 55.3, 52.3. HRMS (ESI-TOF):
m/z calcd for C14H14NO3 [M + H]+ 244.0974, found: 244.0976.
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Eethyl 2-(3,4-dimethoxyphenyl)nicotinate (6e). Yellow oil (98 mg, 72% yield). H NMR (400
MHz, CDCl3): δ 8.73 (dd, J = 4.8, 1.8 Hz, 1H), 8.01 (dd, J = 7.8, 1.8 Hz, 1H), 7.26-7.29 (m, 1H),
7.18 (d, J = 2.1 Hz, 1H), 7.05-7.07 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H),
3.71 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.0, 158.0, 151.0, 149.8, 148.9, 137.7, 132.5,
127.0, 121.4, 121.1, 111.7, 110.7, 55.9, 55.8, 52.4. HRMS (ESI-TOF): m/z calcd for
C15H16NO4[M + H]+ 274.1075, found: 274.1073.
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Methyl 2-(4-chlorophenyl)nicotinate (6f).6c Yellow oil (109 mg, 88% yield). 1H NMR (400 MHz,
CDCl3): δ 8.75-8.76 (m, 1H), 8.09-8.12 (m, 1H), 7.45-7.48 (m, 2H), 7.38-7.41 (m, 2H), 7.32-
7.35(m, 1H), 3.71 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 157.7, 151.4, 138.4, 138.1,
134.9, 129.9, 128.4, 126.7, 121.8, 52.4. HRMS (ESI-TOF): m/z calcd for C13H11ClNO2 [M + H]+
248.0478, found: 248.0471.
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Methyl 2-([1,1'-biphenyl]-4-yl)nicotinate (6g). Yellow oil (118 mg, 82% yield). H NMR (400
MHz, CDCl3): δ 8.78 (dd, J = 4.8, 1.8 Hz, 1H), 8.10 (dd, J = 7.8, 1.8 Hz, 1H), 7.58-7.70 (m, 6H),
7.40-7.48 (m, 2H), 7.28-7.38 (m, 2H), 3.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.7,
158.4, 151.3, 141.5, 140.6, 138.8, 137.9, 129.0, 128.8, 127.5, 127.1, 126.9, 121.5, 52.4. HRMS
(ESI-TOF): m/z calcd for C19H16NO2 [M + H]+ 290.1181, found: 290.1173.
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Methyl 2-(thiophen-2-yl)nicotinate (6h). Yellow oil (58 mg, 53% yield). H NMR (400 MHz,
CDCl3): δ 8.66 (dd, J = 4.8, 1.7 Hz, 1H), 7.79-7.92 (m, 1H), 7.43 (dd, J = 5.1, 1.1 Hz, 1H), 7.33
(dd, J = 3.8, 1.1 Hz, 1H), 7.20-7.23 (m, 1H), 7.02-7.10 (m, 1H), 3.86 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 168.8, 150.9, 150.6, 137.3, 128.5, 127.7, 127.6, 125.8, 121.1, 52.7. HRMS (ESI-
TOF): m/z calcd for C11H10NO2S [M + H]+ 220.0432, found: 220.0431.
Ethyl 2-phenylnicotinate (6i).15a Yellow oil (76 mg, 67% yield). H NMR (400 MHz, CDCl3): δ
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8.75 (dd, J = 4.8, 1.8 Hz, 1H), 8.09 (dd, J = 7.8, 1.8 Hz, 1H), 7.47-7.57 (m, 2H), 7.37-7.43 (m,
3H), 7.30-7.34 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 168.1, 158.9, 151.1, 140.2, 137.8, 128.6, 128.5, 128.1, 127.4, 121.5, 61.5, 13.6.
HRMS (ESI-TOF): m/z calcd for C14H14NO2 [M + H]+ 228.1025, found: 228.1029.
2-Phenylnicotinonitrile (6j).6d Brown oil (48 mg, 53% yield). H NMR (400 MHz, CDCl3): δ
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8.86-8.87 (m, 1H), 8.05-8.08 (m, 1H), 7.90-7.93 (m, 2H), 7.50-7.54 (m, 3H), 7.35-7.38 (m, 1H).
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13C{1H} NMR (100 MHz, CDCl3): δ 161.0,152.6, 141.8, 137.1, 130.2, 128.8, 128.7, 121.5, 117.6,
107.5. HRMS (ESI-TOF): m/z calcd for C12H9N2 [M + H]+ 181.0766, found: 181.0773.
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Phenyl(2-phenylpyridin-3-yl)methanone (6k). Yellow oil (100 mg, 77% yield). H NMR (400
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MHz, CDCl3): δ 8.84 (dd, J = 4.8, 1.8 Hz, 1H), 7.84 (dd, J = 7.7, 1.8 Hz, 1H), 7.58-7.67 (m, 2H),
7.47-7.52 (m, 2H), 7.34-7.45 (m, 2H), 7.25-7.30 (m, 2H), 7.18-7.23 (m, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 197.2, 157.4, 150.7, 139.1, 137.1, 136.6, 134.4, 133.3, 129.8, 128.2, 128.8, 128.3,
128.2, 121.5. HRMS (ESI-TOF): m/z calcd for C18H14NO [M + H]+ 260.1075,found: 260.1070.
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Methyl 2,6-diphenylnicotinate (6l). Light yellow solid (97 mg, 67% yield), mp 103-104 C. 1H
NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.2 Hz, 1H), 8.07-8.14 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H),
7.60-7.66 (m, 2H), 7.38-7.50 (m, 6H), 3.70 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 158.5,
138.9, 138.2, 129.7, 128.8, 128.7, 128.6, 128.0, 127.3, 124.9, 117.8, 52.2. HRMS (ESI-TOF): m/z
calcd for C19H16NO2 [M + H]+ 290.1181,found: 290.1175.
Methyl 6-methyl-2-phenylnicotinate (6m). Yellow oil (74 mg, 65% yield). 1H NMR (400 MHz,
CDCl3): δ 7.99 (d, J = 7.9 Hz, 1H), 7.46-7.51 (m, 2H), 7.34- 7.43 (m, 3H), 7.16-7.18 (m, 1H), 3.65
(s, 3H), 2.63 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.5, 160.9, 158.7, 140.4, 138.2, 128.5,
128.4, 128.1, 123.9, 121.1, 52.1, 24.8. HRMS (ESI-TOF): m/z calcd for C14H14NO2 [M + H]+
228.1025, found: 228.1023.
(Z)-Methyl-3-((5-oxocyclopent-1-en-1-yl)amino)-3-phenylacrylate (4g′). Yellow solid (14 mg, 11%
yield), mp 94-96 oC.. 1H NMR (400 MHz, CDCl3): δ 10.08 (b, 1H), 7.36-7.43 (m, 3H), 7.31-7.34
(m, 2H), 5.24 (t, J = 3.0 Hz, 1H), 4.96 (s, 1H), 3.72 (s, 3H), 2.32-2.35 (m, 2H), 2.28-2.31 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 203.3, 169.3, 157.4, 139.6, 135.6, 133.0, 129.8, 128.6, 127.8,
93.5, 50.9, 32.2, 24.1. HRMS (ESI-TOF): m/z calcd for C15H16NO3 [M + H]+ 258.1130, found:
258.1128.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Detail preparation procedure and characterization data of substrates (PDF)
Copies of NMR spectra (PDF)
X-ray crystallographic structure of 2a (CIF)
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X-ray crystallographic structure of 4k (CIF)
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AUTHOR INFORMATION
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Corresponding Author
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*E-mail: gaopeng_hx@bjwlxy.edu.cn; 313967158@qq.com; guanzhh@nwu.edu.cn
Notes
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The authors declare no competing financial interest
ACKNOWLEDGEMENT
Financial support from National Science Foundation of China (No. 21622203), China Postdoctoral
Science Foundation (No. 2019T120936), Natural Science Foundation of Shaanxi Province (No.
2019JQ-274), Shaanxi Provincial Key Laboratory Project (NO. 19JS004), Undergraduate Training
Programs for Innovation and Entrepreneurship Shaanxi Province (No. 201827035), and Baoji
University of Arts and Science (No. 2018XJ032) are greatly appreciated.
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