Iodine/Copper Iodide-Mediated C-H Functionalization: Synthesis of Imidazo[1,2-a]pyridines and Indoles from N-Aryl Enamines

Article abstract of DOI:10.1021/acs.joc.6b01960

A practical intramolecular C-H functionalization reaction of N-aryl enamines has been carried out with molecular iodine (I₂) as the sole oxidant in the presence of copper iodide (CuI). The efficient and versatile synthetic method described here

Full text of DOI:10.1021/acs.joc.6b01960

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Article
Iodine/Copper Iodide-Mediated C#H Functionalization: Synthesis
of Imidazo[1,2-a]pyridines and Indoles from N-Aryl Enamines
Jing Liu, Wei Wei, Ting Zhao, Xuanyu Liu, Jie Wu, Wenquan Yu, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01960 • Publication Date (Web): 12 Sep 2016
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Iodine/Copper IodideꢀMediated C‒H Functionalization: Synthesis
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of Imidazo[1,2ꢀa]pyridines and Indoles from NꢀAryl Enamines
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Jing Liu, Wei Wei, Ting Zhao, Xuanyu Liu, Jie Wu, Wenquan Yu,* and Junbiao
Chang*
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College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,
Henan Province 450001, China
ABSTRACT: A practical intramolecular C‒H functionalization reaction of Nꢀaryl
enamines has been carried out with molecular iodine (I2) as the sole oxidant in the
presence of copper iodide (CuI). The efficient and versatile synthetic method
described here is compatible with both Nꢀheteroaryl and Nꢀaryl substituted enamines
and produces diverse imidazo[1,2ꢀa]pyridine and indole derivatives via I2ꢀmediated
oxidative C‒N and C‒C bond formation, respectively. This ligandꢀfree C‒H
functionalization methodology also works well with crude enamines, which allows for
the sequential synthesis of the products directly from arylamines and ketones (or
alkynes) without purification of the enamine intermediates.
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■ INTRODUCTION
Indole1 and imidazo[1,2ꢀa]pyridine2 structures are widely distributed in a broad
variety of natural products and synthetic molecules with diverse pharmaceutical
properties and considerable efforts have been made to synthesize these 5,6ꢀfused
bicyclic frameworks.1aꢀc, 2aꢀd In addition to Fischer indole synthesis, one of most
straightforward strategies is oxidative cyclization of Nꢀaryl enamines which are
readily accessible via direct C‒H functionalization3 (Scheme 1). Such transformations
have been previously accomplished using oxidants such as Cu(OAc)2,3a hypervalent
iodine(III) reagents,3b and NBS,3c or by Pd(II) or Cu(I) catalyzed aerobic oxidation.3dꢀf
These are elegant methods, but it remains important to develop simpler and more
efficient approaches, especially those that could lead to both these heterocyclic
skeletons.
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The C−H functionalization reaction has emerged as a valuable tool for the
transformation of unreactive C‒H bonds in an atomꢀ and stepꢀeconomic fashion.4 The
benefits of this synthetic strategy include no preliminary activation of the reaction
centers, facilitative preparation of the required substrates, and formation of fewer
wasteful byꢀproducts. In recent years, impressive achievements have been made in
heterocycle synthesis by such convenient methods from simple and readily available
c
precursors.4a,
These crossꢀdehydrogenative coupling reactions have been
successfully achieved via metalꢀcatalyzed aerobic oxidation,4a iodine(III)ꢀmediated
oxidative cyclization,4b or radical pathways.4c Alternatively, we developed several
C−H functionalization reactions using molecular iodine (I2) as the sole oxidant to
synthesize 1,3,4ꢀoxadiazoles,5 pyrazoles,6 and quinazolinꢀ4(3H)ꢀones.7 As a
continuation of this research, we describe in this paper a versatile and efficient
method for the synthesis of imidazo[1,2ꢀa]pyridines and indoles8 by I2/CuIꢀmediated
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oxidative C‒N and C‒C bond formation, respectively, from C‒H bond.
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Scheme 1. Two Important Strategies to Construct Indole and Imidazo[1,2ꢀa]pyridine
Skeletons: Fischer Indole Synthesis and Direct C−H Functionalization of NꢀAryl
Enamines
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■ RESULTS AND DISCUSSION
We began this study by investigating the oxidative cyclization of the enamine 1c,
obtained through the pꢀTsOHꢀcatalyzed condensation of 5ꢀmethylpyridinꢀ2ꢀamine and
1,3ꢀcyclohexanedione (see the Supporting Information). Treatment of 1c with
molecular iodine under basic conditions gave only the vinyl iodide (2c') in 60% yield
(Scheme 2). The CuIꢀcatalyzed coupling cyclization of 2c' afforded the
imidazo[1,2ꢀa]pyridine (2c) in excellent yield. These two steps were carried out in the
same solvent, so we examined the feasibility of the direct conversion of substrate 1c
to the desired product (2c) in a oneꢀpot reaction. Indeed, I2/CuIꢀmediated oxidative
C‒H functionalization of 1c in the presence of Cs2CO3 in 1,4ꢀdioxane at reflux
temperature resulted in 2c in a higher overall yield (88%). Further optimization
indicated that toluene is the most effective solvent for this transformation.
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Scheme 2. Synthesis of Fused Imidazo[1,2ꢀa]pyridine 2c from Enamine 1ca
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aOptimal reaction conditions: 1c (0.5 mmol), CuI (0.1 mmol), I2 (0.6 mmol), Cs2CO3 (1.5 mmol),
toluene, reflux (Isolated yields are given).
A range of Nꢀpyridylcyclohexenamines (1) (Scheme 3) were subjected to the optimal
reaction conditions above, to examine the scope and generality of this method. All the
substrates bearing methyl groups and halogens at the different positions of the pyridyl
moiety were smoothly cyclized to the corresponding fused imidazo[1,2ꢀa]pyridines
(2a−h) in moderate to excellent yields. In addition, both Nꢀpyrazyl and
cyclopentenamino substrates were also transformed into the desired products (2i−j).
Scheme 3. Substrate Scope for Synthesis of Fused Imidazo[1,2ꢀa]pyridines 2a
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aOptimal reaction conditions: 1 (0.5 mmol), CuI (0.1 mmol), I2 (0.6 mmol), Cs2CO3 (1.5 mmol),
toluene, reflux (Isolated yields are given).
NꢀPyridylenaminone substrates (3) were easily prepared by conjugated addition of
2ꢀaminopyridines to α,βꢀynones (see the Supporting Information). Under the optimum
C‒H functionalization conditions, all these enamine substrates were converted into
the expected products in excellent yield (Scheme 4). This methodology can tolerate
both electronꢀdonating groups (EDGs) (4b‒e) and electronꢀwithdrawing groups
(EWGs) (4f‒h) on the pyridine ring. Pyrazidoimidazoles (4i) and pyrimidoimidazoles
(4j) were also produced by this synthetic process. Substituents on the phenyl ring at
the R4 position (4k‒o) and replacement of this phenyl with βꢀnaphthyl or 2ꢀthienyl
groups (4p‒q) did not affect the conversion. The yields were slightly reduced due to
the presence of substituents at the R3 position of the phenyl ring (4r‒t). To simplify
the synthetic procedure operationally, we probed the feasibility of direct synthesis
from 2ꢀaminopyridines and ynones, omitting purification of the enamine
intermediates. Taking the preparation of 4c and 4r as examples, after the firstꢀstep
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addition was complete, the reaction mixture was filtered and concentrated, and the
resulting crude enamines were subjected directly to the I2/CuIꢀmediated oxidative
cyclization conditions. The desired products were produced in yields (Scheme 5) that
were equally good to those obtained in the reactions via purified enanimes. The
2ꢀmethylꢀ3ꢀacetyl derivative (4u) was successfully prepared directly from 5ꢀmethyl
pyridinꢀ2ꢀamine and acetylacetone, without isolation of the unstable condensation
intermediate (Scheme 6).
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Scheme 4. Substrate Scope for Synthesis of Imidazo[1,2ꢀa]pyridines 4a
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aOptimal reaction conditions: 3 (0.5 mmol), CuI (0.1 mmol), I2 (0.6 mmol), Cs2CO3 (1.5 mmol),
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toluene, reflux (Isolated yields are given).
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Scheme 5. Sequential Synthesis of Imidazo[1,2ꢀa]pyridines 4c and 4r from
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2ꢀAminopyridines and Ynones
Scheme 6. Sequential Synthesis of Imidazo[1,2ꢀa]pyridine 4u from Acetylacetone
In the light of these encouraging results, we further extended the substrate scope of
this C–H functionalization reaction using Nꢀphenylenamines (5) for indole synthesis
(Scheme 7). Further optimization of the reaction conditions showed 1,4ꢀdioxane to be
the optimal solvent for the transformation of 5 to the indoles (6). The reaction is
compatible with both EDGs (6b‒c, 6g) and EWGs (6d‒f) on the phenyl ring, and
either aryl (6h‒i, 6k) or alkyl substituents (6j, 6l) at the R2 and R3 positions. In
particular, oxidative cyclization of the enamine 5l produced the 2ꢀcyclopropyl
substituted indole (6l) in excellent yield and the reaction conditions had no effect on
the sensitive cyclopropane ring. The structure of 6l was confirmed by Xꢀray
crystallography9 (see the Supporting Information). In addition, a 2,3ꢀdimethyl ester
derivative (6m) was also obtained by addition of aniline to dimethyl 2ꢀbutynedioate,
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followed by I2/CuIꢀmediated oxidative C–C bond formation.
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Scheme 7. Substrate Scope for Synthesis of Indoles 6a
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O
R4
R3
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R1
I2, CuI, Cs2CO3
NH
O
R1
1,4-dioxane, reflux
69-95%
R3
O
R4
N
H
5
6
O
O
Ph
Ph
Ph
Ph
Me
MeO
Ph
Ph
N
N
H
N
H
H
6a, 93%
6b, 95%
6c, 95%
O
O
O
Ph
Ph
Ph
Ph
Cl
Br
O2N
Ph
Ph
N
H
N
H
N
H
6f, 81%
6d, 91%
6e, 93%
S
O
O
O
Me
Ph
Me
Me
Ph
Ph
Ph
N
N
N
H
Me
6h, 88%
6i, 69%
H
H
O
6g
,
95%
O
Ph
Me
Me
Cl
Ph
N
N
H
6j
, 72%
H
6k, 91%
O
Ph
CO2Me
Me
Me
CO2Me
N
N
H
H
6l, 95%
6m, 95%
aOptimal reaction conditions: 5 (0.5 mmol), CuI (0.1 mmol), I2 (0.6 mmol), Cs2CO3 (1.5 mmol),
1,4ꢀdioxane, reflux (Isolated yields are given).
Based on the experimental results, a plausible mechanism for this I2/CuIꢀmediated
C–H functionalization reaction is proposed (Scheme 8). Using the formation of
imidazo[1,2ꢀa]pyridine 2c as an example, the reaction of enamine 1c with molecular
iodine under basic conditions produces the βꢀiodo enamide 2c'. Then oxidative
addition of Cu(I) to the iodide 2c' followed by a baseꢀpromoted cyclization results in
intermediate B. Finally, the subsequent reductive elimination affords the
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imidazo[1,2ꢀa]pyridine framework 2c and restores the copper(I) catalyst.
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Scheme 8. Proposed Mechanism for the Formation of Imidazo[1,2ꢀa]pyridine 2c
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■ CONCLUSIONS
A practical and efficient I2/CuIꢀmediated direct C‒H functionalization reaction has
been established. The versatile synthetic method described here is compatible with
both Nꢀheteroaryl and Nꢀaryl substituted enamines and produces diverse
imidazo[1,2ꢀa]pyridine and indole derivatives. Under the optimum reaction conditions,
imidazo[1,2ꢀa]pyridines and indoles were obtained in good yield from the
corresponding precursors by I2ꢀmediated oxidative C‒N and C‒C bond formation,
respectively. This ligandꢀfree C‒H functionalization reaction works well with crude
enamines, and this allows for the sequential synthesis of the expected products
directly from arylamines and ketones (or alkynes) without purification of the enamine
intermediates.
■ EXPERIMENTAL SECTIONS
General Information. H and 13C NMR spectra were recorded on a 400 MHz (100
1
MHz for 13C NMR) spectrometer. Chemical shift values are given in parts per million
(ppm) with tetramethylsilane (TMS) as the internal standard. The peak patterns are
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indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext,
sextet; hept, heptet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets. The
coupling constants (J) are reported in Hertz (Hz). Melting points were determined on
a micromelting point apparatus and are uncorrected. Highꢀresolution mass spectra
(HRMS) were obtained on a TOFꢀQ mass spectrometer equipped with an electrospray
ion source (ESI), operated in the positive mode. Flash column chromatography was
performed over silica gel 200‒300 mesh and the eluents were distilled prior to use.
Toluene, used in the synthesis of 1, 2, and 4, was analytical reagent grade and used
without any pretreatment; 1,4ꢀdioxane, in the synthesis of 2c' and 6, was dried over 4
Å molecular sieves prior to use; THF, in the preparation of 3, was distilled from
sodium/benzophenone ketyl under nitrogen, and MeOH, in the preparation of 5, were
dried over 4 Å molecular sieves prior to use.
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General Procedure A for the Preparation of Enamines 1. To a solution of
substituted 2ꢀaminopyridine (5 mmol, 2ꢀaminopyrazine for 1i) in toluene (20 mL) at
room
temperature
was
added
1,3ꢀcyclohexanedione
(6.25
mmol,
1,3ꢀcyclopentanedione for 1j) and pꢀtoluenesulfonic acid monohydrate (190 mg, 1
mmol) in sequence. The reaction was heated to reflux under a nitrogen atmosphere
until the consumption of the 2ꢀaminopyrimidine as monitored by TLC was complete.
After cooling to room temperature, the reaction mixture was treated with cold 5%
NaHCO3 (20 mL), and extracted with CH2Cl2 (20 mL × 5). The combined organic
layer was dried over anhydrous Na2SO4, concentrated, and then purified through silica
gel column chromatography, giving the enamine (1) in 26‒90% yield.
3ꢀ(Pyridinꢀ2ꢀylamino)cyclohexꢀ2ꢀenone (1a).10 4 h; eluent: EtOAc/petroleum ether
1
(PE) 67:33; yield: 292 mg, 31%; brown solid, mp 176ꢀ177 ºC; H NMR (400 MHz,
CDCl3): δ 8.30 (d, J = 4.8 Hz, 1H), 7.65ꢀ7.58 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H),
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6.98ꢀ6.95 (m, 1H), 6.39 (s, 1H), 2.59 (t, J = 6.0 Hz, 2H), 2.41 (t, J = 6.0 Hz, 2H),
2.09ꢀ2.03 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.4, 158.7, 152.7, 148.4, 138.0,
118.6, 114.1, 104.1, 36.6, 30.0, 21.7; HRMS (m/z) [M + Na]+ calcd for C11H12N2NaO
211.0842, found 211.0847.
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3ꢀ((6ꢀMethylpyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1b). 4 h; eluent: EtOAc/PE
1
67:33; yield: 627 mg, 62%; pale yellow solid, mp 180ꢀ181 ºC; H NMR (400 MHz,
CDCl3): δ 7.51 (t, J = 7.6 Hz, 1H), 7.27 (br, s, 1H, overlapped with the peak of
chloroform), 6.90 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.38 (s, 1H), 2.56 (t, J
= 6.0 Hz, 2H), 2.46 (s, 3H), 2.40 (t, J = 6.0 Hz, 2H), 2.08ꢀ2.02 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 199.3, 158.7, 157.7, 151.9, 138.2, 118.1, 111.0, 103.9, 36.6,
30.2, 24.2, 21.8; HRMS (m/z) [M + Na]+ calcd for C12H14N2NaO 225.0998, found
225.0997.
3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1c).10 4 h; eluent: EtOAc/PE
1
67:33; yield: 678 mg, 67%; offꢀwhite solid, mp 162ꢀ164 ºC; H NMR (400 MHz,
CDCl3): δ 8.13 (s, 1H), 7.51ꢀ7.44 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 2.56
(t, J = 6.4 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H), 2.08ꢀ2.02 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 199.3, 159.4, 150.5, 148.1, 138.7, 128.2, 114.2, 103.1, 36.6,
29.8, 21.8, 17.8; HRMS (m/z) [M + Na]+ calcd for C12H14N2ONa 225.0998, found
225.0998.
3ꢀ((4ꢀMethylpyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1d). 4 h; eluent: EtOAc/PE
1
67:33; yield: 617 mg, 61%; pale yellow solid, mp 188ꢀ190 ºC; H NMR (400 MHz,
CDCl3): δ 8.14 (d, J = 5.2 Hz, 1H), 7.71 (br, s, 1H), 6.98 (s, 1H), 6.80 (d, J = 5.2 Hz,
1H), 6.28 (s,1H), 2.57 (t, J = 6.4 Hz, 2H), 2.40 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H),
2.08ꢀ2.02 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.3, 158.9, 152.7, 149.7, 147.9,
120.1, 114.8, 103.6, 36.6, 30.1, 21.7, 21.2; HRMS (m/z) [M + Na]+ calcd for
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C12H14N2NaO 225.0998, found 225.0996.
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3ꢀ((3ꢀMethylpyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1e). 4 h; eluent: EtOAc/PE
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8
1
67:33; yield: 496 mg, 49%; yellow solid, mp 100ꢀ102 ºC; H NMR (400 MHz,
9
CDCl3): δ 8.22ꢀ8.21 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.98ꢀ6.94 (m, 1H), 6.80 (br, s,
1H), 6.34ꢀ6.30 (m, 1H), 2.60 (t, J = 6.0 Hz, 2H), 2.37 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H),
2.10ꢀ2.02 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.2, 159.2, 151.2, 145.9, 139.1,
123.5, 119.6, 104.8, 36.6, 29.8, 21.9, 17.3; HRMS (m/z) [M + Na]+ calcd for
C12H14N2NaO 225.0998, found 225.0997.
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3ꢀ((5ꢀChloropyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1f). 4 h; eluent: EtOAc/PE
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67:33; yield: 991 mg, 89%; white solid, mp 173ꢀ175 ºC; H NMR (400 MHz,
CD3OD): δ 8.28 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.93 (s,
1H), 2.64 (t, J = 5.6 Hz, 2H), 2.37 (t, J = 6.0 Hz, 2H), 2.06ꢀ2.03 (m, 2H); 13C NMR
(100 MHz, CD3OD): δ 201.7, 161.2, 152.4, 145.7, 137.4, 125.1, 114.9, 104.2, 35.7,
28.8, 21.6; HRMS (m/z) [M + Na]+ calcd for C11H11ClN2NaO 245.0452, found
245.0446.
3ꢀ((5ꢀBromopyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1g). 14 h; eluent: EtOAc/PE
1
67:33; yield: 868 mg, 65%; yellow solid, mp 191ꢀ193 ºC; H NMR (400 MHz,
CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.8, 2.8 Hz, 1H), 7.48 (br, s, 1H),
6.97 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 2.58 (t, J = 6.0 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H),
2.09ꢀ2.03 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.5, 158.3, 151.5, 149.1, 140.4,
115.1, 113.5, 105.1, 36.6, 30.0, 21.7; HRMS (m/z) [M + Na]+ calcd for
C11H11BrN2NaO 290.9927, found 290.9926.
3ꢀ((3,5ꢀDibromopyridinꢀ2ꢀyl)amino)cyclohexꢀ2ꢀenone (1h). 21 h; eluent:
EtOAc/PE 50:50; yield: 779 mg, 45%; white solid, mp 137ꢀ138 ºC (lit.10 mp 132ꢀ134
ºC); 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H),
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7.05 (s, 1H), 6.86 (br, s, 1H), 2.61 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 6.4 Hz, 2H),
2.13ꢀ2.07 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.6, 155.5, 148.8, 147.3, 142.3,
111.9, 108.7, 108.5, 36.6, 30.2, 21.8; HRMS (m/z) [M + Na]+ calcd for
C11H10Br2N2NaO 368.9032, found 368.9019.
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3ꢀ(Pyrazinꢀ2ꢀylamino)cyclohexꢀ2ꢀenone (1i). 4 h; eluent: EtOAc/PE 67:33; yield:
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246 mg, 26%; brown solid, mp 179ꢀ181 ºC; H NMR (400 MHz, CD3OD): δ
8.32ꢀ8.31 (m, 2H), 8.13 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 2.68 (t, J = 6.0 Hz, 2H),
2.40 (t, J = 6.4 Hz, 2H), 2.11ꢀ2.04 (m, 2H); 13C NMR (100 MHz, CD3OD): δ 201.9,
160.5, 151.3, 141.7, 136.6, 136.2, 105.7, 35.8, 28.7, 21.5; HRMS (m/z) [M + Na]+
calcd for C10H11N3NaO 212.0794, found 212.0796.
3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)cyclopentꢀ2ꢀenone (1j). 4 h; eluent: EtOAc/PE
1
67:33; yield: 847 mg, 90%; yellow solid, mp 233ꢀ234 ºC; H NMR (400 MHz,
DMSOꢀd6): δ 10.01 (s, 1H), 8.14 (s, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d, J =
8.4 Hz, 1H), 6.30 (s, 1H), 2.75 (t, J = 4.8 Hz, 2H), 2.22ꢀ2.19 (m, 5H); 13C NMR (100
MHz, DMSOꢀd6): δ 205.9, 169.8, 152.0, 147.9, 139.1, 127.0, 112.7, 107.0, 32.8, 29.2,
17.6; HRMS (m/z) [M + Na]+ calcd for C11H12N2NaO 211.0842, found 211.0850.
General Procedure B for the Preparation of Enamines 3. A stirred mixture of
[Pd(PPh3)2Cl2] (70 mg, 0.1 mmol) and CuI (38 mg, 0.2 mmol) in THF (20 mL) was
stirred and degassed with nitrogen before Et3N (0.7 mL, 5 mmol), acyl chloride (5
mmol), and aryl acetylene (5 mmol) were added successively. The reaction mixture
was then stirred for 1 h at room temperature (TLC indicated that the reaction was
complete). The solvents were evaporated and the residue was purified through silica
gel column chromatography (eluent: EtOAc/PE 0:100 to 5:95) as a lightꢀyellow oil or
solid in 75‒95% yields. A solution of the above ynone (3 mmol) in THF (10 mL) was
treated with substituted 2ꢀaminopyridine (3.6 mmol) and tꢀBuOK (673 mg, 6 mmol)
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in sequence, and then stirred at room temperature for 1 h (TLC indicated that the
reaction was complete). The reaction mixture was filtered through a neutral Al2O3 pad.
The filtrate was concentrated, and then purified through silica gel column
chromatography to give the enamine (3) in 38‒71% yield.
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(Z)ꢀ1,3ꢀDiphenylꢀ3ꢀ(pyridinꢀ2ꢀylamino)propꢀ2ꢀenꢀ1ꢀone (3a). Eluent: EtOAc/PE
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10:90; yield: 496 mg, 55%; yellow solid, mp 103ꢀ104 ºC (lit.3f mp 107ꢀ109 ºC); H
NMR (400 MHz, CDCl3): δ 12.69 (s, 1H), 8.21 (dd, J = 4.8, 1.2 Hz, 1H), 7.99ꢀ7.97
(m, 2H), 7.52ꢀ7.32 (m, 9H), 6.84 (dd, J = 6.8, 5.2 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H),
6.17 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.2, 158.9, 153.0, 148.6, 139.7, 137.0,
136.4, 131.6, 129.8, 128.6, 128.4, 128.0, 127.5, 118.5, 115.4, 99.5; HRMS (m/z) [M +
Na]+ calcd for C20H16N2NaO 323.1155, found 323.1161.
(Z)ꢀ3ꢀ((6ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3b).3f Eluent:
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EtOAc/PE 10:90; yield: 547 mg, 58%; yellow solid, mp 95ꢀ97 ºC; H NMR (400
MHz, CDCl3): δ 12.71 (s, 1H), 7.98ꢀ7.95 (m, 2H), 7.46ꢀ7.30 (m, 8H), 7.15 (t, J = 8.0
Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.12ꢀ6.10 (m, 2H), 2.32 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 189.9, 159.1, 157.6, 152.2, 139.7, 137.3, 136.5, 131.6, 129.7, 128.6,
128.4, 128.0, 127.5, 118.0, 112.3, 99.1, 24.1; HRMS (m/z) [M + H]+ calcd for
C21H19N2O 315.1492, found 315.1482.
(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3c). Eluent:
1
EtOAc/PE 10:90; yield: 556 mg, 59%; yellow solid, mp 116ꢀ117 ºC; H NMR (400
MHz, CDCl3): δ 12.70 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.98ꢀ7.96 (m, 2H), 7.51ꢀ7.33
(m, 8H), 7.16 (dd, J = 8.4, 2.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 2.19 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 190.0, 159.3, 150.7, 148.6, 139.8, 137.8, 136.5,
131.5, 129.6, 128.6, 128.4, 128.0, 127.4, 115.4, 98.8, 17.7; HRMS (m/z) [M + H]+
calcd for C21H19N2O 315.1492, found 315.1492.
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(Z)ꢀ3ꢀ((4ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3d). Eluent:
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EtOAc/PE 10:90; yield: 566 mg, 60%; yellow oil; H NMR (400 MHz, CDCl3): δ
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12.68 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.99ꢀ7.96 (m, 2H), 7.52ꢀ7.34 (m, 8H), 6.68 (d,
J = 4.8 Hz, 1H), 6.29 (s, 1H), 6.16 (s, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 190.2, 159.3, 153.0, 148.4, 148.1, 139.7, 136.6, 131.6, 129.6, 128.5, 128.4, 128.0,
127.5, 119.9, 116.2, 99.3, 21.0; HRMS (m/z) [M + H]+ calcd for C21H19N2O 315.1492,
found 315.1482.
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(Z)ꢀ3ꢀ((3ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3e). Eluent:
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EtOAc/PE 10:90; yield: 594 mg, 63%; yellow solid, mp 82ꢀ83 ºC; H NMR (400
MHz, CDCl3): δ 12.85 (s, 1H), 8.00ꢀ7.97 (m, 2H), 7.81 (dd, J = 4.8, 1.6 Hz, 1H),
7.52ꢀ7.28 (m, 9H), 6.79 (dd, J = 7.6, 4.8 Hz, 1H), 6.27 (s, 1H), 2.51 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 190.7, 160.9, 151.6, 145.5, 139.7, 138.6, 137.5, 131.6, 129.2,
128.5, 128.1, 127.7, 127.5, 124.0, 119.1, 100.0, 17.7; HRMS (m/z) [M + H]+ calcd for
C21H19N2O 315.1492, found 315.1487.
(Z)ꢀ3ꢀ((5ꢀChloropyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3f).11 Eluent:
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EtOAc/PE 5:95; yield: 653 mg, 65%; pale yellow solid, mp 122ꢀ123 ºC; H NMR
(400 MHz, CDCl3): δ 12.70 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.98ꢀ7.96 (m, 2H),
7.52ꢀ7.36 (m, 8H), 7.30 (dd, J = 8.8, 2.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 6.19 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 190.5, 158.5, 151.4, 147.2, 139.5, 136.8, 136.1,
131.9, 130.0, 128.8, 128.5, 127.9, 127.5, 125.9, 115.9, 100.0; HRMS (m/z) [M + H]+
calcd for C20H16ClN2O 335.0946, found 335.0932.
(Z)ꢀ3ꢀ((5ꢀBromopyridinꢀ2ꢀyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (3g). Eluent:
EtOAc/PE 5:95; yield: 694 mg, 61%; pale yellow solid, mp 137ꢀ139 ºC (lit.3f mp
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140ꢀ142 ºC); H NMR (400 MHz, CDCl3): δ 12.67 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H),
7.98ꢀ7.96 (m, 2H), 7.53ꢀ7.37 (m, 9H), 6.28 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H); 13C
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NMR (100 MHz, CDCl3): δ 190.5, 158.3, 151.7, 149.4, 139.5, 139.4, 136.0, 131.8,
130.0, 128.8, 128.5, 127.9, 127.5, 116.3, 113.8, 100.1; HRMS (m/z) [M + Na]+ calcd
for C20H15BrN2NaO 401.0260, found 401.0255.
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EtOAc/PE 5:95; yield: 935 mg, 68%; yellow solid, mp 148ꢀ149 ºC; H NMR (400
MHz, CDCl3): δ 12.86 (s, 1H), 8.02ꢀ7.99 (m, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.85 (d, J
= 2.0 Hz, 1H), 7.55ꢀ7.50 (m, 1H), 7.48ꢀ7.44 (m, 2H), 7.41ꢀ7.32 (m, 5H), 6.35 (s, 1H);
13C NMR (100 MHz, CDCl3): δ 191.0, 158.4, 149.4, 146.9, 142.7, 139.1, 137.0, 132.1,
129.3, 128.5, 128.3, 127.7, 127.4, 112.8, 110.8, 102.4; HRMS (m/z) [M + Na]+ calcd
for C20H14Br2N2NaO 480.9346, found 480.9340.
(Z)ꢀ1,3ꢀDiphenylꢀ3ꢀ(pyrazinꢀ2ꢀylamino)propꢀ2ꢀenꢀ1ꢀone (3i). Eluent: EtOAc/PE
10:90; yield: 551 mg, 61%; yellow solid, mp 114ꢀ115 ºC (lit.3f mp 114ꢀ116 ºC); H
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NMR (400 MHz, CDCl3): δ 12.71 (s, 1H), 8.14ꢀ8.08 (m, 2H), 8.00ꢀ7.98 (m, 2H), 7.82
(s, 1H), 7.55ꢀ7.38 (m, 8H), 6.28 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.8, 158.0,
149.9, 142.5, 139.2, 138.3, 137.5, 135.8 132.1, 130.2, 129.0, 128.5, 127.8, 127.6,
100.9; HRMS (m/z) [M + Na]+ calcd for C19H15N3NaO 324.1107, found 324.1100.
(Z)ꢀ1,3ꢀDiphenylꢀ3ꢀ(pyrimidinꢀ2ꢀylamino)propꢀ2ꢀenꢀ1ꢀone
(3j).3f
Eluent:
EtOAc/PE 10:90; yield: 353 mg, 39%; offꢀwhite solid, mp 103ꢀ104 ºC; 1H NMR (400
MHz, CDCl3): δ 12.55 (s, 1H), 8.30 (d, J = 4.8 Hz, 2H), 8.01ꢀ7.98 (m, 2H), 7.54ꢀ7.34
(m, 8H), 6.76 (t, J = 4.8 Hz, 1H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.7,
159.1, 157.7, 157.6, 139.4, 137.4, 132.0, 129.3 128.5, 128.1, 127.7, 127.5, 115.0,
102.4; HRMS (m/z) [M + Na]+ calcd for C19H15N3NaO 324.1107, found 324.1101.
(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone
(3k).
Eluent: EtOAc/PE 10:90; yield: 581 mg, 59%; yellow solid, mp 114ꢀ115 ºC; 1H NMR
(400 MHz, CDCl3): δ 12.68 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H),
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7.44ꢀ7.33 (m, 5H), 7.26ꢀ7.23 (m, 2H, overlapped with the peak of chloroform), 7.15
(dd, J = 8.0, 2.0 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 2.40 (s, 3H), 2.18 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 189.8, 158.9, 150.8, 148.5, 142.1, 137.7, 137.1,
136.6, 129.6, 129.1, 128.5, 128.0, 127.9, 127.5, 115.2, 98.8, 21.5, 17.7; HRMS (m/z)
[M + H]+ calcd for C22H21N2O 329.1648, found 329.1642.
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(Z)ꢀ1ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀ((5ꢀmethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀo
ne (3l). Eluent: EtOAc/PE 10:90; yield: 651 mg, 63%; yellow solid, mp 118ꢀ119 ºC;
1H NMR (400 MHz, CDCl3): δ 12.65 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.98ꢀ7.96 (m,
2H), 7.45ꢀ7.33 (m, 5H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 6.95ꢀ6.92 (m, 2H), 6.31 (d, J =
8.4 Hz, 1H), 6.10 (s, 1H), 3.86 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
189.0, 162.4, 158.6, 150.8, 148.5, 137.7, 136.7, 132.5, 129.53, 129.48, 128.5, 128.0,
127.7, 115.1, 113.6, 98.7, 55.4, 17.7; HRMS (m/z) [M + H]+ calcd for C22H21N2O2
345.1598, found 345.1591.
(Z)ꢀ1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ((5ꢀmethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀon
e (3m). Eluent: EtOAc/PE 10:90; yield: 544 mg, 52%; yellow solid, mp 138ꢀ139 ºC;
1H NMR (400 MHz, CDCl3): δ 12.70 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.91 (d, J =
8.4 Hz, 2H), 7.43ꢀ7.34 (m, 7H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 6.33 (d, J = 8.4 Hz,
1H), 6.06 (s, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.5, 159.8, 150.5,
148.6, 138.1, 137.8, 137.7, 136.3, 129.8, 128.8, 128.62, 128.61, 128.3, 128.0, 115.4,
98.2, 17.7; HRMS (m/z) [M + H]+ calcd for C21H18ClN2O 349.1102, found 349.1089.
(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylꢀ1ꢀ(3ꢀ(trifluoromethyl)phenyl)prop
ꢀ2ꢀenꢀ1ꢀone (3n). Eluent: EtOAc/PE 10:90; yield: 608 mg, 53%; yellow solid, mp
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155ꢀ156 ºC; H NMR (400 MHz, CDCl3): δ 12.76 (s, 1H), 8.21 (s, 1H), 8.15 (d, J =
8.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz,
1H), 7.45ꢀ7.36 (m, 5H), 7.18 (dd, J = 8.0, 2.0 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 6.09
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(s, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.0, 160.5, 150.3, 148.7,
140.4, 137.9, 136.1, 130.9 (q, JCꢀF = 32.5 Hz), 130.6, 129.9, 129.0, 128.7, 128.6,
128.0, 127.9 (q, JCꢀF = 3.6 Hz), 124.3 (q, JCꢀF = 3.8 Hz), 124.0 (d, JCꢀF = 270.8 Hz),
115.6, 98.0, 17.7; HRMS (m/z) [M + H]+ calcd for C22H18F3N2O 383.1366, found
383.1366.
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(Z)ꢀ1ꢀ(2ꢀMethoxyphenyl)ꢀ3ꢀ((5ꢀmethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀo
ne (3o). Eluent: EtOAc/PE 10:90; yield: 393 mg, 38%; yellow solid, mp 143ꢀ145 ºC;
1H NMR (400 MHz, CDCl3): δ 12.51 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.70 (dd, J =
7.6, 1.6 Hz, 1H), 7.43ꢀ7.30 (m, 6H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 7.03ꢀ6.99 (m, 1H),
6.95 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 3.88 (s, 3H), 2.19 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 191.2, 157.8, 157.4, 150.9, 148.5, 137.7, 136.6,
131.8, 130.8, 130.1, 129.4, 128.4, 128.1, 127.7, 120.6, 115.4, 111.6, 104.1, 55.8, 17.7;
HRMS (m/z) [M + H]+ calcd for C22H21N2O2 345.1598, found 345.1581.
(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀon
e (3p). Eluent: EtOAc/PE 10:90; yield: 776 mg, 71%; yellow solid, mp 150ꢀ151 ºC;
1H NMR (400 MHz, CDCl3): δ 12.80 (s, 1H), 8.49 (s, 1H), 8.10ꢀ8.06 (m, 2H), 7.95 (d,
J = 7.6 Hz, 1H), 7.91ꢀ7.86 (m, 2H), 7.57ꢀ7.37 (m, 7H), 7.17 (d, J = 8.0 Hz, 1H), 6.36
(d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.8,
159.4, 150.7, 148.6, 137.8, 137.1, 136.6, 135.0, 132.8, 129.7, 129.4, 128.6, 128.2,
128.1, 127.7, 127.6, 126.5, 124.2, 115.4, 99.0, 17.7; HRMS (m/z) [M + H]+ calcd for
C25H21N2O 365.1648, found 365.1646.
(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ3ꢀphenylꢀ1ꢀ(thiophenꢀ2ꢀyl)propꢀ2ꢀenꢀ1ꢀone
(3q). Eluent: EtOAc/PE 10:90; yield: 519 mg, 54%; yellow solid, mp 126ꢀ127 ºC; 1H
NMR (400 MHz, CDCl3): δ 12.38 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.68ꢀ7.67 (m, 1H),
7.54ꢀ7.53 (m, 1H), 7.43ꢀ7.33 (m, 5H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.11ꢀ7.09 (m,
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1H), 6.32 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 182.7, 159.0, 150.6, 148.5, 146.7, 137.8, 136.3, 131.5, 129.7, 129.0, 128.6, 128.0,
127.9, 115.2, 98.7, 17.7; HRMS (m/z) [M + H]+ calcd for C19H17N2OS 321.1056,
found 321.1056.
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(Z)ꢀ3ꢀ((5ꢀMethylpyridinꢀ2ꢀyl)amino)ꢀ1ꢀphenylꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone
(3r).
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Eluent: EtOAc/PE 10:90; yield: 483 mg, 49%; yellow solid, mp 96ꢀ98 ºC; H NMR
(400 MHz, CDCl3): δ 12.68 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.98ꢀ7.95 (m, 2H),
7.50ꢀ7.41 (m, 3H), 7.34ꢀ7.32 (m, 2H), 7.17ꢀ7.15 (m, 3H), 6.33 (d, J = 8.4 Hz, 1H),
6.12 (s, 1H), 2.38 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.9, 159.4,
150.8, 148.5, 140.0, 139.9, 137.7, 133.5 131.4, 129.3, 128.3, 128.0, 127.9, 127.4,
115.4, 98.6, 21.4, 17.7; HRMS (m/z) [M + H]+ calcd for C22H21N2O 329.1648, found
329.1642.
(Z)ꢀ3ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀ((5ꢀmethylpyridinꢀ2ꢀyl)amino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀo
ne (3s). Eluent: EtOAc/PE 10:90; yield: 548 mg, 53%; yellow solid, mp 126ꢀ127 ºC;
1H NMR (400 MHz, CDCl3): δ 12.66 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.98ꢀ7.96 (m,
2H), 7.50ꢀ7.41 (m, 3H), 7.39ꢀ7.36 (m, 2H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 6.87 (d, J =
8.8 Hz, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 3.83 (s, 3H), 2.20 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 189.8, 160.9, 159.1, 151.0, 148.6, 140.0, 137.8, 131.4,
129.6, 128.5, 128.4, 128.0, 127.4, 115.6, 114.0, 98.4, 55.4, 17.7; HRMS (m/z) [M +
H]+ calcd for C22H21N2O2 345.1598, found 345.1594.
(Z)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ((5ꢀmethylpyridinꢀ2ꢀyl)amino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀon
e (3t). Eluent: EtOAc/PE 10:90; yield: 733 mg, 70%; yellow solid, mp 107ꢀ109 ºC;
1H NMR (400 MHz, CDCl3): δ 12.66 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.97ꢀ7.95 (m,
2H), 7.52ꢀ7.42 (m, 3H), 7.38ꢀ7.31 (m, 4H), 7.25ꢀ7.23 (m, 1H), 6.45 (d, J = 8.4 Hz,
1H), 6.11 (s, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.2, 158.1, 150.4,
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148.6, 139.6, 138.1, 135.6, 135.2, 131.7, 129.4, 128.8, 128.5, 128.3, 127.5, 115.4,
99.0, 17.7; HRMS (m/z) [M + Na]+ calcd for C21H17ClN2NaO 371.0922, found
371.0912.
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General Procedure C for the Preparation of Enamines 5. A mixture of the
corresponding ynone (2.5 mmol, obtained according to General Procedure B,
dimethyl 2ꢀbutynedioate for 5m) and substituted aniline (2.5 mmol) in MeOH (5 mL)
was stirred in an ovenꢀdried sealed tube at 80 °C for 6 h (TLC indicated that the
reaction was complete). After cooling to room temperature, the reaction was
concentrated, and then purified through silica gel column chromatography to afford
the enamine (5) in 22‒95% yield.
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(Z)ꢀ1,3ꢀDiphenylꢀ3ꢀ(phenylamino)propꢀ2ꢀenꢀ1ꢀone (5a).3e Eluent: EtOAc/PE 5:95;
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yield: 718 mg, ≥ 95%; yellow solid, mp 95ꢀ96 ºC; H NMR (400 MHz, CDCl3): δ
12.90 (s, 1H), 7.98ꢀ7.96 (m, 2H), 7.50ꢀ7.31 (m, 8H), 7.12 (t, J = 8.0 Hz, 2H), 6.98 (t,
J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 2H), 6.09 (br, s, 1H); 13C NMR (100 MHz,
CDCl3): δ 189.7, 161.5, 139.9, 139.4, 135.8, 131.3, 129.7, 128.7, 128.6, 128.4, 127.3,
124.1, 123.2, 97.0; HRMS (m/z) [M + Na]+ calcd for C21H17NNaO 322.1202, found
322.1202.
(Z)ꢀ1,3ꢀDiphenylꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone (5b). Eluent: EtOAc/PE 5:95;
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yield: 736 mg, 94%; yellow solid, mp 127ꢀ129 ºC (lit.3e mp 127ꢀ128 ºC); H NMR
(400 MHz, CDCl3): δ 12.90 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.50ꢀ7.31 (m, 8H), 6.92
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(d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 6.06 (br, s, 1H), 2.23 (s, 3H); C NMR
(100 MHz, CDCl3): δ 189.5, 161.8, 140.0, 136.8, 135.9, 133.9, 131.2, 129.6, 129.4,
128.5, 128.43, 128.39, 127.3, 123.3, 96.6, 20.8; HRMS (m/z) [M + Na]+ calcd for
C22H19NNaO 336.1359, found 336.1347.
(Z)ꢀ3ꢀ((4ꢀMethoxyphenyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone
(5c).
Eluent:
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EtOAc/PE 5:95; yield: 815 mg, ≥ 95%; yellow solid, mp 122ꢀ123 ºC (lit.3e mp
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122ꢀ123 ºC); H NMR (400 MHz, CDCl3): δ 12.91 (s, 1H), 7.98ꢀ7.95 (m, 2H),
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13C NMR (100 MHz, CDCl3): δ 189.3, 162.2, 156.5, 140.0, 135.9, 132.5, 131.2, 129.6,
128.51, 128.49, 128.4, 127.2, 124.9, 114.0, 96.1, 55.4; HRMS (m/z) [M + Na]+ calcd
for C22H19NNaO2 352.1308, found 352.1293.
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(Z)ꢀ3ꢀ((4ꢀChlorophenyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone
(5d).
Eluent:
EtOAc/PE 5:95; yield: 751 mg, 90%; yellow solid, mp 146ꢀ147 ºC (lit.3e mp 142ꢀ143
ºC); 1H NMR (400 MHz, CDCl3): δ 12.85 (s, 1H), 7.96 (d, J = 6.8 Hz, 2H), 7.52ꢀ7.34
(m, 8H), 7.09 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.11 (br, s, 1H); 13C NMR
(100 MHz, CDCl3): δ 190.0, 161.1, 139.7, 138.2, 135.5, 131.5, 129.9, 129.4, 128.9,
128.8, 128.5, 128.4, 127.3, 124.3, 97.5; HRMS (m/z) [M + Na]+ calcd for
C21H16ClNNaO 356.0813, found 356.0796.
(Z)ꢀ3ꢀ((4ꢀBromophenyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone
(5e).
Eluent:
EtOAc/PE 5:95; yield: 851 mg, 90%; yellow solid, mp 151ꢀ152 ºC (lit.3e mp 155ꢀ156
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ºC); H NMR (400 MHz, CDCl3): δ 12.84 (s, 1H), 7.97ꢀ7.95 (m, 2H), 7.52ꢀ7.33 (m,
8H), 7.24ꢀ7.22 (m, 2H), 6.66ꢀ6.63 (m, 2H), 6.11 (br, s, 1H); 13C NMR (100 MHz,
CDCl3): δ 189.9, 160.9, 139.6, 138.6, 135.4, 131.8, 131.5, 129.9, 128.7, 128.4, 128.3,
127.3, 124.5, 117.0, 97.6; HRMS (m/z) [M + Na]+ calcd for C21H16BrNNaO 400.0307,
found 400.0295.
(Z)ꢀ3ꢀ((4ꢀNitrophenyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (5f). Eluent: EtOAc/PE
5:95; yield: 189 mg, 22%; yellow solid, mp 166ꢀ167 ºC; 1H NMR (400 MHz, CDCl3):
δ 12.89 (s, 1H), 8.00ꢀ7.97 (m, 4H), 7.56ꢀ7.40 (m, 8H), 6.80ꢀ6.76 (m, 2H), 6.26 (s, 1H);
13C NMR (100 MHz, CDCl3): δ 190.8, 159.1, 145.9, 142.8, 139.1, 135.0, 132.1, 130.5,
129.2, 128.6, 128.1, 127.5, 124.8, 121.3, 100.3; HRMS (m/z) [M + Na]+ calcd for
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C21H16N2NaO3 367.1053, found 367.1044.
(Z)ꢀ3ꢀ((3,5ꢀDimethylphenyl)amino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀenꢀ1ꢀone (5g).3e Eluent:
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EtOAc/PE 5:95; yield: 778 mg, 95%; yellow oil; H NMR (400 MHz, CDCl3): δ
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12.88 (s, 1H), 7.97ꢀ7.95 (m, 2H), 7.49ꢀ7.31 (m, 8H), 6.62 (s, 1H), 6.40 (s, 2H), 6.05
(br, s, 1H), 2.12(s, 6H); 13C NMR (100 MHz, CDCl3): δ 189.4, 161.6, 140.0, 139.2,
138.3, 136.1, 131.2, 129.6, 128.5, 128.4, 128.3, 127.3, 125.9, 120.9, 96.7, 21.2;
HRMS (m/z) [M + Na]+ calcd for C23H21NNaO 350.1515, found 350.1514.
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(Z)ꢀ1ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone (5h). Eluent:
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EtOAc/PE 5:95; yield: 881 mg, ≥ 95%; yellow solid, mp 178ꢀ179 ºC; H NMR (400
MHz, CDCl3): δ 13.00 (s, 1H), 8.47 (s, 1H), 8.07 (dd, J = 8.8, 1.6 Hz, 1H), 7.95ꢀ7.85
(m, 3H), 7.56ꢀ7.49 (m, 2H), 7.45ꢀ7.33 (m, 5H), 6.94 (d, J = 8.4 Hz, 2H), 6.71 (d, J =
8.4 Hz, 2H), 6.21 (br, s, 1H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.2,
161.8, 137.2, 136.8, 135.9, 134.8, 133.9, 132.8, 129.6, 129.34, 129.28, 128.5, 128.4,
128.1, 127.8, 127.7, 127.4, 126.4, 124.1, 123.2, 96.8, 20.8; HRMS (m/z) [M + Na]+
calcd for C26H21NNaO 386.1515, found 386.1504.
(Z)ꢀ3ꢀPhenylꢀ1ꢀ(thiophenꢀ2ꢀyl)ꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone (5i).12 Eluent:
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EtOAc/PE 5:95; yield: 783 mg, ≥ 95%; yellow solid, mp 106ꢀ107 ºC; H NMR (400
MHz, CDCl3): δ 12.57 (s, 1H), 7.64 (dd, J = 3.6, 0.8 Hz, 1H), 7.51 (dd, J = 5.2, 1.2
Hz, 1H), 7.41ꢀ7.31 (m, 5H), 7.09 (dd, J = 4.8, 3.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H),
6.65 (d, J = 8.4 Hz, 2H), 5.92 (br, s, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 182.3, 161.4, 146.9, 136.8, 135.7, 133.9, 131.0, 129.7, 129.4, 128.6, 128.42, 128.39,
128.0, 123.1, 96.4, 20.8; HRMS (m/z) [M + Na]+ calcd for C20H17NNaOS 342.0923,
found 342.0916.
(Z)ꢀ1ꢀCyclohexylꢀ3ꢀphenylꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone
(5j).
Eluent:
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EtOAc/PE 5:95; yield: 751 mg, 94%; yellow solid, mp 99ꢀ101 ºC; H NMR (400
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MHz, CDCl3): δ 12.38 (s, 1H), 7.37ꢀ7.26 (m, 5H), 6.88 (d, J = 8.4 Hz, 2H), 6.60 (d, J
= 8.4 Hz, 2H), 5.37 (s, 1H), 2.37ꢀ2.29 (m, 1H), 2.21 (s, 3H), 1.92ꢀ1.79 (m, 4H),
1.70ꢀ1.67 (m, 1H), 1.50ꢀ1.40 (m, 2H), 1.35ꢀ1.20 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 203.4, 160.2, 137.1, 135.9, 133.3, 129.4, 129.2, 128.4, 128.3, 122.9, 98.5,
50.7, 29.8, 26.1, 26.0, 20.7; HRMS (m/z) [M + Na]+ calcd for C22H25NNaO 342.1828,
found 342.1829.
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(Z)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀphenylꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone (5k).12 Eluent:
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EtOAc/PE 5:95; yield: 852 mg, ≥ 95%; yellow solid, mp 117ꢀ119 ºC; H NMR (400
MHz, CDCl3): δ 12.82 (s, 1H), 7.96ꢀ7.94 (m, 2H), 7.49ꢀ7.44 (m, 3H), 7.34ꢀ7.29 (m,
4H), 6.95 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 6.02 (s, 1H), 2.25 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 189.6, 160.4, 139.8, 136.6, 135.7, 134.4, 134.2, 131.4,
129.8, 129.5, 128.9, 128.4, 127.3, 123.4, 96.6, 20.9; HRMS (m/z) [M + Na]+ calcd for
C22H18ClNNaO 370.0969, found 370.0952.
(Z)ꢀ3ꢀCyclopropylꢀ1ꢀphenylꢀ3ꢀ(pꢀtolylamino)propꢀ2ꢀenꢀ1ꢀone
(5l).
Eluent:
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EtOAc/PE 5:95; yield: 631 mg, 91%; offꢀwhite solid, mp 93ꢀ95 ºC; H NMR (400
MHz, CDCl3): δ 13.31 (s, 1H), 7.87ꢀ7.85 (m, 2H), 7.46ꢀ7.39 (m, 3H), 7.22ꢀ7.16 (m,
4H), 5.51 (s, 1H), 2.36 (s, 3H), 1.78ꢀ1.72 (m, 1H), 0.99ꢀ0.97 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 188.6, 168.3, 140.6, 135.9, 135.5, 130.6, 129.7, 128.2, 126.9, 125.1,
86.3, 21.0, 12.8, 10.0; HRMS (m/z) [M + Na]+ calcd for C19H19NNaO 300.1359,
found 300.1345.
Dimethyl 2ꢀ(pꢀtolylamino)fumarate (5m).13 Eluent: EtOAc/PE 5:95; yield: 455 mg,
73%; yellow oil; 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H),
6.80 (d, J = 8.4 Hz, 2H), 5.33 (s, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 2.30(s, 3H); 13C
NMR (100 MHz, CDCl3): δ 170.0, 164.9, 148.4, 137.7, 134.1, 129.8, 120.9, 92.6,
52.8, 51.2, 20.8; HRMS (m/z) [M + Na]+ calcd for C13H15NNaO4 272.0893, found
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Synthesis of Vinyl Iodide 2c'. A stirred mixture of substrate 1c in 1,4ꢀdioxane (10
mL) was treated sequentially with K2CO3 (207 mg, 1.5 mmol) and iodine (152 mg,
0.6 mmol), and then heated to reflux under a nitrogen atmosphere until the
consumption of 1c as monitored by TLC, was complete (1.5 h). After cooling to room
temperature, the reaction was quenched with 5% Na2S2O3 (5 mL) followed by
addition of brine (10 mL), then extracted with EtOAc (15 mL × 3). The combined
organic layer was dried over anhydrous Na2SO4, concentrated, and then purified
through silica gel column chromatography (eluent: EtOAc/PE 25:75), affording the
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product (2c'). Yield: 98 mg, 60%; offꢀwhite solid, mp 121ꢀ123 ºC; H NMR (400
MHz, CDCl3): δ 8.20 (s, 1H), 7.68 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0
Hz, 1H), 3.09 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.02ꢀ1.97 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 191.0, 162.1, 149.6, 148.6, 139.0, 129.5, 115.5,
82.2, 36.5, 29.2, 22.1, 17.8; HRMS (m/z) [M + Na]+ calcd for C12H13IN2NaO
350.9965, found 350.9958.
General Procedure D for the Synthesis of Imidazo[1,2ꢀa]pyridines 2 and 4. A
stirred mixture of enamine (1 or 3, 0.5 mmol) in toluene (10 mL) was treated with
Cs2CO3 (489 mg, 1.5mmol), CuI (19 mg, 0.1 mmol) and iodine (152 mg, 0.6 mmol) in
sequence, and then heated to reflux under a nitrogen atmosphere until consumption of
the substrate was complete (as monitored by TLC). After cooling to room temperature,
the reaction was quenched with 5% Na2S2O3 (5 mL), followed by addition of brine
(10 mL), then extracted with CH2Cl2 (15 mL × 3). The combined organic layer was
dried over anhydrous Na2SO4, concentrated, and then purified through silica gel
column chromatography to afford the product (2 or 4) in 43‒95% yield.
7,8ꢀDihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2a).
4
h; eluent:
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EtOAc/PE 75:25; yield: 42 mg, 45%; white solid, mp 139ꢀ141 ºC, (lit.14 mp 142ꢀ144
ºC); 1H NMR (400 MHz, CDCl3): δ 9.29 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H),
7.51ꢀ7.47 (m, 1H), 7.07ꢀ7.03 (m, 1H) 3.08 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H),
2.29ꢀ2.23 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 188.3, 160.3, 147.9, 129.5, 128.4,
119.6, 116.8, 114.4, 38.4, 25.5, 23.8; HRMS (m/z) [M + H]+ calcd for C11H11N2O
187.0866, found 187.0869.
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1ꢀMethylꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2b). 3.5 h;
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eluent: EtOAc/PE 75:25; yield: 60 mg, 60%; white solid, mp 169ꢀ170 ºC; H NMR
(400 MHz, CDCl3): δ 7.51 (d, J = 8.8 Hz, 1H), 7.43ꢀ7.39 (m, 1H), 6.79 (d, J = 7.2 Hz,
1H), 3.07 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H), 2.68 (t, J = 6.0 Hz, 2H), 2.25ꢀ2.18 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 185.6, 162.6, 150.5, 141.1, 130.3, 122.1, 115.6, 114.3,
39.8, 26.7, 23.1, 23.0; HRMS (m/z) [M + H]+ calcd for C12H13N2O 201.1022, found
201.1025.
2ꢀMethylꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2c).15 2.5 h;
eluent: EtOAc/PE 75:25; yield: 99 mg, ≥ 95%; white solid, mp 105ꢀ107 ºC; 1H NMR
(400 MHz, CDCl3): δ 9.11 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 9.2, 1.6 Hz,
1H), 3.05 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.27ꢀ2.21 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 188.2, 160.2, 146.9, 132.3, 126.5, 124.5, 119.4, 116.1,
38.4, 25.5, 23.8, 18.1; HRMS (m/z) [M + H]+ calcd for C12H13N2O 201.1022, found
201.1032.
3ꢀMethylꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2d). 3.5 h;
eluent: EtOAc/PE 75:25; yield: 83mg, 83%; offꢀwhite solid, mp 104ꢀ106 ºC (lit.16 mp
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108ꢀ109 ºC); H NMR (400 MHz, CDCl3): δ 9.13 (d, J = 6.8 Hz, 1H), 7.43 (s, 1H),
6.87 (dd, J = 6.8, 1.2 Hz 1H), 3.04 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.48 (s,
3H), 2.27ꢀ2.21 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 187.9, 160.6, 148.4, 141.2,
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127.5, 119.4, 116.8, 115.6, 38.3, 25.5, 23.8, 21.7; HRMS (m/z) [M + H]+ calcd for
C12H13N2O, 201.1022, found 201.1024.
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4ꢀMethylꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2e). 6.5 h;
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eluent: EtOAc/PE 75:25; yield: 46 mg, 46%; offꢀwhite solid, mp 95ꢀ97 ºC; H NMR
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(400 MHz, CDCl3): δ 9.16 (d, J = 6.8 Hz, 1H), 7.28 (d, J = 6.0 Hz, 1H, overlapped
with the peak of chloroform), 6.95 (t, J = 6.8 Hz, 1H), 3.09 (t, J = 6.4 Hz, 2H),
2.68ꢀ2.65 (m, 5H), 2.29ꢀ2.22 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 188.3, 159.7,
148.0, 128.6, 126.7, 126.1, 120.0, 114.4, 38.4, 25.6, 23.9, 17.0. HRMS (m/z) [M +
H]+ calcd for C12H13N2O, 201.1022, found 201.1031.
2ꢀChloroꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2f).16 3.5 h;
eluent: EtOAc/PE 60:40; yield: 96mg, 87%; offꢀwhite solid, mp 105ꢀ106 ºC; 1H NMR
(400 MHz, CDCl3): δ 9.35ꢀ9.34 (m, 1H), 7.63ꢀ7.60 (m, 1H), 7.47ꢀ7.44 (m, 1H), 3.07
(t, J = 6.4 Hz, 2H), 2.69ꢀ2.66 (m, 2H), 2.28ꢀ2.25 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 188.4, 160.6, 146.1, 130.5, 126.3, 122.6, 119.8, 117.1, 38.3, 25.4, 23.7.
HRMS (m/z) [M + H]+ calcd for C11H10ClN2O, 221.0476, found 221.0483.
2ꢀBromoꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2g). 6 h; eluent:
EtOAc/PE 60:40; yield: 102 mg, 77%; offꢀwhite solid, mp 126ꢀ128 ºC (lit.16 mp
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121ꢀ123 ºC); H NMR (400 MHz, CDCl3): δ 9.44 (s, 1H), 7.59ꢀ7.53 (m, 2H),
3.08ꢀ3.05 (m, 2H), 2.69ꢀ2.66 (m, 2H), 2.29ꢀ2.23 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 188.5, 160.4, 146.3, 132.7, 128.4, 119.7, 117.4, 109.1, 38.3, 25.4, 23.7;
HRMS (m/z) [M + H]+ calcd for C11H10BrN2O 264.9971, found 264.9979.
2,4ꢀDibromoꢀ7,8ꢀdihydrobenzo[4,5]imidazo[1,2ꢀa]pyridinꢀ9(6H)ꢀone (2h). 7 h;
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eluent: EtOAc/PE 30:70; yield: 141 mg, 82%; white solid, mp 186ꢀ188 ºC; H NMR
(400 MHz, CDCl3): δ 9.43 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 3.12 (t, J =
6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.30ꢀ2.23 (m, 2H); 13C NMR (100 MHz, CDCl3):
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δ 188.9, 160.4, 144.5, 134.4, 127.5, 120.9, 111.3, 108.2, 38.3, 25.5, 23.6; HRMS (m/z)
[M + H]+ calcd for C11H9Br2N2O 344.9056, found 344.9056.
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8,9ꢀDihydrobenzo[4,5]imidazo[1,2ꢀa]pyrazinꢀ6(7H)ꢀone (2i). 5.5 h; eluent:
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EtOAc/PE 60:40; yield: 47 mg, 50%; white solid, mp 168ꢀ170 ºC; H NMR (400
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MHz, CDCl3): δ 9.20 (d, J = 1.6 Hz, 1H), 9.10 (dd, J = 4.4, 1.2 Hz, 1H), 8.18 (d, J =
4.4 Hz, 1H), 3.14 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.34ꢀ2.27 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 189.4, 160.3, 143.0, 141.7, 132.3, 120.5, 119.9, 38.6,
25.4, 23.6; HRMS (m/z) [M + H]+ calcd for C10H10N3O 188.0818, found 188.0817.
7ꢀMethylꢀ2,3ꢀdihydroꢀ1Hꢀcyclopenta[4,5]imidazo[1,2ꢀa]pyridinꢀ1ꢀone (2j). 3.5 h;
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eluent: EtOAc/PE 75:25; yield: 40 mg, 43%; white solid, mp 147ꢀ149 ºC; H NMR
(400 MHz, CDCl3): δ 8.44ꢀ8.43 (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.37ꢀ7.34 (m,
1H), 3.12ꢀ3.09 (m, 2H), 3.06ꢀ3.03 (m, 2H), 2.39 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 188.3, 175.3, 153.4, 132.5, 125.7, 125.2, 124.3, 117.0, 41.4, 22.2, 17.9;
HRMS (m/z) [M + H]+ calcd for C11H11N2O 187.0866, found 187.0868.
Phenyl(2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)methanone (4a). 3.5 h; eluent:
EtOAc/PE 20:80; yield: 148 mg, ≥ 95%; white solid, mp 130ꢀ132 ºC (lit.3f mp
130ꢀ132 ºC); 1H NMR (400 MHz, CDCl3): δ 9.55 (dt, J = 7.2, 1.2 Hz, 1H), 7.81 (dt, J
= 8.8, 1.2 Hz, 1H), 7.55ꢀ7.50 (m, 3H), 7.34ꢀ7.31 (m, 2H), 7.27ꢀ7.23 (m, 1H,
overlapped with the peak of chloroform), 7.15ꢀ7.06 (m, 6H); 13C NMR (100 MHz,
CDCl3): δ 187.4, 155.0, 147.4, 138.7, 134.0, 131.8, 130.2, 129.6, 129.2, 128.3, 127.8,
120.0, 117.5, 114.6; HRMS (m/z) [M + H]+ calcd for C20H15N2O 299.1179, found
299.1178.
(5ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4b).3f 3.5 h;
eluent: EtOAc/PE 20:80; yield: 155 mg, ≥ 95%; yellow solid, mp 88ꢀ90 ºC; 1H NMR
(400 MHz, CDCl3): δ 7.82ꢀ7.80 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.49ꢀ7.46 (m, 2H),
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7.43ꢀ7.37 (m, 2H), 7.28ꢀ7.24 (m, 2H, overlapped with the peak of chloroform),
7.18ꢀ7.14 (m, 3H), 6.78 (d, J = 6.8 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 188.0, 150.1, 147.8, 138.3, 137.9, 133.6, 133.3, 130.4, 129.4, 128.4, 128.1,
128.0, 127.6, 120.5, 115.3, 115.0, 22.3; HRMS (m/z) [M + H]+ calcd for C21H17N2O
313.1335, found 313.1337.
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(6ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4c).17 3.5 h;
eluent: EtOAc/PE 20:80; yield: 151 mg, ≥ 95%; white solid, mp 163ꢀ164 ºC; 1H NMR
(400 MHz, CDCl3): δ 9.37 (m, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.52ꢀ7.49 (m, 2H), 7.38
(dd, J = 9.2, 2.0 Hz, 1H), 7.32ꢀ7.30 (m, 2H), 7.27ꢀ7.22 (m, 1H), 7.14ꢀ7.05 (m, 5H),
2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 187.3, 154.8, 146.4, 138.8, 134.1, 132.1,
131.7, 130.1, 129.6, 128.1, 127.7, 126.1, 124.6, 119.8, 116.7, 18.5; HRMS (m/z) [M +
H]+ calcd for C21H17N2O 313.1335, found 313.1335.
(7ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4d). 3.5 h;
eluent: EtOAc/PE 20:80; yield: 153 mg, ≥ 95%; white solid, mp 142ꢀ144 ºC (lit.18 mp
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140ꢀ142 ºC); H NMR (400 MHz, CDCl3): δ 9.45 (d, J = 7.2 Hz, 1H), 7.56 (m, 1H),
7.50ꢀ7.48 (m, 2H), 7.32ꢀ7.29 (m, 2H), 7.26ꢀ7.22 (m, 1H), 7.14ꢀ7.04 (m, 5H), 6.93 (dd,
J = 6.8, 1.6 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 187.1, 155.3, 147.9,
140.9, 138.8, 134.1, 131.6, 130.2, 129.5, 128.2, 127.7, 127.5, 119.8, 117.1, 116.1,
21.6; HRMS (m/z) [M + H]+ calcd for C21H17N2O 313.1335, found 313.1339.
(8ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4e). 3.5 h;
eluent: EtOAc/PE 10:90; yield: 155 mg, ≥ 95%; offꢀwhite solid, mp 139ꢀ141 ºC (lit.18
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mp 139ꢀ141 ºC); H NMR (400 MHz, CDCl3): δ 9.41 (d, J = 6.8 Hz, 1H), 7.51ꢀ7.48
(m, 2H), 7.35ꢀ7.31 (m, 3H), 7.26ꢀ7.22 (m, 1H), 7.14ꢀ7.05 (m, 5H), 7.00 (t, J = 7.2 Hz,
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1H), 2.73 (s, 3H); C NMR (100 MHz, CDCl3): δ 187.4, 154.5, 147.6, 138.8, 134.3,
131.6, 130.3, 129.5, 128.1, 127.72, 127.67, 127.5, 126.0, 120.5, 114.6, 17.1; HRMS
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(m/z) [M + H]+ calcd for C21H17N2O 313.1335, found 313.1344.
(6ꢀChloroꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4f).19 3.5 h;
eluent: EtOAc/PE 20:80; yield: 165 mg, ≥ 95%; white solid, mp 122ꢀ124 ºC; 1H NMR
(400 MHz, CDCl3): δ 9.62 (dd, J = 2.0, 0.8 Hz, 1H), 7.76ꢀ7.73 (m, 1H), 7.52ꢀ7.48 (m,
3H), 7.33ꢀ7.26 (m, 3H, overlapped with the peak of chloroform), 7.17ꢀ7.07 (m, 5H);
13C NMR (100 MHz, CDCl3): δ 187.3, 155.0, 145.6, 138.2, 133.5, 132.1, 130.4, 130.1,
129.6, 128.5, 127.84, 127.83, 126.2, 122,9, 120.2, 117.7; HRMS (m/z) [M + H]+ calcd
for C20H14ClN2O 333.0789, found 333.0787.
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(6ꢀBromoꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4g). 3.5 h;
eluent: EtOAc/PE 20:80; yield: 187 mg, ≥ 95%; white solid, mp 135ꢀ137 ºC (lit.3f mp
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135ꢀ137 ºC); H NMR (400 MHz, CDCl3): δ 9.71 (d, J = 1.6 Hz, 1H), 7.70ꢀ7.68 (m,
1H), 7.60ꢀ7.57 (m, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.32ꢀ7.30 (m, 2H), 7.28ꢀ7.26 (m, 1H,
overlapped with the peak of chloroform), 7.16ꢀ7.07 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 187.3, 154.9, 145.7, 138.2, 133.5, 132.5, 132.1, 130.1, 129.6, 128.5, 128.4,
127.83, 127.82, 120.1, 118.0, 109.4; HRMS (m/z) [M + H]+ calcd for C20H14BrN2O
377.0284, found 377.0277.
(6,8ꢀDibromoꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)(phenyl)methanone (4h).20 3.5
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h; eluent: EtOAc/PE 10:90; yield: 205 mg, 90%; white solid, mp 258ꢀ259 ºC; H
NMR (400 MHz, CDCl3): δ 9.63 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.50 (d,
J = 7.2 Hz, 2H), 7.35ꢀ7.33 (m, 2H), 7.31ꢀ7.27 (m, 1H), 7.17ꢀ7.07 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ 187.5, 154.8, 143.9, 137.8, 134.1, 133.1, 132.4, 130.4, 129.6,
128.7, 127.92, 127.89, 127.4, 121,3, 111.9, 108.3; HRMS (m/z) [M + Na]+ calcd for
C20H12Br2N2NaO 478.9189, found 478.9174.
Phenyl(2ꢀphenylimidazo[1,2ꢀa]pyrazinꢀ3ꢀyl)methanone (4i).3f 3.5 h; eluent:
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EtOAc/PE 25:75; yield: 148 mg, ≥ 95%; white solid, mp 146ꢀ148 ºC; H NMR (400
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