A Chemoselective N-Arylation Reaction of 2-Aminopyridine Derivatives with Arynes

Article abstract of DOI:10.1021/acs.joc.7b01405

A chemoselective N-arylation reaction of 2-aminopyridine derivatives with arynes in good to excellent yields has been described. The N-arylation products could be further applied to the facile construction of benzoisoquinuclidines and isoquinuclidines as

Full text of DOI:10.1021/acs.joc.7b01405

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Article
A Chemoselective N-Arylation Reaction of 2-
Aminopyridine Derivatives with Arynes
Bin Cheng, Jian Wei, Bing Zu, Jianfei Zhao, Taimin Wang,
Xiaoguang Duan, Renqi Wang, Yun Li, and Hongbin Zhai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01405 • Publication Date (Web): 15 Aug 2017
Downloaded from http://pubs.acs.org on August 16, 2017
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A Chemoselective N-Arylation Reaction of 2-Aminopyridine Deriva-
tives with Arynes
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Bin Cheng,*,† Jian Wei,† Bing Zu,† Jianfei Zhao,† Taimin Wang,† Xiaoguang Duan,† Renqi Wang,† Yun
⊥
Li,† and Hongbin Zhai*,†,‡,
† The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou Uni-
versity, Lanzhou 730000, China
‡ Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
⊥ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
Supporting Information Placeholder
ABSTRACT: A chemoselective N-arylation reaction of 2-aminopyridine derivatives with arynes in good to excellent yields has
been described. The N-arylation products could be further applied to the facile construction of benzoisoquinuclidines and isoquinu-
clidines as well as pyrido[1,2-a]benzimidazoles.
INTRODUCTION
1-Arylpyridin-2(1H)-imine motif widely occurs in bioactive
molecules and therapeutic agents, for example pyrido[1,2-
a]benzimidazole derivatives (Figure 1), which have received
substantial attention owing to their pronounced pharmaceutical
and optical properties.1 Moreover, it could be a potential
Diels-Alder diene partner for the construction of isoquinu-
clidine framework (i.e., 2-azabicyclo[2.2.2]octane) like its
analogue 2-pyridone.2 However, synthetic approaches to ac-
cess this unique and simple unit have been rarely developed,3
as the most straightforward methods involving transition metal
mediated C-N bond formation reaction of 2-aminopyrines with
aryl halides or aryl boronic acids all afford N-arylpyridin-2-
amine derivatives as the sole products.4 Considering the im-
portance of this motif (i.e., 1-arylpyridin-2(1H)-imine) and the
lack of efficient strategy for its synthesis, we sought to devel-
op a facile protocol utilizing N-arylation reaction of 2-
aminopyridines with arynes.
Over the last decades, o-(trimethylsilyl)aryl triflate,5 a new
aryne precursor, has attracted much attention from organic
chemists, and it has been successfully employed as a reactant
in the reaction with a multitude of aniline derivatives.6 For
example, Larock and co-workers, and others have recently
accomplished N-arylation of anilides with arynes generated
from o-(trimethylsilyl)aryl triflates as arylation reagents (eq a
and b). Moreover, Cheng disclosed the reaction of 2-pyridyl
carboxylates with benzynes to form 1-(2-acylphenyl)-2-
pyridones (eq c).7 Indeed, for this challenging N-arylation
reaction of 2-aminopyridines with arynes, there exist multiple
potential side reaction pathways arising from N-arylation of
the amide, aryne insertion into the amide bond, nucleophilic
attack of the pyridino nitrogen on the aryne followed by cy-
clization with the carbamate,8 and Diels-Alder reaction of di-
hydropyridine. Herein, we would like to disclose our results of
selective N-arylation of 2-aminopyridines with arynes and its
application to the syntheses of benzoisoquinuclidines and iso-
quinuclidines as well as pyrido[1,2-a]benzimidazoles (Scheme
1).
Figure 1. Some Pharmaceutical Relevant Pyrido[1,2-
a]benzimidazole Derivatives
Me2N
Cl
CO2Et
OH
N
Cl
Scheme 1. Reaction of Arylamines with Arynes
N
HN
F
F
N
N
N
CN
CN
CN
N
N
N
antifugal
antitumor
antiviral
1-phenylpyridin-2(1H)-imine
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COCF3 1:1.8
COCF3 1:1.8
COCF3 1:1.8
KF (2.0)
CsF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
THF
79
79
1
2
3
4
CH3CN
CH3CN
CH3CN
CH3CN
9e
10
11
35
f
H
Me
1:1.8
1:1.8
g
5
6
7
8
aReaction conditions: 1 (0.3 mmol), 2, fluoride source (0.6 mmol),
b
18-Crown-6 (0.6 mmol), solvent (3 mL), rt, air. Isolated yield.
cWithout 18-Crown-6. dThe amounts of 18-Crown-6 were in-
creased to 3.0 equiv. eBnEt3NCl (2.0 equiv) was used as the addi-
9
f
tive instead. No desired product was isolated. gN-Methyl-N-
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phenylpyridin-2-amine was isolated in 56% yield.
When the optimal reaction conditions were determined, we
sought to elucidate the scope of this transformation. As pre-
sented in Table 2, apart from 2,2,2-trifluoro-N-(pyridin-2-
yl)acetamide, other acylated 2-aminopyridines proceeded
smoothly and formed the corresponding products (3b–3e) in
71-90% yields. Then, a series of substituted 2-aminopyridines
were investigated under the reaction conditions. In general,
electron-donating methyl derivatives of 2-aminopyridine were
well-tolerated, delivering the desired products (3f–3h) in 84–
91% yields. However, 2,2,2-trifluoro-N-(6-methylpyridin-2-
yl)acetamide, gave the desired product 3i in 24% yield, while
66% yield of amide bond insertion product 3i’
was observed.6
RESULTS AND DISCUSSION
We speculated that it was probably due to the unfavorable
steric interaction between the methyl group and incoming ben-
zyne. 2-Aminopyridine with a weak electron-withdrawing
bromo group at 5-position furnished the desired product 3j in
moderate yield (61%), as it could readily undergo deacylation
under the reaction conditions. Changing R1 to benzoyl group
rendered the product 3k in a slightly higher yield of 69%. In
Initially, we performed the reaction o-(trimethylsilyl)phenyl
triflate (1a) and 2,2,2-trifluoro-N-(pyridin-2-yl)acetamide (2a)
in the presence of KF/18-Crown-6 in CH3CN at room tem-
perature (Table 1, entry 1). Delightfully, 75% yield of the de-
sired product 3a was observed when slight excess of 2a was
used (1a:2a = 1:1.2) under the reaction conditions. Interesting-
ly, no any side products were detected on TLC. Control exper-
iment carried out in the absence of 18-Crown-6 showed 4% of
product formation, which indicates the crucial role of 18-
Crown-6 as an additive (entry 2). The replacement of 18-
Crown-6 with another additive BnEt3NCl gave only 35% yield
of the product (entry 9). Further enhancement in the yield was
observed when the amounts of 2a was increased to 1.8 equiv
(entry 4). However, further increasing the amounts of 2a or
KF/18-Crown-6 (entries 5 and 6) or changing the fluoride
source or solvent (entries 7 and 8) did not improve the yields.
Unfortunately, the use of free amine (R1 = H) did not yield any
desired product. Moreover, if R1 was methyl group, N-
phenylation occurred at the amino group and N-methyl-N-
phenylpyridin-2-amine was isolated as the sole product.
addition,
1-aminoisoquinoline
derivative
and
2-
benzoxazolinone were also compatible substrates, affording 3l
and 3n in 84 and 72% yields, respectively. Similar to 3i, 44%
yield of 3m was obtained along with 25% yield of insertion
product 3m
of o-(trimethylsilyl)aryl triflates (1b
nishing the expected products (3o 3r) in satisfactory yields.
’
due to the steric hindrance. Furthermore, a variety
–
1e) were examined, fur-
–
Of note, 3-methoxyl aryne precursor 1c afforded 3p as a single
regioisomer due to the steric and electronic effects. The regio-
chemistry of 3p was confirmed with high-resolution H-NMR
and NOE experiments (see SI). Finally, it should be pointed
out that the reaction of 3a could be scaled up to 4 mmol, 88%
of yield could be obtained, without obvious deterioration in
the yield and selectivity.
1
Table 2. Scope of N-Arylation Reactiona,b
Table 1. Optimization of the Reaction Conditionsa
TMS
OTf
fluoride source
additive, solvent, rt
N
NR1
+
N
NHR1
3
1a
2
fluoride
source
yieldb
(%)
entry
R1
1a:2
solvent
(equiv)
1
2c
3
COCF3 1:1.2
COCF3 1:1.2
COCF3 1:1.5
COCF3 1:1.8
COCF3 1:2.1
COCF3 1:1.8
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (3.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
75
4
88
89
89
85
4
5
6d
3a, 88%e
3b, 75%
3c, 71%
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3d, 90%
3e, 80%
3f, 91%
5
6
7
8
KF/18-Crown-6
entry
1:2a
yieldb (%)
1
(equiv)
1
3:1
3:1
5:1
5:1
5:1
5:1
5:1
3
3
5
5
5
5
5
3a (32)
3a (36)
3a (0)
3a (0)
3o (0)
4a (61)
4a (51)
4a (82)
4a (85)
4d (0)
1a
1a
1a
1a
1b
1c
1e
2c
3
3g, 85%
3j, 61%
3h, 84%
3k, 69%
3i, 24%c
3l, 84%
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4d
5d
6d
7d
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3p (trace)
3r (trace)
4c (0)
4b (68)
aReaction conditions: 2a (0.3 mmol, 0.025 M), 1, KF/18-Crown-6,
CH3CN, rt, air. bIsolated yield. c50 oC was employed instead. dThe
concentration of 2a (0.01 M) was applied instead.
3m, 44%d
3n, 72%
3q, 78%
3o, 58%
3r, 77%
We speculated that 4 probably was derived from 2 via N-
arylation reaction followed by Diels-Alder reaction in a tan-
dem manner. To demonstrate it, we allowed 1a to react with a
variety of 1-arylpyridin-2(1H)-imine derivatives, and all of
them proceeded smoothly and afforded a library of diverse
benzoisoquinuclidines (Table 4, 4a–4i) in moderate to good
3p, 75%
yields, even with the substrate 3f bearing a methyl group at the
3-position of 1-arylpyridin-2(1H)-imine to construct quater-
nary carbon center. It should be pointed out that trifluoroa-
cetamide substrate 3a exhibited better performance than that
of benzamide 3d, R2 had little effects on the transformation
aReaction conditions: 1 (0.5 mmol), 2 (0.9 mmol), KF (1.0 mmol),
18-Crown-6 (1.0 mmol), CH3CN (5 mL), rt (25 C), air. Isolated
yield. 3i’ was obtained in 66% yield along with 3i. 3m’ was
obtained in 25% yield along with 3m. eThe reaction was conduct-
ed in 4 mmol scale.
o
b
c
d
(e.g., 3r), and substituent R3 of dienes (3f
–3h) strongly influ-
enced the efficiency of Diels-Alder reaction, resulting in con-
siderable amounts of starting material of 3 retained when ex-
cessive benzyne had depleted.
Table 4. Diels-Alder Reaction of 1a with 3a
While optimizing the reaction conditions, it was observed
that increasing the amounts of 1a and 18-Crown-6 at lower
concentration, 4a could be isolated as the major product in 61%
yield along with 32% yield of 3a (Table 3, entry 1). Increasing
the reaction temperature to 50 oC led to lower yield of 4a (en-
try 2). The best result was obtained when 5.0 equiv of 1a was
used with respect to 2a, in the presence of 5.0 equiv of KF/18-
Crown-6 in CH3CN (0.01 M) at rt and the yield of 4a was
enhanced to 85% (entry 4). Unfortunately, electron-
withdrawing substrate 1b failed to undergo this transformation.
Of particular note, even 3o was not observed under the reac-
tion conditions (entry 5). In order to further understand the
results, previously synthesized dihydropyridines 3a, 3b, or 3o
(see Table 2) were used as diene substrates to react with 1b,
however Diels-Alder products were still not observed. In addi-
tion, 3-methoxybenzyne precursor 1c was also found to be
inapplicable substrate, as 4c was not observed (entry 6). How-
ever, aryne precursor 1e with weak electron-donating substitu-
ents proceeded smoothly to furnish benzoisoquinuclidine 4b in
68% yield (entry 7).
4a, 79%
4g, 41%
4e, 46%
4h, 63%
4f, 80%
4i, 65%
aReaction conditions: 3 (0.2 mmol, 0.01 M), 1a (2.5 equiv),
KF/18-Crown-6 (2.5 equiv), CH3CN, rt, air. Isolated yield.
To further explore the utility of the products obtained via N-
arylation reaction of 2-aminopyridine derivatives, we per-
formed the Diels-Alder reaction of 3c with an ordinary dieno-
phile, such as N-methylsuccinimide, leading to the formation
of 5c in 71% yield under thermal conditions (Scheme 2). The
Table 3. Optimization and Diels-Alder Reaction of Arynes
with 2aa
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relative stereochemistry of 5c was confirmed by NOE experi-
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filtered, concentrated, and purified by flash chromatography to
1
2
3
4
5
6
7
8
ments and X-ray diffraction studies (see SI). Furthermore, we
also tried the cyclization reaction of 3c through deprotecting
and modified copper mediated cyclization reaction,9 and pyri-
do[1,2-a]benzimidazole (6c) was obtained in 24% yield over
two steps without further optimization. It should be mentioned
that this is the first case of (aryl) C-N (amidinyl) bond forming
reaction as the key step to construct pyrido[1,2-
a]benzimidazole, to the best of our knowledge.10
afford acylated 2-amino pyridine derivative. An additional deac-
ylation step (conditions: NaOH/MeOH/dioxane) was used to get
the desired substrate 2d (N-(pyridin-2-yl)benzamide), because
diacylated product was often obtained as the major product. 2a–
2m are all known except substrate 2l, and for 2a–2e, 2h–2k there
are data reported in literature. 2n is commercially available.
General Procedure for the Syntheses of 3a–3r via N-Arylation
of 2-Amino Pyridine Derivatives.
9
To a solution of o-(trimethylsilyl)phenyl trifluoromethanesul-
fonate (1a, 90 mg, 0.30 mmol), 2,2,2-trifluoro-N-(pyridin-2-
yl)acetamide (2a, 103 mg, 0.540 mmol), and 18-Crown-6 (158 mg,
0.600 mmol) in CH3CN (3 mL), KF (35 mg, 0.60 mmol) was
added and the resulting solution was stirred at room temperature
for 10 h. After removing the solvent under reduced pressure, the
resulting residue was purified by flash chromatography (EA) to
give 3a (71 mg, 89%) as a yellow solid.
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Scheme 2. Diels-Alder Reaction of 3c with N-
Methylsuccinimide and Cyclization Reaction of 3c
Scale-up Experiment: To a solution of o-(trimethylsilyl)phenyl
trifluoromethanesulfonate (1a, 1.19 g, 4.00 mmol), 2,2,2-trifluoro-
N-(pyridin-2-yl)acetamide (2a, 1.37 g, 7.20 mmol), and 18-
Crown-6 (2.11 g, 8.00 mmol) in CH3CN (40 mL), KF (465 mg,
8.00 mmol) was added and the resulting solution was stirred at
room temperature for 10 h. After removing the solvent under re-
duced pressure, the resulting residue was purified by flash chro-
matography (EA) to give 3a (941 mg, 88%) as a yellow solid.
Other N-arylation reactions of acylated 2-amino pyridine deriv-
atives 2 were conducted following a similar method. Reaction
conditions: 1 (0.5 mmol), 2 (0.9 mmol, 1.8 equiv), KF (1.0 mmol,
2.0 equiv), 18-Crown-6 (1.0 mmol, 2.0 equiv), CH3CN (5 mL), rt,
air, 10–24 h.
General Procedure for Diels-Alder Reaction of 2a and Aryne.
To a solution of 2,2,2-trifluoro-N-(pyridin-2-yl)acetamide (2a,
57 mg, 0.30 mmol), o-(trimethylsilyl)phenyl trifluoromethanesul-
fonate (1a, 447 mg, 1.50 mmol), and 18-Crown-6 (396 mg, 1.50
mmol) in CH3CN (30 mL), KF (87 mg, 1.5 mmol) was added and
the mixture was stirred at room temperature for 24 h. After re-
moving the solvent under reduced pressure, the resulting residue
was purified by flash chromatography (PE:EA = 15:1) to give 4a
(88 mg, 85%) as a yellow oil.
CONCLUSIONS
In summary, a chemoselective N-arylation reaction of 2-
aminopyridine derivatives and arynes generated in situ from o-
(trimethylsilyl)aryl triflates has been developed and good to
excellent yields were obtained. The products obtained from
this transformation can be further applied to the facile con-
struction of benzoisoquinuclidines via Diels-Alder reaction
with arynes in one pot or stepwise and isoquinuclidines via a
two-step protocol, where the second step involves the reaction
with a dienophile. The useful transformation of an N-arylation
product to pyrido[1,2-a]benzimidazole is also demonstrated.
EXPERIMENTAL SECTION
General Information. All isolated compounds were character-
ized on Varian 300, Bruker 400, JEOL 400, and Varian 600 MHz
spectrometers in CDCl3, DMSO-d6 or (CD3)2CO. Chemical shifts
were reported as δ values relative to internal CHCl3 (δ 7.26 for 1H
NMR and 77.00 for 13C NMR), DMSO (δ 2.50 for H NMR and
39.52 for 13C NMR), and (CH3)2CO (δ 2.05 for H NMR and
1
1
29.84 for 13C NMR). 19F NMR chemical shifts were determined
as δ values relative to external standard PhCF3 at -63.00. High-
resolution mass spectra (HRMS) were obtained on a 4G mass
spectrometer by using electrospray ionization (ESI) analyzed by
quadrupole time-of-flight (QTof). All melting points were meas-
ured with the samples after column chromatography and uncor-
rected. Column chromatography was performed on silica gel.
Anhydrous THF and toluene were distilled over sodium benzo-
phenone ketyl under Ar. All other solvents and reagents were used
as obtained from commercial sources without further purification.
General Procedure for the Syntheses of Acylated 2-Amino
Pyridine Derivatives (2a–2m).
To a solution of 2-aminopyridine (1 mmol, 1.0 equiv) and tri-
ethylamine (1.5 equiv) in DCM (10 mL) at 0 oC was added acyla-
tion reagent such as trifluoroacetic anhydride or acyl chloride (1.5
equiv), which was then allowed to stir for 24 h at room tempera-
ture. The mixture was quenched with Sat. NH4Cl and extracted
with DCM. The combined organic layers were dried over Na2SO4,
Other Diels-Alder reactions of 2a and aryne were conducted
following a similar method. Reaction conditions: 2a (0.3 mmol), 1
(1.5 mmol, 5 equiv), KF (1.5 mmol, 5 equiv), 18-Crown-6 (1.5
mmol, 5 equiv), CH3CN (30 mL), rt, air, 24 h.
General Procedure for Diels-Alder Reaction of 3 with 1a.
To a solution of 2,2,2-trifluoro-N-(1-phenylpyridin-2(1H)-
ylidene)acetamide
(3a,
53
mg,
0.20
mmol),
o-
(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 149 mg,
0.500 mmol), and 18-Crown-6 (132 mg, 0.500 mmol) in CH3CN
(20 mL), KF (29 mg, 0.50 mmol) was added and the mixture was
stirred at room temperature for 24 h. After removing the solvent
under reduced pressure, the resulting residue was purified by flash
chromatography (PE:EA = 15:1) to give 4a (53 mg, 79%) as a
yellow oil.
Other Diels-Alder reactions of 3 with 1a were conducted fol-
lowing a similar method. Reaction conditions: 3 (0.2 mmol), 1a
(0.5 mmol, 2.5 equiv), KF (0.5 mmol, 2.5 equiv), 18-Crown-6
(0.5 mmol, 2.5 equiv), CH3CN (20 mL), rt, air, 24 h.
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Procedure for Diels-Alder reaction of N-Methylsuccinimide
and 3c.
ESI-HRMS m/z calcd for C8H8F3N2O [M+H]+ 205.0583, found
205.0583.
1
2
3
4
5
6
7
8
To
a
mixture of 3c (27 mg, 0.10 mmol) and N-
2,2,2ꢀTrifluoroꢀNꢀ(4ꢀmethylpyridinꢀ2ꢀyl)acetamide 2g. Compound
o
1
methylsuccinimide (33 mg, 0.30 mmol, 3.0 equiv) was added
toluene (1 mL) under Ar, the resulting solution was heated at 130
oC for 48 h. After cooling and removing the solvent under reduced
pressure, the resulting residue was purified by flash chromatog-
raphy (PE:EA = 15:1) to give 5c (27 mg, 71%) as a white solid.
Procedure for Cyclization Reaction of 3c.
2g was isolated as a white solid; mp 76–77 C. H NMR (300
MHz, CDCl3) δ 10.53 (br s, 1H), 8.17 (d, J = 4.8 Hz, 1H), 8.04–
7.99 (m, 1H), 7.00 (d, J = 4.8 Hz, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.4 (q, J = 37.9 Hz), 150.9, 149.6, 147.3,
122.6, 116.0, 115.7 (q, J = 339.7 Hz), 21.3; 19F NMR (282 MHz,
CDCl3) δ -75.70 (s, 3F); ESI-HRMS m/z calcd for C8H8F3N2O
[M+H]+ 205.0583, found 205.0584.
9
To a solution of (3c, 86 mg, 0.32 mmol) in DCE (3.2 mL),
ZnBr2 (179 mg, 0.795 mmol, 2.5 equiv) was added and the mix-
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2,2,2ꢀTrifluoroꢀNꢀ(5ꢀmethylpyridinꢀ2ꢀyl)acetamide 2h. 1H NMR
(300 MHz, CDCl3) δ 9.04 (br s, 1H), 8.18–8.14 (m, 1H), 8.07 (d,
o
ture was stirred at 80 C for 1 h. After cooling, the solution was
1
diluted with EA (50 mL), quenched with Sat. Na2CO3 (10 drops),
and stirred for additional 20 min. The resulting mixture was di-
rectly dried over Na2SO4, filtered, concentrated to give the crude
1-phenylpyridin-2(1H)-imine, which was used for the next step
without further purification for its high polarity.
To a solution of above-mentioned 1-phenylpyridin-2(1H)-imine
and Cu(OAc)2 (58 mg, 0.32 mmol, 1.0 equiv) in DMSO (1 mL),
HOAc (96 mg, 1.6 mmol, 5.0 equiv) was added. Then the mixture
was evacuated, backfilled with O2, and heated at 120 oC for 48 h.
After finishing, the solution was cooled, diluted with Et2O, and
added with Sat. Na2CO3. Then the mixture was filtered through a
short plug of celite. The organic layer was separated and washed
with Sat. NaCl twice. Next, the organic layer was dried over
Na2SO4, filtered, concentrated, and purified by flash chromatog-
raphy (PE:EA:TEA = 1:1:1%) to give 6c (13 mg, 24%, 2 steps) as
a yellow solid.
J = 8.4 Hz, 1H), 7.64–7.58 (m, 1H), 2.34 (s, 3H). H NMR data
correspond to the reported values.16
2,2,2ꢀTrifluoroꢀNꢀ(6ꢀmethylpyridinꢀ2ꢀyl)acetamide 2i. 1H NMR
(300 MHz, CDCl3) δ 8.74 (br s, 1H), 7.94 (d, J = 8.4 Hz, 1H),
1
7.70–7.63 (m, 1H), 7.02 (d, J = 7.5 Hz, 1H), 2.46 (s, 3H). H
NMR data correspond to the reported values.17
Nꢀ(5ꢀBromopyridinꢀ2ꢀyl)ꢀ2,2,2ꢀtrifluoroacetamide 2j. 1H NMR
(300 MHz, CDCl3) δ 8.76 (br s, 1H), 8.41 (d, J = 2.4 Hz, 1H),
1
8.12 (dd, J = 8.7, 0.6 Hz, 1H), 7.91 (dd, J = 8.7, 2.7 Hz, 1H). H
NMR data correspond to the reported values.18
Nꢀ(5ꢀBromopyridinꢀ2ꢀyl)benzamide 2k. 1H NMR (400 MHz,
CDCl3) δ 8.57 (br s, 1H), 8.36–8.32 (m, 2H), 7.93–7.89 (m, 2H),
7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.62–7.56 (m, 1H), 7.51 (t, J = 7.6
Hz, 2H). 1H NMR data correspond to the reported values.19
2,2,2ꢀTrifluoroꢀNꢀ(quinolinꢀ2ꢀyl)acetamide 2l. Compound 2l was
o
1
isolated as as a white solid; mp 95–96 C. H NMR (400 MHz,
CD3COCD3) δ 14.47 (br s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.03 (d,
J = 6.4 Hz, 1H), 8.00–7.93 (m, 2H), 7.85–7.73 (m, 1H), 7.56 (d, J
= 6.8 Hz, 1H); 13C NMR (150 MHz, CD3COCD3) δ C (C=O, due
to the poor solubility of 2l, peak of C=O is obscure), 138.8, 135.2,
129.4, 128.4, 128.3, 128.0, 127.8, 125.8, 118.1 (q, J = 285.0 Hz),
115.9; 19F NMR (282 MHz, CD3COCD3) δ -76.13 (s, 3F); ESI-
HRMS m/z calcd for C11H8F3N2O [M+H]+ 241.0583, found
241.0580.
Characterization Data of Substrates 2a–2m.
2,2,2ꢀTrifluoroꢀNꢀ(pyridinꢀ2ꢀyl)acetamide 2a. 1H NMR (400 MHz,
CDCl3) δ 9.26 (br s, 1H), 8.35 (dd, J = 4.8, 0.8 Hz, 1H), 8.19 (d, J
= 8.4 Hz, 1H), 7.86–7.77 (m, 1H), 7.19 (ddd, J = 7.2, 4.8, 0.4 Hz,
1H). 1H NMR data correspond to the reported values.11
1
Methyl pyridinꢀ2ꢀylcarbamate 2b. H NMR (300 MHz, CDCl3) δ
10.03 (br s, 1H), 8.34 (d, J = 4.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H),
7.70 (t, J = 7.5 Hz, 1H), 7.05–6.95 (m, 1H), 3.83 (s, 3H). 1H NMR
data correspond to the reported values.12
2,2,2ꢀTrifluoroꢀNꢀ(isoquinolinꢀ1ꢀyl)acetamide 2m. Compound 2m
was isolated as a white solid; mp 235–237 oC. 1H NMR (400 MHz,
CDCl3) δ 8.27 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.84
(d, J = 8.4 Hz, 2H), 7.74 (td, J = 8.4, 1.5 Hz, 1H), 7.60–7.49 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 157.3 (q, J = 38.2 Hz), 150.0,
144.7, 139.7, 130.7, 127.7, 126.4, 126.3, 115.7 (q, J = 286.5 Hz),
115.1; 19F NMR (282 MHz, CDCl3) δ -76.23 (s, 3F); ESI-HRMS
m/z calcd for C11H8F3N2O [M+H]+ 241.0583, found 241.0583.
Characterization Data of Products (3a–3r, 3i’, 3m’ 4a–4i, 5c,
and 6c).
2,2,2ꢀTrifluoroꢀNꢀ(1ꢀphenylpyridinꢀ2(1H)ꢀylidene)acetamide.
Compound 3a ( 71 mg, Y = 89%, Rf = 0.6 (EA)) was isolated as a
yellow solid; mp 98–99 oC. 1H NMR (400 MHz, CDCl3) δ 8.38 (d,
J = 8.8 Hz, 1H), 7.87–7.79 (m, 1H), 7.77 (dd, J = 6.8, 1.2 Hz, 1H),
7.51–7.41 (m, 3H), 7.35–7.27 (m, 2H), 6.90 (td, J = 6.8, 0.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 163.2 (q, J = 34.5 Hz), 160.1,
142.2, 141.3, 139.6, 129.4, 129.1, 126.1, 122.1, 117.0 (q, J =
286.3 Hz), 114.1; 19F NMR (282 MHz, CDCl3) δ -76.48 (s, 3F);
ESI-HRMS m/z calcd for C13H10F3N2O [M+H]+ 267.0740, found
267.0737.
1
tertꢀButyl pyridinꢀ2ꢀylcarbamate 2c. H NMR (400 MHz, CDCl3)
δ 8.66 (br s, 1H), 8.33–8.28 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H),
7.66 (td, J = 7.8, 2.0 Hz, 1H), 6.94 (dd, J = 7.2, 5.2 Hz, 1H), 1.54
(s, 9H). 1H NMR data correspond to the reported values.13
Nꢀ(Pyridinꢀ2ꢀyl)benzamide 2d. 1H NMR (400 MHz, CDCl3) δ
8.84 (br s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.22 (dq, J = 5.2, 0.8 Hz,
1H), 7.95–7.90 (m, 2H), 7.75 (td, J = 7.8, 2.0 Hz, 1H), 7.56 (tt, J
= 7.2, 2.0 Hz, 1H), 7.52–7.46 (m, 2H), 7.05 (ddd, J = 7.2, 4.8, 0.8
Hz, 1H). 1H NMR data correspond to the reported values.14
1
Nꢀ(Pyridinꢀ2ꢀyl)pivalamide 2e. H NMR (300 MHz, CDCl3) δ
8.30–8.21 (m, 2H), 8.03 (br s, 1H), 7.74–7.66 (m, 1H), 7.07–7.00
1
(m, 1H), 1.33 (s, 9H). H NMR data correspond to the reported
values.15
2,2,2ꢀTrifluoroꢀNꢀ(3ꢀmethylpyridinꢀ2ꢀyl)acetamide 2f. Compound
o
1
2f was isolated as a white solid; mp 104–105 C. H NMR (300
MHz, CDCl3) δ 8.14 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H),
7.22–7.14 (m, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.6 (q, J = 36.9 Hz), 150.2, 141.4, 141.3, 131.0, 121.2, 116.3 (q,
J = 285.8 Hz), 17.6; 19F NMR (282 MHz, CDCl3) δ -75.54 (s, 3F);
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Methyl (1ꢀphenylpyridinꢀ2(1H)ꢀylidene)carbamate. Compound 3b
( 86 mg, Y = 75%, Rf = 0.2 (EA)) was isolated as a yellow solid;
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8 (q, J = 34.4
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3
4
5
6
7
8
Hz), 158.4, 144.3, 141.3, 137.8, 129.2, 129.0, 126.0, 124.6, 121.6,
117.1 (q, J = 286.2 Hz), 17.2; 19F NMR (282 MHz, CDCl3) δ -
76.28 (s, 3F); ESI-HRMS m/z calcd for C14H12F3N2O [M+H]+
281.0896, found 281.0894.
o
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mp 114–115 C. H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2
Hz, 1H), 7.54–7.37 (m, 5H), 7.35–7.27 (m, 2H), 6.46 (td, J = 6.8,
1.2 Hz, 1H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3,
160.3, 142.0, 139.0, 138.4, 129.2, 128.6, 126.3, 119.9, 109.0, 52.0;
ESI-HRMS m/z calcd for C13H13N2O2 [M+H]+ 229.0972, found
229.0970.
2,2,2ꢀTrifluoroꢀNꢀ(6ꢀmethylꢀ1ꢀphenylpyridinꢀ2(1H)ꢀ
ylidene)acetamide. Compound 3i (34 mg, Y = 24%, Rf = 0.5 (EA))
o
1
was isolated as a white solid; mp 95–96 C. H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 9.2 Hz, 1H), 7.75 (dd, J = 8.8, 7.6 Hz, 1H),
7.58–7.43 (m, 3H), 7.16–7.10 (m, 2H), 6.81 (d, J = 7.2 Hz, 1H),
2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6 (q, J = 35.1
Hz), 161.6, 149.0, 142.0, 139.0, 129.6, 129.2, 126.2, 119.1, 117.0
(q, J = 286.4 Hz), 115.2, 22.0; 19F NMR (282 MHz, CDCl3) δ -
76.23 (s, 3F); ESI-HRMS m/z calcd for C14H12F3N2O [M+H]+
281.0896, found 281.0895.
tertꢀButyl (1ꢀphenylpyridinꢀ2(1H)ꢀylidene)carbamate. Compound
3c ( 96 mg, Y = 71%, Rf = 0.2 (EA)) was isolated as a yellow
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solid; mp 95–96 C. H NMR (400 MHz, CDCl3) δ 7.76 (d, J =
9.6 Hz, 1H), 7.46–7.40 (m, 2H), 7.39–7.33 (m, 2H), 7.30 (d, J =
7.2 Hz, 3H), 6.31 (td, J = 6.8, 0.8 Hz, 1H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.6, 159.5, 142.2, 138.3, 138.2, 129.1,
128.4, 126.6, 120.1, 108.1, 78.1, 28.2; ESI-HRMS m/z calcd for
C16H19N2O2 [M+H]+ 271.1441, found 271.1443.
Nꢀ(5ꢀBromoꢀ1ꢀphenylpyridinꢀ2(1H)ꢀylidene)ꢀ2,2,2ꢀ
Nꢀ(1ꢀPhenylpyridinꢀ2(1H)ꢀylidene)benzamide. Compound 3d
(124 mg, Y = 90%, Rf = 0.4 (EA)) was isolated as a yellow solid;
trifluoroacetamide. Compound 3j (105 mg, Y = 61%, Rf = 0.5
(PE:EA = 2:1)) was isolated as a yellow solid; mp 125–126 oC. 1H
NMR (300 MHz, CDCl3) δ 8.38 (d, J = 9.6 Hz, 1H), 7.90 (d, J =
2.1 Hz, 1H), 7.86 (dd, J = 9.3, 2.4 Hz, 1H), 7.56–7.46 (m, 3H),
7.39–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.8 (q, J =
35.0 Hz), 159.0, 144.6, 140.7, 139.4, 129.8, 129.3, 126.0, 122.8,
116.8 (q, J = 286.0 Hz), 106.3; 19F NMR (282 MHz, CDCl3) δ -
75.85 (s, 3F); ESI-HRMS m/z calcd for C13H9BrF3N2O [M+H]+
344.9845, found 344.9844.
o
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mp 115–116 C. H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 9.2
Hz, 1H), 7.96–7.87 (m, 2H), 7.57–7.40 (m, 5H), 7.39–7.28 (m,
3H), 7.23 (t, J = 7.4 Hz, 2H), 6.49 (td, J = 6.8, 1.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 173.8, 159.2, 142.2, 139.7, 138.7, 138.5,
130.5, 129.0, 128.9, 128.6, 127.4, 126.5, 121.2, 110.3; ESI-
HRMS m/z calcd for C18H15N2O [M+H]+ 275.1179, found
275.1175.
Nꢀ(1ꢀPhenylpyridinꢀ2(1H)ꢀylidene)pivalamide. Compound 3e
(102 mg, Y = 80%, Rf = 0.2 (EA)) was isolated as a brown oil. 1H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 9.2 Hz, 1H), 7.50–7.38 (m,
5H), 7.35–7.28 (m, 2H), 6.43 (td, J = 6.8, 1.2 Hz, 1H), 1.00 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 188.8, 158.5, 142.3, 139.0,
138.1, 128.7, 128.3, 126.6, 120.7, 109.0, 41.1, 27.6; ESI-HRMS
m/z calcd for C16H19N2O [M+H]+ 255.1492, found 255.1498.
2,2,2ꢀTrifluoroꢀNꢀ(3ꢀmethylꢀ1ꢀphenylpyridinꢀ2(1H)ꢀ
Nꢀ(5ꢀBromoꢀ1ꢀphenylpyridinꢀ2(1H)ꢀylidene)benzamide.
Com-
pound 3k (123 mg, Y = 69%, Rf = 0.4 (PE:EA = 2:1)) was isolat-
ed as a yellow solid; mp 125–126 oC. 1H NMR (400 MHz, CDCl3)
δ 8.34 (d, J = 10.0 Hz, 1H), 7.93–7.85 (m, 2H), 7.66 (d, J = 2.0
Hz, 1H), 7.60–7.43 (m, 4H), 7.43–7.30 (m, 3H), 7.24 (t, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 174.3, 157.6, 142.2,
141.5, 138.2, 130.9, 129.1, 129.0, 127.5, 126.5, 122.0, 102.1, (2C
missing); ESI-HRMS m/z calcd for C18H14BrN2O [M+H]+
353.0284, found 353.0285.
ylidene)acetamide. Compound 3f (127 mg, Y = 91%, Rf = 0.2
o
1
(EA)) was isolated as a yellow solid; mp 121–122 C. H NMR
(400 MHz, CDCl3) δ 7.80 (dd, J = 16.0, 7.2 Hz, 2H), 7.50–7.38
(m, 3H), 7.36–7.27 (m, 2H), 7.05 (t, J = 6.8 Hz, 1H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.0, 157.0 (q, J = 34.5 Hz),
143.0, 141.0, 137.8, 133.4, 129.8, 129.4, 129.2, 125.0, 117.3 (q, J
= 285.3 Hz), 116.1, 18.0; 19F NMR (282 MHz, CDCl3) δ -75.55 (s,
3F); ESI-HRMS m/z calcd for C14H12F3N2O [M+H]+ 281.0896,
found 281.0894.
2,2,2ꢀTrifluoroꢀNꢀ(2ꢀphenylisoquinolinꢀ1(2H)ꢀylidene)acetamide.
Compound 3l (132 mg, Y = 84%, Rf = 0.5 (EA)) was isolated as a
o
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white solid; mp 153–154 C. H NMR (400 MHz, CDCl3) δ 8.39
(d, J = 8.4 Hz, 1H), 7.90–7.81 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H),
7.73–7.64 (m, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.53–7.39 (m, 5H),
7.30 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.0,
157.8 (q, J = 35.4 Hz), 141.6, 136.7, 134.7, 132.3, 129.6, 129.5,
129.4, 129.4, 126.9, 125.4, 124.1, 117.2 (q, J = 285.6 Hz), 115.1;
19F NMR (282 MHz, CDCl3) δ -75.08 (s, 3F); ESI-HRMS m/z
calcd for C17H12F3N2O [M+H]+ 317.0896, found 317.0894.
2,2,2ꢀTrifluoroꢀNꢀ(4ꢀmethylꢀ1ꢀphenylpyridinꢀ2(1H)ꢀ
ylidene)acetamide. Compound 3g (119 mg, Y = 85%, Rf = 0.6
o
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(EA)) was isolated as a yellow solid; mp 123–124 C. H NMR
(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.51–
7.41 (m, 3H), 7.35–7.26 (m, 2H), 6.77 (dd, J = 6.8, 1.6 Hz, 1H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9 (q, J = 34.3
Hz), 159.3, 155.4, 141.0, 138.7, 129.2, 129.0, 126.1, 121.2, 117.1
(q, J = 286.3 Hz), 116.3, 21.8; 19F NMR (282 MHz, CDCl3) δ -
75.75 (s, 3F); ESI-HRMS m/z calcd for C14H12F3N2O [M+H]+
281.0896, found 281.0894.
2,2,2ꢀTrifluoroꢀNꢀ(1ꢀphenylquinolinꢀ2(1H)ꢀylidene)acetamide.
Compound 3m (69 mg, Y = 44%, Rf = 0.4 (PE:EA = 2:1)) was
o
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isolated as a yellow solid; mp 130–131 C. H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.80
(dd, J = 7.6, 1.2 Hz, 1H), 7.65–7.49 (m, 4H), 7.48–7.41 (m, 1H),
7.28–7.20 (m, 2H), 6.93 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 164.1 (q, J = 35.3 Hz), 161.0, 141.2, 139.7, 137.9, 131.9,
129.9, 129.4, 128.6, 127.7, 125.1, 122.9, 119.2, 118.1, 116.8 (q, J
= 286.3 Hz); 19F NMR (282 MHz, CDCl3) δ -76.11 (s, 3F); ESI-
HRMS m/z calcd for C17H12F3N2O [M+H]+ 317.0896, found
317.0892.
2,2,2ꢀTrifluoroꢀNꢀ(5ꢀmethylꢀ1ꢀphenylpyridinꢀ2(1H)ꢀ
ylidene)acetamide. Compound 3h (118 mg, Y = 84%, Rf = 0.7
o
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(EA)) was isolated as a yellow solid; mp 111–112 C. H NMR
(400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 9.2,
2.4 Hz, 1H), 7.61 (s, 1H), 7.51–7.42 (m, 3H), 7.35–7.27 (m, 2H),
4ꢀPhenyloxazolo[4,5ꢀb]pyridinꢀ2(4H)ꢀone. Compound 3n (76 mg,
Y = 72%, Rf = 0.5 (EA)) was isolated as a white solid; mp 212–
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213 C. H NMR (300 MHz, DMSO-d6) δ 6.92 (dd, J = 6.9, 0.9
Hz, 1H), 6.82–6.54 (m, 6H), 6.04 (t, J = 7.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 162.5, 159.5, 144.0, 139.3, 131.1, 129.8,
129.6, 125.7, 112.5, 112.4; ESI-HRMS m/z calcd for C12H9N2O2
[M+H]+ 213.0659, found 213.0656.
Hz), 118.7, 118.2, 117.0 (q, J = 289.5 Hz), 117.0, 113.1, 110.8,
24.3; 19F NMR (282 MHz, CDCl3) δ -68.81 (s, 3F); ESI-HRMS
m/z calcd for C14H12F3N2O [M+H]+ 281.0896, found 281.0894.
2,2,2ꢀTrifluoroꢀ1ꢀ(2ꢀ(quinolinꢀ2ꢀylamino)phenyl)ethanꢀ1ꢀone.
Compound 3m’ (40 mg, Y = 25%, Rf = 0.5 (PE:EA = 5:1)) was
isolated as an orange-yellow solid; mp 135–136 oC. 1H NMR (400
MHz, CDCl3) δ 11.17 (s, 1H), 9.52 (d, J = 8.4 Hz, 1H), 8.05–7.87
(m, 3H), 7.77–7.59 (m, 3H), 7.45–7.33 (m, 1H), 7.06–7.00 (m,
1H), 6.97 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
182.2 (q, J = 33.5 Hz), 152.4, 147.0, 146.9, 137.8, 137.4, 131.8 (q,
J = 4.1 Hz), 129.8, 127.6, 127.4, 124.7, 124.4, 119.6, 119.6, 117.0
(q, J = 289.5 Hz), 115.1, 113.6; 19F NMR (282 MHz, CDCl3) δ -
69.14 (s, 3F); ESI-HRMS m/z calcd for C17H12F3N2O [M+H]+
317.0896, found 317.0894.
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Nꢀ(1ꢀ(3,4ꢀDifluorophenyl)pyridinꢀ2(1H)ꢀylidene)ꢀ2,2,2ꢀ
trifluoroacetamide. Compound 3o (88 mg, Y = 58%, Rf = 0.5
o
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(EA)) was isolated as a yellow solid; mp 138–139 C. H NMR
(400 MHz, CDCl3) δ 8.43 (d, J = 9.2 Hz, 1H), 7.91–7.84 (m, 1H),
7.80–7.74 (m, 1H), 7.37–7.24 (m, 2H), 7.17–7.08 (m, 1H), 6.94
(td, J = 6.8, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.6 (q,
J = 34.9 Hz), 160.2, 151.5 (dd, J = 84.2, 10.7 Hz), 149.1 (dd, J =
79.3, 10.8 Hz), 142.6, 139.2, 137.1 (dd, J = 7.9, 3.9 Hz), 122.9
(dd, J = 6.8, 4.0 Hz), 122.1, 117.8 (dd, J = 18.7, 0.8 Hz), 116.9 (q,
J = 286.2 Hz), 116.6 (dd, J = 20.1, 1.0 Hz), 114.1; 19F NMR (282
MHz, CDCl3) δ -76.58 (s, 3F), -134.11 (m, 1F), -134.62 (m 1F);
ESI-HRMS m/z calcd for C13H8F5N2O [M+H]+ 303.0551, found
303.0549.
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Compound 4a (88 mg, Y = 85%, Rf = 0.2 (PE:EA = 5:1)) was
1
isolated as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.55–7.48
(m, 1H), 7.38–7.29 (m, 3H), 7.28–7.20 (m, 1H), 7.21–7.12 (m,
4H), 7.11–7.03 (m, 2H), 6.01 (dd, J = 5.6, 2.4 Hz, 1H), 5.79 (dd, J
= 4.8, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.2, 165.9 (q,
J = 35.8 Hz), 140.9, 139.6, 139.0, 137.0, 136.9, 129.0, 127.6,
126.8, 126.3, 125.0, 124.0, 122.2, 116.6 (q, J = 286.1 Hz), 66.1,
50.0; 19F NMR (282 MHz, CDCl3) δ -76.13 (s, 3F); ESI-HRMS
m/z calcd for C19H14F3N2O [M+H]+ 343.1053, found 343.1051.
Compound 4b (87 mg, Y = 68%, Rf = 0.4 (PE:EA = 5:1)) was
2,2,2ꢀTrifluoroꢀNꢀ(1ꢀ(3ꢀmethoxyphenyl)pyridinꢀ2(1H)ꢀ
ylidene)acetamide. Compound 3p (111 mg, Y = 75%, Rf = 0.6
(EA)) was isolated as a yellow solid; mp 89–90 oC. 1H NMR (400
MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 1H), 7.88–7.73 (m, 2H), 7.36
(t, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.2 Hz, 1H), 6.93–6.80 (m,
3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.2 (q, J =
34.5 Hz), 160.0, 159.8, 142.2, 142.1, 139.6, 129.8, 122.1, 118.1,
117.0 (q, J = 286.3 Hz), 115.5, 114.1, 112.0, 55.4; 19F NMR (282
MHz, CDCl3) δ -76.40 (s, 3F); ESI-HRMS m/z calcd for
C14H12F3N2O2 [M+H]+ 297.0845, found 297.0843.
1
isolated as a yellow oil. H NMR (600 MHz, CDCl3) δ 7.40 (s,
1H), 7.24–7.18 (m, 2H), 7.14–7.07 (m, 2H), 7.03 (d, J = 1.8 Hz,
1H), 6.94 (dd, J = 7.8, 1.8 Hz, 1H), 5.93 (dd, J = 5.4, 1.8 Hz, 1H),
5.70 (dd, J = 5.4, 1.8 Hz, 1H), 2.95–2.84 (m, 8H), 2.13–2.06 (m,
4H); 13C NMR (150 MHz, CDCl3) δ 171.9, 165.9 (q, J = 35.7 Hz),
145.3, 144.0, 143.0, 142.3, 139.6, 138.0, 137.6, 137.4, 137.2,
124.6, 122.1, 121.5, 120.1, 118.6, 116.7 (q, J = 286.0 Hz), 67.0,
50.2, 32.8, 32.5, 32.5, 25.6, 25.5, (1C missing); 19F NMR (282
MHz, CDCl3) δ -76.05 (s, 3F); ESI-HRMS m/z calcd for
C25H22F3N2O [M+H]+ 423.1679, found 423.1678.
Nꢀ(1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)pyridinꢀ2(1H)ꢀylidene)ꢀ2,2,2ꢀ
trifluoroacetamide. Compound 3q (121 mg, Y = 78%, Rf = 0.5
o
1
(EA)) was isolated as a yellow solid; mp 128–129 C. H NMR
(300 MHz, CDCl3) δ 8.36 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 7.2 Hz,
1H), 7.79 (d, J = 6.6 Hz, 1H), 6.98–6.80 (m, 3H), 6.75 (dd, J = 8.1,
1.8 Hz, 1H), 6.05 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.2 (q,
J = 34.6 Hz), 160.3, 148.3, 147.9, 142.0, 139.9, 135.0, 122.0,
119.5, 117.0 (q, J = 286.3 Hz), 114.0, 108.0, 107.5, 102.1; 19F
NMR (282 MHz, CDCl3) δ -75.72 (s, 3F); ESI-HRMS m/z calcd
for C14H10F3N2O3 [M+H]+ 311.0638, found 311.0637.
Compound 4e (32 mg, Y = 46%, Rf = 0.5 (PE:EA = 3:1)) was
1
isolated as a brown oil. H NMR (400 MHz, CDCl3) δ 8.04–7.96
(m, 2H), 7.46–7.26 (m, 9H), 7.23–7.18 (m, 1H), 7.16–7.10 (m,
2H), 7.07–7.01 (m, 2H), 5.90 (dd, J = 5.2, 2.8 Hz, 1H), 5.68 (dd, J
= 4.4, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.0, 164.6,
141.7, 141.2, 140.0, 137.1, 136.8, 131.7, 129.6, 128.7, 127.8,
126.4, 126.3, 126.0, 124.7, 124.3, 121.8, 64.5, 49.6, (1C missing);
ESI-HRMS m/z calcd for C24H19N2O [M+H]+ 351.1492, found
351.1493.
Nꢀ(1ꢀ(2,3ꢀDihydroꢀ1Hꢀindenꢀ5ꢀyl)pyridinꢀ2(1H)ꢀylidene)ꢀ2,2,2ꢀ
trifluoroacetamide. Compound 3r (118 mg, Y = 77%, Rf = 0.5
o
1
(EA)) was isolated as a yellow solid; mp 131–132 C. H NMR
(400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 1H), 7.89–7.72 (m, 2H),
7.29 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H),
6.90 (t, J = 6.4 Hz, 1H), 3.01–2.88 (m, 4H), 2.20–2.07 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 163.1 (q, J = 34.5 Hz), 160.2,
145.6, 145.4, 141.8, 140.0, 139.4, 124.5, 123.8, 122.1, 121.9,
117.1 (q, J = 286.3 Hz), 114.1, 32.6, 32.4, 25.3; 19F NMR (282
MHz, CDCl3) δ -76.24 (s, 3F); ESI-HRMS m/z calcd for
C16H14F3N2O [M+H]+ 307.1053, found 307.1052.
Compound 4f (61 mg, Y = 80%, Rf = 0.5 (PE:EA = 3:1)) was
1
isolated as a brown oil. H NMR (400 MHz, CDCl3) δ 7.58–7.72
(m, 1H), 7.38–7.33 (m, 1H), 7.24–7.15 (m, 3H), 7.12 (t, J = 3.6
Hz, 2H), 7.02 (s, 1H), 6.93 (dd, J = 8.0, 1.2 Hz, 1H), 6.02 (t, J =
3.4 Hz, 1H), 5.77 (t, J = 3.4 Hz, 1H), 2.90 (t, J = 7.6 Hz, 4H),
2.09 (quint, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.4,
166.0 (q, J = 35.9 Hz), 145.4, 144.2, 141.0, 139.2, 137.9, 137.1,
136.9, 126.8, 126.3, 125.1, 124.7, 122.2, 122.1, 122.0, 116.6 (q, J
= 286.0 Hz), 66.7, 50.2, 32.8, 32.5, 25.5; 19F NMR (282 MHz,
CDCl3) δ -75.96 (s, 3F); ESI-HRMS m/z calcd for C22H18F3N2O
[M+H]+ 383.1366, found 383.1367.
2,2,2ꢀTrifluoroꢀ1ꢀ(2ꢀ((6ꢀmethylpyridinꢀ2ꢀyl)amino)phenyl)ethanꢀ
1ꢀone. Compound 3i’ (92 mg, Y = 66%, Rf = 0.6 (PE:EA = 5:1))
o
1
was isolated as an orange-yellow solid; mp 59–60 C. H NMR
(400 MHz, CDCl3) δ 10.87 (s, 1H), 8.83 (d, J = 8.8 Hz, 1H),
7.94–7.85 (m, 1H), 7.63–7.56 (m, 1H), 7.52 (t, J = 7.8 Hz, 1H),
6.93 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.0
Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 181.7 (q, J
= 33.3 Hz), 157.1, 153.2, 147.8, 138.0, 137.1, 131.7 (q, J = 4.0
Compound 4g (29 mg, Y = 41%, Rf = 0.25 (PE:EA = 3:1)) was
isolated as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.34–7.28 (m, 2H), 7.28–
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7.22 (m, 1H), 7.22–7.17 (m, 1H), 7.11 (dd, J = 6.8, 5.6 Hz, 1H),
Notes
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2
3
4
5
6
7
8
7.04–6.96 (m, 2H), 6.76 (dd, J = 6.8, 1.6 Hz, 1H), 5.57 (dd, J =
5.6, 1.6 Hz, 1H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.6, 160.4 (q, J = 36.4 Hz), 142.6, 142.0, 141.3, 141.0, 136.8,
129.8, 128.3, 126.7, 126.2, 124.1, 122.6, 122.1, 116.3 (q, J =
286.5 Hz), 66.9, 55.1, 14.9; 19F NMR (282 MHz, CDCl3) δ -74.49
(s, 3F); ESI-HRMS m/z calcd for C20H16F3N2O [M+H]+ 357.1209,
found 357.1212.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank NSFC (21472072, 21302077, and 21290183), Program
for Changjiang Scholars and Innovative Research Team in Uni-
versity (PCSIRT: IRT_15R28), FRFCU (lzujbky-2016-ct02,
lzujbky-2014-188) and “111” Program of MOE for financial sup-
port. We thank Dr. Hanwei Hu and Dr. Vaneet Saini for assis-
tance in polishing the manuscript and Prof. Hai-Chao Xu for as-
sistance in electrosynthetic attempt of pyrido[1,2-a]benzimidazole.
Compound 4h (45 mg, Y = 63%, Rf = 0.5 (PE:EA = 3:1)) was
9
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isolated as a brown oil. H NMR (400 MHz, CDCl3) δ 7.53–7.48
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(m, 1H), 7.41–7.36 (m, 2H), 7.35–7.28 (m, 1H), 7.31–7.26 (m,
1H), 7.24–7.15 (m, 4H), 6.63 (dt, J = 5.6, 2.0 Hz, 1H), 5.74–5.66
(m, 2H), 2.11 (d, J = 2.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
171.5, 166.0 (q, J = 35.9 Hz), 148.6, 141.5, 139.7, 139.1, 129.3,
129.0, 127.6, 126.6, 126.5, 124.8, 124.0, 121.6, 113.8 (d, J =
285.9 Hz), 66.6, 55.4, 18.8; 19F NMR (282 MHz, CDCl3) δ -76.15
(s, 3F); ESI-HRMS m/z calcd for C20H16F3N2O [M+H]+ 357.1209,
found 357.1214.
Compound 4i (46 mg, Y = 65%, Rf = 0.5 (PE:EA = 3:1)) was
isolated as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J =
6.4 Hz, 1H), 7.40–7.34 (m, 3H), 7.30–7.25 (m, 1H), 7.23–7.14 (m,
4H), 6.60 (dt, J = 6.0, 1.8 Hz, 1H), 5.86 (d, J = 6.0 Hz, 1H), 5.45
(d, J = 1.6 Hz, 1H), 2.06 (d, J = 1.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.6, 166.0 (q, J = 35.9 Hz), 147.3, 140.8, 139.8, 139.7,
129.1, 128.9, 127.7, 127.1, 126.2, 124.8, 124.4, 122.1, 116.6 (q, J
= 285.9 Hz), 70.9, 49.6, 18.2; 19F NMR (282 MHz, CDCl3) δ -
76.06 (s, 3F); ESI-HRMS m/z calcd for C20H16F3N2O [M+H]+
357.1209, found 357.1212.
REFERENCES
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Compound 5c (27 mg, Y = 71%, Rf = 0.3 (PE:EA = 2:1)) was
o
1
isolated as a white solid; mp 164–165 C. H NMR (300 MHz,
CDCl3) δ 7.43–7.33 (m, 2H), 7.30–7.20 (m, 3H), 6.65–6.57 (m,
1H), 6.52–6.44 (m, 1H), 5.10–5.00 (m, 1H), 4.88–4.78 (m, 1H),
3.64 (dd, J = 8.1, 4.2 Hz, 1H), 3.45 (dd, J = 8.1, 3.3 Hz, 1H), 2.92
(s, 3H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 175.2, 174.7,
162.2, 161.1, 140.5, 132.2, 131.7, 129.2, 126.9, 124.8, 80.5, 58.1,
46.7, 40.9, 40.6, 28.1, 25.0; ESI-HRMS m/z calcd for C21H24N3O4
[M+H]+ 382.1761, found 382.1763.
Benzo[4,5]imidazo[1,2ꢀa]pyridine. Compound 6c (13 mg, Y = 24%
1
for 2 steps, Rf = 0.1 (EA)) was isolated as a yellow solid; H
NMR (400 MHz, CD3COCD3) δ 8.91 (d, J = 6.8 Hz, 1H), 8.19 (d,
J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H),
7.58–7.47 (m, 2H), 7.40–7.33 (m, 1H), 6.97 (t, J = 6.8 Hz, 1H).
1H NMR data correspond to the reported values.20
ASSOCIATED CONTENT
Supporting Information
(4) For free amine see: (a) Rao, D. N.; Rasheed, S.; Aravinda, S.;
Vishwakarma, R. A.; Das, P. RSC Adv. 2013, 3, 11472. (b) Kim,
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Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481. For
amide see: (d) Inukai, T.; Takeuchi, J.; Yasuhiro, T.; Wolf, M. A.;
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2015, WO 2015068767. (e)Taniguchi, T.; Yoshikawa, M.; Miura,
K.; Hasui, T.; Honda, E.; Imamura, K.; Kamata, M.; Kamisaki, H.;
Quinn, J. F.; Raker, J.; Camara, F.; Wang, Y. PCT Int. Appl. 2011,
WO 2011163355.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Copies of 1H, 13C NMR, 19F NMR, and 1D NOE spectra for sub-
strates and all new compounds (PDF)
X-ray Crystallographic information for compound 5c (CIF)
AUTHOR INFORMATION
Corresponding Author
(5) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
*E-mail: chengb@lzu.edu.cn.
*E-mail: zhaihb@pkusz.edu.cn.
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