Overcoming Electron-Withdrawing and Product-Inhibition Effects by Organocatalytic Aerobic Oxidation of Alkylpyridines and Related Alkylheteroarenes to Ketones

Article abstract of DOI:10.1021/acs.joc.9b03205

An organocatalyzed aerobic benzylic C-H oxidation of alkyl and aryl heterocycles has been developed. This transition metal-free method is able to overcome the electron-withdrawing effect as well as product-inhibition effects in heterobenzylic radical oxidation. A variety of ketones bearing N-heterocyclic groups could be prepared under relatively mild conditions with moderate to high yields.

Full text of DOI:10.1021/acs.joc.9b03205

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Note
Overcoming Electron-Withdrawing and Product-Inhibition
Effects by Organocatalytic Aerobic Oxidation of Alkyl
Pyridines and Related Alkylheteroarenes to Ketones
Hua Wang, Jie Liu, Jian-Ping Qu, and Yan-Biao Kang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03205 • Publication Date (Web): 23 Jan 2020
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The Journal of Organic Chemistry
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Overcoming Electron-Withdrawing and Product-Inhibition Effects
by Organocatalytic Aerobic Oxidation of Alkyl Pyridines and Re-
lated Alkylheteroarenes to Ketones
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Hua Wang,† Jie Liu,† Jian-Ping Qu,‡* and Yan-Biao Kang†*
† Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡ Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
ABSTRACT: An organocatalyzed aerobic benzylic C-H oxidation of alkyl- and aryl heterocycles has been developed. This transition
metal-free method is able to overcome the electron-withdrawing effect as well as product-inhibition effects in heterobenzylic radical
oxidation. A variety of ketones bearing N-heterocyclic groups could be prepared under relatively mild conditions with moderate to
high yields.
Ketones bearing N-heterocyclic groups are important moie-
ties frequently found in natural products, bioactive reagents as
well as agrochemicals and useful intermediates in the synthesis
of pharmaceuticals, such as antihistamines and acrivastine. The
preparation of such compounds normally involves organome-
tallic reagents. For example, the Friedel-Crafts acylation for the
synthesis of acylarenes is not feasible for electron-deficient het-
erocycles, and 2-acetylpyridine is prepared by acylation of 2-
bromopyridine via the Grignard reagent. Another method to
prepare ketones bearing electron-deficient heterocycles is to use
heterobenzylic C-H oxidation from corresponding alkyl hetero-
cycles. On the other hand, the use of molecular oxygen as a
green and sustainable oxidant has attracted considerable atten-
tion due to its highly atom-economical, abundant, and environ-
mentally friendly characteristics.1 Considering that alkyl- and
aryl heterocycles are relatively readily available starting mate-
rials, the synthesis of N-heterocyclic ketones by catalytic aero-
hydroxyphthalimide (NHPI) catalysis, they found the electro-
chemical oxidation was necessary for higher yield.6
Scheme 1. Catalytic Aerobic Oxidation of Heterobenzylic
Methylenes
bic oxidation of alpha-C-H bond under environment-friendly
2-9
conditions would provide a good alternative.
However, the
utilization of metals as catalysts in aerobic oxidation often suf-
fers product-inhibition by the chelation of heterocycle and
newly formed carbonyl to metal-catalysts, resulting in the us-
ages of additives or special treatments. For example, Maes and
co-workers developed a base metal (copper and iron) catalyzed
oxidation of benzyl pyridine via an acid-promoted imine-
enamine tautomerization.3a It works effectively with 2- and 4-
benzyl pyridine albeit incompetently with 3-benzyl pyridine
and 2-methyl pyridine (Scheme 1a). Gao et al. reported an io-
dide-promoted aerobic oxidation, in which the heterocycles are
activated by acetic acid, but only limited to of 2- or 4-benzyl
pyridines.4 Lei et al. found that one equivalent of chloroacetate
can promote the aerobic oxidation of heterobenzylic methyl-
enes by forming pyridium salts in the presence of copper cata-
lyst and DMF at 130 oC.5 This method can be used for both ali-
phatic and aromatic substituted 2-methylpyridines.
Recently, we reported that NHPI-tBuONO (TBN) system
could mediate the benzyl ammoxidation under transition metal-
free conditions,10 in which the regeneration of PINO radical
from NHPI is promoted by TBN under O2. Herein we report our
latest results in the development of NHPI catalyzed heteroben-
zylic oxygenation of alkylpyridines and the related heteroarenes
in the presence of O2 to achieve heterocyclic ketones (Scheme
1b). The transition metal-free conditions avoid the chelation of
Besides, the oxygenation of C–H bonds on benzylic positions
which are directly adjacent to an alkyl group is even more chal-
lenging. For example, Stahl et al. investigated the aerobic oxy-
genation
of
(hetero)arenes
via
a
cobalt(II)/N-
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pyridine or acylpyridines to metal catalysts. In addition, the
large amount of TBN ensures the high efficiency for PINO re-
generation, which is necessary for high efficient generation of
benzylic radical intermediates. This method provides a practical
and convenient access to pharmaceuticals containing substi-
tuted aromatic ketones from the environmental and economic
viewpoints.
Page 2 of 7
afforded the desired product 2a in 39% yield (Table 1, entry 1).
Among the solvents screened, PhCN gave the optimal yield (en-
tries 1-6). To improve the reactivity of the reaction, the amounts
of reagent NHPI, TBN, and the reaction time were investigated.
It was found that 2a was obtained in high yield in with 5 mol%
NHPI catalyst and 2.0 equiv TBN for 24 h (entries 6−8, and
10−11). NHPI is better than hydroxybenzotriazole (HOBt) or 1-
Hydroxy-7-azabenzotriazole (HOAt) (entries 12-14). The ne-
cessity of both NHPI and TBN is also confirmed by control ex-
periments (entries 15-17).
1
2
3
4
5
6
7
8
Initially, the reaction conditions were investigated using 2-
benzylpyridine 1a as a model substrate. Stoichiometric NHPI
o
and TBN in the presence of O2 atmosphere in DMF at 80 C
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Table 1. Screening of Reaction Conditionsa
entry
1
x
y
solvent
DMF
temperature(oC)
t(h)
12
12
12
12
12
12
12
12
12
12
12
24
24
24
24
24
24
2a(%)b
39
86
6
3
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
HOBt
HOAt
NHPI
none
100
100
100
100
100
100
10
10
10
10
5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
0
80
80
80
80
80
80
80
80
90
70
80
80
80
80
80
80
80
2
(CF3)2CHOH
THF
3
4
PhCl
66
90
80
85
82
72
60
56
89
43
54
35
0
5
PhCN
MeCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
6
7
8
9
10
11
12
13
14
15
16
17c
a
5
5
5
5
5
2.0
2.0
NHPI
5
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Conditions: 1a (0.5 mmol), solvent (1 mL). b 1H NMR yield was reported using nitromethane and tert-butyl methyl ether as internal
standard. c In the absence of O2.
Subsequently, the scope of the substrate has been investi-
gated under optimized conditions (Table 1, entry 12). Various
hetero-benzylic methylenes bearing different functional groups
were subjected to the optimized conditions, and the correspond-
ing ketone products were obtained in moderate to good yields
(Scheme 2). A variety of heterobenzylic methylene derivatives
bearing electron withdrawing substituents in aryl groups such
as cyano-, chloro-, and bromo aryl groups were well oxidized
to the corresponding ketones (2b, 2e-h). The substrates with
electron donating heterocyclic substituents gave lower yields
(2m-n), while the substrates with electron donating aryl substit-
uents gave moderate to good yields (2o-p). Other alkyl on the
N-containing five-membered heterocycles were evaluated and
the corresponding ketones were achieved in 49-82% yields (2q-
2u). 2-Ethylpyridine 1v is less reactive substrate under standard
conditions, because the electron deficient heterocycles is not fa-
vorable for the stabilization of the benzylic radical intermedi-
ates. Increasing the loading of NHPI results in improved yields
of 2v. Oxidations of 1w-z under similar conditions afforded 2w-
z in good yields too.
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The Journal of Organic Chemistry
Scheme 2. Scope of Aryl Heterocyclic Benzylic Oxidationa
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a Standard conditions: 1 (0.5 mmol), NHPI (5 mol %.), TBN ( 2 equiv), PhCN (0.5 M), 80 °C, O2, 24 h, isolated yield. b NHPI (10 mol%).
c NHPI (15 mol %). d NHPI (50 mol %), MeCN (0.5 M). e NHPI (50 mol %), TBN (1.0 equiv), MeCN (0.5 M).
A comparison of reactivity of 1x and 1zA shows that this
metal-free method has no obvious negative effect for heterocy-
cles (Scheme 3).
acylpyri-dines and related derivatives from corresponding al-
kyl- or aryl heteroarenes. This reaction provides a powerful
method for overcoming the electron-withdrawing effect as well
as product-inhibition effects in heterobenzylic radical oxida-
tion. A variety of N-heterocyclic ketones could be prepared un-
der relatively mild conditions.
Scheme 3. Competitive Reaction between Aryl Heterocyclic
Benzylic oxidation and Aryl Benzylic Oxidation
EXPERIMENTAL SECTION
General information. All reactions were carried out under
atmospheric pressure. Solvents were pre-dried over activated 4
Å molecular sieves and heated to reflux over calcium hydride
(PhCN, CH3CN, DCM, Et3N, THF, DMF, DCE, PhCl, HFIP,
DMSO) under argon atmosphere and collected by distillation.
1H, 13C NMR spectra were recorded on a Bruker 400 spectrom-
eter; Chemical shifts are reported in δ units relative to CDCl3
[1H δ = 7.26, 13C δ = 77.16]. HRMS were recorded by the mass
spectrometry service at University of Science and Technology
In conclusion, we have developed a metal-free organocata-
lyzed aerobic heterobenzylic C-H oxidation for the synthesis of
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Page 4 of 7
of China (Cl-35, Br-79). Methylarenes and other chemicals
without notes in experimental section were purchased from
commercial sources.
temperature and diluted with CH2Cl2 (2 mL), concentrated and
purified by column chromatography to give the pure product 2.
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Procedure for the Synthesis of Starting Compounds 1.
Compounds 1f, 1g, 1j, 1k, 1m, and 1s were synthesized by re-
ported procedure.2a
Gram-Scale Preparation of 2g. N-hydroxyphthalimide 3
(0.5 mmol, 0.05 equiv, 81.5 mg) was weighted into a Schlenk
tube. After dried in vacuum for 15 min, dry PhCN (20 mL) was
added under an oxygen atmosphere followed by the addition of
tBuONO (20 mmol, 2.0 equiv, 2.4 mL). 1g (10 mmol, 1.0 equiv,
2.73g) was then added and the reaction mixture was stirred at
80 oC by oil bath for 24h. Next, the reaction mixture was cooled
to room temperature and purified by column chromatography
(PE/EA =10:1) to give the pure product 2g, light yellow solid
(2.44g, 85% yield).
6-(4-Chlorobenzyl)nicotinonitrile (1f). Obtained as a yellow
solid. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.86 (dt, J =
8.1 Hz, 1.7 Hz, 1H), 7.29 (dd, J = 8.2 Hz, 1.1 Hz, 2H), 7.23 (d,
J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 4.18 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 164.8, 152.2, 139.7, 136.3, 132.8,
130.5, 129.0, 123.0, 116.8, 107.7, 44.1. HRMS (ESI−TOF) m/z:
[M+H]+ calcd for C13H10ClN2 229.0527, found 229.0532. Melt-
ing point: 62-64 °C.
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Phenyl(pyridin-2-yl)methanone (2a).6 2a was prepared ac-
cording to the general procedure using NHPI (0.025 mmol, 0.05
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
column chromatography (PE/EA =10:1), light yellow oil (74.2
6-(2-Bromobenzyl)nicotinonitrile (1g). Obtained as a light
1
orange oil. H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 1.9 Hz,
1H), 7.83 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H),
7.29 (d, J = 4.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.11-7.17 (m,
1H), 4.36 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0,
152.2, 139.6, 137.3, 133.1, 131.8, 128.9, 127.9, 124.9, 123.1,
116.8, 107.6, 44.8. HRMS (ESI−TOF) m/z: [M+H]+ calcd for
C13H10BrN2 273.0022, found 273.0023.
1
mg, 81% yield). H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H),
8.00-8.06 (m, 3H), 7.83-7.90 (m, 1H), 7.54-7.59 (m, 1H), 7.43-
7.49 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 155.1,
148.6, 137.1, 136.3, 132.9, 131.0, 128.2, 126.2, 124.6.
(4-Chlorophenyl)(pyridin-2-yl)methanone (2b).5 2b was pre-
pared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =20:1), light
white solid (82.7 mg, 76% yield). 1H NMR (400 MHz, CDCl3)
δ 8.72 (d, J = 3.3 Hz, 1H), 8.07 (d, J = 7.4 Hz, 3H), 7.92 (t, J =
7.4 Hz, 1H), 7.45-7.52 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 192.5, 154.7, 148.6, 139.5, 137.3, 134.6, 132.6, 128.6,
126.5, 124.8.
(2-(4-Chlorobenzyl)pyrimidine) (1j). Obtained as a light yel-
low oil. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.9 Hz, 2H),
7.25-7.31 (m, 4H), 7.13 (t, J = 4.9 Hz, 1H), 4.26 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 157.3, 136.6, 132.4,
130.5, 128.6, 118.7, 45.2. HRMS (ESI−TOF) m/z: [M+H]+
calcd for C11H10ClN2 205.0527, found 205.0529.
4-Benzyl-2-chloropyrimidine (1k). Obtained as a deep orange
solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 5.1 Hz, 1H),
7.33-7.37 (m, 2H), 7.25-7.31 (m, 3H), 7.00 (d, J = 5.1 Hz, 1H),
4.11 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 161.3,
159.5, 136.5, 129.4, 129.1, 127.4, 118.9, 44.0. HRMS
(ESI−TOF) m/z: [M+H]+ calcd for C11H10ClN2 205.0527, found
205.0527. Melting point: 56-57 °C.
Phenyl(pyridin-3-yl)methanone (2c). 6 2c was prepared ac-
cording to the general procedure using NHPI (0.05 mmol, 0.1
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
column chromatography (PE/EA =3:1), light yellow oil (49.4
1
mg, 54% yield). H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H),
8.82 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.4 Hz, 2H),
7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.46 (q, J =
4.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 153.0,
151.1, 137.3, 136.8, 133.3, 130.2, 128.8, 123.5.
Phenyl(pyridin-4-yl)methanone (2d).6 2c was prepared ac-
cording to the general procedure using NHPI (0.05 mmol, 0.1
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
column chromatography (PE/EA =3:1), light yellow oil (60.4
mg, 66% yield). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 5.9
Hz, 2H), 7.81 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.58
(d, J = 5.9 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ 195.1, 150.3, 144.4, 135.9, 133.6, 130.2, 128.7,
123.0.
6-Benzoylnicotinonitrile (2e) 2a 2e was prepared according to
the general procedure using NHPI (0.025 mmol, 0.05 equiv),
TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash column
chromatography (PE/EA =10:1), light yellow solid (78.1 mg,
75% yield). 1H NMR (400 MHz, CDCl3) δ 8.97 (t, J = 1.9 Hz,
0.9 Hz, 1H), 8.13-8.20 (m, 2H), 8.04-8.06 (m, 2H), 7.62-7.66
(m, 1H), 7.51 (t, J = 7.9 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 192.1, 157.4, 151.2, 140.6, 135.2, 133.8, 131.1, 128.5,
124.4, 116.1, 112.1. HRMS (ESI−TOF) m/z: [M+H]+ calcd for
C13H9N2O 209.0709, found 209.0708. Melting point: 92-93 °C.
2-Benzyl-5-methoxypyridine (1m). Obtained as a light yel-
1
low solid. H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.9 Hz,
1H), 7.24-7.32 (m, 4H), 7.21 (t, J = 7.0 Hz, 1H), 7.07-7.12 (m,
1H), 7.03 (d, J = 8.5 Hz, 1H), 4.11 (s, 2H), 3.80 (d, J = 11.1 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 153.1, 140.1,
136.6, 129.0, 128.6, 126.3, 123.2, 121.4, 55.6, 43.7. HRMS
(ESI−TOF) m/z: [M+H]+ calcd for C13H14NO 200.1070, found
200.1071. Melting point: 62-64 °C.
2-(2-Bromobenzyl)benzo[d]thiazole (1s). Obtained as a light
yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.2 Hz,
1H), 7.79 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.43-
7.47 (m, 1H), 7.40-7.42 (m, 1H), 7.28-7.36 (m, 2H), 7.17 (td, J
= 7.8 Hz, 1.7 Hz, 1H), 4.60 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 169.8, 153.3, 137.0, 135.7, 133.3, 131.5, 129.3, 128.0,
126.1, 125.0, 124.9, 122.9, 121.6, 40.8. HRMS (ESI−TOF) m/z:
[M+H]+ calcd for C14H11BrNS 303.9790, found 303.9792.
Melting point: 68-69 °C.
General Procedure for Aerobic heterobenzylic C-H oxi-
dation. N-hydroxyphthalimide 3 (0.05-0.5 equiv) was weighted
into a Schlenk tube. After dried in vacuum for 15 min, dry
PhCN (1 mL) was added under an oxygen atmosphere followed
t
by the addition of BuONO (1.0-2.0 equiv). 1 (0.5 mmol) was
then added and the reaction mixture was stirred at 80 oC by oil
bath and monitored by TLC analysis until the complete con-
sumption of 1. Next, the reaction mixture was cooled to room
6-(4-Chlorobenzoyl)nicotinonitrile (2f). 2f was prepared ac-
cording to the general procedure using NHPI (0.025 mmol, 0.05
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
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The Journal of Organic Chemistry
column chromatography (PE/EA =10:1), light yellow solid
Hz, 2H), 7.99 (dd, J = 8.2 Hz, 1.0 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.43-7.47 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
191.3, 162.6, 157.4, 135.0, 133.7, 130.9, 128.4, 122.3. HRMS
(ESI−TOF) m/z: [M+H]+ calcd for C11H9N2O 185.0709, found
185.0710.
(105.6 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 8.97 (s,
1H), 8.16-8.22 (m, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.48 (d, J =
8.5 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 190.6, 157.0,
151.2, 140.8, 140.5, 133.6, 132.6, 128.9, 124.5, 116.1, 112.4.
HRMS (ESI−TOF) m/z: [M+H]+ calcd for C13H8ClN2O
243.0320, found 243.0327. Melting point: 125-127 °C.
1
2
3
4
5
6
7
8
(5-Methoxypyridin-2-yl)(phenyl)methanone (2m).2a 2m was
prepared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =5:1), light or-
6-(2-Bromobenzoyl)nicotinonitrile (2g). 2g was prepared ac-
cording to the general procedure using NHPI (0.025 mmol, 0.05
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
column chromatography (PE/EA =10:1), light yellow solid
(125.2 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 8.89 (s,
1H), 8.22 (qd, J = 8.1 Hz, 0.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H),
7.44-7.48 (m, 2H), 7.38-7.43 (m, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 194.5, 155.6, 151.9, 140.8, 139.2, 133.2, 132.4,
130.2, 127.5, 123.4, 120.3, 116.1, 112.8. HRMS (ESI−TOF)
m/z: [M+H]+ calcd for C13H8BrN2O 286.9815, found 286.9820.
Melting point: 125-128 °C.
1
ange oil (54.7 mg, 51% yield). H NMR (400 MHz, CDCl3) δ
9
8.37 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.04 (d, J =
7.0 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H),
7.32 (dd, J = 7.8 Hz, 1.9 Hz, 1H), 3.93 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 193.0, 157.8, 147.6, 137.0, 136.7, 132.5,
130.9, 128.1, 126.4, 120.2, 55.9.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5-Methylpyridin-2-yl)(phenyl)methanone (2n).2a 2n was pre-
pared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =10:1), light yel-
(6-Chloropyridin-2-yl)(phenyl)methanone (2h).2a 2c was pre-
pared according to the general procedure using NHPI (0.05
mmol, 0.1 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =50:1), light yel-
1
low oil (47.5 mg, 48% yield). H NMR (400 MHz, CDCl3) δ
8.54 (s, 1H), 8.05 (d, J = 7.1 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J =
7.8 Hz, 2H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
194.0, 152.7, 149.2, 137.5, 136.7, 136.7, 132.9, 131.1, 128.2,
124.5, 18.8.
(3-Methoxyphenyl)(pyridin-2-yl)methanone (2o)12 2o was
prepared according to the general procedure using NHPI (0.075
mmol, 0.15 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =5:1), brown liq-
uid (84.1 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 8.71-
8.72 (m, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H),
7.60-7.62 (m, 2H), 7.46-7.49 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H),
7.12-7.15 (m, 1H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 193.8, 159.5, 155.2, 148.7, 137.6, 137.1, 129.3, 126.3,
124.7, 124.0, 119.6, 115.2, 55.5.
(3-Methoxyphenyl)(pyridin-4-yl)methanone (2p)13 2p was
prepared according to the general procedure using NHPI (0.075
mmol, 0.15 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =5:1), white
solid (63.8 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.80-
8.81 (m, 2H), 7.58-7.59 (m, 2H), 7.32-7.43 (m, 3H), 7.17-7.20
(m, 1H), 3.87 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
195.0, 159.9, 150.4, 144.5, 137.2, 129.7, 123.1, 122.9, 120.1,
114.2, 55.6.
1
low oil (80.1 mg, 74% yield). H NMR (400 MHz, CDCl3) δ
8.08-8.10 (m, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 7.8 Hz,
1H), 7.59-7.63 (m, 1H), 7.47-7.54 (m, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 192.0, 155.4, 150.4, 139.8, 135.6, 133.4, 131.2,
128.4, 127.2, 123.3.
(2-Bromophenyl)(pyrimidin-2-yl)methanone (2i).11 2i was
prepared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =3:1), light yel-
1
low solid (116.0 mg, 88% yield). H NMR (400 MHz, CDCl3)
δ 8.93 (d, J = 4.9 Hz, 2H), 7.60-7.62 (m, 2H), 7.46 (q, J = 12.0
Hz, 2H), 7.39 (dt, J = 7.4 Hz, 1.8 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 193.6, 161.2, 157.8, 139.6, 133.2, 132.6, 130.8,
127.6, 122.7, 120.7.
(4-Chlorophenyl)(pyrimidin-2-yl)methanone (2j).2a 2j was
prepared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =3:1), light yel-
1
low solid (104.4 mg, 95% yield). H NMR (400 MHz, CDCl3)
δ 8.95 (d, J = 4.9 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.50 (t, J =
4.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 190.0, 162.2, 157.5, 140.3, 133.5, 132.4, 128.8, 122.5.
HRMS (ESI−TOF) m/z: [M+H]+ calcd for C11H8ClN2O
219.0320, found 219.0320. Melting point: 90-92 °C.
Benzo[d]oxazol-2-yl(phenyl)methanone (2q)3b 2q was pre-
pared according to the general procedure using NHPI (0.075
mmol, 0.15 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =20:1), light yel-
(2-Chloropyrimidin-4-yl)(phenyl)methanone (2k).2k was
prepared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =10:1), light yel-
1
low solid (65.2 mg, 58% yield). H NMR (400 MHz, CDCl3) δ
8.54-8.56 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.70 (q, J = 8.2 Hz,
2H), 7.54-7.59 (m, 3H), 7.48 (t, J = 8.2 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 180.7, 157.2, 150.5, 140.9, 135.1, 134.4,
131.1, 128.8, 128.6, 125.7, 122.5, 112.0.
1
low oil (58.0 mg, 53% yield). H NMR (400 MHz, CDCl3) δ
8.89 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.81 (d, J =
5.0 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.1 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 164.3, 161.5, 161.0,
134.4, 134.3, 131.1, 128.7, 118.9. HRMS (ESI−TOF) m/z:
[M+H]+ calcd for C11H8ClN2O 219.0320, found 219.0319.
Benzo[d]thiazol-2-yl(phenyl)methanone (2r).3b 2r was pre-
pared according to the general procedure using NHPI (0.025
mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =20:1), light yel-
Phenyl(pyrimidin-2-yl)methanone (2l). 2l was prepared ac-
cording to the general procedure using NHPI (0.025 mmol, 0.05
equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by flash
column chromatography (PE/EA =3:1), light yellow oil (67.2
mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 4.9
1
low solid (98.5 mg, 82% yield). H NMR (400 MHz, CDCl3) δ
8.57 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.2 Hz, 1H), 8.00 (d, J =
7.7 Hz, 1H), 7.65-7.69 (m, 1H), 7.54-7.58 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3) δ 185.4, 167.2, 153.9, 137.1, 135.0,
134.0, 131.4, 128.6, 127.7, 127.0, 125.8, 122.3.
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Benzo[d]thiazol-2-yl(2-bromophenyl)methanone (2s). 2s
MHz): δ 193.8, 168.8, 136.1, 131.3, 127.3, 126.4, 125.3, 122.6,
122.0, 116.2, 28.0, 24.2.
1
2
3
4
5
6
7
8
was prepared according to the general procedure using NHPI
(0.025 mmol, 0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h,
and purified by flash column chromatography (PE/EA =20:1),
1-(Thiophen-2-yl)ethan-1-one (2z).16 2z was prepared ac-
cording to the general procedure using NHPI (0.25 mmol, 0.5
equiv), TBN (1.0 mmol, 2.0 equiv), MeCN (1 mL), 24 h, and
purified by flash column chromatography (PE/EA =20:1), light
yellow oil (44.2 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ
7.67 (dd, J = 3.8 Hz, 1.1 Hz, 1H), 7.61 (dd, J = 5.0 Hz, 1.1 Hz,
1H), 7.10 (dd, J = 5.0 Hz, 3.8 Hz, 1H), 2.53 (s, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 190.8, 144.6, 133.9, 132.6, 128.2,
26.9.
1
light yellow solid (77.9 mg, 49% yield). H NMR (400 MHz,
CDCl3) δ 8.16-8.18 (m, 1H), 8.01-8.03 (m, 1H), 7.70-7.74 (m,
2H), 7.54-7.59 (m, 2H), 7.48 (td, J = 7.5 Hz, 1.1 Hz, 1H), 7.43
(td, J = 7.7 Hz, 1.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 188.4, 165.8, 153.8, 138.1, 137.6, 133.8, 132.5, 130.8, 128.1,
127.2, 127.2, 126.1, 122.5, 120.7. HRMS (ESI−TOF) m/z:
[M+H]+ calcd for C14H9BrNOS 317.9583, found 317.9586.
Melting point: 103-105 °C.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(Benzo[b]thiophen-2-yl)ethan-1-one (2t).14 2t was pre-
pared according to the general procedure using NHPI (0.075
mmol, 0.15 equiv), TBN (0.5 mmol, 1.0 equiv), 24 h, and puri-
fied by flash column chromatography (PE/EA =20:1), light yel-
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.
NMR spectra (PDF).
1
low solid (52.5 mg, 60% yield). H NMR (400 MHz, CDCl3) δ
7.94 (s, 1H), 7.88 (t, J = 8.5 Hz, 2H), 7.45-7.49 (m, 1H), 7.39-
7.43 (m, 1H), 2.67 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
192.4, 144.1, 142.7, 139.2, 129.8, 127.6, 126.0, 125.1, 123.1,
26.9.
1-(Benzo[d]thiazol-2-yl)ethan-1-one (2u)5 2u was prepared
according to the general procedure using NHPI (0.025 mmol,
0.05 equiv), TBN (1.0 mmol, 2.0 equiv), 24 h, and purified by
flash column chromatography (PE/EA =20:1), light yellow
solid (61.8 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 8.18
(ddd, J = 8.2 Hz, 1.2 Hz, 0.9 Hz, 1H), 7.98 (ddd, J = 8.4 Hz, 1.3
Hz, 0.6 Hz, 1H), 7.51-7.60 (m, 2H), 2.83 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 193.3, 166.6, 153.7, 137.5, 127.8, 127.1,
125.6, 122.6, 26.3.
1-(Pyridin-2-yl)ethan-1-one (2v).5 2v was prepared accord-
ing to the general procedure using NHPI (0.25 mmol, 0.5
equiv), TBN (1.0 mmol, 2.0 equiv), MeCN (1 mL), 24 h, and
purified by flash column chromatography (PE/EA =10:1), light
yellow oil (42.4 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ
8.61 (s, 1H), 7.94-7.98 (m, 1H), 7.75-7.78 (m, 1H), 7.39-7.42
(m, 1H), 2.64-2.66 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 200.1, 153.5, 149.0, 136.8, 127.1, 121.6, 25.8.
1-(Pyridin-3-yl)ethan-1-one (2w) 5 2w was prepared accord-
ing to the general procedure using NHPI (0.25 mmol, 0.5
equiv), TBN (1.0 mmol, 2.0 equiv), MeCN (1 mL), 24 h, and
purified by flash column chromatography (PE/EA =10:1), light
yellow oil (40.0 mg, 66% yield). 1H NMR (400 MHz, CDCl3) δ
9.05 (s, 1H), 8.66-8.68 (m, 1H), 8.11-8.13 (m, 1H), 7.26-7.33
(m, 1H), 2.55 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
196.7, 153.5, 149.8, 135.4, 132.1, 123.6, 26.6.
1-(Pyridin-4-yl)ethan-1-one (2x).5 2x was prepared accord-
ing to the general procedure using NHPI (0.25 mmol, 0.5
equiv), TBN (1.0 mmol, 2.0 equiv), MeCN (1 mL), 24 h, and
purified by flash column chromatography (PE/EA =10:1), light
yellow oil (44.0 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ
8.76 (d, J = 5.4 Hz, 2H), 7.68 (d, J = 5.8 Hz, 2H), 2.58 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 151.0, 142.7, 121.2,
26.7.
1,1'-(1H-indole-1,3-diyl)bis(ethan-1-one) (2y) 15 2y was pre-
pared according to the general procedure using NHPI (0.25
mmol, 0.5 equiv), TBN (0.5 mmol, 1.0 equiv), MeCN (1 mL),
24 h, and purified by flash column chromatography (PE/EA
=5:1), light yellow oil (71.5 mg, 71% yield). 1H NMR (CDCl3,
400 MHz): δ 8.33-8.36 (m, 2H), 7.99-8.03 (m, 1H), 7.39-7.40
(m, 2H), 2.70 (s, 3H), 2.56 (s, 3H). 13C{1H} NMR (CDCl3, 100
AUTHOR INFORMATION
Corresponding Author
* E-mail: ybkang@ustc.edu.cn
* E-mail: ias_jpqu@njtech.edu.cn
ORCID
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Notes
Any additional relevant notes should be placed here.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(21602001, 21922109, 21672196, 21831007), the Start-Up Fund-
ingfrom Nanjing Tech University (39837134), and the Fundamen-
tal Research Funds for the Central Universities of China
(WK2060190086) for financial support.
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