Oxidative Cleavage of Enamides with Hypervalent Iodine(III)/TMSN 3 under an Air Atmosphere

Article abstract of DOI:10.1055/s-0036-1589041

An oxidative cleavage of C-C double bonds of enamides promoted by hypervalent iodine(III)/TMSN ₃ under an air atmosphere is developed. This reaction provides a new approach to construct various cyanobenzamides, which offers further synthetic potential for the preparation of industrial and pharmaceutical nitrogen- and oxygen-containing molecules, and exhibits good functional group tolerance, broad substrate scope and mild conditions.

Full text of DOI:10.1055/s-0036-1589041

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
G. Liu et al.
Paper
Synthesis
Oxidative Cleavage of Enamides with Hypervalent Iodine(III)/
TMSN3 under an Air Atmosphere
Ge Liu
O
Yan Li*
NHAc
NHAc
R
R
Jie Sheng
Xi-Sheng Wang*
0
0
0
0
0-
0
0
3
2-
3
9
8
5-
6
6
9
PhI(OAc)2, TMSN3
under air
R = Alkyl, Ph, halogen, CO2Me
NHAc
15 examples, 62–92% yields
O
Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry, University of Science and Technology of
China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. of China
liyan08@ustc.edu.cn
NHAc
N
R
R
1–3
1–3
xswang77@ustc.edu.cn
R = Alkyl, halogen, CO2Me
13 examples, 49–80% yields
Received: 29.03.2017
Accepted after revision: 05.05.2017
Published online: 20.06.2017
More remarkably, different from known methods to
construct only oxygen-containing motifs, the Jiao group has
recently developed a TEMPO-catalyzed oxygenation and ni-
trogenation through selective cleavage of simple alkenes
with molecular oxygen as the terminal oxidant, which af-
forded various oxonitriles for the further synthesis of nitro-
gen- and oxygen-containing molecules.8 However, this
transformation was not efficient under an air atmosphere,
and required a relatively high temperature. Moreover, only
simple alkenes were compatible with this reaction, and
electron-rich alkenes such as enamides have not been stud-
ied. Herein, we report a mild and easily handled method for
the oxidative cleavage of enamides, in which PhI(OAc)2
(PIDA) was used to promote the reaction with TMSN3 under
an air atmosphere.9
DOI: 10.1055/s-0036-1589041; Art ID: ss-2017-h0205-op
Abstract An oxidative cleavage of C–C double bonds of enamides pro-
moted by hypervalent iodine(III)/TMSN3 under an air atmosphere is de-
veloped. This reaction provides a new approach to construct various cy-
anobenzamides, which offers further synthetic potential for the
preparation of industrial and pharmaceutical nitrogen- and oxygen-
containing molecules, and exhibits good functional group tolerance,
broad substrate scope and mild conditions.
Key words oxidative cleavage, enamides, hypervalent iodine(III),
TMSN3, air atmosphere
Oxidative cleavage of carbon–carbon double bonds of
alkenes represents an essential transformation in organic
synthesis for both academic research and industrial appli-
cations.1 The most common and fundamental protocols for
the direct cleavage of C–C double bonds are ozonolysis2 and
Lemieux–Johnson oxidation,3 although the safety concerns
and toxicity of the oxidants has limited their utility to some
extent. A recent alternative protocol is transition-metal ca-
talysis using oxometals as oxygen-transfer agents in combi-
nation with a co-oxidant,4 but there are still concerns re-
garding toxicity and the use of expensive metals. In accor-
dance with the green trends in organic chemistry, metal-
free oxidation has emerged as an attractive approach to
cleave alkene double bonds. For instance, Ochiai and co-
workers have developed an ecofriendly method using or-
ganoiodine reagents as catalysts and mCPBA as the co-oxi-
dant.5 The Vinod group has introduced an iodonium ion,
generated from the oxidation of 4-iodobenzoic acid by Ox-
one in situ,6 to facilitate the cleavage of alkenes. Meanwhile,
Jiao et al. have reported an N-hydroxyphthalimide (NHPI)-
catalyzed oxidative cleavage of olefins with molecular oxy-
gen as the oxidant.7
Our initial study started with N-[1-(biphenyl-4-yl)vi-
nyl]acetamide (1a) as the model substrate in the presence
of the Zhdankin reagent (BI-N3) and a catalytic amount of
CuCl (5 mol%) in toluene at 80 °C for 24 hours under an air
atmosphere. To our delight, the desired product 2a was ob-
tained successfully in 23% yield (Table 1, entry 1). While
copper salts were believed to promote the N–I(III) bond dis-
connection in previous reports,10 our control experiment
showed that CuCl was not involved in this reaction (entry
2). Next, a careful solvent screening revealed that MeCN af-
forded the oxidative diacylamine product in 57% yield,
while diethyl ether and NMP gave none of the desired prod-
uct (entries 3–7). Considering that BI-N3 was prepared from
the hypervalent iodine(III) reagent BI-OAc and TMSN3, we
tried to generate the analogue of BI-N3 in situ with readily
available I(III) reagents and TMSN3 or NaN3 (entries 9–13).
Gratifyingly, the easiest to handle, PhI(OAc)2, gave a higher
yield of 76% with TMSN3 (1.5 equiv) as the co-reagent at
40 °C. Given that some by-products could be detected un-
der the reaction conditions, a reduction of the reaction time
to 12 hours and decreasing the reaction temperature to 0 °C
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
G. Liu et al.
Paper
Synthesis
gave an enhanced 87% yield (entry 19). Finally, the addition
of molecular sieves led to a slightly higher yield of 92% (en-
try 20). Of note is that only a 24% yield was obtained when
using Jiao’s method8 to cleave the C–C double bond of
enamide 1a (entry 21).
With optimized reaction conditions in hand, a range of
enamides was subjected to this oxidative cleavage reaction
to investigate the scope. First, a variety of acyclic aryl enam-
ides with different substituents were studied.
As shown in Scheme 1, investigation of the effects of
substituents on the phenyl ring showed that both electron-
donating groups (Me, OMe, and Ph) and electron-with-
drawing groups (F, Cl, Br, CF3, and CO2Me) were well tolerat-
ed in this transformation, affording the corresponding
products in moderate to high isolated yields after smooth
cleavage of the C–C double bonds. Besides para-substitu-
ents on the phenyl rings, ortho- and meta-substituents
were also compatible with this oxidative cleavage, which
indicates that steric hindrance may not have a major effect
on the transformation.
Inspired by the efficient oxidative cleavage of acyclic
aryl enamides, we next surveyed cyclic enamides in this re-
action to produce the corresponding bifunctional products.
As shown in Scheme 2, to our delight, the C–C double bonds
in cyclic enamides could also be successfully cleaved, af-
fording the desired cyano diacylamine products, but with
slightly lower isolated yields compared with the acyclic aryl
enamides. The structures of the products further confirmed
that the β-carbons in the enamides were converted into cy-
ano groups.
Table 1 Optimization of the Reaction Conditionsa
O
NHAc
NHAc
Ph
Ph
1a
2a
Entry Reagent (equiv)
Solvent
Temp (°C) Yield (%)b
1c
2
3
4
5
6
7
8
9
BI-N3 (1.0)
toluene
toluene
toluene
Et2O
80
80
60
60
60
60
60
40
40
40
40
40
40
40
40
40
40
r.t.
0
23
BI-N3 (1.0)
31
BI-N3 (1.0)
39
BI-N3 (1.0)
0
O
BI-N3 (1.0)
MeNO2
NMP
39
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
NHAc
NHAc
BI-N3 (1.0)
0
R
R
MeCN, 0 °C, 4 Å MS, 12 h
BI-N3 (1.0)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
57
2
1
BI-N3 (1.0)
62
O
O
O
BI-OAc (1), TMSN3 (1.5)
PhI(OAc)2 (1), TMSN3 (1.5)
PhI(OCOCF3)2 (1), TMSN3 (1.5)
PhIO (1), TMSN3 (1.5)
PhI(OAc)2 (1), NaN3 (1.5)
PhI(OAc)2 (1), TMSN3 (1.1)
PhI(OAc)2 (1), TMSN3 (2)
PhI(OAc)2 (1.6), TMSN3 (2)
PhI(OAc)2 (1), TMSN3 (1.5)
PhI(OAc)2 (1), TMSN3 (1.5)
PhI(OAc)2 (1), TMSN3 (1.5)
PhI(OAc)2 (1), TMSN3 (1.5)
54
NHAc
NHAc
NHAc
10
76d
41d
63d
43d
66d
70d
70d
76d
75d
87d
92d
24d
Ph
11
2a, 92%
2b, 83%
2c, 90%
12
O
O
O
13
NHAc
NHAc
NHAc
14
MeO
F
Me
15
2d, 67%
2e, 63%
2f, 78%
O
16
O
O
17e
18e
19e
20e,f
21g
O
NHAc
NHAc
NHAc
F3C
Cl
Br
2g, 73%
2h, 85%
2i, 62%
O
O
O
0
NHAc
TEMPO (15 mol%), TMSN3 (1.5) MeCN
80
NHAc
NHAc
O
O
MeO2C
O
2j, 92%
Me 2l, 86%
2k, 79%
OMe
I
I
N3
OAc
O
O
O
NHAc
NHAc
NHAc
BI-N3
BI-OAc
a Reaction conditions: 1a (0.1 mmol, 1 equiv), solvent (2 mL), 24 h, under
Me
2m, 81%
2n, 75%
Br
2o, 85%
F
air.
b GC yield.
c CuCl (10 mol%) was used.
d Yield of isolated product.
e Reaction time = 12 h.
f 4 Å MS (200 mg) were added.
g Reaction run under O2 (1 atm).
Scheme 1 Substrate scope of acyclic aryl enamides. Reagents and con-
ditions: 1 (0.1 mmol, 1 equiv), PhI(OAc)2 (1 equiv), TMSN3 (1.5 equiv),
MeCN (2 mL), 4 Å MS (200 mg), 0 °C, 12 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
G. Liu et al.
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Synthesis
trace water in MeCN. Addition of radical scavengers inhibit-
ed the oxidation, which indicated that the process may in-
volve a radical pathway (eqs 4 and 5, Scheme 1).
O
NHAc
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
NHAc
R
R
CN
1–3
MeCN, 0 °C, 4 Å MS, 12 h
1–3
3
4
O
O
O
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
4b, R = F, 55%
4c, R = Cl, 55%
4d, R = Br, 49%
NHAc
NHAc
NHAc
CN
NHAc
CN
(1)
(2)
Ph
MeCN, 0 °C, 12 h, Ar
Ph
1a
2a, 15%
R
4a, 60%
O
NHAc
O
O
O
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
NHAc
CN
NHAc
CN
MeO
NHAc
CN
NHAc
CN
MeCN, 0 °C, 12 h, Ar
3f
4f, 9%
Br
4g, 65%a
4e, 64%
4f, 66%
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
H218O (2 equiv)
O
O
O
O
NHAc
NHAc
NHAc
CN
Br
(3)
NHAc
CN
NHAc
CN
Ph
MeCN, 0 °C, 12 h, air
Ph
1a
2a, 85%
MeO
no 18O-2a was dectected
OMe
4i, 73%
4j, 63%a
4h, 51%
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
galvinoxyl (1 equiv)
O
O
O
NHAc
NHAc
NHAc
O
(4)
(5)
NHAc
NHAc
CN
Ph
MeCN, 0 °C, 12 h, air
Ph
Ph
NHAc
1a
1a
2a, 8%
CN
CN
MeO2C
PhI(OAc)2 (1 equiv)
TMSN3 (1.5 equiv)
4-tert-butylcatechol (1 equiv)
Ph
4m, 71%
O
4k, 70%
4l, 80%b
NHAc
Scheme 2 Substrate scope of cyclic enamides. Reagents and conditions:
1 (0.1 mmol, 1 equiv), PhI(OAc)2 (1 equiv), TMSN3 (1.5 equiv), MeCN
(2 mL), 4 Å MS (200 mg), 0 °C, 12 h. a Li2CO3 was added. b Reaction at
–10 °C.
MeCN, 0 °C, 12 h, air
Ph
2a, trace
Scheme 3 Control experiments
The electronic and steric effects of substituents on the
phenyl rings were not obvious, as electron-withdrawing
(CO2Me), electron-donating (OMe) and ortho-substituted
(Br, OMe) cyclic aryl enamides were all smoothly cleaved
and bifunctionalized. Five- (3a–e), six- (3f–k) and seven-
(3l) membered cyclic enamides gave the corresponding cy-
ano diacylamines in good yields, which showed that ring
strain had almost no effect on this protocol. Aliphatic cyclic
enamide 3m was also suitable for this transformation af-
fording N-acetyl δ-cyanopentanamide 4m in 71% yield.
To gain some insights into the mechanism of this trans-
formation, a series of control experiments was carried out
(Scheme 3). First, the reaction was performed under an ar-
gon atmosphere, which resulted in the yield of 2a being sig-
nificantly decreased to 15%, whilst the cyanobenzamide
product 4f was obtained in only 9% yield (eqs 1 and 2,
Scheme 3), which indicated that PhI(OAc)2 was not the sole
oxidant and that molecular oxygen in air was involved in
the reaction. Next, two equivalents of H218O were included
in the standard conditions without the addition of molecu-
lar sieves. In this case, none of the 18O-containing product
was obtained, however, almost the same yield of 2a was ob-
tained [eq 3, Scheme 1 (see Table 1, entry 19)]. This result
further demonstrated that the oxygen atom of the benzoyl
group in 2a originated from molecular oxygen and not the
Based on the results mentioned above and previous re-
ports on the Zhdankin reagent,11 a plausible mechanism via
a radical path can be proposed. As shown in Scheme 4, the
ligand exchange between PhI(OAc)2 and TMSN3 affords
PhI(N3)2 or PhI(OAc)N3 in situ, which undergoes thermal
homolytic cleavage to generate an azide radical. The azide
radical is then captured by the carbon–carbon double bond
of the enamide to produce a benzyl radical, which is subse-
quently trapped by molecular oxygen to form a peroxy rad-
ical. Heterolysis of the O–O bond and release of N2 cleaves
the C–C bond to give the cyano diacylamine, as described in
previous reports.8,10,12
PhI(OAc)N3
TMSN3
or
N3
PhI(OAc)2
PhI(N3)2
NHAc
N3
N3
CN
O
refs. 8, 10
and 12
O
O
O2
NHAc
NHAc
NHAc
Scheme 4 A plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
G. Liu et al.
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Synthesis
In conclusion, we have developed a method for the oxi-
dative cleavage of the C–C double bonds of enamides, which
was promoted by hypervalent iodine(III) under mild reac-
tion conditions with O2 as the terminal oxidant. This proto-
col exhibits good functional group tolerance with both acy-
clic and cyclic enamides to afford useful diacylamine prod-
ucts. Further studies on the synthetic applications of this
process for the total synthesis of complex molecules are on-
going in our lab.
1H NMR (400 MHz, CDCl3): δ = 9.10 (s, 1 H), 7.92–7.83 (m, 2 H), 7.60
(t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.7 Hz, 2 H), 2.61 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 166.0, 133.4, 132.8, 129.1,
127.9, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C9H9NO2Na: 186.0531; found:
186.0526.
N-Acetyl-4-methoxybenzamide (2d)
White solid; yield: 13 mg (67%); mp 110–116 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (s, 1 H), 7.85 (d, J = 7.7 Hz, 2 H),
6.97 (d, J = 7.7 Hz, 2 H), 3.87 (s, 3 H), 2.60 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.9, 165.2, 163.8, 130.0, 124.8,
114.3, 55.7, 25.7.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO3Na: 216.0637; found:
216.0630.
Enamides 1 were prepared according to the reported procedure.13 All
commercially available compounds were used without further purifi-
cation. TLC was performed on plates precoated with silica gel F254,
purchased from Shandong Huanghai Chemical Co. Ltd., and visualized
with a UV lamp (254 nm). Yields refer to those of chromatographical-
ly purified compounds. Column chromatography was performed on
silica gel (200–300) purchased from Shandong Huanghai Chemical
Co. Ltd. Melting points were obtained using a Beijing Tektronix X-4
digital microscopic melting point apparatus. NMR spectra were re-
corded on a Bruker-400 (400 MHz for 1H; 100 MHz for 13C) instru-
ment and the spectra are internally referenced to SiMe4 at δ 0.00 for
1H, and the CDCl3 signal at δ 77.16 for 13C. High-resolution mass spec-
tra were recorded on P-SIMS-Gly of BrukerDaltonics Inc. Waters Xevo
G2 QTof using ESI-TOF (electrospray ionization–time of flight).
N-Acetyl-4-methylbenzamide (2e)
White solid; yield: 11 mg (63%); mp 146–149 °C.
1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.78 (d, J = 8.0 Hz, 2 H),
7.29 (d, J = 8.0 Hz, 2 H), 2.60 (s, 3 H), 2.42 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.6, 165.6, 144.3, 129.8, 127.8, 25.7,
21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO2Na: 200.0687; found:
200.0678.
Diacylamines 2 and 4; General Procedure
N-Acetyl-4-fluorobenzamide (2f)
Enamide 1 or 3 (0.1 mmol, 1.0 equiv), PhI(OAc)2 (32.2 mg, 0.1 mmol,
1.0 equiv), TMSN3 (19.6 μL, 0.15 mmol, 1.5 equiv), 4 Å MS (200 mg)
and MeCN (2 mL) were combined in a 35 mL sealed tube. The reaction
mixture was stirred at 0 °C for 12 h. After cooling to r.t., the reaction
mixture was filtered through a plug of silica, washed with EtOAc, con-
centrated under vacuum and the residue purified by column chroma-
tography on silica gel (gradient elution: PE and EtOAc) to give the cor-
responding product.
White solid; yield: 14 mg (78%); mp 106–109 °C.
1H NMR (400 MHz, CDCl3): δ = 9.24 (s, 1 H), 7.95 (t, J = 8.3 Hz, 2 H),
7.18 (t, J = 8.3 Hz, 2 H), 2.60 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.2, 165.9 (d, J = 255.5 Hz), 164.9,
130.6 (d, J = 9.3 Hz), 128.9 (d, J = 3.0 Hz), 116.3 (d, J = 22.1 Hz), 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C9H8FNO2Na: 204.0437; found:
204.0433.
N-Acetyl-[1,1′-biphenyl]-4-carboxamide (2a)
N-Acetyl-4-chlorobenzamide (2g)
White solid; yield: 22 mg (92%); mp 166–168 °C.
White solid; yield: 14 mg (73%); mp 135–139 °C.
1H NMR (400 MHz, CDCl3): δ = 9.18 (s, 1 H), 7.85 (d, J = 8.5 Hz, 2 H),
7.48 (d, J = 8.5 Hz, 2 H), 2.61 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 165.0, 139.9, 131.1, 129.4,
129.3, 25.7.
1H NMR (400 MHz, CDCl3): δ = 9.00 (s, 1 H), 7.96 (d, J = 8.3 Hz, 2 H),
7.72 (d, J = 8.2 Hz, 2 H), 7.63 (d, J = 7.4 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 2 H),
7.42 (t, J = 7.2 Hz, 1 H), 2.64 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 165.7, 146.2, 139.6, 131.3,
129.1, 128.54, 128.49, 127.7, 127.4, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C9H8ClNO2Na: 220.0141; found:
220.0136.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13NO2Na: 262.0844; found:
262.0844.
N-Acetyl-4-bromobenzamide (2h)
N-Acetyl-2-naphthamide (2b)
White solid; yield: 21 mg (85%); mp 147–159 °C.
1H NMR (400 MHz, CDCl3): δ = 9.18 (s, 1 H), 7.77 (d, J = 8.6 Hz, 2 H),
7.64 (d, J = 8.6 Hz, 2 H), 2.60 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.2, 165.2, 132.4, 131.6, 129.5,
128.5, 25.9.
White solid; yield: 18 mg (83%); mp 147–152 °C.
1H NMR (400 MHz, CDCl3): δ = 9.16 (s, 1 H), 8.42 (s, 1 H), 8.07–7.80
(m, 4 H), 7.71–7.46 (m, 2 H), 2.67 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 166.0, 135.6, 132.5, 129.9,
129.4, 129.13, 129.07, 128.8, 128.0, 127.3, 123.7, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C13H11NO2Na: 236.0687; found:
236.0680.
HRMS (ESI): m/z [M + Na]+ calcd for C9H8BrNO2Na: 263.9636; found:
263.9637.
N-Acetyl-4-(trifluoromethyl)benzamide (2i)
N-Acetylbenzamide (2c)
White solid; yield: 14 mg (62%); mp 139–144 °C.
White solid; yield: 15 mg (90%); mp 114.4–121.3 °C.
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G. Liu et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 1 H), 8.01 (d, J = 8.2 Hz, 2 H),
7.78 (d, J = 8.3 Hz, 2 H), 2.63 (s, 3 H).
N-Acetyl-2-methylbenzamide (2o)
White solid; yield: 15 mg (85%); mp 82–83 °C.
13C NMR (101 MHz, CDCl3): δ = 173.8, 164.8, 136.1, 134.9 (q, J = 33.3
Hz), 128.4, 126.2 (q, J = 4.0 Hz), 123.6 (q, J = 272.7 Hz), 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C10H8F3NO2Na: 254.0405; found:
1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H), 7.48–7.35 (m, 2 H), 7.32–
7.18 (m, 2 H), 2.58 (s, 3 H), 2.49 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.0, 168.0, 137.6, 134.0, 131.9,
131.7, 127.0, 126.2, 25.6, 20.2.
254.0408.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO2Na: 200.0687; found:
200.0683.
N-Acetyl-4-(methoxycarbonyl)benzamide (2j)
White solid; yield: 20 mg (92%); mp 107–108 °C.
1H NMR (400 MHz, CDCl3): δ = 9.10 (s, 1 H), 8.15 (d, J = 8.1 Hz, 2 H),
7.95 (d, J = 8.1 Hz, 2 H), 3.95 (s, 3 H), 2.62 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.7, 166.0, 165.1, 136.5, 134.3,
130.2, 127.9, 52.7, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C11H11NO4Na: 244.0586; found:
N-Acetyl-2-(cyanomethyl)benzamide (4a)
White solid; yield: 12 mg (60%); mp 135–138 °C.
1H NMR (400 MHz, CDCl3): δ = 8.92 (s, 1 H), 7.67–7.53 (m, 3 H), 7.47
(s, 1 H), 4.08 (s, 2 H), 2.57 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.3, 166.9, 132.9, 132.4, 130.9,
244.0582.
130.8, 128.7, 128.0, 117.7, 25.7, 22.3.
HRMS (ESI): m/z [M + Na]+ calcd for C11H10N2O2Na: 225.0640; found:
225.0634.
N-Acetyl-3-methoxybenzamide (2k)
White solid; yield: 15 mg (79%); mp 85–88 °C.
1H NMR (400 MHz, CDCl3): δ = 9.02 (s, 1 H), 7.50–7.34 (m, 3 H), 7.12
(d, J = 7.7 Hz, 1 H), 3.86 (s, 3 H), 2.60 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 165.8, 160.1, 134.1, 130.1,
119.9, 119.8, 112.7, 55.6, 25.9.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO3Na: 216.0637; found:
N-Acetyl-2-(cyanomethyl)-4-fluorobenzamide (4b)
Brown solid; yield: 12 mg (55%); mp 130–134 °C.
1H NMR (400 MHz, CDCl3): δ = 8.78 (s, 1 H), 7.72–7.63 (m, 1 H), 7.36
(d, J = 9.0 Hz, 1 H), 7.18–7.15 (m, 1 H), 4.10 (s, 2 H), 2.56 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.4, 166.0, 164.7 (d, J = 256.5 Hz),
134.4 (d, J = 8.6 Hz), 130.6 (d, J = 9.4 Hz), 128.5 (d, J = 3.0 Hz), 118.4 (d,
J = 23.6 Hz), 117.1, 115.7 (d, J = 21.6 Hz), 25.7, 22.4.
216.0629.
N-Acetyl-3-methylbenzamide (2l)
HRMS (ESI): m/z [M + Na]+ calcd for C11H9FN2O2Na: 243.0546; found:
White solid; yield: 15 mg (86%); mp 76–79 °C.
243.0548.
1H NMR (400 MHz, CDCl3): δ = 9.00 (s, 1 H), 7.77–7.60 (m, 2 H), 7.47–
7.33 (m, 2 H), 2.60 (s, 3 H), 2.42 (s, 3 H).
N-Acetyl-4-chloro-2-(cyanomethyl)benzamide (4c)
13C NMR (101 MHz, CDCl3): δ = 173.8, 166.1, 139.1, 134.1, 132.7,
White solid; yield: 13 mg (55%); mp 137–139 °C.
1H NMR (400 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.61 (s, 1 H), 7.57 (d, J =
8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 4.07 (s, 2 H), 2.57 (s, 3 H).
129.0, 128.5, 124.9, 25.7, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO2Na: 200.0687; found:
13C NMR (101 MHz, CDCl3): δ = 173.0, 165.9, 139.3, 133.0, 131.0,
200.0681.
130.6, 129.2, 129.0, 117.0, 25.7, 22.2.
N-Acetyl-3-fluorobenzamide (2m)
HRMS (ESI): m/z [M + Na]+ calcd for C11H9ClN2O2Na: 259.0250; found:
White solid; yield: 15 mg (81%); mp 79–83 °C.
259.0247.
1H NMR (400 MHz, CDCl3): δ = 9.10 (s, 1 H), 7.63 (t, J = 9.3 Hz, 2 H),
7.49 (dd, J = 13.5, 7.9 Hz, 1 H), 7.35–7.27 (m, 1 H), 2.61 (s, 3 H).
N-Acetyl-4-bromo-2-(cyanomethyl)benzamide (4d)
13C NMR (101 MHz, CDCl3): δ = 173.9, 164.7, 163.0 (d, J = 250.7 Hz),
135.0 (d, J = 6.9 Hz), 130.8 (d, J = 7.8 Hz), 123.3 (d, J = 2.7 Hz), 120.5 (d,
J = 21.1 Hz), 115.4 (d, J = 23.3 Hz), 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C9H8FNO2Na: 204.0437; found:
204.0431.
Pale brown solid; yield: 14 mg (49%); mp 159–160 °C.
1H NMR (400 MHz, CDCl3): δ = 8.90 (s, 1 H), 7.76 (s, 1 H), 7.62 (d, J =
8.3 Hz, 1 H), 7.50 (d, J = 8.3 Hz, 1 H), 4.06 (s, 2 H), 2.56 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.1, 166.1, 133.9, 133.0, 132.0,
131.1, 129.2, 127.6, 117.1, 25.7, 22.1.
HRMS (ESI): m/z [M + Na]+ calcd for C11H9BrN2O2Na: 302.9745; found:
302.9746.
N-Acetyl-3-bromobenzamide (2n)
White solid; yield: 18 mg (75%); mp 136–140 °C.
1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 1 H), 8.06 (s, 1 H), 7.80 (d, J =
N-Acetyl-3-bromo-2-(cyanomethyl)benzamide (4e)
7.7 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), 2.61 (s, 3
H).
13C NMR (101 MHz, CDCl3): δ = 173.8, 164.6, 136.3, 134.7, 131.2,
130.6, 126.3, 123.3, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C9H8BrNO2Na: 263.9636; found:
263.9637.
White solid; yield: 18 mg (64%); mp 197–198 °C.
1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.82 (d, J = 7.9 Hz, 1 H),
7.55 (d, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 4.17 (s, 2 H), 2.59 (s, 3
H).
13C NMR (101 MHz, CDCl3): δ = 172.7, 166.3, 136.9, 135.9, 130.2,
127.5, 126.8, 116.5, 25.7, 21.9.
HRMS (ESI): m/z [M + Na]+ calcd for C11H9BrN2O2Na: 302.9745; found:
302.9743.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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Synthesis
N-Acetyl-2-(2-cyanoethyl)benzamide (4f)
13C NMR (101 MHz, CDCl3): δ = 172.7, 167.0, 165.8, 138.5, 137.6,
133.4, 132.4, 129.0, 127.7, 119.0, 52.8, 29.6, 25.7, 19.4.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14N2O4Na: 297.0851; found:
297.0846.
White solid; yield: 14 mg (66%); mp 99–104 °C.
1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.52 (t, J = 7.5 Hz, 2 H),
7.43–7.35 (m, 2 H), 3.10 (t, J = 7.1 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H), 2.55
(s, 3 H).
N-Acetyl-2-(3-cyanopropyl)benzamide (4l)
13C NMR (101 MHz, CDCl3): δ = 172.9, 167.5, 138.6, 133.5, 132.4,
White solid; yield: 18 mg (80%); mp 52.7–55.4 °C.
131.8, 127.8, 127.6, 119.3, 29.8, 25.6, 19.6.
1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 1 H), 7.47 (t, J = 7.3 Hz, 2 H),
7.32 (t, J = 7.0 Hz, 2 H), 2.92 (t, J = 7.1 Hz, 2 H), 2.55 (s, 3 H), 2.38 (t, J =
7.1 Hz, 2 H), 2.08–1.89 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C12H12N2O2: 239.0797; found:
239.0790.
N-Acetyl-2-(2-cyanoethyl)-5-methoxybenzamide (4g)
13C NMR (101 MHz, CDCl3): δ = 172.9, 167.8, 140.1, 133.9, 132.0,
131.2, 127.3, 127.0, 119.6, 32.3, 27.4, 25.5, 16.9.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14N2O2Na: 253.0953; found:
253.0950.
Pale brown solid; yield: 16 mg (65%); mp 95–97 °C.
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 7.52 (d, J = 8.6 Hz, 1 H),
6.91 (s, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 3.88 (s, 3 H), 3.12 (t, J = 7.1 Hz, 2
H), 2.80 (t, J = 7.0 Hz, 2 H), 2.55 (s, 3 H).
N-Acetyl-5-cyano-4-phenylpentanamide (4m)
13C NMR (101 MHz, CDCl3): δ = 173.2, 166.8, 162.6, 141.8, 129.9,
Colorless liquid; yield: 17 mg (71%).
125.1, 119.4, 117.8, 112.8, 55.7, 30.3, 25.5, 19.5.
1H NMR (400 MHz, CDCl3): δ = 8.86 (s, 1 H), 7.35 (t, J = 7.3 Hz, 2 H),
7.29 (d, J = 7.0 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 2 H), 3.03 (td, J = 11.7, 6.8
Hz, 1 H), 2.64 (d, J = 7.0 Hz, 2 H), 2.44 (t, J = 6.7 Hz, 2 H), 2.26 (s, 3 H),
2.24–2.14 (m, 1 H), 2.12–2.00 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 173.3, 172.0, 140.5, 129.2, 128.0,
127.3, 118.4, 41.5, 34.8, 29.3, 25.3, 25.1.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14N2O3Na: 269.0902; found:
269.0904.
N-Acetyl-2-(2-cyanoethyl)-4-methoxybenzamide (4h)
White solid; yield: 13 mg (51%); mp 119.4–121 °C.
1H NMR (400 MHz, CDCl3): δ = 8.78 (s, 1 H), 7.53 (d, J = 8.6 Hz, 1 H),
6.89 (d, J = 2.5 Hz, 1 H), 6.84 (dd, J = 8.6, 2.5 Hz, 1 H), 3.86 (s, 3 H), 3.10
(t, J = 7.1 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H), 2.52 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H16N2O2Na: 267.1109; found:
267.1111.
13C NMR (101 MHz, CDCl3): δ = 173.4, 166.9, 162.5, 141.7, 130.0,
125.0, 119.4, 117.7, 112.6, 55.6, 30.2, 25.5, 19.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14N2O3: 269.0902; found:
Funding Information
269.0899.
We gratefully acknowledge the National Science Foundation of China
(21602213, 21522208, 21372209) for financial support.
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N-Acetyl-2-(2-cyanoethyl)-3-methoxybenzamide (4i)
White solid; yield: 18 mg (73%); mp 140.6–141.5 °C.
Supporting Information
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 7.33 (t, J = 8.0 Hz, 1 H),
7.05 (t, J = 8.2 Hz, 2 H), 3.88 (s, 3 H), 3.11 (t, J = 7.5 Hz, 2 H), 2.68 (t, J =
7.5 Hz, 2 H), 2.55 (s, 3 H).
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589041.
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13C NMR (101 MHz, CDCl3): δ = 172.7, 167.4, 158.3, 135.8, 128.8,
126.5, 119.9, 118.8, 113.7, 55.9, 25.6, 23.4, 17.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14N2O3Na: 269.0902; found:
References
269.0898.
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N-Acetyl-5-bromo-2-(2-cyanoethyl)benzamide (4j)
White solid; yield: 19 mg (63%); mp 132.6–136.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1 H), 7.72–7.58 (m, 2 H), 7.39–
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H).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G