Functionalization of amides via copper-catalyzed oxyalkylation of vinylarenes and decarboxylative alkenylation of sp3 C-H

Article abstract of DOI:10.1021/jo501274f

An efficient protocol was developed to prepare a series of derivatives from amides by copper-catalyzed oxyalkylation of vinylarenes and decarboxylative alkenylation of sp³ C-H. This method is simple, practical, and inexpensive.

Full text of DOI:10.1021/jo501274f

Article
pubs.acs.org/joc
Functionalization of Amides via Copper-Catalyzed Oxyalkylation of
Vinylarenes and Decarboxylative Alkenylation of sp3 C−H
Hong Yan, Linhua Lu, Guangwei Rong, Defu Liu, Yang Zheng, Jie Chen, and Jincheng Mao*
Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient protocol was developed to prepare
a series of derivatives from amides by copper-catalyzed
oxyalkylation of vinylarenes and decarboxylative alkenylation
of sp3 C−H. This method is simple, practical, and inexpensive.
application in medicinal chemistry, we have great interest in
preparation of these functionalized amides. Up to the present
day, most methods to synthesize this class of amides are
through traditional metal-catalyzed allylic substitution reac-
tions5 or through preparation of the prerequisite activated
materials in multistep reactions.6 Therefore, an inexpensive and
direct way to synthesize these amides is highly desirable until
now.
INTRODUCTION
It is well-known that the allylic amide and N-(3-oxoalkyl)
amide motifs appear in many natural products (Figure 1). For
■
In the past few years, sp3 C−H bond functionalization7 has
been extensively studied, resulting in new, powerful methods
for streamlining organic synthesis by using simple starting
material. Despite significant developments, syntheses of allylic
amides and N-(3-oxoalkyl) amides by sp3 C−H functionaliza-
tion of N-alkyl amide remain challenging. Previous methods for
allowing access to allylic amides were through the addition
reactions of the sp3 C−H bond into alkynes and either involved
a costly iridium complex or afforded an undesirable mixture of
E/Z isomers.8 In the long run, our group and others have been
devoted to the cheap, metal-catalyzed sp3 C−H functionaliza-
tion related to cinnamic acids9 and olefins10 in recent years.
Synthesizing these kinds of functionalized amides from
commercially available olefins or cinnamic acids seems feasible
and interesting.9,10b−d,11 Kantam et al. and we independently
developed a similar method to prepare N-substituted
formamides.12 To be noted, 5-allylic γ-lactams was successfully
synthesized in Kantams et al.’s work. Just recently, Wang and
co-workers reported the nickel-catalyzed decarboxylative cross-
coupling of α,β-unsaturated carboxylic acids to prepare N-(3-
oxoalkyl) amides.13 In order to expand our understanding of
sp3 C−H functionalization of amides, herein, we report a novel
and direct method to selectively synthesize N-(3-oxo-3-
Figure 1. Useful amide moieties in biologically active compounds.
example, compound A is a potent antimicrotubule agent that is
highly effective at inhibiting the growth of tumors, which
proved more potent in in vitro cytotoxicity and antimitotic
activity than its analogues, such as the natural product
hemiasterlin B.1 Compound C (DNK 333) has been discovered
as a potent and balanced neurokinin (tachykinin) NK1/NK2
receptor antagonist.2 Compound D represents a new class of
proteasome inhibitors bearing N-allyl vinyl ester based
peptides.3 In addition, a series of novel Asp32-replacement
tetrapeptide analogues (E) have been proved as potent and
selective CCK-A agonists.4 In consideration of their wide
Received: June 7, 2014
Published: July 16, 2014
© 2014 American Chemical Society
7103
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
phenylpropyl)acetamide and N-cinnamylacetamide derivatives
efficiently from N-alkylamides via oxyalkylation of olefins or
decarboxylation of cinnamic acids.
(entry 17). Finally, extending the reaction time to 48 h gave the
best result (65% yield, entry 19).
Subsequently, the reactions of a variety of alkenes 1 and
amides 2 were investigated under the optimized conditions. As
demonstrated in Table 2, the reactions of olefins 1b−1f bearing
both electron-rich and electron-deficient functional groups at
the para-position of the aryl ring afforded the corresponding
oxyalkylative products (3ba−3fa) in moderate to good yields.
Moreover, 3,4,5-trimethoxyl styrene (1g) was successfully
employed as the substrate, and the desired product 3ga was
obtained with a moderate yield (50%). 1-Vinylnaphthalene was
also a suitable substrate, and the expected oxyalkylative product
3ha was obtained in 59% yield. In addition to terminal alkenes,
internal alkenes were examined. Symmetrical stilbene reacted
with DMA, giving a single product (3ia) in 43% yield, whereas
the unsymmetrical 4-methoxystilbene 1k was not a suitable
substrate. Having demonstrated the scope on styrene
derivatives, we next investigated the scope of amides. 1a, 1b,
1c, and 1e were chosen to react with N-methylacetamide 2b,
and the results showed that the substituted group of styrene
greatly influenced the reactivity. The corresponding alkylative
products (3ab, 3bb, and 3eb) were formed in moderate yields,
whereas, for 3cb, the yield was very low (13%). N,N-
Dimethylpropionamide 2c was also a suitable substrate for
this reaction system, which could react with styrenes 1a
smoothly to produce the desired oxyalkylative product in
moderate yield. By contrast, diethylacetamide was a less
reactive substrate, only affording 3ad and 3bd in low yields.
In addition, the reaction between DMF (N,N-dimethylfor-
mamide) and styrene was performed under the standard
condition A, and the products were complicated. However,
when the reaction was carried out in the presence of Cu2O as
the catalyst and sodium persulfate as the oxidant at 100 °C for
48 h (Scheme 1), N-cinnamyl-N-methylformamide 3ag and
N,N-dimethylcinnamamide 3ag′ were afforded in 45%
combined yield with 3:1 regioselectivity, which suggested that
the C−H functionalization of the methyl was more favorable.
Because cinnamic acid and its derivatives are cheap and
commercially available substitutes for styrenes via oxidative
decarboxylation, we further expanded our oxidative conditions
to cinnamic acid. As shown in Table 3, the copper catalyst did
not afford the oxyalkylation product, but the decarboxylative
alkenylation product. Under the condition of CuO as catalyst
and DTBP as oxidant in the argon atmosphere, we obtained N-
cinnamyl-N-methylacetamide 5aa in 63% yield.
With this optimized catalytic system in hand, we next
explored substrate scope for carboxylic acids and amides (Table
4). The electron-donating methoxy, methyl, and isopropyl
group substituted 4b−4d, 4j−4k, and 4o were well tolerated
and resulted in their corresponding decarboxylative coupling
products (5ba−5da, 5ja−5ka, 5oa) with moderate to good
yields. Only 3-methoxycinnamic acid (4l) showed low reactivity
and produced the expected product (5la) in poor yield. In
addition, this protocol can also be successfully applied to
cinnamic acids bearing electron-withdrawing halogen atoms,
such as F and Cl, and ester groups, such as COOMe and CF3 as
well as CN. Notably, the ester group OAc and hydroxyl group
were well tolerated and afforded the corresponding coupling
products (5ma, 47% yield, and 5na, 57% yield), respectively.
The reaction of 1-naphthylacrylic acid proceeded smoothly as
well and gave a highly selective product with 54% yield.
Electron-rich heteroarylacrylic acids including 2-thienylacrylic
acid and 2-furylacrylic acid were suitable substrates, and the
RESULTS AND DISCUSSION
■
Initially, we performed the oxyalkylation of styrene 1a in DMA
(N,N-dimethylacetamide) 2a in the presence of copper
catalysts and TBHP as oxidant. The related results are listed
in Table 1. In the control experiment, the oxyalkylation could
Table 1. Screening Catalytic Conditions in the Copper-
a
Catalyzed Oxyalkylation of Styrene in DMAc
entry
catalyst
CuSO4
oxidant
solvent
yield [%]
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
DCP
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
toluene
DMSO
DMAc
DMAc
DMAc
trace
25
Cu(OTf)2
CuO
NR
30
CuI
NR
45
Cu
CuF2·2H2O
FeF3
50
10
FeF2
40
b
10
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
CuF2·2H2O
15
11
12
13
14
15
16
NR
NR
trace
NR
trace
trace
60
DDQ
Na2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
c
17
d
18
ce
,
35
19
65
a
Catalytic conditions: styrene (0.5 mmol), DMAc (2 mmol), catalyst
(20 mol %), oxidant (2 mmol), solvent (1.5 mL), 100 °C, 12 h, air.
b
c
d
TBHP (5−6M) in decane. Catalyst (10 mol %). Catalyst (5 mol
e
%). 48 h.
not occur without the copper catalyst (entry 1). When copper
catalyst was added, the oxyalkylation procceded smoothly,
which indicated that the copper catalyst played a critical role in
the reaction (entry 2). Next, various copper sources were
screened. Different copper salts had distinct effects on the yield
of N-methyl-N-(3-oxo-3-phenylpropyl)acetamide 3aa (entries
3−7). The product was not acquired at all when the reaction
was conducted using Cu(OTf)2 or CuI (entries 3 and 5).
Copper fluoride exhibited the best catalytic efficiency among
these copper salts (50% yield, entry 7). In addition, iron
sources were also able to catalyze the reaction. However, they
were less efficient than copper fluoride (entry 7 vs entries 8−9).
Other than TBHP, oxidants such as DTBP, DCP (dicumyl
peroxide), DDQ, and Na2S2O8 did not give the oxyalkylative
product at all (entries 10−14). If the reaction was performed in
toluene or DMSO (2 mL) as the solvent and 4 equiv of DMA
was employed as the substrate, only a trace amount of 3aa was
observed (entries 15−16). Subsequently, the catalyst loading
was studied (entries 17−18) and the oxyalkylative product was
obtained in 60% yield when 10 mol % loading catalyst was used
7104
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
ab
,
Table 2. Copper-Catalyzed Oxyalkylation of Vinylarenes
a
b
Catalytic conditions: vinylarene (0.5 mmol), amide (1.5 mL), catalyst (10 mol %), TBHP (2 mmol), 100 °C, 48 h, air. TBHP (1 mmol).
Scheme 1. Copper-Catalyzed Oxyalkylation of Styrene in DMF
corresponding decarboxylative products were obtained in 52%
and 71% yields, respectively. However, the electron-deficient
heteroarylacrylic acid (3-pyridylacrylic acid) did not afford the
desired product.
Different from arylacrylic acids, 3-methylbut-2-enoic acid
reacting with DMA did not produce the expected decarbox-
ylative coupling product under the standard conditions B.
However, a cross-dehydrogenative coupling reaction occurred
and gave 5ta in 65% yield as shown in Scheme 2.
To gain insight into the possible mechanism, a series of
experiments were conducted as shown in Scheme 3. The
reaction of styrene was carried out with DMA in an argon
atmosphere under the same conditions. It was found that the
yield of 3aa just slightly decreased. It is assumed that the main
oxygen source was TBHP. When styrene or cinnamic acid
reacted with DMA in the presence of a radical scavenger, such
as 2,6-di-tert-butyl-4-methylphenol (BHT), both of the
reactions were significantly inhibited. It is indicated that the
radical processes might be involved.
copper catalyst, and the oxidant first generates tert-butoxy
radical and hydroxyl radical. Then, tert-butoxy radical abstracts
a H atom from the strong C−H bond of DMA, to give the
acetamidomethyl radical F,14 whose addition to olefin results in
formation of the alkyl radical species G.15 Subsequently, the
oxidization of G provides 3 and intermediate H.10b
Intermediate H, which could also be formed from the
combination of alkyl radical G and hydroxyl radical, is further
converted to 3. In the oxidative decarboxylation of cinnamic
acids, DTBP is the catalytic cycle initiator, which gives tert-
butoxy radical by homolysis. Similarly, acetamidomethyl radical
F is formed by the abstraction of a H atom from DMA and then
affords the intermediate I by addition to cupric cinnamate.9b In
contrast to the former reaction mechanism, N-cinnamyl-N-
methylacetamide 5 is ultimately formed by the decarboxylative
elimination from intermediate I in the last step.
CONCLUSIONS
■
In summary, we have developed a new strategy for selective
synthesis of the important class of N-(3-oxo-3-phenylpropyl)-
acetamide and N-cinnamylacetamide derivatives via the copper-
catalyzed oxidative coupling between N,N-substituted amides
On the basis of the experiments and previous mechanistic
studies, we propose the following mechanism (Scheme 4). The
oxidative aminoalkylation of olefin with DMA is initiated by a
7105
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
N-Methyl-N-(3-oxo-3-phenylpropyl)acetamide (3aa).13 White
Table 3. Screening Catalytic Conditions of Copper-
Catalyzed Decarboxylative Alkenylation of Cinnamic
Acids
solid. 66.7 mg, 65%. The ratio of two conformational isomers is about
1
a b
,
2:1. H NMR (400 MHz, CDCl3) δ 7.95 (t, J = 9.3 Hz, 2H), 7.59−
7.54 (m, 1H), 7.50−7.43 (m, 2H), 3.78−3.72 (m, 2H), 3.31−3.20 (m,
2H), 3.07 (s, 2H), 2.94 (s, 1H), 2.15 (s, 1H), 2.05 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 198.8, 197.5, 170.7, 170.4, 136.5, 136.2,
133.5, 133.1, 128.7, 128.5, 127.9, 127.8, 45.7, 44.1, 37.3, 36.8, 36.6,
33.0, 21.8, 21.2. HRMS (TOF MS CI+) [M + H]+ calculated for
C12H16NO2 206.1181, found 206.1173.
N-Methyl-N-(3-oxo-3-(p-tolyl)propyl)acetamide (3ba).13 Yel-
low oil. 71.3 mg, 65%. The ratio of two conformational isomers is
entry
cat.
Fe3O4
solvent
T (°C)
yield [%]
1
2
3
4
5
6
7
8
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DCE
110
110
110
110
110
110
110
110
80
NR
NR
NR
18
1
about 2:1. H NMR (400 MHz, CDCl3) δ 7.87 (t, J = 9.4 Hz, 2H),
ferrocene
FeCl3
7.31−7.26 (m, 2H), 3.79−3.73 (m, 2H), 3.29−3.22 (m, 2H), 3.09 (s,
2H), 2.96 (s, 1H), 2.44 (s, 1H), 2.42 (s, 2H), 2.17 (s, 1H), 2.08 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.6, 198.3, 170.8, 170.5,
144.5, 144.0, 134.1, 133.8, 129.4, 129.2, 128.2, 128.0, 45.9, 44.3, 37.5,
36.7, 36.6, 33.1, 21.9, 21.6, 21.5, 21.2. HRMS (TOF MS CI+) [M +
H]+ calculated for C13H18NO2 220.1338, found 220.1335.
Cu
CuBr
29
CuO
63
CuF2·2H2O
Cu(OTf)2
CuO
trace
trace
NR
trace
trace
trace
N-(3-(4-Methoxyphenyl)-3-oxopropyl)-N-methylacetamide
(3ca).13 Yellow oil. 58.8 mg, 50%. The ratio of two conformational
b
9
1
b
isomers is about 2:1. H NMR (400 MHz, CDCl3) δ 7.94−7.88 (m,
10
b
CuO
PEG-400
AcOH
pyridine
110
110
110
2H), 6.93−6.88 (m, 2H), 3.85−3.83 (m, 3H), 3.76−3.68 (m, 2H),
3.21−3.15 (m, 2H), 3.04 (s, 2H), 2.91 (s, 1H), 2.12 (s, 1H), 2.03 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.5, 196.0, 170.8, 170.5,
163.8, 163.5, 130.3, 130.2, 129.7, 129.4, 113.8, 113.7, 55.4, 55.4, 45.9,
44.4, 37.4, 36.4, 33.1, 30.8, 21.9, 21.2. HRMS (TOF MS CI+) [M +
H]+ calculated for C13H18NO3 236.1287, found 236.1286.
11
CuO
b
12
CuO
a
Catalytic conditions: cinnamic acid (0.3 mmol), catalyst (20 mol %),
b
DTBP (4 equiv), solvent (2 mL), 12 h, in Ar. DMAc (25 equiv).
N-(3-(4-(tert-Butyl)phenyl)-3-oxopropyl)-N-methyl-
acetamide (3da). Yellow oil. 60.1 mg, 46%. The ratio of two
conformational isomers is about 2:1. H NMR (400 MHz, CDCl3) δ
and olefins or cinnamic acids. A wide scope of substrates is
successfully acquired using our protocol. It is noteworthy that
this method is simple, practical, and inexpensive, which may be
potentially useful in the industrial synthesis. Moreover, amides
3 and 5 could be potential precursors for the preparation of β-
amino carbonyls and cinnamyl amines by further hydrolysis.
Application of this method in the synthesis of bioactive and
more complicated amides is currently in progress.
1
7.91−7.86 (m, 2H), 7.50−7.45 (m, 2H), 3.77−3.71 (m, 2H), 3.27−
3.20 (m, 2H), 3.06 (s, 2H), 2.93 (s, 1H), 2.14 (s, 1H), 2.05 (s, 2H),
1.32 (d, J = 4.2 Hz, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.6,
197.2, 170.8, 170.5, 157.4, 157.0, 134.0, 133.7, 128.0, 127.9, 125.7,
125.5, 45.9, 44.3, 37.5, 36.7, 35.1, 35.0, 33.2, 31.0, 31.0, 21.9, 21.2.
HRMS (TOF MS CI+) [M + H]+ calculated for C16H24NO2 262.1807,
found 262.1802.
N-(3-(4-Fluorophenyl)-3-oxopropyl)-N-methylacetamide-
EXPERIMENTAL SECTION
(3ea). Yellow oil. 61.4 mg, 55%. The ratio of two conformational
■
1
isomers is about 2:1. H NMR (400 MHz, CDCl3) δ 8.01−7.94 (m,
General Information. Reactions were carried out under an argon
atmosphere condition or in air. Solvents were dried and degassed by
standard methods, and all vinylarenes, cinnamic acids, and N,N-
substituted amides were commercially available. Flash column
chromatography was performed using silica gel (300−400 mesh).
Analytical thin-layer chromatography was performed using glass plates
precoated with 200−400 mesh silica gel impregnated with a
fluorescent indicator (254 nm). NMR spectra were measured in
CDCl3 on a 400 or 300 MHz NMR spectrometer with TMS as an
2H), 7.16−7.09 (m, 2H), 3.77−3.69 (m, 2H), 3.25−3.19 (m, 2H),
3.06 (s, 2H), 2.92 (s, 1H), 2.14 (s, 1H), 2.04 (s, 2H). 13C{1H} NMR
(75 MHz, CDCl3) δ 197.4, 196.0, 170.9, 170.5, 167.3 (d, J = 253.5
Hz), 133.1 (d, J = 3.0 Hz), 133.0 (d, J = 3.0 Hz), 132.8 (d, J = 9.8 Hz),
130.5, 115.9 (d, J = 21.8 Hz), 115.7 (d, J = 21.8 Hz), 45.7, 44.4, 37.5,
36.7, 33.2, 21.9, 21.2. HRMS (TOF MS CI+) [M + H]+ calculated for
C12H15FNO2 224.1087, found 224.1089.
N-(3-(4-Chlorophenyl)-3-oxopropyl)-N-methylacetamide
(3fa).13 Yellow oil. 56.3 mg, 47%. The ratio of two conformational
isomers is about 2.9:1. 1H NMR (400 MHz, CDCl3) δ 7.92−7.87 (m,
2H), 7.47−7.42 (m, 2H), 3.78−3.70 (m, 2H), 3.27−3.20 (m, 2H),
3.08 (s, 2.3H), 2.94 (s, 0.8H), 2.15 (s, 0.8H), 2.06 (s, 2.3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 197.8, 196.4, 171.0, 170.5, 140.1, 139.7,
134.9, 134.6, 129.5, 129.3, 129.1, 128.9, 45.7, 44.4, 37.6, 36.9, 36.8,
33.2, 21.9, 21.3. HRMS (TOF MS CI+) [M + H]+ calculated for
C12H15ClNO2 240.0791, found 240.0787.
N-Methyl-N-(3-oxo-3-(3,4,5-trimethoxyphenyl)propyl)-
acetamide (3ga). Yellow oil. 73.8 mg, 50%. The ratio of two
conformational isomers is about 3.1:1. 1H NMR (400 MHz, CDCl3) δ
7.21 (d, J = 32.0 Hz, 2H), 3.90 (s, 6H), 3.89 (s, 3H), 3.78−3.69 (m,
2H), 3.25−3.18 (m, 2H), 3.07 (s, 2.2H), 2.94 (s, 0.7H), 2.14 (s, 0.7H),
2.05 (s, 2.2H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 196.2,
170.8, 170.4, 153.0, 152.9, 142.4, 142.2, 131.7, 131.4, 105.4, 105.3,
60.8, 60.7, 56.2, 56.1, 45.8, 44.6, 37.4, 36.6, 36.5, 33.1, 21.8, 21.2.
HRMS (TOF MS CI+) [M + H]+ calculated for C15H22NO5 296.1498,
found 296.1494.
1
internal reference. Products were characterized by comparison of H
NMR, 13C NMR, and HRMS.
General Procedure for Copper-Catalyzed Oxyalkylation of
Vinylarenes. To a test tube equipped with a magnetic stir bar was
added N-substituted acetamide (1.5 mL), CuF2·2H2O (0.05 mmol, 6.9
mg), styrene (0.5 mmol, 0.058 mL), and TBHP (tert-butyl
hydroperoxide, 70% in water, 2 mmol, 0.267 mL) in air. The resulting
reaction mixture was kept stirring at 100 °C for 48 h. At the end of the
reaction, the reaction mixture was cooled to room temperature. After
removal of the solvent, the residue was subjected to column
chromatography on silica gel using ethyl acetate and petroleum
ether mixtures to afford the desired product in high purity.
General Procedure for Copper-Catalyzed Decarboxylative
Alkenylation. To a Schlenk tube equipped with a magnetic stir bar
was added under argon CuO (0.06 mmol, 4.8 mg) and cinnamic acid
(0.3 mmol, 44.4 mg). Under argon, N-substituted acetamide (2.0 mL)
and DTBP (di-tert-butyl peroxide, 1.2 mmol, 0.226 mL) were added.
The resulting reaction mixture was kept stirring at 110 °C for 24 h. At
the end of the reaction, the reaction mixture was cooled to room
temperature. After removal of the solvent, the residue was subjected to
column chromatography on silica gel using ethyl acetate and
petroleum ether mixtures to afford the desired product in high purity.
N-Methyl-N-(3-(naphthalen-1-yl)-3-oxopropyl)acetamide
(3ha). Yellow oil. 75.3 mg, 59%. The ratio of two conformational
1
isomers is about 2:1. H NMR (400 MHz, CDCl3) δ 8.70−8.64 (m,
1H), 8.05−7.87 (m, 3H), 7.63−7.49 (m, 3H), 3.86−3.81 (m, 2H),
7106
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
a b c d
, , ,
Table 4. Copper-Catalyzed Decarboxylative Couplings between Cinnamic Acids with N,N-Substituted Amides
a
b
c
Catalytic conditions: cinnamic acid (0.3 mmol), CuO (20 mol %), DTBP (4 equiv), N,N-substituted amide (2 mL), 12 h, Ar. DTBP (2 equiv). 8
d
h. 24 h.
39.9, 37.6, 33.2, 22.0, 21.3. HRMS (TOF MS CI+) [M + H]+
calculated for C16H18NO2 256.1338, found 256.1340.
Scheme 2. Copper-Catalyzed Coupling between 3-
Methylbut-2-enoic Acid and DMA
N-Methyl-N-(3-oxo-2,3-diphenylpropyl)acetamide (3ia). Yel-
low oil. 60.5 mg, 43%. The ratio of two conformational isomers is
1
about 2.5:1. H NMR (400 MHz, CDCl3) δ 7.92 (t, J = 9.3 Hz, 2H),
7.46−7.19 (m, 8H), 5.25−4.79 (m, 1H), 4.00−3.65 (m, 2H), 2.87 (s,
0.8H), 2.73 (s, 2H), 2.00 (s, 2H), 1.83 (s, 0.8H). 13C{1H} NMR (100
MHz, CDCl3) δ 199.1, 197.9, 171.4, 171.3, 137.4, 136.5, 136.4, 135.9,
133.4, 133.1, 129.5, 129.1, 128.8, 128.7, 128.7, 128.5, 128.4, 128.1,
128.0, 127.5, 54.1, 53.0, 52.4, 51.5, 38.8, 33.8, 22.0, 20.9. HRMS (TOF
MS CI+) [M + H]+ calculated for C18H20NO2 282.1494, found
282.1496.
3.41−3.34 (m, 2H), 3.11 (s, 2H), 2.98 (s, 1H), 2.19 (s, 1H), 2.08 (s,
2H). 13C{1H} NMR (75 MHz, CDCl3) δ 202.8, 201.4, 170.9, 170.6,
135.1, 134.8, 134.0, 133.9, 133.5, 133.1, 130.1, 130.0, 128.5, 128.5,
128.3, 128.1, 126.7, 126.4, 125.7, 125.5, 124.4, 124.3, 46.2, 44.7, 40.2,
7107
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
2H), 3.04 (s, 2H), 2.94 (s, 1H), 2.42−2.26 (m, 2H), 1.19−1.09 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.2, 199.1, 174.1, 174.0,
136.8, 136.7, 133.3, 133.1, 128.7, 128.5, 128.2, 128.1, 44.8, 43.0, 37.0,
36.7, 31.3, 26.8, 17.5, 9.2. HRMS (TOF MS CI+) [M + H]+ calculated
for C13H18NO2 220.1338, found 220.1337.
Scheme 3. Copper-Catalyzed Functionalization of Amides in
the Presence of BHT
N-Ethyl-N-(4-oxo-4-phenylbutan-2-yl)acetamide (3ad). Yel-
low oil. 35.0 mg, 30%. The ratio of two conformational isomers is
about 2:1. 1H NMR (400 MHz, CDCl3) δ 8.00−7.91 (m, 2H), 7.60−
7.42 (m, 3H), 4.64−4.36 (m, 1H), 3.67−3.03 (m, 4H), 2.20 (s, 1H),
2.03 (s, 2H), 1.38−1.28 (m, 3H), 1.22−1.08 (m, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 199.0, 197.1, 170.6, 170.4, 136.9, 136.6, 133.6,
133.2, 128.8, 128.6, 128.3, 128.0, 50.7, 49.7, 43.6, 43.6, 43.4, 36.1, 22.7,
22.2, 19.9, 18.7, 15.3, 14.7. HRMS (TOF MS CI+) [M + H]+
calculated for C14H20NO2 234.1494, found 234.1495.
N-Ethyl-N-(4-oxo-4-(p-tolyl)butan-2-yl)acetamide (3bd). Yel-
low oil. 32.2 mg, 26%. The ratio of two conformational isomers is
about 2:1. 1H NMR (400 MHz, CDCl3) δ 7.89−7.80 (m, 2H), 7.27−
7.22 (m, 2H), 4.62−4.35 (m, 1H), 3.69−2.99 (m, 4H), 2.40 (s, 1H),
2.38 (s, 2H), 2.20 (s, 1H), 2.03 (s, 2H), 1.36−1.26 (m, 3H), 1.21−
1.06 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.6, 196.7,
170.6, 170.5, 144.5, 144.0, 134.4, 134.1, 129.5, 129.3, 128.4, 128.1,
50.8, 49.8, 43.5, 43.4, 36.2, 22.7, 22.2, 21.7, 21.1, 19.9, 18.7, 15.2, 14.7.
HRMS (TOF MS CI+) [M + H]+ calculated for C15H22NO2 248.1651,
found 248.1649.
N-(3-Oxo-3-phenylpropyl)acetamide (3ab).16 Yellow oil. 31.0
mg, 54%. H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H),
7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 6.31 (s, 1H), 3.67−
3.62 (m, 2H), 3.22 (t, J = 5.5 Hz, 2H), 1.93 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 199.6, 170.2, 136.4, 133.5, 128.7, 128.0, 38.2,
34.3, 23.3. HRMS (TOF MS CI+) [M + H]+ calculated for
C11H14NO2 192.1025, found 192.1027.
1
N-Cinnamyl-N-methylacetamide (5aa).8b Colorless oil. 35.8
mg, 63%. The ratio of two conformational isomers is about 0.50:0.50.
1H NMR (400 MHz, CDCl3) δ 7.38−7.23 (m, 5H), 6.51−6.44 (m,
1H), 6.18−6.10 (m, 1H), 4.15 (d, J = 6.8 Hz, 1H), 4.06−4.05 (m,
1H), 2.98 (s, 1.5H), 2.98 (s, 1.5H), 2.14 (s, 1.5H), 2.13 (s, 1.5H).
13C{1H} NMR (75 MHz, CDCl3) δ 170.8, 170.5, 136.5, 136.1, 132.8,
131.7, 128.7, 128.5, 127.9, 127.6, 126.4, 124.5, 123.6, 52.6, 49.3, 35.4,
33.5, 21.8, 21.3. HRMS (ESI-TOF) [M + Na]+ calculated for
C12H15NONa 212.1051, found 212.1052.
(E)-N-(3-(4-Methoxyphenyl)allyl)-N-methylacetamide (5ba).
Colorless oil. 38.2 mg, 58%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.28−7.25 (m, 2H),
6.82 (t, J = 8.4 Hz, 2H), 6.42−6.35 (m, 1H), 5.99−5.91 (m, 1H), 4.08
(d, J = 6.8 Hz, 1H), 3.99 (d, J = 4.8 Hz, 1H), 3.77 (s, 1.5H), 3.76 (s,
1.5H), 2.93 (s, 1.5H), 2.93 (s, 1.5H), 2.10 (s, 1.5H), 2.08 (s, 1.5H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 170.5, 159.5, 159.3, 132.3,
131.3, 129.4, 128.9, 127.6, 127.5, 122.3, 121.3, 114.1, 114.0, 55.3, 55.3,
52.7, 49.4, 35.4, 33.4, 21.8, 21.3. HRMS (TOF MS CI+) [M + H]+
calculated for C13H18NO2 220.1338, found 220.1340.
N-(3-Oxo-3-(p-tolyl)propyl)acetamide (3bb). Yellow oil. 54.4
1
mg, 53%. H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 7.6 Hz, 2H), 6.25 (s, 1H), 3.64−3.60 (m, 2H), 3.17 (t, J =
5.5 Hz, 2H), 2.38 (s, 3H), 1.91 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 198.3, 169.2, 143.5, 132.9, 128.4, 127.1, 37.0, 33.3, 22.3,
20.7. HRMS (TOF MS CI+) [M + H]+ calculated for C12H16NO2
206.1181, found 206.1185.
N-(3-(4-Methoxyphenyl)-3-oxopropyl)acetamide (3cb). Yel-
low oil. 14.4 mg, 13%. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.9
Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.28 (s, 1H), 3.86 (s, 3H), 3.66−
3.61 (m, 2H), 3.16 (t, J = 5.5 Hz, 2H), 1.93 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 197.1, 169.2, 162.8, 129.3, 128.5, 112.8, 54.5,
36.8, 33.4, 22.3. HRMS (TOF MS CI+) [M + H]+ calculated for
C12H16NO3 222.1130, found 222.1131.
N-(3-(4-Fluorophenyl)-3-oxopropyl)acetamide (3eb). Yellow
oil. 42.9 mg, 41%. 1H NMR (400 MHz, CDCl3) δ 7.99−7.92 (m, 2H),
7.13 (t, J = 8.0 Hz, 2H), 6.28 (s, 1H), 3.66−3.62 (m, 2H), 3.19 (t, J =
5.1 Hz, 2H), 1.93 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9,
169.3, 164.9 (d, J = 254.3 Hz), 131.8 (d, J = 3.0 Hz), 129.7 (d, J = 9.8
Hz), 114.8 (d, J = 21.8 Hz), 37.1, 33.3, 22.2. HRMS (TOF MS CI+)
[M + H]+ calculated for C11H13FNO2 210.0930, found 210.0933.
N-Methyl-N-(3-oxo-3-phenylpropyl)propionamide (3ac). Yel-
low oil. 54.8 mg, 50%. The ratio of two conformational isomers is
about 2:1. 1H NMR (400 MHz, CDCl3) δ 7.97−7.91 (m, 2H), 7.60−
7.52 (m, 1H), 7.50−7.40 (m, 2H), 3.77−3.71 (m, 2H), 3.28−3.17 (m,
(E)-N-Methyl-N-(3-(p-tolyl)allyl)acetamide (5ca). Colorless oil.
25.6 mg, 42%. The ratio of two conformational isomers is about
0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.27−7.25 (m, 2H), 7.13 (t,
J = 8.0 Hz, 2H), 6.48−6.42 (m, 1H), 6.12−6.04 (m, 1H), 4.13 (d, J =
6.4 Hz, 1H), 4.04 (d, J = 5.2 Hz, 1H), 2.97 (s, 3H), 2.34 (s, 1.5H),
2.33 (s, 1.5H), 2.14 (s, 1.5H), 2.12(s, 1.5H). 13C{1H} NMR (75 MHz,
Scheme 4. Possible Mechanism
7108
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
CDCl3) δ 170.8, 170.5, 137.8, 137.5, 133.7, 133.3, 132.7, 131.7, 129.3,
129.2, 126.2, 123.4, 122.5, 52.6, 49.3, 35.4, 33.4, 21.8, 21.3, 21.1.
HRMS (TOF MS CI+) [M + H]+ calculated for C13H18NO 204.1388,
found 204.1387.
7.24−7.18 (m, 1H), 6.93−6.76 (m, 3H), 6.16−6.09 (m, 1H), 4.14 (d, J
= 6.8 Hz, 1H), 4.04−4.02 (m, 1H), 3.82 (s, 1.5H), 3.82 (s, 1.5H), 2.96
(s, 3H), 2.13 (s, 1.5H), 2.10 (s, 1.5H). 13C{1H} NMR (100 MHz,
CDCl3) δ 170.7, 170.3, 156.6, 156.4, 128.9, 128.6, 127.6, 127.0, 126.9,
126.7, 125.4, 125.0, 124.9, 124.1, 120.5, 110.8, 110.7, 55.3, 55.3, 53.0,
49.6, 35.2, 33.3, 21.8, 21.3. HRMS (TOF MS CI+) [M + H]+
calculated for C13H18NO2 220.1338, found 220.1341.
(E)-N-Methyl-N-(3-(m-tolyl)allyl)acetamide (5ka). Colorless oil.
32.3 mg, 53%. The ratio of two conformational isomers is about
0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.23−7.16 (m, 3H), 7.06 (t,
J = 9.0 Hz, 1H), 6.47−6.41 (m, 1H), 6.16−6.07 (m, 1H), 4.13 (d, J =
6.4 Hz, 1H), 4.05−4.03 (m, 1H), 2.97 (s, 1.5H), 2.96 (s, 1.5H), 2.34
(s, 1.5H), 2.33 (s, 1.5H), 2.13 (s, 1.5H), 2.12 (s, 1.5H). 13C{1H} NMR
(100 MHz, CDCl3) δ 170.7, 170.4, 138.2, 138.0, 136.4, 135.9, 132.8,
131.8, 128.6, 128.5, 128.4, 127.0, 127.0, 124.2, 123.5, 123.4, 123.3,
52.6, 49.2, 35.3, 33.4, 21.8, 21.3, 21.2. HRMS (TOF MS CI+) [M +
H]+ calculated for C13H18NO 204.1388, found 204.1393.
(E)-N-(3-(3-Methoxyphenyl)allyl)-N-methylacetamide (5la).
Colorless oil. 17.1 mg, 26%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.26−7.19 (m, 1H),
6.95 (t, J = 4.0 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.82−6.77 (m, 1H),
6.47−6.40 (m, 1H), 6.16−6.08 (m, 1H), 4.13 (d, J = 6.8 Hz, 1H),
4.05−4.03 (m, 1H), 3.81 (s, 1.5H), 3.79 (s, 1.5H), 2.97 (s, 1.5H), 2.96
(s, 1.5H), 2.13 (s, 1.5H), 2.12 (s, 1.5H). 13C{1H} NMR (75 MHz,
CDCl3) δ 170.8, 170.4, 159.8, 159.7, 137.9, 137.5, 132.6, 131.5, 129.6,
129.5, 124.8, 123.9, 119.0, 118.9, 113.5, 113.4, 111.7, 111.4, 55.2, 55.1,
52.5, 49.2, 35.4, 33.4, 21.8, 21.2. HRMS (TOF MS CI+) [M + H]+
calculated for C13H18NO2 220.1338, found 220.1343.
(E)-3-(3-(N-Methylacetamido)prop-1-en-1-yl)phenyl Acetate
(5ma). Colorless oil. 34.9 mg, 47%. The ratio of two conformational
isomers is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.35−7.28
(m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 0.8 Hz, 1H), 6.96 (d, J =
9.6 Hz, 1H), 6.47−6.41 (m, 1H), 6.17−6.10 (m, 1H), 4.13 (d, J = 6.0
Hz, 1H), 4.05 (d, J = 4.8 Hz, 1H), 2.97 (s, 1.5H), 2.96 (s, 1.5H), 2.30
(s, 1.5H), 2.29 (s, 1.5H), 2.12 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 170.8, 170.5, 169.4, 151.0, 150.9, 138.2, 137.7, 131.7, 130.7,
129.6, 129.5, 125.8, 124.9, 124.0, 124.0, 121.0, 120.7, 119.3, 52.5, 49.2,
35.5, 33.5, 21.8, 21.3, 21.1. HRMS (TOF MS CI+) [M + H]+
calculated for C14H18NO3 248.1287, found 248.1286.
(E)-N-(3-(3-Hydroxyphenyl)allyl)-N-methylacetamide (5na).
Colorless oil. 35.1 mg, 57%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, DMSO) δ 9.42 (s, 0.5H), 9.40
(s, 0.5H), 7.14−7.09 (m, 1H), 6.88−6.80 (m, 2H), 6.66 (d, J = 6.6 Hz,
1H), 6.38 (d, J = 16.8 Hz, 1H), 6.24−6.18 (m, 0.5H), 6.10−6.03 (m,
0.5H), 4.02 (t, J = 6.6 Hz, 2H), 2.93 (s, 1.5H), 2.81 (s, 1.5H), 2.02 (s,
3H). 13C{1H} NMR (100 MHz, DMSO) δ 169.7, 169.6, 157.6, 157.6,
137.8, 137.6, 131.6, 131.1, 129.6, 129.6, 124.9, 117.4, 117.3, 114.8,
114.7, 113.0, 112.8, 51.8, 48.3, 35.2, 32.8, 21.6, 21.2. HRMS (TOF MS
CI+) [M + H]+ calculated for C12H16NO2 206.1181, found 206.1183.
(E)-N-(3-(3,4-Dimethoxyphenyl)allyl)-N-methylacetamide
(5oa). Colorless oil. 44.9 mg, 60%. The ratio of two conformational
isomers is about 0.55:0.45. 1H NMR (400 MHz, CDCl3) δ 6.88−6.82
(m, 2H), 6.76 (t, J = 8.6 Hz, 1H), 6.36 (t, J = 15.0 Hz, 1H), 5.99−5.90
(m, 1H), 4.06 (d, J = 6.4 Hz, 1H), 3.98 (d, J = 5.2 Hz, 1H), 3.85−3.81
(m, 6H), 2.93 (s, 1.3H), 2.92 (s, 1.7H), 2.09 (s, 1.3H), 2.07 (s, 1.7H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 170.3, 148.9, 148.8, 148.8,
(E)-N-(3-(4-Isopropylphenyl)allyl)-N-methylacetamide (5da).
Colorless oil. 35.4 mg, 51%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.31−7.29 (m, 2H),
7.18 (t, J = 8.4 Hz, 2H), 6.49−6.42 (m, 1H), 6.12−6.04 (m, 1H), 4.13
(d, J = 6.8 Hz, 1H), 4.04 (d, J = 5.2 Hz, 1H), 2.96 (s, 3H), 2.91−2.84
(m, 1H), 2.13 (s, 1.5H), 2.11 (s, 1.5H), 1.24 (d, J = 2.8 Hz, 3H), 1.23
(d, J = 2.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 170.4,
148.9, 148.5, 134.1, 133.7, 132.7, 131.6, 126.7, 126.6, 126.3, 126.3,
123.5, 122.6, 52.6, 49.3, 35.3, 33.8, 33.4, 23.9, 21.8, 21.2. HRMS (TOF
MS CI+) [M + H]+ calculated for C15H22NO 232.1701, found
232.1709.
(E)-Methyl 4-(3-(N-methylacetamido)prop-1-en-1-yl)-
benzoate (5ea). White solid. 18.5 mg, 25%. The ratio of two
conformational isomers is about 0.50:0.50. 1H NMR (400 MHz,
CDCl3) δ 7.97 (t, J = 8.8 Hz, 2H), 7.42−7.39 (m, 2H), 6.52−6.47 (m,
1H), 6.29−6.22 (m, 1H), 4.16 (d, J = 6.0 Hz, 1H), 4.08 (d, J = 4.8 Hz,
1H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 3.00 (s, 1.5H), 2.98 (s, 1.5H), 2.13
(s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 170.8, 170.6, 166.8,
166.7, 141.0, 140.5, 131.6, 130.7, 130.0, 129.9, 129.4, 129.0, 127.4,
126.5, 126.3, 126.2, 52.5, 52.1, 52.0, 49.3, 35.7, 33.6, 21.7, 21.3. HRMS
(TOF MS CI+) [M + H]+ calculated for C14H18NO3 248.1287, found
248.1288.
(E)-N-Methyl-N-(3-(4-(trifluoromethyl)phenyl)allyl)-
acetamide (5fa). Colorless oil. 16.2 mg, 21%. The ratio of two
conformational isomers is about 0.57:0.43. 1H NMR (400 MHz,
CDCl3) δ 7.58−7.54 (m, 2H), 7.47−7.43 (m, 2H), 6.52−6.47 (m,
1H), 6.28−6.20 (m, 1H), 4.16 (d, J = 6.0 Hz, 1H), 4.10−4.08 (m,
1H), 3.00 (s, 1.7H), 2.98 (s, 1.3H), 2.13 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 170.8, 170.6, 140.1, 139.5, 131.2, 130.3, 129.9, 129.4
(d, J = 32.4 Hz), 127.5, 126.6, 126.6, 126.5, 125.6 (q, J = 2.9 Hz),
125.5 (q, J = 2.9 Hz), 122.8, 122.7, 52.4, 49.2, 35.7, 33.6, 21.8, 21.3.
HRMS (TOF MS CI+) [M + H]+ calculated for C13H15NOF3
258.1106, found 258.1109.
(E)-N-(3-(4-Cyanophenyl)allyl)-N-methylacetamide (5ga).
Colorless oil. 16.7 mg, 26%. The ratio of two conformational isomers
is about 0.55:0.45. 1H NMR (400 MHz, CDCl3) δ 7.61−7.57 (m, 2H),
7.43 (t, J = 7.4 Hz, 2H), 6.49−6.44 (m, 1H), 6.31−6.24 (m, 1H), 4.16
(d, J = 6.0 Hz, 1H), 4.1 (d, J = 4.8 Hz, 1H), 3.00 (s, 1.7H), 2.97 (s,
1.3H), 2.13 (s, 1.7H), 2.12 (s, 1.3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 170.8, 170.7, 141.0, 140.4, 132.5, 132.4, 130.7, 129.8, 128.8,
127.9, 126.9, 126.8, 118.8, 118.7, 111.2, 110.8, 52.4, 49.2, 35.8, 33.7,
21.7, 21.2. HRMS (TOF MS CI+) [M + H]+ calculated for
C13H15N2O 215.1184, found 215.1184.
(E)-N-(3-(4-Fluorophenyl)allyl)-N-methylacetamide (5ha).
Colorless oil. 36.7 mg, 59%. The ratio of two conformational isomers
is about 0.55:0.45. 1H NMR (400 MHz, CDCl3) δ 7.33−7.29 (m, 2H),
7.02−6.95 (m, 2H), 6.45−6.39 (m, 1H), 6.08−5.99 (m, 1H), 4.11 (d, J
= 6.4 Hz, 1H), 4.03 (d, J = 5.2 Hz, 1H), 2.97 (s, 1.6H), 2.95 (s, 1.4H),
2.12 (s, 1.4H), 2.11 (s, 1.6H). 13C{1H} NMR (75 MHz, CDCl3) δ
170.7, 170.5, 162.4 (d, J = 245.9 Hz), 162.3 (d, J = 245.6 Hz,), 132.7
(d, J = 3.2 Hz,), 132.2 (d, J = 3.2 Hz), 131.5, 130.5, 127.9 (d, J = 7.8
Hz), 127.8 (d, J = 7.8 Hz), 124.3, 123.4, 115.5 (d, J = 21.5 Hz), 115.4
(d, J = 21.4 Hz), 52.5, 49.2, 35.5, 33.4, 21.8, 21.2. HRMS (TOF MS
CI+) [M + H]+ calculated for C12H15NOF 208.1138, found 208.1141.
(E)-N-(3-(4-Chlorophenyl)allyl)-N-methylacetamide (5ia).
Colorless oil. 18.0 mg, 27%. The ratio of two conformational isomers
148.6, 132.3, 131.2, 129.4, 129.0, 122.3, 121.4, 119.4, 119.3, 111.0,
110.8, 108.6, 108.4, 55.7, 55.6, 55.6, 52.4, 49.2, 35.3, 33.3, 21.6, 21.1.
HRMS (TOF MS CI+) [M + H]+ calculated for C14H20NO3 250.1443,
found 250.1443.
1
is about 0.50:0.50. H NMR (400 MHz, CDCl3) δ 7.29 (s, 2H), 7.28
(E)-N-Methyl-N-(3-(naphthalen-1-yl)allyl)acetamide (5pa).
Colorless oil. 38.1 mg, 53%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 8.10−8.02 (m, 1H),
7.84 (t, J = 5.8 Hz, 1H), 7.78 (t, J = 9.0 Hz, 1H), 7.58−7.41 (m, 4H),
7.26−7.20 (m, 1H), 6.19−6.10 (m, 1H), 4.26 (d, J = 6.4 Hz, 1H), 4.14
(d, J = 4.8 Hz, 1H), 3.05 (s, 1.5H), 3.04 (s, 1.5H), 2.19 (s, 1.5H), 2.14
(s, 1.5H). 13C{1H} NMR (75 MHz, CDCl3) δ 170.7, 170.4, 134.2,
133.8, 133.5, 130.9, 130.9, 129.9, 129.1, 128.5, 128.5, 128.2, 128.0,
127.7, 126.9, 126.2, 126.0, 125.8, 125.7, 125.5, 125.5, 123.9, 123.6,
(s, 2H), 6.46−6.40 (m, 1H), 6.16−6.08 (m, 1H), 4.13 (d, J = 6.4 Hz,
1H), 4.06−4.05 (m, 1H), 2.99 (s, 1.5H), 2.97 (s, 1.5H), 2.13 (s, 1.5H),
2.13 (s, 1.5H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 170.5,
135.0, 134.5, 133.5, 133.1, 131.3, 130.3, 128.7, 128.6, 127.5, 127.5,
125.2, 124.3, 52.4, 49.2, 35.5, 33.4, 21.7, 21.2. HRMS (TOF MS CI+)
[M + H]+ calculated for C12H15NOCl 224.0842, found 224.0845.
(E)-N-(3-(2-Methoxyphenyl)allyl)-N-methylacetamide (5ja).
Colorless oil. 44.1 mg, 67%. The ratio of two conformational isomers
is about 0.50:0.50. 1H NMR (400 MHz, CDCl3) δ 7.41−7.37 (m, 1H),
7109
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
123.4, 52.8, 49.4, 35.4, 33.5, 21.8, 21.3. HRMS (TOF MS CI+) [M +
H]+ calculated for C16H18NO 240.1388, found 240.1396.
(E)-N-Methyl-N-(3-(thiophen-2-yl)allyl)acetamide (5qa). Col-
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
orless oil. 30.5 mg, 52%. The ratio of two conformational isomers is
1
about 0.50:0.50. H NMR (400 MHz, CDCl3) δ 7.16−7.12 (m, 1H),
6.96−6.92 (m, 2H), 6.58 (t, J = 14.0 Hz, 1H), 5.99−5.91 (m, 1H),
4.09 (d, J = 6.4 Hz, 1H), 4.00 (d, J = 5.2 Hz, 1H), 2.97 (s, 1.5H), 2.95
(s, 1.5H), 2.11 (s, 1.5H), 2.10 (s, 1.5H). 13C{1H} NMR (75 MHz,
CDCl3) δ 170.7, 170.4, 141.6, 141.0, 127.4, 127.2, 126.1, 125.8, 125.6,
124.8, 124.5, 124.2, 124.1, 123.2, 52.2, 48.9, 35.4, 33.4, 21.7, 21.3.
HRMS (TOF MS CI+) [M + H]+ calculated for C10H14NOS
196.0796, found 196.0798.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jcmao@suda.edu.cn (J.M.).
Notes
■
The authors declare no competing financial interest.
(E)-N-(3-(Furan-2-yl)allyl)-N-methylacetamide (5ra). Colorless
oil. 38.2 mg, 71%. The ratio of two conformational isomers is about
0.50:0.50. H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 10.4 Hz, 1H),
ACKNOWLEDGMENTS
■
1
We are grateful for the grants from the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry, the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, The Project of
Scientific and Technologic Infrastructure of Suzhou
(SZS201207), and the Key Laboratory of Organic Synthesis
of Jiangsu Province.
6.36−6.20 (m, 3H), 6.08−6.01 (m, 1H), 4.09 (d, J = 6.4 Hz, 1H), 4.01
(d, J = 4.8 Hz, 1H), 2.96 (s, 1.5H), 2.94 (s, 1.5H), 2.10 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 170.9, 170.5, 152.1, 151.6, 142.1,
141.9, 123.0, 122.1, 120.9, 119.8, 111.3, 111.1, 108.3, 107.7, 52.2, 48.8,
35.5, 33.5, 21.7, 21.1. HRMS (TOF MS CI+) [M + H]+ calculated for
C10H14NO2 180.1025, found 180.1022.
(N-Methylacetamido)methyl 3-methylbut-2-enoate (5ta).
Colorless oil. 36.1 mg, 65%. The ratio of two conformational isomers
1
is about 0.33:0.67. H NMR (400 MHz, CDCl3) δ 5.65 (s, 1H), 5.40
REFERENCES
■
(s, 0.7H), 5.35 (s, 1.3H), 3.09 (s, 1H), 2.98 (s, 2H), 2.17 (d, J = 18.4
Hz, 5H), 2.10 (s, 1H), 1.89 (s, 2H), 1.86 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 171.9, 166.3, 165.7, 159.1, 158.2, 115.3, 114.9, 73.8,
70.5, 36.1, 33.6, 27.4, 27.4, 21.9, 21.1, 20.3, 20.2. HRMS (TOF MS
CI+) [M + H]+ calculated for C9H16NO3 186.1130, found 186.1131.
(1) (a) Nieman, J. A.; Coleman, J. E.; Wallace, D. J.; Piers, E.; Lim, L.
Y.; Roberge, M.; Andersen, R. J. J. Nat. Prod. 2003, 66, 183−199.
(b) Loganzo, F.; Discafani, C. M.; Annable, T.; Beyer, C.; Musto, S.;
Hari, M.; Tan, X.; Hardy, C.; Hernandez, R.; Baxter, M.; Singanallore,
T.; Khafizovca, G.; Poruchynsky, M. S.; Fojo, T.; Nieman, J. A.; Ayral-
Kaloustian, S.; Zask, A.; Andersen, R. J.; Greenberger, L. M. Cancer
Res. 2003, 63, 1838−1845.
(2) Gerspacher, M.; Lewis, C.; Ball, H. A.; Howes, C.; Subramanian,
N.; Ryffel, K.; Fozard, J. R. J. Med. Chem. 2003, 46, 3508−3513.
(3) Baldisserotto, A.; Franceschini, C.; Scalambra, F.; Trapella, C.;
Marastoni, M.; Sforza, F.; Gavioli, R.; Tomatis, R. J. Pept. Sci. 2010, 16,
659−663.
N-Cinnamylacetamide (5ab).17 White solid. 23.1 mg, 44%. H
1
NMR (400 MHz, CDCl3) δ 7.36−7.29 (m, 4H), 7.25−7.22 (m, 1H),
6.52 (d, J = 16.0 Hz, 1H), 6.22−6.15 (m, 1H), 5.69 (s, 1H), 4.03 (t, J
= 12.0 Hz, 2H), 2.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
170.0, 136.4, 132.3, 128.6, 127.7, 126.3, 125.4, 41.7, 23.2. HRMS
(TOF MS CI+) [M + H]+ calculated for C11H14NO 176.1075, found
176.1076.
N-Cinnamyl-N-methylpropionamide (5ac). Colorless oil. 24.4
mg, 40%. The ratio of two conformational isomers is about 0.50:0.50.
1H NMR (400 MHz, CDCl3) δ 7.36−7.19 (m, 5H), 6.45 (t, J = 15.4
Hz, 1H), 6.17−6.07 (m, 1H), 4.14 (d, J = 6.4 Hz, 1H), 4.04 (d, J = 5.2
Hz, 1H), 2.97 (s, 1.5H), 2.95 (s, 1.5H), 2.38−2.35 (m, 2H), 1.18−1.14
(m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 173.5, 136.5,
136.0, 132.6, 131.5, 128.5, 128.4, 127.8, 127.5, 126.2, 124.7, 123.9,
51.5, 49.4, 34.4, 33.5, 26.7, 26.1, 9.5, 9.2. HRMS (TOF MS CI+) [M +
H]+ calculated for C13H18NO 204.1388, found 204.1386.
(4) Elliott, R. L.; Kopecka, H.; Tufano, M. D.; Shue, Y.-K.; Gauri, A.
J.; Lin, C.-W.; Bianchi, B. R.; Miller, T. R.; Witte, D. G.; Stashko, M.
A.; Asin, K. E.; Nikkel, A. L.; Bednarz, L.; Nadzan, A. M. J. Med. Chem.
1994, 37, 1562−1568.
(5) (a) Banerjee, D.; Jagadeesh, R. V.; Junge, K.; Junge, H.; Beller, M.
Angew. Chem., Int. Ed. 2012, 51, 11556−11560. (b) Johannsen, M.;
Jørgensen, K. A. Chem. Rev. 1998, 98, 1689−1708. (c) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921−2943.
(6) Velingkar, V. S.; Dandekar, V. D. Chin. J. Chem. 2011, 29, 504−
510.
(E)-N-Ethyl-N-(4-phenylbut-3-en-2-yl)acetamide (5ad). Color-
less oil. 39.1 mg, 60%. The ratio of two conformational isomers is
(7) For selected recent sp3 C−H bond functionalization reviews, see:
(a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−1314.
1
about 0.60:0.40. H NMR (400 MHz, CDCl3) δ 7.37−7.23 (m, 5H),
6.49−6.40 (m, 1H), 6.25−6.15 (m, 1H), 5.42−5.36 (m, 0.6H), 4.60−
4.54 (m, 0.4H), 3.49−3.12 (m, 2H), 2.17 (s, 1.2H), 2.14 (s, 1.8H),
1.44 (d, J = 6.8 Hz, 1.2H), 1.35 (d, J = 6.8 Hz, 1.8H), 1.21−1.14 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 170.0, 136.7, 136.2,
130.7, 130.5, 130.2, 129.5, 128.6, 128.5, 127.9, 127.5, 126.3, 126.3,
54.8, 50.2, 39.0, 37.0, 22.1, 21.8, 18.7, 17.4, 16.4, 14.9. HRMS (TOF
MS CI+) [M + H]+ calculated for C14H20NO 218.1545, found
218.1544.
́
(b) D.-Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379−3394.
(c) Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40,
1937−1949. (d) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902−4911.
(e) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931−
942. (f) Xie, J.; Pan, C.; Abdukader, A.; Zhu, C. Chem. Soc. Rev. 2014,
43, 5245−5256. (g) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem.,
Int. Ed. 2014, 53, 74−100. (h) Rouquet, G.; Chatani, N. Angew. Chem.,
Int. Ed. 2013, 52, 11726−11743. (i) Campos, K. R. Chem. Soc. Rev.
2007, 36, 1069−1084.
(E)-1-Methyl-5-styrylpyrrolidin-2-one (5ae).12a Colorless oil.
1
28.4 mg, 47%. H NMR (400 MHz, CDCl3) δ 7.40−7.28 (m, 5H),
(8) (a) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T. Org.
Lett. 2009, 11, 1821−1823. (b) Sun, M.; Wu, H.; Bao, W. Org. Biomol.
Chem. 2013, 11, 7076−7079.
(9) (a) Yang, H.; Sun, P.; Zhu, Y.; Yan, H.; Lu, L.; Qu, X.; Li, T.;
Mao, J. Chem. Commun. 2012, 48, 7847−7849. (b) Yang, H.; Yan, H.;
Sun, P.; Zhu, Y.; Lu, L.; Liu, D.; Rong, G.; Mao, J. Green Chem. 2013,
15, 976−981. (c) Zhao, J.; Zhou, W.; Han, J.; Li, G.; Pan, Y.
Tetrahedron Lett. 2013, 54, 6507−6510.
(10) (a) Wei, W.-W.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.;
Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52,
3638−3641. (b) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11,
2908−2911. (c) Sun, H.; Zhang, Y.; Guo, F.; Zha, Z.; Wang, Z. J. Org.
6.57 (d, J = 15.6 Hz, 1H), 6.05−5.99 (m, 1H), 4.13−4.08 (m, 1H),
2.79 (s, 3H), 2.54−2.27 (m, 3H), 1.88−1.80 (m, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 175.0, 135.9, 133.0, 128.9, 128.7, 128.1, 126.5,
63.0, 30.0, 27.9, 25.7. HRMS (TOF MS CI+) [M + H]+ calculated for
C13H16NO 202.1232, found 202.1231.
(E)-5-Styrylpyrrolidin-2-one (5af).12a White solid. 21.9 mg, 39%.
1H NMR (400 MHz, CDCl3) δ 7.38−7.31 (m, 4H), 7.28−7.24 (m,
1H), 6.54 (d, J = 16.0 Hz, 1H), 6.16−6.10 (m, 1H), 6.02 (s, 1H),
4.36−4.30 (m, 1H), 2.46−2.32 (m, 3H), 1.99−1.88 (m, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 178.1, 136.0, 131.2, 129.8, 128.7, 128.0,
126.5, 56.5, 29.9, 28.5. HRMS (TOF MS CI+) [M + H]+ calculated for
C12H14NO 188.1075, found 188.1073.
7110
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111

The Journal of Organic Chemistry
Article
Chem. 2012, 77, 3563−3569. (d) Xie, J.; Huang, Z.-Z. Chem. Commun.
2010, 46, 1947−1949.
(11) (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am. Chem. Soc. 2011, 133,
10756−10759. (b) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Angew. Chem.,
Int. Ed. 2013, 52, 2256−2259. (c) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.;
Wang, H.; Liu, Z.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 7156−7159.
(d) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D.
Angew. Chem., Int. Ed. 2013, 52, 9747−9750.
(12) (a) Priyadarshini, S.; Joseph, P. J. A.; Kantam, M. L. RSC Adv.
2013, 3, 18283−18287. (b) Yan, H.; Yang, H.; Lu, L.; Liu, D.; Rong,
G.; Mao, J. Tetrahedron 2013, 69, 7258−7263.
(13) Zhang, J.-X.; Wang, Y.-J.; Wang, N.-X.; Zhang, W.; Bai, C.-B.; Li,
Y.-H.; Wen, J.-L. Synlett 2014, 25, 1621−1625.
(14) (a) Friedma, L. Tetrahedron Lett. 1961, 7, 238−242. (b) Mignai,
S.; Merenyi, R.; Janousek, Z.; Viehe, H. G. Tetrahedron 1985, 41, 769−
773.
(15) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. J. Am. Chem. Soc.
2012, 134, 3338−3341.
(16) Gooßen, L. J.; Ghosh, K. Eur. J. Org. Chem. 2002, 3254−3267.
(17) Mukhopadhyay, M.; Reddy, M. M.; Maikap, G. C.; Iqbal, J. J.
Org. Chem. 1996, 60, 2670−2676.
7111
dx.doi.org/10.1021/jo501274f | J. Org. Chem. 2014, 79, 7103−7111