Synthesis of α-ketoamides from Aryl methyl ketones and N, N -dimethylformamide via copper-catalyzed aerobic oxidative coupling

Article abstract of DOI:10.1055/s-0033-1339109

A copper-catalyzed aerobic oxidative coupling of aryl methyl ketones with N,N-dimethylformamide was developed, which afforded α-ketoamides by a sequence of dioxygen activation, C-H bond functionalization, and amide formation with N,N-dimethylformamide as

Full text of DOI:10.1055/s-0033-1339109

SPECIAL TOPIC
▌1853
special topic
Synthesis of α-Ketoamides from Aryl Methyl Ketones and N,N-Dimethyl-
formamide via Copper-Catalyzed Aerobic Oxidative Coupling
Oxygenation and Amide Formation
Mingxin Zhou, Qiuling Song*
Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Blvd, Xiamen,
Fujian 361021, P. R. of China
E-mail: qsong@hqu.edu.cn
Received: 23.02.2014; Accepted after revision: 13.04.2014
cause of its low toxicity, easy availability, and abundance.
Recently we have been interested in copper-catalyzed aer-
obic oxidation/oxygenation with cheap, commercially
available starting materials to construct new carbon–
Abstract: A copper-catalyzed aerobic oxidative coupling of aryl
methyl ketones with N,N-dimethylformamide was developed,
which afforded α-ketoamides by a sequence of dioxygen activation,
C–H bond functionalization, and amide formation with N,N-di-
methylformamide as the nitrogen source. Molecular oxygen was carbon and carbon–heteroatom bonds.9 As continuation of
found to play a crucial role in this transformation.
our interest in this area, herein we report a copper-cata-
lyzed aerobic oxidation to synthesize α-ketoamides from
aryl methyl ketones and N,N-dimethylformamide.
Key words: aryl methyl ketones, DMF, copper, oxygen, α-keto-
amides
On the basis of our own current research and the above re-
ported literature, it is rational that the reaction between
aryl methyl ketones and N,N-dimethylformamide could
afford α-ketoamides in the presence of copper catalyst un-
der an oxygen atmosphere. There are three known meth-
ods to convert N,N-dimethylformamide into amino group:
acid, imidazole, and the TBAI/TBHP system.6b Because
peroxide was needed in the TBAI/TBHP system, we de-
cided to focus on the first two methods. In our initial
study, acetophenone was chosen as the model substrate
and an added acid to promote the formation of amino
group from N,N-dimethylformamide in the presence of
Cu(OAc)2 at 130 °C under oxygen atmosphere. To our de-
light, 50% of α-ketoamide 3a was detected when PivOH
was added. After screening, it turned out that acetic acid
gave the best result among TFA, PhCO2H, and imidazole.
Catalysts screening showed that Cu2O gave the highest
yield of desired product (Table 1, entries 2, 6–13). Further
investigation indicated that temperature is very important
for this transformation. When the temperature was in-
creased to 150 °C, the yield of the desired product was
dropped to 30%, yet when the temperature was lowered to
120 °C, 75% of desired product was obtained in GC yield
with 65% isolated yield (Table 1, entries 14, 15). When
catalyst loading was reduced to 10 mol%, the yield
dropped to 62% (Table 1, entry 16), and addition of other
solvent such as toluene to N,N-dimethylformamide
caused notorious effect and only trace amount of the de-
sired product was detected (Table 1, entry 17). No desired
product was formed in the absence of oxygen or copper
catalyst (Table 1, entries 18, 19), which demonstrated that
both oxygen and copper catalyst played crucial roles in
the reaction. Eventually, the optimized reaction condi-
tions emerged as: aryl methyl ketone (0.5 mmol), Cu2O
(20 mol%), and acetic acid (2 equiv) in N,N-dimethyl-
formamide (1 mL) under oxygen atmosphere at 120 °C.
α-Ketoamides, as a kind of important organic compounds,
are widely found in natural products and bioactive com-
pounds,1 and they also show broad applications in various
functionality transformations.2 Many methods have been
reported for the synthesis of α-ketoamides,3 such as the
traditional condensation of α-keto acids or α-keto acyl
halides with amines,3a,b many interesting oxidative
approaches,3c,g,4 and palladium-catalyzed double carbon-
ylation of diaryliodonium salts or aryl halides.5 Among
the oxidative reactions, copper-catalyzed oxidative ami-
dation/diketonization of terminal alkynes with anilines,4a
oxidative coupling of arylacetaldehydes and secondary
amines,4b and oxidative coupling of aryl methyl ketones
and amines4c are the most attractive ones. Yet in most cas-
es, expensive substrates (α-keto acids, α-keto acyl halides,
terminal alkynes, and arylacetaldehydes) and special reac-
tion conditions were still required. N,N-Dimethylform-
amide as a ubiquitous solvent, is very cheap and has been
widely used in all kinds of reactions, and recently, many
methods have been developed using N,N-dimethylform-
amide as a reactant, acting as CHO, amide, CN, or amino
group surrogates.6 Aryl methyl ketones as cheap and com-
mercially available starting materials, have attracted sig-
nificant attention in organic and pharmaceutical synthesis.
And lately functionalization of sp3 C–H bond in aryl meth-
yl ketones became a hot topic and many efficient methods
have been developed based on catalytic functionalization
of sp3 C–H bond adjacent to carbonyl group in aryl methyl
ketones.4c,7 Very recently, Wang et al. reported an α-ke-
toamide formation reaction by treating an aryl methyl ke-
tone with N,N-dimethylformamide;8 this reaction needs
both peroxide and iodine as oxidants. Compared to perox-
ides and iodine, molecular oxygen is an ideal oxidant be-
With the optimized conditions in hand, we examined the
scope of substituted acetophenones (Scheme 1). Both
electron-rich and electron-poor aryl methyl ketones were
SYNTHESIS 2014, 46, 1853–1858
Advanced online publication: 28.05.2014
DOI: 10.1055/s-0033-1339109; Art ID: ss-2014-c0127-st
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1854
M. Zhou, Q. Song
SPECIAL TOPIC
readily converted into the desired products (Scheme 1, were used, only reasonable to low yields of the desired
3a–q, t). Furthermore, substituents at different positions products were obtained (Scheme 1, 3v–x).
of the arene group (p-, m-, and o-position) did affect the
efficiency (Scheme 1, 3b–d, 3e–g, 3h,i, 3j,k, 3m–o), with
To gain the preliminary insight into the mechanism of the
reaction, several control experiments were conducted
ortho-position giving lower yields probably due to the ste-
(Scheme 2). Thus, acetophenone was reacted with N,N-di-
ric hindrance (Scheme 1, 3d, 3f, 3i, 3j, and 3m). Halo-
methylformamide in the presence of 18O2 (1 atm) under
substituted aryl methyl ketones survived well leading to
standard conditions. The product obtained was character-
halo-substituted products (Scheme 1, 3b–i), which could
ized as 18O-3a by GCMS, which indicated that the new
be further transformed into other functionalities. Apart
carbonyl group should come from O2. When the reaction
from the halo-substituted aryl methyl ketones, 4-trifluoro-
was carried out under a nitrogen atmosphere, no product
methyl, methyl, ethyl, isopropyl, methoxy, nitro, and 1-
3a was obtained (Table 1, entry 16), which demonstrated
that molecular oxygen acted both as an oxidant and initi-
ator for this reaction. Reactions carried out with α-hy-
and 2-naphthyl methyl ketones were all well tolerated un-
der the standard conditions and gave the corresponding
products in moderate to good yields (Scheme 1, 3j–t).
droxyacetophenone and α-carbonyl aldehyde in the
Thiophene methyl ketone also gave a decent yield of the
standard conditions afforded the desired product 3a in
45% and 56% yield, respectively.
desired product (Scheme 1, 3u). When other formamides
Table 1 Optimization of the Reaction Conditionsa
O
O
Me
N
O
cat., solvent
temp, time
Me
Me
+
N
H
O
Me
1a (0.5 mmol)
3a
2
Entry
Catalyst
Atmosphere Acid
Solvent
Temp
( °C)
Time
(h)
Yield
(%)b
(2 equiv, 1 mmol)
1
2
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OTf)2 (20 mol%)
Cu(TFA)2 (20 mol%)
CuBr2 (20 mol%)
CuSO4 (20 mol%)
Cu2O (20 mol%)
CuO (20 mol%)
CuBr (20 mol%)
CuI (20 mol%)
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
N2
O2
PivOH
AcOH
TFA
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
DMF (1 mL)
130
130
130
130
130
130
130
130
130
130
130
130
130
150
120
130
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
50
60
3
51
4
PhCO2H
imidazole
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
trace
trace
27
5
6
7
52
8
7
9
34
10
11
12
13
14
15
16
17
18
19
70
34
40
41
Cu2O (20 mol%)
Cu2O (20 mol%)
Cu2O (10 mol%)
Cu2O (20 mol%)
Cu2O (20 mol%)
–
30
75 (65)c
62
DMF (5 equiv) + 1.5 mL toluene 130
trace
0
DMF (1 mL)
DMF (1 mL)
130
130
0
a Reaction conditions: acetophenone (1; 0.5 mmol), acid (2 equiv, 1 mmol), catalyst, DMF (1 mL) in a sealed tube under corresponding atmo-
sphere.
b GC yields using dodecane as internal standard.
c Isolated yield.
Synthesis 2014, 46, 1853–1858
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxygenation and Amide Formation
1855
O
O
Me
N
O
Cu2O
R
Ar
O
Ar
Me
N
R
H
+
O
AcOH, O2
2
1
3
O
Me
Me
N
O
Me
N
N
Cl
Me
Me
Me
O
O
O
Cl
3b, 100 °C, 18 h, 55%
3a, 120 °C, 21 h, 65%
3c, 100 °C, 24 h, 67%
O
Me
N
Cl
O
Me
N
Br
O
Me
N
Me
Me
Me
O
O
O
Br
3e, 110 °C, 24 h, 46%
3d, 100 °C, 16 h, 24%
3f, 110 °C, 25 h, 33%
O
Me
N
O
Me
N
F
O
Me
N
Br
Me
Me
Me
O
O
O
F
3g, 100 °C, 24 h, 50%
3h, 100 °C, 36 h, 62%
3i, 120 °C, 25 h, 53%
Me
O
O
Me
CF3
O
Me
N
N
N
Me
Me
Me
O
O
O2N
3l, 110 °C, 28 h, 31%
Me
O
F3C
3k, 120 °C, 18 h, 50%
Me
3j, 120 °C, 28 h, 42%
O
O
Me
N
O
N
N
Me
Me
Me
O
O
O
3m, 130 °C, 10 h, 56%
3n, 120 °C, 36 h, 61%
Me
3o, 130 °C, 25 h, 50%
O
O
O
Me
N
O
Me
N
N
Me
Me
Me
O
O
Et
3q, 120 °C, 24 h, 70%
Me
3r, 130 °C, 24 h, 62%
3p, 130 °C, 18 h, 51%
Me
O
O
O
N
Me
N
Me
Me
S
N
O
O
O
Me
MeO
3u, 110 °C, 24 h, 40%
3t, 130 °C, 10 h, 53%
3s, 130 °C, 10 h, 72%
O
O
O
O
N
N
N
O
O
O
3v, 40%
3w, 31%
3x, <5%
Scheme 1 Reaction of DMF with various aryl methyl ketones. Reaction conditions: acetophenone derivative (0.5 mmol), Cu2O (20 mol%),
AcOH (1 mmol, 2 equiv), formamide (1 mL), at the corresponding temperature under O2 atmosphere in a sealed tube, isolated yield.
On the basis of these results and the previous reports, a was obtained by oxidation of intermediate 5 by copper salt
mechanism was postulated as depicted in Scheme 3: ace- and oxygen.
tophenone was first oxidized into α-carbonyl aldehyde 4
in the presence of copper salt and oxygen, the aldehyde
To summarize, a copper-catalyzed aerobic oxidative syn-
thesis of α-ketoamides from aryl methyl ketones and N,N-
then reacted with the amino group, which was generated
dimethylformamide was developed. This reaction pro-
in situ from N,N-dimethylformamide and acid, to give the
ceeds smoothly by a sequence of dioxygen activation, C–
hemiaminal intermediate 5. Eventually α-ketoamide 3a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1853–1858

1856
M. Zhou, Q. Song
SPECIAL TOPIC
α-Ketoamides from Aryl Methyl Ketones and DMF; Phenyl-
N,N-dimethyl-2-oxoacetamide (3a);10 Typical Procedure
A Schlenk tube was charged with acetophenone (1a; 60 mg, 0.5
mmol), AcOH (60 mg, 1 mmol), and Cu2O (14.3 mg, 0.1 mmol, 20
mol%) in DMF (1 mL). The resulting solution was stirred at 120 °C
under O2. Upon completion of the reaction [monitored by TLC (el-
uent: PE–EtOAc, 6:1) and GC], EtOAc (20 mL) was added. The or-
ganic layer was washed with sat. aq NaHCO3 (2 × 15 mL) and brine
(20 mL). The combined aqueous layers were extracted with EtOAc
(2 × 15 mL) and the combined organic layers were dried (Na2SO4).
The solvents were removed via rotary evaporator and the residue
was purified with flash chromatography [silica gel 200–300 mesh,
petroleum ether–EtOAc, 5:1] to give 3a; yield: 57.5 mg (65%); yel-
low oil.
O
Me
N
O
O
O
Cu2O, 18O2
AcOH, DMF
Me
Me
N
H
H
+
+
O
Me
18O-3a was obtained
O
Me
N
O
Cu2O, N2
Me
Me
N
AcOH, DMF
O
Me
no 3a was obtained
O
O
Me
N
OH
standard condtions
[CAS Reg. No. 51579-87-4]
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 4 Hz, 2 H) 7.62 (t, J =
8 Hz, 1 H) 7.49 (t, J = 2 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.7, 166.7, 134.7, 133.1, 129.7,
129.0, 37.1, 34.0.
Me
Me
Me
O
3a, 45%
O
O
Me
N
H
standard condtions
standard condtions
2-(4-Chlorophenyl)-N,N-dimethyl-2-oxoacetamide (3b)10
[CAS Reg. No. 74491-48-8]
O
O
3a, 56%
Yield: 58 mg (55%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.4 Hz, 2 H), 7.46 (d,
J = 8.5 Hz, 2 H), 3.09 (s, 3 H), 2.94 (s, 3 H).
O
O
Me
N
OH
O
13C NMR (100 MHz, CDCl3): δ = 190.3, 166.5, 141.3, 131.5, 131.0,
O
129.4, 37.0, 34.1.
3a, trace
Scheme 2 Control experiments
2-(3-Chlorophenyl)-N,N-dimethyl-2-oxoacetamide (3c)10
Yield: 70.7 mg (67%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.91 (t, J = 2 Hz, 1 H), 7.82 (m, 1
H), 7.59 (m, 1 H), 7.44 (t, J = 7.6 Hz, 1 H), 3.11 (s, 3 H), 2.95 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 190.2, 166.3, 135.4, 134.7, 134.6,
130.5, 130.3, 129.4, 127.8, 37.0, 34.1.
H bond functionalization, and amide formation with N,N-
dimethylformamide as the nitrogen source. Molecular ox-
ygen was found to play a crucial role in this transforma-
tion.
2-(2-Chlorophenyl)-N,N-dimethyl-2-oxoacetamide (3d)10
All experiments were conducted in a Schlenk tube. Flash column
chromatography was performed over silica gel (200–300 mesh). 1H
NMR spectra were recorded on a Bruker AVIII 400 M spectrome-
ter. Chemical shifts (in ppm) were referenced to the residual solvent
peak (CDCl3 at 7.26 ppm or DMSO-d6 at 2.50 ppm). 13C NMR spec-
tra were obtained by using the same NMR spectrometers and were
calibrated against the control line of the solvent signal (CDCl3 at
77.00 ppm or DMSO-d6 at 39.6 ppm). Unless otherwise noted, ma-
terials obtained from commercial suppliers were used without fur-
ther purification. Petroleum ether (PE) used was the fraction boiling
in the range of 60–90 °C.
[CAS Reg. No. 668992-53-8]
Yield: 25.3 mg (24%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.2 Hz, 1 H), 7.49 (t,
J = 5.6 Hz, 1 H), 7.41 (m, 2 H), 3.08 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 190.2, 166.9, 134.3, 133.7, 133.5,
132.2, 130.8, 127.3, 37.1, 34.5.
2-(4-Bromophenyl)-N,N-dimethyl-2-oxoacetamide (3e)10
[CAS Reg. No. 1267453-29-1]
O
O
H
O
Cu(I)/O2
O
1a
4
Me
"
"
Me
HN
Me
+
AcOH
H
N
Me
O2
O
Me
N
O
Me
N
Cu(II)
Cu(I)
Me
Me
OH
O
5
3a
Scheme 3 Plausible mechanism
Synthesis 2014, 46, 1853–1858
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxygenation and Amide Formation
1857
Yield: 58.7 mg (46%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.6 Hz, 2 H), 7.63 (d,
J = 8.6 Hz, 2 H), 3.09 (s, 3 H), 2.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 189.2, 165.6, 151.1, 137.6, 130.8,
126.4, 124.1, 123.9, 37.1, 34.3.
N,N-Dimethyl-2-oxo-2-(o-tolyl)acetamide (3m)10
[CAS Reg. No. 1403603-11-1]
13C NMR (100 MHz, CDCl3): δ = 190.5, 166.4, 132.4, 131.9, 131.1,
130.2, 37.0, 34.1.
Yield: 53.5 mg (56%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 7 Hz, 1 H), 7.48 (t, J =
6.6 Hz, 1 H), 7.31 (t, J = 6.8 Hz, 2 H), 3.11 (s, 3 H), 2.97 (s, 3 H),
2.66 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 193.8, 167.8, 141.4, 133.7, 132.6,
132.6, 131.6, 126.2, 37.0, 34.0, 21.7.
2-(2-Bromophenyl)-N,N-dimethyl-2-oxoacetamide (3f)11
[CAS Reg. No. 1115951-84-2]
Yield: 42.1 mg (33%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J1 = 7.5 Hz, J2 = 2 Hz, 1
H), 7.63 (dd, J1 = 7.6 Hz, J2 = 1 Hz, 1 H), 7.42 (m, 2 H), 3.09 (s, 3
H), 3.07 (s, 3 H).
N,N-Dimethyl-2-oxo-2-(p-tolyl)acetamide (3n)
[CAS Reg. No. 51579-89-6]
13C NMR (100 MHz, CDCl3): δ = 190.9, 166.3, 135.5, 134.1, 134.1,
132.7, 127.8, 121.6, 37.3, 34.7.
Yield: 58.3 mg (61%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.0 Hz, 2 H), 7.33 (d,
J = 8.0 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H), 2.43 (s, 3 H).
2-(3-Bromophenyl)-N,N-dimethyl-2-oxoacetamide (3g)11
[CAS Reg. No. 1426249-30-0]
Yield: 63.8 mg (50%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 191.6, 167.2, 146.0, 131.0, 130.6,
129.7, 129.7, 37.0, 33.9, 21.8.
1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.88 (d, J = 7.7 Hz,
1 H), 7.76 (d, J = 7.3 Hz, 1 H), 7.39 (m, 1 H), 3.12 (s, 3 H), 2.97 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 190.1, 166.2, 137.5, 134.9, 132.4,
130.6, 128.3, 123.3, 37.0, 34.1.
N,N-Dimethyl-2-oxo-2-(m-tolyl)acetamide (3o)
[CAS Reg. No. 51579-90-9]
Yield: 47.8 mg (50%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 3.2 Hz, 2 H), 7.44 (d,
J = 7.5 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 3.10 (s, 3 H), 2.94 (s, 3
H), 2.40 (s, 3 H).
2-(4-Fluorophenyl)-N,N-dimethyl-2-oxoacetamide (3h)10
[CAS Reg. No. 126086-37-1]
Yield: 60.5 mg (62%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 192.0, 167.2, 139.0, 135.6, 133.1,
130.0, 128.9, 126.9, 37.0, 34.0, 21.2.
1H NMR (400 MHz, CDCl3): δ = 7.97 (m, 2 H), 7.17 (t, J = 8.6 Hz,
2 H), 3.10 (s, 3 H), 2.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.0, 168.0, 166.7, 165.4, 132.5,
2-(4-Ethylphenyl)-N,N-dimethyl-2-oxoacetamide (3p)
[CAS Reg. No. 1267457-91-9]
132.4, 129.7, 116.4, 116.2, 37.0, 34.1.
Yield: 52.3 mg (51%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.31 (d,
J = 8.2 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H), 2.71 (q, J = 7.6 Hz, 2
H), 1.25 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.6, 167.3, 152.1, 130.9, 129.9,
128.6, 37.1, 34.0, 29.1.
2-(2-Fluorophenyl)-N,N-dimethyl-2-oxoacetamide (3i)10
[CAS Reg. No. 1426249-31-1]
Yield: 51.7 mg (53%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.97 (m, 1 H), 7.6 (m, 1 H), 7.31
(d, J = 8 Hz, 1 H), 7.15 (m, 1 H), 3.09 (s, 3 H), 3.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 188.2, 167.4, 163.9, 161.4, 136.5,
131.0, 124.9, 116.7, 36.8, 34.1.
2-(4-Isopropylphenyl)-N,N-dimethyl-2-oxoacetamide (3q)
[CAS Reg. No. 1268109-94-9]
Yield: 76.6 mg (70%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.34 (d,
J = 8.3 Hz, 2 H), 3.09 (s, 3 H), 2.94 (s, 3 H), 1.25 (d, J = 6.9 Hz, 6 H).
N,N-Dimethyl-2-oxo-2-[2-(trifluoromethyl)phenyl]acetamide
(3j)
Yield: 51.5 mg (42%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.80 (m, 2 H), 7.66 (m, 2 H), 3.10
(s, 3 H), 3.08 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.5, 167.3, 156.6, 131.0, 129.9,
127.2, 37.1, 34.5, 34.0, 23.5.
13C NMR (100 MHz, CDCl3): δ = 190.4, 165.6, 134.5, 132.4, 132.0,
131.6, 127.2, 127.2, 37.1, 34.8.
N,N-Dimethyl-2-(naphthalen-1-yl)-2-oxoacetamide (3r)
[CAS Reg. No. 51579-92-1]
N,N-Dimethyl-2-oxo-2-[4-(trifluoromethyl)phenyl]acetamide
Yield: 70.4 mg (62%); yellow oil.
(3k)
1H NMR (400 MHz, CDCl3): δ = 9.25 (d, J = 8.8 Hz, 1 H), 8.11 (d,
J = 8.4 Hz, 1 H), 7.99 (d, J = 6.2 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H),
7.70 (m, 1 H), 7.56 (m, 2 H).
[CAS Reg. No. 1456807-74-1]
Yield: 61.3 mg (50%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8 Hz, 2 H), 7.77 (d,
J = 8.4 Hz, 2 H), 3.1 (s, 3 H), 2.98 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.3, 166.1, 135.8, 135.5, 130.0,
13C NMR (100 MHz, CDCl3): δ = 194.2, 167.7, 136.3, 135.9, 134.3,
134.1, 131.0, 129.9, 129.3, 128.7, 128.5, 127.0, 125.8, 124.6, 37.2,
34.2.
126.03, 125.99, 37.0, 34.2.
N,N-Dimethyl-2-(naphthalen-2-yl)-2-oxoacetamide (3s)10
N,N-Dimethyl-2-(4-nitrophenyl)-2-oxoacetamide (3l)10
[CAS Reg. No. 431059-81-3]
[CAS Reg. No. 51579-91-0]
Yield: 81.7 mg (72%); yellow oil.
Yield: 34.4 mg (31%); yellow solid; mp 132–134 °C (Lit.10 mp
136–138 °C).
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.8 Hz, 2 H), 8.13 (d,
J = 8.8 Hz, 2 H), 3.14 (s, 3 H), 3.00 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.44 (s, 1 H), 8.03 (dd, J1 = 8.4 Hz,
J2 = 1.6 Hz, 1 H), 7.96 (m, 2 H), 7.89 (d, J = 8.2 Hz, 1 H), 7.64 (t,
J = 7.0 Hz, 1 H), 7.57 (t, J = 7.0 Hz, 1 H), 3.18 (s, 3 H), 3.00 (s, 3 H)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1853–1858

1858
M. Zhou, Q. Song
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): δ = 191.9, 167.2, 136.4, 133.0, 132.5,
130.5, 129.9, 129.4, 129.1, 128.0, 127.1, 123.7, 37.2, 34.1.
1996, 39, 4089. (e) Muldoon, J.; Brown, S. N. Org. Lett.
2002, 4, 1043. (f) Holenz, J.; Mercè, R.; Díaz, J. L.; Guitart,
X.; Codony, X.; Dordal, A.; Romero, G.; Torrens, A.; Mas,
J.; Andaluz, B.; Hernández, S.; Monroy, X.; Sánchez, E.;
Hernández, E.; Pérez, R.; Cubí, R.; Sanfeliu, O.;
Buschmann, H. J. Med. Chem. 2004, 48, 1781. (g) Chen, Y.-
H.; Zhang, Y.-H.; Zhang, H.-J.; Liu, D.-Z.; Gu, M.; Li, J.-Y.;
Wu, F.; Zhu, X.-Z.; Li, J.; Nan, F.-J. J. Med. Chem. 2006, 49,
1613.
2-(4-Methoxyphenyl)-N,N-dimethyl-2-oxoacetamide (3t)10
[CAS Reg. No. 51579-95-4]
Yield: 54.8 mg (53%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 3.6 Hz, 2 H), 6.93 (d,
J = 7.2 Hz, 2 H), 3.84 (s, 3 H), 3.06 (s, 3 H), 2.91 (s, 3 H).
N,N-Dimethyl-2-oxo-2-(thiophen-2-yl)acetamide (3u)10
[CAS Reg. No. 26878-17-1]
(2) (a) Jesuraj, J. L.; Sivaguru, J. Chem. Commun. 2010, 46,
4791. (b) Zhang, Z.; Zhang, Q.; Ni, Z.; Liu, Q. Chem.
Commun. 2010, 46, 1269. (c) Tomita, D.; Yamatsugu, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
6946. (d) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-
X. J. Am. Chem. Soc. 2009, 131, 10390.
(3) (a) Singh, R. P.; Shreeve, J. N. M. J. Org. Chem. 2003, 68,
6063. (b) Heaney, F.; Fenlon, J.; McArdle, P.; Cunningham,
D. Org. Biomol. Chem. 2003, 1, 1122. (c) Zhang, C.; Zong,
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(d) Lamani, M.; Prabhu, K. R. Chem. Eur. J. 2012, 18,
14638. (e) Zhang, X.; Yang, W.; Wang, L. Org. Biomol.
Chem. 2013, 11, 3649. (f) Wei, W.; Shao, Y.; Hu, H.; Zhang,
F.; Zhang, C.; Xu, Y.; Wan, X. J. Org. Chem. 2012, 77,
7157. (g) Mupparapu, N.; Khan, S.; Battula, S.; Kushwaha,
M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R. A. Org.
Lett. 2014, 16, 1152.
(4) (a) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2009, 132, 28.
(b) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem. Int.
Ed. 2011, 50, 11088. (c) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012,
3, 460. (d) Lamani, M.; Prabhu, K. R. Chem. Eur. J. 2012,
18, 14638.
(5) (a) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett.
2009, 11, 1321. (b) Iizuka, M.; Kondo, Y. Chem. Commun.
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Yield: 36.6 mg (40%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.79 (m, 2 H), 7.16 (m, 1 H), 3.08
(s, 3 H), 3.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 183.5, 165.9, 140.1, 136.4, 136.1,
128.6, 37.3, 34.4.
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3v)10
[CAS Reg. No. 14377-63-0]
Yield: 43.5 mg (40%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.95 (dd, J1 = 8.8 Hz, J2 = 0.8 Hz,
2 H), 7.64 (m, 1 H), 7.51 (t, J = 7.2 Hz, 2 H), 3.71 (m, 2 H), 3.29 (m,
2 H), 1.70 (m, 4 H), 1.55 (m, 2 H).
1-Morpholino-2-phenylethane-1,2-dione (3w)10
[CAS Reg. No. 40991-78-4]
Yield: 33.9 mg (31%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.97 (m, 2 H), 7.67 (m, 1 H), 7.53
(t, J = 7.6 Hz, 2 H), 3.80 (s, 4 H), 3.66 (m, 2 H), 3.39 (t, J = 4.8 Hz,
2 H).
Acknowledgment
We are grateful for financial support from the National Science
Foundation of China (21202049), the Recruitment Program of Glo-
bal Experts (1000 Talents Plan), Fujian Hundred Talents Program,
and Research Funds of Huaqiao University.
(6) (a) Muzart, J. Tetrahedron 2009, 65, 8313. (b) Ding, S.;
Jiao, N. Angew. Chem. Int. Ed. 2012, 51, 9226.
(7) (a) Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; Yuan, J.-J.;
Gao, Q.-H.; Wu, A.-X. Chem. Commun. 2012, 48, 9086.
(b) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2013, 135, 16074.
(8) Zhao, Q.; Miao, T.; Zhang, X.; Zhou, W.; Wang, L. Org.
Biomol. Chem. 2013, 11, 1867.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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nr
i
(9) (a) Song, Q.; Feng, Q.; Zhou, M. Org. Lett. 2013, 15, 5990.
(b) Song, Q.; Feng, Q.; Yang, K. Org. Lett. 2014, 16, 624.
(c) Feng, Q.; Song, Q. J. Org. Chem. 2014, 79, 1867.
(d) Feng, Q.; Song, Q. Adv. Synth. Catal. 2014, 356, in press;
DOI: 10.1002/adsc.201301001.
(10) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Biomol. Chem.
2013, 11, 4573.
(11) Li, D.; Wang, M.; Liu, J.; Zhao, Q.; Wang, L. Chem.
Commun. 2013, 49, 3640.
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Synthesis 2014, 46, 1853–1858
© Georg Thieme Verlag Stuttgart · New York