Copper-catalyzed aerobic oxidative synthesis of α-ketoamides from methyl ketones, amines and NIS at room temperature

Article abstract of DOI:10.1039/c2ob26586a

A simple, efficient and practical copper-catalyzed aerobic oxidative synthesis of α-ketoamides from aryl methyl ketones, aliphatic amines and N-iodosuccinimide (NIS) has been developed. The one-pot reaction may proceed smoothly at room temperature in the open air. The possible mechanism for the formation of α-ketoamides was proposed. Molecular oxygen in air functions as both an oxidant and an oxygen source.

Full text of DOI:10.1039/c2ob26586a

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PAPER
Copper-catalyzed aerobic oxidative synthesis of α-ketoamides from methyl
ketones, amines and NIS at room temperature†
Juan Zhang,a Ying Wei,a Shaoxia Lin,a Fushun Liang*a and Pengjun Liu*b
Received 10th August 2012, Accepted 11th October 2012
DOI: 10.1039/c2ob26586a
A simple, efficient and practical copper-catalyzed aerobic oxidative synthesis of α-ketoamides from aryl
methyl ketones, aliphatic amines and N-iodosuccinimide (NIS) has been developed. The one-pot reaction
may proceed smoothly at room temperature in the open air. The possible mechanism for the formation of
α-ketoamides was proposed. Molecular oxygen in air functions as both an oxidant and an oxygen source.
aerobic oxidative reactions of acetophenone, amines and NIS,
Introduction
giving access to α-ketoamides (Scheme 1).11,12 The reaction pro-
α-Ketoamides constitute key motifs in biologically active natural
products.1 They are also versatile intermediates in organic syn-
thesis.2 Representative methods for the construction of α-keto-
amides include amidation of α-keto acids and α-keto acyl
halides,3 oxidation of α-hydroxyamides and α-aminoamides,4
transition-metal-catalyzed double carbonylative amination of
aryl halides,5 and reaction of isocyanide with aromatic acyl
chloride or anhydride followed by hydrolysis of the resulting
α-ketoimidoyl chloride.6 Nevertheless, most reactions are
restricted by precursor availability, low yields, harsh conditions,
multistep processes, and utilization of expensive transition-metal
catalysts. Therefore, the development of mild, convenient and
efficient methods toward α-ketoamides is still required.
Recently, aerobic oxidative reactions have been developed as
novel, efficient and environmentally friendly methods to syn-
thesize α-ketoamides, as demonstrated by Zhang and Jiao7a,b
and Du and Ji.7c Molecular oxygen has been used as an ideal
oxidant and oxygen source in organic synthesis because of its
abundance, low cost, and lack of toxic byproducts.8 Thus, dioxy-
gen activation and the utilization of molecular oxygen for the
construction of various oxygen-containing organic compounds
have attracted great interest.9 In our research on halogen acti-
vated organic reactions,10 we reported halonium-initiated cas-
cades leading to 3(2H)-furanones and dihydrofuropyridinones by
using N-halosuccinimide as the electrophilic agent.10a,b Herein,
we would like to report the most recent result, copper-catalyzed
ceeded efficiently at room temperature in the open air.
Results and discussion
Initially, the model reaction of 4-bromoacetophenone (1a),
piperidine (2a), and NIS was examined in the presence of a
copper catalyst (Table 1). When CuBr (20% mol) was selected
as the catalyst, the reaction in DMF at room temperature gave
1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3a) in 53% yield
(entry 1). With other solvents like THF, DCE, and MeCN, the
yields were increased (Table 1, entries 2–4). Among the solvents
screened, toluene was the most effective, affording 3a in 95%
yield (Table 1, entry 5). Comparatively, in the absence of NIS,
product 3a could not be obtained at all (Table 1, entry 6). In the
absence of CuBr catalyst, the yield of 3a was dramatically
decreased to 55% under otherwise identical conditions (Table 1,
entry 7). Decreasing the amount of CuBr catalyst to 10 mol%
gave an unsatisfactory result (Table 1, entry 8). CuI exhibited the
same reactivity (Table 1, entry 9). Cu(II) catalysts were also
investigated, and proved to be effective (Table 1, entries 10–12).
For example, with CuBr2 (20 mol%) as the catalyst, the yield of
3a reached up to 91% (Table 1, entry 11). Surprisingly, when
NBS was used as the halogenation reagent, the yields of 3a were
fairly low (Table 1, entry 13).13 The structure of 3a was
confirmed unambiguously by X-ray single crystal diffraction
(Fig. 1).
With the optimized conditions in hand, the scope of the
ketones was investigated (Table 2). Catalyzed by CuBr, aryl
aDepartment of Chemistry, Northeast Normal University, Changchun
130024, China. E-mail: liangfs112@nenu.edu.cn;
Fax: (+86) 431-85099759
bCollege of Chemistry and Chemical Engineering, Hainan Normal
University, Haikou 571158, China. E-mail: liupj12@126.com
†Electronic supplementary information (ESI) available: Experimental
details and characterization for all new compounds and crystal structure
data (CIF file). CCDC 884565 (3a). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob26586a
Scheme 1
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Table 1 Optimization of the conditions
methyl ketones containing both electron-withdrawing and elec-
tron-rich groups could react with piperidine smoothly, giving the
desired products 3a–h (Table 2, entries 1–9). A wide range of
functionalities such as nitro and halogen groups were tolerated
under the reaction conditions. 5 g-scale preparation of compound
3a was achieved in 89% yield (entry 2). The naphthyl-substi-
tuted ketone was also tolerated in this transformation, generating
3i in 85% yield (Table 2, entry 10). Heteroaryl methyl ketones
such as 2-acetylpyridine, 2-acetylfuran and 2-acetylthiophene
were compatible with this reaction, affording 3j–l in moderate
yields (Table 2, entries 11–13). Selected reactions with CuBr2 as
the catalyst were also conducted (Table 1, entries 1, 6 and 8) and
comparable yields were attained.
The amine scope of the copper-catalyzed aerobic oxidative
coupling leading to α-ketoamides was investigated (Table 3).
The results indicate that secondary aliphatic amines (cyclic and
acyclic) (Table 3, entries 1–6) and primary aliphatic amines
(Table 3, entries 7–9) could be smoothly transformed into the
desired products in moderate to high yields. However, reactions
with aromatic amines, e.g. 4-methylaniline, did not occur
(Table 3, entry 10). Notably, in the reactions of 1-(4-methoxy-
phenyl)ethanone with piperidine (Table 2, entry 2) and acetophe-
none with primary amines (Table 3, entries 7–9), the
corresponding α-ketoamides were separated in fairly low yields.
It was found that amide by-products were formed in the reac-
tions. In isolated reactions, amides 4a and 4b were separated in
33% and 37% yields (Scheme 2).
Entrya
NXS
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
NIS
NIS
NIS
NIS
NIS
—
NIS
NIS
NIS
NIS
NIS
NIS
NBS
CuBr (20%)
CuBr (20%)
CuBr (20%)
CuBr (20%)
CuBr (20%)
CuBr (20%)
—
CuBr (10%)
CuI (20%)
CuCl2 (20%)
CuBr2 (20%)
Cu(OAc)2 (20%)
CuBr (20%)
DMF
THF
DCE
53
56
72
80
95
0
55
52
95
90
91
85
11
MeCN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
a Reaction conditions: 1a (1 mmol), 2a (2.5 mmol), CuI (20 mol%),
solvent (4 mL), room temperature, 35 h. b Yield of isolated product.
In order to elucidate the possible mechanism for the copper-
catalyzed oxidative amidation reaction, several control experi-
ments were carried out. Decreasing the amount of piperidine to
1.1 equiv. gave 3a in 31% yield (Scheme 3). Obviously, 2.0
equiv. of amine were required, which was consistent with the
possible mechanism described later. To judge the origin of the
two oxygen atoms of the α-ketoamide, the reaction of 4-bromo-
acetophenone with piperidine was conducted under N2 protec-
tion and in the open air, respectively (Scheme 4). In both cases,
anhydrous toluene was used as the solvent and 4 Å MS were
Fig. 1 ORTEP drawing of 3a.
Table 2 Scope of ketonesa
Table 3 Scope of aminesa
Entry
Ar
3
Yieldb (%)
1
2
3
4
5
6
7
8
4-BrC6H4
4-BrC6H4 (1a, 5 g)
Ph
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
95 (94)c
89d
Entry
Amine
3
Yieldb (%)
90
4-CH3OC6H4
4-MeC6H4
2-MeC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
2-Naphthyl
2-Pyridyl
40e
1
2
3
4
5
6
7
8
Pyrrolidine
Morpholine
Dimethylamine (aq.)
Diethylamine
Dibutylamine
N-Methylbenzylamine
Benzylamine
4-Methylbenzylamine
2-Chlorobenzylamine
2-Phenylethylamine
4-Methylaniline
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
73
84
45
75
83
89 (84)d
94
91 (88)d
92
81
9
73
10
11
12
13
85
90
45
76
42c
40c
45c
33c
n.r.
3j
3k
3l
2-Furyl
2-Thienyl
9
10
11
a Reaction conditions: 1 (1.0 mmol), 2a (2.5 equiv.), CuBr (20%), NIS
(1.2 equiv.), in toluene (4 mL), room temperature, 17–35 h. b Yield of
isolated product. c Yields with CuBr2 (20 mol%) as the catalyst. d The
product was purified by recrystallization in a mixture of petroleum ether
and ethyl ether. e Amide by-product 4a was obtained (see Scheme 2).
a Reaction conditions: 1a (1.0 mmol), 2 (2.5 equiv.), CuBr (20 mol%),
NIS (1.2 equiv.), in toluene (4 mL), room temperature, 17–35 h. b Yield
of isolated product. c Amide by-products 4 were observed.
9238 | Org. Biomol. Chem., 2012, 10, 9237–9242
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generated from dioxygen in air during the oxidation of Cu(I) into
Cu(II), which adds to the iminium III immediately to afford
radical intermediate IV. Intramolecular cyclization gives key
aminodioxetane intermediate V. During this process, Cu(II) was
reduced to Cu(I) by single electron transfer (SET) to accomplish
the catalytic cycle.15 Ring-opening through O–O bond hetero-
lysis leads to intermediate VI. C–N bond cleavage in VI
furnishes the final α-ketoamide 3. Alternatively, amide by-
product 4 would be generated via C–C bond cleavage.16
Scheme 2 Amide by-products involved in the reactions.
Conclusion
In summary, we have developed a simple, efficient and practical
copper-catalyzed one-pot oxidative synthesis of α-ketoamides by
the reaction of aryl methyl ketones, amines and NIS. A possible
mechanism was proposed and the formation of the α-ketoamides
and amide by-products was attributed to the different elimination
fashion upon ring-opening of the four-membered aminodioxe-
tane intermediates. The notable features of the reaction are cheap
catalysts, readily available starting materials, mild conditions
(e.g. room temperature) and utilization of air as the dioxygen
source (instead of an O2 balloon). Further work on halogen
reagent-mediated organic reactions is ongoing in our laboratory.
Scheme 3 Effect of amine amount on the reaction.
Scheme 4 Effect of dioxygen (air) on the reaction.
Experimental
General methods
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR
and 13C NMR spectra were recorded at 25 °C on a Varian
500 MHz and 125 MHz, respectively, and TMS as the internal
standard. Elemental analyses were measured on an E-2400 ana-
lyzer (Perkin-Elmer). Mass spectra were recorded on an Agilient
1100 LCMsD mass spectrometer.
General procedure for the synthesis of 3 (3a as an example)
To a solution of acetophenone 1a (0.117 mL, 1.0 mmol) in
toluene (4 mL) was added NIS (270 mg, 1.2 mmol), CuBr
(28.7 mg, 0.2 mmol) and piperidine (0.247 mL, 2.5 mmol). The
mixture was stirred at room temperature for about 30 h. After the
starting material 3a was consumed as indicated by TLC, the
reaction mixture was poured into water and then extracted with
CH2Cl2 (3 × 10 mL). The combined organic phase was washed
with water (3 × 10 mL), dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (silica gel, petroleum ether :
ether = 6 : 1) to give 3a (280 mg, 95%) as a white solid.
Scheme 5 Possible mechanism for the formation of α-ketoamides 3
and amide by-products 4.
added to remove the water generated in the reaction system. As a
result, the reaction under N2 protection gave trace amounts of 3a,
while the reaction performed in the open air gave 3a in >95%
yield. The above experimental results indicate that dioxygen in the
air was involved in the reaction leading to α-ketoamides.
Based on all the results described above and recent research
12a
by Zhang and Jiao,7a,b Du and Ji7c and Zhang and Wang,
a
Physical data of compounds isolated
possible mechanism for the formation of α-ketoamides is shown
in Scheme 5. Firstly, enamine I is formed from aryl methyl
ketone 1 and amine, followed by iodination to generate inter-
mediate II.12a,b Nucleophilic substitution of excess amines gives
α-amino substituted iminium III, in which CuBr facilitates the
C–I bond cleavage.14 Meanwhile, a superoxide radical (O2˙−) is
1-(4-Bromophenyl)-2-(piperidin-1-yl)ethane-1,2-dione
(3a).
1
White solid. m.p. 87–89 °C. H NMR (CDCl3, 500 MHz, ppm):
δ = 7.83–7.81 (d, J = 8.5 Hz, 2H), 7.67–7.65 (d, J = 8.5 Hz,
2H), 3.71–3.70 (d, J = 5.5 Hz, 2H), 3.29–3.27 (t, J = 5.5 Hz,
2H), 1.701–1.697 (d, J = 2 Hz, 4H), 1.56 (s, 2H); 13C NMR
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(CDCl3, 125 MHz, ppm): δ = 190.6, 164.7, 132.3, 131.9, 130.8,
130.0, 46.9, 42.1, 26.1, 25.3, 24.2. MS calcd m/z 295.0, found
296.0 [(M + 1)]+. Anal. Calcd for C13H14BrNO2: C, 52.72;
H, 4.76; N, 4.73; Found: C, 52.60; H, 4.77; N, 4.72.
J = 4.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 189.5,
164.0, 150.9, 137.5, 130.5, 124.0, 46.9, 42.3, 26.2, 25.3, 24.1.
MS calcd m/z 262.1, found 263.1 [(M + 1)]+. Anal. Calcd for
C13H14N2O4: C, 59.54; H, 5.38; N, 10.68; Found: C, 59.61;
H, 5.39; N, 10.67.
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3b). White solid.
m.p. 109–111 °C. 1H NMR (CDCl3, 500 MHz, ppm): δ =
7.96–7.95 (m, 2H), 7.66–7.63 (m, 1H), 7.53–7.50 (t, J = 7.5 Hz,
2H), 3.71 (s, 2H), 3.31–3.29 (t, J = 5.5 Hz, 2H), 1.71–1.70 (t,
J = 3 Hz, 4H), 1.56–1.55 (d, J = 5.5 Hz, 2H); 13C NMR
(CDCl3, 125 MHz, ppm): δ = 191.9, 165.4, 134.6, 133.2, 129.5,
129.0, 47.0, 42.1, 26.2, 25.4, 24.3. MS calcd m/z 217.1, found
218.1 [(M + 1)]+. Anal. Calcd for C13H15NO2: C, 71.84;
H, 6.96; N, 6.45; Found: C, 71.72; H, 6.95; N, 6.46.
1-(3-Nitrophenyl)-2-(piperidin-1-yl)ethane-1,2-dione
(3f).
1
Yellow solid. H NMR (CDCl3, 500 MHz, ppm): δ = 8.77 (s,
1H), 8.51–8.49 (m, 1H), 8.31–8.29 (d, J = 8.0 Hz, 1H),
7.79–7.76 (t, J = 8.0 Hz, 1H), 3.75–3.74 (d, J = 5.0 Hz, 2H),
3.36–3.34 (t, J = 5.5 Hz, 2H), 1.74–1.73 (d, J = 2.5 Hz, 4H),
1.61 (s, 2H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 190.5,
164.9, 141.2, 131.7, 130.9, 129.4, 47.0, 42.2, 26.2, 25.4, 24.3.
MS calcd m/z 262.1, found 263.1 [(M + 1)]+. Anal. Calcd for
C13H14N2O4: C, 59.54; H, 5.38; N, 10.68; Found: C, 59.61;
H, 5.39; N, 10.67.
1-(4-Methoxyphenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3c).
1
Yellowish oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.93–7.9
(m, 2H), 6.99–6.96 (m, 2H), 3.89 (s, 3H), 3.70–3.69 (d, J =
5.5 Hz, 2H), 3.30–3.28 (t, J = 5.5 Hz, 2H), 1.70–1.68 (t, J =
2.5 Hz, 4H), 1.55–1.53 (t, J = 5.5 Hz, 2H); 13C NMR (CDCl3,
125 MHz, ppm): δ = 190.6, 165.7, 164.7, 131.9, 126.2, 114.2,
55.5, 46.9, 42.0, 26.1, 25.4, 24.3. MS calcd m/z 247.1, found
248.1 [(M + 1)]+. Anal. Calcd for C14H17NO3: C, 68.00;
H, 6.93; N, 5.66; Found: C, 68.11; H, 6.92; N, 5.67.
1-(Naphthalen-2-yl)-2-(piperidin-1-yl)ethane-1,2-dione
(3i).
1
Yellowish solid. m.p. 80–82 °C. H NMR (CDCl3, 500 MHz,
ppm): δ = 8.45 (s, 1H), 8.04–8.02 (m, 1 Hz, 1H), 7.98–7.96 (d,
J = 8.0 Hz, 1H), 7.95–7.93 (d, J = 9.0 Hz, 2H), 7.89–7.87 (d,
J = 8.0 Hz, 1H), 7.65–7.62 (t, J = 8.0 Hz, 1H), 7.58–7.55 (t, J =
8.0 Hz, 1H), 3.78–3.76 (t, J = 4.5 Hz, 2H), 3.33–3.31 (t, J =
5.5 Hz, 2H), 1.71 (s, 4H), 1.56–1.54 (t, J = 6.0 Hz, 2H); 13C
NMR (CDCl3, 125 MHz, ppm): δ = 192.0, 165.4, 136.1, 132.7,
132.2, 130.4, 129.7, 129.2, 128.9, 127.8, 127.0, 123.4, 47.0,
42.1, 26.0, 25.3, 24.2. MS calcd m/z 267.1, found 268.1
[(M + 1)]+. Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41;
N, 5.24; Found: C, 76.31; H, 6.40; N, 5.25.
1-(Piperidin-1-yl)-2-p-tolylethane-1,2-dione (3d). Yellowish
1
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.85–7.83 (d, J =
8.5 Hz, 2H), 7.32–7.30 (d, J = 8.0 Hz, 2H), 3.70 (s, 2H),
3.29–3.27 (t, J = 5.5 Hz, 2H), 2.43 (s, 3H), 1.70–1.68 (t, J =
3 Hz, 4H), 1.55–1.53 (d, J = 5.5 Hz, 2H); 13C NMR (CDCl3,
125 MHz, ppm): δ = 191.6, 165.6, 145.8, 130.7, 129.63, 129.59,
46.9, 42.0, 26.1, 25.4, 24.3, 21.8. MS calcd m/z 231.1, found
232.1 [(M + 1)]+. Anal. Calcd for C14H17NO2: C, 72.70;
H, 7.41; N, 6.06; Found: C, 72.79; H, 7.40; N, 6.05.
1-(Piperidin-1-yl)-2-(pyridin-2-yl)ethane-1,2-dione (3j). Yel-
lowish oil. 1H NMR (CDCl3, 500 MHz, ppm): δ = 8.76–8.75 (d,
J = 3.5 Hz, 1H), 8.12–8.11 (d, J = 8.0 Hz, 1H), 7.92–7.88 (m,
1H), 7.54–7.51 (m, 1H), 3.73 (s, 2H), 3.29–3.27 (t, J = 5.5 Hz,
2H), 1.72–1.64 (m, 4H), 1.59–1.53 (m, 2H); 13C NMR (CDCl3,
125 MHz, ppm): δ = 192.2, 166.2, 151.5, 150.0, 137.2, 127.9,
123.1, 47.0, 42.2, 25.9, 25.2, 23.8. MS calcd m/z 218.1, found
219.1 [(M + 1)]+. Anal. Calcd for C12H14N2O2: C, 66.04; H,
6.47; N, 12.84; Found: C, 65.97; H, 6.48; N, 12.83.
1-(Piperidin-1-yl)-2-o-tolylethane-1,2-dione
(3e). Yellowish
1
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.72–7.71 (d, J =
8.0 Hz, 1H), 7.49–7.46 (m, 1H), 7.33–7.27 (m, 2H), 3.70–3.69
(d, J = 5.0 Hz, 2H), 3.32–3.29 (t, J = 5.5 Hz, 2H), 2.67 (s, 3H),
1.70–1.67 (t, J = 3 Hz, 4H), 1.57–1.55 (t, J = 5.5 Hz, 2H); 13C
NMR (CDCl3, 125 MHz, ppm): δ = 193.8, 166.0, 141.4, 133.5,
132.7, 132.5, 131.5, 126.1, 47.0, 42.0, 26.0, 25.3, 24.3, 21.8.
MS calcd m/z 231.1, found 232.1 [(M + 1)]+. Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06; Found: C, 72.79;
H, 7.40; N, 6.05.
1-(Furan-2-yl)-2-(piperidin-1-yl)ethane-1,2-dione (3k). Yel-
1
lowish oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.72–7.71
(m, 1H), 7.35–7.34 (m, 1H), 6.62–6.61 (m, 1H), 3.68–3.66 (t,
J = 6.0 Hz, 2H), 3.39–3.37 (t, J = 6.0 Hz, 2H), 1.72–1.65 (m,
4H), 1.61–1.58 (m, 2H); 13C NMR (CDCl3, 125 MHz, ppm):
δ = 178.9, 164.0, 150.2, 148.6, 121.9, 112.8, 47.0, 42.4, 25.6,
24.7, 23.9. MS calcd m/z 207.1, found 208.1 [(M + 1)]+. Anal.
Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76; Found:
C, 63.66; H, 6.33; N, 6.75.
1-(4-Chlorophenyl)-2-(piperidin-1-yl)ethane-1,2-dione
(3f).
Yellowish oil. 1H NMR (CDCl3, 500 MHz, ppm): δ = 7.91–7.88
(d, J = 8.5 Hz, 2H), 7.50–7.47 (d, J = 8.5 Hz, 2H), 3.71–3.69 (t,
J = 5.2 Hz, 2H), 3.30–3.27 (t, J = 5.6 Hz, 2H), 1.73–1.67 (m,
4H), 1.58–1.53 (m, 2H); 13C NMR (CDCl3, 125 MHz, ppm):
δ = 190.5, 164.9, 141.2, 131.7, 130.9, 129.4, 47.1, 42.3, 26.3,
25.4, 24.4. MS calcd m/z 251.1, found 261.1 [(M + 1)]+. Calcd
for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56; Found:
C, 52.61.85; H, 5.62; N, 5.55.
1-(Piperidin-1-yl)-2-(thiophen-2-yl)ethane-1,2-dione (3l). Yel-
1
lowish oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.80–7.79
(m, 2H), 7.20–7.18 (m, 1H), 3.69–3.67 (t, J = 6.0 Hz, 2H),
3.39–3.37 (t, J = 5.5 Hz, 2H), 1.72 (s, 4H), 1.63–1.56 (m, 2H);
13C NMR (CDCl3, 125 MHz, ppm): δ = 183.9, 164.4, 140.5,
136.3, 1135.9, 128.2, 47.1, 42.4, 26.2, 25.4, 24.3. MS calcd m/z
223.1, found 224.1 [(M + 1)]+. Anal. Calcd for C11H13NO2S:
C, 59.17; H, 5.87; N, 6.27; Found: C, 59.28; H, 5.86; N, 6.28.
1-(4-Nitrophenyl)-2-(piperidin-1-yl)ethane-1,2-dione
(3g).
Yellow solid. m.p. 94–96 °C. 1H NMR (CDCl3, 500 MHz,
ppm): δ = 8.37–8.35 (t, J = 7.5 Hz, 2H), 8.15–8.14 (d, J =
7.0 Hz, 2H), 3.74–3.73 (d, J = 5.5 Hz, 2H), 3.33–3.31 (t, J =
6.0 Hz, 2H), 1.73–1.72 (d, J = 3.0 Hz, 4H), 1.59–1.58 (d,
1-Phenyl-2-(pyrrolidin-1-yl)ethane-1,2-dione (3m). Yellowish
1
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 8.00–7.99 (m, 2H),
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7.66–7.62 (m, 1H), 7.53–7.49 (t, J = 8.0 Hz, 2H), 3.68–3.65 (t,
J = 7.0 Hz, 2H), 3.44–3.42 (t, J = 6.0 Hz, 2H), 1.99–1.93 (m,
4H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 191.6, 164.9,
134.6, 132.9, 129.9, 128.9, 46.6, 45.2, 25.9, 24.0. MS calcd m/z
203.1, found 204.1 [(M + 1)]+. Anal. Calcd for C12H13NO2:
C, 70.92; H, 6.45; N, 6.89; Found: C, 70.80; H, 6.44; N, 6.90.
2H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 187.5, 161.5,
137.1, 134.4, 133.3, 131.2, 128.8, 128.5, 127.9, 127.8, 43.4. MS
calcd m/z 239.1, found 240.1 [(M + 1)]+. Anal. Calcd for
C15H13NO2: C, 75.30; H, 5.48; N, 5.85; Found: C, 75.16; H,
5.47; N, 5.86.
N-(4-Methylbenzyl)-2-oxo-2-phenylacetamide (3t). Colorless
oil. 1H NMR (CDCl3, 500 MHz, ppm): δ = 8.35–8.34 (t, J = 7.0
Hz, 2H), 7.63–7.60 (t, J = 7.5 Hz, 1H), 7.49–7.46 (t, J = 7.5 Hz,
2H), 7.25 (s, 1H), 7.23–7.21 (d, J = 8.0 Hz, 2H), 7.17–7.15 (d,
1-Morpholino-2-phenylethane-1,2-dione (3n). Yellowish oil.
1H NMR (CDCl3, 500 MHz, ppm): δ = 7.97–7.96 (t, J = 7.0 Hz,
2H), 7.68–7.65 (m, 1H), 7.55–7.52 (t, J = 8.5 Hz, 2H),
3.82–3.79 (m, 4H), 3.67–3.65 (m, 2H), 3.40–3.38 (t, J = 4.5 Hz,
2H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 191.0, 165.2,
134.9, 132.8, 129.5, 129.0, 66.53, 66.45, 46.0, 41.4. MS calcd
m/z 219.1, found 220.1 [(M + 1)]+. Anal. Calcd for C12H13NO3:
C, 65.74; H, 5.98; N, 6.39; Found: C, 65.81; H, 5.99; N, 6.38.
J = 8.0 Hz, 2H), 4.53–4.51 (d, J = 6.0 Hz, 2H), 2.34 (s, 3H); 13
C
NMR (CDCl3, 125 MHz, ppm): δ = 187.5, 161.4, 137.5, 134.4,
134.0, 133.3, 131.2, 129.4, 128.4, 127.9, 43.2, 21.1. MS calcd
m/z 253.1, found 254.1 [(M + 1)]+. Anal. Calcd for C16H15NO2:
C, 75.87; H, 5.97; N, 5.53; Found: C, 75.74; H, 5.96; N, 5.34.
N-(2-Chlorobenzyl)-2-oxo-2-phenylacetamide (3u). Yellowish
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 8.35–8.33 (m, 2H),
N,N-Dimethyl-2-oxo-2-phenylacetamide (3o). Yellowish oil.
1H NMR (CDCl3, 500 MHz, ppm): δ = 7.96–7.94 (t, J = 7.5 Hz,
2H), 7.66–7.63 (t, J = 7.0 Hz, 1H), 7.53–7.50 (t, J = 8.0 Hz,
2H), 3.13 (s, 3H), 2.97 (s, 3H); 13C NMR (CDCl3, 125 MHz,
ppm): δ = 191.8, 167.0, 134.7, 132.9, 129.6, 129.0, 37.0, 33.9.
MS calcd m/z 177.1, found 178.1 [(M + 1)]+. Anal. Calcd for
C10H11NO3: C, 67.78; H, 6.26; N, 7.90; Found: C, 67.92; H,
6.25; N, 7.91.
1
7.63–7.60 (t, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.49–7.46 (t, J =
8.0 Hz, 2H), 7.43–7.38 (m, 2H), 7.27–7.24 (m, 2H), 4.67–4.66
(d, J = 6.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz, ppm): δ =
187.4, 161.6, 134.6, 134.5, 133.8, 133.3, 131.5, 131.3, 130.2,
129.7, 129.3, 128.9, 128.5, 127.2, 43.4. MS calcd m/z 253.1,
found 254.1 [(M + 1)]+. Anal. Calcd for C15H12ClNO2: C,
65.82; H, 4.42; N, 5.12; Found: C, 65.71; H, 4.41; N, 5.13.
N,N-Diethyl-2-oxo-2-phenylacetamide (3p). Colorless oil. 1H
NMR (CDCl3, 500 MHz, ppm): δ = 7.95–7.93 (m, 2H),
7.66–7.62 (m, 1H), 7.53–7.50 (m, 2H), 3.59–3.55 (m, 2H),
3.27–3.23 (m, 2H), 1.31–1.28 (m, 3H), 1.17–1.15 (m, 3H); 13C
NMR (CDCl3, 125 MHz, ppm): δ = 191.6, 166.7, 134.6, 133.2,
129.6, 128.9, 42.1, 38.7, 14.1, 12.8. MS calcd m/z 205.1, found
206.1 [(M + 1)]+. Anal. Calcd for C12H15NO2: C, 70.22; H,
7.37; N, 6.82; Found: C, 70.09; H, 7.36; N, 6.83.
1
2-Oxo-N-phenethyl-2-phenylacetamide (3v). Colorless oil. H
NMR (CDCl3, 500 MHz, ppm): δ = 8.31–8.29 (t, J = 7.5 Hz,
2H), 7.63–7.60 (m, 1H), 7.48–7.45 (t, J = 8.0 Hz, 2H),
7.34–7.31 (t, J = 7.5 Hz, 2H), 7.26–7.24 (m, 4H), 7.12 (s, 1H),
3.68–3.64 (m, 2H), 2.93–2.90 (t, J = 7.0 Hz, 2H); 13C NMR
(CDCl3, 125 MHz, ppm): δ = 187.5, 161.5, 137.1, 134.4, 133.3,
131.2, 128.8, 128.5, 127.9, 127.8, 43.4. MS calcd m/z 253.1,
found 254.1 [(M + 1)]+. Anal. Calcd for C16H15NO2: C, 75.87;
H, 5.97; N, 5.53; Found: C, 75.92; H, 5.91; N, 5.52.
1
N,N-Dibutyl-2-oxo-2-phenylacetamide (3q). Colorless oil. H
NMR (CDCl3, 500 MHz, ppm): δ = 7.94–7.93 (t, J = 7.0 Hz,
2H), 7.65–7.62 (t, J = 7.5 Hz, 1H), 7.52–7.49 (t, J = 7.5 Hz,
2H), 3.51–3.48 (t, J = 7.5 Hz, 2H), 3.17–3.13 (t, J = 7.5 Hz,
2H), 1.70–1.64 (m, 2H), 1.57–1.51 (m, 2H), 1.44–1.40 (m, 2H),
1.21–1.16 (m, 2H), 1.01–0.98 (t, J = 7.4 Hz, 3H), 0.83–0.80 (t,
J = 7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 191.6,
167.1, 134.5, 133.4, 129.6, 128.9, 47.4, 44.0, 30.6, 29.3, 19.9,
19.8, 13.8, 13.7. MS calcd m/z 261.2, found 262.2 [(M + 1)]+.
Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36; Found:
C, 73.36; H, 8.86; N, 5.37.
(4-Methoxyphenyl)(piperidin-1-yl)methanone (4a). Yellowish
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 7.37–7.35 (d, J =
1
8.5 Hz, 2H), 6.91–6.89 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.83
(s, 2H), 1.68–1.67 (d, J = 4.0 Hz, 2H), 1.59 (s, 4H); 13C NMR
(CDCl3, 125 MHz, ppm): δ = 190.6, 165.7, 164.7, 131.9, 126.2,
114.2, 55.5, 46.9, 42.0, 26.1, 25.4, 24.3. MS calcd m/z 247.1,
found 248.1 [(M + 1)]+. Anal. Calcd for C13H17NO2: C, 71.21;
H, 7.81; N, 6.39; Found: C, 71.13; H, 7.82; N, 6.38.
1
N-Phenethylbenzamide (4b). Colorless oil. H NMR (CDCl3,
500 MHz, ppm): δ = 7.70–7.68 (t, J = 7.0 Hz, 2H), 7.50–7.47 (t,
J = 7.5 Hz, 1H), 7.42–7.39 (t, J = 7.5 Hz, 2H), 7.35–7.33 (t, J =
8.0 Hz, 2H), 7.27–7.24 (t, J = 8.0 Hz, 3H), 6.11 (s, 1H),
3.75–3.71 (m, 2H), 2.96–2.93 (t, J = 6.5 Hz, 2H); 13C NMR
(CDCl3, 125 MHz, ppm): δ = 167.5, 138.9, 134.7, 131.4, 128.8,
128.6, 126.8, 126.6, 41.1, 35.7. MS calcd m/z 225.1, found
226.1 [(M + 1)]+. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71;
N, 6.22; Found: C, 79.79; H, 6.70; N, 6.23.
N-Benzyl-N-methyl-2-oxo-2-phenylacetamide (3r). Yellowish
oil. H NMR (CDCl3, 500 MHz, ppm): δ = 8.00–7.96 (m, 4H),
1
7.66–7.63 (t, J = 7.5 Hz, 2H), 7.53–7.50 (t, J = 8.0 Hz, 4H),
7.39–7.25 (m, 10H), 4.74 (s, 2H), 4.40 (s, 2H), 3.00 (s, 3H),
2.85 (s, 3H); 13C NMR (CDCl3, 125 MHz, ppm): δ = 191.6,
167.3, 167.2, 135.8, 135.0, 134.8, 133.3, 133.1, 132.3, 130.9,
129.8, 129.1, 129.0, 128.91, 128.85, 128.7, 128.4, 128.2, 127.9,
127.8, 53.5, 49.9, 34.5, 31.4. MS calcd m/z 253.1, found 254.1
[(M + 1)]+. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
5.53; Found: C, 75.71; H, 5.96; N, 5.67.
Acknowledgements
N-Benzyl-2-oxo-2-phenylacetamide (3s). Colorless oil. 1H
NMR (CDCl3, 500 MHz, ppm): δ = 8.37–8.35 (t, J = 7.5 Hz,
2H), 7.64–7.61 (t, J = 7.0 Hz, 1H), 7.50–7.47 (t, J = 8.0 Hz,
2H), 7.43 (s, 1H), 7.38–7.29 (m, 4H), 4.58–4.57 (d, J = 6.0 Hz,
Financial support from the NSFC (No. 20972027 and
21172034), Program for New Century Excellent Talents in Uni-
versity (NCET-11-0611), the Department of Science and Tech-
nology of Jilin Province (201215002), the Fundamental
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Research Funds for the Central Universities (11SSXT129)
and Open Project of State Key Laboratory of Supramolecular
Structure and Materials (sklssm201225) is gratefully
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and Ar.
9242 | Org. Biomol. Chem., 2012, 10, 9237–9242
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