Copper-catalyzed one-pot synthesis of α-ketoamides from 1-arylethanols

Article abstract of DOI:10.1055/s-0034-1379975

A copper-catalyzed one-pot strategy for the synthesis of α-ketoamides from 1-arylethanols is described. This triple oxidation of 1-arylethanols involves alcohol oxidation, sp³ C-H oxidation, and oxidative amidation with amines. The protocol is highly efficient, delivering α-ketoamides in good to excellent yields.

Full text of DOI:10.1055/s-0034-1379975

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 726–736
paper
726
N. Sharma et al.
Paper
Synthesis
Copper-Catalyzed One-Pot Synthesis of α-Ketoamides from
1-Arylethanols
Nidhi Sharma
sp3 C–H oxidation/
oxidative amidation
Surya Srinivas Kotha
Nabajit Lahiri
alcohol oxidation
OH
O
O
R2
Govindasamy Sekar*
N
NHR2R3
9–59 h
R3
CuI, TBHP
Department of Chemistry, Indian Institute of Tech-
nology Madras, Chennai, Tamil Nadu 600 036, India
gsekar@iitm.ac.in
O
O2, 50 °C, 3–8 h
R1
R1
R1
R2–R3 = alkyl, benzyl
21 examples
47–91% yield
R
1 = H, Me, OMe, NO2, halides
aerobic oxidation
Received: 14.11.2014
Accepted after revision: 15.12.2014
Published online: 28.01.2015
O
O
NH
Cl
DOI: 10.1055/s-0034-1379975; Art ID: ss-2014-t0695-op
Abstract A copper-catalyzed one-pot strategy for the synthesis of α-
ketoamides from 1-arylethanols is described. This triple oxidation of 1-
arylethanols involves alcohol oxidation, sp3 C–H oxidation, and oxida-
tive amidation with amines. The protocol is highly efficient, delivering
α-ketoamides in good to excellent yields.
F3C
OMe
O
cytokine inhibitor
O
O
N
O
N
S
O
Key words copper catalyst, one-pot synthesis, oxidative amidation,
α-ketoamides, 1-arylethanols
caspase-3 inhibitor
OH
α-Ketoamides are important structural motifs found in
various biologically active compounds1,2 and in key precur-
sors for the synthesis of a wide range of organic molecules
(Figure 1).3
CHO
HN
O
HN
N
Traditionally, these compounds were prepared by react-
ing α-keto acids or α-keto acyl halides with amines.4 Later,
α-ketoamides were synthesized by metal-catalyzed oxida-
tion of alkynes5 or ynamides,6 oxidative double carbonyla-
tion reactions,7 oxidative coupling of isocyanides and alde-
hydes,8 amidation of α-oxocarboxylic acids,9 aerobic oxida-
tion of arylacetamides10 and metal-catalyzed or metal-free
cross-dehydrogenative coupling of α-ketoaldehydes with
amines.11 In addition, α-ketoamides have been prepared
from acetophenones and amines using oxidative coupling
processes,12 including an iodine/tert-butyl hydroperoxide
(I2/TBHP) mediated synthetic procedure.13 Although a great
deal of research has been conducted in this field, an effi-
cient methodology to synthesize α-ketoamides from alco-
hols and free amines has yet to be developed.
O
O
H2N
HN
NH
O
NH
Ph
NH
HN
O
O
O
cyclotheonamide A
N
O
CF3
oxerin receptor anatagonist
Figure 1 Representative examples of biologically active compounds
containing an α-ketoamide structural motif
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 726–736

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Synthesis
As part of our ongoing research on copper-catalyzed or-
ganic reactions,14 herein, we report for the first time, the
copper-catalyzed one-pot synthesis of α-ketoamides from
1-arylethanols and free amines under an oxygen atmo-
sphere (Scheme 1).
We commenced our investigations using 1-phenyletha-
nol (1a) as a model substrate and the one-pot reaction was
carried out using copper(I) iodide (CuI) (30 mol%) in aceto-
nitrile under an oxygen atmosphere at 50 °C. After 12
hours, only a trace amount of 1-phenylethanol (1a) had
been converted into the corresponding ketone 2a. Next,
piperidine was added to the reaction mixture and after
eight hours, a trace amount of the desired α-ketoamide 3a
had formed. When the same reaction was carried out in the
presence of tert-butyl hydroperoxide (5–6 M in decane) in-
stead of oxygen, the reaction returned about 60% of ketone
2a, however, the formation of 3a was not observed. To our
surprise, the same reaction yielded 56% of product 3a when
carried out with two equivalents of tert-butyl hydroperox-
ide under an oxygen atmosphere (Table 1, entry 1). It is im-
portant to note that the formation of 3a was not observed
in the absence of the copper salt.
sp3 C–H oxidation/
alcohol oxidation
oxidative amidation
O
NHR1R2
OH
O
Cu (cat.)
NR1R2
Ar
Ar
Ar
O
1
2
3
Scheme 1 Copper-catalyzed one-pot synthesis of α-ketoamides
Table 1 Screening of the Reaction Parameters for the One-Pot Synthesis of α-Ketoamidesa
Cu salt (30 mol%)
oxidant (2 equiv)
OH
O
O
piperidine
N
O2, 50 °C
O
3a
1a
2a
Entry
Cu salt
Oxidant
Solvent
Time (h)
Yield (%)b
1
2
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
xylene
toluene
DMF
12 (4 + 8)
56
40
CuBr
Cu2O
CuCl2
22 (9 + 13)
28 (9 + 19)
28 (8 + 20)
28 (8 + 20)
20 (6 + 14)
22 (6 + 16)
30 (9 + 21)
27 (8 + 19)
21 (6 + 15)
20 (4 + 16)
24 (9 + 15)
18 (5 + 13)
24 (10 + 14)
25 (7 + 18)
18 (6 + 12)
35 (12 + 23)
28 (3 + 25)
c
3
–
c
4
–
c
5
Cu(OAc)2·H2O
–
6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
38
50
62
38
74
90
30
33
7
8
9
10
11
12
13
14
15
16
17
18
hexanes
neat
30% aq H2O2
neat
TEMPO
DCP
neat
c
neat
–
c
DTBP
neat
–
70% aq TBHP
TBHP
neat
78
neat
65d
75e
TBHP
neat
a Reaction conditions: 1a (1 mmol), piperidine (3 mmol).
b Yield of isolated product.
c No reaction.
d With 1 equiv of TBHP.
e With 3 equiv of TBHP.
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To increase the efficiency of this one-pot reaction, dif-
ferent copper salts were screened (Table 1, entries 1–5). The
use of copper(I) iodide led to good yields for the alcohol ox-
idation and sp3 C–H oxidation/oxidative amidation. Other
copper salts such as copper(I) oxide (Cu2O), copper(II) chlo-
ride (CuCl2) and copper(II) acetate monohydrate
[Cu(OAc)2·H2O] were inefficient in this reaction. Although
they provided considerable amounts of the ketone, the de-
sired product 3a was not formed. To understand the role of
counterions (iodide or bromide), we used sodium iodide
(NaI) (30 mol%) with copper(I) oxide, copper(II) chloride
and copper(II) acetate monohydrate under the same reac-
tion conditions and 40%, 50% and 49% yields of 3a were iso-
lated, respectively. These results show that the copper
counterion (iodide or bromide) plays a major role in cata-
lyzing the reaction. Next, the reaction was screened with
different solvents such as 1,4-dioxane, toluene, hexanes,
etc. (Table 1, entries 6–10). Hexanes proved to be the best
solvent affording a 74% yield of 3a. When the same reaction
was carried out without a solvent, the yield increased con-
siderably to 90% (Table 1, entry 11). The use of other oxi-
dants such as 30% aqueous hydrogen peroxide (H2O2),
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), dicumyl
peroxide (DCP) and di-tert-butyl peroxide (DTBP) gave infe-
rior results (Table 1, entries 12–15). Employing 70% aque-
ous tert-butyl hydroperoxide afforded a 78% yield of 3a (Ta-
ble 1, entry 16), whilst decreasing or increasing the quanti-
ty of tert-butyl hydroperoxide (1 or 3 equiv) led to reduced
yields of the product (Table 1, entries 17 and 18).
Next, the scope of the reaction under the optimized
conditions (Table 1, entry 11) was investigated using differ-
ent substituted alcohols and amines, and the results are
summarized in Table 2. It was found that alcohols with
electron-withdrawing or electron-releasing groups on the
phenyl ring were well tolerated. Substrates with strong
electron-withdrawing groups such as nitro gave better re-
sults than those possessing electron-donating groups (3b vs
3f). The reaction also worked well when different second-
ary amines were employed.15
Table 2 Copper-Catalyzed One-Pot Synthesis of α-Ketoamidesa,b
CuI (30 mol%)
TBHP (2 equiv)
O
OH
O
NHR1R2 (3 equiv)
NR1R2
Ar
O2, 50 °C
Ar
Ar
O
1
2
3
Entry
1
1-Arylethanol
OH
Amine
Product
Time (h)
Yield (%)c
O
N
3a
3b
20 (4 + 16)
90
HN
O
OH
O
N
2
3
4
15 (4 + 11)
26 (6 + 20)
26 (6 + 20)
91
72
83
HN
HN
HN
O
O2N
O2N
OH
OH
O
N
N
3c
O
Br
Cl
Br
Cl
O
3d
O
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Table 2 (continued)
Entry
1-Arylethanol
Amine
Product
Time (h)
Yield (%)c
OH
O
N
5
3e
37 (8 + 29)
50
HN
HN
O
OH
OH
O
N
6
3f
19 (4 + 15)
52d
O
MeO
MeO
O
N
7
8
3g
3h
20 (5 + 15)
31 (3 + 28)
65
47
HN
HN
O
OH
O
N
O
NC
NC
OH
OH
O
O
N
N
9
3i
3j
21 (6 + 15)
80
70
HN
HN
O
Br
Br
10
14 (4 + 10)
O
O
NO2
NO2
OH
O
O
O
O
N
11
12
3k
3l
24 (4 + 20)
16 (4 + 12)
65
65
HN
HN
OH
O
O
N
O
O2N
O2N
OH
O
O
O
N
13
3m
25 (6 + 19)
62
HN
O
Cl
Cl
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Table 2 (continued)
Entry
1-Arylethanol
Amine
Product
Time (h)
Yield (%)c
OH
OH
O
O
O
O
N
14
3n
30 (3 + 27)
55
HN
O
NC
NC
O
O
N
15
3o
21 (6 + 15)
62
HN
Me
O
Br
Br
OH
O
Me
N
N
H
16
17
3p
3q
37 (4 + 33)
40 (6 + 34)
80
65
O
OH
OH
O
Me
N
Me
Me
Me
N
H
O
Br
Br
O
Me
N
N
H
18
19
20
21
3r
3s
3t
3u
37 (6 + 31)
22 (5 + 17)
58 (4 + 54)
64 (5 + 59)
70
61
56
55
O
Cl
Cl
OH
O
Me
N
N
H
O
O2N
O2N
OH
O
NBoc
NBoc
NBoc
N
O
HN
HN
O
OH
NBoc
N
O
a Reaction conditions: 1-arylethanol 1 (1 mmol).
b The corresponding amide was isolated as a side product in all the reactions, ranging from a trace amount up to 5%.
c Yield of isolated product.
d The corresponding amide (16%) was isolated.
To understand the mechanism of this one-pot reaction,
several control experiments were carried out and the re-
sults are shown in Scheme 2. The one-pot reaction did not
yield α-ketoamide 3a when a copper salt was not used, but
an 11% yield of the corresponding ketone 2a was obtained
(Scheme 2, eq 1). This transformation could have taken
place via tert-butyl hydroperoxide mediated homolytic
cleavage (to some extent) under heating (50 °C). This was
confirmed by carrying out the same reaction at room tem-
perature during which ketone 2a was not detected. When
the same reaction was carried out without tert-butyl hy-
droperoxide, only a 14% yield of 2a was obtained (Scheme
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Synthesis
OH
O
O
piperidine (3 equiv)
O2, 50 °C, 24 h
TBHP (2 equiv)
O2, 50 °C, 12 h
N
O
(1)
2a
11%a
3a
0%
1a
OH
O
O
piperidine (3 equiv)
O2, 50 °C, 24 h
CuI (30 mol%)
O2, 50 °C, 12 h
N
O
(2)
2a
14%a
3a
6%a
1a
CuI (30 mol%)
TBHP (2 equiv)
O
OH
O
piperidine (3 equiv)
N2, 50 °C, 24 h
N
N2, 50 °C, 5 h
O
3a
0%
1a
2a
60%b
(3)
Scheme 2 Control experiments. a 1H NMR yield. b Isolated yield.
2, eq 2), and the same reaction with tert-butyl hydroperox-
ide yielded 60% of 2a. These results indicate that the cop-
per/tert-butyl hydroperoxide combination is responsible
for oxidation of the alcohol. When the reaction was carried
out under a nitrogen atmosphere (without O2), product 3a
was not formed, however ketone 2a (60%) was isolated
(Scheme 2, eq 3). This confirms that the copper/oxygen sys-
tem is responsible for the sp3 C–H oxidation and oxidative
amidation steps. Moreover, no product was formed when
primary or tertiary amines were used, which indicated that
the reaction might proceed via a pathway involving enam-
ine intermediate 6 (see Scheme 4). This intermediate is ob-
tained through reaction of the ketone formed after oxida-
tion of the alcohol, with secondary amines. The results
clearly show that copper is the main oxidant for the alcohol
oxidation, sp3 C–H oxidation and hemiaminal oxidation.
Moreover, copper acting as a Lewis acid should favor the
hemiaminal formation.
Based on the preliminary results obtained from the con-
trol experiments, a possible mechanism is shown for this
one-pot reaction (Scheme 3). Initially, copper(I) is oxidized
by tert-butyl hydroperoxide or oxygen to give copper(II).
This copper(II) species will be reduced to copper(I) during
the oxidation reactions, and the copper/tert-butyl hydro-
peroxide (Cu/TBHP) system should oxidize the alcohol to
give arylmethyl ketone 2. The ketone 2 then undergoes cop-
per-catalyzed oxidation in the presence of oxygen to afford
α-oxoaldehyde 4. This α-oxoaldehyde 4 is converted into
hemiaminal 5 in the presence of the amine, facilitated by
the Lewis acid nature of copper. Finally, hemiaminal oxida-
tion by copper/oxygen gives the α-ketoamide 3.
In all the reactions, trace quantities of the correspond-
ing amides were observed (up to 5%); in the case of 1-(4-
methoxyphenyl)ethanol (1f), the side product amide, (4-
methoxyphenyl)(piperidin-1-yl)methanone, was isolated in
16% yield. This shows that the oxidative amidation step may
proceed via an aminodioxetane intermediate 7 (Scheme
4).12a Cleavage of the O–O bond in 7 should give the α-
oxoaldehyde 4 as the major product, whereas C–C bond
cleavage should give amide 8 as the minor product. Since
O–O bond cleavage should be easier than C–C bond cleav-
age, α-ketoamides are formed as the major products.
In conclusion, a novel, efficient and cost-effective cop-
per-catalyzed one-pot synthesis of α-ketoamides has been
developed using 1-arylethanols as precursors. This one-pot
method yielded various α-ketoamides in good to excellent
yields. Preliminary results show that the copper/tert-butyl
hydroperoxide system is responsible for the oxidation of
the alcohol and that the copper/oxygen system is responsi-
ble for oxidative amidation.
All reactions were carried out in reaction tubes under an oxygen at-
mosphere. Solvents were obtained from Merck, India. CuI was ob-
tained from Alfa-Aesar. The 1-arylethanols were purchased from Alfa-
Aesar and Sigma-Aldrich. 1-Phenylethanol, piperidine, morpholine,
N-Boc-piperazine and 70% aq TBHP were obtained from Spectrochem
Pvt. Ltd., Mumbai, India. N-Methylbenzylamine was purchased from
Avra and TBHP (5–6 M in decane) was obtained from Sigma-Aldrich.
Reactions were carried out using temperature-controlled IKA mag-
netic stirrers. Reactions were monitored by thin-layer chromatogra-
phy (TLC) using Merck silica gel 60 F254 precoated plates (0.25 mm)
and visualized by UV fluorescence following elution using appropri-
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Synthesis
alcohol oxidation/sp3 C–H oxidation/oxidative amidation
R2
N
O
CuI (30 mol%), TBHP (2 equiv)
O2, 50 °C
OH
R1
Ar
Ar
NHR1R2 (3 equiv)
O
1
3
alcohol
oxidation
hemiaminal
oxidation
CuI, TBHP
CuI, O2
R2
O
O
CuI, O2, NHR1R2
NHR1R2
O
N
R1
Ar
Ar
Ar
OH
sp3 C–H oxidation
O
hemiaminal
formation
2
4
5
Scheme 3 A plausible mechanism for the one-pot synthesis of α-ketoamides from 1-arylethanols
O–O bond
cleavage
O
O
R2
N
NHR1R2
Cu, O2
Ar
Ar
R1
O
O
4
3
R2
major product
O
NR1R2
O
N
R1
HNR1R2
Cu, O2
O
Ar
Ar
Ar
H
H
2
6
7
O
Ar
NR1R2
C–C bond
cleavage
8
minor product
Scheme 4 A plausible pathway for the synthesis of α-ketoamides and amides
ate mixtures of ethyl acetate and hexanes. Silica gel (particle size:
100–200 mesh) was purchased from SRL India and Avra and was used
for column chromatography with mixtures of hexanes and EtOAc as
eluents. Melting points were obtained using a Toshniwal melting
point apparatus. FTIR spectra were recorded on a Nicolet 6700 spec-
trophotometer and are reported in wavenumbers (cm–1). 1H and 13C
NMR spectra were recorded on Bruker 400 or 500 MHz spectrome-
ters. 1H NMR spectra are reported relative to Me4Si (δ 0.0) or residual
CDCl3 (δ 7.26). 13C NMR are reported relative to CDCl3 (δ 77.16). High-
resolution mass spectra (HRMS) were recorded on a Q-Tof Micromass
spectrometer.
α-Ketoamides; Typical Procedure
The 1-arylethanol (1 mmol) was added to a mixture of CuI (30 mol%)
and TBHP (5–6 M in decane, 2 equiv) in a reaction tube at r.t. under an
O2 atm (O2 balloon). The resulting mixture was stirred at 50 °C for 3–8
h (TLC monitoring). After complete disappearance of the 1-aryletha-
nol, the amine (3 equiv) was added at r.t. and the mixture was stirred
at 50 °C until completion of the reaction. The mixture was allowed to
cool to r.t. and then filtered through Celite. The filter cake was rinsed
with CH2Cl2 and the filtrate concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (hex-
anes–EtOAc) to afford pure α-ketoamide 3.
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Synthesis
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3a)12e
13C NMR (100 MHz, CDCl3): δ = 191.8, 165.8, 146.0, 131.0, 129.8,
129.7, 47.1, 42.2, 26.3, 25.6, 24.5, 22.0.
Yield: 195.6 mg (90%); light yellow solid; mp 90–92 °C; Rf = 0.32 (20%
HRMS: m/z [M + H]+ calcd for C14H18NO2: 232.1338; found: 232.1329.
EtOAc in hexanes).
IR (KBr): 3064, 2857, 1675, 1638, 1536, 1446, 720 cm–1
.
1-(4-Methoxyphenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3f)12b
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 7.6 Hz, 2 H), 7.64 (t, J = 7.2
Hz, 1 H), 7.51 (t, J = 7.2 Hz, 2 H), 3.71 (br s, 2 H), 3.37–3.32 (m, 2 H),
1.70 (br s, 4 H), 1.55 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 192.1, 165.6, 134.8, 133.5, 129.7,
129.1, 47.2, 42.3, 26.4, 25.6, 24.6.
Yield: 128.6 mg (52%); yellow liquid; Rf = 0.21 (10% EtOAc in hexanes).
IR (neat): 3053, 2860, 1671, 1641, 1500, 1266, 1129, 862 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 7.2 Hz, 2 H), 6.96 (d, J = 7.2
Hz, 2 H), 3.87 (s, 3 H), 3.70–3.62 (m, 2 H), 3.27 (t, J = 4.4 Hz, 2 H),
1.70–1.63 (m, 4 H), 1.55–1.48 (m, 2 H).
HRMS: m/z [M + Na]+ calcd for C13H15NO2Na: 240.1002; found:
13C NMR (125 MHz, CDCl3): δ = 190.8, 165.9, 164.9, 132.1, 126.5,
240.1005.
114.4, 55.7, 47.2, 42.2, 26.3, 25.6, 24.5.
HRMS: m/z [M + H]+ calcd for C14H18NO3: 248.1287; found: 248.1283.
1-(4-Nitrophenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3b)10c
Yield: 239 mg (91%); light yellow solid; mp 95–97 °C (Lit.12h 94–96;
Rf = 0.33 (30% EtOAc in hexanes).
IR (KBr): 3103, 2867, 1686, 1637, 1536, 1468, 1346, 1281, 844 cm–1
1-(Naphthalen-2-yl)-2-(piperidin-1-yl)ethane-1,2-dione (3g)12h
.
Yield: 174 mg (65%); yellow-brown solid; mp 72–74 °C; Rf = 0.33 (20%
1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.8 Hz, 2 H), 8.13 (d, J = 8.8
Hz, 2 H), 3.75–3.68 (m, 2 H), 3.31 (t, J = 5.2 Hz, 2 H), 1.76–1.68 (m, 4
H), 1.62–1.54 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 189.6, 164.3, 151.2, 137.9, 130.8,
124.3, 47.3, 42.7, 26.5, 25.6, 24.6.
EtOAc in hexanes).
IR (KBr): 3058, 2858, 1668, 1633, 1446, 1352 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.44 (s, 1 H), 8.05–8.00 (m, 1 H), 7.99–
7.92 (m, 2 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.57 (t,
J = 7.2 Hz, 1 H), 3.77 (t, J = 5.6 Hz, 2 H), 3.33 (t, J = 5.2 Hz, 2 H), 1.77–
1.68 (m, 4 H), 1.60–1.51 (m, 2 H).
.
HRMS: m/z [M + Na]+ calcd for C13H14N2O4Na: 285.0851; found:
13C NMR (100 MHz, CDCl3): δ = 192.2, 165.7, 136.5, 132.9, 132.6,
130.8, 130.0, 129.5, 129.2, 128.1, 127.2, 123.8, 47.3, 42.4, 26.4, 25.7,
24.6.
285.0859.
1-(4-Bromophenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3c)13
HRMS: m/z [M + H]+ calcd for C17H18NO2: 268.1338; found: 268.1326.
Yield: 213.3 mg (72%); yellow oil; Rf = 0.53 (30% EtOAc in hexanes).
IR (neat): 3021, 2853, 1680, 1644, 1581, 872, 743 cm–1
.
4-[2-Oxo-2-(piperidin-1yl)acetyl]benzonitrile (3h)12a
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.0
Hz, 2 H), 3.72–3.65 (m, 2 H), 3.28 (t, J = 5.6 Hz, 2 H), 1.73–1.65 (m, 4
H), 1.58–1.51 (m, 2 H).
Yield: 114 mg (47%); yellow-brown solid; mp 70–72 °C; Rf = 0.45 (40%
EtOAc in hexanes).
IR (KBr): 3095, 2857, 2230, 1686, 1641, 1448, 848 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 190.9, 165.0, 132.5, 132.3, 131.1,
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 8.4
Hz, 2 H), 3.70 (t, J = 5.2 Hz, 2 H), 3.29 (t, J = 5.2 Hz, 2 H), 1.76–1.65 (m,
4 H), 1.60–1.55 (m, 2 H).
130.2, 47.2, 42.4, 26.4, 25.6.
HRMS: m/z [M + Na]+ calcd for C13H14NO2BrNa: 318.0106; found:
318.0111.
13C NMR (100 MHz, CDCl3): δ = 190.0, 164.3, 136.5, 132.9, 130.1,
117.8, 47.2, 42.6, 26.4, 25.6, 24.5.
1-(4-Chlorophenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3d)12h
HRMS: m/z [M + H]+ calcd for C14H15N2O2: 243.1134; found: 243.1141.
Yield: 209 mg (83%); yellow liquid; Rf = 0.53 (30% EtOAc in hexanes).
IR (neat): 3021, 2846, 1680, 1638, 1581, 851 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 8.0
.
1-(3-Bromophenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3i)10a
Yield: 237 mg (80%); yellow liquid; Rf = 0.56 (30% EtOAc in hexanes).
Hz, 2 H), 3.70 (br s, 2 H), 3.28 (br s, 2 H), 1.70 (br s, 4 H), 1.55 (br s, 2
H).
13C NMR (100 MHz, CDCl3): δ = 190.7, 165.1, 141.4, 131.9, 131.1,
129.5, 47.2, 42.4, 26.4, 25.6, 24.5.
HRMS: m/z [M + Na]+ calcd for C13H14NO2ClNa: 274.0611; found:
IR (neat): 3059, 2856, 1680, 1643, 1445, 869, 765 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H),
7.75 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 3.73–3.67 (m, 2 H),
3.28 (t, J = 5.6 Hz, 2 H), 1.74–1.64 (m, 4 H), 1.59–1.52 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 190.5, 164.8, 137.6, 135.2, 132.4,
274.0605.
130.7, 128.4, 123.4, 47.2, 42.4, 26.4, 25.6, 24.5.
HRMS: m/z [M + Na]+ calcd for C13H14NO2BrNa: 318.0106; found:
1-(Piperidin-1-yl)-2-(p-tolyl)ethane-1,2-dione (3e)12b
Yield: 115.6 mg (50%); light yellow liquid; Rf = 0.33 (20% EtOAc in hex-
318.0093.
anes).
1-(3-Nitrophenyl)-2-(piperidin-1-yl)ethane-1,2-dione (3j)
IR (neat): 3039, 2862, 1669, 1640, 1453, 850 cm–1
.
Yield: 184 mg (70%); yellow liquid; Rf = 0.30 (30% EtOAc in hexanes).
IR (neat): 3109, 2854, 1682, 1634, 1528, 1444, 1346, 771, 715 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.77 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H),
8.28 (d, J = 7.6 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 3.73 (br s, 2 H), 3.33 (t,
J = 4.4 Hz, 2 H), 1.72 (br s, 4 H), 1.59 (br s, 2 H).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0
Hz, 2 H), 3.72–3.66 (m, 2 H), 3.27 (t, J = 5.6 Hz, 2 H), 2.42 (s, 3 H),
1.71–1.64 (m, 4 H), 1.57–1.48 (m, 2 H).
.
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13C NMR (100 MHz, CDCl3): δ = 189.1, 164.1, 148.8, 135.1, 134.9,
13C NMR (100 MHz, CDCl3): δ = 190.0, 165.0, 132.7, 132.1, 131.2,
130.4, 128.8, 124.5, 47.3, 42.7, 26.5, 25.6, 24.5.
130.7, 66.9, 66.8, 46.5, 41.9.
HRMS: m/z [M + H]+ calcd for C13H15N2O4: 263.1032; found: 263.1029.
HRMS: m/z [M + H]+ calcd for C12H13NO3Br: 299.0048; found:
299.0043.
1-Morpholino-2-phenylethane-1,2-dione (3k)12b
N-Benzyl-N-methyl-2-oxo-2-phenylacetamide (3p)12a
Yield: 142.9 mg (65%); yellow liquid; Rf = 0.26 (30% EtOAc in hexanes).
Yield: 202.6 mg (80%); light yellow liquid; Rf = 0.28 (15% EtOAc in hex-
anes).
IR (neat): 3077, 2854, 1671, 1641, 1574, 1107, 719 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.6 Hz, 2 H), 7.66 (t, J = 7.6
Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 3.79 (br s, 4 H), 3.65 (t, J = 4.8 Hz, 2 H),
3.38 (t, J = 4.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 165.6, 135.1, 133.3, 129.8,
129.2, 66.9, 66.8, 46.4, 41.8.
IR (neat): 3058, 2986, 2934, 1683, 1645, 1494, 1448, 731 cm–1
.
1H NMR (400 MHz, CDCl3): δ (47.6:52.4 mixture of cis/trans isomers)
= 7.99–7.92 (m, 4 H), 7.65–7.59 (m, 2 H), 7.52–7.46 (m, 4 H), 7.40–
7.27 (m, 8 H), 7.25–7.20 (m, 2 H), 4.71 (s, 2 H), 4.37 (s, 2 H), 2.97 (s, 3
H), 2.82 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.7, 167.5, 167.3, 135.9, 135.0,
134.9, 133.3, 133.2, 129.9, 129.8, 129.2, 129.1, 129.0, 128.9, 128.5,
128.47, 128.35, 128.1, 128.0, 53.7, 50.0, 34.6, 31.5.
HRMS: m/z [M + H]+ calcd for C12H14NO3: 220.0973; found: 220.0975.
1-Morpholino-2-(4-nitrophenyl)ethane-1,2-dione (3l)12g
Yield: 172.8 mg (65%); creamy-white solid; mp 138–140 °C; Rf = 0.43
(40% EtOAc in hexanes).
HRMS: m/z [M + H]+ calcd for C16H16NO2: 254.1181; found: 254.1179.
IR (KBr): 3073, 2862, 1683, 1639, 1525, 1454, 1347, 1113, 833 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.8 Hz, 2 H), 8.16 (d, J = 8.8
Hz, 2 H), 3.81 (br s, 4 H), 3.70 (t, J = 5.2 Hz, 2 H), 3.43 (t, J = 5.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 188.8, 164.2, 151.3, 137.6, 131.0,
124.3, 66.9, 66.8, 46.5, 42.1.
.
N-Benzyl-2-(4-bromophenyl)-N-methyl-2-oxoacetamide (3q)
Yield: 216 mg (65%); yellow liquid; Rf = 0.63 (20% EtOAc in hexanes).
IR (neat): 3099, 3056, 2962, 2920, 2854, 1679, 1644, 1489, 848, 698
cm–1
.
1H NMR (400 MHz, CDCl3): δ (47:53 mixture of cis/trans isomers) =
7.88–7.79 (m, 4 H), 7.69–7.63 (m, 4 H), 7.42–7.28 (m, 8 H), 7.25–7.21
(m, 2 H), 4.72 (s, 2 H), 4.39 (s, 2 H), 3.00 (s, 3 H), 2.84 (s, 3 H).
HRMS: m/z [M + Na]+ calcd for C12H12N2O5Na: 287.0644; found:
287.0641.
13C NMR (100 MHz, CDCl3): δ = 190.4, 166.9, 166.7, 135.8, 135.0,
132.6, 132.5, 132.2, 132.0, 131.3, 131.2, 130.4, 129.1, 129.0, 128.44,
124.41, 128.1, 127.9, 53.7, 50.1, 34.6, 31.8.
HRMS: m/z [M + Na]+ calcd for C16H14NO2BrNa: 354.0106; found:
354.0103.
1-(4-Chlorophenyl)-2-morpholinoethane-1,2-dione (3m)9b
Yield: 157.3 mg (62%); light brown solid; mp 111–113 °C; Rf = 0.34
(30% EtOAc in hexanes).
IR (KBr): 3011, 2850, 1675, 1630, 1111, 848 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 8.4
Hz, 2 H), 3.79 (br s, 4 H), 3.66 (t, J = 4.8 Hz, 2 H), 3.38 (t, J = 4.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 189.8, 165.1, 141.8, 131.6, 131.2,
N-Benzyl-2-(4-chlorophenyl)-N-methyl-2-oxoacetamide (3r)12a
Yield: 201.4 mg (70%); yellow liquid; Rf = 0.63 (20% EtOAc in hexanes).
129.6, 66.9, 66.8, 46.4, 41.9.
IR (neat): 3060, 3036, 2931, 2864, 2807, 1682, 1644, 1489, 848 cm–1
.
HRMS: m/z [M
+
H]+ calcd for C12H13NO3Cl: 254.0584; found:
1H NMR (400 MHz, CDCl3): δ (47.8:52.2 mixture of cis/trans isomers)
= 7.93–7.84 (m, 4 H), 7.49–7.42 (m, 4 H), 7.40–7.27 (m, 8 H), 7.24–
7.18 (m, 2 H), 4.70 (s, 2 H), 4.37 (s, 2 H), 2.97 (s, 3 H), 2.82 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.2, 167.0, 166.8, 141.5, 135.8,
135.0, 131.8, 131.7, 131.3, 131.2, 129.6, 129.5, 129.1, 129.0, 128.5,
128.4, 128.1, 127.9, 53.7, 50.1, 34.6, 31.8.
254.0572.
4-(2-Morpholino-2-oxoacetyl)benzonitrile (3n)13
Yield: 134.5 mg (55%); light brown solid; mp 111–113 °C; Rf = 0.37
(40% EtOAc in hexanes).
IR (KBr): 3099, 2854, 2230, 1686, 1641, 1497, 1135, 1024, 848 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.4
Hz, 2 H), 3.80 (br s, 4 H), 3.72–3.63 (m, 2 H), 3.41 (t, J = 4.4 Hz, 2 H).
.
HRMS: m/z [M
+
H]+ calcd for C16H15NO2Cl: 288.0791; found:
288.0786.
N-Benzyl-N-methyl-2-(4-nitrophenyl)-2-oxoacetamide (3s)12a
Yield: 182 mg (61%); yellow liquid; Rf = 0.53 (30% EtOAc in hexanes).
IR (neat): 3144, 3081, 2987, 2920, 2857, 1679, 1637, 1546, 1518,
13C NMR (100 MHz, CDCl3): δ = 189.1, 164.2, 136.2, 133.0, 130.2,
118.1, 117.7, 66.9, 66.8, 46.5, 42.0.
HRMS: m/z [M + H]+ calcd for C13H13N2O3: 245.0926; found: 245.0919.
1377, 831 cm–1
.
1-(4-Bromophenyl)-2-morpholinoethane-1,2-dione (3o)13
1H NMR (400 MHz, CDCl3): δ (48.2:51.8 mixture of cis/trans isomers)
= 8.38–8.27 (m, 4 H), 8.20–8.09 (m, 4 H), 7.43–7.27 (m, 8 H), 7.25–
7.19 (m, 2 H), 4.74 (s, 2 H), 4.44 (s, 2 H), 3.05 (s, 3 H), 2.88 (s, 3 H).
Yield: 184.8 mg (62%); white solid; mp 122–124 °C; Rf = 0.34 (30%
EtOAc in hexanes).
IR (KBr): 3446, 3071, 2948, 2839, 1669, 1630, 1570, 1107, 841, 754
13C NMR (100 MHz, CDCl3): δ = 189.2, 166.2, 165.9, 151.2, 151.1,
137.8, 137.6, 135.5, 134.8, 131.0, 130.9, 129.1, 129.0, 128.5, 128.4,
128.3, 127.8, 124.3, 124.1, 53.7, 50.3, 34.7, 32.2.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.8
Hz, 2 H), 3.79 (br s, 4 H), 3.66 (t, J = 4.8 Hz, 2 H), 3.38 (t, J = 4.8 Hz, 2 H).
HRMS: m/z [M
+
K]+ calcd for C16H14N2O4K: 337.1085; found:
337.1081.
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Synthesis
tert-Butyl 4-(2-Oxo-2-phenylacetyl)piperazine-1-carboxylate (3t)
Invest. 2013, 123, 3861. (c) Hagihara, M.; Schreiber, S. L. J. Am.
Chem. Soc. 1992, 14, 6570. (d) Dubowchik, G. M.; Ditta, J. L.;
Herbst, J. J.; Bollini, S.; Vinitsky, A. Bioorg. Med. Chem. Lett. 2000,
10, 559.
Yield: 178.3 mg (56%); light brown solid; mp 120–122 °C; Rf = 0.24
(20% EtOAc in hexanes).
IR (KBr): 3064, 2976, 2864, 1675, 1647, 1609, 1493, 764 cm–1
.
(3) (a) Wang, X. J.; Etzkorn, F. A. Biopolymers 2006, 84, 125.
(b) Curtin, M.; Glaser, K. Curr. Med. Chem. 2003, 10, 2373.
(c) Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11,
1825. (d) Zhang, Z.; Zhang, Q.; Ni, Z.; Liu, Q. Chem. Commun.
2010, 46, 1269. (e) Natarajan, A.; Wang, K.; Ramamurthy, V.;
Scheffer, J. R.; Patrick, B. Org. Lett. 2002, 4, 1443. (f) Sai, K. K. S.;
Esteves, P. M.; Tanoue da Penha, E.; Klumpp, D. A. J. Org. Chem.
2008, 73, 6506. (g) Tomita, D.; Yamatsugu, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.93 (m, 2 H), 7.66 (t, J = 7.6 Hz, 1
H), 7.52 (t, J = 7.6 Hz, 2 H), 3.77–3.71 (m, 2 H), 3.59–3.52 (m, 2 H),
3.46–3.40 (m, 2 H), 3.36–3.00 (m, 2 H), 1.46 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 165.8, 154.5, 135.1, 133.2,
129.8, 129.3, 80.8, 41.4, 28.5.
HRMS: m/z [M + Na]+ calcd for C17H22N2O4Na: 341.1477; found:
341.1494.
(4) (a) Hua, R.; Takeda, H.; Abe, Y.; Tanaka, M. J. Org. Chem. 2004, 69,
974. (b) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010,
12, 820. (c) Chen, J.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509.
(d) Singh, R. P.; Shreeve, J. N. M. J. Org. Chem. 2003, 68, 6063.
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F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011, 13, 1556. (c) Deshidi,
R.; Kumar, M.; Devari, S.; Shah, B. A. Chem. Commun. 2014, 50,
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Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780. (b) Zhang, C.;
Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2011, 50, 11088.
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5272. (b) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett.
2009, 11, 1321. (c) de la Fuente, V.; Godard, C.; Zangrando, E.;
Claver, C.; Castillon, S. Chem. Commun. 2012, 48, 1695.
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687, 436. (e) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.;
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tert-Butyl 4-[2-(Naphthalen-2-yl)-2-oxoacetyl]piperazine-1-car-
boxylate (3u)
Yield: 202.6 mg (55%); light brown solid; mp 141–143 °C; Rf = 0.45
(30% EtOAc in hexanes).
IR (KBr): 3056, 2854, 1682, 1641, 1595, 1423 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H), 8.05–8.00 (m, 1 H), 7.99–
7.93 (m, 2 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.69–7.63 (m, 1 H), 7.62–7.56
(m, 1 H), 3.83–3.78 (m, 2 H), 3.62–3.57 (m, 2 H), 3.47–3.41 (m, 2 H),
3.40–3.14 (m, 2 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 191.4, 165.9, 154.5, 136.5, 133.2,
132.6, 130.5, 130.1, 129.7, 129.4, 128.1, 127.4, 123.7, 80.8, 46.0, 41.5,
28.5.
HRMS: m/z [M + Na]+ calcd for C21H24N2O4Na: 391.1634; found:
391.1651.
Acknowledgment
(8) (a) Grassot, J.-M.; Masson, G.; Zhu, J. Angew. Chem. Int. Ed. 2008,
47, 947. (b) Bouma, M.; Masson, G.; Zhu, J. J. Org. Chem. 2010,
75, 2748. (c) Giustiniano, M.; Mercalli, V.; Cassese, H.; Di Maro,
S.; Galli, U.; Novellino, E.; Tron, G. C. J. Org. Chem. 2014, 79, 6006.
(9) (a) Zhang, X.; Yang, W.; Wang, L. Org. Biomol. Chem. 2013, 11,
3649. (b) Li, D.; Wang, M.; Liu, J.; Zhao, Q.; Wang, L. Chem.
Commun. 2013, 49, 3640. (c) Wang, H.; Guo, L.-N.; Duan, X.-H.
Org. Biomol. Chem. 2013, 11, 4573.
We thank DST (project No: SB/S1/OC-72/2013) for financial support.
N.S. thanks CSIR, New Delhi for a junior research fellowship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379975.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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2007, 48, 8982. (b) Du, B.; Jin, B.; Sun, P. Org. Biomol. Chem.
2014, 12, 4586. (c) Song, B.; Wang, S.; Sun, C.; Deng, H.; Xu, B.
Tetrahedron Lett. 2007, 48, 8982.
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3280. (b) Shaw, A. Y.; Denning, C. R.; Hulme, C. Tetrahedron Lett.
2012, 53, 4151. (c) Mupparapu, N.; Khan, S.; Battula, S.;
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(15) When acyclic amines such as N,N-diethylamine, N,N-diallyl-
amine, N,N-diisopropylamine and N,N-dibenzylamine were
used under the same reaction conditions, all gave inseparable
complex mixtures (numerous spots by TLC).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 726–736