Coupling of methyl ketones and primary or secondary amines leading to α-ketoamides

Article abstract of DOI:10.1021/jo301117b

A metal-free oxidative coupling of methyl ketones and primary or secondary amines to α-ketoamides has been developed. Four intermediates, α-iodoketone, α-aminoketone, iminium intermediate, and α-hydroxy amine have been identified through a series of control experiments. The atom-economic methodology can be scaled-up, tolerates a variety of functional groups, and is operationally simple.

Full text of DOI:10.1021/jo301117b

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Coupling of Methyl Ketones and Primary or Secondary Amines
Leading to α‑Ketoamides
Wei Wei,† Ying Shao,‡ Huayou Hu,§ Feng Zhang,† Chao Zhang,† Yuan Xu,† and Xiaobing Wan*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, PR China
‡Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou 213164, PR China
§Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin Normal
University, Huaian 223300, PR China
S
* Supporting Information
ABSTRACT: A metal-free oxidative coupling of methyl
ketones and primary or secondary amines to α-ketoamides
has been developed. Four intermediates, α-iodoketone, α-
aminoketone, iminium intermediate, and α-hydroxy amine
have been identified through a series of control experiments.
The atom-economic methodology can be scaled-up, tolerates a
variety of functional groups, and is operationally simple.
C−H oxidation, and α-aminoketone is the nucleophilic
substitution product of amine and α-iodoketone reactants.14
In turn, α-iodoketones can be formed by iodination of a methyl
ketone.15 It is well-known that nucleophilic attack by hydroxide
on a carbonyl carbon atom was involved in the catalytic cycle of
the iodoform reaction (Scheme 1b). In sharp contrast,
nucleophilic attack by an amine on the iodomethyl, not the
carbonyl group, is a key step in this pathway. Transition metal-
catalyzed C−H oxidation is of both fundamental and industrial
interest, enabling clean access to many functionalized
chemicals.2 However, despite their remarkable potential, the
toxicity and expense of transition metals is a concern.
Continuing our recent studies in TBAI (tetrabutylammonium
iodide)-catalyzed chemical transformation,16 we conceived of
converting methyl ketone and amine to the corresponding α-
ketoamides using a similar metal-free approach.
INTRODUCTION
■
The iodoform reaction, discovered in 1822, is one of the oldest
reactions in organic chemistry.1 While the iodoform reaction
has been widely used to prepare carboxylic acids and identify
CH3CO groups, it is surprising that few expansions have been
developed since its discovery. Herein, we combine the old
iodoform reaction with a modern C−H oxidation2 to provide a
new strategy for α-ketoamides synthesis. α-Ketoamides are
prevalent structural motifs found in numerous natural products,
biologically relevant molecules, and marketed drugs.3 They also
serve as useful synthetic intermediates for further trans-
formations.4 As a result, the synthesis of α-ketoamides has
attracted considerable interest.5−13 Although much progress has
been made in this field, the search for a simple and practical
catalytic system remains a challenge for the synthetic chemist.
As shown in our retrosynthetic analysis (Scheme 1a), α-
ketoamides could be synthesized from α-aminoketones through
RESULTS AND DISCUSSION
Initially, we investigated the room temperature reaction of
■
Scheme 1. Design for α-Ketoamides Synthesis
acetophenone 1a with morpholine 2a in the presence of 50 mol
i
% TBAI in PrOH for 13 h. The desired α-ketoamide 3a was
obtained in moderate yield (Table 1, entry 1). The use of KI
under the same conditions lowered the yield (Table 1, entry 2).
Finally, iodine was identified as the best catalyst for this
reaction, affording α-ketoamide 3a in excellent yield (Table 1,
entry 3). No significant amount of product was observed in the
absence of iodine or TBHP (Table 1, entries 4 and 5). The
choice of oxidant was also crucial for this transformation. Other
common oxidants (such as H2O2, m-CPBA, Oxone and O2)
suppressed the formation of desired α-ketoamide 3a (Table 1,
entries 6−9). Notably, no benzoic acid or 4-benzoylmorpholine
Received: June 7, 2012
Published: August 9, 2012
© 2012 American Chemical Society
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a
(Scheme 3b). Notably, only trace amount of α-ketoamide 3b
was observed in the absence of iodine (Scheme 3c). We
suspected α-aminoketone 4 is generated in situ by the
nucleophilic substitution of morpholine 2a on 1-(4-bromo-
phenyl)-2-iodoethanone 5. However, no 1-(4-bromophenyl)-2-
iodoethanone 5 was observed by LC−MS during the reaction,
which might be owing to the fast reaction of morpholine 2a and
1-(4-bromophenyl)-2-iodoethanone 5. As anticipated, when 1-
(4-bromophenyl)-2-iodoethanone 5 was used in the standard
conditions, a 76% yield of α-ketoamide 3b was obtained
(Scheme 3c). On the basis of the above results, both α-
iodoketones and α-aminoketones are reaction intermediates in
the formation of α-ketoamides.
Further investigations into the mechanism were performed.
As shown in Scheme 4a, hydroxide anion is generated in situ
from TBHP in the standard conditions.20 Consequently, when
an 18O-labeled reaction was carried out, both 3b-18O and 3b
were obtained (Scheme 4b). Therefore, we believed the
nucleophilic attack of a water molecule on the iminium-type
intermediate, not by TBHP, is involved in the catalytic cycle.
Notably, benzoylformaldehyde was also a suitable reaction
partner, which suggested the α-hydroxy amine served as an
intermediate in the transformation (Scheme 4c).
Next, a variety of substituted aryl methyl ketones were
subjected to the standard conditions. Representative results are
summarized in Figure 1. A host of aryl methyl ketones with
ortho, meta, or para electron-donating or electron-withdrawing
substituents reacted smoothly with morpholine 2a in moderate
to excellent yields. Interestingly, the presence of bromo and
chloro substituents on the aromatic groups did not interfere
with the C−H oxidation process, affording products 3b, 3e and
3m that could be further functionalized by transition metal-
catalyzed cross-coupling reactions. The reaction was also
compatible with fluoro (3d), benzylic C−H (3f), trifluor-
omethyl (3g), nitriles (3h), esters (3i), alkyne (3j), sulfonate
(3k), nitro (3l and 3o), and ether (3p) groups. Even oxidative
sensitive groups, such as C,C double bond (3i) and an
unprotected hydroxyl group (3n), were tolerated in the
transformation. Finally, steric effects did not significantly
influence the reactivity of the reaction, with product 3q being
obtained in high yield.
Table 1. Optimization of Reaction Conditions
entry
catalyst
oxidant
yield
1
2
3
4
5
6
7
8
9
10
TBAI
KI
I2
TBHP
TBHP
TBHP
TBHP
−
H2O2
m-CPBA
Oxone
O2
54%
40%
90%
b
−
I2
N.O.
<5%
11%
N.O.
13%
<5%
I2
b
I2
I2
I2
c
I2
TBHP
82%
a
Reaction conditions: 0.5 mmol acetophenone 1a, 2.0 mmol
morpholine 2a, 50 mol % catalyst, 3.0 mmol TBHP in 2.0 mL of
b
c
iPrOH at room temperature for 13 h. Not observed. 100 mmol
acetophenone 1a and 400 mmol morpholine 2a were used.
(nucleophilic attack by morpholine on carbonyl group) were
detected as a byproduct. The high selectivity could be
attributed to the strong nucleophilicity of amines and superior
leaving ability of iodide. Importantly, the reaction was scaled up
to 100 mmol and retained its high yield (Table 1, entry 10).
The mild conditions and cheap commercial available starting
materials (catalyst, oxidant and reactant) make the method-
ology applicable in synthetic chemistry and drug discovery.
A proposed reaction mechanism, which differs from Ji’s
report,7d is shown in Scheme 2. In the first step, iodination of
Scheme 2. Proposed Reaction Mechanism
Most recently, Ji and co-workers have developed an elegant
copper-catalyzed oxidative coupling of methyl ketones and
amines using molecular oxygen.7d In their work, the ketones are
limited primarily to aryl methyl ketones. To further showcase
the potential of our methodology, ketones with heteroaryl
substituents were submitted to the optimized conditions. As
shown in Figure 2, both 2-acetylthiophene and 2-acetyl-5-
chlorothiophene were compatible reaction partners for this
transformation, leading to products 6a and 6b in high yields.
Thiazole (6c), pyrazine (6d) and furan (6h) were also tolerated
in the α-ketoamide formation reaction. Finally, 2-acetylpyridine,
3-acetylpyridine, and 4-acetylpyridine afforded the desired α-
ketoamide 6e−6g in moderate yields.
To further define the scope of the α-ketoamide synthesis, we
next applied this process to a series of amines as shown in
Figure 3. Pyrrolidine and piperidine reacted well with
acetophenone 1a to afford 7a and 7c in 73 and 64% yields,
respectively. Acyclic amines also worked well and gave the
corresponding α-ketoamides in moderate to excellent yields
(7b, 7d and 7h). A variety of functional groups, including ether
(7h), pyridine (7i), ester (7l), and tertiary amine (7i), were
unaffected in the reaction, and corresponding α-ketoamides
methyl ketone A forms α-iodoketone B (step a).15 Subsequent
nucleophilic substitution of amine to α-iodoketone B generates
α-aminoketone C (step b).14 Further iodination produces α-
iodo-α-aminoketone D (step c). Ionization of D generates
iminium-type intermediate E under the standard conditions
(step d).17 Nucleophilic attack by H2O on the resulting E gives
the α-hydroxy amine intermediate F (step e).18 Finally,
oxidation of F affords the desired α-ketoamide G (step f).19
A two-step one-pot synthesis of α-ketoamide 3b was carried
out to elucidate the mechanism. Treatment of 4′-bromoaceto-
phenone 1b with morpholine 2a in the presence of 50 mol %
iodine generated the α-aminoketone 4 (detected by LC−MS)
after 1 h at ambient temperature. Subsequent addition of
TBHP resulted in the desired α-ketoamide 3b in 78% yield
(Scheme 3a). When α-aminoketone 4 was subjected to the
standard conditions, α-ketoamide 3b was obtained in 81% yield
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Scheme 3. Investigations into the Reaction Mechanism
CONCLUSIONS
Scheme 4. Investigation into the Reaction Mechanism
■
In summary, we have described an oxidative coupling of methyl
ketones with primary and secondary amines to give α-
ketoamides in moderate to excellent yields. The reaction
makes direct use of simple and abundant starting materials
without requiring transition metal catalysts. In view of the wide
functional group tolerance, the ease of conducting such
reactions, and the mild reaction conditions, we envision this
protocol will be widely adapted in synthetic chemistry.
EXPERIMENTAL SECTION
■
General Methods. All manipulations were carried out under air
atmosphere. Column chromatography was generally performed on
silica gel (300−400 mesh), and reactions were monitored by thin layer
chromatography (TLC) using UV light to visualize the course of the
1
reactions. The H NMR (400 MHz) and 13C NMR (100 MHz) data
were recorded on 400 M spectrometers using CDCl3 as solvent at
room temperature. The chemical shifts (δ) are reported in ppm and
1
coupling constants (J) in Hz. H NMR spectra were recorded with
tetramethylsilane (δ = 0.00 ppm) as internal reference; 13C NMR
spectra were recorded with CDCl3 (δ = 77.00 ppm) as internal
reference.
were obtained in high yields. Synthetically useful benzyl and
tetrahydroisoquinoline are tolerated in the transformation,
giving 7e−7g in good yields. Notably, free hydroxyl (7k) and
removable BocNH group (7j) were inert in the reaction,
leading to expected α-ketoamides in satisfactory yields.
Next, primary amines were used as reaction partners for the
synthesis of α-ketoamides. As shown in Figure 4, these
reactions also tolerate a variety of aromatic substituents
(electron-rich, electron-poor, and heteroaromatic), while
potentially sensitive functional groups (double bond and
benzylic C−H bond) are also unaffected by the reaction
conditions.
General procedures for amides 3a−3q, 6a−6h, 7a−7l, and 8a−8h:
Methyl ketone (0.5 mmol), amine (2.0 mmol), I2 (0.25 mmol, 50 mol
%), TBHP (6.0 equiv, 70% aqueous solution 401 uL), and 2.0 mL of
iPrOH were added to a tube under air. The reaction mixture was
stirred at room temperature or 0 °C for 13 h. The reaction mixture
was quenched with saturated Na2S2O3 solution, extracted repeatedly
with ethyl acetate, and dried over Na2SO4. Removal of the organic
solvent in a vacuum followed by flash silica gel column chromato-
graphic purification (petroleum/ethyl acetate) afforded product.
1-Morpholino-2-phenylethane-1,2-dione (3a). Purified by
flash column chromatography (EtOAc:hexane 1:5). Yellow oil (99
1
mg, 90% yield): H NMR (CDCl3, 400 MHz) δ 7.98−7.95 (m, 2H),
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Figure 1. Scope of methyl ketones. Reaction conditions: 0.5 mmol ketones 1, 2.0 mmol morpholine 2a, 50 mol % iodine, 3.0 mmol TBHP in 2.0 mL
i
of PrOH at room temperature for 13 h.
Figure 2. Scope of heteroaryl ketones. Reaction conditions: 0.5 mmol ketones 1, 2.0 mmol morpholine 2a, 50 mol % iodine, 3.0 mmol TBHP in 2.0
i
mL of PrOH at room temperature for 13 h.
7.68−7.64 (m, 1H), 7.55−7.51 (m, 2H), 3.81 (t, J = 4.0 Hz, 2H), 3.79
(t, J = 4.0 Hz, 2H), 3.66 (t, J = 4.0 Hz, 2H), 3.39 (t, J = 4.0 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 191.0, 165.2, 134.8, 132.8, 129.4,
1-(4-Bromophenyl)-2-morpholinoethane-1,2-dione (3b). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
(122 mg, 82% yield): 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, J = 8.6
Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 3.79 (t, J = 4.0 Hz, 4H), 3.67 (t, J =
4.0 Hz, 2H), 3.38 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ
189.8, 164.7, 132.3, 131.7, 130.9, 130.3, 66.5, 66.4, 46.1, 41.5; HRMS
(TOF) m/z [M]+ Calcd for C12H1279BrNO3 297.0001, found
297.0007; Calcd for C12H1281BrNO3 298.9980, found 299.0022; IR
(KBr, cm−1) ν 1676, 1628.
1-Morpholino-2-(naphthalen-1-yl)ethane-1,2-dione (3c). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
(112 mg, 83% yield): 1H NMR (CDCl3, 400 MHz) δ 9.25 (d, J = 8.7
Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.05−8.03 (m, 1H), 7.93 (d, J = 8.1
Hz, 1H), 7.73−7.69 (m, 1H), 7.63−7.55 (m, 2H), 3.88−3.78 (m, 4H),
3.67 (t, J = 4.0 Hz, 2H), 3.44 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3,
128.9, 66.5, 66.4, 46.0, 41.4; HRMS (TOF) m/z [M + H]+ Calcd for
C12H14NO3 220.0968, found 220.0975; IR (KBr, cm−1) ν 1681, 1645.
Scale-up of Product 3a. Acetophenone (100.0 mmol), morpho-
line (400.0 mmol), I2 (50.0 mmol, 50 mol %), TBHP (6.0 equiv, 70%
i
aqueous solution 80.2 mL), and 400.0 mL of PrOH, were added to a
flask under air. The reaction mixture was stirred at room temperature
for 13 h. Then, the reaction mixture was quenched with saturated
Na2S2O3 solution and then extracted three times with ethyl acetate.
Removal of organic solvent got the raw product. Finally, flash silica gel
column chromatographic purification (petroleum/ethyl acetate)
afforded product 3a in 82% yield.
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Figure 3. Scope of amines. Reaction conditions: 0.5 mmol acetophenone 1a, 2.0 mmol amines 2, 50 mol % iodine, 3.0 mmol TBHP in 2.0 mL of
iPrOH at room temperature for 13 h.
Figure 4. Scope of primary amines. Reaction conditions: 0.5 mmol methyl ketone 1, 2.0 mmol amines 2, 50 mol % iodine, 3.0 mmol TBHP in 2.0
i
mL of PrOH at 0 °C for 13 h.
75 MHz) δ 193.4, 165.8, 136.0, 134.3, 133.8, 130.6, 129.3, 128.6,
128.1, 126.9, 125.5, 124.3, 66.41, 66.40, 46.1, 41.5; HRMS (TOF) m/z
[M + H]+ Calcd for C16H16NO3 270.1125, found 270.1136; IR (KBr,
cm−1) ν 1669, 1630.
[M + H]+ Calcd for C12H1335ClNO3 254.0578, found 254.0586; IR
(KBr, cm−1) ν 1676,1628.
1-Morpholino-2-p-tolylethane-1,2-dione (3f). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (84 mg,
1
1-(4-Fluorophenyl)-2-morpholinoethane-1,2-dione (3d). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
72% yield): H NMR (CDCl3, 400 MHz) δ 7.85 (d, J = 8.8 Hz, 2H),
7.32 (d, J = 8.8 Hz, 2H), 3.80−3.76 (m, 4H), 3.65 (t, J = 4.0 Hz, 2H),
3.37 (t, J = 4.0 Hz, 2H), 2.44 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
190.8, 165.5, 146.1, 130.4, 129.7, 129.6, 66.53, 66.46, 46.1, 41.4, 21.8;
HRMS (TOF) m/z [M + H]+ Calcd for C13H16NO3 234.1125, found
234.1134; IR (KBr, cm−1) ν 1675, 1645.
1
(97 mg, 82% yield): H NMR (CDCl3, 400 MHz) δ 8.03−7.99 (m,
2H), 7.22−7.18 (m, 2H), 3.80−3.77 (m, 4H), 3.67 (t, J = 4.0 Hz, 2H),
3.39 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 189.2, 168.3,
164.9, 132.4, 132.3, 129.4, 116.4, 116.1, 66.5, 66.4, 46.1, 41.5; HRMS
(TOF) m/z [M]+ Calcd for C12H12FNO3 237.0801, found 237.0809;
IR (KBr, cm−1) ν 1672, 1633.
1-Morpholino-2-(4-(trifluoromethyl)phenyl)ethane-1,2-
dione (3g). Purified by column chromatography (EtOAc:hexane 1:5).
1-(4-Chlorophenyl)-2-morpholinoethane-1,2-dione (3e). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
1
Yellow solid (102 mg, 71% yield): H NMR (CDCl3, 400 MHz) δ
1
8.10 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 3.82−3.79 (m, 4H),
3.68 (t, J = 4.0 Hz, 2H), 3.41 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 189.6, 164.4, 135.9, 135.6, 135.5, 129.9, 126.03, 126.0,
125.96, 125.9, 124.6, 121.8, 66.6, 66.5, 46.2, 41.7; HRMS (TOF) m/z
(93 mg, 73% yield): H NMR (CDCl3, 400 MHz) δ 7.93−7.90 (m,
2H), 7.52−7.50 (m, 2H), 3.82−3.77 (m, 4H), 3.67 (t, J = 4.0 Hz, 2H),
3.39 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 189.5, 164.7,
141.4, 131.3, 130.9, 129.3, 66.5, 66.4, 46.1, 41.5; HRMS (TOF) m/z
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[M + H]+ Calcd for C13H13F3NO3 288.0842, found 288.0839; IR
(KBr, cm−1) ν 1681, 1630.
41.9; HRMS (TOF) m/z [M + H]+ Calcd for C12H13N2O5 265.0819,
found 265.0818; IR (KBr, cm−1) ν 1685, 1645.
1-(3-Methoxyphenyl)-2-morpholinoethane-1,2-dione (3p).
Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (107 mg, 86% yield): 1H NMR (CDCl3, 400 MHz) δ 7.52−7.50
(m, 2H), 7.45−7.41 (m, 1H), 7.22−7.19 (m, 1H), 3.87 (s, 3H), 3.81−
3.78 (m, 4H), 3.66 (t, J = 4.0 Hz, 2H), 3.38 (t, J = 4.0 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 190.9, 165.2, 159.9, 134.1, 130.0, 122.6,
121.6, 112.6, 66.5 66.4, 55.4, 46.1, 41.4. HRMS (TOF) m/z [M + H]+
Calcd for C13H16NO4 250.1074, found 250.1074; IR (KBr, cm−1) ν
1681, 1646.
4-(2-Morpholino-2-oxoacetyl)benzonitrile (3h). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (65 mg,
1
53% yield): H NMR (CDCl3, 400 MHz) δ 8.09 (d, J = 8.0 Hz, 2H),
7.84 (d, J = 8.0 Hz, 2H), 3.83−3.79 (m, 4H), 3.69 (t, J = 4.0 Hz, 2H),
3.41 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3,100 MHz) δ 188.9, 163.9,
135.8, 132.7, 129.9, 117.7, 117.4, 66.5, 66.4, 46.1, 41.7; HRMS (TOF)
m/z [M + Na]+ Calcd for C13H12N2NaO3 267.0740, found 267.0738;
IR (KBr, cm−1) ν 1686, 1643.
(E)-Methyl 3-(4-(2-morpholino-2-oxoacetyl)phenyl)acrylate
(3i). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (93 mg, 61% yield): 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J =
8.2 Hz, 2H), 7.72 (d, J = 16.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 6.56
(d, J = 16.1 Hz, 1H), 3.84 (s, 3H), 3.81−3.80 (m, 4H), 3.67 (t, J = 4.0
Hz, 2H), 3.40 (t, J = 4.0 Hz, 2H),; 13C NMR (CDCl3, 100 MHz) δ
189.9, 166.4, 164.8, 142.5, 140.2, 133.7, 129.9, 128.3, 121.1, 66.5, 66.4,
51.7, 46.0, 41.4; HRMS (TOF) m/z [M + H]+ Calcd for C16H18NO5
304.1179, found 304.1179; IR (KBr, cm−1) ν 1725, 1667, 1641.
1-Morpholino-2-(4-(phenylethynyl)phenyl)ethane-1,2-dione
(3j). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (121 mg, 76% yield): 1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J =
8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.57−7.55 (m, 2H), 7.39−7.38
(m, 3H), 3.81−3.80 (m, 4H), 3.67 (t, J = 4.0 Hz, 2H), 3.40 (t, J = 4.0
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 190.1, 165.0, 132.0, 131.9,
131.7, 130.0, 129.5, 129.0, 128.4, 122.2, 94.0, 88.3, 66.6, 66.5, 46.1,
41.5; HRMS (TOF) m/z [M]+ Calcd for C20H17NO3 319.1208, found
319.1223; IR (KBr, cm−1) ν 1673, 1642.
4-(2-Morpholino-2-oxoacetyl)phenyl 4-methylbenzenesul-
fonate (3k). Purified by column chromatography (EtOAc:hexane
1:5). Yellow solid (148 mg, 76% yield): 1H NMR (CDCl3, 400 MHz)
δ 7.94−7.91 (m, 2H), 7.75−7.71 (m, 2H), 7.35−7.33 (m, 2H), 7.18−
7.14 (m, 2H), 3.81−3.76 (m, 4H), 3.65 (t, J = 4.0 Hz, 2H), 3.38 (t, J =
4.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 189.2,
164.6, 154.0, 145.9, 131.7, 131.4, 129.9, 128.2, 122.8, 66.5, 66.4, 46.1,
41.5, 21.6; HRMS (TOF) m/z [M]+ Calcd for C19H19NO6S 389.0933,
found 389.0930; IR (KBr, cm−1) ν 1682, 1646.
1-Morpholino-2-o-tolylethane-1,2-dione (3q). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (100 mg,
86% yield): 1H NMR (CDCl3, 400 MHz) δ 7.73−7.71 (m, 1H), 7.52−
7.48 (m, 1H), 7.35−7.31 (m, 2H), 3.80−3.76 (m, 4H), 3.67 (t, J = 4.0
Hz, 2H), 3.40 (t, J = 4.0 Hz, 2H), 2.67 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 192.9, 166.0, 141.4, 133.7, 132.51, 132.48, 131.2, 126.0,
66.42, 66.39, 46.0, 41.4, 21.6; HRMS (TOF) m/z [M]+ Calcd for
C13H15NO3 233.1052, found 233.1054; IR (KBr, cm−1) ν 1673, 1629.
1-Morpholino-2-(thiophen-2-yl)ethane-1,2-dione (6a). Puri-
fied by column chromatography (EtOAc:hexane 1:5). Yellow oil (105
1
mg, 93% yield): H NMR (CDCl3, 400 MHz) δ 7.86−7.82 (m, 2H),
7.21−7.19 (m, 1H), 3.81−3.75 (m, 4H), 3.69 (t, J = 4.0 Hz, 2H), 3.50
(t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 182.7, 164.1, 140.0,
136.7, 136.1, 128.6, 66.6, 66.4, 46.2, 41.7; HRMS (TOF) m/z [M +
H]+ Calcd for C10H12NO3S 226.0532, found 226.0532; IR (KBr,
cm−1) ν 1651.
1-(5-Chlorothiophen-2-yl)-2-morpholinoethane-1,2-dione
(6b). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
1
oil (106 mg, 82% yield): H NMR (CDCl3, 400 MHz) δ 7.67 (d, J =
4.1 Hz, 1H), 7.04 (d, J = 4.1 Hz, 1H), 3.78−3.74 (m, 4H), 3.69 (t, J =
4.0 Hz, 2H), 3.53 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3,100 MHz) δ
181.2, 163.2, 142.7, 138.3, 135.9, 128.1, 66.6, 66.4, 46.3, 41.9; HRMS
(TOF) m/z [M + H]+ Calcd for C10H10ClNO3S 259.0070, found
259.0070; IR (KBr, cm−1) ν 1640.
1-Morpholino-2-(thiazol-2-yl)ethane-1,2-dione (6c). Purified
by column chromatography (EtOAc:hexane 1:5). Yellow oil (59 mg,
1
52% yield): H NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 3.0 Hz, 1H),
1-Morpholino-2-(4-nitrophenyl)ethane-1,2-dione (3l). Puri-
fied by column chromatography (EtOAc:hexane 1:5). Yellow solid (73
7.87 (d, J = 3.0 Hz, 1H), 3.84−3.78 (m, 4H), 3.71 (t, J = 4.0 Hz, 2H),
3.42 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3,100 MHz) δ 182.8, 163.8,
163.1, 146.0, 127.8, 66.34, 66.29, 46.1, 41.7; HRMS (TOF) m/z [M +
H]+ Calcd for C9H10N2O3S 226.0412, found 226.0411; IR (KBr,
cm−1) ν 1686, 1647.
1
mg, 55% yield): H NMR (CDCl3, 400 MHz) δ 8.37 (d, J = 8.0 Hz,
2H), 8.17 (d, J = 8.0 Hz, 2H), 3.83−3.81 (m, 4H), 3.70 (t, J = 4.0 Hz,
2H), 3.43 (t, J = 4.0 Hz, 2H),; 13C NMR (CDCl3, 75 MHz) δ 188.6,
163.9, 151.0, 137.3, 130.7, 124.0, 66.6, 66.4, 46.2, 41.8; HRMS (TOF)
m/z [M + H]+ Calcd for C12H13N2O5 265.0819, found 265.0824; IR
(KBr, cm−1) ν 1686, 1636.
1-(3-Bromophenyl)-2-morpholinoethane-1,2-dione (3m).
Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (112 mg, 75% yield): 1H NMR (CDCl3, 400 MHz) δ 7.98−7.95
(m, 2H), 7.67−7.64 (m, 1H), 7.55−7.51 (m, 2H), 3.82−3.77 (m, 4H),
3.66 (t, J = 4.0 Hz, 2H), 3.39 (t, J = 4.0 Hz, 2H),; 13C NMR (CDCl3,
100 MHz) δ 189.3, 164.4, 137.5, 134.6, 132.1, 130.5, 128.2, 123.1,
66.5, 66.4, 46.1, 41.5; HRMS (TOF) m/z [M]+ Calcd for
C12H1279BrNO3 297.0001, found 297.0013; C12H1281BrNO3
298.9980, found 298.9995; IR (KBr, cm−1) ν 1677, 1634.
1-(3-Ethylpyrazin-2-yl)-2-morpholinoethane-1,2-dione (6d).
Purified by column chromatography (EtOAc:hexane 1:5). Yellow oil
1
(64 mg, 51% yield): H NMR (CDCl3, 400 MHz) δ 8.71 (d, J = 2.2
Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 3.84−3.77 (m, 4H), 3.74−3.72 (m,
2H), 3.41−3.40 (m, 2H), 3.27 (q, J = 8.0 Hz, 2H), 1.35 (t, J = 8.0 Hz,
3H); 13C NMR (CDCl3,100 MHz) δ 191.5, 166.4, 160.9, 147.0, 144.0,
141.3, 66.43, 66.38, 46.1, 41.6, 28.1, 12.6; HRMS (TOF) m/z [M +
H]+ Calcd for C12H15N3O3 249.1133, found 249.1133; IR (KBr, cm−1)
ν 1701, 1643.
1-Morpholino-2-(pyridin-2-yl)ethane-1,2-dione (6e). Purified
by column chromatography (EtOAc:hexane 1:5). Yellow oil (76 mg,
69% yield): 1H NMR (CDCl3, 400 MHz) δ 8.77−8.76 (m, 1H), 8.12−
8.10 (m, 1H), 7.95−7.91 (m, 1H), 7.58−7.55 (m, 1H), 3.84−3.80 (m,
4H), 3.70 (t, J = 4.0 Hz, 2H), 3.36 (t, J = 4.0 Hz, 2H); 13C NMR
(CDCl3,100 MHz) δ 191.5, 166.3, 150.9, 149.8, 137.2, 128.1, 123.0,
66.3, 46.0, 41.4; HRMS (TOF) m/z [M + H]+ Calcd for C11H13N2O3
221.0921, found 221.0921; IR (KBr, cm−1) ν 1702, 1641.
1-Morpholino-2-(pyridin-3-yl)ethane-1,2-dione (6f). Purified
by column chromatography (EtOAc:hexane 1:5). Yellow oil (57 mg,
52% yield): 1H NMR (CDCl3, 400 MHz) δ 9.16−8.86 (m, 2H), 8.30−
8.27 (m, 1H), 7.51−7.48 (m, 1H), 3.82−3.81 (m, 4H), 3.70 (t, J = 4.0
Hz, 2H), 3.44 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ
189.3, 164.0, 154.7, 151.0, 136.6, 128.6, 123.8, 66.5, 66.4, 46.1, 41.7;
HRMS (TOF) m/z [M + H]+ Calcd for C11H13N2O3 221.0921, found
221.0918; IR (KBr, cm−1) ν 1683, 1646.
1-(3-Hydroxyphenyl)-2-morpholinoethane-1,2-dione (3n).
Purified by column chromatography (EtOAc:hexane 1:5). Yellow
1
solid (60 mg, 51% yield): H NMR (CDCl3, 400 MHz) δ 7.94 (brs,
1H), 7.43−7.41 (m, 1H), 7.36−7.29 (m, 2H), 7.09−7.06 (m, 1H),
3.81−3.77 (m, 4H), 3.66 (t, J = 4.0 Hz, 2H), 3.37 (t, J = 4.0 Hz, 2H),;
13C NMR (CDCl3,100 MHz) δ 190.9, 165.9, 157.1, 133.7, 130.3,
122.9, 121.5, 115.6, 66.5, 66.4, 46.3, 41.7; HRMS (TOF) m/z [M +
Na]+ Calcd for C12H13NNaO4 258.0737, found 258.0735; IR (KBr,
cm−1) ν 1681, 1630.
1-Morpholino-2-(3-nitrophenyl)ethane-1,2-dione (3o). Puri-
fied by column chromatography (EtOAc:hexane 1:5). Yellow solid (60
1
mg, 45% yield): H NMR (CDCl3, 400 MHz) δ 8.79−8.78 (m, 1H),
8.51−8.31 (m, 2H), 7.78−7.74 (m, 1H), 3.84−3.82 (m, 4H), 3.71 (t, J
= 4.0 Hz, 2H), 3.46 (t, J = 4.0 Hz, 2H),; 13C NMR (CDCl3,100 MHz)
δ 188.1, 163.8, 148.5, 135.1, 134.4, 130.3, 128.7, 124.4, 66.6, 66.5, 46.2,
1-Morpholino-2-(pyridin-4-yl)ethane-1,2-dione (6g). Purified
by column chromatography (EtOAc:hexane 1:5). Yellow oil (48 mg,
7162
dx.doi.org/10.1021/jo301117b | J. Org. Chem. 2012, 77, 7157−7165

The Journal of Organic Chemistry
Featured Article
1
1
43% yield): H NMR (CDCl3, 400 MHz) δ H NMR (400 MHz,
CDCl3) δ 8.89 (d, J = 5.8 Hz, 2H), 7.78 (d, J = 5.8 Hz, 2H), 3.83−3.79
(m, 4H), 3.70 (t, J = 4.0 Hz, 2H), 3.42 (t, J = 4.0 Hz, 2H); 13C NMR
(CDCl3,100 MHz) δ 189.7, 163.8, 151.2, 138.9, 122.0, 66.7, 66.6, 46.2,
41.8; HRMS (TOF) m/z [M]+ Calcd for C11H12N2O3 220.0848,
found 220.0848; IR (KBr, cm−1) ν 1675, 1643.
(m, 2H), 7.66−7.59 (m, 1H), 7.52−7.45 (m, 2H), 7.25−7.18 (m,
2.5H), 7.12−7.10 (m, 1H), 6.92−6.91 (m, 0.5H), 4.90 (s, 1.28H), 4.53
(s, 0.72H), 3.98 (t, J = 6.0 Hz, 0.7H), 3.60 (t, J = 6.0 Hz, 1.30H), 2.99
(t, J = 6.0 Hz, 0.70H), 2.84 (t, J = 6.0 Hz, 1.30H); 13C NMR (CDCl3,
100 MHz) δ 191.4, 191.2, 165.9, 165.6, 134.73, 134.68, 134.0, 133.3,
132.9, 132.8, 131.6, 131.4, 129.6, 129.5, 128.93, 128.9, 128.8, 128.7,
127.1, 126.7, 126.66, 126.5, 126.46, 125.9, 47.2, 43.4, 43.3, 39.2, 29.0,
28.1; HRMS (TOF) m/z [M + Na]+ Calcd for C17H15NNaO2
288.0995, found 288.1001; IR (KBr, cm−1) ν 1672, 1639.
1-(Benzofuran-2-yl)-2-morpholinoethane-1,2-dione (6h). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
(65 mg, 71% yield): H NMR (CDCl3, 400 MHz) δ 7.76−7.74 (m,
1
2H), 7.63−7.61 (m, 1H), 7.56−7.52 (m, 1H), 7.37−7.34 (m, 1H),
3.81−3.78 (m, 4H), 3.71 (t, J = 4 Hz, 2H), 3.54 (t, J = 4 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 179.7, 163.6, 156.4, 149.8, 129.6, 126.6,
124.4, 123.8, 118.8, 112.6, 66.7, 66.5, 46.3, 42.0; HRMS (TOF) m/z
[M + 1]+ Calcd for C14H14NO4 260, found 260; IR (KBr, cm−1) ν
1655.
1-Phenyl-2-(pyrrolidin-1-yl)ethane-1,2-dione (7a). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (74 mg,
73% yield): 1H NMR (CDCl3, 400 MHz) δ 8.00−7.98 (m, 2H), 7.66−
7.62 (m, 1H), 7.53−7.49 (m, 2H), 3.66 (t, J = 6.5 Hz, 2H), 3.42 (t, J =
6.5 Hz, 2H), 1.98−1.92 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
191.3, 164.7, 134.4, 132.5, 129.5, 128.7, 46.4, 44.9, 25.6, 23.7; ESI-MS
m/z [M + H]+ Calcd for C12H14NO2 204, found 204; IR (KBr, cm−1)
ν 1675, 1634.
N,N-Dimethyl-2-oxo-2-phenylacetamide (7b). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (57 mg,
64% yield): 1H NMR (CDCl3, 400 MHz) δ 7.95−7.93 (m, 2H), 7.66−
7.63 (m, 1H), 7.53−7.49 (m, 2H), 3.11 (s, 3H), 2.95 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 191.7, 166.9, 134.6, 132.8, 129.4, 128.9,
36.9, 33.8; HRMS (TOF) m/z [M + Na]+ Calcd for C10H11NNaO2
200.0682, found 200.0670; IR (KBr, cm−1) ν 1681, 1651.
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione (7c). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (70 mg,
64% yield): 1H NMR (CDCl3, 300 MHz) δ 7.96−7.94 (m, 2H), 7.66−
7.63 (m, 1H), 7.54−7.50 (m, 2H), 3.71 (t, J = 5.0 Hz, 2H), 3.30 (t, J =
5.0 Hz, 2H), 1.72−1.68 (m, 4H), 1.57−1.53 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 191.9, 165.4, 134.6, 133.2, 129.5, 128.9, 47.0,
42.1, 26.1, 25.4, 24.3; ESI (TOF) m/z [M + H]+ Calcd for C13H16NO2
218, found 218; IR (KBr, cm−1) ν 1671, 1645.
N,N-Dihexyl-2-oxo-2-phenylacetamide (7d). Purified by col-
umn chromatography (EtOAc:hexane 1:5). Yellow solid (144 mg, 91%
yield): 1H NMR (CDCl3, 400 MHz) δ 7.95−7.93 (m, 2H), 7.65−7.62
(m, 1H), 7.52−7.49 (m, 2H), 3.49 (t, J = 8.0 Hz, 2H), 3.15 (t, J = 8.0
Hz, 2H), 1.70−1.64 (m, 2H), 1.56−1.52 (m, 2H), 1.41−1.33 (m, 6H),
1.21−1.14 (m, 6H), 0.92 (t, J = 6.6 Hz, 3H), 0.82 (t, J = 6.6 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 191.5, 166.9, 134.4, 133.2, 129.5,
128.8, 47.5, 44.1, 31.4, 31.1, 28.4, 27.2, 26.6, 26.1, 22.5, 22.3, 13.9,
13.8; HRMS (TOF) m/z [M + Na]+ Calcd for C20H31NNaO2
340.2247, found 340.2228; IR (KBr, cm−1) ν 1682, 1644.
N,N-Dibenzyl-2-oxo-2-phenylacetamide (7e). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (148 mg,
90% yield): 1H NMR (CDCl3, 400 MHz) δ 8.01−7.99 (m, 2H), 7.67−
7.63 (m, 1H), 7.54−7.50 (m, 2H), 7.40−7.36 (m, 2H), 7.35−7.30 (m,
6H), 7.26−7.23 (m, 2H), 4.63 (s, 2H), 4.28 (s, 2H). 13C NMR
(CDCl3, 100 MHz) δ 191.2, 167.3, 135.8, 134.7, 134.6, 133.2, 129.6,
128.9, 128.8, 128.7, 128.6, 128.1, 128.0, 127.8, 50.0, 45.9; HRMS
(TOF) m/z [M + Na]+ Calcd for C22H19NNaO2 352.1308, found
352.1310; IR (KBr, cm−1) ν 1679, 1631.
N,N-Bis(2-methoxyethyl)-2-oxo-2-phenylacetamide (7h). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
(126 mg, 95% yield): H NMR (CDCl3, 400 MHz) δ 7.97−7.95 (m,
1
2H), 7.62−7.58 (m, 2H), 7.50−7.46 (m, 2H), 3.78 (t, J = 5.3 Hz, 2H),
3.66 (t, J = 5.4 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H), 3.44 (t, J = 5.4 Hz,
2H), 3.39 (s, 3H), 3.11 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ
190.7, 167.4, 134.0, 133.2, 129.6, 128.4, 70.2, 70.0, 58.5, 58.2, 47.9,
44.9; HRMS (TOF) m/z [M + Na]+ Calcd for C14H19NNaO4
288.1206, found 288.1189; IR (KBr, cm−1) ν 1679, 1641.
1-Phenyl-2-(4-(pyridin-2-yl)piperazin-1-yl)ethane-1,2-dione
(7i). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (118 mg, 80% yield): 1H NMR (CDCl3, 400 MHz) δ 8.20−8.19
(m, 1H), 7.99−7.98 (m, 2H), 7.67−7.65 (m, 1H), 7.55−7.50 (m, 3H),
6.71−6.66 (m, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H),
3.57 (t, J = 4.0 Hz, 2H), 3.49 (t, J = 4.0 Hz, 2H); 13C NMR
(CDCl3,100 MHz) δ 191.3, 165.5, 158.7, 147.9, 137.7, 134.9, 133.0,
129.6, 129.0, 114.2, 107.4, 45.47, 45.46, 45.1, 40.9; HRMS (TOF) m/z
[M + H]+ Calcd for C17H18N3O2 296.1394, found 296.1393; IR (KBr,
cm−1) ν 1678, 1641.
tert-Butyl 4-(2-oxo-2-phenylacetyl)piperazine-1-carboxylate
(7j). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (134 mg, 84% yield): 1H NMR (CDCl3, 400 MHz) δ 7.97−7.95
(m, 2H), 7.69−7.65 (m, 1H), 7.55−7.51 (m, 2H), 3.75 (t, J = 4.0 Hz,
2H), 3.56 (t, J = 4.0 Hz, 2H), 3.44 (t, J = 4.0 Hz, 2H), 3.34 (t, J = 4.0
Hz, 2H), 1.47 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 191.0, 165.4,
154.2, 134.8, 132.8, 129.5, 128.9, 80.4, 45.6, 41.0, 28.2; HRMS (TOF)
m/z [M + Na]+ Calcd for C17H22N2NaO4 341.1472, found 341.1466;
IR (KBr, cm−1) ν 1677, 1650.
1-(4-Hydroxypiperidin-1-yl)-2-phenylethane-1,2-dione (7k).
Purified by column chromatography (EtOAc:hexane 1:5). Yellow solid
1
(84 mg, 72% yield): H NMR (CDCl3, 400 MHz) δ 7.93−7.92 (m,
2H), 7.67−7.64 (m, 1H), 7.54−7.50 (m, 2H), 4.07−3.95 (m, 2H),
3.50−3.44 (m, 2H), 3.18−3.12 (m, 1H), 2.69 (brs, 1H), 1.80−1.49
(m, 4H); 13C NMR (CDCl3,100 MHz) δ 191.7, 165.4, 134.8, 132.8,
129.4, 129.0, 66.1, 43.0, 38.2; HRMS (TOF) m/z [M + H]+ Calcd for
C13H16NO3 234.1125, found 234.1120; IR (KBr, cm−1) ν 1677, 1631.
Methyl 1-(2-oxo-2-phenylacetyl)piperidine-4-carboxylate
(7l). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
solid (121 mg, 88% yield): 1H NMR (CDCl3, 400 MHz) δ 7.95−7.93
(m, 2H), 7.67−7.63 (m, 1H), 7.54−7.50 (m, 2H), 4.46−4.43 (m, 1H),
3.69 (s, 3H), 3.58−3.55 (m, 1H), 3.13−3.06 (m, 2H), 2.66−2.61 (m,
1H), 2.06−2.04 (m, 1H), 1.91−1.68 (m, 3H); 13C NMR (CDCl3,100
MHz) δ 191.4, 173.9, 165.2, 134.7, 132.8, 129.3, 128.9, 51.8, 45.0,
40.3, 40.2, 28.0, 27.4; HRMS (TOF) m/z [M + H]+ Calcd for
C15H18NO4 276.1230, found 276.1230; IR (KBr, cm−1) ν 1733, 1679,
1642.
N-Isopropyl-2-oxo-2-phenylacetamide (8a). Methyl ketones
(0.5 mmol), amines (2.0 mmol), I2 (0.25 mmol, 50 mol %), TBHP
(6.0 equiv, 70% aqueous solution 401 uL), and 2.0 mL of iPrOH, were
added to a tube under air. The reaction mixture was stirred at 0 °C for
13 h. The reaction mixture was quenched with saturated Na2S2O3
solution, extracted repeatedly with ethyl acetate, and dried over
Na2SO4. Then, removal of the organic solvent in a vacuum followed by
flash silica gel column chromatographic purification afforded product
(70 mg, 73% yield) as yellow solid with EtOAc/hexane (1:5) mixtures:
1H NMR (CDCl3, 400 MHz) δ 8.32−8.30 (m, 2H), 7.62−7.58 (m,
N-Benzyl-N-methyl-2-oxo-2-phenylacetamide (7f). Purified
by column chromatography (EtOAc:hexane 1:5). Yellow solid (85
1
mg, 67% yield): H NMR (CDCl3, 400 MHz) δ 8.00−7.95 (m, 2H),
7.64−7.60 (m, 1H), 7.51−7.47 (m, 2H), 7.37−7.36 (m, 2H), 7.32−
7.24 (m, 3H), 4.72 (s, 1.08 H), 4.37 (s, 0.91 H), 2.98 (s, 1.37 H), 2.82
(s, 1.63 H). 13C NMR (CDCl3, 100 MHz) δ 191.4, 191.3, 167.1,
166.9, 135.5, 134.7, 134.6, 134.6, 132.9, 132.8, 129.5, 129.4, 128.9,
128.8, 128.6, 128.6, 128.1, 128.0, 127.7, 127.6, 53.2, 49.5, 34.2, 31.1;
HRMS (TOF) m/z [M + Na]+ Calcd for C16H15NNaO2 276.0995,
found 276.1012; IR (KBr, cm−1) ν 1681, 1645.
1H), 7.47 −7.43 (m, 2H), 7.05 (s, 1H), 4.22−4.10 (m, 1H), 1.25 (d, J
= 6.9 Hz, 3H). 13C NMR (CDCl3,75 MHz) δ 188.0, 160.9, 134.2,
133.3, 131.0, 128.3, 41.6, 22.3; ESI-MS m/z [M + H]+ Calcd for
C11H14NO2 192, found 192; IR (KBr, cm−1) ν 1671,1643.
tert-Butyl 4-(2-oxo-2-phenylacetyl)piperazine-1-carboxylate
(7g). Purified by column chromatography (EtOAc:hexane 1:5). Yellow
1
solid (81 mg, 61% yield): H NMR (CDCl3, 400 MHz) δ 7.99−7.93
7163
dx.doi.org/10.1021/jo301117b | J. Org. Chem. 2012, 77, 7157−7165

The Journal of Organic Chemistry
Featured Article
N-Benzyl-2-oxo-2-phenylacetamide (8b). Purified by column
chromatography (EtOAc:hexane 1:5). Yellow solid (78 mg, 65%
yield): 1H NMR (CDCl3, 400 MHz) δ 8.33−8.31 (m, 2H), 7.62−7.58
(m, 1H), 7.52 (s, 1H), 7.47−7.43 (m, 2H), 7.35−7.28 (m, 5H), 4.54
(d, J = 6.1 Hz, 2H). 13C NMR (CDCl3,75 MHz) δ 187.5, 161.6, 137.0,
134.4, 133.2, 131.1, 128.7, 128.4, 127.8, 127.7, 43.4; ESI-MS m/z [M +
H]+ Calcd for C15H14NO2 240, found 240; IR (KBr, cm−1) ν
1683,1648.
1-(4-Bromophenyl)-2-iodoethanone (5). A mixture of 1-(4-
bromophenyl)ethanone (1 mmol), CuO (1 equiv), and iodine (1
equiv) in methanol was heated at 65 °C for 1 h. Removal of the
organic solvent in a vacuum followed by flash silica gel column
chromatographic purification afforded product (292 mg, 90% yield) as
colorless solid with EtOAc/hexane (1:20) mixtures: 1H NMR (CDCl3,
400 MHz) δ 7.85 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 4.32 (s,
2H); 13C NMR (CDCl3,100 MHz) δ 191.8, 132.13, 132.08, 130.5,
129.1, 1.2; ESI-MS m/z [M + H]+ Calcd for C8H779BrIO 325, found
325; C8H781BrIO 327, found 327; IR (KBr, cm−1) ν 1688.
N-(2-Cyclohexenylethyl)-2-oxo-2-phenylacetamide (8c). Pu-
rified by column chromatography (EtOAc:hexane 1:5). Yellow solid
1
(70 mg, 54% yield): H NMR (CDCl3, 400 MHz) δ 8.32−8.30 (m,
2H), 7.63−7.59 (m, 1H), 7.48−7.45 (m, 2H), 7.13 (s, 1H), 5.51 (t, J =
3.7 Hz, 1H), 3.49−3.44 (m, 2H), 2.22 (t, J = 6.8 Hz, 2H), 2.01−1.96
(m, 4H), 1.64−1.53 (m, 4H). 13C NMR (CDCl3,75 MHz) δ 187.8,
161.7, 134.2, 133.9, 133.2, 131.0, 128.3, 123.9, 37.2, 37.1, 27.8, 25.1,
22.7, 22.2; ESI-MS m/z [M + H]+ Calcd for C16H20NO2 258, found
258; IR (KBr, cm−1) ν 1665.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
N-Cyclohexyl-2-oxo-2-phenylacetamide (8d). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (46 mg,
40% yield): 1H NMR (CDCl3, 300 MHz) δ 8.32−8.29 (m, 2H), 7.59−
7.57 (m, 1H), 7.47−7.43 (m, 2H), 7.08 (s, 1H), 3.87−3.84 (m, 1H),
1.99−1.95 (m, 2H), 1.76−1.62 (m, 3H), 1.38−1.21 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 188.1, 160. 9, 134.1, 133.3, 131.0, 128.3,
48.3, 32.5, 25.2, 24.6; ESI-MS m/z [M + H]+ Calcd for C14H18NO2
232, found 232; IR (KBr, cm−1) ν 1666.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wanxb@suda.edu.cn.
■
ACKNOWLEDGMENTS
■
A Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions
(PAPD). This research was also supported by the National
Natural Science Foundation of China (21072142). Prof. Dr. H.
Hu is grateful to Jiangsu Province NSF (No. BK2011408) and
Jiangsu Province Department of Education (No.
10KJB150002) for their financial support.
N-Butyl-2-oxo-2-p-tolylacetamide (8e). Purified by column
chromatography (EtOAc:hexane 1:5). Yellow solid (70 mg, 64%
1
yield): H NMR (CDCl3, 300 MHz) δ 8.24 (d, J = 8.0 Hz, 2H), 7.26
(d, J = 8.0 Hz, 2H), 7.20 (s, 1H), 3.41−3.37 (m, 2H), 2.41 (s, 3H),
1.60−1.56 (m, 2H), 1.43−1.36 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 187.4, 162.0, 145.4, 131.2, 130.8, 129.1,
39.0, 31.2, 21.7, 20.0, 13.6; ESI-MS m/z [M + H]+ Calcd for
C13H18NO2 220, found 220; IR (KBr, cm−1) ν 1679.
N-Butyl-2-(3-methoxyphenyl)-2-oxoacetamide (8f). Purified
REFERENCES
■
by column chromatography (EtOAc:hexane 1:5). Yellow solid (79 mg,
1
(1) (a) Serullas, G. Ann. Chim. 1822, 20, 165. (b) Fuson, R. C.; Bull,
B. A. Chem. Rev. 1934, 15, 275.
(2) For recent reviews on this topic, see: (a) Li, C.-J. Acc. Chem. Res.
2009, 42, 335. (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010,
46, 677. (c) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110,
681. (d) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
67% yield): H NMR (CDCl3, 400 MHz) δ 7.95−7.93 (m, 1H), 7.81
(s, 1H), 7.38−7.34 (m, 1H), 7.24 (s, 1H), 7.17−7.14 (m, 1H), 3.84 (s,
3H), 3.40−3.35 (m, 2H), 1.62−1.54 (m, 2H), 1.44−1.35 (m, 2H),
0.94 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.6, 161.9,
159.3, 134.4, 129.3, 123.9, 121.1, 114.5, 55.2, 39.0, 31.2 19.9, 13.5;
ESI-MS m/z [M + H]+ Calcd for C13H18NO3 236, found 236; IR
(KBr, cm−1) ν 1662.
́
110, 624. (e) Coperet, C. Chem. Rev. 2010, 110, 656. (f) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g) Mkhalid, I. A. I.;
Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev.
2010, 110, 890. (h) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704. (i) Gunay, A.; Theopold, K. H. Chem. Rev.
2010, 110, 1060. (j) Balcells, D.; Colt, E.; Eisenstein, O. Chem. Rev.
2010, 110, 749. (k) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(m) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (n) Le
Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (o) Ackermann, L.
Chem. Rev. 2011, 111, 1315.
(3) For selected examples, see: (a) Ocain, T. D.; Rich, D. H. J. Med.
Chem. 1992, 35, 451. (b) Knust, H.; Nettekoven, M.; Pinard, E.;
Roche, O.; Rogers-Evans, M. PCT Int. Appl. WO 2009016087, 2009.
(c) Sheha, M. M.; Mahfouz, N. M.; Hassan, H. Y.; Youssef, A. F.;
Mimoto, T.; Kiso, Y. Eur. J. Med. Chem. 2000, 35, 887.
(4) For selected examples, see: (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) Sai, K. K. S.; Esteves, P. M.; da
Penha, E. T.; Klumpp, D. A. J. Org. Chem. 2008, 73, 6506. (d) Tomita,
D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 6946. (e) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J.
Am. Chem. Soc. 2009, 131, 10390. (f) Xu, H.; Wolf, C. Angew. Chem.,
Int. Ed. 2011, 50, 12249. (g) Wang, R.; Chen, C.; Duesler, E.; Mariano,
P. S; Yoon, U. C. J. Org. Chem. 2004, 69, 1215.
(5) (a) Chen, J.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509.
(b) Murata, S.; Suzuki, K.; Miura, M.; Nomura, M. J. Chem. Soc., Perkin
Trans. 1 1990, 361. (c) Singh, R. P.; Shreeve, J. M. J. Org. Chem. 2003,
68, 6063.
N-Butyl-2-(4-fluorophenyl)-2-oxoacetamide (8g). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (72 mg,
1
64% yield): H NMR (CDCl3, 300 MHz) δ 8.44 (d, J = 6.2 Hz, 2H),
7.22 (s, 1H), 7.15 (d, J = 6.2 Hz, 2H), 3.40−3.38 (m, 2H), 1.59−1.57
(m, 2H), 1.41−1.39 (m, 2H), 0.95 (t, J = 7.9 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 186.0, 168.2, 164.8, 161.5, 134.2, 134.1, 129.8,
115.8, 115.5, 39.1, 31.2, 20.0, 13.6; ESI-MS m/z [M + H]+ Calcd for
C12H15FNO2 224, found 224; IR (KBr, cm−1) ν 1656.
N-Butyl-2-oxo-2-(thiophen-2-yl)acetamide (8h). Purified by
column chromatography (EtOAc:hexane 1:5). Yellow solid (67 mg,
1
63% yield): H NMR (CDCl3, 300 MHz) δ 8.41 (d, J = 2.7 Hz, 1H),
7.83 (d, J = 2.7 Hz, 1H), 7.36 (s, 1H), 7.20−7.18 (m, 1H), 3.42−3.36
(m, 2H), 1.60−1.55 (m, 2H), 1.44−1.36 (m, 2H), 0.95 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 178.4, 160.6, 138.5, 137.8, 136.6,
128.0, 39.2, 31.1, 19.9, 13.6; ESI-MS m/z [M + H]+ Calcd for
C12H14NO2S 212, found 212; IR (KBr, cm−1) ν 1685, 1648.
1-(4-Bromophenyl)-2-morpholinoethanone (4). A mixture of
2-bromo-1-(4-bromophenyl)ethanone (1 mmol), morpholine (2
equiv) in dichloromethane was heated at 25 °C for 6 h. Removal of
the organic solvent in a vacuum followed by flash silica gel column
chromatographic purification afforded product (260 mg, 92% yield) as
1
yellow solid with EtOAc/hexane (1:5) mixtures: H NMR (CDCl3,
400 MHz) δ 7.89 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 3.77 (t,
J = 4.0 Hz, 4H), 3.76 (s, 2H), 2.60 (t, J = 4.0 Hz, 4H); 13C NMR
(CDCl3,100 MHz) δ 195.2, 134.5, 131.8, 129.7, 128.5, 66.7, 64.8, 53.8;
HRMS (TOF) m/z [M + H]+ Calcd for C12H1579BrNO2 284.0281,
found 284.0281; C12H1581BrNO2 284.0266, found 286.0262; IR (KBr,
cm−1) ν 1689.
7164
dx.doi.org/10.1021/jo301117b | J. Org. Chem. 2012, 77, 7157−7165

The Journal of Organic Chemistry
Featured Article
(6) (a) Kobayashi, T.; Tanaka, M. J. Organomet. Chem. 1982, 233,
C64. (b) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino,
H.; Izawa, K.; Yamamoto, T.; Yamamoto, A. J. Am. Chem. Soc. 1985,
107, 3235. (c) Mizushima, E.; Hayashi, T.; Tanaka, M. Green Chem.
2001, 3, 76. (d) Tsukada, N.; Ohba, Y.; Inoue, Y. J. Organomet. Chem.
2003, 687, 436. (e) Iizuka, M.; Kondo, Y. Chem. Commun. 2006, 1739.
(f) Rahman, Md. T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I.
Chem. Commun. 2006, 2236. (g) Murphy, E. R.; Martinelli, J. R.;
Zaborenko, N.; Buchwald, S. L.; Jensen, K. F. Angew. Chem., Int. Ed.
2007, 46, 1734. (h) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org.
Lett. 2009, 11, 1321. (i) de la Fuente, V.; Godard, C.; Zangrando, E.;
Lett. 2012, 14, 3384. (o) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang,
Z. Angew. Chem., Int. Ed. 2012, 51, 8077.
(17) For iminium intermediate generated in situ from amine in the
presence of TBHP, see: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126,
11810. (b) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (c) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 3672. (d) Li, Z.; Li, C.-J. Eur. J. Org. Chem.
2005, 3173.
(18) For nucleophilic attack of iminium intermediate by H2O, see:
(a) Dotzauer, M.; Eisfeld, W.; Vilsmaier, E.; Frohlich, K.; Bergstrasser,
̈
̈
U.; Tetzlaff, C. J. Org. Chem. 1996, 61, 8526. (b) Yin, W.; Mitra, K.;
Stearns, R. A.; Baillie, T. A.; Kumar, S. Biochemistry 2004, 43, 5455.
(c) Wang, J.; Xu, H.; Gao, H.; Su, C.-Y.; Zhao, C.; Phillips, D. L.
́
Claver, C.; Castillon, S. Chem. Commun. 2012, 48, 1695.
Organometallics 2010, 29, 42. (d) Basle,
10, 3661.
́
O.; Li, C.-J. Org. Lett. 2008,
(7) (a) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 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) Zhang,
C.; Zong, X.; Zhang, L.; Jiao, N. Org. Lett. 2012, 14, 3280.
(19) For oxidation of α-hydroxy amine, see: (a) Tillack, A.; Rudloff,
I.; Beller, M. Eur. J. Org. Chem. 2001, 523. (b) Yoo, W.-J.; Li, C.-J. J.
Am. Chem. Soc. 2006, 128, 13064. (c) Ekoue-Kovi, K.; Wolf, C. Org.
Lett. 2007, 9, 3429. (d) Reddy, K. R.; Maheswari, C. U.; Venkateshwar,
M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 3619.
(20) For hydroxide anion generated in situ from TBHP, see:
(a) Kharasch, M. S.; Pauson, P.; Nudenberg, W. J. Org. Chem. 1953,
18, 322. (b) Barton, D. H. R.; Le Gloahec, V. N.; Patin, H.; Launay, F.
New J. Chem. 1998, 559. (c) Jones, C. M.; Burkitt, M. J. J. Am. Chem.
Soc. 2003, 125, 6946. (d) McLaughlin, E. C.; Choi, H.; Wang, K.;
Chiou, G.; Doyle, M. P. J. Org. Chem. 2009, 74, 730.
(8) (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44, 8873.
́
(b) El Kaïm, L.; Pinot-Perigord, E. Tetrahedron 1998, 54, 3799.
(c) Grassot, J.-M.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47,
947.
(9) (a) See ref 3a. (b) Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy,
O. E. Org. Lett. 2000, 2, 2769. (c) Banfi, L.; Guanti, G.; Riva, R. Chem.
Commun. 2000, 985. (d) Chiou, A.; Markidis, T.; Constantinou-
Kokotou, V.; Verger, R.; Kokotos, G. Org. Lett. 2000, 2, 347.
(e) Nakamura, M.; Inoue, J.; Yamada, T. Bioorg. Med. Chem. Lett.
2000, 10, 2807. (f) Xu, P.; Lin, W.; Zhou, X. Synthesis 2002, 1017.
(10) (a) Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1982, 104,
4446. (b) Papanikos, A.; Rademann, J.; Medal, M. J. Am. Chem. Soc.
2001, 123, 2176. (c) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J.
Am. Chem. Soc. 2006, 128, 87.
(11) (a) Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. Chem. Lett.
1983, 859. (b) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. Org. Lett. 2002, 4, 1103. (c) Zhu, J.; Wong, H.; Zhang, Z.;
Yin, Z.; Kadow, J. F.; Meanwell, N. A.; Wang, T. Tetrahedron Lett.
2005, 46, 3587.
(12) (a) Wasserman, H. H.; Ho, W. B. J. Org. Chem. 1994, 59, 4364.
(b) Wasserman, H. H.; Petersen, A. K.; Xia, M. Tetrahedron 2003, 59,
6771.
(13) (a) Padwa, A.; Koehler, K. F. J. Chem. Soc., Chem. Commun.
1986, 789. (b) Konstantinova, L. S.; Bol’shakov, O. I.; Obruchnikova,
N. V.; Golova, S. P.; Nelyubina, Y. V.; Lyssenko, K. A.; Rakitin, O. A.
Tetrahedron 2010, 66, 4330.
(14) (a) Rehwald, M.; Gewald, K.; Lankau, H.-J.; Unverferth, K.
Heterocycles 1997, 45, 483. (b) Ji, M.; Chen, J.; Ding, K.; Wu, X.;
Varady, J.; Levantb, B.; Wang, S. Bioorg. Med. Chem. Lett. 2005, 15,
1701.
(15) (a) Hong, R.; Feng, J.; Hoen, R.; Lin, G.-q. Tetrahedron 2001,
57, 8685. (b) Chen, H.-R.; Guo, X.-K.; Zhong, X.-B. Chin. J. Chem.
2006, 24, 1411.
(16) Recently, we and others reported metal free oxidation reaction
using TBHP, see: (a) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li,
H.; Xu, K.; Wan, X. Chem.Eur. J. 2011, 17, 4085. (b) Uyanik, M.;
Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50,
5331. (c) Froehr, T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.;
Nachtsheim, B. J. Org. Lett. 2011, 13, 3754. (d) Wei, W.; Zhang, C.;
Xu, Y.; Wan, X. Chem. Commun. 2011, 47, 10827. (e) Ma, L.; Wang,
X.; Yu, W.; Han, B. Chem. Commun. 2011, 47, 11333. (f) Tang, R.-Y.;
Xie, Y.-X.; Xie, Y.-L.; Xiang, J.-N.; Li, J.-H. Chem. Commun. 2011, 47,
12867. (g) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2012,
48, 979. (h) Chen, S.; Xu, Y.; Wan, X. Org. Lett. 2011, 13, 6152.
(i) Kloeckner, U.; Weckenmann, N. M.; Nachtsheim, B. J. Synlett
2012, 97. (j) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Shu, W.-M.;
Zhang, D.-X.; Cao, L.-P.; She, N.-F.; Wu, A.-X. Org. Lett. 2010, 12,
4026. (k) Xue, W.-J.; Li, Q.; Zhu, Y.-P.; Wang, J.-G.; Wu, A.-X. Chem.
Commun. 2012, 48, 3485. (l) Zhu, Y.-p.; Liu, M.-c.; Jia, F.-c.; Yuan, J.-
j.; Gao, Q.-h.; Lian, M.; Wu, A.-x. Org. Lett. 2012, 14, 3392. (m) He,
T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011, 13, 5016.
(n) Shi, E.; Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.; Wan, X. Org.
7165
dx.doi.org/10.1021/jo301117b | J. Org. Chem. 2012, 77, 7157−7165