Novel Synthesis of α-Keto Esters and Amides by an sp3 C-H Oxidation of Nitromethyl Aryl Ketones Promoted by Ion-Supported (Diacetoxyiodo)benzene

Article abstract of DOI:10.1055/s-0035-1562535

A simple and efficient method is described for the preparation of α-keto esters or amides from nitromethyl aryl ketones. In the presence of nucleophiles (alcohols or amines), the ion-supported (di-acetoxyiodo)benzene-promoted sp³ C-H oxidation of nitromethyl aryl ketones proceeded efficiently under mild conditions to give the corresponding α-keto esters and amides in moderate to good yields. This is the first reported use of (diacetoxyiodo)benzene in the synthesis of α-keto esters and amides. The reaction is ecofriendly and has the -advantages of mild conditions, short reaction times, and a recyclable reagent.

Full text of DOI:10.1055/s-0035-1562535

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Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
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Synlett
X. Jiang et al.
Letter
3
Novel Synthesis of α-Keto Esters and Amides by an sp C–H Oxida-
tion of Nitromethyl Aryl Ketones Promoted by Ion-Supported
(
Diacetoxyiodo)benzene
Xiaoying Jiang
Bing Gan
BF4
N
N
O
O
Jiwei Liu
NO2
I(OAc)2
Nu
Yuanyuan Xie*
R1
+ NuH
R1
solvent, reflux
O
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of
China
NuH = ROH, RNH2, R2NH
18 examples
up to 88% yield
xyycz@zjut.edu.cn
Received: 29.05.2016
Accepted after revision: 23.07.2016
Published online: 05.08.2016
use of Grignard reagents. Phosphoranes have been applied
as carbonyl 1,1-dipole synthons to form α-keto esters and
amides.16 A double carbonylation of diaryliodonium salts to
DOI: 10.1055/s-0035-1562535; Art ID: st-2016-w0368-l
17
give α-keto amides was reported by Zhou and Chen.
Abstract A simple and efficient method is described for the prepara-
tion of α-keto esters or amides from nitromethyl aryl ketones. In the
presence of nucleophiles (alcohols or amines), the ion-supported (di-
Oxidation with organometallic reagents has become
very important in contemporary organic synthesis. Copper-
18
3
catalyzed oxidation of acetophenone, rhodium-catalyzed
acetoxyiodo)benzene-promoted sp C–H oxidation of nitromethyl aryl
19
ketones proceeded efficiently under mild conditions to give the corre-
sponding α-keto esters and amides in moderate to good yields. This
is the first reported use of (diacetoxyiodo)benzene in the synthesis of
α-keto esters and amides. The reaction is ecofriendly and has the
advantages of mild conditions, short reaction times, and a recyclable
reagent.
oxidation of cyanoformate, selenium dioxide oxidation of
20
arylglyoxals,
palladium-catalyzed oxidation of cyana-
21
mides, and iron-catalyzed oxidation of α-keto alcohols or
α-keto acids,22 can all give the corresponding α-keto esters
and amides. However, these methods normally require
harsh reaction conditions, laborious procedures, and ex-
pensive, poisonous, or air-sensitive reagents. Consequently,
attention has increasingly been focused on metal-free reac-
Key words keto esters, keto amides, diacetoxyiodobenzene, ni-
tromethyl aryl ketones, oxidation
16b
23
tions, such as those using dimethyldioxirane,
TBAI,
I2/DMSO,24 TEMPO, oxone/AlCl3, and KI/O2 , all of which
have been successfully applied to the synthesis of α-keto
esters and amides.
25
26
27
Bifunctional α-keto esters and amides are ubiquitous
structural motifs in many biological active substances. Be-
cause of their specific structures, they show promising in-
1
hibition of proteolytic enzymes such as human renin,
Nowadays, organohypervalent iodine reagents play an
important role in organic syntheses. In this context, (diacet-
oxyiodo)benzene (DIB) is a useful and popular reagent that
has the advantages of mild reaction conditions and high se-
lectivity and is environmentally benign.28 Ionic liquids have
been widely used as reaction media due to their intriguing
properties, such as nonvolatility, high thermal stability,
negligible vapor pressure, high loading capacity, and tun-
able polarity.29 By combining the merits of both DIB and
ionic liquids, we developed a metal-free reaction in the
2
3
4
thrombin, histone deacetylase, cysteine proteases, tyro-
5
6
7
sine phosphatases, neutrophil elastase, serine protease,
and pancreatic lipase.8 Consequently, they can possess a
range of pharmacological effects, including antihyperten-
1,2
3
9
6,10
sion, anticancer, antiparasitic, antiinflammatory,
and
11,12
antiviral activities.
Furthermore, α-keto esters and am-
ides are important and versatile intermediates in organic
syntheses and drug development, and they can be readily
reduced to form biologically active chiral α-hydroxy es-
13
14
+
–
ters or α-amino acids, respectively.
presence of ion-supported DIB ([dibmim] [BF ] ; Figure 1)
4
Because of the significance of α-keto esters and amides,
numerous methods have been reported for their synthesis.
Rambaud et al. reported a synthesis of α-keto esters by
that provides a convenient protocol for the preparation of
α-keto esters and amides from nitromethyl aryl ketones.
15
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Synlett
X. Jiang et al.
Letter
or oxygen (entries 9 and 10) were the same as that under
air. We then examined whether the addition of water and a
base (NaOH, NaHCO , Na CO , or Et N) might improve the
BF4
N
N
3
2
3
3
I(OAc)2
+
dibmim] [BF4]–
yield, but no positive results were obtained. Other nucleo-
philes (apart from methanol) were not suitable solvents
because of the poor solubility of the raw materials and
[
+
–
Figure 1 Structure of ion-supported DIB {[dibmim] [BF ] }
4
+
–
[
dibmim] [BF ] in these solvents. We therefore examined
4
Initially, we chose 2-nitro-1-phenylethanone (1a) as a
the effects of various solvents when the nucleophile was
benzyl alcohol (5 equiv) (entries 11–17). Dichloromethane
was identified as the best solvent, affording benzyl
oxo(phenyl)acetate (3p) in 73% yield with an extended reac-
tion time of two hours. On the basis of the above results,
the optimal conditions for the conversion of nitromethyl
aryl ketones (0.5 mmol) into α-keto esters or amides were
model substrate to optimize the reaction conditions. First,
+
–
we examined the effect of the quantity of [dibmim] [BF ]
4
in ethanol (8 mL) as both solvent and nucleophile at reflux
temperature (Table 1, entries 1–4). The yield of ethyl
oxo(phenyl)acetate (3a) increased markedly from 46% to
+
–
8
8% when the amount of [dibmim] [BF ] was increased to
4
+
–
three equivalents (entry 3), but no further increase was ob-
determined to be [dibmim] [BF ] (3 equiv) and nucleophile
4
+
–
served when more [dibmim] [BF ] was added (entry 4).
(5 equiv) in refluxing CH Cl (8 mL). Methanol or ethanol
4
2
2
The effects of the reaction temperature and time were also
investigated (entries 5–8). The best yield of product 3a was
obtained in the reaction carried out at reflux for one hour.
Next, the effects of various gaseous atmospheres were ex-
amined. However, the yields of 3a obtained under nitrogen
can serve as both nucleophile and solvent.
Having determined the optimal conditions, we investi-
gated the reactions of various nitromethyl aryl ketones (1)
and nucleophiles (alcohols or amines) to probe the general-
ity of our system (Table 2). All nitromethyl aryl ketones
Table 1 Optimization of the Reaction Conditions a
O
O
BF4
NO2
N
Nu
NuH
N
+
solvent
O
I(OAc)2
1a
2
3
NuH = ROH, RNH2, R2NH
+
]–(equiv) NuH
b
Entry
[dibmin] [BF
4
Solvent
Temp (°C)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9c
1
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
toluene
MeCN
THF
reflux
reflux
reflux
reflux
0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3p
3p
3p
3p
3p
3p
3p
46
75
EtOH
88
EtOH
82
EtOH
trace
55
EtOH
25
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
73
EtOH
83
EtOH
88
1
1
1
1
1
1
1
1
0d
1
2
3
4
5
6
7
EtOH
87
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
–, NuH, solvent.
trace
trace
–
THF + H
2
O (0.5mL)
–
acetone
54
CH
2
Cl
2
2
68
CH
2
Cl
73
a
b
c
+
Reaction conditions: 1a, [dibmim] [BF]
Yield of isolated and purified product.
Under O .
2
2
Under N .
4
d
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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Synlett
X. Jiang et al.
Letter
were transformed into α-keto esters in moderate to good
yields (Table 2, entries 1–9). Substituted nitromethyl aryl
ketones gave similar yields of the corresponding α-keto es-
ters whether the substituent group was in the ortho, meta,
or para position of the phenyl ring (entries 2–4). Further-
more, electronic effects had little influence on the transfor-
mation; substrates with electron-withdrawing substituents
or electron-donating substituents afforded products in
good yields (entries 4–9). A substrate with a heteroaromatic
substituent (1-furyl) gave a lower yield of the correspond-
ing product (entry 10). However, compared with ni-
tromethyl aryl ketones, the reactions of an aliphatic α-nitro
ketone gave an inferior result (entry 11). Next, we investi-
gated the reactions of other nucleophiles such as methanol,
A plausible mechanism for the formation of α-keto es-
ters and amides is proposed in Scheme 1. On the addition of
+
–
[dibmim] [BF ] , the enol tautomer 4 is initially trans-
4
formed into intermediate 5, which generates intermediate 6
by releasing acetic acid and ion-supported iodobenzene. In-
+
–
termediate 6 is then oxidized by [dibmim] [BF ] to form in-
4
termediate 7. Likewise, intermediate 7 loses acetic acid and
ion-supported iodobenzene to give α-nitro diketone 8. This
is subsequently attacked by nucleophiles to give the α-keto
esters or amides 3 via intermediate 9.
The ion-supported iodobenzene generated from this re-
action could be readily recycled and reused to form more
+
–
[dibmim] [BF ] . When the oxidation reaction was com-
4
plete, hexane was added to the reaction mixture, and ion-
supported iodobenzene was precipitated with a recovery
rate of up to 86%. The recovered ion-supported iodoben-
zene was oxidized by peroxyacetic acid to regenerate [dib-
BuOH, t-BuOH, BnOH, BuOH, and Et N, all of which gave the
2
desired products in yields of 57–87% (entries 12–18). Di-
ethylamine, however, gave a poor yield of product 3r, which
was difficult to separate and purify (entry 18).
+
–
mim] [BF ] , which was then reused in the oxidation of α-
4
nitro ketones 1 (Table 2, entries 1, 7, and 12).
Table 2 Synthesis of α-Keto Esters and Amidesa,30
In conclusion, we have developed an ecofriendly meth-
od for the syntheses of α-keto esters and amides in moder-
ate to good yields by oxidation of nitromethyl aryl ketones
BF4
O
O
N
NuH
+
–
NO2
N
Nu
with [dibmim] [BF ] . Ion-supported iodobenzene, a by-
4
R1
R1
+
solvent
+
–
I(OAc)2
product derived from [dibmim] [BF ] in the oxidative reac-
4
O
1
2
3
tion, could be recovered in good yield, reoxidized, and re-
used in syntheses of α-keto esters and amides. The method
is therefore environmentally benign, with the advantages of
mild reaction conditions, short reaction times, a recyclable
oxidative reagent, and high atom-efficiency.
Entry R1
Timeb
h)
NuH
Solvent
Product Yield (%)
c
(
1
2
3
4
5
6
7
8
9
Ph
1.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
3a
3b
3c
3d
3e
3f
88 (87)d
82
2-MeC
3-MeC
4-MeC
6
H
H
H
4
4
4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
BuOH
BuOH
t-BuOH
BnOH
6
6
79
Acknowledgment
83
We are grateful to the National Natural Science Foundation of China
4-MeOC
4-BrC
4-O NC
4-t-BuC
6
H
4
76
(No. 21576239) and Qianjiang Talent Project of Science Technology
6
H
4
84
Department of Zhejiang Province (No. 2013R10059) for financial sup-
port.
2
6
H
4
4
3g
3h
3i
86 (84)d
82
6
H
3,4-Me
2-furyl
2
C
6
H
3
77
Supporting Information
1
0
1
2
3
4
5
6
7
8
3j
61
Supporting information for this article is available online at
1
1
1
1
1
1
1
PhCH
2
CH
2
3k
3l
80
http://dx.doi.org/10.1055/s-0035-1562535.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
Ph
87 (87)d
70
Ph
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
3m
3n
3o
3p
3q
3r
Primary Data
4-O
Ph
2
NC
6
H
4
78
68
Primary Data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000083 and can
Ph
73
be cited using the following DOI: 10.4125/pd0081th.
Pr
i
m
a
r
yD
a
t
a
P
r
i
m
a
r
yD
a
t
a
1
0
.
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d
0
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8
1
t
h.
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r
i
m
a
r
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a
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a
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i
s
t
r
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Ph
BuNH
Et NH
2
67
1
4-ClC
6
H
4
2
CH
57
a
+
]– (3 equiv), nucleophile
Reaction conditions: 1 (0.5 mmol), [dibmim] [BF
4
References and Notes
(
5 equiv), solvent (8 mL), reflux.
b
c
Time for the reaction to reach completion.
Yield of isolated and purified product.
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d
+
–
Yield with recycled [dibmim] [BF
4
] .
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Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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X. Jiang et al.
Letter
O
O
Nu
NO2
R1
R1
–
HNO2
O
3
O
1
NuH = ROH, RNH2, R2NH
H
O
NO2
BF4
R1
NO2
O
H
R1
N
Nu
N
4
AcO
9
I
2
–
AcOH
OAc
O
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–OAc
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NO2
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–OAc
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H+
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NO2
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NO2
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R1
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I
BF4
– AcOH
2
O2N
OAc
6
O
7
–
AcOH
H
–OAc
Scheme 1 Proposed mechanism for the formation of α-keto esters and amines
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(30) α-Keto Esters 3; General Procedure
+
–
Nitromethyl aryl ketone
1
(0.5 mmol), [dibmim] [BF ]
4
(1.5mmol), and the appropriate nucleophile (5 equiv) were dis-
solved in the appropriate solvent (8 mL), and the mixture was
stirred and refluxed for 1 or 2 h. When the reaction was com-
plete (TLC), hexane (40 mL) was added to precipitate ion-sup-
ported iodobenzene as a white solid that was collected by filtra-
15) Rambaud, A.; Bakasse, M.; Duguay, G.; Villieras, J. Synthesis
1
988, 564.
16) (a) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59, 4364.
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001, 66, 3606. (c) Lee, K. Bull. Korean Chem. Soc. 2010, 31, 2776.
(
2
tion and dried [yield: 0.50 g (86%)]. The filtrate was
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
Synlett
X. Jiang et al.
Letter
concentrated under vacuum, and the residue was purified by
chromatography [silica gel, PE–EtOAc (20:1)].
2 H), 7.63–7.67 (m, 1 H), 7.98–8.01 (m, 2 H). 13C NMR (100 MHz,
CDCl ): δ = 14.2, 62.3, 128.7, 129.8, 132.3, 134.7, 163.6, 186.1.
3
+
Ethyl Oxo(phenyl)acetate (3a)
Yellow oil; yield: 78 mg (88%); H NMR (400 MHz, CDCl ): δ =
ESI-HRMS: m/z [M + Na] calcd for C10H10NaO : 201.0522;
3
1
found: 201.0250.
3
1.43 (t, J = 7.2 Hz, 3 H), 4.46 (q, J = 7.2 Hz, 2 H), 7.50 (t, J = 8.0 Hz,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E