Metal free amide synthesis via carbon-carbon bond cleavage

Article abstract of DOI:10.1016/j.tet.2014.11.003

A metal-free oxidative coupling of methyl ketones and primary amines to amides has been developed. The reaction tolerates a variety of functional groups, and is operationally simple. The reaction is proposed to go through a radical pathway to form the triiodomethyl ketone intermediate and the amide is formed by the nucleophilic attack of amine on triiodomethyl ketone carbonyl.

Full text of DOI:10.1016/j.tet.2014.11.003

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Metal free amide synthesis via carbon–carbon bond cleavage
Chunyin Zhu , Wei Wei , Peng Du , Xiaobing Wan
PII:
S0040-4020(14)01546-4
10.1016/j.tet.2014.11.003
TET 26151
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 September 2014
Revised Date: 28 October 2014
Accepted Date: 3 November 2014
Please cite this article as: Zhu C, Wei W, Du P, Wan X, Metal free amide synthesis via carbon–carbon
bond cleavage, Tetrahedron (2014), doi: 10.1016/j.tet.2014.11.003.
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Metal free amide synthesis via carbon-
carbon bond cleavage
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Chunyin Zhua,b, , Wei Weia, Peng Dua and Xiaobing Wana,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, PR China
b School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China

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Tetrahedron
journal homepage: www.elsevier.com
Metal free amide synthesis via carbon-carbon bond cleavage
Chunyin Zhua,b, , Wei Weia, Peng Dua and Xiaobing Wana,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, PR China
b School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China
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ABSTRACT
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2009 Elsevier Ltd. All rights reserved
.
A metal-free oxidative coupling of methyl ketones and primary amines to amides has been
developed. The reaction tolerates a variety of functional groups, and is operationally simple.
The reaction is proposed to go through a radical pathway to form the triiodomethyl ketone
intermediate and the amide is formed by the nucleophilic attack of amine on triiodomethyl
ketone carbonyl.
Available online
Keywords:
Ketone
Amine
Amide
Iodoform
Radical
Iodine
of the oldest reactions in synthetic organic chemistry.14 While the
iodoform reaction has been widely used to prepare carboxylic acids
1. Introduction
The amides are important structural motif found in
biomolecules (peptides), polymers, natural products and
pharmaceuticals, and serve as useful intermediates for synthetic
organic chemistry.1 Routinely, they were prepared by coupling
reaction of activated carboxylic acid and amines, thus requiring
stoichiometric coupling reagent and/or generating large amounts
of waste products.2 Due to the growing focus on economic and
environmental issue, much attention has been paid to
development of catalytic systems for the amides synthesis under
mild conditions. As results, a variety of powerful methods, such
as the Beckmann rearrangement, 3 the Staudinger reaction, 4 the
Schmidt reaction,5 transamidation of primary amides,6 catalytic
acylation of amines with carboxylic acids,7 hydroamination of
alkynes,8 direct amidation of unactivated carboxylic acids and
amines,9 aminocarbonylation of aryl halides,10 oxidative
amidation of aldehydes11 or alcohols,12 and oxidative amidation
of alkynes with amines and azides,13 have offered attractive
alternatives for amides synthesis.
and test for the a-methyl carbonyl group, few expansion has been
developed since its discovery.15 Also ketones are very common and
readily available starting material in chemistry. So we envisioned
replacement of H2O with amine would provide a simple and practical
method for amides synthesis from reaction of ketones with amines
under oxidizing conditions (Scheme 1).
2. Results and discussion.
To test the viability of amines in the proposed iodoform
reaction, a mixture of acetophenone and n-butyl amine was
treated with oxidant in different solvents (Table 1). As can be
seen in Table 1, no desired product was detected in DMSO,
acetic acid or dioxane (entries 7, 9 and 11), and only trace
amount of product in isopropanol, dichloroethane, toluene,
acetonitrile and DMF (entries 2-6), but the reactions in ethyl
acetate, water, nitromethane and PE (petroleum ether) were able
to show significant amount of desired amide product (entries 1, 8,
10 and 12). The highest yield was obtained from the reaction in
PE using 1.1 equivalents of I2 and 6.0 equivalents of TBHP (tert-
Butyl hydroperoxide) as oxidant. Further investigation
demonstrated that both I2 and oxidant were indispensable for the
reaction (entries 13 and 21) and it would require stoichiometric
amount of I2 to get a decent yield (entries 13-16). Also it was
found TBHP was better oxidant over H2O2, mCPBA (3-
Chloroperbenzoic acid), Oxone and O2 (entries 12-15), and 6.0
equivalents was needed for the optimal condtion (entries 22-24).
Scheme 1 Design for amides synthesis.
The iodoform reaction, reaction of methyl ketone and iodine, is one
———
Corresponding author. e-mail: zhucycn@gmail.com (C. Zhu), wanxb@suda.edu.cn (X. Wan)

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Tetrahedron
Table 1.
Optimization of Reaction Conditionsa
good functional group tolerance. Interestingly, when both amine
and alcohol groups are present, the reaction gave amide product
exclusively, showing excellent chemo-selectivity (entry 4, Table
3)
Table 2.
Substrate scope for ketones a
O
O
yieldb
(%)
I2 ( 1.1 eq ) TBHP (6 eq )
NHBu
entry
solv.
oxidant
BuNH2
R
PE ( 2 ml ), 0 o
C
R
1
2a
3
1
2
EA
IPA
DCE
PhMe
MeCN
DMF
DMSO
H2O
HOAc
MeNO2
Dioxane
PE
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
75
trace
trace
trace
trace
trace
N.D.c
73
entry
1
product
O
isolated yield
O
O
O
83 %
3
NHBu
1
2
3ba
1b
1c
4
F
Cl
Br
F
O
O
5
3ca
3da
3ea
NHBu
NHBu
80 %
82%
6
Cl
Br
7
1d
1e
8
3
4
5
9
N.D.
35
O
O
O
O
O
75 %
78 %
10
11
12
13d
14e
15
16f
17
18
19
20
21
22g
23h
24i
NHBu
NHBu
N.D.
85
O
O
3fa
1f
PE
trace
44
O
PE
3ga
3ha
1g
1h
NHBu
O
82 %
76 %
6
7
PE
85
O
F3C
F3C
PE
84
NHBu
PE
trace
trace
N.D.
trace
N.D.
54
MeO2C
Ph
MeO2C
Ph
PE
mCPBA
Oxone
O2
O
O
80 %
1i
1j
3ia
3ja
8
PE
NHBu
O
O
O
O
PE
79 %
55 %
NHBu
PE
-
9
O2N
TsO
O2N
TsO
PE
TBHP
TBHP
TBHP
NHBu
NHBu
NHBu
3ka
3la
1k
1l
10
PE
82
O
O
O
O
PE
84
64 %
11
12
a0.5 mmol of acetophenone, 2.0 mmol of BuNH2, 0.55 mmol of I2
3.0 mmol of oxidant, 2.0 mL of solvent. bisolated yiled. cnot detected.
dwithout I2. e0.5 equiv. of I2. f1.5 equiv. of I2. g2.0 equiv. TBHP. h4.0
equiv. TBHP. i8.0 equiv. TBHP.
N
N
3ma
3na
1m
1n
83 %
86 %
S
S
O
O
With the optimum conditions in hand, we explored the scope
of the reaction of n-butyl amine with various ketone (Table 2).
We were pleased to find that our reaction conditions provided the
desired amide products across a range of substituted aryl methyl
ketone (entries 1-10, Table 2). Both electron-rich (entries 4 and 5,
Table 2) and electron-deficient aryl substituted ketones (entries 6
and 9, Table 2) were compatible, and fluoro, chloro, bromo, tosyl
groups were tolerated in the reaction (entries 1-3 and 10, Table 2),
which could be used for further functionalization through
transition-metal-catalyzed cross-coupling. Notably, both alkene
and alkyne group could survive the oxidizing reagents, resulting
in good yield for the amide (entries 7 and 8, Table 2). Also, the
reaction worked smoothly for the substrates with hetero aromatic
rings, for example, pyridine, thiophene and furan (entries 7-13,
Table 2).
NHBu
13
O
O
a0.5 mmol of ketone, 2.0 mmol of BuNH2, 0.55 mmol of I2, 3.0
mmol of TBHP, 2.0 mL of solvent.
Interestingly, in most of the experiments, a distinctive color
change from black to yellow was observed and at the end of the
reaction, there would form a layer of precipitate which is
conformed to be iodoform by H and 13C NMR (eq 1, scheme
1
2).16 Also, under the same condition, iodomethyl ketone 4 was
transformed to amide with 79% yield (eq 2, scheme 2), indicating
iodomethyl ketone could be an intermediate for the reaction.
Based on the observations, we proposed the reaction should go
through triiodoketone intermediate which would be likely formed
through a radical pathway instead of an anion one as the case of
traditional haloform reaction (scheme 3), since this reaction took
place in PE under a neutral environment, which usually would
not favor an anion reaction. Also TBHP is believed to work
through radical pathway in a lot of reactions. So, in this reaction,
Subsequently, the scope of amines was studied (Table 3). The
reaction was examined for several amines under the optimized
reaction conditions. In all the cases the reaction worked
smoothly, giving the corresponding amide in good yields with