Copper-catalyzed, hypervalent iodine mediated C=C bond activation of enaminones for the synthesis of α-keto amides

Article abstract of DOI:10.1039/c5cc08843g

An unprecedented C=C bond cleavage of enaminones has been realized by means of copper catalysis in the presence of hypervalent iodine (PhI(OAc)₂). The cascade transformation based on this bond cleavage leads to the synthesis of various α-keto amides. Isotope labeling experiments suggest that water has acted as a source of oxygen atoms during the generation of the new carbonyl group.

Full text of DOI:10.1039/c5cc08843g

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DOI: 10.1039/C5CC08843G
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Copper-catalyzed, hypervalent iodine mediated C=C bond
activation of enaminones for the synthesis of α-keto amides
Jie-Ping Wan,a,* Yunfang Lin,a Xiaoji Cao, b Yunyun Liua and Li Weia
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented C=C bond cleavage of enaminones has been 1).11 Surprisingly, as another class of most universal chemical
realized by means of copper catalysis in the presence of bond, the alkene C=C double bond have been rarely employed
hypervalent iodine (PhI(OAc)2). The cascade transformation based in the synthesis of α-keto amides with success in despite of
on this bond cleavage leads to the synthesis of various α-keto their application in carbonylation-based amide synthesis.12
amides. Isotope labeling experiments suggest that water has acted Enaminones are a class of stable alkene derivatives with highly
as the source of oxygen atom during the generation of the new versatile application in the synthesis of tremendous organic
carbonyl group.
products.13 As our successive efforts in exploring the
application of enaminones in the synthesis of diverse small
organic molecules via C=C bond functionalization,14 we report
herein the first example of generally applicable α-keto amide
synthesis by using enaminones via the cleavage of the C=C
double bond (Eq 3, Scheme 1).
α-Keto amides are a class of special amides possessing
invaluable biological and chemical functions. The α-keto amide
structure presents prevalently in natural products,
pharmaceuticals and biologically relevant lead compounds as
key fragment.1 The unique structural feature of these
compounds makes them privileged candidates in the design of
enzyme inhibitors.2 More over, the α-keto amides are also
highly useful precursors in synthetic organic chemistry because
of their distinct and versatile reactivity.3 Correspondingly, the
synthesis of α-keto amides has been an issue of extensive
research interest. A number of synthetic approaches such as
double carbonylation,4 oxoaldehyde amidation,5 α-keto acid
amidation,6 carbonylation coupling of acyl chlorides/esters,7
and the isocyanide-based coupling carbonylation,8 among
others9 have been developed during the past decades.
Owing to the ubiquitous reactant availability, the synthesis of
α-keto amides using alkynes and alkanes via direct
carbonylation of the raw carbon-carbon bonds and alkyl C-H
bonds has been dominantly employed in recent years. The
alkyne-based synthesis (eq 1, Scheme 1) usually takes place in
the presence of the catalyst/oxidant and an additive.10 On the
other hand, the alkyl C-H bond-based synthesis could be
achieved based on the carbonylation mediated by strong
peroxide oxidant or transition metal catalyst (eq 2, Scheme
Scheme 1 Different routes to α-keto amides
The investigation started from the model reaction of
enaminone 1a. The tentative operation of the reaction in the
presence of CuI and different oxidants disclosed that the
combination of CuI with oxidant such as air, pure molecular
a.College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China. Email: wanjieping@jxnu.edu.cn
b.Research Centre of Analysis and Measurement, Zhejiang University of Technology,
18 Chaowang Road, Hangzhou, Zhejiang 310014, P.R. China
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [Experimental information,
characterization data, 1H and 13C NMR spectra of all products]. See
DOI: 10.1039/x0xx00000x
oxygen, PhI(OAc)2 enabled the production of α-keto amide 2a
,
and PhI(OAc)2 exhibited the best oxidative effect (entries 1-3,
Table 1). On the other hand, TBHP and K2S2O8 were found
unpractical for this reaction (entries 4-5, Table 1). Subsequent
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Table 2 Scope of α-keto amide synthesisa,b
examination on different catalysts, including copper species,
molecular iodine and the blank entries suggested that CuI was
the best catalyst (entries 6-10, Table 1). In further experiments,
entries with different CuI loading showed that increasing the
amount of CuI from 0.4 to 0.6 equiv mol provided evidently
improved yield of 2a (entries 11-13, Table 1). On the other
hand, no enhancement in product yield was observed by
increasing the loading of PhI(OAc)2 (entries 14, Table 1). A brief
screening on the reaction medium proved that DMSO was
most favoured in the reaction (entries 15-17, Table 1). Finally,
variation on the reaction temperature was not able to further
improve the efficiency of the reaction, either (entries 18-19,
Table 1).
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DOI: 10.1039/C5CC08843G
O
O
R2
CuI, PhI(OAc)2
DMSO, 120 o
R2
N
Ph
N
R3
R1
R3
C
O
2
1
O
Me
O
O
N
O
N
O2N
N
O
O
O
c
2b
, 75%
2a
, 72%
2c
, 68%
O
O
N
N
N
O
O
O
H3C
F
Cl
2d
, 78%
2e
, 74%
2f
, 71%
Table 1 Optimization on the conditions for α-keto amide synthesisa
O
O
O
N
N
N
O
O
O
NC
O2N
F3C
2g
, 65%
O
2h
, 63%
O
2i
, 67%
O
N
N
N
O
Entry
1
2
3
4
5
6
7
8
Catalyst
CuI
CuI
CuI
CuI
Oxidant
air
O2
PhI(AcO)2
TBHP
K2S2O8
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
PhI(AcO)2
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
13
O
Cl
O
2j
Cl
, 73%
2l
, 69%
2k
, 65%
27
53
nr
nr
23
27
25
nr
nr
31
72
51
69
25
16
trace
53
O
O
O
N
N
N
CuI
S
O
O
O
d
CuBr
CuCl
Cu(AcO)2
I2
—
CuI
CuI
CuI
CuI
CuI
2o
, 64%
N
2m
2n
, 77%
, 56%
Ph
O
O
O
O
N
O
N
Ph
9
10
11c
12d
13e
14d,f
15d
16d
17d,g
18d,h
19d,i
O
O
d
2q
, 54%
2p
, 72%
2r
, 69%
O
O
O
O
H
N
H
N
N
Ph
O
O
O
CH3
Cl
2t, 66%e
2u, 63%e
CuI
CuI
CuI
CuI
NMP
2s, 62%
CH3CN
DMSO
DMSO
aGeneral conditions: enaminone 1 (0.3 mmol), CuI (0.18 mmol) and PhI(AcO)2 (0.3
mmol) in 2 mL DMSO under open air, stirred at 120 oC for 12 h. bIsolated yield.
cThe reaction time was 16 h. dInstead of PhI(OAc)2, molecular oxygen (1 atm
balloon) was used as the oxidant. eAdditional 0.09 mmol of morpholine was
employed.
70
aUnless specified, the general conditions: 1a (0.3 mmol), copper catalyst (0.12
mmol) and oxidant (0.3 mmol, except in the entries 1-2) in 2 mL solvent, stirred at
120 oC for 12 h, nr = no reaction. bIsolated yield. c0.06 mmol CuI. d0.18 mmol CuI.
e0.24 mmol CuI. 0.45 mmol PhI(OAc)2. gReaction at reflux. hReaction at 110 oC.
f
was observed on the yield of products. As for the amine component,
both acylic and (hetero)cyclic secondary amines were smoothly
utilized in the synthesis. Compared with N,N-dimethylamino
functionalized enaminones, the more bulky acyclic N,N-substituted
amino group in the enaminones displayed negative effect to the
formation of α-keto amides (2n, 2o, Table 2). Notably, besides
secondary amines, primary amines were also found applicable to
the catalytic reaction to enable the synthesis of secondary α-keto
amides (2t and 2u, Table 2) by simply employing morpholine as
additional additive.
iReaction at 130 oC.
On the basis of the above optimization experiment, the
application scope of the present method in synthesizing
different α-keto amides was investigated by employing
different enaminones. According to the results acquired in this
section (Table 2), the present method was generally applicable
in the synthesis of α-keto amides containing different
substructures. Functional groups of distinct properties such as
alkyl, halogen, nitro, cyano and trifluoromethyl etc all
exhibited tolerance to the transformation. Notably, the
heteroaryl-based enaminone was also successfully employed
to provide corresponding product (2m, Table 2). Based on the
results acquired from the entries using enaminones with
different aryl substructure, no evident impact of the aryl ring
In order to probe the source of oxygen in the newly generated
carbonyl, some control experiments were then designed and
conducted. Firstly, the model reaction of 1a was performed
under nitrogen atmosphere, and it was found that the product
2a could be acquired with fair yield (eq 1, Scheme 2). This
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result excluded the possibility that air (molecular oxygen) was enaminones
COMMUNICATION
1
facilitates the incorporation of PhI(OAc)2 to
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the source of carbonyl oxygen. On the other hand, a parallel enaminone,15 which gives intermediaDtOeI: 310..10T3h9e/C5rCeCd0u8c8t4io3Gn
experiment in dry DMSO gave only trace amount of product 2a elimination of
(eq 2, Scheme 2), which implied that presence of water was intermediate
indispensable in the reaction and might act as the source of substitution to afford
oxygen in the newly formed carbonyl. In addition, when this amino ketone which cyclizes to aonther key interme diate
reaction was run under standard condition in the presence of via the promotion of copper salt. Further hydrolysis of
additional H218O, the simultaneous formation of products 2a gives diol species
. The oxidation of
and 18O labeled 2a’ were observed by HRMS analysis, and the oxygen or PhI(OAc)2 could provide 1,2-dioxetane intermediate
relative peak intensity are 2a 2a’ ≈ 1 : 1.27 (eq 3, Scheme 2). . The ring opening of by releasing CO finally produces α-
What’s more, considerably higher ratio of 18O labeled product keto amide
3
by releasing PhI leads to the formation of
which undergoes intramolecular nucleophilic
. The subsequent hydrolysis of yields
4
5
5
6
7
7
then
8
8 with either molecular
:
9
9
2
.
was given by an additional entry performed with dry DMSO In conclusion, under the catalyst system consisting of
under N2 in the presence of identical H218O (the relative peak copper/PhI(OAc)2, we have achieved the synthesis of α-keto
intensity are 2a
: 2a’ ≈ 1 : 1.82, see ESI for ESI-HRMS spectra amides via the cleavage of the C=C double bond in enaminones.
from both entries). Once again, the result demonstrated the The synthetic method has exhibited broad application scope
reliance of the reaction on water.
for the synthesis of both secondary and tertiary α-keto amides.
The easy availability of reactants as well as the employment of
simple catalyst/oxidant ensures the present method as a
useful new option for α-keto amide synthesis.
Acknowledgements
The work is financially supported by the National Natural and
Science Foundation of China (21502625) and National Natural
and Science Foundation of Jiangxi Province (20151BAB203008).
Notes and references
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Scheme 2 Some control experiments
Based on the in hand results from the control experiments, a
possible mechanism of the reaction is proposed as out-lined in
Scheme 3. Originally, the activation effect of copper salt to the
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-PhI
R
N
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I
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OAc R2
4
Ph
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1
3
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3
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R
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H
HO
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OH R2
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-H+
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-OAc-
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5
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OCu
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R
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4
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air(O2)
H2O
O
-CO
R
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N
1R2RN
O
R
R2
O
9
O
2
-Cu+
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OH
1R2RN
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PhI
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PhI(OAc)2
AcOH
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7
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