Copper-catalyzed transformation of ketones to amides: Via C(CO)-C(alkyl) bond cleavage directed by picolinamide

Article abstract of DOI:10.1039/c7ob01636k

Copper catalyzed chemoselective cleavage of the C(CO)-C(alkyl) bond leading to C-N bond formation with chelation assistance of N-containing directing groups is described. Inexpensive Cu(ii)-acetate serves as a convenient catalyst for this transformation. This method highlights the emerging strategy to transform unactivated alkyl ketones into amides in organic synthesis and provides a new strategy for C-C bond cleavage.

Full text of DOI:10.1039/c7ob01636k

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DOI: 10.1039/C7OB01636K
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Copper–Catalyzed Transformation of Ketones to Amides via
C(CO)–C(alkyl) Bond Cleavage Directed by Picolinamide
Haojie Ma, Xiaoqiang Zhou, Zhenzhen Zhan, Daidong Wei, Chong Shi, Xingxing Liu, Guosheng
Huang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper catalyzed chemoselective cleavage of the C(CO)–C(alkyl)
bond leading to C–N bond formation with a chelation-assist from
N-containing directing groups is described. Inexpensive Cu(II)-
acetate serves as a convenient catalyst for the transformation. This
method highlights the emerging strategy to transform unactivated
alkyl ketones into amides in organic synthesis and provides a new
strategy for C–C bond cleavage.
The development of environmentally benign, operationally
simple, and efficient strategies for chemoselective C–C bond
cleavage has emerged as a contemporary challenge1 for
organometallic chemistry
because of
accessibility,2
thermodynamics1b-c,2,3 and uncontrollable selectivity4 of C–C
bonds. Such strategies have also attracted considerable
attention in recent years1b, 1d, 5 since such methodologies are
long standing challenges in synthetic organic chemistry.1a-c, 6
Furthermore, these reactions can be used to synthesize
complex molecular skeletons through nonconventional organic
synthesis.7 Therefore, there is an urgent need for chemists to
find economical and environmentally friendly processes for
these reactions.
Traditionally, C–C bond cleavage has been accomplished by
releasing of the ring strain8 (of three- and four-membered rings).
An alternative strategy is using a directing metal complex9
containing a metal such as Ru10 or Rh9e, 11 to a particular C–C
Scheme1. The C(CO) –C(alkyl) bond cleavage of methyl ketones.
catalyzed aerobic oxidative C–C bond cleavage reaction leading
to the formation of C–N bond (Scheme 1, b).14 They achieved
the exchange of a ketone methyl to another group successfully
through C–C bond cleavage. Picolinamide as a bidentate
directing group has been broadly used in C–H activiation.15 As
far as we know that azides have emerged as powerful synthons
and exhibited enormous potential in metal-catalyzed N atom
transfer reactions for the assembly of nitrogen-containing
frameworks.16 Inspired by pioneering works, herein, we used
Cu-catalyzed picolinamide directed strategy to enable the C–C
bond cleavage and C–N bond formation which converts o-
picolinamide ketones to amides.
Our initial efforts commenced with N-(2-acetylphenyl)-
picolinamide 1a and sodium azide as the model substrates in
the presence of CuI (20 mol %) in DMSO at 80 oC for 9 h, and the
desired N-(2-carbamoylphenyl)picolinamide 2a was isolated in
28% yield (Table 1, entry 1). Encouraged by this result, we
continued to explore the optimal reaction conditions. In order
to find the best additives, we chose AcOH, PivOH, C6H5COOH
and NH2SO3H as candidates. The results showed that using
AcOH as an additive gave the best yield up to 52%, followed by
NH2SO3H (Table 1, entries 2-5). Then, the effect of various
bond with functional groups.
This concept was first
demonstrated in the early 1980s when rhodium was directed by
the nitrogen of a quinoline to activate the C–C bond of a ketone
at the 8-position.2,12 Recently, a large number of C–C bond
cleavage reactions have been reported. In 2012, Wang’s group
achieved a Rh-catalyzed cleavage of an unstrained C–C bond in
ketones using a chelation assisted C–C activation (Scheme 1,
a).13 Subsequently in 2014, Jiao’s group presented a copper-
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou, 730000, China. E-mail: hgs@lzu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Optimization of the Reaction Conditions.a
Table 2. Evaluation of the N–directing group.a
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DOI: 10.1039/C7OB01636K
Entry
Substrate
Product
Yield
1
82%
entry
1
2
3
4
5
6
7
8
catalyst
CuI
CuI
CuI
CuI
additive
None
AcOH
PivOH
C6H5COOH
NH2SO3H
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
solvent Yieldb(%)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
28
52
31
39
44
75
33
66
69
trace
64
50
33
15
nd
71
54
85
2
3
52%
76%
CuI
Cu(OAc)2
CuCl
Cu(acac)2
CuF2·2H2O
CuO
CuBr·SMe2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
9
10
11
12c
13
14
15
16d
17e
18f
a Reaction conditions: 1 (0.2 mmol), NaN3 (0.6 mmol), Cu(OAc)2 (20 mol %),
AcOH (4 equiv), in 1mL of DMSO at 80 oC under O2 atmosphere.
DMF
Xylene
DMSO
DMSO
DMSO
a
Reaction conditions: 1a (0.2 mmol), NaN3 (0.6 mmol), catalyst (20
mol %), additive (4 equiv), solvent (1 mL), 80 oC, under air atmosphere.
b Isolated yields. c Cu(OAc)2 (10 mol %). d 60 C. e 100 C. f Reaction was
o
o
performed under O2 atmosphere.
catalysts on the yield of the target product was investigated and
we found that Cu(OAc)2 was more favorable than other catalysts
(Table 1, entries 2, 6-11). Meanwhile, when the dosage of
Cu(OAc)2 was decrease to 10 mol%, the yield was reduced to 50%
(Table 1,entries, 12). Furthermore, we studied the solvent effect
and found that DMSO was superior to DMA, DMF and xylene
(Table 1, entries 2, 13-15). Additionally, the reaction
temperature was researched and indicated that 80 °C was
beneficial for the formation of the desired product 2a with a
yield of 75% (Table 1, entries 6, 16-17). Gratifyingly, the yield of
2a increased dramatically to 85% when the reaction was carried
out under O2 atmosphere (Table 1, entry 18). Finally, the
optimized reaction conditions were obtained as follows: N-(2-
acetylphenyl)picolinamide (0.2 mmol), NaN3 (0.6 mmol),
Cu(OAc)2 (20 mol%), and AcOH (4 equiv) in 1mL of DMSO at 80
oC under O2 atmosphere.
Figure 1. X-ray crystal structure of 2b
.
With the optimized conditions in hand, we then investigated
the substrate scope of this transformation. As shown in Scheme
2, a series of substituted ketones
transformed smoothly to amides
conditions and gave the corresponding products in excellent
yields (Scheme 2, 2a 2e-2r). Concerning the electronic effects
1
were examined. All of them
2
under standard reaction
，
of substituents on N-(2-acetylphenyl)-picolinamide, the
substrates bearing either electron-withdrawing or electron-
donating groups afforded the desired products in good to
excellent yields (Scheme 2, 2e–2r). It can be seen clearly that
the functional groups at the para-position showed slightly
better reactivities than those at the meta-position, followed by
those at the ortho-position(Scheme 2, 2e-2p). Furthermore, N-
(2-acetyl-4-ethylphenyl)-picolinamide 1j and N-(2-acetyl-5-
chloro-4-methylphenyl)-picolinamide 1r transformed smoothly
to give the desired products (2j, 2r) in 83% and 70% yields,
respectively. Meanwhile, based on the reaction results of N-(2-
acetylphenyl)picolinamides with one or multiple methyl groups
Comparing different directing groups, we confirmed that the
picolinamide group was superior (Table 2). When using N-(2-
acetylphenyl)-6-methylpicolinamide 1b, N-(2-acetylphenyl)-6-
chloropicolinamide 1c and N-(2-acetylphenyl)quinoline-2-
carboxamide 1d as directing groups, each successfully
transformed this reaction with moderate yields. The structure
of 2b
( Figure 1) was further confirmed by X ray
crystallography.17 The highest yield was achieved using N-(2-
(2e-2g, 2i), it was found that the steric effect also has significant
acetylphenyl)picolinamide 1a
.
influence on the efficiency of the reaction.
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Scheme 2. Substrate Scope of N-(2-acetylphenyl)-picolinamide Derivatives.a
N-(2-carbamoylphenyl)picolinamide 2a under tVhieew AsrtticalenOdnalirnde
reaction conditions.
Scheme 4. Control experiments.
DOI: 10.1039/C7OB01636K
Based on the above results and previous literatures, a plausible
reaction mechanism is proposed and shown in Scheme
reaction is initiated by the oxidation of 1a to give the
intermediate A 18
Then chelation of Cu(OAc)2 with the N,N-
bidentate intermediate produces the Cu–complex , which
converts into the intermediate . Subsequently, Cu(OAc)2
promoted oxidation of affords a Cu(III)-complex D. Ligand
exchange with an azide nucleophile gets intermediate , which
undergoes reductive elimination to obtain the compound
5. The
.
A
B
C
C
E
a Reaction conditions: 1 (0.2 mmol), NaN3 (0.6 mmol), Cu(OAc)2 (20 mol %), AcOH
(4 equiv), in 1mL of DMSO at 80 oC under O2 atmosphere.
F.
Finally, F
converts to the desired 2a via redox process.19
Scheme 5. Proposed mechanism.
Having established the broad substrate scope of this
transformation, N-(4-methyl-2-propionylphenyl)-picolinamide
3a was studied under the standard conditions. To our delight,
the corresponding amide 2g was obtained in 20% yields.
Chemoselective cleavage of the C(CO)–C(alkyl) bond for C–N
bond formation catalyzed by copper directed by picolinamide
was achieved with this method.
Scheme 3. Transformation of N-(4-methyl-2-propionyl-phenyl)picolinamide.a
a Reaction conditions: 1 (0.2 mmol), NaN3 (0.6 mmol), Cu(OAc)2 (20 mol %), AcOH
(4 equiv), in 1mL of DMSO at 80 oC under O2 atmosphere.
To gain insight into the reaction mechanism, we carried out
several control experiments. The reaction does not proceed at
all when 1-(2-aminophenyl)ethan-1-one
3
, N-(2-acetylphenyl)-
were used as
acetamide or N-(2-acetylphenyl)-benzamide
4
5
Conclusions
the starting materials under the optimized reaction conditions.
These control experiments indicate that the N-atom plays a key
directing-role in this reaction. In addition, N-(2-formylphenyl)-
In conclusion, we have developed the chemoselective cleavage
of the C(CO)–C(alkyl) bond for C–N bond formation catalyzed by
inexpensive copper with the chelation-assist of an N–containing
directing group. This bidentate directing group was derived
picolinamide 6 and 2-(picolinamido)benzoic acid 7 did not yield
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transformation could lead to insights that could inspire further
development of future catalytic C–C activation reactions.
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