Copper-catalyzed aerobic oxygenative cross dehydrogenative coupling of methyl ketones with: Para -C-H of primary anilines

Article abstract of DOI:10.1039/c6gc02271e

A novel oxygenative cross dehydrogenative coupling of methyl ketones with para-C-H of primary anilines under a copper/oxygen catalytic system is described. This methodology features advantages including readily available starting materials, green oxidant, and broad functional group tolerance.

Full text of DOI:10.1039/c6gc02271e

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Copper-catalyzed aerobic oxygenative cross dehydrogenative
coupling of methyl ketones with para-C-H of primary anilines
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaochen Ji*, Dongdong Li, Xuan Zhou, Huawen Huang* and Guo-Jun Deng*
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) aniline radical formation
A novel oxygenative cross dehydrogenative coupling of methyl
ketones with para-C-H of primary anilines under copper/oxygen
catalytic system is discribed. This methodology features
advantages including readily available starting materials, green
oxidant, and broad functional group tolerance.
O2
NH2
NH2
NH2
NH
CuI
CuII
-H+
X
Oxidative cross dehydrogenative coupling (CDC) has gained
intensive attention in synthetic chemistry over the past decade.1
Copper/oxygen catalytic system is found to be powerful and
versatile in this field, which enables CDC to efficiently
construct CꢀC and Cꢀheteroatom bonds under facile
conditions.2,3 And more importantly, the employment of
oxygen as the oxidant in those oxidative transformations really
features incomparable among those with other oxidants with
respect to the development of sustainable chemical process.4
In particular, the oxidative coupling of the CꢀH bond at the
paraꢀposition of anilines by copper/oxygen catalytic system has
X = C, N, Br, et al
b) This work:
R2
O
R2
O
R1
[Cu]/O2
NH2
+
NH2
R1
O
Scheme 1 Paraꢀselective reactions of primary anilines under
copper/O2 catalytic system.
Our initial investigations began with the coupling of
acetophenone (1a) and aniline (2a) in the presence of copper
catalyst under molecular oxygen (Table 1). Trace of 1ꢀ(4ꢀ
been well known for the polymerizations5 and para
ꢀ
halogenation6 of anilines. Generally, anilines undergo single
electron oxidation and loss of a proton, affording the key highly
active aniline radical. While nitrogenꢀcentred radical enables
aminophenyl)ꢀ2ꢀphenylethaneꢀ1,2ꢀdione
(3aa) was obtained
with Cu(OTf)2 as the catalyst (entry 1). The use of BF3·Et2O as
additive with Cu(OAc)2 catalyst afforded the desired coupled
product 3aa in 23% yield (entry 2). It was discovered that the
identity of the copper catalyst was crucial for obtaining high
yield of the coupled product 3aa. After examining various
catalysts, we were delighted to find that the reaction proceeded
smoothly with CuI as catalyst along with BF3·Et2O as additive,
delivering the desired product 3aa in 81% yield (72% isolated
yield; entries 2ꢀ8). Replacing the additive BF3·Et2O with other
Lewis Acid (FeCl3 and Sc(OTf)2) resulted in less efficiency
(entries 9 and 10). Moreover, the employment of Brønsted acid
(PivOH and CF3CO2H) as additive led to a significant decrease
in the yield (entries 11 and 12). The reaction did not afford the
coupling product in the absence of BF3·Et2O or copper catalyst
(entries 13 and 14). Then the screening of solvent and reaction
temperature indicated that DMSO was irreplaceable for the
coupling and the reaction at 105 oC gave the best result (entries
15 and 19).
the formation of various NꢀX (X=C, N, et al.) bonds,7 para
ꢀ
carbonꢀcentred radical provides desirable opportunities for the
paraꢀCꢀH functionalization (Scheme 1a). However, few
examples of aniline paraꢀCꢀH derivation were realized due to
the highly sensitive free amino group to acid and metal
catalysts.8 Herein, as our continuing effort on copper/oxygen
catalytic transformations,9 we disclose a novel oxygenative
CDC reaction of methyl ketones with the paraꢀposition of
anilines to provide unique access to the motif of anilinꢀ1,2ꢀ
diketones (Scheme 1b). The compatibility of the free amino
group in the procedure highlights this charming copper/oxygen
system to be highly feasible to prepare some active molecules
with aromatic amine moiety.
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105 (China).
E-mail: xcji@xtu.edu.cn, hwhuang@xtu.edu.cn, gjdeng@xtu.edu.cn
Having identified the optimized reaction conditions, we
next investigated the scope of methyl ketone derivatives with
Electronic Supplementary
DOI: 10.1039/x0xx00000x
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available:
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aniline 2a as coupling partner. As shown in Table 2, a broad derivatives (Table 3). A variety of ortho substituted anilines
range of electronꢀwithdrawing and electronꢀdonating smoothly underwent the cross dehydrogenative coupling with
substituents at the aryl para position of acetophenone were well acetophenone, generating the desired products (3ab
tolerated, delivering the corresponding products (3aa 3la) in moderate to good yields. 3ꢀFluoroaniline was also productive in
moderate to good yields. It was worth noting that the functional the reaction, yielding the coupled product 3ah in 60% yield.
ꢀ3ag) in
ꢀ
Table 1 Optimization of the reaction conditionsa
Then, 4ꢀfluoroaniline was tested to examine whether the
coupling reaction could proceed in the ortho position of
anilines, however, <10% yield was observed. Unfortunately, Nꢀ
substituted anilines (2j and 2k) were unsuccessful in the
coupling reaction with acetophenone in this protocol, only trace
of the desired product was detected.
entry
1
2
3
4
5
6
7
8
[Cu] catalyst
Cu(OTf)2
Cu(OAc)2
Cu(TFA)2
CuBr2
CuCl2
CuCl
CuBr
CuI
additive
ꢀ
yieldb
trace
23
58
42
53
51
70
81(72c)
40
Table 2 The coupling of anilineyu with methyl ketonesa
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
FeCl3
9
CuI
10
11
12
13
14
15d
16e
17f
18g
19h
CuI
CuI
CuI
CuI
Sc(OTf)2
PivOH
CF3CO2H
ꢀ
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
58
22
trace
trace
ND
15
trace
ND
75
ꢀ
CuI
CuI
CuI
CuI
CuI
80
a
Reaction conditions: acetophenone 1a (0.3 mmol, 1.0 equiv),
a
Reaction conditions: methyl ketone
1 (0.3 mmol, 1.0 equiv),
aniline 2a (0.33 mmol, 1.1 equiv), copper catalyst (5 mol%),
aniline 2a (0.33 mmol, 1.1 equiv), CuI (5 mol %), and
BF3·Et2O (20 mol%) in 0.5 mL of DMSO at 105 C for 14 h.
Isolated yields. b The reaction was performed for 4 h.
and additive (20 mol%) in 0.5 mL of DMSO at 105 oC for 14 h.
o
b
c
d
GC yield based on 1a is given. Isolated yield. DMF as the
e
f
g
solvent. DMA as the solvent. Toluene as the solvent. At
100 oC. h At 110 oC. ND = not detected.
Table 3 The coupling of acetophenone with anilinesa
groups typically sensitive to lowꢀvalent transition metals or
strong oxidative conditions, such as iodide, hydroxyl, benzyl
ether, thioether, nitrile, and nitro on the benzene ring, were
compatible, enabling the products for further transformations.
Acetophenone bearing methoxy and amide groups at the meta
position of the aryl ring reacted smoothly with 2a to provide the
desired product 3ma and 3na in 80% and 51% yield,
respectively. 1ꢀ(2ꢀMethoxyphenyl)ethanone furnished the
corresponding product 3oa in a slightly attenuated yield,
presumably due to the steric hindrance of the ortho substituent.
In addition, 1ꢀ(naphthalenꢀ1ꢀyl)ethanone and 1ꢀ(naphthalenꢀ2ꢀ
yl)ethanone gave products 3qa and 3ra in moderate yields.
Satisfyingly, heteroaromatic methyl ketone 1s performed well
to afford the coupled product 3sa in 57% yield. Notably, alkyl
substituted methyl ketone 1t (1ꢀcyclopropylethanone) was
identified to be a suitable substrate, although only 35% yield
was obtained.
With the methyl ketones scope established, we then turned
our attention to the generality and the limitation of aniline
2 | J. Name., 2012, 00, 1-3
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a
Reaction conditions: acetophenone 1a (0.3 mmol, 1.0 equiv), intermediated
(0.33 mmol, 1.1 equiv), CuI (5 mol%), and species and subsequent loss of H+ results in intermediate
E,
D. The single electron oxidation of D
by CuII
aniline derivatives
2
o
BF3·Et2O (20 mol%) in 0.5 mL of DMSO at 105 C for 14 h. which is further oxidized to the final product
Isolated yields.
3
. We speculate
the reasion for the unsuccessful Nꢀmethylanilines is the much
better stability of Nꢀcentred radical ( ) than cyclohexadienyl
radical ( ). Actually, couplings of Nꢀmethylanilines at the
A
With respect to the reaction mechanism of para
ꢀ
B
functionaliztion of anilines, a FriedelꢀCraftsꢀtype pathway is methyl group have been widely investigated.1
generally involved. In the present system, however, nitrogenꢀ
alkylꢀsubstituted anilines featured very low reactivity, which
goes against the Friedel–Craftsꢀtype mechanism. Then 2ꢀiodoꢀ
1ꢀphenylethanone (
phenylethanone (5’) were proposed to be the key intermediates.
However, neither nor furnished the target 3aa in the present
4), phenylglyoxal (5) and 2ꢀhydroxyꢀ1ꢀ
4
5
copper catalytic system (Scheme 2aꢀb), and trace amount of
product was detected with 2ꢀhydroxyꢀ1ꢀphenylethanone
(Scheme 2c). Furthermore, the addition of radical trapping
reagent TEMPO or BHT completely quenched the
transformation (Scheme 2d), which revealed that this reaction
probably involved a radical pathway. Finally, aminoꢀ1,2ꢀ
diphenylethanone 6
, prepared by known method,10 was found
Scheme 3 Proposed mechanism.
highly active to transform into 3aa under the standard catalytic
system within 2 h, while much lower yield was obtained in the
absence of trifluoroborane and trace amount of 3aa was given
in the case of no any catalyst (Scheme 2e), indicating
The resultant 1,2ꢀdiketones are versatile building blocks as
handle for further manipulations. For example, the reduction of
3aa with NaBH4 afforded 4ꢀaminophenyl 1,2ꢀdiol
yield. And the annulation of 3aa through condensation with
benzeneꢀ1,2ꢀdiamine under Lewis acid treatment gave 4ꢀ
7 in excellent
compound
6 might be a crucial intermediate in this copper/O2
catalytic system.
aminophenyl quinoxaline
8 in 74% yield.
CuI/O2
BF3 Et2O
O
NH2
NH2
I
+
(a)
(b)
3aa
3aa
Ph
Ph
Ph
DMSO, 105 oC
4
2a
2a
CuI/O2
BF3 Et2O
O
O
+
DMSO, 105 oC
Scheme 4 Transformation of the resultant diketone 3aa
.
5
Reaction conditions: (a) 3aa (0.2 mmol), NaBH4 (2 equiv), H2O
(2 equiv), THF (0.2 M), reflux, 0.5 h; (b) 3aa (0.2 mmol),
benzeneꢀ1,2ꢀdiamine (1.2 equiv), FeCl3 (2 equiv), EtOH (0.2
M), 65 oC, 12 h. An = 4ꢀNH2C6H4.
CuI/O2
BF3 Et2O
O
OH
NH2
(c)
+
3aa
DMSO, 105 oC
trace
5'
2a
CuI/O2
BF3 Et2O
In conclusion, we have developed a copperꢀcatalyzed
oxidative cross dehydrogenative coupling reaction of methyl
ketones with free anilines under molecular oxygen. This
reaction is highly regioselective to proceed at the para position
O
NH2
+
(d)
(e)
3aa
Ph
Ph
DMSO, 105 oC
TEMPO or BHT
(2 equiv)
1a
2a
O
of anilines, providing an easy access to a series of
aminophenyl diketone derivatives. Moreover,
pꢀ
the
O2
3aa
NH2
DMSO, 105 oC, 2 h
extraordinarily broad functionalꢀgroup tolerance, as well as the
employment of green oxidant (O2), makes this protocol an
attractive strategy in synthetic chemistry. Further research on
diverse paraꢀposition functionalizations of anilines for the
construction of CꢀC and Cꢀheteroatom bonds is currently under
investigation in our laboratory.
This work was supported by the National Natural Science
Foundation of China (21602187, 21572194 and 21502161) and
the China Postdoctoral Science Foundation Funded Project
(2015M580691).
yield: trace
6
56% (with CuI)
85% (with CuI and BF3 Et2O)
Scheme 2 Mechanistic investigations.
Based on the mechanistic investigations described above, a
plausible mechanism for the reaction is given in Scheme 3. The
reaction is initiated by the single electron transfer of aniline 2a
to CuII species, which is generated by the oxidation of CuI
catalyst with molecular oxygen. The radical cation
lose H+ and tautomerize into cyclohexadienyl radical
is captured by methyl ketone in its enol form
A tends to
B
, which
1
C
to deliver
Notes and references
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1
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Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047; (b)
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Table of contents entry
Oxygenative cross dehydrogenative coupling of methyl ketones with para-C-H of primary
anilines under copper/oxygen catalytic system