Copper-catalyzed homocoupling of ketoxime carboxylates for synthesis of symmetrical pyrroles

Article abstract of DOI:10.1039/c3gc41800f

A novel and efficient copper-catalyzed homocoupling of ketoxime carboxylates has been developed for the synthesis of symmetrical pyrroles. This reaction tolerates a wide range of functional groups and provides a synthetically useful process to synthesize

Full text of DOI:10.1039/c3gc41800f

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Copper-Catalyzed Homocoupling of Ketoxime Carboxylates for
Synthesis of Symmetrical Pyrroles
Longfei Ran, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
attention have been paid to the coupling reactions of the
A novel and efficient copper-catalyzed homocoupling of
ketoxime carboxylates has been developed for the synthesis of
symmetrical pyrroles. This reaction tolerates a wide range of
functional groups and provides a synthetically useful process
10 to synthesize valuable symmetrical pyrroles under mild
conditions.
oxime carboxylates, because the N-O bond cleavage of the
oxime carboxylates could be worked as an internal oxidant to
40 make reactions proceed under redox-neutral conditions. Thus,
transition-metal catalyzed coupling of oxime carboxylates
with aldehydes, alkynes, and organoboronic acids have
emerged for the synthesis of aza-heterocycles.15 In connection
with our interest in the oximes14a-b,15a and green synthesis of
45 pyrroles,5 we have developed a novel and efficient copper-
catalyzed homocoupling of ketoxime carboxylates for the
synthesis of valuable symmetric pyrroles.
Pyrroles are one of the most important heterocycles which
prevlent in numerous natural products, pharmaceuticals, and
functionalized materials.1 Particularly, a lot of symmetrical
15 pyrroles was recently discovered have remarkable bioactivity
and fluorescence, such as COX-2 isoenzyme inhibitors (a),
DNA minor groove recognition reagent DB884 (b), bio-
antioxidant (c), fluorophores TPPy (d) and NPANPy (e)
(Figure 1).2 Over the past decades, tremendous efforts have
20 been devoted to the synthesis of various substituted pyrroles.3
Apart from the classical protocols,4 many new strategies, such
as cycloaddition reactions,5 multicomponent reactions,6
dehydrogenative cyclization reactions,7 coupling of enamides
with alkynes,8 and oxidative cyclization of N-allylimines9
25 have been developed for the synthesis of pyrroles. However,
most of these methods are focused on versatile unsymmetrical
substituted pyrroles, general protocols for the synthesis of
valuable symmetrical pyrroles has rarely been developed.10
Propiophenone oxime acetate 1a was selected as a model
substrate in the initial experiments to optimize the reaction
50 conditions. Symmetrical pyrrole 2a was obtained in 37%
o
yield when CuBr was used as the catalyst in DMSO at 120 C
(Table 1, entry 1). Then, NaHSO3 which we found good
additive in our previous copper-catalyzed coupling of oxime
Table 1 Optimization of reaction conditions for homocoupling of
55 propiophenone oxime acetate for synthesis of symmetrical pyrrolea
Entry
1
Catalyst
CuBr
CuBr
CuBr
CuI
Additive
---
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
37
68
30
35
64
62
59
31
24
39
72c
0
2
NaHSO3
Na2SO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
3
4
5
CuCl
6
CuCl2
CuBr2
Cu(OAc)2
CuBr
CuBr
CuBr
---
7
8
9
30 Figure 1 Bioactive or fluorescent symmetrical pyrroles
10
11
12
CH3CN
DMSO
DMSO
Oximes and their derivatives are versatile synthetic building
blocks.11 They are well-known fruitful candidates for the
Beckmann rearrangement reactions to prepare amides,12 and
the dehydrations to produce nitriles.13 Recently, reductive
35 acylation of ketoximes have been developed as a practical
method for the synthesis of enamides.14 Meanwhile, much
a
Reaction conditions: propiophenone oxime acetate 1a (0.3 mmol),
catalyst (5 mol %), NaHSO3 (1.2 equiv) in solvent (3 mL) under Ar at 120
oC for 2 h. b Isolated yields. c The reaction was run at 140 oC.
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Table 2 Cu-catalyzed homocoupling of aryl ethyl ketoxime acetatesa
Table 3 Cu-catalyzed homocoupling of various ketoxime carboxylatesa
View Article Online
DOI: 10.1039/C3GC41800F
Yield (%)b
72
Entry
1
Substrate
Product
Yield (%)b
56
Entry
1
Substrate
Product
OAc
N
1a
OAc
N
2
3
N
H
74
63
74
76
70
65
65
68
55
70
67
2
3
66
68
1n
2b
N
H
2o
4
4
52
5
5
6
10
0
OAc
N
6
1r
OAc
N
7
0
7
1g
8
62
56
45
8
OAc
O
O
N
9
O
O
N
H
9
O
O
2i
1i
10
10
11
12
a Reaction conditions: 1 (0.3 mmol), CuBr (5 mol %), NaHSO3 (1.2 equiv)
15 in DMSO (3 mL) under Ar at 140 oC for 2 h. b Isolated yields (averages of
two experiments).
N
H
Cl
Cl
solvents, such as DMF and CH3CN, were screened as well
(Table 1, entries 9-10). However, we found that CuBr and
DMSO are still the most effective catalyst and solvent
20 respectively. Reaction temperature was also varied; the yield
of 2a was further increased to 72% when the reaction was
conducted at 140 °C (Table 1, entry 11). Additionally, no
reaction was observed in the absence of copper catalyst
confirming that Cu species did indeed act as the catalyst in the
25 reaction (Table 1, entry 12).
With the optimized reaction conditions established, the
scope of the reaction was investigated (Table 2). The reaction
showed good functional group tolerance and proved to be a
general methodology for the preparation of symmetrical
30 pyrroles. And the reaction was insensitive to the electronic
effects of the substrates. Propiophenone oxime acetates with
2k
OAc
N
Br
1l
a Reaction conditions: 1 (0.3 mmol), CuBr (5 mol %), NaHSO3 (1.2 equiv)
in DMSO (3 mL) under Ar at 140 oC. b Isolated yields (averages of two
5 experiments).
acetates with aldehydes was added to the reaction.15a The
yield of pyrrole 2a was dramatically improved to 68% (Table
1, entry 2). Na2SO3 shows inferior than NaHSO3. Next, a
series of copper catalysts, such as CuI, CuCl, CuCl2, CuBr2,
10 and Cu(OAc)2 were screened to determine if they improved
reaction efficiency (Table 1, entries 4-8). And various
2
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Page 3 of 5
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NaHSO3
methyl, alkyl, methoxyl, fluoro, and electron-withdrawing
CuI
CuII
CuI CuII
OAc
CuII
HN
groups such as chloro and bromo groups on the aromatic rings
all gave the corresponding symmetrical pyrroles 2b-2l in good
yields. In this manner, the resulting Cl or Br substituted
products 2k-2l, could be further expanded to a wider variety
of functionalized symmetrical pyrroles by undergoing
subsequent cross-coupling reactions. In addition, ortho-
methyl and methoxyl substituted substrates reacted smoothly
and resulted in the desired symmetrical pyrroles 2f-2g and 2i
N
N
N
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DOI: 10.1039/C3GC41800F
Ph
Ph
H
Ph
Ph
B
C
A
1
5
Ph
H
NH
path a
NH2
Ph
NH
NH
- CuI
N
H
- NH3
N
H
Ph
Ph
Ph
Ph
Ph
D
E
2
F
10 in 65-70% yields. These results indicated that steric hindrance
on the aromatic rings of the substrates has little influence on
the reaction (Table 2, entries 6-7, and 9).
Furthermore, a series of phenyl alkyl ketoxime acetates
were investigated for extension of the reaction scope (Table 3).
CuII
CuII
path b
N
OAc
N
Ph
N
N
Ph
Ph
Ph
1
Ph
Ph
H
[CuNHOAc]+
CuII
CuI
F'
E'
D'
15 Ketoxime
acetates
derived
from
butyrophenone,
Ph
Ph
Ph
Ph
N
H
Ph
N
N
valerophenone and α-tetralone reacted smoothly to give the
desired symmetrical pyrroles 2m-2o in 56-68% yields (Table
3, entries 1-3). It should be noted that tetraphenyl pyrrole 2p,
which was fluorophores for glassy blue-light-emitting
20 diodes,2d was obtained in 52% yield when 1, 2-
diphenylethanone oxime acetate 1p was used as the substrate
(Table 3, entry 4). However, acetophenone oxime acetate 1q
gave only 10% yield of the corresponding 2,5-diphenyl
pyrrole 2q under the aforementioned conditions (Table 3,
25 entry 5). And no desired pyrrole products were obtained when
the alkyl alkyl ketoxime acetates, such as cyclohexanone
oxime acetate 1r and pentan-2-one oxime acetate 1s were
employed as the substrates under the standard conditions
(Table 3, entries 6-7). Finally, different propiophenone oxime
30 carboxylates were investigated to determine the reactivity of
them. It was found that the reactivity of the different
carboxylates follows the sequence: acetate > propionate >
pentafluorobenzoate > benzoate (Table 3, entries 8-10).
CuI
H'
2
G'
60 Scheme 1 Proposed mechanism for the Cu-catalyzed homocoupling of
ketoxime carboxylates
Scheme 2 Intramolecular homocoupling of diketoxime diacetates 1w
In summary, we have developed a novel and efficient
65 copper-catalyzed homocoupling of ketoxime carboxylates for
the synthesis of symmetrical pyrroles. The reaction tolerates a
wide range of functional groups and is a reliable method for
the rapid elaboration of readily available ketoxime
carboxylates into a variety of valuable symmetrical pyrroles.
70 Further scope and mechanistic studies of the reaction are
underway and will be reported in due course.
This work was supported by generous grants from the
National Natural Science Foundation of China (NSFC-
21272183, 21002077), and Fund of the Rising Stars of Shanxi
75 Province (2012KJXX-26).
On the basis of the above results and previous studies, the
35 tentative mechanisms for this homocoupling reaction are
proposed in Scheme 1. Firstly, the reaction starts from two-
step single-electron-transfer reduction of ketoxime acetate 1
by CuI to generate imino-CuII complex B.14a-b,15
Tautomerization of imino-CuII complex B gives the enamino-
40 CuII intermediate C. Then, two pathways are possible for the
following steps. In one case (path a), clevage of the N-Cu
bond of the enamino-CuII intermediate C forms a radical
intermediate D.16 Radical coupling of intermediate D affords
diimine intermediate E.17 Intramolecular cyclization of
45 intermediate E followed by elimination of NH3 produces the
pyrrole 2. Alternatively, condensation of enamino-CuII
intermediate C with a second ketoxime acetate 1 gives the
intermediate D’.15a,18 Elimination of intermediate D produces
an enimine intermediate E’. Intramolecular radical cyclization
50 of intermediate E’ assisted by CuII sequence with
tautomerization of intermediate H’ produces the symmetrical
pyrrole 2 (path b).8d,15e,16
Notes and references
a Department of Chemistry & Materials Science, Key Laboratory of
Synthetic and Natural Functional Molecule Chemistry of Ministry of
Education, Northwest University, Xi’an 710069, P. R. China. E-mail:
80 guanzhh@nwu.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
1
procedure, characterization data, H and 13C NMR spectra of products 2..
See DOI: 10.1039/b000000x/
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DOI: 10.1039/C3GC41800F
Table of contents entry:
Copper-Catalyzed Homocoupling of Ketoxime Carboxylates for Synthesis of
Symmetrical Pyrroles
Longfei Ran, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan*
An efficient copper-catalyzed homocoupling of ketoxime carboxylates has been developed for the
synthesis of symmetrical pyrroles.