Oxidative cross-coupling/cyclization to build polysubstituted pyrroles from terminal alkynes and β-enamino esters

Article abstract of DOI:10.1039/c3cc43682a

A novel silver-mediated highly selective synthesis of polysubstituted pyrroles by the C-H/C-H oxidative cross-coupling/cyclization of terminal alkynes with β-enamino esters has been developed. This protocol represents a simple, efficient and selective way to construct polysubstituted pyrroles in good yields from basic chemical materials.

Full text of DOI:10.1039/c3cc43682a

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Oxidative cross-coupling/cyclization to build
polysubstituted pyrroles from terminal alkynes
and b-enamino esters†
Cite this: Chem. Commun., 2013,
49, 7549
Received 16th May 2013,
Accepted 24th June 2013
a
a
Jie Ke,z Chuan He,z Huiying Liu,a Mengjun Lia and Aiwen Lei*ab
DOI: 10.1039/c3cc43682a
www.rsc.org/chemcomm
A novel silver-mediated highly selective synthesis of polysubstituted
pyrroles by the C–H/C–H oxidative cross-coupling/cyclization of
terminal alkynes with b-enamino esters has been developed. This
protocol represents a simple, efficient and selective way to con-
struct polysubstituted pyrroles in good yields from basic chemical
materials.
Scheme 1 Proposal for a silver-mediated oxidative cyclization synthesis of
polysubstituted pyrroles.
Inspired by the current requirements for green and sustainable
chemistry, direct C–H functionalization has begun to alter the and b-enamino esters (Scheme 1). This protocol demonstrates
way towards the formation of C–C and C-heteroatom bonds in a convenient approach for the construction of pyrrole frame-
organic synthesis.1 Compared to the classical transition-metal- works, which expedites the facile synthesis of polyfunctional
catalyzed coupling reactions, the oxidative double C–H functio- heterocycles.
nalization/cross-coupling has inherent advantages and repre-
Our initial studies focused on the reaction of phenylacetylene
sents an ideal chemical synthesis.2 In this field, recently, the 1a and (Z)-methyl 3-(2,6-diisopropylphenyl-amino)but-2-enoate 2a.
efficient and atom-economic synthesis of multifunctional hetero- The employment of bulky groups around the aniline is to stabilize
cycles via direct oxidative C–H functionalization/cyclization has the imine towards hydrolytic cleavage.8 Based on the continued
emerged as an attractive and challenging goal.
efforts toward the C–H functionalization/alkynylation, silver
Heterocyclic compounds are of great chemical and biological salts have been found to display a critical potential to improve
significance in many fields. As important five-membered hetero- the selective transformation and avoid the homocoupling of
cycles,3 pyrroles are the basic constituents of numerous natural terminal alkynes.9 So several silver salts were firstly screened.
products, biologically active alkaloids and pharmaceuticals,4 When Ag2CO3 was employed as the mediator, the target pyrrole
and have also been found broad use in materials science.5 product 3a was obtained in 54% yield in the presence of KOAc
Accordingly, substantial attention has been paid for the con- in DMSO at 80 1C (Table 1, entry 4). Notably, in this reaction,
struction and modification of pyrroles,6 although most of these no terminal alkyne homocoupling byproduct was observed.
methods involve multistep synthetic operations and suffer from Ag2O could also provide the pyrrole product but AgOAc was
low efficiency and low selectivity. The direct, region-defined ineffective (Table 1, entries 2 and 3). Without either silver salts
syntheses of polysubstituted pyrroles from basic chemical materials or base, almost no reaction occurred (Table 1, entries 1 and 5).
are always highly attractive. Very recently, two efficient silver- Then the influence of base on the reaction was also investi-
catalyzed ‘‘click’’ syntheses of oligosubstituted pyrroles from gated. KOtBu turned out to be effective while reducing the yield
cycloaddition of terminal alkynes with isocyanides have been to 36% (Table 1, entry 6). The obvious improvement came from
reported.7 Herein, we communicated our efforts in the silver- DBU, which afforded the desired oxidative cyclization product
mediated synthesis of polysubstituted pyrroles through C–H/C–H in 75% yield (Table 1, entry 7). While other organic amine bases,
oxidative cross-coupling/cyclization between terminal alkynes such as TBD, pyridine and DABCO, all turned out to be less
effective (Table 1, entries 8–10).
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072,
With the optimized conditions in hand, substrate scope of
this silver-mediated oxidative cross-coupling/cyclization was tested
(Scheme 2). The reaction was readily extended to a variety of
Hubei, P. R. China. E-mail: aiwenlei@whu.edu.cn
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, 730000 Lanzhou, P. R. China
aryl-substituted terminal alkynes 1. Both electron-withdrawing
and -donating substituted groups were well tolerated under the
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc43682a
‡ These two authors contributed equally to this work.
c
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Table 1 Optimization of conditions for the reaction of 1a with 2a a
Entry
[Ag]
Base
Yieldb (%)
0
1
2
3
4
5
6
7
8
9
None
AgOAc
Ag2O
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
KOAc
KOAc
KOAc
KOAc
None
KOtBu
DBU
TBD
Pyridine
DABCO
o5
32
54
6
36
75 (71)
29
10
13
10
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), [Ag] (2.0 equiv.), base
b
(2.0 equiv.) in 6 mL of DMSO under N2 at 80 1C for 12 h. Yield determined
by GC analysis with naphthalene as the internal standard; isolated yield
for entry 7 in the parenthesis. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
TBD = 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine. DABCO =
1,4-diazabicyclo[2.2.2]octane.
reaction conditions, such as OMe, SMe, Ac, CO2Me, CO2Et and
Br (3b–3g). Meanwhile, regardless of the substitution pattern
of the aryl ring (ortho, meta, para) of the aryl acetylenes used in
the reaction, the corresponding pyrrole products were also
obtained in good yields (3b–3g). Terminal alkynes containing
a naphthalene moiety could also be employed to yield the
pyrrole scaffold without any difficulties (3h). Moreover, various
different substituted b-enamino esters 2 were also found to be
suitable reaction partners with terminal alkynes 1 in this
reaction. The ester group of 2 could be ranged from methyl to
tert-butyl, benzyl or ethyl esters, all of which reacted with
1-ethynyl-2-methoxybenzene 1b smoothly to afford the corre-
sponding pyrrole pruducts in good yields (3i–3k, 3o). In addi-
tion, the nitrogen protecting aryl groups of b-enamino esters 2
containing bromo or bulky substituents also allowed access to
the pyrrole ring (3b, 3l, 3n). Meanwhile, the corresponding
pyrroles with different substituents on the 2-position could also
be successfully synthesized in good yields (3o, 3p). Further-
more, a one-pot reaction sequence was performed successfully
(Scheme 3). In the presence of the mild Lewis acid catalyst
InBr3 (1 mol%), the b-enamino ester was easily formed at room
temperature by the condensation of 2,6-diisopropylaniline and
methyl 3-oxobutanoate. Then, the in situ formed b-enamino ester
underwent subsequent oxidative cross-coupling/cyclization with
terminal alkyne 1b under the standard conditions to give the
desired pyrrole product 3b in 75% yield. This efficient and
Scheme 2 Oxidative cyclization of terminal alkynes 1 and b-enamino esters 2.
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), Ag2CO3 (0.5 mmol), DBU
(0.5 mmol) in 6 mL of DMSO under N2 at 80 1C for 12 h, isolated yields.
Scheme 3 One-pot synthesis of pyrrole.
modular one-pot construction of pyrrole scaffolds from three Ag2CO3 was added into the DMSO solution of 1a, the peak of
simple and commercially available starting materials comple- 1a (765 cmꢀ1) consumed quickly upon the accumulation of the
ments the Hantsch-type pyrrole synthesis10 and increases its peak of AgHCO3 (802 cm
)
ꢀ1 12 and a new component I (754 cmꢀ1).
practicality.
It is reasonable to figure out that component I might be the
Usually, the reaction of terminal alkynes with silver(I) salts silver acetylide complex I. Actually, the large amount of white
in the presence of a base could afford silver acetylides.11 To precipitate in the reaction solution has a similar characteristic
elucidate the nature of the silver salt in this oxidative trans- to silver acetylide reported in the literature11 and displays low
formation, the stoichiometric reaction between phenylacetylene solubility in DMSO. In addition, to get more information about
1a and Ag2CO3 was firstly monitored by using in situ IR the structure of component I, the Raman spectrum of this white
spectroscopy (Fig. S2 in the ESI†). When an equivalent of precipitate was measured (Fig. S3 in the ESI†). The peak for the
c
7550 Chem. Commun., 2013, 49, 7549--7551
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for the highly selective oxidative alkynylation, which will be
quite important and of benefit for designing new reactions.
This work was supported by the 973 Program (2012CB725302)
and the National Natural Science Foundation of China (21025206
and 21272180). We are also grateful for the support from the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT1030).
Notes and references
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Scheme 4 Proposed mechanism for the silver-mediated oxidative cross-coupling/
cyclization.
CRC stretching mode of phenylacetylene 1a (2110 cmꢀ1) is red
shifted to 1983 cmꢀ1. This suggests that alkynyl carbon binds
covalently with silver and that the CRC bond is weakened by
electron transfer from the silver to the p* orbital of 1a.13 The
above results clearly revealed that silver acetylide (complex I)
was formed easily by the reaction of 1a and Ag2CO3.
According to the above information, a proposed mechanism
is outlined in Scheme 4. Initially, silver acetylide (complex I)
was formed by the reaction of terminal alkyne and Ag2CO3.
Then DBU could promote the monomerization of the polymeric
silver acetylide yielding the active nonpolymeric species
complex II (Fig. S4 in the ESI†), possibly aggregated with
additional Ag(I). Meanwhile, b-enamino esters were deproto-
nated by DBU to afford intermediate III (Fig. S5 in the ESI†),
which could undergo nucleophilic attack on complex II to give
the oxidative cross-coupling intermediate IV via two single-
electron oxidation. Finally, catalyzed by the silver species, the
cycloisomerization process could be facile and afford the final
pyrrole product.
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In summary, we have developed a novel silver-mediated
synthesis of polysubstituted pyrroles by the oxidative cross-
coupling/cyclization of terminal alkynes with b-enamino esters.
From the synthetic point of view, this protocol represents a
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c
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Chem. Commun., 2013, 49, 7549--7551 7551