2,4- vs 3,4-disubsituted pyrrole synthesis switched by copper and nickel catalysts

Article abstract of DOI:10.1021/ol302270z

A novel and efficient copper or nickel catalyzed highly selective denitrogenative annulation of vinyl azides with aryl acetaldehydes has been developed. 2,4- and 3,4-diaryl substituted pyrroles, which are difficult to synthesize by the reported methods, can be highly regioselectively prepared by this protocol simply switched by the selection of the transition metal catalysts. Compared with the reported acidic or basic conditions for polysubstituted pyrrole synthesis, the present reaction conditions are mild, neutral, and very simple without any additives.

Full text of DOI:10.1021/ol302270z

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4926–4929
2,4- vs 3,4-Disubsituted Pyrrole Synthesis
Switched by Copper and Nickel Catalysts
Feng Chen,† Tao Shen,† Yuxin Cui,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China and Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, Shanghai 200062, China
jiaoning@bjmu.edu.cn
Received August 13, 2012
ABSTRACT
A novel and efficient copper or nickel catalyzed highly selective denitrogenative annulation of vinyl azides with aryl acetaldehydes has been
developed. 2,4- and 3,4-diaryl substituted pyrroles, which are difficult to synthesize by the reported methods, can be highly regioselectively
prepared by this protocol simply switched by the selection of the transition metal catalysts. Compared with the reported acidic or basic conditions
for polysubstituted pyrrole synthesis, the present reaction conditions are mild, neutral, and very simple without any additives.
Pyrroles are one of the important classes of heterocyclic
compounds as well as building blocks in many synthetic
pharmaceutical agents,1 natural products,2 and materials
science.3 Various synthetic methods have been developed
for the construction of pyrrole structures.4,5 However,
most known approaches are effective for 2,5-di- or poly-
substituted pyrroles.6 New synthetic strategies for the
generation of simple aryl-substituted pyrroles are of con-
tinuous interest. Particularly, synthetic routes to simple
2,4- or 3,4-diaryl substituted pyrroles are still limited,
especially if two different aryl substitutents are required,7,8
although these compounds have generated considerable
interest owing to their remarkable diversity of biological
activities,9 such as antidiabetic,9a fungicidal,9b or antibacterial9c
† Peking University
‡ East China Normal University
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r
10.1021/ol302270z
Published on Web 09/04/2012
2012 American Chemical Society

properties. Some limitations, such as equivalent reagents,7aÀc
multiple synthetic steps,7dÀf harsh reaction conditions with
high pressure,7g,h and limited substrate scope,7iÀl are involved
in the synthesis of 2,4-diaryl substituted pyrroles. Since
the modification of pyrroles by the electrophilic aromatic
substitution reactions or lithiation reactions preferred the
formation of R-substituted pyrroles, the construction of
3,4-diarylsubstituted pyrroles is very challenging.8b,10
Table 1. Screening of The Reaction Conditionsa
yield (%)b
3aa 4aa
On the other hand, establishing methods that can con-
struct different substituted pyrroles in an efficient manner
from the same readily accessible substrates continues to be
actively pursued. Our continuing interest in reactions using
azido reagents as the N-partner11 has encouraged us to try
the catalytic reaction for the construction of diaryl sub-
stituted pyrroles. Herein, we report a novel and highly
regioselective approach to 2,4- and 3,4-disubsituted pyr-
roles from readily accessible materials switched by copper
and nickel catalyst. Compared to the reported acidic or
basic conditions for polysubstituted pyrrole synthesis, the
present reaction conditions are mild, neutral and very
simple without any additives. In particular, this method
provides a new and unique strategy to synthesize asym-
metric 3,4-disubstituted pyrroles, which are probably the
most difficult to obtain by traditional methods.
entry
catalyst (mol %)
solvent
DMSO
t/°C
1
Cu(OAc)2 (4)
Cu(OAc)2 (4)
Cu(OAc)2 (4)
Cu(OAc)2 (4)
Cu(OAc)2 (2)
NiCl2 (5)
110
110
110
60
56
62
80
20
50
2
EtOH
3c
4c
5c
6c
7
DMSO/EtOH
DMSO/EtOH
DMSO/EtOH
DMSO/EtOH
DMAc
110
110
110
110
60
44
72
54
0
NiCl2 (5)
8
NiCl2 (2)
DMAc
12
0
9
NiCl2 (5)
DMAc
10
11
DMAc
110
110
0
0
HCl (10)d
DMAc
trace
15
a Reaction conditions: 1a (0.6 mmol) and 2a (0.4 mmol), catalyst, and
solvent (1.5 mL) with stirring under argon atomsphere for 4 h. b Isolated
yields. c Mixture solvent with DMSO (0.5 mL) and EtOH (1.0 mL).
d Concentrated hydrochloric acid (37%) was used.
R-Azidostyrene12 has been proven to be a useful
N-partner participating in various heterocyclic compound
syntheses. Recently, Chiba and co-workers reported a
significant Mn-catalyzed polysubstituted pyrrole synthe-
sis from R-azidostyrene.12e We envisioned that 2,4- or
3,4-diaryl substituted pyrroles could be achieved by the
reaction of R-azidostyrene with a selected C-precursor
such as acetaldehyde. The preliminary investigation em-
ployed R-azidostyrene (1a) and 2-phenylacetaldehyde (2a)
as the substrates. We systematically investigated a number
of experimental variables such as catalysts, additives,
reaction temperature, time, and solvents and other param-
eters (see the Supporting Information). Representative
results are summarized in Table 1. Interestingly, when
the reaction was performed in the presence of copper(II)
acetate (4 mol %) at 110 °C in DMSO under argon
atmosphere, 2,4-diphenyl-1H-pyrrole (3aa) was obtained
in 56% yield (entry 1, Table 1). The yield was achieved in
62% by using EtOH as the solvent instead of DMSO (entry 2).
The reaction was found to proceed more efficiently in
a polar solvent. Then the reactions in mixed solvent were
investigated. Significantly, the mixed solvent DMSO/
EtOH led to the highest yield of 3aa (80%, entry 3). Low
yields were obtained upon reducing the amount of catalyst
copper(II) acetate to 2 mol % or decreasing the reaction
temperature to 60 °C (entries 4 and 5, Table 1).
We were delighted to find that 3,4-diphenyl-1H-pyrrole
(4aa) was obtained successfully when nickel chloride
(5 mol %) was used as the catalyst without the detection
of 2,4-diphenyl-1H-pyrrole (3aa) (entry 6, Table 1). The
yield of 4aa was producedin 72% when DMAcwas used as
solvent (entry 7). The yield of 4aa decreased to 50% with
the formation of 3aa (12%) in this reaction condition when
2 mol % NiCl2 was used (entry 8). No product was
generated when the reaction temperature was decreased
to 60 °C (entry 9). Furthermore, trace products were
detected in the absence of catalyst (entry 10, Table 1).
Brønsted acid13 such as HCl has very low catalytic activity
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Org. Lett., Vol. 14, No. 18, 2012
4927

for the formation of one of the pyrrole regioisomers (entry 11,
Table 1). Therefore, 2,4- and 3,4-disubsituted pyrroles
could be easily and highly regioselectively obtained in high
yields just by switching the copper and nickel catalysis.
All these reactions performed with high regioselectivities
under the Cu- and Ni-catalysis, respectively (Scheme 1 and
Table 2).
Table 2. Nickel Catalyzed 3,4-Disubsituted Pyrrole Formationa
Scheme 1. Copper Catalyzed 2,4Disubsituted Pyrrole Formation
a 10% 4ia was obtained.
After optimizing the reaction conditions, we subse-
quently investigated the substrate scope of this highly
regioselective protocol (Scheme 1 and Table 2). Under
the Cu-catalysis conditions, various desired 2,4-disubsi-
tuted pyrroles were obtained in moderate to good yields
from corresponding substituted vinyl azides and phenyl-
acetaldehydes (Scheme 1). The structure of 3aj was
further proven by X-ray diffraction (see the Supporting
Information). The reaction efficiencies were not signifi-
cantly affected by the substituted groups at different
position (para, meta, or ortho-position) of the aromatic
ring of vinyl azides. Additionally, halo-substituted vinyl
azides and phenylacetaldehydes performed well under the
standard conditions generating the halosubstituted prod-
ucts. Furthermore, the heteroaryl-substituted substrate
2-(1-azidovinyl)-1-methyl-1H-indole (3i) was a compati-
ble substrate with the formation of 3ia in 39% yield
(Scheme 1).
a Reaction conditions: see entry 7, Table 1. b Isolated yields. c The
reaction temperature is 130 °C.
To probe the reaction mechanism of the regioselective
formation of 2,4- and 3,4-disubsituted pyrrole, a series
of control experiments have been designed and tested. As
2H-azirine12aÀd is assumed to be an intermediate of the
transformation, the reactions of phenylacetaldehyde (2a)
with 3-(naphthalen-2-yl)-2H-azirine 5 were conducted un-
der copper and nickel catalyzed system, respectively (eq 1, 2).
It was interesting that 3-(naphthalen-2-yl)-4-phenyl-
1H-pyrrole (4ha) was obtained as the sole product in 30
and 90% yield, respectively, in the both Cu- or Ni-cata-
lyzed reactions (eq 1, 2). No 2-(naphthalen-2-yl)-4-phenyl-
1H-pyrrole (3ha) was detected under the Cu-catalytic
conditions (eq 1). These results indicate that 2H-azirines
could be the key intermediate in the Ni-catalysis but not
involved in the Cu-catalyzed reactions. Furthermore, the
results of isotopic labeling experiments demonstrate the
differences of these two catalytic systems. The reaction
of 1a and 2a catalyzed by Cu(OAc)2 using DMSO-d6
(0.6 mL) and CD3OD (0.6 mL) as solvent produced
product [d]-3aa in 69% yield with 80% of 3-H deuterated
(eq 3). In contrast, no hydrogen was deuterated of the
Then NiCl2-catalyzed 3,4-disubsituted pyrrole forma-
tion was investigated (Table 2). The substrate scope is also
broad, with various substituted vinyl azides and phenyla-
cetaldehydes leading to the corresponding asymmetric
3,4-disubstituted pyrroles in moderate to good yields.
(13) (a) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011,
€
€
76, 9353. (b) Schmidt, R. K.; Muther, K.; Muck-Lichtenfeld, C.;
Grimme, S.; Oestreich, M. J. Am. Chem. Soc. 2012, 134, 4421.
4928
Org. Lett., Vol. 14, No. 18, 2012

3,4-disubsituted pyrrole for nickel catalyzed reaction using
DMSO-d6 and CD3OD as solvent (eq 4).
Scheme 2. Proposed Mechanisms
On the basis of above experimental observations, plau-
sible mechanisms for these highly regioselective transforma-
tions are proposed. For the Cu-catalyzed 2,4 disubsituted
pyrrole formation (path a, Scheme 2), Cu(OAc)2 might be
initially reduced by DMSO/EtOH to form a CuI species
or by disproportionation14 to form a CuI species.12j Then,
the radical intermediates A are generated through a deni-
trogenative decomposition pathway of the vinyl azide.12j
Subsequently, the radical coupling of enol tautomers of
the phenylacetaldehydes with the intermediates A generates
the intermediates B, which undergo nucleophilic attack
to the aldehyde leading to the addition intermediates C.
Subsequent protonation generates the intermediates D,
and dehydration of intermediates D yields the target 2,4-
disubsituted pyrroles. The protonation of the Cu-aza-
enolates E could be proved by the results of isotopic labeling
experiments (eq 3).
In summary, we have demonstrated a novel and efficient
copper or nickel catalyzed highly regioselective denitro-
genative annulation of vinyl azides with aryl acetaldehydes.
2,4- and 3,4-diaryl substituted pyrroles, which are difficult
to synthesize by the reported methods, can be high selec-
tively prepared by this protocol simply switched by the
selection of the transition metal catalysts. Compared with
the reported acidic or basic conditions for polysubstituted
pyrrole synthesis, the present reaction conditions are mild,
neutral and very simple without any additives. Further
investigation of the scope and synthetic application of these
reactions are ongoing in our group.
For the Ni-catalyzed 3,4-disubsituted pyrrole forma-
tion (path b, Scheme 2), NiCl2 promoted thermal denitro-
genative decomposition of the vinyl azide 1a generates
2H-azirines H, which could not be produced in the pres-
ence of Cu-catalyst. Subsequent nucleophilic attack by
the enol tautomers of the phenylacetaldehydes affords
the intermediates J. Intramolecular ring-opening of inter-
mediates J yields five-membered species K. The following
β-OH elimination produces the 2H-pyrroles L and Ni
complexes, which react with 2 to regenerate enol inter-
mediates I. Finally 3,4-disubsituted pyrroles are achieved
via the tautomerition of intermediates L.
Acknowledgment. Financial support from National Basic
Research Program of China (973 Program 2009CB825300),
National Science Foundation of China (No. 21172006),
and Peking University are greatly appreciated. We thank
Guolin Wu in this group for reproducing the results of 3ab
and 4da.
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Xifra, R.; Parella, T.; Benet-Buchholz, J.; Schweiger, A.; Mitrikas, G.;
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Sola, M.; Llobet, A.; Stack, T. D. P. J. Am. Chem. Soc. 2010, 132, 12299.
Supporting Information Available. Experimentaldetails,
NMR spectra analysis of the products, and crystal data
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(b) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 1147. (c) Yao, B.; Wang, D.-X.;
Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899. (d) Ribas, X.;
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4929