Synthesis of multi-substituted pyrroles using enamides and alkynes catalyzed by Pd(OAc)2 with molecular oxygen as an oxidant

Article abstract of DOI:10.1039/c3cc49683j

A cyclization reaction between enamides and alkynes catalyzed by palladium(ii) acetate is described. In this method, the molecular oxygen serves as an efficient oxidant for the Pd(ii)/Pd(0) catalytic cycle. The simple reaction conditions permit this methodology to be used as a general tool for the preparation of multi-substituted pyrroles.

Full text of DOI:10.1039/c3cc49683j

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Synthesis of multi-substituted pyrroles using
enamides and alkynes catalyzed by Pd(OAc)2
with molecular oxygen as an oxidant†
Yun-He Xu,*a Tao He,‡a Qiu-Chi Zhang‡a and Teck-Peng Loh*ab
Cite this: Chem. Commun., 2014,
50, 2784
Received 21st December 2013,
Accepted 23rd January 2014
DOI: 10.1039/c3cc49683j
www.rsc.org/chemcomm
A cyclization reaction between enamides and alkynes catalyzed by preformed halogenated substrates and an excess amount of metal
palladium(II) acetate is described. In this method, the molecular oxygen salt as an oxidant is avoided.
serves as an efficient oxidant for the Pd(II)/Pd(0) catalytic cycle. The
The feasibility of the coupling reaction was initially examined
simple reaction conditions permit this methodology to be used as a using enamide 1a and diphenylacetylene (Table 1). A careful exam-
general tool for the preparation of multi-substituted pyrroles.
ination of the solvents in the presence of 10 mol% Pd(OAc)2 and
2 equivalents of NaOAc as additives revealed that DMSO is a better
The pyrrole ring is a core structure that features in a wide variety of choice for this reaction (Table 1, entries 1–5). Different palladium
natural products, organic materials and pharmaceuticals.1 It is also catalysts were tested and only Pd(OAc)2 could afford the deacylation
an important industrial synthetic building block.2 Consequently, the product 3a. Other Pd(II) catalysts afforded the product in poor yield
synthesis of the multi-substituted pyrroles has attracted much atten- and/or chemoselectivity (Table 1, entries 7–10). When different bases
tion among organic chemists.3 Among the methods developed, were added as additives to promote the reaction, NaHCO3 was found
metal-mediated or -catalyzed reaction using enamides as the starting to efficiently afford a mixture of products (3a :3a0 > 95:5 Table 1,
materials is one of the best methods to access the pyrrole products.4 entry 11). Other bases such as K2CO3, Cs2CO3 or Et3N gave the
In 2006, Crawley and co-workers adapted the ‘‘Larock Indole
Synthesis’’ approach and developed an efficient palladium-catalyzed
pyrrole synthesis by the reaction of 2-amino-3-iodoacrylates with
alkynes.5 Following this finding, Stuart and Fagnou reported a
rhodium(III)-catalyzed cyclization reaction of enamides and alkynes
to afford the pyrroles.6 Simultaneously, Glorius found that the multi-
substituted pyrroles could be achieved from the coupling of enamines
with alkynes using [Cp*RhCl2]2 as catalyst via allylic sp3 C–H activa-
tion of enamines.7 Recently, Wang’s and Ackermann’s research
groups, respectively, developed a ruthenium-catalyzed pyrrole syn-
thesis reaction using enamides and alkynes as the starting materials.8
Inspired by these pioneering studies, and following our continuing
interest in direct functionalization of b C–H bonds of palladium-
catalyzed enamides,9 we would like to report a new method to
synthesize the multi-substituted pyrroles via coupling of enamides
with alkynes catalyzed by a palladium catalyst by using molecular
oxygen as an oxidant.10 In this method, the need to use the
Table 1 Optimization of the reaction conditionsa
Entry Catalyst (mol%)
Base
Solvent 3a/3a0 Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(PhCN)2Cl2 (10)
Pd(OTFA)2 (10)
Pd(acac)2 (10)
NaOAc Toluene
NaOAc Dioxane
NaOAc t-Am-OH —
NaOAc DMF
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
—
—
—
—
—
—
—
>99 : 1
>99 : 1
58 : 42 36
98 : 2 32
60 : 40 30
10 : 90 51
53
17c
9
10
11
12
13
14
15
16
17
[Pd(CH3CN)4](BF4)2 (10) NaOAc DMSO
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
NaHCO3 DMSO
K2CO3 DMSO
Cs2CO3 DMSO
>95 : 5
>95 : 5
67
31
>95 : 5 o5
a Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, P.R. China. E-mail: teckpeng@ntu.edu.sg; Fax: +65 6515 8229;
Tel: +65 6513 8475
b Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637616
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/c3cc49683j
‡ T. H. and Q. Z contributed equally to this work.
Et3N
DMSO
DMSO
DMSO
DMSO
>95 : 5
>99 : 1
>99 : 1
>99 : 1
21
67
56
72
KOAc
KOAc
CsOAc
a
Unless noted otherwise, the reaction was carried out on enamide 1a
(0.4 mmol), diphenylacetylene 2a (0.44 mmol), and base (2 equiv.) with
palladium catalyst (10 mol%) under oxygen (1 atm) in solvent (4.0 mL).
b
c
TFA = trifluoroacetyl. Isolated yield. Under 1 atm N2 atmosphere.
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Table 3 Cyclization of enamide 1a with different disubstituted alkynesa
product in poor yield (Table 1, entries 12–14). But it was observed that
KOAc and CsOAc both could generate only 3a in good yield (Table 1,
entries 15 and 17). When the catalyst loading was reduced, a slightly
lower yield of 3a was found (Table 1, entry 16). Due to the moisture
sensitive nature of CsOAc in air, we decided to use KOAc as the
additive.
With the optimized reaction conditions in hand, we next
examined the scope of the enamide in this reaction (Table 2). It
was noticed that the substituent on the phenyl ring of compound
1 affected the product’s yield significantly. The substrates with
an electron-donating group favored this cyclization reaction
(Table 2, entries 3b, 3c and 3d). The naphthalene substituted
substrate could also afford the product in good yield (Table 2,
entry 3e). When the halogens were introduced at the para-
position of the phenyl ring, the desired cyclization products
were still preferred (Table 2, entries 3f, 3g and 3h). The tolerance
of halogen substituents will permit the product to be used for
further functionalization in the next step. However, a low yield of
the product was obtained when N-(1-(furan-2-yl)vinyl)acetamide
was applied in this reaction (Table 2, 3i).
Next, we turned our attention to test the scope of the acetylene
derivatives. We applied the N-(1-phenylvinyl)acetamide (1a) to
react with different acetylene derivatives under the standard
reaction conditions. As outlined in Table 3, all the symmetrical
Table 2 Cyclization of various enamides with diphenylacetylenea
a
Reaction conditions: unless otherwise noted, enamide 1a (0.40 mmol),
alkyne (0.44 mmol), KOAc (2.0 equiv.) and Pd(OAc)2 (10 mol%) in DMSO
b
(4.0 mL) under oxygen (1 atm) was heated for 24 h at 80 1C. Isolated
yields of the products.
diarylsubstituted ethyne could afford the corresponding cycliza-
tion products in good yields (Table 3, entries 1–5). Only 34% yield
of the product 4f was obtained when the 1,2-bis(2-fluoro-
phenyl)ethyne was used as the coupling partner. The aliphatic-
substituted ethyne does not favor this cyclization reaction
(Table 3, entry 8). Furthermore, the non-symmetrical disubsti-
tuted ethynes could be successfully employed in this palladium-
catalyzed cyclization reaction. The products 4 and 40 could be
obtained in reasonable to good yields but with poor regioselec-
tivities (Table 3, entries 9–11).
a
Reaction conditions: enamide 1 (0.4 mmol), diphenylacetylene 2a
(0.44 mmol), KOAc (2.0 equiv.) and Pd(OAc)2 (10 mol%) in DMSO
(4.0 mL) under oxygen (1 atm) was heated for 24 h at 80 1C. Isolated
yields of the products. The reaction time is 36 h.
b
c
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Scheme 1 Possible mechanism for the cyclization reaction catalyzed by
palladium(II) acetate.
Based on the observed results, a possible catalytic cycle was
proposed as shown in Scheme 1. Firstly, a vinylpalladium
species B was formed via the addition of palladium(II) acetate
to the enamide (A) or via direct vinyl C–H bond activation.9b
Next the alkyne replaces DMSO and coordinates with the
palladium center followed by migratory insertion to give inter-
mediate D. The cis-configuration of two phenyl groups favors
the new C–N bond formation. After palladium reductive elim-
ination, the final product was formed under basic hydrolysis.11
The Pd(0) generated was oxidized back to Pd(II) and involved in
the next catalytic cycle.
In conclusion, we have developed a palladium-catalyzed
cyclization reaction of enamides and internal alkynes to pre-
pare multi-substituted pyrroles in reasonable yields. The scope
of tolerated substrates in this work is rather broad. Moreover,
the reaction conditions of this method are quite mild in which
only molecular oxygen was used as the oxidant to recycle the
palladium catalyst.
This work was supported by the National Science Founda-
tion for Young Scientists of China (21202156), the National
Natural Science Foundation of China (21372210), the Funda-
mental Research Funds for the Central Universities
(WK2060190023) and the Natural Science Foundation of Anhui
Province (1308085QB37). The authors also thank the University
Science and Technology of China (USTC) for financial support.
The Singapore Ministry of Education Academic Research Fund
(MOE2011-T2-1-013 and MOE2010-T2-2-067) is also gratefully
acknowledged.
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2786 | Chem. Commun., 2014, 50, 2784--2786
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