Synthesis of tetrasubstituted pyrroles by palladium-catalyzed cyclization of propargylic carbonates with β-enamino esters

Article abstract of DOI:10.1016/j.tetlet.2013.02.019

The reaction of propargylic carbonates with β-enamino esters in the presence of palladium catalyst is described. Various tetrasubstituted pyrroles were regioselectively synthesized via a successive nucleophilic cyclization.

Full text of DOI:10.1016/j.tetlet.2013.02.019

Tetrahedron Letters 54 (2013) 2082–2084
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Tetrahedron Letters
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Synthesis of tetrasubstituted pyrroles by palladium-catalyzed cyclization of
propargylic carbonates with b-enamino esters
⇑
Masahiro Yoshida , Chiyuki Sugimura
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of propargylic carbonates with b-enamino esters in the presence of palladium catalyst is
described. Various tetrasubstituted pyrroles were regioselectively synthesized via a successive nucleo-
philic cyclization.
Received 16 January 2013
Revised 2 February 2013
Accepted 6 February 2013
Available online 13 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reactions
Cyclizations
Palladium
Propargylic carbonates
Pyrroles
Pyrroles are one of the most important class of heteroaromatic
compounds which are components of a structural fragment of
many biologically active natural products,1 pharmaceutical
agents,2 and electronic and magnetic materials.3 From this reason,
constructive effort has been devoted toward developing a novel
methodology for the synthesis of pyrroles.4,5 However, in spite of
the existence of a variety of these approaches, synthesis of highly
substituted pyrroles remains challenging because it has difficult
problems for the regioselectivity and the versatility.
Palladium-catalyzed reactions of propargylic carbonates with
bis-nucleophiles have received considerable attention and have
been extensively studied.6,7 In this reaction, a substrate having
two nucleophilic moieties within the molecule successively re-
2a (Table 1). When 1a and 2a were treated with 5 mol % of
Pd2(dba)3ÁCHCl3, 20 mol % DPPB in THF at 50 °C, tetra- and trisubsti-
tuted pyrroles 3aa and 4aa were obtained in a 7:1 ratio and 81%
yield (Table 1, entry 1). Although the reason is not clear, it is inter-
esting to note that the trisubstituted pyrrole 4aa was produced pre-
dominantly in the presence of bulkier phosphine ligands DPPF,
BINAP, and DPEphos (entries 2–4). On the other hand, when DPPP
was employed in the reaction, the tetrasubstituted pyrrole 3aa
was produced as the sole product in 86% yield (entry 5). The yield
of 3aa was increased to 96% in the reaction using DPPE (entry 6).
The reaction of mesyl-substituted b-enamino ester 2b with 1a in
the presence of DPPE also proceeded to afford the tetrasubstituted
pyrrole 3ab in 67% yield (entry 7). The yield of the corresponding
product 3ac was decreased to 33% yield when p-nitrobenzenesulfo-
nyl-substituted substrate 2c was used (entry 8), but the b-enamino
acted with the
p-propargylpalladium complex, resulting from
propargylic carbonates with palladium, to afford the cyclized prod-
uct (Scheme 1). A variety of substituted hetero- and carbocyclic
molecules can be synthesized in one step by the choice of ade-
quately designed nucleophilic molecules. During the course of
our planning for further investigation of this cyclization process,
we took notice of the nucleophilic activity of b-enamino esters.
We report herein the palladium-catalyzed reaction of propargylic
carbonates with b-enamino esters, in which various tetrasubstitut-
ed pyrroles have been constructed efficiently via a successive
nucleophilic cyclization.
HNu
Nu'H
OCO2R''
R
cat.Pd(0)
R'
+
Pd
Pd
Nu
R'
R
R
R
R'
R'
Nu
Nu'H
Nu
Nu'
Nu'
The initial reactions were attempted using benzyl 1-phenyl-2-
propynyl carbonate (1a)8 and tosyl-substituted b-enamino ester
⇑
Scheme 1. Palladium-catalyzed cyclization of propargylic carbonates with bis-
nucleophiles.
Corresponding author. Tel./fax: +81 88 6337294.
E-mail address: yoshi@tokushima-u.ac.jp (M. Yoshida).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.019

M. Yoshida, C. Sugimura / Tetrahedron Letters 54 (2013) 2082–2084
2083
Table 1
various propargylic carbonates 1b–m with 2a (Table 2). When
the reactions of the substrates 1b and 1c containing a p-methoxy-
phenyl and a p-fluorophenyl group at the propargylic position
were carried out, tetrasubstituted pyrroles 3ba and 3ca were ob-
tained in 91% and 90% yield, respectively (entries 1 and 2). The
substrates 1d and 1e having a 3-furyl and a 1-naphthyl group also
reacted to produce the products 3da and 3ea in good yields (en-
tries 3 and 4). Although the yield was low, the corresponding
product 3fa was obtained in the reaction of the pentyl-substituted
substrate 1f (entry 5). When the propargylic carbonate 1g con-
taining a phenyl group on the alkynyl moiety was subjected to
the reaction, the tetrasubstituted pyrrole 3aa, which was the same
product from the reaction of 1a, was obtained in 92% yield (entry
6). Similarly, the corresponding products 3fa and 3ia were ob-
tained in high yields from the reactions using pentyl- and ethyl-
substituted substrates 1h and 1i (entries 7 and 8). Interestingly,
the reaction of the substrate 1j, which has a cyclohexyl group
on the alkynyl moiety, predominantly afforded the trisubstituted
pyrrole 4ja in 79% yield together with the tetrasubstituted prod-
uct 3ja in 15% yield (entry 9). The diphenyl-substituted substrate
1k uneventfully reacted with 2a to deliver the corresponding
product 3ka in 82% yield (entry 10). When benzyl 1-phenylbut-
2-yn-1-yl carbonate (1l) was subjected to the reaction, the 5-phe-
nyl-substituted pyrrole 3la was selectively produced in 82% yield
along with its regioisomer 4la in 13% yield (entry 11). The same
products 3la and 4la were obtained with a similar ratio from
The reactions of 1a with 2a–2d
OCO2Bn
5 mol %
Pd2(dba)3·CHCl3
20 mol % ligand
MeO2C
MeO2C
+
Ph
Ph
1a
+
THF, 50 ºC
0.5–3 h
Ph
RO2S
N
N
Ts
4aa
NH
O
SO2R
OMe
2a–2d
3aa–3ad
Entry Ligand
R
Products
3aa:4aa = 7:1
3aa:4aa = 1:1.5 92
3aa:4aa = 1:2.2 96
3aa:4aa = 1:2.3 94
Yield (%)
81
1
2
3
4
5
6
7
8
9
DPPB
DPPF
BINAP
p-Tolyl (2a)
p-Tolyl (2a)
p-Tolyl (2a)
DPEphos p-Tolyl (2a)
DPPP
DPPE
DPPE
DPPE
DPPE
p-Tolyl (2a)
p-Tolyl (2a)
Me (2b)
p-Nitrophenyl (2c)
2,4,6-Trimethyl-phenyl
(2d)
3aa
3aa
3ab
3ac
3ad
86
96
67
33
99
ester 2d having a 2,4,6-trimethylbenzenesulfonyl group success-
fully reacted to produce the pyrrole 3ad in 99% yield (entry 9).9
Having identified a useful set of reaction conditions to give tet-
rasubstituted pyrrole 3, we next conducted the reactions of
Table 2
Reactions using various propargylic carbonates 1b–m with 2aa
Entry Substrate 1
OCO2Bn
Product
Yield (%) Entry Substrate 1
Product
Yield (%)
91
MeO2C
OCO2Bn
OCO2Bn
MeO2C
( )4
( )4
1
2
3
N
Ts
91
90
76
7
8
9
N
Ts
OMe
1h
1i
3fa
OMe
3ba
3ca
1b
1c
1d
OCO2Bn
MeO2C
MeO2C
MeO2C
MeO2C
N
Ts
N
Ts
94
F
3ia
F
OCO2Bn
OCO2Bn MeO2C
MeO2C
Cy
Cy
Ph
3ja 15
4ja 79
Cy
N
Ts
N
Ts
N
Ts
O
1j
O
4ja
3da
3ja
OCO2Bn
OCO2Bn MeO2C
Ph
Ph
Ph
N
Ts
N
Ts
4
93
10
82
1k
3ka
3ea
1e
1f
OCO2Bn
( )4
MeO2C
OCO2Bn
Ph
MeO2C
MeO2C
MeO2C
Ph
3la 82
4la 13
( )4
Ph
5
6
31
92
11
12
N
Ts
3fa
N
Ts
N
Ts
1l
4la
Ph
3la
OCO2Bn MeO2C
OCO2Bn MeO2C
Ph
Ph
3la 79
4la 13
Ph
3la
Ph
N
Ts
3aa
N
Ts
N
Ts
1m
1g
4la
a
The reactions were carried out in the presence of 1 and 2a, 5 mol % Pd2(dba)3ÁCHCl3, 20 mol % DPPE in THF at 50 °C for 3 h.

2084
M. Yoshida, C. Sugimura / Tetrahedron Letters 54 (2013) 2082–2084
R2O2S
sive nucleophilic cyclization. Since many biologically active
NH
O
compounds which have a pyrrole component have been reported,
our methodology would provide a new protocol for the synthesis
of these compounds with high efficiency.
OMe
PdLn OBn
OCO2Bn
R1
Pd(0)
2
R1
5
1a–f
Acknowledgment
MeO2C
This study was supported in part by a Grant-in-Aid for the
Encouragement of Young Scientists (B) from the Japan Society for
the Promotion of Science (JSPS).
MeO2C
MeO2C
MeO2C
PdLn
R1
R1
N
N
R1
N
SO2R2
SO2R2
R2O2S
Supplementary data
6
3
7
R1
R1
Supplementary data (experimental procedures and character-
ization of the products) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.02.019.
MeO2C
PdLn
N
SO2R2
4
N
R2O2S
8
References and notes
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OCO2Bn
1g–i
Pd(0)
R1
+ 2
6
3
MeO2C
MeO2C
Pd(0)
1l 1m 2a
or
+
PdLn
Ph
N
Ts
N
Ph
Ts
3la
9
Scheme 2. Proposed reaction mechanism.
the reaction of benzyl 4-phenylbut-3-yn-2-yl carbonate (1m) (en-
try 12).
A plausible mechanism for the production of the pyrroles is
shown in Scheme 2. By reacting with the palladium catalyst, the
propargylic carbonates 1a–f are transformed to the
ladium complex 5, which causes nucleophilic attack of the
of the b-enamino ester 2 leading to the -allylpalladium intermedi-
ate 6. Then the intramolecular nucleophilic attack of the sulfon-
p
-propargylpal-
a
-carbon
p
amide anion to the
p-allylpalladium proceeds regioselectively at
the substituted carbon,10 followed by isomerization of the resulting
7 to produce the tetrasubstituted pyrrole 3. Trisubstituted pyrrole 4
would be formed via the intermediate 8, in which nucleophilic at-
tack occurs at the non-substituted carbon of the p-allylpalladium.
As a reason for the low conversion from the pentyl-substituted
substrate 1f (entry 5 in Table 2), it is expected that b-elimination
of palladium from the corresponding p-propargylpalladium inter-
mediate 5 would occur prior to the nucleophilic attack.11 The re-
sults about the conversion of the propargylic carbonates 1g–i to
the tetrasubstituted products 3 indicate that these reactions pro-
ceed via the formation of a common p-allylpalladium intermediate
6. As a reason for the opposite regioselectivity in the reaction of the
cyclohexyl-substituted substrate 1j (entry 9 in Table 2), it is ex-
pected the nucleophilic attack occurs selectively at the non-substi-
tuted carbon of the p-allylpalladium 8 because of the bulkiness of
the cyclohexyl group. In the case of the substrates 1l and 1m having
a methyl and a phenyl group, the regioselective cyclization would
8. We also attempted the reaction using methyl 1-phenyl-2-propynyl carbonate,
in which the yield of 3aa was slightly decreased in comparison with that of the
benzyl carbonate 1a.
9. We also examined the reactivity of benzyl-substituted b-enamino ester, but the
decomposition of the starting material was observed.
proceed at the phenyl-substituted carbon of the
species 9, presumably because of the electronic effect of the phenyl
group, to afford product 3la as the major product.
In conclusion, the effort described above has led to the develop-
ment of a palladium-catalyzed reaction of propargylic carbonates
with b-enamino esters. This process regioselectively produces tet-
rasubstituted pyrroles having a variety of substituents via a succes-
p-allylpalladium
10. It is known that the intramolecular nucleophilic attack to the p-allylpalladium
predominantly occurs at the more substituted carbon, see Refs. 6,7.
11. Mandai, T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji, J. Tetrahedron Lett. 1993, 34,
7615.