A novel indium-catalyzed three-component reaction: General and efficient one-pot synthesis of substituted pyrroles

Article abstract of DOI:10.1055/s-0030-1258525

A convenient and general approach towards the synthesis of substituted pyrroles from propargylic acetates, silyl enol ethers, and primary amines was described. This novel transformation was catalyzed by indium trichloride in a one-pot synthesis, and high

Full text of DOI:10.1055/s-0030-1258525

LETTER
2345
A Novel Indium-Catalyzed Three-Component Reaction: General and Efficient
One-Pot Synthesis of Substituted Pyrroles
S
ynthesis of Substitute
i
d
Pyrro
n
le
s
Lin,* Lu Hao, Rui-da Ma, Zhuang-ping Zhan
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. of China
Fax +86(592)2180318; E-mail: minlin@xmu.edu.cn
Received 27 May 2010
tions can directly construct complicated pyrrole-contain-
Abstract: A convenient and general approach towards the synthe-
ing molecules from readily accessible starting materials
sis of substituted pyrroles from propargylic acetates, silyl enol
ethers, and primary amines was described. This novel transforma-
under mild conditions.3 Although many advances have
emerged in the past decade, no examples of preparation
for substituted pyrroles directly from propargylic acetates,
silyl enol ethers, and amines have existed. Consequently,
it is highly desirable to explore this interesting field. Here-
in, as a result of the exploitation of metal-catalyzed prop-
argylic substitution reaction in our group,4 we wish to
report a highly efficient one-pot reaction for the synthesis
of substituted pyrroles from propargylic acetates, silyl
enol ethers, and primary amines using indium trichloride
as the catalyst.5
tion was catalyzed by indium trichloride in a one-pot synthesis, and
high yields of various pyrrole derivatives were obtained.
Key words: pyrrole, indium, one-pot reaction, propargylic acetate,
enoxysilane
Pyrrole is an extremely important heterocyclic unit broad-
ly found in naturally occurring and biologically active
molecules and frequently used as building block in mate-
rial science, pharmaceutical chemistry, and organic syn-
thesis.1 Accordingly, substantial attention has been paid to
develop efficient, general, and economic approaches for
their synthesis. Two principal strategies are commonly
used for the preparation of substituted pyrroles: one is the
functionalization of preexisting pyrrole-containing pre-
cursors through the introduction of new functional groups,
and the other is assembly of a new pyrrole ring by cycloi-
somerization of acyclic precursors. The former method is
not generally applicable due to the exceedingly high reac-
tive activity of pyrrole rings which usually polymerized in
the presence of Brønsted or Lewis acids.2 In contrast, the
latter route has greater potential for rapidly obtaining di-
versity in functionalized pyrroles. Among the many new
cycloisomerization reactions, metal-catalyzed one-pot
transformations are the most attractive, since those reac-
Recently, we described a general and effective approach
toward the expeditious assembly of substituted furans
from propargylic acetates and silyl enol ethers.6 It was
proposed that propargylic acetates 1 and silyl entol ethers
2 underwent an FeCl3-assisted nucleophilic substitution in
MeCN, leading to a g-alkynyl ketone intermediates 3
which, upon a subsequent PTSA-catalyzed cycloisomer-
ization, transformed into the final furan compounds 4
(Scheme 1, equation 1). Aiming at expanding the scope of
this novel one-pot reaction, we became interested in de-
veloping synthetic protocols for substituted pyrrole rings
(Scheme 1, equation 2).
In our initial study, we hypothesized that the pyrrole core
6 could be assembled by metal-catalyzed substitution–
cycloisomerization of propargylic acetates 1, silyl enol
R4
R4
R3
R1
OAc
R3
R4
R1
H+
Fe cat.
(1)
prior work
+
OH
R1
R3
O
OTMS
R2
R2
R2
4
2
3
1
R3
R4
R4
R1
OAc
R4
R1
R5
R2
R3
[In]
+
N
H
(2)
this work
R1
R5NH2
R3
OTMS
N
R5
R2
R2
7
1
2
5
6
Scheme 1 Synthesis of substituted furans and pyrroles by metal-catalyzed one-pot approach
SYNLETT 2010, No. 15, pp 2345–2351
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258525; Art ID: W08410ST
© Georg Thieme Verlag Stuttgart · New York

2346
M. Lin et al.
LETTER
ethers 2, and primary amines 7 (Scheme 1, equation 2). To
this end, propargyl acetate 1a and 2.0 equivalents of silyl
enol ether 2a were treated in the presence of 10 mol%
FeCl3 in chlorobenzene at 75 °C for 30 minutes, followed
by adding 2.0 equivalents of aniline (7a). Then, the reac-
tion was heated to refluxing temperature for an additional
12 hours. It was found that 1a, 2a, and 7a underwent the
desired cycloisomerization, affording the targeted pyrrole
6aa in 36% yield along with an acyclic g-alkynyl ketone
8a in 57% yield (Table 1, entry 1). On the basis of our pre-
vious observation, we reasoned that the poor yield of pyr-
role 6aa was probably due to the weak ability of FeCl3 to
activate the alkyne bond. Therefore, AgOTf and
Cu(OTf)2, generally considered possessing stronger
Lewis acidity and alkynophilicity, were adopted as the
catalysts under the same reaction conditions as FeCl3.
Gratifyingly, it was found that the reactions were drasti-
cally improved and the desired product 6aa was obtained
in 71% yield when the transformation was performed in
the presence of 10 mol% Cu(OTf)2 (Table 1, entry 3). In
contrast, the reaction catalyzed by AgOTf resulted in nei-
ther pyrrole nor g-alkynyl ketone (Table 1, entry 2). While
using a combination of AgOTf and Cu(OTf)2 as co-cata-
lyst, we were pleased to find a good yield of pyrrole that
was obtained without any detectable g-alkynyl ketone in-
termediate (Table 1, entry 4). Further screening of metal-
lic Lewis acids brought very different results (Table 1,
entries 5–13), among which InCl3 proved to be the most
effective catalyst and demonstrated higher catalytic effi-
cacy than that of the combination of Cu(OTf)2 and AgOTf
(Table 1, entry 10).
Table 1 Optimization of Catalysts and Solvents for the One-Pot
Synthesis of Substituted Pyrrolesa
Ph
Ph
Ph
N
Ph
6aa
+
Ph
OTMS
OAc
catalyst (10 mol%)
PhCl, reflux
2a
+
Ph
PhNH2
O
1a
Ph
7a
Ph
Ph
Ph
8a
Entry Catalyst
Solvent Time Yield of
Yield of
(h)b
12
24
5
6aa (%)c 8a (%)c
1
2
FeCl3
PhCl
PhCl
PhCl
36
0
57
0
AgOTf
Cu(OTf)2
3
71
85
0
20
0
4
Cu(OTf)2/AgOTf PhCl
3
5
Cu(OAc)2
CuI
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
24
24
24
12
10
1
0
6
0
0
7
CuSO4
0
0
8
BiCl3
71
19
88
0
21
61
0
9
HAuCl3·3H2O
InCl3
10
11
12
13
14
15
16
17
18
19
20
21
22
Notably, reducing the loading of InCl3 from 10 mol% to 5
mol% made a remarkable adverse influence on the reac-
tion, in which the pyrrole 6aa7,8 and the g-alkynyl ketone
8a were obtained in 61% and 19% yields, respectively
(Table 1, entry 17). It was indicative of that utilization of
10 mol% of InCl3 was indispensable to effect the com-
plete conversion of g-alkynyl ketones into the final pyr-
roles. Screening with reaction solvents showed that PhCl
was still the optimal solvent for this one-pot reaction
(Table 1, entries 10, 18–22).
RuCl3·3H2O
Mg(ClO4)2
AlCl3
24
24
24
24
12
24
10
0
0
0
27
0
46
0
Zn(OTf)2
Bi(OTf)3
SnCl4
38
0
29
0
InCl3 (5 mol%)
InCl3
61
0
19
86
19
0
Exhaustive optimization indicated that employment of 10
mol% of InCl3 in chlorobenzene was reasonably efficient
for the construction of pyrrole ring in the same vessel. Im-
portantly, the isolation of g-alkynyl ketone intermediate is
not necessary. Next, with the optimized combination of
catalyst and solvent in hand, the generality of this cyclo-
isomerization reaction was examined. To our delight, we
found this transformation to be very general for a wide
range of propargylic acetates, silyl enol ethers, and prima-
ry amines. Typical results are shown in Table 2, and the
reaction proceeded smoothly without exclusion of mois-
ture or air. The primary aromatic amines reacted very
well, providing the cycloisomerization products in 79–
88% yields (Table 2, entries 1–4), among which electron-
withdrawing as well as electron-donating groups on aro-
matic rings were well tolerated. In contrast, the reactions
of aliphatic primary amines comprising benzylamines
MeCN 10
DCE 24
MeNO2 10
toluene
p-xylene 1
InCl3
76
0
InCl3
InCl3
4
83
59
5
InCl3
0
a All reactions were carried out on a 0.5 mmol scale of 1a using 10
mol% of InCl3, 2.0 equiv of 2a (1.0 mmol) and 2 mL chlorobenzene
at 75 °C for 0.5 h, followed by adding 2.0 equiv of 7a (1.0 mmol).
Imination–cycloisomerization proceeded at reflux for an appropriate
time.
b Reaction time for imination–cycloisomerization.
c Isolated yields based on propargylic acetate 1a.
proceeded much more sluggishly (with prolonged reac-
tion time), but still afforded the desired products in good
Synlett 2010, No. 15, 2345–2351 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Pyrroles
2347
yields. On the other hand, the alkyne part in propaylic sub-
strates bearing either aromatic (R2 = Ar) or aliphatic sub-
stituents (R2 = Alk) smoothly transformed into the
expected products. It was worth mentioning that a TMS
group in the substrates was cleaved under the reaction
conditions (Table 2, entries 11–16). Thiophenyl-substitut-
ed propargylic acetate also gave a good yield (Table 2, en-
try 20). The transformations of the silyl enol ether of
cyclohexanone provided a similar result as good as those
of acetone and acetophenone (Table 2, entries 8, 13, and
14), generating the predicted products in moderate to
good yields.
[In]
OAc
R1
R3
N
R2
R4
R1
1
[In]
TMS
R1
O
R5
R2
R3
R2
isomerization
9
R4
H
2
R3
R4
R3
As a working hypothesis, we proposed the following plau-
sible mechanism to account for the propargylation, imina-
tion, and cycloisomerization cascade of propargylic
acetates 1, silyl enol ethers 2, and primary amines 7 into
the pyrrole units 6 (Scheme 2). First, SN1 substitution of
propargylic cation 9 and silyl enol ethers 2, the former is
generated by assistance of the metal catalyst, leads to g-
alkynyl ketone intermediate 8, which, upon imination by
the primary amine, produces the imine 10. The imine is in
equilibrium with its enamine isomer 11, which after an in-
tramolecular nucleophilic attack of enamine nitrogen at
the In-activated triple bond produces cyclic intermediate
12. The latter can transform into product 6 via the proton–
metal exchange and demetallation sequence. Thus, the
catalyst enters into the next catalytic cycle.
R3
R4
R1
N
R5
H
R4
R1
N
R1
O
R5
R2
CH2R2
6
R2
[In]
8
12
R3
R3
R4
R1
R4
R1
NR5
NHR5
R2
[In]
R2
[In]
11
10
Scheme 2 Proposed mechanism for the one-pot synthesis of pyrroles
a
Table 2 One-Pot Synthesis of Diversely Substituted Pyrroles Catalyzed by InCl3
R4
R3
R1
R4
OAc
OTMS
2
R2
InCl3 (10 mol%)
R1
R3
+
R2
N
R5
6
PhCl, reflux
one-pot
R5NH2
7
1
Entry
1
1 R1; R2
2 R3; R4
7 R5
Product 6
Time (h)b
Yield (%)c
88
Ph
Ph
1a Ph; Ph
2a Ph; H
7a Ph
1
Ph
N
Ph
6aa
Ph
Ph
Ph
N
2
1a Ph; Ph
2a Ph; H
7b 2-MeOC6H4
2
86
MeO
6ab
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2348
M. Lin et al.
LETTER
Table 2 One-Pot Synthesis of Diversely Substituted Pyrroles Catalyzed by InCl3a (continued)
R4
R3
R1
R4
OAc
OTMS
2
R2
InCl3 (10 mol%)
R1
R3
+
R2
N
R5
6
PhCl, reflux
one-pot
R5NH2
7
1
Entry
1 R1; R2
2 R3; R4
7 R5
Product 6
Time (h)b
Yield (%)c
Ph
Ph
Ph
N
3
1a Ph; Ph
2a Ph; H
7c 4-ClC6H4
3.5
84
Cl
6ac
Ph
Ph
Ph
N
4
1a Ph; Ph
2a Ph; H
7d 4-EtOOCC6H4
4.5
79
COOEt
6ad
Ph
Ph
5
6
1a Ph; Ph
1a Ph; Ph
2a Ph; H
2a Ph; H
7e Bn
9
85
82
Ph
N
Bn
6ae
Ph
Ph
Ph
7f n-C8H17
10
N
6
6af
Ph
Ph
7
8
1a Ph; Ph
1a Ph; Ph
2b Me; H
2c (CH2)4
7a Ph
7a Ph
3
90
87
N
Ph
6ag
Ph
Ph
2.5
N
Ph
6ah
Ph
Ph
9
1b Ph; n-Bu
2a Ph; H
7f n-C8H17
10
81
N
4
6
6ba
Synlett 2010, No. 15, 2345–2351 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Pyrroles
2349
Table 2 One-Pot Synthesis of Diversely Substituted Pyrroles Catalyzed by InCl3a (continued)
R4
R3
R1
R4
OAc
OTMS
2
R2
InCl3 (10 mol%)
R1
R3
N
R5
+
R2
PhCl, reflux
one-pot
R5NH2
7
1
6
Entry
10
1 R1; R2
2 R3; R4
7 R5
Product 6
Time (h)b
10
Yield (%)c
86
Ph
1b Ph; n-Bu
2a Ph; H
2a Ph; H
7e Bn
Ph
N
4
Bn
6bb
Ph
11
12
13
14
1c Ph; TMS
1c Ph; TMS
1c Ph; TMS
1c Ph; TMS
7a Ph
7a Ph
7e Bn
7a Ph
3
67
72
72
73
Ph
N
Ph
6ca
Ph
2b Me; H
2c (CH2)4
2c (CH2)4
3
N
Ph
6cb
Ph
3.5
N
Bn
6cc
Ph
6
N
Ph
6cd
Ph
Ph
15
1c Ph; TMS
1c Ph; TMS
2a Ph; H
2a Ph; H
7f n-C8H17
10
63
N
6
6ce
Ph
16
17
7c 4-ClC6H4
3.5
74
83
Ph
N
p-Cl-Ph
6cf
4-BrC6H4
1d 4-BrC6H4; n-Bu 2a Ph; H
7a Ph
3
Ph
N
4
Ph
6d
Synlett 2010, No. 15, 2345–2351 © Thieme Stuttgart · New York

2350
M. Lin et al.
LETTER
Table 2 One-Pot Synthesis of Diversely Substituted Pyrroles Catalyzed by InCl3a (continued)
R4
R3
R1
R4
OAc
OTMS
2
R2
InCl3 (10 mol%)
R1
R3
+
R2
N
R5
6
PhCl, reflux
one-pot
R5NH2
7
1
Entry
18
1 R1; R2
2 R3; R4
7 R5
Product 6
Time (h)b
Yield (%)c
4-MeO2CC6H4
1e 4-MeOOCC6H4;
n-Bu
4
2a Ph; H
7a Ph
4
78
90
N
Ph
Ph
6e
4-MeOC6H4
19
20
1f 4-MeOC6H4; Ph 2a Ph; H
7a Ph
7a Ph
2.5
Ph
N
Ph
Ph
6f
S
1g thiophenyl; Ph 2a Ph; H
3
88
Ph
N
Ph
6g
a All reactions were carried out on a 0.5 mmol scale of 1 using 10 mol% of InCl3, 2.0 equiv of 2 (1.0 mmol) and 2 mL chlorobenzene at 75 °C
for 0.5 h, followed by adding 2.0 equiv of 7 (1.0 mmol). Imination–cycloisomerization proceeded at reflux for 1–10 h.
b Reaction time for imination–cycloisomerization at reflux.
c Isolated yield based on propargylic acetates 1.
In summary, we have developed a general and highly ef-
ficient methodology for the synthesis of substituted pyr-
roles, in which the new rings are assembled by a indium-
catalyzed propargylic substitution and subsequent cyclo-
isomerization of propargylic acetates, enoxysilanes, and
primary amines. This novel transformation is performed
in a one-pot model and a wide range of functionalities are
well tolerated, providing a promising and practical route
to various pyrrole-containing molecules. Also, this work
represents a valuable complement to existing procedures
for the synthesis of multisubstituted pyrroles. Further
studies to expand the scope of synthetic utility of this
reaction are in progress in our laboratory.
References and Notes
(1) For recent reviews and selected examples, see: (a) Fan, H.;
Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108,
264. (b) Novak, P.; Müller, K.; Santhanam, K. S. V.; Haas,
O. Chem. Rev. 1997, 97, 207. (c) D’Souza, D. M.; Müller,
T. J. J. Chem. Soc. Rev. 2007, 36, 1095. (d) Balme, G.;
Bouyssi, D.; Monteiro, N. Heterocycles 2007, 73, 87.
(e) Cadierno, V.; Crochet, P. Curr. Org. Synth. 2008, 5, 343.
(f) Hughes, C. C.; Prieto-Davo, A.; Jensen, P. R.; Fenical,
W. Org. Lett. 2008, 10, 629. (g) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213. (h) Butler, M. S. J. Nat. Prod.
2004, 67, 2141. (i) Balme, G. Angew. Chem. Int. Ed. 2004,
43, 6238. (j) Fürstner, A. Angew. Chem. Int. Ed. 2003, 42,
3582. (k) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998,
97, 207.
(2) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 4th ed.;
Blackwell Science: Oxford, 2000, 237.
Supporting Information for this article is available online at
(3) For recent reviews and selected examples, see: (a) Patil,
N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(b) Eloisa, J.; Echavarren, A. M. Chem. Rev. 2008, 108,
3326. (c) Álvarez-Corral, M.; Muñoz-Dorado, M.;
Rodríguez-Garcia, I. Chem. Rev. 2008, 108, 3174.
(d) Weibe, J.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108,
3149. (e) Kel’in, A. V.; Stromek, A. W.; Gevorgyan, V.
J. Am. Chem. Soc. 2001, 123, 2074. (f) Chernyak, D.;
Gadamsetty, S. B.; Gevorgyan, V. Org. Lett. 2008, 10, 2307.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The research was financially supported by the National Natural Sci-
ence Foundation of China (No. 20772098).
Synlett 2010, No. 15, 2345–2351 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Pyrroles
2351
(4) (a) Ji, W.; Pan, Y.; Zhao, S.; Zhan, Z. Synlett 2008, 3046.
(b) Liu, X.; Huang, L.; Zheng, F.; Zhan, Z. Adv. Synth.
Catal. 2008, 350, 2778. (c) Zhan, Z.; Yu, J.; Liu, H.; Cui,
Y.; Yang, R.; Yang, W.; Li, J. J. Org. Chem. 2006, 71, 8298.
(5) For selected examples for In-catalyzed heterocyclic
synthesis via cycloisomerization, see: (a) Feng, X.; Tan, Z.;
Chen, D.; Shen, Y.; Guo, C.; Xiang, J.; Zhu, C. Tetrahedron
Lett. 2008, 49, 4110. (b) Kim, S. H.; Kim, S. H.; Kim, K. H.;
Kim, J. M. Tetrahedron Lett. 2010, 51, 860.
(8) A Representative Procedure for the Synthesis of
SubstitutedPyrrole2-Benzyl-1,3,5-triphenyl-1H-pyrrole
(6aa)
To a 10 mL flask, propargylic acetate 1a (0.5 mmol),
enoxysilane 2a (1.0 mmol), chlorobenzene (2.0 mL), and
InCl3 (0.05 mmol) were successively added. The reaction
was allowed to stir at 75 °C for 0.5 h, followed by adding
primary amines 7a (1.0 mmol). The reaction mixture was
heated to keep refluxing for an additional 1 h until
completion (monitored by TLC). Upon cooling to r.t., the
reaction mixture was then quenched with 1 M HCl (2 mL).
The organic and aqueous layers were separated, and the
latter was extracted with Et2O (3 × 5 mL). The combined
organic layers were dried over MgSO4 and filtered. The
filtrate was concentrated in vacuo, and then the residue was
purified by silica gel column chromatography (EtOAc–
hexane, 1:100) to afford the corresponding substituted
pyrroles. A yellow solid, mp 146–147 °C; yield 87% (0.167
g). 1H NMR (400 MHz, CDCl3): d = 7.50–7.52 (m, 2 H),
7.33–7.37 (m, 2 H), 7.07–7.24 (m, 12 H), 6.95–6.97 (m, 2
H), 6.88–6.90 (m, 2 H), 6.66 (s, 1 H), 4.04 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): d = 140.5, 139.1, 136.9,
134.8, 133.2, 130.2, 129.0, 128.8, 128.7, 128.3, 128.2,
128.1, 128.0, 127.7, 126.1, 125.9 (3), 124.4, 109.6, 31.5
ppm. IR (film): 1493, 1599, 3024 cm–1. ESI-MS: m/z (%) =
386 (100) [M + H+]. Anal. Calcd (%) for C29H23N: C, 90.35;
H, 6.01; N, 3.63. Found: C, 90.38; H, 6.00, N, 3.63.
(6) Zhan, Z.; Cai, X.; Wang, S.; Yu, J.; Liu, H.; Cui, Y. J. Org.
Chem. 2007, 72, 9838.
(7) General Experimental Methods
Propargylic acetates 1 and enoxysilanes 2 were prepared
according to published procedures. All other compounds are
commercially available and were used without further
purification. Infrared spectra were recorded on a Nicolet
AVATER FTIR360 spectrometer. NMR spectra were
recorded on a Bruker AVANCE DPX-400 instrument at 400
MHz (1H) or 100 MHz (13C). The chemical shift values (d)
are given in parts per million(ppm) and are referred to the
residual peak of the deuterated solvent (CDCl3). MS
measurements were performed on Bruker Reflex III mass
spectrometer. Elemental analyses were performed with a
PerkinElmer 2400 microanalyser. Flash chromatography
was performed with QingDao silica gel (300–400 mesh).
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