An easy one-pot synthesis of tetrasubstituted 3-alkynylpyrroles via multicomponent coupling reaction

Article abstract of DOI:10.1055/s-0028-1087952

A series of tetrasubstituted 3-alkynylpyrroles were synthesized via a three-component reaction of imines, phenylacetylene, and dialkylzinc. This method provided a new strategy for preparing tetrasubstituted 3-alkynylpyrroles which can be converted into mo

Full text of DOI:10.1055/s-0028-1087952

828
LETTER
An Easy One-Pot Synthesis of Tetrasubstituted 3-Alkynylpyrroles via
Multicomponent Coupling Reaction
O
ne-Pot Synthesis
u
of
T
etrasubs
e
tituted 3-A
m
lkynylpyrroles ing Chen,a Lei Hou,b Xingshu Li*a
a
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 51006, P. R. of China
Fax +86(20)39943050; E-mail: lixsh@mail.sysu.edu.cn
b
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering,
Sun Yat-Sen University, Guangzhou, 510275, P. R. of China
Received 28 October 2008
rivatives. The classic methods for pyrroles synthesis are:
(i) the Hantzsch reaction,7 which provides pyrroles from
the reaction of a-chloromethyl ketones with b-keto esters
and ammonia; (ii) the Knorr reaction,8 a method to pre-
pare pyrroles by the reaction of a-aminoketones derived
from a-haloketones with ammonia and b-keto esters; (iii)
the Paal Knorr reaction,9 the reaction of g-diketone with
primary amines (or ammonia) in the presence of various
promoting agents.10 Recently, other strategies including
MCR11 and transition-metal-catalyzed processes12 have
also been investigated.
Abstract: A series of tetrasubstituted 3-alkynylpyrroles were syn-
thesized via a three-component reaction of imines, phenylacetylene,
and dialkylzinc. This method provided a new strategy for preparing
tetrasubstituted 3-alkynylpyrroles which can be converted into
more complex molecules.
Key words: multicomponent reactions, pyrroles, tetrasubstituted 3-
alkynylpyrroles
Multicomponent reactions (MCR), in which multiple reac-
tants are combined into the end product, are powerful
tools for the introduction of molecular diversity in an effi-
cient, economic, and environmentally friendly way in the
synthetic chemistry.1 In the past decade, a great deal of
success have been achieved in this field, and great efforts
continue to be made to develop new MCR.2
Although a lot of methods for the synthesis of pyrroles
have been reported, it is still challenging to prepare
polysubstituted pyrroles with various substituents directly
from readily available materials. To the best of our knowl-
edge, there have been no reports for the preparation of tet-
rasubstituted 3-alkynylpyrroles by one-pot coupling
reaction. Herein, we disclose the synthesis of these pyr-
role derivatives via the one-pot reaction of imines, phenyl-
acetylene, and dialkylzincs.
Pyrrole, one of the most important heterocyclic com-
pounds, and its derivatives have become increasingly im-
portant in medicinal chemistry and organic synthesis.3 It
has been widely used as antitumor,4a anti-inflammato-
ry,4b,c antioxidants,3c antibacterial,4d,e ionotropic,4f,g anti-
fungalagents,4h poly(ADP-ribose) polymerase inhibi-
tors,5a P38kinase,5b prolyl-4-hydroxylase,5c estrogen receptor
b-selective ligands,5d AT1-selective angiotensin II recep-
tor antagonists,5e and minor groove recognition ele-
ments.5f,g Especially, 1,2,3,5-tetrasubstituted pyrrole
derivatives (I, Figure 1) as antimycobacterial agents
showed better activity than streptomycin and isoniazid.6
In our study of enantioselective addition of phenylacety-
lene to imines,13 we found that the reaction of ethyl 2-(4-
methylphenylimino)acetate with phenylacetylene in the
presence of dimethylzinc did not give the normal propar-
gylamines. Instead, it afforded a three-component cou-
pling product, 1-(4-methylphenyl)-2-methyl-5-phenyl-3-
(phenylethynyl)-1H-pyrrole (1a, Scheme 1) and its struc-
ture was confirmed by X-ray crystallographic analysis
(Figure 2).14
N
S
OEt
O
OEt
N
R2
N
O
ZnMe2
NH
I
R1
Figure 1
+
Because of their various usages, many procedures have
been developed for the preparation of pyrrole and its de-
ZnMe2
toluene, r.t.
N
SYNLETT 2009, No. 5, pp 0828–0832
x
x.
x
x.
2
0
0
9
Advanced online publication: 24.02.2009
1a
DOI: 10.1055/s-0028-1087952; Art ID: W17408ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of tetrasubstituted 3-alkynylpyrrole

LETTER
One-Pot Synthesis of Tetrasubstituted 3-Alkynylpyrroles
829
Table 1 One-Pot Syntheses of Tetrasubstituted 3-Alkynylpyrroles
in Various Reaction Conditions
O
OEt
+
N
Me2Zn
toluene, r.t.
N
Entry Solvent Phenylacetylene ZnMe2 (equiv)
(equiv)
Yield (%)a
Figure 2 ORTEP drawing of compound 1a at 50% probability
The possible mechanism for the three-component cou-
pling reaction is shown in Scheme 2. First, reaction of
imine 1 with dimethylzinc gave the amino acid derivative
2. In the presence of excessive dimethylzinc, intermediate
2 then reacted with phenylacetylene to form a tertiary al-
cohol 3, similar to the reaction of aliphatic esters with
alkynyl lithium.15 Finally, the intramolecular cyclization
of 3 and subsequently dehydration led to the target prod-
uct 1a.
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
2
3
5
6
6
6
6
6
3
3
5
6
7
6
6
6
20
37
46
67
61
trace (0 °C)
53
5
Some other reaction parameters such as the choice of sol-
vent, equivalents of phenylacetylene, and dimethylzinc
were examined, and the results are summarized in Table 1.
The equivalents of phenylacetylene and dimethylzinc
were rather significant for the yields of the reaction. The
best result was obtained when the imine was treated with
six equivalents of phenylacetylene and dimethylzinc at
room temperature (Table 1, entry 4). However, when the
temperature was decreased to 0 °C, only trace products
were obtained (Table 1, entry 6). Other solvents, such as
dichloromethane and tetrahydrofuran were also screened
for the reaction, 53% yield was obtained in dichloro-
methane but very low yield was obtained in THF as the
solvent (Table 1, entries 7 and 8).
a Isolated yield.
In order to extend the scope of this reaction to the synthe-
sis of important tetrasubstituted 3-alkynylpyrroles, other
imines and diethylzinc were tested under the established
optimal reaction conditions.16 The results shown in
Table 2 indicated that imines with substituted groups at
the para position of the phenyl ring were favorable for the
reaction (51–67% yields were obtained, Table 2, entries
1–6). However, imines derived from aniline or 3-methyl
Me
O
O
Zn
OEt
OEt
Me2Zn
Ph
H
N
N
Me2Zn
OZnOEt
1
2
N
ZnMe
3
ZnMe
EtOZnO
HO
H2O
– H2O
N
N
N
4
1a
5
Scheme 2 Possible mechanism for the formation of tetrasubstituted 3-alkynylpyrroles
Synlett 2009, No. 5, 828–832 © Thieme Stuttgart · New York

830
X. Chen et al.
LETTER
aniline gave relatively lower yields (Table 2, entries 7–10,
35–46% yield). Furthermore, ortho-substituted imines
and the imine derived from 3-chloride aniline did not give
the corresponding products (Table 2, entries 11 and 12).
O
N
H
OMe
n-Bu
N
EtO
H
Me2Zn
N
+
toluene, r.t.
Table 2 One-Pot syntheses of Tetrasubstituted 3-Alkynylpyrrolesa
n-Bu
O
OMe
Scheme 3 Reaction of imines, alkyne, and dialkylzinc
O
The one-pot four-component reaction of amine, ethyl gly-
oxylate, phenylacetylene, and dimethylzinc was also car-
ried out (Scheme 4) and the result showed that it was
possible to perform the reaction in such a procedure.
However, it was obviously that the reaction of three-
component was favorable for rising the yields.
(R2)2Zn
OEt
+
R1
N
toluene, r.t.
R2
N
R1
Entry
1
R1
R2
Product
1a
Yield (%)b
In conclusion, a series of tetrasubstituted 3-alkynylpyr-
roles were synthesized via a three-component reaction of
imines, phenylacetylene, and dialkylzinc. This work rep-
resents a very simple method to generate these useful
tetrasubstituted 3-alkynylpyrroles. Further studies on the
biological activities of these compounds are under way.
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Ph
Me
Et
67
56
60
54
55
51
46
40
37
35
–
2
1b
3
Me
Et
2a
4
2b
5
Me
Et
3a
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
6
3b
7
Me
Et
4a
8
Ph
4b
Acknowledgment
9
3-MeC6H4
3-MeC6H4
3-ClC6H4
2-ClC6H4
Me
Et
5a
We thank the National Science Foundation of China (20472116)
and the Guangdong Province Natural Science Foundation
(04009804) for financial support of this study.
10
11
12
5b
Me
Me
5a
References and Notes
6a
–
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Scheme 4 One-pot, four-component reaction of amine, ethyl glyoxylate, phenylacetylene, and dimethylzinc
Synlett 2009, No. 5, 828–832 © Thieme Stuttgart · New York

LETTER
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LETTER
mixture was stirred, and then ethyl glyoxalate (12 mmol)
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crude imine (95% yield), which was used for the next step
without purification.
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General Procedure for the Preparation of Pyrrole
Derivatives
To a flask containing phenylacetylene (6 mmol), a 1.2 M
solution of Me2Zn in toluene (6 mmol) was added at r.t. The
resulting solution was stirred for 1 h, and then the imine
(1 mmol) in toluene (1 mL) was added at the same
temperature. The reaction mixture was stirred for 5 h. After
the reaction was completed (monitored by TLC), it was
quenched by addition of H2O (5 mL). The mixture was
diluted with Et2O, stirred for 5 min, and then filtered through
Celite. The collected filtrate was separated, and the aqueous
phase was extracted with Et2O (3 × 3 mL). The combined
organic phases were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced
pressure, the crude product was purified by flash column
chromatography (eluent: EtOAc–PE, 1:50) to afford the
desired pyrrole products.
(13) (a) Liu, J.; Liu, B.; Jia, X.; Li, X.; Chan, A. S. C.
Tetrahedron: Asymmetry 2007, 18, 396. (b) Liu, B.; Liu, J.;
Jia, X.; Huang, L.; Li, X.; Chan, A. S. C. Tetrahedron:
Asymmetry 2007, 18, 1124. (c) Liu, B.; Huang, L.; Liu, J.;
Zhong, Y.; Li, X.; Chan, A. S. C. Tetrahedron: Asymmetry
2007, 18, 2901.
2-Methyl-5-phenyl-3-(phenylethynyl)-1-p-tolyl-1H-
pyrrole (1a)
White solid. 1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H),
2.43 (s, 3 H), 6.60 (s, 1 H), 7.07–7.10 (d, 2 H), 7.16–7.19 (m,
7 H), 7.32–7.41 (m, 3 H), 7.57–7.60 (d, 2 H). 13C NMR (75
MHz, CDCl3): d = 12.75, 21.63, 85.48, 90.72, 103.35,
111.27, 124.78, 126.47, 127.56, 128.28, 128.50, 130.02,
131.47, 132.93, 134.07, 136.40, 136.51, 137.97. HRMS:
m/z calcd for C26H21N [M+]: 347.1679; found: 347.1680.
(14) The CCDC number: 706290.
(15) Humptman, H.; Mader, M. Synthesis 1978, 307.
(16) General Procedure for the Preparation of Imines
To a round-bottomed flask containing the amine (10 mmol)
in toluene (20 mL) was added anhyd Na2SO4 (50 mmol). The
Synlett 2009, No. 5, 828–832 © Thieme Stuttgart · New York

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