One-pot silver-catalyzed and PIDA-mediated sequential reactions: Synthesis of polysubstituted pyrroles directly from alkynoates and amines

Article abstract of DOI:10.1021/ol9026478

(Figure presented) The addition/oxidative cyclization of alkynes with amines In the presence of AgBF₄ catalyst and PIDA oxidant leads to polysubstituted pyrroles. The reaction corresponds to the construction of a pyrrole fragment, which also provides a new way to the formation of C-C bonds.

Full text of DOI:10.1021/ol9026478

ORGANIC
LETTERS
2010
Vol. 12, No. 2
312-315
One-Pot Silver-Catalyzed and
PIDA-Mediated Sequential Reactions:
Synthesis of Polysubstituted Pyrroles
Directly from Alkynoates and Amines
Weibing Liu, Huanfeng Jiang,* and Liangbin Huang
School of Chemistry and Chemical Engineering, South China UniVersity of
Technology, Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received November 17, 2009
ABSTRACT
The addition/oxidative cyclization of alkynes with amines in the presence of AgBF4 catalyst and PIDA oxidant leads to polysubstituted pyrroles.
The reaction corresponds to the construction of a pyrrole fragment, which also provides a new way to the formation of C-C bonds.
Pyrroles are one of the most important classes of heterocyclic
compounds as they are not only a key structural attribute of
many bioactive natural products,1 organic conducting materi-
als,2 and pharmaceutical substances3 but also a useful and
versatile building block in organic synthesis.4 In this regard,
there are many reports for the synthesis of pyrroles,5 such
as the classical Knorr reaction,6 Hantzsch reaction,7 and
Paal-Knorr8 condensation reaction. Recent strategies include
palladium-, platinum-, copper-, and gold-catalyzed cycloi-
somerization, cyclization reactions of a variety of acyclic
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10.1021/ol9026478  2010 American Chemical Society
Published on Web 12/11/2009

precursors,9 reductive coupling,10 aza-Wittig reactions,11
multicomponent coupling methodologies,12 and other mul-
tistep operations.13 However, some of them usually present
significant limitations, such as tedious workup, harsh nature
of reaction conditions, low yields, long reaction times, or
the requirement for an inert atmosphere. Therefore, the
continuous studies for the synthesis of pyrroles in terms of
efficient, environmentally benign, operational simplicity,
economic viability, and high selectivity are still of great
significance. Herein, we report an efficient and straightfor-
ward protocol under mild conditions to the synthesis of
pyrroles, which is also a novel one-pot strategy for silver-
catalyzed and PIDA-mediated sequential reactions.
At the outset of our studies, various silver catalysts were
tested by heating the mixture of dimethyl but-2-ynedioate
(1a) and benzylamine (2a) using PIDA as the oxidant in
dioxane at 100 °C (Table 1), and the expected tetramethyl
1-benzyl-1H-pyrrole-2,3,4,5-tetracarboxylate (3aa) was in-
deed obtained. Among the salts we tested, silver tetrafluo-
roborate (AgBF4) showed the highest activity for this reaction
(Table 1, entries 1-5). A survey of solvents indicated that
this reaction was sensitive to the solvent medium (Table 1,
entries 6-10). Among the various solvents examined,
dioxane, 1,2-dichloroethane (DCE), and acetonitrile (CH3CN)
were practical for this transformation (Table 1, entries 1, 9,
and 10). The reaction time had an obvious effect on this
reaction, and the suitable time was 3 h (Table 1, entries 1,
12, and 13). The dosage of PIDA had no significant impact
Table 1. Optimization of Reaction Conditionsa
catalyst
entry (5 mol %)
temp
(°C)
solvent
time (h) yieldb (%)
1
2
3
4
5
6
7
8
AgBF4
AgOTf
AgClO4
AgNO3
Ag2CO3
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMSO
100
100
100
100
100
100
100
100
80
2
2
2
2
2
2
2
2
2
2
3
4
3
3
75
29
49
32
63
41
27
22
65
72
85
85
89
88
DMA
DCE
9
10
12
13
14c
15d
acetonitrile
dioxane
dioxane
dioxane
dioxane
80
100
100
100
100
a 1a (0.50 mmol), 2a (0.25 mmol), solvent (2 mL), PIDA (1.0 equiv).
b GC yield. c PIDA (1.2 equiv). d PIDA (2.0 equiv).
on the reaction, and the best result was obtained when the
amount of PIDA was 1.2 equiv (Table 1, entries 12, 14, and
15).
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Under the optimized conditions, we explored the scope
of the reaction, and the results are summarized in Table 2.
Treatment of dimethyl but-2-ynedioate (1a) with various
amines 2 furnished the corresponding pyrroles 3 in moderate
to excellent isolated yields (Table 2, entries 1-12). As shown
in Table 2, aromatic amines whether with electron-withdraw-
ing groups or with electron-donating groups are all suitable
for this protocol. Besides, the reaction appears quite tolerant
with respect to the position of the substituent on the benzene
ring of the aromatic amines. For example, the addition/
oxidative cyclization of dimethyl but-2-ynedioate (1a) with
p-toluidine (2d) or m-toluidine (2e) as well as dimethyl but-
2-ynedioate (1a) with 4-chlorobenzenamine (2g) or 2-chlo-
robenzenamine (2h) led to pyrroles in reasonable yields
(entries 4, 5, 7, and 8). However, the reaction is quite
sensitive to the electronic contribution of the substituent on
the benzene ring. For example, the reaction of dimethyl but-
2-ynedioate (1a) with 4-methoxy-phenylamine (2c) afforded
tetramethyl 1-(4-methoxyphenyl)-1H-pyrrole-2,3,4,5-tetra-
carboxylate (3ac) in 78% yield, while 4-fluorobenzenamine
(2f) only resulted in tetramethyl 1-(4-fluorophenyl)-1H-
pyrrole-2,3,4,5-tetracarboxylate (3af) in 53% yield. Interest-
ingly, the amines bearing an aliphatic substituent proved to
be a suitable partner. All the tested aliphatic amines resulted
in excellent yields (Table 2, entries 1 and 9-12). Addition-
ally, diethyl acetylenedicarboxylate (1b), methyl propiolate
(1c), and ethyl but-2-ynoate (1d) can all react with benzy-
lamime (2a) smoothly to give corresponding pyrroles in good
yields (Table 2, entries 13-15).
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Org. Lett., Vol. 12, No. 2, 2010
313

that various substituted pyrroles can be designed and
constructed via the control of the starting materials of alkyne.
To probe the mechanism of reaction, dimethyl 2-(benzy-
lamino)maleate was employed to react with dimethyl but-
2-ynedioate using PIDA as the oxidant in dioxane for 3 h at
100 °C; however, neither the desired product 3aa nor the
hydroamination product 4 of dimethyl 2-(benzylamino)ma-
leate with dimethyl but-2-ynedioate was detected [eq 1].
Additionally, compound 4 which should be formed from the
hydroamination of dimethyl 2-(benzylamino)maleate with
dimethyl but-2-ynedioate was also not detected by GC/MS,
even with 5 mol % of AgBF4 as the catalyst [eq 2]. These
results indicated that 4 could not be a potential intermediate
in the transformation.
Table 2. Synthesis of Polysubstituted Pyrroles from Various
Alkynoates and Aminesa
1
2
yieldb
(%)
entry
(R1; R2)
(R3)
product
1
2
3
4
5
6
7
8
1a (Me; CO2Me) 2a (PhCH2)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3ba
3ca
3da
82
67
78
63
65
53
57
60
85
88
88
87
85
67
73
1a
2b (Ph)
1a
1a
1a
1a
1a
1a
1a
2c (p-MeOC6H4)
2d (p-MeC6H4)
2e (m-MeC6H4)
2f (p-FC6H4)
2g (p-ClC6H4)
2h (o-ClC6H4)
2i (Me)
9
10
11
12
13
14
15
1a
2j (Et)
1a
1a
2k [(CH2)2CH3]
2l [(CH2)3CH3]
2a
2a
2a
1b (Et; CO2Et)
1c (Me; H)
1d (Et; Me)
On the basis of these preliminary results, a plausible
mechanism of this addition/oxidative cyclization was hy-
pothesized as shown in Scheme 2. The first step involved
a 1 (1.0 mmol), 2 (0.5 mmol), PIDA (1.2 equiv), dioxane (2 mL).
b Isolated yield.
In light of the encouraging results, we then examined the
scope of the sequential reactions of benzylamine with the
crossed alkynoates. The reaction of dimethyl but-2-ynedioate
(1a) with diethyl acetylenedicarboxylate (1b) and benzy-
lamime (2a) led to 2,3-diethyl 4,5-dimethyl 1-benzyl-1H-
pyrrole-2,3,4,5-tetracarboxylate (3aba) in 63% isolated yield
(Scheme 1). Alternatively, 1e and 1f can also give reasonable
Scheme 2
.
Mechanistic Rationale for the Addition/Oxidative
Cyclization Reaction
Scheme 1. Diversity of Polysubstituted Pyrrole Synthesis
an activation of the C-C triple bond of the alkyne by Ag(I)
to form intermediate 5, which was followed by the addition
of benzylamine resulting in the formation of enamine
intermediate 8 and regeneration of the silver(I) catalyst. The
intermediate 9, generated by the action of the mild oxidant
PIDA on amides 8,14 reacts with another activated alkyne
and residue to a new intermediate 10. The C-Ag bond in
the intermediate 10 is protonated by acetic acid, and
yields of the desired polysubstituted pyrroles. The successful
sequential reactions are depicted in Scheme 1, which revealed
314
Org. Lett., Vol. 12, No. 2, 2010

nitrenium ion 11 is produced, which undergoes electrocyclic
ring closure to give the carbocation 12 and the subsequent
proton elimination to afford 13.15 Then, the C-I bond in 13
cleaves with concomitant electron-transfer to give another
carbocation 14 by losing one molecule of iodobenzene and
one molecule of acetate ion. Finally, the product 3 was
formed by proton elimination.
reaction. Furthermore, the readily accessible substrates,
relatively cheap oxidant PIDA, and silver catalyst and
moderate to excellent yields make the present reaction
potentially useful in organic synthesis. Now, studies are
ongoing in our laboratory to better understand the reaction
mechanism and apply this C-C bond formation method to
the synthesis of other heterocyclic compounds.
In summary, we have established a facile and highly
efficient C-N and C-C bond formation method to construct
a pyrrole framework directly. In this protocol, various amines
and alkynoates are suitable for this novel addition/oxidative
cyclization sequential reaction. Therefore, this methodology
not only provides a simple and convenient way to construct
polysubstituted pyrrole derivatives but also opens a brand
new way to build C-C and C-N bonds in a one-pot
Acknowledgment. We thank the National Natural Foun-
dation of China (Nos. 20625205, 20772034 and 20932002)
and Guangdong Natural Science Foundation (No. 07118070)
for financial support.
Note Added after ASAP Publication. There was an error
in the Table 1 graphic in the version published ASAP
December 11, 2009; the corrected version published ASAP
December 15, 2009.
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Supporting Information Available: Full experimental
details and copies of NMR spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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OL9026478
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