Direct synthesis of pyrroles via a silver-promoted three-component reaction involving unusual imidazole ring opening

Article abstract of DOI:10.1039/c1cc14716a

A novel silver-promoted three-component reaction toward the synthesis of multifunctionalized pyrroles has been developed. This reaction involves an unusual imidazole ring decomposition, presumably via 1,5-isomerization and subsequent hydrolysis.

Full text of DOI:10.1039/c1cc14716a

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COMMUNICATION
Direct synthesis of pyrroles via a silver-promoted three-component
reaction involving unusual imidazole ring openingw
Jing Zeng, Yaguang Bai, Shuting Cai, Jimei Ma and Xue-Wei Liu*
Received 31st July 2011, Accepted 13th October 2011
DOI: 10.1039/c1cc14716a
A novel silver-promoted three-component reaction toward the
synthesis of multifunctionalized pyrroles has been developed.
This reaction involves an unusual imidazole ring decomposition,
presumably via 1,5-isomerization and subsequent hydrolysis.
Pyrrole is one of the most important heterocyclic structural
motifs present in a large number of natural and synthetic
molecules1 with a wide range of utilities in medicinal chemistry2
Scheme 1 Unexpected three-component reaction.
and material science.3 Consequently, the importance of this
heterocyclic motif has promoted the development of practical
and diversified synthetic methods.4,5 The traditional methods rely
three-component reaction could be a promising method to
synthesize functionalized pyrroles with high efficiency.
Our investigations commenced with the development of an
on the cyclization of amines with ketones or diketones discovered
by Knorr and Paal in 1880’s.6 However, shortcomings including
optimal set of reaction conditions (see ESIw). After screening
numerous conditions, it was found that the use of a quantitative
amount of AgBF4 and 1.5 equivalents of diisopropylethylamine
(DIPEA) as the additive in wet N-methyl-2-pyrrolidinone (NMP)
at 75 1C resulted in formation of the desired pyrrole 4a in 62%
yield. Further optimizations revealed that when a catalytic
amount of AgBF4 (0.2 equiv.) was used in combination with
1.2 equivalents of other silver additives with none or weak Lewis
acidity, such as AgNO3, Ag2CO3, Ag2O and AgF, the desired
pyrrole was still obtained in acceptable yields. Among the silver
additive tested, AgNO3 was found to be most compatible with
this system, displaying the highest efficiency (4a, 61%). Water
was proven to be necessary in the reaction system, when
anhydrous solvents were used instead of wet solvents, only a
trace amount of the desired pyrrole was observed. In all cases,
ketone 5 was obtained as the inevitable by-product.
low yields and stepwise reactions limited the usage of this type of
reactions. Recently, metal-catalyzed synthesis of pyrroles is
becoming increasingly popular due to its high efficiency of
constructing pyrrole motifs.7 Examples include Rh(III) catalyzed
coupling of alkynes with activated enamines,5b Rh(I) catalyzed
[4+1] cycloaddition reactions,7e Cu(II) or Mn(II) promoted
1,4-addition of acetoacetate to vinyl azides7f and more. In
addition, multicomponent reactions were also explored.8 Despite
all these achievements, it is still a big challenge to produce
multifunctionalized pyrroles from readily available and easily
varied substrates via a simple procedure.
In continuation with our interest in the syntheses of hetero-
cycles through multicomponent reactions,9 we observed that
the silver promoted three-component reactions of imidazole-
4-carboxaldehyde 1a, phenylacetylene 2a and morpholine 3a
afforded two unexpected products 3-aminopyrrole 4a (structure
was confirmed by X-ray structural analysis, see ESIw) and
ketone 5 as well as propargyl amine 6 (Scheme 1). 3-Amino-
pyrrole is an important class of pyrrole which exhibits antibacterial,
antiviral, anticonvulsant, analgesic, antiinflammatory, and anti-
pyretic activities.10 These features promoted us to investigate
this unexpected and interesting reaction. We envisioned that this
With these optimized conditions in hand, we embarked on
an investigation of the substrate scope of this interesting
transformation and the results are summarized in Table 1.
A variety of terminal alkynes were tested. Among them, all
aryl alkynes proceeded smoothly under the current conditions
and gave the corresponding pyrroles in good yields. The aryl
alkynes with electron-withdrawing groups produced the
desired pyrroles in slightly higher yields (4g–i) than those
bearing electron-donating groups (4c–f). The yields decreased
dramatically when alkyl alkynes were employed (4j–k). Secondary
amines other than morpholine and piperidine could be incorpo-
rated and the corresponding pyrroles were generated in good
yield (4l).
Division of Chemistry and Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University, 21
Nanyang Link, Singapore 637371. E-mail: xuewei@ntu.edu.sg
w Electronic supplementary information (ESI) available: Synthetic,
spectral and crystallographic details. CCDC 848255. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc14716a
Subsequently, imidazole aldehydes bearing substituents at
1- or 2- or 5-position were examined and the results are
c
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Chem. Commun., 2011, 47, 12855–12857 12855

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Table
1
Silver promoted three-component reaction: substrate
Table 3 Isotopic labelling reactiona
scopea,b
Entry
Additive
Products
Note
—
M = O, X = H
M = O, X = D
M = 18O, X = Hb
1
2
3
4
None
—
4b, 5
10a, 10b
10c, 10d
H2O (10 equiv.)
D2O (10 equiv.)
H218O (10 equiv.)
a
All reactions were carried out using 10 (1 equiv.), AgBF4 (0.2 equiv.),
AgNO3 (1.2 equiv.) and DIPEA (1.5 equiv.) and additive in anhydrous
a
Unless otherwise specified, all reactions were carried out using
aldehyde (0.3 mmol, 1 equiv.), alkyne (0.45 mmol, 1.5 equiv.) and
secondary amine (0.36 mmol, 1.2 equiv.) with AgBF4 (0.06 mmol,
0.2 equiv.), AgNO3 (0.36 mmol, 1.2 equiv.) and DIPEA (0.45 mmol,
1.5 equiv.) in wet NMP (NMP : H2O = 20 : 1, 0.6 mL) at 75 1C.
b
toulene at 75 1C. HR/MS (ESI) calcd for 10c: C16H19N218O [M +
H]+ 257.1540, found 257.1546; calcd for 10d: C12H11N218O [M + H]+
201.0914, found 201.0910.
b
added to the reaction instead of H2O, the deuterium atom was
observed at the 4-position of pyrrole 10a due to silver-D
exchange. The b-position of ketone 10b was also deuterized
while the a-position remained unchanged.11 The deuterization
of the b-position of ketone indicated that a 1,3-isomerisation
occurred. Similarly, a 1,5-isomerisation may be involved in the
formation of pyrrole. When H218O was utilized instead of
H2O, it was observed that the normal oxygen atom of the
carbonyl group of 10c and 10d was replaced by the 18O atom
indicated by HRMS. These experimental results strongly
suggested that the carbonyl moiety was formed via hydrolysis.
Interestingly, our further investigations of this reaction
revealed that the substrates 11 and 13 with functional groups
other than the amino group in the propargylic position could
also tolerate this reaction. However, the corresponding
products were generated in low yields as depicted in Scheme 2.
A plausible mechanism for this reaction is outlined in
Scheme 3 on the basis of the above experimental proofs.
Under optimized conditions, compound 16 was first generated
via silver catalyzed three-component Mannich–Grignard reaction
and it was then converted to compound 18 by cyclization and
silver-proton exchange.9a,12 Presumably, 18 could proceed
along two pathways: 1,3-isomerisation and 1,5-isomerisation.
The 1,3-isomerisation would afford enamine 19 and, from
which, ketone 5 would be formed by hydrolysis. Since imidazole
is a quite stable moiety, a direct hydrolysis is unlikely to take
place on the aromatic imidazole ring, the 1,5-isomerisation
process would destroy aromaticity of the imidazole moiety and
simultaneously create a new aromatic pyrrole moiety to generate
20. Hydrolysis of the imine group of 20 would produce the
carbonyl group, subsequent hydrolysis steps resulted in
the formation of pyrrole 4a, formaldehyde and ammonia. In
the presence of silver salt, the well known silver mirror reaction
would take place consequently to consume the formaldehyde and
ammonia, which would push the hydrolysis equilibrium towards
Isolated yields.
Table 2 Reaction with substituted imidazole-4-carboxaldehydea,b
Starting material
Product (yield)
1
2
3
7 (R1, R3 = H; R2 = Trt) 7a (72%)
—
—
—
8 (R1, R2 = H; R3 = Me) 8a (21%) 8b (23%)
9 (R2, R3 = H; R1 = Me)
—
9b (56%) 9c (11%)
a
All reactions were carried out using aldehyde, phenylacetylene and
b
piperidine under standard reaction conditions. Isolated yields.
depicted in Table 2. It is not surprising that the reaction with
N-substituted imidazole-4-carboxaldehyde 7 only generated
the sole propargylic amine 7a in 72% yield. Noteworthily,
when 2-methyl imidazole-4-carboxaldehyde 8 were employed,
ketone 8b and uncyclized products 8a were obtained in low
yields and only a trace amount of the desired pyrrole-
2-carboxaldehyde was observed by mass spectroscopy. When
5-methylimidazole-4-carboxaldehyde 9 was introduced under
the standard reaction conditions, 2-acetylpyrrole 9b was
formed in 56% yield together with 11% yield of the corres-
ponding ketone 9c. This observation strongly indicated that
the carbonyl carbon of the pyrrole product came from the C5
of imidazole aldehyde, which suggested that unusual ring
opening reactions were involved in the reaction. Therefore,
we deduced that the unusual ring decomposition was caused
by hydrolysis.
To elucidate the hydrolysis process, controlled reactions and
isotopic labelling were performed, as shown in Table 3. In
these reactions, propargylamine 10 was prepared as the substrate.
As depicted before, the reaction did not proceed under anhydrous
conditions. However, when 10 equivalents of H2O were
employed, pyrrole 4b and ketone 5 were obtained in 51%
yield and 11% yield respectively. Interestingly, when D2O was
Scheme 2 Reaction with imidazole derivatives.
c
12856 Chem. Commun., 2011, 47, 12855–12857
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Scheme 3 A plausible mechanism.
the formation of the desired pyrrole product. The silver mirror
was indeed observed in some cases. The reaction precipitate was
further characterized by X-ray diffraction (XRD) (see ESIw).
In conclusion, we have developed a novel method for the
synthesis of multifunctionalized pyrroles through silver promoted
three-component reactions from imidazole aldehydes, secondary
amines and terminal alkynes. In this reaction, an unprecedented
imidazole decomposition was observed. Studies are ongoing to
understand the reaction mechanism and apply this methodology
to the synthesis of pyrrole alkaloids such as prodigiosin
families.1d,e
The authors thank Prof. Sunggak Kim and Prof. Koichi
Narasaka for fruitful discussion. We appreciate Dr Yongxin
Li for X-ray analyses, Mr Jiehua Liu for XRD test, and
gratefully acknowledge Ministry of Health (NMRC/H1N1R/
001/2009), Singapore for financial support.
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Chem. Commun., 2011, 47, 12855–12857 12857