A novel one-pot synthesis of 2-benzoylpyrroles from benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.02.054

We herein report a novel one-pot reaction for benzoylation of pyrrole. The key step in the reaction is generation of di(1H-pyrrol-1-yl)zirconium(IV) chloride complex which reacts with benzaldehydes and methyl benzoates to give 2-benzoylpyrroles as the major product.

Full text of DOI:10.1016/j.tetlet.2010.02.054

Tetrahedron Letters 51 (2010) 2039–2043
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A novel one-pot synthesis of 2-benzoylpyrroles from benzaldehydes
*
Ratnesh Sharma, Mangilal Chouhan, Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, Mohali, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report a novel one-pot reaction for benzoylation of pyrrole. The key step in the reaction is gen-
eration of di(1H-pyrrol-1-yl)zirconium(IV) chloride complex which reacts with benzaldehydes and
methyl benzoates to give 2-benzoylpyrroles as the major product.
Received 16 November 2009
Revised 5 February 2010
Accepted 10 February 2010
Available online 13 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrrole1 is the core unit of many therapeutically active molecules
such as tolmetin, atorvastatin, chlorfenapyr, premazepam, pyrvin-
ium, roseophilin, zomepirac and natural products such as bilins, bil-
anes, phycobilin, porphyrin and chlorophyll.2 Synthesis of pyrrole
derivatives involves two types of strategies: (a) condensation reac-
hyde using a preformed complex of zirconium tetrachloride and
pyrrole.
Thereactionsof pyrrole atposition2 oftenrequirestheuse of pro-
tecting groups at N1 which needs the additional steps of protection
and deprotection.13 In search of a viable methodology by which pyr-
rolecould be functionalizedin a simple and straightforward manner,
we found that a complex of pyrrole and zirconocene dichloride re-
acts with benzaldehyde to afford a mixture of non-isolable com-
pounds. The high rates of these reactions, the uncertainty in the
exact nature of the zirconocene species that initiate the coupling
and the fact that intermediate species have a transitory disposition
which is difficult in identifying make the kinetic and mechanistic
investigations of these reactions more difficult.14 Therefore an alter-
nate strategy was adopted by replacing the cyclopentadienyl group
by pyrrole-1-ide and the resulting zirconium complex was treated
with n-butyllithium followed by the addition of benzaldehyde at
45 °C. Quite interestingly the complex generated in situ reacted with
benzaldehyde to give 2-benzoylpyrrole along with benzyl alcohol
(Scheme 1). The scope of this method was generalized by employing
various substituted benzaldehydes bearing electron-withdrawing
groups and electron-donating groups (Table 1, entries 1–8).
For a detailed examination, the reaction between di(1H-pyrrol-1-
yl)zirconium(IV) chloride and 4-fluorobenzaldehyde (2d) was
considered. The addition of the aldehyde at different tempera-
tures helped us to draw important conclusions regarding the
tions of
a
-aminocarbonyl compounds and activated ketones (Knorr
pyrrole synthesis3) or
a
-halocarbonyl compounds, b-keto esters and
ammonia (Hantzsch pyrrole synthesis4) or 1,4-dicarbonyl com-
pounds and primary amines (Paal–Knorr synthesis5) and (b) func-
tionalization of pyrrole by substitution reactions.6 The reactions of
pyrrole are dominated by electrophilic substitution because of the
lone pair of electrons on the nitrogen and consequent stability of
the
r
-complexes.7 Such reactions necessitate that a delicate bal-
ance8 be achieved between the exploitation of nucleophilicity for
the required electrophilic substitution, and the containment of
nucleophilicity either through electronic or steric means to inhibit
over-substitution and/or unwanted transformations.
2-Benzoylpyrroles have been mostly synthesized using Friedel–
Crafts acylation9 or Vilsmeier–Haack reaction.10 Friedel–Crafts
acylation has posed serious drawbacks. The activation of carboxylic
acid is usually necessary and in most cases it is converted to the
reactive acid chloride in a separate step. The water sensitive Lewis
acid aluminium chloride usually forms a stable complex with the
product making isolation difficult. Also the reagent causes severe
problems in effluent management since neutralization of it results
in a gelatinous mass adding significant threats to the environment.
Further, the Friedel–Crafts reactions are usually carried out in hal-
ogenated solvents or volatile hydrocarbon solvents which are not
eco-friendly. Vilsmeier–Haack reaction is seriously hampered by
the limited substrate availability and substrate specificity. Poly-
merization of pyrrole and substituted pyrroles forming polypyr-
roles, often happens in these reactions leading to poor yields.11
Though it is well known that pyrrole reacts with aldehydes to form
porphyrin,12 in our efforts to obtain functionalized pyrrole, we
have observed the formation of 2-benzoylpyrrole from benzalde-
N
Li
1
OH
H
O
1) ZrCl4
O
2) n-BuLi
+
-78 oC to 45 o
C
N
H
45 oC, 48h
R
R
R
3(a-h)
2(a-h)
4(a-h)
* Corresponding author. Tel.: +91 172 2292045; fax: +91 172 2214692.
E-mail addresses: vnair@niper.ac.in, vn74nr@yahoo.com (V.A. Nair).
Scheme 1. General strategy for synthesis of 2-benzoylpyrroles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.054

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R. Sharma et al. / Tetrahedron Letters 51 (2010) 2039–2043
Table 1
Reactions with benzaldehydes and methyl benzoates
Entry
Starting material
Products (% Yield)
H
O
OH
O
N
H
1
OMe
3a (62%)
OMe
O
OMe
4a (30%)
H
O
OH
N
H
2
3
4
Me
Me
O
Me
4b (31%)
3b (65%)
H
H
O
OH
N
H
3c (45%)
4c (40%)
O
OH
O
N
H
F
F
F
3d (55%)
4d (36%)
OH
H
H
O
O
N
H
5
Cl
Cl
O
3e (63%)
Cl
4e (28%)
O
OH
N
H
6
7
8
Br
Br
O
Br
3f (67%)
4f (23%)
H
H
O
OH
N
H
CN
3g (61%)
CN
O
CN
4g (26%)
O
OH
N
H
NO2
NO2
NO2
3h (74%)
4h (21%)
MeO
O
O
O
N
H
9
Nil
3c (38%)
MeO
O
N
H
10
Nil
F
F
3d (58%)

R. Sharma et al. / Tetrahedron Letters 51 (2010) 2039–2043
2041
Table 1 (continued)
Entry
Starting material
Products (% Yield)
MeO
O
O
O
N
H
11
12
Nil
Nil
Cl
Cl
Br
3e (65%)
MeO
O
N
H
Br
3f (73%)
mechanistic aspects and the intermediates involved (Scheme 2).
Addition of the aldehyde at À78 °C to the complex generated
in situ afforded 1-(4-fluorobenzoyl)pentan-1-ol (5d) as the major
product along with a small amount of 2-(4-fluorobenzoyl)pyrrole
(3d), while addition at room temperature witnessed the forma-
tion of 4-fluorobenzyl alcohol (4d) and 2-(4-fluorobenzoyl)pyrrole
(3d) along with 1-(4-fluorophenyl)pentan-1-ol (5d) as the major
product. When addition was carried out at 45 °C, 4-fluorobenzyl
alcohol (4d) and 2,5-di(4-fluorobenzoyl)pyrrole (6d) were formed
with 2-(4-fluorobenzoyl)pyrrole (3d) as the major product.
No improvement in the reaction was observed with further
increase in temperature. Based on these observations, we tried to
depict a plausible mechanism for the reaction (Scheme 3).
Zirconium tetrachloride reacts with 2 equiv of N-lithiated pyrrole
to afford di(1H-pyrrol-1-yl)zirconium(IV) chloride (II), which on
reaction with benzaldehyde in the presence of n-butyllithium
might form the intermediate (III) and subsequently endure
b-hydride eliminations followed by insertion of benzaldehyde into
the hydride complex (IVa) or undergo a Tishchenko-type reac-
tion15 with benzaldehyde to form the intermediate (IVb) ensued
by a b-hydride elimination to afford bis(2-benzoyl-1H-pyrrol-1-
yl)(benzyloxy)zirconium(IV) hydride (V). Workup of the
reaction mixture yields 2-benzoylpyrrole along with benzyl
alcohol.
CHO
HO
O
Bu
-78 oC
F
48 h
+
N
H
Method A
F
3d
(3%)
F
5d
(97%)
OH
CHO
O
N
H
+
1) ZrCl4
RT
F
48 h
N
Li
F
4d
(13%)
OH
3d (8%)
Method B
2) n-BuLi
F
-78 oC
HO
Bu
+
CHO
F
5d (79%)
O
45 oC
48 h
F
N
H
+
Method C
F
F
4d (36%)
3d (55%)
F
F
+
N
H
O
O
(8%)
6d
Scheme 2. Temperature-based reactions of 4-fluorobenzaldehyde.

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R. Sharma et al. / Tetrahedron Letters 51 (2010) 2039–2043
n-BuLi (2 eq.)
-78 °C
N
Zr
Cl
N
-78 °C
ZrCl4
+
2 eq.
Cl
ArCHO
N
Li
I
II
Ar
Ar
-
H
N
N
H
O
Cl
O
Zr
N
Zr
N
Cl
-
O
O
Ar
H
Ar
H
III
ArCHO
β−hydride
Tishchenko type
reaction
elimination
Ar
H
H
Ar
Ar
O
N
O
N
O
H
Zr
Path 1
Path 2
Zr
N
N
O
H
O
Ar
Ar
H
ArCHO
β−hydride
insertion
elimination
IVa
IVb
Ar
N
O
H
Zr
N
H
O
O
Ar
Ar
V
Ar = Phenyl,
4-substituted phenyl
Ar
2
+
Ar
OH
N
H
O
Scheme 3. Plausible mechanism for the formation of 2-benzoylpyrroles.
Ar
OMe
N
n-BuLi (2 eq.)
-78 °C
N
Cl
N
O
Zr
Ar
N
2
Zr
N
H
ArCO2Me
Cl
O
O
Ar
Ar = Phenyl, 4-substituted phenyl
Scheme 4. Reactions of di(1H-pyrrol-1-yl)zirconium(IV) chloride with esters.
OMe
To add more authenticity to the proposed intermediate (III), the
Acknowledgement
reaction was carried out with different esters (Table 1, entries 9–
12) where the possibility of b-hydride elimination is completely
ruled out (Scheme 4). Interestingly and in agreement to our notion,
the reaction afforded 2-benzoylpyrroles as the only products
which justifies the intermediate involved and the formation of pri-
mary alcohols occurring with benzaldehydes.
To conclude, a novel one-pot reaction for benzoylation of pyrrole
using benzaldehydes and methyl benzoates was developed.16 This
improves upon previous syntheses of 2-benzoylpyrroles, which had
taken place in three to four steps affording products with low yields.
The authors acknowledge the research funding from the Council
of Scientific and Industrial Research (CSIR), India.
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