Synthesis of 2-benzoylpyrrole derivatives via C-H functionalization adjacent to nitrogen of pyrrole

Article abstract of DOI:10.1016/j.tetlet.2015.04.118

A direct transition-metal-free synthesis of 2-benzoylpyrrole derivatives from free (N-H) pyrroles and benzaldehyde has been developed. The benzoylation reaction at the 2 or 5-position of pyrrole proceeded well under the alkali metalation system and with 2

Full text of DOI:10.1016/j.tetlet.2015.04.118

Accepted Manuscript
Synthesis of 2-Benzoylpyrrole Derivatives via C-H Functionalization Adjacent
to Nitrogen of Pyrrole
Zhiqiang Guo, Xuehong Wei, Yupeng Hua, Jianbin Chao, Diansheng Liu
PII:
S0040-4039(15)00775-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.118
TETL 46258
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
1 April 2015
26 April 2015
28 April 2015
Please cite this article as: Guo, Z., Wei, X., Hua, Y., Chao, J., Liu, D., Synthesis of 2-Benzoylpyrrole Derivatives
via C-H Functionalization Adjacent to Nitrogen of Pyrrole, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.04.118
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Synthesis of 2-Benzoylpyrrole Derivatives via C-H
Functionalization Adjacent to Nitrogen of Pyrrole
Zhiqiang Guo,a Xuehong Wei,a, b∗ Yupeng Hua,b Jianbin Chao,a Diansheng Liu a
a Institute of Applied Chemistry, Shanxi University, Taiyuan, 030006, People’s Republic of
China
bSchool of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, 030006, People’s
Republic of China
KEYWORDS: Synthesis; Benzoylation; Pyrrole; alkali metalation; 2, 6-dimethylaniline
ABSTRACT: A direct transition-metal-free synthesis of 2-benzoylpyrrole drivatives from free
(N-H) pyrroles and benzaldehyde has been developed. The benzoylation reaction at the 2 or 5-
position of pyrrole proceeded well under the alkali metalation system and with 2, 6-
dimethylaniline as the additive in moderate to good yields. This strategy offers a simple, efficient
approach to synthesis of the 2-benzoylpyrrole derivatives.
For pyrroles are important units of many biologically active natural products and
pharmaceutical compounds, their synthesis and further functionalization are of considerable
∗ Corresponding author. Tel.: +86 351 7018390, Fax: +86-351-7011688;
E-mail address: gzq@sxu.edu.cn (Z. Guo), xhwei@sxu.edu.cn (X. Wei).
1

importance [1]. Among many efforts, the benzoylation reaction at the 2 or 5-position of pyrroles
attracts much attention in organic synthesis due to they are the key drug intermediate and present
in core structures in many biologically active derivatives [2]. Generally, the traditional synthetic
protocols for 2-benzoylpyrrole derivatives mainly include Friedel-Crafts acylations [3],
Vilsmeier-Haack reactions [4] and Grignard reactions [5]. However, the most frequently used
Friedel-Crafts acylation requires the use of protecting groups at N1 which needs the additional
steps of protection and deprotection [6]. Vilsmeier-Haack reaction is seriously hampered by the
limited substrate availability and substrate specificity. In a word, the existing methods often
involve uncommonly used acylated reagents or unbenign reaction conditions. Therefore, a simple
and efficient approach to synthesis of the 2-benzoylpyrrole derivatives is highly desired.
The direct sp2 C–H bond activation adjacent to nitrogen of pyrrole followed by C–C bond
formation is the most efficient and promising construction of 2-benzoylpyrrole derivatives. So
far, though there have many cases of C-C bond formation through activation of the C-H bond
adjacent to the heteroatom [7], to the best of our knowledge, only two examples reported for
benzoylation of pyrrole using benzaldehydes by Raines [2b] and Nair’ [8] group. In Raines’
studies, the benzoylation reaction was carried out in 54% yield using equimolar quantities of the
sodium derivative of pyrrole and the aromatic aldehyde. No significant change in yield took
place when 2 moles of the aromatic aldehyde were added to 1 mole of the sodium derivative of
pyrrole. In Nair’ paper, one-pot synthesis of 2-benzoylpyrroles from benzaldehydes needs 2
equiv of N-lithiated pyrrole react with Zirconium tetrachloride to afford di(1H-pyrrol-1-
yl)zirconium(IV) chloride, then treated with benzaldehyde in the presence of 2 equiv n-
butyllithium yield 2-benzoylpyrrole along with benzyl alcohol. Herein, we report a simple and
highly efficient reaction to form 2 or 5-substituted benzoylpyrrole derivatives by alkali
metallised pyrrole with benzaldehydes using 2, 6-dimethylaniline as an additive. In this reaction,
2

the C-C bond was formed simultaneously to afford these important heterocyclic compounds in
moderate to good yields.
Our initial studies focused on lithium complexes containing bidentate dianionic pyrrolyl
ligands and their catalytic activity for amidation of aldehydes with amines [9]. Surprisingly, the
yield of acylamide was very low when 2, 6-dimethylaniline was used. After careful separations
and recrystallizations, the benzoylpyrrole compound 3 was isolated partially from reaction
mixture, and its structure was confirmed by NMR spectra and X-ray crystal analysis (Figure 1).
Figure 1. The molecular structure of 3. Thermal ellipsoids are drawn at the 20% probability
level. Hydrogen atoms are omitted for clarity
Thus, we became interested in the 2, 6-dimethylaniline which was used as an additive in the
direct acylation reactions of pyrrole with aldehydes. In view of the byproducts, acylamide,
alcohol and ester, should be produced in the present of lithium complex in this process. After the
2-(tBuNHCH2)C4H3NH was deprotonated with n-BuLi, 1 equiv 2, 6-dimethylaniline and 3 equiv
benzaldehyde was added, the reaction went to completion in 5 h with 90.1% isolated yield (Table
1). Decreasing the amount of aldehyde from 3 equivalents to 2 and 1 equivalents led to a drop in
yield to 87.4% and 49.3% (Table 1, entries 1-3), respectively, and lowering the amount of 2, 6-
3

dimethylaniline from 1 equivalent to 0.5 and 0.3 equivalent did prove its effects is minimal
(Table 1, entries 2, 4-5). However, the isolated yield was only 57.9% without 2, 6-
dimethylaniline (Table 1, entries 6). To further examine the effect of steric and electronic
properties of amines on the reaction. Tert-butylamine, diphenylamine and 2, 6-diisopropylaniline
were investigated (Table 1, entries 7-9), the results indicated the amines play a important role in
this reaction, and the properties of amines affect the reaction. The ortho-position substituted
phenylamine were conducive to the benzoylation of pyrroles. Among the different solvents used
for optimization (Table 1, entries 4, 10-12), ether yielded best results.
Table 1. Optimization of reaction conditionsa
Amine
benzaldehyde
(equiv)
Entry
solvent
Yield (%)
(equiv)
1
3
2
1
2
2
2
2
2
2
2
2
2,6-Dimethylaniline (1)
2,6-Dimethylaniline (1)
2,6-Dimethylaniline (1)
2,6-Dimethylaniline (0.5)
2,6-Dimethylaniline (0.3)
2,6-Dimethylaniline (0)
Tert-butylamine (0.5)
Diphenylamine (0.5)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
90.1
87.4
49.3
87.1
85.9
57.9
68.7
79.8
86.7
71.3
73.4
2
3
4
5
6
7
8
9
2,6- Diisopropylaniline (0.5) Et2O
10
11
2,6-Dimethylaniline (0.5)
2,6-Dimethylaniline (0.5)
Hex
Toluene
4

12
2
2,6-Dimethylaniline (0.5)
THF
63.6
[a] Reaction conditions: 2-(tBuNHCH2)C4H3NH (3 mmol), 30 0C. [b] Isolated yield.
To further investigate the scope of the application for this benzoylation reaction under the
optimized conditions, we paid attention to the representative pyrrole and the other substituted
pyrroles. And the results are summarized in Table 2. Firstly, the pyrrole and different substituted
benzaldehyde were explored. To our delight, benzaldehydes bearing electron-neutral (4-H, 4-
CH3), electron-rich (4-OCH3), and halogenated (4-Br) groups all participated in this reaction
smoothly to afford the desired products in moderate to excellent yields (61.9-88.6%, entries 1-7).
Subsequently, the scope was also extended to some substituted pyrroles. 2, 4-dimethylpyrrole
and 2-(piperidylmethyl)pyrrole were applied to this transformation and giving the corresponding
products in 80.4 and 89.5% yields (Table 2, entries 8-12), respectively. The other aminomethyl
pyrroles also worked well under the optimized reaction conditions and obtained in 81.2-87.1%
yields (Table 2, entries 13-15).
Table 2. The benzoylation reaction of pyrroles with aldehydea
R'
n-BuLi
R'
CHO
R
N
R
2,6-Dimethylaniline
N
H
H
O
Yield
Entry
1
Pyrroles
Aldehyde
Products
（%）
81.5
74.3
N
H
2
N
H
5

3
4
5
6
7
8
61.9
85.8
88.6
67.9
71.8
80.4
N
H
N
H
N
H
N
H
N
H
N
H
9
81.7
83.4
89.5
N
H
10
11
N
H
N
H
6

N
H
12
87.4
N
13
14
15
87.1
81.2
83.6
[a]
Reaction conditions: pyrroles (3 mmol), benzaldehyde (6 mmol), 2, 6-Dimethylaniline (1.5
mmol), Et2O as solvent, 30 0C. [b] Isolated yield
Although the mechanistic details and the role of 2, 6-dimethylaniline are not clear at this stage,
the above experimental results and related literature suggest that there is an equilibrium between
the pyrrole lithium and adding amine (Scheme 1), the steric factors of amine appear to affects the
reaction, the products are mainly amides when R is hydrogen, the products are benzoylpyrrole
derivatives when the R is methyl groups. In other words, the reaction equilibrium shift to the left
when 2, 6-dimethylaniline was used as adding amine, which can be proved by obtained crystal
structure from the concentrated reaction solution of pyrrolyl lithium complex with 2, 6-
dimethylaniline in optimized reaction conditions (see supporting information). And the reaction
equilibrium shift to the right when phenylamine was used as adding amine, unfortunately, despite
repeated attempts using a variety of different methods, no expected intermediates were isolated,
but the reaction process should follows a route similar to that for alkali metal compounds
7

catalyzed amidation reactions is suggested [9]. Further investigations are needed to elucidate the
detailed mechanism.
Scheme 1. Possible mechanism for benzoylation of pyrrole derivatives.
CONCLUSIONS
In conclusion, we demonstrated a simple and efficient method for synthesis of 2 or 5-
substituted benzoylpyrrole derivatives by alkali metallised pyrrole with benzaldehydes using 2,
6-dimethylaniline as additive. This method shows good functional group tolerance and the C-C
bond is formed simultaneously to afford these benzoylpyrrole derivatives in moderate to good
yields.
Acknowledgments
Financial support from the National Natural Science Foundation of China (No. 20572065),
Special Fund for Agro-scientific Research in the Public Interest (No. 201303106) and the Natural
Science Foundation of Shanxi Province (No. 2011021011-1, 2014011049-26) are gratefully
acknowledged.
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Supplementary data
The general experimental procedure and characterization data of the products are available as
supporting information. Supplementary data associated with this article can be found, in the
online version or by direct contacting the authors.
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Graphical abstract
A direct transition-metal-free synthesis of 2-benzoylpyrrole drivatives from free (N-H)
pyrroles and benzaldehyde has been developed. This strategy offers a simple, efficient approach
to synthesis of the 2-benzoylpyrrole derivatives.
11