An approach to the Paal-Knorr pyrroles synthesis catalyzed by Sc(OTf)3 under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.05.085

A facile synthesis of N-substituted pyrroles by the Paal-Knorr condensation has been accomplished using a simple procedure. Among different metal triflates screened, 1 mol % Sc(OTf)₃ efficiently promoted the reaction to give excellent yield (89-98%) under mild reaction conditions. Additionally, Sc(OTf)₃ could be recovered easily after the reactions and reused without evident loss in activity.

Full text of DOI:10.1016/j.tetlet.2006.05.085

Tetrahedron Letters 47 (2006) 5383–5387
An approach to the Paal–Knorr pyrroles synthesis catalyzed
by Sc(OTf) under solvent-free conditions
3
a
a
c
b
b
a,b,
*
Jiuxi Chen, Huayue Wu, Zhiguo Zheng, Can Jin, Xingxian Zhang and Weike Su
a
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, PR China
b
College of Pharmaceutical Sciences, Zhejiang University of Technology, Zhejiang Key Laboratory of Pharmaceutical Engineering,
Hangzhou 310014, PR China
c
Zhejiang Hisoar Pharmaceutical Co., Ltd., Taizhou 318000, PR China
Received 20 February 2006; revised 12 May 2006; accepted 12 May 2006
Available online 13 June 2006
Abstract—A facile synthesis of N-substituted pyrroles by the Paal–Knorr condensation has been accomplished using a simple pro-
cedure. Among different metal triflates screened, 1 mol % Sc(OTf)
3
efficiently promoted the reaction to give excellent yield (89–98%)
under mild reaction conditions. Additionally, Sc(OTf)
in activity.
3
could be recovered easily after the reactions and reused without evident loss
Ó 2006 Elsevier Ltd. All rights reserved.
Pyrrole is one of the most important heterocyclic
compounds, having become increasingly important in
medicinal chemistry and organic synthesis. Conse-
ronment friendly methods for the synthesis of pyrroles
is necessary part of organic synthesis.
1
quently, the enormous number of procedures have been
developed for the construction of pyrroles. The classic
methods for pyrroles synthesis are as follows: (i) the
As the increase in environmental consciousness chemical
research and industry, the challenge for a sustainable
environment calls for clean procedures that can avoid
using harmful organic solvents, or even better, do not
need solvent at all. Metal triflates are unique Lewis acids
2
Hantzsch reaction, which provides pyrroles from reac-
tion of a-chloromethyl ketones with b-ketoesters and
3
7
ammonia; (ii) the Knorr reaction, which assembles pyr-
that are currently of great research interest. Metal tri-
roles by the reaction between a-aminoketones derived
flates have low toxicity, low cost, high stability, ease to
handle and recover from water. In addition, metal tri-
flates are still active in the coexistence of many sub-
strates containing nitrogen, oxygen, phosphorus, and
sulfur atoms. Due to these advantages, they were widely
from a-haloketones and ammonia, and b-ketoesters;
4
(
iii) the Paal Knorr reaction, one of the most common
approaches in which c-diketone are converted to pyr-
roles from the reaction with primary amines (or ammo-
5
8
9
nia) in the presence of various promoting agents; (iv)
used in organic synthesis. Our previous research using
metal triflates stimulated us to investigate unceasingly
the Paal–Knorr reaction under solvent-free conditions.
Although the preparation of N-substituted pyrroles by
Paal–Knorr condensation reaction of amines with
1,4-diketones under solvent-free conditions could be
6
some other methods were also reported.
However, some of these methods often suffer from cer-
tain drawbacks such as hazardous organic solvents, high
cost, long reaction time, use of stoichiometric and even
excess amounts of acids because they can be trapped
by amine in this condensation, and drastic reaction con-
ditions. Therefore, the development of facile and envi-
5
d
achieved using zirconium complex, we found that
metal triflates were also excellent promoters for this
reaction. Herein, the presented protocol not only is
very simple and high-yielding but also greatly decreases
environmental pollution.
Keywords: Scandium triflate; Pyrrole; Paal–Knorr; Solvent-free
conditions.
At the onset of this work, we have investigated a variety
of conditions with the model reaction using metal tri-
flates as catalyst. The results are summarized in Table 1.
*
Corresponding author. Tel./fax: +86 571 88320752; e-mail:
suweike@zjut.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.085

5384
J. Chen et al. / Tetrahedron Letters 47 (2006) 5383–5387
Table 1. Paal–Knorr reaction of acetonylacetone (1a) with aniline
under different reaction conditions
Due to the good results obtained, we applied the opti-
mal protocol to a variety of amines and the results were
a
summarized in Table 2. In all cases, Sc(OTf) -cata-
O
Me
N
3
lyzed Paal–Knorr condensation reaction proceeded
smoothly and gave the corresponding products in excel-
lent yield.
Catalyst
Solvent
Me
Me
+
H N
2
Me
O
As shown in Table 2, a series of aromatic amines bearing
either electron-donating (Table 2, entries 2, 5–7) or elec-
tron-donating (Table 2, entries 3, 4, and 8) groups on
aromatic ring was investigated. The substitution group
on the phenyl ring did not make any difference in the
Paal–Knorr reaction. Moreover, we also examined the
Paal–Knorr reaction of aliphatic amines with 1a (Table
2, entries 9–14, 17). Similarly, the corresponding prod-
ucts were obtained with excellent yield. Under further
observation, it is observed that the reaction of chiral
amine such as (R)-(+)-phenylethanamine with acetonyl-
acetone do not cause any changes to the chirality of
the molecule. This phenomenon is also observed with
(S)-(À)-phenylethanamine when reacted with acetonyl-
acetone.
1a
2a
b
Entry
Solvent
Catalyst
Cu(OTf)
Loading
Yields (%)
(
mol %)
1
2
3
4
5
6
7
8
9
None
None
None
None
None
None
None
None
None
None
None
None
None
None
2
5
5
5
5
5
5
5
5
5
0.5
1
2.5
5
10
5
5
5
5
—
78
47
72
87
90
89
89
88
Mg(OTf)
Bi(OTf)
2
3
Yb(OTf)
Ga(OTf)
3
3
Y(OTf)
3
La(OTf)
Sm(OTf)
3
3
Eu(OTf)
3
88
80
10
11
12
13
14
15
16
17
18
19
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
c
3
3
3
3
3
3
3
93, 92, 89
94
96
96
64
Furthermore, we examined the reactivity of heterocyclic
H
2
O
amines with 1a in the presence of Sc(OTf) . Thus, with
3
CH
CH
2
Cl
NO
2
77
1 mol % Sc(OTf) the Paal–Knorr reaction of hetero-
3
3
2
63
34 (55 )
cyclic amine such as 2-aminopyridine and 1a without
any solvent at 30 °C affords 2-(2,5-dimethyl-1H-pyrrol-
d
None
None
CuCl
None
2
31
1
-yl)pyridine (2s), in 89% yield (Table 2, entry 19). Sim-
a
b
c
3
0 °C for 25 min.
Isolated yield.
Catalyst was reused for three times.
ilarly, 2-amino-5-methylpyridine also gave 5-methyl-2-
(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (2t) in 92% yield
(
Table 2, entry 20). Therefore, heterocyclic amines
d
2
In the presence of 40 mol % CuCl .
exhibited analogous behavior to that of aromatic amines
and aliphatic amines.
We examined different solvents such as CH NO ,
The reaction using Sc(OTf) as catalyst has exhibited
3
2
3
CH Cl , and H O. It shows that dichloromethane is a
one additional important feature, that is the ability to
tolerate various amines including aliphatic, aromatic,
and heterocyclic amines. Interestingly, using the present
protocol, the sterically hindered amines such as 2,6-
diisopropylaniline, sec-butylamine, and 2,6-dimethyl-
2
2
2
better solvent (yield 77%) than other solvents tested
such as water (64%), CH NO (63%)). The best results
(
3
2
were obtained by carrying out the reaction at 30 °C for
2
5 min in the presence of a catalytic amount of Sc(OTf)3
1
0
without any solvent. In contrast, the corresponding
product was obtained in only low yield (31%) in the
absence of metal triflates (Table 1, entry 19). All metal
aniline smoothly reacted with 1a in high yield (Table
2, entries 5, 6, and 14). Unfortunately, no reaction of
tert-butylamine with 1a was observed under the same
conditions. On the other hand, the present protocol that
was also applied to less nucleophilic aromatic amine
such as 1-aminonaphthalen is superior to the previous
triflates with the exception of Mg(OTf) showed good
2
catalytic effects, but Sc(OTf) was particularly effective
3
for this condensation reaction. On the other hand, we
5
e
5e
also examined the activity of recycled Sc(OTf) catalyst
methods by montmorillonite KSF, I2 and Bi(NO3)3Æ
3
5
k
as a representative M(OTf) (Table 1, entry 11). Sc(OTf)
5H O (Table 2, entry 18). That means better yield
n
3
2
could be reused three times without evident loss of activ-
ity (with the yield of the corresponding product being
was obtained in shorter time.
9
3%, 92%, and 89% yield, respectively). Lewis acid CuCl2
To extend the scope of triflate-catalyzed method of pyr-
roles formation, other substituted diketones such as 1, 4-
diphenylbutane-1, 4-dione (1b) and 1-phenylpentane-1,
4-dione (1c) were used. Clean formation of pyrroles
(2u, 2v) was observed with 1b, 1c under solvent-free con-
ditions. The formation of 2u from 1b required longer
time (Scheme 1).
gave lower yield in the presence of 5 mol % (yield 34%)
even up to 40 mol % (yield 55%) of catalyst (Table 1, en-
try 18). In addition, we also studied influence of the
amount of Sc(OTf) on the reaction yields. We found
that the yield was not significantly affected by adding dif-
3
ferent amount of Sc(OTf) Æ1 mol % of Sc(OTf) was suf-
3
3
ficient, excessive amount of catalyst did not increase the
yield remarkably (Table 1, entries, 10–14). In the light
of this, subsequent studies were carried out under the
following optimized conditions, that is, with 1 mol %
Next, we investigated the reaction of diamines with 1a
(Scheme 2). In this reaction, two equivalents of 1a were
required in order to have a complete conversion of
diamines. When aliphatic diamines such as ethylenedi-
Sc(OTf) at 30 °C in the absence of solvent.
3

J. Chen et al. / Tetrahedron Letters 47 (2006) 5383–5387
5385
a
3
Table 2. Sc(OTf) catalyzed synthesis of pyrroles under solvent-free conditions
O
Me
N R
1
mol % Sc(OTf)3
Me
Me
+
H NR
2
Solvent-free
Me
O
1
a
2
b
Entry
Amine
NH
p-(CH )C
p-(Cl)C
p-(I)C
Product
Time (min)
Yield (%)
1
2
3
4
5
6
C
6
H
5
2
2a
2b
2c
2d
2e
2f
25
30
30
40
35
35
2
93
92
91
87
89
90
3
6
H
4
NH
NH
NH
2
6
H
4
2
6
H
4
2
i
2,6-( Pr)
2,6-(CH
2
C
6
H
3
NH
NH
2
2
3
)
2
C
6
H
3
75 (Ref. 10a)
7
8
9
o-(OH)C
p-(NO
CH
p-(OCH
p-(F)C
CH
6
H
4
NH
NH
NH
)C
CH
2
2g
2h
2i
30
30
30
30
30
30
30
40
91
90
94
98
93
95
94
81
2
)C
6
H
4
2
C
6
H
5
2
2
1
1
1
1
1
0
1
2
3
4
3
6
H
4
CH
NH
NH
2
NH
2
2j
6
H
4
2
2
2k
2l
C
6
H
5
2
CH
CH
2
2
CH
CH
3
CH
CH
2
2
CH
2
NH
)NH
2
2m
2n
3
2
CH(CH
3
2
3
00
35
35
72 (Ref. 5d)
92
91
1
1
5
6
R-(+)-C
6
H
5
CH(CH
3
CH(CH )NH
3
)NH
2
2o
2p
S-(À)-C
6
H
5
2
NH2
1
1
7
8
2q
2r
30
94
O
NH2
40
90
6
60
60
0
85 (Ref. 5e)
83 (Ref. 5e)
83 (Ref. 5k)
6
6
1
9
0
2s
30
89
6
0
78 (Ref. 5e)
70 (Ref. 5e)
70 (Ref. 5k)
1
1
500
500
N
NH2
Me
2
2t
40
92
N
NH2
a
Reaction conditions: amine (5 mmol), 1a (5 mmol), and Sc(OTf)
Isolated yield.
3
(1 mol %), 30 °C.
b
O
Ph
N
amine and hexylenediamine were examined, the corre-
sponding bis-pyrrole products (3a,b) were obtained
in 94% and 93% yields, respectively. However, sterically
more hindered aromatic diamine such as 1,2-benzenedi-
amine was examined, the reaction gave the only mono-
pyrrole product (3c) in the presence of two equivalents
and even three equivalents 1a.
Ph
Ph
1 mol % Sc(OTf)
3
+
H N
2
2 h
Ph
O
1b
yield 76 %, 2u
O
Me
1
mol % Sc(OTf)3
Me
Ph
N
+
In summary, a new catalytic protocol to synthesize pyr-
roles by Paal–Knorr condensation has been developed.
Compared to previous reported methodologies, the
present protocol features simple work-up, short reaction
time, environmentally benign, easy recovery and reuse
of metal triflates and mild reaction conditions with
50 min
H N
2
Ph
yield 84 %, 2v
O
1c
Scheme 1. Paal–Knorr condensation was carried out at 35 °C under
solvent-free conditions.

5386
J. Chen et al. / Tetrahedron Letters 47 (2006) 5383–5387
O
O
Me Me
Me
Me
1 mol % Sc(OTf)
Solvent-free
3
+
H N
NH2
N
N
2
n
n
Me
Me
n=0, yield 94 % 3a
n=4, yield 93 % 3b
1
a
O
O
Me H N
2
H N
2
1 mol % Sc(OTf)3
Me
Me
+
N
Solvent-free
H N
2
Me
yield 78 % 3c
1a
Scheme 2. Paal–Knorr condensation was conducted with diamines at 30 °C under solvent-free conditions.
excellent yield. Currently, studies on the extension of
this protocol are ongoing in our laboratory.
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