I2-Promoted Condensation/Cyclization of Aryl Methyl Ketones with Anilines for Facile Synthesis of 1,2,4-Triarylpyrroles

Article abstract of DOI:10.1002/ejoc.201501477

A novel iodine-mediated cascade condensation-cyclization of aryl methyl ketones with anilines has been successfully developed. According to this strategy, a variety of 1,2,4-triarylpyrroles were straightforwardly synthesized in moderate to good yields from very simple and readily available starting materials. A tentative reaction mechanism is presented. A novel iodine-mediated cascade condensation/cyclization of aryl methyl ketones with anilines has been successfully developed. According to this straightforward strategy, a variety of 1,2,4-triarylpyrroles were synthesized in moderate to good yields from very simple and readily available starting materials.

Full text of DOI:10.1002/ejoc.201501477

DOI: 10.1002/ejoc.201501477
Communication
Polysubstituted Pyrroles
I2-Promoted Condensation/Cyclization of Aryl Methyl Ketones
with Anilines for Facile Synthesis of 1,2,4-Triarylpyrroles
[
a]
[a]
[b]
[a]
Hui Xu, Fang-Jian Wang, Ming Xin, and Ze Zhang*
Dedication to Professor Tien-Yau Luh on the occasion of his 70th birthday
Abstract: A novel iodine-mediated cascade condensation-cy- triarylpyrroles were straightforwardly synthesized in moderate
clization of aryl methyl ketones with anilines has been success- to good yields from very simple and readily available starting
fully developed. According to this strategy, a variety of 1,2,4- materials. A tentative reaction mechanism is presented.
Introduction
lined in Scheme 1, including palladium-catalyzed arylation of
[
5]
2
,4-biarylpyrroles (a), condensation/cyclization of ꢀ-formyl
Polysubstituted pyrroles, including 1,2,4-triarylpyrroles, are key
structural units in numerous natural products. They have also
[
6]
[7]
aryl ketones (b), or γ-bromodypnones (c) with anilines, and
[
1]
most recently reported gold-catalyzed hydroamination/cycliza-
[
2]
been widely used for synthesis of bioactive molecules, phar-
[
8]
tion of α-amino aryl ketones with phenylacetylenes (d). Most
of these approaches are sufficiently powerful, but they often
involve special or expensive starting materials, preliminary
preparation of some kind of intermediates or precursors, and
employ noble- or heavy-metal catalysts. To overcome these
problems for more environmental and economical construction
of such N-heterocycles, an efficient strategy is oxidative C–H
amination from some easily available starting materials by
[
3]
[4]
maceuticals and functional materials. Currently, there are
several methods for the synthesis of 1,2,4-triarylpyrroles as out-
[
9]
metal-free reactions, in which molecular iodine has turned
[
10]
out to be a good alternative.
In view of the above points, we herein wish to present a
novel and simple one-pot synthesis of 1,2,4-triarylpyrroles by
iodine-promoted cascade condensation/cyclization from easily
available aryl methyl ketones and anilines.
Results and Discussion
Initially, we tentatively performed a reaction of acetophenone
(1a) with 4-methylaniline (2a) in heated 1,2-dichloroethane
(DCE) in the presence of iodine and obtained a product in
Scheme 1. Approaches to the synthesis of 1,2,4-triarylpyrroles.
somewhat low yield (Table 1, Entry 1). Structural analysis con-
firmed that this product is 1,2,4-triphenylpyrrole (3a). To the
best of our knowledge after comprehensive survey, we found
that it is a new organic transformation. This interesting result
prompted us to further optimize the reaction conditions for a
highly efficient synthesis of 1,2,4-triphenylpyrrole through this
novel one-pot condensation/cyclization process by screening
solvents, temperature, and molar ratio of the starting materials.
The results are summarized in Table 1.
[
a] School of Biological and Chemical Engineering, Anhui Polytechnic
University
Wuhu 241000, P. R. China
E-mail: zhangze@ustc.edu.cn
www.ahpu.edu.cn
[
b] College of Chemical Engineering, Zhejiang University of Technology
Hangzhou 310014, P. R. China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501477.
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Communication
Table 1. Optimization of the reaction conditions.[a]
Under the optimized reaction condition, various substituted
acetophenones and anilines were employed, and a series of
1,2,4-triarylpyrroles were obtained in moderate to good yields.
The results are summarized in Table 2.
From Table 2 it can be seen that anilines bearing either elec-
tron-donating or -withdrawing groups can afford the corre-
sponding products efficiently. In contrast, anilines with elec-
tron-donating groups exhibited higher efficiency. As to aceto-
phenones, those containing electron-withdrawing groups
worked very well, while those bearing electron-donating
Entry
Ratio
1a/2a/I
Base
[1 equiv.]
Solvent
T
[°C]
Yield
[%][
b]
[
2
]
1
2
3
4
5
6
7
8
9
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:2:1
2:2:1
2:2:1
2:2:2
2:2:0
2:2:1
2:2:1
–
–
–
–
–
–
–
DCE
toluene
PhCl
dioxane
MeCN
DMF
DMSO
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
28
30
38
groups (p-CH ) exhibited relatively lower efficiencies. In addi-
3
trace
n.d.[
c]
c]
c]
tion, 4-methoxyacetophenone has also been investigated, but
the desired product was hardly formed. This obvious electron
effect from the substituents may be understood from a poten-
tial point of view in that the formation of product 3 may un-
dergo in situ generation of a ketimine from the corresponding
acetophenone and aniline, during which electron-donating
groups in the acetophenone and electron-withdrawing groups
in the aniline are counterproductive. It should be pointed out
that a substituent in 2-position of the aniline or acetophenone
exhibited a significant steric effect. Taking 2-methoxylaniline as
an example, the corresponding product 3t was obtained in only
20 % yield. When 2-chloroacetophenone was employed to react
with aniline under the standard conditions, the corresponding
product cannot be detected.
[
n.d.
n.d.[
33
NaHCO
Na CO
CO
3
2
3
trace
trace
28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
K
2
3
KF
CsF
NaOH
DMAP
DBU
36
n.d.[
trace
trace
22
c]
Et
3
N
–
–
–
–
–
–
–
59
67
83
100
140
140
140
140
140
78
n.d.[
38
c]
[
d]
ionic liquid
PEG-400
In addition, we have also explored some aliphatic amines
including hexylamine and benzylamine. Unexpectedly and in-
terestingly, 2,4,6-trisubstituted pyridines (5a, 5b) were obtained
in excellent yields, while the corresponding 1,2,4-trisubstituted
pyrroles cannot be obtained at all (Table 3). This result is similar
trace
[
(
a] Reaction conditions: a mixture of 1a (1.0 mmol), 2a, I
4 mL) was stirred for 10 h. [b] Isolated yield based on 1a. [c] Not detected. [d]
The ionic liquid used herein is 1-butyl-3-methylimidazolium tetrafluoroborate.
2
, and base in solvent
to Jiang's work, which was achieved by a Cu(OTf) -catalyzed
formal C–N bond cleavage of amines.
2
Based on the structure of product 3a and the role of I as a
2
[11]
mediator but not a catalyst, we first fixed the molar ratio of
acetophenone (1a)/4-methylaniline (2a)/I2 at 2:1:1 to investi-
gate this reaction in different solvents at 80 °C (Entries 2–7).
The results demonstrated that strongly polar solvents such as
acetonitrile (MeCN), dimethyl sulfoxide (DMSO) and N,N-dim-
ethylformamide (DMF) cannot afford the product at all (En-
tries 5–7), while chlorobenzene exhibited the highest efficiency
to afford the desired product 3a in 38 % yield (Entry 4). Consid-
ering that HI was formed during the process, we speculated
that addition of base may promote the reaction to some extent.
Therefore, various organic and inorganic bases were employed
with PhCl as fixed solvent (Entries 8–16). Unfortunately, all of
these bases did not improve the efficiency of the reaction, but
instead inhibited it to some extent. Then we increased the
amount of 4-methylaniline (2a) and raised the reaction temper-
ature. To our delight, significant improvement was achieved
As to the reaction mechanism for the formation of 1,2,4-
triarylpyrroles 3, we initially hypothesized it as shown in
Scheme 2.
To verify this proposal, ketimine 6 was preliminarily prepared
[
12]
from acetophenone and 4-methoxylaniline. Under the stand-
ard conditions, the reactions of ketimine 6 with other different
acetophenones 1 were investigated [Scheme 3, (1)]. According
to the hypothesis in Scheme 2, we wished to obtain the corre-
sponding triarylpyrroles 8 with different substituents at 2- and
4
-positions. Unexpectedly, triarylpyrroles 8 cannot be observed
in these reactions. Instead, all these cases exclusively afforded
product 3d, and the added different acetophenones did not
participate in the reaction at all. Furthermore, the yield of 3d
was even higher than that in the above-mentioned one-pot
procedure. To further clarify the reaction mechanism, we carried
out another experiment [Scheme 3, (2)]. That is, ketimine 6 was
directly treated with iodine in chlorobenzene at 140 °C for 10 h.
Interestingly, the reaction afforded the product 3d in almost
quantitative yield, accompanied by a white precipitate, which
was proved to be 4-methoxyanilinium iodide since it was easily
transformed into 4-methoxyaniline after treatment with aque-
(
Entries 17–19), and the desired product 3a was obtained in a
good yield of 83 % when the reaction was performed in PhCl
at 140 °C with a molar ratio of acetophenone (1a)/4-methylani-
line (2a)/I at 2:2:1 (Entry 19). Further controlled experiments
2
implied that stoichiometric iodine was crucial since the absence
of I led to no product 3a (Entry 21), and a large excess of
2
ous Na CO .
I2 failed to promote the formation of the product (Entry 20).
Furthermore, some green reaction medium such as an ionic
liquid (Entry 22) and PEG-400 (Entry 23) have also been tested, precedent, we then proposed the following reaction mecha-
2
3
Based on these experimental results and related literature
[
13]
but unfortunately afforded very poor results.
nism (Scheme 4), which may involve the following steps: (a)
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Communication
Table 2. I
2
-promoted condensation/cyclization of acetophenones with anilines for the synthesis of 1,2,4-triarylpyrroles.[a,b]
[
a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), and I
2
(0.5 mmol) in PhCl (4 mL) at 140 °C for 10 h. [b] Isolated by column chromatography. [c] Isolated
yield combined from two parallel runs.
formation of ketimine 6; (b) iodization of the methyl group in aldol-like condensation to afford intermediate III; (f) enamin-
ketimine 6; (c) formation of the quaternary ammonium iodide ation of III to intermediate IV; (g) aromatization by deamination
salt I; (d) enamination of I to intermediate II; (e) intramolecular and elimination to achieve the formation of the final product,
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Communication
Table 3. I
phenones and aliphatic amines.
2
-promoted construction of 2,4,6-trisubstituted pyridines form aceto-
3 (Table 1, Entries 8–16) may be ascribed to the fact that they
would inhibit the enamination of I to intermediate II [step (d)]
or the enamination of III to intermediate IV [step (f)]. Further-
more, the reason why the reactions of aliphatic amines cannot
proceed in this way to afford the corresponding 1,2,4-triarylpyr-
roles may lie in two aspects: difficult formation of ketimines
and relatively low reactivity of the methyl group in the so-
formed imines.
[
a,b]
[
a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), and I
2
(0.5 mmol) in PhCl
(
4 mL) at 140 °C for 10 h. [b] Isolated by column chromatography.
Scheme 4. Proposed reaction mechanism for the synthesis of 1,2,4-triaryl-
pyrroles.
Conclusions
A novel iodine-mediated cascade condensation/cyclization re-
action of aryl methyl ketones with anilines has been success-
fully developed. According to this straightforward strategy, a
variety of 1,2,4-triarylpyrroles were synthesized in moderate to
good yields. This method exhibited several advantages, such as
being metal-free, no need to employ special or expensive start-
ing materials, and no need for preliminary preparation of any
intermediate or precursor, which make it a potential alternative
to traditional methods for the synthesis of 1,2,4-trisubstituted
pyrroles.
Scheme 2. Initially hypothesized reaction mechanism.
Experimental Section
General Procedure for the Synthesis of 3 and 5 (3a as an Exam-
ple): In a sealed Schlenk tube, a mixture of acetophenone (1a;
120.1 mg, 1.0 mmol), 4-methylaniline (2a; 107.1 mg, 1.0 mmol), mo-
lecular iodine (126.9 mg, 0.5 mmol), and chlorobenzene (4.0 mL)
was stirred at 140 °C for 10 h. After completion of the reaction
Scheme 3. Control experiments.
(
detected by TLC), the reaction mixture was washed with aqueous
sodium thiosulfate, dried with magnesium sulfate, and concen-
,2,4-triarylpyrrole 3. Although the structure of products 3 im- trated under reduced pressure. The residue was purified by column
1
plies a ratio of 2:1 for acetophenones/anilines, it can be under- chromatography on silica gel with dichloromethane/petroleum
stood from this mechanism that the molar ratio at 1:1 is essen- ether as the eluent to afford the desired product 3a as a white solid
(
128.3 mg, 83 % yield).
tial for the one-pot synthesis of these 1,2,4-triarylpyrroles, and
the released anilinium iodide cannot go into the next reaction
Supporting Information (see footnote on the first page of this
cycle to further generate ketimine 6. In addition, the reason article): Experimental details, characterization data, and copies of
1
13
why the presence of bases inhibited the formation of products
928
H and C NMR spectra of all products.
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Communication
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Received: November 23, 2015
Published Online: January 22, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim