Straightforward approach to synthesize 3,3'-bipyrroles by oxidative homocoupling of 1,2,5-trisubstituted pyrroles

Article abstract of DOI:10.1246/cl.130253

A method is developed for efficient and straightforward synthesis of 3,3'-bipyrroles by oxidative C-H homocoupling of 1,2,5-trisubstituted pyrroles in the presence of FeCl₃ in a mixture solvents of CH ₂Cl₂ and MeNO₂.

Full text of DOI:10.1246/cl.130253

doi:10.1246/cl.130253
836
Published on the web May 29, 2013
Straightforward Approach to Synthesize 3,3¤-Bipyrroles
by Oxidative Homocoupling of 1,2,5-Trisubstituted Pyrroles
Tao Yin and Ruimao Hua*
Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
(Received March 24, 2013; CL-130253; E-mail: ruimao@mail.tsinghua.edu.cn)
R
R
A method is developed for efficient and straightforward
R'
synthesis of 3,3¤-bipyrroles by oxidative C-H homocoupling of
1,2,5-trisubstituted pyrroles in the presence of FeCl3 in a mixture
solvents of CH2Cl2 and MeNO2.
R
N
H
Oxidative C-H Homocoupling
N
R'
N
R
FeCl3
R
R'
R
3,3'-bipyrrole
Biheteroaryls are some of the most interesting heterocyclic
compounds that show important biological and physiological
activities, and they are employed as synthon and ligands.
Although there are many methods for the synthesis of
biheteroaryls, the oxidative C(sp2)-H homo- or cross-coupling
reaction of two heteroarenes providing an efficient and straight-
forward approach to biheteroaryls has become one of the most
important research topics in recent years.1
Scheme 1. Synthesis of 3,3¤-bipyrroles via oxidative C-H
homocoupling.
Table 1. Synthesis of 1,1¤,2,2¤,5,5¤-hexaphenyl-3,3¤-bipyrrole
(2a) via the oxidative coupling of 1,2,5-triphenylpyrrole (1a)a
Ph
Ph
Ph
Ph
Ph
N
Fe(III) or Cu(II)
CH2Cl2 / MeNO2
r.t.
H
N
N
Ph
Not only does bipyrrole motif occur in natural products,2 but
also bipyrrole-containing compounds show functional diversi-
ty.3 However, the studies on the synthesis and application of
bipyrroles focused on 2,2¤-bipyrrole derivatives3,4 and reports on
the syntheses5 and application6 of functional 3,3¤-bipyrroles are
rare. On the basis of our previous studies on the CuCl-catalyzed
cycloaddition of 1,3-butadiynes with primary amines, providing
an easy and efficient method for the synthesis of 1,2,5-
trisubstituted pyrroles,7 and with the aim of developing the
application of 1,2,5-trisubstituted pyrroles, we present herein
a novel and practical oxidative C-H homocoupling of 1,2,5-
trisubstituted pyrroles in the presence of FeCl3 to afford 3,3¤-
bipyrroles, which are considered to be the versatile and
important intermediates in the synthesis of 3,3¤-bipyrrole-based
N-heterocyclic molecules (Scheme 1).
The choice of FeCl3 as the promoter for the oxidative C-H
homocoupling of 1,2,5-trisubstituted pyrroles was due to its
known ability to mediate the intramolecular coupling8 and
intermolecular cross-coupling of C(sp2)-H bond.9 We first
examined the reaction of 1,2,5-triphenylpyrrole (1a) in the
presence of FeCl3 under different reaction conditions to optimize
the homocoupling system, and the results are presented in
Table 1.
As shown in Table 1, the desired 1,1¤,2,2¤,5,5¤-hexaphenyl-
3,3¤-bipyrrole (2a) could be obtained in 13% isolated yield,
when 1a was stirred in CH2Cl2 at room temperature in the
presence of 2.0 equivalents of FeCl3 (Entry 1), and prolonging
the reaction time to 12 h resulted in a great increase in the yield
of 2a (Entry 2). The addition of MeNO2 could improve the
homocoupling reaction, and 2a could be obtained in 41% yield
even when the reaction was performed within 2 h (Entry 3).
Also, the yield could be increased considerably by either
prolonging the reaction time or increasing the amount of MeNO2
(Entries 4 and 5). The considerable cosolvent effect on the
formation of 2a in the presence of MeNO2 is probably due to the
well-dissolved FeCl3 in the mixture of solvents. In addition, the
Ph
Ph
1a
Ph
3,3'-bipyrrole
2a
Metal salt
(equiv)
CH2Cl2/MeNO2
Entry
Time/h Yield/%b
(mL)
1
2
3
4
5
6
7
8
9
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (2)
FeCl3 (3)
FeBr3 (2)
CuCl2 (2)
Cu(OTf)2 (2)
CuBr2 (2)
30/0
30/0
30/1
30/1
30/4
30/4
30/4
30/4
30/4
30/4
3
12
2
3
3
3
3
3
3
13
54
41
48
63
64
66
NR
NR
9
10
3
aThe reactions were carried out with the use of 1.0 mmol of 1a.
bIsolated yield.
yield of 2a could be slightly increased with the increase in
the FeCl3 amount (Entry 6) and the use of FeBr3 (Entry 7).
Furthermore, since cupric salts have been well applied as
promoters in the oxidative C-H coupling reactions,1c we also
examined the homocoupling of 1a in the presence CuX2
(X = Cl, OTf, and Br). We found that CuCl2 and Cu(OTf)2
showed no activity at all (Entries 8 and 9), and CuBr2 mediated
the present homocoupling to give 2a in a low yield (Entry 10).
Because FeBr3 is a much more expensive reagent than
FeCl3, we chose the reaction conditions of Entry 5 as the
optimal conditions to investigate the generality of the present
homocoupling reactions with the use of N-substituted-2,5-
diarylpyrroles as the starting materials. As summarized in
Table 2,10,11 the homocoupling reaction greatly depended on
the characteristics of the substituted groups. The reactions
of substrates bearing electron-rich group (e.g., R¤ = n-C3H7,
Chem. Lett. 2013, 42, 836-837
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

837
Table 2. FeCl3-mediated synthesis of 3,3¤-bipyrroles via the
formation of 3,3¤-bipyrroles is proposed to be through FeCl3-
mediated electron-transfer reactions and cation radical dimeri-
zation, as suggested in the initial step of polymerization of
pyrrole.13 Indeed, the polymerization is also observed when
pyrrole is subjected to the standard reaction conditions as shown
in Table 2 to give the insoluble polymer.
In summary, we have developed a FeCl3-mediated conven-
ient method for synthesis of hexasubstituted 3,3¤-bipyrroles via
oxidative C-H homocoupling of 1,2,5-trisubstituted pyrroles at
room temperature. Like the application of 2,2¤-bipyrrole deriv-
atives, 3,3¤-bipyrrole derivatives are expected to also have the
potential usages in the synthesis of N-heterocyclic compounds
and functionalized molecules, and some of these are now
underway in our laboratory.
oxidative homocoupling of 1,2,5-trisubstituted pyrrolesa
R
R'
R
R
N
FeCl3 (2.0 equiv)
H
N
N
R
R'
CH2Cl2, MeCN, r.t., 3-4 h
R'
R
R
1
2
3,3'-bipyrrole
Entry
R
R¤
Yield/%
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
n-C3H7
t-C4H9
p-MeOC6H4 1d 2d
PhCH2
p-FC6H4
1b 2b
1c 2c
38
36
24
56
50
55
75
23
17
36
1e 2e
1f 2f
1g 2g
1h 2h
1i 2i
1j 2j
1k 2k
p-(n-C3H7)C6H4 Ph
p-(n-C5H11)C6H4 Ph
p-FC6H4
p-F3CC6H4
2,4-F2C6H3
This project was supported by the National Natural Science
Foundation of China (Nos. 21273125 and 21032004) and by the
Specialized Research Fund for the Doctoral Program of Higher
Education (No. 20110002110051).
Ph
Ph
Ph
10
aThe reactions were carried out with the use of 1.0 mmol of 1,
2.0 mmol of FeCl3 in CH2Cl2 (30 mL) and MeCN (4.0 mL) at
room temperature for 3-4 h.
References and Notes
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Figure 1. Molecular structure of 2h. Hydrogen atoms and
n-pentyl groups are omitted for clarity.
9
t-C4H9, p-MeOC6H4) on the pyrrole nitrogen afforded the
corresponding 3,3¤-bipyrrole derivatives in fair yields (Table 2,
Entries 1-3), and when the R¤ groups are PhCH2 and p-FC6H4,
the desired 3,3¤-bipyrroles formed in good isolated yields
(Table 2, Entries 4 and 5), indicating that substrates with an
electron-deficient group on the pyrrole nitrogen favored the
formation of 3,3¤-bipyrroles. In contrast, the electron-rich groups
bonded to the 2 and 5 positions of pyrroles resulted in the
formation of 3,3¤-bipyrroles in better yields (Table 2, Entries 6
and 7) than those reactions with the use of substrates having
electron-deficient groups attached to the 2 and 5 positions
(Table 2, Entries 8-10). In addition, the structure of 2 was
inferred by its 1H- and 13C NMR spectroscopic, and HRMS data,
and one of their structures 2h was unambiguously confirmed by
X-ray diffraction study (Figure 1).12
10 Under the standard reaction conditions, all the starting materials were
completely converted. After separation of the desired 3,3¤-bipyrroles,
there are some insoluble by-product, which are considered to be the
oligomer or polymer of 1,2,5-trisubstituted pyrroles.
11 Supporting Information (including characterization data of products,
1H- and 13C NMR charts of products, and X-ray diffraction data of
2h) is available electronically on the CSJ-Journal Web site, http://
www.csj.jp/journals/chem-lett/index.html.
12 Crystal for X-ray diffraction analysis was obtained by recrystalliza-
tion from a mixture of CH2Cl2 and cyclohexane. CCDC 930809
contains supplementary crystallographic data for compounds 2h.
These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk.
13 Selected reports, see: a) M. Can, H. Özaslan, Ö. Işıldak, N. Ö.
Pekmez, A. Yıldız, Polymer 2004, 45, 7011. b) D.-V. Brezoi, J. Sci.
Arts 2010, 53.
The detailed mechanism of the present reaction remains
to be elucidated, but one of the most probable routes for the
Chem. Lett. 2013, 42, 836-837
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/