Approach to trisubstituted 1 H -pyrroles from alkynoates and amines mediated by tert -butyl perbenzoate

Article abstract of DOI:10.1055/s-0032-1318505

A simple and concise tandem cyclization of alkynoates with amines in the presence of tert-butyl perbenzoate (TBPB) leads to 1,2,4-trisubstituted 1H-pyrroles. A variety of aromatic amines and aliphatic amines can be used in this approach, and a wide range of functionalized 1,2,4-trisubstituted 1H-pyrroles are obtained in good to excellent yields. This protocol not only corresponds to the construction of a pyrrole fragment, but also provides a new way to form C-C and C-N bonds. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1318505

LETTER
▌991
lAettper proach to Trisubstituted 1H-Pyrroles from Alkynoates and Amines
Mediated by tert-Butyl Perbenzoate
Trisubstituted 1H-Pyrroles
Weibing Liu,* Liquan Tan, Peng Zhou, Cui Chen, Qing Zhang
School of Chemistry and Life Science, Guangdong University of Petrochemical Technology, 2 Guangdu Road, Maoming 525000, P. R. of China
Fax +86(68)2923529; E-mail: lwb409@yahoo.com.cn
Received: 17.01.2013; Accepted after revision: 08.03.2013
the explored reaction than other partners (entries 4–13). It
Abstract: A simple and concise tandem cyclization of alkynoates
is noteworthy that the reaction did not occur in the pres-
with amines in the presence of tert-butyl perbenzoate (TBPB) leads
ence of several types of peroxides and persulfides, such as
cyclohexanone peroxide, benzoyl peroxide, ammonium
to 1,2,4-trisubstituted 1H-pyrroles. A variety of aromatic amines
and aliphatic amines can be used in this approach, and a wide range
of functionalized 1,2,4-trisubstituted 1H-pyrroles are obtained in persulfate, oxone, and potassium persulfate (entries 4–7
good to excellent yields. This protocol not only corresponds to the
construction of a pyrrole fragment, but also provides a new way to
form C–C and C–N bonds.
and 9). Results of the screening study of the amount of
TBPB indicated that 2.3 equivalent of TBPB was suffi-
cient for the reaction (entries 14–16). Finally, we investi-
gated the effect of solvent for this protocol and found that
Key words: 1H-pyrroles, oxidation, cyclization, alkynoates,
amines
dioxane was most suitable (entries 15 and 17–20).
We then conducted a survey of the substrate scope of this
protocol. The results, compiled in Table 2, demonstrate
In the past decades, peroxides1 have received much atten-
that a range of reactions could be performed with various
tion from chemists and drug design experts, which is re-
alkynoates 1 and amines 2. It was observed that all the re-
flected by the plethora of publications and reviews.2–8
actions were quite sensitive to the electronic contribution
This class of compounds are widely used not only in aca-
of the substituents on the benzene ring of the aromatic
demic research as oxidant, cross-linking agent, and po-
amines; amines such as 2a–g, with electron-donating
lymerization initiator, but also in the production of
groups on the benzene ring, all afforded the corresponding
cosmetics and pharmaceuticals as active components.9–16
1,2,4-trisubstituted 1H-pyrrole 3aa–ag in good to excel-
tert-Butyl perbenzoate (TBPB) is a typical example of an
lent isolated yields, whereas substrates with electron-
organic peroxide that contains more than 8.1% active ox-
withdrawing groups on the benzene ring, such as 4-nitro-
ygen. In this paper, we describe an expeditious synthetic
benzenamine and 2,4-dinitrobenzenamine, did not react,
approach to 1,2,4-trisubstituted 1H-pyrroles17,18 through
presumably due to the strong electron-withdrawing effect
TBPB-promoted tandem cyclization of alkynoates and
of the nitro group on the benzene ring. All the tested ali-
amines (Scheme 1). It is well-known that the pyrrole
phatic amines reacted smoothly and afforded the corre-
fragment19,20 is an important synthon, due to the occur-
sponding product 3ah and 3ai in excellent isolated yield.
rence of this unit in many molecules that are of biological
Additionally, diethyl but-2-ynedioate (1b) also reacted
and pharmaceutical interest.21–24
with p-toluidine (2a) to smoothly give the corresponding
Initially, optimization of the reaction conditions was con-
ducted; the results are summarized in Table 1. The model
reaction of dimethyl but-2-ynedioate (1a) and p-toluidine
(2a) in dioxane at 100 °C occurred in the presence of tert-
butyl peroxide (TBHP) and resulted in formation of the
product dimethyl 1-p-tolyl-1H-pyrrole-2,4-dicarboxylate
(3aa) in 57% GC yield (entry 1). After screening reaction
times, we found that three hours was optimal for comple-
tion of this reaction (entries 1–3). Among the various ox-
idants examined, TBPB was found to be more efficient for
pyrrole 3ba in good isolated yield. This result demonstrat-
ed that diethyl but-2-ynedioate was a good partner of di-
methyl but-2-ynedioate for this protocol. However, when
other types of electron-deficient alkynoates, such as ethyl
3-phenylpropiolate, ethyl but-2-ynoate, and methyl oct-2-
ynoate, were used as partners of dimethyl but-2-ynedioate
in this protocol, none of the desired product was observed.
To probe the mechanism of this transformation, two con-
trol experiments were performed. Dimethyl 2-(p-tolyl-
R1O2C
100 °C, 3 h
R2
N
R2 NH2
R1O2C
CO2R1
2
+
TBPB
CO2R1
Scheme 1 Synthesis of 1,2,4-trisubstituted 1H-pyrroles
SYNLETT 2013, 24, 0991–0994
Advanced online publication: 22.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318505; Art ID: ST-2013-W0045-L
© Georg Thieme Verlag Stuttgart · New York

992
W. Liu et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
Table 2 Substrate Scope with Isolated Yields
NH2
R1O2C
CO2R1
MeO2C
CO2Me
dioxane
100 °C
100 °C, 3 h
R2–NH2
R2
N
+
2
+
N
TBPB (2.3 equiv)
dioxane (2.0 mL)
2
hyperoxide
(2.0 equiv)
CO2R1
CO2R1
CO2Me
CO2Me
3
2
1
1a
2a
3aa
1
R1
2
R2
3
Yield (%)
Entry Solvent
Time Peroxide (2.0 equiv)
(h)
Yield
(%)b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
4-MeC6H4
4-MeOC6H4
3-MeC6H4
4-ClC6H4
Ph
3aa
3ab
3ac
3ad
3ae
3af
89
94
83
78
82
86
81
85
85
79
1
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
TBHP
57
2b
2c
2d
2e
2f
TBHP
65
3
TBHP
65
4
ammonium persulfate
benzoyl peroxide
oxone
none
none
none
none
51
5
4-BrC6H4
1-naphthyl
Bn
6
2g
2h
2i
3ag
3ah
3ai
7
potassium persulfate
dicumyl peroxide
cyclohexanone peroxide
TBHP
8
Bu
9
none
32
2j
4-MeC6H4
3ba
10
11
12
13
14
15
16
17
18
19
we were pleased to find that the reaction proceeded
smoothly and gave product 3aa in almost quantitative
yield when using 2-(p-tolylamino)but-2-enedioate as the
substrate. However, no desired product 3aa was detected
when 1-p-tolyl-1H-pyrrole-2,3,4,5-tetracarboxylate was
used as the substrate.
TBPB
88
cumene hydroperoxide
47
methyl ethyl ketone peroxide 26
TBPB (1.0 equiv)
TBPB (2.3 equiv)
TBPB (3.0 equiv)
TBPB (2.3 equiv)
TBPB (2.3 equiv)
TBPB (2.3 equiv)
63
92
92
63
47
33
On the basis of these preliminary results, a plausible
mechanism of this peroxidation was hypothesized as
shown in Scheme 3, exemplified by the formation of 3aa.
The first step involves peroxide decomposition;25,26 TBPB
generates two oxy radicals during the thermal homolytic
cleavage process. During the course of the reaction, large
numbers of gas bubbles were evolved that were confirmed
as carbon dioxide by a lime water test; this phenomenon
indicated that the oxy radicals continuously reacted with
TBPB or decomposed to produce other radicals (Scheme
3, a).27,28 The following step involves the formation of hy-
droamination product 4 (Scheme 3, b). The resulting per-
oxyl radical from TBHP can react with aminyl to form the
unstable aminyl radical 5. Through 1,3-hydrogen radical
DMSO
DCE (80 °C)
a Reaction conditions: 1a (0.50 mmol), 2a (0.25 mmol), solvent (2.0
mL).
b GC yield.
amino)but-2-enedioate and tetramethyl 1-p-tolyl-1H-
pyrrole-2,3,4,5-tetracarboxylate were employed as reac-
tants under the same conditions (Scheme 2). Interestingly,
MeO2C
CO2Me
TBPB (2.3 equiv)
dioxane (2.0 mL)
CO2Me
N
H
N
100 °C, 3 h
CO2Me
0.25 mmol
3aa 96%
MeO2C
CO2Me
CO2Me
MeO2C
TBPB (2.3 equiv)
dioxane (2.0 mL)
N
x
N
100 °C, 3 h
CO2Me
MeO2C
0.25 mmol
3aa 0%
Scheme 2 Control experiments
Synlett 2013, 24, 991–994
© Georg Thieme Verlag Stuttgart · New York

LETTER
Trisubstituted 1H-Pyrroles
993
O
O
a)
O
O
O
Δ
O
CH3
+
+
CO2
+ +
O
O
O
O
O
O
Δ
+
CO
+
+
O2
+
RH
O
R
R
+
O
O
=
CH3
CH4
RH
=
CO2Me
CO2Me
CO2Me
b)
Δ
2a
Δ
MeO2C
CO2Me
CO2Me
R
N
N
1a
4
5
H
RH
1a
CO2Me
CO2Me
CO2Me
CO2Me
Δ
N
N
H
N
N
H
R
H
8
6
CO2Me
CO2Me
7
MeO2C
N
CO2Me
RH
Δ
CO2Me
3aa
CO2Me
CO2Me
9
Scheme 3 Hypothesized mechanism
transfer, 5 can easily rearrange to allylic radical 6, which
reacts with RH to generate a new carbon radical 7 by elim-
ination of one equivalent of RCO2Me under the high tem-
perature conditions. Radical attack of 7 on the C–C triple
bond of alkynoate 1a then affords another radical, 8,
which quickly converts into the new aminyl radical 9
through 1,5-hydrogen radical transfer. Subsequent radical
attack of 9 on the olefinic carbon affords the final product
3aa accompanied by elimination of RCO2Me.
Acknowledgment
We thank the Guangdong Natural Science Foundation (No.
S2012040007868) and Guangdong University of Petrochemical
Technology of China for financial support of this work.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
In summary, we have discovered a practical, general
method involving peroxidation to directly construct a
1,2,4-trisubstituted pyrrole framework.29 The approach
requires short reaction times, uses an inexpensive organic
peroxide as the oxidant, and provides the product selec-
tively in good to excellent yield. Furthermore, although a
large body of literature exists on thermally induced perox-
idation by peroxides, this protocol, which involves oxida-
tive cleavage of a C–C bond mediated by TBPB, has not
been documented. Further investigations focusing on clar-
ifying the mechanism and extending the application of
this reaction are underway in our group, and the results
will be reported in the near future.
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Synlett 2013, 24, 991–994

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LETTER
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(29) Synthesis of Dimethyl 1-p-Tolyl-1H-pyrrole-2,4-
dicarboxylate (3aa); Typical Procedure: A mixture of 1a
(284 mg, 2.0 mmol), p-toluidine (107 mg, 1.0 mmol), TBPB
(446 mg, 2.3 mmol) and dioxane (2.0 mL) was added
successively to a Schlenk tube. After stirring for 3 h at
100 °C, the solution was directly subjected to isolation by
PTLC (GF254; PE–EtOAc, 10:2) to afford the desired
product 3aa (243 mg, 89%). Yellow oil; IR (KBr): 2951,
2857, 1717, 1640, 1516, 1475, 1443, 1257, 1160, 1044, 978,
912, 167, 740 cm–1; 1H NMR (CDCl3, 400 Hz): δ = 7.21–
7.14 (q, J = 8.4 Hz, 4 H), 6.77–6.76 (d, J = 3.2 Hz, 1 H),
6.22–6.22 (d, J = 3.2 Hz, 1 H), 3.81 (s, 3 H), 3.71 (s, 3 H),
2.37 (s, 3 H); 13C NMR (CDCl3, 100 Hz): δ = 164.4, 162.1,
138.3, 136.7, 129.7, 127.0, 125.0, 124.9, 119.1, 110.8, 52.3,
51.6, 21.0; MS (EI): m/z (%) = 242.05 (100.00), 273.05
(86.88); Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N,
5.13. Found: C, 66.07; H, 5.45; N, 5.30.
Synlett 2013, 24, 991–994
© Georg Thieme Verlag Stuttgart · New York

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