Efficient synthesis of substituted pyrroles through Pd(OCOCF3)2-catalyzed reaction of 5-hexen-2-one with primary amines

Article abstract of DOI:10.1016/j.tetlet.2016.10.029

An efficient and facile Pd(OCOCF₃)₂-catalyzed one-pot cascade protocol has been developed for the synthesis of multiple substituted pyrroles in good to excellent yields. Unlike the reported method starting from the 2-alkenal-1,3-carbonyl compounds, the process utilizes the less reactive 5-hexen-2-one and the method has great potential as a complement to the current developed methods.

Full text of DOI:10.1016/j.tetlet.2016.10.029

Accepted Manuscript
Efficient synthesis of substituted pyrroles through Pd(OCOCF3)2-catalyzed re-
action of 5-hexen-2-one with primary amines
Xi Chen, Meng Yang, Min Zhou
PII:
S0040-4039(16)31332-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.029
TETL 48199
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 August 2016
1 October 2016
8 October 2016
Please cite this article as: Chen, X., Yang, M., Zhou, M., Efficient synthesis of substituted pyrroles through
Pd(OCOCF3)2-catalyzed reaction of 5-hexen-2-one with primary amines, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.029
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Efficient synthesis of substituted pyrroles through
Pd(OCOCF3)2-catalyzed reaction of 5-hexen-2-one with
primary amines
Xi Chen*, Meng Yang, Min Zhou
School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, Jiangsu,
223005, China
Corresponding author:
chenxi.wozai@163.com

Abstract Graphic
Abstract
An efficient and facile Pd(OCOCF3)2-catalyzed one-pot cascade protocol has been
developed for the synthesis of multiple substituted pyrroles in good to excellent yields.
Unlike the reported method starting from the 2-alkenal-1,3-carbonyl compounds, the
process utilizes the less reactive 5-hexen-2-one and the method has great potential as an
complement to the current developed methods.
Keywords: pyrroles, palladium, intermolecular, 5-hexen-2-one

Introduction
Pyrroles are the privileged nitrogen-containing heterocycles and are widely encountered in
2
the scaffolds of bioactive natural products1 and pharmaceutical agents, exhibiting
pronounced bioactivities such as antitumor,3 anti-inflammatory,4 antibacterial5 and
antifungal effects6. Moreover, they are also employed as building blocks in organic
synthesis to construct the more structurally complicated scaffolds. 7 Therefore, there has
been a long interest in developing novel synthetic methods for the efficient construction of
pyrroles. Traditional synthetic methods include the Knorr, 8 Pall-Knorr,9 and Hantzsch
reactions,10 which have been used for more than a century. While, the increasing
applications of this highly important class of compounds demand novel and more efficient
synthetic approaches from the readily available starting materials under mild reaction
conditions with good to excellent yields. Among these novel reported approaches, the
convenient access of hydroamination of functionalized alkynes or alkenes catalyzed by the
transition-metal catalysts such as Pd,11 Fe,12 Ag,13 Au,14 Cu15 to pyrroles is a very common
strategy and highly attractive from the atom- and step-economical points of view. For
example, Li’s group has disclosed Pd(OCOCF3)2-catalyzed cascade Aza-Wacker type
reaction of 2-alkenal-1,3-dicarbonyl compounds with primary amines to synthesize highly
substituted pyrroles in moderate to excellent yields (Scheme 1A).11b Additionally, Liu’s
group has reported the formation of tetrasubstituted pyrroles via FeCl3-mediated sequential
amination/annulation reaction of 2-propynyl-1,3-dicarbonly compounds with primary
amine.12 Within these two exemplified reactions, the involved 1.3-dicarbonly compounds
facilitated the formation of the enamine and made the subsequent attack of nitrogen on the
alkene or alkyne proceed smoothly to generate the pyrroles products. To the best of our
knowledge, Pd(II)-catalyzed intermolecular Wacker-type reaction of 5-hexen-2-one with
primary amines, leading to the formation of functionalized pyrroles has not been reported,
which is more challenging due to the less reactivity of mono-ketone compared to the
1,3-diketone. Toward this end, we wish to report a highly efficient Pd(II)-catalyzed

cascade Wacker-type reaction of 5-hexen-2-one with primary amines for the synthesis of
multiple substituted pyrroles in moderate to excellent yields. This protocol not only
provides a complement to the currently available methods, but also broadens the
application of Wacker-type reaction to synthesize heterocyclic compounds.
SCHEME 1. Palladium-catalyzed intermolecular annulation to pyrroles
Results and Discussion
Initially, 5-Hexen-2-one 1a and aniline 2a were chosen as model substrates to explore the
optimal reaction conditions for the synthesis of multiple substituted pyrrole 3a. As shown
in Table 1, We were pleased to found that the most promising reaction yield was obtained
when the reaction was performed in toluene in the presence of Pd(OAc)2 as catalyst under
an atmosphere of ambient air (entry 6), whereas the other solvents such as DMF, CH3CN,
DMSO, THF, DCE gave the desired products in poor to moderate yields (entries 1-5).
Screening of
a
variety of different palladium catalysts revealed that
Pd(OCOCF3)2-catalyzed reaction of 1a with 2a under air atmosphere afforded the desired
product 3a in 75% yield (entry 7), which was dramatically higher than those reactions
catalyzed by PdCl2, Pd(OAc)2, PdCl2(PPh3)2, PdCl2(CH3CN)2, Pd(PPh3)4 (entries 8-10).
Subsequently, we turned our attentions to the effects of oxidants on the reaction yields. The
reaction yield was increased to 85% when the O2 was involved to replace air (entry 11).
While compared to the reaction done with O2, the reaction yields dropped significantly

upon employing K2S2O8, Cu(OAc)2.H2O, CuCl2, AgNO3, Ag2CO3 as
Table 1. Optimization of reaction conditions
Entrya
1
Solvent
DMF
Catalyst
Pd(OAc)2
Oxidant
air
Yieldb (%)
13
2
CH3CN
DMSO
THF
Pd(OAc)2
air
18
3
Pd(OAc)2
air
5
4
Pd(OAc)2
air
35
5
DCE
Pd(OAc)2
air
46
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Pd(OAc)2
air
60
7
Pd(OCOCF3)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
Pd(PPh3)4
air
75
8
air
56
9
air
48
10
11
12
13
14
15
16
17
18
air
20
Pd(OCOCF3)2
Pd(OCOCF3)2
O2
85
K2S2O8
40
Pd(OCOCF3)2 Cu(OAc)2.H2O
54
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
-
CuCl2
AgNO3
Ag2CO3
N2
50
40
35
trace
NPc
O2
a Asolution of 1a (0.6 mmol, 1.2 eq) and 2a (0.5 mmol, 1 eq) with catalyst (0.05 mmol, 0.1
eq) and oxidant (0.6 mmol 1.2 eq) in solvent (2 mL) was stirred at 100 oC for 12 h. b
Isolated yield. c NP indicated no desired product 3a was obtained.
oxidants respectively (entries 12-16). These results demonstrated the O2 was a highly

effective oxidant for this transformation. If the reaction was carried out under nitrogen,
only a trace of amount of the product 3a was obtained (entry 17), indicating that the O2 was
essential for the catalyst recycling. Moreover, no targeting product 3a was obtained when
the reaction was conducted in the absence of Pd(OCOCF3)2 (entry 18).
With the optimal conditions in hand, we next surveyed the generality of this process to the
synthesis of structurally diverse pyrroles 3. As shown in Table 2, this method was
compatible with significant structural variations both in the amines and 5-hexen-2-one
substrates. Only limited impact on the reaction yields imposed by the substitution patterns
on the phenyl ring was observed (3a-g). The anilines possessing electron-donating groups
on the phenyl ring such as the phenoxyl, acetamido gave the higher yields under the same
conditions (3h-i). However, the electron-withdrawing groups (EWG) on the phenyl ring
such as the ester, nitro, fluorine resulted in the significant drop on the yields (3j-n). It was
believed that the EWG significantly reduced the nucleophilic activities of the amines. It
was well worth mentioning that this process was tolerated with a wide range of functional
groups on the phenyl ring such as bromine, chlorine, ester, amide and nitro to generate the
corresponding products in 40-92% yields (3i-q). These products had great potential as
building blocks to construct structurally more complicated compounds. We noted that in
addition to the aromatic amines, the aliphatic amines could smoothly involve in the process
to afford the corresponding
Table 2. Scope of Pd(OCOCF3)2-catalyzed synthesis of Pyrroles 3

pyrroles in excellent yields. For example, over 90% yields were observed when the
primary amines such as benzyl, cyclohexanemethyl, propyl, 2-methoxyethyl,
2-phenylethyl, isobutyl, 2,2-diphenylethyl amines participated in this transformation (3r,

3u-3z). The N-Boc-protected diamines could also perform well in the reaction and afforded
the corresponding products in excellent yields (3s, 3aa). While, the more sterically
hindered isopropylamine caused a decrease in the yield (3ab), furthermore the
tert-butylamine couldn’t afford the desired product due to the steric hindrance of the
tert-butyl group (3ac). Probing the 5-hexen-2-one substrates implied that the more
hindered R2= isopropyl appeared to be a good candidate for this process (3ad), while
switch R2 on 1 from methyl to phenyl resulted in a significant drop in the yield (3ae).
Additionally, we examined the challenging non-terminal alkene substrates, and found the
process proceeded with high regioselectivity. Only pyrrole 3af was afforded in acceptable
yield.
It was attractive that the protocol was sufficiently efficient to afford the bipyrroles products
in 88-94% yields when the diamines such as 1,4-phenylenediamine, ethylenediamine,
4-aminobenzylamine were involved (Table 3, 3ag-ai).
Table 3. The bipyrroles products
A plausible mechanism for the reaction of 5-Hexen-2-one 1a with primary amine 2 is
illustrated in Scheme 2, in which neutral ligands are omitted. Coordination of enamine A
generated from 5-hexen-2-one 1and primary amine 2 to PdII center and subsequent
nucleophilic attack on the resulting intermediate A by the nitrogen take place to form
Pd-alkyl intermediate B with the loss of HX. The intermediate B undergoes a -hydride
elimination to release intermediate C, which can undergo acid-catalyzed isomerization to
give the pyrroles 3. Alternatively, Pd(H) can reinsert into the alkene C to form the Pd-alkyl

intermediate D again. The intermediate D undergoes the second -hydride elimination to
aromatize the system to generate the pyrroles 3. Catalyst PdII is regenerated through Pd(0)
oxidized by O2.
Scheme 2. A proposed mechanism for the reaction
Conclusions
In summary, we have disclosed an efficient palladium-catalyzed cascade Wacker-type
process of the less reactive 5-hexen-2-one with primary amines for the synthesis of the
synthetically and biologically meaningful pyrroles. It represents a facile access to multiple
substituted pyrroles from the readily available reagents in moderate to excellent yields for a
diverse range of substrates and an excellent complement to the currently available
synthetic methods.
ACKNOWLEGEMENTS
We gratefully thank the financial support from HuaiAn Science and Technology Bureau
(HAG2015020), and Research Foundation of Jiangsu Food & Pharmaceutical Science
College for Outstanding Young Teachers.

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Highlights




A palladium-catalyzed cascade access to multiple substitute pyrroles was explored.
The less reactive 5-hexen-2-one was involved as the substrate
The method broadens the application of Wacker reaction to construct pyrroles.
This method is complementary to the current synthetic approaches to pyrroles.