Synthesis of 2,3,4,5-tetra-substituted pyrroles via a base-promoted double Michael reaction of oxime-enoates with nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2013.05.100

A new method of synthesizing 2,3,4,5-tetra-substituted pyrroles from oxime-enoates with nitroolefins is described. This reaction involves a base-promoted double Michael reaction, followed by dehydrative aromatization.

Full text of DOI:10.1016/j.tetlet.2013.05.100

Tetrahedron Letters 54 (2013) 4073–4075
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Tetrahedron Letters
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Synthesis of 2,3,4,5-tetra-substituted pyrroles via a base-promoted
double Michael reaction of oxime-enoates with nitroolefins
⇑
Yusuke Kuroda, Kazuto Imaizumi, Ken-ichi Yamada, Yosuke Yamaoka, Kiyosei Takasu
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method of synthesizing 2,3,4,5-tetra-substituted pyrroles from oxime-enoates with nitroolefins is
described. This reaction involves a base-promoted double Michael reaction, followed by dehydrative
aromatization.
Received 30 April 2013
Revised 18 May 2013
Accepted 23 May 2013
Available online 1 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrroles
Oximes
Nitroolefins
Domino reaction
Michael addition
Pyrrole nuclei are important chemical cores found in natural
products1 and pharmaceuticals.2 They are useful as reagents, cata-
lysts, and substances in the context of organic synthesis.3 The pyr-
role scaffold has received much attention in material science
because of its special optical and electronic properties.4 Poly-
substituted pyrroles play increasingly important roles as promising
pharmacophores in medicinal chemistry (Fig. 1).5 The broad appli-
cability of substituted pyrroles has inspired significant efforts to-
ward investigating their synthesis.6,7 Classical methods, such as
the Knorr, Hantzsch, and Parr–Knorr syntheses, are widely recog-
nized as relevant for the preparation of pyrroles; however, a facile
and efficient procedure for the synthesis of multi-substituted pyr-
roles remains highly desirable.
highly substituted pyrroles by means of a double Michael se-
quence9 (Scheme 1b).
The substrates were prepared from the corresponding 4-oxo-
butenoates via condensation with
a hydroxylamine HCl salt
(Scheme 2). The oxime-dienoate 1, which possessed no geometri-
cal isomers around the C@N bond, was obtained from diethyl
(E,E)-4-oxo-2,5-heptadienedioate in 96% yield. The oxime ether 2
was also prepared from methoxyamine hydrochloride in 50% yield.
The asymmetrical oxime 3 was prepared from the commercially
available ethyl (E)-4-oxo-4-phenylbutenoate10 in 72% yield as an
inseparable mixture of isomers (syn/anti = 29:71).
When oxime 1 was treated with b-nitrostyrene (4a) in the pres-
ence of KOH (1.1 equiv) in EtOH, 1 was fully consumed within
30 min at 0 °C to give the desired tetra-substituted pyrrole 5a in
56% yield (Table 1, entry 1). The structure of 5a was elucidated
Recently, Zhong and co-workers reported the preparation of
poly-substituted N-hydroxypyrroles by means of an amine-cata-
lyzed reaction of 1,3-diketo-2-oximes with
a,b-unsaturated alde-
hydes.8 The reaction was assumed to begin with a Michael
addition of the nitrogen atom of the oximes to the b-position of
the unsaturated iminiums that were generated in situ from the
aldehydes with an amine catalyst. An intramolecular aldol conden-
sation, followed by aromatization, furnished the N-hydroxypyr-
roles in good yields (Scheme 1a). These compounds could be
successfully reduced into the corresponding pyrroles. Inspired by
this brilliant work, we envisaged that the reaction of the oxime-
O
Ph
NHPh
NC
Br
N
CF3
N
H
Cl
O
OH
enoate with
a,b-unsaturated carbonyl compounds could afford
OH
CO2H
atorvastatin (Lipitor)
HMG-CoA reductase inhibitor
chlorfenapyr
pesticide against insects
⇑
Corresponding author. Tel.: +81 75 753 4553; fax: +81 75 753 4604.
E-mail address: kay-t@pharm.kyoto-u.ac.jp (K. Takasu).
Figure 1. Biologically active tetra-substituted pyrroles.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.100

4074
a. Zhong's pyrrole synthesis
Y. Kuroda et al. / Tetrahedron Letters 54 (2013) 4073–4075
SO2Ar
O
ArSO2Cl
O
dehydrative
Michael
N
3
R3
aromatization
+
R3
PhHN
CO2Me
(syn : anti
= 29 : 71)
R
R3
N
R
pyridine
HO
HO
HO
Ph
CO2Me
CH2Cl2, 0oC
N
N
N
CHO
CHO
R2
R2
R1
R2
8,
92%
syn-7, 55%
(based on anti-3)
(based on syn-3)
R1
R1
aldol
OH
O
O
O
O
NaOMe
b. this work
MeOH, rt
Michael
dehydrative
R3
R3
aromatization
3
, 29%
EWG
Michael
OR1
R3
HO
(syn : anti = 89 : 11)
HO
HN
R2
N
N
EWG
CO2R1
EWG
R2
Scheme 3. Preparation of syn-3. Ar = 3,5-(CF3)2C6H3.
R2
CO2R1
O
Scheme 1. Pyrrole synthesis from oximes: (a) Zhong’s Michael/aldol strategy, and
(b) our double Michael strategy.
Table 2
Reaction of 1 with a variety of nitroolefins 4b–g to give the highly substituted
pyrrolesa
Entry
Nitroolefin 4 (R2)
Product
Yield (%)
RO
1
2
3
4
5
6
4b (pBrC6H4)
4c (pCF3C6H4)
4d (pMeOC6H4)
4e (oMeC6H4)
4f (Cyclohexyl)
4g (Pentyl)
5b
5c
5d
5e
5f
60
55
61
58
59
66
O
N
RONH2•HCl
EtOH, rt, 5 h
EtO2C
O
CO2Et
EtO2C
CO2Et
1
: R = H (96%)
2: R = CH3 (50%)
5g
OH
N
HO
Ph
HONH2•HCl
a
N
Conditions: 1 (0.2 mmol), 4 (1.3 equiv), NaOMe (1.1 equiv), MeOH (1.0 mL),
0 °C, 30 min.
MeOH, rt, 5 h
Ph
CO2Me
Ph
CO2Me
CO2Me
anti-3
syn-3
(72%, syn : anti = 29 : 71)
gen atom of 1 was enhanced under the strongly basic conditions.
The reaction of the asymmetrical oxime 3 (syn:anti = 29:71) with
4a was carried out in the presence of NaOMe in MeOH to yield pyr-
role 6a in 18% yield (entry 7). In the reaction, anti-3 was recovered
(17%) but no syn-isomer was detected.
Scheme 2. Synthesis of the substrates 1–3.
Table 1
The above results (Table 1, entry 7) indicated an interesting ste-
reochemical outcome in the reactions of the syn/anti-oximes; that
is, the geometry around the nitrogen lone pair of 3 was important
for the formation of the pyrrole. This result is consistent with the
proposed mechanism that the oximes can act as N-selective nucle-
ophiles in a double Michael reaction. The mixture of geometrical
isomers of 3 was difficult to separate; therefore, the preparation
of each isomer was assessed through chemical transformations
(Scheme 3). Sulfonylation of a mixture of 3 was carried out using
3,5-bis(trifluoromethyl)benzenesulfonyl chloride at 0 °C to yield
the oxime sulfonate syn-7 as a pure geometrical isomer, along with
amide 8. In the process, only anti-3 spontaneously underwent a
Beckman rearrangement after sulfonylation at this temperature
due to the higher electron-donating properties of the phenyl group
of the anti-7 relative to the enoate moiety of the syn-7. The syn-3
was obtained by treatment of syn-7 with NaOMe, although the
overall yield was unsatisfactory. Unfortunately, a small amount
of syn-3 was isomerized into anti-3 during silica gel chromatogra-
phy purification. No isomerization was observed under the condi-
tions used for the pyrrole synthesis (NaOMe in MeOH at 0 °C).
Anti-3, which was obtained in the above reaction (Table 1, entry
7) as a pure stereoisomer, did not react under the conditions de-
scribed above, and anti-3 was recovered in 61% yield. By contrast,
the syn-enriched 3 (anti:syn = 89:11) afforded pyrrole 6a in 53%
yield. The results clearly indicated that the geometry of the nitro-
gen lone pair of 3 was important for the formation of the pyrrole.
These results were consistent with the proposed mechanism, in
which the oximes acted as N-selective nucleophiles8 in a double
Michael reaction.
Synthesis of the pyrroles via a double Michael additiona
R2
base (1.1 equiv)
NO2
HN
R1
+
1-3
R2
4a
NO2
solvent
: R2 = Ph
(1.3 equiv)
0
oC, 30 min
CO2Et
: R1 = CO2Et, R2 = Ph
5a
6a
: R1 = R2 = Ph
Entry
Substrate
Base
Solvent
Product
Yield (%)
1
2
3
4
1
1
1
1
1
2
3c
KOH
NaOH
NaOEt
Na2CO3
DBU
NaOH
NaOMe
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
5a
5a
5a
5a
5a
5a
6a
56
73
74
0
5
0
0
6
7b
18
a
Conditions: 1–3 (0.2 mmol), 4a (1.3 equiv), base (1.1 equiv), solvent (1.0 mL),
0 °C, 30 min.
b
2.0 equiv of 4a was used.
A mixture of the isomers (syn:anti = 29:71) was used.
c
by 1H and 13C NMR spectroscopy, and the regiochemistries of the
substituents were fully assigned according to HMBC. The NaOH
base afforded 5a in 73% yield (entry 2). The use of NaOEt as a base
suppressed the decomposition of 1 and 4a, and the yield of 5a was
improved to 74% (entry 3).11 Alcohols were clearly crucial as the
solvents. No desired product was obtained in DMSO or acetonitrile.
In the presence of the weaker bases, such as Na2CO3 or DBU, the
reaction did not proceed, even when the reaction time was elon-
gated (entries 4 and 5). Interestingly, no reaction occurred from
oxime ether 2 (entry 6). These results indicated that deprotonation
of the hydroxyl group of 1 drove the promotion of the first Michael
addition to nitrostyrene 4a. Thus, the nucleophilicity of the nitro-
Finally, we examined the pyrrole synthesis of oxime 1 via reac-
tion with various nitroolefins (Table 2). The nitoroolefins 4b–e,
which featured an electron-withdrawing or -donating aryl group,
were good substrates and afforded the pyrroles 5b–e, respectively,

Y. Kuroda et al. / Tetrahedron Letters 54 (2013) 4073–4075
4075
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in a reaction with 1 (entries 1–4). Good yields were achieved with
the nitroolefins 4f and 4g, which included alkyl group substituents
at the b positions (entries 5 and 6). By contrast, no formation of the
desired pyrrole was observed in the reaction with
esters or nitriles instead of nitroolefins.
a,b-unsaturated
In summary, we describe a facile synthesis of the tetra-substi-
tuted pyrroles from oxime-enoates and nitroolefins in the presence
of a strong base. The reaction sequence involved a double Michael
addition and a dehydrative aromatization. The oxime-enoates, in
particular, acted as N-selective nucleophiles in the initial Michael
addition. The new strategy should have broad applications to the
synthesis of biologically important heterocyclic compounds and
organic materials.
Acknowledgments
This work was supported by Grants-in Aid for Scientific Re-
search and Platform for Drug Design, Discovery and Development
from MEXT, Japan, and the Takeda Science Foundation.
Supplementary data
8. Tan, B.; Shi, Z.; Chua, P.-J.; Li, Y.; Zhong, G. Angew. Chem., Int. Ed. 2009, 48, 758–
761.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
100.
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11. General procedure for the preparation of pyrrole: To a stirred solution of 1
References and notes
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