New Synthesis of 3-Arylpyrroles

Article abstract of DOI:10.1055/s-2003-42047

3-Arylpyrroles were synthesized by reduction of 3- and 4-pyrrolin-2-ones with 9-borabicyclo[3.3.1]nonane (9-BBN).

Full text of DOI:10.1055/s-2003-42047

LETTER
2013
New Synthesis of 3-Arylpyrroles
New
Synthesis of
3
-Arylpyrrol
i
e
s
do Verniest, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Gent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 28 August 2003
According to the physiological importance of these pyr-
roles, substantial attention has been paid to develop effi-
cient synthetic approaches. One of the synthetic pathways
consists of the use of 3- and 4-pyrrolin-2-ones to obtain 2-
oxygenated or 2-halogenated pyrroles.13–16
Abstract: 3-Arylpyrroles were synthesized by reduction of 3- and
4-pyrrolin-2-ones with 9-borabicyclo[3.3.1]nonane (9-BBN).
Key words: pyrroles, reductions, heterocycles, isomerizations, ring
closure
O
OCH3
NH
Functionalized 3-arylpyrroles exhibit a wide range of
agrochemical and pharmacological properties.1–5 Pyr-
rolnitrin (1, Figure 1) is used in agriculture as crop protec-
tion agent because of its antifungal and antimycobacterial
activity. Its derivatives fenpiclonil (2a) (Beret®), active
against fungi on seeds, and fludioxonil (2b) (Saphire®),
active against fungi on leafs, have already established
their market position.6–8 Pyrrolnitrin, isolated from the
bacterium Pseudomonas pyrociniae, P. cepacia and P.
fluorescens also revealed promising activity against My-
cobacterium avium and M. tuberculosis, strains which ac-
quired considerable resistance towards conventional
antibiotics and cause problems in chemotherapy of nu-
merous diseases (tuberculosis, AIDS, …).9 Recently some
halogenated 3-arylpyrroles were patented as herbicidal
agents.10
N
O
N
N
H
O
Br
3 AWD 140-190
Figure 2
4 razinilam
To the best of our knowledge only one article has been
published using a reductant (DIBALH) to synthesize 3-
substituted pyrroles without the introduction of an addi-
tional functionality at the 2-position.17 That publication
deals only with 4-methoxy-3-pyrrolin-2-ones, which can
be seen as enol ethers and, as a consequence, reveal differ-
ent electronic properties as compared with the corre-
sponding 4-arylpyrrolinones. In the present article,
various reducing agents were evaluated for their ability to
reduce 4-aryl-3-pyrrolin-2-ones and the isomeric 4-pyr-
rolinones towards 3-arylpyrroles. After evaluation of var-
ious reducing agents, only 9-borabicyclo[3.3.1]nonane
(9-BBN) was found to yield pyrroles from pyrrolinones in
good yield. In addition, 1-methyl-3-phenylsuccinimide
was transformed direcly to the corresponding pyrrole
using 9-BBN.
NC
Cl
NH
NH
X
NO2
X
Cl
fenpiclonil
fludioxonil
2a X = Cl
2b X = -O-CF2-O-
1 pyrrolnitrin
Figure 1
As it was found by us that 3- and 4-pyrrolin-2-ones were
suitable substrates for conversion into pyrroles, efforts
were done to develop a convenient route to these starting
materials. 5-Methyl-4-phenyl-4-pyrrolin-2-one (9a) was
synthesized by reacting phenylacetone with t-BuOK and
chloroacetamide (6a) in DMSO.18 Deprotonation of
phenylacetone (5a) at C-1 and subsequent reaction with
chloroacetamide yields 4-oxo-3-phenylpentanamide via
nucleophilic substitution (Scheme 1). At the reaction tem-
perature (80 °C) this intermediate cyclizes spontaneously
and results in pyrrolinone 9a after elimination of water.
The same procedure was used to synthesize the N-propyl
derivative 9b, which isomerized towards the more sta-
ble 3-pyrrolin-2-one 10b within three days at room
temperature.
From a pharmacological point of view, the drug AWD
140-190 (3), proved to exert potent anticonvulsant activi-
ty, indicating that this substance has a potential for an an-
tiepileptic therapy.11 The natural alkaloid razinilam (4,
Figure 2) is interesting because of its ability to mimic the
cellular effects of the anticancer drug paclitaxel.12 Many
other 3-arylpyrroles exhibit antiinflammatory, analgesic,
antiallergic and anti-HIV activities.1,3
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Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42047; Art ID: G22103ST
© Georg Thieme Verlag Stuttgart · New York

2014
G. Verniest, N. De Kimpe
LETTER
R1
1.1 equiv KOtBu,
DMSO, 80°C, 3 h
O
O
Cl
R2
+
R2
N
N
O
H
R1
H
O
6a R2 = H
6b R2 = n-Pr
6c R2 = i-Pr
7a R1 = H, R2 = H (not isolated)
7b R1 = H, R2 = n-Pr (not isolated)
7c R1 = H, R2 = i-Pr (69%)
5a R1 = H
5b R1 = OCH3
7d R1 = OCH3, R2 = i-Pr (72%)
7a and 7b: spontaneous ring closure in DMSO
7c and 7d: cat. H2SO4, CH2Cl2, ∆, 1.5 h
O
N
O
O
9b–d
R2
-H2O
R2
N
R2
N
HO
R1
R1
R1
10b R1 = H, R2 = n-Pr (86%)
10c R1 = H, R2 = i-Pr (75%)
10d R1 = OCH3, R2 = i-Pr (75%)
8
9a R1 = H, R2 = H (35%)
9b R1 = H, R2 = n-Pr (63%)
9c R1 = H, R2 = i-Pr (not isolated)
9d R1 = OCH3, R2 = i-Pr (not isolated)
Scheme 1
With N-isopropyl-2-chloroacetamide (6c) as reactant to
obtain 1-isopropylpyrrolinones 9c and 9d, no ring closure
occurred due to the steric hindrance of the isopropyl moi-
ety, resulting in N-isopropyl-3-aryl-4-oxopentanamides
7c and 7d (Scheme 1). To induce cyclization, the g-keto-
amides were dissolved in DMSO and heated at 100 °C for
1 hour. These reaction conditions however, yielded a mix-
ture of 3-pyrrolinones 10 and 4-pyrrolinones 9, which
could be separated by column chromatography. When the
ketoamides 7c,d were refluxed in dichloromethane with a
catalytic amount of sulfuric acid, only 3-pyrrolinones
10c,d were formed in good yield.
Table 1 Reduction of 3-Pyrrolin-2-one 10c with 9-BBN
Reaction conditions (dry, under N2-atmosphere) Pyrrole 15d (%)
1.1 equiv 9-BBN, THF, 25 °C, 24 h
1.1 equiv 9-BBN, THF, D, 4 h
1.1 equiv 9-BBN, THF, D, 15 h
0
19
25
21
1.1 equiv 9-BBN added in portions during 6 h,
THF, D, 15 h
2.5 equiv 9-BBN, THF, D, 15 h
46
39
2.5 equiv 9-BBN added in portions during 6 h,
In addition to the synthesis of the pyrrolinones outlined
above, 1-methyl-4-phenyl-3-pyrrolin-2-one, 1-methyl-3-
phenyl-3-pyrrolin-2-one, 1,4-dimethyl-3-pyrrolin-2-one
and 1,3-dimethyl-3-pyrrolin-2-one (12, see Table 2, en-
tries 1–4) were synthesized according to literature proce-
dures.19,20
THF, D, 15 h
2.5 equiv 9-BBN, dioxane, D, 15 h
2.5 equiv 9-BBN, toluene, D, 15 h
3 equiv 9-BBN, toluene, D, 15 h
22
50
53
To synthesize pyrroles from the obtained 3- and 4-pyrro-
lin-2-ones, different reactions were evaluated using vari-
ous reducing agents (Table 1). Reaction of pyrrolinone
10c with NaBH4 in diethyl ether, THF or toluene (0 °C or
25 °C or reflux) did not lead to pyrrole 15d, but yielded
mixtures of starting material 10c and the isomeric 4-pyr-
rolinone 9c. The use of LiAlH4 in analogous reactions
yielded more complex reaction mixtures, which also con-
tained starting material and 4-pyrrolinone 9c. The use of
non-ionic reducing agents like borane (BH3·THF) in THF
at room temperature yielded complex reaction mixtures,
which contained only traces of pyrrole 15d (2–5%). No
improvement was obtained when higher temperatures or
more equivalents (up to 3 equiv) of borane were used. Af-
ter reaction of pyrrolinone 10c with 1 equivalent of BH3
in toluene (reflux, 15 h), pyrrole 15d was isolated in very
low yield (9%) from the complex reaction mixture, which
also contained pyrrolinones 10c and 9c.
Finally, 3-pyrrolinone 10c was treated with 1.1 equiva-
lents of 9-borabicyclo[3.3.1]nonane (9-BBN) in refluxing
Synlett 2003, No. 13, 2013–2016 © Thieme Stuttgart · New York

LETTER
New Synthesis of 3-Arylpyrroles
2015
THF for 15 hours. This procedure did not result in a com-
plex reaction mixture, but yielded only pyrrole 15d, pyr-
rolinone 10c and 9c in a ratio 25:45:30 (calculated from
1H NMR data). In an attempt to optimize these surprising
results, various reaction conditions were evaluated (see
Table 1). The best yields were obtained using 3 equiva-
lents of 9-BBN in refluxing toluene for 15 hours, under
N2-atmosphere using dry glassware and solvents. When
more equivalents of 9-BBN were used, the yield did not
increase and residual hydride was recovered [11B NMR:
d = 27 ppm (R2B-H)].21 A decrease in yield was observed
when less equivalents of 9-BBN were used and starting
material 10c and the isomeric pyrrolinone 9c were partial-
ly recovered, even when the hydride was added in por-
tions (5 × 0.2 equiv) with time intervals of 1.5 hours.
O
4 equiv 9-BBN
N CH3
N CH3
toluene, ∆, 15 h
O
16
Scheme 3
15b (26%)
9-BBN at reflux for 15 hours. The reaction indeed yielded
1-methyl-3-phenylpyrrole (15b), however, in rather low
yield (see Scheme 3).
In conclusion, various new 4-aryl-3-pyrrolin-2-ones, 4-
aryl-4-pyrrolin-2-ones and succinimides were synthe-
sized and reduced with 9-borabicyclo[3.3.1]nonane to-
wards 3-arylpyrroles 15, an interesting class of
compounds with broad physiological importance.
Using the optimized reaction conditions, various substi-
tuted 3-arylpyrroles were synthesized (Scheme 2,
Table 2). Only in the case of 1,3-dimethylpyrrole (15a)
the yields were very low, probably due to the volatility of
the final product.
N-Isopropyl-4-oxo-3-phenylpentanamide (7c). To a solution of
potassium t-butoxide (14.98 g, 133.48 mmol, 1.1 equiv) in 100 mL
of DMSO was added slowly phenylacetone (16.26 g, 121.35 mmol)
at r.t. Subsequently 1.1 equiv of N-isopropyl-2-chloroacetamide
(18.09 g, 133.48 mmol), which was prepared from chloroacetyl-
chloride and isopropylamine using a Schotten–Baumann procedure,
These results encouraged us to verify whether succinim-
ides could be transformed directly to pyrroles by reduc-
tion with 9-BBN. 1-Methyl-3-phenylsuccinimide (16)
was dissolved in toluene and treated with 4 equivalents of
Table 2 Synthesis of Substituted Pyrroles 15 from Pyrrolin-2-ones 11 or 12 (Scheme 2)
Entry
Pyrrole
15a
15a
15b
15b
15c
Starting material R1
R2
CH3
H
R3
R4
Yield (%)
1
2
3
4
5
6
7
8
12
CH3
H
H
15
12
48
55
21
53
50
58
12
CH3
CH3
CH3
H
CH3
H
12
C6H5
H
H
H
12
C6H5
C6H5
C6H5
C6H5
4-CH3OC6H4
H
11
H
CH3
CH3
CH3
CH3
15d
15e
11 or 12
11 or 12
11 or 12
i-Pr
n-Pr
i-Pr
H
H
15f
H
O
B
R2
R3
O
N
R2
N R1
R4
R1
R3
R2
R3
R4
13
3 equiv 9-BBN
11
12
N R1
toluene, ∆, 15 h
O
R2
R3
R4
15
B
R2
R3
O
N R1
R4
R1
N
R4
14
Scheme 2
Synlett 2003, No. 13, 2013–2016 © Thieme Stuttgart · New York

2016
G. Verniest, N. De Kimpe
LETTER
was added portion wise. The reaction mixture was stirred at 80 °C
during 3 hours. After cooling, the mixture was poured into ice water
and the resulting suspension was extracted with chloroform
(3 × 100 mL). The combined extracts were washed with water and
after drying (MgSO4) and evaporation of the solvent, 19.51 g (69%)
of pentanamide 7c was obtained, which was purified by column
chromatography (hexane/EtOAc/Et3N 13/7/1, Rf = 0.17). 1H NMR
(CDCl3): d = 1.02 (3 H, d, J = 6.6 Hz, CHCH3aCH3b), 1.10 (3 H, d,
J = 6.6 Hz, CHCH3aCH3b), 2.11 (3 H, s, CH3C=O), 2.34 (1 H, dd,
J = 14.7 Hz, 5.4 Hz, CHaHb), 2.95 (1 H, dd, J = 14.7 Hz, 9.3 Hz,
CHaHb), 3.94–4.02 [1 H, m, CH(CH3)2], 4.28 (1 H, dd, J = 5.4 Hz,
9.3 Hz, CHCH2), 5.41 [1 H, d(br), J = 6.3 Hz, NH], 7.19–7.36 (5 H,
m, CHar). 13C NMR (CDCl3): d = 22.55 [CH(CH3)2], 29.08
(CH3C=O), 39.53 (CH2), 41.31 [CH(CH3)2], 55.24 (CHCH2),
127.57 (CHar,para), 128.16 (2 × CHar), 129.06 (2 × CHar), 137.84
(Car,quat), 170.10 (CONH), 207.67 (CH3C=O). IR (KBr): n = 3300
(NH), 1714 (C=O), 1644 (C=Oamide), 1548 (C=C) cm–1. MS: m/z
(%) = 216 (100) [M – H2O + H+].
46.65 [CH(CH3)2], 54.75 (CH3O), 107.19 (NCHCH), 113.42
(2 × CHar), 114.32 (NCHCH), 121.06 (Cquat), 123.27 (Cquat), 128.90
(2 × CHar), 130.08 (Cquat), 157.07 (Car-OCH3). IR (KBr): n = 1612,
1559, 1508, 1459 (C=C), 1243 cm–1. MS: m/z (%) = 230 (100) [M
+ H+].
Acknowledgment
The authors are indebted to the IWT (Flemish Institute for the
Promotion of Scientific-Technological Research in Industry) and
Ghent University (GOA) for financial support.
References
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Tetrahedron 1978, 34, 179.
1-Isopropyl-5-methyl-4-phenyl-3-pyrrolin-2-one (10c) and 1-
Isopropyl-5-methyl-4-phenyl-4-pyrrolin-2-one (9c). One drop of
concentrated sulfuric acid was added to a solution of 2 g (8.58
mmol) of pentanamide 7c in 10 mL of toluene and the mixture was
refluxed for 1.5 h. The resulting mixture of 3-pyrrolinone 10c and
4-pyrrolinone 9c was column chromatographed (hexane/EtOAc
16/4, Rf,10c = 0.07, Rf,9c = 0.25); mp10c = 76 °C; yield10c 62%, yield9c
13%. Compound 10c: 1H NMR (CDCl3): d = 1.37 [6 H, d, J = 6.9
Hz, CH(CH3)2], 1.42 (3 H, d, J = 6.8 Hz, CHCH3), 4.29 [1 H, sept,
J = 6.9 Hz, CH(CH3)2], 4.65 (1 H, qd, J = 6.8 Hz, 0.9 Hz, CHCH3),
6.28 (1 H, d, J = 0.9 Hz, CHC=O), 7.37–7.46 (5 H, m, CHar). 13C
NMR (CDCl3): d = 18.85 and 19.61 [CH(CH3)2], 21.04 (CHCH3),
43.60 [CH(CH3)2], 56.46 (CHCH3), 119.91 (C=CH-C=O), 126.13
(2 × CHar), 128.12 (2 × CHar), 128.86 (CHar,para), 130.91 (Car,quat),
159.57 (C=CH-C=O), 169.42 (C=O). IR (KBr): n = 1671 (C=O)
cm–1. MS m/z (%) = 216 (100) [M + H+]. Compound 9c: 1H NMR
(CDCl3): d = 1.47 [6 H, d, J = 7.0 Hz, CH(CH3)2], 2.18 (3 H, t,
J = 2.4 Hz, =CCH3), 3.30 (2 H, q, J = 2.4 Hz, CH2), 4.19 [1 H, sept,
J = 7.0 Hz, CH(CH3)2], 7.17–7.40 (5 H, m, CHar). 13C NMR
(CDCl3): d = 11.86 (CH3), 19.79 (2 × CH3), 39.14 (CH2), 44.17
(NCH), 112.49 (CH2C=C), 125.32 (CHar,para), 126.67 (2 × CHar),
127.73 (2 × CHar), 134.48 (C=CCH3), 135.78 (Car,quat), 175.45
(C=O). IR (KBr): n = 1698 (C=O), 1496, 1405, 1355 cm–1. MS:
m/z (%) = 216 (100) [M + H+].
1-Isopropyl-3-(4-methoxyphenyl)-2-methylpyrrole (15f). To a
solution of pyrrolinone 12f (1 g, 4.08 mmol) in 5 mL of dry toluene,
was added
3 equiv (1.49 g, 20.24 mmol) 9-borabicyc-
lo[3.3.1]nonane as a solid dimer. The mixture was allowed to reflux
overnight (15 h) and was subsequently poured in 25 mL of water.
Extraction with Et2O (3 × 25 mL), drying (MgSO4) and evaporation
of the solvents in vacuo afforded pyrrole 15f, which was purified by
column chromatography (hexane/EtOAc 95/5, Rf = 0.25); yield
58%. 1H NMR (CDCl3): d = 1.41 [6 H, d, J = 6.7 Hz, CH(CH3)2],
2.30 (3 H, s, CH3), 3.78 (3 H, s, CH3O), 4.28 [1 H, sept, J = 6.7 Hz,
CH(CH3)2], 6.22 (1 H, d, J = 3.0 Hz, NCHCH), 6.70 (1 H, d, J = 3.0
Hz, NCHCH), 7.10 (2 H, d, J = 8.7 Hz, CHar), 7.30 (2 H, d, J = 8.7
Hz, CHar). 13C NMR (CDCl3): d = 10.28 (CH3), 23.22 (2 × CH3),
(20) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437.
(21) Contreras, R. Z. Naturforsch. B: Chem. Sci. 1980, 35, 1236.
Synlett 2003, No. 13, 2013–2016 © Thieme Stuttgart · New York