Effective synthesis of polysubstituted pyrroles from (E)-Dimethyl 2-(Bromomethyl)-3-(diethoxyphosphoryl) fumarate

Article abstract of DOI:10.1080/00397910903013770

Methyl 1-alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrroles-3- carboxylate 4 was synthesized from the reaction of dimethyl 2-(bromomethyl)-3- (diethoxyphosphoryl) fumarate 3-E and primary amines in good yields.

Full text of DOI:10.1080/00397910903013770

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Effective Synthesis of Polysubstituted
Pyrroles from (E)-Dimethyl 2-
(Bromomethyl)-3-(diethoxyphosphoryl)
Fumarate
Aïcha Arfaoui a , Feten Béji a & Hassen Amri a
a Laboratory of Organic and Organometallic Chemistry , Tunis El
Manar University, Faculty of Science , Tunis, Tunisa
Published online: 04 Feb 2010.
To cite this article: Aïcha Arfaoui , Feten Béji & Hassen Amri (2010) Effective Synthesis of
Polysubstituted Pyrroles from (E)-Dimethyl 2-(Bromomethyl)-3-(diethoxyphosphoryl) Fumarate,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:5, 766-771, DOI: 10.1080/00397910903013770
To link to this article: http://dx.doi.org/10.1080/00397910903013770
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Synthetic Communications1, 40: 766–771, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903013770
EFFECTIVE SYNTHESIS OF POLYSUBSTITUTED
PYRROLES FROM (E)-DIMETHYL 2-(BROMOMETHYL)-
3-(DIETHOXYPHOSPHORYL) FUMARATE
´
A¨ıcha Arfaoui, Feten Beji, and Hassen Amri
Laboratory of Organic and Organometallic Chemistry, Tunis El Manar
University, Faculty of Science, Tunis, Tunisa
Methyl 1-alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylate
was synthesized from the reaction of dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl)
4
fumarate 3-E and primary amines in good yields.
Keywords: Cyclization reaction; dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl) fumarate; polysubsti-
tuted methyl 5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylate primary amines
INTRODUCTION
Over the past few decades, several reports have shown the usefulness of dimethyl
a-(bromomethyl) fumarate 1[1–4] as a versatile and a powerful electrophilic reagent. It
reacts with miscellaneous nucleophiles, leading to the synthesis of interesting products
such as pyrrolin-2-ones,[4] c-butyrolactones,[5] and c-butyrolactames.[6,7]
In connection with our work on the electrophilic reactivity of the allyl bromide 1
with diethylphosphite sodium salt, we reported that the diethylphosphite anion reacts
rapidly and regioselectively with 1 in anhydrous tetrahydrofuran (THF) at ꢀ78 ꢁC to
give exclusively 2-(diethoxy-phosphoryl)-3-methylene-succinic acid dimethyl ester 2[8]
in excellent yield (80%), resulting from a SN20 substitution reaction (Scheme 1). It is
worth mentioning here that some homologous functional allyl phosphonates have
been reported by Basavaiah and Pandiaraju[9] via the reaction coupling of Baylis–
Hillman acetates and triethyl phosphite at 80 ꢁC for 30 min to provide, after thermal
Arbusov rearrangement, an E=Z stereoisomeric mixture of allyl phosphonates.
RESULTS AND DISCUSSION
In the light of our previous studies on the reaction of functional allyl bromide
1, we report herein a convenient procedure for the synthesis of a new electrophilic
multifunctional allyl bromide 3 starting from allyl phosphonate 2, subjected to the
Received February 12, 2009.
Address correspondence to Hassen Amri, Laboratoire de Chimie Organique et Organometallique,
´
Universite de Tunis El Manar, Faculte des Sciences, Campus Universitaire, 2092-Tunis, Tunisie. E-mail:
´
hassen.amri@fst.rnu.tn
´
766

EFFECTIVE SYNTHESIS OF POLYSUBSTITUTED PYRROLES
767
Scheme 1. Synthesis of 2(diethoxyphosphoryl)-3-methylenesuccinic acid dimethyl ester 2 from allyl
bromide 1.
Scheme 2. Stereoselective synthesis of dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl) fumarate 3-E.
Scheme 3. Synthesis of polysubstituted pyrroles from functional allyl bromide 3-E and primary amines.
Table 1. Synthesis of methyl 1-alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-
dihydro-1H-pyrrole-3-carboxylate 4a–h
4a–h
R
Time (h)
Yield (%)
4a
4b
4c
4d
PhCH2
Ph(CH3)CH
3
67
75
71
59
4
p-ClC6H4CH2
p-MeOC6H4CH2
3.5
8
4e
5
67
4f
cC6H11
iPr
nBu
6
83
60
79
4g
4h
3.5
3

´
A. ARFAOUI, F. BEJI, AND H. AMRI
768
reaction of bromine in carbon tetrachloride at room temperature. The obtained
intermediate dibromide underwent dehydrobromination in the presence of triethla-
mine as a base at 0 ꢁC to give dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl)
fumarate 3-E in 77% yield (Scheme 2).
As part of our continuing work on the electrophilic reactivity of allyl bromide to
primary amines in general,[10–13] we report here two significant results. First, we have
shown that the compound 3 could be utilized as a good reagent for the synthesis of
polysubstituted pyrroles 4 as a result of its coupling with primary amines (1 equiv.)
in absolute methanol at 0 ꢁC. The mechanism of the reaction includes a two-step
sequence: SN2 substitution of atom bromide per amine, followed by an intramolecu-
lar cyclization (5-exo-trig process),[14] leading to the formation of a new family of
methyl 1-alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylate
4 in fair to good yields (Scheme 3, Table 1). Second, the unexpected configuration E of
the starting allyl bromide 3 after the lactamization reaction is also justified, because
the cyclization process does not occur from the Z-isomer 3.
In summary, we have developed an efficient alternative synthesis of tetrasubsti-
tuted allyl bromide 3-E, and we have demonstrated that the latter can be used as a
powerful electrophilic reagent to access to a new family of polysubstituted pyrroles 4.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC) on silica-gel
plates (Fluka Kieselgel 60F254). For column chromatography, Fluka Kieselgel (70–
1
230 mesh) was used. H and 13C NMR spectra (fully decoupled) were recorded on
a Bruker AMX 300 instrument in CDCl3 as solvent and tetramethylsilane (TMS)
as the internal standard. Infrared (IR) spectra were recorded with a Perkin-Elmer
paragon 1000 Fourier transform (FT)–IR spectrophotometer. Mass spectrometry
(MS) was performed on an Autospec 200 Micromass (Waters) instrument.
Synthesis of Dimethyl 2-(Bromomethyl)-3-(diethoxyphosphoryl)
Fumarate 3-E
Typical procedure. A solution of bromine (0.36 mL, 7.08 mmol) in anhydrous
carbon tetrachloride (6 mL) was added dropwise at 25 ꢁC to 2 g (6.79 mmol) of
dimethyl b-diethoxyphosphoryl-a-methylene succinate 2 at such a rate that the
bromine color gradually disappeared. The end of the reaction is indicated after 3 h
by the persistence of a brownish color. After cooling at 0 ꢁC for 3 h, 1.51 mL
(1.02 mmol) of anhydrous triethylamine was added, and the formed ammonium salt
was filtered under reduced pressure. Evaporation of the solvent led to a brownish
residue, which was purified by chromatography on silica gel (AcOEt=hexane, 4:6).
Dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl) fumarate 3. Yield
1.95 g (77%) as a viscous yellow oil; nmax (liquid film) 1738 (CO2Me), 1733 (CO2Me),
1
1613 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz): 4.76 (s, 2H), 4.21 (q, 2H,
=
J ¼ 7.00), 3.84 (s, 3H), 3.83 (s, 3H), 1.37 (t, 3H, J ¼ 7.00). 13C NMR (CDCl3, d
=
ppm): 165.75 (C O), 164.32 (C O), 144.29 (C C), 135.35 (C C), 63.78 (OCH2),
=
=
=

EFFECTIVE SYNTHESIS OF POLYSUBSTITUTED PYRROLES
769
53.05 (OCH3), 25.40 (CH2ꢀBr), 16.23 (CH3). HRMS calcd. for C11H18BrO7P:
371.9974; found: 371.9974.
Synthesis of Methyl 1-Alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-
dihydro-1H-pyrrole-3-carboxylate 4a–h
General procedure. One equivalent of amines (1.35 mmol) diluted in 5 mL of
ꢁ
absolute methanol was added dropwise at 0 C to a stirred mixture of ethyl
2-(bromomethyl)-3-cyanoacrylate 3-E (0.5 g, 1.35 mmol) and absolute methanol
(15 mL) in a 50-mL flask. After completion of the reaction and evaporation of the
methanol, the obtained oil was purified by chromatography on silica gel (AcOEt=
petroleum ether, 4:6).
Methyl 1-Benzyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrrole-
3-carboxylate 4a. Yield 0.33 g (67%) as a yellow oil; nmax (liquid film) 1738
1
(CO2Me), 1704 (CON), 1603 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz): 7.29
=
(m, 5H), 4.48 (s, 2H), 4.15 (q, 2H, J ¼ 7.00), 3.91 (s, 3H), 3.78 (s, 2H), 1.35 (t, 3H,
13
=
=
J ¼ 7.00). C NMR (CDCl3, d ppm): 195.64 (HOꢀC C), 168.50 (C O), 160.32
=
=
(C C), 136.84 (aromatic C C), 128.82 (aromatic ¼ CH), 127.70 (aromatic ¼ CH),
126.75 (aromatic ¼ CH), 63.10 (OCH2), 53.02 (OCH3), 43.38 (PhꢀCH2), 40.77
(CH2ꢀN), 16.38 (CH3). HRMS calcd. for C17H22NO6P: 367.1185; found: 367.1188.
Methyl 4-(Diethoxyphosphoryl)-5-oxo-1-(1-phenylethyl)-2,5-dihydro-1H-
pyrrole-3-carboxylate 4b. Yield 0.39 g (75%) as a yellow oil; nmax (liquid film) 1738
(CO2Me), 1715 (CON), 1607 (C C) cmꢀ1; 1H NMR (CDCl , d ppm, J Hz): 7.28 (m,
=
3
5H), 4.16 (q, 2H, J ¼ 7.00), 3.89 (s, 3H), 3.77 (s, 2H), 3.50 (m, 1H), 2.17 (s, 3H), 1.33 (t,
3H, J ¼ 7.00). 13C NMR (CDCl3, d ppm): 190.63 (HOꢀC C), 168.40 (C O), 160.46
=
=
=
=
=
(C C), 128.86 (aromatic C C), 128.43 (C C), 128.23 (aromatic ¼ CH), 127.81
(aromatic ¼ CH), 126.83 (aromatic ¼ CH), 63.27 (OCH2), 53.18 (CHꢀCH3), 52.89
(OCH3), 40.63 (CH2ꢀN), 16.98 (CH3ꢀCHꢀN), 16.26 (CH3). HRMS calcd. for
C18H24NO6P: 381.1341; found: 381.1337.
Methyl 1-(4-Chlorobenzyl)-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-
pyrrole-3-carboxylate 4c. Yield 0.38 g (71%) as a purple oil; nmax (liquid film) 1792
(CO2Me), 1724 (CON), 1614 (C C) cmꢀ1; 1H NMR (CDCl3, d ppm, J Hz): 7.55, 7.31
=
(2 m, 4H), 4.77 (s, 2H), 4.22 (q, 2H, J ¼ 7.00), 3.85 (s, 3H), 3.78 (s, 2H), 1.37 (t, 3H,
13
=
=
J ¼ 7.00). C NMR (CDCl3, d ppm): 165.05 (OꢀC O), 164.62 (NꢀC O), 144.27
=
=
=
=
(C C), 135.40 (C C), 133.15 (ClꢀC C), 129.65 (aromatic HC C), 128.38
=
=
(C CH), 120.56 (C C), 63.71 (OCH2), 53.26 (OCH3), 53.00 (PhꢀCH2ꢀN), 46.89
(CH2ꢀN), 16.23 (CH3). HRMS calcd. for C17H21ClNO6P: 401.0795; found: 401.0790.
Methyl 4-(Diethoxyphosphoryl)-1-(4-methoxybenzyl)-5-oxo-2,5-dihydro-
1H-pyrrole-3-carboxylate 4d. Yield 0.32 g (59%) as a yellow oil; nmax (liquid film)
1
1741 (CO2Me), 1714 (CON), 1606 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz):
=
7.56, 7.24 (2 m, 4H), 4.44 (q, 2H, JAB ¼ 14.23), 4.17 (q, 2H, J ¼ 7.00), 3.84 (s, 3H),
3.78 (s, 2H), 3.37 (s, 3H), 1.32 (t, 3H, J ¼ 7.00). 13C NMR (CDCl3, d ppm): 166.81
=
=
=
=
(OꢀC O), 165.08 (NꢀC O), 158.65 (C C), 158.55 (OꢀC C), 129.48 (aromatic
=
=
=
HC C), 128.65 (C CH), 120.68 (C CH), 113.71 (C CH), 63.56 (OCH2), 53.15
=

´
A. ARFAOUI, F. BEJI, AND H. AMRI
770
(OCH3), 52.81 (PhꢀCH2ꢀN), 48.65 (CH2ꢀN), 46.86 (CH2), 16.23 (CH3). HRMS
calcd. for C18H24NO7P: 397.1290; found: 397.1288.
Methyl 4-(Diethoxyphosphoryl)-5-oxo-1-(pyridin-2-ylmethyl)-2,5-dihydro-
1H-pyrrole-3-carboxylate 4e. Yield 0.33g (67%) as a yellow oil; nmax (liquid film)
1
1739 (CO2Me), 1715 (CON), 1604 (C C) cmꢀ1; H NMR (CDCl , d ppm, J Hz):
=
3
7.21 (m, 1H), 7.08 (m, 1H), 6.89 (m, 1H), 6.81 (m, 1H), 4.27 (m, 2H), 3.92 (q, 2H,
J ¼ 7.00), 3.79 (s, 3H), 3.69 (s, 2H), 1.33 (t, 3H, J ¼ 7.00). 13C NMR (CDCl , d
3
=
=
=
=
ppm): 172.18 (OꢀC O), 168.31 (NꢀC O), 151.59 (C C), 151.18 (NꢀC C), 145.66
=
=
=
(aromatic HC N), 129.30 (aromatic ¼ CH), 121.26 (C CH), 116.56 (C CH),
=
113.48 (C CH), 63.95 (OCH2), 52.80 (OCH3), 49.14 (C6H4NꢀCH2ꢀN), 45.69
(CH2ꢀN), 16.41 (CH3). HRMS calcd. for C16H21N2O6P: 368.1137; found: 368.1134.
Methyl 1-Cyclohexyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-
pyrrole-3-carboxylate 4f. Yield 0.40 g (83%) as a purple oil; nmax (liquid film)
1
1736 (CO2Me), 1714 (CON), 1605 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz):
=
4.16 (q, 2H, J ¼ 7.00), 3.89 (s, 3H), 3.77 (s, 2H), 3.35 (m, 5H), 3.21 (m, 5H), 1.64
13
=
(m, 1H), 1.34 (t, 3H, J ¼ 7.00). C NMR (CDCl3, d ppm): 190.83 (HOꢀC C),
=
=
168.32 (OꢀC O), 160.39 (C C), 63.17 (OCH2), 53.22 (OCH3), 52.93 (CHꢀN),
40.56 (CH2ꢀN), 38.79 (CH2ꢀCH), 36.98 (CH2ꢀCH2), 29.70 (CH2ꢀCH2), 15.27
(CH3). HRMS calcd. for C16H26NO6P: 359.1498; found: 359.1497.
Methyl 4-(Diethoxyphosphoryl)-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-
3-carboxylate 4g. Yield 0.26 g (60%) as a yellow oil; nmax (liquid film) 1732
1
(CO2Me), 1713 (CON), 1606 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz): 4.17
=
(m, 1H), 4.16 (m, 2H), 3.84 (s, 3H), 3.78 (s, 2H), 1.38 (d, 3H, J ¼ 7.00), 1.30 (t,
13
=
=
3H, J ¼ 7.00). C NMR (CDCl3, d ppm): 166.77 (OꢀC O), 165.09 (NꢀC O),
=
=
148.02 (C C), 126.98 (C C), 63.74 (OCH2), 53.21 (OCH3), 46.84 (CH3ꢀCH),
25.33 (CH3ꢀCH), 16.35 (CH3). HRMS calcd. for C13H22NO6P: 319.1185; found:
319.1188.
Methyl 1-Butyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate 4h. Yield 0.35 g (79%) as a yellow oil; nmax (liquid film) 1739 (CO2Me),
1
1696 (CON), 1609 (C C) cmꢀ1; H NMR (CDCl3, d ppm, J Hz): 4.16 (q, 2H,
=
J ¼ 7.00), 3.90 (s, 3H), 3.77 (s, 2H), 3.45 (m, 6H), 1.12 (t, 3H, J ¼ 7.00), 1.34 (t,
13
=
=
3H, J ¼ 7.00). C NMR (CDCl3, d ppm): 190.52 (HOꢀC C), 168.29 (C O),
=
160.29 (C C), 63.08 (OCH2), 53.34 (OCH3), 40.54 (CH2ꢀN), 40.35 (CH2ꢀCH2ꢀN),
36.94 (CH2ꢀCH2), 16.36 (CH2), 16.20 (CH3ꢀCH2), 16.07 (CH3). HRMS calcd. for
C14H24NO6P: 333.1341; found: 333.1337.
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