Synthesis of polysubstituted pyrroles

Article abstract of DOI:10.2174/157017809788681338

Cross coupling metathesis reactions from two ethylenic compounds 4 and 5 easily led to Michael acceptors 6ab and 7a-b. Reaction of these compounds, or of enone 5', with p-toluenesulfonylmethyl isocyanide (TosMIC) provided the disubstituted pyrroles 9a-c a

Full text of DOI:10.2174/157017809788681338

Letters in Organic Chemistry, 2009, 6, 359-361
359
Synthesis of Polysubstituted Pyrroles
Céline Poulard, Julien Cornet, Stéphanie Legoupy*, Gilles Dujardin, Robert Dhal and François
Huet*
Laboratoire de Synthèse Organique, UCO2M, UMR CNRS 6011, Université du Maine, Avenue Olivier Messiaen, 72085
Le Mans cedex 9, France
Received September 30, 2008: Revised May 04, 2009: Accepted May 06, 2009
Abstract: Cross coupling metathesis reactions from two ethylenic compounds 4 and 5 easily led to Michael acceptors 6a-
b and 7a-b. Reaction of these compounds, or of enone 5’, with p-toluenesulfonylmethyl isocyanide (TosMIC) provided
the disubstituted pyrroles 9a-c and 10a-b. The analogous reaction of compounds 6a-b and 5’, but in presence of Ph3SnCl,
provided the trisubstituted pyrroles 11a-c. All of these compounds 9-11 were thus obtained in two steps only.
Keywords: Lavendamycin, pyrroles, TosMIC, Michael acceptors, cross metathesis.
INTRODUCTION
functional groups at the 3 and 4 or 2, 3 and 4 positions.
Although a variety of synthetic approaches to access highly
functionalized pyrroles have been reported, some of these
lead to low yields, give regioisomers and need synthesis of
elaborated intermediates [6]. We then envisioned synthetic
pathways towards 9, 10 and 11, in which the 1,2-
disubstituted Michael acceptors 6 and 7, obtained by cross
methatesis [7] with compounds 4 and 5, were used in a
regioselective reactions with p-toluenesulfonylmethyl
isocyanide (TosMIC) 8 [8] to prepare the desired pyrroles 9,
10 and 11 (Scheme 1).
Our interest in synthesis of analogues of lavendamycin 1
[1] (Fig. 1), a natural product that displayed antimicrobial
and cytotoxic properties [2] and a significant activity against
topoisomerases I [3], led to a first publication from our
group several years ago [4]. More recently, we prepared
several new analogues 2 [5]. A part of this work dealt with
obtaining conformationally restricted derivatives. We then
tried to extend our investigations to other molecules 3,
equally including a pyrrole moiety, and we needed to prepare
starting pyrrole compounds substituted with different
O
R'
N
O
O
O
O
R
N
N
OH
N
CO2H
H2N
N
H2N
N
O
N
N
R = H, OCH3
R' = H, Et
HN
1
3
CO2CH3
CO2CH3
2
Fig. (1).
R1
R1
R2
p-Ts
NC
4
8
+
R1
R3
R2
R4
N
or 8 + Me3SnCl
or 8 + Ph3SnCl
H
6 : R2 = COEt
7 : R2 = CO2Et
R2
9 : R4 = H, R2 = COEt
10 : R4 = H, R2 = CO2Et
11 : R4 = SnMe3 or SnPh3, R2 = COEt
5
R3 = H or Me
Scheme 1.
RESULTS AND DISCUSSION
The first attempts to obtain Michael acceptors were
carried out from pent-1-en-3-one 5 and compounds 4a,b in
the presence of the second generation Grubbs catalyst and
with dichloromethane as solvent. However, in none of these
*Address correspondence to this author at the Laboratoire de Synthèse
Organique, UCO2M, UMR CNRS 6011, Université du Maine, Avenue
Olivier Messiaen, 72085 Le Mans cedex 9, France; Tel: +33 2 43 83 30 96;
Fax: +33 2 43 83 39 02; E-mail: slegoupy@univ-lemans.fr
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

360 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Poulard et al.
Mes
N
N
Mes
Ph
Cl
Ru
R1
R3
Cl
PCy3
75°C
R1
COEt
COEt
6a : R1 = CH2NHBoc, 55%
6b : R1 = CH2OBn, 76%
5' : R3 = Me
4a : R1 = CH2NHBoc
4b : R1 = CH2OBn
Scheme 2.
cases, the reactions produced significant amounts of the
cross coupling products. Fortunately the desired products
6a,b were obtained in satisfying yield with 4a and 4b
respectively, and 5 not only as the reagent but also as solvent
(Scheme 2). Hex-4-en-3-one 5' was also used as the solvent
with 4a and 4b, and the results were much more satisfying
probably due to its better stability and to its better solvent
power.
purified. The presence of the stannyl group at the expected
position was confirmed by observation of 1H-1H correlations
between H-5 and H to a C-4 on the COSY spectra of
compounds 11a-c. These compounds might lead to several
other trisubstituted products by substitution reaction. For
instance the 2-bromo derivatives would be available [9a]
while bromination of compounds 9a-c mainly leads to the 5-
bromo derivatives.
COEt
COEt
Preparation of compounds 7a and 7b (Scheme 3) were
carried out in similar conditions. Ethyl acrylate was used as
the reagent and the solvent, and coupled with compounds 4a
and 4b, in the presence of the second generation Grubbs
catalyst to give 7a and 7b in satisfying yield [9].
BnO
BocHN
SnPh3
SnPh3
Me
N
N
H
H
11b (40%)
11a (41%)
BocHN
CO2Et
BnO
CO2Et
COEt
7b 71%
7a 55%
Scheme 3.
SnPh3
N
H
Reactions of compounds 6a,b, enone 5' or of compounds
7a,b with TosMIC in the presence of n-BuLi proved to be a
convenient method to prepare disubstituted pyrroles 9a-c and
10a,b respectively in 40 to 51% yield (Scheme 4).
11c (62%)
Scheme 5.
COEt
COEt
BnO
BocHN
EXPERIMENTAL SECTION
NMR spectra were recorded on a Bruker Avance 400 or
on a DPX 200 spectrometers. All melting points are
uncorrected. High resolution mass spectra were recorded on
Waters-MicromassGCT Premier spectrometers.
N
H
N
H
9b (50%)
9a (40%)
Me
COEt
Preparation of compound 6a: N-Boc-allylamine 4a
(151 mg, 0.96 mmol) in hex-4-en-3-one 5’ (1 mL, 8.21
mmol) was added under argon and with stirring to the second
generation Grubbs catalyst (18 mg, 0.02 mmol). The reaction
mixture was heated at 80°C for 12 h. Cooling, evaporation,
and then purification by column chromatography on silicagel
(cyclohexane/Et2O 3:2) provided 6a (112 mg, 55%) as an oil.
Compounds 6b and 7a,b were obtained in similar
conditions with slight modifications (heating at 75°C for 24
h, and some variations in eluents for chromatographies).
Preparation of compound 9a: n-BuLi (956 μL of a 1.6 M
solution in hexane, 1.5 mmol) was added dropwise at –78°C
under argon and with stirring to a solution of TosMIC (194
mg, 1.0 mmol) in dry THF (9.7 mL). After 40 min of
stirring, compound 6a (107 mg, 0.50 mmol) in dry THF (4.9
mL) was added. After 40 min at –78°C hydrolysis with a
saturated solution of NH4Cl (18 mL), warming to room
temperature, stirring for 20 min, extraction (EtOAc),
washing of the combined organic phase with water and then
N
H
9c (42%)
CO2Et
CO2Et
BocHN
BnO
N
H
N
H
10a (51%)
10b (46%)
Scheme 4.
Using the same reaction in the presence of
trimethylstannyl chloride[9] led to the expected trisubstituted
derivatives (Scheme 1, R4 = Me3Sn). However purification
of these compounds was difficult. Reactions in the presence
of triphenylstannyl chloride led to better results (Scheme 5).
The products 11a-c were thus obtained and were more easily

Synthesis of Polysubstituted Pyrroles
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
361
with a saturated solution of NaCl, drying (MgSO4),
evaporation and then column chromatography on silicagel
(CH2Cl2/AcOEt 10:1) provided 9a (50 mg, 40%) as an oil.
Compounds 9b,c and 10a,b were obtained in similar
conditions with slight modifications. Preparation of
compounds 11a-c were carried out from 3.0 mmol of
TosMIC and 6.3 mmol of n-BuLi in analogous conditions.
The reaction mixture was stirred for 5 min then Ph3SnCl (6.0
mmol) in THF was added, and then, after 5 min more, enone
6a, 6b or 5' (2.8 mmol). The reaction was slowly allowed to
warm up to room temperature overnight before hydrolysis.
Data for new compounds, 6a: 1H NMR (200 MHz, CDCl3)
ꢀ 6.76 (1H, dt, J = 16.1, 4.9 Hz), 6.20 (1H, dt, J = 16.1, 1.5
Hz), 4.78 (1H, br s), 3.93 (2H, m), 2.59 (2H, q, J = 7.3 Hz),
1.46 (9H, s), 1.10 (3H, t, J = 7.3 Hz). 13C NMR (50 MHz,
128.2, 128.0, 127.8, 125.4, 121.0, 72.2, 64.9, 33.5, 8.4.
HRMS (DCI+/CH4) calcd for C33H32NO2Sn (M + H)+:
594.1455, found 594.1499. 11c: Mp 103°C. H NMR (400
MHz, CDCl3) ꢀ 8.21 (1H, br s), 7.73-7.25 (15H, m), 6.71
(1H, s), 2.81 (2H, q, J = 7.3 Hz), 2.34 (3H, s), 1.12 (3H, t, J
= 7.3 Hz). 13C NMR (100 MHz, CDCl3) ꢀ 198.3, 139.1,
138.5, 137.2, 133.4, 128.7, 128.4, 123.4, 119.8, 34.1, 13.2,
8.4. HRMS (CI+/NH3) calcd for C20H20NOSn (M - C6H5)+:
410.0567, found 410.0574.
1
CONCLUSION
Finally the sequence exposed above is efficient to
prepare several pyrrole compounds polysubstituted with
functional groups. Thanks to the facile access to the Michael
acceptors by cross metathesis reaction, compounds 9a,b,
10a,b and 11a-c were thus obtained in two steps only. The
combination of the Grubbs procedure with the Van Leusen
TosMIC preparation which is described here enhance the
interest of the latter for the synthesis of complexe pyrroles.
CDCl3) ꢀ 200.6, 155.7, 142.5, 129.2, 79.8, 41.5, 33.4, 28.3,
.
7.9. HRMS (FI+) calcd for C11H19NO3 [M]+ : 213.1365,
1
found 213.1362. 6b: H NMR (200 MHz, CDCl3) ꢀ 7.40-
7.10 (5H, m), 6.84 (1H, dt, J = 15.9, 4.5 Hz), 6.39 (1H, dt, J
= 15.9, 2.0 Hz), 4.57 (2H, s), 4.20 (2H, dd, J = 4.5, 2.0 Hz),
2.59 (2H, q, J = 7.3 Hz), 1.10 (3H, t, J = 7.3 Hz). 13C NMR
(50 MHz, CDCl3) ꢀ 200.7, 141.8, 137.7, 129.1, 128.5, 127.9,
127.7, 72.9, 68.9, 33.7, 8.0. HRMS (FI+) calcd for C13H16O2
ACKNOWLEDGEMENT
.
1
[M]+ : 204.1150, found 204.1145. 9a: H NMR (200 MHz,
CDCl3) ꢀ 9.26 (1H, m), 7.39 (1H, dd, J = 3.2, 2.0 Hz), 6.60
(1H, m), 6.01 (1H, m), 4.26 (2H, d, J = 6.3 Hz), 2.80 (2H, q,
J = 7.3 Hz) 1.41 (9H, s), 1.19 (3H, t, J = 7.3 Hz). 13C NMR
(50 MHz, CDCl3) ꢀ 198.2, 156.5, 125.5, 122.8, 121.9, 119.2,
We thank the local section of Sarthe of the Ligue
Nationale contre le Cancer for a fellowship to C. P.
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