Short and efficient synthesis of 2H-pyrroles from 7-oxanorbornadiene derivatives

Article abstract of DOI:10.1016/j.tet.2010.11.080

A microwave-assisted tandem [3+2] cycloaddition/retro-Diels-Alder reaction of azomethine ylides derived from imines of α-amino esters to dimethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate derivatives is described. The procedure delivers, in a s

Full text of DOI:10.1016/j.tet.2010.11.080

Tetrahedron 67 (2011) 698e705
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Short and efficient synthesis of 2H-pyrroles from 7-oxanorbornadiene derivatives
a
a
,
y
b
a
a,
*
€
ꢀ
Adrien Soret , Christine Muller , Regis Guillot , Luis Blanco , Sandrine Deloisy
ˇ
a
ꢁ
ꢀ
ꢀ
Laboratoire de Synthese Organique et Methodologie, I.C.M.M.O. (UMR 8182-CNRS), Bat. 420, Universite Paris-Sud 11, 91405 Orsay cedex, France
ˇ
b
ꢀ
Service de Cristallographie, I.C.M.M.O. (UMR 8182-CNRS), Bat. 420, Universite Paris-Sud 11, 91405 Orsay cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2010
Received in revised form 15 November 2010
Accepted 23 November 2010
Available online 27 November 2010
A microwave-assisted tandem [3þ2] cycloaddition/retro-DielseAlder reaction of azomethine ylides de-
rived from imines of a-amino esters to dimethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
derivatives is described. The procedure delivers, in a short reaction time, pyrrolines in high yields. In
a such sequence, the oxanorbornadiene derivatives behave as masked forms of dimethyl acetylenedi-
carboxylate. Subsequent oxidation of the synthesized 3-pyrrolines with DDQ affords 2H-pyrroles with
yields in the 76e88% range. If this three-step sequence is run on the non-substituted 7-oxa-
bicycloheptadienedicarboxylate, purification of the intermediate 3-pyrrolines is avoided to afford
2H-pyrroles in less than 2 h.
Keywords:
Heterocycles
Cycloadditions
Microwave chemistry
Pyrrolines
Ó 2010 Elsevier Ltd. All rights reserved.
2H-Pyrroles
1. Introduction
unsubstituted in the 5 position was reported from 5-[2-(N,N-
dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-3-pyrrolines.
2H-Pyrroles are interesting intermediates to prepare various
types of heterocyclic compounds.1,2 For example, the Battersby’s
group has reported a very intensive work where 2H-pyrroles were
used to access to porphyrinsin order to sustain a proposed biogenetic
synthetic way.3,4 Even if the first synthesis of a 2H-pyrrole (the
pentachloro derivative) was reported in 1897,5ꢀ7 few methods allow
an efficient preparation of these compounds. The alkylation of
magnesium derivatives of 2,5-disubstituted pyrroles,8,9 the addition
of nitrile ylides with vinylphosphonium derivatives,9 vinylsulfones10
or acetylenic compounds,11 the base-induced addition of ketones to
2H-azirines,12,13 and the cyclization of 1,4-diones in the presence of
ammonium acetate andacetic acid14 were found amongthe methods
that should begeneralized. When anhydrogenatomis presenton the
carbon 2, tautomerization occurs and a 1H-pyrrole is isolated, but
recently was described the isolation of a boron complex of the parent
unsubstituted 2H-pyrrole.15,16 2H-Pyrroles were also easily obtained
by reaction of acetylenic compounds with 3-aza-1-metalla-1,3-di-
enes,17,18 or by cyclization of 5-aza-1-metalla-1,3,5-trienes.19
Cleavage of the CeC bond between the pyrroline core and the
heterocyclic substituent occurred easily by heating with elimination of
the pyrrolinic nitrogen proton.22 Our strategy is based on oxidation of
3-pyrrolines.
Recently, we have reported the preparation of some 3-pyrro-
lines by metal salt/base-catalyzed cycloadditions of azomethine
ylides generated from N-arylidene-a-amino esters with a dimethyl
7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate derivative 2
and a subsequent thermal retro-DielseAlder reaction. The oxabi-
cycloheptadienic dicarboxylate 2, prepared by reaction of dimethyl
acetylenedicarboxylate (DMAD) with a furanic compound 1, ap-
pears like a masked form of the acetylenic reagent (Scheme 1).23
CO2Me
R
N
Ar
R
E
E
CO2Me
and/or
E
E
Ar
NH2
O
NH
O
O
DBU, MX
E
E
Ar
R'
R'
R'
Among the class of 2H-pyrroles, compounds with ester groups on
the 3 and 4 positions20 could be prepared by reactions of dimethyl
acetylenedicarboxylate with nitrile ylides11a,c,d,21 or from 3-aza-1-
metalla-1,3-dienes.18a,b Recently, formation of some 2H-pyrroles
2
Δ
E = CO2Me
Δ
DMAD
O
R
Ar
NH2
CO2Me
NH
E
E
E
E
R'
1 R' = CH2-C6H4-OBn
* Corresponding author. Tel.: þ33 1 69 15 32 36; fax: þ33 1 69 15 62 78; e-mail
address: sandrine.deloisy@u-psud.fr (S. Deloisy).
Ar
y
€
Present address: Institut fur Organische Chemie, Johannes-Gutenberg
Scheme 1. From Refs. 23 and 24.
€
Universitat Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.080

A. Soret et al. / Tetrahedron 67 (2011) 698e705
699
Table 1
Whatever the salt used to catalyze the cycloaddition (silver acetate
Reaction of maleate adducts 2,
7
or
8
with imines 3aeh under microwave
or lithium bromide), the scope of the reaction was limited. The
expected cycloadducts or the resulting 3-pyrrolines were not
detected in the reactions with the valine or the phenylglycine de-
rivatives. Moreover, in the presence of lithium bromide, the cy-
cloaddition of phenylglycinate or leucinate derivatives yielded,
exclusively or as a secondary product, primary benzylamines
irradiationa
Imine
Maleate Furan
adduct
Pyrroline 4b
R
Ar
Yieldc Yieldc lit.d Yield
[%]
[%]
[%]
3a
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
2
2
2
2
7
8
2
2
2
1
1
1
1
1
5
6
1
1
1
73
85
88
63
90
d
71e
85
82
39
89
84
80
86
81
76
d
g
resulting from an unusual Michael addition of the C
g-atom of the
3b Me
3c Ph
lithiated azomethine ylides.24
53
34
d
d
d
d
16
d
3df i-Pr
3e i-Bu
3e i-Bu
3e i-Bu
Until now, some 7-oxabicyclo[2.2.1]hepta-2,5-diene derivatives
have been used with various nucleophiles,25 organic azides, and ni-
trile oxides26 to allow the preparation of ethylenic and heterocyclic
compounds. We emphasize the usefulness of such 7-oxanorborna-
dienes derivatives as masked forms of acetylenic partners.
We herein report a more general and efficient method to pre-
pare 3-pyrrolines by a microwave-assisted tandem [3þ2] cycload-
dition/retro-DielseAlder reaction based on oxanorbornadiene
derivatives type 2 and iminoesters. Facile oxidation of these het-
erocycles into 2H-pyrroles is also described.
d
3f 4-BzOeC6H4eCH2 Ph
3g Ph
3h Ph
87
83
80
4-MeOeC6H4
4-BreC6H4
a
Reactions were carried out in toluene during 16 min (maximum power: 300 W,
maximum temperature: 180 ꢁC).
b
Generally, a 3-pyrroline was obtained.
Isolated yields after silica gel column chromatography.
See Ref. 29.
A 1-pyrroline was isolated.
c
d
e
f
Reaction was carried out in xylene during 20 min (maximum power: 300 W,
maximum temperature: 210 ꢁC).
2. Results and discussion
g
Contrary to the claim, compound 4b was not obtained (see Ref. 23).
2.1. Preparation of 3-pyrrolines
a short time, 3-pyrrolines with yields in the 76e89% range. It is
noteworthy that, in few cases, a decrease of the reaction rates was
noticed mainly with new reactor vessels or freshly distilled imines.
These could be restored by introduction of some additives30 (tri-
butylammonium chloride, water) or by previous washing of the
vessel with successively a 1 M NaOH aqueous solution and water.
The reaction time was selected in order to optimize the yield of
the pyrroline. For example, when a mixture of imine 3g and com-
pound 2 was irradiated during 7 min under the same maximum
temperature (180 ꢁC), the isolated yield of pyrroline 4g was lower
(46%) than that obtained after 16 min (81%). Increasing the reaction
time (30 min or 1 h) did not improve the yield.
With the glycinate derivative 3a, 1-pyrroline 4a resulting from
a double bond migration in the initially formed 3-pyrroline was
obtained. This 1-pyrroline 4a showed the two methoxycarbonyl
groups and the phenyl in successively trans and cis relationships.23
Reaction of the valinate derivative 3d gave the pyrroline 4d in
a lower yield because degradation does occur at the high tempera-
ture required to increase the rate of the [3þ2] cycloaddition. The
microwave-assisted reaction with the imine 3c, delivered a 70/30
mixture of the cis-pyrroline 4c and another product. The pure solid
cis-4c29 was easily isolated after trituration in diethyl ether of this
separated mixture. A pure sample of the unexpected product was
alsoobtainedbypreparativesilicagelthinlayerchromatography, and
its spectroscopic data were in agreement with a trans-3-pyrroline. In
particular, 1H NMR spectrum of the trans-4c shows a singlet attri-
buted to the proton linked to the carbon 5 of the pyrrolinic core at
a lower field (5.49 ppm) than that of the major cis-isomer (5.37 ppm).
Colorless single crystals of trans-4c suitable for X-ray analysis were
obtained. An X-ray diffraction study of this crystalline compound
supports unambiguously our proposed structure (Fig. 1).31
Microwave(MW)-assisted [3þ2] cycloadditions of azomethine
ylides were already reported.27,28 By comparison with the thermal
conditions (oil bath), the MW-assisted reactions showgenerallya large
decrease of the reaction time and frequently an increase of the yields.
The [3þ2] cycloadditions of the maleate-like dipolarophile 2
with the azomethine ylides obtained by 1,2-prototropy in the N-
benzylidene amino esters 3aeh were run in closed vessels with
a monomode microwave oven. Generally, toluenic solutions of
equimolar amounts of the maleate 2 and the iminoester 3aeh were
irradiated (maximum power 300 W) in order to reach 180 ꢁC. Under
these conditions, the target was hit after 2 min and the internal
pressure reached 4e4.5 bar. After 16 min, excepted for the valine
derivative 3d, quasi-complete conversions were noticed. In-
terestingly,1H NMR spectra of the reaction mixtures showed mainly
the presence of the furan derivative 1 and a pyrroline 4 (Scheme 2).
The reaction conditions brought about the retro-DielseAlder
reaction of the [3þ2] cycloadducts. In the case of the valinate de-
rivative 3d under the previous conditions, incomplete reaction was
observed. An increase of both the temperature (210 ꢁC, xylene was
used at the place of toluene) and of the reaction time (20 min)
allowed the complete conversion but various unidentified products
wereobtained in addition tofuran1 and pyrroline 4d. Table 1 reports
the yields of the easily separated products and, for comparison,
yields noted byGriggetal. forthe synthesisofpyrrolinesfromDMAD
and azomethine ylides.29 In this direct method, various by-products
arose from the intermediates formed by the Michael addition of the
3-pyrroline to the acetylenic partner.29 Generally, our tandem [3þ2]
cycloaddition/retro-DielseAlder reaction sequence delivers, in
CO2Me
R
N
From imine 3g and 3h, similar 65/35 and 70/30 mixtures, res-
pectively, of the cis- and trans-stereoisomers 4g and 4h were
obtained. These stereoisomers were separated in order to confirm
their structures. From imines 3b and 3def, 1H NMR spectra of the
reaction mixtures obtained after irradiation show, in addition to the
signal of the cis-3-pyrroline 4,23,24 a minor signal (ꢂ10%) at a lower
field, which could be attributed to the trans-stereoisomer. The for-
mation of trans-stereoisomers was probably due to a partial
stereomutation of the azomethine ylides.32 The isolated cis-3-pyr-
roline 4c remained unchanged after microwave-assisted heating at
180 ꢁC in the same reaction conditions than previously, in the
R2
R1
CO2Me
3a-h
E
E
E
E
E
E
Ar
+
or
O
O
N
NH
Toluene,
MW
Ar
R'
Ar
4b-h
R'
2
7
8
R' = CH2-C6H4-OBn
R' = CH2-Ph
R' = CH2-CH3
1
4a
5
cis
R
R
1 = CO2Me
2 = R
6
trans R1 = R
R
2 = CO2Me
E = CO2Me
Scheme 2. Microwave-assisted synthesis of pyrrolines 4.

700
A. Soret et al. / Tetrahedron 67 (2011) 698e705
CHO
CO2Me
MeO2C NH3Cl
E
E
Toluene, NEt3
+
2
+
+
1
NH
MW, 180 °C,
16 min
(95%)
Ph
E = CO2Me
4e (~ 40%)
Scheme 3. Domino synthesis of pyrroline 4e: imine formation, [3þ2] cycloaddition
and retro-DielseAlder reaction.
isolated, this side-reaction seemed to be less important (generally,
close to equimolar amounts of furan 1 and of pyrroline 4 were
present in the crude reaction mixtures). Moreover, treatment of an
equimolar mixture of imine 3e and DMAD in our standard MW-
assisted conditions afforded a 10/90 mixture of pyrroline 4e and 3e.
So, from the maleate derivative 2 and the iminoesters 3, formation
of pyrroline 4 via the DMAD29 obtained by retro-DielseAlder
reaction should be of little importance.
2.2. Synthesis of 2H-pyrroles
Fig. 1. ORTEP31 drawing of trans-pyrroline 4c with the atom labeling scheme. Ellip-
soids are drawn at the 50% probability level.
Various groups have reported the formation of 1H-pyrroles by
oxidation of 3-pyrrolines bearing hydrogen atoms at carbons 2 and
5 with, for example, MnO2,37 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ)38 or o-iodoxybenzoic acid (IBX).39 Oxidation of 2,2-
disubstituted 3-pyrrolines with tetrapropylammonium per-
ruthenate (TPAP) in the presence of N-methylmorpholine N-oxide
(NMO) gave 2H-pyrroles.40 In some cases, 2,2,4,5-tetrasubstituted
pyrrolines obtained from methyl propiolate and azomethine ylides
proved to be difficult to purify and these were characterized after
oxidation with DDQ. Formation of 2H-pyrroles was suspected but
the isolated 1H-pyrroles should result from migration of an ester
group from the carbon 2 to the carbon 3.29
Treatment of the mixtures of cis- and trans-3-pyrrolines 4beh
with DDQ (1.2 equiv) in dichloromethane at room temperature
allowed the facile formation of the unknown 2H-pyrroles 9beh
with yields in the 76e88% range after separation from the by-
products by silica gel chromatography (Scheme 4, Table 2).
absence or presence of 0.2 equiv of imine 3c. Substantial dipole
stereomutation was reported in the case of phenylglycinate
derivatives.33
Results of these MW-assisted reactions were better than those
obtained with classical heating. For example, heating during 16 min
a toluenic solution of phenylglycinate derivative 3c and maleate 2,
withanoilbathat180ꢁC,inthesamereactionvesselthanthatusedin
the microwave oven gave the pyrroline 4c (cis/trans¼71/29) and the
furan 1 in, respectively, 53 and 55% yield. Similar yields (55%) were
obtained when this reactionwas runwith an oil bath at 150 ꢁC during
1.5 h. Complete conversionof the reactants was observed after 15 h at
150 ꢁC (in a vacuum-sealed bulb), but thin layer chromatography and
1H NMR spectrum of the reaction mixture showed the presence the
furan 1 (isolated in 95% yield) and various unidentified products.
Clearly the pyrroline 4c was degradated under these reaction con-
ditions. Someattemptswerealsomadetopreparethepyrroline4dby
heating mixtures of the valinate derivative 3d and maleate 2 with an
oil bath. The furan 1 could be isolated from the reaction mixtures
(yields were, respectively, 20 and 70% after 63 h at 100 ꢁC or 15 h at
150 ꢁC) but pyrroline 4d was completely degradated.
H
MeO2C
R
MeO2C
R
N
N
DDQ
CH2Cl2, 1 h
Ar
Ar
E
E
E
E
E = CO2Me
4b-h
9b-h
Microwave-assisted reactions of the leucinate derivative 3e in
toluene (180 ꢁC, 16 min) with 7-oxanorbornadiene derivatives 7
and 8,34 easily accessible from 2-benzylfuran 535 or commercially
available 2-ethylfuran 6, delivered also the pyrroline 4e in 84 and
80% yield, respectively (Scheme 2, Table 1).
A three-component reaction was also attempted since forma-
tion of azomethine ylides by heating a mixture of an aminoester
and an aromatic aldehyde is well-established in the literature.27d,36
1H NMR spectrum of the crude mixture obtained after reaction,
under our standard MW-assisted conditions, of an equimolar
mixture of benzaldehyde, methyl leucinate hydrochloride, tri-
ethylamine and the maleate derivative 2 showed the complete
conversion of the DielseAlder adduct 2 and the presence of furan 1
and pyrroline 4e in the ratio 1/0.35. Thin layer chromatography of
the reaction mixture showed various unidentified products with Rf
values close to that of the pyrroline 4e. So, impure pyrroline 4e
(∼40% yield, Scheme 3) was isolated.
Scheme 4. Preparation of 2H-pyrroles 9 by oxidation of 3-pyrrolines 4.
Table 2
Synthesis of 2H-pyrroles 9 from purified or unpurified pyrrolines 4a
R
Ar
From purified
pyrroline 4
From
adduct 10b
Yield
[%]c
Overall
Overall
yield
[%]e
yield
[%]d
9b
9c
9df
9e
9f
9g
9h
9i
Me
Ph
i-Pr
i-Bu
Ph
Ph
Ph
Ph
83
87
76
86
88
88
81
d
71
71
30
77
76
71
61
d
d
d
d
75
80
d
81
61
4-BzOeC6H4eCH2
Ph
Ph
Ph
Ph
4-MeOeC6H4
4-BreC6H4
4-CNeC6H4
a
Unless otherwise noted, oxidations were carried out in dichloromethane during
1 h with 1.2 equiv of DDQ at room temperature.
Crude pyrrolines 4 were obtained by reaction of DielseAlder adduct 10 with
imines 3 under microwaves (see text and Table 1 for the conditions).
The high molar amount of furan 1 compared to pyrroline 4e
could be explained by the instability of the DielseAlder adduct 2 in
the reaction conditions. Indeed, microwave-assisted heating at
180 ꢁC of a toluenic solution of adduct 2 gave, after 16 min, a 33/67
mixture of adduct 2 and furan 1. For the reactions reported in Table
1, with the benzylidene derivatives 3 previously prepared and
b
c
Isolated yields after silica gel column chromatography from purified pyrrolines 4.
Overall yields calculated from DielseAlder adduct 2.
Overall yields after silica gel column chromatography from DielseAlder adduct 10.
Oxidation was carried out in dichloromethane during 3 h with 2 equiv of DDQ.
d
e
f

A. Soret et al. / Tetrahedron 67 (2011) 698e705
701
The presence of a tetrasubstituted carbon signal between 85 and
92 ppm in the 13C NMR spectra of 2H-pyrroles 9 was in agreement
with the attributed structure. An X-ray diffraction study of the
crystalline compound 9c supports unambiguously our proposed
structure (Fig. 2).41 Comparison of the structures of compounds
trans-4c and 9c shows in the former a N(1)eC(5) bond length of
Oxidation of the intermediate pyrroline 4i in toluene appeared
much slower than the reaction in dichloromethane and the entire
sequence was less time-consuming with a change of solvent.
Comparison of these three-step sequences with or without
purification of the intermediate pyrrolines 4 shows the uselessness
of such purification since any by-product of the one-pot two-step
tandem reaction was prejudicial to the final chromatography and
similar overall yields were obtained.
ꢂ
ꢂ
1.4699 A, which is 1.2945 A in the oxidized product.
3. Conclusion
In conclusion, we described a new sequence to prepare 3-pyr-
rolines in good yields by [3þ2] cycloaddition of dimethyl 7-oxabi-
cyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate derivatives with
azomethine ylides obtained by 1,2-prototropy in N-arylidene-a-
amino esters followed by a retro-DielseAlder reaction. Under
microwave activation, these two steps occur simultaneously and
transformations were over in less than 20 min. Efficiencyof this two-
step sequence underlined the synthetic interestof the masked forms
of the acetylenic partner. Moreover, oxidation of the 3-pyrrolines
with DDQ allowed generally the preparation of 2H-pyrroles in good
yields in 1 h.
Molecular diversity in 3-pyrrolines and 2H-pyrroles should be
theoretically increased by the use of acetylenic compounds bearing
two different electron-withdrawing groups. DielseAlder reactions
between furan and/or mono-substituted furans with such acety-
lenic dienophiles is poorly described in the literature. Study of the
regioselectivity in the [4þ2] and/or [3þ2] cycloadditions is under
current investigation.
Fig. 2. ORTEP41 drawing of 2H-pyrrole 9c with the atom labeling scheme. Ellipsoids
are drawn at the 50% probability level.
Various attempts to transform the pyrroline 4b into the
2H-pyrrole 9b by action of MnO2 were completely unsuccessful
whatever the solvent (toluene or dichloromethane), the tempera-
ture (20 ꢁC or reflux) and the amount of oxidant.
4. Experimental
4.1. General
In order to obtain a more efficient method to prepare 2H-pyr-
roles 9, we decided to avoid the purification step of the inter-
mediate pyrrolines 4. We choose the unsubstituted dimethyl
7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate 1042 with
the purpose to liberate the volatile furan in the retro-DielseAlder
reaction of the intermediate [2þ3] cycloadducts (Scheme 5).
1H and 13C NMR spectra were recorded on Bruker AC250 (250
and 62.9 MHz, respectively), Bruker DRX300 (300 and 75.5 MHz,
respectively), Bruker AM360 (360 and 90.6 MHz, respectively) or
Bruker DRX400 (400 and 100.6 MHz, respectively) spectrometers.
Chemical shifts (
(CDCl3) signals as internal standards (CHCl3
¼77.14 ppm). Assignments were aided by JMOD pulse sequences
d
) are given in parts per million using solvent
d
¼7.27 ppm; CDCl3
d
CO2Me
and heteronuclear two-dimensional experiments (HSQC, HMBC).
Positive electrospray (ESþ) mass spectra (MS) and high resolution
mass spectra (HRMS) were recorded with a Finnigan MAT 95S
spectrometer or a Waters-Micromass spectrometer (Gif-sur-Yvette,
France). Positive chemical ionization (CIþ) mass spectrum was
recorded with a Thermo Scientific DSQ spectrometer. Infrared (IR)
spectra were recorded using an FT-IR PerkineElmer spectropho-
tometer (Spectrum One). Elemental analyses were performed by
the Microanalysis Service of the I.C.S.N. (Gif-sur-Yvette, France).
MeO2C
R
N
E
E
R
Ar
(i), (ii)
+
O
N
E = CO2Me
E
E
Ar
10
3e, f, h, i
9e, f, h, i
Scheme 5. Preparation of 2H-pyrroles 9 without purification of the intermediates.
Reagents and conditions: (i) Toluene, MW, 300 W, 180 ꢁC, 16 min; (ii) DDQ, CH2Cl2, rt,
1 h.
€
After microwave-assisted reactions of the oxanorbornadiene 10
with the imines 3e, 3f and the bromo- and cyano-phenyl de-
rivatives 3h and 3i in our standard MW-assisted conditions, oxi-
dation with DDQ was run in dichloromethane (1 h) after
evaporation of toluene and the extruded furan. After the first part of
the procedure with the cyanophenyl derivative 3i, 1H NMR spec-
trum of the crude reaction mixture showed signals at 5.46 and
5.54 ppm in the ratio 62/38, attributed, respectively, to the cis- and
the trans-pyrrolines 4i (for the brominated pyrrolines 4h, the cor-
responding signals appear at 5.35 and 5.45 ppm with a 64/36 ratio).
The unusual higher internal pressure (6.5 bar) noticed in the re-
action vessel with this cyanophenyl imine 3i is an indication of
intensive decomposition. After oxidation and column chromato-
graphy, the 2H-pyrroles 9e, f, h and i were isolated with overall
yields in the 61e81% range for this three-step sequence with
a single purification process (Scheme 5, Table 2).
Melting points were determined with a Buchi B-545 apparatus.
Microwave irradiation experiments were carried out with a mono-
mode CEM-Discover apparatus, operating at
a frequency of
2.45 GHz with continuous irradiation power from 0 to 300 W. All
experiments were performed in MW process vials (10 mL) with
control of the temperature by infrared detection and measure of
the pressure. After completion of the reaction, the vial was cooled
to 50 ꢁC with air jet. X-ray diffraction data were collected by using
a Kappa X8 APPEX II Bruker diffractometer with graphite-mono-
ꢂ
chromated MoK
a
radiation (
l
¼0.71073 A). The temperature of the
crystal was maintained at 100 K by means of a 700 series Cryo-
stream cooling device to within an accuracy of ꢃ1 K. Data were
corrected for Lorentz polarization and absorption effects. The
structures were solved by direct methods using SHELXS-9743 and
refined against F2 by full-matrix least-squares techniques using
SHELXL-9744 with anisotropic displacement parameters for all

702
A. Soret et al. / Tetrahedron 67 (2011) 698e705
non-hydrogen atoms. Hydrogen atoms were located on a difference
Fourier map and introduced into the calculations as a riding model
with isotropic thermal parameters. All calculations were performed
by using the Crystal Structure crystallographic software package
WINGX.45
Microwave-assisted reactions were conduced with toluene of
technical purity, which was spent on a basic alumine column and
kept under argon on molecular sieves. Imines 3aei,46 furan de-
rivatives 125c and 5,35b and DielseAlder cycloadducts 2,25c 834 (6
and 3 equiv of DMAD, toluene, 110 ꢁC, 4 h, 96% yield), 1026,42c
(1.4 equiv of furan, DMAD, toluene, sealed-tube, 80 ꢁC, 14 h, 63%
yield after distillation) were prepared according to the literature,
and their spectroscopic data are comparable to those described.
NMR (90.6 MHz, CDCl3):
d
¼51.9 (CO2CH3), 52.2 (CO2CH3), 52.9
(CO2CH3), 68.9 (C-5), 79.3 (C-2), 126.6 (CHAr), 127.5 (CHAr), 127.9
(CHAr), 128.20 (CHAr), 128.22 (CHAr), 128.6 (CHAr), 139.9 (C-2eCAr),
140.3 (C-5eCAr), 140.7 (C-3), 141.7 (C-4), 163.1 (CO2CH3), 163.7
(CO2CH3), 171.8 (C-2eCO2CH3) ppm. IR (KBr):
n
¼3361, 3027, 2950,
1739, 1732, 1714, 1664, 1439, 1357, 1328, 1286, 1198, 1035, 1026,
699 cmꢀ1. MS (ESþ): m/z (%)¼418 (100) [MþNa]þ, 419 (23). HRMS
(ESþ): calcd for C22H21O6NNa [MþNa]þ 418.1261; found 418.1269.
C22H21O6N (395.41): calcd C 66.83, H 5.35, N 3.54; found C 66.23, H
5.42, N 3.48.
4.3.3.2. Trimethyl (trans)-2,5-diphenyl-2,5-dihydro-1H-pyrrole-
2,3,4-tricarboxylate (trans-4c). Colorless crystals: mp 100 ꢁC. 1H
NMR (360 MHz, CDCl3):
3.69 (s, 3H, CO2CH3), 3.88 (s, 3H, CO2CH3), 5.49 (s, 1H, 5-H),
d
¼3.50 (br s, 1H, NH), 3.61 (s, 3H, CO2CH3),
4.2. Preparation of DielseAlder cycloadduct 7
7.28e7.47 (m, 8H, CHAr), 7.53e7.58 (br d, J¼7.4 Hz, 2H, CHAr) ppm.
4.2.1. Dimethyl 1-benzyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-di-
carboxylate (7). A solution of 2-benzylfuran 5 (1.57 g, 9.9 mmol) and
distilled dimethyl acetylenedicarboxylate (3.7 mL, 29.8 mmol) in
toluene (11 mL) was heated at reflux, under argon, for 4 h. After
cooling to room temperature and concentration in vacuo, the crude
product was purified by silica gel column chromatography (petro-
leum ether/Et2O, 2:1) to afford cycloadduct 7 (2.62 g, 88%) as a pale
13C NMR (62.9 MHz, CDCl3):
d
¼52.3 (CO2CH3), 52.4 (CO2CH3), 53.2
(CO2CH3), 67.9 (C-5), 79.5 (C-2), 127.3 (CHAr), 128.0 (CHAr), 128.3
(CHAr), 128.6 (CHAr), 138.4, 140.0, 140.4 and 143.6 (C-3, C-4, 2CAr),
163.5 (CO2CH3), 163.8 (CO2CH3), 172.8 (C-2eCO2CH3) ppm. IR (KBr):
n
¼3375, 3063, 3034, 2998, 2949, 2848, 1737, 1727, 1644, 1490, 1458,
1436, 1385, 1328, 1282, 1255, 1227, 1207, 1153, 1114, 1023 cmꢀ1. MS
(ESþ): m/z (%)¼304 (17), 336 (22), 358 (20), 396 (26) [MþH]þ, 418
(100) [MþNa]þ, 419 (27). HRMS (ESþ): calcd for C22H21O6NNa
[MþNa]þ 418.1267; found 418.1254.
yellowoil.1H NMR(360 MHz, CDCl3):
d
¼3.52(s, 2H, CH2ePh), 3.76 (s,
3H, CO2CH3), 3.78 (s, 3H, CO2CH3), 5.67 (d, J¼2.2 Hz,1H, 4-H), 7.05 (d,
J¼5.0 Hz,1H, 6-H), 7.15 (dd, J¼5.0, 2.2 Hz,1H, 5-H), 7.20e7.30 (m, 5H,
CHAr) ppm. 13C NMR (62.9 MHz, CDCl3):
d¼34.9 (CH2ePh), 52.00
4.3.4. Trimethyl (cis)-2-isopropyl-5-phenyl-2,5-dihydro-1H-pyrrole-
2,3,4-tricarboxylate (4d). Following the general procedure, the
reaction mixture was irradiated to 210 ꢁC in xylene for 20 min at
300 W maximum power. Eluent: pentane/Et2O (2/1). Yield: 39%
(furan 1 was isolated in 63% yield). Pale yellow oil. 1H NMR
(CO2CH3), 52.01 (CO2CH3), 83.2 (C-4), 97.3 (C-1), 126.6 (CHAr), 128.1
(CHAr), 129.8 (CHAr), 135.8 (CAr), 144.2 (C-5), 144.9 (C-6), 151.2 and
155.5 (C-2, C-3), 162.4 (CO2CH3), 165.0 (CO2CH3) ppm. IR (neat):
n
¼3031, 2953, 1717, 1640, 1455, 1436, 1319, 1268, 1230, 1214, 1202,
1115,1081, 703 cmꢀ1. MS (ESþ): m/z (%)¼165 (42) [DMADþNa]þ,181
(11) [5þNa]þ, 297 (13), 323 (100) [MþNa]þ. HRMS (ESþ): calcd for
C17H16O5Na [MþNa]þ 323.0890; found 323.0897.
(250 MHz, CDCl3):
d
¼0.82 (d, J¼6.6 Hz, 3H, CHeCH3), 1.03 (d,
J¼6.6 Hz, 3H, CHeCH3), 2.50 (sept, J¼6.6 Hz, 1H, CHeCH3), 2.84 (br
s, 1H, NH), 3.57 (s, 3H, CO2CH3), 3.81 (s, 3H, CO2CH3), 3.87 (s, 3H,
CO2CH3), 5.12 (s, 1H, 5-H), 7.29e7.37 (m, 5H, CHAr) ppm. 13C NMR
4.3. Typical procedure for the preparation of pyrrolines
4 under microwave irradiation
(62.9 MHz, CDCl3):
d
¼16.1 (CHeCH3), 17.2 (CHeCH3), 34.7
(CHeCH3), 52.0 (CO2CH3), 52.4 (CO2CH3), 52.8 (CO2CH3), 70.0 (C-5),
82.0 (C-2), 127.8 (CHAr), 128.1 (CHAr), 128.6 (CHAr), 137.0 (C-4), 141.4
(CAr), 143.9 (C-3), 162.3 (CO2CH3), 165.2 (CO2CH3), 172.8 (C-
Amixtureofthe givenDielseAlderadduct 2, 7, 8or 10 (0.26mmol),
imine 3aeh (0.26 mmol) and toluene (1 mL) wasirradiated in a closed
vessel to 180 ꢁC for 16 min at 300 W maximum power. After cooling,
the reaction mixture was concentrated under vacuum and the crude
residue was purified by silica gel column chromatography to give the
expected pyrrolines 4aeh. In the reactions from DielseAlder adducts
2 and 7, furan 1 and 5 were also isolated.
2eCO2CH3) ppm. IR (neat):
n
¼3354, 3031, 2955, 2875, 1737, 1729,
1658, 1456, 1435, 1322, 1281, 1246, 1201, 1148, 1028, 914, 733,
699 cmꢀ1. MS (CIþ): m/z (%)¼360 (11), 362 (100) [MþH]þ, 363 (20).
HRMS (ESþ): calcd for C19H24O6N [MþH]þ 362.1598; found
362.1607.
4.3.5. Trimethyl (cis)-2-isobutyl-5-phenyl-2,5-dihydro-1H-pyrrole-
2,3,4-tricarboxylate (4e)24. Eluent: petroleum ether/Et2O (2/1).
Yield: 89% (furan 1 was isolated in 90% yield). Pale yellow crystals:
mp 42e43 ꢁC.
4.3.1. Trimethyl (cis,trans)-2-phenyl-3,4-dihydro-2H-pyrrole-3,4,5-
tricarboxylate (4a)23. Eluent: petroleum ether/AcOEt (9/1). Yield:
71% (furan 1 was isolated in 73% yield).
4.3.2. Trimethyl
(cis)-2-methyl-5-phenyl-2,5-dihydro-1H-pyrrole-
4.3.6. Trimethyl (cis)-2-[4-(benzoyloxy)phenylmethyl]-5-phenyl-2,5-
dihydro-1H-pyrrole-2,3,4-tricarboxylate (4f)23. Eluent: petroleum
ether/Et2O (3/1). Yield: 86% (furan 1 was isolated in 87% yield).
2,3,4-tricarboxylate (4b)23. Eluent: petroleum ether/Et2O (1/1).
Yield: 85% (furan 1 was isolated in 85% yield).
4.3.3. Trimethyl (cis and trans)-2,5-diphenyl-2,5-dihydro-1H-pyr-
role-2,3,4-tricarboxylate (4c). Eluent: petroleum ether/Et2O (1/1).
Chromatography afforded furan 1 in 88% yield and a 70/30 mixture
of cis-4c and trans-4c in an 82% overall yield. Further preparative
silica gel TLC (petroleum ether/Et2O: 2/1, five elutions) gave pure
samples of each isomer.
4.3.7. Trimethyl (cis and trans)-5-(4-methoxyphenyl)-2-phenyl-2,5-
dihydro-1H-pyrrole-2,3,4-tricarboxylate (4g). Eluent: petroleum
ether/Et2O (1/1). Chromatography afforded furan 1 in 83% yield and
a 65/35 mixture of cis-4g and trans-4g in 81% overall yield. Further
preparative silica gel TLC (petroleum ether/Et2O: 1/1, three elu-
tions) gave pure samples of each isomer.
4.3.3.1. Trimethyl
2,3,4-tricarboxylate (cis-4c). White solid: mp 136 ꢁC (lit.29 mp
135e137 ꢁC). 1H NMR (360 MHz, CDCl3):
¼3.22 (br s, 1H, NH), 3.61
(s, 3H, CO2CH3), 3.79 (s, 3H, CO2CH3), 3.84 (s, 3H, CO2CH3), 5.37 (s,
1H, 5-H), 7.32e7.41 (m, 8H, CHAr), 7.49e7.52 (m, 2H, CHAr) ppm. 13
(cis)-2,5-diphenyl-2,5-dihydro-1H-pyrrole-
4.3.7.1. Trimethyl (cis)-5-(4-methoxyphenyl)-2-phenyl-2,5-dihy-
dro-1H-pyrrole-2,3,4-tricarboxylate (cis-4g). Colorless crystals: mp
d
143 ꢁC (lit.29 mp 141e143 ꢁC). 1H NMR (400 MHz, CDCl3):
s, 1H, NH), 3.61 (s, 3H, CArOCH3), 3.77 (s, 3H, CO2CH3), 3.80 (s, 3H,
d
¼3.17 (br
C
CO2CH3), 3.83 (s, 3H, CO2CH3), 5.31 (s, 1H, 5-H), 6.88 (br d, J¼8.8 Hz,

A. Soret et al. / Tetrahedron 67 (2011) 698e705
703
2H, CHAr), 7.26e7.39 (m, 5H, CHAr), 7.48 (br d, J¼8.8 Hz, 2H,
CHAr) ppm. 13C NMR (90.6 MHz, CDCl3):
(CO2CH3), 53.2 (CO2CH3), 55.4 (CArOCH3), 68.7 (C-5), 79.4 (C-2),
114.3 (CHAr), 126.9 (CHAr), 128.2 (CHAr), 128.5 (CHAr), 129.0 (CHAr),
132.2 (CAreC-5), 140.6, 140.7 and 142.4 (C-3, C-4, CAreC-2), 159.8
(OCAr), 163.6 (CO2CH3), 164.0 (CO2CH3), 172.2 (C-2eCO2CH3) ppm.
HRMS (ESþ): calcd for C22H20BrO6NNa [MþNa]þ 496.0366; found
d
¼52.3 (CO2CH3), 52.5
496.0352.
4.4. Typical procedure for the oxidation of 3-pyrrolines 4 into
2H-pyrroles 9
IR (KBr):
n
¼3390, 2997, 2954, 2840, 1740, 1714, 1659, 1609, 1510,
To a solution of pyrrolines 4beh (0.30 mmol) in dichloro-
methane (1 mL) was introduced DDQ (0.36 mmol). After stirring for
1 h at room temperature, the reaction mixture was hydrolyzed with
a saturated aqueous NH4Cl (or NaHCO3) solution. The organic layer
was then separated and the aqueous phase was extracted three
times with CH2Cl2. The combined organic fractions were dried over
magnesium sulfate and the solvent was removed under reduced
pressure. The residue was purified by silica gel column chroma-
tography to afford 2H-pyrroles 9beh.
1440, 1345, 1304, 1249, 1198, 1121, 1109, 1031, 1006 cmꢀ1. MS (ESþ):
m/z (%)¼448 (100) [MþNa]þ, 449 (25). HRMS (ESþ): calcd for
C23H23O7NNa [MþNa]þ 448.1367; found 448.1375.
4.3.7.2. Trimethyl (trans)-5-(4-methoxyphenyl)-2-phenyl-2,5-di-
hydro-1H-pyrrole-2,3,4-tricarboxylate (trans-4g). Pale yellow oil. 1H
NMR (300 MHz, CDCl3):
d
¼3.63 (s, 3H, CO2CH3), 3.69 (s, 3H,
CO2CH3), 3.80 (s, 3H, CArOCH3), 3.84 (br s, 1H, NH), 3.87 (s, 3H,
CO2CH3), 5.44 (s, 1H, 5-H), 6.86 (br d, J¼8.7 Hz, 2H, CHAr), 7.28e7.44
(m, 5H, CHAr), 7.48 (br d, J¼8.1 Hz, 2H, CHAr) ppm. 13C NMR
4.4.1. Trimethyl 2-methyl-5-phenyl-2H-pyrrole-2,3,4-tricarboxylate
(9b). Eluent: petroleum ether/Et2O (1/1). Yield: 83%. White solid:
(75.5 MHz, CDCl3):
d¼52.3 (CO2CH3), 52.4 (CO2CH3), 53.2 (CO2CH3),
55.4 (CArOCH3), 67.5 (C-5), 79.4 (C-2), 114.1 (CHAr), 127.3 (CHAr),
128.3 (2CHAr), 129.2 (CHAr), 132.1 (CAreC-5), 138.1, 140.5 and 144.1
(C-3, C-4, CAreC-2), 159.6 (OCAr), 163.6 (CO2CH3), 164.0 (CO2CH3),
mp 90e91 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼1.82 (s, 3H, CeCH3),
3.69 (s, 3H, CO2CH3), 3.86 (s, 3H, CO2CH3), 3.92 (s, 3H, CO2CH3),
7.40e7.52 (m, 3H, CHAr), 7.76 (br d, J¼7.5 Hz, 2H, CHAr) ppm. 13C
172.9 (C-2eCO2CH3) ppm. IR (neat):
n
¼3355, 3062, 3003, 2954,
NMR (100.6 MHz, CDCl3):
(CO2CH3), 53.3 (CO2CH3), 85.0 (C-2),128.0 (CHAr),128.9 (CHAr),131.4
(CHAr), 132.5 (CAr), 140.5 (C-4), 156.2 (C-3), 161.1 (CO2CH3), 165.0
d
¼19.8 (CeCH3), 52.8 (CO2CH3), 53.1
2841, 1738, 1732, 1716, 1652, 1610, 1514, 1435, 1318, 1243, 1176, 1114,
1032, 912 cmꢀ1. MS (ESþ): m/z (%)¼334 (24), 366 (18), 426 (53)
[MþH]þ, 427 (13), 446 (11), 448 (100) [MþNa]þ, 449 (27). HRMS
(ESþ): calcd for C23H23O7NNa [MþNa]þ 448.1367; found 448.1369.
(CO2CH3), 167.9 (C-2eCO2CH3), 170.1 (C-5) ppm. IR (KBr):
n
¼3035,
3004, 2955, 2925, 2851, 1758, 1742, 1720, 1625, 1540, 1493, 1449,
1437, 1371, 1349, 1327, 1312, 1286, 1231, 1123, 1111, 1064, 1014 cmꢀ1
.
4.3.8. Trimethyl (cis and trans)-5-(4-bromophenyl)-2-phenyl-2,5-
dihydro-1H-pyrrole-2,3,4-tricarboxylate (4h). Eluent: petroleum
ether/Et2O (2/1 then 1/1). Chromatography afforded furan 1 in 80%
yield and a 70/30 mixture of cis-4h and trans-4h in 76% overall
yield. Further preparative silica gel TLC (petroleum ether/Et2O: 2/1)
gave pure samples of each isomer.
MS (ESþ): m/z (%)¼288 (13), 354 (100) [MþNa]þ, 355 (19). HRMS
(ESþ): calcd for C17H17O6NNa [MþNa]þ 354.0948; found 354.0961.
4.4.2. Trimethyl 2,5-diphenyl-2H-pyrrole-2,3,4-tricarboxylate (9c).
Eluent: petroleum ether/Et2O (1/1). Yield: 87%. White solid: mp
127 ꢁC. 1H NMR (360 MHz, CDCl3):
d
¼3.80 (s, 3H, CO2CH3), 3.81 (s,
3H, CO2CH3), 3.92 (s, 3H, CO2CH3), 7.29e7.58 (m, 8H, CHAr), 7.86 (br
4.3.8.1. Trimethyl (cis)-5-(4-bromophenyl)-2-phenyl-2,5-dihydro-
d, J¼7.5 Hz, 2H, CHAr) ppm. 13C NMR (75.5 MHz, CDCl3):
¼52.7
d
1H-pyrrole-2,3,4-tricarboxylate (cis-4h). Colorless crystals: mp
(CO2CH3), 53.0 (CO2CH3), 53.6 (CO2CH3), 90.6 (C-2), 127.9 (CHAr),
128.1 (CHAr), 128.3 (CHAr), 128.6 (CHAr), 128.8 (CHAr), 131.6 (CHAr),
132.1 (CAr),133.4 (CAr),140.1 (C-4),156.6 (C-3),161.2 (CO2CH3),164.6
159 ꢁC. 1H NMR (250 MHz, CDCl3):
d
¼3.17 (br s, 1H, NH), 3.63 (s, 3H,
CO2CH3), 3.78 (s, 3H, CO2CH3), 3.85 (s, 3H, CO2CH3), 5.35 (s, 1H,
5-H), 7.25 (br d, J¼8.5 Hz, 2H, CHAr), 7.33e7.42 (m, 3H, CHAr),
(CO2CH3), 167.2 (C-2eCO2CH3), 171.3 (C-5) ppm. IR (KBr):
n
¼3076,
7.45e7.51 (m, 4H, CHAr) ppm. 13C NMR (62.9 MHz, CDCl3):
d¼52.4
3032, 3007, 2953, 2848, 1759, 1732, 1716, 1627, 1603, 1545, 1492,
1447, 1437, 1428, 1323, 1290, 1232, 1200, 1147, 1118, 1062, 1020,
990 cmꢀ1. MS (ESþ): m/z (%)¼287 (5), 350 (4), 416 (100) [MþNa]þ,
417 (24), 432 (4) [MþK]þ. HRMS (ESþ): calcd for C22H19O6NNa
[MþNa]þ 416.1105; found 416.1112. C22H19O6N (393.39): calcd C
67.17, H 4.87, N 3.56; found C 66.82, H 4.98, N 3.50.
(CO2CH3), 52.6 (CO2CH3), 53.3 (CO2CH3), 68.4 (C-5), 79.6 (C-2),
122.5 (BrCAr), 126.7 (CHAr), 128.4 (CHAr), 128.6 (CHAr), 129.5 (CHAr),
132.0 (CHAr), 139.3, 140.4, 141.0 and 141.4 (C-3, C-4, 2CAr), 163.1
(CO2CH3), 163.9 (CO2CH3), 172.0 (C-2eCO2CH3) ppm. IR (KBr):
n
¼3358, 3060, 3026, 3007, 2952, 2844, 1741, 1731, 1713, 1667, 1483,
1436, 1404, 1341, 1325, 1286, 1209, 1171, 1123, 1077, 1035, 1009,
934 cmꢀ1. MS (ESþ): m/z (%)¼382 (26) and 384 (24), 414 (18) and
416 (18), 474 (36) and 476 (36) [MþH]þ, 496 (98) and 498 (100)
[MþNa]þ, 512 (8) and 514 (8) [MþK]þ. HRMS (ESþ): calcd for
C22H21BrO6N [MþH]þ 474.0547; found 474.0542. C22H20BrO6N
(474.30): calcd C 55.71, H 4.25, N 2.95; found C 55.44, H 4.32, N 2.88.
4.4.3. Trimethyl
2-isopropyl-5-phenyl-2H-pyrrole-2,3,4-tricarbox-
ylate (9d). Following the general procedure, pyrroline 4d was ox-
idized with 2 equiv of DDQ at room temperature for 3 h. Eluent:
petroleum ether/Et2O (1/1). Yield: 76%. Pale yellow oil. 1H NMR
(250 MHz, CDCl3):
d
¼0.67 (d, J¼6.8 Hz, 3H, CHeCH3), 1.32 (d,
J¼6.8 Hz, 3H, CHeCH3), 3.17 (sept, J¼6.8 Hz, 1H, CHeCH3), 3.69 (s,
3H, CO2CH3), 3.85 (s, 3H, CO2CH3), 3.86 (s, 3H, CO2CH3), 7.39e7.55
(m, 3H, CHAr), 7.76 (br d, J¼7.8 Hz, 2H, CHAr) ppm. 13C NMR
4.3.8.2. Trimethyl (trans)-5-(4-bromophenyl)-2-phenyl-2,5-dihy-
dro-1H-pyrrole-2,3,4-tricarboxylate (trans-4h). Pale yellow oil. 1H
NMR (360 MHz, CDCl3):
3.69 (s, 3H, CO2CH3), 3.87 (s, 3H, CO2CH3), 5.45 (s, 1H, 5-H), 7.28 (br
d
¼3.42 (br s, 1H, NH), 3.63 (s, 3H, CO2CH3),
(62.9 MHz, CDCl3):
d¼16.1 (CHeCH3), 19.9 (CHeCH3), 34.6
(CHeCH3), 52.8 (CO2CH3), 52.9 (CO2CH3), 53.1 (CO2CH3), 91.9 (C-2),
128.1 (CHAr), 128.7 (CHAr), 131.0 (CHAr), 132.7 (CAr), 138.8 (C-4),
156.8 (C-3), 162.0 (CO2CH3), 164.3 (CO2CH3), 167.7 (C-2eCO2CH3),
d, J¼8.6 Hz, 2H, CHAr), 7.34e7.41 (m, 3H, CHAr), 7.44e7.51 (m, 4H,
CHAr) ppm. 13C NMR (62.9 MHz, CDCl3):
(CO2CH3), 53.3 (CO2CH3), 67.0 (C-5), 79.5 (C-2), 122.3 (BrCAr), 127.2
(CHAr), 128.4 (CHAr), 128.5 (CHAr), 129.7 (CHAr), 131.8 (CHAr), 138.9,
139.3, 140.3 and 142.6 (C-3, C-4, 2CAr), 163.49 (CO2CH3), 163.50
d
¼52.42 (CO2CH3), 52.46
171.3 (C-5) ppm. IR (neat):
n
¼3027, 2957, 2872, 1741, 1731, 1630,
1539, 1490, 1447, 1434, 1300, 1262, 1231, 1128, 1011 cmꢀ1. MS (ESþ):
m/z (%)¼286 (8), 308 (9), 318 (17), 340 (10), 382 (100) [MþNa]þ,
383 (22). HRMS (ESþ): calcd for C19H21O6NNa [MþNa]þ 382.1267;
found 382.1265.
(CO2CH3), 172.6 (C-2eCO2CH3) ppm. IR (neat):
n
¼3355, 3059, 3022,
2953, 2844, 1739, 1731, 1714, 1652, 1589, 1486, 1434, 1316, 1276,
1258, 1239, 1156, 1114, 1071, 1011 cmꢀ1. MS (ESþ): m/z (%)¼382 (19)
and 384 (18), 414 (13) and 416 (12), 474 (25) and 476 (25) [MþH]þ,
496 (100) and 498 (99) [MþNa]þ, 512 (10) and 514 (10) [MþK]þ.
4.4.4. Trimethyl 2-isobutyl-5-phenyl-2H-pyrrole-2,3,4-tricarboxylate
(9e). Eluent: petroleum ether/Et2O (1/1). Yield: 86%. Pale yellow

704
A. Soret et al. / Tetrahedron 67 (2011) 698e705
solid: mp 78 ꢁC. 1H NMR (360 MHz, CDCl3):
d
¼0.81 (d, J¼6.8 Hz, 3H,
(100) [MþNa]þ, 495 (24) and 497 (24), 510 (8) and 512 (9) [MþK]þ.
HRMS (ESþ): calcd for C22H18BrO6NNa [MþNa]þ 494.0210; found
494.0206. C22H18BrO6N (472.29): calcd C 55.95, H 3.84, N 2.97;
found C 56.31, H 4.15, N 2.69.
CHeCH3), 0.86 (d, J¼6.8 Hz, 3H, CHeCH3), 1.25e1.40 (m, 1H,
CHeCH3), 2.33 (dd, J¼14.0, 6.5 Hz, 1H) and 2.72 (dd, J¼14.0, 5.8 Hz,
1H) (AB system, CH2), 3.67 (s, 3H, CO2CH3), 3.86 (s, 3H, CO2CH3),
3.91 (s, 3H, CO2CH3), 7.39e7.53 (m, 3H, CHAr), 7.76 (br d, J¼7.5 Hz,
2H, CHAr) ppm. 13C NMR (62.9 MHz, CDCl3):
d
¼24.1 (CHeCH3), 24.5
4.5. Typical procedure for the direct preparation
of 2H-pyrroles from cycloadduct 10
(CHeCH3), 42.4 (CH2), 52.7 (CO2CH3), 53.0 (CO2CH3), 53.3 (CO2CH3),
88.5 (C-2), 127.9 (CHAr), 128.8 (CHAr), 131.2 (CHAr), 132.4 (CAr), 141.1
(C-4), 155.4 (C-3), 161.3 (CO2CH3), 164.9 (CO2CH3), 167.7 (C-
A mixture of the DielseAlder adduct 10 (0.26 mmol), imine 3e, f,
h or i (0.26 mmol) and toluene (1 mL) was irradiated in a closed
vessel to 180 ꢁC for 16 min at 300 W maximum power. After
cooling, the reaction mixture was concentrated under vacuum and
diluted with dichloromethane (1 mL). After introduction of DDQ
(0.31 mmol) and stirring for 1 h at room temperature, the reaction
mixture was hydrolyzed with a saturated aqueous NH4Cl (or
NaHCO3) solution. The organic layer was then separated and the
aqueous phase was extracted three times with CH2Cl2. The com-
bined organic fractions were dried over magnesium sulfate and the
solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography to afford, res-
pectively, 2H-pyrroles 9e, f, h or i.
2eCO2CH3), 170.4 (C-5) ppm. IR (KBr):
n
¼3008, 2958, 2869, 1755,
1742, 1722, 1627, 1541, 1492, 1450, 1436, 1346, 1322, 1310, 1292,
1219, 1168, 1129, 1040, 1017, 1002 cmꢀ1. MS (ESþ): m/z (%)¼217 (4),
330 (5), 396 (100) [MþNa]þ, 397 (23). HRMS (ESþ): calcd for
C20H23O6NNa [MþNa]þ 396.1418; found 396.1423.
4.4.5. Trimethyl 2-[4-(benzoyloxy)phenylmethyl]-5-phenyl-2H-pyr-
role-2,3,4-tricarboxylate (9f). Eluent: petroleum ether/Et2O (1/2).
Yield: 88%. Pale yellow oil. 1H NMR (360 MHz, CDCl3):
d¼3.76 (s, 3H,
CO2CH3), 3.79 (s, 3H, CO2CH3), 3.86 (d, J¼13.3 Hz, 1H) and 4.01 (d,
J¼13.3 Hz, 1H) (AB system, CH2), 3.92 (s, 3H, CO2CH3), 6.99 (d,
J¼8.5 Hz, 2H, m-CHAr of Bn), 7.08 (d, J¼8.5 Hz, 2H, o-CHAr of Bn),
7.36e7.54 (m, 5H, CHAr of Ph), 7.57e7.67 (m, 3H, p-CHAr and m-CHAr
of Bz), 8.16 (br d, J¼7.5 Hz, 2H, o-CHAr of Bz) ppm. 13C NMR
4.5.1. Trimethyl 5-(4-cyanophenyl)-2-phenyl-2H-pyrrole-2,3,4-tri-
carboxylate (9i). Eluent: petroleum ether/Et2O (2/3). Yield: 61%.
(62.9 MHz, CDCl3):
d
¼39.4 (CH2), 52.8 (CO2CH3), 52.9 (CO2CH3),
53.4 (CO2CH3), 88.0 (C-2), 120.9 (m-CHAr of Bn), 127.8 (CHAr), 128.6
(CHAr), 128.7 (CHAr), 129.7 (CAr), 130.1 (o-CHAr of Bz), 131.2 (p-CHAr
of Ph, o-CHAr of Bn), 131.5 (CAr), 132.3 (CAr), 133.5 (p-CHAr of Bz),
142.2 (C-4), 150.1 (OCAr), 153.9 (C-3), 161.3 (CO2CH3), 164.3
(CO2CH3), 165.0 (CO2CAr), 167.5 (C-2eCO2CH3), 171.2 (C-5) ppm. IR
White solid: mp 128 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼3.81 (s, 3H,
CO2CH3), 3.83 (s, 3H, CO2CH3), 3.92 (s, 3H, CO2CH3), 7.31e7.44 (m,
5H, CHAr), 7.76 (br d, J¼8.2 Hz, 2H, CHAr), 7.96 (br d, J¼8.2 Hz, 2H,
CHAr) ppm. 13C NMR (90.6 MHz, CDCl3):
(CO2CH3), 53.8 (CO2CH3), 91.4 (C-2), 115.1 (NCCAr), 118.1 (CN), 127.9
(CHAr), 128.6 (CHAr), 129.0 (2CHAr), 132.5 (m-CHAr of NCC6H4), 133.0
(CAr), 136.3 (CAreC-5), 139.0 (C-4), 158.2 (C-3), 161.3 (CO2CH3), 164.0
d
¼52.9 (CO2CH3), 53.2
(neat):
n
¼3066, 3034, 3003, 2955, 2848, 1744, 1739, 1732, 1634,
1602, 1539, 1508, 1493, 1447, 1435, 1330, 1267, 1200, 1167, 1122,
1082, 1063, 1025, 1006 cmꢀ1. MS (ESþ): m/z (%)¼550 (100)
[MþNa]þ, 551 (32), 552 (7), 566 (5) [MþK]þ. HRMS (ESþ): calcd for
C30H25O8NNa [MþNa]þ 550.1472; found 550.1472.
(CO2CH3), 166.6 (C-2eCO2CH3), 169.9 (C-5) ppm. IR (KBr):
n
¼3066,
3010, 2955, 2844, 2229, 1741, 1732, 1631, 1535, 1492, 1433, 1405,
1340, 1317, 1282, 1251, 1152, 1116, 1062, 1023, 1001 cmꢀ1. MS (ESþ):
m/z (%)¼329 (9), 375 (61), 419 (6) [MþH]þ, 441 (100) [MþNa]þ, 442
(28), 457 (8) [MþK]þ. HRMS (ESþ): calcd for C23H18O6N2Na
[MþNa]þ 441.1057; found 441.1060.
4.4.6. Trimethyl 5-(4-methoxyphenyl)-2-phenyl-2H-pyrrole-2,3,4-
tricarboxylate (9g). Eluent: petroleum ether/Et2O (1/1). Yield: 88%.
Pale yellow solid: mp 154e155 ꢁC. 1H NMR (250 MHz, CDCl3):
d
¼3.79 (s, 3H, CO2CH3), 3.80 (s, 3H, CO2CH3), 3.86 (s, 3H, CArOCH3),
Acknowledgements
3.93 (s, 3H, CO2CH3), 6.96 (br d, J¼9.0 Hz, 2H, CHAr), 7.27e7.42 (m,
5H, CHAr), 7.83 (br d, J¼9.0 Hz, 2H, CHAr) ppm. 13C NMR (62.9 MHz,
ꢁ
We thank the Ministere de l’Education Nationale, de la Recher-
CDCl3):
d
¼52.5 (CO2CH3), 52.9 (CO2CH3), 53.4 (CO2CH3), 55.3 (CAr
-
che et de la Technologie for a Ph.D. grant attributed to A.S. and the
Socrates-Erasmus student exchange program for a grant to C.M. We
are also grateful to J.-P. Baltaze, I.C.M.M.O., for performing NMR
experiments and for our useful discussions.
OCH3), 90.1 (C-2), 114.1 (m-CHAr of MeOC6H4), 124.5 (CAreC-5),
127.7 (CHAr), 128.1 (CHAr), 128.4 (CHAr), 129.8 (o-CHAr of MeOC6H4),
133.5 (CAr), 140.1 (C-4), 155.9 (C-3), 161.1 (CO2CH3), 162.2 (OCAr),
164.9 (CO2CH3), 167.3 (C-2eCO2CH3), 170.2 (C-5) ppm. IR (KBr):
n
¼3106, 3065, 3039, 3010, 2951, 2847, 1756, 1735, 1721, 1633, 1609,
1507, 1491, 1447, 1428, 1282, 1258, 1232, 1207, 1179, 1118, 1061,
1021 cmꢀ1. MS (ESþ): m/z (%)¼380 (14), 446 (100) [MþNa]þ, 447
(25), 448 (6), 462 (3) [MþK]þ. HRMS (ESþ): calcd for C23H21O7NNa
[MþNa]þ 446.1210; found 446.1195.
References and notes
1. Formation of pyrroles: (a) Chiu, P.-K.; Sammes, M. P. Tetrahedron Lett. 1987, 28,
2775e2778 and references cited therein; (b) Patterson, J. M.; Soedigdo, S. J. Org.
Chem. 1968, 33, 2057e2061; (c) Chung, M. W. L.; Lai, T.-F.; Sammes, M. P. J.
Chem. Res., Synop. 1987, 366e367. Formation of pyridines: (d) Plancher, G.;
Ponti, U. Rend. Acc. Lincei 1909, 18 II, 469e474. Formation of 3-pyrrolin-2-ones:
(e) See Ref. 40. Dienic partner in [4þ2] cycloadditions: (f) Jung, M. E.; Shapiro, J.
J. J. Am. Chem. Soc. 1980, 102, 7862e7866; (g) Ramash, B. K.; Gladstone, C. M.;
Wong, J. L. J. Org. Chem. 1981, 46, 3036e3040; see also Ref. 6. Dienophile in
[4þ2] cycloadditions: (h) Tahdi, A.; Lafquih-Titouani, S.; Soufiaoui, M.; Komiha,
N.; Kaltoum-Kabbaj, O.; Hegazi, S.; Mazzah, A.; Eddaif, A. Tetrahedron 2002, 58,
1507e1512. Partner in [3þ2] cycloadditions: (i) Eddaif, A.; Kitane, S.; Soufiaoui,
M.; Mison, P. Tetrahedron Lett. 1991, 32, 3709e3710; (j) Belloir, P. F.; Laurent, A.;
Mison, P.; Lesniak, S.; Bartnik, R. Synthesis 1986, 683e686.
4.4.7. Trimethyl 5-(4-bromophenyl)-2-phenyl-2H-pyrrole-2,3,4-tri-
carboxylate (9h). Eluent: petroleum ether/Et2O (1/1 then 1/2).
Yield: 81%. Yellow solid: mp 129 ꢁC. 1H NMR (300 MHz, CDCl3):
d
¼3.807 (s) and 3.812 (s) (6H, 2CO2CH3), 3.92 (s, 3H, CO2CH3),
7.30e7.44 (m, 5H, CHAr), 7.61 (br d, J¼6.8 Hz, 2H, CHAr), 7.73 (br d,
J¼6.8 Hz, 2H, CHAr) ppm. 13C NMR (90.6 MHz, CDCl3):
¼52.8
d
(CO2CH3), 53.1 (CO2CH3), 53.7 (CO2CH3), 90.9 (C-2), 126.4 (CAreC-5),
127.9 (CHAr), 128.4 (CHAr), 128.8 (CHAr), 129.7 (o-CHAr of BrC6H4),
131.1 (BrCAr), 132.1 (m-CHAr of BrC6H4), 133.2 (CAr), 139.6 (C-4), 157.1
(C-3), 161.2 (CO2CH3), 164.4 (CO2CH3), 166.9 (C-2eCO2CH3), 170.3
2. (a) For an old review concerning 2H-pyrroles, see: Patterson, J. M. Synthesis
1976, 281e304; (b) For a compilation of papers concerning the synthesis of 2H-
pyrroles, see: Battersby, A. R.; Baker, M. G.; Broadbent, H. A.; Fookes, C. J. R.;
Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1987, 2027e2048.
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R. J. Chem. Soc., Perkin Trans. 1 1998, 1493e1508 and references cited therein.
4. See also: Bullock, E.; Johnson, A. W.; Markham, E.; Shaw, K. B. Nature 1960, 185,
607e609.
(C-5) ppm. IR (KBr):
n
¼3091, 3063, 3003, 2952, 2844, 1760, 1723,
1628, 1593, 1489, 1439, 1428, 1400, 1317, 1284, 1230, 1203, 1117,
1063, 1016, 989 cmꢀ1. MS (ESþ): m/z (%)¼396 (5) and 398 (5), 428
(35) and 430 (36), 472 (6) and 474 (6) [MþH]þ, 494 (100) and 496
€
5. Anschutz, R.; Schroeter, G. Justus Liebigs Ann. Chem. 1897, 295, 67e93.

A. Soret et al. / Tetrahedron 67 (2011) 698e705
705
6. Confirmation of the structure of this 1-azadiene was given latter: Daniels, P. H.;
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435e440.
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32 II, 28e33.
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31. X-ray Crystal Data of trans-4c: C22H21NO6, M¼395.40, monoclinic, space group
¼104.608(2)ꢁ,
ꢂ
ꢂ
ꢂ
b
P 21/c, Z¼4, a¼9.5727(7) A, b¼12.8658(10) A, c¼16.0689(11) A,
3
3
ꢂ
V¼1915.1(2) A , d¼1.371 g/cm , R1¼0.0501, wR2¼0.1296, 6791 independent
reflections were collected (Rint¼0.0499). CCDC-756013 contains the supple-
mentary crystallographic data for this compound. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
€
15. Hill, M.; Kehr, G.; Frohlich, R.; Erker, G. Eur. J. Inorg. Chem. 2003, 3583e3589.
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€
C7eC11; (b) Aumann, R.; Heinen, H.; Goddard, R.; Kruger, C. Chem. Ber. 1991,
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8417e8420.
ꢀ
2003, 68, 4674e4683; (c) Campos, P. J.; Caro, M.; Lopez-Sola, S.; Sampedro, D.;
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45, 1195e1197.
39. Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126,
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127, 911e920.
20. See also: Kostik, E. I.; Abiko, A.; Oku, A. J. Org. Chem. 2001, 66, 1638e1646.
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41. X-ray Crystal Data of 9c: C22H19NO6, M¼393.38, orthorhombic, space group P 21
3
ꢂ
ꢂ
ꢂ
ꢂ
21 21, Z¼4, a¼7.6851(5) A, b¼10.3295(6) A, c¼24.1423(15) A, V¼1916.5(2) A ,
d¼1.363 g/cm3, R1¼0.0613, wR2¼0.1411, 5304 independent reflections were
collected (Rint¼0.0564). CCDC-756014 contains the supplementary crystallo-
graphic data for this compound. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
42. (a) Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1931, 490, 243e257; (b) Diels, O.;
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€
€
Gottingen: Gottingen, Germany, 1997.
44. Sheldrick, G. M. SHELXL-97, Program for the Refinement of Crystal Structures from
€
€
Diffraction Data; University of Gottingen: Gottingen, Germany, 1997.
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