Microwave-Assisted [3 + 2] Cycloadditions of Azomethine Ylides

Article abstract of DOI:10.1021/ol0361195

(Equation Presented) The microwave-assisted intramolecular [3 + 2] cycloaddition reaction of azomethine ylides to activated and nonactivated alkenes and alkynes is described. The procedure allows the synthesis of pyrrolidines and pyrrole products in good to excellent overall yields in short reaction times. It appears from parallel comparative studies that the microwave procedure favors the reaction times and overall purity of the crude reaction mixture. The reactions can also be performed in the absence of solvent.

Full text of DOI:10.1021/ol0361195

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4915-4918
Microwave-Assisted [3 + 2]
Cycloadditions of Azomethine Ylides
George Bashiardes,* Imad Safir, Achmet Said Mohamed, Francis Barbot, and
Joelle Laduranty
De´partement de Chimie, Me´thodologie et Synthe`se de Biomole´cules, SFA-UMR 6514,
UniVersite´ de Poitiers, 40 aVenue du Recteur Pineau, 86022 Poitiers, France
george.bashiardes@uniV-poitiers.fr
Received October 30, 2003
ABSTRACT
The microwave-assisted intramolecular [3 + 2] cycloaddition reaction of azomethine ylides to activated and nonactivated alkenes and alkynes
is described. The procedure allows the synthesis of pyrrolidines and pyrrole products in good to excellent overall yields in short reaction
times. It appears from parallel comparative studies that the microwave procedure favors the reaction times and overall purity of the crude
reaction mixture. The reactions can also be performed in the absence of solvent.
The use of microwaves for carrying out reactions in the
laboratory provides advantages for the synthesis of numerous
types of compounds.1-3 When the technique is applied
successfully, the most evident improvements are reduced
time of reaction, cleaner reactions due to fewer side-reactions,
and the use of minimal quantities of solvent. Thus, microwave-
assisted synthesis can be considered as more economical and
environmentally friendly. We have explored the use of
microwaves in the [3 + 2] cycloaddition reaction. This
reaction is a useful tool for the synthesis of heterocyclic
compounds when 1,3-dipolar azomethine ylides are added
to alkenes or alkynes4 to provide pyrrolidines or pyrroles
efficiently from readily available starting materials. The
obtained compounds can carry diverse substitution patterns
by choice and, as such, could be employed as templates for
screening for biological activity.5
In the present report, we describe the use of microwave
conditions for the condensation of O-allylic and O-propar-
gylic salicylaldehydes with R-amino esters. The cycloaddition
reaction involves a polar 1,3-dipole intermediate. We there-
fore reasoned that, as such, the reaction should be well suited
for this mode of activation. Since our objective was to
explore the influence of the microwaves on the reaction as
opposed to simple heating, parallel comparative reactions
were performed. Each pair of reagents was treated under
different conditions in order to elucidate the parameters
influencing the reaction and thus determine the effect of the
microwaves on the outcome of the reaction.
(1) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A.
Tetrahedron 1999, 55, 10851-10870. Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199-9223 and references therein.
(2) Examples: Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.;
Besson, T. Tetrahedron Lett. 2003, 44, 4455-4458. Jiao, G.-S.; Castro, J.
C.; Thorensen, L. H.; Burgess, K. Org. Lett. 2003, 5, 3675-3677. Paul,
S.; Gupta, M.; Gupta, R.; Loupy, A. Synthesis 2002, 75.
(3) De La Hoz, A.; Diaz-Ortiz A.; Langa, F. In MicrowaVes in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Germany, 2003. Cheng, Q.; Zhang,
W.; Tagami, Y.; Oritani, T. J. Chem. Soc., Perkin Trans. 1 2001, 452-456.
(4) Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett.
2003, 44, 8417-8420.
(5) Pinna, G. A.; Pirisi, M. A.; Chelucci, G.; Mussinu, J. M.; Murineddu,
G.; Loriga, G.; D’Aquila, P. S.; Serra, G. Bioorg. Med. Chem. 2002, 10,
2485-2496. Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Minarini,
A.; Rosini, M.; Tumiatti, V.; Melchiorre, C. J. Med. Chem. 2001, 44,
105-109. Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951-
8955.
10.1021/ol0361195 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/18/2003

and the other was submitted to microwave irradiation8
(conditions 3). For the two latter procedures, if both starting
materials were solids, a minimal amount of nonpolar solvent
(xylene) was added if necessary to ensure thorough contact
between the components. Also, identical quantities of
reagents and glassware were employed. In all cases, the
evolution of the reaction was monitored by thin-layer
chromatography (TLC) or gas chromatography (GC) to
follow the total consumption of starting aldehyde. All the
products were isolated by flash column chromatography on
silica gel after workup.
Scheme 1. Cycloadditions to Provide Pyrrolidines and
Pyrroles
Condensation of the O-allylic compounds 4a-e with ethyl
sarcosinate 6a proceeded to provide benzopyrano-pyrro-
lidines 7a-e in yields ranging from 70 to 98% (Scheme 3).
According to the choice of functionality, the procedure
would provide final products able to be employed as diversi-
fied scaffolds for the exploration of possible biological
activity.
Scheme 3. General Scheme for the Synthesis of Compounds
7a-da
Starting from salicylaldehyde, O-alkylation using allylic
or propargylic bromides proceeds in good to excellent yields.6
Varied starting materials were thus selected for the prepara-
tion of ω-unsaturated salicylaldehydes 4 and 5 containing
diverse substitution in order to investigate the effect of
functionality on the microwave-catalyzed reaction.
a Conditions: (1) toluene, reflux; (2) no solvent or minimal
xylene, heat in a preheated oil bath at 130 °C; (3) no solvent or
minimal xylene, microwave irradiation.
Scheme 2. O-Allyl and O-Propargylsalicylaldehydes
The results of the above condensations are provided in
Table 1. In the cases of compounds 7a,b,d, and e, the all-
cis6 compounds formed in the reaction were accompanied
by approximately 5% of a single diasteroisomer in which
the ring junction was trans. Compound 7c was obtained as
a 1:1 mixture of diastereoisomers in which the ring junction
was either cis or trans.6
Indeed, all the reactions performed under microwaves were
completed rapidly after a few minutes, except for 7d, which
was the exception. There is a clear advantage in using this
mode as compared to the thermal conditions. Also, the yields
under microwaves are often the highest, compared to those
under thermal conditions. This reflects a cleaner reaction with
fewer side-products, as observed on analysis of the crude
reaction mixtures, and thus easier purification. In both cases
of the activated O-allylic salicylaldehydes 4b and 4c, shorter
reaction times were observed, the ester-substituted compound
being much faster, as would be expected. Lower yields and
longer reaction times were observed under thermal conditions
for compound 7d, which contains a quaternary bridgehead
methyl moiety. Although longer than the other examples,
the reaction times were short and greatly improved yields
were achieved under microwaves. Interestingly, 5-chloro-
O-allylsalicylaldehyde 4e, which contains an unactivated
double bond, rapidly underwent condensation with ethyl
sarcosinate. Again, under microwave conditions, significant
acceleration of the reaction was observed.
The condensation of compounds 4 and 5 with R-amino
esters 6 was performed by three different protocols. In the
first instance (conditions 1) the reactions were performed in
round-bottom flasks using a Dean-Stark apparatus for the
removal of the 1 equiv water that is produced in the reaction,
thus calling for a minimum dilution of approximately 0.15
mol/L in the solvent (toluene).7 Two other procedures
were performed in test tubes surmounted with a condensing
tube, although this latter arrangement was not obligatory. In
these cases, one experiment was performed by heating the
mixture in a preheated oil bath at 130 °C (conditions 2),
(6) Broggini, G.; Zecchi, G. Synthesis 1996, 1280-1282.
(7) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175-
7178. Kanemasa, S.; Sakamoto, K.; Tsuge, O. Bull. Chem. Soc. Jpn. 1989,
62, 1960-1968. Grigg, R.; Duffy, L. M.; Dorrity, M. J.; Malone, J. F.;
Rajviroongit, S.; Thornton-Pett, M. Tetrahedron 1990, 46, 2213-2230.
Harwood, L. M.; Lilley, I. A. Tetrahedron Lett. 1993, 34, 537-540.
(8) Reactions were carried out under atmospheric pressure on a CEM
Discover apparatus.
4916
Org. Lett., Vol. 5, No. 25, 2003

and propargylic aldehydes provide further diversity.3 The
practical procedure followed for these examples involves
heating the two components in order to achieve cycloaddition
(consumption of starting aldehyde) followed by the in situ
addition of sulfur and continued heating. As above, three
comparative experiments were performed for each example
(conditions 1-3). Conditions 1 and 2 involved mixing the
two starting compounds and heating in a preheated oil bath
at 130 °C either using a Dean-Stark apparatus (ap-
proximately 0.15 mol/L ) conditions 1) or in the absence
of solvent (if necessary, a minimal quantity of xylene to help
mixing ) conditions 2). For conditions 3, the mixture was
submitted to microwave irradiation in the absence of solvent.
The combined results are summarized in Table 2.
Table 1. Comparative Results for Condensation to Pyrrolidines 7
Table 2. Comparative Results for Preparation of Pyrroles 8
a Conditions 1: 0.15 mol/L in toluene, reflux, Dean-Stark apparatus.
b Conditions 2 and 3 are identical in setup; they differ in the mode of heating,
i.e., preheated oil bath at 130 °C or microwave irradiation. c Settings: 100W,
130 °C. d For clarity, only one enantiomer is depicted here.
The next series of reactions that were investigated
concerned the preparation of pyrrolic compounds 8a-d
(Scheme 4).
a Conditions 1: 0.15 mol/L in toluene, reflux, Dean-Stark apparatus.
b Conditions 2 and 3 are identical in setup; they differ in the mode of
heating, i.e., preheated oil bath or microwave irradiation. c Settings: 100W,
130 °C.
Scheme 4. Condensations for the Preparation of Compounds
8a-d
The results indicate once more that there is a clear
advantage in terms of reaction time when working under
microwave conditions. The yields of isolated pyrrole com-
pounds 8a-d in this one-pot procedure are comparable,
regardless of the reagents used or the experimental conditions
applied. Since the completion of the experiments described
in the table above, an additional procedure was explored. In
this additional procedure, the aldehyde 5b, the R-amino ester
6c, and sulfur were all mixed in a tube with 0.5 mL of xylene
and then heated under microwave irradiation for 15 min
(settings 100W, 130 °C). After purification, the expected
pyrrole 8d was obtained in 90% yield.
This procedure is a new process for the one-pot multi-
component synthesis of benzopyrano-pyrroles. Indeed, work
is currently underway in our laboratory to apply this
procedure for the synthesis of other and simpler pyrroles by
an intermolecular [3 + 2] cycloaddition.
In conclusion, we present new procedures for microwave-
assisted [3 + 2] cycloadditions of azomethine ylides to
Condensation of ω-propargylic benzaldehydes 5a,b with
methyl sarcosinate 6b and ethyl N-benzylglycinate 6c,
followed by in situ oxidation either by air9 or, more con-
veniently, by sulfur,10 efficiently provides substituted ben-
zopyrano-pyrroles 8. Other combinations of R-amino esters
(9) Vo Quang, L.; Gaessler, H.; Vo Quang, Y. Ang. Chem., Int. Ed. Engl.
1981, 20, 880-881.
(10) Rhee, M.-H.; Vogel, Z.; Barg, J.; Bayewitch, M.; Levy, R.; Hanusˇ,
L.; Breuer, A.; Mechoulam, R. J. Med. Chem. 1997, 40, 3228-3233.
Org. Lett., Vol. 5, No. 25, 2003
4917

activated or nonactivated alkenes and alkynes. The applica-
tion to pyrrolidines and pyrroles is described. In all cases,
the explored comparative study concluded that under mi-
crowave conditions the times of reaction are very short. The
procedures described allow the efficient synthesis of diverse
pyrrolidine compounds selectively, including new examples
containing chiral quaternary bridgehead substituents. The
process also allows the preparation of pyrroles in a one-pot
multicomponent reaction. The yields are generally high to
excellent, and the experimental procedures are straightfor-
ward. In most cases where one or more of the reagents
employed are liquid, the reactions can be performed without
solvent.
Supporting Information Available: Typical experimen-
tal procedures and selected analytical data for compounds
7b, 7d, and 8a. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0361195
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Org. Lett., Vol. 5, No. 25, 2003