Angewandte
Communications
Chemie
Metal Carbenes
Synthesis of Pyrrolidines and Pyrrolizidines with a-Pseudoquaternary
Centers by Copper-Catalyzed Condensation of a-Diazodicarbonyl
Compounds and Aryl g-Lactams
Abstract: N-aryl g-lactams react intermolecularly with
acceptor–acceptor diazo reagents, usually dicarbonyl com-
pounds, in a copper-catalyzed process to yield functionalized
pyrrolidines with a-pseudoquaternary centers. As 1,2-acyl or
-
phosphoryl migration is preferred, single regioisomers are
obtained. Furthermore, in the presence of a Lewis acid,
subsequent Friedel–Crafts reactions yield tricyclic pyrrolizi-
dines in excellent yields (90–96%) and diastereoselectivities
(
up to > 20:1).
T
ertiary amides and lactams are known to react with
diazoester reagents and form carbonyl ylide intermediates
A in the presence of catalytic amounts of metal salts or
[
1]
complexes (Scheme 1, top). As a rule, these 1,3-dipoles
undergo [3+2] cycloadditions with alkenes and alkynes,
yielding elaborate polycyclic frameworks in intramolecular
[
2]
reactions. Of interest for the current study, when silyl
substituents are present on the diazo reagent, epoxide
intermediates B are formed, which, after silyl group migra-
Scheme 1. Top: General reactivity of amides (lactams) with diazocar-
bonyl derivatives under metal catalysis. Bottom: Copper-mediated
condensation of ester diazo derivatives with g-aryl lactams and
subsequent pyrrolizidine formation.
[3,4]
tion, are transformed into amino silyl enol ethers.
Herein,
the intermolecular reactivity of N-aryl g-lactams 1 with
a-diazodicarbonyl compounds 2 is reported (Scheme 1,
[
5]
bottom).
Highly functionalized pyrrolidines
3
with
a-pseudoquaternary centers are obtained in good yields (up
Recently, metal-catalyzed decompositions of acceptor–
acceptor a-diazodicarbonyl reagents have been studied by
our group to afford an extended range of reactivities in the
[
6]
to 83%). In fact, amide groups are transformed into amines
with adjacent acetyl and 2-oxoethanoate chains in one step.
This transformation, which involves acyl (or phosphoryl)
group migration, proceeds with very high regioselectivity and
is specifically catalyzed by copper salts (10 mol%). In the
presence of Lewis acids, intramolecular Friedel–Crafts reac-
tions can further occur (3!4), yielding tricyclic pyrrolizidines
in excellent yields (90–96%) and selectivities (diastereomeric
ratio, d.r. ꢀ 18:1). In view of their valuable heterocyclic
[
8]
presence of Lewis bases. For instance, under CpRu catalysis
and using aldehydes, ketones, lactones, and cyclic carbonates
as substrates, dioxolene ketals, orthoesters, and orthocarbon-
[9]
ates were obtained. In view of these transformations
involving carbonyl ylide intermediates, reactions of diazodi-
carbonyl reagents with amides and lactams were attempted.
For this study, N-aryl pyrrolidinones were selected as
substrates. In a first experiment, 1-phenyl-2-pyrrolidinone
(1a) was treated with methyl diazoacetoacetate (2A) in
dichloromethane (DCM) in the presence of [CpRu-
[
7]
structures, products 3 and 4 should be of interest in a variety
of fields, for example, in peptide or medical chemistry, with
their preparation by other routes being difficult to imagine.
(
(
CH CN) ][BAr ]
2.5 mol% each). While the reaction was rather unproduc-
complex
and
1,10-phenanthroline
3
3
f
tive, a product was isolated in low yield (< 10%). This
1
3
[
*] Dr. S. Goudedranche, L. Egger, Prof. J. Lacour
Dꢀpartement de Chimie Organique, Universitꢀ de Genꢁve
quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
E-mail: jerome.lacour@unige.ch
compound, 3aA, presented interesting characteristics in C
NMR and IR spectroscopy, and an increase in molecular mass
of 114.10 Da (equivalent to one carbene moiety). In fact,
data indicated the disappearance of the amide and the
presence of two ketones and one ester functional group; the
pyrrolidine structure of 3aA was finally confirmed by X-ray
diffraction in the course of the study (see Figure 2).
[10]
Homepage: http://www.unige.ch/sciences/chiorg/lacour/
Dr. C. Besnard
Laboratoire de Cristallographie, Universitꢀ de Genꢁve
quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
Encouraged by this finding, we searched for conditions
that enable the exclusive formation of 3aA. In diazo
decomposition chemistry, reactivity is often controlled by
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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