Unusual Selectivity of Unprotected Aziridines in Palladium-Catalyzed Allylic Amination Enables Facile Preparation of Branched Aziridines

Article abstract of DOI:10.1021/ja049242f

Functionalized branched aziridines can be prepared in high yields and with high levels of regioselectivity using unprotected aziridines as nitrogen sources in palladium-catalyzed allylic amination. High levels of enantioselectivity can be achieved with BINAP on palladium. This methodology allows for strategic placement of an aziridine-containing fragment within a complex molecule environment for further elaboration. Copyright

Full text of DOI:10.1021/ja049242f

Published on Web 04/03/2004
Unusual Selectivity of Unprotected Aziridines in Palladium-Catalyzed Allylic
Amination Enables Facile Preparation of Branched Aziridines
Iain D. G. Watson, Sarah A. Styler, and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, The UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada, M5S 3H6
Received February 11, 2004; E-mail: ayudin@chem.utoronto.ca
The allylamine functionality is found in a wide range of
biologically active compounds.1,2 Allylamines are also valuable
synthetic intermediates for the preparation of R- and â-amino
acids,3a alkaloids,3b-e and aza-carbohydrate derivatives.3f,g The
allylamine functionality can be introduced by nucleophilic substitu-
tion at the allylic position or by direct allylic amination of olefins.4
The transition metal-catalyzed allylic amination of allyl alcohol
derivatives is particularly attractive because the C-N bond can be
installed with high regio- and stereoselectivity.1,5
Unprotected aziridines have not been extensively used in
transition metal-catalyzed reactions.6 Recent results from our lab
Figure 1. Dependence of the regiochemistry of products in allylic amination
as a function of amine (1 mol % [Pd(η3-C3H5)Cl]2 and 2 mol % BINAP in
THF, room temperature).
suggest that aziridines tolerate a range of oxidative conditions and
was sluggish with PPh3 as a ligand, BINAP provided complete
participate in transition metal-catalyzed coupling chemistry.7 The
conversion within 6 h in THF at room temperature (Figure 1). This
present paper details the unusual behavior of aziridines in allylic
result is particularly interesting because there appears to be only
amination and underscores the facility with which simple aziridine-
one other example of the palladium-catalyzed allylic amination of
containing building blocks can be installed in complex environments
a terminal allyl ester or carbonate resulting in predominant
for further elaboration.
formation of the branched isomer.10 Other classes of nitrogen
nucleophiles including primary11a and secondary alkylamines,11b
azide,11c,d and amides11e all favor the linear allylamine product under
similar palladium-catalyzed conditions. When we performed the
reaction between piperidine and prenyl acetate, only the linear
isomer was detected. Likewise, the use of benzylamine resulted in
exclusive formation of the linear product as a mixture of mono-
and dialkylated compounds. To exclude the possibility of initial
Because conventional methods of making aziridines8 often pose
formation of linear product followed by its in situ conversion into
functional group compatibility issues, modification of aziridine-
containing starting materials should be a viable means for making
highly functionalized nitrogen-containing molecules. At present,
there are only a few reactions that fall into this category.9 Our
interest in synthetic applications of N-allyl aziridines suggested
alkylation of unprotected aziridines with allyl halides as a possible
entry into this class of compounds. However, due to N,N′-diallyl
aziridinium ion formation and subsequent ring-opening by the halide
ion, low selectivity was observed. We subsequently found that
unprotected aziridines undergo facile palladium-catalyzed allylic
amination with allyl acetates and carbonates. The optimal reaction
conditions were found using cyclohexene imine and allyl acetate
as model substrates. With 1 mol % of [Pd(η3-C3H5)Cl]2 as the
source of palladium and 4 mol % PPh3 as a ligand, full conversion
of cyclohexene imine to N-allyl cyclohexene imine was achieved
in THF in 30 min. Allyl carbonates gave full conversion, although
at a slower rate. We noticed that if the reaction was left longer
than 30 min, formation of the O-acyl N,N′-diallyl amino alcohol
byproduct (6) took place, presumably through ring-opening by acetic
acid (Table 1, entry 12). This byproduct formation was suppressed
by the addition of 2 equiv of K2CO3 or by the use of allyl
carbonates.
the isolated branched aziridine, we synthesized 7-(3-methylbut-2-
enyl)-7-aza-bicyclo[4.1.0]heptane (10) which was subjected to
typical reaction conditions. No branched product was observed,
indicating that linear to branched interconversion does not operate
under our conditions, which points to the unusual behavior of
aziridine nucleophiles in allylic amination.
Geranyl acetate also led to the branched isomer (3g) as the major
product. However, the reaction was sluggish relative to the case of
prenyl acetate, and higher catalyst loading was required to achieve
full conversion. When [Pd(η3-C3H5)Cl]2 was used as the source of
palladium, BINAP, P(OEt)3, and PPh3 gave full conversions and
good regioselectivities while P(o-Tol)3 did not induce any reaction.
Significant amounts of volatile byproducts reduced the selectivity
to around 50% in the best case. These products resulted from a
background reaction between geranyl acetate and Pd(0) that
produced a mixture of myrcene, (E)-ocimene, and (Z)-ocimene via
competing â-hydride elimination.12,13 Fortuitously, this elimination
was suppressed with a 1:4 Pd(CO2CF3)2/PPh3 catalyst that provided
a linear to branched ratio of 12:88 and full conversion within 48 h.
The competing â-hydride elimination was not an issue for prenyl
In the reaction of prenyl acetate with cyclohexene imine, the
branched isomer (3e) was unexpectedly found to be the only
detectable product, isolated in 89% yield. Although the reaction
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10.1021/ja049242f CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of N-Allyl Aziridines by Palladium-Catalyzed
Allylic Amination
Preliminary results indicate that this chemistry can be applied
to the preparation of enantiomerically enriched aziridines15 via
enantioselective allylation. The use of (R)-BINAP as a ligand
afforded the N-allyl aziridine 2j in 98% ee. Under similar reaction
conditions, cyclohexene imine afforded the corresponding N-allyl
aziridine (2h) in 97% ee.
In summary, we have uncovered the first example of palladium-
catalyzed allylic amination reaction using unprotected aziridines.
The observed regioselectivity favors valuable branched products
in the cases of aliphatic acetates, underscoring the decisive effect
of the amine on the course of allylic amination. The reasons for
these unusual regioselectivity patterns are the subject of ongoing
investigations. The process allows for the asymmetric allylic
amination of unprotected aziridines with high enantioselectivities
and creates a possibility to introduce aziridine moieties into
functionalized environments with high levels of regio- and enan-
tioselectivities, and high isolated yields.
Acknowledgment. We thank NSERC, CFI, ORDCF, ACS-PRF,
the University of Toronto, and Affinium Pharmaceuticals for
financial support. A.K.Y. is a Cottrell Scholar of Research
Corporation. I.D.G.W. would like to acknowledge an Ontario
Graduate Scholarship. S.A.S. is grateful to Pfizer for the 2003
Undergraduate Summer Fellowship. Mr. Greg Chen is acknowl-
edged for the preparation of 1c.
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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