Palladium-catalyzed ring-forming aminoacetoxylation of alkenes

Article abstract of DOI:10.1021/ja051406k

A mild, palladium(II)-catalyzed ring-forming aminoacetoxylation of alkenes is described. Treatment of a range of nitrogen nucleophiles with catalytic palladium(II) in the presence of PhI(OAc)₂ as oxidant resulted in alkene aminoacetoxylation, a

Full text of DOI:10.1021/ja051406k

Published on Web 05/06/2005
Palladium-Catalyzed Ring-Forming Aminoacetoxylation of Alkenes
Erik J. Alexanian, Chulbom Lee, and Erik J. Sorensen*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
Received March 4, 2005; E-mail: ejs@princeton.edu
Vicinal difunctionalizations of alkenes are among the most
results were obtained using undistilled commercial solvents under
powerful transformations known in the field of chemical synthesis.1
One such method is the osmium-catalyzed asymmetric cis amino-
hydroxylation of alkenes,2 yielding vicinal amino alcohols that are
present in many biologically active molecules and natural products.3
In the course of our studies in the area of complex molecule
synthesis, we sought a catalytic, stereoselective, mechanistically
distinct aminooxidation reaction to facilitate the construction of
nitrogen-containing heterocycles and the development of new
reaction types.
The palladium(II)-catalyzed addition of nitrogen nucleophiles to
alkenes is a well developed process for forming C-N bonds.4 A
wide variety of nitrogen nucleophiles are known to attack the
palladium(II)-activated alkene to give an alkyl palladium(II)
intermediate. Although methods for the direct functionalization of
alkyl palladium(II) intermediates (e.g., carbonylation5 and halogen-
ation1f,g) exist, â-hydride elimination can be a rapid process (eq
1).4a,6 Our aim was to substitute the palladium center for acetate in
the course of a mild oxidation event (eq 2, X ) OAc). If successful,
an air atmosphere (88% yield).
Encouraged by these results, we applied the aminoacetoxylation
protocol to a number of substrates (Table 1). Control experiments
indicated that no aminoacetoxylation occurred in the absence of
palladium, except for a slow background reaction under acidic
conditions (condition C).8 Palladium(II)-catalyzed ring-forming
aminoacetoxylation of 5-hexenyl-1-nosylsulfonamide afforded a
mixture of regioisomers resulting from 6-exo and 7-endo ring
closures (entry 1). N-Tosyl amides were also effective substrates
(entry 2), although this substrate displayed a high tendency for
â-hydride elimination; fortunately this pathway could be suppressed
by the substitution of PdCl2(PhCN)2 for Pd(OAc)2 as catalyst.9 In
this case, the catalyst loading could be lowered to 1 mol %,
producing the γ-lactam 6 in 65% yield. Carbamates also performed
well with 5 mol % PdCl2(PhCN)2; however, minor byproducts
resulting from an aminochlorination of the alkene were isolated
(∼10%). The allyl alcohol-derived carbamate furnished acetoxym-
ethyl N-tosyl oxazolidinone 7 in 66% yield as a single regioisomer
(entry 3), and the homoallyl alcohol-derived substrate underwent
clean 6-exo closure to yield aminoacetoxylated product 8 (entry
4). PhI(OAc)2 is known to oxidize tosylanilides, and 2-allyl
N-tosylanilide was tested in order to examine its potential as a
nucleophile (entry 5). Although both substrate and product were
found to be susceptible to aromatic oxidation,10 lowering the amount
of oxidant to 1 equiv facilitated the difunctionalization, affording
products 9 and 10 (1.9:1). 2-(1-Propenyl)cyclopentylnosylsul-
fonamide (entry 6) underwent cyclization to an 8:1 mixture of 11
and 12, demonstrating the ability of the aminoacetoxylation to form
fused bicyclic architectures. Further alkene substitution was permit-
ted (entry 7), as this nosylsulfonamide with a 1,1-disubstituted
alkene underwent exclusive 6-endo cyclization to give 13 as a single
regioisomer in 80% yield.
this palladium-catalyzed method would permit attractive ring-
forming aminoacetoxylations of alkenes. On the foundation of some
recent reports showing that Pd-C σ-bonds are easily oxidized by
iodine(III)-based oxidants,7 we developed a mild method for
achieving this goal. Our initial observations on this process are
described below.
To gain insight into the mechanism of the aminoacetoxylation
process, as well as to explore the diastereoselectivity of the reaction,
cinnamyl alcohol-derived N-tosyl carbamates 14 and 16 were
studied (eqs 4 and 5). Upon subjection of the predominantly cis
Our studies commenced with simple alkenyl nosylsulfonamide
1 (eq 3). Electron-withdrawing protecting groups were utilized
thoughout our studies to prevent poisoning of the catalyst and
undesired oxidation of the substrates by hypervalent iodine.
Treatment of 1 with 10 mol % Pd(OAc)2 in the presence of 2.0
equiv of PhI(OAc)2 and 1.0 equiv of Bu4NOAc in CH2Cl2 at 25
°C for 15 min resulted in the formation of a 1.5:1 mixture of
aminoacetoxylation products 2 and 3 in 72% yield. After some
experimentation, the regioselectivity could be increased to 9:1 (2:
3) using a 1:1 mixture of AcOH/Ac2O as solvent in 87% yield,
without requiring the addition of exogenous base. Importantly, this
reaction was neither air- nor moisture-sensitive, and comparable
carbamate to reaction conditions involving 10 mol % Pd(OAc)2 as
catalyst and 1.0 equiv of Bu4NOAc as base in CH3CN (0.1 M), a
successful aminoacetoxylation afforded 4-acetoxyphenyl N-tosyl
9
7690
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10.1021/ja051406k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Palladium(II)-Catalyzed Aminoacetoxylation of Alkenesa
intermediate could then be oxidized by PhI(OAc)2 to an alkyl Pd-
(IV) intermediate.13 Finally, C-O bond forming reductive elimina-
tion from the Pd(IV) center would complete the aminoacetoxylation
process and regenerate the catalyst.7
In conclusion, we developed a mild, palladium(II)-catalyzed ring-
forming aminoacetoxylation of alkenes that is applicable to a range
of nitrogen nucleophiles and alkene substitution patterns. Our studies
indicate the possibility for high levels of reaction regio- and
stereocontrol, making this a potentially attractive method in organic
synthesis. Current work is aimed at exploring the scope of the
reaction with respect to both substrates and oxidants, the potential
for asymmetric induction in the aminoacetoxylation process, and
applications in complex molecule synthesis.
Acknowledgment. We thank Dr. Istvan Pelczer for NMR
spectroscopic assistance and Prof. Martin Semmelhack for helpful
discussions. This work was supported by a Bristol-Myers Squibb
Unrestricted Grant in Synthetic Organic Chemistry, Merck, Prin-
ceton University, and predoctoral fellowships from the ACS/
GlaxoSmithKline (E.J.A.) and Bristol Myers-Squibb (E.J.A.).
Supporting Information Available: Experimental procedures and
product characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a All reactions run with 1 equiv of substrate (0.2 M) and 2 equiv of
1
PhI(OAc)2 at 25 °C. All regio- and diastereoselectivities calculated by H
NMR. b Condition A: 10 mol % Pd(OAc)2, 1 equiv of Bu4NOAc, CH2Cl2.
Condition B: 5 mol % PdCl2(PhCN)2, CH2Cl2. Condition C: 10 mol %
Pd(OAc)2, 1:1 AcOH/Ac2O. c Isolated yields. d 1 equiv of PhI(OAc)2 used.
e Product 11 obtained as 2.3:1 (â: R) mixture of diastereomers.
References
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Scheme 1. Proposed Catalytic Cycle
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2-oxazolidinone in high yield (92%). We were pleased to find that
this reaction also proceeded with a high level of stereocontrol (9.5:1
dr from 10:1 Z:E mixture of 14).11 Although requiring thermal
instigation, the pure trans carbamate was a viable substrate as well,
yielding 17 in a highly diastereoselective fashion (>20:1 dr). From
these experiments, it appears that the aminoacetoxylation process
is a stereoselective trans alkene difunctionalization, and thus a
useful alternative to related cis-selective, metal-catalyzed alkene
aminohydroxylation processes.2
A possible catalytic cycle based on our findings is shown in
Scheme 1, although a number of details remain to be elucidated.
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(13) Cu(OAc)2 (2.0 equiv), a standard oxidant for mediating Pd0/PdII cycle
catalysis, was ineffective.
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