Catalytic enantioselective allylic amination of unactivated terminal olefins via an Ene reaction/[2,3]-rearrangement

Article abstract of DOI:10.1021/ja307851b

The enantioselective allylic amination of unactivated terminal olefins represents a direct and attractive strategy for the synthesis of enantioenriched amines. We have developed the first use of a nitrogen-containing reagent and a chiral palladium catalyst to convert unfunctionalized olefins into enantioenriched allylic amines via an ene reaction/[2,3]-rearrangement.

Full text of DOI:10.1021/ja307851b

Communication
pubs.acs.org/JACS
Catalytic Enantioselective Allylic Amination of Unactivated Terminal
Olefins via an Ene Reaction/[2,3]-Rearrangement
Hongli Bao and Uttam K. Tambar*
Department of Biochemistry, Division of Chemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry
Hines Boulevard, Dallas, Texas 75390-9038, United States
S
* Supporting Information
metal-nitrenoids9 (Scheme 1, path a).10 In theory, chiral
ABSTRACT: The enantioselective allylic amination of
unactivated terminal olefins represents a direct and
attractive strategy for the synthesis of enantioenriched
amines. We have developed the first use of a nitrogen-
containing reagent and a chiral palladium catalyst to
convert unfunctionalized olefins into enantioenriched
allylic amines via an ene reaction/[2,3]-rearrangement.
versions of these metal complexes could facilitate the
enantioselective formation of chiral amine products. Despite
recent progress in metal-catalyzed enantioselective aminations
of activated benzylic C−H bonds11 and intramolecular
enantioselective allylic aminations of olefins,12 there are no
general examples of intermolecular catalytic enantioselective
allylic amination of unactivated terminal olefins.13
We were drawn to a conceptually distinct allylic amination
strategy that is based on an uncatalyzed conversion of
unfunctionalized olefins into racemic chiral amines via an ene
reaction/[2,3]-rearrangement of reactive zwitterion 1 (Scheme
1, path b).14 In this approach, an imido-sulfur or imido-
selenium compound acts as the source of nitrogen.
Unfortunately, since its discovery over 30 years ago, this
protocol was thought to be incompatible with enantioselective
catalysis because of the propensity of reactive zwitterions such
as 1 to undergo facile thermal [2,3]-rearrangement in the
absence of a catalyst.15,16 We recently developed a palladium-
catalyzed enantioselective [2,3]-rearrangement of zwitterionic
amine N-oxides.17 We hypothesized that a similar catalytic
manifold may be applicable to the rearrangement of zwitterion
1, which would provide an opportunity to develop a catalytic
enantioselective allylic amination of terminal olefins.
Our initial experiments focused on the identification of a
high oxidation state nitrogen source that would couple with a
terminal olefin to form an ene adduct, such as 1, which would
not undergo a background [2,3]-rearrangement in the absence
of a chiral catalyst. This proved challenging, since most imido-
sulfur and imido-selenium oxidants that are suitable for allylic
amination strategies participate in uncatalyzed thermal ene
reactions followed by [2,3]-rearrangements. For example, the
early work of Sharpless and Kresze highlighted the racemic
allylic amination of terminal olefins at room temperature with
arylsulfonyl sulfurdiimide reagents through the two-step
pericyclic reaction sequence.14
he direct conversion of hydrocarbons into chiral function-
Talized molecules has remained an important goal in
chemistry for decades.1 Advances in this area provide more
efficient and practical strategies for designing and manipulating
molecular structures, with broad applications in fields such as
medicine and materials science.2 The stereoselective incorpo-
ration of nitrogen atoms into hydrocarbons, such as olefins, is
of particular interest, given the prevalence of chiral amines in
pharmaceutical drugs.3 Although many powerful chemical
methods have been developed for the incorporation of nitrogen
atoms into hydrocarbons,4 the catalytic enantioselective
conversion of hydrocarbons into chiral amines has to date
remained an unsolved problem.5,6 In this communication, we
describe a catalytic enantioselective intermolecular allylic
amination of unactivated terminal olefins for the synthesis of
chiral amines in high enantiomeric excess (Scheme 1).
The metal-catalyzed activation of inert C−H bonds has
emerged as one efficient strategy for transforming terminal
olefins into allylic amines via metal-π-allyl intermediates7,8 or
Scheme 1
Upon reexamination of these arylsulfonyl sulfurdiimide
oxidants, we discovered that benzenesulfonyl sulfurdiimide 3
and 1-octene 2a formed stable ene adduct 4a at 4 °C in high
yield (Table 1). This zwitterionic intermediate was purified by
simple filtration without any chromatography and did not
rearrange at temperatures below 0 °C, even after several days
(entry 1). Coupling between nitrogen-containing oxidant 3 and
terminal olefins at low temperatures was therefore selected as
Received: August 7, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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Communication
Table 1. Optimization of the Enantioselective Allylic
Amination
Table 2. Substrate Scope of the Enantioselective Allylic
Amination
the platform for our catalytic enantioselective allylic amination
of olefins.
In our early attempts to accelerate the [2,3]-rearrangement
of zwitterion 4a, palladium(II) salts such as Pd(OAc)2 were
promising catalysts for the desired rearrangement (entry 2).
After an extensive screening of reaction parameters (including
solvent, chiral ligand, and palladium source), we identified
Pd(TFA)2 and bisoxazoline ligand 6 as the optimal catalyst
complex for generating allylic sulfonamide product 5a in 89%
yield and 96% enantiomeric excess (ee) at −15 °C in
anhydrous methanol (entry 12).18 The overall two-step
protocol only requires one chromatographic purification,
which simplifies the operation of this reaction on large scale.
Having identified optimized reaction conditions for the
enantioselective conversion of olefins into allylic amines, we
explored the substrate scope of this process on a preparative
scale (2−4 mmol). Table 2 highlights the efficiency of this
enantioselective process in the absence of any directing
functional groups in the substrate. For example, allylic amines
were generated with linear hydrocarbon chains (entries 1−3) as
well as hindered branched hydrocarbons (entries 4−6). In all
these cases, the allylic sulfonamide products were obtained in
high yields with greater than 90% ee. Given the paucity of
enantioselective methods for converting achiral hydrocarbons
into chiral products, the success of the enantioselective allylic
amination reaction with substrates that lack directing groups is
noteworthy.
a
b
Isolated yield for 2 steps, based on sulfurdiimide 3. 3−5 equiv of
c
olefin. Reaction temperature was −5 °C.
such as free alcohols and carboxylic acids, were not tolerated in
the enantioselective allylic amination, presumably because of
competitive addition into the electrophilic benzenesulfonyl
sulfurdiimide 3 prior to the hetero-ene reaction. However, the
mild reaction conditions were compatible with protected
heteroatoms, including a benzyl ether (entry 9) and a
nitrogen-bearing phthalimide (entry 10). Reactive electrophilic
functional groups, such as nitriles (entry 11), aldehydes (entry
12), and primary alkyl chlorides (entries 13−15), could be
incorporated into the products without affecting the overall
efficiency of the allylic amination process. The absolute
stereochemistry of the allylic amination products was
determined by examining crystals of the product in entry 6
that were suitable for X-ray diffraction.
As a preliminary mechanistic proposal, we hypothesize that
the palladium(II)-bisoxazoline catalyst acts as a chiral π-acid to
activate zwitterion 4, which then undergoes aminopalladation
to generate heterocycle 7 as an intermediate (Scheme 2). Grob-
type fragmentation eventually reveals allylic amine 5 and the
palladium(II)-bisoxazoline catalyst, which can reenter the
The compatibility of this reaction with a wide range of
reactive functional groups was also examined. Polyunsaturated
terminal olefins selectively incorporated a single nitrogen atom
via a hetero-ene reaction with one molecule of benzenesulfonyl
sulfurdiimide 3 (entries 7−8). Nucleophilic functional groups,
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Communication
Scheme 2
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Uttam.Tambar@utsouthwestern.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the W. W. Caruth, Jr.
Endowed Scholarship, the Robert A. Welch Foundation (Grant
I-1748), the American Cancer Society Petroleum Research
Fund (PRF# 51710-DNI1), and the National Institutes of
Health (1R01GM102604-01). We thank Dr. Vincent Lynch for
X-ray structural analysis. We also thank John T. Watson and
Tian Zhao for experimental assistance.
catalytic cycle. This cyclization-induced mechanism, which is
similar to Overman’s proposal for the [3,3]-rearrangement of
allylic trichloroacetimidates,19 is consistent with a crossover
experiment between two differentially substituted zwitterionic
substrates that only yield non-crossover products (see
Supporting Information).20
The utility of this enantioselective allylic amination reaction
in the synthesis of biologically active, nitrogen-containing chiral
molecules is exemplified by the conversion of commercially
available unsaturated ester 8 into enantioenriched antiepileptic
drug Vigabatrin (Scheme 3).21 The enantioselective allylic
amination protocol yielded chiral sulfonamide 9, which was
then deprotected to reveal the enantioenriched HCl salt of
Vigabatrin (10).
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NOTE ADDED AFTER ASAP PUBLICATION
■
Scheme 1 was incomplete in the version published ASAP
October 29, 2012. The corrected version was re-posted on
October 30, 2012.
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