A new highly asymmetric chelation-controlled heck arylation

Article abstract of DOI:10.1021/ja029646c

This communication describes the development of a new highly asymmetric chelation-controlled Heck arylation. The methodology permits formation of 2-aryl-2-methyl cyclopentanones in good to very good two-step yields (45-78%) with excellent chiral enrichmen

Full text of DOI:10.1021/ja029646c

Published on Web 02/27/2003
A New Highly Asymmetric Chelation-Controlled Heck Arylation
Peter Nilsson, Mats Larhed, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala UniVersity, P.O. Box 574,
SE-751 23 Uppsala, Sweden
Received December 9, 2002 ; E-mail: anders.hallberg@farmkemi.uu.se
Scheme 1
The interest in effective and robust methods that generate
carbon-aryl bonds in the R-position to a ketone has increased since
the discovery of the Pd(0)-catalyzed arylation of ketone enolates.1
Recently, this direct methodology was further developed to allow
formation of 2-aryl-2-methyl cycloalkanone derivatives with good
to excellent enantioselectivities.2 In 2001, we reported on the use
of a coordinating auxiliary to facilitate the synthesis of 2,2-diarylated
acetaldehydes3 via a palladium-catalyzed Heck coupling procedure.4
Scheme 2
Because this chelation-accelerated Heck protocol5 proved to be both
selective and effective in generating highly substituted double bonds,
we decided to explore the arylation of the tetra-substituted and two-
carbon oxygen-nitrogen tethered enol ether 1 (Scheme 1). The
couplings of 1 were performed with 2-iodoanisole 2a, 2-iodotoluene
Scheme 3
2c, and 3-iodoanisole 2e as arylating agents and potassium carbonate
as the base. After reaction times of 42-72 h followed by rapid
hydrolyses of 3, the compounds 4a, c, and e were obtained in good
two-step yields. In contrast to the direct coupling to the enolate of
the cyclic ketone, the Heck arylation of the corresponding 1 requires
neither a strong base nor a blocking of the R-methylene carbon.
These initial examples demonstrated that the highly substituted
Scheme 4
enol ether 1 is reactive under the standard Heck conditions
employed. This outcome is probably attributed to a chelation-
accelerated and regioselective insertion, after coordination of the
oxidative addition complex to the amino group (A, Scheme 2) and
subsequent π-complex formation (B).
Considering that olefin 1 contains a prochiral double bond, the
obvious question arose whether a chiral tertiary amino group could
results are presented in Table 1. Full conversions of the arylating
agents were achieved in all cases, and the nonoptimized yields in
the two-step sequence varied from 45 to 78%.
direct the oxidative addition complex exclusively from a selected
face (π-complex C) and thus control the diastereotopicity of the
insertion. To the best of our knowledge, there is only one previous
report on an asymmetrical, intermolecular Heck reaction relying
on chelation-control.6 The inexpensive and commercially available
amino alcohol (S)-1-methyl-2-pyrrolidine-methanol was selected as
a suitable chiral metal-coordinating auxiliary7 for stereoselective
Heck arylations. The prolinol vinyl ether 6a was prepared, via an
acid-catalyzed acetalization-elimination protocol, from 5 (Scheme
3), similar to the method used for the preparation of the achiral 1.
The substrate for the arylation reaction (6a) was smoothly separated
from the regioisomeric product (6b) by silica chromatography.
Pure 6a (1.3 equiv) was arylated with nine different aryl halides
(2a-i) (0.60 mmol scale, 1 equiv). A phosphine-free catalytic
palladium system (3% Pd) was utilized to minimize interference
from metal coordinating ligands.8 Operationally, all components
were added to aqueous DMF, and the vessel was sealed under air
and heated for 18-68 h. Most rewardingly, the presenting power
of the tertiary amino group in 6a proved to be sufficiently effective
for a regio- and stereoselective R-arylation to occur (Scheme 4).
After the syn â-hydrogen elimination generating 7a-g, a convenient
acid mediated hydrolysis provided enantiomerically enriched cy-
clopentanones 4a-g (90-98% ee). Notably, the quaternary chiral
center was created with excellent enantioselectivity.9 The preparative
As is evident from Table 1, there was no obvious structure/
enantioselectivity relationship (cf. entries 1 and 8), although both
of the large 1-naphthyl halides 2f and 2g furnished lower yields
and enantioselectivities (entries 6 and 7). In contrast, sterically
demanding ortho-substituted 2a and 2c (entries 1 and 3) produced
optical purities similar to those of the nonhindered isomers 2b and
2e (entries 2 and 5). In fact, entry 1 represents the highest reported
stereoselectivity obtained in an asymmetric Heck arylation where
a kinetic resolution process was not involved.
Although no mechanistic studies have been conducted, an
involvement of a N-chelated π-intermediate similar to D (Chart
1)10 might account for the excellent regio- and stereochemical
outcome of the arylation.11
The major diastereomer of 7 is likely to be formed through Si-
face insertion via the intermediate D.12 The complex D is expected
to adopt a gauche conformation relative to the O-CdC plane to
avoid steric interactions between the methylene group attached to
the oxygen atom and the methyl group on the double bond.13 Upon
Pd-coordination, the nitrogen becomes chiral, and the metal will
thus coordinate the amine in a cisoid fashion relative to the hydrogen
at the neighboring chiral carbon. After insertion, the nitrogen can
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10.1021/ja029646c CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Chelation-Controlled Asymmetric Arylation of 6a with
Aryl Halides
methylcyclopentanones that delivers good to very good two-step
yields. The reactions were performed under air with a weak base,
and the enantioselectivities of the produced cyclopentanones are
the highest reported so far. An extension to other cyclic ketones
and new classes of chelating substrates seems promising.
Acknowledgment. We thank the Swedish Foundation for
Strategic Research, the Swedish Research Council, and Dr. Boris
Schmidt and Dr. Wilfried A. Ko¨nig for help with the chiral GC.
Supporting Information Available: Experimental procedures, and
spectroscopic and analytical data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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a Cumulative two-step yield after silica column chromatography (>95%
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or chiral GC. c Yield calculated after intermediate isolation of 7g (53%)
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Chart 1. Proposed Structure of Chelated π-Intermediate D
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(8) General experimental procedure: Olefin 6a (0.78 mmol), aryl halide 2a-i
(0.60 mmol), LiCl (1.2 mmol), NaOAc (0.72 mmol), K2CO3 (0.72 mmol),
Pd(OAc)2 (0.018 mmol), and H2O (0.2 mL) were mixed in 2 mL of DMF
and heated at a given time and temperature (Table 1).
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D was obtained by
participate in the generation of the six-membered palladacycle prior
to the subsequent â-elimination. The presentation of the oxidative
addition complex via nitrogen coordination explains the high
reactivity of the system14 and why the quaternary center can be
created. To investigate the difference in reaction rate enhancement,
a competitive experiment3,15 with 1 (0.5 equiv) and 6a (0.5 equiv)
semimanual modeling, see Supporting Information.
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(12) For
a discussion regarding the diastereoselectivity, see Supporting
Information.
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1
and phenyl iodide (4 equiv) was performed at 50 °C. A H NMR
analysis after 45 h proved that nearly equal amounts of phenylated
3d and 7d had been formed. This result suggests that the
accelerating capacities of the dimethylamino- and the N-methylated
pyrrolidin frameworks are comparable.
In conclusion, the described chelation-controlled Heck methodol-
ogy provides an alternative and mild approach to 2-aryl-2-
(14) We have previously shown that chelating tertiary amine tethered vinyl
ethers are more reactive than the noncoordinating alkyl counterparts in
Heck arylations (see refs 3 and 5c,d).
(15) Westwell, A. D.; Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1 1996,
1-2.
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