Desymmetrization of cyclic olefins via asymmetric Heck reaction and hydroarylation

Article abstract of DOI:10.1039/c3cc47551d

An asymmetric Heck reaction allows desymmetrization of substituted cyclic olefins in high dr and ee. A bisphosphine oxide is uniquely stereoselective for this purpose. Desymmetrization of bicyclic olefins via hydroarylation can also be realized in high ee.

Full text of DOI:10.1039/c3cc47551d

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Desymmetrization of cyclic olefins via asymmetric
Heck reaction and hydroarylation†
Cite this: DOI: 10.1039/c3cc47551d
Sijia Liu and Jianrong (Steve) Zhou*
Received 2nd October 2013,
Accepted 22nd October 2013
DOI: 10.1039/c3cc47551d
www.rsc.org/chemcomm
An asymmetric Heck reaction allows desymmetrization of substituted
cyclic olefins in high dr and ee. A bisphosphine oxide is uniquely
stereoselective for this purpose. Desymmetrization of bicyclic olefins
via hydroarylation can also be realized in high ee.
Asymmetric, intermolecular Heck reaction was first reported by
Hayashi et al. in 1991, which was performed between aryl triflates
and 2,3-dihydrofuran.1 Since then, the reaction has been tested
using numerous phosphorus ligands,2 most of which are bisphos-
phines, mixed oxazoline–phosphines and bisphosphites.3 Although
excellent ee was realized with simple olefins such as cyclopentene
and 2,3-dihydrofuran, structural diversity of asymmetric Heck
products remained rather low, as compared to the intramolecular
versions.4 Recently, Sigman et al. reported the asymmetric Heck–
Matsuda reaction between acyclic olefins bearing alcohol groups
and aryldiazonium salts and provided arylated ketones and
aldehydes in good ee.5 Herein, we report desymmetrization of
both monocyclic and bicyclic olefins that formed more than
one stereocenter in high ee and excellent dr (Fig. 1).
Fig. 1 Catalyst discovery for a model Heck reaction.
We first attempted a model reaction between p-acetylphenyl
triflate and a substituted cyclopentene to seek a stereoselective
palladium catalyst.6 The family of bisphosphine oxides, which (R)-SDP(O) are technically pseudoenantiomers and they gave
we used for asymmetric Heck reaction of simple cyclic olefins, opposite enantiomers as major Heck products.
gave very promising results (Fig. 1).7 For example, (R)-BINAP(O)
In comparison, when bisphosphine ligands, (R)-BINAP and
gave predominantly the trans isomer with 84% ee.8 The ratio of (R)-Xyl-SDP were used, the trans isomer was formed in poor ee and
the amount of the trans isomer to the sum of two minor isomers, or as the minor isomer in a complex mixture of six isomers (judged
the s ratio, was determined to be 4 : 1 by GC. The trans configu- by GC). In addition, when tBu-PHOX was used, the trans isomer
ration of the major isomer was established using X-ray diffractional was produced together with four isomers and the s value was only
analysis of one product derivative.
1.2 : 1. The other two PHOX ligands showed very poor activity.
During our condition optimization, we found that several
In the model reaction, we found that 1,10-spirobiindane-7,70-
bisphosphine oxide or SDP(O) led to 90% ee and an s ratio of bases worked well, including iPr2NEt, 2,6-lutidine, Li2CO3 and
26 : 1. If P-phenyl groups in SDP(O) were changed to m-xylyl, the LiOAc. Trialkylamine Et3N, however, led to about 20% reduction of
selectivity was improved to 97% ee. Notably, (R)-BINAP(O) and ArOTf to arene, via donation of hydride to cationic arylpalladium
species.9 With respect to the choice of solvents, excellent ee was
Division of Chemistry and Biological Chemistry, School of Physical and
obtained in THF, dioxane and toluene.
In terms of the scope of olefins, various substituted cyclo-
pentenes reacted selectively to furnish the trans isomers (Fig. 2). Esters,
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371, Singapore. E-mail: jrzhou@ntu.edu.sg; Fax: +65 67911961
† Electronic supplementary information (ESI) available: Experimental procedures
nitriles and free alcohols can be present on the olefins. However, if the
R group on the olefin was benzyl, no insertion occurred.
and characterization of new compounds. CCDC 963964. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc47551d
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Fig. 4 Top: derivatization of one Heck product. Bottom: ORTEP diagram of a diol
derivative with 50% thermal ellipsoid and hydrogen atoms omitted for clarity.
Fig. 2 Examples of cyclic olefins in Heck reaction.
took place predominantly anti to the siloxy group to avoid steric
repulsion. The relative configuration in the diol derivative was
established using X-ray crystallography.
A wide array of aryl triflates coupled well with a model cyclo-
pentene (Fig. 3). On the aryl rings, both electronic perturbation
and ortho-substituents can be present. Many polar groups such
as esters, ketones and aldehydes were tolerated. Some hetero-
aryl triflates based on indoles and benzothiazole also reacted
efficiently in good ee. One example of alkenyl triflate was
included to show the scope beyond aryl ones.
Stereoselective olefin manipulation of asymmetric Heck
products was performed, such as dihydroxylation, epoxidation
and cyclopropanation (Fig. 4).10 The relative configuration of the
cyclopropane and epoxide derivatives was established by nOe
analysis. Notably, cyclopropanation occurred almost exclusively
syn to the siloxy group, presumably due to pre-coordination of
siloxy oxygen to organozinc reagents. The cis-dihydroxylation
The Xyl-SDP(O) catalyst can be applied to asymmetric hydro-
arylation of bicyclic olefins (Fig. 5). Sodium formate served as the
hydride donor. Excellent ee was obtained in all cases, which was
not seen previously in Pd-catalyzed hydroarylations.11 In reactions
of norbornadiene, no double hydroarylation was observed. The
coupling of benzonorbornadiene also proceeded smoothly.
The new hydroarylation method can find use in asymmetric
synthesis of epibatidine, an alkaloid possessing potent analgesic
properties.12 Another target is an orally available therapeutic agent
for the treatment of osteoporosis.13 Only recently, Rh-catalyzed
hydroarylation between azacyclic olefins and arylboronic acids
gave high ee.14 Hartwig et al. also reported iridium-catalyzed
hydroheteroarylation of norbornene in >90% ee via selective
CH activation of some heteroarenes.15
The absolute configuration of one product, exo-2-phenyl-
norbornane was determined to be 2R, by comparison with reported
optical rotation.16 This assignment is consistent with 5S configu-
ration of the major Heck isomers in Fig. 2 via aryl insertion at the
less hindered face of cyclopentenes.
In conclusion, we realized the Heck reaction of substituted
cyclopentenes that gave almost exclusively trans isomers and
Fig. 3 Examples of aryl and vinyl triflates in Heck reaction.
Fig. 5 Asymmetric hydroarylation of bicyclic olefins using (R)-Xyl-SDP(O) ligand.
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82% ee: C. R. D. Correia, C. C. Oliveira, A. G. Salles and E. A.
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to give this kind of selectivity. Applications to hydroarylation of
bicyclic olefins also led to high ee, which was not seen previously
in Pd catalysis.
We thank the Singapore National Research Foundation (NRF-
RF2008-10) and Nanyang Technological University for financial
support. We thank Johnson Matthey for a gift of palladium.
8 Oestreich et al. first reported the use of chiral BINAP(O) ligand in
¨
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.