Sulfoxide-alkene hybrids: A new class of chiral ligands for the Hayashi-Miyaura reaction

Article abstract of DOI:10.1021/ol200841x

Sulfoxide-alkene hybrids are introduced as a new class of chiral heterodentate ligands for the Hayashi-Miyaura reaction. The synthesis of these ligands was achieved without the use of protecting groups. A chiral resolution was performed via simple column-chromatographic separation of the diastereomeric ligands. Both diastereomers proved to be excellent ligands in Rh-catalyzed 1,4-addition reactions, furnishing chiral products with high enantioselectivities and, remarkably, opposite stereoconfigurations.

Full text of DOI:10.1021/ol200841x

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3182–3185
SulfoxideÀAlkene Hybrids:
A New Class of Chiral Ligands for the
HayashiÀMiyaura Reaction
Tobias Thaler, Li-Na Guo, Andreas K. Steib, Mihai Raducan, Konstantin Karaghiosoff,
Peter Mayer, and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse
€
5-13, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 27, 2011
ABSTRACT
SulfoxideÀalkene hybrids are introduced as a new class of chiral heterodentate ligands for the HayashiÀMiyaura reaction. The synthesis of these
ligands was achieved without the use of protecting groups. A chiral resolution was performed via simple column-chromatographic separation of
the diastereomeric ligands. Both diastereomers proved to be excellent ligands in Rh-catalyzed 1,4-addition reactions, furnishing chiral products
with high enantioselectivities and, remarkably, opposite stereoconfigurations.
The Rh-catalyzed 1,4-addition of boronic acids to en-
ones, also known as the HayashiÀMiyaura reaction,1 has
been well established as an important and versatile tool for
the enantioselective Michael addition.2 Chiral dienes3 and
most recently chiral bissulfoxides4 have proven very effec-
tive for achieving high levels of enantioselectivity in this
type of reaction. The easy preparation5 and resolution of
chiral diastereomeric sulfoxides, which can be performed
via simple column chromatographic separation,4aÀc,6 led
us to envision novel modular hybrid ligands that combine
both alkenes and sulfoxides as coordinative elements.
So far, tert-butylsulfinylphosphines represent the only
class of chiral sulfoxide-based hybrid ligands employed in
the HayashiÀMiyaura reaction,7 and alkene hybrid li-
gands are restricted to either phosphorus8 or nitrogen9 as
second coordinating moiety. Herein, we report the pre-
parationand use of the first chiralsulfoxideÀalkene hybrid
ligands in the HayashiÀMiyaura reaction with a direct
comparative study on the relative influences of the alkenyl
and sulfoxide group on the reactivity and enantioselec-
tivity of the Rh(I) catalyst.
Inspired by Hayashi’s well-studied phosphorusÀolefin
hybrid ligand,8e,i we designed a straightforward, protec-
tive-group free synthesis of 1 and 2 from norbornene (3) in
four steps (Scheme 1). Thus, the functionalization of 3 with
NBS (N-bromosuccinimide) in H2O and subsequent
Swern oxidation8e,i furnished bromo ketone 4 in 55%
yield. LaCl3 2LiCl-mediated addition10 of 4-anisylmagne-
3
sium bromide to 4 followed by acidic elimination of H2O
using MsOH (methanesulfonic acid) directly gave the
racemic alkene 5 with 67% overall yield without unneces-
sary protectionÀdeprotection steps. Br/Li exchange on 5
using t-BuLi, subsequent transmetalation with MgCl2, and
quenching with (À)-menthyl (S)-p-toluenesulfinate (6;
Andersen sulfinate)11 furnished the two diastereomeric
ligands 1 and 2 with 72% yield and 99% ee,12 which could
be easily separated via column chromatographic
purification.13 No preparative HPLC separation was
required.8e,i
1H and 13C NMR experiments on the Rh-complexes of 1
and 2 obtained by reacting them with [(coe)2RhCl]214 (coe:
cyclooctene; 0.5 equiv) in 1,4-dioxane-d8 clearly proved the
coordination of both the alkene and the sulfoxide moiety
(1) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
(2) For selected reviews, see: (a) Miyaura, N. Bull. Chem. Soc. Jpn.
2008, 81, 1535. (b) Hayashi, T. Russ. Chem. Bull. 2003, 52, 2595. (c)
Hayashi, T. Synlett 2001, 879.
r
10.1021/ol200841x
Published on Web 05/18/2011
2011 American Chemical Society

stoichiometric amount of CsOH H2O in 1,4-dioxane and
3
water. The resulting in situ formed catalyst 7 (2.5 mol %)
was then directly used without isolation in the 1,4-addition
reactions of various aryl- and alkenylboronic acids to
cyclic R,β-unsaturated carbonyl compounds (Table 1).
The expected chiral addition products 8À10 were obtained
with 61À99% yield and high enantioselectivities (82À
97% ee) using only a slight excess of the respective boronic
acid (1.2 equiv). The addition of arylboronic acids to
cyclohex-2-enone typically proceeded with enantioselec-
tivities between 90 and 93% ee. The (S)-configured pro-
ducts were obtained preferentially.16 Lower stereoselectivi-
ties were observed with sterically more demanding (8c;
89% ee; entry 3) or electron-rich arylboronic acids (8f;
88% ee and 8i; 82% ee; entries 6 and 9). The reactions of
(E)-styryl- and (E)-4-methylstyrylboronic acid with cyclo-
hex-2-enone gave the chiral addition products 8nÀo with
61À66% yields and high enantiomeric excesses (92À95%
ee; entries 14and 15). Withcyclopent-2-enone as substrate,
even higher enantioselectivities were achieved (9aÀi;
94À97% ee; entries 16À24). In this case, switching from
aryl- to alkenylboronic acids did not result in a deteriora-
tion of the yield (9i; entry 24). The use of heterocyclic N-
benzyl maleimide as substrate led to the chiral (S)-config-
ured addition products 10aÀc with good yields (84À88%)
and high enantioselectivities (88À97% ee; entries 25À27).
Next, we examined diastereomeric 2 and its performance
as a chiral ligand in the Rh-catalyzed HayashiÀ-Miyaura
reaction (Table 2). To our delight, we found that the
corresponding Michael adducts were produced with
equally high enantioselectivities and yields (79À92%;
90À99% ee), but remarkably, the absolute configurations
of the products were opposite to those obtained with 1,
clearly hinting at predominant stereocontrol through the
chiral environment around the alkenyl moiety.
Scheme 1. Synthesis and Chiral Resolution of Ligands 1 and 2
to the Rh atom with the signals for the respective C-atoms
shifted upfield and split into doublets.15
To test the efficacy and scope of 1 as a chiral ligand in the
HayashiÀMiyaura reaction, we prepared the Rh complex
7 by treating 1 with [(coe)2RhCl]2 (0.5 equiv) and a
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Org. Lett., Vol. 13, No. 12, 2011
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Table 1. Enantioselective 1,4-Addition of Boronic Acids to
Various Electron-deficient Alkenes Using 1 as Chiral Ligand
Table 2. Enantioselective 1,4-Addition of Boronic Acids to
Various Electron-Deficient Alkenes Using 2 as Chiral Ligand
a Isolated yield of analytically pure product. b Determined via chiral
HPLC analysis. c Absolute configurations determined by comparison
with reported chiral HPLC data.16 d Reaction time: 12 h. Compound
racemizes when stored at room temperature. e Reaction time: 12 h.
complex with its si face in the case of 1 and with its re face
in the case of 2. Despite a strong coordination of the
Scheme 2. Tentative Stereochemical Model Explaining the Op-
posite Configurations of the Addition Products Obtained with
Ligands 1 and 2
a Isolated yield of analytically pure product. b Determined via chiral
HPLC analysis. c Absolute configurations determined by comparison
with reported chiral HPLC data.16 d Reaction time: 12 h. Compound
racemizes when stored at room temperature.
Moreover, the addition of phenylboronic acid to hetero-
cyclic Cbz-protected 2,3-dihydropyridin-4(1H)-one furnished
14 with 92% yield and 99% ee (entry 9). To rationalize the
opposite stereochemical outcomes obtained with the dia-
stereomeric ligands 1 and 2, we propose the model outlined
in Scheme 2. Since sulfinyl groups are known to be strong
σ-donors to Rh,4b a trans-configuration of the aryl group
and the alkene moiety of the ligand in the complex can be
assumed as it is reported for the related phosphineÀolefin
hybrid ligands.8e The stereoselectivity is controlled by the
chiral environment around the alkenyl unit, which forces
the substrate via steric interactions to bind to the Rh
sulfinyl group to Rh the central chirality at the sulfur has
only a minor influence on the observed enantioselectivities.
Finally, we examined the influence of electronic and
steric modulations at the sulfoxideÀolefin hybrid ligand
on reactivity and enantioselectivity of the Rh complex in
the HayashiÀMiyaura reaction. For this purpose, we
3184
Org. Lett., Vol. 13, No. 12, 2011

prepared the analogues 15aÀc bearing different sulfinyl
moieties using subsequent addition of the corresponding
Grignard reagents to (S)-TMPOO (N-tosylmethylphenyl-
1,2,3-oxathiazolidine 2-oxide).17 To investigate the role of
the alkenyl moiety, we prepared 16 with a more electron-
rich 4-dimethylaniline substituent at the CdC double
bond. These ligands were then submitted to the Rh-
catalyzed 1,4-addition of various arylboronic acids to
cyclohexen-2-one (Table 3). Both increasing and reducing
the electron-density at the sulfoxide (15a,b) led to an
overall deterioration of yield and enantioselectivity
(entries 1À7 of Table 3). Interestingly, the use of elec-
tron-poor arylboronic acids as nucleophiles proved ad-
vantageous to yield and enantioselectivity with both
ligands (entries 4 and 7). A negative effect of electron-rich
arylboronic acids on the stereoselectivity was also found
with1 asligand (entries 6 and 9 of Table1). Withligand 15c
bearing a sterically highly congested tBu group at the
sulfoxide no reaction took place at all (entry 8 of Table 3).
This is probably due to a loss of coordination between the
sulfinyl group and Rh. The alkenyl moiety alone is not
sufficient for efficiently binding to the Rh center, thus
underlining the vital role of the sulfinyl group for chelation
and formation of the reactive complex. An increase of the
electron-density at the CdC bond (16) led only to a
deterioration of yields, without impairing the enantioselec-
tivities (entries 9 and 10).
Table 3. Enantioselective 1,4-Addition of Boronic Acids to
Cyclohex-2-enone Using Analogues 15aÀc and 16 as Chiral
Ligands
In summary, we have developed a concise, protective-
group free synthesis of sulfoxideÀalkene hybrid ligands.
Chiral resolution is achieved via simple column chromato-
graphic separation of the diastereomeric ligands, which
can both be used in the HayashiÀMiyaura reaction,
furnishing the chiral products with excellent yields, equally
high enantioselectivities. and opposite stereoconfigura-
tions. Experiments with analogues of 1 and 2 displaying
different steric and electronic properties showed that co-
ordination of the sulfinyl group represents a crucial factor
for efficient chelation and formation of the reactive Rh
complex. Although efficient binding of the alkenyl moiety
to the Rh center is less important for the reaction to
proceed, its chiral environment dictates the stereochemical
outcome.
a Isolated yield of analytically pure product. b Determined via chiral
HPLC analysis. See the Supporting Information for details. c Absolute
configurations determined by comparison with reported chiral HPLC
data.16
Programme (FP7/2007-2013), ERC grant agreement no.
227763. We thank BASF AG, W. C. Heraeus GmbH,
Chemetall GmbH, and Solvias AGforthe generousgiftsof
chemicals. L.-N.G. thanks the Alexander von Humboldt
Foundation for financial support.
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Su, X.;
Wilkinson, H. S.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H. Tetra-
hedron 2005, 61, 6386. (b) Han, Z.; Krishnamurthy, D.; Grover, P.;
Wilkinson, H. S.; Fang, Q. K.; Su, X.; Lu, Z.-H.; Magiera, D.;
Senanayake, C. H. Angew. Chem., Int. Ed. 2003, 42, 2032.
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