On the stereochemical course of palladium-catalyzed cross-coupling of allylic silanolate salts with aromatic bromides

Article abstract of DOI:10.1021/ja910804u

The stereochemical course of palladium-catalyzed cross-coupling reactions of an enantioenriched, a-substituted, allylic silanolate salt with aromatic bromides has been investigated. The allylic silanolate salt was prepared in high geometrical (Z/E, 94:6) and high enantiomeric (94:6 er) purity by a coppercatalyzed S_N2′ reaction of a resolved allylic carbamate. Eight different aromatic bromides underwent crosscoupling with excellent constitutional site-selectivity and excellent stereospecificity. Stereochemical correlation established that the transmetalation event proceeds through a syn S_E′ mechanism which is interpreted in terms of an intramolecular delivery of the arylpalladium electrophile through a key intermediate that contains a discrete Si-O-Pd linkage.

Full text of DOI:10.1021/ja910804u

Published on Web 02/17/2010
On the Stereochemical Course of Palladium-Catalyzed
Cross-Coupling of Allylic Silanolate Salts with Aromatic
Bromides
Scott E. Denmark* and Nathan S. Werner
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
Received December 22, 2009; E-mail: sdenmark@illinois.edu
Abstract: The stereochemical course of palladium-catalyzed cross-coupling reactions of an enantioenriched,
R-substituted, allylic silanolate salt with aromatic bromides has been investigated. The allylic silanolate
salt was prepared in high geometrical (Z/E, 94:6) and high enantiomeric (94:6 er) purity by a copper-
catalyzed SN2′ reaction of a resolved allylic carbamate. Eight different aromatic bromides underwent cross-
coupling with excellent constitutional site-selectivity and excellent stereospecificity. Stereochemical correlation
established that the transmetalation event proceeds through a syn SE′ mechanism which is interpreted in
terms of an intramolecular delivery of the arylpalladium electrophile through a key intermediate that contains
a discrete Si-O-Pd linkage.
product can be classified into three general types (Figure 1).2–4
Type 1 represents the diastereoselective coupling of chiral,
Introduction
The ability of transition-metal-catalyzed cross-coupling reac-
tions to unify carbon atoms at various levels of hybridization
in myriad organic substrates distinguishes it from other
carbon-carbon bond-forming reactions. The pairwise combina-
tions of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and allyl
organometallic donors and organic electrophiles encompass all
hybridizations of the carbon atom (sp3, sp2, and sp).1 However,
a vast majority of transition-metal-catalyzed cross-coupling
reactions employ organic subunits of sp or sp2 hybridization at
the reactive carbon and commonly do not form chiral products.
Nevertheless, a multitude of asymmetric cross-coupling reactions
for the enantioselective synthesis of chiral compounds can be
envisioned, but the extraordinary potential of these constructs
has not been realized.
enantioenriched substrates by internal selection.5 Among the
reactions of this type are palladium-catalyzed nucleophilic
allylations (Type 1-A),6-8 including those reported in this work,
and formation of atropisomeric biaryls (Type 1-B).9 Type 2
reactions employ chiral, configurationally labile substrates and
afford enantiomerically enriched products through external
selection5 by a chiral catalyst. Examples of this type include
the coupling of secondary, benzylic Grignard reagents (Type
2-A),2c,d and nickel-catalyzed cross-coupling of secondary alkyl
bromides with organometallic donors based on silicon, boron,
zinc, and indium (Type 2-B).10 Finally, Type 3 couplings
constitute the reactions of achiral substrates and afford chiral,
enantiomerically enriched products via external selection with
a chiral catalyst. The majority of known asymmetric cross-
coupling reactions fall into this category and include the Heck
Those transformations in which a transition-metal-catalyzed
cross-coupling reaction creates a stereogenic element in the
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I.,
Ed.; Wiley-Interscience: New York, 2002.
(2) (a) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000. (b) Tietze, L. F.; Ila, H.; Bell, H. P. Chem.
ReV. 2004, 104, 3453–3516. (c) Hayashi, T. J. Organomet. Chem.
2002, 653, 41–45. (d) Hayashi, T. ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer
Verlag: Heidelberg, 1999; Vol. II, Chapt. 25. (e) Blystone, S. L. Chem.
ReV. 1989, 89, 1663–1679.
(5) For a definition of internal and external selection, see: Denmark, S. E.;
Almstead, N. G. Allylation of Carbonyls: Methodology and Stereo-
chemistry. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; pp 299-402.
(6) (a) Hatanaka, Y.; Goda, K.-I.; Hiyama, T. Tetrahedron Lett. 1994,
35, 1279–1282. (b) Hiyama, T.; Matsuhashi, H.; Fujita, A.; Tanaka,
M.; Hirabayashi, K.; Shimizu, M.; Mori, A. Organometallics 1996,
15, 5762–5765. (c) Kalkofen, R.; Hoppe, D. Synlett 2006, 1959–1961.
(7) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2007, 129, 12650–12651.
(8) Recently developed, transition-metal-catalyzed additions of organic
groups to aldehydes and imines are also not considered to be cross-
coupling reactions. See: (a) Skukas, E.; Ngai, M.-Y.; Komanduri, V.;
Krische, M. J. Acc. Chem. Res. 2007, 40, 1394–1401. (b) Patman,
R. L.; Bower, J. F.; Kim, I. S.; Krische, M. J. Aldrichim. Acta 2008,
41, 95–104.
(3) The trivial case of cross-coupling of chiral subunits where the newly
formed carbon-carbon bond is not a stereogenic unit is excluded.
(4) By far the largest category of transition-metal-catalyzed, carbon-
carbon and carbon-heteroatom bond-forming reactions involves the
asymmetric capture of π-allylmetals derived from palladium, molyb-
denum, rhodium, and iridium with a wide range of nucleophiles. These
powerful reactions have been thoroughly reviewed and therefore will
not be categorized here. See: (a) Lu, Z.; Ma, S. Angew. Chem., Int.
Ed. 2008, 47, 258–297. (b) Trost, B. M.; Crawley, M. L. Chem. ReV.
2003, 103, 2921–2943. (c) Pfaltz, A.; Lautens, M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer Verlag: Heidelberg, 1999; Vol. II, Chapt. 24.
(9) (a) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–
5427. (b) Bringmann, G.; Walter, R.; Wirich, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977–991.
(10) (a) Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 8347–8349. (b)
Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656–
2670.
9
3612 J. AM. CHEM. SOC. 2010, 132, 3612–3620
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Stereochemical Course of Cross-Coupling of Allylic Silanolates
A R T I C L E S
reaction,11 allylations of organic electrophiles with allylic
organometallic donors (both Type 3-A),12 arylation of enolates
(Type 3-B),13 and formation of atropisomeric biaryls (Type
3-C).14
In this context, we recently reported the palladium-catalyzed
cross-coupling of allylic silanolate salts with aromatic bromides
(Scheme 1).16 Sodium allyldimethylsilanolate (Na+1-) under-
goes cross-coupling with aromatic bromides without the need
for external activators (fluoride)6a,b or added ligands (phosphine).
In addition, the coupling of sodium 2-butenyldimethylsilanolate
(Na+2-) affords the γ-coupled products 5 with high site-
selectivity when the olefinic ligands dibenzylideneacetone (dba)
and norbornadiene (nbd) are used. The results of these studies
are interpreted in terms of a closed, SE′ transmetalation of the
arylpalladium(II) silanolate ii, followed by reductive elimination
from iii facilitated by the π-acidic dba ligand to afford 5 with
high γ-selectivity.
Scheme 1a
a Abbreviations: OA, oxidative addition; Dis., displacement; TM, trans-
metalation; RE, reductive elimination.
The selective formation of the chiral, γ-coupled product 5
under the influence of dba and nbd naturally suggested the
possibility of setting this center enantioselectively through the
influence of chiral, olefinic ligands (i.e., a Type 3 reaction).
However, the use of Na+2- in asymmetric catalysis represents
a significant challenge because the chiral olefin ligand must
control not only the enantioselectivity of the coupling17,18 but
also the site-selectivity of C-C bond formation. Thus, to achieve
this goal, we felt it prudent to first establish the geometrical
details of the (putative) stereochemistry-determining transmeta-
lation step by investigating a diastereoselective reaction of Type
1. This paper describes the synthesis of enantioenriched
R-substituted allylic silanolate salts and the determination of
the stereochemical course of their cross-coupling with aromatic
bromides.
Figure 1. General classification of asymmetric transition-metal-catalyzed
cross-coupling reactions.
Organizing these reactions in this manner provides a clear
view of the stereochemical landscape and makes apparent not
only the significant achievements but also the opportunities for
development of asymmetric transition-metal-catalyzed cross-
coupling reactions. Specifically, the lack of reports on allylic
cross-coupling reactions of Type 1-A and Type 3-A represents
a deficiency, and for good reason. These reactions require control
over both constitutional site-selectivity (i.e., R- vs γ-coupling)
in addition to either diastereo- or enantiodifferentiation.15
Moreover, a study of the stereodifferentiating steps in Type 1-A
processes would provide important insights for the development
of catalytic, enantioselective variants of Type 3-A.
Background
The stereochemical course of an analogous reaction, namely
the addition of allylic silanes and allylic stannanes to aldehydes,
has been thoroughly investigated in these and other laboratories.5
These studies established that the two stereochemically defining
(11) (a) Shibasaki, M.; Vogl, E. M.; Ohshima, T. AdV. Synth. Catal. 2004,
346, 1533–1552. (b) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004; Vol. 2, Chapt. 5. (c) Dounay, A. B.; Overman,
L. E. Chem. ReV. 2003, 103, 2945–2963.
(12) (a) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35,
704–705. (b) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett.
2006, 35, 1368–1369. (c) Yamamoto, Y.; Takada, S.; Miyaura, N.;
Iyama, T.; Tachikawa, H. Organometallics 2009, 28, 152–160.
(13) (a) Martˆın, R.; Buchwald, S. L. Org. Lett. 2008, 10, 4561–4564. (b)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
(14) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. ReV.
2009, 38, 3193–3207. (b) Ogasawara, M.; Watanabe, S. Synthesis 2009,
1761–1785. (c) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns,
N. Angew. Chem., Int. Ed 2001, 40, 3284–3308.
(16) Denmark, S. E.; Werner, N. S. J. Am. Chem. Soc. 2008, 130, 16382–
16393.
(17) Chiral, olefinic ligands are widely employed in asymmetric, transition-
metal-catalyzed reactions. However, their use in asymmetric, pal-
ladium-catalyzed reactions remains elusive. See: Defieber, C.; Gru¨tz-
macher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482–
4502.
(18) Trauner reported the preparation of a chiral diene-ligated palladium
catalyst; however, the use of this catalyst in a palladium ene reaction
provided only racemic products. See: Grundl, M. A.; Kennedy-Smith,
J. J.; Trauner, D. Organometallics 2005, 24, 2831–2833.
(15) Itzumi, Y.; Tai, A. Stereo-Differentiating Reactions. The Nature of
Asymmetric Reactions; Academic Press: New York, 1975.
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J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010 3613

A R T I C L E S
Denmark and Werner
factors of the allylation reaction are (1) the pairwise diastereo-
selection between the faces of the reacting double bonds (i.e.,
relative topicity) and (2) the disposition of the electrofuge (MLn)
with respect to the attacking electrophile (SE′ process). For the
allylations studied herein, only the latter feature is relevant
(Figure 2). To determine the orientation of MLn during the
electrophilic attack, two attributes of the product must be
established: (1) the configuration of the resulting double bond
and (2) the configuration of the newly created stereogenic center.
The fundamental stereoelectronic requirement is that the C-MLn
bond be oriented such that overlap with the double bond is
strong (i.e., (30° from perpendicular to the atomic plane). To
satisfy this stereoelectronic requirement and avoid A1,3 strain,
the acyclic, allylic organometallic reagent reacts via a conforma-
tion in which the allylic hydrogen atom eclipses the double bond,
as shown in Figure 2.19 The electrophile can then approach the
defined half-space which contains the electrofuge (syn-SE′) or
the half-space opposite to that occupied by the electrofuge (anti-
SE′). The configurations of the new stereogenic center and
carbon-carbon double bond are therefore dependent upon the
conformation of the allylic moiety and the direction of elec-
trophile attack relative to the electrofuge. For allylmetal-aldehyde
addition reactions promoted by Lewis acids, the stereochemical
course is overwhelmingly anti-SE′,20 though with other elec-
trophiles in sterically biased systems, syn-SE′ processes are
known.21
and a closed mechanism involving a Pd-F-Si interaction for
reaction with CsF.
Scheme 2
Miyaura and Yamamoto investigated the details of the
transmetalation and enantioselection in the cross-coupling of
crotyltrifluoroborates with aromatic bromides (Scheme 3).12c
Hammett studies displayed a small negative F-value (-0.50)
for the reaction of five electronically differentiated, preformed
arylpalladium complexes 9 (containing bis(di-tert-butylphos-
phino)ferrocene) with (E)-crotyltrifluoroborate 10. These results
are interpreted to imply formation of a cationic palladium(II)
species iW prior to transmetalation. DFT calculations suggest
that this process occurs by an open SE′ process through
transition-state structure W, because the closed transition-state
structure Wi had slightly higher energy (+2.0 kcal/mol) in THF.
The position of the palladium electrophile relative to the
orientation of the trifluoroborate electrofuge (syn- or anti-SE′)
was not established.
Figure 2. Stereochemical control elements in SE′ reactions (priority: E >
CHdCH > R1).
Of greater relevance to the reaction at hand are studies on
the stereochemical course of palladium-catalyzed substitution
of allylic organometallic reagents with aromatic electrophiles.
In 1994, Hiyama reported that, in the reaction of enantioenriched
allyldifluorophenylsilanes with aryl tosylates under palladium
catalysis, two mechanisms are operative and depend on the
fluoride source and the solvent (Scheme 2).6a For example, the
combination of (R)-6, aryl tosylate 7, and tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF) in dimethylform-
amide leads to the formation of (S)-(E)-8 via an anti-SE′
pathway. However, when CsF and tetrahydrofuran are used, (R)-
(E)-8 predominates (via a syn-SE′ pathway), albeit with attenu-
ated enantiospecificity (es).22 These results are explained by the
operation of an open mechanism for the reaction with TASF
Scheme 3
A recent communication from Oshima and Yorimitsu de-
scribes the diastereoselective synthesis of (arylalkenyl)silanes
by retroallylation of homoallylic alcohols such as (S)-11 in the
presence of arylpalladium halides (Scheme 4).7 The authors
propose a closed, chairlike SE′ transition-state structure with the
C(2) methyl group oriented in a pseudo-equatorial position,
preventing unfavorable 1,3-diaxial steric interactions with the
silicon substituent. However, only aryl bromides bearing ortho
substituents afforded products with high diastereoselectivities.
(19) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am. Chem.
Soc. 1987, 109, 650–663.
(20) (a) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1994, 59, 5130–
5132. (b) Denmark, S. E.; Hosoi, S. J. Org. Chem. 1994, 59, 5133–
5135.
(21) Fleming, I.; Au-Yeung, B.-W. Tetrahedron 1981, 37, 13–24.
(22) The term enantiospecificity [es ) (eeproduct/eestarting material) × 100%]
provides a convenient method of describing the conservation of
configurational purity for a reaction.
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3614 J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010

Stereochemical Course of Cross-Coupling of Allylic Silanolates
A R T I C L E S
Scheme 4
Figure 3. Synthetic strategy to determine the stereochemical course of
transmetalation.
of 4-trimethylsilyl-3-butyn-2-ol (14) by double deprotonation
of 3-butyn-2-ol (13) with n-butyllithium, addition of TMSCl,
and workup with 3 M HCl to provide 14 in 90% yield (Scheme
5).24 Lipase-catalyzed kinetic resolution of 14 provided (S)-14
in 46% yield and >99:1 er.25 The phenyl carbamate necessary
for SN2′ displacement was installed by treatment of (S)-14 with
phenyl isocyanate and 4-dimethylaminopyridine (DMAP) in
hexane at room temperature. The TMS group, required for high
selectivity in the kinetic resolution, was then cleaved in situ
with potassium fluoride in methanol to provide (S)-15 in 94%
yield. Platinum-catalyzed hydrosilylation26 of (S)-15 with di-
methylchlorosilane, followed by substitution of the chloride with
potassium tert-butoxide, afforded the protected vinylic silanol
(S)-(E)-16 (the precursor to the SN2′ reaction) in 88% yield over
the two-step sequence.
The goal of the current work was to determine the stereo-
chemical course of the palladium-catalyzed cross-coupling of
allylic silanolate salts with aromatic bromides. To this end,
enantioenriched R-substituted allylic silanolate salts were syn-
thesized and cross-coupled with aromatic bromides, and the
stereochemical course of the cross-coupling reaction was
determined. These studies provide a refined picture of the
geometric details of the critical transmetalation step.
Results
1. Synthetic Strategy To Access Enantiomerically
Enriched r-Substituted Allylic Silanolate Salts. A flexible
synthetic route to R-substituted allylic silanolate salts in
enantiomerically pure form was required to establish the
stereochemical course of their transmetalation in palladium-
catalyzed cross-coupling reactions. In anticipation of the possible
challenges that could be encountered in this endeavor (including,
but not limited to, low enantiomeric purity of the silanolate,
low site-selectivity of the coupling, and low asymmetric
induction of the coupling reaction), a modular route was sought
in which structural variation of the R-substituted silanolate would
be facile. Specifically, the route should allow access to either
geometry of the allylic double bond, various R-substituents, and
high enantiomeric purity of the products (Figure 3). Among
several synthetic strategies considered, the copper-catalyzed SN2′
reaction of allylic carbamates23 with various nucleophiles was
identified to meet these criteria for several reasons: (1) the
precursor to the SN2′ reaction can be synthesized in enantio-
merically pure form from readily available starting materials,
(2) both E and Z terminally substituted allylic silanes can be
prepared from this precursor, depending upon the organometallic
nucleophile used, and (3) the SN2′ reaction permitted a variety
of R-substituents to be installed with high enantiomeric purity
at a late stage in the synthesis. However, in view of the strongly
basic conditions needed to carry out the SN2′ reaction (organo-
lithium base and organomagnesium nucleophile), a masked or
protected silanol would be required. Ultimately, the silanol
would be unveiled and converted to the sodium salt, and the
stereochemical course of the cross-coupling reaction would be
determined.
Scheme 5
2. Synthesis of the r-Substituted Allylic Silane. The synthesis
of the R-substituted allylic silane commenced with preparation
(24) Tan, Z.; Negishi, E.-I. Org. Lett. 2006, 8, 2783–2785.
(25) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129–
6139.
(23) (a) Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979, 101, 1035–
1036. (b) Goering, H. L.; Kantner, S. S.; Tseng, C. C. J. Org. Chem.
1983, 48, 715–721. (c) Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem.
Soc. 1998, 120, 12998–12999. (d) Smitrovich, J. H.; Woerpel, K. A.
J. Org. Chem. 2000, 65, 1601–1614.
(26) (a) Speier, J. L.; Webster, J. A.; Barnes, G. H. J. Am. Chem. Soc.
1957, 79, 974–979. (b) Chandra, G.; Lo, P. Y.; Hitchcock, P. B.;
Lappert, M. F. Organometallics 1987, 6, 191–192.
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J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010 3615

A R T I C L E S
Denmark and Werner
Scheme 6
The SN2′ reaction was carried out under conditions developed
by Woerpel without further optimization.23d iso-Butylmagne-
sium chloride was chosen as the nucleophile because it provides
good yields and high geometrical purity of the allylic silane
product.23c,d Also, the steric bulk of the iso-butyl group should
ensure a high selectivity for the formation of an E double bond
in the product of the cross-coupling reaction (later in the
synthetic sequence) and thereby simplify the interpretation of
the transmetalation. Thus, the SN2′ reaction was effected by
deprotonation of the phenyl carbamate with methyllithium at
-78 °C, followed by addition of copper iodide and i-BuMgCl
to provide the protected allylic silanol (R)-(Z)-17 in good yield
(79%) and high geometrical purity (94:6, Z/E) as determined
by capillary gas chromatography.
3. Synthesis of the r-Substituted Allylic Silanolate Salt
and Derivatization for Enantiomeric Analysis. At this point all
batches of (R)-(Z)-17 were combined for the synthesis of the
silanol and its derivatization for enantiomeric analysis, and to
provide silanolate of uniform enantiomeric and geometrical
purity for the cross-coupling reactions. The tert-butyl protecting
group was readily removed with 0.2 M HCl to afford a 93%
yield of the R-substituted allylic silanol (R)-(Z)-18 (Scheme 6).27
Chemical degradation of (R)-(Z)-18 provided material suitable
for determination of enantiomeric composition and absolute
configuration.28 This transformation was accomplished by
diimide reduction,29 Tamao-Fleming oxidation,30 and esteri-
fication to afford the 3,5-dinitrobenzoate (DNB) of (S)-2-
methylheptan-4-ol ((S)-19).31 The DNB (S)-19 was determined
to be 94:6 er by chiral stationary phase, supercritical fluid
chromatography (CSP-SFC), and the absolute configuration of
the stereogenic center was assigned by comparison of optical
rotation data.32 The correlation of the R configuration of 18
along with its enantiomeric and geometric composition is
congruent with the stereochemical model proposed for the
copper-catalyzed SN2′ reaction of Grignard reagents with allylic
carbamates.23d The remaining silanol (R)-(Z)-18 was then
deprotonated with washed sodium hydride in hexane to provide
Na+(R)-(Z)-18- (97% yield) as a stable, free-flowing powder.
4. Optimization of the Cross-Coupling Reaction. The cross-
γ-selectivity.34 Previous studies had established that increasing
the π-acidity of the olefinic ligand increased the γ-selectivity
of the coupling reaction.16 Gratifyingly, when only 5 mol % of
4,4′-(trifluoromethyl)dibenzylideneacetone35 22 was employed
with allylpalladium chloride dimer (APC) as the precatalyst,
an increase in γ-selectivity was observed (entry 2). Increasing
the ligand loading to 20 mol % (4.0 equiv/Pd) further increased
the γ-selectivity of the reaction (entry 3). Moreover, the loading
of APC could be reduced to 0.5 mol % while maintaining high
yield (entry 4). However, to preserve high γ-selectivity, the
loading of 22 with respect to the limiting reagent (3a) needed
to be kept at 20 mol % regardless of the palladium loading
(entries 4 and 5).
Table 1. Cross-Coupling Reaction Optimizationa
33
coupling of Na+(()-(Z)-18- was first attempted using the
conditions optimized for the reaction of sodium 2-butenyldi-
methylsilanolate (Na+2-).16 Thus, Na+(()-(Z)-18-, bromoben-
zene, Pd(dba)2, and nbd were combined in toluene and heated
to 70 °C in a preheated oil bath (Table 1, entry 1). Surprisingly,
these conditions provided the allylated product with only modest
entry
Pd source
loading, %
ligand
loading, %
yield,b
%
(E)-20a/21ac
1d
2
Pd(dba)2
APC
APC
APC
APC
5.0
2.5
2.5
0.5
0.5
nbd
22
22
22
22
5.0
5.0
20
10
20
76
74
75
70
84
6.2:1
8.6:1
33:1
14:1
32:1
3e
4
5
a Reactions performed on 0.25 mmol scale. b Yield of (E)-20a
determined by GC analysis. c Peak area ratio of crude reaction mixture
determined by GC analysis. d 2.0 equiv of Na+(()-(Z)-18- used.
e Average of three experiments.
(27) Denmark, S. E.; Baird, J. D. Tetrahedron 2009, 65, 3120–3129.
(28) Woerpel has established the stereochemical outcome of the copper-
catalyzed SN2′ reaction of Grignard reagents with allylic carbamates;
see ref 23d. However, the stereochemical identity and purity of the
R-substituted allylic silanol was too important to be assumed from
analogous precedent.
5. Preparative Cross-Coupling Reactions of the r-Substituted
Allylic Silanolate Na+(R)-(Z)-18-. The optimized conditions for reac-
tion of Na+(()-(Z)-18- [(1.5 equiv), aryl bromide 3 (1.0 equiv), APC
(29) (a) Corey, E. J.; Mock, W. L.; Pasto, D. J. Tetrahedron Lett. 1961,
11, 347–352. (b) Hu¨nig, S.; Mu¨ller, H. R. Angew. Chem., Int. Ed.
Engl. 1962, 1, 213–214.
(30) (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun.
1984, 29–31. (b) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M.
Organometallics 1983, 2, 1694–1696.
(34) The crotylation of bromobenzene with sodium 2-butenyldimethylsi-
lanolate under these conditions provides high γ-selectivity (26:1) as
determined by GC/MS analysis of the crude reaction mixture. See ref
15.
(35) (a) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Org. Lett. 2004, 6,
4435–4438. (b) Fairlamb, I. J. S. Org. Biomol. Chem. 2008, 6, 3645–
3656.
(31) Cho, B. T.; Kim, D. J. Tetrahedron 2003, 59, 2457–2462.
(32) (S)-2-Methylheptan-4-ol: [R]2D2 +11.5 (c ) 1.1, MeOH). Lit. [R]2D2
+13.3 (c ) 1.1, MeOH); see: Takenaka, M.; Takikawa, H.; Mori, K.
Liebigs Ann. 1996, 1963–1964.
(33) Racemic Na+18- was used for cross-coupling optimization and was
synthesized by a similar route using racemic 13.
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Stereochemical Course of Cross-Coupling of Allylic Silanolates
A R T I C L E S
(0.5-2.5 mol % wrt 3), and 22 (20 mol % wrt 3) in toluene at 70 °C]
were then employed in the cross-coupling of enantioenriched allylic
silanolate Na+(R)-(Z)-18- (94:6 er) with a variety of aromatic bromides
(Table 2). The substrates chosen for these experiments were selected
to illustrate the scope of compatible aryl bromides including unsub-
stituted, ortho-substituted, electron-rich, electron-poor, and heteroaro-
matic bromides. Bromobenzene (3a) (entry 1), along with electron-
rich (entry 5) and electron-poor (entry 7 and 8) aryl bromides without
sterically biasing substituents in the ortho position, provided good yield
and high isomeric purity favoring the E-γ-coupled product (87-98%
E-γ). Likewise, aromatic bromides with ortho substitution cross-
coupled in good yield and isomeric purity (entries 2-4). In addition,
a heteroaromatic bromide cleanly coupled to afford the E-γ-coupled
product selectively (entry 6).
purpose, the allylic arenes (R)-(E)-20a-e and (R)-(E)-20g,h
were transformed to 2-arylpropanols (S)-23a-e and (S)-23g,h
by ozonolysis followed by in situ ozonide reduction with sodium
borohydride. The enantiomeric composition of the 2-arylpro-
panols was then determined by CSP-SFC analysis. Significantly,
five of the substrates examined were of 98:2 er (Table 3, entries
1-3, 5, and 7), and the other three were of g99:1 er (entries 4,
6, and 8). In addition, derivatization produced five 2-arylpro-
panols with known optical rotations and assigned absolute
configurations (entries 1, 3-5, and 7) and thus allowed for
unambiguous assignment of the configuration of the benzylic
stereogenic center.
Table 3. Cross-Coupled Product Derivatization and Enantiomeric
Analysis
Table 2. Preparative Cross-Couplings of Na+(R)-(Z)-18-
c
entry
product
yield,a
%
erb
[R]D
lit. [R]D
1
2
3
4
5
6h
7
8
23a
23b
23c
23d
23e
20f
66
59
72
53
75
N/A
47
60
98:2
98:2
98:2
99:1
98:2
-14.2
-5.32
+26.5
+5.27
-15.5
-10.9
-14.1
-10.0
-11.7, (S)d
N/A
+19.2, (S)e
-4.1, (R)f
-15.4, (S)g
N/A
>99:1
23g
23h
98:2
+13.3, (R)i
N/A
>99:1j
a Yield of isolated, purified material. b Determined by CSP-SFC
analysis of silica gel chromatographed products. c See Supporting
Information for details. d Reference 36. e Reference 37. f Reference 38.
g Reference 39. h Derivatization was not necessary for enantiomeric
analysis. i Reference 40. j Further derivatization of the alcohol to a
3,5-dinitrophenylcarbamate was necessary for analysis of enantiomeric
composition.
Discussion
To determine the stereochemical course of the cross-coupling
of allylic silanolate salts, enantioenriched R-substituted allylic
silanolate Na+(R)-(Z)-18- was synthesized and coupled with
aromatic bromides under palladium catalysis. The starting
silanol, (R)-(Z)-18, and the crotylation products, (R)-(E)-20a-e
and (R)-(E)-20g,h, were degraded to known materials to
establish their enantiomeric compositions and assign their
absolute configurations. These synthetic sequences allowed the
process of diastereodifferentiation,15 and thus the enantiospeci-
ficity of the cross-coupling reaction could be determined. The
products of the cross-coupling reaction, (R)-(E)-20a-h, from
enantioenriched Na+(R)-18- were of high enantiomeric and
geometrical purity. In addition, these compounds all possessed
the same absolute configuration at the stereogenic center (R)
and geometry of the double bond (E), suggesting a common
pathway for the transmetalation of allylic silanolates and a direct
relationship between the educt and the product.
a Reactions performed on 2.0 mmol scale. b Yield of isolated
analytically pure material. c Ratio of the E-γ isomer relative to E-R, Z-γ,
and/or Z-R isomer(s) of purified products determined by GC analysis.
d 0.5 mol % APC used. e 2.5 mol % APC used. f Determined by 1H
NMR analysis (103:1 S/N).
(36) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi,
Y. Org. Lett. 2008, 10, 1719–1722.
(37) Menicagli, R.; Piccolo, O.; Lardicci, L. Chim. Ind. 1975, 57, 499–
500.
(38) Lebibi, J.; Pelinski, L.; Maciejewski, L.; Brocard, J. Tetrahedron 1990,
46, 6011–6020.
(39) Spino, C.; Beaulieu, C.; Lafreniere, J. J. Org. Chem. 2000, 65, 7091–
7097.
6. Derivatization of Cross-Coupled Products for
Enantiomeric Analysis. The products of the preparative cross-
coupling reactions required derivatization for determination of
enantiomeric composition and absolute configuration. For this
(40) Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713–1716.
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J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010 3617

A R T I C L E S
Denmark and Werner
1. Site-Selectivity of the Cross-Coupling of Na+(R)-
(Z)-18-. The cross-coupling of Na+(R)-(Z)-18- with aromatic
bromides produced the E-γ-coupled isomer with high selectivity,
although the quantity and number of isomeric products varied
depending upon the aryl bromide employed. For example, very
high E-γ-selectivities were observed for bromobenzene (98%
E-γ) and 4-bromoanisole (97% E-γ), and the lowest E-γ-
selectivity was observed with 4-bromobenzotrifluoride (87%
E-γ). These results are similar to those previously reported
wherein aryl bromides bearing electron-withdrawing substituents
afforded lower γ-selectivity (i.e., increased R-coupling) when
π-acidic olefin ligands were used to facilitate reductive elimina-
tion.16 Moreover, the reaction of bromobenzene with Na+(R)-
(Z)-18- produced only two isomers as determined by capillary
GC. The minor isomer was the R-coupled product as determined
by 1H NMR analysis of a cross-coupling carried out under less
γ-selective conditions (Pd(dba)2, nbd).41 Chemical degradation
of the products (S)-23a-e and (S)-23g,h allowed for the removal
of the R-coupled isomer(s); therefore, their presence did not
complicate the stereochemical analysis of the γ-coupled products.
2. Stereospecificity of the Cross-Coupling of Na+(R)-
(Z)-18-. The products of the cross-coupling reaction were
degraded for determination of enantiomeric composition and
absolute configuration. Five of the seven derivatives were known
compounds with reported optical rotations and assigned absolute
configurations. Therefore, an unambiguous assignment of S to
the configuration of the benzylic stereogenic center of 23a,
23c-e, and 23g was possible by comparison of the sign of their
optical rotations.42 The enantiomeric analysis of the 2-arylpro-
panols and (R)-(E)-20f by CSP-SFC revealed very high enan-
tioenrichment (>98:2 er). Thus, the conversion of silanolates
Na+(R)-(Z)-18- to the cross-coupling products (R)-(E)-20 oc-
curred with complete enantiospecificity.22,43
4. Stereochemical Analysis. Four diastereomeric 1-methyl-
iso-heptenyl arenes can be formed from a γ-selective coupling
of Na+(R)-(Z)-18- (Figure 4). These four products represent
pairwise combinations of the two possible olefin geometries and
the two possible configurations at the newly generated stereo-
center, which in turn are established by (1) the reactive
conformation of Na+(R)-(Z)-18- in the transmetalation and (2)
the stereochemical course of the SE′ process (syn or anti). Figure
4 illustrates the consequences of these two variables operating
independently. In limiting conformer A, the hydrogen on the
stereogenic center is in the olefin plane, which will lead to the
formation of an E double bond in the product. An intramolecular
transmetalation corresponds to a syn SE′ pathway and leads to
the formation of (R)-(E)-20. Alternatively, an intermolecular
transmetalation can proceed via both syn and anti SE′ pathways
to afford both (R)-(E)-20 and (S)-(E)-20, although the anti
process is expected to be favored on the basis of extensive
precedent (see Background section). In limiting conformer B,
the iso-butyl group is synplanar to the olefin, which will lead
to the formation of a Z double bond in the product. Application
of the same analysis to conformer B predicts the formation of
(S)-(Z)-20 from an intramolecular transmetalation (syn SE′), or
both (S)-(Z)-20 and (R)-(Z)-20 from an intermolecular trans-
metalation, the latter arising from an anti SE′ pathway.
3. Mechanistic Considerations. Previous studies in these
laboratories on the cross-coupling of alkenyl-44 and arylsilano-
lates45 have led to the formulation of a mechanism that involves
the formation of an arylpalladium silanolate by attack of the
starting silanolate salt on the arylpalladium(II) halide. The
intermediacy of a discrete species containing an Si-O-Pd
linkage has since been demonstrated in a number of different
cross-coupling reactions.46 Moreover, evidence for an Si-O-Pd-
containing intermediate in the cross-coupling of allylic silano-
lates was also forthcoming during optimization of the reactions
with Na+2-.16 Specifically, when t-Bu2P(2-biphenyl) was used
in combination with Pd(dba)2 as the catalyst, only trace amounts
of products resulting from carbon-carbon bond formation were
observed; the major product of the reaction was the result of
carbon-oxygen bond formation. This result is interpreted in
terms of a direct reductive elimination of the arylpalladium(II)
silanolate which precludes transmetalation.
Figure 4. Possible pathways for the transmetalation of allylic silanolates
(R ) i-Bu; RE, reductive elimination).
(41) Na+18- (1.5 equiv), 3a (1.0 equiv, 1.0 mmol), Pd(dba)2 (5 mol %),
nbd (5 mol %), toluene, 70 °C, 69% yield (5.2:1 E-γ/R).
(42) By analogy, the absolute configurations of 23b, 20f, and 23h are
assigned as S, R, and S, respectively.
From the results described above, we established that the
product from all cross-coupling reactions possessed the structure
(R)-(E)-20 and is thus believed to arise from an intramolecular
transmetalation via limiting conformer A through a syn SE′
process. A more detailed view of a transition-state structure that
leads to (R)-(E)-20 is illustrated in Scheme 7. Under the
assumption that a syn SE′ pathway arises from an intramolecular
transmetalation, a chairlike transition-state structure can be
considered. In structure Wiii, the Si-O-Pd linkage controls the
delivery of the palladium electrophile to the γ-terminus of the
allylic silane. The palladium is tricoordinate, and the alkene
(43) The fact that the enantiospecificity of this process is greater than 100%
is most likely caused by a hidden kinetic resolution. The minor
component in Na+(R)-(Z)-18- is actually Na+(S)-(E)-18-, which arises
from the copper-catalyzed SN2′ reaction. The lesser kinetic competence
of Na+(S)-(E)-18- has the secondary effect of removing the contribu-
tion of the minor enantiomer to the product mixture; see refs 23c, d.
(44) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876–
4882.
(45) Denmark, S. E.; Smith, R. C. J. Am. Chem. Soc. 2010, 132, 1243–
1245.
(46) Denmark, S. E. J. Org. Chem. 2009, 74, 2915–2927.
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3618 J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010

Stereochemical Course of Cross-Coupling of Allylic Silanolates
A R T I C L E S
takes up the fourth coordination site in the square planar
complex. Although a true chair conformation is not realistically
feasible, nevertheless, a critical feature is the pseudo-equatorial
orientation of the iso-butyl group, which assures high selectivity
in the formation of an E double bond in the product. In addition,
the allylic methyl group is positioned orthogonal to the ligand
plane of palladium, which also avoids unfavorable steric
interactions.47 An alternative transition-state structure (ix) that
also involves an intramolecular delivery of the palladium moiety
suffers from severe 1,3-diaxal steric strain between the iso-butyl
and allylic methyl groups. This transition-state structure would
lead to the formation of (S)-(Z)-20, which is not observed. Thus,
the iso-butyl group played a key role in facilitating the
interpretation of the transmetalation step.
Scheme 7a
Figure 5. Refined catalytic cycle.
intimate connectivity between the palladium moiety and
the stereodetermining transmetalation event bodes well for the
development of catalytic, enantioselective cross-coupling reac-
tions. The results from these studies will be disclosed in due
course.
a Si denotes SiMe2 and was abbreviated for clarity.
Experimental Section
A refined catalytic cycle can now be constructed for the
palladium-catalyzed cross-coupling of allylic silanolate salts with
aromatic bromides (Figure 5). The cycle begins with oxidative
addition of the aromatic bromide onto a palladium(0) complex.
Displacement of bromide by the allylic silanolate Na+(R)-(Z)-
18- forms the palladium(II) silanolate x. Transmetalation
through a syn SE′ process forges a bond between the γ-carbon
of Na+(R)-(Z)-18- and palladium via transition structure Wiii.
Reductive elimination of the σ-bound palladium species xi is
facilitated by the π-acidic olefin ligand and preempts σ-π
isomerization via xii and xiii. The γ-coupled product, (R)-(E)-
20, is formed with excellent enantio- and geometrical specificity,
completing the catalytic cycle.
For general experimental discussion, see the Supporting Informa-
tion.
Preparation of (R)-((E)-1,5-Dimethyl-2-hexenyl)benzene
((R)-(E)-20a) from Bromobenzene Using Na+(R)-18-. To a 50-
mL, single-necked, round-bottomed flask containing a magnetic stir
bar and equipped with a three-way argon inlet capped with a septum
were added APC (3.7 mg, 0.010 mmol, 0.0050 equiv) and dba(4,4′-
CF3) 22 (148 mg, 0.40 mmol, 0.20 equiv). The flask was then
sequentially evacuated and filled with argon three times. Bro-
mobenzene (314 mg, 2.0 mmol) was then added by syringe. The
R-substituted allylic silanolate Na+(R)-18- (625 mg, 3.0 mmol, 1.5
equiv), preweighed into a 10-mL two-necked, round-bottomed flask
in a drybox, was then dissolved in toluene (4.0 mL) and added by
syringe. The reaction mixture was heated in a preheated oil bath to
70 °C with stirring under argon. After 24 h, the mixture was cooled
to room temperature and filtered through silica gel (2 cm × 1 cm)
in a glass-fritted funnel (coarse, 2 cm × 5 cm), and the filter cake
was washed with ether (3 × 15 mL). The filtrate was concentrated
in Vacuo, and the residue was purified by silica gel chromatography
(30 mm × 20 cm, hexane), C-18 reverse-phase chromatography
(25 mm × 16 cm, MeOH/H2O, 9:1f20:1), and Kugelrohr distil-
lation (70 °C, 0.7 mmHg, ABT) to afford 288 mg (76%) of (R)-
Conclusion
An enantioenriched, R-substituted, allylic silanolate salt
undergoes palladium-catalyzed cross-coupling with aromatic
bromides with excellent stereospecificity. The transmetalation
event proceeds through a syn SE′ mechanism in which the
stereogenic center in the educt controls the configuration of the
newly formed stereogenic center in the product. These studies
allow the construction of a detailed model of the stereodeter-
mining step of the coupling of allylic silanolate salts. In addition,
the high enantioinduction of all aromatic bromides surveyed
implies that this pathway is general for many substrate types.
The combination of the crucial Si-O-Pd linkage and the
1
(E)-20a as a clear, colorless oil. Data for (R)-(E)-20a: H NMR
(500 MHz, CDCl3) δ 7.35-7.32 (m, 2 H), 7.27-7.20 (m, 3 H),
5.62 (ddt, J ) 15.3, 6.7, 1.2 Hz, 1 H), 5.48 (dtd, J ) 15.3, 7.1, 1.2
Hz, 1 H), 3.47 (ap, J ) 7.0 Hz, 1 H), 1.96-1.93 (m, 2 H),
1.69-1.61 (m, 1 H), 1.38 (d, J ) 7.0 Hz, 3 H), 0.92 (d, J ) 3.5
Hz, 3 H), 0.91 (d, J ) 3.5 Hz, 3 H); 13C NMR (126 MHz, CDCl3)
δ 146.5, 136.1, 128.3, 128.0, 127.2, 125.9, 42.3, 41.9, 28.5, 22.33,
22.27, 21.6; IR (film) ν 3027, 2959, 2927, 2870, 1602, 1492, 1452,
1384, 1367, 1017, 971, 758, 698, 537; MS (EI, 70 eV) m/z 188,
145, 131, 118, 105, 91, 77; [R]2D3 -5.80 (c ) 2.1, CHCl3); Rf 0.72
(hexane). Anal. Calcd for C14H20: C, 89.29; H, 10.71. Found: C,
89.06; H, 10.75.
(47) In other closed, transition-state structures of palladium-catalyzed
allylations, the vinylic methyl group positioned coplanar with the
square plane of palladium ligands was suggested to be disfavored.
See: Iwasaki, M.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K.
J. Am. Chem. Soc. 2007, 129, 4463–4469.
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J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010 3619

A R T I C L E S
Denmark and Werner
Preparation of (S)-ꢀ-Methyl-benzeneethanol ((S)-23a) from
(R)-((E)-1,5-Dimethyl-2-hexenyl)benzene. To a 25-mL, single-
necked, round-bottomed flask containing a magnetic stir bar,
equipped with a three-way adapter and gas dispersion tube, were
combined (R)-((E)-1,5-dimethyl-2-hexenyl)benzene (161 mg, 0.857
mmol) and CH2Cl2 (17 mL). The solution was then cooled to -78
°C under nitrogen. Ozone (scrubbed with 2-propanol/dry ice) was
then bubbled through the solution until it turned blue (approximately
2 min). Nitrogen was then bubbled through the solution until
colorless. While still at -78 °C, a freshly prepared solution of
sodium borohydride (324 mg, 8.57 mmol, 10 equiv) in ethanol (17
mL) was added dropwise by syringe. The contents were then
allowed to warm to room temperature with stirring and without
removal of the cooling bath. After 18 h, the mixture was diluted
with ether (25 mL), and 0.2 M HCl (50 mL) was added slowly by
pipet. The biphasic mixture was then stirred for 1 h. The aqueous
phase was separated in a 250-mL separatory funnel and was
extracted with ether (2 × 25 mL). The three separate organic
extracts were sequentially washed with H2O (2 × 25 mL) and brine
(25 mL) and then combined, dried over MgSO4 until flocculent,
and filtered. The filtrate was concentrated in Vacuo, and the residue
was purified by silica gel chromatography (20 mm × 20 cm,
pentane/EtOAc, 4:1f1:1 pentane/EtOAc) followed by Kugelrohr
distillation (90 °C, 1.5 mmHg, ABT) to afford 77 mg (66%) of
(S)-23a as a clear, colorless oil. Data for (S)-23a:36 1H NMR (500
MHz, CDCl3) δ 7.37-7.34 (m, 2 H), 7.27-7.25 (m, 3 H), 3.7 (d,
J ) 6.8 Hz, 2 H), 2.96 (sextet, J ) 7.0 Hz, 1 H), 1.62 (br, 1 H),
1.30 (d, J ) 7.0 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 143.7,
128.6, 127.4, 126.6, 68.6, 42.4, 17.5; IR (film) ν 3356, 3084, 3062,
3028, 2962, 2930, 2875, 1602, 1494, 1452, 1384, 1193, 1092, 1068,
1034, 1014, 911, 761, 700, 606; MS (EI, 70 eV) m/z 136, 105, 91,
80; HRMS calcd for C9H12O 136.0888, found 136.0887; [R]2D3 -14.2
(c ) 1.6, CHCl3); Rf 0.21 (hexanes/EtOAc, 4:1).
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (R01 GM63167) and
Johnson-Matthey for the gift of Pd2(dba)3. N.S.W. thanks the
Aldrich Chemical Co. for a Graduate Student Innovation Award
and Eli Lilly and Co. for a Graduate Fellowship.
Supporting Information Available: Detailed experimental
procedures and full characterization of all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA910804U
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3620 J. AM. CHEM. SOC. VOL. 132, NO. 10, 2010