Cross-coupling of aromatic bromides with allylic silanolate salts

Article abstract of DOI:10.1021/ja805951j

The sodium salts of allyldimethylsilanol and 2-butenyldimethylsilanol undergo palladium-catalyzed cross-coupling with a wide variety of aryl bromides to afford allylated and crotylated arenes. The coupling of both silanolates required extensive optimization to deliver the expected products in high yields. The reaction of the allyldimethylsilanolate takes place at 85°C in 1,2-dimethoxyethane with allylpalladium chloride dimer (2.5 mol %) to afford 73-95% yields of the allylation products. Both electron-rich and sterically hindered bromides reacted smoothly, whereas electron-poor bromides cross-coupled in poor yield because of a secondary isomerization to the 1-propenyl isomer (and subsequent polymerization). The 2-butenyldimethylsilanolate (E/Z, 80:20) required additional optimization to maximize the formation of the branched (γ-substitution) product. A remarkable influence of added alkenes (dibenzylideneacetone and norbornadiene) led to good selectivities for electron-rich and electron-poor bromides in 40-83% yields. However, bromides containing coordinating groups (particularly in the ortho position) gave lower, and in one case even reversed, selectivity. Configurationally homogeneous (E)-silanolates gave slightly higher γ-selectivity than the pure (Z)-silanolates. A unified mechanistic picture involving initial γ-transmetalation followed by direct reductive elimination or σ-π isomerization can rationalize all of the observed trends.

Full text of DOI:10.1021/ja805951j

Published on Web 11/11/2008
Cross-Coupling of Aromatic Bromides with Allylic Silanolate
Salts
Scott E. Denmark* and Nathan S. Werner
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
Received July 29, 2008; E-mail: denmark@scs.uiuc.edu
Abstract: The sodium salts of allyldimethylsilanol and 2-butenyldimethylsilanol undergo palladium-catalyzed
cross-coupling with a wide variety of aryl bromides to afford allylated and crotylated arenes. The coupling
of both silanolates required extensive optimization to deliver the expected products in high yields. The
reaction of the allyldimethylsilanolate takes place at 85 °C in 1,2-dimethoxyethane with allylpalladium chloride
dimer (2.5 mol %) to afford 73-95% yields of the allylation products. Both electron-rich and sterically hindered
bromides reacted smoothly, whereas electron-poor bromides cross-coupled in poor yield because of a
secondary isomerization to the 1-propenyl isomer (and subsequent polymerization). The 2-butenyldimeth-
ylsilanolate (E/Z, 80:20) required additional optimization to maximize the formation of the branched (γ-
substitution) product. A remarkable influence of added alkenes (dibenzylideneacetone and norbornadiene)
led to good selectivities for electron-rich and electron-poor bromides in 40-83% yields. However, bromides
containing coordinating groups (particularly in the ortho position) gave lower, and in one case even reversed,
selectivity. Configurationally homogeneous (E)-silanolates gave slightly higher γ-selectivity than the pure
(Z)-silanolates. A unified mechanistic picture involving initial γ-transmetalation followed by direct reductive
elimination or σ-π isomerization can rationalize all of the observed trends.
Introduction
Allylated arenes represent an important class of substituted
aromatic compounds since many natural products possess an
allylic arene component.1 Moreover, the allylic substituent is
synthetically useful because of the multitude of asymmetric,
oxidative, and reductive transformations that olefins undergo.2
In addition, the olefin functional group of an allylated arene
can serve in complex molecule synthesis in a number of ways,
e.g., as a dienophile3 or metathesis partner.4 Therefore, methods
for the direct installation of an allyl group are desirable.
Figure 1. Polar allylation disconnections.
The two fundamental disconnections for the polar con-
struction of allylic arenes are shown in Figure 1.5 The
classical manifestation of the aryl nucleophile/allyl electro-
phile disconnection A is the Friedel-Crafts allylation of an
aromatic ring using allylic halides or alcohols and an acid
catalyst.6 The Friedel-Crafts reaction often produces a
complex mixture of products stemming from instability of
the product in the reaction conditions. Additionally, in
electrophilic aromatic substitution the arene partner must be
activated, and substituted benzene substrates suffer from low
site-selectivity of the coupling. Alternatively, allylic arenes
(1) (a) Wenkert, E.; Fernandes, J. B.; Michelotti, E. L.; Swindell, C. S.
Synthesis 1983, 701–703. (b) Demotie, A.; Fairlamb, I. J. S.; Lu, F.-
J.; Shaw, N. J.; Spencer, P. A.; Southgate, J. Bioorg. Med. Chem.
Lett. 2004, 14, 2883–2887. (c) Trost, B. M.; Toste, F. D. J. Am. Chem.
Soc. 2000, 122, 11262–11263. (d) Trost, B. M.; Thiel, O. R.; Tsui,
H.-C. J. Am. Chem. Soc. 2002, 124, 11616–11617. (e) Corey, E. J.;
Weigel, L. O.; Floyd, D.; Bock, M. G. J. Am. Chem. Soc. 1978, 100,
2916–2918.
(2) (a) ComprehensiVe Organic Functional Group Transformations;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Elsevier Science
Inc.: New York, 1995. (b) ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: New
York, 1999. (c) The Chemistry of Alkenes; Patai, S., Zabicky, J., Eds.;
The Chemistry of Functional Groups Series; John Wiley and Sons:
New York, 1964; Vols. 1 and 2. (d) Supplement A: The Chemistry of
Double-Bonded Functional Groups; Patai, S., Ed.; The Chemistry of
Functional Groups Series, Parts 1 and 2; John Wiley and Sons: New
York, 1997; Vols. 1 and 2.
(3) Brown, M. A.; Kerr, M. A. Tetrahedron Lett. 2001, 983–985.
(4) (a) Fu¨rstner, A.; Thield, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731–
3734. (b) Yan, B.; Spilling, C. D. J. Org. Chem. 2004, 69, 2859–
2862.
(5) Among the classical nonpolar constructions of allylated arenes, the
aromatic Claisen rearrangement is most noteworthy. (a) Rhodes, S. J.;
Raulins, N. R. Org. React. 1975, 22, 1–252. (b) Castro, A. M. L. Chem.
ReV. 2004, 104, 2939–3002.
(6) (a) Price, C. C. Org. React. 1946, 3, 1–82. (b) Improved yields are
observed using a modified method with a multicomponent Lewis acid
system: Kodomari, M.; Nawa, S.; Miyoshi, T. J. Chem. Soc., Chem.
Commun. 1995, 1895–1896.
(7) (a) Posner, G. H. Org. React. 1975, 22, 253–400. (b) Rahman, N. T.;
Nahar, S. K. J. Organomet. Chem. 1987, 329, 133–138. (c) Hirao, T.;
Misu, D.; Yao, K.; Agawa, T. Tetrahedron Lett. 1986, 27, 929–932.
9
16382 J. AM. CHEM. SOC. 2008, 130, 16382–16393
10.1021/ja805951j CCC: $40.75
2008 American Chemical Society

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
are prepared by the reaction of arylcoppers7a or arylmagne-
sium halides7b,c with allylic halides. The use of reactive
Grignard reagents is restricted to substrates without sensitive
functional groups. A palladium-catalyzed variant of this
disconnection is also well known in which arylmetal nucleo-
philes react with π-allylpalladium(II) electrophiles.1b,8
The disconnection B in Figure 1 represents the combination
of an aryl electrophile and an allyl nucleophile. Examples of
this approach include palladium- and copper-catalyzed reaction
of aryl halides with allylic Grignard reagents.9 Milder versions
of this process can be accomplished through the use of allylic
organometallic donors based on tin, boron, and silicon. These
reagents react with aromatic halides (and their equivalent) in
the presence of palladium(0) to afford allylated arenes (Scheme
1). Because the reactive site of the electrophile is predetermined
by placement of the halide, a high degree of site-selectivity on
the arene is achieved.10 With unsubstituted or symmetrically
substituted allylic donors, allylic site-selectivity is not an issue.
However, with unsymmetrically substituted allylic donors, for
example 2-butenyl (Scheme 1, R ) Me), the coupling can afford
a mixture of products: a branched, γ-coupled product along with
linear, R-coupled products as E and Z isomers.
R-coupled products is observed.14 Tsuji was able to obtain
modest yields of the (E)-R-coupled product for a narrow
substrate scope using triphenylarsine and LiCl. However, when
triphenylphosphine was employed, the γ-coupled product was
isolated albeit in low yield.15
A variety of allylboronic acid derivatives participate in cross-
coupling reactions with electron-rich and electron-poor aryl
bromides and triflates.16,17 However, the use of linear, substituted
allylic boranes has not been described. Unsubstituted allylic
boronic esters couple with a variety of aryl iodides and
bromides18 and a few vinyl triflates.19 Recently, Szabo showed
that allylboronic acids formed in situ couple with aromatic
iodides to afford high yields and site-selectivities.20 Ortho-
substituted organic electrophiles are incompatible, and aromatic
bromides are not reported. A γ-selective allylation of aryl
bromides using trifluoroborate donors has been reported by
Miyaura.21 Ligands with large bite angles are required to achieve
high γ-selectivity, e.g., 1,1′-bis(di-tert-butylphosphino)ferrocene.
An enantioselective variant of this reaction has been described
using a Mandyphos ligand (er > 88.5:11.5).22
Although not formally organometallic donors, homoallylic
alcohols do transfer an allyl group through a ꢀ-carbon elimina-
tion reaction.23 Yorimitsu and Oshima recently described the
palladium-catalyzed allylation of aromatic halides and triflates
in good yields with high γ-selectivity.24 Although an intriguing
process, the coupling reactions produce a seven- or nine-carbon
ketone byproduct while transferring only a four-carbon unit to
the electrophile.
Scheme 1
The first use of allylic silanes in palladium-catalyzed cross-
coupling was reported by Hiyama in 1991.25 The cross-coupling
reaction of substituted allylic trifluorosilanes with organic halides
or triflates, catalyzed by (Ph3P)4Pd and promoted by tetra-
butylammonium fluoride (TBAF), provides constitutionally pure
γ-coupled products. Studies on the mechanism of transmetala-
tion using enantiomerically enriched allylic silanes revealed that
electrophilic attack of palladium took place exclusively at the
γ-carbon.26 In addition, either the R- or γ-coupled product can
be formed in high yield from allylic trifluorosilanes with an
appropriate choice of ligand.27 In the palladium-catalyzed cross-
coupling reaction of (E)-2-butenyltrifluorosilane with 4-bro-
Allylic tin, boron, and silicon organometallic donors undergo
palladium-catalyzed allylation.11 Cross-coupling technology10
was first extended to the use of allylmetal donors by Migita in
1977, wherein allyltributyltin successfully transferred an allyl
group to an aryl halide in the presence of a palladium(0)
catalyst.12 Since then, the cross-coupling of allyltributyltin
donors has been exhaustively studied.13 A variety of electron-
rich and electron-poor aryl iodides, bromides, and triflates
undergo this reaction in good yield. However, when substituted
allylic tin reagents are used, a mixture of γ-coupled and
(14) (a) Godschalx, J.; Stille, J. K. Tetrahedron Lett. 1980, 21, 2599–2602.
(b) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478–5486. (c) Labadie, S. S. J. Org. Chem. 1989, 54, 2496–2498.
(15) Obora, Y.; Tsuji, Y.; Kobayashi, M.; Kawamura, T. J. Org. Chem.
1995, 60, 4647–4647.
(16) Doucet, H. Eur. J. Org. Chem. 2008, 2013–2030.
(17) Fu¨rstner has reported the use of an alkylborane, B-allyl-9-
borobicyclo[2.2.1]nonane (B-allyl-9-BBN), as a donor: Fu¨rstner, A.;
Seidel, G. Synlett 1998, 161–162.
(8) (a) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257–267.
(b) Orita, A.; Watanabe, A.; Tsuchiya, H.; Otera, J. Tetrahedron 1999,
55, 2889–2898. (c) Owton, W. M.; Brunavs, M. Synth. Commun. 1991,
21, 981–987. (d) Hayashi, T.; Konishi, M.; Kumada, M. J. Chem.
Soc., Chem. Commun. 1984, 107–108.
(18) Kotha, S.; Manoranjan, B.; Shah, V. R. Synlett 2005, 1877–1880.
(19) Occhiato, E. G.; Trabocchi, A.; Guara, A. J. Org. Chem. 2001, 66,
2459–2465.
(20) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo, K. J. Am. Chem.
Soc. 2006, 128, 8150–8151.
(9) (a) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg,
W. Organometallics 2007, 26, 6453–6461. (b) Johnson, D. K.;
Cravarri, J. P.; Ishmael, F. T.; Schillinger, K. J.; van Geel, T. A. P.;
Stratton, S. M. Tetrahedron Lett. 1995, 36, 8565–8568.
(10) Metal-Catalyzed Cross-Coupling Reactions; Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004.
(21) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35, 704–
705.
(22) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35, 1368–
1369.
(23) Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1–20.
(24) (a) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2006, 128, 2210–2211. (b) Iwasaki, M.; Hayashi, S.; Hirano, K.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 4463–4469.
(25) Hatanaka, Y.; Ebina, Y.; Hiyama, T. J. Am. Chem. Soc. 1991, 113,
7075–7076.
(11) Allyl germatranes are also known to undergo palladium-catalyzed
cross-coupling: Faller, J. W.; Kultyshev, R. G. Organometallics 2002,
21, 5911–5918.
(12) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977,
301–302.
(26) Hatanaka, Y.; Goda, K.-I.; Hiyama, T. Tetrahedron Lett. 1994, 35,
1279–1282.
(13) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1–652. (b) Gajare, A. S.; Jensen, R. S.; Toyota, K.; Yoshifuji, M.;
Ozawa, F. Synlett 2005, 144–148.
(27) Hatanaka, Y.; Goda, K.-I.; Hiyama, T. Tetrahedron Lett. 1994, 35,
6511–6514.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16383

A R T I C L E S
Denmark and Werner
Scheme 2
moacetophenone, those ligands with large bite angles, such as
1,3-bis(diphenylphosphino)butane (dppb) or alternatively Ph3P,
give rise to the γ-coupled product. In contrast, the use of ligands
with smaller bite angles, such as 1,3-bis(diphenylphosphino)-
ethane (dppe) or 1,3-bis(diphenylphosphino)propane (dppp),
yields the R-coupled product. These reactions demonstrate the
power of ligand control on the site-selectivity of cross-coupling
of substituted allylic organometallic donors. However, the
dependence of the method on the use of trifluorosilanes and
activation with TBAF limits its application.
Background
The use of organosilicon donors has many advantages.
Primary among these are the low toxicity28 and ease of synthesis
of these reagents from inexpensive materials. However, the
requirement for activation of organosilicon donors by fluoride
represents a drawback, as organic-soluble fluoride sources are
expensive, corrosive, and incompatible with silicon protecting
groups. The development of “fluoride-free” cross-coupling
reactions of organosilanes has been actively investigated in these
laboratories.29 We have discovered that organosilanols undergo
palladium-catalyzed cross-coupling in the presence of a variety
of Brønsted bases, including NaOt-Bu, Cs2CO3, and potassium
trimethylsilanolate.30 Under these conditions, alkenyl-,30 aryl-,31
and heteroarylsilanols32 cross-couple with aryl halides (and their
equivalent) in high yields. Moreover, isolated alkali metal
silanolates have been prepared and are stable, storable solids
that can be used directly in cross-coupling reactions.33,34
Initial studies in these laboratories of the fluoride-free
coupling of allylic silanols began with the reaction of allyldi-
methylsilanol (1) in the presence of potassium tert-butoxide and
1-iodonaphthalene under catalysis by allylpalladium chloride
dimer (APC).35 Unfortunately, this reaction afforded an insepa-
rable mixture of products in low yield (Scheme 2). However,
these experiments predated the introduction of preformed alkali
metal silanolates where strongly basic activators are not needed.
We believed that the mild conditions provided by the use of
these preformed reagents would allow for clean cross-coupling
reactions of allylic silanolate salts with organic electrophiles.
The goals of this work were to synthesize alkali metal allylic
dimethylsilanolate salts and study their stability and reactivity
in palladium-catalyzed cross-coupling reactions. Initial cross-
coupling experiments focused on sequential evaluation of
reaction conditions (stoichiometry, catalyst, solvent). After
optimal conditions were found, compatibility with aryl bromides
bearing a variety of functional groups was explored. Unsubsti-
tuted allylic silanolates were evaluated first to avoid complica-
tions arising from the site-selectivity of the coupling, after which
the use of substituted silanolates was examined.
Results
1. 2-Propenyl(allyl)silanol. 1.1. Synthesis of Sodium Allyl-
dimethylsilanolate (Na+1-). Alkali metal allylic silanolates were
prepared to evaluate their stability and reactivity in palladium-
catalyzed cross-coupling reactions. Allyldimethylsilanol (1) was
prepared from commercially available allyldimethylchlorosilane
using a modified procedure for the hydrolysis of silyl ethers
(Scheme 3).36,37 Deprotonation of silanol 1 using sodium hydride
in THF provided Na+1- as a white, free-flowing powder upon
concentration.38 The silanolate Na+1- could be stored at room
temperature in an anhydrous environment for months with no
discernible change in purity or reactivity.
Scheme 3
1.2. Optimization of Cross-Coupling of Na+1- with 4-Bro-
moanisole. Orienting experiments on the reactivity of Na+1- in
palladium-catalyzed cross-coupling reactions were carried out
under reaction conditions (APC dimer, toluene, 70 °C) used
successfully for the cross-coupling of other isolated
silanolates.29a The stoichiometric loading of Na+1-, with respect
to 4-bromoanisole (7a), was then examined (1.3-3.0 equiv).
A mixture of Na+1-, 4-bromoanisole, APC, biphenyl (internal
standard), and toluene was prepared in a drybox, removed, and
heated under argon at 70 °C in a preheated oil bath (Table 1).
Gratifyingly, 4-allylanisole (8a) was the major product in all
these experiments. The ratio of Na+1- to 7a was observed to
have a dramatic effect on the yield of 8a. Incomplete conversion
and low yield of the desired product were observed when 1.3
equiv of silanolate was used (entry 1). A significant increase in
yield of 8a was observed when the amount of Na+1- was
increased from 1.3 to 2.0 equiv (entry 2). Increasing the
(28) Cragg, S. T. In Patty’s Toxicology; Bingham, E., Cohrssen, B., Powell,
C. H., Eds.; Wiley: Hoboken, 2001; Vol. 7, pp 657-664.
(29) (a) Denmark, S. E.; Regens, C. S. Acc. Chem. Res., published online
Aug 6, 2008, http://dx.doi.org/10.1021/ar800037p. (b) Denmark, S. E.;
Baird, J. D. Chem. Eur. J. 2006, 12, 4954–4963. (c) Denmark, S. E.;
Sweis, R. F. Acc. Chem. Res. 2002, 35, 835–846.
(30) Denmark, S. E.; Sweis, R. J. J. Am. Chem. Soc. 2001, 123, 6439–
6440.
(31) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357–1360.
(32) Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6, 3649–3652.
(33) (a) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793–795. (b)
Denmark, S. E.; Kallemeyn, J. M. J. Am. Chem. Soc. 2006, 128,
15958–15959.
(34) A number of silanols and silanolate salts are now commercially
available: 4-methoxyphenyldimethylsilanol (Aldrich cat. no. 667951),
1,4-bis(hydroxydimethylsilyl)benzene (Aldrich cat. no. 497193), (N-
boc-2-pyrrolyl)dimethylsilanol (Aldrich cat. no. 669164), (N-boc-2-
indolyl)dimethylsilanol (Aldrich cat. no. 667900), dimethyl(2-
thienyl)silanol (Aldrich cat. no. 667099), dimethylphenylsilanol
(Aldrich cat. no. 667110), sodium dimethylphenylsilanolate (Aldrich
cat. no. 673269), and sodium 2-furyldimethylsilanolate (Aldrich cat.
no. 673250).
(36) Denmark, S. E.; Kallemeyn, J. M. Org. Lett. 2003, 5, 3483–3486.
(37) Allyldimethylchlorosilane 6 could also be made on multigram scale
by addition of allylmagnesium bromide to dimethyldichlorosilane, see:
Chihi, A.; Weber, W. Inorg. Chem. 1981, 20, 2822–2824.
(38) Attempts to synthesize the corresponding potassium salt of 1 by
treatment of 1 with potassium hydride resulted in viscous oils that
(35) Kallemeyn, J. M. Ph.D. Thesis, University of Illinois at Urbana-
1
Champaign, 2007.
showed multiple products by H NMR spectroscopic analysis.
9
16384 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
Table 3. Preparative Allylation of Substituted Aryl Bromidesa
Table 1. Effect of Silanolate Loading on Allylation of
4-Bromoanisolea
entry
Na+1-, equiv
conversion,b
%
yield,c
%
1
2
3
4
1.3
2.0
2.6
3.0
87
100
100
100
51
80
84
93
a Reactions performed on 0.4 mmol scale. b Based on consumption of
7a. c Yield of 8a by gas chromatography (GC) with respect to an
internal standard (biphenyl).
silanolate loading further resulted in only moderate increases
in the yield of 8a (entries 3 and 4). The remainder of the
optimization reactions used 2.5 equiv of silanolate because it
provided an acceptable yield without overloading.
The next set of experiments evaluated a number of different
variables in reactions executed under an inert atmosphere outside
the drybox (Table 2). As seen from the results in entry 1, the
reaction performed under otherwise identical conditions failed.
The outcome is not surprising, as no stabilizing ligands for
palladium were present. More robust conditions could be found
by using palladium(0) sources bearing stabilizing ligands. The
use of Pd(dba)2, containing the weakly coordinating olefin ligand
dibenzylideneacetone (dba), afforded a modest increase in
conversion of 7a (entry 2), whereas (Ph3P)4Pd, containing a
more strongly coordinating phosphine ligand, improved the
conversion markedly (entry 3). Coordinating solvents were next
examined. Although no reaction occurred in acetonitrile at 70
°C (entry 4), and reactions in THF led to incomplete conversion
after 6 h (entry 5), reactions in 1,2-dimethoxyethane (DME)
and dioxane both provided complete consumption of 7a (entries
6 and 7). The lower-boiling DME was chosen for preparative
reactions to expand substrate scope.
a Reactions performed on 1.0 mmol scale. b Yields of isolated,
purified products. c 3.0 equiv of Na+1- was used. d Dioxane at 100 °C,
1.0 equiv/Pd of Ph3PO, and 5.0 equiv of Na+1- were used.
Table 2. Benchtop Allylation of 4-Bromoanisolea,b
(entries 1-5 and 10). Electronically neutral aryl bromides cross-
coupled well using these conditions (entries 6, 8, and 9), and
silicon protecting groups were left intact (entry 7). The sterically
demanding 2-bromomesitylene (7j) could be allylated in good
yield, although 5.0 equiv of silanolate, Ph3PO (1.0 equiv/Pd),
and elevated temperature (100 °C) were required to effect
complete conversion (entry 11).
entry
Pd source
solvent
temp, °C time, h conversion,c
%
yield,d
%
1e
2f
3f
4
5
6
APC
Pd(dba)2
(Ph3P)4Pd toluene
APC
APC
APC
APC
toluene
toluene
70
70
70
70
65
20
20
20
20
6
10
31
72
trace
79
100
100
5
28
59
0
77
93
96
The substrate survey showed that electron-rich and electron-
neutral ortho-, meta-, and para-substituted aryl bromides reacted
well under optimized conditions, whereas electron-deficient aryl
bromides were less useful. Activated aryl bromides bearing
cyano, trifluoromethyl, carboxylate, and ketone functional
groups were consumed under the reaction conditions yet did
not provide any discernible products (GC/MS). After evaluating
many activated aryl bromides, we found that 4-bromobenzo-
phenone (7k) afforded one major product under the optimized
conditions. However, that product was 1-(E)-propenyl ketone
9, which arose from isomerization of the allyl unit (Scheme 4).
The isomerization to 9 was likely an ex post facto Brønsted
base-mediated process. To test this hypothesis, 4-allylbenzo-
phenone39 and sodium allyldimethylsilanolate (1.0 equiv) were
combined in deuterated THF, and the progress of the reaction
CH3CN
THF
DME
85
100
6
6
7
dioxane
a Reactions performed on 0.5 mmol scale. b The same batch of each
reagent was used, and all solvents were purified (see Supporting
Information). c Based on consumption of 7a. d Yield of 8a by GC with
respect to an internal standard (biphenyl). e Average of three
experiments. f 5.0 mol % catalyst used.
1.3. Preparative Allylations with Na+1- and Substituted
Aromatic Bromides. The scope of the allylation reaction was
next evaluated with a wide range of substrates (Table 3). Aryl
bromides bearing electron-donating groups such as NMe2 and
OMe underwent allylation readily under the optimized condi-
tions to provide good yields of the isolated, purified products
(39) Yokoyama, Y.; Ito, S.; Takahashi, Y.; Murakami, Y. Tetrahedron Lett.
1985, 26, 6457–6460.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16385

A R T I C L E S
Denmark and Werner
synthetic sequence, as the white, free-flowing powder Na+13-
consisted of an 80:20, E/Z mixture of isomers.
Scheme 4
2.2. Cross-Coupling of Na+13- with 1-Bromonaphthalene.
Initial attempts at cross-coupling Na+13- were performed under
the optimized conditions for allylation with 1-bromonaphthalene.42
Both R- and γ-products of this cross-coupling reaction have been
well characterized.24a,43 The combination of Na+13- (2.5 equiv)
with 7h using APC as the catalyst in DME at 85 °C produced an
inseparable 50:50 mixture of the γ- and R-coupled products in 58%
yield (Scheme 7). Although Na+13- cross-coupled in good yield,
the lack of site-selectivity stimulated a systematic optimization to
obtain one of the isomers in high constitutional purity.
1
was monitored by H NMR spectroscopy. After 3 h at 25 °C,
isomerization was not observed; however, after an additional
13 h at 50 °C, a 50:50 mixture of 8k and the conjugated double
bond isomer 9 was observed (Scheme 5).
Scheme 7
Scheme 5
In view of the known effects of ligands on the site-selectivity
of palladium-catalyzed allylation reactions,15,21,25 an initial
survey of ligands was undertaken (Table 4). In a coupling
performed in the absence of a ligand, a slight preference for
the γ-coupled product was observed (entry 1). Next, a variety
of mono- (entries 2 and 3) and bidentate (entries 5-8) phosphine
ligands were evaluated, as well as the more weakly coordinating
triphenylarsine (entry 4). Unlike the large differences in site-
selectivity observed between triphenylphosphine and 1,3-
bis(diphenylphosphino)propane in other palladium-catalyzed
crotylation reactions,21,25 these ligands had little effect on the
site-selectivity of the coupling (entries 2 and 5). Only small
variations in site-selectivity were seen with other bidentate
phosphine ligands (entries 6-8). Of the phosphines evaluated
under these conditions, Ph3P provided the highest, albeit modest,
selectivity (entry 2) and was chosen for further optimization.
Thus, allylated arenes bearing electron-withdrawing groups
are incompatible with the basic conditions of the reaction. This
incompatibility represents a limitation of the allylation process,
and a number of options to avoid this isomerization were
considered. The most appealing of these was the use of
substituted silanolates to reduce the kinetic acidity of the product
and increase the structural generality.
2. 2-Butenyl(crotyl)silanols. 2.1. Preparation of Sodium 2-Bute-
nyldimethylsilanolate (Na+13-). Sodium 2-butenyldimethyl-
silanolate (Na+13-) was prepared to test the hypothesis that
substituted allylic silanolates could suppress olefin isomerization
while simultaneously introducing the issue of site-selectivity in the
coupling. The synthesis of Na+13- began by reaction of com-
mercially available 1-chloro-2-butene (E/Z, 80:20) with trichlo-
rosilane using copper(I) chloride as the catalyst to produce
2-butenyltrichlorosilane (11) in 88% yield (Scheme 6).40 Trichlo-
rosilane 11 could then be converted to the 2-butenyldi-
methylchlorosilane (12) by addition of 2.0 equiv of methyllithium.
Buffered hydrolysis of 12 then provided 2-butenyldimethylsilanol
(13).36 The purified silanol 13 rapidly dimerized to the correspond-
ing disiloxane upon concentration. Therefore, an ethereal solution
of the silanol obtained after silica gel chromatography was treated
directly with sodium hydride to afford Na+13- in 81% yield over
two steps.41 Olefin isomerization was not observed over the
Table 4. Effect of Ligand on Crotylation of 1-Bromonaphthalenea
b
γ:R
entry
ligand
ligand, equiv/Pd
conversion,b
%
1c
2
none
Ph3P
Cy3P
Ph3As
dppp
dppf
BINAP
Josiphos
N/A
2.0
1.0
2.0
1.0
1.0
0.5
0.5
82
58
62
100
53
73
1.3:1
1.7:1
1.1:1
1.5:1
1.4:1
1.4:1
Scheme 6
3
4c
5
6
7
8
85
82
1:1.1
1:1.1
a Reactions performed on 0.25 mmol scale. b Ratio of GC peak areas
of the crude reaction mixture. c Average of two experiments.
The modest effects of ligands on the site-selectivity of the
coupling prompted a broader evaluation of palladium catalysts.
A broad range of palladium sources of varying oxidation states
with halide, acetate, phosphine, carbene, and olefinic ligands
9
16386 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
a
Table 6. Effect of Ligand on Crotylation Using Pd(dba)2
were then tested (Table 5). Although no reaction was observed
with PdCl2 (entry 1), PdBr2 and Pd(OAc)2 provided low site-
selectivity (entries 2 and 3). Catalysts containing the electron-
rich, sterically bulky tri-tert-butylphosphine ligand (pallada-
cycle44 15 and (t-Bu3P)2Pd) were examined, and the former
resulted in improved γ-selectivity compared to the latter (entries
4 and 5). Poor site-selectivity was seen with the carbene-ligated
PEPPSI catalyst45 (entry 6). Most notable were the selectivities
observed with the olefin-ligated palladium(0) catalysts Pd2(dba)3
and Pd(dba)2, wherein increasing the ratio of the olefin ligand
to palladium increased the γ-selectivity (entries 7 and 8).
Moreover, removing the phosphine ligand from the reaction
considerably increased the site-selectivity to 10:1 (entry 9).
d
γ:R
entry
ligand
ligand, equiv/Pd conversion,b
%
yield γ,c
%
1
Ph3As
4.0
1.0
2.0
1.0
2.0
2.0
1.0
2.0
2.0
75
47
21
81
55
70
29
90
77
40
16
trace
25
trace
20
14
2.0:1
6.3:1
N/A
1.7:1
N/A
3.3:1
2.2:1
9.5:1
16:1
2e,f Cy3P
3e
4
o-tol3P
dpppO
5g,h t-Bu2(2-biphenyl)P
6e
7
8
15i
16j
cod
dba
30
40
Table 5. Effect of Palladium Source on Crotylation of
1-Bromonaphthalenea
9
a Reactions performed on 0.25 mmol scale. b Conversion of 7h by
GC with respect to an internal standard (biphenyl). c Yield of γ-14h by
GC with respect to an internal standard (biphenyl). d Ratio of GC peak
areas of the crude reaction mixture. e At 20 h. f Reaction inhibition was
observed when 2.0 equiv/Pd was used. g At 3 h. h Major product was
1-naphthol (15% at 3 h, 3% at 6 h). i 15 ) 2′,6′-dimethoxy[1,1′-biphenyl]-2-
yldiphenylphosphine. j 16 ) diphenyl[2′,4′,6′-tris(1-methylethyl)[1,1′-bi-
phenyl]-2-yl]phosphine.
b
entry
Pd source
ligand
conversion,b
%
γ:R
1c
2c
3
4
5
PdCl2
PdBr2
Ph3P
Ph3P
Ph3P
none
none
none
Ph3P
Ph3P
none
0
12
58
59
100
40
57
59
47
N/A
2.1:1
2.5:1
2.3:1
4.7:1
1.5:1
3.9:1
5.0:1
10:1
vided good conversion of 7h but a low yield and selectivity for
formation of γ-14h (entry 4). Reactions carried out with Buchwald-
type ligands provided low yields and selectivities of γ-14h (entries
5-7). Interestingly, 1-naphthol (17) was observed as the major
product when the sterically demanding ligand 2-(di-tert-butylphos-
phino)biphenyl was used. When this reaction was scaled to 1.0
mmol and 2.0 equiv of Na+13- was used, 56% of 17 was isolated
(Scheme 8).
Pd(OAc)2
(t-Bu3P)2Pd
15
PEPPSI
Pd2(dba)3
Pd(dba)2
Pd(dba)2
6
7d
8
9
a Reactions performed on 0.25 mmol scale. b Ratio of GC peak areas
of the crude reaction mixture. c At 20 h. d 2.5 mol % catalyst used.
Scheme 8
However, the most striking result in this study was the effect
of added olefinic ligands. Whereas the addition of 1,5-cyclo-
octadiene (cod) maintained a selectivity similar to that observed
previously without added ligand (compare Table 6, entry 8 and
Table 5, entry 9), an additional 2.0 equiv of dba (per Pd) further
increased the site-selectivity to highly favor the γ-coupled
product by 16:1 (Table 6, entry 9).
Olefinic ligands are known to have a variety of effects on
transition metal-catalyzed reactions.46 The most important in
the context of this reaction is an increased rate of reductive
elimination attributed to the π-acidity of the ligand.47 To this
end, a variety of olefinic ligands with a range of electronic and
steric attributes were examined (Table 7). The use of π-acidic
1,4-benzoquinone provided good selectivity, albeit in low yields
of γ-14h (entries 2-4). 1,4-Benzoquinone is known48 to oxidize
The increased site-selectivity provided by Pd(dba)2 demanded
further investigation. A variety of ligands were examined to
understand and improve the γ-selectivity provided by Pd(dba)2
(Table 6). The weakly coordinating ligand Ph3As provided a good
yield of coupling products, albeit with low site-selectivity (entry
1). Increased γ-selectivity was observed using the electron-rich
alkyl phosphine Cy3P (entry 2). Very slow conversion of 7h was
observed when 2.0 equiv/Pd of the sterically demanding o-tol3P
was used (entry 3). The reaction using the P,O-chelating bidentate
bis(diphenylphosphino)propane mono-oxide (dpppO) ligand pro-
(40) Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30, 1099–
1102.
(41) Na+13- was stable for months without any discernible change in purity
or reactivity when stored in an anhydrous environment.
(42) Ph3PO was added to provide a more stable catalyst, see: Denmark,
S. E.; Smith, R. S.; Tymonko, S. A. Tetrahedron 2007, 63, 5730–
5738.
(46) (a) Rovis, T.; Johnson, J. B. Angew. Chem., Int. Ed. 2008, 47, 840–
871. (b) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2008, 47, 4482–4502.
(43) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem. Eur. J. 2007, 13,
5197–5206.
(44) Werner, H.; Kuhn, A. J. Organomet. Chem. 1979, 179, 439–445.
(45) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J.
2006, 12, 4743–4748.
(47) Kurosawa, H.; Emoto, M.; Urabe, A.; Miki, K.; Kasai, N. J. Am. Chem.
Soc. 1985, 107, 8253–8254.
(48) Ba¨ckvall, J.-E.; Gogoll, A. J. Chem. Soc., Chem. Commun. 1987, 1236–
1238.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16387

A R T I C L E S
Denmark and Werner
Table 8. Effect of π-Acidic Ligands on Crotylation Using APCa
a
Table 7. Effect of Olefin Ligand on Crotylation Using Pd(dba)2
d
d
entry
ligand
ligand, equiv/Pd conversion,b
%
yield γ,c
%
γ:R
entry
ligand
ligand, equiv/Pd conversion,b
%
yield γ,c
%
γ:R
1
2
3
4
5
6
7
8
9
none
N/A
2.0
4.0
8.0
1.0
2.0
4.0
6.0
4.0
2.0
6.0
2.0
2.0
4.0
45
72
28
13
74
28
7
50
41
18
41
69
29
28
21
32
18
11
31
8
trace
25
18
6
11:1
9.1:1
19:1
61:1
13:1
15:1
N/A
9.6:1
6.5:1
8.9:1
10:1
7.0:1
6.6:1
19:1
1
2
3
4
5
6
7
8
dba
dba
dba
dba
18f
4.0
6.0
8.0
64
71
80
85
72
61
80
54
92
20
59
100
100
100
45
31
28
32
45
30
26
14
20
28
trace
18
51
25
39
16
7.9:1
9.4:1
12:1
18:1
5.1:1
12:1
1.3:1
3.8:1
2.0:1
N/A
6.2:1
3.6:1
6.0:1
3.4:1
1.2:1
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
norbornadiene
norbornadiene
norbornadiene
10
4.0
4.0
4.0
8.0
1.0
2.0
4.0
4.0
4.0
2.0
4.0
19g
cod
cod
norbornylene
tetramethylethylene
9
10
11
norbornadiene
norbornadiene
diallyl ether
10 dicyclopentadiene
11 maleic anhydride
12 diallylcarbonate
13e diallyl ether
18
35
8
12e (MeO)3P
13e (PhO)3P
14e (N-pyrrolyl)3P
15e 20h
14e diallyl ether
12
a Reactions performed on 0.25 mmol scale. b Conversion of 7h by
GC with respect to an internal standard (biphenyl). c Yield of γ-14h by
GC with respect to an internal standard (biphenyl). d Ratio of GC peak
areas of the crude reaction mixture. e 2.0 equiv of silanolate used.
a Reactions performed on 0.25 mmol scale. b Conversion of 7h by
GC with respect to an internal standard (biphenyl). c Yield of γ-14h by
GC with respect to an internal standard (biphenyl). d Ratio of GC peak
areas of the crude reaction mixture. e 2.0 equiv of silanolate used. f 18 )
bis(4-methoxybenzylidene)acetone.
g 19
)
bis(4-trifluoromethyl-
palladium(0) to palladium(II), which under these conditions
cannot re-enter the catalytic cycle. Norbornadiene (nbd) provided
good site-selectivity (at low yield) but was seen to inhibit the
reaction at loadings greater than 2.0 equiv/Pd (entries 5-8).
The electron-rich tetramethylethylene and the electron-poor
maleic anhydride gave similar conversions and yields, yet the
electron-deficient olefin provided higher γ-selectivity (entries
9 and 11). Decreased selectivity was observed when diallyl-
carbonate was added to the reaction (entry 12). However, when
diallyl ether was used, good γ-selectivity was observed at
increased loadings, 4.0 equiv/Pd, but at the cost of decreased
reactivity (entries 13 and 14).
To separate the site-selectivity contribution of the dba ligand of
Pd(dba)2 from the effects of added ligands, the palladium source
was changed to APC, which can generate ligandless palladium(0)
after reduction by a silanolate nucleophile.49 A variety of olefinic
ligands along with π-acidic phosphine ligands were surveyed in
combination with APC in the same solvent and at the same
temperature. Slightly lower γ-selectivity was observed for APC
with 20 mol % of dba (i.e., 4.0 equiv dba/Pd) and Pd(dba)2 alone
(compare Table 8, entry 1 and Table 7, entry 1). Derivatives of
dba50 with appended electron-withdrawing groups provided higher
site-selectivity than those with electron-donating groups (Table 8,
entries 5 and 6). Low selectivity and decreased conversion were
seen with cod when the loading was increased to 8.0 equiv/Pd
(Table 8, entries 7 and 8). The use of 4,4-dimethylcyclohexadienone
(20)51 resulted in low site-selectivity (entry 15). The π-acidic
ligands52 (MeO)3P, (PhO)3P, and (N-pyrrolyl)3P gave varying
selectivity; (PhO)3P gave the highest selectivity of any phosphorus-
containing ligand used (entry 13). With APC, only the electron-
poor olefins diallyl ether, dba (and its derivatives), and the π-acidic
triphenylphosphite provided site-selectivities greater than 5:1
benzylidene)acetone. h 20 ) 4,4-dimethylcyclohexadienone.
(entries 1-6, 11, 13). Moreover, in general, increasing the dba
loading increased the rate, yield, and site-selectivity of the reaction
(entries 1-4).
2.3. Final Optimization of Silanolate Stoichiometry. The
final stage of optimization involved adjustment of silanolate
stoichiometry. This parameter was evaluated using Pd(dba)2
(5 mol %) and additional dba ligand (4.0 equiv/Pd, see
previous section) in toluene at 70 °C (Table 9). With 1.0
equiv of silanolate, the reaction was only 49% complete at
3 h, whereas by increasing the amount of silanolate to 1.5
equiv, the conversion increased to 85% (entries 1 and 2).
Increasing the amount of silanolate to 2.0 equiv did not
change the amount of 7h consumed but did increase the yield
of the desired product from 44% to 54% (entries 2 and 3).
Since using more than 2.0 equiv of silanolate did not affect
the reaction significantly (entries 5 and 6), 2.0 equiv of
silanolate was chosen to evaluate substrate scope.
2.4. Preparative Cross-Coupling with Na+13-. The optimized
conditions developed above (5 mol % Pd(dba)2 and 2.0 equiv
Table 9. Effect of Silanolate Loading on Crotylation of
1-Bromonaphthalene
d
entry
Na+13-, equiv
conversion,b
%
yield γ,c
%
γ:R
1
2
3
4
5
1.0
1.5
2.0
2.5
3.0
49
85
86
90
90
20
44
54
53
54
9.1:1
14:1
14:1
11:1
11:1
(49) Denmark, S. E.; Smith, R. C. Synlett 2006, 18, 2921–2928.
(50) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Org. Lett. 2004, 6, 4435–
4438.
a Reactions performed on 0.25 mmol scale. b Conversion of 7h by
GC with respect to an internal standard (biphenyl). c Yield of γ-14h by
GC with respect to an internal standard (biphenyl). d Ratio of GC peak
areas of the crude reaction mixture.
(51) Hopf, H.; Kampen, J.; Bubenischek, P.; Jones, P. G. Eur. J. Org. Chem.
2002, 1708–1721.
(52) Jackstell, R.; Klein, H.; Beller, M.; Wiese, K.-D.; Ro¨ttger, D. Eur. J.
Org. Chem. 2001, 3871–3877, and references therein.
9
16388 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
Table 10. Preparative Crotylation of Substituted Aryl Bromidesa
a Reactions performed on 1.0 mmol scale. b Yields of isolated, purified products. c Ratio, γ:R, determined by GC analysis of purified products. d 2.0
equiv Na+13- used. e Reaction run at 85 °C. f Reaction run at 110 °C. g Ratio, γ:R, determined by 1H NMR analysis of purified product.
of Na+13- in toluene at 70 °C) were used to evaluate substrate
scope. Norbornadiene was used in these studies because it
provided good site-selectivity in the product and conversion of
the electrophile at low loadings (1.0 equiv/Pd) when used in
conjunction with Pd(dba)2 (Table 7, entry 5). The results of these
cross-coupling reactions with electron-neutral, electron-rich, and
electron-poor aryl bromides bearing a variety of ortho-, meta-,
and para-functional groups are compiled in Table 10. Good
yields and excellent γ-selectivities were observed with unhin-
dered, electron-neutral aryl bromides 7l and 7g (entries 1 and
2). The reaction with electronically neutral 1-bromonaphthalene
(7h) afforded the corresponding product 14h in 50% yield,
which could be increased to 63% by using an extra 0.5 equiv
of Na+13- (entry 4). Silicon protecting groups including
triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) are unaf-
fected by the reaction conditions, and the desired products were
isolated in high yields (entries 5 and 10). Electron-rich aryl
bromides, 4-bromo-N,N-dimethylaniline (7c) and 4-bromoani-
sole (7a) provided the desired products in modest yield at 85
°C after 20 h (entries 8 and 10). The yields of these couplings
could be increased by raising the temperature to 110 °C (entries
9 and 11). A protected indole is compatible under these
conditions and gives the desired γ-coupled product in good yield
and site-selectivity (entry 11).
Although esters and unprotected aldehydes are compatible
with these reaction conditions (entries 18 and 19) and give
satisfactory results, substrates bearing strongly electron-
withdrawing groups (compare entries 14, 15, and 16) yielded
products of lower constitutional purity. Importantly, the cross-
coupling of Na+13- and ketone 7k was carried outwithout
isomerization to afford 14k in 81% yield with high γ-selectivity
(entry 17). Moreover, the allyl unit of linear, R-coupled products
did not isomerize into conjugation with the aromatic ring,
confirming the hypothesis that these products would be less
prone to isomerization (e.g., entry 20).
2.5. Effect of Silanolate Geometry on Site-Selectivity of
Preparative Couplings. Because all of the foregoing coupling
reactions of Na+13- employed an 80:20, E/Z mixture of olefin
isomers, configurationally homogeneous sodium (E)- and (Z)-2-
butenyldimethylsilanolates were needed to examine the reactivity
and selectivity of these individual reagents. Synthesis of (E)-2-
butenyltrichlorosilane ((E)-11) began with LiAlH4 reduction of
2-butynol to yield (E)-2-butenol ((E)-21) in high configurational
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16389

A R T I C L E S
Denmark and Werner
purity (Scheme 9).53 The alcohol (E)-21 was then transformed to
(E)-1-chloro-2-butene ((E)-10) using hexachloroacetone and Ph3P.54
The chloride (E)-10 thus obtained was then combined with
trichlorosilane in the presence of copper(I) chloride to provide (E)-
11.
Table 11. Preparative Couplings with Geometrically Pure (E)- and
(Z)-Silanolates
Scheme 9
yieldb, % (γ:R)c
olefin geometry of Na+13-, E/Z
entry
product
80:20
>97:3
<4:96
1
14h
14a
14k
14r
14u
50 (14:1)
46 (7.2:1)
81 (14:1)
62 (3.4:1)
82 (1:2.5e)
51 (25:1)
46 (18:1)
79 (24:1)
74 (3.6:1)
82 (1:2.5f)
51 (13:1)
59 (4.0:1)
82 (11:1)
68 (2.6:1)
79 (1:2.5g)
2d
3
4
5
a Reactions performed on 1.0 mmol scale. b Yields of isolated,
purified products. c Ratio determined by GC analysis of purified
products. d Reaction run at 110 °C. e 8.3:1, E/Z. f 8.4:1, E/Z. g 8.4:1, E/Z.
of the branched, γ-coupled product than did the (Z)-isomer. The
selectivity difference with 7a at elevated temperature was
observed to be the most pronounced for the geometrically pure
(E)- and (Z)-silanolates (entry 2). Interestingly, the geometry
of the silanolate had very little impact on the site-selectivity of
coupling with 7u, which remained γ/R, 1:2.5 regardless of the
silanolate geometry (entry 5).
(Z)-2-Butenyltrichlorosilane ((Z)-11) was obtained by reaction
of 1,3-butadiene and trichlorosilane catalyzed by (Ph3P)4Pd
(Scheme 10).40 The configurationally pure trichlorosilanes (E)-
and (Z)-11 were then separately treated with methyllithium in
diethyl ether, the resulting monochlorosilanes were hydrolyzed,
and the silanols were deprotonated in a sequence similar to that
described above. Accordingly, sodium (E)- and (Z)-2-bute-
nyldimethylsilanolates were produced in good yield without
erosion of the configurational purity as determined by com-
Discussion
The primary aim of this work was to develop a palladium-
catalyzed cross-coupling reaction using isolated allylic alkali metal
silanolates. To this end, allylic silanolates were prepared and studied
as organometallic donors. These reagents were found to be readily
prepared, stable, easily handled, and more importantly, competent
in palladium-catalyzed cross-coupling reactions.
1
parison of the allylic signals in their H NMR spectra.
Scheme 10
1. Preparative Allylation with Substituted Aromatic Bromides.
The optimized reaction conditions (2.5 equiv of Na+1-, 2.5 mol
% of APC, 0.5 M DME at 85 °C) were successfully applied to
electron-rich and electron-neutral aryl bromides. These opti-
mized conditions could be successfully modified to accom-
modate highly sterically demanding substrates such as the ortho-
disubstituted 2-bromomesitylene 7j, which using the standard
optimized conditions provided very long reaction times (>40
h) and low yields of the desired product. Nucleophile degrada-
tion over the long reaction time was believed to be the main
problem with this reaction. This issue was readily overcome
by increasing the silanolate stoichiometry and the temperature
(100 °C in dioxane) and adding a stabilizing ligand (Ph3PO).
However, electron-deficient aryl bromides were problematic.
In these reactions, the aryl bromide was consumed but no major
products were observed. The products of these reactions contain
doubly activated protons that are both allylic and benzylic.
Moreover, when the aromatic ring is substituted with an
electron-withdrawing group, the acidity of these protons is
increased and Brønsted base-mediated allylic isomerization is
observed. While a preformed silanolate eliminated the necessity
of a strongly basic Brønsted base activator and allowed for
successful coupling of electronically neutral aryl bromides,
Na+1- is still a basic reagent. The kinetic basicity of Na+1-
could potentially be attenuated by the use of other, more
covalently bound alkali metal silanolate salts (Li), but this would
To evaluate the reactivity and selectivity of the geometrically
pure 2-butenylsilanolates, aryl halides were chosen that dis-
played a wide range of reactivity (i.e., electron-rich and electron-
poor aryl bromides). Also included in this survey were 7h, the
substrate used to optimize the reaction, and tert-butyl 2-bro-
mobenzoate (7u), the only substrate to yield the product arising
from R-coupling as the major isomer. The results of these studies
are compiled in Table 11. In all of the cases studied, the
geometrically pure Na+(E)-13- produced a greater proportion
(53) Denmark, S. E.; Harmata, M. A.; White, K. S. J. Org. Chem. 1987,
52, 4031–4042.
(54) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. Tetrahedron Lett. 1977,
35, 2999–3002.
9
16390 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
also diminish the nucleophilicity of the silanolate and hinder
the necessary displacement step of the catalytic cycle.55
2. Cross-Coupling Site-Selectivity Using 2-Butenylsilanolate
Na+13-. Experiments using substituted allylic silanolate Na+13-
were conducted to address the issue of site-selectivity and test the
hypothesis that these reagents would provide less base-sensitive
products. A brief digression to a general discussion of the proposed
mechanism of the palladium-catalyzed cross-coupling of allylic
organometallic donors is necessary to put the remainder of this
discussion in context. Allylic organometallic donors are believed
to undergo transmetalation through two discrete processes: (1) SE2′,
forging a bond between the γ-carbon to the allylic unit and
palladium, and (2) SE2, forming a bond between the R-carbon and
palladium(Scheme 11).21,25 Direct SE2 transmetalation is favorable
3. Bulky Phosphine Ligands. Different phosphine ligands
were investigated to improve the site-selectivity of the coupling.
The palladacycle catalyst 15, containing 1.0 equiv of t-Bu3P to
palladium, increased the γ-selectivity substantially, but this
selectivity was still only moderate. In addition, when the catalyst
(t-Bu3P)2Pd was used, lower site-selectivity was observed.
Interestingly, the use of t-Bu2(2-biphenyl)P caused a dramatic
change in product distribution (Scheme 12). The major product
of the reaction was 1-naphthol (17), resulting from CsO bond
formation, and only a trace of the CsC bond coupled products
was observed. In addition, 17 was consumed over time when
only 1.0 equiv of silanolate was used. The formation of 17 is
believed to result from a facile reductive elimination of the
palladium-bound silanolate 23.59 After cleavage of the silyl ether
by Na+13-, 1-naphthoxide 26 and disiloxane 25 are produced,
of which the former can re-enter the catalytic cycle. It seems
that t-Bu2(2-biphenyl)P was too effective in facilitating a facile
reductive elimination and that a balance of transmetalation and
reductive elimination would be necessary to provide CsC bond
formation and avoid σ-π interconversion.
Scheme 11
Scheme 12
only with allylic stannanes, presumably because of the long (2.14
Å)56 and weak (65 kcal/mol)57 tin-carbon bond. When silicon or
boron donors are used, transmetalation to the γ-carbon through an
SE2′ process is proposed. After transmetalation, the σ-bound
palladium species can either reductively eliminate to yield the γ-
or R-coupled products or interconvert through an η3, π-allyl-
palladium species.58 Highly site-selective couplings are proposed
to arise from a fast reductive elimination of the initially formed
σ-bound intermediate.21,25 However, if σ-π interconversion occurs,
the geometry of the olefin can become isomerized and lead to a
mixture of geometrical as well as constitutional isomers. As
previously mentioned, ligands can have a marked effect on the
outcome of this process, and ligands that provide a facile reductive
elimination of the initially formed σ-bound palladium species can
allow for one constitutional isomer of the product to be formed
exclusively.
4. Effect of Dibenzylideneacetone on Site-Selectivity. A more
preparatively useful balance of transmetalation and reductive
elimination was found with the Pd(dba)2 catalyst. Initial
experiments with Pd(dba)2 included added phosphine ligands
and somewhat masked the beneficial effect of the dba ligand.
When Ph3P (2.0 equiv/Pd) was used, only moderate γ-selectivity
was observed. Substituting Ph3P for a bulkier alkyl phosphine
ligand, Cy3P (2.0 equiv/Pd), slightly increased the γ-selectivity
of the reaction, but in general all added phosphine ligands
diminished the γ-selectivity that was observed when Pd(dba)2
was used alone. However, without added ligand these reactions
stalled before complete consumption of 7h. Therefore, a ligand
to stabilize the catalyst was required. This ligand would need
to be less “palladaphilic” than a phosphine so as to not interfere
with the γ-selectivity provided by the dba ligand.
The use of olefinic ligands cod and nbd, as well as additional
dba, provided complete consumption of the electrophile. In
addition, similar and often superior γ-selectivity was observed
when these ligands were used. The electron-deficient olefin
ligands 1,4-benzoquinone and diallyl ether were particularly
beneficial to the γ-selectivity of the reaction. However, during
studies using APC as catalyst, only dba and its electron-deficient
derivative 19 were observed to provide reactions with site-
selectivity greater than 10:1, γ:R. Also, increasing the stoichi-
ometry of dba led to reactions with increased conversion of the
electrophile and better γ-selectivity. Since the use of added dba
The substituted allylic silanolate Na+13- underwent cross-
coupling with 1-bromonaphthalene to produce the γ- and
R-coupled products in nearly equal amounts under the optimized
allylation conditions (APC, Ph3PO, DME). Many perturbations
of these initial conditions did not significantly change this site-
selectivity, including the use of ligands reported to impact site-
selectivity with other allylic metal donors. For example, dppp,
which gave good results in the cross-couplings of both
substituted allylic trifluorosilanes and trifluoroborates, gave a
mere 1.4:1, γ:R ratio with Na+13-.
(55) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876–
4882.
(56) Mackay, K. M. In The Chemistry of Organic Germanium, Tin and
Lead Compounds; Patai, S., Ed.; Wiley: New York, 1995; Chap. 2.
(57) (a) Jackson, R. A. J. Organomet. Chem. 1979, 166, 17–19. (b) Poller,
R. C. ReV. Silicon, Germanium, Tin Lead Compd. 1978, 3, 243.
(58) Vrieze, K.; Praat, A. P.; Cossee, P. J. Organomet. Chem. 1968, 12,
533–547.
(59) The ligand t-Bu2P(2-biphenyl) was developed for and successfully used
in Pd-catalyzed C-O bond-forming reactions: Aranyos, A.; Old,
D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 4369–4378.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16391

A R T I C L E S
Denmark and Werner
Scheme 13
can complicate purification, a stabilizing ligand that could be
used at low loadings was sought.
5. Effect of Norbornadiene. At low loadings (1.0 equiv/Pd),
when used in conjunction with Pd(dba)2, norbornadiene in-
creased the consumption of the aryl halide and marginally
increased the site-selectivity of the coupling. The increased
turnover of the palladium catalyst provided by the use of
norbornadiene is not completely understood; however, two
scenarios in which this effect would manifest are proposed. First,
electron-deficient olefins can effectively slow oxidative addition
through π-back-bonding to palladium(0).60 As norbornadiene
is a somewhat electron-rich olefin, when ligated to palladium(0)
it could aid in the oxidative addition step of the catalytic cycle.
Second, norbornadiene may stabilize the resting state of the
catalyst, allowing for increased catalyst turnover. Importantly,
experiments using norbornadiene with APC produced very low
site-selectivity. This suggests that norbornadiene alone does not
provide enhanced γ-selectivity but does allow for increased
lifetime of the palladium catalyst.
6. Substituent Effect of the Aryl Bromide on the Site-
Selectivity of Cross-Coupling of Na+13-. The electronic nature of
aryl groups bound to palladium is known to affect the rate of
reductive elimination.61 In the allylation reaction, this effect
contributes to the site-selectivity of the coupling. Excellent
γ-selectivities were observed in reactions with electron-rich aryl
bromides, for example 4-bromoanisole (7a) or 6-bromo-N-Boc-
indole (7n). However, some of the lowest γ-selectivities were seen
when electron-poor aryl bromides (such as 1-bromo-3,5-bis(tri-
fluoromethyl)benzene, 7r) were used. This electronic effect can
be rationalized by invoking either a more facile σ-π isomerization
of an electron-deficient palladium(II) complex or a slower reductive
elimination of the electron-deficient aryl groups. The latter hy-
pothesis contradicts the trends observed in other arylsalkyl
reductive eliminations, in which aryl groups bearing electron-
withdrawing substituents reductively eliminate to form alkyl arenes
more quickly than those with electron-donating substituents.62 It
should not be overlooked that a weaker, more labile Pd-dba bond
resulting from less π-back-bonding of palladium(II) bearing an
electron-deficient aryl group would also effectively slow reductive
elimination and decrease the site-selectivity of the coupling.
Substituent effects not related to electronic contributions were
also apparent. Aryl bromides bearing Lewis basic substituents
affected the site-selectivity of the coupling. Lower than expected
γ-selectivity was observed for the coupling of electron-rich
4-bromo-N,N-dimethylaniline (7c). Also, very low selectivity was
observed for 4-bromobenzonitrile (7p). These results suggest that
competitive ligation of palladium by Lewis basic substituents can
lower the site-selectivity of the reaction. The carboxyl group of
tert-butyl 2-bromobenzoate (7u) plays a significant role in the site-
selectivity of the coupling. As this is the only substrate in which
an R-coupled product was predominant, it may provide insight into
the composition of the species from which reductive elimination
occurs. The coordination of the olefin of an allylic silanolate to
palladium after halide displacement would effectively occupy two
coordination sites (Scheme 13). When 17u is used, if the remaining
two sites are occupied by the aryl group and ester function,63 this
would produce the coordinatively saturated palladium species 27.64
Thus, the dba ligand would be excluded from this complex, and
the γ-selectivity imparted by the dba ligand would be bypassed.
7. Effect of Silanolate Geometry. Geometrically pure (E)- and
(Z)-2-butenyldimethylsilanolates were studied under the opti-
mized reaction conditions to evaluate the effects of olefin
geometry on the site-selectivity and stereoselectivity of the
coupling. These studies established that the configuration of the
double bond did in fact affect the site-selectivity of the reaction.
Higher γ-selectivity was observed in all cases in which the pure
(E)-silanolate was used. To explain this outcome, the immediate
products of transmetalation must be considered (Scheme 14).For
Scheme 14
the purposes of this analysis, we will assume an intramolecular
transmetalation as we have described for alkenyl-
silanolates.55 The two species (32 and 35) formed upon initial
γ-selective transmetalation (via transition structures 31 and 34,
respectively) are different conformers of the enantiomeric
products. It is proposed that a more facile reductive elimination
pathway is available for conformer 32 to afford the γ-substitu-
tion product 33 compared to that for conformer 35. Conformer
35 experiences greater A1,3 strain, which may facilitate σ–π
isomerization and thus lead to formation of both ent-33 and
R-substituted product R-14, resulting in attenuated overall
selectivity. In addition, the geometry of the double bond of the
silanolate is not preserved in the geometry of the double bond
of the R-coupled product, suggesting that the R-coupled product
is generated after formation of a π-allylpalladium intermediate.
(63) A palladium(II) lactone [Pd(C6H4COO)(P(CH3)3)2] that would require
similar geometry about palladium has been isolated: Nagayama, K.;
Kawataka, F.; Sakamoto, M.; Shimizu, I.; Yamamoto, A. Bull. Chem.
Soc. Jpn. 1999, 72, 573–580.
(64) A reviewer suggested that the high R-selectivity observed with 7u could
be a simple consequence of the steric influence of the carboxyl group.
This reasonable explanation could be eliminated, as 2-bromotoluene
provided the γ-coupled product in high selectivity (γ/R, 13:1) under the
same conditions. We thank the reviewer for this suggestion.
(60) Mace, Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand, A. Organometallics
2006, 25, 1795–1800.
(61) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936–1947.
(62) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398–3416.
(65) Gomes, P.; Gosmini, C.; Perichon, J. Org. Lett. 2003, 5, 1043–1045.
9
16392 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Cross-Coupling of Aromatic Bromides with Silanolates
A R T I C L E S
Preparation of 4-(2-Propenyl)anisole (8a) from 4-Bromoani-
sole Using Na+1-. To a 5-mL, single-necked, round-bottomed flask
containing a magnetic stir bar, equipped with a reflux condenser
and an argon inlet capped with a septum, was added [allylPdCl]2
(9.2 mg, 0.025 mmol, 0.025 equiv). The flask was then sequentially
evacuated and filled with argon three times. 4-Bromoanisole (187
mg, 1.0 mmol) was then added by syringe. Sodium 2-propenyldi-
methylsilanolate (346 mg, 2.5 mmol, 2.5 equiv), preweighed into
a 10-mL, two-necked, round-bottomed flask in a drybox, was then
dissolved in DME (2.0 mL) and then added by syringe. The reaction
mixture was heated in a preheated oil bath to 85 °C under argon.
After 3 h, the mixture was cooled to room temperature and filtered
through silica gel (2 cm × 2 cm) in a glass-fritted filter (coarse, 2
cm × 5 cm), and the filter cake was washed with ether (3 × 10
mL). The filtrate was concentrated in Vacuo, and the residue was
purified by silica gel chromatography (20 cm × 20 mm, hexane/
EtOAc, gradient 100:0 to 20:1) followed by Kugelrohr distillation
(90 °C, 10 mmHg, ABT) to afford 119 mg (80%) of 8a as a clear,
colorless oil. Data for 8a:65 1H NMR (500 MHz, CDCl3) 7.14 (d,
J ) 8.5, 2 H), 6.87 (d, J ) 8.5, 2 H), 5.99 (ddt, J ) 16.8, 10.3,
8. Mechanistic Hypothesis. All the results described herein
can be accommodated by the mechanistic hypothesis presented
in Figure 2. This proposal has three important features: (1) after
oxidative addition, displacement of the bromide by Na+13-
forms a Si-O-Pd linkage,29b,55 (2) an SE2′ transmetalation
occurs from the palladium-bound silanolate, and (3) facile
reductive elimination of the γ-bound palladium intermediate (37,
L ) dba) affords the product γ-14 with high site-selectivity.
The first conclusion is supported by the observation of 1-naph-
thol in reactions using t-Bu2(2-biphenyl)P, which must arise
from C-O bond formation. The second conclusion is cor-
roborated by the fact that the configuration of a geometrically
pure silanolate is not conserved in the R-coupled product.
Therefore, the R-coupled product must be produced after
generation of a π-allylpalladium intermediate from σ-π isomer-
ization, and not from facile reductive elimination of an SE2
transmetalation. The third conclusion finds support in the low
site-selectivity observed in the absence of dba.
6.6, 1H), 5.09 (m, 2 H), 3.81 (s, 3 H), 3.36 (d, J ) 6.6, 2 H); 13
C
NMR (126 MHz, CDCl3) 158.2, 138.2, 132.4, 129.8, 115.7, 114.1,
55.5, 39.6; IR 3077, 3032, 3003, 2978, 2954, 2934, 2906, 2835,
1639, 1611, 1584, 1511, 1464, 1441, 1321, 1301, 1247, 1177, 1111,
1038, 1012, 995, 914, 842, 830, 815, 761, 708, 639, 624; MS (EI,
70 eV) 148, 133, 121, 105, 91, 77; Rf 0.35 (hexanes/EtOAc, 20:1).
Preparation of 1-(1-Methyl-2-propenyl)naphthalene (14h) from
1-Bromonaphthalene Using Na+13-. To an oven-dried, 5-mL,
single-neck, round-bottomed flask containing a magnetic stir bar,
equipped with a reflux condenser and an argon inlet capped with a
septum, was added Pd(dba)2 (28.8 mg, 0.050 mmol, 0.050 equiv).
The flask was then sequentially evacuated and filled with argon
three times. 1-Bromonaphthalene (207 mg, 1.0 mmol) was then
added by syringe. Sodium 2-butenyldimethylsilanolate (386 mg,
2.5 mmol, 2.5 equiv), preweighed into a 10-mL, two-necked, round-
bottomed flask in a drybox, was then dissolved in toluene (2.0 mL),
and then norbornadiene (5.2 µL, 0.050 mmol, 0.050 equiv) was
added by syringe. The solution of Na+13- and norbornadiene in
toluene was then added by syringe. The reaction mixture was heated
in a preheated oil bath to 70 °C under argon. After 6 h, the mixture
was cooled to room temperature and filtered through silica gel (2
cm × 2 cm) in a glass-fritted filter (coarse, 2 cm × 5 cm), and the
filter cake washed with ether (3 × 10 mL). The filtrate was
concentrated in Vacuo, and the residue was purified by silica gel
chromatography (20 cm × 20 mm, pentane) followed by Kugelrohr
distillation (120 °C, 1 mmHg, ABT) to afford 116 mg (63%, 13:1,
γ:R) of 14h as a clear, colorless oil. Data for 14h:43 1H NMR (500
MHz, CDCl3) 8.15 (d, J ) 8.4, 1 H), 7.88 (d, J ) 7.9, 1 H), 7.74
(d, J ) 8.1, 1 H), 7.49 (m, 4 H), 6.18 (ddd, J ) 17.7, 10.0, 5.8, 1
H), 5.15 (m, 2 H), 4.32 (ap, J ) 7.0, 1 H), 1.53 (d, J ) 7.0, 3 H);
13C NMR (126 MHz, CDCl3) 143.1, 141.7, 134.2, 131.7, 129.1,
127.0, 126.0, 125.8, 125.6, 123.9, 123.7, 113.9, 38.1, 20.5; IR 3048,
2967, 2931, 2874, 1923, 1830, 1700, 1684, 1653, 1636, 1596, 1509,
1452, 1410, 1395, 1369, 1250, 1235, 1167, 1016, 997, 912, 859,
797, 777; MS (EI, 70 eV) 182, 167, 152, 128; Rf 0.42 (pentane).
Figure 2. Proposed catalytic cycle.
Conclusion
Allyl- and (2-butenyl)silanolate salts are stable, isolable solids
that undergo facile cross-coupling with aryl bromides under
palladium catalysis. Electron-neutral and electron-rich aryl
bromides undergo cross-coupling in high yield with sodium
2-propenyldimethylsilanolate (Na+1-), although with this nu-
cleophile electron-poor substrates were problematic. Increased
substrate scope, good yields, and high γ-selectivities were
obtained with sodium 2-butenyldimethylsilanolate (Na+13-).
The use of dba-derived palladium catalysts was crucial to the
high γ-selectivities observed. In addition, increased γ-selectivity
was observed using geometrically pure (E)-Na+13-. Configu-
rational isomerization of the R-coupled products leads to the
conclusion that these reagents suffer transmetalation through
an SE2′ process. Evidence supporting the SisOsPd linkage
prior to transmetalation was discovered in the formation of CsO
bonds when bulky phosphine ligands were used. Further studies
on the mechanism of transmetalation and asymmetric variants
of this reaction are currently underway.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (R01 GM63167) and
Johnson-Matthey for a gift of Pd2(dba)3.
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.
Experimental Section
General Experimental. See Supporting Information.
JA805951J
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16393