Palladium-catalysed cross-coupling of vinyldisiloxanes with benzylic and allylic halides and sulfonates

Article abstract of DOI:10.1002/chem.201200431

The Hiyama cross-coupling reaction is a powerful method for carbon-carbon bond formation. To date, the substrate scope of this reaction has predominantly been limited to sp²-sp² coupling reactions. Herein, the palladium-catalysed Hiyama type cross-coupling of vinyldisiloxanes with benzylic and allylic bromides, chlorides, tosylates and mesylates is reported. A wide variety of functional groups were tolerated, and the synthetic utility of the methodology was exemplified through the efficient total synthesis of the cytotoxic natural product bussealin A. In addition, the antiproliferative ability of bussealin A was evaluated in two cancer-cell lines. Copyright

Full text of DOI:10.1002/chem.201200431

FULL PAPER
DOI: 10.1002/chem.201200431
Palladium-Catalysed Cross-Coupling of Vinyldisiloxanes with Benzylic and
Allylic Halides and Sulfonates
Elizabeth C. Frye,[a] Cornelius J. OꢀConnor,[a] David G. Twigg,[a] Bryony Elbert,[a]
Luca Laraia,[a, c] David G. Hulcoop,[b] Ashok R. Venkitaraman,[c] and David R. Spring*[a]
Abstract: The Hiyama cross-coupling
reaction is powerful method for
carbon–carbon bond formation. To
date, the substrate scope of this reac-
tion has predominantly been limited to
sp2–sp2 coupling reactions. Herein, the
benzylic and allylic bromides, chlorides,
tosylates and mesylates is reported. A
wide variety of functional groups were
tolerated, and the synthetic utility of
the methodology was exemplified
through the efficient total synthesis of
the cytotoxic natural product busse-
AHCTUNGTRENNGaUN lin A. In addition, the antiproliferative
ability of bussealin A was evaluated in
two cancer-cell lines.
a
À
Keywords: C C coupling · cytotox-
icity · cross-coupling · palladium ·
palladium-catalysed
Hiyama
type
synthetic methods
cross-coupling of vinyldisiloxanes with
Introduction
In 2010, Professors Richard Heck, Ei-chi Negishi and Akira
Suzuki were awarded the Nobel Prize for chemistry, for
their work developing palladium-catalysed cross-coupling
reactions in organic synthesis. Carbon–carbon bond-forming
reactions are widely used in both academia and industry for
the synthesis of new medicines, agrochemicals and synthetic
materials for the electronics industry.[1] Organotin (Stille),[2]
organoboron (Suzuki–Miyaura),[3] organozinc (Negishi)[4]
and Grignard reagents (Tamau–Kumada–Corriu)[5] are well-
established organometallics employed in transition-metal
cross-couplings. Because of their low toxicity, high chemical
stability and ease of synthesis, organosilanes have emerged
in recent years as an attractive alternative to the conven-
tional reagents for cross-coupling reactions.[6] Some natural
products, which have been synthesised by using Hiyama
type coupling reactions, are shown in Figure 1.
Figure 1. a) Natural products synthesised by using Hiyama type cou-
plings;[11] b) examples of different siloxane functionality used in cross-
coupling reactions.
Pioneering work by Hiyama and Hatanaka established
the cross-coupling of organosilanes with aryl and vinyl hal-
À
ides through activation of the Si C bond by using fluoride
to facilitate transmetalation.[7] Subsequently, Denmark,
Baird, and Regens developed base-activated silanolate
cross-couplings, which precluded the requirement for fluo-
ride activation.[8] To date, substrate scope has been predomi-
nantly limited to sp2–sp2 cross-couplings[8] and a paucity of
examples of cross-couplings of organosilanes with sp3 hal-
ides (or equivalents thereof).[9] The first example was report-
ed by Hiyama and co-workers in 1991, who effected the
cross-coupling of fluoride activated allyltrifluorosilanes with
cinnamyl acetate in the presence of a palladium catalyst.[9a]
The reaction was performed in a sealed tube at elevated
temperature and provided the product in 54% yield.
[a] E. C. Frye, Dr. C. J. OꢀConnor, D. G. Twigg, B. Elbert, L. Laraia,
Dr. D. R. Spring
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (+44)-1223-336362
E-mail: spring@ch.cam.ac.uk
[b] Dr. D. G. Hulcoop
GlaxoSmithKline
Gunnelswood Road, Stevenage (UK)
[c] L. Laraia, Prof. A. R. Venkitaraman
MRC Hutchison/Cancer Cell Unit
Later, Fu and co-workers reported the cross-coupling of
fluoride activated aromatic alkoxysilanes with alkyl bro-
mides and iodides.[9b] The choice of palladium catalyst and
Addenbrookes Hospital, Hills Road, Cambridge (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200431.
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Table 1. Optimisation of cross-coupling reaction.
phosphine ligand had a dramatic effect on the reaction yield
with palladium dibromide and bis-tert-butylmethyl phos-
phine proving optimal to effect the transformation. In 2007,
the Fu laboratory disclosed the cross-coupling of fluorinated
aromatic silanes with activated and unactivated secondary
alkyl halides by using a nickel–norephedrine catalytic sys-
tem.[9c] In addition, Fu and colleagues later described a very
elegant asymmetric cross-coupling of alkoxysilanes with rac-
emic a-bromo esters, using a chiral nickel–diamine catalytic
complex.[10] To expand the scope of existing cross-coupling
methodology to incorporate a wider variety of sp3 substrates,
we sought to develop a protocol for the efficient, regio- and
stereoselective Hiyama type cross-coupling of vinyldisilox-
anes with benzylic and allylic alkyl halides.
An on-going area of interest within our research group is
the use of disiloxanes as masked silanols in cross-coupling
reactions.[12] Disiloxanes have been shown to exist in equilib-
rium with silanolate species when activated, and we have
harnessed this phenomenon for the development of both
fluoride-activated and fluoride-free cross-coupling reactions
between a variety of aromatic- and vinyldisiloxanes with
aryl and heteroaryl halides.[12] In a detailed mechanistic
study of the fluoride-activated reaction between silanols or
their masked equivalents with aromatic halides, Denmark
demonstrated that regardless of the organosilicon starting
material, the species that participates in the transmetalation
step is thought to be a fluoride-activated disiloxane.[13]
Unlike silanols and silanolates, disiloxanes display enhanced
stability, present good levels of functional-group tolerance
and, therefore, offer significant advantages over other orga-
nosilane coupling agents in the context of multistep synthe-
sis.[12a,14]
Catalyst
PdCl2A(MeCN)2
(PPh3)4
(OAc)2
TBAF [equiv]
Yield[a,b] [%]
1
2
3
4
5
6
7
8
9
U
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
0.2
52
15
76
19
19
82
77
83
68
19
Pd
Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
PdCl2
Pd
Pd
Pd
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
ACHTUNGTRENNUNG
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
10
[a] Reactions were performed by using disiloxane (1.0 equiv) and alkyl
halide (1.5 equiv). [b] Isolated yield after column chromatography.
pound 2 was formed in 83% yield as a single isomer
(Table 1, entry 8). The reactions were performed by using
1.0 equivalent of vinyldisiloxane and 1.5 equivalents of
halide. Since both vinyl groups in a single disiloxane mole-
cule are transferred, this corresponds so a slight excess of
disiloxane, which ensures the reaction goes to completion.
Next, we focused on determining whether other benzylic
halides and indeed halide equivalents could be effectively
cross-coupled by using the same conditions. Fortunately, in
addition to bromide substrates, benzylic chlorides, tosylates
and mesylates underwent clean conversion to the corre-
sponding product 2, all in good yield (Table 2, entries 1–3).
To determine the scope of the reaction, vinyldisiloxane
1 was reacted with a number of commercially available ben-
zylic halides (Table 2). Gratifyingly, the electronic nature of
the halide substrate did not significantly affect the outcome
of the reaction: electron rich (Table 2, entry 8), neutral
(Table 2, entry 1) and deficient (Table 2, entry 6) benzylic
halides underwent facile conversion to their corresponding
products all in good yield. In general, yields were higher for
meta- and para-substituted benzylic halides (Table 2, en-
tries 7 and 8) than more sterically hindered ortho-substituted
substrates (Table 2, entries 4 and 9). The reaction was also
successfully carried out with heteroaromatic substrates
(Table 2, entries 10 and 11), which demonstrated the poten-
tial applicability of this reaction for the synthesis of natural
products or pharmaceuticals. Pleasingly, a wide variety of
functional groups were tolerated. Entry 9 from Table 2 dem-
onstrated the selectivity profile of the reaction, in which no
cross-coupling was observed between the sp2 halide and the
disiloxane. In addition, the secondary halide, benzhydryl
chloride, was effectively cross-coupled in excellent yield, al-
though the more sterically demanding trityl chloride proved
beyond the orbit of this methodology. Unfortunately, the
methodology could not be extended to the cross-coupling of
benzylic halides containing beta hydrogens, for example, 1-
bromo-1-phenyl ethane.
Results and Discussion
Our study began with the reaction between vinyldisiloxane
1 (which can be easily synthesized through the hydosilyla-
tion of para-ethynylanisole)[12a] and benzyl bromide in the
presence of a range of palladium catalysts (Table 1) and
a source of fluoride to activate the disiloxane species. A
wide variety of palladium catalysts proved effective at cata-
lysing the reaction to some degree with [Pd2ACTHNUGTRNE(UNG dba)3] and [al-
lylPdCl]2 (APC) proving optimal (Table 1, entries 6 and 8).
The activation of the disiloxane species was accomplished
by using Lewis base catalysis. Several bases were investigat-
ed including KOtBu in tBuOH, but tetrabutylammonium
fluoride (TBAF) proved most effective. Highest yields were
obtained when 3.0 equivalents of TBAF were used.
The effect of temperature on the reaction was also stud-
ied. No appreciable difference was observed in yield when
the reaction was performed at 08C or at room temperature,
but significantly lower temperatures did result in a decrease
in yield. The optimum concentration for the reaction was
determined to be 0.5m.
By using our optimized reaction conditions (TBAF,
3.0 equiv; APC, 5 mol%, 0.5m; 4 h; RT), the desired com-
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Palladium-Catalysed Cross-Coupling of Vinyldisiloxanes
FULL PAPER
Table 2. Hiyama type cross-coupling of vinyldisiloxanes with benzylic hal-
ides and sulfonates.
tunately, this unwanted side product could be removed by
column chromatography, and the geometrically pure Z-ben-
zylstyrene (14) was isolated in good yield (76%).
The cross-coupling of more challenging allylic substrates
was also investigated. The effective cross-coupling of allylic
halides with vinyldisiloxanes would enable the formation of
skipped dienes, an important motif present in a plethora of
natural products (Figure 2). The presence of a hydrogen
Yield[a]
[%]
Product
1
2
3
4
88
86
79
50
5
6
70
70
Figure 2. Three examples of natural-products-containing the “skipped
diene” motif: a) arachidonic acid,
a
common fatty acid;[15a] b) ripo-
AHCTUNGTRENNUNG
statin A, an antibiotic that targets eubacterial RNA polymerase;[15b] and
7
8
9
84
87
64
c) jerangolid D, a potent antifungal agent.[15c]
atom in the beta position should allow the possibility of b-
hydride elimination upon oxidative addition of the halide;
however, when a variety of allylic halides were subjected to
the reaction conditions, none of the corresponding allenic
products were observed. The scope of this methodology was
investigated by cross-coupling a range of vinyldisiloxanes
with an array of allyl halides (Table 3). In general, yields for
the reaction were typically good-to-excellent, with only the
amino-containing disiloxane (Table 3, entry 6) giving the de-
sired diene in moderate yield, which could be attributed to
a competing amino-substitution reaction.
The possibility of cross-coupling non-aromatic vinyldisi-
loxanes using this methodology was also investigated. Grati-
fyingly, both alkyl substituted and terminal vinyldisiloxanes
were also tolerated as cross-coupling partners (Table 3, en-
tries 9 and 10). All of the reported yields correspond to geo-
metrically pure products. However, small quantities (<5%)
of isomeric products could be observed, if prolonged reac-
tion times were used.
10
11
85
67
12
85
0
13
[a] Isolated yield after column chromatography.
A possible mechanism for the reaction is shown in
Scheme 2. We suggest that the underlying mechanism fol-
lows the usual sequence of oxidative addition to a coordina-
tively unsaturated palladium complex 26, followed by trans-
metalation with a fluoride-activated disiloxane species 27[13]
and subsequent reductive elimination to give the coupled
product. Although a detailed mechanistic study is beyond
the scope of this report, we tentatively propose that the sim-
ilar reactivity displayed by bromides, chlorides, tosylates and
mesylates in this reaction indicate that oxidative addition is
rapid, and that either transmetalation or reductive elimina-
tion is the rate-determining step. In a detailed mechanistic
study of the fluoride-activated cross-coupling of alkenylsila-
Pleasingly the cross-coupling reaction could also be per-
formed by using Z-vinyldisiloxanes (Scheme 1). However,
a small degree of isomerization was observed; approximate-
ly 6% (relative ratio) of the E-benzylstyrene could be seen
1
in the H NMR spectrum of the crude reaction mixture. For-
Scheme 1. Cross-coupling of Z-vinyldisiloxane with benzyl bromide.
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D. R. Spring et al.
Table 3. Cross-coupling of vinyldisiloxanes with allylic halides.
Yield[a]
[%]
R1
Product
1
2
88
64
3
80
4
5
72
88
Scheme 2. Possible mechanism for the Hiyama type cross-coupling of
vinyl disiloxanes with benzylic and allylic halides and sulfonates.
cant advantages over alternative methods, which are often
blighted by the formation of isomeric compounds. For exam-
ple, separate reports by Chen et al.[16] and Fernꢂndez
et al.,[17] both of which employed Friedel–Crafts methodolo-
gy to synthesize this class of compound, document signifi-
cant isomeric contamination (up to 20% in some cases). In
addition, the mild reaction conditions and high functional-
group tolerance represent a notable improvement over anal-
ogous Suzuki type methodology, which demand elevated
temperatures (50–808C)[18] and extended reaction times on
occasion.[19]
6
35
7
8
73
53
To further demonstrate the potential utility of this meth-
odology, we sought to synthesize the cytotoxic natural prod-
uct bussealin A—an extract of the endemic Malagasy plant
Bussea sakalava.[20] Therefore, we carried out the cross-cou-
pling of disiloxane 32 with benzylic bromide 33 (Scheme 3).
The cross-coupling reaction proceeded in good yield, and re-
duction of the resulting olefin gave the desired product
quantitatively.
9
89
90
10
H
[a] Isolated yield after column chromatography.
nols with aryl iodides, Denmark reported a correlation be-
tween the rate of the reaction and silanol concentration,
which supported transmetalation as the turnover-limiting
step in the transformation, as is the case in the cross-cou-
pling of organostannanes. It is therefore possible that trans-
metalation is similarly turnover limiting in the cross-cou-
pling of vinyldisiloxanes with benzylic and allylic halides
and sulfonates.
This methodology represents a new approach for the syn-
thesis of 1,3-diphenylpropene derivatives and offers signifi-
Scheme 3. Total synthesis of bussealin A.
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Palladium-Catalysed Cross-Coupling of Vinyldisiloxanes
FULL PAPER
Polyphenolic compounds are employed in a variety of di-
verse functional roles in biological systems, from providing
resistance against bacterial[21] and viral[22] infections, to pro-
tecting against DNA-damaging solar radiation.[23] In addi-
tion, diphenylpropyl polyphenolic compounds and deriva-
tives thereof have exhibited anti-inflammatory,[24] antifun-
gal,[25] antivascular[26] and antiadipogenic activities.[27] We
therefore sought to further characterize the biological activi-
ty of bussealin A by testing its ability to inhibit the prolifer-
ation of an osteosarcoma-cell line (U2OS) and an adenocar-
cinomic human alveolar basal epithelial cell line (A549) by
using a sulforhodamine B (SRB) assay.[28] It was shown to
inhibit the proliferation of both cell lines with moderate po-
tency, with half maximal inhibitory concentration (IC50)
values of 17 mm (U2OS) and 52 mm (A549). Bussealin A has
previously been shown to display antiproliferative activity
against the human ovarian-cancer-cell line A2780 (IC50 =
36 mm).[20] Bussealin A was also screened for its ability to
arrest U2OS cells in mitosis by using a high-content screen-
ing approach (HCA). By treating U2OS cells with com-
pounds for 24 h and staining with a phosphohistone H3 anti-
body, cells arrested in mitosis can be detected. Although no
significant increase in mitotic cells was observed, clear signs
of cytotoxicity were observed despite the short timeframe
(Figure 3).
Experimental Section
General experimental procedure for the Hiyama type cross-coupling of
vinyldisiloxanes with alkyl halides: A solution of TBAF (3.0 equiv, 1.0m
in THF) was added to a mixture of disiloxane 1 (1.0 equiv, 120 mg,
0.30 mmol), benzyl bromide (1.5 equiv, 77 mg, 0.45 mmol) and [allyPdCl]2
(5 mol%). The reaction mixture was stirred at RT for 4 h. The mixture
was then filtered through a small layer of SiO2, eluted with ethyl acetate,
and the solvent was removed in vacuo. The crude material was purified
by flash-column chromatography (petroleum ether/ethyl acetate 100:0 to
99:1) providing the desired product
2 as a colourless oil (84 mg,
0.37 mmol, 83%). Rf =0.21 (SiO2; petroleum ether/ethyl acetate 49:1);
1H NMR (400 MHz, CDCl3): d=7.30 (2H, d, J=9.0 Hz, C-
À
(OCH3)CHCH), 7.33–7.28 (5H, m, Ar CH), 6.84 (2H, d, J=9.0 Hz, C-
(OCH3)CH), 6.41 (1H, d, J=15.5 Hz, CH=CHCH2), 6.22 (1H, dt, J=
15.5 Hz, 7.0 Hz, CH=CHCH2), 3.80 (3H, s, OCH3), 3.54 ppm (2H, d, J=
7.0 Hz, CH2); 13C NMR (101 MHz, CDCl3): d=158.8 (C
AHCTUNGTRENNUNG
À
À
À
(Ar C), 130.4 (CH=CHCH2), 130.3 (Ar CACTHNUTRGNEUNG(OCH3)CHCHC), 128.7 (Ar
À
À
À
CH), 128.5 (Ar CH), 127.2 (Ar CH), 127.1 (Ar CH), 126.1 (CH=
CHCH3), 113.9 (C(OCH3)CH), 55.3 (OCH3), 39.3 ppm (CH2); IR (neat):
AHCTUNGTRENNUNG
À
À
À
À
n˜max =3027 (w, C H), 2956 (w, C H), 2907 (w, C H), 2834 (w, C H),
1606 (s, C=C), 1578 (w, C=C), 1509 (s, C=C), 1494 cmÀ1 (m, C=C). This
data is consistent with that previously reported.[31] Experimental details
and characterization data are provided in the Supporting Information.
Acknowledgements
The authors thank GlaxoSmithKline and the EU, EPSRC, BBSRC,
MRC, Cancer Research UK, Wellcome Trust and Frances and Augustus
Newman Foundation for funding.
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To summarize, we have developed a new procedure for the
effective cross-coupling of vinyldisiloxanes with benzylic
and allylic halides and sulfonates. The reaction proceeds
under mild conditions and tolerates a wide variety of func-
tional groups. The procedures described herein offer a new,
cost-effective, operationally simple and robust method for
the preparation of a wide variety of 1,3-diphenylpropenes
and skipped dienes under mild conditions. Currently, we are
utilizing this approach for the synthesis of functionally di-
verse small molecules,[29] the anti-mitotic activity of which
will be assessed by using HCA as part of our chemical ge-
netic-screening program.[30]
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Received: February 9, 2012
Published online: && &&, 0000
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Palladium-Catalysed Cross-Coupling of Vinyldisiloxanes
FULL PAPER
Cross-Coupling
E. C. Frye, C. J. OꢀConnor,
D. G. Twigg, B. Elbert, L. Laraia,
D. G. Hulcoop, A. R. Venkitaraman,
D. R. Spring* ................. &&&& — &&&&
Palladium-Catalysed Cross-Coupling
of Vinyldisiloxanes with Benzylic and
Allylic Halides and Sulfonates
The Hiyama type cross-coupling of
aryl and alkyl vinyldisiloxanes with
activated alkyl halides and pseudoha-
lides is reported. This methodology is
an important expansion of current
methods for Csp2–Csp3 bond formation
(see scheme). The synthetic utility of
the methodology is exemplified in the
total synthesis of the natural product
bussealin A. In addition, the antiproli-
ferative ability of bussealin A was eval-
uated in two cancer-cell lines.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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&
ÞÞ
These are not the final page numbers!