Vinyldimethylphenylsilanes as safety catch silanols in fluoride-free palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/jo048746t

A series of five structurally diverse vinyldimethylphenylsilanes have been shown to undergo a fluoride-free one-pot palladium-catalyzed cross-coupling reaction with phenyl iodide to give ipso coupled products in 62-86% yield. The limitations of this present protocol lie in the activation of Si-Ph vs protodesilylation by KOTMS/18-C-6, which seems sensitive to the sterics of cis substituents, but not geminal substituents.

Full text of DOI:10.1021/jo048746t

SCHEME 1
Vinyldimethylphenylsilanes as Safety
Catch Silanols in Fluoride-Free
Palladium-Catalyzed Cross-Coupling
Reactions
James C. Anderson* and Rachel H. Munday
School of Chemistry, University of Nottingham,
Nottingham, NG7 2RD, United Kingdom
j.anderson@nottingham.ac.uk
Received July 22, 2004
Abstract: A series of five structurally diverse vinyldim-
ethylphenylsilanes have been shown to undergo a fluoride-
free one-pot palladium-catalyzed cross-coupling reaction
with phenyl iodide to give ipso coupled products in 62-86%
yield. The limitations of this present protocol lie in the
activation of Si-Ph vs protodesilylation by KOTMS/18-C-6,
which seems sensitive to the sterics of cis substituents, but
not geminal substituents.
advance into the cross coupling of organo silicon com-
pounds has been the advent of “safety catch” silanols.7
These are derivatives that are, ideally, stable to a wide
range of reaction conditions and workup procedures, but
which can be selectively unmasked to give the more
reactive Si-OH or Si-X coupling partner under specific
conditions. Examples of these include methylsilacyclobu-
tanes,8 silyl hydrides,9 2-pyridylsilanes,10 2-thienylsi-
lanes,11 and benzyldimethylsilanes.12 It has recently been
shown that the vinylbenzyldimethylsilyl group is robust
to acidic and basic hydrolysis and that standard silyl
ethers can be deprotected in its presence.12 Unmasking
of the benzyldimethylsilane, to prepare for palladium-
catalyzed coupling, takes place with fluoride ion which
negates the possibility of using this coupling procedure
in the presence of silyl ether protecting groups which are
a prominent feature of many multistep syntheses. We
had previously reported that treatment of vinyldimeth-
ylphenylsilanes with KOtBu and 18-C-6 in THF gives a
vinyl silanol and have therefore been investigating the
use of the robust dimethylphenylsilyl group as a safety
catch silanol.13 Here we report a one-pot fluoride-free
cross-coupling procedure in which a range of vinyldim-
ethylphenylsilanes have been unmasked and the result-
ing vinyl silanols coupled regioselectively with phenyl
iodide in good yield. The use of the dimethylphenylsilyl
group as an extremely stable cross-coupling partner
under fluoride-free cross-coupling conditions offers the
possibility of its use as a safety catch silanol in multistep
syntheses with silyl ether protecting groups present.
Carbon-carbon bond formation by palladium-catalyzed
cross-coupling reactions is now a general and powerful
method in organic synthesis.1 The most notable examples
of cross coupling between organometallic nucleophiles
and organic halides (or triflates) are the Suzuki coupling
of organoboranes,2 the Stille coupling of organostan-
nanes,3 and the Negishi coupling of organozincs.4 Despite
their wide utility these methods have specific disadvan-
tages such as toxicity, ease of handling, functional group
compatibility, or air sensitivity. Over the past decade the
palladium-catalyzed cross coupling of organo silicon
compounds with organic halides has been developed as
an alternative cross-coupling procedure.5 Organo silicon
compounds are usually activated to cross coupling by
addition of a fluoride source, which forms a silicon ate
complex that is able to participate in transmetalation.
Heteroatom-substituted alkenyl and aryl silanes such as
haloorganosilanes, silanols, and silyl ethers are usually
required for the reaction to take place.6 However, these
are sensitive to acidic and/or basic hydrolysis and are
generally incompatible with silicon-based protecting
group strategies. These limitations preempt the early
stage incorporation of these silicon-based cross-coupling
partners in multistep syntheses. A recent significant
Results and Discussion. Our previous communica-
tion reported the one-pot cross-coupling procedure of
vinyl silane 1 (Scheme 1).13 Treatment of 1 with KOtBu
and 18-C-6 in THF gave the corresponding silanol 2,
which could be isolated and coupled to give the cine
(1) (a) Metal catalysed cross coupling reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Tsuji, J.
Palladium Reagents and Catalysts, Innovations in Organic Synthesis:
Wiley: Chichester, UK, 1995. (c) Heck, R. F. Palladium Reagents in
Organic Synthesis; Academic Press: New York, 1985.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Suzuki, A. Metal Catalysed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2.
(3) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1.
(c) Mitchell, T. N. Metal Catalysed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 4.
(4) Bates, R. Organic Synthesis using Transition Metals; Sheffield
Academic Press: Malden, MA, 2000.
(5) (a) Hiyama, T. Metal Catalysed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany,
1998; Chapter 10. (b) Denmark, S.; Ober, M. Aldrichim. Acta 2003,
36, 75.
(6) (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(b) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531.
(7) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Curr. Org. Synth.
2004, 1, 211.
(8) (a) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121,
5821. (b) Denmark, S. E.; Wang, Z. Synthesis 2000, 999. (c) Denmark,
S. E.; Wu, Z. Org. Lett. 1999, 1, 1495.
(9) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221.
(10) (a) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei,
T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577. (b) Itami, K.;
Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 5600. (c) Itami,
K.; Mitsudo, K.; Nokami, T.; Kamei, T.; Koike, T.; Yoshida, J. J.
Organomet. Chem. 2002, 653, 105.
(11) Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 138.
(12) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5,
1895.
(13) Anderson, J. C.; Anguille, S.; Bailey, R. Chem. Commun. 2002,
2018.
10.1021/jo048746t CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/09/2004
J. Org. Chem. 2004, 69, 8971-8974
8971

SCHEME 2a
SCHEME 3a
a Reagents: (i) base (3 equiv), 18-C-6 (3 equiv), THF, rt. Product
distribution of crude reaction mixture by 1H NMR when base is
KOH, 2:4, 4:1 after 7 h; KOTMS, 2 after 2 h; KOAc, 1 after 14 h.
a Reagents: KOtBu or KOtBu and 18-C-6 or 18-C-6, TBAF, PhI,
Pd2dba3, rt, 3 h. Product distribution of crude reaction mixture
by 1H NMR with KOtBu 2:4, 10:1, KOtBu and 18-C-6 2:4, 13:1,
18-C-6 5.
formation was complete (TLC, silica, 2% EtOAc/petrol),
followed by addition of TBAF, Pd2dba3, and PhI allowed
coupling to proceed and gave a 3:1 mixture of ipso coupled
product 5:starting material 1. Silanol formation was then
investigated with a range of other bases in combination
with an equimolar amount of 18-C-6 as this had been
found to be necessary when investigating silanol forma-
tion with KOtBu (Scheme 3). The success of KOTMS to
promote silanol formation was of particular interest as
Denmark had used this base as an activator in fluoride-
free cross-coupling reactions of silanols.15 We inferred
that this base would not inhibit the palladium chemistry
of the coupling reaction and could also lead to the
development of a one-pot cross-coupling reaction using
the dimethylphenylsilyl group as a “safety catch silanol”
without the need for TBAF. Treatment of dimethylphe-
nylsilane 1 with KOTMS and 18-C-6 at room tempera-
ture for 30 min followed by addition of Pd2dba3 and PhI
and the mixture heated to reflux for 2 h gave 86% of ipso
coupled product 5. Performing the reaction at room
temperature alone led to a mixture of silanol 2, disilox-
ane, and ipso coupled product 5, even with continued
stirring for several days or addition of TBAF.
With a protocol for a one-pot coupling established we
returned to our original reaction,13 which had originally
given cine coupled product 3 (Scheme 1), but with varying
equivalents of KOtBu and 18-C-6 and slight alterations
of reaction conditions gave variable ratios of 3, silanol 2,
and protodesilylated material 4. A possible explanation
for the formation of cine coupled product 3 could be a
Heck reaction of protodesilylated material 4, the forma-
tion of the latter we knew from other work was suscep-
tible to moisture and the quality of reagents.17 Submit-
ting alkene 4, formed via protodesilylation of the vinyl
silane 1, to conditions used to cross-couple silanol 2 gave
almost quantitative conversion to cine product 3 with
heating (eq 1).18 Therefore a possible explanation for the
results obtained previously by us was that protodesily-
lation was rapid with consumption of most of the base
that then allowed a Heck reaction to proceed.
substitution product 3. Combining the two reactions to
give a one-pot procedure gave an 85% yield of the same
cine product (Scheme 1). The cine product presumably
arises from a Heck-type process or Pd(0) carbene species
rather than transmetalation from Si to Pd as Denmark
observes in his silanol cross couplings.6 We wished to in-
vestigate the generality of this procedure and the stereo-
specificity of the reaction with respect to E, Z and more
substituted alkenes. We knew the reaction proceeds
through the intermediacy of a silanol (2) and the use of
these groups as a coupling handle with many different
electrophilic coupling partners has been well documented.7
Before synthesizing a range of vinyl silanes we re-
peated our initial experiments with vinyl silane 1 and
found the reaction to be very sensitive to small differences
in reaction conditions. In addition to the previously
observed cine coupled product 3 we observed silanol 2
and protodesilylated material 4. From our previous work
we had good evidence13 that the reaction proceeded via
a silanol intermediate and therefore carried out studies
to maximize the conversion of phenyl silane to silanol.
Treatment of vinyl silane 1 with 3 equiv of both KOtBu
and 18-C-6 gave complete conversion to silanol 2 in ∼30
min at room temperature. However, using these condi-
tions in our one-pot procedure gave no coupled product,
with only a 5:2 mixture of silanol 2:protodesilylated
material 4 (Scheme 2). Subjection of silanol 214 to
Denmark’s cross-coupling conditions15 gave complete
conversion to ipso coupled product 5 (Scheme 2) rather
than cine coupled product 3. We reasoned that excess
KOtBu or 18-C-6 could be inhibiting the one-pot reaction
and indeed when we attempted to repeat the coupling of
silanol 2 in the presence of KOtBu or KOtBu and 18-C-6
or 18-C-6 alone, we only observed coupled product in the
absence of KOtBu (Scheme 2). It seemed that KOtBu was
inhibiting the palladium catalyst either by competing
with silyloxide for the palladium center, which Denmark
had noted while developing fluoride-free cross-coupling
conditions,16 or by degradation of dba ligand. To develop
a one-pot procedure we rationalized two possible proto-
cols: use KOtBu to form silanol and then quench the
excess base before adding reagents for coupling, or find
another base to effect silanol formation which did not
inhibit the coupling reaction.
To investigate the scope and limitations of our one-
pot coupling procedure we synthesized four representa-
tive alkenes 6-9 (Figure 1). Vinyldimethylphenylsilanes
6 and 7 were chosen to ascertain whether double bond
geometry was conserved during coupling. Alkenes 8 and
9 were chosen to probe whether more hindered trisub-
stituted alkenes could be prepared stereoselectively. The
A brief study showed that addition of a slight molar
excess of AcOH (1.1 equiv), to KOtBu, after silanol
(14) Prepared by analogy to: Hirabayashi, K.; Takahisa, E.; Nishi-
hara, Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 1998, 71, 2409.
(15) Denmark, S. E.; Pan, W. J. Organomet. Chem. 2002, 653, 98.
(16) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439.
8972 J. Org. Chem., Vol. 69, No. 25, 2004

TABLE 1. Scope of Safety Catch Silane with Respect to Alkene
entry
alkene
R1
R2
R3
conversionb
yield,c %
1
2
1
6
H
H
H
(CH2)3Ph
(CH2)3Ph
>95% ipso
10:1 ipso:
desilylated
3:1 ipso:
desilylated
2:1 ipso:
86
82
(CH2)3Ph
3
4
5
7
8
9
(CH2)3Ph
(CH2)3Ph
H
H
H
62d
H
Me
67d
desilylated
100% ipso
Me
(CH2)3Ph
76d,e
a Reagents: KOTMS (2.0 equiv), 18-C-6 (2.0 equiv), THF, rt, 30 min; PhI (1.1 equiv), Pd2dba3 (5 mol %), 67 °C, 2 h. b Measured from
1
crude H NMR. c Isolated yield of pure ipso coupled product. d Structure of product confirmed by nOe (see the Supporting Information).
e Reaction mixture heated to 67 °C during silanol formation.
SCHEME 4a
FIGURE 1.
diastereoisomers of 8 and 9 could not be prepared in pure
form and so were not investigated.
A conventional route was used to convert alkyne 10
into both E-vinyl silane 6 and Z-vinyl silane 7, although
the stereoselective ruthenium catalyzed hydrosilylation
of terminal alkynes with dimethylphenylsilane is known.19
Treatment of 10 with DIBAL and I220 gave E-vinyl iodide
11,21 which was subsequently metalated and quenched
with dimethylphenylsilyl chloride in good yield to give 6
a Reagents: (i) DIBAL, I2; (ii) t-BuLi, PhMe2SiCl; (iii) n-BuLi,
(Scheme 4). Conversely, treatment of the silyl alkyne 12,
derived from 10, with DIBAL and then H2O22 gave 7 in
PhMe2SiCl; (iv) DIBAL, H2O; (v) s-BuLi, MeI; (vi) s-BuLi, Ph(CH2)3I.
excellent yield. Trisubstituted alkene 8 was accessed from
acetylene 12 by hydroalumination with DIBAL and
with cis substituents 7 and 8 were more likely to undergo
quenching with iodine.23 Stereospecific metalation and
protodesilylation, but still gave synthetically useful
alkylation with methyl iodide gave 8 in good yield.24
isolated yields of ipso coupled products (entries 3 and 4).
Similarly 1425 was stereospecifically converted into 15
From these results it would seem that the limitations of
and the resultant vinyl anion isomerized26 and converted
this present protocol lie in the activation of Si-Ph vs
into 9 in good yield (Scheme 4).18
protodesilylation by KOTMS/18-C-6, which seems sensi-
The four vinyl silanes 6-9 were then submitted to the
tive to the sterics of cis substituents, but not geminal
optimized one-pot cross-coupling procedure developed for
substituents. We can conclude that the phenyldimethyl-
1 (eq 2, Table 1). Phenyl-vinyl silanes 1, 6, and 9 without
silyl group is a viable safety catch silanol for use in
substituents cis to the silyl group gave excellent yields
fluoride-free palladium-catalyzed cross-coupling reactions
of ipso coupled products under these fluoride-free one-
and should be of use in multistep organic syntheses in
pot reaction conditions (entries 1, 2, and 5). Substrates
the presence of silyl ether protecting groups.
(17) Anderson, J. C.; Whiting, M. J. Org. Chem. 2003, 68, 6160.
Experimental Section
(18) 1H NMR of the crude reaction mixture showed 3:5 (10:1), which
gave a 78% isolated yield of cine product 3.
General Procedure for Cross Coupling. To a solution of
vinyldimethylphenylsilane (0.20 mmol) in THF (1.5 mL) was
added KOTMS (2.0 equiv) and 18-C-6 (2.0 equiv) at room
temperature and the solution was stirred for 30 min. PhI (1.1
equiv) was added and after a further 10 min Pd2dba3 (5 mol %)
was added and the mixture was then heated at reflux for 2 h.
The reaction mixture was purified by filtering through a silica
plug and eluting with Et2O, column chromatography (petrol),
and where necessary bulb-to-bulb distillation to give the coupled
product.
(19) Katayama, H.; Taniguchi, K.; Kobayashi, M.; Sagawa, T.;
Minami, T.; Ozawa, F. J. Organomet. Chem. 2002, 645, 192.
(20) On, H. P.; Werner, J. A.; Zweifel, G. University of California,
Davis, unpublished results.
(21) Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.; Capdevila,
J. H.; Falck, J. R. Org. Lett. 2003, 5, 4759.
(22) Molander, G. A.; Mautner, K.; J. Org. Chem. 1989, 54, 4042.
(23) Zweifel, G.; Lewis, W. J. Org. Chem. 1978, 43, 2739
(24) Structure confirmed by nOe, details in the Supporting Informa-
tion.
(25) Mao, S. S. H.; Liu, F.-Q.; Tilley, T. D. J. Am. Chem. Soc. 1998,
120, 1193.
(26) Zweifel, G.; Murray, R. E.; On, H. P. J. Org. Chem. 1981, 46,
1292.
Acknowledgment. This work is part of the Ph.D.
Thesis of R.H.M., University of Nottingham. We thank
J. Org. Chem, Vol. 69, No. 25, 2004 8973

data for all compounds, and 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
the EPSRC and GlaxoSmithKline for financial support,
Dr. N. J. Parr for helpful discussions, and Mr. T.Holling-
worth and Mr. D. Hooper for providing mass spectra.
Supporting Information Available: Experimental de-
tails for the synthesis of vinyl silanes, full characterization
JO048746T
8974 J. Org. Chem., Vol. 69, No. 25, 2004