Diversity-oriented synthesis of disubstituted alkenes using masked silanols

Article abstract of DOI:10.1021/ol100895d

(Figure presented) The regio- and stereoselective synthesis and subsequent Hiyama cross coupling of pentafluorophenyldimethylvinylsilanes has been developed, thus providing a convenient and robust method for the diversity-oriented synthesis of (E)-, (Z)- and α-disubstituted alkenes from terminal alkynes. Pentafluorophenyldimethylvinylsilanes undergo cross-coupling reactions with excellent selectivity and in good yields, offering an attractive alternative to existing masked silanols.

Full text of DOI:10.1021/ol100895d

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2806-2809
Diversity-Oriented Synthesis of
Disubstituted Alkenes Using Masked
Silanols
Hannah F. Sore, David T. Blackwell, Simon J. F. MacDonald, and
David R. Spring*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW
spring@ch.cam.ac.uk
Received April 19, 2010
ABSTRACT
The regio- and stereoselective synthesis and subsequent Hiyama cross coupling of pentafluorophenyldimethylvinylsilanes has been developed,
thus providing a convenient and robust method for the diversity-oriented synthesis of (E)-, (Z)- and r-disubstituted alkenes from terminal
alkynes. Pentafluorophenyldimethylvinylsilanes undergo cross-coupling reactions with excellent selectivity and in good yields, offering an
attractive alternative to existing masked silanols.
Diversity-oriented synthesis (DOS) is an efficient method
for the synthesis of structurally diverse compounds by
variation of the core molecular scaffold and stereochemistry.1
In this context, the development of functional group meth-
odologies of broad synthetic utility that allow the regio- and
stereoselective synthesis of (E)-, (Z)- and R-disubstituted
alkenes from a single common precursor would be valuable.
Such chemistries could be exploited in reagent-based branch-
ing pathways to facilitate rapid structural diversification from
a common functionalized starting material, increasing mo-
lecular diversity and generating products suitable for further
modification and diversification. Herein, we report the
development of a methodology for the synthesis of all viable
disubstituted alkene isomers from terminal alkynes.
palladium catalyzed cross coupling; however, poor ste-
reospecificity in the hydrometalation and/or loss of double-
bond geometry on cross coupling as well as poor reagent
stability and toxicity remain ongoing issues.2,3 To address
this synthetic problem, numerous catalysts have been de-
veloped for the synthesis of vinylorganosilyl species ste-
reospecifically.3 Additionally, in more recent years, the
development of organosilicon reagents as effective coupling
nucleophiles has aroused interest, particularly because of their
greater stability, mild cross-coupling conditions, and low
toxicity compared to other organometallic nucleophiles.4,5
(2) (a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100,
3257. (b) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957. (c)
Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, 1998. (d) Corbet, J.-P.; Mignani, G. Chem. ReV.
2006, 106, 2651. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442. (f) Stille, J. K. Angew. Chem., Int. Ed.
Engl. 1986, 25, 508. (g) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
The synthesis of disubstituted alkenes from terminal
alkynes can be achieved via hydrometalation and subsequent
(1) (a) Schreiber, S. L. Nature 2009, 457, 153. (b) Galloway, W. R. J. D.;
Spring, D. R. Expert Opin. Drug DiscoVery 2009, 4, 467. (c) Nielsen, E.;
Screiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48. (d) Spandl, R.; Bender,
A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149. (e) Spandl, R.; Diaz-
Gavilan, M.; O’Connell, K. M. G.; Thomas, G. L.; Spring, D. R. Chem.
Rec. 2008, 8, 129.
2457
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(3) Trost, B. M.; Ball, Z. T. Synthesis 2005, 6, 853
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(4) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (b)
Denmark, S. E.; Smith, R. C.; Chang, W.-T. T.; Muhuhi, J. M. J. Am. Chem.
Soc. 2009, 131, 3104. (c) Denmark, S. E.; Neuville, L.; Christy, M. E. L.;
Tymonko, S. A. J. Org. Chem. 2006, 71, 8500
.
10.1021/ol100895d  2010 American Chemical Society
Published on Web 05/21/2010

After extensive research by Denmark et al., the potential of
organosilanols to cross couple under base activation was
realized and subsequently exploited to great effect.6 Since
these fundamental discoveries, a variety of masked silanols
have been developed offering the advantage of increased
stability relative to the silanol, thus providing the potential
to modify and carry the silyl species through multiple steps.7
It was anticipated that development of pentafluorophe-
nyldimethylvinylsilanes as masked silanols would allow for
further elaboration prior to cross coupling and/or their direct
application in the selective synthesis of all possible geometric
isomers of disubstituted alkenes.8 We envisaged that such
methodology would prove to be a valuable advance with
potential applications in both target- and diversity-oriented
synthesis.
Table 1. Hydrosilylation of Terminal Alkynes (2) Using
Pentafluorophenyldimethylsilane (1)
Early attempts by Brennan and Gilman to develop the
hydrosilylation of terminal alkynes with pentafluorophe-
nyldimethylsilane (1) suffered from poor regioselectivity,
with mixtures of R- and ꢀ-vinylsilanes being produced when
H2PtCl6 was employed as the catalyst.9 Advances in the Pt-
catalyzed hydrosilylation of terminal alkynes has led to the
exclusive synthesis of (E)-ꢀ-vinylsilanes with a variety of
silanes, when the organically soluble (tBu3P)Pt(DVDS)
complex was used.10,7h Application of the Pt complex to the
hydrosilylation of terminal alkynes with silane 1 resulted in
excellent selectivity: only the (E)-isomer was observed by
1H NMR analysis of the crude reaction mixture (Table 1,
entries 1, 4, 6, and 8). Significantly, further modification of
the vinylsilane (3) was possible prior to cross coupling,
building upon the diversity (Table 1, entry 10).
Historically, generation of the (Z)-ꢀ-vinylsilanes by ste-
reoselective hydrosilylation of terminal alkynes has proven
to be a more complex and difficult task than formation of
the corresponding thermodynamically favored (E)-ꢀ-vinyl-
silanes.3 Accordingly, the synthesis of 3-(Z) was more
challenging. Rh-, Ir- and Ru-based catalysts were all
explored. The Ru complex, RuHCl(CO)(PCy3), developed
a Reaction conditions: (A) silane (1 equiv), alkyne (1.1 equiv),
(tBu3P)Pt(DVDS) (0.1 mol %), toluene, 0 °C to rt; (B) silane (1 equiv),
alkyne (1 equiv), RhHCl(CO)(PCy3)2 (5 mol %), DCM, rt; (C) silane (1.05
equiv), alkyne (1 equiv), [Cp*Ru(MeCN)3]PF6 (1 mol %), DCM, 0 °C to
rt; (D) (i) silane (1 equiv), propargyl amine (1 equiv), (tBu3P)Pt(DVDS)
(0.1 mol %), toluene, 0 °C to rt, (ii) benzoyl chloride (1.2 equiv),
triethylamine (1.2 equiv), THF, 0 °C. b Determined by 1H NMR spectroscopy
c Isolated yield. d 10 mol % catalyst used.
(5) (a) Denmark, S. E. J. Org. Chem. 2009, 74, 2915. (b) Denmark,
S. E.; Baird, J. D. Chem.sEur. J. 2006, 12, 4954
.
(6) (a) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486.
(b) Denmark, S. E.; Sweis, R. Acc. Chem. Res. 2002, 35, 835. (c) Denmark,
S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439.
(7) Examples of masked silanols: (a) Denmark, S. E.; Wehrli, D.; Choi,
J. Y. Org. Lett. 2000, 2491. (b) Denmark, S. E. J. Org. Chem. 2009, 74,
2915. (c) Denmark, S. E.; Baird, J. D. Chem.sEur. J. 2006, 12, 4954. (d)
Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821. (e) Sore,
H. F.; Boehner, C. M.; MacDonald, S. J. F.; Norton, D.; Fox, D. J.; Spring,
D. R. Org. Biomol. Chem. 2009, 7, 1068. (f) Prukala, W. Synlett 2008, 19,
3026. (g) Denmark, S. E.; Butler, C. R. J. Am. Chem. Soc. 2008, 130, 3690.
(h) Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073. (i) Anderson, J. C.;
Munday, R. H. J. Org. Chem. 2004, 69, 8971. (j) Anderson, J. C.; Anguille,
S.; Bailey, R. Chem. Commun. 2002, 18, 2018. (k) Denmark, S. E.; Liu,
J. H.-C. J. Am. Chem. Soc. 2007, 129, 3737. (l) Trost, B. M.; Machacek,
M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895. (m) Itami, K.; Mitsudo, K.;
Nokami, T.; Kamei, T.; Koike, T.; Yoshida, J.-i. J. Organomet. Chem. 2002,
653, 105. (n) Itami, K.; Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001,
123, 5600. (o) Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 31,
138.
by Ozawa,11 was the most promising, producing 3-(Z) with
reasonable selectivity and in a modest yield (Table 1, entry
2). Alternative strategies were investigated for the exclusive
synthesis of the (Z)-isomer.
Markovnikov addition of silanes across terminal al-
kynes has been achieved with excellent regioselectivity
using the cationic cyclopentadienylruthenium complex,
[Cp*Ru(MeCN)3]PF6.12 Pleasingly, treatment of silane 1
with a range of terminal alkynes produced the R-isomer
exclusively, when catalyzed by the Ru complex (Table 1,
entries 3, 5, and 7). Interestingly, in order to drive the reaction
(8) It was anticipated that the lower pKa (pentafluorobenzene pKa ) 25)
of the pentafluorophenyl group relative to existing “masked silanols” would
faciliate its deprotection and subsequent participation in the regio- and
stereoselective cross coupling under mild conditions.
(11) Ozawa, F.; Katayama, H.; Taniguchi, K.; Kobayashi, M.; Sagawa,
T.; Minami, T. J. Organomet. Chem. 2002, 645, 192.
(9) Brennan, T.; Gilman, H. J. Organomet. Chem. 1969, 16, 63.
(10) Chandra, G.; Lo, P. Y.; Hitchcock, P. B.; Lappert, M. F. Organo-
(12) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644.
(b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
metallics 1987, 6, 191
.
Org. Lett., Vol. 12, No. 12, 2010
2807

to completion with the more sterically demanding pheny-
lacetylene, an increased catalyst loading was required;
however, excellent selectivity was maintained at the higher
catalyst loading (Table 1, entry 9).
yielding the desired disubstituted double bonds with complete
retention of configuration (Table 2, enteries 1-4 and 6).13
The different stereochemical outcomes observed when
cross-coupling vinylsilanes (3) under base or fluoride activa-
tion indicate that these methods proceed through alternative
mechanisms. The fluoride activation pathway is believed to
proceed via a pentacoordinate silicate intermediate,14 whereas
under base activation a tetracoordinate transition state
involving a covalent Pd-O-Si bond has been reported.5,15
It is reasonable to conclude that the fluoride activation
pathway appears to be less susceptible to steric or electronic
changes in the vinylsilane, consequently leading to a higher
proportion of the desired ipso-substituted product.
With the regio- and stereoselective synthesis of 3-(E) and
3-r vinylsilanes established, their effectiveness at cross
coupling under mild reaction conditions and with retention
of configurations was examined. Two alternative methods
of activation were explored. Initial investigation into the base
activated cross coupling of vinylsilanes looked promising,
with good yields and excellent selectivity for the ipso-
subsituted product (direct substitution of the C-Si bond with
no regioisomerization) being obtained when the aryl-
substituted (E)-vinylsilane was reacted (Table 2, entry 5).
Synthesis of 3-(Z) via hydrosilylation with silane 1 and
terminal alkynes (2) was met with limited success; conse-
quently, an alternative approach involving the synthesis and
subsequent reduction of the alkynylsilane was investigated.
A variety of alkynes were successfully deprotonated with
nBuLi and treated with the commerically available chlorosi-
lane 6 forming the corresponding alkynylsilanes in excellent
yields. A number of reduction conditions were explored,
some protocols led to over reduction forming the alkane and/
or mixtures of isomers being observed. In an approach similar
to those of Panek16 and Anderson,7i it was found that
treatment of the alkynylsilanes with diisopropylaluminium
hydride produced the respective (Z)-vinylsilanes in good
yields and selectivity. Telescoping the synthesis of the
alkynylsilane, reduction, and subsequent cross coupling
ultimately produced the desired (Z)-disubstituted alkenes
5-(Z) with excellent geometrical purity and in an overall good
combined yield for the four steps (Table 3).
Table 2. Hiyama Cross Coupling of (E)- and R-Vinylsilanes
Table 3. Synthesis of (Z)-Alkenesa
a Reaction conditions: (A) vinylsilane (1 equiv), aryl iodide (0.75 equiv),
TBAF (2 equiv), Pd(dba)2 (5 mol %), THF, rt; (B) vinylsilane (1 equiv),
aryl iodide (0.75 equiv), KOH (3 equiv), Pd(dba)2 (2.5 mol %), MeOH, rt.
b Isolated yield of isomerically pure material.
However, on expanding the substrate scope of the vinylsilane,
loss of selectivity was observed under base activation
conditions when aryl-substituted R-vinylsilanes or alkyl-
substituted vinylsilanes were reacted. The nature of the
substituent and the double-bond orientation were both highly
influential on the successful outcome of the base-activated
reaction. Pleasingly, on switching the activation source to
fluoride, improved selectivity for the ipso-subsituted product
was observed. Aryl- and alkyl-substituted (E)- and R-vinyl-
silanes readily participated in cross coupling with aryl iodides
a
n
Reaction procedure: (i) alkyne (1 equiv), BuLi (1.6 M in hexanes,
1.05 equiv), THF, -78 °C, (ii) chlorosilane (1.05 equiv), -78 °C to rt,
work up, (iii) DIBAL (1 M in toluene, 5 equiv), Et2O, 0 °C, (iv) aryl iodide
(0.75 equiv), TBAF (2 equiv), Pd(dba)2 (5 mol %), THF, rt. b Isolated yield
of isomerically pure material (combined yield over four steps).
2808
Org. Lett., Vol. 12, No. 12, 2010

Scheme 1. Synthesis of Resveratrol Analogues
To display the utility of the newly developed methodology
in a DOS context, all geometric isomers of trimethoxyres-
ervatrol were synthesized from the same commercially
available terminal alkyne and aryl halide (Scheme 1).
Resveratrol and its analogues show a range of therapeutic
activities including cardiovascular prevention, anti-inflam-
matory and anticancer properties.17 Synthesis of the inter-
mediate silanes proceeded smoothly via either hydrosilylation
or nucleophilic substitution of the chlorosilane. On subjecting
the intermediate silanes to fluoride-induced cross coupling
(with prior reduction for the (Z)-isomer), excellent selectivity
was achieved and the corresponding (E)-, R-, and (Z)-
disubstituted alkenes were isolated in good yields.
In summary, a convienent and versatile method has been
developed for the synthesis of (E)-, (Z)-, or R-disubsituted
alkenes from terminal alkynes utilizing pentafluorophe-
nyldimethylsilyl intermediates. The vinylsilane intermediates
were formed with excellent regio- and stereoselectivity and
under the appropriate conditions were transformed into the
corresponding alkenes without loss of selectivity. Such
chemistries thus provide an efficient means of achieving
molecular diversification from common alkyne starting
materials (through variation of the reagents employed); as
such, these methods are expected to prove valuable in
branching, reagent-based DOS pathways. These methods are
currently being used in the preparation of structurally diverse
small molecule collections. Furthermore, we anticipate that
these new methodologies will prove valuable in a wider
synthetic context, with potentially broad applications in the
synthesis of natural products and pharmaceutical agents. In
addition, this work contributes to the ongoing development
of silicon cross coupling as a viable and practical alternative
to existing strategies.
Acknowledgment. We are grateful to the EPSRC, BBSRC,
and GlaxoSmithKline for their generous financial support.
Supporting Information Available: General experimental
procedures, characterization of synthesized compounds, and
spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100895D
(13) Aryl bromides cross couple in comparable yields.
(14) Denmark, S. E.; Sweis, R. F.; Wehrli, D. J. Am. Chem. Soc. 2004,
126, 4865.
(15) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876.
(16) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006, 71,
3639.
(17) (a) Moro, A. V.; Cardoso, F. S. P.; Correia, C R. D. Tetrahedron
Lett. 2008, 49, 5668. (b) Roberti, M.; Pizzirani, D.; Simoni, D.; Rondanin,
R.; Baruchello, R.; Bonora, C.; Buscemi, F.; Grimaudo, S.; Tolomeo, M.
J. Med. Chem. 2003, 46, 3546.
Org. Lett., Vol. 12, No. 12, 2010
2809