Stereoselective Synthesis of β-(Chloro)vinylsilanes Using a Regio-and (E)-Stereoselective Bis-Stannylation of Unsymmetrically Substituted Butadiynes: Application to the Synthesis of a Masked Triyne

Article abstract of DOI:10.1021/ol035536e

(Equation Presented) A highly regio- and stereoselective bis-stannylation of unsymmetrically substituted butadiyne 3 provides bis-stannane 4. Selective lithiation of the internal tin residue effects a 1,4-retro-Brook rearrangement to afford vinylsilane 5.

Full text of DOI:10.1021/ol035536e

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3971-3974
Stereoselective Synthesis of
â-(Chloro)vinylsilanes Using a Regio-
and (E)-Stereoselective Bis-Stannylation
of Unsymmetrically Substituted
Butadiynes: Application to the
Synthesis of a Masked Triyne
Simon M. E. Simpkins, Benson M. Kariuki, Caterina S. Arico´, and Liam R. Cox*
School of Chemistry, UniVersity of Birmingham, Edgbaston, Birmingham B15 2TT, UK
l.r.cox@bham.ac.uk
Received August 14, 2003
ABSTRACT
A highly regio- and stereoselective bis-stannylation of unsymmetrically substituted butadiyne 3 provides bis-stannane 4. Selective lithiation
of the internal tin residue effects a 1,4-retro-Brook rearrangement to afford vinylsilane 5. This was elaborated into the novel diethynylethene
1, which also functions as a masked triyne.
The shape and reactivity of the alkyne functional group,
particularly when it is incorporated into highly conjugated
systems and rings, can lead to problems in a synthesis. These
can be circumvented by temporarily masking this functional
group and releasing the alkyne at a later stage in the
synthesis. A wide variety of approaches have been developed
for achieving this type of masking strategy.1
â-(Halo)vinylsilanes are an attractive type of masked
alkyne that have only rarely been used in synthesis.2
Exposure to fluoride or base effects elimination and provides
a mild and selective route to the corresponding alkyne. We
are interested in exploiting this type of protected alkyne
functionality for synthesizing masked triynes for potential
application in natural product synthesis, as well as for
generating new monomeric building blocks for the prepara-
tion of nonaromatic, highly conjugated organic oligomers.3
To this end, we required a synthesis of the masked triyne 1
(Scheme 1).
(2) (a) Sukeda, M.; Ichikawa, S.; Matsuda, A.; Shuto, S. J. Org. Chem.
2003, 68, 3465-3475. (b) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000,
65, 630-633. (c) Schmitz, C.; Rouanet-Dreyfuss, A.-C.; Tueni, M.;
Biellmann, J.-F. J. Org. Chem. 1996, 61, 1817-1821. (d) Shakespeare, W.
C.; Johnson, R. P. J. Am. Chem. Soc. 1990, 112, 8578-8579. (e) Oda, H.;
Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron 1985, 41,
3257-3268. (f) Yamaguchi, R.; Kawasaki, H.; Yoshitome, T.; Kawanisi,
M. Chem. Lett. 1982, 1485-1486. (g) Danheiser, R. L.; Carini, D. J. J.
Org. Chem. 1980, 45, 3925-3927. (h) Cunico, R. F.; Dexheimer, E. M. J.
Am. Chem. Soc. 1972, 94, 2868-2869.
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T. J. Am. Chem. Soc. 2003, 125, 5614-5615. (b) Eisler, S.; Chahal, N.;
McDonald, R.; Tykwinski, R. R. Chem. Eur. J. 2003, 9, 2542-2550. (c)
Adamson, G. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1996, 1535-
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Tetrahedron Lett. 1971, 3475-3478.
10.1021/ol035536e CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/25/2003

bulk of the silyl substituents hindering reaction of the internal
alkyne with the Si-Pd-Sn intermediate.4,6 This did not bode
well for future studies where we require the incorporation
of silyl groups containing even bulkier substituents. We
therefore sought an alternative approach.
Scheme 1. (E)-4-Chloro-3-silylhex-3-ene-1,5-diynes as Masked
Triynes
Bis-stannylation of alkynes is one of the most widely used
metalometalation reactions.7 Like silylstannylation, it is
usually a palladium-catalyzed syn-selective process and also
proceeds best on terminal alkynes or activated internal
alkynes.7 We were attracted to an intriguing alternative
methodology employing copper mediation. Zweifel and
Leong have reported that unsymmetrically substituted
butadiynes react with the stannylcopper species, Me3SnCu‚
SMe2‚LiBr, in a highly regio- and stereoselective fashion to
afford (E)-bis-stannane products directly.8 Furthermore they
went on to show that the internal stannyl substituent could
be selectively lithiated and trapped with simple electrophiles.8
We envisaged that we might be able to apply this methodol-
ogy, which had previously been demonstrated on only two
simple examples, to a system that would allow subsequent
elaboration into our target molecule 1.
To maximize the flexibility of the end product, we set
ourselves a number of conditions that our synthetic strategy
would have to satisfy. We required the internal double bond
to be a single (E)-stereoisomer, to facilitate dechlorosilyla-
tion, and that the termini of the appended alkynes be
differentiated such that we could attach additional substit-
uents to the framework in a sequential fashion.
After considering a number of approaches to 1, it quickly
became apparent that the lynchpin step would be that of
incorporating the vinylsilane moiety. The direct installation
of this functionality through a silylstannylation of an ap-
propriately substituted alkyne was an attractive option which
we examined first.4 Palladium-catalyzed silylstannylation of
alkynes is highly syn-selective,4 although we hoped that
isomerization to the desired thermodynamically more stable
(E)-stereoisomer might be achievable in a number of ways
at a later stage.4a,b Silylstannylation only works well on
terminal alkynes or on internal alkynes that are activated with
electron-withdrawing groups.4 We therefore considered di-
methyl acetylenedicarboxylate as a starting material that
could potentially be elaborated into our target. Heating
equimolar quantities of (tert-butyldimethylsilyl)tributyl-
stannane4a and dimethyl acetylenedicarboxylate in the pres-
ence of Pd(OAc)2 and 1,1,3,3-tetramethylbutyl isocyanide
provided a single stereoisomeric product 2 in low yield5 after
prolonged (24 h) heating (Scheme 2).6
Our retrosynthesis is outlined in Scheme 3. Bis-stannyla-
tion of the unsymmetrically substituted butadiyne 3 would
Scheme 3. Retrosynthetic Analysis for Masked Triyne 1
Employing an (E)-Selective Bis-stannylation
Scheme 2. Silylstannylation of Dimethyl
Acetylenedicarboxylate
provide bis-stannane 4. Selective monolithiation at the
internal site would then generate a nucleophilic vinyllithium
species set up to undergo a 1,4-retro-Brook rearrangement,9
installing the vinyl silane 5 in a regioselective fashion and
(5) We have assigned the (Z)-configuration of the olefin in 2 on the basis
of literature precedence (ref 4). A reviewer has suggested that the low yield
of 2 may due to the formation of byproducts from the reaction between the
acetylenedicarboxylate and the isocyanide ligand.
We were unable to improve upon this low yield and
attributed the poor efficiency of the reaction to the steric
(6) Murakami, M.; Amii, H.; Takizawa, N.; Ito, Y. Organometallics 1993,
12, 4223-4227.
(3) (a) Poly(diacetylenes): Takayama, Y.; Delas, C.; Muraoka, K.; Sato,
F. Org. Lett. 2003, 5, 365-368. (b) Poly(triacetylenes): Walker, J. A.; Bitler,
S. P.; Wudl, F. J. Org. Chem. 1984, 49, 4733-4734. (c) Poly(pentaacety-
lenes): Schenning, A. P. H. J.; Arndt, J.-D.; Ito, M.; Stoddart, A.; Schreiber,
M.; Siemsen, P.; Martin, R. E.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M.;
Gramlich, V.; Diederich, F. HelV. Chim. Acta 2001, 84, 296-334.
(4) (a) Chenard, B. L.; van Zyl, C. M. J. Org. Chem. 1986, 51, 3561-
3566. (b) Mitchell, T. N.; Wickenkamp, R.; Amamria, A.; Dicke, R.;
Schneider, U. J. Org. Chem. 1987, 52, 4868-4874. (c) For a review:
Suginome, M.; Ito, Y. Chem. ReV. 2000, 100, 3221-3256.
(7) Beletskaya, I.; Moberg, C. Chem. ReV. 1999, 99, 3435-3461.
(8) Zweifel, G.; Leong, W. J. Am. Chem. Soc. 1987, 109, 6409-6412.
(9) (a) Baudoux, G.; Norberg, B.; Bousbaa, J.; Krief, A.; Evrard, G. Acta
Crystallogr. Sect. C 1998, 54, 1944-1945. (b) Gibson, C.; Buck, T.; Walker,
M.; Bru¨ckner, R. Synlett 1998, 201-205. (c) Behrens, K.; Kneisel, B. O.;
Noltemeyer, M.; Bru¨ckner, R. Liebigs Ann. 1995, 385-400. (d) Lautens,
M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H. J. Org. Chem. 1992, 57,
3270-3272. (e) Kim, K. D.; Magriotis, P. A. Tetrahedron Lett. 1990, 31,
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3972
Org. Lett., Vol. 5, No. 21, 2003

at the same time freeing up the alcohol for subsequent
elaboration into the second alkyne.
selectivity of the key bis-stannylation by sterically blocking
the proximal alkyne group.14 To investigate this further we
prepared butadiynes 3e and 3f in which aryl substituents
replaced the silyl groups as terminating species. Bis-
stannylation of both diynes under the standard reaction
conditions provided bis-stannanes 4e and 4f with the same
regio- and stereochemical outcome as before (Scheme 4).
The factors affecting the regioselectivity of this bis-stan-
nylation and its extension to related systems will be the focus
of future studies.
We were aware that the presence of an electron-withdraw-
ing silyloxy substituent and its potential directing ability
could also affect the regioselectivity of the subsequent
lithiation step. However, treatment of 4 with 1.0 equiv of
nBuLi provided the desired 1,4-retro-Brook rearrangement
product 5 in good yield (Scheme 5).9 Use of MeLi (low
We considered this approach to be attractive for a number
of reasons. In particular, we hoped that tethering the latent
silyl electrophile to the proximal alcohol, thereby allowing
installation of the vinylsilane through an intramolecular
delivery pathway,10 might prove especially beneficial for
incorporating less electrophilic silyl groups containing bulkier
substituents, which we require for a later stage of our research
program. Furthermore, since the two alkyne substituents
would be incorporated in separate stages we would satisfy
the second of our design criteria, namely that we could
differentiate the two alkyne termini.
At the outset, we did not know how the propargylic
silyloxy group might affect the regio- and stereoselectivity
of the bis-stannylation reaction. We were therefore delighted
to observe that reaction of the stannylcopper reagent,
prepared from equimolar quantities of Me3SnLi and CuBr‚
Me2S,11 with butadiyne 3a12 at -50 °C, provided the desired
bis-stannane 4a as a single stereo- and regioisomer in very
good yield. We used 119Sn NMR to confirm the stereochem-
Scheme 5. Synthesis of Masked Triynes 1a
istry of this product. A 3J
119Sn-119
Sn coupling constant of 686
Hz falls within the range expected for a trans-substituted bis-
vinylstannane (coupling constants for cis-substituted bis-
stannanes are generally lower than 500 Hz).13 The selectivity
was equally good for both TMS- and TIPS-substituted
butadiynes and was not affected by the size of the silyl ether
substituent with TES, TIPS, and TBDPS ethers all providing
the desired bis-stannylated product 4 (Scheme 4).
Scheme 4. Stereo- and Regioselective Bis-stannylation of
Aryl- and Silyl-Substituted Butadiynesa
a Reaction conditions: (a) nBuLi (1.0 equiv), THF, -78 °C, 5a
(60%), 5b (50%), 5c (58%), 5d (68%); (b) CuCl2 (2.2 equiv), THF,
0 °C to rt, 6a (74%), 6b (98%), 6c (97%), 6d (99%); (c) MnO2 (20
equiv), CH2Cl2, rt, 7a (84%), 7b (95%), 7c (99%), 7d (89%); (d)
CBr4 (2.0 equiv), PPh3 (4.0 equiv), CH2Cl2, 0 °C, 8a (89%), 8b
(89%), 8c (99%), 8d (76%); (e) LDA (6.0 equiv), THF, -78 °C,
1a (84%), 1b (97%), 1c (97%), 1d (98%); (f) LDA (6.0 equiv),
TMSCl (10.0 equiv), THF, -78 °C, 9b (79%), 9c (93%), 9d (95%);
(g) NaHMDS (1.1 equiv), THF, -78 °C, 10d (70%).
a Reaction conditions: (a) Me3SnCu‚SMe2‚LiBr (2.6 equiv),
THF, -50 °C 4a (89%), 4b (54%), 4c (48%), 4d (82%), 4e (75%),
4f (64%).
chloride concentration) led to no significant improvement
in yield, while an excess of nBuLi led to appreciable
quantities of the bis-protodestannylated product. A crystal
structure of 5d confirmed the regioselectivity of the lithiation
It is tempting to propose that the presence of the silicon
protecting group at the diyne terminus governs the regio-
(10) For a review on the use of a temporary connection in synthesis:
Cox, L. R.; Ley, S. V. In Templated Organic Synthesis; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1999; Chapter 10, pp 275-395.
(11) San Filippo, J., Jr.; Silbermann, J. J. Am. Chem. Soc. 1982, 104,
2831-2836.
(12) Silyl ethers 3 were prepared from the corresponding alcohols. 3a:
Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841-6844. 3b-d:
Holmes, A. B.; Jennings-White, C. L. D.; Schulthess, A. H.; Akinde, B.;
Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1979, 840-842.
(13) (a) Betzer, J.-F.; Le Me´nez, P.; Prunet, J.; Brion, J.-D.; Ardisson,
J.; Pancrazi, A. Synlett 2002, 1-15. (b) Mitchell, T. N.; Nettelbeck, C.
Magn. Reson. Chem. 1987, 25, 879-882. (c) Mitchell, T. N.; Amamria, A.
J. Organomet. Chem. 1983, 252, 47-56.
(14) Hwu, J. R.; Wang, N. Chem. ReV. 1989, 89, 1599-1615. We
acknowledge that electronic effects may also be important in controlling
the regioselectivity of this reaction.
Org. Lett., Vol. 5, No. 21, 2003
3973

and that silylation had proceeded with retention of config-
uration (Figure 1). Subsequent elaboration of 5 into our target
at 3308 cm-1 in the IR spectrum of 1b. The lithiated
acetylene intermediate in this rearrangement could also be
trapped with TMSCl to provide a more stable silylalkyne 9
in excellent yield. Furthermore, by replacing the LDA base
with NaHMDS we were able to isolate the E2-elimination
product 10.18 This bromoalkyne further increases the number
of cross-coupling strategies available for subsequent elabora-
tion of this system.19
In summary, we have described a general synthesis of a
novel diethynylethene containing an internal trans-substituted
â-(chloro)vinylsilane. The key step involves a highly regio-
and (E)-stereoselective bis-stannylation of an unsymmetri-
cally substituted butadiyne. This transformation allows the
sequential installation of the silyl and chloro groups in a
selective and predictable fashion through a relatively unusual
1,4-retro-Brook rearrangement and a stereospecific chloro-
destannylation reaction using CuCl2, respectively. Since the
two pendant alkynes have been incorporated in a sequential
fashion, this also ensures that the termini of our target
diethynylethene are differentiated, which allows us to
elaborate our products in a unidirectional fashion. We are
currently investigating methods for incorporating this masked
alkyne into long-chain conjugated organic molecules.
Figure 1. ORTEP plots of 5d (left) and 6d (right) confirming the
stereochemistry of the internal olefin. Atomic displacement pa-
rameters at 293 K.
molecule was straightforward (Scheme 5). Chlorodestan-
nylation of the remaining tin residue with CuCl2 installed
the vinyl chloride 6.15 A crystal structure of 6d again
confirmed that this reaction had also proceeded as expected
in a stereospecific fashion with retention of configuration
(Figure 1).
Acknowledgment. We are grateful to the Leverhulme
Trust (F/00 094/T) for financial support and a postdoctoral
research fellowship to S.M.E.S. and to the University of
Birmingham for a studentship to C.A.
Supporting Information Available: General experimen-
tal procedures for 4-8, 1, 9, and 10, representative spectra
for 1d, 4d-10d, and 4a,e, and X-ray crystallographic files
(in CIF format) for compounds 5d and 6d. This material is
available free of charge via the Internet at http://pubs.acs.org.
Allylic oxidation to the aldehyde 7 with MnO2 and
subsequent dibromoolefination16 both proceeded uneventfully
to provide dibromoolefin 8 in excellent yield (Scheme 5).
This underwent a Fritsch-Buttenberg-Wiechell rearrange-
ment17 on exposure to an excess of LDA at -78 °C to
provide the target acetylene 1 in excellent yield, as evidenced
by the appearance of a characteristic acetylenic C-H stretch
OL035536E
(17) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 272, 319-323. (b)
Buttenberg, W. P. Liebigs Ann. Chem. 1894, 272, 324-337. (c) Wiechell,
H. Liebigs Ann. Chem. 1894, 272, 337-344. (d) Ko¨brich, G. Angew. Chem.,
Int. Ed. Engl. 1965, 4, 49-68.
(18) Boden, C. D. J.; Pattenden, G.; Ye T. J. Chem. Soc., Perkin Trans.
1 1996, 2417-2419.
(19) Metal-catalysed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998.
(15) (a) Madec, D.; Fe´re´zou, J.-P. Tetrahedron Lett. 1997, 38, 6661-
6664. (b) Takeda, T.; Kanamori, F.; Matsusita, H.; Fujiwara, T. Tetrahedron
Lett. 1991, 32, 6563-6566.
(16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
3974
Org. Lett., Vol. 5, No. 21, 2003