Stereoselective synthesis of disubstituted butadienes via copper-mediated coupling of alkenyl silanes

Article abstract of DOI:10.1055/s-0030-1261150

A strategy is described for the stereoselective synthesis of substituted (E)-, (Z)-, and -disubstituted butadienes from terminal alkynes by the copper-mediated coupling of geometrically-defined alkenyl silanes. Proof-of-concept results that demonstrate the feasibility of this approach are presented. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1261150

2140
LETTER
Stereoselective Synthesis of Disubstituted Butadienes via Copper-Mediated
Coupling of Alkenyl Silanes
Stereoselective
Sy
a
nthesis of
D
v
isubstituted
i
B
utadi
denes T. Blackwell, Warren R. J. D. Galloway, David 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
Received 7 April 2011
(or latent functional equivalents), which could ideally be
Abstract: A strategy is described for the stereoselective synthesis
of substituted (E)-, (Z)-, and a-disubstituted butadienes from termi-
nal alkynes by the copper-mediated coupling of geometrically-de-
fined alkenyl silanes. Proof-of-concept results that demonstrate the
feasibility of this approach are presented.
selectively generated from a common alkyne starting ma-
terial. We were interested in examining the use of alkenyl-
silanes (of the general form 4–6) in this context: there are
a number of reactions that seemingly involve silicon–cop-
per transmetalations,7 and a range of catalytic methods
have been developed for the stereoselective hydrosilyla-
tion of (terminal) alkynes, allowing the formation of E-,
Z-, and a-isomers in a controllable fashion.8 Thus if an
alkenyl silane moiety capable of undergoing stereospecif-
ic transmetalation to copper could be identified, it may be
possible to effect the stereoselective formation of geomet-
rically-defined alkenylsilanes 4–6 containing this moiety
(by hydrosilylation using the parent silane 7, Scheme 1)
and convert these into the corresponding alkenylcopper
species for subsequent coupling. Overall, it was envisaged
that this sequence could provide access to all possible E-,
Z-, and a-disubstituted butadiene isomers 1–3 from a
common terminal alkyne precursor 8. In this letter we
present proof-of-concept results that demonstrate the fea-
sibility of this approach.
Key words: copper, coupling, diversity-oriented synthesis, buta-
dienes, hydrosilylation
Conjugated polyene systems are a commonly encountered
structural feature in natural products1 and some optical
materials;2 consequently the development of methods to
access such bonding arrangements in a stereoselective
fashion has attracted interest amongst synthetic chemists.3
Herein we outline a strategy for the regio- and stereoselec-
tive synthesis of (E)-, (Z)-, and a-disubstituted butadienes
from a common terminal alkyne precursor. Such chemis-
tries could offer an efficient means of rapidly achieving
structural diversification from a common starting materi-
al; as such, they could also be exploited in reagent-based
diversity-oriented synthesis (DOS) pathways.4,5
Our synthetic strategy was dependent upon the identifica-
tion of (E)-, (Z)-, and a-alkenylsilane precursors that
could be readily prepared with geometrical control and
undergo stereospecific transmetalation to copper under
mild conditions. Ideally, all desired geometrical isomers
of such alkenylsilanes could be generated by hydrosilyla-
tion from the same starting material through variation in
the catalyst employed. Yoshida et al. have reported that
In line with our group’s continued interest in copper-
based methods for carbon–carbon bond construction6 we
were interested in exploring the thermolytic dimerisation
of geometrically-defined alkenylcopper species as a route
towards the desired E-, Z-, and a-substituted butadiene ar-
chitectures (1–3, Scheme 1). It was envisaged that such
copper species could be accessed by transmetalation from
suitable geometrically-defined alkenylmetal precursors
R
R
R
[Si]
1
4
R
(i) hydro-
silylation
(ii) transmetalation to copper
[Si]
2
R
R
R
[Si]
(iii) thermolytic dimerisation
H
R
R
8
5
6
7
R
3
[Si]
geometrically-defined
alkenylsilanes
geometrically-defined
butadienes
Scheme 1 Outline of our strategy for the stereoselective synthesis of disubstituted butadienes via the homocoupling of alkenylsilanes
SYNLETT 2011, No. 15, pp 2140–2144
x
x
.x
x
.2
0
1
1
Advanced online publication: 31.08.2011
DOI: 10.1055/s-0030-1261150; Art ID: D10711ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of Disubstituted Butadienes
2141
alkenyl(2-pyridyl)dimethylsilanes 9 can bind to copper(I) When the methylthiomethyllithium was treated with di-
in a bidentate fashion, presumably through the pyridine ethyl ether prior to addition of the chlorosilane, the de-
lone pair and alkene p system, to form isolable complexes sired product 12 was obtained in an unoptimised 25%
such as 10 (Scheme 2).9
yield (Scheme 3).8
With silane 12 in hand, stereoselective hydrosilylation of
phenylacetylene (15) proceeded smoothly to give (E)-alk-
enylsilane 16 with excellent geometrical selectivity
(Scheme 4). Treatment of 16 with caesium fluoride and
copper(I) iodide in acetonitrile at reflux provided the de-
sired (E)-butadiene 17 as the sole isolated product in an
excellent yield (Scheme 4). There was no evidence in the
1H NMR of the crude product material for any Z- or a-sub-
stituted products suggesting that both the silicon–copper
transmetalation and thermolytic coupling processes pro-
ceed with retention of the double-bond geometry present
in the starting silane.
N
R
Si
CuI, CsF
R
R
MeCN, r.t.
9
11
I
2
Cu
N
R
Si
10
Scheme 2 Silicon–copper transmetalation using alkenyl-(2-pyri-
dyl)dimethylsilanes 9 as described by Yoshida et al.9
This result was considered sufficiently promising to merit
further investigation of thioether-substituted silanes. The
Z-selective hydrosilylation of phenylacetylene (15) with
silane 12 was therefore investigated. Unfortunately, nei-
ther Chang’s12 nor Hiyama’s13 catalysts furnished the de-
sired compound with useful selectivity; the former system
gave a 1:1:0.45 mixture of the E-, Z-, and 1,1-disubstitut-
ed isomers, while the latter gave very little conversion. A
thioether-functionalised (Z)-alkenyl silane 18 was ulti-
mately obtained via a two-step sequence. Silylation of the
lithium acetylide of phenylacetylene (15) with chlorosi-
lane 19 generated chloride 20. Hydroboration and pro-
todeborylation with acetic acid followed by chloride
displacement with potassium ethanethiolate in methanol
furnished the silane 18 (Scheme 4). Attempts to access the
corresponding a-substituted silane from phenylacetylene
(15) were unsuccessful. Therefore an alternative a-substi-
tuted silane bearing the thioether moiety was desired so
that the general behaviour of the a-species under the cou-
pling reaction conditions could be examined. Thus the a-
substituted alkenylsilane 21 was prepared by a two-step
sequence. Hydrosilylation of the known alkyne 22 with
chloromethyldimethylsilane, promoted by Trost’s cata-
lyst,8d furnished an inseparable mixture of the a- and (Z)-
alkenylsilanes 23. As with 20, displacement with potassi-
um ethanethiolate proceeded smoothly, and 21 could be
isolated in a geometrically pure form in good yield after
purification by column chromatography (Scheme 4).
Copper-mediated oxidative homocoupling of thioether-
functionalised (Z)- and a-alkenylsilanes 18 and 21 in ace-
tonitrile was sluggish at room temperature, but furnished
the desired butadienes 24 and 25, respectively, in good
yields at a concentration of 0.2 M when heated at reflux
(Scheme 4); as was the case with the corresponding E-iso-
mer 17, the sole observable byproduct was desilylated
starting material. Importantly, the geometry of the starting
silylalkenes was retained in the products; there is no evi-
dence of isomerisation during the transmetalation and
subsequent coupling.14
Treatment of these complexes with caesium fluoride re-
sults in the formation of E-symmetrical butadienes of the
general form 11, presumably via silicon–copper transmet-
alation followed by the thermolysis of the alkenylcopper
species thus formed.9 This coordination-driven transmet-
alation offers an appealing mechanism for achieving ste-
reospecific silicon–copper exchange. However, the 2-
pyridylsilanes have some significant drawbacks: the prep-
aration of 2-pyridyldimethylsilane is low-yielding, and
the silane is obtained in high purity only after multiple dis-
tillations, and while catalytic E-selective hydrosilylation
of terminal alkynes with 2-pyridyl(dimethyl)silane has
been shown to proceed in good yield,10 Z- and a-selective
hydrosilylations with 2-pyridyl(dimethyl)silane have not
been reported; in the authors’ hands preliminary attempts
at effecting these reactions gave none of the desired prod-
ucts. Alternative silanes bearing metal-coordinating func-
tionality were therefore sought.
Our focus turned towards the use of alkenylsilanes bear-
ing a thioether moiety which we envisaged would be ca-
pable of interacting with copper in a similar fashion to the
pyridyl group present in Yoshida’s silane 9. Towards this
end we initially targeted the synthesis of thioether-func-
tionalised (E)-silane 12 (Scheme 3). We first investigated
the reaction of methylthiomethyllithium [prepared by the
treatment of dimethylsulfide (13) with n-BuLi and
TMEDA] with dimethylchlorosilane. Unfortunately, the
only identifiable product obtained was the silane 14.11
Si
Me2Si(H)Cl
56%
n-BuLi
TMEDA
S
S
14
S
i) Et2O
ii) Me2Si(H)Cl
pentane
13
S
Si
H
25%
12
In an attempt to better delineate the progress of these cou-
pling reactions the interactions of the (E)-, (Z)-, and a-si-
lanes 16, 18, and 21 with copper(I) salts were studied by
Scheme 3 Preparation of (methylthiomethyl)dimethylsilane 12
Synlett 2011, No. 15, 2140–2144 © Thieme Stuttgart · New York

2142
D. T. Blackwell et al.
LETTER
silane (12)
Pt(DVDS)/PtBu3
CsF
CuI
Ph
Ph
Si
SMe
Ph
MeCN, reflux,
2 h, 94%
17
THF
65%
16
Ph
15
i) n-BuLi
ii) Me2Si(CH2Cl)Cl (19)
i) HBCy2, THF
ii) AcOH
Ph
CsF
CuI
Si
SEt
KSEt
Cl
Si
Si
Ph
Ph
Ph
18
THF
93%
58%
MeOH
85%
24
MeCN, reflux,
2 h, 85%
Ph
Cl
20
EtSH
K2CO3
MeOH
OBn
OBn
cat. Cp*Ru(MeCN)3PF6
HSi(CH2Cl)Me2
CsF
CuI
BnO
Si
SEt
OBn
Si
acetone
87%
94%
BnO
22
25
MeCN, reflux,
2 h, 91%
Cl
21
23
Scheme 4 Preparation of geometrically-defined thioether-substituted alkenyl silanes and their subsequent homocoupling to furnish (E)-, (Z)-,
and a-substituted butadienes
1H NMR (Table 1). The spectra of the free ligands were and a-alkenylsilanes 26–28, respectively, bearing a pen-
recorded in appropriate solvents and compared to those dant tertiary amine, were prepared with high levels of geo-
obtained in the presence of one equivalent of a copper metrical selectivity (Scheme 5). As with the thioether-
salt.15 When 16 was treated with one equivalent of the cat- functionalised silanes, these species all underwent trans-
ionic copper(I) species Cu(MeCN)4PF6 in CH2Cl2-d2, sig- metalation to copper and oxidative dimerisation to yield
nificant changes in the spectrum were observed, with the corresponding butadienes in good yields (Scheme 5).
large decreases in the chemical shifts of the alkenyl pro- NMR analysis of their complexes with copper showed
tons in the complexed material relative to the free ligand similar changes in chemical shift to those observed with
and smaller increases in the chemical shift of the protons the thioether-functionalised silanes; however, with the
of the thioether moiety (Table 1, entry 1). These data are more strongly coordinating pyrrolidine group, the chang-
consistent with the binding of copper to both the alkene es in chemical shift were observed in acetonitrile as well
and the thioether.16 Similar changes in the chemical shifts as in dichloromethane (Table 1, entries 4–6). In spite of
of the alkenyl protons were observed with the Z- and a- this, the yields obtained for the thermolytic dimerisation
configured silanes 18 and 21 in the presence of with the amine-functionalised silanes did not differ signif-
Cu(MeCN)4PF6 in CH2Cl2-d2, suggesting that these too icantly from those obtained with the thioether-functiona-
are capable of binding to copper (Table 1, entries 2 and 3). lised species (Scheme 5). Once again there was no
1
A control experiment was performed using (E)-(styryl)tri- evidence in the H NMR spectra of the crude product
ethylsilane, which lacks coordinating functionality be- materials for any undesired geometrical isomers of the
sides the alkene; its spectrum in CH2Cl2-d2 was essentially products, suggesting that both the silicon–copper trans-
unchanged on adding one equivalent of Cu(MeCN)4PF6, metalation and thermolytic coupling processes proceed
which suggests that silylalkenes alone are not capable of with retention of the double-bond geometry present in the
binding to copper(I) in the same way as are the thioether- starting silane. Hence, both the amine-functionalised si-
substituted alkenylsilanes 16, 18, and 21.
lanes 26–28 and those bearing pendant thioethers 16, 18,
and 21 satisfy the requirements for an alkenylmetal pre-
cursor that is readily prepared with geometrical control
To assess the effect of using a more strongly coordinating
alkenylsilane on the transmetalation process, (E)-, (Z)-,
HN
Pt(DVDS)/PtBu3
HSiMe2(CH2Cl)
CsF
CuI
Ph
Ph
Ph
Si
N
Ph
Si
Cl
THF
MeCN, reflux
86%
MeCN, reflux
71%
17
26
Ph
HN
15
Ph
CsF
CuI
Si
N
see Scheme 4
Si
Cl
Ph
Ph
Ph
MeCN, reflux
89%
27
MeCN, reflux
83%
24
HN
OBn
CsF
CuI
BnO
N
Si
see Scheme 4
Si
OBn
MeCN,
reflux
92%
MeCN, reflux
87%
BnO
22
25
Cl
BnO
28
23
Scheme 5 Preparation of geometrically-defined pyrrolidine-functionalised alkenyl silanes and their subsequent homocoupling to furnish (E)-,
(Z)-, and a-substituted butadienes.
Synlett 2011, No. 15, 2140–2144 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Disubstituted Butadienes
2143
Table 1 Studying the Interactions of Thioether- and Amine-Func-
tion with a given silane using different conditions. Thus
far this remains an unmet goal, and studies towards this
end are ongoing. Nevertheless, proof-of-concept results
demonstrate the general feasibility of our approach: (E)-,
(Z)-, and a-alkenyl silane intermediates containing chelat-
ing amine and thioether functionalities could be formed
with excellent regio- and stereoselectivity, and they could
be transformed to the corresponding (E)-, (Z)-, and a-
butadienes upon heating in the presence of copper(I) io-
dide without loss of selectivity and in good yields. Exper-
imental observations and NMR studies are consistent with
a process involving transmetalation from the alkenyl si-
lane to form a neutral organocopper species followed by
thermolytic dimerisation to yield the coupled product.
This strategy potentially offers an efficient means of
achieving molecular diversification from common alkyne
starting materials (through variation of the reagents em-
ployed); as such, it may prove valuable in branching, re-
agent-based DOS pathways.1 Furthermore, we anticipate
that these new methodologies could prove valuable in a
wider synthetic context, with potentially broad applica-
tions in target-oriented synthesis (e.g., the synthesis of
natural products and pharmaceutical agents). The scope of
the methodologies described herein is currently being ex-
plored and developed further, and its application to the
preparation of structurally diverse small-molecule collec-
tions will be reported in due course.
tionalised Alkenylsilanes with Cu(I) by 1H NMR Spectroscopya
Entry
1b
Substrate
Proton
DdH (ppm)
4
1
2
3
4
–0.2
–0.7
+0.2
+0.2
S
2
Ph
3
Si
1
16
4
1
2
3
4
NAd
–0.7
+0.1
+0.3
3
S
2b
3b
4c
Ph
Si
1
2
18
4
3
S
1
2
3
4
–0.3
–0.4
+0.3
+0.3
1 H
2 H
Si
X
X = (CH2)3OBn
21
1
2
3
4
–0.2
–0.4
+0.2
+0.2
4
N
2
Ph
3
Si
1
26
Supporting Information for this article is available online at
X
Si
N
1
2
3
4
–0.3
–0.4
+0.3
+0.2
http://www.thieme-connect.com/ejournals/toc/synlett.
4
3
5c
H
1
H
2
References and Notes
X = (CH2)3OBn
(1) Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002,
999.
28
1
2
3
4
–0.3
–0.3
+0.2
+0.2
(2) See for example: Robinson, B. H.; Dalton, L. R.; Harper, A.
W.; Ren, A.; Wang, F.; Zhang, C.; Todorova, G.; Lee, M.;
Aniszfeld, R.; Garner, S.; Chen, A.; Steier, W. H.;
Houbrecht, S.; Persoons, A.; Ledoux, I.; Zyss, J.; Jen, A. K.
Y. Chem. Phys. 1999, 245, 35.
2
3
4
6c
1
Si
N
Ph
27
a Values in the column DdH indicate the observed difference in the
chemical shift of the proton of interest in the copper-complexed spe-
cies relative to that of the free ligand in the same solvent at the same
concentration; negative values indicate that the shift in the complex is
less than that in the free ligand; 20 mg substrate in 0.75 mL of solvent
with 1 equiv of Cu(I) salt relative to substrate in all cases.
b Conditions: Cu(MeCN)4PF6, CH2Cl2.
(3) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005,
127, 8004.
(4) For recent reviews on DOS, see: (a) Galloway, W. R. J. D.;
Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 801.
(b) Schreiber, S. L. Nature (London) 2009, 457, 153.
(c) Nielsen, E.; Schreiber, S. L. Angew. Chem. Int. Ed. 2008,
47, 48. (d) Galloway, W. R. J. D.; Bender, A.; Welch, M.;
Spring, D. R. Chem. Commun. 2009, 2446. (e) Cordier, C.;
Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C.
Nat. Prod. Rep. 2008, 25, 719.
(5) We have previously reported the development of related
methodology for the DOS of (E)-, (Z)-, and a-disubstituted
alkenes from a common alkyne precursor: Sore, H. F.;
Blackwell, D. T.; MacDonald, S. J. F.; Spring, D. R. Org.
Lett. 2010, 12, 2806.
c Conditions: CuI, MeCN.
d NA = not applicable. The signal of this proton is coincident with
those of the aromatic ring in the copper complex and, consequently,
DdH could not be determined.
and undergoes transmetalation to copper under mild con-
ditions.
(6) (a) Aves, S. J.; Pike, K. G.; Spring, D. R. Synlett 2010, 2839.
(b) Kenwright, J. L.; Galloway, W. R. J. D.; Blackwell, D.
T.; Isidro-Llobet, A.; Hodgkinson, J.; Wortmann, L.;
Bowden, S. D.; Welch, M.; Spring, D. R. Chem. Eur. J.
2011, 17, 2981. (c) Su, X. B.; Fox, D. J.; Blackwell, D. T.;
Tanaka, K.; Spring, D. R. Chem. Commun. 2006, 3883.
(d) Su, X. B.; Surry, D. S.; Spandl, R. J.; Spring, D. R. Org.
In conclusion, we have described a strategy for the stereo-
selective synthesis of substituted E-, Z-, and a-disubstitut-
ed butadienes from terminal alkynes by the copper-
mediated coupling of geometrically-defined alkenyl si-
lanes. Ideally, we envisage generating the required silanes
from a common alkyne starting material by hydrosilyla-
Synlett 2011, No. 15, 2140–2144 © Thieme Stuttgart · New York

2144
D. T. Blackwell et al.
LETTER
Lett. 2008, 10, 2593. (e) Su, X. B.; Thomas, G. L.;
Galloway, W. R. J. D.; Surry, D. S.; Spandl, R. J.; Spring, D.
R. Synthesis 2009, 3880. (f) Surry, D. S.; Fox, D. J.;
Macdonald, S. J. F.; Spring, D. R. Chem. Commun. 2005,
2589. (g) Surry, D. S.; Spring, D. R. Chem. Soc. Rev. 2006,
35, 218. (h) Surry, D. S.; Su, X. B.; Fox, D. J.;
another. When the chlorosilane is added, it will be attacked
by the organolithium to form 12; however, as there will be
one or more molecules of the organolithium still coordinated
to the sulfur atom of the newly formed 12, intra-aggregate
transfer of the organic group of this coordinated organo-
lithium to the proximal silicon atom may be more rapid than
an intermolecular on a second molecule of the chlorosilane.
If this was the case, it was reasoned that the addition of a
more strongly coordinating solvent (Et2O) should reduce the
extent to which the organolithium is complexed by the
thioether, and might thus prevent this second attack.
(12) Na, Y. G.; Chang, S. B. Org. Lett. 2000, 2, 1887.
(13) Mori, A.; Takahisa, E.; Yamamura, Y.; Kato, T.; Mudalige,
A. P.; Kajiro, H.; Hirabayashi, K.; Nishihara, Y.; Hiyama, T.
Organometallics 2004, 23, 1755.
(14) If either CsF or CuI are omitted from the reaction mixtures,
no coupled product is observed; with extended reaction
times (48 h), partial desilylation of the starting material is
observed if CsF is present but not CuI.
(15) Interestingly, while CuI in MeCN together with CsF
promotes complete conversion of the (E)-silane 16
Franckevicius, V.; Macdonald, S. J. F.; Spring, D. R. Angew.
Chem. Int. Ed. 2005, 44, 1870.
(7) See, for example: (a) Shindo, M.; Matsumoto, K.; Shishido,
K. Synlett 2005, 176. (b) Taguchi, H.; Ghoroku, K.; Tadaki,
M.; Tsubouchi, A.; Takeda, T. J. Org. Chem. 2002, 67, 8450.
(8) For E-selective hydrosilylation see, for example:
(a) Chandra, G.; Lo, P. Y.; Hitchcock, P. B.; Lappert, M. F.
Organometallics 1987, 6, 191. For Z-selective hydro-
silylation see, for example: (b) Na, Y.; Chang, S. Org. Lett.
2000, 2, 1887. (c) Mori, A.; Takahisa, E.; Yamamura, Y.;
Kato, T.; Mudalige, A.; Kajiro, H.; Hirabayashi, K.;
Nishihara, Y.; Hiyama, T. Organometallics 2004, 23, 1755.
(d) Katayama, H.; Taniguchi, K.; Kobayashi, M.; Sagawa,
T.; Minami, T.; Ozawa, F. J. Organomet. Chem. 2002, 645,
192. For the selective hydrosilylation of terminal alkenes to
give 1,1-disubstituted alkenylsilanes (a) see, for example:
(e) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127,
17644.
(9) Itami, K.; Ushiogi, Y.; Nokami, T.; Ohashi, Y.; Yoshida, J.
I. Org. Lett. 2004, 6, 3695.
(10) Itami, K.; Mitsudo, K.; Nishino, A.; Yoshida, J. J. Org.
Chem. 2002, 67, 2645.
(11) Compound 14 was presumably formed by displacement of
both the chloride and the hydride from the chlorosilane. This
can be rationalised as follows: suppose that lithiation of 13
proceeds to completion. In the absence of other Lewis basic
donors, it might be expected that the sulfur atom of one
lithiated molecule of 13 will coordinate to the lithium of
(Scheme 4), the addition of 1 equiv of CuI did not induce any
change in the spectrum of 16 in MeCN-d3.
(16) Since thioethers are almost pure s-donors, with no vacant
low-energy orbitals suitable for metal–ligand back bonding,
donation of the lone pair of sulfur to the metal might be
expected to decrease the electron density at (and thus
deshield) the carbons proximal to the sulfur atom, resulting
in the observed increase in the chemical shift of their
attached protons. Unlike the thioether, the alkene has a low-
energy p* orbital suitable for metal–ligand back bonding,
and so back donation from the metal to the alkene might
account for the observed decrease in the chemical shift of the
alkenyl protons in the presence of copper.
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