Geometric E→Z Isomerisation of Alkenyl Silanes by Selective Energy Transfer Catalysis: Stereodivergent Synthesis of Triarylethylenes via a Formal anti-Metallometallation

Article abstract of DOI:10.1002/anie.201910169

An efficient geometrical E→Z isomerisation of alkenyl silanes is disclosed via selective energy transfer using an inexpensive organic sensitiser. Characterised by operational simplicity, short reaction times (2 h), and broad substrate tolerance, the reaction displays high selectivity for trisubstituted systems (Z/E up to 95:5). In contrast to thermal activation, directionality results from deconjugation of the π-system in the Z-isomer due to A^1,3-strain thereby inhibiting re-activation. The structural importance of the β-substituent logically prompted an investigation of mixed bis-nucleophiles (Si, Sn, B). These versatile linchpins also undergo facile isomerisation, thereby enabling a formal anti-metallometallation. Mechanistic interrogation, supported by a theoretical investigation, is disclosed together with application of the products to the stereospecific synthesis of biologically relevant target structures.

Full text of DOI:10.1002/anie.201910169

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Accepted Article
Title: Geometric E→Z Isomerisation of Vinyl Silanes by Selective
Energy Transfer Catalysis: Stereodivergent Synthesis of
Triarylethylenes via a Formal Anti-Metallometallation
Authors: Svenja Fassbender, John Molloy, Christian Mück-Lichtenfeld,
and Ryan Gilmour
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910169
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10.1002/anie.201910169
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Geometric E→Z Isomerisation of Vinyl Silanes by Selective Energy
Transfer Catalysis: Stereodivergent Synthesis of Triarylethylenes via a
Formal Anti-Metallometallation
Svenja I. Faßbender,+ John J. Molloy,+ Christian Mück-Lichtenfeld and Ryan Gilmour*
Dedicated to Prof. Dr. Alois Fürstner
Abstract: An efficient geometrical E→Z isomerisation of vinyl silanes is
disclosed via selective energy transfer using an inexpensive organic
sensitiser. Characterised by operational simplicity, short reaction times (2
h), and broad substrate tolerance the reaction displays high selectivity for
trisubstituted systems (Z:E up to 95:5). In contrast to thermal activation,
directionality results from deconjugation of the π-system in the Z-isomer
due to A1,3-strain thereby inhibiting re-activation. The structural importance
of the β-substituent logically prompted an investigation of mixed bis-
nucleophiles (Si, Sn, B). These versatile linchpins also undergo facile
metallometallation in alkyne functionalisation, and the preparative
advantages of realising a formal anti-metallometallation via geometric
isomerisation (Scheme 2).[11]
To validate this platform for the stereodivergent synthesis of tri-
arylethylenes from
a common precursor, vinyl silanes that are
synonymous with the venerable Hiyama-Denmark coupling[12] were
investigated (Scheme 1). Elegant studies by Denmark have
unequivocally established the stereospecific nature of this palladium-
mediated transformation rendering it ideal for this task.[2f,h,13] These
studies also highlight the fact that trisubstituted Z-substrates are more
laborious to prepare than their E-congeners.[2e-h] Although numerous
strategies exist to access Z-configured vinyl silanes,[14] the emphasis
isomerisation, thereby enabling
a
formal anti-metallometallation.
Mechanistic interrogation, supported by a theoretical investigation, is
disclosed together with application of the products to the stereospecific
synthesis of biologically relevant target structures.
remains largely on 1,2-disubstituted systems.
A
geometric
isomerisation of multiply substituted E-vinyl silanes to the
corresponding Z-isomers would thus complement the existing pallete
of methods. Herein, an operationally facile E→Z isomerisation of vinyl
silanes has been developed via selective energy transfer catalysis.[9]
Both geometric isomers can be further functionalised by stereospecific
transformations. Furthermore, by introducing a second metal or
metalloid (R = Nuc = Sn, B, Si), sequential orthogonal coupling
enables the stereocontrolled synthesis of triarylethylenes, from a single
scaffold: This constitutes a formal anti-metallometallation.
Stereodivergent routes to highly functionalised alkenes require access
to both E- and Z-geometric isomers of the vinyl nucleophile to translate
the stereochemical information encoded at the substrate level to the
product via stereospecific coupling.[1,2,3] Generating both E- and Z-
substrate isomers is, however, often complicated by mechanistic and/or
thermodynamic constraints,[4] requiring independent synthesis routes to
be developed to prepare both substrates. Conceptually, geometric
alkene isomerisation[5] streamlines this problem by allowing pre-
existing synthesis routes to the major (e.g. E) isomer to be utilised,[6]
with the addition of a one-step isomerisation addendum at the end of
the sequence (E→Z). In the case of styrenyl systems that contain an
embedded chromophore, energy transfer catalysis offers a practical
activation method to achieve efficient geometrical
E → Z
isomerisation.[4,5,7,8] Predicated on selective energy transfer from an
excited state photosensitiser to the starting material,[4,5,9] this platform
ensures that only the E-geometric isomer is activated. The resulting
intermediate can collapse to either geometric isomer (Scheme 1, inset).
Since the product cannot be re-excited, the Z-isomer accumulates
thereby mitigating microscopic reversibility.[10] In an initial assessment
of this energy transfer concept to access Z-configured nucleophiles for
cross coupling and subsequent stereospecific modification, we recently
disclosed the geometric isomerisation of styrenyl organoboron
systems.[8k] Despite the high Z-selectivity, efficiency was offset by
lengthy reaction times and an expensive Ir(III) photocatalyst.
Moreover, attempts to develop a chemoselective transmetallation of
bis-nucleophiles for stereodivergent synthesis were unsuccessful. The
latter challenge is pertinent given the practical importance of cis-
M.Sc. S. I. Faßbender, Dr. J. J. Molloy, Dr. C. Mück-Lichtenfeld, Prof. Dr.
R. Gilmour
Organisch Chemisches Institut,
Westfälische Wilhelms-Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
Scheme 1. Conceptual framework of the stereodivergent synthesis of di- and
triarylethylenes via chemoselective, stereospecific cross coupling.
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201910169
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Whereas irradiation at >400 nm with various photocatalysts proved
ineffective (entries 2-5), the reaction with benzophenone at 365 nm
efficiently catalysed the isomerisation of E-1 to Z-1 (Z/E = 93:7, entry
6). Please see absorption spectra (Table 1, inset).
Performing the reaction in acetonitrile led to small, but detectable,
substrate degradation. However, changing the reaction medium to
cyclohexane resolved this issue and further enhanced the selectivity
(Z/E = 95:5, entry 7). Furthermore, the reaction time could be reduced
to only 2 hours (entries 8-10) with no impact on selectivity or
efficiency. Confirmation that the process proceeds in a clean and
highly selective manner is evident from reaction progress analysis via
HPLC (Figure 1).
Scheme 2. Bypassing the challenge of anti-metallometalation of terminal
alkynes.
To identify suitable conditions for the title transformation, the photo-
isomerisation of vinyl silane E-1 to Z-1 was investigated (Table 1).
Initially, direct irradiation of E-1 at 365 nm was attempted in the
absence of a catalyst. Whilst this led to partial isomerisation (Z/E
12:88) after 24 h, the need for a photocatalyst was apparent. To that
end, the reaction was explored in the presence of a variety of small
molecule organocatalysts. In all cases, 5 mol% catalyst loading was
employed and the Z:E ratios determined by 1H NMR spectroscopy.
100
90
80
70
60
Z-isomer
E-isomer
50
Table 1. Optimisation of the photocatalytic isomerisation of E-1 → Z-1.[a]
40
30
20
10
0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140
Reaction time [min]
1.2
benzophenone
1
E-isomer
0.8
Figure 1. Reaction progress monitoring of E-1 to Z-1 via HPLC using a
CHIRACEL OJ H column, hexane/iPrOH = 99:1, 0.5 mL/min, tR(E-1) = 7.2 min,
tR(Z-1) = 6.4 min.
Z-isomer
0.6
0.4
0.2
0
Having identified suitable photoisomerisation reaction conditions, the
scope and limitations of the transformation were investigated (Table 2).
Specifically, a process of substrate editing was initiated to establish the
effect of the β-substituent, the aryl group, and the silyl-motif on
efficiency. This test-set of vinyl-silanes were then sequentially exposed
to the standard isomerisation conditions.
200
250
300
350
400
450
Wavelength [nm]
Irradiation
wavelength
(nm)
Z/E
Initially, α,β-unsubstituted vinyl-silanes (R1 = H) were investigated.
Since reaction selectivity is predicated on deconjugation through allylic
strain in the product (Scheme 1, lower left),[8f] these scaffolds lacking a
sufficiently bulky R1 group were expected to be most challenging.
Remarkably, however, moderate levels of selectivity favoring the Z-
isomer were observed (Z/E 66:34, Z-2). Increasing the steric demand of
the silyl group from TMS to TBDMS and TIPS (Z-3 and Z-4,
respectively) was well tolerated and led to comparable yields and
selectivities. As a control experiment, Z-4 was independently subjected
to the standard reaction conditions and led to the same photostationary
composition as that of the E-isomer. Comparison with the β-Me- and
β-Et-species, which proceed with high levels of stereoselectivity (Z-5
and Z-1, Z/E 90:10 and 95:5, respectively), further underscore the
importance of the β-substituent to induce A1,3-allylic strain. This
translates directly to high Z-selectivity. Electronic modulation of the
aryl ring at the para-position was well tolerated. Examples that include
electron-deficient halides (Z-6 and Z-7) and electron-rich motifs (Z-8
and Z-9) consistently furnished excellent Z/E ratios (up to 95:5).
Entry
Catalyst
Solvent
t (h)
ratio[b]
1
2
-
cyclohexane
MeCN
24
24
24
24
24
24
24
12
6
365
450
450
402
402
365
365
365
365
365
12:88
0:100
48:52
1:99
(–)-riboflavin
Ir(ppy)3
3
MeCN
4
benzil
MeCN
5
thioxanthone
benzophenone
benzophenone
benzophenone
benzophenone
benzophenone
cyclohexane
MeCN
89:11[c]
93:7[c]
95:5
6
7
cyclohexane
cyclohexane
cyclohexane
cyclohexane
8
95:5
9
95:5
10
2
95:5
[a] Reactions were performed in degassed solvent on a 0.1 mmol scale at
ambient temperature under argon atmosphere, using 5 mol% of the catalyst.
[b] Z:E selectivity was determined by 1H NMR spectroscopy. [c] 1H NMR
spectrum of the crude reaction mixture confirmed partial decomposition.
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Table 2. Establishing substrate scope.[a]
Scheme 3. Stereospecific deuteration of E and Z vinyl silanes. Complete
consumption of the starting materials observed.
Motivated by the venerable history of benzylsilanes and siletanes in the
evolution of cross-coupling, substrates,[13a] E-14 and E-15 were
investigated. Both substrate classes can be converted to more reactive
heterofunctional silanes upon activation by a fluoride source rendering
their inclusion in this study valuable (Scheme 4).[16] Pleasingly, both E-
14 and E-15 were excellent substrates for this transformation (Z/E 95:5
and 90:10, respectively). To demonstrate the utility of the protocol
towards scale-up, both reactions were performed on a 1 mmol scale
with no erosion of stereoselectivity. Representative functionalisations
of Z-14 included a Hiyama-Denmark coupling to generate the skipped
diene Z-17 in 58% with no loss of stereochemical integrity. Siletane Z-
15 was smoothly processed to the Z-configured stilbene Z-18 and the
conjugated diene Z-19 (59%). Finally, Umpolung of the vinyl
nucleophile Z-15 to generate the electrophilic species Z-16 proved
facile (82%).
[a] Reactions were performed in degassed cyclohexane on a 0.1 mmol scale
at ambient temperature using 5 mol% benzophenone and irradiated for 2 h
(365 nm); Z:E selectivity was determined by 1H NMR spectroscopy; yields
refer to isolated, purified mixture of E- and Z-isomer. [b] Product isomer
labelled as (E), based on the higher IUPAC priority of Si than C.
Introducing a substituent at the meta-position of the ring had no
tangible effect on the stereoselectivity (Z-10, 95:5). To further explore
the effect of A1,3 strain, the ortho-methyl derivative E-11 was
synthesised and subjected to the reaction. Interestingly, this
modification led to a notable increase in selectivity (Z/E 78:22) when
compared to Z-2 (Z/E 78:22 versus 66:34). To expand the synthetic
versatility of the substrate scope, the para-Bpin Z-12 and bis-silyl
species E-13, were accessed to provide a platform for orthogonal and
bidirectional coupling. Gratifyingly, smooth and efficient isomerisation
was observed in both scenarios with excellent levels of geometric
control [Z/E 91:9 and E/Z 90:10, respectively (note that E-13 reflects
the higher IUPAC priority of Si over C)].
Scheme 4. Isomerisation of benzylsilanes and siletanes, and stereospecific
derivatisation. [a] Standard conditions for isomerisation: Silane (1.0 eq.),
benzophenone (5 mol%), cyclohexane, 2h, rt, 365 nm. [b] Reactions
conditions: Z-15 (1.0 eq.), N-iodosuccinimide (1.2 eq.), MeCN, 20 min, rt. [c] Z-
Prior to extending the study to a broader scope of silane derivatives for
subsequent cross-coupling, deuteration of E- and Z-2 was performed to
ensure that the stereochemical information in the substrate would be
efficiently translated to the product (Scheme 3). In line with seminal
studies by Fleming and co-workers,[15] independently exposing the
geometric isomers to DCl in D2O led to 62% and 42% deuterium
incorporation, respectively.
14 (0.1 eq.), allyl acetate (8.0 eq.), TBAF (1.0
M in THF, 6.2 eq.),
Pd2(dba)3·CHCl3 (0.1 eq.), THF, rt, 18 h. [d] Z-15 (1.2 eq.), aryl iodide (1.0 eq.),
TBAF•3H2O (3.0 eq.), Pd(dba)2 (7.5 mol%), THF, rt, 18 h.
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isomers. Variation of the silyl rest was also tolerated as indicated by
the benzylsilane (E-24 → Z-24, 81:19). Electronic modulation of the
aryl ring by para- and meta-substitution had little influence on the
selectivity of β-Sn derivatives, and incorporation of a p-chloro group
To further extend the scope of the isomerisation, a model silanol (E-
20) was investigated due to the efficiency of these systems in
stereospecific Hiyama-Denmark coupling processes.[17] Exposure to the
standard conditions developed in Table 1 furnished Z-20 in 93% yield
and with a Z:E ratio of 92:8. As a coupling partner for the Hiyama-
Denmark reaction, 4-iodoanisole was selected due to structural
importance of ether units in bioactive triarylethylenes such as the
Tamoxifen, Droloxifene, Clomifene and Idoxyfene (Scheme 5).[18]
Gratifyingly, the stilbene Z-21 was isolated in 80% yield as a single
geometric isomer.
on the phenyl group provides
a third vector for subsequent
functionalisation (E-25-27). Finally, to validate the utility of this
transformation, the stereocontrolled synthesis of both geometric
isomers triarylethylenes Z- and E-29 was conducted (Scheme 6, lower).
Scheme 5: Isomerisation of vinylsilanol E-20 and stereospecific coupling. [a]
Z/E selectivity determined by 1H NMR spectroscopy.
To extend the methodology to include triarylethylene scaffolds, which
are privileged in medicinal chemistry, the feasibility of bis-vinyl
nucleophiles (R = Si, Sn, B) was examined. As delineated in the
introduction, vinyl silanes containing an adjacent nucleophile would
provide a formal solution to the anti-metallometallation challenge, and
thus streamline routes for the chemoselective, stereocontrolled
construction of tri-arylethylenes (Scheme 6, top).
The generation of bis-nucleophilic species via syn-addition to
phenylacetylene is well-established with complete regiocontrol.[19]
Despite these advances in regiocontrol, achieving geometric control
(formal anti-products) remains conspicuously challenging.[20]
Facilitated by the ease of substrate preparation, various β-Sn and β-
BPin substituted E-vinyl silanes were prepared and subjected to the
isomerisation conditions (Scheme 6, middle).
Scheme 6. Stereocontrolled construction of triarylethylenes Z- and E-29 from
a single precursor (E-23). Isomerisation reactions were performed on a 0.1
mmol scale under standard conditions; a: Styrenyl BPin (1.0 eq.), Aryl bromide
(1.05 eq.), Pd(OAc)2 (5 mol%), SPhos (10 mol%), K3PO4 (3.0 eq.), H2O (5 eq.),
1,4-dioxane, 80 ˚C, 4 h; b: Styrenyl silane (1.0 eq.), NIS (1.2 eq.), MeCN, rt, 16
h; then Styrenyl iodide (1.0 eq.), Aryl BPin (1.05 eq.), Pd(OAc)2 (5 mol%),
SPhos (10 mol%), K3PO4 (3.0 eq.), H2O (5 eq.), 1,4-dioxane, 80 ˚C, 4 h; c:
reactions performed using thioxanthone as catalyst.
Despite significant changes to both the electronic and steric profiles of
the substrates, efficient isomerisation was observed thereby providing a
solution to this intractable problem. TMS-vinyl silane Z-22 bearing a
stannyl residue, as well as a boronic acid pinacol ester E-23, were
smoothly converted to the corresponding easily isolable, geometric
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Substrate E-23 containing the β-BPin vinyl silane motif served as a
convenient starting point for this endeavour. Exposure to
benzophenone under irradiation rapidly furnished the easily isolable Z-
23. Isomers E-23 and Z-23 were then independently subjected to
Suzuki-Miyaura conditions, resulting in β-arylation with high yields
[Z-28 and E-28]. Finally, iodination and coupling with a boronic ester
provides a stereospecific route to geometric triarylethylenes Z-29 and
E-29.
preventing re-conjugation of the styrenyl chromophore, thus inhibiting
re-excitation, the ramifications on electronic structure required
clarification. To that end, a computational study of the isomerisation of
E-2 → Z-2 (R=H) and E-1 → Z-1 (R=Et) was conducted at the DFT
level of theory (Figure 2, please see the Supporting Information).[21]
In the case of the unsubstituted system (R = H), the net contra-
thermodynamic isomerisation process (E-2 → Z-2, ∆G = +3.5
kcal•mol-1), vertical (S0
→ S1) excitations of 100.5 and 102.3
kcal•mol-1 were determined from the ground state E and Z isomers,
respectively (TD-DFT, BLYP/def2-TZVP). The analogous, spin-
forbidden (S0 → T1) excitations were calculated to be 69.8 and 74.0
kcal•mol-1 (Figure 2, top). In the case of the substituted systems E- and
Z-1, the substituent combination rendered the transformation
essentially thermo-neutral (E-2 → Z-2, ∆G = -0.2 kcal•mol-1).
However, the difference between the E and Z isomer is larger for the
first singlet (S0 → S1) excitation (102.2 versus 106.6 kcal•mol-1) and
the forbidden (S0 → T1) excitation (74.2 versus 87.1 kcal•mol-1).
In both ground (S0) states of (E)-1 and (Z)-1, the HOMO and LUMO
are constituted mainly by the π/π* orbitals of the ethene bond, with
significant mixing of phenyl π orbitals (Figure 3). The (forbidden) first
triplet excitation to the T1 of E-1 corresponds to a HOMO-LUMO
excitation (see SI). In this case, the two singly occupied orbitals of T1
are both delocalised over the styrenyl system and add up to localisation
of spin density in the vinyl group (Figure 5), promoting rotation around
the vinyl C-C bond to the energy minimum of the tripelt state.
Figure 3. Frontier orbitals of T1 state of E-1 at S0 geometry (PWPB95/def2-
TZVP). Top left (α-HOMO), bottom left (α-HOMO-1), top right (β-LUMO+1),
bottom right (β-LUMO).
The more distorted styrenyl moiety of Z-1, however, shows a
significantly higher energy of the forbidden first vertical triplet
excitation (87 kcal/mol) in the TD-DFT (B-LYP) calculation and of the
energy of the (relaxed) T1 wave function (100 kcal/mol with PWPB95-
D3) at the same geometry. The larger torsional angle (61.6°)
aggravates the mixing of ethene and phenyl π orbitals and leads to two
rather localised α spin orbitals in the T1 state (Figure 4). Consequently,
spin density is largely accumulated in the phenyl ring.
Figure 2. Energy profile for the photo-isomerisation of E-2 to Z-2 (R = H, top)
and E-1 to Z-1 (R = Et, bottom).
The generality of this isomerisation and the importance of the vinyl
silane core was a powerful impetus to interrogate the underlying origin
of selectivity. Whilst allylic strain in the product is clearly essential in
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areas of 2D chemical space and find application in the stereocontrolled
construction of well-defined aromatic scaffolds. This is particularly
true given the facile manner in which triaryl-ethylenes can be
converted to their tetra-substituted analogues.[23]
A computational investigation to interrogate the origin of selectivity
revealed that inducing A1,3-strain causes significant differences in the
localisation of spin density in energetically comparable isomers. The
vertical (S0→T1) excitation in the E-scenario leads to an accumulation
of spin density in the alkene, thus enabling bond rotation. This finding
further underscores the importance of understanding structure –
function interplay[24] in giving directionality to contra-thermodynamic
or thermo-neutral processes.
Acknowledgements
Figure 4. Frontier orbitals of T1 state of Z-1 at S0 geometry (PWPB95/def2-
TZVP). Top left (α-HOMO), bottom left (α-HOMO-1), top right (β-LUMO+1),
bottom right (β-LUMO).
We acknowledge generous financial support from the WWU
Münster and the Alexander von Humboldt Foundation (post-
doctoral fellowship to JJM).
A comparison of the calculated spin densities of E-1 and Z-1 (Figure 5)
clearly illustrate this distinction and thus it is conceivable that in the E-
scenario the (S0→T1) excitation leads to accumulation of spin density
in the vinyl group, facilitating rotation around that C-C bond. Whilst
A1,3-strain is ultimately responsible for the conformation, the reactivity
differences between these energetically comparable isomers is a
consequence of differences in the initial localisation of spin density.
This may prove to be a valuable strategy to direct thermo-neutral
reactions at the structure/conformation level.[22]
Keywords: alkenes • catalysis • Hiyama-Denmark coupling •
geometric isomerisation • medicinal chemistry
[1]
[2]
For excellent reviews on stereodivergence, see: (a) S. Krautwald, E. M.
Carreira, J. Am. Chem. Soc. 2017, 139, 5627-5639; (b) I. P. Beletskaya, C.
Nájera, M. Yus, Chem. Rev. 2018, 118, 5080−5200.
For selected reviews highlighting stereospecific cross-coupling, see: a) K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44, 4442 –
4489; Angew. Chem. 2005, 117, 4516 – 4563; b) S. E. Denmark, R. F. Sweis,
Acc. Chem. Res. 2002, 35, 835 – 846. For selected examples of stereospecific
cross-coupling, see: c) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett.
1979, 20, 3437 – 3440; d) J. K. Stille, B. L. Groh, J. Am. Chem. Soc. 1987, 109,
813 – 817; e) S. E. Denmark, J. Y. Choi, J. Am. Chem. Soc. 1999, 121, 5821 –
5822; f) S. E. Denmark, D. Wehrli, Org. Lett. 2000, 2, 565 – 568; g) G. A.
Molander, L. A. Felix, J. Org. Chem. 2005, 70, 3950 – 3956; h) S. E. Denmark,
J. M. Kallemeyn, J. Am. Chem. Soc. 2006, 128, 15958 – 15959; i) G. Wang, S.
Mohan, E. Negishi, Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 11344 – 11349.
For the importance of stereospecific cross coupling in medicinal chemistry,
see: S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 – 3479.
J. B. Metternich, R. Gilmour, Synlett 2016, 27, 2541 – 2552.
[3]
[4]
[5]
(a) J. J. Molloy, T. Morack, R. Gilmour, Angew. Chem. Int. Ed. 2019,
doi.org/10.1002/ange.201906124; (b) C. M. Pearson, T. N. Snaddon, ACS Cent.
Sci. 2017, 3, 922-924.
Figure 5. Comparison of the calculated spin densities of the triplet states for
E-1 (left) and Z-1 (right) at the S0 geometry (R = Et). Spin density isosurface in
blue: +0.005, red: -0.005 a.u.
[6]
[7]
[8]
For selected examples, see: a) S. –S. P. Chou, H. –L. Kuo, C. –J. Wang, C. –Y.
Tsai, C. –M. Sun, J. Org. Chem. 1989, 54, 868 – 872; b) N. Chatani, N.
Amishiro, T. Morii, T. Yamashita, S. Murai, J. Org. Chem. 1995, 60, 1834 –
1840; c) J. –C. Shi, E. Negishi, J. Organomet. Chem. 2003, 687, 518 – 524; d)
R. Alfaro, A. Parra, J. Alemán, J. L. G. Ruano, M. Tortosa, J. Am. Chem. Soc.
2012, 134, 15165 – 15168; e) Y. Nagashima, D. Yukimori, C. Wang, M.
Uchiyama, Angew. Chem. Int. Ed. 2018, 57, 8053 – 8057; Angew. Chem. 2018,
130, 8185 – 8189.
In conclusion, an operationally simple, geometric E→Z isomerisation
of vinyl silanes has been developed based on selective energy transfer
catalysis at 365 nm using inexpensive benzophenone as the catalyst (1
kg = 45 Euro). The transformation is efficient (2 h) and is compatible
with a range of common Si-groups, including (benzyl)silanes, silanols
and siletanes. Conveniently, the isomerisation can be added to pre-
existing E-selective synthetic sequences thereby enabling
sterodivergence. The concept has been extended to include non-
symmetric bis-nucleophilic systems (R = Si, Sn and B) thereby
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of isomerising bis-vinyl nucleophiles containing metals and/or
metalloids, prior to transmetallation, constitutes a formal solution to
the challenge of anti-metallometallation. Given the ubiquity of
triarylethylenes in pharmaceutical design, it is envisaged that this
“ethylene vector synthon” strategy will facilitate the exploration of new
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Entry for the Table of Contents
Svenja I. Faßbender+, John J. Molloy+
Christian Mück-Lichtenfeld and Ryan
Gilmour*
Page No. – Page No.
Geometric E→Z Isomerisation of Vinyl
Silanes by Selective Energy Transfer
Catalysis: Stereodivergent Synthesis of
Triarylethylenes via a Formal Anti-
Metallometallation.
Text for Table of Contents
An efficient geometrical E→Z isomerisation of vinyl silanes is disclosed via selective energy transfer using an inexpensive organic sensitiser. Characterised
by operational simplicity, short reaction times (2 h), and broad substrate tolerance the reaction displays high selectivity for trisubstituted systems (Z:E up
to 95:5). The structural importance of the β-substituent logically prompted an investigation of mixed bis-nucleophiles (Si, Sn, B). These versatile linchpins
also undergo facile isomerisation, thereby enabling a formal anti-metallometallation. Computational analysis reveals significant differences in spin
delocalisation in the core styrene moiety of the substrate and product. Mechanistic interrogation, supported by a theoretical investigation, is disclosed
together with application of the products to the stereospecific synthesis of biologically relevant target structures.
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