Styrene coupling

Attention was next directed towards modelling the reactivity of styrene with high-valent copper intermediate Int-4. It was initially anticipated that the alkene coordination and migratory insertion steps would occur analogously to those processes described for the palladium-catalysed Heck reaction.²¹⁵ However, in contrast to the Heck reaction, it was predicted that the stilbene formation would occur by an E2-type process rather than by a β-hydride elimination. This hypothesis derives from the observed production of alkene products that do not lie in conjugation with the introduced arene (Scheme 136).¹⁵⁵ Such compounds are not consistent with the β-hydride elimination behaviour of palladium species with acylic alkene substrates.²¹⁶ Computational investigations therefore targeted a reaction profile involving two key transition states: a concerted carbocupration to transfer the aryl group (597) and an E2-type elimination to furnish the stilbene product (598) (Figure 14).

Scheme 136 – Gaunt’s copper-catalysed arylation of alkene 301 to give non-conjugated product 302¹⁵⁵

Figure 14 – Expected styrene functionalisation transition states

On introduction of styrene to the copper(III) intermediate Int-4, it was interesting to note that copper(III)-alkene adducts could only be identified with copper-alkene binding dominantly occurring through the alkene terminus. This binding mode differs from the expected Dewer-Chatt-Duncanson-type bonding where both alkene p-orbitals participate in the metal–alkene interaction.²⁸ An example of this interesting alkene-copper binding mode can be seen with Int-5 (Figure 15). The observed unsymmetrical alkene binding can be rationalised through the electron-deficient copper centre acting to strongly polarise the bound alkene, formally placing a negative charge at the alkene terminus and building positive charge at the styrene benzylic position. Such extreme induced polarity is evidenced by the lengthened C=C bond and shortened C–Ph bond computed for the styrene in Int-5 relative to the free alkene 35 (Figure 16, Int-5: 1.41 Å, 1.43 Å respectively; styrene: 1.35 Å, 1.47 Å).

Me Me

10 mol% Cu(OTf)₂ 2.0 equiv. DTBP CH₂Cl₂ (0.1 M), 70 ºC, 20 h

301 302 72%, 3.5:1

TfO I

168 (2 equiv.) +

Me 302a +

TfO Cu 597 TfO

Cu O TfO

H N

O 598 S O CF₃ concerted

carbocupration E2

elimination

Figure 15 – Terminal π-bound styrene-Cu(III) complex Int-5

Figure 16 – Shortening of styrene C=C bond and lengthening of C–Ar bond on binding to Int-5

From Int-5, only one transition state (TS-3) was discovered that would lead towards the desired 1,2-substituted adduct (ΔG^‡ = +2.3 kcal mol^-1, Figure 17). Intriguingly, this transition structure appears to most closely resemble an early reductive elimination transition state.²¹⁷ Such reactivity can be rationalised by considering Int-5 at its charge-separated resonance extreme 600, bearing a formal alkyl-copper bond. Reductive elimination from such an anionic alkyl-copper(III) centre reflects the computed behaviour (Scheme 137).

Figure 17 – Transition state leading to the desired stilbenium connectivity (TS-3)

Scheme 137 – Rationale of alkene functionalisation through copper(III)-induced polarisation of alkene π-bond

With transition state TS-3 in hand, work was carried out to elaborate a plausible functionalisation pathway towards the observed stilbene product (Scheme 138). It was calculated that styrene-bound adduct Int-5 could be produced with only a slight energetic penalty on alkene association to the κ² -stabilised copper(III) intermediate Int-4 (ΔG = +6.8 kcal mol^-1). Subsequent aryl insertion occurs via computed transition state TS-3 to furnish the aryl-coupled intermediate Int-6 with a large associated gain in energy (ΔG = –30.1 kcal mol^-1). In line with our hypothesis, an E2 transition state (TS-4) was identified to lie 8.5 kcal mol^-1 higher in energy than arylated intermediate adduct, providing exergonic access to stilbene-bound copper(I) triflate anion Int-7. Dissociation of the coupled stilbene product was computed to be thermodynamically favourable, allowing regeneration of the free anionic copper(I) triflate species 178.

Cu OTf O

S O

Int-4 O F₃C

TfO Cu

TfO R

TfO Cu

TfO R

TfO Cu

OTf R

‡

R alkene association

reductive elimination

599 Int-5 600 TS-3

Scheme 138 – Association of styrene 35 to key κ²-bound copper(III) species Int-4 and reaction towards trans-stilbene production (Gaussian 09 - BP86 functional, Def2QZVP (SDD) [Cu], 6-311G+(2d,p) [C,H,O,F,S,N]);

energies given as ΔG (kcal mol^-1)

Based on the observed reductive elimination-like chemistry of TS-3, it was considered that Int-6 could alternatively be viewed as ionically-paired copper(I) anion-carbocation complex. Interestingly, the dissociation of Int-6 into the free benzylic-stabilised carbocation 601 and copper(I) triflate anion 178 was determined to be favourable (Scheme 139, ΔG = –1.0 kcal mol^-1). Importantly, this result implies that copper-catalysed alkene arylation can take place to give free carbocationic intermediates with the charge localised at the most stabilising position. This is consistent with many of the experimental observations described in the literature and allows rationalisation of elimination, fragmentation, isomerisation and hydride-shift processes (see Schemes 63 and 66, Section 1.5.5).153,155,157

Scheme 139 – Dissociation of Int-6 to stilbenium ion 601 and copper(I) triflate anion 178 (Gaussian 09 - BP86 functional, Def2QZVP (SDD) [Cu], 6-311G+(2d,p) [C,H,O,F,S]); energies given as ΔG (kcal mol^-1)

However, the free carbocationic behaviour detailed above does not explain the potential for functionalisation at the non-nucleophilic position of alkene substrates.¹⁷⁴ Although no such reaction product is observed on the reaction of styrene with diaryliodonium salts under copper-catalysis, attention was turned towards further evaluating the reactivity of the copper(III)-styrene adduct. Mechanistic pathways were sought that would give functionalistion of the styrene with opposite regioselectivity to that described above. Interestingly, on re-orientating the bound alkene to give complex Int-8, a concerted carbocupration transition state (TS-5) could be identified leading to 1,1-disubstuted adduct Int-9 (Scheme 140). It should be noted that this complex is calculated to have alkyl-copper bond length of 2.02 Å, considerably shorter than the computed analogous bond length for the 1,2-substituted adduct Int-6 (2.16 Å). The relative difference in bond length implies a stronger copper-carbon interaction for the 1,1-insertion intermediate, indicative of a true copper(III) intermediate. Intriguingly, the transition state for this carbocupration process lies only very slightly higher in energy than the transition state calculated to give the stilbene product (TS-5 vs. TS-3, ΔΔG^‡ = +0.2 kcal mol^-1). This result implies the kinetic accessibility of two transition states giving regioisomeric products, offering a potential explanation for observed regiodivergence in the functionalisation of allylic amides.¹⁷⁴

Scheme 140 – Association of styrene 35 to key κ²-bound copper(III) species Int-4 and reactions towards 1,1-diphenylethylene production (Gaussian 09 - BP86 functional, Def2QZVP (SDD) [Cu], 6-311G+(2d,p)

[C,H,O,F,S]); energies given as ΔG (kcal mol^-1)

It is anticipated that elimination processes from Int-9 will be unfavourable due to the energetic penalty of losing the stabilising co-ordination of the aryl group. Such an energy barrier allows the absence of 1,1-diphenylethylene in the crude reaction mixture to be rationalised. Furthermore, given the relatively high energy of arylated intermediate Int-9, it is possible that the carbocupration process proceeding through TS-5 will be reversible. Finally, an alternative explanation for the absence of 1,1-diphenylethylene in the reaction mixture would be the occurrence of a 1,2-aryl migration from Int-9 to give the more stable Int-6, thereby ultimately giving stilbene formation.

4.2.3. Summary

Whilst further work is required to more fully understand the copper-catalysed arylation of alkenes with diaryliodonium salts, the investigations described in the above sections have given insight into the functionalisation modes that alkenes may undergo in the presence of high-valent copper intermediates.

Tentatively, it can be concluded that at least two energetically accessible alkene functionalisation processes exist under such a reaction manifold. These two computed arylation modes resemble a reductive-elimination-like process (TS-3, Figure 18a) and a concerted carbocupration process (TS-5, Figure 18b) respectively and proceed to give regiosiomeric reaction products.

Figure 18 – Computed styrene functionalisation transitions states