Herramientas CASE

The regiodivergent arylation mechanisms computed for the reactivity of styrene were next applied to the allylic amide arylation process investigated in chapter 2. Initial efforts were directed towards rationalising the outcome of a simple racemic model reaction shown to give both enamide and oxazine products (Scheme 141). As more oxazine product is observed in the crude reaction, it was anticipated that the transition state leading to oxazine formation would be slightly lower in energy than that giving enamide formation (ΔΔG^‡ 0–1 kcal mol^-1).

Scheme 141 – Racemic regiodivergent allylic amide arylation to furnish oxazine 428 and enamide 602 (NMR yields with 1,3,5-trimethoxybenzenetricarboxylate)

The functionalisation of the allylic amide towards oxazine 428 was first evaluated. In analogy with the computed reaction of styrene to give stilbene formation, alkene-binding adducts resembling the key styrene-bound intermediate Int-5 were sought. Given the coordinating nature of the allylic amide carbonyl group, calculations were directed towards the generation of bidentate adducts. Cationic copper(III) complex Int-10 was identified to fit these constraints (Figure 19).

10 mol% CuTC 2.0 equiv. DTBP CH₂Cl₂ (0.05 M), 50 ºC, 24h

428 +

50%

315 O

NH Me₃C

247 (2.0 equiv.) TfO

I ^Me

Me

Me O

NH Me₃C N

O Me₃C

602 18%

+

Figure 19 – Computed bidentate cationic allylic amide-bound copper(III) adduct Int-10

With Int-10 in hand, an energy profile for reductive-elimination-like substrate arylation towards oxazine formation was generated to ultimately give arylated allylic amide complex Int-11 (Scheme 142).

These investigations indicated arylation of the substrate by this mechanism to be energetically accessible, though significantly higher in energy than the comparative styrene functionalisation (TS-6 vs. TS-3:

ΔG^‡ = 9.1 kcal mol^-1 vs. 14.0 kcal mol^-1). It is proposed that arylated intermediate Int-11 may be converted to the oxazine product through carbocation dissociation and carbonyl trapping (Scheme 143).

Scheme 142 – Reaction of amide 315 with Int-4 towards oxazine formation (Gaussian 09 - BP86 functional, Def2SVP (SDD) [Cu], 6-31G+(d,p) [C,H,O,F,S]); energies given as ΔG (kcal mol^-1)

Scheme 143 – Proposed generation of oxazine 428 from copper-bound intermediate Int-11

Interestingly, there appears to be a close resemblance between the transition state leading to oxazine formation and that leading to the production of stilbene (Figure 20). The styrene functionalisation appears to be stabilised by a hydrogen-bonding interaction from the alkene to a triflate ligand, placing a triflate oxygen where the carbonyl appears to bind to the copper centre for allylic amide arylation.

Figure 20 – Isostructural arylation transition states with styrene and allylic amide 315 respectively

Attention was next directed towards the identification of a concerted carbocupration transition state leading to enamide formation. Surprisingly, all efforts to coordinate the allylic amide to the copper centre in the expected reactive conformation led directly to the production of insertion intermediate Int-12.

Interestingly, this species is observed to be lower in energy than the comparable intermediate leading to oxazine formation (Int-11), thereby implying a thermodynamic preference for enamide generation. No intermediate alkene-bound complex (604) or carbocupration transition state (605) could be identified on path towards the formation of Int-12 (Scheme 144).

TfO Cu

O NH

CMe₃

O NH

CMe₃

CuOTf

DTBP

DTBPH

O N

CMe₃

Int-11 603 428

Scheme 144 – Reaction of amide 315 with Int-4 towards enamide formation (Gaussian 09 - BP86 functional, Def2SVP (SDD) [Cu], 6-31G+(d,p) [C,H,O,F,S]); energies given as ΔG (kcal mol^-1)

An enamide-formation energy profile with identifiable intermediate adducts was computed for a different substrate using a more rigorous basis set (Scheme 145). It was revealed that cationic bidentate allylic amide copper(III) adduct Int-14 is more stable than the neutral bistriflated species Int-13.

Interestingly, the carbocupration transition state (TS-7) leading to enamide formation was calculated to lie just 2.1 kcal mol^-1 higher in energy than Int-14. The low calculated activation energy explains the difficulty encountered for the convergence of alkene-bound intermediates in the above study.

Scheme 145 – Reactivity of amide 361 with Int-4 towards enamide formation (Gaussian 09 - BP86 functional, Def2QZVP (SDD) [Cu], 6-311G+(2d,p) [C,H,O,F,S]); energies given as ΔG (kcal mol^-1)

Disappointingly, a transition state analogous to TS-6 (oxazine formation, Scheme 142) could not be converged at the desired level of theory with para-tolyl substrate 361. As such, no direct comparisons between the reaction profiles leading to oxazine and enamide generation can be made. However, it appears that the concerted carbocupration process giving enamide formation is remarkably facile, whilst the energetic profile calculated towards oxazine production appears too high in energy to be competitive (Scheme 142). It is therefore anticipated that a lower-energy process giving oxazine formation must exist on the potential-energy surface for the copper-catalysed arylation of allylic amides with diaryliodonium salts.

4.3.1. Future calculations

Owing to time limitations, no further work could be carried out to improve our understanding of the origins of the observed regiodivergence. It is hoped that further investigations in this area will be pursued in the future. In this eventuality, work should be first directed towards computing two other potential reaction pathways for oxazine formation:

Firstly, in direct analogy with the styrene functionalisation process, the reaction of allylic amide 315 with the key phenyl-Cu(III) electrophile Int-4 should be computed with monodentate alkene binding (Scheme 146). As is discussed in Section 2.9, reaction through such a mechanism would allow for the rationalisation of oxazine selectivity with electron-rich iodonium salts

Scheme 146 – Possible monodentate allylic amide functionalisation mechanism towards oxazine formation Secondly, the computations detailed in Scheme 142 should be re-computed with the amide deprotonated. It is anticipated that this change would give increased charge donation to the copper centre, stabilising the reductive elimination-like transition state (Scheme 147).

Scheme 147 – Formally anionic allylic amide functionalisation towards oxazine formation

Following the identification of a low-energy alkene functionalisation pathway giving oxazine formation, the effect of changing the aryl-group electronics should be investigated. It is anticipated that more

Cu O

606 OTf

O S O CF₃

Cu O OTf

O S O CF₃

Cu O

608 O S

O CF₃ N TfO

H O

CMe₃ N

H O

CMe3

NH O

CMe3

‡

607

Cu TfO O

N

R

Cu TfO O

N

R

611 TfO

Cu O

N CMe₃

‡

609 610

electron-rich aryl groups will alter the energies of the alkene functionalisation transition states to bias oxazine formation. Contrastingly, it is expected that more electron-poor aryl groups will relatively lower the energy of the carbocupration transition state, thereby favouring enamide formation.

4.4 Summary

Although the studies detailed in this section are incomplete, some important insights have been gained into the behaviour of copper-catalysed alkene functionalisation processes using iodonium salts. Firstly, it has been evidenced that little energy input is required to generate copper(III) intermediates from the combination of copper(I) species and iodonium salts. Furthermore, these copper(III) adducts have so far been computationally demonstrated to react with alkenes by two mechanisms, consistent with behaviour that has been observed experimentally. One such process resembles reductive elimination, directly coupling the aryl group from the iodonium salt to the more nucleophilic alkene position. The second reactivity mode appears as a concerted carbocupration – transferring the aryl group to the less intrinsically nucleophilic position of the alkene. The former process has been demonstrated to allow the formation of free carbocations in the reaction mixture, whilst the latter pathway permits rationalisation of the functionalisation of the non-nucleophilic alkene position. Further work is required to more fully understand and apply the behaviour of these systems.