1 Introduction – The Catalytic Generation and Reaction of Aryl and Alkenyl
1.5 The Reactivity of Aryl and Alkenyl-Copper(III) Intermediates with Carbon
1.5.2. Non-classical aromatic functionalisation with Cu(III) electrophiles
During the course of studies into indole arylation with copper and iodonium salts, Gaunt noted that the natural C-3 selectivity of the reaction could be overturned with the use of N-acetylated indole 209 (Scheme 37).108
Scheme 37 – Gaunt’s C-2 selective N-acyl indole arylation108
The switch in regioselectivity is attributable to the steering ability of the pendant carbonyl moiety, mechanistically explainable in two ways. Firstly, it is possible that the indole reacts through the C-3 position to generate Cu(III) adduct 211, in line with the observation of C-3 arylation in the absence of a coordinating group (Scheme 31). The carbonyl group of the acetylated indole can then induce a C-3 to C-2 migration giving 213 via intermediate 212 (Scheme 38 – upper cycle). Reductive elimination would furnish the desired C-2 substituted product. Alternatively, the carbonyl group could directly bind aryl-copper(III) intermediate 214. A concerted metalation-deprotonation process at the C-2 position would then directly generate catalytic intermediate 213 through a transition state such as 215 (Scheme 38 – lower cycle).
Y
X I +
20 mol% Cu(OTf)2 4.0 equiv. 79 DCE (0.2 M), 70 ºC, 72 h
MeO
Bn2N 10 mol% Cu(OTf)2
0.5 equiv. 168 1.0 equiv. DTBP DCE (0.4 M), 50 ºC, 16 h
207 208
77% 62%
= OMe (205)
= NBn2 (206) Y
= BF4 (79)
= OTf (168) X
TfO I
209 168 (1.5 equiv.)
N +
210 83%
10 mol% Cu(OTf)2 1.5 equiv. DTBP DCE (0.1 M), 60 ºC, 18 h O
Me
N O
Me
Scheme 38 – Proposed mechanistic origins of the Gaunt’s C-2 selective N-acyl indole arylation procedure Gaunt questioned whether the directing ability of carbonyl groups would allow for the non-natural functionalisation of other arene rings. Pursuing this strategy, he published in 2009 a highly meta-selective copper-catalysed pivanilide arylation (Scheme 39a).126 The observed behaviour is in direct contrast with Daugulis’ analogous palladium-catalysed ortho-arylation using the exact same substrate.127 Interestingly, the anti-Friedel-Crafts reactivity could be reproduced on the copper-catalysed arylation of other α-aryl carbonyl species such as 218, a structural analogue of pivanilide 216 (Scheme 39b).128
Scheme 39 –Gaunt’s meta-selective arylation of a) pivanilides126 and b) other α-aryl carbonyl species128
Cu OTf
216 168 (2.0 equiv.)
+
218 168 (2.0 equiv.)
+
The origins of the non-natural selectivity of Gaunt’s pivanilide arylation were computationally investigated by the Wu and Ding groups,129,130 both evaluating the mechanism of the reaction using a simplified acetylanilide substrate (Scheme 40). It is computed that the ground-state Cu(III)-amide intermediate 219 initially re-orientates with an energetic penalty of +14.4 kcal mol-1 to give the apical aryl-associated copper(III) adduct 220. This intermediate then undergoes a concerted carbocupration process, simultaneously ortho-cuprating and meta-arylating the anilide to give intermediate 222. The transition state 221 for the meta-arylation process is calculated to lie at an accessible +19.2 kcal mol-1 above adduct 219. Elimination, releasing an equivalent of triflic acid, re-aromatises the anilide ring and furnishes the coupled-product-bound copper(I) species 223. Product dissociation and re-oxidation gives resting copper(III) intermediate 180 ready for amide association to regenerate the starting complex.
Scheme 40 – Wu’s computational evaluation of Gaunt’s copper-catalysed meta-selective anilide arylation;129 bold quantities denote the relative energy of the system at that stage of the mechanism (kcal mol-1)
The Wu and Ding groups have also calculated the energetic barrier to the formation of the Friedel-Crafts-favoured ortho-arylated product. Both studies predict that the ortho-functionalisation would occur through a concerted metalation-deprotonation pathway with triflate acting as the base. Wu calculated an intermolecular carbonyl-directed CMD process whilst Ding computed an amide N–H directed bond formation/cleavage process. In both instances the energies of the transition states are calculated to be
HN
higher in energy than those leading to meta-functionalisation (ΔG‡ = +2–7 kcal mol-1). Interestingly, the relative energetic similarity of the ortho- and meta-arylation transitions states imply the accessibility of two potential processes for the functionalisation of arenes (carbocupration vs. CMD) under the investigated copper/iodonium salt manifold. The computed accessibility of a CMD process with a pivanilide substrate supports the second mechanistic proposal for the C-2 indole arylation described above (Scheme 38, lower cycle).
Gaunt’s modular synthesis of the indolocarbazole natural product staurosporinone 230 employs both meta- and ortho-selective copper-catalysed arylation procedures. These reactions are employed to introduce pendant phenyl groups to an aniline core, later constructed via five further C–H functionalisation processes into the desired product (Scheme 41).131 This strategy allowed the synthesis of staurosporinone in ten steps and in 12.7% overall yield. It was envisaged that the use of derivatised iodonium salts in the synthetic route would allow for the generation of a range of unsymmetrical staurosporinone analogues.
Scheme 41 – Gaunt’s total synthesis of staurosporinone 230 employing two copper-catalysed arylations131
Shi has further elaborated the concept of directing functionalisation to non-natural ring positions. His group has described a C-6 selective indole arylation/alkenylation procedure using copper and iodonium salts. Inspired by previous palladium-catalysed studies giving C-7-selective indole functionalisation,132 the reaction uses a phosphinic amide to direct reactivity towards the desired position (Scheme 42).133
Bn2N
Me Bn2N
Me
HN
Me Et
O
HN
Me Et
O2N O HN
N O
Ar HN
NH O
HN
225 226
227
228
229 230
10 mol% Cu(OTf)2 1.3 equiv. 168 1.3 equiv. DTBP DCE, 50 ºC, 24 h
10 mol% CuI 10 mol% AgOTf
2.0 equiv. 168 2.0 equiv. NaHCO3
DCE, 50 ºC, 24 h protecting group
manipulations
further C–H functionalisations Cadogan cyclisation
deprotection
76%
71%
ten steps seven C–H functionalisations
12.7% overall yield TfO
I
168
Scheme 42 – Shi’s C-6 selective indole arylation intramolecularly directed by a phosphinic amide moiety133 It is proposed that the steric bulk of the tert-butyl groups of phosphinic amide 231 helps orientate the directing group towards the six-membered ring portion of the indole. From here, the mechanistic proposal is analogous to that described by Wu and Ding in their computational investigations into the meta-selective anilide arylation. Co-ordination of the phosphoryl moiety to the aryl-copper(III) intermediate 180 places the electrophilic metal centre under the indolic C-7 position and the aryl group under C-6. A concerted carbocupration process provides the desired carbon-carbon connectivity, generating formal alkyl copper intermediate 234. Elimination of this species would regenerate copper(I) and furnish the observed C-6 functionalised indole (Scheme 43).
Scheme 43 – Proposed mechanism for Shi’s C-6 selective indole arylation