Branch-Selective Alkene Hydroarylation by Cooperative Destabilization: Iridium-Catalyzed ortho-Alkylation of Acetanilides

An iridium(I) catalyst system, modified with the wide-bite-angle and electron-deficient bisphosphine dFppb (1,4-bis(di(pentafluorophenyl)phosphino)butane) promotes highly branch-selective hydroarylation reactions between diverse acetanilides and aryl- or alkyl-substituted alkenes. This provides direct and ortho-selective access to synthetically challenging anilines, and addresses long-standing issues associated with related Friedel–Crafts alkylations.

to provide branched products 1b at the expense of linear isomers 1a. [14] This process employs weakly coordinating carbonyl directing groups,and tolerates both aryl-and alkylsubstituted alkenes.R elated branch-selective hydroarylation methods invariably require strongly coordinating N-based directing groups and are limited to styrenes [15a-d] or, more recently,e nol ethers as the olefinic partner. [15e, 16,17] In this report, we extend our strategy to the branch-selective orthoalkylation of acetanilides (Scheme 1b). [18] Significantly,t his work expands our approach to encompass a) electron-rich arenes,a nd b) inherently more demanding six-ring metallacycles (2 vs. 4). Indeed, to the best of our knowledge,t his study outlines the first intermolecular branch-selective Murai-type alkene hydroarylations that proceed via six-ring chelates.I nc ombination with earlier work, [12] these results suggest that au nified approach to branch-selective alkene hydroarylation is achievable and underpin ongoing efforts towards enantioselective variants.
in 34 %y ield and with complete branch selectivity (entry 1). Lower reaction temperatures or longer reaction times resulted in diminished yields of 6a (entries 2-4). However, as trong dependence upon the Ir counterion was observed, and increased yields were achieved using more strongly associating variants.This resulted in the conditions in entry 6, which deliver 6a in 85 %y ield and, importantly,w ith complete branch selectivity and full selectivity for monoortho-alkylation. Higher loadings of styrene offered no appreciable benefit (entry 6v s. entry 7). Solvents other than dioxane can be employed, but marginally lower yields of 6a were obtained (entries [8][9][10][11]. Interestingly,f or reactions run in 1,2-dichlorobenzene (1,2-DCB), the BARF counterion was superior to triflate (entry 8v s. entry 9). Thes econdary acetamide directing group of 5a is crucial to the process and the corresponding N-methylated derivative (entry 12) as well as carbamate-, tosyl-, formyl-, and pivaloyl-protected substrates were all ineffective. [19] Thescope of the aniline component is outlined in Table 2. Hydroarylation of styrene with ortho-substituted derivatives 5b-5e provided target compounds 6b-6e in high yield and with complete branch selectivity in all cases.F or optimal efficiencies,fine-tuning of the styrene loading was required on acase by case basis.For example,hydroarylation to afford 6b occurred in only 54 %y ield with 200 mol %s tyrene,b ut a73% yield was achieved using 450 mol %. Thetolerance to ortho-substitution contrasts our earlier work with aryl ketones and benzamides,w here analogous processes were not feasible. [12] Lower loadings of styrene can be used for substrates with electron-donating groups at the C3 position. Fore xample, 6c and 6d were both generated in excellent yield using just one equivalent of the alkene.A niline derivatives 5f-5j have two different ortho C À Hb onds available,a nd regioselectivity is strongly influenced by the meta-substituent. For 5f-5h,hydroarylation occurred preferentially at the less hindered site to afford adducts 6f-6h (4:1 to > 25:1 ortho-regioselectivity);the structures of 6h and iso-6h were determined by single-crystal X-ray diffraction. [20] For 5i and 5j,h ydroarylation was moderately selective for the ortho C À Hb ond adjacent to the heteroatom substituent. [21] para-Substituted anilines 5k and 5m participated smoothly, and products 6k and 6m were formed in good yield. Conversely,h ydroarylation using para-trifluoromethyl derivative 5l was not efficient, and adduct 6l was formed in 21 % yield. Complete branch selectivity and complete selectivity for mono-ortho-alkylation (> 95:5 mono/bis) were observed for 6f-6m.
We have also examined the scope of the alkene component using acetanilide 5f,a nd, again, complete branch selectivity was achieved in all cases (Table 3). Electronically diverse styrenes are well tolerated, and the target compounds 7a-7e were formed in moderate to quantitative yield, with complete selectivity for mono-alkylation at the less hindered ortho-site.P rocesses involving alkyl-substituted alkenes required separate optimization. Changing the precatalyst counterion from triflate to BARF and switching the solvent from dioxane to 1,2-DCB provided as ystem that delivered targets 7f-7i in 33-99 %y ield, albeit with 600 mol %o ft he alkene component. For 7g,p ropylene gas was delivered at atmospheric pressure to introduce the ortho-isopropyl moiety in 92 %yield. Isopropyl groups are challenging to install using Pd-catalyzed cross-couplings, [8a] and the present method provides ad irect and atom-economic alternative.S terically  [a] In all cases, branched/linear > 25:1.

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Chemie demanding alkenes are challenging,and the conversion of 5f into 7h occurred in only 33 %y ield;h owever, even here, branch selectivity was maintained. Them echanism of the hydroarylation process is likely analogous to that outlined in our earlier work (Scheme 1a). [12] Hydroarylation of [D 2 ]-8 with aniline 5fdelivered deuterated 7c,inwhich deuterium incorporation at both the methyl and methine positions indicates reversible alkene hydrometalation prior to product-determining C À Cb ond formation (Scheme 2). Thel ack of deuterium incorporation at the C6 position suggests that C À Hinsertion of the Ir catalyst is,in this case,s elective for the more sterically accessible ortho C À Hbond. Indeed, exposure of aniline 5fto the Ir system in the absence of the alkene,but in the presence of D 2 O, resulted in 92 %d euterium incorporation at the C6 position and in < 5% at the C2 position;f urther exchange experiments are outlined in the Supporting Information. TheX-ray structures of 6h and iso-6h [20] show that the secondary alkyl substituent of the products causes the acetamide moiety to twist from the plane of the arene,such that directed insertion of Ir I into the remaining ortho CÀHbond is challenging;consequently,bisortho-alkylation is not observed. This effect must be finely balanced given that ortho-substituted acetanilides 5b-5e participate smoothly in the hydroarylation reaction.
Akey feature of the processes described here is the use of the wide-bite-angle and electron-deficient bisphosphine ligand d F ppb.T he branched/linear selectivity for 5a to 6a/ iso-6a has been evaluated as af unction of ligand bite angle (Scheme 3). [22] Ap rogression from low linear to complete branch selectivity is observed as the ligand is varied from d F ppm to d F ppb.A lthough as trong bite-angle effect is evident, as ignificant electronic influence is also operative. Non-fluorinated ligands,namely dppm, dppe,dppp,and dppb, show the same bite-angle trend, but provide lower branch selectivities.O ne explanation is that secondary alkyl ligands are better able to stabilize amore electron-deficient Ir center, and so the equilibrium branched/linear ratio of the alkyl-Ir III intermediates (see 3b vs. 3a)i ncreases when fluorinated ligands are used. [23,24] Another option is that electrondeficient ligands a) shorten the iridium-alkyl bond by enhancing s-donation, and b) shorten the iridium-phosphine bonds by increasing p-backbonding. [25] This results in ac ontraction of the coordination sphere to provide am ore congested environment, such that steric destabilization of the branched alkyl-Ir III intermediate is amplified further, and its propensity for reductive elimination increases.

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Communications approach, the N-acetyl group is incorporated into the heteroaromatic target. Other transformations required conversion into aniline 12. [28] This intermediate underwent condensation with ethyl acetoacetate,a nd subsequent Pdcatalyzed oxidative cyclization delivered indole 13 in 52 % yield (over 2steps). [29] Classical methods towards heteroaromatic compounds are also effective.F or example,the Cohn variant of the Skraup quinoline synthesis delivered 14 in 68 % yield. [30] Thep rocesses in Scheme 4v alidate concise and diversifiable entries to heteroaromatic targets that might be difficult to prepare by other means.
To conclude,weoutline adirect and controlled approach to ortho-branched aniline derivatives,w hich addresses longstanding issues associated with related Friedel-Crafts alkylations.M ore fundamentally,t his work extends our "cooperative destabilization" strategy [12] to include processes that involve electron-rich arenes and proceed via six-ring metallacycles.Both aspects represent asignificant expansion to the emerging area of branch-selective Murai-type hydroarylations. [12,15] Thec atalyst design features used here will guide efforts in our laboratory aimed at developing ag eneral and enantioselective alkene hydroarylation method.