It has been two decades since the group of Murai, Kakiuchi, and Chatani reported their groundbreaking work on ruthenium-catalyzed ortho-alkylation of aromatic ketones with olefins . This olefin hydroarylation reaction features ketone-directed oxidative addition of the ortho C–H bond to ruthenium as one of key elementary steps, and has opened a new opportunity for regioselective aromatic alkylation that goes beyond the conventional Friedel–Crafts chemistry. The scope of the directing group-assisted olefin hydroarylation has been significantly expanded by further development of not only ruthenium catalysts but also rhodium and other transition-metal catalysts . Over the past several years, our group has demonstrated competence of cobalt catalysts for such transformations through the development of a series of pyridine- or imine-directed olefin hydroarylation reactions [3, 4], which often feature mild reaction conditions and/or unique regioselectivity. However, regardless of the two decades of development, there exists a common limitation in this type of aromatic alkylation. Except for some limited cases [5, 6], secondary alkylation is not feasible for several reasons, such as anti-Markovnikov selectivity for terminal olefins, rapid isomerization of olefins containing allylic hydrogens, and intrinsically low reactivity of multisubstituted olefins. In addition, some olefins such as cyclobutene are not readily available from commercial sources.
In the past several years, an alternative ortho-alkylation strategy using alkyl halides as alkylating agents has emerged . However, even with this strategy, secondary alkylation has not been trivial, presumably because of poor reactivity of secondary alkyl halides toward oxidative addition. Indeed, only limited examples of secondary alkylation have been reported for representative catalytic systems, including ruthenium catalysis of 2-arylpyridines and aryl imines, cobalt catalysis of benzamides, and palladium catalysis of arenes bearing a bidentate nitrogen-directing group . Herein, we report on a significant expansion of the scope of this alkylation strategy achieved with a cobalt–N-heterocyclic carbene (NHC) catalytic system, which allows ortho-alkylation of aromatic imines using a variety of unactivated primary and secondary alkyl chlorides and bromides under mild conditions (Scheme 1) .
Optimization of cobalt–NHC catalyst
With the above background and our previous studies on cobalt–NHC-catalyzed ortho C–H functionalization using electrophiles such as aryl aldimines and aryl chlorides [10–12], we initiated the present study with optimization of the alkylation reaction using acetophenone imine 1a and n-octyl chloride 2a under a catalytic system consisting of CoBr2 (10 mol%), NHC preligand (10 mol%), and neopentylmagnesium bromide (2 equiv) (Table 1). While popular NHC derivatives such as IMes•HCl (1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride) and IPr•HCl (1,3-bis(2,6-diisopropylphenyl)imidazolium chloride) performed only modestly (entries 1–3), simple diisopropylimidazolinium salt L1 and its benzo-fused analogue L4 significantly improved the yield of the alkylation product 3aa (entries 4 and 7). Diisopropylimidazolium salt L2 and di(tert-butyl)imidazolinium salt L3 gave rise to much reduced catalytic activities (entries 5 and 6). The catalytic systems with L1 and L4 also efficiently promoted the reaction using n-octyl bromide instead of n-octyl chloride (entries 8 and 9). In contrast, the yield became significantly lower with n-octyl iodide because it largely decomposed through dehydrohalogenation (entries 10 and 11).
Primary and secondary alkylations
With the optimized catalytic systems in hand, we first explored alkylation of acetophenone imine 1a using primary alkyl chlorides and bromides (Scheme 2). The reaction using n-hexyl bromide 2b proceeded efficiently on a 10 mmol scale, affording the corresponding alkylation product in 77 % yield. Alkyl halides with steric hindrance around the β-position (2d and 2e) or functional groups such as olefin (2f), acetal (2g), and secondary amide (2h) could be tolerated, while the reaction becomes sluggish in the presence of a coordinating pyridyl moiety in the alkyl chloride (2i). Reactions using dihalogenated reactants showed notable chemoselectivities. Thus, 1-bromo-4-chlorobutane 2j reacted exclusively at the C–Br bond in good yield, the C–Cl bond being entirely intact. Exclusive cleavage of an alkyl chloride moiety was also achieved in the presence of an aryl chloride moiety (2k). In addition, 6-bromohexene 2l, a potential source of 5-hexenyl radical, afforded a simple alkylation product and its internal olefin isomer as the major and minor products, respectively, but did not produce any products arising from 5-exo cyclization.
The present catalytic systems also allowed ortho-alkylation with a variety of secondary alkyl chlorides and bromides (Scheme 3). Cycloalkyl halides of various ring sizes (2m–2q) participated in the reaction to afford the corresponding alkylation products in moderate to good yields. The reaction tolerated 4-bromo-N-Boc-piperidine 2r albeit in a modest yield. The reaction of acyclic alkyl halides 2s–2u also produced the desired secondary alkylation products in moderate yields along with minor amount of primary isomers. Exo-chloronorbornane 2v afforded the exo-arylation product as the major product with the exo/endo ratio of 9:1. Trans- and cis-isomers of 1-chloro-4-tert-butylcyclohexane (2w and 2x) both afforded a mixture of trans- and cis-arylation products with the same trans/cis ratio of 7:3. Thus, these stereochemical probes demonstrate that the reaction is not stereospecific and suggest involvement of a radical intermediate (vide infra).
Next, the scope of aryl imines was explored using cycloalkyl halides as the reaction partners (Scheme 4). The reaction of imine derived from 4-methoxyacetophenone with cycloheptyl chloride was achieved on a 10 mmol scale to afford the product 3bp in 81 % yield. The regioselectivity of C–H functionalization of unsymmetrically substituted imines appears to be governed by a steric factor for the case of imine derived from 3-acetylfluorene (see 3dm) and by secondary coordination of the oxygen atom for the case of imine bearing a methylenedioxy group at the 3,4-position (see 3en). Heteroaromatic C–H bonds of thiophene and indole could also be alkylated albeit in modest yields (see 3hm and 3io).
Derivatization of alkylation product
The product of the cycloalkylation reaction, 3bp, could be transformed into unique spirocycles by making use of both the acetyl and the cycloalkyl groups (Scheme 5). Conversion of the acetyl group into an ethynyl group via an enol phosphate was followed by platinum-catalyzed carbocyclization, affording a spirocyclic indene 5 in a moderate overall yield of 43 % . A sequence of diazo transfer to the acetyl group and rhodium-catalyzed intramolecular C–H insertion allowed preparation of a spirocyclic indanone 7 albeit in a low overall yield.
On the basis of our experimental observations as well as previous studies of Yorimitsu and Oshima on cobalt-catalyzed C–C bond formation involving alkyl halides and Grignard reagents , we propose a mechanistic framework involving radical processes (Scheme 6). The reaction of the cobalt precatalyst and the Grignard reagent initially generates a low-valent organocobalt species, which undergoes cyclometalation of the aryl imine to afford a cobaltacycle species while liberating an alkane (R–H) . The cobaltacycle species then undergoes single-electron transfer to the alkyl halide, which results in one-electron oxidation of the cobalt center and generation of an alkyl radical. Recombination of this radical pair is followed by reductive elimination and transmetalation with the Grignard reagent, affording the ortho-alkylation product and regenerating the initial cobalt species. The radical-based mechanism is consistent with the reaction outcomes of the stereochemical probes (Scheme 3) . For the reaction of 6-bromohexene that afforded the simple alkylation product (Scheme 2), we speculate that the radical recombination took place at a faster rate than the 5-exo cyclization .
In summary, we have developed cobalt–NHC catalytic systems for ortho-alkylation of aromatic imines with alkyl halides. The reaction is applicable to a variety of primary and secondary alkyl chlorides and bromides, and features notable chemoselectivity, mild room-temperature conditions, and reasonable scalability for laboratory-scale synthesis . The proposed mechanism features the combination of cyclometalation and electron-transfer processes, which may hold promise for further development of stereoselective alkylation reactions with racemic alkyl halides.
This work was supported by Singapore National Research Foundation (NRF-RF2009-05), Nanyang Technological University, and JST, CREST.
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A collection of invited papers based on presentations at the 17th International IUPAC Conference on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS-17), Fort Collins, Colorado, USA, 28 July–1 August 2013.