α‐Arylation of Carbonyl Compounds through Oxidative C−C Bond Activation

Abstract A synthetically useful approach for the direct α‐arylation of carbonyl compounds through a novel oxidative C−C bond activation is reported. This mechanistically unusual process relies on a 1,2‐aryl shift and results in all‐carbon quaternary centers. The transformation displays broad functional‐group tolerance and can in principle also be applied as an asymmetric variant.

The appendage of an aryl substituent to the a-position of ac arbonyl moiety remains at ransformation of central importance in synthetic organic chemistry.T he advent of powerful metal-catalysed coupling processes has paved the way for the introduction of catalytic (involving mainly organometallic complexes of Pd and Cu) coupling reactions that join aryl halides (or equivalents) to carbonyl-derived enolates. [1,2] Prior to and following these advances,u seful transition-metal-free a-arylation processes have been developed that involve stoichiometric reactions of enolate anions (or equivalents) with electrophilic aromatic derivatives of Bi V , [3] Pb IV , [4] I(III), [5] S(IV), [6] or benzyne. [7] Stepwise methods via initial formation of N-alkoxyenamines [8] or enolonium equivalents followed by nucleophilic attack have also been used for the a-arylation of ketones. [9b,d] We have established ar esearch program exploiting the electrophilic activation of amides by drawing on pioneering work from the groups of Ghosez, [10] and more recently Charette, [11] Movassaghi,[12] Huang, and others. [13] Ac urrent focus of interest resides in the implications of an umpolung strategy that exploits pyridine N-oxide-mediated formation of enolonium equivalents [9,14] under mild conditions,t hereby enabling aseries of novel transformations for the a-functionalization of amides. [15] During these studies,a nu nexpected result caught our attention (Scheme 1b). Substrate A,w hich bears ap henyl group in the b-position of the amide,generated trace amounts of an unexpected product (C). Our mechanistic interpretation of this result suggested that fragmentation of the enolonium B was triggered by nucleophilic attack of the neighboring arene to generate phenonium intermediate D. [16] Ring opening by weakly nucleophilic triflate accounts for formation of the unexpected product C.
Aiming to capitalize on this serendipitous observation in amore general context, we hypothesized that ametal-free aarylation that proceeds through skeletal reorganization could be developed (Scheme 1c). Our mechanistic postulate involved the conversion of ag eneric a-disubstituted ketone nucleophile (1)t oa ne nolonium (F). [9a-c] We then hoped to funnel this intermediate selectively to the phenonium intermediate G,ring opening of which would effectively constitute an ovel approach to the a-arylation of carbonyl compounds and formation of aq uaternary center.H erein we report the development of this approach into af ormal metal-free aarylation through oxidative CÀCb ond activation. Anumber of potential pitfalls are readily apparent in this ambitious proposal. Most notably,1 )intermediate F has areadily available elimination pathway accessible to generate ap articularly stable b-aryl-a,b-unsaturated carbonyl compound (3)and 2) even if it survives elimination, intermediate F can suffer direct attack by any nucleophile in solution to form (in this case) undesired a-functionalized umpolung products 2. [9a] Bearing these possible problems in mind, we began our investigations on the proposed oxidative C À Cbond activation reaction with ketoester 1a,acompound that exists to as ignificant extent in the favorable enol form. Aiming to develop an operationally simple method, we explored the use of commercially available ethyl 2-benzylacetoacetate 1a and different oxidants to mediate the proposed process (see the Supporting Information for ad etailed optimization). After considerable experimentation, we found that iodosobenzene (1.2 equiv) and MsOH (2.4 equiv) enable the reorganization of 1a to a-arylation product 4a through oxidative CÀCbond activation in an excellent 81 %yield (Scheme 2).
With optimized conditions in hand, we then turned our attention to the scope of this transformation (Scheme 2). First, we evaluated ar ange of 2-benzyl-substituted 1,3dicarbonyl compounds under our conditions,i ncluding ketoester 4a,k etoamide 4b,d iketone 4j,o rk etonitrile 4h. Ther eactions proceeded smoothly,a ffording the desired products in good chemical yield. Furthermore,t his transformation exhibited good tolerance to diverse aromatic substitution (4i-4n). Finally,w et urned our attention to nucleophiles other than methanesulfonate (MsO À ). Gratifyingly,w hen Pyridine·9 HF was used instead of MsOH, the bfluoride product 4o was obtained in moderate yield.
After these promising investigations on oxidative C À C bond activation of active methylene compounds,w et urned our attention to simple ketones.O ur investigations showed that ketone-derived silyl enol ethers featuring an arene residue in the allylic position are also amenable to this transformation, resulting in a-arylated products (Scheme 3). As shown, electron-donating groups such as 3,4-di-OMe are well tolerated in the migrating arene (6d). Their electronpoor counterparts (e.g., p-CF 3 in 6m) [16b] afforded lower yields,likely as aconsequence of diminished migratory ability. Interestingly,t his approach can be employed to convert b,bdiphenyl-substituted ketones into product 6n in very good yield and as as ingle diastereoisomer.
In ap reliminary effort to identify asymmetric variants of this oxidative C À Cbond formation, chiral hypervalent iodane 7 [17] was prepared and examined in the reaction of silyl enol ether 5a (Scheme 4). Promisingly,t he reaction proceeded in good yield and an enantioselectivity value of 70 % ee was obtained after only 5m inutes at À78 8 8C. Ther esulting aarylated ketones lend themselves to further functionalization.
In conclusion, am etal-free,stereoselective a-arylation of carbonyl compounds through oxidative CÀCbond activation was developed. Theability to use simple and easily available reagents under mild condition is ad istinctive feature of this process,which effectively cleaves and reorganize C À Cbonds in simple carbonyl-containing feedstocks.