Redox‐Neutral Dual Functionalization of Electron‐Deficient Alkenes

Abstract Visible‐light photoredox catalysis has been utilized in a new multicomponent reaction forming β‐functionalized δ‐diketones under mild conditions in an operationally convenient manner. Single‐electron reduction of in situ generated carboxylic acid derivatives forms acyl radicals that react further via 1,2‐acylalkylation of olefins in an intermolecular, three‐components cascade reaction, giving valuable synthetic entities from readily available starting materials. A diverse set of substrates has been used, demonstrating robust methodology with broad substrate scope.

Abstract: Visible-light photoredoxc atalysis has been utilized in an ew multicomponent reactionf orming b-functionalized d-diketones under mild conditions in an operationallyc onvenient manner.S ingle-electron reductiono f in situ generated carboxylic acid derivativesf orms acyl radicalst hat react furtherv ia 1,2-acylalkylationo fo lefins in an intermolecular,t hree-components cascade reaction, giving valuable synthetic entitiesf rom readily available startingm aterials. Ad iverse set of substrates has been used, demonstrating robustm ethodology with broad substrate scope.
Inr ecent years, synthetic chemistry hase volveda ts uch ap ace that molecular complexity can be rapidly achievedw ith high selectivity.O ne of the moste fficient methods to construct molecular complexity is by utilizing multicomponent reactions (MCRs) and cascade-typet ransformations. [1] MCRs are convergent reactions, in which three or more starting materials are reactedt ogether to form as ingle product with high atom efficiency. [1a] Opposed to the classical sequential synthetic approach to construct complex molecules, MCRs enablet he assembly of complex molecules in as ingle operation. The product is formed via ac ascade of elementaryc hemical reactions through as eries of reactionequilibrium, ideally ending in an irreversible step to give the desired product. MCRsh ave become av ery popular tool in many areaso fa pplied chemistry due to its labor efficient way to access av ast array of structural space. [1e,f] Recently,v isible-light-mediated photoredox catalysis has emerged as ac ompetitive method forf unctional-group interconversionsg enerating reactive radicali ntermediates under mild and environmentally benign conditions. [2] Contributions to this field from our group include the formation of acyl radicals via single-electron reduction of aromatic carboxylic acid derivatives ( Figure 1b). [3] This approach combines the benefits of using readily available andi nexpensive starting materials with as ynthetic method that extends beyond the existing routest oa ccess acyl radicals. [4] Mixeda nhydride intermediates, formedi ns itu from simple carboxylic acids by reaction with dimethyl dicarbonate (DMDC) have provent ob ee fficient oxidative quenchers of the exciteds tate of the photocatalyst fac-Ir(ppy) 3 (tris[2-phenylpyridinato-C 2 ,N]iridium(III)) to generate the desired acyl radicals pecies, along with CO 2 and methanolate as the only byproducts. [3b] Capitalizing on this mild way to accessa cyl radicali ntermediates, we envisioned that MCRs could be engagedi naradical contextu nder redox-neutral conditions.
Electron-richa cyl radicals have ap ronounced reactivity preferencet owards electron-deficient alkenes, ap roperty that can   This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. be exploited in am ulticomponent settingb ya chieving selectivity towards electron-poor coupling partners in the presence of electron-rich olefins. Strategically,s uch ac ombination of coupling partners would provide access to the synthetically challenging 1,2-dicarbofunctionalization of alkenes ( Figure 1c).
The majorityo fp ublished photoredox-mediated MCRs rely on radicalp olar crossover transformations, in which free radical-based bond formations are combined with nucleophilic trapping of an intermediate carbocation, typicallyb yasolvent or co-solvent. [5] Photoredox-mediated MCRs, in which two or more CÀC bonds are formed in ap ure radicalf ashion, remainr elatively unexplored. [6] Moreover,M CRs based on classical free-radical chemistry are typically characterized by the need of externalo xidants, UV irradiation, high CO pressure, high temperature or tin-, borane, or leadbased reagents, as well as stannylated and silylated phosphanes as precursors. [7] Herein,w er eport the first redox-neutral approach for the mild visible-light-mediated multicomponent 1,2-acylalkylation of alkenes giving convenient access to b-functionalized d-diketones ( Figure 1c).
Preliminary studies of the three-component reaction were investigated by using benzoic acid 1a,m ethyl acrylate 2a,a nd tert-butyldimethyl((1-phenylvinyl)oxy)silane 3a as the acyl radical precursor,e lectron-deficient and electron-rich couplingp artners, respectively. In addition to the specified substrates, fac-Ir(ppy) 3 , DMDC, and 2,6-lutidine were added to the protocol, and the reactionw as conducted under visible-light irradiation( Ta ble S1, the Supporting Information). The choice of the photocatalyst was based on previous studies, which demonstrated that fac-Ir(ppy) 3 is capable of reducing mixed anhydride I to the corresponding acyl radicals pecies III as depicted in Figure 2. [3b] To our delight, initial experiments validated our approach and provided the corresponding product 4a in am odest yield (Table S1, the Supporting Information). Subsequento ptimizations revealed that employing 3 as the limiting reagent in combinationw ith ac atalyst loading of 2-5 mol %p rovided robusta nd optimal conditions for the transformation.
Control experiments performed in the absence of the photocatalyst, DMDC, or light irradiationd id not result in the formation of the desired product (entries 14-16 in Table S1, the Supporting Information), observations that validated our mechanistic rational. With optimized reaction conditions in hand, the scope of the reaction in terms of structural diversity of all components was examined. As shown in Ta ble 1, the reactionp roceeded in modest to excellent yields (4an,T able 1) for aw ide range of mono-or disubstituted benzoica cids (1a-l,T able S2, the SupportingI nformation), as well as for heteroaromatic substrates, such as 5-methylthiophene-2-carboxylic acid and 2-furoic acid (1m-n,T ableS2, the Supporting Information). In gen- [a] Reaction was performed by using 2-5 mol %o ffac-Ir(ppy) 3 ,2,6-lutidine (0.5 equiv), DMDC (3 equiv), 1 (2 equiv), 2a (2 equiv)a nd 3 (1 equiv) on a0 .2 mmol scale (detailed description is given in the Supporting Information). Isolated yields. eral, unfunctionalized and electron-richc arboxylic acids provided higher yields compared to their electron-deficientc ounterparts (e.g., 4a and c). However,t he inclusion of strongly electron-withdrawing groups,s uch as trifluoromethyl or nitro moieties, at the para-position of the carboxylic acid gave very low yields ( 10 %). For these substrates, the background reaction (i.e.,t he conversion of the acid into the corresponding unreactive methyle sters) was evidently faster than the redox chemistry (Table S2 and NMR spectra in the Supporting Information). [8] Notably,c arboxylic acids bearing free hydroxy or amino groups (1e and l,T able S2, the Supporting Information) smoothly furnished the corresponding carbonate and carbamate derivatives withouta ffecting the yields in ad eleterious way (4e and l, Ta ble 1).
The scope of the reaction was further explored with regards to the olefin substrates 2 and 3 (Table 1a nd 2). p-Anisic acid (1c)a nd methyl acrylate (2a)t ogether with various electronrich olefins( 3c-f,T able S3,t he Supporting Information) gave the desired products in generally good yields (4o-t,T able 1). The reactiona ppears to tolerate both mono-and disubstituted aryls, as well as heteroaromatic derivates of the silylenolether 3,a lthough possible limitations include strongly electron-deficient aryl groups (trifluromethyl (4ad), Table S3, the Supporting Information) or non-aromatic silylenolethers (tert-butyl (4ae), Table S3, the Supporting Information). In as imilar manner, different electron-poor olefinsw ith an umber of electron-withdrawing groups (2b-h,T able S4 in the Supporting Information)w ere evaluateda sc oupling partners together with benzoica cid (1a)o rp-anisic acid (1c)a nd silylenolethers 3a or 3b.Common acrylic derivatives were compatible with the optimized conditions providing the corresponding products in fair yields (4u-aa,T able 2). Ta ken together,t he protocol gives an ew entry to 1,2-acylalkylated alkenes in the form of b-functionalized d-diketones.T he protocol demonstrates ar elatively broad scope with respect to the different substrates, with yields ranging from 58 to 99 %f or each individual CÀCb ondforming reaction.
Scheme1.Examples of accessible transformations of 1,5-diones: a) Mojr et al. [10] b) Foster et al. [11] c) Wang et al. [12] d) Padmavathi et al. [13] Transformations of 4c into cyclized compounds 5a and b following published literature procedures. [9] Chem.E ur. J.2017, 23,7444 -7447 www.chemeurj.org In conclusion, an ew photoredox-catalyzed multicomponent reactionf or the formation of variously b-functionalized d-diketones under mild visible-light conditions was presented. The use of simple carboxylic acids as acyl radical precursors promoted by visible light allowed the development of this intermolecular cascade reaction, which combines three compounds in ar adical process. The overall reaction proceeds in ar edox neutralf ashion avoiding the need for stoichiometrica mounts of external electron donors or oxidants. Furthermore, the possibility of accessing al arge variety of structures by the straightforwardd erivatization of compound 4c showcases the synthetic utility of the presentedm ethod. Exploration of the reactivity of acyl radicals under photoredox catalyzed conditions and exploitation of this chemistry in unprecedented multicomponent reactionsa re currently under investigation in our laboratory.