Electro‐Oxidative Selective Esterification of Methylarenes and Benzaldehydes

Abstract A mild and green electro‐oxidative protocol to construct aromatic esters from methylarenes and alcohols is herein reported. Importantly, the reaction is free of metals, chemical oxidants, bases, acids, and operates at room temperature. Moreover, the design of the electrolyte was found critical for the oxidation state and structure of the coupling products, a rarely documented effect. This electro‐oxidative coupling process also displays exceptional tolerance of many fragile easily oxidized functional groups such as hydroxy, aldehyde, olefin, alkyne, as well as neighboring benzylic positions. The enantiomeric enrichment of some chiral alcohols is moreover preserved during this electro‐oxidative coupling reaction, making it overall a promising synthetic tool.

Electro-oxidative strategies occupy an increasingly important place in the synthetic method toolbox. Indeed, the vast majority of organic building blocks possess numerous CÀHb onds, making electro-oxidation ap rivilegeda nd arguably still underappreciated tool for the design of step and atom economic coupling reactions. In this context, carboxyl esters are among the mostp revalent functional groups encountered in very diverse areas of organic chemistry,f rom liquid crystal polymers, to cosmetics, pharmaceuticals, artificial fragrances, agrochemicals and food additives. [1] Moreover, they constitute ar elatively straight-forward retrosynthetic disconnection. Indeed,t raditional methods of esterification are typically accomplished by reactingc arboxylic acids or their activated derivatives (e.g. acyl chlorides, anhydrides and activated esters) with alcohols and related substrates. [2] In those cases, pre-oxidationa nd pre-activation are thus necessary,usuallya ssociated with strongc hemical oxidants and their typically poor functional group toler-ance.M oreover,t he strong acids or bases typically employed in those methods further limit the associated substrate scopes. Alternative routes through the oxidative esterificationo fa ldehydes [3] and benzyl alcohols [4] have also been developed. However,s uch methodologies generally still require stoichiometric amountso fs tronga nd toxic oxidants, high temperature and/ or transition-metal catalysts (Scheme 1a). Thus, in this context, the concept of directo xidative esterificationo fm ethylarenes with ubiquitousa lcohols still constitutes ap riority objective. Such as trategyc an be implementedb yu sing harsh reaction conditions with metal catalysts, strong chemical oxidants, and high reaction temperatures (Scheme 1b). [5] Inspiring flow chemistry techniquesw ere moreover applied, such as the electrochemical oxidative esterification of 4-methoxytoluenei naflow reactor. [6] Alternatively,p hotocatalytic methodsh ave also been developed, howevero ften relying on onerous photocatalysts, stoichiometric amounts of CBr 4 or strong acids. Moreover, in those cases, strong chemical oxidants remaini ndispensable. Thus, the corresponding substrates scopes tend to be limited, in particular towardf ragile easily oxidized functional groupss uch as hydroxy,e ther,a ldehyde as well as other benzylic positions (Scheme 1c). [7] Herein, we report am ilda nd green protocol to construct esters from methylarenes and alcohols with electricity [8] as the only "oxidant." This electro-oxidativem ethod is associatedw ith ab road fragile functionalg roup tolerance (Scheme 1d).
We started our investigations from 4-methylanisole 1a as the model substrate reactingw ith methanol 1b in an undivided cell (pictures shown in Figure 1). Carbon was used as the anode,w hile nickel was found to be the best cathode. [9] Three products can be formed in this reaction: the target oxidative coupling product ester 1c,t he aldehyde 1d and the acetal 1e. Diverse electrolytes were tested under several currents showing as ignificant impact on thet ransformation's selectivity with respectt ot hese three products.A se xpected, lower currents were found to favor acetalization.I nc ontrast,h igherc urrents favor the esterification product, suggesting the intermediacy of 1e and/or 1d in the formation of ester coupling product 1c.
In all cases, the optimal reactiont ime wasf ound to be 18 hf or reachingf ull conversion.
Importantly,t he electrolyte seems to have an influenceo n the electro-oxidative coupling reaction's outcome. The common ammonium electrolytes favor the formationo facetals ( Figure 1a,b). The best conditions for acetalization were obtained with tetrabutylammonium p-toluenesulfonate N2 under a5mA current, giving a6 6% NMR yield of acetal 1e.I nc ontrast, the phosphonium salts, which are rarely used as electrolytes, favor the esterification process (Figure 1c,d). The best conditions for esterification were obtained with tributyl(tetradecyl)phosphonium methanesulfonate P2 as the electrolyte under ac urrent of 15 mA, providing a6 3% NMR yield of ester 1c.T hus, the electro-oxidativec oupling reaction's outcome seems to depend on the electrolyte's structure, phosphonium salts leading to higher oxidation than ammonium salts (P2 > P1 > N2 > N1), and sulfonate anionl eadingt oh igher oxidation than tetrafluoroborate.
To investigate the electrolyte's influence, as eries of initial mechanistic experiments werec onducted. Firstly,i nsitu NMR of the crude reaction mixture showedt hat neither representative electrolytes N1 nor P2 were chemically alteredd uring the Figure 1. Electro-oxidativeproductr atios, depending on electrolytes and currents. Yields determined by 1 HNMR analysiso fthe crude reaction mixture with 1,3,5-trimethoxybenzene as an internalstandard. Chem.E ur.J.2021, 27,3682 -3687 www.chemeurj.org 2020 The Authors. Published by Wiley-VCH GmbH reaction. Thus, ac hemical involvement of the electrolyte can be reasonably excluded. The cyclic voltammetry (CV) profiles of N1 and P2 were then measured with Ferrocenea sa ni nternal standard (Figure 2a-d). Interestingly,t he phosphonium electrolyte P2 showed ac lear oxidation potential above + 2V , while the ammonium electrolyte N1 did not. Next, the cyclic voltammograms of methylarene substrate 1a and the two subsequent reactioni ntermediates acetal 1e and aldehyde 1d were measured in combination with both reference electrolytes N1,and thereafter P2.Thoseseem to follow the oxidation potentialt rend: 1a< 1e< 1d.M oreover, interestingly,e lectrolyte P2 seems to maket he oxidation potentials of these compoundsg lobally higher than electrolyte N1.T his may explain why ammonium electrolytes tend to favor acetal product 1e, while phosphonium electrolyte P2 may be more suitable for furthero xidative esterification towardp roduct 1c.T he precise mechanistic principles responsible for the latter electrolyte effects remainu nclear however,a nd are being further studied in our laboratory.D iverse alternative electrolytes, electrodes as well as diverse reaction conditions have also been investigated, none of which provided superior results,w hether toward acetalization or esterification (see SI).
The electro-oxidative esterification substrate scope was thereafter investigated. The para position with respect to the methylarene reaction site provedt ob ei mportant,w ith paramethoxy-and para-bromo-providing superior results. This par-ticularity allows for remarkableb enzylic group tolerance on the other (non-reactive) positions of the arene substrate (Table 1, 3c, 5c, 7c, 9c, 10 c). This reaction is also remarkably tolerant to an umber of other oxidations ensitive functional groups such as aldehyde(  (Table 1, 20 c)a re also tolerated in this reaction. Many alcohols have also been found to be effective coupling partnersf or the reaction (Table 1, 21 c-32 c). For instance, (R)-(À)-1-Methoxy-2-propanol (31 b)a nd (R)-(+ +)-1-Phenylethanol (32 b)w ere successfully used in the reaction, while maintaining their enantiomeric enrichment (31 c was obtained with 96 % ee and 32 c with 98 % ee).
The electro-oxidative acetalization reaction was thereafter investigated. Acetalization is au seful synthetic technique to protect aldehydes of variousm ultifunctional organic molecules. [10] Besides, acetals are also important organic synthons and intermediates as well as common functional group in naturalp roducts. [11] In the fine chemical industries, acetals are also widely used. [12] Traditional routes to acetalization usually start from aldehydes, [10,13] alcohols [14] or olefins. [15] Startingf rom methylarenes has been less reported. [16] Therefore, we investigated the scope of the herein described electro-oxidative acetalization of  (Table 2), with suitable electrolytes. For electronrich arenes such as 1a,t he acetalization was achieved under a low 5mAc urrent. In other cases, ah igherc urrent was needed. In general, the ammonium electrolyte N2 was found to be optimal for electro-oxidativea cetalization. However,s ome exceptions were noted, such as substrate 2e which requires phosphonium electrolyte P2.
Next, we established that acetals and aldehydes are also competent substrates in this electro-oxidative esterification re-action ( Figure 3). The dehydrogenative esterification of benzaldehydes with alcohols was therefore investigated, as it represents am eaningfuls ynthetic method. Indeed, in traditional methods, [3] transition metals or/ands trong chemical oxidants are usually required and the functional group tolerance typically limited. Remarkably,NHC catalysis has also been used for oxidativee sterifications of aldehydes,h owever with an organic terminalo xidant. [17] Under al ow 5mAc urrent in combination with electrolyte P2,avariety of aldehydesc ould be dehydro- [a] Isolated yields. [b] Electrolyte N1 was used instead of P2.
Some further selected mechanistic experiments were then performed. Firstly,w hen electricity was replaced by chemical oxidants such as tert-butyl peroxide, sodium metaperiodate or potassium permanganate, under otherwisei denticalr eaction conditions, none of the three expected oxidationp roducts (1c-e)c ould be observed. However, when CAN (ceric ammonium nitrate), or DDQ were used instead of electricity,s ome oxidation occurredf orming the corresponding aldehyde 1d in 23 %a nd 8% NMR yield, respectively (Scheme 2a). This indicates that an aryl radical cation is most likely formed as af irst reactioni ntermediate, in line with Yoshida's "radical-cation pool" concept. [18] This also explains the selective reaction at the para positiont ot he electron-donating groups as well as the tolerance of some"fragile functional groups" located at different positions.M oreover,c ontrol aldehyde 1d'-without an electron donating para-methoxy functional group-could not be converted, thush ighlighting the importance of the electron donating group (Scheme 2b). Based on these elements, a mechanistic scenarioisp roposed in Scheme3.
The aryl radicalc ation a' can be formed initially at the anode,f ollowed by deprotonation and oxidationt of ormq uinone methide derivative a''.T he latter would then be trapped Figure 3. Esterification yields, depending on starting materials and currents. Yields determined by 1 HNMR analysiso ft he crude reaction mixture with 1,3,5-trimethoxybenzene as an internalstandard. Table 3. Substrate scope for the electro-oxidative esterification of benzaldehydes. [a] [a] Isolated yields. [b] 1.0 equivalent electrolyte was applied.
[c] Electrolyte P2 was used instead of N2.
by the alkoxide formed at the cathode, or simply by the high concentration excess alcohol. Further anodic oxidation events would delivera cetal intermediate e,f ollowed by the oxidative formationo ft he corresponding orthoester,w hich in turn would hydrolyze either in situ or duringw ork-up to ester product c.T he factt hat the orthoester was typically not found may suggest the former scenario to be correct.A lternatively,t he direct oxidationo fa cetal e at the anode towarde ster product c (withoutt he intermediacy of an orthoester) might also occur.
In summary,w eh ave developed am ild andg reen electrooxidative methodt oc onstructe sters and acetals from methylarenes and benzaldehydes. This electro-oxidativem ethod shows special tolerance to many easily oxidized structures such as hydroxys, aldehydes, olefins, alkynes, as well as other benzylic positions making it valuable in synthetic chemistry.