N‐Heterocyclic Carbene Acyl Anion Organocatalysis by Ball‐Milling

Abstract The ability to conduct N‐heterocyclic carbene‐catalysed acyl anion chemistry under ball‐milling conditions is reported for the first time. This process has been exemplified through applications to intermolecular‐benzoin, intramolecular‐benzoin, intermolecular‐Stetter and intramolecular‐Stetter reactions including asymmetric examples and demonstrates that this mode of mechanistically complex organocatalytic reaction can operate under solvent‐minimised conditions.

The ability to conduct N-heterocyclicc arbene-catalysed acyl anion chemistry under ball-milling conditions is reported for the first time. This process has been exemplified throughapplications to intermolecular-benzoin, intramolecular-benzoin, intermolecular-Stetter andi ntramolecular-Stetter reactions including asymmetric examples and demonstrates that this mode of mechanistically complex organocatalytic reactionc an operate under solvent-minimised conditions. Mechanochemistry is characterised by the input of mechanical energy into chemical bonds to initiater eactivity of those bonds. [1] Chemical reactions brought about by ball-milling constitute an area of mechanochemistry.T hat ar eactiont akes place under ball-milling conditions does, however, not necessarily meant hat the process is mechanicallyd riven.I ndeed, ballmilling reactions also typically feature solvent-free or solventminimised, high-concentrationa nd occasionally high-instantaneous/bulk-temperature conditions. Many of these factors are inextricably linked and may never be fully delineated.Nonetheless, the fields of mechanochemistrya nd ball-milling, in combination with reactive extrusion,a re capable of delivering a more sustainable approacht osome aspects of chemical synthesis andc hemical manufacturing. [2] Given the complex interrelated nature of parameters, one approachtog ain ab etter insight into theset echniques is through attrition, that is, gaining many experimental data points and building ap ictureo fu nderstanding as aw hole. In recent years the community in this area has been building towards this vision. [3] In several instances there have emerged trends and conceptual frameworks, and in others there is simply at ranslation to as olvent-minimised process. However,p erhaps the most exciting aspect of this approachi st he increased opportunity for serendipitous discoveries by exploring this unchartered chemical reactor en-vironment. [4] As part of this process the field has recently been movingt owards assessing the possibility of running complex catalytic reactions and enantioselective processes under milling conditions. [5] The area of organocatalysis is one such area where the proposed reaction pathways requires everald iscrete steps and enantioselectivity rests on the organisation of complex transition states. Of the many areas of organocatalysis (some of which are shown in Figure 1A), only secondary amines ystems have been well studied under millingc onditions, with pioneering contributionsf rom Bolm and co-workers. [6] It has been established that severalr eaction manifolds accessible by secondary amine organocatalysis in solutionc an also operate under milling conditions. [7] Given the wealth of transformations and activation modes we were intrigued by the prospecto fc onductingn ucleophilic heterocyclic carbene (NHC) catalysis under milling conditions. NHC organocatalysis has been rapidly established as ak ey area for catalyst-mediated synthesis, with many activation modes established for aw ide range of substrates ( Figure 1B). [8] The first established activation mode of acyl anions stemmed from the pioneering work of Breslow on thiamine-catalysed reactions and has led to numerous examples across ar ange of carbonyl functional groups. [9] These include benzoin, Stetter and hydroacylation reactions, with demonstration of homo-, cross-, inter-a nd intramolecular examples. Herein we report the first resultso fc ombining this NHC activation mode with ball-milling ( Figure 1C). [10] Our initial investigations commencedw ith the intermolecular homo-benzoin reaction of 4-chlorobenzaldehyde under planetary milling conditions. Ar ange of ten NHC precatalysts based on thiazolium,i midazolium and triazolium heterocycles were screened, along with five bases [K 3 PO 4 ,K 2 CO 3 ,C s 2 CO 3 ,1,.0]undec-7-ene( DBU) and Et 3 N] and three grinding auxiliaries. [11] Pleasingly, it was found that the pentafluorophenyl bearing triazolium tetrafluoroborate NHC precatalyst 8 was the most effective at 10 mol %loading.
Combining the 4-chlorobenzaldehyde with the precatalyst, Cs 2 CO 3 ,sand (as ag rinding auxiliary) and grinding in aplanetary mill at 300 rpm for 15 min furnished the homo-benzoin product 11 in 72 %i solated yield (Scheme 1, conditions A). However,e xtending these conditions to as mall range of substrates did not return positive outcomes in every case. The literature concerning NHC-catalysed benzoin reactions demonstrates that severalo ft he reactions teps can be equilibrium processes, in which the reversibilityo fi ndividual steps is highly dependent on the catalyst and substrate combinations. [12] We hypothesised that the presence of liquids/solvents may help to stabiliseo rd rive reactions forward, and, in the solid state, crystal lattice enthalpies may also play acritical role in determining the positiono fe quilibrium for reactions featuring solid products and/or startingm aterials (notably,4 -chlorobenzaldehyde is as olid, and other benzaldehyde derivatives are liquids). With this in mind, we screened the addition of 100 mLo fs everal LAG (Liquid-AssistedG rinding) materials, including EtOAc, tetrahydrofuran (THF), dichloromethane (DCM), hexafluoroisopropanol (HFIP), isopropanol (IPA), EtOH, dimethylformamide (DMF),M eCN, dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO). It was found that addition of IPAw as optimal and permitted 76 %i solated yield of 14 (in the case of benzaldehyde) and6 3% yield of 12 (in the case of 4-tolaldehyde). With these conditions in hand, at otal of six aldehydes were then assessed under "noL AG" and "IPAL AG" (100 mL) conditions (Scheme 1, inter-benzoin). It appears that milling with LAG gives the most robust conditions, that is, those that permitt he greatest chances of successu nder this milling protocol. As commoni nm any solvent-based approaches, it too was found that the reaction is highly dependent on the purity of the aldehyde introduced into the reaction; trace carboxylic acid appears to have ad isproportionately negative effect on the outcome of the reaction. Pleasingly,t he "no LAG" conditions could also be directly appliedt ot he intra-cross-benzoin reaction of tethered ketone-aldehyde substrates to yield a-hydroxychromanone products in good yields (Scheme 1, intrabenzoin). With confirmation in hand of carbene generation and its engagementi nc atalysis through acyl anion activation, our attentiont urned to demonstrating this reactivity also in the case of the Stetter reaction. Application of previously optimised conditions At oamodel inter-Stetter reaction featuring 4-chlorobenzaldehyde and chalcone did not return favourable yields of the desired product.H owever,c onditions A( 5mol % precatalyst) were applicablet oarange of intramolecular Stetter reactions to furnish the corresponding chromanones and 3-oxo-2,3-dihydrobenzofurans in good-to-excellent yields (Scheme 2, intra-Stetter 6,6 and intra- Stetter 6,5). Indeed, further reaction screening was required to deliver the intermolecular Stetter reactionu nder millingc onditions. Again, screening ar ange of precatalysts, bases, grinding auxiliaries, LAGs and milling speeds delivered optimal results. We were pleased to find that the archetypal thiazolium catalysts were highly effective under these conditions with K 3 PO 4 serving as base (and likely the grinding auxiliary). Thiazolium pre-NHC 1 was optimal and afforded conditions B( Scheme2), requiring3hmilling at 700 rpm. With these conditions in hand, as ample of nine intermolecular Stetter reactions was explored. Ac ombination of three aldehydes with three different chalcone derivativesa f-fordedm oderate-to-good yields in all nine cases. Attention was then turned to exploring if enantioselectivity could be impartedt ot his reaction manifold under milling conditions. Conditions Aw ere chosen to be explored, and the pentafluorophenylbearing triazolium pre-NHC 8 was switched forthe privileged aminoindane-basedt riazolium pre-NHC 33,r eported by Kerr and Rovis. [13] Three of the reaction modes were explored, including intra-benzoin, inter-benzoina nd both the 6,6-and 6,5-intra-Stetterr eactions. All experiments were run with 10 mol %c atalyst loading, and preliminary resultss how that it is indeed possible to transmite nantioselectivity under these conditions (Scheme 3). For the intra-benzoinr eaction, it was found that addition of IPAa sL AG permitted the reaction to return increased yield and slightly increased enantiomeric excess( 24 %y ield, 72 % ee withoutL AG vs.5 2% yield and 82 % ee with LAG). The 6,6-intra-molecular Stetter reaction returned the highest ee of 92 %(with an isolated yield of 96 %).
Despite these results, some of the ee values are lower than those reportedu nder solution conditions, perhaps pointingt owards poorer temperature control of the milled process. [5k] However, these are complex reactions, and clearly the balance of all reaction parameters requires significant fine-tuningtodeliver optimal conditions for maximum enantioselectivity,a nd this would have to be compared directly with af ully optimized solution protocol. Thus, the conclusion proposed herei st hat imparting enantioselectivity of NHC-catalysed reactions under ball-milling is possible and can deliver excellent results, althoughh ow these compare directly against solution-phase conditions is not yet clear. Nonetheless,i ti sp articularly notable that carbenes can be used catalytically in complex reaction pathways and also imparts tereocontrol in the absence of solvent and under millingc onditions.
In summary,b all-milling has been used as at echnique to conductN HC catalysis for the first time. Ar ange of catalysts, bases and grindinga uxiliaries have been screened to reach general conditions for the acyl anion activationm ode, which has been demonstrated in four application areas:i ntermolecular-benzoin, intramolecular-benzoin, intermolecular-Stetter and intramolecular-Stetter.N otably,t hese reactions are run without precaution to obscure air and moisture from the reaction vessel, and in general this works well, although,i ns ome instances,i ncreased catalyst loadings compared to solvent-based techniques are used. Notably,a mong all catalysts screened, perhaps the simplest and longest-known thiazolium pre-NHC 1 is the most optimal catalyst for the intermolecular Stetter reaction under ball-milling conditions. Finally,i th as been demonstratedt hat several of the reactionm odes can also be rendered asymmetric under milling conditions.

Experimental Section
Information about the data that underpins the results presented in this article, including how to access them, can be found in the Cardiff University data catalogue at http://doi.org/10.17035/ d.2019.0087455694. Further experimental details can be found in the Supporting Information·