Electron‐Transfer and Hydride‐Transfer Pathways in the Stoltz–Grubbs Reducing System (KOtBu/Et3SiH)

Abstract Recent studies by Stoltz, Grubbs et al. have shown that triethylsilane and potassium tert‐butoxide react to form a highly attractive and versatile system that shows (reversible) silylation of arenes and heteroarenes as well as reductive cleavage of C−O bonds in aryl ethers and C−S bonds in aryl thioethers. Their extensive mechanistic studies indicate a complex network of reactions with a number of possible intermediates and mechanisms, but their reactions likely feature silyl radicals undergoing addition reactions and SH2 reactions. This paper focuses on the same system, but through computational and experimental studies, reports complementary facets of its chemistry based on a) single‐electron transfer (SET), and b) hydride delivery reactions to arenes.

Abstract: Recent studies by Stoltz, Grubbse tal. have shown that triethylsilane and potassium tert-butoxide react to form ahighly attractive and versatile system that shows (reversible) silylation of arenes and heteroarenes as well as reductive cleavage of C À Ob onds in aryl ethers and C À Sb onds in aryl thioethers.Their extensive mechanistic studies indicate acomplex network of reactions with an umber of possible intermediates and mechanisms,b ut their reactions likely feature silyl radicals undergoing addition reactions and S H 2reactions. This paper focuses on the same system, but through computational and experimental studies,r eports complementary facets of its chemistry based on a) single-electron transfer (SET), and b) hydride delivery reactions to arenes.
Recently,Stoltz, Grubbs et al. [1] have discovered as imple and elegant system comprising Et 3 SiH (2)a nd KOtBu which achieves an umber of remarkable reactions:1 )converting arenes and heteroarenes,a nd their alkylated counterparts, into silyl-substituted products,o ften with excellent regiocontrol [1a-c] (e.g. 1!3;S cheme 1);2 )achieving reductive C À S bond cleavage in aryl thioethers (e.g. 4!5)i nareaction which has potential importance in removing sulfur traces from hydrocarbon fuels; [1d] 3) triggering reductive CÀObond cleavage in aryl ethers (e.g. 6!7)inareaction with potential applications to controlled lignin degradation. [1a,d] Anumber of intermediates likely arise from reaction of these two reagents, and spectroscopic evidence has resulted in informed proposals being made for their structures.T hese reactions have proved puzzling, but arecent coordinated study by synthetic, mechanistic, and computational chemists has allowed significant advances to be made. [1e,f] Thec onclusions are:1 )the combination of Et 3 SiH and KOtBu leads to triethylsilyl radicals which have am ajor role to play in the reductive cleavage of the C À Oand C À Sbonds, [1d] 2) triethylsilyl radicals are also likely to be involved in the silylation reactions, although nonradical routes to the silylation have also been considered in depth and may also play acentral role. [1e,f] The mechanistic details are not fully in place,for example,onhow formation of the silyl radicals occurs,b ut rational working hypotheses have been advanced. [1e] We had wondered if single-electron transfer mechanisms were playing as ignificant role in some of these reactions, notably for the cleavage of CÀOa nd CÀSb onds.A ne arly suggestion [1a] mentioned pentavalent silicates (e.g. 13 b;s ee Scheme 2) as reagents that were likely involved in the CÀO cleavage,b ut the more recent computational studies on the substrates 4 and 6 instead support an alternative mechanism. [1d] In this regard, Scheme 1s hows ipso addition to the carbon atom of the CÀOb ond by triethylsilyl radicals, followed by CÀOb ond cleavage in conversion of 6 into 7.
Our recent interest in reductive chemistry carried out by reactions involving KOtBu attracted us to this area. [2] Studies mentioned above [1e] suggest that the reactive species produced could include the radical anion 12 b (Scheme 2) and the silicate anion 13 b. [1a,e] Because of their subsequent importance in this paper,wemention here that the radical anions 12 may be formed in anumber of ways,two of which are shown (inset) in Scheme 2( see Figure 14 in Ref. [1e] for an addi-tional route). Forthese studies,w eused the computationally less costly trimethylsilyl group instead of the triethylsilyl group. [1d,e] To these,w ea dd the triethylsilyl anion 14 b as another putative intermediate.A tf irst sight, these compounds are potentially excellent electron donors,although, as will be seen below,computational chemistry is very helpful in eliminating species and mechanisms which are unlikely to contribute.Inrecent years,wehave reported on many highly reducing organic electron donors that demonstrate remarkable behavior. [3] We were therefore keen to test the KOtBu/ Et 3 SiH system for evidence of single-electron transfer (SET) activity and, if found, to calibrate the systemsreactivity.
Aliterature search reveals that N-benzylindole substrates are reductively cleaved to indoles and toluenes with two reagents-both involving electron transfer.T he first uses Birch chemistry [4] and the second uses low-valent titanium reagents. [5] Accordingly,w eprepared ar ange of N-benzylindole substrates (15-23;S cheme 2), to test for cleavage with silane and tert-butoxide,a nd the outcomes are shown in Table 1. In each case,r eactions afforded the debenzylated products,w hile blank reactions (no silane) led to excellent recovery of starting materials.T he examples 15-22 also afforded volatile products from the benzyl unit. To counteract this,t he naphthylmethyl substrate 23 was subjected to the reaction and afforded 1-methylnaphthalene (30), in addition to 3-methylindole (26), and recovered 23 (entry 18).
To understand the site of electron transfer in these reactions,w em odelled the formation and reaction of two radical anions-those arising by electron transfer to the indole 17 and carbazole 22.I nb oth cases (Figure 1), the SOMO showed spin density on the heterocycle,r ather than on the benzyl group.These data is consistent with the greater delocalization available in either the bicyclic or tricyclic heterocycle for the transferred electron.
We now use computational methods to compare the cleavage of the N-benzyl group of 15 by an SET mechanism (Table 2) with the three potential electron donors 12 a-14 a.
Here it is seen that electron transfer from 12 a to 15 is almost barrierless and is exergonic (entry 1; the scheme also shows facile fragmentation of the radical anion 31), while the electron-transfer reactions from 13 a and 14 a (entries 2and 3) show prohibitive energy profiles.   ( 88) Yields of products and recovered substrates are those for the isolated compounds.
We also tested energy profiles for the debenzylation reaction with two possible competing pathways (Table 2; lower panels). Thefirst of these recognizes that 13 a could be avery powerful hydride-transfer agent and might facilitate an S N 2reaction, although an unusual one,atthe benzylic carbon center. However,t ransfer of hydride from 13 a to 15 shows abarrier of 36.9 kcal mol À1 for the benzyl cleavage,and so this type of reaction will not occur under our reaction conditions in the laboratory.T he second competing reaction type would involve an S H 2r eaction by aR 3 Si radical at the benzylic carbon center.T his path would also be an unexpected reaction, as radical displacements at tetrahedral carbon centers are almost unknown, and indeed the kinetic barrier (44.3 kcal mol À1 )isagain insurmountable.F rom these results, SET from 12 a is overwhelmingly the most likely of the computed candidate mechanisms for benzyl group cleavage. In effect, cleavage occurred to afford N-methylaniline, 41, which was converted into the more easily isolated 42 following acetylation (56 %o ver 2s teps;S cheme 3). When the reaction was repeated, but in the absence of Et 3 SiH, no cleavage was observed, with the starting material 40 recovered (97 %). We next varied the protecting group on our indole substrates from benzyl to allyl. Given that the computational results showed electron transfer to the indole group in the substrates 17 and 22,r ather than to the benzyl group,t hen the reagent should also to be able to cleave Nallylindoles by an SET mechanism, because of the stabiliza-tion of the allyl radical leaving group. [6] Accordingly,t he substrates 43 and 45 were prepared. Thei ndole products 26 and 46 were indeed formed from these substrates (35 %a nd 33 %respectively). Thelow yields may indicate the wealth of alternative reactions open to this reagent system. Indeed, asecond product was isolated from the reaction of 43,namely o-isopropylaniline (44;18%), although we have not explored the mechanism of its formation as yet. It was clear that the KOtBu/Et 3 SiH system is am ore than competent electrondonating system.
In amore challenging probe for electron-transfer potency, we subjected the benzyl methyl ether 47 to reduction by this system (Scheme 3). Ac lose analogue of this substrate had proven avery tough substrate in previous studies. [3h] It did not undergo fragmentation until two electrons had been transferred. In this case,t he reduced product 48 was produced in 52 %y ield [a blank reaction afforded recovered starting material exclusively (62 %)].A dditionally,s ubjecting the nitrile 49 [7] to the reaction afforded the hydrocarbon 50 as the sole product, consistent with electron transfer followed by loss of cyanide anion.
We calculated the oxidation potential of 12 a [8] to be E = À3.74 Vvs. SCE (MeCN). This potential makes it much more powerful than alkali metals.S uch ap owerful electron donor should provide ag ood probe for the Marcus inverted region of SET reactions with substrates that show low reorganization energies,( e.g. polycyclic arenes). [9] Stoltz, Grubbs et al. reported [1d] small amounts of partially reduced arenes from reduction of naphthalenes.Inour hands,and in the presence of excess of KOtBu/Et 3 SiH, anthracene,p henanthrene,a nd naphthalene all afforded significant amounts of their dihydro counterparts (Scheme 4). These compounds would be expected products from Birch-type electron-transfer processes,but to probe the mechanism we undertook computational studies of electron transfer from 12 a to the hydrocarbons 51-53 to yield the corresponding radical anions 60-62. ( Table 3) Here,t he expected normal order of reactivity is 51 > 52 > 53. [10] This order is also reflected in the DG rel values shown in Table 3. However,t he reverse pattern is seen for the DG* values.S ET to 51 from the radical anion 12 a shows an

Angewandte Chemie
Communications extraordinary barrier of 90 kcal mol À1 , [11] while reduction of 52 and 53 show progressively lower barriers;i ft his can be verified by detailed experimental studies,itwill be avery rare intermolecular ground-state illustration of the Marcus inverted region, (stronger driving force leads to retarded electron transfer). In comparison, hydride transfer from 13 a to afford the corresponding anions 63-65 featured low barriers and favorable thermodynamics (Table 4). At least for the reduction of anthracene,hydride transfer from 13 a is indeed likely to occur.With the other substrates,hydride-transfer reactions again show lower barriers than electron transfer from 12 a and this will of course be modulated by the concentration of the reducing species present. Finally,t he alkyne 54 and stilbene 55 were reacted and gave (PhCH 2 ) 2 59 as the sole product (21 and 93 %respectively;S cheme 4). [12] In summary,the KOtBu/Et 3 SiH system provides access to ab road range of mechanisms for reductive chemistry,n ow including electron transfer and hydride delivery to arenes. Thee lectron-donor 12 b is identified as au niquely powerful agent.