Transforming LiTMP Lithiation of Challenging Diazines through Gallium Alkyl Trans‐Metal‐Trapping

Abstract This study establishes a new trans‐metal‐trapping (TMT) procedure based on a mixture of LiTMP (the base) and tris(trimethylsilylmethyl)gallium [Ga(CH2SiMe3)3, GaR3] (the trap) that, operating in a tandem manner, is effective for the regioselective deprotonation of sensitive diazines in hydrocarbon solution, as illustrated through reactions of pyrazine, pyridazine, and pyrimidine, as well as through the N‐S heterocycle benzothiazole. The metallo‐activated complexes of all of these compounds were isolated and structurally defined.

Asone of the most used strategies in synthetic campaigns, metalation chemistry is currently enjoying ar emarkable period of advancement. [1] Lithium alkyls and amides remain front-runners for base candidates in routine C À HtoC À metal transformations,b ut for non-routine,m ore formidable substrates,base selection is generally far from straightforward. [2] One of naturesmost important class of heterocycles utilized widely in agrochemicals,f oodstuffs,p harmaceuticals,a nd many other commercial commodities,d iazines are firmly in the formidable category,e specially parent naked diazines devoid of substituents capable of assisting the direction of the metalation. [3] To avoid competition from nucleophilic addition caused by alow-lying LUMO in the heteroaromatic ring, bulky LiTMP (TMP is 2,2,6,6-tetramethylpiperidide) is preferred to more basic alkyllithium reagents as the base for these p-deficient diazines,a sf irst noted by QuØguiner. [4] However,lithiated diazine intermediates are generally unstable,s oK nochel, [5] Kondo, [6] Mongin, [7] and Hevia [8] have employed coalitions of components typically but not exclusively based on the softer metal zinc to improve stabilities and to perform metalation under milder conditions.T hough excellent progress has been made,these coalition approaches still have their limitations,a sf or example in the zincation of pyrazine using [(THF)LiZn(TMP)tBu 2 ], where no stoichiometric control is possible because only 2,5-dizincation occurs in a1 :1 base:pyrazine stoichiometry. [8] Moreover,alack of definitive structural information still impoverishes understanding of this area, which in the most extreme "black box" cases leads to am isidentification of the actual metalating base. [9] This paper reports an ew trans-metal-trapping (TMT) procedure based on amixture of LiTMP and tris(trimethylsilylmethyl)gallium [Ga(CH 2 SiMe 3 ) 3 ,GaR 3 ]that is effective for regioselective diazine and benzothiazole deprotonation in hydrocarbon solution. Whereas alkyllithium reactions are generally irreversible,L iTMP reactions tend to be pK adependent equilibria. In TMT,t hese equilibria are shifted towards the desired lithiated substrate product by its interception by atrapping agent (Scheme 1). [10] We have previously employed the diorganoaluminum amide iBu 2 Al(TMP) as atrapping agent. [10] Forthis challenging diazine work, we elected to test GaR 3 as atrap because its bulkiness compromises its ability to form aw eakly basic ate complex with LiTMP and it has the potential to sedate the sensitive incipient carbanions on account of galliumss trong carbophilicity (stronger than that of aluminum). Moreover, this organometallic trap exhibits good hydrocarbon solubility and does not require low temperature procedures,g iving it ad ecided advantage over salt traps (for example,M gCl 2 , ZnCl 2 ), [11] which generally need the use of ethereal solvents and often require low temperatures to avoid competing salt metathesis reactions.T his potential has been duly realized through isolation and characterization (crystallographic, elemental analyses,a nd NMR spectroscopic) of an unprecedented series of gallium diazide and related complexes.A s well as launching the concept of gallium TMT,t his study reports the first crystal structures of metallodiazine complexes made by metalation (CÀHt oC Àmetal) reactions for gallium and indeed, bar one exception for zinc, [8] fora ny metal. Furthermore,t he study highlights that two-metal synergistic reactions are not confined to concerted, synchronized processes where the metals belong within the same reagent, but can be extended to tandem, stepwise processes involving two separately added reagents that do not form ac o-complex.
Thes tudy first established through NMR spectroscopy that LiTMP and GaR 3 remain separate in benzene solution [12] (Supporting Information). Such separation is essential to action the lithiation step of TMT because,w hereas free LiTMP is as trong base,c ombining it with, for example, iBu 3 Al to form aluminate LiAl(TMP)(iBu) 3 greatly diminishes deprotonating power. [10a] TMT was then attempted on three classical naked diazines,p yrazine,p yridazine,a nd pyridimine,a sw ell as the related nitrogen-sulfur ring compound benzothiazole.
It may seem surprising that sensitive pyrazinyl mono-and di-carbanions can be trapped in crystalline form at room temperature and structurally defined, but this is where the structures become informative as they show that the heterocyclic units of 1 (Figure 1) and 2 ( Figure 2) are cooperatively stabilized through coordination by both the Li and Ga centers that tie up the lone pairs of the Na nd Ca toms,r espectively. Both structures are monomeric with aggregation blocked at Li by tridentate PMDETA, though centrosymmetric 2 is tetranuclear having two Ga and two Li centers.N otably, 2 is the more congested structure with its GaR 3 units having proximal dispositions to the (PMDETA)Li units;w hereas in 1 these units have a1 ,3-separation. TheG a Àsp 2 C(diazide) bond lengths show little variation with each other or with the Ga À sp 3 C(R group) bonds (see the Supporting Information for full crystallographic details and supporting NMR characterization).

Angewandte Chemie
Communications monitoring of the reaction revealed an important effect of the order of metal reagent addition on reaction regioselectivity. Thus,when LiTMP is added as asolid to the hexane solution of GaR 3 and pyridazine, 3 is obtained in a7 8% yield, along with small amounts of the C4-gallated regioisomer (16 % yield). Contrastingly,i ft he substrate is added to the hexane suspension of LiTMP and GaR 3 ,t he yield of 3 decreases to 50 %, and more C4 metalated product is seen (36 %). These contrasting results suggest an activating effect of the GaR 3 component, which perhaps can initially coordinate to the Lewis basic Na toms of the heterocycle,f acilitating its lithiation at C3. Thec rystal structure of 3 ( Figure 3) shows GaR 3 elects to sit at the most acidic 3-position adjacent to one N( confirmed in solution by NMR spectra;S upporting Information). An ovel feature is the Li(PMDETA) unit bridging the two diazine Natoms [Li À Nbond lengths 2.093(5) and 2.043(5) for the non-disordered molecule of the Z' = 2 structure] leading to a1 ,"2.5"-separation. Consequently,the spiro Li center, connecting the 3-and 2 5-atom rings,has a5coordinate geometry.
Because pyrimidine was found to be totally inert to LiTMP from 0 8 8Ct or eflux temperatures, [4] it seemed the greatest challenge to TMT.H owever,a si nt he case of 1-3, TMT was demonstrated tangibly through isolation and crystallographic characterization of am etalated derivative, here [1-(PMDETA)Li-6-(GaR 3 )-(C 4 H 3 N 2 )], 4.This was made in a2 7% isolated crystalline yield, though NMR monitoring of the reaction shows that under the conditions studied 4 forms in ah igher 59 %y ield. Its structure ( Figure S13) exhibits many of the features in 1-3 with the proximal 1,6separation of its GaR 3 and (PMDETA)Li akin to that of those in dimetalated pyrazine 2.
In view of the fact that the 2-lithiated derivative of the related nitrogen-sulfur heterocycle benzothiazole is known to exist simultaneously in ring-closed and ring-open forms,a s best evidenced by Boches 13 CNMR studies in D 8 -THF at À75 8 8C, we extended the TMT study to this fused heterocycle. [14] Run at room temperature in hexane solution Significantly, 5 is quantitative in solution with no ring-opened metallo(2-isocyano)thiophenolate isomer detected. Deprotonative gallation of the C2 center was evident from its downfield resonance at 209.5 ppm in the 13 CNMR spectrum. In the crystal, 5 follows the pattern in the TMT diazine series with the GaR 3 and Li(PMDETA) units adjacent on deprotonated Cand Natoms,respectively,with aGa1-C13-N1-Li1 torsion angle of À13.9(4)8 8 (Figure 4). This first Ga TMT reaction of aN -S heterocycle is competitive with Mongins LiTMP/CdCl 2 ·TMEDAi nT HF solution approach, which used excess (1.5) base equivalents for a9 7% yield of 2iodobenzothiazole after I 2 quenching, though no metallo intermediate was identified. [7b, 15] Fors ynthetic campaigns,i ti si mportant that the new C À Ga bonds in these systems are accessible to electrophiles.I n preliminary NMR spectroscopic experiments (see the Supporting Information for full details), on subjecting the gallated benzothiazole 5 to methyl trifluoromethanesulfonate (methyl triflate,M eOTf) we obtained ay ield of 62 %o ft he desired methylated product and did not observe any opening of the azole ring. In contrast, though this strong electrophile did quench the monogallated pyrazine 1,i tp roved too aggressive and decomposition ensued. Therefore,w et urned to as econd electrophile in trimethylsilyl chloride,w hich offers another potential pitfall in being too bulky.R eassur- ingly,this pitfall proved unfounded and the heterocyclic rings of both 1 and 5 were successfully converted to Me 3 Si derivatives at their CÀGa sites (59 and 88 %y ields,r espectively). These promising results demand that afull systematic, optimized study of all of these new gallated compounds is now undertaken with as eries of electrophiles.
In summary,b ecause LiTMP trans-metal-trapping via ag allium alkyl has been substantiated here with challenging sensitive unactivated diazines and benzothiazoles,t his can potentially open the floodgates to ag eneral improvement in many other metallation reactions with various sensitive and non-sensitive substrates where LiTMP and related bulky bases give only low-to-moderate yields of products.

Experimental Section
Full experimental details and copies of NMR spectra are included in the Supporting Information. CCDC 1494979 (1), 1494980 (2), 1494981 (3), 1494982 (4), and 1494983 (5)c ontain the supplementary crystallographic data for this paper.T hese data can be obtained free of charge from TheC ambridgeC rystallographic Data Centre.