LiTMP Trans‐Metal‐Trapping of Fluorinated Aromatic Molecules: A Comparative Study of Aluminum and Gallium Carbanion Traps

Abstract Fluoroaromatic scaffolds pose a challenge to lithiation due to low stability of lithiated intermediates. Here we apply trans‐metal‐trapping (TMT) to a series of key fluorinated aromatics. In TMT, LiTMP performs the metalation, while an organometallic trap intercepts the emergent carbanion. This study contrasts the trapping abilities of iBu2AlTMP and Ga(CH2SiMe3)3, structurally mapping their TMT reactions and probing relative stabilities of metalated fluoroaromatic intermediates by NMR studies. Results show the installed Al−C(aryl) bonds are more prone to decomposition by benzyne formation and Li‐F liberation, than the Ga−C(aryl) species. The latter are thus better for onward reactivity as demonstrated in cross‐coupling reactions with benzoyl chloride that produce ketones.

In2017, we witness the centenary of the advent of organolithium chemistry by Schlenk and Holtz. [1] Since then organolithium reagents have played leading roles in the synthesis of organic compounds especially through metalation (C À Ht o CÀmetal) applications. [2] Fluorinated aromatic compounds represent as pecial challenge to organolithium reagents on account of the instability of metalated intermediates. [3] This point and the profound complexity involved (e.g., benzyne formation, autometalation, cascade processes) are exemplified in Schlossersclassic report of multiple hydrogen/lithium interconversions induced by lithiation of 1,3,5-trifluorobenzene. [4] Significantly,f luoroaromatic compounds are rarely found in nature, [5] meaning that nearly all aryl fluorides utilized in pharmaceutical manufacture (as synthetic building blocks) must be generated synthetically.I ncentivized by the growing importance of fluorinated aromatic compounds in active pharmaceutical ingredients (where it is estimated that 20-25 %offorthcoming drugs contain at least one Fatom), [6,7] we pondered whether emerging metalation methodologies could improve on the performances of the classical organolithium reagents.N otable advances to this end have been made with respect to either reaction rate or regioselectivity. Collum and co-workers demonstrated arate enhancement on lithiating various fluorinated aromatics using lithium diisopropylamide in THF at À78 8 8Cbya dding catalytic quantities of LiCl. [8] Knochel and co-workers disclosed that specific aryllithium species can be selectively trapped from amixture of isomers by transmetalation with asubstoichiometric quantity of dichlorozirconocene. [9] Here we approach these challenging metalations through trans-metal-trapping (TMT), where two non-interacting organometallic reagents work in tandem (Scheme 1). [10] Thef irst stage of TMT harnesses the bulky amide base,L iTMP (TMP = 2,2,6,6tetramethylpiperidide) to deprotonate as ubstrate (these metalations can exist in equilibria lying towards starting materials). Thes econd stage utilizes ab ulky,s oluble Lewis acidic organometallic trap to rapidly intercept and stabilise emergent carbanions,t hereby driving equilibria toward metalated products.S till in its infancy, TMT has only been reported with ah andful of organic/organometallic substrates using iBu 2 AlTMP as the trap [11a,b] and with aseries of diazines using aG a(CH 2 SiMe 3 ) 3 trap. [11c] We also note that Knochels Group used as imilar Al reagent, iBu 2 AlCl, to trap aromatic carbanions after lithium halogen exchange,t hough this proceeded with LiX elimination and thus gave neutral Al species as opposed to the ate species discussed here. [12] Here, in applying TMT to challenging fluorinated aromatic substrates we present the first comparative study between Al and Ga traps,structurally mapping TMT reactions both crystallographically and spectroscopically,e lucidating the complex reaction pathways that diminish the effectiveness of the Al trap,a nd establishing that the greater carbophilicity and, or the reduced fluorophilicity of the Ga trap makes its products the preferred candidates for performing follow on reactions with electrophiles.
Initial TMT studies focused on the LiTMP/iBu 2 AlTMP system with ar ange of fluorinated aromatic substrates. Reaction of 3-F-anisole with LiTMP and iBu 2 AlTMP in hexane at À78 8 8Cgave asolid that 1 HNMR analysis confirms contains metalated substrate (in the 2-position) as indicated by three new resonances between 6.94 and 6.19 ppm. 19 Fand 7 Li NMR spectra support formation of one product, displaying one resonance in each case.X -ray crystallography revealed this product to be the contacted ion pair 1  (4) ). Thus it is anticipated that as the Fc ontent increases the carbanionic charge decreases,a nd in theory the trapping step should become less facile.Unfortunately full characterization of 2-4 was hampered by poor yields and propensity of crystals to decompose into oils.
Themoderate yields of 1-4 prompted more investigation. Using 1 as ar epresentative example,t he 1 HNMR spectrum of its reaction filtrate revealed four aromatic resonances each integrating to one H, consistent with an asymmetric 1,3disubstituted anisole.F rom this we suggest that as econdary competing process is occurring. After initial metalation with LiTMP,r apid loss of aluminate LiAlF(TMP)iBu 2 occurs to generate ab enzyne intermediate and TMPH, which can add across and trap the incipient benzyne affording 1-(3-methoxyphenyl)-2,2,6,6-tetramethylpiperidine (I;c onfirmed by aqueous work-up and 1 Ha nd 13 CNMR spectra of the resulting oil). Importantly,t his process could not be arrested even at cryogenic temperatures.Acontrol reaction between 1 and TMPH in C 6 D 6 in aJ .Y oung NMR tube established that I can be prepared via this pathway (see the Supporting Information). However,w ec annot rule out the possibility that an autometalation process may also be contributing to the formation of the TMP-substituted product. LiTMP is more nucleophilic than neutral TMPH, thus any present in solution (due to variations in stoichiometry or rapid generation of the benzyne before the LiTMP has all reacted) could also react with the benzyne,w hereupon the generated lithiated species could deprotonate asecond substrate molecule.
Thedecomposition pathways were probed further.Reaction between 3-F-anisole,L iTMP,a nd iBu 2 AlTMP·THF was monitored over time in aJ.Young NMR tube in C 6 D 6 at room temperature.Initially the 1 HNMR spectrum displayed signals corresponding to 1 and coproduct I,a lbeit after forming the metalated compound slowly decomposes.C onfirming that coproduct TMPH, or potentially some unreacted LiTMP,i s necessary for formation of I,t he 1    fied by NMR spectroscopy as the known Diels-Alder cycloaddition product 1-methoxy-9-10-diphenyl-9-10-epoxyanthracene in 86 %( from 1)o r4 9% (in situ mixture) yield. That 1,anaryl aluminum decomposes via benzyne formation is interesting albeit not entirely unknown. Ar elated process was seen during the sodium mediated ortho-zincation of chlorobenzene using [TMEDA)·Na(m-TMP)(m-tBu)Zn-(tBu)]. [13] Metalation of fluoroarenes using the LiTMP/ iBu 2 AlTMP TMT system is thus more complex than seen with other non-fluorobenzene-based systems.S pecifically, trapping appears too sluggish to prevent benzyne formation and autometalation side reactions even at low temperature. Further,e ven metalated products are unstable in relatively innocent hydrocarbon solvents suggesting that the propensity of the aluminated species to eliminate Li-F as part of an aluminate has ap articularly deleterious effect on C-Al bond stability.
Importantly, 5 establishes that TMT can be used not only to trap carbanions but also to trap novel monomeric modifications of high lattice energy salts,t hat is,s pecies that usually exist as polymeric or network lattices.T his study unequivocally maps out structurally and spectroscopically the varied reaction pathways available to metallo-fluoroarenes, by trapping both organic and inorganic components of decomposition alongside that of the target metalated product. Clearly the new TMT-installed AlÀCb onds are sensitive enough to facilitate decomposition by benzyne formation and concomitant ate elimination.
Next we turned to the gallium trapping reagent (Ga-(CH 2 SiMe 3 ) 3 ). Reaction of LiTMP and Ga(CH 2 SiMe 3 ) 3 with fluorobenzene in hexane at À78 8 8Cfor one hour,followed by PMDETAaddition gave aprecipitate,that was recrystallized in 67 %y ield. An X-ray diffraction study of these crystals revealed 2-Ga(CH 2 SiMe 3 ) 3 -1-F-C 6 H 4 ·Li(PMDETA), 6 (see the Supporting Information) proving that, as expected, fluorobenzene was selectively metalated ortho to the F substituent (Ga1 À C1 2.051 (3) ). Interestingly,t his distance is shorter than the Al-C Ar distances in 1-4,s ignifying enhanced Ga carbophilicity.T he Fa tom interacts with aL i·PMDETAunit (F1ÀLi1 1.867(6) ), resulting in aC IP structure.T he 1 HNMR spectrum of 6 in C 6 D 6 displayed four aromatic resonances consistent with the solid-state arrangement. The 19 FNMR spectrum displays as inglet at À111.35 ppm whereas the 7 Li NMR spectrum has two singlets at 0.52 and À0.22 ppm with ab road featureless hump inbetween suggestive of af luxional process.
Thesolution stability of gallated fluoroarene 6 was probed by monitoring its 1 HNMR spectra in C 6 D 6 over time against  ferrocene as an internal standard. In contrast to the aluminated fluoroarenes,ca. 77 %of6 is intact after 48 h, and 65 % after 160 h, highlighting the profound synthetic advantage of the Ga trap over Al for stabilization of sensitive fluoroaromatic anions.Furthermore asample of 8 in [D 8 ]THF shows little sign of decomposition, even after 6days,signifying that donor solvents enhance the stability of these systems,a nd evidence points to SSIP constitutions of these gallated structures.Arelated factor regarding the stability enhancement of the gallium complexes is the greater fluorophilicity of aluminum. Thus formation of Al À Fb onds is promoted, hastening decomposition. Asimilar effect was reported by the group of Gessner in the stabilization of fluorine carbenoids with the heavier alkali metals. [14] Thef inal piece of this comparative study was to quantify how the distinct properties of these Al and Ga TMT systems would affect onward reactivity in an organic application. We chose aPd(PPh 3 ) 4 -catalyzed cross-coupling reaction between the metalated TMT products of 1,3,5-trifluorobenzene with benzoyl chloride ( Table 1). Note that LiTMP on its own proved ineffective in this reaction over avariety of conditions. Thea luminated product 3 gave poor yields of ketone 10 (6-8%)with 19 FNMR spectra of isolated solid from the quench reaction in [D 8 ]THF solution implying several F-containing side products.I nc ontrast, the analogous gallated product 8 reacted with benzoyl chloride more efficiently affording ab est yield of 10 of 80 %a sq uantified by NMR studies using ferrocene as internal standard. Hydrolysis at the onset of the reaction, presumably through moisture contamination, appears to be the only side reaction (see the Supporting Information for experimental details). Though Huang and coworkers have previously prepared ketones in good yield from benzoyl chloride and assorted lithium tetraorganogallates without ac atalyst, the transferred nucleophiles were much less sensitive than the fluorinated examples probed here. [15] In our case reactions were more efficient with the catalyst. Note, however, that examples of organogallium participation in organic synthesis is relatively uncommon, [16] and furthermore, in cross-coupling chemistry it is exceptionally rare. [15,17] In conclusion, this study has (i)shown the ability of TMT to generate and stabilize sensitive fluoroaromatic carbanions, (ii)e xtended TMT for the trapping of molecular forms of inorganic salts,( iii)u nravelled key complex decomposition pathways involved in metalation of fluoroarenes,a nd (iv) established the greater robustness of arylgallium intermediates versus arylaluminum species thus opening potential new synthetic uses for the heavier group 13 metal.