Controlling Chemoselectivity in the Lithiation of Substituted Aromatic Tertiary Amides

Abstract

Aromatic compounds can be elaborated by directed lithiation in a number of ways [1] and both ortho and lateral metallation have been employed as synthetic tools generally [2] and in a host of recent total syntheses specifically. [3,4] Whereas ortho metallation occurs both because the directing group can inductively raise the acidity of the ortho hydrogen atom and also because the incoming organometallic substrate closely approaches this position, lateral metallation results from the directing function coordinating an organometallic substrate whilst conjugatively withdrawing electrons from a benzylic group. Consequently, the processes are competitive and, as such, result from the presence of similar directing agents. Recently, ring substitution and lateral-group branching [5] have been employed, in addition to the use of a-silyl lateral groups, [6] as means of controlling the regioselectivity of deprotonation. The use of deuterium as a protecting group at kinetically acidic positions has been reported both for amides [7] and N-heterocyclic systems. [8] Overall, studies to date have clearly established that, for either class of reaction, amide-type groups are among the most useful directors of reaction.[2]Transformations of ortho-and laterally lithiated tertiary amides have been investigated, [9] with directing effects having been attributed to the rate-determining deprotonation of a substrate-organolithium complex. [10][11][12] However, it is only very recently that solid-state structural evidence has been presented in support of the nature of lithiated intermediates in either reaction pathway. For 1 and 2 ortho lithiation has led to the characterization of solid-state dimers, 3, and isostructural N,N-diisopropyl-2-lithionaphthamide-THF complex, 4, respectively. These are based on core C···Li interactions, support of the metals coming from (amide)OÀLi bonding with concomitant modulation of the sterically induced twist angle between the amide and the plane of the aromatic ring.[13] Contrastingly, the laterally deprotonated salt of 5 reveals a tris(thf) solvate, 6, in which the metal center is only coordinated by O atoms with no C···Li interaction, thus allowing the amide and aromatic planes to be near to perpendicular in the solid state.[14] These data suggest a link between the number of donor atoms per solvent molecule (solvent denticity) and reaction chemoselectivity and lead us to report here on the competitive deprotonation of 2-ethyl-N,N-diisopropyl-1-benzamide, 7.Treatment of 7 in THF/toluene at À78 8C with 1 equivalent of tBuLi gave a maroon solution from which, on storage at À30 8C, crystals were deposited. Surprisingly, in light of previous work, [2,12,15] these were identified as N,N-diisopropyl-2-ethyl-6-lithiobenzamide-THF, 8, by X-ray crystallography. [16] In accordance with our own recent studies, [13] 8 forms a solid-state dimer based on the stabilization of each metal component in a {(CLi) 2 } core (C2ÀLi1 = 2.345(5) , C2A À Li1 = 2.187(5) ] by an amide-O center (O1 À Li1 = 1.972(5) ) and one THF m...

Ligand Effects in the Formation of Tertiary Carbanions from Substituted Tertiary Aromatic Amides

“…Consistent with previous studies, [12] the presence of a monodentate Lewis base (Et 2 O) promoted orthodeprotonation and the formation of 5-Li o (Scheme 2).…”

“…Treatment of 5 in Et 2 O/toluene (1:3) at À78 8C with 1 equivalent of tBuLi gave a dark purple solution from which crystals deposited at À30 8C. Consistent with previous studies, [12] the presence of a monodentate Lewis base (Et 2 O) promoted orthodeprotonation and the formation of 5-Li o (Scheme 2).…”

“…Whereas previous work on the lithiation of (dialkyl)aryl-A C H T U N G T R E N N U N G amides has focused on orthometalation in the presence of ethers, [9,12] we have shown that the presence of stoichiometric tridentate Lewis base promoted lateral deprotonation in the reaction of 3 with tBuLi. [12] The reaction of 5 with tBuLi was therefore attempted in the presence of 1 equivalent of either PMDTA or diglyme (DGME).…”

“…[12] The reaction of 5 with tBuLi was therefore attempted in the presence of 1 equivalent of either PMDTA or diglyme (DGME). Remarkably, in spite of there being a tertiary aliphatic group at the 2-position in the substrate, X-ray crystallography revealed that PMDTA was able to favor benzylic (lateral) deprotonation, giving 5-Li l ·PMDTA (Scheme 2 and Figure 2; see the Supporting Information).…”

“…[11] In the case of amide 3, the choice of solvent dictated the regioselectivity of the deprotonation: in the presence of THF, amide 3 gave the ortholithiated dimer 3-Li o ·THF, while in the presence of PMDTA laterally metalated 3-Li l ·PMDTA was formed (PMDTA = N,N,N',N'',N''-pentamethyldiethylenetriamine, Scheme 1). [12] Recently, the search for new and more highly tunable reactivity in the field of directed arene elaboration has led to the development of heterometallic organyl (R) amido (e.g., TMP = 2,2,6,6-tetramethylpiperidide) bases. These have offered particular synthetic benefits by virtue of their poor nucleophilicity, typically rendering the directing group chemically passive during reaction.…”