Charles T. O'Hara

Directed ortho-meta′- and meta-meta′-dimetalations: A template base approach to deprotonation

The regioselectivity of deprotonation reactions between arene substrates and basic metalating agents is usually governed by the electronic and/or coordinative characteristics of a directing group attached to the benzene ring. Generally, the reaction takes place in the ortho position, adjacent to the substituent. Here, we introduce a protocol by which the metalating agent, a disodium-monomagnesium alkyl-amide, forms a template that extends regioselectivity to more distant arene sites. Depending on the nature of the directing group, ortho-meta′ or meta-meta′ dimetalation is observed, in the latter case breaking the dogma of ortho metalation. This concept is elaborated through the characterization of both organometallic intermediates and electrophilically quenched products. A network of sodium and magnesium ions helps direct double deprotonation of aryl rings. Bring your own template for deprotonation When manufacturing pharmaceuticals and agrochemicals, chemists need to add substituents to specific carbon sites in hexagonal benzene rings. If theres already a substituent on the ring, it can often direct a base to deprotonate the site next to it. But what if you want the base to attack the site two carbons away? Martínez-Martínez et al. devised a method to do this by taking advantage of the sodium and magnesium counterions associated with their base. These ions form a template that orients the base to attack the more distant site. Science, this issue p. 834

Unmasking Representative Structures of TMP-Active Hauser and Turbo-Hauser Bases†

The molecular engines that drive enhanced magnesiations are unveiled through structural elucidation of a 2,2,6,6-tetramethylpiperidide (TMP) Hauser base and its turbo model (see structure; Mg green, Li violet, C purple, O red, N blue, Cl yellow).

Pre-inverse-crowns: synthetic, structural and reactivity studies of alkali metal magnesiates primed for inverse crown formation

Two new alkali metal monoalkyl-bisamido magnesiates, the potassium compound [KMg(TMP)2nBu] and its sodium congener [NaMg(TMP)2nBu] have been synthesised in crystalline form (TMP = 2,2,6,6-tetramethylpiperidide). Devoid of solvating ligands and possessing excellent solubility in hydrocarbon solvents, these compounds open up a new gateway for the synthesis of inverse crowns. X-ray crystallography established that [KMg(TMP)2nBu] exists in three polymorphic forms, namely a helical polymer with an infinite KNMgN chain, a hexamer with a 24-atom (KNMgN)6 ring having endo-disposed alkyl substituents, and a tetramer with a 16-atom (KNMgN)4 ring also having endo-disposed alkyl substituents. Proving their validity as pre-inverse-crowns, both magnesiates react with benzene and toluene to generate known inverse crowns in syntheses much improved from the original, supporting the idea that the metallations take place via a template effect. [KMg(TMP)2nBu] reacts with naphthalene to generate the new inverse crown [KMg(TMP)2(2–C10H7)]6, the molecular structure of which shows a 24-atom (KNMgN)6 host ring with six naphthalene guest anions regioselectively magnesiated at the 2-position. An alternative unprecedented 1,4-dimagnesiation of naphthalene was accomplished via [NaMg(TMP)2nBu] and its NaTMP co-complex “[NaMg(TMP)2nBu]·NaTMP”, manifested in [{Na4Mg2(TMP)4(2,2,6-trimethyl-1,2,3,4-tetrahydropyridide)2}(1,4-C10H6)]. Adding to its novelty, this 12-atom (NaNNaNMgN)2 inverse crown structure contains two demethylated TMP ligands as well as four intact ones. Reactivity studies show that the naphthalen-ide and -di-ide inverse crowns can be regioselectively iodinated to 2-iodo and 1,4-diiodonaphthalene respectively.

Isolation and characterisation of the mixed-metal alkyl amide [(TMEDA)Na(μ-Bu)(μ-TMP)Mg(TMP)], an unexpected chelate-trapped intermediate in the formation of inverse crowns

Only two-fold amination occurs when 3 molar equivalents of TMPH are offered to a 1:1 BuNa-Bu2Mg mixture; adding TMEDA gives the mixed alkyl amide [(TMEDA)Na(mu-Bu)(mu-TMP)Mg(TMP)], which itself affords the phenyl-bridged analogue when reacted with benzene.

Mixed lithium amide–lithium halide compounds: unusual halide-deficient amido metal anionic crowns

Alkali metal halide salts can dramatically influence the reactivity/selectivity of organic transformations in either beneficial or detrimental ways.1 In many circumstances, the metal halide salt formed in situ in a metathesis reaction is dismissed as an innocent by-product. Recently, more cases have come to light where lithium halides affect organometallic reactions in a non-innocent, often dominant way. Knochel et al. has exploited this effect by adding stoichiometric amounts of LiCl to conventional Grignard or Hauser reagents to induce an enhanced reactivity with respect to that of monometallic magnesium reagents.2 Collum et al. presented the surprising and profound role that LiCl plays in a series of deprotonation3 and addition reactions,4 establishing that LiCl catalysis is detectable with miniscule quantities of LiCl, and that “striking accelerations” (70 fold) are elicited by less than 1.0 mol % LiCl for 1,4-addition reactions of lithium diisopropylamide to unsaturated esters.4 Despite this, firm structural evidence of the crucial halide-incorporated species that may be involved in these reactions is rare.1h, 5 In one example, we recently synthesized and characterized the magnesiate [(thf)2Li(μ-Cl)2Mg(TMP)(thf)] and found that it functions identically to Knochel’s in situ Grignard system (TMP=2,2,6,6-tetramethylpiperidide).6

Building an extended inverse crown motif via alkali-metal-mediated α-magnesiation of furan

deprotonated selectively at the -position by the mixed-metal alkyl-amido base [(TMEDA) x Na(Bun)(TMP)Mg(TMP)] to generate a transient intermediate which undergoes disproportionation to the disodium dimagnesium hexafuryl tri(thf) complex [{{(thf)3 x Na2}{(TMEDA) x Mg2}(2-C4H3O)6}infinity], a new type of inverse crown structure with triply-stabilized (through Mg-C , Na-O and Na...C-C interactions) furyl guest anions, and the tris(amide) [(TMEDA)x.NaMg(TMP)3].

Sodium-mediated magnesiation of thiophene and tetrahydrothiophene: structural contrasts with furan and tetrahydrofuran

Sulfur-containing heterocycles are currently attracting a great deal of interest in several diverse fields. For instance, substituted tetrahydrothiophenes[1] have received considerable attention due to their extremely wide-ranging chemical and biological applications.[2] These include their use as potent a-glucosidase inhibitors,[3] as an inhibitor of copper amine oxidases[4] and as selective A3 agonists and antagonists.[5] In addition, they have been utilised in chemical transformations, such as catalytic asymmetric epoxidation, catalytic intramolecular cyclopropanation, and asymmetric metal catalysis hydrogenation.[6] From a nanochemical perspective, the adsorption chemistries and physical properties of various thiophenes and tetrahydrothiophenes on gold surfaces have recently come to the fore.[7] Polythiophenes are also key compounds in modern materials research, currently utilised in, for example, the fabrication of semi-conducting, fluorescent, and electronic and optoelectronic materials.[8]In this work, metallation (exchange of a hydrogen atom with a metal atom) of the parent heterocycles, tetrahydrothiophene (THT) and thiophene is considered. Metallation is one of the most fundamental reactions in modern day synthesis and is a key tool in the preparation of functionalised aromatic and heterocyclic compounds. It is usually achieved by the utilisation of commercially accessible organolithiums (or lithium amides); however, these reactions do have their drawbacks, including the intolerance of certain functional groups, the need for cryoscopic temperatures and the inadvertent reactivity with polar reaction solvents.

Isolation and characterisation of a (−)-sparteine coordinated mixed alkyl/amido sodium magnesiate, a chiral variant of an important utility ate base

When a 1:1 nBuNa-n,sBu2Mg mixture is treated with two molar equivalents of TMP(H) (TMP=2,2,6,6-tetramethylpiperidide) and one molar equivalent of (-)-sparteine in hydrocarbon medium, a new chiral mixed-metal, mixed alkyl-amide [{(-)-sparteine}.Na(micro-Bu)(micro-TMP)Mg(TMP)] can be isolated.

Evaluating cis-2,6-dimethylpiperidide (cis-DMP) as a base component in lithium-mediated zincation chemistry.

Most recent advances in metallation chemistry have centred on the bulky secondary amide 2,2,6,6-tetramethylpiperidide (TMP) within mixed metal, often ate, compositions. However, the precursor amine TMP(H) is rather expensive so a cheaper substitute would be welcome. Thus this study was aimed towards developing cheaper non-TMP based mixed-metal bases and, as cis-2,6-dimethylpiperidide (cis-DMP) was chosen as the alternative amide, developing cis-DMP zincate chemistry which has received meagre attention compared to that of its methyl-rich counterpart TMP. A new lithium diethylzincate, [(TMEDA)LiZn(cis-DMP)Et2] (TMEDA=N,N,N′,N′-tetramethylethylenediamine) has been synthesised by co-complexation of Li(cis-DMP), Et2Zn and TMEDA, and characterised by NMR (including DOSY) spectroscopy and X-ray crystallography, which revealed a dinuclear contact ion pair arrangement. By using N,N-diisopropylbenzamide as a test aromatic substrate, the deprotonative reactivity of [(TMEDA)LiZn(cis-DMP)Et2] has been probed and contrasted with that of the known but previously uninvestigated di-tert-butylzincate, [(TMEDA)LiZn(cis-DMP)tBu2]. The former was found to be the superior base (for example, producing the ortho-deuteriated product in respective yields of 78 % and 48 % following D2O quenching of zincated benzamide intermediates). An 88 % yield of 2-iodo-N,N-diisopropylbenzamide was obtained on reaction of two equivalents of the diethylzincate with the benzamide followed by iodination. Comparisons are also drawn using 1,1,1,3,3,3-hexamethyldisilazide (HMDS), diisopropylamide and TMP as the amide component in the lithium amide, Et2Zn and TMEDA system. Under certain conditions, the cis-DMP base system was found to give improved results in comparison to HMDS and diisopropylamide (DA), and comparable results to a TMP system. Two novel complexes isolated from reactions of the di-tert-butylzincate and crystallographically characterised, namely the pre-metallation complex [{(iPr)2N(Ph)C=O}LiZn(cis-DMP)tBu2] and the post-metallation complex [(TMEDA)Li(cis-DMP){2-[1-C(=O)N(iPr)2]C6H4}Zn(tBu)], shed valuable light on the structures and mechanisms involved in these alkali-metal-mediated zincation reactions. Aspects of these reactions are also modelled by DFT calculations.

Transamination chemistry of sodium TMP-zincate: synthesis and crystal structure of a chiral amidozincate

In a new type of reactivity for sodium TMP-zincate [(TMEDA)NaZn((t)Bu)(2)(TMP)] (1), transamination reactions with the amines diisopropylamine, DA(H), hexamethyldisilazane, HMDS(H) and chiral (R)-N-benzyl-alpha-methylbenzylamine have produced new sodium amido-di-tert-butyl zincates (all structurally characterised) with concomitant loss of TMP(H).