Ortholithiation

The first crystal structure of an ortho-lithium phosphinothioic amide complexed with tetramethylethylenediamine 12 is reported. The complex consists of a spirane in which the spirolithium is N,N- and C,S-chelated by the diamine and organophosphorus ligands, respectively. The analogous ortho anion 14 obtained by Sn(IV)/Li transmetallation in THF has also been synthesized. Nuclear magnetic resonance study of both anions showed that they exist as monomers in solution and are involved in dynamic processes including the restricted rotation around the P-N bond...

Rate and mechanistic studies of ortholithiations by lithium 2,2,6,6-tetramethylpiperidide focus on four arenes: 1,4-bis(trifluoromethyl)benzene, 1,3-bis(trifluoromethyl)benzene, 1,3-dimethoxybenzene, and 4,4-dimethyl-2-phenyl-2-oxazoline. Metalations occur via substrate-dependent combinations of monosolvated monomer, disolvated monomer, and tetrasolvated dimer (triple ions). Density functional theory computational studies augment the experimental data. We discuss the challenges presented by shifting dimer-monomer proportions in determining the observable reaction orders and our mathematical treatment of such shifting in reactant structure...

The coupling of ortho- and para-phenols with secondary and tertiary boronic esters has been explored. In the case of para-substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3 BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (-)-4-(1,5-dimethylhex-4-enyl)-2-methyl phenol. For ortho-substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required...

[This corrects the article DOI: 10.3762/bjoc.10.291.].

Full details on the design, development, and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortho lithiation with aldehyde electrophiles and utilizes the chiral memory of a preoriented atropisomeric amide axis for stereocontrol. For direct transformation of sterically hindered amides to isochromanones, efficient and mild one-pot protocols involving either O-alkylation or acidic microwave activation were developed. The procedures may be applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high protective group tolerance...

Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis and utilizes a predictive enoylreductase alignment, and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account of our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented...

Lithiation of 1,4-bis(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran at -78 °C occurs under conditions at which the rates of aggregate exchanges are comparable to the rates of metalation. Under such nonequilibrium conditions, a substantial number of barriers compete to be rate limiting, making the reaction sensitive to trace impurities (LiCl), reactant concentrations, and isotopic substitution. Rate studies using the perdeuterated arene reveal odd effects of LiCl, including catalyzed rate acceleration at lower temperature and catalyzed rate inhibition at higher temperatures...

The diastereoselective oxazoline-directed lithiation of calix[4]arenes is reported with diastereoselective ratios of greater than 100:1 in some instances. Notably, it has been found that the opposite diastereomer can be accessed via this approach merely through the choice of an alkyllithium reagent. The inherently chiral oxazoline calix[4]arenes have also been preliminarily examined as ligands in the palladium-catalyzed Tsuji-Trost allylation reaction, returning results comparable to their planar chiral ferrocene counterparts pointing towards future application of these types of compounds...

Lithiation of 1,4-difluorobenzene with lithium diisopropylamide (LDA) in THF at -78 °C joins the ranks of a growing number of metalations that occur under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. As such, a substantial number of barriers vie for rate limitation. Rate studies reveal that rate-limiting steps and even the choice of reaction coordinate depend on subtle variations in concentration. Deuteration shifts the rate-limiting step and markedly alters the concentration dependencies and overall rate law...

The sense of asymmetric ortholithiation directed by a chiral oxazoline may be inverted simply by the choice of achiral ligand. Comparison of results with a number of ferrocenyl oxazoline derivatives suggests that lithiation takes place by coordination to the oxazoline nitrogen irrespective of the ligand used.

Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at -78 °C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Autocatalysis stems from ArLi-catalyzed deaggregation of LDA proceeding via 2:2 LDA-ArLi mixed tetramers...

The stereochemical determination of the potent respiratory chain inhibitors ajudazols A and B and the total synthesis of ajudazol B are reported. Configurational assignment was exclusively based on biosynthetic gene cluster analysis of both ketoreductase domains for hydroxyl-bearing stereocenters and one of the first predictive enoylreductase alignments for methyl-bearing stereocenters. The expedient total synthesis resulting in unambiguous proof of the predicted stereochemistry involves a short stereoselective approach to the challenging isochromanone stereotriad by an innovative asymmetric ortholithiation strategy, a modular oxazole formation, and a late-stage Z,Z-selective Suzuki coupling...

Several late transition metal and main group orthometallated imine complexes were synthesized by utilizing ortholithiated imine precursors. Magnesium, aluminum, zinc, copper(I), and tin(IV) complexes were isolated and characterized. Subsequent reactions with electrophiles such as Ph(2)PCl, MeI and I(2) yielded several functionalized products, including a new iminophosphine ligand and its corresponding copper(I) complex. The coordination modes of the orthometallated imine ligands, as well as the structures of the metal complexes, were studied in the solid state using small molecule X-ray diffraction when possible...

Ortholithiation of 1-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C displays characteristics of reactions in which aggregation events are rate limiting. Metalation with lithium-chloride-free LDA involves a rate-limiting deaggregation via dimer-based transition structures. The post-rate-limiting proton transfers are suggested to involve highly solvated triple ions. Autocatalysis by the resulting aryllithiums or catalysis by traces (<100 ppm) of LiCl diverts the reaction through di- and trisolvated monomer-based pathways for metalation at the 2 and 6 positions, respectively...

Employing a chiral oxazoline as an ortholithiation directing group allows the synthesis of inherently chiral calix[4]arenes suitable for elaboration into planar chiral molecules. An important finding has been that the diastereoselectivity of the reaction can be tuned by the choice of additive. These results have bearing on the elucidation of the general mechanism of oxazoline-directed ortholithiation.

Polyhalogenated 4,4'-bipyridines were conveniently synthesized in a single step starting from dihalopyridines. A mechanism was proposed on the basis of experiments performed with 2-chloro-5-bromopyridine 1a. 2-Chloro-4-lithio-5-bromopyridine A1 was produced via ortholithiation of 1a by using either LDA or t-BuLi bases. When LDA was used, dimer 3a containing two chlorines and two bromine atoms was formed predominantly accompanied by several byproducts whose structure and mechanism of formation are discussed...

Treatment of 2,6-difluoropyridine with lithium diisopropylamide in THF solution at -78 degrees C effects ortholithiation quantitatively. Warming the solution to 0 degrees C converts the aryllithium to 2-fluoro-6-(diisopropylamino)pyridine. Rate studies reveal evidence of a reversal of the ortholithiation and a subsequent 1,2-addition via two monomer-based pathways of stoichiometries [ArH*i-Pr(2)NLi(THF)](double dagger) and [ArH*i-Pr(2)NLi(THF)(3)](double dagger). Computational studies fill in the structural details and provide evidence of a direct substitution without the intermediacy of a Meisenheimer complex...

A general asymmetric synthesis of inherently chiral calix[4]arenes is described: using a chiral oxazoline derived from L-valine, an ortholithiation strategy is employed to give inherently chiral calix[4]arenes with high (93%) enantiomeric excesses. A crystal structure of a phosphine oxide intermediate has been obtained, unambiguously assigning the major diastereomer in the reaction; a mechanism explaining this result is proposed.

Ortholithiations of a range of arenes mediated by lithium diisopropylamide (LDA) in THF at -78 degrees C reveal substantial accelerations by as little as 0.5 mol % of LiCl (relative to LDA). Substrate dependencies suggest a specific range of reactivity within which the LiCl catalysis is optimal. Standard protocols with unpurified commercial samples of n-butyllithium to prepare LDA or commercially available LDA show marked batch-dependent rates--up to 100-fold--that could prove significant to the unwary practitioner...

Ortholithiation of 3-fluorophenyl-N,N-diisopropyl carbamate by lithium diisopropylamide (LDA) in THF at -78 degrees C affords unusual rate behavior including linear decays of the carbamate, delayed formation of LDA-aryllithium mixed dimers, and evidence of autocatalysis. A mechanistic model in conjunction with numeric integration methods accounts for the time-dependent changes in concentration. The two critical rate-limiting steps in the model entail (1) an LDA dimer-based metalation of arylcarbamate, and (2) a rate-limiting condensation of the resulting aryllithium with the LDA dimer to form two isomeric LDA-ArLi mixed dimers...