Regioselective Ortho-lithiation Research Articles

Highly regioselective lithiation of pyridines bearing an oxetane unit by n-butyllithium.

The first regioselective ortho-lithiation at the 4-position of simple pyridine derivatives containing a 3-oxetane unit has been achieved using n-butyllithium as base. Electrophilic quenching of the resulting lithio species provides a rapid access to a broad range of new functionalized pyridine oxetane building blocks.

Exploiting the Lithiation‐Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2‐Aryloxetane Scaffolds under Mild Conditions

Oxetane nudges in the DoM direction! Regioselective ortho-lithiation induced by an oxetane ring has been achieved. The reaction provides easy access to ortho-functionalized 2-aryloxetanes also through a lithiation/borylation Suzuki–Miyaura cross-coupling. The lithiation-directing ability of oxetane and the proton transfer mechanism have been investigated by competitive metalation and kinetic isotope effect studies.

A convenient synthesis of cyclopenta[b]pyridin-2,5-dione as a non- glycosidic cardiotonic agent

A straightforward synthesis of cyclopenta(b)pyridin-2,5-dione is reported starting from the commercially available 2-bromo-6-methoxypyridine. The overall route consists in a first sequence of regioselective ortho lithiation and methoxycarbonylation followed by Heck vinylation, alkene reduction, cyclization and decarboxylation.

First regioselective ortho-lithiation induced by a 2-chloropyridyl group complexation.

It is shown that t-BuLi in Et(2)O promotes an exclusive regioselective metalation of 2-aryl-6-chloropyridine compounds at the aromatic ortho position demonstrating that the 2-chloropyridyl moiety may be considered as a directing group. This functionally directed metalation group was successfully used for the selective lithiation of substituted aromatics and for the straightforward preparation of new N,P ligands.

Synthesis of novel halopyridinylboronic acids and esters. Part 2: 2,4, or 5-Halopyridin-3-yl-boronic acids and esters

This paper describes a general method for the synthesis and the isolation of novel 2,4, or 5-halopyridin-3-yl-boronic acids and esters 4 , 7 , 10 , 13 , 15 . These compounds are prepared taking into account a regioselective halogen–metal exchange using nBuLi or a regioselective ortho-lithiation using lithium diisopropylamide and subsequent quenching with triisopropylborate starting from appropriate mono or dihalopyridines. All substrates studied to date provided a single regioisomeric boronic acid or ester product. Additionally, these compounds have been found to undergo Pd-catalyzed coupling with a range of arylhalides and authorize a strategy to produce new pyridines libraries.

Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

A highly convergent, asymmetric synthesis of L-768,673, an I ks Class III antiarrythmic drug candidate, is described. Synthesis of the recemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(±)-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolution-racemization of (±)-amine provided the desired (±)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)benzene with n-BuLi in the presence of a catalytic amount of 2,2′,6,6′-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.

Reaction of organolithiums with fluoro-N,N-diallylanilines: A benzyne-mediated anionic cascade leading to 3,4-disubstituted indolines

Regioselective ortho-lithiation of either 2-fluoro- ( 2) or 3-fluoro-N,N-diallylaniline ( 3) initiates an anionic cascade leading to an N-allyl-3,4-disubstituted indoline. The transformation involves loss of LiF from the ortho-lithiated species, regioselective intermolecular addition of the organolithium to the benzyne intermediate, and cyclization of the resulting [6-substituted-2-(N,N-diallylamino)phenyl]lithium.

Regioselective ortho-lithiation of chloro and bromo substituted fluoroarenes

Deprotonation of fluoroarenes carrying chlorine or bromine as additional substitutents occurs always at a fluorine adjacent position if accomplished with potassium tert-butoxide activated butyllithium or lithium 2,2,6,6-tetramethylpiperidide.

Studies of the New Herbicide KIH-6127. Part I. Novel Synthesis of Methyl 6-Acetylsalicylate as a Key Synthetic Intermediate for the Preparation of 6-Acetyl Pyrimidin-2-yl Salicylates and Analogues

A novel synthesis of methyl 6-acetylsalicylate as a key synthetic intermediate for methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-(methoxyimino) ethyl]benzoate (KIH-6127) was studied, and directed at 6-substituted pyrimidin-2-yl salicylate herbicides and their analogues. Three synthetic approaches were successful : a modification of the Sandmeyer reaction of 6-acetylanthranilate (Method A), a direct ring-opening reaction of 3-methylphthalide using potassium permangamate and magnesium nitrate (Method B), and a regioselective ortholithiation of the protected 3-hydroxyacetophenone (Method C). These methods were applicable for the synthesis of various 6-acyl salicylates.

A Practical Synthesis of 6-Acetylsalicylic Acid Methyl Ester

Abstract A new and efficient synthesis of the title compound is reported. The method includes a regioselective ortho-lithiation step in none polar solvents at an ambient temperature and the overall yield for 5 steps is more than 70% from a commercially available 3-hydroxyacetophenone.

Regioselective ortho-Lithiation of Halopyridines. Syntheses of ortho-Disubstituted Pyridines and a Convenient Generations of 3,4-Pyridyne

The regioselective ortho-lithiation of 3-chloro (4), 3-fluoro (7), 3-bromo- (10), 2-chloro- (22), and 4-chloropyridine (25) with lithium diisopropylamide affords, after quenching with various electrophiles, the corresponding ortho-disubstituted pyridines in yields from 16-96%. Halogen-metal exchange between 4-iodo-3-chloropyridine (6a) and tert-butyllithium or n-butyllithium provides a convenient generation of 3,4-pyridyne (1), which is trapped in a Diels-Alder reaction with furan and 2,5-dimethylfuran to give 31 and 32 (24-38%)

ChemInform Abstract: tert‐Butyldimethylsilyl Ethers of Phenols: Their One‐Step Conversion to Benzyl or Methyl Ethers and Utility in Regioselective ortho Lithiation.

AbstractThe silyl phenol ethers (I), (IV), and (VIa) are allowed to react with the alkyl halides (II) in the presence of potassium fluoride to produce the corresponding methyl or benzyl ethers (III), (V), or (VIb).

Formula omitted]-Butyldimethylsilyl ethers of phenols: Their one-step conversion to benzyl or methyl ethers and utility in regioselective [formula omitted] lithiation

A new method for the one-step conversion of tert -butyldimethylsilyl ethers of phenols to benzyl or methyl ethers and the blocking effect of the tert -butyldimethylsilyloxy group in regioselective ortho lithiation are described.

Synthesis of (±)-sesbanine via directed metalation of tertiary nicotinamides

Racemic sesbanine was synthesized by using regioselective ortho lithiation of N,N-dialkylnicotinamides and subsequent condensation with 3-cyclopentenone as key reactions.

Review on the metallation of π -deficient heteroaromatic compounds : Regioselective ortho-lithiation of 3-fluoropyridine: Directing effects and application to synthesis of 2,3- or 3,4-disubstituted pyridines

Metallation of π-deficient heterocyclic compounds is first reviewed, which shows the important recent developments in this research area. A particular aspect of this reaction is then given with the study of the 3-fluoropyridine metallation regioselectivity. Lithiation of 3-fluorophyridine is chemoselective at low temperatures using butyllithium-polyamine chelates or lithium diisopropylamide. Protophilic attack by these strong bases can be directed either at the 2- or 4-position depending on the lithiation conditions. Various reaction parameters are thus studied such as solvent, temperature, reaction time, lithium-chelating agent as well as metallating agent. The high regioselectivity of 3-fluoropyridine lithiation is theoretically discussed, in particular in terms of kinetic of thermodynamic control of the metallation. Chelation between butyllithium and 3-fluoropyridine is proposed, which completely modifies the heterocycle reactivity toward the lithiating agent. This is confirmed by theoretical quantum calculations performed on different models of 3-fluoropyridine using the CNDO/2. These results allow to select the best 3-fluoropyridine-metallation conditions which lead to 3-fluoro-2-lithiopyridine on the one hand and to 3-fluoro-4-lithiopyridine on the other hand. Each of the lithiated isomers is then reacted with a great variety of electrophiles which gives very conveniently the corresponding 2,3- or 3,4-disubstituted pyridines.

Regioselective ortho lithiation of halopyridines

Regioselective ortho lithiation of 2-, 3-, and 4-halopyridines is achieved with lithium diisopropylamide (−78°, tetrahydrofuran) to afford, upon quenching with electrophilic reagents, 2,3- and 3,4-disubstituted pyridines in good to excellent yield.