Ortho lithiation of 2-, 3-, and 4-methoxypyridines

The ortho lithiation of 2-,3-, and 4-methoxypyridine was effected using mesityllithium as the metalating base.     

Preparation of 2-, 3-, 4- and 7-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans and their BLT1 and/or BLT2 inhibitory activities

Several 2-alkylcarbamoyl-1-alkylvinylbenzo[b]furans were designed to find a selective leukotriene B4 (LTB4) receptor antagonist. 2-(2-Alkylcarbamoyl-1-alkylvinyl)benzo[b]furans having a substituent group at the 3-position, 4-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans having a substituent group at the 3-position, and 7-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans and 3-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans were prepared and evaluated for LTB4 receptor (BLT1 and BLT2) inhibitory activities. (E)-3-Amino-4-[2-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-1-methylvinyl]benzo[b]furan ((E)-17c) showed potent and selective inhibitory activity for BLT2. On the other hand, (E)-7-(2-diethylcarbamoyl-1-methylvinyl)benzo[b]furan ((E)-27a) showed potent inhibitory activity for both BLT1 and BLT2.     

Syntheses of 3-acetoacetylaminobenzo[b]furan derivatives having cysteinyl leukotriene 2 receptor antagonistic activity

Novel 3-acetoacetylaminobenzo[b]furan derivatives having a modified triene system at the 3-position were synthesized starting with 3-aminobenzo[b]furans. The enol isomers, 3-[(3-hydroxybut-2-enonyl)amino]benzo[b]furans (), of the 3-acetoacetylaminobenzo[b]furans were obtained as stable isomers owing to formation of a hydrogen bonding between the enol hydroxyl group and the amidocarbonyl group. The planarity of the C-2 substituent through the C-3 side chain suggested the existence of a modified conjugational triene system in the enol compound. Cysteinyl leukotriene 1 and 2 receptor antagonistic activities for these compounds were evaluated. 2-(4-Cyanobenzoyl or ethoxycarbonyl)-3-[(2-cyano-3-hydroxybut-2-enonyl)amino]benzo[b]furans (, ) were moderately active.     

CNDO/II treatment of proton abstraction step in aromatic lithiation reaction

All valence MO calculation employing CNDO/II treatment for hydrogen abstraction step in aromatic ortho lithiation reaction is done. The predicted proton abstraction is supported by experimental observation. The lithiation of N-methyl-β-naphthamide occurs at the 1 position and not at the 3 position.     

Preparation of 1,3-disubstituted isoquinoline derivatives from N-boc-3-substituted-1,2-dihydroisoquinolines

3-Substituted N-Boc-1,2-dihydroisoquinolines 2 can be functionalized at the 1-position via lithiation and subsequent electrophilic trapping. The resulting products 3 can be deprotected and oxidized to afford the corresponding 1,3-disubstituted isoquinolines 5 . Deprotection of dihydroisoquinoline 3k followed by sodium borohydride reduction affords the cis-1,3-disubstituted tetrahydroisoquinoline 11 . The 1,3-disubstituted N-Boc-1,2-dihydroisoquinoline 3g is efficiently alkylated at the 1-position to give 1,1,3-trisubstituted analogs 12 .     

New synthesis of 2-aryl-3-substituted benzo[b]furans from benzyl 2-halophenyl ethers

Treatment of benzyl 2-halophenyl ethers with 3 equiv of t-BuLi results in Li-halogen exchange and lithiation at benzylic methylene simultaneously. These dianions do not undergo Wittig rearrangement and can be trapped with electrophiles. Their reactions with carboxylic esters afford the corresponding 2-aryl-3-hydroxy-2,3-dihydrobenzo[b]furans as a mixture of diastereoisomers. Subsequent acid-catalyzed or mediated dehydration gives moderate to good overall yield of a variety of 2-aryl-3-substituted benzo[b]furans.     

Preparation of 3-acetoacetylaminobenzo[b]furan derivatives with cysteinyl leukotriene receptor 2 antagonistic activity

Novel 3-acetoacetylaminobenzo[b]furan derivatives with a modified triene system at the 3-position were prepared through acylation of the 3-aminobenzo[b]furans with 5-methylisoxazole-4-carboxylic acid chloride followed by basic cleavage of the isoxazole ring and several of these compounds showed moderate cysteinyl leukotriene receptor 2 antagonistic activity.     

A new and efficient synthesis of 4-functionalized benzo[b]furans from 2,3-dihalophenols

Tandem Sonogashira coupling/5-endo-dig cyclization reactions on 2,3-dihalophenols suppose a straightforward entry to 4-halobenzo[b]furans, which can be easily transformed into 4-functionalized benzo[b]furans, that are difficult to synthesize by other procedures. On the other hand, the starting 2,3-dihalophenols are efficiently prepared from commercially available 3-halophenols, via their N,N-diethyl carbamates by selective lithiation at the 2-positions by treatment with s-BuLi/TMEDA or LDA at low temperature and reaction with halogen electrophilic reagents.     

Synthesis of some 4-substituted and 4,6-disubstituted dibenzothiophenes

The synthesis is described of various 4-substituted ( 1 ) and 4,6-disubstituted ( 2 ) dibenzothiophenes by lithiation reactions. The factors controlling the formation of 4,6-disubstituted dibenzothiophenes by the lithiation of 4-methyl- and 4-ethyl-dibenzothiophene at the 6-position versus lithiation at the α-carbon of the 4-substituent are examined.     

Lithiation of 1-alkyl-1H-1,2,4-triazol-5-yl phosphonic acid esters: Novel anion-mediated carbon-to-carbon phosphonate migrations

The lithiation chemistry of 1-alkyl-1H-1,2,4-triazol-5-yl phosphonic acid esters 3 has been investigated. Lithiation occurs exclusively on the 1-alkyl group, α to nitrogen, to give carbanionic intermediates 10 . No evidence was found for any lithiation at the 3-position of the triazole ring. On warming, intermediates 10 undergo an unusual anion-mediated phosphonate migration, giving rise to 1H-1,2,4-triazol-1-yl-methylphos-phonates 14 .     

A new efficient route to 2-substituted azulenes based on sulfonyl group directed lithiation

Directed lithiation of p-tolyl 1-azulenyl sulfone (1) at the 2-position of the azulenyl group was achieved by using lithium 2,2,6,6-tetramethylpiperidide (LTMP). The azulenyllithium thus generated could be efficiently trapped with various electrophiles to form 2-substituted derivatives 2 in moderate to good yields. p-Tolyl 2-trimethylsilyl-1-azulenyl sulfone (2a) was transformed into cyclic sulfone derivative 3a through the directed lithiation in the p-tolyl group and subsequent intramolecular ring closure at the 8-position. 2-(Phenylsulfanyl)-1-azulenyl p-tolyl sulfone (2b) suffered from desulfonylation to form 2-phenylsulfanylazulene (4). The Suzuki coupling reaction of 2-iodo-1-azulenyl p-tolyl sulfone (2d) with arylboronic acids followed by desulfonylation efficiently gave 2-arylazulenes 10.     

Nucleophilic alkylations of 3-nitropyridines

3-Nitropyridine and 4-substituted-3-nitropyridines were reacted with chloroform, methyl chloroacetate and ethyl 2-chloropropionate under vicarious nucleophilic substitution (VNS) conditions. Substitution was obtained in the ortho or para position to the nitro group with acceptable to good yields and regioselectivity. With potassium 5-nitropyridine-2-sulfonate the substitution took place in the 4-position. Further substitution of the sulfonate group proved to be possible.     

2-Oxazolines as activating groups towards metallation and stabilising groups against polymerization in N-substituted pyrroles

Benzaldehyde is shown to be a more suitable electrophile than carbon dioxide in reactions involving the lithio derivatives of 2-(N-methylpyrrol-2-yl) oxazolines. The relative reactivities of the C3-Li and C5-Li bonds in ethereal solvents are examined. The 2-oxazolino group at a 2-position in N-substituted pyrrole is shown to possess an activating effect on the 5-position towards lithiation, and eliminates the propensity of the pyrrole nucleus towards polymerisation. The conditions for removal of the 2-protecting group are explored.     

On the orientation in lithiation and bromination of dithieno[3,4-b:3′,2′-d]pyridine

The 3-position of dithieno[3,4-b:3′,2′-d]pyridine was found to be most reactive with regard to lithiation, bromination and halogen-metal exchange. The lithium compounds were trapped as the formyl derivatives by reaction with N,N-dimethylformamide.     

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.     

A simple and efficient method for synthesis of 5-substituted 2'-deoxyuridine nucleosides using metal-halogen exchange reaction of 5-iodo-2'-deoxyuridine sodium salt

Treatment of the sodium salt of 2'-deoxy-3', 5'-bis-O-(tert-butyldimethylsilyl)-5-iodouridine (3) with n-BuLi effected regioselective lithiation at the 5-position and the following reaction with various electrophiles afforded 5-substituted 2'-deoxyuridines including 1b, the precursor of stable spin-labeled 1a, in good yields.     

Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

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 Ph₃BiF₂ 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. Subsequent ortho ‐lithiation and borylation gave the coupled product, again with complete stereospecificity.     

Synthesis of potential fungicides based on N-(3-furanyl)pyrrolecarboxamides and N-(3-furanyl)pyrazolecarboxamides

Abstract  

An efficient synthesis of novel N-(3-furanyl)pyrrolecarboxamides and N-(3-furanyl)pyrazolecarboxamides is presented starting from furan-3-carboxylic acid. Two complementary strategies to 2-aryl-3-furanamines with directed ortho lithiation, functionalization of the 2-position, and subsequent cross-coupling reaction as key steps were developed. Acylation of these intermediates with appropriate acid chlorides led finally to the target compounds.     

Regioselective lithiation and functionalization of 3-(benzyloxy)isothiazole: application to the synthesis of thioibotenic acid

Direct functionalization of the 3-oxygenated isothiazole heteroaromatic parental system has not yet been reported in the literature. Here, we report the first regioselective lithiation of the 5-position of 3-(benzyloxy)isothiazole (4) using LDA in diethyl ether. The versatility of the methodology was explored by quenching with a variety of electrophiles to give the desired products 7a,b,d-g in 54-68% yield. Only benzoylation aiming at the synthesis of 7c was unsuccessful. Furthermore, a highly convergent synthesis of thioibotenic acid (1), the sulfur analogue of the neurotoxic natural product ibotenic acid, was carried out.     

The trifluoromethoxy group: a long-range electron-withdrawing substituent

Judged by its capacity to promote a hydrogen/metal permutation at an ortho position, the trifluoromethoxy group is superior to both the methoxy and trifluoromethyl groups. Moreover, like CF(3) and unlike OCH(3), OCF(3) exerts a long-range effect that still considerably lowers the basicity of arylmetal compounds when located in a more remote meta or even para position. As a consequence, 4-(trifluoromethoxy)anisole is deprotonated by sec-butyllithium mainly, and by tert-butyllithium exclusively, at a position adjacent to the OCH(3) group rather than next to the strongly electron-withdrawing CF(3)O group. 1,3-Benzodioxole undergoes ortho lithiation only six times faster than anisole, whereas 2,2-difluoro-1,3-benzodioxole reacts about 5000 times faster, as evidenced by competition experiments. The structure and distance dependence of substituent effects can be rationalized by assuming superposing sigma- and pi-polarizing interactions.