Regioselective Lithiation Research Articles

Synthesis of Pinacol Esters of 1‐Alkyl‐1H‐pyrazol‐5‐yl‐ and 1‐Alkyl‐1H‐pyrazol‐4‐ylboronic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective lithiation of aryl benzyl ethers

The lithiation of a series of aryl benzyl ethers containing –F and –OMe groups has been studied. It was found that the presence of one or two fluorine atoms in the meta position relative to the oxygen atom prevents the lithiation at the benzyl carbon atom. 3-(3′,5′-Dimethoxybenzyloxy)fluorobenzene was lithiated and next reacted with DMF to give 2-(3′,5′-dimethoxybenzyloxy)-6-fluorobenzaldehyde. A three-step procedure was applied to remove three hydrogen atoms from 1,3-difluoro-5-(3′,5′-dimethoxybenzyloxy)benzene and replace them with methyl groups by reactions of the lithiated compounds with MeI.

Regioselective Lithiation of Chiral 3‐Acylamino‐2‐alkylquinazolin‐4(3H)‐ones: Application in Synthesis.

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Synthesis of pinacol esters of 1‐alkyl‐1H‐pyrazol‐5‐yl‐ and 1‐alkyl‐1H‐pyrazol‐4‐ylboronic acids

AbstractStarting from 1H‐pyrazol, a wide number of 1‐alkyl‐1H‐pyrazol‐4‐yl and 1‐alkyl‐1H‐pyrazol‐5‐ylboronic acids and their pinacol esters were synthesized and characterized. The key step in the described methodology is the regioselective lithiation of the pyrazole ring. The synthesized pinacolates are stable under prolonged storage and can be used as convenient reagents in organic synthesis.

Stabilised 2,3‐Pyridyne Reactive Intermediates of Exceptional Dienophilicity

AbstractThe enhanced dienophilicity of 4‐methoxy, 4‐aryloxy and 4‐thiophenoxy analogues 6−9 of 2,3‐pyridyne (2) relative to 2 itself is reported. The regioselective lithiation of 4‐alkoxy‐ (22, 23 and 25) and 4‐thiophenoxy‐2‐chloropyridine (24) at low temperatures, followed by elimination of lithium chloride affords 4‐alkoxy‐ and 4‐thiophenoxypyridynes, which can be trapped in situ in a [4+2] cycloaddition reaction with furan to give endoxides 28−31 in moderate to good yields (25−58%). In contrast, precursors with a hydrogen (18) or methyl (12) substituent at C‐4 give no evidence for pyridyne formation under these conditions. Attempts to generate 6‐isopropoxy‐2,3‐pyridyne (10) from the low‐temperature lithiation of 2‐chloro‐6‐isopropoxypyridine were unsuccessful due to the instability of the 2‐chloro‐6‐isopropoxy‐5‐lithiopyridine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Regioselective Lithiation of Pyridine Rings

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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.

Synthesis and application to asymmetric allylic amination of substituted monodonor diazaphospholidine ligands

The synthesis of a series of substituted monodonor diazaphospholidine ligands is described. A regioselective lithiation process is a key step in one of these syntheses. The compounds are designed to be incorporated into soluble polymer and other solid phase supports. Enantiomeric excesses of up to 88% were observed when these compounds were employed in palladium-catalysed asymmetric amination reactions.

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.

Efficient Functionalization of Indole Ring via Regioselective Lithiations

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Triazolopyridines 22.1 Description of new 7,9-di(2-pyridyl)[1,2,3]triazolo[5',1':6,1]pyrido[3,2-d]pyrimidines

The new heteroaromatic compounds, 7,9-di(2-pyridyl)(1,2,3)triazolo(5',1':6,1)pyrido(3,2-d) pyrimidines 11a-c, were synthesized in two steps from readily available triazolopyridines 1a-c. Regioselective lithiation of 1a-c followed by treatment with 2-cyanopyridine gave a mixture of compounds 5a-c, and 11a-c in moderate to low yields, together with gums. Similar reactions with the triazolopyridine 1d gave as the only identified compound the triazolopyridine derivative 5d.

ChemInform Abstract: Regioselective Lithiation and Functionalization of 3‐(Benzyloxy)isothiazole: Application to the Synthesis of Thioibotenic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

NMR and calculational studies on the regioselective lithiation of 1-methoxynaphthalene.

1-Methoxynaphthalene (1) undergoes regioselective lithiation in position 2 (n-BuLi/TMEDA) or in position 8 (t-BuLi), respectively. The detected formation of a n-BuLi/1 complex (1:1 n-BuLi/1 mixture) appears to have only minor influence on the regioselectivity (both products are obtained). The exchange of hydrogen atom H2 by deuterium results in a remarkably reduced reaction rate for the lithiation with n-BuLi in THF-d(8). This isotope effect and the formation of the thermodynamically less favorable 2-lithio compound suggest a kinetically controlled mechanism. The lack of an isotope effect for the reaction of 8-deuterio-1-methoxynaphthalene with t-BuLi and the formation of the thermodynamically preferred 8-lithiated product indicate a thermodynamically controlled mechanism. Slow conversion of the 2- into the 8-lithiated species (at higher temperatures) gives further evidence that n-BuLi and t-BuLi afford the kinetically and thermodynamically preferred products, respectively.

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.

位置選択的リチオ化反応を利用したインドール環の効率的官能化

This article reviews the regioselective lithiations of indole derivatives. The C-2 lithiation can be readily achieved by utilizing directed lithiation promoted by a protecting (directing) group on indole nitrogen. The C-3 lithiation has been carried out mainly by halogen-lithium exchange of N-protected 3-bromo (or iodo) indoles. The lithiation at the benzenoid portion of indole has been performed by several unique methods, which are designed by considering the specific properties of indole ring and N-protecting groups. These regioselective lithiations have been nicely applied for the short-step synthesis of a number of indole-containing natural products.

Regioselective Hydroxylation of 2,4-Lutidine: A Practical Synthesis of 4-Hydroxymethyl-2-methylpyridine

A practical synthesis of 4-hydroxymethyl-2-methylpyridine has been developed which makes use of Evans’ regioselective lithiation of readily available 2,4-lutidine and trapping with dimethylformamide.

The Synthesis of the Kynurenamines K1 and K2, Metabolites of Melatonin

An efficient synthesis of the kynurenamines K1 and K2, the major brain and antioxidant metabolites of melatonin 1 is described. Regioselective lithiation of tert-butyl(4-methoxyphenyl) carbamate and iodination provided the (2-iodoaryl)carbamate which when coupled with N-acetyl-propargylamine underwent a Sonogashira reaction. Simultaneous alkyne hydration and N-formyl­ation produced K2, whereas alkyne hydration only, produced K2.

Regioselective lithiations of a pterocarpan skeleton: the first synthesis of (±)-4′-dehydroxycabenegrin A-I

Maackiain O-MOM derivative 3b was regioselectively lithiated at the C-10 position of D-ring and reacted with electrophiles. Regioselective lithiation of the C-10 TMS-substituted derivative 5d , followed by organocopper formation and treatment with prenyl bromide, enabled the desired prenylation at C-4. The obtained compound 6d was employed in the first synthesis of racemic 4′-dehydroxycabenegrin A-I, 4 . Moreover, dialkylation of 3b at the two most reactive sites could be effected through the generation of a dilithiated species. A preliminary result dealing with diethylcarbamate derivative 3c is also shown.

Substituted 3,4-pyridynes: clean cycloadditions

The stabilisation of 3,4-pyridyne (1) by an alkoxy group adjacent to the ring nitrogen is reported. The regioselective lithiation of 2-ethoxy- (14), 2-methoxy- (18), 2-isopropoxy- (19) and 6-isopropoxy- (26) -3-chloropyridines with tert-butyllithium at low temperatures, followed by elimination of lithium chloride affords 2- and 6-alkoxy-3,4-pyridynes. These species are trapped in situ with furan in a Diels–Alder reaction to give 5–8 in 66–89% yield, and do not give products typical of polymerisation or nucleophilic addition to the 3,4-pyridyne intermediates. As a comparison treatment of 3-chloropyridine with furan and LDA gives only 19% of adduct (4). We also report the novel use of the isopropoxy (rather than methoxy) group in these systems, which can act as a heteroatomic electron donating group which inhibits α-lithiation by tert-butyllithium because of its increased steric bulk.

ChemInform Abstract: Regioselective Lithiation of Resorcinol Derivatives: Synthesis of Mono O‐MOM‐ and O‐Benzylresorcinols Prenylated at C‐2 or C‐4 Positions

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.