Regioselective ortho lithiation of 3-aryl and 3-styryl furans

[structure: see text]. An unusual regioselectivity pattern for the ortho lithiation of 3-aryl and 3-styryl furans has been uncovered wherein lithiation occurs preferentially at the sterically encumbered 2-position. The results are attributed, at least in part, to stabilization of the intermediate furyl anion by through-space donation of pi-electron density from the substituent appended at the 3-position to the lithium cation. This ortho lithiation reaction may be applied as a useful synthetic tool for accessing 2,3-disubstituted furans.     

Directed ortho lithiation of N-alkylphenylaziridines

The ortho lithiation-trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides. The importance of the aziridine N-substituent in this DoM reaction is stressed as well. [reaction: see 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.     

TMSCH2Li-LiDMAE: a new nonnucleophilic reagent for C-2 lithiation of halopyridines

A new superbasic reagent has been discovered by combining TMSCH₂Li and LiDMAE in hexane. This reagent was found highly efficient for the C-2 lithiation of sensitive chloro- and fluoropyridines. The metallation occurred chemo- and regioselectively at 0 °C avoiding the nucleophilic addition or substrate degradation commonly obtained with other alkyllithiums even at lower temperatures.     

Regioselective quinazolinone-directed ortho lithiation of quinazolinoylquinoline: practical synthesis of naturally occurring human DNA topoisomerase I poison luotonin a and luotonins B and E

A regioselective quinazolinone-directed ortho lithiation on an adjacent quinoline moiety has been used as a key step for a short, efficient, and practical synthesis of the human DNA topoisomerase I poison luotonin A and luotonins B and E. The quinazolinoylquinoline 5 on treatment with in situ-generated nonnucleophilic mesityllithium furnished the desired dilithiated intermediate 6, which on treatment with formaldehyde followed by Mitsunobu ring closure reaction gave luotonin A (1a) in very good yield. The reaction of dilithiated intermediate 6 with DMF directly furnished luotonin B (1b) in 81% yield. Luotonin B (1b) on methylation with p-TSA/methanol gave luotonin E (1c) in 82% yield.     

Regioselective lithiation of II-(arene)chromium tricarbonyl complexes

Chromium tricarbonyl complexes of 3-methoxybenzyl alcohol and related compounds were selectively lithiated at the 4-position in contrast to the corresponding metal free arene compounds. The resulting 4-lithio complexes were converted to the 4-substituted arene compounds in moderate to excellent yields through the reactions with proper electrophiles and subsequent demetalation.     

Regioselective formylation of 1,3-disubstituted benzenes through in situ lithiation

A facile method of regioselective formylation of disubstituted benzene via in situ deprotonation/metalation using n-BuLi/TMEDA/DIPA has been developed. Effect of different electron withdrawing and electron donating substituents in 1,3-interrelated aromatic system was studied; the metalation mostly occurred at the 2-position to afford the desired products in high yields.     

Copper‐Catalyzed Regioselective ortho CH Cyanation of Vinylarenes

A copper‐based catalytic technique for the regioselective ortho C? H cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper‐catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction.     

Regioselective lithiation of 1‐benzylpyrazole derivatives: Synthesis of amides derived from pyrazole

A series of brominated 1‐benzylpyrazoles were deprotonated at the pyrazole 5‐position or the benzylic position on treatment with lithium diisopropylamide in tetrahydrofuran at low temperature. The obtained organolithium intermediates were subjected to reaction with Me₃SiCl, t‐BuNCO, ClCONEt₂ or ClCON(i‐Pr)₂ affording the respective silanes or amides after hydrolysis.     

Regioselective lithiation of benzyl imidazole: Synthesis and evaluation of new organocatalysts for trans-diol functionalization.

Abstract

Benzyl imidazole was successfully lithiated using n-BuLi at ?78?°C and verified by deuterium incorporation. The chemical reaction of the lithiated benzimidazole was explored with a series of different electrophiles. This approach was utilized to synthesize new anti and syn diphenyl organocatalysts for trans-diol functionalization.     

Regioselective directed ortho metalation of 3H-naphto[2,1-b]pyrans. Synthesis of methylteretifolione B

The regiospecific lithiation of the 3H-naphtho[2,1-b]pyran system 1 b andits utility as a metalted tertifolione B equivalent 3 is described.     

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.     

Deuterium-labeling and NMR study of the dearomatization of N-alkyl-N-benzyldiphenylphosphinamides through anionic cyclization: ortho and benzylic lithiation directed by complex-induced proximity effects

The mechanism of the anionic cyclization dearomatizing reaction of N-benzyl-N-methyldiphenylphosphinamide (1) upon treatment with s-BuLi in tetrahydrofuran (THF) at -90 degrees C has been analyzed by deuterium-labeling and natural abundance multinuclear magnetic resonance ((1)H, (2)H, (7)Li, (13)C, (31)P) studies. In the absence of coordinating cosolvents such as hexamethylphosphoramide (HMPA), eight major anionic species were identified, which allowed us to unravel the pathway of the metalation reaction. In agreement with the complex-induced proximity effect (CIPE) mechanism, the sequence of transformations emerging from this study involves the coordination of the lithium base to the P=O group of 1 to give four dimeric precomplexes whose NMR data are consistent with structures Va/Vb and VIIIa/VIIIb. The diastereomers Va/Vb are the precursors of the monomeric benzylic anion II, whereas the VIIIa/VIIIb diastereomers are assumed to undergo ortho deprotonation leading to anions I. Translocation from the ortho anion to the benzylic one is not observed. Intramolecular conjugate addition of anion II to the P-phenyl rings happens in a reversible way, affording the monomeric dearomatized anions III, IV, VI, and VII. The reaction progresses to yield a mixture containing only the species I, III, and IV. HMPA acts as a catalyst for the ortho-to-benzylic translocation and anionic cyclization reactions. Two-dimensional (2D) (7)Li,(31)P[(1)H] shift correlations and (7)Li[(31)P] NMR spectra proved to be crucial for the structural assignment of the anionic species. These techniques also demonstrated the diastereotopicity of the two achiral ligands involved in a dimer with s-BuLi (Vb) owing to the slow configuration inversion of the carbanion center.     

Polyhalogenoheterocyclic compounds—321: Radical-anions from halopyridines

Electrochemical reduction of pentafluoropyridine and other polyhalopyridines gives bipyridyl derivatives etc. and it is inferred from the structures of the products that, in the intermediate radical-anion, charge- and spin-density is concentrated at the 1- and 4-positions. This is further supported by measurement of Ep_{$\text{1}\text{2}$} values. Trapping experiments with hydroquinone and carbon dioxide are described.     

Allylic lithiation of methylenecyclobutanes

Methylenecyclobutanes undergo a lithiation reaction in the presence of n-BuLi or n-BuLi/KO^tBu from −78 °C to room temperature or to 40 °C in THF within 3 h and then quenching with a variety of electrophiles to give the corresponding addition products (alcohols) in moderate to good yields within 2 h. The alcohols can be easily oxidized to the ketones, which can be transformed to the substituted cyclopentenes in the presence of AlCl₃ within short reaction time.     

Directed regioselective lithiation of (η-arene) chromium tricarbonyl complexes : Regioselective synthesis of anthraquinones and calamenenes

(3-Methoxybenzylalcohol)chromium tricarbonyl (10) and (7-methoxy-1-tetralol)chromium tricarbonyl (12) are selectively lithiated at the 4- and 6-positions, respectively, by treatment with n-BuLi-TMEDA. Since the directed lithiation of the corresponding chromium free arenes normally proceeds at the 2-and 8-positions, complementarily substituted arenes can be prepared by using the chromium tricarbonyl complexes. The difierent position of lithiation is explained by the relative configuration of the chromium tricarbonyl group in the (arene)Cr(CO)₃ and electrostatic factors. Some anthraquinones, 31,36,42, and 7-hydroxycalamenenes, 43, have been synthesized through the stereo- and regioselective introduction of substituents by means of(η⁶-arene)chromium tricarbonyl complexes.