Synthesis and transformations of 1-(1,3-butadien-1-yl)benzotriazoles

1-[α-(Phenylthio)alkyl]benzotriazoles were converted into the corresponding 1-(1,3-butadien-1-yl)benzotriazoles in good yields by one-pot sequential reactions with (i) lithium diisopropylamide, (ii) allyl bromide or cinnamyl chloride, and (iii) potassium t-butoxide. Diels-Alder and hetero [4 + 2] cycloadditions of 1-(1,3-butadien-1-yl)benzotriazoles and some transformations of their α-lithio derivatives were studied.     

Novel routes to 1-aryl-1,4-dihydro-3(2H)-isoquinolinones and 2-substituted or 2,3-disubstituted benzofurans by intramolecular cyclizations

N-(α-Benzotriazolylalkyl)arylacetamides, readily available from an arylacetamide, an aldehyde and benzotriazole, undergo intramolecular cyclization under acidic conditions to give 1-aryl-1,4-dihydro-3(2H)-isoquinolinones in good to excellent yields. Similarly, 2-(benzotriazol-1-yl)-2-(o-hydroxyphenyl)ethanols, obtained by lithiation of 2-(benzotriazol-1-ylmethyl)phenols followed by quenching with aldehydes or ketones, eliminate a molecule of water and a molecule of benzotriazole yielding 2-substituted and 2,3-disubstituted benzofurans.     

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.     

Efficient synthesis of 3,5‐functionalized isoxazoles and isoxazolines via 1,3‐dipolar cycloaddition reactions of 1‐propargyl‐ and 1‐allylbenzotriazoles

3‐Aryl‐5‐(benzotriazol‐1‐ylmethyl)‐ 10a‐f and 3‐p‐methoxyphenyl‐5‐(α‐benzotriazol‐1‐yl‐α‐ethoxymethyl)‐isoxazole (13) were prepared in high yields by 1,3‐dipolar cycloadditions of 1‐propargyl‐benzotriazole (5) and (α‐ethoxypropargyl)benzotriazole (8), respectively, with nitrite oxides 3a‐f (prepared in situ from benzohydroximoyl chlorides 2a‐f). The benzotriazol‐1‐ylmethyl moiety was further elaborated by sequential lithiation and reaction with aldehydes, alkyl halides and Michael acceptors. Similar 1,3‐cycloadditions using 1‐allylbenzotriazole (6) and 1‐(α‐ethoxyallyl)benzotriazole (7) afforded 3,5‐substituted isoxazolines 11b, f and 12 in excellent yields.     

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 .     

The reaction of benzotriazoles with 3,4-dihydro-4H-pyrane and 2-acetoxymethyl-3,4-dihydro-2H-pyrane

From the reaction of benzotriazoles with 2,3-dihydro-4H-pyrane and 2-acetoxymethyl-3,4-dihydro-2H-pyrane the corresponding 1-(2-tetrahydropyranyl)benzotriazole and cis-and trans-1-(6-acetoxymethyl-2-tetrahydropyranyl)benzotriazole derivatives were obtained. The structures and conformations of these compounds were confirmed by UV and NMR spectra.     

Furopyridines. XV . Synthesis and properties of ethyl 2-(3-furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridyl)acetate

Ethyl 2-(3-furopyridyl)acetates 10a-d were synthesized from furopyridin-3(2H)-ones 4a-d by the Wittig-Horner reaction with diethyl cyanomethylphosphonate, hydrolysis and the subsequent esterification. Reaction of compounds 10a-d with lithium diisopropylamide (IDA) gave the corresponding methylene-lithiated intermediate, and the subsequent reaction with benzaldehyde, acetone and iodomethane afforded the methylene-alkylated product respectively, while N,N-dimethylacetamide did not give any reaction product. The 2-position of 10a, b and d is alkylated by the lithiation with excess of LDA and the successive reaction with an electrophile.     

The Preparation of 4,5-Dihydro-5-Phenyl-5-(2-Phenylethenyl)Isoxazoles, 4,5-Dihydro-5-Methyl-5-(2-Phenylethenyl)Isoxazoles,or 4,5-Dihydro-5,5-DI-(2-Phenylethenyl)Isoxazoles from Dilithiated C(α),O-Oximes and Select α,β–-Unsaturated Ketones

C(α),O-oximes were dilithiated with lithium diisopropylamide and condensed with three α,β-unsaturated ketones: (2E)-1,3-diphenyl-2-propen-1-one, or (1E, 4E)-1,5-diphenyl-1,4-pentadien-3-one, or (3E)-4-phenyl-3-buten-2-one, followed by immediate acid cyclization to variously substituted 4,5-dihydroisoxazoles: 4,5-dihydro-5-phenyl-5-(2-phenylethenyl)isoxazoles, 4,5-dihydro-5-methyl-5-(2-phenylethenyl)isoxazoles, or 4,5-dihydro-5,5-di-(2-phenylethenyl)-isoxazoles.     

General and efficient insertion of carbons carrying benzotriazole

Anions formed from the lithiation of 1-(1-benzotriazolylalkyl)benzotriazoles (1, 6) and 1-(1-methylthioalkyl)benzotriazoles (10 and 10a) with n-BuLi underwent additions to cyclic and acyclic ketones giving intermediates 3a-f, 7b-f, and 11b-d, respectively, in excellent yields. Thermal rearrangements of intermediates 3a,b,d-f and 7b-d,f in the presence of zinc bromide provided one-carbon chain-extended or ring-expanded alpha-benzotriazolyl ketones 4a,b,d-f and 8b-d,f in moderate yields with excellent regioselectivity. By contrast, intermediates 11b-d on treatment with zinc bromide loose a molecule of benzotriazole followed by intramolecular cyclization of the resulting intermediates 12b-d to provide the 2,3- and 1,2,3-substituted indenes 13b-d in good yields.     

Efficient synthesis of new chiral 1,2-benzothiazin-3-one 1,1-dioxide derivatives via lateral lithiation of 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones

Chiral 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones 4a-e derived from (l)- and (d)-amino acids 1a-e undergo lateral lithiation with lithium diisopropylamide and TMEDA in anhydrous THF to provide new optically-active 1,2-benzothiazin-3-one 1,1-dioxide derivatives 5a-e with yields ranging from 63% to 79%.     

Unexpected Products from Carbonylation of Lithiated Quinazolin-4(3H)-one Derivatives

Doubly lithiated 3-pivaloylaminoquinazolin-4(3H)-one reacts with carbon(II) oxide at 0°C to give 77% of a mixture of azetidinone and indole derivatives, each incorporating a diisopropylamide unit from lithium diisopropylamide used for lithiation. No analogous reaction occurs with doubly lithiated 3-acetylaminoquinazolin-4(3H)-one and 3-acyl-2-alkylquinazolin-4(3H)-one. Carbonylation of doubly lithiated 2-alkyl-3-aminoquinazolin-4(3H)-ones at 0°C results in deamination to give 2-alkylquinazolin-4(3H)-ones in good yields.     

Prototropic Isomerization of Spiro[2,3]hexanes 1,1,5-Trisubstituted with Electron-acceptor Groups into 1,3-Disubstituted Bicyclo[1.1.0]butanes

1,1-Dicyano- and 1,1-dialkoxycarbonylspiro[2.3]hexane-1-carbonitriles treated with lithium diisopropylamide or potassium tert-butylate in THF undergo a prototropic isomerization into 3-(2,2-dicyanoethyl)- and 3-(2,2-dialkoxycarbonylethyl)bicyclo[1.1.0]butane-1-carbonitriles respectively.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 2, 2005, pp. 201–204.Original Russian Text Copyright © 2005 by Razin, Ulin.     

A Synthesis Detour to Planar‐Diastereoisomeric Ferrocene Derivatives around an Unexpected Rearrangement of ortho‐Lithiated Kagan's Template [S(S)]‐(p‐Tolylsulfinyl)ferrocene

Usually, ortho lithiation of Kagan's template 1 and quenching with electrophiles leads highly diastereoselectively to planar‐chiral 1,2‐disubstituted ferrocenes. Surprisingly, lithiation of 1 with lithium diisopropylamide (LDA) followed by addition of paraformaldehyde afforded regioisomer (+)‐{[S(S)]‐[4‐(2‐hydroxyethyl)phenyl]sulfinyl}ferrocene ( 2 ), which was converted to (+)‐{[S(S)]‐{4‐{2‐[(methylsulfonyl)oxy]ethyl}phenyl}sulfinyl}ferrocene ( 3 ) (Scheme 1). The desired diastereoisomer (l)‐1‐(hydroxymethyl)‐2‐(p‐tolylsulfinyl)ferrocene ( 5 ) in turn could also be obtained by ortho lithiation of 1 with LDA but by quenching with DMF to yield aldehyde 4 first, which then was reduced with NaBH₄ to 5 . Finally, target compound (l)‐1‐[(dimethylamino)methyl]‐2‐(p‐tolylsulfinyl)ferrocene ( 6 ) was obtained by substitution of the OH group of 5 under mild conditions or directly by ortho lithiation of 1 with lithio‐2,4,6‐triisopropylbenzene (=2,4,6‐triisopropylphenyl)lithium; LTP) followed by quenching with N,N‐dimethylmethyleneiminium chloride. At low temperatures, reaction of 1 with LDA leads, via the preferred diastereoisomeric transition state ‘exo’‐ 7 and under extrusion of a (diisopropylamine)lithium complex of type 8 , in a highly selective manner, to diastereoisomeric ortho‐lithiated chelate (l)‐ 9 (Scheme 2). The reaction of 1 to 2 is explained by a rearrangement of (l)‐ 9 to {[S(S)] [4‐(lithiomethyl)phenyl]sulfinyl}ferrocene 10 , which is acid‐catalyzed by coordinated diisopropylamine in complexes of type 8 . This rearrangement is not observed if LTP is used as base or, in case LDA is applied, if the electrophile is sufficiently reactive at low temperatures.     

Preparation of 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones and 2H-1-benzothiopyran-2-ones from carboxylic esters and methyl salicylates or methyl thiosalicylate

C(α)-Carboxylic acid esters were treated with excess lithium diisopropylamide, condensed with methyl salicylates or methyl thiosalicylate, followed by acid cyclization to either 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones (coumarins), or 2H-1-benzothiopyran-2-ones (thiocoumarins).     

Functionalization of some benzylthioarylboronic acids by benzylic lithiation of their N‐butyldiethanolamine esters or lithium (triisopropoxy)borates

The reaction of benzylthioarylboronic acids protected as N‐butyldiethanolamine esters or as triisopropoxyborates with organolithium bases or lithium diisopropylamide (LDA) has been investigated. The benzylic lithiation occurs selectively using LDA at − 68 °C. The stability of the resultant borio‐lithio intermediates is strongly influenced by the position of the boron atom in the phenyl ring. The reaction with various electrophiles affords new arylboronic acids substituted in the benzylic position. Copyright © 2011 John Wiley & Sons, Ltd.     

The Mitsunobu Reaction: An Alternative Synthesis of 1-(Primary Alkyl)benzotriazoles

1-(Primary alkyl)benzotriazoles are obtained in convenient yields by treating the corresponding alcohol with triphenylphosphine, N-bromosuccinimide and benzotriazole. Under these conditions, the alcohols gave exclusively the corresponding 1-alkyl-benzotriazoles. Allyl and propargyl alcohols also reacted regiospecifically in a typical Sn2 manner, and no products derived from prototropic rearrangement were found.     

On the Acidity and Lithiation-Functionalization of Thiophenes: Revisited for their Use in the Synthesis of Thiophene-Based Novel π-Systems

When lithium diisopropylamide is used for lithiation and functionalization of thiophenes, whose acidity is here measured to be pKa = 35-36 in THF-Hex (5:3), the equilibrated nature of lithiation is to be taken into consideration.     

Directed ortho-lithiation of chloroquinolines. Application to synthesis of 2,3-disubstituted quinolines

2-, 3- and 4-Chloroquinolines were selectively lithiated at low temperature by lithium diisopropylamide at the more acidic C-3, C-4 and C-3 positions respectively. Reaction of 2-chloro-3-lithioquinoline with electrophiles led to various 2,3-disubsthuted quinolines. The versatility of this functionalization methodology is enhanced by the C-2 halogen reactivity towards oxygen or nitrogen nucleophiles. So, a great variety of 2,3-di-substituted quinolines were synthesized, such as 2-chloro, 2-alkoxy, 2-aminoquinolines or 2-quinolones bearing an hydroxy, carbonyl (aldehyde, ketone or carboxylic acid), iodo, trimethylsilyl or boronic acid moiety at the C-3. Some of the resulting 2,3-disubstituted synthons were annelated to tetracyclic polyaromatics, which possess the xanthone or indole structure. This could be achieved via further functionalization of the quinoline ring either by SNAr2 or heteroaromatic cross-coupling reactions, after the first directed-lithiation step.     

A facile access to indigodianiles

Bis‐imidoylchlorides derived from oxalic acid can easily be transformed into the corresponding bis‐imino benzotriazoles. The fact that benzotriazole is a well‐established leaving group has been exploited for an improved synthesis of indigodianiles. Employing metallic lithium, the benzotriazoles can be converted in a cascade reaction into indigo bis‐arylimines in yields up to 45%. Formation of the reduced form of dimeric isocyanides is suggested as a key step.     

Efficient synthesis of new imidazo[1,2-b][1,2]benzothiazine 4,4-dioxide derivatives via lateral lithiation of N-mesitylenesulfonyl hydantoins

N-Mesitylenesulfonyl hydantoins, readily available from commercial α-amino acids, undergo lateral lithiation with an excess of lithium diisopropylamide and tetramethylethylenediamine in the presence of trimethylsilyl chloride to provide new imidazo[1,2-b][1,2]benzothiazin-2-one 4,4-dioxide derivatives in yields ranging from 44-65%.