Application of organolithium and related reagents in synthesis,Part X. Metallation-electrophilic substitution sequence of secondary chlorobenzamides

Summary The lithiation (Bu ⁿLi/THF) of 2-chloro- (1), 3-chloro- (2) and 4-chlorobenzanilides (3) and the subsequent reactions of the corresponding bis-lithiated anilides4–6 with electrophiles (MeI, CH₂=CH-CH₂Br,Me ₃SiCl,MeCHO,o-MeOC₆H₄CHO,p-MeOC₆H₄CHO,Me ₂NCHO andp-MeOC₆H₄CONMe ₂) towards the synthesis of theortho substituted chlorobenzoesic acids derivatives12–14 have been described. The effect of the chlorine substituent upon the generation and stability of the bis-lithiated chloro-anilides4–6 has been studied. It has been found that the bis-lithiated chloro-anilide5 derived fromm-chloro-benzanilide (2) at a temperature above –30°C converts into the corresponding benzyne9. The anilide moiety (masking group) of the formedortho-substituted chlorobenzanilides appeared to be effectively removable on acid-driven hydrolysis.

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Anwendungen von Organolithium und verwandten Reagenzien in organischen Synthesen, 10. Mitt. Metallierung und nachfolgende elektrophile Substitution sekundärer Chlorbenzamide

Zusammenfassung Die Lithiierung (Bu ⁿLi/THF) der 2-Chlor-(1), 3-Chlor- (2) and 4-Chlorbenzanilide (3) und nachfolgende Reaktion der entsprechenden doppellithiierten Anilide4–6 mit elektrophilen Reagenzien (MeI, CH₂=CH-CH₂Br,Me ₃SiCl,MeCHO,o-MeOC₆H₄CHO,p-MeOC₆H₄CHO,Me ₂NCHO undp-MeOC₆H₄CONMe ₂) zur Synthese vonortho-substituierten Benzoesäurederivaten12–14 wird beschrieben. Der Einfluß des Chlorsubstituierten auf die Bildung und Stabilität der doppellithiierten Chloranilide4–6 wurde untersucht. Es wurde festgestellt, daß das doppellithiierte, vomm-Chlorbenzanilid erhaltene Chloranilid5 bei Temperaturen über –30°C das entsprechende Arin9 bildet. Der Anilidrest (eine maskierende Gruppe) der gebildetenortho-substituierten Chloranilide kann durch saure Hydrolyse abgespalten werden.

     

Application of organolithium and related reagents in synthesis,part VI. A general study of the lithiation of secondary picoline- and isonicotine amides

Summary The lithiation of secondary picoline- (1) and isonicotine-amides (2) and the subsequent reaction of the corresponding (N- and 3-)lithiated amides (3 and4) with N,N-dimethylbenzamide towards the synthesis of the C³-benzoylated picoline (12 a) and isonicotine acids (13 a) has been investigated. The effect of the N-substituent upon the generation of the lithiated amides3 and4 has been studied. As a result it was found that the anilide function should be considered the best choice for direct metallation of the masked picoline- and isonicotinecarboxylic acids. The effects at various temperatures upon the generation of the lithiated reactive intermediates and the problems concerning their reactions with an acid (deuteriation) and an carbonyl electrophile are discussed.

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Anwendungen von Organolithium und verwandten Reagenzien in organischen Synthesen, Teil VI. Zur Metallierung von sekundären Picolinsäure- und Isonicotinsäureamiden

Zusammenfassung Die Metallierung sekundärer Amide von Picolin- (1) und Isonicotinsäure (2) und nachfolgende Reaktion der entsprechenden (N- und 3-)metallierten Amide3 und4 mit N,N-Dimethylbenzamid — zur Synthese von C³-benzoylierten Picolin- (12 a) und Isonicotinsäuren (13 a) — wurde untersucht. Der Einfluß des N-Substituenten auf die Bildung der metallierten Amide3 and4 wurde studiert und dabei festgestellt, daß der Anilidrest für eine direkte Metallierung der maskierten Picolin- und Isonicotinsäure gut geeignet ist. Der beobachtete Einfluß des Substituenten bei verschiedenen Temperaturen bei Bildung der metallierten Spezies und die Probleme ihrer Reaktivität gegen Säuren (MeOD) und Carbonyl-Elektrophilen wurden diskutiert.

     

Application of organolithium and related reagents in synthesis XVI: Synthetic strategies based on aromatic metallation. A concise regiospecific conversion of chlorobenzoic acids into their benzylated derivatives

Summary The reaction of benzyl bromide withbis-(N- and C-ortho)-lithiated chloroanilides4,5, and6 has been examined. It has been found that in the case where the lithiated compound was derived frommeta-methoxyanilides, pre-addition of LiBr orTMEDA was required to achieve C-benzylation. These results were accounted for by the conversion of the usually formed dimer into a mixed dimer with the LiBr orTMEDA complex in which the C-lithium bond appears to be more accessible towards electrophiles. The practical synthesis of -benzylchlorobenzoic acids10,11, and12 was accomplishedvia ionic reductive cleavage (Et₃SiH/TiCl₄) of the corresponding phthalides18,19, and20. The acids10,11b, and11c afforded the corresponding anthrones, upon treatment with trifluoroacetic anhydride which were oxidized by chromium trioxide to the new chloroantraquinones21,22, and23.

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Anwendung von Organolithium und verwandten Reagenzien in organischen Synthesen, 16. Mitt.: Synthesen mittels aromatischer Metallierung. Eine bequeme regiospezifische Umwandlung von Chlorbenzoesäuren in ihre Benzylderivate

Zusammenfassung Die Reaktion von Benzylbromid mit denbis-(N- und C-ortho)-lithiierten Chloraniliden4,5 und6 wurde untersucht. Im Falle lithiierter Verbindungen ausmeta-Methoxyaniliden ist die Zugabe von LiBr oderTMEDA während des Lithiierungsprozesses für die C-Benzylierung erforderlich. Diese Ergebnisse werden durch Umwandlung des gewöhnlich enstehenden Dimers in ein gemischtes Dimer mit dem LiBr- oderTMEDA-Komplex erklärt, in welchem die C-Li-Bindung für Elektrophile leichter zugänglich ist. Diese praktische Synthese dero-Benzylchlorbenzoesäuren10,11 und12 wird durch reduktive Spaltung der entsprechenden Phthalide18,19 und20 mit Et₃SiH/TiCl₄ ergänzt. Bei der Reaktion der Säuren10,11b und11c mit Trifluoressigsäureanhydrid entstehen die erwarteten Anthrone, die durch Oxidation mit Chromtrioxid in die neuen Chloranthrachinone21,22 und23 umgewandelt wurden.

     

Application of organolithium and related reagents in synthesis. Part 25: Novel specific synthesis of the 4-arylisochroman-3-acetic acids via conversion of benzoic acids

The transformation of the benzanilides 1 into 4-arylisochroman-3-acetic acids 8 applying the following sequence of reactions is described. At first, the 3-arylphthalides 3 were obtained via metallation [n-BuLi] of benzanilides 1 and subsequent treatment of the generated bis-lithiated anilides 2 with aromatic aldehydes. Next, the 3-arylphthalides 3 were reduced [LiBH₄] to phthalanes 5 and then, via reductive metallation [Li/C₁₀H₈] and reaction of the generated bis-lithiated species 6 with dimethylformamide, 3-hydroxy-4-arylisochromans 7 were produced. In the final step the isochromans 7 were treated with 1-methoxy-1-trimethylsilyloxyethene in the presence of titanium tetrachloride and furnished 4-arylisochromans-3-acetic acid methyl esters 8 as trans stereoisomers (Ψ-e/e).     

Efficient and selective synthesis of quinoline derivatives

The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination of 1,2,3,4-tetrahydroquinoline (7) in efficient yields (75 and 90%, respectively). 6-Bromo- (4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (6) were converted to 6-bromo- (1) and 6,8-dibromo quinolines (2), respectively, by aromatization with DDQ in 83 and 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared via lithium-halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi followed by quenching with electrophiles [Si(CH₃)₃Cl, S₂(CH₃)₂, I₂] regioselectively proceeded at C-4 and C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation of tribromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield. Copper-induced nucleophilic substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxyquinoline (17) in 60% yield.     

Vinyl-copper derivatives XII : Stereospecific synthesis of allylic amines by aminomethylation of organocopper reagents

the carbocupration or hydroalumination of alkynes followed by amino-methylation yields allylic amines. The stereochemical integrity of the alkenyl moiety is completely retained in both cases.     

Synthesis of phosphorylated isoindolinone derivatives

The synthesis of diethyl [2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)ethyl]phosphonates and diethyl [3-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propyl]phosphonates, via metallation (sec-BuLi) of N-substituted isoindolin-1-ones and then the reaction of the generated lithiated species 4 with diethyl vinylphosphonate or diethyl 3-bromopropylphosphonate, respectively, is described.     

A synthesis of 2-fluoroglucal derivatives

3,4,6-Tri-O-methyl-d-glucal, readily prepared from 3,4,6-tri-O-acetyl-d-glucal, undergoes lithiation at −78 °C in THF with t-BuLi to afford a vinyl carbanion, which can be trapped with electrophiles in moderate overall yields. The palladium coupling and Dötz-type reactions of these intermediates are also described.     

Synthesis and structures of some di- and triferrocenylmethane derivatives

Some triferrocenylmethane derivatives were prepared by reaction of triferrocenylmethanol (5) with triphenylcarbenium tetrafluoroborate followed by a nucleophile. Crystal structure analyses of triferrocenylmethane (7) and of 1,1,1-triferrocenyl-2,2-dimethylpropane (11) show that the conformation adopted by the triferrocenylmethyl group differs significantly with the steric bulk of the substituent at the central carbon atom. Treatment of 1,1′-bis(tributylstannyl)ferrocene (13) with 1 equiv. of butyllithium followed by chloroethylformiate affords complexes with one (14), two (15) or three ferrocenyl units (16) depending on the amount of chloroethylformiate used. Compound 16 is the first triferrocenylmethane derivative with substituents at the opposite cyclopentadienyl ring. Threefold lithiation of this compound is shown to work using butyllithium followed by dimethylformamide.     

The chemistry of pentavalent organobismuth reagents : Part XII. Synthesis of isoflavanones and 3-aryl-4-hydroxycoumarins

The arylation of chroman-4-one and 4-hydroxycoumarin derivatives by pentavalent arylbismuth reagents has been carried out. Chroman-4-one gives the 3-diphenyl derivative, whereas 3-formyl and 3-oxalyl derivatives are phenylated to isoflavanones in moderate to high yields. Arylation of 4-hydroxycoumarins by various Bi(V) reagents gives rise to functionally substituted 3-aryl-4-hydroxycoumarins in high yields.     

Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII

Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) have been prepared and their structural information on these nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) using (1)HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide.     

Reactions of organolithium and grignard reagents with the cyclopentadienyliron tricarbonyl cation and its derivatives

Reactions of CH₃Li, C₆H₅Li, and C₆H₅CH₂MgCl with [(C₅H₅)Fe(CO)₂Y]⁺-[B(C₆H₅)₄]⁻ [Y  Co, P(C₆H₅)₃, and CS] have been investigated. The organolithium reagents used act either as reducing agents or as nucleophilic reagents towards the cyclopentadienyliron tricarbonyl cation and its thiocarbonyl analogue. Benzyl-magnesium chloride reacts with the cyclopentadienyl ring of [(C₅H₅)Fe(CO)₃]⁺ and [(C₅H₅)Fe(CO)₂P(C₆H₅)₃]⁺ producing neutral cyclopentadiene complexes.     

Highly efficient synthesis of stereodefined multisubstituted 1,4-dicyano- and 1-cyano-1,3-butadienes and their reactions with organolithium reagents

Stereodefined multisubstituted 1-cyano- and 1,4-dicyano-1,3-butadiene derivatives were obtained in excellent yields of the isolated product from their corresponding monohalo- and dihalobutadienes and CuCN. This reaction proceeded with high stereoselectivity and retention of the stereochemistry of the starting halobutadienes. A study of the utility of the thus-obtained 1-cyano- and 1,4-dicyano-1,3-butadiene derivatives was demonstrated by their reactions with organolithium reagents. 2H-Pyrrole or iminocyclopentadiene derivatives were formed in high yields from 1-cyano-4-halo-1,3-butadienes and organolithium reagents. When 1,4-dicyano-1,3-butadienes were treated with organolithium reagents followed by trapping with electrophiles, a tandem process took place to afford 2H-pyrrolyl nitriles in excellent yields. Reduction of 1,4-dicyano-1,3-butadiene derivatives with LiAlH4 showed novel reaction patterns relative to normal nitriles.     

Studies in fluorinated 1,3-diketones and related compounds Part XII. Synthesis and spectroscopic studies of some new polyfluorinated 1,3-diketones,and their copper 1,3-diketonates

New polyfluorinated 1,3-diketones have been prepared from polyfluorinated acetophenones and appropriate esters in the presence of sodamide. The corresponding copper 1,3-diketonates have been obtained by treating a methanolic solution of polyfluorinated 1,3-diketone with methanolic solution of copper acetate. The polyfluorinated 1,3-diketones have been characterized by elemental as well as by spectral studies, viz: I.R., ¹H N.M.R. and ¹⁹F N.M.R. In I.R., characteristic absorptions observed are: CF stretching bands (1300 ? 1000) cm^?1, CF deformation modes (900 ? 700 cm^?1) and intramolecular hydrogen bonding (3000 ? 2500 cm^?1). In ¹H N.M.R. methine ( = C$\text{H}$) signal is observed at δ 6.2 ? 6.8 ppm and enolic proton resonance signal at δ 13 ? 15 ppm indicating the presence of strong hydrogen bonding in such polyfluorinated 1,3-diketones.     

Application of Organolithium and Related Reagents in Synthesis. Part XXVIII [1]. Synthesis Strategies Based on Aromatic Metallation: A Conversion of Benzoic Acids into Arylthiomethyl Aromatic Carboxylic Acids

Summary.  A convenient two step protocol preparation of ortho-phenylthiomethyl aromatic carboxylic acids from aromatic carboxylic acids anilides is reported. The phenylthiolation of phthalides with benzenethiol as a key step is described. Corresponding author. E-mail: epsztajn@krysia.uni.lodz.pl Received June 21, 2002; accepted July 9, 2002     

Evidence for conformational isomerism. II. Synthesis of 1-alkyl-2-carboazetidines using organolithium reagents

Treatment of 1-alkylazetidine-2-carboxylic acids with several organolithium reagents leads to the corresponding 1-alkyl-2-carboazetidines in near quantitative yield. Additional evidence is presented for conformational isomerism in the title compounds on the basis of infrared carbonyl stretching frequencies.     

Synthesis and structure of ferrocenylmethylphosphines, their borane adducts, and some related derivatives

Syntheses of the known ferrocenylmethylphosphines FcCH₂PH₂ (2, Fc = (η⁵-C₅H₄)Fe(η⁵-C₅H₅)), (FcCH₂)₂PH (3), and (FcCH₂)₃P (4) have been reinvestigated. The reaction of [FcCH₂NMe₃][I] with P(CH₂OH)₃, generated from [P(CH₂OH)₄][Cl] and KOH, gave a mixture of the major product (FcCH₂)P(CH₂OH)₂ (1) and over-alkylated (FcCH₂)₂P(CH₂OH) (9). Treatment of pure 9 with Na₂S₂O₅ gave the secondary phosphine 3; slow addition of Na₂S₂O₅ to 1 gave 2 in improved yield. Reaction of 1 with [FcCH₂NMe₃][I], followed by treatment with NEt₃, gave the tertiary phosphine (FcCH₂)₃P (4), along with the known phosphonium salt [(FcCH₂)₄P][I] (5), which could be prepared in higher yield by adjusting the stoichiometry. Phosphine 4 oxidized slowly in air to yield (FcCH₂)₃P(O) (12), was protonated by HBF₄(OMe₂) to give [(FcCH₂)₃PH][BF₄] (13), and reacted with Pt(COD)Cl₂ or PtCl₂ to yield a mixture of cis- and trans-Pt(P(CH₂Fc)₃)₂Cl₂ (14). Silylation of 2 with n-BuLi/Me₃SiCl gave FcCH₂P(SiMe₃)₂ (10); treatment of 1 with Me₃SiCl/Et₃N gave FcCH₂P(CH₂OSiMe₃)₂ (11). The phosphine-borane adducts FcCH₂PH₂(BH₃) (6), (FcCH₂)₂PH(BH₃) (7), (FcCH₂)₃P(BH₃) (8) and (FcCH₂)P(CH₂OSiMe₃)₂(BH₃) (15) were prepared from the corresponding phosphines and BH₃(SMe₂). The phosphines 2, 3, and 4, phosphonium salts 5 and 13, phosphine oxide 12, Pt complex trans-14, and phosphine-boranes 6, 7 and 8 were structurally characterized by X-ray crystallography. The solid cone angle of (FcCH₂)₃P, 139°, in Pt complex 14 showed that 4 was bulkier than PPh₃, but less sterically demanding than P(t-Bu)₃. The structural changes observed on quaternization of P (shorter P-C bonds and larger angles at P), along with results from NMR and IR spectroscopy and DFT calculations, were consistent with the expected rehybridization at phosphorus. Related observations for analogous methylphosphines suggest that methyl and ferrocenylmethyl phosphorus substituents have similar properties.     

Activated nitriles in heterocyclic synthesis. Part III. Synthesis of N-amino-2-pyridone,pyranopyrazole and thiazolopyridine derivatives

The reaction of 2-cyanoethanoic acid hydrazide and arylidenemalononitrile was studied as a new route for the synthesis of N-amino-2-pyridones. Pyrano[2,3-c]pyrazole and thiazolo[2,3-a]pyridine could be prepared from the reaction of arylideneazolones with the same reagent.