Lithiation of 2-Alkyl-3-amino- and 2-Alkyl-3-(methylamino)-4(3H)-quinazolinones(1)

3-Amino-2-methyl-4(3H)-quinazolinone has been doubly lithiated, on nitrogen and in the 2-methyl group, with n-butyllithium. The lithium reagent thus obtained reacts with a variety of electrophiles (D(2)O, benzophenone, cyclohexanone, cyclopentanone, acetophenone, benzaldehyde, tetraisopropylthiuram disulfide (TITD)) to give the corresponding 2-substituted derivatives in very good yields. Reactions of the dilithio reagent with 2 molar equiv of methyl iodide or phenyl isocyanate give disubstituted derivatives. Double lithiation of the 2-ethyl and 2-propyl analogues have been achieved using LDA, and subsequent reactions with most electophiles are then similar. In the reaction of the dianion of the 2-ethyl compound with TITD, deamination from position 3 takes place with the formation of the 2-substituted derivative. In reactions with prochiral ketones, the dianion of the 2-ethyl compound gives very high diastereoselectivity. Lithiation and subsequent reactions of 3-(methylamino) analogues take place in a similar manner, thus providing access to a range of substituted 3-(methylamino)-2-alkyl-4(3H)-quinazolinones by a general procedure. Lithiation of 3-(dimethylamino)-2-ethyl-4(3H)-quinazolinone did not take place under similar conditions. Lithiation of 3-amino-2-unsubstituted-4(3H)-quinazolinone was also unsuccessful.     

2-(3-ethyl-2,2-dimethylcyclobutyl-methyl)-4(3H)-quinazolinones

Anthranilic acid and its 5-bromo and 4-chloro derivatives react with pinanoic and pinonoic acid chlorides to give the corresponding N-acyl derivatives. The pinanoyl derivatives give the corresponding 2-(3-ethyl-2,2-dimethyl-cyclobutylmethyl)-4-(3H)-quinazolinones when refluxed in formamide. Pinanoylanthranilic acid reacts with dicyclohexylcarbodiimide to give 2-(3-ethyl-2,2-dimethylcyclobutylmethyl)benz-3,1-oxazin-4(H)-one and subsequently with hydrazine hydrate to give 3-amino-2-(3-ethyl-2,2-dimethylcyclobutylmethyl)-4(3H)-quinazolinone. Refluxing of the pinanoyl- and pinonoylanthranilic acids with acetic anhydride gives acetylanthranilic acid, and pinonoylanthranilic acid gives 4(3H)-quinazolinone with formamide.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lanet.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 811–817, June, 1999.     

Synthesis of 5S-(1-Oxoalkyl and Aryl)-2-pyrrolidinone Derivatives1

N-Benzyl pyroglutamate esters react with aryllithium reagents and methyllithium to give moderate to good yields of 5-(1-oxoaryl) or 5-(1-oxoalkyl)-2-pyrrolidinone derivatives. The reaction proceeds without racemization, but is accompanied by formation of 5-(1-hydroxy-1-alkyl)-2-pyrrolidinone derivatives. This reaction gives very poor yields of ketone products with most other alkyl organolithium reagents such as n-butyllithium. Grignard reagents react to give primarily the alcohol.     

Palladium-catalyzed cyclocarbonylation of o-iodoanilines with heterocumulenes: regioselective preparation of 4(3H)-quinazolinone derivatives

A catalyst system comprising palladium acetate-bidentate phosphine is effective for the cyclocarbonylation of o-iodoanilines with heterocumulenes at 70-100 degrees C for 12-24 h to give the corresponding 4(3H)-quinazolinone derivatives in good yields. Utilizing o-iodoaniline with isocyanates, carbodiimides, and ketenimines for the reaction, 2,4-(1H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones were obtained, respectively. The nature of the substrates including the electrophilicity of the carbon center of the carbodiimide, and the stability of the ketenimine, influence the product yields of this reaction. Urea-type intermediates are believed to be generated first in situ from the reaction of o-iodoanilines with heterocumulenes, followed by palladium-catalyzed carbonylation and cyclization to yield the products.     

Reactions of 6-Alkoxy(alkylthio)carbonylamino-4-hydroxy-2H-pyran-2-ones with Some Electrophilic Reagents

Alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones readily react with electrophiles to give substitution products at C³. Hard electrophilic reagents replace hydrogen both in position 3 and in position 5 of the pyran ring. Methylation of 6-alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones with diazomethane leads to formation of O- and N-methyl derivatives.     

Formation and reactivity of dianions derived from 2- and 3-thiophencarboxylic acids

Dianions (3) and (6) can be generated in high yield from the corresponding thiophencarboxylic acids with lithium diisopropylamide and react with a number of representative electrophiles to give fair to good yields of 5-substituted-thiophen-2-carboxylic acids and 2-substituted thiophen-3-carboxylic acids respectively.     

Lithiation of 1-chloromethylbenzotriazole: generation and elaboration of benzotriazolyloxiranes

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 degrees C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of alpha-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.     

Stereoselective Synthesis and Reactions of Secondary Alkyllithium Reagents Functionalized at the 3‐Position

Secondary alkyllithium reagents bearing an OTBS group (TBS=tert‐butyldimethylsilyl) at the 3‐position can be prepared stereoconvergently through an I/Li exchange from a diastereomeric mixture of the corresponding secondary alkyl iodides. These lithium reagents react with a range of electrophiles, including carbon electrophiles, with retention of configuration to yield various 1,3‐difunctionalized derivatives with good diastereoselectivities. Kinetic studies show that the 3‐siloxy group strongly accelerates the epimerization at the lithium‐substituted carbon atom. This method offers a new way to construct chiral open‐chain molecules with excellent stereoselectivity.     

Strontium chloride-catalyzed one-pot synthesis of 4(3H)- quinazolinones under solvent-free conditions

<正>Strontium chloride was used as an efficient and recyclable catalyst in one-pot condensation of anthranilic acid,ortho esters and amines leading to the formation of 4(3H)-quinazolinone derivatives in good yields at room temperature under solvent-free conditions.     

Isoprene-catalyzed lithiation of imidazole: synthesis of 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles

2-Lithioimidazole was prepared by means of a new protocol, which consists of a slight excess of lithium metal in the presence of a substoichiometric amount of isoprene (20 mol%) in THF at room temperature. By reacting this organolithium with carbonyl electrophiles 2-(hydroxyalkyl)imidazoles 3 were obtained, in good yields. As a result of the reaction of the mentioned lithium intermediate with imines 4, the corresponding 2-(aminoalkyl)imidazoles 5 were isolated in excellent yields.     

Versatile three-component procedure for combinatorial synthesis of 2-aminospiro[(3'H)-indol-3',4-(4H)-pyrans

A convenient method of synthesis of substituted and annulated 2-amino-spiro[(3' H)-indol-3',4-(4 H)-pyrans] at mild conditions and in good yields is developed. Three component reaction of wide variety of substituted isatins, cyanoacetic acid derivatives, and carbonyl compounds or phenols gives the target compounds. Forty new spiropyrans were obtained, and their structures were proved by elemental analysis and 1H NMR and IR spectral data. It is shown that the use of a not very large set of starting compounds can lead to the synthesis of a thousand-member 2-amino-spiro[(3' H)-indol-3',4-(4 H)-pyran] library.     

Chemistry of α-(benzotriazol-l-yl)alkylpyridines. Unusual nucleophilic attack at c-3a of the benzotriazolyl ring

Lithiation of 2-, 3- and 4-[α-(benzotriazol-l-yl)methyl]pyridines with butyllithium followed by reactions with electrophiles (alkyl halides, aldehydes, ethyl benzoate and diphenyl disulfide) gave the corresponding α-sub-stituted derivatives in good yields. Repetition of the reaction sequence allowed substitution of the second α-proton by an electrophile. 2-[α-(Benzotriazol-l-yl)-α-(phenylthio)pentyl]pyridine thus obtained gave an unusual attack of the Grignard reagents at C-3a of the benzotriazole system on treatment with arylmagnesium bromides.     

Synthesis and characterization of chalcogen (S and Se) derivatives of 4-chloro- and 4-methoxy-N,N-diisopropylpyridine-2-carboxamide: X-ray structure of 4-methoxy-3-(sulfanylmethyl)- and 4-chloro-3-(selenenylbenzyl)-N,N-diisopropylpyridine-2-carboxamide

Synthesis of chalcogen (S and Se) derivatives of 4-chloro- and 4-methoxy-N,N-diisopropylpyridine-2-carboxamide (1a and 1b respectively) has been reported. 1a and 1b were lithiated with 2 equiv. of n-BuLi or LDA at ?78 °C. Addition of elemental sulfur or selenium to the carbanion led to the formation of corresponding thiolate or selenolate anions respectively. The selenolate anions were aerial oxidized to afford the corresponding diselenides. The thiolate/selenolate anions were quenched with a variety of electrophiles to give unsymmetrical thio/selenoalkanes in moderate to good yields. Reductive cleavage of Se–Se bond has also been studied. The synthesized compounds were characterized by elemental analysis, NMR (¹H, ¹³C and ⁷⁷Se), FT-IR and mass spectral techniques. Crystal structures of two compounds, 6b and 7a, were determined by single crystal X-ray crystallography. Their crystal structure exhibits 1,4-type S?OCH₃ and Se?Cl intramolecular secondary interactions respectively. The relative thermal stability of 3a, 3b and 4a has also been established by thermogravimetric analysis.     

Pyridine-substituted hydroxythiophenes. IV. Preparation of 3- and 4-(2-, 3- and 4-pyridyl)-2-hydroxythiophenes

3-(2-, 3- and 4-Pyridyl)-2-methoxythiophenes have been prepared in good yields through the Pd(0)-cat-alyzed coupling of the three isomeric bromopyridines with 3-trimethylstannyl-2-methoxythiophene. This compound was prepared through halogen-metal exchange of 3-bromo-2-methoxythiophene followed by stannylation. 3-Bromo-2-methoxythiophene was prepared by dibromination and α-debromination of 2-methoxythiophen. Most attempts to demethylate 2-methoxy-3-pyridylthiophenes using a large variety of reagents failed, probably due to the instability and high reactivity of the desired 3-pyridyl-2-hydroxythiophene systems. Only 2-methoxy-3-(3-pyridyl)thiophene reacted with boron tribromide to give 3-(3-pyridyl)-3-thiolene-2-one, which only was stable in ether solution at ?20°. The attempted demethylation of 2-methoxy-3-(2-pyridyl)thiophene with trimethylsilane chloride/sodium iodide in refluxing acetonitrile led to a dimer. Demethylation of the 2-methoxy-3-pyridylthiophenes with dibenzyl diselenide and sodium borohydride gave 3-pyridylthiophan-2-ones. A number of other routes to prepare 3-pyridyl-2-hydroxythiophenes were also explored, but none of them gave the desired compounds. On the other hand, the 4-(2-, 3-, and 4-pyridyl)-2-hydroxythiophene systems could easily be prepared by hydrogen peroxide oxidation of the corresponding 4-pyridyl-2-thiopheneboronic esters, which were obtained from 2-bromo-4-pyridylthiophenes by halogen-metal exchange followed by reaction with ethyl borate. The 2-bromo-4-pyridylthiophenes were prepared by dibromination of the known 3-pyridylthiophenes to the 2,5-dibromo derivatives, and removal of the 2-bromine by halogen-metal exchange at ?100°, followed by hydrolysis. The ¹H nmr and ir spectroscopic investigations show that these quite stable 2-hydroxythiophene systems exist exclusively in the 4-pyridyl-3-thiolen-2-one forms.     

Noncryogenic I/Br-Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-bis[2-(N,N-dimethylamino)ethyl] ether complexes

[reaction: see text] Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide-magnesium exchange with isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to afford the corresponding Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford arylboronic acids in good to excellent yields.     

α-Lithiation and electrophilic substitution of 1,4,4-trimethyl-3,4-dihydroquinolin-2-one

Treatment of 1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (2) with lithium diisopropylamide (LDA) followed by a wide range of electrophiles give the corresponding 4,4-dimethyl-3-substituted-3,4-dihydroquinolin-2-ones (3-13), providing a very mild electrophilic substitution of the 4,4-dimethyl-1,2,3,4-tetrahydroquinoline core.     

beta-acylvinyl anion and dianion equivalents: lithiation of 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole: preparation and elaboration of 1-(2-oxiranylvinyl)-1H-benzotriazoles

The allyllithium generated from 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole (5) and LDA, in the presence of HMPA, reacts with enolizable and nonenolizable carbonyls solely at the CCl terminus to give 1-(2-oxiranylvinyl)benzotriazoles 6a-g in 61-82% yields. Allyllithiums generated from 6a,c reacted exclusively at the CBt terminus to give 10a-d in 68-88% yields. Acidic hydrolysis of (oxiranylvinyl)benzotriazoles 6a-g and 10a-d provided 4-hydroxyalk-2-en-1-one derivatives 12a,b,c,e,g, 13a-d, and furan 14 in 54-86% yields.     

Synthesis of functionalized pyridazin-3(2H)-ones via nucleophilic substitution of hydrogen (SNH)

Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded 4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the first examples of cine substitution in which the anionic σ(H)-adduct is quenched by electrophiles (other than a proton) before elimination takes place. Insight into the reaction mechanism led to the direct transformation of 2-benzylpyridazin-3(2H)-one (7) and 2-benzyl-6-chloropyridazin-3(2H)-one (9) into the corresponding C-4 alkyl and aryl derivatives (when Br(2) was used as the electrophile).     

Formation and reactivity of dilithiated N-furfurylbenzamides. Synthesis of α-substituted N-furfurylbenzamides

Dianion $\text{3}$ can be efficiently and regioselectively generated from N-furfurylbenzamide with lithium diisopropylamide/tetrahydrofuran/?78°C and react with various electrophiles to give α-substituted N-furfurylbenzamide derivatives in good yields.     

3-(Acylamino)-3-amino-2-nitroacrylonitriles from N-Acyl-S-methyl-3,3-diamino-2-nitroacrylthioimidates

Reaction of N-acyl-3,3-diamino-2-nitroacrylthioamides 1 with MeI at room temperature leads to N-acyl-S-methyl-3,3-diamino-2-nitroacrylthioimidates 2 in moderate yields. The latter react with Hg(OAc)₂ in DMF yielding 3-(acylamino)-3-amino-2-nitroacrylonitriles 8 . The structures of 2a and 8a were established by X-ray crystallography.