Synthesis of N6-phosphorylated sydnone imines and their functionalization via 4-Li derivatives. Novel bicyclic sydnone imines

The highly efficient gram-scale method for preparation of up to date hardly available N₆-phosphorylated sydnone imines based on the reaction of sydnone imine hydrochlorides with substituted phosphinate or phosphonate acids chlorides in the presence of a base was elaborated. A possibility of straight deprotonation of sydnone imines with n-BuLi followed by the reaction 4-Li-derivatives thus obtained with electrophiles was demonstrated. Novel representatives of bicyclic sydnone imines fused via 4,5-edge of the oxadiazolium ring were obtained. Also sydnone imines containing both phosphorus and sulfur functionalities were obtained with high yields.     

N6-tert-Butoxycarbonyl derivatives of sydnone imines: Preparation and synthetic use

A highly efficient gram-scale method for the C(4)-functionalization of sydnone imine hydrochloride derivatives was developed. This new approach was realized through consecutive reactions including the preparation of a C(3)-substituted N₆-tert-butoxycarbonyl sydnone imine derivative, deprotonation with n-BuLi and reaction of the lithiated-intermediate with an electrophilic agent, and removal of the Boc protecting group.     

Generation of azomethine imines via opening of the diaziridine ring in unsymmetrically substituted 6-aryl-1,5-diazabicyclo-[3.1.0]hexanes and their transformations

Thermally induced opening of the diaziridine ring at the carbon-nitrogen bond in unsymmetrically substituted 6-aryl-1,5-diazabicyclo[3.1.0]hexanes is characterized by low regioselectivity which is likely to be determined by the inductive effect of substituents in the trimethylene bridge. 1,3-Dipolar cycloaddition of the resulting azomethine imines to phenyl isocyanate is regioselective: it occurs at the double carbon-nitrogen bond with predominant formation of the corresponding cis adducts due to dipolarophile approach to Z-azomethine imine at the sterically less hindered side. Analogous approach of dipolarophile is also observed in the reaction with N-arylmaleimides.     

Reaction of N-phenyl(benzylidene,phenoxy)acetyl-1,4-benzoquinone imines with sodium azide

N-Phenyl(benzylidene, phenoxy)acetyl-1,4-benzoquinone imines reacted with sodium azide to give the corresponding 1,4-addition products, N-(4-hydroxyphenyl) carboxamides. Quantum chemical calculations showed that the initial step in the examined reaction is addition of azide ion to neutral quinone imine molecule.     

Aza-Wittig reaction of N-phosphorylalkyl phosphazenes with carbonyl compounds and phenylisocyanate. Synthesis of 4-amino-3-phosphoryl-2-azadienes and pyrazine-phosphonates

Simple and functionalized N-phosphorylalkyl imines and N-phosphorylalkyl-N′-phenyl-carbodiimides are obtained by aza-Wittig reaction of phosphazenes derived from aminophosphonates with carbonyl compounds and phenyl isocyanate. The reaction with dimethylformamide diethyl acetal (DMF-DEA) of these functionalized imines leads to the synthesis of 4-amino-3-phosphoryl-2-azadienes. N-Phosphorylmethyl imine derived from benzaldehyde can be used for the preparation of substituted pyrrole-phosphonates, while acid treatment of 4-dimethylamino-3-diethylphosphoryl-1-phenyl-2-azadiene gives diethyl 5-diethylphosphorylpyrazin-2-ylphosphonate.     

Distinct chemoselectivity in the reaction of N-(thio)phosphoryl imines with diethylzinc

This report describes the reaction of N-(thio)phosphoryl imines with diethylzinc under different conditions. An interesting and distinct chemoselectivity between hydrogen-addition and ethyl-addition to imine double bond is disclosed: in weakly polar solvent, e.g. toluene, N-(thio)phosphoryl imines were exclusively reduced in excellent yields via a β-H transfer from diethylzinc to imine double bond; in polar solvents like THF, the reduction product was competitively formed as a major product together with the minor product resulting from ethyl-addition to imine double bond; in sharp contrast, in the presence of strong coordinative additive N,N,N′,N′-tetramethylethylenediamine (TMEDA), the ethylation product was formed exclusively from the reaction of N-(thio)phosphoryl imine with diethylzinc. These results are discussed and explained in terms of the coordination interactions between the imine, solvent, and additive with diethylzinc.     

Carbon-carbon bond formations at the benzylic positions of N-benzylxanthone imines and N-benzyldi-1-naphthyl ketone imine

Two N-benzyl imines are designed to allow for carbon-carbon bond formations at the aminated benzylic positions. Direct benzylic arylation reactions of N-benzylxanthone imine with aryl chlorides proceed under palladium catalysis in the presence of cesium hydroxide, yielding the corresponding benzhydrylamine derivatives. Alkylation reactions of N-benzyldi-1-naphthyl ketone imine with alkyl halides in the presence of potassium tert-butoxide afford the corresponding 1-phenylalkylamines in high yields. Conjugate addition of N-benzyldi-1-naphthyl ketone imine is also described.     

A new synthesis of amides and γ-lactones based on the conjugate addition of lithium enolate of amides to 1-chlorovinyl p-tolyl sulfoxides

Reaction of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from chloromethyl p-tolyl sulfoxide and ketones or aldehydes, with lithium enolate of N,N-dimethylacetamide gave the adducts in good to quantitative yields. The adducts were converted to several kinds of amides in high overall yields. Treatment of the adducts with trifluoroacetic anhydride in the presence of NaI resulted in the formation of γ-tolylsulfanylated γ-lactones in high yields. The scope and limitations of this method and the mechanism of the reactions are also discussed. These procedures offer a new and effective method for the synthesis of amides and γ-lactones having substituents on the β-carbon from N,N-dimethylacetamide with carbon elongation.     

Reaction of <Emphasis Type="Italic">N</Emphasis>-chloro-1,4-benzoquinone imines with thiols

N-Chloro-1,4-benzoquinone imines reacted with arenethiols to give different products, depending on the conditions and initial quinone imine structure. N-(Arylsulfanyl)-1,4-benzoquinone imines were obtained as a result of nucleophilic substitution of the chlorine atom, and 1,4-benzoquinone imines containing an aryl-sulfanyl substituent in the quinoid ring were formed according to the radical mechanism. The reactions of N-chloro-1,4-benzoquinone imines with heterocyclic thiols afforded only the corresponding chlorine substitution products.     

Activated sterically strained C=N bond in <Emphasis Type="Italic">N</Emphasis>-substituted <Emphasis Type="Italic">p</Emphasis>-quinone mono- and diimines: XV. Synthesis,structure, and reactions with alcohols of <Emphasis Type="Italic">N</Emphasis>-carbamoyl-1,4-benzoquinone imines

The reaction of 4-aminophenols with N-nitrourea or with sodium cyanate in acetic acid gave the corresponding 4-ureidophenols which were oxidized to N-carbamoyl-1,4-benzoquinone imines, substituted N-(4-oxocyclohexa-2,5-dien-1-ylidene)ureas. N-(2,6-Dimethyl-4-oxocyclohexa-2,5-dien-1-ylidene)urea possessing activated sterically strained C=N bond reacted with alcohols to afford N-(1-alkoxy-2,6-dimethyl-4-oxocyclohexa-2,5-dienyl)ureas.     

Trichloropyruvate N-acylimines. Reactions with phosphorus nucleophiles

Reactions of N-aroyltrichloroethaneimines CCl₃C(R)=NCOAr (II, R = COOMe, CN) with phosphorus nucleophiles were studied. The reaction of imines II with o-phenylenediethylamidophosphite proceeded as [4+1]-cycloaddition leading to formation of stable spirocyclic phosphoranes. The structure of one of them was proved by the XRD analysis. The reaction of imine II with acyclic P(III) derivatives [Ph₃P, Ph₂POEt, (PhO)₃P] also includes the formation of labile monocyclic phosphoranes which eliminate phosphine oxide and undergo chlorotropic transfer leading to trichloroazadienes CCl₂=C(R)N=C(Cl)Ar. The reaction of imines II with (EtO)₂POH in the presence of triethylamine leads to the formation of (EtO)₂P(O)Cl and the corresponding dichlorovinylamides CCl₂=C(R)NHCOAr.     

Heterodienophiles—V : A stereochemical study of aldimine-diene cycloadditions

A study has been made of exo/endo ratios in the formation of azabicyclics via cycloadditions of cyclopenta- or cyclohexa-1,3-diene with N-carbethoxy and N-p -toluenesulfonyl trichloromethyl imines, N-p-toluenesulfonyl trifluoromethyl imine, and N-phenyl-5-methoxyhydantoin. For N-carbethoxy imines both thermal and acid catalyzed cycloadditions were investigated with acid catalysis being notably evident. Cyclic Z-imines afford endo adducts while acyclic imines afford exo/endo mixtures.     

Anionic N-heterocyclic carbenes by decarboxylation of sydnone-4-carboxylates

Unstable N-heterocyclic carbenes can be masked and stabilized as pseudo-cross-conjugated hetarenium-carboxylates which decarboxylate on warming. This study deals with the decarboxylation of carboxylates of mesoionic compounds to generate anionic N-heterocyclic carbenes. Lithium sydnone-4-carboxylates were therefore prepared via 4-bromosydnones by halogen-lithium exchange with nBuLi and subsequent treatment with carbon dioxide. Protonation gave the corresponding sydnone-4-carboxylic acids. Thermogravimetric measurements in addition to temperature dependent IR spectroscopy proved the decarboxylation of lithium sydnone-4-carboxylates and formation of the corresponding sydnone anions which can be represented as anionic N-heterocyclic carbenes. In DMSO-d6 solution, water favors the decarboxylation. Calculations have been performed to elucidate the mechanism of the decarboxylation in the absence and presence of water.     

Erstes Beispiel einer H-Verschiebung in ‘Thiocarbonyl-aminiden’ (N-(Alkylidensulfonio)aminiden)

First Example of an H-Shift in ‘Thiocarbonyl Aminides’ (N-(Alkylidenesulfonio)aminides) Reaction of benzyl azide ( 15a ) with the sterically hindered C?S group of 4,4-dimethyl-1,3-thiazole-5(4H)-thiones 14 (Scheme 3) and 1,1,3,3-tetramethylindane-2-thione ( 17 , Scheme 4) at 80° leads to the corresponding imines in high yield, without formation of any by-product. In contrast, 15a and 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 7 ) under the same conditions yielded, in addition to imine 19 , products 20a and 21 (Scheme 5). For the formation of 20a , a reaction mechanism via [1,4]-H shift in the intermediate ‘thiocarbonyl aminides’ 23 is proposed (Scheme 6). Product 21 as well as the dithiazole derivative 22 , which is formed only in the reaction with 4-nitrobenzyl azide ( 15c ), are formal adducts of the dipole 23 . Whereas precedents are known for the formation of cycloadducts of type 22 , the pathway to 21 is not known. Two possible mechanisms of its formation are proposed in Schemes 8 and 9.     

Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected α-amino acids and amino ketones

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO₃ under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-butylsulfinyl protected α-amino acids or α-amino ketones are accessible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.     

Asymmetric synthesis of syn and anti methyl 2,3-diamino-3-phenylpropanoate derivatives from N-substituted imines and Schöllkopf's bislactim ether

The reaction between differently N-substituted benzaldimines and (2R)-Schöllkopf's bislactim ether was studied: the azaenolate addition to imines followed by hydrolysis of the resulting adducts gave syn-(2S,3R) and anti-(2S,3S)-methyl 2,3-diamino-3-phenylpropanoate derivatives in good yields. The configurations of the newly formed stereocenters of α,β-diamino acids were assigned on the basis of the ¹H NMR analysis and by comparison with known products. The diastereoisomeric ratios were explained taking into account the effect of the substituent present on the imine nitrogen on the transition state stability. This method represents a new approach for stereoselective synthesis of α,β-diamino acids.     

Synthesis of conjugated enynes from ketones and aldehydes by 1,2-CC insertion and 1,2-CH insertion of carbenoids as the key reactions

The addition reactions of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of the adducts with Grignard reagents resulted in the formation of conjugated enynes in good to high yields via the 1,2-carbon-carbon insertion (1,2-CC insertion) reaction of the generated magnesium carbenoid intermediates. On the other hand, the addition reactions of 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes with lithium acetylides directly gave conjugated enynes bearing a p-tolyl sulfinyl group at the 1-position through the 1,2-carbon-hydrogen insertion (1,2-CH insertion) reaction of the generated lithium carbenoid intermediates. These procedures provide a good way for the synthesis of multi-substituted conjugated enynes from ketones and aldehydes.     

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.     

Isomerization and 1,3-dipolar cycloaddition of gem-difluorinated NH-azomethine ylides in the reaction of difluorocarbene with diarylmethanimines

Reaction of difluorocarbene with diarylmethanimines leads to the formation of gem-difluorinated NH-azomethine ylides, two types of competing transformations of which are found to be characteristic: a formal 1,2-H shift into N-(difluoromethyl)imines and 1,3-dipolar cycloaddition to electron-deficient multiple bonds. α,α,α-Trifluoroaceto-phenones are efficient dipolar traps for difluoro NH-ylides, the addition of which to the dipole proceeds regioselectively with the formation of 4-fluoro-2,5-dihydrooxazoles. According to the quantum-chemical calculations by the DFT B3LYP/6-31G* method, 1,3-dipolar cycloaddition of difluorinated NH-azomethine ylides to a C=O bond with the formation of 4-fluoro derivatives of oxazole has lower barrier of activation than the reaction, leading to another regioisomer; the formal 1,2-H shift in the ylide occurs intermolecularly with participation of an imine, a precursor of the ylide.     

New synthesis of multisubstituted cyanocyclopropanes by the intramolecular SN2 alkylation and 1,3-CC insertion reaction of magnesium carbenoids as the key reactions

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides derived from ketones and aldehydes with lithium α-cyano carbanions gave nitrile adducts in high to quantitative yields. Treatment of the nitrile adducts derived from acetonitrile with excess i-PrMgCl in THF resulted in the formation of cyanocyclopropanes via the intramolecular S_N2 alkylation of the generated magnesium carbenoids. The intermediate of this reaction was proved to be a cyclopropylmagnesium chloride and was reactive with electrophiles to give multisubstituted cyanocyclopropanes. On the other hand, the reaction of the nitrile adducts derived from arylacetonitriles with i-PrMgCl resulted in the formation of 2-arylcyanocyclopropanes by the 1,3-carbon–carbon (1,3-CC) insertion reaction of the generated magnesium carbenoid intermediates. This reaction was found to proceed in a highly stereospecific manner. The key reactions, intramolecular S_N2 alkylation and 1,3-CC insertion reaction of the magnesium carbenoids, are the first examples for the reaction of the magnesium carbenoids bearing a nitrile functional group.