A new general approach for the stereocontrolled synthesis of functionalised γ- and δ-lactams

A new flexible approach for the stereoselective synthesis of substituted 1H-pyrrol-2(5H)-ones and 3,6-dihydro-1H-pyridin-2-ones has been developed. The general strategy employed the stereoselective reduction of a series of α,β-unsaturated ketones under chelation control to give the corresponding allylic alcohols. Overman rearrangement to install the key C-N bond followed by conversion to either prop-2-enoyl or but-3-enoyl derivatives and a ring closing metathesis reaction gave the target unsaturated γ- and δ-lactams. The synthetic utility of these compounds as building blocks was demonstrated by the preparation of the N-Boc derivative of (-)-coniine.     

Total synthesis of (+)-phomopsolide C by ring-size selective ring-closing metathesis/cross-metathesis

[reaction: see text]A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM) and its application to a short total synthesis of (+)-phomopsolide C are described. The key bond-forming reactions in this approach are a chemoselective cross-metathesis (CM) and RCM.     

4-Amino-1,5-dihydro-2H-pyrrol-2-one aus Bortrifluorid-katalysierten Umsetzungen von 3-Amino-2H-azirinen mit Carbonsäure-Derivaten

4-Amino-1,5-dihydro-2H-pyrrol-2-ones from Boron Trifluoride Catalyzed Reactions of 3-Amino-2H-azirines with Carboxylic Acid Derivatives Reaction of 3-amino-2H-azirines 1 with ethyl 2-nitroacetate ( 6a ) in refluxing MeCN affords 4-amino-1,5-dihydro-2H-pyrrol-2-ones 7 and 3,6-diamino-2,5-dihydropyrazines 8 , the dimerization product of 1 (Scheme 2). Thus, 6a reacts with 1 as a CH-acidic compound by C? C bond formation via C-nucleophilic attack of deprotonated 6a onto the amidinium-C-atom of protonated 1 (Scheme 5). The scope of this reaction seems to be rather limited as 1 and 2-substituted 2-nitroacetates do not give any products besides the azirine dimer 8 (see Table 1). Sodium enolates of carboxylic esters and carboxamides 11 react with 1 under BF₃ catalysis to give 4-amino-1,5-dihydro-2H-pyrrol-2-ones 12 in 50–80% yield (Scheme 3, Table 2). In an analogous reaction, 3-amino-2H-pyrrole 13 is formed from 1c and the Li-enolate of acetophenone (Scheme 4). A reaction mechanism for the ring enlargement of 1 involving BF₃ catalysis is proposed in Scheme 6.     

Synthesis of New Substituted 2,3-Dihydro-1,4-dioxin-2-ones and 1,4-Dioxan-2-ones

3-Alkyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones reacted with acetyl chloride in the presence of zinc(II) chloride to give 5-acetyl-3-alkyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones. Oxidation of the latter with hydrogen peroxide in formic acid, followed by treatment with magnesium bromide, afforded 3-alkyl-6-methyl-1,4-dioxane-2,5-diones. Chlorination of 6-hydroxymethyl-1,4-dioxan-2-ones with thionyl chloride and subsequent dehydrochlorination led to formation of 6-methylene-1,4-dioxan-2-ones.     

A Convenient One-Pot Synthesis of Cyclohexenic Primary Amines

The reaction between Grignard reagents prepared from allylic or propargylic halides and the N-phenylsulfenimine derived from the heptane-2,6-dione affords primary 1-alkenyl (or alkynyl)-3-methylcyclohex-2-enamines in good yields.     

Reactions of 1,2-diaza-1,3-dienes with thiol derivatives: a versatile construction of nitrogen/sulfur containing heterocycles

The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines, 1,4-benzothiazines and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol affords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Cycloacylation of 3-oxo-3-R1-N-R2-propanethioamides by 3-aryl-2-propenoyl chlorides

The products of cyclocondensation of 3-oxo-3-R¹-N-R²-propanethioamides with 3-aryl-2-propenoyl chlorides in acetone in the presence of potassium carbonate are 5-acyl-1-aryl(alkyl)-4-aryl-6-thioxopiperidin-2-ones, 5-acyl-2-aryl-6-aryl(alkyl)amino-2,3-dihydro-4H-thiopyran-4-ones, and 2-acetonylidene-3,6-diaryl-5,6-dihydro-4H-1,3-thiazin-4-ones, the structure of which is proven by both spectral methods and chemical conversions. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 623–628, April, 2006     

Chemistry of Ethanediyl S,S-Acetals. VII. A Stereoselective Synthesis of Allylic Alcohols with cis-Configurated Double Bond

A new high yielding coupling reaction of C-2 monosubstituted 5,6-dihydro-1,4-dithiins with aldehydes is reported. In this way allylic alcohols having the cis-substituted double bond tied up by a sulfur-containing ring can be readily prepared. Subsequent stereoselective sulfur removal then affords allylic alcohols with cis-configurated double bond.     

Ring forming reactions of imines of 2-aminobenzaldehyde and related compounds

By addition of organometallic reagents to 2-aminobenzonitriles followed by quenching with suitable electrophiles (acyl halides, aldehydes and ketones), several types of 6-membered benzofused aromatic and non-aromatic nitrogen heterocycles could be obtained. Rearrangements leading to 1,2-dihydro-3H-1,4-benzodiazepin-3-ones and preparation of various quinazolines are described.     

5,6,7,8-Tetrafluoro-4-hydroxycoumarin derivatives in reactions with o-phenylenediamine

The reactions of 5,6,7,8-tetrafluoro-4-hydroxycoumarin derivatives with o-phenylenediamine occur with pyrone heterocycle cleavage and formation of substituted benzodiazepin-2-ones. 5,6,7,8-Tetrafluoro-4-hydroxycoumarin affords 4-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-one, 3-acetimidoyl-5,6,7,8-tetrafluoro-4-hydroxycoumarin produces 3-(3,4,5,6-tetrafluoro-2-hydroxybenzoyl)-4-methyl-1,2-dihydro-1H-1,5-benzodiazepin-2-one, and 3-acetyl-5,6,7,8-tetrafluoro-4-hydroxycoumarin yields both these heterocycles.     

Aminomethylation of 3-aryl-7-hydroxycoumarins

The reaction of the analogs of natural 3-arylbenzopyran-2-ones with electrophilic reagents of aminal structure was studied. Substituted 8-aminomethyl-3-aryl-7-hydroxycoumarins were synthesized. The optimum conditions were determined for the production of 9-alkyl- and 9-(het)arylmethyl derivatives of 3-aryl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-one in the series of analogs of natural 3-arylbenzopyran-2-ones.     

Study of the addition of Grignard reagents to 2-aryl-3H-indol-3-ones

Grignard reagents are added to the carbonyl group of 2-aryl-3H-indol-3-ones to generate 3-alkyl(or phenyl)-2-aryl-3H-indol-3-ols, which are in turn rearranged to yield 2-alkyl(or phenyl)-2-aryl-1,2-dihydro-3H-indol-3-ones.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Action des composes organomagnesiens sur les pyrones-2-VII : Etude de la stabilite relative des hydroxy-6 dihydro-5,6 2h-pyrannes et des cetols tautomeres correspondants

In the reaction between organomagnesium compounds and 2-pyrones, the relative stability of the 6-hydroxy 5,6-dihydro 2H-pyrans and their tautomeric forms (ketols) has no influence on the reaction pathway. When ethylenic ketols are obtained, the corresponding tautomeric dihydropyranols are prepared in a selective way by reaction of nucleophilic reagents on the 3,6-dihydro-2-pyrones. In the other hand, the exclusive formation either of the dihydropyranols or of the unsatured ketols E, during these two reactions, shows up that here is no equilibrium between these two entities in the experimental conditions.     

An approach to substituted 4-hydroxypyran-2-ones

We examined a method for the preparation of 4-hydroxypyran-2-ones in two steps from aryl ketones and ethyl malonyl chloride (or ethyl 2-methylmalonyl chloride). These 4-hydroxypyran-2-ones are useful precursors as they may be transformed in two steps to the 2-methoxypyran-4-ones, which is found in phenoxan—a naturally occurring compound discovered to have anti-HIV activity.     

A facile four-component tandem protocol for the synthesis of novel 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones

A one-pot, four-component reaction of 1-(phenylsulfinyl)- or 1-(4-chlorophenylsulfinyl)propan-2-one, aromatic aldehydes and ammonium acetate in a 1:2:1 molar ratio affords a series of new 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones. This reaction proceeds presumably via a double Mannich reaction-elimination tandem sequence.     

New investigations on the chemical behavior of 4-keto-1H-4,5-dihydro-1,2,5-benzotriazepines

The chemical behavior of 4-keto-1H-4,5-dihydro-1,2,5-benzotriazepines towards basic reagents has been investigated. Evidence is given that 4-keto-1H-4,5-dihydro-1,2,5-benzotriazepines unsubstituted at position 3 are cleaved by sodium hydroxide and alkoxides furnishing sodium cyanide and 2-amino-3-keto-quinoxalines. The same benzotriazepines substituted by a carbamidoximo- or a carbohydrazino-group at position 3 undergo, when treated with the same reagents, isomerization reactions yielding 3-amino-4-arylazo-isoxazolin-5-ones and 4-arylazo-pyrazolidin-3,5-diones respectively. The structure of these products is demonstrated and a mechanism for their formation is proposed.     

Ringerweiterungen und Ringverengungen bei der Umsetzung von 1, 3-Oxazolidin-2, 4-dionen und 1, 3-Thiazoiidin-2, 4-dion mit 3-Amino-2H-azirinen

Ring Enlargements and Ring Contractions in the Reaction of 1, 3-Oxazolidine-2, 4-diones and l, 3-Thiazolidine-2, 4-dione with 3-Amino-2H-azirines The reaction of 3-amino-2H-azirines 1 and 1, 3-oxazolidine-2, 4-diones 2 in MeCN at room temperature leads to 3, 4-dihydro-3-(2-hydroxyacetyl)-2H-imidazol-2-ones 3 in good yield (Scheme 2, Table 1). A reaction mechanism proceeding via ring enlargement of the bicyclic zwitterion A to give B, followed by transannular ring contraction to C, is proposed for the formation of 3 . This mechanism is in accordance with the result of the reaction of 2a and the ¹⁵N-labelled 1a *: in the isolated product 3a *, only N(3) is labelled (Scheme 1). The analogous reaction of 1 and 1, 3-thiazolidine-2, 4-dione ( 5 ) is more complex (Schemes 4 and 5, Table 2). Besides the expected 3, 4-dihydro-3-(2-mercaptoacetyl)-2H-imidazol-2-ones 7, 5-amino-3, 4-dihydro-2H-imidazol-2-ones of type 8 and/or N-(1, 4-thiazin-2-ylidene)ureas 9 are formed. In the case of 2-(dimethylamino)-1-azaspiro[2. 3]hex-1-ene ( 1d ), the postulated eight-membered intermediate 6d could be isolated. Its structure as well as that of 9f has been determined by X-ray structure analysis. A reaction mechanism for the formation of the 1, 4-thiazine derivatives of type 9 is proposed in Scheme 6.     

2-(<Emphasis Type="Italic">N</Emphasis>-Alkylamino)-1-(trifluoroacetimidoyl)vinyl ketone derivatives as potential reagents in heterocyclic synthesis

A reaction of 3-acetyl-4-amino-5,5,5-trifluoropent-3-en-2-one diphenylboron chelate and ammonia or primary amines affords 4-amino- or 4-alkylamino-3-trifluoroacetimidoylpent-3-en-2-ones, new reagents which can be used for the synthesis of pyrimidines with trifluoromethyl group.