Domino reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: general and stereoselective synthesis of gamma-alkylidenebutenolides

The Lewis acid catalyzed cyclization of oxalyl chloride with 1,3-bis(trimethylsilyloxy)-1,3-dienes 3, derived from 1,3-dicarbonyl compounds 1, provides a new and general approach for the synthesis of gamma-alkylidenebutenolides 4, a pharmacologically and synthetically important class of substances. A variety of butenolides were efficiently prepared in good yields and with very good regio- and stereoselectivities. An up-scaling of the reaction was possible. The use of the Lewis acid trimethylsilyl-trifluoromethanesulfonate (TMSOTf) proved to be superior to other activation conditions. Sterically undemanding gamma-alkylidenebutenolides could be prepared alternatively by reaction of the corresponding 1,3-dicarbonyl dianions with N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). In contrast to the dianion method, the Lewis acid catalyzed reaction also facilitated the cyclization of sterically hindered, base-labile, cyclic and functionalized substrates. From a methodology viewpoint, the dianion reaction represents the first cyclization of a bis-Weinreb amide and the first cyclization of an oxalic acid-synthon with an ambident dianion. The TMSOTf-catalyzed reactions are both the first cyclizations of 1,3bis(trimethylsilyloxy)-1,3-dienes with a C2 dielectrophile and the first cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes with a carboxylic acid dichloride or a related dielectrophile.     

Reaction of 1,3-Dibromo- and 1,3-Dichloroacetone with 2-Aminoazaheterocycles

The reactions of 1,3-dibromoacetone with 2-aminoazines and 2-aminoazoles has been carried out for the first time and the pure intermediate quaternary salts have been isolated. They undergo cyclization to the corresponding imidazoazines and imidazoazoles containing a bromomethyl group. Similar condensations were carried out with 1,3-dichloroacetone.     

The syntheses of ethoxycarbonyl-1,3-dioxoles and oxazoles from the copper catalyzed thermolysis of ethyl diazopyruvate in the presence of ketones,aldehydes and nitriles

The copper salt-catalyzed interaction of ethyl diazopyruvate with ketones, aldehydes and nitriles was examined. A variety of 1,3-dioxoles and oxazoles was obtained in moderate yield. The formation of enol ethers, epoxides, carbon-carbon insertion products, aziridines, and azetidines, typical products of carbene reactions with carbon-heteroatom multiple bonds, was not observed. Evidence for the operation of a 1,3-dipolar cycloaddition reaction is presented.     

Photocyclization of 2-chloro-substituted 1,3-diarylpropan-1,3-diones to flavones

The photochemical behavior of 2-halo-substituted 1,3-diarylpropan-1,3-dione strongly depends on the nature of the halogen atom bonded and the presence of electron-donor groups on the phenyl ring. In the case of 2-chloro-1,3-diphenylpropan-1,3-dione and 1-(3,5-dimethoxyphenyl)-3-phenylpropan-1,3-dione, cyclization to flavones was the sole reaction pathway, whereas in the case of 2-chloro-1,3-di(4-methoxyphenyl)propan-1,3-dione, only products derived from alpha-cleavage were observed. 2-Fluoro derivatives of 1,3-diarylpropan-1,3-diones were photostable; on the other hand, 2-chloro-2-fluoro derivates resulted in 3-fluoroflavones.     

Conversion of epoxides to 1,3-dioxolanes catalyzed by tin(II) chloride

Anhydrous tin(II) chloride is an efficient catalyst for the reaction of epoxides with acetone to prepare 2,2-dimethyl-1,3-dioxolanes (acetonides) in good to excellent yields. Mono-, di-, and trisubstituted epoxides participate equally well in this diastereospecific reaction. The use of single enantiomer epoxides under the reported conditions results in significant erosion of optical activity.     

Reductive spiroannulation of nitriles with secondary electrophiles

The scope of reductive decyanation and spiroannulation reactions has been expanded to include secondary electrophiles for potentially useful transformations. Secondary phosphates and chlorides, as well as terminal epoxides, cyclize in a stereospecific fashion. Both endo and exo modes of cyclization were observed with terminal epoxides.     

The first 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene and its application to the regioselective synthesis of chlorinated arenes

Chlorinated phenols, benzophenones, and butenolides are prepared by various one-pot cyclization reactions of the first 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadiene.     

Chelation control in the [3+3] annulation reaction of alkoxy-substituted 1,1-diacylcyclopropanes with 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Functionalized arenes were prepared by chelation-controlled ‘[3+3] cyclization/homo-Michael’ reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with benzyloxy- or methoxy-substituted 1,1-diacylcyclopropanes.     

Ruthenium-catalyzed cyclization of alkyne-epoxide functionalities through alternation of the substituent and structural skeleton of epoxides

Treatment of 1-(o-ethynylphenyl)-2-alkyl-2-aryl epoxides with TpRuPPh(3)(CH(3)CN)(2)PF(6) catalyst (10 mol %) in hot toluene (100 degrees C, 12 h) led to an atypical cyclization and gave 1-aryl-2-alkyl-1H-indene derivatives and carbon monoxide efficiently. The cyclization of 1-cis-enynyl-2-alkyl epoxides with this catalyst in hot toluene (10 mol %, 100 degrees C, 12 h) gave 2,5-disubstituted phenols in 45-72% yields. Under the same conditions, 1-cis-enynyl- 2,2-dialkyl epoxides and 1-cis-enynyl- 2-alkyl-2-aryl epoxides gave the corresponding 6,6-disubstituted cyclohexa-2,4-dien-1-ones in good yields (85-91%). Mechanisms for these new cyclization reactions are proposed on the basis of trapping experiments and isotope labeling experiments. The formation of 1H-indene products likely involves ruthenium-acyl intermediates whereas cyclohexa-2,4-dien-1-ones are thought to derive from ruthenium-ketene intermediates.     

Chelation-control in the formal [3+3] cyclization of 1,3-bis-(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. One-pot synthesis of 3-aryl-3,4-dihydroisocoumarins

The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones resulted in the one-pot formation of 3-aryl-3,4-dihydroisocoumarins. The reactions proceeded by regioselective cyclization to give 6-(2-aryl-2-chloroethyl)salicylates, which underwent a silica gel-mediated lactonization. The cyclizations of protected 1-amino-5-silyloxy-hex-4-en-3-ones proved to be not regioselective.     

Tandem one-pot synthesis of polysubstituted pyridines using the Blaise reaction intermediate and 1,3-enynes

A tandem one-pot method for the construction of a pyridine moiety with selective control of substitution patterns has been developed through the sequential reactions of nitrile with a Reformatsky reagent and 1,3-enyne involving regio- and chemoselective addition of the Blaise reaction intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatization cascade.     

Alkylation of sterically hindered 1,3-diketones under phase-transfer conditions

Sterically hindered 1,3-diketones react selectively with propargyl and allyl bromides under conditions of phase transfer catalysis to giveC-alkylated products, whereas reactions with butyl and benzyl chlorides yield mixtures ofC- andO-isomers. An increase in the size of the substituents present in the initial 1,3-diketone hampers introduction of the second propargyl group. The propargyl-substituted 1,3-diketones undergo cyclization under the alkylation conditions to give substituted furans.     

New Addition Reactions of Organometal Compounds with 4,4-Dimethyl-1,3-thiazole-5(4H)-thiones

Addition reactions of organometallic reagents with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones were studied. Whereas the reactions with alkyllithium and alkyl Grignard reagents occurred in the thiophilic manner, the carbophilic addition was observed with allyllithium and allyl Grignard reagents. A radical reaction mechanism is proposed for rationalizing these observations (Scheme 5). A radical cyclization of the prepared 5-allyl-4,5-dihydro-1,3-thiazole-5-thiol derivatives yielded 1,6-dithia-3-azaspiro[4.4]non-2-enes (Table 4).     

Unprecedented Cu-catalyzed coupling of internal 1,3-diynes with azides: one-pot tandem cyclizations involving 1,3-dipolar cycloaddition and carbocyclization furnishing naphthotriazoles

A one-pot protocol for the synthesis of triazole-annulated polyheterocycles via metal-catalyzed coupling of internal 1,4-disubstituted 1,3-diynes and organic azides has been described. The mechanistic rationale for the reaction suggests tandem cyclizations involving copper-catalyzed cycloaddition and 6-endo carbocyclization reactions. The cascade cyclization leads to an increase in molecular complexity to furnish naphtho[1,2-d]triazoles in satisfactory yields. The generality of the method has been demonstrated by using a series of aromatic/aliphatic azides and symmetrical internal 1,3-diynes.     

Synthesis of 1,3-benzothiazines by intramolecular dehydrogenative C–S cross-coupling in a flow electrolysis cell

Dehydrogenative cyclization of thioamides is an attractive approach for the synthesis of S-heterocycles. Reported herein is an electrochemical dehydrogenative cyclization reaction of N-benzyl thioamides in a flow electrolysis cell. The continuous-flow electrosynthesis has addressed the limitations associated with previously reported methods for the cyclization of alkylthioamides and provide a transition metal-and oxidizing reagent-free access to various functionalized 1,3-benzothiazines in good yields.     

Synthesis of chromanes by sequential ‘[3+3]-cyclization/Williamson’ reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes

Functionalized chromanes were prepared by sequential ‘[3+3]-cyclization/Williamson’ reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes with 1,1,3,3-tetramethoxypropane, 3-silyloxyalk-2-en-1-ones, and 1,1-diacetylcyclopropane. The first step of the sequence involves [3+3] cyclizations of the starting materials to give 2-(3-chloropropyl)phenols. The subsequent cyclization proceeds by intramolecular nucleophilic substitution. 6-(2-Hydroxybenzoyl)chromanes were prepared based on sequential ‘[3+3]-cyclization/Williamson’ reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes with 3-formylchromones.     

Studies on the intramolecular oxa-Pictet-Spengler rearrangement of 5-aryl-1,3-dioxolanes to 4-hydroxy-isochromans

The success and stereochemical outcome of the TiCl₄-promoted oxa-Pictet-Spengler cyclization of 5-aryl-1,3-dioxolanes to produce 1,3-disubstituted-4-hydroxy-isochromans, is influenced by the length and nature of the side chains bound to C-2 and C-4 of the dioxolane. Methyl groups yield a mixture of 4-hydroxy-isochromans in which the 1,3-trans diastereomer predominates, while bulkier substituents give 1,3-cis diastereomers. Functional groups in the C-2 side chain of the dioxolane ring may hinder cyclization by complexation with the promoter.     

Cationic cyclization of 2-alkenyl-1,3-dithiolanes: diastereoselective synthesis of trans-decalins

An unprecedented and highly diastereoselective 6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has been developed yielding trans-decalins, an important scaffold present in numerous di- and triterpenes. The novelty of this 6-endo-trig cyclization stands in the stepwise mechanism involving 2-alkenyl-1,3-dithiolane, acting as a novel latent initiator. It is suggested that the thioketal opens temporarily under the influence of TMSOTf, triggering the cationic 6-endo-trig cyclization, and closes after C-C bond formation and diastereoselective protonation to terminate the process. DFT calculations confirm this mechanistic proposal and provide a rationale for the observed diastereoselectivity. The reaction tolerates a wide range of functionalities and nucleophilic partners within the substrate. We have also shown that the one-pot 6-endo-trig cyclization followed by in situ 1,3-dithiolane deprotection afford directly the corresponding ketone. This improvement allowed the achievement of the shortest total synthesis of triptophenolide and the shortest formal synthesis of triptolide.     

Synthesis of novel 2-phenyl-5-substituted dihydropyrimidines using 2-phenyl-1,3-diaza-1,3-butadienes and electron-deficient olefins

A novel synthetic method for 2,5-disubstituted dihydropyrimidines was developed. The cyclization of 1,3-diaza-4-dimethylamino-1,3-butadienes having a N-protecting group (N-Boc, N-Cbz, N-n-C₄H₉, N-Bn or N-Ph) with electron-deficient olefins, such as α,β-unsaturated carbonyl compounds, phenyl vinyl sulfone, and acrylonitrile was studied in detail. The cyclization smoothly proceeded to afford 4-dimethylamino-1,4,5,6-tetrahydropyrimidines or 1,6-dihydropyrimidines in good yields. The isolated 4-dimethylamino-1,4,5,6-tetrahydropyrimidines were converted to 2,5-disubstituted-1,6-dihydropyrimidines through the β-elimination of the dimethylamino group. 2,5-Disubstituted-1,4(6)-dihydropyrimidines were obtained after removal of the N-Boc or N-Cbz group. Independent tautomers of the resulting dihydropyrimidines were observed.     

A facile synthesis of 4-methylene-1,3-oxazolidines from γ-hydroxybutynoate and N-tosylimines

Both nucleophilic and basic catalysts have been used to promote the cyclization reactions between γ-hydroxybutynoate and N-tosylimines to afford 4-methylene-1,3-oxazolidines in good yields. E- and Z-isomers of the final products have been isolated and characterized by NMR spectroscopy and X-ray data.