Mechanistic studies of the formation of cyclopropane-bearing systems through photoconversion of tropolone Diels–Alder adducts

Irradiation of alkyltropolone Diels–Alder adducts bearing β,γ-unsaturated ketone chromophores leads to fused polycyclic systems containing cyclopropane moieties in good yields. A detailed mechanistic study, which included the use of deuterium labeling in combination with HRMS and NMR experiments, revealed that the process is highly stereoselective, proceeds through the formation of allyl radical and ketene intermediates, and involves participation of the solvent.     

A tandem oximation-cyclization route to Δ-isoxazolines

3,5-Disubstituted Δ²-isoxazolines can be prepared from the corresponding β,γ-unsaturated ketones by treatment with hydroxylamine hydrochloride and sodium hydroxide. Evidence indicates that the mechanism of this reaction involves the formation of three intermediates; oximation of the ketone, rearrangement of the alkene, and intramolecular Michael addition of the resulting α,β-unsaturated oxime.     

Synthesis of 3-substituted indole by AlCl3-promoted reaction of β,γ-unsaturated ketone with indole

A one-pot Lewis acid-promoted reaction condition of β,γ-unsaturated ketone with indole was developed for the synthesis of 3-substituted indoles with moderate to good yields. A Lewis acid such as AlCl₃ was shown to be a promising promoter for in situ isomerization of β,γ-unsaturated ketone to its corresponding α,β-unsaturated ketone, then undergoing Friedel–Crafts Michael addition reaction with indole to afford 3-substituted indole.     

A synthesis of di- and tri-substituted β,γ-unsaturated esters from aldehydes by the magnesium carbenoid 1,2-CH and 1,2-CC insertion as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from aldehydes, with lithium enolate of tert-butyl acetate at −78 °C in THF gave adducts in high yields. Treatment of these adducts with Grignard reagents resulted in the formation of magnesium carbenoids via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, carbenoid 1,2-CH insertion reaction took place from the magnesium carbenoids to afford β,γ-unsaturated butyric esters having a substituent at the β-position. On the other hand, when the adducts were derived from electron-rich aromatic aldehydes, carbenoid 1,2-CC insertion reaction took place from the magnesium carbenoids to give β,γ-unsaturated butyric esters having the aromatic group at the γ-position. Highly stereospecific 1,2-CC insertion reactions were observed in the latter reactions. When the addition reactions were quenched with iodoalkanes, the alkylated adducts were obtained in quantitative yields. Tri-substituted β,γ-unsaturated esters, or in some case γ,δ-unsaturated esters, were obtained by the treatment of the alkylated adducts with EtMgCl. These procedures provide a good way for a new synthesis of di- and tri-substituted β,γ-unsaturated esters from aldehydes with two or three carbon-carbon bond-formations.     

A new synthesis of β,γ-unsaturated esters from three components, aldehydes, chloromethyl p-tolyl sulfoxide, and tert-butyl acetate, via magnesium carbenoid 1,2-CH and 1,2-CC insertion as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from various aldehydes, with lithium enolate of tert-butyl acetate at −78 °C in THF gave adducts in high yields. Magnesium carbenoids were generated by treatment of these adducts with Grignard reagents via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, carbenoid 1,2-CH insertion reaction took place from the magnesium carbenoids to afford β,γ-unsaturated butyric esters having a substituent at the β-position. On the contrary, when the adducts were derived from electron-rich aromatic aldehydes, carbenoid 1,2-CC insertion reaction took place from the magnesium carbenoids to give β,γ-unsaturated butyric esters having the aromatic group at the γ-position. Highly stereospecific 1,2-CC insertion reactions were observed in the latter reactions. This procedure provides a good way for a synthesis of β,γ-unsaturated esters from aldehydes with two carbon-carbon bond-formations.     

Direct Asymmetric α-Selective Mannich Reaction of β,γ-Unsaturated Ketones with Cyclic α-Imino Ester: Divergent Synthesis of Cyclocanaline and Tetrahydro Pyridazinone Derivatives

The first regio-, diastereo-, and enantioselective direct Mannich reaction of β,γ,-unsaturated ketones with benzoxazinone cyclic imines was enabled by Lewis acid/Brønsted base cooperative catalysis. The dinuclear zinc complex catalyzed the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, leading to corresponding adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–99 % ee range. These products were used as general intermediates in the synthesis of multisubstituted cyclocanalines, tetrahydro pyridazinones, and 4H-furo[2,3-b][1,4]benzoxazine derivatives.     

Controlling the α/γ-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

The first regio-, diastereo-, and enantioselective direct Michael reaction of β,γ-unsaturated ketones with nitroolefins is enabled by Brønsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–98 % ee range.     

The cycloaddition of the 1,3-butadiene radical cation with acrolein and methyl vinyl ketone

The 1,3-butadiene radical cation reacts with acrolein and methyl vinyl ketone to produce ‘stable’ adducts. The nature of the reaction and the structures of the adducts were investigated by collisional activation decomposition (CAD) combined with tandem mass spectrometry (MS/MS), and also by Fourier transform mass spectrometry. The CAD spectra of gas-phase adducts were compared with those of suitable model compounds. On that basis, it was determined that the 1,3-butadiene radical cation undergoes a cycloaddition with these α,β-unsaturated carbonyl compounds. The butadiene radical cation serves as the ‘ene’, and the acrolein and methyl vinyl ketone react as dienes, forming cycloadducts having 2-ethenyl-2,3-dihydropyran radical cation structures.     

Organocatalytic asymmetric Michael-type reaction between β,γ-unsaturated α-keto ester and α-nitro ketone

A Michael-type reaction of β,γ-unsaturated α-keto ester and α-nitro ketone was established. With a thiourea catalyst derived from cinchona alkaloid, the reactions afford products in 47-94% yields with 68-96% ee.     

Radical reduction of Passerini 3CR adducts by SmI2/HMPA

The Passerini 3-CR adducts of substituted cinnamaldehydes,isocyanides and acetic acid were treated with SmI₂/HMPA in dry tetrahydrofuran（THF） at room temperature,andβ,γ-unsaturated amides were obtained in moderate yields.The reaction was supposed involving a radical reduction procedure.     

ZrCl4-catalyzed X-C/C-C bond formation for the geometric selective synthesis of (E)-β-iodo aza Morita-Baylis-Hillman (MBH) adducts

A geometric selective synthesis of (E)-β-iodo and β-alkyl vinyl ketones (MBH amino adducts) has been developed through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate intermediates via the α,β-unsaturated addition of TMS-I to 3-butyn-2-one followed by a carbonyl addition onto N-aryl imines in the presence of ZrCl₄ catalyst. The resulting β-iodo allylic amines can be readily converted into β-alkyl Morita-Baylis-Hillman adducts by performing Suzuki and Kumada cross-couplings.     

烯胺与全卤代氟卤乙烷的亲卤反应研究——一种β-CF_3取代的α，β不饱和酮的合成法

在无引发剂或紫外光照的情况下，烯胺能与CF_3CXYZ(X,Y,Z=Cl, Br)进行自发 的反应，得么以Z-式异构体为主的 β-CF_3取代的 α，β不饱和酮，产率为50%左 右。反应可能是经由电子转移引发的自由基型机理进行的。     

Asymmetric cycloaddition of β,γ-unsaturated α-ketoesters with electron-rich alkenes catalyzed by a chiral Er(OTf)3/N,N'-dioxide complex: highly enantioselective synthesis of 3,4-dihydro-2H-pyrans

The asymmetric inverse-electron-demand hetero-Diels-Alder (HDA) reactions of β,γ-unsaturated α-ketoesters with electron-rich alkenes were investigated, with an N,N'-dioxide/erbium(III) complex employed as the catalyst. Quantitative conversion of the β,γ-unsaturated α-ketoesters and excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >99:1 d.r.) were observed for a broad range of substrates by using a 0.5-0.05 mol% catalyst loading under mild reaction conditions. The reaction could be scaled up to the gram scale with the same results. In addition, this was the first application of Er(OTf)(3) to the asymmetric inverse-electron-demand HDA reaction and it behaved as an efficient catalyst. Moreover, the synthetic utility of this methodology was demonstrated with the synthesis of key intermediates of some natural products.     

Highly enantioselective and efficient organocatalytic aldol reaction of acetone and β,γ-unsaturated α-keto ester

An effective organocatalytic asymmetric aldol reaction of acetone to β,γ-unsaturated α-keto ester has been developed. In the presence of 5 mol % of 9-amino (9-deoxy)-epicinchona alkaloid and 10 mol % of 4-nitrobenzoic acid, the aldol adducts containing a chiral tertiary alcohol moiety were obtained in excellent yields and enantioselectivities.     

α-Branched Ketone Dienolates: Base-Catalysed Generation and Regio- and Enantioselective Addition Reactions

In this study, the unique capacity of bifunctional Brønsted bases to generate α-branched ketone dienolates and control both site- and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented. We demonstrate that by using selected chiral tertiary amine/squaramide catalysts, the reactions of β,γ-unsaturated cycloalkanones proceed through the dienolate Cα almost exclusively and provide all-carbon quaternary cyclic ketone adducts in good yields with very high enantioselectivities. A minor amount (<5 %) of γ-addition is observed when nitroolefins are used as electrophiles. The parent acyclic ketone dienolates proved to be less reactive under these conditions, and thus still constitute a challenging class of substrates. Quantum chemical calculations correctly predict these differences in reactivity and explain the observed site-specificity and enantioselectivity.     

Organocatalytic asymmetric aldol reaction of hydroxyacetone with β,γ-unsaturated α-keto esters: facile access to chiral tertiary alcohols

An efficient direct asymmetric aldol reaction between hydroxyacetone and β,γ-unsaturated α-keto esters has been successfully developed. In the presence of 9-amino-9-deoxy-epi-cinchonine and trifluoroacetic acid, the direct aldol reaction of O-protected hydroxyacetone proceeded in a highly enantioselective manner, affording the desired adducts containing a chiral tertiary alcohol in high yields and with excellent enantioselectivities. The aldol products obtained are valuable precursors for the synthesis of 2-substituted glycerol derivatives.     

Stereoselective synthesis of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids

Enantiomerically pure δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids were stereoselectively synthesized starting from (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) and suitable β-heteroaryl-α,β-unsaturated aldehydes. The stereocontrolled addition gave a mixture of two diastereoisomers whose configurations were assigned on the basis of spectroscopic data and the accepted model for aldol condensation of the Schöllkopf’s reagent. Upon controlled hydrolysis the adducts were transformed into the corresponding methyl esters of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids.     

Cascade reaction of β,γ-unsaturated α-ketoesters with phenols in trityl chloride/TFA system. Highly selective synthesis of 4-aryl-2H-chromenes and their applications

The treatment of β,γ-unsaturated α-ketoesters with phenols in the presence of trityl chloride and 4 ? molecular sieves in refluxing trifluoroacetic acid afforded 4-aryl-2H-chromenes in high yields, in which a reverse of the regiochemistry of J?rgensen-Rutjes chromane synthesis was observed. The isolation of 4H-chromene intermediates, confirmed by single-crystal X-ray analysis, indicates that the early stage of the reaction involves a Friedel-Crafts alkylation/cyclodehydration processes. Stirring of the 4H-chromene intermediate with trityl chloride in deuterotrifluoroacetic acid under reflux afforded the 2H-chromene and triphenylmethane in high yields, which implies the late stage of the reaction involves a hydrogen transfer process. Highly selective derivation of the hydroxyl esters to the corresponding hydroxyl amides, amino acids, amino esters and Friedel-Crafts adducts was further accomplished. Our endeavors will lead to a better understanding of the controlling elements behind their structural motifs. The products were confirmed unambiguously from their spectra and by single-crystal X-ray analysis.     

New transformations involving squarate esters. Multi-channel rearrangement options available to 2-(dimethoxy-methyl)-1-cycloalken-1-yl adducts

The Vilsmeier-Haack reaction of cyclic ketones with PBr₃ and DMF is an effective means for generating β-bromo-α,β-unsaturated aldehydes, which are readily transformed into their dimethyl acetals. These bromides are conveniently amenable to halogen-metal exchange in the presence of tert-butyllithium. The resultant organometallic intermediates, when treated with an equimolar amount of diisopropyl squarate, undergo 1,2-addition to deliver α-hydroxy ketone adducts that have proven to be sensitive to different rearrangements when in the presence of silica gel or boron trifluoride etherate. Although both processes involve net ring expansion of the cyclobutene ring with loss of methanol, the similarity stops there. In the first instance, spirocyclic diketones are produced by 1,2-shift of either of two ring carbons. In the second, extensively conjugated lactones are generated. The behavior of the adduct originating from a lithiated quinone bisketal has also been scrutinized.     

Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters with silyl nucleophiles

The Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters, which are easily prepared by the acetalization of β,γ-unsaturated α-keto esters, with silyl nucleophiles is presented. By employing trimethylsilyl enolate and allyltrimethylsilane as nucleophiles, the BF₃-promoted reactions of a series of β,γ-unsaturated α,α-dimethoxy esters bearing aromatic and aliphatic substituents proceeded at the γ-position in an SN2′ manner to furnish γ-substituted α,β-unsaturated α-methoxy esters in good yields with high regioselectivity. In contrast, the reaction using trimethylsilyl cyanide predominantly occurred at the α-position, and the reaction of silyl hydride resulted in a mixture of α- and γ-regioisomers in favor of the γ-substitution products.