Grob-type fragmentation of 5-oxabicyclo[2.1.1]hexane system: a strategy for synthesis of annulated and 2,2,5-trisubstituted tetrahydrofurans

Acid mediated, efficient Grob-type fragmentation reaction facilitated by vicinal ketal and ester moieties in variety of 5-oxabicyclo[2.1.1]hexanes leading to the corresponding annulated and 2,2,5-trisubstituted tetrahydrofurans is reported. Among the Brønsted and Lewis acids tested, BF₃·OEt₂ appears to give the best results, furnishing near quantitative yield (>99%) of tetrahydrofuran tricarboxylate derivatives under mild reaction condition. In case of unsymmetrical monosubstituted 5-oxabicyclo[2.1.1]hexanes two regioisomeric products are obtained. A strategy to transform one of the ester groups of the title compounds to protected hydroxymethyl moiety was evolved, which allows access to differentially protected 2-hydroxymethyl THF derivatives upon fragmentation. Employing TiCl₄/R or S-BINOL as chiral Lewis acid, an enantioselective fragmentation (up to 66% ee) was described for the meso bis-furan derivative.     

Water‐Soluble Non‐Classical Benzene Mimetics

A new generation of saturated benzene mimetics, 2‐oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2‐oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta‐disubstituted benzenes.     

Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2-Oxabicyclo[2.1.1]hexanes

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres of benzenoids in modern drug discovery. Here, we report a BF₃-catalyzed [2π+2σ] cycloaddition of aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2-oxabicyclo[2.1.1]hexanes. A new kind of BCB containing an acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve as a handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides can also be utilized as substrates which undergo cycloaddition with BCBs after in situ rearrangement to aldehydes. We anticipate that our results will promote access to challenging sp³-rich bicyclic frameworks and the exploration of BCB-based cycloaddition chemistry.     

Lewis Acid Catalyzed Formal (3+2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes

Design, synthesis and application of benzene bioisosteres have attracted a lot of attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes have emerged as highly attractive bioisosteres for ortho- and meta-substituted benzenes. Herein we report a mild, scalable and transition-metal-free protocol for the construction of highly substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition of bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance as documented by the successful preparation of various 3-alkyl-3-aryl as well as 3,3-bisalkyl bicyclo[2.1.1]hexan-2-ones (26 examples, up to 89 % yield). Postfunctionalization of the exocyclic ketone moiety is also demonstrated.     

2-Azabicyclo[2.1.1]hexanes. 2. Substitutent effects on the bromine-mediated rearrangement of 2-azabicyclo[2.2.0]hex-5-enes

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 have been prepared by photoirradiation of appropriately substituted 1,2-dihydropyridines. Torquoselectivity is observed in the synthesis of the 3-endo-methyl- and 3-endo-phenyl-2-azabicyclo[2.2.0]hexenes 6c-e from 2-methyl- and 2-phenyl-1,2-dihydropyridines 5c-e. Products formed upon addition of bromine to 3-endo-, 4-, and 5-methyl- and 3-endo-phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6a-f were substituent dependent. For 6a,b, which lack substituents at C(3) or C(5), mixtures of unrearranged dibromides 8a,b and rearranged dibromides 9a,b were obtained. With the 3-endo-substituents in 6c-e, only rearranged dibromides 9c-e were formed; 5-methyl substitution afforded mainly unrearranged dibromide 8f and some allylic bromide 10. Both unrearranged 5-endo,6-exo-dibromo-2-azabicyclo[2.2.0]hexanes 8 and rearranged 5-anti-6-anti-dibromo-2-azabicyclo[2.1.1]hexanes 9 are formed stereoselectively. The dibromoazabicyclo[2.1.1]hexanes 9 have been reductively debrominated to afford the first reported 2-azabicyclo[2.1.1]hexanes 11 with alkyl or aryl substituents at C-3.     

Synthesis,including asymmetric synthesis,of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon–hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.     

5-Carboxy-2-azabicyclo[2.1.1]hexanes as precursors of 5-halo, amino, phenyl, and 2-methoxycarbonylethyl methanopyrrolidines

Novel 5-X-substituted-2-azabicyclo[2.1.1]hexanes (X = 5-syn-Cl, -Br, -I, -Ph, -NHCOOR (R = Me, Bn, t-Bu), -CH2CH2COOMe and X = 5-anti-Br, -I, -Ph) were synthesized from the X = 5-syn-carboxy derivative. New 5-anti-X-2-azabicyclo[2.1.1]hexanes, X = NHCOOR (R = Me, Bn), were prepared stereoselectively from the X = 5-anti-carboxy substrate.     

Synthesis of novel 2-azabicyclo[2.2.0]- and [2.1.1]hexanols

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 were reacted with NBS in wet DMSO to afford bromohydrins. Mixtures of unrearranged 6-exo-bromo-5-endo-hydroxy-2-azabicyclo[2.2.0]hexanes 7a,b and rearranged 5-anti-bromo-6-anti-hydroxy-2-azabicyclo[2.1.1]hexanes 8a,b were formed stereoselectively from the parent alkene 6a and 4-methyl alkene 6b. The 5-methyl alkene 6c affords only unrearranged bromohydrin 7c and dibromohydrin 9. By contrast, solely rearranged 3-endo-substituted-2-azabicyclo[2.1.1]hexane bromohydrins 8d-f result from additions to 3-endo-methyl alkene 6d, 3-endo-4-dimethyl alkene 6e, and 3-endo-phenyl alkene 6f. As an alternative route to bromohydrins, the parent 5,6-exo-epoxide 10a and 5-endo-methyl-5,6-exo-epoxide 10b were ring opened with bromine/triphenylphosphine to afford unrearranged 5-endo-bromo-6-exo-hydroxy-2-azabicyclo[2.2.0]hexanes 11a,b, while the 3-endo-methyl epoxide 10c afforded solely the rearranged 5-anti-bromo-6-anti-hydroxy-3-exo-methyl-2-azabicyclo[2.1.1]hexane isomer 8g. Tributyltin hydride reduction of bromohydrins 7a,b and 11a afforded novel 2-azabicyclo[2.2.0]hexan-5-ols 13a,b and -6-ol 14, and bromohydrins 8a,b, 8d-g afforded new 2-azabicyclo[2.1.1]-hexan-5-ols 15a,b and 15d-g.     

Second-chance rearrangement route to novel 5(6)-syn,anti-difunctional 2-azabicyclo[2.1.1]hexanes

[reaction: see text] The first syntheses of 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing syn-hydroxy and syn-fluoro substituents have been effected in a stereocontrolled manner. The key reactions are regioselective additions to the aziridinium ions formed from 6-exo-iodo(bromo)-5-endo-X-2-azabicyclo[2.2.0]hexanes (X = F, OH) upon silver or mercury salt enhancement of iodide nucleofugacity.     

A short synthesis of 3-oxa- and 3-azabicyclo[3.1.0]hexanes from α,β-unsaturated esters based on the 1,5-CH insertion reaction of cyclopropylmagnesium carbenoids

1-Chlorocyclopropyl p-tolyl sulfoxides bearing an alkoxymethyl group at the 2-position were easily prepared from α,β-unsaturated esters with dichloromethyl p-tolyl sulfoxide and alkylhalides in three steps in good overall yields. Treatment of the 1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl resulted in the formation of 3-oxabicyclo[3.1.0]hexanes in up to 89% yield as a single diastereomer via the 1,5-CH insertion reaction of the generated cyclopropylmagnesium carbenoid intermediates. This procedure provides a good way for the synthesis of 3-oxabicyclo[3.1.0]hexanes from α,β-unsaturated esters in only four steps. 3-Aza- and 3-thiabicyclo[3.1.0]hexanes were also obtained from the corresponding precursors via the 1,5-CH insertion reaction of the cyclopropylmagnesium carbenoid intermediates, though the yields were low to moderate.     

The serendipitous synthesis of an oxabicyclo [3.2.0] heptadiene

5,6-Dihalobicyclo [2.1.1]hexanes resist simple nucleophilic displacement in several ways. Least expected of these is the 2→1 rearrangement.     

Unusual reactions of N-allylic difluoroenamines under thermal conditions

N-Allylic difluoroenamines exhibited unusual behaviors under thermal conditions; N-allyl difluoroenamines in refluxing xylene afforded not only aza-Claisen rearrangement products, but also 2-azabicyclo[2.1.1]hexanes, whose formation could be explained via intramolecular [2+2]-cycloaddition, whilst N-prenyl difluoroenamine underwent an ene reaction to give the pyrrolidine as a sole product.     

Stereochemical assignments of the 6-phenyl-2-oxabicyclo[3.1.0]hexanes

Preparation and stereochemical assignments of the 6-phenyl-2-oxabicyclo[3.1.0]hexanes are reported. The stereochemical assignments are based on chemical as well as nmr data.     

Saturated Bioisosteres of ortho-Substituted Benzenes

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed a similar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.     

The rearrangement route to 3-carboxy- and 3-hydroxymethyl-2-azabicyclo[2.1.1]hexanes: 3,5-methanoprolines

Improved stereocontrolled syntheses of 5-anti-hydroxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]hexanes have been effected from pyridine. The key step in the electrophilic addition-rearrangement of 2-azabicyclo[2.2.0]hex-5-ene precursors incorporates either a 3-endo-phenyl group, as an acid precursor, or a 3-endo-phenyldimethylsilylmethyl group, as a potential hydroxymethyl and acid precursor.     

Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles and bicyclobutane precursors is described. The strain-release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale-up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.     

Studies of vacuum pyrolysis of 3-sila- and 3-germa-3,3′-spirobi(6-oxabicyclo[3.1.0]hexanes) and low-temperature matrix stabilization of monomeric silicon dioxide from the gas phase

Vacuum pyrolysis of 3-sila-3,3′-spirobi(6-oxabicyclo[3.1.0]hexanes) leads to the formation of monomeric silicon dioxide and 1,3-butadienes, whereas under the same conditions 3-germa-3,3′-spirobi(6-oxabicyclo[3.1.0]hexanes) afford germanium monoxide, the corresponding divinyl ethers, and 1,3-butadienes. A multistage mechanism of pyrolytic decomposition of the above spirobicyclohexanes was proposed on the basis of experimental data and calculations. The different behavior of the silicon and germanium compounds having similar structures can be explained by an increase in the bivalent state stability and by a decrease in the energy of the metal-oxygen double bond on the transition from silicon to germanium.     

The Synthesis of 5,6-Disubstituted Bicyclo[2.1.1]hexenes and 3,5-Disubstituted Tricyclo[2.2.0.02,6]hexanes

There are relatively few methods for synthesizing bicyclo[2.1.1]-hexenes and tricyclo[2.2.0.0^2,6]hexanes.¹ However, now that benzvalene (I), the highly strained structural isomer of benzene has become a readily available compound,² it is possible to prepare disubstituted compounds like II and III in a straightforward fashion.     

Novel selectfluor and deoxo-fluor-mediated rearrangements. New 5(6)-methyl and phenyl methanopyrrolidine alcohols and fluorides

Stereoselective syntheses of novel 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing 5-anti-fluoro or hydroxyl in one methano bridge and a variety of syn- or anti-chloro, fluoro, hydroxy, methyl, or phenyl substituents in the other methano bridge have been effected. Rearrangements of iodides to alcohols were initiated using Selectfluor. Rearrangement of alcohols to fluorides was initiated using Deoxo-Fluor. Ring opening of 2-azabicyclo[2.2.0]hex-5-ene exo-epoxide with organocopper reagents is regioselective at C(5).     

Intramolecular photochemical dioxenone-alkene [2 + 2] cycloadditions as an approach to the bicyclo[2.1.1]hexane moiety of solanoeclepin A.

A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A (1), the most active natural hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2] photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition or via a Nozaki-Hiyama-Kishi reaction. Photolysis of the unsubstituted alkene 14 led to the expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However, several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively. Their structures were proved by a combination of extensive NMR measurements, X-ray analyses, and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural product.