Formation of Tetraacetal Oxa-Cages and Convex Oxa-Cages on Ozonolysis of Bicyclo[2.2.2] Octenes

Tetraacetal oxa-cage compounds 5a and 5b and convex oxa-cage compounds 7a and 8b are synthesized in a short sequence. Ozonolysis of endo adducts 2a and 2b in dichloromethane at ?78 °C followed by reduction with dimethylsulfide gave tetraacetal oxa-cages 5a and 5b in 35% yields respectively. Ozonolysis of 2a in dichloromethane at ?78 °C followed by treatment with triethylamine gave the convex oxa-cage 7a in 34% yield. These results support an acid-base proton transfer between the final ozonides and the base. The reasons that these oxa-cage compounds formed in low yields are discussed. The synthesis of tetraacetal oxa-cage 14, possessing aromatic substitutents directly on the skeleton of the oxa-cage, is accomplished.     

Synthesis of Novel Triacetal Trioxa-Cage Compounds by Ozonolysis of Bicyclo[2.2.1]Heptenes and Bicyclo[2.2.2]Octenes

Several novel triacetal trioxa-cage compounds 11a-11g, 13, 15, 17 and 19 are synthesized in a short sequence. Ozonolysis of bicyclo[2.2.1]heptenes 4a-4c, 8a-8c, 10a, 10b and 14 in dichloromethane at ?78 °C followed by reduction with dimethyl sulfide gave triacetal oxa-cages 11a-11g, 13 and 15 in moderate yields, respectively. Ozonolysis of bicyclo[2.2.2]octenes 16 and 18 under the same reaction conditions gave triacetal oxa-cages 17 and 19 in moderate yields, respectively.     

Synthesis of Novel Tetraacetal Oxa-Cage Compounds from 2-Methylthiofurans

Several novel tetraacetal oxa-cage compounds 9a-9f were synthesized from the corresponding 2-methylthiofurans la-lf by a short sequence. The structures of these tetraoxa-cage compounds were deduced from their spectral data and proven by X-ray analysis of 9a . Ozonolysis of the endo adducts 5a-5f in CH₂C1₂ at ?78 °C followed by reduction with dimethyl sulfide gave the tetraoxa-cages 9a-9f in 65-75% yields, respectively. Ozonolysis of the exo adduct 6a under the same reaction conditions gave the tetracarbonyl compound 10 . The phenylthio group substituted tetraoxa-cage 13 and the tetraacetal oxa-cage 17, with one more carbon atom on the apex position, were also synthesized in a similar sequence.     

Synthesis of a carbon analogue of N-acetylmannosamine via acetolysis on a relatively stable ozonide

After a 2-methylpropenyl group was added to a carbohydrate framework through regioselective opening of a glucose-derived epoxide, hydrolysis or acetolysis of the methyl glycoside in various derivatives was problematic. Ozonolysis of the olefin followed by brief treatment with dimethyl sulfide gave a mixture of diastereomeric ozonides that proved to be stable for weeks at room temperature. Acetolysis of these ozonides at low temperature allowed selective cleavage of the methyl glycoside in the presence of the 1,2,4-trioxolane as well as selective formation of the alpha-acetate.     

‘Reductive ozonolysis’ via a new fragmentation of carbonyl oxides

This account describes the development of methodologies for ‘reductive’ ozonolysis, the direct ozonolytic conversion of alkenes into carbonyl groups without the intermediacy of 1,2,4-trioxolanes (ozonides). Ozonolysis of alkenes in the presence of DMSO produces a mixture of aldehyde and ozonide. The combination of DMSO and Et₃N results in improved yields of carbonyls but still leaves unacceptable levels of residual ozonides; similar results are obtained using secondary or tertiary amines in the absence of DMSO. The influence of amines is believed to result from conversion to the corresponding N-oxides; ozonolysis in the presence of amine N-oxides efficiently suppresses ozonide formation, generating high yields of aldehydes. The reactions with amine oxides are hypothesized to involve an unprecedented trapping of carbonyl oxides to generate a zwitterionic adduct, which fragments to produce the desired carbonyl group, an amine, and ¹O₂.     

Synthesis of 4-oxo- and 4-anti-formyl-8,10,12,13-tetraoxapentacyclo-[5.5.1.0.0.0]tridecanes

The synthesis of 4-oxo- and 4-anti-formyl-8,10,12,13-tetraoxapentacyclo[5.5.1.0^2,6.0^3,11.0^5,9]tridecanes has been accomplished. Ozonolysis of compounds 10a,b and 12a-c in dichloromethane at −78 °C followed by reduction with dimethyl sulfide gave the title compounds, 4-oxo-tetraoxa-cages 11a,b and 14a-c, in moderate yields. Ozonolysis of the endo-syn isomers 15a,b and 18a,b under the same reaction conditions gave 4-anti-formyl-tetraoxa-cages 17a,b and 20a,b, respectively.     

Fragmentation of carbonyl oxides by N-oxides: an improved approach to alkene ozonolysis

[Structure: see text] Ozonolysis of alkenes in the presence of amine N-oxides results in the direct formation of aldehydes. This reaction, which appears to involve an unprecedented trapping and fragmentation of the short-lived carbonyl oxide intermediates, avoids the hazards associated with generation and isolation of ozonides or other peroxide products.     

Synthesis of tetrasubstituted ozonides by the Griesbaum coozonolysis reaction: diastereoselectivity and functional group transformations by post-ozonolysis reactions

The diastereoselectivity of the Griesbaum coozonolysis reaction with O-methyl 2-adamantanone oxime and 4-substituted cyclohexanones reveals that the major tetrasubstituted ozonide isomers possess cis configurations, suggesting a preferred axial attack of the carbonyl oxide on the cyclohexanone dipolarophiles. It is evident that these tetrasubstituted ozonides are quite stable to triphenylphosphine, borohydrides, hydrazine, alkyllithiums, Grignard reagents, mercaptides, and aqueous KOH as illustrated by the synthesis of amine, alcohol, acid, ester, ether, sulfide, sulfone, and heterocycle-functionalized ozonides by a wide range of post-ozonolysis transformations.     

Synthesis of new acetal aza-cage compounds via ozonolysis of bis-endo-diol- and diacylnorbornene derivatives

We synthesized acetal aza-cage compounds directly via ozonolysis of 2,3-bis-endo-diol- and diacylnorbornenes in dichloromethane at ?78 °C. Ozonolysis of the diols followed by addition of amines gave the aza-cage compounds in high yields. The reaction mechanism for the formation of this type of aza-cage compounds is proposed to proceed via the hydroperoxide intermediate. Ozonolysis of the diacetyl norbornene followed by addition of (1) primary amines gave monoaza-cages and diaza-cage, (2) tert-butylamine gave hydroxyl lactone and diaza-cages, and (3) amino acid ester gave optically active aza-cages, in which one compound was converted into chiral aminoalcohol and structure of another was proven by X-ray analysis. A mechanism via the final ozonide and the imine intermediates is proposed for the formation of this type of aza-cages.     

Synthesis of Tetraacetal Tetraoxa-Cage Compounds with Alkyl Substituents at Different Sites of the Oxa-Cage Skeleton

Tetraacetal tetraoxa-cage compounds 3a, 3b, 4a, 4b, 7, 13,14 , and 15 were synthesized by a short sequence. They were obtained from ozonolysis of endo adducts la, lb, 2a, 2b , and 6 in dichloromethane at ?78 °C followed by reduction with dimethyl sulfide. Ozonolysis of 7-anti-trimethylsilyl-5,6-bis-endo-diacetylnorbornene 8 under the same reaction conditions did not give the tetraoxa-cage 9 . The methylsulfinyl oxa-cage 13 derived from l-methylthio-5,6-bis-endo-diacetylnorbornene 11 was converted to compounds 14 and 15.     

Approach for the Preparation of Various Classes of Peroxides Based on the Reaction of Triketones with H2O2: First Examples of Ozonide Rearrangements

The reaction of β,δ‐triketones with an ethereal solution of H₂O₂ catalyzed by heteropoly acids in the presence of a polar aprotic co‐solvent proceeds via three pathways to form three classes of peroxides: tricyclic monoperoxides, bridged tetraoxanes, and a pair of stereoisomeric ozonides. The reaction is unusual in that produces bridged tetraoxanes and ozonides with one of the three carbonyl groups remaining intact. In the synthesis of bridged tetraoxanes, the peroxide ring is formed by the reaction of hydrogen peroxide with two carbonyl groups at the β positions. The synthesis of ozonides from ketones and hydrogen peroxide is a unique process in which the ozonide ring is formed with the participation of two carbonyl groups at the δ positions. Rearrangements of ozonides were found for the first time after more than one century of their active investigation. Ozonides are interconverted with each other and rearranged into tricyclic monoperoxides, whereas ozonides and tricyclic monoperoxides are transformed into bridged tetraoxanes. The individual reaction products were isolated by column chromatography and characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. One representative of each class of peroxides was characterized by X‐ray diffraction.     

Darstellung und Strukturanalyse von Natriumozonid

Synthesis and Crystal Structure Analysis of Sodium Ozonide Solutions of sodium ozonide in ammonia have been obtained starting from cesium ozonide via cation exchange in liquid ammonia. After addition of dimethyl amine and removing the solvent mixture pure sodium ozonide precipitates as a bright red microcrystalline powder. According to X‐ray powder data, NaO₃ is isotypical with NaNO₂ (I m2m; a = 3.5070(2) Å, b = 5.7703(3) Å, c = 5.2708(3) Å; Z = 2; Rietveld profile fitting, R_Int = 3.71%). The O–O‐distances (1.353(3) Å) are the longest observed so far in ionic ozonides, the angle of 113.0(2)° is the smallest. The frequencies of the fundamental vibrations of the ozonide anion as obtained by Infrared and Raman spectroscopy are shifted to higher wave numbers as the cation diameter is decreasing. Unlike the ozonides of the heavy alkalimetals NaO₃ represents a magnetically strongly coupled system (μ_eff = 1.45 μ_B at 250 K).     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Biomimetic synthesis of the tetracyclic core of berkelic acid

Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 degrees C, followed by CH2N2 esterification, gave a 4:1:4:1 mixture of diastereomers 15b-18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83% yield) with the complete skeleton of berkelic acid. A similar condensation at 0 degrees C afforded 15b-18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift.     

Ozonolysis of 18α-Oleanane triterpenoid with an alkenenitrile moiety in the five-membered ring A

A novel synthetic protocol of ozonolytic cleavage of 18α-oleanane triterpenoid with the five-membered α,β-alkenenitrile moiety dissolved in dichloromethane to selectively synthesize a 1,3-secotriterpene derivative with 78% yield was developed. Spontaneous condensations of the synthesized 19β,28-epoxy-1,3-seco-2-nor-18α-olean-3-al-1-oic acid followed by formation of unsubstituted 1,3- and 1,4-lactones were registered in reactions with sodium borohydride as a reducing reagent or oxalyl chloride as an activating agent, respectively. α-Methoxy- and α-ethoxy-substituted 1,3-lactones were obtained when the polar protic solvents methanol or ethanol were used for the ozonolysis of the alkenenitrile. Experiments on ozonolysis were carried out in combination with reduction with dimethyl sulfide. Ozonolysis of alkenenitrile in dichloromethane without reductive treatment was found out to have resulted in stable triterpene ozonide.     

Oxidative Deamination of Benzylic Amines Induced by Phenyl Dichlorophosphate

Treatment of benzyiic amines with phenyl dichlorophosphate and dimethyl sulfoxide followed by sequential addition of triethylamine and oxalic acid gave rise to the corresponding carbonyl compounds.     

Direct measurement of Criegee intermediate (CH2OO) reactions with acetone, acetaldehyde, and hexafluoroacetone

Criegee biradicals, i.e., carbonyl oxides, are critical intermediates in ozonolysis and have been implicated in autoignition chemistry and other hydrocarbon oxidation systems, but until recently the direct measurement of their gas-phase kinetics has not been feasible. Indirect determinations of Criegee intermediate kinetics often rely on the introduction of a scavenger molecule into an ozonolysis system and analysis of the effects of the scavenger on yields of products associated with Criegee intermediate reactions. Carbonyl species, in particular hexafluoroacetone (CF(3)COCF(3)), have often been used as scavengers. In this work, the reactions of the simplest Criegee intermediate, CH(2)OO (formaldehyde oxide), with three carbonyl species have been measured by laser photolysis/tunable synchrotron photoionization mass spectrometry. Diiodomethane photolysis produces CH(2)I radicals, which react with O(2) to yield CH(2)OO + I. The formaldehyde oxide is reacted with a large excess of a carbonyl reactant and both the disappearance of CH(2)OO and the formation of reaction products are monitored. The rate coefficient for CH(2)OO + hexafluoroacetone is k(1) = (3.0 ± 0.3) × 10(-11) cm(3) molecule(-1) s(-1), supporting the use of hexafluoroacetone as a Criegee-intermediate scavenger. The reactions with acetaldehyde, k(2) = (9.5 ± 0.7) × 10(-13) cm(3) molecule(-1) s(-1), and with acetone, k(3) = (2.3 ± 0.3) × 10(-13) cm(3) molecule(-1) s(-1), are substantially slower. Secondary ozonides and products of ozonide isomerization are observed from the reactions of CH(2)OO with acetone and hexafluoroacetone. Their photoionization spectra are interpreted with the aid of quantum-chemical and Franck-Condon-factor calculations. No secondary ozonide was observable in the reaction of CH(2)OO with acetaldehyde, but acetic acid was identified as a product under the conditions used (4 Torr and 293 K).     

Singlet oxygen photooxygenation of furans : Isolation and reactions of (4+2)-cycloaddition products (unsaturated sec.-ozonides)

Tetraphenylporphin-photosensitized oxygenations of furan (19), 2-methylfuran (26), 2-ethylfuran (39), furfurylalcohol (24), 2-acetylfuran (40), 2-methoxyfuran (42), 2,5-dimethylfuran (30), furfural (25) and 5-methylfurfural (41) in non-polar aprotic solvents yield the corresponding monomeric unsaturated secondary ozonides due to a (4+2)-cycloaddition of singlet oxygen to these furans. With the exception of the ozonide derived from 25, the ozonides were isolated and characterized (¹H- and ¹³C-NMR spectra, etc.). In non-polar aprotic solvents, the ozonides derived from 19, 26 and 39 undergo thermal rearrangements to the corresponding cis-diepoxides and epoxylactones. Ozonide 31, derived from 30, however, dimerizes, only above about 60° is a cis-diepoxide formed from either 31 or its dimer. Rose bengal-photosensitized oxygenations of the furans in alcohols (MeOH, EtOH, i-PrOH) also produce the corresponding ozonides as the primary products of (4+2)-cycloadditions of singlet oxygen to these furans. However, reactions of the alcohols with the ozonides are too fast to allow the ozonides to be isolated. Instead, the same products are obtained as are isolated from reactions carried out by dissolving the ozonides in the alcohols. Depending on the structure of the ozonide, three pathways are available to ozonide/alcohol (ROH) interactions:(1) addition of ROH to yield alkoxy hydroperoxides; one out of several possible isomers is formed in a completely stereoselective and regiospecific reaction; (2) elimination of a bridgehead proton by ROH as a base, as observed with the ozonide derived from 19 to give hydroxy butenolide (78) in yields between 20 and 60%, and (3) ROH-attack on a carbonyl side-chain under elimination of the corresponding alkyl ester, as observed with furfural photooxygenation which yielded hydroxy butenolide (78) in high yields (95%). Interaction of ozonide 31 with tert.-butyl alcohol (t-BuOH) yields quantitatively cis-3-oxo-1-butenylacetate (81) by a Baeyer-Villiger-type rearrangement with vinyl group migration Hydrogenbonding between the alcohol and the peroxy group of the ozonides assist the heterolysis of the C—O bonds in the ozonides; the most stabilized cation develops. Front-attack of ROH on this cation explains the stereoselectivity as well as the regiospecificity of the alkoxy hydroperoxide formation; with a bulky alcohol like t-BuOH, ROH-attack on the cation is sterically hindered thus allowing a rearrangement to occur. 1,3-Dipolar cycloaddition of p-nitrophenyl azide to ozonide 31 proceeds stereoselectively to one of the isomers 87a/87b. Finally, kinetic results of furan photooxygenation in methanol show the following order of furan-reactivity towards singlet oxygen: 30 > 42 > 26 > 19 > 41 > 25, with absolute rate constants ranging from 1.8 × 10⁸ (with 30) to 8.4 × 1O⁴ M^-1P^-1 (with 25).     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

臭氧化物生成机理研究综述

以Criegee三步反应机理为核心对烯烃臭氧化反应中的臭氧化物生成机理进行了综述。论述了初级臭氧化物的生成与分解和臭氧化物生成过程的选择性和立体化学。讨论了烯烃结构和反应各步骤的选择性和立体化学的关系。