Stereo- and regioselectivity in dynamic gas-phase thermoisomerization (DGPTI): novel route to alpha-campholanic acid and derivatives

[reaction: see text] Dynamic gas-phase thermoisomerization (DGPTI) of (-)-2-phenylisoborneols effects stereo- and regioselective ring opening under formation of (+)-trans-alpha-campholanic acid derivatives. Similarly, (-)-alpha-2-phenylfenchol underwent under DGPTI conditions ring opening to (-)-fencholic acid derivatives. In both cases, DGPTI led to cleavage of the weakest bond in the isomeric bicyclic structures. A reaction mechanism involving a diradical intermediate is supported by a deuterium labeling study.     

Thermal Isomerization of Isoborneols and Dehydroisoborneols to New Chiral Building Blocks in Terpenoid Synthesis

The substituted isoborneols 1a – 1g and 5,6‐dehydroisoborneols 6a – 6c , readily prepared in excellent yields from (+)‐camphor and (+)‐5,6‐dehydrocamphor ( 2 ) by aryl, vinyl, or alkyl Grignard addition in the presence of stoichiometric amounts of CeCl₃, were thermally isomerized in a flow reactor system under DGPTI (dynamic gas‐phase thermo‐isomerization) conditions at temperatures between 480 and 630° to give the enantiomerically pure monocyclic carbonyl compounds 7a – 7d, 19a , b, 23 , and 24 . In all cases, product formation proceeded highly regio‐ as well as stereoselectively. The absolute configurations of the new stereogenic centers were determined by ¹H‐NOE measurements. DGPTI of the aryl substrates 1a – 1d is proposed to effect initial cleavage of the weakest single bond in the molecule under formation of a diradical intermediate state followed by intramolecular H‐abstraction to afford the acetophenone derivatives 7a – 7d . This reaction path was further supported by a ²H‐labeling study showing the OH group to be the exclusive H‐source. In contrast, DGPTI of the vinyl substrates 1e and 6b allowed concerted retro‐ene and oxy‐Cope rearrangements. In the case of 5,6‐dehydro‐2‐phenylisoborneol ( 6a ), concomitant diradical and retro‐Diels–Alder reaction pathways could be observed. In addition, a new route to (+)‐trans‐α‐campholanic acid ( 9 ) and (+)‐trans‐α‐dihydrocampholytic acid ( 14 ) is presented by regioselective Baeyer–Villiger oxidation and subsequent hydrolysis of 7c and 7d , respectively.     

Diradical‐Promoted Two‐Carbon Ring‐Expansion Reactions by Thermal Isomerization: Synthesis of Functionalized Macrocyclic Ketones

A new method for the smooth and highly efficient preparation of functionalized macrocyclic ketones has been developed. Pyrolysis of medium‐ and large‐ring 3‐vinylcycloalkanones by dynamic gas‐phase thermo‐isomerization (DGPTI) at 600–630° yielded, under insertion of a previously attached vinyl side chain by means of a 1,3‐C shift, the corresponding γ,δ‐unsaturated cycloalkanones. The yield of the two‐carbon ring‐expanded ketones greatly depended on the relative ring strains of substrate and product (5–87%, cf. Table 5). The formation of minor amounts of one‐carbon ring‐expanded cycloalkenes (<10%) can be ascribed to a subsequent decarbonylation step. A reaction mechanism involving initial cleavage of the weakest single bond in the molecule has been established (cf. Scheme 6). Recombination within the generated diradical intermediate in terminal vinylogous position led to the observed products, while reclosure gave recovered starting material. Substituents on the vinyl moiety were transferred locospecifically into the ring‐expanded products. An isopropenyl group did not significantly affect the isomerization process, whereas substrates bearing a prop‐1‐enyl group in β‐position enabled competing intramolecular H‐abstraction reactions, leading to acyclic dienones (cf. Schemes 9–11). DGPTI of the 13‐membered analogue directly yielded 4‐muscenone, which, upon hydrogenation, led to the valuable musk odorant (±)‐muscone. Increasing the steric hindrance on the vinyl moiety gave rise to diminishing amounts of the desired γ,δ‐unsaturated cycloalkanones. This novel two‐carbon ring‐expansion protocol was also successfully applied to 3‐ethynylcycloalkanones, giving rise to the corresponding ring‐expanded cyclic allenes (cf. Scheme 13).     

Unsymmetrical diaryl sulfones and aryl vinyl sulfones through palladium-catalyzed coupling of aryl and vinyl halides or triflates with sulfinic acid salts

The palladium-catalyzed reaction of sulfinic acid salts with a wide variety of aryl and vinyl halides or triflates provides unsymmetrical diaryl sulfones and aryl vinyl sulfones in good to excellent yields. The reaction is strongly influenced by the presence of nBu4NCl, and the use of Xantphos, a rigid bidentate ligand with a wide natural bite angle, was found to be crucial for the success of the reaction. With neutral, electron-rich, and electron-poor aryl iodides best results were obtained by using Pd2(dba)3, Xantphos, Cs2CO3, and nBu4NCl, in toluene at 80 degrees C. Two general procedures were employed with aryl bromides and triflates: sodium p-toluenesulfinate, Pd2(dba)3, Xantphos, Cs2CO3, 120 degrees C, in toluene with nBu4NCl (procedure A: neutral, electron-rich, and slightly electron-poor aryl bromides or triflates) and without nBu4NCl (procedure B: electron-poor aryl bromides or triflates). With vinyl triflates best results were obtained at 60 degrees C omitting nBu4NCl.     

One-Pot synthesis of gamma,delta-unsaturated carbonyl compounds from allyl alcohols and vinyl or isopropenyl acetates catalyzed by [IrCl(cod)]2

One-pot synthesis of gamma,delta-unsaturated carbonyl compounds from allyl alcohols and vinyl or isopropenyl acetates was achieved through in situ generation of allyl vinyl ethers by the action of the [IrCl(cod)]2 complex followed by Claisen rearrangement of the resulting ethers. For instance, the reaction of trans-2-methyl-3-phenyl-2-propen-1-ol with isopropenyl acetate in the presence of [IrCl(cod)]2 (1 mol %) and Cs2CO3 (5 mol %) at 100 degrees C for 3 h followed by 140 degrees C for 15 h afforded 5-methyl-4-phenyl-5-hexen-2-one in 72% yield. When vinyl acetate was employed in place of isopropenyl acetate, 4-methyl-3-phenyl-4-pentenal was obtained in 83% yield.     

Addition to electron deficient olefins of alpha-oxy carbon- centered radicals, generated from cyclic ethers and acetals by the reaction with alkylperoxy- lambda(3)-iodane

Thermal decomposition of 1-tert-butylperoxy-1,2-benziodoxol-3(1H)-one in cyclic ethers and acetals at 50 degrees C generates alpha-oxy carbon-centered radicals, which undergo an addition reaction with vinyl sulfones and unsaturated esters.     

CuI/N,N-dimethylglycine-catalyzed coupling of vinyl halides with amides or carbamates

The CuI-catalyzed coupling reaction of vinyl halides with amides or carbamates proceeds well at room temperature to 80 degrees C in dioxane to give enamides using N,N-dimethylglycine as the promoter and Cs(2)CO(3) as the base. The geometry of the C-C double bond is retained during the reaction course. [reaction: see text]     

Palladium-catalyzed alkylation of vinyl oxiranes with substituted allenes. Direct access to bifunctionalized allylic alcohols

The first palladium-catalyzed alkylation of vinyl oxiranes with substituted allenes to form functionalized allylic alcohols is described. The reaction of activated allenes 5 with vinyl oxiranes 1 in the presence of catalytic amounts of Pd(PPh(3))(4) (10 mol %) and 1,3-bis(diphenylphosphino)propane (dppp) (20 mol %) in THF at 60 degrees C gave the corresponding allylic alcohols 6 in good to excellent yields. The allylic alcohols were obtained in different ratios of trans/ cis isomers.     

Diradical-promoted (N + 2 - 1) ring expansion: an efficient reaction for the synthesis of macrocyclic ketones

[reaction: see text] A diradical-promoted (n + 2 - 1) ring expansion reaction based on vinyl side chain insertion (+2C) and decarbonylation (-1C) has been developed. Flash vacuum pyrolysis (FVP) of medium- and large-ring 2-trimethylsilyloxy-2-vinyl-cycloalkanones at 500-600 degrees C affords the one-carbon ring-expanded cycloalkanones in good yields. Methyl groups on the vinyl moiety are transformed regiospecifically as corresponding alpha- and beta-substituents, respectively. 2-Ethynyl precursor analogues react in a manner similar to give alpha,beta-unsaturated cyclic ketones.     

A mild,convenient, and inexpensive procedure for conversion of vinyl halides to alpha-haloketones

Treatment of a vinyl chloride with commercially available aqueous sodium hypochlorite solution in a 2:5 mixture of acetic acid/acetone at 0 degrees C for about 1 h cleanly leads to the corresponding alpha-chloroketone. Similarly, if a vinyl bromide is exposed to sodium hypobromite (freshly prepared from bromine and sodium hydroxide) at 0 degrees C in 2:5 acetic acid/acetone as solvent, an alpha-bromoketone is produced. This methodology has been applied to a number of vinyl chlorides and vinyl bromides, and the transformations generally proceed in high yields. The mild reaction conditions are compatible with a variety of functional groups including amides, esters, and imines.     

L-proline promoted Ullmann-type reaction of vinyl bromides with imidazoles in ionic liquids

The Ullmann-type coupling reaction of vinyl bromides and imidazoles in ILs at 90-110 degrees C gave the corresponding N-vinylimidazoles in good to excellent yields by using L-proline as the ligand; the double bond geometry of the vinyl bromides was retained under the reaction conditions.     

Formation of 1,4-disilyl-2-butenes from vinyl grignard reagent and chlorosilanes catalyzed by a titanocene complex

Symmetrical 1,4-disilyl-2-butenes 1 have been prepared by the reaction of vinyl Grignard reagent with chlorosilanes. This reaction proceeds efficiently in the presence of a catalytic amount of titanocene dichloride at 0 degrees C in THF. When dichlorodiphenylsilane was used, 1,1-diphenyl-1-silacyclo-3-pentene 2 was obtained in a good yield.     

Chiral phosphine Lewis base catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone and phenyl acrylate

In the aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone (MVK) promoted by chiral phosphine Lewis base: (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol (10 mol%), the aza-Baylis-Hillman adducts 1 were obtained in good yields with high ee (70-94% ee) at -30 degrees C in THF. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate gave the adducts 2 in high yields (60-97%) with moderate ee (52-77%).     

Platinum-catalyzed intermolecular hydroamination of vinyl arenes with carboxamides

[reaction: see text] Reaction of benzamide with 4-methylstyrene catalyzed by a 1:2 mixture of [PtCl(2)(H(2)C=CH(2))](2) and P(4-C(6)H(4)CF(3))(3) (5 mol %) in mesitylene at 140 degrees C for 24 h led to the isolation of N-(1-p-tolylethyl)benzamide in 85% yield. Electron-rich, electron-poor, and hindered vinyl arenes underwent Markovnikov hydroamination with a range of carboxamides and amide derivatives in moderate to good yield with excellent regioselectivity.     

The first examples of ring-closing olefin metathesis of vinyl chlorides

[reaction: see text] Ring-closing metathesis (RCM) of olefinic vinyl chlorides can be effected by using the second generation Grubbs catalyst (10 mol %, PhH, 65 degrees C) to produce a variety of carbocyclic and heterocyclic five-, six-, and seven-membered rings in excellent yields.     

Cyclopropanation with Fischer acyloxycarbene complexes: preparation of cyclopropane and cycloheptane-fused gamma-lactones

[reaction: see text] A sequential acylation-intramolecular cyclopropanation reaction takes place upon treatment of a series of tetraalkylammonium acylchromates with beta,gamma-unsaturated acyl chlorides at -10 degrees C. The reaction leads to 2-oxabicyclo[3.1.0]hexan-3-ones with exo selectivity in good yields. The diastereoselectivity of the reaction allows the preparation of cis-divinyl cyclopropanes, which evolve via Cope sigmatropic reaction toward cycloheptadiene derivatives. Furthermore, the aromatic Cope rearrangement of a series of cis-aryl vinyl cyclopropanes prepared by means of this methodology has been studied.     

Novel intramolecular reactivity of oximes: synthesis of cyclic and spiro-fused imines

Under conventional heat (135-145 degrees C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a novel sp3 C-H activated cyclization to produce the corresponding isoindoles, and aliphatic oximes afford the corresponding dihydropyrroles. The cyclization occurs with various substrates in good yield (46-82%) leading to unique spiro-fused and cyclic imines. An initial mechanistic investigation suggests the reaction occurs via a nitrenium or vinyl nitrene intermediate. [reaction: see text]     

Highly efficient allyl cross-coupling reactions of allylindiums with organic electrophiles

This paper describes highly efficient allyl cross-coupling reactions of allylindiums with organic electrophiles such as aryl and vinyl triflates, vinyl halides, dibromoolefin, and alkynyl iodide. The reactions were carried out using 4 mol % Pd(PPh3)4 in the presence of 3 equiv of LiCl in DMF at 100 degrees C under a nitrogen atmosphere. Allylindium, generated from the reaction of 1 equiv of indium with 1.5 equiv of allyl halide, gave the best result as a coupling partner. The present method is mild and simple to apply, and it produces a diverse range of allylic compounds in good to excellent yields.     

Rearrangement of allyl homoallyl ethers to gamma,delta-unsaturated carbonyl compounds catalyzed by iridium complexes

Iridium complexes were found to promote the conversion of allyl homoallyl ethers to gamma,delta-unsaturated carbonyl compounds. For example, treatment of 1-allyl-1-allyloxycyclohexane in the presence of catalytic amounts of [Ir(cod)Cl](2), PCy(3), and Cs(2)CO(3) in toluene at 100 degrees C afforded 4-cyclohexyliden-2, 3-dimethylbutanal in 74% yield. The reaction presumably proceeds through double bond migration to allyl vinyl ethers, which then undergo the Claisen rearrangement.     

NaOH-catalyzed thiolysis of alpha,beta-epoxyketones in water. A key step in the synthesis of target molecules starting from alpha,beta-unsaturated ketones

NaOH (0.02-0.3 molar equiv) is an efficient catalyst for the thiolysis reactions of alpha,beta-epoxy ketones with alkyl and aryl thiols in water. Thiolysis of 3,4-epoxyheptan-2-one (1) with thiols 2a-d has been accomplished in mild conditions (30 degrees C and pH 6 or 9) with complete C-alpha-regioselectivity and anti-stereoselectivity, and the corresponding anti-beta-carbonyl-beta-hydroxysulfides 3a-d have been prepared in excellent yields (95-98%). Compounds 3a-d, depending on their nature and pH conditions, have undergone dehydration, C-3 epimerization reaction, and retroaldol condensation. Dehydration of anti-3a-d has been chemoselectively carried out by in situ acidic treatment at 70 degrees C, giving stereoselectively the related (Z)-vinyl sulfides 4 in 89-94% overall yields. Under NaOH-catalyzed thiolysis conditions, cyclic alpha,beta-epoxyketones 6-9 have shown C-alpha attack only and spontaneously dehydrated to furnish the corresponding vinyl sulfides in high yields (90-96%). The reactions of calchone oxide (10) with thiols 2b-d have exclusively resulted in the formation of beta-carbonylsulfides 10b-d (82-93% yield), coming from the nucleophilic attack at the alpha-position and retroaldol condensation. To highlight the synthetic utility of this procedure, one-pot multisteps preparation of vinyl sulfides 7b and 7c, vinyl sulfoxides 12 and 13, and 1,5,6,7-tetrahydro-4H-1,2,3-benzotriazol-4-one (14) starting from 2-cyclohexen-1-one (11) have also been reported.