Cyclohexenyl acetate

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

Solvolyses of these cyclic vinyl triflates at 100 in 50% aqueous ethanol, buffered with triethylamine, lead exclusively to the corresponding cyclo-alkanones. Treatment of 176 with buffered CH3COOD gave a mixture of cyclohexanone (85%) and 1-cyclohexenyl acetate (15%). Mass spectral analysis of this cyclohexanone product showed that the amount of deuterium incorporation was identical to that amount observed when cyclohexanone was treated with CH3COOD under the same conditions. This result rules out an addition-elimination mechanism, at least in the case of 174, and since concerted elimination is highly unlikely in small ring systems, it suggests a unimolecular ionization and formation of a vinyl cation intermediate in the solvolysis of cyclic triflates (170). The observed solvent m values, 174 m =. 64 175 m =. 66 and 16 m =. 16, are in accord with a unimolecular solvolysis. 

The hydrolytic DKR of allyl esters has been studied as a DKR of esters. The first DKR was accomplished through Pd-catalyzed racemization and enzymatic hydrolysis of allylic acetates in a buffer solution. However, the DKR under these conditions was limited to cyclohexenyl acetates to give symmetrical palladium-allyl intermediates. Among them, 2-phenyl-2-cyclohexenyl acetate 9 was the only substrate to have been resolved with good results (81% yield, 96% ee). 

Moreover, a few chiral ferrocenylsulfur-imine ligands were investigated in the palladium-catalysed asymmetric allylic alkylation of 1,3-diphenylpropenyl acetate and cyclohexenyl acetate with dimethyl maionate (Scheme... 

Scheme 5.15 DKR of cyclohexenyl acetate to give a (-)-cyclohexenol with P. fluorescens lipase immobilized in an Si02 sol-gel matrix [62].

If an excess of sodium hydride has been used, the product contains varying amounts of the /3,7-isomer, ethyl cyclohexenyl-acetate. To ensure against the occurrence of this side reaction, a 5-10% excess of the phosphonate ester can be used. 

Alkenes reacted with RuCyaq. CH3CO3H/CH3CN-CH2CI2 giving a-ketols thus cix-5-(methoxycarbonyl)-2-cyclohexenyl acetate (1) gave (2R, 35, 5R )-3-acetoxy-2-hydroxy-5-(methoxycarbonyl)-l-cyclohexanone (2) (Fig. 3.9, Table 3.2). Cortisone acetate was isolated in this way from epiandrosterone after a number of steps [179]. 

The chiral nonracemic bis-benzothiazine ligand 75 has been screened for activity in asymmetric Pd-catalyzed allylic alkylation reactions (Scheme 42) <20010L3321>. The test system chosen for this ligand was the reaction of 1,3-diphenylallyl acetate 301 with dimethyl malonate 302. A stochiometric amount of bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc were added to the reaction mixture. A catalytic amount of chiral ligand 75 along with a variety of Pd-sources afforded up to 90% yield and 82% ee s of diester 303. Since both enantiomers of the chiral ligand are available, both R- and -configurations of the alkylation product 303 can be obtained. The best results in terms of yield and stereoselectivity were obtained in nonpolar solvents, such as benzene. The allylic alkylation of racemic cyclohexenyl acetate with dimethyl malonate was performed but with lower yields (up to 53%) and only modest enantioselectivity (60% ee). 

The proposed mechanism for allyhc acetoxylation of cyclohexene is illustrated in Scheme 15. Pd -mediated activation of the allyhc C - H bond generates a Jt-allyl Pd intermediate. Coordination of BQ to the Pd center promotes nucleophilic attack by acetate on the coordinated allyl ligand, which yields cyclohexenyl acetate and a Pd -BQ complex. The latter species reacts with two equivalents of acetic acid to complete the cycle, forming Pd(OAc)2 and hydroquinone. The HQ product can be recycled to BQ if a suitable CO catalyst and/or stoichiometric oxidant are present in the reaction. This mechanism reveals that BQ is more than a reoxidant for the Pd catalyst. Mechanistic studies reveal that BQ is required to promote nucleophilic attack on the Jt-allyl fragment [25,204-206]. 

Use of some other diphosphines and monophosphines is also possible for this purpose. Osborn and his coworkers reported a highly enantioselective allylic alkylation of 2-cyclohexenyl acetate with malonates by using duthixantphospholane 18a (up to 93% ee) (Equation (21)).i d7a,i7b co-workers succeeded in obtaining... 

Asymmetric nickel-catalyzed allylic alkylation with soft carbon-centered nucleophiles was reported in 1996 by Mortreux and his co-workers. Use of a catalytic amount of [Ni(cod)2] together with chiral diphosphines 138 promotes the allylic alkylation of a cyclic ester such as 2-cyclohexenyl acetate with dimethyl malonate in the presence of BSA and gives the corresponding alkylated compounds only with a moderate enantioselectivity (40% ee) (Equation (42)). 

Palladium(II) and nitrate ion with oxygen as final oxidant give an excellent yield of cyclohexenyl acetate from cyclohexene (92% at 50°C).703 The catalyst reoxidation sequence includes a palladium nitro-nitrosyl redox couple. 

Fig. 97. Solvent retained by nitrocellulose films (50/i thickness) after exposure to air at 25°C (Baelz [48]). I—Cyclohexenyl acetate, II—methyl cyclohexanone, III—diacetone alcohol, IV—cyclohexanone, V—cellosolve acetate, VI—amyl acetate-ethyl alcohol I 1, VII—amyl acetate, VIII— methyl cellosolve acetate, IX—amyl acetate-toluene 1 1, X—butyl acetate-ethyl alcohol 1 1, XI—butyl acetate, XII—cellosolve, XIII—methyl-ethyl ketone, XIV—cellosolve-toluene 1 1, XV—methyl cellosolve, XVI—ethyl acetate, XVII—acetone.

Oxidation of alkenes by Co(OAc)3 preferentially occurs at the allylic positions, yielding 2-alkenyl acetate. Oxidation of cyclohexene by Co(OAc)3 and TFA in AcOH results in the formation of cyclohexenyl acetate along with minor amounts of the corresponding allyl alcohol.550 The oxidation of ethylene by Co(TFA)3 in TFA affords ethylene glycol bis(trifluoroacetate).552... 

Oxidation of cyclohexene by peroxydisulfate in the presence of copper(II) salts results in the formation of cyclopentanecarboxaldehyde as the main product in an aqueous acetonitrile solution (equation 261), and 2-cyclohexenyl acetate in an acetic acid solution (equation 262).588,589 Reaction (261) has been interpreted as the formation of a radical cation (186) by oxidation of cyclohexene with S2Og, followed by hydrolysis of (186) to the /3-hydroxy alkyl radical (187), which is oxidized by copper(II) salts to the rearranged aldehydic product (188 equation 263).589... 

Loss of stereospecificity, however, has also been reported in the addition of amines. The use of homogeneous Pd° catalysts in the addition of dimethylamine to a cyclohexenyl acetate led to substantial stereochemical scrambling (equation 186). Employment of polymer-bound Pd° catalysts, however, gave complete stereospecificity via ligand addition.398 The epimerization noted in this reaction is apparently due to acetate attack at the metal center, which is prohibited by steric congestion of the metal in the polymer matrix (equation 187).398... 

The addition of sodium phenylsulfinate nucleophiles to stereodefined acyclic allylic chlorides was reported to proceed with complete overall retention of configuration, indicating that this nucleophile adds with inversion of configuration, i.e. via attack at the allyl ligand (equation 193).21S A cyclohexenyl acetate substrate also showed predominant ligand addition, but some isomeric product was also produced (equation 194).216 This loss could be due to acetate epimerization of starting material, ir-allyl epimeriza-tion by PdL2, or by attack of the sulfur at the metal, followed by reductive elimination. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

By changing the relative reactivity of the allylic leaving groups, namely acetate and the more reactive carbonate, either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. The Pd-catalysed reaction of the allylic acetate moiety of 150 with malonate affords 151. Acetylation of 151 and Pd-catalysed 1,4-elimination of... 

Reverse annulation reactions of bromoacetaldehyde cyclohexenyl acetals 261 catalyzed by 255 using NaBUt as the stoichiometric reducing agent provided bicycles 262 in 40-71% yield (Fig. 64, entry 5) [314, 315]. Cathodic reduction at — 1.8 V was also successfully applied to regenerate 255 or vitamin B12 247 in radical 5-exo cyclizations of 261 under optimized conditions (entry 6) [316, 317]. Less than 10% of the cyclic reduced products 263 were detected. 

A further variant is the oxidation of olefins by Mn(III) acetate in the presence of halide ions. Thus, oxidation of cyclohexene by Mn(III) acetate in acetic acid at 70°C is slow, but addition of potassium bromide leads to a rapid reaction. Cyclohexenyl acetate was formed in 83% yield.223 In contrast to what would be expected for an electron transfer mechanism, norbomene (ionization potential 9.0 eV) was unreactive at 70°C, whereas cyclohexene (ionization potential 9.1 eV) and bicyclo[3,2,l] oct-2-ene reacted rapidly. The low reactivity of norbomene can be explained, if oxidation involves attack at the allylic position... 

An even more interesting result, recently obtained with LiAl[OC(Ph)(CF3)2]4 (107), is applicable to similar allylic substitutions. Reagent 107 is readily prepared by treatment of a toluene suspension of LiAlH4 with 4 equiv. HO-C(Ph)(CF3)2 under reflux conditions. The X-ray crystal structure of 107 shows that the lithium is hexa-coordinated with two internal oxygen and four internal fluorine atoms. By use of 10 mol % 107, cyclohexenyl acetate 108 and Si-3 were coupled successfully to furnish 109 in 92 % yield (Sch. 51) [100]. 

Cyclopropane formation was also observed as a side reaction (1 9 up to 1 1) in the palladium-catalyzed coupling of ketene alkyl silyl acetals with open-chain and cyclic allyl acetates. The reaction is interpreted as proceeding via nucleophilic central attack of a jr-allyl intermediate. Although cyclopropane formation proceeds only with low yields, a highly stereospecific pathway was observed with substituted 3-cyclohexenyl acetates. ... 

S,S)-chiraphos, enantioselectivity drops to 15%, as there is 25% background reaction in the presence (PPh3)2NiCl2. When cyclohexenyl acetal 38 is treated with (S,S)-chiraphosNiCl2, 39 is obtained in only 11% ee and 80% yield. Remarkably, when the in situ method is utilized, (S)-39 is formed in 92% ee (90% yield). Control experiments clearly indicate that it is the excess PPhj present in the in situ method is responsible for the dramatic improvement in enantioselec-... 

Scheme 13. Ni-catalyzed addition of alkylmagnesium halides to unsaturated cyclohexenyl acetals is significantly more enantioselective in the presence of excess PPh3...

Hard nucleophiles also react with cyclic allylic acetates and halides. For example, cyclohexenyl acetate reacts with a vinylmagnesium species in the presence of PROLIPHOS to give the product of allylic alkylation in 30% ee [108]. 

Ethyl (/ )-2,6,6-Trimethy]-2-cyclohexenyl acetate (12) Single Procedure405 ... 

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