Cyclohexenones, 5-substituted

When an aryl substituent is placed at C-5 of a 4-substituted cyclohexenone, a new product type containing a cyclobutanone ring is formed. 

Meyer s route to the tricyclic ketone takes advantage of an original method for the preparation of asymmetric 4-substituted cyclohexenone derivatives (288). The asymmetry was ensured by use of the bicyclic... 

The titanium tetrachloride-promoted addition of allyltrimethylsilane to methylcyclohexenones and methylcycloheptenones has been explored (68,69) results are summarized in Eqs. [l]-[6] of Scheme 32. With the exception of 4-substituted cyclohexenones and cycloheptenones, good to excellent facial selection is observed (Eqs. [2], [5], and [6], Scheme 32). The major products obtained are those predicted by axial attack of the nucleophile on the more stable conformer of the acceptor. Although there are some similarities, the results show some significant deviations from the corresponding cuprate additions. Addition to the bicyclic enone 32.1 occurs from the convex face, producing exclusively the cis-fused decalone (Eq. [7], Scheme 32) (5). In this case, the product is formally the result of equatorial attack of the allylsilane on the a,/ -unsaturated ketone. 

The second synthesis is based on the acid-catalysed fission of the Dieb-Alder adduct (60) to give the 4-substituted cyclohexenone (61). Further elaboration and chromatographic separation yielded the ester (62) (stereochemistry of the isobutyl group unassigned). Reduction of this compound with calcium in liquid ammonia followed by oxidation gave racemic juvabione. 

The catalyzed Diels-Alder reaction of nonauxiliary-controlled homodienophiles has received much less attention than the auxiliary-controlled one. Systematic studies of aluminum chloride catalyzed addition of acyclic dienes 2 to substituted cyclohexenones l4 and 7 s have been undertaken. The nature of the substituent exerts a strong influence on the steric course of the reaction addition of the diene taking place from the less hindered face of the dienophile, anti to the substituent. The effect is stronger for 5- than for 4-substituted cyclohexenones. For some adducts cisjtrans isomerization under these reaction conditions has been observed4,5. 

Several of the earlier syntheses of eremophilane sesquiterpenes have utilized the Robinson annelation reaction as a key step ". However, the synthesis of nootkatone outlined below is based on acid catalyzed rearrangement of the Diels-Alder adduct (B), directly available from a 1-methoxycyclohexa-l,4-diene (A), to a 4-substituted cyclohexenone which undergoes ring closure in formic acid to give the desired eremophilane skeleton. 

Knochel et al. described Pd-catalyzed Negishi cross-coupling reactions between zinc organometallics and aryl iodides in [BMMlM][Bp4]. Scheme 5.2-20 illustrates the reaction for the formation of a 3-substituted cyclohexenone from 3-iodo-2-cyclo-hexen-l-one [82]. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aklol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

The enol ethers of P-dicarbonyl compounds are reduced to a, 3-unsaturated ketones by LiAlH4, followed by hydrolysis.115 Reduction stops at the allylic alcohol, but subsequent acid hydrolysis of the enol ether and dehydration leads to the isolated product. This reaction is a useful method for synthesis of substituted cyclohexenones. 

An alternative, in situ source of (Ph3P)CuH can be fashioned from CuCl/PPhs/ TBAF and PhMe2SiH (1.2 equivalents) in DMA, initially made at 0° with the reaction then being run at room temperature [25]. Unhindered acyclic enones require 20 mol% of CuCl, PPhs, and TBAF for best results (Eq. 5.15). Cyclic examples are more demanding, with substituted cyclohexenones such as carvone undergoing reduction when excess reagents are present (1.6 equivalents). Acetylcyclohexene was unreactive to the catalytic conditions above. 

When organocuprates are added either to 4-substituted cydopentenones 1, or to 4-substituted or 5-substituted cyclohexenones (4 and 7), the trans addition product is generally obtained with good to excellent levels of diastereoselectivity (Scheme 6.1) [2-4]. The 6-substituted cydohexenone 10, however, predominantly gave the syn addition product [5, 6j. 

Addition of Lewis acids may not only accelerate the reaction rate of a conjugate addition but may also alter the stereochemical outcome of a cuprate addition. Interestingly when the 6-t-butyl-substituted cyclohexenone derivative 17 was exposed to dibutylcuprate, followed by silylation of the resulting enolate, the cis enol ether 18 was obtained (Scheme 6.3) [8]. If, however, the cuprate addition was performed in the presence of chlorotrimethylsilane, the stereochemical outcome of the conjugate addition reaction was reversed to give trans enol ether 19. 

Scheme 6.4. Diastereoselectivity in conjugate addition of organocopper reagents to alkoxy-substituted cyclohexenones 20 and 21 (Bn = benzyl, TBS = t-butyidimethylsilyl).

Steric considerations, which influence the relative proportions of the three hydrodimers, are demonstrated by the reduction of substituted cyclohexenones 28 in acetonitrile (Table 3.6). The ratio of products is influenced by steric hindrance at the radical centres and also depends on the concentration of water in the solvent. 

A simple synthesis of 2-substituted cyclohexenones has been developed. Although the yields are only 25-30%, it is carried out as a one-pot process using the sequence of reactions shown below. Explain the mechanistic basis of this synthesis and identify the intermediate present after each stage of the reaction. 

Highly substituted cyclohexenones 321 are efficiently prepared from dienamines and 5(47/)-oxazolones (Scheme 7.106). ... 

For a related synthesis of 5- and 6-substituted cyclohexenones see 2,2,6-lrimelhyl-1,3-dioxolenone (this volume). 

Allenylsilanes react with a,p-unsaturated acylsilanes to give trimethylsilyl-sub-stituted cyclopentenes (equation I) the reaction of allenylsilanes with a-methyl-a,p-unsaturated acylsilanes results in silyl-substituted cyclohexenones.2... 

Since a wide range of 3-substituted-4-chloromethylisoxa-zoles can be easily prepared, the isoxazole annelation sequence allows one to construct a variety of substituted cyclohexenone systems. 

A nickel-catalysed alkyne insertion between the carbonyl carbon and the -carbon of the cyclobutanone was achieved by combining a ketone-alkyne coupling reaction with a /3-carbon elimination process (Scheme 79).121 The reaction uses cyclobutanones as a four-carbon unit and provides access to substituted cyclohexenones. 

The formation of trans-products is observed to a lesser extent in the reaction of 3-alkoxycarbonyl-substituted cyclohexenones, in the reaction with electron-deficient alkenes and in the reaction with olefinic reaction partners, such as alkynes and allenes, in which the four-membered ring is highly strained (Scheme 6.11). The ester 26 reacted with cyclopentene upon irradiation in toluene to only two diastereomeric products 27 [36]. The exo-product 27a (cis-anti-cis) prevailed over the endo-product 27b (cis-syn-cis) the formation of trans-products was not observed. The well-known [2 + 2]-photocycloaddition of cyclohexenone (24) to acrylonitrile was recently reinvestigated in connection with a comprehensive study [37]. The product distribution, with the two major products 28a and 28b being isolated in 90% purity, nicely illustrates the preferential formation of HH (head-to-head) cyclobutanes with electron-acceptor substituted olefins. The low simple diastereoselectivity can be interpreted by the fact that the cyano group is relatively small and does not exhibit a significant preference for being positioned in an exo-fashion. 

Cyclohexenones are even flatter than cydohexenes, but it is convenient to draw them in a similar conformation. Conjugate addition to this substituted cyclohexenone gives the trans product. 

For weak acids, the proton is directly transferred from the acid to the substrate in a reagent-controlled manner and, in order to increase the selectivity, extremely shielded 2 -substituted m-terphenyls have been developed as concave protonating reagents inspired by the geometry of enzymes. Thus, the diastereoselective protonation by a series of substituted phenols of endocyclic keto enolates, obtained by the stereocontrolled 1,4-addition of lithiocuprates onto substituted cyclohexenones, was reported by Krause and coworkers354 355 and applied to the synthesis of racemic methyl dihydroepijasmonate356. 

The present radical formation was then applied to intramolecular cyclization. 3-Substituted cyclohexenone derivative 64 which has a (tributylstannyl)methylthio group in the side chain was irradiated (hv > 300 nm) in methanol. The desired spiro compound 65 was, however, obtained in low yield (23%) along with methyl sulfide 66 (60%) and dienone 67 (S%). In contrast, when 64 was irradiated in the presence of a 0.3 molar amount of 1,4-dicyanonaphthalene (DCN) as sensitizer in acetonitrile with 5 molar amounts of water, spiro ketone 65 was produced in 84% yield without a detectable amount of 66 and 67. Thus, by employing the DCN-mediated one-electron oxidation, the intramolecular coupling reaction proceeds smoothly (Scheme 27). 

The Hill synthesis 104) of 4-nitro-2,6-diphenylphenol from nitro-malonaldehyde and dibenzylketone was the first example of a useful synthesis by which many similar 2,6-diaryl-substituted cyclohexenone- and 2,6-diarylphenol derivatives have since been prepared. 

Trifluoroethyl 2-(trifluoromethyI)prop-2-enoate reacts with various dienes to provide cycloadducts in high yields. A typical example is the reaction with ( )-l-methoxy-2-methyl-3-(trimethylsiloxy)buta-l,3-diene leading to the trifluoromethyl-substituted cyclohexenone 13 which was used as a precursor of 16,16,16-trifluororetinal." The reaction has also been performed with a chiral dienophile."... 

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