Cyclohexenones aromatization

They can be prepared from acyclic compounds. In an industrial process, dimethyl malonate is condensed with 4-alken-3-ones (or a mixture of the respective ketones with 5-chloroalkan-3-ones) to give a substituted 3-hydroxy-2-cyclohexenone. Aromatization, in good yield is achieved by reaction of the hydroxycyclohexenones... 

The only other functional group is the conjugated unsaturated ester. This functionality is remote from the stereocenters and the ketone functionality, and does not play a key role in most of the reported syntheses. Most of the syntheses use cyclic starting materials. Those in Schemes 13.4 and 13.5 lead back to a para-substituted aromatic ether. The syntheses in Schemes 13.7 and 13.8 begin with an accessible terpene intermediate. The syntheses in Schemes 13.10 and 13.11 start with cyclohexenone. Scheme 13.3 presents a retrosynthetic analysis leading to the key intermediates used for the syntheses in... 

OO stretch cyclohexenone carbonyl C—C stretch, aromatic and cyclic unsaturation OC stretch, aromatic C-0 stretch, aryl methoxyl... 

The effect of cryptands on the reduction of ketones and aldehydes by metal hydrides has also been studied by Loupy et al. (1976). Their results showed that, whereas cryptating the lithium cation in LiAlH4 completely inhibited the reduction of isobutyraldehyde, it merely reduced the rate of reduction of aromatic aldehydes and ketones. The authors rationalized the difference between the results obtained with aliphatic and aromatic compounds in terms of frontier orbital theory, which gave the following reactivity sequence Li+-co-ordinated aliphatic C=0 x Li+-co-ordinated aromatic C=0 > non-co-ordinated aromatic C=0 > non-co-ordinated aliphatic C=0. By increasing the reaction time, Loupy and Seyden-Penne (1978) showed that cyclohexenone [197] was reduced by LiAlH4 and LiBH4, even in the presence of [2.1.1]-cryptand, albeit much more slowly. In diethyl ether in the absence of... 

Wipf has shown that this method is quite general and tolerates several functional groups, such as ethers, thioethers, silanes, halides, aromatic rings, and olefins. The iodoalkyne 64 is readily carbometalated and after treatment with the dialkynylcuprate 59 furnishes the functionalized copper reagent 65, which smoothly undergoes 1,4-addition reactions with enones. Thus, in the case of 2-cyclohexenone, the functionalized ketone 66 is produced in 85% yield (Scheme... 

They showed that use of the phosphonium IL resulted in milder conditions and yields comparable with conventional solvents. Both aliphatic and aromatic amines reacted well in presence of phosphonium ILs, in contrast with ammonium ILs where only aliphatic amines acted as Michael donors. Yang et al. demonstrated the use of aromatic amines and N-heterocycles as Michael donors in presence of a basic IL such as [emim]OH. They reacted cyclohexenone with aniline in presence of [emim]OH at room temperature to give the corresponding Michael adduct, Scheme 25. 

A further reaction then takes place in this particular instance (see Preparation 26), but in the general case the reaction goes no further. The compounds so obtained are all derivatives of cyclohexenone. These latter compounds may be transformed by various reactions into cyclo-paraffins on the one hand, and aromatic compounds on the other. This affords a method of passing from simple aliphatic to aromatic compounds (see Preparation 446). (A., 281, 25.)... 

Hydrogenation of 2,4,4-trimethyl-2-cyclohexenone with rrans-RuCl2(tolbinap)(dpen) and (CH3)3COK under 8 atm of hydrogen gives 2,4,4-trimethyl-2-cyclohexenol quantitatively with 96% ee (Scheme 1.70) [256,275,276]. In this case, unlike in the reaction of aromatic ketones, the combination of the R diphosphine and S,S diamine most effectively discriminates the enantiofaces. The chiral allylic alcohol is a versatile intermediate in the synthesis of carotenoid-derived odorants and other bioactive terpens such as a-damascone and dihydroactinidiolide [277]. 

Protonated phenols and phenol ethers formed in superacids can be trapped by aromatics (benzene, naphthalene, tetrahydroquinoline). The products are either cyclohexenone derivatives301 [Eq. (5.112)] or aryl-substituted phenols. In the reaction of phloroglucinol with benzene, the diphenyl-substituted derivative is the main product [Eq. (5.113)], whereas 1,3,5-trimethoxybenzene gives selectively the monophenyl derivative (80% yield). Protonated dicationic species, such as 76, detected by Olah and Mo302 using NMR, were suggested to be intermediates in these processes. 

The final step in a recent synthesis of cannabichromene (2) is the aromatization of the cyclohexenone ring of 1. Reagents used for this purpose also attack the double bond in the side chain, but the desired reaction was effected by treatment of the lithium enolate of 1 with benzeneselenenyl chloride followed by selenoxide elimination in the presence of 3,5-dimethoxyaniline.5... 

Aromatization, of cyclohexenones, 35, 197 Aroyl cyanides, 434 Arylacetic acids, 148, 189... 

Aromatization of cyclohexenonesf This reaction is possible by selenenylation of (lie lithium enolate of the cyclohexenone, followed by oxidation of the resulting xclcnide. To obtain satisfactory yields of the phenol, an aromatic amine is added in llu oxidation step to react selectively with the benzeneselenenic acid formed. For this pin pose, 3,5-dimethoxyaniline is the most satisfactory amine. 

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

Microwave irradiation of a mixture of cyclohexenones and ethyl acetoacetate adsorbed on the surface of solid lithium 5-(2)-prolinate leads to the stereoselective construction of bicyclo[2.2.2]octanone (69) systems through Michael addition and subsequent intramolecular aldolization (Ranu et al., 2000). Electron-rich aromatic compounds react with formaldehyde and a secondary amine under solvent-free condition and microwave irradiation in a microwave oven to produce amino ethylated products (70) in good to excellent yields (Mojtahedi et al., 2000). 

The aromatization of cyclohexenones is an important process that can be easily accomplished by the use of selenium-based reagents using similar techniques to those previously discussed for other carbonyl species. Thus, enolates derived from a,3-enones readily undergo selenenylation at the a -position and on oxidation and elimination afford the corresponding phenols. ... 

Potassium hydride and potassium hexamethyldisilazide are the most commonly used metal sources to generate the alkoxide . But recently, the indium(I)-mediated tandem carbonyl addition-oxy-Cope rearrangement of y-pentadienyl anions to cyclohexenones and conjugated aromatic ketones has been reported. For example, indium alkoxide 8.32, obtained after the addition of 5-bromopenta-1,3-diene (8.31) to the aromatic conjugated ketones 8.30, undergoes a spontaneous oxy-Cope rearrangement to give 8.33 in 55% yield (Scheme 8.9). 

Hauser has used repetitive annelations of this type tor synthesis of linear aromatic systems. This methodology provides a simple regiospecific route to the tetracyclic system of the antibiotic anthracyclinones. For this purpose 5-ethoxy-2(5Ff)-furanone (2) is used as the Michael acceptor in the first annelation of the anion of 1. After methylation, 3 is obtained in 65% yield. It is then converted into 4, for a second annelation with cyclohexenone or a derivative (5). The reaction results in a tetracyclic hydronaphthacene 6. 

S)-4-Anilino-3-methylamino-l-butanol (22a) and (S)-4-(2,6-xylidino)-3-methylamino-l-butanol (22b), tridentate chiral auxiliaries, are easily derived from (S)-aspartic acid. A complex (56a) prepared from equimolar amounts of LAH and (22a) in THF reduces aromatic ketones to (S)-carbinols in 51-88% ee. This complex is also effective in reducing several enones to (S)-allylic alcohols (Scheme 12), whereas the complex (56b) affords the () )-enantiomers. Particularly noteworthy is the virtually complete en-antiofacial differentiation of cyclohexenone giving (S)-2-cyclohexenol. ... 

The Birch reduction of aromatic hydrocarbons and ethers to the 2,5-dihydro derivatives proceeds most satisfactorily when the substitution pattern allows the addition of hydrogen to two unsubstituted positions in a para relationship. If this requirement is satisfied, better yields are obtained from more highly substituted aromatic rings than from (say) anisole itself, which affords a substantial amount (20%) of 1-methoxycyclohexene (c/. Scheme 1). Extra substitution presumably hinders protonation at the terminus of the dienyl anion (which would lead to a conjugated diene and overreduction). The utilization of anisole moieties as precursors to cyclohexenones has been of very limited value with many 1,2,3-substitution patterns and more densely substituted derivatives. Compounds (23) to (26), for example, have only been reduced by employing massive excesses (200-600 equiv.) of lithium metal,2 while the aromatic ring in (28) is completely resistant to reduction. ... 

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