2-Cyclohexenone synthesis

An elegant complementary variation of the 2-cyclohexenone synthesis in (4.63) has been achieved in using the dioxenone as photoreactant (4.73) 485). 

FUJIMOTO - BELLEAU Cyclohexenone Synthesis Synthesis of fused cyclohexenones from lactones (an alternative to the Robinson annulation). 

A 4,4-disubstituted cyclohexenone synthesis has been developed by Holmes and Madge. The procedure is based upon PAA oxidation of anisole-derived bicyclo[2.2.2]oct-S-en-2-ones, followed by acid-catalyzed isomerization of the products (Scheme 21). 

Epoxy sulphides convert to 3-trimethylsiloxy-l,2-thiiranium salts which with nitrogen nucleophiles give 1-substituted 3-hydroxy 2-thioether and siloxycyclopnq)anesareintraniediate in cyclohexenone synthesis, while siloxycyclobutanecarboxylic esters ring open with RCHO to... 

Ficini, J. Touzin, A. M. "Cycloaddition of an ynamine to cyclohexenones. Synthesis of aminobicyclo[4.2.0]octenones Tetrahedron Lett. 1972, 2093. Ficini, J. Touzin, A. M. "Stereochemical control of an asymmetric center formed a to the carboxyl function by hydrolysis of bicyclic en amines. Stereoselective synthesis of diastereoisomericy-keto acids" Tetrahedron Lett. 1972, 2097. Ficini, J. d Angelo, J. Noire, J. "Stereospecific Synthesis of c//-Juvabione" J. 

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

Total Synthesis. Poor yields encountered duriag the manufacture of vitamin D stimulated early attempts to synthesize vitamin D. In 1959 Inhoffen synthesized vitamin from 3-methyl-2-(2-carboxyethyl)-2-cyclohexenone (40), uskig the Wittig reaction extensively (103). 

The synthesis of this series involved the reaction of disubstituted or benzo fused 6-keto(formyl)-2-cyclohexenones with hydroxylamine (Scheme 176), Base degradation gave a-cyanoketones which can be further degraded to diacids (67AHC(8)277, 80IJC(B)406). 

In recent years the application of photocycloaddition reactions to organic synthesis has been growing in importance. - The procedure described is illustrative of a general method based on a photocycloaddition reaction for the introduction of an activated alkyl group specifically to the a-carhon atom of an a,/3-unsaturated cyclohexenone. Especially significant is the fact that the method is also applicable to... 

Ethoxy-2-cyclohexenone is a useful intermediate in the synthesis of certain cyclohexenones. The reduction of 3-ethoxy-2-cyclohexenone with lithium aluminum hydride followed by hydrolysis and dehydration of the reduction product yields 2-cyclo-hexenone. Similarly, the reaction of 3-ethoxy-2-cyclohexenone with Grignard reagents followed by hydrolysis and dehydration of the addition product affords a variety of 3-substituted 2-cyclo-hexenones. ... 

The Y appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y- to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward. Another synthesis of 191 (free acid) is outlined in... 

The parent TMM precursor (1), now commercially available, has played a pivotal role in the execution of many synthetic plans directed at natural and unnatural targets. Reaction of (1) with 2-(methoxycarbonyl)cyclohexenone (14, R=C02Me) in the presence of palladium acetate and triethyl phosphite produced the adduct (15) in near quantitative yield. This cycloadduct is a critical intermediate in the total synthesis of a hydroxykempenone (16), a component of the defensive substances secreted by termites (Scheme 2.5) [12]. In accord with a previous observation by Trost that unactivated 2-cyclohexenone reacts poorly with TMM-Pd [13], the substrate (14, R=Me) was essentially inert in the cycloaddition. 

A convenient synthesis of 3,3-dimethylcyclohexanone, a compound obtained otherwise with difficulty, involves hydrogenolysis of 5,5-dimethyl-l,3-cydohexanedione (55). The reduction is believed to go through 3,3-dimelhyl-cyclohexenone (24). Hydrogenation virtually ceases after absorption of 2 mol of hydrogen. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

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 Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

In the synthesis of spirocyclic systems via an intramolecular Sakurai reaction, allylsilanes with an allyl moiety attached to the 3-position of the 2-cyclohexenone are required as starting materials. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

Similarly, cycloaddition of the cyclohexenone-like dienophile 40 with 2-tri-methylsilyloxy-1,3-butadiene (41) allowed [7] the regio- and stereoselective synthesis of tetracyclic compound 42, in high yield (Equation 5.5). 

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