Cyclohexene from Diels-Alder reaction

Next, in order to learn more about the rates of dehydrogenation of cyclohexenes resulting from Diels-Alder reactions between butadiene and olefins, VCH, HCH and MCH were earlier subjected to thermal reactions at 530- 665 C ( ). The main reactions in these cases were reverse Diels-Alder reactions and dehydrogenations. Dehydrogenations which are related to the productions of cyclohexa-diene and benzene homologues were 1 10 in selectivity as compared to that of the reverse Diels-Alder reaction. An interesting observation related to cyclic compound formation is that, in the case of MCH pyrolysis, cyclohexadiene and cyclopentene are formed at almost the same rates as butadiene and propylene. So that, in this case, about 60% of MCH is employed in the formation of cyclic compounds. 

Dimerization.—Unsaturated acids, whether monoenoic or polyenoic, furnish dimers which are in demand because of the valuable surface-active properties of their various derivatives. Methods of dimerization have therefore been extensively examined, but understanding of the reaction and the structural identification of the products have lagged behind. Dimerization is effected in several ways but clay catalysts are the most widely employed, and it is now recognized that such catalysts operate in several ways. They may promote modification of monoenoic and dienoic acids to more reactive monomers in addition to assisting both the dimerization process and the subsequent changes in the dimer molecules. In particular, hydrogen transfer seems to be important monoenoic acids are thereby converted to more reactive dienoic acids and the dimer (probably a cyclohexene derivative resulting from Diels-Alder reaction) is converted to a substituted aromatic compound. ... 

Cyclohexene derivatives can be oxidatively cleaved under mild conditions to give 1,6-dicarbonyl compounds. The synthetic importance of the Diels-Alder reaction described above originates to some extent from this fact, and therefore this oxidation reaction is discussed in this part of the book. 

Diels-Alder Reactions. The important dimerization between 1,3-dienes and a wide variety of dienoplules to produce cyclohexene derivatives was discovered in 1928 by Otto Diels and Kurt Alder. In 1950 they won the Nobel prize for their pioneering work. Butadiene has to be in the j -cis form in order to participate in these concerted reactions. Typical examples of reaction products from the reaction between butadiene and maleic anhydride (1), or cyclopentadiene (2), or itself (3), are <7 -1,2,3,6-tetrahydrophthaHc anhydride [27813-21 -4] 5-vinyl-2-norbomene [3048-64-4], and 4-vinyl-1-cyclohexene [100-40-3], respectively. 

Other methods for the preparation of cyclohexanecarboxaldehyde include the catalytic hydrogenation of 3-cyclohexene-1-carboxaldehyde, available from the Diels-Alder reaction of butadiene and acrolein, the reduction of cyclohexanecarbonyl chloride by lithium tri-tcrt-butoxy-aluminum hydride,the reduction of iV,A -dimethylcyclohexane-carboxamide with lithium diethoxyaluminum hydride, and the oxidation of the methane-sulfonate of cyclohexylmethanol with dimethyl sulfoxide. The hydrolysis, with simultaneous decarboxylation and rearrangement, of glycidic esters derived from cyclohexanone gives cyclohexanecarboxaldehyde. 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

In the Diels-Alder transition state, the two alkene carbons and carbons 1 and 4 of the diene rehybridize from sp2 to sp 5 to form two new single bonds, while carbons 2 and 3 of the diene remain sp2-hybridized to form the new double bond in the cyclohexene product. We ll study this mechanism at greater length in Chapter 30 but will concentrate for the present on learning more about the characteristics and uses of the Diels-Alder reaction. 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Harano and colleagues [48] found that the reactivity of the Diels-Alder reaction of cyclopentadienones with unactivated olefins is enhanced in phenolic solvents. Scheme 6.28 gives some examples of the cycloadditions of 2,5-bis-(methoxycar-bonyl)-3,4-diphenylcyclopentadienone 45 with styrene and cyclohexene in p-chlorophenol (PCP). Notice the result of the cycloaddition of cyclohexene which is known to be a very unreactive dienophile in PCP at 80 °C the reaction works, while no Diels-Alder adduct was obtained in benzene. PCP also favors the decarbonylation of the adduct, generating a new conjugated dienic system, and therefore a subsequent Diels-Alder reaction is possible. Thus, the thermolysis at 170 °C for 10 h of Diels-Alder adduct 47, which comes from the cycloaddition of 45 with 1,5-octadiene 46 (Scheme 6.29), gives the multiple Diels-Alder adduct 49 via decarbonylated adduct 48. In PCP, the reaction occurs at a temperature about 50 °C lower than when performed without solvent, and product 49 is obtained by a one-pot procedure in good yield. 

Retro-Diels-Alder reactions can be used to regenerate dienes or alkenes from Diels-Alder protected cyclohexene derivatives under pyrolytic conditions144. Most of the synthetic utility of this reaction comes from releasing the alkene by diene-deprotection. However, tetralin undergoes cycloreversion via the retro-Diels-Alder pathway to generate o-quinodimethane under laser photolysis (equation 89)145. A precursor of lysergic acid has been obtained by deprotection of the conjugated double bond and intramolecular Diels Alder reaction (equation 90)146. 

Figure 5.60 displays a portion of the Diels-Alder reaction profile in the neighborhood of the TS complex. In this case the IRC profile is rather unsymmetric around s = 0, ascending slowly from the reactant side toward the TS summit, then plummeting rapidly toward the product cyclohexene limit, which lies about 29 kcal mol-1 below the reactants (and 54 kcal mol-1 below the TS). 

Mechanistic and theoretical studies of the Diels-Alder reaction have resulted in the characterization of this reaction as a concerted, although not necessarily synchronous, single-step process28-31 45. The parent reaction, the addition of 1,3-butadiene to ethylene yielding cyclohexene, has been the subject of an ongoing mechanistic debate. Experimental results supported a concerted mechanism, whereas results from calculations seemed to be dependent on the method used. Semi-empirical calculations predicted a stepwise mechanism, whereas ab initio calculations were in favor of a concerted pathway. At the end of the 80s experimental and theoretical evidence converged on the synchronous mechanism29-31. 

An exo-type cyclization, proceeding through a cycloalkylidene carbene (49 n = 1, 3, 4), was proposed to explain the formation of enynes (50) and (52) from alkynyl lithium species (48). The proposed carbene (49) could be trapped by addition to cyclohexene and the cycloalkyne intermediate (51) was trapped by Diels-Alder reaction with 1,3-diphenylisobenzofiiran. 

Every discussion of the Diels-Alder reaction for 1,3-butadiene includes the observation that cycloaddition should occur only from the s-cis conformer to produce czs-cyclohexene. This conformational selectivity, however, further implies that cycloaddition of s-trans- 1,3-butadiene should lead to trans-cyclohexene, but the s-trans region of this potential surface has remained unexplored. A study of this problem shows that the concerted and stepwise reaction paths exist for both diene conformers, connecting them to the respective cyclohexene isomers.661 It is also demonstrated that the usual paradigm for the Diels-Alder reactions is incomplete a thorough understanding of this archetypal reaction requires consideration of the full range of processes shown in Scheme 6.10, not just those involving the s-cis conformer. 

Although ion-molecule processes would be possible in some electron impact reactions, this process would not lead to the formation of dimeric products formed in the present experiments (20). Ethylene was the major gaseous product. Ethylene and butadiene may be produced from the reverse Diels-Alder reaction of cyclohexene (10) since they were also... 

Oxidation of thiochromones does not lead to the sulfoxide or sulfone derivatives these are better prepared from the corresponding thiochromanones by oxidation followed by bromination and dehydrobromination. The 1-oxide is an extremely reactive species and gives a Diels-Alder adduct with butadiene. The 1,1-dioxide is also very reactive. Photolysis in benzene affords a 2 1 adduct in 30% yield (116) (79TL1097) via an initial [2 + 2] addition followed by a Diels-Alder reaction. Simple [2 + 2] addition is found with cyclohexene. 

Diels-Alder reactions are, of course, reversible, and the pathway followed for the reverse reaction (2,3 arrows) can sometimes be as telling as the pathway for the forward reaction. The direction in which any pericyclic reaction takes place is determined by thermodynamics, with cycloadditions, like the Diels-Alder reaction, usually taking place to form a ring because two n-bonds on the left are replaced by two Diels-Alder reaction can be made to take place in reverse when the products do not react with each other rapidly, as in the pyrolysis of cyclohexene 2.3 at 600°. It helps if either the diene or the dienophile has some special stabilization not present in the starting material, as in the formation of the aromatic ring in anthracene 2.15 in the synthesis of diimide 2.16 from the adduct 2,14, and in... 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

The total synthesis of ( )-lycoricidine (214) from the aryl cyclohexene 272, which was accessed by a Diels-Alder reaction of the carbinol 46, has been... 

Finally we can investigate the 1,6-dicarbonyl approach by reconnection 2d to give a cyclohexene that seems destined for synthesis by a Diels-Alder reaction from isoprene 11 and the enone 10 that can probably be made by a Mannich reaction on ethyl acetoacetate. 

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