Cyclohexenones sequence

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. 

The presence of the catalyst can also favor multiple Diels-Alder reactions of cycloalkenones. Two typical examples are reported in Schemes 3.6 and 3.7. When (E)-l-methoxy-1,3-butadiene (14) interacted with 2-cyclohexenone in the presence of Yb(fod)3 catalyst, a multiple Diels-Alder reaction occurred [21] and afforded a 1 1.5 mixture of the two tricyclic ketones 15 and 16 (Scheme 3.6). The sequence of events leading to the products includes the elimination of methanol from the primary cycloadduct to afford a bicyclic dienone that underwent a second cycloaddition. Similarly, 4-acetoxy-2-cyclopenten-l-one (17) (Scheme 3.7) has been shown to behave as a conjunctive reagent for a one-pot multiple Diels-Alder reaction with a variety of dienes under AICI3 catalysis, providing a mild and convenient methodology to synthesize hydrofluorenones [22]. The role of the Lewis acid is crucial to facilitate the elimination of acetic acid from the cycloadducts. The results of the reaction of 17 with diene... 

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... 

Japanese workers (50,51) were the first to observe optical activity in the addition of thiols to electron-poor olefins (eq. [9]) The e.e. was not determined, but these observations led us to attempt using a cinchona alkaloid as the catalyst in the addition of thiophenol to cyclohexenone. The reaction lends itself admirably to a scope, limitations, and mechanism study, and the results have been published in detail (19). An important mechanistic difference between the addition of the dodecanethiol to isopropenyl methyl ketone and the addition of thiophenol to a cyclohexenone (eq. [1]) lies in the sequence of chirality-producing steps. In the former case, chirality is produced when the proton adds to the a-caibon atom of the ketone—after thiol addition has taken place. In the latter... 

In 1978 Oppolzer and Petrzilka reported the first enantioselective total synthesis of natural (+)-luciduline from (i )-5-methyl-2-cyclohexenone (31) by a sequence of seven steps in 33% overall yield [9]. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

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. 

A series of sesquiterpenoid cyclohexenones (1-abolones) has been studied395, and it was found empirically that in the naturally occurring diastereomer 14 the C-7 methyl protons resonate at <5 = 0.80, whereas in the synthetic diastereomer this value is 3 = 0.93. The same sequence and chemical shift difference was found for another eleven pairs of diastereomers with the same skeleton. 

Other removal procedures include reaction of the bicyclic lactam 4 with hydride (R6 = H) or an alkyl metal (R6 = alkyl). After hydrolysis of the bicyclic azahemiketal 5, ketoaldehydes or diketones 6 result. These can then be used in intramolecular aldol-type reactions to furnish enantiomerically pure cyclopentenones 7 (n = 1). The same reaction sequence can be used to prepare cyclohexenones (see Table 9)3-6 7l 1 ... 

Coupling our own methodology with research developed by Wender et al.25 allowed us to devise a five-step sequence for the preparation of the cyclialkylation precursor 63 (Scheme 5.6). In the first step, the organolithium species 60 derived from isopropyl-veratrole24 was used to prepare cyclohexenone 61 through reaction with epoxide 59.25 The... 

Some potentialities of the 8-ketodithioesters are illustrated by the easy conversions of the dithioester group in ester and amide functions [332]. The overall sequences are indirect 1,4-addition on 2-cyclohexenone of, respectively, an ester enolate for (4) or an amide enolate for (5). 

Cyclic products can be formed by aldol additions provided the donor carbanion and acceptor carbonyl are part of the same molecule. For example, consider how the synthesis of 3-methyl-2-cyclohexenone could be achieved from acyclic substances. The carbon-carbon bond formed in this process of aldol addition closes the ring and ultimately becomes the double bond in the conjugated system when the aldol product undergoes dehydration. Working backwards, we have the sequence... 

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. 

Photoaddition of l,2-bis(trimethylsiIoxy)cyclobutene 214 to various cyclohexenones followed by subsequent fragmentation of the produced four-membered ring was elegantly applied for the synthesis of various sesquiterpenes and diterpenes101. The photoaddition of 214 was applied102 in the total synthesis of the sesquiterpene (+)-daucene 217, which was obtained in a three-step sequence from the naturally occurring (—)-piperitone 213 (Scheme 46). 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

To complete the reaction sequence of Figure 13.35, the desired alkylated ketone needs to be released from the kethydrazone. Ozonolysis cannot be used in the present case. Ozonoly-sis would cleave not only the C=N double bond but also the C=C double bond. Another method must therefore be chosen. The kethydrazone is alkylated to give an iminium ion. The iminium ion is much more easily hydrolyzed than the hydrazone itself, and mild hydrolysis yields the deshed -enantiomer of 6-methyl-2-cyclohexenone. The other product of hydrolysis is a RAMP derivative. This RAMP derivative carries a methyl group at the N atom and cannot be recycled to the enantiomerically pure chiral auxiliary A that was employed initially. 

Enolate D of Figure 13.71 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexenone to an enolizable ketone. The reaction sequence of Figure 13.71 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

Thioamides exhibit a pronounced nucleophilic character due to their nitrogen atom. Alkyl halides often react at room temperature to give thioimi-doester salts which may be subsequently used. This reaction was applied [134] to the preparation of an enaminoketone, the cyclohexenone ring being formed by base treatment of a ketone and intramolecular reaction with the iminium salt. A similar sequence [135] was mentioned in Scheme 28. 

Robinson annulation reaction (Section 23.12) a multistep sequence for building a new cyclohexenone ring onto a ketone. The sequence involves an initial Michael reaction of the ketone followed by an internal aldol cyclization. 

An entirely different approach for the synthesis of quadrone was chosen by Yoshii et al Yoshii s group started the assemblage of 62 from cyclohexenone 73 (Scheme 3.17), as a precursor of ring C. The synthetic sequence consisted of only 12 steps and was accomplished in an overall yield of 2.6%. The key steps in this synthesis, involving intermediates 74-78, are shown in Scheme 3.17. 

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