Highly substituted diene

A new catalytic elimination/isomerization pathway of stereodefined enol triflates capable of providing the corresponding functionalized, highly substituted, 1,3-dienes in synthetically useful yields has been discovered. Preliminary mechanistic studies support a distinct catalytic pathway that rationalizes the stark reactivity differences between E and Z enol triflates through stereoisomeric cationic vinyl palladium(II) complexes. 

X. Zhang, R. C. Larock, Org. Lett. 2003, 5, 2993-2996. Synthesis of highly substituted 1,3-dienes and 1,3,5-trienes by the palladium-catalyzed coupling of vinylic halides, internal alkynes, and organoboranes. 

Several novel conjugated 1.3-dienes, which have substituents that are able to be transformed into other functionalities, or react in the Diels-Alder reaction, have been prepared this year. An -mixture of the highly substituted 1,3-diene (41)... 

Despite this overwhelming body of evidence, two-step mechanisms have been suggested for the Diels-Alder reaction, probably inspired by special cases, where highly substituted dienes and/or dienophiles have been found to react through zwitterionic or biradicalintermediates (Scheme 1.2). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Steric effects play a dominant role with more highly substituted dienes. Hexachloro-cyclopentadiene, for example, shows a higher endo preference than cyclopentadiene because the 5-chlorine causes steric interference with exo substituents.13... 

The reactivity of dienes in Diels-Alder reactions is also controlled by the diene conformation. The two planar conformations of 1,3-butadiene are referred to as s-trans and s-cis (equation 16). Calculations have shown the s-trans conformation to be 2-5 kcalmol-1 more stable than the s-cis conformation. Open-chain dienes can only react in their cisoid conformation. Thus, 2-substituted dienes are generally more reactive than 1,3-butadiene due to their stronger preference for the s-cis conformation. 1 -Cis substituted 1,3-butadienes are almost exclusively in the s-trans conformation and are not reactive in Diels-Alder reactions. Highly substituted dienes may, however, be present in the s-cis conformation during a sufficient amount of time to participate in Diels-Alder reactions, even if a 1 -cis substituent is present62. 

As observed with alkenes, bromine addition to sterically hindered dienes shows a peculiar behavior. Highly substituted dienes, existing predominantly in non-planar conformations, often present a chemical reactivity distinctly different from that of planar... 

Assuming isomerism occurs to give the mosl stable (most conjugated and most highly substituted) dienes during the reactions, the two piperidines would undergo Hofmann exhaustive methyl-ation and subsequent ozonolysis as shown below. The diflerent orientation patterns are then reflected in the constitutions of the aldehydes and ketones that are formed. 

The alcohol 10 looks like it might be formed by the addition of a Grignard reagent to an aldehyde. In fact, Patrick Steel of the University of Durham prepared 10 (Tetrahedron Lett. 44 9135,2003) by Diels-Alder addition of the transient silene derived from 7 to the diene 8. More highly substituted dienes lead to more complex arrays of stereogenic centers. The intermediate silacyclohexenes, exemplified by 9, should also engage in the other reactions of allyl silanes. 

The regiochemical features of this process can be seen in the results of a study by Kim and Weinreb using several highly substituted dienes and a dehydrohydantoin precursor (Scheme 2-IV).34 It was found that as the substituent R becomes more electron donating, the ratio of regioisomeric adducts changes in the order one would expect based on the Scheme 2-1... 

Only one study detailing DTDA reactions of the pseudo-acyclic 1,1- or 3,3-cyclo[3]dendralenes has been reported, most likely owing to the difficulties associated with DA reactions of such highly substituted dienes. The prototypical, and not yet reahzed, DTDA cascade of l,l-cyclo[3]dendralene 17 is presented in Scheme 12.12. If the first DA reaction occurs at the more sterically demanding exocyclic diene site, spiro-bicycle 65 is produced, which could react further to generate the... 

To further examine the interaction of SmCp 2 with more highly substituted dienes, reactions of the unsolvated reductant with isoprene and myrcene were examined (Evans et al., 2001). Addition of isoprene or myrcene to a toluene solution of SmCp 2 at —36°C generated single products whose crystal structures were consistent with [(Cp )2Sm]2[/x- 7 r] CH2CHC(CH3)CH2] and [(Cp )2Smh[fi-t] 74-CH2CHC(CH2)-CH2CH2CHC(CH3)2] respectively (eq. (123)). Attempts to run the reactions at room... 

Methoxy-2-trimethylsilyloxyfuran is also a highly efficient diene under the influence of Lewis acids this compound is substituted readily at position 5 with a wide variety of agents (Scheme 74) (82TL353). 

Whereas tropones usually act as dienes in cycloaddition reactions (Section 5.4), tricarbonyl (tropone) iron 59 displays a reactivity that is almost identical to that of a normal enone. High pressure cycloadditions of 59 with 1-oxygen substituted dienes 60 gave the desired cycloadducts 61 in good to excellent yields (Equation 5.9). The subsequent decomplexation of the cycloadducts has been accomplished by treatment with CAN [20]. 

Towards the end of this section it may be worthwhile to point out some new reactions with high-valent metals and TBHP. The first is a pyridinium dichromate PDC-TBHP system134. Nonsubstituted or alkyl-substituted conjugated dienes, such as 1,3-cyclooctadiene (87) and others (also linear dienes), yield keto allyl peroxides 88 (equation 18), whereas phenyl-substituted dienes such as 1,4-diphenylbutadiene (89) gave diketo compounds, 90 (equation 19). In further research into a GIF-type system135 with iron and TBHP, limonene gave a mixture of products with carvone as the major product. The mechanism is thought to proceed initially by formation of a Fe(V)-carbon... 

Among early and group III transition metals, the yttrocene catalysts have been studied in greatest detail. However, related metallocenes show great promise as catalysts for reductive cyclization. Neodymocene-catalyzed cyclization of 1,5- and 1,6-dienes 14a and 15a proceeds readily in the presence of silane to afford cyclopentanes 14b and 15b.37 Lutetocenes and samarocenes also catalyze silane-mediated cyclization of 1,5-diene 14a to cyclopentane 14b.38 39 In the case of the samarium-based metallocenes, the feasibility of borane-mediated cyclization has been established, as demonstrated by the highly diastereoselective conversion of phenyl-substituted diene 16a to cyclopentane 16b (Scheme ll).40... 

Yamamoto and co-workers found that BLA 76a is one of the best catalysts for the enantioselective and selective cycloaddition of a-substituted ajl-enals to highly reactive dienes such as cyclopentadiene. The results in the presence of (J )-76a are summarized in Table 5-2. The major enantiomer has, in several cases, been demonstrated to have the predicted absolute configuration. 

As far as catalytic enantioselective cycloadditions to imines are concerned, the only non-Zr-catalyzed process is a Cu-catalyzed protocol reported by Jorgensen (Eq. 6.22) [112]. It should be noted, however, that high enantioselectivities are attained only with highly substituted versions of the Danishefsky diene. 

Scheme 11.18. Aminocyclopropanation of the more highly substituted double bond in a conjugated diene a mechanistic rationalization [H6].

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