Cycloadditions with substituted dienes

Cycloaddition with substituted systems 3.2323 Diene, C—O and cycloa itions... 

Much attention has been directed to the chemistry of p-heteroatom-substituted allylic cations (5), especially oxyallyl cations (7), from both synthetic and mechanistic viewpoints. One of the characteristic reactions of oxyallyls (7) is their [4 -i- 3] 7 cycloadditions with conjugated dienes, which provide a... 

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). 

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 ... 

Substituted azocine systems are much more stable than the parent compound, and 2-methoxy derivatives have been intensively examined. Starting from cyclohexa-1,4-diene (3), a [2 + 2] cycloaddition with chlorosulfonyl isocyanate, followed by removal of the chlorosulfonyl group, leads to the /3-lactam 4, which can be transformed by O-methylation with Meerwein s salt into the corresponding imidate. Monobromination with A-bromosuccinimide and subsequent treatment with base results in a methoxyazabicyclo[4.2.0]octatriene derivative, which spontaneously isomerizes to 2-methoxyazocine (5).13,14... 

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]. 

The sterically unbiased dienes, 5,5-diarylcyclopentadienes 90, wherein one of the aryl groups is substituted with NO, Cl and NCCHj), were designed and synthesized by Halterman et al. [163] Diels-Alder cycloaddition with dimethyl acetylenedicarbo-xylate at reflux (81 °C) was studied syn addition (with respect to the substituted benzene) was favored in the case of the nitro group (90a, X = NO ) (syrr.anti = 68 32), whereas anti addition (with respect to the substituted benzene) is favored in the case of dimethylamino group (90b, X = N(CH3)2) (syn anti = 38 62). The facial preference is consistent with those observed in the hydride reduction of the relevant 2,2-diaryl-cyclopentanones 8 with sodium borohydride, and in dihydroxylation of 3,3-diarylcy-clopentenes 43 with osmium trioxide. In the present system, the interaction of the diene n orbital with the o bonds at the (3 positions (at the 5 position) is symmetry-forbidden. Thus, the major product results from approach of the dienophile from the face opposite the better n electron donor at the (3 positions, in a similar manner to spiro conjugation. Unsymmetrization of the diene % orbitals is inherent in 90, and this is consistent with the observed facial selectivities (91 for 90a 92 for 90b). 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyridyl)-1,2,4,5-tetrazine was investigated by Engberts (Eq. 12.56).127 Again, the rate of the reaction increased dramatically in water-rich media. Through kinetic studies, they showed that the solvent effects on the... 

Amino-substituted dienes are also important dienophiles in Diels-Alder reactions. Recently, chiral and achiral 2-amino-l,3-dienes have been prepared to study their reactivity (see also asymmetric Diels-Alder reaction Section 8.1.2). The reaction of 2,3-diamino-l,3-butadienes with nitrostyrene gives unusual [3+2]carbocyclization products, 2-aminocyclopentanones, which are not formed by the direct cycloaddition but derived from the Michael addition products (see section discussing the Michael addition Section 4.1.3).42... 

Benzothiopyrylium salts have also been shown to undergo [4+2+]-polar cycloadditions with 1,3-dienes in dry 1,2-dichloroethane at room temperature <1996J(P1)2227>. Treatment of 43 with 2,3-dimethylbuta-l,3-diene 41a afforded benzo-fused bicyclic sulfonium salts 22, as shown in Equation (12) and Table 6. The 4-cyano-substituted benzothiopyrylium salt 43d proved to be the most reactive of these substrates (see entry 4). 

Regiospecilic intramolecular cycloadditions of nitrones to sulfur-substituted dienes, with 3-sulfolene precursors, has been realized (Scheme 2.217). The stereochemical outcome of these reactions is affected by the structure of the substituent (sulfide or sulfone) in the diene and by the chain length connecting the diene and nitrone (a) and (b) (see Scheme 2.211). The bicyclic products obtained from these reactions have been converted to interesting heterocyclic compounds (709). 

The nickel-catalyzed [4 + 4]-cycloaddition of butadiene to form cyclooctadiene was first reported by Reed in 1954.90 Pioneering mechanistic and synthetic studies largely derived from the Wilke group advanced this process to an industrially important route to cyclodimers, trimers, and other molecules of interest.91-94,943 95,96 While successful with simple dienes, this process is not useful thus far with substitutionally complex dienes as needed in complex molecule synthesis. In 1986, Wender and Ihle reported the first intramolecular nickel-catalyzed [4 + 4]-reaction of... 

A more practical BLA has been designed to improve the scope of dienophiles in reactions with less reactive dienes. 3,5-Bis(trifluromethyl)-phenylboronic acid (80) was chosen as the Lewis acidic metal component in the new BLAs 77-79. These new BLAs show higher catalytic activity in enantioselective cycloaddition of both a-substituted and a-unsubstituted a,/ -enal with various dienes. 

Two other applications of catalyst 364, i.e. in cycloaddition reactions of a-substituted acroleins with dienes 374 and 376, have been depicted in equations 110 and 111237. Cycloadducts 375 and 377 have been used as precursors in the syntheses of cassiol and gibberellic acid, respectively. The use of catalysts 364 and 369b in cycloadditions with acrolein resulted in low enantioselectivities with opposite face selectivities. 

The asymmetric induction by catalyst 379 was extensively studied in the cycloadditions of simple dienes with substituted a,/)-unsaturated aldehydes. It proved that a-substitution on the dienophile increased the enantioselectivity, whereas -substitution dramatically decreased it. In the case of substrates having both a- and -substituents, high enantiose-lectivities were observed240. 

The regiochemistry of nickel mediated cycloadditions of substituted norbomadienes has been investigated in detail. The regioselectivity, exo/endo selectivity and site selectivity seem to depend strongly on the substituents on both diene and dienophile. Tetracya-noethene, for example, reacted with 2-acetyloxymethyl substituted norbomadiene on the distal side331. 

An extensive review of the use of chiral Lewis acid catalysts in Diels-Alder cycloadditions has been presented. Brpnsted acid-assisted chiral Lewis acids have been shown to be highly efficient catalysts for the enantioselective Diels-Alder reactions of a- and /3-substituted-Q, /i-enals with numerous dienes. The chiral Lewis acid-catalysed Diels-Alder reaction between cyclopentadiene and alkenoyloxazolidi-nones can be catalysed by bis(oxazolone)magnesium catalysts. ... 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

---