Cydization reactions

Intramolecular nucleophilic displacement reactions of aromatic nitro group by various nucleophiles include cydization reactions, which provide practical methods for the synthesis of a variety of heterocycles. 1 hope that the text of this review suggests a wide range of potential of this reaction in organic synthesis of various heterocycles. However, it is necessary to stress that some structural types described in this review could be prepared with similar, or even better yields by other methods. In spite of this, there are many heterocyclic systems for the synthesis of which the denitrocyclization strategy is a method of choice. 

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

Enantioselective variants of the rhodium-catalyzed reductive cydization reaction using both cationic and neutral complexes have been reported. When 5 mol % of [Rh(cod)2]2 SbF6 was reacted with 129a, MeEt2SiH, and chiral ligand 163 a 76% yield of 154a was achieved with 88% ee (Scheme 33) [97]. Other substrates gave 50-75% chemical yields and 77-89% ee [97,98]. 

The readily available 2 -aminochalcones provide easy access to 2-aryl-l,2,3,4-tetrahy-dro-4-quinolones in yet another solvent-free cydization reaction using montmorillo-nite K 10 clay under microwave irradiation conditions [150] the products are valuable precursors for the medicinally important quinolones (Scheme 6.47). 

Another possibility is that the antibody alters the mechanism of the cydization reaction. This is unlikdy, however, in light of subsequent experimental evidence discussed later. 

Scheme 16 Tandem intermolecular addition-cydization reactions...

Highly enantioselective atom transfer radical cydization reactions catalyzed by chiral Lewis acids have been reported by Yang et al. [80]. Two main advantages of these enantioselective cyclizations include installing multiple chiral centers and retaining a halogen atom in the product, which allows for further functionalization. 

Scheme 20.16 11 H-Benzo[b]fluorenes via the Schmittel cydization reaction.

MeMurry Rico Tetrahedron Lett. 1989, 30. 1169. For other cydization reactions of dialdchydes and ketoal-... 

R. S. Davidson,. W. Goodwin and G. Kemp. Advances in Physical Organic Chemistry, vol. 20, Academic Press (1984), p. 191. The photochemistry of aryl halides and related compounds is reviewed, including substitution and cydization reactions. 

However, if there is a lower enetgy decomposition pathway available, then an alternative degradation reaction dominates. There is a growing body of evidence to suggest that cydization reactions to form small stable ring compounds are one such decomposition pathway, especially for polyamides containing monomers with four to six carbon atoms (77,78) (eq. 7). The first example of this is the formation of cyclic amines, which is the principal decomposition pathway in nylon-4,6 (in eq. 7, n = 1 and R = H) (79) this has also been observed in MPMD-containing polyamides (in eq. 7, n = 2,... 

Cycloaddition Reactions. Isocyanates undergo cycloadditions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cydization reactions has been widely explored for the synthesis of heterocyclic systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

Tandem Diels-Alder-Nitronic Ester Cydization Reactions... 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

Applications of Radical Cydization Reactions in Total Syntheses of Naturally Occurring Indole Alkaloids... 

In a similar manner, Lu and Liu have more recently utilized the hetero-Michael addition of lithium propargylic alkoxides to alkylidene malonates in a synthesis of stereodefined allylidene tetrahydrofurans, based on the use of allylic chloride as coupling partner [98]. In this case, the cydization reaction is initiated by a catalytic amount of palladium salt [Pd(OAc)2] rather than by an organopalladium species as mentioned above. 

Based upon the previously described cydization reactions, a possible transition state for the ISMS condensations leading to product 111 can be postulated (Figure 13.5) [68-70, 78]. It appears that the reaction proceeds through the chair-like transition state 170, in which all the bulky substituents adopt the thermodynamically preferred equatorial positions. 

Cooke, M. P. Widener, R. K. Lithium—halogen exchange-initiated cydization reactions. 3. Intramolecular conjugate addition reactions of unsaturated acylphosphoranes. J. Org. Chem. 1987, 52,1381-1396. 

The use of 2-propanol for these substrates, besides its role as hydrogen source, allows suppression of cydization reactions promoted by the acidity of the catalyst. Nevertheless, when cydization leads to valuable products, as in the case of 3,3,5-trimethylpyran derived from sulcatol, it is possible to steer the reaction in this direction by using molecular hydrogen and a hydrocarbon solvent [27]. 

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