Consecutive cyclization

Aromatic Claisen rearrangement is a powerful tool for the introduction of substituents into coumaran and chroman derivatives [66]. 

The )5-methyl substituent on the allyl moiety in the substrate of the aromatic Claisen rearrangement accelerates the formation of the coumaran derivative, often observed as a byproduct arising from the initially formed ortho allyl phenol. 

This sequential cyclization is strongly dependent on the nature of the solvent used [67]. As shown in the reaction of methallyl phenyl ether 17, the formation of coumaran 43 was accelerated in phenolic solvent. On the other hand, N,N-dimethyl-aniline dramatically depressed the isomerization of double bond and cyclizahon and it was the best solvent to obtain the ortho allyl phenol derivahve 83. 

A Lewis-acid-catalyzed reaction often facilitates not only the rearrangement reaction but also the consecuhve cyclization as shown below [34a, 68]. Furthermore, additional substituent(s) on the allyl moiety of the substrates effects this consecutive cyclization, giving rise to coumaran derivatives in good yield. 

The Claisen rearrangement of y-phenoxy-a,jff-enoate 85, although high temperature was required for the rearrangement reaction, accompanied the following lac-tonization to give benzofuranone derivative 86 in good yield [69]. 

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This intramolecular Heck cyclization can be extended to diunsaturated aryl iodides, which can undergo two consecutive cyclizations to form polycyclic systems.7 Examples ... 

Scheme 2.21 Sequential insertion of ynamines through consecutive cyclization/cycloreversion processes.

Multiple carbonylative cyclizations can take place with substrates containig several double bonds. Up to three consecutive cyclizations can take place in good overall yields and high diastreoselectivity. All five- and six-membered cycles are formed in x (9-processes (Scheme 19). ... 

Consecutive Cyclization of 3-Amino-1,2,4-triazoles by Reaction with One-Carbon Followed by Two-Carbon Fragments... 

The first step in the reaction of aminocycloalkenones with quinones is a normal Michael addition to yield hydroquinone adducts, as is known from the Nenitzescu reaction with / -ketoenamines. However, the consecutive cyclization is quite different, and the structure of the heterocycles formed depends on the substitution at the nitrogen and the size of the cycloalkane ring. 

However, with the slimmer 3,4-dimethoxybenzyl ether or the 3,4-dioxymcthylene compound consecutive cyclization and dehydration occurs, to give a dihydronaphthalene [87],... 

The atom transfer methodology is used in the formal total synthesis of racemic albene82. Addition of 1-butynyl radicals to an activated norbornene derivative occurs exclusively from the. w-face. and consecutive cyclization yields the rw-cvu-annulated system. Conversion of the anhydride to the dimethyl ether and reductive deiodination yields the intermediate diester. Further transformations give 3, a direct precursor to albene, in 32% overall yield. 

With the exciting validation of our expedient strategy to form the tetracyclic cage structure using the oxidative dearomatization/Diels-Alder approach followed by consecutive cyclizations, we were now in position to modify each component to best serve the needs to realize a successful total synthesis of vinigrol. 

The bicychc complex is foraied by two consecutive cyclizations, each characterized by its own microscopic effective molarity. Owing to the symmetry of the bicychc complex, it is reasonable to assume that the two EM values are equal. Then, the chelate cooperative factor jS is given by Eq. [49], where 1/9 is the statistical factor of the equilibrium shown in Fig. 16 ... 

Photolysis of 1 in the presence of hexa-2,4-diyne gave two compounds in high yield, of which one was easily identified as the propynylsilirene 13 (Scheme 4). Elucidation of the constitution of the 2 1 cycloadduct of the disilene 3 and hexa-2,4-diyne was more difficult finally use of a combination of NMR methods and X-ray crystallography demonstrated the formation of the bicyclic product 12. The mechanism of formation of 12 presumably begins with the addition of two molecules of disilene 3 to the C=C triple bond, followed by a thermally allowed sigmatropic 1,5-hydrogen shift. Silyl radicals could be formed by homolysis of the thus-formed cyclobutane ring and then two consecutive cyclization steps would furnish the isolated bicyclic product 12 [8]. 

A number of examples such as 1,3-dioxanes, macrolactones, °° ring-containing biaryls, ° spirooxindoles, alkaloid-like compounds, and polycyclic compounds from the Schreiber group illustrate this approach to natural product-like libraries (see Chapter 11). An early example converted shikimic acid into intermediate tetracyclic y-butyrolactones, which were then functionalized around the core structure (see Chapter 11, Subsection 11.10.2). y-Butyrolactones, found in about 10% of all natural products and which exhibit a broad range of biological activities, are a key element in a number of recent natural product-like compounds. A more recent example, inspired by the rich skeletal diversity of indole alkaloids, utilized the rhodium(II)-catalyzed consecutive cyclization-cycloaddition reactions developed by Padwa and coworkers (Scheme 1.4). A stereocontrolled tandem reaction utilizing the versatile scaffold allowed for multiple modes of intramolecular reactions. 

The following two examples from our recent work also illustrate the limitations of our systematic approach to Lewis acid promoted alkylations of aliphatic tt systems. The reaction of cumyl chloride 26 with tetramethyl-ethylene in presence of various Lewis acids gave complex mixtures of products, probably because of the strain generated during the formation of the regular addition product. Titanium tetrachloride, however, induces a rapid consecutive cyclization, and the TiCl catalyzed reaction of 26 with tetramethylethylene yields hexamethylindan in 72% yield. Since the aromatic ring can be oxidized under Ru(VIII) catalysis, the reaction sequence shown in Figure 16 allows the construction of acyclic compounds with adjacent quaternary carbon atoms. 

If an ester group is present in the molecxde of the alcohol on the a or p carbon, consecutive cyclization reactions take place, for example ... 

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