Double annulations

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

The syntheses of stemodin and stemodinone, structural relatives of aphidicolin, were accomplished using the A/B double annulation and B/C spiro annulation processes developed for the assembly of aphidicolin. 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

The 6-endo activated epoxy alcohol cyclization process was also expected to play a central role in the annulation of pyran ring G of the natural product (see Scheme 22). Silylation of the free secondary hydroxyl group in compound 131 furnishes, after hydrobora-tion/oxidation of the double bond, compound 132. Swern oxidation of alcohol 132 produces an aldehyde which reacts efficiently with (ethoxycarbonylethylidene)triphenylphosphorane in the presence of a catalytic amount of benzoic acid in benzene at 50 °C, furnishing... 

Hydrogen usually adds to benzo-annulated oxepins in the presence of noble-metal catalysts such as platinum or palladium with saturation of the nonbenzenoid C-C double bonds to give 6152,154 and 7.17-89-93... 

Substituted and benzo-annulated oxepins readily undergo addition of bromine across the nonaromatic double bond. Bromination of 3,6-bridged oxepins can occur in two different ways, either as a 1,2-addition164 or as formal 1,4-addition to the diene system of the corresponding benzene oxide to give products i.129 138-140 164... 

Except for several chapters in the comprehensive monograph on heterocyclic chemistry (84MI1) no special articles covering the recent past are available. This review is an attempt to discuss the literature up to Volume 117 (1992) covered by Chemical Abstracts together with some accessible papers published in 1993. Only isolable or spectroscopically identifiable thio-, seleno-, and teluropyrans without exocyclic double bonds (hetero-pyrones and heteropyranylidene derivatives) are considered. All benzo derivatives and their annulated heteroanalogs (spiroheteropyrans) are excluded. 

If the substance shared between two solvents can exist in different molecular states in them, the simple distribution law is no longer valid. The experiments of Berthelot and Jungfleiscli, and the thermodynamic deduction show, however, that the distribution law holds for each molecular state separately. Thus, if benzoic acid is shared between water and benzene, the partition coefficient is not constant for all concentrations, but diminishes with increasing concentration in the aqueous layer. This is a consequence of the existence of the acid in benzene chiefly as double molecules (C6H5COOH)2, and if the amount of unpolymerised acid is calculated by the law of mass action (see Chapter XIII.) it is found to be in a constant ratio to that in the aqueous layer, independently of the concentration (cf. Nernst, Theoretical Chemistry, 2nd Eng. trans., 486 Die Verteilnngssatz, W. Hertz, Ahrens h annulling, Stuttgart, 1909). 

A double linear annulation was observed in the benzannulation reaction of the helical biscarbene complex 27 with 3-hexyne along with a product bearing... 

With regard to the mechanism of the cycloisomerization, Fiirstner et al. found strong evidence of a metallacyclic intermediate. By labeling the allylic position of enynes 46 and 48, they showed that reactions yielding traws-annulated rings 47 transferred the deuterium atom to the exocychc double bond (eq. 1 in Scheme 10), whereas c -annulated rings 49 formed with complete preservation of the position of the deuterium atom (eq. 2 in Scheme 10). This corresponds well to a metallacycUc... 

A combination of a Diels-Alder and a Fisher carbene-cyclopentannulation is described as the last example in this subgroup. Thus, Barluenga and coworkers used a [4+2] cycloaddition of 2-amino-l,3-butadienes 4-115 with a Fischer alkoxy-arylalky-nylcarbene complex 4-116 this is followed by a cyclopenta-annulation reaction with the aromatic ring in 4-116 to give 4-117 (Scheme 4.25) [36]. An extension of this domino process is the reaction of 4-118 with 2equiv. of the alkynyl carbene 4-119 containing an additional C-C-double bond (Table 4.2) [37]. The final product 4-120, which was obtained in high yield, is formed by a second [4+2] cycloaddition of the primarily obtained cyclopenta-annulated intermediate. 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

The above examples represent Jl-heteroaromatic annulation involving the reaction of allyl anions whose double bond is a part of the heterocyclic ring system (Scheme 1). The corresponding a-oxoketene dithioacetals (1,3-electrophilic component) were generally derived from nonheterocyclic carbonyl precursors. Alternatively the Jl-heteroaromatic annulation can also be employed to a-oxoketene dithioacetals derived from heterocyclic ketones (1,3-bielectrophile) and hetero/nonheteroallyl anions (1,3-binucleophile). These reactions are described below. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

Double metalation of iV-phenyl pyrrole by using 2 equiv of -butyllithium in presence of TMEDA (2 equiv) and carbonylation with ethyl AyV-dimethylcarbamate afforded the benzo-annulated pyrrolizinone 52 in 84% yield (Scheme 62) <2004JOC5476>. 

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