Cyclization-carbonylation reaction sequence

The second example in Table 5 shows the cyclization-carbonylation-allylation sequence, in which 5-hexenyl radical cyclization precedes CO trapping. Because of the nucleophilic nature of acyl radicals, in a mixed alkene system comprised of an electron deficient alkene and allyltin, they favor the electron deficient alkene first and the resulting product radical, which have an electrophilic character, and then smoothly add to allyltributyltin. This four-component coupling reaction provides a powerful radical cascade approach leading to y -functionalized, -unsaturated ketones, which are not readily accessible by other methods [52]. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Ikegami has devised an interesting approach based upon 1,3-cyclooctadiene monoepoxide as starting material (Scheme LX) Transannular cyclization, Sharpless epoxidation, and silylation leads to 638 which is opened with reasonable regioselec-tivity upon reaction with l,3-bis(methylthio)allyllithium. Once aldehyde 639 had been accessed, -amyllithium addition was found to be stereoselective, perhaps because of the location of the te -butyldimethylsilyloxy group. Nevertheless, 640 is ultimately produced in low overall yield. This situation is rectified in part by the initial formation of 641 and eventual decarboxylative elimination of 642 to arrive at 643. An additional improvement has appeared in the form of a 1,2-carbonyl transposition sequence which successfully transforms 641 into 644... 

A phosphorus ylide serves as the carbanionic component in a synthesis of pyran-2-ones from 1,3-diketones (70ACS343). A Wittig reaction between the ylide and one of the carbonyl groups is envisaged as the first step in the sequence and the resulting keto ester spontaneously cyclizes. The reaction is conducted under pressure and yields are low. 

A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the 7-carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to constmct polyclic frameworks of natural products in a subsequent Diels-Alder reaction. 

Dioxolanone 33 is obtained when the unsaturated silyldiazoester 30 is decomposed by Rh2(pfb)4 in the presence of an aldehyde or of acetone (Scheme 11) [21]. The reaction sequence is likely to include formation and (probably reversible) 1,5-cyclization of carbonyl ylide 31, and Cope rearrangement of the allylvinylether 32. In analogy to carbonyl ylide 21, the SiMe3 should occupy the exo-position in 31, thereby bringing the ester carbonyl in a geometry that is favorable to the cyclization step. Again, the choice of catalyst determines the product pattern, since CuOTf catalysis affords not only 33, but also oxirane 22 and the intramolecular cyclopropanation product 34. 

The Nef reaction often represents the key transformation in a reaction sequence in which it is involved. The synthesis of simple aliphatic ketones or aldehydes is probably not the most useful application of the Nef reaction. More important is the access to dicarbonyl compounds for intramolecular cyclization reactions leading to a large variety of carbocycles or heterocycles. However, the method can be capricious and success depends on the structure of the substrate. In order to overcome synthetic drawbacks, several roundabout methods have been devised for application to peculiar polyfunctionalized molecules. The number of modifications of the Nef reaction which can be carried out under a wide variety of conditions clearly reveals that no procedure is of general application. The scope and limitations of the different modifications will be discussed considering the structure of desired carbonyl derivative. 

It is possible to combine ring-opening reactions of the cyclobutoxy radical with a subsequent carbonylation/oxidation sequence (Scheme 4-48) [84]. The pattern of Cl-substitution affects the final products, cyclized or uncyclized, and this can be ascribed to the different reactivity of formyl and acyl functionalities to electrophilic attack by an acyl cation. 

For the Bucherer-Bergs reaction,16 similar reaction partners to the Strecker reaction are involved. The one major point of divergence is the addition of a carbon dioxide source. Thus the final product from this reaction is hydantoin 19, which could be hydrolyzed to give a Strecker-like product, if so desired. Mechanistically, a reaction sequence analogous to the Strecker reaction can be invoked to generate a-aminonitrile 18 from carbonyl compound 8. In the presence of the carbon dioxide source, the a-aminonitrile product 18 is trapped and results in the formation of cyclized product 19. 

More interesting reactions are possible when the carbonyl-alkene cyclizations are applied in a tandem reaction sequence [4b]. The three precursor motifs of spiro , separated , and fused ring systems 22, 24 and 26, respectively, were each constructed however, not all cyclized readily (Scheme 6). In each reaction the intermediate alkene bearing the EWG, which both receives the radical and transfers the radical in the last cyclization, was activated for addition from the <9-stannyl ketyl. With the appropriate placement of the alkene tether in the starting substrate, complex ring structures can be synthesized in a one-pot procedure. 

Phosphonium salts may be intermediates in different reactions. The Morita-Baylis-Hillman reaction follows such a protocol. In a typical reaction sequence, a,P-unsaturated carbonyl compounds react with aldehydes in the presence of nucleophiles, such as a trialkylphosphine, to afford aldol-like products (Scheme 75/1), while in another example, unsaturated carbonyl compounds with bromo atom at the end of the chain are cyclized to cycloalkene derivatives (Scheme 75/2). In both... 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

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