Cascade reactions carbocyclization

Keyword Carbocycles a Cascade Reactions a Cycloadditions a Combinatorial Chemistry a Domino Reactions a Enantioselective Transformations a Ene Reactions a Eieterocydes a Natural products a Preservation of Resources and Environment a Sigmatropic Rearrangements a Tandem Reactions a Transition Metal-Catalyzed Transformations... 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

Intramolecular Heck reactions leading to carbocycles involving domino, tandem, or cascade reactions teminated with tethered alkenes and other nncleophiles will be covered in Sect. IV3.1 and V.3.2, respectively. 

Two-component cascade reactions are of paramount importance in the synthesis of cyclic products. There are a lot of examples in organocatalysis dealing with different reactants and activation modes. We wiU try to summarize the most relevant ones. First, we will describe the synthesis of different carbocycles based on the ring size. Then we will focus on cascade reactions that render acyclic compounds. 

The synthesis of carbocycles via a two-component cascade reaction in an asymmetric fashion has attracted much attention from the chemical community. Due to his importance in natural products, the synthesis of cyclopropanes, cyclopentanes, and cyclohexanes has been one of the common goals for organocatalytic methodologies. The high stereoselectivity achieved, green procedures, and soft conditions make this organocatalytic approximation one of the most attractive ones to build complex cyclic scaffolds. 

The hydrosilylation of unsaturated carbon-rhodium-catalyzed silylcarbocyclizations. In the presence of Rli4(CO)i2 and triethoxysilane, a rigid triyne backbone can undergo a silylcarbotricyclization cascade reaction to yield [5,6,5]-tricycles (eq 16). Similar to the results observed by Sieburth for the hydrosilylation of enamines, the alkoxysilane functionality provides significant rate enhancement in comparison to silylcarbocyclizations using alkyl- and arylsilane reagents. The incorporation of carbonyl functionality as terminal electrophiles into these cyclizations has also been successful. Rhodium-catalyzed carbonylative silylcarbocyclizations proceed in the presence of carbon monoxide (10 atm) to incorporate a carbonyl unit, usually as the aldehyde. Both of these tandem ad-dition/cyclization strategies produce functionalized carbocycles with simultaneous incorporation of sUyl functionality as aryl- and vinylsilanes. These alkenylsilanes can then be exploited for further synthetic manipulations as discussed above. "" ... 

Palladium and chiral amine co-catalyzed enantioselective dynamic cascade reaction of simple starting materials leads to the synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter (Scheme 6.14) [16]. 

Ma, G., Afewerki, S., Deiana, L., Palo-Nieto, C., Liu, L., Sun, J., Ibrahem, I., Cordova, A. (2013). A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter. Ange-wandte Chemie International Edition, 52, 6050-6054. 

Miscellaneous Gold- and Iron-Catalyzed Cascade Reactions The car-benic reactivity of gold catalysis was exploited toward the synthesis of stereoselective six-membered ring carbocycles, through cyclopropanation reactions incorporated in cascade sequences [31]. 

In 2001, Larock and Tian reported a palladium-catalyzed cascade reaction of aryl halides and 1-aryl-l-aIkynes to synthesize 9-aIkylidene-9/f-fluorenes 167 [66] (Scheme 6.44). Based on the active role of Pd(IV) in organopalladium chemistry, the authors proposed a mechanism involving the formation, transformation, and reductive elimination of Pd(IV) intermediates and aryl C—H bond activation. It is noteworthy that both carbocyclic and heterocyclic aryl iodides, such as pyridine and thiophene, could be introduced in this reaction. Later, Zhao and Larock reported an efficient palladium-catalyzed cascade reaction for the synthesis of substituted carbazoles 169 from A/-(3-iodophenyl)anilines 168 and alkynes [67] (Scheme 6.45). 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

Considering the rapid growth of asymmetric construction of oxindoles, Sun et al. recently reported their assembly of chiral spirooxindoles by combining secondary amine and palladium catalysis in a cascade reaction [55]. The reaction was initiated by the reversible Michael addition of 3-substituted oxindole to enal, which was followed by a metal/organic-cocatalyzed carbocyclization of the aUcyne tether (Scheme 9.60). Similar to the aforementioned dynamic kinetic asymmetric transformations, this chemistry highlighted the cooperative effects of the two catalysts in the same reaction vessel, while either catalyst could not solely promote the overall reaction, and unsatisfactory results were observed when this reaction was conducted in a two-step mode. 

It is worth noting that product 443 was not obtained without silicon assistance, which means that the reaction is in fact initiated by an Si-[Rh] species (Scheme 112). Fused tricyclic benzenes such as 443 are formed exclusively using an exactly stoichiometric amount of silane. On the other hand, 2 equiv. of silane preferably lead to the formation of silylated benzenes such as 447 through a hydrosilyIation-carbocyclization-/ -hydride elimination cascade process. 

Cascade silylcarbocyclization reactions tiave been developed based on the fact that it is possible to realize successive intramolecular carbocyclizations, as long as the competing reductive elimination is slower than the carbometallation. For example, the reaction of dodec-6-ene-l,ll-diyne 67 with PhMe2SiH catalyzed by Rh(acac)(CO)2 at 50°C under 1 atm CO gives bis(exo-methylenecyclopentyl) 68 in 55% yield [44]. The reaction is stereo-specific that is, (6 )- and (6Z)-dodec-6-ene-l,ll-diynes, ( )-67 and (Z)-67, afford R, R )-68 and (S, R -68 respectively. A possible mechanism for this reaction is outlined in Scheme 7.20. It should be noted that none of the tricyclic product is formed even though a third carbocyclization in the intermediate III.2c is conceptually possible. 

This chapter covers the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions from 1993 to early 2005. In addition, technical development in carbonylation processes with the use of microwave irradiation as well as new reaction media such as supercritical carbon dioxide and ionic liquids are also discussed. These carbonylation reactions provide efficient and powerful methods for the syntheses of a variety of carbonyl compounds, amino acids, heterocycles, and carbocycles. 

Reaction of 3,3-disubstituted-l,4-pentadiene 92 with a primary amine under cyclohydrocarbonylation conditions yielded cyclopenta[. ]pyrrole 96 as the predominant product accompanied by a small amount of cyclopentanone 95 (Scheme 15). This unique reaction is proposed to proceed through a cascade hydrocarbonylation-carbonylation process. The first hydrocarbonylation of 92 and the subsequent carbocyclization formed cyclopentanoylmethyl-Rh complex 93. If 93 immediately reacts with molecular hydrogen, 2-methylcyclopentanone 95 is formed. However, if CO insertion takes place faster than the hydrogenolysis, cyclopentanoylacetyl-Rh complex 94 is generated, which undergoes the Paal-Knorr condensation with a primary amine to yield cyclopenta[. ]pyrrole 96. ... 

In the pioneering work by Wilcox and Gaudino, a straightforward route to the carbocyclic analogue of D-fructofuranose, 64, and its 6-phosphate derivative was delineated [14a,b]. As shown in Scheme 9, the first move consisted of Wittig olefination of benzyl-protected arabinose 60 with carboxy-tert-butylmethylene triphenyl phosphorane to deliver unsaturated ester 61, which was then cleverly elaborated into dibromide 62 via a reaction cascade encompassing Swem oxidation of the secondary OH, ester hydrolysis, diastereoselective addition of dibromomethyl lithium, and carboxylic acid methylation. 

The addition of thiyl and sulfonyl radicals, either in stoichiometric or in catalytic amounts, is used as the first step of tandem processes which have been widely applied to prepare carbocyclic compounds. The catalytic procedure will be further described in Section 5.5.4.3 during the discussion of cascade processes involving fragmentation reactions. The mechanism of the stoichiometric procedure, which can involve thiols, disulfides, or any sulfonyl radical precursor, is represented in Scheme 7. It consists of (i) the initial addition step, (ii) the cyclization with formation of the final radical species, and (iii) the quenching of the final radical to give the product. 

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