Tandem addition

Curtin SA, Deming TJ (1999) Initiators for end-group functionalized polypeptides via tandem addition reactions. J Am Chem Soc 121 7427-7428... 

Tandem addition-cyclization reactions can be used for a simultaneous construction of the central and terminal rings. This is illustrated in Equation (10) by the synthesis of 121 from 120 <2002BMC1275>. 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

Tandem addition-aldol reaction with methyl propiolate... 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

Addition of hydroxylamines to Michael acceptors 44 possessing an ally lie leaving group results in formation of tandem addition-elimination products of type 45 (equation 30)". ... 

Scheme 2.2.5.14 Formation of bicyclic sugars by single extension of a,co-dialdehydes upon attempted tandem addition to glutaric dialdehyde 38.

In this respect it is interesting to note that the tandem aldolization technique proved amenable also to the synthesis of a first C-glycosidic aza sugar (Scheme 2.2.5.19) [29, 36]. A rather simple dihydroxylated azido dialdehyde was generated from racemic azidocyclohexene 60 and subjected to FruA catalysis. The latter effected a smooth tandem addition to provide a diastereoisomerically pure bispyranoid azido C-disaccharide 61, from which the pyrrolidine-type aza sugar 62 was... 

Derivatives of trifluoroethanethiol have limited though interesting chemistry. Unfortunately, metallated difluorothioenol chemistry has not been reported, because rapid nucleophilic attack occurs even by hindered bases such as LDA. Nakai et al. exploited this high electrophilicity in a tandem addition/elimina-tion-rearrangement sequence [146], but more recent applications have concerned free radical chemistry (Eq. 46). Chlorination of trifluoroethyl phenyl sulfide followed by exposure to tin hydride in the presence of an allylstannane resulted in C-C bond formation with a reasonable level of stereocontrol [147]. 

Dihydrooxazoles are also effective ortho directors for nucleophilic addition to naphthalene and some heteroaromatic derivatives. Tandem additions result if the reaction mixtures are quenched with electrophiles (Scheme 72). 

Tandem addition of trimethyltin followed by cyclization in a 1,6-heptadiene system [Eq, (7)] proceeds with surprising efficiency [30]. Oxidative destannylation of the primary product gives a synthetically useful dimethyl acetal. An acetylene-terminated tandem addition is shown in Eq. (8) [31]. 

Kvicala, J. Plocar, J. Vlasakova, R. Paleta, O. Pelter, A. 2-Fluoro-2-buten-4-olide, a new fluorinated synthon. Preparation 1,2-, 1,4-and tandem additions. Synlett 1997, 986-988. 

Meyers, A. I. Licini, G. Intramolecular asymmetric tandem additions to chiral naphthyl 489 oxazolines. Tetrahedron Lett. 1989, 30, 4049-4052. 

Multicomponent tandem addition reactions have been investigated by Russell and coworkers. Addition of t-butyl radical to the allyl acrylate 70 with termination from dimethyldisulfide furnishes butyrolactone 71 as a diastereomeric mixture (remote center). However, the ring junction stereochemistry is exclusively trans [95JA3645],... 

Enynes are also excellent substrates for tandem addition reactions. Pandey and co-workers have reported a photoinduced electron transfer (PET) promoted reaction of a selenium radical addition to an enyne [95T1483]. The high stereoselectivity observed in this cyclization is noteworthy. 

The use of perfluoroalkyliodide in group transfer tandem additions has been examined by Wang and Lu for the preparation of butyrolactones [95T2639]. The mild reaction conditions, high chemical yield, and excellent control of alkene stereochemistry are the highlights of this methodology. 

Pancrazi and co-workers have reported a 6-endo-trig cyclization of enyne 112 in a synthetic approach to the A-B ring of forskolin [95TL7247], The tandem addition process using tributyltin hydride provides the tricyclic compound 113 in 60% yield. 

A group transfer tandem addition of bromotrichloromethane to diallyl amine 157 has been reported [95SC3529]. The radical reaction can be initiated using either azobisisobutyronitrile (AIBN) or manganese(III) acetate electrochemically. It should be noted that the cis diastereomer is formed as the major product. 

Wu et al.91 published a tandem addition-cyclization reaction using 2-alkynyl-benzenamines 89 (Scheme 5.40). The reaction proceeded under AgOTf catalysis... 

In polyenes even tandem additions are possible. The best known and the most impressive example is the biosynthesis of steroid structures from squalene or squalene epoxide (Figures 14.12 and 14.13). The corresponding biomimetic syntheses of the steroid structure are simply beautiful. 

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

Bertrand, S., Hoffmann, N., Humbel, S., and Pete, J.P. (2000) Diastereoselective tandem addition-cydization reactions of unsaturated tertiary amines initiated by photochemical electron transfer (PET). Journal of Organic Chemistry, 65, 8690-8703. 

The reactions in this section proceed through stepwise tandem additions of singlet oxygen. The overoxidation of unsaturated hydrocarbons 15 (in Freon-11 oracetone-d6),... 

Fig. 42 Tandem addition/cyclization sequences of 1,6-dienes and CCI4...

Yang and Burton studied reductive radical additions of iododifluoroacetate 37 to olefins 38 and dienes catalyzed by 6-17 mol% of a catalyst generated from NiCl2 and stoichiometric amounts of zinc in the presence of water (Fig. 8) [90, 91]. Olefins gave the reductive addition products 40a in 60-83% yield, while 1,5-hexadiene or 1,8-nonadiene provided double addition products exclusively in 55% and 73% yield. 1,7-Hexadiene gave an inseparable mixture of the expected acyclic double addition product and a tandem addition/cyclization product, in which the former dominated. The radical nature of the addition is supported by inhibition of the reaction by para-dinitrobenzene. The reaction proceeds probably via initially formed atom transfer product 39, which is subsequently reduced by nickel(0) and zinc. This is supported by deuterium incorporation, when D20 was used instead of water. No deuterium incorporation was observed with THF-dg, thus ruling out hydrogen transfer from the solvent. 

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