Allenes, cyclization heterocycles

It was reported that Pd(0)-catalyzed coupling reactions of allenic alcohols, amines and acids with hypervalent iodonium salts afforded cyclized heterocyclic tetrahydrofurans, tetrahydropyrans, pyrrolidines, piperidines, or lactones under mild conditions <99SL324>. Intramolecular 1,5-hydrogen atom transfer radical cyclization reaction of pyrrolidine derivatives was examined. Reaction of 3,4-dialiyloxy-JV-(0-bromobenzyl)pyrtolidine gave hexahydro-... 

Recently, a further unique domino methodology has been reported by Lu and coworkers (Scheme 2.74) [173]. Herein, a triphenyl phosphine-catalyzed umpolung addition/cyclization of allenes and alkynes containing an electron-withdrawing group 2-316-2-318 followed by reaction with a double nucleophile 2-319 is assumed to account for the production of a broad palette of various heterocycles 2-321 and 2-323 via 2-320 and 2-322, respectively. Dihydrofurans, piperazines, morpholines and diazepanes were obtained during the process. 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

The examples illustrated in the almost 100 schemes in this chapter demonstrate how versatile donor-substituted allenes can be in synthetic processes. The major applications concern addition reactions and cycloadditions to the allenic double bonds, which furnish products with valuable functional groups. Of particular interest are metalations - usually at C-l of the allene unit - followed by reactions with electrophiles that deliver compounds which can often be used for cyclization reactions. A variety of highly substituted and functionalized heterocycles arises from these flexible methods, which cannot be obtained by other reactions. Many of these transformations proceed with good regioselectivity and excellent stereoselection. 

Application of silver-catalyzed cydization is a key step in the synthesis of clavepic-tines A and B, a synthesis which also established the absolute configuration for these compounds. With regard to the allene unit and the heterocycle, enantiomeri-cally pure precursor 129 was prepared and then cyclized to the quinolizidine 130 with AgN03 in a diastereoselective manner (Scheme 15.40) [89, 90]. The synthesis was conducted with an inseparable 1 1 mixture of diastereomers at C-14 from the diastereomerically pure allene with regard to the axial chirality of the allene a 7 1 mixture of diastereomers (at C-10) was formed. 

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

The intramolecular nucleophilic attack of a nitrogen atom on an allylpalladium complex was also used to construct a five and a six membered heterocycle in the same step. TV-substituted 2-iodobenzamides bearing an allene function in the appropriate distance from the iodine underwent cyclization through the carbopalladation of the allene moiety by the arylpalladium complex, formed in the first step of the catalytic cycle. The intermediate allylpalladium complex, part of a nine membered ring, cyclized readily to give the pyrroloisoquinolone derivative in excellent yield (4.23.). The nature of the added ligand and the solvent both had a marked influence on the efficiency of the transformation.26... 

Allenes can also act as the -participant in electrophilic heteroatom cyclizations. Reviews of electrophilic additions to allenes discuss early examples of this type of cyclization.ld le-202 Numerous examples of cyclizations of a-functionalized allenes, including carboxylic acids, phosphonates, sulfinates and alcohols, to form five-membered heterocycles (equation 84) are cited in these reviews. The silver nitrate-mediated conversion of ot-allenic alcohols to 2,5-dihydrofurans203 has recently been applied to trimethylsilyl-substituted systems.204... 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

The corresponding nitrogen-containing heterocycles are accessible by silver-catalyzed cyclization of allenic amines, amides, or oximes.334 Thus, Dieter and Yu335 have reported the efficient transformation of various a-aminoallenes 397 or 399 into mono- or bicyclic 3-pyrrolines 398 or 400 in the presence of AgN03 (Scheme 116). Unfortunately, a rather high catalyst loading was required. 

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

Heterocycles. The intramolecular cyclization of o-allylphenols to form 2//-l-benzopyrans and coupling of iodoalkenylamines and (o-iodoaryl)alkylamines with allenes to give azacyclic productsare useful preparative methods. 

Kang et al. demonstrated that the palladium-catalyzed tandem cyclization—silastannation of the bis(allene) 72 with trimethylsilyltributyltin 70 produced the trans fused heterocycle 73 (Scheme 25),... 

Grigg et al. reported that the palladium-catalyzed cyclization of 580 with allene gave the polycyclic heterocycle 581 in a high yield (Scheme 179).253... 

---