Addition-cyclization

Heteroatom radical addition-cyclization and its synthetic application 99H(50)505. 

Other possibilities for practical application of resin catalysis include some organic reactions involving addition, cyclization, and structural rearrangement. Increased stability and specific control of structure has led to the increased use of cation exchange resins as catalysts. As in the case of cation exchange resins many... 

A new approach to indoloquinohne alkaloids from Cryptolepis sanguino-lenta has been reported based on the cyclization of an o-substituted vinyl isocyanate 244 imder microwave irradiation and further additional cyclization based on an Aza-Wittig reaction carried out in the presence of microwaves [159]. The apphcation of this synthetic scheme to the synthesis of Cryptotackienine 247 is reported in Scheme 91. 

In the stochastic theory of branching processes the reactivity of the functional groups is assumed to be independent of the size of the copolymer. In addition, cyclization is postulated not to occur in the sol fraction, so that all reactions in the sol fraction are intermolecular. Bonds once formed are assumed to remain stable, so that no randomization reactions such as trans-esterification are incorporated. In our opinion this model is only approximate because of the necessary simplifying assumptions. The numbers obtained will be of limited value in an absolute sense, but very useful to show patterns, sensitivities and trends. 

Good yields in conjunctive reductive/addition/cyclization reactions carried out with (R0)2P(0)H compounds were obtained by Parson et al. [28] (Scheme 10). 

There are related reactions in which the sulfur is at the sulfoxide or sulfilimine oxidation level. Another example of the addition-cyclization route involves a-haloesters, which react to form epoxides by displacement of the halide ion. 

Trimethylsilylepoxides can be prepared by an addition-cyclization process. Reaction of chloromethyltrimethylsilane with sec-butyllithium at very low temperature gives an a-chloro lithium reagent that leads to an epoxide on reaction with an aldehyde or ketone.291... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

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. 

Scheme 2.123. Synthesis of indols via a domino carbolithiation/addition/cyclization process.

Scheme 3.37. Domino radical addition/cyclization-reaction for the asymmetric synthesis of (3-aminobutyrolactones.

Scheme 3.81. Domino 2-indolylacyl radical addition/cyclization reaction.

Entry Alkene Addition-cyclization Yield [%] Addition Product Yield [%]... 

Scheme 10.14. Domino radical addition-cyclization process of oxime ethers.

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

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 new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction <06JOC3656>. This reaction proceeds with complete regioselectivity to create the 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers. 

Entropic contributions to the acceleration of first-order reactions by microwaves should be negligible (AS = = 0). When ionization (SN1 or E,) or intramolecular addition (cyclizations) processes are involved a microwave effect could be viewed as resulting from a polarity increase from GS to TS, because of the development of dipolar intermediates (Scheme 3.5). 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

Alkoxides that arise from simple carbonyl additions have also functioned as excellent in situ nucleophiles for intramolecular hydroalkoxylation reactions. Garbinols derived from the addition of allyltin reagents have proved to be potent nucleophiles in reactions of this type (Equation (99)),349 and this approach has also been used for the combined addition-cyclization of alkynals under Pd(n)350 or Cu(i)351 catalysis, and alkynones under Pd(n) catalysis.352... 

Ma et al. described the palladium(0)-eatalyzed three-component tandem double-addition-cyclization reaction of 2-(2,3-allenyl)malonate 218, Phi, and A-Ts-imine 219 for the stereoselective synthesis of 2,5-m-pyrrolidine 220... 

Examples of tandem intermolecular addition-cyclization under iodine atom-transfer conditions are depicted in Scheme 16 [38,41],... 

The efficient addition-cyclization sequence described above could be successfully applied to the preparation of the polyhydroxylated y-amino acid (-)-detoxinine [73], The crucial key step in this fairly short synthesis is the chelate-controlled addition of lithiated benzyloxyallene 120 (R = Bn) to the chiral N-benzyl-substituted imine 121 as shown in Scheme 8.31. The required skeleton of the natural product was generated in good overall yield. 

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