Allenes three-component reactions

Ma and co-workers have reported the selective synthesis of pyrrolidine derivatives through a three-component reaction based on a conceptually related strategy (Scheme 8.29) [72], Beginning with the catalytic intermolecular carbopalladation of y-allenic malonate 57 in the presence of a base, they succeeded in intercepting the internal carbonucleophile 58 with an imine such as the N-benzylidene p-toluenesulfonamide 59. The attack of the newly formed heteronucleophile on the 7r-allyl palladium intermediate affords the functionalized pyrrolidine 60 with high... 

A three-component reaction based on the umpolung of re-allylpalladium (II) complexes indium metal was reported by Grigg and co-workers (Scheme 8.31) [74]. In this reaction, the electrophilic nature of the n-allyl palladium species generated from aryl halides and allenes is reversed by transmetallation with indium metal. The resultant nucleophilic allylindium reagent subsequently adds to the third component - aldehyde [75] or imine [76] - to give the corresponding homo-allylic alcohol 64 or amine 65 respectively. 

The Pd-catalyzed three-component reaction of the enol triflate 63, allene (64,) and 2-methyl-l,3-cyclopentanedione (65) gives 66 in high yield, which is converted to the steroid skeleton 67 [31]. 

A palladium-catalyzed three-component reaction with 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines to prepare fV-substituted 4-methylene-3,4-dihydro-1 (27/)-isoquinolin-1 -ones was disclosed <02TL2601>. A synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via a Cp2TiMe2-catalyzed, intramolecular hydroamination/cyclization of aminoalkynes was also reported <02TL3715>. Additionally, a palladium-catalyzed one-atom ring expansion of methoxyl allenyl compounds 79 to prepare compounds 80 that can serve as precursors to isoquinolones was reported <02OL455,02SL480>. 

A ruthenium-catalyzed three-component reaction between propargylic alcohols, 1,3-dicarbonyl compounds, and primary amines leading to fully substituted pyrroles was developed <07CEJ9973>. Cyclohexa[a]pyrroles ( azabicyclo[4.3.0] systems ) were formed by a three-component sequence involving allenic ketones, primary amines, and acryloyl chloride <07SL431>. An oxidative dimerization sequence involving arylpyruvates in the presence of ammonia was the key step in an approach to the pyrrole natural product, lukianol A <07S608>. 

Scheme 4.25 Three-component reaction of chiral allenes, aldehydes, and silanes evolving through chirality transfer.

Scheme 4.33 Pseudo-three-component reaction of isocyanates and allenes.

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

The Ma group has reported some very elegant multibond forming processes to synthesize dendralenes, including both palladium(II)- and rhodium(I)-catalyzed cycloisomerizations of di-allenes 106 to form cyclic dendralenes 107 (Scheme 1.15) [68, 69, 71], and also the remarkable palladium(0)-catalyzed three-component reaction of di-allenes 108, propargylic carbonates 109, and boronic acids 110 to form bicyclic [3]dendralenes 111 (Scheme 1.15) [70]. Similar, intermolecular transformations to those used to form dendralenes 107 had been reported earlier by Alcaide, to synthesize dihydrofuran-containing dendralenes [72, 73]. 

Arylative or silylative cyclizations of allenyl aldehydes or ketones have been reported (Equations (101) and (102)).459,459a The intermolecular process, that is, three-component coupling reaction of aldehydes, allenes, and arylboronic acids, is catalyzed by palladium as well (Equation (103)).46O 46Oa These reactions are proposed to proceed through nucleophilic attack of the allylpalladium intermediates to the carbonyl groups. 

As seen in Scheme 55, with the simple addition of a balloon of CO to the [5 + 2]-reaction of VCPs and alkynes or allenes, the [5 + 2]-reaction can be diverted via a nine-membered metallacycle to produce initially an eight-membered ring product. This Rh(l)-catalyzed three-component [5 + 2 + l]-reaction is mechanistically similar to the previously mentioned [6 + 2]-reaction (Section 10.13.2.5.2) differing only in regard to the insertion of CO in the pathway versus its incorporation in starting material (Scheme 56). 

The concept of employing three components, all of which contribute one carbon atom to the final allene unit (see Scheme 5.4), is illustrated in its purest form by the reaction of carbon dioxide (165) with 2 equiv. of an alkylidenetriphenylphosphorane 166, the process very likely involving the generation in the first step of a ketene intermediate 167, which subsequently reacts with further 166 to yield the allene product 168 (Scheme 5.25) [66]. 

Three-component assembly of allenes, organic halides and arylboronic acids has been reported in which Suzuki coupling of a Jt-allylpalladium complex with an orga-noboronic acid is utilized (Scheme 16.26) [31], Addition of phosphorus ligands to the reaction mixture greatly decreases either the product yields or E/Z ratios. The decrease in E/Z ratio may be explained based on the fact that donor ligands readily promote anti-syn rearrangement of a Jt-allylpalladium species via a cr-allylpalladium intermediate. 

Acyl-allylboronates are smoothly provided through a palladium-mediated three-component assembly reaction of an acyl chloride, an allene and a diboron with high regioselectivity and E-stereoselectivity (Scheme 16.56) [62]. 

The chemo- and regiospecific palladium-catalyzed four-component reaction of aryl iodides followed by incorporation of carbon monoxide, a polymer-supported allene, and a range of secondary cyclic amines has been reported as a short and high-yielding route to complex heterocycles with three points of diversity, such as 7 <2000CC2241>. 

Grigg et al. [61] have recently reported a one-pot reaction involving the initial three-component condensation with a 2-halo-benzylamine 112, ethyl glyoxylate 113 and an aryl boronic acid 114, followed by Pd cyclization in the presence of carbon monoxide to give 116, or in the presence of allene to form dihydroisoquinoline amino acid derivatives 117 (Scheme 7.15). 

This palladium-catalyzed three-component coupling reaction was recently applied to the synthesis of the key intermediate 50 of indafonan, a novel herbicide (Scheme 8.25). However, in this reaction, allene cannot be introduced to the vessel at the beginning of the reaction since a competitive reaction occurs. Therefore, the third component was bubbled into the mixture of the two other components in the presence of the palladium catalyst [67]. 

A new class of 2-acylallylboronates was synthesized via palladium-catalyzed three-component assembling reaction using allenes, acyl chlorides, and B2pin2 (Equation (36)) 239,240 The proposed mechanism was an insertion of an allene double bond to the acylpalladium(n) chloride, followed by coupling of the diboron with the resulting 7r-allylpalladium(n) intermediate. 

Muller and coworkers have recently developed a coupling-isomerization reaction, initially identified as a side reaction which occurred under standard Sonogashira conditions [79]. As demonstrated below, the coupling reaction is followed by a shuffling of oxidation states via an alkyne-allene isomerization [80]. The product, a,P-unsaturated ketone 146, is reminiscent of a product which would be obtained from a Heck reaction. The utility of this reaction was further demonstrated when diamine 147 was added to the reaction pot. Following a conjugate addition reaction and imine formation, compound 148 resulted from the three-component, one-pot reaction sequence enabled by the coupling-isomerization reaction. 

This sulfoxide-magnesium exchange reaction could be successfully applied to a new synthesis of allenes (Scheme 3.12) [6]. The procedure is a novel method for synthesis of allenes from three components, ketones, chloromethyl p-tolyl sulfoxide, and sulfones, in relatively short steps. A key step is an attack of the lithium a-sulfonyl carbanion on the electron-deficient carbene carbon. /1-Elimination of the sulfoxyl group then occurs to give the allene. 

This indium-mediated palladium-catalyzed Barbier-type allylation of aldehydes is expanded to cascade reactions with allenes, which give three-component coupling products (Tab. 8.12 and 8.13) [89]. 

Arylamines undergo. V-contains titanium tetraisopn the amino group is unhinder Homoallyl alcohols. homoallylic alcohols in the three-component condensat moiety from allene and ary 1 indium. A relayed process tl intricacy of such a reaction... 

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