Three-component coupling, reaction mechanism

Palladium-mediated cydization based on the reactivity of o-alkynyl or alkenyl-phenyl isonitriles have been developed [105]. On the basis of their earlier studies on the three-component synthesis of allyl aryl cyanamides [106], Yamamoto and co-workers reported a palladium-catalyzed three-component coupling reaction of 2-alkynylisocyanobenzenes 122 with allyl methyl carbonate and trimethylsilylazide leading to N-cyanoindoles 125 [107]. One of the key steps of the proposed mechanism is the formation of 7i-allylpalladium carbodiimide 123 and its isomerization to rc-allylpalladium cyanamide complex 124 (Scheme 8.50). 

Closer examination of tetrahydropyrans 173 clearly reveals that two molecules of aldehyde 174 have been appended onto allylsilane 171 via a novel three-component coupling reaction. Marko et al. proposed the mechanism depicted in Scheme 13.61 [65], Formation of heterocycles 173 is described as a sequence of two processes an initial ene-type reaction [80] which leads to alcohol 177 via the chair-like transition state 176, in which both the aldehydic R-group and the OTMS substituent assume an equatorial position. The high regio- and stereoselectivity observed in this ene-reaction can be nicely explained by considering the stabilizing /(-silicon effect and the repulsive 1,3-diaxial interactions. Transition state 176 contains no 1,3-diaxial interactions and benefits fully from the stabilizing /(-silicon effect [81, 82] (for more detailed transition-state discussion see ref. [63]). 

The mechanism of this three-component coupling reaction is probably analogous to the aforementioned insertion of acyl chlorides (above). One can imagine assembling an intermediate acylpalladium species either by oxidative addition to an acyl chloride or, in this case, by oxidative addition to the aromatic iodide followed by migratory insertion into carbon monoxide. Once formed, the acylpalladium intermediate can insert into the SCB to furnish a 7-(chlorosilyl)propyl ketone, which cyclizes in the presence of the amine to afford cyclic enol ethers. 

Scheme 5. Possible mechanism of the three-component coupling reaction.

The photolysis of a-phenylselenoacetate and related compounds in the presence of an alkene and CO leads to acyl selenides via group transfer carbonylation. The mechanism of this three-component coupling reaction involves the addition of an a-(alkoxycarbonyl)methyl radical to an alkene, the trapping of the produced alkyl free radical by CO, and termination of the reaction by a phenylselenenyl group transfer from the starting material (Scheme 4-43) [73]. 

Thus, a new type of Lewis acid, lanthanide triflates, is quite effective for the catalytic activation of imines, and has achieved imino Diels-Alder reactions of imines with dienes or alkenes. The unique reactivities of imines which work as both dienophiles and azadienes under certain conditions were also revealed. Three-component coupling reactions between aldehydes, amines, and dienes or alkenes were successfully carried out by using Ln(OTf)3 as catalysts to afford pyridine and quinoline derivatives in high yields. The triflates were stable and kept their activity even in the presence of water and amines. According to these reactions, many substituted pyridines and quinolines can be prepared directly from aldehydes, amines, and dienes or alkenes. A stepwise reaction mechanism in these reactions was suggested from the experimental results. 

A possible mechanism of these three-component coupling reactions is shown in Scheme 8.7. Intermediate 22 is quenched by water and methanol generated in situ to afford 20 and 21, respectively. While 18 is predominantly... 

Scheme 7.13 Proposed mechanism for ruthenium-catalyzed three-component coupling reaction of of, -unsaturated imines with CO and alkenes.

Based on the established mechanism for titanium-catalyzed hydroamination, the authors propose a reversible reaction between a titanium imide complex and the alkyne to form metalloazacyclobutene 86, which in turn undergoes 1,1-insertion of the isonitrile into the Ti-C bond. The generated five-membered ring iminoacyl-amido complex 87 with the new C-C bond is protonated by the primary amine to afford the desired three-component coupling product, with regeneration of the catalytic imidotitanium species. Very recently, titanium-catalyzed carbon-carbon bond-forming reactions have been reviewed.122... 

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. 

An extension of Tsuji s methodology has recently been reported by Liang in which he is able to perform a three-component coupling for the preparation of tetrasubstituted furans [154]. A combination of methyl or ethyl acetoacetate with propargyl bromide or carbonate and an aryl iodide enables the formation of tetrasubstituted furans 184. The proposed mechanism for this transformation is similar to that of Tsuji in that an allenyl-palladium intermediate is postulated. However, a three-component reaction is possible because the initial oxidative addition in this reaction is with the aryl iodide. Interaction of this Pd(II) intermediate with the propargyl bromide or carbonate leads to the allenyl-palladium species and, eventually, the product 184. 

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

To test the validity of this mechanism, it was reasoned that a weak add (t-BuOH or water) should quench the zwitterion 21 and suppress or at least decrease the formation of by-products. This is indeed the case, although the addition of more alkene increases the quantity of by-products, even in the presence of t-BuOH. It should be noted that the presence of these protic additives is not innocent, since it also increases the reaction rates and affects the enantioselectivity. For example adding 20 equivalents of t-BuOH to the reaction of PH(Is)Me with tert-butyl acrylate halves the time for the completion of the reaction (from 5 to 2 days) and doubles the enantiomeric excess from 28% to 56%. The latter enantioselectivity is the best obtained to date with the systems discussed in this section. More evidence for the Michael addition mechanism came from trapping intermediate 21 with electrophiles other than a proton. Scheme 6.12 shows that performing the hydrophosphination reaction in the presence of benzaldehyde produced some of the three-component coupling product 25. 

Mycophenolic acid was synthesized by a three-component coupling between the lactone 26, isoprene and dimethyl malonate (Eq. (23)) [47]. The reaction proceeds by the usual mechanism, with oxidative addition of the aryl halide to Pd(0) and subsequent insertion of isoprene into the Pd-aryl bond to give a t-allyl complex followed by nudeophilic attack by the malonate carbanion. Compound 27 was subsequently transformed to mycophenolic add. 

Further inquiry into the reaction mechanism resulted in the development of a new three-component coupling that led to the formation of the E-vinyl chlorides 198. This was achieved by carrying out the ruthenium-catalyzed coupling of alkynes with vinylketones in the presence of ammonium chloride and a cat-... 

The palladium-catalyzed multicomponent coupling reactions have attracted considerable interest.12,12a 12e A reaction using allylstannane 39 and allyl chloride 40 was applied to the three-component diallylation of benzylidenema-lonitrile and its congeners by Yamamoto et al 2 Analogous diallylation of isocyanate 41 was studied by Szabo et al. (Scheme 7).12a The reaction mechanism can be explained by formation of an amphoteric bis-allylpalladium intermediate 43 which undergoes an initial electrophilic attack on one of the allyl moieties followed by a nucleophilic attack on the other. 

Although the vulcanization mechanisms are well established for other elastomers, vulcanization of CR is a complicated process and has not been, until now, well understood. To our knowledge, there are only a few studies that discuss the vulcanization chemistry of CR [87]. The vulcanization mechanism for CR proposed in these pioneering studies was considered to be a planar three-component reaction mechanism in which the structural and special peculiarities were fully taken into consideration. Here, we propose an explanation of the chemical coupling mechanism between the CR matrix and electron-modified PTFE powder based on the similar vulcanization mechanism of CR. Such a mechanism can also be applied to vulcanization of CR in the presence of a ethylenethiourea compound. 

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