Sequential coupling reaction

Another example of a [2s+2sh-1c+1co] cycloaddition reaction was observed by Barluenga et al. in the sequential coupling reaction of a Fischer carbene complex, a ketone enolate and allylmagnesium bromide [120]. This reaction produces cyclopentanol derivatives in a [2S+2SH-1C] cycloaddition process when -substituted lithium enolates are used (see Sect. 3.1). However, the analogous reaction with /J-unsubstituted lithium enolates leads to the diastereoselective synthesis of 1,3,3,5-tetrasubstituted cyclohexane- 1,4-diols. The ring skeleton of these compounds combines the carbene ligand, the enolate framework, two carbons of the allyl unit and a carbonyl ligand. Overall, the process can be considered as a for-... 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

Furthermore, this protocol can be employed for the highly efficient introduction of two (159) and even three allene entities (161) into an aromatic workbench (Scheme 2.51). Thus, by starting with two different halides, e.g. 162 (or with identical halides in different positions of a heteroaromatic substrate), two diverse allenic groups can be introduced by sequential coupling reactions. Furthermore, a structurally different bisallene 166 was also assembled via a twofold coupling of the bispro-pargyl bromide 165 with the functionalized aryl iodide 164 [85],... 

A variety of substituted seven-membered annulated pyrroles can be synthesized in a one-step process in good yields from readily accessible N-bromoalkyl pyrroles 75 and aryl iodides. The synthesis is based on a palladium-catalyzed/ norbornene-mediated sequential coupling reaction involving an aromatic sp C-H functionalization as the key step. The proposed mechanism suggests that orffzo-alkylation with the formation of intermediate 76 most likely precedes aryl-heteroaryl coupling (Scheme 15 (20060L2043)). 

As described in the former section, silyl-, boryl- and germyl-substituted gem-dizinc reagents are easily prepared. These dizinc reagents also perform the sequential coupling reaction as shown in Scheme 2622,24,25. 

Because 2-haloanilines are strongly electronically deactivated with regard to oxidative addition, it may be expected that there is sufficient disparity in reactivity between N-benzyl-2-chloroaniline and 4-chloroanisole for them to undergo the sequential coupling reaction. Very little carbazole product is formed, however, the major product being the intermediate 5a. In this case it seems that the rate of the... 

SCHEME 6.34 Palladium-catalyzed sequential coupling reactions. 

Instead of quenching with deuterium chloride, the intermediary organozinc compound 16 can be used as a nucleophile. Not only allylic halide but also alkenyl or aryl halide can be used as an electrophile in the reaction with gem-dizinc. In Scheme 8.27, the sequential coupling reactions of fois(iodozincio)methane are summarized. In the case of the coupling with a bromoalkene, a nickel catalyst was more effective than a palladium catalyst. 

Fig. 5. Representative block copolymer structures, (a) Routes to SIS i, coupling reaction ii, sequential, (b) Three and four-arm SI stars, (c) (Sllih radial, (d) (SEB)2B2 radial.

In the event, treatment of a rapidly stirred solution of 3 and sodium acetate in MeOH-tbO at 38 °C with PdCl2 results in the fomation of carpanone (1) in 46% yield. The ordered unimolecular transition state for the oxidative coupling reaction furnishes putative bis(quinodimethide) 2 stereoselectively. Once formed, 2 readily participates in an intramolecular Diels-Alder reaction4 to give carpanone (1). Two new rings and all five contiguous stereocenters are created in this spectacular sequential transformation.5... 

We have broadened the scope of this reverse addition protocol to prepare a variety of boronic acids bearing different functional groups for use in Suzuki coupling reactions. The yield and quality of the boronic acid prepared by this reverse addition protocol is usually better than the sequential approach. The boronic acids can be used without further purification (formation of pinacols) in Suzuki coupling reactions. 

Scheme 6.20 Sequential one-pot nucleophilic aromatic substitution and Suzuki cross-coupling reactions.

Stewart and Whiting have reported a useful application of sequential Heck and Suzuki coupling reactions of a vinylborane pinacol ester with palladium catalysis to generate a tetraene (equation 147)260. 

TMS group and the Suzuki cross-coupling reaction is again repeated. This sequential process allows for the introduction of different aromatic groups at positions 3 and 4 of the pyrrole system. The synthesis of the Furstner intermediate (6) is completed by removal of the sulfonamide group. 

A more successful strategy for developing sensitive and facile assays to monitor PLCBc activity involves converting the phosphorylated headgroup into a colorimetric agent via a series of enzyme coupled reactions. For example, phosphatidylcholine hydrolysis can be easily monitored in a rapid and sensitive manner by enzymatically converting the phosphorylcholine product into a red dye through the sequential action of alkaline phosphatase, choline oxidase, and peroxidase [33]. This assay, in which 10 nmol of phosphorylcholine can be readily detected, may be executed in a 96-well format and has been utilized in deuterium isotope and solvent viscosity studies [34] and to evaluate inhibitors of PLCBc [33] and site-directed mutants of PLCBc [35,36]. 

A four-component coupling reaction proceeds, forming a cyclopentane ring through sequential selective addition and cyclization, although the product is obtained as a mixture of stereoisomers (Scheme 40).202... 

Kinetic schemes involving sequential and coupled reactions, where the reactions are either first-order or pseudo-first order, lead to expressions for concentration changes with time that can be modeled as a sum of exponential functions where each of the exponential functions has a specific relaxation time. More complex equations have to be derived for bimolecular reactions where the concentrations of reactants are similar.19,20 However, the rate law is always related to the association and dissociation processes, and these processes cannot be uncoupled when measuring a relaxation process. 

A Pd(II)-catalyzed sequential cyclization-coupling reaction of allenyl N-tosylcar-bamates and acrolein has been developed (Scheme 16.97) [103]. The proposed mechanism involves intramolecular aminopalladation of an allene, followed by insertion of acrolein and carbon-Pd bond protonolysis. 

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