Stepwise cross-coupling reactions

Novel heteroquaterphenoquinones were synthesized by a stepwise cross-coupling reaction or by a more convenient one-pot oxidative homocoupling reaction of the heterocycle-substituted phenols (Scheme 20, <96JOC4784 see also 95TL8055>). 

In symmetrically substituted 3,4-dihalothiophenes, several stepwise cross-coupling reactions have been performed <2005T2245>. Thus, 3,4-dibromothiophene undergoes a Negishi coupling with benzylzinc bromide to yield the monobromothiophene 84. This can be subjected to a Kumada cross-coupling to give the unsymmetrically substituted thiophenes 85. 

Scheme 5-2 Synthesis of unsymmetrical cyclic dienediyne 53 by stepwise cross-coupling reactions.

To make the transformation even more useful, different carbon electrophiles should be connected sequentially in a stepwise manner. For this purpose, a transition-metal-catalyzed cross-coupling reaction opened the way. As shown in Scheme 22, cinnamyl chloride is treated with bis(iodozincio)methane (3) in the presence of palladium catalyst with various phosphine ligands. Phosphine ligands, having an electron-withdrawing group, such as tris[3,5-bis(trifluoromethyl)phenyl]phosphine and tris(2-furanyl)phosphine, show excellent results47. 

The one-pot Stille cross-coupling reaction of compound 256 produced all four isomeric thieno[3,2-c]naphthyridines (1994JHC11). The stepwise formation of the C(7)-C(7a) and C(4)-N(5) bonds of the thieno[3,2-c]pyridine system can be considered as a modification of the above-described approaches. For example, aldehyde 256 reacts with arene 265 to give 266 reduction of its nitro group is accompanied by cyclization to form thieno[3,2-c]isoquinoline A-oxide (267) (1990JHC1127). 

The addition of diboron compounds to alkynes is an excellent method for the synthesis of c -diboryl alkenes (Scheme 2-11) [34], The reaction is catalyzed by Pt(PPh3)4 at 80 and works well not only with terminal but also with internal alkynes. The addition of the Si-B [35] or Sn-B [36] bonds to alkynes gives mixed-metal alkenylboron reagents which have potential ability for use in the stepwise double cross-coupling reaction at both metallated carbons. 

Selective and stepwise couplings of polyiodobenzene with tenninal acetylenes are also reported. In the course of the synthesis of rigid, benzene-centered, star-like porphyrin arrays, triply coupled derivative 75 has been prepared by Pd/Cu-catalyzed cross-coupling reactions with different terminal acetylenes under normal conditions from 1,3,5-triiodobenzene 74 in a stepwise manner (Scheme 29). ... 

Scheme 14.12 shows another example of the stepwise synthesis of azacalix[n] pyrazines that has been reported by Zhao and Wang [48]. Reaction of 2,6-bis (methylamino)pyrazine 38 and 2,6-dichloropyrazine 37 produced trimer 39 effectively. Attempted convergent macrocyclic cross coupling reaction of 39 with 38 failed to afford the targeted azacahx[4]pyrazine. Instead, a linear tetramer 40 was produced in 47 % yield along with the recovery of 31 % yield of reactant 39. Catalyzed by Pd2(dba)3, moderate yields of azacalix[4]pyrazine (21 %) and its macrocychc octamer, namely, azacalix[8]pyrazine (31 %) were achieved from 40 when the reaction was carried out in 1,4-dioxane in the presence of DavePhos as a ligand and CS2CO3 as a base (Scheme 14.12). Following the same strategy, the same authors reported very recently the preparation of azacalix[3n]pyrazine[n] pyridines (n = l, 2) when the linear trimer 39 was reacted with 2,6-bis (methylamino)pyridine [49].

A stepwise mechanism permitted the use of two different alkynes in a cross-coupling reaction that increased the functional diversity of obtained amines. [50]... 

Linear procedures involving the stepwise constmction of the ligands by appropriate methods such as Krohnke synthesis or metalSonogashira cross-coupling reactions, followed by successive steps involving attachment of appropriate metal precursors (e.g., Ru, Os, Re, Ir. ..), thereby affording heteronuclear complexes. 

Scheme 3 Stepwise versus domino cross-coupling-cydoaddition reactions on 8-oxabi-cyclo[3.2.l]octa-2,6-dienes [22]...

The synthetic sequence to methylene-bridged poly(phenylene)s 71 represents the first successful employment of the stepwise process to ladder-type macromolecules involving backbone formation and subsequent polymer-analogous cyclization. As shown, however, such a procedure needs carefully tailored monomers and reaction conditions in order to obtain structurally defined materials. The following examples demonstrate that the synthesis of structurally defined double-stranded poly(phenylene)s 71 (LPPP) via a non-concerted process is not just a single achievement, but a versatile new synthetic route to ladder polymers. By replacing the dialkyl-phenylenediboronic acid monomer 68 by an iV-protected diamino-phenylenediboronic acid 83, the open-chain intermediates 84 formed after the initial aryl-aryl cross-coupling can te cyclized to an almost planar ladder-type polymer of structure 85, as shown recently by Tour and coworkers [107]. 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

---