Cross-coupling stepwise

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>). 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

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. 

Recently, a total synthesis of salmochelin SX (70) has been reported which used cross-coupling of acetobromo-a-D-glucose 96 with arylzinc derivative 97 to furnish 98, followed by full deacylation and perbenzylation to give 99. Subsequent saponification of the methyl/benzyl ester, formation of the acid chloride, and addition of a protected L-serine unit yielded 100. Final deprotection formed the glucosyl-DHB-serine 70 in 28% overall yield (Fig. 17) [121]. This strategy involved the stepwise addition of the aryl moiety and serine (76a) to the sugar portion, which is in the opposite order to the biosynthetic rationale. 

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). 

Scheme 10.7 depicts the synthesis of an OPE3 one-terminal wire compound by repeated Sonogashira cross-couplings [13c]. The synthesis takes advantage of the more reactive iodide as compared with the bromide, which allows for stepwise scaffolding. Thus, two concomitant Pd-catalyzed cross-couplings of 23 produced 24. The terminal alkyne obtained after desilylation was subsequently cross-coupled with 1 to afford 25. 

Potential difference in reactivity between two G-B bonds allowed the transformation of l,2-bis(boryl)-l-alkenes to 1-alkenylboranes via a cross-coupling with the aryl, 1-alkenyl, benzyl, and cinnamyl halides (Equation (23)).211-213 This tandem procedure synthetically equivalent to a yy/z-carboboration of alkynes was used for synthesizing Tamoxifen derivatives via stepwise double coupling with two of the G-B bonds.212,213 Hydrogenation of the resulting bisborylalk-enes with a chiral rhodium catalyst is synthetically equivalent to an asymmetric diboration of alkenes (Equation (24)).214... 

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

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. 

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]. 

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. 

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

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). 

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