Double Suzuki coupling

Equation 11.21 Double Suzuki coupling generating a precursorto an HIV-protease inhibitor. 

Equation 11.26 Synthesis of a linear HIV-protease inhibitor by a double Suzuki coupling. 

A new synthetic approach to polycyclic aromatic compounds has been developed based on double Suzuki coupling of polycyclic aromatic hydrocarbon bis(boronic acid) derivatives with o-bromoaryl aldehydes to furnish aryl dialdehydes. These are then converted to larger polycyclic aromatic ring systems by either (a) conversion to diolefins by Wittig reaction followed by photocyclization, or (b) reductive cyclization with trifluoromethanesulfonic acid and 1,3-propanediol (Eq. (12)) [30]. 

Dihydroxytropolone derivatives have emerged as the foremost representatives of a new class of potent, competitive inhibitors of inositol monophosphatase. The first successful preparations of mono- and disubstituted 3,7-dihydroxytropolones were accomplished by single or double Suzuki coupling reactions between these permethylated monobromo- and... 

The method consists of the one-step synthesis of (Z)-l,2-(bis-benzo-dithienyl)ethenes 10 using double Suzuki coupling between stereochemi-caUy defined diboronic acid esters 11 and 2-iodo-benzodithiophene 12. The (Z)-alkenes thus obtained can be easily and efficiently photochemicaUy cyclized to the corresponding substituted tetrathia[7]helicenes. This methodology can also be applied to the synthesis of stilbenoid derivatives with two different heterocyclic systems such as the phosphole 13 (Figure 3) (2014CEJ12373). 

The results of double Suzuki coupling are summarized in Table 31.9 [8]. 

Zhang236 has also reported a Pd(0)-catalyzed cyclization-arylation cascade of 1,6-enynes that proceeds via the formation of a 7r-allylpalladium intermediate and the subsequent Suzuki coupling, yielding adducts with stereo-defined exocyclic double bonds (Scheme 60). 

Snieckus described short syntheses of ungerimine (121) and hippadine by Suzuki couplings of boronic acid 118 with 7-bromo-5-(methylsulfonyloxy)indoline (116) and 7-iodoindoline (117), respectively [130]. Cyclization and aerial oxidation also occur. Treatment of 119 with Red-Al gave ungerimine (121) in 54% yield, and oxidation of 120 with DDQ afforded hippadine in 90% yield. Indoline 116 was readily synthesized from 5-hydroxyindole in 65% overall yield by mesylation, reduction of the indole double bond, and bromination. Indoline 117 was prepared in 67% yield from N-acetylindoline by thallation-iodination and basic hydrolysis. 

Another resin-capture approach has been pubhshed in relation to the synthesis of tetrasubstituted ethylenes via Suzuki coupling reactions (Scheme 20) [42, 53]. A 25-member hbrary was synthesized using five alkynes, five aryl halides, and a polymer-bound aryl iodide. The alkynes 55 were converted into bis(boryl)alkenes 56 in solution, and the crude intermediates were used in Suzuki reactions with an excess of aryl halide. When all of the bis(boryl)alkene 56 had been consumed, the aryl iodide resin 59 was added to the reaction mixture and the reaction continued on the solid support. Side products such as 58, arising from a double Suzuki reaction, remained in solution and could be washed away. Compounds 60 were cleaved from the polymer using trifluoroacetic acid and products 61 were obtained in > 90% purity. 

Scheme 45. Peptides containing the IZD heterocyclic pTyr mimetics were synthesised in 10-11 linear steps from readily available starting materials such as 5-chloro-isothiazol-3-one 169, synthesised according to Method C, and amino acid derivatives 170. The key synthetic reaction was a novel Suzuki coupling of chloroheterocycle 169 with 4-phenylalanineboronic acid 170 to afford the fully protected scaffold 171. The J -terminus of 171 was subsequently elaborated via peptide coupling and the dipeptide 172 was deprotected to give inhibitor 173. The 4,5 double bond of 172 was reduced, isomers were separated, and each of them was further elaborated to afford compoimds 174 (Scheme 45).

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