Suzuki reaction synthesis

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-aryhndoles fEq. 10.50. 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole " and 5-amino-7-ethoxycarbonyhndole for use in synthesis of l//-pyrrolo[3,2-g quina2ohne ring system fEq. 10.51 " have been prepared from the appropriate o-nitrotoluene. 

The utility of the Suzuki reaction in the challenging arena of natural product total synthesis has been explored. The constitution of bombykol (106) (see Scheme 26), a well-known pheromone, lends itself to a Suzuki coupling. Indeed, in a short stereospecific synthesis of 106, Suginome et al. demonstrated that ( )-vinylboronic acid ( )-104 can be smoothly cross-coupled with (Z)-l-pentenyl bromide [(Z)-105] 44 the configurations of both coupling partners are preserved in the C-C bond forming process. 

The Suzuki reaction has proved extremely versatile and has found extensive use in natural product. synthesis. " Arylboronic acids [ArB(OH)2 are the usual substrates in this reaction together with arylhalides or triflates (Ar X, X = halogen... 

There are also several examples of the use of Suzuki reactions in scale-up synthesis of drug candidates. In the synthesis of CI-1034, an endothelin antagonist, a triflate,... 

The two major subunits were coupled by a Suzuki reaction in Step H-3. The Multistep Syntheses synthesis was then completed by reductive opening of the 1,3-dioxane ring, oxidation of the terminal alcohol to the carboxylic acid, carbamoylation, deprotection, and lactonization. 

Shibasaki and coworkers [87] described the first enantioselective combination of this type in their synthesis of halenaquinone (6/1-162) (Scheme 6/1.43). The key step is an intermolecular Suzuki reaction of 6/1-159 and 6/1-160, followed by an enantioselective Heck reaction in the presence of (S)-BINAP to give 6/1-161. The ee-value was good, but the yield was low. 

For the domino transition metal-catalyzed synthesis of macrocycles, conditions must be found for two distinct cross-coupling reactions, of which one is inter- and the other intramolecular. For this purpose, Zhu s group [115] has developed a process of a Miyura arylboronic ester formation followed by an intramolecular Suzuki reaction to give model compounds of the biphenomycin structure 6/1-232 containing an endo-aryl-aryl bond. 

An intramolecular Pd-catalyzed ring closure of an allylic halide, acetate or carbonate containing an allene moiety as 6/1-256, followed by a Suzuki reaction, was used by Zhang and coworkers for the synthesis of five-membered carbo- and heterocycles 6/1-257 and 6/1-258 (Scheme 6/1.67) [125]. 

A paper concerned with the synthesis of pyridazino[3,4-fe]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work <06T121>. 

The Suzuki reaction (the palladium-catalyzed cross-coupling of aryl halides with boronic acids) is arguably one of the most versatile and at the same time also one of the most often used cross-coupling reactions in modern organic synthesis [32], Carrying out high-speed Suzuki reactions under controlled microwave conditions can today be considered almost a routine synthetic procedure, given the enormous literature precedent for this transformation [7]. 

A recent publication by the group of Barbarella has disclosed the rapid preparation of poorly soluble unsubstituted and modified a-quinque- and sexithiophenes by the extensive use of bromination/iodination steps and microwave-assisted Suzuki and Sonogashira cross-couplings (Scheme 6.16) [42]. Suzuki reactions were either carried out under solvent-free conditions on a strongly basic potassium fluoride/ alumina support for the synthesis of soluble oligothiophenes, or in solution phase for the preparation of the rather insoluble a-quinque- and sexithiophenes. In both cases, 5 mol% of [l,l -bis(diphenylphosphino)ferrocene]dichloropalladium(II)... 

Pd(dppf)Cl2] was used as the catalyst. A particularly noteworthy aspect of this publication is the introduction of a one-pot borylation/Suzuki reaction of 5-bromo-terthiophene with commercially available bis(pinacolato)diboron. The resulting sex-ithiophene was obtained within 10 min of microwave irradiation in 84% isolated yield. The same concept was also applied for the synthesis of modified oligothio-... 

An alternative method of producing indole-containing compounds involves a bis-Suzuki reaction of 2,3-dihaloindoles 114 with 2 equiv of boronic acids 115 with 10 mol % Pd(OAc)2 [75]. The paper describes the difference in electronic effects of the boronic acids. Electron-rich boronic acids give better yields (85-95%) whilst the electron-deficient boronic acids give poorer yields (44-55%). Scheme 28 shows the general synthesis of these compounds. 

Recognizing the distinct difference in reactivity for each site of N-protected 2,4,5-triiodoimidazole 23, Ohta s group successfully arylated 23 regioselectively [32, 33], In the total synthesis of nortopsentin C, they coupled 23 with one equivalent of 3-indolylboronic acid 24 to elaborate imidazolylindole 25. The Suzuki reaction occurred regioselectively at C(2) of the imidazole ring. 

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed crosscoupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a -carboline natural product [50], Or/fio-lithiation of 2,3-dichloro-A-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another p-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy p-carbolines have also been synthesized in the same fashion [3,51]. 

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