Suzuki conditions

The first total synthesis of 87 was published in 1990 (90TL1523). 5-Hydroxyindole (88) was mesylated and then reduced with sodium cyanoborohydride to give an indoline which was brominated to afford the bromoindoline 89 in good yield (Scheme 33). Cross-coupling with ortho-formyl boronic acid under Suzuki conditions, followed by air oxidation of the resulting cyclized product, followed by reduction of the lactam formed with excess Red-Al gave the target compound 87. 

The Suzuki-Miyaura and Heck reactions were recently also reported under conventional heating conditions [39,40]. A variety of 3-chloro pyrazinones were reacted with commercially available (hetero)aryl boronic acids or the alkyl-9-BBN derivatives under either classical or slightly modified Suzuki conditions to generate the 3-substituted analogues, however having the drawback of longer reaction times of up to 12 h of reflux. 

Nickel catalysis has been used in a sequential synthesis of terphenyls, starting with 2-, 3-, or 4-bromophenyl neopentanesulfonates. Conventional Pd-catalyzed Suzuki conditions were used for the first step involving coupling of the bromide and then nickel catalysis was utilized for coupling the sulfonate. 

Recently, the groups of Fu and Buchwald have coupled aryl chlorides with arylboronic acids [34, 35]. The methodology may be amenable to large-scale synthesis because organic chlorides are less expensive and more readily available than other organic halides. Under conventional Suzuki conditions, chlorobenzene is virtually inert because of its reluctance to oxidatively add to Pd(0). However, in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(f-Bu)3 or tricyclohexylphosphine], enhanced reactivity is acquired presumably because the oxidative addition of an aryl chloride is more facile with a more electron-rich palladium complex. For... 

In the intervening years, indoleboronic acids substituted at all indole carbon positions have found use in synthesis. For example, Claridge and co-workers employed 94 in a synthesis of isoquinoline 95 under standard Suzuki conditions in high yield [114], Compound 95 was subsequently converted to the new Pd-ligand l-methyl-2-diphenylphosphino-3-(l -iso-quinolyl)indole. 

Boronic acids 96 and 97 couple very well with vinyl triflates 98 and 99 under typical Suzuki conditions (Pd(PPh3)4/Na2C03/LiCl/DME) to give indoles 100 and 101, respectively, in 76-92% yield [115, 116]. Enol triflates 98 and 99 were prepared in good yield (73-86%) from N-substituted 3-piperidones, wherein the direction of enolization (LDA/THF/-78 °C PhNTf2) is dictated by the tf-substituent. 

Indoleboronic acid 96 was employed by Neel to prepare bis(indolyl)maleimides such as 109 [119]. However, since the standard Suzuki conditions failed (triflate 108 apparently decomposing under the reaction conditions), the use of a phosphine-free Pd catalyst [120] and cesium fluoride [121] was necessary and gave 109 in an acceptable yield of 55%. 

The medicinal importance of 2-aryltryptamines led Chu and co-workers to develop an efficient route to these compounds (130) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 128 with arylboronic acids 129 [137]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 128. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70-100%). 2-Phenyl-5-(and 7-)azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [19]. 

Suzuki cross-coupling has found applications in the preparation of specialty polymers, too. Rigid rod polymers may have very useful properties (the well-known Kevlar, poly(p-phenyleneterephtalamide) belongs to this family, too) but they are typically difficult to synthetize, characterize and process. Such materials with good solubility in organic solvents [38] or in water [39] were obtained in the reactions of bifunctional starting compounds under conventional Suzuki conditions with [Pd(PPh3)4] and [Pd(TPPMS)3] catalysts, respectively (Scheme 6.15). 

A different approach to the synthesis of oligo[2]calenanes was chosen by Mullen et al. in 1995 [57]. The bromo-substituted in/out catenane 111 was coupled with appropriate comonomers under Suzuki conditions [58]. The degree of polymerization was between one and five for the resulting oligomers 112 (Figure 45). In 1997 the same group reported the first synthesis of poly[2]catenanes of the... 

Coupling with vinyl, alkenyl, and aryl bromides.1 This reagent couples with these bromides under Suzuki conditions (14, 124-125 cat. Pd, base) to give the corresponding methylated products. 10-CH3-9-BBN is not useful for this coupling because it is spontaneously flammable in air. 

In a subsequent study, the impact of replacing one or both of the amide bonds with either a diacylhydrazine or a 1,3,4-oxadiazole was explored [36]. (fi)-Bromoallyl ethers were employed in the PI and Pi positions and similarly subjected to Suzuki conditions using the two aryl boronic acids that gave the most potent inhibitors in the previous study. Potent plasmepsin inhibitors were produced however, no real improvements in activity compared to the parent compound were observed (Scheme 5). The use of the preligand, [(f-Bu3)PH]BF4 [37], in combination with barium hydroxide was found beneficial although the yields were very low in these reactions. 

Because of the different reactivities of iodo and bromo substituents in the Suzuki reaction, selective coupling can be realized. For example, 8-bromo-2-(4-methoxyphenyl)-l,10-phenanthroline (15) can be prepared by reacting the 4-boronic acid derivative of anisole with bromo(iodo)phenanthroline under Suzuki conditions (Eq. (44)) [75]. 

Restricted rotation about the biaryl axis as a result of bulky substituents leads to the existence of atropisomers. Depending upon the degree of steric hindrance due to the ortho substituents, three or four substituents are needed to produce a sufficient barrier to rotation at room temperature. This particular form of axial chirality is not generally resistant to heat. To produce acceptable yields of hindered biaryls under Suzuki conditions, high temperatures (60-110 °C) [78, 85] and reaction times of several hours are required. In atropisomer-selective reactions, these conditions would be deleterious to the discrimination between dia-stereomeric transition states and could racemize the biaryls formed. As a consequence, it is necessary to carry out such Suzuki reactions at ambient temperature. Recently, conditions employing Pd(OAc)2 and 95 % ethanol were used to generate mono-ortho-substituted biaryls at 20 °C (Eq. (54)) [86],... 

Completely aromatic, hyperbranched polyphenylenes were synthesized as monodendrons from AB2 type monomers by Kim and Webster [111, 112]. These dendrimers were prepared either by the homocoupling of 3,5-dibromophenyl boronic acid under modified Suzuki conditions, or by aryl-aryl coupling reactions involving 3,5-dihalo-phenyl Grignard reagents in the presence of Ni(II) catalysts as shown in Scheme 7. 

Thiadiazoles have also been used in pharmaceuticals, especially as Mi (muscarinic) selective agonists for the treatment of Alzheimer s disease. The synthesis of a series of alkylsulfanyl bioisosteric congeners of xanomeline is described by Jung et al. <03AP230>. The cyanohydrin 324 is converted to aminonitrile 325, which upon treatment with sulfur monochloride in DMF furnishes 1,2,5-thiadiazole 326. The 1,2,5-thiadiazole 326 is further transformed into compounds such as 327 as bioisosters of xanomeline <03AP230>. Merschaert et al. have reported palladium-catalyzed cross coupling reactions of commercially available 3,4-dichloro-l,2,5-thiadiazole under Stille and Suzuki conditions <03H(60)29>. 

Aryl boronic ester 389 was cross-coupled with 2-iodobenzimidazole 388 under Suzuki conditions to give 2-arylbenz-imidazole 390 in good yield (Scheme 93) <2003TL8967>. 

Suzuki conditions (PdfPPh.i /Na COj/LiCI/DME) to give indoles 100 and 101, respec-... 

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