Azulenesulfonium Salts: Accessible,Stable, and Versatile Reagents for Cross‐Coupling

Azulenesulfonium salts may be readily prepared from the corresponding azulenes by an S_EAr reaction. These azulene sulfonium salts are bench‐stable species that may be employed as pseudohalides for cross‐coupling. Specifically, their application in Suzuki–Miyaura reactions has been demonstrated with a diverse selection of coupling partners. These azulenesulfonium salts possess significant advantages in comparison with the corresponding azulenyl halides, which are known to be unstable and difficult to prepare in pure form.     

Azulenesulfonium Salts: Accessible,Stable, and Versatile Reagents for Cross‐Coupling

Azulenesulfonium salts may be readily prepared from the corresponding azulenes by an S_EAr reaction. These azulene sulfonium salts are bench‐stable species that may be employed as pseudohalides for cross‐coupling. Specifically, their application in Suzuki–Miyaura reactions has been demonstrated with a diverse selection of coupling partners. These azulenesulfonium salts possess significant advantages in comparison with the corresponding azulenyl halides, which are known to be unstable and difficult to prepare in pure form.     

Diversity synthesis using the complimentary reactivity of rhodium(II)- and palladium(II)-catalyzed reactions

Rhodium(II)-catalyzed reactions of aryldiazoacetates can be conducted in the presence of iodide, triflate, organoboron, and organostannane functionality, resulting in the formation of a variety of cyclopropanes or C-H insertion products with high stereoselectivity. The combination of the rhodium(II)-catalyzed reaction with a subsequent palladium(II)-catalyzed Suzuki coupling offers a novel strategy for diversity synthesis.     

A ring expansion-annulation strategy for the synthesis of substituted azulenes. Preparation and Suzuki coupling reactions of 1-azulenyl triflates

[structure: see text]. A new strategy for the synthesis of substituted azulenes is reported, based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves intramolecular addition of a rhodium carbenoid to an arene pi-bond, electrocyclic ring opening, beta-elimination, tautomerization, and trapping to produce 1-hydroxyazulene derivatives. The synthetic utility of the method is enhanced by the ability of the triflate derivatives to participate in Suzuki coupling reactions, as illustrated in a synthesis of the antiulcer drug egualen sodium (KT1-32).     

Synthesis and derivatization of ethynyl alpha,alpha-dibromomethyl ketones: formation of highly functionalized vinyl triflates

[reaction: see text] We describe the synthesis of alpha,alpha-dibromomethyl ynones (8) and their subsequent derivatization to vinyl acetates (10). These vinyl acetates feature a 1,1-dibromo-olefin moiety, which is readily exploited in palladium-catalyzed Sonogashira, Stille, and Suzuki cross-coupling reactions with alkynes, stannanes, and boronic acids, respectively. A novel one-pot process then directly converts the resulting vinyl acetates 11-13 to the vinyl triflate derivatives 14a-j.     

Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot

The rapid and efficient synthesis of various 2,6-disubstituted-3-amino-imidazopyridines using a microwave-assisted one-pot cyclization/Suzuki coupling approach is described. The utility of a 2-aminopyridine-5-boronic acid pinacol ester as a robust and versatile building block for the synthesis of diverse compound libraries is emphasized. The boronate functional group is remarkably tolerant to the Lewis acid catalyzed cyclizations, and the subsequent Pd(0)-catalyzed Suzuki coupling reactions proceed cleanly in the presence of magnesium salts. This work highlights the vast potential of microwave-assisted, metal-catalyzed, multicomponent reactions.     

Insights into long-range structural effects on the stereochemistry of aldol condensations: a practical total synthesis of desoxyepothilone F.

A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), has been accomplished. The route is highly convergent. The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucial point of departure from previous syntheses of dEpoB and dEpoF involves presentation of the C1-C11 sector for Suzuki coupling with C3 in reduced form. Hitherto, the required S stereochemistry at C3 had been implemented via reduction of a keto function after Suzuki coupling. Whereas that chemistry worked quite well in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction of the keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very difficult. In our current approach, two consecutive aldol reactions are used to fashion the acyl sector. In the first aldol condensation, C6 becomes attached to C7. Following protection at C7, a two-carbon acetate equivalent is used to join C2 and C3 with very high asymmetric induction at C3. Only after this center has been implemented is the Suzuki reaction conducted. This major advance allowed us to synthesize dEpoF in a straightforward fashion. These findings found ready application in the total synthesis of dEpoB. Another part of the study involved analysis of the factors associated with aldol condensations joining C6 to C7. In the work described herein, the consequences of the status of C3 in promoting the C6-C7 aldol coupling are probed in detail. Dramatic stereochemical long-range effects uncovered during the study are described, and a working model to explain these effects has emerged.     

Synthesis and palladium-catalyzed coupling reactions of enantiopure p-bromophenyl methyl sulfoximine

[reaction: see text] The asymmetric synthesis and chemical modification of p-bromophenyl methyl sulfoximine (2) is described. Starting from p-bromophenyl menthyl sulfinate (5), enantiopure 2 can be obtained in a short reaction sequence involving a well-established substitution reaction followed by stereospecific imination with O-mesitylenesulfonylhydroxylamine (MSH). Palladium-catalyzed Buchwald/Hartwig, Suzuki, and Stille coupling reactions allow a broad variation of the sulfoximine aryl group, which is otherwise difficult to achieve. The incorporation of a p-morpholino-substituted derivative into a pseudotripeptide demonstrates the applicability of the novel sulfoximine derivatives.     

A highly efficient microwave-assisted suzuki coupling reaction of aryl perfluorooctylsulfonates with boronic acids

[reaction: see text] A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acids to form biaryls under general microwave conditions. Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel. Application of this tagging strategy to multistep synthesis of biaryl-substituted hydantoin is also described.     

4-Bromomethyl-2-chlorooxazole--a versatile oxazole cross-coupling unit for the synthesis of 2,4-disubstituted oxazoles

The synthesis of the novel oxazole building block, 4-bromomethyl-2-chlorooxazole, and its palladium-catalysed cross-coupling reactions to make a range of 2,4-disubstituted oxazoles, is described. Selectivity for the 4-bromomethyl position is observed, with Stille coupling effected in good to excellent yields, or Suzuki coupling in moderate yields, to provide a range of 4-substituted-2-chlorooxazoles. Subsequent coupling at the 2-chloro-position can be achieved through either Stille or Suzuki reactions in excellent yields.     

An efficient access to 2,3-diarylimidazo[1,2-a]pyridines via imidazo[1,2-a]pyridin-2-yl triflate through a Suzuki cross-coupling reaction-direct arylation sequence

An efficient method to prepare 2,3-diarylimidazo[1,2-a]pyridines is described. The procedure involves a Suzuki cross-coupling reaction followed by a direct arylation at position 3. Imidazo[1,2-a]pyridin-2-yl triflate was identified as a suitable coupling partner, permitting access to a variety of highly functionalized 2,3-diarylimidazo[1,2-a]pyridines.     

Intramolecular double or triple Suzuki coupling reaction of substituted di- or tribromobenzenes. An easy synthesis of fused tri- or tetracycles with a benzene core

Double or triple intramolecular Suzuki coupling reaction has been developed for the efficient synthesis of tri- or tetracyclic products with a benzene core in good yields. The reaction was realized via a one-pot procedure combining the hydroboration of the CC bond in the starting aryl halides and the intramolecular Suzuki coupling.     

Synthesis of bromo-, boryl-, and stannyl-functionalized 1,2-bis(trimethylsilyl)benzenes via Diels-Alder or C-H activation reactions

1,2-Bis(trimethylsilyl)benzenes are key starting materials for the synthesis of benzyne precursors, Lewis acid catalysts, and certain luminophores. We have developed efficient, high-yield routes to functionalized 4-R-1,2-bis(trimethylsilyl)benzenes, starting from either 1,2-bis(trimethylsilyl)acetylene/5-bromopyran-2-one (2) or 1,2-bis(trimethylsilyl)benzene (1)/bis(pinacolato)diborane. In the first reaction, 5 (R = Br) is obtained through a cobalt-catalyzed Diels-Alder cycloaddition. The second reaction proceeds via iridium-mediated C-H activation and provides 8 (R = Bpin). Besides its use as a Suzuki reagent, compound 8 can be converted into 5 with CuBr(2) in i-PrOH/MeOH/H(2)O. Lithium-bromine exchange on 5, followed by the addition of Me(3)SnCl, gives 10 (R = SnMe(3)), which we have applied for Stille coupling reactions. A Pd-catalyzed C-C coupling reaction between 5 and 8 leads to the corresponding tetrasilylbiphenyl derivative. The bromo derivative 5 cleanly undergoes Suzuki reactions with electron-rich as well as electron-poor phenylboronic acids.     

Synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated Heck, Stille, and Suzuki reactions

A regio- and stereoselective synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated coupling reactions was developed. The comparison and optimization of stereoselectivity of the Heck, Stille, and Suzuki reactions of 7-bromo or 7-triflate-3-quinolinecarbonitrile are described. Compound 7 and 10 were potent inhibitors of Src kinase and Raf/Mek activity, respectively.     

Nanoporous phenanthroline polymer locked Pd as highly efficient catalyst for Suzuki-Miyaura Coupling reaction at room temperature

Because of the intrinsic advantages, Suzuki coupling reactions have been one of the most popular coupling reactions in organic synthesis, however developing a high-performance heterogeneous catalyst for Suzuki coupling reactions in aqueous media at low temperature (e.g. room temperature) is still a challenge. Herein, a heterogeneous catalyst with coordinated Pd as active site and a designed conjugated phenanthroline based porous polymer (CPP) as support was fabricated. Systematically investigation on CPP support by Fourier transform infrared spectroscopy (FT-IR), Thermogravimetric analysis (TGA), Transmission electron microscopy (TEM), N₂ adsorption–desorption isotherm and Scanning electron microscopy (SEM) show that the derived CPP catalyst support owns a porous structure, moderately good surface area (141 m²/g) and an excellent thermal stability. As a heterogeneous catalyst for the synthesis of biphenyl derivatives via Suzuki coupling, Pd/CPP achieves an excellent catalytic performance and recycling ability towards Suzuki reaction of various reactants at room temperature in ethanol-water medium.     

The first Suzuki cross-couplings of aryltrimethylammonium salts

The first Suzuki cross-coupling reaction of aryltrimethylammonium triflates based on the use of an IMes.Ni(0) catalyst system is described. A wide range of electron-withdrawing and electron-donating substituents are tolerated on both the aryltrimethylammonium triflate and the boronic acid components of this reaction. In addition to arylboronic acids, the scope of the reaction is extended to encompass both boronate esters and alkenylboranes. This methodology constitutes a novel, mild method to activate anilines for metal-catalyzed cross-coupling reactions.     

Reactivity of cyclic sulfamidates towards phosphonate-stabilised enolates: synthesis and applications of alpha-phosphono lactams

Five and six ring a-phosphono lactams 14-20 are available by reaction of 1,2- and 1,3-cyclic sulfamidates respectively with enolates derived from ethyl dialkylphosphonoacetates 3 and 4. Subsequent Wadsworth-Emmons olefination provides the enantiomerically pure exo-alkylidene variants e.g. 25, which is efficiently converted to vinyl triflate 29 (> 98% ee). Suzuki coupling of 29 to a range of aryl and vinyl boronic acids leads to a structurally diverse range of pyrrolidinones exemplified by 30 and 34. The degree of epimerisation at the base-sensitive C(5) stereocentre during the Suzuki coupling of 29 is shown to be dependent on both the nature of the aryl boronic acid and the reaction conditions used.     

Synthesis and characterization of monodisperse oligofluorenes

An efficient synthesis of 9,9-bis(2-ethylhexyl)fluorene oligomers up to the heptamer is reported, with repetitive Suzuki and Yamamoto coupling reactions employed in the synthesis. The key steps for preparation of the essential intermediates include Pd-catalyzed transformation of aryl bromides to aryl boronic esters (Miyaura reaction) and the application of the much higher reactivity of aryl boronic esters over aryl bromides in the Pd-catalyzed cross-coupling reaction with aryl diazonium salts. Variation of the UV/Vis absorption and photoluminescence characteristics with chain length is reported. Moreover, glass transition and liquid-crystal characteristics of the oligomers are described and compared with those of the polymer.     

First total synthesis of vialinin A, a novel and extremely potent inhibitor of TNF-alpha production

Vialinin A, a powerful inhibitor (IC50 90 pM) of TNF-alpha production, was synthesized from sesamol in 11 steps with 28% overall yield. The key reactions include a double Suzuki coupling of electron-rich aryl triflate with phenylboronic acid and an oxidative deprotection of bis-MOM ether. In addition, the related synthetic studies also suggest the necessity for structural revision of ganbajunin C, a positional isomer of vialinin A.     

A traceless perfluoroalkylsulfonyl (PFS) linker for the deoxygenation of phenols

[reaction: see text]. The synthesis of a novel perfluoroalkylsulfonyl (PFS) fluoride is described for use as a traceless linker in solid-phase organic synthesis. Attachment to the resin and subsequent coupling of a phenol affords a stable arylsulfonate that behaves as a support-bound aryl triflate. Palladium-mediated reductive cleavage of a wide variety of phenols generated the parent arenes. The resin-bound aryl triflate was shown to be stable to reductive amination conditions, and the traceless synthesis of Meclizine is reported.