Synthesis of aryl- and heteroaryl-substituted 3-benzyloxyisothiazoles via Suzuki and Negishi cross-coupling reactions

Introduction of aryl and heteroaryl substituents into the 5-position of 3-benzyloxyisothiazole (1) using palladium-catalyzed Suzuki and Negishi cross-coupling reactions was investigated. Attempts to generate synthetically viable nucleophilic species from 1 for Suzuki- or Negishi-type cross-couplings were unsuccessful. However, using 3-benzyloxy-5-iodoisothiazole 2 as an intermediate, a range of aromatic and heteroaromatic substituents were successfully introduced under Suzuki or Negishi cross-coupling conditions in good to excellent yields.     

Palladium(0)-catalyzed suzuki-miyaura cross-coupling reactions of potassium aryl- and heteroaryltrifluoroborates with alkenyl bromides

Efficient palladium(0)-catalyzed Suzuki-Miyaura cross-couplings are described. The reactions involving potassium aryl- and heteroaryltrifluoroborates with alkenyl bromides can generally be carried out using < or =2 mol % of palladium catalyst and 3 equiv of base in toluene/H2O. When stereodefined alkenyl bromides are employed, the resulting styrene derivatives are accessed stereospecifically. A variety of functional groups are tolerated in both coupling partners.     

Regioselective zincation of indazoles using TMP2Zn and Negishi cross-coupling with aryl and heteroaryl iodides

The metalation of various SEM-protected functionalized indazoles with TMP(2)Zn provides 3-zincated indazoles which undergo palladium-catalyzed Negishi cross-couplings in good yields.     

One-Pot Sequential Kumada–Tamao–Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl

We report a general and rapid chemoselective Kumada–Tamao–Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPent^Cl ( C4 ). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo–chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.     

Application of vinyl tris(trimethylsilyl)germanes in Pd-catalyzed couplings

The oxidative treatment of vinyltris(trimethylsilyl)germanes with hydrogen peroxide (NaOH/H(2)O/THF) or tert-butyl peroxide (KH/THF) generates reactive germanol or germanoxane species that undergo Pd-catalyzed cross-couplings with aryl and alkenyl halides and aryl triflates in the presence of Pd(PPh(3))(4). Vinylgermanes having either a conjugated or isolated double bond serve as versatile transmetalation reagents. The E-germanes undergo coupling with retention of stereochemistry under aqueous and anhydrous conditions, while coupling of Z-germanes occurs with less stereoselectivity to produce a mixture of E/Z products.     

Synthesis of the multisubstituted halogenated olefins via cross-coupling of dihaloalkenes with alkylzinc bromides

[reaction: see text] The 1-fluoro-1-haloalkenes undergo Pd-catalyzed Negishi cross-couplings with primary alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective giving pure Z-fluoroalkenes in most cases. The highest yields were obtained with Pd2(dba)3 and PdCl2(dppb) catalysts but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4. The tertiary alkylzincs also produced desired fluoroalkenes in high yields. Coupling of beta,beta-dichlorostyrene with organozinc reagent resulted in the formation of monocoupled product.     

The first Negishi cross-coupling reaction of two alkyl centers utilizing a Pd-N-heterocyclic carbene (NHC) catalyst

The development of an NHC-based system capable of cross-coupling sp(3)-sp(3) centers in high yield has been a long-standing challenge. This communication describes the use of a Pd-NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated, primary bromides and alkyl organozinc reagents with a variety of functionality. [reaction: see text]     

Unification of anion relay chemistry with the Takeda and Hiyama cross-coupling reactions: identification of an effective silicon-based transfer agent

The unification of Anion Relay Chemistry (ARC) with the Takeda and Hiyama palladium-mediated cross-coupling processes to provide aryl-aryl, alkenyl-aryl, and alkenyl-alkenyl coupled products by exploiting a common silicon-based transfer agent has been achieved. These results provide a practical solution for intermolecular cross-coupling of organolithium reagents without the problematic lithium-halogen exchange and/or undesired homocoupling that has kept organolithium cross-couplings from achieving the same level of utility asother palladium-mediated methods (e.g., Suzuki organoboron, Negishi organozinc, Stille organotin, Kumada organomagnesium, etc.).     

Solid phase palladium-catalysed CC bond formation in the pyridine series: access to aryl and alkynyl pyridylpiperazines

The underdeveloped topic of solid phase CC bond formation in pyridine series has been investigated. Stille, Negishi, Suzuki and Sonogashira cross-couplings have been performed leading to aryl and alkynyl pyridylpiperazines in acceptable to good yields.     

Stereoselective Negishi-like couplings between alkenyl and alkyl halides in water at room temperature

Mix in water and then stir. That is all that is required in this new approach to stereoselective sp(3)-sp(2) cross-couplings between an alkyl and alkenyl halide. Prior formation of organozinc reagents is not required.     

Nickel-catalyzed asymmetric negishi cross-couplings of secondary allylic chlorides with alkylzincs

Complementing previous advances in allylation chemistry, an effective nickel/Pybox catalyst for regioselective asymmetric Negishi cross-couplings of racemic secondary allylic chlorides with readily available organozinc halides has been developed. The method has been applied in two key steps of a formal total synthesis of fluvirucinine A1.     

Pd-catalyzed cross-coupling of α-(acyloxy)-tri-n-butylstannanes with alkenyl, aryl, and heteroaryl electrophiles

Racemic and scalemic α-(acyloxy)-tri-n-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides, and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classes of electrophiles that typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl and stannyl-substituted stereocenters.     

Nickel-catalyzed Negishi cross-couplings of 6-chloropurines with organozinc halides at room temperature

An efficient method for the synthesis of 6-alkyl or 6-aryl purines (nucleosides) was developed via nickel-catalyzed Negishi cross-couplings of 6-chloropurines and organozinc halides. The ligand-free process gave good to excellent isolated yields at room temperature.     

"On water" sp3-sp2 cross-couplings between benzylic and alkenyl halides

Organic-solvent-free cross-couplings between benzylic and alkenyl halides have been developed. Various alkenyl halides can be efficiently benzylated by combining the precursor halides in the presence of Zn dust and a Pd catalyst at room temperature, in water as the only medium.     

New regiospecific isothiazole C-C coupling chemistry

Regioselective palladium catalysed coupling reactions are achieved in good to high yields, starting from either 3,5-dichloro- or 3,5-dibromoisothiazole-4-carbonitriles 1 and 2, providing 3-halo-5-(hetero/aryl, alkenyl and alkynyl)isothiazoles 3, 4, 6-9 from Stille couplings, 3-halo-5-(hetero/arylethynyl)isothiazoles 14-19 from Sonogashira and 5,5'-bi(3-chloroisothiazole-4-carbonitrile) (13) from an Ullmann type coupling. 3,5-Dibromoisothiazole-4-carbonitrile 2 is more reactive than the dichloroisothiazole-4-carbonitrile 1 and effective enough for Stille, Negishi and Sonogashira couplings. 5,5-Bi(3-chloroisothiazole-4-carbonitrile) (13) is prepared by a palladium catalysed Ullmann coupling from 3-chloro-5-iodoisothiazole-4-carbonitrile (11). A variety of 3-substituted isothiazoles (3-substituents = Cl, Br, OMs, OTs and OTf) are less reactive and fail to give successful Suzuki couplings at the isothiazole C-3 position. The 3-iodo-5-phenyl-isothiazole-4-carbonitrile (28), prepared via Sandmeyer iodination, participates successfully in Suzuki, Ullmann type, Stille, Negishi and Sonogashira coupling reactions. All products are fully characterized.     

Peripheral covalent modification of diruthenium compounds – New approach toward robust molecular architectures

This short review describes the carbon–carbon bond formation chemistry at the periphery of inorganic/organometallic diruthenium species. The types of reactions applicable include the Sonogashira, Suzuki, Negishi and Heck cross-couplings. The structural, spectroscopic and voltammetric studies revealed that these peripheral modifications have exerted a minimal perturbation on the electronic structures of the diruthenium species.     

Catalytic asymmetric synthesis of secondary nitriles via stereoconvergent Negishi arylations and alkenylations of racemic α-bromonitriles

The first method for the stereoconvergent cross-coupling of racemic α-halonitriles is described, specifically, nickel-catalyzed Negishi arylations and alkenylations that furnish an array of enantioenriched α-arylnitriles and allylic nitriles, respectively. Noteworthy features of this investigation include: the highly enantioselective synthesis of α-alkyl-α-aryl nitriles that bear secondary α-alkyl substituents; the first examples of the use of alkenylzinc reagents in stereoconvergent Negishi reactions of alkyl electrophiles; demonstration of the utility of a new family of ligands for asymmetric Negishi cross-couplings (a bidentate bis(oxazoline), rather than a tridentate pybox); in the case of arylzinc reagents, carbon-carbon bond formation at a remarkably low temperature (-78 °C), the lowest reported to date for an enantioselective cross-coupling of an alkyl electrophile; a mechanistic dichotomy between Negishi reactions of an unactivated versus an activated secondary alkyl bromide.     

Pd(DPEPhos)Cl2-catalyzed Negishi cross-couplings for the formation of biaryl and diarylmethane phloroglucinol adducts

Several functionalized biaryls and diarylmethanes containing the phloroglucinol subunit were synthesized in 55-85% yields using Negishi cross-couplings of 2,4,6-trimethoxyphenylzinc chloride with aryl and benzyl halides in the presence of catalytic quantities of Pd(DPEPhos)Cl₂. These simple to prepare couplings were generally complete in 1-24 h depending on the halide, and were applicable to aryl and benzyl halides containing both electron-donating and electron-withdrawing groups.     

Concise, convergent syntheses of (±)-trichostatin A utilizing a Pd-catalyzed ketone enolate α-alkenylation reaction

Two concise, convergent syntheses of (±)-trichostatin A (1), a potent histone deacetylase inhibitor, have been accomplished. The key step in both is a Pd-catalyzed α-alkenylation reaction between ketone 2 and either dienyl bromide 3 or alkenyl bromide 9 using a modification of cross-coupling conditions described by Negishi and Hartwig. A brief investigation has shown the potential utility of a Ni-catalyzed version of this reaction. The overall synthetic routes are short and amenable to scaleup, providing access to trichostatin A via trichostatic acid as a direct precursor.     

Pd-catalyzed carbocyclization-Negishi cross-coupling cascade: a novel approach to 1alpha,25-dihydroxyvitamin D3 and analogues

[reaction: see text] A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.