Negishi reactions

Aryl and vinyl mesylate behave silimilarly [54]. The reaction has been used for the synthesis of 10,11-dihydroleukotriene B4 and related metabolites [55,56]. 

Cross-coupling reaction of aryl iodides with organozinc iodides in the presence of Ni(acac)2 can proceed smoothly. An extension to the corresponding resin-substituted aryl iodides also affords the coupling products. It is noteworthy that amides or esters remain intact under the reaction conditions [57]. 

In situ generated Ni(0) on charcoal has been shown to be an efficient heterogeneous catalyst for mediating carbon-carbon bond formation involving chloro-arenes and functionalized organozinc reagents [58]. 

Aryl chlorides are known to undergo nickel-catalyzed cross-coupling reaction of aryl Grignard reagents in the presence of zinc [59[. Vinylphosphates [60] and sulfoxides or sulfones [61] behave similarly to yield the corresponding coupling products. 

The carbon-nitrogen bond in substituted nitroethenes can be replaced by a carbon-carbon bond in good to excellent yield upon treatment with organozinc halides in the presence of Ni(acac)2 and a diamine ligand [62]. 

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A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

Recently, the required heteroaromatic organozinc halides for the Negishi reaction have also been prepared using microwave irradiation [23]. Suna reported that a Zn - Cu couple (activated Zn), prepared using a slightly modified LeGoff procedure from Zn dust and cupric acetate monohydrate, allowed the smooth preparation of (3-pyridinyl)zinc iodide and (2-thienyl)zinc iodide... 

Alkylzinc halides have also been prepared under microwave irradiation. The Reformatsky reagents (2-t-butoxy-2-oxoethyl)zinc bromide and [(2-dibenzylamino)-2-oxoethyl]zinc bromide were synthesized from the corresponding bromides via reaction with zinc in THF (Scheme 5) [24], The oxidative addition was executed at 100 °C in 5 min. The obtained reagents were subsequently used in Negishi reactions on 2-bromopyridine, 3-bromopyridine, 2-bromo-5-nitropyridine, and 2-bromo-5-trifluoromethyl-pyridine using Pd(PPh3)4 as a catalyst (Scheme 5). 

Negishi reaction 157 Nitriles, reduction/hydrolysis 25 Nitrogen heterocycles, on-resin cyclization, minopropenones 108 C-Nucleoside analogues 274... 

Very recently Chen and co-workers have applied the previously mentioned Ni-based dimetallic pre-catalyst 14 in the Negishi reaction. Remarkable results were obtained even when unactivated aryl chlorides were chosen as reaction partners providing an alternative to the more expensive Pd-based catalysts. The fact that dinuclear pre-catalyst 14 is more active than its mononuclear analogue 13 indicates a possible cooperative effect between the two metal centres [86] (Scheme 6.23). 

Cross-coupling reactions with Zn acetylenides are the most convenient and selective routes to terminal acetylenes. In this reaction Zn is markedy superior to other metals, including Sn (24).116 The higher reactivity of Zn acetylides allowed assembly of hexaethynylbenezenes in two steps, with the last three groups introduced at the second stage by the Negishi reaction (25).117... 

As in the Negishi reaction, various alkylboron reagents have also been successfully coupled with electrophile partners. Suzuki et al. coupled 1-bromo-l-phenylthioethene with 9-[2-(3-cyclohexenyl)ethyl]-9-BBN (27), prepared by a simple addition of 9-borabicyclo[3.3.1]nonane (9-BBN) to 4-vinyl-1-hexene (26), to furnish 4-(3-cyclohexenyl)-2-phenylthio-1-butene (28) in good yield [36],... 

For Negishi reactions in which the pyridines are nucleophiles, the pyridylzinc reagents are usually prepared from the corresponding halopyridines [6, 20, 21]. An excess of 2-chlorozincpyridine /V-oxide (26), arising from 2-bromopyridine N-oxide hydrochloride (25), was coupled with vinyl triflate 27 in the presence of Pd(Ph3p)4 to furnish adduct 28 [20]. Recently, an efficient Pd-catalyzed cyanation of 2-amino-5-bromo-6-methylpyridine (29) using zinc cyanide has been reported to afford pyridyl nitrile 30 [22]. 

Treating 2-furyltithium (derived from deprotonation of furan with n-BuLi) with ZnCh gave 2-furylzinc chloride, which then was coupled with 1,3-dibromobenzene to furnish bis-furylbenzene 12 [20, 21]. In addition, 2-furylzinc chloride was coupled with 4-iodobenzoic acid to give adduct 13. The Negishi reaction conditions were compatible with the carboxylic acid [22],... 

These couplings exemplify the functional group tolerance of the Negishi reaction conditions. Carboxylic acids, esters, amides, and even free anilines are compatible with the reaction conditions, as illustrated by the synthesis of furylaniline 21 [25],... 

Iodooxazole 15, prepared from the corresponding 2-lithiooxazole, underwent a Negishi reaction with 2-oxazolylzinc chloride to give bis-oxazole 16 in the presence of Pd(dba)2 and trifuranylphosphine (TFP) [4]. 

Scheme 28 Brown-Negishi reaction selective formation of secondary and tertiary alkyl radicals...

A modified version of the Brown-Negishi reaction using B-alkylcatechol-boranes was reported (Scheme 32). This novel method is based on a simple one-pot procedure involving the hydroboration of various substituted alkenes with catecholborane, followed by treatment with catalytic amount of oxygen/DMPU/water and a radical trap. Efficient radical additions to a,ft-unsaturated ketones and aldehydes have been reported. Primary alkyl radicals are efficiently generated by this procedure and the reaction has been applied to a 300 mmol scale synthesis of the y-side chain of (-)-perturasinic... 

Negishi reactions have also been used to insert methyl and ethyl groups at the 2-position of quinazolines <1998BML2891>. 

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