Arylzinc reagent

Aryl and alkyl organozincate reagents, generated in situ by reaction of Grignard reagents and sub-stoichiometric amounts of ZnCl2, cross-couple smoothly in refluxing THF with functionalized aryl and alkenyl as well as primary and secondary alkyl chlorides in the presence of Pd(dppf)Cl2.  

---

Even if hundreds of chiral catalysts have been developed to promote the enantioselective addition of alkylzinc reagents to aldehydes with enantioselectivities over 90% ee, the addition of organozinc reagents to aldehydes is not a solved problem. For example, only very few studies on the addition of vinyl groups or acetylides and even arylzinc reagents to aldehydes have been published, in spite of the fact that the products of these reactions, chiral allylic, propargylic and aryl alcohols, are valuable chiral building blocks. 

These results were comparable to those obtained for the related additions to aldehydes. Furthermore, it was shown that this ligand was also efficient for the addition of arylzinc reagents, providing enantioselectivities of up to 96% ee, as shown in Scheme 4.12. ... 

The use of expensive and unstable ZnPli2 in the preparation of chiral di-arylmethanol derivatives, with electronically and sterically similar aryl rings, made this approach less attractive for the enantioselective synthesis. In order to avoid this inconvenience, other alternative preparations of arylzinc reagents were evaluated.As a first choice, Yus et al. proposed the use of arylboronic adds as a viable source of phenyl (Scheme 4.19). Thus, the reaction of various boronic acids with an excess of ZnEt2 at 70 °C gave the corresponding arylzinc intermediates (probably aryl(ethyl)zincs), which were trapped by reaction with dif-... 

Commercially available Pd(PtBu3)2 is a unique, air-stable 14e Pd° complex, an excellent catalyst for cross-coupling reactions of aryl chlorides. The ability of P Bu3 to stabilize such a coordin-atively unsaturated, extremely reactive, and yet easily manageable form of Pd° is one of the most amazing and fruitful recent findings in Pd-based catalysis. The cross-coupling of arylzinc reagents with aryl or vinyl chlorides can be readily accomplished with as little as 0.03% of this catalyst. Both electron-rich and sterically hindered substrates are welcome in this protocol.404... 

During the past decade, the main focus of studies related to the well-known349 CeCl3- or SnCl2-catalyzed reactions of allylzinc and benzylzinc halides with imines was the application of polymer-supported chiral imines.350,351 An example of such reactions is shown in Scheme 135.350 It should be noted that attempts using arylzinc reagents in... 

Arylzinc reagents can be made from aryl halides with activated zinc118 or from Grignard reagents by metal-metal exchange with zinc salts.119... 

The functionalized arylzinc reagents are best prepared either starting from an aryllithium obtained by halogen-lithium exchange followed by a low-temperature (-80°C) transmetalation with ZnBrj or by performing an iodine-magnesium exchange reaction. The latter reaction tolerates temperatures up to -30°C and is more convenient for industrial applications. ... 

An important issue was the fact that isolated diphenylzinc had to be used in this protocol and that samples of this arylzinc reagent prepared in situ (and presumably still containing lithium or magnesium salts) led to products with lower enantioselectivities. Thus, although pure diphenylzinc was commercially available, its high price was expected to hamper large-scale applications of this catalyzed asymmetric phenyl transfer process [36, 37]. 

It is important to mention that the catalysis with this modified arylzinc reagent not only leads to improved enantioselectivity (at high product yield), but also that in this process swfestoichiometric quantities of diphenylzinc could be applied. This also meant that now both of the phenyl groups could be activated and transferred to the aldehydes. A reaction profile obtained by FT-IR studies revealed that the modification of the zinc reagent had a significant effect on its reactivity [41]. 

The formation of arylzinc reagents can also be accomplished by using electrochemical methods. With a sacrificial zinc anode and in the presence of nickel 2,2-bipyridyl, polyfunctional zinc reagents of type 36 can be prepared in excellent yields (Scheme 14) . An electrochemical conversion of aryl halides to arylzinc compounds can also be achieved by a cobalt catalysis in DMF/pyridine mixture . The mechanism of this reaction has been carefully studied . This method can also be applied to heterocyclic compounds such as 2- or 3-chloropyridine and 2- or 3-bromothiophenes . Zinc can also be elec-trochemically activated and a mixture of zinc metal and small amounts of zinc formed by electroreduction of zinc halides are very reactive toward a-bromoesters and allylic or benzylic bromides . ... 

In contrast to the extensive investigation of fluorovinylzinc reagents and their synthetic utility, only limited literature exists on fluorinated arylzinc reagents. Bis(pentafluorophenyl) zinc can be prepared by the reaction of zinc chloride with either pentafluorophenyllithium or pentafluorophenylmagnesium bromide (equation 70)64,65. An alternative route is via decarboxylation of zinc bis(pentafluorobenzoate) (equation 71)65. 

Arylzinc reagents are completely inert towards alkenes and alkynes in the absence of any added catalyst, whereas the reported examples of uncatalyzed intermolecular carbozincations involving alkylzincs appear to be restricted to the more nucleophilic di(tert-butyl)zinc. 

Support-bound stannanes have been prepared from phenyllithium bound to macro-porous polystyrene and chlorostannanes [14,41], by treatment of support-bound alkyl chlorides with lithiated stannanes [21,41], and by radical or palladium-mediated addition of stannanes to alkenes and alkynes (Figure 4.7 [42-47]). The chloride of poly-styrene-bound chlorostannanes can be displaced by treatment with arylzinc reagents, thereby yielding resin-bound arylstannanes [46]. Polystyrene-bound stannanes have also been prepared by copolymerization of 4-[2-(dibutylchlorostannyl)ethyl]styrene with styrene and divinylstyrene [48],... 

The direct addition of in situ-prepared arylzinc to aldehydes with chiral binaphthyl-derived amino alcohols (24) as catalysts has afforded optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99% ee).106 By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes. 

The (R) allene 121 was obtained with high anti stereoselectivity in the reaction of (i )-(—)-l-trifluoroacetoxy-l-phenyl-2-propyne (120) with PhZnCl. 2-Alkynyloxiranes react smoothly with alkynyl, alkenyl and arylzinc reagents. Reaction of 2-methyl-2-(l-propynyl)oxirane (122) with vinylzinc chloride (123) yields 2,4-dimethyl-2,3,5-hexatrien-l-ol (124) [31],... 

Catalytic asymmetric 1,6-additions to 2,4-dien-l-ones have been realized with up to 98% ee using a chiral bisphosphine-rhodium catalyst, arylzinc reagents, and a chlorosilane.120... 

These methods of zinc activation complement the known chemical methods and are useful efficient alternatives, since no excess of halide or reducing agent is required, and the electrochemical setting is very simple. They are unfortunately not preparatively convenient for aromatic halides. Such a reaction (Equation 8.16) has been reported,13 but the yields of arylzinc reagent are quite low when expressed on the basis of the starting aryl halide instead of the amount of zinc dissolved. 

Fluorinated arylzinc reagents can also be applied provided that 15, either isolated or generated in situ, was used as the catalyst precursor (entry 23) [63]. 

---