Zirconacycle synthesis

A general method for the synthesis of highly substituted styrenes as 6/4-91, vinyl-cyclohexadienes and related compounds was developed by Xi, Takahashi and coworkers [301] by reacting an intermediately formed five-membered zirconacycle 6/4-89 with propargyl derivatives 6/4-90 or allyl bishalides in the presence of CuCl (Scheme 6/4.21). 

Scheme 1.15. Synthesis of other three-membered zirconacycles.

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

For a long time, zirconacyclopentadiene was considered to be inert towards carbon-carbon bond formation. However, through transmetalation to Cu, Ni, Zn, Li, and Al, various kinds of carbon—carbon bond-formation methodologies have been widely developed. One major advantage of this chemistry is that zirconacyclopentadienes can be conveniently prepared in situ, in high yields and with excellent selectivities, from two different alkynes. Combination of the selective formation of zirconacyclopentadienes and the chemistry of Cu, Ni, Zn, Li, or Al provides useful tools in organic synthesis. In the near future, it can be expected that more metals will be used for the transmetalation reactions of zirconacycle derivatives and some catalytic reactions will hopefully be developed. 

Watt and Drummond, were considered to be inert for C-C bond forming reactions. However, by the expedient of transmetallation to Cu, Ni, Zn, Li, and Al, methodologies for the stereoselective synthesis of olefins and dienes, as well as unusual heterocycles, aromatics and their ring-annulated products are now available which are beginning to make impact on material science, e. g. synthesis of pentacenes and polyphenylenes. Takahashi and Li provide evidence that, with further developments in transmetallation and handling the zirconacycles outside of the Schlenk tube techniques, synthetic utility will increase and new catalytic reactions will be developed. 

Synthesis of an unsymmetrically substituted bis-zirconacycle was achieved by the sequence shown in Eq. (28).76... 

The synthesis of cyclopropanes from carbonyl compounds represents a new approach for converting zirconacycles into carbocycles via a deoxygenative ring contraction under Lewis acid activation. It differs in that from the spontaneous Kulinkovich process. Further progress would involve extension to the synthesis of 1,2-substituted cyclopropanes and the development of catalytic and enantioselective variants. 

Reductive cleavage of zirconacyclopentene was utilized for the synthesis of various zirconacycles by C-C bond cleavage/formation sequences [99]. 

Indole synthesis. A novel route to 4-iodoindoles involves reaction of N-allyl-N-bcnzyl-2-bromoaniline (I) with this zirconoccnc to form the zirconacycle 2, which is converted into 3 by iodination and elimination. This product undergoes ene reactions... 

Considering the experimental data and DFT calculations disclosed above, a possible reaction mechanism for the synthesis of cumulenols is outlined in Scheme 5 First of all, a fast equilibrium between seven-membered zirconacycle 3 and five-membered zirconacycle 2 exists in the reaction mixture, in which 3 is more stable, whereas 2 is more reactive. The addition of carbonyl group to the propargyl zirconium moiety in 2 proceeds to generate a nine-membered oxazirconacycle 7 via a cyclic Se2 process, and hydrolysis of 7 affords the cumulenol 5. 

As described in the definition of Buchwald indoline synthesis, this reaction involves the formation of a zirconocene-stabilized benzyne complex that intramolecularly inserts to an A-allyl group to give a tricyclic indoline zirconacycle. In the presence of oxidating reagent or electrophiles, the indoline zirconacycle decomposes into indoline derivatives. ... 

Sulfur dichloride was also used in the synthesis of 2,5-bis(trimethylsilyl)-EDOT 52, from which EDOT could be obtained by reaction with fluoride [123], The basis of the route is a zirconocene coupling generating zirconacyclopentadiene 51 from the reaction of two alkynes, linked with a 0(CH2)20 tether, with zirconocene dichloride (bis(cyclopentadienyl)zirconium(IV) dichloride). The zirconacycle reacted with sulfur dichloride generating the thiophene ring of 52 (Scheme 76). 

Scheme 76 The synthesis of a thiophene via the reaction of a zirconacycle with sulfur dichloride [123]...

The following protocols describe the synthesis of zirconacycle 45 from 1,6-heptadiene and its characterisation by NMR spectroscopy. Zirconacycle 45 is then elaborated into alcohol 49 by reaction with carbon monoxide, and alcohol 54 (R = Ph) by tandem insertion of lithium chloroallylide and benzaldehyde. 

In this chapter, the scope, mechanism, and recent progress of zirconocene (Il)-mediated cyclization reactions are introduced. Zirconocene(II) is a very important reagent for organometallic chemistry, synthetic chemistry, and polymer chemistry. Zirconocene(II) is capable of coordinating with unsaturated compounds. Further reactions could lead to zirconocene(IV) species, zirconacycles, C-C bond formation, C-X bond formation, and synthesis of carbocycles and heterocycles. Zirconocene(lI)-mediated cyclization of bis(alkynyl)silane gives zirconacyclobu-tene-silacyclobutene complexes, which could react with alkyne, bis(alkynyl)silane, ketone, nitrile, and isocyanate and could be applied in the synthesis of various valuable products. 

These bicyclic zirconacycles have been used in the synthesis of complicated natural products [17-19]. 

Chen C, Xi C (2010) Zirconacycle-mediated synthesis of carbocycles. Chin Sci Bull... 

The reaction of zirconacyclobutene-silacyclobutene fused compound 46 formed from Si-tethered diyne 45 with Cp2Zr(II) species has been used in the synthesis of fused aromatic heterocycles 47 (Scheme 11.18) [20]. When the zirconacycles 46 reacted with nitriles, the corresponding pyrrolo[3,2-c]pyridines 47 were formed. This indicates the unexpectedly strong effects of the alkynylsilyl groups on this unusual skeletal rearrangement of zirconacycles. 

Synthesis of Substituted Heterocycles Cu-mediated intermolecular coupling reaction of zirconacycles with dihalogenated heteroaromatic compounds is applicable for the synthesis of fused aromatic heterocycles. Zirconacyclopentadi-ene reacted with 2-iodo-3-bromothiophene in the presence of 2 equiv of CuCl and DMPU at 50 °C to afford the corresponding benzothiophenes 71. When 2-chloro-3-iodopyridine and 4-chloro-3-iodopyridine were used, the corresponding substituted quinolines 72 and isoquinolines 73 were obtained in high yields, respectively (Scheme 11.28) [28],... 

Cyclic gem-metallozirconocene compounds such as a-lithiated zirconacyclopentadienes, a-stannyl or gallio-zirconacyclopentenes, and a,o -bis(trimethylstannyl) zirconacyclopentadienes have been prepared (Fig. 3) [21-25]. These multifunctionalized zirconacycles can be expected to have useful applications in organic synthesis. 

Carbonylation of five-membered zirconacycles has been applied for synthesis of complexed and natural products. Stereocontrolled one-pot synthesis of tricyclic ketone with only cis isomer was achieved by Negishi and coworkers (Eq.43) [45]. 

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