Hydrozirconation conditions

Dienols with 2 equiv. of 1 gave the corresponding bimetallic alkoxide organozir-conocene complexes however, protolysis allowed recovery of the alcohol functionality (Scheme 8-29) [107]. Alcohols can also be easily converted to ethers. Alkyl, aryl, silyl [85,112,183, 210] and THP [17, 153, 211, 219] ethers are stable under hydrozirconation conditions side products were observed only with the trimethylsUyl group [220, 221]. 

True to its nature as an early transition metal, zirconium displays considerable Lewis acidity and binds to hard Lewis bases such as carbonyl groups, thus facilitating hydride transfer and reduction. In general, amides, ketones, aldehydes, and nitriles are not compatible with alkene and alkyne hydrozirconation conditions. Alkynes are selectively hydrozirconated in the presence of esters, but only stericaUy hindered triisopropylsilylesters survive the slower hydrozirconation of alkenes. Acylsilanes are also readUy tolerated in hydrozirconation, and carbamates, acetals, epoxides, sUylethers, alkyl- and phenylethers. 

Hydrozirconation of the sterically less hindered double bond in conjugated dienes is generally observed [103]. However, the presence, as the minor regioisomer, of the allyhc product has been reported [5, 86]. Depending on the reaction conditions and the reagents used in the subsequent transformation, the allylic isomer did not form (Scheme 8-12) [2]. 

Since the initial reports of Schwartz s reagent ([Cp2Zr(H)Cl]n, 1) over 30 years ago there has been explosive growth of zirconocene chemistry. Hydrozirconation is an efficient method of hydrometalation because of (i) the mild nature of the conditions involved, (ii) the excellent regio- and stereo-chemical control of hydrozirconation, (iii) the one-pot nature of the procedure, and (iv) the price of Zr, which is one of the... 

It was shown (654) that the sequence terminal alkyne hydrozirconation, Zr to Zn exchange and addition to nitrones, is a good method to the stereoselective synthesis of (E)-N-allylhydroxylamines, under mild conditions and in good yield. 

Cleavage of Zr—C a bonds occurs readily on treatment with H20 or dilute acids, while the Zr—Cp bond usually survives mild protonolysis conditions. The use of D20 or DC1/D20 permits the replacement of Zr with D. Deuterolysis provides a generally reliable method for establishing the presence of Zr—C bonds. Protonolysis or deuterolysis of Zr—Csp bonds proceeds with retention of configuration [97]. In the hydrozirconation of terminal alkynes, deuterium can be introduced at any of the three positions in the vinyl group in a completely regio- and stereoselective manner, as shown in Scheme 1.18. Although relatively little is known about the mechanistic details, the experimental results appear to be consistent with concerted c-bond metathesis (Pattern 13) between C—Zr and H— X bonds. 

In the case of nonracemic homopropargylic ether 17, hydrozirconation/carbonylation was followed by exposure of the intermediate to molecular iodine (Scheme 4.12) [39]. The ( )- and (Z)-forms of the acyl iodide presumed to be formed in situ were seemingly in equilibrium under the reaction conditions and intramolecular attack followed by dealkylation afforded (S)-(+)-parasorbic acid. 

As an alternative to hydrozirconation of acetylenic tellurides or selenides, Dabdoub and co-workers have more recently described the first additions of the Schwartz reagent (one equivalent) to acetylenic selenide salts 51 (Scheme 4.30) [52]. Subsequent alkylation at selenium produces 1,1-dimetallo intermediates 52, which are cleanly converted in a one-pot process to stereodefined products 53. It is noteworthy that ketene derivatives 52 are of ( )-geometry, the opposite regiochemistry to that which results from hydrozirconation of acetylenic tellurides (vide supra). This new route also avoids the mixtures of regio-isomers observed when seleno ethers are used as educts. The explanation for the stoichiometric use of Cp2Zr(H)Cl in these reactions, in contrast to the requirement for two equivalents with seleno ethers, may be based on cyclic intermediates 54, in which Li—Cl coordination provides an additional driving force. Curiously, attempted hydrozirconation of the corresponding telluride salt 55 under similar conditions was unsuccessful (Scheme 4.31) (Procedure 12, p. 143). 

It should be pointed out that, compared to a-bromoboronic esters, p-bromoboronic esters are much less stable. For instance, dibutyl (2-bromoethyl)boronate readily undergoes P-elimination, even under solvolytic conditions [87]. Therefore, the reaction of 18 with NBS also reaffirms the regioselectivity of the hydrozirconation step. The reaction is highly general and works equally well for the preparation of a-chloro- and a-iodoboronic... 

Transmetalation reactions of organozirconium reagents were pioneered by Schwartz [130-132], with improved procedures developed more recently by Lipshutz [133] and Wipf [134]. The hydrozirconation of 1-hexene with H(Cl)ZrCp2 at 25 °C under sonication conditions produces the n-hexylzirconium complex 127, which adds to cyclohexenone in the presence of CuBr-Me2S (10 mol%) to afford the desired product 128 in 79% isolated yield (Scheme 2.61) [134]. 

For the asymmetric 1,4-addition of alkenyl groups in aprotic media, alkenyl zirconium reagents can be used, which are generated by hydrozirconation of terminal alkynes (Figure 3.30). Under these conditions, alkenyl groups derived from alkylacetylenes are efficiently installed, but those from arylacetylenes are not as effective (entry 3). 

The reaction with styrene or 1,3-butadiene under the same conditions (benzene-ether) results in r-butylzircohation (equation 1). However, in reactions conducted in benzene alone, hydrozirconation is observed. 

Of course, these findings do not automatically mean that such functional groups cannot be tolerated that depends upon relative rates. For instance, hydrozirconation of nitriles can be relatively slow complete reaction of RCN under standard conditions required 72 h, 14 h and 1.5 h, respectively for R = Me, Ph, Bn, Consistent with previous indications that alkynes are more reactive than alkenes towards (6), hydrozirconation of an alkyne can be carried out in the presence of a nitrile group (see Table 5), whereas methacrylonitrile gives only C N hydrozirconation (equation 20). ... 

The total synthesis of apoptolidin was accomplished in the laboratory of K.C. Nicolaou. The key C12-C28 vinyl iodide fragment was prepared using the Schwartz hydrozirconation of an internal alkyne followed by trapping of the alkenylzirconium intermediate with iodine (I2). The vinyl iodide was formed as a 6 1 mixture of regioisomers. Under the reaction conditions, the methyl orthoester was converted to the methyl glycoside moiety at C21, which was presumably facilitated by the complexation of Zr with the pyranoside oxygen atom. 

Chloride abstraction of (alkylideneamido)zirconocene chlorides Cp2ZrCl(N=CHR) (R = Me,/>-tolyl), prepared by a hydrozirconation reaction, with lithium butylborate Li+[/z-BuB(C6F5)3] at ambient temperature gives the transient cation [Cp2Zr(N=CHR)]+, which readily dimerizes under the reaction conditions to form the cis/trans-isomers of the dimeric /x-alkylideneamido zirconocene dications 728563 (Scheme 179). Treatment of these dications with acetonitrile leads to the respective mononuclear monocationic adduct complexes. 

Stork s strategy towards racemic morphine comprises a Diels-Alder cycloaddition reaction of a benzofuran to establish the B- and C-ring of morphine as the key step [53]. The reaction sequence started with the ketahzation of iodoisovaniUin 97 (Scheme 15). Subsequently, the phenol was reacted with methyl propiolate to afford 98 as precursor for the installation of the benzofuran moiety via a palladium-catalyzed Heck cyclization (99). Next, the key intermediate was prepared for the Diels-Alder reaction. Hydrolysis of the acetal under acidic conditions and Wittig homologation afforded aldehyde 100, which was converted to diene 101 via hydrozirconation of acetylene 105 employing the Schwartz reagent and subsequent reaction with aldehyde 100 followed by sUylation of the secondary alcohol. 

Despite the low intrinsic reactivity of alkylboranes, Pd-catalyzed alkylation with alkylboron compounds holds considerable promise as a unique and chemoselective alkylation method. It is uifique in part because hydroboration of alkenes is by far the most general and dependable method for stoichiometricaUy converting alkenes into organometals and in part because alkylboron compounds thus generated can satisfactorily participate in Pd-catalyzed alkylation under basic conditions, hi this connection, it should be noted that the current scopes of hydroalumination and hydrozirconation of alkenes are much more Umited than... 

Hydrozirconation of thioketones affords a versatile intermediate, which can be converted into a range of organosulphur compounds depending upon the work-up conditions. Of particular interest is the reaction of these intermediates with CO-Br2 in the presence of alcohols to provide a new synthesis of ethers (Scheme 2). 

Various reactions via hydrozirconation have been reported. The alkylzirconium intermediates are inexpensive and easy to prepare, requiring only moderate care in their handling, and undergoing a wide range of transformations under mild conditions with high yield. Hydrozirconation may prove an attractive alternate to hydroboration or hydroalumination processes, particularly when facile rearrangement of the functionalization unit is required... 

An improved procedure for the synthesis of alkyl iodides from organoboranes (and thus ultimately from alkenes), involving the use of iodine and sodium meth-oxide, has been shown to entail inversion at the C-B bond, and is employed in a new route to optically active iodides from alkenes e.g. Scheme 30). A similar sequence for conversion of alkenes to primary halides via hydrozirconation (Scheme 31) has been reviewed. Zr also catalyses addition of lithium aluminium hydride to alkenes under mild conditions, and the alanes so formed can likewise be converted into alkyl halides (Scheme 32). 

The synthesis of 63 (Scheme 15) followed the pathways that were previously developed, as shown in Scheme 14. Hydrozirconation of 52 followed by acylation with 47, MeOH addition, and deprotection provided the desired hybrid. A two-step protocol was employed for the deprotection since the benzoate ester of the hybrid was only partially cleaved under the BU4NF-mediated conditions. Purification was delayed until the final deprotection step because of the mixtures that resulted from partial deprotection in the earlier steps. Although the yield of this sequence was a modest 22%, a sufficient quantity of material was isolated for cytotoxicity studies. We named 63 pedestatin as an homage to Robert Petit, who first reported the isolation of irciniastatin A, because of his frequent use of the statin suffix in the cytostatic natural products that his group has isolated and studied. 

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