Hydrozirconation of Internal Alkynes

As for alkenes, the rate of hydrozirconation of alkynes decreases with increasing substitution on the alkyne. An unsymmetrical diyne reacts with 1 preferentially at the less-substituted triple bond [85]. 

Hydrozirconation is useful for regiospecific and/or stereospecific deuterium labeling [177]. Formation of diastereomerically pure dideuterated 3,3-dimethyl-butylzirconium(IV) complexes by successive hydrozirconation sequences showed 

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The steric demand of the zirconocene moiety leads to rearrangements in the case of hydrozirconation of internal double bonds. Regardless of position or configuration of the double bond in the substrate, zirconium migrates to the terminal position of the alkyl chain via insertion and /TH-elimination steps. Such isomerization does not occur upon hydrozirconization of internal alkynes. 

The hydrozirconation of alkynes by Cp2ZrHCl has been studied in detail . The addition of Zr-H is uniquely cis, and in 1-alkynes the zirconium attaches to the terminal carbon atom with high regioselectivity ( 98%). The direction of cis-fi addition of Zr-H to internal alkynes is sensitive to the steric bulk of the two substituents of the alkyne and, in the absence of excess Zr-H, is subject to kinetic control. The presence of excess Zr-H results in rapid equilibration of the initial mixture. The results of some hydrozirconations of internal alkynes are shown in Table H. 

The crucial issue in the processes shown in Scheme 66 is the regioselectivity of the hydrometallation, which tends to be generally less than satisfactory (<90-95%). Fortunately, HZrCp2Cl displays a > 95% regioselectivity in the hydrozirconation of internal alkynes with Me as one of the two substituents, This has been exploited in the re-gioselective syntheses of complex natural products represented by 1 and 2, such as reveromycin (Scheme 67) and /3-amino acid Adda. It should be mentioned that attempts to exploit Stille coupling for the constraction of C7—Cg bond in the synthesis of reveromycin B proved to be unsuccessful. ... 

Hydrozirconation of terminal triple bonds is an essential method to obtain alkenes with defined stereochemistry. In the case of internal alkynes the zirconocene moiety adds to the sterically less hindered position of the triple bond. C/s-selectivity is high, but the regioselectivity is sometimes moderate depending on the nature of the substrate.8... 

As mentioned earlier, hydrozirconation of internal alkenes gives terminal alkylzir-conium compounds. The isomerization occurs so quickly that no intermediates are observed. The mechanism of the reaction is a series of insertions and /8-hydride eliminations. Isomerization does not occur upon hydrozirconation of alkynes. 

Metallated acetylenes, obtained by hydrozirconation, hydroalumination or hydroboration, react with elemental iodine to give ( )-iodoalkene. Terminal alkynes 229 (R = octyl or decyl) add hydrogen iodide, generated from the boron triiodide/A,A-diethylaniline complex and acetic acid, in a Markovnikov sense to afford the iodoalkenes 230. cw-Addition of hydrogen iodide, produced in situ from trimethylsilyl chloride and aqueous sodium iodide, to a number of internal alkynes has been reported... 

Some hydrometalation reactions have been shown to be catalyzed by zirconocene. For instance, CpiZrCf-catalyzed hydroaluminations of alkenes [238] and alkynes [239] with BU3AI have been observed (Scheme 8-34). With alkyl-substituted internal alkynes the process is complicated by double bond migration, and with terminal alkynes double hydrometalation is observed. The reaction with "PrjAl and Cp2ZrCl2 gives simultaneously hydrometalation and C-H activation. Cp2ZrCl2/ BuIi-cat-alyzed hydrosilation of acyclic alkenes [64, 240] was also reported to involve hydrogen transfer via hydrozirconation. 

The addition of Cp2Zr(H)Cl, known as the Schwartz reagent [30], to different alkenes and alkynes is known to be a facile process [31]. Therefore, the hydrozirconation of a variety of readily available enynes 12 is among the first methods developed for the stereoselective preparation of dienyl zirconium reagents 13. This process is both completely chemo- and regioselective with a syn addition of the zirconium hydride across the alkyne [32] (Scheme 5). From the same intermediate, the Zr atom can be isomerized in its internal position such as in 15 via a zirconacyclopropene intermediate 14. Moreover, the addition of trimethylstannyl chloride to 14 led to the stannylated dienyl zirconocene 16 [33] (Scheme 5). 

Examples of reported hydrozirconations of alkenes and alkynes are summarized in Tables 2-6. Simple alkenes appear always to react as long as they are no more than trisubstituted. The only reported failure is that of a long chain internal alkene, triacont-15-ene, but such alkenes have subsequently been successfully hydrozirconated, albeit at slightly elevated temperature. The order of reactivity, based primarily on qualitative observations, is terminal alkene > internal alkene (cis = trans) > exocyclic alkene > cyclic alkene = trisubstituted alkene. Trisubstituted cyclic olefins and tetrasubstituted olefins do not react. Representative examples are shown in Table 2. 

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. 

One of the major sources of access to alkenylzirconocene intermediates [2] is through the hydrozirconation of alkynes with the Schwartz reagent Cp2Zr(H)Cl. Kinetically and thermodynamically favored syn-addition of this complex onto a terminal or internal alkyne followed by in situ treatment with electrophiles affords polysubstituted alkenes in high stereochemical purity (Scheme 12.1). 

Hydrozirconation occurs with yyn-addition of the Zr-H bond across a C=C or C=C bond (equation 8.16). Due to lower steric hindrance, the addition also tends to be regiospecific, with the zirconium attached to the less substituted position (just as in hydroboration). Internal alkenes and alkynes isomerize to 1-alkyl and 1-alkenyl complexes, respectively—presumably by alternating reactions of insertion and deinsertion—until the complex with the least steric hindrance is formed. 

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