Terminal alkynes hydrozirconation

Palladium-catalyzed alkenylation reactions involving pyrimidines can be achieved with hydrozirconated terminal alkynes, although the reaction is carried out in the presence of zinc chloride, so transmetallation to the zinc species is presumed to occur prior to the palladium-mediated coupling <1996ACS914, B-2002MI409>. Selective reaction at the 4-position of both 2,4-dichloropyrimidine and 2,4-dichloroquinazoline can be achieved. 

Zirconium Reagents. Ethenylation can be effected via hydrozirconated terminal alkynes (Scheme 83). The alkenylzirconocene gives the -aUcenyl product. The reaction is carried out in the presence of zinc chloride. Presumably metal metathesis occurs before the palladium-mediated coupling takes place. The coupling is regiospecific with initial... 

The alkenylzirconium 685, prepared by hydrozirconation of a terminal alkyne with hydrozirconocene chloride, reacts with alkenyl halide to afford the conjugated diene 686(545]. The Zr reagent can be used even in the presence of the carbonyl group in 687, which is sensitive to Al and Mg reagents. 

Hydrozirconation of terminal alkynes R-C=CH (R= aryl, alkyl) with 1 affords terminally ( )-Zr-substituted alkenes with high efficiency and excellent stereochemical and regiochemical control (>98%). These alkenylzirconocene complexes are of particular interest for synthetic use [136, 143, 144]. Moreover, beside the electropositive halogen sources [145] and heteroatom electrophiles [3] used in the pioneering studies to directly cleave the Zr-C bond, ( )-vinyl-Zr complexes were recently transformed into a number of other trans-functionalized alkenes such as ( )-vinyl-sul-fides[146], vinylic selenol esters [147], vinyl-sulfones [148], vinyl-iodonium [149], vinyl-(R0)2P(0) [150], and vinilic tellurides [143]. 

Scheme 8-18 Regio- and stereo-selectivity in hydrozirconation of terminal alkynes...

Nitriles [153, 211] are tolerated by an equivalent of reagent in the presence of a particularly reactive site of unsaturation, such as a terminal alkyne or vinyl function, whereas methacrylonitrile gives only C N hydrozirconation (Scheme 8-26) [215]. 

Carboxylic acids can be protected as oxazolines [96, 105-107, 186, 191] or as ester functions. Alkynic esters such as silyl esters [153, 211], tert-butyl esters [216], and even benzyl esters [153, 211] have been successfully hydrozirconated when the reactive site was a terminal alkyne or vinyl group (Scheme 8-27). 

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. 

Despite the great success of the transmetalation process in the enantiose-lective arylation of ketones, its extension to allylation or alkynylation reactions failed, providing the corresponding tertiary alcohols with enantiomeric excesses never higher than 50% ee. On the other hand, more success has been found in the alkenylation of ketones. The process started with the hydrozirconation of terminal alkynes to give the corresponding alkenylzirconium intermediates, which were transmetalated by reaction, in this case, with various ketones in the presence of the HOCSAC ligand. This protocol tolerated the presence of other carbon-carbon multiple bonds on the alkyne, as well as different functionalities and achieved excellent results for alkyl ketones, a,(3-unsaturated ketones and even dialkylketones, as shown in Scheme 4.22. 

As Scheme 16 shows, vinyl(methyl)zinc compounds 17 were obtained from the hydrozirconation of terminal alkynes with Cp2ZrHGl, followed by treatment with dimethylzinc. The initially formed vinyl zirconium complex undergoes rapid transmetallation with ZnMe2 to yield the product.44... 

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. 

Scheme 1.18. Synthesis of non-deuterated, partially deuterated, and fully deuterated vinyl derivatives via hydrozirconation of terminal alkynes.

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). 

Another protocol was reported by Wipf and Xu. The hydrozirconation of terminal alkynes followed by the addition of dimethylzinc forms (E)-alkenylmethylzinc (equation 18)58. The chiral amino thiol 38 has been employed as a catalyst for this reaction59. Li and Walsh found that ketones as well as aldehydes are alkenylated by alkenylzinc using the chiral catalyst 3460. 

Catalytic asymmetric vinylation of ketones has been achieved. Vinylzinc reagents have been generated by hydrozirconation of terminal alkynes which are then transmet- allated with zinc.199 A titanium(IV) complex of a tims-cyclohexane-bis(sulfonamide) provides chiral catalysis it also facilitates dienylation of ketones, with ees also >90% in this case. 

When the above-mentioned process is applied to 1-lithio-l-chloroethene 66 [52] and vinyl zirconocene 67, arising from hydrozirconation of terminal alkynes, a stereospecific formation of 2-zirconated dienes 68 is obtained, affording terminal dienes after protonation [53] (Scheme 24). 

Allylic zirconocenes, generated by hydrozirconation (see Hydrozirconation) of allenic systems, react with terminal alkynes when activated with MAO to regioselectively afford 1,4-dienes. The same MAO catalyzed process, applied to haloalkynes, leads to excellent yields of the 1,4-enyne (100) (Scheme 23). ... 

Alkynes are universally hydrozirconated as well the only failure in the literature is that of a perfluori-nated compound, C7Fi5(2sCH. Alkynes appear to be more reactive than alkenes, both by qualitative comparison and from the results on enynes (Table 6 also see Section 3.9.3.3.1), Furthermore, hydrozirconation of alkynes can compete with reduction of unsaturated functional groups such as nitriles and esters (Table 5), which is generally not true for alkenes. Dienes can be cleanly monohydrozirconated if one of the double bonds is terminal other cases are considered in Section 3.9.3.3.I. 

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. 

Coupling reactions with organozirconium reagents have hardly been explored in azines. In 1995 it was reported, however, that alkenylation can be effected by alkenylzirconocenes. The latter, in the trans configuration, are available by hydrozirconation of terminal alkynes 1-hexyne was hydrozirconated and coupled in situ with 2,4-dichloropyrimidine. Selective reaction in the 4-position gave the 4-alkenylpyrimidine (201) (Equation (13)). 

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... 

Instead of the commercially available CpZrHCl, this reagent can be prepared in situ from Cp2ZrCl2 and lithium triethylborohydride. The reaction mixture hydrozirconates terminal acetylenes without affecting e.g. an ester or trimethylsilyl functionality in the alkyne. An application of the Schwartz reagent in natural product synthesis is the hydrozirconation of the terminal triple bond of Me3SiC=C(CH2)4C=CH. A review on hydrozirconation has been published . ... 

Cross-coupling of acetylenes with aryl halides E)-alkenylarenes. (E)-Atkenyl-zirconium compounds (1), obtained by hydrozirconation of terminal alkynes, react smoothly with aryl bromides and iodides in the presence of 10 mole % of Nl[P(CeH5)3]4 to form (E)-alkenylarenes (2) in yields generally of 70-95%. ... 

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