Acylzirconocene chloride

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

Acylzirconocene chloride derivatives are easily accessible in a one-pot procedure through the hydrozirconation of alkene or alkyne derivatives with zirconocene chloride hydride (Schwartz reagent) [Cp2Zr(H)Cl, Cp = cyclopentadienyl] and subsequent insertion of carbon monoxide (CO) into the alkyl— or alkenyl—zirconium bond under atmospheric pressure (Scheme 5.1) [2],... 

Transfer of the acyl group from the acylzirconocene chloride to aluminum (transmetala-tion) by treatment with aluminum chloride has been reported to give an acylaluminum species in situ, and the possibility of the acylaluminum acting as an acyl anion donor has been suggested (Scheme 5.5) [7]. However, the acyl anion chemistry through this trans-metalation procedure appears to be limited since only protonolysis to the aldehyde proceeds in good yield, which could be achieved by direct hydrolysis of the acylzirconocene chloride. 

Clear formation of ketene—zirconocene complexes upon treatment of acylzirconocene chlorides with a hindered amide base indicates that the carbonyl group of the acylzirconocene chloride possesses usual carbonyl polarization (Scheme 5.10). However, these zirconocene—ketene complexes are exceptionally inert due to the formation of strongly bound dimers [13a], Conversion of the dimer to zirconocene—ketene—alkylaluminum complexes by treating with alkylaluminum and reaction with excess acetylene in toluene at 25 °C has been reported to give a cyclic enolate in quantitative yield. Although the ketene—zirconocene—alkylaluminum complex reacts cleanly with acetylene, it does not react with ethylene or substituted acetylenes [13b]. Thus, the complex has met with limited success as a reagent in organic synthesis. 

I 5.4 Reactions of Acylzirconocene Chlorides as Unmasked Acyl Group Donors... 

Although the chemistry described in Sections 5.3.2.1 and 5.3.2.2 indicates an attractive feature of the acylzirconocene chloride complex for carbon—carbon bond formation, application to the synthesis of metal-free organic molecules has not been extensively studied. 

To replace the aforementioned acyl-main group and acyl-transition metal complexes, the natural course of events was to search for a stable and easy-to-handle acyl-metal complex that reacts as an unmasked acyl anion donor. Thus, the salient features of acylzirconocene chlorides as unmasked acyl anion donors remained to be explored. In the following, mostly carbon—carbon bond-forming reactions with carbon electrophiles using acylzirconocene chlorides as acyl group donors are described. 

Synthetic routes to a-ketol through the reactions of an unmasked acyl anion with carbonyl compounds are not numerous. The first practical application of an acylzirconocene chloride as an unmasked acyl anion donor was reported in the reaction with aldehydes in 1998 (Scheme 5.12 and Table 5.1) [19]. 

The reactivity of acylzirconocene chlorides towards carbon electrophiles is very low, and no reaction takes place with aldehydes at ambient temperature. In the reaction described in Scheme 5.12, addition of a silver salt gave the expected product, albeit in low yield (22—34%). The yield was improved to 79% by the use of a stoichiometric amount of boron trifluoride etherate (BF3OEt2) (1 equivalent with respect to the acylzirconocene chloride) at 0 °C. Other Lewis acids, such as chlorotitanium derivatives, zinc chloride, aluminum trichloride, etc., are less efficient. Neither ketones nor acid chlorides react with acylzirconocene chlorides. In Table 5.1, BF3 OEt2-mediated reactions of acylzirconocene chlorides with aldehydes in CH2C12 are listed. 

Thus, the involvement of one of the following three possible mechanisms has been suggested (i) nucleophilic addition of the acylzirconocene chloride to the Lewis acid activated aldehyde, (ii) nucleophilic addition of the cationic species of the acylzirconocene chloride formed by an Ag(I) salt or a Lewis acid, or (iii) transmetalation of the acylzirconocene chloride with the Lewis acid and subsequent nucleophilic addition. 

Table 5.2. Yb(OTf)3/TMSOTf (20 mol%, l l)-catalyzed reactions of acylzirconocene chlorides with imines.

Although the reactivity of acylzirconocene chlorides towards imine derivatives under Yb(OTf)3/TMSOTf (20 mol%, l l)-catalyzed conditions is not necessarily very high, the direct access to a-amino ketone derivatives indicates the usefulness of acylzirconocene chlorides as unmasked acyl anion donors. 

The reactions of acylzirconocene chlorides with imines also proceed under Bransted acid-catalyzed conditions, even with aqueous acids (Table 5.3) [23],... 

It is interesting to note that the reaction of N-salicylideneaniline, which possesses a free phenolic hydroxyl group at the ortho position in the benzylidene portion, with the acylzirconocene chloride gives the a-amino ketone in 67 % yield in the absence of any additive (Scheme 5.16) [23]. Similarly, N-(p-hydroxybenzylidene)aniline reacts with the acylzirconocene chloride to give the a-amino ketone in 58 % yield. The reaction of N-(m-hydroxyben-zylidene)aniline, however, gives the a-amino ketone in just 12 % yield. Neither N-(o-MeO-benzylidenejaniline nor N-(p-MeO-benzylidene)aniline gives an appreciable amount of product in the absence of additive. 

These results also indicate that the protonation of the imine group is important for the reaction. In the o-OH and p-OH isomers, resonance between the protonated imine and quinoido species would contribute in facilitating the protonation of the imine portion (Scheme 5.17). In the m-OH isomer, however, no such resonance contribution is possible. Thus, the poor additive effect of phenol in the reaction of N-benzylideneaniline with the acylzirconocene chloride (entry 1, Table 5.3) might imply less efficient protonation of the imine, as in the case of the m-OH isomer (Scheme 5.16). 

R)-product. Although there is still room for further improvement of the enantioselectivity, this first example of an enantioselective reaction with a,(S-unsaturated ketones reveals the potential of acylzirconocene chlorides as unmasked acyl anion donors. 

Table 5.6. Pd-catalyzed reactions of a,p-ynones with saturated acylzirconocene chlorides.

Scheme 5.29. Pd-catalyzed cross-coupling of acylzirconocene chlorides.

Reactions of Acylzirconocene Chlorides as "Unmasked Acyl Group Donors 5.4.4.5 Cu-catalyzed cross-coupling reactions... 

In the Pd-catalyzed cross-coupling reactions of acylzirconocene chlorides with allylic halides and/or acetates (Section 5.4.4.4), the isolation of the expected p,y-unsaturated ketone is hampered by the formation of the a, P-un saturated ketone, which arises from isomerization of the p,y-double bond. This undesirable formation of the unsaturated ketone can be avoided by the use of a Cu(I) catalyst instead of a Pd catalyst [35], Most Cu(I) salts, with the exception of CuBr - SMe2, can be used as efficient catalysts Thus the reactions of acylzirconocene chlorides with allyl compounds (Table 5 8 and Scheme 5 30) or propargyl halides (Table 5.9) in the presence of a catalytic amount (10 mol%) of Cu(I) in DMF or THF are completed within 1 h at 0°C to give ffie acyl--allyl or acyl-allenyl coupled products, respectively, in good yields. ill... 

Allyl tosylate is also an excellent reactant (entry 2, Table 5.8), while allyl acetate is not under Cu(I)-catalyzed conditions. Not only saturated acylzirconocene chlorides, but also a,(3-unsaturated acylzirconocene chlorides give coupling products in good yields (entry 8, Table 5.8). Prenyl bromide also reacts with acylzirconocene chlorides under identical conditions to give a mixture of regioisomers (Scheme 5.30). However, a longer reaction time (10 h) is required for the completion of the reaction as compared to the reaction of allyl bromide (1 h). 

The formation of an allenyl ketone as the sole product can be achieved by using an excess (2 equiv.) of propargyl bromide (entries 3—6, Table 5.9). Use of an increased amount (3 equiv.) of the acylzirconocene chloride in the reaction with propargyl bromide and/or tosylate yields a significant amount of a 1,4-dicarbonyl compound derived from Michael-type addition of the acylzirconocene chloride to the initially formed allenyl ketone (entry 2, Table 5.9). The Michael-type addition of acylzirconocene chlorides to allenyl ketones under Cu(I)-catalyzed conditions has been confirmed by an independent experiment (Scheme 5.31). 

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