Organozinc iodides

The general utility of the oxidative addition of functionalized organic halides to zinc was demonstrated by the formation of organozinc iodides 28 from protected (3- and 7-amino acids (Scheme 26).73 The organozinc iodides prepared in this manner were neither sufficiently stable nor sufficiently reactive in THF, but excellent yields were obtained in more polar aprotic solvents, such as DMF and DMSO. 

Crucially, this allows organozinc reagents to be prepared from less reactive aryl bromides and secondary or tertiary alkyl bromides. Alternatively, organozinc iodides can be prepared by means of a palladium(0)-catalyzed reaction between alkyl iodides and Et2Zn (Scheme 2.25) [53-56]. 

The 500 MHz H-NMR of the primary organozinc iodides 44a and 44b have been reported . The methylenic protons a to the zinc atom occur as the AB part of an ABC spin system, indicating slow inversion rates. Applying equation 34 (see Appendix, Section IV.A) to the given chemical shifts and coupling constants, a lower limit for the free activation energy can be established as AG > 15 kcalmol" in DMF-rfv or THF-rfg at 25 °C. No further attempts to approach closer to the coalescence temperature were undertaken (equation 26). 

This observation is in agreement with the behavior of organozinc iodides (RZnl) but is in sharp contrast with what has been reported for BrZnCHaBr . Many soluble halomethylzinc complexes have been fully characterized in solution by H and NMR spectroscopies, and the characteristic chemical shifts are shown in Table 2. 

The addition to a, -unsaturated esters is usually difficult. However, under appropriate conditions, the 1,4-addition of diorganozincs to enoates is possiblc As mentioned above, Michael-addition reactions can also be catalyzed by Ni(II) salts . The 1,4-addition of functionalized organozinc iodides to enones in the presence of Ni(acac)2, a diamine as ligand and TMSCl provides, after hydrolysis, the Michael adducts in satisfactory yields . 

A more comprehensive study on the behavior of 5-acetylenic iodides in the presence of zinc was later reported21 and clearly revealed that when iodide 14 was treated with acid-washed zinc (pre-treated with Mel for activation and removal of traces of moisture) in a mixture of benzene and DMF, the acyclic organozinc iodide 21 and the cyclic vinyl iodide 22 were both produced. The amount of 22 increased significantly when the reaction mixture was sonicated rather than stirred or if a zinc-copper couple was used. The accumulation of compound 22 was consistent with its inability to be converted to an alkenyl organozinc species by reaction with metallic zinc under these conditions. However, no substantial cyclization of the open-chain organozinc 21 was observed. The formation of the five-membered ring compound 22 was attributed to a free-radical process... 

It was reported that the iodine-zinc exchange process induced by treatment of alkyl iodides with EbZn could be catalyzed by Cul, leading to shorter reaction times and reduction of the amount of Et2Zn38. The use of palladium or nickel catalysts turned out to be also extremely efficient but produced an organozinc iodide instead of a dialkylzinc, with evolution of ethane and ethylene34 (equation 20). 

Scheme 5.16 Ni-catalyzed carboxylation of organozinc iodide reagents under mild conditions [53].

However, for other palladium catalysed reactions of organozinc iodides with electrophiles, THF is a good choice of solvent. The incompatibility of THF and acid chlorides at ambient temperature can also be overcome, in some cases, by the use of a carbonylative cross-coupling in which an iodobenzene derivative is used as the precursor.17... 

The application of organozinc iodides prepared in THF is illustrated in Protocols 4 and 5, which describe the palladium catalysed cross-coupling of a serine-derived organozinc iodide with a vinyl iodide, and the palladium catalysed carbonylative cross-coupling of another serine-derived organozinc iodide with a functionalized aromatic iodide. In the reaction with the vinyl iodide, it is important to transfer the solution of the organozinc iodide from the residual zinc, since this can react unproductively with the electrophile. In the case of the carbonylative coupling with the functionalized aromatic iodide, such a transfer is unnecessary, since the zinc does not react with the electrophile under the reaction conditions. These two protocols also illustrate how to conduct such reactions on different scales. 

Preparation of a serine-derived organozinc iodide in THF, and coupling with methyl 3-iodopropenoate... 

Preparation of an aspartic acid-derived organozinc iodide in DMF, and its coupling with iodobenzene... 

Transfer the solution of the organozinc iodide to the second three-necked flask and cool to -78°C. Add the solution of trimethylsilylmethyllithium in pentane dropwise over 5 min and then stir for 1 h, slowly warming to -40 °C. 

Fig. 13.21. Representative mechanism of the Pd(0)-catalyzed arylation and alkenylation of organozinc iodides. Steps 1,2, and 4-6 correspond to steps that can also be found—in some cases with different numbers—in Figures 13.7 and 13.14. Step 3, which is new, represents a ligand exchange reaction of the aryl-Pd(II) complex.

Lithium halides (bromide or Iodide) may well modify the Lewis character of the zinc atom, probably via a zincate species [53], and prevent the efficient coordination of the zinc atom to the double bond, coordination which is required for the carbocyclization. Thus, in the Rieke method, it is essential to wash the active zinc thoroughly since the lithium naphthalenide reduction of zinc bromide also generates lithium bromide, which is detrimental to the success of the reaction. Indeed, the insertion of Rieke s zinc in the presence of LiBr leads to the linear organozinc iodide but not to the cyclic product [52]. 

Treatment of 6-iodo-l-heptene 52 with Rieke s zinc, in ether, leads quantitatively to the cyclized organozinc iodide in less than 20 min [55, 56], as shown by iodinolysis of the reaction mixture [57] (Scheme 7-46). 

Moreover, at lower temperature, a clean and rapid oxidative insertion of activated zinc metal into the carbon-iodine bond is observed and leads to the acyclic zinc derivative 53 in 95% yield, contamined by 5% of cyclized product. The formation of the linear organozinc iodide 53 and its subsequent cyclization by warming to room temperature can be taken as a hint of the absence of a one-electron transfer process in the cyclization [55]. These... 

Combining the possibility of carrying out the intramolecular carbozincation of secondary organozinc iodides with their tolerance to functional groups led the authors to consider the a-bromoalkyl acetate 57. Thus, the latter upon treatment with Zn in ether leads to 58 in moderate yields (the balance being the uncyclized material) but with a much better diastereomeric cis/trans ratio (86 14) than that obtained (58 42) via the strategy depicted in Scheme 7-39 [52] (Scheme 7-50). 

The high propensity of organozinc iodide to form a metallated cyclic product is due to the internal metal-double-bond interaction [40d, 50]. However, the diastereoselectivity is disappointing cis/trans, 1.4 1) (Scheme 7-40). This can be explained if one takes into account the chair-like transition state in which the acetoxy group occupies an unfavorable axial position due to an intramolecular chelation. 

For comparison purposes, the methyl-substituted analog was examined. Under the same experimental conditions, the cyclic organozinc iodide 50 was obtained and, after iodinolysis, the diastereomeric ratio (tmns/cis, 93 7) as well as the chemical yield (80%) was in good correlation with the carbolithiation reaction (see Scheme 7-38). This result indicates clearly that the stereocontrol is attributed to steric interactions where the methyl group now occupies a pseudo-equatorial position in the six-membered chair-like transition state [49] (Scheme 7-41). 

Although the direct iodine-to-Zn-exchange allows cyclizations of functionalized molecules, the iodine-to-organolithium and iodine-to-organozinc iodide exchanges were studied on the simple l-iodo-5-hexene, and the tremendous importance of the nature of the lithium halides present in solution was noticed. Indeed, as shown in Scheme 7-44, the cyclization that is somewhat similar to that of Scheme 7-41 does not operate any more, although performed in ether The only difference lies in the presence of Lil (foimed in the first step) and LiBr (formed in the transmetallation step). 

Far milder reaction conditions are possible if a transmetallation of the zinc organometallic (21) to the mixed c< >per-zinc derivative (22) is first performed and if the reaction is carried out in the presence of 2 equiv. of BFa-OEb. wide range of fimctional groups are tolerated in ctanpounds (21) and (22), and high yields are usually obtained (68-93% see Scheme 8), the reaction showing a good chemoselecdvity. The treatment of a 1 1 mixture of boizaldehyde and acetophenone with the organozinc iodide (23 2 h at... 

At the T used for these reactions, disproportionation of the first-formed products, RZnI, to R2Zn and Znij may result, but at lower T, e.g., 85-90°C with EtI and Zn dust, the organozinc iodides can be isolated". As R Zn compounds can inflame in air, an inert atmosphere, e.g., COj, should be provided. Dialkyl sulfates also react with.Zn metal with... 

---