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In order to understand the chemoselectivity of the different zinc reagents towards aryl halides, bearing acidic OH protons, we next examined their relative reactivity towards and also their stability in the presence of relatively acidic hydrogens. To evaluate the relative reactity of various types of organozinc compounds, we have treated an equimolar mixture of PhZnI·LiCl (73a), OctZnBr·LiCl (74a) and PhCH2ZnCl·LiCl (75a) with various amounts of iPrOH (Scheme 37).Interestingly, we have observed that a chemoselective protonation occurs. Thus, after the addition of one equivalent of iPrOH at –10 °C, 80 % of PhZnI·LiCl (73a) and 20 % of OctZnBr·LiCl (74a) were protonated, whereas almost no protonation of PhCH2ZnCl·LiCl (75a) was observed. After the addition of the second equivalent of iPrOH, the protonation of more than 97 % of PhZnI·LiCl (73a) and 90 % of OctZnBr·LiCl (74a) was observed. These results indicate the relative reactivity of zinc reagents towards acidic hydrogens: arylzinc halide > alkylzinc halide > benzylzinc halide.98

98 _{For the reactivity of 1,1-bimetallic species towards protonation see also: P. Knochel, J. F. Normant,} Tetrahedron Lett.1986, 27, 1043

Table 17. Selective protonation of organozinc reagents.

PhZnI·LiCl PhCH₂ZnCl·LiCl OctZnBr·LiCl

73a 75a 74a 0-2 equiv

PhCH2-H Ph-H + + -10 °C Oct-H + + iPrOH

Yield of active zinc reagent [%]a

Amount of

iPrOH added _{PhZnI·LiCl (73a) OctZnBr·LiCl (74a) PhCH2ZnCl·LiCl (75a)}

0 100 100 100

1 20 80 > 97

2 < 3 10 85

a _{Yields are determined by quenching with CuCN/allyl bromide in THF and GC-analysis using tetradecane as} internal standard.

In order to investigate the stability of organozinc compounds in the presence of acidic protons, these organometallics were treated with an equimolar amount of an amine or an alcohol (for aniline see Figure 5). Thus, N-butylamine was added to a solution of PhZnI·LiCl (73a), OctZnBr·LiCl (74a) or PhCH2ZnCl·LiCl (75a) in THF (0.4 M, Figure 6). In the case of this comparatively weak acid, all three zinc reagents are quite unreactive. After 24 h only 25 % of PhZnI·LiCl (73a) are protonated. The less basic alkylzinc bromide 74a led to only 8 % of protonation and almost no protonation of benzylzinc chloride (75a) occurred (98 % of active zinc reagent). These stabilities are in accordance with the results obtained in the cross-coupling reactions with primary and secondary amines (Table 1, entries 16-20), where long reaction times still led to full conversion of the aryl bromides prior to the protonation of the zinc reagents.

The same experiment with iPrOH as proton source led to a rapid protonation of all three organozinc compounds (Figure 7). PhZnI·LiCl (73a) was protonated immediately (0 % of active zinc reagent after 30 s) and 73 % of OctZnBr·LiCl (74a) was protonated after 5 min PhCH2ZnCl·LiCl (75a) was slightly more stable and after 15 min still 55 % of the active zinc reagent was detected. These results can explain the quite different reactivity of the three zinc reagents with various aryl halides, bearing acidic OH functions (Table 13). The strongly basic arylzinc reagents can only be coupled with sterically hindered alcohols and better yields can be obtained with more reactive aryl iodides, whereas alkylzinc bromides also tolerate less hindered alcohol functions. The least basic benzylic zinc reagents even tolerate more acidic phenolic protons. Using phenol as proton source led to an instant hydrolysis of phenylzinc iodide (73a) and octylzinc bromide (74a, 0 % of the active zinc reagent was observed after

30 s). Although ca. 70 % of PhCH2ZnCl·LiCl (75a) were protonated with phenol after 30 s, the stability seems to be sufficient to undergo cross-coupling reaction prior to the capture of a proton, if the concentration of the reactive palladium species is high enough to react with the benzylic zinc compound.

R-ZnX·LiCl R-H BuNH2 (1.0 equiv) THF, 25 °C 40 50 60 70 80 90 100 0 5 10 15 20 time [h]

yield of active zinc reagent [%]

a

BnZnCl OctZnBr PhZnI

Figure 6. Stability of organozinc reagents towards butylamine.a _{Yields are determined by quenching with} CuCN/allyl bromide in THF and GC-analysis using tetradecane as internal standard.

R-ZnX·LiCl R-H iPrOH (1.0 equiv) THF, 25 °C 0 20 40 60 80 100 0 10 20 30 40 50 60 time [min]

yield of active zinc reagent [%]

a

BnZnCl OctZnBr PhZnI

Figure 7. Stability of organozinc reagents towards iPrOH.a _{Yields are determined by quenching with CuCN/allyl} bromide in THF and GC-analysis using tetradecane as internal standard.

R-ZnX O NH2 Ph R-H (1.0 equiv) THF, 25 °C 0 20 40 60 80 100 0 10 20 30 40 50 60 time [min]

yield of active zinc reagent [%

]

a

BnZnCl OctZnBr PhZnI

Figure 8. Stability of organozinc reagents towards benzamide. a _{Yields are determined by quenching with} CuCN/allyl bromide in THF and GC-analysis using tetradecane as internal standard.

R-ZnX O N H Ph Bn R-H (1.0 equiv) THF, 25 °C 0 20 40 60 80 100 0 10 20 30 40 50 60 time [min]

yield of active zinc reagent [%

]

a

BnZnCl OctZnBr PhZni

Figure 9. Stability of organozinc reagents towards N-benzyl-benzamide. a _{Yields are determined by quenching} with CuCN/allyl bromide in THF and GC-analysis using tetradecane as internal standard.

Finally, similar experiments were conducted with a pimary and a secondary amide (Figure 8 and 9). Thus, a 0.4 M solution of OctZnBr (74a) is completlely protonated within 25 min at 25 °C when treated with 1 equivalent of benzamide (Figure 8). From the duration

for 50 % conversion of the zinc reagent (< 1 min for PhZnI, 2.5 min for OctZnBr and 20 min for BnZnCl) one can derive approximate structure reactivity relationships. For secondary amides, the protonation rate is somewhat lower, but 50 % of the zinc reagent are protonated within 30 min (for PhZnI), 60 min (for OctZnBr) and 2.5 h (for BnZnCl, Figure 9).

These results indicate the same relative reactivity: arylzinc halide > alkylzinc halide >

benzylzinc halide. The reason for this different relative basicity of organozinc reagents compared to those of carbanions or organolithium compounds (alkyl > aryl > benzyl)99 may result from different aggregation of zinc and lithium reagents.