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the coordination of Zn(C6F5)2 to the substrate to facilitate the
arylation process.6 By-product PhZnOMe reacts in turn with
Zn(C6F5)2 to form (C6F5)ZnOMe (the ultimate by-product of the
reaction, Scheme 1a and b), along with the regeneration of 0.5
equivalents of ZnPh2 and Zn(C6F5)2, resulting from the redis-
tribution of PhZn(C6F5) (Scheme 1b).6,12 The regenerated ZnPh2
can react further with N,O-acetal, whilst the unreacted 0.5
equivalents of Zn(C6F5)2 enable the continued recycling of
PhZnOMe that is formed in the reaction. In this regard almost
identical 19F NMR spectra are obtained when combining iso-
lated [PhZnOMe]4 (4) with Zn(C6F5)2 (0.25 : 1 ratio), or a mixture
of isolated [(C6F5)ZnOMe]4 (6), ZnPh2 and Zn(C6F5)2 (0.25 :
0.5 : 0.5 ratio) (Fig. S8, ESI†).
Fig. 2 Molecular structures of (a) [{PhCH(NC5H10)2}Zn(C6F5)2] (7) and
(b) [(C6F5)ZnOMe]4, (8). Thermal ellipsoids shown at 30% probability.
Hydrogen atoms and solvent molecules of crystallisation omitted for clarity.
The participation of Zn(C6F5)2 enables the use of 50 mol% of
ZnPh2, which can be particularly useful when employing more
N,N0-aminal coordinates to the Zn centre in a chelating fashion complex aryl scaffolds on zinc, as only limiting amounts are
via its two N atoms (Fig. 2a). Interestingly, 7 is significantly required to achieve high yields, in contrast to other methods
more robust that I in solution and it does not undergo arylation where an excess of the organozinc reagent is typically needed.8
with ZnPh2 even under forcing refluxing conditions. This can
We also found that when 1a is reacted with 0.5 equiv. ZnEt2
be attributed to the greater strength of the C–N bonds in the no alkylation is observed, whereas introducing Zn(C6F5)2
N,N0-aminal versus the C–O bond in 1f.10 Related to these (0.5 equiv.) furnishes 3q in a 76% yield (Scheme 1c). This can
findings it can be hypothesised that the coordination of N,O- be attributed to the reduced Lewis acidity of ZnEt2 (in compar-
acetal to the Lewis acid would increase the electrophilicity of ison to ZnPh2), so on its own it cannot activate 1a towards C–O
the substrate and enable the less nucleophilic PhZnOMe inter- bond cleavage, requiring the initial formation of coordination
mediate to transfer its remaining Ph group. However, no other adduct akin to I (Scheme 1a) which can then react with ZnEt2.
Lewis acids appeared to promote the reaction and 50 mol% of
Having gained some mechanistic insights, we then went on
Zn(C6F5)2 is needed, implying that its role is not catalytic in to explore the scope of the reaction (Fig. 3). Diarylmethanamine
nature. Instead, we observed that Zn(C6F5)2 reacts directly with products (3b–3g) were realised in high isolated yields (84–92%)
the PhZnOMe by-product to regenerate the more nucleophilic using a range of diarylzinc reagents (2b–g) furnished with
diarylzinc reagent together with the formation of (C6F5)ZnOMe electron-donating or electron-withdrawing groups, ortho-
(Scheme 1a and b). This would justify the necessity for requir- substituents and even heteroaryls. For the synthesis of 3d and
ing 50 mol% Zn(C6F5)2 to enable complete transfer of both aryl 3g, the reaction was performed at 90 1C due to the poor
groups from the zinc reagent. Similarly to 4, treating a toluene solubility of the ZnAr2 species in toluene. In all cases, although
solution of freshly sublimed Zn(C6F5)2 with equimolar MeOH the reactions were complete within 1 hour, it was critical that
yields the tetrameric species [(C6F5)ZnOMe]4 (8) (Fig. 2b). Inter- the diarylzinc reagents were free of residual Et2O to enable the
estingly, the 1H and 19F NMR signals for 8 appear to differ transformation. Next, the scope of the N,O-acetals was probed
slightly when compared to in situ ‘(C6F5)ZnOMe’, prepared from (Fig. 3). The reaction was successfully carried out with a variety
isolated [PhZnOMe]4 (4) with regeneration of the nucleophilic of substrates bearing different functional groups in the aro-
diarylzinc reagent (Fig. S4–S5, ESI†). We attribute these differ- matic ring. Product yields and reaction times remained con-
ences to the formation of different aggregates and/or solvates in sistent in the case of both electron-donating and electron-
solution, but the possibility of heteroleptic/mixed aryl zinc withdrawing groups. Compounds 3b, 3c and 3e could be
alkoxides cannot be fully discarded. However, on spiking each prepared in similar yields when compared to varying the ZnAr2
of the three (C6F5)ZnOMe solutions with THF, almost identical reagent, offering a second route to mixed-diarylmethanamine
19F NMR spectra were obtained, consistent with the hypothesis species. Additionally, products 3k and 3l, containing sensitive
that different aggregates/solvates coexist (Fig. S6, ESI†). cyano and nitro-functional groups, could be obtained in good
Furthermore, ZnPh2 (now as the THF adduct) can be identified yields (81% and 58% respectively) with no significant signs of
1
by H NMR spectroscopy (Fig. S7, ESI†), illustrating the ability substrate decomposition or side-products. N,O-acetals prepared
of Zn(C6F5)2 to regenerate the more nucleophilic diarylzinc from amines other than piperidine also reacted smoothly with
reagent. Overall, we propose that Zn(C6F5)2 first coordinates ZnPh2 under the optimised conditions. Compound 3m, derived
to the N,O-acetal 1, forming adduct I, activating the substrate from morpholine, was obtained in 86% yield, while compound
towards arylation by nucleophilic ZnPh2 to give the corres- 3n containing N-methylpiperazine, was isolated in 72% yield.
ponding diarylmethanamine 3 and PhZnOMe (Scheme 1a and Compound 3n is commonly known as Cyclizine, and is a widely
b). This step may occur via the in situ formation of an iminium employed anticholinergic drug, which highlights the potential
intermediate or in a concerted manner.5,11 The marked solvent of the reaction to access relevant bioactive molecules. The
effect observed in these transformations, with Lewis donor THF reaction could also be performed with the acyclic N,O-acetal,
completely inhibiting formation of 3, supports the key role of resulting in product 3o in 76% yield. Finally, the reaction was
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Chem. Commun.