Silyl formates as hydrosilane surrogates for the transfer hydrosilylation of ketones

A transfer hydrosilylation of ketones employing silyl formates as hydrosilane surrogates under mild conditions is presented. A total of 24 examples of ketones have been successfully converted to their corresponding silyl ethers with 61–99% yields in the presence of a PNHP-based ruthenium catalyst and silyl formate reagent. The crucial role of the ligand for the transformation is demonstrated.


Introduction
Catalytic hydrosilylation is a convenient method to reduce carbonyl compounds, providing access to alcohols via silyl ether intermediates. [1] The latter are also an important class of protecting groups for alcohols. Their direct synthesis from the corresponding ketone is hence valuable. Transfer hydrosilylation has emerged as an alternative process for this transformation, [2] avoiding the use of difficult to handle hydrosilanes, such as the gaseous Me3SiH. This concept was pioneered by Studer [3] and Oestreich, [4] who independently reported the use of silicon-substituted cyclohexa-1,4-dienes through radical and ionic processes, respectively (Scheme 1A). However, the production of quantitative arene derivatives as byproducts remains as a significant drawback for these reagents.
We have reported an atom economic alternative using silyl formates as renewable liquid surrogates of hydrosilanes, whose only byproduct is gaseous CO2. [5] The recyclability of these reagents is ensured since they are synthesized in excellent yields from formic acid, a reagent readily available from biomass [6] or carbon dioxide. [7] Silylformates were initially employed as hydrosilane surrogates in alcohol silylation with iron [8] or ruthenium-based catalysts. [9] Transfer hydrosilylation of aldehydes was successfully developed using the Ru-Triphos catalyst 1 (Scheme 1B). [5] During these transformations, the metal-mediated silyl formate decarboxylation generates a metal hydride species that will provide a metal-alcoxy intermediate upon reaction with the substrate. Final silylation step provides the desired product, closing the catalytic cycle. Interestingly, we could show that silyl hydride species are never formed along this process. Unfortunately, these protocols were ineffective towards the reduction of ketones. In this case, it seems that the steric hindrance around the metal alkoxide intermediate hampers the final silylation step. [5] In order to increase the nucleophilicity of the oxygen atom, we envisioned the possibility of weakening the ruthenium-alkoxide interaction through the action of a cooperative ligand, able to develop H-bonds. We chose the PN H P-Ruthenium catalyst 2, that bears a well-known ligand for its participation in metal catalyzed reactions through his N-H bond. [10] Major contributions on complexes bearing PN H P ligands were achieved by Milstein, [11] Beller, [10b,12] Gusev, [13] and Kuriyama. [14] These species were successfully applied to the reduction of challenging substrates such as esters or amides. [10b,14,15] However, beyond hydrogenation, the use of participative PN H P ligandbased catalysts in hydrosilylation is scarce, [16] and, to the best of our knowledge, it was never reported in transfer hydrosilylation reactions.

Results
To test our hypothesis, acetophenone (3a) was submitted for reaction with triethylsilyl formate (5a) and Ru-Triphos catalyst 1 in acetonitrile at 90 ºC, classical conditions for the transfer hydrosilylation of aldehydes. Under these conditions, no conversion was observed (Table 1, entry 1). Changing catalyst 1 by the Ru-PN H P catalyst 2 provided silyl ether 4a in 78% yield (Table 1, entry 2). While substituting CD3CN with d2dichloromethane completely suppress the reactivity (Table 1, entry 3), the use of d8-THF, d8-toluene or d6-benzene increased the yields to 99%, 92% and 99%, respectively (Table 1, entries 4-6). Among them, we finally selected d6-benzene due to a lower reaction time (1.5 h). Reducing the catalyst loading from 3 mol% to 1.5 mol% results in a drop of yield to 79% ( The influence of the silicon coordination sphere on the reactivity was tested by reaction of acetophenone (3a) with different silylformates 5a-g under the optimized conditions (Scheme 2).
The reaction worked efficiently with triethyl-, trimethyl-or dimethylphenylsilyl formates (5a-c) and acetophenone (3a), giving compounds 4a-4ac with yields above 93%. It is worthy to highlight that the possibility to use trimethylsilyl formate (5b) represents a major synthetic advantage on the use of these surrogates, because its parent hydrosilane Me3SiH is gaseous. The increase of the bulkiness on the substituents around the silicon core, implied a decrease on the yield for the transformation. While methyldiphenylsilylated alcohol 4ad was still obtained in 71% yield, tertbutyldimethylsilyl or triisopropylsilyl formates (5e and 5f) completely supressed the reduction of the ketone. Finally, the use of the more acidic triethoxysilyl formate (5g) led to a significant drop of yield providing the silylated alcohol 4ag in 38% yield. This trend highlights the importance of the steric and electronic parameters of the silyl moiety on the outcome of the reaction.
Under the optimized conditions, a number of ketones were tested for transfer hydrosilylation with triethylsilyl or trimethylsilyl formates (5a and 5b) as hydrosilanes surrogates (Scheme 3). Several substituted acetophenones were successfully hydrosilylated in short reaction times. Electron-donating substituents (4b-c) or electron-withdrawing groups (4d-h) were well tolerated with yields above 82%. Remarkably, on the last group of compounds, 4-iodoacetophenone (3e) reacted without any loss of the iodine core. With more challenging ortho substituted acetophenones, 4i and 4j were obtained in 88% and 99% yield, respectively. Elongating the alkyl chain (4k) did not affect the reactivity. However, when phenyl isopropyl ketone (3l) was submitted to the reaction, the yield of hydrosilylated alcohol 4la dropped to 33% due to the higher steric hindrance present in the molecule. Hydrosilylation of this type of substrates could be carried out with higher yield if the less hindered trimethylsilyl formate (5b) was used, providing 4lb in 75% yield. This proves the importance of the steric hindrance for this transformation. Benzophenone derivatives 3n and 3o were also hydrosilylated in 79% and 99% yield, respectively. In these cases, to perform the transformation within a reasonable reaction time, the amount of silylformate reagent was increased to two equivalents. Another proof for the importance of the steric hindrance in this transformation was obtained with 4,4'-dimethylbenzophenone (3p). In this case, the reaction with triethylsilyl formate (5a) gave silyl ether 4pa in 89% yield, but required a longer reaction time (42 h). Reducing the bulkiness on the reagent by using trimethylsilyl formate (5b) afforded 4pb with a comparable yield of 76% with a significantly reduced reaction time (13 h). More challenging substrates, such as α,β-unsaturated ketones 3q-s, [17] were successfully hydrosilylated with a 1,2-selectivity in 61-81% yields. Among them, compound 4r was obtained in only 61% yield due to the formation of the conjugated enolether byproduct. Heteroaromatic silylated alcohols 4t and 4u were obtained in 81% and 93%, respectively. Finally, dialkyl ketones 3v and 3w could also react under these conditions giving 95% yield of the hydrosilylated products in both cases. The selectivity between ketones and aldehydes was studied in the transfer hydrosilylation of 4-acetylbenzaldehyde (3x) with only one equivalent of silyl formate 5a. Not surprisingly, the aldehyde group was fully hydrosilylated after 2 h of reaction, while the ketone moiety remained intact (Scheme 4A).
To verify the origin of the hydride, deuterated silyl formate 5a-d1 was synthesized and submitted to reaction. Deuterosilylated product 4a-d1 was obtained as the only product, confirming that the hydride source is indeed the formate group (Scheme 4B). To evaluate the importance of the role of the N-H bond present in the PN H P ligand on catalyst 2, an analogous complex, where the N-H bond is methylated (2-Me), was synthesized. While catalyst 2 was able to reduce acetophenone (3a) and benzaldehyde (6), the parent 2-Me catalyst could reduce aldehyde 6 but not ketone 3a (Table 2). This observation is consistent with the requirement of the N-H motif for the reduction of ketones. Based on these observations, a putative mechanism for this transformation is illustrated in Scheme 5. An initial reaction of catalyst 2 with silyl formate 5 generates the active catalyst ruthenium formate A, which through decarboxylation leads to the ruthenium hydride species B, [18] whose presence was confirmed by NMR analysis (see supporting information, Figures S8 and S9). Interaction of ketone 3 with the rutheniumhydride complex B results in its reduction, presumably assisted by a hydrogen bond formed between the carbonyl group and the ligand PN H P (C) [19] . The same type of interaction in the generated intermediate D favours the attack of the alkoxyde to the silicon center of a new molecule of silyl formate 5, generating the final hydrosilylated product 4, regenerating the active catalyst species A, and closing the catalytic cycle.

Scheme 5.
Putative mechanism for the transfer hydrosilylation of ketones with silyl formates.

Conclusion
In summary, we have unlocked the possibility of using silyl formates in the transfer hydrosilylation of ketones by selecting a suitable PN H P-based ruthenium catalyst 2. In addition, as shown in the control experiments, evidence of the crucial role of the N-H bond in the catalyst ligand was provided. This transformation opens the possibility of applying silyl formates as hydrosilanes surrogates to reduce the more challenging ketones.