Phosphonium salts and aldehydes from the convenient, anhydrous reaction of aryl acetals and triphenylphosphine hydrobromide

The reactions of aryl acetals/ketals and triphenylphosphine hydrobromide gave the corresponding aldehydes/ketones and alkyl phosphonium bromides. This reaction was applied to convert acetals/ketals to the corresponding aldehydes/ketones under an anhydrous and convenient condition (50 ºC, 5 min, up to 90% yield), and acid sensitive functional groups were compatible.


Introduction
Preparation and removal of acetals/ketals are often encountered in organic synthesis since the two functionalities are the primary protecting groups for aldehydes and ketones. 1 The deprotection of acetals/ketals is usually achieved by acidic, aqueous hydrolysis. 1,2However, such conditions may cause problems for moisture-or acid-sensitive substrates.Several reagents, such as (trimethylsilyl)-bis(fluorosulfuryl)imide, 3 dimethyldioxirane (DMDO), 4 iodine, 5 trimethylsilyl triflate, 6 acetyl chloride/zinc chloride, 7 phosphorus triiodide, 8 and photocleavage, 9 have been developed to accomplish the deprotection under an anhydrous condition.We have found that the reaction of aryl acetals with the stable, non-hygroscopic, metal-free and commercially available salt, triphenylphosphine hydrobromide (PPh3•HBr) 10 , provides the corresponding aldehydes/ketones and phosphonium salts in good yields.This paper reports our work to develop this reaction as a convenient and selective anhydrous deprotection method for aryl acetals and ketals (Equation 1).

Results and Discussion
We previously reported that PPh3•HBr was able to cleave benzyl ethers, 11 which prompted us to apply this reagent to other functional groups.It was interesting to observe that aryl acetals/ketals were also susceptible to PPh3•HBr, but in a different reaction pathway.The reaction mixture of 2-phenyl-1,3-dioxolane (1) and PPh3•HBr, refluxed in dichloromethane for 3 h, provided the two products: benzaldehyde (68%) and (2-hydroxyethyl)triphenylphosphonium bromide (2, 73%), which were isolated and characterized.The spectroscopic data ( 1 H, 13 C, 31 P NMR) and mass analysis of this ionic product were consistent with those of (2hydroxyethyl)triphenylphosphonium bromide. 12The separation of the products could be easily achieved by adding diethyl ether to the concentrated product mixture, and the phosphonium salt precipitated.
To further improve the efficiency of this protocol, we applied microwave assisted heating and shortened the reaction time to 5 min at 50 ºC in a sealed tube.Alternatively, conventional heating using 1,2-dichloroethane (bp 83 ºC) also reduced the reaction time to 30 min.The results for the deprotection of some aryl acetals/ketals by PPh3•HBr were summarized in Table 1.The reaction of 2-methyl-2-phenyl-1,3-dioxolane (3) provided the same salt 2 and acetophenone, showing that this reaction pathway is general for both aryl acetals and ketals (entry 2).
The six-membered 2-phenyl-1,3-dioxane (4) generated (3-hydroxypropyl)triphenylphosphonium bromide (6, 13 84%, entry 3).The acyclic acetal 5 gave ethyltriphenylphosphonium bromide (7, 14 66%, entry 4), in addition to the benzaldehyde.Both electron donating (entries 5, 6 and 9) and withdrawing groups (entries 7, 8, 10 and 11) on the aromatic ring were acceptable for this reaction, although the substrates with the electron withdrawing nitro group gave the lower yields.The non-reducing nature of PPh3•HBr is beneficial for transformations involving the reducing agent sensitive compounds, such as those with nitro or bromo-substituents.2,6-Dichlorophenyl acetal 14 and naphthyl acetal 15 also underwent the reaction smoothly (entries 11 and 12).The anhydrous reaction conditions and water free work-up procedures are favorable for the acetals/ketals bearing acid and moisture sensitive functional groups (Equation 2, Table 2).We found that common protecting groups for hydroxyls, such as the silyl groups (TBDPS and TBS, entries 1-2) and the substituted methyl ethers (MOM and Bn, entries 3-4) remained intact under this protocol.In contrast to the aryl acetal, the aliphatic, 1,3-dioxolane moiety of 20a was also compatible with triphenylphosphine hydrobromide (entry 5).The results from the substrates 19a and 20a demonstrated that the aryl acetals are far more reactive to PPh3•HBr than the benzyl ether and the aliphatic acetal.This trend is consistent with the relative hydrolysis rate of aryl versus alkyl acetals, which suggests that the formation of the intermediate, oxocarbenium ion, is the rate determining step for both reactions (vide infra). 15) 4-Substituted dioxolanes 21 and 22 were prepared to further explore this reaction.16 In addition to benzaldehyde, (2-hydroxypropyl)-and (2-hydroxy-2-phenylethyl)triphenylphosphonium salts 23 17 and 24 18 (Equation 3) were produced.However, the other possible phosphonium salts, 25, with a primary hydroxyl group, were not observed (Scheme 1).These results indicated that triphenylphosphine only attacked the sterically less hindered primary carbon, rather than the secondary carbon or the sp 2 carbon, of the intermediate oxocarbenium ion. Th latter pathway was observed in the reactions of the less hindered triethylphosphine. 19 Ths unique property of PPh3•HBr could be applied to prepare the corresponding phosphonium salts, such as 23 and 24, directly from the aryl acetals/ketals, rather than the sequence of deprotection, bromination and the formation of phosphonium salt, as shown in the reported syntheses.20 (3) Scheme 1. Proposed reaction mechanism for the reactions of the aryl acetals and PPh3•HBr.

Conclusions
To our knowledge, the reaction of aryl acetals/ketals and triphenylphosphine hydrobromide was only briefly described. 19We developed this reaction as a convenient, deprotection method for aryl acetals/ketals and a direct preparation of the corresponding phosphonium salts.Its efficiency, mildness and anhydrous conditions could be useful for substrates with these concerns.The formation of the phosphonium salts is selective when the substituted dioxolanes are applied, and this process is different from that of triethylphosphine hydrobromide.
Standard procedure for the acetal deprotection.A solution of acetal (0.66 mmol), triphenylphosphine hydrobromide (0.73 mmol) in dry dichloromethane (0.5 mL) was placed in a reaction tube (10 mL, for microwave reaction).The tube was capped and heated to 50 ºC for 5 minutes in a microwave oven (CEM Discover).After cooling to room temperature, the reaction mixture was concentrated under vacuum.The alkyl phosphonium salts precipitated after adding diethyl ether, and the aldehyde was harvested after concentrating the filtrate.Alternatively, the separation of the two products could be achieved by flash column chromatography.