PAPER 309 Deacylation of Esters, Thioesters and Amides by a Naphthalene-Catalysed Lithiation Naphthalene-Catalysed Lithiation Cherif Behloul, David Guijarro, Miguel Yus* Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain Fax +34(96)5903549; E-mail: yus@ua.es Received 18 July 2005 Dedicated to Professor Günther Wilke on the occasion of his 80 th birthday SYNTHESIS 2006, No. 2, pp 0309–0314xx.xx.2005 Advanced online publication: 21.12.2005 DOI: 10.1055/s-2005-918501; Art ID: Z14205SS © Georg Thieme Verlag Stuttgart · New York Abstract: The reaction of different esters, thioesters and amides de- rived from pivalic, benzoic and 4-tert-butylbenzoic acids with an excess of lithium and a catalytic amount of naphthalene (8 mol%) led, after methanolysis, to the corresponding alcohols, thiols and amines, respectively, through a reductive non-hydrolytic procedure. This methodology represents a reasonable alternative to other non- reductive protocols. Key words: esters, thioesters, amides, deacylation, lithium Acyl derivatives of alcohols, thiols and amines (esters, thioesters and amides, respectively) are very often used to protect those functional groups, because they fit the gen- eral requirements for that purpose: (a) easy preparation by standard acylation methods, and (b) relative easy depro- tection under different conditions to liberate again the corresponding deacylated compound. 1 Concerning hydrolysis under basic conditions (nucleophilic cleavage) the reactivity follows the series: thioesters > esters > amides, the latter being rather resistant to this process. Other methodologies for acyl removal involve acidic hy- drolysis, 2 b-elimination processes (for instance, for fluo- renylmethoxycarbonyl derivatives), 3 reduction with dissolving metals, 4 hydride sources 5 or electrolysis, 6 and enzymatic methods. 7 On the other hand, in the last few years we have been us- ing an arene-catalysed lithiation to perform metallations under very mild reaction conditions. 8–10 Among other uses, 11 this methodology has been shown to be applicable to the cleavage of trityl ethers 12 and amines, 13 for the de- silylation of silylated alcohols, amines and thiols, 14 as well as for the deprotection of allyloxy- or benzyloxycar- bonyl-protected alcohols, amines and thiols. 15 In this pa- per we wish to report on the use of a naphthalene- catalysed lithiation to perform the deacylation of repre- sentative esters, thioesters and amides under very mild non-hydrolytic conditions. The reaction of different alkyl or aryl pivalates 1a–e with an excess of lithium (1:9 molar ratio) and a catalytic amount of naphthalene (1:0.16 molar ratio) in THF at 0 °C for two to four hours led, after quenching with methanol, to the corresponding alcohols 2a–d and phenol 2e (Equation 1 and Table 1, entries 1–5). The same process can also be applied to a dipivalate like compound 1f, which under the same reaction conditions afforded after one hour the expected diol 2f in almost quantitative yield (Table 1, entry 6). Very good results were obtained for ar- omatic esters, such as benzoates 1g and 1h and the corre- sponding 4-tert-butyl derivative 1i, which gave alcohols 2a or 2d in almost quantitative yield (Table 1, entries 7– 9). Equation 1 When pivalic or benzoic acid derived thioesters 1j–l were treated using the same protocol, the expected thiols 2j and 2k were obtained in variable yields (Equation 1 and Table 1, entries 10–12). Finally, both pivalamides 1m–p and the benzamide 1q under the aforementioned reductive deprotection conditions furnished deacylated amines 2m– p, generally in good yields (Equation 1 and Table 1, en- tries 13–17). The reductive removal of the pivaloyl group of N-octylpivalamide was also attempted following the same procedure previously used by us in the deprotection of tritylated primary amines, 13 (deprotonation with n-bu- tyllithium and treatment with trimethylsilyl chloride be- fore performing the lithiation step) however, the reaction failed in this case, the starting amide being quantitatively recovered. In general, the deprotection of pivaloyl bearing substrates gave the expected products in good yields, except those in which the R substituent was cyclohexyl (Table 1, entries 4 and 11) or a sterically hindered group, like a tertiary alkyl (Table 1, entry 3) or an aryl group substituted at both ortho positions (Table 1, entry 5). The application of the methodology to the functionalised amide 1o gave only a moderate yield (Table 1, entry 15), probably due to the participation of the generated lithium amide as a base in b-elimination processes. All substrates bearing a benzoyl (1g, 1h, 1l and 1q) or a 4- tert-butylbenzoyl group (1i) gave excellent yields of the debenzoylated products, being in some cases higher than the obtained with the corresponding pivaloyl derivatives (compare entry 4 with 8 and entry 10 with 12). i) Li, C 10 H 8 (8 mol%), THF, 0 °C ii) MeOH, 0–20 °C 1 2 R YH RY R' O