Convenient method for preparing benzyl ethers and esters using 2-benzyloxypyridine

Convenient method for preparing benzyl ethers and esters using 2-benzyloxypyridine Susana S. Lopez and Gregory B. Dudley* Full Research Paper Address: Department of Chemistry and Biochemistry, Florida State University Tallahassee, FL 32306-4390 USA. Fax: (850) 644-8281 Email: Gregory B. Dudley* - * Corresponding author Open Access Beilstein Journal of Organic Chemistry 2008, 4, No. 44. doi:10.3762/bjoc.4.44 Received: 19 October 2008 Accepted: 25 November 2008 Published: 26 November 2008 © 2008 Lopez and Dudley; licensee Beilstein-Institut. License and terms: see end of document. Keywords: alcohols; alkylation; benzyl; electrophilic substitution; esters; ethers; protecting groups; reagent Abstract 2-Benzyloxy-1-methylpyridinium triflate (1) is emerging as a mild, convenient, and in some cases uniquely effective new reagent for the synthesis of benzyl ethers and esters. This article provides a revised benzyl transfer protocol in which N-methylation of 2-benzyloxypyridine delivers the active reagent in situ. Observations on the appropriate choice of solvent (toluene vs. trifluorotoluene) and the extension of this methodology to the synthesis of other arylmethyl ethers are included. Introduction As organic and medicinal chemists tackle synthetic targets of ever increasing complexity [1], the need for specialized reagents [2] and protecting groups [3,4] increases. Few protecting groups are as widely used as the benzyl (Bn) group, but protection of complex alcohol substrates as benzyl ethers is often frustrated by the need to employ basic or acidic conditions that may not be compatible with intricate systems. Reagents that can install protecting groups under neutral conditions find immediate use in chemical synthesis [5]. 2-Benzyloxy-1-methylpyridinium triflate (1, Figure 1) is one such reagent [6,7]. This neutral organic salt mirrors the reactivity of benzyl trichloroacetimidate [8-11], but it does not require acidic conditions for activation [12]. Benzyloxypyridinium 1 releases an electrophilic benzyl species upon warming; application to the synthesis of benzyl ethers from alcohols for which other protocols were unsuitable has been demonstrated independently (eq 1 [13] and 2 [14,15] in Scheme 1). N-Methylation of 2-benzyloxypyridine (2) furnishes crystalline 1, which is collected by filtration and may be stored for later use [16-18]. For routine and repeated use, isolation and storage of 1 is most convenient. Alternatively, in situ activation of 2 without isolation of the active salt presents certain advantages, such as described for the synthesis of PMB ethers [19]. Page 1 of 5 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2008, 4, No. 44. Results and Discussion 2-Benzyloxypyridine was prepared in 97% yield by heating a mixture of benzyl alcohol, 2-chloropyridine (1.1 equiv), and solid potassium hydroxide at reflux in toluene for 1 h (Scheme 2). This protocol differs slightly from those previously reported [16,21], which included 18-crown-6 (5 mol%); omission of 18-crown-6 simplifies the process. Figure 1: Benzyl bromide, benzyl trichloroacetimidate, and 2-benzyloxy-1-methylpyridinium triflate (1). Herein we report new reaction protocols that build on recent reports from this laboratory [6,7,16,20] and provide the following new observations: 1. Benzyl ethers can be prepared in good to excellent yield by in situ methylation of 2-benzyloxypyridine in the presence of alcohols and magnesium oxide. 2. This simple protocol extends to the synthesis of other arylmethyl ethers and esters. 3. Toluene is a suitable solvent for most applications, although trifluorotoluene is required in at least one case. 4. 2-Benzyloxypyridine is conveniently prepared, now without using 18-crown-6. 2-Benzyloxypyridine serves as a surrogate of (or replacement for) benzyl trichloroacetimidate: alkylation of 2-benzyloxypyridine with methyl triflate provides an active reagent similar to the species produced by protonation of benzyl trichloroacetimidate using triflic acid, except that alkylation under neutral conditions is compatible with acid- (and base-) sensitive substrates. Scheme 2: Preparation of 2-benzyloxypyridine (2). For the synthesis of benzyl ethers, a mixture of the alcohol substrate (3), 2-benzyloxypyridine (2), and magnesium oxide in toluene was cooled to 0 °C and treated with methyl triflate. The reaction mixture was allowed to warm to room temperature and then heated at 90 °C for 24 h. Table 1 summarizes the results from the benzylation of a representative group of functionalized alcohols under these new conditions (Method A), as well as results obtained under the previously reported conditions using pre-formed pyridinium salt 1 and trifluorotoluene as the solvent (Method B, entries 2, 4, and 6). Benzylations of monoglyme (3a) and Roche ester (3b) were accomplished with similar efficiency whether the active reagent 1 was formed in situ (entries 1 and 3) or isolated prior to use (entries 2 and 4). Glucose derivative 3c failed to react in toluene, but switching the solvent to trifluorotoluene restored reactivity (entry 5, 93%). Toluene is a cheaper and more common solvent than trifluorotoluene, but toluene has a lower dipole moment and also is subject to Friedel–Crafts benzylation under the reaction conditions [6,22]. Trifluorotoluene (also known as benzotrifluoride or BTF) is recommended as a “green” solvent alternative to dichloromethane [23]. Benzylation reactions of N-Boc-serine 3d (entry 7, 84%) and methyl Scheme 1: Published syntheses of benzyl esters from alcohols using neutral reagent 1; other benzylation procedures were not successful. Page 2 of 5 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2008, 4, No. 44. lactate (3e, 79%) verify compatibility with esters and carbamates. Note that the benzylation of N-Boc-serine methyl ester (3d) compares favourably to analogous reactions reported previously [24], because the neutral reaction conditions described herein are compatible with the acid-labile Boc group and the base-labile β-hydroxy ester. Minor modification of the above procedure renders it suitable for the formation of benzyl esters from carboxylic acids (Scheme 3). In order to avoid the potential for competing N-methylation of triethylamine, which is the optimal acid scavenger for the benzylation of carboxylic acids [20], methyl triflate was added to a toluene solution of Mosher’s acid 5 and 2-benzyloxypyridine (2) prior to addition of triethylamine. Heating the resulting mixture for 24 h furnished benzyl ester 6 in 98% yield. Neutral, isolable pyridinium triflate salts are suitable for the synthesis of halobenzyl ethers [25], which are emerging from Scheme 3: Synthesis of a benzyl ester from a carboxylic acid. their niche in natural products synthesis [26] because of their growing importance in carbohydrate chemistry [27-31]. The experiment outlined in Scheme 4 suggests that the observations (...truncated)