A Lewis acid-promoted Pinner reaction

A Lewis acid-promoted Pinner reaction Dominik Pfaff, Gregor Nemecek and Joachim Podlech* Full Research Paper Address: Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany Open Access Beilstein J. Org. Chem. 2013, 9, 1572–1577. doi:10.3762/bjoc.9.179 Email: Joachim Podlech* - Received: 23 May 2013 Accepted: 11 July 2013 Published: 02 August 2013 * Corresponding author Associate Editor: T. J. J. Müller Keywords: carbonitriles; carboxylic esters; Lewis acids; Pinner reaction; Ritter reaction © 2013 Pfaff et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract Carbonitriles and alcohols react in a Lewis acid-promoted Pinner reaction to carboxylic esters. Best results are obtained with two equivalents of trimethylsilyl triflate as Lewis acid. Good yields are achieved with primary alcohols and aliphatic or benzylic carbonitriles, but the straightforward synthesis of acrylates and benzoates starting with acrylonitrile and benzonitrile, respectively, is similarly possible. Phenols are not acylated under these reaction conditions. The method has been used for the first total synthesis of the natural product monaspilosin. In the reaction of benzyl alcohols variable amounts of amides are formed in a Ritter-type side reaction. Introduction In 1877 Pinner and Klein discovered the proton-induced imidate syntheses [1,2]. They passed anhydrous gaseous hydrogen chloride through a mixture of isobutyl alcohol and benzonitrile. A crystalline product precipitated, which they identified as an imidate hydrochloride (Scheme 1). Best results in the Pinner reaction are obtained with primary or secondary alcohols and aliphatic or aromatic nitriles. A plausible mechanism (Scheme 2) starts with a protonation of the nitrile by the strong acid hydrogen chloride leading to a highly activated nitrilium cation, which can be attacked by the alcohol component. Proton transfer (P.T.) yields the imidate hydrochloride [3]. Scheme 1: Imidate hydrochloride synthesis discovered by Pinner and Klein [1,2]. Various transformations are possible with the imidate hydrochlorides: Hydrolysis at low pH leads to carboxylic esters, where basic hydrolysis yields imidates. Reaction with amines furnishes amidinium compounds and the reaction with alcohols 1572 Beilstein J. Org. Chem. 2013, 9, 1572–1577. While developing a total synthesis of altenuic acid II [11], we observed the reaction of an aliphatic hydroxy group with acetonitrile in the presence of two equivalents of hafnium triflate [Hf(OTf)4] yielding the respective acetate. A detailed investigation on this reaction is reported in this article [12]. Results and Discussion Scheme 2: Mechanism of the Pinner reaction. gives rise to ortho esters. A less frequently used pyrolysis leads to carboxamides (Scheme 3) [3-5]. The Lewis acid-mediated Pinner reaction of aliphatic alcohols with nitriles was first observed by us, when hafnium triflate was present in the reaction mixture. We first aimed to replace this rather expensive Lewis acid with a more favorable substitute. As a test reaction for optimization we used the acylation of 9H-fluoren-9-ylmethanol (1) with acetonitrile as the nitrile component and solvent (Scheme 4). This substrate and the respective ester 2 are simply detected by thin-layer chromatography (TLC) and their molecular weights prevent losses during evaporation procedures. Scheme 4: Reaction used for optimizations. Scheme 3: Transformations of imidate hydrochlorides. The harsh reaction conditions preclude a broad application of the Pinner reaction. The high toxicity and the laborious handling of gaseous hydrogen chloride are further drawbacks of this reaction. Nevertheless, milder protocols have developed over the decades: Luo and Jeevanandam used trimethylsilyl chloride (TMSCl) and ethanol for an in situ generation of hydrogen chloride [6]. Watanabe et al. reported on a Pinner reaction with a 4 N hydrogen chloride solution in cyclopentyl methyl ether (CPME) [7]. An ionic liquid based on a sulfonic acid was used by Jiang et al. [8], where this method has only been applied to aliphatic nitriles. A transition metal-catalyzed Pinner reaction using dihydridotetrakis(triphenylphosphano)ruthenium ([RuH2(PPh3)4]) as catalyst has been applied to aliphatic nitriles and alcohols and was similarly used for intramolecular reactions [9]. Schaefer et al. reported a basecatalyzed Pinner reaction, which gave only poor yields because of the setting of an equilibrium [10]. A 72% yield was achieved, when two equivalents of hafnium(IV) triflate were used and when the nitrile was used as the solvent (Table 1, entry 1). Catalytic amounts of this Lewis acid led to unsatisfactory yields, when the reaction was performed in acetonitrile or in mixtures of acetonitrile with water (Table 1, entries 2 and 3). The 3% yield in acetonitrile/ water (10:1) suggests that water is detrimental in the Pinner reaction. Among various tested Lewis acids, the best results were obtained with aluminium tribromide at 50 °C (65%, Table 1, entry 5) and with trimethylsilyl triflate at room temperature (83%, Table 1, entry 7). The less expensive trimethylsilyl chloride turned out to be an unsuitable alternative (Table 1, entry 8). The yield could not be improved, when two equivalents of aluminium bromide were used together with catalytic amounts of hafnium triflate (Table 1, entry 6). Since two equivalents of a Lewis acid are necessary for optimum results, we presume activation of both the alcohol and the nitrile. A plausible mechanism includes formation of a silyl ether and an N-nitrilium cation. The former should be more nucleophilic than an alcohol and the latter should be an efficient electrophile (Scheme 5). Reaction of silyl ether and nitrilium cation leads to a cationic N,O-bis(trimethylsilyl)imino ester, which is hydrolyzed to a carboxylic ester. Formation of 1573 Beilstein J. Org. Chem. 2013, 9, 1572–1577. Table 1: Selection of optimization experiments. # Lewis acid (equiv) Conditions Yield (s. m.)a [%] 1 2 3 4 5 6 7 8 9 Hf(OTf)4 (2.0) Hf(OTf)4 (0.2) Hf(OTf)4 (0.2) AlBr3 (2.0) AlBr3 (2.0) AlBr3 (2.0), Hf(OTf)4 (0.1) TMSOTf (2.0) TMSCl (2.0) TMSOTf (2.0) MeCN, rt, 48 h MeCN, rt, 65 h MeCN/H2O 10:1, rt, 65 h MeCN, rt, 65 h MeCN, 50 °C, 90 h MeCN, rt, 65 h MeCN, rt, 65 h MeCN, rt, 65 h MeCN, Et3Nb, rt, 65 h 72 (15) 25 (69) 3 (81) 50 (39) 65 (20) 64 (24) 83 (9) 33 (59) 80 (10) aYields of recovered starting material (s. m.) given in parentheses. bEt N (1 equiv) was added. 3 herein reported Lewis acid promoted Pinner reaction furnished 52% of this substrate, where a less-sensitive substrate could be applied without the necessity of an inert atmosphere. The comparatively low yields in the reactions with benzonitrile are most probably caused by the lower electrophilicity of the benzonitrilium ion. The positive charge is significantly stabilized by the +M effect of the π sys (...truncated)