A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

Conditions enabling the single-step preparative synthesis of chiral 4-fluoropolyhydro-2H-chromenes in good yields through a reaction between monoterpenoid alcohols with para-menthane skeleton and aldehydes were developed for the first time. The BF3·Et2O/ H2O system is used both as a catalyst and as a fluorine source. The reaction can involve aliphatic aldehydes as well as aromatic aldehydes containing various acceptor and donor substituents. 4-Hydroxyhexahydro-2H-chromenes were demonstrated to be capable of converting to 4-fluorohexahydro-2H-chromenes under the developed conditions, the reaction occurs with inversion of configuration. Introduction Recently, we have found that a reaction between para-mentha6,8-dien-2,3-diol (1) and aromatic aldehydes in the presence of K10 montmorillonite clay forms chiral heterocyclic compounds with the hexahydro-2H-chromene scaffold 2 (Scheme 1) [1-4]. Products of these reactions are of interest as many of them exhibit a significant analgesic activity in vivo [2-4]. In terms of structure–activity relationship studies of hexahydro2H-chromenes and similar compounds it is important to replace the hydroxy group at the C(5) position by another functional group. Thus, the approaches for synthesis of thio[5] and Scheme 1: Reaction between monoterpenoid 1 and aromatic aldehydes in the presence of K10 montmorillonite clay. Beilstein J. Org. Chem. 2016, 12, 648–653. 649 Scheme 2: The Prins reaction between homoallylic alcohols and aldehydes. nitrogen [6] containing analogous with reasonable yields (50−80%) by using a third component (corresponding thiols or acetonitrile) were elaborated. Of particular interest is the introduction of a fluorine atom into the molecule of the biologically active compound. The introduction of a highly electronegative centre can lead to an increase in stability and changes in lipophilicity. Furthermore, it alters the patterns of reactivity of the C–F versus the C–H or the C–OH bond [7-9]. As a result it can have a significant impact on the biological activity of a compound. To create halogenated tetrahydropyranyl rings the Prins reactions between homoallylic alcohols and aldehydes catalyzed by appropriate halogen-containing Lewis acids or ionic liquids are usually used (Scheme 2) [10-16]. However, only a few examples of reactions for introducing a fluorine atom via the haloPrins cyclization have been reported to date [15-21]. In these reactions, BF3·Et2O acts both as a catalyst and as a fluorine source. At the same time, as a rule, reactions in the presence of BF3·Et2O involved relatively simple homoallylic alcohols, such as but-3-en-1-ol (3) and its analogues, as substrates (Scheme 2). If more complex substrates, such as isopulegol (4) or geraniol (5), were involved in transformations, the formation of nonfluorinated heterocyclic products was observed (Scheme 2) [22,23]. The aim of the present study was to find conditions for the synthesis of fluorinated chiral hexahydrochromenes based on monoterpenoids. Results and Discussion The interaction of para-mentha-6,8-dien-2,3-diol (1) with 3,4,5trimethoxybenzaldehyde (6a) in the presence of BF3·Et2O was chosen as a model reaction. The study was started with the investigation of the effect of the reaction conditions and the reactant ratio on the yield of a fluorinated product (Table 1). The addition of an equimolar amount of BF3·Et2O to a mixture of monoterpenoid 1 and aldehyde 6a at room temperature (Table 1, entry 1) resulted, after 1 h, in the formation of a reaction mixture containing compounds 2a and 7a as the major low molecular weight products and only minor amounts of target compound 8a. It is important that the reaction is accompanied by a significant resinification. The addition of water to the initial reactants enabled the reduction of the amount of undesirable products 2a and 7a and had a minor effect on the amount of compound 8a. This indicates a significant contribution of side processes that are likely related to the formation of high molecular weight products. Lowering the reaction temperature to 2 °C made it possible to reduce a contribution of resinification processes that led to an increase in the amount of product 8a to 31%, but with incomplete conversion of monoterpenoid 1. When the reaction time was increased to 8 h, the conversion increased, but was still not quantitative. The complete conversion of compound 1 was achieved by using a 1.5-fold excess of BF3·Et2O, and the use of a slight excess of aldehyde led to a marked increase in the amount of fluorinated Beilstein J. Org. Chem. 2016, 12, 648–653. 650 Table 1: The variation of reaction conditions. Entry Reagent ratio 1:6:BF3·Et2O:H2O Temp (°C) Time (h) Conv. 1 (%) Yield (%)a