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.

In terms of structure-activity relationship studies of hexahydro-2H-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 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][8][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][11][12][13][14][15][16]. However, only a few examples of reactions for introducing a fluorine atom via the halo-Prins cyclization have been reported to date [15][16][17][18][19][20][21]. In these reactions, BF 3 ·Et 2 O acts both as a catalyst and as a fluorine source. At the same time, as a rule, reactions in the presence of BF 3 ·Et 2 O 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.
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 BF 3 ·Et 2 O 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 BF 3 ·Et 2 O, and the use of a slight excess of aldehyde led to a marked increase in the amount of fluorinated a The yields of products obtained from the GC-MS chromatograms using the standard (2,5-hexanediol) and the correction factors. b Olefin 7a is a mixture of double bond position isomers, and amount of 7a shown in the table corresponds to the total yield of the olefin isomers. The structure of 7a shown on the scheme is the major olefin isomer.
Preparative production under the chosen conditions provided 72% of 8a by GC-MS and after separation by column chromatography the target fluorinated product 8a was isolated in 69% yield; the yield of compound 2a was 7% (Table 2). Thus, we found for the first time the conditions enabling production of chiral fluoro-containing heterocyclic compounds from a monoterpenoid using the halo-Prins cyclisation.
It should also be noted that preparative isolation of compounds of type 7a is complicated by the presence of their double bond position isomers in the reaction mixtures. In this study, we did not seek to isolate the individual byproducts.
Compounds 2a and 8a produced by a reaction of diol 1 with aldehyde 6a are formed as a mixture of diastereomers differing in the position of substituents at the C(5) carbon. The (S)isomer predominates in the case of compound 2a, while the (R)isomer is the major one in the case of compound 8a ( Table 2). The ratio of the major and minor diastereomeric products of types 2 and 8 was determined from 1 H NMR spectra by integration of the Ha-3 signal ( Table 2). The methyl group at the C(5) carbon atom is axial in the (S)-isomers and equatorial in the (R)isomers. Consequently, in the (R)-isomers the axial OH or F group causes a paramagnetic shift to a weak field of the Ha-3 signal due to the 1,3-diaxial interaction in comparison with the corresponding signal in the (S)-isomers.
The next stage of our research was to study the effect of substituents at the aldehyde aromatic ring on the yield and the ratio of the reaction products. Thus, a reaction of monoterpenoid 1 with benzaldehyde (6b) under previously chosen conditions provided fluorinated product 8b in 55% yield. In addition, compound 2b was isolated from the reaction mixture in 24% yield ( Table 2).
Introduction of one or two methoxy groups into the aldehyde aromatic ring reduced the yield of fluorinated products 8c and 8d to ca. 35%, without affecting the yields of compounds 2.
To find out how much this reaction is sensitive to steric hindrances, we studied a reaction of monoterpenoid 1 with 2,4,6trimethoxybenzaldehyde (6e), in which both ortho-positions are occupied. Previously, using the aldehyde as a reactant in a reaction with diol 1 catalyzed by K10 montmorillonite clay led to a sharp decrease in the yield of product 2e [2]. In our case, the yields of products containing a fluorine atom (8e) and a hydroxy group (2e) were 42% and 35%, respectively (Table 2).
Interestingly, in the case of 2,4,5-trimethoxybenzaldehyde (6f), containing one of the three methoxy groups at the ortho-position, the overall yield of reaction products unexpectedly decreased, and the yield of fluorinated product 8f was only 20%. In addition to the expected products 2f and 8f, tricyclic compound 9f with an epoxychromene scaffold was isolated from the reaction mixture (Scheme 3), whose formation was previously observed only when using K10 clay [24]. The use of 4-nitrobenzaldehyde (6g) required the increase of the reaction time to 72 h for achieving complete conversion of monoterpenoid 1, which is obviously due to the electron-withdrawing effect of the nitro group; the yield of compound 8g was 53%. Reactions with 4-halogen-substituted aldehydes 6h-j proceeded similarly and provided target products 8h-j with yields of 47−60%.
Aliphatic aldehydes 6k and 6l were comparable in terms of reactivity with benzaldehyde (6b) and its methoxyderivatives; complete conversion was achieved after 8 h. It should be noted that the presence of a double bond in aldehyde 6l had no significant effect on the reaction; yields of fluorinated products 8k and 8l were about 60%.
A reaction of diol 1 with 3-methoxy-4-hydroxybenzaldehyde (6m) in the presence of BF 3 ·Et 2 O and water for 8 h also produces fluoro-containing hexahydrochromenes 8m in 60% yield despite the presence of a phenolic group in the aldehyde aromatic ring.  [27,28]. Based on these data, it may be supposed that in the case of a 5-fold excess of water relative to BF 3 ·Et 2 O, the reaction medium may contain both BF 3 ·H 2 O and products of the partial hydrolysis of BF 3 ·Et 2 O that may act both as catalysts and as fluorine sources.
Presumably Isopulegol (4), like diol 1, has a hydroxy group and an isopropenyl group at the 1-and 2-positions; these two groups are trans-located in compound 4 (while cis-located in monoterpenoid 1).
When a reaction of isopulegol (4) with 3,4,5-trimethoxybenzaldehyde (6a) was conducted under the conditions previously optimised for diol 1, fluorinated product 11 with the chromene scaffold and its analogue 12 with a hydroxy group were obtained in 76% and 15% yield, respectively (Scheme 5).

Conclusion
We developed for the first time conditions enabling the singlestep preparative production of chiral 4-fluoropolyhydro-2Hchromenes via a reaction between monoterpenoid alcohols with the para-menthane skeleton and aldehydes. The BF 3 ·Et 2 O/H 2 O system is used both as a catalyst and as a fluorine source. The reaction can involve saturated and unsaturated aliphatic aldehydes as well as aromatic aldehydes containing various acceptor and donor substituents, including a phenolic hydroxy group. The yield of target fluorinated products usually ranges from 53% to 76%; byproducts having a hydroxy group instead of the fluorine atom are formed in smaller quantities. The possibility of a transformation of 4-hydroxyhexahydro-2H-chromenes to 4-fluorohexahydro-2H-chromenes with inversion of the configuration was demonstrated.

Supporting Information
Supporting Information File 1 Detailed experimental procedures, compound characterization data, and copies of NMR spectra.