Synthesis of halogenated bicyclic molecules involving Prins cyclization from aldehydes and non-conjugated diene alcohol

Department of Chemistry, School of Science and Engineering, Kindai University, Kowakae 3-4-1, Higashi-Osaka, Osaka 577-8502, Japan Faculty of Science, Yamagata University, Kojirakawa-Machi 1-4-12, Yamagata 990-8560, Japan Faculty of Life Science, Kyushu Sangyo University, Matsukadai 2-3-1, Higashi-Ku, Fukuoka 813-8503, Japan Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashi-Osaka, Osaka 577-8502, Japan E-mail: kmatsumo@chem.kindai.ac.jp, ando@sci.kj.yamagata-u.ac.jp


Introduction
Prins cyclization and related chemistry have attracted much attention, because the simple operation using aldehydes and homo allylic alcohols with some kinds of chemical reagents produces various tetrahydropyran rings [1][2][3]. The reactions often play an important role in the field of the total synthesis of natural products [4][5][6][7][8]. Among them, the integrated Prins cyclization [9][10], in which the Prins cyclization and another type of reactions have been combined, is one of the most widely explored transformations in organic synthesis [11][12][13][14]. For instance, Reddy and co-workers have extensively studied the tandem cyclization involving Prins cyclization so far [15][16][17][18][19][20][21][22]. Scheme 1. Prins cyclization followed by (a) the fluorination (our work) [23] and (b) the halogenation such as chlorination and bromination (this work). TMS = trimethylsilyl Recently, we have reported the integrated Prins cyclization using various aldehydes and a non-conjugated diene alcohol, (E)-octa-3,7-dien-1-ol. In the presence of BF3·Et2O and a catalytic amount of TMSCl, the cyclization gave the corresponding bicyclic compounds in good yields (Scheme 1 (a)) [23]. A single fluorine atom was contained in the cyclized products. If we succeed in combining other halogenation reactions, such as chlorination and bromination, with the bicyclization, it would greatly increase the value of our reaction because the halogen group introduced is useful for subsequent derivatization processes [24][25][26][27][28][29][30][31][32]. In this work, we have studied the possibility of the introduction of Cl and Br atoms in the termination of the integrated Prins cyclization using (E)-octa-3,7-dien-1-ol (Scheme 1(b)). The simple and accessible syntheses of the halogenated bicyclic compounds have been attained. In addition, we have theoretically investigated the key mechanism of the chlorination of a bicyclic carbocation, which leads to the formation of the end products. Table 1 shows the results of the reaction optimization. The non-conjugated diene alcohol, (E)-octa-3,7-dien-1-ol (2), was synthesized according to our previous report [23]. We employed the basic reaction condition of reagents and halide source reported by Liu et al [26]. The reaction of n-octanal (1a, 0.25 mmol) and 2 (0.25 mmol) in the presence of TMSCl (2 eq) and AlCl3 (0.05 eq) in CH2Cl2 (2 mL) at −40 o C did not give the desired product 3aCl at all (entry 1). Likewise, the increased amount of 1a such as 0.50 mmol (2 eq) with AlCl3 (0.05 eq) or without AlCl3 did not yield 3aCl (entries 2-3).

Results and Discussion
However, the reaction using AlCl3 (1 eq) at −40 o C gave the corresponding product 3aCl in 89% yield (entry 4). As for the reaction temperature, the condition of −5 o C was also examined, and the results are summarized in entries 5 to 8. The reaction in the absence of AlCl3 afforded 3aCl in 20% yield (entry 5). The combination of TMSCl (2 eq) and AlCl3 (0.05 eq) gave 3aCl in 12% yield (entry 6). Interestingly, the combination of TMSCl (2 eq) and AlCl3 (1 eq) gave 3aCl in 87% yield (entry 7), in which the ratio of diastereomers associated with the Cl position was 1.2:1. The 1 H NMR analysis clarified that the major diastereomer has the Cl group on the axial position. In addition, the use of AlCl3 (2 eq) in the absence of TMSCl also produced 3aCl in 90% yield (entry 8).
These results highlight the importance of a sufficient amount of AlCl3 for a better yield, although entry 5 evidently shows that TMSCl can act as a chloride source. Based on the above investigations, the conditions of entries 4, 7 and 8 can be regarded as optimized parameters. Here, given the good performance reported by Liu et al [26] and a high yield of 3aCl, we adopted the condition of entry 7, in which the combined use of TMSCl (2 eq) and AlCl3 (1 eq) would facilitate the Cl introduction to various cyclized carbocation intermediates. We adopted −5 o C rather than −40 o C for easy handling.
As for the introduction of a Br atom into the cyclized compounds, we employed a condition similar to entry 7. The use of TMSBr (2 eq) and AlBr3 (1 eq) in CH2Cl2 surprisingly produced a mixture of 3aBr and 3aCl in a total yield of 86% yield (entry 9). This indicates that Cl − or its equivalent originating from CH2Cl2 might also attack an intermediate of a cyclized carbocation. To avoid the contamination of 3aBr and 3aCl, we used the CH2Br2 as a solvent, which actually gave 3aBr in 91% yield (entry 10).
Because it turns out that the reaction optimization was achieved, we now discuss the scope and limitations of the bicyclization reactions accompanied by the Cl introduction ( Table 2). The reaction of benzaldehyde (1b) using the optimized condition produced the desired product 3bCl bearing a Cl moiety in 87% yield (entry 1). The aromatic aldehyde derivatives such as 4-methylbenzaldehyde (1c), 3methylbenzaldehyde (1d), 4-chlorobenzaldehyde (1e), 3-chlorobenzaldehyde (1f), 4nitrobenzaldehyde (1g), and 3-nitrobenzaldehyde (1h) were also promising starting substrates, leading to the corresponding cyclized and chlorinated compounds in good yields (entries 2-7). In the case of 2-nitrobenzaldehyde (1i), three diastereomers were formed in good yield of 3iCl, in which diastereomer ratio was 1.  The reaction was carried out using 1a (0.25 mmol or 0.50 mmol) and 2 (0.25 mmol) with chemical reagents in CH2Cl2 (2 mL) at T o C for 24 h; b Isolated yields after the preparative GPC separation of crude materials; c n.d. = no detection; d Diastereomer ratio was determined using 1 H NMR spectra, which were derived from isolated and purified products. The ratio of diastereomers is given in the order of major diastereomer of 3 : minor diastereomer of 3, shown in Scheme 3. In most entries, the 1 H NMR spectra imply a small amount of third diastereomer contamination, which has not been unambiguously confirmed yet; e 3aBr and 3aCl were obtained as a mixture. The isolated yield was calculated using the average molecular weight of 3aBr and 3aCl and the 3aBr and 3aCl contributions to 13 C NMR spectra, instead of the strongly overlapping 1 H NMR spectra. The ratio of 3aBr/3aCl was 1.1:1. For both of 3aBr and 3aCl, diastereomer ratio was 1.6:1; f CH2Br2 (2 mL) was used instead of CH2Cl2 in order to avoid the formation of 3aCl.
In the cases of 4-methoxybenzaldehyde (1j), 3-methoxybenzaldehyde (1k) and 2methoxybenzaldehyde (1l), the reactions smoothly proceeded to give the products of 3jCl, 3kCl and 3lCl in 85%, 80%, and 79% yields, respectively (entries 9-11). The stereo-selectivity of 3lCl is less obvious in entry 11, compared with the other entries in Table2, which might be attributed to the substituent at the ortho postion in the aromatic ring. In addition, the reaction of 2-naphthaldehyde (1m) and 2 led to the formation of the corresponding 3mCl in <91% yield (entry 12). It is worth noting that cinnamaldehyde (1n) was tolerant, despite of the presence of a carbon-carbon double bond, enough to afford bicyclic molecule 3nCl in 76% yield (entry 13).
We could clarify the detailed structure of the minor diastereomer of 3cCl (vide supra) by using X-ray analysis ( Figure 1). Both of 4-MeC6H4 and the Cl atom in the minor diastereomer of 3cCl were located in the equatorial position. This is consistent with the 7 above-mentioned fact that the major diastereomer of 3aCl has the Cl atom on the axial position (Table 1, entry 7). Table 2. Scope and limitations. a 8 a The reaction was carried out using 1 (0.50 mmol) and 2 (0.25 mmol) with TMSCl (2 eq) and AlCl3 (1 eq) in CH2Cl2 (2 mL) at −5 o C for 24 h; b Isolated yields after the preparative GPC separation of crude materials; c Diastereomer ratio was approximately determined by 13 C NMR spectra, which were derived from isolated and purified products. Diastereomer ratio could not be calculated by 1 H NMR spectra, because of the overlapping. In most entries, the 1 H NMR spectra suggest that a small amount of third diastereomer seems to be contained. Taking a typical example, we assessed the applicability of the reaction to a scale-up condition (Scheme 2). That is, 1b (2.5 mmol) and 2 (1.25 mmol) were reacted in the presence of TMSCl (2 eq) and AlCl3 (1 eq) in CH2Cl2 (8 mL) at −5 o C for 24 h. The reaction gave the corresponding product 3bCl in 93% yield (0.29 g), which was purified by the preparative GPC separation using the recycle HPLC. The result indicates that the scale-up condition does not notably affect the chemical yield of this reaction. After the formation of the intermediate D, the sequential bicyclization affords the carbocation E, which is terminated by a halide ion (Cl − or Br − ) to give the final product 3 (Scheme 3 (4)). The same process is described in a previous report [23]. As for the final step of halogenation of E, such as chlorination, there is the possibility that Cl − derived from TMSCl, AlCl3, [HOAlCl3] − , and/or CH2Cl2 solvent would react with E to form 3. In the literature of Liu et al. [26], TMSCl played a critical role as a primary chloride source. This is consistent with entry 5 in Table 1. In addition, entries 8 and 9 of Table 1 showed that AlCl3 and CH2Cl2 could also serve as chloride sources.
Therefore, the clear identification of a single Cl − source seems to be difficult in the current reactions. Focusing on the synthesis of 3cCl (Table 2, entry 2) whose structure is well characterized, we theoretically studied the process of Clintroduction to the carbocation E (Scheme 3 (4), R = 4-MeC6H4 group). By referring to the previous study conducted by Liu et al. [26], we assumed that TMSCl is the chloride source in the theoretical calculations. As shown in Scheme 3 (4), we obtained two diastereomers as end products. The major diastereomer, denoted by 3cCl (major), has the Cl group on the axial position. The minor diastereomer, denoted by 3cCl (minor), has the Cl group on the equatorial position, as is shown in the X-ray crystal structure (Figure 1). The experimental yield of 3cCl (major) and that of 3cCl (minor) are 60% and 30% yields, respectively. Figure 2 displays the enthalpy diagram together with the equilibrium geometries, which were obtained by using the density functional theory (DFT) calculations incorporating the solvation effects of CH2Cl2. Note that we discuss the enthalpy change rather than the Gibbs free energy change because the calculated entropies and, thus, the Gibbs energies were not reliable due to low-frequency normal modes. The energy scale of Figure 2 is relative to the total enthalpy of E and TMSCl at infinite separation. The equilibrium geometry of E, shown in Figure 2, exhibits sp 2 hybridization on the cationic C atom, to which only one H atom is attached. In fact, this C atom has a positive natural atomic charge (+0.33 e), and E exhibits an almost planar structure around the C atom. When the Cl atom of TMSCl approaches the cationic C atom in the out-of-sp 2 -plane direction, there occurs Claddition to E. Depending on from which side the Cl atom approaches the cationic C atom on the sp 2 plane, the addition can yield different diastereomers, 3cCl (major) and 3cCl (minor). To the Cl atom of each of the diastereomers, TMS + is bound by the electrostatic attraction (Si-Cl length ~ 2.33 Å). As shown in Figure 2, the enthalpy of 3cCl (major)-TMS + cluster and also that of 3cCl (minor)-TMS + cluster are more stable than the total enthalpy of E and TMSCl at infinite separation (-4.81, -4.79 kcal/mol, respectively). Although the enthalpy of 3cCl (major)-TMS + cluster is more stable than that of 3cCl (minor)-TMS + cluster, the difference is almost negligible (0.02 kcal/mol). This small enthalpy difference is attributed presumably to the weak steric repulsion in the clusters, regardless of the different configurations ( Figure 2). Even after TMS + is eliminated, the enthalpy difference between 3cCl (major) and 3cCl (minor) remains very small (0.48 kcal/mol).
This TMS + elimination requires overcoming enthalpy destabilization (Figure 2) for breaking the electrostatic attraction between TMS + and Cl. The destabilization is somewhat large, that is, 16.17 kcal/mol for 3cCl (major) and 15.67 kcal/mol for 3cCl (minor). We added water, a highly polar solvent, for quenching the reaction, which reduces the enthalpy destabilization of TMS + elimination; in water, the corresponding destabilization is 14.82 kcal/mol for 3cCl (major) and 14.29 kcal/mol for 3cCl (minor).
It turns out that there are, on the whole, only subtle differences between the reaction leading to 3cCl (major) and that leading to 3cCl (minor) in terms of the enthalpy diagram in Figure 2. This is consistent with the limited stereo-selectivity of 3cCl.
Transition states can play a crucial role in kinetically controlled reactions. To locate the transition states for Claddition and TMS + elimination, we manually changed a key bond length (i.e., C-Cl length for Claddition and Si-Cl length for TMS + elimination) and performed computational optimization of all geometrical parameters, except for the key bond length. In the potential energy curves obtained, however, there are no transition states, or activation energy barriers, for both processes; the potential energy profile for Claddition is purely downhill (Figure 3 (a)) and the profile for TMS + elimination is purely uphill (Figure 3 (b)). In addition, the potential energy profile for the path to 3cCl (major) is very similar to that for the path to 3cCl (minor). All of these observations demonstrate that TMSCl can actually act as a chloride source and the chlorination can readily form both of the two bicyclic diastereomers. In the future, we plan to experimentally and theoretically clarify the overall reaction mechanism in greater detail.

Conclusion
In summary, we have successfully constructed the halogenated bicyclic molecules bearing Cl and Br via Prins cyclization using (E)-octa-3,7-dien-1-ol. Focusing on the bicyclization accompanied by chlorination, we showed that the present reaction can be applicable for various aldehydes such as aliphatic and aromatic substituents as well as cinnamaldehyde. The reaction efficiently took place under a scale-up condition. The reaction optimization helped the achievement of a good yield and revealed that TMSCl, AlCl3, and/or CH2Cl2 can be chloride sources in our reaction. We theoretically investigated the chlorination of a typical bicyclic carbocation, thereby confirming that TMSCl can act as a chloride source. There are no transition states for the chlorination, resulting in the formation of the two bicyclic diastereomers. We plan to deepen the understanding of the reaction mechanism, including the role of AlCl3. Further synthetic application is currently underway. All reactions were carried out under N2 atmosphere, unless mentioned.

Experimental
Quantum chemical calculations. We employed Gaussian 09 program [35]. Using B3LYP functional [36][37][38] and cc-pVDZ basis set [39][40], we performed the DFT optimization. After obtaining the optimized geometries, we verified, by means of the frequency analysis, that they are indeed equilibrium geometries. For all of the equilibrium geometries, we performed self-consistent-field stability analysis (i.e., instability check) to assess the reliability of the electronic structures. The solvation effects of CH2Cl2 were incorporated by employing the polarizable continuum model [41]. The thermochemistry analysis was performed at −5 o C.  Table S1. Selected bond lengths and bond angles are listed in Table S2. CCDC: 2070265 (3cCl).

X-ray Crystal
Materials. Dry CH2Cl2 was prepared as follows. CH2Cl2 was washed with distilled water by several times to remove a trace amount of MeOH. P2O5 was added and dried overnight. Then, CH2Cl2 was distilled. The reflux of CH2Cl2 in the presence of dried K2CO3, and CH2Cl2 was directly redistilled. Finally, activated molecular sieves 4A were added to CH2Cl2 for the storage.
Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. The alcohol 2 was prepared according to the previous literature [23].