Construction of 2,2-Dimethyloxepane Frameworks from Ene-Diols Catalyzed by Metal Catalyst or Brønsted Acid via 7-Endo-Trig Cyclization

Abstract

The synthesis of 2,2-dimethyloxepane frameworks based on the 7-endo-trig cyclization of ene-diol using a catalytic amount of metal catalysts (Au, Ag) or Brønsted acid (TfOH) has been developed. Also, the spiro-type dioxabicyclic products were also derived from the diene-diols. For the condition using metal catalysts, the cyclization selectively reacted between the 1,1,3-trisubstituted alkenes and alcohols to form the 2,2-dimethyloxepane frameworks. On the other hand, the TfOH reacted with not only the 1,1,2-trisubstituted alkene, but also the 1-substituted and 1,2-disubstituted alkenes providing the corresponding cyclic ethers, which is quite different from the conditions of the metal catalysts.

Introduction

The 2,2-dimethyloxepane, which is an oxygen-containing 7-membered ring having a quaternary carbon next to an oxygen atom, is one of the significant frameworks in natural products (Fig. 1). For example, Heliannuol C,^1,2) Sodwanone S³, Zoapatanol,^4–6) Montanol,⁴⁾ Tomentol,⁷⁾ and Tomentanol⁷⁾ possessing interesting bioactivities are composed of the common 2,2-dimethyloxepane skeletons as the core framework. Thus, further development of the 2,2-dimethyloxepane synthesis is desired.

Fig. 1. Natural Products Based on 2,2-Dimethyloxepane Framework

Various types of oxepane syntheses have already been reported.^8–11) On the other hand, the 2,2-dimethyloxepane synthesis is limited to specific conditions.^12–15) For instance, the Bhat group reported the 2,2-dimethyloxepane synthesis from alkene-alcohols with zeolite and Amberlyst. The self-assembled resorcin[4]arene hexamer catalyzed transformation from alkene-alcohols into 2,2-dimethyloxepane derivatives was reported by Catti and Tiefenbacher in 2015.¹⁵⁾ Based on these results, further diversity of the reaction conditions for the formation of the 2,2-dimethyloxepane derivatives is required.

Recently, we developed new synthetic methods to react with ene-diol derivatives giving cyclic ethers containing the 2,2-dimethyloxepane derivatives, which was enabled by both a gold catalyst featuring the Z-type ligand and silver catalyst.¹⁶⁾ In addition, we newly found that a simple Brønsted acid (TfOH) was also applicable for preparation of the 2,2-dimethyloxepane frameworks. The present report describes the details of further studies of this transformation of enediols into 2,2-dimethyloxepane derivatives and other cyclic ethers.

Gold Catalyst Featuring Z-ligand ([Au(DPB^Cl)]SbF₆)

Our recent endeavor focused on the cyclization of 7-membered ring systems. Since 2015, we have developed the efficient synthesis of various types of 7-membered ring systems based on gold catalysts featuring the σ-acceptor of the Z-ligand, which expected that the gold center would be activated due to accepting the electron on gold by the neighboring Z-ligand of the borane atom.¹⁷⁾ Thus, we first examined the Au→Z catalyzed 7-endo-trig cyclization of the ene-diol derivatives. When we treated the ene-diol 1a with 2 mol% of Au(DPB^F)SbF₆, which was prepared from Au(DPB^F)Cl and AgSbF₆, in dichloroethane (DCE) at 100 °C under microwave irradiation for 20 min, the desired oxepane derivative 2a was observed in 96% yield (Table 1, entry 1). In case of the Au(DPB^Cl)SbF₆, 2a was provided in a higher yield (99%, entry 2). Although the general Au catalysts without the Z-ligand, such as [Au(JohnPhos)](NCMe)SbF₆, Au(IPr)SbF₆, and Au(PPh₃)SbF₆, also provided 2a, the chemical yields (95, 86, 88%) were slightly decreased (entries 3–5). When the reaction was carried out under the condition of entry 2 without microwave (MW) at 60 °C, there was no difference in the reaction time and chemical yield (entry 6). Thus, the conditions of entry 6 were determined to be the standard condition.

Table 1. The Au(I)-Catalyzed 7-Endo-Trig Cyclization of Ene-Diol 1a

Next, other ene-diol derivatives were examined for the syntheses of the oxepane derivatives (Table 2). When the substrate 1b had an p-trifluoromethylbenzyl group at R, the desired product 2b was observed in 96% yield. Also, substrates 1c having a p-methoxybenzyl at R provided the desired oxepane derivatives 2c (88%) in high yields. In case of the substrate 1d, which is protected by the tert-butyldimethylsilyl (TBS) group on one side of the diol, the cyclized product 2d had a moderate yield (52%). The monosubstituted (allyl) or 1,2-disubstituted (cinnamyl) alkenes in substrates 1e,f did not react with an alcohol under the Ag-catalyzed condition, which gave the monocyclic oxepane derivatives 2e (60%) and 2f (87%), respectively. The oxepane 2g was also derived from substrate 1g having an alkyl chain (ⁿBu) at the R group in 95% yield.

Table 2. The [Au(DPB^Cl)]SbF₆-Catalyzed 7-Endo-Trig Cyclization of Ene-Diol 1

For the further investigation of the reactivity between an alkene and alcohol, the bicyclic reaction using the diene-diol was examined. The diene-diol 1h bearing the 2-methylallyl group gave the desired spiro 5/7 bicyclic product 3h in 98% yield via the simultaneous 5-exo-trig and 7-endo-trig cyclizations (Chart 1). In addition, the 7/7 bicyclic product (3i: 89%) was also observed from the diene-diol 1i.

Chart 1. Construction of Spiro-Type Oxepane Derivatives 3h,i from Diene-Diols 1h,i

Silver Catalyst (AgSbF₆)

Although the Ag-catalyzed cyclizations with alkynes^18,19) have been developed, the reaction of a simple alkene moiety^20–23) is still limited. Recently, we found that the Ag-catalyst (AgSbF₆) worked with alkenes for the cycloisomerization and deprotection reaction.^24,25) Therefore, we next examined the AgSbF₆-catalyzed 7-endo-trig cyclization of ene-diols. The results are shown in Table 3. The products were completely the same for the conditions with the Au→Z catalysts. Also, there were no changes in the chemical yields of the products 2a–g, 3h, i. Thus, the AgSbF₆ catalyst showed the same catalytic activity as the previous [Au(DPB^Cl)]SbF₆ catalyst. In other words, the expected Au activation by the Z-ligand effect was not seen in these reaction modes.

Table 3. AgSbF₆-Catalyzed Cyclization of Alkene-Alcohol 1

TfOH

In general, the additions of alcohols to alkenes using Brønsted acids²⁶⁾ are well known as classical reactions in organic chemistry. For example, Hartwig and colleagues reported that the TfOH-catalyzed 6-endo-trig cyclization of 2-allyl-5-methylhex-4-enol formed the corresponding 2,2-dimethyltetrahydropyran derivatives.²⁷⁾ Also, the authors described that several types of metal species (Fe, Cu, Ag, Au, Ru) were also applicable for the same cyclization as the catalysts. This paper encouraged us to investigate the TfOH-catalyzed 7-endo-trig cyclization of alkene-alcohol for the formation of the 2,2-dimethyloxepane derivatives.

As a preliminary examination, a quantitative amount of the Brønsted acid was applied to the reaction. The treatment of the ene-diol 1b with 100 mol% TfOH in DCE at 60 °C for 1 h afforded the desired product 2b in 97% yield (Table 4, entry 1). The reaction with the weaker Brønsted acids of acetic acid or TFA did not provide the cyclized product (entries 2, 3). A catalytic amount of TfOH (10 mol%) also provided 2b in a comparable yield (entry 4).

Table 4. The Acid-Catalyzed 7-Endo-Trig Cyclization of Ene-Diol 1b

Next, the scope and limitations were examined. The results are summarized in Table 5. Substrates 1a,c having a benzyl or p-methoxybenzyl at R provided the desired oxepane derivatives 2a (98%) and 2c (91%) in high yields. The oxepane 2g having an alkyl chain (ⁿBu) at the R group was also observed in 96% yield. Double cyclization of the diene-diols 1h,i,j was also applicable to afford the spiro 5–7/7 bicyclic products 3h (95%), 3i (60%) and 3j (92%) respectively.

Table 5. The TfOH-Catalyzed Cyclization of Alkene-Alcohol 1

In case of the substrate 1d, which is protected by the TBS group on one side of the diol, the product was not the cyclized product 2d, but the cyclized and deprotected alcohol derivative 2a²⁸⁾ in 67% yield, which is quite different from the condition with the metal catalysts (Chart 2).

Chart 2. Cyclization of Mono-O-protected Alkene-Alcohol 1d

In addition, monosubstituted (allyl) or 1,2-disubstituted (cinnamyl) alkenes in substrates 1e, f also reacted with the alcohol to afford the bicyclic oxepanes 3e (69%, dr = 1.1 : 1) and 3f (83%, dr = 1.5 : 1) (Chart 3). When the metal catalysts (Au or Ag) were applied instead of TfOH, the monocyclic oxepanes 2e, f were formed. Thus, depending on the substrate, a product different from the condition using metal catalysts could be obtained by the reaction using TfOH as the catalyst.

Chart 3. Double Cyclization of Diene-Diols 1e,f

In conclusion, we have developed the Au→Z or Ag-catalyzed 7-endo-trig cyclization of ene-diols for the formation of the 2,2-dimethyloxepane frameworks. In this reaction, the spiro-type dioxabicyclic products were also derived from the diene-diols. Unfortunately, there was no difference between the Au→Z and Ag catalyst in this reaction, and the specific effect of the Z-type ligand as the σ-acceptor was not observed. The TfOH-catalyst was also applicable for the formation of the 2,2-dimethyloxepane frameworks via the 7-endo-trig cyclization of the ene-diol. In this reaction, depending on the substrate, the product was different from the results using metal catalysts. Further examination involving the synthesis of the 2,2-dimethyloxepane framework is currently underway.

Acknowledgments

This study was supported by JSPS KAKENHI Grant Numbers JP20H03370, JP18H04244, JP17K08209 to F. I., for which we are thankful.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

• 1) Macias F. A., Molinillo J. M. G., Varela R. M., Torres A., Fronczek F. R., J. Org. Chem., 59, 8261–8266 (1994).
• 2) Kamei T., Shindo M., Shishido K., Tetrahedron Lett., 44, 8505–8507 (2003).
• 3) Bon C. F., Berrué F., Thomas O. P., Reyes F., Amade P., J. Nat. Prod., 68, 1284–1287 (2005).
• 4) Levine S. D., Adams R. E., Chen R., Cotter M. L., Hirsch A. F., Kane V. V., Kanojia R. M., Shaw C., Wachter M. P., Chin E., Huettemann R., Ostrowski P., Mateos J. L., Noriega L., Guzmán A., Mijarez A., Tovar L., J. Am. Chem. Soc., 101, 3404–3405 (1979).
• 5) Chen R., Rowald D. A., J. Am. Chem. Soc., 102, 6609–6611 (1980).
• 6) Wani M. C., Vishnuvajjala B. R., Swain W. E. Jr., Rector D. H., Cook C. E., Petrow V., Reel J. R., Allen K. M., Levine S. G., J. Med. Chem., 26, 426–430 (1983).
• 7) Oshima Y., Cordell G. A., Fong H. H. S., Phytochemistry, 25, 2567–2568 (1986).
• 8) Fadel A., Salaün J., Tetrahedron, 41, 413–420 (1985).
• 9) Janda K. D., Shevlin C. G., Lerner R. A., J. Am. Chem. Soc., 117, 2659–2660 (1995).
• 10) McDonald F. E., Wang X., Do B., Hardcastle K. I., Org. Lett., 2, 2917–2919 (2000).
• 11) Sabatino D., Damha M. J., J. Am. Chem. Soc., 129, 8259–8270 (2007).
• 12) Reddy P. V., Bhat S. V., J. Indian Chem. Soc., 75, 688–689 (1998).
• 13) Singh S. A., Kabiraji S., Khandare R. P., Nalawade S. P., Uper K. B., Bhat S. V., Synth. Commun., 40, 74–80 (2009).
• 14) Basu S., Waldmann H., Bioorg. Med. Chem., 22, 4430–4444 (2014).
• 15) Catti L., Tiefenbacher K., Chem. Commun., 51, 892–894 (2015).
• 16) The results of Table 1 entry 6, Table 2, Chart 1, Table 3, Table 4 entries 2 and 3 have already been reported as a preliminary examination. See: Maeda K., Murakami R., Inagaki F., Tetrahedron Lett., 60, 151038 (2019).
• 17) Murakami R., Inagaki F., Tetrahedron Lett., 60, 151231 (2019).
• 18) Sekine K., Yamada T., Chem. Soc. Rev., 45, 4524–4532 (2016).
• 19) Fang G., Bi X., Chem. Soc. Rev., 44, 8124–8173 (2015).
• 20) Li Y., Jiang X., Zhao C., Fu X., Xu X., Tang P., ACS Catal., 7, 1606–1609 (2017).
• 21) Dolan N. S., Scamp R. J., Yang T., Berry J. F., Schomaker J. M., J. Am. Chem. Soc., 138, 14658–14667 (2016).
• 22) Rigoli J. W., Weatherly C. D., Alderson J. M., Vo B. T., Schomaker J. M., J. Am. Chem. Soc., 135, 17238–17241 (2013).
• 23) Maestre L., Sameera W. M. C., Diaz-Requejo M. M., Masera F., Prez P. J., J. Am. Chem. Soc., 135, 1338–1348 (2013).
• 24) Inagaki F., Matsumoto M., Hira S., Mukai C., Chem. Pharm. Bull., 65, 822–825 (2017).
• 25) Inagaki F., Hira S., Mukai C., Synlett, 28, 2143–2146 (2017).
• 26) Smith M. B., March J., “March’s Advanced Organic Chemistry,” John Wiley and Sons, New York, 2001.
• 27) Rosenfeld D. C., Shekhar S., Takemiya A., Utsunomiya M., Hartwig J. F., Org. Lett., 8, 4179–4182 (2006).
• 28) Although this cyclization reaction was carried out under the same conditions as in Tables 2 and 3, a deprotected 2a was produced. It is assumed that moisture is contained in the reaction conditions.