Catalytic β-Bromohydroxylation of Natural Terpenes : Useful Intermediates for the Synthesis of Terpenic Epoxides

In a one-step procedure, various β-bromoalcohols were synthesized from natural terpenes in good to excellent yields. Using different catalysts, the reaction was carried out at room temperature, with H2O as nucleophile and N-bromosuccinimide as a bromine source under mild reaction conditions. (e synthesized β-bromoalcohols were subsequently converted in situ to the corresponding epoxides in good yields.


Introduction
Terpenes, the major constituents of essential oils, present a class of natural products which are cheap and abundantly available.is pool of chiral substances can be transformed into valuable substances of considerable interest mostly for the industrial production of pharmaceuticals, cosmetics, fragrances, perfumes, and flavors, besides useful synthetic intermediates and chiral building blocks [1].
ere is a vast literature on catalytic transformations of terpenes for a broad variety of purposes.
e preparation of β-bromoalcohols has been reported directly from simple olefins by reaction with N-bromosuccinimide (NBS), which is a better choice compared to hazardous molecular halogens and other brominating agents, using several catalysts such as ionic liquids [17], β-cyclodextrin as a supramolecular catalyst [18], diphenyldiselenide (PhSeSePh) [19], NH 4 OAc [20], and iodine [21].A significant progress has been made in recent years regarding vicinal hydroxybromination of alkenes and their subsequent functionalization.However, limited examples using terpenes as a material source have been reported.
Recently, we have described an efficient process for the preparation of vic-aminoalcohols directly from simple alkenes in good yields [22].Our approach is based initially on the preparation of bromoalcohols by treating the corresponding alkenes at room temperature in the presence of NBS as a source of bromine and a catalytic amount of SiO 2 in water, followed by in situ addition of amine to form aminoalcohols.In our efforts to develop this methodology and to continue with our interest in the valorization of natural terpenes [23][24][25][26][27], we report here an expanded study of this process to natural terpenes.e scope and limitations of these transformations are discussed.

General Procedure for Bromohydroxylation of Terpenes.
In a typical experiment, N-bromosuccinimide (1.3 equiv.)and 0.04 g of catalyst were added to a vigorously stirred solution of terpene (0.4 g) in aqueous acetone (4 : 1, v/v).e mixture was stirred at room temperature for 15 min.e reaction was monitored by GC.At the end of the reaction, the mixture was diluted with water and extracted three times with EtOAc (10 mL).e organic layer was dried over Na 2 SO 4 and then concentrated, and the residue was purified by column chromatography using silica gel with EtOAcheptane (3 : 7, v/v) as eluent.
e obtained pure bromoalcohols were characterized by mass spectrometry, ATR-IR, MS/ESI measurements, and NMR spectroscopy.Characterization data can be found in ESI.

General Procedure for In Situ Synthesis of Epoxides.
First, the respective bromoalcohols were prepared by the method described above.
en, in the same reactor, two equivalents of amine were added and the resulted mixture was stirred at room temperature for 2 hours.e reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL).e combined organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure.Pure epoxide was obtained by column chromatography over silica gel using a mixture of EtOAcheptane (2 : 8, v/v) and characterized by mass spectrometry, ATR-IR, MS/ESI measurements, and NMR spectroscopy.Characterization data can be found in ESI.
e structures of 2a and 3a were confirmed by comparison with literature data [29] and an authentic sample.

Synthesis of Bromoalcohol 2a.
In connection with our ongoing effort to prepare aminoalcohols from terpenes, we first focused on the optimization of bromohydrin synthesis to improve published results regarding limonene substrates.In general, it is a reaction that proceeds at a yield of 70-87% [29,30].Hence, we studied bromohydroxylation of limonene 1a under various reaction conditions (Scheme 1).
Limonene 1a, which contains two different double bonds, was mainly bromohydroxylated to 2a at the internal double bond, while the external double bond remained unchanged (Table 1).e reaction proceeded smoothly at room temperature under extremely mild conditions.Systematic investigation in the presence of various catalytic systems was undertaken to define the best reaction conditions.
As depicted in Table 1, among the catalysts studied, CeO 2 nanopowder and Dowex Marathon A, Cl − form, appeared to be the most suitable (entries 11, 12).ey produced 2a in 70% yield within 15 min.But the differences in conversion and yield were not so significant whether acidic or basic catalysts were used.Probably, the generation of electrophilic bromine species forming halonium ion intermediates with the terpene followed by the nucleophilic attack of H 2 O was possible at all polar catalyst surfaces.
e most efficient catalyst (Dowex Marathon A) was subsequently used for the next steps of the optimization.e effect of NBS was also evaluated (Table 2).Hence, the increase of NBS amount had a boosting effect on the conversion of 1a.When it was treated with at least 1.7 equivalents of NBS in an aqueous solution of acetone, 1a was totally converted (entries 7, 8).However, the maximum yield of the corresponding bromoalcohol 2a (70%) was obtained with only a slight surplus of NBS (1.3 equiv.)(entry 3).Using a larger excess, various by-products coming probably from side reactions (bromohydroxylation of exo-double bond) during the formation of bromohydrin were detected by gas chromatography.
e yield of bromoalcohol 2a could be also influenced by the nature of the solvent (Table 3).As can be seen in Table 3, the highest efficient protocol was achieved in acetone, methanol DMSO and THF (entries 1-5).In nitromethane, acetonitrile, and dichloroethane less than 50% yield was obtained (entries 6-8).An improvement of conversion and yield was achieved in acetone by lowering the reaction temperature to 0 °C (entry 2).e reaction of 1a with NBS in methanol led selectively to the corresponding bromomethoxylated product in good yield (entry 3).
Subsequently, the influence of the catalyst amount was also studied (Table 4).
e best result was achieved with catalyst/substrate ratio of 1 : 10 (w/w; entry 2).Under high ratio the yield decreased probably due to the formation of byproducts resulting from consecutive reactions (entries 3, 4).

In Situ Addition of Amines to β-Bromoalcohol 2a.
e aim of this reaction sequence was the synthesis of vicinal limonene aminoalcohol in one-pot procedure via   β-bromoalcohol under optimized conditions (e.g. 4, Scheme 2).erefore, β-bromoalcohol 2a formed in situ was treated by different amines as nucleophiles (Table 5).However, the epoxide 3a was obtained instead of the desired aminoalcohol in spite of increasing the amount of amine.e added amine acts as a base in the HBr elimination to afford the oxirane ring [31].
As seen in Table 5, the use of aniline did not lead to any target product, neither to vic-aminoalcohol nor to the epoxide (entry 1). is study shows that diethylamine is the best base both in acetone or THF as solvent (entries 2, 3).When the less basic and more bulky phenylethylamine was used, the yield decreased, and only 38% of 3a was obtained (entry 4).It should be noted that in the case of phenylethylamine and aniline, the formation of the respective Schiff base of acetone was observed.In order to avoid this undesired competitive reaction, the conversion was carried out in THF.en, azomethines were not found any longer.However, in the case of phenylethylamine, both conversion of 1a and yield of epoxide 3a decreased (entry 5).

Bromohydroxylation and Epoxidation of Further
Terpenes.After optimization of reaction conditions using limonene, and to assess the scope and limitation of the reaction, we extended this methodology to a variety of natural terpenes such as citronellol, geraniol, carvone, citronellal, citral, and α-and β-pinene.
In a first series of experiments, the terpenes 1b-1f were converted to the corresponding β-bromoalcohols 2b-2f in very good yields (Table 6).In the case of geraniol 1c, carvone 1d, or citral 1f, the allylic hydroxy or carbonyl group prevented the bromohydroxylation at the neighbouring double bond.In contrast to limonene 1a, the double bond of the isopropenyl group reacted selectively.e products were isolated and purified by column chromatography and analytically characterized (see ESI).Afterwards, the in situ procedure optimized for limonene was applied to the other terpenes.Two equivalents of diethylamine were added to the reaction mixtures containing the intermediary bromoalcohols 2b-2f, which were converted to the corresponding epoxides after 2 h.In the case of bromoalcohol 2e, an aldol condensation between the aldehyde group and the solvent acetone beside epoxidation was observed and led to the epoxide 3e.αand β-pinene did not react under the optimized conditions even after 24 hours.e gas chromatogram documented the formation of a variety of products with small peak areas resulting from isomerization of the pinenes.

Conclusion
e catalytic synthesis of β-bromoalcohols of different terpenes succeeded via smooth reaction using NBS and H 2 O as the nucleophile.
e in situ treatment of these bromoalcohols with a variety of amines did not lead surprisingly to the expected vicinal aminoalcohols, but to the corresponding epoxides.
e formed bromoalcohols underwent rapid dehydrohalogenation by the amine which played the role of base.We were subsequently able to isolate several epoxides in good yields.e synthesized β-bromoalcohols of natural terpenes can serve as an easily accessible platform for further structural elaboration.

6
Journal of Chemistry

Table 1 :
Influence of the catalyst on the bromohydroxylation of 1a.

Table 2 :
Effect of NBS amount on bromohydroxylation of 1a.

Table 3 :
Solvent effect on the bromohydroxylation of 1a.

Table 4 :
Influence of the catalyst amount on the bromohydroxylation of 1a.

Table 5 :
Amine effect on the synthesis of epoxide 3a.