# Catalytic Allylic Chlorination of Natural Terpenic Olefins Using Supported and Nonsupported Lewis Acid Catalysts

Authors: Ayoub Abdelkader Mekkaoui; Mouhsine Laayati; Hamza Orfi; Larbi El Firdoussi; Soufiane El Houssame
Journal: Journal of Chemistry
 (2020)

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## Abstract

A mild and convenient method for the allylic chlorination of naturally occurring terpenic olefins was investigated in the presence of different supported and non-supported Lewis acid catalysts. The reaction has been tested on carvone as a model substrate in the presence of sodium hypochlorite as chlorine donor. The scope and limitations of transition metal-based Lewis acid catalysts, stoichiometry, and substrate structure were evaluated. Among the iron precursors used, FeCl3 and FeCl2 provide the promise of a general approach to allylic or vinylic chlorination reaction. Various terpenic olefins were examined in the presence of FeCl3/NaOCl combination system. The catalytic chlorination proceeds under mild conditions with short reaction time and shows a high selectivity affording the corresponding chlorides in good to excellent yields.


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## Body

## 1. Introduction

Allyl, vinyl, or isopropenyl groups are present in different naturally occurring products as part of their structures [1–3]. They have been used repeatedly as starting materials to reach new natural products derivatives or more complex atomic arrangements [4, 5]. Among the versatile natural products bearing these groups, terpenes represent a sustainable supply of intermediates for several functionalization segments of the fine chemical industry, for example, the manufacture of flavors and fragrances [6–8]. Allylic chlorination represents a convenient way to functionalize terpenes bearing an allyl, vinyl, or isopropenyl group since further manipulation on the chloride may lead to several functional groups for the synthesis of natural products [9–13]. Previously, we have reported the allylic substitution of optically active natural terpenic allylic chloride derivatives in good yields [14, 15]. Moreover, isoprenoid chlorides are remarkably interesting for the synthesis of α-monoterpenes or vitamin A intermediates such as pseudoionone [16–18].Allylic chlorination represents a convenient alternative method for allylic olefins functionalization. Various methodologies developing the allylic chlorination are reported in the literature, allowing the preparation of allyl chloride derivatives from the corresponding allylic alcohols using different reagents, such as thionyl chloride [19], hydrochloric acid [20], titanium (IV) chloride [21], N-chlorosuccinimide (NCS) [22], chlorosilanes [23, 24], methanesulfonyl chloride/lithium chloride [25], or iridium catalyst [26, 27]. Moreover, allylic chloride intermediates could be synthesized from aldehydes through olefination-reduction-halogenation sequences [28]. Torii et al. have reported electrochemical methods using sodium chloride as halogen source for the allylic chlorination of variety of isoprenoids [29, 30]. In organic synthesis, diselenides were also used as catalysts for the allylic chlorination of olefins [31–33]. Barrero et al. have reported a solid-phase selenium catalyst for the selective allylic chlorination of polyprenoids [34]. Recently, we have prepared an efficient new organoselenide for the allylic chlorination of various terpenic olefins [35]. In the presence of NCS, the allylic chloride can be prepared from olefins using Yb(OTf)3–TMSCl or aniline catalyst [36, 37], while the allylic chlorination could be performed by a direct molecular chlorine bubbling through the reaction medium but suffer from disadvantages such as difficulties of handling chlorine gas [38]. On the other hand, reports are focused on the use of calcium hypochlorite [39, 40] or by a combination of Vilsmeier reagent and H2O2, but this excludes the use of acid-sensitive substrates [41]. In addition, sodium hypochlorite and acetic acid were used for the chlorine generation with limitation to nonsensitive substrates [42].In the last two decades, the use of Brønsted acid (acetic acid) instead of Lewis acid has gained considerable importance. The method has the advantage of mild reaction conditions when the reaction occurs in a smoothly two-phase system (CH2Cl2/H2O) [38]. Different metallic Lewis acids in combination with NaOCl were studied for the allylic chlorination of terpenic olefins such as CeCl3, InCl3, or MoCl5 [38, 43, 44]. The optimum solvent was reported to be the biphasic system of dichloromethane and water with addition of sodium hypochlorite under vigorous stirring to ensure the homogeneous distribution of the in situ generated electrophilic chlorine [38]. Moreover, Lewis acids such as NbCl5 and NbBr5 are reported to be efficient for the allylic and allenic chlorination via a mediated alkoxide rearrangements [28].As part of our studies directed towards the valorization of natural terpenes via new catalytic systems [45–47], herein we report an efficient and convenient method for the allylic chlorination of terpenes using a combination of sodium hypochlorite and Lewis acid catalyst. The allylic chlorination was achieved in a high degree of efficiency and selectivity. Among the Lewis acids used, aluminum and iron salts exhibit multiple interesting features such as their high abundance, low environmental impact, high chemoselectivity, and tolerance to aqueous media. The method represents a good choice for the preparation of new functionalized compounds derived from natural products under mild conditions (Scheme 1).Scheme 1
Allylic chlorination of terminal olefins catalyzed by MClx.


## 2. Results and Discussion

The scope and limitation of the allylic chlorination was examined first using carvone, chosen as model substrate, in the presence of supported and nonsupported Lewis acid catalysts (Scheme 2). The results are summarized in Table 1.Scheme 2
Allylic chlorination of carvone.Table 1
Allylic chlorination of carvone using different Lewis acid catalysts.
EntryCatalystCatalyst/substrate∗ConversionSelectivitya (%)b (%)c (%)e (%)1AlCl3/SiO2 10% wt%40% wt./wt.2564, 702AlCl3/SiO2 10% wt%3 eq. of AlCl374532003AlCl3374601404FeCl338468605FeCl2399412846Fe(NO3)33993315527Fe(acac)3300008MoCl5399751014∗Reaction conditions: NaOCl (3 eq.), CH2Cl2/H2O (1 : 1, 10 mL), RT, and 30 min.First, we have checked the reaction in the presence of a prepared supported catalyst AlCl3/SiO2 10% wt% (Table 1, entries 1-2). A slight conversion is observed when the reaction is carried out with a catalytic amount of a prepared supported catalyst AlCl3/SiO2 10% wt% (entry 1). However, a conversion of 74% with selectivity of 53% (b) and 10% (c) were obtained with a stoichiometric amount of AlCl3/SiO2 10% wt% (entry 2). From entries 1 and 2, we can assume that supported catalyst is less efficient for the allylic chlorination of terminal olefins due to the need of a stoichiometric amount of the Lewis acid.The use of nonsupported catalyst AlCl3 leads to similar result (entry 3). Table 1 shows that FeCl3 was the most reactive and selective catalyst towards monochloride (b) (entry 4). The catalytic activity of different iron Lewis acid catalysts has been performed (entries 4–7). While the presence of FeCl3 orients the reaction towards the formation of the allylic monochloride (b), FeCl2 gave mainly the vinyl allyl dichloride (e) with 86% of yield (entry 5). The examination of iron(III) Lewis catalyst ligands effect indicates that with acetylacetone practically no reaction took place which could be due to the ligand steric hindrance effect (entry 7). When the reaction was carried out with MoCl5, the corresponding monochloride (b) is formed as the major product (entry 8). It appeared that the molybdenum catalyst promotes the formation of allylic monochloride (b) with a moderate selectivity of dichloride (c) and vinyl allyl dichloride (e) contrarily to what was reported previously [44].The catalytic chlorination of carvone (a) was performed by varying the amount of FeCl3 (Figure 1). In the absence of Lewis acid catalyst, no reaction was observed even after stirring for a long reaction time. The increase of the FeCl3 equivalence resulted in the increase of the conversion of carvone (a) with the formation of both the mono- and dichloride product. The best result was obtained with 0.5 equivalence of catalyst, and a conversion of 84% was obtained. The 0.75 equivalence amount reached a slight increase of conversion with no significant increase of selectivity.Figure 1
Effect of FeCl3 amount.The effect of NaOCl on the allylic chlorination reaction was evaluated using 0.5 eq. of FeCl3 (Figure 2). In the absence of NaOCl as a chlorination agent, no reaction took place even in presence of Lewis acid catalyst. An excess of NaOCl up to 4 equivalence resulted in a maximum of conversion (96%) and a maximum of selectivity of (b) (82%).Figure 2
Effect of NaOCl amount.According to the literature [38, 43, 44], the modest selectivity of dichlorinated product proved its presence for the first time in Lewis acid catalytic system. In order to confirm the formation of dichloride compound, a chlorination reaction starting from monochloride (b) was carried out and no conversion was observed. Based on this result, we can predict that the dichlorinated product is formed by direct addition on the double bond.Under the optimized conditions with FeCl3 as a catalyst, allylic chlorination of various nonfunctionalized olefins has been carried out (Table 2). All the proposed terpenic olefins (α-pinene d, β-pinene e, and limonene f) were converted totally to the corresponding monochlorinated g and the dichlorinated h. At lower temperature of 0°C, no improvement on the selectivity is detected. In addition, a complex mixture was obtained.Table 2
Allylic chlorination of nonfunctionalized terpenic olefinsa.
aReaction conditions: FeCl3 (0.5 eq.), NaOCl (4 eq.), CH2Cl2/H2O (1 : 1, 10 mL), RT, and 30 min. bConversion was determined by GC using dodecane as an internal standard.To shed more light on the activity of FeCl3, we have extended the allylic chlorination to a much more demanding functionalized terpenic olefins such as limonene oxide, pulegone, perillyl aldehyde, limona ketone and nootkatone (Table 3). The results depicted in Table 3 demonstrate that functionalized terpenic olefins were found to be more reactive than the nonfunctionalized ones. Except for limona ketone (entry 5), all substrates were converted to the corresponding allylic monochlorides as a major product (entries 1–4 and 6). It is noteworthy that perillyl aldehyde and carvone lead to the formation of a new vinyl allyl dichlorides in moderate yield (entries 5-6 (Table 1) and entry 4 (Table 3)). As vinyl chloride derivatives represent great interest in organic synthesis and biological activity [38, 48, 49], this procedure may serve as a tool for their synthesis in a simple one step. All isolated pure products were fully characterized by 1H, 13C NMR, and mass spectroscopy (Supporting Information, Figures S1–S41).Table 3
Allylic chlorination of functionalized terpenesa.
aReaction conditions: FeCl3 (0.5 eq.), NaOCl (4 eq.), CH2Cl2/H2O (1 : 1, 10 mL), RT, and 30 min. bConversion was determined by GC using dodecane as an internal standard.Despite no reaction took place in the absence of Lewis acid catalyst, it has been reported that chlorine is usually generated from NaOCl [38, 43, 44]. The allylic chlorination reaction is probably based on the mild generation of electrophilic chlorine from NaOCl to a chlorination of the corresponding alkene. The loss of proton of the cationic intermediate leads to the formation of the major allylic chlorinated product (Scheme 3).Scheme 3
Proposed mechanism of allylic chlorination of terpenic olefins.


## 3. Conclusion

An efficient methodology for the catalytic allylic chlorination of naturally occurring terpenes using inexpensive and readily available Lewis acid catalysts combined with NaOCl has been investigated. The reaction was performed with a high degree of efficiency and selectivity. All the proposed terpenic olefins exhibit marked activity under mild conditions and lead to the corresponding mono- or dichlorides derivatives in good yields. Various supported and nonsupported Lewis acid catalysts were studied. Different iron precursors have been checked and interesting results have been obtained with FeCl3 and FeCl2. The reaction provides a useful entry to new functionalized terpenic olefin products.


## 4. General Procedure

In a typical procedure, terpenic olefin (1 mmol) in 10 mL of CH2Cl2 is added to a vigorously stirred solution of FeCl3 (0.5 eq.) in 10 mL of H2O. The mixture is vigorously stirred and a diluted NaOCl (4 eq.) is added dropwise for 5 min. After 30 min, a saturated aqueous Na2SO3 solution is added and the mixture is extracted with CH2Cl2 (3 × 10 mL). The organic layer is dried over anhydrous Na2SO4. Then, the solvent was removed under reduced pressure. The pure chlorinated products were obtained by column chromatography over silica gel using hexane and ethyl acetate as eluents. The isolated pure products were fully characterized by 1H, 13C NMR, and GC-MS.Carvone monochloride b1H NMR (300 MHz) d 6.69 (m, 1H, =CH), 5.19 (s, 1H, =CH2), 4.99 (s, 1H, =CH2), 4.03 (s, 2H,–CH2Cl), 2.9 (m, 1H, CH), 2.61 (m, 2H, CH2), 2.4 (m, 2H, CH2), 1.75 (s, 3H, –CH3). 13C NMR (75 MHz) d 198.8 (C=O), 146.5 (=C–), 144.1 (=CH–), 135.5 (=C–), 115.0 (=CH2), 46.9 (CH2Cl), 43.0 (CH2), 37.8 (CH), 31.3 (CH2), 15.6 (CH3). MS (EI): m/z = 184.0176 [M]+.Carvone dichloridec1H NMR (300 MHz) d 7.21 (m, 1H, =CH), 3.45 (m, 2H, –CH2Cl), 2.5 (m, 2H, CH2), 2.3 (m, 1H, CH), 2.15 (m, 2H, CH2), 1.71 (s, 3H, –CH3), 1.19 (s, 3H, –CH3). 13C NMR (75 MHz) d 198.0 (C=O), 144.15 (=CH–), 135.30 (=C–), 72.69 (–C–Cl), 52.60 (CH2Cl), 41.64 (CH), 39.36 (CH2), 26.28 (CH2), 21.80 (CH3), 15.62 (CH3). MS (EI): m/z = 220.0758 [M]+.Carvone vinyl allyl dichloridee1H NMR (300 MHz) d 6.74 (m, 1H, =CH), 6.12 (s, 1H, =CHCl), 4.20 (s, 2H,–CH2Cl), 3.00 (m, 1H, CH), 2.60 (m, 2H, CH2), 2.49 (m, 2H, CH2), 1.70 (s, 3H, –CH3). 13C NMR (75 MHz) d 197.97 (C=O), 143.69 (=CH–), 139.70 (=C–), 135.77 (=C–), 119.91 (=CHCl), 42.40 (–CH2Cl), 42.0 (CH2), 39.56 (CH), 31.15 (CH2), 15.62 (CH3). MS (EI): m/z = 218 [M]+.Limonene oxide monochloride1H NMR (300 MHz) d 4.96 (s, 1H, =CH2), 4.95 (s, 1H, =CH2), 4.02 (s, 2H,–CH2Cl), 2.99 (m, 1H, –O–CH–), 2.36 (m, 1H, CH), 1.35–1.93 (m, 6H), 1.30 (s, 3H, –CH3). 13C NMR (75 MHz) d 148.76 (=C–), 113.65 (=CH2), 58.97 (O–CH), 57.12 (O–C), 47.37 (CH2Cl), 32.42 (CH), 30.70 (CH2), 28.46 (CH2), 24.66 (CH2), 22.96 (CH3). MS (EI): m/z = 185.0668 [M]+.Limonene oxide dichloride1H NMR (300 MHz) d 3.55 (s, 2H,–CH2Cl), 3.02 (m, 1H, –O–CH–), 2.05 (m, 1H, CH), 2.01–1.50 (m, 6H), 1.33 (s, 3H, –CH3), 1.13 (s, 3H, –CH3). 13C NMR (75 MHz) d 73.37 (–C–Cl), 58.78 (O–CH), 57.66 (O–C), 53.23 (CH2Cl), 39.78 (CH), 30.58 (CH2), 24.89 (CH2), 22.85 (CH3), 22.96 (CH3), 20.45 (CH2). MS (EI): m/z = 220.9909 [M]+.Pulegone monochloride1H NMR (300 MHz) d 5.20 (s, 1H, =CH2), 5.14 (s, 1H, =CH2), 2.35–2.80 (m, 2H, CH2), 2.30 (m, 2H, CH2), 1.96 (m, 1H, CH), 1.90 (m, 3H, –CH3), 1.84 (m, 2H,CH2), 1.06 (d, 3H, –CH3). 13C NMR (75 MHz) d 203.76 (C=O), 143.44 (=C–), 115.25 (=CH2), 76.09 (–C–Cl), 45.54 (CH2), 37.97 (CH2), 34.39 (CH), 29.64 (CH2), 21.48 (CH3), 20.58 (CH3). MS (EI): m/z = 186.1188 [M]+.Pulegone dichloride1H NMR (300 MHz) d 2.38–2.86 (m, 2H, CH2), 2.15 (m, 1H, CH), 1.79–2.38 (m, 2H, CH2), 1.79 (m, 2H, CH2), 1.44 (s, 3H, –CH3), 1.35 (s, 3H, –CH3), 1.05 (d, 3H, –CH3). 13C NMR (75 MHz) d 208.21 (C=O), 75.13 (–C–Cl), 74.96 (–C–Cl), 46.63 (CH2), 35.22 (CH2), 29.49 (CH2), 25.52 (CH), 21.99 (2CH3), 18.15 (CH3). MS (EI): m/z = 222.9984 [M]+.Perillyl aldehyde monochloride1H NMR (300 MHz) d 9.43 (s, 1H, HC=O), 6.83 (m, 1H, =CH), 5.23 (s, 1H, =CH2), 5.02 (s, 1H, =CH2), 4.09 (s, 2H,–CH2Cl), 2.02–2.53 (m, 2H, CH2), 2.25 (m, 1H, CH), 1.42–1.72 (m, 2H, CH2), 0.87–1.24 (m, 2H, –CH2). 13C NMR (75 MHz) d 193.74 (HC=O), 149.82 (=CH–), 148.25 (=C–), 141.15 (=C–), 114.20 (=CH2), 47.56 (CH2Cl), 36.21 (CH), 32.13 (CH2), 26.51 (CH2), 21.46 (CH2). MS (EI): m/z = 184.0441 [M]+.Perillyl aldehyde vinyl allyl dichloride1H NMR (300 MHz) d 9.45 (s, 1H, HC=O), 6.82 (m, 1H, =CH), 6.12 (m, 1H, =CHCl), 4.29 (s, 2H,–CH2Cl), 1.58–2.59 (m, 2H, CH2), 1.99 (m, 1H, CH), 1.26 (m, 2H, –CH2), 0.87–2.30 (m, 2H, CH2). 13C NMR (75 MHz) d 193.51 (HC=O), 148.79 (=CH–), 141.26 (=C–), 141.10 (=C–), 119.00 (=CHCl), 40.11 (CH2Cl), 37.86 (CH), 31.81 (CH2), 26.28 (CH2), 21.40 (CH2). MS (EI): m/z = 218.0015 [M]+.Limona ketone dichloride1H NMR (300 MHz) d 4.04 (m, 1H,–CHCl), 2.82 (m, 1H, CH), 1.89–2.35 (m, 2H, CH2), 2.17 (s, 3H, –CH3), 1.76–1.95 (m, 2H, CH2), 1.56–1.76 (m, 2H, CH2), 1.35 (s, 3H, –CH3). 13C NMR (75 MHz) d 211.13 (C=O), 71.46 (–CCl), 64.75 (–CHCl), 44.64 (CH), 32.62 (CH2), 31.80 (CH2), 28.14 (CH3), 27.32 (CH3), 23.28 (CH2). MS (EI): m/z = 206.9165 [M]+.Nootkatone monochloride1H NMR (300 MHz) d 5.66 (m, 1H, =CH), 5.09 (s, 1H, =CH2), 4.90 (s, 1H, =CH2), 4.01 (s, 2H,–CH2Cl), 2.47 (m, 2H, CH2), 2.29 (m, 1H, CH), 2.15 (m, 2H, CH2), 1.91 (m, 2H, CH2), 1.27 (m, 1H, CH), 1.04–1.97 (m, 2H, CH2), 1.04 (s, 3H, –CH3), 0.87 (d, 3H, –CH3).13C NMR (75 MHz) d 199.08 (C=O), 169.58 (=C–), 148.67 (=C–), 124.74 (=CH–), 113.80 (=CH2), 47.70 (CH2Cl), 44.17 (CH2), 41.95 (CH2), 40.30 (CH), 39.35 (–C–), 35.72 (CH), 32.85 (CH2), 31.91 (CH2), 16.67 (CH3), 14.87 (CH3). MS (EI): m/z = 252.0591 [M]+.Nootkatone dichloride1H NMR (300 MHz) d 5.76 (m, 1H, =CH), 3.57 (m, 1H, CH2Cl), 3.64 (m, 1H, CH2Cl), 2.40 (m, 1H, CH), 2.23–2.50 (m, 2H, CH2), 2.06 (m, 2H, CH2), 1.99–2.29 (m, 2H, CH2), 1.87–2.12 (m, 2H, CH2), 1.25 (m, 1H, CH), 1.19 (s, 3H, –CH3), 1.10 (m, 3H, –CH3), 0.98 (m, 3H, –CH3).13C NMR (75 MHz) d 199.50 (C=O), 170.08 (=C–), 124.62 (=CH–), 73.33 (–CCl), 53.47 (CH2Cl), 42.04 (CH2), 40.53 (CH), 39.96 (CH), 39.68 (CH), 32.72 (CH2), 27.70 (CH2), 26.67 (CH2), 21.22 (CH3), 16.75 (CH3), 14.96 (CH3). MS (EI): m/z = 288.0343 [M]+.



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*Source: 2563634-2020-10-22.xml*