untitled European Journal of Chemistry 5 (3) (2014) 383‐387 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2014 Eurjchem Publishing ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.5.3.383‐387.1029 European Journal of Chemistry Journal homepage: www.eurjchem.com Comparative study of reactivity of (‐)‐R‐carvone, (‐)‐R‐linalool and (‐)‐(1S,4S)‐camphor derivatives: Synthesis of new heterocycles Mohamed Rouani a, Bouchra Rahmouni a, Malika Chammache b, Aziz El‐Mebtoul a and Abdelkader Ilidrissi a,* a Department of Chemistry, Laboratory of Plant Chemistry, Organic and Bio‐organic Synthesis, Faculty of Sciences, University Mohammed V. Agdal, Rabat, BP1014, Morocco b Department of Chemistry, Heterocyclic Chemistry Laboratory, Faculty of Sciences, University Mohammed V Agdal, Rabat, BP1014, Morocco *Corresponding author at: Department of Chemistry, Laboratory of Plant Chemistry, Organic and Bio‐organic Synthesis, Faculty of Sciences, University Mohammed V. Agdal, Rabat, BP1014, Morocco. Tel.: +212.066.8547336. Fax: +212.053.7775440. E‐mail address: a.ilidrissi@yahoo.fr (A. Ilidrissi). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.5.3.383‐387.1029 Received: 03 February 2014 Received in revised form: 10 March 2014 Accepted: 17 March 2014 Online: 30 September 2014 KEYWORDS Reactivity comparison by 1,3‐dipolar cycloaddition of the three dipolarophiles (‐)‐R‐Carvone (I), (‐)‐R‐Linalool (II) and derivative of (‐)‐(1S,4S)‐camphor (III) has been studied. By reactions of p‐chlorophenylnitrile oxide, new heterocycles are obtained by stereospecific reactions for cyclic Terpenoids I and III (regardless of the length of the side chain). However the aliphatic dipolarophile II gives two diastereoisomers. Terpenoids (‐)‐R‐Carvone I (‐)‐R‐ Linalool II and (‐)‐(1S,4S)‐Camphor 1 are isolated respectively from Moroccan species Mentha viridis (L.), Lavandula officinalis (L.) and Artemisia herba halba (Asso). The new heterocycles obtained were identified by combination of chromatographic and spectroscopic methods. Mentha Artemisia Lavandula Terpenoids Cycloaddition Phenylnitrile oxide 1. Introduction In the trials of valorisation of Moroccan plants traditionally known for their medicinal and aromatic power [1‐13], we have undertaken a comparative study of reactivity of the major compounds of the essential oils from three different species. There are the (‐)‐R‐Carvone (I) extracted from Mentha viridis (L.), (‐)‐R‐Linalool (II) contained in Lavandula officinalis (L.) and dipolarophile (III) synthesized from (‐)‐(1S,4S)‐Camphor, 1. The latter is isolated from the species Artemisia herba halba (Asso.) (Scheme 1). In literature, it is shown that there are many cycloaddition reactions on the terminal double bonds towards the nitrile oxides, both inter‐molecular and intra‐molecular. These reactions are often carried out on dipolarophiles whose stereochemistry is often not given [14‐20]. In this work, we have tried to synthesize new molecules that may have some pharmacological applications, or that have interesting olfactory properties. To do this, we have chosen three dipolarophiles I, II and III (pure enantiomers) from the class of terpenoids where the terminal double bond fills various positions. In the dipolarophile III, the double bond is located on a long side chain compared to that of the dipolarophile I [1], while in the dipolarophile II, it fills an aliphatic chain. We first found that, from a stereo selective point of view, p‐chloro phenylnitrile oxide oxygen atom always bonds to the most substituted carbon of the terminal double bond. Moreover, we noticed that the presence of the terpene cycle plays an important role in the stereospecificity of the reaction. The 1,3‐ dipolar cycloaddition on dipolarophile I and III (cyclic dipolarophiles) are indeed stereospecific; however dipolarophile II (aliphatic dipolarophile) provides a mixture of diastereoisomers. We wanted to check, if the stereospecificity in dipolarophile III is due solely to the presence of the terpenic ring. For this, we did the epoxidation of the terminal double bond. This reaction provided a mixture of stereoisomers, which shows that the size of the isoxazolinic cycle also plays a certain role in the stereospecificity of the reaction. This result is consistent with the literary data regarding the epoxidation of the terminal double bonds in dipolarophile I and II [21‐23]. 384 Rouani et al. / European Journal of Chemistry 5 (3) (2014) 383‐387 Scheme 1 2. Experimental 2.1. Instrumentation Melting points were measured with Banc‐Kofler and were confirmed on Buchi B‐545. Infrared spectra were measured on Perkin‐Elmer 577 and Bruker‐Tensor 27. Products are dispersed solid phase in KBr. 1H and 13C NMR spectra were taken on Bruker Spectroscopin AC 200 and Perkin Elmer R24A in deuteriochloroform with Me4Si as an internal standard. Chemical shifts are reported in ppm downfield from internal standard, with coupling constants in Hertz. Mass spectra were recorded with Wewlett‐Packar 5995B. Optical rotations were measured on Perkin Elmer 141 polarimeter and were confirmed on electronic polarimeter ADP 220 Belligham. 2.2. Preparation of (R)‐5‐((S)‐3‐(4‐chlorophenyl)‐5‐methyl‐ 4,5‐dihydroisoxazol‐5‐yl)‐2‐methylcyclohex‐2‐enone (I’) In a 200 mL erlenmeyer flack, equipped with a bromine funnel, were introduced 1.00 g of (‐)‐(R)‐carvone (6.66 mmol) and 1.03 g of 4‐chlorobenzaldehyde oxime in CHCl3 (30 mL). The solution was stirred at 0 °C for 4 h, while 25 mL of Javel water 24° (NaOCl) were added dropwise. The mixture was stirred at room temperature for 48 h. The progress of the reaction was followed by TLC. The aqueous phase was washed with CH2Cl2 (50 mL), the combined organic phases were dried (Na2SO4) and evaporated to dryness. The oil residue was taken up with Et2O (25 mL). A white solid appeared which was isolated by filtration (Scheme 2). (R)‐5‐((S)‐3‐(4‐chlorophenyl)‐5‐methyl‐4,5‐dihydroisoxazol‐ 5‐yl)‐2‐methylcyclohex‐2‐enone (I’): Color: White. Yield: 70%. M.p.: 165‐167 °C. IR (KBr, ν, cm‐1): 1660 (C=O), 1620 (C=C). 1H NMR (200 MHz, CDCl3, δ, ppm): 1.82 (s, 3H, Me(12)), 1.53 (s, 3H, Me(13)), 2.20 (m, 2H, CH2(11)), 2.32‐2.83 (m, 3H, H‐C(6), CH2(7)), 3.09; 3.20 (AB, J = 16 Hz, 2H, CH2(4)), 6.76‐6.84 (m, 1H, H‐C(10)), 7.41 (d, J = 9 Hz, 2H, H‐C(3’), H‐C( 5’)), 7.63 (d, J = 9 Hz, 2H, H‐C(2’), H‐C( 6’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 16.06 (C(13)), 23.39 (C(12)), 27.52 (C(4)), 40.01 (C(6)), 44.21 (C(7)), 44.28 (C(11)), 88.82 (C(5)), 128.10 (C(3’), C(5’)), 128.45 (C(4’)), 129.43 (C(2’), C( 6’)), 135.95 (C(1’)), 136.41 (C(9)), 144.72 (C(10)), 155.28 (C(3)), 199.12 (C(8)). MS (EI, m/z (%)): 303 (M+, 80), 288 (34), 273 (28), 194 (60), 179 (40), 68 (56). 2.3. Preparation of compounds IIa and IIb In a 200 mL erlenmeyer flack, equipped with a bromine funnel, were introduced 1.50 g of 4‐chlorobenzaldehyde oxime in CHCl3 (60 mL) and 1.50 mL of (‐)‐(R)‐linalool. The solution was stirred at 0 °C for 45 min, while 50 mL of Javel water 24° (NaOCl) were added dropwise. The aqueous phase was washed with CH2Cl2 (50 mL), the combined organic phases were dried (Na2SO4) and evaporated to dryness. The obtained oil residue showed two separated spots on TLC (Rf : 0.52 and 0.62; CHCl3, on Silica gel). The two products IIa and IIb are separated on a silica gel column (Eluent: CHCl3:AcOEt, 90:10, v:v) (Scheme 3). (R)‐2‐((S)‐3‐(4‐chlorophenyl)‐4,5‐dihydroisoxazol‐5‐yl)‐6‐ methylhept‐5‐en‐2‐ol (IIa): Color: White. Yield: 70%. M.p.: 230‐ 232 °C. IR (KBr, ν, cm‐1): 3330 (OH), 1600 (C=C). 1H NMR (300 MHz, CDCl3, δ, ppm): 1.15 (s, 3H, Me(11)), 1.44 (m, 1H, OH(6)), 1.66 (s, 3H, Me(12)), 1.71 (s, 3H, Me(13)), 1.87 (m, 2H, CH2(7)), 2.13 (m, 2H, CH2(8)), 3.22 (m, 2H, CH2(4)), 4.59 (m, 1H, H‐C(5)), 5.11 (m, 1H, H‐C(9)), 7.26 (d, J = 9 Hz, 2H, H‐C(3’), H‐C( 5’)), 7.56 (d, J = 9 Hz, 2H, H‐C(2’), H‐C( 6’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 21.59 (C(11)), 22.26 (C(7)), 22.42 (C(8)), 23.00 (C(12)), 35.05 (C(13)), 39.02 (C(4)), 72.82 (C(6)), 86.80 (C(5)), 123.84 (C(10)), 127.82 (C(2’), C( 6’)), 127.91 (C(4’)), 128.50 (C(3’), C(5’)), 131.99 (C(1’)), 135.90 (C(9)), 156.32 (C(3)). MS (EI, m/z (%)): 307 (M+, 90), 289 (65), 180 (45), 145 (48), 112 (40), 109 (20). 2‐((R)‐3‐(4‐chlorophenyl)‐4,5‐dihydroisoxazol‐5‐yl)‐6‐methyl hept‐5‐en‐2‐ol (IIb): Color : White. Yield: 70%. M.p.: 204‐206 °C. IR (KBr, ν, cm‐1): 3326 (OH), 1610 (C=C). 1H NMR (300 MHz, CDCl3, δ, ppm): 1.32 (s, 3H, Me(11)), 1.46 (m, 1H, OH(6)), 1.68 (s, 3H, Me(12)), 1.75 (s, 3H, Me(13)), 1.89 (m, 2H, CH2(7)), 2.16 (m, 2H, CH2(8)), 3.36 (m, 2H, CH2(4)), 4.69 (m, 1H, H‐C(5)), 5.15 (m, 1H, H‐C(9)), 7.35 (d, J = 9 Hz, 2H, H‐C(3’), H‐C( 5’)), 7.59 (d, J = 9 Hz, 2H, H‐C(2’), H‐C( 6’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 21.93 (C(11)), 22.42 (C(7)), 22.26 (C(8)), 23.18 (C(12)), 35.28 (C(13)), 39.05 (C(4)), 72.94 (C(6)), 86.83 (C(5)), 123.89 (C(10)), 127.61 (C(2’), C( 6’)), 127.91 (C(4’)), 128.89 (C(3’), C(5’)), 132.21 (C(1’)), 134.20 (C(9)), 156.35 (C(3)). MS (EI, m/z (%)): 307 (M+, 70), 289 (75), 180 (45), 145 (52), 112 (60), 109 (32). 2.4. Preparation of (1S,4S,E)‐1,7,7‐trimethylbicyclo[2.2.1] heptan‐2‐one O‐allyloxime (III) In a balloon we dissolve 1.36 g of NaOH (34 mmol) and 2.26 g (32 mmol) of H2NOH/HCl in 10 mL of distilled H2O, then we add 2 g (13 mmol) of (‐)‐(1S,4S)‐Camphor in 30 mL of ethanol, we obtain a limpid solution. 20 hours of reflux was necessary, then the ethanol was evaporated, the aqueous phase was cooled. It's form a crystal of oxime that we recrystallized in pentane (P.F.: 120 °C, Yield: 85%). On a solution with 4 g (23.9 mmol) of oxime in 50 mL of toluene we add with little fraction 0.65 g (23.9 mmol) of NaH under nitrogen and agitation. After 5 min, 23 mmol of allylbromure was introduced; the mixture was left under agitation at room temperature for 12 hours. The organic phase extract was dried; the toluene was eliminated under low pressure. The residue was separated and purified on silica gel (Hexane:AcOEt, 95:5, v:v), to give compound III. Rouani et al. / European Journal of Chemistry 5 (3) (2014) 383‐387 385 Scheme 2 Scheme 3 N O CH CH2 Br O 1 III 1' 2' 3' 1 2 345 6 7 8 9 1) NH2OH / NaOH 2) / NaH 10 Scheme 4 (1S,4S,E)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one o‐allyl oxime (III): Color: White. Yield: 72%. M.p.: 154‐156 °C. IR (KBr, ν, cm‐1): 3010 (C‐H), 1645 (C=N), 1640 (C=C). 1H NMR (300 MHz, CDCl3, δ, ppm): 0.82 (s, 3H, Me(10)), 0.94 (s, 3H, Me(8)), 1.02 (s, 3H, Me(9)), 1.55‐1.92 (m, 5H, CH(4), CH2(5), CH2(6)), 2.22 (m, 2H, CH2(3)), 5.12 (d, J = 3 Hz, 1H, CHa(3’)), 5.22 (d, J = 3 Hz, 1H, CHb(3’)), 5.43 (d, J = 2 Hz, 2H, CH2(1’)), 6.04 (m, 1H, CHc(2’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 12.52 (C(4)), 18.62 (C(5)), 19.75 (C(6)), 27.50 (C(1)), 32.50 (C(3)), 34.56 (C(7)), 44.15 (C(10)), 48.22 (C(9)), 52.32 (C(8)), 74.54 (C(1’)), 118.62 (C(2’)), 135.24 (C(3’)), 170.22 (C(2)). 2.5. Preparation of compound IIIa In a 200 mL erlenmeyer flack, equipped with a Br2 funnel, were introduced 1.30 g of 4‐chlorobenzaldehyde oxime in CHCl3 (80 mL) and 1.84 g (9.60 mmol) of III. The solution was stirred at 0 °C for 60 min. With the same I’ obtention procedure, the reaction gave an isoxazolinic compound IIIa in pure form for analysis (Scheme 4 and 5). (1S,4S,E)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one o‐((3‐(4‐ chlorophenyl)‐4,5‐dihydroisoxazol‐5‐yl)methyl) oxime (IIIa): Color: White. Yield: 82%. M.p.: 218‐220 °C. IR (KBr, ν, cm‐1): 1640 (C=N), 1620 (C=C), 1045 (C‐H). 1H NMR (300 MHz, CDCl3, δ, ppm): 0.92 (s, 3H, Me(16)), 0.97 (s, 3H, Me(15)), 1.04 (s, 3H, Me(14)), 1.72‐1.94 (m, 5H, CH(11), CH2(9), CH2(10)), 2.32 (m, 2H, CH2(12)), 4.12 (d, J = 3 Hz, 1H, H‐C(6)), 4.16 (d, J = 3 Hz, 1H, H‐C(6)), 3.62 (m, 2H, CH2(4)), 4.71 (m, 1H, H‐C(5)), 7.42 (d, J = 9 Hz, 2H, H‐C(3’), H‐C( 5’)), 7.72 (d, J = 9 Hz, 2H, H‐C(2’), H‐C( 6’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 20.74 C(13)), 21.40 (C(11)), 24.15 (C(10)), 27.94 (C(9)), 39.45 (C(8)), 44.20 (C(4)), 52.67 (C(15)), 54.20 (C(14)), 56.40 (C(16)), 67.82 (C(6)), 82.25 (C(5)), 127.41 (C(2’), C( 6’)), 128.15 (C(4’)), 129.15 (C(3’), C(5’)), 132.41 (C(1’)), 158.21 (C(3)), 167.63(C(7)). MS (EI, m/z (%)): 360 (M+, 94), 345 (38), 211 (40), 193 (60), 158 (30), 167 (75), 152(25), 149 (65). 2.6. Preparation of (1S,4S,E)‐1,7,7‐trimethylbicyclo[2.2.1] heptan‐2‐one O‐oxiran‐2‐ylmethyl oxime (IIIb) Under moderate agitation and ambient temperature we dissolved 0.50 g (2.40 mmol) of the compound III and 0.83 g (4.80 mmol) of metachloroperbenzoic acid in 10 mL of CH2Cl2. 386 Rouani et al. / European Journal of Chemistry 5 (3) (2014) 383‐387 Scheme 5 The reaction is left overnight, the mixture is then cooled to remove the formed benzoic acid. The filtrate is washed by the sodium bisulfite 20%, then by Na2SO4 10% and finally by a saturated solution of NaCl. The organic phase is dried on MgSO4 and evaporated to dry. The resulting residue provides IIIb after purification on silica gel (Eluent, Hex:AcOEt, 90:10, v:v) (Scheme 4 and 5). (1S,4S,E)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one o‐oxiran ‐2‐ylmethyl oxime (IIIb): Color: Yellow. Yield: 70%. IR (Film, ν, cm‐1): 1075 (C‐O‐C), 1653 (C=N). 1H NMR (300 MHz, CDCl3, δ, ppm): 0.84 (s, 3H, Me(10)), 0.92 (s, 3H, Me(8)), 1.10 (s, 3H, Me(9)), 1.66‐1.85 (m, 5H, CH(4), CH2(5), CH2(6)), 2.28 (m, 2H, CH2(3)), 2.21, 3.22 (ABX, 3H, CH2(3’), H‐C(2’)), 4.02 (d, J = 2 Hz, 2H, CH2(1’)). 13C NMR (50 MHz, CDCl3, δ, ppm) : 13.04 C(4)), 19.12 (C(5)), 20.14 (C(6)), 28.12 (C(1)), 32.75 (C(3)), 35.22 (C(7)), 47.12 (C(10)), 50.22 (C(9)), 55.12 (C(8)), 62.20 (C(2’)), 68.17 (C(3’)) 70.40 (C(1’), 172.15 (C(2)). 3. Results and discussion 3.1. Formation of compound I’ (‐)‐R‐Carvone I, [α]20D = ‐61±2 ° was isolated from Mentha viridis (L.), a plant cultivated in Morocco. It was identified by combination of chromatographic and spectroscopic methods. This compound alone represents 70% of the essential oil of the plant. Addition of p‐chlorophenylnitrile oxide to (‐)‐R‐Carvone took place in a chloroform environment with stirring at 0 °C. The addition has affected only the double bond in C8 to give isoxazoline I’ (Scheme 2). 3.2. Formation of compounds IIa and IIb (‐)‐R‐Linalool II, [α]20D = ‐ 20±2 ° is the majority (60‐70%) constituent of the essential oil from Lavandula officinalis (L.). It was isolated by fractionary distillation using a micro oven and identified by spectroscopic methods. The addition of the dipole was held in chloroform medium, under agitation at 0 °C. The reaction has only affected the less substituted vinyl double bond, giving an appreciable quantity of two separable diastereoisomers (Scheme 3). 3.3. Formation of compound III The natural camphor is a main constituent of several essential oil [8,11,12]. The dextrogyre isomeric is the most shed in nature, then that his enantiomeric levogyre is then rare. The Moroccan Artemisia herba alba (Asso) is rich into this last compound, and will present a particular interest [8]. In our study, our choice was tacked of levogyre camphor for two reasons: First, his rarity in nature then that Moroccan Artemisia contains about 70% of it into his essential oil. The second reason that it used rarely in organic synthesis. These two reasons give originality for our compounds that we have synthesised. (‐)‐(1S,4S)‐Camphre 1 was isolated from Artemisia herba alba (Asso) his natural site. This species harvested in Morocco at flowering period, was passed on hydro distillation in dry state. The essential oil obtained was distilled under moderate temperature until draining all light products. After cooling a residue, (‐)‐(1S,4S)‐Camphre 1 deposit. Filtered and recrystal‐ lized in pentane, the (‐)‐(1S,4S)‐Camphre 1 was obtained in a pure state. PF = 178 °C; []D20 = ‐42.5±2° (c = 10, Ethanol). When NH2OH react on 1, this reaction was followed by the action of the allylbromure into toluene in the presence of NaH, at ambient temperature; we got the compound O‐alkylated III (Scheme 4). 3.4. Formation of compounds IIIa and IIIb In order to synthesize new molecules susceptible to present some pharmacodynamic applications from camphor derivative, we have added p‐chlorophenylnitrile oxide to dipolarophile III. The reaction took place in the presence of Javel water 24° with stirring at 0 °C for 36 hours. We obtained new compound, with heterocyclic structure isoxazoline IIIa (Scheme 5). The same camphor derivative III furnish a mixture of epoxid (2’R,2’S) IIIb after action of metachloroperbenzoic acid (CPBA) (Scheme 5). 4. Conclusion Under identical operating conditions, we reacted in the presence of p‐chlorophenylnitrile oxide, the constituents of the Moroccan medicinal plants, namely: (‐)‐R‐Carvone, (‐)‐R‐ Linalool, and (‐)‐(1S,4S)‐camphor. The new heterocycles obtained allowed us to obtain the following findings: from structural point of view, we noticed that the oxygen atom of the dipole always binds to the more substituted carbon. Stereochemical terms, we noticed that the presence of the terpene cycle (regardless of the length of the side chain) has played an important role in the guidance and the stereospecificity of the reaction. Rouani et al. / European Journal of Chemistry 5 (3) (2014) 383‐387 387 Acknowledgement The authors thank strongly the CNRST‐UATRS services for work performed in spectroscopy. References [1]. El‐Mebtoul, A.; Rouani, M.; Chammache, M.; Bouidida, H.; Ilidrissi, A. Helvetica Chim. Acta 2011, 94, 433‐437. [2]. Bouidida, H.; Alaoui, K.; Cherrah, Y.; Ilidrissi, A. Phytotherapie 2004, 4, 120‐125. [3]. Bouidida, H.; Alaoui, K.; Cherrah, Y.; Ilidrissi, A. S. F. P. T. Therapie 2006, 4, 1‐6. [4]. Talbaoui, A.; Jamaly, N.; Aneb, M.; Ilidrissi, A. J. Med. Plants Res. 2012, 6, 4593‐4600. [5]. 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