Acta Chim. Slov. 2004, 51, 223-230. 223 Scientific Paper CATALYTIC OXIDATIVE CLEAVAGE OF TERPENIC OLEFINS: USEFUL ROUTE TO CHIRAL POLY-FUNCTIONALISED CYCLOBUTANES AND CYCLOPROPANES Hosni Ziyat, Mustapha Ait Ali,* Abdalah Karim, Catherine Meliet, Yves Castanet, and Andre Mortreux Laboratoire de Chimie de Coordination, Faculté des Sciences-Semlalia BP 2390 Marrakech (Morocco), E-mail: aitali@ucam.ac.ma Laboratoire de Catalyse de Lille, Groupe de Chimie Organique Appliaué, UPRESA 8010, ENSC Lille, BP 108, 59642 Villeneuve d’Ascq (France) Received 22-11-2003 Abstract Catalytic oxidation of terpenic olefins (?-pinene, 2-carene and 3-carene) with Ru04 generated in situ, produces the cyclobutane and cyclopropane isolable keto-aldehydes which evolve in prolonged reaction tirne to the corresponding keto-acids with excellent yields (90-100%). As these compounds can serve as building block for the synthesis of cyclobutane aminoacids and pyrethroid derivatives, the reaction affords a simple access to this class of compounds. Key words: ruthenium, oxidation, cleavage, terpenes Introduction Since the discovery of highly potent pyrethroids like Deltamethrin1 and Cypermethrin2 there has been thorough activity in the field of synthesis of new acid compounds of the pyrethroids series. Several compounds in these families have been prepared by total synthesis3"7 with chrysanthemic acid derivatives often serving as the ultimate source of the chirality of the cyclopropanoid systems. However, it might be argued that naturally occurring monoterpenes such as carene can be used as inexpensive source of chiral cyclopropyl-containing synthons. Homologues of these synthons have been prepared by oxidative cleavage of carene and ?-pinene using the known methods based on KMn048"9 or ozono^sis3"5'10"11 for example (+)-cis permethrimic acid12 has been obtained from (+)-3-carene according to this method. Ruthenium tetroxide (Ru04) generated in situ under Sharpless conditions13"16 oxidatively cleaves carbon-carbon single and double bonds17 and is an efficient reagent H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... 224 Acta Chim. Slov. 2004, 51, 223-230. in oxidation of tertiary and secondary inactivated C-H bonds of saturated hydrocarbons.18 Such a procedure has been used for oxidation of (-)-?-pinene, verbenone and verbenol.19'20 However, the authors did not mention the presence of the corresponding aldehyde. Results and discussion We report here an application of this procedure in the oxidative cleavage of (+)-?-pinene 1, (+)-2-carene 2, and (+)-3-carene 3 directed towards an efficient synthesis of a series of chiral ketoaldehydes and ketoacids containing cyclobutane and cyclopropane rings. The latter can be used as potential precursors for the synthesis of cyclobutane dehydroaminoacids19 and pyrethroid derivatives.12 RuCI3-Nal04 O H20 - CH3CN CCI4 H O O OH O RuCI3-Nal04 CH3OH - CH3CN CCI4 MeO. OMe 10 Scheme 1 Table 1 summarises some representative results obtained with ?-pinene using freshly prepared Ru04 as catalyst and NaI04 (stoichoimetric) as oxidant. ?-pinene was readily cleaved to the corresponding ketoaldehyde 4 with high selectivity (Table 1 entry 1) by quenching the reaction after 40 min (Scheme 1). Increasing the reaction tirne (2 h) led to further oxidation of the aldehyde into the acid 7 (entry 2) which was obtained with 96% selectivity. H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... Acta Chim. Slov. 2004, 51, 223-230. 225 Table 1. Oxidative cleavage of (+) ?-pinene" 1 using the system RuCl3-NaI04. Entry Solvent S/Cb Time (h) Conversionc (mol %) Selectivity c (%) Aldehyde 4 Acid 7 1 CCl4/MeCN/H20 50 0.7 100 100 0 2 CCl4/MeCN/H20 50 2 100 4 96 3 CC14/H20 50 24 100 30 47 4 MeCN/H20 50 24 100 28 12 5 CCl4/MeCN/H20 100 4.5 95 0 93 6 CCl4/MeCN/H20 500 15 90 0 90 Conditions: ?-pinene = 3.16 mmol; periodic acid = 12.6 mmol; NaOH = 12.6 mmol; H20 6 mL; CH3CN = 4 mL; CC14 c determined by GC. 4 mL; Temperature =20 °C; S/C substrate/catalyst; An increase of the substrate/catalyst ratio (500 instead 50) led as expected to a slower reaction but interestingly high yield and selectivity into the acid were maintained at long reaction tirne. On the other hand modification of the reaction medium corresponding to the absence of CH3CN or CC14 induced the precipitation of ruthenium tetroxide and led to poor results as total conversion was only reached after 24 h with low aldehyde and acid selectivities. Finally when water was replaced by methanol, the oxidation of ?-pinene occurred via other reaction path to give the dimethoxylimonene 10 resulting from the opening of the cyclobutane ring rather than the double bond cleavage. Under identical conditions 2- and 3-carene behave similarly (Scheme 2, Table 2) and proceeded via the isolable keto-aldehydes 5 and 6 (entries 7 and 9) which were rapidly formed and oxidised in a slower step into the acids 8 and 9 (entries 8 and 10), without opening of the cyclopropane ring. O O OH 25 O O O O 69 Scheme 2 a O 8 3 H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... 226 Acta Chim. Slov. 2004, 51, 223-230. As in the čase of ?-pinene the acid selectivity was only slightly affected by a decrease of the catalyst/substrate ratio. On the other hand a decrease in the NalOVsubstrate ratio had a very detrimental effect on both conversion and selectivity The spectroscopic data of isolated compounds described below confirmed that the oxidative cleavage of (+)-?-pinene 1, (+)-2-carene 2 and (+)-3-carene 3 by RuCl3-NaI04 provided c/s-poly-functionalised cycloalcanes without epimerisation.19 The presence of one isomer was evidenced by the absorption signals for the CH3 protons and carbons of the gem-dimethyl substitution, which shows only one set of signals both in lH and 13C-NMR.19 On the other hand, we have reported that the use of the same procedures for the synthesis of new poly-functionalised cyclopropanes by oxidation of dichloro- and dibromo-cyclopropan-epoxy-limonene took plače without epimerisation.21 Table 2. (Mdative cleavage of 2 and 3 using the system RuCl3-NaI04.a ntiy Substrate NaI04/S S/C Time (h) Conversion (%) 100 Aldehyde selectivity*(%) 95 (6)c Acid selectivir/ (%) 7 3 4 50 0.7 0 8 3 4 50 2 100 0 92 (9)c 9 2 4 50 0.7 100 98 (5) 0 10 2 4 50 2 100 0 96 (8) 11 3 3 50 48 100 75 (6) 10 (9) 12 3 2 50 48 79 49 (6) 07 (9) 13 3 1 50 48 40 18 (6) 0 14 3 4 100 4 90 0 90 (9) 15 3 4 500 16 92 0 80 (9) 16 2 4 100 4 96 0 95 (8) 17 2 4 500 16 95 0 87 (8) a Conditions: substrate = 3.16 mmol, periodic acid = 12.6 mmol, NaOH = 12.6 mmol, H20 = 6 mL, CH3CN = 4 mL, CC14 = 4 mL, Temperature = 20 °C. * determined by GC analysis. c numbers in parentheses refer to the corresponding obtained products. Conclusion In conclusion, we have developed an effective and very easy way (in comparison to the known method based on ozonolysis3"5'10"n) to synthesise chiral poly-functionalised cycloalcanes. These products can be used, for example, in the čase of cyclopropanic compounds as starting material for the synthesis of pyrethroid homologues, which constitute an upper class of pesticides with high biological H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... Acta Chim. Slov. 2004, 51, 223-230. 227 activity.5'22"25 This method is based on the oxidative cleavage of cheap and readily available terpenes with a simple catalytic system and allows to obtain chiral ketoaldehydes or ketoacids in high yields without epimerisation. Experimental General Ali reagents and solvent were purchased from commercial sources (Aldrich, Acros) and used as received. The reaction mixture were analysed on a Trace 2000 series chromatograph equipped with an FID detector, using silica capillary columns CPSH5CB (10 m × 0.33 mm, Chrompack). Liquid chromatographies were performed on silica gel (Merk 60, 220-440 mesh; eluents: hexane-OAcEt). A BP5 (25 m × 0.25 mm) capillary column was used for GC/MS coupled analyses with a Saturn 2000 spectrometer. lH NMR and 13C NMR spectra were recorded on a Bruker Model AVANCE 300 using CDC13 as the solvent and SiMe3 as the internal standard. Optical rotations were measured on a Perkin-Elmer 343 polarimeter. General procedure for oxidative cleavage of terpenes In a typical procedure, water (6 mL), periodic acid (2.88 g, 12.6 mmol) and NaOH (0.5 g, 12.5 mmol) were introduced in a three necked flask equipped with a magnetic stirrer bar. The mixture was stirred and cooled at 0 °C (ice bath). Then, at this temperature were successively added CC14 (4 mL), CH3CN (4 mL) and RuCl3-3H20 (16.45 mg, 0.063 mmol). After 15 min, the substrate (0.422 g, 3.1 mmol) was added. The ice bath was removed and the reaction, conducted at room temperature, was monitored by gas chromatography of samples taken at regular tirne interval. At the end of the reaction, 25 mL of CHC13 were added, and the organic layer was washed, dried (MgS04), filtered on silica gel in order to remove the precipitated Ru04 and then concentrated. Products characterizations (3-Acetyl-2,2-dimethyl-cyclobutyl)-acetaldehyde (4). Yield 84 6% [?]20D +42.5 ° (c 1, EtOH); MS, m/z: 168 (M+). 'H NMR (300 MHz, CDC13) ? 0.75 (s, 3H), 1.25 (s, 3H), H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... 228 Acta Chim. Slov. 2004, 51, 223-230. 1.80-1.90 (m, 2H), 1.95 (s, 3H), 2.3-2.4 (m, 1H), 2.45 (dd, 7 2.19, 1.28 Hz, 2H), 2.84 (dd, 7 12.0, 14.2 Hz, 1H), 9.64 (d, 7 1.28 Hz, 1H); 13C NMR (75 MHz, CDC13) ? 17.4 (CH3), 22.6 (CH2), 29.9 (CH3), 30.1 (CH3), 35.6 (CH), 43.1 (Cq), 44.9 (CH2), 54.1 (CH), 201.3 (CHO), 207.3 (C=0). 2,2-Dimethyl-3-(3-oxo-butyl)-cyclopropanecarbaldehyde (5). Yield 71.5%. [?]20D +25.8° (c 1, EtOH). MS, m/z: 168 (M+). lH NMR (300 MHz, CDC13) ? 1.14-1.25 (m, 1H), 1.19 (s, 3H), 1.33 (s, 3H), 1.42-1.61 (m, 1H), 1.92-2.05 (m, 2H), 2.14 (s, 3H), 2.40-2.49 (m, 2H), 9.46 (d, 7 4.8 Hz, 1H). 13C NMR (75 MHz, CDC13) ? 14.9 (CH3), 18.6 (CH3), 28.9 (CH3), 29.9 (CH), 30.1 (Cq), 37.0 (CH2), 38.4 (CH), 43.4 (CH2), 201.6 (CHO), 207.9 (C=0). [2,2-Dimethyl-3-(2-oxo-propyl)-cyclopropyl]-acetaldehyde (6). Yield 75 6% [?]20D -5.2° (c 1, EtOH). MS, m/z: 168 (M+). lH NMR (300 MHz, CDC13) ? 0.90 (s, 3H), 0.9-1.20 (m, 2H), 1.14 (s, 3H), 2.16 (s, 3H), 2.29-2.38 (m, 4H), 9.77 (t, 7 1.8 Hz, 1H). 13C NMR (75 MHz, CDC13) ? 15.2 (CH3), 17.2 (Cq), 19.5 (CH), 21.4 (CH3), 28.5 (CH), 29.6 (CH3), 39.4 (CH2), 39.7 (CH2), 201.7 (CHO), 208.1 (C=0). (3-Acetyl-2,2-dimethyl-cyclobutyl)-acetic acid (7). Yield 85.5%. [?]20D +57 2° (c 1, EtOH). MS, m/z: 184 (M+). lH NMR (300 MHz, CDC13) ? 0.80 (s, 3H), 1.26 (s, 3H), 1.78-1.94 (m, 2H), 1.98 (s, 3H), 2.14-2.23 (m, 1H), 2.27 (d, 7 5.12 Hz, 2H), 2.83 (dd, 7 9.6, 11.4 Hz, 1H), 10.5 (m, 1H). 13C NMR (75 MHz, CDC13) ? 17.1 (CH3), 22.7 (CH2), 29.9 (CH3), 30.0 (CH3), 34.7 (CH2), 37.5 (CH), 43.1 (Cq), 53.9 (CH), 178.6 (COOH), 207.9 (C=0). 2,2-Dimethyl-3-(3-oxobutyl)-cyclopropanecarboxylic acid (8). Yield 81.4%. [?]20D +34.4° (c 1, EtOH). MS, m/z: 184 (M+). lH NMR (300 MHz, CDC13) ? 1.12 (s, 3H), 1.17 (s, 3H), 1.15 (td, 7 9.52, 7.1 Hz, 1H), 1.36 (d, 7 9.52 Hz, 1H), 1.84-1.96 (m, 2H), 2.1 (s, 3H), 2.42 (td, 77.1, 2.77 Hz, 2H). 13C NMR (75 MHz, CDC13) ? 14.1 (CH3), 17.9 (CH2), 27.0 (Cq), 28.3 (CH), 29.0 (CH3), 29.8 (CH), 33.8 (CH3), 43.3 (CH2), 177.9 (COOH), 209.0 (C=0). H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage... Acta Chim. Slov. 2004, 51, 223-230. 229 [2,2-Dimethyl-3-(2-oxo-propyl)-cyclopropyl]-acetic acid (9). Yield 88.47%. [?]20D -10.5° (c 1, EtOH). MS, m/z: 184 (M+). lH NMR (300 MHz, CDC13) ? 0.87 (s, 3H), 0.89 (td, J 9.92, 6.74 Hz, 1H), 0.92 (td, J 9.92, 6.7 Hz, 1H), 1.07 (s, 3H), 2.13 (s, 3H), 2.24 (d, J 6.74 Hz, 2H), 2.33 (dd, J 6.7, 2.16 Hz, 2H). 13C NMR (75 MHz, CDCI3) ? 14.9 (CH3), 17.2 (Cq), 21.0 (CH), 21.4 (CH), 28.6 (CH3), 29.6 (CH3), 30.0 (CH2), 39.3 (CH2), 179.2 (COOH), 209.1 (C=0). 6-Methoxy-4-(l-methoxy-l-methyl-ethyl)-l-methyl-cyclohexane (10). This compound was prepared following the procedure described above by replacing water with methanol. Yield 56.4%. MS, m/z: 198 (M+). lH NMR (300 MHz, CDC13) ? 1.09 (s, 3H), 1.11 (s, 3H), 1.74 (d, J 1.27 Hz, 3H), 1.84-2.00 (m, 4H), 2.08 (dd, J 13.67, 1.91 Hz, 1H), 3.18 (s, 3H), 3.38 (s, 3H), 3.45 (t, J 236 Hz, 1H), 5.57 (dd, J 4.2, 1.5 Hz, 1H). 13C NMR (75 MHz, CDC13) ? 21.0 (CH3), 22.4 (CH3), 22.7 (CH3), 26.8 (CH2), 27.2 (CH2), 34.7 (CH), 48.6 (CH30), 57.1 (CH30), 76.1(CqO), 78.0 (CH-O), 125.8 (=CH), 133.2 (=Cq). 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Povzetek Katalitska oksidacija terpenskih olefinov (?-pinen, 2-caren in 3-caren) z RuO4, generiranem in situ, vodi do nastanka ustreznih ciklobutan- in ciklopropan-ketoaldehidov, ki se po daljšem času pretvorijo v keto-kisline z odličnimi izkoristki (90-100%). Te spojine lahko služijo kot gradniki v sintezi ciklobutan-aminokislin in podobnih derivatov. H. Ziyat, M. Ait Ali, A. Karim, C. Meliet, Y. Castanet, A. Mortreux: Catalytic Oxidative Cleavage...