Synthesis of Carboxylic Acids, Esters, Alcohols and Ethers Containing a Tetrahydropyran Ring Derived from 6-Methyl-5-hepten-2-one

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1 Journl of Oleo Science Copyright 202 y Jpn Oil Chemists Society J. Oleo Sci. 6, () (202) Synthesis of Croxylic Acids, Esters, Alcohols nd Ethers Contining Tetrhydropyrn Ring Derived from 6-Methyl-5-hepten-2-one Yohko Hnzw, Khoko Hshimoto 2, Yoshio Ksshim *, Yoshiko Tkhshi 3, Tkshi Mino 4, Msmi Skmoto 4 nd Tsutomu Fujit 4 Eduction Center, Fculty of Engineering, Chi Institute of Technology, Shizono 2--, Nrshino-shi, Chi , Jpn 2 Deprtment of Life Environmentl Sciences, Fculty of Engineering, Chi Institute of Technology, Tsudnum 2-7-, Nrshino-shi, Chi , Jpn 3 Grdute School of Science nd Technology, Chi University, Yyoi-cho -33, Inge-ku, Chi-shi, Chi , Jpn 4 Grdute School of Engineering, Chi University, Yyoi-cho -33, Inge-ku, Chi-shi, Chi , Jpn Astrct: 3-hydroxy cids, 3-hydroxy-3,7-dimethyloct-6-enoic cid () nd 3-hydroxy-2,2,3,7- tetrmethyloct-6-enoic cid (2), were prepred from 6-methyl-5-hepten-2-one, nd they were susequently used to prepre (2,6,6-trimethyltetrhydropyrn-2-yl)cetic cid (3) nd 2-methyl-2-(2,6,6- trimethyltetrhydropyrn-2-yl)propnoic cid (4), respectively, vi cycliztion with n cidic ctlyst such s oron trifluoride diethyl etherte or iodine. The rection of croxylic cids 3 nd 4 with lcohols, including methnol, ethnol, nd -propnol, produced the corresponding methyl, ethyl, nd propyl esters, which ll contined tetrhydropyrn ring. Reduction of croxylic cids 3 nd 4 fforded the corresponding lcohols. Susequent rections of these lcohols with severl cyl chlorides produced novel esters. The lcohols lso rected with methyl iodide nd sodium hydride to provide novel ethers. A one-pot cycliztion esterifiction of to produce esters contining tetrhydropyrn ring, using iodine s ctlyst, ws lso investigted. Key words: tetrhydropyrn ring; cycliztion, esterifiction INTRODUCTION Compounds contining tetrhydropyrn ring, such s rose oxide nd linlool oxide, re highly vlule in the perfume industry. One method for the formtion of the tetrhydropyrn ring is the cycliztion of 5-methyl-4-hexen- -ol using ctionic ctlyst. One common compound tht contins this unit is 3,7-dimethyl-,6-octdien-3-ol linlool. The synthesis of 6-ethenyltetrhydro-2,2,6-trimethyl-2H-pyrn-3-ol linlool oxide y the cycliztion of linlool using ctionic ctlyst hs een reported previously 3. Croxylic cids contining tetrhydropyrn ring cn e synthesized y the cycliztion of the corresponding 3-hydroxy cids tht contin the 5-methyl-4-hexen--ol unit. These croxylic cids re vlule in the perfume industry ecuse the side chin of the tetrhydropyrn cn e further modified. Roin et l. reported the cycliztion of -ethyl 4-methyl 2-hydroxy-2-4-methyl-3-penten--yl utnediote to produce the tetrhydropyrn ring 4. Cliezi et l. 5 nd Iwmoto et l. 6 seprtely reported the cycliztion of esters of 3-hydroxy-3,7-dimethyloct-6-enoic cid using ctionic ctlyst. However, Fkyert et l. reported tht this cycliztion ws ccompnied y hydrolysis of the esters y the ctionic ctlyst, which consequently, decresed the product yield 7. Therefore, in this report, the cycliztion of 3-hydroxy-3,7-dimethyloct-6-enoic cid, rther thn n ester, ws ttempted using ctionic ctlyst to prepre the croxylic cid contining tetrhydropyrn ring. In ddition, 3-hydroxy-2,2,3,7-tetrmethyloct-6-enoic cid 2, which hs structure similr to tht of the croxylic cid, ws synthesized. Ester, lcohol, nd ether derivtives of croxylic cids nd 2 were susequently produced. * Correspondence to: Yoshio Ksshim, Eduction Center, Fculty of Engineering, Chi Institute of Technology, Shizono 2--, Nrshino-shi, Chi , Jpn E-mil: yoshio.ksshim@it-chi.c.jp Accepted June 9, 202 (recieved for review Novemer 2, 20) Journl of Oleo Science ISSN print / ISSN online

2 Y. Hnzw, K. Hshimoto, Y. Ksshim et l. 2 EXPERIMENTAL 2. Generl NMR spectr were otined using 400 or 300 MHz FT-NMR spectrometer JEOL JNM-LA-400 or Bruker DPX-300 with Me 4 Si s n internl stndrd nd CDCl 3 s the solvent. IR spectr were recorded on JASCO FT/ IR-230 spectrometer. Mss spectr were recorded on JEOL JMS-HX0A, JEOL JMS-AX500, or Thermo Fischer Exctive type spectrometer. 2.2 Syntheses 2.2. Synthesis of 3-hydroxylic cids 6-Methyl-5-hepten-2-one ws otined from Tokyo Chemicl Industry Co., Ltd., nd used s received. Tetrhydrofurn 50 ml, nphthlene 6.0 g, 25 mmol, lithium.74 g, 250 mmol, nd diethylmine 8.3 g, 250 mmol were dded to 500 ml flsk equipped with reflux condenser, nitrogen inlet nd dropping funnel. The mixture ws stirred under dry nitrogen until the lithium ws fully dissolved. A solution of 2-methylpropnoic cid 8.8 g, 00 mmol in tetrhydrofurn 60 ml ws dded dropwise over.5 h, nd the mixture ws then stirred for n dditionl h. Next, solution of 6-methyl- 5-hepten-2-one 0. g, 80 mmol in tetrhydrofurn 60 ml ws dded dropwise over h, nd the rection mixture ws stirred t room temperture for 24 h. The mixture ws extrcted three times with 2 M queous sodium hydroxide solution 30 ml. The queous lyer ws cidified with 2 M hydrochloric cid, nd extrcted three times with diisopropyl ether 30 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 30 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified using column chromtogrphy nd eluted with hexne/ethyl cette 50/. A totl mss of.2 g 75 yield of ws otined. 2 ws prepred using similr procedure. 3-Hydroxy-3,7-dimethyloct-6-enoic cid H-NMR δ, CDCl 3 :.3 3H, s,.62 3H, s,.69 3H, s, H, m, H, m, 2.53, H, ABq, J 5.8Hz, 5. H, t, J 7,Hz 3 C-NMR δ, CDCl 3 : 8., 23.0, 26., 27.0, 42., 45.2, 7.8, 24., 32.7, 77.7 IR net, cm : 3394, 2972, 70,087 HRMS ESI-MS m/z clcd for C 0 H 8 O 3 N , found Hydroxy-2,2,3,7-tetrmethyloct-6-enoic cid 2 H-NMR δ, CDCl 3 :.23 6H, s,.28 3H, s, H, m,.64 3H, s,.70 3H, s, H, m, H, m, 3 C-NMR δ, CDCl 3 : 8., 2.3, 2.6, 2.7, 22.6, 26.2, 36.9, 50.7, 76.5, 24.5, 33.0, 82.2 IR net, cm : 335, 2977, 2653, 697, 089 HRMS ESI-MS m/z clcd for C 2 H 22 O 3 N , found Cycliztion of 3-hydroxy cids Typicl procedure: Boron trifluoride diethyl etherte 86 mg, toluene 25 ml, nd g, 2.5 mmol were plced in 50 ml flsk equipped with reflux condenser, nd the mixture ws stirred t 50 for 8 h. Next, wter 20 ml ws dded, nd the mixture ws extrcted three times with diisopropyl ether 20 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified using column chromtogrphy nd eluted with hexne/ethyl cette 8/. A totl mss of g 86 yield of 2,6,6-trimethyltetrhydropyrn-2-yl cetic cid 3 ws otined. 2-methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnoic cid 4 ws synthesized using similr procedure. 2,6,6-Trimethyltetrhydropyrn-2-yl cetic cid 3 H-NMR δ, CDCl 3 :.30 3H, s,.33 3H, s,.37 3H, s, H, m, 2.52, H, ABq, J 5.6Hz 3 C-NMR δ, CDCl 3 : 6.3, 26.8, 28., 32.6, 34.5, 36.4, 49.4, 74.0, 75.0, 72.4 IR net, cm : 3087, 2937, 2697, 708 HRMS FAB-MS m/z clcd for C 0 H 8 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnonic cid 4 White crystls m.p H-NMR δ, CDCl 3 :.9 3H, s,.22 3H, s,.32 3H, s,.35 6H, s, H, m 3 C-NMR δ, CDCl 3 : 6.2, 20.8, 2.3, 27.6, 33.3, 36., 52., 75.3, 79.0, 78.3 IR net, cm : 3060, 297, 697 HRMS FAB-MS m/z clcd for C 2 H 22 O 3 H , found Esterifiction of 3 nd 4 Typicl procedure: Methnol 25 ml, p-toluenesulfonic cid 95 mg, 0.5 mmol, nd g, 2.5 mmol were plced in 50 ml flsk equipped with reflux condenser, nd the mixture ws stirred with refluxing for 8 h. After cooling to room temperture, wter 20 ml ws dded nd the mixture ws extrcted three times with 2 M sodium hydroxide queous solution 0 ml in order to remove the cidic mteril. The queous lyer ws extrcted three times with diisopropyl ether 0 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The 632 J. Oleo Sci. 6, () (202)

3 Synthesis of croxylic cids, esters, lcohols, nd ethers contining tetrhydropyrn ring product ws purified using column chromtogrphy nd eluted with hexne/ethyl cette 40/. A totl mss of 0.46 g 83 yield of methyl 2-2,6,6-trimethyltetrhydropyrn-2-yl cette 5 ws otined. Other esters of 3 or 4 were synthesized using similr procedure. Methyl 2-2,6,6-trimethyltetrhydropyrn-2-yl cette 5 H-NMR δ, CDCl 3 :.7 3H, s,.22 3H, s,.3 3H, s, H, m, 2.46, H, ABq, J 3.3Hz, H, s 3 C-NMR δ, CDCl 3 : 6.7, 28.3, 29.9, 3.7, 34.3, 36.7, 48.3, 5.7, 72.2, 72.8, 72. IR net, cm : 2973, 726 HRMS ESI-MS m/z clcd for C H 20 O 3 N , found Ethyl 2-2,6,6-trimethyltetrhydropyrn-2-yl cette 5 H-NMR δ, CDCl 3 :.7 3H, s,.22 3H, s,.26 3H, t, J 7.Hz,.32 3H, s, H, m, 2.43, H, ABq, J 3.2Hz, 4. 2H, q, J 7.Hz 3 C-NMR δ, CDCl 3 : 4.7, 6.8, 28.3, 29.9, 3.6, 34.3, 36.8, 48.5, 60.4, 72.2, 72.9, 7.6 IR net, cm : 2975, 2935, 734 HRMS ESI-MS m/z clcd for C 2 H 22 O 3 N , found Propyl 2-2,6,6-trimethyltetrhydropyrn-2-yl cette 5c H-NMR δ, CDCl 3 : H, t, J 7.4Hz,.7 3H, s,.2 3H, s,.32 3H, s, H, m, H, m, 2.43, H, ABq, J 3.2Hz, H, t, J 6.5Hz 3 C-NMR δ, CDCl 3 : 0.9, 6.8, 22.4, 28.3, 30.0, 3.6, 34.5, 36.8, 48.5, 66.2, 72.2, 72.9, 7.8 IR net, cm : 297, 734 HRMS ESI-MS m/z clcd for C 3 H 24 O 3 N 25.68, found Methyl 2-methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnote 6 H-NMR δ, CDCl 3 :.07 3H, s,.4 3H, s,.7 3H, s,.8 3H, s,.2 3H, s, H, m, H, m, H, s 3 C-NMR δ, CDCl 3 :6.9, 2.2, 22.2, 27.7, 29.8, 33.6, 36.5, 5.7, 52., 7.6, 76.6, 77.7 IR net, cm : 2973, 2933, 728 HRMS FAB-MS m/z clcd for C 3 H 24 O 3 H , found Ethyl 2-methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnote 6 H-NMR δ, CDCl 3 :.08 3H, s,.4 3H, s,.7 6H, s,.22 3H, s,.25 3H, t, J 7.Hz, H, m, H, m, H, t, J 7.Hz 3 C-NMR δ, CDCl 3 : 4.7, 6.9, 2.3, 22.3, 27.8, 29.8, 33.6, 36.5, 5.9, 60.4, 7.5, 76.5, 77.2 IR net, cm : 2974, 293, 720 HRMS ESI-MS m/z clcd for C 4 H 26 O 3 N , found Propyl 2-methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnote 6c H-NMR δ, CDCl 3 : H, t, J 7.4Hz,.09 3H, s,.5 3H, s,.8 6H, s,.22 3H, s, H, m, H, m, H, t, J 6.6Hz 3 C-NMR δ, CDCl 3 :., 6.9, 2.2, 2.3, 22.3, 22.4, 27.8, 29.8, 33.6, 36.5, 52., 66., 7.5, 76.5, 77.3 IR net, cm : 2969, 2877, 722 HRMS ESI-MS m/z clcd for C 5 H 28 O 3 N , found Reduction of 3 nd 4 Typicl procedure: Lithium luminum hydride.7 g, 45 mmol, nd tetrhydrofurn 50 ml were plced in 500 ml flsk equipped with reflux condenser, nitrogen inlet, nd dropping funnel. The flsk ws cooled with iced wter, nd solution of g in tetrhydrofurn 20 ml ws dded dropwise over h. After refluxing for 8 h, wter 00 ml ws dded dropwise to the rection mixture, followed y the ddition of 0 hydrochloric cid 00 ml. The mixture ws extrcted three times with diethyl ether 30 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified using column chromtogrphy nd eluted with hexne/ethyl cette 20/. A totl mss of 2.27 g 88 yield of 2-2,6,6-trimethyltetrhydropyrn-2-yl ethnol 7 ws otined. 2-2,6,6-Trimethyltetrhydropyrn-2-yl ethnol 7 H-NMR δ, CDCl 3 :.9 3H, s,.24 3H, s,.30 3H, s, H, m, H, m, 3.93 H, t, J 7.3Hz 3 C-NMR δ, CDCl 3 : 6.6, 26.6, 27.8, 33.6, 34.9, 36.8, 46., 60., 72.7, 76.3 IR net, cm : 345, 373, 20 HRMS FAB-MS m/z clcd for C 0 H 20 O 2 H , found J. Oleo Sci. 6, () (202) 633

4 Y. Hnzw, K. Hshimoto, Y. Ksshim et l. 2-Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propnol 8 H-NMR δ, CDCl 3 : H, s, H, s,.9 3H, s,.25 3H, s,.28 3H, s, H, m, H, m, 4.39 H, t, J 7.4Hz 3 C-NMR δ, CDCl 3 :6.6, 2.0, 2.2, 2.5, 27.8, 29.5, 33.6, 36.6, 42.2, 7.6, 72.7, 8.2 IR net, cm : 2973, 380, 097 HRMS FAB-MS m/z clcd for C 2 H 24 O 2 H , found Esterifiction of 7 nd 8 Typicl procedure: g, 2.5 mmol, triethylmine g, 3.8 mmol, DMAP 50 mg, nd tetrhydrofurn 20 ml were plced in 00 ml flsk equipped with funnel. A solution of cetyl chloride g, 3.8 mmol in tetrhydrofurn 20 ml ws dded dropwise to the mixture over 30 min, then stirred overnight. Next, the rection mixture ws extrcted three times with diisopropyl ether 0 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified y column chromtogrphy nd eluted with hexne/ethyl cette 40/. A totl mss of 0.46 g 86 yield of 2-2,6,6-trimethyltetrhydropyrn-2-yl methyl propnote 9 ws otined. The other esters of 7 nd 8 were synthesized using similr procedure. 2-2,6,6-Trimethyltetrhydropyrn-2-yl ethyl cette 9 H-NMR δ, CDCl 3 :.7 3H, s,.20 3H, s,.22 3H, s, H, m, H, s, H, m 3 C-NMR δ, CDCl 3 : 6.8, 2.5, 28., 29.6, 3.9, 35.2, 37.0, 42.2, 6.9, 7.8, 72.4, 7.7 IR net, cm : 2973, 2935, 736 HRMS FAB-MS m/z clcd for C 2 H 22 O 3 H 23.49, found ,6,6-Trimethyltetrhydropyrn-2-yl ethyl propnote 9 H-NMR δ, CDCl 3 :.3 3H, t, J 7.5Hz,.7 3H, s,.2 3H, s,.22 3H, s, H, m, 2.3 2H, q, J 7.5Hz, H, m 3 C-NMR δ, CDCl 3 : 9.5, 6.8, 28., 29.7, 3.9, 35.3, 37.0, 42.3, 6.8, 7.8, 72.4, 75.0 IR net, cm : 2979, 2937, 738 HRMS FAB-MS m/z clcd for C 3 H 24 O 3 H , found ,6,6-Trimethyltetrhydropyrn-2-yl ethyl utnote 9c H-NMR δ, CDCl 3 : H, t, J 7.4Hz,.7 3H, s,.2 3H, s,.22 3H, s, H, m, H, t, J 7.4Hz, H, m 3 C-NMR δ, CDCl 3 : 4., 6.8, 8.9, 28., 29.7, 3.9, 35.2, 26.8, 37.0, 42.3, 6.7, 7.8, 72.5, 74.3 IR net, cm : 736 HRMS FAB-MS m/z clcd for C 4 H 26 O 3 H , found ,6,6-Trimethyltetrhydropyrn-2-yl ethyl 2-methylpropnote 9d H-NMR δ, CDCl 3 :.4 3H, s,.7 6H, d, J 7.0Hz,.2 3H, s,.22 3H, s, H, m, 2.54 H, quin, J 7.0Hz, H, m 3 C-NMR δ, CDCl 3 : 6.8, 9.4, 28., 29.7, 3.9, 34.4, 35.3, 37.0, 42.3, 6.7, 7.8, 72.5, 77.7 IR net, cm : 2973, 733 HRMS FAB-MS m/z clcd for C 4 H 26 O 3 H , found ,6,6-Trimethyltetrhydropyrn-2-yl ethyl enzote 9e H-NMR δ, CDCl 3 :.4 3H, s,.23 3H, s,.28 3H, s, H, m, H, m, H, t, J 7.6Hz, H, m, H, m 3 C-NMR δ, CDCl 3 : 6.8, 28., 29.7, 32.0, 35.4, 42.4, 62.4, 7.8, 72.5, 28.7, 29.9, 3.0, 33.2, 67.2 IR net, cm : 297, 2935, 720, 72 HRMS FAB-MS m/z clcd for C 7 H 24 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propyl cette 0 H-NMR δ, CDCl 3 : H, s, H, s,.0 3H, s,.8 6H, s, H, m, H, m, H, s, 4.0, 4.2 2H, ABq, J 0.8Hz 3 C-NMR δ, CDCl 3 : 6.7, 9.9, 20., 2.6, 2.9, 27.9, 29.5, 33.6, 36.7, 42.5, 70.4, 7.2, 76.5, 72.0 IR net, cm : 2973, 74 HRMS FAB-MS m/z clcd for C 4 H 26 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propyl propnote 0 H-NMR δ, CDCl 3 : H, s, H, s,.09 3H, s,.5 3H, t, J 7.6Hz,.8 6H, s, H, m, H, q, J 7.6Hz, 4.02, 4.3 2H, ABq, J 0.8Hz 634 J. Oleo Sci. 6, () (202)

5 Synthesis of croxylic cids, esters, lcohols, nd ethers contining tetrhydropyrn ring 3 C-NMR δ, CDCl 3 : 9.7, 6.7, 9.9, 20., 2.9, 27.9, 28.3, 29.5, 33.6, 36.7, 42.6, 70.2, 7.2, 76.5, 75.3 IR net, cm : 2974, 738 HRMS FAB-MS m/z clcd for C 5 H 28 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propyl utnote 0c H-NMR δ, CDCl 3 : H, s, H, s, H, t, J 7.4Hz,.0 3H, s,.8 6H, s, H, m, H, m, H, t, J 7.4Hz, 4.02,4.3 2H, ABq, J 0.8Hz 3 C-NMR δ, CDCl 3 : 4., 6.7, 9.0, 20., 2.9, 27.9, 29.5, 33.6, 36.7, 42.6, 70., 7.2, 76.5, 77.0, 74.5 IR net, cm : 2970, 2877, 734 HRMS FAB-MS m/z clcd for C 6 H 30 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propyl 2-methylpropnote 0d H-NMR δ, CDCl 3 : H, s,.0 3H, s,.7 6H, d, J 7.0Hz,.8 6H, s, H, m, 2.56 H, quin, J 7.0Hz, H, ABq, J 0.8Hz 3 C-NMR δ, CDCl 3 : 6.8, 9.5, 9.9, 20., 2.9, 27.9, 29.5, 33.6, 34.8, 36.7, 70., 7.2, 77.0, 77.9 IR net, cm : 2973, 2877, 734 HRMS FAB-MS m/z clcd for C 6 H 30 O 3 H , found Methyl-2-2,6,6-trimethyltetrhydropyrn-2-yl propyl enzote 0e H-NMR δ, CDCl 3 :.02 6H, s,.3 3H, s,.2 3H, s,.25 3H, s, H, m, 4.29, H, ABq, J 0.8Hz, H, m, H, m, H, m 3 C-NMR δ, CDCl 3 : 6.8, 20.2, 20.4, 22.0, 27.9, 33.6, 36.7, 43.0, 70.9, 7.3, 76.6, 28.7, 29.9, 3.3, 33., 67.4 IR net, cm : 2972, 720, 72 HRMS FAB-MS m/z clcd for C 9 H 28 O 3 H , found Etherifiction of lcohol 3 or 4 Typicl procedure: Tetrhydrofurn 30 ml nd 60 sodium hydride in prffin solution 0.20 g, 3.0 mmol were plced in 00 ml flsk equipped with funnel. A solution of g, 2.5 mmol in tetrhydrofurn 5 ml ws dded dropwise over 30 min. The mixture ws stirred for 2 h, nd then solution of methyl iodide g, 3.75 mmol in tetrhydrofurn 5 ml ws dded dropwise over 3 h. The rection mixture ws stirred overnight, nd then wter 20 ml ws dded dropwise with cooling. Next, the rection mixture ws extrcted three times with diisopropyl ether 0 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified using column chromtogrphy nd eluted with hexne/ethyl cette 40/. A totl mss of g 73 yield of 2-2-methoxyethyl -2,6,6-trimethyltetrhydropyrn ws otined. ws synthesized using similr procedure. 2-2-Methoxyethyl -2,6,6-trimethyltetrhydropyrn H-NMR δ, CDCl 3 :.20 3H, s,.2 3H, s,.22 3H, s, H, m, H, s, H, m 3 C-NMR δ, CDCl 3 : 6.9, 28.4, 30.2, 3.6, 35.5, 37.2, 42.9, 59.0, 69.7, 7.7, 72.7 IR net, cm : 297, 2933, 2870, 8 HRMS ESI-MS m/z clcd for C H 22 O 2 N , found Methoxy-,-dimethylethyl -2,6,6-trimethyltetrhydropyrn H-NMR δ, CDCl 3 : H, s, H, s,.0 3H, s,.5 3H, s,.8 3H, s, H, m, 3.24, H, ABq, J 9.5Hz, H, s 3 C-NMR δ, CDCl 3 : 6.8, 20.0, 20.3, 22.0, 28.0, 29.5, 33.7, 36.9, 43.2, 59.7, 7.0, 76.5, 77.0, 79.2S IR net, cm : 2927, 0 HRMS ESI-MS m/z clcd for C 3 H 26 O 2 N , found One-pot syntheses of esters 5-c from Typicl procedure: Iodine 0.32 g, 0.5 mmol, toluene 25 ml, nd g, 2.5 mmol were plced in 00 ml flsk, nd the mixture ws stirred t 50 for 8 h. After cooling to room temperture, ethnol 25 ml ws dded. A reflux condenser ws ttched to the flsk, nd the mixture ws stirred for 8 h with refluxing. After the rection mixture ws chilled to room temperture, wter 20 ml ws dded. Next, sodium thiosulfte 2.0 g ws dded with stirring, nd the rection mixture ws extrcted three times with diisopropyl ether 0 ml. The orgnic lyer ws wshed twice with queous sodium chloride solution 20 ml, dried with nhydrous sodium sulfte, nd evported. The product ws purified y column chromtogrphy nd eluted with hexne/ethyl cette 20/. A totl mss of g 7 yield of ethyl 2-2,6,6-trimethyltetrhydropyrn-2-yl cette 5 ws otined. The other esters of 5 nd 5c were synthesized using similr procedure. J. Oleo Sci. 6, () (202) 635

6 Y. Hnzw, K. Hshimoto, Y. Ksshim et l. 3 Results nd discussion hs een reported to e otined y the hydrolysis of the corresponding nitrile 8. However, in this study, croxylic cids nd 2 were synthesized y the rection of 6-methyl-5-hepten-2-one with cetic cid or 2-methylpropnoic cid, respectively, using lithium nphthlenide nd diethylmine, ecuse the rections could e crried out under milder conditions. The method using lithium nphthlenide hs een previously reported 9. The 3-hydroxy cids nd 2 were otined in moderte yields, 75 ; 2, 5. Cycliztion of the 3-hydroxy cid ws performed using oron trifluoride diethyl etherte or iodine s ctlyst nd the results re summrized in Tle. Cycliztion rections were crried out t 5: molr rtio of mteril to ctlyst. In the cse of iodine, with cetonitrile s the solvent, nd rection temperture t room temperture, the desired product ws successfully otined. Spectroscopic dt cquired for the product indicted the shown structure of the croxylic cid, which contins tetrhydropyrn ring 3. The chieved yield ws 62 entry, ut this decresed to 53 when the temperture ws rised to 80 entry 2. When the solvent ws chnged to hexne or diethyl ether, cycliztion did not occur entries 3 nd 4. We previously reported tht cetonitrile ws suitle solvent for the solution rection using iodine s ctlyst 0 nd similr results were oserved in this work. Boron trifluoride diethyl etherte ws used s n cidic ctlyst. When the rection ws crried out under the sme conditions s entry 2 solvent: cetonitrile, temperture: 80, 3 ws otined in 73 yield entry 5. When the solvent ws chnged to toluene entry 6, the yield incresed to 86. Thus, from, croxylic cid contining tetrhydropyrn ring ws otined in high yield. A possile rection mechnism is illustrted in Scheme. Addition of hydrogen to the doule ond forms tertiry croction, which n electron pir from the hydroxyl group then ttcks the tertiry croction producing tetrhydropyrn ring. In the cse of iodine, hydrogen iodide, which is initilly formed y the interction of iodine with the hydroxyl group, cts s n cidic ctlyst 0. Cycliztion of 3-hydroxy cid 2 ws crried out using cidic ctlysts such s iodine, oron trifluoride diethyl etherte, nd p-toluenesulfonic cid nd the results re il- Scheme Tle Intrmoleculr etherifiction of. Entry Ctlyst Solvent Time h Temp. Yield I 2 cetonitrile 3 r.t. c 62 2 I 2 cetonitrile I 2 hexne 3 r.t. c d 4 I 2 diethyl ether 3 r.t. c d 5 BF 3 OEt 2 cetonitrile BF 3 OEt 2 toluene BF 3 OEt 2 toluene Rection conditions: 3-hydroxy cids 2.5 mmol, ctlyst 0.5 mmol, solvent 25 ml. Iodine. Boron trifluoride diethyl etherte. c Room temperture. d 3 ws not otined. 636 J. Oleo Sci. 6, () (202)

7 Synthesis of croxylic cids, esters, lcohols, nd ethers contining tetrhydropyrn ring Tle 2 Intrmoleculr etherifiction of 2. Entry Ctlyst Solvent Temp. Yield I 2 2 I 2 3 I 2 4 I 2 5 BF 3 OEt 2 6 BF 3 OEt 2 7 BF 3 OEt 2 8 BF 3 OEt 2 toluene toluene 0 57 cetonitrile cetonitrile toluene toluene 0 50 cetonitrile cetonitrile p-tsoh c toluene p-tsoh c toluene 0 60 p-tsoh c cetonitrile p-tsoh c cetonitrile Rection conditions: 3-hydroxy cids 2.5 mmol, ctlyst 0.5 mmol, solvent 25 ml, time 24 h. Iodine. Boron trifluoride diethyl etherte. c p-toluenesulfonic cid. Tle 3 Esterifiction of 3. Entry R 2 Product Ctlyst Yield methyl 5 I 2 2 methyl 5 p-tsoh 83 3 ethyl 5 I 2 4 ethyl 5 p-tsoh 78 5 propyl 5c I 2 6 propyl 5c p-tsoh 95 Rection conditions: mmol, ctlyst.0 mmol, lcohols 50 ml, refluxing for 8 h. Iodine. p-toluenesulfonic cid lustrted in Tle 2. In the cse of iodine entries -4, the cycliztion proceeded to produce the croxylic cid 4, ut the yields were modest, rnging from 42 to 73. In the cse of p-toluenesulfonic cid entries 9-2, the yields incresed somewht, rnging from 60 to 79. Using oron trifluoride diethyl etherte, the yield incresed even further. When toluene ws used s solvent nd the rection temperture ws 50 entry 5, the yield ws the highest out of ll the rections 83. Esterifiction of the croxylic cid 3 with lcohols ws performed using iodine or p-toluenesulfonic cid s ctlyst nd the results re summrized in Tle 3. Iodine hs J. Oleo Sci. 6, () (202) 637

8 Y. Hnzw, K. Hshimoto, Y. Ksshim et l. Tle 4 Esterifiction of 4. Entry R 2 Product Ctlyst Yield methyl 6 p-tsoh 2 methyl 6 sulfuric cid 44 3 ethyl 6 sulfuric cid 37 4 propyl 6c sulfuric cid 44 Rection conditions: croxylic cid mmol, ctlyst.0 mmol, lcohols 50 ml, refluxing for 8 h. p-toluenesulfonic cid. 6 ws not otined. previously een reported to e n effective ctlyst for the esterifiction rection, 2. In the production of the methyl ester 5 entries, 2, ethyl ester 5 entries 3,4, nd propyl ester 5c entries 5,6, oth iodine nd p-toluenesulfonic cid were effective s ctlysts. The yield of ech ws ove 74. Esterifiction of 4 with severl different lcohols ws lso ttempted Tle 4. When p-toluenesulfonic cid ws used s ctlyst in the production of the methyl ester, esterifiction did not proceed entry. Accordingly, the ctlyst ws chnged to sulfuric cid, nd the methyl ester 6 ws otined in 44 yield entry 2. Similrly, the production of the ethyl ester 6 entry 3 or propyl ester 6c entry 4 ws ttempted. Ech ester ws otined in moderte yield. These reltively low yields were ttriuted to the steric hindrnce of croxylic cid 4. Reduction of croxylic cid 3 or 4 to produce the novel corresponding lcohol contining tetrhydropyrn ring ws crried out using lithium luminum hydride in tetrhydrofurn, s shown in Scheme 2. The lcohol 7 ws otined in 88 yield, nd 8 ws produced in 93 yield. Using these lcohols with severl cyl chlorides nd triethylmine, novel esters were produced. The results using 7 re summrized in Tle 5. In the cse of ech liphtic cyl chloride used, the esters 9-d were otined in excellent yields entries -4. However, when enzyl chloride ws used, the yield decresed considerly entry 5. This ws ttriuted to the rectivity of enzyl chloride eing Tle 5 Esterifiction of lcohol 7. Entry R 3 group Yield of 9 methyl 86 2 ethyl 93 3 c propyl 92 4 d isopropyl 90 5 e phenyl 77 Rection conditions: lcohol 2.5 mmol, triethylmine 3.8 mmol, cyl chloride 3.8 mmol, DMAP 0.4 mmol, solvent tetrhydrofurn 0 ml, time 2 h. lower thn tht of the liphtic cyl chlorides. The results using 8 re shown in Tle 6. Similr to the esterifiction of 7, esters 0 were produced in excellent yields using liphtic cyl chlorides, ut the yield decresed slightly in the esterifiction with enzyl chloride entry 5. Etherifiction of the lcohol 3 or 4 with methyl iodide using sodium hydride ws crried out s shown in Scheme 3. The yield of the ether ws 73, nd tht of ws 43. The lower yield of ws ttriuted to the steric hindrnce of the two methyl groups. As mentioned ove, iodine ws n effective ctlyst in the esterifiction of 3 s well s in the cycliztion of. Ac- Scheme 2 Scheme J. Oleo Sci. 6, () (202)

9 Synthesis of croxylic cids, esters, lcohols, nd ethers contining tetrhydropyrn ring Tle 6 Esterifiction of lcohol 8. Entry R 3 group Yield of 0 methyl 90 2 ethyl 90 3 c propyl 9 4 d isopropyl 99 5 e phenyl 84 Rection conditions: lcohol 2.5 mmol, triethylmine 3.8 mmol, cyl chloride 3.8 mmol, DMAP 0.4 mmol, solvent tetrhydrofurn 0 ml, time 2 h. cordingly, one-pot method of cycliztion-esterifiction of ws ttempted. First, 2.5 mmol nd iodine 0.5 mmol nd toluene were dded to flsk, nd the mixture ws stirred t 50 for 8 h. Second, fter cooling to room temperture, ethnol 25 ml ws dded to the flsk, nd the mixture ws stirred with refluxing for 8 h. In the cses where ethnol ws dded, iodine ws not dded. The yield of 5 from ws 7 entry 2, which ws higher thn tht in the cses of the cycliztion, nd the esterifiction ws crried out seprtely. The results of this one-pot method re illustrted in Tle 7. When methnol ws used, the yield of 5 from ws 66 entry. In the cse of -propnol, the yield of 5c ws 63 entry 3. Thus, using iodine s ctlyst, the one-pot method of cycliztion-esterifiction of proceeded smoothly. In conclusion, the rection of 6-methyl-5-hepten-2-one with cetic cid or 2-methylpropnoic cid ffords the corresponding 3-hydroxy cids, which susequently rect using oron trifluoride diethyl etherte or iodine s n cidic ctlyst to give croxylic cids contining tetrhydropyrn ring. The rections of these croxylic cids with lcohols produce esters. Reduction of these croxylic Tle 7 One-pot syntheses of esters 5-c from. Entry R 2 Product Yield methyl ethyl propyl 5c 63 Rection conditions: 2.5 mmol, ctlyst iodine 0.5 mmol, solvent toluene 25 ml, lcohols 25 ml, first step 50 for 8 h, second step refluxing for 8 h. cids using lithium luminum hydride produces lcohols. These lcohols tht contin the tetrhydropyrn ring could e derivtized to esters or ethers. Additionlly, one-pot method of cycliztion esterifiction of gives esters 5 without the requirement for isoltion of the croxylic cids. References Mousseron-cnet, M.; Levllois, C.; Wylde, J. L OXY- DE DU LINALOL. Tetrhedron Lett. 7, Iwski, S.; Okuno, T. Jpn. Pt., Miywki, H.; Yukw, C. Jpn. Pt., Roin, J.; Dhl, R.; Dujrdin, G.; Girodier, L.; Mevellec, L.; Poutot, S. The First Semi-synthesis of Enntiopure Homogrringtonine vi Anhydrohomohrringtonine from Chirl Acyl Moiety. Tetrhedron Lett. 40, Cliezi, A.; Lederer, E.; Schinz, H. Zur surektlysierten Cyclistion von ungesttigten β-oxy-suren der Terpen- und Sesquiterpenreihe. Helv. Chim. Act 34, Iwmoto, M.; Fujit, A.; Tkgi, K.; Kuot, N.; Kogmi, K.; Jpn. Pt Fkyert, A.; Burki, N.; Tcchi, R. Enntioselective Synthesis of 3-Hydroxycitronellic Acid Isolted from Certocystis fimrit sp. pltni. Tetrhedron Asymmetry 7, Colonge, J.; Lgier, A. Sur les cides α-lcools tertiires δ-ethyleniques. Bull. de l Societe Chim. de Frnce Fujit, T.; Sug, K.; Wtne, S.; Yngi, R. A Convenient Preprtive Method of 3-Hydroxy Acids, nd the Rection of 3-Hydroxy Acids with Acidic Mterils. J. ppl. Chem. Biotechnol. 27, J. Oleo Sci. 6, () (202) 639

10 Y. Hnzw, K. Hshimoto, Y. Ksshim et l. 0 Ksshim, Y.; Fujimoto, H.; Mino, T.; Skmoto, M.; Fujit, T. An Efficient Synthesis of Five-memered Cyclic Ehters from,3-diols Using Moleculr Iodine s Ctlyst. J. Oleo Sci. 57, Rmling, K.; Vijylkshmi, P.; Kiml. T. N. B. A mild nd efficient method for esterifiction nd trnsesterificton ctlyzed y iodine. Tetrhedron Lett. 43, Jere, M.; Vrzic, D.; Zupn, M. Dul ehviour of lcohols in iodine-ctlyzed esterifiction under solventfree conditions. Tetrhedron Lett. 50, J. Oleo Sci. 6, () (202)