Synthesis of chiral 2-methyl-5,6,7,8-tetrahydroquinolines from naturally occurring monoterpenes

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1 Generl Ppers ARKIVC 2004 (xiv) Synthesis of hirl 2-methyl-5,6,7,8-tetrhydroquinolines from nturlly ourring monoterpenes Giorgio Chelui,* Ginmuro rrù, nd Frno Soolini Diprtimento di Chimi, Università di Sssri, vi Vienn 2, I Sssri, Itly E-mil: (reeived 17 Mr 04; epted 09 Aug 04; pulished on the we 22 Aug 04) Astrt The synthesis is reported of hirl sustituted 2-methylpyridines, in whih the pyridine rings re nnulted t the 5,6-positions to the hirl frmeworks originting from (-)-β-pinene, (-)-isopinompheol nd (+)-mphor. Two proedures hve een evluted for their preprtion. Keywords: Chirl tetrhydroquinolines, hirl pyridines, hirl nitrogen heteroyles, Kröhnke nnultion Introdution During our study on the synthesis of hirl P,-lignds with pyridine -donors, 1,2 we needed set of hirl sustituted 2-methylpyridines ering stereogeni entre on the ron onded to the 6-position of the heteroyle. Sine these ompounds should e otined from inexpensive hirl ompounds, monoterpenes, esily ville uilding loks originting from the hirl pool, were seleted s pproprite strting mterils. Herein, we wish to report the synthesis of the three hirl sustituted 2-methylpyridines 1-3 in whih the pyridine rings re nnulted t the 5,6-positions to hirl frmeworks originting from (-)-β-pinene, (-)-isopinompheol nd (+)-mphor ISS Pge 44

2 Generl Ppers ARKIVC 2004 (xiv) Results nd Disussion At the strt of our investigtion, we envisged tht the most diret pproh to tetrhydroquinolines 1-3 ould involve the Kröhnke methodology for the synthesis of pyridines. 3 This route demnds the retion of β-ketolkylpyridinium slt with n α,β-unsturted ronyl ompound in the presene of mmonium ette/eti id. Thus, to test the fesiility of this ide, 1-(2-oxopropyl)pyridinium romide (6) 4 ws prepred y retion of romoetone 5 with pyridine (Sheme 1). An ttempt to prepre the nlogue iodide y retion of etone with iodine in pyridine, s reported y Sxen et l. 5 filed. Insted we otined 1,3-(dipyridinium-1-yl)propn-2-one diiodide (7) in 15% yield (Sheme 1). Slt 6 ws then treted with the α-methylene ketone 9 6 whih ws seleted s typil sustrte to develop optiml retion onditions. Compound 9 ws prepred in two steps from the ketone 8 otined in turn y oxidtion of (-)-β-pinene 7 (Sheme 2). The Kröhnke-type yliztion gve the expeted pyridine 1 ut in low yield. Although mny permuttions of onditions were explored, in no se the yield of the desired pyridine ws >15%. 5 Br Br I I - : Br 2, 2 C 3, CCl 4 ; : pyridine, Et 2 ; : I 2, pyridine, MeH. Sheme 1 The unstisftory outome of these experiments prompted us to exmine n lterntive proedure 8 (Sheme 2). Aordingly, dimethylhydrzone 10, prepred y tretment of the (+)- nopinone (8) with,-dimethylhydrzine, ws deprotonted (n-buli, THF, -78 C, 2 h) nd then quenhed with 2-(2-romoethyl)-2,5,5-trimethyl-[1,3]dioxne (12). The lkyltion produt 11 ws not isolted, ut diretly onverted into the tetrhydroquinoline 1 y heting in ritol (35% yield sed on 10). The overll yield (31% yield sed on 8) of this proess ws muh higher thn tht otined following the Kröhnke-type yliztion (10% yield sed on 8). Hving otined the desired pyridine 1, the lkyltion-znnultion-romtiztion sequene ws extended to the iyli ketones 14, prepred y oxidtion of (-)-isopinompheol, nd (+)- ISS Pge 45

3 Generl Ppers ARKIVC 2004 (xiv) mphor (17) (Sheme 3 nd 4). Thus, the dimethylhydrzones 15 nd 18, fforded pyridines 2 nd 3 in 32 nd 17% yield, respetively. d (-)-β-pinene g e 10 f 11 : TM, s 4, Py, t-buh/h 2, then I 4, r.t., reflux, 2h, 66%; : H 2, Bz, reflux, 15h; then isopentyl formte, r.t., 4h, finlly HCl, 71%; : 2 C 3, HCH, r.t., 40 min, 99%; d: 6, MeH, AH 4, reflux, 20h, 15%; e: H 2 Me 2, EtH, reflux; f: n-buli, THF, -78 C then 12; g: ritol, HCl, reflux, 6h. Br 12 Sheme 2 The overll yield of the proess ws omprle for pyridines 1 nd 2 (32-35%), ut muh lower (17%) for pyridine 3 derived from mphor. This result n e ttriuted to the steri hindrne of the mphor ronyl group tht redues the ility of this ketone to undergo the znnultion step. 9 H (-)-isopinompheol d 2 16 : Cr 3, H 2 S 4, etone, 82%; : H 2 Me 2, EtH, reflux; : n-buli, THF, -78 o C then 12; d: ritol, HCl, reflux, 6h Sheme 3 ISS Pge 46

4 Generl Ppers ARKIVC 2004 (xiv) (+)-mphor : H 2 Me 2, EtH, reflux; : n-buli, THF, -78 o C then 12; : ritol, HCl, reflux, 6h Sheme 4 With the pyridines 1-3 in hnd, we ttempted to trnsform them into the relted pyridinephosphine lignds 20 (Sheme 5). Unexpetedly, severl ttempts to prepre 20 y metlltion of the 2-methyl group of ompounds 1-3 with vrious ses (LDA, n-buli, PhLi, et.), followed y tretment with hlorodiphenylphosphine, filed. 10 R R * * PPh Sheme 5 Conlusions Although the synthesis of the pyridine-phosphines of the type 20 hs een unsuessful, we hve explored two proedures for prepring hirl sustituted 2-methylpyridines from monoterpenes, mking ville new hirl pyridines whih ould e useful hirl uilding loks for the synthesis of more omplex heteroyles. 11 Experimentl Setion Generl Proedures. All regents nd solvents were purhsed from Aldrih nd used s reeived. THF ws distilled from sodium-enzophenone ketyl nd degssed thoroughly with dry nitrogen diretly efore use. Melting points were determined on Bühi 510 pillry pprtus nd re unorreted. The 1 H-MR spetr were otined with Vrin VXR-300 spetrometer t 300 MHz. Chemil shifts re reported in ppm downfield from internl Me 4 Si in CDCl 3 if not otherwise stted. ptil rottions were mesured with Perkin-Elmer 241 polrimeter in 1 dm tue. Elementl nlyses were performed on Perkin-Elmer 240 B nlyser. ISS Pge 47

5 Generl Ppers ARKIVC 2004 (xiv) (2-xopropyl)pyridinium romide (6) ws prepred ording to reported proedure. 4 (1R,5R)-6,6-Dimethyliylo[3.1.1]heptn-2-one ((+)-nopinone, 8) nd (1R,2S,5S)-2,6,6- trimethyliylo[3.1.1]heptn-3-one (14) were prepred y oxidtion of (-)-β-pinene (99% pure, Aldrih) 7 nd (-)-isopinompheol (98% pure, 95% ee y GLC, Aldrih), 12 respetively. (1R,5R)-6,6-Dimethyl-3-methyleneiylo[3.1.1]heptn-2-one (9) ws prepred from (+)- nopinone (8). 7 (+)-Cmphor (17) nd 2-(2-romoethyl)-2,5,5-trimethyl-[1,3]-dioxne (12) were purhsed from Aldrih. Generl proedure for the preprtion of,-dimethylhydrzones 13 A solution of the ketone (0.02 mol),,-dimethylhydrzine (2.7 g, mol) nd tlyti mount of 4-toluenesulfoni id in solute EtH (25 ml) ws heted under reflux for 7 dys. The solvent ws removed nd the residue tken up with old (0 C) 5% HCl (2 x 15 ml) nd Et 2 (20 ml). The queous lyer ws seprted, sified with 10% solution of H (40 ml) nd extrted with Et 2 (2 x 20 ml). The orgni extrts were dried over nhydrous 2 S 4 nd the solvent ws evported. The residue ws purified y distilltion under redued pressure to give pure,-dimethylhydrzones. (1R,5R)-,-Dimethyl-'-(6,6-dimethyliylo[3.1.1]hept-2-ylidene) hydrzine (10). This ompound ws otined in 93% yield sed on the onverted ketone 8: p 100 C (10 mm Hg), 1 H-MR: δ (m, 3H), 2.45 (s, 6H), (m, 4H), 1.43 (d, 1H, J = 9.9 Hz), 1.28 (s, 3H), 0.78 (s, 3H). Cld for C 11 H 20 2 : C, 73.28; H, 11.18;, Found: C, 73.32; H, 11.14;, (1R,2S,5S)-,-Dimethyl-'-(2,6,6-trimethyliylo[3.1.1]hept-3-ylidene) hydrzine (15). This ompound ws otined in 93% yield sed on the onverted ketone 14: p 115 C (10 mm Hg), 1 H-MR: δ (m, 1H), (m, 2H), 2.46 (s, 6H), (m, 1H), (m, 1H), (m, 1H), 1.25 (s, 3H), 1.18 (d, 3H, J = 7.2 Hz), 1.08 (d, 1H, J = 10.5 Hz), 0.83 (s, 3H). Anl. Cld for C 12 H 22 2 : C, 74.17; H, 11.41;, Found: C, 74.22; H, 11.48;, ,-Dimethyl-'-(1,7,7-trimethyliylo[2.2.1]hept-2-ylidene)hydrzine (18). This ompound ws otined in 87% yield sed on the onverted mphor: p 65 C (4 mm Hg), 1 H- MR: δ (m, 1H), 2.45 (s, 6H), 2.00 (d, 1H, J = 18 Hz), (m, 2H), 1.68 (dt, 1H, J = 12, 4 Hz), 1.37 (dt, 1H, J = 12, 4 Hz), 1.21 (dt, 1H, J = 12, 4 Hz), 1.03 (s, 3H), 0.97 (s, 3H), 0.82 (s, 3H). Cld for C 12 H 22 2 : Anl. Cld for C 12 H 22 2 : C, 74.17; H, 11.41;, Found: C, 74.12; H, 11.37;, ,3-(Dipyridinium-1-yl)propn-2-one diiodide (7). A solution of iodine (101.6 g, 0.4 mol) etone (29.3 ml, 0.4 mol), pyridine (80.9 ml, 1.0 mol) in MeH (600 ml) ws heted under reflux for 10 h. The formed solid ws filtered off nd rerystllized from 50% queous methnol to give white rystls: 14.0 g (15% yield sed on the iodine), mp C. 1 H-MR ((CD 3 ) 2 S): δ 8.72 (d, 4H, J = 5.4 Hz), 8.75 (t, 2H, J = 7.8 Hz), 8.75 (t, 4H, J = 6.9 Hz), 6.02 (s, 4H). Anl. Cld for C 13 H 14 I 2 2 : C 33.36, H 3.01, Found: C 33.45, H 3.09, ISS Pge 48

6 Generl Ppers ARKIVC 2004 (xiv) (6R,8R)-(+)-5,6,7,8-Tetrhydro-2,7,7-trimethyl-6,8-methnoquinoline (1). A mixture of 1-(2- oxopropyl)pyridinium romide (6) (2.16 g, 0.01 mol), mmonium ette (7.7 g, 0.1 mol) nd (1R,5R)-6,6-dimethyl-3-methyleneiylo[3.1.1]heptn-2-one (9) (1.5 g, 0.01 mol) in solute MeH (50 ml) ws heted under reflux for 20 h. After ooling the solvent ws evported nd the residue ws tken up in H 2 (200 ml) nd extrted with Et 2 (3 x 30 ml). The etherel phse ws extrted with 10% solution of HCl (3 x 10 ml). The queous phse ws sified with 10% solution of H (40 ml) nd extrted with Et 2 (2 x 50 ml). The omined orgni phses were dried over nhydrous ( 2 S 4 ), the solvent ws evported nd the residue ws purified y flsh hromtogrphy (petroleum ether/ethyl ette = 9/1) to give pure 1 s ple yellow oil: 0.28 g (15%), [α] 25 D ( = 3.12, CHCl 3 ): H-MR: δ 7.21 (d, 1H, J = 6.9 Hz), 6.84 (d, 1H, J = 6.9 Hz), 2.87 (t, 1H, J = 5.7 Hz), 2.80 (s, 2H), (m, 1H), 2.40 (s, 3H), (m, 1H), 1.32 (s, 3H), 1.18 (d, 1H, J = 9.6 Hz), 0.58 (s, 3H). 13 C MR: δ 169.2, 153.1, 137.7, 127.8, 120.1, 52.3, 49.4, 46.5, 33.3, 34.4, 24.5, 23.2, Anl. Cld for C 13 H 17 : C 83.37, H 9.15, Found: C 83.46, H 9.17, Generl proedure for the preprtion of hirl 2-methyl-5,6,7,8-tetrhydroquinolines A solution of the proper,-dimethylhydrzone (0.02 mol) in nhydrous THF (5 ml) ws dded dropwise to ooled (-78 C) solution of n-utyllithium (0.02 mol, 12.5 ml of 1.6 M solution in hexne) in nhydrous THF (50 ml). The resulting solution ws stirred t -78 C for 2 h nd then t 0 C for 1 h. After ooling t -78 C, solution of 2-(2-romoethyl)-2,5,5- trimethyl-[1,3]dioxne (12) (5.47 g, 0.02 mol) in nhydrous THF (5 ml) ws dded dropwise. After 15 min t -78 C, the solution ws llowed to reh slowly room temperture (overnight) nd were then quenhed with H 2. The mixture ws extrted with ethyl ether. The orgni phse ws seprted, dried ( 2 S 4 ) nd the solvent ws evported. The flsk ws onneted to distilltion hed nd heted under redued pressure (0.1 mm Hg) to distill off unonverted hydrzone nd dioxne. The residue ws tken up with ritol (30 ml), idified with few drops of HCl nd heted under reflux for 6 h. After ooling, the mixture ws tken up with H 2 (500 ml) nd extrted with ethyl ether (3 x 50 ml). The etherel phse ws extrted with 10% solution of HCl (3 x 50 ml). The queous phse ws sified with 10% solution of H nd extrted with ethyl ether. The orgni phse ws dried on nhydrous 2 S 4, nd the solvent ws evported. The residue ws distilled under redued pressure (13 mm Hg) olleting the frtion distilling etween C. The distillte ws finlly purified y flsh hromtogrphy (petroleum ether/ethyl ette = 9/1) to give pure tetrhydroquinolines. (6R,8R)-(+)-5,6,7,8-Tetrhydro-2,7,7-trimethyl-6,8-methnoquinoline (1). Yield: 1.31 g (35%). The 1 H-MR spetrum ws identil to tht otined in the ove reported method. (5R,7R,8S)-(-)-5,6,7,8-Tetrhydro-2,6,6,8-tetrmethyl-5,7-methnoquinoline (2). Yield: 1.28g (32%), oil, [α] 25 D ( = 1.18, CHCl 3 ): H-MR: δ 7.06 (d, 1H, J = 7.5 Hz), 6.81 (d, 1H, J = 7.5 Hz), (m, 1H), 2.68 (q, 1H, J = 6.3 Hz), (m overlpping, 1H), 2.51 (s, 3H), (m, 1H), 1.39 (s, 3H), 1.37 (d, 3H, J = 7.2 Hz), 1.28 (d, 1H, J = 9.9 Hz), 0.62 ISS Pge 49

7 Generl Ppers ARKIVC 2004 (xiv) (s, 3H). 13 C MR: δ 168.9, 154.2, 137.4, 128.5, 119.9, 56.5, 49.8, 45.3, 33.5, 31.2, 25.3, 24.8, 21.9, Anl. Cld for C 14 H 19 : C 83.53, H 9.51, Found: C 83.61, H 9.53, (5S,8R)-(+)-5,6,7,8-Tetrhydro-2,8,9,9-tetrmethyl-5,8-methnoquinoline (3). 8 Yield: 0.68 g (17%), oil, [α] 20 D ( = 1.44, CHCl 3 ): H-MR: δ 7.22 (d, 1H, J = 7.2 Hz), 6.80 (d, 1H, J = 7.2 Hz), 2.79 (d, 1H, J = 4.2 Hz), 2.51 (s, 3H), (m, 1H), 1.83 (dt, 1H, J = 12.3, 3.6 Hz), 1.32 (s, 3H), (m, 2H), 0.97 (s, 3H), 0.54 (s, 3H). 13 C MR: δ 169.6, 153.8, 137.8, 128.1, 119.5, 56.5, 53.9, 51.0, 31.6, 26.2, 26.1, 24.1, 19.8, Anl. Cld for C 14 H 19 : C 83.53, H 9.51, Found: C 83.48, H 9.49, Aknowledgements Finnil support from MIUR (PRI Chirl lignds with nitrogen donors in symmetri tlysis y trnsition metl omplexes. ovel tools for the synthesis of fine hemils) nd from the University of Sssri is grtefully knowledged y G. C. Referenes 1. For reent review on pyridine-phosphine lignds, see: Chelui, G.; rrù, G.; Pinn, G. A. Tetrhedron 2003, 59, Chelui, G.; S, A.; Soolini, F. Tetrhedron 2001, 57, Kröhnke, F. Synthesis 1976, 1 nd referenes therein. 4. Kröhnke, F.; Shmidt, E.; Zeher, W. Chem. Ber. 1964, 97, Sxen, J. P.; Gelr, M. A. Aust. J. Chem. 1967, 20, Ginini, M.; von Zelewsky, A. Synthesis 1996, () Grimshw,.; Grimshw, J. T.; Junej, H. R. J. Chem. So., Perkin Trns , 50. () Brown, H. C.; Weissmn, S. A.; Peruml, P. T.; Dhokte, U. P. J. rg. Chem 1990, 55, Chelui, G.; Gldili, S.; Mrhetti, M. J. Heteroyli Chem. 1988, 25, Chelui, G.; Delogu, G.; Gldili, S.; Soolini, F. J. Heteroyli Chem. 1986, 23, For the method on relted 2-pioline, see: ewkome, G. R. Chem. Rev. 1993, 93, For referenes on the synthesis of hirl pyridine derivtives, see: Chelui, G.; Thummel, R. P. Chem. Rev. 2002, 102, Bessière-Chrétien, Y.; Grison, C. Bull. So. Chim. Fr. 1970, ewkome G. R.; Fishel, D. L. J. rg. Chem. 1996, 31, 677. ISS Pge 50