J. CHEM. soc. PERKIN TRANS. I 1983 75 1 3-Methylcyclohex-2-enone Derivatives as Initiators of Cyclisation. Part 2.t Monocyclisations to Six-membered Rings Joseph A. Amupitan, Enamul Huq, Michael Mellor, Edward G. Scovell, and James K. Sutherland Chemistry Department, The Victoria University of Manchester, Manchester MI 3 9PL Cyclisation of 3-methylcyclohex-2-enones and the derived epoxides containing alkene, alkyne, and aryl side-chains yields bicyclo 4.4.0decane derivatives when the alkene or alkyne is electronically biased towards six-membered ring formation and when the alkene is electronically unbiased. We have examined the reaction of the epoxide (5) with a number of Lewis acids; varying quantities of cyclisation product (9) and ring-contracted dione (11) are formed.The structure of (1 1) derives from spectroscopic evidence v,,. (CHC13) 1745 and 1 715 cm-'; r 4.3 (1 H, m), 5.1 (2 H, m), 8.7 (3 H, s), alkaline hydrolysis to the acid (12) r 4.2 (1 H, m), 5.0 (2 H, m), 8.8 (3 H, d, J 7 Hz), and precedent.' Spectroscopic data for (9) v,, (CCI,) 3 495 and 1 715 cm-'; r(300 MHz) 5.23 (1 H, m), 5.28 (1 H, m), and 9.15 (3 H, s) established the part-structure (3), where C* is either C-1, -2, -3, or -10. The structures derived from C-1 and -2 bonding were rejected on mechanistic grounds leaving (9) and the bridged structure from C-3 bonding. The latter could be excluded by showing that the diols from borohydride reduc- tion had a CH(0H) n.m.r. signal of greater multiplicity than the two singlets required for the isomers of the bridged struc- ture.The cis ring junction in (9) follows from the existence of intramolecular hydrogen bonding. This is possible only in the 'non-steroid 'conformation of a cis-decalin as was con- firmed by the absence of such bonding in the 5a-and 5p-hydroxycholestan4ones kindly donated to us by Dr.J. R. Bull, Pretoria. In the Table the ratio cyclisation :ring con- traction for a variety of Lewis acids and solvents is sum- marked. If it is accepted that gas-phase metal-oxygen bond strengths give a rough measure of Lewis acidity for oxygen then a trend for the stronger Lewis acids giving more cyclis- ation product is discernible. In line with this, TiCI4-CH2CI2 converted (5) into the ketol(9) (40) and the diols (13) (23) without any ring-contracted product.This effect could arise from the C-O-metal bond in the cyclisation transition state + being stabilised to a greater extent than the GO-metal bond in the ring-contraction transition state. In the latter case the stronger the 0-metal bond, the less might be the resonance stabilisation. The enone (1) has been cyclised (using Ac,O-HClO,-EtOAc) to a decalone derivative? This is a preparatively more useful reaction than the epoxide cyclis- ation. The epoxide (6) was treated with BF3*OEt2-CH2C12 at -20 "C to give a complex reaction mixture from which (10) (20) T 4.30 (2 H, m), 9.00 (3 H, d, J 7 Hz), 9.15 (3 H, s) and (14) (40) r 4.63 (1 H, m), 8.35br (3 H, s), and 9.10 (3 H, s) were isolated.The ketone (14) was reduced with NaBH4 to a mixture of dioIs which on periodate oxidation gave a ketoaldehyde whose spectroscopic properties v,,. 1 730 and 1 715 cm-'; T 0.31 (1 H, t, J 1.5 Hz), 4.30 (1 H, m), 8.30 (3 H, t, J 1.6 Hz), and 8.83 (3 H, s) established that the double bond was not allylic to the hydroxy-group in (14).$ The two ketols (14) and (10) were again the major products f Part 1, preceding paper. It was necessary to carry out this degradation to establish that an unexpected rearrangement observed in another cyclisation had not occurred here. ci CH, 12 CH=CHz t(2 1 CH212 CH=CHMe CH, l2 C6H40Me -m (4 CH,,C=CH */ R (9) R=H (10) R=Me moH using TiCI4, BCl3, and SnCI4 as Lewis acids; the ratios of (14) :(10) were 3.4, 3.8, and 5.3 respectively.The experiment using BC13 was carried out at -20 "C in CH2Clz. When the reaction was conducted at -78 "C small amounts of the previously mentioned compounds were formed, but a new major (84) product appeared. It is formulated as (15) but only on mechanistic and spectroscopic grounds vmx. 3 600 cm-l; mass spec. 1 H exchangeable with 2H20; r 8.79 (3 H, s) and 9.10 (3 H, s). Cyclisation of the enone (2) with (CF3-CO)20-CF3COzH (which presumably occurs via the dienol trifluoroacetate) gave, after hydrolysis, the ketone (1 6) (23)A,,. (MeOH) 245 nm (E 12 600); vmx. 1 670 and 1 610 cm-'; T 8.91 (6 H, s), the ketol (17) (26) v,,,. 3 600 and 1 710 cm-'; r 6.65 (1 H, m, W, 27 Hz), 9.00 (3 H, d, J 7 Hz),and 9.35 (3 H,s) and the cis-isomer (18) (15) vmx 3 600 and 1710 cm-'; r 6.55 (1 H, m, W+25 Hz),9.01 (3 H, s), 752 J.CHEM. SOC. PERKIN TRANS. I 1983 Table Ratio Lewis acid Solvent (9) :(11) TiCI, AlCl3 CH2C12 CHZClz 00 3.0 FeC13 CHzC12 1.1 SnCll CHZCIZ 0.6 ZnClz CHZCIZ 0.3 BF,*OEtz BFj*OEtiBFj*OEt2 ZnClz CHZC12 C6H6 EtZO EtZO 0.8 0.6 0.1 0.1 Ratios determined by g.1.c. and 9.12 (3 H, d, J 8 Hz). The ring-junction stereochemistry of (17) and (18) is assigned using the chemical shifts of the angular methyl groups while the W, of the CH(0) protons are in accord with the secondary methyl and the hydroxy- groups being equatorial. In the formation of (15) and (16) the initially formed secondary carbonium ion is transformed to a tertiary carbonium ion either by H+ elimination-H+ addition or by 1,2-hydride migration.In the formation of (16) the latter route was established by carrying out the cyclisation with CF3COZ2H; one deuterium (v~,~~.2 170 cm-') was incorporated. On treatment with NaOH-HrO-dioxan this deuterium was exchanged. These results illustrate the difficulties of obtaining pre- paratively useful yields of cyclisation products when different termination mechanisms are evenly balanced. In the epoxide cyclisations control of the direction of elimination might be achieved using Fleming's device of R3Si elimination instead of H. This might also be applicable in the enone cyclisations and divert termination from the competing rearrangement and nucleophilic attack.Two participating groups which terminate cyclisation by a single mechanism are the acetylenic and aryl functions. Reaction of (7) with BF3*OEtr or SnCI4 in CHrC12 gave (19) (45) r 2.95 (1 H, m), 3.30 (2 H, m), 8.63 (3 H, s) and (20) (45) r 2.90 (2 H, d, J 7 Hz), 3.30 (2 H, m), and 8.75 (3 H, s). A mixture of (1 9) and (20) was reduced to diols with NaBH, and oxidised with periodate to give the ketoaldehydes derived from (19) h,,,,,. (EtOH) 274 nm (E 1 410); vmax, 1 725 and 1 710 cm-'; r 0.49 (1 H, t, J 1.6 Hz), 2.93 (1 H, dd, J8.5 and 7.5 Hz), 3.35 (2 H, m), 6.17 (3 H, s), and 8.54 (3 H, s) and (20) h,,,,,. (EtOH) 279 nm (E 1440); vnlnx. 1 730 and 1 710 cm-'; 'I0.44 (1 H, t, J 1.5 Hz), 2.89 (1 H, d, J 8.5 Hz), 3.29 (1 H, dd, J8.5 and 2.5 Hz), 3.43 (1 H, d, J2.5 Hz), 6.26 (3 H, s).and 8.68 (3 H, s). When TiCI, was used (19) and (20) were formed but the major product was formulated as the dihydrophenanthrene (21) (50) Xnli,x.(EtOH) 278 nm (E 29 800); r 2.40 (2 H, dt), 2.90 (2 H, m), 3.20 (2 H, m), 6.20 (3 H, s), 7.20br (4 H, s), and 7.65 (3 H, s). It is not obvious why TiCI4 should divert attack of the aryl ring from co-ordinated epoxide to co-ordinated carbonyl group. Cyclisation of the acetylene (8) with BF3*OEt, or TiCl, gave (22) (90) A,,,,. (CHC13) 3 480 and 1 715 cm-'; T 4.35 (1 H, s) and 9.05 (3 H, s). Degradation by borohydride reduction followed by periodate cleavage gave a keto-aldehyde whose properties supported structure (22).These experiments are in accord with prior result^.^ Where the alkene double bond is electronically unbiased then 6-endo- Trigonal-cyclisation formation is favoured over 5-exo-Trig. 6-endo-Digonal cyclisation is favoured only with a terminal alkyne7 Both u-and p-attack by the anisyl ring is not surpris- (17) (trans) (19) R'=H, RZ=OMe (18) (cis 1 (20) R'=OMe. R2=H (21) (22) ing but the equivalent rates of attack are and suggest an unselective and reactive cationic intermediate. From a pre- parative viewpoint only the alkyne cyclisations would appear to be useful. Experimental M.p.s were determined on a Kofler block and are uii-corrected. 1.r. spectra were recorded on a Perkin-Elmer 257 instrument in CHCIJ solution. N.m.r.spectra were recorded at 60 and 90 MHz on Perkin-Elmer R12B and R32 instru- ments using CDC13 as solvent. High-resolution mass spectra were measured on an AEI MS30 instrument on samples judged to be pure by t.1.c. The statement 'worked up in the usual way ' implies that the organic extract was washed with saturated brine, dried over Na2S04 or MgS04, and the solvent evaporated under reduced pressure. G.1.c. was carried out on a Perkin-Elmer F11 using a 6 ft PEGA column. Reaction of (5) with BF3-OEt2.-BF3*OEt2 (400 pl) was added to a stirred solution of (5)(120 mg) in CH2C12 (10 ml) at -20 "C under Nr. After 30 min water was added and the mixture extracted with CHZCI2. Work-up in the usual way gave an oil (103 mg) which contained three major components by g.1.c.Chromatography on silica gel (12 g) and elution with light petroleum (b.p. 40-60 "C)-ether (7: 3) gave the dione (11) (40 mg) (g.1.c. R, 1.8 min/l80 "C) (Found: C, 72.9; H, 8.9. C11H,,02 requires C, 73.3; H, 8.8) followed by the ketul(9) (30 mg) (g.1.c. R, 4.25 min/l80 "C (Found: C, 73.4; H, 9.0. CIIH,,02 requires C, 73.3; H, 8.8). Reduction of (9) with sodium borohydride gave an oily mixture of diols, r 4.41 (2 H, m) and 6.22-6.60 (1 H, m) (Found: M+, 182.131 1. C,,HI8O2requires M, 182.1307). Reaction of(5) with TiCl4.-TiC1, (250 pl) was added to a stirred solution of (5)(217 mg) in CHzClp at -20 "C. Work-up as above gave an oil (196 mg) which was chromatographed on silica gel.Elution with light petroleum (b.p. 40-60 "C)-ether (1 : 1) first gave an oil (52 mg) (mainly starting material) followed by (9) (67 mg). Elution with ether gave the diols (13) (42 mg), m.p. 115-123 "C (ethyl acetate) (Found: C, 66.6; H, 9.1. C11H180j requires C, 66.6; H, 9.2). Hydrolysis of the Dione (I l).-The crude product (100 mg) from reaction of BF3 and (5) was dissolved in EtOH (15 ml) and ~M-N~OH (15 ml) added. After being refluxed for 3 h the mixture was extracted with Et,O and worked up in the J. CHEM. SOC. PERKIN TRANS. I 1983 usual way to give (9). Acidification of the aqueous layer followed by Et20 extraction and work-up in the usual way gave the acid (12) (35 mg) as an oil m/z198; r 4.10 (1 H, m), 5.00 (2 H, m), and 8.80 (3 H, d, J 7 Hz).Reaction of (6) with BF3-OEt2.-BF3*OEt2 (0.5 ml) was added to a stirred solution of (6) (512 mg) in CH2C12 (35 ml) at -20 "C under a N2 atmosphere. After 2 h no epoxide remained (t-1.c.) and the mixture was diluted with water, extracted with ether, and worked up in the usual way to give an oil (526 mg). G.1.c. showed five main peaks with /I50 "C 2.23, 4.35, 4.76, 6.35, and 8.87 min in a ratio 5 :3 : 17 :7 :4. The crude product (512 mg) was dissolved in EtOH (20 ml) and 2~ NaOH (20 ml) added. After 2 h reflux dilution with water, extraction with CHC13, and work-up in the usual way gave an oil (450 mg). G.1.c. showed that the second peak had disappeared. Chromatography on silica gel and elution with light petroleum (b.p.40-60 "C)-Et20 (1 : 1) gave the ketol (14) (202 mg) as an oil R, (150 "C) 4.76 min (Found: C, 73.8; H, 9.2. C12H1802requires C, 74.2; H, 9.3) and the isomer (10) (105 mg) R, (150 "C) 6.35 min (Found: C, 74.1; H, 9.4). Degradation of (14).-The ketol(l4) (29 mg) in EtOH (1 ml) was reduced with NaBH, (40mg). After addition of water the EtOH was evaporated off and the residue extracted with Et20 and worked up in the usual way to give a mixture of oily diols (28 mg) (Found: M+, 196.1464. C12H2002requires M, 196.1463). The diols (19 mg) were dissolved in THF-water (3 :1 ;2 ml) and sodium periodate (54 mg) added. After being stirred overnight, the mixture was diluted with water and extracted with Et20; work-up in the usual way of the extract gave the ketoaldehyde (1 8 mg) (Found :M+: 194.1308.C12H18-O2requires M, 194.1307). Reaction of (6) with BC13.-BC13 (>2 equiv.) was added to the epoxide (6) (160 mg) in CH2CI2(5 ml) at -78 "C. After 2 h dilution with water, extraction with Et20, and the usual work-up gave an oil which was chromatographed on silica gel. Elution with hexane-Et20 (1 : 1) gave the chloride (15) (142 mg), m.p. 120-122 "C (light petroleum b.p. 60-80 "C) (Found: C, 62.7; H, 7.9; CI, 15.0. C12Hlv02Clrequires C, 62.5; H, 8.2; CI, 15.4). Cyclisation of (2).-A mixture of CF3C02H (8 ml) and (CF,C0)20 (4 ml) was added to the ketone (2) (500 mg). After 12 h water was added and the mixture evaporated to dryness under reduced pressure. The residue was hydrolysed with NaHC03-MeOH.Addition of water, extraction with Et,O, and the usual work-up procedure gave an oil (431 mg) which was separated by preparative t.1.c. on silica gel using hexane-Et20 (I :I) into three fractions. In order of increasing polarity these were the ketone (16) (116 mg) (Found: M+: 178.1358. Cl2HlY0requires M, 178.1358), the cis-isomer (18) (80 mg) (mlz 196), and the trans-isomer (17) (137 mg) (m/z 196). Cyclisation qf(7) with SnCI,.-SnCI, (0.8 ml) was added to a solution of (7) (200 mg) in CH2C12(10 ml) cooled to -20 "C under a N2 atmosphere. After 2 h addition of water followed by extraction with Et20 and work-up in the usual way gave a gum (205 mg). Chromatography on silica gel using light petroleum (b.p.40-60 "C)-Et20 (1 : 1) as eluant gave the ketol (20) (89 mg), m.p. 96-98 "C (Et20), v,,,,. 3 480 and 1710 cm-' (Found: C, 74.1; H, 7.8. CI6HZ0O3requires C, 73.8; H, 7.7) and the isomer (19) (91 mg) m.p. 123-124 "C (Et20)vmax.3 480 and 1 710 cm-I (Found: C, 73.8; H, 7.8). Similar results were obtained using BF3*OEt2. Degradation of the Mixture of (19) and (20).-The mixture of ketols (19) and (20) (208 mg) obtained as above was reduced with NaBH4 (202 mg) in EtOH (5 ml). The usual work-up gave a mixture of diols (202 mg) (Found: M+, 262.1571. C16HZ203requires M, 262.1 569). The diols (1 3 1 mg) in THF-water (3: 1) (4 ml) were oxidized with sodium periodate (269 mg) to give an oil (125 mg).Chromatography on silica gel light petroleum (b.p. 40-60 "C)-Et,O gave, first, the ketoaldehyde derived from (20) (46 mg) v",:,~.1 725 and 1 710 cm-'; h,,,,. 274 nm (E 1410); 'I: 0.49 (1 H, t, J 1.6 Hz), 2.93 (1 H, dd, J 8.5 and 7.5 Hz), 3.34 (2 H, m), and 8.54 (3 H, s) (Found: M+, 260.1411. CI6H20O3 requires M, 260.1412), then the ketoaldehyde ex. (19) (49 mg) 1 725 and 1 710 cm-I; h,,,,,,.279 nm (E 1440); r 0.45 (1 H, t, J 1.5 Hz), 2.89 (1 H, d, J 8.5 Hz), 3.29 (1 H, dd, J 8.5 and 2.5 Hz), 3.43 (1 H, d, J 2.5 Hz), and 8.68 (3 H, s) (Found: M+ : 260.141 4). Cyclisation of (7) with TiCI,.-The epoxide (7) (236 mg) was cyclised as above but using TiCI,. A viscous gum (241 mg) was obtained which was chromatographed on silica gel light petroleum (b.p.40-60 "C)-Et,O, 1 :I to give the dihydrophenanthrene (21) (120 mg), m.p. 70-71 "C (light petroleum b.p. 60-80 "C) (Found: M+ 224.1196. C16H16O requires M, 224.1201). Accurate combustion analyses ( >1) could not be obtained owing to facile oxidation of the com- pound. The ketols (19) and (20) were also isolated. Cyclisation of (8).-BF3-OEt2 (0.8 ml) was added to a solution of (8) (175 mg) in CH2C12(15 ml) at -20 "C under a N2 atmosphere. After 3 h the reaction was worked up as before to give a brown oil (220 mg) which crystallised with time at ambient temperature. A sample was recrystallised from light petroleum (b.p. 40-60 "C), m.p. 84-85 "C (Found: C, 61.8; H, 7.1; CI, 16.4. CIIHl,CIO, requires C, 61.5; H, 7.0; C1, 16.5). Similar results were obtained on cyclisation with TiCI4. Acknow1edgements We thank the University of Ahmadu Bello, Zaria, Nigeria, for leave of absence to J. A., the Bangladesh University of Engineering and Technology for leave of absence to E. H., and the S.E.R.C. for financial support to M. M. and E. G. S. References 1 H. 0. House and R. L. Wasson, J. Am. Chem. Soc., 1957, 79, 1488. 2 L. Brewer and G. M. Rosenblatt, Ado. High Temp. Cltetii., 1969, 2. 3 J. L. Cooper and K. E. Harding, Teirahedrott Lett., 1977, 3321. 4 L. M. Jackman and S. Sternhell, ' Applications of NMR Spec-troscopy in Organic Chemistry,' Pergamon, Oxford and New York,1969, 2nd edn., p. 243. 5 1. Fleming, A. Pearce, and R.L. Snowden, J. Chem. Soc., Chem. Commun., 1976, 182. 6 For reviews see W. S. Johnson, Bio-org. Chem., 1976, 5, 51; E. E. van Tamelen, Acc. Chem. Rex, 1975, 8, 152; J. K. Suther-land, Chem. Soc. Reu., 1980, 9, 265. 7 J. E. Baldwin, J. Chem. Soc., Chem. Commitn., 1976, 734. Receiued 27th July 1982; Paper 2/1294
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