Conclusions and future work
3 Experimental
iH NMR spectra were obtained using a Varian Gemini 200 MHz spectrometer unless otherwise stated, in which case the spectrum was obtained using a Bruker AM 300 spectrometer. The majority of the NMR spectra were run at 75 MHz using the Bruker mentioned above unless othei*wise stated, in which case the spectrum was run at 50 MHz on the Gemini mentioned above. All samples were dissolved in deuterated chloroform unless otherwise stated, using Me^^Si as an internal standard. GC/MS work was carried out using a Finnigan Incos 50 quadmpole mass spectrometer interfaced with a Hewlett-Packard HP5890 capillary gas chromatograph fitted with a column coated with methyl silicone as the stationary phase. Mass spectra were obtained with 70 eV electron impact ionisation on a Kratos M25RF spectrometer. Solvents which have been removed using a rotatory evaporator are referred to as being evaporated. All NaOH and HCl solutions were approximately 2M. Chromatographic purification was carried out using silica gel (either Sorbsil C60 40/60A or BDH 40-63 p.m) eluting with the given solvent mixture. Each experimental procedure is referred to the corresponding scheme in the results and discussion section to allow a quick reminder of the actual reaction discussed. Some molecular structures have also been included in this section to aid assignment of carbon and hydrogen spectra.
120 l-C yclopentylcyclohexa-2,5-diene-l-carboxylic acid (15) (Scheme 1 2)
Ammonia (600 cm3) was added to benzoic acid (10 g, 82 mmol) with careful stirring. To this, Li (1.6 g, 0.231 mol) was added portionwise until a pennanent blue colour persisted, followed by drop wise addition of bromocyclopentane (25 cm3,0.233 mol). The reaction mixture was left for Ih whilst the NHg evaporated and ice was added to the remaining solid followed by dilute H2SO4. The product was extracted with ether (3 x 150 cm^) and the
combined ethereal extracts were dried (MgSO^) and the solvent was evaporated leaving a solid which was recrystallised in light petroleum, yielding the title compound as fine white crystals (7.5 g, 48%t), mp 115“C (lit.,13 mp 96'C) (Found: C, 75.28; H, 8.58. Calc, for C12H16O2: C, 74.95; H, 8.40%); ôjj 1.2-1.4 (2 H, m, methylene-H, cyclopentyl ring)
1.4-1.7 ( 6 H, m, methylene-H, cyclopentyl ring ), 2.3-2.5 (1 H, q*, / 8, r-H, cyclopentyl
ring), 2.6-2.7 (2 H, s, allylic-H), 5.7-6.0 (4 H, m, olefinic-H); Ôc 25.7, 26.5, 27.2 (5 x methylene-C), 47.8 (f-C), 49.8 (quaternary-C), 125.9, 126.4 (4 x olefinic-C), 180.2 (carbonyl-C).t Concentration of the mother liquors gave a further 3.95 g of product (crude yield 71%).
l “^-ButyIcyc!ohexa“2,5-diene-l-carboxylic acid (16) (Scheme 1 2)
Prepared by essentially the same procedure as described above, except that the reaction mixture was quenched with f-butyl bromide. Purification by dry flash chromatography, eluting with 2 0% ethyl acetate in light petroleum yielded the title compound as white
crystals (2.6 g, 18%), mp lO rC (lit.,13 mp 105°C) (Found: C, 73.47; H, 9.35. Calc, for C11H16O2: C, 73.30; H, 8.95%); 6^ 1.00 (9 H, s, f-butyl-H), 2.57-2.63 (2 H, s, allylic-
H), 5.88-6.10 (4 H, m, olefinic-H); 5c 26.0 (3 x methyl-C), 26.2 (allylic-C), 38.6 (quaternary-C), 52.9 (quaternary-C), 125.5, 126.2 (4 x olefinic-C), 180.4 (carbonyl-C).
l-BenzylcycIohexa"2,5-diene-I-carboxyllc acid (17) (Scheme 1 2)
Prepared by essentially the same procedure as described above, except that the reaction was quenched with benzyl chloride. The title compound was obtained in pure form after recrystallisation from cyclohexane (7.24 g, 41%t), mp 76-77“C (lit.,13 mp 76"C) (Found:
121
C, 78.17; H, 6.67. Calc, for C ^H i^O ^: C, 78.48; H, 6.59%); ôy 2.27-2.63 (2 H, m, allylic-H), 3.03 (2 H, s, benzylic-H), 5.80-5.90 (4 H, m, olefinic-H), 7.11-7.29 (5 H, m, arom-H); 25.0 (allylic-C), 46.1 (benzylic-C), 48.8 (quaternary-C), 126.5, 126.7, 127.9, 130.7, 136.1 (10 x olefinic, arom-C), 179.7 (carbonyl-C). fConcentration of the mother liquors provided a further 7.68 g of product (crude yield 85% and quantitative on a
1 g scale).
l-/-B utyIcyclohexa-2,5-diene-l-carboxylic acid (16) (Scheme 12)
Ammonia (300 cm3) was added to benzoic acid (3 g, 24.6 mmol) and to this was added Li (0.48 g, 69.2 mmol) causing the solution to turn blue. The mixture was stimed for 0.5h and quenched with f-butyl iodide (13.2 g, 72 mmol) causing immediate decolourisation. The reaction was worked up in a manner identical to previously described, yielding a pale yellow solid (4.0 g) containing the title compound (2 g, 45%), benzoic acid and 1,4- dihydrobenzoic acid. The title compound (1.3 g, 29%) was obtained as a pale brown crystalline solid by dry flash chromatography, eluting with 25% ethyl acetate in light petroleum. The product gave identical ^H and NMR spectra identical to those given previously.
3-C ycIopentyIcycIohexanone (18)
Radical reaction involving carboxylic acid 15 and cyclohexenone (Scheme 13) l-Cyclopentylcyclohexa-2,5-diene-l-carboxylic acid (Ig, 5.2 mmol), cyclohexenone (0.5g, 5.2 mmol) and f-butyl peroxybenzoate! (O.lg, 10%wt) were dissolved in benzene (5 cm3) and refluxed for 1 week, during which a further 4 portions of initiator were added (0.55 g, 55% wt. overall). Analysis of the reaction mixture by GC/MS indicated the presence of unreacted cyclohexenone, 3-cyclopentylcyclohexanone and phenylcyclopentanek The reaction contents were diluted with ether (50 cm3) and washed with NaOH (3 x 25 cm3). The alkaline extracts were combined, washed with light petroleum and the organic fractions were combined, dried (MgSO^) and the solvent was evaporated yielding an oil (0.91 g; 0.51 g, 59%, 3-cyclopentylcyclohexenone and 0.07 g,
122 9%, phenylcyclopentane). The mixture was purified by column chromatography using 5% ethyl acetate in light petroleum, yielding the title compound as a colourless oil (0.27 g, 31%), (lit.,36 bp 82°C at 1 mmHg); 6^ (300 MHz) 1.02-1.22 (2 H, m, methylene-H, Ô to
carbonyl), 1.34-1.44 (1 H, m, methylene-H, (3 to carbonyl), 1.45-1.80 (9 H, m; 8 H,
methylene-H, cyclopentyl ring and 1 H, (3 to carbonyl), 1.87-2.00 (1 H, m, r-H, cyclohexyl ring), 2.00-2.13 (2 H, m, methylene-H, a to carbonyl), 2.20-2.42 (2 H, m, methylene-H, a to carbonyl), 2.43-2.54 (1 H, f-H, cyclopentyl ring); 0^ 25.2, 25.4 (2 x C, methylene-C, cyclopentyl ring), 30.3, 30.4, 30.7 (4 x methylene-C), 41.5 (methylene- C, a to carbonyl), 45.0 (f-C), 46.2 (f-C), 47.5 (methylene-C, a to carbonyl), 212.4 (carbonyl-C);m/z 166 (M+, 27%), 148 (10), 123 (38), 108 (53), 97 (100), 81 (18), 69 (40), 67 (42), 55 (48) (Found: M+, 166.1365. C nH igO requires 166.1358). The acid compounds were regenerated using excess H2SO4, extracted with ether, dried (MgS0 4)
and the solvent was evaporated yielding benzoic acid (1 .1 2 g) as the only product.
iDibenzoyl peroxide and f-butyl peroxybenzoate were both found to be appropriate initiators. ^Identified by comparison with a sample prepared by the procedure below.
Phenylcyclopentane (Scheme 16)^4
Polyphosphoric acid (184 g) was heated on an oil bath at 80-85°C followed by the addition of cyclopentanol (18.4 g, 0.21 mol) and benzene (49.7 g, 1.56 mol). The mixture was refluxed for 1.5h, the reaction contents were diluted with H2O (900 cm^) and the aqueous
layer was extracted with benzene (100 c m 3 ) . The combined organic extracts were dried (MgSÛ4), the majority of the benzene was evaporated and the title compound was obtained
as a clear, colourless liquid after distillation (7.5 g, 24%), bp 92°C at 12 mmHg (lit.,^4 bp 215-217"C at atmospheric pressure); Ôy 1.6-2.0 (6 H, m, methylene-H, cyclopentyl ring),
2.1-2.3 (2 H, m, methylene-H, cyclopentyl ring), 3.0-3.2 (1 H, q', J 10, f-H, cyclopentyl ring), 7.2-7.5 (5 H, m, aromatic-H); 5c25.4, 34.5, 45.8, 125.5, 127.0, 128.1, 146.4.
3-f-B utylcyclohexanone (22)
Radical reaction involving carboxylic acid 16 and cyclohexenone (Scheme 17) l-f-Butylcyclohexa-2,5-diene-l-carboxylic acid 16 (1.0 g, 6 mmol) cyclohexenone (0.54
g, 6 mmol) and dibenzoyl peroxide (0.5 g, 50% wt.) were refluxed in benzene (5 cm3) for
24 h. Analysis of the reaction mixture by GC/MS indicated the presence of 3-f- butylcyclohexanone, the phenyl adduct, f-butyl benzene, benzoic acid, unreacted cyclohexenone and two other compounds, one of which was a small amount of the unreacted starting acid 16 The product mixture was extracted with NaOH (5 cm^) and the alkaline fraction was extracted with benzene (2 x 10 cm^). The aqueous fraction was acidified with excess acid and extracted with ether (3 x 25 cm3), the ethereal extracts were combined, dried (MgSO^.) and the solvent was evaporated yielding a solid (0.54 g) which was a mixture of benzoic acid and also some unreacted acid 16. The original benzene fractions were combined, dried (MgSO^) and the solvent was evaporated to yield an orange 011 (0.55 g). An attempt to isolate the adduct by flash chromatography resulted in poor recovery of material. The yields were estimated from the iH NMR of the mixture which indicated 25% of the title compound and 3% of f-butylbenzene.
3-B enzylcyclohexanone (23)
Radical reaction involving carboxylic acid 17 and cyclohexenone (Scheme 18) l-Benzylcyclohexa-2,5-diene-l-carboxylic acid (2.5 g, 1 2 mmol), cyclohexenone (1.13 g,
12 mmol) and dibenzoyl peroxide (0.25 g, 10% wt) were refluxed in benzene (20 cm^) under an atmosphere of N2 for 5 days, during which a further 0.75 g (40% wt. overall) of
initiator was added. Analysis of the reaction mixture by GC/MS indicated the presence of cyclohexenone, diphenylmethane, 3-benzylcyclohexanone and benzoic acid. The reaction contents were diluted with ether (50 cm3) and extracted with NaOH (3 x 10 cm3). The combined alkaline extracts were washed with light petroleum ( 2 0 cm^), neutralised with
excess HCl and extracted with ether (3 x 50 cm3). The combined ethereal extracts were dried (MgSO^) and the solvent was evaporated yielding a brown solid (2.08 g; 1.11 g unreacted starting acid 28; 0.96 g benzoic acid). The original ether fraction was combined
with the petroleum washing, dried (MgSO^) and the solvent was evaporated yielding an oil (1.42 g). This was purified by column chromatography yielding the title compound as a pale yellow oil (0.64 g 52%t); 8^$ 1.35-2.50 (9 H, m, methylene, methine-H), 2.60-2.67
(2 H, d, J 6.2, benzylic-H), 7.10-7.40 (5 H, m, arom-H); ôc (50MHz), 25.3, 31.0 (2 x methylene-C), 41.0, 41.6, 43.1, 48.0 (4 x C; 3 x methylene-C and 1 x r-C), 126.3 (p- arom-C), 128.5, 129.2 (4 x arom-C), 139.5 (/pjo-arom-C), 211.8 (carbonyl-C). fBased
on the amount of acid reacted. ^Identical ^H NMR spectrum to that given by Yamamoto.37
3-C ycIopentylpropionitriIe (24)
Radical reaction involving carboxylic acid 15 and acrylonitrile (Scheme 20) l-Cyclopentylcyclohexa-2,5-diene carboxylic-1-acid 15 (0 .5 g, 2 .6 mmol), acrylonitrile
(0.138 g, 2.6 mmol), di-f-butyl peroxide (0.1 g, 20% wt.) and benzene (5 cm3) were added to a test tube which was degassed using the "freeze, pump and thaw" method, sealed and heated in an oven at 100°C for 7h. The tube was cooled in liquid nitrogen, opened and a sample was submitted for GC/MS; peak no. 151. 3-cyclopentylpropionitrile 24, m/z
(relative intensity), 122 (9), 108 (7), 95 (54), 82 (35), 69 (38), 55 (100), 41 (6 6), 27 (21);
peak no. 200. phenylcyclopentane, 146 (M+), 117 (100), 104 (83), 91 (58), 77 (21), 39 (29); peak no. 238. benzoic acid; peak no. 325. double addition product 25, 135 (54), 122
(18), 108 (22), 95 (35), 82 (40), 6 8 (48), 55 (84), 41 (100), 27 (22); peak no. 479. triple
addition product 26, 221 (16), 188 (7), 147 (51), 23 (44), 105 (50), 95 (30), 83 (48), 77
(53), 73 (94), 41 (100), 54 (64), 28 (59), 36 (41). NaOH (30 cm^) was added and the layers were separated. The alkaline fraction was extracted with benzene (10 cm^) and the combined organic extracts were dried (MgSO/^) and the solvent was evaporated leaving a yellow oil; ôjj 1.5 (m, methylene-H, cyclopentyl ring, 24, 25, 26), 1.6-2.0 (m, methylene-H, aliphatic chain, 24, 25, 26), 2.25 (t, J 8.5, r-H, 24, 25, 26), 2.5 (m, adduct, 24, 25, 26). Unfortunately it was not possible to determine the yield of the adduct from this spectrum. The acid compounds were regenerated using H2SO4, extracted with
ether, the combined extracts were dried (MgSO^) and evaporated to give a white solid, shown by ^H NMR to contain benzoic acid and unreacted starting acid.
2-C yclopentylethyl benzoate (30)
Radical reaction involving carboxylic acid 15 and vinyl benzoate (Scheme 21) l-Cyciopentylcyclohexa-2,5-diene-l-carboxylic acid 15 (0.5 g, 2.6 mmol), vinyl benzoate (0.385 g, 2.6 mmol), dibenzoyl peroxide (50 mg, 10% wt.) and benzene (5 cm^) were refluxed at BO“C, with magnetic stirring, for 5 days, during which a further 100 mg of dibenzoyl peroxide was added portionwise (4 x 25 mg). Analysis of the reaction mixture by GC/MS indicated the presence of unreacted vinyl benzoate, phenylcyclopentane, benzoic acid, biphenyl, 2-cyclopentylethyl benzoate and another compound which was not
identified from it's mass spectrum. NaOH (30 cni3) was added to the mixture, the layers were separated and the aqueous fraction was extracted with benzene (10 cm3). The combined organic fractions were dried (MgSO^) and the solvent was evaporated to yield a brown oil (0.39 gt; 2-cyclopentylethyl benzoate 36%, double addition product 21%,
phenylcyclopentane 21%); 1.0-1.25 (m, aliphatic-H, adduct, double addition product, phenylcyclopentane), 3.1 (1 H, q \ ./ 10, phenylcyclopentane), 4.3-4.6 (3 H, m; 2 H,
methylene-H, a to O, adduct and 1 H, methine-H, a to O, double addition product), 4.7- 4.8 (1 H, dd / 6.2, 1.8, olefinic-H, vinyl benzoate), 5.0-5.2 (1 H, dd J 14.0, 1.8, olefinic-H, vinyl benzoate), 5.3-5.6 (broad multiplet, unidentified), 7-7.7 (m, arom-H,
vinyl benzoate, adduct, double addition product and 1 H, olefinic-H, vinyl benzoate), 7.8- 8.2 (m, arom-H, vinyl benzoate, adduct, double addition product). The acid compounds were regenerated using excess H2SO4, extracted with ether (2 x 50 cm^), the ethereal
fractions were combined, dried (MgS0 4) and the solvent was evaporated leaving a white
solid (0.52 g) which was shown by iH NMR to be a mixture of benzoic acid (0.38 g) and unreacted starting acid (0 .1 2 g). fYield based on mass of staiting acid reacted.
/r««s-2-(Prop-2-ynyIoxy)cyclohexanol (44) (Scheme 23)^5
fra«5-Cyclohexane-l,2-diol 43 (15 g, 0.129 mol) was added to a stirred mixture of DMSO (150 cm3) containing KOH (9 g, 0.161 mol), followed immediately by addition of propargyl bromide (19.2 g, 0.129 mol), and the mixture was left stirring for 2.5h. This was poured into H2O (800 cm3) and the product was extracted with dichloromethane (3 x
300 cm3). The dichloromethane extracts were washed with H2O (5 x 100 cm^), dried
(MgSO^) and the solvent evaporated, yielding an orange coloured liquid, (1 1 .2 g; 9.4 g,
47%, 44 and 1.8 g, 7%, 44 a ). Of this mixture 5 g was purified by column chromatography eluting with 35% ethyl acetate in light petroleum, and the title compound (3.0 g) was obtained as a clear, colourless liquid; 5^ 1.12-1.35 (4 H, m, methylene-H), 1.53-1.80 (2 H, m, methylene-H), 1.98-2.17 (2 H, ni, methylene-H), 2.42-2.50 (1 H, m, alkyne-H), 2.60-2.74 (1 H, m, OH), 3.20-3.52 (2 H, m, methine-H), 4.20-4.30 (2 H, m, propargylic-H); ôc (50 MHz) 24.3, 24.6, 29.5, 32.6, 56.6, 73.0, 74.0, 80.7, 83.5. The dialkylated product was also obtained in pure form (1.2 g); Ôh 1.15-1.30 (4 H, m, methylene-H), 1.58-1.71 (2 H, m, methylene-H), 1.95-2.08 (2 H, m, methylene-H), 1.95-2.03 (2 H, m, alkyne-H), 3.33-3.48 (2 H, m, methine-H), 4.25-4.37 (4 H, m, propargylic-H); ôc (50 MHz) 23.9, 30.8, 57.7, 74.2, 81.1, 81.2.
Attempted bromination of alcohol 44 (Scheme 23)
(i) Triphenylphosphine and bromine^^
Triphenylphosphine (1.58 g, 6.0 mmol) was added to alcohol 44 (0.86 g, 5.6 mmol) dissolved in DMF (7 cm^) and the stirred mixture was cooled in an ice bath. To this mixture, bromine (0.91 g, 5.7 mmol) dissolved in DMF (2 cm^) was added dropwise and the resulting mixture was left stirring for 2h. The reaction contents were added to H2O (150
cm3), the organic material was extracted with ether (3 x 50 cm^), washed with H2O, (3 x
25 cm3), dried (MgSO^) and the solvent was evaporated yielding a solid (1.48 g).which was found to be triphenylphosphine oxide. The aqueous fraction was extiacted with dichloromethane (3 x 50 cm^), washed with H2O, (2 x 25 cm^) and dried (MgSO^) to give
an orange liquid (0.27 g), which was shown by ^H NMR to be unreacted starting material.
(ii) Phosphorus tribromide^^
PBr3 (6.62 g, 24.5 mmol) dissolved in dry ether (10 cm^) was added dropwise to a stirred
solution of the alcohol 44 (9.4 g, 61 mmol) and pyridine (1.35 g, 17 mmol) dissolved in di7 ether (15 cm^) and cooled to -5“C. The mixture was left stirring at 0°C for 1.5h and the
127
temperature was allowed to rise for 0.5h. The reaction contents were added to ether (150 cm^), washed with H2O ( 1 0 0 cm3), the ether layer was dried (MgS0 4) and the ether
evaporated yielding a brown oil which was shown by NMR to be a mixture of phosphorus compounds which were not identified.
(Hi) Thionyl Brom idef*
Thionyl bromide (1.03 g, 5.9 mmol) was added to a mixture of the alcohol, 44 (0.51 g, 3.3 mmol) dissolved in deuterated chloroform (5 cm3) and pyridine (0.074 g, 9.3 mmol) stirred at 0“C. After 10 min a sample was submitted for iR NMR which indicated that the OH signal had disappeared. The work-up involved was analogous to the method used in (ii), and this yielded a brown liquid (0.45 g) which was shown by ^H NMR to be the starting material.
fr«ns:-l-B rom o-2-(2-propyn-l-yioxy)cyclohexane (35) (scheme 2 4 )1 ^
Cyclohexene (19 g, 0.23 mol), propargyl alcohol (38.9 g, 0.69 mol) and dichloromethane (20 cm3) were stirred at -20°C under an atmosphere of N2. N-Bromosuccinimide (50 g,
0.28 mol) was added over the course of 40 min and the resulting mixture was stirred at the same temperature for 2h and then at room temperature for a further 15h. To the resulting mixture H2O (75 cm3) was added and the product was extracted with dichloromethane (3 x
25 cm3). The combined organic extracts were washed with NaHSOg (IM, 75 cm3), K2CO3 (IM, 75 cm3) and H2O (75 cm^), dried (MgSO^) and the solvent removed. The
title compound was obtained as a clear, colourless liquid by distillation (31.9 g, 64%), bp 70-75'C at 10-12 mmHg; 0^1 (300 MHz) 1.25-1.45 (3 H, m, methylene-H), 1.65-1.95 (3 H, m, methylene-H), 2.15-2.25 (1 H, m, methylene-H, cyclohexyl ring), 2.25-2.40 (1 H, m, methylene-H, cyclohexyl ring), 2.42-2.45 (1 H, t , ./ 2.3, 9-H), 3.52-3.60 (1 H, td, J
8.4, 4.4, 6-H), 3.95-4.04 (1 H, ddd, 7 10, 8.2, 4.3, 5-H), 4.29-4.32 (2 H, dd, 7 2.3,
I.3, 7-H); ÔC 23.0, 25.0 (2 x 2,3-C), 30.6, 35.3, (2 x 1,4-C) 54.9 (6-C), 57.0 (7-C),
(M+), (1), 216 (1), 162 (1), 119 (5), 107 (9), 95 (32), 82 (100), 81 (72), 79 (31), 67 (43), 55 (19), 39(29). ^Identical to the published NMR spectrum.
1
2
35 46
A ttem pted p rep aratio n of l-[2"(propyn-3-yloxy)cyclohexyI]cycIohexa-2,5- dîene-1-carboxyIic a d d (31) (Scheme 25)
Benzoic acid (5 g, 41 mmol) was dissolved in ammonia (300 cm^) to which Li (0.8 g, 0.12 mol) was added portionwise, causing the solution to turn deep blue. frfl«5-l-Bromo-2-(2-
propyn-l-yloxy)cyclohexane, 64 (5 g, 23 mmol) dissolved in dry ether (50 cm^) was added dropwise, causing the solution to turn yellow. After the NH3 had evaporated, NaOH
(150 cm^) was added. This was washed with dichloromethane (2 x lOOcm^), the carboxylic acids were regenerated by adding excess HCl, extracted with ether (2 x 200 cm^), dried (MgSO^) and the solvent was evaporated, yielding a solid (5.93 g) shown by Ih NMR to be a mixture of benzoic acid and 1,4-dihydrobenzoic acid. The combined
I dichloromethane extracts were dried (MgSO^) and the solvent removed to give a liquid (2.91 g) which was shown by ^H NMR to contain mainly the bromide 35 and the alcohol 44.
A ttem pted p reparation of frn rts-l-io d o -2 -(2 -p ro p y n ”l-y Io x y )cy clo h ex an e (46) (Scheme 26)20
Dry Nal (16.3 g, 0.109 mol) was added to a mixture of fra/î.S'-l-bromo-2-(2-propyn-l- yloxy)cyclohexane 35 (18.85 g, 87 mmol), dissolved in acetone (110 cm^). This mixture was refluxed for 3.5 days. The acetone was evaporated leaving the sodium salts and the organic compounds. These were dissolved in dichloromethane (150 cm^) which was washed with H2O (3 x 150 cm^). The combined aqueous washings were washed with
the solvent was evaporated yielding a dark brown liquid (~30g). This was taken up in dichloromethane (150 cm^) and washed with an excess of Na2S2 0g until the colour of the
organic layer became lighter. The layers were separated, the organic layer dried (MgSO^) and the solvent was evaporated to give a brown liquid which was purified by Kugelrohr distillation to give a faintly coloured liquid (14.6g). NMR and NMR corresponded exactly to the starting material.
fra«s-l-Iodo-2-(2-propyn-l-yloxy)cyclohexane (46) (Scheme 27)21
Iodine (21.6 g, 85 mmol) was added over the course of 0.5h to a mixture of cyclohexene (9.35 g, 0.114 mol), Cu(0 Ac)2.H2 0 (11.4 g, 57 mmol) and propargyl alcohol (100 cm^)
under N2. This mixture was stirred mechanically for 15h. The reaction contents were
filtered, the filtrate was washed with H2O (2 x 200 cm^), dried (MgSO^) and the solvent
was evaporated to yield an orange liquid (24.64 g); GC/MS; peak no. 362. diiodo olefin (see scheme 28), m/z (relative intensity), 310 (M+) (11), 183 (8 8), 153 (28), 55 (52); peak
no. 388, 1,2-diiodocyclohexane^, 127 (15), 99 (16), 81 (8 8), 43 (100), 39 (14); peak no.
399, fraft5'-l-iodo-2-(2-propyn-l-yloxy)cyclohexane 46, 137 (26), 127 (8), 109 (5), 91
(8), 81 (100), 69 (48), 55 (16), 39 (46). 7 g of the mixture was purified by
chromatography, eluting with 1 0% ethyl acetate in light petroleum, yielding a yellow
liquid. The title compound was then obtained as a clear colourless liquid after Kugelrohr distillation (1.92 g, 23%+), bp 80°C at 0.15 mmHg (Found: C, 40.77; H, 5.09. Calc, for C9H13OI: C, 40.93; H, 4.96%); ôy (300 MHz) 1.20-1.50 (3 H, m, methylene-H) 1.50-
1.70 (1 H, m, methylene-H), 1.75-1.90 (1 H, m, methylene-H), 1.92-2.05 (1 FI, m, methylene-H), 2.16-2.3 (1 H, m, methylene-H), 2.34-2.40 (1 H, m, methylene-H), 2.42- 2.46 (1 H, t, J 2.4, 9-H), 3.53-3.62 (1 H, td, J 8.6, 4.3, 6-H), 4.04-4.14 (1 H, ddd, J
10.4, 8.6, 4.2, 5-H), 4.27-4.30 (2 H, t, 7 2.3, 7-H); 23.6, 27.0 (2 x 2,3-C), 31.2 (1
or 4-C), 34.8 (6-C), 37.7 (4 or 1-C), 56.9 (7-C), 74.4 (9-C), 80.1 (8-C), 81.9 (5-C);
GC/MS peak no. 399. m/z (relative intensity) 137 (26), 127 (8), 109 (5), 91 (8), 69 (48),
55 (16), 39 (46). +Identification based on the tendency of diiodo compounds to lose I and then HI in the GC (i.e. m/z =81).+Yield based on the proportion of product purified.
A ttem pted preparation of l-[2-(prop yn -3-yloxy)cyclohexyl]cyclohexa-2,5- diene-l-carboxylic acid (31) (Scheme 29)
Benzoic acid (1 g, 82 mmol) was dissolved in ammonia (60 cm^) with magnetic stirring and to this Li (0.16 g, 23 mmol) was added portionwise causing the solution to turn deep blue. frart5-l-Iodo-2-(2-propyn-l-yloxy) cyclohexane, 46 (1.50 g, 5.7 mmol) dissolved in
dry ether (5 cm^) was added dropwise. After the NH3 had evaporated, HCl (25 cm^) was
added and the organic compounds were extracted into ether ( 2 x 1 0 0 cm^), the ethereal
extracts were combined, dried (MgSO/^) and the solvent was evaporated yielding a brown solid which was shown by ^H NMR to be a mixture of 1,4-dihydrobenzoic acid and benzoic acid. Neither the title compound or unreacted iodide were obtained.
9-m eth ylen e-7-oxab icyclo[4.3.0]h ep tane (39)
Tin hydride mediated cyclisation of bromide 35 (Scheme 29a)
fra«5-l-Bromo-2-(2-propyn-l-yIoxy)cyclohexane 35 (2 g, 9.2 mmol), tributyltin hydride
(2.91 g, 10 mmol) and benzene (5 cm3) were added to a 1 cm diameter nM R tube and irradiated using a medium pressure 125 W Hg lamp for 8h at room temperature. A sample
of the reaction mixture was analysed by GC/MS; peak no. 253. propyn-3- yloxycyclohexane, m/z (relative intensity), 138 (M+) (4), 109 (9), 95 (54), 82 (95), 81 (100), 79 (18), 67 (72), 55 (75), 41 (49), 39 (74); peak no. 264. 9-methylene-7-
oxabicyclo[4.3.0]heptane 39, 138 (M+) (27), 120 (26), 109 (61), 95 (8 6), 81 (95), 79
(6 8), 6 8 (56), 67 (100), 41 (47), 39 (45). The benzene was removed by distillation at room
temperature and the product was distilled using a Kugelrohr (0.2 mmHg) and collected in a liquid nitrogen trap (0.78 g, 61%); 0^ (300 MHz) 1.10-1.20 (8 H, m, methylene-H),
2.50-2.60 (1 H, m, f-allylic-H), 3.95-4.00 (1 H, qd, J 7.8, 1.4, f-H), 4.25-4.32 (1 H, dq\7 12.5, 1.4, methylene allylic-H), 4.42-4.50 (1 H, dq, J 12.3, 1.9, methylene allylic- H), 4.82-4.85 (1 H, q, J 2.0, olefinic-H), 4.88-4.91 (1 H, q ,./ 2.0, olefinic-H); 5c 21.2,
23.0, 27.0, 27.6, 43.3, 69.6, 77.8, 102.4, 152.6; m/z 138 (M+, 27%), 137 (55), 124 (10), 119 (13), 109 (30), 95 (40), 91 (29), 82 (63), 79 (50), 67 (100), 55 (57) (Found:
3-HydroxycycIohexene (Scheme 31)^^
Cyclohexenone (2 g, 21 mmol) was dissolved in a 0.4 M solution of CeCl3.7H2 0 (7.82 g)
in Analar methanol (50 cm^). To this NaBH^ (0.79 g, 2 1 mmol) was added over a 2 min
period and the resulting mixture was left stirring for a further 4 min followed by the addition of H2O (100 cm^). The product was extracted into ether (2 x 75 cm^), the ethereal
extracts were combined and dried (MgSO^). The solvent was evaporated and the title compound was obtained as a clear, colourless liquid by distillation (1.4 g, 6 8%); Ôy 1.50-
2.10 (7 H, m; 6 H, methylene-H and 1 H, hydroxyl-H), 4.10-4.25 (1 H, m, f-H), 5.65-
5.90 (2 H, m, olefinic-H); Ôq (50 MHz) 19.5, 22.5, 32.4 (3 x methylene-C), 69.9 (f-C), 130.5, 130.8 (2 X olefinic-C).
Attempted preparation of 3-(2'-chloroethoxy)cycIopentene (48) (Scheme 32)
(i) Using KOH as base
Finely powdered KOH (8.1 g, 0.144 mol) was added to DMSO (70 cm^). After allowing the mixture to stir for 5 min, 2-cyclopenten-l-ol (3 g, 36 mmol) was added, followed by 1- bromo-2-chloroethane (6.2 g, 43.2 mmol) and this mixture was left stirring for 5h. To the mixture H2O (300 cm^) was added and the mixture was extracted with dichloromethane (3
X 75 cm^), the combined organic extracts were washed with H2O (6 x 100 cm^), dried
(MgSO^) and the solvent was evaporated yielding a very small quantity of a brown oil (0.1 g), which did not contain the desired product.
(ii) Using NaH as base
NaH (1.44 g, 36 mmol) was stirred in dry THF (70 cm^) for 5 min, the solvent was removed using a cannula and fresh, dry THF (70 cm^) was added. 2-Cyclopenten-1 -ol (3 g, 36 mmol) dissolved in dry THF (20 cm^) was added to the reaction mixture over a 2 min period at -20°C. The reaction was left stirring for 0.5h before l-bromo-2-chloroethane (6.2 g, 43.2 mmol) dissolved in dry THF (10 cm^) was added over a 20 min period. The reaction mixture was filtered, washed with H2O (1 0 0 cm3) and the solvent was evaporated
132
(iii) Using BuLi as base
The alcohol (1.5 g, 18 mmol) was dissolved in dry THF (75 cm^) under N2. To the
mixture BuLi (1.3 g, 20 mmol) was added at -40°C and after a 40 min period l-bromo-2- chloroethane (3.2 g, 2 2 mmol) was added and the mixture was left stining overnight. The
solvent was evaporated to yield a yellow liquid (1.41 g) which was shown by ^H NMR to be 2-cyclopenten-l-ol and l-bromo-2-chloroethane. Another reaction was attempted which was left stirring for 3 days under N2 before work-up. The reaction was monitored by TLC
but no significant change was observed and the starting materials were again recovered after work-up.
3-Brom ocydohexene (Scheme 34)24
Cyclohexene (238 g, 2.89 mol) and A/-bromosuccinimide (188 g, 1.06 mol) were added to carbon tetrachloride (725 cm3) and to this dibenzoyl peroxide (1.5 g) was added as initiator. The mixture was stirred at room temperature for 2h and refluxed for 2h. The succinimide was filtered off and the majority of the carbon tetrachloride was evaporated. The title compound was obtained as a clear, colourless liquid by distillation (108 g, 64%), bp 60°C at 10-12 mmHg (lit.,24 bp 57-58°C at 12 mmHg); Ôh L60-2.35 (6 H, m,