J. CHEM. SOC. PERKIN TRANS. 1 1990 The Conversion of Phenols to Primary and Secondary Aromatic Amines via a Smiles Rearrangement Ian G. C. Coutts" and Mark R. Southcott Department of Chemistry and Physics, Nottingham Polytechnic, Clifton Lane, Nottingham NG7 I 8NS The conversion of phenols to 2-aryloxy-2-methylpropanamides (1) and the Smiles rearrangement of these to N-aryl-2- hydroxy-2-methyl propanamides are described; hydrolysis of the latter compounds yields anilines. The scope and limitations of reaction are discussed. Routes, some involving a-lactams, from phenols to N-substituted derivatives of (1) have been developed. Under the conditions of the Smiles rearrangement these secondary 2-methylpropanamides can form directly anilides, N-al kylani Iines, or benzoxazinones.There are few general methods for the direct conversion of phenols to anilines. Transformations involving 4-chloro-2- phenylquinazoline are limited to substrates resistant to high temperatures and basic conditions, while a more versatile route via diethyl phosphate esters of phenols requires the use of toxic diethyl chlorophosphate and of potassium in liquid ammonia. The well known Bucherer reaction is restricted to naphthalenes and related heterocycles. It has, however, been reported that 2-aryloxy-2-methyl- propanamides (l),on treatment with base, undergo a Smiles rearrangement to give N-aryl-2-hydroxy-2-methylpropan-amides (2) which, after acid or base hydrolysis yield anilines (Scheme 1). For ethers (1) in which the aryl moiety contains ArOC(Me,)CONH, --+ ArNHCOC(Me,)OH -ArNH, (1) (2) Scheme 1.electron-withdrawing subtituents, the rearrangement can be effected by sodium hydride in N,N-dimethylformamide (DMF), but for electron-donating substituents reactions have to be carried out in hexamethylphosphoric triamide (HMPA). This promising solution to the problem of phenol-aniline conversion appears to have been neglected, and we here report a study into the scope and limitations of the reaction. In the previous investigation 'phenols were converted to ethers (1) via aryloxy-2-methylpropanoic acids prepared by reaction of the phenol with acetone, alkali, and chloroform. This, in our experience,* is an erratic procedure, and a simpler route to (1) was devised in which the sodium salt of the phenol was treated in dioxane with 2-bromo-2-methylpropanamide(3), readily obtained from commercially available 2-bromoisobutyryl bromide (2-bromo- 7-methylpropanoyl bromide).ArONa + BrC(Me2)CONH, --+(1) (3) By this method were prepared in moderate to good yields (Table 1) the 2-methylpropanamides (la)+). As expected, there are steric constraints to this reaction, ethers (1) not being formed from 2,6-dimethyl-, -di-t-butyl-, or -diphenyl-phenols. The bromoamide (3) also did not react with the anions of 4- hydroxybenzaldehyde, methyl salicylate, methyl 4-hydroxy- benzoate, or umbelliferone. In all these anions the negative charge is in conjugation with a carbonyl group, reducing the nucleophilicity of the intermediate, but the sodium salts of methyl 3-hydroxybenzoate and of dihydroumbelliferone, in Table 1.Yields for the conversions: ArOH -ArOC(Me,)CONH, -ArNHCOC(Me,)OH (1) or (1 4 (2) or (1 f) * - Ar Compound Yield Compound Yield Ph 67 4-ClC6H4 75 4-MeOC6H4 85 4-PhC6H4 98 4-MeC6H4 82 2-MeOC,H4 49 2-FC6H4 75 2-ClC6H4 69 2-BrC,H4 40 2-IC6H4 48 3-MeO2CC6H4 63 2-PhC6H4 77 1-Naphthyl 2-Naphthyl 5,6,7,8-Tetrahydro-2-naphthyl 8-Quinol yl 2-Dibenzofur yl Dih ydroumbelliferyl 98 92 83 31 45 51 77 88 a Dihydroumbelliferyl = 3,4-dihydro-2-0~0-2H-l-benzopyran-7-y1. which this conjugation is absent, reacted readily to give amides (lk) and (lr) respectively. A serious drawback to the original method was the use of the carcinogenic HMPA as a solvent for unreactive substrates.N,N-Dimethyl-N,N-propyleneurea DMPU; 1,3-dimethyltetrahydropyrimidin-2(lH)-one has been advocated as a non-toxic replacement for HMPA, and in initial experiments it was established that 2-methyl-2-phenoxy- propanamide (la) on treatment with sodium hydride in a 10 solution of DMPU in DMF rearranged smoothly and in high yield at 100 "C to N-phenyl-2-hydroxypropanamide(2a).These conditions were used in all subsequent rearrangement studies. Generally, the rearrangement of aryloxyisobutyramides to anilides proceeded smoothly in satisfactory (60-98) yields (see Table 1). However, from the reaction of the dihydro- umbelliferone derivative (lr) with sodium hydride in DMF- DMPU a complex mixture was obtained.This is possibly due to abstraction of benzylic protons from (lr), or to attack by nucleophiles on the lactone carbonyl; the lower susceptibility of the aromatic ester (lk) to such side reactions might account 768 J. CHEM. SOC. PERKIN TRANS. 1 1990 for its successful conversion to (2k). Rearrangement of the dibenzofuran derivative (lq) proceeded extremely slowly and in Me 0 poor (21) yield. This may be attributed to steric strain in the Br +(:Meisenheimer intermediate (4) and molecular modelling Me NR Me (10) calculations tend to support this explanation; from an AMPAC computation the heat of formation of (4) was higher (3.7 kJ mol-') than that of the corresponding structure without the carbon-carbon aryl bond.In striking contrast to the sluggish reaction of (lq), the Smiles rearrangement of the related amide (11) which lacks a constraining furan ring proceeded rapidly in neat DMF, perhaps another example of the steric acceleration of Smiles rearrangement noted previously by Bunnett and Okamoto. lo Conversion of Phenols to N-Substituted Ani1ides.-A recent paper emphasises the problems of preparing N-alkylanilines, and the prospect of preparing such compounds from phenol precursors by an extension of the above methodology is appealing. The obvious route is shown in Scheme 2, but ArONa + BrC(Me2)CONHR * ArOC(Me2)CONHR ArNHR -ArN(R)COC(Me2)OH (8) (7) Scheme 2. unexpected difficulties were encountered in the preparation of (6bH6f) (Table 2) by the reaction of appropriate phenols and bromoamides (5bH5f) with sodium hydride in dioxane.Product yields were low, and reaction was incomplete even after prolonged periods. It was initially suspected that this might be due to the low solubility of some of the sodium phenolates in dioxane, but substitution of this solvent by tetrahydrofuran, diglyme, or even DMPU gave no improvement. From the reaction of the N-phenylbromisobutyramides(5) and (5j) with sodium phenolate in DMF, the sole products isolated were the oxazolidinones (9). Such compounds have been described by DAngeli and co-workers,12 and are thought to arise from addition of ions (10) or derived aziridinones (11) to DMF; this led us to suspect that formation of (11) might be a competing process in Scheme 2.Aziridinones are reported 13-15 to undergo cleavage of the acyl-nitrogen bond exclusively upon treatment with ionic, aprotic nucleophiles (salts) and predominant cleavage of the alkyl-nitrogen bond by non-ionic, protic nucleophiles. Although such a simple explanation of selectivity in ring-opening reactions of aziridinones has been recently challenged,16 it was decided to determine whether phenoxyisobutyramides (6) might be more efficiently obtained by the reaction of phenols on preformed a-lactams. Treatment of bromoamides (5f) and (5g) with sodium hydride in THF gave stable a-lactams (lla) and (llb) respectively, which reacted with phenol to form phenoxyamides (6i) and (63.In an extension of this method, sodium hydride Mew Me Me R R (12) a ; R = 1-adamantyl a;R=Me b; R = Bu' b ;R = 1-adamantyl LO-(14) was added to THF solutions of bromoamides (5) at -20 to -40 OC, the formation of the a-lactam being followed by TLC and IR spectroscopy; subsequent addition of the appropriate phenol gave amides (6) in good to high yields. Phenols with bulky substituents in the 2- and 6-position gave no product with a-lactams, but 2,6-dimethylphenol formed (61). The preparation of an aziridinone from N-neopentyliso- butyramide (5a) presented unexpected difficulties, as the compound was totally inert towards sodium hydride. Significantly the amide (5a) reacted virtually quantitatively with sodium phenoxide in dioxane to afford (6a), which again suggests that a-lactam formation is a complication of Scheme 2.A third route to amides (6) is an extension of the previously described synthesis of primary isobutyramides in which phenols are converted to intermediate aryloxyisobutyric acids; by this method were obtained (6p) and (6q). Predictably the rearrangement of (6) to (7) is strongly influenced by steric factors (see Table 2). Treatment of the N- arylamides (6b) and (6p) with sodium hydride in DMF- DMPU gave the anilides (7a) and (7b) but the amides (6i)-(61), all with bulky substituents, were recovered unchanged. The failure of the amide (6a) to react may be due to resistance to proton abstraction rather than to steric crowding during rearrangement.Although 2-halogenophenoxybutyramides (1gHlj) had rearranged to the expected anilides, it was expected that in the N-substituted amides such as (6h), the greater steric restraints to formation of a spiro-Meisenheimer intermediate might lead to alternative attack at the halogenated position of the aromatic ring, yielding benzoxazinones (12). Indeed, treatment in DMF-DMPU with sodium hydride of the amides (6m) and (6n) gave (12a), while the amide (60)afforded (12b), the reactions being almost quantitative. This novel preparation of (12) compares favourably in ease and yield with methods previously reported.' J. CHEM. SOC. PERKIN TRANS. 1 1990 Table 2. Products from the rearrangement of (6).~~ (5)RNHCOCMe,Br R Ar CH2But3 Me3,5-(CF3)2C6H3 CH,Ph Me CH,Ph Me Et 1- Adamantyl Bu' C6H 11 Me Me Me 1-Adamantyl Ph CH2Ph 4-MeOC6H4 The most interesting results come from the rearrangements of the N-alkyl-amides (6c)--(6h), and (Q). The products obtained in 4698 yield were not the anilides (7), but the corresponding N-alkyl-anilines (8).This is an unexpected finding, as anilides (7) are usually cleaved only by heating with moderate alkali or strong acids. It has recently been reportedI8 that the Smiles rearrangement of 3-(2,4,6-trichlorophenoxyacetamido)pyridine to (13) is followed by alkaline hydrolysis to the resonance- stabilised anion (14). However, in our study, it is the aromatic anilides (7a) and (7b) which are isolated uncleaved.Whatever the mechanism, this serendipitous reaction provides under moderately mild conditions a smooth transformation of phenols to N-alkylanilines. Since the alkyl group may be benzyl, it also allows access by standard deblocking procedures to primary arylamines. A limited investigation into the application to more complex molecules of the phenol-aniline conversion has been carried out. Both estrone (Ha) and estradiol (1) were transformed via aryloxyamides (15c) and Rgfy-(15) a, R=OH, X=CO; b, R=OH, X=CHOH, c, R= OCMe,CONH,, X = CO; d, R = OCMe,CONH,, X = CHOH; e, R = NHCOCMe,OH, X = CO; f, R = NHCOCMe,OH, X = CHOH; g, R = OCMe,CONHMe, X = CHOH; h, R = NHMe, X = CHOH. (15d) to anilides (1) and (15f).Estradiol also reacted with N-methylisobutyramide (5c) to give (15g) which again rearranged in good yield to the aniline (15h).Estrone, by the a-lactam method, can be converted to the amide (M),but this gave complex mixtures on attempted rearrangement. Experimental IR spectra were recorded using a Perkin-Elmer 683 grating 769 Product from (6) + NaH-DMPU-DMF ( yield) (6)RNHCOCMe,OAr (7)Anilide (8)Aniline (12)Benzoxazinone spectrophotometer. 'H NMR spectroscopy was performed using a Hitchi-Perkin-Elmer R24B 60 MHz spectrometer with tetramethylsilane as the internal standard. 3C NMR spectra were recorded on a JEOL JNM FX60Q 60 MHz Fourier transform spectrometer. Elemental analyses were determined by the analytical sections of either ICI Pharmaceuticals Division or Nottingham University.M.p.s were measured using open capilliaries in a Gallenkamp apparatus and are not corrected. THF was dried over calcium hydride, and other solvents using 5 A molecular sieves. Light petroleum has b.p. 60-80 "C unless otherwise stated. 2-Bromo-2-methylprupanamide(3).-To a vigorously stirred solution of 2-bromo-2-methylpropanoyl bromide (11 ml) in light petroleum (250 ml) at 0 "Cwas added in portions aqueous ammonia (d0.88; 40ml). Stirring was continued for a further 30 min, and the resulting precipitate collected and washed using water to give the bromoamide, m.p. 147-148 OC (from chloroform-light petroleum) (lit.," 147-148 "C). General Preparation of Aryluxyamides (l),(15c),and (15d).-The appropriate phenol (2 g) was stirred in dry dioxane (20 ml) with sodium hydride (1.1 mol equiv.) for 1 h.2-Bromo-2- methylpropanamide (1.0 mol equiv.) was added and the re- action mixture was heated at 100"C for 4 h. After cooling, the precipitated sodium bromide was filtered off, the filtrate evaporated under reduced pressure, and the residual solid triturated with dilute base and recrystallised from toluene to give compounds (l),(15c), and (IS).Analytical data are in Table 3. Smiles Rearrangement of Aryloxyamides (l).-To a solution of the aryloxyamide (1 g) in dry DMPU (1 ml) and dry DMF (10 ml) was added sodium hydride (1.1 mol equiv.) and the mixture was heated on a steam-bath for 1 h. The solution was poured into water (400ml) and extracted with ethyl acetate (400ml); the organic layer was washed with water (3 x 500 ml), dried (MgSO,), and evaporated.The residue was purified by distillation or by crystallisation from cyclohexane or toluene to give compounds (2), (He), or (15f). Analytical data are in Table 3. 770 J. CHEM. SOC. PERKIN TRANS. I 1990 Table 3. Analytical data for compounds (l),(2), and (15). Found, Required, Found, Compound M.p. t/T Molecular formula C H N C H N C H N Compound M.p. or b.p., t/T(p/mmHg) 183-185 C16H1 lNo2 75.3 7.0 5.4 75.3 6.7 5.5 74.9 6.7 5.4 (2d) 167-168 147-148 133-1 34 Cl 1 Hl ,NO, cl lHl SN03 68.8 63.3 8.0 7.4 7.2 6.5 68.4 63.1 7.8 7.2 7.2 6.7 68.5 62.9 8.4 7.3 6.9 6.4 (2e) (2f) 82-84 143- 144 93-94 89-90 78-80 101-1 02 142- 143 ClOHl $NO2 ClOH1 zClN02 Cl OH1 amp;NO, ClOH lPO2 CIZHl SN04 61.2 56.2 46.6 39.4 60.9 5.9 5.8 4.8 4.2 6.4 7.2 6.3 5.5 4.7 5.9 60.9 56.2 46.5 39.3 60.8 6.1 5.7 4.6 3.9 6.3 7.1 6.5 5.4 4.6 5.9 61.0 56.5 46.8 39.6 60.9 6.0 5.2 5.1 4.4 6.4 7.0 6.6 5.7 4.4 5.7 (2s) (2h) (29 (2j) (2k) 140 (0.02) 161 (0.6) 150 (0.3) 174 (0.2) 124-125 96-97 C16H1 7N02 75.0 7.0 5.5 75.3 6.7 5.5 75.5 6.8 5.5 (21) 148- 149 119-120 C14H1 SN02 73.8 6.6 5.9 73.3 6.6 6.1 73.7 6.8 6.1 (21x1) 16 1-1 62 1 1 8-1 1 9 C14H1 SNo2 73.2 6.7 6.0 73.3 6.6 6.1 73.2 6.6 6.0 (2n) 159-160 113-114 178-179 C14H1 gN02 cl 3H 14N202 72.2 67.8 8.4 6.0 5.9 12.0 72.1 67.8 8.2 6.1 6.0 12.2 71.9 68.2 8.2 6.2 5.6 11.9 (20) (2p) 97-98 123-124 154-1 55 153-1 54 cl gH1 SN03 C13H15N04 71.4 62.3 5.7 6.1 4.8 5.8 71.4 62.6 5.6 6.1 5.2 5.6 71.1 5.7 5.2 (2q) 165-1 66 167-168 198-200 C22H29N03 C22H31N03 73.9 74.4 8.2 8.2 3.6 3.4 74.3 74.1 8.2 8.5 3.9 3.9 74.0 73.9 8.1 8.8 3.2 3.8 (1) (15f) 133-134' 203-204 From EtOH.From EtOH-cyclohexane. 'From cyclohexane-Et,O. Amides (la)-(lc) and (2a)-(2c) have previously been Preparation of Oxazolidinones (9).-Equimolar quantities of described. N-phenyl-2-bromo-2-methylpropanamideand sodium hydride In the mass spectra (EI) of new compounds, parent ions were heated in dry DMF at 100deg;C for 1 h. The solvent was corresponded to the calculated M, value.removed under reduced pressure, and the residue triturated with dilute sodium hydroxide and recrystallised from hexane Preparation of the Bromoamides (5).--Compounds (5) were to give the oxazolidinone (9a), m.p. 100-101 "C (lit.,23 101-wassynthesised by the reaction of 2-bromo-2-methylpropanoyl 102 "C). From a similar reaction with the bromoamide (3)bromide with the appropriate amine under standard Schotten- obtained 3-(4-methoxyphenyZ)-5,5-dimethyl-2-dimethy~amino Baumann conditions. By this method were made the known oxazolidin-4-one (9b), m.p. 89-90 "C (from hexane) (Found: compounds (5c), m.p. 5940deg;C (lit.," 5840deg;C);(M),m.p. C, 64.0; H, 7.7; N, 10.3. C14H20N203requires C, 63.6; H, 7.6; 71-73 "C (lit.," 71 "C); (Se), m.p. 57-59 "C (lit.," 57-58 "C); N, 10.6); v,,,(KBr) 1 700 cm-' (GO);GH(CDCl,) 6.8-7.4 (4 (5f), m.p.77-79 "C (lit.,20 77 "C); (5g), m.p. 84-86 "C (lit.," H, A2B2, ArH), 6.05 (1 H, s, CH), 3.8 (3 H, s, OMe), 2.4 (6 H, 84-86 "C); (5h), m.p. 107-108 "C (lit.," 108-109 "C); (5i), s, C-CH,), and 1.5-1.6 (6 H, d, N-CH,). m.p. 83-84 "C (lit.," 83 "C), and the new amides (5a), m.p. 91-92deg;C (from light petroleum) (Found: C, 45.7; H, 7.8; N, Novel Products from the Rearrangement of N-Substituted-2-5.9, C9HlsBrN0 requires C, 45.7; H, 7.6; N, 5.9); (5b), Aryloxy-2-methylpropanamiamp;s.-The anilide (701) had m.p. m.p. 122-123 "C (from cyclohexane) (Found: C, 38.5; H, 2.6; 141-142 "C (from cyclohexane) (Found: C, 61.6; H, 4.2; N, 3.0. N, 3.7. C12HloBrF6N0 requires C, 38.1; H, 2.6; N, 3.7); C24H18F6NO2 requires C, 61.7; H, 4.0; N, 3.0); v,,,(KBr) (5j), m.p.87-88 "C (from cyclohexane) (Found: C, 48.2; 3 260 and 1 680 cm-'. The anilide had m.p. 102-103 "C (from H, 5.2; N, 5.1. CllH14BrN02 requires C, 48.5; H, 5.1; N, cyclohexane) (Found C, 75.6; H, 6.7; N, 5.4.C16H17N02 5.1). requires C, 75.3; H, 6.7; N, 5.4); v,,,(KBr) 3 260 and 1670 cm-'. 3-Desoxy-3-methylamino-~-estradiolhydrochloride (15h) N-Substituted-2-aryloxy-2-methylpropanamides(6), (15g), (60 yield) had m.p. 258-260deg;C (from EtOH-H,O) (Found: and(l5i).-MethodA. This involved heating the bromoamide (5) C, 70.7; H, 8.9; N, 4.2. Cl9HZ7ClNO requires C, 71.1; H, 8.4; with the sodium salt of a phenol in dry dioxane, as described N, 4.4). for the formation of (1).All other N-alkylanilines obtained from the rearrangement Method B. This involved formation of an a-lactam of (6)had m.p. or b.p. and IR and NMR spectra in agreement intermediate. To the amide (5) (5 g) in dry THF (50 ml) at a with those of authentic compounds. controlled temperature (given in parentheses in Table 4) was added sodium hydride (1 mol equiv.) and the mixture was Preparation of the Benzoxazinones (12).-Standard treat-stirred. At regular intervals, aliquots were removed and ment with sodium hydride in DMF-DMPU of the amides examined by liquid cell IR spectroscopy and by TLC. When (6m)or (6n)gave 2,2,4-trimethyl-2H-1,4-benzoxazin-3(4H)-one conversion of (5) to the a-lactam v(C--O) 1 830-1 840 cm-'1 (12a) (98 yield), b.p. 110 "C at 0.5mmHg (Found: C, 69.2; was complete, the appropriate phenol (1 mol equiv.) was added, H, 6.6; N, 6.8.C11H13N02 requires C, 69.1; H, 6.8; N, 7.2); GH(CDCl,) 7.0 (4 H, s, Ar), 3.3and stirring was continued for 4 h at the temperature of a-v,,,(KBr) 1 670 cm-I (0); lactam formation. The solution was allowed to reach room (3 H, s, CH,-N), and 1.5 (6 H, s, CH,-C); Gc(CDCI3), 23.9 temperature, the solvent removed, and the residue purified by (CH,-C-), 28.6 (CH,-N), 77.9 (C-Me,), 114.1, 117.5, 122.2, crystallisation or distillation. 123.7 (Arc-H), 130.1 (Arc-N), 143.5 (Arc-0), and 169.0 From the amide (60) was obtained 4-adamantyZ-2,2-Method C. 2-Methyl-2-phenoxypropanoicacid was treated (GO). For dimethyZ-2H-l,4-benzoxazin-3(4H)-onewith thionyl chloride and amine as previously de~cribed.~ (12b) (98), b.p.180 "C (6q) the acid in methylene chloride was condensed with at 0.2 mmHg (Found: C, 76.9; H, 8.3; N, 4.3. C20Hz,N02 benzylamine in the presence of dicyclohex ylcarbodiimide. requires C, 77.2,H, 8.0; N, 4.5); v,,,(film) 1 680 cm-'. J. CHEM.SOC. PERKIN TRANS. 1 1990 771 Table 4. N-Substituted-2-aryloxy-2-methylpropanamides. Found, Required, Compound Method Yield M.p. or b.p. r/"C(p/mmHg) Molecular formula C H N C H N ~~ ~ ~ A A A A A A B(-40) B(-40) B(10) B(10) B(-20) B(-40) B(-40) B(-40) B(10) C C A B(-40) 90 66 50 49 17 51 96 84 51 90 55 54 84 92 81 53 94 88 82 86-87" 63-64 38-39 160-16lC 106107" 150 (0.3) 160(0.2)80-81 150 (0.1) 95-96 135 (0.3)180 (0.2) 180 (0.2) 154 (0.3) 150(0.5) 138-1 39" 115-1 16" 139-140d 95-96 C1SH23N02 C24H19F6N02 C11H14C1N02 cl 7H1 SClN02 cl 7H19N02 C23H23N02 c1 1 3N02 cl ZH1 C20H2SN02 C14H21NO2 Cl lH14ClNO2 Cl,Hl,NO2 C16H23N02 1fH 1sN02 cl lHl4IN02 C21H30N03 C17H19N02 C23H33N03 C23H31N03 72.5 9.5 61.6 4.2 58.0 6.2 72.9 5.8 75.5 7.0 80.3 6.7 68.3 8.3 69.2 8.1 76.4 8.5 71.7 9.5 73.9 8.6 70.7 8.5 58.0 6.2 42.0 4.6 74.0 8.0 75.5 6.0 75.6 7.6 74.3 9.0 74.4 8.6 5.6 2.9 6.0 4.2 5.0 4.0 7.2 6.4 3.9 5.9 5.3 6.2 6.2 4.3 3.6 5.9 5.7 3.7 3.8 72.3 9.2 61.7 4.1 58.0 6.1 73.3 5.9 75.8 7.0 80.0 6.7 68.4 7.8 69.6 8.2 76.4 8.9 71.5 8.9 73.6 8.8 70.6 8.6 58.2 6.3 41.4 4.4 74.1 8.4 75.3 6.7 75.8 7.2 74.6 8.6 74.8 8.5 5.6 3.0 6.1 4.6 5.0 4.1 7.2 6.8 4.4 5.9 5.4 6.3 6.1 4.4 3.9 5.5 5.3 3.8 3.8 a From cyclohexane.From hexane. From EtOAc. From Et,O-cyclohexane. Acknowledgements 13 1. Lengyel and J. C. Sheehan, Angew. Chem., Int. Ed. Engl., 1968,7,25. We thank Dr. R. W. Turner and Dr. N. F. Elmore of ICI 14 H.E. Baumgarten, J.Am. Chem. SOC.,1962,84,4975. Pharmaceuticals for helpful discussion, and Dr. D. Gilmore of 15 G.L'abbe, Angew. Chem., Int. Ed. Engl., 1980,19,276. ICI Pharmaceuticals for the results of the molecular modelling 16 E. R. Talaty, J. A. Gomez, J. A. Dillon, E. Palomino, M. 0.Agho, B. C. Batt, K. J. Gleason, S.Park, J. R. Hernandez, M. M. Yusoff, calculations on (4). G. A. Rupp, F. C. Malone, M.F. Brummett, C. L. Finch, S. A. Ismail, N.Williams, and M. Aghakhani, Synth. Commun., 1987, 17, 1063. 17 J. W. Cook, J.P. Loudon, and P. McCloskey, J. Chem. Soc., 1952,References 3904, E. Honkanen and A. E. Virtanen, Acta. Chem. Scand., 1961,1 R. A. Scherrer and H. R. Beatty, J. Org. Chem., 1972,37, 1681. 15,221.2 K.Matsumoto, P. Stark, and R. G. Master, J. Med. Chem., 1977,20, 18 A. Greiner, Tetrahedron Lett., 1989,30,931.17. 19 'Dictionary of Organic Compounds,' 5th edn, ed. J. Buckingham,3 D. F. Morrow and R. M. Hofer, J. Med. Chem., 1966,9,249. Chapman and Hull, 1982. 4 R. B. Conrow and S. Bernstein, Steroids, 1968,11,151. 20 H.Quast, R. Franck, B. Freudenreid, P. Scheifer, and E. Schmitt,5 S. A. Sadek, S.M. Shaw, W. V. Kessler, and G. C. Wolf, J. Org. Liebigs Ann. Chem., 1979,74.Chem., 1981,46,3259. 21 J. C. Sheehan and I. Lengyel,J.Am. Chem. Soc., 1964,86,1356.6 R.A. Rossi and J. F. Bunnett, J.Org. Chem., 1972,37,3570. 22 F. Maran, E. Vianello, F. DAngeli, G. Cavicchioni, and G. Vecchiati, 7 R.Bayles, M. C.Johnson, R.F. Maisey, and R.W.Turner, Synthesis, J. Chem. Soc., Perkin Trans. 2,1987,33.1977,31,33. 22 G. Cavicchioni, P. Scrimin, A. C. Veronese, G. Balboni, and F. 8 I. G. C. Coutts and M. R.Southcott, J. Chem. Res. (S), 1988,(S)241; DAngeli, J. Chem. Soc., Perkin Trans. 2, 1982,2969. (M)1921. 9 T. Mukhopadhyay and D. Seebach, Helu. Chim. Acra, 1982,39,385. 10 J. F. Bunnett and T. Okamoto, J. Am. Chem. Soc., 1956,78,5363. 11 A. R. Katritzky, M. Drewniak, and J. M. Aurrecoechea, J. Chem. Soc., Perkin Trans. I, 1987,2539. Paper 9/03290H 12 P. Scrimin, G. Cavicchioni, F. DAngeli, A. Goldblum, and F. Received 2nd August 1989 Maran, J. Chem. Soc., Perkin Trans. 1,1988,43. Accepted 13th September 1989
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