Azabenzocycloheptenones. Part 20. Synthesis and utilisation of 4-amino-1,2,3,4-tetrahydro-1(1H)-benzazepines

摘要

J. Chem. Soc. Perkin Trans. 1 1997 3261 Azabenzocycloheptenones. Part 20. Synthesis and utilisation of 4-amino-1,2,3,4-tetrahydro-1(1H)-benzazepines Kevin I. Booker-Milburn,a Ian R. Dunkin,a Frances C. Kelly,a Abedawn I. Khalaf,a David A. Learmonth,a George R. Proctor *,a and David I. C. Scopes †,b a Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK G1 1XL b Glaxo Wellcome Research and Development Park Road Ware Herts UK SG12 0DP 1,2,3,4-Tetrahydro-6- and -7-methoxy-4-oxo-1-(p-tolylsulfonyl)quinolines 3 (R = tosyl X = 6- and 7-OMe) and 1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-7-methoxy-4-oxoquinoline 3 (R = CH2CO2Et X = 7-OMe) have been ring-expanded in two steps to 2,3,4,5-tetrahydro-7- and -8-methoxy-4-oxo-1-(p-tolylsulfonyl)- 1H-1-benzazepines 2 (R = tosyl X = 7- and -8-OMe) and 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-8- methoxy-4-oxo-1H-1-benzazepine 2 (R = CH2CO2Et X = 8-OMe).Reduction of the oximes gives 4-amino-2,3,4,5-tetrahydro-7-methoxy-1-(p-tolylsulfonyl)-1H-1-benzazepine 1 (R = tosyl X = 7-OMe) 4-amino-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 1 (R = H X = 8-OMe) and 4-amino-1- ethoxycarbonylmethyl-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 1 (R = CH2CO2Et X = 8-OMe). From these several N-substituted and N,N-disubstituted compounds have been obtained and 3-amino- 2,3,4,5-tetrahydro-1-(p-tolylsulfonyl)-1H-1-benzazepine 12 (X = NH2 Y = H) has been made by similar means. Two routes are described to 2,3,4,5-tetrahydro-8-methoxy-5-oxo-1-(p-tolylsulfonyl)-1H-1- benzazepine 13 (R1 = tosyl R2 = H) which is converted to 2,3,4,5-tetrahydro-8-methoxy-4-methoxyimino- 5-oxo-1-(p-tolylsulfonyl)-1H-1-benzazepine 17 (R = Me) and thence to 5-2-(ethoxycarbonyl)ethynyl- 2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-methoxyimino-1-(p-tolylsulfonyl)-1H-1-benzazepine 18 (R = C CCO2Et) and 5-2-(ethoxycarbonyl)ethyl-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-methoxyimino- 1-(p-tolylsulfonyl)-1H-benzazepine 18 R = (CH2)2CO2Et.Reduction of oximino ketone 17 (R = H) in two steps gives both cis- and trans-4-acetamido-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-1- (p-tolylsulfonyl)-1H-1-benzazepines 22 and 21 which are separately deacetylated and cyclised with ethyl chloroacetate to cis- and trans-2,3,4,4a,5,6,7,11b-octahydro-9-methoxy-3-oxo-7-(p-tolylsulfonyl)- 1,4oxazino3,2-d1benzazepine 26 and 25. By similar methodology cis- and trans-2,3,4,5-tetrahydro-5- hydroxy-8-methoxy-4-propionamido-1-(p-tolylsulfonyl)-1H-1-benzazepines 28 and 27 have been obtained separated and the latter reduced to trans-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-(n-propylamino)-1- (p-tolylsulfonyl)-1H-1-benzazepine 29.In three steps the latter is converted to trans-2,3,4,4a,5,6,7,11boctahydro- 9-methoxy-4-(n-propyl)-7-(p-tolylsulfonyl)1,4oxazino3,2-d1benzazepine 33. In several papers of this series we have pioneered the syntheses and explored the chemistry of 1-benzazepine derivatives.1–10 These have included some studies on annelation,1 substitution 9 and bridging 10 reactions. We have now developed these themes further and in connection with constrained b-phenylethylamine structures,11,12 it has now become of interest to gain access to 4- amino-2,3,4,5-tetrahydro-1-benzazepine intermediates 1 and related systems which allow access to tricyclic structures.The Wittig–Prévost protocol 13,14 for conversion of a-tetralones into benzosuberan-6-ones ‡ has expedited introduction of amino functionality 11,12 to the 6-position of the latter ring system. Accordingly it appeared promising to apply a similar approach to tetrahydro-1-benzazepin-4-ones 2 potentially available from tetrahydroquinolin-4-ones 3. In this paper we address this question and also describe refinement of a more established method which hinges on a-oximation of tetrahydro- 1-benzazepin-5-ones 4. Discussion Although originally 13 we described the synthesis of the 1- benzazepine derivative 5 by the Wittig–Prévost approach the enolic nature of the product makes it unsuitable for general use.Accordingly we have concentrated attention on methylenation † Present address Oxford Glyco Sciences (UK) Ltd. 10 The Quadrant Abingdon Science Park Abingdon UK OX14 3YS. ‡ IUPAC name benzo7annulen-6-one. NR NH2 X NR O X NR X X NR O O 1 2 3 4 N Ts Cl CN OH NH MeO N NR MeO O O O N Ts H H X 5 6 7 8 3262 J. Chem. Soc. Perkin Trans. 1 1997 rather than cyanomethylenation in the Wittig step. Thus in the ring-expansion step (Prévost) the ultimate 5-carbon atom of the benzazepine is unsubstituted we also stress that by contrast with the original hot anhydrous alcoholic conditions for this reaction we have discovered it is advantageous to use aqueous alcohol at room temperature. The substrate 1-(p-tolylsulfonyl)- 7-methoxy-4-oxo-1,2,3,4-tetrahydroquinoline 3 R = tosyl (ptolylsulfonyl) X = 7-OMe 15 was chosen and was obtained as described by Speckamp15b et al.Interestingly the latter ascribed the appearance of two different melting solids (mp 104–106 and 115–119 8C) to polymorphism however on chromatographic separation we were able to isolate the isomers 3 (R = tosyl X = 7-OMe mp 116– 117 8C) and 6 (R = tosyl mp 154 8C). This can be explained as the result of an intramolecular Friedel–Crafts cyclisation giving both substitution para and ortho to the methoxy group as had been previously suggested.15a Other workers have opined that only one isomer is found from this reaction.16 To obtain the ketone 3 (R = H X = 7-OMe)15b the corresponding amino acid was cyclised in polyphosphoric acid (PPA);17a,b again the isomer 6 (R = H)17c was also isolated.Methylenation of the quinolone 3 (R = tosyl X = 7-OMe) using Ph3P1CH3I2–BunLi gave the exo-methylene compound 7 (X = 7-OMe) in 38 yield. Many variations were explored including Ph3P1CH3Br2–BunLi Ph3P1CH3I2–NaH–DMSO Zn–CH2I2–TiCl4,18 the Tebbe reagent 19 and zirconocene dichloride–Zn–CH2I2:20 none was an improvement. Reaction of 7 (X = 7-OMe) with silver nitrate–iodine (2 :1) in THF–H2O– MeOH (2:1:1) for 30 min at room temperature gave the ketone 2 (R = tosyl X = 8-OMe) in 92 yield. In similar fashion methylenation of quinolone 3 (R = tosyl X = 6-OMe)21,22 gave the alkene 7 (R = tosyl X = 6-OMe) (44) which was converted as before to the ketone 2 (R = tosyl X = 7-OMe) (77). Protection of the nitrogen atom as a sulfonamide is not essential for this series of reactions; the tertiary amino keto ester 3 (R = CH2CO2Et X = 7-OMe) could be methylenated also in poor (36) yield and then expanded to give ketone 2 (R = CH2- CO2Et X = 8-OMe) which was substantially less stable than the N-sulfonamido ketones.The ketones 2 were converted to oximes and reduced to the required amines 1. LiAlH4 caused detosylation as well as reduction of the oxime of 2 (R = tosyl X = 8-OMe) giving the diamine 1 (R = H X = 8-OMe) while the same treatment merely reduced the oxime of ketone 2 (R = tosyl X = 7-OMe) to the compound 1 (R = tosyl X = 7-OMe). The primary amino group in diamine 1 (R = H X = 8-OMe) can be protected as a phthalimido derivative 8. Reduction of the oxime of ketone 2 (R = CH2CO2Et X = 8-OMe) gave the unstable amino ester 1 (R = CH2CO2Et X = 8-OMe).Unlike the corresponding carbocyclic analogue,12 the ketone 2 (R = tosyl X = 8-OMe) failed to form an enamine with di-npropylamine neither could it be aminated on treatment with sodium triacetoxyborohydride and n-propylamine the product being the alcohol 9. On the other hand the 4-amino-1,2,3,4- tetrahydrobenzazepines 1 could be bis-N-alkylated with sodium triacetoxyborohydride and propanal in acetic acid to give 10 N Ts MeO OH NR NPrn 2 MeO NH N MeO Ac R N Ts X Y 9 10 11 12 (R = H X = 8-OMe) and 10 (R = tosyl X = 7-OMe). Diamine 1 (R = H X = 8-OMe) was selectively acetylated to 11 (R = H) which unexpectedly was alkylated by ethyl bromoacetate and Hunig’s base to yield 11 (R = CH2CO2Et). Incidentally it is possible to introduce an amino group at the 3-position of the 1-benzazepine system by methodology analogous to the above.Thus the ketone 12 (X Y = O)5 was converted to the oxime 12 (X Y = NOH) which could be reduced by Raney nickel 23 to the amine 12 (X = H Y = NH2). The previously unknown24 methoxybenzazepinone 13 (R1 = tosyl R2 = H) was required for the next stage of the work; two syntheses have now been developed. Firstly methoxyanthranilate 14 (R1 = R2 = H) can be obtained from m-anisidine via the isatin 15 (cf. ref. 25) using adaptations of the literature methods.26 In particular it was essential to use PPA in the cyclisation leading to isatin 15; sulfuric acid caused significant demethylation. The N-tosylanthranilate 14 (R1 = tosyl R2 = H) was alkylated with ethyl 4-bromobutyrate according to precedents 2,27 and cyclised to keto ester 13 (R1 = tosyl R2 = CO2Et) which was decarboxylated to tosyl ketone 13 (R1 = tosyl R2 = H) (see Experimental section).The second synthesis proceeded from 7-methoxy-a-tetralone by Beckmann rearrangement of the O-tosyl oxime28 which yielded exclusively the lactam 16 (X Y = O R = H).29 Reduction of the latter with LiAlH4 gave the amine 16 (X = Y = R = H)30 which could be acetylated to 16 (R = Ac X = Y = H) or tosylated to 16 (R = tosyl X = Y = H) all in good yield. Oxidation 31 of either of these gave the ketones 13 (R1 = tosyl R2 = H or R1 = Ac R2 = H) in moderate yield (see Experimental section). Either synthesis is satisfactory for large scale work. a-Oximation 32,33 of the tosyl ketone 13 (R1 = tosyl R2 = H) proceeded efficiently to compound 17 (R = H) which can be methylated to 17 (R = Me).In order to make progress towards a pyridobenzazepine ring system it was necessary to introduce a 3-carbon unit to C-5 of the benzazepine ring this was achieved using the lithium derivative of ethyl propiolate 12,34 (LiC CCO2Et) which provided compound 18 (R = C CCO2Et). Catalytic reduction of the latter led to 18 (R = CH2CH2CO2Et) but further progress was not possible since treatment of 18 (R = CH2CH2CO2Et) with borane–THF gave an unexpected polar substance C21H28N2O5S. Although the originally expected structure 19 (C21H26N2O4S) was supported by mass spectroscopy (m/z 402) elemental analysis points to a formula containing an extra two hydrogen atoms and one oxygen atom (i.e. 402 M 2 H2O). Structure 20 (a or b) is a tentative assignment. By contrast reductions of the unmethylated oximino ketone 17 (R = H) proceeded normally.Thus catalytic hydrogenation in the presence of acetic anhydride gave rise to the acetylamino ketone 13 (R1 = tosyl R2 = NHCOCH3) which could be reduced by sodium borohydride to a separable mixture of two diastereomeric N-acetylamino alcohols (21 and 22) (Scheme 1). The latter were individually deacetylated and cyclised to the trans- and cis-oxazinobenzazepines 25 and 26 which are mem- NR 1 O R2 MeO NR MeO CO2Me MeO NR1 R2 X Y NH MeO O O 13 14 15 16 J. Chem. Soc. Perkin Trans. 1 1997 3263 bers of a previously unknown ring system (Scheme 1). To obtain N-substituted examples it proved advantageous to proceed as shown in Scheme 2. In this approach the N-protecting group was introduced at an early stage and reduction with borane (27 æÆ 29 28 æÆ 30) caused no problems.However insufficient quantities of the cis-isomer 30 precluded continuation of the synthesis of the cis-analogue of 33. The latter however was obtained in fair yield. Experimental For general remarks see J. Chem. Soc. Perkin Trans. 1 1996 2545. 1H NMR spectra were recorded at 250.13 MHz unless otherwise stated. 1,2,3,4-Tetrahydro-7-methoxy-4-oxo-1-(p-tolylsulfonyl)quinoline 15 3 (R 5 tosyl X 5 7-OMe) To a stirred suspension of N-(m-methoxyphenyl)-N-(p-tolylsulfonyl)- 3-aminopropanoic acid (100 g 0.28 mol) in dry benzene (250 cm3) at 0 8C was added in portions phosphorous pentachloride (59 g 0.29 mol). After the addition was complete the resulting suspension was heated until the evolution of HCl gas ceased (5 h).The dark solution was cooled and stannic chloride (70 cm3 0.61 mol) in dry benzene (100 cm3) was added at such a rate that the temperature did not exceed 5 8C. The resulting dark suspension was stirred at room temperature overnight whereupon diethyl ether (500 cm3) and hydrochloric acid (500 cm3; 5 M) were added and the suspension was stirred for a further 2 h. The organic layer was separated and washed successively with water (200 cm3) aqueous potassium hydroxide (200 cm3; 2 M) and water again (200 cm3) then dried and the solvent was removed in vacuo to give a solid. Recrystallisation from ethanol gave the title compound as white crystals (51 g 53) mp 116–117 8C (lit.,15b 115–117 8C) (Found C 61.8; H 5.15; N 4.15; S 9.55. Calc. for C17H17NO4S C 61.6; H 5.15; N 4.2; S 9.65); nmax(Nujol)/cm21 1675 (C O) and 1600 (C C); dH 7.85 (1H d aryl) 7.5 (2H d aryl) 7.35 (1H d aryl) 7.2 (2H d aryl) 6.75 (1H dd aryl) 4.15 (2H t CH2) 3.9 (3H s OCH3) and 2.3 (5H t 1 s CH2 1 CH3 tosyl).Chromatography (Al2O3–Et2O) of the mother liquors gave 1,2,3,4-tetrahydro-5- methoxy-4-oxo-1-(p-tolylsulfonyl)quinoline 6 (8.1 g 5) mp 154 8C (Found C 61.4; H 5.1; N 4.1; S 9.4. C17H18NO4S requires C 61.6; H 5.15; N 4.25; S 9.65); nmax(Nujol)/cm21 1670 (C O) 1600 (C C); dH 7.6–7.3 (4H m aryl) 7.3–7.1 (2H N Ts MeO N Ts MeO R NOMe HO O NOR 17 18 N Ts MeO NH HO H N Ts MeO NH3 HO O– 19 20a N Ts MeO NH2 HO OH 20b + d aryl) 6.8 (1H dd aryl) 4.1 (2H t CH2) 3.85 (3H s OCH3) and 2.35 (5H t 1 s CH3 tosyl CH2). 1,2,3,4-Tetrahydro-7-methoxy-4-methylene-1-(p-tolylsulfonyl)- quinoline 7 (X 5 7-OMe) To a stirred solution of methyltriphenylphosphonium iodide (12.2 g 30.2 mmol) in dry THF (120 cm3) at 0 8C under nitrogen was added n-butyllithium (19 cm3 30.4 mmol; 1.6 M solution in hexanes) and the suspension was stirred for 30 min.To the resulting deep red solution was added a solution of the ketone 3 (R = tosyl X = 7-OMe) (10 g 30.2 mmol) in dry THF (50 cm3) dropwise and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue was taken up in dichloromethane (150 cm3) and washed with water (4 × 150 cm3). The organic layer was then dried and the solvent was removed in vacuo to give a gum. Flash chromatography (triethylamine–diethyl ether–hexane 1 80 19) gave the product as a white solid (3.79 g 38) mp 112–113 8C (Found C 66.1; H 6.1; N 4.15; S 9.8.C18H19NO3S requires C 65.65; H 5.8; N 4.2; S 9.7); nmax(Nujol)/cm21 1605 (C C); dH(90 MHz) 7.6–7.1 (16H m aryl) 6.6 (1H dd aryl) 5.35 (1H s vinyl) 4.65 (1H s vinyl) 3.75–3.7 (5H s 1 t OCH3 1 CH2) and 2.4–2.3 (5H s 1 t CH3 tosyl 1 CH2). 2,3,4,5-Tetrahydro-8-methoxy-4-oxo-1-(p-tolylsulfonyl)-1H-1- benzazepine 2 (R 5 tosyl X 5 8-OMe) Silver nitrate (1.96 g 10 mmol) was dissolved in methanol (10 cm3) and water (10 cm3) at room temperature. To this vigorously stirred solution was added the alkene 7 (X = 7-OMe) (1.88 g 5 mmol) in THF (20 cm3) in one portion followed immediately by iodine (1.45 g 5 mmol) in one portion. The resulting yellow suspension was stirred at room temperature for 30 min after which the precipitated silver iodide was filtered off. The filtrate was concentrated in vacuo and the residue was taken up Scheme 1 Reagents and conditions i C5H11ONO Et2O HCl(g); ii H2 Pd/C Ac2O THF; iii NaBH4 EtOH room temp.; iv NaOH EtOH heat; v NaH ClCH2CO2Et PhCH3 80 8C N Ts MeO O N Ts MeO O NOH i 13 (R1 = tosyl R2 = H) 17 (R = H) N Ts MeO HO NHAc N Ts MeO HO NHAc N Ts MeO O NHAc iii ii 21 3:1 22 13 (R1 = tosyl R2 = NHAc) N Ts MeO HO NH2 iv iv N Ts MeO HO NH2 23 24 N Ts MeO NH O O H H N Ts MeO NH O O H H v v 25 26 3264 J.Chem. Soc. Perkin Trans. 1 1997 in chloroform (100 cm3) and washed with saturated aqueous sodium hydrogen carbonate (2 × 50 cm3) and brine (50 cm3). The organic phase was then dried and the solvent was removed in vacuo to give a pale yellow oil. Flash chromatography (ethyl acetate–hexane 20 80) gave the title compound as a viscous clear oil (1.58 g 92) (Found C 62.4; H 5.45; N 3.9; S 9.3.C18H19NO4S requires C 62.6; H 5.5; N 4.05; S 9.3); nmax- (liquid film)/cm21 1708 (C O) and 1600 (C C); dH(90 MHz) 7.65 (2H d aryl) 7.4 (2H d aryl) 7.1–6.75 (3H m aryl) 3.9 (2H t CH2) 3.75 (3H s OCH3) 3.25 (2H s CH2) 2.65 (2H t CH2) and 2.45 (3H s CH3 tosyl). 1,2,3,4-Tetrahydro-6-methoxy-4-methylene-1-(p-tolylsulfonyl)- quinoline 7 (X 5 6-OMe) To a stirred suspension of methyltriphenylphosphonium iodide (12.2 g 32.2 mmol) in dry THF (150 cm3) at 0 8C under nitrogen was added dropwise n-butyllithium (19 cm3 30.4 mmol; 1.6 M solution in hexanes) and the suspension was stirred for 30 min. To the resulting deep red solution was added a solution of the ketone 22 3 (R = tosyl X = 6-OMe) (10 g 30.2 mmol) in dry THF (100 cm3) dropwise and the mixture was stirred at room Scheme 2 Reagents and conditions i H2 Pd/C (CH3CH2CO)2O THF; ii NaBH4 EtOH room temp.1 h; iii BH3–THF room temp. 3 h; iv ClCH2COCl NaOH Cl(CH2)2Cl–H2O; v KOH EtOH room temp. 16 h; vi BH3–THF room temp. 12 h 17 (R = H) i N Ts MeO O NHCEt N Ts MeO O NOCEt + O 13 (R1 = tosyl R2 = NHCOEt) 17 (R = EtCO) ii N Ts MeO HO NHCEt O N Ts MeO HO NHCEt O + (3:1) 27 28 iii iii N Ts MeO HO NHPrn 29 N Ts MeO HO NHPrn 30 iv N Ts MeO ClCH2CO NPrn O COCH2Cl N Ts MeO NPrn O H H O N Ts MeO NPrn O H H vi v 31 32 33 O temperature overnight. The solvent was then removed in vacuo and the residue was taken up in dichloromethane (200 cm3) and washed with water (4 × 150 cm3). The organic layer was then dried and the solvent was removed in vacuo to give an oil.Flash chromatography (triethylamine–ethyl acetate–hexane 1 20 79) gave the title compound as a white solid (4.37 g 44) mp 119– 120 8C (Found C 66.0; H 5.9; N 4.4; S 9.8. C18H19NO3S requires C 65.65; H 5.8; N 4.2; S 9.7); nmax(Nujol)/cm21 1605 (C C); dH 7.75 (1H m aryl) 7.45 (2H d aryl) 7.3 (2H d aryl) 6.9 (1H d aryl) 6.85 (1H dd aryl) 5.4 (1H s vinyl) 4.7 (1H s vinyl) 3.9–3.8 (5H s 1 t OCH3 1 CH2) 2.35 (3H s CH3 tosyl) and 2.3 (2H t CH2). 2,3,4,5-Tetrahydro-7-methoxy-4-oxo-1-(p-tolylsulfonyl)-1H-1- benzazepine 2 (R 5 tosyl X 5 7-OMe) Silver nitrate (3.2 g 18.9 mmol) was dissolved in methanol (20 cm3) and water (20 cm3) at room temperature. To this vigorously stirred solution was added the alkene 7 (X = 6-OMe) (3.1 g 9.4 mmol) in THF (40 cm3) in one portion followed immediately by iodine (2.4 g 9.4 mmol) in one portion.The resulting yellow suspension was stirred at room temperature for 30 min after which the precipitated silver iodide was filtered off. The filtrate was concentrated in vacuo and the residue was taken up in dichloromethane (150 cm3) and washed with saturated aqueous sodium hydrogen carbonate (2 × 50 cm3) dilute aqueous sodium metabisulfite (50 cm3) water (2 × 50 cm3) and brine (50 cm3). The organic phase was then dried and evaporated in vacuo to give an oil. Flash chromatography (ethyl acetate–hexane 20 80) gave the title compound as a white solid (2.51 g 77) mp 107–109 8C (Found C 62.4; H 5.6; N 4.1; S 9.4. C18H19NO4S requires C 62.6; H 5.5; N 4.05; S 9.3); nmax(liquid film)/cm21 1710 (C O) and 1600 (C C); dH 7.6 (2H d aryl) 7.4 (2H d aryl) 7.2 (1H m aryl) 6.75 (1H dd aryl) 6.7 (1H d aryl) 3.9 (2H t CH2) 3.8 (3H s OCH3) 3.2 (2H s CH2) 2.65 (2H t CH2) and 2.4 (3H s CH3 tosyl).2,3,4,5-Tetrahydro-4-hydroxy-8-methoxy-1-(p-tolylsulfonyl)- 1H-1-benzazepine 9 Procedure (a). Sodium triacetoxyborohydride (2.04 g 9.64 mmol) was added in portions to a stirred solution of ketone 2 (R = tosyl X = 8-OMe) (2 g 5.8 mmol) and n-propylamine (0.69 g 11.6 mmol) in 1,2-dichloroethane (25 cm3) and acetic acid (0.5 cm3) at 0–5 8C under nitrogen. The resulting suspension was stirred at room temperature for 16 h whereupon aqueous sodium hydroxide (30 cm3; 2 M) was added cautiously over 30 min. The phases were separated and the aqueous phase was extracted with dichloromethane (2 × 30 cm3). The combined organic layers were dried and the solvent was removed in vacuo to give a brown oil.Flash chromatography (ethyl acetate– hexane 80 20) gave unreacted starting material (0.74 g 37) (identified by TLC and 1H NMR spectral comparison with an authentic sample) and the title compound as a viscous clear oil (0.62 g 49). Procedure (b). To a stirred solution of ketone 2 (R = tosyl X = 8-OMe) (0.6 g 1.7 mmol) in ethanol (20 cm3) at room temperature under nitrogen was added sodium borohydride (0.08 g 2.03 mmol) in one portion. The resulting suspension was stirred for 3 h and acetic acid (1 cm3) and water (100 cm3) were added. The mixture was extracted with dichloromethane (4 × 50 cm3) and the combined organic extracts were dried and evaporated in vacuo to give an oil. Flash chromatography gave the title compound as an oil (0.42 g 70) This product was identical (TLC IR and 1H NMR spectroscopy) to the product obtained by procedure (a) (Found C 62.1; H 6.3; N 3.9; S 9.3.C18H21NO4S requires C 62.2; H 6.05; N 4.0; S 9.2); nmax(liquid film)/cm21 3560–3200 (br OH) and 1605 (C C); dH 7.65 (2H d aryl) 7.15 (2H d aryl) 7.0 (1H d aryl) 6.75 (1H d aryl) 6.7 (1H dd aryl) 3.9 (2H br CH2) 3.8 (3H s OCH3) 3.7 (1H br CHOH) 2.5 (2H m CH2) 2.4 (3H s CH3 tosyl) and 1.9–1.7 (3H br CH2 1 exch. CHOH). J. Chem. Soc. Perkin Trans. 1 1997 3265 2,3,4,5-Tetrahydro-4-hydroxyimino-8-methoxy-1-(p-tolylsulfonyl)- 1H-1-benzazepine (oxime of 2; R 5 tosyl X 5 8-OMe) A mixture of the ketone (4.1 g 12 mmol) hydroxylamine hydrochloride (1.25 g 18 mmol) and pyridine (2 cm3) in ethanol (20 cm3) was heated at reflux for 3 h.The reaction mixture was allowed to cool to room temperature and then poured into chloroform (100 cm3). The organic phase was washed with hydrochloric acid (2 × 50 cm3 2 M) and water (2 × 50 cm3) then dried and the solvent was removed in vacuo to give a gum. Trituration with diethyl ether gave a solid which was recrystallised from ethanol to give the title compound as colourless needles (4.0 g 96) mp 136–137 8C (Found C 60.1; H 5.7; N 7.7; S 8.9. C18H20N2O4S requires C 60.0; H 5.6; N 7.8; S 8.9); nmax(Nujol)/cm21 3450–3250 (oxime OH) and 1600 (C C); dH 8.1 (1H br exch. NOH) 7.4 (2H m aryl) 7.3 (2H m aryl) 7.2–7.0 (1H m aryl) 6.8 (2H m aryl) 3.9 (2H m CH2) 3.7 (3H s OCH3) 3.4 1 3.1 (2H 2 × s CH2 benzylic E 1 Z) 2.9 1 2.5 (2H 2 × t CH2 E 1 Z) and 2.4 (3H s CH3 tosyl).4-Amino-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 1 (R 5 H X 5 8-OMe) To a solution of the oxime (prepared above) (1.0 g 2.78 mmol) in dry THF (20 cm3) at room temperature under nitrogen was added lithium aluminium hydride (12.6 cm3 12.6 mmol; 1.0 M solution in THF). After the initial vigorous effervescence had subsided the resulting yellow solution was heated at reflux for 18 h during which time the reaction mixture became deep red it was cooled to 0 8C and excess hydride was destroyed by the cautious addition of ‘wet’ diethyl ether (10 cm3). The mixture was diluted with ethanol (50 cm3) and the inorganic material was filtered off. The filtrate was dried and the solvent was removed in vacuo to give an oil. Flash chromatography (dichloromethane–ethanol–ammonia 50:8:1) gave the title compound as an off-white solid (0.26 g 49) mp 98–99 8C (Found C 68.5; H 8.2; N 14.5.C11H16N2O requires C 68.75; H 8.3; N 14.6); nmax(Nujol)/cm21 3340 3250 (NH 1 NH2) and 1610 (C C); dH 7.0 (1H d aryl) 6.4 (1H dd aryl) 6.3 (1H d aryl) 3.8 (3H s OCH3) 3.2–3.1 (1H qd CHNH2) 3.1–2.9 (2H m CH2) 2.8 (2H d CH2) 2.0 (1H m CH2) 1.9 (1H m CH2) and 1.85–1.5 (3H br exch. NH 1 NH2). 2,3,4,5-Tetrahydro-8-methoxy-4-di-n-propylamino-1H-benzazepine 10 (R 5 H X 5 8-OMe) Sodium triacetoxyborohydride (0.495 g 2.3 mmol) was added in portions to a stirred mixture of amine 1 (R = H X = 8-OMe) (0.14 g 0.73 mmol) propanal (0.157 g 2.7 mmol) and glacial acetic acid (0.15 g 2.5 mmol) in 1,2-dichloroethane (60 cm3) at room temperature under nitrogen. The resulting suspension was stirred for 3 h and then treated with dichloromethane (30 cm3) and aqueous sodium hydroxide (30 cm3; 2 M).The mixture was stirred vigorously for 30 min and the phases were separated. The aqueous phase was extracted with dichloromethane (2 × 30 cm3) and the pooled organic layers were washed with water (2 × 50 cm3) dried and evaporated in vacuo to give an oil (0.24 g 38) which was taken up in ethanol (10 cm3) and treated with ethereal hydrogen chloride. The solvent was removed in vacuo and the residue was crystallised from ethyl acetate–hexane to give the title compound as the hygroscopic dihydrochloride salt mp 125–127 8C (Found C 58.5; H 8.7; N 8.35; Cl 20.4. C17H28N2O?2HCl requires C 58.4; H 8.6; N 8.0; Cl 20.3); nmax(Nujol)/cm21 3320 (NH) and 1610 (C C); dH(free-base) 7.4 (1H d aryl) 7.1 (1H dd aryl) 6.9 (1H d aryl) 3.8 (3H s OCH3) 3.1 (2H m CH2) 3.0–2.7 (7H m 2 × CH21CH2 1 CHN) 2.1–2.0 (2H m CH2) 1.85–1.6 (5H m 2 × CH2 1 exch.NH) and 1.2 (6H t 2 × CH3). 2,3,4,5-Tetrahydro-4-hydroxyimino-7-methoxy-1-(p-tolylsulfonyl)- 1H-1-benzazepine (oxime of 2; R 5 tosyl X 5 7-OMe) A solution of the ketone (1.0 g 2.9 mmol) hydroxylamine hydrochloride (0.3 g 4.35 mmol) and pyridine (0.5 cm3) in ethanol (20 cm3) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was then poured into chloroform (100 cm3). The organic phase was washed with hydrochloric acid (2 × 50 cm3) and water (2 × 50 cm3) then dried and the solvent was removed in vacuo to give a gum. Trituration with diethyl ether gave an off-white solid which was recrystallised from ethanol to afford the title compound as colourless crystals (0.95 g 91) mp 131–133 8C (Found C 60.1; H 5.7; N 7.7; S 8.6.C18H20N2O4S requires C 60.0; H 5.55; N 7.8; S 8.9); nmax(Nujol)/cm21 3450–3200 (OH oxime) and 1600 (C C); dH 8.2 (1H br exch. NOH) 7.6 (2H d aryl) 7.2 (2H d aryl) 7.1 (1H dd aryl) 6.8 (2H m aryl) 3.9–3.7 (5H t 1 s CH2 1 OCH3) 3.4 1 3.1 (2H 2 × s CH2 benzylic E 1 Z) 2.9 1 2.6 (2H 2 × t CH2 E 1 Z) and 2.4 (3H s CH3 tosyl). 4-Amino-2,3,4,5-tetrahydro-7-methoxy-1-(p-tolylsulfonyl)-1H- 1-benzazepine 1 (R 5 tosyl X 5 7-OMe) To a stirred solution of the oxime (prepared above) (0.9 g 2.5 mmol) in dry THF (20 cm3) at room temperature under nitrogen was added dropwise a solution of lithium aluminium hydride (14 cm3 14 mmol; 1.0 M solution in THF). The resulting mixture was heated at reflux for 18 h and then cooled to 0 8C.Excess hydride was destroyed by the addition of ‘wet’ diethyl ether (10 cm3). The inorganic salts were filtered off and the filtrate was diluted with diethyl ether (20 cm3). The organic phase was washed with water (30 cm3) dried and the solvent was removed in vacuo to give an oil. Flash chromatography (dichloromethane–ethanol–ammonia 100:8:1) afforded the title compound as an unstable viscous oil (0.48 g 56); nmax- (liquid film)/cm21 3340 3250 (NH2) and 1610 (C C); dH 7.8 (1H d aryl) 7.5 (2H d aryl) 7.3 (1H d aryl) 7.2 (2H d aryl) 6.75 (1H dd aryl) 3.95 (1H m CH2) 3.8 (3H s OCH3) 3.5 (1H m CH2) 3.2–3.1 (1H qd CHN) 2.5 (2H m CH2) 2.45 (3H s CH3 tosyl) and 2.0–1.7 (4H br CH2 1 exch. NH2). An accurate elemental analysis could not be obtained.2,3,4,5-Tetrahydro-7-methoxy-4-di-n-propylamino-1-(p-tolylsulfonyl)- 1H-1-benzazepine 10 (R 5 tosyl X 5 7-OMe) Sodium triacetoxyborohydride (0.2 g 0.96 mmol) was added in portions to a stirred mixture of amine 1 (R = tosyl X = 7-OMe) (0.11 g 0.3 mmol) propanal (0.06 g 1.03 mmol) and glacial acetic acid (2 drops) in 1,2-dichloroethane (15 cm3) at room temperature under nitrogen. The mixture was stirred for 3 h and then treated with dichloromethane (20 cm3) and aqueous sodium hydroxide (15 cm3; 2 M). The phases were separated and the aqueous phase was extracted with dichloromethane (2 × 30 cm3). The pooled organic layers were washed with water (2 × 50 cm3) then dried and the solvent was removed in vacuo to give a pale yellow oil (0.09 g 38). This oil was taken up in ethanol (5 cm3) and treated with ethereal hydrogen chloride.The solvent was removed in vacuo and the residue was crystallised from diethyl ether–hexane to give the title compound as the hygroscopic dihydrochloride salt mp 118–120 8C (Found C 57.7; H 7.55; N 5.5; S 6.3; Cl 14.3. C24H34N2O3S?2HCl requires C 57.3; H 7.2; N 5.6; S 6.4; Cl 14.1); nmax(Nujol)/cm21 1610 (C C); dH(Free-base) 7.6 (2H d aryl) 7.4 (2H d aryl) 7.05– 6.95 (2H m aryl) 6.8 (1H dd aryl) 4.05 (1H m CH2) 3.8 (3H s OCH3) 3.6 (1H m CH2) 3.05–2.6 (7H m CHN 1 2 × CH21CH2) 2.45 (3H s CH3 tosyl) 2.0–1.8 (6H m 2 × CH2 1 CH2) and 1.1–1.0 (6H t 2 × CH3). 2,3,4,5-Tetrahydro-8-methoxy-4-phthalimido-1H-1-benzazepine 8 4-Amino-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine (10 mg 5.2 × 1025 mol) N-ethoxycarbonyl phthalimide (11 mg 5.2 × 1025 mol) and triethylamine (0.1 cm3) in THF (10 cm3) were heated at reflux for 18 h.The reaction mixture was cooled to room temperature and the solvent was removed under 3266 J. Chem. Soc. Perkin Trans. 1 1997 reduced pressure. The residue was dissolved in dichloromethane and washed with 10 aqueous sodium hydrogen carbonate. The organics were dried over sodium sulfate and concentrated under reduced pressure to yield the desired product mp 145– 147 8C (Found M1 322.1248. C19H18N2O3 requires M 322.1311); dH 7.9 (4H m aryl) 7.0 (1H d J 8.2 aryl) 6.4 (1H dd J 8.3 2.2 aryl) 6.3 (1H d J 2 aryl) 3.7 (3H s OCH3) 3.4 (1H m CHNP) 2.9 (2H m CH2) 2.7 (2H m CH2) 1.9 (2H m CH2) and 1.2 (1H m NH). Hydrolysis of methyl N-(m-methoxyphenyl)-3-aminopropanoate To a stirred solution of the ester 15b (100 g 0.447 mol) in ethanol (450 cm3) was slowly added aqueous sodium hydroxide (18 g 0.477 mol in 115 cm3 water).The solution was heated gently (never refluxing) until TLC indicated absence of the ester. The ethanol was removed and the aqueous layer was acidified (pH 4) with 2 M hydrochloric acid. The reaction mixture was then extracted with chloroform the extracts combined and washed with brine dried over sodium sulfate and the solution was removed under reduced pressure to yield a brown oil. This was taken to the next stage without further purification; it was assumed to be N-(m-methoxyphenyl)-3-aminopropanoic acid.17b 1,2,3,4-Tetrahydro-7-methoxy-4-oxoquinoline 3 (R 5 H X 5 7-OMe) To the stirred crude acid (from above) (40 g 0.2 mol) at room temperature polyphosphoric acid 17 (85 400 g) was added.The reaction was stirred at room temperature for 0.5 h and then to 60 8C over 0.5 h and further at 60 8C overnight. The temperature was raised to 70–80 8C for 2 h and then 100 8C for 1 h. The reaction mixture was then poured onto ice basified with ammonia to pH 8–9. The solid precipitate formed was removed by filtration dried and recrystallised from ethanol to yield the desired product (22 g 61) mp 134–136 8C (lit.,15b mp 139– 140 8C) (lit.,17b mp 137–138 8C); nmax/cm21 3361 (NH) (Found C 67.6; H 6.2; N 7.8; M1 177.0726. Calc. for C10H11NO2 C 67.8; H 6.2; N 7.9; M 177.0786); dH(cf.17b) 7.8–7.7 (1H d aryl) 6.3 (1H dd aryl) 6.0 (1H d aryl) 4.5 (1H br NH) 3.8 (3H s CH3) 3.5–3.4 (2H td CH2) 2.6 (2H t CH2); dC 37.9 (CH2) 42.5 (CH2) 55.5 (OCH3) 98.1 (aryl) 106.9 (aryl) 113.9 (aryl) 129.9 (aryl) 154.2 (aryl) 165.5 (aryl) and 192.5 (C O).1,2,3,4-Tetrahydro-5-methoxy-4-oxoquinoline 6 (R 5 H)17c The aqueous layer from the above reaction was extracted with dichloromethane. The solvent was dried and removed under reduced pressure to yield a yellow solid (3.6 g 10) mp 176– 178 8C (lit.,17c mp 183–184 8C) (Found C 67.8; H 6.3; N 7.8. Calc. for C10H11NO2 C 67.7; H 6.2; N 7.9); dH 2.7 (2H m CH2) 3.25 (2H m CH2) 3.8 (3H s OCH3) 6.3 (2H m aryl) and 7.2 (1H m aryl). Ethyl (1,2,3,4-tetrahydro-7-methoxy-4-oxo-1-quinolyl)acetate 3 (R 5 CH2CO2Et X 5 7-OMe) Under nitrogen the ketone 3 (R = tosyl X = 7-OMe) (5 g 28 mmol) dry toluene (50 cm3) Hunig’s base (13 cm3) and ethyl bromoacetate (5 cm3) were heated together to 90 8C for 90 h.The reaction was cooled and the solid formed was filtered off. The aqueous layer was extracted with chloroform and the combined organics were washed with water dried over sodium sulfate and the solvent was removed to yield a brown oil which crystallised on standing. The crystals were combined and recrystallisation from ethanol yielded the desired product (3.72 g 51) mp 92–94 8C (Found C 63.6; H 6.3; N 5.2; M1 263.1165. C14H17NO4 requires C 63.9; H 6.5; N 5.3; M 263.1152); nmax/cm21 1753 (C O); dH 8.1–8.0 (1H d aryl) 6.5 (1H dd aryl) 6.1 (1H d aryl) 4.4–4.2 (2H q CH2) 4.1 (2H s CH2) 3.8 (3H s OCH3) 3.7 (2H t CH2) 2.9–2.8 (2H t CH2) and 1.5–1.4 (3H t CH3). Ethyl (1,2,3,4-tetrahydro-7-methoxy-4-methylene-1-quinolyl)- acetate 7 (X 5 7-OMe CH2CO2Et for Ts) To a solution of ethyl (1,2,3,4-tetrahydro-7-methoxy-4-oxo-1- quinolyl)acetate (0.5 g 1.9 mmol) in THF cooled to 0 8C was added Tebbe reagent 19 (6 cm3; 0.5 M).After 30 min diethyl ether (20 cm3) was added followed by the addition of 5–10 drops of aqueous NaOH (0.1 M) while stirring to destroy active aluminium compounds. The reaction mixture was then dried over sodium sulfate filtered through Kieselguhr and concentrated in vacuo to yield a brown oil. Flash column chromatography SiO2 (pretreated with ammonia to prevent isomerisation) dichloromethane yielded the desired product (0.13 g 27) and starting material (0.21 g 42) (Found M1 261.1317. C15H19NO3 requires M 261.1359); nmax/cm21 1753 (C O) 1625 (C C); dH 7.4 (1H d J 8.6 aryl) 6.3–6.2 (1H dd J 2.4 8.6 aryl) 6.06 (1H d J 2.7 aryl) 5.26 (1H s vinyl) 4.68 (1H s vinyl) 4.2–4.0 (2H m CH2CH3) 3.9 (2H s CH2CO2) 3.7 (3H s OCH3) 3.4 (2H t J 6.2 CH2) 2.6 (2H t J 6.1) 1.3 (3H m CH3).Ethyl (2,3,4,5-tetrahydro-8-methoxy-4-oxo-1H-1-benzazepin- 1-yl)acetate 2 (R 5 CH2CO2Et X 5 8-OMe) Silver nitrate (2.2 g 0.013 mol) methanol (24 cm3) and water (24 cm3) were stirred vigorously. Ethyl (1,2,3,4-tetrahydro-7- methoxy-4-methylene-1-quinolyl)acetate (1.7 g 6.5 mmol) in tetrahydrofuran (38 cm3) was added immediately followed by the addition of iodine (1.6 g 6.5 mmol) all at once. After being stirred at room temperature for 1 h the reaction was filtered and the solvent evaporated. The residue was dissolved in chloroform washed with aqueous sodium hydrogen carbonate dilute aqueous sodium metabisulfite dried and the solvent removed to yield a clear oil (1.2 g 66) (Found M1 277.1507.C15H19NO4 requires M 277.1577). Instability of this product prevented acquisition of satisfactory data. 4-Acetamido-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 11 (R 5 H) Acetyl chloride (0.075 cm3 1.05 mmol) in dry THF (5 cm3) was added in one portion to a stirred solution of 4-amino- 2,3,4,5-tetrahydro-8-methoxy-1(1H)-benzazepine 1 (R = H X = 8-OMe 0.2 g 1.05 mmol) and trimethylamine (0.15 cm3 1.05 mmol) in dry THF (15 cm3) and the resulting suspension stirred at 278 8C for 0.5 h. The reaction mixture was stirred for a further 2 h at room temperature dilute hydrochloric acid (2 M 100 cm3) was added and the mixture washed with chloroform. The aqueous layer was basified (2 M NaOH) and extracted with chloroform. The chloroform extracts were dried and the solvent removed in vacuo to give a brown oil.Flash chromatography SiO2–dichloromethane–ethanol–ammonia (DEA) 300:8:1 and trituration with diethyl ether gave the product as a white solid (0.2 g 81) mp 139–141 8C (Found C 66.1; H 7.7; N 11.6. C13H18N2O2 requires C 66.55; H 7.75; N 11.95); nmax(Nujol)/cm21 3330 (NH) 3240 (NH) 1600 (C C); dH 7.05 (1H d aryl) 6.45 (1H dd aryl) 6.3 (1H d aryl) 5.45 (1H br exch. NH amine) 4.25 (1H m >CHNHAc) 3.8 (3H s OMe) 3.25–2.95 (3H m CH2 1 CH benzylic) 2.8 (1H dd CH benzylic) 2.0 (5H m 1 s CH2 NHCOCH3) and 1.8–1.45 (1H br exch. NH amide). 4-(N-Acetyl-N-ethoxycarbonylmethylamino)-2,3,4,5-tetrahydro- 8-methoxy-1H-benzazepine 11 (R 5 CH2CO2Et) 4-Acetamido-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 11 (R = H 0.42 g 1.8 mmol) ethyl bromoacetate (0.24 cm3 2.16 mmol) and N,N-diisopropylethylamine (0.63 cm3 3.6 mmol) were heated together in toluene at 110 8C for 16 h under nitrogen.The cooled reaction mixture was poured onto chloroform (100 cm3) and washed with dilute hydrochloric acid dried and the solvent removed in vacuo to give a brown oil. Flash chromatography (SiO2–DEA 300:8:1) gave a white solid (0.485 g 84) mp 134–135 8C (Found C 63.6; H 7.8; N 8.5. C17H24N2O4 requires C 63.7; H 7.55; N 8.75); nmax(CHCl3)/ cm21 3320 (NH amide) 1730 (C O ester) 1640 (C O amide); dH 7.0 (1H d aryl) 6.45 (1H dd aryl) 6.3 (1H d aryl) 5.95 J. Chem. Soc. Perkin Trans. 1 1997 3267 (1H br exch. NH) 4.4–4.2 (3H q 1 m >CHNH CO2CH2- CH3) 4.0 (2H dd J 20 CH2CO2Et) 3.8 (3H s OCH3) 3.3–3.0 (3H m CH2 CH benzylic) 2.85 (1H dd CH benzylic) 1.95 (5H m 1 s CH2 NRCOCH3) and 1.3 (3H t CO2CH2CH3).2,3,4,5-Tetrahydro-3-hydroxyimino-1-(p-tolylsulfonyl)-1H-1- benzazepine 12 (X Y 5 NOH) 2,3,4,5-Tetrahydro-3-oxo-1-(p-tolylsulfonyl)-1H-1-benzazepine (12; X Y = O 2 g 6.35 mmol),5 hydroxylamine hydrochloride (0.67 g 9.53 mmol) and pyridine (1.2 cm3) were refluxed together in ethanol (20 cm3) for 2 h. The reaction mixture was poured into chloroform (100 cm3) and washed with dilute hydrochloric acid. The chloroform extracts were dried and the solvent removed in vacuo to give an oil which solidified on standing. Recrystallisation from ethanol gave the title product as white crystals (1.8 g 86) mp 186 8C (decomp.) (Found C 61.3; H 5.1; N 8.3; S 9.6. C17H18N2O3S requires C 61.8; H 5.5; N 8.5; S 9.7); nmax(Nujol)/cm21 3250 (OH) 1600 (C C); dH 8.0–7.0 (9H m aryl OH exch.) 4.65 1 4.35 (2H 2s CH2 E 1 Z) and 2.7–2.05 (7H m CH3 tosyl 2 × CH2).3-Amino-2,3,4,5-tetrahydro-1-(p-tolylsulfonyl)-1H-1-benzazepine 12 (X 5 NH2 Y 5 H) To 2,3,4,5-tetrahydro-3-hydroxyimino-1-(p-tolylsulfonyl)-1H- 1-benzazepine 12 (X Y = NOH) (1.5 g 4.5 mmol) ethanol (30 cm3) and aqueous sodium hydroxide (4 M; 30 cm3) was added Raney nickel alloy (2.25 g 1 1 Ni/Al) in one portion at room temperature. The resulting suspension was stirred for 1 h after which the nickel was collected by filtration (CAUTION pyrophoric). The filtrate was concentrated in vacuo extracted with chloroform (100 cm3) dried and the solvent removed in vacuo to give an oil. Flash chromatography (SiO2–DEA 300:8:1) gave the title product as a clear oil (0.87 g 62) (Found C 64.4; H 6.05; N 8.6; S 9.55.C17H20N2O2S requires C 64.55; H 6.35; N 8.85; S 10.15); nmax(film)/cm21 3360 (NH2) 1600 (C C); dH 7.65 (2H d aryl) 7.3–7.05 (6H m aryl) 4.2 (1H d CH2) 3.2 (1H m CH2) 2.9 (1H m >CHNH2) 2.7–2.4 (5H m 1 s CH2 CH3 tosyl) 2.05 (1H m CH2) 1.3 (1H m CH2) and 1.45 (2H s exch. NH2). 1,2,3,4-Tetrahydro-7-methoxy-1-hydroxyiminonaphthalene 28 7-Methoxy-1-tetralone (100 g 0.568 mol) sodium hydroxide (120 g 3 mol) hydroxylamine hydrochloride (96.2 g 1.38 mol) and ethanol (100 cm3) were heated at reflux for 2 h. The mixture was then allowed to cool to room temperature and water (3000 cm3) was added. The mixture was extracted with dichloromethane (4 × 500 cm3) the combined organic layers were dried and the solvent was removed in vacuo to give the title compound as an off-white solid (96.96 g 89).Recrystallisation was from light petroleum (60–80 8C) mp 86–88 8C (lit.,28 mp 87–88 8C) (Found C 69.15; H 7.3; N 7.3. Calc. for C11H13- NO2 C 69.1; H 6.8; N 7.3); nmax(Nujol)/cm21 3360 (OH oxime) and 1620 (C C); dH(90 MHz) 7.7 (1H s exch. NOH) 7.45 (1H d aryl) 7.0 (2H m aryl) 3.8 (3H s OCH3) 2.8–2.7 (4H m 2 × CH2) and 1.85 (2H m CH2). 1,2,3,4-Tetrahydro-7-methoxy-1-(p-tolylsulfonyloxyimino)- naphthalene 28 To the oxime of 7-methoxy-1-tetralone (96.9 g 0.507 mol) in acetone (250 cm3) at 0 8C was added dropwise aqueous potassium hydroxide (500 cm3; 10). When the addition was complete a solution of toluene-p-sulfonyl chloride (98.43 g 0.517 mol) in acetone (300 cm3) was added dropwise. The resulting mixture was stirred at room temperature for 3 h.The solid was filtered off washed with water (500 cm3) and dried in air to give the title compound as an off-white solid (182.6 g 97) purified by recrystallisation from ethanol mp 130–132 8C (lit.,28 mp 130– 131 8C) (Found C 62.9; H 6.0; N 4.1; S 9.2. Calc. for C18H19NO4S C 62.6; H 5.5; N 4.05; S 9.3); nmax(Nujol)/cm21 1620 (C C); dH(90 MHz) 7.85 (2H d aryl) 7.3–7.1 (5H m aryl) 3.8 (3H s OCH3) 2.85–2.7 (4H m 2 × CH2) 2.4 (3H s CH3 tosyl) and 1.8 (2H m CH2). 2,3,4,5-Tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine 16 (R 5 H X Y 5 O)28,29 A suspension of the oxime tosylate (64.4 g 0.187 mol) in glacial acetic acid (1000 cm3) and water (800 cm3) was stirred at 60 8C overnight during which time the solid dissolved. The solution was allowed to cool and the solvent was removed in vacuo to give a brown oil which was cooled (0 8C) and aqueous sodium hydrogen carbonate (1000 cm3; 2 M) was added with stirring.The precipitated solid was filtered and dried in air (28.07 g 78) mp 128–130 8C (lit.,29 mp 129–131 8C) (Found C 68.8; H 6.8; N 7.3. Calc. for C11H13NO2 C 69.1; H 6.8; N 7.3); nmax(Nujol)/cm21 3210 (NH) and 1685 (C O); dH(90 MHz) 8.65 (1H s exch. NH) 7.1 (1H d aryl) 6.7–6.65 (1H dd aryl) 6.6 (1H d aryl) 3.8 (3H s OCH3) 2.75–2.7 (2H t CH2) 2.4–2.3 (2H t CH2) and 2.25–2.15 (2H m CH2). 2,3,4,5-Tetrahydro-8-methoxy-1H-1-benzazepine 16 (R 5 X 5 Y 5 H) To a suspension of lithium aluminium hydride (16 g 0.42 mol) in dry THF (400 cm3) at 0 8C under nitrogen was added dropwise a solution of lactam 16 (R = H X Y = O)29 (16 g 0.084 mol) in dry THF (100 cm3).The resulting suspension was heated at reflux for 3 h and then cooled to 0 8C. Excess hydride was destroyed by the cautious addition of ethanol (50 cm3) followed by saturated aqueous sodium sulfate (150 cm3). The inorganic salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was taken up in diethyl ether (200 cm3) and washed with water and brine then dried and the solvent was removed in vacuo to give a brown oil (11.33 g 86) which was used without further purification. The N-acetate made in the usual way (pyridine acetyl chloride diethyl ether 0 8C) had mp 62–64 8C. 2,3,4,5-Tetrahydro-8-methoxy-1-(p-tolylsulfonyl)-1H-1-benzazepine 16 (R = tosyl X = Y = H) To a cooled (0 8C) solution of compound 16 (R = X = Y = H)30 (8.5 g 48 mmol) in pyridine (30 cm3) was added toluene-psulfonyl chloride (9.29 g 48 mmol) in portions.The resulting deep red mixture was stirred at room temperature for 3 h whereupon ice-cooled water (50 cm3) and dilute hydrochloric acid (50 cm3) were added. The mixture was extracted with diethyl ether (4 × 100 cm3) and the combined organic extracts were washed with water then dried and the solvent was removed in vacuo to give a red oil which solidified on standing to a yellow solid (15.25 g 96) which was chromatographed (Al2O3 diethyl ether–light petroleum 1 5) giving colourless crystals mp 82–83 8C (softens 52–54 8C) (Found C 65.25; H 6.45; N 4.15; S 9.65; M1 331.1252. C18H21NO3S requires C 65.25; H 6.4; N 4.25; S 9.65; M 331.1242). 2,3,4,5-Tetrahydro-8-methoxy-5-oxo-1-(p-tolylsulfonyl)-1H-1- benzazepine 4 (R 5 tosyl X 5 8-OMe) To a cooled (0 8C) solution of compound 16 (R = tosyl X = Y = H) (13.3 g 40.2 mmol) and acetic acid (100 cm3) was added a solution of chromium trioxide (18.94 g 189 mmol) in acetic acid (132 cm3) and water (50 cm3) dropwise over 3 h.31 The resulting dark green mixture was stirred at room temperature overnight and then cooled to 0 8C.Aqueous sodium hydroxide (200 cm3; 10) was added dropwise and the solution was stirred for 1 h and then extracted with dichloromethane (4 × 250 cm3). The combined organic extracts were washed with water (2 × 250 cm3) and brine then dried and the solvent was removed in vacuo to give a green oil. Chromatography on alumina (ethyl acetate–hexane 30 70) gave a yellow solid (11.84 g) which was recrystallised from propan-2-ol to give the title compound as colourless crystals (10.26 g 74) mp 86–88 8C (Found C 62.5; H 5.6; N 4.1; S 9.4.C18H19NO4S requires C, 3268 J. Chem. Soc. Perkin Trans. 1 1997 62.6; H 5.5; N 4.05; S 9.3); nmax(Nujol)/cm21 1708 (C O) 1605 (C C); dH 7.7 (1H d aryl) 7.6 (2H d aryl) 7.3 (2H d aryl) 6.9 (1H d aryl) 6.85–6.8 (1H dd aryl) 3.85–3.8 (5H t 1 s CH2 1 OCH3) 2.45–2.35 (5H s 1 t tosyl 1 CH2) and 2.0–1.9 (2H m CH2). N-Acetyl-2,3,4,5-tetrahydro-8-methoxy- 5-oxo-1H-1-benzazepine 4 (R = Ac X = 8-OMe) was obtained similarly 31 and had mp 76–78 8C (Found C 67.0; H 6.6; N 5.95. C13H15NO3 requires C 66.95; H 6.5; N 6.0); nmax(Nujol)/cm21 1660 1600 and 1580; dH 7.9 (1H d aryl) 6.94 (1H dd aryl) 6.7 (1H d aryl) 3.87 (3H s OMe) 2.61 (2H m CH2) 1.90–1.97 (5H m CH2 1 CH3 CO) and 1.48–1.5 (2H m CH2).2-Hydroxyimino-39-methoxyacetanilide (cf. ref. 26) To trichloroacetaldehyde hydrate (90 g 0.54 mol) in water (1200 cm3) was added in order anhydrous sodium sulfate (568 g) in water (750 cm3) a solution of m-anisidine (61.5 g 0.5 mol) in water (300 cm3) containing concentrated hydrochloric acid (43 cm3) and finally hydroxylamine hydrochloride (110 g 1.58 mol) in water (500 cm3). The mixture was slowly heated with stirring until vigorous boiling commenced after about 45 min. After 1 or 2 min boiling the reaction was complete and the contents of the flask were cooled immediately. The brown solid that separated was filtered and dried to yield 84 g which was used without further purification. 6-Methoxyisatin 15 Method (a). 2-Hydroxyimino-39-methoxyacetanilide (20 g) was added with stirring to concentrated sulfuric acid (100 cm3) at 50 8C.The rate of addition was such that the temperature did not rise above 70 8C. After the addition was complete the reaction mixture was heated to 80 8C for 10 min then cooled to room temperature and poured onto 1 l of ice. The chloroform extracts were dried and evaporated in vacuo to yield bright orange crystals which recrystallised from acetone–light petroleum to give 0.65 g of 15 (mp 154–157 8C) (Found C 60.8; H 3.85; N 7.9; M1 177.0425. C9H7NO3 requires C 61.0; H 4.0; N 7.9; M 177.0426); nmax/cm21 3240 (NH amide) 1620 shoulder at 1640 (C O) 1600 (C C); dH 7.6–7.4 (1H d aryl) 7.2–7.0 (1H dd aryl) 7.95 (1H d aryl) 3.9 (3H s OMe) and 10.95 (1H br exch. NH). Method (b). 2-Hydroxyimino-39-methoxyacetanilide (40 g) was added with stirring to polyphosphoric acid (400 g) at 50 8C in the same manner as for method (a).After 10 min stirring at 80 8C the mixture was immediately poured onto a large excess of ice and the solid filtered off. The dried solid was purified by reprecipitation with dilute hydrochloric acid from dilute aqueous sodium hydroxide to yield 24 g of 15 (66) identical to that found in method (a). 4-Methoxyanthranilic acid 14 (R1 5 R2 5 H CO2H for CO2Me) 6-Methoxyisatin (5 g 0.03 mol) was dissolved in water (150 cm3) containing sodium hydroxide (8 g 0.2 mol). To this solution at 25–30 8C was added dropwise 30 w/v aqueous hydrogen peroxide (8 cm3) in water (70 cm3). When the addition was complete the reaction mixture was stirred at room temperature for 24 h. Neutralisation with dilute hydrochloric acid followed by filtration yielded the product as an off-white solid (3.98 g 78).Identified by comparison with a genuine sample (mp 174–176 8C IR NMR spectroscopy TLC) prepared by the literature method.35 Ethyl 4-methoxyanthranilate 14 (R1 5 R2 5 H CO2Et for CO2Me) 4-Methoxyanthranilic acid (1 g 6 mmol) was refluxed in ethanol (50 cm3) saturated with dry hydrogen chloride gas overnight. The reaction mixture was poured onto an excess of aqueous sodium hydrogen carbonate and the ethanol evaporated in vacuo. The chloroform extracts were dried and evaporated in vacuo to yield a light purple oil which crystallised on standing. Recrystallisation from diethyl ether–light petroleum gave light purple needles (0.624 g 52) mp 67–68 8C (Found C 61.3; H 6.75; N 6.9 M1 195.0895.C10H13NO3 requires C 61.55; N 7.2; H 6.65; M 195.0895); nmax(TCE)/ cm21 3500 3360 (NH) 1680 (C O ester); dH 7.8 (1H s aryl) 6.2 (1H dd aryl) 6.1 (1H d aryl) 5.7 (2H br exch. NH) 4.3 (2H q CH2CH3) 3.75 (3H s OMe) and 1.3 (3H t CH2CH3). Ethyl 4-methoxy-N-(p-tolylsulfonyl)anthranilate 14 (R1 5 H R2 5 tosyl CO2Et for CO2Me) To a solution of ethyl 4-methoxyanthranilate (4.3 g 0.022 mol) in dry pyridine (30 cm3) was added toluene-p-sulfonyl chloride (5.5 g 0.029 mol). The resulting mixture was stirred at 90 8C for 6 h and cooled to room temperature overnight. The reaction mixture was then poured onto ice and concentrated hydrochloric acid (6 1). The solid was filtered and recrystallised from methanol to give white needles (5.8 g 78) mp 144–146 8C (Found C 58.2; H 5.4; N 3.95; M1 349.0971.C17H19NO5S requires C 58.45; H 5.5; N 4.0; M 349.0984); nmax(TCE)/ cm21 1660 (C O ester) 1600 (C C); dH 7.8 (3H m aryl) 7.3 (3H m aryl) 6.5 (1H dd aryl) 4.3 (2H q CH2CH3) 3.8 (3H s OCH3) 2.35 (3H s CH3 tosyl) 1.35 (3H t CH2CH3) and 10.95 (1H br exch. NH). Methyl 4-methoxyanthranilate 14 (R1 5 R2 5 H) Method (a). 4-Methoxyanthranilic acid (10 g 60 mmol) was refluxed for 18 h in methanol (80 cm3) containing boron trifluoride–methanol complex (19.6 cm3 180 mmol). The methanol was evaporated in vacuo to yield a dark solid which was treated with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The extracts were dried and evaporated in vacuo to yield a dark oil. Kugelrohr distillation yielded two products the fraction boiling at 100 8C at 0.02 mbar (3.1 g) was identified as m-anisidine by comparison with a genuine sample (IR and NMR spectroscopy bp TLC).The second fraction yielded the title product as a pale yellow oil which slowly solidified on standing (bp 150 8C at 0.02 mmHg 0.56 g 5) mp 73–75 8C (Found C 60.0; H 6.4; N 7.8; M1 181.0726. C9H11NO3 requires C 59.7; H 6.1; N 7.7; M 181.0739); nmax(TCE)/cm21 3490 3380 (NH2) 1680 (C O ester); dH 7.8 (1H d aryl) 6.2 (2H m aryl) 5.8–5.2 (2H br exch. NH2) 3.85 (3H s OMe ester) and 3.8 (3H s OMe aryl). Method (b). 4-Methoxyanthranilic acid (5 g 30 mmol) was refluxed for 24 h with thionyl chloride (15.5 cm3 210 mmol) in dry dichloromethane (30 cm3). The reaction mixture was evaporated in vacuo to yield the intermediate acid chloride as a dark oil. To this oil in dry dichloromethane (20 cm3) was added dry methanol (20 cm3) and the resulting solution stirred for 1 h at room temperature.The solvents were removed in vacuo and the resulting oil treated with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The chloroform extracts were dried and the solvent removed in vacuo to yield a dark solid. Column chromatography yielded the title product as an off-white solid (3.8 g 70) identified by comparison with the product from method (a) above (IR and NMR spectroscopy TLC). Methyl 4-methoxy-N-(p-tolylsulfonyl)anthranilate 14 (R1 5 H R2 5 tosyl) Toluene-p-sulfonyl chloride (14.9 g 78 mmol) was added in portions to a stirred solution of methyl 4-methoxyanthranilate (9.33 g 52 mmol) in dry pyridine (30 cm3). The resulting yellow solution was stirred overnight at room temperature and then poured into ice and concentrated hydrochloric acid (6 1).The resulting white solid was filtered off and recrystallised from methanol to yield the title product as white needles (16.2 g 94) mp 104–105 8C (Found C 57.1; H 5.0; N 4.1; S 9.4; M1 335.0816. C16H17NO5S requires C 57.3; H 5.1; N 4.2; S 9.6; M 335.0827); nmax(TCE)/cm21 1675 (C O ester) 1600 J. Chem. Soc. Perkin Trans. 1 1997 3269 (C C); dH 7.8 (3H m aryl) 7.3 (3H m aryl) 6.55 (1H dd aryl) 3.85 (3H s OMe ester) 3.8 (3H s OMe aryl) 2.35 (3H s CH3 tosyl) and 10.9 (1H br exch. NH). Ethyl 4-N-(2-ethoxycarbonyl-5-methoxyphenyl)-p-tolylsulfonamido butyrate 14 (R1 5 CH2CH2CH2CO2Et R2 5 tosyl CO2- Et for CO2Me) Ethyl 4-methoxy-N-toluene-p-sulfonylanthranilate 14 (R1 = H R2 = tosyl CO2Et for CO2Me) (5 g 0.014 mol) in dry DMF (60 cm3) was added dropwise to a stirred suspension of sodium hydride (60 oil dispersion; 0.616 g 0.016 mol) under nitrogen.This was then stirred for 2 h at room temperature after which ethyl 4-iodobutyrate (4.1 g 0.017 mol) in dry DMF was added dropwise. The reaction mixture was then stirred for 12 h at room temperature after which it was heated to 90 8C for 6 h. The cooled mixture was treated with methanol and poured onto an excess of water. The chloroform extracts were washed with water dried and evaporated in vacuo to yield a pale yellow oil. Chromatography EtOAc–light petroleum (60–80 8C) 3 7 gave an almost clear oil (5.6 g 84) (Found C 60.8; H 6.7; N 3.0; S 7.15; M1 463.1624. C23H29NO7S requires C 59.6; H 6.3; N 3.0; S 6.9; M 463.1665); nmax(film)/cm21 1710 (C O ester) 1600 (C C); dH 7.9 (1H d aryl) 7.6–7.1 (4H m aryl) 6.9 (1H dd aryl) 6.5 (1H d aryl) 4.4–3.95 (4H dq CH2CH3) 3.9–3.5 (5H m OCH3 NCH2) 2.4 (5H m CH3 CH2) 1.9 (2H m CH2) and 1.3 (6H dt CH2CH3).4-Ethoxycarbonyl-2,3,4,5-tetrahydro-8-methoxy-5-oxo-1-(ptolylsulfonyl)- 1H-1-benzazepine 13 (R1 5 tosyl R2 5 CO2Et) To a suspension of sodium hydride (3.3 g 0.07 mol; 50 oil dispersion) in dry DMF (20 cm3) was added dropwise methyl 4-methoxy-N-(p-tolylsulfonyl)anthranilate 14 (R1 = H R2 = tosyl) (19.3 g 0.058 mol) in dry DMF (100 cm3) and the resulting mixture stirred at room temperature for 2 h under nitrogen. To this mixture at room temperature was added dropwise ethyl 4-iodobutyrate (15.5 g 0.064 mol) in dry DMF (20 cm3) and the resulting solution then stirred at 80 8C for 24 h.After cooling at room temperature a further equivalent of sodium hydride was added and after the initial effervescence had subsided the reaction mixture was heated to 80 8C for 2 h. To the cooled (ice) reaction mixture was added water (400 cm3) and 2 M hydrochloric acid (100 cm3). The resulting suspension was poured onto a large excess of water and the solid filtered. Recrystallisation from ethanol gave a solid (17.7 g 74) mp 108–110 8C (Found C 60.0; H 5.5; N 3.3; S 7.8; M1 417.1246. C21H23NO6S requires C 60.4; H 5.5; N 3.4; S 7.7; M 417.1245); nmax(TCE)/cm21 1660 (C O ester) 1600 (C C); dH 7.5–7.3 (3H m aryl) 7.3–7.15 (3H m aryl) 7.15–6.85 (1H dd aryl) 4.3–3.95 (4H m CH2 CH3CH2) 3.85 (3H s OCH3) 2.5–2.2 (5H m CH3 CH2) 1.3 (3H t CH2CH3) and 11.9 (1H d enolic OH).2,3,4,5-Tetrahydro-8-methoxy-5-oxo-1-(p-tolylsulfonyl)-1H-1- benzazepine 13 (R1 5 tosyl R2 5 H) The keto ester 13 (R1 = tosyl R2 = CO2Et) (21.5 g 0.052 mol) glacial acetic acid (130 cm3) concentrated hydrochloric acid (22 cm3) ethanol (45 cm3) and water (22 cm3) were refluxed together for 24 h. The reaction mixture was cooled to room temperature poured onto a large excess of water and extracted with dichloromethane. The extracts were dried and the solvent removed in vacuo to yield a pale brown oil which gave a white solid on trituration with diethyl ether. Recrystallisation from propan-2-ol gave the title compound (12.5 g 70) mp 86–88 8C identical to material obtained as above. 2,3,4,5-Tetrahydro-8-methoxy-5-oxo-1H-1-benzazepine 13 (R1 5 R2 5 H) The tosyl ketone 13 (R1 = tosyl R2 = H) (1.85 g 5.4 mmol) concentrated sulfuric acid (10 cm3) and glacial acetic acid (15 cm3) were stirred together at 80 8C for 2 h.The cooled mixture was poured onto ice basified with powdered sodium hydroxide and extracted with dichloromethane. The extracts were dried and the solvent was removed in vacuo to yield an off-white solid (0.78 g 76). Chromatography (silica gel chloroform) gave the product as a white solid mp 92–95 8C (Found C 68.75; H 6.7; N 7.25; M1 191.0948. C11H13NO2 requires C 69.1; H 6.8; N 7.3; M 191.0946); nmax(TCE)/cm21 3360 (NH amine) 1650 (C O ketone) 1600 (C C); dH 7.75 (1H d aryl) 6.4 (1H dd aryl) 6.2 (1H d aryl) 4.65 (1H br exch. >NH) 3.8 (3H s OCH3) 3.25 (2H t CH2) 2.8 (2H t CH2) and 2.15 (2H q CH2).2,3,4,5-Tetrahydro-8-methoxy-4-hydroxyimino-5-oxo-1-(p-tolylsulfonyl)- 1H-1-benzazepine 17 (R 5 H) To a stirred solution of ketone 4 (R = tosyl X = 8-OMe) (2 g 5.8 mmol) in dry diethyl ether (150 cm3) at room temperature was added dropwise a solution of isoamyl nitrite (1.36 g 11.6 mmol)32,33 in dry diethyl ether (15 cm3) whilst a continuous stream of dry hydrogen chloride gas was passed through the reaction mixture. The yellow reaction mixture was stirred for 1 h during which time a copious precipitate formed. The precipitate was filtered off and was washed with diethyl ether (50 cm3) to give the title compound as a white powder (1.97 g 91) mp 212–214 8C (from ethanol) (Found C 57.9; H 4.7; N 7.2; S 8.55; M1 374.0933. C18H18N2O5S requires C 57.75; H 4.8; N 7.5; S 8.55; M 374.0937); nmax(Nujol)/cm21 3260 (OH oxime) 1700 (C O) and 1620 (C C); dH(DMSO) 12.35 (1H s exch. NOH) 7.7 (1H d aryl) 7.5 (2H d aryl) 7.35 (2H d aryl) 7.1–7.05 (1H dd aryl) 6.7 (1H d aryl) 3.9 (2H t CH2) 3.8 (3H s OCH3) 2.8 (2H t CH2) and 2.4 (3H s CH3 tosyl). 2,3,4,5-Tetrahydro-8-methoxy-4-methoxyimino-5-oxo-1- (p-tolylsulfonyl)-1H-1-benzazepine 17 (R 5 Me) To sodium hydride (0.48 g 12 mmol; 60 dispersion in mineral oil) in dry THF (50 cm3) at 0 8C under nitrogen was added compound 17 (R = H) (3.6 g 9.62 mmol) in portions. The resulting suspension was stirred at room temperature for 1 h and then cooled to 0 8C whereupon a solution of methyl iodide (1.64 g 11.55 mmol) in dry THF (5 cm3) was added dropwise. When the addition was complete the reaction mixture was stirred at room temperature overnight.The solvent was then removed in vacuo and the residue was taken up in ethyl acetate (100 cm3) and washed with water (2 × 100 cm3) and brine then dried and the solvent was removed in vacuo to give a red oil. Flash chromatography (ethyl acetate–hexane 1 1) gave the title compound as an off-white solid (2.73 g 73) mp 144–146 8C (Found C 58.8; H 5.4; N 7.25; S 8.15; M1 388.1086. C19H20N2O5S requires C 58.8; H 5.15; N 7.2; S 8.2; M 388.1093); nmax(Nujol)/cm21 1700 (C O) and 1615 (C C); dH 7.8 (1H d aryl) 7.4 (2H d aryl) 7.2 (2H d aryl) 7.1 (1H d aryl) 6.9 (1H dd aryl) 3.95–3.8 (8H t 1 s CH2 1 2 × OCH3) 2.8–2.7 (2H t CH2) and 2.4 (3H s CH3 tosyl). 5-2-(Ethoxycarbonyl)ethynyl-2,3,4,5-tetrahydro-5-hydroxy-8- methoxy-4-methoxyimino-1-(p-tolylsulfonyl)-1H-1-benzazepine 18 (R 5 C CCO2Et) To ethyl propiolate (0.304 g 3.1 mmol) in dry THF (10 cm3) at 278 8C under nitrogen was added dropwise n-butyllithium (2 cm3 3.1 mmol; 1.6 M solution in hexanes).The resulting mixture was stirred for 30 min whereupon a solution of compound 17 (R = Me) (1.0 g 2.58 mmol) in dry THF (15 cm3) was added dropwise and the mixture was stirred at 278 8C for 1 h. Acetic acid (0.5 cm3) was added and the mixture was slowly allowed to reach room temperature. Diethyl ether (25 cm3) was added and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine then dried and the solvent was removed in vacuo to give a red oil. Flash chromatography (ethyl acetate–hexane 1 1) gave a pale yellow solid which was recrystallised from ethanol to give the title compound as white crystals (1.14 g 91) mp 130–131 8C (Found C 59.15; H 5.4; N 5.6; S 6.75; M1 486.1479.C24H26N2O7S requires C 59.25; H, 3270 J. Chem. Soc. Perkin Trans. 1 1997 5.35; N 5.75; S 6.6; M 486.1461); nmax(Nujol)/cm21 3450 (OH) and 1735 (C O ester); dH 7.85 (1H d aryl) 7.7 (2H d aryl) 7.3 (2H d aryl) 6.9 (1H dd aryl) 6.75 (1H d aryl) 4.3 (1H s exch. OH) 4.25–4.2 (2H q CO2CH2CH3) 3.95 (1H m CH2N) 3.8 (3H s ArOCH3) 3.75 (3H s NOCH3) 3.7– 3.65 (1H m CH2N) 3.3–3.2 (1H m CH2C N) 2.6–2.55 (1H m CH2C N) 2.4 (3H s CH3 tosyl) and 1.3 (3H t CO2- CH2CH3); dC 160.6 (C NOCH3) 155.0 (CO2CH2CH3) 153.4 (ArOCH3 ipso) 143.9 (ArSO2 ipso) 137.9 (aryl) 137.3 (ArCH3 ipso) 130.4 (aryl) 129.7 (2 × aryl) 129.6 (aryl) 128.0 (2 × aryl) 114.5 (2 × aryl) 86.0 (O2CC C) 77.6 ArC(OH)C 72.4 (OCC C) 62.6 ( NOCH3) 62.4 (CO2CH2CH3) 55.7 (ArOCH3) 47.1 (CH2N) 25.5 (CH2CH2N) 21.8 (ArCH3) and 14.2 (CO2CH2CH3).5-2-(Ethoxycarbonyl)ethyl-2,3,4,5-tetrahydro-5-hydroxy-8- methoxy-4-methoxyimino-1-(p-tolylsulfonyl)-1H-1-benzazepine 18 R 5 (CH2)2CO2Et Compound 18 (R = C CCO2Et) (0.5 g 1.03 mmol) acetic acid (4 cm3) and platinum(IV) oxide catalyst (0.1 g) in ethanol (120 cm3) was hydrogenated at an initial hydrogen pressure of 45 psi for 4 days. The catalyst was then removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on alumina (ethyl acetate–hexane 3 7) to give the title compound as a white solid (0.45 g 90) mp 91–92 8C (Found C 58.55; H 6.3; N 5.7; S 6.65; M 1 H1 491. C24H30N2O7S requires C 58.8; H 6.1; N 5.7; S 6.5; M 1 H 491); nmax(Nujol)/cm21 3440 (OH) and 1745 (C O ester); dH 7.85– 7.8 (3H m aryl) 7.35 (2H d aryl) 6.85–6.8 (1H dd aryl) 6.55 (1H d aryl) 4.45 (1H s exch.OH) 4.2–4.15 (1H m CH2N) 4.1-4.0 (2H q CO2CH2CH3) 3.85 (3H s ArOCH3) 3.7 (3H s NOCH3) 3.3–3.2 (1H m CH2C N) 3.15–3.05 (1H m CH2N) 2.8–2.7 (1H m CH2C N) 2.65–2.55 (1H m CH2CO2) 2.5–2.4 (4H s 1 m CH3 tosyl 1 CH2CO2) 2.35–2.2 (2H m CH2) and 1.3–1.2 (3H t CO2CH2CH3); dC 173.9 (CO2CH2CH3) 159.4 (C NOCH3) 158.3 (ArOCH3 ipso) 144.0 (ArSO2 ipso) 139.0 (aryl) 138.4 (ArCH3 ipso) 133.0 (aryl) 130.1 (2 × aryl) 129.0 (aryl) 127.5 (2 × aryl) 113.4 112.7 (aryl) 77.0 ArC(OH)CH2 62.3 ( NOCH3) 60.5 (CO2CH2CH3) 55.5 (ArOCH3) 48.5 (CH2N) 34.6 (CH2CO2) 29.1 (CH2CH2CO2) 25.8 (CH2CH2N) 21.8 (ArCH3) and 14.4 (CO2CH2CH3).Diborane reduction of 5-2-(ethoxycarbonyl)ethyl-2,3,4,5-tetrahydro- 5-hydroxy-8-methoxy-4-methoxyimino-1-(p-tolylsulfonyl)- 1H-1-benzazepine 18 R 5 (CH2)2CO2Et To a cooled (0 8C) solution of the title compound (0.27 g 0.55 mmol) in dry THF (10 cm3) under nitrogen was added dropwise borane–THF complex (2.8 cm3 2.8 mmol; 1.0 M solution in THF). After the initial vigorous effervescence had subsided the clear solution was stirred at room temperature for 12 h. The mixture was then cooled to 0 8C and excess hydride was destroyed by the cautious addition of water (5 cm3). Hydrochloric acid (5 cm3; 5 M) was added and the mixture was heated at reflux for 1 h. The solvent was removed in vacuo and water (15 cm3) was added to the residue which was basified (pH 10) with solid sodium hydroxide.The mixture was extracted with chloroform (4 × 50 cm3) and the combined organic layers were washed with water and brine then dried and the solvent was removed in vacuo to give a clear oil. Flash chromatography (dichloromethane –ethanol–ammonia 40:8:1) gave the product as a white solid (0.202 g 88) mp 182–183 8C. This is formulated as 20a or b Found C 60.0; H 6.2; N 6.5; S 7.65; M1 402.1613. C21H26N2O5S requires C 60.05; H 6.7; N 6.65; S 7.65; M (2 H2O) 402.1613; nmax(Nujol)/cm21 3300–3100 (br OH and NH) and 1610 (C C); dH 7.85 (3H m aryl) 7.4 (2H d aryl) 6.8 (1H dd aryl) 6.4 (1H d aryl) 4.3 (1H dt CH2N) 3.65 (3H s OCH3) 3.6–3.55 (2H t CH2O) 3.1–3.05 (1H m CH2N) 2.75–2.65 (2H m CHNH 1 CH2) 2.5–2.4 (4H s 1 m CH3 tosyl 1 CH2) 2.0 (1H m CH2) 1.9–1.7 (2H br exch.NH 1 OH) 1.6–1.5 (2H m CH2) and 1.3–1.25 (1H m CH2). Not all exchangeable protons could be identified. 4-Acetamido-2,3,4,5-tetrahydro-8-methoxy-5-oxo-1-(p-tolylsulfonyl)- 1H-1-benzazepine 13 (R1 5 tosyl R2 5 NHAc) Oxime 17 (R = H) (3.5 g 9.36 mmol) acetic anhydride (8.5 g 83.33 mmol) and 10 palladium on charcoal catalyst (0.1 g) in dry THF (150 cm3) were hydrogenated at an initial hydrogen pressure of 45 psi overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give an oil. Flash chromatography (ethyl acetate–hexane 9 1) gave a white solid that was recrystallised from ethanol to give the title compound as colourless prisms (2.52 g 67) mp 162–164 8C (Found C 59.45; H 5.7; N 6.85; S 8.2; M1 402.1257. C20H22N2O5S requires C 59.7; H 5.5; N 7.0; S 8.0; M 402.1250); nmax(Nujol)/cm21 3350 (NH amide) 1708 (C O) and 1680 (C O amide); dH 7.85–7.8 (3H m aryl) 7.3–7.25 (3H m aryl) 6.8–6.75 (1H dd aryl) 6.55–6.5 (1H d J 6.2 exch.NHCO) 4.65–4.45 (2H m CHNHCO 1 CH2N) 3.85 (3H s OCH3) 3.4–3.35 (1H m CH2N) 3.0–2.85 (1H m CH2) 2.4 (3H s CH3 tosyl) 2.0 (3H s CH3CO) and 1.7–1.6 (1H m CH2). cis- and trans-4-Acetamido-2,3,4,5-tetrahydro-5-hydroxy-8- methoxy-1-(p-tolylsulfonyl)-1H-1-benzazepine 22 and 21 To compound 13 (R1 = tosyl R2 = NHAc) (1.9 g 4.73 mmol) in ethanol (50 cm3) at room temperature under nitrogen was added sodium borohydride (0.2 g 5.29 mmol) in portions. The