HETEROCYCLES

Paper | Special issue | Vol. 82, No. 1, 2010, pp. 349-370
Received, 19th January, 2010, Accepted, 18th March, 2010, Published online, 19th March, 2010.
DOI: 10.3987/COM-10-S(E)5

■ Synthesis of 1,2,3,4,5,7-Hexahydro-6H-azocino[4,3-b]indol-6-ones as Intermediates for the Synthesis of Apparicine

Jason G. Kettle, David Roberts, and John A. Joule*

The School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.

Abstract

1-Phenylsulfonylindole is converted in eight steps into 2-(2-iodo-(Z)-but-2-en-1-yl)-6-methyl-1,2,3,4-tetrahydroazocino[4,3-b]indole, previously converted in one step into the indole alkaloid apparicine. The syntheses of other hexahydroazocino[4,3-b]indole potential precursors to the alkaloid are also described.

INTRODUCTION
The indole alkaloid apparicine emerged from Carl Djerassi’s onslaught on the structures of alkaloids from South American Aspidosperma species; the paper1 describing its structure determination was already XLVIII in his series ‘Alkaloid Studies’. Apparicine, named for the Brazilian botanist Apparicio Duarte, and first isolated from Aspidosperma dasycarpon, was the first of what is now a substantially sized group of indole alkaloids2 which lack one of the two ethanamine side-chain carbons of biosynthetic precursor tryptophan, having instead only one carbon between indole C-3 and the basic nitrogen, i.e. apparicine has a gramine unit and indeed the well-known reactivity of this moiety was utilized in the structural elucidation.1

This structural parallelism prompted our first approach3 to a synthesis of apparicine since it was known that gramine is formed easily from indole in a Mannich reaction: the piperidinyl-indolyl-ketal 1 was constructed via 2-acylation of the Grignard derivative of 4,5,6,7-tetrahydroindole (a pyrrole in reactivity terms), dehydrogenation to an indole, ketalisation, and reduction of the pyridine ring. Intramolecular Mannich reaction and hydrolysis of the acetal produced tetracycle 2 with the ring skeleton of apparicine.

Our recent investigations relating to apparicine were not published since we were not able to complete the total synthesis, however, in 2009, Bennasar et al. described4 the conversion (Scheme 1) of tricycle 3 into the alkaloid – this key intermediate was one of several with potential for forming the fourth, piperidine ring, that we had prepared. Our method of construction of this key intermediate and other similar compounds is now described in this paper; it is completely different to that of the Spanish group, which was based on ring-closing metathesis to form the eight-membered ring.

RESULTS AND DISCUSSION
Since a ring-closing Mannich process had successfully produced tetracycle 2, we determined to retain this reaction as a key element of a revised strategy in which the goal was to be a 1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one of general form 4. This would have a carbonyl for eventual conversion into exocyclic methylene and a functionalised N-substituent with potential for forming the piperidine ring, by a process that perhaps might also involve the ketone. This type of substance was to be formed via an intramolecular Mannich process but since this requires the absence of the deactivating carbonyl group, a precursor of the general form 5 was required.

In earlier work,5 1-phenylsulfonylindole was lithiated at C-26 and thus reacted with the imide 1-benzoyl-2-pyrrolidone giving ketone 6. Treatment with lithium aluminium hydride produced alcohol-amine 7 which closed very satisfactorily under high dilution conditions to 8, thus establishing the viability of the approach (Scheme 2). However complications7 arose on removal of the N-benzyl group and we sought a variation that would allow us the flexibility to introduce various functionalized N-side-chains to a tricyclic compound.

In our first sequence, the whole of the indol-2-yl side-chain of the Mannich substrate was introduced at once. Reductive amination of crotonaldehyde with 4-aminobutanal diethyl acetal produced amine 9 which was N-formylated (→ 10) before revealing the aldehyde function in 11 using iodotrimethylsilane. Reaction of the aldehyde with lithium 2-lithioindole-1-carboxylate8 produced alcohol 12 requiring only formamide hydrolysis (→ 13) before Mannich ring closure to 14, manganese dioxide oxidation of the indolylic alcohol (→ 15) and N-protection then producing the ketone 16. An alternative route to alcohol 13 is described later.

This approach required a decision as to which N-side-chain to incorporate, at an early stage, so we developed an improvement that allows the side-chain unit to be introduced later in the sequence (Scheme 4). 2-Lithio-1-phenylsulfonylindole was reacted with 1-phenylsulfonyl-2-pyrrolidone 17 generating the key ketone 18. This, with its acidic sulfonamide N-hydrogen, could be simply N-alkylated under mild conditions with a variety of halides, and thus were produced 19, 21, and 23. Each of these was simply and efficiently reduced to the alcohol oxidation level (→ 20, 22, and 24) that was to be needed for the Mannich ring closure.
The removal of phenylsulfonyl N-protection is not always easy and in these intermediates both an indole-N-phenylsulfonyl and an amine-N-phenylsulfonyl needed to be removed prior to Mannich cyclisation. Sodium amalgam proved relatively satisfactory (55%) for the conversion of 20 into the previously prepared butenyl-amine 13. Mg-NH4Cl in methanol9 was an excellent choice for the conversion of 22 into amine 25 and Mannich closure of this gave the corresponding alkynyl-azocino-indole 26 in 95% yield, then oxidised (→ 27) and N-protected forming ketone 28 (Scheme 5). Application of the Mg-NH4Cl-MeOH method to iodo-butenyl alcohol 24 unfortunately removed the iodine as well as the phenylsulfonyl groups producing only butenyl-amine 13, once again.

Our attention now turned to the missing carbon of the apparicine skeleton – that which is an exocyclic methylene in the alkaloid. Methyl Grignard addition to the still-protected ketones 19 and 21 proceeded unexceptionally (→ 29, 32), and after removal of the phenylsulfonyl groups, both of the resulting alcohols 30 and 33, took part in Mannich ring closures very efficiently giving 31 and 34 respectively (Scheme 6).

It remained to produce an azocino-indole with an iodo-butenyl side-chain (Scheme 7). To this end, we developed two variants: the alkynyl-alcohol 33 was hydrostannylated giving 35. Although there are no examples of hydrostannation of propargylamines, we predicted the regiochemistry and stereochemistry of the hydrostannation based on analogy with the comparable reactions of propargylic alcohols, such as but-2-ynol, in which the tin attaches to C-2 giving a (Z)-vinylstannane.10 Stannane 35 was then reacted with iodine, the ipso displacement of tin in a vinylstannane with iodine with retention of configuration being a well-recognised conversion.10,11 This introduction of iodine was not a clean reaction in the sense that two products were formed, the desired 36a and a product 36b in which iodination at the indole 3-position had also taken place. Intriguingly, both of these underwent Mannich cyclisation to 37. Dehydration of this alcohol produced 3, the intermediate which, it was ultimately shown,4 could be converted in one step into apparicine. The identity of this compound with that produced by the Spanish route also confirms the regio- and stereochemistry of the hydrostannation. Alternatively, the alkynyl-azocino-indole 34 could be hydrostannylated (→ 38) then converted into iodide 37.
In conclusion, we have described an efficient route to variously N-substituted 1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ones, utilizing a high-dilution intramolecular Mannich reaction to form the eight-membered ring; one of these can be converted into apparicine in one step.4 The precursors for the cyclisation were prepared via the use of 1-phenylsulfonyl-2-pyrrolidone in reaction with 2-lithio-1-phenylsulfonylindole: this, by selective reaction at the ring carbonyl then ring opening, generated an indol-2-yl 3-(phenylsulfonylamido)propyl ketone, the acidic N-hydrogen in which was then used for N-alkylations. This is the first time that 1-phenylsulfonyl-2-pyrrolidone has been used in this way and seems to offer an efficient general route to ketones of the type R1C(O)(CH2)3NHR2.

EXPERIMENTAL
General
Flash column chromatography was performed using Merck Kieselgel 60 (230-400 mesh) silica. Tetrahydrofuran (THF) was dried by distillation from sodium-benzophenone; toluene (toluene) and dichloromethane were dried by distillation from calcium hydride; dimethylformamide was dried over 4 Å molecular sieves; organic extracts were dried over anhydrous MgSO4. Solutions of n- and t-butyllithium and methylmagnesium chloride were purchased from the Aldrich chemical company and used without titration. UV spectra were recorded on a Shimadzu-260 UV-VIS recording spectrophotometer at fast scan speed, path length 1 cm in EtOH solution. IR spectra were recorded on a Perkin-Elmer 1710 Infra Red Fourier transform spectrometer as films. 1H NMR spectra were recorded on a Varian AC 300E NMR spectrometer operating at 300 MHz or a Varian Gemini 200 spectrometer operating at 200 MHz. Chemical shifts are reported in parts per million downfield from tetramethylsilane. Peak multiplicities are denoted by s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet) and m (multiplet) or by a combination of these e.g. dd (double doublet). 13C NMR spectra were recorded on a Varian AC 300E NMR spectrometer at 75 MHz. Mass spectra were recorded on a Kratos MS 25 spectrometer. The modes of ionisation used are indicated as follows: electron impact (EI), chemical ionisation (CI) and fast atom bombardment (FAB). Accurate mass measurements were recorded on a Kratos concept. All reactions were carried out under a dry atmosphere of nitrogen or argon unless otherwise stated.

4-(N-(E-but-2-en-1-yl)amino)butanal diethyl acetal 9. 4-Aminobutanal diethyl acetal (10.0 mL, 11.6 mmol) and but-2-enal (10.0 mL, 24.4 mmol) were stirred in EtOH (150 mL) at 0 °C for 3 h. The reaction mixture was concentrated in vacuo then EtOH (100 mL) added. The solution was cooled to 0 °C and NaBH4 (1.0 g, 23.3 mmol) added slowly. The mixture was allowed to come to rt and after 3 h, H2O (50 mL) was added and the organic solvent evaporated. The product was extracted with Et2O, the extract dried filtered and concentrated leaving the amine 9 as a yellow oil (12.4 g, 100%), showing a single spot on tlc (toluene:EtOAc, 1:1 plus 1% Et3N) and used as such for the next step, νmax 3312, 2974, 2931, 1673 cm–1, δH (CDCl3, 200 MHz) 5.53 (2H, m, NCH=CH), 4.46 (1H, t, J = 5 Hz, OCHO), 3.53 (4H, m, 2xOCH2), 3.12 (2H, d, J = 5 Hz, NCH2C=C), 2.57 (2H, m, CH2CH2N), 1.64 (3H, d, J = 5 Hz, CH3C=C), 1.57 (4H, m, CHCH2CH2), 1.17 (6H, t, J = 6.5 Hz, 2xCH3); m/z (CI) 216 (MH+, 39%), 186 (9), 170 (17), 124 (19), 84 (20); C12H25NO2 requires 215.1885. Found 215.1884.

4-(N-(E-but-2-en-1-yl)formamido)butanal diethyl acetal 10. To a stirred solution of acetic formic anhydride (1.4 g, 16.0 mmol) in dry THF (20 mL) at –70 °C was added 4-(N-(E-but-2-en-1- ylamino)butanal diethyl acetal 9 (2.87 g, 13.0 mmol) in THF (5 mL). The mixture was allowed to reach rt then stirred for 18 h. After concentration in vacuo, the residue was partitioned between Et2O (20 mL) and H2O (20 mL), the layers separated and the aqueous layer re-extracted with Et2O (2x20 mL). The combined organic extracts were dried, filtered and evaporated leaving a red oil which was purified by chromatography over silica (toluene:EtOAc, 1:1) giving the formamide 10 as an orange oil (2.82 g, 87%), νmax 2973, 1669 cm–1; δH (CDCl3, 200 MHz) 8.05 (1H, s, CH=O), 5.65 (1H, m, HC=C), 5.33 (1H, m, C=CH), 4.48 (1H, m, OCHO), 3.87 (1H, d, J = 6 Hz, one of NCH2C=C), 3.75 (1H, d, J = 6 Hz, one of NCH2C=C), 3.54 (4H, m, 2xCH2CH3), 3.25 (2H, m, CH2CH2N), 1.71 (2H, m, two of CH2CH2), 1.58 (11H, m, two of CH2CH2 plus 3xCH3); m/z (FAB) 243 (M+, 3%), 198 (100), 144 (15), 98 (40); C13H25NO3 –C2H5OH requires 198.1480. Found 198.1494.

4-(N-(E-But-2-en-1-yl)formamido)butanal 11. To a stirred solution of 4-(N-(E-but-2-en-1-yl)- formamido)butanal diethyl acetal 10 (9.37 g, 39.0 mmol) in dry CH2Cl2 (100 mL) at rt was added iodotrimethylsilane (6.44 mL, 43.0 mmol) dropwise to give a deep red solution. Stirring was continued for 30 min, the reaction mixture washed with aq Na2S2O3 (100 mL, 1M) and dried. Concentration gave an orange oil which was purified by chromatography over silica (toluene:EtOAc, 1:1) to give the aldehyde 11 as an orange oil (4.45 g, 68%), νmax 2937, 1722, 1668 cm–1; δH (CDCl3, 200 MHz) 9.80 (1H, m, CH2CH=O), 8.05 (1H, s, NCH=O), 5.66 (1H, m, HC=C), 5.36 (1H, m, C=CH), 3.85 (1H, d, J = 6 Hz, one of NCH2C=C), 3.75 (1H, d, J = 6 Hz, one of NCH2C=C), 3.27 (1H, t, J = 6 Hz, one of NCH2CH2), 3.24 (1H, t, J = 6 Hz, one of NCH2CH2), 2.50 (2H, m, CH2C=O), 1.86 (2H, m, CH2CH2CH2), 1.75 (3H, d, J = 6 Hz, CH3); m/z (CI) 170 (MH+, 100%); C9H15NO2 requires 169.1103. Found 169.1104.

4-(N-(E-But-2-en-1-yl)formamido)-1-(indol-2-yl)butan-1-ol 12. To a stirred solution of indole (0.41 g, 3.5 mmol) in dry THF (10 mL) at –70 °C was added n-butyllithium (1.6 M solution in hexane, 2.39 mL, 3.8 mmol). The resulting suspension was held at –70 °C for 30 minutes, then CO2 bubbled through to give a colourless solution, which was stirred for a further 10 min. The solvent was removed in vacuo (< 10 °C) to give a white crystalline solid that was redissolved in THF (10 mL). The solution was recooled to –70 °C and t-butyllithium (1.7 M solution in pentane, 5.77 mL, 3.8 mmol) added slowly to give a bright yellow solution which was stirred for 1 h at –70 °C. A solution of 4-(N-(E-but-2-en-1-yl)- formamido)butanal 11 (0.59 g, 3.5 mmol) in THF (5 mL) was added dropwise, the reaction mixture stirred for a further hour at –70 °C and subsequently allowed to warm to rt. The solution was poured into saturated aq NH4Cl (30 mL), and extracted into Et2O (2 x 20 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography (EtOAc) to give the alcohol 12 as an orange oil (0.34 g, 34%), λmax (log εmax) 220 (4.14), 271 (3.75), 279 (3.74), 2.88 (3.63); νmax 3298, 2934, 1654 cm–1; δH (CDCl3, 300 MHz) 8.82 (1H, bs, indol-1-yl-H), 8.00 (1H, s, CH=O), 7.56 (1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.15 (2H, m, ArH), 6.33 (1H, s, indol-3-yl-H), 5.62 (1H, m, HC=C), 5.36 (1H, m, C=CH), 4.92 (1H, t, J = 7 Hz, CHOH), 3.83 (1H, d, J = 7 Hz, one of NCH2C=C), 3.66 (1H, d, J = 7 Hz, one of NCH2C=C), 3.34 (1H, t, J = 7 Hz, one of NCH2CH2), 3.14 (1H, t, J = 7 Hz, one of NCH2CH2), 1.86 (2H, quint, J = 7 Hz, CH2CH2CH2), 1.67 (5H, m+d, NCH2CH2CH2 plus C=CCH3); m/z (CI) 286 (M+, 6%), 269 (78), 170 (53), 158 (23), 146 (27), 118 (60), 102 (48), 100 (61), 84 (33). Further elution (EtOH:Et3N, 99:1) gave amine 13 (0.112 g, 12%) (see below for characterisation).

4-(E-But-2-en-1-ylamino)-1-(indol-2-yl)butan-1-ol 13. Method (a): 4-(N-(E-But-2-en-1-yl)formamido)- 1-(indol-2-yl)butan-1-ol 12 (0.28 g, 1.0 mmol) and potassium hydroxide (1 g) were heated at reflux in ethanol (15 mL) for 2 h. The reaction mixture was poured into water (50 mL) and product extracted into EtOAc (2 x 30 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography (EtOH:Et3N, 99:1) to give the amine 13 as waxy solid (0.15 g, 60%), λmax (log εmax) 218 (4.07), 271 (3.78), 280 (3.78), 288 (3.68); νmax 3500, 3285, 2935 cm–1; δH (CDCl3, 200 MHz) 8.87 (1H, bs, indol-1-yl-H), 7.58 (1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.16 (1H, apparent t, J = 7.5 Hz, ArH), 7.10 (1H, apparent t, J = 7.5 Hz, ArH), 6.27 (1H, s, indol-3-yl-H), 5.61 (2H, m, HC=CH), 4.96 (1H, dd, J = 7.5, 2.3, Hz, CHOH), 4.22 (2H, bs, OH plus NH), 3.20 (2H, d, J = 7.5 Hz, NCH2C=C), 2.76 (1H, m, one of NCH2CH2), 2.63 (1H, m, one of NCH2CH2), 2.18 (1H, m, one of CH2CH2CH2), 2.03 (1H, m, one of CH2CH2CH2), 1.88 (1H, m, one of CH2CH2CH2), 1.74 (4H, d+m, one of CH2CH2CH2 plus CH3); m/z (CI) 259 (MH+, 100%), 241 (80); C16H22N2O requires 258.1732. Found 258.1729.
Method (b): To a stirred solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonyl-
indol-2-yl)butan-1-ol 20 (1.0 g, 1.9 mmol) and Na2HPO4 (2.6 g, 7.0 mmol) in dry MeOH (50 mL) at rt was added 6% sodium amalgam (10 g) gradually. Stirring was continued for 5 h, then the solution decanted from the residues, concentrated and partitioned between water (50 mL) and CH2Cl2 (50 mL). The aqueous layer was washed with CH2Cl2 (2 x 30 mL) and the combined organic extracts dried. Concentration gave a brown oil which was purified by chromatography (toluene:EtOAc:EtOH, 1:1:1) to give the amine 13 as a colourless waxy solid (0.266 g, 55%).

2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 14. Formalin (1.75 mL, 40%) and AcOH (1.75 mL) were added to a stirred solution of 4-(E-but-2-en-1-ylamino)-1- (indol-2-yl)butan-1-ol 13 (0.16 g, 0.6 mmol) in glyme (75 mL). After 30 min at rt the solution was concentrated in vacuo to ~3 mL then aq NaOH (10 mL, 3M) and Et2O (10 mL) were added and the layers separated. The aqueous phase was extracted twice more with Et2O, the combined extracts dried, filtered and evaporated leaving an oil (0.185 g) which was purified by chromatography over silica (toluene:EtOAc, 1:1 plus 1% Et3N) giving the tricycle 14 as an orange oil (56 mg, 33%), λmax (log εmax) 223 (4.02), 274 (3.90), 281 (3.92), 289 (3.89); νmax 3398, 3222, 2918, 2854 cm–1; δH (CDCl3+D2O, 300 MHz) 7.54 (1H, d, J = 8.3 Hz, ArH), 7.35 (1H, d, J = 8.3 Hz, ArH), 7.20 (1H, t, J = 8.3 Hz, ArH), 7.13 (1H, t, J = 9 Hz, ArH), 5.70 (2H, m, CH=CH), 4.90 (1H, t, J = 3.8 Hz, CHO), 4.20 (1H, d, J = 15.8 Hz, one of ArCH2N), 3.16 (1H, d, J = 15.6 Hz, one of ArCH2N), 3.38 (1H, m, one of NCH2C=C), 3.27 (1H, m, one of NCH2C=C), 2.90 (1H, m, one of CH2CH2N), 2.59 (1H, m, one of CH2CH2N), 2.07 (1H, m, one of CH2CH2), 1.94 (2H, m, two of CH2CH2), 1.75 (4H, d+m, J = 7.5 Hz, one of CH2CH2 plus CH3); m/z (CI) 271 (MH+, 100%), 253 (38), 173 (33), 84 (30), 70 (25), 70 (25); C17H22N2O requires 270.1732. Found 270.1729.

2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 15. To a stirred solution of 2-(E-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 14 (0.47 g, 1.7 mmol) in CH2Cl2 (100 mL) at rt was added MnO2 (1.5 g). The resulting suspension was stirred for 72 h and then the solid filtered off and washed with CH2Cl2. Concentration of the solution gave a brown solid which was purified by chromatography (EtOAc:EtOH, 9:1). This gave the ketone 15 as a white crystalline solid (0.235 g, 51%), mp 139-141 °C, λmax (log εmax) 206 (4.26), 225 (3.98), 313 (4.12); νmax 3329, 2918, 2812, 1629 cm–1; δH (CDCl3, 300 MHz) 9.10 (1H, bs, indol-1-yl-H), 7.67 (1H, d, J = 8.0 Hz, ArH), 7.40 (1H, d, J = 8 Hz, ArH), 7.38 (1H, t, J = 8 Hz, ArH), 7.19 (1H, t, J = 8.0 Hz, ArH), 5.54 (2H, bs, HC=CH), 4.45 (2H, bs, indol-3-ylCH2N), 3.08 (4H, m, NCH2C=C plus NCH2CH2), 2.65 (2H, m, CH2C=O), 2.10 (2H, m, NCH2CH2CH2), 1.71 (3H, d, J = 7.5 Hz, CH3); m/z (EI) 268 (M+, 100%), 213 (38), 185 (33), 170 (15), 157 (76), 143 (24), 129 (100), 110 (40), 84 (55); C17H20N2O requires C, 76.1; H, 7.5; N, 10.4%. Found C, 76.4; H, 7.6; N, 10.4%.

2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-7-phenylsulfonyl-6H-azocino[4,3-b]indol-6-one 16. To a stirred solution of 2-(E-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 15 (0.88 g, 3.3 mmol) in dry DMF (50 mL) at rt was added NaH (60% dispersion in mineral oil, 0.144 g, 3.6 mmol). The solution was stirred until the evolution of H2 had ceased (ca. 1 h), then PhSO2Cl (0.46 mL, 3.6 mmol) was added dropwise. Stirring continued for a further 1 h and then the reaction mixture was poured into water (100 mL) and product extracted into CH2Cl2 (2 x 40 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography using (toluene:EtOAc, 99:1) to give N-phenylsulfonyl-ketone 16 as a yellow oil (0.9 g, 67%), λmax (log εmax) 220 (4.26); νmax 2932, 1688 cm–1; δH (CDCl3, 300 MHz) 8.16 (2H, d, J = 8.0 Hz, ArH), 7.98 (1H, d, J = 8.0 Hz, indol-7-yl-H), 7.60-7.28 (6H, m, ArH), 5.50 (2H, m, HC=CH), 3.72 (2H, s, indol-3-ylCH2N), 3.13 (2H, d, J = 5.5 Hz, NCH2C=C), 2.74 (4H, m, CH2CH2CH2), 2.00 (2H, m, CH2CH2CH2), 1.65 (3H, d, J = 5.5 Hz, CH3); m/z (CI) 409 (MH+, 100%), 269 (36), 267 (40), 160 (23), 94 (31); C23H25N2O3S requires 409.1586. Found 409.1577.

1-Phenylsulfonyl-2-pyrrolidone 17. Method (a). To a stirred solution of 2-pyrrolidone (20.0 g, 0.24 mol), n-Bu4NHSO4 (0.5 g, 1.5 mmol) and powdered NaOH (20.0 g, 0.5 mol) in dry CH2Cl2 (1 L) at 0 °C was added PhSO2Cl (33 mL, 45.3 g, 0.26 mol). The suspension was stirred for 18 h then poured into water (1 L). The organic layer was separated and the aqueous layer washed with CH2Cl2 (2 x 200 mL). The combined organic extracts were dried then concentration gave an orange oil which yielded the sulfonamide 17 as a white crystalline solid upon trituration with ethanol (11.90 g, 22%, mp 79-81 °C), νmax 2985, 1739 cm–1; δH (CDCl3, 200 MHz) 8.02 (2H, d, J = 8 Hz, H-2',6'), 7.70-7.48 (3H, m, H-3',4',5'), 3.93 (2H, t, J = 8 Hz, NCH2), 2.12 (2H, t, J = 8 Hz, CH2C=O), 2.03 (2H, quint, J = 8 Hz, CH2CH2CH2); m/z (EI) 226 (MH+, 18%), 161 (100), 141 (20), 106 (72), 77 (90); C10H12NO3S requires 226.0538; Found 226.0529.
Method (b). To a stirred solution of 2-pyrrolidone (5 g, 6 mmol) in THF (150 mL) NaH (2.6 g, 60% dispersion in mineral oil, 6.6 mmol) was added carefully. The solution was stirred until the evolution of hydrogen had ceased (ca. 1 h), then PhSO2Cl (8.25 mL, 6.6 mmol) was added dropwise. Stirring was continued for a further 1 h then the reaction mixture was poured into water (200 mL) and product extracted into CH2Cl2 (2 x 100 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography (toluene:EtOAc, 9:1) giving the sulfonamide 17 as white needles (5.42 g, 41%). All spectra as in Method (a).

4-Phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18. To a stirred solution of 1-phenylsulfonylindole (20.0 g, 78.0 mmol) in dry THF (2 L) at –70 °C was added n-BuLi (1.6 M solution in hexane, 53.5 mL, 86.0 mmol) dropwise. The reaction mixture was allowed to rise to 0 °C over 30 min to give a deep orange solution which was then recooled to –70 °C. 1-Phenylsulfonyl-2-pyrrolidone 17 (17.5 g, 78.0 mmol) in THF (100 mL) was added dropwise and the solution allowed to rise to rt. Water (50 mL) was added and the reaction mixture concentrated in vacuo to ca. 50 mL. The solution was poured into saturated aq NH4Cl (150 mL), and extracted into Et2O (2 x 100 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography using (toluene:EtOAc, 19:1→4:1) to give the ketone 18 as a pale brown crystalline solid (17.32 g, 46%), then triturated with EtOH, mp 111-113 °C; λmax (log εmax) 216 (5.26), 273 (5.11), 281 (5.11); νmax 3291, 2936, 1690 cm–1; δH (CDCl3, 200 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.92 (2H, d, J = 7.5 Hz, ArH) 7.60-7.20 (11H, m, ArH), 7.09 (1H, s, indol-3-yl-H), 4.82 (1H, bs, NH), 3.10 (4H, m, CH2CH2CH2), 2.00 (2H, quint, J = 7.5 Hz, CH2CH2CH2); δC (CDCl3, 75 MHz) 194.1 (s), 139.9 (s), 139.3 (s), 138.5 (s), 137.9 (s), 134.0 (d), 132.6 (d), 129.1 (d), 129.0 (d), 128.5 (s), 127.6 (d), 127.3 (d), 127.0 (d), 124.5 (d), 123.0 (d), 117.0 (d), 115.6 (d), 42.4 (t), 39.1 (t), 24.1 (t); m/z (CI) 500 (MNH4+, 100%), 483 (MH+, 4), 360 (87), 343 (38), 327 (36), 243 (53), 185 (42), 160 (71); C24H22N2O5S2 + NH4 requires 500.1314. Found 500.1311.

4-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 19. To a stirred solution of 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (1.94 g, 4.0 mmol) in dry DMF (100 mL) at rt was added NaH (60% dispersion in mineral oil, 0.161 g, 4.0 mmol). The solution was stirred until the evolution of H2 had ceased (ca. 1 h) then crotyl bromide (0.5 mL, 4.0 mmol) was added dropwise. Stirring continued for a further 1 h and then the reaction mixture was poured into water (100 mL) and extracted into CH2Cl2 (2 x 40 mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography (toluene:EtOAc, 99:1) to give the ketone 19 as a white crystalline solid (1.72 g, 80%) mp 95-97 °C; λmax (log εmax) 207 (4.29), 273 (4.12), 281 (4.11); νmax 2936, 1690 cm–1; δH (CDCl3, 300 MHz) 8.10 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.95 (2H, d, J = 7.5 Hz, ArH), 7.80 (2H, d, J=7.5 Hz, ArH), 7.60-7.27 (9H, m, ArH), 7.15 (1H, s, indol-3-yl-H), 5.61 (1H, m, HC=C), 5.23 (1H, m, C=CH), 3.79 (2H, d, J = 6.0 Hz, NCH2C=C), 3.25 (2H, t, J = 6.0 Hz, NCH2CH2), 3.03 (2H, t, J = 6 Hz, CH2C=O), 2.00 (2H, quint, J = 6 Hz, CH2CH2CH2), 1.60 (3H, s, CH3); m/z (CI) 554 (MNH4+, 100%), 537 (MH+, 12%), 414 (37), 257 (17), 177 (38), 160 (44); C28H28N2O5S2 requires C, 62.7; H, 5.2; N, 5.3; S, 11.9%. Found C, 62.9; H, 5.2; N, 5.3; S, 12.2%.

4-((N-But-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21. In a similar manner, 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (9.68 g, 20.0 mmol), NaH (60% dispersion in mineral oil, 0.8 g, 20.0 mmol) and bromobut-2-yne (2.57 g, 20.0 mmol) in DMF (500 mL) afforded a brown oil which was purified by chromatography (toluene:EtOAc, 99:1) to give ketone 21 as a white crystalline solid (10.72 g, 100%) mp 121-123 °C; λmax (log εmax) 217 (4.67), 285 (4.36); νmax 3066, 2921, 1691 cm–1; δH (CDCl3, 300 MHz) 8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 8.03 (2H, d, J = 7.5 Hz, ArH), 7.88 (2H, d, J = 7.5 Hz, ArH), 7.66-7.34 (9H, m, ArH), 7.18 (1H, s, indol-3-yl-H), 4.12 (2H, q, J = 1.5 Hz, ΝCH2C≡C), 3.34 (2H, t, J = 7.5 Hz, NCH2CH2), 3.12 (2H, t, J = 7.5 Hz, CH2C=O), 2.10 (2H, quint, J = 7.5 Hz, CH2CH2CH2), 1.58 (3H, t, J = 1.5 Hz, CH3); δC (CDCl3, 75 MHz) 194.0 (s), 139.4 (s), 138.9 (s), 138.6 (s), 138.3 (s), 133.8 (d), 132.6 (d), 120.1 (s), 128.9 (s), 128.7 (s), 128.5 (d), 127.8 (d), 127.5 (d), 127.4 (d), 124.4 (d), 122.9 (d), 116.8 (d), 115.5 (d), 81.9 (s), 71.5 (s), 45.6 (t), 39.1 (t), 36.9 (t), 21.8 (t), 3.3 (q); m/z (CI) 535 (MH+, 40%), 395 (42), 160 (100); C28H27N2O5S2 requires 535.1361. Found 535.1366.

4-(N-(2-Iodo-Z-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 23. In a similar manner, 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (12.0 g, 25.0 mmol), NaH (60% dispersion in mineral oil, 1.0 g, 27.0 mmol) and 1-bromo-2-iodo-Z-but-2-ene (6.5 g, 25.0 mmol) in DMF (500 mL) afforded a brown oil which was purified using chromatography (toluene:EtOAc, 99:1) to give the ketone 23 as a white crystalline solid (8.0 g, 49%) mp 131-132 °C, λmax (log εmax) 219 (5.03), 271 (4.56), 284 (4.57); νmax 3063, 2928, 2875, 1690 cm–1; δH (CDCl3, 300 MHz) 8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 8.00 (2H, d, J = 7.5 Hz, ArH), 7.86 (2H, d, J = 7.5 Hz, ArH), 7.64-7.31 (9H, m, ArH), 7.14 (1H, s, indol-3-yl-H), 5.96 (1H, q, J = 6.8 Hz, C=CH), 4.15 (2H, s, NCH2C=C), 3.33 (2H, t, J = 7.5 Hz, NCH2CH2), 3.04 (2H, t, J = 7.5 Hz, CH2C=O), 2.02 (2H, quint, J = 7.5 Hz, CH2CH2CH2), 1.76 (3H, d, J = 6.8 Hz, CH3); m/z (CI) 680 (MNH4+, 18%), 497 (22), 177 (23), 160 (100); C28H27IN2O5S2 + NH4 requires 680.0750; Found 680.0781.

4-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 20. To a stirred solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 19 (0.115 g, 0.2 mmol) in absolute ethanol (10 mL) at rt was added sodium borohydride (20 mg, 0.4 mmol). The solution was stirred for 3 h, water (2 mL) added, and stirring continued for a further 2 h. The solvent was removed in vacuo and the residue partitioned between water (10 mL) and CH2Cl2 (10 mL). The aqueous phase was re-extracted with CH2Cl2 (2 x 20 mL) and the combined organic extracts dried. Concentration gave an orange oil which was purified by chromatography (toluene:EtOAc, 85:15) to give the alcohol 20 as a colourless oil (0.105 g, 91%), λmax (log εmax) 204 (4.74), 255 (4.60); νmax 3509, 2921 cm–1; δH (CDCl3, 300 MHz) 8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.81 (4H, m, ArH), 7.58-7.17 (9H, m, ArH), 6.69 (1H, s, indol-3-yl-H), 5.60 (1H, m, HC=C), 5.22 (2H, m, C=CH plus CHOH), 3.78 (2H, d, J = 6 Hz, NCH2C=C), 3.23 (2H, t, J = 7 Hz, NCH2CH2), 2.05-1.70 (4H, m, NCH2CH2CH2), 1.60 (3H, d, J = 6 Hz, CH3); m/z (CI) 538 (M+, 6%), 521 (27), 399 (47), 160 (100); C28H30N2O5S2 + NH4 requires 556.1940. Found 556.1954.

4-(N-(But-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 22. In a similar manner, 4-([N-but-2-ynyl]phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21 (3.28 g, 6.1 mmol) and sodium borohydride (0.57 g, 14.0 mmol) in ethanol (200 mL) afforded a yellow oil which was purified by chromatography (toluene:EtOAc, 85:15) to give the alcohol 22 as a white crystalline solid (2.49 g, 76%) mp 131.5-133 °C, λmax (log εmax) 210 (5.59), 244 (4.91); νmax 3529, 3067, 2921, 2871, 2226 cm–1; δH (CDCl3, 300 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.90 (2H, d, J = 7.5 Hz, ArH), 7.84 (2H, d, J = 7.5 Hz, ArH), 7.60-7.25 (9H, m, ArH), 6.73 (1H, s, indol-3-yl-H), 5.30 (1H, m, CHOH), 4.13 (2H, s, NCH2C≡C), 3.37 (2H, m, NCH2CH2), 2.12 (2H, m, CH2CHOH), 1.90 (2H, m, CH2CH2CH2), 1.55 (3H, s, CH3); m/z (CI) 554 (MNH4+, 2%), 536 (M+, 1%), 519 (5), 239 (15), 160 (100), 118 (27); C28H28N2O5S2 requires C, 62.7; H, 5.2; N, 5.2; S, 11.9%. Found C, 62.5; H, 5.3; N, 5.3; S, 12.2%.

4-(N-(2-Iodo-(Z)-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 24. In a similar manner, 4-(N-(2-Iodo-(Z-)-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)- butan-1-one 23 (8.0 g, 12.0 mmol) and sodium borohydride (1.0 g, 27.0 mmol) in ethanol (500 mL) afforded a yellow oil which was purified by chromatography (toluene:EtOAc, 85:15) to give the alcohol 24 as a colourless oil (4.55 g, 57%), λmax (log εmax) 216 (5.18), 248 (4.70), 290sh (4.07); νmax 3528, 2924 cm–1; δH (CDCl3, 300 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.86 (2H, d, J = 7.5 Hz, ArH), 7.83 (2H, d, J = 7.5 Hz, ArH), 7.61-7.19 (9H, m, ArH), 6.70 (1H, s, indol-3-yl-H), 5.95 (1H, q, J = 7.5 Hz, C=CH), 5.68 (1H, m, CHOH), 4.13 (2H, s, NCH2C=C), 3.34 (2H, t, J = 7.5 Hz, NCH2CH2), 2.00 (2H, m, NCH2CH2CH2), 1.78 (5H, d+m, CH2CH2CH2 plus CH3); m/z (CI) 664 (M+, 30%), 647 (20), 497 (32), 469 (22), 371 (19), 355 (35), 160 (100); C28H29IN2O5S2 + NH4 requires 682.0892. Found 682.0892.

4-(But-2-ynylamino)-1-(indol-2-yl)butan-1-ol 25. Method A. To a stirred solution of 4-(N-(but-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 23 (0.42 g, 0.8 mmol), Na2HPO4 (0.433 g, 3.0 mmol) in dry MeOH (50 mL), 6% sodium amalgam (10 g) was added gradually. After 5 h stirring, the solution was decanted off, solvent evaporated and the residue partitioned between water (40 mL) and CH2Cl2 (40 mL). The dried organic extract was evaporated and the residue purified by chromatography giving the alcohol 25 as a white crystalline solid (0.158 g, 75%), mp 94-95 °C, λmax (log εmax) 218 (4.62), 265 (4.00), 280 (3.97), 288 (3.87); νmax 3287, 2918, 2855 cm–1; δH (CDCl3, 300 MHz) 8.83 (1H, bs, indol-1-yl-H), 7.60 (1H, d, J = 7.5 Hz, ArH), 7.40 (1H, d, J = 7.5 Hz, ArH), 7.19 (1H, t, J = 7.5 Hz, ArH), 7.13 (1H, t, J = 7.5 Hz, ArH), 6.29 (1H, s, indol-3-yl-H), 4.98 (1H, m, CHOH), 4.19 (2H, bs, OH plus NH), 3.40 (2H, m, NCH2C≡C), 2.90 (1H, m, one of NCH2CH2), 2.73 (1H, m, one of NCH2CH2), 2.17 (1H, m, one of NCH2CH2CH2), 2.07 (1H, m, one of NCH2CH2CH2), 1.88 (4H, m+s, one of NCH2CH2CH2 plus CH3), 1.75 (1H, m, one of NCH2CH2CH2); m/z (CI) 257 (MH+, 70%), 239 (100%). (MM 257.1654. C16H21N2O requires 257.1654).
Method B. A suspension of magnesium (10 g, 0.42 mol) and ammonium chloride (0.19 mol) in dry MeOH (500 mL) containing 4-(N-(but-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)- butan-1-ol 22 (5.41 g, 10.0 mmol) was vigourously stirred for 2 h, then water (100 mL) added and the reaction mixture concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with water (50 mL) and dried. Concentration gave a pale brown crystalline solid that was purified by chromatography to give the alcohol 25 as a white crystalline solid (2.63 g, 98%). All spectra were identical to those given above.

2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 26. To a stirred solution of 4-(but-2-ynylamino)-1-(indol-2-yl)butan-1-ol 25 (0.73 g, 2.9 mmol) in 1,2-dimethoxyethane (1 L) at rt was added formalin (8 mL, 40%) and AcOH (8 mL). After 30 min the solution was concentrated in vacuo to ca. 5 mL and aqueous NaOH (20 mL) and Et2O (20 mL) were added. The aqueous phase was re-extracted with Et2O (2 x 20 mL) and the combined organic extracts dried. Concentration gave a brown oil which was purified by chromatography (toluene:EtOAc:EtOH. 2:2:1). This gave the azocino-indole 26 as a colourless oil (0.76 g, 95%), λmax (log εmax) 223 (4.56), 274 (4.35), 288sh (4.24); νmax 3396, 3225, 3056, 2918 cm–1; δH (CDCl3, 300 MHz) 8.28 (1H, bs, indol-1-yl-H), 7.51 (1H, d, J = 7.5 Hz, ArH), 7.35-7.12 (3H, m, ArH), 4.90 (1H, m, CHOH), 4.16 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.90 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.60 (2H, m, NCH2C≡C), 2.82 (2H, t, J = 6 Hz, NCH2CH2), 2.10-1.75 (4H, m, NCH2CH2CH2), 1.90 (3H, t, J = 1.8 Hz, CH3); m/z (CI) 269 (MH+, 100%), 196 (12); C17H20N2O requires 268.1576; Found 268.1582.

2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 27. A mixture of 2-(but-2-ynyl)- 1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 26 (0.77 g, 2.9 mmol) and manganese dioxide (2.5 g) was stirred in CH2Cl2 (50 mL) at rt for 72 h. Filtration and evaporation afforded a brown solid which was purified by chromatography (EtOAc). This gave the ketone 27 as a white crystalline solid (0.18 g, 23%), mp 162-163 °C, λmax (log εmax) 207 (4.36), 235sh (4.11), 312 (4.27); νmax 3312, 2919, 2200, 1638 cm–1; δH (CDCl3, 300 MHz) 9.31 (1H, bs, indol-1-yl-H), 7.90 (1H, d, J = 8 Hz, ArH), 7.42 (2H, m, ArH), 7.22 (1H, t, J = 8 Hz, ArH), 4.63 (2H, s, indol-3-yl-CH2N), 3.20 (2H, q, J = 1.6 Hz, NCH2C≡C), 3.13 (2H, t, J = 8 Hz, NCH2CH2), 2.68 (2H, t, J = 8 Hz, CH2C=O), 2.20 (2H, quint, J = 8 Hz, NCH2CH2CH2), 1.90 (3H, t, J = 1.6 Hz, CH3); m/z (CI) 267 (MH+, 100%); C17H18N2O requires 266.1419. Found 266.1414.

2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-7-phenylsulfonyl-6H-azocino[4,3-b]indol-6-one 28. To a stirred solution of 2-(but-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 27 (0.155 g, 0.58 mmol) in dry DMF (10 mL), were added NaH (60% dispersion in mineral oil, 26 mg, 0.6 mmol) then, after H2 evolution ceased, PhSO2Cl (0.081 mL, 0.6 mmol) dropwise. After 1 h the mixture was poured into water (50 mL) and poduct extracted into CH2Cl2. The dried extract was evaporated giving a brown oil which was purified by chromatography (toluene:EtOAc, 99:1) to give the sulfonamido-ketone 28 as a white crystalline solid (78 mg, 33%), mp 149-151 °C, λmax (log εmax) 206 (4.80), 246sh (4.37), 293sh (4.02); νmax 2920, 2210, 1691 cm–1; δH (CDCl3, 300 MHz) 8.15 (2H, d, J = 7.5 Hz, ArH), 8.02 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.60-7.30 (6H, m, ArH), 3.87 (2H, s, indol-3-ylCH2N), 3.40 (2H, s, NCH2C≡C), 2.84 (4H, m, NCH2CH2CH2), 2.02 (2H, m, NCH2CH2CH2), 1.83 (3H, t, J = 1.5 Hz, CH3); m/z (CI) 407 (MH+, 100%), 267 (90); C23H23N2O3S requires 407.1429. Found 407.1423.

5-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 29. To a stirred solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)- butan-1-one 19 (0.5 g, 0.9 mmol) in dry THF (50 mL) at rt was added MeMgCl (3 M solution in THF, 0.37 mL, 1.1 mmol) dropwise. The reaction mixture was heated at refluxed for 1 h, allowed to cool, then poured into water (100 mL). The aqueous phase was extracted with Et2O (3 x 30 mL) and the combined organic extracts dried. Concentration gave a yellow oil which was purified by chromatography (toluene:EtOAc, 9:1) to give the alcohol 29 as a colourless oil (0.48 g, 93%), λmax (log εmax) 207 (4.51), 242sh (4.20), 291sh (3.60); νmax 3530, 2939 cm–1; δH (CDCl3, 300 MHz) 8.04 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.83 (4H, m, ArH), 7.62-7.16 (9H, m, ArH), 6.70 (1H, s, indol-3-yl-H), 5.50 (1H, m, HC=C), 5.20 (1H, m, C=CH), 4.95 (1H, bs, OH), 3.74 (2H, d, J = 7.5 Hz, NCH2C=C), 3.18 (2H, m, NCH2CH2), 2.13 (2H, t, J = 7.5 Hz, CH2CHOH), 1.77 (3H, s, CH3), 1.60 (5H, d+m, C=CCH3 plus CH2CH2CH2); m/z (CI) 552 (M+, 30%), 535 (74), 395 (92), 160 (100); C29H32N2O5S2 + NH4 requires 570.2096. Found 570.2110.

5-(E-But-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 30. A mixture of 5-(N-[E-but-2-en-1-yl]- phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 29 (0.42 g, 0.8 mmol), Na2HPO4 (0.433 g, 3 mmol) and 6% sodium amalgam (10 g) were stirred together in dry MeOH (50 mL) at rt. Decantation and evaporation followed by chromatography gave the alcohol 30 as a white crystalline solid (0.158 g, 75%), mp 78-80 °C), λmax (log εmax) 226 (4.61), 274 (4.68); νmax 3285, 3056, 2922, 2853 cm–1; δH (CDCl3, 300 MHz) 8.95 (1H, bs, indol-1-yl-H), 7.60 (1H, d, J = 7.5 Hz, ArH), 7.49 (1H, d, J = 7.5 Hz, ArH), 7.14 (2H, m, ArH), 6.20 (1H, s, indol-3-yl-H), 5.60 (2H, m, HC=CH), 4.79 (2H, bs, OH plus NH), 3.17 (2H, d, J = 7 Hz, NCH2C=C), 2.75 (1H, m, one of NCH2CH2), 2.63 (1H, m, one of NCH2CH2), 2.34 (1H, m, one of NCH2CH2CH2), 2.00 (1H, m, one of NCH2CH2CH2), 1.75 (5H, d+m, C=CCH3 plus two of NCH2CH2CH2), 1.63 (3H, s, CCH3); m/z (CI) 273 (MH+, 26%), 255 (100); C17H24N2O requires 272.1889. Found 272.1900.

2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 31. 5-(E-But-2-en-1- ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 30 (0.117 g, 0.43 mmol), formalin (1.25 mL, 40%) and AcOH (1.25 mL) in 1,2-dimethoxyethane (100 mL) were stirred togegher at rt for 0.5 h. Concetration and extraction of product into Et2O (2 x 20 mL) produced brown oil which was purified by chromatography (toluene:EtOH, 85:15). This gave the azocino-indole 31 as a white crystalline solid (0.122 g, 100%), mp 56-58 °C, λmax (log εmax) 230 (4.54), 284 (4.12); νmax 3430, 3263, 2916, 2813 cm–1; δH (CDCl3, 300 MHz) 9.60 (1H, bs, indol-1-yl-H), 7.45 (1H, d, J = 7.5 Hz, ArH), 7.37 (1H, d, J = 7.5 Hz, ArH), 7.20 (1H, t, J = 7.5 Hz, ArH), 7.14 (1H, t, J = 7.5 Hz, ArH), 5.19 (2H, m, HC=CH), 4.26 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.68 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.39 (1H, m, one of NCH2C=C), 3.25 (1H, m, one of NCH2C=C), 3.00 (1H, t, J = 9 Hz, one of NCH2CH2), 2.58 (1H, t, J = 9 Hz, one of NCH2CH2), 2.02 (1H, t, J = 9 Hz, one of NCH2CH2CH2), 1.83 (3H, s, CCH3), 1.75 (3H, d, J = 7 Hz, C=CCH3), 1.84-1.63 (3H, m, one of NCH2CH2CH2 plus NCH2CH2CH2); m/z (CI) 285 (MH+, 100%), 267 (18); C18H24N2O requires 284.1889. Found 284.1888.

5-((N-But-2-ynyl)phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 32. To a stirred solution of 4-((N-but-2-ynyl)phenylsulfonylamino)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21 (5.77 g, 10.8 mmol) in dry tetrahydrofuran (200 mL) at rt was added methylmagnesium chloride (3 M solution in THF, 4.7 mL, 14.0 mmol) dropwise then the mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool, then poured into water (500 mL). The aqueous phase was extracted with Et2O (3 x 300 mL) and the combined organic extracts dried. Evaporation and chromatography (toluene:EtOAc, 9:1) gave the alcohol 32 as an orange oil (4.53 g, 76%), λmax (log εmax) 232 (4.55), 258 (4.68); νmax 3531, 3300, 2939, 2280 cm–1; δH (CDCl3, 300 MHz) 8.04 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.87 (4H, m, ArH), 7.61-7.20 (9H, m, ArH), 6.74 (1H, s, indol-3-yl-H), 4.99 (1H, s, OH), 4.08 (2H, s, NCH2C≡C), 3.25 (2H, t, J = 7.5 Hz, NCH2CH2), 2.21 (2H, m, CH2C(Me)(OH)), 1.78 (3H, s, CH3), 1.55 (5H, s+m, CH2C≡C, CH2CH2CH2); δC (CDCl3, 75 MHz) 147.5 (s), 139.0 (s), 138.1 (s), 137.8 (s), 133.8 (d), 132.5 (d), 129.1 (d), 129.0 (s), 128.7 (d), 127.8 (d), 127.0 (d), 126.6 (d), 125.2 (d), 124.3 (d), 121.2 (d), 115.6 (d), 112.6 (d), 81.8 (s), 71.6 (s), 71.5 (s), 46.5 (t), 39.5 (t), 36.9 (t), 28.0 (q), 22.7 (t), 3.1 (q); m/z (CI) 550 (M+, 23%), 533 (100%), 411 (30), 393 (60), 227 (43), 160 (50), 78 (42); C29H30N2O5S2 + NH4 requires 568.1940. Found 568.1946.

5-(But-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33. A suspension of Mg (10.0 g, 0.42 mol) and NH4Cl (0.19 mol) in dry MeOH (500 mL) containing 5-((N-but-2-ynyl)phenylsulfonylamino)- 2-methyl-2-(1-phenylsulfonylindol-2-yl)butan-2-ol 32 (4.5 g, 8.0 mmol) was vigorously stirred for 2 h (Caution – exothermic), then water (100 mL) added and the reaction mixture concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with water (50 mL) and dried. Filtration and concentration gave a brown oil which was purified by chromatography (toluene:EtOAc:EtOH, 2:2:1) to give the amine 33 as an orange oil (1.14 g, 52%), λmax (log εmax) 222 (4.66), 271 (4.33), 279 (4.31), 286 (4.20); νmax 3410, 3292, 2920 cm–1; δH (CDCl3, 300 MHz) 8.84 (1H, bs, indol-1-yl-H), 7.58 (1H, d, J = 7.5 Hz, ArH), 7.40 (1H, d, J = 7.5 Hz, ArH), 7.16 (1H, t, J = 7.5 Hz, ArH), 7.12 (1H, t, J = 7.5 Hz, ArH), 6.28 (1H, s, indol-3-yl-H), 3.55 (2H, bs, OH and NH), 3.32 (2H, s, NCH2C≡C), 2.88 (1H, m, one of NCH2CH2), 2.51 (1H, m, one of NCH2CH2), 2.32 (1H, m, one of NCH2CH2CH2), 2.00 (1H, m, one of NCH2CH2CH2), 1.85 (3H, s, CH3), 1.73 (2H, m, one of NCH2CH2CH2), 1.60 (3H, s, CH3); δC (CDCl3, 75 MHz) 146.6 (s), 134.9 (s), 129.3 (s), 120.8 (d), 120.0 (d), 119.5 (d), 110.9 (d), 96.3 (d), 79.9 (s), 75.9 (s), 70.6 (s), 48.4 (t), 42.9 (t), 37.6 (t), 31.9 (q), 24.4 (t), 3.5 (q); m/z (CI) 271 (MH+, 23%), 253 (100), 239 (25); C17H23N2O requires 271.1810. Found 271.1810.

2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 34. To a stirred solution of 5-(but-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33 (0.25 g, 0.9 mmol) in 1,2-dimethoxyethane (250 mL), formalin (3 mL, 40%) and AcOH (3 mL) were added at rt. The solution was concentrated in vacuo to ca. 5 mL and aqueous sodium hydroxide (10 mL) and Et2O (20 mL) were added. The layers were separated, the aqueous phase re-extracted (Et2O, 2 x 20 mL) and the combined organic extracts dried. Evaporation after filtration gave a brown oil which was purified by chromatography (toluene:EtOH, 85:15). This gave the azocino-indole 34 as a white crystalline solid (0.23 g, 88%) mp 178-180 °C, λmax (log εmax) 230 (4.22), 284 (4.07), 292 (4.02); νmax 3440, 3266, 2918 cm–1; δH (CDCl3, 300 MHz) 9.03 (1H, bs, indol-1-yl-H), 7.46 (1H, d, J = 7.5 Hz, ArH), 7.34 (1H, d, J = 7.5 Hz, ArH), 7.15 (2H, m, ArH), 4.20 (1H, d, J = 15 Hz, one of indol-3-yl-CH2N), 3.89 (1H, d, J 15 Hz, one of indol-3-yl-CH2N), 3.57 (1H, q, J = 1.6 Hz, one of NCH2C≡C), 3.52 (1H, q, J = 1.6 Hz, one of NCH2C≡C), 2.80 (2H, m, NCH2CH2), 2.02-1.63 (4H, m, NCH2CH2CH2), 1.86 (3H, t, J = 1.6 Hz, C≡CCH3), 1.74 (3H, s, CH3); δC (CDCl3, 75 MHz) 138.6 (s), 134.0 (s), 127.4 (s), 125.6 (d), 121.6 (d), 119.4 (d), 118.0 (d), 110.7 (s), 81.7 (s), 73.1 (s), 69.3 (s), 55.1 (t), 50.9 (t), 48.0 (t), 43.0 (t), 27.6 (q), 24.7 (t), 3.6 (q); m/z (CI) 282 (M+, 20%), 265 (38), 249 (34), 229 (38), 182 (40), 173 (100), 152 (67); C18H22N2O requires 282.1732. Found 282.1730.

5-(2-Tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 35. A solution of 5-(but-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33 (0.613 g, 2.3 mmol), n-Bu3SnH (6 mL, 7.7 mmol) and AIBN (0.1 g) in PhH (20 mL) was heated at reflux for 30 h. Concentration gave a yellow liquid which was filtered through a short column of silica to remove excess n-Bu3SnH. The silica was extracted with MeOH and concentration of the extract gave a brown oil which was purified by chromatography (EtOAc) to give the stannane 35 as an orange oil (0.53 g, 42%), λmax (log εmax) 228 (4.28), 274 (4.05), 280 (4.06), 288 (3.96); νmax 3301, 2956, 2925, 2853 cm–1; δH (CDCl3, 300 MHz) 8.66 (1H, bs, indol-1-yl-H), 7.55 (1H, d, J=7.5 Hz, ArH), 7.32 (1H, d, J=7.5 Hz, ArH), 7.10 (2H, m, ArH), 6.20 (2H, s+m, indol-3-yl-H plus C=CH), 3.21 (2H, s, NCH2C=C), 2.67 (1H, m, one of NCH2CH2), 2.52 (1H, m, one of NCH2CH2), 2.26 (1H, m, one of NCH2CH2CH2), 1.96 (1H, m, one of NCH2CH2CH2), 1.75 (5H, d+m, J=7 Hz, C=CCH3 plus two of NCH2CH2CH2), 1.70-1.20 (18H, m, Sn(CH2CH2CH2)3, 1.55 (3H, s, CCH3), 0.90 (9H, t, J=10 Hz, 3xCH2CH3); m/z (EI) 563 (MH+, 4%), 545 (5), 487 (100), 368 (20), 350 (20), 182 (49); (MM 487.2142. C29H50N2OSn – H2O – C4H9 requires 487.2135).

5-(Z-2-Iodobut-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 36a and 5-(Z-2-Iodobut-2-en-1- ylamino)-2-methyl-2-(3-iodoindol-2-yl)pentan-2-ol 36b. Method (a). To a stirred solution of 5-(2-tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 35 (0.1 g, 0.21 mmol) in CH2Cl2 (5 mL) at rt was added I2 (52 mg, 0.21 mmol). The solution was stirred for 15 min then decolourised by washing with 1N aq Na2S2O3 solution and dried. Concentration gave a purple oil which was purified by chromatography using (toluene:EtOH, 9:1) to give the iodide 36a as a colourless oil (14 mg, 17%), λmax (log εmax) 228 (4.36), 276 (4.28), 288 (4.17); νmax 3420, 3286, 2922, 2852 cm–1; δH (CDCl3, 300 MHz) 8.70 (1H, bs, indol-1-yl-H), 7.56 (1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.12 (2H, m, ArH), 6.19 (1H, s, indol-3-yl-H), 5.75 (2H, q, J = 7 Hz, C=CH), 3.36 (2H, s, NCH2C=C), 2.73 (2H, bs, OH, NH), 2.63 (1H, m, one of NCH2CH2), 2.45 (1H, m, one of NCH2CH2), 2.32 (1H, m, one of NCH2CH2CH2), 1.96 (1H, m, one of NCH2CH2CH2), 1.75 (3H, d, J = 7 Hz, C=CCH3), 1.73-1.52 (2H, m, two of NCH2CH2CH2), 1.57 (3H, s, CCH3); m/z (EI) 398 (M+, 8%), 380 (22), 365 (80), 280 (30), 253 (75), 210 (50), 184 (55), 157 (100); C17H23IN2O requires 398.0855. Found 398.0862.
Method (b). In a similar manner, 5-(2-tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2- yl)pentan-2-ol 35 (0.53 g, 1.09 mmol) in CH2Cl2 (10 mL) and I2 (1.38 g, 5.5 mmol) gave a purple oil from which product was obtained by chromatography (toluene:EtOH, 9:1) to give firstly diiodide 36b as a colourless oil (0.2 g, 35%), λmax (log εmax) 230 (4.70), 278 (4.89); νmax 3410, 3286, 2922, 2850 cm–1; δH (CDCl3, 300 MHz) 9.38 (1H, bs, indol-1-yl-H), 7.39 (2H, m, ArH), 7.18 (2H, t, J = 7.5 Hz, ArH), 5.81 (2H, q, J = 7 Hz, C=CH), 3.40 (2H, s, NCH2C=C), 3.33 (1H, m, one of NCH2CH2), 3.27 (2H, bs, OH, NH), 3.02 (1H, m, one of NCH2CH2), 2.66 (1H, m, one of NCH2CH2CH2), 1.86 (1H, m, one of NCH2CH2CH2), 1.76 (3H, d, J = 7 Hz, C=CCH3), 1.70 (2H, m, one of NCH2CH2CH2), 1.62 (3H, s, CCH3); m/z (EI) 525 (M+, 50%), 399 (37), 381 (62), 316 (42), 253 (38), 160 (40). Next from the column was iodide 36a as a colourless oil (0.1 g, 23%). All spectra were as above.

2-(2-Tri-n-butylstannyl-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 38. 2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 34 (230 mg, 0.82 mmol) was dissolved in PhH and the solution degassed under nitrogen. Azobisisobutyronitrile (50 mg, 0.30 mmol) and tri-n-butyltin hydride (2 mL, 7.4 mmol) were added and the mixture heated at reflux for 3 h. Most of the solvent was removed in vacuo and the resulting solution filtered through a short pad of silica, eluting first with petroleum ether:Et3N, 99:1, to remove excess tin hydride, and then with petroleum ether:EtOAc:Et3N, 49.5:49.5:1 to give the stannane 38 as a yellow oil (310 mg, 65%), λmax (log εmax) 228 (4.56), 284 (3.89); νmax 3272, 2954, 2924, 1460, 740 cm–1; δH (CDCl3, 300 MHz) 9.15 (1H, bs, indol-1-yl-H), 8.40 (1H, bs, OH), 7.50 (1H, m, ArH), 7.31 (1H, m, ArH), 7.17 (1H, m, ArH), 6.49 (1H, q, J = 6.4 Hz, C=CH), 4.37 (1H, d, J = 15.8 Hz, one of indol-3-ylCH2N), 3.63 (1H, d, J = 15.8 Hz, one of indol-3-ylCH2N), 3.49 (1H, d, J=14.2 Hz, one of NCH2C=C), 3.32 (1H, d, J = 14.2 Hz, one of NCH2C=C), 3.00 (1H, m, one of NCH2CH2), 2.55 (1H, m, one of NCH2CH2), 2.07 (1H, m, one of NCH2CH2CH2), 1.95-1.35 (27H, m, 3xSnCH2CH2CH2 plus one of NCH2CH2CH2 plus C=CCH3 plus CCH3 plus CH2CH2CH2), 0.98 (9H, t, J = 7.2 Hz, 3xCH2CH3); δC (CDCl3, 75 MHz) 139.2 (s), 138.2 (d), 134.1 (s), 127.7 (s), 122.5 (s), 121.4 (d), 119.2 (d), 117.9 (d), 111.0 (d), 110.6 (s), 69.3 (s), 66.5 (t), 57.1 (t), 50.8 (t), 43.1 (t), 29.3 (t), 27.7 (q), 27.5 (t), 24.6 (t), 20.3 (q), 13.8 (q), 10.3 (t); m/z (CI) 575 (MH+, 100%), 557 (62), 517 (10), 499 (20); C26H41N2O120Sn (i.e. M-C4H9) requires 517.2240. Found 517.2223.

2-(2-Iodo-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 37. Method (a): 5-(2-Iodo-Z-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 36a (0.1 g, 0.25 mmol), formalin (1 mL, 40%) and AcOH (1 mL) in 1,2-dimethoxyethane (100 mL) were stirred together for 30 min. Concentration in vacuo to ca. 5 mL, addition of aq NaOH (10 mL) and Et2O (20 mL), separation of the layers, re-extraction of the aq layer, and finally drying of the organic solution and evaporation produced a brown oil which was purified by chromatography (toluene:EtOH, 85:15). This gave the azocino-indole 37 as a colourless oil (0.085 g, 83%), λmax (log εmax) 228 (4.77), 278 (4.87); νmax 3420, 3264, 2917 cm–1; δH (CDCl3, 300 MHz) 9.62 (1H, bs, indol-1-yl-H), 7.41 (1H, d, J = 7.5 Hz, ArH), 7.35 (1H, d, J = 7.5 Hz, ArH), 7.19 (1H, t, J = 7.5 Hz, ArH), 7.14 (1H, t, J = 7.5 Hz, ArH), 5.94 (1H, q, J = 7 Hz, C=CH), 4.22 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.76 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.12 (2H, s, NCH2C=C), 2.95 (1H, t, J = 9 Hz, one of NCH2CH2), 2.52 (1H, t, J = 9 Hz, one of NCH2CH2), 2.05 (1H, t, J = 9 Hz, one of NCH2CH2CH2), 1.80 (3H, s, CCH3), 1.75 (3H, d, J = 7 Hz, C=CCH3), 1.84-1.65 (3H, m, three of NCH2CH2CH2); δC (CDCl3, 125 MHz) 138.7 (s), 134.8 (d), 133.8 (s), 127.4 (s), 121.6 (d), 119.3 (d), 117.7 (d), 110.9 (d), 110.3 (s), 104.5 (s), 71.9 (t), 69.2 (s), 56.7 (t), 50.9 (t), 42.9 (t), 27.6 (q), 24.6 (t), 22.1 (q); m/z (CI) 411 (MH+, 100%), 393 (42), 316 (23), 269 (28), 211 (36); C18H23IN2O requires 410.0857. Found 410.0856.
Method (b): To a solution of 2-(2-tri-n-butylstannyl-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6- methylazocino[4,3-b]indol-6-ol 38 (285 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added I2 (632 mg, 2.50 mmol) and the resulting mixture stirred at rt for 35 min, quenched with aq Na2S2O3 and product extracted into CH2Cl2. Evaporation gave crude material which was purified by chromatography over silica (toluene:EtOAc, 95:5→9:1). Further partitioning between petroleum ether and MeCN gave highly pure product 37 (74 mg, 36%).

2-(2-Iodo-Z-but-2-en-1-yl)-1,2,3,4,-tetrahydro-6-methylazocino[4,3-b]indole 3. 2-(2-Iodo-(Z)-but-2- en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 37 (80 mg, 0.20 mmol) was dissolved in PhH with heating to 50 °C. p-toluenesulfonic acid (10 mg, 0.05 mmol) was added and the mixture heated at 50 °C for 30 min. The solvent was evaporated in vacuo and the residue partitioned between aq NaHCO3 and CH2Cl2. The organic extract was dried and evaporated to give the alkene 3 as an oil (52 mg, 66%), λmax (log εmax) 234 (4.34), 296 (4.11); νmax 3408, 2927, 2913, 1644 cm–1; δH (CDCl3, 300 MHz) 8.04 (1H, bs, indol-1-yl-H), 7.59 (1H, d, J = 7.5 Hz, ArH), 7.34 (1H, d, J = 7.5 Hz, ArH), 7.14 (2H, t, J = 7.5 Hz, ArH), 5.84 (2H, m, 2xC=CH), 4.00 (2H, s, indol-3-ylCH2N), 3.37 (2H, s, NCH2C=C), 2.72 (2H, m, NCH2CH2), 2.18 (5H, s+m, NCH2CH2 plus CCH3), 1.80 (3H, d, J = 7 Hz, C=CCH3); m/z (EI) 392 (M+, 19%), 183 (55), 168 (60), 133 (41); C18H21IN2 requires 392.0751. Found 392.0766.

ACKNOWLEDGEMENTS
JGK thanks the SERC and EPSRC for maintenance grants and DR similarly acknowledges his University of Manchester Gratrix scholarship.

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