Synthesis of functionalised indolines by radical-polar crossoverreactions

摘要

J. Chem. Soc. Perkin Trans. 1 1997 1549 Synthesis of functionalised indolines by radical-polar crossover reactions John A. Murphy,*,dagger;,a Faiza Rasheed,Dagger;,a Steacute;phane Gastaldi,b T. Ravishanker b and Norman Lewis c a Department of Chemistry University of Nottingham University Park Nottingham UK NG7 2RD b Department of Pure and Applied Chemistry University of Strathclyde 295 Cathedral Street Glasgow UK G1 1XL c SmithKline Beecham Pharmaceuticals Old Powder Mills Leigh nr. Tonbridge Kent UK TN11 9AN Functionalised indolines have been prepared by treating tetrathiafulvalene (TTF) with 2-(N-acyl-Nallylamino) benzenediazonium tetrafluoroborates. N-Benzoyl-protected substrates afford complex reaction mixtures due to competing radical cyclisation onto the benzoyl group. Acetamides react more efficiently affording good yields of product alcohols when the reactions are carried out in moist acetone Introduction Indolines feature abundantly in Nature and many of these compounds are of pharmaceutical interest.The family includes the complex alkaloids aspidospermidine strychnine and vinblastine which pose many intriguing challenges to the synthetic chemist. The synthesis of naturally occurring indolines is therefore a very active field and one of the most popular recent approaches has involved the use of radicals 1ndash;7 as precursors. However despite all these developments our recently discovered radical-polar crossover reactions could have unique and important advantages not only in avoiding the troublesome and toxic tin radicals but also more especially in controlling stereochemistry of more complex polycyclic indolines.A preparative strategy for complex indoline skeletons such as 4 present in many medicinally important indoline alkaloids would involve formation of the aryl radical 1 from the corresponding diazonium salt by treatment with tetrathiafulvalene (TTF) and cyclisation of 1 to a new radical 2 which then undergoes radical-polar crossover ultimately leading to the cation 3.8 A cis ring junction can be predicted in formation of 2 leaving dagger; Current address Department of Pure and Applied Chemistry University of Strathclyde 295 Cathedral Street Glasgow UK G1 1XL. Dagger; Current address ICI Chemicals and Polymers Limited PO Box 8 The Heath Runcorn Cheshire UK WA7 4QD. the side-chain containing the group N9HR so disposed as to favour the all-cis stereochemistry of the desired product 4.The stereocontrol in the final cyclisation is totally dependent on unimolecular substitution via a mandatory carbocation intermediate 3. Prior trapping of the radical 2 (e.g. leading to an iodide) 1 from the less hindered face would afford9 product 5 (X = I) and this would either suffer direct closure of the fourth ring with inversion of configuration affording the wrong stereochemistry or at the least require two sequential inversions at the neopentyl carbon bearing the iodine firstly by an intermolecular nucleophile and then by N9HR in order to incorporate the desired stereochemistry in the fourth ring. However before embarking on complex syntheses it was necessary to investigate if simple indolines could be formed using the radical-polar crossover approach and how such chemistry would be affected by the choice of nitrogen-protecting group.These topics form the subject of this paper.10 Scheme 1 1550 J. Chem. Soc. Perkin Trans. 1 1997 Benzamide derivatives Nucleophilic aromatic substitution of 2-bromonitrobenzene 6 with prop-2-enylamine 7 led to 8 which was benzoylated to afford 10a as microanalytically pure pale yellow needles. Reduction to 11a followed by diazotisation furnished 12a as a fine colourless powder. In parallel synthesis of 12b was also undertaken to compare whether the product ratio would be altered by changing the terminus of the radical acceptor C C bond. A different synthetic approach was adopted in this case. Benzoylation of 2- nitroaniline afforded 9 as yellow needles. Subsequent deprotonation by sodium hydride was conveniently achieved in tetrahydrofuran and followed by alkylation with 2-methyl-4- bromobut-2-ene (prenyl bromide) to give 10b.Reduction to 11b followed by diazotisation afforded 12b the cyclisation precursor as a pale yellow powder. Reaction of 12a and 12b with TTF in moist acetone afforded the products shown in Scheme 3. The product distributions here were of particular interest because Togo3 had observed the exclusive formation of 13a (100) when the bromo compound 14 analogous to 12a was subjected to standard reductive conditions (Bu3SnHndash;AIBN) in toluene. This reaction has assumed further importance since it fits into a picture 11 in which the intriguing regioselectivity of certain anilide aryl radical addition reactions could be neatly rationalised. Our reactions afforded a greater variety of products and (as pointed out by a reviewer) since the same radical features in both cases the fact that we observed formation of an indoline whereas Togo did not was surprising.To probe this point we have now repeated the experiment of Togo on many occasions. The crude NMR spectrum consistently shows two products compound 13a and N-benzoyl-3-methylindoline 19 in a 73 27 ratio (as well as the tin by-products). Separation of these two compounds from each other is non-trivial although they can be separated from the tin residues without difficulty; the mixture of the two compounds clearly shows all the signals later identified as the indoline. Dihydroxylation of the mixture with osmium tetroxide affords the polar diol 20 which is easily separated from the indoline 19.The isolation of indoline 19 from these experiments makes it clear that the same radical can feature in both our reactions and those of Togo. The mechanisms of formation of the products derived from reaction of 12a,b are worthy of consideration. The biphenylamines 15a,b were formed via ipso cyclisation of the aryl radical onto the aromatic ring.12ndash;14 In this case after the initial Scheme 2 Reagents and conditions i reflux 48 h 87; ii PhCOCl DMAP py; (a) at 80 8C 84; (b) at RT 93; iii Cu(acac)2 NaBH4 EtOH 3 h; (a) 75; (b) 77; iv Aq. HBF4 isoamyl nitrite EtOH; (a) and (b) 80; v NaH THF 0 8C then prenyl bromide; 73 cyclisation of the radicals derived from 12a,b 22 is formed as an intermediate radical which either rearranges to 21 by a neophyl rearrangement or rearomatises leading to the amidoyl radical 23 (Scheme 4).Radicals of this type are known to be quite stable and cannot rapidly decarbonylate 5 to give an aminyl radical 26. Hence it was concluded that TTF?1 must be playing an active role in decarbonylation in order to produce 15. Combination of TTF?1 with 23 would give 24 (see Scheme 4) which would then be readily attacked by water to give the carbamic acid 25. This could now readily decarboxylate the entropic driving force leading to the formation of carbon dioxide and 15. Formation of 13a,b may arise by ipso addition giving 22 followed by arrangement or alternatively by direct formation of the 6-membered ring in 21. Hey13 and Grimshaw14 have studied cyclisations of similar aryl radicals generated photochemically and electrolytically.In their substrates the amide group is transposed i.e. with the radical being generated on the benzoyl ring; they also observed products arising from cyclisations to 5- and 6-membered rings. In addition to the products described above the other products which have been characterised can all be rationalised from the intermediates 17a or 17b. The 1H NMR spectrum of 17a formed from reaction of 12a with TTF in 17 yield was dif- ficult to interpret. This was not surprising due to the expected presence of diastereoisomers as well as the rotamers around the amide bond. Attempts to obtain a 1H NMR spectrum of 17a at elevated temperatures in deuteriated dimethyl sulfoxide were Scheme 3 J. Chem. Soc. Perkin Trans. 1 1997 1551 fruitless. Decomposition products were observed as the temperature was raised.The sulfonium tetrafluoroborate 17a was formed via the aryl radical cyclising onto the pendant alkene to afford an intermediate alkyl radical which was then trapped by TTF?1. As predicted no sign of the corresponding alcohol 18a was observed. This would require substitution by an SN1 reaction 8 which is not possible since it would require the intermediacy of a primary cation. Reaction of 12b with TTF afforded 18b as the major product. The 1H NMR spectrum revealed broadened signals at room temperature in CDCl3 due to the hindered rotation about the amide bond. To aid interpretation both the 1H and 13C NMR spectra were recorded in deuteriated dimethyl sulfoxide at 353 K. In contrast to 17a the corresponding sulfonium salt 17b was not isolated. In addition a minor product was isolated in the reaction of 12b and this was fully characterised as the indole 16b which displayed a characteristic indole ring singlet at 7.03 ppm in the 1H NMR spectrum.The indole 16b arises through the mechanism shown in Scheme 5. Loss of TTF from 17b gives the carbocation 27 which can react with residual moisture present in acetone to give 18b or can lose a proton to give 28 which isomerises to 16b. Acetamide precursors In view of the complications observed in the benzoyl case a series of precursors 33andash;c featuring acetyl protecting groups2 were synthesised. 2-Nitroacetanilide 15 29 was obtained as a yellow crystalline solid in 94 yield by acylation of 2-nitroaniline. Deprotonation followed by alkylation with the commercially available appropriately substituted alkenyl bromides 30andash;c furnished 31andash;c in good to excellent yields as deep orange viscous oils.In general the NMR spectra of these indicated the existence of rotameric mixtures at ambient temperatures. Hence their 1H NMR spectra were recorded in deuteriated dimethyl sulfoxide at 398 K and could then be conveniently interpreted. In the case of 31c the 1H NMR spectrum at 398 K Scheme 4 gave broader signals with loss of resolution hence the spectrum recorded at 298 K has been quoted. The corresponding amines 32andash;c were isolated as stable colourless powders with sharp melting points. The diazonium tetrafluoroborates 33andash;c were prepared by the usual method in good yields as crystalline solids. The next step was cyclisation with TTF and this was performed in moist acetone as before. With 33a reaction with TTF gave a product tentatively identified as 34 a yellow powder obtained by precipitation from diethyl ether as the sole product of the reaction.13C NMR spectroscopy indicated the compound to be present as a pair of diastereoisomers. The diastereotopic protons a to the sulfur Scheme 5 Scheme 6 Reagents and condtitions i NaH THF 27 then 28 16 h; (a) 68; (b) 83; (c) 78; ii Cu(acac)2 NaBH4 EtOH 3 h; (a) 97; (b) 72; (c) 65; iii HBF4 isoamyl nitrite EtOH 0 8C; (a) 73; (b) 85; (c) 91 Scheme 7 1552 J. Chem. Soc. Perkin Trans. 1 1997 appeared at 3.94 (1 H dd J 13 6.7 Hz) and 4.02 (1 H dd J 13 6.7 Hz) respectively. The benzylic proton and those a to the acetamide nitrogen were observed as complex multiplets. The signals at 6.98 (major isomer) 6.84 (minor isomer) 7.38 7.43 8.23 and 8.12 (minor isomer) ppm were attributable to the TTF portion of the molecule.The 13C NMR spectrum was similar to that of 17a. Repeated efforts to purify this compound fully by column chromatography were unsuccessful. The reaction of 33b with TTF afforded only 35b as a 1 1 diastereoisomeric mixture as the only product of the reaction in 59 yield. Finally 33c was treated with TTF in moist acetone and two products in the ratio of 1 12 were isolated after chromatography. The more polar product was indeed the alcohol 35c as was expected isolated as a pale waxy solid (mp 108ndash;111 8C) in good yield. Its NMR data were easy to analyse due to the absence of diastereoisomers. A molecular ion which fitted the proposed formula was observed by electron impact mass spectrometry (Found M1 219.1258.C13H17NO2 requires M 219.1259). The less polar product was isolated in 5 yield as a pale powder. Extensive purification by chromatography was required on this product as it co-migrated with TTF byproducts. The 1H NMR spectrum recorded at 400 MHz was significantly different from that of 35c. Signals at 1.24 and 1.39 (3 H d J 21.4 Hz) ppm were attributed to the methyl protons and a signal at 2.25 ppm to the methyl of the acetyl group. The doublet structure for two of the methyl groups suggested that the compound was the fluoride 36c. This indeed was seen to be the case. In the 13C spectrum the two methyl carbons at 23.1 (2JCF 24.1 Hz) and 24.5 (2JCF 24.2 Hz) ppm as well as the methine carbon at 49.7 (2JCF 24.2 Hz) ppm all appeared as doublets. In addition the methylene carbon at 51.1 ppm also appeared as a doublet (3JCF 7.7 Hz).Particularly noticeable was the quaternary carbon at 96.8 ppm appearing as a doublet (1JCF 170 Hz). Mass spectrometry gave a molecular ion for the proposed molecular formula (Found MH1 222.1292. C13H16FNO requires MH 222.1294). Further evidence to confirm the structure of 36c came from the undecoupled 19F spectrum recorded at 235 MHz using deuteriated chloroform as solvent with CFCl3 (0.2) as the internal reference. The two broad multiplets at 275.7 (minor) and 276.47 (major) ppm were attributable to the fluorine coupling to the benzyl and methyl protons. The presence of two signals also indicates that the compound exhibits hindered rotation about the amide bond. Formation of the fluoride 36c is analogous to the Schiemann reaction which involves heating of an arenediazonium tetrafluoroborate to produce aryl fluorides.Conclusion Functionalised indolines can indeed be prepared using the lsquo;radical-polar crossoverrsquo; approach. The nature of the protecting group is important. Whereas complications are experienced with N-benzoyl protection the use of acetamide protection proceeds smoothly. These results suggest that the methodology may indeed be useful for the synthesis of complex natural indolines. We are currently investigating this approach. Experimental General procedures Mps were carried out on a Kofler hot-stage apparatus and are uncorrected. Microanalyses were determined using a Perkin- Elmer 240B elemental analyser. IR spectra were obtained on a Perkin-Elmer 1720-X FTIR or Pye-Unicam SP3-100 spectrometer.lsquo;Discrsquo; refers to spectra that were recorded from compounds prepared in a KBr disc. Mass spectra were recorded on an AE1 MS-902 or a MM- 701 CF instrument using either electron impact ionisation (EI at 70 eV) fast-atom bombardment (FAB) or ionspray (IS) techniques at the University of Nottingham. High-resolution FAB or CI mass spectra were recorded on a JLSX 102 instrument (SB). Alternatively the high-resolution FAB spectra were also recorded on a VG-AUTOSPEC instrument (at 25 kV) and the CI spectra were obtained on a VG ZAB-E instrument (at 8 kV) using peak-matching techniques at the EPSRC Mass Spectrometry Centre Swansea. 1H NMR spectra were recorded at 250 MHz on a Bruker WM250 at 270 MHz on a JEOL EX270 or at 400 MHz on a Bruker AM400 machine. 13C NMR spectra were similarly recorded at 67.5 MHz on a JEOL EX270 or at 100 MHz on a Bruker AM400 machine.NMR experiments were in general carried out in deuteriochloroform (CDCl3) unless otherwise specified using tetramethylsilane (TMS) as the internal reference for 1H and chloroform as standard for the 13C NMR. 13C NMR spectra were acquired on a broad band decoupled mode with the multiplicities obtained using a DEPT sequence. The alternative deuteriated solvents employed were 2H6acetone or 2H6dimethyl sulfoxide the latter used to conduct variabletemperature studies. Chemical shifts (d) are quoted in parts per million (ppm) from TMS as the internal standard. The following abbreviations are used for the multiplicities s = singlet d = doublet t = triplet q = quartet app = apparent br = broad and m = multiplet.Coupling constants (J) are reported in Hz. Where mixtures of isomers are obtained they are distinguished in the NMR spectra by using the word lsquo;minorrsquo; to denote less prevalent isomer(s). In cases where superimposition of two or more isomers occurred the signals have been reported as multiplets (m) unless coupling constants for each isomer could be ascertained. The 19F NMR spectrum for 36c was recorded at 235 MHz on a Bruker WM250 machine in CDCl3 using CFCl3 (0.2) as the internal reference. Flash chromatography was performed using Sorbisil C60 (May and Baker) Merck silica Keiselgel 60 (Art 9385) or Kieselgel HF254 silica gels. Thin layer chromatography (TLC) was performed using Merck silica gel 60 F254 pre-coated plastic plates. Visualisation was achieved under UV light and the plates developed with methanolic phosphomolybdic acid (10ndash;20 w/v) or acidic p-anisaldehyde (10 v/v) or acidic ethanolic vanillin solutions.Where necessary organic solvents were routinely dried and/ or distilled prior to use and stored over molecular sieves under nitrogen. Unless otherwise stated LP refers to light petroleum (bp 40ndash;60 8C). Diethyl ether cyclohexene toluene and benzene were dried over sodium wire. Other solvents were dried by distillation from the following tetrahydrofuran (sodiumndash; benzophenone); dichloromethane N,N-dimethylformamide dimethyl sulfoxide and pyridine (calcium hydride); methanol (magnesium methoxide) and prop-2-enylamine (potassium hydroxide). In experiments where sodium hydride (60 suspension in mineral oil) has been utilised as a base it was washed with THF at least twice prior to use.All reactions requiring anydrous conditions were performed in flame- or oven-dried apparatus under a nitrogen or argon atmosphere. Organic extracts were in general dried over anhydrous magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4). N-(2-Nitrophenyl)-N-prop-2-enylamine 8 Freshly distilled prop-2-enylamine (7.5 ml 5.7 g 100 mmol) was added to 2-bromonitrobenzene (8.24 g 41 mmol) and the mixture heated at reflux for 48 h.15 After cooling the deep brown residue was dissolved in ethyl acetate (350 ml) and the organic phase separated and washed with water (3 times; 400 ml). The aqueous phase was back-washed with ethyl acetate (3 times; 300 ml) and the combined organic phase was concentrated in vacuo to yield a brown viscous oil. The crude compound was further purified by column chromatography on silica gel using LPndash;ethyl J.Chem. Soc. Perkin Trans. 1 1997 1553 acetate (90 10) as eluent to afford the title compound 8 as a bright orange oil (6.31 g 35 mmol 87) (Found C 60.57; H 5.69; N 15.61; M1 178.0732. C9H10N2O2 requires C 60.64; H 5.66; N 15.72; M 178.0756); nmax(film)/cm21 3386 3086 3009 2984 2855 1618 1574 1511 1351 1331 995 923 and 743; dH(270 MHz) 1.58 (1 H br s NH) 3.98 (2 H br d J 5 CH2) 5.23 (2 H m HC CH2) 5.96 (1 H m HC CH2) 6.66 (1 H dd J 7 7 ArH) 6.82 (1 H d J 9 ArH) 7.45 (1 H dd J 7 7 ArH) and 8.17 (1 H d J 9 ArH); dC(67.5 MHz) 45.27 (CH2) 114.07 (CH) 115.51 (CH) 117.07 (CH2) 126.85 (CH) 133.2 (CH) 136.12 (CH) and 145.32 (2C); m/z (EI) 178 (M1 100) 130 (90) 119 (58) 105 (100) 91 (23) 77 (40) and 55 (38).N-(2-Nitrophenyl)-N-(prop-2-enyl)benzamide 16 10a To a stirred solution of N-(2-nitrophenyl)-N-prop-2-enylamine 8 (6.31 g 35 mmol) in dry pyridine (50 ml) cooled to 0 8C was added 4-(N,N-dimethylamino)pyridine (500 mg 4 mmol). Benzoyl chloride (4.5 ml 4.92 g 39 mmol) was added to the reaction mixture which was then heated at reflux (3 h). After cooling the mixture was concentrated by removal of the excess pyridine by evaporation under reduced pressure; the residue was then taken up in ethyl acetate. The solution was subsequently washed with sulfuric acid (1 M; 3 times; 500 ml) saturated aqueous sodium hydrogen carbonate (3 times; 500 ml) water (3 times; 500 ml) and brine (2 times; 500 ml) dried and evaporated under reduced pressure to yield a deep brown residue. This was chromatographed on silica gel eluting with LPndash;ethyl acetate (90 10) to yield the title compound 10a as bright yellow needles (8.36 g 30 mmol 84) mp 83ndash;84 8C (lit.,16 88ndash;89 8C from ethyl acetatendash;LP) (Found C 67.98; H 4.96; N 9.80; M1 282.0992.C16H14N2O3 requires C 68.08; H 5.00; N 9.92; M 282.1004); nmax(disc)/cm21 3084 2922 2835 1651 1605 1526 1345 1309 996 and 741; dH(CD3COCD3 270 MHz) spectrum indicated the presence of two rotameric forms 4.13 (1 H br m CH2) 4.36 (1 H br m CH2) 5.13 (2 H m HC CH2) 6.05 (1 H m HC CH2) and 7.20ndash;8.05 (9 H br m ArH); dC(CD3COCD3 100 MHz) 53.3 (CH2) 118.9 (CH2) 126.2 (CH) 128.9 (CH) 129.4 (CH) 129.9 (CH) 130.7 (CH) 133.1 (CH) 134.1 (CH) 134.9 (CH) 136.6 (C) 137.7 (C) 147.2 (C) and 169.8 (C); m/z (EI) 282 (M1 11) 252 (45) 236 (35) 160 (20) 131 (53) 105 (100) and 77 (100).N-(2-Nitrophenyl)benzamide 17 9 To a stirred solution of 2-nitroaniline (3.04 g 22 mmol) and 4- (N,N-dimethylamino)pyridine (245 mg 2 mmol) in dry pyridine (100 ml) at 0 8C was added benzoyl chloride (3.8 ml 4.64 g 33 mmol) under nitrogen over a period of 0.5 h; the solution was then warmed to room temperature. Excess of pyridine was removed via rotary evaporation and the residue dissolved in dichloromethane. The solution was washed with aqueous sulfuric acid (1 M; 3 times; 500 ml) saturated aqueous sodium hydrogen carbonate (3 times; 500 ml) water (3 times; 500 ml) and brine (2 times; 500 ml) dried and evaporated under reduced pressure to yield the title compound 9 as fine yellow crystals (4.96 g 20.5 mmol 93) mp 93.5ndash;94 8C (lit.,17 92ndash;94 8C from ethanol) (Found C 64.12; H 4.07; N 11.31.C13H10N2O3 requires C 64.46; H 4.16; N 11.56); nmax(CHCl3)/cm21 3358 1687 1609 1588 and 1342; dH(400 MHz) 7.22 (2 H ddd J 7.5 7.5 1.3 ArH) 7.57 (2 H m ArH) 7.72 (1 H ddd J 8.7 8.7 1.5 ArH) 8.01 (2 H dd J 8.8 1.5 ArH) 8.27 (1 H dd J 8.5 1.5 ArH) 9.02 (1 H dd J 7.5 1.1 ArH) and 9.18 (1 H br s NH); dC(100 MHz) 122.0 (CH) 123.2 (CH) 125.8 (CH) 127.3 (CH) 128.9 (CH) 129.2 (CH) 133.9 (C) 135.2 (C) 136.1 (CH) 136.3 (C) and 165.6 (C). N-(2-Nitrophenyl)-N-(3-methylbut-2-enyl)benzamide 10b To a slurry of washed sodium hydride (60 suspension in mineral oil; 396 mg 10 mmol) in dry tetrahydrofuran (200 ml) was added compound 9 (1.51 g 6 mmol) portionwise over a period of 10 min under nitrogen; the mixture was then stirred for 0.5 h leading to the development of a deep red colouration.4- Bromo-2-methylbut-2-ene (1.2 ml 0.93 g 10.4 mmol) was then added dropwise to the mixture after which it was stirred in the dark (12 h). Excess of tetrahydrofuran was removed by evaporation under reduced pressure after which the yellow residue was partitioned between ethyl acetate and water (50 50 v/v; 300 ml) the aqueous phase was separated and further extracted with ethyl acetate (2 times; 150 ml). The combined organic extracts were dried and concentrated in vacuo to furnish the title compound 10b as a crystalline yellow solid (1.41 g 4.6 mmol 73) mp 80.5ndash;82.5 8C (from ethyl acetatendash;LP) (Found C 69.52; H 5.83; N 8.76; MH1 311.1411. C18H18N2O3 requires C 69.66; H 5.85; N 9.03; MH 311.1396); nmax(CHCl3)/cm21 2935 2858 1648 1603 1580 1534 1350 and 966; dH(CD3SOCD3 400 MHz at 405 K) 1.35 (3 H s CH3) 1.55 (3 H s CH3) 4.33 (2 H d J 6.3 CH2) 5.23 (1 H m HC C) 7.25 (5 H m ArH) 7.44 (2 H m ArH) 7.63 (1 H ddd J 8 8 1.5 ArH) and 7.86 (1 H dd J 7 1.2 ArH); dC(67.5 MHz) 17.5 (CH3) 25.7 (CH3) 47.7 (CH2) 118.5 (CH) 125.4 (CH) 127.3 (CH) 127.4 (CH) 128.0 (CH) 129.9 (CH) 132.2 (CH) 133.6 (CH) 135.5 (C) 137.8 (C) 146.4 (C) 146.5 (C) and 169.8 (C); m/z (FAB) 311 (MH1) 36 105 (100) and 77 (35).N-(2-Aminophenyl)-N-prop-2-enylbenzamide 11a Sodium boranuide (1.67 g 44 mmol) was added to a rapidly stirred solution of copper(II) acetylacetonate (744 mg 2.9 mmol) in ethanol (250 ml) to give a brown suspension. Stirring was continued until a dark solid was precipitated and the opaque solution turned clear. Compound 10a (4.06 g 14 mmol)18 was then added as a solution in ethanol (10 ml) to the mixture over 20 min.After being stirred for 3 h the reaction mixture was poured into water (200 ml) filtered and concentrated to low volume under reduced pressure. The aqueous phase was extracted with dichloromethane (3 times; 150 ml) and the combined extracts were dried and evaporated under reduced pressure to yield the crude amine. After work-up the crude amine (660 mg) was purified by chromatography on silica gel using LPndash;ethyl acetatendash;isopropylamine (80 18 2) as eluent to afford the title compound 11a as a fine colourless powder (2.72 g 11 mmol 75) mp 76ndash;78 8C (from diethyl etherndash;LP) (Found M1 252.1247. C16H16N2O requires M 252.1262); nmax- (CHCl3)/cm21 3402 3342 3068 3034 2973 2931 2871 1616 1572 1504 1351 1001 968 926 791 746 and 724; dH(250 MHz) 3.91 (2 H br s NH2) 4.12 (1 H dd J 14 7 CH2) 4.56 (1 H dd J 14.3 6 CH2) 5.21 (2 H m HC CH2) 6.03 (1 H m HC CH2) 6.52 (1 H dd J 7 7 ArH) 6.65 (1 H d J 8 ArH) 6.70 (1 H d J 8 ArH) 7.0 (1 H dd J 7 7 ArH) 7.18 (3 H m ArH) and 7.35 (2 H d J 7 ArH); dC(67.5 MHz) 51.1 (CH2) 115.9 (CH) 118.1 (CH) 118.6 (CH2) 127.5 (CH) 127.7 (CH) 128.5 (CH) 128.6 (CH) 129.8 (CH) 132.7 (CH) 135.5 (C) 142.5 (2C) and 171.2 (C); m/z (EI) 252 (M1 19) 250 (25) 234 (100) 105 (58) and 77 (42).N-(2-Aminophenyl)-N-(3-methylbut-2-enyl)benzamide 11b Sodium boranuide (395 mg 10.4 mmol) was added to a rapidly stirred solution of copper(II) acetylacetonate (220 mg 0.83 mmol) in ethanol (250 ml) to give a brown suspension. Stirring was continued until a dark solid was precipitated and the opaque solution turned clear. Compound 10b (1.02 g 3.3 mmol) was then added as a solution in ethanol (10 ml) to the mixture over 20 min.After being stirred for 3 h the reaction mixture was poured into water (200 ml) filtered and concentrated to low volume under reduced pressure. The aqueous phase was extracted with dichloromethane (3 times; 150 ml) and the combined extracts were dried and evaporated under reduced pressure to yield the crude amine. This was recrystallised to afford the title compound 11b as a colourless crystalline solid (711 mg 2.5 mmol 77) mp 142.5ndash;144 8C (from diethyl etherndash; LP) (Found MH1 281.1661. C18H20N2O requires MH 281.1654); nmax(CHCl3)/cm21 3490 3394 1633 1577 908 and 860; dH(400 MHz) spectrum shows this compound to be a mixture of rotamers 1.46 (3 H s CH3) 1.60 (3 H s CH3) 3.91 1554 J. Chem. Soc.Perkin Trans. 1 1997 (2 H br s NH2) 4.14 (1 H dd J 14 8 CH2) 4.51 (1 H dd J 13 7.3 CH2) 5.46 (1 H m HC C) 6.50 (1 H dd J 7.5 7.5 ArH) 6.63 (1 H d J 7.2 ArH) 6.68 (1 H d J 8.3 ArH) 6.98 (1 H dd J 7.3 7.3 ArH) 7.20 (3 H m ArH) and 7.36 (2 H d J 7 ArH); dC(67.5 MHz) 17.5 (CH3) 25.6 (CH3) 45.9 (CH2) 115.7 (CH) 118.2 (CH) 118.9 (CH) 127.5 (CH) 127.7 (CH) 128.4 (CH) 128.7 (C) 129.6 (CH) 130.4 (CH) 135.8 (C) 136.9 (C) 142.6 (C) and 171.2 (C); m/z (FAB) 281 (MH1) (36) 213 (36) 195 (16) 119 (100) 105 (100) 89 (13) and 77 (26). 2-(N-Benzoyl-N-prop-2-enylamino)benzenediazonium tetra- fluoroborate 12a Compound 11a (2.64 g 10.5 mmol) was dissolved in ethanol (3 ml) and aqueous fluoroboric acid (48 solution; 2 ml 32 mmol) was added to the solution; the mixture was then cooled to 25 8C. Isoamyl nitrite (1.7 ml 1.48 g 13 mmol) was added dropwise to the mixture and stirring continued for 0.5 h.Dilution of the mixture with diethyl ether (50 ml) led to precipitation of the title compound 12a as a fine colourless powder (2.95 g 8.4 mmol 80) mp 102ndash;103 8C (decomp. from acetonendash; diethyl ether) (Found C 54.48; H 4.04; N 12.17. C16H14BF4N3O requires C 54.73; H 4.02; N 11.97) (Found M1 264.1145. C16H14N3O requires M 264.1145); nmax(disc)/ cm21 3084 2924 2853 2263 1657 1586 968 951 769 and 730; dH(CD3COCD3 250 MHz) 4.79 (2 H ddd J 6 2 2 CH2) 5.20 (2 H m HC CH2) 6.02 (1 H m HC CH2) 7.48ndash;7.63 (3 H br m ArH) 7.73 (2 H ddd J 7 7 2 ArH) 7.95 (1 H ddd J 8 8 2 ArH) 8.11 (1 H dd J 8 2 ArH) 8.43 (1 H ddd J 8 8 2 ArH) 8.86 (1 H dd J 8 2 ArH); dC(CD3COCD3 67.5 MHz) 55.2 (CH2) 113.1 (C) 119.9 (CH2) 128.6 (CH) 129.3 (CH) 129.3 (CH) 129.5 (CH) 132.2 (CH) 134.3 (CH) 134.9 (CH) 143.6 (CH) 145.2 (2C) and 172.1 (C); m/z (FAB) 264 (M1 43) 236 (100) 195 (12) 105 (84) 89 (33) and 73 (66).2-(N-Benzoyl-N-3-methylbut-2-enylamino)benzenediazonium tetrafluoroborate 12b Compound 11b (640 mg 2.3 mmol) was dissolved in ethanol (1.4 ml) and aqueous fluoroboric acid (48 solution; 1.4 ml 7 mmol) was added to the solution; the mixture was then cooled to 25 8C. Isoamyl nitrite (380 ml 331 mg 2.78 mmol) was added dropwise to the mixture and stirring was continued for 0.5 h. Dilution of the mixture with diethyl ether (50 ml) led to precipitation of the title compound 12b (695 mg 1.8 mmol 80) as a pale yellow powder mp 109ndash;111 8C (decomp. from acetonendash; diethyl ether); nmax(CHCl3)/cm21 2927 2853 2268 1658 1588 and 1000; dH(CD3COCD3 400 MHz) 1.44 (3 H s CH3) 1.63 (3 H s CH3) 4.71 (2 H d J 7 CH2) 5.4 (1 H br m HC C) 7.55 (3 H m ArH) 7.71 (2 H m ArH) 7.94 (1 H dd J 8.4 8.4 ArH) 8.08 (1 H d J 8.4 ArH) 8.41 (1 H dd J 8 8 ArH) and 8.83 (1 H dd J 8.4 1.3 ArH); compound decomposed in solution during acquisition of the 13C spectrum; m/z (IS) 292.4 (M1 12).Reaction of compound 12a with tetrathiafulvalene Tetrathiafulvalene (376 mg 1.84 mmol) in acetone (2.5 ml) was added dropwise to a solution of compound 12a (460 mg 1.72 mmol) in degassed acetone (2 ml) and the mixture was stirred at room temperature for 5 min. It was then concentrated to low volume and poured into diethyl ether to precipitate a dark solid (380 mg) which was collected by filtration under a nitrogen atmosphere and retained.The filtrate was evaporated under reduced pressure to yield a deep brown oil (564 mg). Column chromatography of this oil on silica gel eluting with LPndash; dichloromethane (80 20) separated the products 5-prop-2- enyl-phenanthridin-6-one 13a and N-prop-2-enylbiphenyl-2- amine 15a which were further purified by chromatography as indicated below. Compound 13a 3 was purified by column chromatography eluting with LPndash;ethyl acetate the solvent polarity being gradually increased (98 2 95 5 90 10 80 20 and 50 50) to furnish the phenanthridinone (46 mg 0.2 mmol 11.4) as a pale yellow oil which solidified with time mp 94ndash;96 8C (lit.,3 98ndash;100 8C) (Found M1 235.0976. C16H13NO requires M 235.0976); nmax(CHCl3)/cm21 1640 1610 1587 and 977; dH(250 MHz) 5.07 (2 H d J 4.4 CH2) 5.20 (1 H d J 17.5 HC CH2) 5.24 (1 H d J 10.4 HC CH2) 6.03 (1 H ddt J 17.5 10.3 4.5 HC CH2) 7.34 (2 H m ArH) 7.51 (2 H m ArH) 7.77 (1 H dd J 7.3 7.3 ArH) 8.28 (2 H d J 8 ArH) and 8.55 (1 H d J 8 ArH); dC(67.5 MHz) 45.1 (CH2) 115.8 (CH2) 116.9 (CH) 119.5 (C) 121.6 (CH) 122.5 (CH) 123.3 (CH) 125.5 (C) 127.9 (CH) 129.0 (CH) 129.4 (CH) 131.9 (CH) 132.5 (CH) 133.8 (C) 138.4 (C) and 161.0 (C); m/z (EI) 235 (M1 38) 220 (100) 195 (12) and 178 (17).The second product 15a was chromatographed twice on silica gel with LPndash;dichloromethane (80 20) to give compound 15a (73 mg 0.35 mmol 22) as a pale yellow oil (Found M1 209.1222. C15H15N requires M 209.1204); nmax(film)/cm21 3429 3077 2918 1645 1604 748 and 704; dH(250 MHz) 3.73 (2 H br d J 5 CH2) 5.08ndash;5.25 (2 H m HC CH2) 5.81ndash;5.97 (1 H m HC CH2) 6.68 (1 H d J 8 ArH) 6.78 (1 H dd J 7.4 7.4 ArH) 7.08 (1 H dd J 6 1.4 ArH) 7.24 (1 H dd J 8 8 ArH) 7.32 (1 H m ArH) and 7.43 (4 H m ArH); dC(67.5 MHz) 46.4 (CH2) 110.7 (CH) 115.9 (CH2) 117.1 (CH) 127.2 (CH) 127.6 (C) 128.6 (CH) 128.9 (CH) 129.4 (CH) 130.2 (CH) 135.3 (CH) 139.4 (C) and 144.8 (C); m/z (EI) 209 (M1 100) 182 (45) 167 (34) 152 (20) and 77 (15).The dark solid from the initial precipitation was purified by chromatography twice on silica gel eluting with dichloromethanendash;acetone (66 34) to furnish 1-(1-benzoyl-2,3- dihydroindol-3-ylmethyl)tetrathiafulvalen-1-ium tetrafluoroborate 17a as a yellow powder (129 mg 0.29 mmol 17) mp 112ndash; 115 8C (from acetonendash;diethyl ether) (Found M1 440.0273. C22H18NOS4 requires M 440.0271); nmax(disc)/cm21 1634 1558 1084 and 663; dH(CD3COCD3 400 MHz NMR shows this compound to be a mixture of diastereoisomers) 3.77 (d J 5.6 CH2S minor) 3.87 (2 H m CH2S major) 4.13 (2 H m CH2N) 4.39 (1 H br m CHAr) 6.80 (1 H d J 6 CHS major) 6.86 (d J 6 CHS minor) 7.07 (2 H m ArH) 7.19 (1 H d J 6 CHS) 7.32 (1 H d J 6 CHS) 7.38ndash;7.60 (7 H m ArH) 8.17 (1 H d J 6 CHS) and 8.21 (1 H d J 6 CHS); dC(CD3COCD3 100 MHz) 37.1 (CH) 37.7 (CH) 52.6 (CH2) 53.0 (CH2) 55.5 (CH2) 56.0 (CH2) 84.9 (C) 85.1 (C) 110.8 (CH) 112.8 (CH) 111.1 (2CH) 122.7 (CH) 123.4 (CH) 123.9 (CH) 125.0 (CH) 125.7 (CH) 126.0 (CH) 127.7 (CH) 127.9 (CH) 129.3 (CH) 129.4 (CH) 129.7 (CH) 131.2 (CH) 132.2 (CH) 137.8 (C) 137.9 (C) 143.7 (C) 143.8 (C) 145.1 (CH) 145.7 (CH) 161.9 (C) 164.0 (C) and 169.2 (C); m/z (FAB) 440 (M1 12) 235 (95) 204 (89) 105 (73) 89 (45) and 77 (53).Reaction of compound 12b with tetrathiafulvalene Compound 12b (300 mg 0.8 mmol) was treated with tetrathiafulvalene (176 mg 0.86 mmol) in degassed acetone (4 ml) and the resultant solution was poured into diethyl ether (100 ml) to precipitate a black solid. The filtrate was evaporated under reduced pressure to a yellow oil which was adsorbed onto silica gel (from acetone) and chromatographed eluting with LPndash; dichloromethane (90 10) to separate the following products 13b 15b 16b and 18b. N-(3-Methylbut-2-enyl)phenanthridin-6-one 13b. This was further purified by chromatography eluting with LPndash;ethyl acetate (90 10) to give a pale oil (9.5 mg 0.04 mmol 5) which solidified to a waxy solid upon refrigeration mp 78ndash;81 8C (Found MH1 264.1380. C18H17NO requires MH 264.1388); nmax(film)/cm21 2856 1640 1610 and 1586; dH(400 MHz) 1.74 (3 H s CH3) 1.93 (3 H s CH3) 5.03 (2 H d J 5.5 CH2) 5.22 (1 H br t J 6 HC C) 7.30 (1 H ddd J 8 8 1 ArH) 7.38 (1 H d J 8.4 ArH) 7.52 (1 H ddd J 7.2 7.2 1.4 ArH) 7.58 (1 H ddd J 8 8 1 ArH) 7.75 (1 H ddd J 8.4 8.4 1.7 ArH) 8.30 (2 H dd J 7 7 ArH) and 8.55 (1 H dd J 8 1 ArH); dC(100 MHz) 18.4 (CH3) 25.6 (CH3) 41.3 (CH2) 119.5 (C) 119.7 J.Chem. Soc. Perkin Trans. 1 1997 1555 (CH) 121.6 (CH) 122.3 (CH) 123.3 (CH) 125.6 (C) 127.9 (CH) 128.9 (CH) 129.4 (CH) 132.4 (CH) 132.4 (CH) 133.6 (C) 135.8 (C) 137.4 (C) and 161.3 (C); m/z (FAB) 264 (MH1) 12 196 (10) 91 (6) 77 (23) 69 (72) and 55 (96). N-(3-Methylbut-2-enyl)biphenyl-2-amine 15b. This was puri- fied by column chromatography on silica gel eluting with LPndash; ethyl acetate (97 3) to give a pale yellow oil (25.4 mg 0.11 mmol 13.5) (Found M1 237.1516.C17H19N requires M 237.1517); nmax(film)/cm21 3419 3057 2969 2926 2854 1674 1603 1581 770 747 and 703; dH(250 MHz) 1.66 (3 H s CH3) 1.69 (3 H s CH3) 3.65 (2 H d J 6.5 CH2) 3.88 (1 H br s NH) 5.21 (1 H tm J 6.5 HC C) 6.68 (1 H d J 8.2 ArH) 6.76 (1 H ddd J 7.4 7.4 1.1 ArH) 7.09 (1 H dd J 7.5 1.6 ArH) 7.24 (1 H ddd J 8 8 1.6 ArH) 7.35 (1 H m ArH) and 7.45 (4 H m ArH); dC(67.5 MHz) 18.0 (CH3) 25.1 (CH3) 42.0 (CH2) 110.6 (CH) 116.9 (CH) 121.7 (CH) 127.1 (CH) 127.6 (C) 128.6 (CH) 128.8 (CH) 129.3 (CH) 130.2 (CH) 135.3 (C) 139.5 (C) and 145.1 (C); m/z (EI) 237 (M1 60) 222 (20) 180 (17) 169 (100) and 77(5). 1-Benzoyl-3-isopropylindole 16b. This was chromatographed on silica gel eluting with LPndash;ethyl acetate (40 1) to yield a pale oil (4.4 mg 0.02 mmol 2) (Found MH1 264.1367.C18H17NO requires MH 264.1388); nmax(CHCl3)/cm21 2929 2854 1679 and 1603; dH(400 MHz) 1.31 (6 H d J 6.9 2CH3) 3.12 (1 H septet J 7 CH) 7.03 (1 H s N-CH) 7.20ndash;7.45 (2 H m ArH) 7.53 (2 H dd J 7 7 ArH) 7.60 (2 H ddd J 7.4 7.4 1.5 ArH) 7.71 (2 H dd J 7 1.6 ArH) and 8.36 (1 H d J 8 ArH); dC(100 MHz) 22.5 (2CH3) 25.3 (CH) 116.6 (CH) 119.4 (CH) 122.1 (CH) 123.53 (CH) 124.85 (CH) 128.56 (CH) 129.02 (CH) 129.50 (C) 130.51 (C) 131.6 (CH) 135.00 (C) 136.7 (C) and 168.5 (C); m/z (FAB) 264 (MH1) 59 220 (11) 196 (59) 105 (100) 91 (15) 77 (34) 69 (84) and 55 (65). 1-Benzoyl-2,3-dihydro-3-(2-hydroxypropan-2-yl)indole 18b. This was isolated from the initial elution without the need for further purification as a pale oil (42 mg 0.16 mmol 21) which solidified with time to a beige powder mp 109ndash;111 8C (Found MH1 282.1512.C18H19NO2 requires MH 282.1494); nmax(CHCl3)/cm21 3378 2930 2853 1684 1636 and 1595; dH(CD3SOCD3 400 MHz at 353 K) 0.99 (3 H s CH3) 1.13 (3 H s CH3) 3.26 (1 H dd J 9 4.3 CH) 4.00 (2 H m N-CH2) 7.00 (1 H ddd J 7.5 7.5 1.1 ArH) 7.13 (1 H dd J 8 8 ArH) 7.39 (1 H d J 7.6 ArH) and 7.39ndash;7.54 (6 H m ArH); dC(100 MHz) 25.4 (CH3) 26.4 (CH3) 50.5 (CH) 52.4 (CH2) 70.6 (C) 115.7 (CH) 122.7 (CH) 125.9 (CH) 126.3 (CH) 126.8 (CH) 128.05 (CH) 129.6 (CH) 133.1 (C) 136.8 (C) 142.95 (C) and 167.3 (C); m/z (FAB) 282 (MH1) 8 223 (6) 147 (7) and 105 (33). Tributyltin hydride-mediated radical cyclisation of the bromide 14 The bromide 14 (0.104 g 0.328 mmol) in toluene (1.6 ml) was heated under reflux whilst AIBN (0.010 g 0.0678 mmol) and tributyltin hydride (0.124 g 0.427 mmol) were added in toluene (2 ml) to the mixture using a syringe pump over 1 h.The resulting solution was heated under reflux for 2 h after which evaporation of toluene led to a mixture which was shown by 1H NMR spectroscopy to contain tributyltin residues as well as a mixture of phenanthridinone 13a and 1-benzoyl-3-methyl-2,3-dihydroindole 19 in a 73 27 ratio. Column chromatography eluting with (hexanendash;ethyl acetate 16 1) removed the tributyltin residues. Authentic dihydroindole was then isolated as below. Separation of compound 19. A mixture of phenanthridinone 13a and compound 19 (0.07 g 0.297 mmol) from the above experiment was added in a mixture of acetone and water (9 1; 20 ml) to osmium tetroxide (0.8 ml of a solution in ButOH 0.0297 mmol).4-Methylmorpholine N-oxide (0.0418 g 0.0357 mmol) was added to the mixture which was then stirred for 24 h at room temperature. After this solid sodium metabisulfite (1 g) was added to the mixture followed by aqueous sodium metabisulfite 0.7 g in water (5 ml); the mixture was then stirred for 45 min. After this the orange solution was filtered through Kieselguhr to remove osmium residues and then most of the acetone was removed in vacuo. The resulting solution was extracted with dichloromethane (3 times; 10 ml) dried (MgSO4) filtered and evaporated to dryness to give a pale yellow oil. This was subjected to column chromatography eluting with hexanendash; ethyl acetate (4 1) and gave compound 19 as a white solid (18 mg) together with dihydroxylation derivative 20 (42 mg) also as a white solid.1-Benzoyl-3-methyl-2,3-dihydroindole 19. Mp 101ndash;102 8C. (diethyl etherndash;LP) (lit.,19 101ndash;102 8C); nmax(KBr)/cm21 1638 1478 and 1393; dH(250 MHz) 1.48 (d 3 H J 7 Me) 3.48 and 3.50 (m 1 H CHMe) 3.60 (br s 1 H NCH2) 4.23 (br s 1 H NCH2) and 7.06ndash;8.26 (m 9 H ArH); m/z (EI) 237 (M1 10) 130 (10) and 105 (100). 5-(2,3-Dihydroxypropyl)phenanthridin-6-one 20. Mp 147ndash; 148 8C; nmax(KBr)/cm21 3381 3335 2923 2853 and 1640; dH(250 MHz) 3.34 (br s 2 H 2 times; OH) 3.50 (dd 1 H J 11.2 2.2 NCH2) 3.62 (dd 1 H J 11.2 3.2 NCH2) 4.05 (m 1 H OCH) 4.25 (dd 1 H J 13.5 5.5 OCH2) 4.25 (dd 1 H J 13.5 7.5 OCH2) 7.18ndash;7.56 (m 4 H ArH) 7.73 (t 1 H J 8 ArH) 8.25 (t 2 H J 8 ArH) and 8.45 (d 1 H J 8); dC(CD3COCD3 62.9 MHz) 46.7 (CH2) 65.0 (CH2) 71.4 (CH) 117.2 (CH) 120.2 (C) 123.0 (CH) 123.6 (CH) 124.4 (CH) 126.2 (C) 128.9 (CH) 129.3 (CH) 130.6 (CH) 133.8 (CH) 134.9 (C) 138.9 (C) and 163.1 (C).N-(2-Nitrophenyl)acetamide 20 29 To a warmed solution of 2-nitroaniline (10.4 g 75 mmol) in benzene (10 ml) ethanoic anhydride (8 ml 8.7 g 85 mmol) was added dropwise followed by concentrated sulfuric acid (0.5 ml); this led to a vigorous reaction causing the benzene to reflux. The resulting mixture was warmed at reflux for 4 h after which it was cooled and evaporated in vacuo to furnish the title compound 29 as yellow needles (12.9 g 71.6 mmol 94.5) mp 93ndash; 95 8C (lit.,20 92ndash;93 8C from dilute aqueous ethanol) (Found M1 180.0497. C8H8N2O3 requires M 180.0535); nmax(disc)/ cm21 3372 3090 2926 1703 1611 1586 1510 1343 836 795 and 751; dH(270 MHz) 2.30 (3 H s CH3) 7.10 (1 H dd J 8 8 ArH) 7.65 (1 H dd J 8 8 ArH) 8.20 (1 H d J 8 ArH) 8.75 (1 H d J 8 ArH) and 10.34 (1 H br s NH); dC(67.5 MHz) 25.2 (CH3) 128.1 (CH) 122.9 (CH) 125.3 (CH) 134.5 (C) 135.5 (CH) 136.0 (C) and 168.8 (C); m/z (EI) 180 (M1 17) 138 (100) and 92 (36).N-(2-Nitrophenyl)-N-prop-2-enylacetamide 31a To a slurry of washed sodium hydride (60 suspension in mineral oil; 213 mg 5 mmol) in dry tetrahydrofuran (15 ml) was added compound 29 (525 mg 2.92 mmol) portionwise over a period of 10 min under nitrogen; the mixture was then stirred for 0.5 h. Prop-2-enyl bromide 30a (500 ml 358 mg 5 mmol) was then added dropwise to the mixture after which it was stirred in the dark (12 h). Excess of tetrahydrofuran was then removed from the mixture by evaporation under reduced pressure and the yellow residue was partitioned between ethyl acetate and water (50 50 v/v; 300 ml) the aqueous phase was further extracted with ethyl acetate (2 times; 150 ml).The combined organic extracts were dried filtered and evaporated to yield a yellow oil which was adsorbed onto silica gel (from dichloromethane) and chromatographed using LPndash;dichloromethanendash;methanol (70 20 10) as eluent to furnish the title compound 31a (412 mg 2 mmol 68) as an orange oil (Found MH1 221.0927. C11H12N2O3 requires MH 221.0926); nmax(film)/cm21 3081 3012 2983 2931 1672 1604 1579 1530 1457 1436 1353 1098 993 929 and 850; dH(CD3SOCD3 400 MHz at 398 K; the spectrum shows this compound to be a 5 1 rotameric mixture) 1.86 (3 H s CH3) 4.19 (2 H br m CH2) 5.09 (2 H m HC CH2) 5.83 (1 H m HC CH2) 7.32 (1 H dd J 7 2 ArH) 7.61 (1 H ddd J 7.6 7.6 1.5 ArH) 7.76 (1 H ddd J 7.6 7.6 1.5 ArH) and 8.02 (1 H dd J 7.2 ArH); dC(67.5 MHz) 21.4 (CH3 minor) 21.9 (CH3) 51.3 (CH2) 54.2 (CH2 minor) 117.6 1556 J.Chem. Soc. Perkin Trans. 1 1997 (CH2 minor) 118.7 (CH2) 124.5 (CH minor) 125.0 (CH) 125.4 (CH minor) 129.2 (CH minor) 129.8 (CH) 131.6 (CH) 131.8 (CH) 132.3 (CH minor) 133.5 (CH minor) 133.9 (CH) 134.4 (C) 135.1 (C minor) 146.0 (C minor) 146.6 (C) 169.1 (C) and 170.7 (C minor); m/z (FAB) 221 (MH1) 100 179 (69) 145 (32) 133 (25) 119 (15) 105 (12) 91 (8) and 77 (15). N-(2-Nitrophenyl)-N-but-2-enylacetamide 31b In a manner analogous to that for the preparation of 31a compound 29 (2.06 g 11.4 mmol) sodium hydride (60 suspension in mineral oil; 680 mg 17.7 mmol) and 4-bromobut-2-ene 30b (1.3 ml 1.73 g 12.9 mmol) were allowed to react in dry tetrahydrofuran (10 ml).The resulting crude yellow oil was adsorbed onto silica gel (from dichloromethane) and chromatographed using LPndash;dichloromethanendash;methanol (70 20 10) as eluent to furnish the title compound 31b (2.10 g 9.5 mmol 83) as a mustard coloured oil (Found C 61.95; H 6.06; N 11.79; MH1 235.1086. C12H14N2O3 requires C 61.53; H 6.02; N 11.96; MH 235.1004); nmax(film)/cm21 3010 2967 2919 2857 1666 1602 1578 1530 1352 1005 and 754; dH(CD3- SOCD3 400 MHz at 398 K; the spectrum shows the compound to be a 3 1 rotameric mixture) 1.56 (3 H d J 5 CH3) 1.84 (3 H s CH3) 4.12 (2 H br m NCH2) 5.46 (2 H m HC CH) 7.45 (1 H dd J 8 1.2 ArH) 7.48 (d J 8 ArH minor) 7.60 (1 H dd J 7.8 7.8 ArH) 7.78 (1 H ddd J 7.7 7.7 1.5 ArH) and 8.00 (1 H dd J 8 1.5 ArH); dC(67.5 MHz) 12.3 (CH3 minor) 17.6 (CH3) 21.9 (CH3 minor) 22.6 (CH3) 44.9 (CH2 minor) 51.2 (CH2) 123.7 (CH minor) 124.8 (CH) 125.1 (CH minor) 125.3 (CH) 128.0 (CH minor) 129.4 (CH) 131.0 (CH) 132.1 (CH) 133.8 (CH minor) 134.0 (CH) 135.7 (C) 136.1 (C minor) 146.0 (C minor) 147.6 (C) 169.6 (C) and 171.0 (C minor); m/z (FAB) 235 (MH1) 56 191 (11) 139 (35) 119 (14) 91 (23) 77 (25) 55 (100) and 43 (85).N-(2-Nitrophenyl)-N-(3-methylbut-2-enyl)acetamide 31c In a manner analogous to that for the preparation of 31a compound 29 (2.48 g 14 mmol) sodium hydride (60 suspension in mineral oil; 846 mg 56.4 mmol) and 4-bromo-2-methylbut-2- ene 30c (3.3 ml 28 mmol) were allowed to react in dry tetrahydrofuran (100 ml). The resulting crude yellow oil was adsorbed onto silica gel (from dichloromethane) and chromatographed using LPndash;dichloromethanendash;methanol (70 20 10) as eluent to furnish the title compound 31c (2.58 g 10.4 mmol 78) as an orange oil (Found C 62.70; H 6.63; N 11.06; MH1 249.1240.C13H16N2O3 requires C 62.89; H 6.50; N 11.28; MH 249.1239); nmax(film)/cm21 2973 2933 1672 1602 1578 1353 and 734; dH(CD3SOCD3 400 MHz at 298 K; the spectrum showed this compound to be a rotameric 4 1 mixture) 1.23 (3 H s CH3) 1.49 (s CH3 minor) 1.53 (3 H s CH3) 1.64 (s CH3 minor) 1.73 (3 H s CH3) 2.14 (s CH3 minor) 4.09 (2 H d J 7.6 CH2) 4.96 (1 H br t J 6 CH major) 5.34 (br t J 6 CH minor) 7.45 (m ArH minor) 7.56 (1 H dd J 7.8 1.4 ArH) 7.66 (1 H ddd J 7.8 7.8 1.3 ArH) 7.71 (dd J 8 8 ArH minor) 7.79 (1 H ddd J 7.6 7.6 1.5 ArH) 7.91 (d J 8 ArH minor) and 8.04 (1 H dd J 8 1.5 ArH); dC(67.5 MHz) 16.7 (CH3) 17.2 (CH3 minor) 21.2 (CH3) 21.5 (CH3 minor) 25.2 (CH3) 45.7 (CH2) 49.6 (CH2 minor) 117.7 (CH) 118.7 (CH minor) 124.6 (CH minor) 124.9 (CH) 127.6 (CH minor) 129.2 (CH) 129.7 (CH minor) 131.7 (CH) 133.4 (CH minor) 133.8 (CH) 135.2 (C) 135.8 (C minor) 136.5 (C minor) 137.8 (C) 146.3 (C minor) 147.2 (C) 169.2 (C) and 170.5 (C minor); m/z (FAB) 249 (MH1) 57 205 (9) 181 (19) 139 (42) 91 (17) and 77 (19).N-(2-Aminophenyl)-N-prop-2-enylacetamide 32a Sodium boranuide (154 mg 4 mmol) was added to a rapidly stirred solution of copper(II) acetylacetonate (70 mg 0.3 mmol) in ethanol (25 ml) to give a brown suspension. Stirring was continued until a dark solid was precipitated and the opaque solution turned clear. Compound 31a (260 mg 1.3 mmol) was then added as a solution in ethanol over 20 min to the reaction which was then stirred for 3 h.After this it was poured into water (200 ml) filtered and concentrated to low volume under reduced pressure. The aqueous phase was extracted with dichloromethane dried and evaporated under reduced pressure to yield the crude amine which was recrystallised to afford the title compound 32a as a yellow powder (from diethyl etherndash; LP) (215 mg 1.21 mmol 97) (Found M1 190.1115. C11H14N2O requires M 190.1106); nmax(film)/cm21 3437 3349 3078 3037 2978 2928 1651 1583 988 926 and 748; dH(250 MHz; the spectrum showed this compound to be a 9 1 rotameric mixture) 1.85 (s CH3 minor) 1.88 (3 H s CH3) 3.87 (2 H br s NH2) 3.97 (1 H dd J 14 7 CH2) 4.44 (1 H dd J 14 7 CH2) 5.11 (1 H dt J 16 1 HC CH2) 5.11 (1 H dt J 9 1 HC CH2) 5.91 (1 H m HC CH2) 6.80 (2 H m ArH) 6.94 (1 H d J 8 ArH) and 7.12 (1 H dd J 8 8 ArH); dC(67.5 MHz) 21.0 (CH3 minor) 21.9 (CH3) 48.7 (CH2 minor) 50.3 (CH2) 116.1 (CH) 118.4 (CH2) 121.8 (CH minor) 127.7 (C) 129.0 (CH) 129.2 (CH) 129.3 (CH) 132.8 (CH) 143.0 (C) and 171.4 (C); m/z (EI) 190 (M1 74) 172 (50) 147 (36) 119 (71) 107 (100) 92 (18) and 77 (18).N-(2-Aminophenyl)-N-but-2-enylacetamide 32b Sodium boranuide (305 mg 12.7 mmol) was added to a rapidly stirred solution of copper(II) acetylacetonate (309 mg 1.17 mmol) in ethanol (100 ml) to give a brown suspension. Stirring was continued until a dark solid was precipitated and the opaque solution turned clear. Compound 31b (735 mg 3.14 mmol) was then added as a solution in ethanol to the mixture over 20 min.After the reaction mixture had been stirred for 3 h it was poured into water (200 ml) filtered and concentrated to low volume under reduced pressure. The aqueous phase was extracted with dichloromethane and the extract dried and evaporated under reduced pressure to yield the crude amine. After work-up the crude amine was recrystallised to yield the title compound 32b as a colourless low density powder (457 mg 2.2 mmol 72) mp 96ndash;97 8C (from diethyl etherndash;LP) (Found MH1 205.1333. C12H16N2O requires MH 205.1341); nmax(CHCl3)/cm21 3491 3398 2919 2855 1649 1615 970 and 640; dH(400 MHz; the spectrum shows this compound to be a rotameric mixture) 1.63 (3 H d J 5 CH3) 1.85 (3 H s CH3) 3.88 (2 H br s NH2) 3.92 (1 H dd J 13.3 5.5 CH2) 4.32 (1 H dd J 13 5.1 CH2) 5.56 (2 H m HC CH) 6.72 (1 H ddd J 7.6 7.6 1.3 ArH) 6.78 (1H dd J 8 1.2 ArH) 6.93 (1 H dd J 7.8 1.5 ArH) and 7.13 (1 H ddd J 7.8 7.8 1.5 ArH); dC(67.5 MHz) 17.6 (CH3) 22.0 (CH3) 49.6 (CH2) 116.0 (CH) 118.5 (CH) 125.5 (CH) 128.0 (C) 129.1 (CH) 129.4 (CH) 130.0 (CH) 143.1 (C) and 171.3 (C); m/z (FAB) 205 (MH1) 100 187 (13) 161 (27) 119 (23) 77 (15) and 55 (34).N-(2-Aminophenyl)-N-(3-methylbut-2-enyl)acetamide 32c Sodium boranuide (384 mg 10 mmol) was added to a rapidly stirred solution of copper(II) acetylacetonate (234 mg 0.9 mmol) in ethanol (100 ml) to give a brown suspension. Stirring was continued until a dark solid was precipitated and the opaque solution turned clear. Compound 31c (803 mg 3.24 mmol) was then added as a solution in ethanol to the mixture over 20 min. After the reaction mixture had been stirred for 3 h it was poured into water (200 ml) filtered and concentrated to low volume under reduced pressure.The aqueous phase was extracted with dichloromethane (3 times; 50 ml) and the extract dried and evaporated under reduced pressure to yield the crude amine. After work-up the crude amine was recrystallised to yield the title compound 32c as a cream powder (460 mg 2.1 mmol 65) mp 122.5ndash;124 8C (from diethyl etherndash;LP) (Found MH1 219.1475. C13H18N2O requires MH 219.1419); nmax- (CHCl3)/cm21 3493 3398 1642 1615 858 and 637; dH(400 MHz) 1.45 (3 H s CH3) 1.67 (3 H s CH3) 1.84 (3 H s CH3) 3.79 (2 H br s NH2) 4.09 (1 H dd J 14 7.8 CH2) 4.30 (1 H dd J 14 7.3 CH2) 5.28 (1 H m HC C) 6.71 (2 H m ArH), J. Chem. Soc. Perkin Trans. 1 1997 1557 6.93 (1 H dd J 7.8 1.5 ArH) and 7.13 (1 H ddd J 8 8 1.5 ArH); dC(100 MHz) 17.5 (CH3) 22.0 (CH3) 25.6 (CH3) 44.9 (CH2) 115.9 (CH) 118.5 (CH) 119.0 (CH) 128.1 (C) 129.00 (CH) 129.3 (CH) 138.8 (C) 143.00 (C) and 171.2 (C); m/z (FAB) 219 (MH1) 100 203 (10) 175 (48) 151 (73) 133 (36) 119 (38) 109 (54) 93 (22) and 77 (16).2-(N-Acetyl-N-prop-2-enylamino)benzenediazonium tetrafluoroborate 33a Compound 32a (133 mg 0.75 mmol) and aqueous fluoroboric acid (48 solution; 200 ml 0.1 mmol) were mixed in ethanol (1 ml) and the mixture was cooled to 25 8C. Isoamyl nitrite (120 ml 105 mg 0.9 mmol) was added dropwise to the mixture and the stirring continued for 0.5 h. Dilution of the mixture with diethyl ether (50 ml) resulted in precipitation of the title compound 33a as a yellow solid (151 mg 0.55 mmol 73) mp 90.5ndash;92 8C (decomp.from acetonendash;diethyl ether) (Found M1 202.0987. C11H12N3O requires M 202.0980); nmax(disc)/cm21 3081 3010 2926 2266 1673 1586 974 and 772; dH(CD3COCD3 400 MHz) 2.44 (3 H s CH3) 4.73 (2 H br m CH2) 5.33 (2 H br m HC CH2) 6.17 (1 H m HC CH2) 7.85 (2 H m ArH) 8.38 (1 H dd J 7 7 ArH) and 8.75 (1 H d J 8 ArH); dC compound decomposed in solution during acquisition of the 13C spectrum; m/z (FAB) 202 (M1 100) and 174 (48). 2-(N-Acetyl-N-but-2-enylamino)benzenediazonium tetrafluoroborate 33b In a procedure similar to that described for the preparation of 33a compound 32b (230 mg 1.1 mmol) aqueous fluoroboric acid (48 solution; 700 ml 350 mg 4 mmol) and isoamyl nitrite (250 ml 105 mg 1.8 mmol) were allowed to react in ethanol (1 ml) to furnish the title compound 33b (295 mg 1 mmol 85) as a cream solid mp 73ndash;75 8C (decomp.from acetonendash;diethyl ether) nmax(CHCl3)/cm21 2274 1679 1590 and 969; dH(CD3- COCD3 400 MHz) 1.70 (3 H d J 5 CH3) 2.84 (3 H br s CH3) 4.66 (2 H br m CH2) 5.80 (2 H br m HC CH) 7.89 (1 H dd J 7.4 7.4 ArH) 7.98 (1 H d J 8.4 ArH) 8.38 (1 H dd J 8.4 8.4 ArH) and 8.76 (1 H d J 8 ArH); dC compound decomposed in solution during acquisition of the 13C spectrum; m/z (IS) 216.2 (M1 20). 2-N-Acetyl-N-(3-methylbut-2-enyl)aminobenzenediazonium tetrafluoroborate 33c In a procedure similar to that described for the preparation of 33a compound 32c (392 mg 1.8 mmol) aqueous fluoroboric acid (48 solution; 800 ml 4 mmol) and isoamyl nitrite (320 ml 279 mg 2.3 mmol) were allowed to react in ethanol (2 ml) to afford the title compound 33c as a pale yellow powder (523 mg 1.6 mmol 91) mp 87ndash;89.5 8C (decomp.from acetonendash; diethyl ether); nmax(CHCl3)/cm21 2273 1678 1590 and 1003; dH(CD3COCD3 400 MHz) 1.68 (br s CH3 minor) 1.72 (6 H br s 2 CH3) 2.83 (3 H br s CH3) 4.69 (2 H br m CH2) 5.48 (1 H br m HC C) 7.89 (1 H dd J 6 6 ArH) 7.94 (1 H d J 8.3 ArH) 8.40 (1 H ddd J 8.5 8.5 1.3 ArH) and 8.75 (1 H d J 8 ArH); dC compound decomposed in solution during acquisition of the 13C spectrum; m/z (IS) 230.2 (M1 5). 1-(1-Acetyl-2,3-dihydroindol-3-ylmethyl)tetrathiafulvalen-1-ium tetrafluoroborate 34 Tetrathiafulvalene (46.3 mg 0.23 mmol) was added in one portion to compound 31a (52.5 mg 0.19 mmol) in dry degassed acetone (2 ml) and the mixture stirred for 5 min; it was then poured into diethyl ether (50 ml) to precipitate a dark solid which was filtered off.Purification of this solid by column chromatography was carried out twice on silica gel eluting with dichloromethanendash;acetone (66 33) to give a dark brown waxy solid. This was dissolved in acetone and precipitated from diethyl ether to afford the title compound 34 (31.2 mg 0.13 mmol 68) as a bright yellow powder mp 107ndash;110 8C (from acetonendash;diethyl ether); nmax(disc)/cm21 2925 1684 1654 1596 1084 and 758; dH(CD3COCD3 400 MHz; the spectrum shows this compound to be a mixture of diastereoisomers) 2.08 (s CH3 minor) 2.18 (3 H s CH3) 3.77 (d J 13 CH2S minor) 3.94 (1 H dd J 13 6.7 CH2S) 4.02 (1 H dd J 13 6.7 CH2S) 4.26 (1 H m CH) 4.40 (m CH2N minor) 4.53 (2 H m CH2N) 6.84 (d J 6 CHS minor) 6.98 (1 H d J 6 CHS) 7.01 (1 H d J 8 ArH) 7.16ndash;7.28 (3 H m ArH) 7.38 (1 H d J 7.3 CHS) 7.43 (1 H d J 7.4 CHS) 8.12 (d J 7.3 CHS minor) and 8.23 (1 H d J 6 CHS); dC(CD3COCD3 100 MHz) 24.2 (CH3) 37.5 (2 CH) 53.8 (CH2) 53.9 (CH2) 85.2 (C) 85.6 (C) 112.5 (CH) 117.6 (CH) 117.7 (CH) 122.5 (CH) 122.8 (CH) 123.2 (CH) 123.6 (CH) 124.2 (CH) 125.5 (CH) 125.6 (CH) 129.6 (CH) 129.8 (CH) 131.0 (C) 144.2 (C) 145.3 (CH) 145.5 (CH) 163.0 (C) 163.7 (C) and 169.2 (2C); m/z (FAB) 378 (M1 22) 307 (13) 204 (61) 174 (16) and 77 (48).1-Acetyl-2,3-dihydro-3-(1-hydroxyethyl)indole 35b Compound 33b (20 mg 0.07 mmol) and tetrathiafulvalene (14.4 mg 0.07 mmol) were allowed to react in a degassed acetonendash;water mixture (99 1 v/v; 1 ml) which was stirred at room temperature for 5 min. Evaporation and chromatography of the mixture gave a deep brown residue which on silica gel eluting with LPndash;dichloromethane of gradually increasing polarity (90 10 80 20 50 50) and then ethyl acetate led to the title compound 35b (8.3 mg 0.04 mmol 59) as a pale yellow oil which solidified to a waxy yellow solid mp 75ndash;77 8C (Found M1 205.1103.C12H15NO2 requires M 205.1103); nmax(CHCl3)/ cm21 3381 2854 1652 1597 and 806; dH(400 MHz; the spectrum shows this compound to be a 1 1 diastereoisomeric mixture) 1.10 (3 H d J 6.3 CH3) 1.26 (3 H d J 6.3 CH3) 2.23 (3 H s CH3) 3.40 (1 H m CHAr) 3.51 (1 H m CHAr) 4.10 (3 H m CH2 CHOH overlapping) 7.03 (1 H m ArH) 7.23 (2 H m ArH) and 8.19 (1 H d J 8.1 ArH); dC(67.5 MHz) 18.7 (CH3) 20.5 (CH3) 24.1 (CH3) 46.7 (CH) 47.3 (CH) 49.8 (CH2) 50.7 (CH2) 68.7 (CH) 69.8 (CH) 116.9 (CH) 123.5 (2CH) 124.3 (CH) 124.9 (CH) 128.2 (CH) 128.3 (CH) 131.6 (2C) 143.2 (C) 143.6 (C) 168.7 (C) and 168.9 (C); m/z (CI) 205 (M1) 5.Reaction of compound 33c with tetrathiafulvalene Compound 33c (145.3 mg 0.46 mmol) and tetrathiafulvalene (107 mg 0.52 mmol) were allowed to react in a degassed acetonendash;water mixture (99 1 v/v). The deep red residue was adsorbed onto silica gel (from acetone) and then chromatographed on silica gel eluting first with LPndash;dichloromethane (90 10) and then with mixtures of gradually increasing polarity (75 25 50 50 25 75 100 dichloromethane) and then ethyl acetate (100) to separate two products 35c and 36c. Compound 35c was further purified by chromatography on silica gel using ethyl acetatendash;dichloromethane (50 50) as eluent to afford N-acetyl-2,3-dihydro-3-(2-hydroxypropan-2-yl)indole as a pale waxy solid (58 mg 0.26 mmol 59) mp 108ndash;111 8C (Found M1 219.1258.C13H17NO2 requires M 219.1259); nmax(CHCl3)/cm21 3370 2992 2930 2854 1652 1594 and 642; dH(400 MHz) 1.18 (3 H s CH3) 1.27 (3 H s CH3) 1.65 (1 H br s OH) 2.25 (3 H s CH3) 3.36 (1 H dd J 8.1 5 HC-Ar) 4.06 (2 H m CH2) 7.01 (1 H ddd J 7.5 7.5 1 ArH) 7.25 (1 H ddd J 7 7 0.7 ArH) 7.32 (1 H d J 7.5 ArH) and 8.23 (1 H d J 8 ArH); dC(100 MHz) 24.2 (CH3) 26.0 (CH3) 27.1 (CH3) 51.1 (CH) 51.6 (CH2) 72.8 (C) 117.0 (CH) 123.3 (CH) 125.8 (CH) 128.3 (CH) 131.3 (C) 143.6 (C) and 168.5 (C); m/z (EI) 219 (M1 5) 201 (2) 161 (25) 118 (100) 91 (15) 77 (5) and 59 (22). Compound 36c was further purified by column chromatography on silica gel using LPndash;ethyl acetate (50 50) as eluent to furnish N-acetyl-2,3-dihydro-3-(2-fluoropropan-2-yl)indole as a cream powder (5 mg 0.02 mmol 5) mp 103ndash;105.5 8C (Found MH1 222.1292.C13H16FNO requires MH 222.1294); nmax(CHCl3)/cm21 2934 1652 1596 1402 and 1341; dH(400 MHz) 1.24 (3 H d 3JHF 21.4 CH3) 1.39 (3 H d 3JHF 22 CH3), 1558 J. Chem. Soc. Perkin Trans. 1 1997 2.25 (3 H s CH3) 3.63 (1 H m CH) 3.96 (1 H dd J 11.2 4 CH2) 4.06 (1 H dd J 11.2 4 CH2) 7.01 (1 H dd J 7.4 7.4 ArH) 7.28 (2 H m ArH) and 8.22 (1 H d J 8.2 ArH); dF235 MHz CDCl3 with CFCl3 (0.2) as internal reference spectrum showed this compound to be a mixture of rotamers 275.73 (m minor) and 276.5 (m major); dC(100 MHz) 23.1 (d 2JCF 24.1 CH3) 24.2 (CH3) 24.5 (d 2JCF 24.2 CH3) 49.7 (d 2JCF 24.2 CH) 51.1 (d 3JCF 7.7 CH2) 96.8 (d 1JCF 170 C) 117.1 (CH) 123.5 (CH) 125.5 (CH) 128.7 (CH) 130.1 (C) 143.5 (C) and 168.4 (C); m/z (FAB) 222 (MH1) 68 178 (5) 144 (11) 128 (7) 118 (45) 91 (31) 69 (66) and 55 (95).Acknowledgements We thank the EPSRC for support and EPSRC and SmithKline Beecham for a CASE studentship. We also thank the EPSRC Mass Spectrometry Service Centre Swansea for mass spectra. We thank the Alliance Programme for Anglo-French cooperation for the award of a grant (S. G.) and Nadeem Bashir for assistance. References 1 A. L. J. Beckwith and W. B. Gara J. Chem. Soc. Perkin Trans. 2 1975 593 795. A. L. J. Beckwith and G. F. Meijs J. Org. Chem. 1987 52 1922. 2 J. P. Dittami and H. Ramanathan Tetrahedron Lett. 1988 29 45. 3 H. Togo and O. Kikuchi Tetrahedron Lett. 1988 29 4133; H. Togo and O. Kikuchi Heterocycles 1989 28 373. 4 A. J. Clark and K. Jones Tetrahedron 1992 48 6875; K. Jones and J. M. D. Storey J.Chem. Soc. Chem. Commun. 1992 1766; K. Jones T. C. T. Ho and J. Wilkinson Tetrahedron Lett. 1995 36 6743. 5 G. B. Gill G. Pattenden and S. J. Reynolds J. Chem. Soc. Perkin Trans. 1 1994 369. 6 D. L. Boger and J. A. McKie J. Org. Chem. 1995 60 1271. 7 D. P. Curran H. Yu and H. Liu Tetrahedron 1994 50 7343. 8 J. A. Murphy C. Lampard and N. Lewis J. Chem. Soc. Chem. Commun. 1993 295; R. Fletcher C. Lampard J. A. Murphy and N. Lewis J. Chem. Soc. Perkin Trans. 1 1995 623. 9 T. J. Mills and J. A. Murphy unpublished results. 10 For a preliminary account see J. A. Murphy C. Lampard F. Rasheed N. Lewis M. B. Hursthouse and D. E. Hibbs Tetrahedron Lett. 1994 35 8675. 11 K. Jones and J. Wilkinson J. Chem. Soc. Chem. Commun. 1992 1767; D. P. Curran and N. C. DeMello J. Chem. Soc. Chem. Commun.1993 1314. 12 N. S. Narasimhan and I. S. Aidhen Tetrahedron Lett. 1988 29 2987; L. Friedman Tetrahedron Lett. 1961 7 238; W. B. Motherwell A. M. K. Pennell and F. Uzzainwalla J. Chem. Soc. Chem. Commun. 1992 1067; W. B. Motherwell and A. M. K. Pennell J. Chem. Soc. Chem. Commun. 1991 877; A. Citterio R. Sebastiano A. Maronati R. Santi and F. Bergamini J. Chem. Soc. Chem. Commun. 1994 1517. 13 D. H. Hey C. W. Rees and A. R. Todd J. Chem. Soc. C 1967 1518; D. H. Hey G. H. Jones and M. J. Perkins J. Chem. Soc. C 1971 116. 14 (a) J. Grimshaw R. J. Haslett and J. Trocha-Grimshaw J. Chem. Soc. Perkin Trans 1 1977 2448; (b) J. Grimshaw and R. J. Haslett J. Chem. Soc. Perkin Trans 1 1980 657. 15 L. F. Fieser and E. L. Martin J. Am. Chem. Soc. 1935 57 1835. 16 F. Mandyuk and R. V. Sendega Zh.Org. Khim. 1974 10 364. 17 P. Ruggli and J. Rohner Helv. Chim. Acta 1942 1533. 18 K. Hanaya T. Muramitsu and H. Kudo J. Chem. Soc. Perkin Trans. 1 1979 2409. 19 D. E. Armes H. R. Ansari A. D. G. France A. C. Lovesey B. Novitt and R. Simpson J. Chem. Soc. C 1971 3088. 20 L. F. Fieser and E. L. Martin J. Am. Chem. Soc. 1935 57 1835. Paper 6/07060D Received 16th October 1996 Accepted 27th January 1997 J. Chem. Soc. Perkin Trans. 1 1997 1549 Synthesis of functionalised indolines by radical-polar crossover reactions John A. Murphy,*,dagger;,a Faiza Rasheed,Dagger;,a Steacute;phane Gastaldi,b T. Ravishanker b and Norman Lewis c a Department of Chemistry University of Nottingham University Park Nottingham UK NG7 2RD b Department of Pure and Applied Chemistry University of Strathclyde 295 Cathedral Street Glasgow UK G1 1XL c SmithKline Beecham Pharmaceuticals Old Powder Mills Leigh nr.Tonbridge Kent UK TN11 9AN Functionalised indolines have been prepared by treating tetrathiafulvalene (TTF) with 2-(N-acyl-Nallylamino) benzenediazonium tetrafluoroborates. N-Benzoyl-protected substrates afford complex reaction mixtures due to competing radical cyclisation onto the benzoyl group. Acetamides react more efficiently affording good yields of product alcohols when the reactions are carried out in moist acetone Introduction Indolines feature abundantly in Nature and many of these compounds are of pharmaceutical interest. The family includes the complex alkaloids aspidospermidine strychnine and vinblastine which pose many intriguing challenges to the synthetic chemist. The synthesis of naturally occurring indolines is therefore a very active field and one of the most popular recent approaches has involved the use of radicals 1ndash;7 as precursors.However despite all these developments our recently discovered radical-polar crossover reactions could have unique and important advantages not only in avoiding the troublesome and toxic tin radicals but also more especially in controlling stereochemistry of more complex polycyclic indolines. A preparative strategy for complex indoline skeletons such as 4 present in many medicinally important indoline alkaloids would involve formation of the aryl radical 1 from the corresponding diazonium salt by treatment with tetrathiafulvalene (TTF) and cyclisation of 1 to a new radical 2 which then undergoes radical-polar crossover ultimately leading to the cation 3.8 A cis ring junction can be predicted in formation of 2 leaving dagger; Current address Department of Pure and Applied Chemistry University of Strathclyde 295 Cathedral Street Glasgow UK G1 1XL.Dagger; Current address ICI Chemicals and Polymers Limited PO Box 8 The Heath Runcorn Cheshire UK WA7 4QD. the side-chain containing the group N9HR so disposed as to favour the all-cis stereochemistry of the desired product 4. The stereocontrol in the final cyclisation is totally dependent on unimolecular substitution via a mandatory carbocation intermediate 3. Prior trapping of the radical 2 (e.g. leading to an iodide) 1 from the less hindered face would afford9 product 5 (X = I) and this would either suffer direct closure of the fourth ring with inversion of configuration affording the wrong stereochemistry or at the least require two sequential inversions at the neopentyl carbon bearing the iodine firstly by an intermolecular nucleophile and then by N9HR in order to incorporate the desired stereochemistry in the fourth ring.However before embarking on complex syntheses it was necessary to investigate if simple indolines could be formed using the radical-polar crossover approach and how such chemistry would be affected by the choice of nitrogen-protecting group. These topics form the subject of this paper.10 Scheme 1 1550 J. Chem. Soc. Perkin Trans. 1 1997 Benzamide derivatives Nucleophilic aromatic substitution of 2-bromonitrobenzene 6 with prop-2-enylamine 7 led to 8 which was benzoylated to afford 10a as microanalytically pure pale yellow needles.Reduction to 11a followed by diazotisation furnished 12a as a fine colourless powder. In parallel synthesis of 12b was also undertaken to compare whether the product ratio would be altered by changing the terminus of the radical acceptor C C bond. A different synthetic approach was adopted in this case. Benzoylation of 2- nitroaniline afforded 9 as yellow needles. Subsequent deprotonation by sodium hydride was conveniently achieved in tetrahydrofuran and followed by alkylation with 2-methyl-4- bromobut-2-ene (prenyl bromide) to give 10b. Reduction to 11b followed by diazotisation afforded 12b the cyclisation precursor as a pale yellow powder. Reaction of 12a and 12b with TTF in moist acetone afforded the products shown in Scheme 3. The product distributions here were of particular interest because Togo3 had observed the exclusive formation of 13a (100) when the bromo compound 14 analogous to 12a was subjected to standard reductive conditions (Bu3SnHndash;AIBN) in toluene.This reaction has assumed further importance since it fits into a picture 11 in which the intriguing regioselectivity of certain anilide aryl radical addition reactions could be neatly rationalised. Our reactions afforded a greater variety of products and (as pointed out by a reviewer) since the same radical features in both cases the fact that we observed formation of an indoline whereas Togo did not was surprising. To probe this point we have now repeated t