Novel indole-ring formation by thermolysis of 2-(N-acylamino)-benzylphosphonium salts. Effective synthesis of 2-trifluoromethylindoles

摘要

WNovel indole-ring formation by thermolysis of 2-(N=acylamino)- mbenzylphosphonium salts. Effective synthesis of 2-trifluoromethyl-nz II indoles F-Kazuyuki Miyashita, Katsunori Kondoh, Katsutoshi Tsuchiya, Hideto Miyabe and Takeshi Imanishi * Faculty oj'Pharmuceuticu1 Sciences, Osaka University, 1-6 Yumaduoka, Suitu, Osaka 565, Japan Thermolysis of 2-(N-acylamino)benzyl methyl ethers, in the presence of an acid catalyst and triphenylphosphine, or 2-(N-acylamino)benzylphosphonium salts is found to serve as a novel method for indole formation, in particular for the synthesis of 2-trifluoromethylindoles.The reaction of the benzyl methyl ethers is suggested to involve a phosphonium intermediate, which thermally decomposes to the indoles. Tndole derivatives, widely distributed in nature as the amino acid tryptophan (1) and its metabolites, indole-alkaloids, are very useful as lead compounds for the discovery or development of novel, biologically ictive compounds, as they are known to have various significant biological activities.Consequently, synthetic methods for the construction of the indole ring have been studied for some time.3 On the other hand, in the field of medicinal chemistry, introduction of fluorine or a perfluoroalkyl group into the lead molecule has been employed as one of the most efficient methods for modification of the lead compound and many successful examples have been rep~rted.~ However, examples of fluorinated or perfluoroalkylated indoles are rare, and deal with indoles modified with fluorine only on the benzene ring5 From such a viewpoint, we are interested in the biological activities of the 2-trifluoromethyl derivatives 2.H H tryptophan 1 2 3 4: X = OMe 5: X = P'Ph3 Although the synthesis of 2-trifluoromethylindole (2, R' = R2 = H) has been achieved via direct trifluoromethylation of indole6 and by the use of 3-trifluoromethylquinoline as the starting material,7 there still remain problems in the regioselectivity of trifluoromethylation and the number of reaction steps. As another possible method of preparing various 2-trifluoromethylindoles 2, pyrrole ring formation from 24N-trifluoroacety1amino)toluene derivatives 3 would be suitable. Although available methods for the synthesis of indoles by pyrrole ring formation of 3 are represented by the Madelung reaction and its modified reactions,' all involve nucleophilic attack of the benzylic carbanion, generated by the action of a strong base, at the amide carbonyl carbon.However, because of the base-labile nature of the trifluoromethyl group,7 this approach cannot be applied in our case. In this paper we Table 1 Solvent effects for the indole formation reaction OMe PPh3, cat. p-TsOH Solvent, heat * QCLCF3 H 4a Run Solvent (bp/"C) 1 toluene (1 11) 2 toluene (1 11) 3 chlorobenzene (132) 4 DMF(153) 5 p-cymene (1 77) 6 O-DCB(180.5) 7 DMSO (189) H 12a TPC tlh Yield()" reflux 12 - 180' 12 44(69) reflux 6 - reflux 19 36 (84) reflux 8 48 reflux 6 60 reflux 1 -~ "Yield in parentheses is based on the consumed starting material.'Reaction was carried out in a sealed tube. describe two methods for indole-ring formation, starting from 2-(N-acylamino)benzyl methyl ether 4 and 2-( N-acy1amino)ben- zylphosphonium salt 5,both of which are especially effective for the synthesis of 2-trifluoromethylindoles 2. Results and discussion 2-(N-Trifluoroacetylamino)benzylmethyl ethers 4 were pre- pared from the nitrobenzaldehydes 6, nitrobenzyl alcohol 7, or nitrotoluenes 8 as shown in Scheme 1 (see Experimental section). By choosing the appropriate starting material, it is possible to synthesize benzyl methyl ethers 4 bearing various types of oxygen substituent on the benzene ring.After several attempts it was found that, when a toluene solution of the 4,5-methylenedioxy derivative 4a and tri-phenylphosphine (PPh,) in a sealed tube was heated at 180 "C in the presence of a catalytic amount of toluene-p- sulfonic acid (p-TsOH), the 2-trifluoromethylindole 12a was obtained in 44 yield. The structure of the reaction product 12a was confirmed by spectroscopic methods. The effect of solvent is summarized in Table 1, which shows that solvent polarity does not affect the reaction to any great extent. The reaction is, however, dependent on the boiling point of the solvent used, which means that the reaction temperature is an important factor for this reaction and that, by employing N,N-J.Chem. Soc., Perkin Trans. I, 1996 1261 R2 6 /iv 8 9 Scheme 1 Reugents und conditions: i, ref. 12; ii, NaH, MeI, DMF, room temp.; iii, ref. 15; iv, MeONa, MeOH, room temp.; v, Raney-Ni, EtOH, room temp.; vi, PhCHO, C,H,, room temp., then NaBH,CN, MeOH, room temp.; vii, (CF,CO),O, pyridine, 0deg;C then room temp. (For the substituents R'-R4,see Table 2.) Table 2 Indole formation reaction of 2-(N-trifluoroacetylamino)ben-zyl methyl ethers 4 PPh3,cat. p-TsOH toluene, 180"C, 12; R4 R' I R' 4 12 Run Comp. R' R2 R3 R4 Yield()" l a H H -0CH2- 44 (69) 2 b H H H H 3 c I3 H Me0 Me0 60 (67) 4 d H H H Me0 48 (52) 5 e H H Me0 H 6 f H Ph H H - 7 8 gh H H p-MeOPh Ph H Me0 H H 49 34 9 i H Ph Me0 Me0 57 10 j Bz Ph Me0 Me0 82 11 k Bz Ph Me0 H - 12 1 Bz Ph H Me0 54 a Yield in parentheses is based on the consumed starting material.Bz = benzyl. dimethylformamide (DMF), p-cymene or o-dichlorobenzene (o-DCB) as the solvent, it is not necessary to introduce the dangers of using a sealed tube. Despite dimethyl sulfoxide (DMSO) having the highest boiling point of all the solvents examined, when it was used the indole 12a was not formed. This is probably because the PPh, was consumed by the reduction of DMSO to dimethyl sulfide and, furthermore, the benzylic cation intermediate might have been quenched by the dimethyl sulfide generated. We applied this procedure to compounds 4b-1 and examined the effects of the substituents on the benzene ring on the reaction (Table 2).Obviously, these substituents play an important role in this reaction and the oxygen function at the para-position was found to be essential for this reaction (runs 1-5). Although, when R2 is a phenyl group, the benzylic cation is expected to be stabilized by the two phenyl rings, this does not seem to be sufficient for the reaction because the reaction of 4f did not afford the indole (run 6)." It is interesting that the compound 4g bearing a p-methoxy group on the phenyl group of R2 afforded the indole 12g in moderate yield (run 7). These results indicate that the formation and stabilization of the 1262 J. Chem. SOC.,Perkin Trans. 1,I994 benzylic cation are crucial steps for this reaction.Similar tendencies for the reactions of the N-benzyl derivatives to those of the N-unsubstituted derivatives were also observed. Comparison of the reactions of 4e, h and k (runs 5,8 and 1 I), all of which have a methoxy group at the meta-position (R3= OMe), suggests the effects of the substituents R' and R2. In these compounds, the methoxy group may not be helpful for stabilization of the benzylic cation but may increase the electron density of the benzene ring. Therefore, another phenyl group at a suitable position (4h, R2 = Ph), able to stabilize the benzylic cation, may be required for the reaction. However, the results of the reactions of 4h and 4k (runs 8 and 1I) suggested that the substituent R' could also affect the reaction and that the electron-donating property of the nitrogen to the carbonyl centre also has an effect on the reactivity. As described in the above reactions, the crucial step is the formation of the benzylic cation, which limits the applicability of this reaction. These results prompted us to examine the reaction of the phosphonium salt, for the following reasons.(i) This reaction seems to proceed via the phosphonium intermedi- ate formed by the nucieophilic attack of PPh, on the benzylic cation. (ii) If formation of the phosphonium salt is the rate- determining step and requires an oxygen-substituent at the correct position to stabilize the benzylic cation precursor, then it may be possible to expand the application of this reaction by starting from the phosphonium salt.The phosphonium salts 5, containing various types of N-acyl substituents and lacking an oxygen-function on the benzene ring, were prepared by two methods as shown in Scheme 2 (see Experimental section). Pfph3 X- PPh3 CI- i. ii NHCOR NHCOR N'H3 CI- 13a: R = CF3 5a-g 14 b: R C2F5= Scheme 2 Reagents and conditions: i, NBS, CCI,, reflux (ref. 14); ii, PPh,, toluene, 60 "C; iii, RCOCl, pyridine-DMF, 0 OC then room temp. The indole 15a was obtained without acid catalyst or PPh,, simply by heating in the solvent shown in Table 3. Other phosphonium salts 5b-g were also examined under similar conditions. The indoles 15c-g not bearing a fluorinated group Table 3 Indole formation reaction of the phosphonium salts 5 r 1 5 15 16 Run Comp.R X Solvent t/h Yield () l a CF3 Br toluene" 12 28 2 a CF, Br U-DCB 7 82 3 a CF3 Br DMSO 7 - 4 a CF3 Br DMF 15 82 5 6 7 b c d C2F5 PhCH, Ph Brc1c1 DMF U-DCB U-DCB 12 7 7.5 92 42 29 8 9 e f p-NOZC,jH, CH3C0 CIc1 U-DCB U-DCB 8 1 48 19 10 g Et02C c1 O-DCB 7.5 53 '' Reaction was carried out in a sealed tube at 180 "C. at C-2 were also obtained, although their yields were lower than those of 15a and b. Interestingly, in the case of 5f, the quinolone 16 was obtained as the major product, in addition to the indole 15f. Concerning the reaction mechanism, the formation of the benzylic cation is apparently important for the reaction starting from the methyl ether 4 but not for the reaction starting from the phosphonium salt 5.This strongly suggests that formation of the phosphonium intermediate does occur by the nucleophilic attack of PPh, as the next step from the benzylic cation as shown in Scheme 3. The Wittig-type reaction of the 2-H' :PPh3 r , 4 i1 5 -Ph,P=o (N-acy1amino)benzylphosphoniumsalt to give the indole by employing a strong base has been reported9hd and a mechanistic study revealed that the phosphorus ylide is involved as an intermediate.9c However, our reaction from the phosphonium salt seems to proceed in a different manner from the Wittig-type reaction, as strong base is not used in our reaction and polar solvents such as DMF do not accelerate the reaction rate (Table 1).This suggests that our reaction does not involve the formation of a polar intermediate such as a phosphorus ylide. Although the latter part of the reaction from the phosphonium intermediate to the indole is unclear, a possible reaction mechanism is shown in Scheme 3. That a phosphonium salt rather than an ammonium or sulfonium salt is effective for this reaction? suggests that, as a consequence of the greater affinity of phosphorus for oxygen, the nucleophilic attack of the carbonyl oxygen to phosphorus occurs to form the P-0 bond initially. The fact that the reaction temperature rather than the polarity of the solvent is important suggests that this reaction may involve a concerted process.Therefore, subsequent thermal elimination of triphenylphosphine oxide might take place to afford the indole.$ In the case of the pyruvamide derivative 5f (Table 2, run 9), it is possible that reaction between the terminal carbonyl oxygen and the phosphonium functionality took place preferentially to afford the quinolone 16. In conclusion, these two methods, starting from the benzyl methyl ether 4 and the benzylphosphonium salt 5, are complementary to each other and are particularly useful for the synthesis of 2-trifluoromethylindoles. It should be emphasized that the source of the trifluoromethyl group in this reaction is trifluoroacetic acid, which is safe, easy to handle and cheap. Experimental All melting points were taken on a Yanagimoto micro-melting point apparatus and are uncorrected.IR spectra were measured on a JASCO FT/IR-200 Fourier-transfer infrared spectrometer. 'H NMR spectra were measured on a JEOL GX-500 (500 MHz), Hitachi R-250HT (250 MHz), or Varian VXR-200 (200 MHz) spectrometer with tetramethylsilane as an internal standard; J values are given in Hz. "F NMR spectra were taken on a Varian VXR-200 (1 80 MHz) with hexafluorobenzene (0 ppm) as an internal standard. 13C NMR spectra were taken on a JEOL EX-270 (67.5 MHz) with CDCl, (77.0 ppm) as an internal standard. Low and high resolution mass spectra were obtained with a JEOL D-300 mass spectrometer. For silica gel and alumina column chromatography, E. Merck Kieselgel 60 (0.063-0.200 mm) and Merck Aluminiumoxid 90 (0.063-0.200 mm) were used, respectively.4,5-Methylenedioxy-2-nitroben-zyl alcohol 7a, 4,5-dimethoxy-2-nitrobenzylalcohol 7c, 4-methoxy-2-nitrotoluene 8d, and 5-methoxy-2-nitrotoluene 8e were purchased from the Aldrich chemical company. Synthesis of a-phenylbenzyl alcohols 7f-i Grignard reaction of nitrobenzaldehydes 6 according to the literature procedure afforded the a-phenylbenzyl alcohols, which were immediately used for methylation as described below. 4,5-Dimethoxy-2-nitrobenzylmethyl ether 1Oc A solution of the alcohol 7c (1.02 g, 4.8 mmol) in DMF (10 cm3) was added dropwise to a stirred suspension of NaH (60, 0.21 g, 5.3 mmol) in THF (10 cm3) at room temperature and stirring was continued for 1 h at the same temperature.Methyl iodide (0.33 cm3, 5.3 mmol) was added dropwise to the reaction mixture and the whole was stirred for 6 h at the same temperature. After addition of saturated aq. NaHCO,, the t Reaction of the corresponding triethylammonium derivative instead of the phosphonium salt under the same conditions afforded the bromomethyl derivative, which is a product of the attack by the counter anion (Br-) at the benzylic position, while, by employing the dimethylsulfonium derivative, the 4H-3,I -benzoxazine derivative, which is a product of the attack by the carbonyl oxygen at the benzylic position, was detected in the reaction mixture. These results suggest that nucleophilic attack at the carbon centre is the preferred mode of reaction in both cases.1It is well known that the Wittig reaction involves an elimination of triphenylphosphine oxide from an oxaphosphetane intermediate to afford the double bond. '' Thermal extrusion of triphenylphosphine oxide from the stable oxaphosphetane intermediate possessing two trifluoromethyl groups has been reported. '* Similar reaction from an a-oxophosphorus ylide to afford the alkyne has also been reported previously.' J. Chem. SOC.,Perkin Trans. 1,1996 1263 reaction mixture was extracted with chloroform and the chloroform layer was washed with saturated NaHCO,, water, and saturated aq. NaCI, dried over Na,SO,, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane-ethyl acetate, 2 :1) and recrystallisation with ethanol to afford the title compound 1Oc (0.41 g, 38) as colourless crystals, mp 99-101 "C (lit.,', 101.5-101.8 "C).Other methyl ethers 10a, f-i and I were prepared from the corresponding alcohols 7 by methylation according to the method described for lOc, while 10b was prepared according to a literature method. 4,5-(Methylenedioxy)-2-nitrobenzyl methyl ether 10a. Yield 39, colourless crystals, mp 112-1 14 "C (ethanol) (Found: M+, 21 1.0479. C,H9N05 requires M, 21 1.0479); v,,,(KBr)/cm-' 2823, 1618, 1514, 1484, 1324, 1262, 11 10 and 1032; d,(CDCI,) 3.48 (3 H, s, OMe), 4.78 (2 H, s, benzylic H), 6.12 (2 H, s, OCH,O), 7.23 (1 H, s, 6-H) and 7.72 (1 H, s, 3-H); m/z21 1 (M+, 45) and 179 (1 0).2-Nitro-a-phenylbenzyl methyl ether 1Of. Yield 49, a yellow oil (Found: M+ -H, 242.0817. Cl,Hl,N03 requires M, 242.08 17); v,,,(KBr)/cm-' 2988, 1608, 1527, 1355, 1094 and 701;GH(CDC1,) 3.36 (3 H, s, OMe), 5.96 (I H, s, benzylic H) and 7.2-7.9 (9 H, m, aromatic H); m/z 242 (M+ -H, 0.3) and 21 1 (29).a-(4-Methoxyphenyl)-2-nitrobenzyl methyl ether log. Yield 87, yellow crystals, mp 33-34 "C (ethanol) (Found: C, 66.0; H, 5.6; N, 5.1. C,,H,,NO, requires C, 65.92; H, 5.53; N, 5.16); v,,,(KBr)/cm ' 2934, 2823, 1525, 1462, 1354, 1248, 1173, 1092, 1033 and 853; G,(CDCI,) 3.33 (3 H, s, OMe), 3.79 (3 H, s, PhOMe), 5.90 (1 H, s, benzylic H), 6.86 and 7.24 (each 2 H, d, J 8.5, aromatic H) and 7.3-7.9 (4 H, m, aromatic H); m/z 273 (Mf, 2) and 241 (17).5-Methoxy-2-nitro-a-phenylbenzyl methyl ether 10h. Yield 85, colourless crystals, mp 87-89 "C (ethanol) (Found: C, 65.8; H, 5.6; N, 5.1. C,,H15N04 requires C, 65.92; H, 5.53; N, 5.13); v,,,(KBr)/cm-' 2939, 2824, 1516, 1483, 1350, 1237, 1092, 1032 and 848; GH(CDC13) 3.39 (3 H, s, OMe), 3.90 (3 H, s, PhOMe), 6.1 1 (1 H, s, benzylic H), 6.87 (1 H, dd, J 2.5, 9.0, 4- H), 7.2-7.4 (6 H, m, aromatic H) and 8.05 (I H, d, J 9.0, 3-H); mjz 272 (M+ -H, 0.3) and 242 (9). 4,5-Dimethoxy-2-nitro-a-phenylbenzylmethyl ether 1Oi. Yield 88, yellow crystals, mp 103-105 "C (ethanol) (Found: C, 63.3; H, 5.6; N, 4.6. C16H17N05 requires C, 63.36; H, 5.69; N, 4.62); v,,,(KBr)/cm-' 2937, 2924, 1580, 1520, 1332, 1273, 1091 and 1060; GH(CDCl,) 3.38 (3 H, s, OMe), 3.94 and 3.98 (each 3 H, s, PhOMe), 6.11 (1 H, s, benzylic H), 7.2-7.4 (6 H, m, aromatic H) and 7.60 (I H, s, 3-H); m/z 303 (M', 6) and 271 (24).4-Methoxy-2-nitro-a-phenylbenzyl methyl ether 101.Yield 87, a yellow oil (Found: M+ -H 272.0910. C,,H,,NO, requires M, 272.0920); v,,,(KBr)/cm 2933, 2824, 1621, 1532, 1358, 1244, 1091, 1035 and 700; G,(CDCl,) 3.42 (3 H, s, OMe), 3.85 (3 H, s, PhOMe), 5.88 (1 H, s, benzylic H), 7.13 (I H, dd, J 2.5 and 8.5, 5-H), 7.2-7.35 (5 H, m, aromatic H), 7.40 (1 H, d, J 2.5,3-H) and 7.53 (1 H, d, J 8.5,6-H); m/z 272 (M+ -H, 0.7) and 241 (100). 4-Methoxy-2-nitrobenzyl methyl ether 10d Under a nitrogen atmosphere, a solution of sodium methoxide (0.52 g, 9.6 mmol) in methanol (5 cm3) was added dropwise to a stirred solution of the bromide 9d (1.2 g, 4.8 mmol), prepared from the toluene derivative 8d according to the literature procedure, in methanol (5 cm3) at room temperature and the whole was stirred for 2.5 h at room temperature.After addition of saturated aq. NaHCO,, the reaction mixture was extracted with chloroform and the chloroform layer was washed with saturated aq. NaHCO,, water, and saturated aq. NaCI, dried over Na,SO, and concentrated under reduced pressure to afford the crude product, which was purified by recrystallisation 1264 J. Chem. SOC.,Perkin Trans. I, I996 from ethanol to give the title compound 1Od (0.72 g, 76) as light yellow crystals, mp 64-64.5 "C (Found: C, 54.6; H, 5.6; N, 7.0.C,H,,NO, requires C, 54.82; H, 5.62; N, 7.10); v,,,(KBr)/cm-l 2934, 2833, 1570, 1523, 1458, 1345, 1239, 1106, 1035 and 846; d,(CDCl,) 3.46 (3 H, s, OMe), 3.87 (3 H, s, PhOMe), 4.76 (2 H, s, benzylic H), 7.18 (1 H, dd, J 2.5 and 8.8, 5-H), 7.57 (I H, d, J2.5, 3-H) and 7.64 (I H, d, J 8.8, 6-H); mjz 197 (M+, 6) and 165 (72). 5-Methoxy-2-nitrobenzyl methyl ether 10e. Compound 10e was prepared from 8e via the bromide 9e by the same method described for 1Od as colourless crystals (80), mp 4244deg;C (ethanol) (Found: C, 54.7; H, 5.6; N, 7.1. C9H,,N04 requires C, 54.82; H, 5.62; N, 7.10); v,,,(KBr)/crn-' 2941, 2830, 1590, 1342, 1245, 1109, 1073 and 847; dH(CDC13) 3.53 (3 H, s, OMe), 3.92 (3 H, s, PhOMe), 4.88 (2 H, s, benzylic H), 6.87 (1 H, dd, J 2.5and9.3,4-H),7.30(1 H,d7J2.5,6-H)and8.17(1 H,d,J9.3, 3-H); m/z 197 (M', 9) and 165 (5).4,5-Dimethoxy-2-(N-trifluoroacetylamino)benzylmethyl ether 4c An ethanolic suspension of Raney-Ni (2 cm3) was added to a stirred solution of the nitro compound 1Oc (320 mg, 1.4 mmol) in ethyl acetate (5 cm3)-ethanol (5 cm3) and the reaction mixture was stirred at room temperature. After disappearance of the starting material by TLC, the catalyst was filtered off and washed with ethyl acetatesthanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aq. NaHCO,, water, and saturated aq. NaCI, dried over Na,S04 and concentrated under reduced pressure to give the crude amine llc (R' = H) as a brown oil, which was used for the next reaction without further purification; GH(CDCI3) 3.35 (3 H, s, OMe), 3.80 and 3.83 (each 3 H, s, PhOMe), 4.40 (2 H, s, benzylic H), 6.30 (1 H, s, 3-H) and 6.65 (1 H, s, 6-H).Trifluoroacetic anhydride (0.20 cm3, 1.4 mmol) was added dropwise to a stirred solution of amine 1 lc in pyridine (4 cm3) at 0 "C and stirring was continued overnight at room temperature. After the addition of saturated aq. NaHCO,, the reaction mixture was extracted with ethyl acetate and the ethyl acetate layer washed with 5 HCl, water, saturated aq. NaHCO,, and saturated aq. NaCl, dried over Na,SO,, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-dichloromethane, 1 :2) to afford the title compound 4c (185 mg, 45) as colourless crystals, mp 96-98 "C (hexane-benzene) (Found: C, 49.2; H, 4.8; N, 4.9.C,,H,,NO,F, requires C, 49.15; H, 4.81; N, 4.78); v,,,(KBr)/cm-' 3277, 2940, 2841, 1720, 1623, 155 1, 1221, 1151, 1103 and 871; dH(CDC1,) 3.45 (3 H, S, OMe), 3.87 and 3.9 1 (each 3 H, s, PhOMe), 4.54 (2 H, s, benzylic H), 6.68 (1 H, s, 6-H), 7.86 (1 H, s, 3-H) and 9.86 (1 H, br s, NH); G,(CDCl,) 85.4; m/z 293 (Mf, 71), 262 (31) and 261 (37). Other amide derivatives 4a,b,d-i were synthesized from the corresponding nitro compounds uia amines according to the procedure described for 4c. 2-Amino-4,5-(methylenedioxy)benzylmethyl ether 1 la (R'= H). A brown oil; G,(CDCl,) 3.31 (3 H, s, OMe), 3.83 (2 H, s, NH,), 4.36 (2 H, s, benzylic H), 5.84 (2 H, s, OCH,O), 6.27 (1 H, s, 3-H) and 6.58 (1 H, s, 6-H).4,5-(Methylenedioxy)-2-(N-trifluoroacetylamino)benzyl methyl ether 4a. Yield 81 from 10a, colourless needles, mp 134-136deg;C (ethanol) (Found: C, 47.7; H, 3.8; N, 5.15. C,,H,,NO,F, requires C, 47.66; H, 3.64; N, 5.05); v,,,(KBr)/cm-' 3254, 2921, 1722, 1568, 1206, 1153, 1088, 1039 and 882; G,(CDCl,) 3.43 (3 H, s, OMe), 4.47 (2 H, s, benzylic H), 5.99 (2 H, S, OCHZO), 6.66 (1 H, S, 6-H), 7.72 (1 H, S, 3-H) and 9.78 (1 H, br s, NH); G,(CDCl,) 85.5; m/z 277 (Mf, 13) and 245 (51). 2-Aminobenzyl methyl ether 1 lb (R'= H). A colourless oil; GH(CDC13) 3.31 (3 H, s, OMe), 4.07 (2 H, br s, NH,), 4.45 (2 H, s, benzylic H) and 6.6-7.2 (4 H, m, aromatic H).2-(N-Trifluoroacetylamino)benzyl methyl ether 4b. Yield 97 from lob, a light yellow oil (Found: M', 233.0658. CloH1,NO2F, requires M, 233.0661); v,,,(KBr)/cm-' 3291, 2938,1735,1595,1541,1458,1158 and 1088;d,(CDCI,) 3.46 (3 H, s, OMe), 4.60 (2 H, s, benzylic H), 7.1-7.4 (3 H, m, aromatic H), 8.21 (1 H, d, J8. I, 3-H) and 9.80 (1 H, br s, NH); GF(CDC1,) 85.5; m/z 233 (M', 72) and 202 (15). 2-Amino-4-methoxybenzyl methyl ether 1 Id (R'= H). A brown oil; GH(CDC13) 3.38 (3 H, s, OMe), 3.73 (3 H, s, PhOMe), 3.83 (2 H, br s, NH,), 4.40 (2 H, s, benzylic H), 6.25 (2 H, m, 3, 4-H) and 6.95 (1 H, d, J 8.2, 6-H). 4-Methoxy-2-(N-trifluoroacetylamino)benzylmethyl ether 4d. Yield 49 from 10d, colourless crystals, mp 55-58 "C (hexane- dichloromethane) (Found: C, 48.45; H, 4.4; N, 5.2.Cl,H,,N0,F,-1/2H,0 requires C, 48.53; H, 4.81; N, 5.15); v,,,(KBr)/cm-l 3273, 2943,2840, 1728, 1597, 1210, 1174, 1079, 1038 and 869; d,(CDCI,) 3.43 (3 H, s, OMej, 3.83 (3 H, s, PhOMe), 4.54 (2 H, s, benzylic H), 6.68 (1 H, dd, J 2.5, 8.5, 5-H),6.70(1 H,d, J2.5,6-H),6.89(1 H,dd, J2.5and8.8,4-H),7.2-7.4 (5H, m, aromatic H), 8.11 (1 H, d, J8.8,3-H) and 9.73 (1 H, br S, NH); GF(CDC1,) 85.5; m/z 339 (M+, 57) and 307 (69). 2-Amino-4,5dimethoxy-a-phenylbenzyl methyl ether 1 li (R'= H). A brown oil; G,(CDCI,) 3.42 (3 H, s, OMe), 3.76 and 3.83 (each 3 H, s, PhOMe), 5.26 (1 H, s, benzylic H), 6.27 (1 H, s, 3-H), 6.62 (1 H, s, 6-H) and 7.2-7.4 (5 H, m, aromatic Hj. 4,5-Dimethoxy-a-phenyl-2-(N-trifluoroacetylamino)benzyl methyl ether 4i.Yield 74 from loi, a light yellow oil (Found: M +,369.1 185. C, *HI ,NO,F, requires M, 369.1 185); v,,,(K-Br)/cm-' 3290, 2939, 2834, 1728, 1617, 1540, 1326, 1220, 1160 and 1103;d,(CDCl,) 3.48 (3 H, s, OMe), 3.82 and 3.91 (each 3 H, s, PhOMe), 5.34 (1 H, s, benzylic H), 6.60 (1 H, s, 6-Hj, 7.2.- 7.4 (5 H, m, aromatic H), 7.89 (1 H, s, 3-H) and 9.94 (1 H, br s, NH); G,(CDCl,) 85.4; m/z 369 (M', 100)and 337 (85). 2-(N-Benzylamino)-4,5-dimethoxy-a-phenylbenzyl methyl ether llj (R'= Bz). A mixture of a solution of the nitro compound 1Oi (3.20 g, 10.6 mmol) in ethyl acetate (30 cm3j-H),7.09(1H,d,J8.5,6-H),7.86(1H,d,J2.5,3-H)and9.95(1ethanol (30 cm3) and an ethanolic suspension of Raney-Ni (10 H, br s, NH); GF(CDC1,) 85.4; m/s263 (M', 91) and 232 (92).cm3) was treated and worked up according to the procedure 2-Amino-5-methoxybenzyl methyl ether lle (R' = H). A described for 1Oc. To a stirred solution of the resultant crude brown oil; S,(CDCI,j 3.35 (3 H, s, OMe), 3.59 (2 H, br s, NH,), 3.74 (3 H, s, PhOMe), 4.43 (2 H, s, benzylic H) and 6.5-6.8 (3 H, m, aromatic H). 5-Methoxy-2-(N-trifluoroacetylamino)benzyl methyl ether 4e. Yield 50 from 10e, colourless crystals, mp 49-50 "C (hexane- dichloromethane) (Found: C, 50.2; H, 4.6; N, 5.4. C,,H,,NO,F, requires C, 50.19; H, 4.50; N, 5.32); v,,,(KBr)/cm ' 3297, 2939, 2837, 1728, 1615, 1281, 1159, 1087 and 1045;G,(CDCI,) 3.44 (3 H, s, OMe), 3.81 (3 H, s, PhOMe), 4.54 (2 H, s, benzylic H), 6.74 (1 H, d, J2.8, 6-H), 6.89 (1 H, dd, J2.8 and 8.3,4-H), 8.09 (1 H, d, J8.3, 3-H) and 9.70 (1 H, br s, NH); G,(CDCI,) 85.5; m/z 263 (M', 73) and 231 (58).2-Amino-a-phenylbenzyl methyl ether 1 If (R'= H). A brown oil; GH(CDC1,) 3.40 (3 H, s, OMe), 3.90 (2 H, br s, NH,), 5.29 (1 H, s, benzylic H), 6.61 (1 H, d, J7.7,3-H), 6.71 (1 H, t-like, J7.7, 5-Hj, 7.01 (1 H, d, J7.7, 6-H), 7.10 (1 H, t-like, J7.7,4-H) and 7.2-7.4 (5 H, m, aromatic H). a-Phenyl-2-(N-trifluoroacetylamino)benzyl methyl ether 4f. Yield 79 from lOf, colourless crystals, mp 54-56 "C (hexane- dichloromethane) (Found: M', 309.0976. C,,H,,NO,F, requires M, 309.0976); umax(KBr)/cm-'3294, 2940, 1734, 1593, 1542, 1456, 1155, 1074 and 759; G,(CDCl,) 3.48 (3 H, s, OMe), 5.42 (1 H, s, benzylic H), 7.1-7.5 (8 H, m, aromatic Hj, 8.23 (1 H, d, J 8.5,3-H) and 10.00 (1 H, br s, NH); GF(CDC1,) 85.4;m/z 309 (Mf, 70) and 277 (53).2-Amino-a-(4-methoxyphenyl)benzyl methyl ether 1 lg (R'= H). A yellow oil; G,(CDCI,) 3.40 (3 H, s, OMe), 3.80 (3 H, s, PhOMe), 4.04 (2 H, br s, NH,), 5.26 (I H, s, benzylic H) and 6.6-7.4 (8 H, m, aromatic H). a-(4-Methoxyphenyl)-2-(N-trifluoroacetylamino)benzyl methyl ether 4g. Yield 63 from log, colourless crystals, mp 78-80 "C (hexane-dichloromethane) (Found: C, 60.0; H, 4.8; N, 4.1. C,,H,,NO,F, requires C, 60.18; H, 4.75; N, 4.13); v,,,(KBr)/crn-l 3281,2938,2836, 1733, 1613, 1592, 1250, 1157, 1082 and 760; G,(CDCl,) 3.45 (3 H, s, OMe), 3.79 (3 H, s, PhOMe), 5.37 (1 H, s, benzylic H), 6.87 (2 H, d, J 8.5, 3'-H), 7.0-7.5(5H,m,aromaticH),8.24(1H,d,J8.5,3-H)and10.11 (I H, br s, NH); GF(CDC1,) 85.4; m/z 339 (M+, 63) and 307 (86).2-Amino-5-methoxy-a-phenylbenzyl methyl ether 11 h (R'= H). A brown oil; G,(CDCI,) 3.42 (3 H, s, OMe), 3.72 (3 H, s, PhOMe), 5.27 (1 H, s, benzylic H), 6.4-6.8 (3 H, m, aromatic H) and 7.0-7.4 (5 H, m, aromatic H).5-Methoxy-a-phenyl-2-(N-trifluoroacetylamino)benzylmethyl ether 4h. Yield 65 from 10h, colourless crystals, mp 78-80 "C (Found: C, 60.2; H, 4.8; N, 4.2. C1,H1,No3F3 requires C, 60.18; H, 4.75; N, 4.13); v,,,(KBr)/cm-' 3300, 2943, 2830, 1722, 1610, 1539, 1225, 1159, 1087, 1037 and 699; GH(CDC1,) 3.47 (3 H, s, OMe), 3.79 (3 H, s, PhOMe), 5.34 (1 H, s, benzylic amine in benzene (40 cm3j, benzaldehyde (1.04 cm3, 1.2 mmol) was added and the reaction mixture was stirred overnight and then concentrated under reduced pressure to give the imine, which was immediately suspended in methanol (40 cm3).NaBH,CN (1.60 g, 25.5 mmol) was added in portions to the solution at 0 "C and the reaction mixture was stirred at room temperature overnight. After the addition of saturated aq. NaHCO,, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aq. NaHCO,, water and saturated aq. NaCl, dried over Na,SO, and concentrated under reduced pressure. The resultant crude product was purified by alumina column chromatography (hexane-ethyl acetate, 25: 1) to afford the title compound llj (2.50 g, 65) as a white powder (Found: M+, 363.1836.C,,H,,NO, requires M, 363.1835); vma,(KBr)/cm-' 3418,2933, 2829, 1592, 1451, 1221, 1088, 1029, 729 and 698; G,(CDCI,) 3.40 (3 H, s, OMe), 3.75 and 3.76 (each 3 H, s, PhOMej, 4.23 (2 H, d, J 5.0, NCH,Ph), 4.85 (1 H, br s, NH), 5.27 (1 H, s, benzylic H), 6.24 (1 H, s, 3-Hj, 6.65 (1 H, s, 6-H) and 7.1-7.4 (10 H, m, aromatic H); m/z 363 (M+, 76) and 331 (54). Other benzylamine derivatives Ilk and 1 were synthesized starting from nitro compounds according to the above procedure. 2-(N-Benzylamino)-5-methoxy-a-phenylbenzyl methyl ether Ilk (R'= Bz). Yield 83 from 10h, a yellow oil (Found: M+, 333.1728. C,,H,,NO, requires M, 333.1728); vmaX(KBr)/cm-' 3418, 2933, 2829, 1514, 1221, 1090, 1044, 728 and 698; dH(CDC13)3.40 (3 H, s, OMe), 3.72 (3 H, s, PhOMe), 4.21 (2 H, s, NCH,Ph), 4.73 (1 H, br s, NH), 5.29 (1 H, s, benzylic H), 6.4-6.8 (3 H, m, aromatic Hj and 7.0-7.5 (10 H, m, aromatic H); m/z 333 (M+, 100) and 301 (44).2-(N-Benzylamino)-4-methoxy-a-phenylbenzylmethyl ether 111 (R'= Bz). Yield 68 from 101, a yellow oil (Found: M', 333.1734. C,,H,,NO, requires M 333.1728); v,,,(KBr)/cm-' 3420, 2933, 2838, 1615, 1585, 1524, 1214, 1087, 1045, 728 and 697; GH(CDC1,) 3.39 (3 H, s, OMe), 3.72 (3 H, s, PhOMej, 4.23 (2 H, d, J 5.0, NCH,Ph), 5.24 (1 H, br s, NH), 5.29 (1 H, s, benzylicH),6.14(1 H,d, J2.5,3-H),6.20(1 H,dd, J2.5,8.5,5-H), 6.91 (1 H, d, J8.5, 6-H) and 7.0-7.4 (10 H, m, aromatic H); m/z 333 (M', 73) and 301 (59).Trifluoroacetylation of 2-(N-benzylamino)benzyl methyl ethers5 Trifluoroacetylation of the N-benzylamino derivatives was 9 24N-Benzyl-N-trifluoroacety1amino)-a-phenylbenzylmethyl ethers 4j-1 were obtained as a mixture of two diastereoisomers due to atropisomerism, which was used for the indole formation reaction without separation. J. Chem. SOC.,Perkin Trans. I, 1996 1265 achieved by treatment with trifluoroacetic anhydride in pyridine and subsequent purification by silica gel column chromatography (hexane- dichloromethane, 3 :4) according to the procedure for the trifluoroacetylation of N-unsubstituted aminobenzyl alcohols. 2-(N-Benzyl-N-trifluoroacetylamino)-4,5-dimethoxy-a-phen-ylbenzyl methyl ether 4j. Yield 79 (obtained as a ca.2: 3 mixture of stereoisomers), colourless crystals, mp 83-85 "C (hexane-dichloromethane) (Found: C, 64.1; H, 5.7; N, 2.9. C,,H,,NO4F,~I/2H,O requires C, 64.10; H, 5.38; N, 2.99); v,,,(KBr)/cm ' 2938, 1695, 1516, 1455, 1267, 1213, 1178, 1150, 1084 and 1029; G,(CDCl,) 3.36, 3.41, 3.43 and 3.45 (total 6 H, each s, OMe and PhOMe), 3.72 and 3.96 (total 3 H, each s. PhOMe), 2.84, 4.23, 5.34 and 5.84 (total 2 H, each d, J 14, NCH,Ph), 5.29 and 5.36 (total 1 H, each s, benzylic H), 5.83 and 5.92 (total 1 H, each s, 3-H) and 6.7-7.6 (total 11 H, m, aromatic H); GF(CDCI,) 93.6 and 93.9; vn/z 459 (M', 29), 428 (29) and 368 (32). 2-(N-Benzyl-N-trifluoroacetylamino)-5-methoxy-a-phenylben-zyl methyl ether 4k. Yield 69 (obtained as a ca.1 :1 mixture of stereoisomers), light yellow crystals, mp 114-1 16 "C (hexane-dichloromethane) (Found: C, 67.1; H, 5.4; N, 3.2. C,,H,,NO,F, requires C, 67.13; H, 5.16; N, 3.26); v,,,(KBr)/cm ' 2939, 2825, 1695, 1496, 1207, 1 155, 1084 and 1046; G,(CDCI,) 3.35 and 3.40 (total 3 H, each s, OMe), 3.70 and 3.85 (total 3 H, each s, PhOMe), 2.84, 4.25, 5.24 and 5.77 (total 2 H, each d, J 14, NCH,Ph), 5.28 and 5.34 (total 1 H, each s, benzylic H) and 6.3-7.4 (total 13 H, m, aromatic H); G,(CDCI,) 93.7 and 93.9; m/z429 (M', 18), 397 (1 1) and 338 (27).2-(N-Benzyl-N-trifluoroacetylamino)-4-methoxy-a-phenylben-zyl methyl ether 41.Yield 66 (obtained as a ca. 1: 1 mixture of stereoisomers), colourless crystals, mp 83-85 "C (hexane-dichloromethane) (Found: C, 67.0; H, 5.3; N, 3.3.C,,H,,NO,F, requires C, 67.13, H, 5.16; N, 3.26); v,,,(KBr)/cm-' 2939, 1695, 1610, 1502, 1455, 1248, 1205, 1170, 1150 and 1082; G,(CDCI,) 3.32 and 3.40 (total 3 H, s, OMe), 3.52 and 3.54 (total 3 H, s, PhOMe), 3.12, 4.29, 5.32 and 5.81 (total 2 H, each d, J 14, NCH,Ph), 5.22 and 5.35 (total 1 H, each s, benzylic H), 6.04 and 6.08 (total 1 H, each d, J2.0,3-H), 6.75- 7.7 (total 12 H, m, aromatic H); G,(CDCI,) 93.7 and 94.0; m/z 429 (M', 1 I), 398 (23) and 338 (47). General procedure for indole formation from benzyl methyl ethers A mixture of the methyl ether 4 (0.050 mmol), toluene-p- sulfonic acid (1 .0 mg, 0.005 mmol) and PPh, (17.0 mg, 0.065 mmol) in toluene (0.2 cm3) was sealed in a glass tube under an Ar atmosphere and heated at 180 "C for 12 h.After being cooled to room temperature, the reaction mixture was diluted with chloroform, washed with saturated aq. NaHCO,, water and saturated aq. NaCI, dried ovzr Na,SO, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography to afford the indole 12. 6-Trifluoromethyl-5H-1,3 dioxolo 4,5--indole 12a. Colour-less needles, mp 134-1 36 "C (hexane-dichloromethane) (Found: C, 52.6; H, 2.9; N, 6.1. C,,H,NO,F, requires C, 52.41; H, 2.64; N, 6.11); v,,,(KBr)/cm-' 3408, 2890, 1611, 1557, 1478, 1260, 11 75-11 19 and 1042;G,(CDCl,) 5.97 (2 H, s, OCH,O), 6.79 and 6.84 (each 1 H, s, 4, 8-H), 7.00 (1 H, s, 7-H) and 8.27 (1 H, br s, NH); G,(CDCI,) 101.6; G,(CDCl,) 92.0, 99.8, 101 .O, 104.5, 120.6, 121.2 (9, J 267), 124.1 (q, J 39), 131.5, 144.1 and 147.1; m/s 229 (M', loo), 210 (7) and 209 (11).5,6-Dimethoxy-2-trifluoromethylindole12c. Colourless crys- tals, mp 86-88 "C (hexane-dichloromethane) (Found: C, 53.8; H, 4.2; N, 5.8. Cl,H10N02F3 requires C, 53.88; H, 4.11; N, 5.71); vmax(KBr)/cm-'3325, 2947, 2830, 1633, 1598, 1556, 1485, 1250, 1170, I1 10 and 1005;G,(CDCI,) 3.92 (6 H, s, OMe), 6.81 and 6.88 (each 1 H, s, 4,7-H), 7.00 (1 H, s, 3-H) and 8.27 (1 H, br s, NH); G,(CDCI,) 101.7; G,(CDCI,) 56.0, 56.2, 94.1, 1266 J. Chern. SOC.,Perkin Truns. 1, 1996 102.5, 104.2, 119.4, 121.3 (q, J266), 124.0(q, J39), 130.8, 146.1 and 149.1; in/=245 (Mf, loo), 230 (54) and 202 (35).6-Methoxy-2-trifluoromethylindole 12d. Colourless crystals, mp 89-91 "C (hexane-dichloromethane) (Found: C, 55.8; H, 3.9; N, 6.45. C,,H,NOF, requires C, 55.82; H, 3.75; N, 6.51); v,,,(KBr)/cm-' 3304,2969,2840, 1628, 1595,1560,1265,1177, 11 16 and 1018; GH(CDC1,) 3.86 (3 H, s, OMe), 6.86 (1 H, d, J 8.3, 5-H), 6.87 (1 H, S, 7-H), 7.07 (1 H, S, 3-H), 7.54 (1 H, d, J 8.3, 4-H), 8.27 (1 H, br s, NH); G,(CDCl,) 101.4; G,(CDCI,) 55.6,94.2, 104.4, 111.9, 120.8, 121.3 (q, J267), 122.8, 124.4(q, J 39), 137.1 and 158.3; m/3 215 (M+, loo), 200 (91) and 172 (33).3-(4-Methoxyphenyl)-2-trifluoromethylindole 12g. Colourless crystals, mp 160-1 62 "C (hexane-dichloromethane) (Found: C, 65.9; H, 4.3; N, 4.8. C,,H, ,NOF, requires C, 65.98; H, 4.1 5;N, 4.81); v,,,(KBr)/cm-' 3314, 2964, 2842, 161 1, 1587, 1511, 1240, 1175, 1110 and 1024;G,(CDCI,) 3.88 (3 H, s, OMe).7.01 (2 H, d, J 9.2, 3'-H), 7.19 and 7.35 (each 1 H, t, J 7.3, 5, 6-H), 7.45 (3 H, br d, Jca. 8,2', 7-H), 7.64 (1 H, d, J7.3,4-H) and 8.45 (1 H, br s, NH); GF(CDC1,) 104.8;G,(CDCl,) 55.3, 1 I 1.6, 113.9, 119.5 (4. J 2), 121.0 (9, J 34), 121.1, 121.2, 121.7 (9, J 269), 124.3, 125.1, 127.5, 131.0, 134.9 and 159.1; mi; 291 (M', loo), 276 (44), 272 (2) and 248 (9). 5-Methoxy-3-phenyl-2-trifluoromethylindole12h. A colour-less oil (Found: M+, 291.0865. C1,Hl,NOF3 requires M, 29 1.0868); v,,,(KBr)/cm-' 3407, 2960, 2838, 1626, 1608, 1567, 1497, 1249, 1167, 11 18 and 1029;G,(CDCI,) 3.79 (3 H, s, OMe), 7.0-7.1 (2 H, m, 4, 6-H), 7.3-7.6 (6 H, m, 7-H and aromatic H) and 8.40 (1 H, br s, NH); GF(CDCI3) 104.9; G,(CDCl,) 55.8, 101.5, 112.6, 116.3, 119.4 (9, J4), 121.6 (4, J270), 121.8 (q, J 38), 127.5, 127.7, 128.4, 129.8, 130.0, 132.3 and 155.2; mi: 291 (M', loo), 276 (30) and 248 (10).5,6-Dimethoxy-3-phenyI-2-trifluoromethylindole12i. Colour-less crystals, mp 160-162 "C (hexane-dichloromethane) (Found: C, 63.4; H, 4.6; N, 4.4. C,,H,,NO,F, requires C, 63.55; H, 4.39; N, 4.36); v,,,(KBr)/cm 3324, 2960, 2836, 1635, 1609, 1564, 1497, 1271, 1166, 1112 and 1011; GH(CDCI3) 3.86 and 3.95 (each 3 H, s, OMe), 6.91 and 6.99 (each 1 H, s, 4, 7-H), 7.3-7.6 (5 H, m, aromatic H) and 8.32 (1 H, br s, NH); O',(CDCl,) 105.4;G,(CDCI,) 56.1, 56.2, 93.9, 101.3, 119.5 (q, J 37), 119.7 (q, J 4), 120.0, 121.7 (q, J 269), 127.4, 128.4, 129.5, 129.7, 132.5, 146.3 and 149.4;m/z 321 (M', loo), 306 (39) and 278 (1 3).l-Benzyl-5,6-dimethoxy-3-phenyI-2-trifluoromethylindole12j. Colourless crystals, mp 96-97 "C (hexane-dichloromethane) (Found: C, 70.0; H, 5.0; N, 3.5. C,,H,,NO,F, requires C, 70.07; H, 4.90; N, 3.40); vmax(KBr)/cmp'2960, 2838, 1628, 1607, 1558. 1496, 1244, 1167, 1100 and 1030; GH(CDC1,)3.81 and 3.82 (each 3 H, s, OMe), 5.48 (2 H, s, benzylic H), 6.64 and 6.89 (each 1 H, s, 4, 7-H) and 7.0-7.6 (10 H, m, aromatic H); G,(CDCI,) 107.9;GC(CDC1,) 48.6, 56.1, 56.2,93.0, 101.6, 119.6, 120.8 (9, J 35), 120.8 (9, J 4), 122.0 (q, J 270), 125.9, 127.3, 127.5, 128.1, 128.6, 130.3, 132.2, 133.2, 137.1, 146.4 and 149.7; m/z41 1 (M +,7373,396 (3) and 320 (65).l-BenzyI-6-methoxy-3-phenyl-2-trifluoromethylindole121. A colourless oil (Found: M', 381.1329. C,,H,,NOF, requires M, 381.1337); v,,,(KBr)/cm 2960, 2839, 1623, 1606, 1566, 1497, 1260, 1174, 11 13 and 1032;GH(CDC1,)3.76 (3 H, s, OMe), 5.48(2H,s, benzylicH),6.65(1 H,s,7-H),6.81 (1 H,d,J7.3,5- H), 7.10 (2 H, d, J 7.3, 4-H and aromatic H) and 7.2-7.6 (9 H, m, aromatic H); cT,(CDCI,) 107.7; amp;(CDCI,) 48.4, 55.5, 93.2, 11 1.7, 121.2 (q, J 35), 121.1 (q, J 4), 121.3, 122.0 (4, J 270), 122.2, 126.0, 127.4, 127.5, 128.0, 128.7, 130.4, 132.9, 137.0, 138.4 and 158.7; HI/: 381 (M+, 59) and 290 (69). 2-(N-Trifluoroacetylamino)benzyltripheny lphosphonium bromide 5a Rromination of 13a was carried out according to the literature procedure.I4 A solution of the bromide (1 .0 g, 3.55 mmol) and PPh, (1.1 g, 4.25 mmol) in toluene (10 cm3) was warmed to 60 "C and stirred overnight. After cooling, the precipitate was collected by filtration, washed with dry diethyl ether, and dried under reduced pressure to afford the phosphonium salt 5a as a white powder (1.8 g, 9373, v,,,(KBr)/cm-l 1723, 1588, 1545, 1437, 1161, 1029 and 755; G,(CDCl,) 5.77 (2 H, d, J 13.9, benzylic H), 6.98 (2 H, m, aromatic H), 7.4-7.9 (17 H, m, aromatic H) and 11.I6 (1 H, s, NH); G,(CDCl,) 88.6.2-(N-Pentafluoropropanoylamino)benzyl triphenylphos-phonium bromide 5b. Compound 5b was prepared from 13b by the same method described for 5a, as a white powder (68); v,,,(KBr)/cm-' 1714, 1588, 1534, 1438, 1216, 1027 and 751; G,(CDCI,) 5.76 (2 H, d, J 13.9, benzylic H), 6.94 (2 H, m, aromatic H) and 7.4-8.0 (17 H, m, aromatic H); d,(CDCl,) 41.9 (3 F, s) and 79.4 (2 F, s).General procedure for the preparation of 2-(N-acylamino)ben- zyl triphenylphosphonium chlorides 5c-g Phosphonium salts 5c-g were prepared from the (2-amino- benzy1)triphenylphosphonium salt 14l6 according to the literature" with some modification as follows. Acid chloride (0.55 mmol) was added dropwise to a stirred solution of 14 (200 mg, 0.45 mmol) in a mixture of DMF (0.5 cm3) and pyrid- ine (0.15 cm3) at 0 "C. After being stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform.The chloroform solution was washed with 5 HCI and saturated aq. NaCI, dried over Na,SO, and concentrated under reduced pressure. The resultant residue was washed with diethyl ether several times and dried under reduced pressure to afford the desired phosphonium salt. 2-(N-Phenylacetylamino)benzyltriphenylphosphonium chlo- ride 5c. Yield 84, a white powder; v,,,(KBr)/cm-' 1685, 1586, 1526, 1438, 1030 and 750; G,(CDCI,) 3.67 (2 H, s, NCOCH,Ph), 5.65 (2 H, d, J 14.5, benzylic H), 6.6-7.0 (2 H, m, aromatic H), 7.0-7.8 (22 H, m, aromatic H) and 10.96 (1 H, s, NH). 2-(N-Benzoylamino)benzyltriphen ylphosphonium chloride 5d. Yield 45, a white powder; v,,,,,(KBr)/cm-' 1660, 1585, 1516, 1437, 1298, 1027 and 750;GH(CDC13) 5.83 (2 H, d, J 13.5, benzylic H), 6.82 (2 H, m, aromatic H), 7.0-7.8 (17 H, m, aromatic H), 8.24 (2 H, d, J 4.8) and 10.90 (1 H, s, NH).{ 2-N-(4-Nitrobenzoyl)aminobenzy1 } triphenylphosphonium chloride 5e. Yield 76, a yellow solid; v,,,(KBr)/cm-' 1668, 1586, 1521, 1438, 1346, 1268, 1014, 850 and 750; G,(CDCl,) 5.79 (2 H, d, J 14.0, benzylic H), 6.8-7.0 (2 H, m, aromatic H), 7.0-7.8 (17 H, m, aromatic H), 8.0-8.6 (4 H, m, aromatic H) and 11.29 (1 H, s, NH). (2-N-(2-Oxopropanoyl)aminobenzyl) triphenylphosphonium chloride 5f. Yield 48, a white powder; v,,,(KBr)/cm 3370, 1722, 1685, 1587, 1522, 1437, 1248, 1137 and 749; GH(CDCI,) 2.28 (3 H, s, COMe), 5.83 (2 H, d, J 13.7, benzylic H), 6.8-7.0 (2 H, m, aromatic H), 7.4-7.8 (17 H, m, aromatic H) and 10.71 (1 H, s, NH). (2-N-(Ethox ycarbon ylform yl)amino benzyl) triphenylphos- phonium chloride 5g.Yield 61, a white powder; v,,,(KBr)/ cm-' 1745, 1694, 1588, 1538, 1436, 1246, 1181, 1016 and 755; dH(CDC13) 1.40 (3 H, t, J 7.3, OCH,CH,), 4.34 (2 H, 9, J7.3, OCH,CH,), 5.89 (2 H, d, J 14.6, benzylic H), 6.91 (2 H, m, aromatic H), 7.4-8.0 (1 7 H, m, aromatic H) and I I .25 (1 H, s, NH). General procedure for indole formation from phosphonium salts 5 A solution of the phosphonium salt 5 (0.18 mmol) in o-DCB or DMF (3 cm3) was refluxed under an Ar atmosphere for the period as indicated in Table 3. After concentration under reduced pressure, the residue was dissolved in chloroform and the chloroform solution was washed with saturated aq.NaHCO,, water and saturated aq. NaCI, dried over Na,SO,, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography to afford the indole derivative 15. The structures of indoles 15a, c-g and the quinolone 16 were identified by comparison of their spectral data and melting points with those reported in the literature; 15a, colourless crystals, mp 107-108 "C (hexane) lit.,6" 107- 108 "C (hexane); 15c, colourless crystals, mp 80-81 "C (ethanol) lit.,' 84-85 "C (hexane); 15d, colourless crystals, mp 190-191 "C (ethanol) lit.,9c 189-190 "C (ethanol); 15e, yellow crystals, mp 253-255 "C (ethanol) lit.,9c 249-251 "C (ethanol); l5f, colourless crystals, mp 154-1 56 "C lit.,9d 150 "C (benzene-hexane); 15g, colourless crystals, mp 121- 123 "C (ethanol) lit.,9d 123 "C (ethanol); 16, colourless crystals, mp 232-234 "C (ethanol) lit.,9d 234 "C (ethanol).2-Pentafluoroethylindole 15b. Colourless crystals, mp 93- 94 "C (hexane) (Found: C, 50.8; H, 2.8; N, 6.1. C,,H,NF, requires C, 51.08; H, 2.57; N, 5.96); v,,,(KBr)/cm ' 3398, 1551, 1429, 121 1, 1180, 1148 and 1027; d,(CDCI,) 6.97 (1 H, s, 3-H), 7.1-7.4 (2 H, m, 5, 6-H), 7.45 and 7.70 (each 1 H, d, J 8.0 4, 7-H) and 8.40 (1 H, br s, NH); GF(CDCI,) 49.9 (2 F, s) and 77.2(3 F,s);m/z235(M+, 74),216(4), 166(100)and 119(10). References 1 A part of this work appeared as a preliminary communication: K. Miyashita, K. Tsuchiya, K. Kondoh, H.Miyabe and T. Imanishi, Heterocycles, 1996, 42, 5 1 3. 2 The Alkaloids, Chemistry and Physiology, ed. R. H. F. Manske, Academic Press, New York and London, 1965, vol. 8; W. A. Creasey, in Indoles, Part 4: The Monoterpenoid Indole Alkaloids, ed. J. E. Saxton, Wiley-Interscience, Chichester, 1983, p. 783; in Monoterpenoid Indole Alkaloids, Supplement to Part 4, ed. J. E. Saxton, Wiley-Interscience, Chichester, 1994, p. 7 15; R. A. Glennon, J. Med. Chem., 1986,30, 1. 3 Recent review articles: G. W. Gribble, Contemp. Org. Synth., 1994,1, 145; R. J. Sunberg, Prog. 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