J. CHEM. SOC. PERKIN TRANS. I 1983 Observations on the Pictet-Spengler Synthesis of 1,2,3,4-Tetrahydro-p-carbolines Ronald Grigg," H. Q. Nimal Gunaratne, and Edward McNaghten Chemistry Department, Queen's University, Belfast B T9 5AG, Northern Ireland The Pictet-Spengler cyclisation df the benzylideneimine of tryptophan methyl ester in xylene, contrary to literature reports, occurs extremely slowly, if at all, in the absence of acids. The cyclisation is Bronsted acid catalysed and the rate of cyclisation is related to the PKa of the Bronsted acid and its concentration.All the acid catalysts studied give essentially the same stereoisomeric mixture of tetrahydro- P-carbolines (cis : trans, ca. 1.2 :1). The benzylideneimine of tryptamine smoothly cyclises under the same conditions.Cook et a1.1*2have described, in a series of papers, the cyclisation of tryptophan imines (1) in benzene to tetrahydro- P-carbolines (2). The imines (1) were generated in situ from tryptophan methyl ester and the appropriate aldehyde. The current interest in the Pictet-Spengler reaction 3-5 prompts us to correct the assertion ls2 that the cyclisation (1) +(2) occurs in benzene in the absence of acids. The cyclisation (1) -+ (2) is generally considered to proceed via a transient spiro-imine (3).6 This cyclisation (1) *(3) formally constitutes an example of a disfavoured 5-endo-trig process.' Hence the direct, geometrically favoured, 6-endo-trig cycli-sation (1) -(2) might seem more probable for the Pictet- Spengler cyclisat ion producing tetrahydro-P-carbolines.How-ever, there are a growing number of formal 5-endo-trig processes 8*9 especially in nitrogen-containing systems, Un- fortunately, in most cases, there is insufficient evidence to rule out alternative mechanisms involving geometrically favoured processes. Thus the isolation of the spiroindoline (4),'O from a Pictet-Spengler cyclisation in the presence of Raney nickel, is not necessarily significant support for a spiro-intermediate in tetrahydrocarboline formation.The immonium ion precursor of (4) could participate in ring-chain equili- bration without leading to tetrahydrocarboline. Similarly the recently reported stereospecific Pictet-Spengler cyclisation (5) --+ (6) provides strong evidence for an exo-tet process involving (7).However (5) -e (6) does not distinguish between a 5-exo-tet process, studied in detail in indoles by Jackson and his co-workers," and a 6-exo-tet process, nor does it establish unequivocally that (6) is the kinetically controlled product. Our interest in 5-endo-trig cyclisations prompted us to re-examine the Pictet-Spengler cyclisation (la) +(2a,b) in aprotic solvents reported earlier by Cook et ~l.'*~The cyclis- ation of the pre-formed imine (la) in benzene at 80 "C .. R' (1) a; R=H,R'=Ph (2) a; R =Ph,R'=H I Me b; R =H,R'=Ph C02Me / (3) xco2Me 'C02Me 'H (7) undertaken and the reactions were conveniently run in 2Hlo- o-xylene and followed by n.m.r. spectroscopy (Table).The cyclisation (la) ---t (2a,b) was found to be catalysed by a range of acids. The rate of cyclisation is directly related to the PKa of the added acid catalyst and its concentration (Table). The strongest acid (CF3C02H, PKa = 0) studied gave the fastest rate of cyclisation and the weakest (p-nitrophenol, pK, = 7.14) gave the slowest rate of cyclisation. The rate of essentially fails to proceed. Even at 110 "C in 2Hlo-o-xylene the half-life of (la) is cu. 151 h (Table). A repeat of Cook's original work (tryptophan methyl ester, benzaldehyde, benzene, 80 "C, 48 h), i.e. generating the Schiffs base in situ, gave only the Schiffs base (la) and no P-carboline (2a,b). Less than 50 conversion into P-carbolines (2a,b) occurred when tryptophan methyl ester was heated (48 h) in boiling benzene with benzaldehyde containing 2 (w/w) of benzoic acid.A repeat of the reaction with benzaldehyde containing 10 (w/w) benzoic acid gave a mixture of Schiffs base (la) (cu. 37) and P-carbolines (2a,b) (ca.63). In both cases the ratio of cis to truns p-carbolines (2a : 2b) was cu. 1.3 : 1. This is the reverse of that reported by Cook et ~1.'~We thus conclude that the cyclisation (la) (2a,b) undrr Cook's conditions is due to acidic impurities. A more systematic study of the cyclisation of (la) was 186 J. CHEM. SOC. PERKIN TRANS. I 1983 Table." Effect of pKa of acid catalyst on rate of cyclisation of (la) (0.2~solution in 2H,,-o-xylene) Pseudo-first-order PKa of rate constant Yield Acid (M) acid T/"C (2a) : (2b) ( x 10-5) (s-1) c t+/min () * -110 1.21 f 0.03 -9060 f 30 -Benzoic acid (0.05) 4.2 110 1.17 f 0.01 3.16 f 0.06 366 f 7 -Benzoic acid (0.10) 4.2 110 1.20 f 0.01 11.4 f 0.10 101.3 f 0.9 92 Benzoic acid (0.15) 4.2 110 1.20 f.0.01 14.2 f 0.10 81.3 f 0.5 -Benzoic acid (0.20) 4.2 110 1.23 amp; 0.03 27.6 f 0.50 41.8 f 0.7 -p-Nitrophenol (0.10) 7.14 110 1.36 f 0.02 1.02 f 0.03 1132 f 32 96 Formic acid (0.10) 3.7 60 1.20 f 0.06 1.56 f 0.13 740 f 57 -o-Nitrobenzoic acid (0.10) 2.17 60 1.23 f 0.04 Dichloroacetic acid (0.10) 1.3 60 1.21 f 0.05 34.9 f 0.27 33 f 3.7 -Trifluoroacetic acid (0.10) 0 60 1.31 -f 0.04 48.8 f 2.8 23.7 f 1.3 94 a Kinetics were measured in the probe of a Brucker WH90 spectrometer, spectral width 1 OOO Hz, 4K data points.Temperature accurate to 50.5 "C. Errors refer to statistical errors. Yields calculated from the n.m.r. spectra using an internal standard. the solvent gave a pale yellow residue whose n.m.r. spectrum showed it to be N-benzylidenetryptophan methyl ester. The solid was crystallised from methanol to give (1 a) (2.38g, 78) as colourless prisms, m.p. 128-129 "C (lit.,' m.p. 120 "C). (b) The above experiment was repeated on half scale with the addition of benzoic acid (10mg). An aliquot was removed after 48 h, the solvent evaporated, and the residue dissolved in cyclisation of (la) in the presence of o-nitrobenzoic acid (pK, 'H,dimethyl sulphoxide. The 'H n.m.r. spectrum of the 2.17) was too fast to measure at 110 "C, whilst at 60 "C the sample showed it comprised N-benzylidenetryptophan methyl ester (la) (56.25) and the tetrahydro-fi-carbolines(2a,b)acid was only partially soluble.The tetrahydrocarboline from (43.75). The ratio of cis-(2a) to trans-carboline (2b) was (la) is always obtained as a mixture of stereoisomers (2a,b) in 1.33 : 1. All product ratios were estimated from the lH n.m.r. these cyclisations. The major product is always the cis-isomer, spectrum by comparing the imine proton signal at 6 8.17withthe cis : trans ratio being ca. 1.2 : 1 in all cases. This contrasts the C(1)-H signals for cis-carboline (2a) (6 5.22) and trans- with Cook's work which reports the trans-isomer as the major product.12 In all cases the cyclisation occurred cleanly and in carboline (2b) (6 5.34).high yield (Table; estimated by n.m.r. spectroscopy). We (c) Experiment (a) was repeated on half-scale with the cannot explain the discrepancy between Cook's work l1 addition of benzoic acid (50 mg). Work-up of an aliquot as described above gave a mixture of (la) (37.5) and (2a,b) and our own with regard to the isomer ratio of the product. (62.5). The ratio of cis-(2a) to trans-carboline (2b) was Our ratios were estimated directly from the n.m.r. spectra of 1.31 : 1.the crude reaction mixture and confirmed by comparison with spectra of the pure isomers obtained by t.1.c. separation. 1 -Phenyl- 1,2,3,4-tetrahydro-P-carboline.-N-Benzylidene-(cis, m.p. 201-202 "C, trans, m.p. 176 "C; lit.," cis, m.p. tryptamine (25 mg, mol) and benzoic acid (6.1 mg, 5 x201-203 "C, trans, m.p.175-176 "C). Finally, it was of interest to compare the rate of cyclisation lo-' mol) were dissolved in o-xylene (0.5 ml) and heated at of (la) with that of (8) +(9) in view of the assertion that 110 "C for 24 h. On cooling the product crystallised (16 mg, tryptamine and benzaldehyde do not cyclise to (9) in boiling 64) and was separated by filtration, m.p. 168 "C (lit.,14 benzene. This assertion is based on the preparation of (8) by 168 "C). Jackson and Smith l3 under conditions (tryptamine, freshly distilled benzaldehyde, benzene, 80 "C, 30 min) which clearly Acknowledgementsminimise catalysis by adventitious benzoic acid. We find that the rate of cyclisation of (8) (0.2~in ZHlo-o-We thank the S.E.R.C.and Queen's University for support. xylene) to (9) (64 isolated yield) in the presence of benzoic acid (0.IM) is approximately half as fast (pseudo-first-order References rate constant = 5.74 x lop5s-l) * as the cyclisation (la) -w 1 D. Soerens, J. Sandrin, F. Ungemach, P. Mokry, S. G. Wu,(2a,b) (Table). E. Yamanaka, L. Hutchins, M. Di Pierro, and J. M. Cook, J. Org. Chem., 1979, 44, 535. 2 J. Sandrin, D. Soerens, L. Hutchins, E. Richfield, F. Ungemach Experimental and J. M. Cook, Heterocycles, 1976, 4, 1101 ; J. Sandrin, D. N.m.r. experiments were performed in sealed tubes previously Soerens, P. Mokry, and J. M.Cook, ibid., 1977, 6, 1133; G. Wu, E. Yamanaka, and J. M. Cook, ibid., 1978, 9, 175.flushed with argon.3 S. N. Quessy and L. R. Williams, Aust. J. Chem., 1979, 32, Reaction of Tryptophan Methyl Ester with Benza1dehyde.- 13 17 ;H. A. Bates, J. Org. Chem., 1981, 46, 4931 ;T. Hudlicky,T. M. Kutchan, G. Shen, V. E. Sutliff, and C. J. Coscia, ibid.,(a) Tryptophan methyl ester (2.2 g, 0.01 mol) and benzalde- 1981,46, 1738. hyde (1.0g, 0.01 mol) were dissolved in dry benzene (50 ml) 4 H. Ernst, B. Hauser, and E. Winterfeldt, Chem. Ber., 1981,114, and the mixture boiled under reflux for 48 h. Evaporation of 1894; D. M. Harrison, Tetrahedron Lett., 1981, 22,2501. 5 M.Lounasmaa and A. Koskinen, Tetrahedron Lett., 1982, 23, 1489.* Product precipitation interfered with later data collection, so 6 F. Ungemach and J. M. Cook, Heterocycles, 1978, 9, 1089. the value is an approximate one based on ca.40 reaction. 7 J. E. Baldwin, J. Chem. SOC., Chem. Commun., 1976, 734. J. CHEM. SOC. PERKIN TRANS. I 1983 8 R. Grigg, J. Malone, and A. Tangthongkum, J. Chem. SOC., Chem. Commun., 1980, 648 and references therein. 9 C. P. Reddy, S. M. Singh, and R. Balaji Rao, Tetrahedron Lett., 1981, 22, 973; M.J. Perkins, P. C. Wong, J. Barrett, and G. Dhaliwal,J. Org. Chem., 1981, 46, 2196. 10 J. R. Williams and L. R. Unger, J. Chem. SOC.,Chem. Commun., 1970, 1605. 11 K.M.Biswas and A. H. Jackson, Tetrahedron, 1969, 25, 227; R. Iyer, A. H. Jackson, P.V.R. Shannon, and B. Naidoo, J. Chem. SOC.,Perkin Trans. 2, 1973, 872; R.Iyer, A. H. Jackson, and P. V. R. Shannon, ibid., 1973,878; A. H. Jackson, P. V.R. Shannon and A. C. Tinker, J. Chem. Soc., Chem. Commun., 1976, 796. 12 F. Ungemach, D. Soerens, R. Weber, M.Di Pierro, 0.Campos,P. Mokry, J. M.Cook,and J. V.Silverton, J. Am. Chern. Soc., 1980, 102,6976. 13 A. H. Jackson and A. E. Smith, Tetrahedron, 1968,24,403. 14 B. Robinson and G. F. Smith, J. Chem. Suc., 1960,4574. Received 21st June 1982; Paper 2/1029
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