Copper-Catalyzed Protodecarboxylation and Aromatization of Tetrahydro-β-Carboline-3-Carboxylic Acids

Abstract

An efficient synthetic methodology has been developed to construct aromatic β-carbolines from tetrahydro-β-carboline-3-carboxylic acids by copper-promoted sequential decarboxylation and oxidative aromatization.

Key words

tetrahydro-β-carboline-3-carboxylic acids - decarboxy­lation - aromatization - copper - aromatic β-carboline

The aromatic β-carboline moiety is found in a wide variety of natural products and synthetic congeners.[1] Compounds containing this fragment display a wide range of biological properties including antimalarial,[2] antitumor,[3] and anti-HIV activities.[4] β-Carbolines also exhibit potent binding affinities toward benzodiazepine receptors in the central nervous system, thereby acting as diazepam antagonists.[5] As a result of their significant potential as therapeutics, interest has grown in the development of methods for the efficient and rapid synthesis of β-carboline derivatives. A general synthetic method for its preparation is the dehydrogenation of a suitable tetrahydro-β-carboline precursor. Typical reported methods[6] involve heating the substrate with palladium on carbon,[6a] [b] [c] sulfur,[7] and SeO₂ [8] for extended reaction times.

Decarboxylation of aromatic carboxylic acids by copper has been widely investigated since the 1960s by Sheppard,[9] Cohen,[10] Nilsson,[11] and others.[12] Sheppard et al. reported that cuprous arylcarboxylates readily decarboxylate on heating. Myers developed a palladium-catalyzed decarboxylative Heck-type reaction in 2002.[13] Gooßen reported a practical and an efficient large-scale synthesis of biaryls by using decarboxylative coupling.[14] Carboxylic acids have many advantages as surrogates of organometallic nucleophiles. They are stable, easy to make and store, and readily available. In addition, they generate carbon dioxide as a byproduct in the decarboxylation process instead of producing metal waste. A variety of decarboxylative coupling reactions of carboxylic acids have been developed over the past few decades.[15]

In this Letter, we describe a simple method for the synthesis of aromatic β-carbolines by sequential decarboxy­lation and aromatization of tetrahydro-β-carboline-3-carboxylic acids by employing 10 mol% of CuCl₂ without any ligand. We initiated our studies by examining the reaction of tetrahydro-β-carboline-3-carboxylic acid in the presence of a catalytic amount (10 mol%) of copper salts, without any ligand, in DMF at 130 °C as shown in Table [1]. After examining various copper salts, the best outcome was obtained by using 10 mol% of CuCl₂ (Table [1], entry 4). Cu(OAc)₂ also catalyzed the reaction similarly (Table [1], entry 5). Copper(I) salts can also perform the reaction but with less efficiency (Table [1], entry 1–3).

Table 1 Screening of Reaction Conditions

Entry	Cu salt (mol%)	Time (h)	Yield (%)a
1	CuI (10)	6	76
2	CuBr (10)	6	72
3	CuCl (10)	6	74
4	CuCl2 (10)	1	81
5	Cu(OAc)2 (10)	3	75

^a Isolated yields.

After having optimized reaction conditions, we attempted the decarboxylation–aromatization of various tetrahydro-β-carboline-3-carboxylic acid derivatives, obtained by Pictet–Spengler condensation of l-tryptophan with the appropriate aldehyde,[16] to explore the scope and generality of the reaction. The outcomes of the reactions[17] are presented in Table [2]. Yields were generally good and were observed to be dependent on the electronic characteristics of the substituent at C(1); substrates containing electron-donating groups (Table [2], entries 2 and 4) affording higher yields than those with electron-withdrawing groups (Table [2], entry 5). Finally, the conditions proved to be tolerant of aromatic functional groups.

Table 2 Cu-Mediated Decarboxylation and Aromatization of Tetrahydro-β-Carboline-3-Carboxylic Acids

Entry	Substrate	Product	Yield (%)a
1	1a	2a	81
2	1b	2b	84
3	1c	2c	77
4	1d	2d	87
5	1e	2e	63

^a Isolated yields.

Based on previous reports,[18] a possible mechanism is outlined in Scheme [1]. Initially, the copper catalyst inserts into the carboxylate bond to give intermediate 4 which undergoes oxidative addition to provide intermediate 5. ­Finally, a rapid reductive elimination provides the decarboxylation to produce intermediate 6. On protonolysis, the intermediate 6 is converted into tetrahydro-β-carboline 7 which then transforms into the aromatic β-carboline by oxidative aromatization.

Scheme 1 Proposed mechanism for copper-mediated decarboxy­lation and aromatization of tetrahydro-β-carboline-3-carboxylic acids

In summary, we have developed a convenient protocol for the synthesis of aromatic β-carbolines via copper(II)-­mediated decarboxylation and subsequent aromatization of tetrahydro-β-carboline-3-carboxylic acid precursors in the absence of a ligand.

Acknowledgement

Financial support of this research provided by the Research University Grant Scheme of Universiti Sains Malaysia (RUT-USM) is gratefully acknowledged by the authors.

• References and Notes


For reviews on the chemistry and biology of β-carbolines, see:
• 1a Love BE. Org. Prep. Proced. Int. 1996; 28: 3
• 1b Cao R, Peng W, Wang Z, Xu A. Curr. Med. Chem. 2007; 14: 479
• 2a Shilabin AG, Kasanah N, Tekwani BL, Hamann MT. J. Nat. Prod. 2008; 71: 1218
• 2b Winkler JD, Londregan AT, Hamann MT. Org. Lett. 2006; 8: 2591
• 2c Boursereau Y, Coldham I. Bioorg. Med. Chem. Lett. 2004; 14: 5841
• 3a Guan H, Chen H, Peng W, Ma Y, Cao R, Liu X, Xu A. Eur. J. Med. Chem. 2006; 1167
• 3b Rashid MA, Gustafson KR, Boyd MR. J. Nat. Prod. 2001; 64: 1454
• 3c Prinsep MR, Blunt JW, Munro MH. G. J. Nat. Prod. 1991; 54: 1068
• 4a Tang JG, Wang YH, Wang RR, Dong ZJ, Yang LM, Zheng YT, Liu JK. Chem. Biodiversity 2008; 5: 447
• 4b Wang YH, Tang JG, Wang RR, Yang LM, Dong ZJ, Du L, Shen X, Liu JK, Zheng YT. Biochem. Biophys. Res. Commun. 2007; 355: 1091
• 4c Yu X, Lin W, Li J, Yang M. Bioorg. Med. Chem. Lett. 2004; 14: 3127
• 5a Hagen TJ, Skolnick P, Cook JM. J. Med. Chem. 1987; 30: 750
• 5b Hagen TJ, Guzman F, Schultz C, Cook JM, Skolnick P, Shannon HE. Heterocycles 1986; 10: 2845
• 5c Müller WE, Fehske KJ, Borbe HO, Wollert U, Nanz C, Rommelspacher H. Pharmacol., Biochem. Behav. 1981; 14: 693
• 6a Soerens D, Sandrin J, Ungemach F, Mokry P, Wu GS, Yamanaka E, Hutchins L, DiPierro M, Cook JM. J. Org. Chem. 1979; 44: 535
• 6b Hibino S, Miko O, Masataka I, Kohichi S, Takashi I. Heterocycles 1985; 23: 261
• 6c Coutts RT, Micetich RG, Baker GB, Benderly A, Dewhurst T, Hall TW, Locock AR, Pyrozko J. Heterocycles 1984; 22: 131
• 6d Hagen TJ, Skolnick P, Cook JM. J. Med. Chem. 1987; 30: 750
• 6e Huang W, Li J, Ou L. Synth. Commun. 2007; 37: 2137
• 6f Agarwal SK, Saxena AK, Jain PC, Malviya B, Chandra H, Anand N. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1987; 26: 757
• 7a Cain M, Weber RW, Guzman F, Cook JM, Barker SA, Rice KC, Crawley JN, Paul SM, Skolnick P. J. Med. Chem. 1982; 25: 1081
• 7b Still IJ. W, McNulty J. Heterocycles 1989; 29: 2057
• 7c Qifeng W, Rihui C, Manxiu F, Xiangdong G, Chunming M, Jinbing L, Huacan S, Wenlie P. Eur. J. Med. Chem. 2009; 44: 533
• 8a Gatta F, Misiti D. J. Heterocycl. Chem. 1987; 24: 1183
• 8b Cain M, Campos O, Guzman F, Cook JM. J. Am. Chem. Soc. 1983; 105: 907
• 8c Campos O, DiPierro M, Cain M, Mantei R, Gawish A, Cook JM. Heterocycles 1980; 14: 975
• 9 Cairncross A, Roland JR, Henderson RM, Sheppard WA. J. Am. Chem. Soc. 1970; 92: 3187
• 10a Cohen T, Schambach RA. J. Am. Chem. Soc. 1970; 92: 3189
• 10b Cohen T, Berninger RW, Wood JT. J. Org. Chem. 1978; 43: 837
• 11a Nilsson M. Acta Chem. Scand. 1966; 20: 423
• 11b Bjçrklung C, Nilsson M. Acta Chem. Scand. 1968; 22: 2585
• 11c Chodowska-Palicka J, Nilsson M. Acta Chem. Scand. 1970; 24: 3353
• 11d Nilsson M, Ullenius C. Acta Chem. Scand. 1971; 25: 2428
• 11e Chodowska-Palicka J, Nilsson M. Acta Chem. Scand. 1971; 25: 3451
• 12a Shepard AF, Winslow NR, Johnson JR. J. Am. Chem. Soc. 1930; 52: 2083
• 12b Shang R, Liu L. Sci. China Chem. 2011; 54: 1670
• 12c Gooßen LJ, Rodriguez N, Gooßen K. Angew. Chem. Int. Ed. 2008; 47: 3100 ; Angew. Chem. 2008, 120, 3144
• 12d Gooßen LJ, Gooßen K, Rodriguez N, Blanchot M, Linder C, Zimmermann B. Pure Appl. Chem. 2008; 80: 1725
• 13 Myers AG, Tanaka D, Mannion MR. J. Am. Chem. Soc. 2002; 124: 11250
• 14 Gooßen LJ, Deng G, Levy LM. Science 2006; 313: 662
• 15a Gooßen LJ, Knauber T. J. Org. Chem. 2008; 73: 8631
• 15b Fu Z, Huang S, Su W, Hong M. Org. Lett. 2010; 12: 4992
• 15c Shang R, Yang Z, Zhang S, Liu L. J. Am. Chem. Soc. 2010; 132: 14391
• 15d Rodrίguez N, Goossen L. J. Chem. Soc. Rev. 2011; 40: 5030
• 15e Chou C.-M, Chatterjee I, Studer A. Angew. Chem. Int. Ed. 2011; 50: 8614
• 16 Cao R, Peng W, Chen H, Hou X, Guan H, Chen Q, Ma Y, Xu AE. Eur. J. Med. Chem. 2005; 40: 249
• 17 General Procedure To 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (1 mmol) in DMF (10 mL) was added CuCl₂ (10 mol%) and stirred for 1 h at 130 °C. On completion of the reaction (TLC), H₂O (5 mL) was added to the reaction, and the mixture was basified to pH 9 with 1 M NaOH. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over anhydrous Na₂SO₄. The CH₂Cl₂ was evaporated, and the residue was purified by chromatography which afforded pure 9H-pyrido[3,4-b]indole (2a) as a white solid. ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.63 (1 H, s), 8.89 (d, J = 0.5 Hz, 1 H), 8.31 (d, J = 5.5 Hz, 1 H), 8.2 (d, J = 7.0 Hz, 1 H), 8.09 (dd, J ₁ = 0.5 Hz, J ₂ = 1.0 Hz, 1 H), 7.60 (d, J = 10.0 Hz, 1 H), 7.55–7.53 (m, 1 H), 7.24–7.21 (m, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 140.5, 137.9, 135.9, 133.7, 128.5, 127.6, 121.7, 120.4, 119.4, 114.7, 112.1. GC–MS: 168 [M⁺].
• 18a Cohen T, Schambach RA. J. Am. Chem. Soc. 1970; 92: 3189
• 18b Goossen LJ, Thiel WR, Rodríguez N, Linder C, Melzer B. Adv. Synth. Catal. 2007; 349: 2241