Preparation of 4-aryl-β -carboline-3-carboxamides by Suzuki–Miyaura cross-coupling applied to a 4-iodo precursor obtained by ortho - directed lithiation

The 4-iodo-β -carboline-3-carboxamide derivative 2 was obtained by ortho - directed metalation of the phenylcarboxamide precursor 5 using methyllithium and iodine followed by in situ N - methylation with methyl iodide. Compound 2 reacted with a variety of aryl-and heteroarylboronic acids under classical Suzuki–Miyaura palladium-catalyzed


Introduction
β-Carbolines represent an important heterocyclic system, being found both as constituents of many natural products and in a number of pharmacologically active compounds. 1,2In particular, β-carboline-3-carboxylates and -carboxamides have been shown to possess high affinities for the benzodiazepine (e.g., Valium®) binding site of the γ-aminobutyric acid (GABA) receptor of the central nervous system. 3Such compounds thus have potential as anti-epileptic, anxiolytic or mnemotonic drugs.However, while many β-carboline analogues have been synthesized which demonstrate potentially clinically useful profiles, none has found its way into use as a drug for humans.Thus, there is a need to find β-carboline-3-carboxylic acid derivatives which, while maintaining pharmacological activity, are more selective, more bio-available and/or less toxic.
The C-4 position of β-carboline-3-carboxylates is well known to accept a wide range of substituents allowing pharmacomodulation with little or no loss, and sometimes even remarkable increase, in receptor affinity. 4,5In this connection, we have previously described the selective introduction of halogen atoms (Br, I) at C-4 of phenyl β-carboline-3-carboxamide (1 and 2, Scheme 1) [6][7][8] via ortho-directed lithiation/electrophilic substitution. 9Metalation of the C-4 position was successfully accomplished only when methyllithium was used as the lithiating agent.Furthermore, among the many possible N-9 β-carboline protecting groups, only the N,Ndimethylsulfamoyl group was found to be sufficiently stable under the lithiating reaction conditions.Both C-4 halogenated derivatives 1 and 2 were subsequently used to introduce other substituents using palladium-catalyzed coupling reactions.Thus, the 4-bromo-3-carboxamide 1 was converted 7,8 into 4-amino derivatives (3) using Buchwald conditions. 10However, the application of Stille-or Heck-type coupling reactions to the 4-iodo analogue of 1 required prior transformation of the secondary to a tertiary carboxamide in order to avoid complexation and deactivation of the palladium catalyst. 8Thus, these palladium-catalyzed reactions were successful starting from the 4-iodo-3-N-methyl-N-phenylcarboxamido-β-carboline 2, allowing introduction of unsaturated C-C bonded substituents at C-4 (4).In an effort to provide further structural diversity, we now describe the preparation of 4-aryl-β-carboline-3-carboxamides by way of Suzuki-Miyaura cross-coupling reactions and modified versions thereof.

Scheme 2
Compound 2 was then used to study the reaction with arylboronic acids under Suzuki-Miyaura palladium-catalyzed coupling conditions. 11Thus, treatment of 2 with phenylboronic acid 6a in the presence of 3 mol.%Pd(PPh 3 ) 4 and 2 eq Na 2 CO 3 for 24 h in a mixture of ethanoltoluene at reflux provided the 4-phenyl derivative 7a in 90% yield (Table 1).The 4-ethylphenylβ-carboline 7b was formed in slightly lower yield (85%), while boronic acids with potentially sterically hindering ortho-substituents (2-methoxy, 2-fluoro, 2-formyl), on the phenyl ring also gave satisfactory yields of coupled product (7c, 7d, 7f, respectively).The presence of three methoxy groups on the phenyl ring (6e), however, completely inhibited the coupling reaction, and the formation of 7e was not observed.The introduction of heterocycles at C-4 using the same reaction conditions was also studied.Starting from 3-thienyl-and 3-furan-boronic acids, the coupled compounds 7g and 7h were obtained in good yields.However, in the case of pyridine-4-boronic acid, only traces of the expected coupled product 7i could be detected.The 3,4,5-trimethoxyphenyl group is a common unit found in many cytotoxic compounds, particularly those known to interact with tubulin (e.g., colchicine, combretastatin, podophyllotoxin).For this reason, we decided to investigate reaction conditions which would allow preparation of the trimethoxyphenyl-β-carboline derivative 7e from 2, the classical Suzuki coupling conditions having failed.In particular, modifications of the base, solvents and palladium catalysts used in this reaction were made (Table 2).Thus, while replacement of sodium carbonate by potassium phosphate as the base had no beneficial effect (entries 1 and 2), use of potassium fluoride allowed isolation of compound 7e in 22 % yield (entry 3).Use of DME-ethanol instead of toluene-ethanol as solvent system produced a small increase in yield of 7e (27%, entry 4).While little improvement was observed when the reaction was conducted in the same solvent mixture but in the presence of cesium fluoride (entry 5), the yield of 7e increased to 38% when this latter base was employed in dioxane-methanol (entry 6).Finally, using conditions described by Broutin and Colobert 12 for the efficient formation of o-substituted biaryls (palladium diacetate in the presence of dppf as ligand, dioxane-ethanol, cesium fluoride and 4 h reflux), compound 7e could be obtained in a very satisfactory 79% yield (entry 7).Application of these optimized conditions to the coupling of 4-iodo-β-carboline 3 with pyridine 4-boronic acid 6i did not, however, have any beneficial effect on the formation of compound 7i.Some of these substituted 4-aryl β-carbolines could be used for further transformations, as illustrated in Scheme 3. Thus, reaction of the o-formyl derivative 7f with benzylamine in acetic acid in the presence of sodium acetate, followed by reduction of the resulting imine with sodium borohydride in ethanol, provided the dibenzylamine 8. Treatment of the latter with sodium hydride in THF then provided, albeit in modest yield, the novel benzazepino-β-carboline 9.

Scheme 3
As we have previously demonstrated, the N,N-dimethylsulfamoyl protecting group of the N-9 position of β-carbolines can be efficiently cleaved using samarium iodide or trifluoromethanesulfonic acid 7 as well as electrochemically. 13In the case of the 4-aryl βcarbolines, treatment of 7a-e with a 1:10:1 mixture of trifluoromethanesulfonic acid, trifluoroacetic acid and anisole at room temperature for 1 h provided the corresponding N-9 deprotected derivatives 10a-e in yields of 84 to 92% (Scheme 4).In conclusion, the N-9-protected 4-iodo-N-methyl-N-phenyl-β-carboline-3-carboxamide 2, obtained by ortho-directed metalation of β-carboline-3-carboxamide 5, undergoes efficient Suzuki cross-coupling reactions with a variety of aryl-and heteroaryl-boronic acids to give the corresponding 4-aryl-β-carboline-3-carboxamides.While these cross-coupling reactions were generally successful using the classical Suzuki-Miyaura conditions, the reaction parameters required optimization in order to prepare the 3,4,5-trimethoxyphenyl derivative 7e.These compounds can be conveniently deprotected to afford novel β-carboline derivatives (10a-e) suitable for pharmacological evaluation, notably with respect to the GABA A receptor.Finally, the incorporation of functional groups on the C-4 phenyl ring can allow further transformations to potentially active β-carboline derivatives as shown by the preparation of the benzazepino-βcarboline 9 from the 4-(2-formylphenyl) precursor 7f.

Experimental Section
General Procedures.Melting points were measured in capillary tubes on a Büchi B-540 apparatus and are uncorrected.IR spectra were recorded with a Perkin Elmer Spectrum BX FT-IR spectrometer. 1 H NMR and 13 C NMR spectra were measured respectively at 300 MHz, 250 MHz or 75 MHz on a Bruker Aspect 3000 (300 MHz) instrument.RT denotes room temperature.Chemical shifts are given as δ values with reference to Me 4 Si as internal standard.Electronimpact-and chemical-ionization-mass spectra were recorded on an Automass Multi Thermo Finnigan and AEI MS-9 spectrometer, respectively.High-resolution mass spectra were obtained using an ESI-TOF Micromass LCT spectrometer.TLC and preparative chromatography were performed on Merck silica gel 60 plates with fluorescent indicator.The plates were visualized with UV light (254 and 366 nm) or with a 3.5% solution of phosphomolybdic acid in ethanol.All column chromatography was conducted on Merck 60 silica gel (230-400 mesh) at medium pressure (200 mbar).All solvents were distilled before use.Reagents and chemicals were purchased from the Aldrich Chemical Co. and were used without further purification.Elemental analyses were performed at the ICSN, CNRS, Gif-sur-Yvette.

General procedure for the preparation of 4-aryl-β-carboline-3-carboxamides 7
To a solution of compound 2 (54 mg, 0.1 mmol) in toluene-ethanol (12 mL of a 1:1 mixture) were added aqueous sodium carbonate (3 mL of a 1.5 M solution; 4.5 mmol), the arylboronic acid (0.2 mmol) and palladium tetrakis(triphenylphosphine) (0.003 mmol, 3 mol%).The mixture was degassed with argon for 5 min and heated at reflux for 24 h.The reaction mixture was then cooled, diluted with ethyl acetate (15 mL) and washed with water (20 mL).The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure leaving the crude product which was purified by column chromatography on silica gel (dichloromethane-ethyl acetate, 3:1).

Table 1 .
Suzuki cross-coupling of arylboronic acids with compound 2