Synthesis of Heteroaryl ortho-Phenoxyethylamines via Suzuki Cross-Coupling: Easy Access to New Potential Scaffolds in Medicinal Chemistry

Abstract Heteroaryl ortho-phenoxyethylamines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands. Herein an efficient, fast, and general method for the synthesis of heteroaryl phenoxyethylamines via Suzuki cross-coupling is reported. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered (thiophene, furan, thiazole, pyrazole, imidazole) or six-membered (pyridine, pyrimidine) heteroaromatic rings for appropriate libraries of ligands. All the compounds presented here have never been synthesized before and a full structural characterization is given.

Despite the important role of these chemical entities in several fields of medicinal chemistry, a general method for heteroaryl ortho-phenoxyethylamine synthesis has not yet been reported. From a practical point of view, the assembly of these building blocks could be achieved via cross-coupling of two monocyclic units. Among the various method-ologies available, 10 the Suzuki-Miyaura reaction, one of the most popular and powerful methods for the joining of arylaryl and aryl-heteroaryl moieties, was chosen. 11 Thanks to its compatibility with a variety of functional groups, the stability, commercial availability, and low toxicity of a wide range of boronic starting materials, along with the ease of working up the reaction mixtures, this reaction has found many applications, in both research laboratories and largescale industrial processes. 12 In this work, we describe the synthesis of several heteroaryl ortho-phenoxyethylamines via Suzuki cross-coupling. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered electronrich (thiophene, furan), six-membered electron-poor (pyridine, pyrimidine), or five-membered rings with two heteroatoms (thiazole, pyrazole, imidazole) for appropriate libraries of ligands.
In an attempt to find a convenient and versatile strategy to build the ortho-substituted biaryl scaffold, we took into account several factors: i) the different nature of the heterocycle to be coupled: electron-rich or electron-poor; ii) the presence of sterically hindered ortho-substituted substrates; iii) the presence of LiAlH 4 -sensitive heterocycles such as pyrimidine; iv) the presence of heteroatoms such as sulfur or nitrogen that may drastically reduce the yields of some steps (i.e., reduction) due to the poisoning of the catalyst; and v) the opportunity to start from a common precursor (nitrile or masked amine) by inserting the structural diversity in the last step of the synthesis.
It is well known that the optimal conditions for Suzuki coupling is the electron-poor nature of aryl halide and the electron-rich nature of arylboronic acid. Keeping this in mind, we designed a synthetic approach, employing a common key intermediate 9, which directly underwent Suzuki

Paper Syn thesis
In this paper, we describe the synthesis of exemplary 2arylfuran or -thiophene derivatives, via palladium-catalyzed coupling, starting from the corresponding electronically activated boronic acids. It is known that 2-thiophenylor 2-furanylboronic acids easily undergo deboronation under the basic conditions of the Suzuki-Miyaura coupling. 15 Here we have developed an optimized procedure in which the degree of deboronation is negligible or absent, as attested by the good/excellent yields reported for heterobiaryls 11 and 12 (70 and 93%, respectively).
We found that the best reaction conditions were tetrakis(triphenylphosphine)palladium(0) as a catalyst in combination with the cheap base potassium carbonate; a mixture of toluene and ethanol was more effective than DMF as a reaction solvent, as attested by the higher yields, compared to those previously reported. 13 However, when a mixture of toluene-ethanol (1:1 v/v) was employed, along with the desired product 11 (55% yield), the corresponding ethyl ester (14%) was isolated, due to the alcoholysis of the nitrile. Since the presence of an alcohol may improve water/toluene miscibility and consequently the activation of the boronic acid to boronate by the hydroxyl anion, in order to prevent the formation of the ethyl ester, the amount of ethanol was lowered (toluene-ethanol, 3:1 v/v). Under these conditions the ester was found in trace amounts and 11 was isolated in good yield (70%). By using the same coupling conditions described for 11, the 2-furanyl derivative 12 was synthetized in excellent yield (93%) without any optimization steps.
These coupling conditions allow a variety of heterobiaryls to be obtained in good/high yields, starting from the corresponding electron-rich boronic acids, even in the presence of a base sensitive group.
Conversely, since it is known that Suzuki reactions of electron-deficient 2-heterocyclic boronates, such as 2-pyridyl, generally give low conversions, 16 13 was obtained by reacting the corresponding commercially available bromo derivative with the pinacolboronic ester 10. Pinacol boronates are a very attractive synthon since they are air-, moisture-, temperature-, and chromatography-stable. However, for ortho-substituted substrates, as for 9, the synthesis of the corresponding boronic ester provides very low yields and also requires harsh conditions, due to the steric hindrance created by the ortho-substituent. 17 In an attempt to obtain the pinacolboronic intermediate 10 in high yields, the results published by several groups concerning the Suzuki coupling of sterically hindered substrates were investigated. 17,18 In fact, it has been reported that the employment of a phosphine ligand might improve the borylation of ortho-substituted aryl halides under mild conditions. A series of commercially available palladium-based catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)dipalladium(0) [Pd 2 (dba) 3 ], and palladium(II) acetate [Pd(OAc) 2 ] alone or in combination with palladium ligands such as JohnPhos [1,1′biphenyl]-2-yl-di-tert-butylphosphine or Cy-JohnPhos [(2biphenyl)dicyclohexylphosphine], were considered.
In Table 1, the optimization of the borylation reaction, including solvent (Et 3 N or DMF) and reaction time, is shown. The optimal reaction conditions were found to be associated with the employment of Pd(OAc) 2 and a biphenylphosphine ligand. In particular, a molar ratio of 4:1 ligand (Cy-JohnPhos) to catalyst [Pd(OAc) 2 ] afforded 10 with the highest yield (95%) and the lowest reaction time (2 h) ( Table  1, entry 8). Thus, the pinacolboronic ester 10 was allowed to react with 2-bromo-or 3-bromopyridine using the same coupling conditions described for 11, to afford the pyridinyl derivatives 13 and 14 in good (68%) and moderate (40%) yields, respectively. The same conditions were successfully applied for the coupling of highly electronically deactivated aryl halides, such as bromopyrimidine (data not shown).

Paper Syn thesis
Finally, the desired amines 15-18 were obtained in good/high yields (60-92%) after reduction of the nitriles 11-14 by LiAlH 4 . Unfortunately, in the case of pyrimidinyl biaryls the use of highly reactive reducing agents, such as LiAlH 4 , resulted in the degradation of the pyridimidine moiety.
Investigation with thiazole analogues led to similar results. This side-reaction can be explained by the low aromatic stability and/or the electron-poor nature of these rings that easily undergo reduction under the conditions required for the conversion of the nitrile to amine. An attempt to increase the chemoselectivity (i.e., by lowering the temperature to 0 °C) resulted in very low yields of the desired amine.
Thus, for the synthesis of biaryls incorporating LiAlH 4sensitive heterocycles, such as pyrimidine, thiazole, or pyrazole, a second version of the synthetic pathway was designed that involved the introduction of a masked amino group before the construction of the biaryl scaffold. In particular, the tert-butyloxycarbonyl group (Boc) was chosen as the protecting group for the primary amine, due to its stability under the basic conditions required for the coupling and to the ease of removal (Scheme 2). Briefly, the Boc-protected amine 19, synthesized in accordance with the literature, 19 was reacted with 2-iodophenol to obtain the intermediate 20 that was quantitatively converted into the corresponding pinacolboronate derivative 21, using the optimized conditions reported for 10 ( Table 1, entry 8). The pinacolboronic ester 21 was reacted with the selected commercially available bromo derivatives under the same con-ditions as described for 11 to provide the biaryls 22-27. Finally, deprotection of 22-27 under acidic conditions afforded the desired amines 28-33.
In summary, a versatile and efficient method for the synthesis of heteroaryl ortho-phenoxyethylamines has been described. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered rings with one (thiophene, furan) or two (thiazole, pyrazole, imidazole) heteroatoms and six-membered (pyridine, pyrimidine) heteroaromatic cycles starting from electronpoor aryl halide or electron-rich arylboronic acids. To date, a number of new compounds have been synthesized using this procedure and currently they are under investigation in a field as important as medicinal chemistry.
Reagents, solvents, and other chemicals were used as purchased without further purification, unless otherwise specified. Air-or moisture-sensitive reactants and solvents were employed in reactions carried out under N 2 atmosphere, unless otherwise noted. Flash column chromatography purification (medium-pressure liquid chromatography) was carried out using Merck silica gel 60 (230-400 mesh, ASTM). The structures of all the isolated compounds were ensured by NMR spectra and elemental analysis (C,H,N). NMR data ( 1 H and 13 C, 1D and 2D experiments) were obtained using a DPX 400 Avance spectrometer (Bruker). Chemical shifts are expressed in δ (ppm). 1 H NMR chemical shifts are relative to TMS as an internal standard. 13

Suzuki-Coupling Reactions of 9; General Procedure A
A 100 mL round-bottomed flask, equipped with a condenser and a magnetic stir bar, was charged with o-iodophenoxyacetonitrile (9; 1 equiv), Na 2 CO 3 (2 equiv), and toluene-EtOH mixture (20 mL, 3:1 v/v). Thereafter, the corresponding commercially available arylboronic acid (1.2 equiv) was added to the resulting suspension. The mixture was degassed, purged with N 2 for 15-20 min, and then Pd(PPh 3 ) 4 (10 mol%) was added. The reaction mixture was heated at 90 °C for 8 h under stirring. The reaction mixture was allowed to cool to r.t., brine (20 mL) was added, and the mixture stirred for 30 min. The organic layer was then diluted with EtOAc, transferred to a separatory funnel, washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting residue was purified on silica gel to provide the title compound as an oil.

Suzuki-Coupling Reactions of Pinacolboronate Esters 10 and 21; General Procedure B
A 100 mL round-bottomed flask, equipped with a condenser and a magnetic stir bar, was charged with the corresponding bromoheteroaryl (1 equiv), Na 2 CO 3 (2 equiv) and toluene-EtOH (20 mL, 3:1 v/v). Thereafter, compound 10 or 21 (see below for the preparation of 21) (2.0 equiv) was added to the resulting suspension. The mixture obtained was degassed, purged with N 2 for 15-20 min, and then Pd(PPh 3 ) 4 (10 mol%) was added. The reaction mixture was stirred and heated at 90 °C for 8 h. The mixture was allowed to cool to r.t., brine (20 mL) was added, and stirred for 30 min. The organic layer was then diluted with EtOAc, transferred to a separatory funnel, washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting residue was purified on silica gel to provide the title compound as an oil.

LiAlH 4 Reduction of Nitriles; General Procedure C
The selected nitrile derivative (1 equiv) was dissolved in anhydrous Et 2 O (1-9 mL) and added dropwise to a suspension of LiAlH 4 (3 equiv) in anhydrous Et 2 O (2 mL) at 0 °C. The excess of the reducing agent was immediately and carefully quenched with H 2 O and 5% aq NaOH. The reaction mixture was stirred for 15 min and then EtOAc was added. The resulting organic phase was washed with brine, dried (Na 2 SO 4 ), filtered, and evaporated under reduced pressure. The crude product was used in the next synthetic step without any purification.

Paper Syn thesis
resulting solution under N 2 at 0 °C. The reaction mixture was stirred at r.t. for 4 h. The mixture was then washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give the title product as a dark liquid; yield: 2.91 g (16.21 mmol, 99%), which was used directly in the next synthetic step.

tert-Butyl [2-(2-Iodophenoxy)ethyl]carbamate (20)
Compound 19 (4.9 g, 27.27 mmol) and KI (7.55 g, 45.46 mmol) were added to a solution of o-iodophenol (5.0 g, 22.73 mmol) in anhydrous DMF (80 mL) in the presence of K 2 CO 3 (9.43 g, 68.2 mmol). The reaction mixture was magnetically stirred and refluxed for 4 h. Then the reaction mixture was cooled to r.t. and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in EtOAc, and the EtOAc layer was washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to afford the title compound as a dark oil; yield: 8.

Hydrolysis of Boc Esters; General Procedure D
A 25 mL round-bottomed flask was charged with the selected NHBoc derivative (1 equiv) and EtOH (5 mL). The solution was cooled to 0 °C in an ice water bath and 1.25 M HCl in EtOH (15 equiv) solution was added dropwise. The reaction was allowed to warm to r.t. and re-fluxed for 2 h. The reaction was monitored by TLC (eluent: cyclohexane-EtOAc, 1:1). The resulting suspension was cooled to r.t. and the solvent was removed under reduced pressure. The crude solid product was dissolved in H 2 O and then aq 5% NaOH was added until pH 12. The resulting solution was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to afford the corresponding pure product.