Pd-Catalyzed Functionalization of Aryl Amines on a Soluble Polymer Support

A. Sofia Santos; M. Manuel B. Marques

doi:10.1055/s-0040-1707261

Synlett, Table of Contents

Synlett 2020; 31(20): 2027-2034
DOI: 10.1055/s-0040-1707261

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Pd-Catalyzed Functionalization of Aryl Amines on a Soluble Polymer Support

A. Sofia Santos

,

M. Manuel B. Marques ∗

LAQV@REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal Email: msbm@fct.unl.pt

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Abstract

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Abstract

Herein we report the use of a soluble polymer support PEG-2000 on Pd-catalyzed reactions to improve the functionalization of aromatic amines and the synthesis of N-heterocycles. Compatibility of metal-catalyzed reactions for assembling privileged structures such as functionalized anilines were studied. PEG-supported anilines were found to be suitable substrates for Pd-catalyzed N-arylation, Sonogashira and Heck reactions. PEGylated substrates were prepared in yields up to 94%. This work consists on a proof of concept on the use of PEGylated anilines on Pd-catalyzed cross-coupling reactions. Indole core was attained in 82% and 62% yields, via two different routes.

Key words

aryl amine - metal-catalyzed - PEG - functionalization - anilines

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References

References and Notes
1 Kim EJ, Matuszek AM, Yu B, Reynisson J. Aust. J. Chem. 2011; 64: 910
2 Rauws TR. M, Maes BU. W. Chem. Soc. Rev. 2012; 41: 2463
3 Biajoli AF. P, Schwalm CS, Limberger J, Claudino TS, Monteiro AL. J. Braz. Chem. Soc. 2014; 25: 2186
4 Ruiz-Castillo P, Buchwald SL. Chem. Rev. 2016; 116: 12564
5 Muci AR, Buchwald SS. L. S. Cross-Coupling Reactions . In Topics in Current Chemistry, Vol. 219. Springer Nature; Switzerland: 2002: 131-209
6 Honey MA, Blake AJ, Campbell IB, Judkins BD, Moody CJ. Tetrahedron 2009; 65: 8995
7 Hirai Y, Uozumi Y. Chem. Asian J. 2010; 5: 1788
8 Ruhland T, Bang KS, Andersen K. J. Org. Chem. 2002; 67: 5257
9 Koradin C, Dohle W, Rodriguez AL, Schmid B, Knochel P. Tetrahedron 2003; 59: 1571
10 Harris JM, Chess RB. Nat. Rev. Drug Discovery 2003; 2: 214
11 Kang JS, DeLuca PP, Lee KC. Expert Opin. Emerging Drugs 2009; 14: 363
12 Lee S, Greenwald RB, McGuire J, Yang K, Shi C. Bioconjugate Chem. 2001; 12: 163
13 Filpula D, Zhao H. Adv. Drug Delivery Rev. 2008; 60: 29
14 Leonard J, Baker DE. Ann. Pharmacother. 2015; 49: 360
15 Zhao H. Curr. Bioact. Compd. 2011; 7: 3
16 Dias Pires MJ, Purificação SI, Santos AS, Marques MM. B. Synthesis 2017; 49: 2337
17 Blettner CG, König WA, Stenzel W, Schotten T. J. Org. Chem. 1999; 64: 3885
18 Corma A, García H, Leyva A. J. Catal. 2006; 240: 87
19 Xia M, Wang Y. J. Chem. Res. 2002; 173
20 Carvalho LC. R, Dias Pires MJ, Fernandes E, Marques MM. B. RSC Adv. 2013; 3: 25711
21 Gimenez D, Dose A, Robson NL, Sandford G, Cobb SL, Coxon CR. Org. Biomol. Chem. 2017; 15: 4081
22 Dijkstra G, Kruizinga WH, Kellogg RM. J. Org. Chem. 1987; 52: 4230
23 General Procedure for PEGylation Reaction: Synthesis of Ester and Amide-Linker-Bound Substrates To a PEG-OTs or PEG-NH₂ (1 equiv) solution in DMF (1.1 mL) was added Cs₂CO₃ (3 equiv) and aniline 1a, 1c, or 1e (3 equiv). The mixture was stirred at room temperature for 24 h. After solvent removal by distillation, DCM was added to the crude and washed with water, saturated NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and the solvent evaporated to dryness. The resulting oil was dissolved in a small amount of DCM, and the solid obtained precipitated and was washed with cold diethyl ether, affording the compounds as a solid. PEG–Bis(3-amino-2-bromobenzoate) (2a) Obtained as a white solid (484.3 mg, 93%). IR (KBr): ν_max = 3466, 3352, 2919, 1967, 1731, 1621, 1455, 1349, 1110 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.14 (t, ArH, J = 8.2 Hz, 1 H), 6.93 (m, ArH, 1 H), 6.80 (d, J = 7.3 Hz, 1 H), 4.40–4.27 (m, PEG CH₂, 2 H), 3.72–3.69 (m, PEG CH₂, 2 H), 3.63–3.41 (m, PEG CH₂, 84 H) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 165.7 (C=O), 150.9 (C-3), 134.9 (C-1), 131.1 (C-5), 120.2 (C-4), 115.1 (C-6), 107.4 (C-2), 71.3 (CH₂ PEG), 69.8 (CH₂ PEG), 64.5 (CH₂ PEG) ppm.
24 General Procedure for the N-Arylation Reaction A sealed tube equipped with a magnetic stirring bar was charged with Pd₂(dba)₃ (4 mol%), XantPhos (8 mol%), NaOt-Bu (2 equiv) and PEGylated substrate (1 equiv) in dry toluene (c 0.2 M), followed by phenyl iodide (1.2 equiv). The reaction was stirred for 6 h at 110 °C. The solvent was removed and the crude vacuum dried. The final compound was isolated by precipitation using cold diethyl ether. PEG–Bis(2-bromo-N-phenylaniline) (3b) Isolated as a brown solid (90%). IR (KBr): ν_max = 3521, 2871, 1961, 1643, 1594, 1468, 1109 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.29 (m, ArH, 3 H), 7.19–7.10 (m, ArH, 3 H), 7.05–7.00 (m, ArH, 2 H), 4.64 (s, H-7, 2 H), 3.77–3.57 (m, CH₂ PEG, 112 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 141.96 (C-3), 141.70 (CAr), 138.90 (C-1), 129.59 (CAr), 127.70 (CAr), 122.80 (C-6), 120.47 (CAr), 115.23 (C-2), 73.37 (C-7), 70.86 (CH₂ PEG), 70.71 (CH₂ PEG), 70.29 (CH₂ PEG) ppm.
25 Purificação SI, Dias Pires MJ, Rippel R, Santos S, Marques MM. B. Org. Lett. 2017; 19: 5118
26 Dias Pires MJ, Poeira DL, Purificação SI, Marques MM. B. Org. Lett. 2016; 18: 3250
27 Dias Pires MJ, Poeira DL, Marques MM. B. Eur. J. Org. Chem. 2015; 7197
28 Estevão MS, Carvalho LC. R, Freitas M, Gomes A, Viegas A, Manso J, Erhardt S, Fernandes E, Cabrita EJ, Marques MM. B. Eur. J. Med. Chem. 2012; 54: 823
29 General Procedure for Sonogashira Reaction DMF was previously degassed 7 times by applying vacuum when the mixture is completely frozen and then flushed with nitrogen. Three solutions were prepared with the degassed DMF, and the solids were dried under vacuum before DMF addition. Solution A A round-bottom flask was charged with product of C–N cross-coupling reaction (1 equiv), DIPEA (3.2 equiv), and DMF (c 0.47 M) and the final solution degassed thrice. Solution B A round-bottom flask was charged with CuI (5 mol%), PdCl₂(PPh₃)₂ (3 mol%), and DMF (c 0.0137 M) and the final solution degassed thrice. Solution C A round-bottom flask was charged with ethynylbenzene (2.1 equiv) and DMF (c 0.5M) and the final solution degassed thrice. Solution A was added via syringe to solution B, then was degassed twice; and finally, solution C was added. The mixture was degassed one more time, then allowed to warm-up to 110 °C and stirred for 24 h. After reaction completion, DMF was evaporated; DCM was added to the residue and washed with sat. NH₄Cl and water. The combined organic layers were dried over Na₂SO₄, the desiccant filtered, the solvent concentrated, and the product was vacuum dried. PEG–Bis[4-amino-3-(phenylethynyl)benzoate] (3e) Isolated as a brown solid (73%). IR (KBr): ν_max = 3466, 3350, 3217, 2916, 1962, 1705, 1622, 1454, 1118 cm^–1. ¹H NMR (400 MHz, (CD₃)₂CO): δ = 8.01 (s, ArH-2, 1 H), 7.79 (dd, ArH-6, J = 8.6, 1.7 Hz, 1 H), 7.67–7.60 (m, ArH, 2 H), 7.43 (d, ArH, J = 5.9 Hz, 3 H), 6.88 (d, ArH-5, J = 8.6 Hz, 1 H), 4.39 (t, CH₂ PEG J = 6 Hz, 2 H), 3.81 (t, CH₂ PEG, J = 4 Hz, 2 H), 3.72–3.51 (m, CH₂ PEG, 102 H) ppm. ¹³C NMR (101 MHz, (CD₃)₂CO): δ = 166.27 (C=O), 154.25 (C-4), 135.00 (C-2), 132.39 (C-6), 132.29 (CAr), 129.44 (CAr), 129.34 (CAr), 124.11 (C-1), 114.18 (C-5), 106.80 (C-3), 95.35 (C-8), 86.08 (C-7), 71.29 (CH₂ PEG), 69.91 (CH₂ PEG), 64.40 (CH₂ PEG).
30 Barluenga J, Fernández MA, Aznar F, Valdéz C. Chem. Eur. J. 2005; 11: 2276

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