Chemoselective Synthesis of N-(Aminoalkyl/amidino)phenyl Naphthalene-1-carboxamides and 5,6,7,8-Tetrahydronaphthalene-1-carboxamides and Their Anticoagulant Screening

Abstract

N-[(Aminoalkyl)phenyl]-1-naphthamides and N-[(amino­alkyl)phenyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamides were selectively synthesized from the corresponding cyanonaphthamides by catalytic hydrogenation. N-(Amidinophenyl)-1-naphthalenecarbox­amides and N-(amidinophenyl)-5,6,7,8-tetrahydronaphthalene-1-carboxamides were chemoselectively obtained from the corresponding O-acetylamidoximes or amidoximes, respectively, by catalytic hydrogenation. The products were screened for their anticoagulant effects in human plasma, as measured by the activated partial thromboplastin time and the prothrombin time in vitro. Amidines and 5,6,7,8-tetra­hydronaphthamides were more active than aminoalkyl compounds and naphthamides.

Key words

reduction - amidines - naphthamides - tetrahydro­naphthamide - catalytic hydrogenation

• References and Notes

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• 18 N-[(Aminoalkyl)phenyl]-2-ethoxynaphthalene-1-carboxamide Hydrochlorides 4–6; General Procedure 10% Pd/C (12 mg) and concd HCl (6.93 mg, 0.19 mmol) were added to a solution of the appropriate nitrile 1–3 (0.19 mmol) in absolute EtOH (15 mL), and the mixture was hydrogenated (40 psi) at r.t. for 3 h. The mixture was filtered through a Celite pad that was washed with cold EtOH. The filtrate was evaporated under reduced pressure to give a beige solid that was crystallized from EtOH–Et₂O to give pure white or pale-yellow crystals. N-[3-(Aminomethyl)phenyl]-2-ethoxy-1-naphthamide Hydrochloride (4) White solid; yield: 31 mg (51%); mp 88–89 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.57 (s, 1 H, NH), 8.25 (br s, 3 H, NH₂·HCl), 8.03 (d, J = 9.2 Hz, 1 H, H-8), 8.00 (s, 1 H, H-2′), 7.93 (d, J = 8.4 Hz, 1 H, H-5), 7.69 (d, J = 8.4 Hz, 1 H, H-4), 7.63 (d, J = 8.0 Hz, 1 H, H-6′), 7.47–7.55 (m, 2 H, H-3,7), 7.35–7.44 (m, 2 H, H-6,5′), 7.26 (d, J = 7.2 Hz, 1 H, H-4′), 4.24 ( q, J = 6.8 Hz, 2 H, OCH₂), 3.96 (s, 2 H, CH₂) 1.29 (t, J = 6.8 Hz, 3 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.5 (C=O), 152.6 (C-2), 139.7 (C-3′), 136.0 (C-1′), 131.0 (C-4), 130.9 (C-5′), 130.6 (C-7), 129.1 (C-8a), 128.2 (C-5), 128.1 (C-4a), 127.3 (C-6), 124.0 (C-4′), 123.8 (C-3), 123.6 (C-8), 122.0 (C-6′), 119.2 (C-2′), 115.4 (C-1), 64.8 (OCH₂), 42.6 (CH₂), 15.0 (CH₃). DIP-MS (EI): m/z = 320 [M – HCl]⁺. HRMS (FAB): m/z [M + H]⁺ calcd for C₂₀H₂₀N₂O₂: 321.1603; found: 321.1621.