Novel Synthesis of Naphthobenzazepines from N-Bromobenzylnaphthyl­amines by Regioselective C-H Activation Utilizing the Intramolecular Coordination of an Amine to Pd

Abstract

In a biaryl coupling reaction of N-bromobenzylnaphthyl­amine using Pd reagent, the intramolecular coordination of the benzylamino group to Pd causes the regioselective C-H activation at the peri-position to the amine group on the naphthalene ring to produce a new skeletal compound, naphthobenzazepine, in good to excellent yield.

C-H activation - heterocycles - palladium - regioselectivity - synthetic methods

References

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10

6-Bromo-3-isopropoxy-2-methoxybenzyl bromide (6a) was prepared from 3-isopropoxy-2-methoxybenzaldehyde [11] in 54% yield via reduction with NaBH₄ and bromination with Br₂.

11 Banwell MG. Flynn BL. Stewart SG. J. Org. Chem.  1998,  63:  9139 

12

Selected ¹H NMR data (200 MHz, CDCl₃): Compound 9a: δ = 3.01 (3 H, s, N-Me), 6.57 (1 H, br. d, J = 7.0 Hz), 6.86 (1 H, d, J = 8.5 Hz), 7.02 (1 H, s), 7.08 (1 H, br. d, J = 7.0 Hz), 7.14 (1 H, t, J = 7.0 Hz), 7.41 (1 H, d, J = 8.5 Hz). Compound 11a: δ = 2.75 (3 H, s, N-Me), 7.11 (1 H, s), 7.75 (1 H, s).

13

Compound 13 was prepared from 6-bromo-3-hydroxy-2-methoxybenzaldehyde [14] in 48% yield via etherification with isopropyl bromide, reductive alkylation with 6,7-methylenedioxy-1-naphthylamine and NaBH₄, and N-acetylation.

14 Nakanishi T. Suzuki M. J. Prod. Chem.  1998,  61:  1263 

15

Selected ¹H NMR data (200 MHz, CDCl₃): Compound 14: δ = 3.80 (1 H, d, J = 15.4 Hz, ArCH _AH_BN), 6.25 (1 H, d, J = 15.4 Hz, ArCH_A H _BN), 6.93 (1 H, d, J = 8.6 Hz), 7.13 (1 H, s), 7.28 (1 H, s), 7.52 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d, J = 8.6 Hz), 7.69 (1 H, d, J = 8.6 Hz).Compound 15: δ = 3.93 (1 H, d, J = 15.8 Hz, ArCH _AH_BN), 5.97 (1 H, d, J = 15.8 Hz, ArCH_A H _BN), 6.84 (1 H, d, J = 8.8 Hz), 7.10 (1 H, dd, J = 7.6, 1.4 Hz), 7.17 (1 H, s), 7.29 (1 H, t, J = 7.8 Hz), 7.59 (1 H, d, J = 8.8 Hz), 7.61 (1 H, dd, J = 7.8, 1.4 Hz).

16

6,7-Dimethoxy-N-methyl-1-naphthylamine (7f) and 7-isopropoxy-6-methoxy-N-methyl-1-naphthylamine (7h) were prepared from 6,7-dimethoxy-1-naphthylamine [13] and 7-isopropoxy-6-methoxy-1-naphthylamine [17] in 86% and 76% yields, respectively, via trifluoroacetylation, methylation with MeI and hydrolysis with alkaline aqueous EtOH.

17 Stermitz FR. Gillespie JP. Amoros LG. Romero R. Stermitz TA. J. Med. Chem.  1975,  18:  708 

18

Selected ¹H NMR data (200 MHz, CDCl₃): Compound 9b: δ = 3.05 (3 H, s, N-Me). Compound 9c: δ = 2.97 (3 H, s, N-Me), 7.06 (1 H, s). Compound 9d: δ = 3.08 (3 H, s, N-Me), 6.92 (1 H, d, J = 8.6 Hz), 7.14 (1 H, d, J = 8.6 Hz). Compound 9e: δ = 3.00 (3 H, s, N-Me), 6.88 (1 H, d, J = 8.6 Hz), 7.03 (1 H, s), 7.45 (1 H, d, J = 8.6 Hz). Compound 9f: δ = 2.98 (3 H, s, N-Me), 3.48 (3 H, s, OMe), 7.07 (1 H, s). Compound 9g: δ = 3.03 (3 H, s, N-Me), 3.48 (3 H, s, OMe), 6.85 (1 H, d, J = 8.8 Hz), 7.03 (1 H, s), 7.27 (1 H, d, J = 8.8 Hz).

19

Selected ¹H NMR data (200 MHz, CDCl₃): Compound 10f: δ = 2.65 (3 H, s, N-Me), 7.14 (1 H, s), 7.54 (1 H, d, J = 8.6 Hz), 7.66 (1 H, s), 7.79 (1 H, d, J = 8.6 Hz). Compound 10g: Mp 180-183 °C (lit. [20] 186-188 °C). Compound 10h: δ = 2.63 (3 H, s, N-Me), 7.14 (1 H, s), 7.53 (1 H, d, J = 8.6 Hz), 7.69 (1 H, s), 7.78 (1 H, d, J = 8.6 Hz). Compound 10i: δ = 2.62 (3 H, s, N-Me), 6.94 (1 H, d, J = 8.4 Hz), 7.13 (1 H, s), 7.50 (1 H, d, J = 8.4 Hz), 7.51 (1 H, d, J = 8.6 Hz), 7.69 (1 H, s), 7.71 (1 H, d, J = 8.6 Hz).

20 Wu S.-J. Chen I.-S. Chern C.-Y. Teng C.-M. Wu T.-S. J. Chin. Chem. Soc.  1996,  43:  195 

21

Selected ¹H NMR data (200 MHz, CDCl₃): Compound 11f: δ = 2.82 (3 H, s, N-Me), 7.04 (1 H, dd, J = 7.4, 1.2 Hz), 7.13 (1 H, s), 7.63 (1 H, s). Compound 11g: δ = 2.84 (3 H, s, N-Me), 6.86 (1 H, dd, J = 8.0, 1.4 Hz), 7.12 (1 H, s), 7.59 (1 H, s). Compound 11h: δ = 2.81 (3 H, s, N-Me), 7.02 (1 H, dd, J = 7.6, 1.2 Hz), 7.13 (1 H, s), 7.62 (1 H, s). Compound 11i: δ = 2.84 (3 H, s, N-Me), 6.87 (1 H, dd, J = 8.0, 1.2 Hz), 7.11 (1 H, s), 7.56 (1 H, s). Compound 12g: δ = 6.56 (1 H, br d, J = 7.2 Hz), 7.02 (1 H, s), 7.10 (1 H, s). Compound 12h: δ = 6.55 (1 H, dd, J = 7.0, 1.4 Hz), 7.12 (1 H, s), 7.18 (1 H, s). Compound 12i: δ = 6.60 (1 H, dd, J = 7.4, 1.2 Hz), 7.01 (1 H, s), 7.11 (1 H, s).

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