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.

Key words

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

References

• 1a Tsuji J. Palladium Reagents and Catalysts   John Wiley and Sons, Inc.; New York: 1995.  p.125-252  
• 1b Li JJ. Gribble GW. Palladium in Heteocyclic Chemistry   Pergamon; Oxford: 2000. 
• 1c Hassan J. Sevignon M. Gozzi C. Schulz E. Lemaire M. Chem. Rev.  2002,  102:  1359 
• 2a Harayama T. Akiyama T. Akamatsu H. Kawano K. Abe H. Takeuchi Y. Synthesis  2001,  444 
• 2b Harayama T. Akamatsu H. Okamura K. Miyagoe T. Akiyama T. Abe H. Takeuchi Y. J. Chem. Soc., Perkin Trans. 1  2001,  523 
• 3a Harayama T. Shibaike K. Heterocycles  1998,  49:  191 
• 3b Harayama T. Akiyama T. Nakano Y. Nishioka H. Abe H. Takeuchi Y. Chem. Pharm. Bull.  2002,  50:  519 
• 4 Harayama T. Akiyama T. Nakano Y. Shibaike K. Akamatsu H. Hori A. Abe H. Takeuchi Y. Synthesis  2002,  237 
• 5 Harayama T. Sato T. Nakano Y. Abe H. Takeuchi Y. Heterocycles  2003,  59:  293 
• 6 Harayama T. Hori A. Nakano Y. Akiyama T. Abe H. Takeuchi Y. Heterocycles  2002,  58:  159 
• 7a Cope AC. Friedrich EC. J. Am. Chem. Soc.  1968,  90:  909 
• 7b Bruce MI. Angew. Chem., Int. Ed. Engl.  1977,  16:  73 
• 8 Dyker G. Angew. Chem. Int. Ed.  1999,  38:  1698 
• 9a Clark PW. Dyke SF. J. Organomet. Chem.  1985,  243:  389 
• 9b Martín-Mature B. Matero C. Cárdenas DJ. Echavarren AM. Chem.-Eur. J.  2001,  7:  2341 
• 9c Dyker G. Chem. Ber.  1997,  243:  1567 
• 9d Jia C. Piao D. Oyamada J. Lu W. Kitamura T. Fujiwara Y. Science  2000,  287:  1992 
• 11 Banwell MG. Flynn BL. Stewart SG. J. Org. Chem.  1998,  63:  9139 
• 14 Nakanishi T. Suzuki M. J. Prod. Chem.  1998,  61:  1263 
• 17 Stermitz FR. Gillespie JP. Amoros LG. Romero R. Stermitz TA. J. Med. Chem.  1975,  18:  708 
• 20 Wu S.-J. Chen I.-S. Chern C.-Y. Teng C.-M. Wu T.-S. J. Chin. Chem. Soc.  1996,  43:  195 
• 22a Vila JM. Suarez A. Pereira MT. Gayoso E. Gayoso M. Polyhedron  1987,  6:  1003 
• 22b Teijido B. Fernández A. López-Torres M. Castro-Juiz S. Suárez A. Ortigueira JM. Vila JM. Fernández JJ. J. Organomet. Chem.  2000,  598:  71 

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.

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.

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.

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).

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).