Functionalized 2,5-Disubstituted Benzazepines: Stereoselective Synthesis of 3-Methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-2-carbonitrile and Related Derivatives

Abstract

A stereoselective synthesis of 2-carbonitrile and 2-aminomethyl-substituted 5-phenylbenzazepine derivatives was developed starting from [4-hydroxy-3-(methyloxy)phenyl]acetic acid. The key step in the synthesis is a stereoselective addition of cyanide to 3-methyl-1-phenyl-2,3-dihydro-1H-3-benzazepine (4) to give a 15:1 trans/cis mixture of 2-carbonitrile-5-phenyl benzazepine dia­stereomers 5a/5b in 83% yield. The stereochemistry of the major product was deduced by ¹H NMR NOESY analysis. The carbonitrile diastereomers could be separated and further manipulated by reduction to the corresponding aminomethyl derivatives 3a and 3b in a stereoselective manner. The aminomethyl benzazepine template 3 has potential to serve as a handle for the synthesis of a variety of derivatives modified at the 2-position of the benzazepine scaffold, as illustrated by an acylation of the primary amine of 3 ­followed by mild deprotection of the 7-phenol functionality.

Key words

2,5-trans-disubstituted 2-aminomethyl 3-benzazepine - cyanide addition - stereoselective synthesis

References

• Recent reviews of 3-benzazepines:
• 2a Bourne JA. CNS Drug Reviews  2001,  7:  399 
• 2b Kawase M. Saito S. Motohashi N. Int. J. Antimicrob. Agents  2000,  14:  193 
• 3a Walter LA, and Chang WK. inventors; U.S. Patent  3393192. 
• 3b Kasparek S. Adv. Heterocycl. Chem.  1974,  17:  45 
• 3c Berger JG. Chang WK. Clader JW. Hou D. Chipkin RE. McPhail AT. J. Med. Chem.  1989,  32:  1913 
• 3d Chumpradit S. Kung MP. Billings JJ. Kung HF. J. Med. Chem.  1991,  34:  877 
• 4 Gerritz SW. Smith JS. Nanthakumar SS. Uehling DE. Cobb JE. Org. Lett.  2000,  2:  4099 
• For examples and further references see:
• 6a Heathcock CH. Norman MH. Dickman DA. J. Org. Chem.  1990,  55:  798 
• 6b Mitch CH. Tetrahedron Lett.  1988,  29:  6831 
• 6c Grierson DS. Harris M. Husson H.-P. J. Am. Chem. Soc.  1980,  102:  1064 
• 7 A related reaction with a 1-benzazepine substrate has been reported: Corbel JC. Uriac P. Huet J. Martin CAE. Advenier C. J. Med. Chem.  1995,  30:  3 
• 8 For an analogous route to a secondary, rather than tertiary lactam, see: Berney D. Schuh K. Helv. Chim. Acta  1981,  64:  373 

1

Current address: Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139.

5

Because of the IUPAC priority system, the substituent on the carbon adjacent to the benzazepine nitrogen results in the phenyl substituent being at the 5-position rather than the 1-position as in compounds described in ref. [3]

9

Synthesis of 3-Methyl-7-(methyloxy)-8-{[(methyloxy)methyl]oxy}-1-phenyl-2,3-dihydro-1 H -3-benzazepine ( 4): To a -78 °C solution of lactam 9 (2.63 g, 7.72 mmol) in anhyd THF (50 mL) under N₂ was added via syringe 1.5 M DIBALH in toluene (6.69 mmol, 10.04 mmol). The mixture was stirred at -78 °C for 2 h, allowed to warm to ambient temperature and stirred for 16 h. The mixture was quenched by slow addition of sat. aq NH₄Cl (75 mL). The mixture was extracted with 1:1 hexane-EtOAc (150 mL). The organic layer was separated and stirred rapidly for 2 h with sat. aq sodium potassium tartrate. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to afford a yellow oil. Purification by silica gel chromatography (2:1 hexanes-EtOAc as eluant) gave 1.29 g (51%) of product. ¹H NMR (400 MHz, CDCl₃): δ = 2.62 (s, 3 H), 3.43 (s, 3 H), 3.49-3.56 (m, 2 H), 3.85, (s, 3 H), 4.42 (d, 1 H, J = 5.2 Hz), 5.02 (d, 1 H, J = 11.2 Hz), 5.06 (d, 1 H, J = 6.4 Hz), 5.10 (d, 1 H, J = 6.4 Hz), 5.88 (d, 1 H, J = 11.2 Hz), 6.63 (s, 1 H), 6.73 (s, 1 H), 7.08 (d, 2 H, J = 7.6 Hz), 7.16 (t, 1 H, J = 7.2 Hz), 7.25 (d, 2 H, J = 7.6 Hz).

10

Synthesis of trans-3-Methyl-8-(methyloxy)-7-{[(methyloxy)methyl]oxy}-5-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine-2-carbonitrile ( 5a): To a solution of enamine 4 (1.29 g, 3.96 mmol) in MeOH (70 mL) was added KCN (1.29 g, 19.8 mmol) followed by pH 7.2 phosphate buffer (15 mL). The mixture was stirred at ambient temperature for 3 d. The solvent was removed and the mixture was partitioned between H₂O (50 mL) and 2:1 hexane-EtOAc (75 mL). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to afford 1.16 g (83%) of product as a pale yellow solid judged to be a >15:1 mixture of 5a:5b by ¹H NMR. Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.56; H, 6.86; N, 7.95. Found: C, 71.29; H, 7.09; N, 7.55. A sample of diastereomerically pure 5a (0.63 g) was obtained by recrystallization from Et₂O as a white solid, mp 157-158 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.47 (s, 3 H), 2.71 (dd, 1 H, J = 15.0, 6.1 Hz), 3.02 (t, 2 H, J = 6.7 Hz), 3.48 (m, 1 H), 3.50 (s, 3 H), 3.87 (m, 1 H), 3.88 (s, 3 H), 4.15 (d, 1 H, J = 4.8 Hz), 5.18 (d, 1 H, J = 6.9 Hz), 5.21 (d, 1 H, J = 6.9 Hz), 6.69 (s, 1 H), 6.98 (s, 1 H), 7.08 (d, 2 H, J = 7.5 Hz), 7.17 (t, 1 H, J = 7.6 Hz), 7.24-7.28 (m, 2 H). ¹H NMR NOESY analysis indicated that 5a is the trans diastereomer as assigned.

11

cis -3-Methyl-8-(methyloxy)-7-{[(methyloxy)methyl]oxy}-5-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine-2-carbonitrile ( 5b): The foregoing 15:1 mixture of trans/cis benzazepines 5a and 5b (1.40 g, 3.97 mmol) was dissolved in anhyd THF (60 mL) and the solution was cooled under N₂ to -78 °C. A solution of KHMDS in toluene (11.9 mL of 0.5 M solution, 5.96 mmol) was added and the mixture was stirred for 20 min. A solution of 2,6-tert-butylhydroxytoluene (1.54 g, 7.0 mmol) in THF (10 mL) was added slowly via syringe. The mixture was stirred for 1 h at -78 °C, allowed to warm to 0 °C, and partitioned between sat. aq NaHCO₃ and 1:1 hexane-EtOAc. The organic layer was separated and dried over Na₂SO₄, filtered and concentrated. Purification by silica gel chromatography (2:1 hexane-EtOAc) afforded in order of mobility 5a (0.76 g, 2.15 mmol) and 5b (mp 137-138 °C) (0.44 g, 1.25 mmol). Compound 5b: ¹H NMR (400 MHz, CDCl₃): δ = 2.49 (s, 3 H), 2.92 (dd, 1 H, J = 12.4, 9.6 Hz), 2.99-3.08 (m, 2 H), 3.28 (s, 3 H), 3.48 (d, 1 H, J = 14.8 Hz), 3.84 (s, 3 H), 4.06 (d, 1 H, J = 4.8 Hz), 4.18 (d, 1 H, J = 9.6 Hz), 4.89 (s, 2 H), 6.27 (s, 1 H), 6.73 (s, 1 H), 7.17 (s, 1 H), 7.19 (s, 1 H), 7.29 (t, 1 H, J = 7.2 Hz), 7.35-7.39 (m, 2 H). ¹H NMR NOESY analysis indicated that 5b is the assigned cis diastereomer.

12

Reduction of Nitrile 5a or 5b to Give Aminomethyl Benzazepines 3a and 3b. Compound 3a as major diastereomer: To a solution of 50 mg of 5a (0.142 mmol) in THF (2.0 mL) was added 4 µL H₂O, followed by 15 mg (0.395 mmol) LiAlH₄. The mixture was stirred for 45 min and an additional 17 mg (0.45 mmol) of LiAlH₄ was added. The mixture was stirred for 30 min and, after cooling to 0 °C quenched by addition of 30 µL H₂O, 30 µL 15% NaOH and 60 µL H₂O. The mixture was filtered through a pad of Celite and concentrated to afford a quantitative yield of product 3 judged by ¹H NMR to be an 11:1 mixture of 3a and 3b. ¹H NMR (400 MHz, CDCl₃): δ = 2.42 (s, 3 H), 2.60-2.73 (m, 2 H), 2.75-2.84 (m, 2 H), 3.10 (dd, 1 H, J = 14.0, 10.0 Hz), 3.20-3.30 (m, 4 H), 3.38 (s, 3 H), 3.75 (t, 1 H, J = 4.5 Hz), 3.85 (s, 3 H), 4.40 (dd, 1 H, J = 8.0, 3.0 Hz), 4.98 (d, 1 H, J = 6.4 Hz), 5.01 (d, 1 H, J = 6.4 Hz), 6.48 (s, 1 H), 6.67 (s, 1 H), 7.15 (d, 2 H, J = 7.0 Hz), 7.25 (t, 1 H, J = 7.0 Hz), 7.32 (t, 1 H, J = 7.0 Hz). Compound 3b as major diastereomer: The same procedure as was employed above was carried out on 5b (101.4 mg, 0.288 mmol) using 6 µL H₂O (0.33 mmol) and 27 mg (0.71 mmol) LiAlH₄ in 4 mL THF to supply a quantitative yield of 3 judged to be a 1:7 mixture of 3a:3b. ¹H NMR (400 MHz, CDCl₃): δ = 2.60 (s, 3 H), 2.63-2.81 (m, 4 H), 2.99 (dd, 1 H, J = 14.4, 3.2 Hz), 3.21 (d, 1 H, J = 14.1 Hz), 3.32 (s, 3 H), 3.47 (dd, 1 H, J = 14.4, 10.0 Hz), 3.71-3.74 (m, 2 H), 3.83 (s, 3 H), 4.46 (dd, 1 H, J = 10.0, 2.8 Hz), 4.91 (d, 1 H, J = 6.4 Hz), 4.93 (d, 1 H, J = 6.4 Hz), 6.38 (s, 1 H), 6.62 (s, 1 H), 7.11 (d, 2 H, J = 6.8 Hz), 7.23 (t, 1 H, J = 6.8 Hz), 7.31 (t, 2 H, J = 7.2 Hz).

13

A possible explanation for the difference in the high diastereoselectivity of the cyanide addition to 4 (Scheme [2] ) compared to poor selectivity of the LiAlH₄ reduction under anhydrous conditions may be the fact that both are under thermodynamic control but involve distinct amine protonation states. At pH 7.2 there may be a strong thermodynamic preference for the protonated form of 5a relative to the protonated form of 5b, while under the conditions of the reduction there may be little thermodynamic bias between free base 5a and 5b. Experiments to further examine this question by attempting the epimerization of 5a or 5b under more basic conditions in the presence of a proton source have not been carried out.

14

N -{[(2 R *,5 R *)-7-Hydroxy-3-methyl-8-(methyloxy)-5-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepin-2-yl]methyl}-1-methyl-1 H -indole-2-carboxamide Hydrochloride ( 11): To a solution of 7:1 cis/trans benzazepines 3b:3a obtained from the foregoing procedure (27.3 mg, 0.077 mmol) and N,N-diisopropylethylamine (27 µL, 0.154 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 mg, 0.112 mmol), and N-methyl indole-2-carboxylate (21 mg, 0.12 mmol) followed by 1-hydroxybenzotriazole monohydrate (3 mg, 0.02 mmol). The solution was stirred at ambient temperature for 15 h. The mixture was partitioned between H₂O and EtOAc. The organic layer was separated, washed with sat. aq NaCl, filtered and concentrated to afford the crude product, which was purified by silica gel chromatography to give 26.0 mg (66% yield) of the pure MOM protected ether amide product as a 7:1 mixture of diastereomers by ¹H NMR. ¹H NMR (major, cis diastereomer) resonances include: δ = 2.67 (s, 3 H), 2.78 (dd, 1 H, J = 15.0, 7.2 Hz), 2.97 (br s, 1 H), 3.03 (d, 1 H, J = 14.4 Hz), 3.19 (dt, 1 H, J = 7.7, 3.6 Hz), 3.33 (s, 3 H), 3.53-3.61 (m, 2 H), 3.84 (s, 3 H), 4.04 (s, 2 H), 4.50 (d, 1 H, J = 8.4 Hz), 4.94 (s, 2 H), 6.41 (s, 1 H), 6.66 (s, 1 H), 6.74 (s, 1 H), 7.11-7.15 (m, 3 H), 7.24-7.38 (m, 5 H), 7.61 (d, 1 H, J = 7.9 Hz). This material was dissolved in MeOH (1.0 mL) and 1.0 N aq HCl was added (1.0 mL). The mixture was stirred at ambient temperature for 1.5 h. The solvent was removed and the mixture was resubjected to the above conditions and lyophilized to 24.6 mg of the product phenol hydrochloride salt 11 as a cream colored powder judged to be a 7:1 mixture of cis/trans diastereomers. Low res. MS = 470.2 [M + H]. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.96 (s, 1.5 H), 3.00-3.10 (m, 3 H), 3.15 (s, 1.5 H), 3.40-3.60 (s, 1.5 H), 3.63 (s, 1.5 H), 3.63-3.80 (m, 1 H), 4.00 (s, 3 H), 4.00-4.10 (m, 1 H), 4.60 (d, 0.5 H, J = 8.0 Hz), 5.85 (s, 0.5 H), 5.95 (s, 0.5 H), 6.80-6.95 (m, 1 H), 7.05-7.70 (m, 11 H), 8.62-8.80 (m, 1 H), 8.80-8.81 (s, 0.5 H), 10.06 (br s, 1 H). Anal. Calcd. for C₂₉H₃₁N₃O₃·1.9HCl: C, 64.64; H, 6.15; N. 7.80. Found: C, 64.70; H, 6.10; N, 7.66.