Abstract
1,3-Disubstituted-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines were prepared through the ring-closure reactions of the aminobenzylnaphthols with substituted aryl- and heteroarylaldehydes.
Keywords: Biological activity; ring-closure reactions; naphth-1,3-oxazines; amino-benzylnaphthols
Introduction
The development of simple synthetic routes to widely used organic compounds using readily available reagents is one of the main objectives of organic synthesis. Nitrogen heterocycles are of special interest because they constitute an important class of natural and nonnatural products, many of which exhibite useful biological activities. Investigation of the 1,3-oxazine heterocycles has shown that they possess varied biological properties such as analgesic, anticonvulsant, antitubercular, antibacterial and anticancer activity [1,2,3,4]. Particular attention has been paid to these compounds since the discovery of the non-nucleoside reverse transcriptase inhibitor trifluoromethyl-1,3-oxazine-2-one, which shows high activity against a variety of HIV-1 mutant strains [5]. In addition, naphthoxazine derivatives have exhibited therapeutic potential for the treatment of Parkinson’s disease [6,7]. Furthermore, they can be used as intermediates in the synthesis of N-substituted aminoalcohols or in enantioselective syntheses of chiral amines. The tautomeric character of 1,3-O,N-heterocycles offers a great number of synthetic possibilities [8,9,10]. Previously, naphth-1,3-oxazine derivatives have been prepared using 2-naphthol and various substituted aryl- and heteroarylaldehydes in the presence of dry methanolic ammonia [11,12,13]. Our present aim was to extend the synthetic utility of aminobenzylnaphthol by examining its use in the preparation of new heterocyclic 1,3-oxazine compounds.
Results and Discussion
Condensation of 2-naphthol with two equivalents of heteroarylaldehydes or substituted benzaldehydes in the presence of ammonia at room temperature (rt) gave compounds 1a-h. The structures of the aldehyde components, reaction conditions and yields are summarized in Table 1
Table 1.
Synthesis of 1,3-oxazines 1a-h.
| Compound | Ar (Yield, %) | Conditions | Compound | Ar (Yield, %) | Conditions |
|---|---|---|---|---|---|
 |
 |
||||
| 1a | 48 h, rt | 1e | 48 h, rt | ||
| 45 | 52 | ||||
 |
 |
||||
| 1b | 24 h, rt | 1f | 48 h, rt | ||
| 71 | 61 | ||||
 |
 |
||||
| 1c | 48 h, rt | 1g | 24 h, rt | ||
| 51 | 59 | ||||
 |
 |
||||
| 1c | 48 h, rt | 1g | 24 h, rt | ||
| 49 | 56 |
Then, compounds 1b,c and e were hydrolysed under acidic conditions to give aminobenzyl-naphthols (Betti bases) 2b,c and e, respectively. Results are given in Table 2.
Table 2.
Synthesis of aminobenzylnaphthols 2b,c,e.
| Compound | Ar | Yield, % | Conditions |
|---|---|---|---|
|
|||
| 2b | 73 | 6 h, reflux | |
|
|||
| 2c | 69 | 6 h, reflux | |
|
|||
| 2e | 72 | 6 h, reflux |
Finally, the reactions of the Betti bases 2b,c,e with equivalent amounts of aldehydes/heteroaldehydes afforded the corresponding 1,3-disubstituted-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines 3a-f (Table 3).
Table 3.
Synthesis of 1,3-oxazines 3a-f.
| Compound | 3a | 3b | 3c | 3d | 3e | 3f |
|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
| Ar | ||||||
|
|
|
|
|
|
|
| Ar′ | ||||||
| Yield, % | 46 | 43 | 51 | 50 | 42 | 53 |
| Conditions | 48 h, rt | 48 h, rt | 48 h, rt | 48 h, rt | 48 h, rt | 48 h, rt |
The Betti reaction, a Mannich-type aminoalkylation, offers a convenient route for preparing 1‑(aminosubstituted methyl)-2-naphthols 2 under mild (rt) conditions. Access to these Mannich–type phenolic bases make the aminoalkylation reaction of naphthol derivatives a subject of current chemical interest [5,6,7]. Subsequent reaction of the aminobenzylnaphthtols with an equivalent amount of a substituted aldehyde in absolute MeOH at ambient temperature gave 1,3-naphthoxazines 3.
The structures of all the new compounds were confirmed by FTIR, mass spectrometry, NMR and elemental analysis results. Thus, for example, the characteristic C=O bands of the aldehydes disappeared and absorption bands corresponding to NH groups were observed at 3320-3357 cm-1 in the IR spectra of the 1,3-oxazines, while NCH proton singlets at 5.47 and 5.78 ppm and NH proton singlets at 2.8-3.00 were observed in the 1H-NMR spectra.
Conclusions
Substituted aminobenzylnaphthols were synthesized in moderate to good yields by the reactions of 2-naphthols with appropriate aldehydes. Some new 1,3-disubstituted-2,3-dihydro-1H-naphth[1,2-e]-[1,3]oxazines 1 and 3, that are expected to show biological activities, were obtained by the ring-closure reactions of these aminobenzylnaphthols and various aldehydes. In addition, if substituted-1,3-amino-alcohols 2 were to be prepared in enantiopure form, they could be useful in the synthesis of chiral ligands.
Experimental
General
NMR spectra were recorded on Bruker Digital FT-NMR ‘Avance 400’ spectrometer (CDCl3 solvent) with TMS as internal reference. Results are expressed in ppm. IR spectra were recorded on Perkin Elmer FT-IR spectrometer (KBr). GC-EIMS spectra were measured on a Varian SAT2100T mit GC3900 spectrometer using FAB ionization. Melting points were measured on a Gallenkamp melting point apparatus. Silica gel 60 (Merck) was used for column separations. TLC was conducted on standard aluminium sheets precoated with a 0.2 mm layer of silica gel. Elemental analysis were performed using a Flash EA 1112 series apparatus.
General procedure for the synthesis of [1,3]oxazines 1a-h.
The aryl- or heteroarylaldehyde (2 mmol; freshly distilled if a liquid) and 25 % methanolic ammonia solution (0.5 mL) were added to a solution of 2-naphthol (1 mmol) in absolute MeOH (0.5 mL). The mixture was left to stand at ambient temperature for 2 days, during which the crystalline products 1a-h separated out. The crude crystals were filtered off, washed with cold MeOH (2 x 2mL) and purified by recrystallization from bp. 40-60°C petroleum ether or by column chromatography (CC), eluting with the indicated solvents.
1,3-Di(3,4-dimethylphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1a): Colorless crystals; yield 45 %; mp. 110 oC (recrystallized); 1H-NMR (CDCl3): δ = 2.27 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.35 (s, 3H, CH3 ), 5.41 (s, 1H, CH), 6.10 (s,1H, CH), 6.72-7.81 (m,12H, ArH); 13C-NMR (CDCl3): δ = 20.77, 21.56, 55.26, 82.44, 112.33, 125.83, 127.54, 130.28, 154.21; Anal. Calcd. for C28H27NO: C: 85.46; H: 6.92, N: 3.56. Found: C: 85.21, H: 6.93, N: 3.68; MS: m/z 393.
1,3-Di(3,4-dimethoxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1b): Colorless crystals; yield 71 %; mp. 122.5 oC (CC, 3:1 ethyl acetate/n-hexane) 1H- NMR (CDCl3): δ = 3.70 (s, 3H, OCH3 ), 3.75 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 5.63 (s, 1H, NCH), 6,12 (s, 1H, CH), 6.69-7.92 (m, 12H, ArH); 13C-NMR (CDCl3): δ = 53.91, 55.25, 82.22, 111.52, 112.20, 120.15, 121.85, 126.85, 129.25, 130.12, 152.63; Anal. Calcd. for C28H27NO5: C: 73.51, H: 5.95, N: 3.06. Found: C: 73.53, H: 5.93, N: 3.08; MS: m/z 457.
1,3-Di(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1c): Colorless crystals; yield 51 %; mp. 137.4oC (CC, 1:2 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.71(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 5.61 (s, 1H, CH), 6,10 (s, 1H, CH), 6.69-7.88 (m, 10H, ArH); 13C-NMR (CDCl3): δ = 54.5, 55.36, 81.20, 112.03, 120.78, 127.38, 128.32, 129.45, 130.11, 148.57, 153.40; Anal. Calcd. for C30H31NO7: C: 69.62, H: 6.04, N: 2.71. Found: C: 69.68, H: 5.99, N: 2.73; MS: m/z 517.
1,3-Di(3-hydroxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1d): Pale yellow crystals; yield 49 %; mp. 101.2oC (CC, 1:5 ethyl acetate/chloroform); 1H-NMR (CDCl3): δ = 5.58 (s, 1H, CH), 5.98 (s, 1H, CH), 6.73-7.82 (m, 14H, ArH); 13C-NMR (CDCl3): δ= 56.20, 81.60, 112.84, 114.92, 117.36, 128.65, 130.38, 143.87, 157.10, 160.44; Anal. Calcd. for C24H19NO3: C: 78.03, H: 5.18, N: 3.79. Found: C: 77.99, H: 5.21, N: 3.66; MS: m/z 369.
1,3-Di(3-phenoxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1e): Reddish crystals; yield 52 %; mp. 106.1oC (CC, 3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 5.51 (s, 1H, CH), 6.12 (s, 1H, CH), 6.92-7.91 (m, 24H, ArH); 13C-NMR (CDCl3): δ = 54.80, 81.50, 117.31, 121.23, 126.80, 129.50, 130.21, 144.90, 152.61, 162.10; Anal. Calcd. for C36H27NO3: C: 82.90, H: 5.22, N: 2.69. Found: C: 82.87, H: 5.23, N: 2.71; MS: m/z 521.
1,3-Di(5-bromo-2-hydroxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1f): Pale yellow crystals; yield 61 %; mp. 197.8oC (CC, 3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 5.21 (s, 1H, CH), 5.72 (s, 1H, CH), 6.75-7.67 (m, 12H, ArH); 13C-NMR (CDCl3): δ = 56.44, 81.73, 112.56, 114.76, 117.46, 127.75, 130.10, 143.87, 158.24, 159.81; Anal. Calcd. for C24H17Br2NO3 C: 57.67, H: 3.25, N: 2.65. Found: C: 57.61, H: 3.23, N: 2.63; MS: m/z 527.
1,3-Di(2-pyridinyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1g): Pale yellow crystals; yield 59 %; mp. 159.4 oC (CC, 3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 5.24 (s, 1H, CH), 5.86 (s, 1H, CH), 7.12-7.89 (m, 10H, ArH), 8.50-8.89 (m, 4H, pyridine); 13C-NMR (CDCl3): δ = 56.23, 81.69, 124.33, 133.67, 139.76, 148.27, 150.52, 154.3; Anal. Calcd. for C22H17N3O: C: 77.86, H: 5.05, N: 12.38. Found: C: 77.89, H: 5.05, N: 12.40; MS: m/z 339.
1,3-Di(2-thienyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (1h): Colorless crystals; yield 56 %; mp. 171 oC (recrystallized); 1H-NMR (CDCl3): δ = 5.45 (s, 1H, CH), 5.68 (s, 1H, CH), 6.72-7.91 (m, 12H, ArH); 13C-NMR (CDCl3): δ = 53.12, 78.80, 111.56, 120.45, 127.65, 128.53, 129.46, 146.34, 151.57; Anal. Calcd. for C20H15NOS2: C: 68.74, H: 4.33, N: 4.01. Found: C: 68.77, H: 4.31, N: 3.91; MS: m/z 349.
General procedure for the synthesis of 1‑(aminosubstituted methyl)-2-naphthols 2b,c and e.
1b, c or e (1 mmol) were suspended in 20 % HCl (20 mL) and the mixture was stirred and refluxed for 6 h, whereby the crystalline hydrochloride of 2b,c,e separated out and was filtered off and washed with EtOAc. The hydrochloride was suspended in H2O and the mixture was treated with conc. NH4OH (3 mL) and extracted with EtOAc (3 x 5mL). After drying (Na2SO4) and evaporation of the EtOAc phase, crude crystalline compounds 2b,c,e were obtained, which were further purified by column chromatography, eluting with the indicated solvents.
1-[Amino-(3,4-dimethoxyphenyl)methyl]-2-naphthol (2b): Colorless crystals; yield 73 %; mp. 126 oC (3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.72 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 5.97 (s,1H, CH), 6.97-7.64 (m, 9H, ArH); 13C-NMR(CDCl3): δ = 54.20, 55.25, 113.23, 114.43, 122.38, 124.18, 126.56, 127.10, 129.34, 134.46, 152.10, 153.13; Anal. Calcd. for C19H19NO3: C:73.76, H: 6.19, N: 4.53. Found: C: 73.74, H: 6.20, N: 4.54; MS: m/z 309.
1-[Amino-(3,4,5-trimethoxyphenyl)methyl]-2-naphthol (2c): Colorless crystals; yield 69 %; mp. 119 oC (3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.72 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 5.97 (s, 1H, CH), 6.97-7.64 (m, 8H, ArH); 13C-NMR (CDCl3): δ= 54.34, 55.88, 59.24, 107.23, 115.43, 124.38, 126.58, 127.10, 129.74, 137.46, 152.10, 156.13; Anal. Calcd. for C20H21NO4:C: 70.78, H: 6.23, N: 4.13. Found: C: 70.79, H: 6.23, N: 4.14; MS: m/z 339.
1-[Amino-(3-phenoxyphenyl)methyl]-2-naphthol (2e): Colorless crystals; yield 72 %; mp. 114 oC (4:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 5.99 (s, 1H, CH), 6.85-7.64 (m, 15H, ArH); 13C- NMR (CDCl3): δ = 54.34, 55.88, 115.43, 116.43, 122.38, 123.58, 127.10, 129.74, 131.46, 145.33, 152.10, 155.13; Anal. Calcd. for C20H21NO4: C:80.91, H: 5.61, N: 4.10, Found: C: 80.92, H: 5.63, N: 4.11; MS: m/z 341.
General procedure for the synthesis of 1,3-naphthoxazines 3a-f.
To a solution of the appropriate aminonaphthol 2b,c or e (1 mmol) in absolute MeOH (20 mL), an equivalent amount of aryl- or heteroarylaldehyde was added, and the mixture was left to stand at ambient temperature for 48h. The crystalline products were filtered off and then purified by column chromatography, eluting with the indicated solvents.
1-(3,4-Dimethoxyphenyl)-3-(3,4,5-trimethoxhyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3a): Pale yellow crystals; yield 46 %; mp. 133 oC (3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.73 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.921 (s, 3H, OCH3), 5.47 (s, 1H, CH), 5.61 (s, 1H, CH), 7.2-8.8 (m, 11H, ArH); 13C-NMR (CDCl3): δ = 54.20, 56.25, 81.70, 112.23, 121.38, 123.18, 126.86, 129.10, 130.14, 156.78, 160.03; Anal. Calcd. for C29H29NO6: C: 71.44, H: 5.99, N: 2.87. Found: C: 71.39, H: 5.97, N: 2.86; MS: m/z 487.
1-(3,4-Dimethoxyphenyl)-3-(3-phenoxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3b): Pale yellow crystals; yield 43 %; mp. 127 oC (3:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.86 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.52 (s, 1H, CH), 5.71 (s, 1H, CH), 7.24-8.82 (m, 18H, ArH); 13C-NMR (CDCl3): δ = 55.20, 55.68, 81.45, 112.12, 120.20, 121.56 123.65, 126.80, 129.54, 152.67, 162.12; Anal. Calcd. for C32H27NO4: C: 78.50, H: 5.55, N: 2.86. Found: C: 78.47, H: 5.57, N: 2.87; MS: m/z 489.
1-(3,4-Dimethoxyphenyl)-3-(2-pyridinyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3c): Pale yellow crystals; yield 51 %; mp. 143 oC (4:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.69 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 5.50 (s, 1H, CH), 6.40 (s, 1H, CH), 7.2-8.8 (m, 13H, ArH); 13C- NMR (CDCl3): δ = 55.21, 55.43, 79.80, 112.66, 123.34, 126.93, 128.80, 129.72, 130.23, 148.27, 153.88; Anal. Calcd. for C25H23N 2O3: C:75.36, H: 5.56, N:7.03. Found: C: 75.22, H: 5.57, N: 7.04; MS: m/z 398.
1-(3,4,5-Trimethoxyphenyl)-3-(2-pridinyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3d): Pale yellow crystals; yield 50 %; mp. 112 oC (4:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.75 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.52 (s, 1H, CH), 5.87 (s, 1H, CH), 7.22-8.81 (m, 12H, ArH); 13C-NMR (CDCl3): δ = 53.25, 54.01, 81.23, 112.34, 121.45, 126.67, 127.34, 130.78, 157.20; Anal. Calcd. for C26H24N2O4: C: 72.88, H: 5.64, N: 6.53. Found: C: 72.90, H: 5.62, N: 6.56; MS: m/z 428.
1-(3,4,5-Trimethoxyphenyl)-3-(2-thienyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3e): Pale yellow crystals; yield 42 %; mp. 148 oC (5:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 3.74 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.52 (s, 1H, CH), 5.81 (s, 1H, CH), 7.25-8.88 (m, 11H, ArH); 13C-NMR (CDCl3): δ = 56.4, 80.79, 111.80, 120.32, 123.65, 126.34, 128.23, 133.67, 147.23, 152.78; Anal. Calcd. for C25H22NO4 S: C: 69.42, H: 5.13, N: 3.23, S: 7.41 Found: C: 69.41, H: 5.17, N: 3.19, S: 7.33; MS: m/z 432.
1-(3-Phenoxyphenyl)-3-(2-thienyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (3f): Pale yellow crystals; yield 53 %; mp. 153oC (4:1 ethyl acetate/n-hexane); 1H-NMR (CDCl3): δ = 5.53 (s, 1H, CH), 6.11 (s, 1H, CH), 7.27-8.89 (m, 18H, ArH); 13C-NMR (CDCl3): δ= 54.40, 81.10, 112.45, 120.89, 123.47, 126.67, 128.48, 133.85, 145.98, 154.65; Anal. Calcd. for C28H21NO2 S: C: 77.22, H: 4.97, N: 3.22, S: 7.34. Found: C: 77.36, H: 4.81, N: 3.19, S: 7.33; MS: m/z 435.
Acknowledgments
The authors would like to express their gratitude to Yıldız Technical University for its financial support (BAP project 26-01-02-02).
Footnotes
Sample Availability: Samples of the compounds are available from authors.
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