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Journal of the Chilean Chemical Society

versión On-line ISSN 0717-9707

J. Chil. Chem. Soc. v.52 n.4 Concepción  2007

http://dx.doi.org/10.4067/S0717-97072007000400001 

 

J. Chil. Chem. Soc, 52, N° 4 (2007), págs: 1277-1280

 

SYNTHESIS OF CHROMANOLS BY TANDEM RADICAL ADDITION/CYCLIZATION MEDIATED BY TRIS(TRI METHYLSILYL)SILANE

 

LUZ MARINA JARAMILLO-GÓMEZ, a* JAIME MARTINb AND LUZ AMALIA RÍOSc

a Department of Chemistry, Universidad del Valle. Cali-Colombia.
b Department of Chemistry, Universidad del Cauca, Popayán-Colombia.
c Universidad de Caldas, Manizales-Colombia.


ABSTRACT

Sisyl radicals generated from frá(trimethylsilyl)silane were reacted with allyloxy benzaldehydes and the sequential radical process of was studied. After desisylation, the corresponding chromanols were successfully obtained.

Keywords: O-sisyl ketyl radicals, radical addition / cyclization, allyloxybenzaldehydes, chromanols, sisyl ether, tris(trimethylsilyl)silane.


INTRODUCTION

Tributyltin hydride and frá(trimethylsilyl)silane (TTMS) are effective chain propagators for homolytic processes. When reacting with aldehydes and ketones, these compounds are good hydrostannylating1 and hydrosilylating agents.2 Under radical conditions, the intermediates, tributyltin and sisyl radicals3, Chemoselectively attack the oxygen atom of the carbonyl group to generate O-stannyl ketyl" or O-sisyl ketyl radicals.5 These radicals could be directly reduced or undergo cyclization to generate diverse derivatives. For instance, O-stannyl ketyl radicals generated from 5-hexenyl aldehydes have been intramolecularly trapped by C=C double bonds to give cyclopentanes ring products.6 Allylic O-stannyl ketyl radicals, generated from a,p-unsaturated ketones, could also undergo very similar Chemistry.6,7 In addition, this method was extended to the preparation of hydroxy pyrrolidines and piperidines from amino aldehydes8 and the synthesis of hydro xy tetrahydrofuranes, chromanols and quinolines using Bu3SnH as a Chain carrier.9

On the other hand, the cyclizations through the generation of O-sisyl ketyl radicals have not been sufficiently exploited. In this context, the hydrosilylation and cyclization of 7-methyl-6-octen-2-one and 2,6-dimethyl-5-heptenal in the presence of TTMS / AIBN to afford a mixture of cyclopentane isomers has been reported.5 Meanwhile, it was demonstrated that sisyl radicals react with the carbonyl group of p-alkenyloxyenones allowing the formation of p-alkylated enones and/or substituted tetrahydrofurans.10

TTMS is a more environmental friendly and safer reagent for free radical cyclizations compared to Bu3SnH.n Herein, we report the formation of chromanols by consecutive radical addition / cyclization process from allyloxybenzaldehydes with TTMS, followed by desisylation.

EXPERIMENTAL SECTION

General information. All reagents were purchased from commercial sources and used without further purification. Melting points were measured on an Electrothermal IA 9100 digital apparatus without correction. Thin-layer chromatography (TLC) was performed on Silica Gel F254 plates (Merck); flash column chromatography were performed by using Silica Gel (230-400 mesh, Merck). 1H and 13C NMR spectra were recorded on a Varían, Gemini- 300 or a Mercury- 400 spectrometer. Chemical shifts of protons are reported in ppm (8) downfield form tetramethylsilane (TMS) and carbons are reported in ppm (8) taking as reference the solvent peak of CDC13 (8 77.16). Mass spectra were recorded on a Finnigan 4021 quadrapole GC-MS spectrometer, Kratos MS-80 and MS-50 mass spectrometer using electron impact ionization (EI), Chemical ionization (CI) or electrospray (ESI.)

General procedure for salicylaldehyde alkylation. Method (a). To a stirred suspension of f-BuOK (1.2 eq) in dry THF (7.0 niL) was added a solution (0.18M, THF) of each salicylaldehyde 1. After stirring for 10 min at r. t. the corresponding alkenyl halide (1.3 eq) was added drop wise and the reaction mixture stirred and heated at 50 ° C until complete consumption of the starting materials (≈ 3-4 h). Method (b). To a stirred suspension of K2C03 (0.54 M, 2 eq) in dried acetone, was added a solution (1.0 M, acetone) of each salicylaldehyde 1 via syringe. After stirring for 10 min at r.t. the corresponding alkenyl halide was added and the reaction mixture stirred and heated at 65 °C, until the complete disappearance of the starting materials was observed by TLC. The dried crude products were purified by flash column chromatography (FCC).

2'-(3-methyl-but-2-enyloxy)benzaldehyde (2.1a). This compound was obtained through method (a) in 85% yield. 1H-NMR (300 MHz, CDCl3), δ 10.49 (s, 1H, -CHO), 7.83 (dd, 1H, J1 = 1.8 Hz, J2 = 7.5 Hz, H-arom), 7.53 (ddd, 1H, J1 = 1.8 Hz, J2 = 7.2 Hz, J3 = 12.0 Hz, H-arom), 7.03-6.97 (m, 2H, H-arom), 5.50 (m, 1H, =CH), 4.63 (d, 2H, J = 6.6 Hz, 0-CH2-), 1.81 (s, 3H, Me), 1.76 (s, 3H, Me); 13C-NMR (75 MHz, CDCl3) δ 190.3, 136.0, 128.5, 120.8, 119.2, 113.1, 65.7, 26.0, 18.5; HRMS caled for C12H14O2 190.0993, found 190.0990.

2'-(3-Phenyl-prop-2-enyloxy)benzaldehyde (2.1b). This compound was obtained through method (b) in 95% yield. 1H-NMR (300 MHz, CDCl3) δ 10.58 (s, 1H, -CHO), 7.87 (dd, 1H, J1 = 1.8 Hz, J2 = 7.8 Hz, H-arom), 7.55 (td, 1H, J1 = 1.8 Hz, J2 = 8.1 Hz, H-arom), 7.49-7.26 (m, 6H, H-arom), 7.05 (m, 1H, H-arom), 6.77 (d, 1H, J = 15.9 Hz, arom-CH=), 6.43 (dt, 1H, J1 = 5.7 Hz, J2 = 15.9 Hz, =CH-), 4.8 (dd, 2H, J1 = 1.2 Hz, J2 = 5.4 Hz, -CH2-O); 13C-NMR (75 MHz, CDC13), δ 190.0, 161.2, 136.3, 136.1, 133.8, 128.9, 128.7, 128.4, 126.9, 125.4, 123.8, 121.1, 113.2, 69.4; HRMS caled for C16H14O2 238.0994, found 238.0991.

2'-(3-Methoxycarbonyl-prop-2-enyloxy)benzaldehyde (2.1c). This compound was obtained through method (b) in 74% yield. 1H-NMR (300 MHz, CDC13) δ 10.54 (s, 1H, -CHO), 7.85 (d, 1H, J = 6.0 Hz, H-arom), 7.536 (dd, 1H, J1 = 7.5 Hz, J2 = 8.4 Hz, H-arom), 7.15-7.04 (m, 2H, H-arom, =CH-), 6.93 (d, 1H, J = 8.7 Hz, H-arom), 6.23 (d, 1H, J = 15.9 Hz, =CH-CO), 4.830 (td, 2H, J= 1.8 Hz, 0-CH2-), 3.76 (s, 3H. OMe); 13C-NMR (75 MHz, CDC13) δ 189.5, 163.0, 160.0, 141.7, 136.1, 129.1, 122.5, 122.9, 121.7, 112.7, 67.0, 52.0; HRMS caled for C12H1204 220.0736, found 220.0734.

5'-Methyl-2'-(3-methyl-but-2-enyloxy)benzaldehyde (2.2a). This compound was obtained through method (a) in 73% yield. 1H-NMR (300 MHz, CDC13) δ 10.40 (s, 1H, -CHO), 7.60 (d, 1H, J = 2.1 Hz, H-arom), 7.30 (dd, 1H, J1 = 2.1 Hz,J2 = 8.4Hz, H-arom), 6.86 (d, 1H, J= 8.4 Hz, H-arom), 5.46 (tm, 1H, J = 6.6 Hz, =CH-), 4.58 (d, 2H, J = 6.6 Hz,), 2.28 (s, 3H, arom-CH3), 1.77 (s, 3H, C-CH,), 1.72 (s, 3H, H-arom C-CH3); 13C-NMR (75 MHz, CDC13) δ 190.0, 159.4, 138.0, 136.4, 129.9, 128.2, 124.8, 119.1, 113.0, 65.6, 25.7, 20.2, 18.2.

5'-Methyl-2'-(3-phenyl-prop-2-enyloxy)benzaldehyde (2.2b). This compound was obtained through method (b) in 80% yield. 1H-NMR (400 MHz, CDC13) δ 10.58 (s, lH,-CHO), 7.65 (d, 1H, J = 2.4 Hz, H-arom), 7.41 (d, 2H, J = 7.2 Hz, H-arom), 7.34 (d, 3H, J1 = 7.2 Hz, J2 = 8.0 Hz, H-arom), 7.29-7.25 (m, 1H, H-arom), 6.94 (d, 1H, J = 8.8 Hz, H-arom), 6.62 (d, 1H, J = 15.0 Hz, arom-CH=), 6.30 (dt, 1H, J1 = 1.6 Hz, J2 = 15.0 Hz, =CH-), 4.80 (dd, 2H, J1 = 1.6 Hz, J2 = 5.6 Hz, 0-CH2), 2.31 (s, Me); 13C-NMR (100 MHz, CDC13) δ 190.2, 159.3, 136.8, 136.3, 133.6, 130.6, 128.9, 128.7, 128.4, 126.8, 125.0, 123.9, 113.2,69.5,20.5.

5'-Methyl-2'-(3-methoxycarbonyl-prop-2-enyloxy)benzaldehyde (2.2c). This compound was obtained through method (b) in 74% yield. 1H-NMR (300 MHz, CDCl3) δ 10.50 (s, 1H, -CHO), 7.65 (d, 1H, J = 2.7 Hz, H-arom), 7.35 (dd, 1H, J1 = 2.7 Hz, J2 = 8.7 Hz, H-arom), 7.08 (dt, 1H, J1 =4.2 Hz, J2 = 15.9 Hz, =CH-COO), 6.80 (d, 1H, J = 8.7 Hz, H-arom), 6.20 (dt, 1H, J1 = 1.8 Hz, J2 = 15.9 Hz, =CH-), 4.80 (dd, 2H, J1 = 2.2 Hz, J2 = 4.1 Hz, 0-CH2-), 3.78 (s, 3H, COOMe), 2.33 (s, 3H, arom-Me); 13C-NMR (75 MHz CDC13) δ 188.0, 165.0, 157.0, 141.0, 135.0, 130.0, 128.1, 124.0, 121.0, 112.0, 66.0,51.2,20.2.

5'-Chloro-2'-(3-methyl-but-2-enyloxy) benzaldehyde (2.3a). This compound was obtained through method (a) in 65% yield, m.p. 55-57 °C 1H-NMR (300 MHz, CDC13) δ 10.41 (s, 1H, -CHO), 7.77 (d, 1H, J = 2.4 Hz, H-arom), 7.45 (dd, 1H, J1 = 2.4 Hz, J2 = 8.8 Hz, H-arom), 6.93 (d, 1H, J = 8.8 Hz, H-arom), 5.47 (m, 1H,-CH=), 4.621 (d, 2H,J = 6.8 Hz,-CH2-0), 1.80 (s,3H, Me), 1.75 (s, 3H, Me); 13C-NMR (75 MHz, CDC13) δ 188.9, 161.3, 139.5, 135.5 128.1, 126.4, 123.7, 118.8, 114.8, 66.1, 26.0, 18.6. MS (ESI) m/z: 246.86 [M + Na]+, 262.89 [M+K]+.

5'-Chloro-2'-(3-phenyl-prop-2-enyloxy) benzaldehyde (2.3b). This compound was obtained through method (b) in 78% yield. 1H-NMR (300 MHz, CDC13) δ 10.40 (s, 1H, -CHO), 7.74 (d, 1H, J = 2.7 Hz, H-arom), 7.44-7.20 (m, 6H, H-arom), 6.88 (d, 1H, J= 8.7Hz, H-arom), 6.69 (d, 1H, J= 15.9 Hz, arom-CH=), 6.33 (dt, 1H, J = 5.7, 15.9 Hz, =CH-), 4.80 (dd, 2H, J = 1.2,5.7 Hz, 0-CH2); 13C-NMR (75 MHz, CDC13) δ 188.4, 159.4, 135.9, 135.3, 134.0, 128.7, 128.5, 128.3, 128.0, 126.6, 126.0, 122.9, 114.2, 69.6.

5'-Chloro-2'-(3-methoxycarbonyl-prop-2-enyloxy) benzaldehyde (2.3c). This compound was obtained through method (a) in 44% yield. 1H-NMR (300 MHz, CDC13) δ 10.47 (s, 1H, -CHO), 7.82 (d, 1H, J = 3.0 Hz, H-arom), 7.48 (dd, 1H, J1 = 2.4 Hz, J2 = 9.0 Hz, H-arom), 7.10 (dt, 1H, J1 = 4.2 Hz, J2 = 15.6 Hz, =CH-), 6.89 (d, 1H, J = 9.0 Hz, H-arom), 6.19 (dt, 1H, J1 = 1.8 Hz, J2 = 15.9 Hz, =CH-COO), 4.82 (dd, 1H, J1 = 1.8 Hz, J2 = 4.2 Hz, 0-CH2-), 3.77 (s, 3H, MeO); 13C-NMR (75 MHz, CDC13) δ 188.1, 165.0, 161.3, 141.4, 135.6, 128.6, 122.6, 114.4, 109.1,98.8,67.4,52.1.

4'-Methoxy-2'-(3-methyl-but-2-enyloxy) benzaldehyde (2.4a). This compound was obtained through method (b) in 76% yield. 1H-NMR ( 300 MHz, CDC13) δ 10.31 (s, 1H, -CHO), 7.81 (d, 1H, J = 8.7 Hz, H-arom), 6.53 (dd, 1H, J1 = 1.8 Hz, J2 = 8.7 Hz, H-arom), 6.44 (d, 1H, J = 1.8 Hz, H-arom), 5.49(m, 1H, =CH-), 4.60 (d,2H,J = 6.6 Hz, 0-CH2-), 3.68 (s,3H, MeO), 1.80 (s, 3H, Me), 1.76 (s, 3H, Me); 13C-NMR (75 MHz, CDC13) δ 188.8, 163.4, 160.9, 130.6, 119.1, 105.9, 99.2, 98.8, 65.7, 55.8, 26.0, 19.3.

4'Methoxy-2'-(3-phenyl-prop-2-enyloxy) benzaldehyde (2.4b). This compound was obtained through method (b) in 82% yield, m.p. 60-61 °C; 1H-NMR (300 MHz, CDC13) δ 10.38 (s, 1H, -CHO), 7.84 (d, 1H, J = 8.0 Hz, H-arom), 7.42 (d, 2H, J = 8.0 Hz, H-arom), 7.34 (t, 2H, J =7.6 Hz, H-arom), 7.28 (t, 1H, J = 7.6 Hz, H-arom), 6.77 (d, 1H, J = 16.0 Hz, arom-CH=), 6.56 (dd, 1H, J1 = 2.4Hz, J2 = 8.8 Hz, H-arom), 6.50 (d, 1H, J= 1.6 Hz, H-arom), 6.418 (dt, 1H, J1 = 5.6 Hz, J2 = 15.2 Hz, =CH-), 4.79 (d, 2H, J = 5.6 Hz, 0-CH2), 3.87 (s, 3H, arom-OMe); 13C-NMR (75 MHz, CDC13) δ 188.6, 166.2, 158.6, 136.3, 133.8, 130.8, 128.9, 128.4, 126.8, 123.5, 106.2, 99.4, 98.8, 69.3, 55.8.

4'-Methoxy-2'-(3-methoxycarbonyl-prop-2-enyloxy) benzaldehyde (2.4c). This compound was obtained through method (b) in 70% yield, m.p. 78 °C; 1H-NMR (300 MHz, CDC13) δ 10.36 (s, 1H, -CHO), 7.84 (d, 1H, J =8.8  Hz, H-arom), 7.10 (dt, 1H, J1 = 4.0 Hz, J2 = 16.0 Hz, =CH-COO), 6.58 (dd, 1H,.J1, = 1.6 Hz, J2 = 8.8 Hz, H-arom), 6.39 (d, 1H,J =1.6 Hz, H-arom), 6.22 (ddd, 1H, J1 = 1.6 Hz, J2 = 2.4 Hz, J3 = 16.4 Hz, =CH-), 4.79 (dd, 2H, J = 2.4 Hz, J2 = 4.0 Hz, 0-CH2-), 3.86 (s, 3H, Me), 3.77 (s, 3H, Me); 13C-NMR (75 MHz, CDC13) δ 172.0, 160.0, 159.4, 132.5, 131.0, 108.6, 101.7, 101.4, 67.6, 65.5, 65.1, 55.6, 55.5, 52.1, 36.8, 33.7, 33.2, 31.6.

General procedure for addition/cyclization reaction with iris(trimethylsiryl) silane. A solution of allyloxy benzaldehyde 2 (1.0 eq), AIBN (0.24 eq) in toluene (25 mL) was deoxygenated for 30 min by bubbling dryAr. Then TTMS (1.2 eq.) was added via syringe. The reaction mixture was stirred and heated at 90-95 °C under Ar for 5-7 h, until the disappearance of the starting material. When the reaction mixture reached the room temperature, it was concentrated in vacuo and the residue purified by flash column chromatography or directly submitted to desisylation.

cis-3-Isopropyl-4-/rts(trimethylsilyl)silanyloxy chromane (4.1a) Compound 4.1a was isolated as colorless oil, in 57 % yield. 1H-NMR (300, CDC13) δ 7.20-7.15 (m, 2H, H-arom), 6.84 (td, 1H, J1 = 1.2 Hz, J2 = 7.2 Hz, H-arom), 6.79 (dd, 1H, J = 1.2, 8.4 Hz, H-arom), 4.48 (s, 1H, H-4e), 4.234 (dd, 1H, J1 = 4.2 Hz, J2 = 10.5 Hz, H-2e), 4.147 (t, 1H, J=10.5 Hz, H-2a), 1.6-1.8 (m, 1H, CHMe2), 1.4-1.6 (m, 1H, H-3a), 1.04 (d, 3H, J = 6.9 Hz, Me), 0.95 (d, 3H, J = 6.6 Hz, Me), 0.13 (s, 27H, -Si(SiMe3)3); 13C-NMR (75 MHz, CDC13) 8 130.4, 130.1, 119.7, 116.6, 69.0, 64.7, 45.9, 25.1, 21.0, 0.8; HRMS (EI) m/z 365.1781 [M-73]+.

3-Methoxycarbonyhnethyl- 4-tris(trimethylsüyl)silanyloxy chromane (4.1c). A mixture of cis- and trans-stereoisomers was obtained in 68% yield as colorless oil. 1H-NMR ( 400 MHz, CDCl3) δ 7.26 -7.13 (m, 4H, H-arom), 6.88 (t, 2H, J = 7.2 Hz, H-arom), 6.81 (d, 1H, J = 8.0 Hz, H-arom), 6.76 (d, 1H, J = 8.4 Hz, H-arom), 4.63 (d, 1H, J = 4.0 Hz, H-4e trans), 4.32 (d, 1H, J = 10.5 Hz, H-4a cis), 4.27 (dd, 1H, J1 = 5.6 Hz, J2 = 11.2 Hz, H-2e, trans), 4.14-4.09 (m, 3H, H-4a cis, H-2a trans), 3.68 (s, 3H, MeO), 3.68 (s, 3H, MeO), 2.59-2.49 (m, 2H, H-3 cis, H-3 trans), 2.34-2.23 (m, 3H,), 2.09 (dd, 1H, J1 = 9.6 Hz, J2 = 20.0 Hz), 0.20 (s, 27 H, -Si(SiMe3)3); 13C-NMR (100 MHz, CDCl3) δ 173.4, 172.5, 153.7, 131.5, 129.7, 129.4, 128.6, 124.5, 122.9, 120.6, 120.4, 116.9, 116.9, 116.2, 72.2, 71.3, 66.3, 63.7, 51.9, 51.8, 36.6, 35.2, 32.7, 29.5, 0.8, 0.6. HRMS (EI) caled for C21H40O4Si4 468.2004, found 468.2001.

cis-6-Methyl-3-isopropyl-4-tris(trimethylsilyl)silanyloxy chromane (4.2a). This isomer was obtained as colorless oil in 50% yield. 1H-NMR (300 MHz, CDC13) δ 6.98 (d, 1H, J = 8.7 Hz, H-arom), 6.97 (s, 1H, H-arom), 6.69 (d, 1H, J= 8.7 Hz, H-arom), 4.44 (d, 1H, J= 1.5 Hz, H-4-e), 4.20 (ddd, 1H, J1 = 1.2 Hz, 4.2, J2 = 10.2 Hz, H-2e), 4.13 (dd, 1H, J1 = 10.2 Hz, J2 = 10.8 Hz, H-2a), 2.25 (s, 3H, Me), 1.74-1.62 (m, 1H, H-3a), 1.49-1.39 (m, 1H, CHMe2), 1.03 (d, 3H, J = 3.9 Hz, Me), 0.71 (d, 3H, J = 3.9 Hz, Me); 13C-NMR(75 MHz, CDCl3) δ 152.2, 130.5, 130.4, 128.2, 124.3, 116.2, 68.9, 64.4, 45.8, 29.7, 24.9, 20.8, 20.5, 0.6 (Si(SiMe3)3); IR(neat, cm-1) 2960, 2900, 1690, 1620, 1500, 1380, 1250, 1060, 835; LRMS (CI) 189 [M-OSi(SiMe3)3]+, 263 [OSi(SiMe3)3]+, 379 [M-SiMe3]+ 100%, 437 [M-Me]+, 451 [M-H]+, 452 [M]+, 453 [M+H]+; HRMS (EI) caled for C22H44O2Si4 452.2418, found 452.2418.

6-Methyl-3-methoxycarbonylmethyl-4-tris(trimethylsilyl)silanyloxy chromane (4.2c). The cis and irans-isomers (1.4:1) were obtained as colorless oil in 84% yield, trans Isomer: 1H-NMR (300 MHz, CDCl3) δ 6.95 (dd, 1H, J1 = 2.2 Hz, J2 = 8.2 Hz, H-arom), 6.91 (d, 1H, J = 2.2 Hz, H-arom), 6.69 (d, 1H, J = 8.2 Hz, H-arom), 4.27 (dd, 1H, J, = 2.2 Hz, J2 = 10.7 Hz, H-2a), 4.06 (dt, 1H, J1 = 1.7 Hz, J2 = 10.7 Hz, H-2e), 4.04 (dd, 1H, J1 = 1.7 Hz, J2 = 3.6 Hz, H-4e), 3.40 (s, 3H, CO2CH3), 2.40-2.27 (m, 2H, H-3e, CHCO2Me), 2.26 (s, 3H, Ar-Me), 2.09 (dd, 1H, J1 = 9.0 Hz, J2 = 19.5 Hz, CHCOO), 0.19 (s, 27H, Si(SiMe3)3); LRMS (CI) 409 [M-SiMeJ+ 100%, 467 [M-Me]+, 481 [M-H]+, 483 [M+H]+; HRMS (CI) caled for C22H4304Si4 (M+1) 483.2239, found 483.2238. cis-Isomer: 1H-NMR (300 MHz, CDC13) δ 7.04 (d, 1H, J = 2.2 Hz, H-arom), 6.93 (dd, 1H, J1 = 2.5 Hz, J2 = 8.2 Hz, H-arom), 6.63 (d, 1H, J = 8.2 Hz, H-arom), 4.59 (d, 1H, J = 4.1 Hz, H-4a), 4.22 (dd, 1H, J1 = 5.8 Hz, J2 = 11.3 Hz, H-2a), 4.07 (dd, 1H, J1 = 2.7 Hz, J2 = 11.3 Hz, H-2e), 3.64 (s, 3H, CO2CH3), 2.54 (dd, 1H, J1 = 4.1 Hz,J2= 16.5 Hz, CHCO2Me), 2.51-2.42 (m, 1H, H-3e), 2.24 (s, 3H, arom-Me), 2.23 (dd, 1H, J1 = 9.0 Hz, J2 = 16.5 Hz, CHCO2Me), 0.19 (s, 27H, -Si(SiMe3)3). 13C-NMR (75 MHz, CDC13) 8 172.0, 156.0, 130.0, 128.4, 126.7, 126.6,113.2, 77.9,72.4, 50.4, 41.0, 27.4, 21.2, 0.18; LRMS (CI) 409 [M-SiMe3]+ 100%, 467 [M-Me]+, 481 [M-H]+, 483 [M+H]+; HRMS (CI) caled for C22H4304Si4 [M+1]+ 483.2239, found 483.2238.

cis-6-Chloro-3-isopropyl-4-tris(trimethylsilyl)silanyloxy chromane (4.3a). This isomer was isolated as colorless oil in 47% yield. 1H-NMR (300, CDC13) δ 7.15-7.11 (m, 2H, H-arom), 6.73 (d, 1H, J= 8.0 Hz, H-arom), 4.42 (bs, 1H, H-4e), 4.22 (dd, 1H, J1 = 4.0 Hz, J2 = 10.8 Hz, H-2e), 4.14 (dd, 1H, J1 = 10.4Hz, J2= 10.8 Hz, H-2a), 1.76-1.64 (m, 1H, H-3a), 1.48-1.41 (m, 1H, CHMe2), 1.03 (d, 3H, J = 6.4 Hz, CH3), 0.94 (d, 3H, J = 6.4 Hz, CH3), 0.13 (s, 27H,-Si(SiMe3)3); 13C-NMR (75 MHz, CDC13) 8 153.3, 129.8, 129.5, 126.4, 124.2, 118.1, 68.9, 65.0, 45.6, 25.1, 21.1, 20.9, 0.8.

trans-6-Chloro-3-benzyl-4-fris(trimethylsilyl)silanyloxy chromane (4.3b). This isomer was isolated as colorless oil in 56% yield. 1H-NMR (300 MHz, CDC13) δ 7.40-7.10 (m, 7H, H-arom), 6.81 (d, 1H, J= 8.7 Hz, H-arom), 4.25 (dd, 1H, J1 = 2.2 Hz, J2 = 10.7 Hz, H-2e.), 4.07 (d, 1H, J = 2.2 Hz, H-4e), 3.97 (ddd, 1H, J1 = 1.9 Hz, J2 = 10.7 Hz, H-2a), 2.47 (d, 2H, J = 8.2 Hz, CH2-arom), 2.01 (dd, 1H, J1 = 2.2 Hz, J2 = 8.2 Hz, H-3e), 0.19 (s, 27 H, Si(SiMe3)3); 13C-NMR (75 MHz, CDC13) δ 157.1, 141.1, 130.4, 130.0, 129.3, 128.8, 127.6, 126.6, 125.3, 124.5, 121.2, 120.4, 117.1, 67.8, 64.8, 41.7, 29.9.

6-Chloro-3-methoxycarbonylmethyl-4-tris(trimethylsilyl)silanyl xy chromane (4.3c). This compound was not characterized because it was difficult to differentiate the isomers cis and trans. So, the residue after flash chromatography was submitted directly to desysilation to afford the trans chromanol 5.4c and the lactone 6.4c.

General procedure for TBAF desisylation. A solution of purified sisylated chromane 4 (0.03 M, 1.0 eq.) in dry THF at 0 °C (or the crude reaction mixture of 4), was slowly added to a freshly prepared TBAF/THF solution (0.068 M, 2.0 eq)at0 °C. After stirring for 10 min the reaction mixture was left to reach the room temperature and the starting material had disappeared. Then, the solvent was evaporated, the residue treated with brine and extracted with ethyl acetate (x 3), the organic phase dried over sodium sulphate, concentrated in vacuo and purified by flash column chromatography.

cis-3-Isopropylchroman-4-ol (5.1a). It was isolated in 85% yield. 1H-NMR (300 MHz, CDC13) δ 7.26-7.19 (m, 2H, H-arom), 6.91 (t, 1H, J = 5.1 Hz, H-arom), 6.85 (d, 1H, J = 7.8 Hz, H-arom), 4.75 (s, 1H, H-4e), 4.29 (dd, J1 = 2.4 Hz, J2 = 11.4 Hz, H-2e), 4.01 (t, 1H, J = 11.4 Hz, H-2a), 1.81-1.76 (m, 1H, H-3a), 1.63-1.56 (m, 1H, CHMe2), 1.13 (d, 3H, J = 6.6 Hz, Me), 1.01(d,3H,J = 6.6Hz,Me);13C-NMR(75MHz,CDCl3)δ 158.6, 130.6, 130.2, 120.6, 117.1, 64.7, 64.3, 45.0, 25.2, 21.1, 20.8; HRMS (EI) caled for C12 H16O2192.1150, found 192.1151.

trans-3-Benzyl chroman-4-ol (5.1b). It was isolated as a solid in 42% yield, m.p. 129-132 °C; 1H-NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 7H, H-arom), 6.96 (dd, 1H, J1 = 7.2 Hz, J2 = 9.2 Hz, H-arom), 6.88 (d, 1H,J= 8.0 Hz, H-arom ), 4.51 (s, 1H, H-4e), 4.23 (dd, 1H, J1 = 2.4 Hz, J2 = 11.6 Hz, H-2e), 3.98 (dd, 1H, J1 = 4.0 Hz, J2 = 11.2 Hz, H-2a), 2.71 (dd, 1H, J1 = 6.4 Hz, J2 = 14.0 Hz, CH-arom), (dd, 1H, J1 = 8.8 Hz, J2 = 14.0 Hz, CH-arom), 2.25 (m, 1H, H-3e), 1.8 (da, J = 4.0 Hz, OH); 13C-NMR(100MHz, CDC13) δ 155.7, 139.4, 130.4, 130.0, 129.3, 128.8, 126.6, 121.1, 120.4, 117.2, 67.8, 64.8, 41.7, 34.8.; HRMS (EI) caled for C16H16O2240.1150, found 240.1149.

trans-3-Benzyl—6-methylchroman-4-ol (5.2b). It was obtained as a solid in 48% yield (overall yield after two steps), m.p. 140-143 °C; 1H-NMR (400 MHz, CDC13) 8 7.33-7.18 (m, 5H, H-arom), 7.13 (d, 1H, J = 2.0 Hz, H-arom), 7.05 (dd, 1H, J1 = 2.4 Hz, J2 = 8.4 Hz, H-arom), 6.78 (d, 1H, J = 8.0 Hz, H-arom), 4.46 (s, 1H, H-4e), 4.19 (dd, 1H, J1 = 2.4 Hz, J2 = 11.2 Hz, H-2e), 3.95 (dd, 1H, J1 = 5.2 Hz, J2 = 11.6 Hz, H-2a), 2.70 (dd, 1H, J1 = 6.4 Hz, J2 = 13.6 Hz, CH-arom), 2.35 (dd, 1H, J1 = 8.8 Hz, J2 = 13.6 Hz, CH-arom), 2.30 (s, 3H, Me-arom), 2.24-2.16 (m, 1H, H-3e), 1.83 (d, 1H, J = 4.8 Hz, OH); 13C-NMR (100 MHz, CDC13) δ 152.3, 151.1, 139.5, 130.7, 130.5, 130.3, 129.3, 128.7, 126.5, 116.9, 102.7, 94.7, 67.9, 34.9, 20.7; HRMS (EI) caled for C17H18O2254.1308, found 254.1305.

trans-3-(Methoxycarbonylmethyl)-6-Chlorochroman-4-ol ( 5.3c ). This isomer was obtained in 32% yield. The desisylation was carried out affording the cis and trans chromanol in 80% overall yield, however the CM-chromanol was not isolated, instead the lactone 6.3c was obtained with lactone / trans-chromanol ratio = 1.4 : 1.0. 1H-NMR ( 400 MHz, CDCl3) δ 7.32 (d, 1H, J = 2.4 Hz,          H-arom), 7.15 (dd, 1H, J1 = 2.4 Hz, J2 = 8.8 Hz, H-arom), 6.77 (d, 1H, J = 8.8 Hz, H-arom), 5.04 (d, 1H, OH), 5.59 (d, 1H, J = 3.2 Hz, H-4e), 4.30 (dd, 1H, J1 = 3.2 Hz, J2 = 11.6 Hz, H-2e), 4.11 (dd, 1H, J1 = 5.2 Hz, J. = 11.2 Hz, H-2a), 3.70 (s, 3H, MeO-arom), 2.50-2.40 (m, 1H, H-3e), 2.38-2.30 (m, 2H, CH2CO2Me); 13C-NMR (100 MHz, CDC13) δ 177.7, 152.8, 129.9, 129.5, 125.9, 124.7, 118.5, 67.893, 66.1, 52.2, 36.7, 33.3; HRMS (EI) caled for C12H13ClO4256.0502, found 256.0501.

8-Chloro-3-a,9-b-dihydro-3H, 4H-furo [3,2c] chromen-2-one (6,3c). The lactone was obtaines as colorless oil in 48% yield. 1H-NMR(400 MHz, CDCl3) δ 7.35 (d,1H, J = 3.2 Hz, H-arom), 7.16 (dd, 1H J1 = 2.4 Hz, J2 =8.8 Hz, H-arom), 6,84 (d, 1H, J = 5.2 Hz, H-4a), 4,04 (dd, 1H, J1 = 5,6 HZ, J2 = 11.2 Hz, H-2e), 3.58 (t, J = 10.8 Hz, 1H, H-2a), 2.78-2.70 (m, 1H, H-36), 2.21 (ddd, 1H, J1 = 2.8 Hz, J2 = 8.4 Hz, J3 = 13.6 Hz, CH-(CO)O) ; 13C-NMR (100 MHz. CDCl3) δ 177.8, 152.8, 129.9, 129.5, 129.9, 124.7, 118.5, 67.9, 66.1, 52.2, 36.7, 33.3.

cis-3-Isopropyl7-methoxychroman-4-ol (5.4a). This isomer was obtaines in 37% yield (overall yield after two steps). 1H-NMR(400 MHz, CDCl3) δ 7.15 (d J = 8.4 Hz, 1H, H-arom), 6.49 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz, 1H, H-arom) 6.38 (d, J = 2.4 Hz, 1H H-arom) 4.70 (s, 1H, H-2e), 4.27 (ddd, 1H J1 = 1.2 Hz, J2 = 4.8 Hz, J3 = 11.1 Hz, H-2e), 3.99 (dd, 1H J1 = 11.1 Hz, J2 = 12.3 Hz, H-2a), 3.77 (s, 3H, MeO-arom), 1.80-1.70 (m, 1H, H-3a), 1.61-1.50 (m, 1H, CHMe2), 1.12 (d, 3H, J = 6.6 Hz, Me), 1.02 (d, 3H,J = 6.0 Hz, Me); 13C-NMR(100 MHz, CDC13) δ 153.1, 131.3, 107.8, 98.8, 92.2, 77.8, 64.4, 55.5, 45.2, 25.2, 21.1, 20.7; HRMS (EI) caled for C13H1803 222.1255, found 222.1258.

trans - 3-Benzyl-7-methoxyCHroman-4-ol ( 5.4b ). This isomer was obtained in 30% overall yield after two steps, m.p. 110-111 °C; 1H-NMR (400 MHz, CDC13) δ 7.32-7.17 (m, 6H, H-arom), 6.55 (dd, 1H, J1 = 2.4 Hz, J2 = 8.8 Hz, H-arom), 6.42 (d, 1H, J = 3.2 Hz, H-arom), 4.46 (t, 1H, J = 4.4 Hz, H-4e), 4.22 (dd, 1H, J1 = 2.4 Hz, J2 = 11.2 Hz, H-2e), 3.97 (dd, 1H, J1 = 4.0 Hz, J2 = 11.2 Hz, H-2a), 3.79 (s, 3H, MeO-arom), 2.67 (dd, 1H, J1 = 2.8 Hz, J2 = 14.0 Hz, CH-arom), 2.52 (dd, 1H, J1 = 8.8 Hz, J2 = 13.6 Hz, CH-arom), 2.22-2.17 (m, 1H, H-3e), 1.73(d, 1H, J = 5.2 Hz, OH); 13C-NMR (100 MHz, CDC13) δ 131.14, 129.33, 128.75, 126.55, 108.45, 101.44, 67.42, 64.69, 55.56, 41.76, 34.81; HRMS (EI) caled for C17H1803 270.1255, found 270.1251.

trans -3-Methoxycarbonylmethyl -7-methoxyCHroman-4-ol ( 5.4c ). This isomer was isolated in 22% yield. The overall yield of cyclization and desisylation steps was 60%, again the chromanol cis-isomer was not isolated, instead the lactone 6.4c was obtained with lactone: frans-chromanol ratio = 1.7:1). 1H-NMR ( 400 MHz, CDCl3) δ 7.21 (d, 1H,J= 9.2 Hz, H-arom), 6.53 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, H-arom), 6.37 (d, 1H, J = 2.4 Hz, H-arom), 4.45 (dd, 1H, J1 = 4.0 Hz, J2 = 5.0 Hz, H-4e), 4.32 (dd,lH, J1 = 3.2 Hz, J2 = 11.6 Hz, H-2e), 4.08 (dd, 1H, J1 = 3.6 Hz, J2 = 11.2 Hz, H-2a), 3.76 (s, 3H, COOMe), 3.695 (s, 3H, MeO-arom), 3.592 (dd, 1H, J=10.4, 11.2 Hz, H-2a), 2.50-2.38 (m, 1H, H-3e), 2.35-2.33 (m, 2H), 1.95 (db, 1H, J = 5.0 Hz); 13C-NMR(100 MHz, CDC13) δ 172.8, 161.7, 155.3, 131.0, 115.5, 108.5, 101.6, 72.0, 67.6, 55.5, 52.1, 33.7, 33.2. HRMS (EI) caled for C13H1605 252.0997, found 252.1000.

7-Methoxy-3a, 9b-d1Hydro-3H,4H-furo[3,2-c]CHromen-2-one ( 6.4c ). The lactone was obtained as colorless oil in 38 % yield. 1H-NMR (400 MHz, CDC13) δ 7.29 (d, 1H, J = 8.0 Hz, H-arom), 6.60 (dd, 1H, J1 = 2.4 Hz, J2 = 8.0 Hz, H-arom), 6.43 (d, 1H, J = 2.4 Hz, H-arom), 5.43 (d, 1H, J = 5.6 Hz, H-4a), 4.18 (dd, 1H, J1 = 4.8 Hz, J2 = 11.2 Hz, H-2a), 4.08 (dd, 1H, J1 = 3.6 Hz, J2 = 11.2 Hz, H-2e), 3.78 (s, 3H, COOMe), 3.20-2.92 (m, H-3e), 2.85 (dd, 1H, J1 = 8.0 Hz, J2= 16.8 Hz, CHCO2Me), 2.50-2.38 (m, 1H, CHCO2Me); 13C-NMR(100MHz,CDCl3)δ 172.8, 161.7, 161.1, 131.9, 109.6, 108.8, 101.7, 101.4, 74.6, 55.6, 36.8, 36.5.

RESULTS AND DISCUSSION

Starting from commercially available salicylaldehyde derivatives 1 and various allyl bromides, compounds 2 were prepared by using 'BuOK / THF at r.t. (Method a) or K2C03 / acetone under reflux (Method b). The radical cyclization was carried out in toluene by mixing the  o-allyloxybenzaldehydes 2 with TTMS (1.2 equiv.) in the presence of AIBN (0.24 eq.) at 90 °C for 5-7 h (Scheme 1).


The desired sisyl ethers 4 were obtained with 47-84 % yields (Table 1). The sisyl group was readily removed by tetrabutylammonium fluoride (TBAF)12 from 4.1a and 4.3c, to give the chromanols in 85 and 80 % yields, respectively. When the 4.1b, 4.2b and 4.1a-c crude mixtures were directly subjected to desisylation, the corresponding chromanols were isolated in 30-60% overall yields for two steps (entries 2, 5, 10, 11 and 12 in Table 1).


It was noted that the sisyl ethers cyclics 4.3 c and 4.4 c (entries 9 and 12, Table 1) containing an ester group, afforded after desisylation, the bicycle lactones 6 3.c and 6.4.calong with the corresponding fraas-chromanols 5.3c and 5.4c in ratios 1.5:1 and 1.7:1 respectively. These results represent roughly the diastereoselectivity tran/cis ratio, obtained in the cyclization of the precursors 2.1c to 2.4c. Besides the cyclization occurred more rapidly and the yields of the sisyl ethers 4.1c, 4.2c and 4.3c were higher than for the other systems, presumably due to the nucleophilic nature of the O-sisyl ketyl radicals, and the activated double bond exhibiting the electron withdrawing group ester.

The stereoselectivity of the cyclization reactions reported here, was variable depending of the electronic density on the C=C double bond, influenced by the polar CHaracter of the susbstituents. Thus, with precursors 2.1c, 2.2c, 2.3c, and 2.4c, with olefin moieties bearing electron withdrawing groups, the starting material was quickly consumed, and the yields of products 4.1c, 4.2c and 4.3c were higher than for the other compounds, presumably due to the nucleophilic nature of the O-sisyl ketyl radicals, and their enhanced reactivity toward activated double bonds.

The configuration assignment of carbons C3-C4inthe bicyclic sisyl ethers 4 and chromanols 5 was based on their 1H NMR spectra. The two protons on C2 gave different Chemical shifts and these protons provided the key to recognizing the configuration of the H-3 proton. The cis or trans configuration around the C3-C4 bond was determined according to the coupling constants of the H-3 and H-4 signals. Figure 1 (structures I through III) depicts the corresponding relationship between the H-2, H-3 and H-4 protons.


Bicyclic compounds 5.1b, 5.2b, 4.3b and 5.4b with the phenylmethyl appendix were in accordance with the structure I-trans. In these cases one of the coupling constants of the H-2a proton (—10 Hz), corresponds to the gem coupling of two diastereotopic protons. The other coupling constant (1.9-5.2 Hz) was associated with an axial-equatorial coupling between the H-2a and H-3 protons, being the last one necessarily equatorial. On the other hand, a broad singlet for the H-4 proton, suggest also an equatorial orientation, fixing therefore the stereoChemistry trans around the C3-C4 bond.

Likewise, compounds 5.1a, 4.2a, 4.3a and 5.4a, generated from precursors with 3-methyl-2-butenyl appendix, were associated with the structure II-cis. The H-2a protons signals snowed coupling constants up to 10 Hz, therefore the H-3 proton was assigned as an axial orientation. The H-4 proton was established as equatorial because it showed either a bulky singlet or a doublet with the coupling very small constant. In conclusion, the stereoChemistry of the pyranoside ring for these systems is cis on the C3-C4 bond.

Finally, compounds 4.1c, 4.2c, 5.3c and 5.4c, generated from precursors with 3-methoxycarbonyl-2-propenyl appendix, were correlated with both cis and trans isomers and their structures were illustrated as Ill-trans and III-cis.

In both cases, the H-2a proton displayed a very small coupling constant, whiCH confirmed the equatorial orientation of the H-3 proton. As a result, it was concluded that H-4 proton must be equatorial in the ll-trans isomer and axial in the Ill-cis lactone product (Figure 1).

CONCLUSIONS

The cyclization reaction of allyloxybenzaldehydes systems by free radical methodology led to the formation of pyranoside heterocycle rings via the intramolecular addition of previously generated O-sisyl ketyl radicals over the olefin moiety. The nature of the substituents on the double bond showed a dramatic effect over the products stereoChemistry. With the 3-methyl-2-butenyl appendix, the cis diastereomers were generated after ring-closure. While with the 3-phenyl-2-propenyl group, fraas-isomers were produced. Electron withdrawing groups on the olefin moiety accelerated the reaction but resulted in poor stereoselectivities; both cis- and frans-isomers were observed. The TBAF behaved as an efficient deprotective agent of sisyl ethers in dry THF, affording the corresponding chromanols in good yields.

ACKNOWLEDGMENTS

The authors want to acknowledge COLCIENCIAS- (Bogotá-Colombia) for the financial support through the project 1106-05-10108. The authors also thank Universidad del Cauca, Universidad de Caldas and Universidad del Valle (Colombia). The analysis and technical support from the Research Group of P.G. Wang in Wayne State University (MI, USA) are greatly appreciated.

 

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*To whom correspondence should be addressed.

e-mail: luzmaja@univalle.edu.co

 

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