Unexpected dimerization reaction of 5-methyl-6,7-methylendioxy-1- tetralone in the presence of TMSCl-ethylene glycol

Transcription

1 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) Unexpected dimerization reaction of 5-methyl-6,7-methylendioxy-- tetralone in the presence of TMSCl-ethylene glycol Gema Esteban and Joaquín Plumet * Unversidad Complutense. Facultad de Química. Departamento de Química rgánica. E-28040, Madrid. Spain plumety@quim.ucm.es Dedicated to Professor Joan Bosch on his 60 th birthday Abstract Unprecedented dimerization reactions of the title compound using TMSCl as reagent and ethylene glycol as solvent has been observed and rationalized. Keywords: Dimerization, tetralone, trimethylsilyl chloride, ethylene glycol, Mukaiyama reaction Introduction During our approach to the synthesis of the hydrophenalene ring system of pseudopterosines, it was necessary to protect the -tetralone derivative as cyclic acetal 5 or dithiane 6. Thus, the reaction of with,2-ethanedithiol in presence of BF 3 Et 2 afforded 6 (88% isolated yield). 2 In contrast, when reacts with ethylene glycol (benzene, reflux) in the presence of TsH, compound 5 was isolated with maximum (and difficult to reproduce) 47% yield (Figure ). X X Figure 5, X = 6, X = S During the search for an alternative method for the preparation of 5, the use of ethylene glycol as solvent in the presence of trimethylsilyl chloride 3 was considered as an appealing ISSN Page 82

2 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) possibility. In this way, when (2,0 mmol) was subjected to reaction with 8,2 mmol of TMSCl in 0 ml of ethylene glycol (rt, 72h), no traces of compound 5 were observed and instead a mixture of compounds 2, 3 and 4 were isolated by column chromatography (Si 2, hexane- AcEt, 20:). (Scheme ) Cl 2 TMSCl (4 eq.) HCH 2 CH 2 H (Sovent); rt; 72h. 3 Scheme 4 The structures of these new compounds were established on the basis of their spectroscopic ( H-, 3 C-NMR, MS) and analytical data. Thus, in all cases the H- and 3 C-NMR spectra show double signals which suggest the dimeric nature of these compounds. That was confirmed by MS as well as by the presence of chlorine in compound 2. A probable reaction for the formation of the major product 2 is depicted in Scheme 2. Reaction of with Me 3 SiCl 4 should afford five-coordinate complex 7 which can exist in equilibrium with cation 8. 5 The nucleophilic attack of ethylene glycol on 8 should give intermediate 9. Now two possible reaction paths are conceivable for 9. Path a) involves the intramolecular addition of the remaining H group to give the expected and not observed compound 5. Alternatively, chloride ion may act as basic reagent inducing β-elimination reaction (path b) giving intermediate 0 which, by intramolecular reaction with 8 (nucleophilic addition to carbonyl-activated group) of afforded. Final nucleophilic substitution reaction of chlorine anion on, should give 2. ISSN Page 83

3 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) Me 3 SiCl SiMe 3 7 Cl 8 SiMe 3, Cl HCH 2 CH 2 H 5 + Me 3 SiH + HCl path a + Cl SiMe 3 H + HCl SiMe 3 H H 9 path b Me 3 SiH + HCl + 8, Cl SiMe 3 H 0 Scheme 2 2 Regarding the formation of compounds 3 and 4, these may be formed via a Mukaiyama-type aldol reaction 6 between silylenolether 2 (arising from 8 via Cl - induced enolization) and protonated ketone, to give intermediate 3 which, after recovering of catalyst (Me 3 SiCl) and dehydration should afford compound 3. Further aromatization of 3 (probably during the work-up of the reaction) gave 4 (Scheme 3). ISSN Page 84

4 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) H Cl + HCl 8 SiMe 3 2 SiMe 3 + HCl + Cl H 2 H H SiMe 3 Cl + Me 3 SiCl H 2 Scheme 3 4 In summary, the results here presented constitute a convenient procedure for the synthesis of dimeric structures of tetralone derivatives avoiding the use of any organometallic catalytic reagent. Experimental Section General Procedures. The reaction was carried out under a positive pressure of dry Ar using freshly distilled solvents under anhydrous conditions. Reagents and solvents were handled by ISSN Page 85

5 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) using standard syringe techniques. Ethylene glycol and TMSCl were commercial and used as received. 5-Methyl-6,7-methylendioxy--tetralone () was synthesized as previously described. 7 IR spectra were recorded on a Perkin-Elmer 297 spectrophotometer. H-NMR and 3 C-NMR were obtained on Varian XL-300 and Bruker AM-300 spectrometers. Silica gel Merck ( mesh) and Merck 60F 254 plates were used for conventional and analytical (TLC) chromatography respectively. Reaction of 5-Methyl-6,7- methylendioxy--tetralone with ethylene glycol and TMSCl () 90 mg. Trimethylsilyl chloride (.04 ml; 8.2 mol) was added to a suspension of (408 mg; 2,0 mmol) in ethylene glycol (0 ml) at room temperature (22-24 ºC) under Ar. After stirring the resulting mixture at rt for 72 h, dilution with Et 2 (20 ml), addition of a solution of NaHC 3 (5%) and decantation of the organic phase, the aqueous layer was extracted with Et 2 (3 x 5 ml). The combined organic extracts were washed with H 2, a saturated solution of NaCl and dried over MgS 4. After removing the solvent in vacuo, 382 mg of an orange oil was isolated and chromatographed twice (Si 2, hexane-acet 20:). The following fractions were isolated and characterized. 8-{-2-[(5-chloro-9-methyl-5,6,7,8-tetrahydronaphto [2,3 [,3]dioxol-5-yl)oxy] ethoxy}-4- methyl-5,6-dihydronaphto [2,3-d] [,3]dioxole (2) 87 mg as a pale yellow oil. H-NMR (CDCl 3, ppm): δ (m, 2H, CH 2 ); 2.3 (s,3h, ); 2.2 (s,3h, ); (m, 2H, CH 2 ); 2.49 (t, 2H, J=7.5Hz, CH 2 ); 2.58 (t, 2H, J=7.8 Hz, CH 2 ); 2.95 (m, 2H, CH 2 ); 3.76 (t, 2H, J=5.9Hz, CH 2 ); 4.47 (t, 2H, J=5.9 Hz, CH 2 ); (t, H, J=4.5 Hz, =CH); 5.89 (s, 2H, CH 2 ); 5.95 (s, 2H, CH 2 ); 6.73 (s, H, CH); 7.35 (s, H, CH). 3 C-NMR (CDCl 3, ppm): δ.4 ( );.7 ( ); 22.9 (CH 2 ); 23.9 (CH 2 ); 29.6 (CH 2 ); 33.7 (CH 2 ); 4.8 (CH 2 ); 64.2 (CH 2 CH 2 ); 00.3 (CH 2 );0.2 (CH 2 ); 09.9 (CH); 08.2 (CH); 6.7 (C); 8.5 (C); 22.2 (C); 22.6 (C); 28.8 (C); 29.6 (C); 36.3 (C); 39.8 (C); 44.4 (C); 47.7 (C); 44.8 (C); 49.6 (C); 66.8 (C). IR (CHCl 3, cm - ) ν max: 2780; 590; 930 (C--C); 750 (C-Cl). MS 437(); 472(3); 47(3, M + ); 470(0); 22(0); 25(9); 23(27); 20(30); 202(00); 99(25); 93(28); 89(26); 87(35); 49(37); 5(22). Elem. Anal: Calcd. for C 26 H 27 Cl 6 : C, 66.3; H, Found: C, 66.56; H, ,9'-dimethyl-7,7',8,8'-tetrahydro-5,6'-binaphto[2,3-d][,3]-dioxol-5'(6'H)-one (3) 6 mg as pale yellow oil. H-NMR (CDCl 3, ppm) δ 2.7 (s, 6H, 2x ); (m, 8H, 4xCH 2 ); 3.69 (dd, H, J=7.2 and 4.5 Hz, CH); 5.66 (t, H, J=4.5 Hz, =CH); 5.89 (d, 2H, J=. Hz, CH 2 ); 6.00 (s, 2H, CH 2 ); 6.56 (s, H, CH); 7.45 (s, H, CH). 3 C-NMR (CDCl 3, ppm): δ.5 ( );.9 ( ); 23.0 (CH 2 ); 23.8 (CH 2 ); 24.7 (CH 2 ); 28.2 (CH 2 ); 50. (C); 00.5 (CH 2 ); 0.4 (CH 2 ); 02.3 (CH); 04.5 (CH); 6.6 (C); 7.9 (C); 24.6 (CH); 27.9 (C); 28.0 (C); 30.0 (C); 35.3 (C); 39.7 (C); 45.0 (C); 46.0 (C); 50.7 (C); 98.9 (C=). IR (CHCl 3, cm - ) ν max: 3040; 720 (C=); 660 (C=C); 930 (C--C). MS: 39 (0); 390(37, M + ); 388 (9); 205(3); 204 (67); 203 (27); 202 (44); 99 (9); 90 (9); 89 (64); 87 (38); 86 ISSN Page 86

6 Issue in Honor of Prof. Joan Bosch ARKIVC 2007 (iv) (24); 77 (30); 75 (25); 74 (7); 49 (00); 48 (86). Elem. Anal: Calcd. for C 24 H 22 5 : C, 78.83; H, Found: C, 73.46; H, ,9'-dimethyl-7',8'-dihydro-5,6'-binaphto [2,3-d] [,3]-dioxol-5'(6'H)-one (4) 8 mg as reddish oil. H-NMR (CDCl 3, ppm) δ 2.20 (s, 3H, ); 2.48 (s, 3H, ); (m, 4H, 2 x CH 2 ); 4.32 (m, H, CH); 5.99 (s, 2H, CH 2 ); 6.02 (s, 2H, CH 2 ); 6.73 (s, H, CH); 7.03 (d, H, CH); 7.32 (dd, H, CH); 7.50 (s, H, CH); 7.78 (s, H,CH). IR (CHCl 3, cm - ) ν max 2980, 720 (C=); 940 (C--C). MS: 389 (2); 388 (6, M + ); 386 (2); 220 (7); 89 (22); 67 (5); 48 (27); 3 (2); (2); 96 (2); 9(6). Elem. Anal: Calcd. for C 24 H 20 5 : C, 74.2;H, 5.9. Found: C, 74.40; H, 5.2. Acknowledgements This research was supported by PharmaMar S.A. References and Notes. Benoit-Marquie, F.; Csákÿ, A. G.; Esteban, G.; Martínez, M. E.; Plumet, J. Tetrahedron Lett. 2000, 4, Esteban, G.; López, B.; Plumet, J.; del Valle, A. Heterocycles 997, 45, Chan, T. H.; Brook, M. A.; Chaly, Y. Synth. Comm. 983, For recent reviews on the use of silicon Lewis Acids in organic synthesis, see: (a) Dilman, A. D.; Joffe, S. L. Chem. Rev. 2003, 03, 733. (b) Rendler, S.; estreich, M. Synthesis 2005, 727. (c) rito, Y.; Nakajima, M. Synthesis 2006, Prakash, G. K. S.; Bae, C.; Rasul, G.; lah, G. A. J. rg. Chem. 2002, 67, For recent uses of cyclohexanone derivatives in Mukaiyama Aldol reactions, see: (a) Wadamoto, M.; zasa, N.; Yanagisawa, A.; Yamamoto, H. J. rg. Chem. 2003, 68, (b) Han, L. B.; Zhao, C. Q. J. rg. Chem. 2005, 70, 02. (c) Sarabèr, F. C. E.; Dratch, S.; Bosselaar, G.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2006, 62, 77, and references quoted in these papers. 7. Esteban, G.; López-Sánchez, M. A.; Martínez, M. E.; Plumet, J. Tetrahedron 998, 54, 97. ISSN Page 87