PDF herunterladen
Synlett 2003(6): 0813-0816
DOI: 10.1055/s-2003-38728
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

The First Synthesis of Spiro (1,4-Benzodioxin-2,4′-Piperidines) and Spiro (1,4-Benzodioxin-2,3′-Pyrrolidines)

Y. Harraka, G. Guillaumetb, M. D. Pujol*a
a Laboratori de Química Farmacèutica, Fac. Farmàcia, Unitat associada al CSIC, Universitat de Barcelona, Av. Diagonal 643, 08028-Barcelona, Spain
Fax: +34(93)4035941; e-Mail: mdpujol@farmacia.far.ub.es;
b Institut de Chimie Organique et Analytique, UMR CNRS-6005, Université d"Orléans, Rue de Chartres, BP-6759, 45067-Orléans Cedex-2, France
Weitere Informationen

Publikationsverlauf

Received 5 February 2003
Publikationsdatum:
17. April 2003 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

Abstract

A convenient procedure for the synthesis of spiro (1,4-benzodioxin-2,4′-piperidines) and spiro (1,4-benzodioxin-2-3′-pyrrolidines) has been developed from 2-fluorophenol. Condensation of the 2-fluorophenol with the corresponding epoxide under acid catalyst provides the primary alcohol directly. The 1,4-benzodioxine ring closure was achieved by treatment of the primary alcohols with NaH in DMF. An isomerization process can take place due to exposure to basic media in the course of cyclization.

Key words

1,4-Benzodioxine - fluoro derivatives - epoxide cleavage - spiropiperidines - spiropyrrolidines

14

Analytical data: Spiro [(2,3-dihydro-1,4-benzodioxine)-2,4′-( N -benzylpiperidine)] ( 12). White solid. Mp: 89-91 ºC (hexane-EtOAc). IR (NaCl, cm-1): 1493, 1265, 1110. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.67 (m, 4 H, CH2-C); 2.47 (dt, J 1 = 11 Hz, J 2 = 3.2 Hz, 2 H, CHax-N); 2.65 (m, 2 H, CHeq-N); 3.65 (s, 2 H, CH2-Ar); 3.90 (s, 2 H, CH2-O); 6.85 (m, 4 H, H-3, H-4, H-5, H-6); 7.33 (m, 5 H, C6H5). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 31.4 (CH2, CH2-C); 48.6 (CH2, CH2-N); 63.1 (CH2, CH2-Ar); 71.1 (C, C-2); 71.3 (CH2, CH2-O); 116.9 (CH, C-8); 117.7 (CH, C-5); 120.9* (CH, C-6); 121.7* (CH, C-7); 127.1 (CH, C-4′′);128.2 (CH, C-2′′ and C-6′′); 129.1 (CH, C-3′′ and C-5′′); 138.3 (C, C-1′′); 141.9 (C, C-8a); 142.6 (C, C-4a). Anal. Calcd for C19H22NO2: C, 76.99; H, 7.48; N, 4.73. Found: C, 77.22; H, 7.23; N, 4.68.
* Interchangeable
N -Methyl-2-oxa-6-azaspiro[2,5]heptane ( 18). Oil. IR (NaCl, cm-1): 1287, 1195. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.89 (m, 1 H, CH-C), 2.16 (m, 1 H, CH-C); 2.68 (m, 6 H, CH2-N and CH2-O); 3.62 (m, 2 H, CH2-Ar); 7.28 (m, 5 H, C6H5). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 31.2 (CH2, CH2-C); 51.6 (CH2, CH2-N); 53.5 (CH2, CH2-N); 58.8 (C, C-1); 60.7 (CH2-Ar); 62.9 (CH2, CH2-O); 127.1 (CH, C-4′); 128.2 (CH, C-2′ and C-6′); 128.8 (CH, C-3′ and C-5′); 138.4 (C, C-1′). Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 8.45. Found: C, 76.12; H, 7.23; N, 8.35.
N -Benzyl-3-(2-fluorophenoxy)-3-hydroxymethyl-pyrrolidine ( 19). Oil. IR (NaCl, cm-1): 3545, 3219, 1466, 1231, 1088. 1H NMR (CDCl3, 200 MHz) δ (ppm): 2.18 (m, 2 H, CH2-C); 3.67 (m, 4 H, CH2-N); 4.08 (s, 2 H, CH2-Ar); 4.26 (s, 2 H, CH2-O); 7.05 (m, 4 H, H-5, H-6, H-7, H-8); 7.45 (m, 5 H, C6H5).
N -Benzyl-4-(2-fluorophenoxy)-4-hydroxymethyl-piperidine ( 20). White solid. Mp: 73-75 ºC (hexane-EtOAc). IR (KBr, cm-1): 3527, 1504, 1260, 1108. 1H NMR (CDCl3, 200 MHz) δ (ppm): 2.04 (m, 4 H, CH2-C); 3.20 (m, 4 H, CH2-N); 3.89 (s, 2 H, CH2-Ar); 4.20 (s, 2 H, CH2-O); 5.25 (bs, 1 H, OH); 6.98 (m, 4 H, H-3, H-4, H-5, H-6); 7.42 (m, 5 H, Ar). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 31.4 (CH2, CH2-C); 48.2 (CH2, CH2-N); 61.6 (CH2, CH2-Ar); 67.1 (C, C-4′); 75.9 (CH2, CH2-O); 114.9 (CH, C-5); 115.7 (CH, J = 18 Hz, C-3); 121.5 (CH, J = 7 Hz, C-4); 124.3 (CH, J = 4 Hz, C-6); 128.8 (CH, C-2′′ and C-6′′); 129.0 (CH,
C-4′′); 130.3 (CH, C-3′′ and C-5′′); 130.5 (C, C-1′′); 146.0 (C, J = 11 Hz, C-1); 152.2 (C, J = 235 Hz, C-2). Anal. Calcd for C19H22NO2F: C, 76.99; H, 7.48; N, 4.73. Found: C, 77.12; H, 7.72; N, 4.58.
N -Benzyl-4-(2-fluorophenoxymethyl)-4-hydroxy-piperidine ( 22). Oil. IR (NaCl, cm-1): 3418, 1504, 1259, 1109. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.77 (t, J = 5 Hz, 4 H, CH2-C); 2.38 (m, 2 H, CHax-N); 2.64 (m, 2 H, CHeq-N); 3.55 (s, 2 H, CH2-Ar); 3.86 (s, 2 H, CH2-O); 7.00 (m, 4 H, H-3, H-4, H-5, H-6); 7.32 (m, 5 H, Ar). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 33.7 (CH2, CH2-C); 48.8 (CH2, CH2-N); 63.1 (CH2, CH2-Ar); 68.9 (CH2, CH2-O); 76.8 (C, C-4′); 115.1 (CH, C-5); 116.2 (CH, J = 18 Hz, C-3); 121.4 (CH, J = 7 Hz, C-4); 124.1 (CH, J = 4 Hz, C-6);126.9 (CH, C-4′′); 128.1 (CH, C-2′′, C-6′′); 129.1 (CH, C-3′′, C-5′′); 138.1 (C,C-1′′); 146.6 (C, J = 11 Hz, C-1); 152.9 (C, J = 245 Hz, C-2). Anal. Calcd for C19H22NO2F: C, 76.99; H, 7.48; N, 4.73. Found: C, 77.02; H, 7.71; N, 4.95.
Spiro [(2,3-dihydro-1,4-benzodioxine)-2,3′-( N -benzyl-pyrrolidine)] ( 23). Oil. IR (NaCl, cm-1): 1477, 1205, 1123. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.25 (m, 2 H, CH2-C); 2.02 (m, 2 H, CHax-N); 2.82 (m, 2 H, CHeq-N); 3.74 (s, 2 H, N-CH2-Ar); 4.04 (m, 2 H, CH2-O); 6.85 (m, 4 H, H-5, H-6, H-7, H-8); 7.31 (m, 5 H, Ar). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 34.6 (CH2, CH2-C); 52.8 (CH2, CH2-N); 60.0 (CH2, CH2-N); 61.7 (CH2, N-CH2-Ar); 69.9 (CH2, C-3); 81.7 (C, C-2); 116.9 and 117.8 (CH, C-5 and C-8); 121.2 and 121.6 (CH, C-6 and C-7); 127.3 (CH, C-4′′); 128.3 (CH, C-2′′ and C-6′′); 128.9 (CH, C-3′′ and C-5′′); 138.1 (C, C-1′′); 142.1 and 142.6 (C, C-4a and C-8a). Anal. Calcd for C18H20NO2F: C, 71.74; H, 6.69; N, 4.65. Found: C, 71.56; H, 6.82; N, 4.52.
Spiro [(2,3-dihydro-1,4-benzodioxine)-2,4′-piper-idine] ( 24). White solid. Mp: 83-85 ºC (hexane-EtOAc). IR (NaCl, cm-1): 3424, 1495, 1268, 1041. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.59 (m, 2 H, CH2ax-C); 1.80 (m, 2 H, CH2eq-C); 2.40 (bs, 1 H, NH); 2.90 (m, 2 H, CHax-N); 3.04 (m, 2 H, CHeq-N); 3.91 (s, 2 H, CH2-O); 6.86 (m, 4 H, H-3, H-4, H-5, H-6). 13C NMR (CDCl3, 50.3 MHz) δ (ppm): 31.9 (CH2, CH2-C); 41.4 (CH2, CH2-N); 71.0 (C, C-2); 71.4 (CH2, CH2-O); 116.8 (CH, C-8); 117.6 (CH, C-5); 121.0* (CH, C-6); 121.7* (CH, C-7); 141.8 (C, C-8a); 142.5 (C, C-4a).
* Interchangeable