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

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

References

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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, CH_ax-N); 2.65 (m, 2 H, CH_eq-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, CH_ax-N); 2.64 (m, 2 H, CH_eq-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, CH_ax-N); 2.82 (m, 2 H, CH_eq-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, CH_2ax-C); 1.80 (m, 2 H, CH_2eq-C); 2.40 (bs, 1 H, NH); 2.90 (m, 2 H, CH_ax-N); 3.04 (m, 2 H, CH_eq-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