References and Notes
1a
Govaert F.
Beyaert M.
Bull. Soc. Chim. Belg.
1946,
55:
106
1b
Litherland A.
Mann FG.
J. Chem. Soc.
1938,
1588
1c
Govaert FJ.
Proc. Acad. Sci. Amsterdam
1934,
37:
156
1d Engel W, Eberlein W, Trummlitz G, Mihm G, Doods H, Mayer N, and De Jonge A. inventors; Eur. Patent, EP 417631.
1e
Hillier MC.
Chen C.-Y.
J. Org. Chem.
2006,
71:
7885
2
Stocks MJ.
Hamza D.
Pairaudeau G.
Stonehouse JP.
Thorne P.
Synlett
2007, in press
3 For synthesis and reactions of 1 see ref. 2 and: Bartholomew D.
Stocks MJ.
Tetrahedron Lett.
1991,
32:
4795
4 Prolonged reaction times (>30 min) resulted in significant quantities of the des-chloro reduction product.
5 1-Benzyl-3-chloromethylazetidine-3-carbaldehyde (3): 1H NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 7.23-7.34 (m, 5 H), 3.95 (s, 2 H), 3.65 (s, 2 H), 3.43 (d, J = 8.2 Hz, 2 H), 3.27 (d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 200.1, 137.1, 128.4 (2 × C), 127.3, 62.7, 57.3, 49.7, 44.9. GC-MS: purity = 97.8%, base peak = 91, molecular ion = 223. HRMS: m/z [M + H]+ calcd for C12H14NOCl: 224.0842; found: 224.0849.
6
Preparation of 2-Benzyl-6-phenyl-2,6-diaza-spiro[3.3]heptane (7a): To a stirred solution of (1-benzyl-3-chloromethylazetidin-3-ylmethyl)phenylamine (0.209 g, 0.695 mmol, 1 equiv) in THF (1.5 mL) was added t-BuOK (1.53 mL, 1.53 mmol, 1.0 M solution in THF, 2.2 equiv) and the reaction was heated at 70 °C in a sealed tube. After 90 min further t-BuOK (0.7 mL, 0.7 mmol, 1.0 M solution in THF, 1 equiv) was added and heating was continued for a further 1 h. The reaction was then allowed to cool to ambient temperature, filtered to remove KCl and the solvents were evaporated. The residue was purified by column chromatography eluting with 20-100% EtOAc in isohexanes to afford 7a (209 mg, 0.487 mmol, 70%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.17-7.33 (m, 7 H), 6.73 (dt, J = 1.0, 14.6 Hz, 1 H), 6.41-6.45 (m, 2 H), 3.92 (s, 4 H), 3.58 (s, 2 H), 3.38 (s, 4 H). 13C NMR (75 MHz, CDCl3): δ = 151.6, 138.0, 128.9, 128.5, 128.4, 127.1, 117.7, 111.6, 64.5, 63.7, 62.3, 34.8. HPLC-MS: purity = 98.58%, λ = 220 nm, [M + H]+ = 265.2. HRMS: m/z [M + H]+ calcd for C18H21N2: 265.1704; found: 265.1700.
7a
Huszthy P.
Bradshaw JS.
Krakowiak KE.
Wang T.
Dalley NK.
J. Heterocyl. Chem.
1993,
30:
1197
7b
Latli B.
D’Amour K.
Casida JE.
J. Med. Chem.
1999,
42:
2227
7c
De Kimpe N.
De Smaele D.
Tetrahedron Lett.
1994,
35:
8023
7d
De Kimpe N.
De Smaele D.
Tetrahedron
1995,
51:
5465
8 DMF was found to give cleaner reaction profiles than aq NMP, DMA or pyridine mixtures.
9
Preparation of 2-Benzyl-6-(4-fluorobenzyl)-2,6-diaza-spiro[3.3]heptane (9a): (1-Benzyl-3-chloromethylazetidin-3-ylmethyl)(4-fluorobenzyl)amine (75 mg, 0.225 mmol) was dissolved in DMF-H2O (9:1, 3.5 mL) and heated in a sealed tube at 110 °C with stirring. After 90 min, H2O (0.4 mL) was added and the reaction was heated for a further 3 h. The reaction was allowed to cool to ambient temperature and loaded on to an SCX ion-exchange cartridge preconditioned in MeOH. After washing with MeOH the product was eluted with NH3 (1 M in MeOH) and solvents were evaporated. The residue was purified by flash column chromatography eluting with 1-30% EtOH in CH2Cl2 to afford 9a (49 mg, 0.164 mmol, 73%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 6.95-6.99 (m, 2 H), 7.18-7.31 (m, 7 H), 3.55 (s, 2 H), 3.50 (s, 2 H), 3.32 (s, 4 H), 3.29 (s, 4 H). 13C NMR (125 MHz, CDCl3): δ = 161.8 (d, J
C-F = 244.9 Hz), 137.8, 133.6 (d, J
C-F = 3.2 Hz), 129.7 (d, J
C-F = 7.8 Hz), 128.24, 128.15, 126.9, 114.9 (d, J
C-F = 21.2 Hz), 64.3, 64.2, 63.4, 62.6, 34.5. HPLC-MS: purity = 98.23%, λ = 220 nm, [M + H]+ = 297.2. HRMS: m/z [M + H]+ calcd for C19H22N2F: 297.1767; found: 297.1767.
10
Yamashita M.
Ojima I.
J. Am. Chem. Soc.
1983,
105:
6339
11
Bartholomew D.
Stocks MJ.
Tetrahedron Lett.
1991,
32:
4799
12 Compound 11 was heated in a sealed tube in 20% aq DMF at 130 °C for 20 h and monitored by LC-MS.
