Synthesis of Orthogonally Protected 2,6-Diazaspiro[3.5]nonane and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building Blocks in Medicinal Chemistry

Abstract

A novel and efficient synthesis of orthogonally protected spirocyclic amines is described for the first time.

Key words

spirocyclic amine - 2,6-diazaspiro[3.5]nonane - 2,6-diazaspiro[3.4]octane - azetidine deprotection - orthogonal protecting groups

• References and Notes

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• 15 Typical Procedure for Nosyl Group Removal Cs₂CO₃ (22.64 g, 0.069 mol) and thiophenol (5.21 mL, 0.051 mol) were successively added to a solution of nosyl-protected spiro amine 10 (18.6 g, 0.046 mol) in MeCN (150 mL). The mixture was stirred at r.t. for 16 h. After this time the starting material was consumed as judged by TLC. The reaction mixture was filtered through a short layer of Celite. The cake was washed first with EtOAc (300 mL) and further with CH₂Cl₂–MeOH–NH₃ (7 M in MeOH, 80:18:2, 3 × 100 mL), and the collected organic layer was concentrated to give in total 31.3 g of the crude oil, which was absorbed on the minimum of silica gel and poured into a chromatography column containing a 1 cm layer of silica gel. The elution was carried out with EtOAc to wash off unpolar impurities and then with the system CH₂Cl₂–MeOH–NH₃ (7 M in MeOH, 80:18:2) to give the product 11 (8.8 g, 89% yield) as yellow oil. LCMS (214 nm): t _R = 7.8 min (89.1% content), [M + H]⁺ = 217.0. TLC analysis: R_f = 0.07 in CH₂Cl₂–MeOH–NH₃ (7 M in MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 7.36–7.19 (m, 5 H), 3.51 (s, 2 H), 3.38–3.33 (m, 4 H), 2.53–2.28 (m, 4 H), 1.65 (s, 2 H), 1.60–1.51 (m, 2 H). ¹³C NMR (101 MHz, CD₃OD): δ = 137.93, 128.91, 127.92, 126.84, 62.73, 61.32, 55.05, 53.12, 38.27, 33.82, 21.78.
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• 18 The p-toluenesulfonamide derivative of intermediate 18 was obtained, and the deprotection to spirocyclic amine 19 was carried out with Red-Al^® in toluene under reflux; however, the isolated yield of was lower.