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Synlett
Volumn , Issue 16, 2007, Pages 2587-2589
Concise synthesis of novel 2,6-diazaspiro[3.3]heptan-1-ones and their conversion into 2,6-diazaspiro[3.3]heptanes
Author keywords

Combinatorial chemistry; Heterocycles; Lactams; Ring closure; Spiro compounds
Indexed keywords

2,6 DIAZASPIRO[3.3]HEPTAN 1 ONE; 2,6 DIAZASPIRO[3.3]HEPTANE; HEPTANE DERIVATIVE; HETEROCYCLIC COMPOUND; KETONE DERIVATIVE; LACTAM DERIVATIVE; SPIRO COMPOUND; UNCLASSIFIED DRUG;
EID: 35349028474     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2007-986649     Document Type: Article
Times cited : (8)
References (27)
  • 4
    • 33749176923 scopus 로고    scopus 로고
    • To the best of our knowledge the azetidine-derived spirocyclic β-lactam (2,6-diazaspiro[3.3]heptan-1-one) ring system has not previously been prepared in the chemical literature. Proline-derived spirocyclic β-lactams are represented in the chemical literature and are useful as β-turn mimetics. For examples, see: (a) Macías, A.; Morán Ramallal, A.; Alonso, E.; del Pozo, C.; González, J. J. Org. Chem. 2006, 71, 7721.
    • To the best of our knowledge the azetidine-derived spirocyclic β-lactam (2,6-diazaspiro[3.3]heptan-1-one) ring system has not previously been prepared in the chemical literature. Proline-derived spirocyclic β-lactams are represented in the chemical literature and are useful as β-turn mimetics. For examples, see: (a) Macías, A.; Morán Ramallal, A.; Alonso, E.; del Pozo, C.; González, J. J. Org. Chem. 2006, 71, 7721.
  • 8
    • 33845257278 scopus 로고    scopus 로고
    • For recent syntheses of piperidine-derived spirocyclic β-lactams, see: e
    • For recent syntheses of piperidine-derived spirocyclic β-lactams, see: (e) Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
    • (2006) Org. Lett , vol.8 , pp. 5325
    • Arnott, G.1    Clayden, J.2    Hamilton, S.D.3
  • 12
    • 35348993945 scopus 로고    scopus 로고
    • Optimised experimental conditions for the synthesis of 4 from the readily available precursor 3 are given. To cold EtOH (250 mL) at 0-5°C was added Na metal (25.5 g, 1.5 equiv, The solution was allowed to warm to r.t. and was stirred for 1 h. To the reaction mixture was added a solution of compound 3 (190 g) in EtOH (100 mL) and the reaction was stirred for 14 h at r.t. The reaction mixture was slowly poured into ice-cold H2O and extracted with PE (3 x 250 mL, The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude reaction product (110 g) was dissolved in toluene (800 mL) and K2CO3 (110 g, 2.2 equiv) added. The reaction mixture was refluxed for 16 h, cooled, and filtered. The residue was purified over silica gel eluting with 8% EtOAc in isohexane to give 1-benzyl-3- chloromethylazetidine-3-carboxylic acid ethyl ester (60 g) as pale yellow liquid. 1H N
    • 3): δ = 7.37-7.22 (m, 5 H), 4.23 (q, J = 7.1 Hz, 2 H), 4.05 (s, 2 H), 3.64 (s, 2 H), 3.43 (d, J = 8.5 Hz, 2 H), 3.31 (d, J = 8.5 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
  • 13
    • 35348934532 scopus 로고    scopus 로고
    • Hydrolysis of 4 was previously reported to afford 6; see ref. 3 for details.
    • Hydrolysis of 4 was previously reported to afford 6; see ref. 3 for details.
  • 14
    • 35348951202 scopus 로고    scopus 로고
    • Compound 7 can be stored under dry nitrogen for up to four weeks.
    • Compound 7 can be stored under dry nitrogen for up to four weeks.
  • 15
    • 35348956607 scopus 로고    scopus 로고
    • Preparation of 1a To a stirred suspension of NaH (60% in mineral oil, 0.349 g) in THF (30 mL) was added 1-benzyl-3-chloromethylazetidine-3- carboxylic acid phenylamide (2.5 g) in THF (15 mL) and the mixture stirred for 2 h at r.t. Then, H2O was added and the mixture was extracted with EtOAc. The organic phase was dried with anhyd MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography eluting with EtOAc to give 6-benzyl-2-phenyl-2,6-diazaspiro[3.3]heptan-1-one (2.14 g) as a white solid after recrystallisation from Et2O-i-hexane; mp 122-123°C MS: m/z, 279.2 [M, H, 99.3% purity. Anal. Calcd. for: C 77.67; H, 6.52; N, 10.06. Found: C, 77.57; H, 6.55; N, 10.13. 1H NMR (400 MHz, CDCl3, δ, 7.35-7.24 (m, 9 H, 7.10-7.06 (m, 1 H, 3.86 (s, 2 H, 3.66 (s, 2 H, 3.61 (d, J, 1.5 Hz, 4 H, 13C NMR 100 MHz, CDCl3, δ, 165.8
    • 3): δ = 165.8, 138.0, 137.4, 129.1, 128.5, 128.4, 127.2, 123.9, 116.3, 62.9, 58.2, 51.6, 50.3.
  • 16
    • 35349007122 scopus 로고    scopus 로고
    • The free azetidine 9 can be readily functionalised by reaction with, for example: (a) acid chlorides to generate amides; (b) aldehydes to generate N-substituted alkyl amines; (c) isocyanates to generate ureas and (d) sulfonyl chlorides to generate sulfonamides under standard reaction conditions.
    • The free azetidine 9 can be readily functionalised by reaction with, for example: (a) acid chlorides to generate amides; (b) aldehydes to generate N-substituted alkyl amines; (c) isocyanates to generate ureas and (d) sulfonyl chlorides to generate sulfonamides under standard reaction conditions.
  • 17
    • 35348956083 scopus 로고    scopus 로고
    • 3): δ = 166.1, 138.0, 129.1, 124.0, 116.3, 54.1, 51.7, 51.5.
    • 3): δ = 166.1, 138.0, 129.1, 124.0, 116.3, 54.1, 51.7, 51.5.
  • 18
    • 33749151609 scopus 로고    scopus 로고
    • For a recent synthesis of this interesting ring system, see: a
    • For a recent synthesis of this interesting ring system, see: (a) Hillier, M. C.; Chen, C.-Y. J. Org. Chem. 2006, 71, 7885.
    • (2006) J. Org. Chem , vol.71 , pp. 7885
    • Hillier, M.C.1    Chen, C.-Y.2
  • 19
    • 35349022734 scopus 로고    scopus 로고
    • For an application of the use of 2,6-diazaspiro[3.3]heptanes in drug discovery, see: Engel, W.; Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer, N.; De Jonge, A. EP 417631, 1991.
    • (b) For an application of the use of 2,6-diazaspiro[3.3]heptanes in drug discovery, see: Engel, W.; Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer, N.; De Jonge, A. EP 417631, 1991.
  • 20
    • 0025024813 scopus 로고
    • For some examples of the reduction of β-lactams to azetidines, see: a
    • For some examples of the reduction of β-lactams to azetidines, see: (a) Brayer, J. L.; Alazard, J. P.; Thal, C. Tetrahedron 1990, 46, 5187.
    • (1990) Tetrahedron , vol.46 , pp. 5187
    • Brayer, J.L.1    Alazard, J.P.2    Thal, C.3
  • 26
    • 35348951736 scopus 로고    scopus 로고
    • The high stoichiometry of the reduction makes this reaction incompatable with library synthesis. However, a new synthesis of 2,6-diazaspiro[3.3]heptanes, amenable to library synthesis, will be communicated separately.
    • The high stoichiometry of the reduction makes this reaction incompatable with library synthesis. However, a new synthesis of 2,6-diazaspiro[3.3]heptanes, amenable to library synthesis, will be communicated separately.
  • 27
    • 35349002446 scopus 로고    scopus 로고
    • Preparation of 2a To a stirred solution of AlCl3 (0.20 g) in Et2O (3 mL) was added LiAlH4 in Et2O (1 M, 1.49 mL) and the mixture stirred at 40°C for 15 min before being cooled to r.t. and 6-benzyl-2-phenyl-2,6-diazaspiro[3.3]heptan-1-one (0.139 g) in THF (1 mL) was added. The reaction was warmed to 40°C for 1 h before being cooled to r.t. Then, H2O (0.2 mL, followed by 15% NaOH solution (0.2 mL, and finally H2O (0.6 mL) were added. The mixture was stirred for 15 min and filtered. The solution was concentrated and the residue purified by chromatography on silica gel eluting with 2-5% 0.7 N NH3 in MeOH in CH2Cl2 to afford 2-benzyl-6-phenyl-2,6-diazaspiro[3.3] heptane (0.077 g) as an oil. MS: m/z, 265.17 [M, H, 1H NMR (400 MHz, CDCl3, δ, 7.34-7.18 (m, 7 H, 6.73 (t, J, 7.5 Hz, 1 H, 6.44 d, J, 7.0 Hz, 2 H
    • 3): δ = 151.4, 137.7, 128.8, 128.4, 128.3, 127.1, 117.6, 111.5, 64.4, 63.5, 62.2, 34.7.

* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.