Concise Synthesis of Novel 2,6-Diazaspiro[3.3]heptan-1-ones and Their Conversion into 2,6-Diazaspiro[3.3]heptanes

Abstract

A concise synthesis, amenable to library production of 2,6-diazaspiro[3.3]heptan-1-ones and their subsequent conversion into 2,6-diazaspiro[3.3]heptanes is reported.

ring closure - spiro compounds - combinatorial chemistry - lactams - heterocycles

References and Notes

For some recent applications of parallel synthesis in drug design, see:

1a Habashita H. Kokubo M. Hamano S.-I. Hamanaka N. Toda M. Shibayama S. Tada H. Sagawa K. Fukushima D. Maeda K. Mitsuya H. J. Med. Chem.  2006,  49:  4140 

1b Edwards PJ. IDrugs  2006,  9:  347 

1c Lu S.-F. Chen B. Davey D. Dunning L. Jaroch S. May K. Onuffer J. Phillips G. Subramanyam B. Tseng J.-L. Wei RG. Wei M. Ye B. Bioorg. Med. Chem. Lett.  2007,  17:  1883 

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:

2a Macías A. Morán Ramallal A. Alonso E. del Pozo C. González J. J. Org. Chem.  2006,  71:  7721 

2b Bittermann H. Gmeiner P. J. Org. Chem.  2006,  71:  97 

2c Khasanov AB. Ramirez-Weinhouse MM. Webb TR. Thiruvazhi M. J. Org. Chem.  2004,  69:  5766 

2d Alonso E. Lopez-Ortiz F. del Pozo C. Peralta E. Macias A. Gonzalez J. J. Org. Chem.  2001,  66:  6333 

For recent syntheses of piperidine-derived spirocyclic β-lactams, see:

2e Arnott G. Clayden J. Hamilton SD. Org. Lett.  2006,  8:  5325 

2f Macias A. Alonso E. del Pozo C. Gonzalez J. Tetrahedron Lett.  2004,  45:  4657 

2g Clayden J. Hamilton SD. Mohammed RT. Org. Lett.  2005,  7:  3673 

3a Bartholomew D. Stocks MJ. Tetrahedron Lett.  1991,  32:  4795 

3b

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 × 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 NMR (300 MHz, CDCl₃): 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).

4

Hydrolysis of 4 was previously reported to afford 6; see ref. 3 for details.

5

Compound 7 can be stored under dry nitrogen for up to four weeks.

6

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-chloromethyl-azetidine-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, 138.0, 137.4, 129.1, 128.5, 128.4, 127.2, 123.9, 116.3, 62.9, 58.2, 51.6, 50.3.

The free azetidine 9 can be readily functionalised by reaction with, for example:

7a

acid chlorides to generate amides;

7b

aldehydes to generate N-substituted alkyl amines;

7c

isocyanates to generate ureas and

7d

sulfonyl chlorides to generate sulfonamides under standard reaction conditions.

8

Analysis of 2-phenyl-2,6-diazaspiro[3.3]heptan-1-one (9): mp 149-150 °C. GC-MS: m/z = 188 [M]⁺; 100% pure. Anal. Calcd for: C, 70.19; H, 6.43; N, 14.79. Found: C, 70.05; H, 6.51; N, 14.79. ¹H NMR (400 MHz, CDCl₃): δ = 7.35-7.30 (m, 4 H), 7.11-7.07 (m, 1 H), 4.27 (d, J = 9.6 Hz, 2 H), 3.86 (s, 2 H), 3.79 (d, J = 9.6 Hz, 2 H), 1.83 (s, 1 H). ¹³C NMR (100.5 MHz, CDCl₃): δ = 166.1, 138.0, 129.1, 124.0, 116.3, 54.1, 51.7, 51.5.

For a recent synthesis of this interesting ring system, see:

9a Hillier MC. Chen C.-Y. J. Org. Chem.  2006,  71:  7885 

9b Engel W, Eberlein W, Trummlitz G, Mihm G, Doods H, Mayer N, and De Jonge A. inventors; EP  417631.  For an application of the use of 2,6-diaza-spiro[3.3]heptanes in drug discovery, see:

For some examples of the reduction of β-lactams to azetidines, see:

10a Brayer JL. Alazard JP. Thal C. Tetrahedron  1990,  46:  5187 

10b Ojima I. Zhao M. Yamato T. Nakahashi K. Yamashita M. Abe R. J. Org. Chem.  1991,  56:  5263 

10c Yamashita M. Ojima I. J. Am. Chem. Soc.  1983,  105:  6339 

10d Ojima I. Yamato T. Nakahashi K. Tetrahedron Lett.  1985,  26:  2035 

11a Van Brabandt W. De Kimpe N. Synlett  2006,  2039 

11b Van Elburg PA. Reinhoudt DN. Heterocycles  1987,  26:  437 

12

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.

13

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), 3.94 (s, 4 H), 3.60 (s, 2 H), 3.40 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): 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.