Novel Dithia-aza-norbornanes as ‘Stiff’ Bicyclic Dithiazines

Abstract

Addition of lithiated 4,5-dihydro-1,3,5-dithiazines to in situ generated N-silylimines in THF produces 2-(α-aminoalkyl)dithiazines, which rearrange into 3,5-dithia-1-azabicy­clo[2.2.1]heptanes upon aqueous workup. These novel bicyclic dithiazines can in turn be lithiated at the position 4 and added to carbonyl compounds.

Key words

heterocycles - sulfur - carbanions - nucleophilic additions - diastereoselectivity - desulfurization

References

• 1 Kang J. Kim JI. Lee JH. Bull. Korean Chem. Soc.  1994,  15:  865 
• 2 Ranu BC. Chakraborty R. Sarkar DC. Synth. Commun.  1991,  21:  1619 
• 3 Allin SM. Page PCB. Org. Prep. Proced Int.  1998,  30:  145 
• 4 For a review see: Vedejs E. Adv. Sulfur Chem.  1994,  1:  1 
• 5 Mitkin OD. Kurchan AN. Wan Y. Schiwal BF. Kutateladze AG. Org. Lett.  2001,  3:  1841 
• Synthesis of 3a as an example of a general procedure for 3a-c .
• 6a N-Silyl benzaldimine: A solution of 5.32 g(33 mmol) of 1,1,1,3,3,3-hexamethyldisilazane in 100 mL of freshly distilled THF was cooled to 0 °C, and 21.46 mL of n-butyllithium (1.6 M solution in hexanes, 34 mmol) was added with stirring under N₂ atmosphere. The reaction mixture was stirred at this temperature for 1.5 h. Next, 3.49 g (33 mmol) of benzaldehyde was slowly added, and the resulting mixture was stirred at 0 °C for 1.5 h; see also: Gyenes F. Bergmann KE. Welch JT. J. Org. Chem.  1998,  63:  2824 
• 6b

  Lithiated methyldithiazine was prepared by addition of 20.35 mL of 1.6 M n-BuLi in hexane (32 mmol) under nitrogen to a solution of 4 g dithiazine (30 mmol) in 100 mL of anhydrous THF at -78 °C. The reaction mixture was stirred for 2 h at -78 °C and a solution of silylated benzaldimine (33 mmol) in 100 mL of anhydrous THF was added dropwise. The solution was stirred at -78 °C for one hour and then allowed to warm to room temperature. The solvent was removed under reduced pressure to give orange oil, to which 150 mL of saturated NH₄Cl was added. The resulting two phase system was stirred for 12 hours at room temperature. The insoluble residue was dissolved in EtOAc, and the water phase was additionally extracted with EtOAc (2 × 50 mL). The organic extracts were combined and dried over Na₂SO₄. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc-hexanes, 1:20) resulting in 3.4 g of colorless crystals (54.7% yield). ¹H NMR (CDCl₃, 400 MHz), δ 7.48-7.28 (5 H, m), 5.16 (1 H, d, J = 1.4 Hz), 4.80 (1 H, s), 4.73 (1 H, dd, J ₁ = 9.0 Hz, J ₂ = 1.9 Hz), 4.28 (1 H, dd, J ₁ = 9.4 Hz, J ₂ = 2.3 Hz), 4.16 (1 H, d, J = 9.0 Hz), 3.95(1 H, d, J = 9.4 Hz). C¹³ NMR (CDCl3, 100 MHz), δ (ppm) 135.3, 128.5,127.6, 127.2, 82.4, 61.7, 59.5, 56.2. MS (EI) m/z (relative intensity) 209 (M⁺ 40), 142 (20), 134 (35), 118 (50), 91 (100), 77 (20), 64 (20). Calcd. for C₁₀H₁₁NS₂, %:
  C 57.38, H 5.30; Found, %: C 57.72, H 5.53.

• 8 Liguori A. Romeo G. Sindona G. Uccella N. Chem. Ber.  1988,  121:  105 

7

General procedure. 2.8 mmol of 3a or 3c was dissolved in 30 mL of freshly distilled THF and cooled to -78 °C, under nitrogen atmosphere. Then 2.0 mL (3.2 mmol) of n-BuLi 1.6 M solution in hexane was added dropwise. The reaction mixture was stirred for 2 hours at -30 °C and 3.6 mmol of the respective aldehyde in 10 mL of THF was added dropwise. The temperature was maintained at -78 °C for one more hour and then allowed to warm up overnight. The resulting red solution was washed with 50 mL of saturated NH₄Cl, the organic layer separated and the water phase extracted with 30 mL of CHCl₃. The organic layers were combined, dried over Na₂SO₄ and the solvent was removed in vacuum to give a yellow oil, which was purified by column chromatography. Additional column separation was required to isolate the diastereomers in a pure state. Diastereomers 5: (the stereochemistry is assigned based on Raney-Ni desulfurization) 5- RR(SS): ¹H NMR (CDCl₃, 400 MHz), δ (ppm) 7.86-7.80 (2 H, m), 7.46-7.40 (3 H, m), 7.31-7.20 (3 H, m), 7.16-7.12 (2 H, m), 5.61 (1 H, d, J = 3.2 Hz), 4.61 (1 H, d, J = 8.8 Hz), 4.59 (1 H, d, J = 8.8 Hz), 4.27 (1 H, d, J = 8.8 Hz), 4.11 (1 H, d, J = 8.8 Hz), 4.02 (1 H, s), 2.45 (1 H, d, J = 3.2 Hz). ¹³C NMR (CDCl₃, 100 MHz), δ 140.4, 134.9, 129.7, 129.1, 129.0, 128.7, 128.0, 127.4, 85.9, 83.1, 75.4, 62.2, 60.1 5- RS(SR): ¹H NMR (CDCl₃, 400 MHz), δ (ppm) 7.84 (2 H, d, J = 7.4 Hz), 7.52-7.36 (7 H, m), 7.33-7.28 (1 H, m), 5.41 (1 H, d, J = 8.1 Hz), 4.92 (1 H, s), 4.73 (1 H, d, J = 9.5 Hz), 4.70 (1 H, d, J = 9.5 Hz), 4.19 (1 H, d, J = 9.5 Hz), 4.18 (1 H, d, J = 8.8 Hz), 2.87 (1 H, d, J = 7.3 Hz). ¹³C NMR (CDCl₃, 100 MHz), δ 143.6, 134.6, 129.0, 128.9, 128.8, 128.6, 126.6, 87.2, 83.3, 72.8, 62.1, 61.5.