Rapid and Selective Synthesis of Substituted 1,2,5-Thiadiazolidine 1,1-Dioxides

Abstract

The reaction of N,N-dimethylsulfamoyl aziridines with primary amines gives direct access to substituted 1,2,5-thiadiazol­idines in a regioselective manner. Furthermore, the product from ­reaction with 4-methoxybenzyl amine can be subsequently mani­pulated to give the alternative nitrogen substitution pattern in a ­controlled fashion.

heterocycles - aziridines - cyclic sulfamides - regioselective

References and Notes

1a Sparey T. Beher D. Best J. Biba M. Castro JL. Clarke E. Hannam J. Harrison T. Lewis H. Madin A. Shearman M. Sohal B. Tsou N. Welch C. Wrigley J. Bioorg. Med. Chem. Lett.  2005,  15:  4212 

1b Collins IJ, Hannam JC, Harrison T, Lewis SJ, Madin A, Sparey TJ, and Williams BJ. inventors; WO  2002036555. 

1c Collins IJ, Cooper LC, Harrison T, Keown LE, Madin A, and Ridgill MP. inventors; WO  2003093252. 

1d Collins IJ, Hannam JC, Harrison T, Madin A, and Ridgill MP. inventors; WO  2004039800. 

Some other recent approaches to cyclic sulfamides:

2a Zabawa TP. Kasi D. Chemler SR. J. Am. Chem. Soc.  2005,  127:  11250 

2b Espino CG. Williams Fiori K. Kim M. Du Bois J. J. Am. Chem. Soc.  2004,  126:  15378 

2c Nicolaou KC. Longbottom DA. Snyder SA. Nalbanadian AZ. Huang X. Angew. Chem. Int. Ed.  2002,  41:  3866 

3a Ellman JA. Owens TD. Tang TP. Acc. Chem. Res.  2002,  35:  984 

3b Ellman JA. Pure Appl. Chem.  2003,  75:  39 

4 Preparation of tert-butyl sulfinyl aziridines: Morton D. Pearson D. Field RA. Stockman RA. Synlett  2003,  13:  1985 

5

Campbell, A. Merck Sharp and Dohme, Terlings Park. Personal communication: tert-butyl sulfinyl aziridines derived from benzaldehydes undergo reaction with amines at 150 °C in DMSO under microwave irradiation to give a mixture of regioisomers.

6 Gontcharov AV. Liu H. Sharpless KB. Org. Lett.  1999,  1:  783 

7 Jiaxi X. Tetrahedron: Asymmetry  2002,  13:  1129 

8 Alternative synthesis of dimethylsulfamoyl aziridines from alkenes: Greatbanks D. Seden TP. Turner RW. Tetrahedron Lett.  1968,  9:  4863 

9

N ′-{Bicyclo[4.2.1]non-3-en-9-ylidene}- N , N -dimethyl-sulfamide (14). Titanium(IV) ethoxide (12.6 mL, 60 mmol) was added to a solution of bicyclo[4.2.1]non-3-en-9-one¹⁵ (13, 2.72 g, 20 mmol) and N,N-dimethylsulfamide (12.4 g, 100 mmol) in dry THF (20 mL) at r.t. under N₂. The dark red solution was stirred and heated at reflux for 16 h, then allowed to cool to r.t. The reaction mixture was poured into brine (120 mL) with rapid stirring. After 20 min the solid was removed by filtration through Hyflo^®, washing with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 200 mL). The combined extracts were washed with half-sat. aq NaHCO₃, then dried (MgSO₄), filtered and evaporated. The residue was purified by chromatography (silica, 5% EtOAc-isohexane) to give the title compound (2.4 g, 50%) as a colourless solid. ¹H NMR (360 MHz, CDCl₃): δ = 1.48-1.68 (2 H, m), 1.94-2.13 (2 H, m), 2.17-2.38 (3 H, m), 2.56-2.65 (1 H, m), 2.83 (6 H, s), 2.88-2.94 (1 H, m), 3.73-3.80 (1 H, m), 5.54-5.72 (2 H, m). ¹³C NMR (90 MHz, CDCl₃): δ = 25.8, 29.8, 33.3, 34.9, 39.0, 42.4, 46.8, 125.8, 127.9. MS (ES⁺): m/z = 243 [MH⁺].

10

(1′ R ,2 R ,6′ S )- N , N -dimethyl-1 H -spiro{aziridine-2,9′-bicyclo[4.2.1]non[3]ene}-1-sulfonamide (15). NaH (60% disp., 600 mg, 15 mmol) was added portionwise to a stirred solution of trimethylsulfoxonium iodide (3.3 g, 15 mmol) in dry DMSO (25 mL) at r.t. under nitrogen. After 1 h, a solution of imine 14 (2.4 g, 10 mmol) in dry DMSO (25 mL) was added. After 1 h the reaction was quenched with H₂O (50 mL), then extracted with EtOAc (3 × 50 mL). The combined extracts were washed with H₂O (2 × 50 mL), brine (50 mL) then dried (MgSO₄), filtered and evaporated. The residue was purified by chromatography (silica, 10% EtOAc-isohexane) to give the title compound (2.2 g, 87%) as a colourless solid. ¹H NMR (400 MHz, CDCl₃): δ = 1.55-1.61 (2 H, m), 1.93-1.97 (2 H, m), 2.09-2.18 (4 H, m), 2.39 (2 H, s), 2.65 (2 H, dd, J = 3.7, 13.2 Hz), 2.92 (6 H, s), 5.57 (2 H, br s). ¹³C NMR (90 MHz, CDCl₃): δ = 28.4, 34.1, 39.2, 41.3, 44.0, 58.4, 127.5. MS (ES⁺): m/z = 257 [MH⁺]. HRMS: m/z calcd for C₁₂H₂₁N₂O₂S [MH⁺]: 257.1324; found: 257.1322.

11

Typical Procedure for Aziridine Opening. A solution of the aziridine (1 mmol) and the amine (5 mmol) in dry DMSO (15 mL) was stirred and heated at 100 °C for 16 h under N₂. After cooling to r.t. the mixture was diluted with an equal volume of H₂O, then extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine (50 mL) then dried (MgSO₄), filtered and evaporated. The residue was purified by chromatography (silica, EtOAc-isohexane) to give the cyclic sulfamide.

12

Data for (4 S )-4-Benzyl-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide (19a). ¹H NMR (400 MHz, CDCl₃): δ = 0.96 (3 H, t, J = 7.4 Hz), 1.62 (2 H, sext, J = 7.3 Hz), 2.83-2.93 (2 H, m), 2.97-3.05 (2 H, m), 3.07 (1 H, dd, J = 9.2, 7.1 Hz), 3.42 (1 H, dd, J = 9.2, 6.8 Hz), 3.95 (1 H, sext., J = 7.0 Hz), 4.43 (1 H, br d, J = 6.2 Hz), 7.20 (2 H, d, J = 7.0 Hz), 7.26-7.35 (3 H, m). ¹³C NMR (90 MHz, CDCl₃): δ = 11.8, 21.6, 41.1, 48.9, 53.8, 54.0, 127.7, 129.3, 129.5, 136.5. HRMS: m/z calcd for C₁₂H₁₉N₂O₂S [MH⁺]: 255.1167; found: 255.1176. [α]_D ²² -35 (c 1, MeOH). The ee was determined to be >99% by chiral HPLC (CHIRALPAK AD-H, 15% EtOH-isohexane, 1 mL/min). The ee for the aziridine 12 was also found to be >99% by chiral HPLC (CHIRALPAK
AS-H, 7% EtOH-isohexane, 1 mL/min).

13

(3 S )-3-Benzyl-5-(4-methoxybenzyl)-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide (20). NaH (60% disp, 96 mg, 2.4 mmol) was added to a stirred solution of (4S)-4-benzyl-2-(4-methoxybenzyl)-1,2,5-thiadiazolidine-1,1-dioxide (19f, 665 mg, 2 mmol) in dry DMF (20 mL) at 0 °C under N₂. After 1 h, n-propyl bromide (220 µL, 2.4 mmol) was added. The reaction was quenched with H₂O after a further hour, then partitioned between EtOAc (50 mL) and H₂O (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined extracts were washed with brine (50 mL), then dried (MgSO₄), filtered and evaporated. The residue was purified by chromatography (silica, 10% EtOAc-isohexane) to give the cyclic sulfamide (718 mg, 96%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (3 H, t, J = 7.4 Hz), 1.69 (2 H, sext, J = 7.4 Hz), 2.71 (1 H, dd, J = 9.1, 13.5 Hz), 2.78 (1 H, dd, J = 6.6, 9.3 Hz), 2.90 (1 H, dt, J = 13.6, 7.7 Hz), 3.03-3.10 (2 H, m), 3.24 (1 H, dt, J = 13.9, 7.0 Hz), 3.48-3.52 (1 H, m), 3.79 (3 H, s), 3.93 (1 H, d, J = 13.6 Hz), 4.19 (1 H, d, J = 13.6 Hz), 6.85 (2 H, d, J = 8.6 Hz), 7.08 (2 H, d, J = 6.7 Hz), 7.21-7.28 (5 H, m). ¹³C NMR (90 MHz, CDCl₃): δ = 11.8, 22.0, 40.0, 49.8, 50.0, 50.5, 55.7, 58.9, 114.5, 127.3, 127.4, 129.2, 129.6, 130.4, 136.5, 159.9. HRMS: m/z calcd for C₂₀H₂₇N₂O₃S [MH⁺]: 375.1742; found: 375.1736.

14

(3 S )-3-Benzyl-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide (21). A solution of (3S)-3-benzyl-5-(4-methoxybenzyl)-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide (20, 562 mg, 1.5 mmol) in TFA (3 mL) was stirred at r.t. for 2 h. The mixture was then concentrated in vacuo. The residue was taken up in EtOAc (25 mL). The organic layer was washed with brine (25 mL), then dried (MgSO₄), filtered and evaporated. The residue was purified by chromatography (silica, 10-20% EtOAc-isohexane) to give the cyclic sulfamide (378 mg, 99%) as a colourless solid. ¹H NMR (400 MHz, CDCl₃): δ = 0.94 (3 H, t, J = 7.4 Hz), 1.69 (2 H, sext, J = 7.4 Hz), 2.79 (1 H, dd, J = 8.6, 13.6 Hz), 2.92 (1 H, dt, J = 7.8, 13.6 Hz), 3.06 (1 H, dd, J = 5.2, 13.6 Hz), 3.13-3.21 (2 H, m), 3.34 (1 H, dt, J = 7.1, 11.7 Hz), 3.61-3.68 (1 H, m), 4.54 (1 H, t, J = 7.2 Hz), 7.19-7.34 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 11.1, 21.2, 39.0, 44.5, 47.8, 62.3, 126.8, 128.5, 128.9, 135.6. HRMS: m/z calcd for C₁₂H₁₉N₂O₂S [MH⁺]: 255.1167; found: 255.1154.

15 Still WC. Synthesis  1976,  453