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DOI: 10.1055/s-2006-939039
Rapid and Selective Synthesis of Substituted 1,2,5-Thiadiazolidine 1,1-Dioxides
Publication History
Publication Date:
14 March 2006 (online)
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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.
Key words
heterocycles - aziridines - cyclic sulfamides - regioselective
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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, andWilliams BJ. inventors; WO 2002036555. -
1c
Collins IJ,Cooper LC,Harrison T,Keown LE,Madin A, andRidgill MP. inventors; WO 2003093252. -
1d
Collins IJ,Hannam JC,Harrison T,Madin A, andRidgill MP. inventors; WO 2004039800. - Some other recent approaches to cyclic sulfamides:
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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 - 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 - 15
Still WC. Synthesis 1976, 453
References and Notes
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.
9N ′-{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.
11Typical 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).
(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.