One-Pot Synthesis of Cyclic Isothioureas

Abstract

The one-pot synthesis of cyclic isothioureas is reported. This method provides a straightforward and efficient approach to the synthesis of a broad range of cyclic isothioureas with yields of up to 90% and in quantities of up to 5 g. It is of great value for the preparation of classic organocatalysts, such as benzotetramisole and homobenzotetramisole.

Key words

cyclic isothioureas - organocatalysts - asymmetric synthesis - bisaminoaryl disulfides

Publikationsverlauf

Eingereicht: 07. Juni 2021

Angenommen nach Revision: 06. August 2021

Accepted Manuscript online:
06. August 2021

Artikel online veröffentlicht:
18. August 2021

• References and Notes

• 1a Taylor JE, Bull SD, Williams JM. J. Chem. Soc. Rev. 2012; 41: 2109
• 1b Birman VB, Uffman EW, Jiang H, Li X, Kilbane CJ. J. Am. Chem. Soc. 2004; 126: 12226
• 2a Birman VB, Guo L. Org. Lett. 2006; 8: 4859
• 2b Birman VB, Li X. Org. Lett. 2008; 10: 1115
• 2c Li X, Jiang H, Uffman EW, Guo L, Zhang Y, Yang X, Birman VB. J. Org. Chem. 2012; 77: 1722
• 2d Shiina I, Nakata K, Ono K, Sugimoto M, Sekiguchi A. Chem. Eur. J. 2010; 16: 167
• 3 Morrill LC, Lebl T, Slawin AM. Z, Smith AD. Chem. Sci. 2012; 3: 2088
• 4 Yang X, Bumbu VD, Liu P, Li X, Jiang H, Uffman EW, Guo L, Zhang W, Jiang X, Houk KN, Birman VB. J. Am. Chem. Soc. 2012; 134: 17605
• 5 Birman VB, Jiang H, Li X, Guo L, Uffman EW. J. Am. Chem. Soc. 2006; 128: 6536
• 6a Yang X, Birman VB. Angew. Chem. Int. Ed. 2011; 50: 5553
• 6b Liu P, Yang X, Birman VB, Houk KN. Org. Lett. 2012; 14: 3288
• 7 Belmessieri D, Joannesse C, Woods PA, MacGregor C, Jones C, Campbell CD, Johnston CP, Duguet N, Concellón C, Bragg RA, Smith AD. Org. Biomol. Chem. 2011; 9: 559
• 8 Ranieri B, Robles O, Romo D. J. Org. Chem. 2013; 78: 6291
• 9a Liu S, Müller JF. K, Neuburger M, Schaffner S, Zehnder M. Helv. Chim. Acta 2000; 83: 1256
• 9b McKay AF, Whittingham DJ, Kreling M.-E. J. Am. Chem. Soc. 1958; 80: 3339
• 10a Daniels DS. B, Smith SR, Lebl T, Shapland P, Smith AD. Synthesis 2015; 47: 34
• 10b Birman VB, Li X, Han Z. Org. Lett. 2007; 9: 37
• 10c Wei Y, Sastry GN, Zipse H. J. Am. Chem. Soc. 2008; 130: 3473
• 10d Kobayashi M, Okamoto S. Tetrahedron Lett. 2006; 47: 4347
• 11 Lei X, Wang Y, Fan E, Sun Z. Org. Lett. 2019; 21: 1484
• 12 3-Isocyano-3-phenylpropyl 4-Methylbenzenesulfonate (4a); Typical Procedure N-(3-Hydroxy-1-phenylpropyl)formamide (1.79 g, 10 mmol) and TsCl (3.81 g, 20 mmol) were added to CH₂Cl₂ (20 mL) at r.t. 2,4,6-Collidine (2.42 g, 20 mmol) was then added dropwise from a syringe, and the mixture was stirred at r.t. for 4 h. H₂O (20 mL) and CH₂Cl₂ (20 mL) were added, and the two layers were separated. The organic layer was acidified with 1 N aq HCl (10 mL), and the product was extracted with CH₂Cl₂ (×3). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel, PE–EtOAc (4:1)] to give a white oil; yield: 2.65 g (84%). ¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.3 Hz, 2 H), 7.44–7.34 (m, 5 H), 7.34–7.25 (m, 2 H), 4.84 (t, J = 7.2 Hz, 1 H), 4.32–4.17 (m, 1 H), 4.13 (dt, J = 10.4, 5.0 Hz, 1 H), 2.48 (s, 3 H), 2.29–2.11 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.6, 145.2, 136.0, 132.6, 130.0, 129.1, 128.7, 127.9, 125.8, 65.9, 54.9, 37.8, 21.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₈NO₃S: 315.0932; found: 315.0929. 2,3,4,5-Tetrahydro[1,3]diazepino[2,1-b][1,3]benzothiazole (5d); Typical Procedure A mixture of 1a (174 mg, 0.5 mmol), AIBN (8 mg, 0.05 mmol), and NCS (133 mg, 1 mmol) in DCE (3 mL) was stirred at 60 °C for 2 h under N₂. A solution of 4d (269 mg, 1 mmol) in DCE (3 mL) was added. Then, after stirring for 2 h, Et₃N (101 mg, 1.0 mmol) was added, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, PE–EtOAc (2:1, v/v)] to give an off-white solid; yield: 169 mg (83%); mp 124–125 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.50 (m, 2 H), 7.38–7.21 (m, 1 H), 7.06 (td, J = 7.9, 1.0 Hz, 1 H), 3.60 (t, J = 6.6 Hz, 4 H), 2.24–1.98 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.3, 153.3, 130.7, 125.8, 120.6, 118.6, 49.4, 25.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₃N₂S: 205.0753; found: 205.0751. 2-Phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]benzo­thiazine (5e) White solid; yield: 249 mg (89%); mp 142–143 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.30 (m, 2 H), 7.25 (ddd, J = 9.4, 6.3, 3.9 Hz, 5 H), 7.19 (dt, J = 12.1, 6.0 Hz, 2 H), 4.36 (qd, J = 8.9, 5.3 Hz, 1 H), 4.11 (q, J = 13.6 Hz, 2 H), 3.45 (t, J = 8.8 Hz, 1 H), 3.23 (dd, J = 13.6, 5.2 Hz, 1 H), 3.13 (t, J = 8.4 Hz, 1 H), 2.73 (dd, J = 13.5, 9.0 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.5, 138.6, 130.7, 129.6, 129.2, 128.4, 128.1, 127.4, 126.2 (d, J = 11.4 Hz), 66.8, 56.9, 51.4, 41.9. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₇N₂S: 281.1076; found 281.1073.