Compound 8b

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Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

Formation of aminal 8b from dihydroxyacetone (2q) and 2-aminothiazole (7): 2-Aminothiazole (7) was added to a solution of dihydroxyacetone (2q) in water (1 mL, pH 7) or sodium phosphate buffer (1M, pH 7, 1 mL) and stirred at room temperature. The reaction was diluted with DMSO (5 mL) after the specified time (Supplementary Table 6). An aliquot (100 µL) was diluted with DMSO-d₆ (0.6 mL) and ¹H NMR spectra acquired. The formation of aminal 8b was quantified using 1,3,5-trimethoxybenzene as an internal standard (Supplementary Table 6).

Chemoselective one-pot aminal 8b formation from the reaction of dihydroxyacetone (2q), β-mercaptoacetaldehyde (9a) and cyanamide (3): β-Mercaptoacetaldehyde (9a; 1.52 g, 20 mmol) and cyanamide (3; 0.84 g, 20 mmol) were added to sodium phosphate buffer (1M, pH 7, 4 mL). The solution was adjusted to pH 7 with HCl (33 wt %), followed by addition of dihydroxyacetone (2q; 900 mg, 10 mmol) in sodium phosphate buffer (1M, pH 7, 4 mL). The solution was adjusted from pH 6.6 to pH 7.0 using NaOH (4M), and the volume increased to 10 mL with sodium phosphate buffer (1M, pH 7). The stirred hetereogenous mixture was observed to become a homogenous solution within 1 h. The reaction mixture was split into 10 × 1 mL portions. After 1.5 h an aliquot (1 mL) was spiked with D₂O (100 µL), NMR spectra were acquired and the formation of 2-aminothiazole (7; Supplementary Figure 25A) was observed. Conversion of 9a to 7 was complete after 5 h (Supplementary Figure 25B). Further aliquots were quenched after 2, 4, 7 and 14 d by addition of DMSO (6 mL) containing 1,3,5-trimethoxybenzene as an internal standard. Each aliquot was further diluted with DMSO-d₆ and NMR spectra acquired. The formation of aminal 8b was quantified by ¹H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard (Supplementary Figure 25 and Supplementary Table 9).

Synthesised on a preparative scale according to the general procedure outlined in 8. ¹H NMR (600 MHz, DMSO-d₆) δ 7.84 (d, J = 7.6 Hz, 1H, NH), 7.71 (d, J = 7.6 Hz, 1H, NH), 7.03 (d, J = 3.5 Hz, 1H, Ar), 7.02 (d, J = 3.5 Hz, 1H, Ar), 6.64 (d, J = 3.5 Hz, 2H, Ar), 5.41 (td, J = 7.6, 3.9 Hz, 1H, OH), 5.30 (d, J = 5.6 Hz, 1H, (C1')–H), 4.89 (br. s., 1H, OH), 3.77 (qn, J = 5.6 Hz, 1H, (C2')–H), 3.40 (m, 2H, (C3')–H₂). ¹H NMR (600 MHz, DMSO-d₆ + D₂O) δ 7.02 (d, J = 3.7 Hz, 1H, Ar), 7.01 (d, J = 3.7 Hz, 1H, Ar), 6.64 (d, J = 3.7 Hz, 2H, Ar), 5.38 (d, J = 4.0 Hz, 1H, (C1')–H), 3.78 (td, J = 5.8, 4.0 Hz, 1H, (C2')–H), 3.42 (dd, J = 11.2, 5.8, 1H, (C3')–H), 3.38 (dd, J = 11.2, 5.8, 1H, (C3')–H). ¹³C NMR (151 MHz, DMSO-d₆) δ 168.9^*, 168.3^*, 138.8^*, 138.7^*, 107.9^*, 107.8^*, 72.9, 67.1, 62.6 (^*diastereotopic resonance). HRMS ESI [M + H]⁺ cal. for C₉H₁₃N₄O₂S₂ 273.0474; obs. 273.0475. IR (solid, cm^–1): 3325, 3242, 3190, 3113, 2991, 2966, 2899, 1537, 1508, 1465. M.p. 123–126 °C (decomp.). Single crystal X-ray structures: rac-8b, CCD 1477045, (Supplementary Figure 153); D-8b, CCD 1477041, (Supplementary Figure 154); L-8b, CCD 1477042, (Supplementary Figure 155)