Journal of the American Chemical Society integration down to 0.76 Å resolution was carried out using SAINT V7.46 A (Bruker diﬀractometer, 2009) with reﬂection spot size optimization. Absorption corrections were made with the program SADABS (Bruker diﬀractometer, 2009). The structure was solved by the direct methods procedure and reﬁned by least-squares methods against F2 by using SHELXS-97 and SHELXL-97 (Sheldrick, 2008). Non-hydrogen atoms were reﬁned anisotropically. 2-Aminothiazole (7). Mercaptoacetaldehyde 6 and cyanamide 2 (0.5−1.5 equiv) were dissolved in H2O, D2O or phosphate buﬀer (1 mL) at pH/pD 7.0. Reaction progress was monitored by the 1H NMR spectroscopy (see the Supporting Information, Figure S1). An initial concentration of 100 mM led to direct crystallization of 7 (60% isolated yield of crystals). Alternatively, upon complete conversion (by NMR spectroscopy), the solution was concentrated and 7 recovered by sublimation. Compound 7 (1−5 g) was placed in a covered beaker or Erlenmeyer ﬂask and warmed from beneath to 40 °C. Sublimate was collected on ﬂask/beaker sides and cover at ambient temperature (see Figure S4) or on a water-cooled coldﬁnger (5 °C). Crystalline 7 was isolated. IR (solid, cm−1): 3407, 3285, 3120, 3086, 1622, 1518, 1488. 1H NMR (400 MHz; DMSO): δH 6.90 (d, J = 3.7, 1H, H− (C4)), 6.84 (s, 2H, NH2), 6.51 (d, J = 3.7, 1H, H−(C5)). 13C NMR (101 MHz; DMSO): δC 169.5, 139.3, 107.1. MS ESI (pos.) 101 (100%, [M + H]+). Cambridge Crystallographic Data Centre deposition number 864225. One-Pot Synthesis of 2-Aminothiazole (7) and 2-Amino- oxazole (1). Glycolaldehyde 3 (1 equiv), mercaptoacetaldehyde 6 (1 equiv), and cyanamide 2 (0.5−5 equiv) were dissolved in H2O/D2O (1 mL) at pH/pD 7, 10 or 12, or 1 M phosphate buﬀer (1 mL) at pH/ pD 6.5−7.0. Reaction progress was monitored by the 1H NMR spectroscopy (see the Supporting Information, Figure S8−10). An initial concentration of 200 mM of 2, 3 and 6 led to direct crystallization of 15 (5−10% isolated yield of crystals). Alternatively, upon complete conversion (by NMR spectroscopy), the solution was concentrated and 7 and 1 were recovered by sublimation. Compounds 7 and 1 (1:1; 100 mg) as ﬁne powder or ﬁlm (evaporated water) were deposited in a covered glass tube (10 cm × 1 cm). A temperature gradient (40, 50, or 60 °C to ambient temperature) was set up across the tube and a mixture of crystalline thiazole 7 and oxazole 1 were isolated at ambient temperature as a deposit upon the glass wall of the tube. General Procedure for Isolation of Bis-thiazole Aminal Crystals. Aldehyde (0.49−1.0 equiv) was added to a solution of 7 in H2O at pH 7 ± 0.2. The solution was then incubated at room temperature for 5−10 d; the resultant solid was then isolated by ﬁltration or trituration and washed twice with ethanol and once with ice cold water. D-Glyceraldehyde 22/thiazole 7 crystals were then recrystallized from aqueous ethanol (10:1 H2O/EtOH). Glycolaldehyde Bis-thiazole Aminal 17. IR (solid, cm−1): 3213 (br), 2966, 2934, 2869, 1589, 1539, 1497. Cambridge Crystallographic Data Centre deposition number 864235. Glyceraldehyde Bis-thiazole Aminal 19. IR (solid, cm−1): 3326 (br), 3244, 3113, 2948, 2933, 2901, 2882, 1536, 1489. Cambridge Crystallographic Data Centre deposition number 864236. General Procedure for Multicomponent Reaction. Aldehyde (50−250 mM, 1 equiv) was added to a solution of 7 (1.1 equiv) and 5- aminoimidazole-4-carboxamide 16 (1.5−3.0 equiv) in H2O at pH 5.0 ± 0.2. The reaction was stirred under an argon atmosphere until no residual aldehyde was detectable following lyophilization and analysis by 1H NMR. The reaction was lyophilized and puriﬁed by silica gel column chromatography (CH2Cl2/MeOH, 10:0 to 6:4). The major product(s) were concentrated and recrystallized from ethanol/water or dichloromethane/methanol mixtures. 17: Yield 90% Rf = 0.25 (CH2Cl2/MeOH 7:3). IR (solid, cm−1): 3333, 3179, 2977, 2922, 2860, 1636, 1607, 1580, 1558. 1H NMR (400 MHz; D2O): δH 7.22 (s, 1H, Ar), 5.85 (d, J = 6.0, 1H, H−(C1′)), 4.18 (ddd, J = 7.8, 6.0, 4.1, 1H, H−(C2′)), 3.39 (ABX, J = 12.8, 4.1, 1H, H−(C3′)), 3.20 (ABX, J = 7.8, 1H, H−(C3′)). 1H NMR (400 MHz; DMSO): δH 7.26 (d, J = 1.1, 1H, Ar), 5.91 (d, J = 6.1, 1H, H−(C1′)), 4.29−4.25 (ddd, J = 7.0, 6.1, 3.8, 1H, H−(C2′)), 3.41 (ABX, J = 13.0, 3.8, 1H, H−(C3′)), 3.18 (ABX, J = 13.0, 7.0, 1H, H−(C3′)). 13C Article NMR (101 MHz; DMSO): δC 166.6, 161.4, 141.6, 129.4, 111.4, 79.5, 48.0, 42.2. HRMS ESI [M + Na+] calc. for C8H10N6OSNa 261.0535; obs. 261.0526. Cambridge Crystallographic Data Centre deposition number 864226. 18: Yield >85% d.r.= 2.5:1 erythro-18 (minor): Rf = 0.25 (CH2Cl2/ MeOH 7:3). IR (solid, cm−1): 3437, 3387, 3292, 3123, 2975, 2856, 1638, 1613, 1571. 1H NMR (400 MHz; DMSO): δH 7.05 (s, 1H, Ar), 6.97 (s, 2H, NH2), 6.68 (br d, J = 19.9, 2H, NH2), 5.95 (d, J = 6.4, 1H, H−(C1′)), 5.89 (s, 1H, HN), 4.54 (ddd, J = 6.4, 2.5, 1.7, 1H, H− (C2′)), 3.78 (qd, J = 6.4, 2.6, 1H, H−(C3′)), 1.25 (d, J = 6.4, 3H, H− (C4′)). 13C NMR (101 MHz; DMSO): δc 166.7, 165.2, 141.4, 128.4, 111.6, 79.4, 58.6, 46.7, 22.7. HRMS ESI [M + Na+] calc. for C9H12N6OSNa 275.0691; obs. 275.0685. Cambridge Crystallographic Data Centre deposition number 864227. threo-18 (major): Rf = 0.25 (CH2Cl2/MeOH 7:3). IR (solid, cm−1): 3391, 3302, 3103, 2972, 2865, 1651, 1621, 1582. 1H−NMR (400 MHz; DMSO): δH 7.33 (s, 1H), 6.96 (s, 1H), 6.76 (d, J = 27.2, 1H), 6.20 (s, 1H), 6.00 (d, J = 6.1, 1H), 3.85 (dd, J = 9.5, 6.3, 1H), 3.24− 3.17 (m, 1H), 1.31 (d, J = 6.2, 1H). 13C NMR (101 MHz; DMSO): δc 166.7, 159.2, 141.3, 129.7, 111.3, 79.1, 54.6, 48.9, 20.4. HRMS ESI [M + Na+] calc. for C9H12N6OSNa 275.0691; obs. 275.0686. Cambridge Crystallographic Data Centre deposition number 864228. 19: Yield >85% d.r.= 3:1 Rf = 0.25 (CH2Cl2/MeOH 7:3). threo-19 (major): IR (solid, cm−1): 3432, 3371, 3314, 3105, 2966, 2930, 1645, 1604, 1575. 1H NMR (400 MHz; DMSO): δH 7.04 (s, 1H, Ar), 6.97 (s, 2H, NH2), 6.67 (br.s, 2H, NH2), 5.95 (d, J = 6.4, 1H, H−(C1′)), 5.85 (s, 1H, NH), 4.60 (d, J = 6.3, 1H, H−(C2′)), 3.60 (t, J = 6.9, 1H, H−(C3′)), 1.74−1.63 (m, 1H, H−(C4′H)), 1.46−1.35 (m, 1H, H− (C4′H)), 0.94 (t, J = 7.3, 3H, Me). 13C NMR (101 MHz; DMSO): δc 166.8, 165.3, 141.3, 128.3, 111.6, 79.6, 56.5, 52.5, 29.8, 10.6. HRMS ESI [M + Na+] calc. for C10H14N6OSNa 289.0848; obs. 289.0851. Cambridge Crystallographic Data Centre deposition number 864229. 20: Yield >85% d.r.= 4:1 Rf = 0.2 (CH2Cl2/MeOH 7:3). threo-20 (major): IR (solid, cm−1): 3404, 3109, 2923, 2525, 2293, 1605, 1581, 1548, 1512. 1H NMR (400 MHz; DMSO): δH 6.70 (s, 1H, Ar), 5.58 (d, J = 6.4, 1H, H−(C1′)), 4.28 (dd, J = 6.3, 2.1, 1H, NH)), 2.57 (dd, J = 9.0, 2.2, 1H, H−(C2′)), 0.39 (qt, J = 8.1, 4.2, 1H, H−(C3′)), 0.18 (quintet, J = 8.7, 2H, H2−(C4′)), 0.00 (d, J = 3.9, 2H, H2−(C4″)). 13C NMR (101 MHz; DMSO): δc 164.4, 163.1, 138.8, 126.1, 109.2, 77.2, 54.9, 53.6, 15.1, 2.0, 0.0 HRMS ESI [M+Na+] calc. for C11H14N6OSNa 301.0846; obs. 301.0842. Cambridge Crystallographic Data Centre deposition number 864230. 23: Yield >75% d.r.= 1:1. erythro-23 (major): Rf = 0.25 (CH2Cl2/ MeOH 7:3). IR (solid, cm−1): 3363, 3213, 3192, 2920, 2844, 2375, 1626, 1592, 1547, 1519. 1H NMR (400 MHz; D2O): δH 7.23 (s, 1H, Ar), 5.81 (d, J = 7.5, 1H, H−(C1′)), 4.99 (dd, J = 7.5, 2.5, 1H, H− (C2′)), 3.75 (ddd, J = 2.5, 5.9, 5.2 1H, H−(C3′)), 3.53 (ABX, J = 12.5, 5.2, 1H, H−(C4′)), 3.49 (ABX, J = 12.1, 5.9, 1H, H−(C4′)). 1H NMR (400 MHz; DMSO-d6): δH 7.05 (s, 1H, Ar), 6.97 (s, 2H, CONH2), 6.66 (bs, 2H, NH2), 6.05 (s, 1H, NH), 6.02 (d, J = 6.3, 1H, H−(C1′)), 5.29 (t, J = 0.5, 1H, OH), 4.48 (d, J = 5.9, 1H, H−(C2′)), 3.78 (m, 1H, H−(C3′)), 3.60 (m, 1H, H−(C4′)), 3.27 (m, 1H, H−(C4′) partially obscured by DMSO residual solvent signal). 13C NMR (101 MHz; DMSO): δC 166.8, 165.9, 141.2, 128.3, 111.8, 80.2, 65.3, 53.6, 53.0. HRMS ESI [M + Na+] calc. for C9H12N6O2SNa 291.0640; obs. 291.0640. Cambridge Crystallographic Data Centre deposition number 864231. threo-23 (minor): Rf = 0.20 (CH2Cl2/MeOH 7:3). IR (solid, cm−1): 3330, 3212, 3111, 2950, 2926, 2853, 2394, 1631, 1568. 1H NMR (400 MHz; D2O): δH 7.35 (s, 1H, Ar), 5.98 (d, J = 5.9, 1H, H−(C1′)), 4.09 (dd, J = 7.9, 6.5, 1H, H−(C2′)), 3.80 (ABX, J = 12.0, 2.4, 1H, H− (C4′)), 3.62 (ABX, J = 11.9, 5.7, 1H, H−(C4′)), 3.45−3.41 (m, 1H, H−(C3′)). 1H NMR (400 MHz; DMSO): δH 7.31 (s, 1H, Ar), 6.99 (s, 2H, NH2), 6.76 (bd, J = 10.1, 2H, C(O)NH2), 6.35 (s, 1H, NH), 6.02 (d, J = 6.2, 1H, H−(C1′)), 5.21 (dd, J = 6.5, 4.6, 1H, HO), 3.95 (dd, J = 9.7, 6.2, 1H, H−(C2′)), 3.73 (dt, J = 11.1, 3.8, 1H, H−(C4′)), 3.46−3.41 (m, inc. J = 11.1, 1H, H−(C4′) partially obscured by H2O signal), 3.18 (m, inc. J = 7.2, 1H, H−(C3′)). 13C NMR (101 MHz; DMSO): δC 166.5, 159.2, 140.9, 129.3, 111.0, 79.0, 63.2, 54.4, 49.0. 13893 dx.doi.org/10.1021/ja306176n | J. Am. Chem. Soc. 2012, 134, 13889−13895