A Novel Synthesis of the 2-Aminoimidazol-4-carbaldehyde Derivatives, Versatile Synthetic Intermediates for 2-Aminoimidazole Alkaloids

Abstract

The title synthesis was achieved by the reaction of t-but­oxycarbonylguanidine with 3-bromo-1,1-dimethoxypropan-2-one as a key step. Starting with 1-tert-butoxycarbonyl-2-tert-butoxycarbonylaminoimidazol-4-carbaldehyde thus obtained expeditious synthesis of oroidin, hymenidin, dispacamide and monobromodispacamide, the representative 2-aminoimidazole alkaloids, was accomplished.

Key words

2-aminoimidazol-4-carbaldehydes - alkaloids - cyclizations - total synthesis - heterocycles

References and Notes

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7

Physical and spectral data of the representative compounds. Compound 11: amorphous solid. IR (KBr): 3295, 1686, 1625, 1113, 1052 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.02 (s, 3 H, Ac), 3.18 (s, 6 H, OMe), 5.24 [s, 1 H, CH(OMe)₂], 6.65 (s, 1 H, 4-CH), 11.08 (br s, 1 H, NHAc), 11.40 (br s, 1 H, 1-NH). LRMS (EI⁺): m/z = 199 [M⁺], 168, 126, 96. HRMS (EI⁺): m/z calcd for C₈H₁₃N₃O₃: 199.0957; found: 199.0947. Compound 14a: mp 134-136 °C (EtOAc). IR (KBr): 3463, 1740, 1637, 1342, 1121, 1060 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.59 (s, 9 H, t-Bu), 3.37 (s, 6 H, OMe), 5.27 [d, J = 1.2 Hz, 1 H, CH(OMe)₂], 5.56 (br s, 2 H, NH₂), 6.86 (d, J = 1.2 Hz, 1 H, 4-CH). ¹³C NMR (400 MHz, CDCl₃): δ = 28.0, 52.7, 85.0, 99.4, 109.3, 135.6, 149.4, 150.6. LRMS (EI⁺): m/z = 257 [M⁺], 226, 125, 96. Anal. Calcd for C₁₁H₁₉N₃O₄: C, 51.35; H, 7.44; N, 16.33. Found: C, 51.20; H, 7.33; N, 16.36. Compound 16: mp 156-158 °C (hexane-EtOAc). IR (KBr): 3417, 1736, 1640, 1372, 1358, 1127 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.57 (s, 9 H, t-Bu), 6.58 (br s, 2 H, NH₂), 7.21 (t, J = 7.3 Hz, 1 H, Ph), 7.33 (t, J = 7.3 Hz, 2 H, Ph), 7.33 (s, 1 H, 4-CH), 7.71 (d, J = 7.3 Hz, 2 H, Ph). ¹³C NMR (400 MHz, CDCl₃): δ = 28.0, 85.1, 106.1, 125.0, 127.3, 128.5, 133.2, 137.7, 149.4, 150.8. LRMS (EI⁺): m/z = 259 [M⁺], 203, 159. Anal. Calcd for C₁₄H₁₇N₃O₂: C, 64.85; H, 6.61; N, 16.21. Found: C, 64.72; H, 6.57; N, 16.21. Compound 18a: mp 155-157 °C (dec.) (hexane-EtOAc). IR (KBr): 3409, 1711, 1648, 1604, 1170 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.58 (s, 9 H, t-Bu), 7.49 (s, 1 H, 4-CH), 9.59 (s, 1 H, CHO). ¹³C NMR (400 MHz, CDCl₃): δ = 28.2, 82.6, 128.8, 137.6, 147.7, 153.1, 176.9. LRMS (EI⁺): m/z = 211 [M⁺], 155, 111. Anal. Calcd for C₉H₁₃N₃O₃: C, 51.18; H, 6.20; N, 19.89. Found: C, 51.07; H, 6.11; N, 19.93. Compound 19a: mp 112-114 °C (hexane-EtOAc). IR (KBr): 1755, 1697, 1532, 1305, 1152 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.55 (s, 9 H, t-Bu), 1.64 (s, 9 H, t-Bu), 7.70 (s, 1 H, 4-CH), 9.10 (br s, 1 H, BocNH), 9.92 (s, 1 H, CHO). ¹³C NMR (400 MHz, CDCl₃): δ = 27.8, 28.1, 82.5, 88.5, 117.2, 138.1, 142.8, 148.7, 149.6, 187.2. LRMS (EI⁺): m/z = 311 [M⁺], 211, 155, 111. Anal. Calcd for C₁₄H₂₁N₃O₅: C, 54.01; H, 6.80; N, 13.50. Found: C, 53.76; H, 6.63; N, 13.70.

8

The reaction was continued until complete consumption of the starting material was ascertained by TLC analysis.

10

The crystallographic data was deposited at the Cambridge Crystallographic Data Centre. The deposition number is CCDC 605791.

11

When the reaction of 15 and 12a was examined in THF at 50 °C for 3 h (see below), 16 was obtained as an almost sole product in 68% yield along with a trace amount of 17.

12

To a solution of 12a (478 mg, 3.0 mmol) in anhyd THF (3 mL) was added a solution of 10 (197 mg, 1.0 mmol) in anhyd THF (2 mL) under an argon atmosphere. After heating at 50 °C for 6 h, the solvent was removed in vacuo. Purification of the residue by column chromatography (SiO₂, EtOAc) afforded 14a as a colorless solid (159 mg, 62%). An analytical sample of 14a was prepared by recrystallization from EtOAc.

13

We subjected 18a to tritylation, acetylation, triisopropyl-silylation and methoxymethylation under the standard reaction conditions. Although formation of the desired compounds corresponding to 19a was observed in tritylation, acetylation and triisopropylsilylation, these products were found to be too unstable to be isolated in pure states. In the case of methoxymethylation, a complex mixture was obtained as the reaction product.

16

Mp 218-220 °C (dec.) [Lit.⁶ 202-205 °C (dec.)].

18

Amorphous solid (Lit.¹⁹ amorphous solid).

22

¹H NMR spectra of 3 and 4 synthesized by us clearly showed that both samples were contaminated by small amounts of the unnatural Z isomers (ca. 5%).