Angelw: Construction of 2,5-diaminoimidazole and synthesis of Modic by one step reaction

Imidazole fragments not only exist in various natural products and drug structures, but also in histidine However, there are relatively few general synthesis methods, especially the lack of effective methods for the synthesis of 2,5-diaminoimidazole This substructure is a common fragment in many natural products, including ages 1-7 and alkaloid 8-11 (Figure 1) Among them, the former is closely related to diabetic complications, and the latter has important biological activities (picture source: angel Chem Int ed.) 2,5-diaminoimidazole is an important intermediate for the synthesis of the above natural products Recently, David A Spiegel group of Yale University developed a one-step synthesis method of imidazole (scheme 1a) based on condensation, tautomerism, [3,3] - σ rearrangement and ring deamination process, which was used in the total synthesis of age glucosepane 1 (scheme 1b) The synthesis challenge is 2, At last, aminoketone 13 and hydrazine 14 were synthesized by two steps Recently, the research group developed a method to construct 2,5-diaminoimidazole through one-step reaction and used it in the total synthesis of Modic The result was published in angelw Chem Int.ed (DOI: 10.1002 / anie 201911156) (picture source: angelw Chem Int ed.) in the previous work, the author prepared the corresponding amidohydrazide 17a / 17b through the reaction of cyclic (15a) and acyclic (15b) amino ketones with hydrazine 16, and investigated the substrate range of the reaction (Table 1) In the presence of tmscl, the author heated 17a to 130 ℃ by microwave for 16 hours, and obtained two kinds of regional isomer mixtures (imidazole 18a / 19a) Under the same conditions, 18b was obtained from 17b in 12% yield Although the expected products 18a and 18B were obtained, the reaction conditions were severe and the yield was low (image source: angelw Chem Int ed.) the author hypothesized that tmscl could cause 17 to undergo silylation and promote its tautomerism to olefin amines, which could promote [3,3] - rearrangement In order to make the reaction more effective, the author tried to reduce the demand for tmscl by introducing R2 substituent on α - n of guanidine hydrazine 20 It is assumed that the introduction of the substituent will not only change the tautomeric equilibrium, but also promote the formation of imidazole product 18 (Table 2) without the addition of additives In order to test the hypothesis, the author successfully obtained 2,5-diaminoimidazole 18a without forming the unexpected isomer 19A by treating cyclohexanone 15A with guanidine hydrazine 20A instead of PMB However, under the same conditions, the acyclic ketone 15b did not react with 20A When PMB was changed to ethyl, the reaction was similar to that of 15a and 15b The imidazole product 18C was obtained at 15a and 15b did not react It is suggested that amidylhydrazine 20 condenses with cycloaminoketone 15b to form enamine intermediate 22 However, due to the small steric hindrance of guanidine hydrazine n (α) - ethyl, guanidine may deviate from the enamine, which can not meet the conformational requirements of [3,3] - σ rearrangement (Figure 2) Based on this analysis, it is assumed that the conformational equilibrium can be shifted to the desired direction by introducing a large volume alkyl substituent at the α position Large volume substituents make the conformations 23a and 23B unstable, which is conducive to the formation of the conformation 23C needed for [3,3] - rearrangement In addition, using 3,3-dimethylbutyl substituted guanidine hydrazine 20c, the imidazole products 18C and 18D can be obtained in 63% and 58% yields of cyclic and acylamino ketone 15a and 15b, respectively (Table 2) The solvent was changed from CHCl3 to DCE, and the reaction temperature was raised to 80 ℃, the yields of the two were raised to 73% and 69%; after adding molecular sieve to the reaction, the yields of the two were further increased to 79% and 76% (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) later, the author investigated the reactivity of a variety of cyclic α - aminoketones, and discussed the effect of nitrogen atom substituents on 3-piperidone (Table 3) When the nitrogen atom contains ethyl, CBZ and BOC substituents, the corresponding imidazole products can be obtained in medium yield In accordance with the previous calculation, compounds 18G and 18h exist in the form of 1 (H) - imidazole, highlighting the importance of C5 substituents in the stabilization of 1 (H) - imidazole tautomers In addition, the o-methyl group of piperidone had little effect on the reaction Azacyclopentane 15J can yield 4 (H) - imidazole 18J in excellent yield, while bridging α - aminoketone 15K and 3-pyrrolidone 15L can not get any product, which may be caused by the existence of tension ring system in the reaction intermediate α - keto ether 15 m, β - aminoketone 15 N or cyclohexanone 15 o did not react, indicating the necessity of α - aminosubstituent in ketone substrate Next, a series of noncyclic aminoketone substrates (Table 3) were investigated by changing the substituents on aminoketone Imidazole products were obtained from piperidinyl acetone 15p, aminoacetone 15q, 15R and 15s, respectively (image source: angel Chem Int ed.) next, the author investigated the substituent range of guanidine 20 ω - N by reaction with cyclic and acyclic α - aminoketones (15a and 15b) (Table 4) Single substituted guanidine hydrazine reacted with 15a and 15b for 20d to obtain imidazole products 18t and 18u; allyl and piperidine substituted guanidine hydrazine 20E and 20f reacted with 15a and 15b to obtain imidazole products 18v-18y; guanidine hydrazine 20g reacted with 15a and 15b to obtain imidazole products 18z and 18AA, respectively (picture source: angel Chem Int ed.) total synthesis of imidazole crosslinker (Modic, 7) derived from methylglyoxal (scheme2): nucleophilic substitution of lysine 27 with Chloroacetone, deprotection to obtain aminoketone 28, rearrangement / cyclization with 20g to obtain 4 (H) - imidazole 29 Then, we use Pd / C-H 2 to remove all the protection groups to get 7-trifluoroacetate or formate The 1H and 13C NMR data are consistent with the data reported by Lederer group (picture source: angel Chem Int ed.) conclusion: David A Spiegel team has developed a method to synthesize 2,5-diaminoimidazole from α - aminoketone and guanidine hydrazine under mild conditions without additives The method is characterized by that the alkylamine in guanidine makes the in-situ generated enamine easily [3,3] - σ rearrangement / cyclization In addition, the author has completed the first full synthesis of Modic, which provides a useful tool for the study of its role in the biological process, and also provides potential therapeutic interventions for diseases related to the formation of Modic.