Abstract
Using N, N-dimethylformamide dialkyl acetal as alkyl source, different N-alkylation reactions of compounds containing N-H. By studying the effects of solvent, temperature, reaction time, N, N-dimethylformamide dialkyl acetal dosage and other factors on the reaction, the optimal reaction conditions were obtained, and then the effects of different N, N-dimethylformamide dialkyl acetals on the alkylation ability of the substrate were investigated. The reaction has the advantages of simple raw materials, simple operation, mild reaction conditions, good substrate universality and no metal participation.
Compounds containing N are a class of very important intermediates in organic synthesis, and the alkylation of nitrogen atoms in compounds containing N-H is an important way to synthesize these compounds. The most commonly used alkylation reagents for the alkylation of nitrogen atoms in compounds containing N-H include halogenated hydrocarbons, sulfates, sulfonates, aldodes, etc. The method of halogenated hydrocarbons as alkylation reagents is that the nitrogen negative ion intermediates formed by the substrate and strong bases (sodium carbonate, n-butyl lithium, sodium tert-butyl oxide, etc.) at low temperature carry out nucleophilic attack on halogenated hydrocarbons to generate alkane-substituted products. However, this method has harsh reaction conditions, cumbersome operation, and produces inorganic salt by-products that pollute the environment. Sulfate esters (such as dimethyl sulfate, diethyl sulfate, etc.) are a class of active alkylation reagents that can be alkylated under milder conditions, but their toxicity is relatively large and carcinogenic, thus limiting their industrial application. The method of using aldose as an N-alkylation agent is to undergo a reductive amination reaction with an amine substrate. Although this kind of reaction has a wide range of uses, it is easy to produce by-products, which is not conducive to post-processing. Other uncommon N-alkylation methods include alcohols, amides, etc. Amide compounds generally undergo self-alkylation under the condition of strong reducing agents. Alcohols are difficult to react with substrates, but under the action of metal catalysts and oxidants, alcohols are first oxidized to alaldehyde, which then reacts with amine substrates. Due to the high requirements for catalysts, the application of such reactions is limited.
Since N, N-dimethylformamide dialkyl acetals have been reported, they have become important intermediates in organic synthesis due to the diversity of chemical reactions they participate in. N, N-dimethylformamide dialkyl acetals are prepared from N, N-dimethylformamide (DMF) as raw materials, with low economic cost. N, N-dimethylformamide dialkyl acetals are weakly basic and will decompose into DMF and corresponding alkyl alcohols in contact with water. This property makes them have a certain promotion effect on alkylation reaction, and do not need to contain metal bases to participate in the reaction, and the post-treatment is simple. So far, studies on N, N-dimethylformamide dialkyl acetals have mainly focused on condensation reactions on active hydrogen, pyrimidine ring synthesis, carboxylic acid esterification reactions and amide alkylation. Tewoderos et al. studied the reaction of 8-alkoxy adenosine and guanosine with N, N-dimethylformamide dialkyl acetals (Eq.1), which can be efficiently converted into N-alkylation products, but its substrates actually belong to amide compounds. The amide part of such compounds will isomerize into an enol structure. The hydroxyl groups in the enol structure are more active and preferentially combine with acetals to form oxygen anion intermediates. Due to the small pKa value of hydrogen atoms in N-H heterocyclic compounds and their acidic nature, such alkylating agents are rarely studied in N-alkylation reactions. Therefore, it is of certain academic value to carry out new N-alkylation reactions of N, N-dimethylformamide dialkyl acetals. Here, we report a series of N, N-dimethylformamide dialkyl acetals as alkyl sources for N-H heterocyclic compounds without metal participation.
Optimization of reaction conditions
Imidazole is a very important heterocyclic compound containing N-H, which is an important raw material for medicine and pesticides. We first optimized the reaction conditions with imidazole as the substrate (Table 1). Using 1.5 equiv. N, N-dimethylformamide dimethyl acetal (DMFDMA) as an alkylating agent at a temperature of 50 ° C, the effect of different solvents on the methylation of imidazole nitrogen atoms was explored. When using less polar solvents such as n-hexane and toluene, the yield is low (Entries 3, 5, Table 1), while when using more polar solvents such as 1,4-dioxane and DMF, the product can be successfully obtained at a yield of 50% to 65% (Entries 4, 8, Table 1), and the effect is best when using DMF as the solvent. Therefore, DMF was used as the solvent to continue to optimize, and it was found that 90 ° C was the more suitable reaction temperature, and increasing the temperature would reduce the yield (Entry 11, Table 1). When the temperature was reduced to below 50 ° C, the reaction basically did not occur (Entry 7, Table 1). When adjusting the ratio of N, N-dimethylformamide dimethyl acetal to 4 equiv., the methylation reaction is very suitable, and the yield is 91% (Entry 13, Table 1). Continuing to increase the amount of N, N-dimethylformamide dimethyl acetal has no significant effect on improving the yield (Entry 14, Table 1). The more appropriate time for the reaction is 4 h. Shortening the reaction time will reduce the yield (Entry 16, Table 1), and prolonging the reaction time will not increase the yield (Entry 17, Table 1).
| Solvent | Yield (%) |
|---|---|
| n-hexane | low |
| toluene | low |
| 1,4-dioxane | 50-65 |
| DMF | highest |
Source: Chin. J. Org. Chem. 2019, 39, 434~ 442
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