Summary of the application of boronic acid as an efficient catalytic transamidation reaction:
This article (Organic Letters2012, 14, 3202–3205) reports a catalytic amount of The simple and easily available boric acid is used to catalyze the transamidation reaction of amides and amines under solvent-free conditions. This method has been proven to be widely applicable to the reaction between various amides including primary amides, secondary amides, tertiary amides and phthalimides and various amines, and these amines include aliphatic, aromatic, Cyclic and acyclic primary and secondary amines.
Introduction to the application of boric acid as an efficient catalytic transamidation reaction:
The amide bond is one of the most important functional groups in chemistry and plays an important role in living systems. Amides are generally produced by the reaction of amines with acids and their derivatives.
In organic synthetic chemistry, transamidation is an attractive tool. However, the extremely inactive nature of the amide group prevents the transamidation from proceeding under the conditions of heating and without catalyst catalysis. . People want to use more active reagents or catalysts to allow the transamidation reaction to occur at a relatively low temperature. In order to find this more practical method, people have made great efforts. Recently, new copper- and cerium-catalyzed transamidations of amides and ureas were disclosed. However, only one method has been reported for non-metal-catalyzed transamidation. In this method, a large amount of NH2OH·HCl (50 mol%) was used. However, these three methods are limited to reactions between primary amides and most primary amines. Although boron-mediated transamidation has been reported in the literature, equivalent or even excess amounts of boron reagents are used in these reactions.
Therefore, we hope to report a very common solvent-free transamidation reaction between amines, amides and phthalimides catalyzed by boric acid to provide a better Alternatives to existing methods. Our research project is to find a new method for our total synthesis. In this process, we imagine that there should be an easily available, cheap, non-toxic and ecologically friendly boronic acid that can efficiently catalyze the transamidation reaction. .
Application results and discussion of boronic acid as an efficient catalytic transamidation reaction:
First, transamidation between aniline and acetamide The roles were selected to model the system (Table 1). Without boric acid, toluene as a solvent has completely insufficient reactivity at 140°C, so there is no reaction (Table 1, entry 1). Boric acid (10 mol%) was added to the reaction system, and transamidation occurred, but the conditions were still not strong enough (Table 1, entry 2). Therefore, in order to improve the conversion rate, a variety of different ethoxycarbonyl phenylboronic acid solvents were used for screening. We found that as reaction media, aromatic hydrocarbons such as toluene and xylene (Table 1, entries 2, 3) are significantly better than polar aprotic solvents (DMF, DMSO, Table 1, entries 4, 5) or protic solvents (Table 1, entries 6, 7). Even more gratifying is that higher conversion rates can be obtained in the absence of solvent. Satisfactorily, when water is present, there is a positive effect on the conversion rate (1-2 equiv; Table 1, entry 8). To confirm this phenomenon, we conducted two comparative experiments in which all starting materials except boric acid were mixed together (Table 1, entries 10), or only a small amount of water (1 equiv) was added (Table 1, entries 11), only trace amounts of acetamide were detected, which proves that boric acid plays a decisive catalytic role in this reaction. Finally, when the temperature was at 150°C, the conversion rate was significantly improved and the product showed no signs of deterioration (Table 1, entries 12).
With these optimized catalytic conditions, we then studied the generality of this boron-catalyzed transamidation. The results of the study are summarized in Table II. Generally speaking, the reactivity of aliphatic amines is significantly higher than that of aromatic amines, requiring shorter reaction times and lower reaction temperatures (Table 2, entries 1 vs2; 4 vs 5, 8, 9).
Just as benzylamine and phenylethylamine can The higher conversion rate is reflected in the corresponding amide, and steric hindrance seems to determine the reaction result. However, in order to achieve a higher conversion rate when secondary amines such as morpholine, piperidine, dibenzylamine, etc. participate in the reaction, , requiring a higher reaction temperature. And we found that unhindered amides (formamide, acetamide, phenylacetamide) have higher reactivity. Compared with isobutylamide (Table 2, entries 10, 11 vs 12), benzamide has lower reactivity, so the stability of its metal center is also lower, which directly reduces the catalytic efficiency of the catalyst.
It is necessary to emphasize here that most catalytic transamidation methods are limited to primary amides. In contrast, current methods are applicable to primary amides, secondary amides, and even tertiary amides. .
The high reactivity of unsubstituted formamide and benzylamine under boric acid catalytic conditions deeply attracted us. We must know that usually, N-formylation of amines is Dangerous toxic chemicals or unstable reagents (mixed formic_acetic anhydride, cyanomethyl formate, pentafluorophenyl formate, formyl fluoride) need to be used. This leads to…We went to conduct a more extensive study. We wanted to study the scope and limitations of the existing method for formylation (Table 3). We decided to further optimize the reaction between unsubstituted formamide and benzylamine. Although at 50oC, the yield is higher. When a slight excess of formamide (3 equiv) is applied, the temperature can be lowered (Table 3, entry 2) and higher yields can be achieved even without heating (Table 3, entry 3). To our delight, this reaction can be widely applied to aliphatic, aromatic polycarbonate aromatics, heteroaromatic, cyclic and acyclic primary and secondary amines. The reaction involving large sterically hindered primary amines, secondary amines and aromatic amines requires higher temperatures, but the reaction is very clean and no side reactions occur. As shown in some special cases, for example, N-methylaniline, p-methoxycarbonylaniline, p-nitroaniline, m-nitroaniline and 2-amino must also be obtained when these weaker nucleophiles participate in the reaction. Certain yields of the target N-substituted amides. Since N-formyl can serve as a protecting group and as a precursor of isocyanates, this new N-formylation method under mild conditions is very useful. The N-formylation method of amino acid esters and primary amines that has been disclosed now uses a large amount of DMF as the solvent and source of formyl groups, and then uses imidazole as the base to react at 50oC. Compared with these methods, our The method obviously has a wider range of applications, is more convenient and more environmentally friendly.
Finally, we study the boronic acid-catalyzed transamidation between primary amines and phthalimides reaction conditions (Table 4). This is a two-step reaction, with ring opening followed by ring closing, or transimination will provide an alternative method for introducing primary amine protection. The reaction between benzylamine and phthalimide without the use of a catalyst gives a mixture of compounds 5 and 6. When boric acid is used (10 mol%), the starting material is completely converted. This means that boronic acid not only catalyzes ring opening but also catalyzes ring closing. This reaction can be carried out at a lower temperature (Table 4, entry 3). For aliphatic amines (Table 4, entries 5, 6) and aromatic amines (Table 4, entry 7) with greater steric hindrance, the temperature needs to be increased.
It can be seen through experiments that boric acid can catalyze transamidation and even tertiary amides. We envision a mechanism via intermediate A (scheme 1).
Conclusion on the application of boric acid as an efficient catalytic transamidation reaction:
In summary, we have developed a new method for transamidation between amides and amines catalyzed by catalytic amounts of boric acid under solvent-free conditions. This method can be used to obtain many kinds of amides. This method has been proven to be widely applicable to the reaction between various amides, including primary amides, secondary amides, tertiary amides and phthalimides, and various amines, including aliphatic and aromatic amines. , cyclic and acyclic primary and secondary amines. Considering the economic attractiveness, simplicity of operation, and good functional group adaptability of the boric acid homogeneous catalytic system, we are convinced that this operation method has important synthetic value. Using this method, we can obtain a large number of organic compounds, including Amides, lactams, peptides, ureas, nitrogen-containing heterocycles, etc., especially for mass production.
