Pyrimidine ring is a common heterocyclic structure in chemical drug molecules, such as trimethoprim, sulfamethoxypyrimidine, Rettger Wei and so on. At the same time, some important bioactive molecular structures (such as ribonucleotides) all contain pyrimidine ring structural units. Taking the ammonolysis reaction (amino substitution reaction) of 2,4(6)- dihalopyrimidine and its derivatives as an example, this paper discusses the reactivity of 2- halogen atoms with 4 (6)-halogen atoms according to the theoretical knowledge in books and literature examples.
Chemistry of heterocyclic compounds. Volume 52. Pyrimides, page 37 1~372, chapter 6.7.2, the simple ammonolysis of 2- or 4/6- halogenated pyrimidine is related: ammonolysis of active halogenated pyrimidine is one of the most commonly used and important reactions in pyrimidine chemistry. The factors that determine this selectivity are: 1, the type of halogen substituent (f, Cl, Br, i), 2, the position of halogen substituent, 3, the properties of other substituents except halogen on pyrimidine ring, 4, the properties of amine that reacts with halogenated pyrimidine derivatives, 5, the spatial factors related to two reactants (halogenated pyrimidine derivatives and amine), 6. Without detailed kinetic data, we can draw the following conclusions: under the condition of 1, all other factors being the same, the ammonolysis reaction rate of halogenated pyrimidine containing Cl, Br and I substituents is almost the same, while that of halogenated pyrimidine containing F substituent is 60~200 times faster, and that of halogen substituent at 2,4-position or 6- position is faster than that of halogen at 2- position. 3. If the electronic substituents (such as Me, OMe, NMe2, etc. ) is brought to the pyrimidine ring, the ammonolysis rate will decrease; If electron-withdrawing substituents (such as CF3, NO2, etc. ) to the pyrimidine ring, the ammonolysis speed will be greatly accelerated; 4. In the ammonolysis reaction involving n- alkylamines, the reaction rate is not affected by the length of alkyl chains, such as branched alkyl chains and γ-.
Generally speaking, when 2,4 (6)-dihalopyrimidine undergoes aromatic nucleophilic substitution reaction, the activity of halogen substituent at position 4/6 is stronger than that at position 2. Usually, the aromatic nucleophilic substitution reaction of 2,4(6)- dihalopyrimidine produces the 4 (6)-position substitution product, but this does not mean that the halogen substituent at the 4/6- position takes precedence over that at the 2- position.
Pfizer global R&D department (Pfizer global r&; D)Daniel T. Richter, John C. Kath, Michael J. Luzzio, Nandell Keene, Martin A. Berliner and Matthew D. Wessel published relevant research contents in Tetrahedral Express on 20 13. Lewis acid-induced selective addition of amines to 5- trifluoromethyl-2,4-dichloropyrimidine? (doi:10.10/6/j tetlet.2013.06.025), the ammonolysis reaction of 2,4-dihalopyrimidine containing 5-CF3 was studied in this paper. See figure 65438.
At first, when the author studied a series of ammonolysis reactions of 2,4- dichloropyrimidine compounds, he found that in a series of ammonolysis reactions of 5- trifluoromethyl-2,4-dichloropyrimidine, the products were a group of mixtures with a ratio close to 1: 1, which were 2-substituted products and 4-substituted products respectively, while there were other substituents at the 5-position. The author studied this interesting phenomenon, hoping to find a synthetic method of 2- selective amine substitution products of 5- trifluoromethyl-2,4-dichloropyrimidine, because the original method obtained a mixture with the ratio of two isomers close to 1: 1, and the separation was difficult, so it was necessary to use reverse preparative HPLC for separation, and the final separation yield was less than 50%.
At the beginning of the study, the author took the reaction of 5- trifluoromethyl-2,4- dichloropyrimidine with 4-methylaniline as the research object, and studied the effects of temperature and solvent on the reaction selectivity. The results show that the adjustment of temperature only affects the reaction time, but has no effect on the selectivity. When various drying solvents (such as dried THF, dried DCM, etc.) are changed, the reaction selectivity remains unchanged. Then, the author studied the influence of protonic acid, because protonic acid (such as HCl and AcOH) can protonate N atom on pyrimidine ring, which may change the reactivity of substrate 5- trifluoromethyl-2,4-dichloropyrimidine. However, it was found that the solubility of 5- trifluoromethyl-2,4-dichloropyrimidine in various solvents decreased after protonation, which eventually slowed down the ammonolysis reaction. It is speculated that if the protonic acid is replaced by Lewis acid, the reactivity of the substrate 5- trifluoromethyl-2,4-dichloropyrimidine may change, because Lewis acid has the ability to coordinate with pyrimidine N atom.
Next, the author analyzed 18 Lewis acids (ZnCl2, Zn(OAc)2, BF3? –Et2O，
Mg (OTF) 2, MgCl2, MgBr2, CuCl, CuCl2, SNCl2, SNCl4, LiCl, lioac, AgNO3, Agotf, TiCl4, etalcl2, Dip-Cl, Bcl3) were tested (THF, RT,1.63). 1. 1 equivalent of tea, 1.0 equivalent of 4- methylaniline), the results showed that Lewis acid improved the regioselectivity of the reaction, among which zinc salts (ZnCl2, zinc (oac) 2) had the best effect, followed by AgOTf and CuCl2, and ZnCl2 had the strongest effect of substituting the 2-isomer.
Further research shows that the selectivity of other anilines, including electron-donating substituent (EDG) and electron-withdrawing substituent (EWG), has been improved except for p-toluidine. The experimental results are shown in Table 2, but at the same time, some aniline did not show good selectivity. For example, in the reaction in which p-anisidine participates under the action of 1.0 equivalent of ZnCl2, the ratio of 2-substituted products to 4-substituted products is 8: 1, but the selectivity of o-methoxyaniline is almost unchanged, and the products are almost equivalent isomers. The author suspects that the chelation between o-methoxyaniline and zinc chloride may lead to invalid coordination between 2- substituted products and 4- substituted products. When the amount of ZnCl2 _ 2 is increased to 2.0 equivalents, the ratio of 2- substituted products to 4- substituted products will increase. The author suspects that the original complex with ZnCl _ 2 will decompose when using 2.0 equivalents of ZnCl _ 2 (but the author does not give any explanation).
Before further study on the reaction mechanism, it was always thought that the coordination between Lewis acid ZnCl _ 2 and pyrimidine ring led to the change of reaction selectivity, but later research was surprised to find that ZnCl _ 2- pyrimidine complex was not detected. In the previous experiment, zinc chloride was mixed with 5- trifluoromethyl-2,4-dichloropyrimidine before adding amine. The author found that precipitation appeared in the reaction system after adding amine, so the author speculated that ZnCl _ 2 might form a complex with amine instead of pyrimidine ring. Because zinc can coordinate with two N atoms, it can be expected that this selectivity can be seen when Lewis acid ZnCl _ 2 is less than 1 equivalent, which has been proved to be correct. When the amount of zinc chloride is further reduced to 0.25 equivalent, the best selectivity will be obtained.
Under the above optimized experimental conditions, the author tested other 2,4-dichloropyrimidine derivatives, but the results were different from those of 5- trifluoromethyl-2,4-dichloropyrimidine. See table 1 for the experimental results.
In a word, when 2,4 (6)-dihalopyrimidine derivatives undergo aromatic nucleophilic substitution reaction, the reaction site does not always occur at the 4/6 position, and different compounds may produce different results.
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