Promotion of Water as Solvent in Amination of 4-Chloropyrrolopyrimidines and Related Heterocycles under Acidic Conditions

A switch of reaction medium from organic solvents to water can improve the safety and lower the cost of production processes. Hydrochloric acid-promoted amination of fused pyrimidines has been studied using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and aniline as model compounds. Higher rate was observed in water than in four alcoholic solvents and DMF. An important aspect is that the amount of acid should be kept low to minimize the competing solvolysis. The substrate scope for the amination in water was evaluated by reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine with 20 aniline derivatives with variance in steric and electronic properties. Preparative useful reactions were seen for 14 of the 20 derivatives. Unsuited nucleophiles are ortho-substituted anilines with a pKa below 1. Amination of the corresponding quinazoline, thienopyrimidine, and purine also proceeded well in water. Highly lipophilic and crystalline compounds are more efficiently aminated in 2-propanol. Aliphatic and benzylic amines react poorly under acidic conditions, but these aminations can be done in water without acid.


Initial amination reactions in EtOH
To gain better understanding of the process we started by performing reactions with 4-chloro-7H-pyrrolo [2,3-d]pyrimidine (1) and aniline (2a) with varying amounts of HCl (0-5 equiv.) in EtOH.The aminations were monitored by 1 H NMR spectroscopy for 6 h, and integration of the H-2 protons, gave the mole ratio of the starting material 1, the product 3a and the sideproduct 4. Table S1 shows the conversion (%) after 1 h and the mole % of compounds after 6 h.
Table S1.Effect of HCl amount on reaction progress and formation 3a and the side-product 4.

+ HCl
Mole % after 6 h.The degree of conversion after 1 h is indicative of the initial rate of the reaction.Without acid (entry 1) the product was not detected after 1 h, showing that the amination is only slowly catalyzed by EtOH hydrogen bonding.However, as small amount of 3a and HCl is produced, the rate of this reaction is elevated.Overall, the initial rate increases with the amount of acid used, and clearly, HCl has a catalytic effect on the amination.However, at elevated levels of HCl (0.5-5 equiv., entries 3-6), the side product 4 was also produced, consuming starting material.This is explained by excess acid deactivating the aniline by protonation, which allows EtOH to be a competitive nucleophile.The levels of the side-product 4 as a function of HCl equiv.and reaction time is plotted in Figure S1.The highest concentrations were noted early in the process using 1-5 equiv. of HCl.On progression the amount of 4 decreases, showing that 4 is not just a side-product, but also a slow reacting substrate.Thus, the amount of acid should be kept low to minimize side-product formation, and in our model system 0.1 equiv.was suitable (Table S1, entry 2).

Amination of 1 with other acids
Depending on if the chemistry should be performed in an industrial or educational setting, the amination can also be performed with a cheap acid (H 2 SO 4 ) or a safer acid (acetic acid).Figure S2 compares the reaction profile of aminations with HCl, H 2 SO 4 and acetic acid.

Amination in DMF
DMF is a common solvent in nucleophilic aromatic substitution.Figure S3 compares the reaction profile in DMF, DMF/water with that in water only.

Solvent Reaction time (h)
Conv. (%) Yield Product  1 The identity of the product could not be confirmed. 2The identity 21 was confirmed by in-house made material. 4 3 esting of the experiment reported previously 5 : HCl 3 drops corresponds to approximately 1 equiv. of HCl in this setting. 4The reaction temperature was 90 °C.Compound 19 was prepared as described by Reiersølmoen et al. 6 Reaction with 2,2,2-trifluoroethyl-1-phenylamine in water and 0.1 equiv. of HCl gave a low conversion after 22 h (entry 1).Multiple products were formed, however their identity was not confirmed.Possibly, halogen exchange is occurring alongside amination, 7 and this amine is concluded to be an unsuited reactant in acid catalyzed amination.1-Phenylethylamine (entry 2) and cyclohexylmethanamine (entry 4) were as expected poor nucleophiles under these conditions.The reaction with morpholine reached a higher 61% conversion (entry 3), which is due to its lower basicity.
The morpholine and cyclohexylmethylamine derivatives 22 and 23 have previously been synthesized by Jesumoroti et al. 5 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1) was aminated in 2-PrOH using 3 equiv.of amine and conc.HCl (3 drops).We repeated these experiment, and weighting of conc.HCl indicated that the 3 drops corresponded to ca 1 equiv. of HCl in this case, which in essence means the reaction is run under basic conditions.The aminations worked (entries 5 and 8), but proceeded with higher rate if the acid was omitted, and the reactions are conducted in water (entries 6-7 and 9).Thus, acid should not be used in aromatic substitutions with aliphatic and benzylic amines.However, water can be a suitable solvent in basic amination of pyrrolopyrimidine, and the products 22 and 23 were isolated in 88 and 92% yield.The more lipophilic pyrrolopyrimidines 10 and 19 could also be aminated in water with N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine giving 24 and 25 in yields of 86% and 74%, respectively.Due to low solubility, of 19, a reaction temperature of 90 °C was used.

Figure S1 .
Figure S1.Effect of HCl equiv.and reaction time on level of the side-product 4.

Figure S2 .
Figure S2.Comparison of the reaction profile for aminations with HCl, H 2 SO 4 and acetic acid.

Figure S3 .
Figure S3.Comparison of reaction profile for reaction in DMF, DMF/water (1/1 by vol %) with pure water at 80 °C with 0.1 equiv of HCl.