The regioselectivity of substrates with two nitrogen-sites available for alkylation could be also controlled by reagent ratio or choice of the alkyl halide. For instance in the reaction of uracil 17 or 7,8-dimethylalloxazine The required substrate 36 was prepared by mechanochemical condensation [ 35 ] of alloxane 34 and 4,5-dimethyl-1,2-phenylenediamine 35 in the presence of p -toluenesulfonic acid [ 36 — 37 ] Scheme 3.
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A change of the stoichiometry of reagents by milling with an equimolar amount of ethyl bromide resulted in the dominant formation of the mono-alkylated 1-ethyl product Mechanosynthesis of 7,8-dimethylalloxazine 36 and its N -alkylation. The N -alkylated phthalimides 23 and 24 , which were prepared in the previous section were employed in solvent-free Gabriel synthesis of primary amines Scheme 4. In these milling reactions, the hazardous hydrazine hydrate was replaced by 1,2-diaminoethane [ 39 ] and conversion to the corresponding benzylamines was quantitative within 1 h.
In this way, a three-step, two-pot A and B, Scheme 5 Gabriel synthesis of amines was carried out in a ball mill. The synthetically desired development of a three-step, one-pot mechanochemical Gabriel synthesis of amines could not be accomplished, as the complex reaction mixtures containing considerable amounts of various side products such as bisamide The transition-state calculations of the S N 2 reaction of imides and bromides were used to determine the activation energies. These calculations are in good accordance with the experimentally observed results and could be further rationalized by the more nucleophilic character of these two imide N1 positions in comparison to the N3 positions.
We have shown that N -alkylation of imides could be effectively carried out by ball milling, affording the products in high yields. Effective in situ preparation of potassium phthalimide and its alkylation has a potential for the application in mechanochemical Gabriel synthesis of amines. This account illustrates that organic chemists should explore the advantages of mechanosynthesis and apply this method routinely for screening of the best conditions for various organic reactions.
This work is financially supported by the Ministry of science, education and sport of the Republic of Croatia project No. We also thank to Dr. National Center for Biotechnology Information , U. Beilstein J Org Chem.
Marco Lombardo — University of Bologna — Publications
Published online Aug Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received May 3; Accepted Aug 4. This article has been cited by other articles in PMC. Abstract The mechanochemical N -alkylation of imide derivatives was studied. Keywords: ball milling, Gabriel reaction, imides, mechanochemistry, N -alkylation.
Introduction The development of environmentally friendly organic reactions is a growing area of interest [ 1 ]. Results and Discussion The reaction of the norbornene endo -succinimide 1 [ 25 ] with 1,3-dibromopropane 2 was used as a model system for the optimization of the reaction conditions [ 26 ]. Open in a separate window. Scheme 1. Table 1 N -Alkylation of imide 1 with 2.
Scheme 2. Mechanochemical N -alkylation of imide 1. Table 2 Mechanochemical N -alkylation of imide 1. Figure 1. Products of alkylation of imides 11 — Table 3 Mechanochemical N -alkylation of imides 11— Figure 2. Scheme 3. Scheme 4. Scheme 5. Three-step, two-pot Gabriel synthesis of amines in ball mill. Conclusion We have shown that N -alkylation of imides could be effectively carried out by ball milling, affording the products in high yields. Click here to view.
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Acknowledgments This work is financially supported by the Ministry of science, education and sport of the Republic of Croatia project No. Notes This article is part of the Thematic Series "Mechanochemistry".
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