The Use of Formamidine Protection for the Derivatization of Aminobenzoic Acids

Abstract

N,N-Dimethylformamidine and novel N,N-diisopropylformamidine protecting groups were used to carry out a one-pot conversion of aminobenzoic acids into the corresponding amides. General conditions for an in situ transformation of aminobenzoic acids and their heterocyclic analogues into the corresponding formamidine-protected acid chlorides were developed. These chlorides were used in reactions with amines, including poorly reactive anilines. The protected amides were then smoothly deprotected by heating with ethylenediamine derivatives, resulting in a general procedure for the one-pot transformation of aminobenzoic acids into their amides. Our one-pot procedure was successfully applied to the preparation of several compounds of pharmaceutical interest.

Design, Synthesis and Biological Evaluation of 4‐Amino‐N‐(4‐aminophenyl)benzamide Analogues of Quinoline‐Based SGI‐1027 as Inhibitors of DNA Methylation

“…4-Chloro-7-fluoroquinazoline—used to obtain 15 —was synthesized by reaction of N , N -dimethylformamide with 4-fluoro-2-aminobenzoic acid followed by intramolecular cyclization and chloration with thionyl chloride. [18]…”

“…4-Chloro-7-fluoroquinazoline-used to obtain 15-was synthesized by reaction of N,N-dimethylformamide with 4fluoro-2-aminobenzoic acid followed by intramolecular cyclization and chloration with thionyl chloride. [18] The compounds were assayed for their ability to inhibit the catalytic activity of human DNMT3A at 32 and 10 mm (Table 1), with parent compound SGI-1027 as a reference. Compound 10, where a pyridine replaces the quinoline of SGI-1027, inhibited 91 % of the enzyme activity at 32 mm, but this inhibition dramatically dropped at 10 mm (EC 50 value of 13 mm AE 1 was calculated).…”

2-Trifluoromethyl-2-Hydroxypropionamide Derivatives as Novel Reversal Agents of ABCG2 (BCRP)-Mediated Multidrug Resistance: Synthesis and Biological Evaluations

“…However, when 1,3‐Bis(trimethylsilyl)urea was not enough, a byproduct 3‐chloro‐1,1,1‐trifluoro‐2‐methyl‐3‐oxopropan‐2‐yl,3,3‐trifluoro‐2‐methyl‐2‐((trimethylsilyl)oxy) propanoate (compound 4) was synthesized. Another important intermediate 4‐amino‐3‐chloro‐ N ‐(2‐hydroxyphenyl)benzamide was prepared according to the reported procedures with slight modification [Zhichkin et al, ]. Briefly, 4‐amino‐3‐chlorobenzoic acid was simultaneously protected and activated with Vilsmeier reagent and then coupled with aniline to give 4‐amino‐3‐chloro‐ N ‐(2‐hydroxyphenyl)benzamide (compound 5) in good yield.…”

C‐Silyl‐N,N‐dialkyl‐N′‐arylformamidines: Synthesis and Reactions with Phosphorus(III) Chlorides

“…[35] Scheme 5. Synthesis of benzazaphosphole 7. and angles [°]: P-1-C-1 1.858(4), P-1-C-9 1.803(4), P-1-C-14 1.889(4), N-1-C-1 1.360 (6), N-2-C-1 1.286 (6), N-3-C-14 1.363 (5), N-4-C-14 1.288(6); C-1-P-1-C-9 87.1(2), C-1-P-1-C-14 111.3(2), C-9-P-1-C-14 107.87 (19), N-1-C-1-N-2 123.7(4), N-3-C-14-N-4 120.7 (4).…”

“…[1] They are widely used in organic synthesis and medicinal chemistry. [2,3] In organic synthesis, they are used as protective groups for primary amines [4,5] and leaving groups in transamidation reactions. [6] The functionalization of the nitrogen atoms of formamidines by heteroatomic substituents has been actively studied with a view towards the synthesis of new classes of compounds, such as N-sulfonyl- [7] and N-phosphanylformamidines.…”