Aminomethylation reactions of nitrogen and sulfur five membered heterocyclic compounds \If

Five membered nitrogen and sulfur heterocyclic compounds such as isatins, benzimidazole, benzimidazolin-2-thi one, bcnzoxazoli none- 2, bcnzoxazoli n-2-th ione, henzotriazole, benzoth iazoli n-2 -th ione, 1 ,3,4-oxadiazoli n-5-thione and 1,2,4-triazolin-5-thiones have been prepared and subjected to aminomethylation reactions in pres ence of formaldehyde and amines. Secondary as well as primary aromatic amines bearing different substituents have been successfully utilized in the aminomcthylation reaction. The aminomethylated products have been tested for antibacterial, antifungal, antiviral, anticancer, antileishmanial and antifilarial activity. A number of such products have exhibited promising antifungal and antileishmanial activities. and sulfur five membered heterocyclic com pounds active hydrogen atom to nitrogen


4-Chloroisatin 70%
pH 4.5 The isomeric mixture 5 of 4 and 6 ch\oro isatins was dissolved in N/2 NaOH. The solution was filtered. To the filtrate N/2 HCl was gradually added. As the pH dropped below 8 precipitation of 4-chloroisatin commenced which was completed at pH 4. 5 be due to extensive sulfonation of the aromatic ring due to strong activating influence of methoxy group. With a view to moderating the electron donating influence of methoxy group to a considerable extent a bromine/chlorine atom has now been introduced at position-3 of panisidine and position-4 of m-anisidine. The 3-bromo/ chloro-4-methoxy and 4-bromo/ch !oro-3-methox y anilines, thus obtained, were converted to the corresponding isonitrosoacetanilides, which underwent smooth cyclization in cone. sulphuric acid furnishing the mixtures of isomeric pairs consisting of 4-bromo/chloro-5methoxy-, 6-bromo/chloro-5-methoxy-and 5-bromo/ chloro-4-methoxy-, 5-bromo/ch loro-6-methoxy-isatins in 80-85% yields. Thus, mild electron withdrawing or mild electron donating groups give isatins in excellent yields and strong electron donating groups have to be suitably moderated in order to obtain better results (Scheme 4).
During dissolution of isomeric pairs of 4-and 6-substituted isatins in sodium hydroxide solution, the isatin ring opens up resulting in the formation of the sodium salt of the corresponding isatinic acid which on acidification with HCl immediately cyclizes back to isatin (Scheme 4).  The isatinic acid anion corresponding to the 4-substituted isatin is a relatively strong conjugate base, and, therefore, more inclined to accept a proton. It stabilizes at pH 8.0 or above. The lowering of pH value below 8.0 destabilizes the isatinic acid anion resulting in the liberation of isatinic acid which, immediately gets transformed into the 4-substituted isatin. The continuous removal of isatinic acid in the form of 4-substituted isatin prevents the establishment of isatinic acid anion!isatinic acid equilibrium resulting in almost total conversion of isatinic acid anion to the 4-substituted isatin as the pH is progressively brought down to 4.5. The isatinic acid anion corresponding to the 6-substituted isatin is a relatively weak conjugate base and, therefore, less inclined to accept a proton. It continues to remain stable at pH as low as 4.0. The anion gets destabilized when the pH value is lowered below 4.0 leading to the formation of the corresponding isatinic acid which immediately undergoes cyclisation yielding the 6-substituted isatin. The precipitation is complete as the pH is brought down to 2.0.

¢' -~
It is obvious that the precipitation of 4-and 6-substituted isatins from alkaline solution of their isomeric mixtures over widely differing pH values affords a novel and efficient method for their separation. The method, indeed is of wide applicability as it can be used to separate iso-meric binary mixtures of organic acids with a marked difference in their relative acidity. This has been experimentally verified by effecting the separation of ochlorobenzoic acid and p-chlorobenzoic acid from the alkaline solution of their mixtures. As expected the pchlorobenzoic acid, being relatively week acid, precipitated out at a higher pH while the o-chlorobenzoic acid separated out at a lower pH value.
The substituents at 4/6 position of isatin acquire positions ortho!para to the carbonyl group in the conesponding isatinic acid, respectively. The acidity of isatinic acids is determined to a large extent by the proximity of the carbonyl group to the carboxylic group. The relative acidity of an isatinic acid with a substituent ortho to the carbonyl group is apparently less than its isomer with substituent para to the carbonyl group. This is in contrast to the substituted aromatic acids where the orthosubstituted acids are invariably stronger than their paraisomers.
The relative proximity of the substituent ortho to the carbonyl group, greatly reduces ·its inductive effect, thus rendering the isatinic acid relatively week. The substituent para to the carbonyl group, on the other hand, exerts its inductive effect in a normal manner, thereby making the isatinic acid relatively strong. Aminomcthylation of 4-bromo-5-rncthox.yisati 11 and 6-bromo-5mctbox.yisatin 630 isati ns 6 ( 19) thus separated in a pure state were aminomethylated with morpholine in the presence of formalin to yield corresponding !-ami nomethylated products (20,21).
It is interesting to note that the is<itin N-Mannich bases appeared to be more promising as antiviral agents. Next a series of 4-arylthiosemicarbazides were prepared and condensed with isatins in acidic medium. The 3-arylthiosemicarbazono-2-indolinones thus prepared were then treated with formalin and secondary amines leading to aminomethylated-2-indolinones (28).
A number of benzoyl hydrazines, anilino-acetyl hydrazines and phenoxy acetyl hydrazines were prepared by the standard procedures. These hydrazine derivatives were then condensed with isatins as nucleophilesl4-17. The products obtained after condensation were subjected to a1ninomethylation reactions. The aminomethylated products were obtained in excellent yields (32)(33)(34)41) compound (39) was prepared via a number of steps starting from (35) as indicated in the Scheme 5.

Aminomethylation of benzimidazole
Benzimidazole(s) (48) contain an active hydrogen atom attached to nitrogen which can be easily replaced by an aminomethyl group 18 -22 (49) in the presence of formalin and an amine. Many benzimidazoles arc available commercially. If desired they arc easily prepared from appropriately substituted o-phcnylcnc diamine (47) and formic acid. One can also take acetic acid in place of formic acid to get 2 methylbenzimidazolc. Thus by taking appropriate carboxylic acid one can get appropriately 2-substituted benzimidazoles. 2-Substitutents in benzimidazole bulkier l!CS-2

Aminomethylation of benzimidazolin-2-thione
Benzimidazolin-2-thione (55) unlike benzimidazole has two active hydrogen atoms attached to each nitrogen. Both these hydrogens have been replaced with aminomethyl groups 23 -26 (57) in the presence of formalin and an amine. Secondary as well as primary aromatic

Aminomethylation of benzoxazolinone-2
Benzoxazolinone-2 (61) is one of the versatile five membered heterocyclic system which undergoes aminomethylation with ease. In order to prepare benzoxazolinone-2, o-aminophenol and urea are fused 28 together at elevated temperature. The crude product is repeatedly recrystallized from water to get pure material.

632
During fusion with urea considerable decomposition takes place resulting in the lower yields of the material. We have developed a preparative method for benzoxazolinone-2. In this procedure o-aminophenol and urea are heated in dry pryridine. After pyridine is distilled off the residue is poured into water thereby pure benzoxazolinone-2 is obtained in high yields 29 . Aminomethylation of benzoxazolinone-2 has been done in ethanolic medium in the presence of formalin and an amine. Different types of amines have been utilized to obtained the required amino methylated products 30 -4

Aminomethylation of benzoxazolin-2-thione
Next we have taken a closely related system benzoxazolin-2-thione (64) to be studied for amino-methylation reaction. Its method of preparation is described in organic synthesis 41 . The procedure involves treatment of o-aminophenol (63) with potassium ethylxanthate in ethanol followed by acidification of the reaction mixture with acetic acid. The benzoxazolin-2-thione (64) thus obtained has been treated with formalin and amines. The reaction takes place both with secondary as well as with primary aromatic amines 42 -4 4 (69) (Scheme 9).

Aminomethylation of benzotriazole
Benzotriazole, a five membered heterocyclic system with three nitrogen atoms at 1.2,3 positions contains an active hydrogen atom attached to nitrogen atom. It was subjected to aminomethy1ation reaction 45  benzotriazoles (72) can also be obtained by treating l-hydroxymethylbenzotriazole46 (71) with primary aromatic amines, when 1-dimethylaminomethylbenzotriazole (73) was treated with aniline, the dimethylamino group got displaced with aniline (Scheme 10).

Microwave mediated aminomethylation
Microwave mediated synthesis of heterocyclic compounds have attracted more attention of chemists because of shorter reaction time, simple reaction conditions, higher yields and purer products. Many reactions like oxidation, reduction, alkylation, 0-benzylation, hydrazinolysis, esterification, aromatic substitution and decarboxylation proceed smoothly under microwave conditions. Aminomethylation 57 was the further addition to the microwave mediated reactions.

Mechanism of aminomethylation reaction
The aminomethylation reaction 61 -6 7 is believed to tak.-: place in two steps. Initially the amine reacts with formaldehyde to generate an aminomethylol (A). The aminomethylol (A) then reacts with active hydrogen containing substrate [say for instance benzoxazolinone-2 (B)] to furnish amino methylated product (C).
Antileishmanial activity against
Aminomethylated compounds showing promising antifungal and antileishmanial activity are listed in Tables 1  and 2. I.