The Versatility of Mannich Reaction: An Overview

- One of the most significant processes for creating carbon-carbon bonds in organic synthesis is the Mannich reaction. It offers amino carbonyl compounds, crucial synthetic building blocks for many medicines. This Mannich bases are made by combining primary and/or secondary amines, formaldehyde, and active hydrogen molecules. Among those that are active hydrogen compounds include an acid, phenol, ketone, amide, etc. contribution involved the synthesis of 3,5 dimethyl carboxamide using a number of biologically active sulphonamides, which was followed by analysis of elements and spectrum analyses techniques using, IR, UV and 1HNMR. Escherichia coli, Staphylococcus aureus, and Bacillus subtilis were among the pathogenic microorganisms tested for the compounds’ antibacterial efficacy at different doses. We examined the bactericidal effectiveness of parent sulphonamides and derived Mannish bases. To establish whether synthetic Mannish bases were dangerous, the LD50 test was utilised.


Introduction
The average life span has increased significantly as a result of therapeutic medications.Natural ingredients have been utilised for a very long time to create medicines that are used to cure human illnesses.According to Joshi S. et al. [1], many modern medications are enhanced versions of traditional ones that have been altered to make patients feel better.As a result of multiple reactions, a range of therapeutic agents produce superior outcomes and have symbolic properties that can lead to the synthesis of new chemical entities.The Mannich reaction, among well-known reactions, has been significant because of its numerous uses, particularly in medicinal chemistry.For many years, the Mannich reaction has been a crucial method for obtaining molecules with various pharmacological characteristics [2 -5].

The quick growth of research in this area.
Because of its extensive relevance to organic synthesis, the, and Chemical industry professionals can benefit from Mannich reactions.numerous reviews have been published [6 -10].Pharmaceutical research continues to benefit the most from the Mannich reaction [11 -15], industrial [16,17], and macromolecular [18] chemistry, among other domains.It has been discovered that the Mannich Bases have significant applications in the creation of a variety of additives and auxiliaries, as well as polymeric materials, resin, and particularly surface coating materials.They are also employed in the creation of water treatment chemicals [19].
In the current study, we created Mannich Bases, which have significant therapeutic value, using a variety of active hydrogen molecules.A small number of active organic moieties containing hydrogen and a smaller number of chemical moieties or medicines having either primary or secondary amino groups were chosen for precursors for the development of alkylamino derivatives of physiologically active chemical moieties.The present study was carried out to improve the safety and effectiveness of the existing medication compounds using the well-known Mannich reaction.

Materials
E.Merck was the manufacturer of all the chemicals.The solvent was dried and distilled before use.Pure samples of sulphonamides from well-known pharmaceutical businesses were the ones that were used.
The chromatographic approach helped to ensure the purity of chemicals that were produced.Silica gel-G served as the stationary phase.The grade was chromatographic.Alcohol and dichloromethane have been the solvents utilized for the mobile phase.. Prior to usage, they were distilled.The spectral techniques help to make the molecule's structure more clear.UV spectra were recorded using a Shimadzu 160A spectrophotometer.The solutions of the synthesized compounds were made with methanol.The IR spectra of KBr pellets were captured using a Shimadzu IR 8400 S FTIR spectrometer.The pellets were KBr of AR grade.DMSO's NMR spectra were obtained.

Synthesis (i) Primary amines are used to create Mannich bases.
Mannich bases for 3,5-dimethyl pyrazole-1-carboxamide were generated by combining amide (0.01 mol) that was prepared in 20 ml of ethanol with a sulpha drug (0.01 mol).The addition of 2.50 ml (0.01 mol) of formalin solution (37.0 percent, v/v) was done slowly and continuously.To lower the pH to 3.5, the mixture received 0.50ml of 1 mol / l HCl.The liquid was effectively cooled with ice for a half-hour before being refluxed in the water bath.The amount of sulphonamide utilized affected the reflux time.After retaining the refluxed mixture at 0oC for four days, the crystalline product was created.The material was crystallized once more from DMF.

(ii) Using secondary amines to create Mannich bases
In a flask with a flat bottom, 3,5-dimethyl pyrazole-1-carboxamide was dissolved in ethanol to make a solution that included 0.01 mol of secondary amine.A steady, continuous stirring process was used to introduce 0.40 ml (0.015 mol) of a 37.0 percent formaldehyde solution.Depending on the secondary amine, the reactive mixture were agitated for 3 to 8.5 hours at 70 to 75 °C.After one and two hours, respectively, the remainder of the formaldehyde solution was added.The reactive mixture were held in the fridge all night.The additional solvent from the reaction mixture was extracted the following day under reduced pressure.Once more, it was placed in the fridge to crystalize.By recrystallizing the product from DMF, it was made purer.(vi) Compound 3f: C11H20N4O3; yield 85%, M.P. 80-83oC.Analysis.Calculated C, 51.3; H, 7.87; N, 21.86 Found C, 51.0; H, 7.9; N, 21.9.UV (λ max) nm: 191 (C=N), 185 205, 250 for benzene chromophore.IR (KBr) v max in cm-1: 3325 N-H in sec.amide, 2910 C-H in CH2, 1666 C=O 1H NMR (DMF) δ ppm: 4.50 (s, 2H, CH2), 6.04(various ring proton of piperidines), 6.14 (s, CH of pyrazole ring).

Outcome and Conversation
High yields of the Mannich bases generated by the Mannish reaction was reported.The results of the chemical analysis were completely consistent with the calculated values.The UV, IR, and 1HNMR spectrum measurements were in agreement with the expected structure.The Mannish reaction at (2940-2950) has produced distinctive bands in the spectra due to the incorporation of the carbine group between the amine constituents and active hydrogen substrate (1442)(1443)(1444)(1445)(1446)(1447)(1448)(1449)(1450).This demonstrates that the synthetic Mannich bases have an amino-methyl bond.Additionally, the 1H NMR supports the existence of an amino methyl bond (-CH2) between NH2 and active hydrogen substrate (5.04-5.20).The biological significance of Mannich bases was investigated.At dosages of 80, 160, and 320 mg/ml, products were tested for bactericidal properties against harmful E. coli strains, Aureus, and Bacillus subtilis.
Against these infections, all of the identified drugs have impressive in vitro efficacy Additionally, their performance was compared to that of the original sulphonamides.The majority of the compounds had only demonstrated noteworthy action at 320 mg/ml, according to Table 1.On the basis of comparison with the matching sulphonamide, compounds 3a and 3h exhibit exceptional action in the case of E. Coli.When used against S. aureus, compounds 3b, 3c, and 3e have greater activity than the equivalent +test on white mice weighing 25gm.Sulphonamides and Mannich bases are both antibacterial agents however Mannich bases are less hazardous than original sulphonamides.

LD50 Test
All Mannich bases exhibit greater activity than the corresponding sulphonamides in the case of S. Typhi.Mannich bases were discovered to be potent antibacterial agents with lower toxicity than their parent sulphonamide in the LD50 test on white mice weighing.Rats were randomly selected Comparative studies between Mannich bases and sulphonamides proved this.To assess the toxicity of synthetic Mannich bases, the LD50 test was employed.For LD50 test four groups containing 10 mice weighing each (30 to 50) g were observed for 72 hours during each trial.Mice were subjected to both oral and intraperitoneal dosages.Rats were randomly selected for the study and marked to provide individual identifications.Rats were observed immediately after dosing during first 30 minutes, and periodically after every 3 hours for next 72 hours.During the first four hours rats were tested for behavioral (alertness, stero type, irritability, fearfulness, touch response, pain response, spontaneous activity, grooming and restlessness), neurological (righting reflex, limb tone, grip strength, twitching, abdominal tone, pinna reflex, corneal reflex, straub tail, tremors and convulsions) and autonomic responses (defecation, writhing, urination, piloerection, heart rate, respiratory rate, pupil size and skin colour).
The starting doses were 2000 mg/kg.The Mannich bases showed no harmful side effects, even at an oral dose of 1400 mg/kg.However, it was shown that the dose of 800 mg/kg was lethal when administered intraperitoneally.

Conclusion
The results demonstrated that 3,5 dimethyl carboxamide Mannich bases have more powerful antibacterial action.Furthermore, compared to their parent sulphonamides, these derivations of Mannich bases are less hazardous.This research demonstrates the promise of Mannich bases as a source of novel chemicals to prevent bacterial infections.