One-pot synthesis of novel α -amino phosphonates using tetramethylguanidine as a catalyst

α -Aminophosphonates ( 4a-l ) were synthesized in high yields by the Kabachnik–Fields reaction. One-pot simultaneous reaction of indole-3-carboxaldehyde, a dialkyl-or diphenyl phosphite, and different heterocyclic-, cyclic-, or other primary amines in the presence of tetramethylguanidine (10 mole %) as catalyst in toluene at reflux temperature afforded 4a-l. They exhibited moderate to high antimicrobial activity.


Introduction
2][3] Their diverse applications include inhibition of synthase, 4 HIV protease, 5 renin, 6 and PTPases; 7,8 some of these derivatives are potential antibiotics 9 or herbicides. 10α-Aminophosphonates are chief substrates in the synthesis of phosphonopeptides. 11Due to their structural analogy with α-amino acids, these types of organophosphorus compounds are widely used for the development of new inhibitors of enzymes, neuroactive compounds, and plant growth regulators. 12,13Among the number of synthetic approaches to α-aminophosphonates, one of the most powerful methods is the Kabachnik-Fields reaction. 14,15Previous results demonstrated that tetramethylguanidine (TMG) catalyzes the Michael addition of nitromethane to α,β-unsaturated ketones. 16,17TMG has been used only sporadically and has not yet received full recognition as a strong base in organic synthesis.Its catalytic activity in the Kabachnik-Fields reaction is explored in the present investigation.

Antimicrobial activity
The antibacterial activity of (4a-l) was assayed 24 against the growth of Staphylococcus aureus (gram +ve) and Escherichia coli (gram -ve) at three concentrations (100, 50, 25 ppm) (   The compounds 4a-l were screened for their antifungal activity against Aspergillus niger and Helminthosporium oryzae species along with the standard fungicide Griseofulvin (Table 2) by the disc diffusion method 25 at three different concentrations (100, 50, 25 ppm).
It is gratifying to observe that the majority of the compounds 4a-l exhibited higher antifungal activity when compared with the Griseofulvin reference.Significant is the fact that diphenylbenzo[d]thiazol-2-ylamino-1H-indol-3-ylmethyl phosphonate (4c), and dimethylethoxycarbonyl(phenyl)methylamino)(1H-indol-3-yl) methyl phosphonate (4g) exhibited higher activity than the standard Griseofulvin against both the fungi.Thus new compounds with very high antimicrobial/fungicidal activity than the presently used commercial bactericides / fungicides have been discovered.

General procedure for the synthesis of αaminophosphonates (4a-l)
To a stirred solution of indol-3-carboxaldehyde (1) (0.0725 g, 0.005 mole) the amine (3a-l) (0.005 mole) in anhydrous toluene (20 mL) was added dropwise, and then TMG (10 mole %) was added and stirring continued at RT for 1h.Then dimethyl-, diethyl-, or diphenyl phosphite (2) (0.72 g, 0.005 mole) in anhydrous toluene (20 mL) was added dropwise.Stirring was continued at RT for another 0.5 h, then the mixture was heated at gentle reflux for 5-6h.The progress of the reaction was monitored by TLC analysis.After completion of the reaction the solvent was removed under reduced pressure.The residue was purified by column chromatography on silica gel (80-120 mesh) using petroleum-ethyl acetate (8:3) as eluent.

Conclusions
In our current search, we have reported the synthesis of α-aminophosphonates in one-pot synthesis from aldehyde, amines and dialkyl, diaryl phosphite using tetramethylguanidine as catalyst which includes one more method for its synthesis to the existing literature.