Formulation of Alternatives to Interchanged amines using a water based compounds

Synthetically important moieties such as iminium salts (pyridinium salts), -amino phosphonates, geometric analogues of -amino acids, functionalized amines via the Barbier and Reformatsky-type reaction, dihydrocoumarins, monoacylaminals, -aryl glycine derivatives, etc. are all derived from amines. A number of apes and monkeys, for example, have been found to inhibit prostate cancer and prevent the spread of microorganisms by mimicking biocide prototypes. Figure 1.1 shows how aminals can be used as a synthon to precisely create various structurally

significant moieties.

Due to its increased and various usages, such as dimethylaminomethylation in enolates, enolsilylethers, and acidic ketones, aminals have recently been reported as a synthon for the synthesis of eschenmoser and other iminium salts. . Furthermore, -amino phosphonates, structural counterparts of the corresponding -amino acids, are another important class of chemicals displaying a broad spectrum of biological activity. Dihydrocoumarins, a favoured scaffold with therapeutic biological properties including aldose reductase, antioxidant, immunomodulatory, and

ALTERNATIVE AMINALS: GENERAL INFORMATION

Scheme 1.1 : Synthesis of aminals Subsequently in 1955, Stewart. et. al. reported the synthesis of aromatic aminals under azeotropical water removal with 83-98% yield or by utilising a dehydrating agent such boric anhydride with an isolated yield of 64-92%. (Scheme 1.2).

After that, in 1960, Bohme et al. published the synthesis of aminals from the aliphatic aldehydes under basic conditions using fractional distillation as illustrated in Scheme 1.3.

Another synthesis technique for the preparation of aminals was validated by Xu et al. in 2000. They refluxed benzaldehyde and piperidine in benzene for 24 hours using a Dean-Stark trap, and the yield was 72%. (Scheme 1.4).

As an alternative method, Hatano et al. (2008) showed that by using a suspension of aldehyde, dried chromatographic alumina in ether, and secondary amine, and then stirring the reaction mixture overnight while maintaining a low temperature, they were able to produce respective aminals in moderate yields (Scheme 1.5).

However, the reported catalytic systems have significant drawbacks that prevent their widespread use in industrial settings, including the creation of surplus waste, the need for additional additives, the use of toxic organic solvents, increased temperature and reaction time, and the implementation of microwaves. Table 1.1 compares the generic synthetic route maps for the synthesis of substituted aminals, providing a convenient overview of the synthesis of aminals as a whole.

Therefore, it is still difficult for chemists to create a simple catalytic system for the synthesis of aromatic aminals despite the importance of this synthon.

Keeping this motivation in mind, we have devised a sustainable catalytic system for the synthesis of substituted aromatic aminals using water as the catalyst in the current chapter. Following the sustainable principles of green chemistry, the current approach is quick, simple, and environmentally beneficial.

At first, copper triflate and copper oxide nanoparticles (CuO NPs) were used to catalyse a room-temperature, water-based model reaction between benzaldehyde (1) and pyrrolidine (2), as shown in table 1.2 (Entries 1 – 2). In 30 minutes, a 100% conversion to the target aminal (3d) was seen (Entries 1 – 2, Table 1.2). It was intriguing to learn that pure CuO NPs allow for a 100% conversion to product 3d at room temperature (Entry 3, Table 1.2). Surprisingly, in only 30 minutes, under catalyst-free conditions and using water as a solvent, product 3d was formed at room temperature with 95% conversion (entry 4, Table 1.2). This finding suggests that water may be catalysing this process; we conducted control experiments to verify this hypothesis. Catalytic amounts of CuO NPs (5mg) and H2O (37L for 1 mmol scale) were used in the reaction, and 100% conversion was achieved (entry 5, Table

1.2).

After conducting the reaction in the presence of a catalytic amount of H2O (37 L for 1 mmol scale) solely, we were shocked to find that the linked product 3d was generated in 95% yield, shedding light on the involvement of CuO NPs in the reaction (Entry 6, Table 1.2). In addition, when compared to the methods described in the literature, the proposed catalytic system displayed considerable improvements across a wide range of reaction parameters (Entry 6, Table 1.2 and Entries 1 – 9, Table 1.1). 5,6,14,17-23 Following the identification of optimum reaction processes, a variety of substituted aminals were produced by reacting different substrates such amines (2) and aldehydes (1), as depicted in scheme 4b.3. Subsequently, we tested a variety of aromatic aldehydes and found that electron-withdrawing substituents (4- CN, 3-F, 4- Br, 3,5-CF3, 3-Cl, etc.) were well tolerated, with isolated yields of the desired products ranging from 82% to 95%.

Herein is laid forth the chemistry profile of 3h. The 1H NMR spectrum (Figure1.2) of compound 3h showed the signature tetrahydric -CH proton as a singlet at 3.89 ppm. Specifically, the protons in thiomorpholine showed as multiplets between δ2.73 and 2.57 ppm. All three protons showed up as singlets at δ 7.80 and δ7.60 ppm, which is in line with the phenyl ring's aromaticity. As can be seen in figure 3.3, 13C analysis also validated the structure of compound 3h. At 27.49 ppm, the tetrasubstituted carbon aliphatic peak in the aminal nucleus was seen. In addition, the aromatic carbons emerged in the range of δ137.91 to 121.88 ppm, whereas the aliphatic peak corresponding to the thiomorpholine nucleus carbons appeared at 88.20 and 51.14 ppm. In addition, the single crystal data and structure of compound 3h are displayed in figures 1.3 and 1.4, respectively, verifying the expected structural arrangement of the synthesised aminoids. Figure 3: 1H NMR spectrum of compound 3h

Single crystal X-ray diffraction was then used to identify the structure of compound 3i, as displayed in figures 1.6 and 1.7. The X-ray diffraction intensities

Ka radiation (λ = 0.71073Å) using an Oxford CCD diffractometer equipped with the Xcalibur, a sapphire diffraction measurement instrument. Figure 7: Single crystal XRD data of compound 3i

AE = [MW of product] ÷ ∑(MW of stoichiometric reactants) × 100 AE of compound 3d = [230.17 (3d)] ÷ [262.04] × 100 Note: above reaction was performed under catalyst free and solvent free conditions water is used as a catalyst which is green so the mass of water is excluded

In conclusion, we devised a solvent-free, environmentally benign approach for the synthesis of a wide variety of substituted amino acids. With its well-thought-out synthetic arrangement, broad substrate scope, good to exceptional yields, good E-factor of 0.20, and high reaction mass efficiency of 83%, the present approach is advantageous.

1. Li, S. W.; Batey, R. A. Mild lanthanide(III) catalyzed formation of 4,5- diaminocyclopent-2-enones from 2 furaldehyde and secondary amines: A domino condensation/ring-opening/electrocyclization process. Chem. Commun. 2007, 3759 – 3761. 2. Anders, E.; Tropsch, J. G.; Katritzky, A. R.; Rasala, D.; Eynde, J. J. V. N-(l- Haloalkyl)pyridinium Salts: Preparation and use for new syntheses of other N- (l-substituted-alkyl)pyridinium salts, N,N'-(1-Alkylidene)bisamines, and N,N-(l- Alkylidene)bisbenzazoles. J. Org. Chem. 1989, 54, 4808 – 4812. 3. Sansone, M. F.; Koyanagi, T.; Przybyla, D. E.; Nagorski, R. W. Solvent-free synthesis of monoacylaminals from the reaction of amides and aminals as precursors in carbinolamide synthesis. Tetrahedron Lett. 2010, 51, 6031 – 6033. 4. Dezfuli, M. K.; Saidi, M. R. A new protocol for the preparation of aminals from aromatic aldehydes and their facile conversion to phosphonates. Phosphorus, Sulfur, Silicon Relat. Elem. 2004, 179, 89 – 96. 5. Hern´andez-Altamirano, R.; Mena-Cervantes, V. Y.; Perez-Miranda, S.; Fern´andez, F. J.; Flores-Sandoval, C. A.; Barba, V.; Beltr´an, H. I.; Zamudio- Rivera, L. S. Molecular design and QSAR study of low acute toxicity biocides with 4,4‟-dimorpholyl-methane core obtained by microwave-assisted synthesis. Green Chem. 2010, 12, 1036 – 1048. 6. Farmer, R. L.; Biddle, M. M.; Nibbs, A. E.; Huang, X.; Bergan, R. C.; Scheidt, K. A. Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression. ACS Med. Chem. Lett. 2010, 1, 400 – 405. 8. , M.; Angiolini, L. Further advances in the chemistry of mannich bases. Tetrahedron 1990, 46, 1791 – 1837. 9. Bohme, H.; Haake, M. In Advances in Organic Chemistry, edited by Talor, E. C. John Wiley & Sons, New York 1976, 107 – 223. 10. Maier, L. Organic phosphorus compounds 91.1 synthesis and properties of 1- amino-2-arylethylphosphonic and phosphinic acids as well as -phosphine oxides. Phosphorus Sulfur Silicon Relat. Elem. 1990, 53, 43 – 67. 11. Pudovik, A. N.; Konovalova, I. V. Addition reactions of esters of phosphorus(III) acids with unsaturated systems. Synthesis 1979, 2, 81 – 86. 12. Fields, E. K. The synthesis of esters of substituted amino phosphonic acids. J. Am. Chem. Soc. 1952, 74, 1528 – 1531 13. Atmani, A.; Combret, J. C.; Malhiac, C.; Mulengi, J. K. β,γ-Unsaturated α- aminophosphonates: synthesis and reactivity. Tetrahedron Lett. 2000, 41, 6045– 6048.

Research Scholar, Sunrise University, Alwar, Rajasthan