Passerini reaction

Passerini reaction

1. BY Dr . Gurumeet.C.Wadhawa DEPARTMENT OF CHEMISTRY K. B. P . College,Vashi,Navimumbai Pass erini Rea c tions

2. Reaction involving more than two starting compounds react to from a product in such a way that the majority of atoms of the starting material can be found in the product Multicomponent reactions 2

3. MCRs Popular For ….. 3 Simple procedures Time saving Superior atom economy The one-pot character The high yields Ever increasing number of accessible backbones

4. 4

5. Most documented MCRs are Isocyanide based MCRs Free-radical mediated Metal-catalyzed MCRs Organo-boron compounds based 5

6. Passerini Reactions 6 Simple three component reaction Developed by Mario Passerini Product is acyloxy amide It i n v o l v es an oxo c o m ponent, a n iso c y a n i d e and an acid in a single step

7. History 7 Mario Passerini of the University of Florence discovered the first example of the reaction that now bears his name in 1921. This was t h e first e x a m ple of a fa m i l y of rea c tions c a lled isocyani d e- b ased multicomponent reactions (IMCRs) Can be carried out with or without solvents

8. Passerini Reaction is Green in Nature Because.. 8 It is has 100% atom-economy Every atom in the starting materials is incorporated in the product No intrinsic chemical waste associated with the reaction This reaction definitely meets one of the goals of the green chemistry movement

9. The mechanism … 9 It involve the following steps: Addition to protonated aldehyde Addition to nitrilium ion Acyl transfer Tautomerization

10. Isocyanides, also known as isonitriles , are a unique class of organic compounds. The carbon center of the isocyanide group is formally divalent, and it can react with electrophiles and nucleophiles. The first synthetically useful reaction of isocyanides was described by M. Passerini , who reported that isocyanides react with carboxylic acids and carbonyl compounds in one step to provide α acyloxycarboxamides.1 This transformation is known today as the Passerini multicomponent reaction (MCR). The synthetic power of the Passerini reaction is that three reaction partners are combined in one pot under mild conditions (three component reaction or P-3CR ) and the product incorporates most atoms of all three starting materials.

11. These types of transformations coupled with combinatorial chemistry and parallel synthesis techniques allow the quick assembly of a wide array of compounds from simple starting materials . Thegeneral features of the classical Passerini reaction are: 1 ) it is carried out at high concentrations of the starting materials in inert solvents at or below room temperature ; 2) it is accelerated in apolar solvents;2 3 ) a wide variety of aldehydes and ketones undergo the reaction; 4 ) there are rare limitations to the carbonyl component, only sterically hindered ketones and α,β -unsaturated ketones are unreactive ; 5 ) in addition to C-isocyanides, trimethylsilyl isocyanide also undergoes the reaction; 6) when water is used as the nucleophilic component instead of carboxylic acid , the reaction gives the corresponding α- hydroxycarboxamide under acid catalyzed conditions ; 7) when hydrazoic acid is combined with the isocyanide and the carbonyl compound under acidic conditions, α- hydroxyalkyltetrazole is the product ; and 8) catalytic asymmetric variants of the reaction were also developed. By choosing the proper starting materials

12. The final product arises from the intermediate formation For m at i on of in t er m e d ia t e i s m o s t li k ely i r rever s i b le s tep, as sugges ted by t h e asymmetric induction achieved with bulky chiral isocyanide According to this the reaction proceed through a relatively non-polar cyclic transition state 3 1 13 2

13. This can either be 5 or 7 membered depending upon which carboxylate oxygen participate The m echan i sm i s i n ag r ee m e n t with t h e depends fa c t t h at r e a c tion rate on all the three components 17

14. Important in combinatorial chemistry The total synthesis of natural products Synthesis of polycyclics Synthesis of macrocycles heterocycles Phar m aceut i c a l indust r y for t h e synt he s is of drug-like compounds Applications 18

15. en v isioned carboxylic cre a te a usi n g acids 1000 member library 1 i so c y ani d es, 10 and 1 aldehy d es to of compounds. Assuming that each of these reactions is straight-forward and high- yielding, the process could be automated, allowing larger libraries to be readily accessed It is important in the the field of combinatorial chemistry which seeks to synthesize large libraries of similar molecules in a parallel fashion For example, A combinatorial array of reactions can be 19

16. Synthesis of analogs of Azinomycin-a DNA binding and alkylating antibiotic Reported by Armstrong et al. 20

17. 21

18. Synthesis of natural prolyl endopeptidase inhibitor Eurystatin A Reported by Schmidt et. al. 22

19. Passerini reaction of steroid ketones The ch o les t anon e , isocyani d es, a n d benz o ic a c id rea c ted with e ach other to prepare the related products Reported by Baker, R.H. et. al. 23

20. Thre e -co m ponent Passerini rea c ti o n of o -carborane aldehyde. Synthes is of  -ca r b o ran y l -  - ac y l o xy amides prep a red a s pote n ti a l BN C T ( B o ron Neutron Capture Therapy) Reported by Jonnalagadda, S.C. et. al. 24

21. Synthesis of inhibitor libraries based on the 1-isocyanoalkylphosphonate diaryl ester moiety Resulted in formation of phosphonic peptide mimetic inhibitor libraries Reported by Sieczyk, M. et. al. 1-isocyanoalkylphosphonate diaryl ester 25

22. Peptidomimetic 26 These are the  -acyloxyamide derived from benzaldehyde This compound is an important building block in the synthesis of biodegradable polymers Drugs related to Parkinson’s Disease

23. These co m pounds ex h ib i t both a n t i - H I V and anti- malarial activity Cre a tion of library of peptido m ime t ic co m pounds with an α-hydroxy-β-amino acid unit Product contain both ester and amide functionalities 22 compounds were tested for activity against HIV and malaria. 27

24. α-Hydroxyamides 28 The hydrolyzed products of Passerini reactions Common organic building blocks for natural products and drugs Modification of Passerini reaction , called the Ugi reaction, that uses imines instead of aldehydes was investigated by process chemists at Merck as a method for synthesizing the antiretroviral drug, Crixivan®

25. These re a ct i ons are p o werful synthe t ic m et h ods for the synt he s is of st ru c tur a lly diverse molecules The importance and application of these reactions can be further increased by post- condensation and transformations These modifications are usually accomplished by using a suitable functional group and take place spontaneously or upon treatment with additional reagents 29

26. The passerini reaction is a pivotal isocyanide ‐ based MCR—that contribute to huge number biologically active α ‐ acyloxyamides. Some interesting targets were synthesized following this MCR as a key synthetic step. Additionally, some environmentally benign protocols have been remarked and more improvements in this respect are expected in the next years with the increasing concern about the sustainability of the processes. Conclusion 30

27. References 31 1. Chandgude, A. L.; Dömling, A., Green Chemistry, 18, 3718, 2016. 2. Wang, R.; Liu, Z.-Q., Tetrahedron Letters , 56, (50), 7028-7033, 2015. Mo n i, L.; B a nf i , L.; Ba s so, A .; Car c o n e, L.; Ra s parin i , M.; Riva, R ., The Journal of organic chemistry , 80, (7), 3411-3428, 2015. Damkaci, F.; Szymaniak, A., Journal of Chemical Education , 91, (6), 943-945, 2014. Reza Kazemizadeh, A.; Ramazani, A., Current Organic Chemistry , 16, (4), 418-450, 2012. Zahoor, A. F.; Thies, S.; Kazmaier, U., Beilstein journal of organic chemistry , 7, (1), 1299- 1303, 2011.

28. Denmark, S. E.; Fan, Y., Journal of the American Chemical Society , 125, (26), 7825- 7827, 2013. Ramozzi, R.; Morokuma, K., The Journal of organic chemistry , 80, (11), 5652-5657, 2015. Zhang, J.; Lin, S.-X.; Cheng, D.-J.; Liu, X.-Y.; Tan, B., Journal of the American Chemical Society , 137, (44), 14039-14042, 2015. Cai, X.-h.; Hui, G.; Bing, X., International Journal of Chemistry , 3, (1), 216, 2011. Kreye, O.; Tóth, T.; Meier, M. A., Journal of the American Chemical Society , 133, (6), 1790-1792, 2011. 32