Ugi, Passerini and Biginelli reaction along with examples from recent literature for easy understanding.

1. MULTICOMPONENT REACTIONS:
UGI REACTION

2. The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine
an isocyanides and a carboxylic acid to form a bis-amide or α-N-acylamino amide. The reaction is named after Ivar
Karl Ugi, who first reported this reaction in 1959
General Reaction

3. Mechanism

4. Synthesis of synthetic opioid analgesic norsufentanil derivative 2
Chem. Biol. Drug Des., 2018, 91 , 902 —914
Synthesis of Pharmaceutically relevant compounds

5. J. Org. Chem., 2012, 8 , 2085 —2090
Synthesis of (±)-viridic acid using anthranilate derived isonitriles

6. MULTICOMPONENT REACTIONS:
PASSERINI REACTION

7. This is a three-component reaction between a carboxylic acid, a carbonyl compound such as a ketone or
aldehyde, and an isocyanide, offers direct access to α-acyloxy carboxamides.
General Reaction

8. L. Banfi, R. Riva, Organic reactions ( A. B. Charette, Ed.). John Wiley & Sons, Inc.,
Hoboken, NJ, 2005, Vol. 65, pp. 1–140. The Passerini reaction. 2005, 1-140.
Mechanism

9. Acid isosteres in Passerini Reaction
• HN3 and Al(N3)3---------- alpha hydroxy tetrazoles
• TMSN3 -------------------- CIS constrained norstatine analogue
• Silanol--------------------- α-siloxyamides
• sulfinic acid --------------- α-(sulfonyloxy)amides
• Phosphinic acids----------- phosphinyloxy amide
Green Chem. 2016, 18, 3718-3721.
Org. Lett. 2010, 12, 4341-4343.
Synthesis of Pharmaceutically relevant compounds

10. Carbonyl isosteres in Passerini Reaction
• Acylphosphonate --------------- α-amidophosphates
• Alcohols ------------------------- α-acyloxy carboxamide
• Isatins ---------------------------- oxindole derivatives
T. Ngouansavanh, J. P. Zhu, Angew. Chem. Int. Edit.
2006, 45, 3495-3497
T. Kaicharla, S. R. Yetra, T. Roy, A. T. Biju, Green
Chem. 2013, 15, 1608-1614.
Synthesis of Pharmaceutically relevant compounds

11. Passerini reaction in formation of 2,4,5-trisubstituted oxazoles.
caspase 3/7 activators via Passerini reaction
M. Salah Ayoup et al. Eur.J. Med. Chem. 168 (2019) 340-356
L. Wang, Z. L. Ren, M. Chen, M. W. Ding, Synlett 2014, 25, 721-723
Synthesis of Pharmaceutically relevant compounds

12. MULTICOMPONENT REACTIONS:
BIGINELLI REACTION

13. One pot acid catalyzed
cyclocondensation reaction of β-keto
ester, an aldehyde and urea that forms
3,4-dihydropyrimidin-2(H)-ones
(DHPMs)
Biginelli reaction

14. Iminium route
Enamine route
Knoenevagel route
By Kappe in 1997
By Folkers and Johnson in 1993
By Sweet and Fissekis in 1973
Mechanisms

15. Drugs Synthesized using Biginellireaction

16. Asymmetric Biginelli reaction
Eur J Org Chem 2010:3802–3805
The DHPMs are in general obtained as racemic mixtures. However,
it is the chiral DHPMs that are important in a wide range of
pharmacological functions such as calcium channel blocker,
antihypertensive activity, anticancer activity, anti-inflammatory
activity.

17. Org. Lett. 2021, 23, 2699−2703
• The couplings are performed in a planetary ball mill
• Under solvent-free conditions.
• Acetic acid or ytterbium triflate are used as catalysts
Biginelli reaction: Recent Advances

18. Biginelli reaction: Modifications
Atwal Modification (1987)
• Two step process
• Useful in case of poor yielding aliphatic aldehydes and aldehydes having hindered carbonyl function due to ortho-
substituents
• First step: separate synthesis of unsaturated ketoester via Knoevenagel condensation
• Second step: base catalyzed addition of substituted ureas

19. Biginelli reaction: Modifications
J. Heterocycl. Chem., 2005, 42, 703-705
Lett. Org. Chem., 2009, 6, 557-559
Replacing the urea with 5-amino-1,2,4-triazole
Modification at active methylene group:

20. Thank you!

21. Biginelli reaction: Green Perspective
J. Comb. Chem. 2005, 7, 574–583
1. Microwave Irradiation:
2. Using water as solvent:
Catal. Lett., 2009, 131, 469-473

22. Biginelli reaction: Green Perspective
3. Using ionic liquid as solvent:
4. Solvent free reaction:
Chinese J. Chem., 2005, 23, 91-97
Tetrahedron Lett., 2010, 51, 6436-6438

23. APPLICATIONS
Passerini adducts formation
E. El Mamouni, A. Dos Santos, L. El Kaim, H. Ilitki, Synlett 2016, 27, 2571-2574.
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Synthesis of Pharmaceutically relevant compounds