Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous - PowerPoint PPT Presentation

Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous enol-Passerini condensations Ana G. Neo,* Carlos F. Marcos* Laboratory of Bioorganic Chemistry & Membrane Biophysics, School of Veterinary Sciences, University of Extremadura, 10071 Cáceres, Spain E-mail: cfernan@unex.es, aneo@unex.es

Contents 1. Introduction 2. Our proposal 3. Results 4. Conclusions ECSOC 22 2

Introduction  Isocyanides  Multicomponent reactions of isocyanides  Diversity of MCRI ECSOC 22 3

Introduction Isocyanides Reactions of isocyanides: • Cycloadditions • Insertions • Multicomponent reactions (MCRIs) ECSOC 22 4

Introduction Classic MCRIs Passerini three-component condensation Ugi four-component condensation Passerini, M. Gazz. Chim. Ital 1921 , 51 , 126. Ugi, I.; Steinbruckner, C. Angew. Chem. 1960 , 72 , 267. ECSOC 22 5

Introduction Advantages of MCRIs • Atom economy • Efficient • Sustainable • Structural diversity  Post-condensation transformations  Single replacement reactions (SRR) Dömling, A. Chem. Rev. 2006 , 106 , 17-89; Ganem, B. Acc Chem Res 2009 , 42 , 463. Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev . 2010 , 110 , 5235. ECSOC 22 6

Introduction Single replacement reactions (SRR) Amine Acid ECSOC 22 7

Our proporsal Single replacement reactions (SRR) Enols act as the acid component in the Ugi reaction R 3 O EWG EWG OH H NH 2 R 3 H R 4 N CN R 6 R 5 R 5 R 6 N R 4 N + R 3 R 1 R 2 R 1 R 2 O R 1 R 2 R 5 R 6 EWG R 5 R 3 O EWG H N R 4 N R 6 H O R 5 O EWG N R 4 N R 2 R 1 N N R 4 R 6 R 3 H R 3 R 1 R 2 R 1 R 2 Primary adduct Peptidomimetic enamines ECSOC 22 8

Our proporsal Pyrrolidinodiones in MCRIs 1. Predominant enolic form 2. pKa < 5 3. Michael acceptor Vaughan, W. R.; Covey, I. S. J. Am. Chem. Soc. 1958 , 80 , 2197. ECSOC 22 9

Our proporsal Biologically relevant pyrrolidinones Peifer, C et al. J. Med. Chem. 2008 , 51 , 3814; Lampe, J. W et al. J. Med. Chem. 1993 , 36 , 1041; Rose, R. et al. Angew. Chem. Int. Ed. 2010 , 49 , 4129; Jourdan, F. et al. ChemInform 2006 , 37 . ECSOC 22 10

Results Enol-Ugi condensation of pyrrolidinodiones 39 examples Yields up to 95% Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012 , 14 , 6218. ECSOC 22 11

Results Enol-Ugi condensation of pyrrolidinodiones Scope O Ph N N Ph Ph O Ph N Ph N Ph N O O O NC CN CN O O NC NC NC S Ph NC O O EtO 2 C OH EtO 2 C OH EtO 2 C OH O Ph O N O N N O Ph Ph Ph O EtO 2 C OH EtO 2 C OH EtO 2 C OH O O O N N N F Cl H 3 CO Ph Ph Ph ECSOC 22 12

Results Enol-Passerini condensation 14 examples Yields up to 92% Neo, A. G.; Marcos, C. F. Org. Lett . 2018 , 20 , 3875. ECSOC 22 13

Results Enol-Passerini condensation O O O O Ph O O Scope Br NO 2 CN CN O NC NC NC O EtO 2 C OH EtO 2 C OH EtO 2 C OH O O N N O N O Ph Ph Ph O EtO 2 C OH EtO 2 C OH O O N N Cl H 3 CO Ph Ph ECSOC 22 14

Results Enol-Passerini condensation Mechanism ECSOC 22 15

Results Anomalous enol-Passerini condensations 17 examples Yields up to 67% Neo, A. G.; Marcos, C. F. Org. Lett . 2018 , 20 , 3875. ECSOC 22 16

Results Anomalous enol-Passerini condensation Scope O O O O Ph R= CH 3, NO 2 O O Br R CN CN O NC NC Ph NC O MeO EtO 2 C OH EtO 2 C OH EtO 2 C OH O O N N O N O Ph R Ph Ph O R= H, F, Cl, OMe Bulky isocyanides do not react ECSOC 22 17

Results Anomalous enol-Passerini condensations Mechanism ECSOC 22 18

Conclusions  We have used enols for the first time as the acid component in Ugi and Passerini-type reactions.  Careful control of the reaction conditions allows us to obtain Ugi, Passerini or pseudo-enol-Ugi products selectively.  The use of enols as acidic partners in MCRI is an excellent strategy for the preparation of new pyrrolidinones having peptidic or pseudo-peptidic groups on carbon 3. ECSOC 22 19

Acknowledgements We thank Junta de Extremadura and FEDER (IB16095) for the financial support Fondo Europeo de Desarrollo Regional Una manera de hacer Europa ECSOC 22 20