One pot cascade reactions of glyoxylate

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1 Science One pot cascade reactions of glyoxylate By Shyam Sundar Samanta June 12 th 2012

2 One Pot Synthesis of Non-Proteinogenic Amino Acids and Elaborated Peptides

3 One Pot synthesis. 1) The yield is very low in the one pot synthesis. 2) The hemiaminal is unstable to the water, We manage to recover hemi aminal with some starting material. 3) We saw that if you keep the reaction at high temperature for the long time we see some by product in the reaction.

4 Introduction What is cascade or tandem reaction? A cascade reaction or tandem reaction or domino reaction is a consecutive series of intramolecular organic reactions which often proceed via highly reactive intermediates. One pot cascade reactions of glyoxylate for the formation of racemic amino acid derivatives. One pot cascade reactions of glyoxylate using chiral auxliary for the formation of enantiopure or diastereomeric excess amino acid derivatives.

5 Glyoxylate : Glyoxylic acid (1) is a reactive aldehyde, which is stable (and commercially available) in its hydrated form 2. When applied in organic reactions, the acid is often protected as an ester, with the aldehyde present variously as such (3), as the corresponding acetal 4, or as a hemiacetal 5. As they are very reactive some time they have been used in solid support as 6.

6 Ugi Reaction : A first example concerns the Ugi reaction, a multi-component reaction in which a carboxylic acid, an amine, an aldehyde, and an isocyanide react by initial condensation of the aldehyde and amine to form an iminium ion, which is then attacked by the isocyanide. A. V. Zychlinski, I. Ugi, Heterocycles 1998, 49,

7 Condensation of a secondary amine, benzotriazole, and ethyl glyoxylate gave rise to the aminals in good yields. Lewis acid treatment, followed by introduction of a range of aromatic nucleophiles gave the arylglycine derivatives in generally good to excellent yields. H.-J. Grumbach, B. Merla, N. Risch, Synthesis 1999,

8 Tandem synthesis of quinolines via threecomponent reaction of amines, aldehydes, and alkynes Table : Li, X.; Mao, Z.; Wang, Y.; Chen, W.; Lin, X. Tetrahedron 2011, 67,

9 Heteroaryl amino acids from heteroaryl boronic acids Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,

10 Efficient One-Pot Synthesis of Indol-3-yl-Glycines via Uncatalyzed Friedel-Crafts Reaction in Water The three-component reactions of indole or N- methylindole with glyoxalic acid and primary aliphatic amines in water for 1 h afforded the indol-3-yl (2a-e) or N-methylindol-3-yl-glycines. Intramolecular acid catalysis of the Friedel-Crafts reaction of indole with an iminoacid. Ghandi, M.; Taheri, A. Molecules 2009, 14,

11 One-Pot, Regioselective Synthesis of Substituted Arylglycines One-pot, two-step reactions were performed, first by condensation of acylamide with glyoxylic acid in acetic acid at 50ºC, then arenes were reacted at 5ºC using HCl gas as catalyst to afford the desired product in good yield 32-88%. Grundmann, P.; Fessner, W.-D. Advanced Synthesis & Catalysis 2008, 350,

12 The reaction with glyoxylic acid and the amide performed in a one-pot fashion, which made this process an extension of the Pictet-Spengler reaction of less reactive aromatic systems. D. Ben-Ishai, I. Sataty, N. Peled, R. Goldshare, Tetrahedron 1987, 43,

13 One pot synthesis of tetrahydroquinoline carboxylate ester derivatives. Condensation of anilines with glyoxylic acid ester was expected to provide imine intermediates in situ that should react subsequently as heterodienes with electron-rich dienophiles, i.e., freshly prepared cyclopentadiene,furnishing the desired tetrahydroquinoline carboxylate ester derivatives. Saupe, J.; Roske, Y.; Schillinger, C.; Kamdem, N.; Radetzki, S.; Diehl, A.; Oschkinat, H.; Krause, G.; Heinemann, U.; Rademann, J. ChemMedChem 2011, 6,

14 A one-pot three-component synthesis of β-nitroα-amino acids and their N-alkyl derivatives Yield : % A water-based condensation of glyoxylic acid, nitroalkanes and amines is described, offering a straightforward synthesis of -nitro--amino acids and their N-alkyl derivatives. A. Coghlan, P.; J. Easton, C. J. Chem. Soc., Perkin Trans ,

15 I. Model Study, Diastereoselectivity Outcome Another multi-component reaction is the Petasis reaction, in which an amine, an aldehyde, and a vinyl- or arylboronic acid are combined.

A concise three-component synthesis of alphaamino esters derived from phenylglycine and phenylalanine For a functionalized bromobenzene as the halide, the organozinc compound is preformed using Zn

16 A concise three-component synthesis of alphaamino esters derived from phenylglycine and phenylalanine For a functionalized bromobenzene as the halide, the organozinc compound is preformed using Zn dust and CoBr 2 as a catalyst. The following three-component coupling is carried out at 50ºC. Haurena, C.; Sengmany, S.; Huguen, P.; Gall, E. L.; Martens, T.; Troupel, M. Tet. Let. 2008, 49,

17 Another one pot reaction for the formation of alpha amino acid is from sulfamic acid, glyoxylic acid and an aromatic nuecleophilic to afford the corresponding amino acid up to 90% yield, was reported by Bosten and De hejj. Boesten, W. H. J.; Heij, N. A. EP A1, 1993.

18 One-pot, three-component, direct catalytic asymmetric synthesis of functional alpha-amino ester derivatives Table - Córdova, A. Chem. Eur. J. 2004, 10,

19 Asymmetric cascade reation : Using enantiopure (S)-phenylglycinol as the amine.the three-component coupling results in the diastereomerically pure amino acid, which provides enantiomerically pure homophenylalanine upon hydrogenolysis of the auxiliary. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,

Asymmetric transformation in the Mannich reaction The desired product crystallized out from a range of solvents at room temperature (at 40ºC in EtOH, entry 10) in good yields as a single

20 Asymmetric transformation in the Mannich reaction The desired product crystallized out from a range of solvents at room temperature (at 40ºC in EtOH, entry 10) in good yields as a single diastereoisomer. The attempts to carry out the reaction at a higher temperature (>40ºC, entries 11 and 12) led to faster decomposition of the starting materials and resulted in lower yields. Jakubec, P.; Petráš, P.; Ďuriš, A.; Berkeš, D. Tetrahedron: Asymmetry 2010, 21,

21 One pot synthesis of (±)-martinelline core Treatment of a mixture of 4-methoxycarbonylaniline, ethyl glyoxalate and the enamine with 5 mol% of squaric acid in acetonitrile provided the addition products 6 and 7 in a ratio of 2:1 and in 92% yield. Other catalysts were examined such as Lewis acids, also worked for this reaction but lower yields were observed. Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett 2002, 43,

22 Skeletally Diverse Small Molecules Using a Build/Couple/Pair Strategy Uchida, T.; Rodriquez, M.; Schreiber, S. L. Org Lett 2009, 11,

Efficient One-Pot Synthesis of Indol-3-yl-Glycines via Uncatalyzed Friedel-Crafts Reaction in Water

Molecules 2009, 14, 1056-1061; doi:10.3390/molecules14031056 Article OPE ACCESS molecules ISS 1420-3049 www.mdpi.com/journal/molecules Efficient One-Pot Synthesis of Indol-3-yl-Glycines via Uncatalyzed