Phenylglyoxalspotlight Spotlight 387 Compiled by Ali Akbari Ali Akbari Was Born in 1981 in Naghadeh, Iran

SPOTLIGHT ██951

SYNLETT Phenylglyoxalspotlight Spotlight 387 Compiled by Ali Akbari Ali Akbari was born in 1981 in Naghadeh, Iran. He received his This feature focuses on a re- B.Sc. degree in applied chemistry from the Tabriz University in agent chosen by a postgradu- 2005 and completed his master program in the field of organic ate, highlighting the uses and chemistry at the Chemistry and Chemical Engineering Research preparation of the reagent in Center of Iran (CCERCI) in 2009. Since then he has been working current research in the group of Dr. Eftekhari-Sis as a research assistant at the Uni- versity of Maragheh. His research interests focus on the use of phenylglyoxal in synthetic heterocyclic chemistry. Department of Chemistry, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran. E-mail: [email protected] Dedicated to my parents and my research supervisor Dr. Bagher Eftekhari-Sis.

Introduction tone functional group of phenylglyoxal can be converted into other useful groups such as hydroxyl, carboxylic acid Phenylglyoxal is a yellow liquid that polymerized on and ester which are more attractive groups in organic syn- standing which stored as monohydrate form thetic chemistry. Phenylglyoxal has also many indispensi- (PhCOCHO·H2O), a white crystalline solid with a melting ble roles in biological chemistry. As a reagent, it is useful point of 77 °C. It can be prepared via different proce- for the chemical modification of arginine residues in pro- dures,1,2 but the most popular method for synthesis of teins. It reacts with the guanidino group of the arginine phenylglyoxal is the oxidation of acetophenone with sele- residue under mild conditions.4 nium dioxide3 (Scheme 1). Because phenylglyoxal con- O O tains both an aldehyde and ketone functional group it is O O OH useful in both organic and biological chemistry. As a ver- SeO2 H2O satile reagent, it has been used extensively in synthesizing dioxane–H2O H OH a broad range of N-heterocyclic compounds with biologi- reflux cal and pharmaceutical activities. The aldehyde and ke- Scheme 1 Preparation of phenylglyoxal monohydrate

Abstracts

(A) Eftekhari-Sis et al. reported the synthesis of novel 2-aryl-4-chlo- H ro-3-hydroxy-1H-indole-5,7-dicarbaldehydes via Vilsmeier–Haack Cl O 1) NH4OAc, H2O O reaction starting from phenylglyoxal.5 O O HO + O 2) POCl3, DMF Ph

H Ph N H O H

(B) To the best of our knowledge, there are no reports in the litera- MeO ture for the formation of pyrrole-3-ol derivatives via condensation of MeO O 1. DABCO ketones with phenylglyoxal. In this paper, a simple method for the H O, r.t. + O 2 synthesis of new N-alkyl(aryl)-2,4-diaryl-1H-pyrrole-3-ol deriva- Ph N R tives via aldol reaction of 1-(4-methoxyphenyl)propan-2-one with O 2. RNH2, PTSA H PhMe, reflux HO phenylglyoxal in the presence of a catalytic amount of DABCO, fol- Ph This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. lowed by Paal–Knorr cyclization with primary amines is described.6

(C) For the first time, Khalafy and Rimaz7 have reported the synthe- CO Me O 2 sis of pyridazines via condensation of phenylglyoxal with β-keto es- O O O NH2NH2⋅H2O ters in the presence of an excess amount of hydrazine hydrate in 70– Me + Ph 97% yield. O H2O, r.t. N H 70–97% Ph N

SYNLETT 2012, 23, 0951–0952 Advanced online publication: 16.03.20120936-52141437-2096 DOI: 10.1055/s-0031-1290293; Art ID: ST-2011-V0394-V © Georg Thieme Verlag Stuttgart · New York 952 A. Akbari SPOTLIGHT

(D) Disubstituted imidazoles were prepared by reacting phenylgly- O Ph O oxal with different aryl aldehydes in the presence of ammonium ac- N etate. The compounds showed good anti-inflammatory activities in O H NH4OAc, AcOH Ph + carrageenan-induced rat paw edema test with very low ulcerogenic N H H activity. Fair number of compounds were found to have significant R R 8 antimicrobial activity especially against fungal species. R = 2-NO2, 3-NO2, 4-NO2, 2-OH, 3-OH

(E) M. Ayaz et al.9 used phenylglyoxal in a Petasis reaction in order to synthesize quinoxalines, which exhibit a large variety of biologi- O NH2 cal activities such as antibacterial, antimalarial, antifungal, and anti- O 1) MW, 120 °C thrombotic activity. Ph 15 min NHBoc 2) 20% TFA, DCE N H r.t., 18 h + N

B(OH)2

(F) Phenylglyoxal was used in a simple, practical, and a very regio- O O O selective three-component one-step procedure with 6-aminopyri- midines and dimedone for the preparation of a novel pyrrolo[2,3- O O Ph NH + Δ 2 d]pyrimidine ring system, a common motif in several natural prod- H acetic acid, , 9 h ucts and biologically active molecules.10 MeOH NH2 N OH Ph H N N N N 2 H

H2N N NH2

(G) A Pictet–Spengler reaction for the synthesis of 1-substituted β- carboline has been developed. Products A and B were synthesized N NH via a reaction between phenylglyoxal and L-tryptophan in 45% and 2 35% yield, respectively.11 N H CO2H O HO PTSA, MeOH O A + Ph 50 °C, 2 h N + H H N

N H O B

(H) Ishihara and co-workers have reported a CuX2-catalyzed enan- O tioselective intramolecular Cannizzaro reaction of phenylglyoxal. O They have also found that the use of phenylglyoxal provides a solu- N N ∗ tion to the problem of low reactivity in the asymmetric intramolecu- O ∗ 2 2 OH 12 O R R lar Cannizzaro reaction with alcohols. (11 mol%) 1 Ph + R1 OH OR Ph H CuX2 (10 mol%) CH2Cl2, r.t., 24 h O X = OTf, SbF6 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

References (1) von Pechmann, H. Chem. Ber. 1887, 20, 2904. (8) Husain, A.; Drabu, S.; Kumar, N. Acta Pol. Pharm. 2009, (2) Mikol, G. J.; Russell, G. A. Org. Synth. Coll. Vol. V; Wiley 66, 243. & Sons: New York, 1973. (9) Ayaz, M.; Dietrich, J.; Hulme, C. Tetrahedron Lett. 2011, (3) Riley, H. A.; Gray, A. R. Org. Synth. Coll. Vol. II; Wiley & 52, 4821. Sons: New York, 1943. (10) Quiroga, J.; Acosta, P. A.; Cruz, S.; Abonia, R.; Insuasty, B.; (4) Takahashi, K. J. Biol. Chem. 1968, 243, 6171. Nogueras, M.; Cobo, J. Tetrahedron Lett. 2010, 51, 5443. (5) Eftekhari-Sis, B.; Zirak, M.; Akbari, A.; Hashemi, M. M. (11) Yang, M.-L.; Kuo, P.-C.; Damu, A. G.; Chang, R.-J.; Chiou, J. Heterocycl. Chem. 2010, 47, 463. W.-F.; Wu, T.-S. Tetrahedron 2006, 62, 10900. (6) Eftekhari-Sis, B.; Akbari, A.; Amirabedi, M. Chem. (12) Ishihara, K.; Yano, T.; Fushimi, M. J. Fluorine Chem. 2008, Heterocycl. Compd. 2011, 46, 1330. 129, 994. (7) Rimaz, M.; Khalafy, J. ARKIVOC 2010, (ii), 110.