Pivalylation of a Variety of Substituted Indoles and Study on the Regioselectivity Upon Nitration Your Name Here Department of Chemistry, University of Rhode Island, Kingston, RI, United States [email protected] ABSTRACT 0.1eq. DMAP 1.48eq. Et3N 1.5eq. Pivaloyl Chloride N H R CH2Cl2 O °C O 1) Indole in 16 mL Ac 2O -70 °C 2) 8 mL Acetyl nitrate 0.1eq. DMAP 1.48eq. Et 3N 1.5eq. Pivaloyl Chloride N H N CH2Cl2 O °C N R O NO2 N R +/or O N R NO2 O R= H, MeO, Me, Cl, NO2 A regioselective study on the nitration of unsubstituded and substituted indoles was performed using a variety of electron withdrawing and electron donating groups as substituents. Pivalylation of the N-H functionality was performed first to protect the indoles. This synthetic step proceeded smoothly and gave good yields from 40 – 93%. Nitration of the protected indoles on the other hand, was not as successful. The harsh acidic conditions seem to have decomposed the product giving 0% yield for all the indoles. Indoles are chemical compounds of great interest since they have been shown to have action on biological systems1. These compounds are found in many natural products and many times they form part or lead to the formation of important drugs2. Some examples of indole derivatives are: the amino acid tryptophan, indomethacin an anti-inflammatory1 drug, (S)-ethyl indole-2carboxylate, an intermediate in the preparation of 1 B. Narayana, B. V. Ashalatha, K.K. Vijaya Raj, J. Fernandes, B.K. Sarojini, JBioorganic & Medicinal Chemistry, 2005, 13, 4638. 2 Albert Padwa, Michael A. Brodney, Bing Liu, Kyosuke Satake, Tianhua Wu, J. Org. Chem, 1999, 64, 3595. perindopril 1 (a drug used to treat hypertension)3, and CC1065 2 a powerful antitumor drug that contains several indole and indoline moieties4. Figure 1 shows CC-1065 and perindropril. In addition to the before mentioned functions, other indole and indoline (the C2-C3 bond is saturated unlike indoles) derivatives have been found to have antiviral, 3 Arun R. Jagdale, R. Santhosh Readdy, Arumugam Sudalai, Org. Lett. 2009, 11, 803. 4 Dale L. Boger, Robert S. Coleman, J. Org. Chem, 1984, 49, 2240. antibacterial, antimicrobial, antioxidant, and even contrast agents properties5,6,7,8,9. Scheme 1. Synthesis of N-Pivaloylindoles 0.1eq. DMAP 1.48eq. Et 3N 1.5eq. Pivaloyl Chloride OH O O O NH N O N N O N O N H N H N CH2Cl2 O °C O R 3 R= H, Me (methyl), MeO, Cl, NO2 1 H3C N H R OH N H NH2 O OH OCH 3 OCH 3 2 O Figure 1. Examples of important indole containing compounds. Perindopril 1, a drug used to treat hypertension10, and 2 a potent antitumor drug. In order to obtain such functional indole derivatives, substitutions to the indole need to be done so the desired molecule can be built. An important substituent on indole is the nitro group Nitration of indoles is an important synthesis step since it can lead to the formation of products such as amino indoles11. 2-aminoindoles are said to be the starting point for the synthesis of dacarbazine, a compound used to treat malignant melanoma and Hodgkin’s disease12. Due to the importance of indole nitrated products this study was designed to protect and nitrate a variety of indoles, unsubstituted and substituted, to determine if the substituents on the benzene moiety would direct the nitro group to the 2 or 3 positions preferentially. The substituents on the indoles were the electron withdrawing groups (EWG) Cl and NO2, and the electron donating groups (EDG) Me and MeO. The first step in this process was to protect the different indoles using pivaloyl chloride. Sheme 1 shows the reaction performed on the desired indole. The Pivalylation of indoles turned out to give decent to very good % yields. This reaction was very straightforward and for the most part was run at room temperature, only during the first part of the reaction the temperature was kept low. Table 1 shows the results for the pivalylation procedure. Table 1. Pivalylation results R H 4-MeO 4-NO2 4-Cl 5-MeO 5-Me 5-Cl 5-NO2 6-Cl 7-MeO 7-Me 7-Cl 7-NO2 % yield 40 82 76 63 65 93 51 72 41 51 72 50 62 After protecting the indoles, the class attempted to determine any regioselectivity that could arise upon nitration. Scheme 2 shows the reaction performed in an attempt to nitrate the indoles. Scheme 1. Synthesis of protected nitro-indoles. 5 Michele Giampieri, Alessandro Balbi, Mauro Mazzei, Paolo La Colla, Cristina Ibba, Roberta Loddo, Antiviral Research, 2009, 83, 179. 6 Eyunni V. K . Suresh Kumar, Jagan R. Etukala, Seth Y. Ablordeppey, AMini Reviews n Medicinal Chemistry, 2008, 8, 538. 7 Aldo Andreani, Silvia Burnelli-Massimiliano Graniola, Alberto Leoni, Alessandra Locateli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Laura Landi, Cecilia Prata, Michael V. Beridge, Carole Grassa, Heinz-Herbert Fiebig, Gerhard Kelter, Angelika M. Burger, Mark W. Kundel, J. Med. Chem, 2008, 51, 4563. 8 L. C. Heda, Rashmi Sharma, C. Pareek, P. B. Chaudhari, E-Jounal of Chemistry, 2009, 6, 770. 9 Elisabetta Damiani, Beata Kalinska, Adriana canpa, Stefania Canestrari, Michael Wozniak, Ettore Olmo, Lucedio Greci, Free Radical Biology and Medicine, 2000, 28, 1257. 10 Mirian Hurst, Blair Jarvis, Drugs, 2001, 61, 867. 11 Ashley W. Jones, Bambang Purwono, Paul K. Bowyer, Peter S. R. Mitchell, Naresh Kumar, Stephen J. Nugent, Katrina A. Jolliffe, David StC. Black, Tetrahedron, 2004, 60, 10779. 12 Patrizia Diana, Paola Barraja, Antonino Lauria, Anna Maria Almerico, Gaetano Dattolo, Girolamo Cirrincione, Tetrahedron, 2000, 56, 5177. NO2 N R O N R +/or O N R NO2 O 4 R= H, Me, MeO, Cl, NO2 The idea was that the EWG and EDG might direct the nitro group to a specific location. Unfortunately, after the nitration reaction was done, H1-NMR showed that the product was not formed. Table 2 shows the nitration attempted indoles. In fact it seems as if the product decomposed probably due to the conditions used for nitration. Table 1. Protected indoles used for nitration R H 4-MeO 4-NO2 4-Cl 5-MeO 5-Me 5-Cl 5-NO2 6-Cl 7-MeO 7-Me 7-Cl 7-NO2 % yield 0 0 0 0 0 0 0 0 0 0 0 0 0 Indoles are known to be susceptible to acidic conditions11 and even though the procedure used by Pelkey and Gribble for their nitrations13 was used, our indoles could not resist the same conditions In conclusion, protection of the N-H functionality of the unsubstituted as well as the subsitituted indoles using pivaloyl chloride proceeded very smoothly. Unfortunately, nitration regioselectivity could not be determined due to the fact that indoles decomposed during the nitration reaction. This was probably due to the acidic conditions used since indoles are known to be sensitive to acids. Finding a procedure that would not be as harsh, in other words neutral conditions, is one way this problem could be circumvented and the regioselective study can be fully completed. Supporting Information Available: For Experimental procedure as well as H1-NMR and GC-Mass spec. please see attached pages. 13 Erin T. Pelkey, Gordon W. Gribble, Synthesis, 1999, 7, 1117.