Pivalylation of a Variety of Substituted Indoles and Study on the Regioselectivity Upon Nitration

Wendy E. Lopez

Department of Chemistry, University of Rhode Island, Kingston, RI, United States

R= H, MeO, Me, Cl, NO2

ABSTRACT

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 arechemical compounds of great interest since they have been shown to have action on biological systems[1]. These compounds are found in many natural products andmany times they form part or lead tothe formation of important drugs[2]. Some examples of indole derivatives are: the amino acid tryptophan, indomethacin an anti-inflammatory1 drug, (S)-ethyl indole-2-carboxylate, an intermediate in the preparation of perindopril1(a drug used to treat hypertension)[3], and CC-10652 a powerful antitumor drug that contains several indole and indoline moieties[4]. 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, antibacterial, antimicrobial, antioxidant, and even contrast agents properties[5],[6],[7],[8],[9].

Figure 1. Examples of important indole containing compounds. Perindopril1, a drug used to treat hypertension[10], 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 indoles[11]. 2-aminoindoles are said to be the starting point for the synthesis of dacarbazine, a compound used to treat malignant melanoma and Hodgkin’s disease[12].

Due to the importance of indole nitrated products this study was designed to protect and nitrate a variety of indoles, unsubstituted and substituted, todetermine 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) Cland 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.

Scheme 1. Synthesis of N-Pivaloylindoles

R= H, Me (methyl), MeO, Cl, NO2

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 / % yield
H / 40
4-MeO / 82
4-NO2 / 76
4-Cl / 63
5-MeO / 65
5-Me / 93
5-Cl / 51
5-NO2 / 72
6-Cl / 41
7-MeO / 51
7-Me / 72
7-Cl / 50
7-NO2 / 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.

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 / % yield
H / 0
4-MeO / 0
4-NO2 / 0
4-Cl / 0
5-MeO / 0
5-Me / 0
5-Cl / 0
5-NO2 / 0
6-Cl / 0
7-MeO / 0
7-Me / 0
7-Cl / 0
7-NO2 / 0

Indoles are known to be susceptible to acidic conditions11 and even though the procedure used by Pelkey and Gribble for their nitrations[13] 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.

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