Pivalylation of a Variety of
Substituted Indoles and Study on
the Regioselectivity Upon
Nitration
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Department of Chemistry, University of Rhode Island, Kingston, RI, United States
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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.