Efficient method for the synthesis of 2,3-unsubstituted nitro containing indoles from o-fluoronitrobenzenes

Article abstract of DOI:10.1021/ol8027187

(Chemical Equation Presented) A methodology was developed for the efficient synthesis of 2,3-unsubstituted nitro containing indoles via acid catalyzed intramolecular electrophilic cyclization. Subsequent reduction of nitro groups allows the construction o

Full text of DOI:10.1021/ol8027187

ORGANIC
LETTERS
2009
Vol. 11, No. 3
637-639
Efficient Method for the Synthesis of
2,3-Unsubstituted Nitro Containing
Indoles from o-Fluoronitrobenzenes
Kai Liu and Dali Yin*
Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Science, Beijing, China
yindali@imm.ac.cn
Received November 25, 2008
ABSTRACT
A methodology was developed for the efficient synthesis of 2,3-unsubstituted nitro containing indoles via acid catalyzed intramolecular
electrophilic cyclization. Subsequent reduction of nitro groups allows the construction of some indole fused heterocycles and indole quinone
diimines. This strategy provides an efficient method for the preparation of biologically and medicinally interesting molecules.
The construction of privileged structures is an important
strategy in medicinal chemistry. The indole ring system is
one of the most prevalent structural motifs found in biologi-
cally active compounds of both natural and synthetic origin.
For well over 100 years, the synthesis and functionalization
of indoles has been a major area of focus for synthetic
organic chemists, and numerous methods for the preparation
of indoles have been developed.1 Acid catalyzed intramo-
lecular electrophilic cyclization-elimination of 2-anilino
acetals was one of the early concepts for indole construction.
But the first reports of success by this method were found
to be unreproducible even by succeeding authors. A thorough
reinvestigation by Chastrette in 1962 confirmed the general
failure under Brønsted acid conditions, although some
2-substituted indoles could be obtained in fair yields by using
BF3 as catalyst in benzene solution.2,4 Forbes and co-
workers3a subsequently achieved production of some N-alkyl-
(but not N-unsubstituted) indoles from the corresponding
anilino acetals by treatment with BF3-HOAc in trifluoro-
acetic anhydride. Nordlander4a and Sundberg4b and co-
workers modified and realized this method in many cases
by cyclization following initial acylation of the amino
function in 1980s and concluded some experiences of this
method. The protonation of the anilino nitrogen will greatly
deactivate the aromatic ring for the electrophilic cyclization.
The success of their method could be attributed in part to
effectively reducing the aniline nitrogen basicity through
acylation without severe deactivation of the aromatic ring
or acetal function. Substituents deactivating relative to
(2) (a) Kaye, I. A. J. Am. Chem. Soc. 1951, 73, 5467–5468. (b) Blackhall,
A.; Thomson, R. H. J. Chem. Soc. 1954, 3916–3919. (c) Elvidge, J. A.;
Foster, R. G. J. Chem. Soc. 1964, 981–991. (d) Bobbitt, J. M.; Kulkarni,
C. L.; Dutta, C. P.; Kofod, H.; Chiong, K. N. J. Org. Chem. 1978, 43,
3541–3544.
(3) (a) Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron
1971, 27, 1253–1259. (b) Jackson, A. H.; Jenkins, P. R.; Shannon, P. V. R.
J. Chem. Soc., Perkin Trans. 1 1977, 1698–1704.
(1) (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875–
2911. (b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491–2515.
(c) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045–1075. (d)
Zhang, Y.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627–630. (e) Opatz,
T.; Ferenc, D. Org. Lett. 2006, 8, 4473–4475. (f) Du, Y.; Liu, R.; Linn, G.;
Zhao, K. Org. Lett. 2006, 8, 5919–5922.
(4) (a) Nordlander, J. E.; Catalane, D. B.; Kotian, K. D.; Stevens, R. M.;
Haky, J. E. J. Org. Chem. 1981, 46, 778–782. (b) Sundberg, R. J.; Laurino,
J. P. J. Org. Chem. 1984, 49, 249–254. (c) Hewlins, M. J. E.; Jackson,
A. H.; Oliveira-Campos, A. M.; Shannon, P. V. R. J. Chem. Soc., Perkin
Trans. 1 1981, 2906–2911.
10.1021/ol8027187 CCC: $40.75
Published on Web 12/24/2008
2009 American Chemical Society

Scheme 1
Table 2. Examples of Indoles Prepared
hydrogen would thwart the cyclization. The method is also
adversely affected by substituents in the prospective 7-posi-
tion (ortho to amino).4
Table 1. Optimization of Cyclization Conditions
entry
solvent (mL)
acid (equiv)
time
8 h
23 h
8 h
30 min
3 h
20 h
yield (%)
1a
2a
3a
4a
5b
6b
THF (2)
THF (2)
THF (2)
THF (2)
CH2Cl2 (5)
CH2Cl2 (5)
1 M HCl (1.0)
MsOH (0.3)
TFA (10.0)
TiCl4 (1.0)
TFA (5.0)
64
71
81
51
66
92
TFA (1.3)
a Reaction was carried out at reflux. b Reaction was carried out at rt.
Herein, we report an efficient method for the synthesis of
some 2,3-unsubstituted nitro containing indoles from 2,4-
difluoro-1,5-dinitrobenzene or 2,4-difluoronitro-benzene and
aminoacetaldehyde dialkylacetals via acid catalyzed intramo-
lecular electrophilic cyclization. This synthesis was inspired
by an unexpected observation as shown in Scheme 1. When
compound 2a was treated with 1 M HCl in THF to hydrolyze
the acetal group, dinitroindole 3a was obtained in 64% yield
instead of the expected aldehyde. This obviously violated
the conclusion of Nordlander and Sundberg because there
are two deactivating nitro groups on the phenyl ring. After
1
carefully checking of the H NMR of compound 2a, it was
found the chemical shift of the proton between two amino
groups sit at 6.17 ppm, whereas that of unsubstituted benzene
is 7.26 ppm.5 This means that the electron density of the
All yields are of isolated product. a Use 1.3 equiv of TFA. b Use
5.0 equiv of TFA. Reactions were carried out at rt except entry 5.
(5) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512–7515.
638
Org. Lett., Vol. 11, No. 3, 2009

corresponding position is unexpectedly high and promoted
this cyclization.
Scheme 2. Indole Derived Structures
This direct acid catalyzed cyclization provided a fast and
efficient way for the preparation of multisubstituted indoles
which may have the potential to be transformed to many
privileged structures. Considering this, the conditions and
scale of this reaction were further investigated. Compound
2a was first used as the model substrate to optimize the
reaction conditions as shown in Table 1. Strong inorganic
and organic acids were used as catalysts and it was found
TFA in THF gave higher yield. When the solvent was
changed from THF to CH2Cl2, the reaction could finish at
room temperature and the yield could reach 92%. The
reaction finished very fast with 5.0 equiv of TFA (entry 5),
but the yield was low due to the formation of some
unidentified byproducts. Then TFA load was lowered to 1.3
equiv and excellent yield was obtained (entry 6). After
determining the optimized conditionsTFA (1.3 equiv),
CH2Cl2 (0.1 M solution for substrate) at room temperatureswe
tried to examine the substrate scope of the reaction. The
substrates for the cyclization were prepared by reaction of
2,4-difluoro-1,5-dinitrobenzene or 2,4-difluoronitrobenzene
with amines in a separated substitute procedure or a one pot
method according to the literature.6 With all the other
substrates, however, the reaction did not go to completion,
even with prolonged reaction time under the above optimized
condition. When more TFA was loaded (5.0 equiv), a better
result could be obtained. Substrates with different substitu-
tions on amino group were tried for cyclization as shown in
Table 2. Good to excellent yields for the isolated products
were achieved. We also tried to use ethoxy and ethylthio to
replace one of the amino groups to see if the molecules can
also undergo this cyclization, but unfortunately, no corre-
sponding product was found.
Encouraged by the above results, we initiated further
investigation to explore the possibility of preparing other
privileged structures derived from indoles prepared from the
above cyclizations. o-Nitroanilines are versatile substrates
for the construction of benzofused heterocycles.7 It will be
a useful method for the preparation of many indole fused
heterocycles with bioactive interests. Reduction of the nitro
groups of compounds 3f and 3g followed by cyclization,
compounds 5 and 6 were successfully obtained in yields of
79 and 43%, respectively (Scheme 2). Indole-4,7-quinones
were reported to have various bioactivities.8 Indole quinone
diimine is an isostere of indole quinone, it may also have
various activities and expands the diversity of the scaffold,
but no synthetic route to it has been reported. Reduction of
the nitro groups of compound 3a, and left the reaction
mixture exposed to the air, indole quinone diimine 7 was
successfully obtained in 49% yield.
In conclusion, we have developed a method for the
preparation of 2,3-unsubstituted nitro containing indoles from
commercially available 2,4-difluoro-1,5-dinitrobenzene or
2,4-difluoronitrobenzene and 2-aminoacetaldehyde dimethy-
lacetal (or its N-substituted derivatives) under mild condi-
tions. The nitro groups of resulting indoles can be reduced
and then further transformed to other indole fused structures
or indole quinone diimines, that are useful for the construc-
tion of biologically interesting molecules.
Acknowledgment. We are grateful to The Global Alliance
for TB Drug Development (TB alliance) for their financial
support.
Supporting Information Available: Detailed synthetic
1
procedures, characterization data, and H NMR, 13C NMR
of synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL8027187
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