3H-Indolium Salts Efficiently Prepared from N-Substituted Anilines and α-Branched Ketones by an One-pot Synthesis

Article abstract of DOI:10.1002/jhet.5570410117

Starting with the N-substituted anilines 4/12 and the α-branched ketones 3 the 3H-indolium salts 1 and their fused derivatives 13 are prepared by combining a sodium nitrite nitrosation, a zinc dust reduction, a hydrazone formation and a Fischer indolization to a reaction sequence in which the isolation and purification of intermediates is not necessary. The scope and limitations of this effective one-pot synthesis are discussed.

Full text of DOI:10.1002/jhet.5570410117

Jan-Feb 2004
103
3H-Indolium Salts Efficiently Prepared from N-Substituted Anilines
and α-Branched Ketones by an One-pot Synthesis
Thomas Zimmermann∗ and Ortwin Brede
Interdisziplinäre Arbeitsgruppe Zeitaufgelöste Spektroskopie, Fakultät für Chemie und Mineralogie,
Universität Leipzig, Permoserstraße 15, D-04303 Leipzig, Germany
Received August 8, 2003
Starting with the N-substituted anilines 4/12 and the α-branched ketones 3 the 3H-indolium salts 1 and
their fused derivatives 13 are prepared by combining a sodium nitrite nitrosation, a zinc dust reduction, a
hydrazone formation and a Fischer indolization to a reaction sequence in which the isolation and purification
of intermediates is not necessary. The scope and limitations of this effective one-pot synthesis are discussed.
J. Heterocyclic Chem., 41, 103 (2004).
In recent years the improvement of the synthesis of 3H-
sion of sun energy and other modern technologies. Until
now, the most important access to 3H-indolium salts 1
consists in the condensation of N-arylhydrazines with
ketones to N-arylhydrazones, subsequent Fischer indoliza-
tion [4] to indolenines and final N-alkylation and in the
reaction of N-substituted N-arylhydrazines with ketones to
arylhydrazones followed by a Fischer type cyclization [4].
indolium salts 1 [1] has attracted considerable attention
since these salts represent important starting materials for
the preparation of compounds, such as polymethine dyes
[2] or photochromic spiroindolines [3], possessing valu-
able properties for applications in the field of spectral sen-
sitization, laser construction, optical data storage, conver-
1
2
3
4
5
6
4
3
HA
R
R
R
R
R
R
A¯
1
a
a
a
b
c
d
e
f
a
a
a
a
a
a
a
a
a
a
a
a
a
b
c
HClO
HI
Me
Me
Me
Me
Me
Me
Et
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
ClO ¯
I¯
BF ¯
4
a
a´
a´´
b
c
d
e
f
g
h
i
j
k
l
4
4
HBF
4
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
HClO
ClO ¯
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
ClO ¯
4
ClO ¯
4
ClO ¯
4
i-Pr
n-Bu
ClO ¯
4
g
h
i
ClO ¯
4
C H
ClO ¯
4
ClO ¯
4
6
11
CH Ph
CH CH=CH
(CH ) OH
Me
Me
Me
Me
Me
2
j
ClO ¯
2
2
4
k
a
a
a
a
a
ClO ¯
2 2
4
ClO ¯
4
n-Pr
i-Pr
Me
Me
ClO ¯
m
n
o
p
4
d
e
f
ClO ¯
4
ClO ¯
4
(CH )
ClO ¯
4
2 5

104
T. Zimmermann and O. Brede
Vol. 41

Jan-Feb 2004
3H-Indolium Salts Efficiently Prepared
105
In connection with our investigations on spiro[cyclo-
hexadiene-azaheterocycles] [5], a novel class of com-
pounds with photochromic properties [6], which are easily
obtained by ring transformation of 2,4,6-triarylpyrylium
salts with methyleneindolines derived from the 3H-
indolium salts 1, we have shown that the synthesis of the
salts 1 can considerably be improved by combining the
hydrazone formation and the Fischer indolization to an
one-pot procedure [7]. In this way, from N-arylhydrazines
2, α-branched ketones 3 and perchloric acid in ethanol the
3H-indolium perchlorates 1 (A¯= ClO4¯) with a wide range
of substituents in the 1-, 2- and 3-position were prepared in
good yield and high purity. Although this procedure is very
simple, in contrast to the ketones 3 the hydrazines 2 used
are in some cases expensive materials, unstable com-
pounds or have to be prepared in one or more additional
reaction steps. To avoid these disadvantages, the idea arose
to start with the usually more inexpensive and better avail-
able N-substituted anilines 4 and to combine their transfor-
mation to the hydrazines 2 with the hydrazone formation
and the Fischer indolization to a reaction sequence in
which the isolation and purification of intermediates is not
necessary. In this paper we wish to report on the results of
these investigations.
procedures in organic chemistry for which various nitrosa-
tion agents, reduction systems and solvents have been used
[8]. To avoid the isolation of the carcinogenic nitroso com-
pounds they are advantageously reduced in situ to the cor-
responding hydrazines [8]. With subsequent transforma-
tion to the 3H-indolium salts 1 in mind, which should pro-
ceed in the same solvent and without any negative interfer-
ence of the by-products of the nitrosation and reduction
step, the N-substituted anilines 4 were nitrosated with an
aqueous solution of sodium nitrite in glacial acetic acid at
room temperature to the N-nitroso derivatives 5. The sub-
sequent reduction with zinc dust was performed in the
presence of the α-branched ketones 3. In this way, the
hydrazines 2 formed were immediately trapped by the
ketones 3 to give the hydrazones 6 avoiding competition
reactions of the sensitive hydrazine species. Then the reac-
tion mixture was refluxed to effect the thermal cyclization
of the hydrazones 6 to the 3H-indolium derivatives 7,
which is additionally accelerated by the zinc ions formed
in the reduction step that are known to be efficient cata-
lysts in Fischer type indolizations [4]. Finally, the intro-
duction of the desired anion A¯ of 1 was achieved by a spe-
cial work up procedure (cf. Experimental part).
To determine the scope and limitations of this synthesis
of 3H-indolium salts anilines 4 and ketones 3 with various
substituents were tested as starting materials. On reacting
The nitrosation of N-substituted anilines to N-nitrosoani-
lines and their reduction to hydrazines are well established

106
T. Zimmermann and O. Brede
Vol. 41
anilines bearing at the nitrogen an alkyl (4a-g), cycloalkyl
(4h), aralkyl (4i), alkenyl (4j) or hydroxyalkyl (4k) sub-
stituent without (4 a, 4 e-k) or with (4 b-d) an additional
group at the benzene ring and 3-methylbutan-2-one (3a),
the related 3H-indolium salts 1a-k were obtained in yields
up to 60%. Besides 3a other α-branched ketones with
longer alkyl chains (3b-e) as well as cycloalkyl derivatives
(3f) can be used which are performed with N-methylani-
line (4a) to the 3H-indolium salts 1l-p. As shown for the
example 4a + 3a → 1a/1a'/1a'', the anion of the salts 1
(1a: ClO4¯, 1a': I¯, 1a'': BF4¯) can be varied by changing
the acid used for the precipitation in the work-up of the
reaction mixture.
The desired synthesis of indolium salts could be suc-
cessfully extended to N-substituted anilines with a satu-
rated carbon chain connecting the nitrogen with the adja-
cent carbon atom of the benzene ring. In this way, 4,5,5-
trimethyl-2, 5-dihydro-1H- p y r r o l o [ 3 , 2 , 1 -hi]ind olium per-
chlorate (1 3 a), the 1,4,5,6-tetrahydropyrrolo[3,2,1-
ij]quinolinium perchlorates 13b-g and the 1,1,2-trimethyl-
4,5,6,7-tetrahydro-1H-azepino[3,2,1-hi]indolium perchlo-
rate (13h) were obtained from 2,3-dihydroindole (12a), the
tetrahydroquinolines 1 2 b,c and 2,3,4,5-tetrahydro-1H-
benzo[b]azepine (12d), respectively, and α-branched
ketones bearing alkyl (3 a-c, 3e) or cycloalkyl (3 f) sub-
stituents in up to 52% yield.
Surprisingly, then the N-cyanoethylaniline (4l) was
nitrosated and reduced in the presence of 3-methylbutan-2-
one (3a) 3-amino-1-phenyl-4,5-dihydro-1H-pyrazole (11)
was obtained as the sole product (yield 45%) instead of the
expected 3H-indolium salt 1q. In this case the amino group
of the hydrazine derivative 9, intermediately formed via 8
by nitrosation/reduction, obviously does not react with the
ketone 3a but attacks the cyano carbon giving rise to the
imino derivative 10, which is stabilized by a proton shift to
the aminodihydropyrazole 11.
In comparison to our previous reported [7] and to other
known methods for the preparation of 3H-indolium salts 1
and their fused derivatives 13 the one-pot synthesis
described here is more facile and effective. It starts from
inexpensive and well accessible materials, it combines
four reaction steps (nitrosation, reduction, hydrazone
formation, Fischer indolization) to a sequence in which the
isolation of intermediates is not necessary and it provides
well crystallized and easily separable salts with any
desired anion.
Attempts to use N,N-diphenylamine as aniline compo-
nent and react it with sodium nitrite, zinc dust and
3-methylbutan-2-one (3 a) was unsuccessful. Although
from the related N,N-diphenylhydrazine, 3a and perchloric
acid in ethanol the desired 2,3,3-trimethyl-1-phenyl-3H-
indolium perchlorate was prepared in good yield [7], here
no appropriate product was obtained which can be
explained by a retarded nitrosation of the electron deficient
N,N-diphenylamine.
The structure and purity of the indolium salts 1/13 was
proved by elemental analyses, by nmr spectroscopy and in
the case of known compounds by comparison of their
physical data with those reported in the literature. In the 1H
nmr spectra the signals of the protons of the N-bonded car-
bons appear at relatively low field caused by the positive
charged nitrogen. Thus, the singlet of the N-CH3 protons in
1a-d and 1l-p is located at 3.89-4.05 ppm and the triplet of
the NCH2-moiety in 13a-h can be found at 4.27-4.65 ppm.

Jan-Feb 2004
3H-Indolium Salts Efficiently Prepared
107
3
4
5
6
12
3
n
R
R
R
R
13
a
b
c
b
b
b
b
d
a
a
a
b
c
e
f
1
2
2
2
2
2
2
3
H
H
Me
H
H
H
H
H
Me
Me
Me
Et
n-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
a
b
c
d
e
f
(CH )
g
h
2 5
a
Me
Me
aqueous solution, e.g. 70% HClO , 57% HI, 50% HBF ), in 50
4
By the same reason, the protons of the methyl group con-
nected with the iminium carbon in 1 a-k, 1o,p, 1 3 a-c and
1 3 f-hresonate as a singlet at 2.56-2.94 ppm. Because of an
asymmetric carbon centre in 1o and 13f their methylene
hydrogens are diastereotopic by nature and can cause, as
may be observed, resonances at different chemical shifts.
All other protons present in the salts 1/13 show in accor-
dance with the structure signals with the expected chemical
shifts and splitting patterns.
4
ml of ethanol. After addition of ether (50 ml) and cooling, the
precipitated salts 1/13 were filtered by suction and washed with
ether. In many cases the products obtained were pure enough for
further manipulations. If necessary, they can be purified by
recrystallization from ethanol/acetonitrile.
Isolation of the 3-Amino-1-phenyl-4,5-dihydro-1H-pyrazole (11).
According to the General procedure given above 9.13 g (60
mmol) N-cyanoethylaniline (4 l) was nitrosated and reduced in
the presence of 5.17 g (60 mmole) 3-methylbutan-2-one (3a).
After pouring the resulting reaction mixture into
ammonia/water, a precipitate was formed that was filtered by
suction, washed with ethanol, recrystallized from ethanol and
identified to be 3-amino-1-phenyl-4, 5-dihydro-1H-pyrazole
(11), yield 4.35 g (45%), mp 166-167° (lit. 168-169° [10]). The
substance obtained was identical in all respects with an authen-
tic sample [10].
EXPERIMENTAL
The melting points were measured on a Boëtius hot stage
1
apparatus. The H nmr spectra were recorded on a Varian Gemini
200 spectrometer at 199.975 MHz and on a Varian Gemini 2000
spectrometer at 200.041 MHz in dimethyl-d sulfoxide at 25°
6
with hexamethyl disiloxane as internal standard. The 2,3,4,5-
tetrahydro-1H-benzo[b]azepine (12d) was prepared according to
a literature procedure [9]. The other chemicals were purchased
from commercial suppliers (Aldrich: sodium nitrite, glacial
acetic acid, 3a-e, 4a-e, 4g, 4j-l, 12a; Lancaster: 4f, 12b,c; Fluka:
3f, 4h; Acros: zinc dust, 4i).
Acknowledgement.
The financial support by the Sächsisches Staatsministerium für
Wissenschaft und Kunst is gratefully appreciated.
REFERENCES AND NOTES
Synthesis of the 3H-Indolium Salts 1 and their Fused Analogues 13
from N-substituted Anilines 4 and Fused Anilines 1 2, respectively,
and α-Branched Ketones 3. General Procedure (c f. Table 1).
[1] For a review on indoles and their derivatives see: H. Döpp, D.
Döpp, U. Langer and B. Gerding, in Houben-Weyl, Vol E6b /E6b , R. P.
1
2
Kreher, ed, Thieme, Stuttgart, 1994, pp 546-1354.
To 60 mmoles of the aniline 4/12, dissolved in glacial acetic
acid (30 ml), was added dropwise a solution of 4.62 g (66
mmoles) of sodium nitrite in water (10 ml) under magnetic stir-
ring at room temperature in a period of 0.25 hours (slightly
exothermic). After stirring for additional 0.5 hours and addition
of the ketone 3/12 at once, 9.80 g (180 mmoles) zinc dust was
added in small portions to avoid a too vigorous reaction. The
resulting mixture was refluxed for 0.5 hours, cooled to room tem-
perature and poured into a concentrated solution of ammonia in
water (70 ml) under external cooling. The oil formed (anhy-
drobase of 1/13) was extracted with ether (50 ml), the organic
layer was washed with water (30 ml) and added dropwise without
being dried to a magnetically stirred solution of 60 mmoles of the
acid HA, corresponding to the desired anion A¯ (can be used as
[2] R. Raue, Methine Dyes and Pigments, in Ullmann's
Encyclopedia of Industrial Chemistry, 5th ed, Vol A16, VCH, Weinheim,
1990, pp 487-534; R. Raue, Laser Dyes, in Ullmann's Encyclopedia of
Industrial Chemistry, 5th ed, Vol A 1 5, VCH, Weinheim, 1990, pp 151-164.
[3] O rganic Photochromic and Thermochromic Compounds, C.
Crano and R. Guglielmetti, eds, Vol 1, Plenum Press, New York, London,
1999, Vol 2, Kluwer Academic, Plenum Publishers, New York, Boston,
Dordrecht, London, Moscow, 1999, and literature cited therein.
[4] Reviews on the Fischer indole synthesis: [a] B. Robinson,
Chem. Rev., 63, 373 (1963), 69, 227 (1969); [b] B. Robinson, The Fischer
Indole Synthesis, Wiley, New York, 1982; [c] D. L. Hughes, Org. Prep.
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[5a] T. Zimmermann and M. Pink, J. Prakt. Chem./Chem. Ztg.,
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108
T. Zimmermann and O. Brede
Vol. 41
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Thieme, Stuttgart, 1990, pp 588-600.
[9] H. Ahlbrecht, E. O. Düber, J. Epsztajn and R. M. K.
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and O. Brede, J. Photochem. Photobiol. A, 71, 294 (2000).
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