A new technology for the synthesis of 4,5,6,7-tetrahydroindole

Full text of DOI:10.1134/S0012500810110091

ISSN 0012ꢀ5008, Doklady Chemistry, 2010, Vol. 435, Part 1, pp. 307–310. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © B.A. Trofimov, A.I. Mikhaleva, E.Yu. Shmidt, A.M. Vasil’tsov, A.V. Ivanov, N.I. Protsuk, O.A. Ryapolov, 2010, published in Doklady Akademii Nauk,
010, Vol. 435, No. 1, pp. 60–63.
2
CHEMICAL
TECHNOLOGY
A New Technology for the Synthesis of 4,5,6,7ꢀTetrahydroindole
a
a
a
Academician B. A. Trofimov , A. I. Mikhaleva , E. Yu. Shmidt ,
a
a
a
b
A. M. Vasil’tsov , A. V. Ivanov , N. I. Protsuk , and O. A. Ryapolov
Received April 26, 2010
DOI: 10.1134/S0012500810110091
Compounds of indole series occur widely in wildꢀ retard its vinylation. Only the use of expensive RbOH
life. Among them are important regulators of physioꢀ and Bu4NOH provides the yields of indole of 81 and
I
logical processes (serotonin, melatonin, tryptophan, 70%, respectively [6]. In other cases, the yields are not
etc.); indole alkaloids, including those widely used in high, 20–50% [3, 6, 7], and extraction with flammable
medicine (reserpine, strychnine, brevicolline, aimaꢀ and explosive diethyl ether or toxic dichloromethane
line, vincamine, physostigmine, etc.); synthetic pharꢀ is used for isolation of compound
I.
maceuticals (indopan, indomethacin, etc.); horꢀ
mones; enzymes (tryptophanase); hallucinogens [1].
4
5
3
6
Indole is used as a starting material for the indusꢀ
trial synthesis of heteroauxins (3ꢀindolylacetic and 3ꢀ
indolylbutyric acids) and tryptophan and in perfumery
industry for designing fragrance compositions as perꢀ
fume fixative.
HC≡CH
2
+
KOH–DMSO
7
N
N1
NOH
III
H
I
II
Scheme 1.
4,5,6,7ꢀTetrahydroindole (
I) can be used for the
The aim of this work is to create an innovative techꢀ
synthesis of indole and its not readily available 2ꢀfuncꢀ nology for the preparation of 4,5,6,7ꢀtetrahydroindole
tionalized derivatives. As distinct from indole itself, best fit for industrial manufacture and devoid of the
which reacts with electrophilic agents only at the noted drawbacks.
3
ꢀposition, indole I, being pyrrole in chemical nature,
Owing to our systematic study briefly disclosed in
the patent [8], indole was prepared in a yield up to
7% with the use of fundamentally new catalyst IV, a
nanocrystalline aggregate composed of sodium cycloꢀ
hexanone oximate and its DMSO complex in a 1 : 1
ratio (mp 123–126°C, sulfur content 9.0%).
undergoes selective functionalization at the 2ꢀposition
in similar reactions. The further dehydrogenation of
2
tionalized indoles, for example, methylisotrypꢀ
tophan [2].
I
9
ꢀfunctionalized tetrahydroindoles leads to 2ꢀfuncꢀ
NꢀVinylꢀ4,5,6,7ꢀtetrahydroindole (II) can be
readily obtained via the Trofimov reaction [3–5]
between cyclohexanone oxime (III) and acetylene in a
KOH–DMSO superbasic system in a yield up to 90%
ONa • O=S(Me)2
N
2
IV
[
3] (Scheme 1); however, the conditions used for the
synthesis of indole as an intermediate in this reacꢀ
I
Taking into account the known ability of DMSO to
tion—such as addition of water or dioxane, replaceꢀ bind alkali metal cations [9], the electronic structure
ment of KOH by LiOH, NaOH, RbOH, or Bu NOH
ꢀ
of the complex may be represented by
V.
4
Me +
≡
–
–
S ONa
O
O
O
N
N
N
Me
V
a
b
Favorskii Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, ul. Favorskogo 1, Irkutsk, 664033 Russia
UAB Prekybos namai Waldis, D. Vandens 7ꢀ6, Klaipeda LT91246, Lithuania
307

308
TROFIMOV et al.
It is seen from the structure of
V
that the contact ture, the reaction mixture always contains nanocrysꢀ
ion pair of sodium cyclohexanone oximate is sepaꢀ talline clusters in dynamic equilibrium; the clusters
rated by a DMSO molecule that seems to be inserted are a transition form between the crystalline phase and
between the oximate anion and sodium cation thus true solution. These clusters, combining several anions
producing a bulky complex cation with more delocalꢀ of oxime III with attendant sodium cations and
ized charge. Therefore, cation–anion electrostatic DMSO molecules, should have enhanced nucleophiꢀ
interaction in this pair diminishes and the anion of licity due to additional free energy acquired by these
oxime III becomes more basic and nucleophilic, i.e., polyanions on account of repulsion of negative charges
more reactive toward acetylene molecule.
within the cluster.
The catalytic aggregates of sodium cyclohexanone
Owing to exchange with the medium, the reacting
oximate and its complexes with DMSO show limited cyclohexanone oximate anion during reaction with
solubility in a reaction medium at ambient temperaꢀ acetylene gives its place to a new molecule of cycloꢀ
ture; however, upon heating to the reaction temperaꢀ hexanone oxime to form intermediate
Oꢀvinyl oxime
ture (100–130°C), they dissolve passing through a VI [3], which further undergoes rearrangement into
I
phase transition molecular crystals–solvated moleꢀ (Scheme 2) and the catalytic cycle restarts
cules of complex IV. Thus, at the reaction temperaꢀ (Scheme 3).
1
,3ꢀH
[3,3]
O
NH
O
O
N
N
H
VI
–
H O
2
N
H
OH
N
N
I
Scheme 2.
+
–
O /(Me) S—ONa
HC≡CH
2
N
V
+
H O
2
N
H
–
HC
1
I
CH
+
O/(Me) S—ONa
2
N
VII
2
O
N
NOH
VI
III
Scheme 3.
Thus, the key stage of the process is the insertion of
an acetylene molecule into catalytic complex to
form intermediate carbanion VII (reaction ), which
abstracts a proton from a new molecule of III and proꢀ
duces intermediate VI ꢀvinyl oxime, reaction ) and
further indole
DMSO
+
NaOH
IV + H O
2
V
1
NOH
III
(
O
2
Scheme 4.
I.
However, the basicity of the NaOH–DMSO sysꢀ
tem (Н– = 23.6 [10, 11]) is insufficient for the quantiꢀ
Catalyst IV was obtained by reacting oxime III with
NaOH in DMSO at 100–130°C (Scheme 4).
tative preparation of catalyst IV (for oxime III, pK =
a
DOKLADY CHEMISTRY Vol. 435
Part 1
2010

A NEW TECHNOLOGY FOR THE SYNTHESIS OF 4,5,6,7ꢀTETRAHYDROINDOLE
309
24.3 [12]). Therefore, for complete shift of equilibꢀ available on a multiꢀton scale using the nanocrystalꢀ
rium to complex IV, the resultant water was removed line aggregate composed of sodium cyclohexanone
as azeotrope with toluene. For convenience of catalyst oximate and its complex with DMSO as the catalyst.
dosage, it can be prepared as a solution in a mixture The high conversion (70–90%) of the starting comꢀ
with oxime III in DMSO, which remains homogeꢀ pounds (cyclohexanone oxime and acetylene) and
neous at 100–130°C (depending on the content of high selectivity (95–99%) toward the target product,
complex IV).
enhanced safety (the use of atmospheric or close to
atmospheric pressure of acetylene, the absence of
flammable and explosive diethyl ether extractant), and
improved environmental characteristics (lowꢀwaste
production) are the attributes of this technology.
Therefore 4,5,6,7ꢀtetrahydroindole becomes a real
starting material for its industrial dehydrogenation
into indole [14].
Moreover, the use of complex IV as catalyst instead
of free alkalis prevents the irreversible transformation
of the latter into acetates through the known reaction
[
13] with acetylene and water according to Scheme 5.
MOH + HC≡CH + H O
MOCOCH + H2
2
3
(
M is an alkali metal).
Scheme 5.
The general procedure of indole preparation is as
EXPERIMENTAL
follows. A hot (100–130°C) solution of catalyst, a
mixture of complex IV with oxime III, prepared from
NaOH and oxime III in DMSO (by removal of water
as azeotrope with toluene) is added in a nitrogen flow
to a hot (100–130°C) DMSO purged with nitrogen for
removal of oxygen and carbon dioxide. The preferable
concentrations of the components in the reaction
Four liters of DMSO and 1.75 L of a catalyst soluꢀ
tion obtained from 750 g of oxime III, 50 g of NaOH
0.87% of reaction mixture weight), and 1 L of DMSO
using toluene as an azeotropic agent) were placed into
a steel reactor (10 L) equipped with a mechanical stirꢀ
rer, electrical heating jacket, and internal cooling coil.
Nitrogen was passed through the reaction mixture on
heating (120–130°C) and with stirring for 0.5 h at a
rate of 0.8–1.0 L/min, then acetylene was passed at a
rate of 1.25–1.50 L/min (acetylene outlet flow rate is
(
(
mixture (catalyst solution) are 13–17% of oxime III
,
0.5–1.5% of NaOH. Acetylene is passed through the
reaction mixture at 120–130°C at a rate that provides
about 95% conversion. Acetylene supply is terminated
when conversion of oxime III reaches 70–80%. The
reaction mixture is kept at 100–130°C for 0.5–1 h
until dissolved acetylene reacts completely, purged
1
25–150 mL/min, acetylene conversion is 90%) durꢀ
ing 2.5 h. Temperature in the reactor (125–130°C)
was adjusted by varying the rate of acetylene supply
and internal cooling (cold water was passed through
the coil to compensate for exothermic effect). After
completion of acetylene passage, the reaction mixture
was kept for another 0.5 h at 120–130°C and treated
with nitrogen, neutralized (CO ), and vacuum disꢀ
2
tilled. First, 80–90% of DMSO is distilled off (which
can be reused in the process after azeotropic drying
with toluene). Then, the crude product containing
as noted above to give 544 g of indole
oxime III (conversion is 71%). The yield of
with respect to reacted oxime III, purity of 99%
admixture of II is 1%).
I
and 220 g of
DMSO (30–50%), indole
10–20%) is vigorously stirred with an equal volume of
toluene and a 10–20% aqueous solution of NaOH
0.2–0.4 of the fraction volume). The aqueous alkaꢀ
I (30–40%), and oxime III
I
was 96%
(
(
(
line phase is separated, a new portion of aqueous
NaOH is added (0.1–0.2 of the toluene layer volume),
and extraction is repeated. Extraction process comꢀ
pletes when only trace amount of oxime III is detected
ACKNOWLEDGMENTS
This work was supported by the Council for Grants
in the toluene layer. Toluene is distilled off from the of the President of the Russian Federation for State
toluene layer, this is accompanied by simultaneous Support of Leading Scientific Schools (grant no. NSh
azeotropic drying of indole
tion residue. Vacuum distillation of the residue affords
pure indole in 95–97% yield at the conversion of
oxime III of 70–90%. Water is distilled off from the
aqueous alkaline extracts, while the residue containing
DMSO, NaOH, and sodium cyclohexanone oximate
as a complex with DMSO can be further used for the
preparation of catalyst solution.
I
remaining in the distillaꢀ 3230ꢀ010.3).
I
REFERENCES
1
. Sundberg, R.J., The Chemistry of Indoles, San Diego:
Academic, 1997.
2
. Madsen, J.Ø., Meldal, M., Mortensen, S., and
Olsson, B., Acta Chem. Scand. B, 1981, vol. 35, no. 2,
pp. 77–81.
Thus, we have developed a new industrially conveꢀ
nient technology for the synthesis of 4,5,6,7ꢀtetrahyꢀ
droindole from cyclohexanone oxime and acetylene
3
. Trofimov, B.A. and Mikhaleva, A.I., NꢀVinilpirroly
(NꢀVinylprroles), Novosibirsk: Nauka, 1984.
DOKLADY CHEMISTRY Vol. 435
Part 1
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TROFIMOV et al.
4
.
The Chemistry of Hydroxylamines, Oximes and Hydroxꢀ 10. Trofimov, B.A., Vasil’tsov, A.M., and Amosova, S.V.,
amic Acids, Rappoport, Z. and Liebman, J.F., Eds.,
Chichester: Wiley, 2009, pp. 241–243.
Izv. Akad. Nauk SSSR, Ser. Khim., 1986, pp. 751–756.
1
1. Trofimov, B.A., in Sovremennye problemy organicheskoi
khimii (Modern Problems of Organic Chemistry), St.
Petersburg: Izd. St. Peresburg. Univ., 2004, vol. 14,
pp. 131–175.
5
6
7
. Wang, Z., Comprehensive Organic Name Reactions and
Reagents, Part 3, London: Wiley, 2009, pp. 2793–2796.
. Mikhaleva, A.I., Vasil’ev, A.N., and Trofimov, B.A., Zh.
Org. Khim., 1981, vol. 17, no. 9, pp. 1977–1988.
1
2. Bordwell, F.G. and Ji, G.Z., J. Org. Chem., 1992,
vol. 57, no. 11, pp. 3019–3025.
. Mikhaleva, A.I., Trofimov, B.A., and Vasil’ev, A.N., 13. Trofimov, B.A., Geteroatomnye Proizvodnye Atsetilena:
Khim. Geterotsikl. Soedin., 1979, no. 2, pp. 197–199.
Novye Polifunktsional’nye Monomery, Reagenty i Poluꢀ
producty (Heteroatomic Derivatives of Acetylene: New
Polyfunctional Monomers, Reagents, and Intermediꢀ
ary Products), Moscow: Nauka, 1981.
8
9
. RF Patent No. 29710, Byull. Izobret., 2007, No. 11.
. Gordon, J., The Organic Chemistry of Electrolyte Soluꢀ
tions, New York: Wiley, 1975.
14. RF Patent No. 2307830, Byull. Izobret., 2007, No. 28.
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2010