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Catalytic Hydrogenation of Indole.

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-
BOC - ( I ) - O M e
J
2 - - O H H - - 0 M e Z--OH H - - 0 M e
BOC-OH
z-
- 0 M e Z-
-0Me
Z-
-OH
-0Me
H-
Z
-0Me
H
OMe
BOC
BOC-(11)-OMe
J
BOC-(I)-OH
+
H-(11)-OMe
I(anhydrida method)
B OC - ( I - 11)- OMe
J.
H- P h e - P r o - P r o - Phe- Phe-Val- P r o - P r o - A l a - P h e - O H
OMe
7--,
cyclization
BOC--OH H - - 0 M e
BOC
BOC-OH
H - - 0 M e BOC-OH
H-
OMe
- OMe
B OC
- 0 M e BOC
OMe
BOC
-OH
OMe
H-
BOC
-OM<
The terminal protecting group was removed from the
decapeptide and cyclization of the free decapeptide
was then accomplished by means of the anhydride
method "61. The yield was improved by additional
protonation of the free amino terminal during an1161 R . A . Boissonnus and I . Schumunn, Helv. chim. Acta 35,
2229 (1952).
1171 Th. Wielund,J. Fuesel, and H. Fuulstich, Liebigs Ann. Chem.,
in press.
antamanide (I)
hydride formation [171. Antamanide was obtained in
ca. 30 % yield (with reference to the linear zwitterionic
decapeptide). The compound crystallized out when its
solution was seeded with the natural substance. In
mouse experiments a dose of 0.5 mg per kg body
weight, administered subcutaneously, was found to be
effectivz against 5 mg of phalloidine per kg.
The authors are grateful to Fraulein Ch. Carstens and
Fraulein A . Schmitz, who work in the laboratory of
Dr. H . Wick ( C . H. Boehringer Sohn, IngelheimlRhein),
for toxicity determinations, to H.-J. Knorr and E.
Lantzsch, of the same company, for their skillful preparative work and their he& in the isolation of the
natural product, and to Frau H. Schiefer, who obtained
pure antamanide from the fungus harvest of 1966. Professor E. Lederer and Dr. M . Senn, Gif-sur-Yvette,
carried out the first mass spectrometric analyses. The
investigations were supported financially by the Deutsche Forschungsgemeinschaft. Dr. de Vries wishes to
thank the Alexander-von-Humboldt-Stiftungf o r a study
grant.
Received: February 5, 1968
[A 630 IE]
German version: Angew. Chem. 80, 209 (1968)
COMMUNICATIONS
Catalytic Hydrogenation of Indole
By I. Butula and the late R . Kuhn [*I
Willstatter and Juquet
hydrogenated indole ( I ) over
platinum in glacial acetic acid, obtaining octahydroindole
(3). If the hydrogenation was interrupted after absorption
of one molar equivalent of hydrogen, then indoline (2) was
isolated as well as (3). Adkins and Leonrudt [21 obtained (2)
in 60% yield on hydrogenation of (1) over copper chromite
at 170-190 "C and 250 atm, and (3) from ( I ) in 80% yield
on hydrogenation over Ni at 250 O C and 250 atm.
If indole is hydrogenated in glacial acetic acid over Pd(OH)z/
BaS04 at 18 or 60 OC, dark products are formed with an Hz-
(4)
208
absorption of 3-4 molar equivalents. If hydrochloric acid is
added and hydrogenation is effected at 60 O C , 1 molar equivalent of hydrogen is taken up rapidly and reduction then
ceases. Indoline can be isolated in 80 % yield. This product is
hydrogenated in glacial acetic acid over the same catalyst at
60 "C to give octahydroindole (3) (80%). However, if (2) is
hydrogenated in 1 N hydrochloric acid at 60 "C, 3,3a,4,5,6,7hexahydro-2H-indole (4) is obtained in 64 % yield.
Under these conditions Kuhn and Huns 131 obtained cyclohexanone from aniline and suggested that the hydrogenation
proceeds by way of the immonium compound (5). If (2) is
regarded as a substituted aniline, the appearance of the
imine (4) confirms Kuhn and Huns' suggestion. The structure
of ( 4 ) , which was prepared by a different route i.e. as intermediate in the synthesis of erythrinaner", was proved by
IR 151 and NMR spectra.
Zndoline (2) : 2 g of Pd(OH)Z/BaSO4 [61 was prereduced in 50
ml of glacial acetic acid, then 2.34 g of indole in 20 ml of 2 N
HCI was added, and the mixture was hydrogenated in a
shaking-apparatus at 60 O C and atmospheric pressure for
Angew. Chem. internut. Edit. / Vol. 7 (1968) No. 3
1.5 h. The catalyst was filtered off, t h e filtrate evaporated t o
dryness, and the residue dissolved in dilute sodium hydroxide solution and extracted with chloroform. After removal of
the solvent and distillation of residue, 2.1 g (90%) of (2) was
obtained. The I R spectrum was in accord with the Sadtler
spectrum No. 22446.
Octahydroindole (3) : 2.1 g of compound (2) was hydrogenated in 40 ml of glacial acetic acid over 2 g of Pd(OH)2/BaS04
for 14 h at 60 "C. Working up as above afforded 1.7 g (80 %)
of (3). Picrate, m.p. 135-137°C ( [ I ] : 137-139OC).
3,3a,4,5,6,7-Hexahydro-2H-indole ( 4 ) : 4 g of P d ( 0 H ) d
Bas04 was prereduced in 50 ml of distilled water, 3.6 g of
(2) in 1 0 0 m l of 1 N HCI was added, and the mixture was
hydrogenated at 60°C and atmospheric pressure for 20 h
(Hz uptake: 2.4 molar equivalents). The crude product
@
/
(strong -HN=C, absorption band at 1684 cm-1 in the I R
spectrum) was dissolved in dilute aqueous sodium hydroxide,
extracted with CHCl3, and distilled. 64% (2.3 g) of compound ( 4 ) was obtained alongside a little (3). Picrate, m.p.
132-133OC ([4J: 132-133°C).
Received: October 25th, 1967
[Z 650 IE]
German version: Angew. Chem. 80, 189 (1968)
Publication delayed at author's request
[*] Dr. I. Butula
Max-Planck-institut fiir medizinische Forschung,
Abt. fur Chemie
69 Heidelberg (Germany)
New address:
Rhein-Chemie GmbH
68 Mannheim-Rheinau (Germany)
[l] R. Willstutter and D. Jaquet, Ber. dtsch. chem. Ges. 51, 777
(1 918).
[2] H . Adkins and H. L. Leonradt, J. Amer. chem. SOC.63,1563
(1941). See also: F. Zymalkowski: Katalytische Hydrierung,
Enke, Stuttgart 1965, p. 211.
[3] R. Kuhn and H . J. Haas, Liebigs Ann. Chem. 611, 57 (1958).
[4] B. Belleau, J. Amer. chem. SOC. 75, 5765 (1953).
[5] B. Witkop, J. Amer. chem. SOC.78, 2873 (1956).
161 R . Kuhn and I. Butula, Liebigs Ann. Chem., in press.
A New Alkenynylamine Synthesis
By T. C. Sliields, W. E. Billups, and A . N. Kurtz[*]
Alkynylamines have been prepared [ I ] and stimulated considerable interest recently. We wish t o report the extension
of a simple route for alkenynesc2J t o the synthesis of alkenynylamines.
Treatment of isobutenyldimethylamine ( I ) with chloroform
and an excess of potassium tert-butoxide in pentane results
in (2,2-dichIoro-3,3-dimethylcyclopropyl)dimethylamine(2)
in 3 2 % yieldc31. Its N M R spectrum consists of four sharp
singlets at T = 7.73 (6 H, (CH&N group), 8.38 (1 H, cyclopropyl proton), and 8.73 and 8.77 (3 H each, C(CH& group).
Dehydrochlorination of (2) with potassium tert-butoxide in
dimethyl sulfoxide at 25-40°C for five hours affords a
20-30 % yield of dimethyl-(3-methylbut-3-en-l-ynyl)amine
(3). The N M R spectrum of (3) shows a multiplet at T = 5.24
(2 H, = CH2 group), a sharp singlet at 7.30 (6 H, (CH3)zN
group), and a three line pattern centered at 8.23 (3 H, C(CH3)
group). The molecular weight was determined mass spectrometrically (molecular ion at m/e = 109 with other significant
fragments at m/e = 94, 79, and 53). The ultraviolet spectrum
(h$:x('
= 257 nm, E = 8100, in cyclohexane) and infrared
absorption 14.53 p, -C =C-N(CH&], along with elemental
analysis, confirm the structure of (3).
In water, compound (3) is hydrolyzed to N,N-dimethyl-3methylbut-3-enamide (4) which shows N M R multiplets at
T = 5.19 and 5.31 (1 H each, =CH2 group), a singlet at
T = 7.03 (6 H, (CH&N group), and multiplets at 7.14 (2 H,
CH2 group) and 8.25 (3 H, C(CH3) group).
Angew. Chem. internat. Edit. 1 Vol. 7 (1968) / No. 3
KOtBu
(4)
(3)
The mechanism of the conversion of compound (2) into (3)
is not clear; however, attempts to trap a cyclopropene intermediate with nucleophiles have failed [41.
Synthesis of compound (2) :
Isobutenyldimethylamine (121.0 g; 1.22 moles) in n-pentane
(500 ml) is combined with chloroform (150.4 g; 1.26 moles)
and cooled t o 5 'C. Potassium tert-butoxide (179.5 g; 1.6
moles) is added slowly with stirring under a nitrogen atmosphere. Additional n-pentane (100 ml) is added during
this period to reduce the viscosity of the reaction mixture.
After an additional 1.6 hour's stirring, the mixture is quenched in ice water and the organic phase dried over NazS04.
The n-pentane is removed and the product rapidly distilled
through a short-path column whereupon 71 g (32% yield)
of product, b.p. -22 OC/O.7 torr, are obtained. The kettle
temperature should be kept below about 60 "C since the
contents are liable to explode if overheated. Redistillation of
the product is uneventful except for a small amount of decomposition. Analysis by VPC is not practical due t o extensive decomposition in the instrument; however, the compound
is shown t o exist in a very high state of purity by N M R
spectroscopy.
Synthesis of compound (3):
Compound (2) (18.2 g; 0.10 mole) is added slowly to a
solution of potassium tert-butoxide (44.9 g; 0.40 mole) in
dimethyl sulfoxide (300 ml), with stirring, under nitrogen.
The temperature (exothermic reaction) is maintained below
40 "C. After five hours total reaction time the mixture is
quenched in ice water and extracted with n-pentane. The
extract is dried over Na2S04, concentrated, and distilled
through a n 8" Vigreaux column. About 3.5 g of product
(20-30 % yield) is obtained. Purification is easily accomplished via preparative gas chromatography using a n 8 ft.
10 % SE-30 silicone gum rubber column.
Received: July 27th and November 23rd. 1967
[Z 659 IE]
German version: Angew. Chem. 80, 193 (1968)
[*I Dr. T. C. Shields, W. E. Billups, and Dr. A. N. Kurtz
Research and Development Department,
Union Carbide Corporation, Chemicals and Plastics,
P.O.Box 8361,South Charleston,WestVirginia 25 303 (U.S.A.)
[l] H. G. Viehe, Angew. Chem. 79, 744 (1967); Angew. Chem.
internat. Edit. 6, 767 (7967), and literature cited there.
121 T. C. Shields, B. A. Loving, and P . D. Gardner, Chem.
Commun. 1967, 556.
[3] M.Ohno, Tetrahedron Letters 1963,1753, has also described
the addition of dichlorocarbene to alkenylamines.
[4] T . C. Shields, B. A. Shoulders, J. F. Kmuse, C. L. Osborn, and
P. D. Gardner, J. Amer. chem. SOC.87, 3026 (1965).
Hydrogen-substituted Cyclotriphosphazenes
Formed by NH+PH TautomerizationI11
By A . Schmidpeter and J. Ebeling[*l
I-Amino-3-iminodiphosphazenes
[* *I condense readily with
compounds that contain two replaceable nucleophilic substituents on the central atom, yielding six-membered phosphazene heterocycles [21. 1-Amino-3-imino-l.1,3,3-tetraphen-
209
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