Titanium-catalyzed hydroamination of propargyl alcohol derivatives: Synthesis of 3-silyloxy-2-methylindoles via hydrohydrazination

Article abstract of DOI:10.1055/s-2007-973892

A general method for the one-pot synthesis of substituted 3-(tert-butyldimethylsilyloxy)indoles via hydrohydrazination of alkynes and subsequent Fischer indole synthesis has been developed. For the first time titanium-catalyzed hydroaminations of propargy

Full text of DOI:10.1055/s-2007-973892

LETTER
1091
Titanium-Catalyzed Hydroamination of Propargyl Alcohol Derivatives:
Synthesis of 3-Silyloxy-2-methylindoles via Hydrohydrazination
S
ynthesis of 3-Sily
i
loxy-2
c
-
methylind
ooles lle Schwarz, Karolin Alex, Iliyas Ali Sayyed, Vivek Khedkar, Annegret Tillack, Matthias Beller*
Leibniz-Institut für Katalyse e.V., Universität Rostock, Albert-Einstein-Str. 29A, 18059 Rostock, Germany
Fax +49(381)12815000; E-mail: matthias.beller@catalysis.de
Received 24 January 2007
synthesis of functionalized tryptamines and tryptophols
starting from commercially available aryl hydrazines and
chloroalkynes or 3- and 4-silyloxyalkynes.12a,b Based on
this work, we studied the reaction of aniline, isobutyl-
amine and N-methyl-N-phenylhydrazine with tert-butyl-
dimethylsilyl-protected propargyl alcohol in the presence
of a catalytic amount of tetrakis(diethylamino)titan
[Ti(NEt2)4] and different phenols as ligands. While the
former two model reactions gave only low yields (<5%)
of the corresponding internal imine, the catalytic hydro-
hydrazination proceeded with significant conversion
(>80%) in the presence of 2,6-di-tert-butyl-4-methyl-
phenol as ligand! Interestingly, the resulting hydrazone is
easily further converted in the presence of stoichiometric
amounts of ZnCl2 to give the corresponding siloxyindole
in respectable yield (Scheme 1).
Abstract: A general method for the one-pot synthesis of substituted
3-(tert-butyldimethylsilyloxy)indoles via hydrohydrazination of
alkynes and subsequent Fischer indole synthesis has been devel-
oped. For the first time titanium-catalyzed hydroaminations of
propargyl alcohol derivatives are shown.
Key words: alkyne, hydrazine, hydroamination, indole, titanium
The addition of nitrogen compounds across carbon–car-
bon triple bonds continues to be an important subject for
organic synthesis and catalysis.1 Such addition reactions
are perfectly suited to fulfill today’s needs of green chem-
istry because atom economy or atom efficiency is in prin-
ciple 100%. In recent years a variety of catalysts based on
both early as well as late-transition-metal complexes has
been developed. Based on the pioneering work of Berg-
man et al.2 especially metallocenes have become popular
catalysts in these reactions. More recently, Doye,3 Odom,4
Schafer5 and other6 made significant contributions to the
further development of titanium catalysts with respect to
intermolecular hydroaminations. However, in most reac-
tions nonfunctionalized aromatic or simple aliphatic
alkynes were reacted with primary amines as substrates.
Thus, the hydroamination of more functionalized alkynes
is still a challenging task. During our studies on the hy-
droamination of olefins and alkynes,7 we became interest-
ed in the selective hydroamination of propargylic alcohols
and their derivatives, which constitute probably the most
prominent class of functionalized aliphatic alkynes. Here,
we report the first examples of such reactions in the
presence of titanium catalysts.
Me
TBDMSO
TBDMSO
1. Ti(NEt2)4, 2,6-di-tert-butyl-
1
2
4-methylphenol, toluene
N
N
+
R1
R1
R2
N
R2
H2N
3 (Markovnikov)
2. ZnCl2, toluene,
100 °C, 24 h
OTBDMS
R2
Me
N
In addition to being environmentally benign, the hydro-
amination of alkynes opens up interesting possibilities for
novel domino and one-pot reactions based on the resulting
imines, enamines, or hydrazones. Recent examples in-
clude the combination of hydroamination coupled with di-
rect nucleophilic addition of organometallic reagents8 and
electrocyclic rearrangements such as the Fischer indole
synthesis.9 For some time our group has been interested in
the application of catalytic domino sequences such as
hydrohydrazinomethylation of olefins,10 carbonylations,11
and hydrohydrazination of alkynes12 for the synthesis and
refinement of indoles.13 Recently, we developed a one-pot
R1
4
Scheme 1 Hydrohydrazination of silyl-protected propargyl alcohol
to 3-silyloxy-2-methylindoles
To our delight the catalytic hydrohydrazination proceeded
smoothly with high regioselectivity to the Markovnikov
isomer 3,14 which underwent a selective Fischer indole
synthesis to yield exclusively the 2,3-disubstituted indole
4. To the best of our knowledge there is only a character-
ization of 3-phenoxy- and 3-methoxyindoles established
and one different preparation of a special 2-substituted 3-
silyloxyindole known in literature.15 Noteworthy, a simi-
lar structural motif is found in furo[3,2-b]indoles, which
are known to have potent analgesic and anti-inflammatory
SYNLETT 2007, No. 7, pp 1091–1095
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973892; Art ID: G02807ST
© Georg Thieme Verlag Stuttgart · New York

1092
N. Schwarz et al.
LETTER
Table 1 Reaction of tert-Butyldimethylsiloxy-2-propyne (1) with N-Methyl-N-phenylhydrazine (2a)a
OTBDMS
TBDMSO
1. Ti(NEt2)4, 2,6-di-tert-butyl-4-
methylphenol, toluene
1
+
Me
2. ZnCl2, toluene, 100 °C, 24 h
N
Me
Me
N
4a
H2N
2a
Entry
Ti(NEt2)4 (mol%) Ligand (mol%)
Temp (°C)
Ratio
Time (h)
Yield (%)b
hydrazine/alkyne
1
2
3
4
5
6
7
5
10
5
–
100
100
80
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1:1.3
1.3:1
24
24
24
24
24
24
4
42
51
60
65
42
50
53
20
10
10
10
10
10
5
100
120
100
100
5
5
5
a Reaction conditions: hydrohydrazination: see Table 1; Fischer indole cyclization: ZnCl2 (3.0 equiv), 100 °C, 24 h.
b Isolated yield based on tert-butyldimethylsiloxy-2-propyne.
activity16 and act as potent BKCa channel openers for the
Table 2 Reaction of tert-butyldimethylsiloxy-2-propyne (1) with N-
Benzyl-N-phenylhydrazine (2b)a
treatment of neuronal damages or to treat cardiovascular
diseases.17
OTBDMS
TBDMSO
1. Ti(NEt2)4, 2,6-di-tert-butyl-4-
methylphenol, toluene
Selected results of the model reaction of tert-butyldimeth-
ylsiloxy-2-propyne (1)18 with N-methyl-N-phenylhydra-
zine (2a) are shown in Table 1. The best yield of indole 4
(65%) is achieved applying 5 mol% Ti(NEt2)4 and 10
mol% 2,6-tert-butyl-4-methyl-phenol at 100 °C in the
presence of a slight excess of hydrazine (Table 1, entry 4).
Next, the effect of different Lewis acids on the Fischer
indole cyclization was investigated. Therefore the hydro-
hydrazination of tert-butyldimethylsiloxy-2-propyne (1)
and N-benzyl-N-phenylhydrazine (2b) was performed in
the presence of different Lewis and Brønsted acids like
p-toluenesulfonic acid (PTSA),19 polyphosphoric acid
(PPA),20 and iron(III)chloride21 instead of zinc chloride
(Table 2).
1
+
Me
2. Lewis acid, toluene,
100 °C, 24 h
N
Bn
Bn
N
4b
H2N
2b
Entry
Lewis acid
FeCl3
Yield (%)b
1
2
3
4
5
6
7
8
9
<1
<10
<1
NH4Cl
SO2Cl2
AcOH
PPA
<1
<1
However, none of the tested acids gave a better result
compared to ZnCl2 (50%).
PTSA
<1
Finally, we applied the optimized hydrohydrazination–
cyclization protocol to ten different indole products
(Table 3).22 Commercially available aryl hydrazines with
different substituents in the para position such as Me,
OMe, F, Cl, Br, and SO2Me were alkylated with methyl
iodide or benzyl bromide in the presence of base and re-
acted with the in situ titanium catalyst and ZnCl2 to give
the desired 3-siloxyindole derivatives in good to moderate
yields.
Y(OTf)3
Zn(OTf)2
ZnCl2
<10
28
50
a Reaction conditions: hydrohydrazination: tert-butyl-dimethylsiloxy-
2-propyne (1.0 mmol), N-benzyl-N-phenylhydrazine (1.3 mmol),
Ti(NEt2)4 (5 mol%), 2,6-di-tert-butyl-4-methylphenol (10 mol%),
toluene (2 mL), 100 °C, 24 h; Fischer indole cyclization: Lewis acid
(3.0 mmol), 100 °C, 24 h.
b Isolated yield based on tert-butyldimethylsiloxy-2-propyne.
In general, the N-methyl-protected indoles gave a higher
yield compared to the N-benzyl-protected indoles. Note-
worthy, the reaction sequence can be performed easily up
to a 10 g scale without loss in yield.
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LETTER
Synthesis of 3-Silyloxy-2-methylindoles
1093
Table 3 Reaction of tert-Butyldimethylsiloxy-2-propyne (1) with Various Substituted Hydrazines (2a–j)a
Entry
1
Alkyne 1
Hydrazine 2
Product 4
Yield (%)b
65
OTBDMS
Me
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
H2N
N
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
N
Me
Me
OTBDMS
2
3
4
5
6
7
8
9
50
45
40
40
40
35
60
40
H2N
N
Me
N
Bn
Bn
OTBDMS
Me
Br
Br
Br
Br
H2N
N
N
Me
Me
OTBDMS
Me
H2N
N
N
Bn
Bn
OTBDMS
Cl
Cl
Me
H2N
N
N
Me
Me
OTBDMS
Cl
Cl
Me
H2N
N
N
Bn
Bn
OTBDMS
F
F
2g
2h
2i
4g
4h
4i
Me
H2N
N
N
Bn
Bn
OTBDMS
Me
OMe
Me
MeO
H2N
N
N
Bn
Bn
OTBDMS
Me
H2N
N
Me
N
Bn
Bn
Me
O2
S
OTBDMS
O2S
Me
10
2j
4j
20
OTBDMS
Me
H2N
N
N
Bn
Bn
a Reaction conditions: hydrohydrazination: tert-butyldimethylsiloxy-2-propyne (1.0 mmol), arylhydrazine (1.3 mmol), Ti(NEt2)4 (5 mol%),
2,6-di-tert-butyl-4-methyl-phenol (10 mol%), toluene (2 mL), 100 °C, 24 h; Fischer indole cyclization: ZnCl2 (3.0 mmol), 100 °C, 24 h.
b Isolated yield based on tert-butyldimethylsiloxy-2-propyne.
In conclusion, a new efficient method for the synthesis of applied. Starting from commercially available aryl hydra-
functionalized 3-silyloxy-2-methylindoles has been de- zines and silyl-protected propargyl alcohol a variety of
veloped. As key step the first titanium-catalyzed hy- new electron-rich indole derivatives are accessible with
droamination of a propargylic alcohol derivative is high regioselectivity in the presence of Ti(NEt2)4 and
Synlett 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York

1094
N. Schwarz et al.
LETTER
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ceuticals is currently under way in our laboratory.
Acknowledgment
This work has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF (Bundesministerium für Bildung und For-
schung), the Deutsche Forschungsgemeinschaft (Graduiertenkolleg
1213 and Leibniz prize), and the Fonds der Chemischen Industrie
(FCI). We thank Dr. J. Holenz and Dr. J. L. Díaz Fernández (both
Esteve, Spain) for general discussions. We also thank Dr. W.
Baumann, Dr. D. Michalik, Dr. C. Fischer, S. Buchholz, and A.
Lehmann for their excellent technical and analytical support.
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LETTER
Synthesis of 3-Silyloxy-2-methylindoles
1095
(15) For the synthesis of 3-phenoxy- and 3-methoxyindoles, see:
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(22) Representative Procedure: Synthesis of 1-Benzyl-3-(tert-
butyldimethylsilyloxy)-2-methyl-1H-indole (4b)
In an ACE pressure tube under an argon atmosphere the
ligand 2,6-di-tert-butyl-4-methylphenol (22.0 mg, 0.1
mmol) is dissolved in 3 mL dry toluene. To this solution
N-benzyl-N-phenylhydrazine (257.7 mg, 1.3 mmol), tert-
butyldimethylsiloxy-2-propyne (209.0 mL, 1.0 mmol) and
Ti(NEt2)4 (18 mL, 0.05 mmol) were added. The reaction
mixture was heated at 100 °C for 24 h. Then the pressure
tube was opened under argon to add ZnCl2 (410.0 mg, 3.0
mmol). The reaction mixture was heated at 100 °C for
further 24 h. After cooling to r.t. the solution was decanted
and the dark residue was washed with toluene and EtOAc.
After removal of the combined solvents in vacuo and
purification by column chromatography (eluent: hexane–
EtOAc = 10:1) yielded 1-benzyl-3-(tert-butyldimethyl-
silyloxy)-2-methyl-1H-indole (175.8 mg, 50%) as light
yellow solid (mp 69 °C). 1H NMR (300 MHz, CDCl3):
d = 7.45–7.40 (m, 1 H), 7.27–7.21 (m, 3 H, m-, p-Ph), 7.10
(m, 1 H), 6.93 (m, 2 H), 6.86–6.87 (m, 2 H, o-Ph), 5.22 (s, 2
H, CH2Ph), 2.20 (s, 3 H), 0.83 (s, 12 H), 0.15 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): d = 136.4 (i-Ph), 135.6, 133.6,
128.9 (m-Ph), 128.4, 127.8 (p-Ph), 125.8 (o-Ph), 121.7,
120.6, 120.8, 120.7, 108.7, 46.9, 25.8, 18.2, 9.1, –5.3 ppm.
MS (EI, 70 eV): m/z (relative intensity) = 351 (100) [M+],
294 (27), 260 (13), 221 (25), 204 (12), 177 (8), 115 (15), 91
(90), 73 (71), 65 (8), 43 (6). HRMS (EI): m/z calcd for
C22H29NOSi: 351.2013; found: 351.1999.
Synlett 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York

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