Zinc-promoted hydrohydrazination of terminal alkynes: An efficient domino synthesis of indoles

Article abstract of DOI:10.1002/anie.200703823

(Chemical Equation Presented) Indole click chemistry: The quest for better catalysts for the intermolecular hydrohydrazination to indoles leads to zinc salts. A simple one-pot synthesis forms indoles from arylhydrazines and terminal alkynes. The pharmacologically relevant indole building blocks are selectively formed in the presence of zinc triflate (Zn(OTf)₂) or ZnCl ₂ (see scheme).

Full text of DOI:10.1002/anie.200703823

Communications
DOI: 10.1002/anie.200703823
Indole Synthesis
Zinc-Promoted Hydrohydrazination of Terminal Alkynes: An Efficient
Domino Synthesis of Indoles**
Karolin Alex, Annegret Tillack, Nicolle Schwarz, and Matthias Beller*
There is continuing interest in the development of improved
methods for the synthesis of indoles owing to their impor-
tance as one of the most represented building block in natural
bioactive products and marketed drugs.[1,2] Thus, indole and
its derivatives have been termed “privileged pharmacological
structures”as they bind to many biological receptors with
high affinity.[3]
nation. Herein we report the intermolecular zinc-mediated
and -catalyzed hydroamination reactions of alkynes which
provide a general synthesis of indoles.[12,13]
Our initial investigations involved studying the effect of
different metal complexes on the model reaction of N-methyl-
N-phenylhydrazine 1a with 1-octyne 2a (Table 1). The
In recent years, domino sequences in particular have
provided efficient complementary access to various indoles.[4]
Such sequences start in general from easily available sub-
strates. A reactive intermediate is generated with the aid of a
catalyst, which is subsequently transformed to the desired
indole. For example, the domino hydroformylation–Fischer
indole sequence has evolved into a direct method for the one-
pot construction of complex indoles from olefins.[5,6] More
recently, Ackermann and Born reported the use of a
combination of TiCl4 and tBuNH2 as catalyst for the domino
hydroamination–Fischer indole cyclization.[7] In 1991, Berg-
man et al. reported the first zirconium-mediated synthesis of
indoles by trapping a hydrazidozirconocene complex with
alkynes and subsequent addition of hydrochloric acid.[8] Then,
Odom and co-workers described the first titanium-catalyzed
intermolecular hydroamination of arylhydrazines with
alkynes.[9,10] The arylhydrazones obtained have been used
further in the Fischer indole reaction to provide N-alkyl and
N-aryl indoles in high yield. Based on this elegant approach,
we have developed the titanium-catalyzed synthesis of
functionalized tryptamines and tryptamine homologues, and
tryptophol and tryptophol derivatives, starting from commer-
cially available arylhydrazines and alkynes.[11] A problem
which prevents widespread use of this reaction is the
sensitivity of the titanium complexes towards functional
groups, and the necessity for hydrazine protection and
indole deprotection steps.
Table 1: Variation of different metal salts for the indole synthesis.[a]
Entry Metal salt
Equiv
Conversion[b] [%] Yield[b] [%]
1[c]
2
3
4
5
Ti(NEt2)4/L/ZnCl2 0.05/0.1/3 100
85
>99
66
0
Zn(OTf)2
ZnCl2
1
1
100
78
FeCl3·6H2O
HAuCl4
1
1
8
97
0
6
7
8
9
H2PtCl6·6H2O
IrCl3
1
1
1
1
0.5
0.25
0.1
3
1
1
100
100
<5
10
96
72
36
100
79
<5
0
Sc(OTf)3
Yb(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
ZnCl2
<5
<5
94
70
30
97
55
0
10
11
12
13
14
15
ZnBr2
Zn(OAc)2
<5
[a] Reaction conditions: 1 mmol octyne, 1.3 mmol N-methyl-N-phenyl-
hydrazine, 2 mL THF, 1008C, 24 h. [b] Determined by GC with hexade-
cane as internal standard. [c] For hydroamination: 5 mol% Ti(NEt2)4,
10 mol% 2,6-di-tert-butyl-4-methyl-phenol (L), 2 mL toluene, 1008C,
24 h. For Fischer indole cyclization: 3 mmol ZnCl2, 1008C, 24 h.
Our continuing interest in indole syntheses led us to look
for alternative catalysts for the intermolecular hydrohydrazi-
amination reaction proceeds smoothly in the presence of
5 mol% of known titanium catalysts. Subsequent addition of
3 equivalents of ZnCl2 to promote the Fischer indole cycliza-
tion furnished the desired indole in good yield (85%; Table 1,
entry 1). Surprisingly, the overall reaction sequence also
proceeds in good to excellent yield without any titanium
catalyst. Only in the presence of Zn(OTf)2 and ZnCl2
(Table 1) is 4a obtained in > 99 and 66% yields, respectively
(Table 1, entries 2 and 3). Thus, simple zinc salts promote
both the intermolecular hydroamination of the arylhydrazine
1 with the terminal alkyne 2 to the corresponding arylhy-
drazone 3 and subsequently initialize the [3,3]-sigmatropic
cyclization to the corresponding indole 4.
[*] K. Alex, Dr. A. Tillack, N. Schwarz, Prof. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
[**] This work has been funded by the State of Mecklenburg–Western
Pomerania, the Bundesministerium für Bildung und Forschung, the
Deutsche Forschungsgemeinschaft (Graduiertenkolleg 1213 and
Leibniz Prize), and the Fonds der Chemischen Industrie. We thank
Dr. W. Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, and K.
Mevius for their excellent technical and analytical support.
Owing to the highly selective Markovnikov reaction[14] of
the alkyne with the hydrazine, only the 2,3-disubstituted
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Reaction of N-methyl-N-phenylhydrazine or N-phenylhydrazine with various substituted
indole is produced in excellent
alkynes.[a]
yield. Other typical Lewis acids,
such as FeCl3 and rare earth tri-
flates, are not active in this reaction
(Table 1, entries 4, 8, and 9). Fur-
thermore, HAuCl4, H2PtCl6, and
IrCl3, which are active in electro-
philic aromatic substitutions, gave
no desired product (Table 1,
entries 5, 6, and 7).[15] Instead,
oligomers of the alkyne are mainly
formed as side products.
Entry Lewis acid Arylhydrazine 1 Alkyne 2
Indole 4
Yield[b] [%]
94
1
2
ZnCl2
ZnCl2
2a
91
We investigated whether the
reaction also proceeds in the pres-
ence of catalytic amounts of Zn-
(OTf)2. Indeed, with 0.5 and 0.25
equivalents of Lewis acid, the
indole is obtained in 94 and 70%
ZnCl2
Zn(OTf)2
81
96
3
1a
ZnCl2
Zn(OTf)2
95
94
yield,
respectively
(Table 1,
4
5
6
1a
1a
1a
entries 10 and 11). However, a fur-
ther decrease to 0.1 equivalents led
to lower yields (Table 1, entry 12).
Variation of the reaction condi-
tions demonstrated that the model
reaction of N-methyl-N-phenylhy-
drazine with 1-octyne proceeds in
high yield in polar solvents, such as
ZnCl2
ZnCl2
82
97
tetrahydrofuran,
dimethylformamide. Notably, tolu-
ene, which is the commonly used
dioxane,
and
solvent
in
titanium-catalyzed
hydrohydrazinations, gave only a
low yield of 21% (24 h, 1008C,
3 equiv ZnCl2). To achieve full con-
version and high yield, a slight
excess of N-methyl-N-phenylhydra-
zine is advantageous.
7
8
ZnCl2
1b
1a
2e
97
58
We were interested in the scope
and limitations of the procedure
with different alkynes (Table 2). For
this purpose, we studied the reac-
tion of N-methyl-N-phenylhydra-
zine and N-phenylhydrazine with
various alkynes in the presence of
Zn(OTf)2 and ZnCl2. Notably,
applying the unprotected hydrazine
together with 1-octyne, the free
indole 4b is formed in high yield
(91%; Table 2, entry 2). This is the
first example of free indole forma-
tion by hydrohydrazination of
alkynes. Apart from 1-octyne other
alkynes, for example 3-phenyl-1-
propyne and 3-cyclopentyl-1-pro-
pyne, also gave the corresponding
indoles 4c and 4d in up to 96%
yield (Table 2, entries 3 and 4). We
developed a synthesis for pharma-
Zn(OTf)2
9
ZnCl2
1a
50
10
11
ZnCl2
1a
1a
60
53
Zn(OTf)2
[a] Reaction conditions: 1.5 mmol alkyne, 1.95 mmol N-methyl-N-phenylhydrazine or N-phenylhydra-
zine, 3 equiv ZnCl2 or 1 equiv Zn(OTf)2, 4 mL THF, 1008C, 24 h. TBDMS=tert-butyldimethylsilyl.
[b] Yield of isolated product.
ceutically
relevant
tryptophol
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Table 3: Reaction of 1-octyne with various substituted arylhydrazines.[a]
homologues by reaction of silyl-protected (2- and 3-hydroxy-
alkyl)alkynes with N,N-disubstituted arylhydrazines.[11b] The
yield of this reaction using simply ZnCl2 is 82% (Table 2,
entry 5). The particular advantage of this reaction is that by
using ZnCl2, there is no need for protecting groups at the
alkyne or the hydrazine unit. Thus, the tryptophol homologue
4g is obtained in excellent yield (97%) by reacting N-
phenylhydrazine with pentyn-1-ol in the presence of ZnCl2
(Table 2, entry 7). Moreover, the reaction of N-methyl-N-
phenylhydrazine with methyl pent-4-ynoate gave the indo-
methacin analogue 4h (Table 2, entry 8). Similarly, the
phthalimide-protected 6-aminohexyne afforded the trypt-
amine homologue 4i (Table 2, entry 9). Even sensitive
electron-rich 3-silyloxyindoles 4j[16] and 3-methoxyindole 4k
were obtained, although only in moderate yields because of
decomposition. To our knowledge, the latter reaction is the
first example of a hydroamination of a propargylalkylether. In
addition, we carried out some initial trials with internal
alkynes, for example 1-phenyl-1-propyne and diphenylacet-
ylene. However, these substrates resulted only in traces of the
respective indoles under the optimized conditions, and in
these cases, further work is necessary.
Entry
Hydrazine 1
Indole 4
Yield[b] [%]
1
97
2
82
3
4
95
67
5[c]
6[c]
7[c]
97
97
96
We explored the reaction of 1-octyne with various
substituted arylhydrazines 2 in the presence of Zn(OTf)2.
Again, a protection of the arylhydrazine is not necessary, and
the free indole is obtained in good to excellent yields
(Table 3). Comparing ortho-and para-methylphenylhydra-
zine, the former is less reactive. Arylhydrazines substituted
with electron-withdrawing groups required higher temper-
atures and more Zn(OTf)2 for complete conversion (Table 3,
entries 5–9), which is in agreement with the Fischer indole
cyclization of aldehydes. Applying these conditions, all
monohalophenylhydrazines gave product yields of > 95%.
In the case of dihalosubstituted arylhydrazines, somewhat
lower yields were observed (Table 3, entries 8 and 9).
In conclusion, we have developed a convenient one-pot
method for the synthesis of various substituted indoles.
Starting from commercially available arylhydrazines and
terminal alkynes, a range of pharmaceutically relevant
indole building blocks are obtained selectively in the presence
of either Zn(OTf)2 or ZnCl2. No expensive catalyst is required
for this novel environmentally friendly reaction, and for the
first time free indoles, for example, tryptophol derivatives, are
directly available from alkynes.
8[c]
9[c]
10
80
52
97
[a] Reaction conditions: 1.5 mmol 1-octyne, 1.95 mmol arylhydrazine,
1 equiv Zn(OTf)2, 4 mL THF, 1008C, 24 h. [b] Yield of isolated product.
[c] 2 equiv Zn(OTf)2, 4 mL THF, 1208C, 24 h.
Experimental Section
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After removal of the solvent in vacuo, the indole product was purified
by column chromatography (hexane/ethyl acetate).
Received: August 20, 2007
Revised: September 29, 2007
Published online: February 8, 2008
Keywords: alkynes · hydrohydrazinations · indole · zinc
.
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