Highly selective synthesis of hydrazones and indoles from olefins

Article abstract of DOI:10.1016/j.tetlet.2003.11.044

Reaction of aliphatic olefins with synthesis gas and hydrazines in the presence of rhodium phosphine catalysts leads directly to the corresponding hydrazones. Applying Iphos as ligand good to excellent yields and high chemo- and regioselectivities were ob

Full text of DOI:10.1016/j.tetlet.2003.11.044

2
Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 869–873
Highly selective synthesis of hydrazones and indoles from olefins
Moballigh Ahmed, Ralf Jackstell, Abdul Majeed Seayad, Holger Klein
and Matthias Beller*
Leibniz Institut f€ur Organische Katalyse an der Universit€at Rostock e.V. (IfOK), Buchbinderstraße 5-6,
D-18055 Rostock, Germany
Received 1 October 2003; accepted 2 November 2003
Abstract—Reaction of aliphatic olefins with synthesis gas and hydrazines in the presence of rhodium phosphine catalysts leads
directly to the corresponding hydrazones. Applying Iphos as ligand good to excellent yields and high chemo- and regioselectivities
were obtained in toluene under mild conditions. In case of aromatic hydrazines in situ Fischer indole synthesis can be combined with
the new hydrazone preparation to give substituted indoles directly from olefins.
Ó 2003 Elsevier Ltd. All rights reserved.
Hydroamination1 and hydroaminomethylation2 repre-
sent elegant, atom-economic and efficient methods for
the synthesis of various amines from aliphatic olefins.
From both economic and environmental points of view,
these direct preparation routes for nitrogen-containing
compounds from inexpensive feedstock are advanta-
geous compared to classic laboratory procedures such
as nucleophilic substitution reactions. While general
methods for direct hydroamination of olefins are still in
their infancy, the hydroaminomethylation is applicable
on a broader scale. As shown in Scheme 1, this domino
reaction consists of hydroformylation of an olefin to
yield the corresponding aldehyde, subsequent formation
of an enamine (or imine) followed by hydrogenation to
give the desired amine.
importance.4 For some time we have been interested
in improving hydroaminomethylation reactions. As
an example the first selective hydroaminomethylation
reaction of aliphatic olefins using ammonia was
achieved.5 More recently, we developed the first rho-
dium phosphine catalyst systems for highly selective
hydroaminomethylation reactions of internal and ter-
minal olefins to give linear amines.6 Based on this work
we became interested in the use of other N-nucleophiles
instead of amines in domino-hydroformylation–amina-
tion sequences. Here, especially the use of hydrazines
attracted our interest. In the present paper, we describe
for the first time a rhodium-catalyzed one pot synthesis
of hydrazones from terminal olefins. In addition, the
combination of this new method with the classic Fischer
indole synthesis7 to give substituted indoles directly
from olefins is demonstrated. In this respect the work of
Eilbracht et al. is also noteworthy, who developed par-
allel to our work a novel tandem hydroformylation/
Fischer indole synthesis starting from olefins and aryl
hydrazines.8
In spite of the advantages of this one pot reaction, for
example, easy availability of starting materials and atom
efficiency, until recently comparatively few preparative
applications were known.3 Here, the work of Eilbracht
and co-workers, who developed elegant domino reac-
tions with an initial hydroformylation step, is of special
Clearly, the development of a high-yielding hydrazone
synthesis from olefins requires a tailor-made catalyst
system, which provides the desired chemo- and regio-
selectivity. On the one hand the catalyst system should
be sufficiently active for hydrogenation of the interme-
diate acylrhodium complex, but not active for reduction
of the resulting hydrazone. On the other hand the cat-
alyst should provide a high regioselectivity for the
desired linear or branched isomer. Surprisingly, little
is known about the influence of different phosphine
CO/H2
R2R3NH / H2
cat.
CHO
R1
R1
R1
NR2R3
cat.
Scheme 1. Hydroaminomethylation of olefins.
* Corresponding author. Tel.: +49-381-4669313; fax: +49-381-
4669324; e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.044

870
M. Ahmed et al. / Tetrahedron Letters 45 (2004) 869–873
ligands on both chemo- and regioselectivity in hydro-
aminomethylation reactions.6b
(65 °C). The regioselectivity of the model reaction is
highly dependant on the temperature and the partial
pressure of carbon monoxide (see Table 1, entries 1–5).
A slight increase from 65 to 80 °C decreases the n:iso-
selectivity from 88:12 to 77:23. Also an increase of the
synthesis gas pressure from 10 to 20 bar gave a decrease
in selectivity from 88:12 to 75:25. Among the three
solvents (toluene, methanol, tetrahydrofurane) tested,
toluene gave the best results (Table 1, entries 6–8). It is
important to note that the achieved high regioselectivity
in the initial hydroformylation reaction is the key for the
successful methodology development. Otherwise prod-
uct isolation from the different regioisomers is often
extremely difficult.
In order to get an impression of the effect of various
ligands on the chemo- and regioselectivity of the hyd-
roformylation step in the presence of hydrazines, we
studied the reaction of 1-pentene with phenylhydrazine
at different conditions as a model system.9 As shown in
Table 1 (entries 1–8, 12) 2,20-bis(diphenylphosphino-
methyl)-1,10-binaphthyl (Naphos),10 2,20-bis[di(3,5-tri-
fluoromethyl-phenyl)phosphinomethyl]-1,10-binaphthyl
(Iphos)6a;11 and Xantphos12 proved to be excellent
ligands for the desired transformation. Other bidentate
ligands, for example, dppe and dppf were less active
and/or selective (Table 1, entries 10 and 11). Also the
standard ligand PPh3 gave a significantly lower regio-
selectivity (n:iso ¼ 76:24) compared to Naphos, Iphos
and Xantphos. Among the latter three ligands Iphos
leads to the most active catalyst system (>99% yield of
N-hexenyl-N0-phenylhydrazone) at low temperature
Next, we were interested in the compatibility of our new
procedure with a number of aliphatic and aromatic
olefins (Table 2). Apart from N-phenylhydrazine, N,N-
dimethylhydrazine, N-methyl-N-phenylhydrazine, N-4-
chlorophenylhydrazine and N-4-methylphenylhydrazine
Table 1. Reaction of 1-pentene, phenylhydrazine and synthesis gas in the presence of different ligandsa
H
N
H
N
H2N
Cat.
N
N
H
N
+
+
CO/H2
n
iso
Entry
Ligand
PCO=H2 (bar)
Solvent
Temperature
(°C)
Conversionb
(%)
Hydrazone
yield (%)b
n:isoc
1
2
3
4
5
10
10
10
20
40
Toluene
Toluene
Toluene
Toluene
Toluene
65
80
84
100
100
100
100
83
99
99
99
99
88:12
77:23
78:22
75:25
61:39
2
2
P
P
100
65
65
CF3
CF3
CF3
P
P
6
7
8
10
10
10
Toluene
MeOH
THF
65
65
65
100
94
99
91
89
>99:1
98:2
93:7
2
2
91
CF3
9
10
PPh3
dppe
10
10
Toluene
Toluene
65
65
100
32
99
31
76:24
48:52
P(Ph)2
P(Ph)2
Fe
11
12
10
10
Toluene
Toluene
65
65
100
79
98
76
71:29
98:2
O
PPh2
PPh2
a Reaction conditions: 1-pentene (10 mmol), phenylhydrazine (10 mmol), solvent (30 mL), Rh(CO)2acac (0.1 mol %), ligand (0.2 mol %), time (16 h).
b Conversion and yields were determined by GC using bis(methoxyethyl)ether as an internal standard.
c Minor amount of the corresponding azo compound were observed by GC.

M. Ahmed et al. / Tetrahedron Letters 45 (2004) 869–873
Table 2. Rhodium-catalyzed synthesis of hydrazones from various olefinsa
871
Entry
Olefin
Hydrazine
Major product
Conver-
Hydrazone
Hydrazone n:iso
yieldb (%)
sion (%) selectivity
(%)
H
H
N
N
1
2
3
4
5
6
7
8
9
100
99
99
98
99
98
95
85
87
95
98
99
97
99
98
93
84
85
94
93
>99:1c
H2N
N
H
H
N
N
>99:1
73:27
98:2c
H2N
N
N
100
100
98
H2N
H2N
H2N
H2N
H2N
N
N
H
N
H
O
N
O
N
EtO
EtO
H
N
EtO
EtO
78:22c
88:12
88:12
>99:1c
>99:1
N
N
H
H
N
H
N
N
N
99
N
N
N
N
N
H
N
H
N
98
H
N
H
N
99
H2N
H
N
H
N
H2N
95
N
Cl
Cl
a Reaction conditions: olefin (10 mmol), hydrazin (10 mmol), Rh(CO)2acac (0.1 mol %), Iphos (0.2 mol %), toluene (30 mL), CO/H2 (1:1, 10 bar),
temperature (65 °C), time (16 h).
b Yields were determined by GC using bis(methoxyethyl)ether as an internal standard.
c Minor amount of the corresponding azo compound were observed by GC.
have been employed as N-nucleophile. In addition to
simples aliphatic olefins also functionalized alkenes such
as allyl phenyl ether, N,N-dimethylallylamine and 1,1-
dimethoxy-3-propene were used as substrates. In all
cases the conversion was >95% and the yield and
selectivity for hydrazones was good to excellent (85–
99%). In general, the corresponding hydrazone was
isolated as the sole product in excellent yield, however in
some cases (Table 2, entries 1, 4, 5 and 8) minor
amounts of the respective azo compound were also
detected spectroscopically. With regard to the regiose-
lectivity it is interesting to note that N-arylhydrazines
gave a significantly higher selectivity for the linear
isomer compared to N,N-dimethylhydrazine (Table 2,
entry 3) due to steric reasons. Using nonfunctionalized
aliphatic olefins the regioselectivity for the linear isomer
was typically >99:1 (Table 2, entries 1–2, 8 and 9). In
case of the functionalized substrates somewhat lower
selectivities in between 78:22 and 98:2 were observed
(Table 2, entries 4–7).
indole synthesis, which is still one of the most important
approaches to indoles.7 Due to their biological impor-
tance even today the development of new syntheses
of indoles is subject of considerable efforts.13
Indeed cooling of the crude reaction mixture to room
temperature, addition of an excess (4 equiv) of ZnCl2
and heating for several hours provided substituted in-
doles in a one pot reaction from olefins. As shown in
Table 3 various indoles have been isolated in yields from
75% to 85%. Except for the reaction of N-methyl-N-
phenylhydrazine (Table 3, entry 4) all transformations
proceeded highly selective (regioselectivity >99:1), which
is remarkable compared to mechanistically related
hydroaminomethylation reactions. Clearly the key to
success here is the use of our Rh/Iphos catalyst system.
In summary, we have developed the first general syn-
thesis of hydrazones directly from olefins. Good to
excellent chemo- and regioselectivity are achieved under
mild reaction conditions. Further refinement of the
produced hydrazones via the Fischer indole synthesis
leads to a one pot synthesis of indoles from olefins.
Compared to known stepwise procedures the method is
Having a reliable method for the synthesis of hydraz-
ones from olefins in hand we turned our interest to the
combination of this new method with the classic Fischer

872
M. Ahmed et al. / Tetrahedron Letters 45 (2004) 869–873
Table 3. One pot synthesis of indoles from olefinsa
Entry
1
Olefin
Hydrazine
Indol
Yieldb
85
n:iso
H
N
99:1
H2N
N
H
H
O
O
N
2
3
4
5
6
80
80
75
80
85
99:1
99:1
77:23
99:1
99:1
H2N
N
H
H
N
H2N
N
H
N
H2N
N
N
Ph
N
H2N
H
N
Cl
H2N
N
Cl
H
a Reaction conditions: olefin (10 mmol), hydrazine (10 mmol), Rh(CO)2acac (0.1 mol %), Iphos (0.2 mol %), toluene (30 mL), CO/H2 (1:1, 10 bar),
temperature (65 °C), time (16 h), then 4 equiv of ZnCl2 are added, and reaction is heated until conversion is complete.
b Isolated yield based on hydrazine.
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We thank Prof. Peter Eilbracht (Universitat Dortmund)
for general discussions and information about his
work on indole syntheses from olefins. S. Buchholz,
H. Baudisch, K. Reincke, Dr. C. Fischer, Prof. M.
Michalik and Dr. W. Baumann (all IfOK) are thanked
for excellent analytical support. This work has been
financed by the State of Mecklenburg–Western Pom-
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9. General procedure: All carbonylation experiments were
carried out in a Parr stainless steel autoclave (100 mL). In

M. Ahmed et al. / Tetrahedron Letters 45 (2004) 869–873
873
a typical experiment (Table 1, entry 6), the autoclave was
charged with Rh(CO)2acac (0.1 mol %), Iphos (0.2 mol %),
olefin (10.0 mmol), hydrazine (10.0 mmol) and toluene
(30 mL) under argon atmosphere. The autoclave was
pressurized with CO (5 bar) and hydrogen (5 bar) and the
reaction was carried out at 65 °C for 16 h. Then, the
autoclave was cooled to room temperature and depres-
surized. The reaction mixture was transferred to a Schlenk
flask under argon atmosphere, dried over MgSO4 and
analyzed by gas chromatography using bis(methoxy-
ethyl)ether as internal standard. N-Hexenyl-N0-phenyl-
hydrazone was identified by comparison with an
authentic sample by GC (HP5890 series; column: HP5
(Crosslinked 5% PH ME Siloxane) 30 m, 0.25 mm,
0.25 lm). The product was also confirmed by GC–MS,
51, 39, 29. HRMS calcd for C11H21N [Mþ]: 190.14700,
found: 190.14510.
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1
HRMS and NMR. H NMR (400 MHz, CDCl3) d 6.89–
7.35 (m, 5H), 6.60 (t, J ¼ 5 Hz, 1H), 2.23–2.35 (m, 6H),
1.59–1.70 (m, 2H), 1.06 (t, J ¼ 7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 145.4, 141.6, 129.0, 119.2, 112.3,
32.01, 31.31, 26.65, 22.40 13.92. GC–MS (EI, 70 eV):
m=z ¼ 190 [Mþ], 175, 161, 147, 133, 118, 106, 93, 77, 65,