Tandem hydroformylation-hydrazone formation-Fischer indole synthesis: A novel approach to tryptamides

Article abstract of DOI:10.1039/b503396a

A novel one-pot synthesis of indole systems via tandem hydroformylation-hydrazone formation-Fischer indolization starting from allylic amides and aryl hydrazines is described. This tandem procedure directly leads to biologically interesting tryptamides and analogues. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503396a

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A R T I C L E
Tandem hydroformylation–hydrazone formation–Fischer indole
synthesis: a novel approach to tryptamides†
Axel M. Schmidt and Peter Eilbracht*
Universita¨t Dortmund, Fachbereich Chemie, Organische Chemie I, Otto-Hahn-Str. 6, 44227
Dortmund. E-mail: peter.eilbracht@udo.edu; Fax: 49-231-7555363; Tel: 49-231-7553858
Received 8th March 2005, Accepted 5th May 2005
First published as an Advance Article on the web 20th May 2005
A novel one-pot synthesis of indole systems via tandem hydroformylation–hydrazone formation–Fischer indolization
starting from allylic amides and aryl hydrazines is described. This tandem procedure directly leads to biologically
interesting tryptamides and analogues.
But aldehydes undergo side reactions like an aldol reaction
Introduction
or aromatic substitution under the harsh Fischer conditions.
In many natural products and biologically active compounds the
Therefore protected aldehydes are often used instead. Thus
indole core is a privileged substructure. Tryptamine derivatives
acetals, aminals, enol ethers as well as bisulfite adducts are
in particular are involved in numerous biological processes, e.g.
melatonin in the control of the circadian rhythm or serotonin in
neurological processes. Thus tryptamine and its derivatives are
deprotected under Fischer indolization conditions and set the
carbonyl free in situ. In some cases the use of masked carbonyl
compounds like in the Japp–Klingemann modification is useful.
used for the treatment of diverse diseases like migraine (e.g.
Here b-ketoesters are reacted with aryl diazonium salts to give
Sumatriptan), depression (e.g. D-tryptophan), schizophrenia
(e.g. Sertindole) and many others (Scheme 1).
aryl hydrazones after cleavage of acetic acid. Fischer indolization
of the hydrazones thus obtained gives the indole-2-carboxylic
acid ester, which decarboxylates after hydrolysis.2 In summary
the b-ketoesters serve as masked aldehydes. As a matter of fact all
these methodologies require a laborious synthesis of the starting
carbonyl analogue and, in addition, the cleavage of bonds.
The most atom economic and efficient methodologies are
those in which the carbonyl group is formed via chain lengthen-
ing addition reactions. The hydroformylation of olefins is such
a well known and reliable method for the synthesis of aldehydes
being used in industrial processes.3 Surprisingly, only a few
examples are described in which hydroformylation has been used
to generate the aldehydes required for the synthesis of indoles
with sidechains in the 3-position. Thus, hydroformylation of
o-substituted nitrostyrenes gives indoles in fair yields. Here
the olefinic bond is regioselectively hydroformylated and under
the same conditions the nitro group is reduced to an aniline
which condenses intramolecularly then with the aldehyde to give
3-substituted indoles.4 This approach can be compared with
the Reissert indole synthesis,5 the Batcho–Leimgruber indole
synthesis6 or the Sugasawa indole synthesis.7 More recently
Selwood et al. have used hydroformylation for the synthesis of
the migraine drug 4991W93 to control the relative configuration
within the final product albeit with poor regioselectivity.8
Scheme 1
Sheldon et al. have published the synthesis of melatonin via
regioselective hydroformylation of N-allylacetamide followed by
Fischer indole synthesis.9
Due to the pharmaceutical relevance of tryptamine and
its analogues, numerous syntheses have been reported and
the development of new methods is even today a subject of
intensive research. Among established methods, the Fischer
indole synthesis is the most important method for the synthesis
of variably substituted indoles as it is for the synthesis of
tryptamine derivatives.1 In this reaction, carbonyl compounds
are condensed with aromatic hydrazines to give aryl hydra-
zones, which then react in a [3,3]-sigmatropic diaza–Cope type
rearrangement mediated by Brønsted or Lewis acids to give
indoles. For the synthesis of 3-substituted indoles, aldehydes are
used, which leave the 2-position of the indole unsubstituted.
Based on our general interest in tandem hydroformylation
sequences,10 we have recently found that indoles are obtained
directly from olefins under hydroformylation conditions, if
the hydroformylation is performed in the presence of an aryl
hydrazine and a Brønsted acid.11 This tandem reaction includes
three steps: hydroformylation of an olefin 1, condensation with
an aryl hydrazine to an aryl hydrazone 3 and finally Brønsted
acid mediated rearrangement and cyclization (Scheme 2). The
fact that the aldehydes as well as the hydrazones do not have to
be isolated as intermediates in this tandem reaction saves time
and resources. Furthermore, the low stationary concentration
of reactive intermediates suppresses side reactions and enhances
the selectivity of the reaction without an initial protection
of the aldehydes. Thus, starting from simple olefins, non-
functionalized indoles can be directly obtained in a one-pot
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/ob/b5/b503396a/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
2 3 3 3
©

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(5b) is used in a two-fold excess, unsymmetrically substituted
alkyl hydrazine 8 is obtained as a 2 : 1 adduct (Scheme 3).14
Scheme 2 General scheme of the tandem hydroformylation–Fischer
indole synthesis.
procedure with excellent yields, while the use of functionalized
olefins such as allylic alcohols and allylic amines provides direct
access to tryptophols and tryptamines. In addition, we have
found that benzhydrylidene protected aryl hydrazines obtained
from a Buchwald Hartwig amination12 can directly be used in
this tandem procedure giving higher selectivities than the free
aryl hydrazines, presumably due to the fact that the protected
hydrazines do not form salts with the acid in the chosen unpolar
medium. With respect to the high relevance of tryptamine
and homotryptamine units, we describe here in full detail our
extensive investigations on tandem hydroformylation–Fischer
indole synthesis starting from amino olefins and hydrazines. We
have developed efficient control of regioselectivity, alternative
use of different sources of aryl hydrazines and we give examples
for the application of this methodology. Our protocol provides
convenient access to branched as well as linear tryptamines.
Scheme 3 Reagents and conditions: (a) 1 eq 5a, 1 eq hydrazine, 1 mol%
[Rh(cod)Cl]2, dioxane, 90 bar CO, 20 bar H2, 18 h, 110 ◦C; (b) like (a)
but 3 days; (c) 2 eq 5b, 1 eq hydrazine, 1 mol% [Rh(cod)Cl]2, dioxane,
90 bar CO, 20 bar H2, 5 d, 110 ◦C.
Using this protocol for the synthesis of tryptamine derivatives,
allylic amines have to be used. Since hydroformylation of
terminal olefins typically results in a mixture of linear and
branched aldehydes, we decided to first investigate disubstituted
terminal olefins like N-ethyl-N-methallylic amine. Such olefins
undergo regioselective hydroformylation to linear aldehydes and
make the additional use of n-directing ligands obsolete. To
prevent hydrogenation of the starting olefin we have chosen high
carbon monoxide partial pressures to support rate determining
carbon monoxide insertion. Hydroformylation of 9 indeed
gives the desired aryl hydrazone 10, but neither inter- nor
intramolecular reductive amination products of the aldehyde are
observed (Scheme 4). However, approximately 10% of lactam
11 are obtained as a byproduct. Obviously, the rhodium acyl
species partially tends to intramolecular nucleophilic addition
of the secondary amine and formation of lactam 11 instead of hy-
drogenolysis to form the aldehyde. This behavior has previously
been reported for allylic amines15 and can be suppressed with an
appropriate choice of reaction conditions or protecting groups.
Results and discussion
To achieve high chemoselectivities for tandem processes, it is
important that all individual steps are as selective as possible
and that all reagents and reactants required, as well as all
intermediates, are compatible and do not affect each other. To
ensure this, we started our investigations with optimizations of
each step, e.g. hydroformylation of amino olefins, hydroformy-
lation in the presence of hydrazines, Fischer indolization of aryl
hydrazones and finally the complete tandem hydroformylation–
Fischer indole synthesis.
Hydroformylation in the presence of hydrazines
It is well known that hydroformylations can be conducted in
the presence of amines. While tertiary amines increase the
hydrogenation activity of rhodium based hydroformylation
catalysts giving alcohols exclusively,13 primary and secondary
amines condense with aldehydes followed by hydrogenation
of the resulting imines or enamines to amines in an overall
hydroaminomethylation.10 It has to be ensured that hydrazines
do not behave similarly. Therefore the hydroformylation was
conducted in the presence of hydrazines. In fact, hydroformy-
lation of styrene (5a) in the presence of N,N-disubstituted
hydrazines gives the hydrazones 6 in excellent yields. No hydro-
genation product of the intermediate aldehyde or the hydrazone
is observed whereas imines are usually reduced under the harsh
hydroformylation conditions. Obviously, the hydrazine does not
enhance the hydrogenation activity of the catalyst and rather
protects the aldehyde against reduction. Only after prolonged
reaction times can the hydrogenated product 7 be selectively ob-
tained as a result of hydroaminomethylation. If a-methylstyrene
Scheme 4 Reagents and conditions: 1 eq 9, 1 eq phenylhydrazine,
0.3 mol% Rh(acac)(CO)2, 50 bar CO, 10 bar H2, THF, 68 h, 100 ◦C.
2 3 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3

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In fact, methallylic phthalimide (14a) is regioselectively hy-
droformylated in quantitative yields to give aldehyde 15 and its
hydroformylation in the presence of phenylhydrazine yields the
corresponding hydrazone 16 as a mixture of E/Z-isomers in
excellent yields (Scheme 5).
reaction is the precipitation of ammonium salts from the unpolar
solvent. Among all acids, sulfuric acid as well as p-toluene
sulfonic acid (PTSA) showed the best results, leading to full
conversion. Obviously the combination of a less polar solvent
with at least one equivalent of a strong acid provided a fast
and selective conversion of the aryl hydrazones to the desired
tryptamines. In particular, the high conversions observed within
two hours reaction time were encouraging. Together with a slow
hydroformylation step, fast condensation and indolization help
to keep the concentrations of aldehyde and hydrazone low, so
that they do not undergo intermolecular acid mediated side
reactions.
Tandem reaction with methallylic amines
Next, we combined the optimized conditions for each step
with a tandem reaction. In fact, tandem hydroformylation–
Fischer indolization of methallylic phthalimide (14a) with
phenylhydrazine (17a) in the presence of one equivalent of PTSA
gave the desired tryptamine in 60% isolated yield (Table 1).
Here the tosylation of the indole nitrogen helped to separate
the product from impurities. Obviously, the tandem reaction
did not proceed with a selectivity as high as for the single steps.
Nevertheless, simple substituents are tolerated, e.g. the tert-butyl
group, which can be found in a number of in vitro serotonin
receptor antagonists.
Scheme 5 Reagents and conditions: (a) 1 eq 14a, 0.3 mol% Rh(acac)-
(CO)2, THF, 50 bar CO, 10 bar H2, 20 h, 100 ◦C; (b) like (a) but 1 eq
phenylhydrazine, 68 h.
If mixing all reagents in less polar solvents like toluene or
THF, precipitation is observed, due to protonation of the aryl
hydrazine. Therefore solubility problems might be responsible
for the decrease in selectivity. An appropriate protection of the
basic hydrazine on the other hand must allow the conversion
of aldehyde, thus only acid sensitive protecting groups are of
interest. Buchwald et al. have demonstrated, that benzhydryli-
dene protected aryl hydrazines in the presence of carbonyl com-
pounds under acidic conditions undergo Fischer indolization in
high yields.18 While the benzophenone hydrazone itself cannot
cyclize to form an indole, it can only transcondense with a
second carbonyl compound leading to Fischer indolization.
Benzhydrylidene protected aryl hydrazines are either obtained
from commercially available aryl hydrazines or by palladium
catalyzed amination of aryl halides with benzophenone hy-
drazone. Indeed, the use of protected hydrazines increases
the selectivity as well as the yield of the tandem reaction
making a consecutive tosylation of the indole nitrogen obsolete.
Using this methodology, substituted tryptamines are isolated
in up to 83% yield (Table 2). Remarkably, aryl bromides are
tolerable although they are known to undergo oxidative addition
with rhodium(I) complexes19 leading to defunctionalization of
the aryl bromides. In some cases even without a transition
metal catalyst, under conditions of Fischer indolization, bromo
substituents are cleaved. On the other hand, bromo substituted
indoles are valuable starting materials for further derivatization
Even after three days reaction time at higher temperatures, no
hydrogenation of the hydrazone bond can be observed, so that
aryl hydrazones seem to be of higher stability against hydro-
genation than their alkyl analogues. In addition, the hydrazones
obtained from hydroformylation reactions are of high purity.
Apparently, hydrazines do not alter the chemoselectivity of the
hydroformylation catalysts [Rh(cod)Cl]2 and Rh(acac)(CO)2.
Indolization of aryl hydrazones
Having found conditions for a highly selective synthesis of
hydrazones under hydroformylation conditions, we started to
optimize the conditions for the Fischer indolization. These must
be compatible with the hydroformylation step, which therefore
has to be conducted in the same solvent as used for indolization.
Furthermore, it is important that the hydroformylation is not
hampered by the addition of acids. The latter must be tested in
a tandem reaction with fast consumption of starting material
and intermediates, since olefins oligomerize and aldehydes
undergo aldol reactions in the presence of acids. Therefore, we
concentrated on optimizing the Fischer indolization by testing
different solvents and acids. The most common systems for
Fischer indole synthesis are sulfuric acid in alcohols such as
methanol or ethanol. Indeed, there are examples where the
hydroformylation of alkenes has been carried out in an alcoholic
solution. But here, depending on the reaction conditions, the
intermediate rhodium acyl species can be trapped by the alcohol
to give esters,16 or the aldehyde suffers nucleophilic attack by the
alcohols to yield acetals.17 Since acetals are used as protected
aldehydes in Fischer indole synthesis, the use of alcohols as
solvents in the hydroformylation step is an option and would
support the principle of low stationary aldehyde concentrations.
To our surprise, hydrazone 16 did not lead to indolization in the
presence of 4 wt% sulfuric acid, nor in methanol or ethanol. Only
less polar solvents like refluxing THF or toluene, which are also
very common in hydroformylation chemistry, gave satisfying
conversions.
Table 1 Tandem reaction with methallylic amines
Entry
Hydrazine 17
Yield 18
1
2
3
17a (R = H)
60% (18a; R = H)
In the next step we tested different acids, turning our attention
to commercially available and cheap acids. In order to find
small differences in the acids’ activity, we used one equivalent of
each acid, stopped the reaction after two hours and estimated
the conversion by NMR. Our screening contained acids from
pKa = 5 to pKa = −8. A good indication for the starting
17b (R = Cl)
53% (18b; R = Cl)
17c (R = tert-butyl)
48% (18c; R = tert-butyl)
Cond.: 1 eq 14a, 1 eq 17, 1 mol% [Rh(cod)Cl]2, 50 bar CO, 10 bar H2, 1 eq
PTSA, toluene, 3 d, 100 ◦C; then 1 eq tosyl chloride, 50 wt% NaOH in
water, toluene, 20 h, rt.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
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Table 2 Use of benzhydrylidene protected hydrazine in the tandem
reaction with methallylic amines
Table 3 Stability of different protecting groups in the tandem reaction
Entry
Olefin 14
Yield 18
Entry
Hydrazine 17
Yield 18
1
2
3
4
14b (R1 = Et, R2 = ts)
14c (R1 = Et, R2 = bz)
14d (R1 = Et, R2 = ac)
14e (R1 = Et, R2 = eoc)
94% (18k)
85% (18l)
61% (18m)
58% (18n)
1
2
3
4
5
6
17d (R1 = H)
83% (18d; R1 = H)
17e (R1 = 4-F)
17f (R1 = 4-Cl)
17g (R1 = 4-Br)
17h (R1 = 2-CH3)
17i (R1 = 2-Cl)
47% (18e; R1 = 5-F)
78% (18f; R1 = 5-Cl)
50% (18g; R1 = 5-Br)
48% (18h; R1 = 7-CH3)
42% (18i; R1 = 7-Cl)
Cond.: 1 eq 14, 1 eq 17a, 1 mol% Rh(acac)(CO)2, 50 bar CO, 10 bar H2,
THF, 68 h, 120 ◦C, then 4 wt% H2SO4–THF, 2 h, 80 ◦C.
Cond.: 1 eq 14a, 1 eq 17, 1 mol% [Rh(cod)Cl]2, 50 bar CO, 10 bar H2,
desired tryptamides. The acetyl group, however, gave a slightly
decreased yield. Not surprisingly, the boc group is cleaved
under Fischer indolization conditions leading to an unselective
conversion, but with a simple switch from tert-butyloxycarbonyl
to an ethyloxycarbonyl group, the protected tryptamine was
obtained in 58% yield. Thus all protecting groups chosen are
tolerated under the reaction conditions (Table 3).
1 eq PTSA, THF, 3 d, 100 ◦C.
(e.g. by palladium catalyzed cross coupling methodologies of
5-bromoindole20). Therefore tandem hydroformylation–Fischer
indole synthesis offers a convenient pathway to bromo sub-
stituted tryptamine derivatives from easily available starting
materials.
In 2004, Cho and Lim successfully applied a-boc-aryl hy-
drazines in Fischer indolization and obtained indoles with very
high purities.21 Therefore we tested 17j as a substrate for tandem
hydroformylation–Fischer indole synthesis. Here the reaction
has to be conducted in a stepwise manner with subsequent
addition of acid. Since the boc group is stable under hydro-
formylation conditions, a-boc protected aryl hydrazones can
be obtained in quantitative yields. Tandem hydroformylation–
Fischer indolization of 17j gives the pure protected serotonin
analogue 18j22 in nearly quantitative yields without the need
for further purification. A number of different aryl hydrazines,
synthesized using Buchwald’s optimized conditions of the
copper(I) catalyzed N-arylation of amides (Goldberg reaction)23
and the non protected analogues were compared with respect
to their reactivity towards tandem hydroformylation–Fischer
indole synthesis. Only the p-methoxy phenylhydrazine 17j gives
a clearly increased yield (Scheme 6) whereas a-boc-protected
phenylhydrazine 17k gives only 38% of indole 18d. 4-Bromo
substituted a-boc-protected phenylhydrazine 17l gives 50% of
indole 18g.
Application of the hydroformylation–Fischer indolization
protocol to the synthesis of sertindole analogues
Having a reliable protocol in hand, we intended to apply
the hydroformylation–indolization sequence to the synthesis of
pharmacologically active compounds. Scheme 7 illustrates the
importance of a-branched tryptamides, which become more and
more interesting for pharmaceutical applications. LY 156735,
for example, has recently been discovered as a drug against sleep
disorders.24 Above, we have already demonstrated that this sub-
stitution pattern in the side chain can be obtained by the use of
disubstituted terminal olefins in the tandem hydroformylation–
Fischer indole synthesis.
Scheme 7 Recent example of a tryptamide with a branched side-chain.
Besides compounds with linear or branched aliphatic side
chains, there are also tryptamine analogues with additional
cyclic units, such as 3-piperidyl indoles, which have been recog-
nized as important pharmacophores in the last decade. The most
prominent example is N-phenylindole sertindole (Scheme 1).
Among the diverse dopamine and serotonin receptors, sertin-
dole blocks the a1-adrenoceptor predominantly.25 In 2002,
Andersen et al. optimized the structure of sertindole and
increased selectivity towards the a1-adrenoceptor by variation
of the substituents in the 5-position of the indole and of the
piperidyl nitrogen (Scheme 8). In particular, the replacement of
the chloro substituent by heterocyclic substituents in 19 helps
in increasing this selectivity.26 In most cases, these substituents
can be introduced via palladium catalysis starting from the
intermediate 5-bromoindole 21. Tandem hydroformylation–
Fischer indole synthesis offers convenient access to intermediate
21 starting from the easily available olefin 20 via conversion
with commercially available 4-bromo phenylhydrazine 17m and
gives indole 21 in 39% yield. However, in this special case
benzhydrylidene protected 4-bromo phenylhydrazine (17g) gives
no increased yield. Copper catalyzed N-arylation with 4-iodo
Scheme 6 Reagents and conditions: 1 eq 14a, 1 eq 17, 1 mol%
Rh(acac)(CO)2, 50 bar CO, 10 bar H2, THF, 68 h; 120 ◦C, then 4 wt%
H2SO4–THF, 2 h, 80 ◦C.
Stability of different protection groups
For a comparison of the stability of different protecting groups
under tandem hydroformylation–Fischer indole synthesis, var-
ious methallylic amines were N-protected with phthalimide,
acetyl, benzoyl, tosyl and ethyloxycarbonyl groups and con-
verted in a stepwise manner. While hydrazone formation under
hydroformylation conditions in all cases gave excellent yields,
Fischer indolization disclosed differences. The phthalimide has
already been proven to be stable under the selected conditions.
Also the tosylate and the benzamide gave good yields of the
2 3 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3

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selectivity (85%) (Table 4, entry 1). To test the influence of
the protecting group towards n/iso-selectivity, several allylic
amides with protecting groups were hydroformylated with a
Rh(acac)(CO)2–XANTPHOS system (1 : 5) at 70 ◦C. In contrast
to the hydroformylation of disubstituted terminal olefins, a
lower carbon monoxide partial pressure was chosen to ensure
that CO does not displace XANTPHOS from the catalytically
active rhodium complex. Although under these conditions all
hydroformylation experiments proceeded with complete olefin
conversion, aldehyde could only be detected as the minor
product. Instead, 2-hydroxy pyrrolidines (26) were formed in
nearly quantitative yield via intramolecular attack of the primary
amide to the carbonyl group. Jackson et al. have found similar
behavior.29 Since only the n-aldehyde can cyclize, it is removed
from the hydroformylation equilibrium shifting the product
distribution towards the n-aldehyde selectively (Scheme 10).
Scheme 8 Optimized lead of the antipsychotic sertindole.
fluoro benzene leads to the intermediate 22, which is thus
conveniently obtainable in only two steps with multiplying the
literature reported yield (Scheme 9).26
Investigations towards n-selective hydroformylation–indolization
starting from allylic amines
So far we have always used disubstituted terminal olefins leading
to indoles with branched chains in the 3-position. Most of
the biologically active tryptamines, however, are tryptamines
with a non-branched side chain. Here, the hydroformylation–
indolization sequence requires monosubstituted olefins. While
ligand free hydroformylation of terminal disubstituted olefins
regioselectively gives n-aldehydes, ligand free hydroformyla-
tion of monosubstituted olefins leads to a mixture of n-
and iso-aldehydes. n-Selectivity is increased by the use of
sterically demanding bidentate ligands such as the biphosphite
BIPHEPHOS27 or the biphosphane XANTPHOS.28 Both lig-
ands lead to high n-selectivities when simple olefins like 1-hexene
or 1-octene are used. With functionalized olefins, however,
the n-selectivity decreases dramatically in our experience. In
tandem hydroformylation–Fischer indole synthesis, protected
amino olefins have to be used. The nature of the protecting
group strongly affects the n/iso-selectivity. Not only may N-
donor groups attached to the olefin compete with the catalyst
ligand, but also the aryl hydrazines may act as ligands, since
amines in general coordinate to the metal centre and influence
the performance of the hydroformylation.
For an investigation of the n/iso-selectivity, allylic phthalim-
ide (23a) was hydroformylated with the use of Rh(acac)(CO)2–
BIPHEPHOS in a 1 : 4 ratio. Here only a 2 : 1 mixture of n-/
iso-aldehydes was obtained. As an alternative, XANTPHOS
was tested, which according to our experience gives higher
n/iso-ratios in the hydroformylation of functionalized olefins.
Indeed, the use of Rh–XANTPHOS (1 : 5) gives the n-aldehyde
with 81% selectivity. Increasing the catalyst–ligand ratio to
1 : 10 results only in a marginal enhancement of the n-
Scheme 10 Reagents and conditions: 1 eq 23, 0.3 mol% Rh(acac)(CO)2,
1.5 mol% XANTPHOS, 10 bar CO, 10 bar H2, THF, 20 h, 70 ◦C.
Table 4 n-Selective hydroformylation of allylic amides
Entry Olefin 23
Ligand : [Rh] 24–25a,b
1
2
3
4
23a (R1 = R2 = pht)
5 : 1
10 : 1
5 : 1
10 : 1
5 : 1
10 : 1
5 : 1
10 : 1
4 : 1
6 : 1
6 : 1
24a–25a
24e–25e
24f–25f
24g–25g
23e (R1 = Et, R2 = ts)
23f (R1 = Et, R2 = ac)
23g (R1 = Et, R2 = eoc)
6 : 1
11 : 1
12 : 1
13 : 1
14 : 1
Cond.: 1 eq 23, 0.3 mol% Rh(acac)(CO)2, XANTPHOS (see table), 10
bar CO, 10 bar H2, THF, 20 h, 70 ◦C.a Determined by 1H-NMR of the
crude reaction mixture. b Full conversion to the aldehyde.
Scheme◦9 Reagents and conditions: (a) 1 eq 20, 1 eq 17m, 0.3 mol% Rh(acac)(CO)2, 50 bar CO, 10 bar H2, THF, 68 h, 120 ◦C then 4 wt% H2SO4–THF,
2 h, 80 C, 39%. (b) 1 eq 21, 1.2 eq 4-fluoro-iodobenzene, 2.1 eq K3PO4·7H2O, 5 mol% copper(I) iodide, 20 mol% N,Nꢀ-dimethylethylendiamine,
toluene (1 M), 24 h, 110 ◦C, 100%.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
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Table 5 n-Selective tandem hydroformylation–condensation of allylic
amines
It is noteworthy that the tandem hydroformylation–Fischer
indole synthesis of 23h gives tosylated homotryptamine 30f
in good yields. Application of a-boc protected p-methoxy
phenylhydrazine 17j yields the 5-methoxy tryptamine 30c in
excellent yields. Here, no further purification is required.
Conclusions
Entry Olefin 23
Ligand : [Rh] 27–28a,b
With the tandem hydroformylation–Fischer indole synthesis,
we have developed a new tandem sequence, which gives
fast and convenient access to pharmacologically interesting
tryptamides, respectively primary and secondary tryptamines
and homotryptamines, starting from protected aryl hydrazines
as well as allylic and homoallylic amines. The fact that inter-
mediates do not have to be isolated or purified clearly saves
time and resources. Regioselectivity of the tandem reaction can
effectively be controlled with the use of the biphosphane ligand
XANTPHOS. Finally we have given several examples for the
application of this new tandem sequence towards the synthesis of
the serotonin analogues 18j and 30c, the methylester of the plant
growth regulator IBA (29) and of 22, a valuable intermediate in
the synthesis of sertindole analogues.
1
2
3
23a (R1 = R2 = pht)
5 : 1
10 : 1
5 : 1
10 : 1
5 : 1
1 : 1
6 : 1
3 : 1
6 : 1
11 : 1
12 : 1
27a–28a
27b–28b
27c/28c
23e (R1 = Et, R2 = ts)
23f (R1 = Et, R2 = ac)
10 : 1
Cond.: 1 eq 17a, 1 eq 23, 0.3 mol% Rh(acac)(CO)2, XANTPHOS (see
table), 10 bar CO, 10 bar H2, THF, 68 h, 70 ◦C.a Determined by 1H-NMR
of the crude reaction mixture. b Full conversion to the hydrazone.
Consequently, by use of secondary allylic amides this consecu-
tive reaction can be suppressed and the n-aldehydes are obtained
with high yields and selectivities. Among the amides tested, three
different types can be recognized. Those containing two car-
bonyl groups give the lowest n/iso ratios. Here a precoordination
of the catalyst is more probable than in substrates with only one
carbonyl group. The allylic acetamide 23f for example gives an
n/iso ratio of 12 : 1. Ethyloxycarbonyl protected N-ethyl allyl
amine 23g gives the highest n/iso selectivity of approximately
14 : 1 with an optimum of the catalyst ligand ratio at 1 : 10.
Higher catalyst ligand ratios gave no further enhancement of
the n-selectivity in the case of allylic phthalimide.
Experimental
Materials
All reagents and solvents were dried and purified before
use by the usual procedures. Rh(acac)(CO)2 and Xantphos
were purchased. [Rh(cod)Cl]2 and Biphephos31 were pre-
30
pared according to published methods. All aromatic hydrazines
were purchased excluding protected hydrazines. N-Allyl, N-
ethylamides (23e–23g) were synthesized by allylation of the
corresponding secondary amides. All N-ethylamides were pre-
pared by the reaction of ethylamine with the corresponding
acid chloride in the presence of triethylamine and DMAP. All
other protected allylic amines (14b–14e, 23b–23d) were syn-
thesized by the reaction of the corresponding allylic amines
with the corresponding acid chlorides in the presence of tri-
ethylamine and DMAP. 2-(2-Methylallyl)isoindoline-1,3-dione
(14a) and 2-allyl-isoindole-1,3-dione (23a) were synthesized
according to published methods.31 Benzhydrylidene protected
aryl hydrazines18,11a and N-Boc aryl hydrazines23 were prepared
according to published methods.
n-Selective hydroformylation in the presence of phenylhydrazine
In order to study the influence of hydrazines on the n/iso-
selectivity of the rhodium–XANTPHOS catalyst hydroformy-
lation of protected allylic amines, the reactions were conducted
in the presence of phenyl. From the results compiled in Table 5,
it can be concluded that phenylhydrazines are not competing
with the n-directing XANTPHOS. Therefore aryl hydrazones
are obtained with a high degree of n-selectivity starting from
protected allylic amines.
Application of n-selective hydroformylation–indolization in the
synthesis of tryptamides starting from allyl amines
General methods
Using the optimized conditions of the tandem hydroformy-
lation–indolization procedure, olefin 23j gives the methyl ester
of the plant growth regulator 3-indole butanoic acid (IBA, 29)
in 91% isolated yield (Scheme 11). Hydrazone formation and
indolization proceed smoothly after addition of dilute sulfuric
acid.
1H-NMR and 13C-NMR spectra were measured on a Bruker
Advance DRX 400 spectrometer or a Bruker Advance DRX 500
spectrometer using CHCl3 or CH2Cl2 as internal standards. All
samples were dissolved in CDCl3. IR spectra were measured on a
Nicolet Impact 400D FT-IR spectrometer. Column chromatog-
raphy was carried out on 70–230 mesh silica gel (Macherey–
Nagel; silicagel 60). Elemental analyses were performed on a
Leco CHNS-932. High resolution mass analyses were performed
on a Jeol JMS-SX 102A.
General procedure for the tandem hydroformylation–Fischer
indole synthesis followed by tosylation of the crude product
A typical procedure is described. 2-(2-Methylallyl)isoindoline-
1,3-dione (0.66 g, 3.3 mmol), phenylhydrazine (0.36 g,
3.3 mmol), [Rh(cod)Cl]2 (16 mg, 1 mol%) and p-toluenesulfonic
acid monohydrate (0.63 g, 3.3 mmol) are dissolved in anhydrous
toluene (12 ml), placed in an autoclave and pressurized with
Scheme 11 Reagents and conditions: 1 eq 17a, 1 eq 23j, 0.3 mol%
Rh(acac)(CO)2, 3 mol% XANTPHOS, 10 bar CO, 10 bar H2, 68 h,
70 ◦C. (b) 4 wt% H2SO4–THF, 2 h, 80 ◦C.
◦
10 bar H2 and 50 bar CO. After stirring for 3 days at 120 C,
the mixture is poured into a suspension of tetrabutylammonium
hydrogensulfate (0.1 g) in toluene (15 ml) and NaOH (10 g,
50 wt% in water). Tosyl chloride (0.69 g, 3.6 mmol) in toluene
(15 ml) are dropped into the mixture over 10 minutes. After
stirring for 1 hour, the layers are separated and the organic
layer is extracted 3 times with ethyl acetate. The solvent is
If allylic amides and homoallylic amides are subjected to
the same conditions, tryptamines and homotryptamines are
obtained in good yields. All protecting groups are tolerated and
as expected from the results described above, strong electron
withdrawing protecting groups give the best yields (Table 6).
2 3 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3

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Table 6 n-Selective tandem hydroformylation–Fischer indole synthesis towards non-branched tryptamides
Entry Olefin 23
Hydrazine 17 Yield 30
Entry Olefin 23
Hydrazine 17 Yield 30
1
23c (n = 1, R1 = H, 17a
5
23f (n = 1, R1 = Et, 17a
R2 = ts)
R2 = ac)
2
23a (n = 1, R1 =
R2 = pht)
17a
6
23h (n = 2, R1 =
Et, R2 = ts)
17a
17a
3
4
23a (n = 1, R1 =
R2 = pht)
17j
7
8
23g (n = 1, R1 =
Et, R2 = eoc)
23e (n = 1, R1 =
Et, R2 = ts)
17a
23i (n = 1, R1 = Et, 17a
R2 = bz)
Cond.: (a) 1 eq 17, 1 eq 23, 0.3 mol% Rh(acac)(CO)2, 3 mol% XANTPHOS, 10 bar CO, 10 bar H2, 68 h, 70 ◦C. (b) 4 wt% H2SO4–THF, 2 h, 80 ◦C.
evaporated and the residue is purified by flash chromatography
on silica to give 2-{2-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-
propyl}-isoindole-1,3-dione (0.91 g, 60%).
114.7 (CH), 119.5 (CH), 123.3 (2 x CH), 124.3 (C), 125.0 (CH),
126.7 (2 x CH), 129.0 (CH), 129.1 (C), 129.9 (2 x CH), 131.4
(C), 131.8 (C), 133.5 (C), 134.0 (2 x CH), 145.0 (2 x C), 168.3
(2 x C), C not observed. HRMS found [M + H]+, 493.0979,
C26H21ClN2O4S requires [M + H]+, 493.0958.
2-{2-[1-(Toluene-4-sulfonyl)-1H-indol-3-yl]-propyl}-isoindole-
1,3-dione (18a). 1H-NMR: (CDCl3, 400 MHz) d = 1.24 (d,
3H, J = 7.0 Hz, CH3), 2.16 (s, 3H, CH3), 3.43 (m, 1H, CH),
3.64 (dd, 1H, J = 8.9 Hz, J = 13.8 Hz, CHH), 3.88 (dd, 1H,
J = 6.1 Hz, J = 13.8 Hz, CHH), 7.03 (d, 1H, J = 8.3 Hz,
CH), 7.09–7.22 (2H, 2 x CH), 7.38 (s, 1H, CH), 7.56–7.68 (8H,
8 x CH), 7.84 (d, 1H, J = 8.3 Hz, CH). 13C-NMR: (CDCl3,
100 MHz) d = 17.7 (CH3), 21.3 (CH3), 29.9 (CH), 43.4 (CH2),
113.5 (CH), 119.7 (CH), 122.2 (2 x CH), 123.0 (2 x CH), 124.6
(CH), 124.7 (C), 126.6 (2 x CH), 127.7 (CH), 129.6 (2 x CH),
130.0 (C), 131.7 (C), 133.8 (2 x CH), 135.0 (2 x C), 144.6 (C),
168.2 (2 x C, C not observed. IR: m [cm−1] = 2966 (s), 2933 (s),
1770 (vs), 1718 (vs), 1398 (vs), 1184 (vs), 1132 (vs), 717 (vs),
671 (vs). MS (EI, 70 eV): m/z (%) = 458 (M+, 22), 298 (100),
200 (25), 160 (51), 155 (60), 106 (31), 91 (91). HRMS found M+
458.1314, C26H22N2O4S requires M+, 458.1300.
2-{2-[5-tert-Butyl-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propyl}-
isoindole-1,3-dione (18c). The general procedure is followed
with 2-(2-methylallyl)isoindoline-1,3-dione (0.27 g, 1.3 mmol),
4-tert-butyl-phenylhydrazine (0.22 g, 1.3 mmol), Rh(acac)(CO)2
(14 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(0.25 g, 1.3 mmol) to give 2-{2-[5-tert-butyl-1-(toluene-4-
sulfonyl)-1H-indol-3-yl]-propyl}-isoindole-1,3-dione (0.32 g,
48%). 1H-NMR: (CDCl3, 400 MHz) d = 1.20 (s, 9H, 3 x CH3),
1.26 (d, 3H, J = 6.8 Hz, CH3), 2.15 (s, 3H, CH3), 3.44 (m, 1H,
CH3), 3.64 (dd, 1H, J = 8.5 Hz, J = 13.5 Hz, CHH), 3.86
(dd, 1H, J = 6.2 Hz, J = 13.5 Hz, CHH), 7.03 (d, 2H, J =
8.6 Hz, 2 x CH), 7.23 (d, 1H, J = 8.8 Hz, CH), 7.54 (s, 1H,
CH), 7.53–7.55 (2H, 2 x CH), 7.62–7.67 (4H, CH), 7.66 (d, 2H,
J = 8.6 Hz, 2 x CH). 13C-NMR: (CDCl3, 100 MHz) d = 17.7
(CH3), 21.3 (CH3), 26.7 (C), 29.7 (CH), 31.5 (3 x CH3), 43.6
(CH2), 112.9 (CH), 115.6 (CH), 122.1 (CH), 122.6 (CH) 123.0
(2 x CH), 124.9 (C), 126.6 (2 x CH), 129.6 (2 x CH), 129.9 (C),
131.7 (2 x C), 133.0 (C), 133.8 (2 x CH), 135.2 (C), 144.4 (C),
146.1 (C), 168.5 (2 x C). IR: m [cm−1] = 2962 (s), 2870 (m), 1772
(s), 1713 (vs), 1398 (vs), 1398 (vs), 1369 (vs), 1173 (vs). HRMS
found M+, 514.1946, C30H30SN2O4 requires M+, 514.1926.
2-{2-[5-Chloro-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propyl}-
isoindole-1,3-dione (18b). The general procedure is followed
with 2-(2-methylallyl)isoindoline-1,3-dione (1.3 g, 6.5 mmol),
4-chloro-phenylhydrazine (0.92 g, 6.5 mmol), [Rh(cod)Cl]2
(32 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(1.23 g, 6.5 mmol) to give 2-{2-[5-chloro-1-(toluene-4-sulfonyl)-
1H-indol-3-yl]-propyl}-isoindole-1,3-dione (0.82 g, 53%).
1H-NMR: (CDCl3, 500 MHz) d = 1.37 (d, 3H, J = 7.0 Hz,
CH3), 2.35 (s, 3H, CH3), 3.52 (m, 1H, CH), 3.78 (dd, 1H, J =
8.6 Hz, J = 13.6 Hz, CHH), 3.98 (dd, 1H, J = 6.4 Hz, J =
13.6 Hz, CHH), 7.21 (d, 1H, J = 8.2 Hz, CH), 7.26 (d, 1H,
J = 8.7 Hz, CH), 7.52 (s, 1H, CH), 7.69 (s, 1H, CH), 7.73–7.75
(4H, 4 x CH), 7.83–7.88 (4H, 4 x CH). 13C-NMR: (CDCl3,
125 MHz) d = 17.9 (CH3), 21.5 (CH3), 29.9 (CH), 43.5 (CH2),
General procedure for the tandem hydroformylation–Fischer
indole synthesis using benzhydrylidene protected aryl hydrazines
A typical procedure is described. 2-(2-Methylallyl)isoindoline-
1,3-dione (1.32 mg, 6.6 mmol), N-benzhydrylidene-Nꢀ-phenyl-
hydrazine (1.79 g, 6.60 mmol), [Rh(cod)Cl]2 (32 mg, 1 mol%
and p-toluenesulfonic acid monohydrate (1.25 g, 6.60 mmol) are
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
2 3 3 9

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dissolved in anhydrous THF (11 g, 10 wt% olefin), placed in an
autoclave and pressurized with 10 bar H2 and 50 bar CO. After
stirring for 3 days at 100 ◦C, the mixture is filtered through
an alumina pad and the solvent is evaporated to get 3.16 g of
crude product. 1.06 g of the crude product are purified by flash
chromatography on silica to give 2-[2-(1H-indol-3-yl)-propyl]-
isoindole-1,3-dione (0.56 g, 83%).
2-[2-(1H-Indol-3-yl)-propyl]-isoindole-1,3-dione (18d). 1H-
NMR: (CDCl3, 400 MHz) d = 1.44 (d, 3H, J = 7.0 Hz, CH3),
3.73 (m, 1H, CH), 3.87 (dd, 1H, J = 9.0 Hz, J = 13.3 Hz,
CH2), 4.09 (dd, 1H, J = 6.3 Hz, J = 13.3 Hz, CH2), 7.13–7.24
(3H, 3 x CH), 7.37 (d, 1H, J = 8.0 Hz, CH), 7.70–7.87 (5H,
5 x CH), 8.31 (s, 1H, NH). 13C-NMR: (CDCl3, 100 MHz) d =
18.4 (CH3), 30.0 (CH), 44.5 (CH2), 111.1 (CH), 118.3 (C), 119.1
(CH), 119.2 (CH), 120.6 (CH), 121.9 (2 x CH), 123.0 (2 x CH),
126.7 (C), 131.9 (C), 133.8 (CH), 136.2 (2 x C), 168.6 (2 x C). IR:
m [cm−1] = 3406 (s), 2962 (m), 2931 (m), 1770 (vs), 1712 (vs), 1398
(vs), 1034 (s), 714 (vs). HRMS found M+, 304.1219, C19H16N2O2
requires M+, 304.1212.
isoindole-1,3-dione (0.74 g, 50%). 1H-NMR: (CDCl3, 400 MHz)
d = 1.36 (d, 3H, J = 6.9 Hz, CH3), 3.58 (m, 1H, CH), 3.79 (dd,
1H, J = 8.7 Hz, J = 13.8 Hz, CHH), 3.94 (dd, 1H, J = 6.2 Hz,
J = 13.8 Hz, CHH), 7.08–7.16 (3H, 3 x CH), 7.65–7.81 (5H,
5 x CH), 8.27 (s, 1H, NH). 13C-NMR: (CDCl3, 100 MHz) d =
18.4 (CH3), 29.8 (CH), 44.5 (CH2), 112.6 (CH), 112.6 (C), 118.2
(C), 121.6 (CH), 121.8 (CH), 123.1 (2 x CH), 124.8 (CH), 128.6
(C), 131.8 (C), 133.9 (2 x CH), 134.8 (2 x C), 168.5 (2 x C). IR: m
[cm−1] = 3377 (s), 1770 (s), 1716 (vs), 1466 (s), 1433 (s), 1398 (vs),
1354 (s), 1034 (s), 795 (s), 715 (vs). HRMS found M+, 382.0280,
C19H15BrN2O2 requires M, 382.0317. Elementary analysis found
C 59.75%, H 3.95%, N 7.35%, C19H15BrN2O2 requires C 59.55%,
H 3.95%, N 7.31%.
2-[2-(7-Methyl-1H-indol-3-yl)-propyl]-isoindole-1,3-dione (18h).
The general procedure is followed with 2-(2-methylallyl)-
isoindoline-1,3-dione (0.95 g, 4.7 mmol), N-benzhydrylidene-
Nꢀ-o-tolyl-hydrazine (1.35 g, 4.7 mmol), [Rh(cod)Cl]2 (23 mg,
1 mol%) and p-toluenesulfonic acid monohydrate (0.90 g,
4.7 mmol) to give 2-[2-(7-methyl-1H-indol-3-yl)-propyl]-
isoindole-1,3-dione (0.72 g, 48%). 1H-NMR: (CDCl3, 400 MHz)
d = 1.38 (d, 3H, J = 7.0 Hz, CH3), 2.45 (s, 3H, CH3), 3.68 (m,
1H, CH), 3.81 (dd, 1H, J = 8.9 Hz, J = 13.7 Hz, CHH), 4.05
(dd, 1H, J = 6.4 Hz, J = 13.7 Hz, CHH), 6.96–7.11 (3H, 3 x
CH), 7.66–7.82 (5H, 5 x CH), 8.07 (bs, 1H, NH). 13C-NMR:
(CDCl3, 100 MHz) d = 16.5 (CH3), 18.5 (CH3), 30.2 (CH), 44.5
(CH2), 116.9 (CH), 118.9 (C), 119.6 (CH), 120.2 (CH), 120.3
(C), 122.5 (CH), 123.1 (2 x CH), 126.3 (C), 132.0 (C), 133.8 (2 x
CH), 135.8 (2 x C), 168.6 (2 x C). IR: m [cm−1] = 3402 (s), 1770
(s), 1716 (vs), 1466 (s), 1458 (s), 1433 (s), 1398 (vs), 1034 (s),
714 (vs). HRMS found M+, 318.1395, C20H18N2O2 require M+,
318.1368. Elementary analysis found C 75.30%, H 5.80%, N
8.20%, C20H18N2O2 requires C 75.45%, H 5.70%, N 8.80%.
2-[2-(5-Fluoro-1H-indol-3-yl)propyl]-isoindole-1,3-dione (18e).
The general procedure is followed with 2-(2-methylallyl)-
isoindoline-1,3-dione (0.62 g, 3.1 mmol), N-benzhydrylidene-
Nꢀ-(4-fluorophenyl)-hydrazine (0.90 g, 3.1 mmol), Rh(acac)-
(CO)2 (8 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(0.59 g, 3.1 mmol) to give 2-[2-(5-fluoro-1H-indol-3-yl)-propyl]-
isoindole-1,3-dione (0.47 g, 47%). 1H-NMR: (CDCl3, 500 MHz)
d = 1.37 (d, 3H, J = 7.0 Hz, CH3), 3.59 (m, 1H, J = 7.0 Hz,
CH), 3.79 (dd, 1H, J = 8.7 Hz, J = 13.5 Hz, CHH), 3.97 (dd,
1H, J = 6.7 Hz, J = 13.5 Hz, CHH), 6.88 (dd, 1H, J = 9.0 Hz,
J = 9.0 Hz, CH), 7.13 (s, 1H, CH), 7.23 (dd, 1H, J = 9.0 Hz,
J = 9.0 Hz, CH), 7.41 (d, 1H, J = 9.7 Hz, CH), 7.67–7.69 (2H,
2 x CH), 7.78–7.80 (2H, 2 x CH), 8.10 (s, 1H, NH). 13C-NMR:
(CDCl3, 125 MHz) d = 18.4 (CH3), 30.0 (CH), 44.4 (CH2), 104.1
(d, 1C, JC–F = 23 Hz, CH), 110.3 (d, 1C, JC–F = 25 Hz, CH),
111.7 (d, 1C, JC–F = 10 Hz, CH), 116.2 (C), 118.7 (C), 122.3
(CH), 123.1 (2 x CH), 132.0 (2 x C), 133.9 (2 x CH), 157.7
(d, 1C, JC–F = 234 Hz, C), 168.6 (2 x C). IR: m [cm−1] = 3392
(m), 2964 (w), 2933 (w), 1770 (w), 1708 (vs), 1486 (s), 1398 (vs),
1153 (m), 1033 (m). HRMS found M+, 323.1145, C19H15FN2O2
requires M+, 323.1118. Elementary analysis found C 70.38%, H
5.02%, N 8.30%, C19H15FN2O2 requires C 70.80%, H 4.69%, N
8.69%.
2-[2-(7-Chloro-1H-indol-3-yl)-propyl]-isoindole-1,3-dione (18i).
The general procedure is followed with 2-(2-methylallyl)-
isoindoline-1,3-dione (0.93 g, 4.6 mmol), N-benzhydrylidene-
Nꢀ-(2-chlorophenyl)-hydrazine (1.41 g, 4.6 mmol), [Rh(cod)Cl]2
(23 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(0.87 g, 4.6 mmol) to give 2-[2-(7-chloro-1H-indol-3-yl)-propyl]-
isoindole-1,3-dione (0.21 g, 42%). 1H-NMR: (CDCl3, 400 MHz)
d = 1.38 (d, 3H, J = 7.0 Hz, CH3), 3.63 (m, 1H, CH), 3.80 (dd,
1H, J = 8.8 Hz, J = 13.8 Hz, CHH), 4.00 (dd, 1H, J = 6.5 Hz,
J = 13.8 Hz, CHH), 7.00 (dd, 1H, J = 7.8 Hz, CH), 7.15 (s,
1H CH), 7.65–7.70 (4H, 4 x CH), 7.78–7.82 (2H, 2 x CH), 8.38
(bs, 1H, NH). 13C-NMR: (CDCl3, 100 MHz) d = 18.4 (CH3),
30.2 (CH), 44.4 (CH2), 116.5 (C), 117.8 (CH), 119.5 (C), 120.1
(CH), 121.3 (2 x CH), 123.1 (2 x CH), 128.3 (C), 131.9 (2 x
C), 133.5 (C), 133.9 (2 x CH), 168.6 (2 x C). IR: m [cm−1] =
3381(m), 1765 (m), 1705 (vs), 1398 (m), 1032 (m), 893 (m), 717
(m). HRMS found M+, 338.0844, C19H15ClN2O2 requires M,
338.0822. Elementary analysis found C 67.43%, H 4.07%, N
8.10%, C19H15ClN2O2 requires C 67.36%, H 4.46%, N 8.27%.
2-[2-(5-Chloro-1H-indol-3-yl)-propyl]-isoindole-1,3-dione (18f).
The general procedure is followed with 2-(2-methylallyl)-
isoindoline-1,3-dione (0.92 g, 4.6 mmol), N-benzhydrylidene-
Nꢀ-(4-chlorophenyl)-hydrazine (1.40 g, 4.6 mmol), [Rh(cod)Cl]2
(22 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(0.87 g, 4.6 mmol) to give 2-[2-(5-chloro-1H-indol-3-yl)-propyl]-
isoindole-1,3-dione (0.58 g, 78%). 1H-NMR: (CDCl3, 400 MHz)
d = 1.41 (d, 3H, J = 7.0 Hz, CH3), 3.63 (m, 1H, CH), 3.80
(dd, 1H, J = 8.3 Hz, J = 13.6 Hz, CHH), 4.00 (dd, 1H, J =
6.8 Hz, J = 13.6 Hz, CHH), 7.09 (d, 1H, J = 8.2 Hz, CH),
7.14 (s, 1H, CH), 7.24 (m, 1H, CH), 7.69–7.72 (3H, 3 x CH),
7.81–7.83 (2H, 2 x CH), 8.31 (bs, 1H, NH). 13C-NMR: (CDCl3,
100 MHz) d = 18.4 (CH3), 29.9 (CH), 44.5 (CH2), 112.12 (CH),
118.24 (C), 118.5 (CH), 122.0 (CH), 122.2 (CH), 123.1 (2 x CH),
125.0 (C), 128.0 (C), 131.8 (C), 133.9 (2 x CH), 134.5 (2 x C),
168.6 (2 x C). IR: m [cm−1] = 3383 (m), 2964 (w), 2360 (w),
1765 (s), 1705 (vs), 1466 (s), 1429 (s), 1398 (vs), 1032 (s), 717
(s). HRMS found M+, 338.0802, C19H15N2O2Cl requires M+,
338.0822. Elementary analysis found C 66.90%, H 4.35%, N
8.10%, C19H15N2O2Cl requires C 67.36%, H 4.46%, N 8.27%.
General procedure for the tandem hydroformylation–Fischer
indole synthesis with subsequent addition of acid
A typical procedure is described. 2-(2-Methylallyl)isoindoline-
1,3-dione (301 mg, 1.50 mmol), a-Boc-1-(4-methoxyphenyl)-
hydrazine (356 mg, 1.50 mmol) and Rh(acac)(CO)2 (1.16 mg,
0.03 mol%) are dissolved in anhydrous THF (2.71 g, 10 wt%
olefin), placed in an autoclave and pressurized with 10 bar H2
and 50 bar CO. After stirring for 3 days at 120 ◦C, the mixture
is poured into sulfuric acid (15 ml, 4 wt% in THF) and the
resulting mixture is stirred for an additional 2 h under reflux.
Ammonia (10 ml, 30 wt% in water) is added and the mixture is
extracted 3 times with ethyl acetate. The solvent is evaporated
and the residue is chromatographed (ethyl acetate, cyclohexane,
silica) to give 2-[2-(5-methoxy-1H-indol-3-yl)-propyl]-isoindole-
1,3-dione (462 mg, 95%).
2-[2-(5-Bromo-1H-indol-3-yl)-propyl]-isoindole-1,3-dione (18g).
The general procedure is followed with 2-(2-methylallyl)-
isoindoline-1,3-dione (0.79 g, 3.9 mmol), N-benzhydrylidene-
Nꢀ-(4-bromophenyl)-hydrazine (1.38 g, 3.9 mmol), [Rh(cod)Cl]2
(19 mg, 1 mol%) and p-toluenesulfonic acid monohydrate
(0.74 g, 3.9 mmol) to give 2-[2-(5-bromo-1H-indol-3-yl)-propyl]-
2 3 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3

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2-[2-(5-Methoxy-1H-indol-3-yl)-propyl]-isoindole-1,3-dione
(18j). 1H-NMR: (CDCl3, 500 MHz) d = 1.38 (d, 3H, J =
7.0 Hz, CH3), 3.60 (m, 1H, J = 7.0 Hz, CH), 3.78 (dd, 1H, J =
9.0 Hz, J = 13.6 Hz, CHH), 3.85 (s, 3H, CH3), 4.01 (dd, 1H,
J = 6.2 Hz, J = 13.6 Hz, CHH), 6.79 (d, 1H, J = 8.7 Hz, CH),
7.07 (s, 1H, CH), 7.19 (d, 1H, J = 8.7 Hz, CH), 7.27 (s, 1H,
CH), 7.66 (d, 2H, J = 5.4 Hz, 2 x CH), 7.78 (d, 2H, J = 5.4 Hz,
2 x CH), 8.26 (s, 1H, NH). 13C-NMR: (CDCl3, 125 MHz) d =
18.2 (CH3), 30.0 (CH), 44.5 (CH2), 55.7 (CH3), 100.6 (CH),
111.9 (CH), 112.3 (CH), 118.1 (C), 121.3 (CH), 123.0 (2 x CH),
127.2 (C), 131.3 (C), 131.9 (2 x C), 133.8 (2 x CH), 153.8 (C),
168.6 (2 x C). IR: m [cm−1] = 3399 (m), 1770 (m), 1700 (vs),
1484 (s), 1428 (m), 1398 (s), 1376 (m), 1216 (s), 1157 (m), 1037
(s), 713 (s). HRMS found [M]+ 334.1299, C20H18N2O3 requires
[M]+ 334.1318. Elementary analysis found C 71.64%, H 5.38%,
N 8.11%, C20H18N2O3 requires C 71.84%, H 5.43%, N 8.38%.
121.7 (CH), 126.9, 126.2 (C), 136.5, 136.3 (C), 170.6, 170.5 (C).
IR: m [cm−1] = 3271 (s), 2970 (s), 2931 (s), 1631 (s), 1458 (s),
1379 (s), 1033 (m), 742 (s). HRMS found [M + H]+ 245.1682,
C15H20N2O requires [M + H]+ 245.1654.
Ethyl-[2-(1H-indol-3-yl)-propyl]-carbamic acid ethyl ester
(18n). The general procedure is followed with ethyl-(2-
methylallyl)-carbamic acid ethyl ester (0.62 g, 3.6 mmol),
phenylhydrazine (0.39 g, 3.6 mmol) and Rh(acac)(CO)2 (2.8 mg,
0.3 mol%) to give ethyl-[2-(1H-indol-3-yl)-propyl]-carbamic
1
acid ethyl ester (0.58 g, 58%). H-NMR: (CDCl3, 400 MHz)
d = 1.03–1.13 (3H, CH3), 1.28 (t, 3H, J = 7.1 Hz, CH3), 1.39
(bs, 3H, CH3), 3.23–3.72 (5H, 2 x CH2, CH), 4.15–4.20 (2H,
CH2), 7.01, 6.98 (s, 1H, CH), 7.12 (dd, 1H, J = 7.3 Hz, J =
7.3 Hz, CH), 7.19 (dd, 1H, J = 7.3 Hz, J = 7.7 Hz, CH), 7.35
(d, 1H, J = 7.7 Hz, CH), 7.69 (bs, 1H, CH), 8.38 (bs, 1H, NH).
13C-NMR: (CDCl3, 100 MHz) d = 12.9, 13.4 (CH3), 14.6 (CH3),
18.4, 18.1 (CH3), 29.9, 30.7 (CH), 42.3, 42.8 (CH2), 52.9, 53.5
(CH2), 61.0 (CH2), 110.6 (C), 111.3, 111.2 (CH), 119.0 (2 x CH),
119.2 (C), 120.6 (CH), 121.8 (CH), 136.5 (C), 154.7 (C). IR: m
[cm−1] = 3315 (vs), 2973 (s), 2886 (s), 1683 (vs), 1484 (s), 1380
(m), 1172 (s), 1074 (m), 771 (m). HRMS found [M]+ 274.1652,
C16H22N2O2 requires [M]+ 274.1682.
N-Ethyl-N-[2-(1H-indol-3-yl)-propyl]-4-methyl-benzenesulfon-
amide (18k). The general procedure is followed with N-
ethyl-4-methyl-N-(2-methylallyl)-benzenesulfonamide (0.71 g,
2.8 mmol), phenylhydrazine (0.30 g, 2.8 mmol) and Rh(acac)-
(CO)2 (2.2 mg, 0.3 mol%) to give N-ethyl-N-[2-(1H-indol-3-yl)-
propyl]-4-methyl-benzenesulfonamide (0.94 g, 94%). 1H-NMR:
(CDCl3, 500 MHz) d = 1.11 (t, 3H, J = 7.3 Hz, CH3), 1.50
(d, 3H, J = 6.5 Hz, CH3), 2.43 (s, 3H, CH3), 3.29 (q, 2H, J =
7.3 Hz, CH2), 3.40–3.47 (3H, CH2, CH), 7.07 (s, 1H, CH), 7.15
(dd, 1H, J = 7.0 Hz, J = 8.1 Hz, CH), 7.22 (dd, 1H, J = 7.0 Hz,
J = 8.1 Hz, CH), 7.28 (d, 2H, J = 8.0 Hz, 2 x CH), 7.40 (d, 1H,
J = 8.1 Hz, CH), 7.68 (d, 1H, J = 8.1 Hz, CH), 7.72 (d, 2H,
J = 8.0 Hz, 2 x CH), 8.46 (bs, 1H, NH). 13C-NMR: (CDCl3,
125 MHz) d = 13.6 (CH3), 18.2 (CH3), 21.3 (CH3), 30.2 (CH),
43.3 (CH2), 54.0 (CH2), 111.3 (CH), 118.2 (C), 118.6 (CH),
119.0 (CH), 121.0 (CH), 121.7 (CH), 126.4 (C), 127.0 (2 x CH),
129.5 (2 x CH), 136.3 (C), 136.9 (C), 142.9 (C). IR: m [cm−1] =
3398 (s), 2972 (s), 2931 (s), 1599 (s), 1456 (s), 1329 (s), 1153 (m),
741 (m). HRMS found [M]+ 356.1584, C20H24N2O2S requires
[M]+ 356.1558.
Ethyl 4-(5-bromo-1H -indol-3-yl)piperidine-1-carboxylate
(21). The general procedure is followed with ethyl 4-
methylenepiperidine-1-carboxylate (1.75 g, 10.3 mmol), 4-
bromophenylhydrazine (1.93 g, 10.3 mmol) and Rh(acac)(CO)2
(11 mg, 0.3 mol%) to give ethyl 4-(5-bromo-1H-indol-3-
yl)piperidine-1-carboxylate (1.93 g, 39%).1H-NMR: (CDCl3,
500 MHz) d = 1.29 (t, 3H, J = 7.2 Hz, CH3), 1.63 (q, 2H,
J = 11.7 Hz, CH2), 2.00 (d, 2H, J = 13.7 Hz, CH2), 2.92 (t, 3H,
J = 11.7 Hz, CH2), 4.17 (q, 2H, J = 7.2 Hz, CH2), 4.28 (bs,
2H, CH2), 6.92 (s, 1H, CH), 7.20 (d, 1H, J = 8.5 Hz, CH), 7.25
(d, 1H, J = 8.5 Hz, CH), 7.73 (s, 1H, CH), 8.56 (s, 1H, NH).
13C-NMR: (CDCl3, 100 MHz) d = 14.7 (CH3), 32.6 (2 x CH2),
33.4 (CH), 44.4 (2 x CH2), 61.3 (CH2), 112.3 (C), 112.7 (CH),
120.2 (C), 121.0 (CH), 121.4 (CH), 124.6 (CH), 128.2 (C), 135.0
(C), 155.6 (C).
N -Ethyl-N -[2-(1H -indol-3-yl)-propyl]-benzamide (18l).
The general procedure is followed with N-ethyl-N-(2-
methylallyl)-benzamide (0.66 g, 3.3 mmol), phenylhydrazine
(0.35 g, 3.3 mmol) and Rh(acac)(CO)2 (2.5 mg, 0.3 mol%) to
give N-ethyl-N-[2-(1H-indol-3-yl)-propyl]-benzamide (0.82 g,
85%). 1H-NMR: (C2D2Cl4, 400 MHz, 80 ◦C) d = 1.06–1.20 (3H,
CH3), 1.43 (d, 3H, J = 6.5 Hz, CH3), 3.30–3.79 (5H, 2 x CH2,
CH), 7.00 (s, 1H, CH), 7.10 (dd, 1H, J = 7.5 Hz, J = 7.3 Hz,
CH), 7.20 (t, 1H, J = 8.0 Hz, J = 7.0 Hz), 7.27–7.29 (2H, 2 x
CH), 7.35–7.53 (5H, 5 x CH), 8.21 (bs, 1H, NH). 13C-NMR:
(CDCl3, 100 MHz) d = 13.5, 12.5 (CH3), 18.8, 17.8 (CH3),
28.9, 30.4 (CH), 44.0, 39.9 (CH2), 50.6, 54.7 (CH2), 111.3, 114.9
(CH), 118.4, 117.1 (C), 118.7, 118.3 (CH), 120.8, 121.0 (CH),
121.3 (CH), 126.1, 126.5 (2 x CH), 126.8 (C), 128.2, 128.7 (2 x
CH), 128.9, 129.0 (CH), 136.3 (C), 137.1, 136.9 (C), 171.9 (C).
IR: m [cm−1] = 3188 (s), 2972 (s), 2931 (s), 1633 (s), 1456 (s),
1381 (s), 1105 (m), 739 (s).
Ethyl 4-(5-bromo-1-(4-fluorophenyl)-1H-indol-3-yl)piperidine-
1-carboxylate (22). Copper(I) iodide (5.35 mg, 5 mol%), N,Nꢀ-
dimethylethylenediamine (20.2 mg, 20 mol%), potassium phos-
phate heptahydrate (399 mg, 1.18 mmol), 4-fluoro-iodobenzene
(150 mg, 0.67 mmol) and 24 (197 mg, 0.56 mmol) are dissolved
in toluene (1 M). After stirring for 24 h at 110 ◦C, the mixture is
poured into ethyl acetate and filtered through a pad of silica. The
solvent is removed to give ethyl 4-(5-bromo-1-(4-fluorophenyl)-
1H-indol-3-yl)piperidine-1-carboxylate (250 mg, 100%) without
further purification. 1H-NMR: (CDCl3, 500 MHz) d = 1.28 (t,
3H, J = 7.2 Hz, CH3), 1.67 (q, 2H, J = 9.7 Hz, CH2), 2.04 (d,
2H, J = 13.7 Hz, CH2), 2.97 (q, 3H, J = 12.0 Hz, CH2, CH),
4.16 (q, 2H, J = 7.2 Hz, CH2), 4.30 (bs, 2H, CH2), 7.03 (s, 1H,
CH), 7.17 (dd, 2H, J = 8.6 Hz, J = 9.0 Hz, 2 x CH), 7.27 (bs, 2H,
2 x CH), 7.37 (dd, 2H, J = 8.6, J = 9.0 Hz, 2 x CH), 7.78 (s, 1H,
CH). 13C-NMR: (CDCl3, 125 MHz) d = 14.6 (CH3), 32.5 (2 x
CH2), 33.3 (CH), 44.3 (2 x CH2), 61.1 (CH2), 111.8 (CH), 113.01
(C), 116.4 (d, 2C, J = 23 Hz, 2 x CH), 121.3 (C), 124.8 (CH),
125.3 (CH), 125.9 (d, 2C, J = 10 Hz, 2 x CH), 129.3 (C), 135.1
(d, 1C, J = 36 Hz, C), 155.5 (C), 161.0 (d, 1C, J = 248 Hz, C).
IR: m [cm−1] = 2929 (m), 2850 (m), 1693 (vs), 1511 (vs), 1457 (vs),
1442 (s), 1382 (m), 1213 (vs), 1120 (s), 840 (s), 788 (s). HRMS
found [M]+ 444.0864, C22H22BrFN2O2 requires [M]+ 444.0849.
N -Ethyl-N -[2-(1H -indol-3-yl)-propyl]-acetamide (18m).
The general procedure is followed with N-ethyl-N-(2-
methylallyl)-acetamide (0.58 g, 4.1 mmol), phenylhydrazine
(0.44 g, 4.1 mmol) and Rh(acac)(CO)2 (3.2 mg, 0.3 mol%) to
give N-ethyl-N-[2-(1H-indol-3-yl)-propyl]-acetamide (0.61 g,
61%). 1H-NMR: (CDCl3, 500 MHz) d = 1.01, 1.10 (t, 3H, J =
7.1 Hz, CH3), 1.33, 1.41 (d, 3H, J = 6.9 Hz, CH3), 2.06, 1.95 (s,
3H, CH3), 2.97–3.12 (2H, CH2), 3.36–3.55 (2H, CH2), 3.71–3.75
(1H, CH), 6.98, 6.95 (s, 1H, CH), 7.08, 7.03 (d, 1H, J = 8.0 Hz,
CH), 7.15, 7.11 (d, 1H, J = 8.0 Hz, CH), 7.32, 7.34 (d, 1H, J =
8.0 Hz, CH), 7.66, 7.57 (d, 1H, J = 8.0 Hz, CH), 8.81, 9.01 (bs,
1H, NH). 13C-NMR: (CDCl3, 125 MHz) d = 13.5, 12.5 (CH3),
18.6, 18.1 (CH3), 21.4, 21.6 (CH3), 29.2, 30.9 (CH), 43.7, 40.7
(CH2), 51.9, 54.7 (CH2), 111.2, 111.5 (CH), 118.8, 118.5 (CH),
119.0, 117.7 (C), 119.1, 119.4 (CH), 121.0, 120.6 (CH), 121.5,
General procedure for the regioselective tandem
hydroformylation–Fischer indole synthesis
A
typical procedure is described. Methyl pent-4-enoate
(263 mg, 2.30 mmol), phenylhydrazine (249 mg, 2.30 mmol),
Rh(acac)(CO)2 (1.78 mg, 0.3 mol%) and Xantphos (40.0 mg,
3 mol%) are dissolved in anhydrous THF (2.36 g, 10 wt% olefin),
placed in an autoclave and pressurized with 10 bar H2 and 10 bar
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
2 3 4 1

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CO. After stirring for 3 days at 70 ◦C, the mixture is poured into
sulfuric acid (15 ml, 4 wt% in THF) and the resulting mixture
is stirred for an additional 2 h under reflux. Ammonia (10 ml,
30 wt% in water) is added and the mixture is extracted 3 times
with ethyl acetate. The solvent is evaporated and the residue
is chromatographed (ethyl acetate–cyclohexane, silica) to give
methyl 4-(1H-indol-3-yl)butanoate (455 mg, 91%).
Methyl 4-(1H-indol-3-yl)butanoate (29). 1H-NMR: (CDCl3,
500 MHz) d = 2.06 (m, 2H, J = 7.5 Hz, CH2), 2.40 (t, 2H, J =
7.5 Hz, CH2), 2.82 (t, 2H, J = 7.5 Hz, CH2), 3.67 (s, 3H, CH3),
6.97 (s, 1H, CH), 7.12 (dd, 1H, J = 7.1 Hz, J = 7.8 Hz, CH),
7.19 (dd, 1H, J = 7.1 Hz, J = 7.8 Hz, CH), 7.34 (d, 1H, J =
7.8 Hz, CH), 7.62 (d, 1H, J = 7.8 Hz, CH), 8.12 (s, 1H, NH).
13C-NMR: (CDCl3, 125 MHz) d = 24.4 (CH2), 25.3 (CH2), 33.6
(CH2), 51.4 (CH3), 111.0 (CH), 115.4 (C), 118.8 (CH), 119.1
(CH), 121.5 (CH), 121.8 (CH), 127.4 (C), 136.3 (C), 174.2 (C).
NMR data fits with literature.32
80%). 1H-NMR: (CDCl3, 500 MHz) d = 3.11 (t, 2H, J =
7.8 Hz, CH2), 3.85 (s, 3H, CH3), 3.98 (t, 2H, J = 7.8 Hz, CH2),
6.82 (d, 1H, J = 8.8 Hz, CH), 7.06 (s, 1H, CH), 7.16 (s, 1H,
CH), 7.21 (d, 1H, J = 8.8 Hz, CH), 7.69 (d, 2H, J = 5.5 Hz,
2 x CH), 7.81 (d, 2H, J = 5.5 Hz, 2 x CH), 8.04 (s, 1H, NH).
13C-NMR: (CDCl3, 125 MHz) d = 24.5 (CH2), 38.4 (CH2), 55.8
(CH3), 100.3 (CH), 119.1 (CH), 112.1 (C), 112.5 (CH), 122.8
(CH), 123.1 (2 x CH), 127.8 (C), 131.3 (C), 132.2 (2 x C), 133.8
(2 x CH), 156.1 (C), 168.4 (2 x C). Elementary analysis found C
70.82%, H 5.12%, N 8.41%, C19H16N2O3 requires C 71.24%, H
5.03%, N 8.74%. NMR data fits with literature.34
N-Ethyl-N-[2-(1H-indol-3-yl)-ethyl]-4-methyl-benzenesulfon-
amide (30d). The general procedure is followed with N-allyl-
N-ethyl-4-methyl-benzenesulfonamide (349 mg, 1.46 mmol),
phenylhydrazine (158 mg, 1.46 mmol), Rh(acac)(CO)2 (1.13 mg,
0.30 mol%) and Xantphos (25 mg, 3 mol%) to give N-ethyl-N-
[2-(1H-indol-3-yl)-ethyl]-4-methyl-benzenesulfonamide (405 mg,
81%). 1H-NMR: (CDCl3, 500 MHz) d = 1.14 (t, 3H, J =
7.2 Hz, CH3), 2.38 (s, 3H, CH3), 3.03 (dd, 2H, J = 7.7 Hz, J =
8.3 Hz, CH2), 3.29 (q, 2H, J = 7.2 Hz, CH2), 3.41 (dd, 2H,
J = 7.7 Hz, J = 8.3 Hz, CH2), 7.01 (s, 1H, CH), 7.10 (dd, 1H,
J = 7.5 Hz, J = 8.0 Hz, CH), 7.16 (dd, 1H, J = 7.5 Hz, J =
8.2 Hz, CH), 7.24 (d, 2H, J = 8.2 Hz, 2 x CH), 7.35 (d, 1H,
J = 8.2 Hz, CH), 7.57 (d, 1H, J = 8.0 Hz, CH), 7.69 (d, 2H,
J = 8.2 Hz, 2 x CH), 8.41 (s, 1H, NH). 13C-NMR: (CDCl3,
125 MHz) d = 14.8 (CH3), 21.3 (CH3), 25.4 (CH2), 43.0 (CH2),
48.1 (CH2), 111.3 (CH), 112.1 (C), 118.3 (CH), 119.1 (CH),
121.7 (CH), 122.2 (CH), 127.0 (2 x CH), 129.5 (2 x CH), 129.6
(C), 136.9 (C), 142.9 (C). IR: m [cm−1] = 3399 (s), 2954 (s), 2923
(vs), 2856 (s), 1455 (vs), 1332 (s), 1153 (s). HRMS found [M]+
342.1415, C19H22N2O2S requires [M]+ 342.1402.
N -[2-(1H -Indol-3-yl)-ethyl]-4-methyl-benzenesulfonamide
(30a). The general procedure is followed with N-allyl-4-
methyl-benzenesulfonamide (336 mg, 1.59 mmol), phenylhydra-
zine (172 mg, 1.59 mmol), Rh(acac)(CO)2 (1.23 mg, 0.30 mol%)
and Xantphos (28 mg, 3 mol%) to give N-[2-(1H-indol-3-yl)-
ethyl]-4-methyl-benzenesulfonamide (295 mg, 59%). 1H-NMR:
(CDCl3, 500 MHz) d = 2.39 (s, 3H, CH3), 2.90 (t, 2H, J =
6.7 Hz, CH2), 3.25 (dt, 2H, J = 6.0 Hz, J = 6.7 Hz, CH2), 4.71
(t, 1H, J = 6.0 Hz, NH), 6.94 (s, 1H, CH), 7.05 (dd, 1H, J =
7.6 Hz, J = 7.7 Hz, CH), 7.17 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz,
CH), 7.20 (d, 2H, J = 8.2 Hz, 2 x CH), 7.32 (d, 1H, J = 7.7 Hz,
CH), 7.40 (d, 1H, J = 7.6 Hz, CH), 7.64 (d, 2H, J = 8.2 Hz, 2 x
CH), 8.17 (s, 1H, NH). 13C-NMR: (CDCl3, 125 MHz) d = 21.4
(CH3), 25.4 (CH2), 43.0 (CH2), 111.3 (CH), 111.4 (C), 118.4
(CH), 119.4 (CH), 122.1 (CH), 122.6 (CH), 126.8 (C), 126.9 (2 x
CH), 129.6 (2 x CH), 136.3 (C), 136.7 (C), 143.3 (C). NMR
data fits with literature.33
N-Ethyl-N-[2-(1H-indol-3-yl)-ethyl]-acetamide (30e). The
general procedure is followed with N-allyl-N-ethyl-4-acetamide
(276 mg, 2.17 mmol), phenylhydrazine (235 mg, 2.17 mmol),
Rh(acac)(CO)2 (1.68 mg, 0.30 mol%) and Xantphos (18.8 mg,
3 mol%) to give N-ethyl-N-[2-(1H-indol-3-yl)-ethyl]-acetamide
(295 mg, 59%). 1H-NMR: (CDCl3, 500 MHz) d = 1.16, 1.13 (t,
3H, J = 7.0 Hz, CH2), 1.92, 2.13 (s, 3H, CH3), 3.00, 3.03 (t, 2H,
J = 7.3 Hz, CH2), 3.45, 3.23 (q, 3H, J = 7.0 Hz, CH2), 3.53, 3.63
(t, 2H, J = 7.3 Hz, CH2), 6.98, 6.95 (s, 1H, CH), 7.12–7.21 (2H,
2 x CH), 7.33, 7.35 (d, 1H, J = 8.0 Hz, CH), 7.56, 7.65 (d, 1H,
J = 7.7 Hz, CH), 8.67, 8.86 (s, 1H, NH). 13C-NMR: (CDCl3,
125 MHz) d = 14.0, 12.9 (CH3), 21.4, 21.3 (CH3), 24.8, 23.6
(CH2), 40.4, 43.9 (CH2), 46.5, 48.9 (CH2), 111.5, 111.2 (CH),
113.0, 111.7 (C), 118.0, 118.6 (CH), 119.1, 119.3 (CH), 121.7,
121.9 (CH), 122.4, 122.0 (CH), 127.0, 127.4 (C), 136.3 (C), 170.4,
170.2 (C). NMR data fits with literature.35
2-[2-(1H-Indol-3-yl)-ethyl]-isoindole-1,3-dione (30b). The
general procedure is followed with 2-allyl-isoindole-1,3-dione
(322 mg, 1.72 mmol), phenylhydrazine (186 mg, 1.72 mmol),
Rh(acac)(CO)2 (0.13 mg, 0.30 mol%) and Xantphos (29.9 mg,
3 mol%) to give 2-[2-(1H-indol-3-yl)-ethyl]-isoindole-1,3-dione
(255 mg, 51%). The product was obtained as n/iso-isomers.
Analytical data were obtained from the mixture. n-Regioisomer:
1H-NMR: (CDCl3, 500 MHz) d = 3.17 (dd, 2H, J = 7.5 Hz,
J = 8.1 Hz, CH2), 4.02 (dd, 2H, J = 7.5 Hz, J = 8.1 Hz, CH2),
7.08 (s, 1H, CH), 7.13 (dd, 1H, J = 7.3 Hz, J = 8.1 Hz, CH),
7.19 (dd, 1H, J = 7.3 Hz, J = 8.1 Hz, CH), 7.34 (d, 1H, J =
8.1 Hz, CH), 7.50 (d, 1H, J = 7.0 Hz, CH), 7.75 (d, 1H, J =
7.3 Hz, CH), 7.66 (d, 2H, J = 5.5 Hz, 2 x CH), 8.11 (s, 1H, NH).
13C-NMR: (CDCl3, 125 MHz) d = 24.4 (CH2), 38.5 (CH2), 111.1
(CH), 112.9 (C), 118.8 (CH), 119.4 (CH), 122.0 (CH), 123.1
(2 x CH), 127.3 (2 x C), 132.4 (C), 133.6 (2 x CH), 136.2 (2 x
C), 168.3 (2 x C). Characteristic data for the iso-regioisomer
(structure confirmed with 1D-NOESY): 1H-NMR: (CDCl3,
500 MHz) d = 2.44 (s, 3H, CH3), 4.97 (s, 2H, CH2), 7.07 (dd,
1H, J = 7.0 Hz, J = 7.0 Hz, CH), 7.15 (dd, 1H, J = 7.0 Hz,
J = 7.0 Hz, CH), 7.28 (d, 1H, J = 7.0 Hz, CH), 7.50 (d, 1H,
J = 7.0 Hz, CH), 7.66 (d, 2H, J = 5.5 Hz, 2 x CH), 7.8 (d, 2H,
J = 5.5 Hz, 2 x CH), 8.56 (s, 1H, NH). 13C-NMR: (CDCl3,
100 MHz) d = 8.3 (CH3), 32.6 (CH2), 110.1 (C), 110.8 (CH),
119.0 (CH), 119.2 (CH), 122.5 (CH), 123.4 (2 x CH), 128.2 (C),
128.9 (C), 131.9 (2 x C), 134.1 (2 x CH), 135.6 (C), 168.4 (2 x
C). HRMS found [M]+ 290.1068, C18H14N2O2 requires [M]+
290.1055.
N-Ethyl-N-[3-(1H-indol-3-yl)-propyl]-4-methyl-benzenesulfon-
amide (30f). The general procedure is followed with N-
but-3-enyl-N-ethyl-4-methyl-benzenesulfonamide (355 mg,
1.40 mmol), phenylhydrazine (152 mg, 1.40 mmol), Rh(acac)-
(CO)2 (1.09 mg, 0.30 mol%) and Xantphos (12.2 mg,
3
mol%) to give N-ethyl-N-[3-(1H-indol-3-yl)-propyl]-4-
methyl-benzenesulfonamide (290 mg, 58%). 1H-NMR: (CDCl3,
500 MHz) d = 1.09 (t, 3H, J = 7.2 Hz, CH3), 1.94 (m, 2H, J =
7.5 Hz, CH2), 2.39 (s, 3H, CH3), 2.76 (t, 2H, J = 7.5 Hz, CH2),
3.20–3.24 (4H, 2 x CH2), 7.00 (s, 1H, CH), 7.10 (dd, 1H, J =
7.5 Hz, J = 7.5 Hz, CH), 7.18 (dd, 1H, J = 7.2 Hz, J = 8.0 Hz,
CH), 7.23 (d, 2H, J = 8.1 Hz, 2 x CH), 7.35 (d, 1H, J = 8.0 Hz,
CH), 7.53 (d, 1H, J = 8.0 Hz, CH), 7.65 (d, 2H, J = 8.1 Hz, 2 x
CH), 8.14 (s, 1H, NH). 13C-NMR: (CDCl3, 125 MHz) d = 14.0
(CH3), 21.4 (CH3), 22.1 (CH2), 28.7 (CH2), 42.6 (CH2), 47.2
(CH2), 111.1 (CH), 115.1 (C), 118.6 (CH), 119.0 (CH), 121.5
(CH), 121.8 (CH), 127.0 (2 x CH), 127.3 (C), 129.5 (2 x CH),
136.3 (C), 137.0 (C), 142.9 (C). IR: m [cm−1] = 3403 (s), 2935 (s),
1455 (vs), 1336 (vs), 1305 (vs), 1184 (s), 1155 (vs), 1089 (vs), 742
(vs), 715 (s), 551 (s). HRMS found [M]+ 356.1569, C20H24N2O2S
requires [M]+ 356.1558.
2-[2-(5-Methoxy-1H -indol-3-yl)-ethyl]-isoindole-1,3-dione
(30c). The general procedure is followed with 2-allyl-isoindole-
1,3-dione (292 mg, 1.56 mmol), a-Boc-1-(4-methoxyphenyl)-
hydrazine (372 mg, 1.56 mmol), Rh(acac)(CO)2 (0.12 mg,
0.30 mol%) and Xantphos (27.1 mg, 3 mol%) to give 2-[2-(5-
methoxy-1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (400 mg,
2 3 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3

View Article Online
Ethyl-[2-(1H-indol-3-yl)-ethyl]-carbamic acid ethyl ester (30g).
The general procedure is followed with allyl-ethyl-carbamic acid
ethyl ester (302 mg, 1.92 mmol), phenylhydrazine (208 mg,
1.92 mmol), Rh(acac)(CO)2 (1.49 mg, 0.30 mol%) and Xant-
phos (33.3 mg, 3 mol%) to give ethyl-[2-(1H-indol-3-yl)-ethyl]-
9 G. Verspui, G. Elbertse, F. A. Sheldon, M. A. P. J. Hacking and R. A.
Sheldon, Chem. Commun., 2000, 1363.
10 (a) L. Ba¨rfacker, C. Buss, C. Hollmann, B. E. Kitsos-Rzychon, C. L.
Kranemann, T. Rische, R. Roggenbuck, A. Schmidt and P. Eilbracht,
Chem. Rev., 1999, 99, 3329; (b) A. M. Schmidt, P. Eilbracht, in
Transition Metals for Organic Synthesis: Building Blocks and Fine
Chemicals, ed. M. Beller and C. Bolm, Wiley-VCH, Weinheim, 2nd
edn., 2004, pp. 57-111.
11 (a) P. Ko¨hling, A. M. Schmidt and P. Eilbracht, Org. Lett., 2003,
5(18), 3213–3216; (b) Beller et al. have isolated hydrazones from the
hydroformylation of olefins in the presence of hydrazines. In addition,
the authors report that tandem hydroformylation–indolization can
be performed with Lewis acids such as ZnCl2 instead of Brønsted
acids. See: M. Ahmed, R. Jackstell, A. M. Seayad, H. Klein and M.
Beller, Tetrahedron Lett., 2004, 45(4), 869–873 for further details.
12 G. D. Cuny and S. L. Buchwald, J. Am. Chem. Soc., 1993, 115, 2066–
2068.
1
carbamic acid ethyl ester (255 mg, 51%). H-NMR: (CDCl3,
500 MHz) d = 1.12 (bs, 3H, CH3), 1.27 (bs, 3H, CH3), 3.01 (bs,
2H, CH2), 3.32, 3.27 (2 x bs, 2H, CH2), 3.53 (bs, 2H, CH2), 4.14,
4.16 (2 x bs, 2H, CH2), 6.99 (s, 1H, CH), 7.13 (dd, 1H, J = 7.2 Hz,
J = 7.2 Hz, CH), 7.19 (dd, 1H, J = 7.7 Hz, J = 7.2 Hz, CH), 7.35
(d, 1H, J = 7.7 Hz, CH), 7.65 (bs, 1H, CH), 8.27 (s, 1H, NH).
13C-NMR: (CDCl3, 125 MHz) d = 13.4, 13.9 (CH3), 14.7 (CH3),
24.9, 24.3 (CH2), 26.9 (CH2), 42.3 (CH2), 47.3, 48.1 (CH2), 61.0
(CH3), 111.1 (CH), 113.2 (C), 118.7 (CH), 119.2 (CH), 121.9 (2
x CH), 127.4 (C), 136.3 (C), 156.3 (C). IR: m [cm−1] = 3318 (vs),
2977 (vs), 1697 (vs), 1486 (vs), 1280 (vs), 1193 (vs), 1095 (s), 1012
(s), 742 (s). HRMS found [M]+ 260.1490, C15H20N2O2 requires
[M]+ 260.1525.
13 (a) K. Kaneda, M. Yasumura, M. Hiraki, T. Imanaka and S.
Teransihi, Chem. Lett., 1981, 1763; (b) K. Kaneda, T. Imanaka and
S. Teranishi, Chem. Lett., 1983, 1465.
14 T. Rische, PhD Thesis, 1999.
15 K. Wittmann, W. Wisniewski, R. Mynott, W. Leitner, C. L. Krane-
mann, T. Rische, P. Eilbracht, S. Kluwer, J. M. Ernsting and C. J.
Elsevier, Chem.–Eur. J., 2001, 7, 4584–4589.
N-Ethyl-N-[2-(1H-indol-3-yl)-ethyl]-benzamide (30h). The
general procedure is followed with N-allyl-N-ethylbenzamide
(324 mg, 1.71 mmol), phenylhydrazine (185 mg, 1.71 mmol),
Rh(acac)(CO)2 (1.32 mg, 0.30 mol%) and Xantphos (29.7 mg,
3 mol%) to give N-ethyl-N-[2-(1H-indol-3-yl)-ethyl]-benzamide
(160 mg, 32%). 1H-NMR: (CDCl3, 500 MHz) d = 1.27 (bs, 3H,
CH3), 2.94, 3.19 (2 x bs, 2H, CH2), 3.20, 3.51 (2 x bs, 2H, CH2),
3.67, 3.81 (2 x bs, 2H, CH2), 6.83–7.78 (10H, 10 x CH), 8.24 (s,
1H, NH). 13C-NMR: (CDCl3, 125 MHz) d = 25.0, 23.4 (CH2),
44.3, 39.9 (CH2), 45.6, 49.3 (CH2), 111.2 (CH), 118.8 (CH), 119.3
(CH), 126.3 (2 x CH), 126.3 (2 x CH), 128.4 (2 x CH), 129.1,
129.0 (CH), 137.1, 136.2 (C). IR: m [cm−1] = 3181 (s), 2929 (s),
1606 (vs), 1596 (vs), 1467 (m), 1455 (s), 1319 (m), 748 (s). HRMS
found [M]+ 292.1539, C19H20N2O requires [M]+ 292.1575.
16 K. Hakkaku, Y. Sakakibara, JP2000143587, 2000.
17 (a) H. W. Bohnen and B. Cornils, Adv. Catal., 2002, 47, 1–64; (b) B.
Cornils, J. Mol. Catal. A: Chem., 1999, 143, 1–10; (c) M. Beller,
B. Cornils, C. D. Frohning and C. W. Kohlpaintner, J. Mol. Catal.
A: Chem., 1995, 104, 17–85; (d) B. Cornils, W. A. Herrmann and
C. W. Kohlpaintner, Angew. Chem., 1994, 106, 2219, (Angew. Chem.,
Int. Ed. Engl., 1994, 33, 2144); (e) B. Cornils, W. A. Herrmann,
Applied Homogeneous Catalysis with Organometallic Compounds,
VCH, Weinheim, 1996; (f) Rhodium Catalyzed Hydroformylation,
ed. P. W. N. M. van Leeuwen and C. Claver, Kluwer Academic
Publishers, Dordrecht, 2000.
18 (a) S. Wagaw, B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc.,
1998, 120, 6621–6622; (b) S. Wagaw, B. H. Yang and S. L. Buchwald,
J. Am. Chem. Soc., 1998, 121, 10251–10263.
19 T. Ishiyama and J. Hartwig, J. Am. Chem. Soc., 2000, 122(48), 12043–
12044.
Acknowledgements
20 P. Blatcher, M. Carter, R. Hornby, M. R. Owen, WO 9509166, 1995.
21 Y. K. Lim and C. G. Cho, Tetrahedron Lett., 2004, 45, 1857–1859.
22 R. E. Kenton, S. D. Dudlettes and A. T. Shulgin, Biol. Psychiatry,
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The authors thank Degussa AG, Du¨sseldorf and Bayer AG,
Leverkusen for donation of chemicals.
23 M. Wolter, A. Klapars and S. Buchwald, Org. Lett., 2001, 3, 3803–
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 3 3 – 2 3 4 3
2 3 4 3