Synthesis of pharmacologically relevant indoles with amine side chains via tandem hydroformylation/fischer indole synthesis

Article abstract of DOI:10.1021/jo050464l

The sequence of hydroformylation and Fischer indole synthesis starting from amino olefins and aryl hydrazines is described. In a convergent manner, the two units bearing pharmacologically relevant substituents are assembled in the final indolization step. This modular and diversity-oriented approach to tryptamines and homotryptamines can be conducted in water and allows synthesis of branched and nonbranched tryptamines as well as tryptamine-based pharmaceuticals such as the 5-HT_1D agonist L 775 606.

Full text of DOI:10.1021/jo050464l

Synthesis of Pharmacologically Relevant Indoles with Amine Side
Chains via Tandem Hydroformylation/Fischer Indole Synthesis
Axel M. Schmidt and Peter Eilbracht*
Fachbereich Chemie, Organische Chemie I, Universita¨t Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund
peter.eilbracht@udo.edu
Received March 9, 2005
The sequence of hydroformylation and Fischer indole synthesis starting from amino olefins and
aryl hydrazines is described. In a convergent manner, the two units bearing pharmacologically
relevant substituents are assembled in the final indolization step. This modular and diversity-
oriented approach to tryptamines and homotryptamines can be conducted in water and allows
synthesis of branched and nonbranched tryptamines as well as tryptamine-based pharmaceuticals
such as the 5-HT1D agonist L 775 606.
SCHEME 1. Recent Drug Developments
Introduction
Tryptamines are involved in various biological pro-
cesses. Serotonin, for example, is a neurotransmitter and
influences the human nervous system. It controls the
state of mind, affects circadian rhythm, sexual urge, and
body temperature and seems to play a key role in
neurological disorders such as migraine. Tailored sero-
tonin-type tryptamines are therapeutically used to influ-
ence these systems by addressing the responsible recep-
tors selectively. In the past few years, it was found that
in addition to appropriate substituents at C5, more
sophisticated amine moieties have to be attached with
varying distances at C3 to achieve high selectivities
toward subtypes of the serotonin receptor family in
addition to extended substituents at the 5-position
(Scheme 1).1-3
From a synthetic chemist’s point of view, these and
additional features such as the occurrence of branching
in the R- and â-positions or stereochemical issues, as well
as the fact that the nitrogen might be embedded in a
cyclic system such as piperidines, pyrrolidines, or pip-
erazines, are interesting. All these features demand
synthetic strategies that give convenient and fast access
to highly diverse libraries of tryptamines and their
homologues. Therefore, a general protocol is required that
allows simultaneous variations in all medicinally impor-
tant positions. For a modular approach with high diver-
sity, fusion of all building blocks in a late synthetic step
would be desirable with flexible determination of the
chain length and the substitution pattern in the side
chain. Such a convergent strategy should preferably
include the construction of the indole core from building
blocks (amine moiety, side chain fragment, properly
substituted aromatic indole precursor), which are easily
available in large amounts from previous synthetic steps.
(1) Johnson, K. W.; Schaus, J. M.; Durkin, M. M.; Audia, J. E.;
Kaldor, S. W.; Flaugh, M. E.; Adham, N.; Zgombick, J. M.; Cohen, M.
L.; Branchek, T. A.; Phebus, L. A. NeuroReport 1997, 8, 2237-2240.
(2) Harding, V. D.; Macrae, R. J.; Ogilvie, R. J. PCT Int. Appl.
WO9606842A1, 1996.
(3) MacLeod, A. M.; Street, L. J.; Reeve, A. J.; Jelley, R. A.; Sternfeld,
F.; Beer, M. S.; Stanton, J. A.; Watt, A. P.; Rathbone, D.; Matassa, V.
G. J. Med. Chem. 1997, 22, 3501-3503.
Fischer’s method and Larock’s method are the most
common methods used to construct indoles. In the Larock
indole synthesis, o-halo anilines are connected with a
functionalized alkyne under palladium catalysis.4 Syn-
10.1021/jo050464l CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/14/2005
5528
J. Org. Chem. 2005, 70, 5528-5535

Synthesis of Pharmacologically Relevant Indoles
SCHEME 2. Retrosynthesis for L775 606 (4) via
Tandem Hydroformylation/Fischer Indole
Synthesis
thesis of additionally substituted o-halo anilines, how-
ever, requires further steps and is not always easily
achieved. Similarly, the alkyne unit may require labori-
ous synthetic procedures. If the final product bears
additional substituents on the six-membered ring of the
indole core, the substituted o-halo anilines subjected to
the Larock synthesis can cause steric hindrance. Simi-
larly, obtaining the starting materials for Fischer’s indole
synthesis can be laborious. Here carbonyl compounds are
reacted with aryl hydrazines under acid catalysis.5 While
a number of different approaches have been reported for
the synthesis of substituted aryl hydrazines (the degree
of substitution is reduced by one as compared to the aryl
halide required for a Larock synthesis of the same
compound), synthesis of the carbonyl compound very
often requires a large number of simple functional group
transformations (e.g., homologization of the carbon chain,
reduction, oxidation). If aldehydes are needed for the
indolization step, these have to be protected as acetals,
aminals, enol ethers, or bisulfite adducts in order to
prevent aldol condensation and oligomerization under the
harsh conditions of Fischer indole synthesis. This re-
quires additional steps and reagents and may hamper a
general application with broad diversity as demanded for
an ideal synthesis6 and the medicinal chemist’s needs.
Recently, we have given a preliminary report on a new
approach to indoles starting from alkenes and hydrazines
via a combination of rhodium-catalyzed hydroformylation
and Brønsted acid-catalyzed Fischer indole synthesis.7
The aldehyde is generated in situ from the alkene and
trapped by the hydrazine to form the hydrazone, which
is cyclized to the indole product. This one-pot procedure
offers a convenient modular approach toward side chain-
functionalized indoles with high diversity, if the broad
availability of substituted aryl hydrazines and function-
alized alkenes is considered. If amino olefins are used,
aryl- and side chain-functionalized indoles such as
tryptamines and their homologues should be obtainable
from, respectively, two and three easily available building
blocks and CO/H2 (Scheme 2).
documented that the hydrogenation activity of rhodium
catalysts is increased in the presence of catalytic amounts
of tertiary amines.8 In using amino olefins, the amine as
part of the substrate is present in a large excess relative
to the catalyst. Therefore, hydrogenation of the olefin can
result in loss of starting material, while subsequent
hydrogenation of the hydroformylation product leads to
the corresponding alcohol. On the other hand, rhodium
catalysts exhibit double-bond isomerization activity. It
has been reported that allylic amines isomerize to
enamines under rhodium catalysis at mild temperatures,9
and according to our own experience with hydroaminom-
ethylation, such enamines are easily hydrogenated under
hydroformylation conditions.10 Furthermore, even amine
bases can induce aldol condensation reactions of the
aldehydes. All these side reactions may be prevented, if
hydroformylation of amino olefins is conducted in the
presence of hydrazines with trapping of the aldehydes
as hydrazones. Therefore, we started our investigation
with studies of the hydroformylation of amino olefins in
the presence of hydrazines.
We here wish to demonstrate the efficiency of this new
tandem procedure in modular syntheses of linear and
branched tryptamines and their homologues.
Results and Discussion
A modular one-pot synthesis of tryptamine-type indoles
according to the above-described protocol requires ef-
ficient hydroformylation, hydrazone formation, and in-
dolization under optimized conditions for all steps.
Hydroformylation of nonprotected amino olefins and
especially of allylic amines, however, is not trivial since
various unwanted side reactions can occur. It is well
Hydroformylation of Amino Olefins in the Pres-
ence of Aryl Hydrazines. As expected, hydroform-
ylation of N-allylic, N,N-dimethylamine (5a) and of
(4) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(5) (a) Robinson, B. Chem. Rev. 1963, 3, 373. (b) Ishii, H. Acc. Chem.
Res. 1981, 14, 233-247. (c) Robinson, B. The Fischer Indole Synthesis;
Wiley: New York, 1982. (d) Hughes, D. L. Org. Prep. Proced. Int. 1993,
25, 607-632. (e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045.
(6) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997,
765-769.
(7) (a) Ko¨hling, P.; Schmidt, A. M.; Eilbracht, P. Org. Lett. 2003, 5,
18, 3213-3216. (b) Schmidt, A. M.; Eilbracht, P. Org. Biomol. Chem.
2005, 3, 124-134.
(8) (a) Kaneda, K.; Yasumura, M.; Hiraki, M.; Imanaka, T.;
Teransihi, S. Chem. Lett. 1981, 1763. (b) Kaneda, K.; Imanaka, T.;
Teranishi, S. Chem. Lett. 1983, 1465.
(9) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.;
Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am.
Chem. Soc. 1984, 18, 106, 5208-5217.
(10) (a) Eilbracht, P.; Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt,
A. Chem. Rev. 1999, 99, 3329-3366. (b) Schmidt, A. M.; Eilbracht, P.
In Transition Metals for Organic Synthesis: Building Blocks and Fine
Chemicals, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
2004, pp 57-111.
J. Org. Chem, Vol. 70, No. 14, 2005 5529

Schmidt and Eilbracht
TABLE 1. Tandem Hydroformylation/Hydrazone
Formationa
TABLE 2. Synthesis of Linear Tryptamines and
Homotryptaminesa
entry
olefin 5
hydrazine 6
yield
1
2
3
4
5
5a (R1 ) CH3)
5b (R1) (CH2)5)
5b (R1) (CH2)5)
5a (R1 ) CH3)
5b (R1) (CH2)5)
6a (R2 ) H)
quant. (7a)
97% (7b)
93% (7c)
90% (7d)
80% (7e)
6a (R2 ) H)
6b (R2 ) OMe)
6c (R2 ) CN)
6d (R2 ) NO2)
a Conditions: 1 equiv of 5, 1 equiv of 6, 0.3 mol % Rh(acac)(CO)2,
1.5 mol % XANTPHOS, 10 bar CO, 10 bar H2, THF, 3 days,
70 °C.
4-methylene, N-methyl piperidine (5l) does not selectively
lead to amino aldehydes even if phosphane ligands such
as XANTPHOS are added. If, however, hydroformylation
of the same allylic amines is conducted in the presence
of phenylhydrazine (6a), the expected aryl hydrazones 7
can be isolated in almost quantitative yields (Table 1).
No purification is needed; the products can be used for
indolization directly without further purification.11 Under
the chosen conditions, electron-withdrawing as well as
electron-donating substituents at the aromatic hydrazine
are tolerated. Even nitro groups are stable under the
reductive conditions.12 It is also important to mention
that the use of a Rh/XANTPHOS system grants high
n-selectivity in the hydroformylation of terminally mono-
substituted amino olefins.
In all cases, hydrogenation products are not observed,
neither the olefin nor the aldehyde, which is immediately
trapped by the hydrazine. Also, the aryl hydrazone double
bond is not hydrogenated, so a higher stability of aryl
hydrazones toward hydrogenation can be assumed as
compared to the aldehyde precursors. In summary, the
hydrazone group acts as an efficient protecting group for
aldehydes. In contrast to other protection groups, the aryl
hydrazone at the same time is a building block for the
final indole product.
Fischer Indolization. While the hydroformylations
described above are performed in THF, Fischer indoliza-
tion requires a more polar solvent in order to prevent
precipitation of salts formed by protonation of the amino
and/or hydrazine/hydrazone groups. Alcohols are common
solvents in Fischer indole syntheses. However, indoliza-
tion of 7a in ethanol gives tryptamine 8a only in an
unselective conversion with poor yields. Reaction in
methanol does not lead to any improvements, whereas
in aqueous sulfuric acid, fast and highly selective conver-
sion toward indole 8a is found with quantitative yields.
Surprisingly, this method proceeds with such a high
degree of selectivity that a purification of the reaction
product is not required.
a Conditions: (i) 1 equiv of 5, 1 equiv of phenylhydrazine 6a,
0.3 mol % Rh(acac)(CO)2, 1.5 mol % XANTPHOS, 10 bar CO, 10
bar H2, THF, 3 days, 70 °C; (ii) 4 wt % H2SO4, 2 h, 100 °C. Yield
is given for the tandem reaction starting with the olefin. b Pre-
cipitated as hydrochloride salt.
Tandem Hydroformylation/Hydrazone Forma-
tion/Fischer Indolization. A combination of both steps
therefore seems to be a suitable protocol for the synthesis
of tryptamines directly from olefins, if after a hydro-
formylation of the amino olefin in the presence of an aryl
hydrazine the solvent is removed and the remaining aryl
hydrazone is taken up in aqueous sulfuric acid for the
final indolization. The reliability of this protocol is tested
with a number of different allylic and homoallylic amines
as compiled in Table 2.
Without any exception, all indoles are obtained in
excellent yields, and no products stemming from iso-
aldehydes are detected. Thus, the Rh/XANTPHOS sys-
tem is a powerful hydroformylation catalyst for the
regioselective conversion of amino olefins, and in contrast
to other observations13 the positive effect of the ligand is
not suppressed in the presence of the amine and hydra-
zine units. The stability of the carbamate protection
group in 8d and 8f is also surprising. After removal of
this group, the nitrogen is activated for further deriva-
tization as required for target molecules such as phar-
maceutical compound L 775 606 (4, Scheme 1). While
tryptamine 8a (Table 2, entry 1) is known as a prominent
(11) Beller et al. have simultaneously found that aldehydes can be
trapped as aryl hydrazones under hydroformylation conditions. Sub-
sequent indolization was verified by the addition of ZnCl2 to the crude
mixture, but in contrast to our protocol this procedure appears to be
limited to simple alkyl indoles. For further details, see: Ahmed, M.;
Jackstell, R.; Seayad, A. M. Klein, H.; Beller, M. Tetrahedron Lett.
2004, 45, 4, 869-873.
(12) In our experience, aromatic nitro groups can be reduced under
harsh hydroformylation conditions, allowing them to be used as aniline
precursors in hydroaminomethylations. Unpublished results; Rische,
T.; Eilbracht, P.; 1999.
(13) Angelovski, G.; Eilbracht, P. Tetrahedron 2003, 59, 8265-8274.
5530 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Pharmacologically Relevant Indoles
TABLE 3. Synthesis of Branched Tryptamines
FIGURE 1.
structural element in many biologically active indole
derivatives, tryptamines with the nitrogen as part of a
cyclic moiety have become more and more interesting.
Especially the piperazine moiety seems to be very at-
tractive for pharmaceutical use. The structural ele-
ment of 8c, for example, is found in the antipsychotic
Oxypertine (9, Figure 1). For targets of this type, it
was important to prove that both allylic piperazines as
well as homoallylic piperazines are tolerated under the
conditions used to allow the attachment of amines in
varying distances to different indole cores (Table 2,
entries 3, 4, 6). In general, allylation and homoallyla-
tion of amines proceed with excellent yields, thus allow-
ing a modular approach using the method described
above.
Apart from tryptamine analogues with linear side
chains as prepared above, also derivatives with branched
side chains have come into the focus of medicinal chem-
istry. In the past few years, the first examples of such
branched tryptamines possessing pharmacologically in-
teresting properties have been developed. The R-branched
tryptamine LY 156 735 (10, Figure 1), for example, is a
melatonin agonist that helps to alleviate the symptoms
of time shift lag and enhances readaptation of desyn-
chronized circadian rhythms to a new time zone.14
Tryptamines with branches at the â-carbon as found
in various â-carboline derivatives (11) act as potential
drugs against depression anxiety. Most of the known
â-branched tryptamines are tryptophan derivatives and
can be synthesized starting from this essential amino
acid. Therefore, not surprisingly, only a few examples of
â-branched tryptamines are reported, with substituents
not possessing the oxidation level of the carboxylic group
or with substituents not obtainable from this function.
Obviously, there is a need for a method that allows fast
access to branched tryptamines as well.
We have previously demonstrated7 that R-branched
tryptamines can be obtained by using terminally disub-
stituted olefins such as methallylic amines, which can
easily be prepared by simple allylation with methallylic
chloride. The allylic amines required for the synthesis of
â-branched tryptamines are obviously less conveniently
obtained, and in addition, they bear a stereogenic center.
Simple allylation of amines may fail due to poor regiose-
lectivity and problems to control the configuration of the
newly formed stereocenter, if required. A well-described
access toward chiral allylic amines is the Overman
rearrangement of allylic trihalo acetimidates giving
protected primary amines.15 After alkylation, the tertiary
a Conditions: (i) 1 equiv of 5, 1 equiv of phenylhydrazine 6a, 1
mol % Rh(acac)(CO)2, 5 mol % XANTPHOS, 10 bar CO, 10 bar
H2, THF, 3 days, 80 °C; (ii) 4 wt % H2SO4, 2 h, 100 °C. Yield is
given for the tandem reaction starting with the olefin. b Average
of all reactions with 5h. c Determined by HPLC with a Daicel
Chiracel OJ.
chiral amine 5g can be obtained as a racemate. An
alternative method to obtain chiral allylic amines was
published in 2001 by Takeuchi et. al.17 Here, regioselec-
tive allylic amination of allylic carbonates and acetates
has been achieved with an Ir/P(OPh)3 catalyst. In
2002, Hartwig published the first regio- and enantio-
selective allylic amination.18 With this methodology, a
large number of different allylic amines such as 5h are
accessible with varying amine functionalities, as well as
alkyl, homoaryl, and heteroaryl substituents tolerable at
the stereocenter. Use of these methods (Overman rear-
rangement, allylic amination) for selected examples and
the tandem hydroformylation/Fischer indole procedure
affords â-branched indoles in good to excellent yields
(Table 3).
While the allylic amination proceeds with high enan-
tiomeric excesses, the stereocenter may epimerize during
a tandem hydroformylation/Fischer indolization via re-
versible double-bond isomerization either by the transi-
tion metal catalyst or the acid. The tryptamines obtained
from enantiomerically pure allylic amines, however,
reveal complete retention of chirality under hydroformy-
lation conditions. This combination of iridium-catalyzed
enantioselective allylic amination and tandem hydro-
(16) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412-12413.
(17) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J.
Am. Chem. Soc. 2001, 123, 9525-9534.
(14) Nickelsen, T.; Samel, A.; Vejvoda, M.; Wenzel, J.; Smith, B.;
Gerzer, R. Chronobiol. Int. 2002, 9, 5, 915-936.
(15) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597.
(18) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
15164-15165.
J. Org. Chem, Vol. 70, No. 14, 2005 5531

Schmidt and Eilbracht
TABLE 4. Synthesis of Branched Homotryptamines
formylation/Fischer indole synthesis, in contrast to other
methods reported, gives fast access to â-branched
tryptamines, which cannot be derived from tryptophan,
and therefore opens access to a new class of tryptamine
derivatives for biological screenings.
Using the same protocol with branched homoallylic
amines leads to branched homotryptamines. The re-
quired amines are easily obtained via a combination of
Mannich reaction and Wittig olefination or by simple
Barbier-type reactions. For the latter a number of dif-
ferent methods have been published to control the
absolute configuration of stereocenters. The homoallylic
moiety can also be embedded in an exocyclic olefin. If
piperidines with an exocyclic double bond are used, 3-(N-
methyl piperdiyl)-indoles are obtained, containing an
important structural element of active agents such as the
antimigraine drug LY 334 370 (1) or Naratriptan (2,
Scheme 1).
As it can be seen from Table 4, most homotryptamines
can be obtained in good to excellent yields. Halide
substituents are tolerated, allowing further derivatization
with common cross-coupling methodologies. In this re-
spect, substrate 8o may act as a valuable intermediate
for the synthesis of Naratriptan (2).
Second-Generation Protocol for the Tandem Hy-
droformylation/Fischer Indolization. So far, our
protocol for tandem hydroformylation/Fischer indole
synthesis gives fast and convenient access to a large
number of differently substituted tryptamines. However,
the method requires a change of solvent to complete the
procedure, although there is no need for a purification
of the aryl hydrazones obtained. Therefore, it is desirable
to develop a protocol that allows direct access to
tryptamine derivatives from amino olefins. This requires
a solvent with good solubility for all reagents and
reactants. Since alcohol solvents failed in test reactions,
we concentrated on water as the solvent of choice.
Sulfuric acid in water allows a smooth conversion of the
aryl hydrazones to tryptamines and has the advantage
of being environmentally benign. Solubility of the rhodium-
based hydroformylation catalyst in water and even in
aqueous sulfuric acid can be achieved by using sulfonated
ligands such as TPPTS (12) or the analogous derivative
13 of XANTPHOS.We tested this modification with allylic
and homoallylic substrates mostly containing the pip-
eridyl or the piperazinyl moiety duo to their pharmaco-
logical relevance. As shown in Table 5, tandem hydro-
formylation/Fischer indole synthesis in water gives in all
cases excellent results. For 3-piperidyl indoles (entries
1-5), no further purification is required. It is worth
mentioning that sensitive bromine substituents are
known to be cleaved under Fischer indole conditions.
Under the conditions used here the bromine substituent
is maintained, even at prolonged reaction times during
which the aryl halide is treated with mineral acid under
harsh conditions. Clearly, regioselective tandem hydro-
formylation/Fischer indole synthesis in water is not
limited to disubstituted terminal olefins as the substrate.
Conversion of allylic and homoallylic amines also gives
good to excellent yields of the desired tryptamine ana-
logues. High regioselectivities can also be achieved with
sulfonated XANTPHOS 13.
a Conditions: (i) 1 equiv of 5, 1 equiv of 6, 1 mol % Rh(acac)-
(CO)2, 50 bar CO, 10 bar H2, THF, 3 days, 120 °C; (ii) 4 wt %
H2SO4, 2 h, 100 °C. Yield is given for the tandem reaction starting
with the olefin. b Conditions: (i) 1 equiv of 5, 1 equiv of 6, 0.3 mol
% Rh(acac)(CO)2, 1.5 mol % XANTPHOS, 10 bar CO, 10 bar H2,
THF, 3 days, 70 °C; (ii) 4 wt % H2SO4, 2 h, 100 °C. Yield is given
for the tandem reaction starting with the olefin. c Conditions: (i)
1 equiv of 5, 1 equiv of 6, 0.3 mol % Rh(acac)(CO)2, 50 bar CO, 10
bar H2, THF, 3 days, 100 °C; (ii) 4 wt % H2SO4, 2 h, 100 °C. Yield
is given for the tandem reaction starting with the olefin.
thesis of the three antimigraine drugs LY 349 950 (14),
LY 334 370 (1), and L 775 606 (4). The results are
compiled in Table 6.
Although synthesis of the required aryl hydrazines has
been reported,19,20 it turned out to be difficult to obtain
the products with sufficient purity. Obviously, the clas-
Pharmaceuticals. Finally, we tested the tandem
hydroformylation/Fischer indole procedure in the syn-
5532 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Pharmacologically Relevant Indoles
TABLE 6. Synthesis of Migraine Drug Candidates
SCHEME 3. Ligands for the Tandem Reaction in
Water
TABLE 5. Tandem Hydroformylation/Fischer Indole
Synthesis in Water
a Conditions: (i) 1 equiv of 5, 1 equiv of 6, 1 mol % Rh(acac)-
(CO)2, 5 mol % XANTPHOS, 10 bar CO, 10 bar H2, THF, 3 days,
70 °C; (ii) 4 wt % H2SO4, 2 h, 100 °C. Yield is given for the tandem
reaction starting with the olefin. b Conditions: 1 equiv of 5, 1 equiv
of 6, 0.3 mol % Rh(acac)(CO)2, 1.5 mol % TPPTS, 50 bar CO, 10
bar H2, 4 wt % H2SO4, 3 days, 100 °C.
under copper catalysis in good yields. The R-Boc-protected
aryl hydrazines are no longer prone to oxidation and can
easily be purified by LC. Olefin (5) and hydrazine (6) are
assembled in the tandem hydroformylation/Fischer indole
synthesis as the final step, giving the desired drug
candidates in good to excellent yield. Neither hydrolysis
of the amide bonds in LY 334 950 (14) and LY 334 370
(1) nor hydrogenation of the imine-enamine pattern in
L 775 606 (4) is observed.
Conclusion
The combination of modern allylation chemistry with
the tandem hydroformylation/Fischer indolization is an
efficient and highly diversity-oriented strategy for the
synthesis of tryptamine analogues. Both linear as well
as branched olefins can be used, giving nonbranched and
branched tryptamines and homotryptamines. Stereo-
centers close to the olefinic bond can be tolerated and do
not epimerize, leading to enantiomerically pure â-branched
tryptamines. In many cases, the obtained products do not
require further purification, since tandem hydroformy-
lation/Fischer indole synthesis proceeds with high selec-
tivity. The use of sulfonated ligands allows this tandem
reaction to be conducted in water, making it environ-
mentally benign. With this new methodology, simple
model tryptamines as well as recent drug development
candidates can be synthesized more conveniently than
with previously reported methodologies. Usually, the
number of required steps is reduced, since simple func-
tional group transformations (e.g., hydrogenations, ho-
mologization, reduction, oxidation, protection) are re-
a Hydrochlorides were used directly. b Conditions: 1 equiv of
5, 1 equiv of 6, 0.3 mol % Rh(acac)(CO)2, 1.5 mol % 12, 50 bar CO,
10 bar H2, 4 wt % H2SO4, 3 days, 100 °C. c Conditions: 2 equiv of
5, 1 equiv of 6, 0.3 mol % Rh(acac)(CO)2, 3 mol % 13, 10 bar CO,
10 bar H2, 4 wt % H2SO4, 3 days, 100 °C.
sical approach of aniline diazotation and reduction of the
resulting diazonium salts with bisulfites or tin dichloride
suffers from low selectivity. Furthermore, purification of
aryl hydrazines is hard to manage. Therefore, we decided
to use the Goldberg reaction to synthesize the required
hydrazines starting from the corresponding aryl iodides
(19) Xu, Y.-C.; Johnson, K. W.; Phebus, L. A.; Cohen, M.; Nelson,
D. L.; Schenck, K.; Walker, C. D.; Fritz, J. E.; Kaldor, S. W.;
LeTourneau, M. E.; Murff, R. E.; Zgombick, J. M.; Calligaro, D. O.;
Audia, J. E.; Schaus, J. M. J. Med. Chem. 2001, 24, 4031-4034.
(20) Sternfeld, F.; Guiblin, A. R.; Jelley, R. A.; Matassa, V. G.;
Reeve, A. J.; Hunt, P. A.; Beer, M. S.; Heald, A.; Stanton, J. A.; Sohal,
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J. Org. Chem, Vol. 70, No. 14, 2005 5533

Schmidt and Eilbracht
and 50 bar CO. After the mixture was stirred for 3 days (the
reaction is stirred magnetically; with a stirrer that mixes the
gas phase and the liquid phase intensively, the reaction time
can be reduced greatly according to our experience) at 100 °C,
NH3 (10 mL, 30 wt % in water) was added, and the mixture
was extracted with EtOAc. The solvent was evaporated to give
3-(1-methylpiperidin-4-yl)-1H-indole (400 mg, 80%) without
further purification.
duced to a minimum. A protection of the in situ-generated
aldehyde is achieved by trapping the aldehyde as a
hydrazone. This modular approach is remarkable since
substituents at C3 and C5, the type of the amine moiety,
and the distance from the amine moiety to the indole core
are assembled in the final synthetic step. Therefore, this
approach is valuable for the synthesis of substance
libraries with high diversity.
N-[3-(2-Dimethylamino-ethyl)-1H-indol-5-yl]-4-fluoro-
benzamide (14). The first-generation protocol was followed
with N,N-dimethylprop-2-en-1-amine (262 mg, 3.1 mmol),
N-[4-(4-fluoro-benzoylamino)-phenyl]-hydrazinecarboxylic acid
tert-butyl ester (1.06 g, 3.1 mmol), Rh(acac)(CO)2 (8 mg, 1 mol
%), and XANTPHOS (89 mg, 5 mol %). The crude product was
purified by chromatography (silica, CH2Cl2, cyclohexane, NEt3)
to give N-[3-(2-(dimethylamino)-ethyl)-1H-indol-5-yl]-4-fluoro-
Experimental Section
Materials. All reagents and solvents were dried and
purified before use by the usual procedures. Rh(acac)(CO)2,
XANTPHOS, N,N-dimethylprop-2-en-1-amine, and phenylhy-
drazine were purchased.
1
Tandem Hydroformylation/Hydrazone Formation. Di-
methyl-[4-(phenyl-hydrazono)-butyl]-amine (7a). In a
typical procedure N,N-dimethylprop-2-en-1-amine (679 mg,
7.97 mmol), phenylhydrazine (862 mg, 7.97 mmol), Rh(acac)-
(CO)2 (6.2 mg, 0.3 mol %), and XANTPHOS (69 mg, 0.15
mol %) in anhydrous THF (6.1 g, 10 wt % olefin) were
added in an autoclave. The autoclave was pressurized with
10 bar H2 and 10 bar CO. After the mixture was stirred for
68 h (the reaction is stirred magnetically; with a stirrer that
mixes the gas phase and the liquid phase intensively, the
reaction time can be reduced greatly according to our experi-
ence) at 70 °C, the solvent was removed to give dimethyl-[4-
(phenyl-hydrazono)-butyl]-amine (1.64 g, 100%) without fur-
ther purification. Analytical data was obtained from an
inseparable mixture of E/Z isomers. 1H NMR: (CDCl3, 400
MHz) δ ) 1.69-1.72 (2H, CH2); 2.22 (s, 3H, CH3); 2.28-2.33
(4H, 2 x CH2); 6.52-6.81 (1H, CH); 6.97-7.03 (3H, 3 x CH);
7.20-7.23 (2H, 2 x CH). Major isomer: 13C NMR: (CDCl3,
100 MHz) δ ) 23.6 (CH2); 29.8 (CH2); 44.8 (2 x CH3); 56.4
(CH2); 112.2 (2 x CH); 118.8 (CH2); 128.8 (2 x CH); 140.6 (CH);
146.1 (C). Minor isomer: 13C NMR: (CDCl3, 100 MHz) δ )
23.6 (CH2); 24.8 (CH2); 45.3 (2 x CH3); 58.9 (CH2); 112.2 (2 x
CH); 119.0 (CH2); 128.8 (2 x CH); 140.1 (CH); 145.3 (C). IR: ν˜
[cm-1] ) 2943 (vs), 2779 (s), 1603 (vs), 1496 (vs), 1259 (vs),
1115 (s), 750 (vs), 694 (vs). HRMS: found M+ 205.1580,
C12H19N3 requires M+, 205.1579. Elementary analysis: found
C 69.67, H 9.14, N 19.72; C12H19N3 requires C 70.20, H 9.33,
N 20.47.
First-Generation Protocol of Tandem Hydroformyla-
tion/Fischer Indole: [2-(1H-Indol-3-yl)-ethyl]-dimethyl-
amine (8a). In a typical procedure, N,N-dimethylprop-2-en-
1-amine (679 mg, 7.97 mmol), phenylhydrazine (862 mg, 7.97
mmol), Rh(acac)(CO)2 (6 mg, 0.3 mol %), and XANTPHOS (69
mg, 1.5 mol %) in anhydrous THF (6.1 g, 10 wt % olefin) were
added in an autoclave. The autoclave was pressurized with
10 bar H2 and 10 bar CO. After the mixture was stirred for 3
days (the reaction is stirred magnetically; with a stirrer that
mixes the gas phase and the liquid phase intensively, the
reaction time can be reduced greatly according to our experi-
ence) at 70 °C, the solvent was evaporated, and the residue
was taken up in H2SO4 (30 mL, 4 wt % in water). After the
mixture was stirred for 2 h under reflux, NH3 (10 mL, 30 wt
% in water) was added, and the mixture was extracted with
EtOAc. The solvent was evaporated to give [2-(1H-indol-3-yl)-
ethyl]-dimethyl-amine (1.5 g, 100%) without further purifica-
tion. NMR data fit with literature.21
benzamide (440 mg, 44%). H NMR: (CDCl3, 500 MHz) δ )
2.30 (s, 6H, 2 x CH3); 2.62 (t, 2H, J ) 8.0 Hz, CH2); 2.87 (t,
2H, J ) 8.0 Hz, CH2); 6.94 (s, 1H, CH); 7.11 (dd, 2H, J ) 8.7
Hz, J ) 8.2 Hz, 2 x CH); 7.20 (d, 1H, J ) 8.7 Hz, CH); 7.26 (s,
1H, CH); 7.81 (s, 1H, CH); 7.90 (bs, 2H, 2 x CH); 8.13 (s, 1H,
NH); 8.59 (s, 1H, NH). 13C NMR: (CDCl3, 125 MHz) δ ) 23.4
(CH2); 45.3 (2 x CH3); 60.0 (CH2); 114.0 (CH); 111.6 (CH); 114.2
(C); 115.6 (d, 2C, JC-F ) 21 Hz, 2 x CH); 116.9 (CH); 122.8
(CH); 127.6 (C); 129.4 (d, 2C, JC-F ) 8 Hz, 2 x CH); 129.7 (C);
131.4 (C); 134.0 (C); 163.7 (C); 165.3 (d, 1C, JC-F ) 251 Hz,
C). IR: ν˜ [cm-1] ) 3291 (s); 2942 (m); 2823 (m); 1644 (vs); 1602
(vs); 1540 (s); 1481 (vs); 1330 (m); 1232 (s); 1159 (s); 850 (s);
796 (m). HRMS: found [M + H]+ 326.1689 C19H20FN3O
requires [M + H]+, 326.1709.
4-Fluoro-N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-
benzamide (1). The second-generation protocol was followed
with 1-methyl-4-methylene-piperidine (158 mg, 1.42 mmol),
N-[4-(4-fluoro-benzoylamino)-phenyl]-hydrazinecarboxylic acid
tert-butyl ester (491 mg, 1.42 mmol), Rh(acac)(CO)2 (3.7 mg, 1
mol %), and TPPTS (40 mg, 5 mol %) to give 4-fluoro-N-[3-(1-
methyl-piperidin-4-yl)-1H-indol-5-yl]-benzamide (474 mg,
95%) without further purification.1H NMR: (CDCl3, 500 MHz)
δ ) 1.68 (q, 2H, J ) 11.8 Hz, 2 x CH2); 1.86 (d, 2H, J ) 11.2
Hz, CH2); 1.96 (t, 2H, J ) 11.7 Hz, CH2); 2.23 (s, 3H, CH3);
2.60 (t, 1H, J ) 11.0 Hz, CH); 2.82 (d, 2H, J ) 9.7 Hz, CH2);
6.71 (s, 1H, CH); 6.98 (bs, 2H, 2 x CH); 7.11 (d, 1H, J ) 8.3
Hz, CH); 7.18 (d, 1H, J ) 8.3 Hz, CH); 7.84 (bs, 2H, 2 x CH);
7.88 (s, 1H, CH); 8.61 (bs, 1H, NH); 9.27 (s, 1H, NH). 13C
NMR: (CDCl3, 125 MHz) δ ) 32.4 (CH); 32.5 (2 x CH2); 46.1
(CH3); 56.0 (2 x CH2); 111.5 (CH); 112.2 (CH); 115.4 (d, 2C,
JC-F ) 21 Hz, 2 x CH2); 116.8 (CH); 120.6 (C); 121.1 (CH);
126.6 (C); 129.3 (C); 129.4 (d, 2C, JC-F ) 8 Hz, 2 x CH); 131.2
(C); 134.2 (C); 164.5 (d, 1C, J ) 251 Hz, CC); 165.3 (C). IR: ν˜
[cm-1] ) 3291 (s); 2933 (s); 2850 (m); 1646 (vs); 1602 (s); 1540
(s); 1481 (vs); 1328 (m); 1232 (s); 1159 (s); 850 (s); 796 (m).
HRMS found [M]+ 351.1729 C21H22FN3O requires [M]+,
351.1711.
3-(3-{4-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-pro-
pyl)-5-[1,2,4]triazol-4-yl-1H-indole (4). The first-generation
protocol was followed with 1-but-3-enyl-4-[2-(3-fluoro-phenyl)-
ethyl]-piperazine (455 mg, 1.7 mmol), N-(4-[1,2,4]triazol-4-yl-
phenyl)-hydrazinecarboxylic acid tert-butyl ester (477 mg, 1.7
mmol), Rh(acac)(CO)2 (4.5 mg, 1 mol %), and XANTPHOS (50
mg, 5 mol %). The crude product was purified by chromatog-
raphy (silica, CH2Cl2, EtOH, NEt3) to give 3-(3-{4-[2-(3-fluoro-
phenyl)-ethyl]-piperazin-1-yl}-propyl)-5-[1,2,4]triazol-4-yl-1H-
Second-Generation Protocol for the Tandem Hydro-
formylation/Fischer Indole Synthesis in Water. In a
typical experiment, 1-methyl-4-methylenepiperidine (259 mg,
2.33 mmol), phenylhydrazine (252 mg, 2.33 mmol), Rh(acac)-
(CO)2 (1.8 mg, 0.3 mol %), and TPPTS (20 mg, 1.5 mol %) in
H2SO4 (9.3 g, 4 wt % in water, 2.5 wt % olefin) were added in
an autoclave. The autoclave was pressurized with 10 bar H2
1
indole (382 mg, 51%). H NMR: (CDCl3, 500 MHz) δ ) 1.27
(t, 2H, J ) 7.2 Hz, CH2); 1.41 (t, 2H, J ) 7.2 Hz, CH2); 1.89 (p,
2H, J ) 7.5 Hz, CH2); 2.44 (t, 2H, J ) 7.5 Hz, CH2); 2.55-
2.58 (4H, 2 x CH2); 2.74-2.78 (6H, 3 x CH2); 6.84 (d, 1H, J )
8.5 Hz, CH); 6.88 (d, 1H, J ) 8.5 Hz, CH); 6.94 (d, 1H, J ) 7.5
Hz, CH); 7.05 (d, 1H, J ) 8.5 Hz, CH); 7.14 (s, 1H, CH); 7.19
(d, 1H, J ) 7.5 Hz, CH); 7.47 (d, 1H, J ) 8.5 Hz, CH); 7.52 (s,
1H, CH); 8.44 (s, 2H, 2 x CH); 9.51 (s, 1H, NH).13C NMR:
(CDCl3, 125 MHz) δ ) 22.6 (CH2); 27.0 (CH2); 33.0 (CH2); 52.8
(21) Grina, J. A.; Ratcliff, M. R.; Stermitz, F. R. J. Org. Chem. 1982,
47, 13, 2648-2651.
5534 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Pharmacologically Relevant Indoles
(2 x CH2); 53.0 (2 x CH2); 58.0 (CH2); 59.7 (CH2); 112.6 (CH);
112.6 (d, 1C, JC-F ) 21 Hz, CH); 113.2 (CH); 115.4 (d, 1C, JC-F
) 19 Hz, CH); 116.4 (C); 116.5 (CH); 124.3 (CH); 125.8 (C);
127.9 (C); 128.1 (d, 1C, JC-F ) 11 Hz, CH); 129.7 (d, 1C, JC-F
) 8 Hz, CH); 136.1 (C); 142.5 (2 x CH); 142.8 (d, 1C, JC-F ) 6
Hz, C); 162.6 (d, 1C, JC-F ) 246 Hz, C). IR: ν˜ [cm-1] ) 3126
(s); 2940 (vs); 2811 (vs); 2773 (s); 1616 (s); 1587 (vs); 1488 (vs);
1448 (vs); 1267 (s); 1249 (vs); 1157 (s); 1139 (vs); 1093 (vs);
784 (s); 730 (vs).
Acknowledgment. The authors thank Degussa AG,
Du¨sseldorf, and Bayer AG, Leverkusen, for donations
of chemicals.
Supporting Information Available: Full experimental
data for all starting material and all indoles. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050464L
J. Org. Chem, Vol. 70, No. 14, 2005 5535