Tandem hydroformylation/Fischer indole synthesis: A novel and convenient approach to indoles from olefins

Article abstract of DOI:10.1021/ol0350184

(Matrix presented) A novel one-pot synthesis of indole systems via tandem hydroformylation/Fischer indole synthesis starting from olefins and arylhydrazines is described. This tandem procedure leads directly to 3-substituted indoles if unsubstituted phenylhydrazine is used and to 3,5- respectively 3,7-disubstituted indoles if para- or ortho-substituted arylhydrazines are used.

Full text of DOI:10.1021/ol0350184

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3213-3216
Tandem Hydroformylation/Fischer Indole
Synthesis: A Novel and Convenient
Approach to Indoles from Olefins
Petra Ko1hling, Axel M. Schmidt, and Peter Eilbracht*
Fachbereich Chemie, Organische Chemie I, UniVersita¨t Dortmund,
Otto-Hahn-Str. 6, 44227 Dortmund
peter.eilbracht@udo.edu
Received June 6, 2003
ABSTRACT
A novel one-pot synthesis of indole systems via tandem hydroformylation/Fischer indole synthesis starting from olefins and arylhydrazines
is described. This tandem procedure leads directly to 3-substituted indoles if unsubstituted phenylhydrazine is used and to 3,5- respectively
3,7-disubstituted indoles if para- or ortho-substituted arylhydrazines are used.
Due to the great variety of indole units in natural products
and pharmaceutical compounds, even today the development
of new syntheses is the subject of considerable efforts.1 Thus,
numerous indole derivatives with biological activity like the
tissue hormone melatonin (1), the neurotransmitter serotonin
(2), and the essential amino acid tryptophane (3) have been
synthesized by new methods.1
cases, this procedure has been used to generate the aldehydes
required for the Fischer indole synthesis. Thus, hydroformyl-
ation of ortho nitro styrenes yields branched aldehydes and,
under the same conditions, the nitro group is reduced to an
amino group. Intramolecular condensation leads then to the
indole core.6 More recently, Sheldon et al. reported a one-
pot synthesis of melatonin 1 starting from N-allylacetamide
via regioselective hydroformylation and Fischer indole
synthesis, although in this procedure reaction vessels were
changed as well as the reaction conditions.7 Following our
own interests in tandem hydroformylation procedures,8 we
envisaged a protocol allowing the indole formation to
proceed directly under the hydroformylation conditions in
the presence of the aryl hydrazine and a Brønstedt, resp.
Lewis acid. This tandem approach includes three steps: the
(1) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(2) (a) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241. (b) Fischer,
E.; Hess, O.; Chem. Ber. 1884, 17, 559.
(3) Robinson, B. The Fischer Indole Synthesis; John Wiley & Sons:
Chichester, 1982.
(4) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
(5) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J. Mol.
Catal. A 1995, 104, 17.
(6) Ucciani, E.; Bonfand, A. Chem. Commun. 1981, 82.
(7) Verspui, G.; Elbertse, G.; Sheldon, F. A.; Hacking, M. A. P. J.;
Sheldon, R. A. Chem. Commun. 2000, 1363.
Fischer indole synthesis is one of the most important
approaches to indoles.2-4 In this reaction, aldehydes or
ketones condense with arylhydrazines to arylhydrazones,
which undergo a [3,3]-sigmatropic rearrangement to indoles
in the presence of a Brønstedt resp. Lewis acid. Since under
these conditions aldehydes tend toward side reactions, acetals
or aminals are often used instead with in situ generation of
the free aldehydes.3,4
(8) Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.;
Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A.; Eilbracht, E.;
Chem. ReV. 1999, 99, 3329.
For the synthesis of aldehydes, hydroformylation of olefins
is known as an industrially important method5 and, in various
10.1021/ol0350184 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003

in situ generation of oxo aldehyde 6, its conversion to aryl
hydrazones 7, and the [3,3]-sigmatropic rearrangement to the
final product 8. For this, if starting from a terminal olefin 4,
hydroformylation must regioselectively lead to aldehyde 6.
This, without isolation or side reactions, must selectively
condense under the same reaction conditions with the
aromatic hydrazine 5 to give the aryl hydrazone 7, which
again without isolation or hydrogenation should cyclize to
the indole 8 (Scheme 1).
alkenes and phenylhydrazine, we extended the procedure to
functionalized olefins such as methallylic alcohols and
amines. Both allow n-selective hydroformylation, and their
Fischer indolization would lead to pharmaceutically interest-
ing tryptophole and tryptamine derivatives. Use of methallyl
alcohol (9a) provided only a 28% yield of the desired indole
10a (Scheme 2). To prevent potential side reactions such as
Scheme 2. Tandem Hydroformylation/Fischer Indole
Synthesis of Methallylic Alcohols 9 to Tryptopholes 10
Scheme 1. Tandem Hydroformylation/Fischer Indole
Synthesis of Styrenes 4 with Aryl Hydrazines 5 to Indoles 8
intramolecular hemiacetalization, followed by acid-catalyzed
elimination and hydrogenation, the use of protecting groups
appeared to be necessary. While the use of ether groups,
like in ethyl ether 9b or in benzyl ether 9c, did not increase
the yields (25% for 10b and 23% for 10c), the use of
electron-withdrawing groups, like the benzoyl group 9d,
improved the performance to 57% isolated yield 10d
(Scheme 2).
Similar results were obtained with use of methallylic
amines. Here the use of nonprotected amines is not possible,
since it is known that primary and secondary amines undergo
condensation with oxo aldehydes to imines and enamines,
which are then hydrogenated under hydroformylation condi-
tions in an overall “hydroaminomethylation”.8 Of all tested
N-protecting groups (benzyl, acetyl, benzoyl, phthalimide),
only phthalimide 11, as the strongest electron-withdrawing
group, led to a successful tandem hydroformylation/Fischer
indole reaction to form 12a in 60% yield (Table 1). To
simplify purification, the crude products were tosylated.3,4
We started our own investigations with studies to perform
the individual steps under optimized hydroformylation condi-
tions and then combining them to a tandem sequence. First
we tested the indolization of preformed arylhydrazones with
different Brønstedt acids under hydroformylation conditions.
The indolization with 1 equiv of p-toluenesulfonic acid
(PTSA) proceeded smoothly in good yields and without loss
of hydrazone due to hydrogenation. In the next step, we
combined formation of the arylhydrazone and the Fischer
reaction. Therefore, the oxo aldehyde of R-methylstyrene (4a)
was converted to the indole in the presence of phenyl-
hydrazine and PTSA under hydroformylation conditions.
Finally, we merged all three steps together into a single
procedure starting from R-methylstyrene (4a) and 1,1-
diphenylethene (4b). These nonfunctionalized 1,1-disubsti-
tuted olefins, upon hydroformylation, preferably form the
linear aldehydes, whereas hydroformylation of monosubsti-
tuted olefins leads to a mixture of linear and branched
regioisomers and therefore requires additional regiocontrol-
ling P ligands (see below). Under the optimized conditions
(0.5 mol % [RhCl(cod)]2 or Rh(CO)2(acac), 50 bar CO +
20 bar H2, 100-120 °C), R-methylstyrene (4a) and 1,1-
diphenylethene (4b) in the presence of equimolar amounts
of phenylhydrazine (5a) and PTSA gave the substituted
indoles 8a and 8b in 59-67% yield (Scheme 1).9
Table 1. Tandem Hydroformylation/Fischer Indole Synthesis
of Methallylic Phthalimide (11) to Tryptamines 12
hydrazine 5
5a (R ) H)
5b (R ) 4-Cl)
5c (R ) 4-tert-butyl)
yield
60% (12a )
53% (12b)
48% (12c)
Encouraged by these first examples of successful tandem
hydroformylation/Fischer indole sequence starting from
Substituents at the aryl nucleus of the hydrazine are
tolerated, thus 4-chloro-phenylhydrazine 5b and the 4-tert-
butyl analogue 5c lead to indoles 12b (53%) resp. 12c (48%).
(9) For further experimental details, see Supporting Information.
3214
Org. Lett., Vol. 5, No. 18, 2003

(Table 1). Substituents of this type are found in various
pharmaceutically active compounds. No side products were
found in these conversions, which led to protected trypto-
phole and tryptamine derivatives in satisfying yields.
For further optimizations, we thought to protect the
hydrazine unit also, since it was observed that in various
cases the initial reaction mixtures turned solid after a short
period of time, due to protonation of aryl hydrazine. A
heterogeneous system, however, could hamper the perfor-
mance of the whole tandem sequence. An additional protec-
tion of the hydrazine could circumvent this problem if an
acid-sensitive group is chosen that liberates the hydrazine
to allow condensation with the in situ-formed oxo aldehyde.
The benzhydrylidene group appeared to be compatible with
these needs. Buchwald et al. had demonstrated that benz-
hydrylidene aryl hydrazines can be synthesized from aryl
halides by using the palladium-catalyzed amination proto-
col. The products were directly converted via Fischer
indolization.10 Thus, for a tandem hydroformylation/Fischer
indole procedure, various new aryl hydrazines can be
synthesized directly in their protected form starting from aryl
iodides or aryl bromides and benzophenone hydrazone using
Buchwald-Hartwig methodology. On the other hand com-
mercially available aryl hydrazines are easily protected by
condensation with benzophenone.
For initial investigations, the conversion of R-methyl-
styrene (4a) with 4-chloro-phenylhydrazine (5b) resp. its
benzhydrylidene derivative 5d under hydroformylation con-
ditions was compared. As shown in Scheme 2, use of the
protected hydrazine increases the yield of indole 13 from
18 to 68%. The conversion appeared to proceed much
smoother with fewer side reactions, and workup was
facilitated without requiring NH protection via tosylation.
Consequently, the same methodology was applied to meth-
allylic phthalimide (11) and the protected phenylhydrazines
5d-h to obtain tryptamines 12d-h with yields up to 78%
(for 12d). Again, considerably higher yields are achieved if
compared with the results in Table 2. Various halogen
substituents are tolerated in different positions, thus offering
access to further conversions using palladium-catalyzed
Scheme 3. Use of Benzhydrylidene-Protected Aryl Hydrazine
5d in Tandem Hydroformylation/Fischer Indole Synthesis.
cross-coupling reactions with wide variability. Pharmaceuti-
cally active tryptamines and tryptopholes usually contain
linear side chains in the 3-position of the indole core. In
contrast to other established tryptamine syntheses, the tandem
hydroformylation/Fischer indole procedure allows flexible
access to systems with different chain lengths and branched
or substituted side chains depending on the alkene avail-
ability.
On the other hand, nonbranched tryptopholes and trypta-
mines should be obtainable, if starting from allylic alcohols
and amines via n-selective hydroformylation. Typically,
allylic alcohols and amines, however, tend to lower n/iso
ratios if compared to normal terminal alkenes, due to
intramolecular coordination of the hydroformylation catalyst
to the allylic functionality. Therefore, sterically demanding
bidentate ligands such as BIPHEPHOS or XANTHPHOS
are usually added to the reaction mixture leading to higher
n/iso ratios and requiring considerably milder hydroformyl-
ation conditions. For our initial investigations, various pro-
tected allylic alcohols and the phthalimide-protected allylic
amine were used. The results are compiled in Table 3.
Indeed, with BIPHEPHOS these allylic systems exclu-
sively gave the indoles derived from the n-products, although
only in much lower yields as compared to the results with
the analogous methallylic. It is assumed that elimination
Table 2. Use of Benzhydrylidene-Protected Aryl Hydrazines 5
in the Tandem Hydroformylation/Fischer Indole Synthesis of
Methallylic Phthalimide (11) to Tryptamines 12
Table 3. Allylic Alcohols and Allylic Phthalimide 14 in the
Tandem Hydroformylation/Fischer Indole Synthesis Leading to
Tryptopholes and Tryptamines 15
hydrazine 5
yield
olefin
ligand
yield
5d (R1 ) 4-Cl)
5e (R1 ) H)
5f (R1 ) 2-CH3)
5g (R1 ) 4-Br)
5h (R1 ) 2-Cl)
78% (12d ; R1 ) 5-Cl; R2 ) H)
76% (12e; R1 ) H; R2 ) H)
48% (12f; R1 ) 7-CH3,R2 ) H)
50% (12g; R1 ) 5-Br; R2 ) H)
42% (12h ; R1 ) 7-Cl; R2 ) H)
14a (R ) OH)
BIPHEPOS
BIPHEPOS
BIPHEPOS
BIPHEPOS
XANTHPHOS
17% (15a )
20% (15b)
13% (15c)
26% (15d )
46% (15d )
14b (R ) OBn)
14c (R ) OBz)
14d (R ) NPhth)
14d (R ) NPhth)
Org. Lett., Vol. 5, No. 18, 2003
3215

reactions of the products to form sensitive vinyl indoles are
responsible. Indeed, when using allylic alcohol as the starting
olefin, 3-ethylindole was isolated as a product of tryptophole
(15a) formed via dehydration and hydrogenation of the
resulting 3-vinylindole. Protection of the alcohol functionality
could only insufficiently suppress these consecutive reactions
and did not increase the yields (up to 23% for 15b and 15c).
If allylic phthalimide tryptamine was used, 15d was obtained
with only 26% yield and an n/iso ratio of 2:1. The poor n/iso
ratio may be caused by the fact that phosphite ligands are
less stable in the presence of aldehydes and undergo acid-
catalyzed decomposition.11 Therefore, either an increase in
the ligand-to-catalyst ratio or a more stable ligand may solve
this problem. Use of the biphosphane ligand XANTHPHOS
instead of the biphosphite BIPHEPHOS indeed led to
complete n-regioselectivity with increased yields of tryptamine
15d (46%) (Table 3).12 At present, until further optimizations
are successful, the stepwise procedure is advantageous for
higher yields and regioselectivities. Thus, in various ex-
amples, the stepwise hydroformylation of allylic amines in
the presence of aryl hydrazines led to the corresponding
hydrazones with complete n-selectivity and quantitative
yields. Their indolization allows a fast and high-yielding
approach to pharmaceutically potent tryptamine derivatives
and numerous analogues.
Acknowledgment. The authors thank the Fonds der
Chemischen Industrie for financial support and the Degussa
AG, Du¨sseldorf, and the Bayer AG, Leverkusen, for dona-
tions of chemicals.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic and analytical characterization
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0350184
(10) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 6621. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 121, 10251.
(12) Beller, M. independently observed these effects of XANTHPHOS
and similar ligands in hydazone formation from alkenes and hydrazines
under hydroformylation conditions. Beller, M. Personal communication.
(11) van Leeuwen, P. W. N. M. Appl. Catal. A 2001, 212, 61.
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