Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation- Fischer indole synthesis

Article abstract of DOI:10.1039/b809143a

Combination of enantioselective allylation reactions with a tandem hydroformylation-Fischer indole synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and homologues was explored. This modular approach allows the su

Full text of DOI:10.1039/b809143a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Application of iridium catalyzed allylic substitution reactions in the
synthesis of branched tryptamines and homologues via tandem
hydroformylation–Fischer indole synthesis†
Bojan P. Bondzic, Andreas Farwick, Jens Liebich and Peter Eilbracht*
Received 29th May 2008, Accepted 30th June 2008
First published as an Advance Article on the web 13th August 2008
DOI: 10.1039/b809143a
Combination of enantioselective allylation reactions with a tandem hydroformylation–Fischer indole
synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and
homologues was explored. This modular approach allows the substituents at C3 of the indole core, the
type of the amine moiety, and the distance of the amine moiety to the indole core in the final synthetic
step to be defined. The starting materials required for the hydroformylation step were synthesized via
iridium catalyzed enantioselective allylic substitution reactions in high yields and excellent
enantioselectivities. The Rh catalyzed hydroformylation step in the presence of phenyl hydrazine, allows
the in situ formed aldehyde to be trapped as the hydrazone. Subsequent acid catalyzed indolization
furnishes the desired indole structures in moderate to good yields.
Introduction
The indole framework is one of the most frequently found
structural motifs in natural products and pharmaceutically active
compounds.1 Substituted indoles are referred to as “privileged
structures” owing to their binding ability to many different types
of receptors.2 Due to these important properties new methods
for indole synthesis and functionalization continue to attract
attention.3 Among indole derivatives, those with a tryptamine
scaffold (3-aminoethyl indole) are particularly important com-
pounds and many of these are known as synthetic medicines and
physiologically active substances (serotonin, melatonin, psilocin,
etc.).4 Serotonin (5-hydroxy tryptamine, 5-HT, Fig. 1) receptor
Fig. 1 Recently marketed serotonin receptor agonists.
subtypes 5HT1B and 5HT1D have recently attracted considerable
attention as putative targets for novel antimigraine drugs, leading
to the development of selective agonists such as sumatriptan
synthesized starting from this essential amino acid.
(GR43175) and more recently naratriptan, zolmitriptan, rizatrip-
known branched tryptamines are tryptophan derivatives and were
We have recently reported on the synthesis of various
tan, avitriptan, and others (Fig. 1).
branched tryptamine and tryptamide analogues via a tandem
hydroformylation–Fischer indole synthesis sequence (Scheme 1).7
However, neither sumatriptan nor related compounds in use
significantly distinguish between these two subtypes in their
binding activities. In the past few years, it was found that in
addition to appropriate substituents at C5 of the indole core, more
sophisticated amine moieties have to be attached with varying
distances at C3 in order to achieve a discrimination between the
subtypes of the serotonin receptor family.5 From the synthetic
chemist’s point of view these and additional features such as
the occurrence of branching in the a- and b-positions as well
as stereochemical issues are important. Recently, the first exam-
ples of such branched tryptamines possessing pharmacologically
interesting properties have been developed.6 However, most of the
Scheme 1 General scheme of the tandem hydroformylation–Fischer
indole synthesis.
Technische 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
† Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b809143a
This method involves hydroformylation of allylic amines and
amides in the presence of various phenyl hydrazines followed by
Brønsted acid catalyzed indolization. In this convergent method
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highly functionalized building blocks are assembled in the last
synthetic step allowing the introduction of various substituents in
all pharmacologically relevant positions of the indole core.
Herein we report use of this methodology developed in our
laboratory, combined with efficient enantioselective synthesis of
the olefinic starting materials, for the preparation of enantiopure
branched tryptamines and homologues. Thus an approach allow-
ing the introduction of substituents other than those obtainable
from tryptophan is developed, offering a flexible determination of
chain lengths in position C3 of the indole core. Synthetic pathways
(A–C) as envisaged here are shown on Scheme 2.
We envisaged use of Ir catalyzed amination and alkylation
reactions of various allylic carbonates for the synthesis of the
starting materials required for the indole syntheses. Primary
and secondary amines were used for the synthesis of branched
allylic amines, while alkylation agents possessing masked or
protected amine functionalities in appropriate positions were used
for the synthesis of homoallylic amine derivatives and further
homologues (Scheme 2).
Synthesis of starting materials
Reactions towards the synthesis of branched allylic amines
(Scheme 2, Pathway A) were run using conditions as previ-
ously described.11c The active catalyst was prepared by stirring
[Ir(cod)Cl]2 and phosphoramidite ligands 1, 2 or 3 (Fig. 2) with
propylamine in dry THF at 50 ◦C for 30 min. After removing the
excess of propylamine and THF the solid residue was redissolved
in THF to give a stock solution of the active catalyst.
Fig. 2 Phosphoramidite ligands used in this study.
Reaction of cinnamyl carbonate 4a and benzyl amine 5a in
the presence of 1 mol% of the preformed catalyst prepared from
[Ir(cod)Cl]2 and ligand 1 gave product 6a in 58% yield with
90% ee (Table 1, Entry 1). The catalyst preformed with ligand
2 gave product 6a in 76% yield with 94% ee (Table 1, Entry
2) while with ligand 3 product 6a was obtained in comparable
yield and enantioselectivity as with ligand 2 but with opposite
configuration at the chiral center (Table 1, Entry 3). Since ligand
2 gave better yields and ee’s of product 6a than ligand 1, reactions
with all other substrates were run with this ligand. Good yields
and excellent enantioselectivities were obtained in all cases, with
allylic carbonates bearing sp3 as well as sp2 substituents using
both, primary and secondary amines (Table 1). In addition to
amines, imides are good nucleophiles for this reaction as well.
Phthalimide 5d in the reaction with cinnamyl carbonate 4a gave
product 6d in 66% yield with 98% ee (Table 1, Entry 6). The
variety of allylic amines thus synthesized (Table 1) demonstrates
the versatility of this approach towards starting materials for the
tandem hydroformylation–Fischer indole sequence. Aryl and alkyl
groups R1 present in the starting carbonates appear as substituents
in the b position of the final tryptamine molecule. As already
mentioned introducing these substituents by other methods in the
final tryptamine molecule is often a difficult and time consuming
process.
Scheme 2 Envisaged pathway for the synthesis of various tryptamine
homologues.
Results and discussion
As outlined in Scheme 2 a method was required that allows
enantioselective synthesis of all starting materials, such as allylic
amines, homoallylic amines and their derivatives. Although a vast
number of reactions is available for the enantioselective synthesis
of allylic and homoallylic amines, in the last couple of years
Ir catalyzed allylic substitutions have emerged as one of the
most powerful methods. Ir catalyzed allylic amination was first
introduced in 2001 by Takeuchi et al.8 High regioselectivities in
allylic aminations of allylic carbonates and acetates were achieved
with an Ir–P(OPh)3 catalyst. In 2002 Hartwig et al. performed first
enantioselective allylic aminations9 using phosphoramidite type
ligands,10 and achieved excellent regio- and enantioselectivities.
Applications of these ligands were further explored by several
groups in enantioselective amination, etherification and alkylation
reactions.11
Starting materials for the synthesis of branched homotrypto-
phans (Scheme 2, Pathway B), were prepared via Ir catalyzed allylic
alkylation of allylic carbonates with benzophenone glycinate
8. Ir catalyzed allylic substitutions of symmetric nucleophiles
(e.g. sodium dimethylmalonate) and 3-substituted allylic alcohol
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Table 1 Ir catalyzed allylic aminations of various allylic carbonates 4, with amines 5
Entry
R1
Amine, 5
L
6 : 7b
Yieldc, 6 (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph (4a)
5a
5a
5a
5b
5c
5d
5e
5f
5g
5c
5g
5a
5a
5h
1
2
3
2
2
2
2
2
2
2
2
2
2
2
90 : 10
92 : 8
96 : 4
94 : 6
95 : 5
98 : 2
95 : 5
96 : 4
91 : 9
95 : 5
96 : 4
91 : 9
89 : 11
95 : 5
58 (6a)
76 (6a)
75 (6a)
74 (6b)
82 (6c)
66 (6d)
73 (6e)
62 (6f)
91 (6g)
81 (6h)
85 (6i)
62 (6j)
60 (6k)
77 (6l)
90 (R)
94 (R)
97 (S)
97
94
98 (R)
98
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
2-MeOPh (4b)
4-MeOPh (4c)
2-Furyl (4d)
3-Pyridyl (4e)
Et (4f)
91
94
nde
99
98
94
91
nPr (4g)
nPr (4g)
◦
a Method: In THF at 25 C, The ratio of 4 : 5 : “active catalyst” = 100 : 150 : 1. b Ratio determined by 1H-NMR of crude reaction mixture. c Yield of
isolated product. d Determined by HPLC on chiral columns. e Not determined.
derivatives are very well established reactions.12 However, the
use of unsymmetric nucleophiles is a far more challenging task.
Since two new stereogenic centers are formed, not only the
regio- and enantio-selectivity have to be controlled, but also
the diastereoselectivity has to be taken into account in order to
obtain single stereoisomers. In 2003 Takemoto et al.13 published
an elegant approach towards b-substituted a-amino acids using Ir
catalyzed allylic alkylation of benzophenone protected glycinates
as the key step. Binaphthol phosphite type ligands with sulfide
linkers were used. It was noted that the diastereoselectivity is
influenced by the type of the base and the counter cation used,
as well as by the bulk of the ester group of the benzhydrylidene
glycinates. Chiral ligands however, showed minor influence on
the diastereoselectivity but showed a significant influence on the
enantioselectivity of this reaction.
The N-benzhydrylidene group is stable under hydroformylation
conditions and hence protects the sensitive amino group during
the hydroformylation step. However, under the conditions of
subsequent indolization which include reflux in diluted acid this
group is cleaved and releases the primary amine in the final
molecule (Scheme 2, Pathway B). In order to optimize yields
and selectivities of this procedure test substrate 4a was reacted
with benzhydrylidene glycinate 8 in the presence of [Ir(cod)Cl]2
and ligand 6 under various reaction conditions (Table 2). Here Ir
catalyzed alkylation reaction in the presence of 20 mol% DABCO
for the catalyst activation resulted in complete conversion of the
starting carbonate after 16 hours and products 9a and 10a were
isolated in 87% overall yield (Table 2, Entry 1). While the anti
isomer 9a was obtained in slight excess of approximately 3 : 2,
both anti and syn isomers showed excellent ee values of 97 and
95% ee respectively. Notably only 2 mol% of catalyst had to be
used to achieve good conversions in reasonable reaction times.
Next, the effect of countercations of the resulting enolate by
reaction of 4a with various bases was explored with results as
shown in Table 2. Noteworthy, the countercations had a more
significant influence on the diastereoselectivity (9a : 10a) than
on the enantioselectivity of 9a. Preforming the enolate of 8 with
LiHMDS at -78 ◦C gave the expected products with a 4 : 1
ratio of 9a : 10a, however with lower ee’s as compared to the
DABCO method. As expected, ligand 2 gave substantially higher
ee values than ligand 1 (Table 2, Entries 2 and 3). Use of KOH
as a base, which would generate the potassium enolate, affected a
diastereoselectivity in favor of isomer 10a as the major product.
This showed that the diastereoselectivity is controlled by the
geometry of the enolate formed (Table 2, Entry 4). Base free
allylic substitutions are also well known for palladium catalyzed
allylic substitutions using carbonates as substrates.14 The general
mechanism involves coordination of the carbonate to the metal
center and subsequent loss of CO2. Dissociation of the metal
bound alkoxide will then normally provide a sufficiently basic
species, which will act as base during the reaction. Interestingly,
when the catalyst was activated with propylamine11c and the excess
of this base was thoroughly evaporated even after several days of
reaction time no conversion could be observed (Table 2, Entry 5).
Use of DABCO in substoichiometric amounts is crucial for the
success of this procedure. Besides its role in activating the catalyst
DABCO is most probably also taking part in deprotonation of
substrate 8 by making it sufficiently nucleophilic for the alkylation
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Table 2 Ir catalyzed allylic substitution of 8 and 4a under various reaction conditions
Yield, %a
Ratiob
Ee, %c
Entry
Ligand, reaction conditions
Reaction time
9a + 10a
9a : 10a
9a
10a
1
2
3
4
5
2, A
1, B
2, B
2, C
2, D
16 h
3 h
3 h
5 h
7 d
87
80
84
65
—
62 : 38
70 : 30
75 : 25
40 : 60
—
97
65
87
91
—
95
62
ndd
ndd
—
Method A: In THF at 50 ◦C, the ratio of 4a : 8 : [Ir(cod)Cl]2 : 2 : DABCO = 100 : 150 : 2 : 4 : 20; Method B: In THF at -78 ◦C to rt, the ratio of 4a : 8:
[Ir(cod)Cl]2 : 1 or 2 : LiHMDS = 100 : 100 : 2 : 4 : 100; Method C: In THF at rt, the ratio of 4a : 8: [Ir(cod)Cl]2 : 2: KOH = 100 : 100 : 2 : 4 : 100; Method
D: In THF at 25 ◦C, the ratio of 4a : 8 : preformed Ir catalyst was 100 : 100 : 2;a Yield of isolated product after column chromatography. b Determined by
isolation. c Determined by HPLC on chiral columns. d Not determined.
Table 3 Ir-catalyzed allylic substitution of 4b-4f with 8
ratio of anti : syn diastereoisomers with high enantiomeric excesses
(Table 3, Entry 5). The absolute configuration of the isolated
diastereoisomers 9a and 10a was determined by transforming
them into methyl esters and by comparing the optical rotations
of 9a¢ and 10a¢ with literature data.13 Absolute configuration was
determined to be as shown in Scheme 3, and configurations of the
other substrates were ascribed by analogy.
yield, %a
ratiob
ee, %c
Entry
Substrate
9 + 10
9: 10
9
10
1
2
3
4
5
2-MeOPh (4b)
4-MeOPh (4c)
2-Furyl (4d)
3-Pyridyl (4e)
n-C2H5 (4f)
82
97
69
72
65
70 : 30
56 : 44
60 : 40
65 : 35
75 : 25
91
94
95
92
ndd
ndd
91
94
ndd
ndd
Scheme 3 Determination of absolute configuration.
a Yield of isolated product after column chromatography. b Determined by
isolation. c Determined by HPLC on chiral column. d Not determined.
In summary, Ir catalyzed asymmetric allylic alkylation of
benzhydrylidene glycinate 8 and various allyl carbonates using
phosphoramidite type ligand 2 yielded excellent ee values of
both diastereoisomers. These highly valuable starting materials
were obtained in high yields although moderate selectivities were
achieved which is due to the sterically undemanding ester group
of benzhydrylidene glycinate 8 applied.
reaction. Due to the good yields and excellent enantioselectivities
of both diastereoisomers we adopted the “salt free” conditions
with substoichiometric amounts of DABCO as the standard
protocol for conversions of various other allylic substrates 4b-4f
(Table 3).
With all substrates used, again good yields and excellent
enantioselectivities were achieved. The anti isomer was obtained
in excess in all cases, although with poor diastereoselectivities.
Substrates 4c–4e with R1 = p-MeO-Ph, furyl or pyridyl group
respectively, yielded approximately 60 : 40 ratios of 9 : 10 (Table 3,
Entries 2–4) giving both diastereoisomers in enantioselectivities
higher than 90%. Substrate 4b bearing the o-MeO-Ph group,
however, gave a slightly higher ratio of anti : syn of 70 : 30 (Table 3,
Entry 1) as well as substrate 4f with an Et group yielding in a 75 : 25
For the synthesis of olefins required for preparation of
longer chain tryptophan analogues, cyanoacetates were used
as nucleophiles in the Ir catalyzed alkylation reaction. The
nitrile group of cyanoacetates was used as a masked amine
functionality (Scheme 2, Pathway C). Since stereodifferentiation
of the enantiotopic faces of the allyl–metal complex coordi-
nated by chiral ligand is highly independent of the nucleophiles
employed,13 we expected to obtain similar enantioselectivities
with the cyanoacetates as were observed with benzhydrylidene
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Table 4 Ir catalyzed allylic substitution of 11 and 4a under various
was supported by the fact that in this case, under base free
conditions using the preactivated catalyst (by using the propyl
amine activation method) the reaction proceeds with moderate
yields, even after prolonged reaction time of 5 days (Table 4, Entry
5). In contrast to the benzhydrylidene glycinates the methoxide
released is obviously sufficiently basic to deprotonate 11 and make
it more susceptible to the alkylation reaction. Unfortunately we
were not able to separate the diastereoisomers in all cases and
consequently the ee values of syn and anti isomers could not be
determined.
Despite these shortcomings some mentionable observations
were made. Thus, the use of anexternal base dramatically decreases
the reaction time, especially notable in this context were the
reactions employing NaOH and LiHMDS as bases. Here full
conversion was reached within 3 hours. Carbonates were used
as substrates and in no case could hydrolysis of the substrate to
the corresponding alcohol be observed.
reaction conditions
Entry Base, conditions
Time
dra
Yield, %b 12a
1
2
3
4
5
LiHMDS, THF, -78 ◦C to rt
3 h
6 h
3 h
62 : 38 65
43 : 57 62
45 : 55 60
57 : 43 76
Solid KOH, THF, rt
Solid NaOH, THF, rt
DABCO, THF, 50 ◦
C
18 h
Preformed active catalyst
5 days 52 : 48 42
a Diastereomeric ratio (dr) determined by 1H-NMR of the crude reaction
mixture. b Yield of isolated product after column chromatography.
Next allylic alkylations of various carbonates 4 applying
cyanoacetates 11 and 13 as nucleophiles and using DABCO as
a base were investigated. Although showing somewhat slower
reaction rates as compared to other bases this protocol gave the
best yields in the test reactions. Several experiments were set up
first utilizing 13 as the nucleophile (Table 5, Entries 1–5). All
reactions gave a ratio of approximately 1 : 1 for the stereoisomers
in moderate to good yields.
Next attention was turned to cyanoacetate 11 bearing the bulky
t-Bu ester group (Table 5, entries 6–9). Here all products were
obtained in moderate to good yields. Disappointingly, regardless
of substrate used only slightly improved diastereoselectivities were
observed as compared to the methyl ester. Reactions with this
nucleophile showed that the benzhydrylidene protecting group
and its steric demand seems to be vital for obtaining significant
diastereomeric inductions. Due to its sp hybridisation the resulting
shape of the nitrile group is especially small and might be
unsuitable for this kind of diastereoselectivity control. In a
reaction with the ortho-methoxy substituted cinnamyl carbonate
4b (Table 5, Entry 7) a slightly enhanced diastereoselectivity of
70 : 30 was observed. To test whether DABCO as the base
glycinates. Since there are no precedents for Ir catalyzed allylic
alkylations with cyanoacetates as nucleophiles reported in the
literature, optimization of the reaction conditions was required.
We focussed on allylic alkylations using tert-butyl cyanoacetate as
nucleophile hoping that the sterically more demanding tert-butyl
group of 11 would both increase the diastereoselectivity and ease
the separation of the diastereomers (Table 4). Allylic carbonate 4a
was chosen as test substrate. Salt free conditions involving the use
of 20 mol% of DABCO as well as kinetic and thermodynamic
conditions as in the case of benzhydrylidene glycinate 8 were
tested (Table 4). In all cases good yields were obtained but
diastereoselectivities were rather poor even though a bulky ester
group was used. Only approximately 1 : 1 ratios were obtained in
all cases, since the reaction showed small dependence on the bases
and reaction conditions applied. The poor diastereoselectivities
may be due to epimerization under the reaction conditions
since methylene protons of cyanoacetates are more acidic than
those of benzhydrylidene glycinates. Abstraction of the methylene
proton and subsequent reprotonation would presumably produce
a mixture close to 1 : 1 for both diastereoisomers. This assumption
Table 5 Ir-catalyzed allylic alkylation of 11 and 13 with allylic carbonates 4
Entry
R1
R4
Method
Time/h
dr ratioa
Yieldb (%), 12
1
2
3
4
5
6
7
8
9
Ph (4a)
Me
Me
Me
Me
Me
tBu
tBu
tBu
tBu
A
A
A
A
A
A
A
D
A
16
12
3
45
48
48
20
6 days
48
50 : 50
50 : 50
55 : 45
50 : 50
—
65 (12b)
70 (12c)
47 (12d)
50 (12e)
27 (12f)
47 (12g)
70 (12h)
35 (12h)
60 (12i)
4-MeO-Ph (4c)
2-Furyl (4d)
3-Pyridyl (4e)
H (4h)
H (4h)
—
2-MeO-Ph (4b)
2-MeO-Ph (4b)
3-Pyridyl (4e)
70 : 30
68 : 32
52 : 48
Method A: In THF at 50 ◦C, the ratio of 4a : 8: [Ir(cod)Cl]2 : 2: DABCO = 100 : 150 : 2 : 4 : 20; Method D: In THF at 25 ◦C, the ratio of 4a : 8: preformed
Ir catalyst was 100: 100: 2.a Determined by 1H-NMR of crude reaction mixture. b Yield of isolated product after column chromatography.
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Table 6 Protection of primary amines prior to hydroformylation
to complete conversion of the olefin to the aldehyde. Subsequent
indolizations in 4 wt% H2SO4 gave moderate to good yields in all
cases except for entry 10 where the protic acid led to a precipitation
of pyridinium salts of the hydrazone formed. As an alternative,
indolization in the presence of 4 eq. of ZnCl2 in refluxing toluene
for 12 h gave 41% yield of the product. Allylic amides in general
gave slightly higher yields of products than tertiary amines. This
is probably due to the lowered basicity of the side chain nitrogen
in the amides, which eases isolation of the product and prevents
tailing and stacking on SiO2 columns (Table 7, Entries 1, 2, 3, 5,
12, 13).
In summary the combination of iridium catalyzed enantiose-
lective allylic amination and tandem hydroformylation–Fischer
indole synthesis reported here, in contrast to other methods, gives
fast access to b-branched tryptamines which cannot easily be
derived from tryptophan and therefore allows access to a new
class of tryptamine derivatives for biological screenings.
Substrate
Entry
Label
R1
R2
Yield, %a
1
2
3
4
5
6
6a
6a
6b
6j
6k
6l
Ph
Ph
Ph
Et
Bn
Bn
Cy
Bn
Bn
Ph
88 (R) (14a)
85 (S) (14a)
92 (14b)
75 (14c)
nPr
nPr
78 (14d)
76 (14e)
a Yield of isolated product after column chromatography.
For the synthesis of branched homotryptophans (Scheme 2,
Pathway B) via tandem hydroformylation–Fischer indole synthesis
the same conditions were applied as for the synthesis of branched
tryptamines. Since it turned out to be difficult to separate sufficient
amounts of diastereoisomers for indole synthesis, as a proof of
principle a diastereomeric mixture of homoallylic amines 9a and
10a was submitted to the standard stepwise procedure. After
3 days of reaction time, however, the olefin was only partially
hydroformylated as determined by 1H-NMR of the crude reaction
mixture which resulted in only 22% yield of the desired indole 16a.
In order to obtain full conversion of the olefin the reaction time was
prolonged to 5 days leaving other variables the same. This led to full
conversion of the olefin. The ratio of branched : linear aldehydes as
determined by the 1H-NMR of the crude reaction mixture was 95 :
5, and subsequent addition of acid to the reaction mixture led to
indolization of the hydrazones and cleavage of the benzophenone
protecting group yielding in b-branched homotryptophans with
primary amine groups. The product was isolated in 61% yield as a
mixture of diastereoisomers (Scheme 4).
is responsible for this result the catalyst preformed without an
external base was used. Here the same diastereoselectivity was
observed; albeit in this case the reaction rate and yield were lower
(Table 5, Entry 8). Obviously DABCO is not solely controlling
the diastereoselectivity. In addition a substrate control of the
diastereoselectivity might be apparent. Most probably due to
the steric compression caused by the methoxy substituent of
the substrate one of the regioisomeric enolates (E or Z) of 13
is reacting faster with 4b. Since diastereoisomers could not be
separated in any case we decided to use the unseparated mixtures
of diastereoisomers for hydroformylation–Fischer indolization
reactions and try to separate both diastereomers in the later stages
of the synthesis.
Syntheses of indoles
Under hydroformylation conditions primary and secondary allylic
amines may undergo intramolecular “hydroaminomethylation”
reaction.15 Hence, use of protected tertiary amines in the tan-
dem hydroformylation–Fischer indolization sequence is required.
Therefore the secondary amines obtained from the Ir catalyzed
allylic amination reaction with primary amines were protected
with the acetyl group. Here in all cases good yields of acetylation
products were obtained (Table 6).
The acetyl group is stable under hydroformylation conditions
and is often desirable in potentially bioactive molecules as it is
increasing lipophilicity of parent molecules. The starting amines
were submitted to the hydroformylation–Fischer indole synthesis
reaction. An optimized stepwise procedure as previously described
involving tandem hydroformylation–hydrazone formation was
used.7 Here 1 mol% of Rh(acac)(CO)2 and 10 mol% of n-directing
ligand XANTPHOS under 10/10 bar CO–H2 pressure in THF at
80 ◦C for 3 days with subsequent indolization in 4 wt% H2SO4
were applied. The results are summarized in Table 7.
While the allylic aminations proceed with high enan-
tiomeric excesses, the stereocenter may epimerize during tandem
hydroformylation–Fischer indolization via reversible double bond
isomerization either caused by the transition metal catalyst or
the acid. The tryptamines obtained from enantiomerically pure
allylic amines, however, reveal complete retention of enantiopurity
(Table 7, Entries 1, 2, 4 and 6). In all cases hydroformylation led
Scheme 4 Synthesis of branched homotryptophans from allyl glycinates
(9+10) a,f.
A diastereomeric mixture of olefins 9f and 10f was submitted to
the same conditions. The ratio of branched and linear aldehydes
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Table 7 Tandem hydroformylation–Fischer indole synthesis of various allylic amines
Entry Substrate
Product
Yield,a ee%b
Entry Substrate
Product
Yielda
1
14a, R1 = Ph, R2 =
62%, (R) 92%
ee ((+)-15a)
8
6g, R1 = 4-MeO-Ph,
50%, ((-)-15g)
Ac, R3 = Bn
R2 = R3 = piperidine
2
3
14a, R1 = Ph, R2 =
Ac, R3 = Bn
65%, (S) 97%
ee ((-)-15a)
9
6h, R1 = 2-furyl, R2 =
R3 = morpholine
56% (15h)
41% (15i)c
14b, R1 = Ph, R2 =
Ac, R3 = Cy
45%, ((+)-15b) 10
6i, R1 = 3-pyridyl,
R2 = R3 = piperidine
4
6c, R1 = Ph, R2 =
R3 = morpholine
52%, 97% ee
((-)-15c)
11
14c, R1 = Et, R2 = Ac,
R3 = Bn
59% (15j)
n
5
6
7
6d, R1 = Ph, R2 =
R3 = pht
67%, (R)
((+)-15d)
12
13
14d, R1 = Pr, R2 = Ac,
76%, 91% ee
((+)-15k)
R3 = Bn
n
6e, R1 = Ph, R2 =
R3 = pyrrolidine
47%, 98%ee
((-)-15e)
14e, R1 = Pr, R2 = Ac,
66%, ((-)-15l)
R3 = Ph
6f, R1 = 2-MeO-Ph,
R2 = R3 = Et
33%, ((-)-15f)
All indolizations are performed in 4 wt% H2SO4 under reflux for 2 h unless otherwise stated.a Isolated yield after column chromatography. b Determined
by the analysis on chiral HPLC columns, ee not determined unless otherwise stated. c Indolization performed with 4 eq. of ZnCl2 in toluene.
was 94 : 6 as determined by1H-NMR of the crude reaction mixture.
After indolization of the hydrazone, product 16b was isolated
in 46% yield as a mixture of diastereoisomers. An attempted
hydroformylation–Fischer indolization sequence with ZnCl2,16
which should preserve the benzhydrylidene group and yield in
a tertiary tryptophan was unsuccessful. After 24 hours at reflux
temperature with 4 equiv. of ZnCl2 in toluene only the intermediate
hydrazone was quantitatively recovered.
sequence. Moderate yields of the desired primary homotrypto-
phans are obtained after indolization which proceeded in parallel
with deprotection of primary amine functionality in the presence
of Brønsted acid.
Hydroformylation of homoallylic nitriles towards synthesis of
homotryptophan homologues (Scheme 2, Pathway C) proved to
be difficult. Initial test reactions using standard conditions for
hydroformylation of homoallylic amines with allylic cyanoacetate
12a did not yield the desired indole. Therefore all individual steps
of the reaction were tested separately. Performing the reaction in
the absence of phenylhydrazine with the same substrate under the
In summary, Ir catalyzed allylic alkylations of benzhydrylidene
glycinate 8 furnishes a valuable building block for the synthesis of
homotryptophans via the hydroformylation–Fischer indolization
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Table 8 Synthesis of indoles from homoallylnitriles 12
tion is an efficient and highly diversity-oriented strategy for the
synthesis of tryptamines and homologues. Stereocenters close to
the olefinic bond are tolerated and do not epimerize, leading to
enantiomerically pure b-branched tryptamines.
The number of required steps is reduced to a minimum, since
simple functional group transformations (e.g., hydrogenations, ho-
mologization, reduction, oxidation, protection) are not required.
This modular approach is remarkable since substituents at C3,
the type of the amine moiety, and the distance from the amine
moiety to the indole core are predefined by the starting material
and assembled in the final synthetic step. Therefore, this approach
can be used as a valuable tool for the synthesis of highly diverse
substance libraries.
Entry
R1
R2
Yield %,a 17
1
2
3
4
5
Ph
2-MeO-Ph
H
Ph
4-MeO-Ph
tBu
tBu
tBu
Me
Me
60 (17a)
37 (17b)
57 (17c)
39 (17d)
66 (17e)
Acknowledgements
a Yield of isolated product after column chromatography.
The authors wish to thank Professor Dr Bernd Plietker, Stuttgart
for help with chiral HPLC measurements.
same conditions revealed that only 20% of olefin was converted
under these conditions as determined by 1H-NMR of crude
reaction mixture. Increase of the reaction temperature to 100 ◦C
after 5 days yielded in a complete conversion of the olefin 12a.
Hydrazone formation was then carried out under atmospheric
pressure at room temperature within 2 h reaction time. After
indolization under standard conditions the desired indole 17a
was isolated in 60% yield. Control experiments demonstrated that
conversion of the olefin is the decisive factor for a successful
conversion. After the new conditions were established other
substrates were submitted to these conditions. Table 8 summarizes
for indoles thus synthesized, all being obtained in moderate to
good yields as mixtures of diastereoisomers.
It is noteworthy to mention that hydroformylation conditions
as well as subsequent acidic indolization conditions did not have
any influence on the diastereomeric ratio of the products obtained.
For reduction of the nitrile group different conditions using metal
hydrides (i.e. LiAlH4 and NaBH4) were tested but in all cases
complex mixtures of products were observed.
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