Syntheses of tetrahydro-β-carbolines via a tandem hydroformylation- Pictet-Spengler reaction. Scope and limitations

Article abstract of DOI:10.1039/b809157a

A novel one-pot synthesis of tetrahydro-β-carboline systems via tandem hydroformylation-Pictet-Spengler reaction starting from olefins and aryl ethylamines is described. This tandem procedure allows fast and convenient synthesis of various substituted tetrahydro-β-carbolines. The 2008 Royal Society of Chemistry.

Full text of DOI:10.1039/b809157a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Syntheses of tetrahydro-b-carbolines via a tandem
hydroformylation–Pictet–Spengler reaction. Scope and limitations†
Bojan P. Bondzic and Peter Eilbracht*
Received 30th May 2008, Accepted 7th August 2008
First published as an Advance Article on the web 12th September 2008
DOI: 10.1039/b809157a
A novel one-pot synthesis of tetrahydro-b-carboline systems via tandem
hydroformylation–Pictet–Spengler reaction starting from olefins and aryl ethylamines is described. This
tandem procedure allows fast and convenient synthesis of various substituted tetrahydro-b-carbolines.
olefins as precursors of the electrophilic component. In this
Introduction
reaction sequence, the hydroformylation reaction in the presence
of a rhodium catalyst is used to synthesize the aldehyde in situ
from an olefin, thus reducing the functional group transformations
to a minimum. In the presence of a b-arylethyl amine (and a
Brønsted acid), this aldehyde is directly converted to a Schiff base,
which subsequently cyclizes to form tetrahydro-b-carboline or
tetrahydro-isoquinoline ring systems (Scheme 1). To the best of our
knowledge, up to now there is only one precedent in the literature,
where Taddei et al. have used this sequence in solid phase synthesis
of a carboline.8 Here, we describe the first examples of this
reaction in solution, and discuss scope and limitations for further
applications. This methodology allows introduction of various
substituents at C1 without the need of sensitive and sometimes
costly aldehyde components. Furthermore, high concentrations of
the aldehyde are avoided due to the slower hydroformylation step,
which prevents competitive aldehyde self-condensation reactions
resulting in low yields.9 Thus some of the primary limitations of
the conventional Pictet–Spengler reaction are avoided. For high
yields of the desired product, high chemoselectivities are required
in each step of the tandem process. To achieve this, it is important
that all reagents and reactants as well as all intermediates are
compatible and do not affect each other.
The Pictet–Spengler reaction1 is one of the most widely used
methods for building tetrahydroisoquinoline and tetrahydro-b-
carboline (THBC) ring systems, present in numerous natural and
synthetic organic compounds, many of which display useful and
interesting biological activities (Fig. 1).2 In general, the Pictet–
Spengler (PS) reaction comprises an acid catalyzed cycloconden-
sation of b-arylethyl amine derivatives with aldehydes or ketones
involving an iminium ion intermediate.3 Tetrahydro-b-carbolines,
covering a wide range of structural types, are very attractive
targets for synthesis and have stimulated the development of
new synthetic approaches and methodologies, especially in the
Pictet–Spengler reaction. Although the classical version of this
reaction is well established as a method of choice for construction
of THBC frameworks, original strategy has been modified over
the past decades, allowing N-acyl, N-sulfinyl and N-sulfonyl b-
arylethylamines to be used as nucleophilic components.4 On the
other hand, masked ketones, aldehydes and aldehyde equivalents
such as acetals, ketals, enol ethers, thioortho esters, oxazines
and oxazolidines5 as well as acetylene sulfoxides, enamines and
azalactones6 have been employed as electrophilic components.
Fig. 1 Naturally occurring, bioactive tetrahydro-b-carbolines.
Results and discussion
Scheme 1 Tandem hydroformylation–Pictet–Spengler reaction.
Based on our general interest in tandem hydroformylation
sequences,7 we wanted to explore the possibility of combining
a Rh catalyzed olefin hydroformylation reaction and a Pictet–
Spengler reaction into a tandem reaction sequence, involving
Hydroformylation of the olefins, however, in the presence of
amines may yield a variety of products. Primary and secondary
amines are condensing with the aldehydes followed by hydrogena-
tion of the resulting imines or enamines to amines in an overall
hydroaminomethylation.7 It is also known that the rhodium
acyl species, instead of hydrogenolysis to form the aldehyde, are
also undergoing nucleophilic addition of the amine to form the
amide.10 Therefore a synthesis of tetrahydro-b-carbolines under
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. See
DOI: 10.1039/b809157a
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hydroformylation conditions according to the above described
limitations has to consist of an efficient hydroformylation step
leading exclusively to the aldehyde. This without isolation or side
reactions must condense under the same reaction conditions with
b-arylethyl amine to form the imine, while reduction and self con-
densation of aldehydes must be avoided. The intermediate imine
must cyclize so that no reduction leading to hydroaminomethyla-
tion products occurs. Since hydroformylation of terminal olefins
usually results in a mixture of linear and branched aldehydes, in
our initial investigations, disubstituted terminal olefins like 1,1¢-
diphenylethylene or cyclic olefins were preferably used. The former
undergo regioselective hydroformylation to form linear aldehydes
and make the use of n-directing ligands obsolete, whereas the
latter are symmetric compounds and yield only one aldehyde
isomer. To prevent hydrogenation of the starting olefin, and/or
of the intermediate Schiff base, high carbon monoxide partial
pressures were chosen in order to support the rate determining
carbon monoxide insertion. Since it is well known that esters of
tryptophan undergo Pictet–Spengler reaction with aldehydes in
aprotic conditions,3b the conversion of tryptophan methyl ester
and cyclopentene as electrophile precursor under hydroformyla-
tion conditions was chosen as a first model reaction. Cyclopentene
is a cheap and readily available olefin, and hydroformylation
of cyclopentene is well known and described, with conditions
usually involving temperatures of 40–80 ◦C and pressures of 40–
80 bar of syngas.8,11 Therefore, cyclopentene is mixed with (S)-
tryptophan methyl ester in toluene, which is the most commonly
used solvent in conventional PS reactions and a convenient solvent
for hydroformylation reaction as well. This solution is submitted to
hydroformylation in the presence of 1 mol% of Rh(acac)(CO)2 at
80 ◦C and at 30 : 10 bar of CO–H2 pressure. After workup, however,
no Pictet–Spengler products were observed, and only products 4a
and 5a were isolated (Table 1, entry 1), which arise from mono and
double hydroaminomethylation reactions respectively (vide infra).
Obviously, reduction of the intermediate Schiff base under these
conditions is faster than electrophilic attack of the imine to the
aromatic ring of the indole (Scheme 2, pathways b and d). The same
products were isolated in a reaction with cyclohexene (Table 1,
entry 2), although this olefin required higher temperature for
hydroformylation as compared to cyclopentene. Since in toluene
only hydroaminomethylation products were obtained, the reaction
was performed in more polar solvents such as CH2Cl2, THF or
MeOH. In these solvents, Pictet–Spengler products 2a (cis) and 3a
(trans) were isolated in all cases. When starting from cyclopentene
and (S)-tryptophan methyl ester in CH2Cl2 (Table 1, entry 3), 2a
and 3a were isolated in relative ratios of approximately 1 : 1 and
overall yield of 67%. Under these conditions, reduction of the
intermediate Schiff base was widely suppressed, but formation of
two additional side products 6a and 7a was observed. The same
reactants in THF under similar conditions gave rise exclusively
Table 1 Tandem hydroformylation–Pictet–Spengler reaction in aprotic conditions
Yield (%)a
Entry
CO–H2 bar
T/◦C, time/d
Solvent
n (1)
Yield (%)a2 + 3
Ratiob2 : 3
4
5
6
7
1
2
3
4
5
6
7
8
9
10
11
12
13
30 : 10
30 : 10
30 : 10
30 : 10
30 : 10
30 : 10
50 : 10
70 : 10
50 : 10
50 : 10
50 : 10
50 : 10
50 : 10
80 ◦C, 3 d
120 ◦C, 3 d
80 ◦C, 3 d
80 ◦C, 3 d
80 ◦C, 4 d
80 ◦C, 3 d
80 ◦C, 3 d
80 ◦C, 3 d
120 ◦C, 3 d
80 ◦C, 3 d
80 ◦C, 3 d
120 ◦C, 3 d
120 ◦C, 3 d
Toluene
Toluene
CH2Cl2
THF
1 (1a)
—
—
—
—
65 (4a)
60 (4b)
3 (4a)
—
10 (4a)
48 (4a)
1 (4a)
—
10 (5a)
12 (5a)
7 (5a)
—
—
—
5 (5a)
6 (5a)
11 (5b)
—
—
—
—
—
4 (6a)
—
—
—
3 (6a)
5 (6a)
5 (6b)
—
—
—
—
—
—
—
—
—
5 (7b)
—
—
—
2 (1b)
1 (1a)
67 (a)
45 (a)
52 (a)
15 (a)
79 (a)
72 (a)
63 (b)
71 (c)
—
48 : 52
49 : 51
47 : 53
50 : 50
48 : 52
51 : 49
45 : 55
44 : 56
—
1 (1a)
THF
1 (1a)
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1 (1a)
1 (1a)
1 (1a)
2 (1b)
—
3 (1c)
22 (4c)
43 (4d)
41 (4e)
17 (4f)
4 (1d)
—
—
—
Stilbene (1e)
1,1¢-diphenyl
ethylene (1f)
48 (e)
51 : 49
54 : 46
67 (f)c
—
—
a Yield of isolated product after column chromatography. b Ratio based on isolated products after column chromatography. c Isolated as mixture of
inseparable diastereoisomers.
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Scheme 2 Tandem hydroformylation–Pictet–Spengler reaction and formation of side products.
to Pictet–Spengler products 2a and 3a in 45% yield (Table 1,
entry 4), albeit in a lower yield as compared to CH2Cl2 due to
incomplete conversion of 80% in this case. Prolonged reaction
time of 4 days allowed full conversion of the olefin and increased
the yields of 2a and 3a to some extent but also yielded in reduction
product 4a (Table 1, entry 5). Acetals, which are often used
as protected aldehydes in PS reactions, are also formed in situ
under hydroformylation conditions in the presence of alcohols.12
The use of alcohols as a solvent in the hydroformylation step
is therefore a further option and would provide low stationary
aldehyde concentrations. However, when the reaction was run in
MeOH, only 15% overall yield of Pictet–Spengler adducts were
isolated accompanied by 4a as a main product in 48% yield
(Table 1, entry 6). It is obvious that polarity of solvents plays a
crucial role in the distribution of products. In non-polar solvents,
such as toluene, reduction of the intermediate Schiff base is
favoured. The more polar solvents stabilize cationic intermediates
and promote electrophilic attack, hence, the rate of cyclization is
by far higher than that of reduction. As already noted, 4a is formed
by reduction of iminium ion 8a while formation of 5a and 6a can
be explained as depicted in Scheme 2 (pathways c and d). Here the
monoalkylated tryptophan methyl ester 4a reacts with another
molecule of aldehyde giving Schiff base 9a, which undergoes
hydrogenation giving 5a or cyclization giving 6a. This assumption
was tested by control experiments. Isolated products 2a, 3a and
4a were separately submitted to the hydroformylation conditions
in the presence of cyclopentene and indeed, only 4a yielded 6a in
47% yield accompanied with dihydroaminomethylation product
5a, in 22% yield. On the other hand, 2a and 3a gave no product
of hydroaminomethylation presumably due to a higher steric
hindrance at the ring N atom in these cases. Based on these
observations, formation of 6a from 2a or 3a can be ruled out.
It is noteworthy to mention that 6a was isolated exclusively as
the trans isomer. According to earlier reports, the formation of the
trans isomer in this case is both kinetically and thermodynamically
favored, and was explained by a Felkin–Ahn-like attack of the
E-iminium from the face opposite to the ester group (Fig. 2).3b
Cook et al. have demonstrated that if the side chain nitrogen of
tryptophan esters is monoprotected with sterically demanding Bn
or Cbz groups and as such submitted to conventional PS reaction,
the trans adduct will exclusively be formed. Apparently, this is
also the case with monohydroaminomethylated tryptophan esters
4a or 4b when cyclic olefins such as cyclopentene or cyclohexene
are used as aldehyde precursors. By-product 7a was only observed
when CH2Cl2 was used as a solvent and the CH2 fragment that
inserts between the iminium carbon and the indole stems most
probably from the solvent. Since the best yields of 2a and 3a
were obtained in CH2Cl2, this solvent was chosen for further
optimization of reaction conditions. In order to lower the extent
of reduction, carbon monoxide pressure and the CO–H2 ratio
was increased to 50 : 10 and 70 : 10 bar. While a 50 : 10 ratio of
syngas gave 79% yield of 2a and 3a and lower yields of by-products
(Table 1, entry 7), a ratio of 70 : 10 gave slightly lower yields of
Pictet–Spengler adducts (Table 1, entry 8). Therefore, operating
pressures of 50 bar CO and 10 bar H2 were chosen for other
substrates (Table 1, entries 9–13). In the reaction of cyclohexene
and tryptophan methyl ester at 120 ◦C (Table 1, entry 9), 2b and
3b were obtained in a yield of 63% and in a ratio of approximately
1 : 1. Cycloheptene was hydroformylated at 80 ◦C and the products
2c and 3c were obtained in slightly higher yields than in case of
cyclohexene (Table 1, entry 10). Surprisingly, when cyclooctene
was reacted, no Pictet–Spengler products were observed and
the main product was that of mono hydroaminomethylation
reaction, 4d, obtained in 43% yield (Table 1, entry 11). A trend
from cyclopentene to cyclooctene can be observed: the yields of
Fig. 2 Felkin–Ahn model of stereochemical course of Pictet–Spengler
reactions of Nb protected tryptophanes.
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Table 2 Tandem hydroformylation–Pictet–Spengler reaction of trypta-
Pictet–Spengler products decrease until they finally disappear.
This is most probably connected with steric hindrance of the
aldehydes formed, i.e. higher steric hindrance lowers the rate
of cyclization and hence reduction becomes a more competitive
reaction, exclusively yielding the hydroaminomethylation product.
Cyclohexene is an exception here, most probably due to the
harsher reaction conditions required for hydroformylation of this
compound. This trend was also observed when acyclic olefins trans
stilbene 1e and 1,1¢-diphenylethylene 1f were reacted with (S)-
tryptophan methyl ester under hydroformylation conditions. The
former, bearing one Ph group in the a position and one in the b
position, gives PS products 2e and 3e in 48% yield accompanied by
mono hydroaminomethylated by-product 4e (Table 1, entry 12).
The latter, having two Ph groups in the b position of the aldehyde
due to lower steric compression, gives Pictet–Spengler products
2f and 3f in a higher yield of 67% as a mixture of inseparable
diastereoisomers accompanied by mono hydroaminomethylated
by-product 13 in 17% yield (Table 1, entry 13). In summary, a tan-
dem hydroformylation–Pictet–Spengler reaction performed under
aprotic conditions using tryptophan methyl ester as nucleophilic
component proved to be useful tool for the synthesis of simple
tetrahydro-b-carbolines starting from readily available and cheap
olefins.
mine and selected olefins under protic conditions
Alkene
Entry Substrate
1
T/◦C t/h conversion (%)b Yieldc(%), 10
80
72
>99
>95
65 (10a)
2
3
110
80
46 (10b)
80
80
68
72
>99
>99
68 (10c)
59 (10d)
4
5
110
72
>95
64 (10e)
In order to expand the scope of this sequence, we tested
the feasibility of tryptamine as a nucleophilic component in a
tandem sequence. PS reactions of tryptamine often feature harsher
conditions than their tryptophan counterparts. This is due to the
absence of the inductively electron-withdrawing carbonyl group in
tryptophan and thus lower pKa values of tryptamine based Schiff
bases.3i Tryptamine imines are significantly less reactive towards
electrophilic attack, and hence the presence of acid (Brønsted or
Lewis) is required. Brønsted acids such as sulfuric acid (1 eq),
trifluoroacetic acid (TFA) (1 eq), p-toluenesulfonic acid (pTsOH)
(1 eq), and camphorsulfonic acid (CSA) (1 eq) were tested in
the reaction of tryptamine and cyclopentene under optimized
conditions for tryptophan methyl ester. Lewis acids ZnCl2, and
BF3 were tested as well. All reactions were carried out under
the same conditions for 72 hours and yields of products were
determined by isolation. The best results were obtained with
CSA while p-TSOH, sulfuric and trifluoroacetic acid yielded
mainly mixtures of products. In the presence of Lewis acids,
no product was formed. In the absence of acid, no product
of Pictet–Spengler cyclization was observed either. Conditions
optimized for tryptophan methyl ester with addition of 1 eq of
CSA were applied in the reaction of tryptamine with selected
olefins and the results are summarized in Table 2. Here, 5, 7,
and 8 membered carbocyclic olefins required milder conditions
for hydroformylation as compared to other olefins applied. The
6
7
110
110
72
72
>99
>99
49 (10f)
74 (10g)
8
9
110
110
72
72
>99
>99
82 (10h)
51 (10i)
a Reactions were conducted at room temperature on a 1 mmol scale in
CH2Cl2 (10 ml) with a relative mol ratio of tryptamine–olefin–catalyst of
100 : 100 : 1; 1 mol% of Rh(acac)(CO)2, 1 eq CSA, 50 bar CO, 10 bar H2,
CH2Cl2. b Determined by analysis of H-NMR spectra of crude reaction
1
mixture. c Yield of isolated product after column chromatography.
1
yielded only 20% conversion of the olefin as determined by H-
NMR of the crude reaction mixture. The same substrate at 110 ◦C
after 3 days was almost quantitatively consumed and gave product
in quite a fair yield of 64% (Table 2, entry 5). Cyclohexene
and methallylic amines required harsher conditions, therefore
temperatures of 110 ◦C were applied in order to achieve full
conversions of these olefins (Table 2, entries 2, 7 and 8). Substrates
possessing allylic amino functionality had to be protected and used
in the form of tertiary amines in order to prevent intramolecular
cyclizations and formation of lactams under hydroformylation
conditions.10 Yields varied from a moderate 46% for cyclohexane
to very good 74 and 82% yields respectively for methallylic amines
(Table 2, entries 7 and 8). In the reaction mixture of methallylic
amines, products 10g and 10h were accompanied by product 11,
which was isolated in 8% and 12% yield respectively (Scheme 3).
Methallylic alcohol (Table 2, entry 9) required harsher condi-
tions as well; product 10i was isolated in a moderate 51% yield.
◦
reactions were run at 80 C and full conversions of olefins were
observed after 3 days, with good yields of isolated products
(Table 2, entries 1, 2 and 4). Surprisingly, and in contrast to the
aprotic conditions, here we were able to isolate PS product from
the reaction of tryptamine and cyclooctene.
All other substrates gave moderate to good yields in the presence
of 1 eq of camphorsulfonic acid. 1,1-Disubstituted substrates,
as well as hindered internal olefins such as trans stilbene (Ta-
ble 2, entry 5), required harsher conditions for hydroformylation,
therefore, a temperature of 110 ◦C for 3 days was applied.
◦
Hydroformylation of 1,1¢-diphenylethylene at 80 C after 3 days
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Scheme 3 Byproduct isolated after tandem hydroformylation–Pictet–
Spengler reaction with tertiary metallylic amines.
Conclusions
In summary, we have demonstrated that a reaction sequence of
tandem hydroformylation and Pictet–Spengler cyclization can be
applied in the synthesis of various THBCs involving both aprotic
and protic conditions. Problems arise with formation of reduction
byproducts, however, yields of products are synthetically useful in
most cases. The fact that intermediates do not have to be isolated
or purified clearly saves time and resources. Further investigation
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