Ruthenium Catalyzed Tandem Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acs.orglett.0c01485

We report a pyridyl-phosphine ruthenium(II) catalyzed tandem alcohol amination/Pictet-Spengler reaction sequence to synthesize tetrahydro-β-carbolines from an alcohol and tryptamine. Our conditions use a Lewis acid cocatalyst, In(OTf)3, that is compatible with typically base catalyzed amination and an acid catalyzed Pictet-Spengler cyclization. This method proceeds well with benzylic alcohols, heterocyclic carbinols, and aliphatic alcohols. We also show how combining this reaction with a subsequent cycloamination enables a direct synthesis of tetracyclic alkaloids like harmicine.

Full text of DOI:10.1021/acs.orglett.0c01485

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Letter
Ruthenium Catalyzed Tandem Pictet−Spengler Reaction
Anju Nalikezhathu, Valeriy Cherepakhin, and Travis J. Williams*
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ABSTRACT: We report a pyridyl-phosphine ruthenium(II)
catalyzed tandem alcohol amination/Pictet−Spengler reaction
sequence to synthesize tetrahydro-β-carbolines from an alcohol
and tryptamine. Our conditions use a Lewis acid cocatalyst,
In(OTf)3, that is compatible with typically base catalyzed amination
and an acid catalyzed Pictet−Spengler cyclization. This method
proceeds well with benzylic alcohols, heterocyclic carbinols, and
aliphatic alcohols. We also show how combining this reaction with a
subsequent cycloamination enables a direct synthesis of tetracyclic
alkaloids like harmicine.
he indole alkaloids are one of the largest and most
Tmedicinally important classes of the alkaloid natural
products.1 Many feature a tetrahydro-β-carboline (THBC)
core; for example, approved drugs in this group include the
nonsteroidal anti-inflammatory drug etodolac,2 tadalafil,3
reserpine,4 and strictosidine,5 which is a synthetic gateway to
ajmalicine,6 serpentine,7 and quinine8 (Figure 1B). Among the
many routes to tetrahydro-β-carboline derivatives,9 the most
widely used is the biomimetic Pictet−Spengler cyclization,10,11
originally discovered by Ame Pictet and Theodor Spengler in
1911.12 This reaction is employed in the synthesis of simple
THBCs, and the requisite aldehydes are usually prepared from
alcohols. Thus, development of a tandem reaction13 for THBC
formation directly from alcohols is a useful way to enable step
savings in the construction of these scaffolds while obviating
the isolation of a delicate intermediate aldehyde. Further, the
realization of conditions for direct reactions of alcohols opens
the way for a biomimetic cascade sequence in which additional
rings are annulated onto the THBC core.
Hydrogen borrowing catalysis14 enables a green, waste-free,
and cost-efficient approach for alcohol amination.15 Several
ruthenium16 and iridium17 complexes highlight the many
examples of this scheme. We have long considered the
development of a tandem hydrogen borrowing amination
followed by a Pictet−Spengler reaction (PSR) step (Figure
1A), because this is conceptually the same route through which
nature assembles the indole alkaloids.1 Such a strategy has an
intrinsic problem: Pictet−Spengler cyclization is enabled by
the electrophilicity of an intermediate imine, which neces-
sitates a Bronsted or Lewis18 acid catalyst,19,11f whereas most
hydrogen borrowing catalysts rely on a strong base to activate
an alcohol for β-hydride elimination.17h−k This adds a
challenge to the tandem PSR problem that is not present in
the recent tandem aldol−cyclization work.20 Resolving this
dilemma, our group introduced a base-free (pyridyl)phosphine
ruthenium(II) catalyst, [RuCl(η6-cymene){(2-pyridyl)-
Received: April 30, 2020
Figure 1. (A) Proposed synthesis of THBCs. (B) Examples of
pharmaceutically relevant THBCs.
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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CH2PtBu2}]OTf (1), that enables hydrogen borrowing
reactions with excellent functional group tolerance, including
phenols and indoles.16l,mHerein we report the application of
our strategy to the tandem alcohol amination/PSR.
The reaction between benzyl alcohol (6) and tryptamine (7)
catalyzed by complex 1 can produce either N-benzyltryptamine
(8) or N-benzylidenetryptamine (9).16l To realize the tandem
sequence, imine 9 must be generated selectively as an
intermediate, so we found that conducting the reaction in
refluxing toluene gives a full conversion of 7 to 9 selectively
(Table S1 and Figure S3). We next identified the conditions to
cyclize 9 by screening Lewis acid catalysts (Table 1).18 Metal
with 5 or 10 equiv of 6 produced 11 exclusively (entries 4−7)
with the added benefit of protecting the product amine.
With high-yielding conditions for the tandem process, we
moved on to study its substrate scope. While reactions
proceeding from the parent tryptamine afforded useful yields in
many cases (Table S2), we found that side reactions of
tryptamine frustrate material balance. Protecting tryptamine as
its N-benzylamine (8) removes such side reactions and enables
a broad substrate scope (Table 3). We found good functional
Table 3. Substrate Scope for the Tandem Sequence
Table 1. Screening Lewis Acids for the Cyclization Step
a
entry
catalyst
conversion (%)
1
2
3
4
5
6
7
CeCl3
ScCl3
FeCl3
InCl3
Y(OTf)3
ZnBr2
In(OTf)3
22
37
41
52
88
92
100
a
1
Derived from H NMR.
chlorides (entries 1−4) showed some activity, with imine
hydrolysis as a competing reaction. Y(OTf)3 and ZnBr2
showed better activity (entries 5 and 6), and full conversion
was achieved with In(OTf)3 (entry 7).
After optimizing the two independent steps of our proposed
synthetic sequence, we next turned to combining these steps in
a tandem reaction (Table 2). Coupling 7 and 6 (1.5 equiv)
Table 2. Optimization of the Tandem Sequence
a
a
b
c
yield (%)
Isolated yield. With CF3COOH as the acid catalyst. A mixture of
N-benzyltryptamine (0.2 mmol), alcohol (1 mmol), styrene (1
mmol), 1 (1 mol %) and In(OTf)3 (10 mol %) was stirred at 110 °C
entry
BnOH (equiv)
solvent
temp (°C)
10
11
b
b
1
2
3
1.5
2.5
2.5
5
10
5
toluene
toluene
toluene
toluene
toluene
neat
120
120
120
120
120
110
110
43
39
44
33
36
14
72
85
81
60
d
for 96 h in a closed reactor. * shows the carbon in which CH2OH is
attached.
c
4
5
6
7
group tolerance among benzyl alcohols bearing fluoro, bromo,
tert-butyl, and thioether groups at the para position, each
affording the corresponding tetrahydro-β-carboline in a high
yield (entries 2−5). Electron-withdrawing ester (entry 6) and
thiophenyl groups (entries 8 and 11) are also well tolerated.
Oddly, a reaction with methoxybenzyl alcohol was less
successful (entry 7), even in cases where the respective
coupling components were added slowly.
In addition to aryl and heteroaryl carbinols, various aliphatic
alcohols participate in the tandem reaction under slightly
modified conditions (Table 3, entries 9−11). This was
unexpected, whereas we have recently reported that catalyst
loadings well below 1 mol % are needed to enable alcohol
amination with catalyst 1.16m As the low boiling point of the
10
neat
a
b
NMR yield with mesitylene as the internal standard. Yield is based
on tryptamine. 1, 6, and 7 were mixed and refluxed in toluene. After
24 h, 10% In(OTf)3 was added and refluxed for another 24 h.
c
with 1% 1 and 10% In(OTf)3 in toluene yields a mixture of the
expected product 10 and its N-benzylated derivative 11
(entries 1−3). Surprisingly, the combined yield is reduced
when we perform the reaction as a two-step synthesis in a
single reactor (compare entries 2 and 3), although this afforded
higher selectivity for 10. Selectivity for 11 was optimized by
increasing the concentration of benzyl alcohol (6): reactions
B
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aliphatic alcohols prevented us from running their reaction in
an open reactor, we identified suitable closed reactor
conditions incorporating styrene as a hydrogen acceptor.
Introduction of the N-benzylamino group of 8 is not simply
a strategy for improved yield: it is a versatile protecting group
that enables differential substitution of this nitrogen through its
convenient cleavage. While this deprotection has a potential
complication of opening the newly formed piperidine ring, we
find chemoselective cleavage of 11 with hydrogen and Pd/
BaSO4 to give 10 in 80% yield upon screening various
heterogeneous hydrogenation catalysts (Table S6).
While our results demonstrate a unique combination of
hydrogen borrowing amination conditions and the PSR, we
thought it prudent to check whether the few other known
hydrogen borrowing catalysts might also affect the tandem
process. We screened iridium homologues of 1, complexes 2
and 3 (Figure 1),21 and base-free amination catalysts17c,d
[Cp*IrCl2]2 and [Cp*IrI2]2. We found that each of these
complexes returns starting materials, octanol and 8, under the
tandem conditions. Thus, ruthenium complex 1 is the only
catalyst we find for the tandem sequence.
mechanism accounts for the crucial role of the Lewis acid and
explains the distribution of products 10 and 11 observed in
Table 2.
When the reaction proceeds from N-benzyltryptamine 8, it
can take only one pathway (highlighted on the right of Scheme
1). This sequence starts with the formation of iminium ion 8a,
followed by cyclization to give 8b. This formal iminium ion is
more electrophilic than the imine involved in the parent
sequence. We perceive that this is one of the advantages of N-
benzyltryptamine as a substrate for the tandem reaction. This
sequence proceeds without an acid catalyst, albeit at lower
yield (compare 32% to 73% (Table 4)), so indium is important
Table 4. Substituting MgSO4 for In(OTf)3 in the Tandem
Sequence
Since 8, a secondary amine, is a convenient substrate for our
reaction, the intermediate iminium ion resulting from its
condensation with an aldehyde need not be further activated to
enable cyclization. By contrast, imine of the parent tryptamine
must be activated by a proton or Lewis acid. Oddly, reactions
of 8 retain the need for the In(OTf)3 cocatalyst, so we went
about studying the mechanism22 of our reaction to identify the
role of the Lewis acid. We recently reported in detail the role
of the metal catalyst in the amination,16m so we limit this
discussion to the sequence of organic intermediates in the
tandem process.
product and
a
entry
1
X
Y
conditions
yield
H
H
H
1 mol % 1, 1 equiv of MgSO4, neat, 11 (20%)
110 °C, 24 h
b
2
3
4
5
6
H
H
H
1 mol % 1, 10 mol % In(OTf)3,
neat, 110 °C, 24 h
1 mol % 1, no In(OTf)3, neat,
110 °C, 24 h
1 mol % 1, 10 mol % In(OTf)3,
toluene, reflux, 96 h
11 (79%)
11 (32%)
11 (73%)
CH2Ph
CH2Ph
CH2Ph
CH2Ph
b
b
Br 1 mol % 1, 10 mol % In(OTf)3,
toluene, reflux, 96 h
Br 1 mol % 1, 1 equiv of MgSO4,
toluene, reflux, 96 h
12c (78%)
12c (74%)
Pathways for the reactions starting from tryptamine (7) and
N-benzyltryptamine (8) are shown in Scheme 1. In the first,
a
b
NMR yield with mesitylene as the internal standard. Isolated yield.
Scheme 1. Proposed Mechanisms for the Tandem Sequence
but nonessential. When catalytic indium is replaced with 1
equiv of MgSO4 in the reaction of 8 with 4-bromobenzyl
alcohol, we see similar yields, 78% and 74%. In contrast, the
parent tryptamine cyclization yielded product 11 in 20% yield
with MgSO4 compared to 79% with catalytic In(OTf)3. We
speculate that the role of indium or magnesium in reactions of
8 could be a dehydrating agent driving iminium formation,
rather than Lewis acid promoting iminium activation.
Unlike the parent tryptamine reaction, two products are
possible when N-benzyltryptamine reacts with an alcohol,
because either the starting N-benzyl group or the added
alcohol could potentially participate in the cyclization. We
observe one product,23 which has only the added alcohol
participating in cyclization. Isotopic labeling supports this
point (Scheme 2): reaction of 8 and benzyl alcohol-d3, 6-d3,
tryptamine undergoes condensation with benzaldehyde,
generated in situ, to form 9. It can either undergo ring closure
in the presence of indium triflate to afford 10 or be reduced to
8. We compared the relative rates of these potentially
competing reactions by analyzing the product distribution in
the reaction between 9 and 4-fluorobenzyl alcohol under the
catalytic conditions (Scheme S1). We found that 9 converts to
a mixture of 36% of 10 and 38% of 10b and 8b together, where
Ph′ is a fluorophenyl group. This indicates that under the
tandem conditions both 10b and 8b are formed and that the
cyclization step (9 to 10) is faster than the imine reduction (9
to 8) and the second amination step (10 to 10b). This
1
gives 11-d1 along with its H isotopolog (ca. 25%), but no
other labeled species. A 2H NMR spectrum (Figure S15) of the
isolated product shows a singlet at 4.67 ppm corresponding to
2
the aliphatic CD position of 11-d1. No H is observed at the
Scheme 2. Deuterium Labeling Experiment
C
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methylene positions of 11-d1 (3.89 and 3.37 ppm). The
90089-1661, United States; orcid.org/0000-0003-2145-
950X
1
absence of H/2H scrambling combined with the reaction’s
selectivity for 8b indicates that the hydride abstraction from 8
is prohibitively slow. This precludes our mechanism of all C−
H oxidation pathways in which 8 is the hydride donor.
As a first step toward developing a biomimetic cascade
sequence, we exhibit below a tandem reaction of tryptamine
with 1,4-butanediol in the presence of 1 equiv of trifluoroacetic
acid which yields the one-step total synthesis of harmicine
(13), a natural product with antileishmanial24 and antinoci-
ceptive25 activity. The reaction connects three bonds and two
rings in 50% yield overall (Scheme 3), with tryptamine’s
Valeriy Cherepakhin − Donald P. and Katherine B. Loker
Hydrocarbon Institute and Department of Chemistry,
University of Southern California, Los Angeles, California
90089-1661, United States; orcid.org/0000-0003-1966-
9794
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01485
Notes
The authors declare no competing financial interest.
Scheme 3. One-Step Synthesis of Harmicine
ACKNOWLEDGMENTS
■
This work is sponsored by the National Science Foundation
(CHE-1856395). We thank the NSF (DBI-0821671, CHE-
0840366, and CHE-1048807) and NIH (1 S10 RR25432) for
sponsorship of research instrumentation. V.C. acknowledges
Sonosky fellowship support from the USC Wrigley Institute for
Environmental Studies. Fellowship assistance to A.N. from
USC Dornsife College is gratefully acknowledged. We thank
Prof. Valery Fokin and Dr. Dmitry Eremin for their help with
HRMS analysis.
trifluoroacetamide (33%) as the sole side product (Table S5).
Multistep synthesis of (R)-harmicine by enzyme catalysis has
been reported.26 Our method for the fused ring construction
on the THBC core is an important platform for the alkaloid
total synthesis in addition to being a remarkable example of
two hydrogen-borrowing aminations in the presence of an
acid.27 Further studies aiming at more complex heterocycles in
high yield are ongoing.
In conclusion, we report the catalytic, tandem synthesis of
tetrahydro-β-carbolines from N-benzyltryptamine and alcohols.
This method is applicable to benzylic alcohols, heterocycles,
and aliphatic alcohols when styrene is used as a hydrogen
acceptor. Our mechanistic studies suggest two separate
pathways for reactions starting from tryptamine or N-
benzyltryptamine. The latter case involves formation of a free
iminium ion intermediate, so the role of the indium cocatalyst
changes. H/D labeling shows that the secondary amine/imine
equilibrium is prohibitively slow in our system. This governs
the product selectivity for N-benzyltryptamine reactions. The
tandem sequence enables the formation of the ABCD ring of
indole alkaloids like harmicine in a single step.
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Anju Nalikezhathu − Donald P. and Katherine B. Loker
Hydrocarbon Institute and Department of Chemistry,
University of Southern California, Los Angeles, California
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