Metal-Catalyzed Cyclotrimerization Reactions of Cyanamides: Synthesis of 2-Aryl-α-carbolines

Article abstract of DOI:10.1021/acs.orglett.0c00891

The synthesis of annulated 2-aryl-α-carboline heterocycles is described using transition metal catalysis. A linear strategy is described that uses Rh(I) catalysis to form the α-carboline scaffold by [2+2+2] cyclotrimerization. Alternatively, a tandem catalytic approach using a Pd(II) precatalyst afforded the same target molecules by mediating a Sonogashira reaction and a [2+2+2] cyclotrimerization in the same reaction flask. In each case, nine different 2-aryl-α-carbolines have been prepared in high to modest isolated yields.

Full text of DOI:10.1021/acs.orglett.0c00891

pubs.acs.org/OrgLett
Letter
Metal-Catalyzed Cyclotrimerization Reactions of Cyanamides:
Synthesis of 2‑Aryl-α-carbolines
Kyle M. Medas, Robert W. Lesch, Friendship B. Edioma, Sean P. Wrenn, Vincent Ndahayo,
and Seann P. Mulcahy*
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ABSTRACT: The synthesis of annulated 2-aryl-α-carboline hetero-
cycles is described using transition metal catalysis. A linear strategy is
described that uses Rh(I) catalysis to form the α-carboline scaffold by
[2+2+2] cyclotrimerization. Alternatively, a tandem catalytic approach
using a Pd(II) precatalyst afforded the same target molecules by
mediating a Sonogashira reaction and a [2+2+2] cyclotrimerization in
the same reaction flask. In each case, nine different 2-aryl-α-carbolines
have been prepared in high to modest isolated yields.
he challenge of forming multiple bonds or multiple rings
in a single reaction flask has attracted the attention of
T
organic chemists because of the advantages such reactions
might have in terms of synthetic efficiency and atom economy.
Several approaches to solving this problem, including strategic
retrosynthetic disconnections, biomimetic synthesis, and
cascade or multicomponent reactions, have invariably accel-
erated complex molecule construction.1−4 A common feature
of many of these methods involves the strategic use of
transition metals in the development of new reaction
methodologies.5−9 Our group has been interested in the use
of transition metal catalysis for the construction of elaborate
pyridine-containing heterocycles, which are often important
pharmacophores in drug discovery. In particular, we have
disclosed Rh(I)- and Pd(0)-catalyzed methods for the
synthesis of β-carboline heterocycles.10−12 While β-carbolines
have attracted interest from both the academic organic
chemistry community and the pharmaceutical industry,
investigations involving their α-carboline isomer are much
rarer. In this Letter, we describe two new methods for the
construction of complex α-carbolines using transition metal
catalysis.
Figure 1. Naturally occurring α-carbolines.
a lack of reaction methodology to access them. Most current
methods, while robust and high-yielding, typically involve the
coupling of two smaller fragments to build the α-carboline core
that precludes the simultaneous formation of additional ring
annulations.17−20 Thus, we hypothesized that we could adapt
our initial work on the synthesis of β-carbolines to the α-
isomer to access these structures.
In this work, we have adopted a retrosynthetic strategy that
makes use of an intramolecular [2+2+2] cyclotrimeriza-
tion21−24 reaction in the last step of the synthesis to form
the annulated pyrido[2,3-b]indole ring.25,26 This approach
α-Carbolines are pyrido[2,3-b]indoles whose core scaffold is
present in several natural products and bioactive pharmaceut-
icals. For example, mescengricin (1) is a neuronal cell-
protecting substance,13 while implitapide (2) is a microsomal
triglyceride transfer protein inhibitor used to treat athero-
sclerosis.14 Other α-carboline structures include the grossular-
ines 3−5, which are cytotoxic against human and mouse tumor
cells,15 and cryptotackieine 6, which has antiplasmodial activity
against chloroquine-resistant strains of Plasmodium falciparum
(Figure 1).16 α-Carbolines 3−6 are unique in that they contain
additional fused rings that pose a higher level of complexity
from a synthetic standpoint. In fact, very few structure−activity
studies have been performed on annulated α-carbolines due to
Received: March 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00891
© XXXX American Chemical Society
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required us to prepare an intermediate that contained two
alkyne units and a cyanamide functional group. This follows
closely our own precedent for using dialkynyl nitrile
intermediates for [2+2+2] cyclotrimerizations,10−12 but with
the added challenge of introducing a highly reactive and
hydrolytically unstable cyanamide as a key intermediate. The
use of cyanamide intermediates in [2+2+2] cyclotrimerization
reactions was recently described for an intermolecular reaction
between an alkynyl nitrile and an exogenous alkyne using a
nickel(0) catalyst,27 providing good precedent for our strategy.
While this is the only example of a [2+2+2] methodology
toward α-carbolines, only a few substrates were reported. By
contrast, our approach offers the advantage of rapid synthesis
using microwave irradiation that is amenable to further
diversification under mild conditions.
120 °C, annulated α-carboline 14 could be isolated in good
yield after just 20 min. A screen of seven different solvents was
performed, which identified chloroform as the ideal solvent
(see Table S1 for the full details).
We recognized that cyanamide 13 was a privileged
intermediate that could be further functionalized at the
terminal alkyne position via Sonogashira coupling. The
resulting internal alkynes 16a−i that would result could then
undergo [2+2+2] cyclotrimerization to yield a diverse
collection of 2-aryl-substituted annulated α-carbolines 17a−i.
Table 1 summarizes this strategy using nine different
Table 1. Two-Step Synthesis of 2-Aryl-α-carbolines via
Sequential Palladium and Rhodium Catalysis
The synthesis of the cyanamide intermediate is described in
Scheme 1. We began by protecting the commercially available
Scheme 1. Synthesis of the Diynyl Cyanamide Substrate and
Rh(I)-Catalyzed [2+2+2] Cyclotrimerization
a
Standard conditions: 1.0 equiv of 13, 1.1 equiv of 15a−i, 5 mol %
Pd(PPh3)2Cl2, 10 mol % CuI, 10 mol % PPh3, 2:1 Et3N/DMF (0.04
M), 60 °C, 1 h. Standard conditions: 1.0 equiv of 16a−i, 5 mol %
Rh(COD)2BF4, 5 mol % SEGPHOS, CHCl3 (0.01 M), microwave
2-iodoaniline with a benzyl group via reductive amination.
Installation of the first alkyne unit proceeded smoothly via
Sonogashira coupling28 to afford the internal alkyne 10.
Remarkably, this reaction could be performed on a gram
scale with no interference from the free amino groups.
Introduction of a propargyl group, however, proved more
challenging. Using propargyl alcohol as a reagent under
Mitsunobu conditions29 gave a complex mixture that was
inseparable from impurities via column chromatography.
Luckily, selective deprotonation of the sulfonamide N−H
followed by alkylation with propargyl bromide afforded the
terminal alkyne 11 in good yield. Direct incorporation of the
cyanamide functional group by NCS/Zn(CN)2 was unsuc-
cessful and led to modest yields with an appreciable amount of
recovered starting material.30 We did not want to use the
highly toxic reagent cyanogen bromide,31 so we ultimately
decided to perform a two-step procedure involving urea
formation and dehydration with trifluoromethanesulfonic
anhydride.32 This sequence led to the formation of cyanamide
13 in good overall yield. Cyanamide 13 was stable and could
be stored under an inert atmosphere at 4 °C for months
without decomposition. With cyanamide intermediate 13 in
hand, we used Tanaka’s standard conditions25 to perform the
[2+2+2] cyclotrimerization. Under microwave irradiation at
b
irradiation, 120 °C, 300 W, 20 min.
commercially available iodoarenes. The Sonogashira reaction
proceeds smoothly in all cases to afford the internal alkyne as
an isolable intermediate, as long as the reaction is monitored
closely by TLC (vide infra). Employing the standard
cyclotrimerization conditions resulted in the 2-aryl-substituted
annulated α-carbolines in excellent yields. The yields of this
strategy are generally high across a range of functional groups.
Especially notable is the benzonitrile substituent (entry b),
which did not interfere in the [2+2+2] cyclotrimerization.
During this proof-of-principle study, we noticed the
tendency for the Sonogashira couplings to give mixed results
depending on the length of the reaction. We ultimately
discovered that leaving the reaction mixture to stir for longer
periods of time at high temperatures led to the formation of α-
carbolines 17a−i, which reduced the overall yield of the
Sonogashira product but conveniently gave the ultimate target.
This was not surprising to us, because we also observed this
tandem catalysis in the preparation of β-carbolines. Because
this unexpected side reaction offered us an opportunity to
B
https://dx.doi.org/10.1021/acs.orglett.0c00891
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further shorten the synthesis of these substrates, we wanted to
determine whether such tandem palladium catalysis could be
used in the construction of the same set of α-carbolines in
Table 1. Such a strategy is novel because the product will result
only if a single catalyst can perform more than one unique
chemical reaction.
Table 3. Substrate Scope of the Tandem Pd-Catalyzed
[2+2+2] Cyclotrimerization
We chose 2-iodonaphthalene as a model substrate for
identifying reaction conditions suitable for this transformation,
which are summarized in Table 2. Conventional heating of
Table 2. Optimization of the Reaction of the Tandem Pd-
a
Catalyzed [2+2+2] Cyclotrimerization
entry
catalyst (5 mol %)
solvent
CHCl3
MeCN
DMF
PhCH3
yield of 17a (%)
1
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(dba)2
Pd(PPh3)4
PdCl2
Pd2(dba)3
Pd(OAc)2
PdCl2(MeCN)2
Xphos Pd G2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
19
19
30
11
31
10
24
26
21
29
30
16
8
21
46
36
73
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
dioxane
pyridine
a
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Et3N/DMF (2:1)
Standard conditions: 1.0 equiv of 13, 1.1 equiv of 15a−i, 5 mol %
b
b
Pd(PPh3)2Cl2, 10 mol % CuI, 10 mol % PPh3, 2:1 Et3N/DMF (0.015
M), 60 °C, microwave irradiation for 1 h, 90 °C, 300 W, 1 h.
b
b
b
b
b
b
b
b
e
anisole (17g) derivatives. Modest to good yields were obtained
for the other substrates, which include both electron-donating
and electron-withdrawing substituents. These results indicate
that, while tandem palladium catalysis is an attractive route to
some substrates, the isolated yields are more variable than
those of the analogous Rh(I)-catalyzed pathway.
,c
−d
In summary, we have developed two new routes to 2-aryl-
substituted annulated α-carbolines using transition metal
catalysis. These methods demonstrate that Rh(I) and Pd(II)
precursor complexes can mediate reactions that lead to
elaborate pyridine-containing heterocycles via [2+2+2] cyclo-
trimerization reactions. The functional group tolerance of these
pathways is better for the stepwise sequence under Rh(I)
catalysis than the Pd(II)-catalyzed one-pot procedure.
However, the tandem catalytic pathway provides a short
alternative route to these densely functionalized heterocycles.
Research efforts in this area will continue with an increase in
the functional group and architectural diversity of the target
molecules.
decomposition
a
All reactions were performed for 30 min under microwave irradiation
b
c
at 80 °C and 300 W (0.015 M). With 10 mol % PPh3. At 90 °C.
d
e
For 60 min. Conventional heating to 80 °C.
these reaction mixtures resulted in decomposition of the
starting material, so we focused on reducing the reaction time
using microwave irradiation. Reaction solvents other than a 2:1
Et3N/DMF mixture resulted in poor isolated yields. In
addition, Pd(0) precatalysts resulted in yields that were
lower than those with Pd(II) precursors. Finally, the addition
of 10 mol % PPh3 resulted in an increase in the yield of 16a,
with the optimal condition found after heating for 60 min
(entry 17). Optimization of the reaction time provided a
balance among complete consumption of the starting material,
formation of the cyclized product from the Sonogashira
intermediate, and prevention of decomposition. Interestingly,
when substrate 13 was subjected to the microwave irradiation
at 90 °C for 30 min without the addition of an exogenous aryl
iodide, α-carboline 14 was formed in only 34% yield,
suggesting that terminal alkynes are poor substrates for the
[2+2+2] cyclotrimerization reaction.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00891.
Experimental procedures and accompanying analytical
data (1H and 13C NMR, IR, and MS) for all new
compounds (PDF)
Using the optimized conditions, we subjected cyanamide
precursor 13 to tandem catalysis with each of the iodoarene
substrates 15a−i in a multicomponent reaction. These results
are summarized in Table 3. Low yields were obtained with a
few substituents, in particular the benzonitrile (17b) and
AUTHOR INFORMATION
Corresponding Author
■
Seann P. Mulcahy − Department of Chemistry and
Biochemistry, Providence College, Providence, Rhode Island
C
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02918, United States; orcid.org/0000-0003-4444-5119;
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Song, J.; Gentile, M. R.; Mulcahy, S. P. Parallel Strategies for the
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Catalyzed Cyclotrimerization. Tetrahedron Lett. 2018, 59, 4311.
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Concise Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)-
Catalyzed Cyclization. Org. Lett. 2015, 17, 5512.
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Structure of mescengricin, a novel neuronal cell protecting substance
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Email: smulcahy@providence.edu
Authors
Kyle M. Medas − Department of Chemistry and Biochemistry,
Providence College, Providence, Rhode Island 02918, United
States
Robert W. Lesch − Department of Chemistry and Biochemistry,
Providence College, Providence, Rhode Island 02918, United
States
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Matsuo, M.; Mutoh, S. Implitapide, a microsomal triglyceride transfer
protein inhibitor, reduces progression of atherosclerosis in apolipo-
protein E knockout mice fed a Western diet: involvement of the
inhibition of postprandial triglyceride elevation. Biol. Pharm. Bull.
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Neocryptolepine (Cryptotackieine), A Unique Bioactive Natural
Product: Isolation, Synthesis, and Profile of Its Biological Activity.
Eur. J. Org. Chem. 2014, 2014, 7979.
Friendship B. Edioma − Department of Chemistry and
Biochemistry, Providence College, Providence, Rhode Island
02918, United States
Sean P. Wrenn − Department of Chemistry and Biochemistry,
Providence College, Providence, Rhode Island 02918, United
States
Vincent Ndahayo − Department of Chemistry and Biochemistry,
Providence College, Providence, Rhode Island 02918, United
States
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this Letter was supported by a National
Science Foundation grant (RUI 1565987) to S.P.M. and by the
Jean Dreyfus Lectureship for Undergraduate Institutions
program of The Camille & Henry Dreyfus Foundation.
Research reported in this Letter was also supported in part
by the Rhode Island Institutional Development Award (IDeA)
Network of Biomedical Research Excellence from the National
Institute of General Medical Sciences of the National Institutes
of Health under Grant P20GM103430. The authors also thank
Dr. Tun-Li Shen at Brown University for HR-MS measure-
ments and Dr. Al Bach at the University of Rhode Island for
19F NMR measurements.
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