A Unified Strategy for the Synthesis of β-Carbolines, γ-Carbolines, and Other Fused Azaheteroaromatics under Mild, Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.8b02441

An efficient, unified approach for the synthesis of β-carbolines, γ-carbolines, and other fused azaheteroaromatics has been realized under metal-free conditions, from propargylic amines and (hetero)aromatic aldehydes. This unified strategy provides β- and

Full text of DOI:10.1021/acs.orglett.8b02441

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Unified Strategy for the Synthesis of β‑Carbolines, γ‑Carbolines,
and Other Fused Azaheteroaromatics under Mild, Metal-Free
Conditions
Dilipkumar Uredi, Damoder Reddy Motati, and E. Blake Watkins*
Department of Pharmaceutical Sciences, College of Pharmacy, Union University, Jackson, Tennessee 38305, United States
S
* Supporting Information
ABSTRACT: An efficient, unified approach for the synthesis
of β-carbolines, γ-carbolines, and other fused azaheteroar-
omatics has been realized under metal-free conditions, from
propargylic amines and (hetero)aromatic aldehydes. This
unified strategy provides β- and γ-carbolines as well as a range
of fused azaheteroaromatics with a broad substrate scope and
excellent functional group compatibility. The formal synthesis
of oxopropalines D and G has been achieved on gram scale
(3a), in a one-pot reaction from commercially available materials (previous shortest reported route to 3a was 5 steps). NMR
studies of the conversion of imine intermediate 3aa to β-carboline 3a were conducted and revealed that the reaction proceeded
through an allene intermediate.
Hence, the development of efficient methodologies for the
construction of the carboline skeleton has attracted substantial
attention in synthetic chemistry.2 The augmentation of
processes that tease new reactivity out of easily accessible
precursors continues to spur the chemistry community toward
pioneering methodologies that provide rapid access to
nitrogen-containing heterocycles.
arbolines and fused-pyridine heterocycles are ubiquitous
Cstructural motifs prevalent in natural products, pharma-
ceuticals, agrochemicals, materials, and ligand scaffolds among
other examples, thus highlighting the significance of such
structures.1 Among the isomeric α-, β-, γ-, and δ-carbolines, the
most abundant framework in nature is β-carboline.2 β-
Carbolines possess a wide array of pharmacological properties,
including anti-inflammatory, anti-Alzheimer, antimalarial,
antibacterial, antitumor, anti-HIV activities, and others (Figure
1).3 The structural similarity of C1-substituted β-carboline
alkaloids with 2-substituted pyridines revealed their potential
as directing groups for C−H functionalization reactions.4
While the Bischler−Napieralski,5 Pictet−Spengler,6 and
Graebe−Ullmann7 reactions are the conventional approaches
for the synthesis of β- or γ-carboline derivatives, in recent years
several new protocols for the synthesis of β- or γ- carboline
frameworks have been developed using a range of starting
materials and metal catalysts. Examples include the cyclization/
iminoannulation of acetylene derivatives with prefunctional-
ized indoles;8 metal-catalyzed cyclization/functionalization of
various precursors prepared in multiple steps;9 synthesis of 3-
amino-β-carbolines via gold-catalyzed formal [4 + 2] cyclo-
addition of azides and ynamides;10 synthesis of either β- or γ-
carbolines using ruthenium or rhodium catalyzed [2 + 2 + 2]
cycloaddition reactions;11 arene-ynamide cyclization via
copper catalysis;12 palladium-catalyzed, imidoylative cycliza-
tion of tryptophan-derived isocyanides;13 and others.14 In this
regard, while much effort has been devoted to the development
of metal-catalyzed cyclizations, alternative and/or complemen-
tary methods using more practical, environmentally benign and
metal-free conditions are limited.15 Reactions employing mild
and metal-free protocols are ideal because they circumvent the
use of toxic metals, excess oxidant/additive, and the
preconstruction of starting materials in multiple steps. A
metal-free, domino reaction for the synthesis of complex
Figure 1. Representative β-carboline core natural products and
bioactive molecules.
Received: July 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heterocyclic scaffolds is a highly attractive strategy as an atom-
economic and environmentally benign process.
to provide NH-carbolines (3j and 3k), albeit in slightly
diminished yield and a comparatively longer reaction time (24
h). The feasibility of the metal-free conditions was further
explored with various protecting groups on the indole aldehyde
(1c−f) with 2b, affording good to excellent yields of the N-
protected carbolines (3l−o). Moreover, the substituted indole
2-aldehydes (1g−j) were compatible under these conditions
and gave the corresponding β-carbolines (3p−s) in good
yields. As expected, the reaction of 1,3-dimethyl-1H-indole-2-
carbaldehyde (1k) with 2a gave the imine intermediate 3ka in
87% yield, with no subsequent cyclization to the β-carboline
(see SI for details, Scheme S1).
To the best of our knowledge, examples of β- or γ-carboline
synthesis involving metal-free, mild conditions from easily
accessible starting materials in a one-pot operation have not
been reported. In continuation of our work on the synthesis of
heterocyclic derivatives,16 in this letter, we disclose an efficient
and metal-free method in which the combination of a
propargylic amine and (hetero)aromatic aldehyde can be
used to efficiently produce a series of β- and γ-carbolines as
well as a range of fused-azaheteroaromatics which have
important pharmacological properties.
For the optimization of the reaction parameters, we chose 1-
methyl-1H-indole-2-carbaldehyde (1a) as a model substrate in
combination with propargylamine (2a). The investigation of
metal-catalyzed and metal-free conditions with various bases
and solvent systems revealed that the reaction proceeded well
with NaHCO3 at 80 C (see Supporting Information (SI) for
details, Table S1).
Using the optimal reaction conditions, we examined the
scope and generality of this base-mediated, metal-free reaction
(Scheme 1). First, the effect of changing substitution on the
Variously substituted indole 3-aldehydes were also efficient
under the current reaction conditions, providing good yields of
the corresponding γ-carbolines. N-Methylindole 3-aldehyde
(1l) was subjected to the optimal conditions with 2a and 2b
independently to give the γ-carbolines (3t in 92% and 3u in
87%), respectively, in good yields. Impressively, 1H-indole-3-
carbaldehyde (1m) was well-tolerated to give γ-carboline 3v in
69% yield. Bromo (1n) and cyano (1o) substituted NH-indole
3-aldehydes were found to be competent substrates (3w and
3x). Also, fused indole 3-aldehyde (1p) could be subjected to
the optimal reaction conditions resulting in a good isolated
yield of 3y (77%). This demonstrated that our method could
be successfully applied to the synthesis of both β- and γ-
carbolines.
ο
Scheme 1. Synthesis of β- and γ-Carbolines from Indole
a
Aldehydes (1) and Substituted Propargylic Amines (2)
Next, we extended the scope of the reaction with diverse
(hetero)aromatic aldehydes (1q−y), using 2a/2b as amine
coupling partners (Scheme 2). Benzofuran-2-carbaldehyde
Scheme 2. Synthesis of Diverse, Fused Pyridines
a
Reaction conditions: 1 (0.6 mmol), 2 (0.9 mmol), and base (1.2
b
(1q) and benzothiophene-2-aldehyde (1r) gave the corre-
sponding fused-pyridine derivatives in good yields (4a in 79%
and 4b in 83%). Pyrrolopyridine aldehyde (1s) also worked
well in this conversion (4c). Moreover, pyrrole, furan, and
thiophene aldehydes (1t−v) were suitable substrates in this
transformation, generating bicyclic compounds in 62−86%
yields (4d−f). Pleasantly, quinoline-8-carbaldehyde (1w)
reacted smoothly with 2a to afford the phenanthroline (4g)
in 63% yield. Remarkably, polycyclic aldehydes (1x and 1y)
were easily converted to the corresponding fused-pyridine
heterocycles (4h−j) in 82−87% yields, showcasing the
promising synthetic generality and utility of the current
reaction conditions.
mmol). 24 h.
propargylic amine was explored. To our delight, 3-phenylprop-
2-yn-1-amine (2b) and 3-(4-methoxyphenyl)prop-2-yn-1-
amine (2c) were well tolerated under the present conditions,
delivering the corresponding carboline moieties in good yields
(3b in 87% and 3c in 72%, respectively). Similarly, amines with
electron-withdrawing groups (2d−g) were successfully utilized,
yielding the appropriate carbolines 3d−g in excellent yields
(81−93%). Additionally, 1-naphthyl (2h) and 2-thienyl (2i)
propargylic amines could be smoothly converted to carbolines
3h and 3i in synthetically useful yields. Furthermore, N-
substitution on the indole aldehyde was investigated (3j−o).
Interestingly, 1H-indole-2-carbaldehyde (1b) revealed that our
reaction conditions were tolerant of N-unsubstituted aldehydes
After successfully establishing a metal-free process for the
synthesis of β-carbolines, γ-carbolines, and fused-nitrogen
heterocycles, we extended this protocol to the synthesis of
B
DOI: 10.1021/acs.orglett.8b02441
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Organic Letters
Letter
other substituted β-carbolines. Accordingly, the reaction of 1a
with 4-phenylbut-3-yn-2-amine (2j) and but-3-yn-2-amine
(2k) progressed well, to give 3,4-disubstituted β-carbolines
5a and 5b in 81% and 91% yields, respectively. Additionally,
when 4-chlorobut-2-yn-1-amine (2l) was subjected to the
present conditions, it provided the dehydrohalogenated
carboline 5c in 63% yield and a handle for further structural
elaboration (Scheme 3).
Scheme 3. Synthesis of Substituted β-Carbolines from 2j/2k
and 2l
Figure 2. Kinetic profile of the conversion of imine 3aa to carboline
3a.
Scheme 5. Plausible Reaction Mechanism for the Synthesis
of 3a
To investigate the scalability of the present conditions, we
performed the reaction of 1a and 2a on gram scale (6.29
mmol) to afford 3a in 79% isolated yield after 24 h. Scale-up
and the necessary extension of the reaction time resulted in the
formation of a minor side product, the carboline-indole alcohol
6 in 5% yield (Scheme 4). It is worth noting that we have
Scheme 4. Gram-Scale/Formal Synthesis of Oxopropalines
D and G and Synthetic Utility of β-Carboline Derivatives
Cyclization appears to proceed through the allene A via base-
mediated isomerization of intermediate 3aa. The allene then
undergoes a 6π-azacyclization to give intermediate B. Isomer-
ization through a [1,7]-H shift would then establish
aromaticity and complete the reaction pathway to β-carboline
3a.
In conclusion, we have demonstrated a practical and unified
protocol for the synthesis of β-carbolines, γ-carbolines, and
diverse fused-azaheteroaromatics starting from propargylic
amines and (hetero)aromatic aldehydes via base-mediated,
one-pot, and metal-free conditions for the first time. The
reaction proceeded smoothly under mild conditions through
an imine, 6π-azacyclization strategy. Moreover, the present
protocol enables the rapid conversion of abundant feedstock
materials into a range of fused azaheterocycles under metal-free
conditions. Diverse heteroaromatic, polycyclic aldehydes were
compatible with the present approach and provided β-
carbolines, γ-carbolines, and diverse azaheterocycles with
broad substrate scope and in excellent yields. Additionally,
we also extended the applicability of our conditions to the
formal synthesis of oxopropalines D and G, by preparing
compound 3a on gram scale in a one-pot procedure. The
formation of an allene intermediate (A) was demonstrated
using NMR analysis in the conversion of amine 3aa to product
3a.
achieved the synthesis of 3a in one step from easily available
materials under mild and metal-free conditions.17 Additionally,
the reaction of 1z (1 g) with 2a under standard conditions
delivered the MOM-protected carboline 3z in 93% yield. β-
Carbolines 3a and 3z could be converted to oxopropalines D
and G.18 Additionally, the reaction of 3a with isovaleraldehyde
at room temperature provided the oxopropaline analogue 7 in
87% yield.19
To help establish the mechanistic pathway of the reaction
and to identify the intermediates of the reaction, we monitored
1
the conversion of imine 3aa to carboline 3a using H NMR
analysis of the reaction mixture in DMF-d7 at 2-h intervals (see
SI for details, Figure S1). Based on the NMR analysis, a kinetic
profile is drawn showing the change in relative concentrations
of the reaction species in Figure 2.
ASSOCIATED CONTENT
* Supporting Information
■
Based on the literature reports20 and NMR analysis, we
propose a plausible reaction mechanism in Scheme 5. Initially,
the reaction of 1a with 2a at rt produces the imine
intermediate 3aa, which was isolated and fully characterized.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02441.
C
DOI: 10.1021/acs.orglett.8b02441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
General experimental procedures and spectroscopic data
Letter
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of all the compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bwatkins@uu.edu.
ORCID
(11) Nissen, F.; Richard, V.; Alayrac, C.; Witulski, B. Chem.
Commun. 2011, 47, 6656−6658.
Dilipkumar Uredi: 0000-0002-1272-6613
Damoder Reddy Motati: 0000-0002-4000-1548
E. Blake Watkins: 0000-0002-7505-0083
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was funded by Union University. The authors
are grateful for the HRMS data provided by D. R. Phillips and
C.-W. Chou [Proteomics and Mass Spectrometry (PAMS)
Facility, NIH Grant 1S10RR1028859] at the University of
Georgia, Department of Chemistry, Athens, Georgia.
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