One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α-Oxo-acetamidines

Article abstract of DOI:10.1021/acs.orglett.6b00634

A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preform

Full text of DOI:10.1021/acs.orglett.6b00634

Letter
pubs.acs.org/OrgLett
One-Pot Two-Step Multicomponent Process of Indole and Other
Nitrogenous Heterocycles or Amines toward α‑Oxo-acetamidines
Guillermo Martinez-Ariza,† Nicholas McConnell,† and Christopher Hulme*,†,‡
†Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Biological Sciences West Room 351,
1041 East Lowell Street, Tucson, Arizona 85721, United States
‡Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
S
* Supporting Information
ABSTRACT: A cesium carbonate promoted three-component reaction of N−H
containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is
reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an
amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to
form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel
methodology is applied toward the synthesis of various polycyclic heterocycles.
Scheme 1. Exploring the N-1 Reactivity of Indole
itrogenous heterocycles are present in the majority of
small molecule Food and Drug Administration (FDA)
N
approved drugs, with nearly 60% comprised of at least one
nitrogen-containing heterocycle. Indoles in particular are a
ubiquitous chemotype and are incorporated in 17 FDA-
approved drugs.1 Indeed, the indole architecture not only is
frequently utilized in analgesics but also is present in a diverse
set of natural products (e.g., alkaloids), essential amino acids
(e.g., tryptophan), and the neurotransmitter serotonin.1,2 Due
to its biological significance, indole is often considered a
privileged motif in medicinal chemistry and as part of
tryptophan is the most prevalent “hot spot” in mediating
protein−protein interactions.3 As such, this has led to
increasing numbers of new chemical methodologies designed
to enhance the occurrence of the indole scaffold in corporate
compound collections for biological interrogation.4
studied indole C-3 Friedel−Craft alkylation of preformed Schiff
bases between anilines 1 and aryl glyoxaldehydes 2, we
envisioned a one-pot MCR where the N-1 indole position
could feasibly interact with α-imino-ketones to access
compounds of generic structure 6. Herein, we describe
formation of chemotype 7 in expected (E)-stereoselective
fashion and more importantly expand on this concept to other
heterocycles and amines in general, Scheme 2, ultimately using
post-MCR modifications to afford a suite of novel polycyclic
scaffolds. To the best of our knowledge, this is the first report of
Over the past 20 years multicomponent reactions (MCRs),5,6
which generate products from 3 or more starting materials in
one pot, have been heavily exploited to expeditiously garner
new heterocyclic ring systems in processes that are high in
atom-economy, affording molecules with inherent high iterative
efficiency potential for exploitation in the drug discovery
arena.7 In regard to indole-based MCRs, the well established
electrophilic substitution at the C-3 position of indole with
preformed Schiff bases 3, derived from amines 1 and aryl
glyoxaldehydes 2, has been widely exploited to access
compounds of generic structure 5 (Scheme 1)8 whereas N-1
indole reactivity remains largely unexplored beyond simple
alkyl halide alkylations. Given our interest in the development
of novel MCRs and new molecular diversity via subsequent
product manipulation9 and initially inspired by the extensively
2
general base promoted oxidative Csp −N bond formation
between the N-H of azoles (e.g., indoles, benzimidazoles, and
pyrazoles) or amines with α-iminoketones.10
Extensive optimization studies were conducted to evaluate
the effect of solvents, bases, additives, stoichiometry, and
temperatures (Tables S1−S5, Supporting Information (SI)) on
Received: March 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00634
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Letter
Scheme 2. Multicomponent Reaction between
Arylglyoxaldehyes, Anilines, and NH-Containing
Heterocycles
Table 1. Optimization of Reaction Conditions
a
entry
solvent
base
additive
air
yield 7a [%]
1
2
DCE
MeCN
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
TEA
66
63
0
air
3
air
4
air
37
3
5
air
6
air
0
7
DBU
air
57
75
8
Cs2CO3
Cs2CO3
Cs2CO3
Na2SO4, air
Na2SO4, O2
Na2SO4, N2
b
9
73
10
0
a
Optimization reactions were performed on a 0.25 mmol scale at rt for
12 h. Reported % yields are “Area under the Curve” yields of desired
b
product (A%) as judged by LC/MS at UV 254 nm. Under an oxygen
atmosphere (1 atm, balloon), the reaction was carried out at rt for 3 h.
reaction depicted in Scheme 2. Thus, both benzimidazoles and
pyrazoles afforded a final product in reasonable yield under
conditions originally optimized for an indole (7g and 7h,
Scheme 2). Introducing electron-donating (38%, 7e) and
-withdrawing groups (35%, 7f) on the aromatic ring of the
aniline afforded product in modest yields, in similar fashion to
modulation of electron density on the aromatic ring of the
arylglyoxaldehyde (41%, 7b and 35%, 7f). Use of indoline
(7m), where final oxidation is prohibited, or phenethylamine as
aniline replacements and either benzaldehyde or methyl
glyoxylate as an arylglyoxaldehyde replacement, delivered no
identifiable stable products (7l, 7n, 7o, Scheme 2). These
observations suggest that the CN bond is promoted through
the stabilizing effect of adjacent aromaticity via enhanced
conjugation. The structure of 7d was confirmed via X-ray
crystallography (Figure 1).12
the model reaction, and select results are shown in Table 1.
Polar aprotic solvents were found to be optimal, dichloroethane
proving most advantageous with acetonitrile being a reasonable
alternative (entries 1 and 2, Table 1). Cs2CO3 proved to be the
most effective base for the transformation, and notably,
Na2CO3 and K2CO3 (entries 4 and 5, Table 1) were
significantly inferior, possibly exemplifying the well-docu-
mented “cesium-effect”.11 Final oxidation of the intermediate
MCR product 6, Scheme 1, required reaction exposure to air,
and predictably similar yields of 7a were observed under an
atmosphere of oxygen (entries 8 and 9), both in the presence of
Na2SO4 to promote more effective Schiff base formation
through sequestration of water. The latter proved the most
optimal water scavenger (Table S3, SI). As expected, final
product formation of 7a was not observed during reaction
under an inert atmosphere and only starting material was
recovered suggesting a reversible process (entry 10, Table 1).
Moreover, intermediate 6 (Scheme 1) was never isolated
during these studies due to its rapid oxidation to 7.
Gratifyingly, the formation of α-oxo-acetamidines 9 (Scheme
3) was also observed during initial stoichiometry studies on this
reaction when using excess aniline 1a (>1.3 equiv) (Table S4,
Supporting Information), leading to the realization that anilines
and other amines were also effective nucleophiles in
sequestering the α-imino-ketone 3. Six examples with generic
Exploration of the reaction scope showed versatility and
some robustness among indole substituents, Scheme 2. For
example, electron-withdrawing groups were well tolerated (57%
7c, 52% 7d) and moderate decreases in yield were observed
with electron-donating groups (7f). Remarkably, the reaction
proceeded in similar fashion with other heterocyclic rings and
amines, 4, allowing the establishment of the broader generic
Figure 1. X-ray ORTEP diagram at 50% of probability of 7d.12
B
DOI: 10.1021/acs.orglett.6b00634
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Scheme 3. Replacement of Heterocycles for Amines in the
MCR
Scheme 4. Synthesis of Tetracyclic Chemotypes Using a
Bifunctional Approach
Scheme 5. Synthesis of Tricyclic Scaffolds Using an MCR−
Deprotection−Cyclization Approach
In summary, a diverse suite of one-pot multicomponent
transformations have been developed, unveiling the underex-
plored N-1 reactivity of common heterocycles and primary and
secondary amines to access α-oxo-acetamidines with generic
structures 7 and 9. This new reaction was subsequently utilized
to prepare benzimidazole[1,2-c]quinazolines (11a−b), indole-
[1,2-c]quinazolines (11c), and the fused pyrrolo-quinoxaline
(15), delivered in less than three steps.
structure 9 were thus prepared, spanning the anilines (9a−d),
indoline (9e), and aliphatic amines (9f) (Scheme 3). X-ray
crystallography confirmed the structure of 9e (Figure 2),12 and
remarkably a literature search of product 9 showed this product
to have only two-reported syntheses,13 with neither using mild
or metal-free conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00634.
Complete tables of optimization of reaction conditions;
general procedures for the synthesis of 7, 9, 11, 13, and
1
15; and H and 13C NMR spectra (PDF)
X-ray CIF file for compound 7d (CIF)
X-ray CIF file for compound 9e (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hulme@pharmacy.arizona.edu.
Notes
The authors declare no competing financial interest.
Figure 2. X-ray ORTEP diagram at 50% of probability of 9e.12
ACKNOWLEDGMENTS
■
A research grant from the University of Arizona Graduate
Professional Student Council (GPSC) [Award Number
RSRCH-307FY′15] and a doctoral fellowship from the
Mexican National Council for Science and Technology
(CONACyT) [Award Number 215981 (CVU: 464318)] to
G.M.A. is gratefully acknowledged.
At this stage, with a highly generic and fundamentally simple
transformation in place, studies focused on methods to deliver
additional rigidification of these products. Thus, we employed
reagents containing the indole or benzimidazole motif coupled
to the aniline motif in the same molecule (10), a strategy
previously coined the “bifunctional approach” toward rigid-
ification of MCR products.14 This approach led to the synthesis
of benzimidazole[1,2-c]quinazolines and indole[1,2-c]-
quinazolines (11a−c, Scheme 4) in good yields (37−52%)
and one pot. Interestingly, these scaffolds have been reported to
possess antimicrobial activity.15 Additionally, the use of an N-
Boc protected 7-amino-indole 13 enabled a facile three-step
one-pot synthesis of the stable, novel pyrrolo-quinoxaline imine
15 in moderate yield (32%) (Scheme 5).
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