Access to 2-Alkyl/Aryl-4-(1 H)-Quinolones via Orthogonal "nH3" Insertion into o-Haloaryl Ynones: Total Synthesis of Bioactive Pseudanes, Graveoline, Graveolinine, and Waltherione F

Article abstract of DOI:10.1021/acs.orglett.0c00172

An efficient one-pot synthesis of 4-(1H)-quinolones through an orthogonal engagement of diverse o-haloaryl ynones with ammonia in the presence of Cu(I), involving tandem Michael addition and ArCsp₂-N coupling, is presented. The substrate scope of this convenient protocol, wherein ammonium carbonate acts as both an in situ ammonia source and a base toward diverse 2-substituted 4-(1H)-quinolones, has been mapped and its efficacy validated through concise total synthesis of bioactive natural products pseudanes (IV, VII, VIII, and XII), graveoline, graveolinine, and waltherione F.

Full text of DOI:10.1021/acs.orglett.0c00172

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Letter
Access to 2‑Alkyl/Aryl-4-(1H)‑Quinolones via Orthogonal “NH3”
Insertion into o‑Haloaryl Ynones: Total Synthesis of Bioactive
Pseudanes, Graveoline, Graveolinine, and Waltherione F
Shweta Singh, Sharanya Nerella, Srihari Pabbaraja,* and Goverdhan Mehta*
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ABSTRACT: An efficient one-pot synthesis of 4-(1H)-quinolones through an orthogonal engagement of diverse o-haloaryl ynones
with ammonia in the presence of Cu(I), involving tandem Michael addition and ArCsp2-N coupling, is presented. The substrate
scope of this convenient protocol, wherein ammonium carbonate acts as both an in situ ammonia source and a base toward diverse
2-substituted 4-(1H)-quinolones, has been mapped and its efficacy validated through concise total synthesis of bioactive natural
products pseudanes (IV, VII, VIII, and XII), graveoline, graveolinine, and waltherione F.
mong the vast array of nitrogen heterocycles, 4-
quinolones constitute a notable class that has received
In comparison to the methods reported for the synthesis of
N-substituted 4-quinolones, direct approaches to 4-(1H)-
quinolones are relatively less common, and some of the recent
ones are captured in Scheme 1.9 These approaches generally
rely on expensive metal catalysts like Pd, Rh, and Au, employ
relatively harsher reaction conditions, and at times involve
multistep substrate aquisition, thus underscoring the need for
simpler direct approaches. Taking a cue from our recent
observation of nucleophile-mediated one-pot Michael addi-
tion−intramolecular SNAr reaction in suitably crafted ynones
to furnish bicyclic aromatics,10a−c we contemplated a direct,
simple access of general applicability to 4-(1H)-quinolones
from 2-haloaryl ynones employing ammonia as the orthogonal
sticking nucleophile (Scheme 2). Successful implementation
and generalization of this theme and its application to the total
synthesis of several natural products of contemporaray interest
like pseudanes IV, VII, VIII, and XII, graveoline, waltherione F,
and graveolinine are reported herein.
A
widespread attention from medicinal/synthetic and natural
product chemists in view of their broad range of
bioactivities.1,2 The first prototype 4-quinolone analogue to
enter the market was an antibacterial nalidixic acid 1 more than
50 years ago. Since then, the 4-quinolone scaffold with 6-fluoro
and 3-carboxylic acid embellishments has evolved into several
generations of antibacterial drugs with ciprofloxacin 2 being
the best known example.1a Newer 3-substituted 4-quinolone
derivatives like ivacaftor 3,2a marbofloxacin 4,2g and elvitegravir
52d are drugs used for cystic fibrosis, veternary medicine, and
HIV infection (Figure 1).1,2 Apart from these synthetic
quinolone drugs, a number of 2-alkyl/aryl-substituted
quinolone natural products, harboring diverse bioactivities,
have been reported over the years.3 Among these quinolone
alkaloids, 4-(1H)-quinolones are less abundant, with pseudanes
(III−XII) 6−15,3a,b graveoline 16 (N-Me),3d,e and waltherione
F 173c being very recent additions that have attracted the
attention of the synthetic chemistry community mainly owing
to their promising bioactivity profile (Figure 1).1−3 Given the
well-recognized druglike characteristics of N-substituted 4-
quinolones, numerous methods have been developed to access
this scaffold involving both classical cyclizations (like Conrad−
Limpach,4 Niementowski,5 and Camps6) and more contem-
porary diverse metal-catalyzed reactions,7 among others.8
Received: January 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00172
© XXXX American Chemical Society
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A

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Scheme 3. Initial Experiments
was carried out in the absence of CuI (cat.), only Michael
addition product 20 was isolated in 81% yield and its Z
geometry was secured through a single-crystal X-ray analysis
(see Scheme 3). Expectedly, in a control experiment, Michael
adduct 20 was readily converted to 19 in the presence of CuI
in formamide solvent at 100 °C, presumably via C−C bond
rotation.
To map the scope of this simplified and convenient protocol
for the synthesis of 2-alkyl/aryl-4-(1H)-quinolones, diverse o-
haloaryl ynones 18a−j were reacted under optimized
conditions to furnish 19a−j, respectively, in good yields
(Scheme 4). It may be worth noting that among the 4-(1H)-
quinolones reported here, 19g (also termed NSC656158 or
CHM-1) is a selective antitumor agent in human hepatocel-
lular carcinoma and also induces apoptosis through inhibition
Figure 1. 4-Quinolone pharmaceuticals and natural products.
Scheme 1. Recent Approaches to 4-(1H)-Quinolones
Scheme 4. Alkynone Substrate Scope in Accessing
Quinolones
Scheme 2. 2-Alkyl/Aryl-4-(1H)-Quinolones and Synthesis
of Natural Products
The conceptualization (Scheme 2) toward 4-(1H)-quino-
lones commenced with an exploration of the reaction between
readily available11 o-bromoarylynone 18 [1-(2-bromophenyl)-
3-phenylprop-2-yn-1-one] and ammonia generated in situ from
various sources,12 in the presence of CuI and a base (Cs2CO3,
K2CO3, DBU, etc.) in dipolar aprotic solvents at 100 °C.
Pleasingly, in every case, the desired 4-(1H)-quinolone 19 was
realized in broadly comparable yields (see the optimization
table in the Supporting Information). During these preliminary
experiments, it was observed that inexpensive common
laboratory reagent (NH4)2CO3 plays a dual role as both a
base and a source of ammonia, thereby simplifying the
procedure. Thus, exposure of 2-bromoaryl ynones 18 to
(NH4)2CO3 and CuI (cat.) in formamide or DMF at 100 °C
led optimally to the desired 4-(1H)-quinolone 199d in 80%
yield. It was noted that o-halo ynone siblings of 18, bearing o-
Cl (18′) and o-F (18″) substitutions, also reacted with equal
facility to afford 4-(1H)-quinolone 19 in good yield (Scheme
3). Concurrently, it was also observed that when the reaction
B
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of tubulin polymerization.13,14 It is also important to recall that
the precursor 2-haloaryl ynones used in this study were
accessed in two easy steps from commercially available starting
materials, and details can be found in the Supporting
Information.10
Scheme 6. Synthesis of Pseudane Natural Products
To further amplify the substrate diversity, pyridine-derived
2-bromoynones 18k and 18l were deployed for orthogonal
ammonia insertion to furnish potentially bioactive 1,8-
naphthyridinones 19k and 19l, respectively, in good yields14
(Scheme 4).
A plausible mechanism for the smooth orthogonal ammonia
insertion in 2-haloaryl ynones is depicted in Scheme 5 and
Scheme 5. Mechanism of 4-(1H)-Quinolone Formation
Scheme 7. Synthesis of Graveoline 16 and Graveolinine 21
follows from our earlier work10 and literature precedent.7d
Initial 1,4-addition of ammonia and formation of (Z)-
enaminone intermediate 20 have been demonstrated (vide
supra), which under thermal activation conditions can
equilibrate with its isomer through C−C bond rotation
(Scheme 5). Cu coordination in A and orthogonal oxidative
insertion to the aromatic bromide lead to intermediate B,
which upon reductive elimination delivers 4-(1H)-quinolone
19.
To demostrate the utility and efficacy of the present 4-(1H)-
quinolone strategy, it was applied to the total synthesis of
recently isolated pseudanes, a group of 2-alkylated 4-(1H)-
quinolone-based secondary metabolites of marine origin from
Pseudoalteromonas sp. M2 (Figure 1).3a,b These pseudanes
display a wide range of bioactivities that include antimicrobial,
antiplasmodial, anti-inflammatory, antimelanogenic, quorum-
sensing, and anti-MRSA activities and have attracted the
immediate interest of synthetic chemists.3a,b,15 We have
realized the concise synthesis of pseudanes IV (7), VII (10),
VIII (11), and XII (15) in good yields, employing our
“ammonia insertion tactic” to readily assemble (see the
Supporting Information) 2-haloaryl ynones (18m−p)
(Scheme 6).
synthesized from 25 under thermodynamic alkylation−
aromatization conditions and was shown to be spectroscopi-
cally identical17 with the natural product (Scheme 7).
Finally, as an effectual demonstration of our methodology,
we outline a total synthesis of natural product waltherione F
17, recently isolated from the root extract of Waltheria indica.3c
Waltherione F is notable for exhibiting antitrypanosomal
activity against Trypanosoma cruzi, a parasite that causes
Chagas disease. To date, two total syntheses of natural product
17 have been reported by Larghi et al.18 utilizing Suzuki−
Miyaura coupling and microwave-assisted cyclization as the
key reactions (seven steps, 31% overall yield) and by Cox et
al.19 employing Conrad−Limpach synthesis as a key step (five
steps, 11% overall yield).
Next, our attention turned toward quinolone alkaloid
graveoline 16 and its aromatized sibling graveolinine 21
isolated from Ruta graveolens.3d−f Both 16 and 21 are loaded
with diverse bioactivities that range from antibacterial,
antiplatelet aggregator, spasmolytic, and autophagy activity to
apoptosis trigger and cyotoxic activity.3d−f,16,17 To execute
their synthesis, 2-haloaryl ynone precursor 22, embodying the
benzo[d][1,3]dioxole moiety present in the natural product,
was prepared from 2-bromobenzaldehyde 23 and alkyne 24
(Scheme 7). Ammonia insertion in 22 proceeded uneventfully
under the optimized conditions to furnish 4-(1H)-quinolone
25, and further N-methylation led to alkaloid graveoline 16.
The quinoline-based natural product graveolinine 21 was
Our synthesis of 17, grounded in the convenient ammonia
insertion methodology disclosed here, deployed commercially
available 2,4-dibromoanisole 26. Regioselective formylation20
of 26 delivered 27, and further Pd-mediated Suzuki cross-
coupling21 afforded n-octylbromoaldehyde 28 in good yield
(Scheme 8). Aldehyde 28 was elaborated to o-bromoaryl
ynone 29 through propynyl Grignard addition and oxidation.
Exposure of 29 to in situ ammonia as per our protocol afforded
4-quinolone 30 in decent yield. In addition, an -OMe group
ortho to the carbonyl was introduced in two steps involving
NBS-mediated bromination and CuI-catalyzed SNAr type
displacement with NaOMe to deliver waltherione F 17 (six
steps, 33% overall yield) and the value was found to be
C
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Sharanya Nerella − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
Scheme 8. Total Synthesis of Waltherione F 17
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00172
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was carried out under the Indo-French “Joint
Laboratory for Natural Products and Synthesis towards
Affordable Health (NPSAH)” and supported by the Council
of Scientific and Industrial Research (CSIR) and Department
of Science and Technology (DST), New Delhi, under Project
GAP-584. S.S. thanks UGC for a D. S. Kothari postdoctoral
fellowship (DSKPDF). G.M. thanks Dr. Reddy’s laboratory
(DRL) for the award of a Dr. Kallam Anji Reddy Chair
Professorship. The authors thank the Director of CSIR-IICT
(Manuscript IICT/Pubs./2020/015) for providing all of the
required facilities to carry out the work.
spectroscopically identical with the values reported for the
natural product (see the Supporting Information).3c,18,19
In summary, we have devised a concise and practical, one-
pot methodology of general applicability for the synthesis of 2-
substituted 4-(1H)-quinolones through orthogonal insertion of
in situ-generated ammonia into o-haloaryl ynones via tandem
Michael addition and Cu(I)-mediated ArCsp2-N coupling.
Interestingly, the in situ ammonia precursor also doubles as a
base. The efficacy of this convenient protocol has been
validated through short total syntheses of diverse bioactive
natural products like pseudanes, graveoline, graveolinine, and
waltherione F embodying the 4-(1H)-quinolone framework.
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ASSOCIATED CONTENT
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https://pubs.acs.org/doi/10.1021/acs.orglett.0c00172.
Detailed experimental procedures and spectral data (1H,
13C, IR, and HRMS) for all new compounds (PDF)
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CCDC 1966197 and 1977026 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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AUTHOR INFORMATION
Corresponding Authors
■
Srihari Pabbaraja − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India; orcid.org/0000-
0002-1708-6539; Email: srihari@iict.res.in
Goverdhan Mehta − School of Chemistry, University of
Hyderabad, Hyderabad 500046, India; orcid.org/0000-
0001-6841-4267; Email: gmehta43@gmail.com
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Authors
Shweta Singh − Department of Organic Synthesis and Process
Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India; School of Chemistry, University of
Hyderabad, Hyderabad 500046, India
D
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