Regioselective Ring Expansion of Isatins with in Situ Generated α-Aryldiazomethanes: Direct Access to Viridicatin Alkaloids

Article abstract of DOI:10.1021/acs.orglett.8b01417

A novel efficient one-pot regioselective ring-expansion reaction of isatins with in situ generated α-aryl/heteroaryldiazomethanes for the construction of viridicatin alkaloids has been described under metal-free conditions. The utility of this protocol is further demonstrated in the synthesis of naturally occurring viridicatin, viridicatol, and substituted 3-O-methyl viridicatin and their scale up.

Full text of DOI:10.1021/acs.orglett.8b01417

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Ring Expansion of Isatins with In Situ Generated
α‑Aryldiazomethanes: Direct Access to Viridicatin Alkaloids
Yellaiah Tangella,†,§ Kesari Lakshmi Manasa,†,∥ Namballa Hari Krishna,†,∥ B. Sridhar,‡
Ahmed Kamal,*,§,⊥ and Bathini Nagendra Babu*,†,§,∥
‡
†Fluoro-Agrochemicals and Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007,
India
§Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
∥Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037,
India
S
* Supporting Information
ABSTRACT: A novel efficient one-pot regioselective ring-expansion reaction of isatins with in situ generated α-aryl/
heteroaryldiazomethanes for the construction of viridicatin alkaloids has been described under metal-free conditions. The utility
of this protocol is further demonstrated in the synthesis of naturally occurring viridicatin, viridicatol, and substituted 3-O-methyl
viridicatin and their scale up.
eterocyclic compounds have attracted burgeoning
Hattention over the past decade as the most valuable
leads in the area of synthetic and medicinal chemistry, due to
their potential to create a huge number of chemical libraries
against various life-threatening diseases.1 Among them, the
quinolinone skeleton has been recognized as a valuable scaffold
Figure 1. Representative biologically active 4-arylquinolin-2(1H)-one
and 3-hydroxyquinolin-2(1H)-one scaffolds.
in numerous natural products that exhibit a wide range of
pharmacological properties.2 In particular, 4-arylquinolin-
2(1H)-ones and 3-hydroxyquinolin-2(1H)-ones have been
reactions. They can also be synthesized by (i) Diels−Reese
reaction,16 (ii) Knoevenagel condensation/epoxidation, fol-
lowed by decyanative epoxide-arene cyclization of cyanoaceta-
nilides,17 (iii) decarboxylative rearrangement of cyclopenin and
cyclopenol,18 and (iv) PhI(OCOCF3)2-mediated α-hydroxyla-
tion, followed by acid-promoted intramolecular annulation of
N-phenylacetoacetamide (Scheme 1).19
Although the existing methodologies have their own
advantages, unfortunately, they are associated with certain
limitations such as usage of expensive transition metals,
inaccessible substrates, poor breadth of functional group
tolerance, and multistep syntheses coupled with lower yields.
Therefore, alternative, simple, flexible, and straightforward
strategies for the construction of these scaffolds from
commercially available starting materials are strongly needed.
found to possess profound biological activities, including
selective inhibition of HIV-1 reverse transcriptase, neuro-
protection, antibacterial by opening the maxi-K channel, as well
as D-amino acid oxidase (DAAO) inhibitory activity.3−6 For
example, tipifarnib (I), a 4-arylquinolin-2(1H)-one derivative
which is a potent orally active antineoplastic agent, acts by
inhibiting farnesyltransferase,7 whereas natural products such as
viridicatin8 (II), viridicatol9 (III), and 3-O-methyl viridicatin10
(IV) are promising anti-inflammatory agents11 and are also
capable of inhibiting TNF-α-induced HIV replication (Figure
1).12
Consequently, various synthetically feasible protocols have
evolved for the construction of these important and attractive
scaffolds.13−20 Traditional strategies for the synthesis of 4-
arylquinolin-2(1H)-ones include ring expansion of isatins with
either diazomethanes13/EDA under the catalysis of NHC-
dirhodium(II)14/TMS-diazomethane in the presence of TFA,15
followed by C-4 arylation using conventional coupling
Received: May 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a d
−
Scheme 1. Comparison of Our Work with the Previous
Reports for the Synthesis of 3-Hydroxy-4-arylquinolin-
2(1H)-ones
Table 1. Optimization of Reaction Conditions
b
entry
base
DBU
solvent
temp (°C)
time (h)
yield (%)
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
80
rt
12
24
12
12
12
12
12
12
12
12
12
12
12
8
70
-
DBU
c
3
DBU
80
80
80
80
80
80
80
80
80
80
80
80
80
50
80
80
71
27
trace
36
43
78
67
65
69
62
70
86
63
55
-
4
Et3N
5
DMAP
DIPEA
Na2CO3
K2CO3
tBuONa
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
6
7
8
9
10
11
12
13
14
15
16
17
DMF
DMSO
PhMe
EtOH
dioxane
EtOH
EtOH
EtOH
12
16
24
24
d
18
K2CO3
-
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (1 mmol), and
As part of our interest in developing novel synthetic
strategies for structurally/biologically interesting heterocyclic
compounds,20 we envisioned to assemble an oxadiazole ring
onto isatin in a spiroannulation manner by treating with α-
aryldiazomethanes generated in situ from N-tosylhydrazones21
via 1,3-dipolar cycloaddition. Unexpectedly, ring expansion
occurred, resulting in the formation of 3-hydroxy-4-arylquino-
lin-2(1H)-ones (viridicatin alkaloids). This unanticipated
regioselective one-pot ring-expansion reaction of isatins with
α-aryldiazomethanes was described herein, which represents a
valuable complement to the existing elegant strategies.
b
c
base (2 mmol) stirred in open air atmosphere. Isolated yield.
mmol of base is used. Reaction performed in the absence of p-
toluenesulfonylhydrazide (3).
3
d
K2CO3 (2 mmol) in ethanol under refluxing temperature, i.e.,
80 °C.
Having identified the optimal reaction parameters, the
generality and substrate scope of both isatin and aldehyde
partners were examined. Initially, a wide array of aldehydes
substituted with different functional groups were screened,
which underwent ring expansion smoothly and provided the
corresponding viridicatin derivatives in good to excellent yields
(73−96%). Comparably better yields were obtained with
aldehydes bearing electron-donating groups (Scheme 2, 4b−
In order to evaluate the optimal reaction conditions for the
unanticipated strategy, we commenced our investigation by
treating isatin (1a) with benzaldehyde (2a) and p-toluene-
sulfonylhydrazide (3), employing DBU (2.0 equiv) in MeCN
under refluxing temperatures. To our delight, ring-expanded
product 4a (natural product viridicatin) was obtained in 70%
yield (Table 1, entry 1). The structure of the compound was
unambiguously confirmed by spectroscopic and X-ray crystallo-
graphic analysis. This interesting outcome further encouraged
us to optimize the reaction parameters such as base, solvent,
and temperature (Table 1). Performing a reaction at room
temperature failed to deliver 4a, even after 24 h (Table 1, entry
2). There was no noticeable enhancement in yield of 4a, with
the increase in the stoichiometry of base (Table 1, entry 3).
K2CO3 proved to be a superior base among a set of screened
Scheme 2. Substrate Scope of Aldehydes to the Synthesis of
a b
,
3-Hydroxyquinolin-2(1H)-ones
t
bases such as Et3N, DMAP, DIPEA, BuONa, Na2CO3, and
K2CO3, providing the highest conversion of isatin (1a) to
product 4a (Table 1, entries 4−9). Further, a survey was
conducted on alternative solvents such as EtOH, THF, DMF,
DMSO, PhMe, and 1,4-dioxane, which revealed that EtOH was
the optimal solvent of choice (Table 1, entries 10−15). A
decent decrease in the yield was observed at lower temperatures
(Table 1, entry 16). A control experiment lacking either base or
p-toluenesulfonylhydrazide (3) did not deliver any product,
even after prolonged reaction times (Table 1, entries 17 and
18). Hence, after a brief screening, the optimal conditions to be
concluded are 1a (1 mmol), 2a (1 mmol), 3 (1 mmol), and
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), and
K2CO3 (2 mmol) in EtOH was stirred in an open air atmosphere at 80
°C for 8 h. Isolated yield.
b
B
DOI: 10.1021/acs.orglett.8b01417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4d, 4g, 4j, and 4h) than the electron-withdrawing groups
(Scheme 2, 4e, 4f, 4h, 4k, 4l, 4m, 4p, and 4q). As expected, the
position of the substituent on the aryl aldehyde partner had a
considerable influence on the reaction efficacy, where ortho-
substituted aldehydes (OMe, OEt, and Br) delivered
corresponding products in relatively lesser yields than the
meta- and para-substituted aldehydes (Scheme 2, 4b, 4c, and
4j). This may be possibly due to steric hindrance imparted by
the ortho substituents (Scheme 2, 4d, 4g, 4h, and 4m). It is
worth mentioning that synthetically useful halo substituents
such as Cl or Br are stable under the optimized reaction
conditions, which are useful for further functional group
interconversions such as metal-catalyzed coupling reactions.
Notably, hydroxyl-substituted aldehyde was also amenable for
this transformation and provided the corresponding product
(4r or III) in 73% yield, which is a naturally occurring alkaloid,
viridicatol. Besides aryl aldehydes, even heteroaryl aldehydes
such as 4-pyridinecarboxaldehyde and 2-thiophenecarboxalde-
hyde were also compatible with this protocol and delivered
corresponding products 4s and 4t in 80% and 87% yield,
respectively (Scheme 2). To the best of our knowledge,
utilization of heteroaromatic aldehydes for the synthesis of 3-
hydroxy-4-heteroarylquinolin-2(1H)-ones has not been ex-
plored extensively. In contrast, aliphatic aldehydes were found
to be incompatible with this transformation and did not yield
any product, even after stirring for more than 12 h, leaving the
isatin unreacted. N-Protected isatins afforded the correspond-
ing products in slightly higher yields than the unprotected
isatins (Scheme 2).
parably in higher yields than the electron-withdrawing
substituents (Scheme 3).
In addition, to substantiate the synthetic applicability of the
current protocol, several transformations were conducted.
Initially, we were fascinated to investigate the functionalization
of phenolic−OH and amide−NH, which provide a library of
novel viridicatin derivatives. Accordingly, the synthesized
viridicatin was protected as its N- and O-methylated derivative
6 in excellent yield by treating with dimethyl sulfate in the
presence of NaOH (Scheme 4, eq 1). In addition, the
Scheme 4. Synthetic Applicability of the Current Protocol
acetylation of viridicatin with acetyl chloride provided the
corresponding 2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl acetate
(7) in 93% yield (Scheme 4, eq 2). Furthermore, the practical
utility of this protocol was also extended by executing a gram-
scale synthesis. Natural product viridicatin (4a) was prepared in
6.85 g from isatin (1a, 34 mmol) and benzaldehyde (2a, 34
mmol) under the optimized conditions (Scheme 4, eq 3) in
one pot in 85% yield.
With these fruitful results, we next turned our attention to
broadening the substrate scope of isatins. As summarized in
Scheme 3, a diverse range of isatins substituted with electron-
Scheme 3. Substrate Scope of Isatins to the Synthesis of 3-
Based on the literature reports22 and our observations, a
plausible reaction mechanism has been proposed for the
present protocol (Scheme 5). Initially, benzaldehyde condenses
a b
,
Hydroxy-4-arylquinolin-2(1H)-ones
Scheme 5. Plausible Reaction Mechanism
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), and
K2CO3 (2 mmol) in EtOH were stirred in an open air atmosphere at
b
80 °C for 8 h. Isolated yield.
with p-toluenesulfonylhydrazide to generate the corresponding
hydrazone intermediate 8, which subsequently transforms into
diazomethylbenzene intermediate A in the presence of base
under elevated temperatures. Intermediate A then adds onto
carbonyl carbon of isatin (1a) in a nucleophilic addition
manner to yield intermediate B, which is assumed to undergo
cyclization via intramolecular ring expansion by the elimination
of N2 to deliver intermediate C. Intermediate C after
subsequent aromatization delivers the desired product 4a.
In summary, an efficient regioselective ring expansion
reaction of isatins with aldehydes promoted by p-toluenesulfo-
nylhydrazide has been developed to construct various
pharmaceutically important 3-hydroxy-4-arylquinolin-2(1H)-
ones in one step, which proceeds via an in situ generated α-
donating (OMe) as well as electron-withdrawing (Cl and NO2)
substituents at the fifth position of the aromatic ring reacted
smoothly to deliver the corresponding products in good to
excellent yields (5a−5l). Later, the effect of the position of
substitution was also studied where 4,5-dichloro, 7-fluoro, and
5,7-dimethyl isatins were also amenable for this transformation
and provided corresponding products 5m−5p in good yields
irrespective of their electronic nature. Similar to aldehyde
partners, variation in the electronic nature has the discriminable
impact on the reaction efficacy where isatins bearing electron-
donating substituents yielded corresponding products com-
C
DOI: 10.1021/acs.orglett.8b01417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01417.
■
S
Detailed experimental procedures, crystal data, and
spectral data for all compounds (PDF)
Accession Codes
CCDC 1832714 contains 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 emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
(12) Ribeiro, N.; Tabaka, H.; Peluso, J.; Fetzer, L.; Nebigil, C.;
*E-mail: bathini@iict.res.in.
*E-mail: ahmedkamal915@gmail.com.
ORCID
Dumont, S.; Muller, C. D.; Des
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R.; Gois, P. M. P. Eur. J. Org. Chem. 2013, 28, 6280.
Ahmed Kamal: 0000-0002-4107-1775
Bathini Nagendra Babu: 0000-0001-7378-0878
Present Address
⊥School of Pharmaceutical Education and Research (SPER),
Jamia Hamdard University, New Delhi 110062, India.
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Council of Scientific and Industrial
Research (CSIR), and Y.T. is thankful to UGC for a research
fellowship (IICT Comm. No. IICT/Pubs/2018/153).
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