α-Hydroxy acid as an aldehyde surrogate: metal-free synthesis of pyrrolo[1,2-a]quinoxalines, quinazolinones, and other N-heterocyclesviadecarboxylative oxidative annulation reaction

Article abstract of DOI:10.1039/d0ra07093a

A metal-free and efficient procedure for the synthesis of pyrrolo[1,2-a]quinoxalines, quinazolinones, and indolo[1,2-a]quinoxaline has been developed. The key features of our method include thein situgeneration of aldehyde from α-hydroxy acid in the presence of TBHP (tert-butyl hydrogen peroxide), and further condensation with various amines, followed by intramolecular cyclization and subsequent oxidation to afford the corresponding quinoxalines, quinazolinones derivatives in moderate to high yields.

Full text of DOI:10.1039/d0ra07093a

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a-Hydroxy acid as an aldehyde surrogate: metal-
free synthesis of pyrrolo[1,2-a]quinoxalines,
quinazolinones, and other N-heterocycles via
decarboxylative oxidative annulation reaction†
Cite this: RSC Adv., 2020, 10, 37202
a
a
Mayavan Viji,
Manjunatha Vishwanath,
Jaeuk Sim,a Yunjeong Park,a
Chanhyun Jung,a Seohu Lee,a Heesoon Lee,a Kiho Leeb and Jae-Kyung Jung
a
*
A metal-free and efficient procedure for the synthesis of pyrrolo[1,2-a]quinoxalines, quinazolinones, and
indolo[1,2-a]quinoxaline has been developed. The key features of our method include the in situ
generation of aldehyde from a-hydroxy acid in the presence of TBHP (tert-butyl hydrogen peroxide), and
further condensation with various amines, followed by intramolecular cyclization and subsequent
oxidation to afford the corresponding quinoxalines, quinazolinones derivatives in moderate to high yields.
Received 18th August 2020
Accepted 4th October 2020
DOI: 10.1039/d0ra07093a
rsc.li/rsc-advances
Similarly, quinazolinone plays a major role in drugs and
exhibits potential biological activities.7 The substituted quina-
Introduction
zolinones are associated with a range of biological and phar-
macological activities such as an anti-inammatory, anti-
cancer, anti-fungal, anti-bacterial, etc. Additionally, numerous
natural products contain the quinazolinone core unit, for
example, L-Vasicinone, Rutaecarpine, Luotonin E, Boucharda-
tine, Tryptanthrin, and Methaqualone (Fig. 1).8 Vast number of
diverse methodologies has been developed during the past
decades for the synthesis of these compounds.9,10
Decarboxylative coupling reaction has recently emerged as
a green method to construct C–C bonds, in various reactions
such as Heck, cross coupling, oxidative arylation, allylations,
etc.,11 However, most of the reactions utilized metal catalysts.12
Due to expensive and toxicity of metal catalyst, it is highly
required to design an environmentally benign method. Few
reports were utilized the a-hydroxy acids as an aldehyde
equivalent.13 To the best of our knowledge there is no report
related the direct synthesis of quinoxalines from a-hydroxy
Pyrrolo[1,2-a]quinoxaline motifs are shown in a large number of
natural products as well as in several molecules under clinical
trials (Fig. 1). For example, the pyrrolo[1,2-a]quinoxaline core
system is extensively utilized in pharmaceuticals due to its
potential biological activities, including anti-bacterial, anti-
infective, anti-inammatory, anti-HIV, anti-malarial, 5-HTR
affinity etc.1 Furthermore, some of these derivatives have been
utilized in electronic and optical elds.2 Due to their structural
prevalence, signicant efforts have been devoted, and several
synthetic strategies have been developed for the construction of
these compounds.3–5 Conventionally, 2-(1H-pyrrol-1-yl)aniline
(1a) has been used as a starting material and is condensed
with aldehydes4e,f,m,n,p–s or its equivalents to form the pyrrolo[1,2-
a]quinoxaline derivatives.4
However, the existing methods suffer from several limita-
tions in that they require tedious synthetic procedures, expen-
sive transition metal catalysts, stoichiometric reagents, elevated
temperatures, toxic solvents, and catalyst, etc. In addition to
that, aldehydes are prone to convert into acids by aerial oxida-
tion, which may cause decarbonylation, to avoid formation of
additional side products inert condition required to carry out
the experiment (Scheme 1).6 Thus, it would be highly desirable
to develop an environmentally benign method to synthesis of
quinoxalines and its related derivatives.
aCollege of Pharmacy, Medicinal Research Center (MRC), Chungbuk National
University, Cheongju 28160, Republic of Korea. E-mail: orgjkjung@chungbuk.ac.kr;
Fax: +82-43-268-2732; Tel: +82-43-261-2635
bCollege of Pharmacy, Korea University, Sejong 30019, Republic of Korea
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra07093a
Fig.
1 Compounds containing pyrrolo[1,2-a]quinoxalines and
quinazolinones.
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various solvents such as DMSO, water, THF, toluene, and
acetone (entries 13–17). But, unfortunately, other solvents failed
to improve the yield of the reaction. Altering the temperature
led to slightly lower the yield (entry 18). We concluded that the
optimized conditions for the decarboxylative condensation
followed by annulation reaction was 1a (1.0 equiv.), 2a (5.0
ꢀ
equiv.), and TBHP (4.0 equiv.) in DCE at 80 C.
With the optimized reaction conditions in hand, we
expanded the scope of the reaction and with various other
hydroxyl acids and amine derivatives (Table 2). Different a-
hydroxy acids were investigated with 1a and equivalent products
were obtained in moderate to good yields. When we moved from
aliphatic equivalent to aryl equivalent; (here the mandelic acid,
equivalent of benzaldehyde) was tolerated and furnished the
expected product (3b) in good yield (56%).3c Likewise, aliphatic
substituted hydroxy acids afforded the pyrrolo[1,2-a]quinoxa-
line derivatives in good yields. 2-Methyl-2-hydroxypropionic
acid (2-methyllactic acid) equivalent of acetone, 2-methyl-2-
hydroxybutanoic acid equivalent of 2-butanone underwent the
reaction smoothly and provided the expected products (3c & 3d)
in moderate yields.5b,d
Interestingly, phenyllactic acid also produced the acetophe-
none derivative (3e, 65%) in good yield.4o This may be because
benzylic protons are over-oxidized by TBHP. Moreover, the
Scheme 1 Previous and our approaches.
acids as an aldehyde surrogate. In our efforts to develop privi-
leged heterocycles via metal-free approaches,14 herein we
disclose a method to synthesize pyrrolo[1,2-a]quinoxalines and
quinazolinones by utilizing a-hydroxy acids as aldehyde equiv-
alent in the presence of TBHP.
Table 1 Optimization of reaction conditionsa
Results and discussion
Temp.
(ꢀC)
Oxidant
(5.0 equiv.)
Time
(h)
Yieldb
(%)
S. no.
Solvent
In our preliminary investigation, we selected 2-(1H-pyrrol-1-yl)
aniline (1a, 1.0 equiv.) and lactic acid (2a, 5.0 equiv.) as model 1c
substrates to optimize the reaction condition, and the results
are summarized in Table 1. By using FeCl3 (30 mol%) as the
catalyst and tert-butyl hydrogen peroxide (TBHP, 5.0 equiv., 70%
in H2O) as the oxidant in chloroform at 70 ꢀC under the oxygen
atmosphere, the corresponding pyrrolo[1,2-a]quinoxaline (3a)
obtained in 23% yield (Table 1, entry 1).4l Replacing the catalyst
to CuSO4 given the similar result (entry 2). Surprisingly, absence
of a metal catalyst successfully generated the expected product
3a in 28% yield (entry 3). Furthermore, the product yield was
CHCl3
CHCl3
CHCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
H2O
THF
Toluene
Acetone
DCE
80
80
80
70
70
70
70
70
70
70
80
80
80
80
80
80
80
90
TBHP
TBHP
TBHP
TBHP
Oxone
Na2S2O8
K2S2O8
H2O2
20
20
12
12
36
36
36
24
24
24
12
12
24
24
24
24
12
10
23e
24e
28e
52
NR
NR
NR
48
<10
37
63
76
<10
30
2d
3
4
5
6
7
8
9
DTBP
DCP
10
11
12
TBHP
TBHPf
TBHPf
TBHPf
TBHPf
TBHPf
TBHPf
TBHPf
increased to 52% when we, switched the solvent into dichloro- 13
ethane (DCE, entry 4).
14
15
16
17
18
NR
33
SR
71
These above results encouraged us to screen various types of
oxidants such as Oxone, sodium persulfate, and potassium
persulfate, which unfortunately failed to form the desired
product (entries 5–7). Similarly, replacing TBHP with other
peroxide oxidants led to catalyze the reaction, albeit with
slightly lower yields (entries 8–10). Gratifyingly, decreasing the
equivalence of TBHP to 4.0 equiv. and increasing the tempera-
ture to 80 ꢀC, 3a was obtained in 76% yield (entry 12). To
improve the yield of the product, the reaction was screened with
a
Reaction conditions: 2-(1H-pyrrol-1-yl)aniline 1a (1.0 equiv.), lactic
acid 2a (5.0 equiv.), solvent 2.0 mL, stirred at mentioned temperature.
Isolated yield. 30 mol% FeCl3 used as a catalyst. 30 mol% CuSO4
used as a catalyst. Performed under oxygen atm. 4.0 equiv. of TBHP
(tert-butyl hydrogen peroxide) used, DTBP: di-tert-butylperoxide, DCP:
dicumyl peroxide, NR ¼ no reaction, SR ¼ side reaction.
b
c
d
e
f
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Table 2 Synthesis of pyrrolo[1,2-a]quinoxaline derivativesa
derivative was synthesized by using the above aldehyde.5d On
the other hand, only product 3f was previously synthesized by
using equivalent amino acid (leucine).4h Besides, glycolic acid,
which was used as a one-carbon source, also proven to be
appropriate candidate, reacted quite well under the optimal
reaction condition, and provided pyrroloquinoxaline 3o in very
good yield (67%).4a
Subsequently, we have expanded the scope of the decarbox-
ylative condensation reaction with various anthranilamide
derivatives and different a-hydroxy acids to synthesize quina-
zolinone derivatives. As shown in Table 3, we found that various
functionalized anthranilamides successfully underwent this
decarboxylative condensation to afford the expected products in
good to excellent yields. For example, mandelic acid with
anthranilamide produced the target product 5a in excellent
yield (84%).10a Substrates bearing N-benzyl efficiently engaged
and produced the products 5b–c in good yields.9z,10b A wide
range 2-aminophenylbenzamides were synthesized which are
compatible with standard conditions. Likewise, 2-amino-N-
phenyl benzamide reacts with mandelic acid to generate the
corresponding product 5d in 69% yield.10i
Table 3 Synthesis of quinazoline derivativesa
a
Reaction conditions: all the reactions were performed using SM (1.0
equiv.), a-hydroxy acid (5.0 equiv.), TBHP (4.0 equiv.), and DCE (2.0
mL) stirred at 80 ꢀC.
reaction of amine 1a with leucic acid is an equivalent of 3-
methylbutanal, smoothly underwent the reaction generated the
corresponding product 3f in moderate yield.4h
Later, we investigated various substituted aniline derivatives.
Substrate containing methyl, and methoxy substituted aniline
derivatives were compatible with this transformation and
produced the respective products 3g, 3h in good yields.3c It was
found that aniline containing the electron-withdrawing groups
such as F, Br, and Cl could be amenable to the reaction,
providing their equivalent products in good yields. Fluoro
substituted amine was well tolerated under the present condi-
tion and afforded the corresponding quinoxalines in good
yields. Both mandelic and lactic acid are furnishing the desired
products 3i, 3j in good yields.3c,5a To synthesis products of 3a,
and 3j acetaldehyde surrogate is required and acetaldehyde
difficult to handle due to polymerization. Also, some of the re-
ported methods are required either very high temperature,
metal catalyst or strong acidic condition and so on.
Leucic acid also reacted smoothly and provided the nal
product 3k in moderate yield. Similarly, both Br and Cl
substituents furnish the corresponding products (3l–n) in good
yields under the standard reaction condition.5b In general, iso-
valeraldehyde is required to condense with 2-pyrrolyl aniline to
obtain the products 3f, 3k, and 3m. But only one dihydro
a
Reaction conditions: all the reactions were performed using SM (1.0
equiv.), a-hydroxy acid (5.0 equiv.), TBHP (4.0 equiv.), and DCE (2.0
mL) in stirred at 80 ꢀC.
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Scheme 2 Synthesis of other derivatives.
Further, similar results were obtained with phenyl ring
containing methyl, methoxy, acetyl, dimethyl substituted
anthranilamides which react with mandelic acid to afford ex-
pected quinazolinone derivatives (5e–i) in good yields.10e,i,j Also,
N-p-tolyl-anthranilamide reacts with lactic acid to furnish the
corresponding product 5i in high yield as 81%.10g Besides,
cyclohexyl, ethyl cyclohexene, ethylphenyl, triuoroethyl pro-
tected amides also provided expected products (5j–m) in good
yields.10c,f,h Similarly, the chloro substituted anthranilamide
ring also delivered the product 5n in moderate yield.10d More-
over, we applied the optimal condition to glycolic acid, which
reacted with various 2-aminobenzamides to provide the ex-
pected quinazolinone products (5o–q) in good yields.14b To
synthesis of substituted quinazoline derivatives such as 5o, 5p,
and 5q, the reported methods requires harsh reaction condi-
tions such as higher temperature, toxic solvent, longer reaction
time, and so on.
Aer investigating the scope with various anthranilamides,
we next tested the generality of the decarboxylative condensa-
tion reaction with various amine partners (Scheme 2). For
example, the 2-aminobenzenesulphonamide with mandelic
acid produced the target sulfonamide condensed product 6
with moderate yield.9x The reaction between 2-(1H-indol-1-yl)
aniline and mandelic acid under the optimized reaction
condition produced indolo[1,2-a]quinoxaline (7) albeit in lower
yield.5b Besides, under the standard conditions, we synthesized
one of the best-selling sedative-hypnotic drug Methaqualone
(8), which was obtained by the reaction between suitable
substituted anthranilamide with lactic acid, which acts as an
acetaldehyde equivalent to provide the natural product Meth-
aqualone 8 in 63% yield.14b
Scheme 4 Possible reaction mechanism.
To gain more insight into the reaction mechanism, we have
carried out the control experiments shown in Scheme 3. Mixing
the reaction with the radical quencher TMEPO (15.0 equiv.)
given the 5b in less than 10% yield. Other radical scavengers
such as BHT (15.0 equiv.) & 1,1-diphenylethylene (15.0 equiv.)
both are completely inhibiting the reaction and less than 5%
product only obtained. The above radical scavenger experi-
ments reveal that the reaction occurs via radical formation.
Based on the experimental results, the possible mechanism
for the formation of quinazolinone is depicted in Scheme 4.
Initially, TBHP is fragmented into a t-butoxide radical and
a hydroxyl radical. Then, the hydroxyl radical reacts with a-
hydroxy acids to form the aldehyde equivalent I by the elimi-
nation of both CO2 and H2O. Then, the amine 4 reacts with I to
afford the imine intermediate II via condensation with t-but-
oxide radical and yields water as a side product. The dihydro
aminal III is generated from II, through intramolecular cycli-
zation and product 5 is formed by oxidation.
Conclusion
We have developed a TBHP mediated, mild, and efficient
approach to synthesis of various quinoxalines, quinazolinones,
and indoloquinoxaline derivatives via decarboxylation followed
by condensation using a-hydroxy acids as carbonyl source. The
reaction proceeds in the absence of metal catalyst to afford the
expected products in moderate to high yields. A series of
substituted 2-amino benzamides are well suited in this process.
Based on the control experimental results, a possible reaction
mechanism suggests, the reaction occurs via radical mecha-
nism. By utilizing this methodology, we have synthesized the
bioactive natural product (Methaqualone) in good yield.
Experimental section
General information
1H NMR spectra were recorded on a Jeol RESONANCE ECZ 400S
Scheme 3 Control experiments.
(400 MHz). Chemical shis are reported in ppm from
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tetramethylsilane (TMS) with the solvent resonance resulting
from incomplete deuteration as the internal reference (CDCl3:
7.26 ppm) or relative to TMS (d 0.0). Data are reported as follows:
chemical shi, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, br ¼ broad, m ¼ multiplet, dd ¼ doublet of
doublet, td ¼ triplet of doublet), coupling constants (Hz),
number of protons. 13C NMR spectra were recorded on a Jeol
RESONANCE ECZ 400S (100 MHz) with complete proton
decoupling. Chemical shis are reported in ppm from tetra-
methylsilane with the solvent as the internal reference (CDCl3:
77.16 ppm). High-resolution mass spectrometry was performed
with on LCQ Fleet-Thermo Scientics. All reactant or reagent
was purchased from Aldrich, TCI, Alfa Aesar and Acros, and
were directly used without further purications. Silica gel
column chromatography was performed with Silica Gel of Kie-
selgel 60 F254 plate (Merck).
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General procedure for the synthesis of heterocyclic
compounds
A solution of 2-(1H-pyrrol-1-yl)anilines (1.0 equiv.) or 2-amino-
benzamides (1.0 equiv.), a-hydroxy acids (5.0 equiv.), TBHP
(70% in H2O, 4.0 equiv.) and DCE (2.0 mL) was stirred at 80 ꢀC
for particular times (see the individual substrates at the
manuscript). The reaction progress was monitored by TLC.
Then, 10 mL of NH4Cl was added to the reaction mixture and
extracted with EtOAc (15 mL ꢁ 3). The combined organic frac-
tions were dried over MgSO4, ltered, and concentrated under
reduced pressure. The crude residue was then puried by ash
column chromatography on silica gel by using hexanes/ethyl
acetate as eluent to afford the pure product.
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
This work was supported by the National Research Foundation
of Korea grants funded by the Korea Government (MSIT) (MRC
2017R1A5A2015541, and 2020R1A2C1007346). This work was
also supported by the Post-doctoral Fellowship program funded
by the Ministry of Education of the Republic of Korea through
the Chungbuk National University in 2018 (M. V.).
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