Oxidative sp3 C–H Functionalization of Methyl Substituted Aza-Aromatics: An Easy Access to N-Fused Polyheterocycles

Article abstract of DOI:10.1002/ejoc.201901148

An efficient metal-free, one-pot strategy has been developed for the synthesis of diverse N-fused polyheterocycles such as pyrido-/thiazolo-/benzthiazolo-imidazo[4,5-c]quinolines and indolo-/pyrrolo-[1,2-a]quinoxalines mediated by I₂/DMSO in the presence of 10 mol-% TBHP. This protocol involves a cascade sequence of oxidative imination/cyclization/aromatization reactions through sp³ C–H functionalization of methyl-substituted aza-aromatics with a variety of arylamine conjugated heterocycles by means of modified Pictet–Spengler type cyclization. The advantage of the present method includes environmentally benign, atom economy, and mild reaction conditions resulting in various N-fused polyheterocycles.

Full text of DOI:10.1002/ejoc.201901148

DOI: 10.1002/ejoc.201901148
Full Paper
C–H Functionalization
Oxidative sp3 C–H Functionalization of Methyl Substituted Aza-
Aromatics: An Easy Access to N-Fused Polyheterocycles
Bhima Sridevi,[a,b] Satheeshkumar Reddy Kandimalla,[a,b] and B. V. Subba Reddy*[a,b]
Abstract: An efficient metal-free, one-pot strategy has been reactions through sp3 C–H functionalization of methyl-sub-
developed for the synthesis of diverse N-fused polyheterocycles stituted aza-aromatics with a variety of arylamine conjugated
such as pyrido-/thiazolo-/benzthiazolo-imidazo[4,5-c]quinolines heterocycles by means of modified Pictet–Spengler type cycli-
and indolo-/pyrrolo-[1,2-a]quinoxalines mediated by I2/DMSO zation. The advantage of the present method includes environ-
in the presence of 10 mol-% TBHP. This protocol involves a cas- mentally benign, atom economy, and mild reaction conditions
cade sequence of oxidative imination/cyclization/aromatization resulting in various N-fused polyheterocycles.
Introduction
organelle-targetable fluorescent probes (OTFPs) as they exhibit
strong fluorescence emissions in bio-imaging.[10a] On the other
hand, benzo[d]imidazo[2,1-b]thiazoles are important sulfur con-
taining tricyclic scaffolds, which are known to exhibit diverse
biological activities. For instance, compound (E) shows an excel-
lent antimicrobial activity.[10b] In fact, indolo[1,2-a]quinoxaline
derivatives (F) shows a promising in vitro antifungal activity
against phytopathogenic fungi and G acts as a VEGFR3¯ kinase
cell inhibitor.[11] Additionally, pyrrolo[1,2-a]quinoxaline deriva-
tive (H) behaves as a valuable anti-mycobacterial agents (Fig-
ure 1).[12]
Over the past few decades, the synthesis of heterocyclic com-
pounds has received great attention due to their immense ap-
plication in various fields such as pharmaceuticals and agro-
chemicals.[1,2] In particular, quinoline, pyrrole, benzothiazole
and imidazole frameworks are recognized as potential scaffolds
in medicinal chemistry because of their wide spectrum of bio-
logical activities.[3] Furthermore, nitrogen-containing fused
polyheterocycles are frequently found in many natural and syn-
thetic products with versatile applications.[4]
In recent years, transition metal catalyzed C–N and C–C bond
forming reactions have become powerful synthetic tools due
to their ability to provide various biologically important N-het-
erocycles.[5] However, many of these transition metal-catalyzed
reactions suffer from toxicity, tedious work-up and difficulty
their removal from pharmaceuticals. To circumvent some of
these problems, metal-free strategies have gained importance
in organic synthesis. Recently, molecular iodine has attracted
much attention as an alternative to metal catalyzed transforma-
tions because of its low cost, non-toxicity and ready availability.
Furthermore, it acts as a mild Lewis acid,[6] which promotes
C–N and C–C bond forming reactions to construct a wide range
of N-fused heterocycles.[7]
Specifically, imidazo[4,5-c]quinoline skeleton is often found
in various biologically active molecules like Imiquimod (A),
which exhibits a promising immune response modifier activity
by targeting cancer cells through protein kinase inhibition.[8]
Furthermore, annulated dipyridoimidazoles [Glu-P1 (B) and Glu-
P2 (C)] are known to exhibit anti-cancer activity.[9] In addition,
imidazo[1,2-a]pyridine fused indole derivatives (D) behaves as
Figure 1. Representative examples of N-fused polyheterocycles.
Due to their wide applications in polymers, material science,
pharmaceuticals and biological sciences, several synthetic
methods have been developed for the synthesis of such fused
heterocycles by means of Bischler–Napieralski intramolecular
cyclization and Pictet–Spengler reaction.[13,14] Subsequently,
I2/DMSO catalyzed oxidative cross-coupling reactions have
been reported for the synthesis of 2-benzoyl pyridoimidaz-
ole.[15] Later on, iodine-catalyzed one-pot sequential C–N and
C–C bond forming reactions have been developed to generate
N-fused heterocycles.[16] However, there are no reports on the
[a] Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500–007, India
E-mail: basireddy@iict.res.in
https://www.iictindia.org/People/view?id=335
[b] Academy of Scientific and Innovative Research, New Delhi 110025, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901148.
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synthesis of N-fused polyheterocycles through an oxidative sp3
C–H functionalization of methyl-substituted aza-aromatics.
Herein we report an efficient metal-free strategy for the
synthesis of biologically active pyrido-/thiazolo-/benzthiazolo-
imidazo[4,5-c]quinolines, indolo-/pyrrolo[1,2-a]quinoxalines
from methyl aza-aromatics and 2-(imidazo[1,2-a]pyridin-2-yl)-
anilines/2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)anilines/2-(1H-
pyrrol-1-yl)anilines/2-(1H-indol-1-yl)anilines using I2/DMSO in
the presence of TBHP (Scheme 1). The reaction proceeds via the
formation of C–N and C–C bonds by the oxidative cyclization
of various ortho-aminoaryl heterocycles with methyl aza-aro-
matics by means of sp3 C–H functionalization. To the best of
our knowledge, this is the first report on the oxidative function-
alization of benzylic sp3 carbon of methyl aza-aromatic system
using molecular I2.
Table 1. Optimization of reaction conditions for the one-pot synthesis of 3a.[a]
Entry Reagent
Equiv. Co-oxidant Solvent
Temp[°C]
[b]Yield [%]
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
0.2
0.5
1.0
1.2
1.2
1.2
1.2
1.3
1.3
1.5
2.0
1.5
1.5
1.5
1.5
none
air
O2
O2
O2
Neat
toluene
1,2-DCE
1,4-dioxane r.t.
DMF
DMSO
THF
EtOH
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NEAT
r.t.
r.t.
r.t.
ND
ND
ND
Trace
–
26
19
ND
ND
82
r.t.
r.t.
O2
DDQ
DTBP
TBHP
TBHP
TBHP
–-
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
10
11
12
13
14
15
16
17
18
80
Trace
ND
ND
42
24
ND
ND
NIS[c]
TBAI[c]
KI[c]
PhI(OAc)2 1.5
–
I2
[c]
1.5
1.5
Scheme 1. Oxidative cyclization of (1) with heterocyclic anilines (2).
[a] Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), I2 (0.75 mmol,
1.5 equiv.), TBHP (0.05 mmol, 10 mol-%), DMSO (3.0 mL) in a sealed tube at
110 °C for 4–6 h. [b] Isolated yields; ND=Not detected. [c] Amount of reagent:
1.5 equiv.
Results and Discussion
Accordingly, we prepared the required starting material, 2-
(imidazo[1,2-a]pyridin-2-yl)aniline (2) from 1-(2,2-dibromovinyl)-
2-nitrobenzene and commercially available 2-aminopyridine
through a condensation followed by NO2 reduction in good
yields.[7d,17] With a required starting material (2) in hand, we
then started our investigation by treating 2-(imidazo[1,2-a]-
pyridin-2-yl)aniline (2a) with 2-methylquinoline (1a) using sub-
stoichiometric amount of I2 in the absence of oxidant and sol-
vent at room temperature (entry 1, Table 1). But the reaction
was unsuccessful. Therefore, a series of diverse reaction param-
eters were tested, and the results are presented in Table 1. Sev-
eral solvents such as toluene, 1,2-DCE, 1,4-dioxane, DMF, THF,
CH3CN, EtOH and DMSO as well as oxidants like O2, DDQ, DTBP
and TBHP along with stoichiometric amount of iodine were
screened at room temperature to reflux conditions (Table 1,
entries 2–11). Among them, TBHP was found to be the best co-
oxidant and DMSO as an effective oxidant and solvent for this
transformation under reflux conditions. The use of 1.5 equiv. of
iodine gave the best results. It is noteworthy to mention that
no further improvement in yield was observed even by increas-
ing the quantity of I2 up to 2.0 equiv. (Table 1, entry 11). Finally
the best yield was obtained using 1.5 equiv. of iodine at 110 °C
in DMSO in the presence of 10 mol-% TBHP (Table 1, entry 10).
13–14). But low yields were obtained with KI and PhI(OAc)2
(Table 1, entries 15–16). Among different iodide sources, molec-
ular I2 was found to be the best in terms of conversion. In the
absence of iodine, the reaction was unsuccessful (Table 1, en-
tries 17). Meanwhile, DMSO plays a crucial role in this reaction.
In the absence of DMSO, the product was not detected (Table 1,
entry 18). The structure of 3a was established by NMR and
mass analysis.
With these optimized reaction conditions in hand, we ex-
plored the substrate scope by varying substituents of ortho-
aminoaryl imidazopyridines (2a–f). To expand the applicability
of this method, we examined the reactivity of 2-(imidazo[1,2-a]-
pyridin-2-yl)anilines (2a–c) with various methyl azaarenes (1)
such as 2-/4-methylquinolines and 2-/4-methylpyridines. The
corresponding pyrido-imidazo[4,5-c]quinolines were obtained
in 73–86 % yield (3a–e, Table 2).
Subsequently, this method was extended to other substrates
like 2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)anilines (2d–f), which
were synthesized from substituted 2-aminobenzthiazoles and
acetophenones[18] to produce the respective N-polyhetero-
cycles (3f–k, Table 2).
The structure of compound 3i was determined by detailed
However, the product 3a was obtained in low yield in the ab- NMR experiments. The observed characteristic NOE correlations
sence of TBHP (Table 1, entry 12).
between H3–H7, H3–H8 and HMBC (1H-13C) correlations indi-
cates the structure of N-polyheterocyclic compound as repre-
sented below (Figure 2).
On the other hand, a variety of iodine reagents such as
N-iodosuccinimide (NIS), potassium iodide (KI), iodobenzene
diacetate [PhI(OAc)2] and tetrabutylammonium iodide (TBAI)
To demonstrate its scope, we further extended this method
were screened (Table 1, entries 13–16). Unfortunately, no de- to other ortho-aminoaryl heterocycles (Table 3). Gratifyingly, 2-
sired product 3a was formed with NIS and TBAI (Table 1, entries (1H-indol-1-yl)anilines[19] (4a
&
4b) and 2-(1H-pyrrol-1-yl)-
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Table 2. Substrate scope of imidazo-heterocyclic anilines.[a]
Table 3. Substrate scope of indolo-/pyrrolo-heterocyclic anilines.[a]
[a] Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), I2 (0.75 mmol, 1.5 equiv.),
TBHP (0.05 mmol, 10 mol-%), DMSO (3.0 mL) in a sealed tube at 110 °C for
4–6 h.
polar organic solvents like CH2Cl2, CHCl3, CH3CN, EtOAc, MeOH,
EtOH, THF etc.
To elucidate the mechanistic pathway for the synthesis of
fused heterocycles, we performed few experiments with 2-
methylquinoline (1) under optimized conditions. The corre-
sponding quinoline-2-carbaldehyde (J) was obtained, through
the formation of 2-iodomethylquinoline (I) as shown in
Scheme 2a.[21] Subsequent reaction of aldehyde (J) with 2a
gave the product 3a in 84 % yield (Scheme 2b), which was
directly obtained by reacting with 2-methylquinoline
(Scheme 2c) under standard conditions. Furthermore, in the ab-
sence of iodine, the reaction failed to give the desired product
3a (Scheme 2d).
[a] Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), I2 (0.75 mmol, 1.5 equiv.),
TBHP (0.05 mmol, 10 mol-%), DMSO (3.0 mL) in a sealed tube at 110 °C for
4–6 h.
Based on the control experiments and previous reports,[21a]
a probable reaction mechanism for the formation of 6-(quin-
olin-2-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline (3) is shown in
Scheme 3. Initially, 2-methyl aza-arene (1) reacts with I2 in the
presence of TBHP to give the iodomethylazaarene (I).[21b–21d]
Subsequently, the iodo compound (I) would undergo Kornblum
oxidation by DMSO through path-a to afford the corresponding
aldehyde (J), which is simultaneously condensed with 2-(imid-
azo[1,2-a]pyridine-2-yl)aniline (2a) to form the iminium ion (L).
Alternatively, iminium ion (L) can be formed by the oxidation
of secondary amine (K), which is in turn formed from iodo com-
pound (I) and 2-(imidazo[1,2-a]pyridin-2-yl)aniline (2a) by
Figure 2. Characteristic NOEs of compound 3i.
anilines[20] (4c) were treated with various methyl azaarenes (1)
under similar conditions to generate indolo[1,2-a]quinoxalines
(5a-d) and pyrrolo[1,2-a]quinoxalines (5e–h) in 71–86 % and
69–89 % yields respectively.
Furthermore, 2-methylthiophene also gave the desired prod- means of nucleophilic amination as shown in path-b. Further
uct 5i in 74 % yield (5i, Table 3). All the products are soluble in cyclization of compound L would give the dihydro compound
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blum oxidation and for the regeneration of molecular iodine
from HI. On the other hand, TBHP acts as a co-oxidant to accel-
erate the entire process. As mentioned in the Table 1 (entry 12),
in the absence of TBHP, the reaction was slow and requires a
long time. After the addition of a catalytic amount of TBHP
(10 mol-%), the reaction was faster with complete conversion.
Therefore, TBHP accelerates the rate of reaction by reducing the
reaction time and improving yields.
Conclusion
In summary, we have developed a one-pot, highly efficient,
I2/DMSO promoted synthetic approach for the generation of
biologically relevant diverse N-polyheterocycles such as pyr-
ido-/thiazolo-/benzthiazolo-imidazo[4,5-c]quinolines and ind-
olo-/pyrrolo-[1,2-a]quinoxalines by means of the condensation
of 2-(imidazo[1,2-a]pyridin-2-yl)anilines/2-(benzo[d]imidazo-
[2,1-b]thiazol-2-yl)anilines/2-(1H-pyrrol-1-yl)anilines/2-(1H-indol-
1-yl)anilines with various methyl-substituted aza-aromatics us-
ing TBHP as a co-oxidant. The reaction involves the formation
of C–N and C–C bonds through a sequential oxidative imination,
cyclization and aromatization under meta-free conditions. Cer-
tainly, this strategy can be explored for various scaffolds of
pharmacological interest.
Scheme 2. Control experiments for I2-mediated oxidative cyclization.
(M) with a concomitant release of two moles of HI. Finally the
oxidative aromatization of M affords the desired product 3. It is
known that molecular iodine can be regenerated from HI by
DMSO.[16,21e] In this reaction, I2 acts as an iodinating reagent
(1.5 equiv.) and DMSO serves as an oxidant as well as solvent
while TBHP is a co-oxidant (10 mol-%). DMSO is a real oxidant
for the conversion of iodo compound into an aldehyde by Korn-
Supporting Information (see footnote on the first page of
this article): Experimental details, characterization data for com-
1
pounds, copies of H and 13C NMR spectra of products (3a–k),
(5a–i) are provided in the supporting information.
Experimental Section
General: All chemicals and reagents were obtained from commer-
cial source and were used without further purification unless other-
wise indicated. Reactions were monitored by TLC performed on sil-
ica gel 60 GF-254 glass plates, and visualization was achieved by
UV light and iodine indicator, as well as by charring. Column chro-
1
matography was performed with Merck 60–120 mesh silica gel. H
NMR spectra were recorded on Bruker UXNMR/XWIN-NMR
(300 MHz) or Inova Varian-VXR-unity (400, 500 MHz) instruments.
Chemical shifts for 1H NMR spectra are reported in parts per million
(ppm) downfield from an internal tetramethylsilane (TMS) standard
with the solvent resonance as the internal standard (chloroform:
δ = 7.26 ppm). Data are reported as following: chemical shift, multi-
plicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet,
q = quartet, m = multiplet, br = broad signal) coupling constant
(Hz), and integration. The mass spectra were recorded on electro-
spray ionization mass spectrometry (ESI-MS) and high-resolution
mass spectra (ESI-HRMS) were recorded on ESI-QTOF mass spec-
trometer. Melting points were recorded using electrothermal appa-
ratus (Model IA9200) and are uncorrected.
General procedure for the synthesis of pyrido-/thiazolo-/benzthi-
azolo-imidazo[4,5-c]quinolones and indolo-/pyrrolo-[1,2-a]quinox-
alines (3a–k & 5a–i): In a sealed tube, 2-methylquinoline (1)
(0.55 mmol) was dissolved in DMSO (3.0 mL) and I2 (1.5 equiv.) was
added at room temperature and stirred for 30 min. Then ortho-
aminoaryl heterocycles (2 or 4) (0.5 mmol) and TBHP (10 mol-%)
were added at room temperature. The resulting mixture was heated
to 110 °C for 4–6 h. After completion of the reaction as monitored
by TLC, the mixture was quenched with a saturated solution of
Scheme 3. A plausible reaction mechanism.
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sodium thiosulfate and extracted with ethyl acetate. The organic
layer was washed with water followed by brine solution, dried with
128.7, 128.2, 127.7, 127.4, 127.0, 126.6, 125.3, 124.1, 116.4, 115.8,
114.7, 114.1, 113.5, 107. ESI-MS: m/z 302 [M+], HRMS(ESI): calcd. for
anhydrous Na2SO4, filtered and concentrated under reduced pres- C17H12N4S [M + H+]: 303.0626, found 303.0653.
sure. The crude residue was purified by silica gel column chroma-
10-Methyl-6-(quinolin-2-yl)benzo[4′,5′]thiazolo[2′,3′:2,3]imid-
tography using a mixture of ethyl acetate/hexane as eluent to afford
the desired product.
azo[4,5-c]quinoline (3g): Yield: 84 %; yellow solid; mp: 185–187 °C;
1H NMR (500 MHz, CDCl3) δ = 8.69 (d, J = 7.7 Hz, 1H), 8.52 (d, J =
8.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.00 (d,
J = 7.9 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.83–7.61 (m, 4H), 7.45 (s,
1H), 6.45 (d, J = 8.4 Hz, 1H), 5.81 (t, J = 10.6 Hz, 1H), 2.29 (s, 3H);
6-(Quinolin-2-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline (3a):
Yield: 82 %; pale yellow solid; mp: 270–272 °C; 1H NMR (400 MHz,
CDCl3) δ = 9.36 (d, J = 7.1 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.55- 8.38
(m, 2H), 8.26 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.96–7.87 13C NMR (125 MHz, CDCl3) δ = 158.2, 157.8, 151.2, 147.2, 145.3,
(m, 2H), 7.80–7.60 (m, 4H), 7.56–7.48 (m, 1H), 6.82 (t, J = 6.9 Hz, 1H);
144.1, 137.7, 134.7, 131.6, 130.2, 129.7, 129.4, 129.1, 128.4, 127.9,
127.8, 127.60, 127.1, 126.6, 126.2, 123.8, 123.4, 123.0, 122.2, 122.1,
13C NMR (100 MHz, CDCl3) δ = 156.9, 150.1, 148.4, 146.8, 146.7,
144.7, 137.6, 130.6, 130.2, 129.6, 129.1, 128.9, 128.2, 128.0, 127.6, 121.4, 116.2, 21.0; ESI-MS: m/z: 417(M+), HRMS (ESI ): m/z calcd. for
127.1, 122.8, 122.5, 122.0, 121.2, 117.6, 111.3; ESI-MS: m/z 347(M+), C26H17N4S [[M + H]+]:417.1162, found 417.1168.
HRMS (ESI): m/z calcd. for C23H15 N4 [[M + H]+]: 347.1303, found
10-Methoxy-6-(quinolin-2-yl)benzo[4′,5′]thiazolo[2′,3′:2,3]imid-
347.1305.
azo[4,5-c]quinoline(3h): Yield: 78 %; yellow solid; mp: 234–236 °C;
6-(Quinolin-4-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline (3b):
Yield: 86 %; yellow solid; mp: 213-215 °C; 1H NMR (400 MHz, CDCl3)
δ = 9.21 (d, J = 4.2 Hz, 1 H), 8.88 (dd, J = 8.0 Hz, 1.2, 1 H), 8.32 (d,
J = 8.4 Hz, 2 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.88- 7.84 (m, 1 H), 7.81
(td, J = 8.3, 1.3 Hz, 2 H), 7.72 (d, J = 4.2, 1 H), 7.49 (m, 2 H), 7.45–
7.41 (m, 1 H), 7.34 (d, J = 7.0 Hz, 1 H), 6.61 (td, J = 6.9, 1.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ = 150.6, 149.8, 148.7, 147.3, 145.1,
1H NMR (400 MHz, CDCl3) δ = 8.69 (d, J = 7.4 Hz, 1H), 8.53 (d, J =
8.1 Hz, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.00 (d,
J = 8.1 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.79–7.63 (m, 4H), 7.18 (s,
1H), 6.21 (d, J = 7.7 Hz, 1H), 5.89 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ = 157.3, 155.9, 149.1, 144.4, 134.4, 130.6,
129.4, 127.9, 126.9, 126.4, 124.0, 121.9, 114.0, 113.6, 109.0, 55.9; ESI-
MS: m/z: 433(M+), HRMS (ESI): m/z calcd. for C26H17N4OS [[M + H]+]:
143.9, 143.8, 130.4, 130.3, 129.7, 129.3, 128.1, 127.2, 126.6, 126.1, 433.1045, found 433.1168.
124.8, 122.8, 121.8, 121.3, 120.9, 118.1, 112.5; ESI-MS: m/z 347(M+),
10-Methyl-6-(quinolin-4-yl)benzo[4′,5′]thiazolo[2′,3′:2,3]imid-
HRMS (ESI): m/z calcd. for C23H15N4 [[M + H]+]:347.1303, found
azo[4,5-c]quinoline (3i): Yield: 82 %; yellow solid; mp: 205–207 °C;
1H NMR (500 MHz, CDCl3) δ = 9.15 (d, J = 4.2 Hz, 1H), 8.78–8.71 (m,
1H), 8.34–8.26 (m, 2H), 7.85–7.74 (m, 3H), 7.70 (d, J = 4.2 Hz, 1H),
7.65–7.58 (m, 1H), 7.45–7.36 (m, 2H), 6.57 (d, J = 8.5 Hz, 1H), 5.42
(d, J = 8.6 Hz, 1H), 2.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 158.1,
150.6, 150.0, 148.5, 146.0, 144.1, 142.3, 135.2, 130.6, 130.3, 130.0,
347.1305.
6-(Pyridin-2-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline
(3c):
Yield: 79 %; white solid; mp: 217–219 °C; 1H NMR (400 MHz, CDCl3)
δ = 9.08 (d, J = 3.8 Hz, 1 H), 8.86 –8.78 (m, 2 H), 8.32 (d, J = 9.2 Hz,
1 H), 8.27 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.97 (t, J =
5.9 Hz, 1 H), 7.82–7.77 (m, 2H), 7.59–7.49 (m, 2H), 6.75 (s, 1 H); 13C 129.4, 128.9, 128.7, 127.9, 127.3, 127.2, 125.6, 124.8, 124.1, 122.2,
NMR (125 MHz, CDCl3) δ = 149.7, 149.2, 148.2, 147.9, 147.4, 145.9, 121.1, 114.2, 20.9; ESI-MS: m/z: 417(M+), HRMS (ESI): m/z calcd. for
145.0, 141.7, 138.3, 129.9, 129.6, 129.6, 129.3, 128.9, 128.7, 127.2, C26H17N4S [[M + H]+]:417.1176, found 417.1172.
126.6, 122.6, 121.5, 120.4, 118.0, 112.0; ESI-MS: m/z 297(M+), HRMS
10-Methyl-6-(pyridin-4-yl)benzo[4′,5′]thiazolo[2′,3′:2,3]imid-
(ESI): m/z calcd. for C19H13 N4 [[M + H]+]:297.1138, found 297.1135.
azo[4,5-c]quinoline (3j): Yield:73 %; yellow solid; mp: 198–200 °C;
9-Methyl-6-(pyridin-2-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinol-
ine (3d): Yield: 73 %; white solid; mp: 271–273 °C; 1H NMR
(400 MHz, CDCl3) δ = 8.88–8.75 (m, 2H), 8.30 (dd, J = 12.6, 7.8 Hz,
2H), 8.06 (t, J = 7.0 Hz, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.96–7.61 (m,
2H), 7.81–7.24 (m, 1H), 7.57 (s, 2H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 175.2, 157.0, 148.8, 148.3, 147.7, 146.4, 144.5, 137.9,
133.6, 129.4, 128.8, 127.5, 127.0, 125.5, 124.5, 122.8, 121.5, 120.5,
116.7, 18.5; ESI-MS: m/z 311 (M+), HRMS(ESI): m/z calcd. for C20H15N4
[[M + H]+]:311.1291, found 311.1302.
1H NMR (400 MHz, CDCl3) δ = 9.56 (s, 1H), 8.97 (s, 1H), 8.61 (d, J =
7.8 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.7 Hz, 2H), 7.79–
7.67 (m, 3H), 7.60 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ = 158.1, 150.8, 149.2, 145.1, 143.9, 137.6,
134.7, 131.2, 129.2, 128.2, 126.9, 126.7, 124.6, 124.1, 123.8, 123.0,
122.0, 115.4, 20.9; ESI-MS: m/z: 367(M+), HRMS (ESI): m/z calcd. for
C
22H15N4S [[M + H]+]:367.0939, found 367.1018.
10-Methyl-6-(pyridin-2-yl)benzo[4′,5′]thiazolo[2′,3′:2,3]imid-
azo[4,5-c]quinoline (3k): Yield: 76 %; yellow solid; mp: 278–280 °C;
1H NMR (500 MHz, CDCl3) δ = 8.83–8.76 (m, 2H), 8.38 (d, J = 8.1 Hz,
1H), 8.33 (s, 1H), 8.19 (dd, J = 7.7, 1.6 Hz, 1H), 7.93–7.78 (m, 1H),
7.65 (dd, J = 6.6, 5.0 Hz, 2H), 7.59 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H),
9-Chloro-6-(pyridin-2-yl)pyrido[2′,1′:2,3]imidazo[4,5-c]quin-
oline (3e): Yield: 76 %; white solid; mp: 262–264 °C; 1H NMR
(400 MHz, CDCl3) δ = 9.52 (d, J = 1.1 Hz, 1H), 8.87 (d, J = 4.3 Hz,
1H), 8.78 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.29 (d, J = 5.85 (d, J = 8.5 Hz, 1H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =
8.2 Hz, 1H), 8.05 (td, J = 7.8, 1.5 Hz, 1H), 7.95–7.70 (m, 3H), 7.54 (dt,
158.40, 151.19, 149.53, 145.41, 144.24, 137.94, 135.06, 131.53,
J = 9.6, 4.7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 156.8, 148.6, 129.59, 128.54, 127.22, 127.01, 124.92, 124.40, 124.15, 123.38,
148.2, 148.1, 146.4, 144.6, 137.9, 131.3, 129.6, 129.1, 128.6, 127.3, 122.35, 115.78, 21.24; ESI-MS: m/z: 367(M+), HRMS (ESI): m/z calcd.
125.4, 124.7, 122.7, 121.8, 121.0, 119.3, 117.78; ESI-MS: m/z 331 (M+), for C22H15N4S [[M + H]+]:367.1021, found 367.1012.
HRMS(ESI): m/z calcd. for C19H12ClN4 [[M + H]+]:331.0745, found
331.0749.
6-(Quinolin-4-yl)indolo[1,2-a]quinoxaline (5a): Yield: 73 %; yel-
low solid; mp: 196–198 °C; 1H NMR (400 MHz, CDCl3) δ = 9.13 (d,
6-(Pyridin-2-yl)thiazolo[2′,3′:2,3]imidazo[4,5-c]quinoline (3f):
Yield: 79 %; pale orange solid; mp: 202–204 °C; 1H NMR (400 MHz,
CDCl3) δ = 8.95 (d, J = 4.6 Hz, 1H), 8.82 (d, J = 4.1 Hz, 1H), 8.71–
J = 4.3 Hz, 1 H), 8.62 (d, J = 8.3 Hz, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.27
(d, J = 8.5 Hz, 1 H), 8.12 (dt, J = 10.9, 5.4 Hz, 1 H), 8.00 (d, J = 8.3 Hz,
1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.77 (m, 3 H) 7.62 (t, J = 7.4 Hz, 1 H),
8.60 (m, 2H), 8.27 (d, J = 8.2 Hz, 1H), 8.17–7.93 (m, 1H), 7.84–7.64 7.57–7.42 (m, 3 H), 6.83 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ =
(m, 2H), 7.46 (dt, J = 21.0, 10.5 Hz, 1H), 6.90 (d, J = 4.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ = 161.9, 160.9, 147.3, 142.4, 135.8, 129.9, 129.3, 129.2, 129.0, 127.2, 125.6, 125.2, 124.9, 124.5, 123.0, 121.2,
154.0, 153.2, 149.9, 145.8, 135.9, 134.8, 133.1, 130.9, 130.1, 129.9,
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120.9, 118.9, 114.9, 114.6, 110.9, 102.5; ESI-MS: m/z: 346 (M+), HRMS 9.08 (d, J = 4.3 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.06 (t, J = 10.6 Hz,
(ESI): m/z calcd. for C24H16N3 [[M + H]+]:346.1266, found 346.1262.
2H), 8.07–7.91 (m, 3H), 7.76 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 4.3 Hz,
1H), 7.62 (t, J = 7.6 Hz, 1H), 7.56–7.47 (m, 2H), 6.91–6.83 (m, 1H),
6.58 (d, J = 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 152.0, 149.9,
148.9, 143.5, 135.8, 130.5, 129.8, 129.7, 128.4, 127.3, 127.0, 126.2,
126.1, 125.7, 125.6, 121.0, 115.0, 114.3, 113.8, 108.7; ESI-MS: m/z:
296 (M+), HRMS (ESI): m/z calcd. for C20H13N3 [[M + H]+]:296.1189,
found 296.1183.
9-Bromo-6-(quinolin-4-yl) indolo[1,2-a]quinoxaline (5b): Yield:
86 %; pale yellow solid; mp: 169–171 °C; 1H NMR (400 MHz, CDCl3)
δ = 9.13 (d, J = 3.8 Hz, 1 H), 8.54 (d, J = 7.9 Hz, 1 H), 8.43 (d, J =
9.2 Hz, 1 H), 8.27 (d, J = 8.5 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.97
(t, J = 5.9 Hz, 2 H), 7.76 (dt, J = 12.7, 8.2 Hz, 3 H), 7.67 (dd, J = 9.2,
1.9 Hz, 1 H), 7.59–7.47 (m, 2H), 6.75 (s, 1 H); 13C NMR (125 MHz,
CDCl3) δ = 167.7, 149.8, 148.7, 139.3, 135.9, 132.4, 131.7, 131.1,
130.9, 130.6, 130.1, 129.8, 129.6, 128.8, 127.7, 127.4, 125.5, 125.2,
124.9, 121.0, 116.5, 115.9, 114.8, 114.0, 101.6; ESI-MS: m/z: 424(M+),
HRMS (ESI): m/z calcd. for C24H15 BrN3 [[M + H]+]:424.0458, found
424.0444.
4-(Thiophen-2-yl)pyrrolo[1,2-a]quinoxaline (5i): Yield: 74 %;
crème yellow solid; mp: 105–107 °C; 1H NMR (400 MHz, CDCl3) δ =
8.05–7.94 (m, 3H), 7.86 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 4.9 Hz, 1H),
7.53–7.41 (m, 2H), 7.29 (d, J = 3.4 Hz, 1H), 7.24–7.20 (m, 1H), 6.96–
6.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 147.3, 142.4, 135.8,
129.9, 128.7, 128.2, 127.7, 127.4, 127.0, 125.3, 124.1, 114.7, 114.1,
113.5, 107.9; ESI-MS: m/z: 251(M+), HRMS: m/z calcd. for C15H11N2S
[M + H]+ 251.0564, found 251.0636.
6-(Pyridin-2-yl)indolo[1,2-a]quinoxaline (5c): Yield: 71 %; white
solid; mp: 175–177 °C; 1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J =
4.1 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.45 (d, J = 8.6 Hz, 1 H), 8.37
(d, J = 8.0 Hz, 1 H), 8.06–8.00 (m, 2 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.87
(td, J = 7.8, 1.6 Hz, 1 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.8 Hz,
1 H), 7.39 (dt, J = 11.0, 5.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ =
156.9, 153.5, 149.5, 137.4, 136.4, 134.3, 133.3, 131.4, 130.4, 129.5,
128.8, 125.1, 124.9, 124.6, 124.2, 123.8, 123.2, 115.3, 115.1, 104.8;
ESI-MS: m/z 296 (M+), HRMS (ESI): m/z calcd. for C20H14N3 [[M +
H]+]:296.1189, found 296.1183.
Acknowledgments
All the authors thank to Council of Scientific and Industrial Research
(CSIR) and University Grants Commission (UGC), New Delhi, India for
the financial support. CSIR-IICT manuscript communication number:
IICT/Pubs./2019/272.
Conflict of Interest
9-Bromo-6-(pyridin-2-yl)indolo[1,2-a]quinoxaline (5d): Yield:
78 %; yellow solid; mp: 162–164 °C; 1H NMR (400 MHz, CDCl3) δ =
8.88–8.84 (m, 1H), 8.48–8.43 (m, 2H), 8.37 (d, J = 9.1 Hz, 1H), 8.12
(d, J = 1.7 Hz, 1H), 8.10 (d, J = 1.5 Hz, 1H), 8.06 (s, 1H), 7.94 (td, J =
7.8, 1.8 Hz, 1H), 7.66 (tt, J = 4.1, 2.0 Hz, 1H), 7.61 (dd, J = 9.1, 2.0 Hz,
1H), 7.51–7.45 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 154.51,
147.31, 135.32, 129.79, 129.46, 128.76, 127.67, 125.48, 123.81,
123.08, 122.89, 122.05, 114.28, 113.03, 101.94; ESI-MS: m/z 374 (M+),
HRMS (ESI): m/z calcd. for C20H13 BrN3 [[M + H]+]:374.0306, found
374.0287.
The authors declare no conflict of interest.
Keywords: Aza-aromatics · Metal-free reaction · C–H
functionalization · Molecular iodine · N-fused
polyheterocycles
[1] a) E. Torres, E. Moreno, S. Ancizu, C. Barea, S. Galiano, I. Aldana, A. Monge,
S. Perez-Silanes, Bioorg. Med. Chem. Lett. 2011, 21, 3699–3703; b) A.
Carta, M. Loriga, G. Paglietti, A. Mattana, P. L. Fiori, P. Mollicotti, L. Sechi,
S. Zanetti, Eur. J. Med. Chem. 2004, 39, 195–203; c) S. R. Kandimalla, G.
Sabitha, Adv. Synth. Catal. 2017, 359, 3444–3453; d) A. Al-Mulla, Der
Pharma Chemica. 2017, 9, 141–147; e) W. O. Foye, L. Thomas, Foye,s Prin-
ciples Med. Chem. 2007, 6, 201–212; f) A. V. Gulevich, A. S. Dudnik, N.
Chernyak, V. Gevorgyan, Chem. Rev. 2013, 113, 3084–3213; g) L. D. Quin,
J. Tyrell, Fundamentals of Heterocyclic Chemistry: Importance in Nature
and in the Synthesis of Pharmaceuticals, John Wiley & Sons Inc., New York,
2010.
4-(Pyridin-2-yl)pyrrolo[1,2-a]quinoxaline (5e): Yield:78 %; white
1
solid; mp: 167–169 °C; H NMR (400 MHz, CDCl3) δ = 8.81 (d, J =
4.1 Hz, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.06 (dd, J = 8.0, 1.0 Hz, 1 H),
8.01 (d, J = 1.3 Hz, 1 H), 7.92–7.86 (m, 2 H), 7.76 (dd, J = 3.9, 1.0 Hz,
1 H), 7.57–7.51 (m, 1 H), 7.49–7.44 (m, 1 H), 7.44–7.39 (m, 1H), 6.96
(dd, J = 3.8, 2.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ = 156.5, 151.2,
148.9, 136.6, 135.7, 130.4, 128.0, 127.7, 125.1, 124.7, 124.2, 123.4,
114.4, 114.3, 113.7, 110.6; ESI-MS: m/z: 246(M+), HRMS (ESI): m/z
calcd. for C16H12N3 [[M + H]+]:246.0953, found 246.0958.
[2] a) R. Dua, S. Shrivastava, S. K. Sonwane, S. K. Shrivastava, Adv. Biol. Res.
2011, 5, 120–144; b) A. Gomtsyan, Chem. Heterocycl. Compd. 2012, 48,
7–10.
4-(Quinolin-2-yl)pyrrolo[1,2-a]quinoxaline (5f): Yield: 69 %; Yel-
low solid; mp: 182–184 °C; 1H NMR (400 MHz, CDCl3) δ = 8.65 (d,
J = 8.6 Hz, 1H), 8.37–8.27 (m, 2H), 8.13–8.08 (m, 2H), 8.05 (dd, J =
2.7, 1.3 Hz, 1H), 7.93 (dt, J = 11.4, 8.8 Hz, 2H), 7.82–7.75 (m, 1H),
7.65–7.54 (m, 2H), 7.49 (td, J = 7.7, 1.3 Hz, 1H), 7.07–6.98 (m, 1H);
13C NMR (100 MHz, CDCl3) δ = 156.4, 151.1, 147.7, 136.5, 135.9,
130.7, 130.3, 129.7, 128.4, 127.9, 127.8, 127.4, 125.3, 124.9, 120.8,
114.8, 114.4, 113.9, 111.4; ESI-MS: m/z: 296(M+), HRMS (ESI): m/z
calcd. for C20H14N3 [[M + H]+]:296.1188, found 296.1182.
[3] a) J. Yang, Q. Dang, J. Liu, Z. Wei, J. Wu, X. Bai, J. Comb. Chem. 2005, 7,
474–482; b) J. Liu, Q. Dang, Z. Wei, H. Zhang, X. Bai, J. Comb. Chem. 2005,
7, 627–636; c) J. Yang, X. Che, Q. Dang, Z. Wei, X. Bai, Org. Lett. 2005, 7,
1541–1543; d) R. Fu, X. Xu, Q. Dang, X. Bai, J. Org. Chem. 2005, 70, 10810–
10816; e) X. Che, L. Zheng, Q. Dang, X. Bai, Tetrahedron 2006, 62, 2563–
2568; f) L. Zheng, J. Xiang, Q. Dang, S. Guo, X. Bai, J. Comb. Chem. 2005,
7, 813–815; g) L. Zheng, J. Xiang, Q. Dang, S. Guo, X. Bai, J. Comb. Chem.
2006, 8, 381–387; h) J. Liu, Q. Dang, Z. Wei, F. Shi, X. Bai, J. Comb. Chem.
2006, 8, 410–416; i) R. Fu, X. Xu, Q. Dang, F. Chen, X. Bai, Org. Lett. 2007,
9, 571–574.
4-(6-Fluoroquinolin-2-yl) pyrrolo[1,2-a]quinoxaline (5g): Yield:
79 %; white solid; mp: 198–199 °C; 1H NMR (400 MHz, CDCl3) δ =
8.68 (d, J = 8.6 Hz, 1H), 8.29 (t, J = 7.8 Hz, 2H), 8.14–8.07 (m, 2H),
8.05 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.59–7.45 (m, 4H), 7.04–7.00 (m,
1H); 13C NMR (100 MHz, CDCl3) δ = 162.2, 159.7, 155.6, 150.5, 144.6,
135.7, 135.6, 132.6, 132.5, 130.5, 128.3, 125.1, 124.6, 121.3, 119.9,
119.7, 114.6, 114.3, 113.7, 111.1; ESI-MS: m/z 314(M+), HRMS (ESI ):
m/z calcd. for C20H12FN3 [[M + H]+]:314.1093, found 314.1088.
[4] a) E. Brown, Ring Nitrogen and Key Biomolecules, Kluwer Academic Press,
1998; b) A. F. Khlebnikov, M. S. Novikov, M. V. Golovkina, P. P. Petrovskii,
A. S. Konev, D. S. Yufit, H. Stoeckli-Evans, Org. Biomol. Chem. 2011, 9,
3886–3889; c) J. F. Gonzalez, I. Ortin, E. de la Cuesta, J. C. Menendez,
Chem. Soc. Rev. 2012, 41, 6902–6915; d) E. Vitaku, D. T. Smith, J. T. Njar-
darson, J. Med. Chem. 2014, 57, 10257–10274; e) L. Zhang, X.-M. Peng,
G. L. V. Damu, R.-X. Geng, C.-H. Zhou, Med. Res. Rev. 2014, 34, 340–437;
f) S. R. Kandimalla, G. Sabitha, RSC Adv. 2016, 6, 67086–67095.
[5] a) S. Maiti, P. Mal, Org. Lett. 2017, 19, 2454–2457; b) X. Li, L. Yang,
X. Zhang, D. Zhang-Negrerie, Y. Du, K. Zhao, J. Org. Chem. 2014, 79, 955–
962; c) S. R. Kandimalla, S. P. Parvathaneni, G. Sabitha, B. V. S. Reddy, Eur.
4-(Quinolin-4-yl) pyrrolo [1,2-a]quinoxaline (5h): Yield: 89 %;
pale yellow solid; mp: 196–198 °C; 1H NMR (400 MHz, CDCl3) δ =
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Full Paper
J. Org. Chem. 2019, 2019, 1687–1714; d) G. Song, F. Wang, X. Li, Chem.
Soc. Rev. 2012, 41, 3651–3678; e) J. Bariwal, E. Van derEycken, Chem. Soc.
Rev. 2013, 42, 9283–9303; f) L. Li, T.-D. Tan, Y.-Q. Zhang, X. Liu, L.-W. Ye,
Org. Biomol. Chem. 2017, 15, 8483–8492.
David, S. Pellet-Rostaing, M. Lemaire, Tetrahedron 2007, 63, 8999–9006;
d) H. Fang, X. Wu, L. Nie, X. Dai, J. Chen, W. Cao, G. Zhao, Org. Lett. 2010,
12, 5366–5369; e) B. Kundu, P. K. Agarwal, S. K. Sharma, D. Sawant, A. K.
Mandadapu, M. Saifuddin, S. Gupta, Curr. Org. Synth. 2012, 9, 357–376.
[6] a) H. Doi, A. Mawatari, M. Kanazawa, S. Nozaki, Y. Nomura, T. Kitayoshi,
K. Akimoto, M. Suzuki, S. Ninomiya, Y. Watanabe, J. Org. Chem. 2015, 80,
6250–6258; b) L. Ma, X. Wang, W. Yu, B. Han, Chem. Commun. 2011, 47,
11333–11335; c) W.-B. Wu, J.-M. Huang, Org. Lett. 2012, 14, 5832–5835;
d) R. Samanta, J. Lategahn, P. A. Antonchick, Chem. Commun. 2012, 48,
3194–3196; e) H. Batchu, S. Bhattacharyya, S. Batra, Org. Lett. 2012, 14,
6330–6333; f) H. Huang, X. Ji, W. Wu, H. Jiang, Adv. Synth. Catal. 2013,
355, 170–180; g) W.-C. Gao, R.-L. Wang, C. Zhang, Org. Biomol. Chem.
2013, 11, 7123–7128.
[7] a) A. N. French, S. Bissmire, T. Wirth, Chem. Soc. Rev. 2004, 33, 354–362;
b) H. Veisi, Curr. Org. Chem. 2011, 15, 2438–2468; c) T. Aggarwal, S. Ku-
mar, A. K. Verma, Org. Biomol. Chem. 2016, 14, 7639–7653; d) S. Sunkari,
S. P. Shaik, N. H. Krishna, A. V. S. Rao, B. G. Kodiripaka, A. Alarifi, A. Kamal,
Asian J. Org. Chem. 2017, 6, 1830–1837; e) P. N. Reddy, B. V. S. Reddy, P.
Padmaja, Curr. Org. Synth. 2018, 15, 815–838.
[15]
[16]
[17]
A. Kale, C. Bingi, N. C. Ragi, P. Sripadi, P. R. Tadikamalla, K. Atmakur, Syn-
thesis 2017, 49, 1603–1612.
G. S. Mani, A. V. S. Rao, Y. Tangella, S. Sunkari, F. Sultana, H. K. Namballa,
S. Nagul, A. Kamal, New J. Chem. 2018, 42, 15820–15829.
a) J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan, A. Allen, M. A. Olsen, J.
Org. Chem. 2000, 65, 1516–1524; b) A. K. Pandey, R. Sharma, A. Singh, S.
Shukla, K. Srivastava, S. K. Puri, B. Kumar, P. M. S. Chauhan, RSC Adv.
2014, 4, 26757–26770.
[18]
[19]
a) G. Trapani, M. Franco, A. Latrofa, A. Reho, G. Liso, Eur. J. Pharm. Sci.
2001, 14, 209–216; b) N. Aminoa, Y. Ideyamaa, M. Yamanoa, S. Kuromit-
sub, K. Tajindab, K. Samizuc, A. Matsuhisad, M. Kudoha, M. Shibasaki,
Cancer Lett. 2006, 238, 119–127; c) Q. Chao, K. G. Sprankle, K. M. Grotz-
feld, A. G. La T. A. Carter, A. M. Velasco, R. N. Gunawardane, M. D. Cramer,
M. F. Gardner, J. James, P. P. Zarrinkar, H. K. Patel, S. S. Bhagwat, J. Med.
Chem. 2009, 52, 7808–7816.
[8] a) Y. Kim, S. de Castro, Z.-G. Gao, A. P. Ijerman, K. A. Jacobson, J. Med.
Chem. 2009, 52, 2098–2108; b) N. M. Shukla, C. A. Mutz, R. Ukani, H. J.
Warshakoon, D. S. Moore, S. A. David, Bioorg. Med. Chem. Lett. 2010, 20,
6384–6386.
[9] J. M. Chezal, E. Moreau, O. Chavignon, C. Lartigue, Y. Blacheb, J. C. Teu-
lade, Tetrahedron 2003, 59, 5869–5878.
a) A. A. Mir, V. V. Mulwad, J. Chem. Res. 2009, 2009, 290–302; b) N. T.
Patil, R. D. Kavthe, V. S. Raut, V. V. N. Reddy, J. Org. Chem. 2009, 74, 6315–
6318; c) P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu, Eur. J. Org. Chem.
2009, 2, 292–303; d) N. T. Patil, R. D. Kavthe, V. S. Shinde, B. Sridhar, J.
Org. Chem. 2010, 75, 3371–3380.
[10] a) B. Banerji, S. Chatterjee, K. Chandrasekhar, S. Ghosh, K. Mukherjee, C.
Mandal, J. Org. Chem. 2018, 83, 13011–13018; b) T. H. Al-Tel, R. A. Al-
Qawasmeh, R. Zaarour, Eur. J. Med. Chem. 2011, 46, 1874–1881.
[11] a) H. Xu, L.-L. Fan, Eur. J. Med. Chem. 2011, 46, 1919–1925; b) P. T. Lin,
D. B. Salunke, L. H. Chen, C. M. Sun, Org. Biomol. Chem. 2011, 9, 2925–
2937.
[20]
[21]
a) J. Yang, K. I. Amiri, J. R. Burke, J. A. Schmid, A. Richmond, Clin. Cancer
Res. 2006, 12, 950–960; b) Y. Thigulla, M. Akula, P. Trivedi, B. Ghosh, M.
Jhac, A. Bhattacharya, Org. Biomol. Chem. 2016, 14, 876–883.
a) G. S. Mani, S. P. Shaik, Y. Tangella, S. Bale, C. Godugu, Org. Biomol.
Chem. 2017, 15, 6780–6791; b) H. Z. Li, W. J. Xue, A. X. Wu, Tetrahedron
2014, 70, 4645–4651; c) N. Mupparapu, R. A. Vishwakarma, Q. N. Ahmed,
Tetrahedron 2015, 71, 3413–3421; d) J. Lai, L. Chang, G. Yuan, Org. Lett.
2016, 18, 3194–3197; e) Y. P. Zhu, M. Lian, F. C. Jia, M. C. Liu, J. J. Yuan,
Q. H. Gao, A. X. Wu, Chem. Commun. 2012, 48, 9086–9088.
[12] J. Guillon, R. C. Reynolds, J.-M. Leger, M. A. Guie, S. Massip, P. Dallemagne,
C. Jarry, J. Enzyme Inhib. Med. Chem. 2004, 19, 489–495.
[13] a) S. C. Rasmussen, ChemTexts 2016, 2, 16; b) E. Awuah, A. Capretta, J.
Org. Chem. 2010, 75, 5627–5634; c) P.-Q. Huang, Y.-H. Huang, S.-R. Wang,
Org. Chem. Front. 2017, 4, 431–444.
[14] a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036; b)
J. Royer, M. Bonin, L. Micouin, Chem. Rev. 2004, 104, 2311–2352; c) E.
Received: August 5, 2019
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
C–H Functionalization
B. Sridevi, S. Reddy Kandimalla,
B. V. Subba Reddy* ............................ 1–8
Oxidative sp3 C–H Functionalization
of Methyl Substituted Aza-Aromat-
ics: An Easy Access to N-Fused Poly-
heterocycles
A novel one-pot metal-free strategy has oxidative cyclization of methyl-substi-
been devised for the cascade synthesis tuted aza-aromatics with ortho-amino-
of pyrido-/thiazolo-/benzthiazolo-imid- aryl heterocycles through sp3 C–H func-
azo [4,5-c]quinolines and indolo-/ tionalization using I2/DMSO under mild
pyrrolo-[1,2-a]quinoxalines through an conditions.
DOI: 10.1002/ejoc.201901148
Eur. J. Org. Chem. 0000, 0–0
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8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim