Metal-free C-N bond formations: One-pot synthesis of pyrido[2′,1′:2,3]imidazo[4,5-: C] cinnolines, benzo[4′,5']thiazolo- and thiazolo[2′,3′:2,3]imidazo[4,5- c] cinnolines

Article abstract of DOI:10.1039/c6ra15418b

An efficient one-pot synthesis of novel pyrido[2′,1′:2,3]imidazo[4,5-c]cinnoline derivatives has been achieved with moderate to good yields, with two C-N bond formations through C-H functionalization of 2-arylimidazo[1,2-a]pyridines. The reaction proceeds via C-3 regioselective hydrazination with diisopropyl azodicarboxylate followed by oxidative N-arylation mediated by phenyliodine(iii) diacetate (PIDA) in trifluoroacetic acid by means of C-H functionalization to produce pyrido[2′,1′:2,3]imidazo[4,5-c]cinnolines. Other imidazoheterocycles such as 2-arylbenzo[d]imidazo[2,1-b]thiazoles, and 6-arylimidazo[2,1-b]thiazoles underwent similar transformations giving the corresponding cinnolines under transition metal-free and mild conditions.

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Metal-free C-N bond formations: One-pot Synthesis of pyrido[2',1':2,3]imidazo[4,5-
c]cinnolines, benzo[4',5']thiazolo- and thiazolo[2',3':2,3]imidazo[4,5-c]cinnolines
Satheeshkumar Reddy Kandimalla and Gowravaram Sabitha*
Received 00th month 20xx,
Accepted 00th month 20xx
An efficient one-pot synthesis of novel pyrido[2',1':2,3]imidazo[4,5-c]cinnoline derivatives has been
achieved in moderate to good yields with two C-N bond formations through C-H functionalization of 2-
arylimidazo[1,2-a]pyridines. The reaction proceeds via C-3 regioselective hydrazination with diisopropyl
azodicarboxylate followed by an oxidative N-arylation mediated by phenyliodine(III) diacetate (PIDA) in
trifluoroacetic acid by means of C-H functionalization to produce pyrido[2',1':2,3]imidazo[4,5-c]cinnolines.
Other imidazoheterocycles such as 2-arylbenzo[d] imidazo[2,1-b]thiazoles, and 6-arylimidazo[2,1-b]thiazoles
underwent similar transformation giving the corresponding cinnolines under transition metal-free and mild
conditions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Therefore, attention has been paid towards the synthesis of
cinnolines by several approaches9 mainly by copper-catalyzed
Cinnolines and their derivatives are known to exhibit potent
biological and pharmaceutical activities,1 such as anticancer, anti-
inflammatory, antimalarial, antibacterial, antimicrobial, antitumor
and antifungal properties (Figure 1). Studies have demonstrated
that dibenzo[c,h]cinnolines and isoquino[4,3-c]cinnolines can
exhibit potent topoisomerase-I targeting activity with pronounced
cytotoxic activity.2,3 The dihydro derivatives of dibenzo[c,h]
cinnolines also showed in vitro cytotoxic activity against murine
(L1210) and human (K562) leukemia cell lines and some of them
were also tested in vivo against murine P388 leukemia and showed
activity comparable with that of mitoxantrone.4 Indolo[3,2-
c]cinnoline derivatives inhibited the proliferation of leukemia,
lymphoma and solid-tumor-derived cell lines from micromolar to
nanomolar concentrations.5 Pyrazolo[4,3-c]cinnoline derivatives
exhibit potential anti-inflammatory and antibacterial activities.6
Recently, 11H-pyrido-[3,2:4,5]pyrrolo[3,2-c]cinnoline derivatives
have been identified as anticancer agents.7 Furthermore,
compounds containing a cinnoline structural motif demonstrate a
series of interesting physical characteristics, such as luminescent
and nonlinear optical properties.8
dehydrogenative cyclization,10 rhodium-catalyzed annulation of
cinnolinium salts with internal alkynes and azo compounds,11 Pd-
catalyzed annulation of 2-iodophenyltriazenes with an internal
alkyne12 and a copper-mediated tandem C−N bond formaꢀon
reaction.13 Reddy and co-workers14 recently reported a directed
C−H acꢀvaꢀon strategy for the synthesis of benzo[c]cinnolines
through a sequential C−C and C−N bond formaꢀon. A transiꢀon-
metal-free multicomponent coupling cyclization reaction,15 a Rh-
catalyzed redox-neutral annulation reaction between azo and diazo
compounds16 were reported to access cinnolines. To the best of our
knowledge, no reports have been demonstrated to construct
pyrido-imidazo-cinnoline skeleton. However, the imidazo[1,2-
a]pyridine scaffold serves as a core structure in pharmaceutically
active compounds and a number of commercial drugs.17-19 The
construction of the C–N bond is of significant importance as it
opens avenues for the introduction of nitrogen in organic
molecules. Despite significant advancements in this field, the
construction of the C–N bond is still a major challenge for organic
chemists, due to the involvement of harsh reaction conditions or
the use of expensive catalysts in many cases. Thus, it is a challenge
to develop alternative, milder and cheaper methodologies for the
construction of C–N bonds. Inspired by a recent report on a metal-
free hydrazination of imidazo[1,2-a]pyridines,20 herein we disclose
the synthesis of novel pyrido[2',1':2,3]imidazo[4,5-c]cinnoline
derivatives 3 through two C-N bond formation reactions between 2-
Figure 1. Some biologically important cinnolines
H
N
N
N
N
N
cinnoline
HN
N
anti-inflammatory activity
arylimidazo[1,2-a]pyridines
1 and diisopropyl azodicarboxylate
O
N
tBu
OMe
OMe
(DIAD) occuring C-3 regioselective hydrazination and annulation
reaction by PIDA in trifluoro acetic acid.
N
N
N
N
N
anticancer agent
anti-tumor activity
Results and Discussion
*Natural Products Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India.
Our initial investigations focused on the two-step synthesis of
E-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in; Fax: +91-40-
27160512
pyrido[2',1':2,3]imidazo[4,5-c]cinnoline
derivatives
3
via
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of
all compounds.
DOI: 10.1039/x0xx00000x
intermediate compounds, diisopropyl 1-(2-arylimidazo[1,2-a]
pyridin-3-yl)hydrazine-1,2-dicarboxylates 2 (Scheme 1, Route A).
The first step involves C-3 regioselective hydrazination of 2-
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arylimidazo[1,2-a]pyridines (1) and the second step is the oxidative 2.2 eq of phenyliodine(III) diacetate in TFA (entry 14) at 0 oC-r.t. for
N-arylation to produce cinnoline compounds 3.
2 h led to the formation of pyrido[2',1':2,3]imidazo[4,5-c]cinnoline
(3a) in 92% yield.
Scheme 1. Present work: One-pot formation of cinnolines 3
Intially, we attempted the annulation reaction of 2-
phenylimidazo[1,2-a]pyridine (2a) in the presence of K2S2O8 (2.0 eq)
o
as an oxidant in AcOH and also in TFA as solvents at 0 C-r.t. (Table
1, entry 1 & 2), These conditions met with complete failure. Next,
the reaction tested with m-CPBA (1.5 eq) as an oxidant, PhI (0.3 eq)
as an additive in AcOH (entry 3). The reaction failed to give the
product. Then, the reaction performed with m-CPBA (2.0 eq), PhI
(0.3 eq), in TFA (2.0 mL) as a solvent at 0 oC-r.t., 1 h. Surprisingly,
pyrido[2',1':2,3] imidazo[4,5-c]cinnoline (3a) was formed in 40%
yield (Table 1, entry 4) along with the azo carboxylate intermediate
(4a) in 22% yield. The intermediate 4a was isolated and confirmed
by NMR and HRMS data. Further, 4a was converted into 3a using
1.2 eq of PIDA in 90% yield. Next, under similar conditions, we
increased the reaction time to 2 h at 0 oC-r.t. (Table 1, entry 5) and
found low progress in yield (52%). Next, the reaction tested with
oxone (2.0 eq) as an oxidant in TFA as a solvent without additive
(Table 1, entry 6) at 0 oC-r.t., the reaction was failed to give the
desired compound. Further, we performed the reaction with oxone
(2.0 eq), with additive PhI (0.3 eq), in TFA (2.0 mL) as a solvent at 0
oC-r.t., 0.5 h. This reaction gave the desired cinnoline (3a) in 52%
yield along with intermediate (4a) in 30% (Table 1, entry 7). Now,
we increased the equivalants of oxone with reaction time (Table 1,
entry 8, 9 & 10), the desired product yield was increased and side
product was decreased. This interesting results motivated us to
optimize the reaction condition to improve the yield of annulated
product 3a. When we switched the oxidant from oxone to PIDA
(phenyliodine (III) diacetate) (2.0 eq) without additive (PhI), the
yield of the cinnoline product 3a was increased to 77% and the
intermediate 4a was found to be 15% (Table 1, entry 12). We
performed the same reaction with increasing PIDA equivalants and
reaction time (Table 1, entry 13 and 14) delivered the desired
cinnoline in 92% yield. However, no side product was observed.
Accordingly, the hydrazination of 2-phenylimidazo[1,2-a] pyridine
(1a) with 1.5 eq of DIAD using acetonitrile as a solvent furnished the
intermediate, diisopropyl 1-(2-phenylimidazo[1,2-a]pyridin-3-yl)
hydrazine-1,2-dicarboxylate (2a) in 93% yield. The reaction was
o
found to be complete at 80 C in sealed tube within 2 h. Next, our
focus turned to the crucial oxidative N-arylation of 2a into its
cinnoline counterpart. For the second step, a wide range of
oxidants in the combination of additives and solvents were
screened at room temperature as shown in Table 1. We found that
Table 1. Optimization of the N-arylation reaction conditions of 2aa
Enrty oxidant (eq) additive solvent time (h) temp yield (%) 3b yield (%) 4b
1
2
3
K2S2O8 (2.0)
K2S2O8 (2.0)
m-CPBA (1.5)
-
AcOH
TFA
24
24
24
0 oC-rt
0 oC-rt
0 oC-rt
nd
nd
nd
nd
nd
nd
-
PhI
AcOH
In order to study the scope of this protocol, various 2-
arylylimidazo[1,2-a]pyridines 1b-1c with the substituents on
imidazo[1,2-a]pyridine as well as on C-2 phenyl ring were reacted
under similar conditions in a two step fashion and the results are
provided in Table 2.
4
m-CPBA (2.0)
m-CPBA (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.2)
PIDA (1.8)
PhI
PhI
-
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
1
2
0 oC-rt
0 oC-rt
0 oC-rt
0 oC-rt
0 oC-rt
40
52
nd
52
63
73
78
52
77
86
92
22
trace
nd
5
6
24
0.5
1
Table 2. Preparation of hydrazinated (2) and cinnoline derivatives
(3) in a two-step synthesis
7
PhI
PhI
PhI
PhI
-
30
N
R2
N
N
R2
R2
R1
DIAD
PIDA
R1
N
R1
N
N
TFA, 0 oC-r.t., 2 h
8
22
CH3CN, 80oC, 2 h,
Sealedtube
N
NH
CO2iPr
N
N
iPrO2C
H
1
H
2
3
9
2
0
oC-rt
15
N
N
N
N
Br
10
11
12
13
14
2
0 oC-rt
0 oC-rt
0 oC-rt
0 oC-rt
0 oC-rt
trace
20
Br
N
N
N
N
N
NH
NH
CO2iPr
NH
CO2iPr
2c,89%
iPrO2C
iPrO2C
iPrO2C
CO2iPr
0.5
1
2a, 93%
2b,
%
92
PIDA (2.0)
-
15
N
N
N
Br
Br
N
N
N
N
N
N
N
N N
PIDA (2.0)
-
2
trace
nd
3c, 86%
3a, 92%
3b, 90%
PIDA (2.2)
-
2
Reaction conditions: Step 1: 2-phenylimidazo[1,2-a]pyridine 1a (0.495
mmol, 1.0 eq), DIAD (0.742 mmol, 1.5 eq), MeCN (4.0 mL), 80 oC, 2 h; Step 2:
hydrazino compound 2a (0.379 mmol, 1.0 eq), PIDA (0.833 mmol, 2.2 eq),
TFA (2.0 mL), 0 oC-r.t., 2 h. Isolated yields after column chromatography.
aReaction conditions: 2a (0.477 mmol, 1.0 eq), PIDA (1.05 mmol, 2.2 eq), TFA
(2.0 mL),
oC-r.t., h. bYields refer to pure products after column
chromatography; nd = not detected, PIDA = phenyliodine(III) diacetate, TFA
= trifluoroacetic acid.
0
2
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To perform the formation of pyrido[2',1':2,3]imidazo[4,5-c] confirmed by NMR and HRMS analysis (Figure 2). In the literature,
cinnoline derivatives 3 as a "one-pot" process, without isolation of similar observations were reported on the use of iodosylbenzene
the intermediate diisopropyl 1-(2-phenylimidazo[1,2-a]pyridin-3- sulfate (PhIO3.SO3).21
yl)hydrazine-1,2-dicarboxylate derivatives 2, the crude reaction
mixture from the hydarazination of 2-phenylimidazo[1,2-a]pyridine
1a with DIAD was simply evaporated to remove MeCN under
vacuum, and subjected directly to the N-arylation reaction (Scheme
1, Route B). We found that 1.1 eq of DIAD is sufficient in one-pot
synthesis to decrease the unreacted DIAD present in the reaction
medium. As such, we prepared pyrido[2',1':2,3]imidazo[4,5-c]
cinnoline (3a) in 75% yield by conducting hydrazination reaction in a
sealed tube containing a solution of 1.0 eq of 2-phenylimidazo[1,2-
a]pyridine 1a and 1.1 eq of DIAD in MeCN at 80 oC for 2 h, after
completion, the reaction mixture was concentrated under vacuum,
followed by addition of 2.0 mL of TFA and 2.2 eq of PIDA and
subjected to oxidative N-arylation at 0 oC-r.t. for 2 h. The product
was obtained by two successive C-N bond formation reactions.
After optimizing the reaction conditions, we explored the substrate
scope as shown in Table 3. The structure of products was
established by NMR and HRMS analysis.
Scheme. 2 Oxidation of sulfide to sulfoxide
Figure 2. NMR values of compounds
Table 3. One-pot formation of Cinnolines 3
Furthermore, the optimal reaction conditions for cinnoline
preparation were extended to other imidazoheterocyclic cinnolines
to ascertain the scope of the methodology (Table 4). Under the
present reaction conditions, imidazoheterocyclic cinnolines (6a-e)
were obtained in good yields directly in a one-pot procedure from
2-arylbenzo[d]imidazo[2,1-b]thiazole derivatives (5a-c) and 6-
arylimidazo[2,1-b]thiazoles (5d & 5e).
Table 4. Substrate scope one-pot formation of imidazo
heterocyclic cinnolines
Reaction conditions: 2-arylimidazo[1,2-a]pyridine 1 (0.516 mmol, 1.0 eq),
DIAD (0.567 mmol, 1.1 eq), CH3CN (4.0 mL), 80 oC, 2 h, then, PIDA (1.134
mmol, 2.2 eq), TFA (2.0 mL), 0 oC-r.t., 1-2 h. Isolated yields after column
chromatography.
Reaction conditions: 1) 5a (0.255 mmol, 1.0 eq), DIAD (0.280 mmol, 1.1 eq),
o
MeCN (3.0 mL), 80 C, 2-3 h. then, PIDA (0.560 mmol, 2.2 eq), TFA (2.0 mL),
0 oC-r.t., 1-2 h. Yields refer to pure compounds.
Interestingly, the imidazo[1,2-a]pyridines (1t and 1u) containing
electron-donating group such as -SMe on the 2-phenyl ring oxidized
to sulfoxide under similar conditions (Scheme 2). First, we observed
the formation of intermediate compounds (4t and 4u). [4t, HRMS
calcd for C18H19N4O3S 371.1172 (M + H)+, found 371.1176]. Then,
these were converted into cyclised products (3t and 3u) using 1.2
eq of PIDA in TFA. When, the amount of PIDA increased to 4.0 eq,
the compounds 3t and 3u were directly obtained from 1t and 1u
with less yields. But, there was no formation of over oxidized
products (sulfones) observed. The structure of the products was
Based on the controlled experimental results and previous
literature20,22, the plausible reaction mechanism is proposed in
Scheme 3. Similar to the Mitsunobu reaction, DIAD can attack at C-3
position of 1a through a pseudo-Michael reaction to produce
intermediate A. Then, prototropy and restoring conjugation
provides the compound 2a. Now, the deprotection of isopropyloxy
carbonyl group occurs in compound 2a in TFA to give intermediate
B (which could not be isolated) followed by oxidation on nitrogen
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by PIDA to form hypervalent iodine intermediate C with the These (4c, 4f & 4h) were further converted into corresponding
removal of acetic acid. The intermediate C is further converted into cinnolines (3c, 3f & 3h) with 1.2 equiv of PIDA in TFA at oC-r.t.,
an azo compound 4a via removal of iodobenzene and acetic acid within 35 min upto 90% yield.
[compound 4a was established by NMR and HRMS analysis, HRMS
Notably, to the best of our knowledge, this is the first
approach to synthesize pyrido-imidazo-cinnolines and other
imidazo heterocyclic cinnolines from 2-arylimidazo[1,2-a]pyridines
and imidazoheterocyclic compounds respectively in one pot,
proving the practical application of the methodology.
calcd for C17H17N4O2 309.1346 (M + H)+, found 309.1364].
Scheme 3. Plausible reaction mechanism
Conclusion
we have reported a general two-step procedure for the
preparation of novel pyrido-imidazo-cinnolines via hydrazino
compounds as intermediates. Additionally, we also demonstrated
that the two-step route can be performed using a one-pot
synthesis. The scope of the methodology has been extended to 6-
arylimidazo[2,1-b]thiazoles
and
2-arylbenzo[d]imidazo[2,1-b]
thiazole derivatives. Under the present conditions, sulfide was
found to be oxidized to sulfoxide. The advantages of the present
method include the use of easily available starting materials, mild
reaction conditions, moderate to good yields, and the formation of
two C-N bonds in a metal-free one-pot process. Other heterocyclic
cinnolines are under preparation and the results will be reported in
due course.
Experimental section
1
The isopropyl carbamate group in 4a again occurs deprotection and
forms intermediate D followed by oxidation on nitrogen by using
another mole of PIDA furnishing iodinated complex E, in which the
oxidative C-N bond formation via electrophilic annulation step takes
place between the ortho phenyl carbon and the nitrogen, activated
by the electrophilic iodine species generates intermediate F with
the loss of iodobenzene and acetic acid. Which, upon
deprotonation forms cinnoline product 3a.
General Information. H NMR spectra were measured on 400 MHz
and 500 MHz spectrometers. Chemical shifts were recorded as
follows: chemical shift in ppm from internal tetramethylsilane on
the δ scale, multiplicity (s = singlet; d = doublet; t = triplet; q =
quartet; m = multiplet; dd = doublet of doublets; ddd = doublet of
doublet of doublets; br
= broad), coupling constant (Hz),
integration, and assignment. 13C NMR spectra were measured on
100 MHz and 125 MHz spectrometers. Chemical shifts were
recorded in ppm from the solvent resonance employed as the
internal standard (deuterochloroform at 77.0 ppm). High-resolution
mass spectra (HRMS) were measured (ESI) on orbitrap mass
spectrometers. Characteristic peaks in the infrared (IR) spectra
were recorded in wave numbers, cm−1. Melting points were
determined on an Electro thermal melting point apparatus and are
uncorrected. Thin-layer chromatography (TLC) was performed using
0.25 mm silica gel plates (60F-254). The products were purified by
short column chromatography on silica gel 60-120 or 100− 200
mesh.
However, the proposed reaction pathway as shown in Scheme 3
was partly confirmed by the formation of intermediate 4a. With our
interest, some more intermediates were prepared with controlled
experiments using 1.0 eq of PIDA for supporting the proposed
mechanism (Scheme 4). The compound 1 (1.0 eq) was reacted with
DIAD (1.1 eq) in MeCN (4 mL) at 80 oC for 2 h in a sealed tube. Then,
the solvent was evaporated and PIDA (1.0 eq), TFA (2.0 mL) were
added at 0 oC-r.t. After 5-10 minutes, we observed the formation of
4 as major compound, and the corresponding cinnoline 3 as a minor
product. The compounds 3 and 4 were easily separated by column
chromatography.
General procedure for the preparation of hydrazino compounds
2a-2c. In a 10 mL tube 2-phenylimidazo[1,2-a]pyridine 1a (96 mg,
0.495 mmol) and diisopropyl azodicarboxylate (150 mg, 0.742
mmol) were taken in 4 mL of MeCN. Then, the tube was sealed with
a pressure cap and heated to 80 °C for 2-3 h. The reaction was
monitored by TLC. After completion of the reaction, cooled to room
temperature and removed the solvent under reduced pressure. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 4:1) to yield 2a as an orange solid
(182 mg, 93%).
Scheme 4. Controlled Experiments
diisopropyl 1-(2-phenylimidazo[1,2-a]pyridin-3-yl)hydrazine-1,2-
dicarboxylate (2a): Rf = 0.4 (petroleum ether/ethyl acetate, 2:1);
orange solid (182 mg, 93%), mp 167−169 °C; IR (KBr) 2982, 2936,
Reaction conditions: 2-arylimidazo[1,2-a]pyridines 1 (0.516 mmol, 1.0 eq),
DIAD (0.567 mmol, 1.1 eq), CH3CN (4 mL), 80 oC, 2 h. then, PIDA (0.516
mmol, 1.0 eq), TFA (2.0 mL), 0 oC-r.t., 5-10 min. Isolated yields after column
chromatography.
1
1713, 1501, 1466, 1367, 1249, 1181, 1103, 760 cm−1; H NMR (500
MHz, CDCl3) δ 1.35-1.23 (m, 12H), 5.09-4.92 (m, 2H), 6.92 (t, J = 6.7
Hz, 1H), 7.34-7.28 (m, 1H), 7.38 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.4 Hz,
2H), 7.67 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 8.71 (brs, 1H);
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13C NMR (100 MHz, CDCl3) δ 21.6, 21.7, 21.8, 21.9, 70.6, 72.2, 112.5, 123.3, 123.7, 125.3, 132.4, 133.8, 134.1, 142.1, 143.2, 149.1, 149.7;
117.2, 124.6, 125.9, 126.9, 127.1, 128.4, 128.9(2C), 132.7, 132.8, HRMS(ESI) calcd for C13H8N4Br 298.9926 [M + H]+, found 298.9929.
139.3, 142.9, 154.8, 156.4; HRMS(ESI) calcd for C21H25N4O4 3-bromo-10-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3c): Rf
397.1870 [M + H]+, found 397.1867.
Diisopropyl
= 0.3 (petroleum ether/ ethyl acetate, 3:7); pale yellow solid (64
1-(2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl) mg, 72%), mp 283−285 °C; IR (KBr) 3040, 2923, 1686, 1442, 1210,
hydrazine-1,2-dicarboxylate (2b): Rf = 0.4 (petroleum ether/ethyl 1140, 804, 725 cm−1; H NMR (500 MHz, CDCl3) δ 2.63 (s, 3H), 7.10
acetate, 2:1); yellow solid (201 mg, 92%), mp 170−172 °C; IR (KBr) (dd, J1 = 6.9 Hz, J2 = 1.4 Hz, 1H), 7.68 (s, 1H), 7.96 (dd, J1 = 8.8 Hz, J2 =
2982, 2929, 1738, 1511, 1464, 1378, 1255, 1103, 1041, 759 cm−1; 1H 2.0Hz, 1H), 8.57 (d, J = 8.7 Hz, 1H), 8.88 (d, J = 1.7 Hz, 1H), 9.18 (d, J
NMR (500 MHz, CDCl3) δ 1.35-1.22 (m, 12H), 5.10-4.91 (m, 2H), 6.90 = 6.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 22.4, 116.2, 116.3, 118.7,
(d, J = 6.7 Hz, 1H), 7.32-7.27 (m, 1H), 7.64-7.55 (m, 3H), 7.68 (d, J = 123.0, 123.7, 124.3, 132.2, 133.6, 134.5, 142.3, 145.9, 149.1, 150.3;
8.5 Hz, 2H), 8.68 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 21.7, 21.8, HRMS(ESI) calcd for C14H10N4Br 313.0083 [M + H]+, found 313.0084.
21.9(2C), 70.8, 72.4, 112.6, 112.7, 117.3, 122.6, 124.6, 126.3, 126.3, 3-bromo-11-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3d): Rf
128.4, 132.1(2C), 138.2, 142.9, 156.0, 156.3; HRMS(ESI) calcd for = 0.3 (petroleum ether/ ethyl acetate, 3:7); brown color solid (70
1
C21H24BrN4O4 475.0975 [M + H]+, found 475.0992.
mg, 56%), mp 292−294 °C; IR (KBr) 3045, 2923, 1636, 1432, 1218,
diisopropyl1-(2-(4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-3- 1109, 769 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H), 7.18 (t, J =
yl)hydrazine-1,2-dicarboxylate (2c): Rf = 0.4 (petroleum ether/ethyl 6.8 Hz, 1H), 7.62 (dt, J1 = 6.9 Hz, J2 = 1.1 Hz, 1H), 7.98 (dd, J1 = 8.8 Hz,
acetate, 2:1); yellow solid (190 mg, 89%), mp 189−192 °C; IR (KBr) J2 = 2.0 Hz, 1H), 8.66 (d, J = 8.7 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 9.20
2982, 2927, 1743, 1508, 1475, 1372, 1251, 1103, 1042, 925, 771 (d, J = 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.1, 113.4, 118.9,
1
cm−1; H NMR (500 MHz, CDCl3) δ 1.34-1.23 (m, 12H), 2.42 (s, 3H), 122.9, 123.0, 123.9, 128.3, 132.0, 132.3, 133.7, 138.1, 141.9, 147.9,
5.15-4.87 (m, 2H), 6.72 (d, J = 6.7 Hz, 1H), 7.35 (s, 1H), 7.55 (d, J = 149.1; HRMS(ESI) calcd for C14H10N4Br 313.0083 [M + H]+, found
8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 8.54 (brs, 1H); 13C NMR (100 313.0083.
MHz, CDCl3) δ 21.4, 21.5, 21.8, 21.9(2C), 70.7, 72.3, 115.3, 115.6, 3-bromo-8-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3e): Rf =
118.3, 122.4, 123.8, 128.3, 128.6, 132.0, 132.2, 134.9, 137.3, 143.5, 0.3 (petroleum ether / ethyl acetate, 3:7); brown color solid (55 mg,
150.8, 154.6, 156.4; HRMS(ESI) calcd for C21H25BrN4O4Na 511.0951 66%), mp 289−291 °C; IR (KBr) 3074, 2924, 1708, 1583, 1456, 1226,
[M + Na]+, found 511.0923.
1165, 773 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.49 (s, 3H), 7.59 (d, J =
General procedure for the one-pot preparation of cinnoline 8.4 Hz, 1H), 7.74 (dd, J1 = 9.0 Hz, J2 = 7.2 Hz, 1H), 7.86 (d, J = 9.0 Hz,
compounds 3a-3s. In a 10 mL tube 2-phenylimidazo[1,2-a]pyridine 1H), 7.97 (dd, J1 = 8.7 Hz, J2 = 1.7 Hz, 1H), 8.61 (dd, J1 = 8.7 Hz, J2 =
1a (100 mg, 0.516 mmol) and diisopropyl azodicarboxylate (115 mg, 1.5 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
0.567 mmol) were taken in 4 mL of MeCN. Then, the tube was 21.5, 114.0, 115.0, 123.8, 129.5, 131.4, 131.5, 131.8, 132.2, 133.5,
sealed with a pressure cap and heated to 80 °C for 2-3 h. The 133.6, 141.5, 148.1, 150.9; HRMS(ESI) calcd for C14H10N4Br 313.0083
reaction was monitored by TLC. After completion of the reaction, [M + H]+, found 313.0080.
cooled to room temperature and removed the solvent from the 3-bromo-9-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3f): Rf =
reaction mixture under reduced pressure to get the crude 0.3 (petroleum ether / ethyl acetate, 3:7); pale yellow solid (89 mg,
compound 2a, To that (diacetoxyiodo)benzene (365 mg, 1.134 73%), mp 298−300 °C; IR (KBr) 3072, 2919, 1644, 1550, 1486, 1422,
mmol) and TFA (2.0 mL) were added at 0 oC. Then, the reaction 1202, 1109, 806, cm−1; 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.67
mixture was stirred at room temperature for 1-2 h. After (dd, J1 = 9.3 Hz, J2 = 1.7 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.98 (dd, J1 =
completion of the reaction, quenched with ice water and then 8.8 Hz, J2 = 2.0 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.89 (d, J = 1.7 Hz,
neutralized with saturated sodium bicarbonate solution and then 1H), 9.13 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 18.3, 117.3, 118.8,
extracted with ethyl acetate (3 × 10 mL). The organic layer was 122.8, 122.9, 123.6(2C), 132.3, 133.8, 134.1, 136.9, 142.1, 148.9,
washed with brine solution and dried over sodium sulphate & 159.0; HRMS(ESI) calcd for C14H10N4Br 313.0083 [M + H]+, found
concentrated under vacuum to obtain residue. Purification by short 313.0084.
column chromatography on silica gel (petroleum ether/ethyl 3-chloropyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3g): Rf
= 0.3
acetate, 1:1) yielded pyrido[2',1':2,3]imidazo[4,5-c]cinnoline 3a as (petroleum ether/ethyl acetate, 3:7); brown color solid (81 mg,
Off white solid (85.0 mg, 75%).
74%), mp 222−224 °C; IR (KBr) 3052, 1633, 1437, 1376, 1218, 825,
1
pyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3a): Rf = 0.3 (petroleum cm−1; H NMR (500 MHz, CDCl3) δ 7.28 (td, J1 = 6.7 Hz, J2 = 1.0 Hz,
ether/ethyl acetate, 3:7); off white solid (85 mg, 75%), mp 206−208 1H), 7.83 (ddd, J1 = 9.2 Hz, J2 = 6.8 Hz, J3 = 1.2 Hz, 1H), 7.86 (dd, J1 =
°C; IR (KBr) 3055, 1683, 1642, 1564, 1492, 1435, 1206, 1134, 760 8.8 Hz, J2 = 2.1Hz, 1H), 7.96 (dt, J1 = 9.2 Hz, J2 = 1.0 Hz, 1H), 8.67 (d, J
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.25 (td, J1 = 6.7 Hz, J2 = 1.1 Hz, = 8.8 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 9.34 (dt, J1 = 6.8 Hz, J2 = 1.2 Hz,
1H), 7.80 (ddd, J1 = 9.2 Hz, J2 = 6.7 Hz, J3 = 1.4 Hz, 1H), 7.98−7.91 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 113.5, 118.1, 118.4, 123.7, 125.3,
3H), 8.78−8.71 (m, 2H), 9.36 (dt, J1 = 6.8 H z, J2 = 1.1Hz, 1H); 13C 128.9, 131.6, 133.8, 134.0, 135.2, 142.1, 148.9, 149.7; HRMS(ESI)
NMR (125 MHz, CDCl3) δ 113.2, 118.0, 120.1, 122.0, 125.2, 129.3, calcd for C13H8N4Cl 255.0432 [M + H]+, found 255.0433.
130.3, 130.7, 133.2, 134.1, 141.8, 148.7, 149.3; HRMS(ESI) calcd for 3-methoxypyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3h): Rf = 0.3
C13H9N4 221.0821 [M + H]+, found 221.0824.
(petroleum ether/ethyl acetate, 3:7); yellow solid (90 mg, 75%), mp
= 0.3 231−233 °C; IR (KBr) 3063, 2930, 2368, 1682, 1618, 1458, 1428,
3-bromopyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3b): Rf
(petroleum ether/ethyl acetate, 3:7); pale yellow solid (75 mg, 1205, 1133, 1021, 839, cm−1 1H NMR (400 MHz, CDCl3) δ 4.08 (s,
;
78%), mp 250−252 °C; IR (KBr) 3071, 2925, 1666, 1552, 1476, 1427, 3H), 7.22 (td, J1 = 6.7 Hz, J2 = 1.0 Hz, 1H), 7.57 (dd, J1 = 9.1 Hz, J2 = 2.6
1188, 1139, 763, 720 cm−1 1H NMR (500 MHz, CDCl3) δ 7.29 (td, Hz, 1H), 7.78 (ddd, J1 = 9.2 Hz, J2 = 6.8 Hz, J3 = 1.4 Hz, 1H), 7.91 (dt, J1
;
J1=6.7 Hz, J2=1.1 Hz, 1H), 7.84 (ddd, J1=9.2 Hz, J2=6.8 Hz, J3=1.4 Hz, = 9.2 Hz, J2 = 1.0 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 9.1 Hz,
1H), 7.97 (dt, J1 = 9.2 Hz, J2 = 1.1Hz, 1H), 8.01 (dd, J1 = 8.7 Hz, J2 = 1.8 1H), 9.30 (dt, J1 = 6.8 Hz, J2 = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
Hz, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 9.35 (dt, J1 = δ 55.8, 107.4, 108.5, 112.9, 114.9, 117.9, 123.2, 124.0, 125.3, 126.6,
6.9 Hz, J2 = 1.2Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 113.6, 118.1, 133.4, 149.7, 150.5, 160.4; HRMS(ESI) calcd for C14H11N4O 251.0927
[M + H]+, found 251.0925.
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DOI: 10.1039/C6RA15418B
ARTICLE
Journal Name
8-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3i): Rf
= 0.3 7.67 (m, 2H), 7.86 (d, J = 9.2 Hz, 1H), 8.35 (dd, J1 = 9.6 Hz, J2 = 2.4 Hz,
(petroleum ether/ethyl acetate, 3:7); brown color solid (54 mg, 1H), 8.74 (dd, J1 = 9.1 Hz, J2 = 5.6 Hz, 1H), 9.13 (s, 1H); 13C NMR (125
68%), mp 210−212 °C; IR (KBr) 3121, 2923, 1622, 1540, 1429, 1340, MHz, CDCl3) δ 18.3, 113.5 (d, JC-F = 21.3 Hz), 117.0, 117.2, 120.9 (d,
1205, 1122, 801, cm−1; 1H NMR (400 MHz, CDCl3) δ 3.52 (s, 3H), 7.02 JC-F = 25.7 Hz), 122.9, 123.5, 124.5 (d, JC-F = 9.5 Hz), 134.3, 136.8,
(dt, J1 = 7.0 Hz, J2 = 0.8 Hz, 1H), 7.71 (dd, J1 = 9.1 Hz, J2 = 7.0 Hz, 1H), 142.0, 148.8, 149.4 (d, JC-F = 10.3 Hz), 162.3 (d, JC-F = 250.2 Hz);
7.86 (d, J = 9.0 Hz, 1H), 7.97-7.89 (m, 2H), 8.78-8.68 (m, 2H); 13C HRMS(ESI) calcd for C14H10N4F 253.0884 [M + H]+, found 253.0885.
NMR (100 MHz, CDCl3) δ 21.5, 113.7, 114.0, 115.0, 122.1, 128.5, 1,3-dichloropyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3p): Rf = 0.3
129.3, 129.8, 130.2, 132.9, 139.2, 141.4, 147.7, 150.5; HRMS(ESI) (petroleum ether/ethyl acetate, 3:7); brown color solid (57 mg,
calcd for C14H11N4 235.0978 [M + H]+, found 235.0978.
10-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3j): Rf
64%), mp 273−275 °C; IR (KBr) 3061, 2923, 1740, 1636, 1542, 1382,
=
0.3 1242, 1099, 861, 764 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.32 (td, J1 =
(petroleum ether/ethyl acetate, 3:7); off white solid (62 mg, 71%), 6.7 Hz, J2 = 1.0 Hz, 1H), 7.86 (ddd, J1 = 9.2 Hz, J2 = 6.8 Hz, J3 = 1.3 Hz,
mp 199−201 °C; IR (KBr) 3073, 2926, 1681, 1555, 1430, 1390, 1201, 1H), 7.93 (d, J = 2.0 Hz, 1H), 8.08 (dt, J1 = 9.3 Hz, J2 = 1.0 Hz, 1H),
1
1137, 803, cm−1; H NMR (400 MHz, CDCl3) δ 2.62 (s, 3H), 7.08 (dd, 8.68 (d, J = 2.0 Hz, 1H), 9.37 (dt, J1 = 6.7 Hz, J2 = 1.1 Hz, 1H); 13C NMR
J1 = 7.0 Hz, J2 = 1.5 Hz, 1H), 7.70 (s, 1H), 7.94-7.88 (m, 2H), 8.74-8.68 (125 MHz, CDCl3) δ 113.9, 117.3, 118.7, 125.1, 127.9, 128.3, 130.6,
(m, 2H), 9.21 (d, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 22.3, 131.8, 133.9, 134.3, 139.8, 147.7, 149.1; HRMS(ESI) calcd for
114.5, 115.9, 116.3, 120.1, 122.1, 124.3, 129.2, 130.2, 130.4, 145.5, C13H7N4Cl2 289.0042 [M + H]+, found 289.0043.
148.8, 149.3, 149.9; HRMS(ESI) calcd for C14H11N4 235.0978 [M + 1,3-dichloro-10-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline
H]+, found 235.0979.
(3q): Rf = 0.3 (petroleum ether/ethyl acetate, 3:7); brown color solid
9-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3k): Rf
=
0.3 (71 mg, 66%), mp 288−294 °C; IR (KBr) 3055, 2921, 1648, 1543,
1
(petroleum ether/ethyl acetate, 3:7); brown color solid (68 mg, 1385, 1210, 1149, 803, 766 cm−1; H NMR (500 MHz, CDCl3) δ 2,64
70%), mp 207−209 °C; IR (KBr) 3046, 2923, 1709, 1496, 1433, 1246, (s, 3H), 7.15 (dd, J1 = 6.8 Hz, J2 = 1.3 Hz, 1H), 7.85 (s, 1H), 7.90 (d, J =
1
1184, 768, cm−1; H NMR (400 MHz, CDCl3) δ 2.77 (s, 3H), 7.65 (dd, 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 9.22 (d, J = 6.7 Hz, 1H); 13C NMR
J1 = 9.3 Hz, J2 = 1.7 Hz, 1H), 7.95-7.85 (m, 3H), 8.76-8.69 (m, 2H), (125 MHz, CDCl3) δ 22.4, 116.7, 116.9, 117.3, 124.1, 128.1, 130.6,
9.15 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 18.1, 112.0, 117.1, 120.0, 131.5, 133.5, 134.0, 143.1, 146.3, 149.1, 150.4; HRMS(ESI) calcd for
122.0, 122.7, 123.4, 129.1, 129.9, 130.5, 136.5, 143.3, 148.4, 154.4; C14H9N4Cl2 303.0198 [M + H]+, found 303.0199.
HRMS(ESI) calcd for C14H11N4 235.0978 [M + H]+, found 235.0977.
11-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3l): Rf
1-fluoropyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3r): Rf
0.3 (petroleum ether/ethyl acetate, 3:7); yellow solid (50 mg, 72%), mp
= 0.3
=
(petroleum ether/ethyl acetate, 3:7); brown color solid (73 mg, 230−232 °C; IR (KBr) 3101, 2923, 1627, 1552, 1489, 1217, 1131, 929,
67%), mp 204−207 °C; IR (KBr) 3048, 2929, 1773, 1706, 1426, 1371, 767, 616 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.30 (td, J1 = 6.8 Hz, J2 =
1295, 1184, 816, cm−1; 1H NMR (400 MHz, CDCl3) δ 2.84 (s, 3H), 7.16 0.8 Hz, 1H), 7.62 (td, J1 = 7.8 Hz, J2 = 0.8 Hz, 1H), 7.92-7.80 (m, 2H),
(t, J = 6.8 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.95-7.88 (m, 2H), 8.82- 8.06 (d, J = 9.2 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H), 9.38 (d, J = 6.7 Hz,
8.70 (m, 2H), 9.23 (d, J = 6.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 1H); 13C NMR (125 MHz, CDCl3) δ 113.7, 114.8 (d, JC-F = 19.1 Hz),
17.1, 113.2, 120.3, 122.2, 122.8, 128.1, 129.1, 130.1, 130.4, 131.7, 118.5, 118.6, 123.8, 125.0, 126.1 (d, JC-F = 3.6 Hz), 128.9 (d, JC-F = 8.2
139.9, 148.6, 149.8; HRMS(ESI) calcd for C14H11N4 235.0978 [M + Hz), 135.5, 137.9, 139.2, 148.7 (d, JC-F = 8.2 Hz), 149.6, 157.4 (d, JC-F
H]+, found 235.0977.
3-fluoropyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3m): Rf
= 259.7 Hz); HRMS(ESI) calcd for C13H8N4F 239.0727 [M + H]+, found
= 0.3 239.0726
(petroleum ether/ethyl acetate, 3:7); off white solid (101 mg, 78%), 1-fluoro-10-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3s): Rf
mp 225−227 °C; IR (KBr) 3076, 2924, 1626, 1438, 1247, 1181, 1130, = 0.3 (petroleum ether/ ethyl acetate, 3:7); yellow solid (59 mg,
1
863, 762 cm−1; H NMR (400 MHz, CDCl3) δ 7.27 (td, J1 = 6.8 Hz, J2 = 69%), mp 254−255 °C; IR (KBr) 3041, 2919, 1641, 1550, 1490, 1399,
1
1.0 Hz, 1H), 7.71 (ddd, J1 = 9.0 Hz, J2 = 8.3 Hz, J3 = 2.6 Hz, 1H), 7.82 1216, 1137, 1052, 939, 768, 699 cm−1; H NMR (400 MHz, CDCl3) δ
(ddd, J1 = 9.0 Hz, J2 = 6.7 Hz, J3 = 1.3 Hz, 1H), 7.94 (dt, J1 = 9.3 Hz, J2 = 2.64 (s, 3H), 7.13 (dd, J1 = 6.8 Hz, J2 = 1.4 Hz, 1H), 7.59 (ddd, J1 = 9.9
1.0 Hz, 1H), 8.34 (dd, J1 = 9.5 Hz, J2 = 2.4 Hz, 1H), 8.74 (dd, J1 = 9.0 Hz, J2 = 7.8 Hz, J3 = 0.7 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.89-7.82 (m,
Hz, J2 = 5.6 Hz, 1H), 9.34 (dt, J1 = 6.8 Hz, J2 = 1.1 Hz, 1H); 13C NMR 1H), 8.55 (d, J = 8.6 Hz, 1H), 9.23 (d, J = 6.9 Hz, 1H); 13C NMR (125
(125 MHz, CDCl3) δ 113.4, 113.7 (d, JC-F = 21.8 Hz), 117.0, 118.0, MHz, CDCl3) δ 22.4, 114.4 (d, JC-F = 19.1 Hz), 116.6 (d, JC-F = 44.5 Hz),
121.2 (d, JC-F = 25.4 Hz), 124.5 (d, JC-F = 9.1 Hz), 125.3, 133.7, 134.3, 124.1, 124.3, 125.9 (d, JC-F = 4.5 Hz), 128.7 (d, JC-F = 8.2 Hz), 130.5,
142.1, 149.6 (d, JC-F = 10.9 Hz), 149.7, 162.4 (d, JC-F = 250.7 Hz); 132.0, 142.5, 145.9, 149.5, 150.4, 157.5 (d, JC-F = 258.8 Hz);
HRMS(ESI) calcd for C13H8N4F 239.0727 [M + H]+, found 239.0728.
HRMS(ESI) calcd for C14H10N4F 253.0884 [M + H]+, found 253.0883.
3-fluoro-10-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3n): Rf
= 0.3 (petroleum ether/ ethyl acetate, 3:7); yellow solid (106 mg, Analytical data for Intermediates (4a, 4c, 4f & 4h).
81%), mp 245−247 °C; IR (KBr) 3040, 2921, 1635, 1561, 1435, 1244,
1174, 1116, 808, 766 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.64 (s, 3H), isopropyl
(E)-2-(2-phenylimidazo[1,2-a]pyridin-3-yl)diazene-1-
7.11 (dd, J1 = 6.8 Hz, J2 = 1.3 Hz, 1H), 7.72-7.66 (m, 2H), 8.33 (dd, J1 = carboxylate (4a): Rf = 0.6 (petroleum ether/ethyl acetate, 3:7); red
9.6 Hz, J2 = 2.4 Hz, 1H), 8.73 (dd, J1 = 9.0 Hz, J2 = 5.6 Hz, 1H), 9.19 (d, color solid, mp 138−140 °C; IR (KBr) 2982, 2936, 1709, 1520, 1485,
J = 6.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 22.3, 113.4, (d, JC-F
=
1380, 1264, 1180, 1094, 773 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.48
21.3 Hz), 116.1 (d, JC-F = 23.5 Hz), 116.9, 120.8 (d, JC-F = 25.7 Hz), (d, J = 6.2 Hz, 6H), 5.26 (septet, J = 6.2 Hz, 1H), 7.24 (td, J1 = 7.0 Hz,
124.3, 124.5 (d, JC-F = 9.5 Hz), 134.7, 142.3, 145.9, 149.5 (d, JC- F J2 = 1.2 Hz, 1H), 7.54-7.47 (m, 3H), 7.74-7.69 (m, 1H), 7.85 (dt, J1 =
11.0 Hz), 150.3, 162.3 (d, JC-F = 250.2 Hz); HRMS(ESI) calcd for 8.8 Hz, J2 = 1.1 Hz, 1H), 8.54-8.49 (m, 2H), 9.97 (dt, J1 = 6.8 Hz, J2 =
C14H10N4F 253.0884 [M + H]+, found 253.0884. 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9(2C), 71.0, 117.3,
=
3-fluoro-9-methylpyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3o): Rf = 117.6, 128.7(2C), 130.5(2C), 130.7, 131.5, 131.7, 131.9, 133.2,
0.3 (petroleum ether/ ethyl acetate, 3:7); yellow solid (88 mg, 75%), 148.8, 157.8, 161.9; HRMS(ESI) calcd for C17H17N4O2 309.1346 [M +
mp 248−251 °C; IR (KBr) 3072, 2918, 1626, 1558, 1434, 1245, 1208, H]+, found 309.1364.
1112, 803, 740 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.58 (s, 3H), 7.73-
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isopropyl(E)-2-(2-(4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-
3-yl)diazene-1-carboxylate (4c): Rf = 0.6 (petroleum ether/ethyl a]pyridin-3-yl)diazene-1-carboxylate (4u): Rf
isopropyl (E)-2-(7-methyl-2-(4-(methylsulfinyl)phenyl)imidazo[1,2-
0.2 (petroleum
=
acetate, 3:7); red color solid, mp 151−153 °C; IR (KBr) 2977, 2923, ether/ethyl acetate, 1:1); red color semi solid (155 mg, 81%); IR
1704, 1637, 1481, 1375, 1188, 1145, 1106, 1001, 728 cm−1; 1H NMR (Neat) 3037, 2981, 2924, 1715, 1637, 1480, 1401, 1177, 1147, 1092,
1
(500 MHz, CDCl3) δ 1.47 (d, J = 6.2 Hz, 6H), 2.57 (s, 3H), 5.25 (septet, 927, 761 cm−1; H NMR (500 MHz, CDCl3) δ 1.44 (d, J = 6.2 Hz, 6H),
J = 6.2 Hz, 1H), 7.07 (dd, J1 = 6.9 Hz, J2 = 1.5 Hz, 1H), 7.60 (s, 1H), 2.52 (s, 3H), 2.75 (s, 3H), 5.21 (septet, J = 6.2 Hz, 1H), 7.04 (d, J = 7.0
7.64 (d, J = 8.7 Hz, 2H), 8.41 (d, J = 8.7 Hz, 2H), 9.81 (d, J = 6.9 Hz, Hz, 1H), 7.55 (s, 1H), 7.73 (d, J = 7.9 Hz, 2H), 8.61 (d, J = 7.8 Hz, 2H),
1H); 13C NMR (100 MHz, CDCl3) δ 21.9(2C), 22.0, 70.9, 116.7, 119.6, 9.74 (d, J = 6.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 21.9(2C),
125.8, 130.7, 130.8, 131.7, 131.8(2C), 131.9(2C), 145.9, 149.2, 43.8, 70.9, 116.7, 119.8, 123.6(2C), 130.6, 131.1(2C), 131.8, 134.5,
156.9, 161.9; HRMS(ESI) calcd for C18H18BrN4O2 401.0608 [M + H]+, 145.9, 147.7, 149.1, 156.3, 161.8; HRMS(ESI) calcd for C19H21N4O3S
found 401.0608.
385.1329 [M + H]+, found 385.1331.
isopropyl(E)-2-(2-(4-bromophenyl)-6-methylimidazo[1,2-a]pyridin-
3-(methylsulfinyl)pyrido[2',1':2,3]imidazo[4,5-c]cinnoline (3t): Rf =
3-yl)diazene-1-carboxylate (4f): Rf = 0.6 (petroleum ether/ethyl 0.2 (ethyl acetate /methanol, 9.5:0.5); brown color liquid (50 mg,
acetate, 3:7); orange solid, mp 161−163 °C; IR (KBr) 2976, 2926, 67%); IR (Neat) 3041, 2926, 2854, 1629, 1400, 1118, 585 cm−1 1H
1718, 1629, 1544, 1491, 1404, 1251, 1174, 1095, 995, 8312, 730 NMR (500 MHz, CDCl3) δ 2.92 (s, 3H), 7.32 (td, J1 = 6.7 Hz, J2 = 1.7
cm−1 1H NMR (500 MHz, CDCl3) δ 1.48 (d, J = 6.2 Hz, 6H), 2.48 (s, Hz, 1H), 7.87 (ddd, J1 = 9.2 Hz, J2 = 6.7Hz J3=1.4 Hz, 1H), 8.00 (dt, J1 =
;
;
3H), 5.25 (septet, J = 6.2 Hz, 1H), 7.56 (dd, J1 = 8.8 Hz, J2 = 1.5 Hz, 9.2 Hz, J2 = 1.1 Hz, 1H), 8.19 (dd, J1 = 8.5 Hz, J2 = 1.7Hz, 1H), 8.92 (d, J
1H), 7.63 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.7 = 8.5 Hz, 1H), 9.02 (d, J1 = 1.4 Hz, 1H), 9.39 (dt, J1 = 6.7 Hz, J2 = 1.2
Hz, 2H), 9.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 18.6, 21.9(2C), Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 43.9, 113.8, 114.0, 118.2,
71.1, 116.9, 125.6, 128.1, 129.5, 130.8, 131.5, 131.7(2C), 131.8(2C), 124.1, 124.2, 125.5, 126.4, 128.1, 133.9, 139.3, 146.4, 147.1, 149.9;
135.9, 147.7, 156.2, 161.9; HRMS(ESI) calcd for C18H18BrN4O2 HRMS(ESI) calcd for C14H11ON4S 283.0648 [M + H]+, found 283.0648.
401.0608 [M + H]+, found 401.0593.
isopropyl (E)-2-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3- c]cinnoline (3u): Rf = 0.2 (ethyl acetate /methanol, 9.5:0.5); brown
10-methyl-3-(methylsulfinyl)pyrido[2',1':2,3]imidazo[4,5-
yl)diazene-1-carboxylate (4h): Rf = 0.6 (petroleum ether/ethyl color liquid (54 mg, 74%); IR (Neat) 3057, 2935, 2848, 1627, 1410,
acetate, 3:7); orange solid, mp 138−140 °C; IR (KBr) 3071, 2971, 1242, 1129, 599 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.65 (s, 3H), 2.91
1
1704, 1602, 1482, 1410, 1251, 1162, 1086, 775 cm−1; H NMR (500 (s, 3H), 7.13 (dd, J1 = 7.0 Hz, J2 = 1.7 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H),
MHz, CDCl3) δ 1.47 (d, J = 6.2 Hz, 6H), 3.89 (s, 3H), 5.26 (septet, J = 8.15 (dd, J1 = 8.5 Hz, J2 = 1.7 Hz, 1H), 8.89 (d, J = 8.8 Hz, 1H), 8.97 (d,
6.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 7.20 (td, J1 = 7.0 Hz, J2 = 1.4 Hz, J = 1.2 Hz, 1H), 9.23 (d, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
1H), 7.72-7.66 (m, 1H), 7.79 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 9.0 Hz, 22.4, 43.9, 116.4, 116.7, 121.3, 123.9, 124.3, 124.4, 126.2, 129.4,
2H), 9.98 (dt, J1 = 6.7 Hz, J2 = 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) 134.2, 146.7, 147.2, 147.8, 150.3; HRMS(ESI) calcd for C15H13N4OS
δ
21.9(2C), 55.4, 70.8, 114.3(2C), 116.9, 117.3, 124.4, 131.7, 297.0805 [M + H]+, found 297.0816.
132.2(2C), 133.4, 135.1, 146.2, 149.2, 157.9, 162.1; HRMS(ESI) calcd
for C18H19N4O3 339.1452 [M + H]+, found 339.1463.
General procedure for starting materials 5a-5e (Table 4).
Analytical data for Scheme 2 compounds.
2-(4-(methylthio)phenyl)imidazo[1,2-a]pyridine (1t)23: white solid,
1H NMR (400 MHz, CDCl3) δ 2.53 (s, 3H), 6.79 (td, J1 = 6.7 Hz, J2 = 1.0
Hz, 1H), 7.19 (ddd, J1 = 9.1 Hz, J2 = 6.7 Hz, J3=1.2 Hz, 1H), 7.32 (d, J =
8.5 Hz, 2H), 7.65 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J = 8.4 Hz,
2H), 8.12 (dt, J1 = 6.7 Hz, J2 = 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 15.8, 107.8, 112.5, 117.4, 124.8, 125.5, 126.4(2C), 126.7(2C),
130.4, 138.3, 145.2, 145.5; MS m/z 241 (M + H)+.
To a stirred solution of 1Aa (197 mg, 1.037mmol) in Isopropanol
(6.0 mL) was added 1Ab (336 mg, 1.555 mmol). Then, the reaction
mixture was heated to reflux temperature for 6-8 h. After
completion of the reaction, cooled to room temperature and
removed the solvent under vacuum. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate, 4:1) yield 5d as yellow solid (166 mg, 52%).
7-methyl-2-(4-(methylthio)phenyl)imidazo[1,2-a]pyridine
(1u)24
:
white solid, 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 2.52 (s, 3H),
6.66 (d, J = 6.7 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.46 (brs, 1H), 7.75
(s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 6.8 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 15.7, 21.4, 107.3, 115.3, 115.5, 123.3, 124.7, 126.4,
126.6, 128.3, 128.4, 138.1, 139.2, 143.6, 144.5; MS m/z 255 (M +
H)+.
2-phenyl-7-(trifluoromethyl)benzo[d]imidazo[2,1-b]thiazole (5a)25
:
Rf = 0.4 (petroleum ether/ ethyl acetate, 2:1); white color solid (159
1
mg, 40%); H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 7.4 Hz, 1H), 7.43
Isopropyl(E)-2-(2-(4-(methylsulfinyl)phenyl)imidazo[1,2-a]pyridin-
3-yl)diazene-1-carboxylate (4t): Rf = 0.2 (petroleum ether/ethyl
acetate, 1:1); red color semi solid (131 mg, 78%); IR (Neat) 3051,
(t, J = 7.4 Hz, 2H), 7.75-7.68 (m, 2H), 7.90-7.85 (m, 2H), 8.02-7.98
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 106.9, 112.6, 121.8 (q, JC-F
=
3.7 Hz), 123.5 (q, JC-F = 3.7 Hz), 123.6 (q, JC-F = 272.2 Hz), 125.3(2C),
127.2 (q, JC-F = 33.7 Hz), 127.8, 128.6, 128.7(2C), 130.9, 133.2, 134.2,
148.4; HRMS(ESI) calcd for C16H10N2F3S 319.0511 [M + H]+, found
319.0496.
1
2982, 1723, 1628, 1481, 1404, 1177, 1134, 1090, 928, 766 cm−1; H
NMR (500 MHz, CDCl3) δ 1.48 (d, J = 6.2 Hz, 6H), 2.79 (s, 3H), 5.27
(septet, J = 6.2 Hz, 1H), 7.28 (td, J1 = 6.8 Hz, J2 = 0.7 Hz, 1H), 7.74 (m,
1H), 7.79 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.8 Hz, 1H), 8.67 (d, J = 8.4
Hz, 2H), 9.94 (d, J = 6.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
21.9(2C), 43.9, 71.3, 117.7, 117.9, 123.7(2C), 124.2, 131.2(2C),
131.3, 132.0, 133.3, 134.5, 147.9, 148.6, 155.9, 161.6; HRMS(ESI)
calcd for C18H19N4O3S 371.1172 [M + H]+, found 371.1176.
2-(4-fluorophenyl)-5-methoxybenzo[d]imidazo[2,1-b]thiazole (5b):
Rf = 0.4 (petroleum ether/ethyl acetate, 2:1); yellow solid (138 mg,
39%), mp 141−143 °C; IR (KBr) 3076, 2925, 1735, 1542, 1476, 1264,
1
1213, 1139, 1035, 827, 763, 726 cm−1; H NMR (500 MHz, CDCl3) δ
4.09 (s, 3H), 7.00-6.94(m, 1H), 7.11 (t, J = 8.8 Hz, 2H), 7.32-7.28 (m,
2H), 7.86 (dd, J1 = 8.9 Hz, J2 = 5.4 Hz, 2H), 8.21 (s, 1H); 13C NMR (100
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MHz, CDCl3) δ 56.1, 107.9, 110.6, 115.5 (d, JC-F = 21.3 Hz), 116.0(2C), 2H), 8.00 (d, J = 1.7 Hz, 1H), 7.62-7.57 (m, 1H), 8.76-8.70 (m, 2H);
122.3, 125.2(2C), 126.7 (d, JC-F = 8.1 Hz), 130.3 (d, JC-F = 2.9 Hz), 13C NMR (125 MHz, CDCl3) δ 116.5, 118.9, 120.1, 121.4, 126.7,
131.3, 145.7, 147.2, 147.7, 162.2 (d, JC-F = 245.8 Hz); HRMS(ESI) 129.1, 129.9, 130.6, 130.9, 131.0, 131.2, 132.1, 137.2, 144.3, 148.0;
calcd for C16H12ON2FS 299.0648 [M + H]+, found 299.0647.
HRMS(ESI) calcd for C15H8BrN4S 354.964 [M + H]+, found 354.965.
7-bromo-2-phenylbenzo[d]imidazo[2,1-b]thiazole (5c)25: Rf = 0.4 3-fluoro-9-methyl-8-phenylthiazolo[2',3':2,3]imidazo[4,5-c]
(petroleum ether/ ethyl acetate, 2:1); pale yellow solid (142 mg, cinnoline (6d): Rf = 0.2 (petroleum ether/ethyl acetate, 4:6); pale
1
42%); H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 1H), 7.53-7.38 (m, yellow solid (67 mg, 70%), mp 278−281 °C; IR (KBr) 3056, 2922,
3H), 7.60-7.54 (m, 1H), 7.88-7.82 (m, 2H), 8.02-7.91 (m, 2H); 13C 2852, 1720, 1561, 1427, 1247, 1198, 1112, 950, 760, 698 cm−1; H
1
NMR (125 MHz, CDCl3) δ 106.9, 113.6, 117.5, 125.2, 126.9, 127.7, NMR (500 MHz, CDCl3) δ 2.53 (s, 3H), 7.77-7.56 (m, 6H), 8.30 (brs,
127.9, 128.3, 128.7, 129.3, 131.1, 132.0, 133.1, 147.9; HRMS(ESI) 1H), 8.62 (dd, J1 = 9.2 Hz, J2 = 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
calcd for C15H10N2BrS 328.9743 [M + H]+, found 328.9731.
δ 13.6, 112.8 (d, JC-F = 21.3 Hz), 116.7, 121.1 (d, JC-F = 25.7 Hz), 122.4,
6-(4-fluorophenyl)-2-methyl-3-phenylimidazo[2,1-b]thiazole (5d): 124.0 (d, JC-F = 9.5 Hz), 126.8, 128.6(2C), 130.1, 130.2, 130.4(2C),
Rf = 0.4 (petroleum ether/ ethyl acetate, 2:1); yellow solid (166 mg, 136.6, 144.5, 148.0 (d, JC-F = 11.0 Hz), 158.5, 161.8 (d, JC-F = 250.2
52%), mp 129−131 °C; IR (KBr) 3115, 2915, 1600, 1544, 1468, 1400, Hz); HRMS(ESI) calcd for C18H12N4FS 335.0761 [M + H]+, found
1215, 1152, 839, 743, 694 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.41 (s, 335.0761.
3H), 7.05 (t, J = 8.8 Hz 2H), 7.59-7.48 (m, 6H), 7.75 (dd, J1 = 8.8 Hz, J2 8-(4-fluorophenyl)thiazolo[2',3':2,3]imidazo[4,5-c]cinnoline (6e): Rf
= 5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.5, 106.8, 115.4 (d, JC-F = 0.2 (petroleum ether/ ethyl acetate, 4:6); off white solid (55 mg,
= 21.3 Hz), 121.5, 126.6 (d, JC-F = 8.1 Hz), 127.5, 128.9(2C), 129.1, 68%), mp 277−279 °C; IR (KBr) 3016, 2924, 2853, 1713, 1602, 1456,
1
129.2(2C), 129.4, 130.4 (d, JC-F = 2.2 Hz), 145.4, 147.4, 162.8 (d, JC-F
=
1415, 1234, 1094, 807, 757, 698 cm−1; H NMR (500 MHz, CDCl3) δ
245.8 Hz); HRMS(ESI) calcd for C18H14N2FS 309.0856 [M + H]+, found 6.95 (s, 1H), 7.29 (t, J = 8.5 Hz, 2H), 7.92-7.83 (m, 2H), 8.07 (dd, J1 =
309.0855.
8.6 Hz, J2 = 5.2 Hz, 2H), 8.68-8.57 (m, 2H); 13C NMR (100 MHz, CDCl3)
3-(4-fluorophenyl)-6-phenylimidazo[2,1-b]thiazole (5e)26: Rf = 0.4 δ 109.0, 115.9 (d, JC-F = 22.7 Hz), 121.5, 124.1, 128.9, 129.8, 130.7,
1
(petroleum ether/ethyl acetate, 2:1); white solid (160 mg, 48%); H 131.2 (d, JC-F = 8.2 Hz), 135.2, 137.4 (d, JC-F = 3.6 Hz), 139.3, 150.1,
NMR (500 MHz, CDCl3) δ 6.78 (s, 1H), 7.32-7.22 (m, 4H), 7.41 (t, J = 151.7, 160.5, 163.9 (d, JC-F = 250.7 Hz); HRMS(ESI) calcd for
7.6 Hz, 2H), 7.69-7.64 (m, 2H), 7.86-7.83 (m, 2H); 13C NMR (100 C17H10FN4S 321.0605 [M + H]+, found 321.0611.
MHz, CDCl3) δ 107.0, 108.5, 115.6, 116.6 (d, JC-F = 22.0 Hz),
125.3(2C), 127.6, 128.7(2C), 129.0 (d, JC-F = 8.8 Hz), 131.6, 133.7,
Acknowledgement
136.6, 147.7, 150.1, 165.4 (d, JC-F = 259.7 Hz); HRMS(ESI) calcd for
C17H12N2FS 295.0699 [M + H]+, found 295.0686.
KSR thank UGC, India for the award of fellowship. Both the authors
thank CSIR, New Delhi, India for financial support as part of XII Five
Year Plan Programme under title ORIGIN (CSC-0108).
General procedure for the one-pot preparation of heterocyclic
cinnoline compounds 6a-6e: same general one-pot procedure was
followed as described above for 3a-3s.
Keywords: annulation, cinnolines, C-3 regioselective hydrazination,
hypervalent iodine species, metal-free one-pot synthesis.
10-(trifluoromethyl)benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-
c]cinnoline (6a): Rf = 0.2 (petroleum ether/ethyl acetate, 4:6); off
white solid (66 mg, 75%), mp 261−263 °C; IR (KBr) 3062, 2923, 1614,
References
1510, 1452, 1325, 1286, 1111, 1079, 841, 766, 706 cm−1 1H NMR
;
(500 MHz, CDCl3) δ 8.99 (d, J = 8.4 Hz, 1H), 8.75-8.71 (m, 1H), 8.62-
8.58 (m, 1H), 8.15 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.96-7.89 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 115.6, 120.0, 121.4, 121.5 (q, JC-F = 3.7
(1) (a) Lewgowd, W.; Stanczak, A. Cinnoline derivatives with
biological activity. Arch. Pharm. Chem. Life Sci. 2007, 340, 65−80. (b)
Scott, D. A.; Dakin, L. A.; Del Valle, D. J.; Bruce Diebold, R.; Drew, L.;
Gero, T. W.; Ogoe, C. A.; Omer, C. A.; Repik, G.; Thakur, K.; Ye, Q.;
Zheng, X. Bioorg. Med. Chem. Lett. 2011, 21, 1382−1384. (c)
Ruchelman, A. L.; Singh, S. K.; Wu, X.; Ray, A.; Yang, J.-M.; Li, T.-K.;
Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 2002, 12,
3333−3336. (d) Lunniss, C.; Eldred, C.; Aston, N.; Craven, A. Bioorg.
Med. Chem. Lett. 2010, 20, 137−140.
Hz), 123.6 (q, JC-F = 272.9 Hz), 125.1 (q, JC-F = 3.7 Hz), 128.3 (q, JC-F
=
33.7 Hz), 129.2, 129.6, 130.2, 131.3, 134.1, 137.2, 144.4, 148.5,
158.3; HRMS(ESI) calcd for C16H8F3N4S 345.0416 [M + H]+, found
345.0411.
3-fluoro-8-methoxybenzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-
c]cinnoline (6b): Rf = 0.2 (petroleum ether/ethyl acetate, 4:6);
brown solid (51 mg, 72%), mp 220−222 °C; IR (KBr) 3044, 2924,
2852, 1778, 1740, 1598, 1500, 1414, 1277, 1230, 1156, 1037, 846,
(2) Yu, Y.; Singh, S. K.; Liu, A.; Li, T.-K.; Liu, L. F.; La Voie, E. J. Bioorg.
Med. Chem. 2003, 11, 1475−1491.
1
768 cm−1; H NMR (400 MHz, CDCl3) δ 4.26 (s, 3H), 7.19 (d, J = 8.1
(3) Ruchelman, A. L.; Singh, S. K.; Ray, A.; Wu, X.; Yang, J.-M.; Zhou,
N.; Liu, A.; Liu, L. F.; La Voie, E. J. 11H-Isoquino[4,3-c]cinnolin-12-
ones: novel anticancer agents with potent topoisomerase I-
targeting activity and cytotoxicity. Bioorg. Med. Chem. 2004, 12,
795−806.
(4) Stefańka, B.; Arciemiuk, M.; Bontemps-Gracz, M. M.;
Dzieduszycka, M.; Kupiec, A.; Martelli, S.; Borowski, E. Synthesis and
biological evaluation of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-
dione derivatives, a novel group of anticancer agents active on a
multidrug resistant cell line. Bioorg. Med. Chem. 2003, 11, 561−572.
(5) Barraja, P.; Diana, P.; Lauria, A.; Passannanti, A.; Almerico, A. M.;
Minnei, C.; Longu, S.; Congiu, D.; Musiu, C.; La Colla, P. Indolo[3,2-
Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.65 (td, J1
= 8.7 Hz, J2 = 2.3 Hz, 1H), 8.26 (d, J = 9.4 Hz, 1H), 8.61(dd, J1 = 9.1 Hz,
J2 = 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 56.7, 110.5, 112.6 (d,
JC-F = 21.3 Hz), 115.7, 121.5 (d, JC-F = 26.4 Hz), 123.4, 124.1 (d, JC-F
=
8.8 Hz), 127.2, 127.7, 130.3, 135.6, 136.8, 145.3, 148.2 (d, JC-F = 8.1
Hz), 149.1, 159.2, 162.0 (d, JC-F = 250.9 Hz); HRMS(ESI) calcd for
C16H10ON4FS 325.0553 [M + H]+, found 325.0551.
10-bromobenzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-c]cinnoline
(6c): Rf = 0.2 (petroleum ether/ethyl acetate, 4:6); yellow solid (83
mg, 76%), mp 285−290 °C; IR (KBr) 3056, 2924, 2854, 1741, 1621,
1476, 1401, 1312, 1239, 1167, 1101, 766, 695 cm−1 1H NMR (400
;
MHz, CDCl3) δ 7.84 (dd, J1 = 8.6 Hz, J2= 1.8 Hz, 1H), 7.96-7.88 (m,
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DOI: 10.1039/C6RA15418B
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DOI: 10.1039/C6RA15418B
Metal-free C-N bond formations: One-pot Synthesis of pyrido[2',1':2,3]imidazo[4,5-
c]cinnolines, benzo[4',5']thiazolo- and thiazolo[2',3':2,3]imidazo[4,5-c]cinnolines
Satheeshkumar Reddy Kandimalla and Gowravaram Sabitha*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500
607, India. E-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in; Fax: +91-40-27160512
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