A transition metal-free approach towards synthesis of β-carboline tethered 1,3,4-oxadiazoles via oxidative C-O bond formation

Article abstract of DOI:10.1039/c8nj04294b

An efficient protocol has been developed for one-pot synthesis of biologically interesting β-carboline substituted 1,3,4-oxadiazoles via an I₂-assisted oxidative C-O bond formation strategy. This metal-free sequential approach is found to be compatible with diversely substituted 1-formyl β-carbolines and aromatic as well as aliphatic hydrazides, providing access to a variety of multifunctional β-carboline linked 1,3,4-oxadiazole derivatives in good to excellent yields. The methodology was found to be applicable to gram scale synthesis of β-carboline substituted 1,3,4-oxadiazole derivatives. Additionally, β-carboline C1 linked 2-amino-1,3,4-oxadiazoles and bis-1,3,4-oxadiazoles were also synthesized using the same strategy.

Full text of DOI:10.1039/c8nj04294b

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A transition metal-free approach towards
synthesis of b-carboline tethered
1,3,4-oxadiazoles via oxidative C–O bond
Cite this: New J. Chem., 2019,
43, 93
formation†
a
Dharmender Singh,a Sandip Kumar Tiwarib and Virender Singh
*
An efficient protocol has been developed for one-pot synthesis of biologically interesting b-carboline
substituted 1,3,4-oxadiazoles via an I2-assisted oxidative C–O bond formation strategy. This metal-free
sequential approach is found to be compatible with diversely substituted 1-formyl b-carbolines and aromatic
as well as aliphatic hydrazides, providing access to a variety of multifunctional b-carboline linked 1,3,4-
oxadiazole derivatives in good to excellent yields. The methodology was found to be applicable to gram
scale synthesis of b-carboline substituted 1,3,4-oxadiazole derivatives. Additionally, b-carboline C1 linked
2-amino-1,3,4-oxadiazoles and bis-1,3,4-oxadiazoles were also synthesized using the same strategy.
Received 22nd August 2018,
Accepted 6th November 2018
DOI: 10.1039/c8nj04294b
rsc.li/njc
(antihypertensive), ABT-751-oxadiazole and Furamizole15 (Fig. 1)
used for the treatment of various ailments.
Introduction
Naturally occurring b-carboline alkaloids and their synthetic
The medicinal potential of these two privileged scaffolds
derivatives are widely studied due to their broad spectrum of inspired us to construct a new molecular hybrid containing both
pharmacological properties, such as anticancer,1 antibacterial, the frameworks. Interestingly, an analysis of the literature revealed
antimalarial, anti-HIV, anti-Alzheimer etc.2 However, the majority the presence of one narrowly related previous report (Fig. 2) in the
of b-carboline alkaloids display anticancer properties via inter- form of a patent where Guo et al. have disclosed the 8-step synthesis
calation into DNA,3 and inhibition of cyclin-dependent kinases,4 and anti-diabetic properties of tetrahydro-b-carbolines containing
topoisomerases5 and IkK kinase complexes.6 Importantly, the 1,3,4-oxadiazole for the treatment of type 2 diabetes mellitus
b-carboline alkaloids account for nearly one quarter of natural (Fig. 2).16 It was found that these molecular hybrids act as selective
products (Fig. 1) and are also accommodated by several commer- antagonists of the somatostatin subtype receptor 3 and could also
cial drugs (Tadalfil, Abecarnil, Cipargamin etc.).7
be used for the treatment of depression, anxiety, insulin resistance,
Similarly, 1,3,4-oxadiazole is another high value added scaffold hyperglycemia, lipid disorders, obesity and hypertension. The lite-
0
which has attracted considerable attention for decades owing to its rature revealed that dehydration of diacyl-hydrazines (POCl3 SOCl2,
pharmaceutical and biological activities, such as anti inflam- PPA, H2SO4)17 and oxidative cyclization of acylhydrazones utilizing
matory, antibacterial, anticancer, anti-diabetic, analgesic, antiviral, oxidants18 like HgO/I2, PbO2, IBX, DMP, chloramine T, KMnO4,
antifungal etc.8 Apart from this, 1,3,4-oxadiazole has demonstrated CAN, I2, an Br2 or transition metal catalysts (Cu(OTf)2, PdCl2(dppp),
numerous applications in the field of materials science because of CuI, and FeCl3) via C–O coupling reactions are two common
its excellent electron transporting and hole-blocking abilities.9 The approaches employed for the synthesis of 1,3,4-oxadiazoles.19
optoelectronic properties10 of oxadiazole derivatives make them Recently, the Xu group reported a novel Pd-assisted synthesis of 2-
unique among the heterocyclic family. Moreover, the medicinal amino-1,3,4-oxadiazoles through isocyanide insertions into hydr-
significance of this motif is evident from the fact that it is repre- azides.20 Nevertheless, the major drawback associated with existing
sented by numerous drugs such as Raltegravir11 (antiretroviral), reports involves the use of expensive and hazardous reagents, harsh
Zibotentan12 (anticancer), Fenadiazole13 (hypnotic), Nesapidil14 reaction conditions, multistep synthesis and non-scalability. Among
these methods, annulation of acylhydrazides with carbonyl com-
pounds is found to be a more effective approach21 as disclosed by
a Department of Chemistry, Dr B R Ambedkar National Institute of Technology (NIT),
Yu and co-workers.22 However, the substrate scope with acylhydr-
Jalandhar, 144011, Punjab, India
b Drug Discovery and Molecular Synthesis Lab, Centre of Biomedical Research,
azides containing electron withdrawing substituents remains
unexplored. Patel and co-workers have also developed a Cu(OTf)2
SGPGIMS, Lucknow- 226014, Uttar Pradesh, India. E-mail: singhv@nitj.ac.in;
assisted excellent approach toward synthesis of symmetrical and
Fax: +91 172-2214692
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj04294b unsymmetrical oxadiazoles.23 Our group has been involved in the
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substrates. The condensation of 1a with A in methanol at 70 1C
smoothly afforded the benzohydrazone 1aA in 89% yield with-
out any assistance of Bronsted acid. Next, we explored the
oxidative cyclization of the isolated hydrazone 1aA to generate
the 1,3,4-oxadiazole framework. Recent studies have revealed
that molecular iodine is one of the most versatile promoters
and it offers numerous advantages over transition metal cata-
lysts.22,24 Therefore, it has been extensively used in organic
synthesis for a variety of transformations. Accordingly, the
isolated benzohydrazone 1aA was treated with 1.5 equiv. of
iodine in the presence of K2CO3 at 70 1C in MeOH. However,
the reaction was very sluggish and it was not completed in 24 h
(Table 1, entry 1). The purification of the reaction mixture via
column chromatography afforded the desired product, b-carboline
C1 substituted 1,3,4-oxadiazole, 2aA in 25% yield as confirmed on
the basis of spectroscopic data. Nevertheless, 60% of the starting
substrate 1aA was also recovered.
Fig. 1 Representative examples of biologically active b-carboline and
1,3,4-oxadiazole derivatives.
In a quest to improve the yield of product, various reaction
parameters like reagent, base, solvent and the temperature were
modified to obtain the optimum yield (Table 1). Accordingly,
Table 1 Reaction optimisationa
Temp Time
Entry Reagentsb Basec
Solventd (1C)
(h)
Yieldse (%) 2aA
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
I2
I2
I2
K2CO3
K2CO3
NaHCO3 DMSO 90
Cs2CO3 DMSO rt
Cs2CO3 DMSO 90
Cs2CO3 DMSO 120
Cs2CO3 DMF
KOH
—
MeOH 70
DMSO 90
24
1
1.5
10
45 min 85
45 min 85
1.5
1
16
25% + 1a (60%)
77
70
78
90
65
75
Fig. 2 Previous finding related to the synthesis of a designed prototype.
DMSO 90
DMSO 90
66 + polar
impurity
NR
NR
NR
10f
I2
I2
I2
TBAI
NCS
Et3N
DIPEA
—
Cs2CO3 DMSO 90
K2CO3
DMSO 90
DMSO 90
24
24
16
16
12
development of chemical libraries of b-carboline based molecular 11f
12f
AcOH
90
hybrids using sustainable approaches. In a recent finding, we have
demonstrated the I2-mediated synthesis of b-carboline N-fused
13f
NR
14
DMF
90
32 + polar
impurity
NR
NR
NR
—
—
—
imidazoles via decarboxylative oxidation of natural a-amino
15f
DMP
NH4Cl
—
—
—
CH2Cl2 35
DMSO 90
DMSO 90
24
12
12
12
12
12
acids.24a In an extension to our research on the synthesis of
16f
17f,g FeCl3
b-carboline based privileged scaffolds, we have developed a surro-
gate approach for the synthesis of b-carboline substituted 1,3,4- 18f,g CuI
Cs2CO3 DMSO 90
19f,g Cu(OTf)2 Cs2CO3 DMSO 90
20f,g La(OTf)2 Cs2CO3 DMSO 90
oxadiazole derivatives via an iodine-mediated oxidative cyclisation
process (Fig. 2). The details of these studies are presented here.
a
Reaction conditions: All reactions were optimised with 0.134 mmol
b
(1.0 equiv.) benzoylhydrazone 1aA in 1 mL of solvent. Molecular
iodine (1.5 equiv.), KI (2.0 equiv.), TBAI (2.5 equiv.), NCS (2.0 equiv.),
DMP (2.5 equiv.), NH4Cl (2.0 equiv.) was used for oxidative cyclisation.
Results and discussion
c
d
3.0 equiv. of base was used. Reactions were performed in anhydrous
To achieve the synthesis of the designed molecular hybrid,
optimization of the reaction conditions was achieved using
f
solvents (entries 1–21). e Isolated yields of the purified product. NR = No
g
reaction; the starting substrate 1aA was recovered. 20 mol% catalyst was
1-formyl b-carboline 1a and benzohydrazide A as the model used and decomposition of benzoylhydrazone 1aA was observed.
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when the reaction was examined in DMSO using K2CO3 as a
base in the presence of iodine, 1aA was completely consumed
within 1 h and the yield of the anticipated product 2aA was
significantly improved (77%, Table 1, entry 2). Encouraged by
these results, we screened various bases with DMSO as the
solvent and molecular iodine as an oxidant. The reaction in the
presence of NaHCO3 could not enhance the yield and generated
the desired product in 70% yield with some unidentified polar
impurities (Table 1, entry 3). The reaction with 1.5 equiv. of
iodine and 3.0 equiv. of Cs2CO3 in DMSO at ambient tempera-
Scheme 1 Synthesis of b-carboline tethered 1,3,4-oxadiazole 2aA from
1-formyl b-carboline (1a) and benzoic hydrazide (A).
ture afforded a clean reaction (82% yield) but required 10 h for 1aA from the reaction mixture and the desired product was
completion (Table 1, entry 4). Interestingly, when the reaction obtained in 25% yield only. Then the one-pot assembly of
was performed under similar conditions at 90 1C, it was reactants was executed in DMSO but condensation of 1a and
completed within 45 min to give the product in 85% yield A was not completed even after 12 h. It was realised that MeOH
(Table 1, entry 5). However, when the temperature was further was a suitable solvent for hydrazone synthesis 1aA while DMSO
increased to 120 1C, no visible improvement was observed in was suited for oxidative cyclisation. Therefore, an alternate
the reaction time or yield of the product (Table 1, entry 6). It was procedure was adopted where first hydrazone synthesis was
realized that the use of Cs2CO3 took less time as compared to achieved in MeOH within 1 h, then MeOH was evaporated and
other bases and a clean reaction was obtained to yield the the hydrazone was re-dissolved in DMSO and subjected to
product in excellent yield. More importantly, treatment of the oxidative cyclisation with 1.5 equiv. of iodine and 3.0 equiv.
reaction mixture with cold water furnished the desired product of Cs2CO3 at 90 1C for 45 min. To our delight, a clean reaction
as a solid and the analytically pure product could be obtained was observed and no column chromatographic separation was
by simple filtration under vacuum followed by washing with required.
diethyl ether.
With established conditions in hand, the scope of this one-
It was further observed that the reaction in anhydrous DMF pot procedure was investigated for condensation and oxidative
at 90 1C in the presence of molecular iodine completed in 1.5 h cyclisation of 1-formyl b-carbolines24 (1a, 1i and 1k) with substi-
but the product was generated in 65% yield (Table 1, entry 7). tuted acylhydrazides (A–L) to afford the desired b-carboline
The combination of KOH with DMSO in the presence of iodine substituted 1,3,4-oxadiazoles as depicted in Scheme 2. It was
also efficiently produced 1,3,4-oxadiazole 2aA in 75% yield pleasing to see that the methodology worked well and smoothly
(Table 1, entry 8). To our surprise, I2-mediated oxidative cyclisa- yielded the anticipated products 2aA–aK, 2iA, 2kA, 2kG, 2kI
tion in the absence of any base also generated the desired and 2kL via oxidative cyclisation (C–O bond formation) within
product 2aA in 66% yield in 16 h but polar impurities were also 1.75–5 h. The strategy was found compatible with a broad range
formed (Table 1, entry 9). It was found that the use of organic of acylhydrazides (A–K) bearing electron withdrawing as well as
bases (Et3N or DIPEA) failed to deliver the desired product electron donating groups. It was analysed that the acylhydra-
(Table 1, entries 10 and 11). Similarly, the corresponding product zides with an electron-donating group (F) reacted faster and
was not generated when TBAI was used as an iodide source (Iꢀ) afforded higher yield (87%) in comparisons to those bearing
for this transformation instead of molecular iodine (Table 1, electron-withdrawing groups (B–D) (46–76%). The heteroaryl
entry 13) indicating that the iodonium ion (I+) was possibly acylhydrazides (G–I) also reacted efficiently and furnished the
driving the reaction. Recently, we found that NCS could be used corresponding products in good to excellent yields (74–92%).
for decarboxylative oxidation of tetrahydro-b-carbolines so it was Furthermore, this method was extended to aliphatic hydra-
planned to investigate its utility for oxidative cyclisation.24a zides, such as acetylhydrazide K which generated the respective
Interestingly, NCS was able to provide the desired product albeit products 2aK in 50% yield.
in low yield (32%) along with an unidentified polar impurity
Encouraged by these results, we further extended our study
(Table 1, entry 14). The use of DMP, NH4Cl and transition metal by employing N-9 substituted 1-formyl b-carboline derivatives
catalysts like FeCl3, CuI, Cu(OTf)2 and La(OTf)2 failed to deliver (1b–h and 1j) for oxidative cyclisation with benzohydrazide A.
the desired product (Table 1, entries 15–20). Eventually, the To our delight, the reactions under optimum conditions easily
optimization investigations led to the inference that DMSO yielded the corresponding b-carboline C1 substituted 1,3,4-
was the best solvent and Cs2CO3 was a suitable base for the oxadiazole derivatives 2bA–gA and 2jA within 1.5–3 h in good
oxidative cyclization of 1aA in a short duration with 85% yield to excellent yield ranging from 73 to 87% (Scheme 3). It is
(Table 1, entries 5 and 6).
important to mention that N-alkylated derivatives (except
Next, it was considered worthwhile to develop a one-pot N-propargyl, 1f) furnished the desired product in better yield
procedure for this transformation (Scheme 1). Accordingly, and took less time for completion as compared to the free N–H
condensation of 1a with A and successive oxidative cyclisation derivative of b-carboline 1a. Surprisingly, when 1h was sub-
was attempted in MeOH using Cs2CO3 and I2 at 70 1C but jected to annulation with A under optimal reaction conditions,
the formation of b-carboline substituted 1,3,4-oxadiazole 2aA cleavage of the 2-nitrobenzyl group from the N-9 position of the
required more than 24 h due to the precipitation of hydrazone b-carboline ring was observed and 2aA was obtained as the
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Scheme 4 Synthesis of b-carboline tethered bis-1,3,4-oxadiazole.
the synthesis of b-carboline tethered bis-oxadiazoles by employing
b-carboline 1,3-dicarbaldehyde 4 as the precursor prepared
from 3.25 The reaction of dialdehyde 4 with benzohydrazide A
in the presence of I2 and Cs2CO3 at 90 1C smoothly afforded the
desired product 5A in 43% yield (Scheme 4) after a silica gel
column chromatographic separation.
Surprisingly, when formic hydrazide L was used for oxidative
annulation with 1k (Scheme 5), the 1-cyano b-carboline 6 was
obtained as the sole product instead of 2kL as confirmed on the
1
basis of H-, 13C-NMR and HRMS data.
Next, it was envisaged to further extend the scope of this
practical methodology to prepare b-carboline containing 2-amino-
1,3,4-oxadiazole derivatives by replacing benzohydrazide A with
semicarbazide hydrochloride M. However, Kumujian C 1k failed
to react with semicarbazide hydrochloride M in the presence
of I2 and Cs2CO3 in DMSO. The screening of various solvents
indicated that the desired product 2kM could be isolated in
73% yield in 1,4-dioxane at 90 1C, as depicted in Scheme 6.
In order to demonstrate the applicability of this protocol for
industrial application, a one gram scale reaction was also
conducted using 1a and A as substrates and to our pleasure,
the expected product 2aA was obtained in an analytically
pure form (77%) without column chromatographic purification
(Scheme 7).
Scheme 2 Synthesis of b-carboline C-1 tethered 1,3,4-oxadiazole deri-
vatives with the scope of variation in substituted acylhydrazides.
To probe the reaction mechanism, two control experiments
were conducted where the isolated benzohydrazone 1bA was
separately reacted with iodine monochloride (source of I+) and
KI (source of Iꢀ) in the presence of Cs2CO3 in DMSO under
optimised conditions. It was found that ICl readily afforded the
desired b-carboline substituted 1,3,4-oxadiazole, 2bA within 2h
while KI failed to execute the reaction (Scheme 8). These experiments
Scheme 5 Synthesis of 1-cyano b-carboline.
Scheme 3 Synthesis of N-alkylated b-carboline substituted 1,3,4-oxadiazole
derivatives.
product instead of 2hA. It is valuable to mention that the
analytically pure products (2bA–gA and 2jA) could be obtained
by washing the crude product with diethyl ether and column
chromatographic separation was not required.
Delighted by the successful synthesis of b-carboline C1 tethered
Scheme 6 Synthesis of b-carboline C1 tethered 2-amino 1,3,4-oxadiazole
1,3,4-oxadiazoles, we examined the scope of this methodology for from semicarbazide.
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intermediate 8 which may follow base/heat mediated annula-
tion with loss of 1 mole of HI to afford the 1,3,4-oxadiazole
framework 2aA as depicted in Fig. 2. The desired product could
not be produced in the presence of Lewis acids (FeCl3, Cu(OTf)2
and La(OTf)2) which are likely to follow route-II during annula-
tion; therefore, there is good probability that the reaction is
following route-I. The generation of HI during the course of
reaction was confirmed by the pH study of a reaction medium
which was performed in the absence of base (SI). It was observed
that after completion of the reaction under base free conditions,
the pH of the reaction medium was 2.61.
Scheme 7 Gram scale synthesis of 2aA.
Conclusions
In summary, we have developed a transition metal-free approach
for the synthesis of b-carboline C1 tethered 1,3,4-oxadiazoles
as well as 2-amino 1,3,4-oxadiazoles via I2 mediated oxidative
cyclocondensation. This sequential one-pot synthetic procedure
was found to be compatible for the annulation of diversely
substituted hydrazides and 1-formyl b-carboline derivatives and
desired 1,3,4-oxadiazoles could be isolated at a gram scale
without column chromatographic purification. This method-
ology provides easy access to heterocycles with potential phar-
maceutical applications. The investigation of the application of
b-carboline linked 1,3,4-oxadiazoles as a ligand for complexa-
tion with metals and their development as analytical sensors is
currently in progress in our laboratory.
Scheme 8 Control experiments.
indicated that the iodonium ion played a key role in initiation
of this oxidative annulation process.
A plausible mechanism for the formation of b-carboline
substituted 1,3,4-oxadiazoles is presented in Fig. 3 based on
the results of the study. Initially, the condensation of 1-formyl
b-carboline 1a and benzohydrazide (A) resulted in the forma-
tion of isolable benzoylhydrazone 1aA. Then, it is proposed that
Experimental section
General methods
benzoylhydrazone 1aA may undergo Cs2CO3 mediated oxidative The reagents and chemicals were procured from Sigma Aldrich
C-iodination via route-I to generate the intermediate 6. The and Spectrochem Ltd and used as such without additional puri-
successive formation of a new C–O bond via a SN2-type intra- fication. The anhydrous solvents (glacial AcOH, DCM, DMSO,
molecular cyclization of 7 may result in the formation of 1,3,4- DMF, and MeOH) were used as available commercially. TLC was
oxadiazole framework 2aA. Alternatively, benzoylhydrazone 1aA examined on precoated aluminum plates (E. Merck; silica gel
may undergo N-iodination via route-II to generate an N-iodo 60 PF254, 0.25 mm). The column chromatographic separation
Fig. 3 The proposed mechanism for the construction of b-carboline substituted 1,3,4-oxadiazole.
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was conducted on silica gel (SRL; 60–120 mesh). The melting nmax = 3565 (NH), 1701 (CO2CH3), 1620 (CQN), 1265 (C–O),
points were recorded in open-ended capillary tubes on a Precision 1058 (C–O–C); 1H NMR (400 MHz, CDCl3) d = 4.10 (s, 3 H,
Digital melting-point apparatus (LABCO make) that contained CO2CH3), 7.28–7.43 (m, 3 H, ArH), 7.59–7.67 (m, 3 H, ArH), 8.23
silicon oil and are uncorrected. The IR spectra were recorded on (dd, J1 = 15.5 Hz, J2 = 7.7 Hz, 2 H, ArH), 9.00 (s, 1 H, ArH), 10.48
an Agilent FTIR spectrophotometer. 1H and 13C NMR spectra were (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3) d = 53.0, 111.9 (d,
recorded on an Avance III Bruker spectrometer at operating J = 11 Hz), 112.7, 117.1 (d, J = 21 Hz), 119.8, 121.4, 122.0 (d, J =
frequencies of 400 MHz or 100 MHz (13C), as mentioned in the 34 Hz), 124.7, 124.8, 125.2, 130.2 (d, J = 20 Hz), 131.1, 134.1,
individual spectrum, by using TMS as a standard. The HRMS 134.2, 135.9, 138.0, 141.2, 159.2, 162.5 (d, J = 143 Hz), 166.0 ppm;
spectra were recorded on Xevo G2-SQ TOF (Water; USA) or HRMS (ESI) m/z: calcd for C21H13FN4O3 [M + H+]: 389.1050, found:
Thermo Finnigan LCQ Advantage, Ion-Trap Mass Spectrometer. 389.1077.
Elemental analysis was performed on a Carlo–Erba 108 or an
Elementar Vario EL III microanalyzer. During the study, room
Methyl 1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2aC)
temperature varied between 25 and 40 1C. The multiplicity in the
1H NMR spectra is mentioned as follows: s for singlet, d for Yield: 46% (0.163 g from 0.200 g) as a pale yellow solid; m.p. 4
doublet, t for triplet, q for quartet, dd for doublet of doublet, dt for 260 1C; Rf = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax
=
doublet of triplet and m for multiplet.
3483 (NH), 1711 (CO2CH3), 1629 (CQN), 1277 (C–O), 1064
(C–O–C); H NMR (400 MHz, CDCl3) d = 4.12 (s, 3 H, CO2CH3),
7.43 (dt, J1 = 8.0 Hz, J2 = 4.1 Hz, 1 H, ArH), 7.68 (d, J = 3.8 Hz, 2 H,
ArH), 7.70–7.72 (m, 2 H, ArH), 8.15–8.19 (m, 2 H, ArH), 8.24 (dd,
J1 = 7.9 Hz, J2 = 0.7 Hz, 1 H, ArH), 9.02 (d, J = 0.5 Hz, 1 H, ArH), 10.45
1
General procedure (one-pot) for the synthesis of compounds
2aA–aK, 2iA, 2kA, 2kG, 2kI, 2kL, 2bA–hA and 2jA as exemplified
for compound 2aA
The stirred solution of 1-formyl b-carboline 1a (0.200 g, 0.787 mmol) (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3) d = 53.1, 112.7, 120.0,
and benzohydrazide A (0.112 g, 0.826 mmol) in MeOH (10 mL) was 121.6, 122.0, 122.2, 122.4, 125.3, 127.3, 129.1, 130.3, 131.2, 132.6,
refluxed for 1 h. After the condensation was completed as mon- 136.0, 138.1, 141.3, 163.5, 164.6, 166.0 ppm; HRMS (ESI) m/z: calcd
itored by TLC, the solvent was evaporated under reduced pressure. for C21H13BrN4O3 [M + H+]: 449.0249, found: 449.0194.
The resulting benzohydrazone 1aA was re-dissolved in DMSO
Methyl 1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2aD)
(5 mL), followed by addition of cesium carbonate (0.770 g,
2.362 mmol) and molecular iodine (0.300 g, 1.181 mmol) in
sequence and the reaction mixture was stirred at 90 1C for Yield: 76% (0.242 g from 0.200 g) as an off-white solid; m.p. 257–
45 min; the conversion was monitored by the TLC technique. 259 1C; Rf = 0.40 (hexane/EtOAc, 70:30, v/v); IR (neat): nmax = 3512
The reaction mixture was cooled to room temperature and then (NH), 1707 (CO2CH3), 1626 (CQN), 1269 (C–O), 1067 (C–O–C);
the content was poured into ice-cold water followed by treat- 1H NMR (400 MHz, CDCl3) d = 4.12 (s, 3 H, CO2CH3), 7.40–7.44
ment with 5% aq. Na2S2O3 (20 mL), and light brown precipi- (m, 1 H, ArH), 7.54 (d, J = 8.3 Hz, 2 H, ArH), 7.68 (d, J = 3.9 Hz, 2 H,
tates were obtained which were filtered and sintered under high ArH), 8.23 (d, J = 8.3 Hz, 3 H, ArH), 9.01 (s, 1 H, ArH), 10.44 (s, 1 H,
vacuum to get a crude product which was triturated and washed NH) ppm; 13C NMR (100 MHz, CDCl3) d = 53.1, 112.7, 120.0, 121.6,
with diethyl ether (twice) to afford the analytically pure product, 121.7, 122.0, 122.4, 125.3, 129.0, 129.6, 130.2, 131.2, 136.0, 138.0,
b-carboline C1 tethered 1,3,4-oxadiazole 2aA in 80% yield.
138.8, 141.2, 163.5, 164.5, 166.0 ppm; HRMS (ESI) m/z: calcd for
C21H13ClN4O3 [M + H+]: 405.0754, found: 405.0702.
Methyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]
indole-3-carboxylate (2aA)
Methyl 1-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-9H-
pyrido[3,4-b]indole-3-carboxylate (2aE)
Yield: 80% (0.234 g from 0.200 g) as a light brown solid;
m.p. 199–201 1C; Rf = 0.35 (hexane/EtOAc, 70 : 30, v/v); IR (neat): Yield: 51% (0.161 g from 0.200 g) as an off-white solid;
nmax (cmꢀ1) = 3426 (NH), 1710 (CO2CH3), 1626 (CQN), 1261 m.p. 254–256 1C; Rf = 0.40 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
(C–O), 1064 (C–O–C); 1H NMR (400 MHz, CDCl3 + DMSO-d6) d = nmax = 3450 (NH), 1704 (CO2CH3), 1623 (CQN), 1266 (C–O),
4.02 (s, 3 H, CO2CH3), 7.31 (t, J = 7.5 Hz, 1 H, ArH), 7.46–7.52 1060 (C–O–C); 1H NMR (400 MHz, CDCl3) d = 3.92 (s, 3 H,
(m, 3 H, ArH), 7.57 (t, J = 7.6 Hz, 1 H, ArH), 7.69 (d, J = 8.2 Hz, OCH3), 4.13 (s, 3 H, CO2CH3), 7.07 (d, J = 8.9 Hz, 2 H, ArH),
1 H, ArH), 8.14 (d, J = 7.9 Hz, 1 H, ArH), 8.21 (d, J = 7.9 Hz, 2 H, 7.40–7.45 (m, 1 H, ArH), 7.68 (d, J = 3.3 Hz, 2 H, ArH), 8.23–8.27
ArH), 8.93 (s, 1 H, ArH), 10.87 (s, 1 H, NH) ppm; 13C NMR (m, 3 H, ArH), 9.03 (s, 1 H, ArH), 10.51 (s, 1 H, NH) ppm;
(100 MHz, CDCl3 + DMSO-d6) d = 52.8, 112.9, 119.6, 121.2, 13C NMR (100 MHz, CDCl3) d = 53.1, 55.6, 112.6, 114.6, 115.7,
121.6, 121.9, 123.1, 125.3, 127.5, 129.0, 129.8, 130.9, 132.2, 119.7, 121.6, 121.9, 122.3, 125.7, 129.6, 130.1, 131.0, 135.9,
135.6, 137.4, 141.1, 163.1, 165.0, 165.8 ppm; HRMS (ESI) m/z: 137.9, 141.2, 162.9, 163.0, 165.3, 166.1 ppm; HRMS (ESI) m/z:
calcd for C21H14N4O3 [M + Na]: 393.0964, found: 393.1002.
calcd for C22H16N4O4 [M + H+]: 401.1250, found: 401.1254.
Methyl 1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2aB)
Methyl 1-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]
indole-3-carboxylate (2aF)
Yield: 75% (0.230 g from 0.200 g) as a light brown solid; Yield: 87% (0.263 g from 0.200 g) as a pale yellow solid;
m.p. 204–206 1C; Rf = 0.30 (hexane/EtOAc, 70 : 30, v/v); IR (neat): m.p. 233–235 1C; Rf = 0.37 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
98 | New J. Chem., 2019, 43, 93--102
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nmax = 3412 (NH), 1709 (CO2CH3), 1618 (CQN), 1266 (C–O), Methyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]
1126 (C–O–C); 1H NMR (400 MHz, CDCl3) d = 2.47 (s, 3 H, indole-3-carboxylate (2aK)
ArCH3), 4.13 (s, 3 H, CO2CH3), 7.39 (d, J = 7.9 Hz, 2 H, ArH), 7.43
Yield: 50% (0.122 g from 0.200 g) as a light brown solid;
(dd, J1 = 7.9 Hz, J2 = 4.5 Hz, 1 H, ArH), 7.70 (d, J = 3.4 Hz, 2 H,
m.p. 235–237 1C; Rf = 0.30 (hexane/EtOAc, 50 : 50, v/v); IR (neat):
ArH), 8.22 (d, J = 8.0 Hz, 2 H, ArH), 8.26 (d, J = 7.9 Hz, 1 H, ArH),
nmax = 3391 (NH), 1712 (CO2CH3), 1587 (CQN), 1260 (C–O),
9.05 (s, 1 H, ArH), 10.52 (s, 1 H, NH) ppm; 13C NMR (100 MHz,
1086 (C–O–C); 1H NMR (400 MHz, CDCl3) d = 2.74 (s, 3 H, CH3),
4.09 (s, 3 H, CO2CH3), 7.39–7.43 (m, 1 H, ArH), 7.66 (d, J =
CDCl3) d = 21.7, 53.1, 100.1, 112.9, 119.8, 120.5, 121.6, 121.9,
122.3, 127.7, 127.8, 129.9, 130.1, 135.9, 138.0, 141.3, 143.1,
3.8 Hz, 2 H, ArH), 8.22 (d, J = 7.9 Hz, 1 H, ArH), 8.99 (s, 1 H,
ArH), 10.40 (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3) d =
163.1, 165.5, 166.1 ppm; HRMS (ESI) m/z: calcd for C22H16N4O3
[M + H+]: 385.1301, found: 385.1289.
11.5, 53.2, 112.6, 119.8, 121.5, 121.9, 122.3, 125.5, 130.2, 131.1,
136.7, 137.8, 141.2, 163.6, 164.7, 166.0 ppm; HRMS (ESI) m/z:
calcd for C16H12N4O3 [M + H+]: 309.0988, found: 309.0999.
Methyl 1-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-
b]indole-3-carboxylate (2aG)
Isopropyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]
indole-3-carboxylate (2iA)
Yield: 80% (0.235 g from 0.200 g) as a light brown solid; m.p. 4
260 1C; Rf = 0.30 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax
=
3392 (NH), 1714 (CO2CH3), 1595 (CQN), 1261 (C–O), 1107
(C–O–C); H NMR (400 MHz, CDCl3) d = 4.12 (s, 3 H, CO2CH3),
Yield: 90% (0.255 g from 0.200 g) as a light brown solid;
m.p. 197–199 1C; Rf = 0.50 (hexane/EtOAc, 50 : 50, v/v); IR (neat):
1
7.42–7.46 (m, 1 H, ArH), 7.52–7.55 (m, 1 H, ArH), 7.70 (d, J =
4.0 Hz, 2 H, ArH), 8.25 (d, J = 7.9 Hz, 1 H, ArH), 8.58 (dt, J1 =
8.1 Hz, J2 = 1.9 Hz, 1 H, ArH), 8.84 (dd, J1 = 4.8 Hz, J2 = 1.5 Hz,
1 H, ArH), 9.04 (s, 1 H, ArH), 9.55 (d, J = 1.9 Hz, 1 H, ArH),
10.47 (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3) d = 53.2,
112.7, 119.9, 120.1, 121.5, 122.2, 122.4, 124.0, 125.1, 130.3,
131.3, 134.9, 136.0, 138.1, 141.3, 148.7, 153.0, 163.3, 163.8,
165.9 ppm; HRMS (ESI) m/z: calcd for C20H13N5O3 [M + H+]:
372.1097, found: 372.1078.
n
max = 3419 (NH), 1711 (CO2i-Pr), 1598 (CQN), 1234 (C–O), 1108
(C–O–C); 1H NMR (400 MHz, CDCl3) d = 1.53 (d, J = 6.3 Hz, 6 H,
CH(CH3)2), 5.41–5.47 (m, 1 H, CH(CH3)2), 7.40–7.44 (m, 1 H,
ArH), 7.58 (d, J = 7.7 Hz, 3 H, ArH), 7.68 (dd, J1 = 3.7 Hz, J2 = 1.5
Hz, 2 H, ArH), 8.26 (d, J = 7.9 Hz, 1 H, ArH), 8.31 (dd, J1 = 7.8 Hz,
J2 = 1.6 Hz, 2 H, ArH), 8.97 (s, 1 H, ArH), 10.49 (s, 1 H, NH) ppm;
13C NMR (100 MHz, CDCl3) d = 22.2, 69.8, 112.7, 119.7, 121.6,
121.8, 122.3, 123.4, 125.7, 127.7, 129.2, 130.1, 131.0, 132.4,
135.9, 138.7, 141.3, 163.5, 164.9, 165.3 ppm; HRMS (ESI) m/z:
calcd for C23H18N4O3 [M + H+]: 399.1457, found: 399.1443.
Methyl 1-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-
b]indole-3-carboxylate (2aH)
2-Phenyl-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole (2kA)
Yield: 83% (0.243 g from 0.200 g) as a pale yellow solid; m.p. 4
Yield: 77% (0.245 g from 0.200 g) as a brown solid; m.p. 209–
260 1C; Rf = 0.35 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax
=
211 1C; Rf = 0.50 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax
=
3465 (NH), 1630 (CQN), 1249 (C–O), 1088 (C–O–C); 1H NMR
(400 MHz, CDCl3 + DMSO-d6) d = 7.32 (t, J = 7.5 Hz, 1 H, ArH),
7.57–7.62 (m, 4 H, ArH), 7.80 (d, J = 8.2 Hz, 1 H, ArH), 8.14–8.18
(m, 2 H, ArH), 8.27 (d, J = 7.2 Hz, 2 H, ArH), 8.62 (d, J = 5.1 Hz,
1 H, ArH), 10.96 (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3 +
DMSO-d6) d = 112.3, 116.6, 120.0, 120.2, 121.1, 122.9, 125.1, 126.7,
128.5, 128.7, 130.0, 131.5, 133.9, 138.3, 140.8, 163.1, 163.9 ppm;
HRMS (ESI) m/z: calcd for C19H12N4O [M + H+]: 313.1089, found:
313.1067.
3399 (NH), 1719 (CO2CH3), 1623 (CQN), 1260 (C–O), 1107
1
(C–O–C); H NMR (400 MHz, CDCl3) d = 4.12 (s, 3 H, CO2CH3),
7.41–7.46 (m, 1 H, ArH), 7.70 (dd, J1 = 5.9 Hz, J2 = 1.0 Hz, 2 H,
ArH), 8.16 (dd, J1 = 4.5 Hz, J2 = 1.6 Hz, 2 H, ArH), 8.24 (d, J =
8.0 Hz, 1 H, ArH), 8.88 (dd, J1 = 4.5 Hz, J2 = 1.6 Hz, 2 H, ArH),
9.04 (s, 1 H, ArH), 10.50 (s, 1 H, NH) ppm; 13C NMR (100 MHz,
CDCl3) d = 53.2, 112.8, 120.3, 121.0, 121.5, 122.1, 122.4, 124.9,
130.4, 130.5, 131.5, 136.1, 138.1, 141.3, 151.1, 163.5, 164.2,
165.9 ppm; HRMS (ESI) m/z: calcd for C20H13N5O3 [M + H+]:
372.1097, found: 372.1114.
2-(Pyridin-3-yl)-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole
Methyl 1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-
b]indole-3-carboxylate (2aI)
(2kG)
Yield: 74% (0.236 g from 0.200 g) as a brown solid; m.p. 213–
Yield: 92% (0.261 g from 0.200 g) as a pale yellow solid; 215 1C; Rf = 0.35 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax
=
m.p. 255–257 1C; Rf = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): 1628 (CQN), 1225 (C–O), 1122 (C–O–C); 1H NMR (400 MHz,
nmax = 3393 (NH), 1712 (CO2CH3), 1624 (CQN), 1262 (C–O), CDCl3) d = 7.34–7.38 (m, 1 H, ArH), 7.51 (dd, J1 = 7.9 Hz, J2 =
1128 (C–O–C); 1H NMR (400 MHz, CDCl3) d = 4.11 (s, 3 H, 4.9 Hz, 1 H, ArH), 7.64 (d, J = 3.9 Hz, 2 H, ArH), 8.14 (d,
CO2CH3), 6.67 (dd, J1 = 3.5 Hz, J2 = 1.7 Hz, 1 H, ArH), 7.39–7.42 J = 5.0 Hz, 1 H, ArH), 8.18 (d, J = 7.8 Hz, 1 H, ArH), 8.54 (d, J =
(m, 2 H, ArH), 7.65–7.73 (m, 3 H, ArH), 8.23 (d, J = 7.8 Hz, 1 H, 8.0 Hz, 1 H, ArH), 8.66 (d, J = 5.1 Hz, 1 H, ArH), 8.82 (d, J =
ArH), 9.01 (s, 1 H, ArH), 10.49 (s, 1 H, NH) ppm; 13C NMR 4.4 Hz, 1 H, ArH), 9.51 (s, 1 H, ArH), 10.18 (s, 1 H, ArH) ppm;
(100 MHz, CDCl3) d = 53.1, 112.6, 112.7, 116.0, 120.0, 121.5, 13C NMR (100 MHz, CDCl3) d = 112.3, 117.6, 120.1, 121.0, 121.1,
122.0, 122.3, 125.2, 130.2, 131.2, 136.0, 138.0, 139.1, 141.3, 122.1, 123.9, 125.2, 129.7, 130.9, 134.6, 134.8, 139.4, 140.9, 148.4,
146.6, 158.0, 162.6, 166.0 ppm; HRMS (ESI) m/z: calcd for 152.8, 162.8, 164.3 ppm; HRMS (ESI) m/z: calcd for C18H11N5O
C
19H12N4O4 [M + H+]: 361.0937, found: 361.0874.
[M + H+]: 314.1042, found: 314.1042.
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2-(Furan-2-yl)-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole
(2kI)
119.3, 121.1, 121.5, 121.6, 121.9, 123.6, 126.3, 127.5, 129.2, 130.0,
132.2, 132.5, 136.3, 137.1, 143.0, 162.0, 165.9 ppm; HRMS (ESI)
m/z: calcd for C24H20N4O3 [M + H+]: 413.1614, found: 413.1569.
Yield: 85% (0.262 g from 0.200 g) as a yellow solid; m.p. 4
260 1C; Rf = 0.60 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax
=
Methyl 9-allyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2eA)
3409 (NH), 1640 (CQN), 1271 (C–O), 1118 (C–O–C); 1H NMR
(400 MHz, CDCl3) d = 6.67 (dd, J1 = 3.4 Hz, J2 = 1.6 Hz, 1 H, ArH),
7.34–7.38 (m, 1 H, ArH), 7.42 (d, J = 3.5 Hz, 1 H, ArH), 7.62–7.66
(m, 2 H, ArH), 7.72 (d, J = 0.7 Hz, 1 H, ArH), 8.14 (d, J = 5.1 Hz,
1 H, ArH), 8.19 (d, J = 7.9 Hz, 1 H, ArH), 8.66 (d, J = 5.1 Hz, 1 H,
ArH), 10.18 (s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3)
d = 112.3, 112.5, 115.4, 117.5, 121.1, 121.3, 122.1, 125.5, 129.7,
130.8, 134.9, 139.3, 139.6, 141.0, 146.4, 157.7, 163.2 ppm;
HRMS (ESI) m/z: calcd for C17H10N4O2 [M + H+]: 303.0882,
found: 303.0870.
Yield: 86% (0.240 g from 0.200 g) as a light brown solid;
m.p. 160–162 1C; Rf = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
nmax = 1706 (CO2CH3), 1598 (CQN), 1297 (C–O), 1089 (C–O–C);
1H NMR (400 MHz, CDCl3) d = 4.10 (s, 3 H, CO2CH3), 4.57 (d, J =
16.7 Hz, 1 H, =CHH), 4.90 (dd, J1 = 10.5 Hz, J2 = 0.7 Hz, 1 H,
=CHH), 5.48–5.51 (m, 2 H, NCH2), 5.68–5.75 (m, 1 H, NCH2CH),
7.45 (t, J = 7.6 Hz, 1 H, ArH), 7.55–7.60 (m, 4 H, ArH), 7.71 (t, J =
7.2 Hz, 1 H, ArH), 8.24 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 2 H, ArH),
8.29 (d, J = 7.8 Hz, 1 H, ArH), 9.09 (s, 1 H, ArH) ppm; 13C NMR
(100 MHz, CDCl3) d = 47.2, 53.2, 110.9, 116.7, 119.4, 121.2, 121.9,
122.0, 123.7, 126.8, 127.6, 129.2, 130.2, 132.1, 132.2, 132.8, 136.3,
137.7, 143.1, 161.9, 165.8, 165.9 ppm; HRMS (ESI) m/z: calcd for
C24H18N4O3 [M + H+]: 411.1457, found: 411.1491.
Methyl 9-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2bA)
Yield: 84% (0.240 g from 0.200 g) as an off-white solid;
m.p. 228–230 1C; Rf = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
nmax = 1711 (CO2CH3), 1588 (CQN), 1267 (C–O), 1129 (C–O–C);
1H NMR (400 MHz, CDCl3) d = 4.09 (s, 3 H, NCH3), 4.10 (s, 3 H,
CO2CH3), 7.45 (t, J = 7.5 Hz, 1 H, ArH), 7.58 (t, J = 7.6 Hz, 4 H,
ArH), 7.74 (d, J = 7.5 Hz, 1 H, ArH), 8.25–8.28 (m, 3 H, ArH), 9.06
(s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) d = 33.5, 53.2,
110.6, 119.4, 121.0, 121.8, 122.0, 123.7, 126.4, 127.6, 129.2,
130.2, 132.3, 132.4, 137.3, 143.6, 162.0, 165.9, 166.0 ppm;
HRMS (ESI) m/z: calcd for C22H16N4O3 [M + Na]: 407.1120,
found: 407.1070.
Methyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9-(prop-2-yn-1-yl)-9H-
pyrido[3,4-b]indole-3-carboxylate (2fA)
Yield: 75% (0.105 g from 0.100 g) as a light brown solid;
m.p. 205–207 1C; Rf = 0.50 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
nmax = 1710 (CO2CH3), 1622 (CQN), 1275 (C–O), 1127 (C–O–C);
1H NMR (400 MHz, CDCl3) d = 2.00 (t, J = 2.4 Hz, 1 H,
CH2CRCH), 4.11 (s, 3 H, CO2CH3), 5.74 (d, J = 2.4 Hz, 2 H,
NCH2), 7.47 (t, J = 7.5 Hz, 1 H, ArH), 7.55–7.60 (m, 3 H, ArH),
7.64 (d, J = 8.4 Hz, 1 H, ArH), 7.74 (t, J = 7.4 Hz, 1 H, ArH), 8.27
(dd, J1 = 7.9 Hz, J2 = 1.7 Hz, 3 H, ArH), 9.07 (s, 1 H, ArH) ppm;
13C NMR (100 MHz, CDCl3) d = 35.3, 53.2, 73.3, 77.0, 110.7,
119.3, 121.5, 122.1, 122.3, 123.7, 127.0, 127.6, 129.2, 130.4, 132.3,
133.4, 135.8, 138.1, 142.6, 162.1, 165.8, 166.0 ppm; HRMS (ESI)
m/z: calcd for C24H16N4O3 [M + H+]: 409.1301, found: 409.1350.
Methyl 9-ethyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2cA)
Yield: 87% (0.246 g from 0.200 g) as an off-white solid;
m.p. 204–206 1C; Rf = 0.55 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
nmax = 1714 (CO2CH3), 1586 (CQN), 1269 (C–O), 1119 (C–O–C);
1H NMR (400 MHz, CDCl3) d = 1.28 (t, J = 7.2 Hz, 3 H,
NCH2CH3), 4.09 (s, 3 H, CO2CH3), 4.80 (q, J = 7.2 Hz, 2 H,
NCH2CH3), 7.43 (t, J = 7.5 Hz, 1 H, ArH), 7.54–7.62 (m, 4 H,
ArH), 7.69–7.73 (m, 1 H, ArH), 8.23–8.29 (m, 3 H, ArH), 9.06
(s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) d = 14.3, 40.2,
53.1, 110.7, 119.4, 121.3, 121.7, 122.0, 123.6, 126.2, 127.5,
129.2, 130.1, 132.3, 132.7, 136.1, 137.1, 142.6, 162.1, 165.9 ppm;
HRMS (ESI) m/z: calcd for C23H18N4O3 [M + H+]: 399.1457, found:
399.1457.
Methyl 9-benzyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (2gA)
Yield: 83% (0.222 g from 0.200 g) as a light brown solid;
m.p. 144–145 1C; Rf = 0.65 (hexane/EtOAc, 70 : 30, v/v); IR (neat):
nmax = 1714 (CO2CH3), 1628 (CQN), 1257 (C–O), 1149 (C–O–C);
1H NMR (400 MHz, CDCl3) d = 4.06 (s, 3 H, CO2CH3), 6.01 (s,
2 H, NCH2), 6.53 (d, J = 7.3 Hz, 2 H, ArH), 6.90 (t, J = 7.3 Hz, 2 H,
ArH), 6.95 (t, J = 7.1 Hz, 1 H, ArH), 7.48–7.51 (m, 3 H, ArH), 7.55
(d, J = 7.3 Hz, 1 H, ArH), 7.65 (d, J = 8.4 Hz, 1 H, ArH), 7.71–7.75
(m, 1 H, ArH), 8.00 (d, J = 7.1 Hz, 2 H, ArH), 8.35 (d, J = 7.8 Hz,
1 H, ArH), 9.12 (s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3)
d = 48.1, 53.2, 110.8, 119.4, 121.1, 122.1, 122.2, 123.6, 125.8,
Methyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9-propyl-9H-pyrido
[3,4-b]indole-3-carboxylate (2dA)
Yield: 79% (0.110 g from 0.100 g) as an off-white solid; 127.2, 127.5, 128.7, 129.0, 130.4, 132.1, 132.9, 135.4, 136.1,
m.p. 201–202 1C; Rf = 0.65 (hexane/EtOAc, 70 : 30, v/v); IR (neat): 137.7, 143.8, 161.3, 165.8, 165.9 ppm; HRMS (ESI) m/z: calcd
nmax = 1713 (CO2CH3), 1590 (CQN), 1261 (C–O), 1123 (C–O–C); for C28H20N4O3 [M + H+]: 461.1614, found: 461.1661.
1H NMR (400 MHz, CDCl3) d = 0.73 (t, J = 7.1 Hz, 3 H,
Isopropyl 9-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-
pyrido[3,4-b]indole-3-carboxylate (2jA)
NCH2CH2CH3), 1.62-1.67 (m, 2 H, NCH2CH2CH3), 4.09 (s, 3 H,
CO2CH3), 4.71 (t, J = 7.1 Hz, 2 H, NCH2CH2CH3), 7.41 (t, J =
7.2 Hz, 1 H, ArH), 7.53–7.60 (m, 4 H, ArH), 7.67–7.71 (m, 1 H, Yield: 73% (0.203 g from 0.200 g) as a pale yellow solid;
ArH), 8.25 (d, J = 5.0 Hz, 3 H, ArH), 9.05 (s, 1 H, ArH) ppm; m.p. 185–187 1C; Rf = 0.60 (hexane/EtOAc, 50 : 50, v/v); IR (neat):
13C NMR (100 MHz, CDCl3) d = 11.2, 22.6, 46.6, 53.1, 110.9, nmax = 1707 (CO2i-Pr), 1594 (CQN), 1255 (C–O), 1121 (C–O–C);
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1H NMR (400 MHz, CDCl3) d = 1.50 (d, J = 6.2 Hz, 6 H, MeOH (7 mL), 1k (0.150 g, 0.765 mmol) was added and stirring
CH(CH3)2), 4.10 (s, 3 H, NCH3), 5.38–5.45 (m, 1 H, CH(CH3)2), continued at room temperature for 1 h. After the condensation
7.43 (t, J = 7.2 Hz, 1 H, ArH), 7.56–7.59 (m, 4 H, ArH), 7.70–7.74 was completed as monitored by TLC, the solvent was evaporated
(m, 1 H, ArH), 8.25 (d, J = 1.8 Hz, 1 H, ArH), 8.27 (d, J = 7.8 Hz, under reduced pressure. The resulting residue was re-dissolved
2 H, ArH), 8.98 (s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) in 1,4-dioxane (5 mL), followed by addition of cesium carbonate
d = 22.2, 33.5, 69.7, 110.6, 119.0, 121.1, 121.6, 121.9, 123.7, 126.5, (0.748 g, 2.295 mmol) and iodine (0.291 g, 1.147 mmol) in
127.5, 129.2, 130.0, 132.2, 137.1, 137.9, 143.6, 162.2, 164.7, sequence and the reaction mixture was stirred at 90 1C for 1 h;
165.8 ppm; HRMS (ESI) m/z: calcd for C24H20N4O3 [M + H+]: the conversion was monitored by the TLC technique. The reaction
413.1614, found: 413.1637.
mixture was cooled to room temperature and then, the reaction
content was poured into ice-cold water followed by treatment with
5% aq. Na2S2O3 (20 mL), and yellow precipitates were obtained
9H-Pyrido[3,4-b]indole-1-carbonitrile (6)
Yield: 30% (0.030 g from 0.100 g) as a light brown solid; which were filtered and sintered to get a crude product which was
m.p. 201–203 1C; Rf = 0.40 (hexane/EtOAc, 50 : 50, v/v); IR (neat): triturated and washed with diethyl ether (twice) to afford the
n
max = 2239 (CN), 3404 (NH); 1H NMR (400 MHz, CDCl3) d = 7.38 analytically pure product 2kM in 73% yield.
(t, J = 7.4 Hz, 1 H, ArH), 7.61–7.69 (m, 2 H, ArH), 8.16 (dd, J1 =
6.3 Hz, J2 = 4.3 Hz, 2 H, ArH), 8.57 (d, J = 5.1 Hz, 1 H, ArH), 9.10 (s,
1 H, NH) ppm; 13C NMR (100 MHz, CDCl3) d = 112.2, 116.1, 116.7,
118.4, 121.1, 121.6, 122.4, 130.4, 131.0, 138.8, 140.6 ppm; HRMS
(ESI) m/z: calcd for C12H7N3 [M + H+]: 194.0718, found: 194.0780.
5-(9H-Pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazol-2-amine (2kM)
Yield: 73% (0.14 g from 0.150 g) as a pale yellow solid; m.p. 4
260 1C; Rf = 0.30 (hexane/EtOAc, 20 : 80, v/v); 1H NMR (400 MHz,
DMSO-d6) d = 7.29 (d, J = 7.4 Hz, 1 H, ArH), 7.55 (s, 2 H, NH2),
7.59 (d, J = 7.5 Hz, 1 H, ArH), 7.89 (d, J = 8.2 Hz, 1 H, ArH), 8.26
(dd, J1 = 8.9 Hz, J2 = 6.7 Hz, 2 H, ArH), 8.44 (d, J = 5.1 Hz, 1 H,
ArH), 11.57 (s, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3)
d = 113.4, 116.2, 120.0, 120.4, 121.7, 126.8, 128.7, 129.4, 132.5,
138.0, 141.3, 157.1, 164.1 ppm; HRMS (ESI) m/z: calcd for C13H9N5O
[M + H+]: 252.0885, found: 252.0849.
One pot procedure for the synthesis of 5A
A stirred solution of b-carboline 1,3-dicarbaldehyde 4 (0.150 g,
0.670 mmol) and benzohydrazide A (0.182 g, 1.339 mmol) in
MeOH (10 mL) was refluxed for 1 h. After the condensation was
completed as monitored by TLC, the solvent was evaporated
under reduced pressure. The resulting benzohydrazone 4A was
re-dissolved in DMSO (5 mL), followed by addition of cesium
carbonate (1.309 g, 4.017 mmol) and molecular iodine (0.510 g,
2.008 mmol) in sequence and the reaction mixture was stirred
at 90 1C for 1.5 h; the conversion was monitored by the TLC
technique. The reaction mixture was cooled to room temperature
and then the content was poured into ice-cold water followed by
treatment of 5% aq. Na2S2O3 (20 mL), and light brown precipitates
were obtained which were filtered and sintered under high
vacuum to get a crude product which was purified through a
short silica gel column chromatography using EtOAc : hexane
(30 : 70, v/v) as an eluent to afford the analytically pure product,
b-carboline tethered bis-1,3,4-oxadiazole 5A in 43% yield.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
D. S. acknowledges the Council of Scientific & Industrial Research
New Delhi (India), for a Senior Research Fellowship. V. S. grate-
fully acknowledges the financial support in the form of a research
grant from the Science and Engineering Research Board, New
Delhi (EMR/2017/000155 and SB/FT/CS-188/2011) and the Council
of Scientific & Industrial Research ((02)0202/14/EMR-II) New Delhi
(India) and TEQIP-III (NIT Jalandhar). The central instrumenta-
tion facility, Guru Nanak Dev University Amritsar and Tezpur
University, Assam is gratefully acknowledged for recording some
of the spectroscopic data reported in this paper.
5,50-(9H-Pyrido[3,4-b]indole-1,3-diyl)bis(2-phenyl-1,3,4-
oxadiazole) (5A)
Yield: 43% (0.131 g from 0.150 g) as a yellow solid; m.p. 4
260 1C; Rf = 0.70 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax
=
3393 (NH), 1565 (CQN), 1275 (C–O), 1139 (C–O–C); 1H NMR
(400 MHz, CDCl3) d = 7.38–7.42 (m, 1 H, ArH), 7.57–7.61 (m,
6 H, ArH), 7.64–7.67 (m, 2 H, ArH), 8.22 (d, J = 7.9 Hz, 1 H, ArH),
8.27–8.31 (m, 4 H, ArH), 9.06 (s, 1 H, ArH), 10.45 (s, 1 H, NH)
ppm; 13C NMR (100 MHz, CDCl3) d = 112.6, 117.5, 121.3, 121.9,
122.4, 123.4, 124.1, 127.4, 127.7, 129.2, 129.3, 130.4, 131.3, 132.0,
132.5, 133.5, 135.4, 141.3, 163.4, 164.6, 165.3, 166.5 ppm; HRMS
(ESI) m/z: calcd for C27H16N6O2 [M + H+]: 457.1413, found:
457.1454.
Notes and references
1 (a) R. Cao, W. Peng, Z. Wang and A. Xu, Curr. Med. Chem.,
2007, 14, 479; (b) H. Huang, Y. Yao, Z. He, T. Yang, J. Ma,
X. Tian, Y. Li, C. Huang, X. Chen, W. Li, S. Zhang, C. Zhang
and J. Ju, J. Nat. Prod., 2011, 74, 2122; (c) P.-C. Kuo, L.-S. Shi,
A. G. Damu, C.-R. Su, C.-H. Huang, C.-H. Ke, J.-B. Wu,
A.-J. Lin, K. F. Bastow, K.-H. Lee and T.-S. Wu, J. Nat. Prod.,
2003, 66, 1324; (d) K. K. H. Ang, M. J. Holmes, T. Higa,
M. T. Hamann and U. A. K. Kara, Antimicrob. Agents
Chemother., 2000, 44, 1645; (e) K. G. Brahmbhatt, N. Ahmed,
S. Sabde, D. Mitra, I. P. Singh and K. K. Bhutani, Bioorg. Med.
General procedure for the synthesis of compound 2kM
To a stirred solution of semicarbazide hydrochloride M (0.085 g,
0.765 mmol) and sodium acetate (0.063 g, 0.765 mmol) in
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NJC
Chem. Lett., 2010, 20, 4416; ( f ) Y.-H. Wang, J.-G. Tang, 11 A. Savarino, Expert Opin. Invest. Drugs, 2006, 15, 1507.
R.-R. Wang, L.-M. Yang, Z.-J. Dong, L. Du, X. Shen, J.-K. 12 N. D. James and J. W. Growcott, Drugs Future, 2009, 34, 624.
Liu and Y.-T. Zheng, Biochem. Biophys. Res. Commun., 2007, 13 H. Brandenberger and R. A. A. Maes, Clinical Biochemistry:
355, 1091; (g) Y. Liu, H. Song, Y. Huang, J. Li, S. Zhao,
Analytical Toxicology for Clinical, Forensic and Pharmaceutical
Y. Song, P. Yang, Z. Xiao, Y. Liu, Y. Li, H. Shang and Q. Wang,
Chemists, Walter de Gruyter, Berlin, 1997.
J. Agric. Food Chem., 2014, 62, 9987; (h) L. C. Meurer, 14 G. W. Adelstein, C. H. Yen, E. Z. Dajani and R. G. Bianchi,
R. N. Guthikonda, J. L. Huber and F. DiNinno, Bioorg. Med.
Chem. Lett., 1995, 5, 767.
2 (a) W. Horton, A. Sood, S. Peerannawar, N. Kugyela,
A. Kulkarni, R. Tulsan, C. D. Tran, J. Soule, H. LeVine,
J. Med. Chem., 1976, 19, 1221.
15 (a) H. Ichiro, K. Yasuhiko and U. Ryuzo, Nippon Kagaku
Zassi, 1967, 88, 574; (b) M. Ogata, H. Atobe, H. Kushida and
K. J. Yamamoto, Antibiotics, 1971, 24, 443.
¨ ¨
¨ ¨
27, 232; (b) R. Otto, R. Penzis, F. Gaube, T. Winckler,
B. Torok and M. Torok, Bioorg. Med. Chem. Lett., 2017, 16 L. Guo, W. K. Hagmann, S. He, Z. Lai, J. Liu, R. P. Nargund,
S. K. Shah and Q. T. Truong, US2014-8754099, Chem. Abst.,
¨
D. Appenroth, C. Fleck, C. Trankle, J. Lehmann and
2016, 1920231.
C. Enzensperger, Eur. J. Med. Chem., 2014, 87, 6; (c) Y. Rook, 17 (a) V. K. Tandon and R. B. Chhor, Synth. Commun., 2001,
K. U. Schmidtke, F. Gaube, D. Schepmann, B. Wu¨nsch,
J. Heilmann, J. Lehmann and T. Winckler, J. Med. Chem.,
2010, 53, 3611.
3 H. Guan, H. Chen, W. Peng, Y. Ma, R. Cao, X. Liu and A. Xu,
Eur. J. Med. Chem., 2006, 41, 1167.
4 Y. Song, D. Kesuma, J. Wang, Y. Deng, J. Duan, J. H. Wang
and R. Z. Qi, Biochem. Biophys. Res. Commun., 2004,
317, 128.
5 Y. Funayama, K. Nishio, K. Wakabayashi, M. Nagao,
K. Shimoi, T. Ohira, S. Hasegawa and N. Saijo, Mutat. Res.,
1996, 349, 183.
31, 1727; (b) S. Cesarini, N. Colombo, M. Pulici, E. R. Felder
and W. K.-D. Brill, Tetrahedron, 2006, 62, 10223; (c) P. Stabile,
A. Lamonica, A. Ribecai, D. Castoldia, G. Guercio and
O. Curcuruto, Tetrahedron Lett., 2010, 51, 4801.
18 (a) C. Dobrota, C. C. Paraschivescu, I. Dumitru, L. Lavinia,
I. Baciu and L. L. Ruta, Tetrahedron Lett., 2009, 50, 1886;
(b) P. Gao and Y.-Y. Wei, Heterocycl. Commun., 2013, 19, 113;
(c) P. Gao and Y.-Y. Wei, J. Chem. Res., 2013, 506; (d) W. Yu,
G. Huang, Y. Zhang, H. Liu, L. Dong, X. Yu, Y. Li and J. Chang,
J. Org. Chem., 2013, 78, 10337; (e) G. Majji, S. K. Rout, S. Guin,
A. Gogoi and B. K. Patel, RSC Adv., 2014, 4, 5357.
6 A. C. Castro, L. C. Dang, F. Soucy, L. Grenier, H. Mazdiyasni, 19 (a) T. Kawano, T. Yoshizumi, K. Hirano, T. Satoh and
M. Hottelet, L. Parent, C. Pien, V. Palombella and J. Adams,
Bioorg. Med. Chem. Lett., 2003, 13, 2419.
7 (a) L. A. Sorbera, L. Martin, P. A. Leeson and J. Castaner,
Drugs Future, 2001, 26, 15; (b) L. Turski, D. N. Stephens,
M. Miura, Org. Lett., 2009, 11, 3072; (b) M. Nishino,
K. Hirano, T. Satoh and M. Miura, Angew. Chem., Int. Ed.,
2013, 52, 4457; (c) X.-Y. Fan, X. Jiang, Y. Zhang, Z.-B. Chen
and Y.-M. Zhu, Org. Biomol. Chem., 2015, 13, 10402.
L. H. Jensen, E. N. Peterson, B. S. Mel-drum, S. Patel, J. B. 20 T. Fang, Q. Tan, Z. Ding, B. Liu and B. Xu, Org. Lett., 2014,
Hansen, W. Loscher, H. H. Schneider and R. Schmiechen,
J. Pharmacol. Exp. Ther., 1990, 253, 344.
16, 2342.
21 (a) M. Dabiria, P. Salehib, M. Baghbanzadeha and
M. Bahramnejada, Tetrahedron Lett., 2006, 47, 6983;
(b) N. Montazeri and K. Rad-Moghadam, Chin. Chem. Lett.,
2008, 19, 1143; (c) Q. Gao, S. Liu, X. Wu, J. Zhang and A. Wu,
Org. Lett., 2015, 17, 2960; (d) C. Xu, F.-C. Jia, Q. Cai, D.-K. Li,
Z.-W. Zhou and A.-X. Wu, Chem. Commun., 2015, 51, 6629.
8 (a) S. Sharma, P. K. Sharma, N. Kumar and R. Dudhe, Der
Pharma Chem., 2010, 2, 253; (b) S. Bhatia and M. Gupta,
J. Chem. Pharm. Res., 2011, 3, 137; (c) Z. Li, P. Zhan and
X. Liu, Mini-Rev. Med. Chem., 2011, 11, 1130; (d) V. K. R.
Sahu, A. K. Singh and D. Yadav, Int. J. ChemTech Res., 2011,
3, 1362; (e) A. K. Singh, V. K. R. Sahu and D. Yadav, 22 W. Yu, G. Huang, Y. Zhang, H. Liu, L. Dong, X. Yu, Y. Li and
Int. J. Pharm. Sci. Res., 2011, 2, 135; ( f ) C. S. de Oliveira, J. Chang, J. Org. Chem., 2013, 78, 10337.
B. F. Lira, J. M. Barbosa-Filho, J. G. Lorenzo and P. F. 23 S. Guin, T. Ghosh, S. K. Rout, A. Banerjee and B. K. Patel,
de Athayde-Filho, Molecules, 2012, 17, 10192; (g) H. Khalilullah, Org. Lett., 2011, 13, 5976.
M. J. Ahsan, M. Hedaitullah, S. Khan and B. Ahmed, Mini-Rev. 24 (a) D. Singh, V. Kumar, N. Devi, C. C. Malakar, R. Shankar and
Med. Chem., 2012, 12, 789.
9 S. Singh, L. K. Sharma, A. Sarswat, I. R. Siddiqui, H. K. Kheri
and R. K. P. Singh, RSC Adv., 2013, 3, 4237.
10 (a) U. Mitschke and P. Bauerle, J. Mater. Chem., 2000, 10,
1471; (b) N. Rehmann, C. Ulbricht, A. Kohnen, P. Zacharias,
V. Singh, Adv. Synth. Catal., 2017, 359, 1213; (b) D. Singh,
P. Sharma, R. Kumar, S. K. Pandey, C. C. Malakar and V. Singh,
Asian J. Org. Chem., 2018, 7, 383; (c) N. Devi, S. Kumar,
S. K. Pandey and V. Singh, Asian J. Org. Chem., 2018, 7, 6;
(d) V. Singh and S. Batra, Curr. Org. Synth., 2012, 9, 513.
M. C. Gather, D. Hertel, E. Holder, K. Meerholz and 25 (a) D. Singh, C. K. Hazra, C. C. Malakar, S. K. Pandey, B. S.
U. S. Schubert, Adv. Mater., 2008, 20, 129; (c) M. Guan,
Z. Q. Bian, Y. F. Zhou, F. Y. Li, Z. J. Lib and C. H. Huang,
Chem. Commun., 2003, 2708.
Kaith and V. Singh, ChemistrySelect, 2018, 3, 4859; (b) N. Devi,
D. Singh, G. Kaur, S. Mor, V. P. R. K. Putta, S. Polina,
C. C. Malakar and V. Singh, New J. Chem., 2017, 41, 1082.
102 | New J. Chem., 2019, 43, 93--102
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