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

Abstract

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.

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Introduction

Naturally occurring β-carboline alkaloids and their synthetic derivatives are widely studied due to their broad spectrum of pharmacological properties, such as anticancer,¹ antibacterial, antimalarial, anti-HIV, anti-Alzheimer etc.² However, the majority of β-carboline alkaloids display anticancer properties via intercalation into DNA,³ and inhibition of cyclin-dependent kinases,⁴ topoisomerases⁵ and IkK kinase complexes.⁶ Importantly, the β-carboline alkaloids account for nearly one quarter of natural products (Fig. 1) and are also accommodated by several commercial drugs (Tadalfil, Abecarnil, Cipargamin etc.).⁷

Fig. 1 Representative examples of biologically active β-carboline and 1,3,4-oxadiazole derivatives.

Similarly, 1,3,4-oxadiazole is another high value added scaffold which has attracted considerable attention for decades owing to its pharmaceutical and biological activities, such as anti inflammatory, antibacterial, anticancer, anti-diabetic, analgesic, antiviral, antifungal etc.⁸ Apart from this, 1,3,4-oxadiazole has demonstrated numerous applications in the field of materials science because of its excellent electron transporting and hole-blocking abilities.⁹ The optoelectronic properties¹⁰ of oxadiazole derivatives make them unique among the heterocyclic family. Moreover, the medicinal significance of this motif is evident from the fact that it is represented by numerous drugs such as Raltegravir¹¹ (antiretroviral), Zibotentan¹² (anticancer), Fenadiazole¹³ (hypnotic), Nesapidil¹⁴ (antihypertensive), ABT-751-oxadiazole and Furamizole¹⁵ (Fig. 1) used for the treatment of various ailments.

The medicinal potential of these two privileged scaffolds inspired us to construct a new molecular hybrid containing both the frameworks. Interestingly, an analysis of the literature revealed the presence of one narrowly related previous report (Fig. 2) in the form of a patent where Guo et al. have disclosed the 8-step synthesis and anti-diabetic properties of tetrahydro-β-carbolines containing 1,3,4-oxadiazole for the treatment of type 2 diabetes mellitus (Fig. 2).¹⁶ It was found that these molecular hybrids act as selective antagonists of the somatostatin subtype receptor 3 and could also be used for the treatment of depression, anxiety, insulin resistance, hyperglycemia, lipid disorders, obesity and hypertension. The literature revealed that dehydration of diacyl-hydrazines (POCl₃′ SOCl₂, PPA, H₂SO₄)¹⁷ and oxidative cyclization of acylhydrazones utilizing oxidants¹⁸ like HgO/I₂, PbO₂, IBX, DMP, chloramine T, KMnO₄, CAN, I₂, an Br₂ or transition metal catalysts (Cu(OTf)₂, PdCl₂(dppp), CuI, and FeCl₃) via C–O coupling reactions are two common approaches employed for the synthesis of 1,3,4-oxadiazoles.¹⁹ Recently, the Xu group reported a novel Pd-assisted synthesis of 2-amino-1,3,4-oxadiazoles through isocyanide insertions into hydrazides.²⁰ Nevertheless, the major drawback associated with existing reports involves the use of expensive and hazardous reagents, harsh reaction conditions, multistep synthesis and non-scalability. Among these methods, annulation of acylhydrazides with carbonyl compounds is found to be a more effective approach²¹ as disclosed by Yu and co-workers.²² However, the substrate scope with acylhydrazides containing electron withdrawing substituents remains unexplored. Patel and co-workers have also developed a Cu(OTf)₂ assisted excellent approach toward synthesis of symmetrical and unsymmetrical oxadiazoles.²³ Our group has been involved in the development of chemical libraries of β-carboline based molecular hybrids using sustainable approaches. In a recent finding, we have demonstrated the I₂-mediated synthesis of β-carboline N-fused imidazoles via decarboxylative oxidation of natural α-amino acids.^24a In an extension to our research on the synthesis of β-carboline based privileged scaffolds, we have developed a surrogate approach for the synthesis of β-carboline substituted 1,3,4-oxadiazole derivatives via an iodine-mediated oxidative cyclisation process (Fig. 2). The details of these studies are presented here.

Fig. 2 Previous finding related to the synthesis of a designed prototype.

Results and discussion

To achieve the synthesis of the designed molecular hybrid, optimization of the reaction conditions was achieved using 1-formyl β-carboline 1a and benzohydrazide A as the model substrates. The condensation of 1a with A in methanol at 70 °C smoothly afforded the benzohydrazone 1aA in 89% yield without 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 catalysts.^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 °C 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, β-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.

Table 1 Reaction optimisation^a

Entry	Reagents^b	Base^c	Solvent^d	Temp (°C)	Time (h)	Yields^e (%) 2aA
a Reaction conditions: All reactions were optimised with 0.134 mmol (1.0 equiv.) benzoylhydrazone 1aA in 1 mL of solvent. b 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. c 3.0 equiv. of base was used. d Reactions were performed in anhydrous solvents (entries 1–21). e Isolated yields of the purified product. f NR = No reaction; the starting substrate 1aA was recovered. g 20 mol% catalyst was used and decomposition of benzoylhydrazone 1aA was observed.
1	I2	K2CO3	MeOH	70	24	25% + 1a (60%)
2	I2	K2CO3	DMSO	90	1	77
3	I2	NaHCO3	DMSO	90	1.5	70
4	I2	Cs2CO3	DMSO	rt	10	78
5	I 2	Cs 2 CO 3	DMSO	90	45 min	85
6	I2	Cs2CO3	DMSO	120	45 min	85
7	I2	Cs2CO3	DMF	90	1.5	65
8	I2	KOH	DMSO	90	1	75
9	I2	—	DMSO	90	16	66 + polar impurity
10^f	I2	Et3N	DMSO	90	24	NR
11^f	I2	DIPEA	DMSO	90	24	NR
12^f	I2	—	AcOH	90	16	NR
13^f	TBAI	Cs2CO3	DMSO	90	16	NR
14	NCS	K2CO3	DMF	90	12	32 + polar impurity
15^f	DMP	—	CH2Cl2	35	24	NR
16^f	NH4Cl	—	DMSO	90	12	NR
17^f^,^g	FeCl3	—	DMSO	90	12	NR
18^f^,^g	CuI	Cs2CO3	DMSO	90	12	—
19^f^,^g	Cu(OTf)2	Cs2CO3	DMSO	90	12	—
20^f^,^g	La(OTf)2	Cs2CO3	DMSO	90	12	—

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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, 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 temperature afforded a clean reaction (82% yield) but required 10 h for completion (Table 1, entry 4). Interestingly, when the reaction was performed under similar conditions at 90 °C, it was completed within 45 min to give the product in 85% yield (Table 1, entry 5). However, when the temperature was further increased to 120 °C, no visible improvement was observed in the reaction time or yield of the product (Table 1, entry 6). It was realized that the use of Cs₂CO₃ took less time as compared to other bases and a clean reaction was obtained to yield the product in excellent yield. More importantly, treatment of the reaction mixture with cold water furnished the desired product as a solid and the analytically pure product could be obtained by simple filtration under vacuum followed by washing with diethyl ether.

It was further observed that the reaction in anhydrous DMF at 90 °C in the presence of molecular iodine completed in 1.5 h but the product was generated in 65% yield (Table 1, entry 7). The combination of KOH with DMSO in the presence of iodine also efficiently produced 1,3,4-oxadiazole 2aA in 75% yield (Table 1, entry 8). To our surprise, I₂-mediated oxidative cyclisation in the absence of any base also generated the desired product 2aA in 66% yield in 16 h but polar impurities were also formed (Table 1, entry 9). It was found that the use of organic bases (Et₃N or DIPEA) failed to deliver the desired product (Table 1, entries 10 and 11). Similarly, the corresponding product was not generated when TBAI was used as an iodide source (I⁻) for this transformation instead of molecular iodine (Table 1, entry 13) indicating that the iodonium ion (I⁺) was possibly driving the reaction. Recently, we found that NCS could be used for decarboxylative oxidation of tetrahydro-β-carbolines so it was planned to investigate its utility for oxidative cyclisation.^24a Interestingly, NCS was able to provide the desired product albeit in low yield (32%) along with an unidentified polar impurity (Table 1, entry 14). The use of DMP, NH₄Cl and transition metal catalysts like FeCl₃, CuI, Cu(OTf)₂ and La(OTf)₂ failed to deliver the desired product (Table 1, entries 15–20). Eventually, the optimization investigations led to the inference that DMSO was the best solvent and Cs₂CO₃ was a suitable base for the oxidative cyclization of 1aA in a short duration with 85% yield (Table 1, entries 5 and 6).

Next, it was considered worthwhile to develop a one-pot procedure for this transformation (Scheme 1). Accordingly, condensation of 1a with A and successive oxidative cyclisation was attempted in MeOH using Cs₂CO₃ and I₂ at 70 °C but the formation of β-carboline substituted 1,3,4-oxadiazole 2aA required more than 24 h due to the precipitation of hydrazone 1aA from the reaction mixture and the desired product was obtained in 25% yield only. Then the one-pot assembly of reactants was executed in DMSO but condensation of 1a and A was not completed even after 12 h. It was realised that MeOH was a suitable solvent for hydrazone synthesis 1aA while DMSO was suited for oxidative cyclisation. Therefore, an alternate procedure was adopted where first hydrazone synthesis was achieved in MeOH within 1 h, then MeOH was evaporated and the hydrazone was re-dissolved in DMSO and subjected to oxidative cyclisation with 1.5 equiv. of iodine and 3.0 equiv. of Cs₂CO₃ at 90 °C for 45 min. To our delight, a clean reaction was observed and no column chromatographic separation was required.

Scheme 1 Synthesis of β-carboline tethered 1,3,4-oxadiazole 2aA from 1-formyl β-carboline (1a) and benzoic hydrazide (A).

With established conditions in hand, the scope of this one-pot procedure was investigated for condensation and oxidative cyclisation of 1-formyl β-carbolines²⁴ (1a, 1i and 1k) with substituted acylhydrazides (A–L) to afford the desired β-carboline substituted 1,3,4-oxadiazoles as depicted in Scheme 2. It was pleasing to see that the methodology worked well and smoothly yielded the anticipated products 2aA–aK, 2iA, 2kA, 2kG, 2kI and 2kLvia oxidative cyclisation (C–O bond formation) within 1.75–5 h. The strategy was found compatible with a broad range of acylhydrazides (A–K) bearing electron withdrawing as well as electron donating groups. It was analysed that the acylhydrazides with an electron-donating group (F) reacted faster and afforded higher yield (87%) in comparisons to those bearing electron-withdrawing groups (B–D) (46–76%). The heteroaryl acylhydrazides (G–I) also reacted efficiently and furnished the corresponding products in good to excellent yields (74–92%). Furthermore, this method was extended to aliphatic hydrazides, such as acetylhydrazide K which generated the respective products 2aK in 50% yield.

Scheme 2 Synthesis of β-carboline C-1 tethered 1,3,4-oxadiazole derivatives with the scope of variation in substituted acylhydrazides.

Encouraged by these results, we further extended our study by employing N-9 substituted 1-formyl β-carboline derivatives (1b–h and 1j) for oxidative cyclisation with benzohydrazide A. To our delight, the reactions under optimum conditions easily yielded the corresponding β-carboline C1 substituted 1,3,4-oxadiazole derivatives 2bA–gA and 2jA within 1.5–3 h in good to excellent yield ranging from 73 to 87% (Scheme 3). It is important to mention that N-alkylated derivatives (except N-propargyl, 1f) furnished the desired product in better yield and took less time for completion as compared to the free N–H derivative of β-carboline 1a. Surprisingly, when 1h was subjected to annulation with A under optimal reaction conditions, cleavage of the 2-nitrobenzyl group from the N-9 position of the β-carboline ring was observed and 2aA was obtained as the 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.

Scheme 3 Synthesis of N-alkylated β-carboline substituted 1,3,4-oxadiazole derivatives.

Delighted by the successful synthesis of β-carboline C1 tethered 1,3,4-oxadiazoles, we examined the scope of this methodology for the synthesis of β-carboline tethered bis-oxadiazoles by employing β-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 °C smoothly afforded the desired product 5A in 43% yield (Scheme 4) after a silica gel column chromatographic separation.

Scheme 4 Synthesis of β-carboline tethered bis-1,3,4-oxadiazole.

Surprisingly, when formic hydrazide L was used for oxidative annulation with 1k (Scheme 5), the 1-cyano β-carboline 6 was obtained as the sole product instead of 2kL as confirmed on the basis of ¹H-, ¹³C-NMR and HRMS data.

Scheme 5 Synthesis of 1-cyano β-carboline.

Next, it was envisaged to further extend the scope of this practical methodology to prepare β-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 °C, 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 6 Synthesis of β-carboline C1 tethered 2-amino 1,3,4-oxadiazole from semicarbazide.

Scheme 7 Gram scale synthesis of 2aA.

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 I⁻) in the presence of Cs₂CO₃ in DMSO under optimised conditions. It was found that ICl readily afforded the desired β-carboline substituted 1,3,4-oxadiazole, 2bA within 2h while KI failed to execute the reaction (Scheme 8). These experiments indicated that the iodonium ion played a key role in initiation of this oxidative annulation process.

Scheme 8 Control experiments.

A plausible mechanism for the formation of β-carboline substituted 1,3,4-oxadiazoles is presented in Fig. 3 based on the results of the study. Initially, the condensation of 1-formyl β-carboline 1a and benzohydrazide (A) resulted in the formation of isolable benzoylhydrazone 1aA. Then, it is proposed that benzoylhydrazone 1aA may undergo Cs₂CO₃ mediated oxidative C-iodination via route-I to generate the intermediate 6. The successive formation of a new C–O bond via a S_N2-type intramolecular cyclization of 7 may result in the formation of 1,3,4-oxadiazole framework 2aA. Alternatively, benzoylhydrazone 1aA may undergo N-iodination via route-II to generate an N-iodo intermediate 8 which may follow base/heat mediated annulation 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 annulation; 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.

Fig. 3 The proposed mechanism for the construction of β-carboline substituted 1,3,4-oxadiazole.

Conclusions

In summary, we have developed a transition metal-free approach for the synthesis of β-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 β-carboline derivatives and desired 1,3,4-oxadiazoles could be isolated at a gram scale without column chromatographic purification. This methodology provides easy access to heterocycles with potential pharmaceutical applications. The investigation of the application of β-carboline linked 1,3,4-oxadiazoles as a ligand for complexation with metals and their development as analytical sensors is currently in progress in our laboratory.

Experimental section

General methods

The reagents and chemicals were procured from Sigma Aldrich and Spectrochem Ltd and used as such without additional purification. The anhydrous solvents (glacial AcOH, DCM, DMSO, DMF, and MeOH) were used as available commercially. TLC was examined on precoated aluminum plates (E. Merck; silica gel 60 PF254, 0.25 mm). The column chromatographic separation was conducted on silica gel (SRL; 60–120 mesh). The melting points were recorded in open-ended capillary tubes on a Precision Digital melting-point apparatus (LABCO make) that contained silicon oil and are uncorrected. The IR spectra were recorded on an Agilent FTIR spectrophotometer. ¹H and ¹³C NMR spectra were recorded on an Avance III Bruker spectrometer at operating frequencies of 400 MHz or 100 MHz (¹³C), as mentioned in the individual spectrum, by using TMS as a standard. The HRMS spectra were recorded on Xevo G2-SQ TOF (Water; USA) or Thermo Finnigan LCQ Advantage, Ion-Trap Mass Spectrometer. Elemental analysis was performed on a Carlo–Erba 108 or an Elementar Vario EL III microanalyzer. During the study, room temperature varied between 25 and 40 °C. The multiplicity in the ¹H NMR spectra is mentioned as follows: s for singlet, d for doublet, t for triplet, q for quartet, dd for doublet of doublet, dt for doublet of triplet and m for multiplet.

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 β-carboline 1a (0.200 g, 0.787 mmol) and benzohydrazide A (0.112 g, 0.826 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 1aA was re-dissolved in DMSO (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 °C for 45 min; 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 with 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 triturated and washed with diethyl ether (twice) to afford the analytically pure product, β-carboline C1 tethered 1,3,4-oxadiazole 2aA in 80% yield.

Methyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b] indole-3-carboxylate (2aA)

Yield: 80% (0.234 g from 0.200 g) as a light brown solid; m.p. 199–201 °C; R_f = 0.35 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max (cm⁻¹) = 3426 (NH), 1710 (CO₂CH₃), 1626 (C=N), 1261 (C–O), 1064 (C–O–C); ¹H NMR (400 MHz, CDCl₃ + DMSO-d₆) δ = 4.02 (s, 3 H, CO₂CH₃), 7.31 (t, J = 7.5 Hz, 1 H, ArH), 7.46–7.52 (m, 3 H, ArH), 7.57 (t, J = 7.6 Hz, 1 H, ArH), 7.69 (d, J = 8.2 Hz, 1 H, ArH), 8.14 (d, J = 7.9 Hz, 1 H, ArH), 8.21 (d, J = 7.9 Hz, 2 H, ArH), 8.93 (s, 1 H, ArH), 10.87 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃ + DMSO-d₆) δ = 52.8, 112.9, 119.6, 121.2, 121.6, 121.9, 123.1, 125.3, 127.5, 129.0, 129.8, 130.9, 132.2, 135.6, 137.4, 141.1, 163.1, 165.0, 165.8 ppm; HRMS (ESI) m/z: calcd for C₂₁H₁₄N₄O₃ [M + Na]: 393.0964, found: 393.1002.

Methyl 1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido [3,4-b]indole-3-carboxylate (2aB)

Yield: 75% (0.230 g from 0.200 g) as a light brown solid; m.p. 204–206 °C; R_f = 0.30 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3565 (NH), 1701 (CO₂CH₃), 1620 (C=N), 1265 (C–O), 1058 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 4.10 (s, 3 H, CO₂CH₃), 7.28–7.43 (m, 3 H, ArH), 7.59–7.67 (m, 3 H, ArH), 8.23 (dd, J₁ = 15.5 Hz, J₂ = 7.7 Hz, 2 H, ArH), 9.00 (s, 1 H, ArH), 10.48 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 53.0, 111.9 (d, J = 11 Hz), 112.7, 117.1 (d, J = 21 Hz), 119.8, 121.4, 122.0 (d, J = 34 Hz), 124.7, 124.8, 125.2, 130.2 (d, J = 20 Hz), 131.1, 134.1, 134.2, 135.9, 138.0, 141.2, 159.2, 162.5 (d, J = 143 Hz), 166.0 ppm; HRMS (ESI) m/z: calcd for C₂₁H₁₃FN₄O₃ [M + H⁺]: 389.1050, found: 389.1077.

Methyl 1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido [3,4-b]indole-3-carboxylate (2aC)

Yield: 46% (0.163 g from 0.200 g) as a pale yellow solid; m.p. > 260 °C; R_f = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3483 (NH), 1711 (CO₂CH₃), 1629 (C=N), 1277 (C–O), 1064 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 53.1, 112.7, 120.0, 121.6, 122.0, 122.2, 122.4, 125.3, 127.3, 129.1, 130.3, 131.2, 132.6, 136.0, 138.1, 141.3, 163.5, 164.6, 166.0 ppm; HRMS (ESI) m/z: calcd for C₂₁H₁₃BrN₄O₃ [M + H⁺]: 449.0249, found: 449.0194.

Methyl 1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido [3,4-b]indole-3-carboxylate (2aD)

Yield: 76% (0.242 g from 0.200 g) as an off-white solid; m.p. 257–259 °C; R_f = 0.40 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3512 (NH), 1707 (CO₂CH₃), 1626 (C=N), 1269 (C–O), 1067 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 4.12 (s, 3 H, CO₂CH₃), 7.40–7.44 (m, 1 H, ArH), 7.54 (d, J = 8.3 Hz, 2 H, ArH), 7.68 (d, J = 3.9 Hz, 2 H, ArH), 8.23 (d, J = 8.3 Hz, 3 H, ArH), 9.01 (s, 1 H, ArH), 10.44 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 53.1, 112.7, 120.0, 121.6, 121.7, 122.0, 122.4, 125.3, 129.0, 129.6, 130.2, 131.2, 136.0, 138.0, 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-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate (2aE)

Yield: 51% (0.161 g from 0.200 g) as an off-white solid; m.p. 254–256 °C; R_f = 0.40 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3450 (NH), 1704 (CO₂CH₃), 1623 (C=N), 1266 (C–O), 1060 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 3.92 (s, 3 H, OCH₃), 4.13 (s, 3 H, CO₂CH₃), 7.07 (d, J = 8.9 Hz, 2 H, ArH), 7.40–7.45 (m, 1 H, ArH), 7.68 (d, J = 3.3 Hz, 2 H, ArH), 8.23–8.27 (m, 3 H, ArH), 9.03 (s, 1 H, ArH), 10.51 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 53.1, 55.6, 112.6, 114.6, 115.7, 119.7, 121.6, 121.9, 122.3, 125.7, 129.6, 130.1, 131.0, 135.9, 137.9, 141.2, 162.9, 163.0, 165.3, 166.1 ppm; HRMS (ESI) m/z: calcd for C₂₂H₁₆N₄O₄ [M + H⁺]: 401.1250, found: 401.1254.

Methyl 1-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b] indole-3-carboxylate (2aF)

Yield: 87% (0.263 g from 0.200 g) as a pale yellow solid; m.p. 233–235 °C; R_f = 0.37 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3412 (NH), 1709 (CO₂CH₃), 1618 (C=N), 1266 (C–O), 1126 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 2.47 (s, 3 H, ArCH₃), 4.13 (s, 3 H, CO₂CH₃), 7.39 (d, J = 7.9 Hz, 2 H, ArH), 7.43 (dd, J₁ = 7.9 Hz, J₂ = 4.5 Hz, 1 H, ArH), 7.70 (d, J = 3.4 Hz, 2 H, ArH), 8.22 (d, J = 8.0 Hz, 2 H, ArH), 8.26 (d, J = 7.9 Hz, 1 H, ArH), 9.05 (s, 1 H, ArH), 10.52 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 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, 163.1, 165.5, 166.1 ppm; HRMS (ESI) m/z: calcd for C₂₂H₁₆N₄O₃ [M + H⁺]: 385.1301, found: 385.1289.

Methyl 1-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate (2aG)

Yield: 80% (0.235 g from 0.200 g) as a light brown solid; m.p. > 260 °C; R_f = 0.30 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3392 (NH), 1714 (CO₂CH₃), 1595 (C=N), 1261 (C–O), 1107 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 4.12 (s, 3 H, CO₂CH₃), 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) δ = 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.

Methyl 1-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate (2aH)

Yield: 83% (0.243 g from 0.200 g) as a pale yellow solid; m.p. > 260 °C; R_f = 0.35 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3399 (NH), 1719 (CO₂CH₃), 1623 (C=N), 1260 (C–O), 1107 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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.

Methyl 1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate (2aI)

Yield: 92% (0.261 g from 0.200 g) as a pale yellow solid; m.p. 255–257 °C; R_f = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3393 (NH), 1712 (CO₂CH₃), 1624 (C=N), 1262 (C–O), 1128 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 4.11 (s, 3 H, CO₂CH₃), 6.67 (dd, J₁ = 3.5 Hz, J₂ = 1.7 Hz, 1 H, ArH), 7.39–7.42 (m, 2 H, ArH), 7.65–7.73 (m, 3 H, ArH), 8.23 (d, J = 7.8 Hz, 1 H, ArH), 9.01 (s, 1 H, ArH), 10.49 (s, 1 H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 53.1, 112.6, 112.7, 116.0, 120.0, 121.5, 122.0, 122.3, 125.2, 130.2, 131.2, 136.0, 138.0, 139.1, 141.3, 146.6, 158.0, 162.6, 166.0 ppm; HRMS (ESI) m/z: calcd for C₁₉H₁₂N₄O₄ [M + H⁺]: 361.0937, found: 361.0874.

Methyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b] indole-3-carboxylate (2aK)

Yield: 50% (0.122 g from 0.200 g) as a light brown solid; m.p. 235–237 °C; R_f = 0.30 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3391 (NH), 1712 (CO₂CH₃), 1587 (C=N), 1260 (C–O), 1086 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 2.74 (s, 3 H, CH₃), 4.09 (s, 3 H, CO₂CH₃), 7.39–7.43 (m, 1 H, ArH), 7.66 (d, J = 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) δ = 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.

Isopropyl 1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b] indole-3-carboxylate (2iA)

Yield: 90% (0.255 g from 0.200 g) as a light brown solid; m.p. 197–199 °C; R_f = 0.50 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3419 (NH), 1711 (CO₂i-Pr), 1598 (C=N), 1234 (C–O), 1108 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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.

2-Phenyl-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole (2kA)

Yield: 77% (0.245 g from 0.200 g) as a brown solid; m.p. 209–211 °C; R_f = 0.50 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3465 (NH), 1630 (C=N), 1249 (C–O), 1088 (C–O–C); ¹H NMR (400 MHz, CDCl₃ + DMSO-d₆) δ = 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) δ = 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.

2-(Pyridin-3-yl)-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole (2kG)

Yield: 74% (0.236 g from 0.200 g) as a brown solid; m.p. 213–215 °C; R_f = 0.35 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 1628 (C=N), 1225 (C–O), 1122 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 7.34–7.38 (m, 1 H, ArH), 7.51 (dd, J₁ = 7.9 Hz, J₂ = 4.9 Hz, 1 H, ArH), 7.64 (d, J = 3.9 Hz, 2 H, ArH), 8.14 (d, J = 5.0 Hz, 1 H, ArH), 8.18 (d, J = 7.8 Hz, 1 H, ArH), 8.54 (d, J = 8.0 Hz, 1 H, ArH), 8.66 (d, J = 5.1 Hz, 1 H, ArH), 8.82 (d, J = 4.4 Hz, 1 H, ArH), 9.51 (s, 1 H, ArH), 10.18 (s, 1 H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 112.3, 117.6, 120.1, 121.0, 121.1, 122.1, 123.9, 125.2, 129.7, 130.9, 134.6, 134.8, 139.4, 140.9, 148.4, 152.8, 162.8, 164.3 ppm; HRMS (ESI) m/z: calcd for C₁₈H₁₁N₅O [M + H⁺]: 314.1042, found: 314.1042.

2-(Furan-2-yl)-5-(9H-pyrido[3,4-b]indol-1-yl)-1,3,4-oxadiazole (2kI)

Yield: 85% (0.262 g from 0.200 g) as a yellow solid; m.p. > 260 °C; R_f = 0.60 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 3409 (NH), 1640 (C=N), 1271 (C–O), 1118 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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.

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 °C; R_f = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1711 (CO₂CH₃), 1588 (C=N), 1267 (C–O), 1129 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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 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 °C; R_f = 0.55 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1714 (CO₂CH₃), 1586 (C=N), 1269 (C–O), 1119 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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 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; m.p. 201–202 °C; R_f = 0.65 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1713 (CO₂CH₃), 1590 (C=N), 1261 (C–O), 1123 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 0.73 (t, J = 7.1 Hz, 3 H, 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, ArH), 8.25 (d, J = 5.0 Hz, 3 H, ArH), 9.05 (s, 1 H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 11.2, 22.6, 46.6, 53.1, 110.9, 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.

Methyl 9-allyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido [3,4-b]indole-3-carboxylate (2eA)

Yield: 86% (0.240 g from 0.200 g) as a light brown solid; m.p. 160–162 °C; R_f = 0.45 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1706 (CO₂CH₃), 1598 (C=N), 1297 (C–O), 1089 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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 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 °C; R_f = 0.50 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1710 (CO₂CH₃), 1622 (C=N), 1275 (C–O), 1127 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 2.00 (t, J = 2.4 Hz, 1 H, CH₂C≡CH), 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) δ = 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-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 °C; R_f = 0.65 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 1714 (CO₂CH₃), 1628 (C=N), 1257 (C–O), 1149 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 48.1, 53.2, 110.8, 119.4, 121.1, 122.1, 122.2, 123.6, 125.8, 127.2, 127.5, 128.7, 129.0, 130.4, 132.1, 132.9, 135.4, 136.1, 137.7, 143.8, 161.3, 165.8, 165.9 ppm; HRMS (ESI) m/z: calcd for C₂₈H₂₀N₄O₃ [M + H⁺]: 461.1614, found: 461.1661.

Isopropyl 9-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate (2jA)

Yield: 73% (0.203 g from 0.200 g) as a pale yellow solid; m.p. 185–187 °C; R_f = 0.60 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 1707 (CO₂i-Pr), 1594 (C=N), 1255 (C–O), 1121 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 1.50 (d, J = 6.2 Hz, 6 H, CH(CH₃)₂), 4.10 (s, 3 H, NCH₃), 5.38–5.45 (m, 1 H, CH(CH₃)₂), 7.43 (t, J = 7.2 Hz, 1 H, ArH), 7.56–7.59 (m, 4 H, ArH), 7.70–7.74 (m, 1 H, ArH), 8.25 (d, J = 1.8 Hz, 1 H, ArH), 8.27 (d, J = 7.8 Hz, 2 H, ArH), 8.98 (s, 1 H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 22.2, 33.5, 69.7, 110.6, 119.0, 121.1, 121.6, 121.9, 123.7, 126.5, 127.5, 129.2, 130.0, 132.2, 137.1, 137.9, 143.6, 162.2, 164.7, 165.8 ppm; HRMS (ESI) m/z: calcd for C₂₄H₂₀N₄O₃ [M + H⁺]: 413.1614, found: 413.1637.

9H-Pyrido[3,4-b]indole-1-carbonitrile (6)

Yield: 30% (0.030 g from 0.100 g) as a light brown solid; m.p. 201–203 °C; R_f = 0.40 (hexane/EtOAc, 50 : 50, v/v); IR (neat): ν_max = 2239 (CN), 3404 (NH); ¹H NMR (400 MHz, CDCl₃) δ = 7.38 (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) δ = 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.

One pot procedure for the synthesis of 5A

A stirred solution of β-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 °C 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, β-carboline tethered bis-1,3,4-oxadiazole 5A in 43% yield.

5,5′-(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. > 260 °C; R_f = 0.70 (hexane/EtOAc, 70 : 30, v/v); IR (neat): ν_max = 3393 (NH), 1565 (C=N), 1275 (C–O), 1139 (C–O–C); ¹H NMR (400 MHz, CDCl₃) δ = 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) δ = 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.

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 MeOH (7 mL), 1k (0.150 g, 0.765 mmol) was added and stirring continued at room temperature for 1 h. After the condensation was completed as monitored by TLC, the solvent was evaporated under reduced pressure. The resulting residue was re-dissolved in 1,4-dioxane (5 mL), followed by addition of cesium carbonate (0.748 g, 2.295 mmol) and iodine (0.291 g, 1.147 mmol) in sequence and the reaction mixture was stirred at 90 °C for 1 h; the conversion was monitored by the TLC technique. The reaction 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 which were filtered and sintered to get a crude product which was triturated and washed with diethyl ether (twice) to afford the analytically pure product 2kM in 73% yield.

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. > 260 °C; R_f = 0.30 (hexane/EtOAc, 20 : 80, v/v); ¹H NMR (400 MHz, DMSO-d₆) δ = 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) δ = 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.

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. gratefully 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 instrumentation facility, Guru Nanak Dev University Amritsar and Tezpur University, Assam is gratefully acknowledged for recording some of the spectroscopic data reported in this paper.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj04294b

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