10-Camphorsulfonic acid ((±)-CSA) catalyzed facile one-pot synthesis of a new class of 2,5-disubstituted 1,3,4-oxadiazoles

Abstract

A convenient and efficient one-pot synthesis of 2,5-disubstituted-1,3,4-oxadizoles is described. Various carboxylic acid hydrazides reacted efficiently with different carboxylic acid chlorides and 10-camphorsulfonic acid. This methodology was successfully applied to the synthesis of a series of 2H-chromene substituted 1,3,4-oxadiazole derivatives in good to high yields.

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1. Introduction

The study of heterocyclic chemistry is an enduring field in organic chemistry. More than half of the compounds produced by nature have heterocyclic rings in their structures. Amongst different heterocyclic systems, the chemistry of five membered heterocycles has gained importance as many of them exhibit a pronounced bioactive nature. In particular, substituted 1,3,4-oxadiazoles have been much explored for their broad spectrum of biological activities such as antibacterial,^1–3 antimycobacterial,⁴ antifungal,^5,6 anti-inflammatory,⁷ anti-allergy,^8,9 analgesic,¹⁰ anticonvulsant,¹¹ antihypoglycemic,¹² anticancer¹³ and insecticidal properties.¹⁴ Moreover, 1,3,4-oxadiazoles have found wide usage as dyes, photosensitive and electrical materials.¹⁵ Due to these broad applications, the chemistry of 1,3,4-oxadiazoles has evoked keen interest in the field of synthetic organic chemistry. Hence, there is a need to develop new synthetic routes with more practical and efficient pathways for 1,3,4-oxadiazoles.

Up to now, various one-pot protocols are available in the literature for the synthesis of 1,3,4-oxadiazoles. Most of these involve cyclodehydration of semicarbazide derivatives or oxidative cyclization of acyl hydrazones. So far there are a few efficient reagents that have been used for cyclodehydration and oxidative cyclization, including the Burgess Reagent,¹⁶ T3P®,¹⁷ TsCl,¹⁸ EDCI,¹⁹ cyanuric chloride,²⁰ XtalFluor-E,²¹ Dess–Martin reagent,²² bis(trifluoroacetoxy)iodobenzene (BTI)²³ and PbO₂.²⁴ Despite the wide generality and high efficiency of the above-mentioned methodologies, some limitations still remain. These include the use of harsh reagents, the high cost of reagents and the stability of reagents. Very recently, we reported an efficient, direct and general method for the synthesis of oxadiazoles, thiadiazoles and triazoles from various carboxylic acid hydrazides using TMSNCS (trimethylsilyl isothiocyanate).^25–27 As part of our continued interest in the synthesis of heterocycles, we wish to develop a convenient one-pot method for the synthesis of these useful heterocycles using reagents available to researchers worldwide.

Chromene derivatives are an important class of compounds, which are widely present in plants, including edible vegetables and fruits.²⁸ Synthetic analogues have been developed over the years, some of which display remarkable effects as pharmaceuticals,²⁹ including antifungal,³⁰ anti-microbial,³¹ molluscicidal,³² anticoagulant, spasmolytic, diuretic, anticancer and antianaphylactic characteristics.³³ The activities of chromene as well as oxadiazoles led us to synthesize a set of chromene substituted oxadiazole derivatives. While searching for new anti-cancerous inhibitors of an enzyme in an in-house drug discovery program, we were interested in synthesizing chromene substituted 1,3,4- and 1,2,4-oxadiazoles in an efficient manner. An efficient one-pot synthesis of chromene substituted 1,2,4-oxadazoles has been reported using PPTS (pyridinium p-toluenesulfonate), and their cytotoxicity evolution has been established.³⁴ Various 1,2,4-oxadiazole substituted 2H-chromenes are found to have considerable anticancer activity, and their activity on cancer cell lines will be further explored.

Encouraged by these results, we envisaged the integration of the 1,3,4-oxadiazole moiety with a chromene framework to study the cytotoxicity of the combined molecule. In this manuscript, we investigated the synthetic utility of 10-camphorsulfonic acid; to the best of our knowledge, the synthesis of 1,3,4-oxadiazoles utilizing 10-camphorsulfonic acid as a reagent has not yet been reported. 10-Camphorsulfonic acid is a versatile reagent in organic chemistry, which is widely used in asymmetric synthesis,³⁵ Friedel–Crafts alkylation,³⁶ oxidation of sulfides,³⁷ selective inter-and intramolecular addition of alcohols to exo-glycals,³⁸ multi-component reactions and Mannich reactions,³⁹ and is cheap in operational cost. As part of our studies on CAS, we investigated the synthetic utility of 10-camphorsulfonic acid for the synthesis of 1,3,4-oxadiazoles. We report herein a highly efficient one-step protocol to prepare 2,5-disubstituted 1,3,4-oxadiazoles from the reaction of various acid chlorides with different acyl hydrazides in the presence of catalytic amounts of 10-camphorsulfonic acid (5 mol%) at elevated temperatures. The procedure does not require an anhydrous solvent, inert gas atmosphere or any chromatographic purification.

2. Results and discussions

We mainly focused on developing a facile procedure to generate a 2H-chromene substituted 1,3,4-oxadiazole library with a variety of substitution patterns. This required us to investigate the scope of the reaction by screening various functionalities. In the process of this, we applied several traditional methodologies to react 2H-chromene carboxylic acid hydrazide with several acid chlorides to obtain the corresponding 1,3,4-oxadiazoles. The strong acidic conditions and elevated temperatures involved affect the ether linkage of the chromene ring, narrowing the convenient access to derivatized 1,3,4-oxadiazoles.

In the process of evaluating the best methodology, we cross-checked various traditional methodologies by reacting 3-ethoxybenzohydrazide with o-toluoyl chloride to optimize the reaction conditions (Scheme 1). Different reagents and solvents were screened for synthesizing 2,5-disubstituted 1,3,4-oxadiazoles. The results are summarized in Table 1. Among all reagents, 10-camphorsulfonic acid was found to be the best reagent for obtaining 2,5-disubstituted 1,3,4-oxadiazoles with high yields.

Scheme 1 Methodology screening.

Table 1 Reaction system screening results^a

S. no.	Reagent	Reaction conditions	Yield
a Note: (±)-CSA: 10-camphorsulfonic acid.
1	POCl3	Reflux/8 h	35%
2	SOCl2	Reflux/8 h	27%
3	InBr3 (5 mol%)	Dioxane/90 °C	12%
4	Cu(OTf)2 (5 mol%)	DMF/120 °C/16 h	39%
5	p-TSA (5 mol%)	Dioxane/16 h	43%
6	PPTS (10 mol%)	DCE/90 °C/16 h	52%
7	Burgess reagent	THF/rt/5 h	44%
8	(±)-CSA (5 mol%)	Dioxane/100 °C/16 h	75%
9	(±)-CSA (5 mol%)	Dioxane/rt/36 h	15%
10	(±)-CSA (5 mol%)	Dioxane/100 °C/16 h	89%
11	(±)-CSA (5 mol%)	Microwave/120 °C/15 min	59%

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Having these preliminary observations in hand, we wished to extend our methodology to a variety of carboxylic acid hydrazides.

A plausible mechanism for the formation of 2,5-disubstituted 1,3,4-oxadiazoles is shown in Scheme 2. The carboxylic acid hydrazide reacts with the acid chloride to form the corresponding di-substituted carboxylic acid hydrazide (I), which in turn undergoes enolization (II) followed by protonation (III) in the presence of 10-camphorsulfonic acid. Intermediate III in turn eliminates a water molecule and forms a sulfonate complex (IV), which further undergoes enolization (V) followed by elimination of 10-camphorsulfonic acid to form the corresponding 1,3,4-oxadiazole (3).

Scheme 2 Plausible mechanism for the synthesis of 1,3,4-oxadiazoles.

The reaction of 1a–l with o-toluoyl chloride (2) (Scheme 3) in the presence of 5 mol% 10-camphorsulfonic acid gave the corresponding 2,5-substituted-1,3,4-oxadiazoles (3a–l) in high yields (Table 2). As shown in Table 2, carboxylic acid hydrazides carrying an electron-withdrawing group or an electron-donating group reacted efficiently. Carboxylic acid hydrazides with o-, m- or p-substituents reacted more efficiently with o-toluoyl chloride, resulting in 2,5-substituted-1,3,4-oxadiazoles with high yields. We observed that 10-camphorsulfonic acid was more advantageous for the reaction when compared to other acid catalysts, as hydrazides having acid sensitive ether linkages (1e, 1h, 1i and 1j) also reacted well. Hydrazides having heterocyclic compounds in their skeleton (1k and 1l) also reacted efficiently.

Scheme 3 Synthesis of 2,5-substituted-1,3,4-oxadiazoles (3a–l). Method: 5 mol% 10-camphorsulfonic acid/100 °C/16 h.

Table 2 Synthesis of 2,5-substituted-1,3,4-oxadiazoles

Entry	Carboxylic acid hydrazide	Product	Yield (%)
1			89
2			92
3			90
4			78
5			80
6			83
7			85
8			79
9			77
10			76
11			87
12			86

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2H-Chromene-3-carboxylic acid hydrazides (7) were prepared using the literature procedure⁴⁰ (Scheme 4).

Scheme 4 Preparation of chromene hydrazides.

Finally, to demonstrate the generality of our methodology, we extended it to the synthesis of a new class of 2H-chromene substituted-1,3,4-oxadiazoles (Scheme 5) from 2H-chromene acid hydrazides. The reaction of chromene-carboxylic acid hydrazides with different acid chlorides in the presence of 5 mol% of 10-camphorsulfonic acid resulted in the corresponding 2H-chromene substituted 1,3,4-oxadiazoles (9a–n) (Table 3) (Scheme 5) in good yields. To our delight, a variety of aromatic, heteroaromatic and aliphatic carboxylic acid chlorides bearing functional groups such as halo, methoxy and alkyl participated effectively in the reaction with chromene hydrazides, resulting in chromene substituted 1,3,4-oxadiazoles in high yields (Table 3).

Scheme 5 Synthesis of chromene substituted 1,3,4-oxadiazoles (9a–n). Method: 5 mol% 10-camphorsulfonic acid/dioxane/100 °C/16 h.

Table 3 Synthesis of 2H-chromene substituted 1,3,4-oxadiazoles

Entry	Carboxylic acid hydrazide	Acid chloride	Product	Yield (%)
1				88
2				79
3				75
4				83
5				88
6				75
7				86
8				85
9				89
10				91
11				83
12				88
13				88
14				82

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3. Conclusion

In summary, we have developed an efficient one-pot synthetic methodology for the preparation of a new class of 2,5-disubstituted 1,3,4-oxadiazoles and 2H-chromene substituted 1,3,4-oxadiazoles by reacting various carboxylic acid hydrazides with acid chlorides in the presence of 10-camphorsulfonic acid. The significance of this method was that hydrazides containing acid sensitive groups (1e, 1h, 1i and 1j) were also converted to the corresponding 2,5-disubstituted 1,3,4-oxadiazoles in good to high yields. The utility of the present method was successfully demonstrated for the synthesis of novel 2H-chromene derivatives. The experimental procedure is operationally simple, does not require anhydrous solvent, an inert gas atmosphere or any chromatographic purification, and avoids the use of harsh reagents.

4. Experimental section

4.1. Chemistry

Melting points were determined in open capillaries on a Stuart apparatus and are uncorrected. The purity of the compounds was checked by TLC (silica gel H, BDH, ethyl acetate–hexane, 2 : 8). Chemicals and solvents used were purchased either from Fluka or Merck. All the reagents were of analytical grade. All the appropriate acid chlorides and carboxylic acid hydrazides used for the preparation were purchased from commercial sources. Thin-layer chromatography (TLC) was performed on E. Merck AL silica gel 60 F254 plates and visualized under UV light. The IR spectra were recorded on a Perkin Elmer FT-IR spectrometer. The ¹H NMR spectra were recorded in CDCl₃ on a Varian EM-360 spectrometer (300 MHz, 400 MHz). The ¹³C NMR spectra were recorded in CDCl₃ on a Varian EM-360 spectrometer operating at 100 MHz. All the chemical shifts were reported in δ (ppm), using TMS as an internal standard. The mass spectra were recorded on an Agilent ion trap MS.

General procedure for the synthesis of 2,5-substituted 1,3,4-oxadiazoles (3a–l). To a solution of carboxylic acid hydrazide (1a–l) (1.1 mmol) in dioxane (4 ml) was added 10-camphorsulfonic acid (0.055 mmol) followed by o-toluoyl chloride (2) (1.1 mmol), and the resulting mixture was heated at 100 °C for 16 h. Then, the reaction mixture was evaporated under vacuum, saturated Na₂CO₃ (10 ml) was added, and the mixture was extracted into diethyl ether. Then, the resulting organic layers were dried over Na₂SO₄ and distilled in vacuum to obtain 1,3,4-oxadiazole (3a–l) in 75–92% yield without further purification.
2-(3-Ethoxyphenyl)-5-(o-toluoyl)-1,3,4-oxadiazole (3a). Off-white solid; yield 0.27 g (0.98 mmol, 89%); M.R: 70–73 °C; δ_H (400 MHz, CDCl₃) 8.00–7.98 (d, 1H, J: 8 Hz), 7.66–7.61 (m, 2H), 7.40–7.36 (t, 2H, J: 8 Hz), 7.31–7.29 (m, 2H), 7.04–7.02 (d, 1H, J: 8 Hz), 4.11–4.05 (q, 2H, J: 4 Hz), 2.74 (s, 3H), 1.45–1.41 (t, 3H, J: 5.3 Hz); δ_C (100 MHz, CDCl₃) 164.60, 163.86, 159.15, 138.20, 131.60, 131.01, 130.01, 128.73, 125.98, 124.83, 122.78, 1128.93, 118.23, 118.15, 112.10, 63.57, 22.07, 14.58; IR ν_max (film): 3435, 2973, 2924, 1586, 1551, 1540, 1492, 1291, 1213, 1050, 730 cm⁻¹; MS (EI) m/z 281.2 (M + H⁺).
2-(4-Methoxyphenyl)-5-(o-toluoyl)-1,3,4-oxadiazole (3b). Off-white solid; yield 0.29 g (1.1 mmol, 92%); M.R: 123–126 °C; δ_H (400 MHz, CDCl₃) 8.07–8.05 (d, 2H, J: 4 Hz), 8.02–8.01 (d, 1H), 7.43–7.32 (m, 3H), 7.03–0.701 (d, 2H, J: 4 Hz), 3.88 (s, 3H), 2.76 (s, 3H); δ_C (100 MHz, CDCl₃) 164.35, 164.04, 162.27, 138.27, 131.71, 130.99, 128.83, 128.64, 126.09, 123.14, 116.47, 114.48, 55.42, 22.07; IR ν_max (film): 3436, 2919, 2842, 1612, 1502, 1252, 1193, 1182, 1020, 844, 739 cm⁻¹; MS (EI) m/z 267.2 (M + H⁺).
2-(2-Methoxyphenyl)-5-(o-toluoyl)-1,3,4-oxadiazole (3c). White solid; yield 0.29 g (1.08 mmol, 90%); M.R: 96–99 °C; δ_H (400 MHz, CDCl₃) 8.05–8.01 (m, 2H), 7.51–7.46 (t, 1H, J: 7.5 Hz), 7.42–7.29 (m, 3H), 7.10–7.04 (m, 2H), 3.97 (s, 3H), 2.75 (s, 3H); δ_C (100 MHz, CDCl₃) 164.59, 162.89, 157.76, 138.17, 132.89, 131.58, 130.91, 130.26, 128.91, 126.00, 123.14, 120.63, 112.99, 111.86, 55.84, 21.88; IR ν_max (film): 3435, 2921, 2033, 1716, 1604, 1534, 1496, 1434, 1260, 1018, 722 cm⁻¹; MS (EI) m/z 267.1 (M + H⁺).
2-[(4-Fluorophenoxy)methyl]-5-(o-toluoyl)-1,3,4-oxadiazole (3d). Pale yellow solid; yield 0.24 g (0.84 mmol, 78%); M.R: 101–104 °C δ_H (400 MHz, CDCl₃) 7.94–7.92 (d, 1H, J: 8 Hz), 7.42–7.40 (d, 1H, J: 8 Hz), 7.35–7.30 (m, 2H), 7.01–6.99 (d, 4H, J: 1 Hz), 5.30 (s, 2H), 2.69 (s, 3H); δ_C (100 MHz, CDCl₃) 166.02, 161.65, 159.22, 156.83, 153.66, 138.61, 131.76, 131.50, 129.07, 126.16, 122.50, 116.29, 116.01, 60.66, 22.00; IR ν_max (film): 3436, 2922, 1541, 1507, 1491, 1218, 1042, 823, 727 cm⁻¹; MS (EI) m/z 281.3 (M + H⁺).
2-[(2-Chlorophenoxy)methyl]-5-(o-toluoyl)-1,3,4-oxadiazole (3e). Off-white solid; yield 0.24 g (0.8 mmol, 80%); M.R: 88–91 °C; δ_H (400 MHz, CDCl₃) 7.96–7.94 (d, 1H, J: 6 Hz), 7.44–7.29 (m, 4H), 7.27–7.22 (m, 1H), 7.17–7.15 (d, 1H, J: 6 Hz), 7.15–6.96 (t, 1H, J: 13.5 Hz), 5.41 (s, 2H), 2.69 (s, 3H); δ_C (100 MHz, CDCl₃) 166.16, 161.39, 153.22, 138.62, 131.76, 131.52, 130.70, 129.15, 127.90, 126.19, 123.75, 123.28, 122.49, 114.97, 61.16, 22.00; IR ν_max (film): 3434, 2921, 1608, 1541, 1488, 1281, 1229, 1040, 854, 744 cm⁻¹; MS (EI) m/z 301.3 (M + H⁺).
2-(3,5-Dimethoxyphenyl)-5-(o-toluoyl)-1,3,4-oxadiazole (3f). Off-white solid; yield 0.25 g (0.81 mmol, 83%); M.R: 159–163 °C; δ_H (400 MHz, CDCl₃) 8.02–8.00 (d, 1H, J: 6 Hz), 7.70–7.66 (m, 2H), 7.45–7.32 (m, 3H), 6.99–6.97 (d, J: 6 Hz), 3.99 (s, 3H), 3.96 (s, 3H), 2.76 (s, 3H); δ_C (100 MHz, CDCl₃) 164.44, 164.06, 151.95, 149.32, 138.28, 131.70, 131.03, 128.83, 126.08, 123.08, 120.32, 116.52, 111.07, 109.41, 56.09, 22.03; IR ν_max (film): 3436, 2917, 1606, 1498, 1431, 1264, 1142, 1027, 726 cm⁻¹; MS (EI) m/z 297.2 (M + H⁺).
N,N-Dimethyl-4-[5-(o-toluoyl)-1,3,4-oxadiazol-2-yl]aniline (3g). Off-white solid; yield 0.26 g (0.93 mmol, 85%); M.R: 130–133 °C; δ_H (300 MHz, CDCl₃) 8.05–7.96 (m, 4H), 7.47–7.31 (m, 4H), 6.77–6.75 (d, 2H, J: 4 Hz), 3.06 (s, 6H), 2.75 (s, 3H); δ_C (100 MHz, CDCl₃) 164.79, 163.74, 152.29, 138.11, 131.62, 131.15, 130.69, 128.92, 128.26, 126.02, 123.45, 111.57, 40.05, 29.65, 22.07; IR ν_max (film): 3437, 2922, 1614, 1504, 1363, 1196, 1050, 944, 739 cm⁻¹; MS (EI) m/z 280.3 (M + H⁺).
2-[(4-Chloro-2-methyl-phenoxy)methyl]-5-(o-toluoyl)-1,3,4-oxadiazole (3h). Off-white solid; yield 0.23 g (0.71 mmol, 79%); M.R: 111–114 °C; δ_H (400 MHz, CDCl₃) 8.05–8.03 (d, 1H, J: 4 Hz), 7.94–7.92 (d, 1H, J: 8 Hz), 7.45–7.30 (m, 4H), 7.14–7.12 (d, 1H, J: 8 Hz), 6.95–6.93 (d, 1H, J: 6 Hz), 5.32 (s, 2H), 2.78 (s, 3H), 2.69 (s, 3H); δ_C (100 MHz, CDCl₃) 166.05, 161.70, 154.38, 138.46, 131.80, 131.54, 131.17, 130.90, 129.32, 128.94, 126.77, 126.20, 123.02, 122.53, 112.86, 60.42, 22.19, 16.05; IR ν_max (film): 3436, 2921, 1541, 1492, 1250, 1043, 1022, 803, 726 cm⁻¹; MS (EI) m/z 315.1 (M + H⁺).
2-(o-Toluoyl)-5-(phenoxymethyl)-1,3,4-oxadiazole (3i). White solid; yield 0.25 g (0.92 mmol, 77%); M.R: 72–76 °C; δ_H (400 MHz, CDCl₃) 7.93–7.91 (d, 1H, J: 4 Hz), 7.41–7.37 (t, 1H, J: 8 Hz), 7.32–7.27 (m, 4H), 7.04–6.99 (m, 3H), 5.33 (s, 2H), 2.69 (s, 3H); δ_C (100 MHz, CDCl₃) 165.92, 161.80, 157.52, 138.52, 131.68, 131.39, 129.64, 129.04, 126.09, 122.50, 122.09, 114.81, 59.85, 21.96; IR ν_max (film): 3436, 2957, 2921, 1601, 1542, 1495, 1220, 1042, 748, 725 cm⁻¹; MS (EI) m/z 267.4 (M + H⁺).
2-[(2-Methoxyphenoxy)methyl]-5-(o-toluoyl)-1,3,4-oxadiazole (3j). Off-white solid; yield 0.23 g (0.77 mmol, 76%); M.R: 78–82 °C; δ_H (400 MHz, CDCl₃) 7.94–7.92 (d, 1H, J: 8 Hz), 7.41–7.38 (t, 1H, J: 6 Hz), 7.32–7.26 (m, 2H), 7.11–7.09 (d, 1H, J: 8 Hz), 7.03–6.99 (t, 1H, J: 6 Hz), 6.92–6.87 (m, 2H), 5.38 (s, 2H), 3.85 (s, 3H), 2.67 (s, 3H); δ_C (100 MHz, CDCl₃) 165.83, 161.96, 150.05, 146.79, 138.46, 131.61, 131.28, 129.04, 126.02, 123.34, 122.53, 120.83, 116.02, 112.16, 61.46, 55.77, 21.93; IR ν_max (film): 3062, 2921, 2582, 1591, 1507, 1256, 1213, 1016, 729 cm⁻¹; MS (EI) m/z 297.2 (M + H⁺).
2-(o-Toluoyl)-5-(4-pyridyl)-1,3,4-oxadiazole (3k). Pale yellow solid; yield 0.3 g (1.26 mmol, 87%); M.R: 128–131 °C; δ_H (300 MHz, CDCl₃) 8.86–8.84 (d, 2H, J: 3 Hz), 8.06–8.04 (d, 1H, J: 6 Hz), 8.00–7.98 (d, 2H, J: 3 Hz), 7.47–7.45 (d, 1H, J: 6 Hz), 7.41–7.38 (d, 3H, J: 3 Hz), 2.78 (s, 3H); δ_C (100 MHz, CDCl₃) 165.75, 162.33, 150.92, 138.74, 131.95, 131.74, 131.06, 129.11, 126.30, 122.43, 120.31, 22.11; IR ν_max (film): 3431, 3035, 2924, 2348, 1605, 1535, 1458, 1254, 1059, 728 cm⁻¹; MS (EI) m/z 238.1 (M + H⁺).
2-(1H-Indol-3-ylmethyl)-5-(o-toluoyl)-1,3,4-oxadiazole (3l). Off-white solid; yield 0.26 g (0.9 mmol, 86%); M.R: 138–141 °C; δ_H (400 MHz, CDCl₃) 8.52 (brs, 1H), 7.83–7.81 (d, 1H, J: 8 Hz), 7.70–7.68 (d, 1H, J: 8 Hz), 7.35–7.32 (m, 2H), 7.27–7.21 (m, 2H), 7.20–7.11 (m, 3H), 4.40 (s, 2H), 2.62 (s, 3H); δ_C (100 MHz, CDCl₃) 165.33, 165.14, 138.19, 136.18, 131.57, 130.97, 128.82, 126.77, 125.98, 123.16, 122.95, 119.75, 118.55, 111.36, 108.06, 22.10; IR ν_max (film): 3435, 2921, 1604, 1534, 1434, 1260, 1018, 722 cm⁻¹; MS (EI) m/z 290.2 (M + H⁺).

General procedure for the synthesis of chromene substituted-1,3,4-oxadiazoles (9a–n). To a solution of chromene carboxylic acid hydrazide (7) (1.3 mmol) in dioxane (4 ml) was added 10-camphorsulfonic acid (0.065 mmol) followed by acid chloride (8) (1.3 mmol), and the resulting mixture was heated at 100 °C for 16 h. Then, the reaction mixture was evaporated under vacuum, saturated Na₂CO₃ (10 ml) was added, and the mixture was extracted into diethyl ether. Then, the resulting organic layers were dried over Na₂SO₄ and distilled in vacuum to obtain 1,3,4-oxadiazole (9a–n) in 75–92% yield without further purification.
2-(2H-Chromen-3-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (9a). Off-white solid; yield 0.27 g (0.84 mmol, 88%); M.R: 118–122 °C; δ_H (400 MHz, CDCl₃) 7.93–7.91 (d, 1 h, J: 8 Hz), 7.82–7.79 (d, 1H, J: 12 Hz), 7.54–7.49 (q, 1H, J: 6.3 Hz), 7.39 (s, 1H), 7.29–7.19 (m, 2H), 6.99–6.96 (t, 1H, J: 6 Hz), 6.92–6.90 (d, 1H, J: 12 Hz), 5.28 (s, 2H); δ_C (100 MHz, CDCl₃) 164.08, 163.25, 162.02, 161.61, 154.72, 131.66, 130.92, 128.41, 128.22, 125.55, 122.79, 122.08, 120.94, 119.09, 118.88, 116.37, 115.70, 114.17, 113.93, 63.96, 29.67; IR ν_max (film): 3436, 2924, 2854, 1744, 1640, 1604, 1455, 1211, 1123, 1033, 753, 726 cm⁻¹; MS (EI) m/z 295.3 (M + H⁺).
2-(2H-Chromen-3-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (9b). Pale yellow solid; yield 0.23 g (0.75 mmol, 79%); M.R: 181–184 °C δ_H (400 MHz, CDCl₃) 77.82–7.81 (d, 1H, J: 4 Hz), 7.57–7.56 (s, 1H, J: 4 Hz), 7.34 (s, 1H), 7.25–7.17 (m, 3H), 6.97–6.93 (t, 1H, J: 8 Hz), 6.90–6.88 (d, 1H, J: 8 Hz), 5.25 (s, 2H); δ_C (100 MHz, CDCl₃) 161.22, 160.54, 154.68, 131.53, 130.50, 130.08, 128.35, 128.25, 127.84, 124.94, 122.04, 121.02, 116.33, 115.68, 63.99; IR ν_max (film): 3093, 2926, 2846, 1733, 1641, 1585, 1452, 1206, 1008, 851, 750, 721 cm⁻¹; MS (EI) m/z 283 (M + H⁺).
2-(2H-Chromen-3-yl)-5-(benzyl)-1,3,4-oxadiazole (9c). Gummy liquid; yield 0.23 g (0.71 mmol, 75%); δ_H (400 MHz, CDCl₃) 7.35–7.29 (m, 5H), 7.21–7.19 (d, 2H, J: 4 Hz), 7.12–7.10 (d, 1H, J: 8 Hz), 6.94–6.92 (t, 1H, J: 4 Hz), 6.87–6.85 (d, 1H, J: 8 Hz), 5.18 (s, 2H), 4.32 (s, 2H); δ_C (100 MHz, CDCl₃) 165.09, 162.40, 154.61, 133.70, 131.44, 129.32, 128.97, 128.79, 127.74, 127.63, 121.97, 120.91, 116.27, 115.87, 63.96, 31.86; IR ν_max (film): 3430, 2923, 2853, 1641, 1624, 1503, 1275, 1261, 1122, 1018, 750 cm⁻¹; MS (EI) m/z 291.3 (M + H⁺).
2-(2H-Chromen-3-yl)-5-(m-toluoyl)-1,3,4-oxadiazole (9d). White solid; yield 0.25 g (0.79 mmol, 83%); M.R: 112–116 °C; δ_H (400 MHz, CDCl₃) 7.95–7.88 (m, 2H), 7.41–7.30 (m, 3H), 7.22–7.17 (m, 2H), 6.97–6.93 (t, 1H, J: 8 Hz), 6.90–6.88 (d, 1H, J: 8 Hz), 5.27 (s, 2H), 2.44 (s, 3H); δ_C (100 MHz, CDCl₃) 164.41, 161.68, 154.65, 138.99, 132.73, 132.46, 131.44, 128.97, 128.29, 127.64, 127.52, 127.40, 124.19, 124.05, 123.82, 123.48, 122.01, 121.04, 116.30, 115.98, 64.02, 21.30; IR ν_max (film): 3434, 3053, 2921, 2852, 1640, 1522, 1468, 1454, 1210, 1121, 1031, 996, 888, 750 cm⁻¹; MS (EI) m/z 291.2 (M + H⁺).
2-(2H-Chromen-3-yl)-5-(o-toluoyl)-1,3,4-oxadiazole (9e). White solid; yield 0.27 g (0.83 mmol, 88%); M.R: 116–120 °C; δ_H (400 MHz, CDCl₃) 8.01–7.99 (d, 1H, J: 8 Hz), 7.45–7.41 (t, 1H, J: 8 Hz), 7.37–7.33 (m, 3H), 7.26–7.22 (m, 1H), 7.19–7.18 (d, 1H, J: 4 Hz), 6.98–6.94 (t, 1H, J: 8 Hz), 6.92–6.90 (d, 1H, J: 8 Hz), 5.29 (s, 2H), 2.74 (s, 3H); δ_C (100 MHz, CDCl₃) 164.52, 161.31, 154.67, 138.61, 131.82, 131.46, 131.38, 131.15, 129.01, 128.94, 128.31, 127.64, 126.17, 122.70, 122.01, 121.04, 116.31, 115.99, 64.03, 22.18; IR ν_max (film): 3435, 2922, 2837, 1642, 1604, 1484, 1453, 1210, 1121, 1031, 889, 750, 727 cm⁻¹; MS (EI) m/z 291.2 (M + H⁺).
2-(2H-Chromen-3-yl)-5-cyclopropyl-1,3,4-oxadiazole (9f). Gummy material; yield 0.19 g (0.71 mmol, 75%); δ_H (400 MHz, CDCl₃) 7.22–7.21 (d, 1H, J: 4 Hz), 7.18 (s, 1H), 7.15–7.13 (d, 1H, J: 8 Hz), 6.90–6.87 (d, 1H, J: 12 Hz), 5.20 (s, 1H), 2.22–2.18 (m, 1H), 1.25–1.20 (d, 4H, J: 5 Hz); δ_C (100 MHz, CDCl₃) 131.29, 128.19, 126.93, 121.97, 121.04, 120.85, 116.27, 115.94, 64.02, 29.68, 8.67, 6.48; IR ν_max (film): 3442, 2923, 2857, 1636, 1456, 1275, 1261, 1019, 750 cm⁻¹; MS (EI) m/z 241.3 (M + H⁺).
2-(2H-Chromen-3-yl)-5-(3-fluoro-4-methyl-phenyl)-1,3,4-oxadiazole (9g). Pale yellow solid; yield 0.19 g (0.81 mmol, 86%); M.R: 185–188 °C; δ_H (400 MHz, CDCl₃) 7.88–7.86 (d, 1H, J: 8 Hz), 7.83–7.80 (dd, 1H, J: 4 Hz), 7.35 (s, 1H), 7.27–7.23 (m, 1H), 7.20–7.18 (d, 1H, J: 8 Hz), 7.10–7.06 (t, 1H, J: 8 Hz), 6.99–6.95 (t, 1H, J: 8 Hz), 6.92–6.90 (d, 1H, J: 8 Hz), 5.27 (s, 2H), 3.98 (s, 3H); δ_C (100 MHz, CDCl₃) 163.31, 161.61, 154.67, 153.50, 151.03, 150.89, 150.87, 131.51, 128.32, 127.69, 123.84, 122.04, 121.01, 116.32, 115.36, 114.96, 114.74, 113.47, 63.99, 56.32; IR ν_max (film): 3437, 2924, 2852, 2601, 1744, 1640, 1623, 1503, 1454, 1284, 1017, 883, 745 cm⁻¹; MS (EI) m/z 325.2 (M + H₂O⁺).
2-(6-Chloro-2H-chromen-3-yl)-5-(4-ethoxyphenyl)-1,3,4-oxadiazole (9h). Off-white solid; yield 0.27 g (0.75 mmol, 85%); M.R: 174–176 °C; δ_H (300 MHz, CDCl₃) 8.04–8.01 (d, 2H, J: 4.5 Hz), 7.20–7.15 (m, 2H), 7.02–6.99 (d, 2H, J: 4.5 Hz), 6.86–6.83 (d, 1H, J: 9 Hz), 5.28 (s, 2H), 4.15–4.08 (q, 2H, J: 3.5 Hz), 1.48–1.44 (t, 3H, J: 2 Hz); δ_C (100 MHz, CDCl₃) 164.53, 162.05, 160.97, 153.08, 30.83, 128.90, 127.53, 126.75, 125.86, 122.35, 117.62, 117.38, 115.72, 115.02, 64.22, 63.80, 14.67; IR ν_max (film): 3209, 2978, 1609, 1496, 1268, 1179, 1043, 827, 807, 662 cm⁻¹; MS (EI) m/z 355.4 (M + H⁺).
2-(6-Chloro-2H-chromen-3-yl)-5-(3-fluorophenyl)-1,3,4-oxadiazole (9i). Off-white solid; yield 0.26 g (0.79 mmol, 89%); M.R: 169–173 °C; δ_H (300 MHz, CDCl₃) 7.93–7.90 (d, 1H, J: 9 Hz), 7.82–7.79 (d, 1H, J: 9 Hz), 7.56–7.49 (m, 1H), 7.32–7.27 (m, 2H), 7.24–7.18 (m, 2H), 6.87–6.84 (d, 1H, J: 9 Hz), 5.31 (s, 2H); δ_C (100 MHz, CDCl₃) 163.51, 161.67, 157.23, 153.76, 147.86, 131.56, 131.05, 130.96, 127.68, 126.89, 122.83, 122.12, 119.25, 117.70, 114.56, 114.12, 64.10; IR ν_max (film): 3446, 3053, 2854, 1636, 1538, 1485, 1212, 861, 813, 645 cm⁻¹; MS (EI) m/z 329.1 (M + H⁺).
2-(4-tert-Butylphenyl)-5-(6-chloro-2H-chromen-3-yl)-1,3,4-oxadiazole (9j). Off-white solid; yield 0.30 g (0.81 mmol, 91%); M.R: 157–160 °C; δ_H (300 MHz, CDCl₃) 8.05–8.01 (d, 2H, J: 6 Hz), 7.56–7.53 (d, 1H, J: 4.5 Hz), 7.28–7.26 (d, 2H, J: 3 Hz), 7.19–7.17 (d, 2H, J: 3 Hz), 6.86–6.83 (d, 1H, J: 9 Hz), 5.28 (s, 2H), 1.37 (s, 9H); δ_C (100 MHz, CDCl₃) 164.59, 161.23, 155.79, 153.09, 130.90, 127.58, 126.94, 126.76, 126.12, 122.30, 120.63, 117.63, 117.29, 67.20, 35.13, 31.09; IR ν_max (film): 3436, 2961, 1614, 1493, 1480, 1208, 1094, 911, 713 cm⁻¹; MS (EI) m/z 367.4 (M + H⁺).
2-(6-Chloro-2H-chromen-3-yl)-5-cyclopropyl-1,3,4-oxadiazole (9k). Off-white solid; yield 0.18 g (0.74 mmol, 83%); M.R: 114–117 °C; δ_H (300 MHz, CDCl₃) 7.18–7.15 (dd, 1H, J: 3 Hz), 7.12–7.10 (m, 2H), 6.84–6.81 (d, 1H), 5.20 (s, 2H), 2.26–2.18 (m, 1H), 1.21–1.19 (m, 4H); δ_C (100 MHz, CDCl₃) 168.58, 160.85, 152.99, 130.78, 127.49, 126.72, 125.62, 122.24, 117.58, 117.30, 64.15, 11.03, 8.79, 6.46; IR ν_max (film): 3436, 2961, 1614, 1493, 1480, 1208, 1094, 911, 713 cm⁻¹; MS (EI) m/z 275.3 (M + H⁺).
2-(6-Chloro-2H-chromen-3-yl)-5-phenyl-1,3,4-oxadiazole (9l). Off-white solid; yield 0.24 g (0.78 mmol, 88%); M.R: 177–180 °C; δ_H (300 MHz, CDCl₃) 8.13–8.10 (d, 2H, J: 4.5 Hz), 7.56–7.53 (m, 3H), 7.30 (s, 1H), 7.21–7.17 (m, 2H), 6.86–6.84 (d, 1H, J: 6 Hz), 5.29 (s, 2H); δ_C (100 MHz, CDCl₃) 164.48, 161.43, 153.12, 132.07, 131.00, 129.14, 127.61, 127.09, 126.79, 126.43, 123.49, 122.25, 117.66, 117.20, 64.18; IR ν_max (film): 3434, 3052, 1539, 1483, 1211, 1022, 809, 712, 684 cm⁻¹; MS (EI) m/z 311.3 (M + H⁺).
2-(6-Chloro-2H-chromen-3-yl)-5-(2-thienylmethyl)-1,3,4-oxadiazole (9m). Off-white solid; yield 0.26 g (0.78 mmol, 88%); M.R: 148–151 °C; δ_H (300 MHz, CDCl₃) 7.25–7.12 (m, 4H), 7.02–6.99 (m, 2H), 6.84–6.81 (d, 1H, J: 9 Hz), 5.21 (s, 2H), 4.26 (s, 2H); δ_C (100 MHz, CDCl₃) 164.32, 162.11, 153.07, 134.61, 131.02, 127.63, 127.28, 127.17, 126.78, 126.67, 125.57, 122.09, 117.63, 117.02, 64.09, 26.26; IR ν_max (film): 3444, 2925, 1648, 1567, 1482, 1209, 988, 901, 827, 705 cm⁻¹; MS (EI) m/z 331 (M + H⁺).
2-Butyl-5-(6-chloro-2H-chromen-3-yl)-1,3,4-oxadiazole (9n). Off-white solid; yield 0.212 g (0.73 mmol, 82%); M.R: 106–109 °C; δ_H (300 MHz, CDCl₃) 7.19–7.12 (m, 3H), 6.84–6.81 (d, 1H, J: 9 Hz), 5.22 (s, 3H), 2.92–2.87 (t, 2H, 3.75 Hz), 1.86–1.76 (p, 2H, J: 3.75 Hz), 1.49–1.42 (m, 2H), 1.00–0.95 (t, 2H, J: 3.75 Hz); δ_C (100 MHz, CDCl₃) 167.09, 153.04, 130.85, 127.53, 126.74, 125.99, 122.24, 117.61, 117.39, 64.19, 28.56, 25.12, 22.15, 13.56; IR ν_max (film): 3430, 2957, 1645, 1566, 1481, 1208, 923, 814, 646 cm⁻¹; MS (EI) m/z 291.3 (M + H⁺).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra11218k

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