Simple and Efficient Synthesis of Diamino Derivatives of bis-1,2,4-oxadiazole via Tandem Staudinger/aza-Wittig Reaction

Abstract

Two efficient, scalable routes to bis-1,2,4-oxadiazole have been developed by tandem Staudinger/aza-Wittig reaction from the same starting material diaziglyoxime, isocyanates and triphenylphosphonium in good yields.

Background: Two convenient and efficient routes for synthesizing diamino derivatives of bis-1,2,4-oxadiazoles were described.

Objective: This study provides a simple protocol for the synthesis of bis-1,2,4-oxadiazoles.

Methods: The two procedures were based on a tandem Staudinger/aza-Wittig reaction from the same starting material of diaziglyoxime, isocyanates and triphenylphosphonium.

Results: In synthesis method I, diaziglyoxime 1 was treated with various aromatic or aliphatic isocyanates to give diazioxalimides 2 a high yield. Diazioxalimides 2 reacted with Ph₃P to produce the iminophosphoranes 4; the reaction was directly heated from room temperature to 115°C to get the desired diamino derivatives of bis-1,2,4-oxadiazole 4 in 72-92% yields. In synthesis method II, the same target compounds 4 were synthesized in a one-pot reaction by Ph₃P and aromatic or aliphatic isocyanates in toluene for 10 h under 115 °C in 53-71% yields.

Conclusion: The two procedures provide proficient methods of making nitrogen-containing heterocyclic rings. The structures of target compounds 4 were identified by IR, ¹HNMR, ¹³CNMR and HRMS.

1. INTRODUCTION

Oxadiazoles are one of the most important heterocyclic compounds with desirable biological or functional material properties, which are used widely in medicine, pesticidal chemistry and other fields as a stable bioisosterism of esters or amides. As a key member of the oxadiazole family, drugs containing a 1,2,4-oxadiazole core are associated with a diverse range of pharmacological and biological activities, such as anticancer [1, 2], antimicrobial [3], antibacterial activity [4], anti-inflammatory activity [5], pesticidal activities [6] and HDAC inhibitors for Huntington’s disease [7]. In addition, 5-amino-1,2,4-oxadiazoles are used as a very promising energetic component for the preparation of high-energy-density materials (HEDMs) [8, 9] (Fig. 1).

Fig. (1).

Representative application of 1,2,4-oxadiazoles.

Although there were many synthetic methods of oxadiazoles [10, 11], there were only a few pieces of literature on synthesizing bisoxadiazole rings [12-14]. The aza-Wittig reaction becomes a simple, efficient, inexpensive tool for constructing nitrogen-containing heterocyclic rings [15, 16].

A large number of five-, six- and seven-membered heterocycles containing a nitrogen heteroatom could be synthesized via the aza-Wittig reaction in reasonable yields.

Recently, we have synthesized a series of oxazoles [17-19], benzodiazepines [20] and imidazoles [21] using various azides as starting material via the aza-Wittig reaction. Herein, we described two synthetic routes of bis-1,2,4-oxadiazoles via tandem Staudinger/aza-Wittig reaction of diaziglyoxime and diazioxalimides promoted by PPh₃.

2. MATERIAL AND METHODS

Dichloroglyoxime, sodium azide, triphenylphosphine, isocyanates, anhydrous sodium sulfate and the common solvents are commercially available analytical purity and can be used directly without purification. Toluene (C₆H₅CH₃) and chloroform (CHCl₃) were dried with anhydrous calcium chloride for one week.

All melting points were determined on an X-4 model melting point apparatus and uncorrected previously. IR spectra were recorded on a Perkin Elmer-Spectrum One spectrometer as KBr pellets and reported in cm^-1. ¹H NMR and ¹³C NMR spectra were acquired on AVANCE NEO 500M spectrometer (500 and 125 MHz, respectively) in DMSO and resonances relative to TMS. High-resolution mass spectra (HRMS) were performed by an Agilent 6224 TOF LC/MS spectrometer. Monitoring of the reaction progress and assessment of the purity of synthesized compounds was done by TLC on Silica gel (HSGF254) plates, and Silica gel (200-300 mesh) was used for short column chromatography.

2.1. Synthesis of 2a-2h

Diaziglyoxime 1 (1.02 g, 6 mmol) and various aromatic or aliphatic isocyanates (12 mmol) were dissolved in chloroform (15 mL), and the mixture was stirred for about 4 h at room temperature (TLC showed complete conversion). The reaction mixture was poured into 50 mL water and stirred for a few minutes, and a large amount of yellow solid was precipitated from the water. The formed precipitate was filtered off, washed with a small amount of ethanol, and crystallized from n-hexane/ether (6:1) to give the diazioxalimides 2a-2j as yellow solids.

2.1.1. N^'1,N^'2-bis((phenylcarbamoyl)oxy)oxalimidoyl diazide (2a)

Yellow solid (0.82 g, 82%) m.p.240°C; IR (KBr):3384, 2128, 1762, 1441, 1294, 1243, 1172 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.66 (s, NH, 2H), δ 7.45 (d, J = 7.3 Hz, ArH, 4H), 7.29-7.26 (t, ArH, 4H), 6.98-6.95 (t, ArH, 2H); ¹³C NMR (125 MHz, DMSO) δ 150.28, 142.03, 138.11, 129.16, 128.99, 123.68, 119.07.

2.1.2. N^'1,N^'2-bis((p-tolylcarbamoyl)oxy)oxalimidoyl diazide (2b)

Yellow solid (0.77 g, 77%) m.p.:275°C; IR (KBr): 3412, 2160, 1767, 1406, 1303,1179, 1077 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.49 (s, NH, 2H), 7.32 (d, J = 8.5, ArH, 4H), 7.07 (d, J = 8.2 Hz, ArH, 4H), 2.23 (s, CH₃, 6H); ¹³C NMR (125 MHz, DMSO) δ 152.78, 137.39, 130.65, 129.31, 118.38, 20.48.

2.1.3. N^'1,N^'2-bis(((4-chlorophenyl)carbamoyl)oxy)oxalimi-doyl diazi (2c)

Yellow solid (0.71, 71%) m.p.:285-290°C; IR (KBr): 3294, 2107, 1893, 1631, 1590, 1490, 1280, 1084 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.85 (s, NH, 2H), 7.61-7.39 (m, ArH, 4H), 7.39-7.01(m, ArH, 4H). ¹³C NMR (125 MHz, DMSO) δ 152.36, 138.56, 128.63, 125.53, 119.85.

2.1.4. N^'1,N^'2-bis(((4-fluorophenyl)carbamoyl)oxy)oxalimid-oyl diazide (2d)

Yellow solid (0.74 g, 74%) m.p.:234-245°C; IR (KBr): 3401, 2124, 1774, 1611, 1597, 1409, 1253, 1171 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.68 (s, NH, 2H), 7.44 (d, ArH, 4H), 7.10 (d, J = 8.9 Hz, ArH, 4H). ¹³C NMR (125 MHz, DMSO) δ 158.46, 156.56, 152.89, 136.17, 136.15, 120.21, 120.15, 115.50, 115.32.

2.1.5. N^'1,N^'2-bis(((3-chlorophenyl)carbamoyl)oxy)oxalimi-doyl diazide (2e)

Yellow solid (0.62 g, 62%) m.p.:251°C; IR (KBr): 3368, 3306, 2155, 1723, 1617,1522, 1497, 1278, 1215, 1006 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.97 (s, NH, 2H), 7.71 (s, ArH, 2H), 7.48-7.14 (m, ArH, 4H), 7.04 (d, J = 7.7Hz, ArH, 2H). ¹³C NMR (125 MHz, DMSO) δ 152.41, 141.15, 133.37, 130.54, 121.86, 117.93, 116.99.

2.1.6. N^'1,N^'2-bis(((4-bromophenyl)carbamoyl)oxy)oxalim-idoyl diazide (2f)

Yellow solid (0.62 g, 79%) m.p. 194-196°C; IR (KBr): 3387,3300,2150,1767,1634,1595, 1489, 1239, 1073 cm^-1; ¹H NMR (500 MHz, DMSO) δ10.49 (s, NH 2H), 7.54-7.48 (m, ArH, 8H). ¹³C NMR (125 MHz, DMSO) δ150.52, 142.58, 137.90, 132.31, 121.28, 120.74, 115.73.

2.1.7. N^'1,N^'2-bis(((4-nitrophenyl)carbamoyl)oxy)oxalim-idoyl diazide (2g)

Yellow solid(0.68 g, 81%)m.p. >300°C;IR (KBr): 3366, 2128, 1733, 1616, 1554, 1497, 1248, 1177 cm^-1; ¹H NMR (500 MHz, DMSO) δ9.67 (s, NH, 2H), 8.23 (d, ArH, 4H), 7.73 (d, ArH, 4H). ¹³C NMR (125 MHz, DMSO)δ151.82, 145.88, 141.70, 125.35, 118.16.

2.1.8. N^'1,N^'2-bis((cyclohexylcarbamoyl)oxy)oxalimidoyl diazide (2h)

Yellow solid (0.56 g, 63%) m.p.230°C; IR (KBr): 3368, 2155, 1723, 1617, 1522, 1497, 1278, 1215 cm^-1; ¹H NMR (500 MHz, DMSO) δ 5.56 (s, NH, 2H), 1.72-1.48 (m, 11H), 1.28-0.99 (m, 11H). ¹³C NMR (125 MHz, DMSO) δ 152.57, 141.09, 50.69, 32.78, 25.50, 25.08.

2.2. General Procedure for the Preparation Method I of Product 4a-4h

Diazioxalimides 2 (3 mmol) was suspended in 20 mL anhydrous toluene at room temperature, and PPh₃ (1.57 g, 6 mmol) was added in batches. Subsequently, the mixture was stirred at room temperature for 2-3h until complete consumption of the starting materials was monitored by TLC. The reaction mixture was heated at 115°C for about 6 hours. After removal of the solvent under reduced pressure, the residue was purified on silica gel with n-hexane/EtOAc (8:2), and the target compounds 4 were obtained in 45-89% yields.

2.3. General Procedure for the Preparation Method II of Product 4a-4h

A solution of PPh₃ (1.57 g, 6 mmol) in anhydrous toluene (8 mL) was added dropwise to a solution of diaziglyoximes 1 (3 mmol) in anhydrous toluene (15 mL) at room temperature over 30 min. After the mixture was stirred for 1 h, the reaction was completed by TLC monitoring, and the resulting iminophosphorane 5 could proceed to the next step without separation. To the reaction mixture were added various aromatic or aliphatic isocyanates (6 mmol) at room temperature, the reaction mixture was stirred for 6 h at room temperature, and the carbodiimides 6 were completely obtained by TLC monitoring. Subsequently, the reaction mixture was heated in an oil bath at 115°C for about 10 h. The solvent was evaporated in a vacuum, and the obtained residual oil was purified by silica gel column chromatography using n-hexane/EtOAc (8:1) as the eluent. The product was recrystallized from n-hexane/EtOAc (6:1) to afford diamino derivatives of bis-1,2,4-oxadiazole 4a-4f.

2.3.1. N⁵,N^5'-diphenyl-[3,3'-bi(1,2,4-oxadiazole)]-5,5'-diamine (4a)

White solid, m.p.246.5-247.5°C; IR (KBr): 3324, 1594, 1497, 1314, 1231, 1155, 1051 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.66 (d, J = 4.0 Hz, NH, 2H), 7.44 (d, J = 6.0 Hz, ArH, 4H), 7.28 (dd, J = 8.7, 4.7 Hz, ArH, 4H), 7.11-6.79 (m, ArH, 2H). ¹³C NMR (125 MHz, DMSO) δ 152.20, 139.38, 128.47, 121.48, 117.84; HRMS(ESI) m/z: calcd. for: C₁₆H₁₂N₆O₂ [M+H]⁺: 321.3120; found 321.31204.

2.3.2. N⁵,N^5'-di-p-tolyl-[3,3'-bi(1,2,4-oxadiazole)]-5,5'-diamine (4b)

Yellow solid, m.p.255-257°C; IR (KBr): 3269, 1599, 1495, 1377, 1256,1114,1075cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.52 (s, NH, 2H), 7.33 (d, J = 7.1 Hz, ArH, 4H), 7.07 (d, J = 7.0 Hz, ArH, 4H), 2.24 (s, CH₃, 6H); ¹³C NMR (125 MHz, DMSO) δ 152.83, 137.44, 130.66, 129.34, 118.39, 20.52; HRMS(ESI) m/z: calcd. for: C₁₈H₁₆N₆O₂ [M+H]⁺: 349.1335; found 349.1653.

2.3.3. N⁵,N^5'-bis(4-chlorophenyl)-[3,3'-bi(1,2,4-oxadiazole)] -5,5'-diamine (4c)

Yellow solid, m.p.248-251°C; IR (KBr): 3295, 1590, 1491, 1399, 1235, 1085, 1012 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.97 (s, NH, 2H), 7.70 (s, ArH, 2H), 7.35-7.21 (m, ArH, 4H), 7.03 (d, J = 7.5 Hz, ArH, 2H); ¹³C NMR (125 MHz, DMSO) δ 152.51, 138.72, 128.80, 125.65, 119.99; HRMS(ESI) m/z: calcd. for: C₁₆H₁₀Cl₂N₆O₂ [M+Na]⁺: 412.1858; found 412.2208.

2.3.4. N⁵,N^5'-bis(4-fluorophenyl)-[3,3'-bi(1,2,4-oxadiazole)] -5,5'-diamine (4d)

Yellow solid, m.p.227-234°C; IR (KBr): 3293, 1565, 1409, 1296, 1153, 1094, 1012 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.69 (s, NH, 2H), 7.44 (d, ArH, 4H), 7.11 (d, ArH, 4H). ¹³C NMR (125 MHz, DMSO) δ 158.48, 156.59, 152.91, 136.20, 136.18, 120.23, 120.17, 115.51, 115.33; HRMS(ESI) m/z: calcd. for: C₁₆H₁₀F₂N₆O₂ [M+Na]⁺:379.2826; found 379.2420.

2.3.5. N⁵,N^5'-bis(3-chlorophenyl)-[3,3'-bi(1,2,4-oxadiazole)] -5,5'-diamine (4e)

Yellow solid, m.p.247-252°C; IR (KBr): 3289, 1550, 1423, 1286, 1095, 1071 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.97 (s, NH, 2H), 7.71 (s, ArH, 2H), 7.41-7.20 (m, ArH, 4H), 7.03 (d, J = 7.5Hz, ArH, 2H). ¹³C NMR (125 MHz, DMSO) δ 152.42, 141.17, 133.39, 130.54, 121.87, 117.95, 116.99; HRMS (ESI) m/z: calcd. for: C₁₆H₁₀Cl₂N₆O₂ [M+Na]⁺: 412.1858; found 412.2196.

2.3.6. N⁵,N^5'-bis(4-bromophenyl)-[3,3'-bi(1,2,4-oxadiazole)] -5,5'-diamine (4f)

Yellow solid, m.p.262-263°C; IR (KBr): 3296, 1551, 1487, 1389, 1232, 1110, 1064 cm^-1; ¹H NMR (500 MHz, DMSO) δ 8.85 (s, NH, 2H), 7.45-7.40 (m, ArH, 8H). ¹³C NMR (125 MHz, DMSO) δ152.30, 138.99, 131.57, 120.25, 113.41; HRMS (ESI) m/z: calcd. for: C₁₆H₁₀Br₂N₆O₂ [M+Na]⁺: 501.0937; found 501.1206.

2.3.7. N⁵,N^5'-bis(4-nitrophenyl)-[3,3'-bi(1,2,4-oxadiazole)]-5,5'-diamine (4g)

Yellow solid, m.p.288°C; IR (KBr): 3367, 1551, 1412, 1327, 1248, 1177, 1112 cm^-1; ¹H NMR (500 MHz, DMSO) δ9.70 (s, NH, 2H), 8.23 (d, ArH, 4H), 7.73 (d, ArH, 4H). ¹³C NMR (125 MHz, DMSO) δ152.00, 146.05, 141.87, 125.53; HRMS (ESI) m/z: calcd. for: C₁₆H₁₀N₈O₆ [M+Na]⁺: 433.2957 ; found 433.3274.

2.3.8. N⁵,N^5'-dicyclohexyl-[3,3'-bi(1,2,4-oxadiazole)]-5,5'diamine (4h)

White solid, m.p.199-201°C; IR (KBr): 3325, 1572, 1436, 1346, 1271, 1186, 1067 cm^-1; ¹H NMR (500 MHz, DMSO) δ5.60(s, NH, 2H), 1.73-1.59 (m, 11H), 1.26-1.03 (m, 11H).; ¹³C NMR (125 MHz, DMSO) δ 156.93, 47.79, 33.63, 25.62, 24.74. HRMS(ESI) m/z: calcd. for: C₁₆H₂₄N₆O₂ [M + Na]⁺: 335.3978; found 335.3308.

3. RESULTS AND DISCUSSION

Diaziglyoxime 1, the direct nucleophilic substitution reaction of dichloroglyoxime with sodium azide in DMF, was easily obtained in high yield, according to the literature [22]. Diaziglyoxime 1 was the key intermediate for the two reaction routes in this paper, but they will deteriorate after being placed at room temperature for 1-2 days, so they need to be stored in the refrigerator for up to a week.

In synthesis method I, diaziglyoxime 1 was treated with various aromatic or aliphatic isocyanates to obtain diazioxalimides 2a-2h high yield using chloroform as solvent. The reaction could be completed in about 3 h (Table 1).

Table 1.

Preparation of diazioxalimides 2a-2h.

Product 2	R	Reaction Time (h)	Yield (%)[a]
2a	Ph	3	82
2b	4-CH3C6H4	3	77
2c	4-ClC6H4	3	71
2d	4-FC6H4	3	74
2e	3-ClC6H4	3	62
2f	4-BrC6H4	3	79
2g	4-NO2C6H4	3	81
2h	cyclohexyl	3	63

Note: [a] Isolated yields.

Diazioxalimides 2a-2h are also unstable as a double azide compound. They could not be stored at normal temperature, so the vacuum-drying or Freeze-drying method was used instead of the high-temperature Oven-dry method in the drying process. Subsequently, Diazioxalimides 2a-2h were easily converted to iminophosphoranes 3 by treatment with Ph₃P in dry toluene at room temperature, accompanied by the release of nitrogen. Iminophosphoranes 3 are unstable, so they do not need further treatment. The intramolecular aza-Wittig reaction of iminophosphoranes 3 could occur when the reaction was heated at room temperature to 115°C to get the desired target compounds 4 in 72-92% yields (Table 2). The influence of temperature (from R.T. to 115°C) on the reaction was studied as well. The experimental results showed that the temperature below 100°C greatly prolonged the reaction time, and the reaction was incomplete (Scheme 1).

Table 2.

Preparation method II of bis-1,2,4-oxadiazoles 4a-4h.

Product 4	R	Method I		Method II
		Reaction Time (h)	Yield (%)[a]	Reaction Time (h)	Yield (%)[a]
4a	Ph	6	85	10	63
4b	4-CH3C6H4	6	92	10	71
4c	4-ClC6H4	6	81	10	65
4d	4-FC6H4	6	83	10	61
4e	3-ClC6H4	6	79	10	59
4f	4-BrC6H4	6	86	10	69
4g	4-NO2C6H4	6	82	10	58
4h	Cyclohexyl	6	72	10	53

Note: [a] Isolated yield.

Scheme 1.

Synthesis method I of bis-1,2,4-oxadiazoles 4a-4h.

In synthesis method II, diaziglyoxime 1 could be further designed in the Staudinger reaction and intramolecular aza-Wittig reaction to produce diamino derivatives of bis-1,2,4-oxadiazole 4. Diaziglyoxime 1 was treated with triphenylphosphonium to produce iminephosphines 5 via the Staudinger reaction. Iminephosphine 5 reacted with various isocyanates to obtain carbodiimides 6. The hydroxyl in molecule 6 was cyclized with carbodiimide by nucleophilic addition to obtain the same target molecule as the first method. We also attempted to separate the intermediate iminophosphorane 5 and carbodiimides 6; no pure product was obtained because of their stability. The best result was obtained when the reaction was carried out in a one-pot fashion (Scheme 2 and Table 2).

Scheme 2.

Synthesis method II of bis-1,2,4-oxadiazoles 4a-4h.

The synthetic mechanism for synthesizing the diamino derivatives of bis-1,2,4-oxadiazole 4 through two different routes is outlined in Scheme 3. In the synthesis method, I, diamino derivatives of bis-1,2,4-oxadiazole 4 were obtained by tandem Staudinger reaction and the intramolecular aza-Wittig reaction of diazioxalimides 2. In synthesis method II, the same target compounds 4 were synthesized via tandem Staudinger/intramolecular aza-Wittig/nucleophilic addition cyclization reaction in a one-pot reaction. These two reaction routes were simple and efficient based on a series of highly reliable name reactions.

Scheme 3.

The possible reaction mechanism.

The structures of 4a-4h were identified by IR, ¹HNMR, ¹³CNMR and HRMS. Take 4a as an example, The IR of 4a showed N-H at 3324 cm^-1, and the characteristic peaks of the benzene ring could also be found at the corresponding positions. The ¹H NMR showed it could be found the signal for the aromatic protons at d 6.95-7.46 ppm. Furthermore, the structures of 4a were supported by ¹³C NMR. In addition, as shown in the supporting information, when D₂O is added to 4a, the signal of N-H disappears at 8.66 ppm. ¹H NMR spectrum of 4a in D₂O analyses has confirmed the formation of N-H. The supporting information described the preparation and characterization of other compounds 4b-4h in detail.

CONCLUSION

In conclusion, we have elaborated two efficient synthesis routes to rapidly construct diamino derivatives of bis-1,2,4-oxadiazole from diaziglyoximes. Readily available starting materials, mild reaction conditions, and simple operating procedures make this protocol highly beneficial for synthesizing bis-1,2,4-oxadiazoles.

LIST OF ABBREVIATIONS

HEDMs

High-Energy-Density Materials

KBr

Potassium Bromide

NMR

Nuclear Magnetic Resonance

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

We gratefully acknowledge the financial support of this work by the Natural Science Foundation of Shanxi Province (No. 201801D121036) and the key industrial R & D Foundation of Datong City in Shanxi Province (No. 2017012).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

SUPPLEMENTARY MATERIAL

Supportive/Supplementary material will be available on the journal’s website. ¹H, ¹³C spectra of the compounds 4a-h prepared are available as supplementary material.