Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of methyl-azaheteroarenes and hydrazides

Journal Pre-proof Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of methyl-azaheteroarenes and hydrazides Zhi-Hao Shang, Ji-Na Sun, Jiang-Shan Guo, Yuan-Yuan Sun, Wei-Zhao Weng, ZhenXiao Zhang, Zeng-Jing Li, Yan-Ping Zhu PII:

S0040-4020(19)31299-2

DOI:

https://doi.org/10.1016/j.tet.2019.130887

Reference:

TET 130887

To appear in:

Tetrahedron

Received Date: 24 October 2019 Revised Date:

28 November 2019

Accepted Date: 17 December 2019

Please cite this article as: Shang Z-H, Sun J-N, Guo J-S, Sun Y-Y, Weng W-Z, Zhang Z-X, Li Z-J, Zhu Y-P, Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of methylazaheteroarenes and hydrazides, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2019.130887. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

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Facile Synthesis of 1,3,4-Oxadiazoles via Iodine

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Promoted Oxidative Annulation of Methyl-azaheteroarenes and Hydrazides Zhi-Hao Shang,‡ Ji-Na Sun,‡ Jiang-Shan Guo,‡ Yuan-Yuan Sun,‡ Wei-Zhao Weng, Zhen-Xiao Zhang, ZengJing Li, Yan-Ping Zhu,* School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University, Shandong, Yantai, 264005, P. R. China. X

X R1

O

R1 Y

N or

CH3 CH3

1

R

N

Y

O R

I2-DMSO NHNH2

K2CO3

36 examples Up to 82% yield

Oxidative Sp3 C-H bond Metal-free

N

N R1

orth, para-methyl oxidation

Broad scope

Simple conditions

R

N N O N N

R

1

Tetrahedron journal homepage: www.elsevier.com

Facile Synthesis of 1,3,4-Oxadiazoles via Iodine Promoted Oxidative Annulation of Methyl-azaheteroarenes and Hydrazides Zhi-Hao Shang,‡ Ji-Na Sun,‡ Jiang-Shan Guo,‡ Yuan-Yuan Sun,‡ Wei-Zhao Weng, Zhen-Xiao Zhang, Zeng-Jing Li, Yan-Ping Zhu* School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Shandong, Yantai, 264005, P. R. China.

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

An oxidative sp3 C-H bond of methyl-azaheteroarenes protocol was reported for the synthesis of 1,3,4-oxadiazoles via [4+1] annulation with hydrazides. This protocol enables 1,3,4-oxadiazole and quinoline linked diheterocycles via selective oxidation of sp3 C-H bond of methyl-azaheteroarenes in the presence of I2-DMSO. The reaction has a broad substrate scope and good functional group tolerance for methylazaheteroarenes and hydrazides.

Keywords: 1,3,4-Oxadiazoles Methyl-azaheteroarenes Hydrazides Oxidative annulation Iodine Heterocycles

1. Introduction Oxadiazole is an important heterocyclic scaffold which is widely presented in natural products, synthetic drugs (e.g. Furamizole, Tiodazosin, Nesapidil), “ drug like” small molecules, dyestuff industry and materials (Figure 1).[1] In particular, many 1,3,4-oxadiazole contained compounds show significant biological activities and pharmaceutical activities, such as, antimicrobial, antifungal, and anti-inflammatory.[2]

Figure 1. Examples of 1,3,4-oxadiazole containing medicines.

In view of the biological and pharmaceutical activities of oxadiazoles, great attention and efforts have been paid on their synthesis. Up to now, many different synthetic protocols have been reported.[3] The general methods for synthesis of 1,3,4oxadiazole are oxidative cyclization of N-acylhydrazones and the dehydrative cyclization of 1,2-diacylhydrazines, while Nacylhydrazones and 1,2-diacylhydrazines are usually by generating through the condensation of aldehydes or carboxylic acids with hydrazides.[4]

——— *

2019 Elsevier Ltd. All rights reserved.

Recently, I2 as an efficient oxidant or promoter attracted much attention. It could promote simple substrates to form C-C bond, C-X bond and heterocycles.[5] Within this field, some new and efficient protocols were developed for 1,3,4-oxadiazole synthesis from simple and easily available starting materials with mild reaction conditions. For example, the group of Chang in 2013 reported an I2-promoted oxidative annulation of in-situ generated N-acylhydrazone from aldehydes and hydrazides for the synthesis of 1,3,4-oxadiazoles in one-pot (Figure 2a).[6] In 2015, Wu and co-workors developed an elegant approach for synthesis of 1,3,4-oxadiazoles through annulation of simple methyl ketones with hydrazides (Figure 2b). With the condition of I2 and K2CO3 in DMSO-H2O, (het)aryl methyl ketones could couple with hydrazides to access 1,3,4-oxadiazoles via C(CO)−C(methyl) bond cleavage of (het)aryl methyl ketones. Through simple switched base and solvent, the reaction could selectively deliver 2-acyl-1,3,4-oxadiazoles.[7] Subsequently, the group of Huang also demonstrated a graceful domino protocol for one-pot synthesis of 1,3,4-oxadiazoles from diversity substrates styrene, phenyl acetylene and hydrazides (Figure 2c).[8] Interestingly, this protocol could generate 1,3,4-oxadiazoles via oxidative cleavage of C(sp2)−H or C(sp)−H bonds in the presence of I2 and K2CO3 with O2. Inspired by these pioneered works, we envisioned that I2 might oxidize sp3 C-H bond of methyl-azaheteroarenes,[9] followed by annulation with hydrazides to deliver 1,3,4oxadiazoles and azaheteroarenes linked diheterocycles. Herein, we report a novel I2-DMSO promoted oxidative [4+1] annulation of methyl-azaheteroarenes with hydrazides to access 1,3,4-

Corresponding author. e-mail: [email protected] (Y.-P. Zhu). ‡ These authors contributed equally to this work.

2

Tetrahedron

oxadiazoles (Figure 2d). This protocol could selectively oxidate sp3 C-H bond of methyl-azaheteroarenes in the presence of I2DMSO.

Figure 2. The protocols for 1,3,4-oxadiazoles synthesis.

2. Results and discussion Table 1. Optimization of the reaction conditions a

Base Yield (%)b (equiv) 1 1.0 K2CO3 (6.0) 40 2 1.5 K2CO3 (6.0) 56 3 2.0 K2CO3 (6.0) 65 4 2.5 K2CO3 (6.0) 72 (74)c (71)d 5 2.5 Na2CO3 (6.0) 67 6 2.5 Cs2CO3 (6.0) n.r. 7 2.5 NaHCO3 (6.0) 42 8 2.5 KH2PO4 (6.0) n.r. 20 9 2.5 K3PO4 (6.0) 10 2.5 NaOH (6.0) n.r. 11 2.5 K2CO3 (5.0) 69 12 2.5 K2CO3 (4.0) 40 13 2.5 K2CO3 (3.0) 15 a Reaction conditions: 2-methyl quinoline 1a (0.5 mmol), benzohydrazide 2a (0.6 mmol), I2 and base were heated in DMSO (3 mL). b Isolated yields. c 3.0 equivalent of iodine were added. d 4.0 equivalent of iodine were added. Entry

I2 (equiv)

presented either low efficiency or no reactivity (Entry 6-10). Moreover, the amount of K2CO3 was investigated. When decreasing the amount of K2CO3 to 5.0 equivalent, the yield was slightly decreased (69%). Whereas the yield was significantly decreased, when 4.0 and 3.0 equivalent of K2CO3 was employed. With the optimal reaction conditions in hand, we firstly explored the scope of hydrazides (Table 2). Various hydrazides, such as aryl hydrazides, heteroaryl hydrazides, cinnamohydrazide, alkenyl hydrazide and alkyl hydrazide were tested. We firstly studied the aryl hydrazides in which on the phenyl ring had electron-rich substituents (e.g. 2-Me, 3-Me, 4-Me, 4-OMe, 2,4Me2, 3,4-OCH2O), and the annulation reactions proceeded smoothly to deliver products 3ab-3ag in 60-76% yields. While the phenyl ring of hydrazides bearing halogen atoms (e.g. 4-Cl, 2-Br), the reactions could also afford the desired products (3ah and 3ai) in moderate yields. However, the reaction efficiency was low, when 4-nitrobenzohydrazide was employed (3aj). Moreover, the sterically hindered 2-naphthohydrazide 2k, 1naphthohydrazide 2l and 2-phenylbenzohydrazide 2m also reacted smoothly with benzohydrazide (2a) to furnish the target products 3ak-3am in good yields (54-62%). Notably, heteroaryl hydrazides, such as furan-2-carbohydrazide 2n and thiophene-2carbohydrazide 2o, were also tolerant under the standard conditions to generate the expected products 3an and 3ao in good yields. In addition, cinnamohydrazide 2p also reacted smoothly with 2-methyl quinoline to generate the desired product 3ap, in which the double bond of cinnamohydrazide did not affect the reaction. Encouraged by this result, alkenyl hydrazide 2q was also employed, but the reaction efficiency was low and only 35% of 3aq was isolated. Alkyl substrate acethydrazide 2r is also suitable for this reaction. However, only low yield product 3ar was obtained. Table 2. Scope of Substituted Hydrazides. a, b O R

N

1a

NH2

I2 (2.5 equiv.) K2CO3 (6 equiv.)

O

N

DMSO, 110 oC

R

N N

3

2

Me

Me O

N

N N

3ab: 67%

O

Me

N N

3ad: 65%

3ac: 60% O

N

3ae: 71%

O

N

N N

N N

3aa: 72%

N

O

N

OMe

N N

O

N

Me

N N

3af: 69%

Me Br

O

N

O

N N

O

N

3aj: 45%

N

O

Cl

N N

3ah: 68%

NO2

N

O

N

N N

O

3ag: 76%

At the outset, commercially available 2-methyl quinoline (1a) and benzohydrazide (2a) were chosen as model substrates for evaluating the reaction conditions (Table 1). Given the success in using I2-DMSO as reaction conditions for the synthesis of 1,3,4oxadiazoles from methyl ketones, styrene and phenyl acetylene, we initially performed the reaction of 2-methyl quinoline 1a (0.5 mmol) with benzohydrazide 2a (0.6 mmol) in the presence of I2 (1.25 mmol), K2CO3 (3.0 mmol) and DMSO at 110 oC. Delightfully, 1,3,4-oxadiazole 3aa was obtained in 40% yield (Table 1, entry 1). When increasing the amount of I2 to 1.5, 2.0 and 2.5 equivalent, the reaction yield was significantly increased to 56%, 65% and 72%, respectively (Entry 2-4). Further increasing the amount of iodine to 3.0 and 4.0 equivalent, the yield did not increase. Subsequently, a series of bases, such as Na2CO3, Cs2CO3, NaHCO3, KH2PO4, K3PO4 and NaOH, were screened. Among them, Na2CO3 was effective for this transformation, 3aa was afforded in 67% yield. Other bases

N H

3ai: 62%

O

O

N

N N

N N

N N

3ak: 62%

3al: 59%

Ph O

N

N

3an: 61%

3am: 54%

N

O N N

3ap: 40%

O

O

Ph

N

S

N N

3ao: 63%

O

N

N N

3aq: 35%

O

N

N N

N N

O N N

3ar: 32%

a

Reaction conditions: 1a (0.5 mmol), I2 (1.25 mmol) in DMSO (3 mL) at 110 o C for 4-6 h, then added 2 (0.6 mmol), K2CO3 (3.0 mmol) and stirred at 110 o C until the disappearance of 2 (4-6 h, monitored by TLC). b Isolated yields provided.

We next examined the scope of this reaction for methylazaheteroarenes 1 (Table 3). For example, 2-methyl quinolines

3 attached with electron-donating groups (6-Me, 6-OMe) and halogen atoms (6-Cl, 7-Cl, 6-Br, 6-F) were tolerant for this reaction to afford the corresponding products (3ba-3ga). The results showed that 2-methyl quinolines bearing electrondonating groups could give high yields than those bearing halogen atoms substrates. It should be noted that 4-methyl quinoline 1i was also tolerant for this reaction to generate the desired product 3ia (63% yield). Moreover, two heteroatoms containing substrates 2-methylquinoxaline 1j and 2-methyl-1,8naphthyridine 1k were also tolerant to react with benzohydrazide, generating the desired products 3ja and 3ka in 64% and 61% yields, respectively. As we know, multiheterocyclic compounds are important scaffolds, which usually have enhanced biological and pharmaceutical activities. We subsequently examied the reaction of furan-2-carbohydrazide 2n and thiophene-2carbohydrazide 2o with 4-methyl quinoline 1m, 2methylquinoxaline 1j and 2-methyl-1,8-naphthyridine 1k. To our satisfaction, multiheterocyclic scaffolds 3in, 3io, 3jn, 3jo, 3kn and 3ko were obtained in moderate yields under the standard conditions (50-59%). Moreover, the reaction is compatible with monocyclic heteroarenes, such as 2-methyl pyridine and 4methyl pyridine. When 2-methyl pyridine and 4-methyl pyridine were chosen as substrates, the reactions could perform to generate the desired products 3la and 3ma in 10% and 19% yields, respectively. Table 3. Scope of Substituted Methyl-azaheteroarenes and Hydrazinylpyridine. a, b

starting material 1a (0.716 g), giving the desired product 3aa in 72% yield. Even the amount of 1a was increased to 10 mmol scale (1.432 g), the reaction could also proceed smoothly to generate the desired product 3aa in 62% yield. To understand the mechanism of the reaction, some control experiments were conducted (Scheme 2). 2-Methylquinoline could absolutely transfer to quinoline-2-carbaldehyde in 88% yield in the presence of I2 in DMSO at 110 oC for 4 hours, whereas this reaction could not proceed without I2. While the reaction of 2-methylquinoline with iodine performed at 110 oC in DMSO for 30 minutes, 2-(iodomethyl)quinoline and quinolin-2carboxaldehyde could be detected in 42% and 30% yields, respectively (Scheme 2a). There results disclosed I2 is very essential for this transformation. Subsequently, the reaction of 2(iodomethyl)quinoline with benzohydrazide (2a) under standard conditions performed well to generate the desired product 3aa in 75% yield. However, the reaction could not give the desired product without I2. (Scheme 2b). Next, we examined the reaction of quinoline-2-carbaldehyde with benzohydrazide (2a) under standard conditions, the product 3aa could be obtained in good yield (Scheme 2c). The reaction of quinoline-2-carbaldehyde with benzohydrazide (2a) in EtOH at reflux could afford N'(quinolin-2-ylmethylene)benzohydrazide (1ac), which could further transfer to the product 3aa under standard conditions (Scheme 2e). Moreover, N'-(quinolin-2ylmethylene)benzohydrazide (1ac) generated in-situ from quinoline-2-carbaldehyde and benzohydrazide (2a) in EtOH without isolation could also perform the product 3aa under standard conditions (Scheme 2f). These results uncovered that 2(iodomethyl)quinoline, quinoline-2-carbaldehyde and N'(quinolin-2-ylmethylene)benzohydrazide are the potential intermediates in this reaction. Conditions DMSO, 110 oC

N

N

1a

(a)

I

N

CHO

1ab

1aa

standard conditions, without I2: 1aa: not detected standard conditions: 30 mins, 1aa: 30% yield, 1ab: 42% 4 h, 1ab: 88% yield, 1aa: not detected O I

N

Conditions NHNH2

Ph

O

N

(b)

Ph

N N

2a

1aa

Standard conditions: 3aa: 75% yield without I2: 3aa: not observed

O N

CHO

Standard conditions

Ph

O

EtOH, reflux

a

N

CHO

NHNH2

(c)

O N

N

1ac

2a

1ab

Ph

N N 3aa: 89% yield

2a

Ph

O

N

NHNH2

1ab

Reaction conditions: 1 (0.5 mmol), I2 (1.25 mmol) in DMSO (3 mL) at 110 o C for 4-6 h, then added 2 (0.6 mmol), K2CO3 (3.0 mmol) and stirred at 110 o C until the disappearance of 2 (4-6 h, monitored by TLC). b Isolated yields provided.

DMSO, 110 oC

N H

Ph

(d)

O N

N

1ac

Standard conditions N H

3aa: 91% yield EtOH

2a reflux N

1ab

Scheme 1. Scaled-up Reactions for the Synthesis of 1,3,4-Oxadiazoles 3aa.

In order to show the application of this methodology, the scaled-up reaction was performed under the standard conditions. To our satisfied, the reaction could perform with 5 mmol of

CHO

N

Ph

Standard conditions N

O

Ph

N N

O

Ph

(e)

(f)

N N 3aa: 82% yield

Scheme 2. Control Experiments.

On the basis of these mechanistic findings and previous reports,[10] a plausible reaction mechanism was proposed in scheme 3. Firstly, 2-methylpyridine 1a undergoes an iodination

4

Tetrahedron

reaction with I2 to afford the intermediate 2(iodomethyl)quinolone (1aa). Subsequently, 2(iodomethyl)quinolone (1aa) is oxidized by DMSO to generate quinoline-2-carbaldehyde 1ab via Kornblum oxidation. Next, quinoline-2-carbaldehyde 1ab undergoes condensation with benzohydrazide to afford intermediate N'-(quinolin-2ylmethylene)benzohydrazide 1ad, which performs annulation and deprotonation process to finish the product 3aa.

TLC), then added benzohydrazide (2a) (81.6 mg, 0.6 mmol, 1.2 equiv.) , K2CO3 (414.0 mg, 3.0 mmol, 6.0 equiv.) at 110 oC for another 4-6 h. After the reaction completed, and added 50 mL water to the mixture, then extracted with EtOAc 3 times (3 × 50 mL). The extract was washed with 10% Na2S2O3 solution (w/w), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to yield the corresponding product 3aa as a yellow solid (72% yield).

4.3. Characterization data 2-Phenyl-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aa)

Scheme 3. A plausible mechanism for the preparation of 1,3,4oxadiazoles.

3. Conclusion In summary, we developed an oxidative functionalization protocol for the synthesis of 1,3,4-oxadiazoles via [4+1] annulation of methyl-azaheteroarenes with hydrazides. This protocol enables to 1,3,4-oxadiazole and quinoline linked diheterocycles via selective oxidation of sp3 C-H bond of methylazaheteroarenes in the presence of I2-DMSO. It has a broad substrate scope and good functional group tolerance for methylazaheteroarenes and hydrazides. Moreover, this protocol could efficiently afford furan, quinoline and oxadiazole containing multiheterocyclic scaffolds, which might have enhanced biological and pharmaceutical activities. 4. Experimental

Yellow solid, m.p.: 123-126 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.40 (t, J = 8.4 Hz, 2H), 8.33 (s, 1H), 8.27-8.31 (m, 2H), 7.91 (dd, J = 1.2, 8.4 Hz, 1H), 7.83 (dt, J = 1.2, 8.4 Hz, 1H), 7.67 (dt, J = 1.2, 8.4 Hz, 1H), 7.58-7.60 (m, 2H), 7.55-7.56 (m, 1H), 13 C-NMR (100 MHz, CDCl3): δ (ppm) 147.9, 143.4, 137.5, 132.1, 130.6, 130.1, 129.1, 129.0, 128.7, 128.3, 127.8, 127.5, 123.6, 119.9, HRMS (ESI): m/z [M+H]+ calcd for C17H12N3O: 274.0975; found: 274.0985.

2-(Quinolin-2-yl)-5-(o-tolyl)-1,3,4-oxadiazole (3ab) Yellow solid, m.p.: 115-118 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.31 (t, J = 8.8 Hz, 2H), 8.25 (t, J = 8.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 (dt, J = 1.2, 8.4 Hz, 1H), 7.58 (dt, J = 1.2, 8.0 Hz, 1H), 7.41 (dt, J = 1.2, 8.4 Hz, 1H), 7.32-7.35 (m, 2H), 2.78 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 163.5, 147.8, 143.3, 138.7, 137.2, 131.6, 131.3, 130.3, 130.0, 129.3, 128.5, 128.1, 127.6, 126.0, 122.6, 119.6, 22.1. HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O: 288.1131; found: 288.1139.

4.1. General Unless stated otherwise, all solvents and commercially available reagents were obtained from commercial suppliers and used without further purification. In addition petroleumether (b.p. 60-90 oC), which was used for Column chromatography, was distilled prior to use. Non-commercial starting materials were prepared as described below or according to literature procedures. TLC analysis was performed using pre-coated glass plates. Column chromatography was performed using silica gel (200-300 mesh).

2-(Quinolin-2-yl)-5-(m-tolyl)-1,3,4-oxadiazole (3ac) White solid, m.p.: 120-124 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.30 (q, J = 8.4 Hz, 2H), 8.26 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.84 (d, J = 8.4 Hz,1H), 7.77 (t, J = 8.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 2.43 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.8, 163.9, 147.7, 143.2, 138.7, 137.2, 132.7, 130.3, 129.9, 128.8, 128.5, 128.1, 127.7, 127.6, 124.4, 123.2, 119.6, 21.1. HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O: 288.1131; found: 288.1142.

Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Advance 400 MHz spectrometer at ambient temperature using the non or partly deuterated solvent as internal standard (1H: δ 7.26 ppm and 13C{1H}: δ 77.0 ppm for CDCl3). Chemical shifts (δ) are reported in ppm, relative to the internal standard of tetramethylsilane (TMS). The coupling constants (J) are quoted in hertz (Hz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad) or combinations thereof. High resolution mass-spectrometric (HRMS) were obtained on an Apex-Ultra MS equipped with an electrospray source. Melting points were determined using SGW X-4 apparatus and not corrected.

White solid, m.p.: 165-170 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.35 (q, J = 8.4 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.81 (dt, J = 1.6, 7.6, 1H), 7.64 (dt, J = 1.2 , 7.6, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 147.9, 143.5, 142.7, 137.4, 130.5, 130.1, 129.7, 128.6, 128.2, 127.7, 127.4, 120.8, 119.8, 21.7. HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O: 288.1131; found: 288.1137.

4.2 General procedure for synthesis of 5-(quinolin-2-yl)-1,3,4oxadiazoles 3 (3aa as an example)

2-(4-Methoxyphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ae)

A 25 mL pressure vial was charged with 2-methylquinoline (1a) (71.5 mg, 0.50 mmol, 1.0 equiv.), I2 (317.3 mg, 1.25 mmol, 2.5 equiv.) and DMSO (3.0 mL). The vial was sealed and the resulting mixture was stirred at 110 °C for 4-6 h under an air atmosphere, after disappearance of the reactant (monitored by

White solid, m.p.: 196-198 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.28 (t, J = 8.8 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.7.4 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.7, 163.6, 162.5,

2-(Quinolin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole (3ad)

5 147.8, 143.4, 137.2, 130.4, 130.0, 129.2, 128.5, 128.1, 127.7, 119.7, 116.0, 114.4, 55.4. HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O2: 304.1081; found: 304.1090.

2-(2,4-Dimethylphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3af) White solid, m.p.: 169-172 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.34 (t, J = 8.4 Hz, 2H), 8.28 (t, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 2.78 (s, 3H), 2.39 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.1, 163.4, 147.9, 143.4, 141.8, 138.6, 137.2, 132.4, 130.3, 130.0, 129.4, 128.5, 128.0, 127.7, 127.6, 126.8, 119.8, 119.7, 22.1, 21.3. HRMS (ESI): m/z [M+H]+ calcd for C19H16N3O: 302.1288; found: 302.1294.

2-(Benzo[d][1,3]dioxol-5-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ag) White solid, m.p.: 180-183 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.36 (t, J = 8.8 Hz, 2H), 8.27 (d, J = 9.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79-7.85 (dq, J = 1.6, 8.4 Hz, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7,62-7.66 (dt, J = 1.2, 7.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.7, 163.9, 151.0, 148.3, 148.0, 143.5, 137.4, 130.5, 130.1, 128.7, 128.2, 127.8, 122.8, 119.8, 117.4, 108.9, 107.5, 101.9. HRMS (ESI): m/z [M+H]+ calcd for C18H12N3O3: 318.0873; found: 318.0888.

2-(4-Chlorophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ah) Yellow solid, m.p.: 185-188 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.33 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.0, 164.2, 147.9, 143.2, 138.3, 137.4, 130.5, 130.0, 129.4, 128.7, 128.6, 128.3, 127.7, 122.0, 119.8. HRMS (ESI): m/z [M+H]+ calcd for C17H11ClN3O: 308.0585; found: 308.0590.

2-(2-Bromophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ai) Brown solid, m.p.: 175-180 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.38 (q, J = 8.8 Hz, 2H), 8.29-8.31 (m, 1H), 8.28-8.29 (m, 1H), 7.91 (dd, J = 1.2, 8.0 Hz, 1H), 7.81-7.85 (dt, J = 1.6, 8.4 Hz, 1H), 7.66-7.69 (dt, J = 1.2, 8.0 Hz, 1H), 7.55-7.60 (m, 3H), 13 C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 164.2, 148.0, 143.5, 137.4, 132.1, 130.6, 130.2, 129.1, 129.0, 128.7, 128.3, 127.8, 127.5, 123.7, 119.9, HRMS (ESI): m/z [M+H]+ calcd for C17H11BrN3O: 352.0080; found: 352.0089.

2-(4-Nitrophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aj) Brown solid, m.p.: 238-241 °C, 1H-NMR (400 MHz, DMSOd6): δ (ppm) 8.60 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8..0 Hz, 1H), 7.87-7.91 (dt, J = 1.2, 8.4 Hz, 1H), 7.84 (dt, J = 2.4, 8.8 Hz, 2H), 7.71-7.75 (dt, J = 1.2, 8.0 Hz, 1H), 6.76 (t, J = 1.2 Hz, 1H), 6.74 (t, J = 1.2 Hz, 1H), 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 165.9, 162.5, 152.7, 147.2, 143.2, 137.8, 130.8, 129.3, 128.5, 128.19, 128.18, 128.15, 119.5, 113.7, 109.2, HRMS (ESI): m/z [M+H]+ calcd for C17H11N4O3: 319.0826; found: 319.0836.

2-(Naphthalen-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ak) White solid, m.p.: 208-211 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.74 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 2H), 8.27 (s, 1H), 7.97 (t, J = 8.4 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.55-7.58 (m, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 164.2, 147.9, 143.4, 137.4, 134.8, 132.7, 130.5, 130.1, 128.93, 128.90, 128.6, 128.1, 128.0, 127.9, 127.7, 127.1, 123.4, 120.7, 119.8. HRMS (ESI): m/z [M+H]+ calcd for C21H14N3O: 324.1131; found: 324.1149.

2-(Naphthalen-1-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3al) White solid, m.p.: 201-204 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.38 (d, J = 8.4 Hz, 1H), 8.49 (dd, J = 1.2, 7.2 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.92-7.98 (dq, J = 1.2, 8.4 Hz, 2H), 7.82-7.86 (dt, J = 1.2, 8.4 Hz, 1H), 7.72-7.76 (dt, J = 1.2, 8.4 Hz, 1H), 7.65-7.69 (dt, J = 1.2, 8.4 Hz, 2H), 7.61-7.65 (dt, J = 1.2, 8.4 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 163.8, 148.1, 143.4, 137.5, 133.9, 133.0, 130.6, 130.2, 129.2, 128.8, 128.7, 128.3, 127.8, 126.8, 126.3, 124.9, 120.2. 120.0, HRMS (ESI): m/z [M+H]+ calcd for C21H14N3O: 324.1131; found: 324.1143.

2-([1,1'-Biphenyl]-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3am) White solid, m.p.: 142-144 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.21 (t, J = 8.8 Hz, 2H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (dt, J = 1.2, 8.4 Hz, 1H), 7.58-7.65 (m, 2H), 7.51-7.56 (m, 2H), 7.36-7.41 (m, 5H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 163.9, 147.8, 142.9, 142.4, 140.3, 137.1, 131.4, 130.9, 130.3, 130.0, 128.7, 128.4, 128.1, 128.0, 127.6, 127.5, 122.4, 119.2, HRMS (ESI): m/z [M+H]+ calcd for C23H16N3O: 350.1288; found: 350.1297.

2-(Furan-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3an) White solid, m.p.: 130-134 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.36 (q, J = 8.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 1.2, 8.4 Hz, 1H), 7.78-7.83 (dt, J = 1.2, 7.2 Hz, 1H), 7.70 (q, J = 0.8 Hz, 1H), 7.62-7.66 (dt, J = 1.2, 6.8 Hz, 1H), 7.38 (dd, J = 0.8, 3.2 Hz, 1H), 6.64 (q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 163.5, 158.6, 148.0, 146.2, 143.1, 139.2, 137.5, 130.6, 130.2, 128.7, 128.4, 127.8, 119.9, 115.2, 112.3, HRMS (ESI): m/z [M+H]+ calcd for C15H10N3O2: 264.0768; found: 264.0774.

2-(Quinolin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3ao) White solid, m.p.: 187-190 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.34 (q, J = 8.4 H, 2H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 1.2, 3.6 Hz, 1H), 7.88 (dd, J = 1.2, 8.4 Hz, 1H), 7.78-7.82 (dt, J = 1.6, 7.2 Hz, 1H), 7.61-7.65 (dt, J = 1.2, 8.0 Hz, 1H), 7.60 (dd, J = 1.2, 4.8 Hz, 1H), 7.21-7.23 (q, J = 4.8 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 163.6, 162.1, 147.9, 143.2, 137.4, 130.8, 130.5, 130.1, 128.7, 128.3, 128.2, 127.8, 124.8, 119.8, HRMS (ESI): m/z [M+H]+ calcd for C15H10N3OS: 280.0539; found: 280.0545.

(E)-2-(Quinolin-2-yl)-5-styryl-1,3,4-oxadiazole (3ap)

6

Tetrahedron

White solid, m.p.: 112-115 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.08 (d, J = 8.8 Hz, 2H), 8.03 (dt, J = 1.2, 7.2 Hz, 1H), 7.94-7.97 (m, 7H), 7.77 (dt, J = 1.6, 8.4 Hz, 1H), 7.66-7.70 (dt, J = 1.6, 8.8 Hz, 1H), 7.47-7.51 (dt, J = 1.2, 8.4 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 154.6, 147.8, 142.9, 136.5, 136.1, 130.2, 129.8, 129.6, 129.0, 128.9, 127.9, 127.6, 127.5, 126.7, 126.5, 121.5, 117.7, HRMS (ESI): m/z [M+H]+ calcd for C19H14N3O: 300.1131; found: 300.1139.

White solid, m.p.: 190-195 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.38 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.288.29 (m, 1H), 8.27-8.28 (m, 1H), 8.25-8.26 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 2,0 Hz, 1H), 7.58-7.59 (m, 1H), 7.567.57 (m, 1H), 7.55-7.56 (m, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 148.3, 144.3, 137.3, 136.6, 132.2, 129.3, 129.1, 129.0, 128.9, 127.5, 127.0, 123.5, 120.0. HRMS (ESI): m/z [M+H]+ calcd for C17H11ClN3O: 308.0585; found: 308.0590.

2-(Prop-1-en-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aq)

2-(6-Bromoquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3fa)

1

White solid, m.p.: 87-91 °C, H-NMR (400 MHz, CDCl3): δ (ppm) 9.44 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.71-7.75 (dt, J = 1.2, 8.0 Hz, 1H), 7.54-7.58 (dt, J = 1.2, 8.0 Hz, 1H), 2.44 (s, 3H), 13CNMR (100 MHz, CDCl3): δ (ppm) 173.4, 153.2, 148.0, 144.1, 136.6, 130.1, 129.4, 128.4, 127.8, 127.5, 117.6, 32.0, HRMS (ESI): m/z [M+H]+ calcd for C14H12N3O: 238.0975; found: 238.0986.

White solid, m.p.: 206-209 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.39 (s, 1H), 8.37 (s，1H), 8.25 (s, 1H), 8.23-8.24 (m, 1H), 8.22 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 2.4 Hz, 1H), 7.54 (s, 1H), 13 C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 146.5, 143.7, 136.4, 134.1, 132.2, 131.7, 129.9, 129.7, 129.1, 127.5, 123.5, 122.5, 120.7. HRMS (ESI): m/z [M+H]+ calcd for C17H11BrN3O: 352.0080; found: 352.0089.

2-Methyl-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ar)

2-(6-Fluoroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ga)

1

White solid, m.p.: 93-95 °C, H-NMR (400 MHz, CDCl3): δ (ppm) 8.34 (s, 2H), 8.26 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.81 (dt, J = 1.2, 7.6 Hz, 1H), 7.65 (dt, J = 1.2, 8.0 Hz, 1H), 2.72 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.2, 164.4, 147.8, 143.4, 137.6, 130.6, 130.0, 128.7, 128.3, 127.8, 29.7. HRMS (ESI): m/z [M+H]+ calcd for C12H10N3O: 212.0818; found: 212.0825.

White solid, m.p.: 200-205 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.40 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.27 (t, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.57-7.59 (m, 1H), 7.57 (t, J = 2.4 Hz, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 3.2, .8 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 164.0, 162.7, 160.2, 145.1, 142.9, 136.8, 136.7, 132.8, 13.7, 132.1, 129.1, 127.5, 123.6, 121.1, 120.1, 120.6, 111.1, 110.8, HRMS (ESI): m/z [M+H]+ calcd for C17H11FN3O: 292.0881; found: 292.0889.

2-(6-Methylquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ba) White solid, m.p.: 175-180 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.31 (d, J = 8.4 Hz, 1H), 8.24-8.27 (m, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54-7.57 (m, 2H), 7.53-7.54 (m, 1H), 2.55 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.7, 164.3, 146.6, 142.5, 138.6, 136.6, 132.9, 132.0, 129.7, 129.0, 128.8, 127.4, 126.6, 123.7, 119.9, 21.7, HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O: 288.1131; found: 288.1140.

2-(6-Methoxyquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ca) White solid, m.p.: 191-193°C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.30 (d, J = 8.8 Hz, 1H), 8.24-8.26 (m, 2H), 8.17 (q, J = 8.4 Hz, 2H), 7.54-7.56 (m, 2H), 7.52-7.54 (m, 1H), 7.43 (dd, J = 2.8, 9.2 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 3.95 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.6, 164.3, 159.2, 144.1, 140.9, 135.8, 131.9, 131.6, 130.1, 129.0, 127.4, 123.7, 123.5, 120.2, 105.0, 55.7, HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O2: 304.1081; found: 304.1090.

2-(6-Chloroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3da) White solid, m.p.: 180-184 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.77 (s, 1H), 8.26-8.29 (m, 4H), 7.90 (s, 1H), 7.87 (s, 1H), 7.57-7.59 (m, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.2, 162.7, 143.7, 143.0, 141.8, 138.6, 132.4, 131.8, 131.2, 130.0, 129.6, 129.2, 127.6, 123.3, HRMS (ESI): m/z [M+H]+ calcd for C17H11ClN3O: 308.0585; found: 308.0592.

2-(7-Chloroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ea)

2-(Benzo[f]quinolin-3-yl)-5-phenyl-1,3,4-oxadiazole (3ha) White solid, m.p.: 215-219 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.12 (d, J = 8.8 Hz, 1H), 8.67 (d, J = 9.2 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.97 (dd, J = 2.0, 8.0 Hz, 1H), 7.73 (dt, J = 1.6, 9.2 Hz, 1H), 7.53-7.59 (m, 4H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.8, 164.2, 148.2, 142.8, 132.2, 132.1, 132.03, 131.96, 129.2, 129.1, 128.9, 128.1, 127.6, 127.4, 126.6, 123.7, 123.1, 120.3, HRMS (ESI): m/z [M+H]+ calcd for C21H14N3O: 324.1131; found: 324.1142.

2-Phenyl-5-(quinolin-4-yl)-1,3,4-oxadiazole (3ia) White solid, m.p.: 133-135 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.20 (d, J = 8.4 Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), 8.108.15 (m, 3H), 7.96 (d, J = 4.4 Hz, 1H), 7.75 (dt, J = 1.2, 7.6 Hz, 1H), 7.66 (dt, J = 1.2, 7.6 Hz, 1H), 7.48-7.53 (m, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 164.6, 162.7, 149.5, 148.8, 132.1, 130.0, 129.0, 128.4, 127.6, 127.0, 126.0, 123.6, 123.1, 120.2. HRMS (ESI): m/z [M+H]+ calcd for C17H12N3O: 274.0975; found: 274.0979.

2-(Furan-2-yl)-5-(quinolin-4-yl)-1,3,4-oxadiazole (3in) White solid, m.p.: 73-77 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.26 (d, J = 8.8 Hz, 1H), 9.07 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.82 (dt, J = 1.2, 8.4 Hz, 1H), 7.74 (dt, J = 1.2, 8.8 Hz, 1H), 7.71-7.72 (m, 1H), 7.33 (d, J = 4.0 Hz, 1H), 6.65 (q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 162.2, 157.7, 149.7, 149.1, 146.3, 139.0, 130.3,

7 130.2, 128.7, 127.6, 126.2, 123.8, 120.5, 115.2, 112.5, HRMS (ESI): m/z [M+H]+ calcd for C15H10N3O2: 264.0768; found: 264.0776.

(q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 163.1, 159.0, 155.6, 154.9, 146.4, 146.1, 139.2, 138.8, 137.0, 123.7, 123.5, 121.1, 115.6, 112.4, HRMS (ESI): m/z [M+H]+ calcd for C14H9N4O2: 265.0270; found: 265.0285.

2-(Quinolin-4-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3io) White solid, m.p.: 144-148 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.26 (dd, J = 1.2, 8.4 Hz, 1H), 9.08 (d, J = 4.4 Hz, 1H), 8.21 (dd, J = 2.0, 8.4 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.92 (dd, J = 1.2, 3.6 Hz, 1H), 7.81 (dt, J = 1.2, 8.4 Hz, 1H), 7.74 (dt, J = 1.2, 8.8 Hz, 1H), 7.63 (dd, J = 1.2, 5.2 Hz, 1H), 7.23 (dd, J = 4.0, 4.8 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 162.3, 161.2, 149.7, 149.1, 131.1, 130.6, 130.3, 130.2, 128.7, 128.4, 127.7, 126.2, 123.8, 120.4, HRMS (ESI): m/z [M+H]+ calcd for C15H10N3OS: 280.0539; found: 280.0545.

2-(1,8-Naphthyridin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3ko) White solid, m.p.: 75-80 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.23 (q, J = 2.0 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 2.0, 8.4 Hz, 1H), 8.01 (dd, J = 1.2, 3.6 Hz, 1H), 7.59-7.62 (m, 2H), 7.22 (dd, J = 3.6, 8.8 Hz, 1H), 13 C-NMR (100 MHz, CDCl3): δ (ppm) 163.3, 162.7, 155.7, 154.9, 146.3, 138.7, 137.0, 131.1, 128.4, 124.8, 123.6, 123.5, 121.1, HRMS (ESI): m/z [M+H]+ calcd for C14H9N4OS: 281.0492; found: 281.0499.

2-Phenyl-5-(quinoxalin-2-yl)-1,3,4-oxadiazole (3ja) 2-Phenyl-5-(pyridin-2-yl)-1,3,4-oxadiazole (3la)

White solid, m.p.: 210-214 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.41 (d, J = 8.4 Hz, 1H), 8.27-8.28 (br, 2H), 8.25-8.26 (m, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.73-7.76 (dd, J = 2.4, 9.2 Hz, 1H), 7.57-7.58 (m, 2H), 7.55 (s, 1H), 13CNMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 146.4, 143.7, 136.5, 134.3, 132.2, 131.7, 131.6, 129.2, 129.1, 127.5, 126.5, 123.5, 120.8, HRMS (ESI): m/z [M+H]+ calcd for C16H11N4O: 275.0927; found: 275.0934.

White solid, m.p.: 121-124 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.81 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.31 (dt, J = 8.0, 1.2 Hz, 1H), 8.24-8.18 (m, 2H), 7.90 (td, J = 7.6, 1.6 Hz, 1H), 7.597.50 (m, 3H), 7.47 (ddd, J = 6.0, 3.6, 1.2 Hz, 1H).13C-NMR (100 MHz, CDCl3): δ (ppm) 165.5, 163.8, 150.3, 143.6, 137.2, 132.0, 129.0, 127.3, 125.8, 123.5, 123.2, 123.2. HRMS (ESI): m/z [M+H]+ calcd for C13H10N3O: 224.1808; found: 224.1817.

2-(Furan-2-yl)-5-(quinoxalin-2-yl)-1,3,4-oxadiazole (3jn)

2-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazole (3ma)

1

White solid, m.p.: 200-204 °C, H-NMR (400 MHz, CDCl3): δ (ppm) 9.74 (s, 2H), 8.17-8.27 (m, 1H), 7.85-7.88 (m, 2H), 7.72 (q, J = 1.2 Hz, 1H), 7.40 (dd, J = 0.8, 3.6 Hz, 1H), 6.65 (q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 161.9, 158.8, 146.5, 143.7, 143.0, 141.8, 138.9, 138.3, 131.9, 131.3, 130.0, 129.6, 115.7, 112.5, HRMS (ESI): m/z [M+H]+ calcd for C14H9N4O2: 265.0720; found: 265.0733.

White solid, m.p.: 145-147 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.86-8.78 (m, 2H), 8.18-8.10 (m, 2H), 8.03-7.92 (m, 2H), 7.62-7.55 (m, 2H), 7.55-7.51 (m, 1H). 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.4, 162.72, 150.9, 132.2, 131.0, 129.2, 127.1, 123.31, 120.3. HRMS (ESI): m/z [M+H]+ calcd for C13H10N3O: 224.1808; found: 224.1819.

Acknowledgments 2-(Quinoxalin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3jo) White solid, m.p.: 267-269 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.75 (s, 1H), 8.26-8.29 (m, 1H), 8.19-8.22 (m, 1H), 8.01 (dd, J = 0.8, 3.6 Hz, 1H), 7.87-7.90 (m, 2H), 7.64 (dd, J = 1.2, 5.2 Hz, 1H), 7.23 (d, J = 4.2 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 162.5, 162.1, 143.7, 143.0, 141.8, 138.4, 131.8, 131.3, 131.2, 130.0, 129.6, 128.4, 124.5, HRMS (ESI): m/z [M+H]+ calcd for C14H9N4OS: 281.0492; found: 281.0499.

This work was supported by the National Natural Science Foundation of China (21702091) and Key Research & Development Project of Shandong Province (2018GGX109014). This work was also supported by Yantai “Double Hundred Plan” and Talent Induction Program for Youth Innovation Teams in Colleges and Universities of Shandong Province. The College Students Innovation and Entrepreneurship Training Program of Shandong Province (201911066033) are gratefully acknowledged (for J.-N. Sun). The laboratory open project of Yantai University are gratefully acknowledged (for Z.-J. Li and Z.-X. Zhang).

2-(1,8-Naphthyridin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ka) White solid, m.p.: 217-220 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.23 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 7.2 Hz, 3H), 7.55-7.62 (m, 4H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.3, 163.8, 155.6, 154.8, 146.4, 138.7, 137.0, 132.2, 129.1, 129.0, 127.5, 123.4, 121.0. HRMS (ESI): m/z [M+H]+ calcd for C16H11N4O: 275.0927; found: 275.0938.

Supplementary data Supplementary data related to this article can be found online at doi:

References and notes 1.

2-(Furan-2-yl)-5-(1,8-naphthyridin-2-yl)-1,3,4-oxadiazole (3kn) White solid, m.p.: 132-135 °C, 1H-NMR (400 MHz, CDCl3): δ (ppm) 9.22 (q, J = 2.0 Hz, 1H), 8.53 (d, J = 8.4, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 2.4, 8.4 Hz, 1H), 7.70 (q, J = 1.2 Hz, 1H), 7.60 (q, J = 4.0 Hz, 1H), 7.39 (dd, J = 1.2, 4.4 Hz, 1H), 6.64

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·Metal-free

approach

for

oxidation

of

sp3

C-H

bond

of

methyl-azaheteroarenes. ·This protocol enables furan, quinoline and oxadiazole containing multiheterocyclic scaffolds in the presence of I2-DMSO. ·The reaction has a broad substrate scope and good functional group tolerance for methyl-azaheteroarenes and hydrazides. ·This protocol presents a gram scaled-up synthesis.

Declaration of interests √ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: