Synthesis of 2-Alkynyl 1,3,4-Oxadiazoles by Palladium-Catalyzed Cross- Coupling Reaction^[1]

Abstract

Several 2-alkynyl 1,3,4-oxadiazoles have been synthesized efficiently by employing palladium-catalyzed cross-coupling under Sonogashira reaction conditions. This reaction has been applied for the first time for the preparation of oxadiazole derivatives. The products were formed in high yields and no side products were detected.

Oxadiazole derivatives are highly important in pharmaceutical and material sciences. They are used as antimicrobial and anticonvulsant agents.[2] They also act as amide and ester bioisosteres.[3] In addition, substituted oxadiazoles possess multiphoton-absorbing capacities and optoelectronic properties.[4] They are also known to exhibit good electron-transporting and hole-blocking abilities[5] and consequently find application in the development of organic electronics.[6] Herein we report the first application of the Sonogashira reaction[7] for the efficient synthesis of 2-alkynyl 1,3,4-oxadiazoles.

Substituted alkynes are a common unit in natural products and bioactive compounds and are found to be an important feature in various bioactive substances, such as endyne antibiotics.[8] The alkyne moiety can also extend the conjugation of aryl and heteroaryl rings with which it is attached. Thus we realized that 2-alkynyl 1,3,4-oxadiazoles may have bioactivity as well as potential for use in organic materials chemistry.

In continuation of our work[9] on the synthesis of substituted oxadiazoles we discovered that 2-bromo-1,3,4-oxadiazoles (1; readily be prepared from 1,3,4-oxadiazoles[10]) can be subjected to palladium-catalyzed cross-coupling with terminal alkynes under Sonogashira reaction conditions[7] to prepare 2-alkynyl 1,3,4-oxadiazoles (Scheme [1]).

Alkynylation of heterocyclic-based halides using Sonogashira reaction conditions has been frequently employed for the preparation of various novel systems.[11] However, to our knowledge, this reaction has not yet been applied for the generation of oxadiazolyl alkynes (Scheme [1]).

Initially we optimized the reaction conditions with 2-bromo-5-phenyl-1,3,4-oxadiazole (1a) and 2-(4-methylphenyl)acetylene (2a) using various amounts of different palladium catalysts and CuI (Table [1]). Different bases and solvents were also used. In addition, the temperature and the time of the reaction were varied. Considering the yield of the reaction the best result was obtained when PdCl₂(PPh₃)₂ (5mol%), CuI (10 mol%), and Et₃N (2 equiv) were used in DMF at 60 °C for six hours (Table [1], entry 1). In the absence of CuI the yield was low (Table [1], entry 6). When the reaction was conducted with other bases (such as Cs₂CO₃, i-PrNH; Table [1], entries 7 and 8) and other solvents (such as THF, DMSO, dioxane; Table [1], entries 2, 4, and 5) the yield was also low. On increasing the amount of base (Et₃N) no significant change in yield was observed (Table [1], entry 9). The reaction was also carried out at room temperature but the reaction time increased and the yield was lower (Table [1], entry 10).

Table 1 Optimization of Reaction Conditions for the Cross-Coupling of 2-Bromo-5-phenyl-1,3,4-oxadiazole (1a) with 2-(4-Methylphenyl)acetylene (2a) Using Different Metal Catalysts and Various Bases^a

Entry	Catalyst	Base	Solvent	Temp (°C)	Time (h)	Yield (%)b
1	PdCl2(PPh3)2, CuI	Et3N	DMF	60	6	92
2	PdCl2(PPh3)2, CuI	Et3N	THF	60	10	58
3	PdCl2(PPh3)2, CuI	i-Pr2NH	DMF	120	24	68
4	PdCl2(PPh3)2, CuI	Et3N	DMSO	60	16	62
5	PdCl2(PPh3)2, CuI	Et3N	dioxane	60	12	55
6	PdCl2(PPh3)2	Et3N	DMF	60	36	15
7	PdCl2(PPh3)2, CuI	Cs2CO3	DMF	120	24	54
8	PdCl2(PPh3)2, CuI	i-Pr2NH	DMF	120	24	66
9	PdCl2(PPh3)2, CuI	Et3N	DMF	60	6	92d
10	PdCl2(PPh3)2, CuI	Et3N	DMF	27	24	40c

^a Reaction conditions: 2-bromo-5-phenyl-1,3,4-oxadiazole 1a (0.7 mmol), 2 (4-methylphenyl) acetylene 2 (1.0 mmol), (PdCl₂(PPh₃)₂ (5 mol%), CuI (10 mol%), base (2.0 equiv), 60–120 °C, 6–36 h, solvent (3 mL).

^b Isolated yield of 3 after column chromatography.

^c Reaction was carried out at r.t. (27 °C).

^d Base (4.0 equiv).

It was also observed that – with other terminal acetylenes other than 2-(4-methylphenyl)acetylene – longer times were required (Table [2]). The conversion also did not proceed smoothly with 2-chloro-1,3,4-oxadiazoles, requiring longer reaction times and resulting in lower yields.

After optimization of the reaction conditions (Table [1]) several 2-alkynyl-1,3,4-oxadiazoles (3) were prepared successfully from various 2-bromo-1,3,4-oxadiazoles 1 and terminal alkynes 2 (Table [2]). The bromooxadiazoles contained different aromatic moieties at C-5 possessing electron-donating as well as electron-withdrawing groups as well as oxygen and nitrogen heterocycles. The terminal alkynes also contained aromatic and heteroaromatic rings at C-2 and even an alkyne with a long aliphatic chain underwent the transformation smoothly (Table [2], entry 6). The products were formed in high yields within 6–16 hours. All the products were characterized from their spectroscopic data and were compared to known compounds.[9] No side reaction including alkyne homocoupling could be observed.

Table 2 Palladium-Catalyzed Cross-Coupling of Various Terminal Alkynes with 2-Bromo-5-aryl-1,3,4-oxadiazole^a

Entry	R1	R2	Time (h)	Yield (%)b
1	1a Ph	2b 4-MeC6H4	6	3ab 92
2	1a Ph	2c 4-ClC6H4	10	3ac 80
3	1a Ph	2d 4-FC6H4	12	3ad 82
4	1a Ph	2e 2-naphthyl	14	3ae 78
5	1a Ph	2f 2-thienyl	8	3af 84
6	1a Ph	2g heptyl	16	3ag 80
7	1a Ph	2ai 2-MeOC6H4	8	3ai 84
8	1b 4-MeC6H4	2b 4-MeC6H4	7	3bb 87
9	1b 4-MeC6H4	2e 2-naphthyl	10	3be 90
10	1c 4-MeOC6H4	2b 4-MeC6H4	8	3cb 90
11	1c 4-MeOC6H4	2d 4-FC6H4	14	3cd 82
12	1c 4-OMeC6H4	2f 2-thienyl	12	3cf 84
13	1c 4-MeOC6H4	2h cyclohexyl	16	3ch 78
14	1d 4-ClC6H4	2d 4-FC6H4	12	3dd 85
15	1d 4-ClC6H4	2f 2-thienyl	14	3df 86
16	1e 4-F3CC6H4	2e 2-naphthyl	10	3ee 80
17	1f 2-furyl	2b 4-MeC6H4	8	3fb 88
18	1f 2-furyl	2d 4-FC6H4	10	3fd 84
19	1g 2-nicotyl	2a Ph	10	3ga 80
20	1g 2-nicotyl	2b 4-MeC6H4	8	3gb 78

^a Reaction conditions: 2-bromo-5-aryl 1,3,4-oxadiazole 1 (0.7 mmol), alkyne 2 (1.0 mmol), (PdCl₂(PPh₃)₂ (5 mol%), CuI (10 mol%), base (2.0 equiv), 60 °C, 6–16 h, DMF (3 mL).

^b Isolated yield of 3 after column chromatography.

In conclusion, we have successfully applied the Sonogashira reaction for the first time for the synthesis of a series of 2-alkynyl 1,3,4-oxadiazoles. The products were formed under mild reaction conditions and in high yield.

General Experimental Procedure for the Alkynylation of 2-Bromo 1,3,4-Oxadiazoles with Terminal Alkynes

In a 10 mL round-bottom flask under N₂ atmosphere, 2-bromo-1,3,4-oxadiazole (0.7 mmol), alkyne (1.0 mmol), PdCl₂(PPh₃)₂ (5 mol%), CuI (10 mol%), and Et₃N (2.0 equiv) in anhydrous DMF (2.0 mL) were combined. The reaction mixture was stirred at 60 °C for 6–16 h, and progress of reaction was monitored by TLC. After the consumption of the starting materials, the reaction mixture was allowed to cool, and subsequently extracted with Et₂O (2 × 15 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo followed by flash chromatography on silica to afford the corresponding 2-alkynyl-1,3,4-oxadiazole in good yield.

Selected Spectroscopic Data

2-Phenyl-5-(p-tolylethynyl)-1,3,4-oxadiazole (3ab)

IR (neat): 2215, 1601, 1533, 1476, 1279 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 8.09 (2 H, d, J = 8.0 Hz), 7.56–7.48 (5 H, m), 7.22 (2 H, d, J = 8.0 Hz), 2.41 (3 H, s). ¹³C NMR (50 MHz, CDCl₃): δ = 164.9, 150.9, 141.2, 132.8, 132.7, 129.3, 129.0, 127.1, 123.4, 116.8, 97.6, 72.8, 21.8. ESI-MS: m/z = 283 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₂N₂ONa [M + Na]⁺: 283.0847; found: 283.0849.

2-Phenyl-5-(thiophen-2-ylethynyl)-1,3,4-oxadiazole (3af)

IR (neat): 2211, 1544, 1478, 1411, 1211 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 8.13–8.09 (2 H, m), 7.59–7.46 (5 H, m), 7.10 (1 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 165.0, 150.9, 135.5, 132.2, 131.0, 129.1, 127.3, 127.1, 126.9, 123.5, 91.0, 77.1; ESI-MS: m/z 253 [M + H]⁺, 275 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₄H₈N₂OSNa [M + Na]⁺: 275.0255; found: 275.0250.

2-(Non-1-ynyl)-5-phenyl-1,3,4-oxadiazole (3ag)

IR (neat): 2223, 1584, 1451, 1250 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 8.08–7.98 (2 H, m), 7.58–7.44 (3 H, m), 2.59 (2 H, t, J = 8.0 Hz), 1.79–1.70 (2 H, m), 1.59–1.51 (2 H, m), 1.48–1.32 (6 H, m), 0.96 (3 H, t, J = 7.0 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 161.5, 151.9, 131.9, 129.1, 127.9, 126.8, 98.0, 62.9, 33.2, 30.1, 30.0, 29.9, 22.9, 18.0, 13.2. ESI-MS: m/z 291 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₂₀N₂ONa [M + Na]⁺: 291.0689; found: 291.0685.

2-(Naphthalen-1-ylethynyl)-5-p-tolyl-1,3,4-oxadiazole (3be)

IR (neat): 2215, 1612, 1532, 1491, 1195 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 8.40 (1 H, d, J = 8.0 Hz), 8.04 (2 H, d, J = 8.0 Hz), 7.98–7.85 (3 H, m), 7.70–7.48 (3 H, m), 7.31 (2 H, d, J = 8.0 Hz), 2.43 (3 H, s). ¹³C NMR (50 MHz, CDCl₃): δ = 165.0, 150.6, 143.0, 133.0, 132.9, 132.2, 131.4, 130.0, 128.8, 127.9, 127.1, 127.0, 125.9, 125.2, 120.8, 117.6, 95.5, 77.8, 21.4. ESI-MS: m/z = 311 [M + H]⁺. ESI-HRMS: m/z calcd for C₂₁H₁₅N₂O [M + H]⁺ 311.1184; found: 311.1178.

Acknowledgment

The authors thank UGC and CSIR, New Delhi for financial assistance.

• References and Notes

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• References and Notes

• 1 Part 236 in the series ‘Studies on novel synthetic methodologies’.
• 2a Rostom SA. F, Shalaby MA, El-Demellawy MA. Eur. J. Med. Chem. 2003; 38: 959
  CrossrefSearch in Google Scholar
• 2b Jha KK, Samad A, Kumar Y, Shaharyar M, Khosa RL, Jain J, Kumar V, Sing P. Eur. J. Med. Chem. 2010; 45: 4963
  CrossrefPubMedSearch in Google Scholar
• 2c Singh P, Jangra PK. Der Chemica Sinica 2010; 1: 118
  Search in Google Scholar
• 3 Leung D, Du W, Hardouin C, Cheng H, Hwang I, Cravatt BF, Boger DL. Bioorg. Med. Chem. Lett. 2005; 15: 1423
  CrossrefPubMedSearch in Google Scholar
• 4a He GS, Tan L-S, Zheng Q, Prasad PN. Chem. Rev. 2008; 108: 1245
  CrossrefPubMedSearch in Google Scholar
• 4b Guin S, Ghosh T, Rout SK, Banarjee A, Patel BK. Org. Lett. 2011; 13: 5976
  CrossrefPubMedSearch in Google Scholar
• 5 Singh S, Sharma LK, Saraswat A, Siddiqui IR, Kheri HK, Singh RK. P. RSC Adv. 2013; 3: 4237
  CrossrefSearch in Google Scholar
• 6a Mitschke U, Bauerle P. J. Mater. Chem. 2000; 10: 1471
  CrossrefSearch in Google Scholar
• 6b Zarudnitskii EV, Pervak II, Merkulov AS, Yurchenko AA, Tolmachev AA. Tetrahedron 2008; 64: 10431
  CrossrefSearch in Google Scholar
• 7a Thorand S, Krause N. J. Org. Chem. 1998; 63: 8551
  CrossrefSearch in Google Scholar
• 7b Hundertmark T, Litter AF, Buchwald SL, Fu GC. Org. Lett. 2000; 2: 1729
  CrossrefPubMedSearch in Google Scholar
• 7c Chow H.-F, Wan C.-W, Low K.-H, Yeung Y.-Y. J. Org. Chem. 2001; 66: 1910
  CrossrefSearch in Google Scholar
• 7d Sonogashira K. J. Organomet. Chem. 2002; 653: 46
  CrossrefSearch in Google Scholar
• 7e Eberhard MR, Wang Z, Jensen CM. Chem. Commun. 2002; 818
• 7f Choudary BM, Madhi S, Chowdari NS, Kantam ML, Sreedhar B. J. Am. Chem. Soc. 2002; 124: 14127
  CrossrefPubMedSearch in Google Scholar
• 7g Kollhofer A, Pullmann T, Plenio H. Angew. Chem. 2003; 115: 1086
  CrossrefSearch in Google Scholar
• 7h Hierso J.-C, Fihri A, Amardeil R, Meunier P. Org. Lett. 2004; 6: 3473
  CrossrefPubMedSearch in Google Scholar
• 7i Son SU, Jang Y, Park J, Na HB, Park HM, Yun HJ, Lee J, Hyeon T. J. Am. Chem. Soc. 2004; 126: 5026
  CrossrefSearch in Google Scholar
• 7j Feuerstein M, Doucet H, Santelli M. Tetrahedron Lett. 2004; 45: 8443
  CrossrefSearch in Google Scholar
• 8a Tykwinski RR. Angew. Chem. Int. Ed. 2003; 42: 1566
  CrossrefPubMedSearch in Google Scholar
• 8b Lu L, Yan H, Sun P, Zhu Y, Yang H, Liu D, Rong G, Mao J. Eur. J. Org. Chem. 2013; 1644
• 9a Reddy GC, Balasubramanyam P, Salvanna N, Das B. Eur. J. Org. Chem. 2012; 471
• 9b Das B, Reddy GC, Balasubramanyam P, Salvanna N. Tetrahedron 2012; 68: 300
  CrossrefSearch in Google Scholar
• 9c Salvanna N, Reddy GC, Das B. Tetrahedron 2013; 69: 2220
  CrossrefSearch in Google Scholar
• 9d Salvanna N, Reddy GC, Rao BR, Das B. RSC Adv. 2013; 3: 20538
  CrossrefSearch in Google Scholar
• 10 Boga C, Del Vecchio E, Forlani L, Todesco PE. J. Organomet. Chem. 2000; 601: 233
  CrossrefSearch in Google Scholar
• 11a Gelman D, Buchwald SL. Angew. Chem. Int. Ed. 2003; 42: 5993
  CrossrefPubMedSearch in Google Scholar
• 11b Doucet H, Hierso JC. Angew. Chem. Int. Ed. 2007; 46: 834
  Search in Google Scholar
• 11c Wolff O, Waldvogel SR. Synthesis 2007; 761
  Thieme Connect
• 11d Chinchilla R, Najera C. Chem. Rev. 2007; 107: 874
  Search in Google Scholar
• 11e Ullah F, Dang TT, Heinicke J, Villiger A, Langer P. Synlett 2009; 838
  Thieme Connect
• 11f Manarin F, Roehrs JA, Branda O, Nogueira CW, Zeni G. Synthesis 2009; 4001
  Thieme Connect
• 11g Sajith AM, Muralidharan A. Tetrahedron Lett. 2012; 53: 5206
  CrossrefSearch in Google Scholar