Letter pubs.acs.org/OrgLett
Transition-Metal-Free C−CN/C−H Cross-Coupling: Effect of Cyano Group Aizhen Wu,†,§ Quan Chen,†,§ Wei Liu,*,‡ Lijun You,† Yifan Fu,† and Hua Zhang*,† †
College of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031, P. R. China College of Food Science and Technology, Henan University of Technology, Lianhua Street, Zhengzhou 450001, P. R. China
‡
S Supporting Information *
ABSTRACT: The first transition-metal-free C−CN/C−H cross-coupling involving simple aryl nitriles has been developed to prepare 2-arylated benzoxazoles under simple reaction conditions. A variety of functional groups was tolerated, and heteroaryl nitriles were also suitable substrates. Preliminary mechanistic studies indicated that the effect of cyano group as both a good activating group and a good leaving group led to the success of this transformation. This novel protocol would significantly implement the C−CN bond functionalization chemistry and enlarge the utilization of cyano group in organic synthesis.
C
Owing to the importance of 2-aryl azole compounds in pharmaceutical chemistry, agro-chemistry, and material science,7 various C−X/C−H cross-coupling involving azoles and different aryl electrophiles (X = Cl, Br, I, O, S, N, etc.) has been developed via transition-metal-catalysis toward its synthesis.8 Recently, much attention has been paid to the development of transition-metal-free transformation as it could avoid the use and removal of noble transition metal catalysts or toxic metal catalysts, avoid strict manipulation, and meet the requirements of the pharmaceutical industry and for sustainable development.9 Herein, we communicate the first transition-metal-free C−CN/C−H cross-coupling involving simple aryl nitriles and benzoxazoles under simple reaction conditions (Scheme 1). We embarked on our investigation by the arylation of benzoxazole 1a with 2-naphthonitrile 2a in the presence of various bases and solvents at 160 °C for 20 h (Table 1). To our delight, 74% GC yield of desired product 3a was obtained utilizing K3PO4 and DMSO as base and solvent (Table 1, entry 1). No arylation occurred without the use of any bases (Table 1, entry 2). The arylation also worked well in other polar solvents (DMF, DMA) as well as nonpolar solvent (nhexane) (Table 1, entries 3−5). Little or no product was obtained in the presence of diglyme or toluene as solvent (Table 1, entries 6 and 7). The use of other bases in DMSO led to lower yields (Table 1, entries 8−10). After extensive screening, the best result was obtained utilizing the combination of Cs2CO3 and DMF affording 3a in 84% GC yield and 82% isolated yield (Table 1, entry 11). Shortening the reaction time or lowering the reaction temperature both led to decreased yields (Table 1, entries 12 and 13). When the commonly used transition-metal catalysts like Ni or Rh for C−CN activation were employed under the standard conditions, similar yields were obtained (Table 1, entries 14 and 15).
arbon−carbon bonds constitute the skeleton of organic compounds. Thus, C−C bond activation is of significant importance, as widely available and relatively simple molecules could be efficiently converted to complex functionalized products. However, compared with the comprehensive investigated transition-metal-mediated C−C bond formation, transition-metal-mediated C−C bond activation has received much less attention until recently.1 Recently, C−CN bond functionalization has attracted increasing interest2 since it could enable the temporary utilization of cyano functionality including α-C−H acidity, electron-withdrawing property, and ortho-directing ability.3 Numerous transformations involving C−CN bond activation4 including C−CN/C−M crosscoupling5 have been reported in which transition metal catalysts (Ni, Rh, Pd, etc.) were indispensible due to the high bond dissociation energy of C−CN bond (Scheme 1). However, Knochel and Huestis disclosed the alkylation of aryl nitriles in the absence of transition-metal catalyst in which the employed substrates were limited to activated aryl nitriles like cyanopyridines and polycyanoarenes (Scheme 1).6 Scheme 1. C−C Bond Formation via C−CN Bond Cleavage
Received: August 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02473 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. C−H Arylation of 1a with 2a: Effects of Reaction Parametersa
entry
base
solvent
yield [%]b
1 2 3 4 5 6 7 8 9 10 11 12d 13e 14f 15g
K3PO4
DMSO DMSO DMF DMA n hexane diglyme toluene DMSO DMSO DMSO DMF DMF DMF DMF DMF
74 0 57 58 64 18 0 31 42 37 84(82)c 70 70 82 85
K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 KOtBu CsF Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
Scheme 2. Transition-Metal-free C−CN/C−H Coupling of Aryl Nitriles with Benzoxazolesa,b
a
Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), base (0.4 mmol), solvent (1.0 mL), 160 °C, 20 h. bThe yield was determined by GC, calibrated using biphenyl as internal standard. cIsolated yield in parentheses. d12 h. e140 °C. fNi(cod)2 (0.02 mmol), PCy3 (0.04 mmol). g[RhCl(cod)]2 (0.01 mmol).
a Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), Cs2CO3 (0.4 mmol), DMF (1.0 mL), 160 °C, 20 h. bIsolated yield. cK3PO4 (0.4 mmol), DMSO (1.0 mL). dK3PO4 (0.4 mmol), nhexane (1.0 mL).
With the optimized reaction conditions in hand, a variety of aryl nitriles was subjected to this C−CN/C−H cross-coupling reaction (Scheme 2). Simple aryl nitriles like benzonitrile, 4methylbenzonitrile, and 4-phenylbenzonitrile afforded the corresponding arylated products in good yields. Heteroaryl nitriles such as isonicotinonitrile, quinoline-6-carbonitrile, and thiophene-2-carbonitrile were also suitable substrates. In the case of benzonitrile bearing electron-withdrawing trifluoromethyl group and picolinonitrile, no arylation occurred under standard conditions, while employing K3PO4 and DMSO as base and solvent afforded 52% and 82% yield of 3h and 3i, respectively. The reaction of benzonitrile bearing electrondonating methoxy group gave barely any product. To our delight, moderate yield of 3j was obtained in the presence of K3PO4 and nhexane. In a similar manner, halogen substituents including F, Cl, Br, and I could be well tolerated under the same conditions and provide the possibility for additional product functionalization. Benzoxazoles substituted with methyl, tert-butyl, and phenyl group were also suitable substrates giving the desired products in good to high yields. Remarkably, this transformation could be performed in a large scale affording the desired product in good yield (Scheme 3). The fact that no regioisomers were obtained when substituted aryl nitriles were employed as substrates excludes the aryne mechanism. To gather further insight into this novel transition-metal-free C−CN/C−H cross-coupling process, radical scavengers, such as TEMPO and 1,1-diphenylethylene, were employed in the reaction of 1a and 2a under standard conditions (Table 2). Similar and slightly lower yields were obtained ruling out the possibility of radical mechanism. According to the previous reports and above results, a SNAr mechanism was proposed.10 In order to test the effect of cyano group, the cross-coupling reactions of other aryl electrophiles
Scheme 3. Large-Scale Experiment
Table 2. Radical Trapping Experimenta
entry
scavenger
yield [%]b
1 2 3
none TEMPO 1,1-diphenylethylene
82 65 85
a Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), scavenger (0.2 mmol), Cs2CO3 (0.4 mmol), DMF (1.0 mL), 160 °C, 20 h. bIsolated yield.
with 1a under standard conditions were conducted in which no products were obtained in all the reactions (Scheme 4). This phenomenon indicated that the cyano group acts as both a good activating group and a good leaving group leading to the success of this transformation. In summary, the first transition-metal-free C−CN/C−H cross-coupling has been achieved. A variety of functional groups was tolerated, and heteroaryl nitriles were also suitable substrates. The key role of cyano group as both a good activating group and a good leaving group led to the success of this transformation. This novel protocol provides a significant B
DOI: 10.1021/acs.orglett.7b02473 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
8362−8366. (d) Du, B.; Jiang, X.; Sun, P. J. Org. Chem. 2013, 78, 2786−2791. (e) Reddy, M. C.; Jeganmohan, M. Org. Lett. 2014, 16, 4866−4869. (f) Koseki, Y.; Kitazawa, K.; Miyake, M.; Kochi, T.; Kakiuchi, F. J. Org. Chem. 2017, 82, 6503−6510. (4) (a) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 13904−13905. (b) Garcia, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc. 2002, 124, 9547−9555. (c) Patra, T.; Agasti, S.; Akanksha; Maiti, D. Chem. Commun. 2012, 49, 69−71. (d) Zhang, J.-S.; Chen, T.; Yang, J.; Han, L.-B. Chem. Commun. 2015, 51, 7540−7542. (e) Tobisu, M.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2006, 128, 8152−8153. (f) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc. 2007, 129, 2428−2429. (g) Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 12594−12595. (h) Tobisu, M.; Kinuta, H.; Kita, Y.; Remond, E.; Chatani, N. J. Am. Chem. Soc. 2012, 134, 115−118. (5) (a) Liu, N.; Wang, Z.-X. Adv. Synth. Catal. 2012, 354, 1641− 1645. (b) Yu, D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.H.; Shi, Z.-J. Org. Lett. 2009, 11, 3374−3377. (c) Miller, J. A. Tetrahedron Lett. 2001, 42, 6991−6993. (d) Miller, J. A.; Dankwardt, J. W. Tetrahedron Lett. 2003, 44, 1907−1910. (e) Penney, J. M.; Miller, J. A. Tetrahedron Lett. 2004, 45, 4989−4992. (f) Tang, S.; Li, S.-H.; Yan, W.-b. Tetrahedron Lett. 2012, 53, 6743−6746. (6) (a) Chen, Q.; Leon, T.; Knochel, P. Angew. Chem., Int. Ed. 2014, 53, 8746−8750. (b) Thompson, A. D.; Huestis, M. P. J. Org. Chem. 2013, 78, 762−769. (c) Quinio, P.; Roman, D. S.; Leon, T.; William, S.; Karaghiosoff, K.; Knochel, P. Org. Lett. 2015, 17, 4396−4399. (7) (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389−437. (b) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991−9016. (c) Yeh, V. S. C. Tetrahedron 2004, 60, 11995−12042. (8) (a) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201−204. (b) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 46, 2471−2473. (c) So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. - Eur. J. 2011, 17, 761−765. (d) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K. Chem. Eur. J. 2011, 17, 10113−10122. (e) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404−12405. (f) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573−13576. (g) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 169−172. (h) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35−38. (i) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607−3610. (j) Ackermann, L.; Barfuesser, S.; Pospech, J. Org. Lett. 2010, 12, 724−726. (k) Zhu, F.; Tao, J.-L.; Wang, Z.-X. Org. Lett. 2015, 17, 4926−4929. (l) Hanson, M. G.; Olson, N. M.; Yi, Z.; Wilson, G.; Kalyani, D. Org. Lett. 2017, 19, 4271. (9) (a) Rossi, R.; Lessi, M.; Manzini, C.; Marianetti, G.; Bellina, F. Adv. Synth. Catal. 2015, 357, 3777−3814. (b) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58−102. (c) Narayan, R.; Matcha, K.; Antonchick, A. P. Chem. - Eur. J. 2015, 21, 14678−14693. (d) Sun, C.L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219−9280. (e) Liu, P.; Zhang, G.; Sun, P. Org. Biomol. Chem. 2016, 14, 10763−10777. (10) (a) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273−412. (b) Buncel, E.; Dust, J. M.; Terrier, F. Chem. Rev. 1995, 95, 2261− 2280.
Scheme 4. Cross-Coupling of Benzoxazole with Various Aryl Electrophiles
implement of C−CN bond functionalization chemistry and offers a new strategy for the efficient synthesis of complex 2-aryl azole derivatives. Additional exploration of the substrate scope and mechanistic studies are currently underway and will be reported in due course.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02473. Experimental procedures and NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Wei Liu: 0000-0003-1706-1208 Hua Zhang: 0000-0002-4960-0838 Author Contributions §
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the grants from the National Natural Science Foundation of China (21602096) and Nanchang University (startup fund).
■
REFERENCES
(1) (a) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870−883. (b) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100−1105. (c) van der Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759−1792. (d) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610−618. (e) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566−1591. (f) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835−2840. (g) Murakami, M.; Ito, Y. Top. Organomet. Chem. 1999, 3, 97−129. (h) Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1−20. (i) Jun, C.-H.; Park, J.-W. Top. Organomet. Chem. 2007, 24, 117−143. (j) Shi, Z. Homogenous Catalysis for Unreactive Bond Activation; Wiley: Hoboken, NJ, 2014. (2) (a) Kou, X.; Fan, J.; Tong, X.; Shen, Z. Youji Huaxue 2013, 33, 1407−1422. (b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613−8661. (c) Wang, R.; Falck, J. R. RSC Adv. 2014, 4, 1062−1066. (d) Wen, Q.; Lu, P.; Wang, Y. RSC Adv. 2014, 4, 47806−47826. (3) (a) Li, W.; Xu, Z.; Sun, P.; Jiang, X.; Fang, M. Org. Lett. 2011, 13, 1286−1289. (b) Reddy, M. C.; Jeganmohan, M. Chem. Commun. 2015, 51, 10738−10741. (c) Li, W.; Sun, P. J. Org. Chem. 2012, 77, C
DOI: 10.1021/acs.orglett.7b02473 Org. Lett. XXXX, XXX, XXX−XXX
