Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct C−H Cyanoalkylation of Quinoxalin-2(1H)‑ones via Radical C−C Bond Cleavage Lin Yang, Pin Gao, Xin-Hua Duan, Yu-Rui Gu, and Li−Na Guo* Department of Chemistry, School of Science, and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China S Supporting Information *
ABSTRACT: An efficient synthesis of cyanoalkylated heteroarenes via iron-catalyzed direct C−H cyanoalkylation of heteroarenes has been developed. Structurally diverse cyanoalkyl motifs generated through C−C bond cleavage of cyclobutanone oxime esters have been introduced into quinoxalin-2(1H)-ones, flavone, benzothiazoles, and caffeine in good to excellent yields. Remarkably, less-strained cyclopentanone and unstrained cyclohexanone oxime esters were also amenable substrates in this cyanoalkylation reaction.
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bond cleavage process. 6 Furthermore, the radical and palladium-catalyzed ring-opening cleavage of cyclobutanone oxime derivatives has emerged as an efficient strategy to introduce a γ-cyanoalkyl substituent bearing larger aliphatic or functionalized chains into organic molecules via C−C bond cleavage.7,8 For instance, Zard and co-workers reported the first ring opening of cyclobutanone oxime derivatives via a radical process (Figure 1).7a More recently, some elegant C−C bond
uinoxalin-2(1H)-ones are a privileged class of structural motifs found in various bioactive natural products as well as pharmaceutical compounds.1 Because of their significant biological properties, chemists have devoted much effort to the synthesis of these aza-heterocycles.2 One of the traditional methods involves construction of the heterocyclic ring via an intermolecular cyclization of 1,2-diaminobenzene and a suitable partner.2a On the other hand, direct modification of easily available quinoxalin-2(1H)-ones provides facile alternatives to more complex molecules.3 In this field, catalytic direct C3−H functionalization of quinoxalin-2(1H)-ones has emerged as an attractive approach to 3-substituted quinoxalin-2(1H)-ones, which usually exhibit significant pharmaceutical properties.3a,c Recently, several important advances have been reported, including radical C3−H arylation, phosphonation, amination, and acylation of quinoxalin-2(1H)-ones. However, C−H alkylation of quinoxalin-2(1H)-ones is still rare.3 Because of their importance, it is desirable and in demand to introduce alkyl substituents, especially those bearing functional groups, at the 3-position of quinoxalin-2(1H)-ones, which would probably promote their applications in new drug discovery and development.1 Cyanoalkyl moieties not only widely exist in a variety of natural products and pharmaceuticals, but also are a class of versatile building blocks in organic synthesis.4 Therefore, efficient incorporation of a cyanoalkyl group into structurally diverse molecules has attracted much attention.5 Recently, the radical cyanoalkylation reaction has proven to be a powerful tool to achieve this goal. For example, simple acetonitrile has been developed as an efficient cyanomethyl precursor in many radical cross-coupling and cyclization reactions through a C−H © XXXX American Chemical Society
Figure 1. Generation of iminyl radicals via C−C bond cleavage.
cleavages of cyclobutanone oxime derivatives have been established by transition metal or photoredox catalysis.7c−j In this field, our group disclosed a Ni-catalyzed cyanoalkylation of heteroaromatic N-oxides and quinones.9a In addition, we also demonstrated that the γ-cyanoalkyl radicals generated from cyclobutanone oxime esters can react efficiently with activated alkenes, furnishing cyanoalkylated oxindoles and dihydroquiReceived: December 22, 2017
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DOI: 10.1021/acs.orglett.7b03984 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters nolin-2(1H)-ones.9b Compared with extensive α-cyanoalkylation reactions, γ-cyanoalkylation reactions have been less exploited at present.5 Herein we report a simple and efficient Fe-catalyzed C−H cyanoalkylation of quinoxalin-2(1H)-ones with cyclobutanone oxime esters. Initially, quinoxalin-2(1H)-one 1a and cyclobutanone pentafluorobenzoyl oxime 2a were chosen as model substrates to optimize the reaction conditions (Table 1).10 When the
Scheme 1. Scope of Quinolin-2(1H)-ones
Table 1. Optimization of the Reaction Conditionsa
entry
deviation from above
yield (%)b
1 2 3 4 5 6 7 8 9 10 11
15 mol % FeCl2 as the catalyst 15 mol % Fe(OAc)2 as the catalyst 15 mol % FeSO4·7H2O as the catalyst 15 mol % Fe powder as the catalyst 15 mol % Cu(acac)2 as the catalyst 15 mol % Ni(acac)2 as the catalyst 1,4-dioxane as the solvent CH3NO2 as the solvent EtOH as the solvent DMF as the solvent without catalyst
80 72 85 75 65 15 90 87 90 36 trace
a
a An inseparable 1:1 mixture of 6- and 7-methylquinoxalin-2(1H)-ones was used as the substrate.
model reaction was carried out using 15 mol % Fe(acac)2 as the catalyst in MeCN at 100 °C for 18 h, the desired 3cyanopropylated product 3a was isolated in 93% yield. Then a variety of iron catalysts, including FeCl2, Fe(OAc)2, FeSO4· 7H2O, and Fe powder, were tested for this reaction. All of these iron catalysts were effective but gave lower yields than Fe(acac)2 (Table 1, entries 1−4). During the catalyst screening, we found that Cu(acac)2 afforded a 65% yield of 3a, but Ni(acac)2 gave only a 15% yield of 3a (entries 5 and 6). Next, other reaction parameters were surveyed. Among the solvents tested, 1,4-dioxane, CH3NO2, and EtOH were suitable, whereas DMF proved to be less effective (entries 7−10). Furthermore, O-acyl oximes bearing different protecting groups, including BzO, 4-FBzO, and 4-NO2BzO, were also examined, but all of them resulted in somewhat low yields (see Table S1 in the Supporting Information). Finally, a control experiment revealed that only a trace amount of 3a was formed in the absence of iron catalyst (entry 11). After the optimal conditions were determined, we first examined the substrate scope of quinoxalin-2(1H)-ones 1 with oxime ester 2a (Scheme 1). Various quinoxalin-2(1H)-ones bearing electron-donating and electron-withdrawing groups on the aromatic rings engaged in this reaction efficiently, affording the corresponding 3-cyanopropylated products 3b−i in moderate to good yields. A series of functional groups including fluoro, chloro, bromo, nitro, and ester were welltolerated under the optimal conditions. Besides the methyl group, substrates with other protecting groups such as n-propyl, benzyl, and acetate groups were also efficient substrates, furnishing the corresponding products 3j−l in 49−74% yield. N-Unsubstituted quinoxalin-2(1H)-one was also successfully
converted to the desired product 3m in 61% yield. Notably, the representative quinolin-2(1H)-one N,6-dimethylquinolin2(1H)-one (1n) also led to the anticipated product 3n in 60% yield. Satisfactorily, treatment of 2-phenylchromen-4-one (1o) with 2a delivered the desired product 3o in 40% yield. Next, we turned our attention to investigate the cyanoalkylation of quinoxalin-2(1H)-one 1a with various cyclobutanone oxime esters 2 (Scheme 2). A variety of cyclobutanone oxime esters containing aryl, benzyl, and alkyl groups at the 3-position reacted well to give the target products 4a−f in good to excellent yields. It is noteworthy that 3-cyano, carbamate (NHBoc), and benzyloxy cyclobutanone oxime esters also survived well, leading to the desired products 4g−i in good yields. In addition, 3,3-disubstituted oxime esters also participated well in this reaction, affording the desired products 4j and 4k in 72% and 81% yield, respectively. The substrate derived from oxetan-3-one was also amenable, producing the desired product 4l in 48% yield. Notably, the reaction of 1a with 2,3-disubstituted cyclobutanone oxime ester 2n gave the desired product 4m in moderate yield with excellent regioselectivity. Furthermore, oxime esters derived from norcamphor and tricyclo[5.2.1.0(2,6)]decan-8-one also gave the desired products 6a and 6b in 74% and 62% yield, respectively (Scheme 3). Remarkably, cyclopentanone oxime ester 5c without any substituent at the α-position also successfully delivered the cyanoalkylated product 6c in 52% yield, representing a rare example of ring-opening/coupling of less-strained cyclopentanone oxime esters.7,8 Inspired by these results, we tried to exploit the feasibility of the more challenging unstrained cyclohexanone oxime ester. To our delight, simple oxime ester 5d was also applicable, leading to the expected product 6d, albeit in low yield (Scheme 3). For cyclopentanone and
Reaction conditions: 15 mol % catalyst, 1a (0.45 mmol 1.5 equiv), 2a (0.3 mmol, 1.0 equiv), CH3CN (1.5 mL), 100 °C, 18 h, N2. bYields of isolated products.
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DOI: 10.1021/acs.orglett.7b03984 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Cyclobutanone Oxime Esters
Scheme 4. Synthesis of 3a on a Gram Scale and Direct C−H Cyanoalkylation of Benzothiazoles and Caffeine
68% yield, respectively. 3-Cyanoalkylated caffeine 10a was obtained in 49% yield under the modified conditions. Finally, several control experiments were performed to gain insight into the reaction mechanism. Radical trapping experiments were conducted first by addition of TEMPO or BHT to the reaction of 1a and 2a, respectively (eqs 1 and 2). Addition
Scheme 3. Ring Opening of Cyclopentanone and Cyclohexanone Oxime Esters
of TEMPO (1.0 equiv) significantly suppressed this cyanoalkylation reaction, and the cyanoalkyl-TEMPO adduct 11a was isolated in 64% yield. Moreover, the radical inhibitor BHT (1.0 equiv) also led to an obvious decrease in the isolated yield. These results indicate that radical intermediates are involved in this transformation. On the other hand, radical clock experiments were designed and performed. Treatment of cyclobutanone oxime esters 12a and 12b containing double bonds with 1a delivered the ring-closing products 13a and 13b in 53% and 65% yield, respectively (eqs 3 and 4). These results are in favor of radical pathway for this transformation. However, the spirocyclic substrate 12c afforded the product 13c in 89% yield with no ring-expanded product observed (eq 5). A possible mechanism is proposed in Scheme 5. First, single-electron reduction of 2a by Fe(II) affords iminyl radical I, which is transformed into cyanoalkyl radical II through C−C bond cleavage.7 Subsequently, radical addition of II to 1a leads to radical intermediate III, which undergoes single-electron oxidation by Fe(III) followed by loss of H+ to afford the product 3a.
cyclohexanone oxime esters 5c and 5d, FeSO4·7H2O gave better yields than Fe(acac)2. To further demonstrate the applicability of this cynoalkylation reaction, a gram-scale reaction was carried out under the standard conditions (Scheme 4). Satisfactorily, the reaction of 1a and 2a proceeded smoothly to afford the target product 3a in 80% isolated yield. Furthermore, the C−H bonds of benzothiazole and caffeine could also be directly cynoalkylated by using Fe(OTf)3 instead of Fe(acac)2 as the catalyst. Treatment of benzothiazoles 7a and 7b with 2a gave the corresponding 2-cynoalkylated products 8a and 8b in 69% and C
DOI: 10.1021/acs.orglett.7b03984 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
2010, 75, 5768. (c) Chen, D.; Bao, W.-L. Adv. Synth. Catal. 2010, 352, 955. (d) Li, Z.-S.; Wang, W.-X.; Yang, J.-D.; Wu, Y.-W.; Zhang, W. Org. Lett. 2013, 15, 3820. (e) Gao, P.; Gu, Y.-R.; Duan, X.-H. Synthesis 2017, 49, 3407. (3) (a) Nikam, S. S.; Sahasrabudhe, A. D.; Shastri, R. K.; Ramanathan, S. Synthesis 1983, 1983, 145. (b) Lawrence, D. S.; Copper, J. E.; Smith, C. D. J. Med. Chem. 2001, 44, 594. (c) Udilova, N.; Kozlov, A. V.; Bieberschulte, W.; Frei, K.; Ehrenberger, K.; Nohl, H. Biochem. Pharmacol. 2003, 65, 59. (d) Qin, X.; Hao, X.; Han, H.; Zhu, S.; Yang, Y.; Wu, B.; Hussain, S.; Parveen, S.; Jing, C.; Ma, B.; Zhu, C. J. Med. Chem. 2015, 58, 1254. (e) Han, Y.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron Lett. 2010, 51, 2023. (f) Carrër, A.; Brion, J. D.; Messaoudi, S.; Alami, M. Org. Lett. 2013, 15, 5606. (g) Yin, K.; Zhang, R.-H. Org. Lett. 2017, 19, 1530. (h) Paul, S.; Ha, J. H.; Park, G. E.; Lee, Y. R. Adv. Synth. Catal. 2017, 359, 1515. (i) Yuan, J.-W.; Liu, S.-N.; Qu, L.-B. Adv. Synth. Catal. 2017, 359, 4197. (j) Gao, M.; Li, Y.; Xie, L.-J.; Chauvin, R.; Cui, X.-L. Chem. Commun. 2016, 52, 2846. (k) Li, Y.; Gao, M.; Wang, L.-H.; Cui, X.-L. Org. Biomol. Chem. 2016, 14, 8428. (l) Gupta, A.; Deshmukh, M. S.; Jain, N. J. Org. Chem. 2017, 82, 4784. (m) Zeng, X.-B.; Liu, C.-L.; Wang, X.-Y.; Zhang, J.-L.; Wang, X.-Y.; Hu, Y.- F. Org. Biomol. Chem. 2017, 15, 8929. (4) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (b) May, E. L.; Jacobson, A. E.; Mattson, M. V.; Traynor, J. R.; Woods, J. H.; Harris, L. S.; Bowman, E. R.; Aceto, M. D. J. Med. Chem. 2000, 43, 5030. (c) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902. (5) For reviews, see: (a) Fleming, F. F.; Zhang, Z.-Y. Tetrahedron 2005, 61, 747. (b) López, R.; Palomo, C. Angew. Chem., Int. Ed. 2015, 54, 13170. (6) For selected examples, see: (a) Li, Z.-J.; Xiao, Y.-X.; Liu, Z.-Q. Chem. Commun. 2015, 51, 9969. (b) Bunescu, A.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 3132. (c) Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 5443. (d) Bunescu, A.; Wang, Q.; Zhu, J. Org. Lett. 2015, 17, 1890. (e) Ha, T. M.; Chatalova-Sazepin, C.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9249. (f) Chu, X.-Q.; Xing, Z.-H.; Meng, H.; Xu, X.P.; Ji, S.-J. Org. Chem. Front. 2016, 3, 165. (g) Zhang, H.-L.; Zhu, C.-J. Org. Chem. Front. 2017, 4, 1272. (h) Su, H.-M.; Wang, L.-Y.; Rao, H.H.; Xu, H. Org. Lett. 2017, 19, 2226. (7) For examples concerning radical ring opening of cyclobutanone oxime derivatives, see: (a) Boivin, J.; Fouquet, E.; Zard, S. Z. J. Am. Chem. Soc. 1991, 113, 1055. (b) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32, 4299. (c) Nishimura, T.; Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. Org. Lett. 2005, 7, 2425. (d) Yang, H.-B.; Selander, N. Chem. - Eur. J. 2017, 23, 1779. (e) Zhao, B.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56, 12727. (f) Li, L.-Y.; Chen, H.-G.; Mei, M.-J.; Zhou, L. Chem. Commun. 2017, 53, 11544. (g) Yang, H.-B.; Pathipati, S. R.; Selander, N. ACS Catal. 2017, 7, 8441. (h) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2018, 57, 744. (i) Yu, X.-Y.; Chen, J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.; Xiao, W.-J. Angew. Chem., Int. Ed. 2018, 57, 738. (j) Jackman, M. M.; Im, S.; Bohman, S. R.; Lo, C. C. L.; Garrity, A. L.; Castle, S. L. Chem. - Eur. J. 2018, 24, 594. (8) For palladium-catalyzed ring opening of cyclobutanone oxime esters, see: (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049. (b) Nishimura, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org. Chem. 2004, 69, 5342. (9) (a) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.-N. Org. Lett. 2017, 19, 5908. (b) Wu, J.; Zhang, J.-Y.; Gao, P.; Xu, S.-L.; Guo, L.-N. J. Org. Chem. 2018, 83, 1046. (10) For more details, see the Supporting Information.
Scheme 5. Proposed Mechanism
In summary, we have developed an efficient Fe-catalyzed cyanoalkylation reaction of quinoxalin-2(1H)-ones with cyclobutanone oxime esters. This reaction features wide substrate scope, excellent functional group tolerance, and good to excellent yields, thus providing facile and useful access to a variety of 3-cyanoalkylated quinoxalin-2(1H)-ones. Besides cyclobutanone oxime esters, the cyclopentanone and cyclohexanone derivatives were also applicable to this reaction. This protocol offers a new and promising family of direct C−H functionalizations of heteroarenes based on a C−C bond cleavage process. Preliminary mechanistic evidence suggests that the cyanoalkylation reaction proceeds via a radical pathway.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03984. Experimental procedures and spectroscopic data for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Li−Na Guo: 0000-0002-9789-6952 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the Natural Science Basic Research Plan in Shaanxi Province of China (2016JZ002), the National Natural Science Foundation of China (21602168), and the Fundamental Research Funds of the Central Universities (zrzd2017001, xjj2016056, and 1191329724) is greatly appreciated.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03984 Org. Lett. XXXX, XXX, XXX−XXX
