Direct Assembly of 4-Substituted Quinolines with Vinyl Azides as a

Letter Cite This: Org. Lett. 2018, 20, 4434−4438

pubs.acs.org/OrgLett

Direct Assembly of 4‑Substituted Quinolines with Vinyl Azides as a Dual Synthon via CC and C−N Bond Cleavage Jinghe Cen, Jianxiao Li, Yu Zhang, Zhongzhi Zhu, Shaorong Yang,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China

Org. Lett. 2018.20:4434-4438. Downloaded from pubs.acs.org by UNIV OF SUSSEX on 08/04/18. For personal use only.

S Supporting Information *

ABSTRACT: An unprecedented Zn-promoted selective cleavage of vinyl azides for the synthesis of 4-substituted quinolines is developed. In this conversion, vinyl azides function as a dual synthon via CC and C−N bond cleavage with two CC bonds and one CN bond formation in a one-step manner. The reaction is appreciated for its readily accessible substrates, high step economy, mild conditions, and use of air as the sole oxidant.

M

Scheme 1. Vinyl Azides Serve as a Multipurpose Precursor and Its Application

ulticomponent reactions (MCRs) have expanded rapidly in recent decades, since they allow the synthesis of complex molecules, especially natural-product-like molecular frameworks with simplicity and synthetic efficiency.1 Instead of serendipitous discovery, recently, chemists have been focusing on creating logic-based MCRs through rational design or combinatorial tactics.2,3 As one of the innovative strategies to further explore MCRs, the dual synthon approach, which employs one reactant to generate multiple fragments, has garnered increasing attention.4 Such a strategy can effectively minimize competing reactions by reducing the number of starting materials. However, the major challenge that remains in the dual synthon approach is how to achieve the selective cleavage of one reactant and subsequent incorporation into the target molecule. Thus, finding a reaction precursor that can serve as a multiplepurpose fragment may be the key point in addressing this issue. Recently, with the emergence of many molecules that can serve as multipurpose building blocks such as DMF,5 DMSO,6 and MeOH,7 opportunities arose for rational design of MCRs via a dual synthon strategy. According to the reported literature, vinyl azides are energetic and versatile building blocks exhibiting distinct and unprecedented chemical reactivity for the synthesis of a great number of nitrogen heterocycles8 such as pyrroles,9a−c pyrazoles,9d imidazoles,9e,f thiazoles,9g triazoles,9h pyridines,9i quinolines,9j isoquinolines,9k and imidazo[1,2-a] pyridines.9l Among them, the vinyl azides serve as a multipurpose precursor for various units depending on the types of bond (N−N, C−N, CC, and C−C) cleavage (Scheme 1). For example, vinyl azides were employed as a pivotal three-atom synthon to construct N-containing heterocycles through N−N © 2018 American Chemical Society

cleavage with the release of N2.10 Chiba and co-workers11 developed a [4 + 2] annulation by using vinyl azides as an olefin fragment via C−N bond cleavage. Subsequently, Liu’s group12 demonstrated the gold catalyzed CC cleavage of vinyl azides with the methylene (CH2) adding to the terminal alkynyl carbons of propargyl esters. Moreover, a series of elegant studies were also reported by Chiba and other groups13 who adopted vinyl azides as enamine-type nucleoReceived: June 1, 2018 Published: July 20, 2018 4434

DOI: 10.1021/acs.orglett.8b01718 Org. Lett. 2018, 20, 4434−4438

Letter

Organic Letters

reaction was carried out under a N2 atmosphere (Table 1, entry 12), which indicated that O2 as an oxidant may play a crucial role in this transformation. Having identified the optimized conditions, we evaluated the substrate scope of the anilines. As shown in Scheme 2, the

philes toward carbon electrophiles to synthesize amidecontaining molecules by N−N bond and C−C bond cleavages. All these diverse cleavage methods permit vinyl azides to function as an excellent dual synthon candidate. Despite the elegant development of various cleavages of vinyl azides, selective cleavage of vinyl azides and assembly in one molecule have rarely been investigated.14 Inspired by previous work, we envision a unique reaction system wherein two cleavage methods of vinyl azides can be successfully carried out and assembled into one molecule via MCRs. As part of our continuing interest in developing new MCRs to synthesize heterocycles,15 herein, we wish to disclose a Zn-promoted MCR of anilines and vinyl azides to give 4-substituded quinolones, which are not easily obtained in the traditional Povarov reaction.16 Notably, no ligand and additive were required in this procedure. To validate our hypothesis, we chose readily accessible ptoluidine 1a and (1-azidovinyl)benzene 2a as model substrates to optimize the reaction conditions. In the presence of Zn(OTf)2 (0.5 equiv) and using MeCN as solvent, the reaction gained the corresponding quinoline 3a in 43% yield (Table 1, entry 1). A series of Lewis acids, such as ZnCl2,

Scheme 2. Substrate Scope of Anilinesa

Table 1. Optimization of Reaction Conditionsa

entry

Lewis acid

equiv

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12d 13

Zn(OTf)2 ZnCl2 Zn(OAc)2 Mg(OTf)2 Eu(OTf)3 Cu(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 −

0.5 0.5 0.5 0.5 0.5 0.5 1.0 1.5 2.0 1.5 1.5 1.5 −

80 80 80 80 80 80 80 80 80 90 100 90 90

43 28 trace 35 33 n.d. 56 67 66 82 (80)c 74 n.d. n.d.

a

Reaction conditions: a mixture of 1 (0.2 mmol), 2a (0.5 mmol), and Zn(OTf)2 (1.5 equiv) in 2.5 mL MeCN was stirred at 90 °C for 2 h; isolated yields based on 1 were given. bReaction time was 5 h. c1 mmol scale.

electronic effect played a significant role in this reaction. Electron-neutral and electron-rich anilines converted more efficiently than their electron-poor analogues. The anilines with electron-donating groups on the aryl ring at different positions worked well, furnishing 3a, 3c−3f, 3i, 3j, 3l−3o in 75−84% yields. However, yields slightly declined when the substrates contained electron-withdrawing groups 3g, 3h, 3k; they also required a longer reaction time. In addition, more-activated anilines 1p, 1q, 1r gave the desired products in good yields. When 1 mmol of 1r was used as the substrate, the qiunoline product 3r was obtained in 70% yield (Scheme 2). It was noteworthy that when naphthalen-2amine 1s was used in this transformation, the ring closing happened at the more congested α-position instead of the β-position 3s, which reflected the electronic factor, rather than steric factor significantly affecting this reaction. The structure of 3s was further confirmed by single-crystal X-ray analysis (CCDC: 1814447). Naphthalen-1-amine also reacted smoothly and gave 3t in 77% yield. Encouraged by these results, we next examined the general applicability of diverse vinyl azides (Scheme 3). It was found that electron-deficient substituents, including F, Cl, and Br, at the different aryl positions proved to be well-tolerated and generated the corresponding halo-substituted products, which

a

Reaction conditions: a mixture of 1a (0.2 mmol) and 2a (0.5 mmol) in 2.5 mL of MeCN was stirred in air for 2 h. bYields were determined by 1HNMR using bromochloromethane as internal standard. cIsolated yield. dThe reaction was carried out under N2.

Zn(OAc)2, Mg(OTf)2, Eu(OTf)3, and Cu(OTf)2 were also screened, but did not give better results (Table 1, entries 2−6). It should be noted that the product yield was remarkably improved when the Zn(OTf)2 loading was increased from 0.5 to 1.5 equiv (Table 1, entries 7 and 8). Further increasing the amount of Zn(OTf)2 did not result in a higher yield of 3a (Table 1, entry 9). In the following optimization, we were pleased to find that the product yield further improved to 82% by increasing the reaction temperature to 90 °C (Table 1, entry 10). Further increasing the reaction temperature decreased the yield (Table 1, entry 11). In the absence of Zn(OTf)2, no desired product was observed, and the ptoluidine 1a was recovered in quantitative yield. Additionaly, vinyl azide 2a was almost converted into 2H-azirine (Table 1, entry 13). However, no desired product was detected when the 4435

DOI: 10.1021/acs.orglett.8b01718 Org. Lett. 2018, 20, 4434−4438

Letter

Organic Letters Scheme 3. Substrate Scope of Vinyl Azidesa

furnishing the corresponding product 5f in lower yield (30%). These results not only confirm that the 2-position carbon atom of the quinoline product originates from vinyl azides but also indicate that the β-substituted vinyl azides tend to provide the carbon atom in the 2-position of quinoline, while the terminal vinyl azides contribute the olefin moiety. The lower yields in the crossover reaction might be attributed to the side reactions and the difficulties of isolation while increasing the number of the starting materials. To gain insight into the possible mechanism of this transformation, a series of control experiments were investigated. The reaction of 1a proceeded well in the presence of a radical scavenger such as 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) or BHT (2,6-di-tert-4-methylphenol) and generated the quinoline product 3a in excellent yields. Therefore, a radical process could be excluded for this transformation (Scheme 5, eq 1). 2H-Azirine was proposed as an intermediate Scheme 5. Mechanistic Studies and Control Experiments

a

Reaction conditions: 1b (0.2 mmol), 2 (0.5 mmol), and Zn(OTf)2 (1.5 equiv) in 2.5 mL of MeCN were stirred at 90 °C in air for 2 h; isolated yields based on 1b were reported.

could further undergo coupling reactions (Scheme 3, 4a−4c and 4j−4l). To our delight, vinyl azides containing a strong electron-withdrawing group (CF3, CN, CH3COO) were also viable substrates. Notably, vinyl azides bearing pyridine were also effective and gave the corresponding product 4p in 51% yield. Unfortunately, α-alkyl vinyl azides 4n failed to convert into the desired product, probably due to its low activity. We wonder what results will be given in a crossover reaction between two different vinyl azides with aniline (Scheme 4). Scheme 4. Further Exploration of the Present Strategya

of the transformation. However, when p-toluidine and 2Hazirine were employed under the standard conditions, the reaction gave the undesired dimeric product 6a with ptoluidine with 84% recovery (Scheme 5, eq 2). This result might exclude the involvement of 2H-azirine in our reaction system. To further probe the source of the nitrogen atom of the quinoline products, 15N isotope experiments were carried out. When 15N-labeled aniline and vinyl azides were utilized in the reaction, the 15N-labeled product was obtained in 73% yield (Scheme 5, eq 3), detected by HRMS (for details, see the Supporting Information (SI)). This result demonstrates that the nitrogen atom of the quinoline originated from aniline. However, the starting meterials decomposed and no desired product was observed when only β-methyl vinyl azides 2q were employed in the reaction, which demonstrated that terminal vinyl azides were indispensable in this transformation (Scheme 5, eq 4). Furthermore, when aldimine 10a was employed as a substrate under the standard conditions, the desired product

a

Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), 2′ (0.3 mmol), and Zn(OTf)2 (1.5 equiv) in 2.5 mL of MeCN were stirred at 90 °C in air for 5 h. Isolated yields based on 1 were reported.

When one β-substituted vinyl azide and one terminal vinyl azide were chosen to conduct this reaction, to our surprise, only 2,4-disubsituted quinolines were obtained as main products with high regioselectivity. Regarding the terminal vinyl azide partners, it was proven that vinyl azides with an electron-donating group proceeded well with moderate yields (5a−5e). Terminal vinyl azides bearing a halogen atom at the p-position of the aromatic ring exhibited lower reactivity, 4436

DOI: 10.1021/acs.orglett.8b01718 Org. Lett. 2018, 20, 4434−4438

Letter

Organic Letters *E-mail: [email protected].

11a was given in 60% yield (Scheme 5, eq 5). These results suggest that aldimine might be the intermediate involved in this transformation. On the basis of the above preliminary results and the reported literature, a plausible reaction pathway is illustrated (Scheme 6). Initially, intermediate A was formed by the

ORCID

Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

■

Scheme 6. Possible Reaction Mechanism

ACKNOWLEDGMENTS The authors thank the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21420102003, 21502055, and 21642005), and the Fundamental Research Funds for the Central Universities (2015ZY001).

■

coordination of zinc to the azide group, increasing the electrophilicity of the olefin.17 Next, nucleophilic attack by aniline generates intermediate B, with the loss of nitrogen. Then, intermediate B produces the imine intermediate C through C−C bond cleavage18 giving benzonitrile as a byproduct, which was detected by GC-MS (for details, please see the SI). Subsequently, intermediate C undergoes an intramolecular cyclization [4 + 2]-annulation with 2a to produce intermediate E, which further generates intermediate F with the elimination of HN3.11 Finally, aromatization of F by O2 in air furnishes the desired quinoline product. In conclusion, we have discovered an unprecedented transformation of vinyl azides, in which two types of cleavage of vinyl azides were involved in a one-step procedure to assemble 4-substituted quinolines. In this conversion, vinyl azides function as a dual synthon to provide a logic-based strategy to further explore MCRs. The reaction features high step economy, mild conditions, easy operation, and utilization of environmentally friendly air as the sole oxidant. Further studies to clearly understand the reaction mechanism and the synthetic applications are ongoing in our group.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01718. Experimental procedures, condition screening table, characterization data, and copies of NMR spectra for all products (PDF) Accession Codes

CCDC 1814447 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

REFERENCES

(1) (a) Wang, Q.; Wang, D.-X.; Wang, M.-X.; Zhu, J. Acc. Chem. Res. 2018, 51, 1290. (b) Deibl, N.; Ament, K.; Kempe, R. J. Am. Chem. Soc. 2015, 137, 12804. (c) Deibl, N.; Kempe, R. Angew. Chem., Int. Ed. 2017, 56, 1663. (d) Li, Y.; Zhu, F.; Wang, Z.; Wu, X.-F. Chem. Commun. 2018, 54, 1984. (e) Yang, D.; Yu, Y.; Wu, Y.; Feng, H.; Li, X.; Cao, H. Org. Lett. 2018, 20, 2477. (2) For reviews, see: (a) Ganem, B. Acc. Chem. Res. 2009, 42, 463. (b) Godineau, E.; Landais, Y. Chem. - Eur. J. 2009, 15, 3044. (3) For selected examples see: (a) Huang, B.; Zeng, L.; Shen, Y.; Cui, S. Angew. Chem., Int. Ed. 2017, 56, 4565. (b) Liu, Z.; Liu, Z.-Q. Org. Lett. 2017, 19, 5649. (c) Kanazawa, J.; Maeda, K.; Uchiyama, M. J. Am. Chem. Soc. 2017, 139, 17791. (4) (a) Guo, W.; Liao, J.; Liu, D.; Li, J.; Ji, F.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2017, 56, 1289. (b) Xu, C.; Jiang, S.-F.; Wen, X.-H.; Zhang, Q.; Zhou, Z.-W.; Wu, Y.; Jia, F.-C.; Wu, A. Adv. Synth. Catal. 2018, 360, 2267. (c) Das, U. K.; Shimon, L. J. W.; Milstein, D. Chem. Commun. 2017, 53, 13133. (5) Ding, S.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 9226. (6) For selected examples, see: (a) Shen, T.; Huang, X.; Liang, Y.-F.; Jiao, N. Org. Lett. 2015, 17, 6186. (b) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2014, 53, 7144. (c) Ashikari, Y.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2011, 133, 11840. (d) Xu, R.; Wan, J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531. (e) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 6725. (f) Gao, Q.; Wu, X.; Li, Y.; Liu, S.; Meng, X.; Wu, A. Adv. Synth. Catal. 2014, 356, 2924. (g) Jiang, Y.; Loh, T.-P. Chem. Sci. 2014, 5, 4939. (h) Jia, T.; Bellomo, A.; Baina, K. EL; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2013, 135, 3740. (i) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El Baina, K.; Zheng, B.; Walsh, P. J. Angew. Chem., Int. Ed. 2014, 53, 260. (7) (a) For a review, see: Natte, K.; Neumann, H.; Beller, M.; Jagadeesh, R. V. Angew. Chem., Int. Ed. 2017, 56, 6384. (b) For an example, see: Chakrabarti, K.; Maji, M.; Panja, D.; Paul, B.; Shee, S.; Das, G. K.; Kundu, S. Org. Lett. 2017, 19, 4750. (8) For reviews, see: (a) Jung, N.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 12169. (b) Hu, B.; DiMagno, S. G. Org. Biomol. Chem. 2015, 13, 3844. (c) Hayashi, H.; Kaga, A.; Chiba, S. J. Org. Chem. 2017, 82, 11981. (d) Fu, J.; Zanoni, G.; Anderson, E. A.; Bi, X. Chem. Soc. Rev. 2017, 46, 7208. (9) (a) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313. (b) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (c) Wu, Y.; Zhu, L.; Yu, Y.; Luo, X.; Huang, X. J. Org. Chem. 2015, 80, 11407. (d) Zhang, G.; Ni, H.; Chen, W.; Shao, J.; Liu, H.; Chen, B.; Yu, Y. Org. Lett. 2013, 15, 5967. (e) Luo, J.; Chen, W.; Shao, J.; Liu, X.; Shu, K.; Tang, P.; Yu, Y. RSC Adv. 2015, 5, 55808. (f) Shao, J.; Liu, X.; Shu, K.; Tang, P.; Luo, J.; Chen, W.; Yu, Y. Org. Lett. 2015, 17, 4502. (g) Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Org. Lett. 2015, 17, 4698. (h) Liu, Z.; Ji, H.; Gao, W.; Zhu, G.; Tong, L.; Lei, F.; Tang, B. Chem. Commun. 2017, 53, 6259. (i) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (j) Wang, Q.; Huang, J.; Zhou, L. Adv. Synth. Catal. 2015, 357, 2479. (k) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. 4437

DOI: 10.1021/acs.orglett.8b01718 Org. Lett. 2018, 20, 4434−4438

Letter

Organic Letters Ed. 2011, 50, 5927. (l) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.; Adimurthy, S. J. Org. Chem. 2014, 79, 11277. (10) (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500. (b) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (c) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 6411. (d) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (e) Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Org. Lett. 2015, 17, 4698. (f) Zhu, Z.; Tang, X.; Li, J.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Org. Lett. 2017, 19, 1370. (11) Zhu, X.; Wang, Y.-F.; Zhang, F.-L.; Chiba, S. Chem. - Asian J. 2014, 9, 2458. (12) Wagh, S. B.; Liu, R.-S. Chem. Commun. 2015, 51, 15462. (13) (a) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.; Zhu, X.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 4390. (b) Zhang, Z.; Kumar, R. K.; Li, G.; Wu, D.; Bi, X. Org. Lett. 2015, 17, 6190. (c) Lin, C.; Shen, Y.; Huang, B.; Liu, Y.; Cui, S. J. Org. Chem. 2017, 82, 3950. (14) Kanchupalli, V.; Katukojvala, S. Angew. Chem., Int. Ed. 2018, 57, 5433. (15) For selected examples, see: (a) Peng, J.; Gao, Y.; Hu, W.; Gao, Y.; Hu, M.; Wu, W.; Ren, Y.; Jiang, H. Org. Lett. 2016, 18, 5924. (b) Peng, J.; Gao, Y.; Zhu, C.; Liu, B.; Gao, Y.; Hu, M.; Wu, W.; Jiang, H. J. Org. Chem. 2017, 82, 3581. (c) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12, 312. (d) Zhang, M.; Jiang, H.; Liu, H.; Zhu, Q. Org. Lett. 2007, 9, 4111. (e) Cao, H.; Wang, X.; Jiang, H.; Zhu, Q.; Zhang, M.; Liu, H. Chem. - Eur. J. 2008, 14, 11623. (f) Jiang, H.; Yang, J.; Tang, X.; Li, J.; Wu, W. J. Org. Chem. 2015, 80, 8763. (g) Liu, D.; Guo, W.; Wu, W.; Jiang, H. J. Org. Chem. 2017, 82, 13609. For reviews, see: (h) Wu, W.; Jiang, H. Acc. Chem. Res. 2014, 47, 2483. (i) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (j) Li, J.; Yang, S.; Wu, W.; Jiang, H. Eur. J. Org. Chem. 2018, 2018, 1284. (16) Ji, X.; Huang, H.; Li, Y.; Chen, H.; Jiang, H. Angew. Chem., Int. Ed. 2012, 51, 7292. (17) Huang, W.; Liu, S.; Chen, B.; Guo, X.; Yu, Y. RSC Adv. 2015, 5, 32740. (18) Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12, 2052.

4438

DOI: 10.1021/acs.orglett.8b01718 Org. Lett. 2018, 20, 4434−4438