Solvent-controlled divergent annulation of ynones and (iso)quinoline N-oxides: of 3-((iso)quinolin-1-yl)-4H-chromen-4-ones and 13H-isoquinolino[2,1-a]quinolin-13-ones

Wan-Wan Yang a, Lu-Lu Chen a, Pei Chen a, Ya-Fang Ye a, Yan-Bo Wang *a and Xiao Zhang *b
aInstitute of Functional Organic Molecular Engineering, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, 475004, China. E-mail: wangyanbokf@henu.edu.cn
bCollege of Science, State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Changping, Beijing, 102249, China. E-mail: zhangxiao@cup.edu.cn

Received 7th November 2019 , Accepted 16th December 2019

First published on 16th December 2019


An effective annulation of ynones and (iso)quinoline N-oxides was developed to deliver various functionalized 3-((iso)quinolin-1-yl)-4H-chromen-4-ones and 13H-isoquinolino[2,1-a]quinolin-13-ones in moderate to excellent yields, respectively. This protocol exhibits high regioselectivity and broad substrate scope under transition-metal-free conditions. Moreover, the key reaction intermediate was successfully isolated and determined unambiguously by single crystal X-ray crystallography.


Chromone, quinoline and isoquinoline motifs, as six-membered oxygen- and nitrogen-containing heterocyclic compounds, are important structural patterns broadly existing in the skeleton of bioactive natural products.1–3 In view of their intriguing structural units, the combination of the two nucleuses into one molecule may obtain structurally diverse chemicals endowed with amplified or new bioactivities. Additionally, as a significant member of the isoquinoline alkaloid family, N-fused isoquinolines with important biological activity and fascinating luminescence properties have attracted more attention in both pharmaceutical synthesis and materials science.4,5 Consequently, the development of efficient and convenient methods to divergently construct (iso)quinolinyl chromones and N-fused isoquinolines are highly desirable.

The reactions of alkynes with (iso)quinoline N-oxides have been broadly explored,6,7 which could deliver an array of functionalized (iso)quinoline derivatives. Ynones as electron-deficient and polarized alkynes have high activity to react with (iso)quinoline N-oxides.8 With respect to the mechanism for the reaction of ynones with (iso)quinoline N-oxides under metal-transition-free conditions, isoxazolo[3,2-a](iso)quinoline intermediate I is generally thought to be first generated through a [3+2] cycloaddition of ynones with (iso)quinoline N-oxides. Next, a ring opening occurs, affording intermediate IIa, which is in equilibrium with IIb (imine–enamine tautomerization) or IIc (keto-enol tautomerism) (Scheme 1). Although “N” as an active center for the intermediate IIa or “O” as an active center for the intermediate IIc toward further functionalized cyclization has already been demonstrated,9-10 to the best of our knowledge, direct controllable conversion of dual “N” and “O” active points from the same substrates has not been documented yet. Inspired by the reaction of ynones and (iso)quinoline N-oxides and our successful transitions of ynones,11 we envisioned that the cyclization reaction of o-bromoaryl ynones and (iso)quinoline N-oxides may be controlled by the suitable reaction conditions, divergently affording (iso)quinoline derivatives. Herein, we firstly report a novel and efficient solvent-controlled divergent synthesis of 3-((iso)quinolin-1-yl)-4H-chromen-4-one and 13H-isoquinolino[2,1-a]quinolin-13-one from ynones and (iso)quinoline N-oxides with high regioselectivity and broad substrate scope tolerance under transition-metal-free conditions (Scheme 1).


image file: c9cc08713c-s1.tif
Scheme 1 Reaction modes for ynones and (iso)quinoline N-oxides.

To verify our hypothesis, we initially screened the reaction conditions by choosing 1-(2-bromophenyl)-3-(p-tolyl)prop-2-yn-1-one 1a and isoquinoline N-oxide 2a as the model substrates (see the ESI (Table S1)). Pleasingly, substrate 1a reacted with 2a using K2CO3 as a base in DMF at 100 °C, delivering the desired product 3aa in 91% yield (Table S1, entry 1, ESI). Then various organic and inorganic bases were evaluated, but further increasing the yield for product 3aa failed to be observed (Table S1, entries 2–7, ESI). Decreasing the usage of base was also insufficient to prepare product 3aa (Table S1, entry 8, ESI). To our surprise, the properties of the reaction solvents have a profound effect on the selectivity of the products. The highly polar solvents including DMF, DMSO and NMP advantageously generate products 3aa (Table S1, entries 1, 9 and 10, ESI). Conversely, an alternative cyclization reaction proceeded smoothly by simply switching the reaction solvent to 1,4-dioxane or toluene (Table S1, entries 13 and 14, ESI), preferably leading to the generation of product 4aa. Among the further bases tested, K2CO3 is also more effective to afford product 4aa with the highest yield (Table S1, entries 14–21, ESI). Eventually, DMF as a solvent is suitable for product 3aa in 91% yield and toluene as a solvent exhibits superior activity to prepare product 4aa in 78% yield.

With the optimal reaction conditions in hand, the substrate scope and generality to prepare 3-((iso)quinolin-1-yl)-4H-chromen-4-ones using DMF as solvent was explored, as shown in Table 1. Firstly, the R1 substituents anchoring in the alkyne terminal were tested and a variety of ynones 1a–1j bearing alkyl, ether, halo or CF3 groups at the ortho, meta or para positions of the aryl groups could smoothly react with isoquinoline N-oxides 2a, affording the corresponding products 3aa–3ja in moderate to excellent yields. To our delight, when 1.0 mmol of substrate 1a react with 2a under the standard conditions, the desired product 3aa could be given in 82% yield. However, aliphatic products 3ka–3ma were synthesized in relatively low yield due to the existence of unknown byproducts. The substrate 1n (R1 = H) failed to deliver the corresponding product 3na. Notably, product 3oa including nitrogen-, oxygen- and sulfur- heterocyclic structural frameworks was also smoothly prepared in 84% yield. Then, the R2 substituents on the aryl ring were further examined, and the corresponding product 3pa–3ua containing alkyl, ether and halo substituents could be obtained in moderate to excellent yield. Fortunately, the structure of 3ra was unambiguously characterized by X-ray crystallography (see Fig. S1 in the ESI for details). Furthermore, isoquinoline N-oxides bearing various substituents were subjected to the standard conditions, affording the corresponding products 3ab–3ad in good yields. Finally, this current methodology was successfully applied to quinoline N-oxides, delivering quinoline derived products 3ae–3aj in satisfactory yield.

Table 1 Substrate scope using DMF as solventa,b
a Reaction conditions: 0.24 mmol 1, 0.2 mmol 2, 0.3 mmol K2CO3, 2.0 mL DMF, 100 °C, 5 h. b Isolated yield. c 1 mmol 2a was used.
image file: c9cc08713c-u1.tif


Subsequently, the substrate scope to synthesize 13H-isoquinolino[2,1-a]quinolin-13-ones 4 using toluene as solvent was investigated. A variety of ynones 1 and (iso)quinoline N-oxides were studied and the results are summarized in Table 2. Substrates 1a–1j with electron-donating groups or electron-withdrawing groups at the ortho, meta or para positions of the aryl groups (R1) were well tolerated, and the corresponding products 4aa–4ja were obtained in moderate to excellent yield. The structure of 4ga was further confirmed by X-ray crystallography (see Fig. S1 in the ESI for details). Gratifyingly, the yield of product 4aa slightly decreased to 71% when 1.0 mmol of substrate 2a was used. Unfortunately, the substrate 1k or 1n failed to give the product 4ka or 4na. However, the less steric substrates 1l–1m with an alkyl group could obtain the corresponding products 4la–4ma. The heterocyclic product 4oa was well suitable to this annulation reaction in 76% yield. Then, we moved on to substituents (R2), and substrates 1p–1u with different groups were also tolerated, smoothly leading to the desired products 4pa–4ua. Additionally, isoquinoline N-oxides 2b–2d reacted smoothly, giving the corresponding product 4ab–4ad in good yields. Conversely, when isoquinoline N-oxides were changed into quinoline N-oxides, the corresponding quinoline products couldn’t be obtained under standard conditions.

Table 2 Substrate scope using toluene as solventa,b
a Reaction conditions: 0.3 mmol 1, 0.2 mmol 2, 0.3 mmol K2CO3, 2.0 mL toluene, 100 °C, 5 h. b Isolated yield. c 1 mmol 2a was used.
image file: c9cc08713c-u2.tif


When 2-chloroynone or 2-iodoynone was employed to react with 2a under standard conditions, the corresponding product 3aa or 4aa was obtained in moderate to excellent yields (Schemes 2a and b). To better understand the mechanism for this transformation, we attempted to capture and isolate the reaction intermediates. When the reaction of ynone 1a with isoquinoline N-oxide 2a was carried out in the absence of K2CO3, the tautomer (IIa-1, IIb-1 and IIc-1) was obtained in 58% or 45% yield using DMF or toluene as solvent, respectively (Scheme 2c). Fortunately, a single crystal of compound IIa-1 suitable for X-ray structural analysis was obtained from a toluene solution (see Fig. S1 in the ESI for details). Additionally, the tautomer (IIa-1, IIb-1 and IIc-1) was observed by NMR spectra. Subsequently, treating the tautomer (IIa-1, IIb-1 or IIc-1) using K2CO3 as base under standard conditions, the corresponding products 3aa and 4aa were obtained in 94% and 80% yields, respectively (Scheme 2d). These experimental results indicated that compound IIa-1, IIb-1 or IIc-1 might be acting as the key intermediate for the formation of 3aa and 4aa. Additionally, the reaction of substrate 1a with isoquinoline N-oxide 2a was monitored by 1H NMR, and the corresponding high selectivity of the products was further observed (see Fig. S2 and S3 in the ESI for details).


image file: c9cc08713c-s2.tif
Scheme 2 Other 2-haloynones as substrates and controlled experiments.

Based on the experimental results and previous reports,9,10 a plausible mechanism for the divergent synthesis of 3-((iso)quinolin-1-yl)-4H-chromen-4-ones and 13H-isoquinolino[2,1-a]quinolin-13-ones from ynones 1 and (iso)quinoline N-oxides 2 is depicted in Scheme 3. Firstly, isoxazolo[3,2-a](iso)quinoline intermediate I is generated through a [3+2] cycloaddition of ynones 1 and (iso)quinoline N-oxides 2. Subsequently, a ring opening occurs to afford intermediate IIa, which is suitable for the intramolecular Ullmann-type N-arylation reaction to deliver products 4. Furthermore, intermediate IIa is in equilibrium with intermediate IIbvia imine–enamine tautomerism. Intermediate IIb can also tautomerize to give intermediates IIc by keto–enol tautomerization, which is suitable to the intramolecular Ullmann-type O-arylation reaction to deliver products 3.


image file: c9cc08713c-s3.tif
Scheme 3 Plausible mechanism.

In summary, we have demonstrated an efficient solvent-controlled annulation of ynones and (iso)quinoline N-oxides, divergently leading to 3-((iso)quinolin-1-yl)-4H-chromen-4-ones and 13H-isoquinolino[2,1-a]quinolin-13-ones in moderate to excellent yields. This developed method enables transition-metal-free, high regioselectivity and broad functional group tolerance. What's more, the key reaction intermediate has been isolated and structurally characterized by single crystal X-ray crystallography. Further investigation on the applications of this method for both synthetic chemistry and materials science is still ongoing in our laboratory.

This work was financially supported by the National Natural Science Foundation of China (No. U1504205 and 21303264), the Key Research Project of Education Department of Henan Province (No. 17A150002) and Henan University (yqpy20170009).

Conflicts of interest

There are no conflicts to declare.

Notes and references

  1. (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893 CrossRef CAS PubMed ; (b) R. L. Farmer, M. M. Biddle, A. E. Nibbs, X. Huang, R. C. Bergan and K. A. Scheidt, ACS Med. Chem. Lett., 2010, 1, 400 CrossRef CAS PubMed ; (c) A. Gaspar, M. J. Matos, J. Garrido, E. Uriarte and F. Borges, Chem. Rev., 2014, 114, 4960 CrossRef CAS .
  2. (a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166 RSC ; (b) K. Kaur, M. Jain, R. P. Reddy and R. Jain, Eur. J. Med. Chem., 2010, 45, 3245 CrossRef CAS ; (c) J. Colomb, G. Becker, S. Fieux, L. Zimmer and T. J. Billard, J. Med. Chem., 2014, 57, 3884 CrossRef CAS PubMed ; (d) E. J. Koh, M. I. El-Gamal, C. H. Oh, S. H. Lee, T. Sim, G. Kim, H. S. Choi, J. H. Hong, S. G. Lee and K. H. Yoo, Eur. J. Med. Chem., 2013, 70, 10 CrossRef CAS PubMed ; (e) N. G. Jentsch, A. P. Hart, J. D. Hume, J. Sun, K. A. McNeely, C. Lama, J. A. Pigza, M. G. Donahue and J. J. Kessl, ACS Med. Chem. Lett., 2018, 9, 1007 CrossRef CAS PubMed .
  3. (a) A. Tsuboyama, H. Iwawaki, M. Furugori, T. Mukaide, J. Kamatani, S. Igawa, T. Moriyama, S. Miura, T. Takiguchi, S. Okada, M. Hoshino and K. Ueno, J. Am. Chem. Soc., 2003, 125, 12971 CrossRef CAS PubMed ; (b) C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, J. M. Brown, A. R. Cowley, D. I. Hulmes and A. J. Blacker, Org. Process Res. Dev., 2003, 7, 379 CrossRef CAS ; (c) V. G. Kartsev, Med. Chem. Res., 2004, 13, 325 CrossRef CAS ; (d) K. Bhadra and G. S. Kumar, Med. Res. Rev., 2011, 31, 821 CrossRef CAS PubMed .
  4. (a) M. Chrzanowska and M. D. Rozwadowska, Chem. Rev., 2004, 104, 3341 CrossRef CAS PubMed ; (b) M. Chrzanowska, A. Grajewska and M. D. Rozwadowska, Chem. Rev., 2016, 116, 12369 CrossRef CAS PubMed .
  5. B. Liu, Z. Wang, N. Wu, M. Li, J. You and J. Lan, Chem. – Eur. J., 2012, 18, 1599 CrossRef CAS PubMed .
  6. For selected metal-free reaction, please see: (a) D.-F. Chen, Z.-Y. Han, Y.-P. He, J. Yu and L.-Z. Gong, Angew. Chem., Int. Ed., 2012, 51, 12307 CrossRef CAS PubMed ; (b) K. Graf, C. L. Rühl, M. Rudolph, F. Rominger and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2013, 52, 12727 CrossRef CAS PubMed ; (c) D. V. Patil, S. W. Kim, Q. H. Nguyen, H. Kim, S. Wang, T. Hoang and S. Shin, Angew. Chem., Int. Ed., 2017, 56, 3670 CrossRef CAS PubMed ; (d) Y.-Q. Zhang, X.-Q. Zhu, Y.-B. Chen, T.-D. Tan, M.-Y. Yang and L.-W. Ye, Org. Lett., 2018, 20, 7721 CrossRef CAS PubMed ; (e) S. W. Kim, T.-W. Um and S. Shin, J. Org. Chem., 2018, 83, 4703 CrossRef CAS PubMed ; (f) D. V. Patil and S. Shin, Asian J. Org. Chem., 2019, 8, 63 CrossRef CAS .
  7. For selected metal-catalyzed reaction, please see: (a) K. S. Kanyiva, Y. Nakao and T. Hiyama, Angew. Chem., Int. Ed., 2007, 46, 8872 CrossRef CAS PubMed ; (b) L. Ye, L. Cui, G. Zhang and L. Zhang, J. Am. Chem. Soc., 2010, 132, 3258 CrossRef CAS PubMed ; (c) D. Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade, A. Das and R.-S. Liu, Angew. Chem., Int. Ed., 2011, 50, 6911 CrossRef CAS PubMed ; (d) J. Xiao and X. Li, Angew. Chem., Int. Ed., 2011, 50, 7226 CrossRef CAS PubMed ; (e) L. Zhang, Acc. Chem. Res., 2014, 47, 877 CrossRef CAS PubMed ; (f) T. Wang, S. Shi, M. M. Hansmann, E. Rettenmeier, M. Rudolph and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2014, 53, 3715 CrossRef CAS PubMed ; (g) X. Zhang, Z. Qi and X. Li, Angew. Chem., Int. Ed., 2014, 53, 10794 CrossRef CAS PubMed ; (h) D. Qian, H. Hu, F. Liu, B. Tang, W. Ye, Y. Wang and J. Zhang, Angew. Chem., Int. Ed., 2014, 53, 13751 CrossRef CAS PubMed ; (i) M. Chen, Y. Chen, N. Sun, J. Zhao, Y. Liu and Y. Li, Angew. Chem., Int. Ed., 2015, 54, 1200 CrossRef CAS PubMed ; (j) L. Li, B. Zhou, Y.-H. Wang, C. Shu, Y.-F. Pan, X. Lu and L.-W. Ye, Angew. Chem., Int. Ed., 2015, 54, 8245 CrossRef CAS ; (k) X. Chen, S. A. Ruider, R. W. Hartmann, L. González and N. Maulide, Angew. Chem., Int. Ed., 2016, 55, 15424 CrossRef CAS PubMed ; (l) J. Li, H.-W. Xing, F. Yang, Z.-S. Chen and K. Ji, Org. Lett., 2018, 20, 4622 CrossRef CAS ; (m) N. Hamada, A. Yamaguchi, S. Inuki, S. Oishi and H. Ohno, Org. Lett., 2018, 20, 4401 CrossRef CAS PubMed .
  8. (a) Z.-S. Chen, F. Yang, H. Ling, M. Li, J.-M. Gao and K. Ji, Org. Lett., 2016, 18, 5828 CrossRef CAS PubMed ; (b) K. Ji, F. Yang, S. Gao, J. Tang and J. Gao, Chem. – Eur. J., 2016, 22, 10225 CrossRef CAS PubMed .
  9. (a) B. Zhang, L. Huang, S. Yin, X. Li, T. Xu, B. Zhuang, T. Wang, Z. Zhang and A. S. K. Hashmi, Org. Lett., 2017, 19, 4327 CrossRef CAS PubMed ; (b) X. Li, G. Zhou, X. Du, T. Wang and Z. Zhang, Org. Lett., 2019, 21, 5630 CrossRef CAS .
  10. X. Li, T. Wang and Z. Zhang, Adv. Synth. Catal., 2019, 361, 696 CrossRef CAS .
  11. (a) P. Chen, Q.-Q. Zhang, J. Guo, L.-L. Chen, Y.-B. Wang and X. Zhang, Org. Biomol. Chem., 2018, 16, 8336 RSC ; (b) L.-L. Chen, J.-W. Zhang, W.-W. Yang, J.-Y. Fu, J.-Y. Zhu and Y.-B. Wang, J. Org. Chem., 2019, 84, 8090 CrossRef CAS PubMed ; (c) L.-L. Chen, J.-W. Zhang, P. Chen, S. Zhang, W.-W. Yang, J.-Y. Fu, J.-Y. Zhu and Y.-B. Wang, Org. Lett., 2019, 21, 5457 CrossRef CAS PubMed ; (d) J.-W. Zhang, W.-W. Yang, L.-L. Chen, P. Chen, Y.-B. Wang and D.-Y. Chen, Org. Biomol. Chem., 2019, 17, 7461 RSC ; (e) W.-W. Yang, J.-W. Zhang, L.-L. Chen, J.-Y. Fu, J.-Y. Zhu and Y.-B. Wang, Chem. Commun., 2019, 55, 12607 RSC .

Footnote

Electronic supplementary information (ESI) available. CCDC 1956830, 1956831 and 1959692. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc08713c

This journal is © The Royal Society of Chemistry 2020