Controllable synthesis of 3-iodo-2H-quinolizin-2-ones and 1,3-diiodo-2H-quinolizin-2-ones via electrophilic cyclization of azacyclic ynones

Wan-Wan Yang , Jing-Wen Zhang , Lu-Lu Chen , Ji-Ya Fu , Jun-Yan Zhu and Yan-Bo Wang *
Institute of Functional Organic Molecular Engineering, Henan Engineering Laboratory of Flame-Retardant and Functional Materials, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, 475004, China. E-mail: wangyanbokf@henu.edu.cn

Received 12th August 2019 , Accepted 16th September 2019

First published on 16th September 2019


An effective electrophilic annulation reaction of azacyclic ynones was reported, divergently affording various functionalized 3-iodo-2H-quinolizin-2-ones and 1,3-diiodo-2H-quinolizin-2-ones in moderate to excellent yields with different iodide reagents. This reaction shows high regioselectivity and broad substrate scope under metal-free, room temperature conditions in air. In addition, the products with highly active C–I bonds have an opportunity for further functionalization.


Quinolizidine derivatives, as important azabicyclic alkaloids, have been drawing more attention due to their broad application in bioactive natural products and pharmaceuticals.1 Consequently, various methodologies for the construction of quinolizidine frameworks have been reported.2 However, the preparation of 2H-quinolizin-2-ones, as one significant family of quinolizidine-derived alkaloids and proven potential anti-HCV drugs targeting NS5B polymerase3 or p38α MAP kinase inhibitors,4 is generally limited to harsh heat-induced strategies.5 More recently, a method to access 2H-quinolizin-2-ones via the cyclization reaction of azacyclic ynones has been described (Scheme 1).6 For example, the cyclization reaction of the pyridine-ynone species, which were formed in situ via the acylation of 2-picoline, has already been demonstrated with moderated yields under harsh thermal conditions (Scheme 1a).6a A simple and scalable approach to 2H-quinolizin-2-ones from azacyclic ynones was also reported under silver(I)-catalyzed conditions (Scheme 1b).6b Subsequently, the silver(I)-mediated synthesis of 1-amino-2H-quinolizin-2-ones from azacyclic ynones and diazenes was also reported (Scheme 1c).6c Although the above methodologies are favorable, they usually suffer from some limitations, such as the use of high temperature or metal reagents. Therefore, the development of an efficient and metal-free approach for the preparation of 2H-quinolizin-2-ones under mild conditions is still highly desirable.
image file: c9cc06250e-s1.tif
Scheme 1 Synthesis of 2H-quinolizin-2-ones involving azacyclic ynones.

It is well established that strong electrophilic iodide reagents, including I2, N-iodosuccinimide (NIS) and ICl could activate a triple bond to generate the active C–I bond, which may provide a good opportunity for further functionalization.7 Inspired by the iodine-mediated cyclization reaction of alkynes and our success in the catalytic transformation of alkynes8 or ynones,9 we initially envisioned that the cyclization reaction of azacyclic ynones mediated by suitable iodide electrophiles may afford 3-iodo-2H-quinolizin-2-one derivatives under metal-free conditions. To our surprise, the expected 3-iodo-2H-quinolizin-2-ones and unexpected 1,3-diiodo-2H-quinolizin-2-ones were divergently obtained by using different iodide electrophiles. Herein, we for the first time report a novel and efficient divergent synthesis of 3-iodo-2H-quinolizin-2-ones and 1,3-diiodo-2H-quinolizin-2-ones from azacyclic ynones. This method showed high regioselectivity and broad substrate scope under metal-free, room temperature conditions in air (Scheme 1d).

We initially chose 4-phenyl-1-(pyridin-2-yl)but-3-yn-2-one 1a as the model substrate to screen reaction conditions (see the ESI (Table S1)). When substrate 1a reacted with different electrophiles (I2, NIS, and ICl) in CH2Cl2 at room temperature, the divergent products were observed. Single product 2a was obtained in 55% yield using 1.2 equiv. I2 as electrophile (Table S1, entry 1, ESI). Both products 2a and 3a were given using NIS or ICl as electrophile (Table S1, entries 2 and 3, ESI). The structures of products 2a and 3a were unambiguously determined by X-ray crystallography (see Fig. S1 in the ESI for details). Based on above experimental results, increasing the loading of NIS would be instrumental in generating the product 3a (Table S1, entries 4–6, ESI). Next, the effect of other reaction parameters, including solvent, additive and reaction time, was further investigated. These results showed that the electrophile I2 was advantageous to give product 2a in 87% yield (Table S1, entry 13, ESI), and the electrophile NIS exhibited high activity to deliver product 3a in 90% yield (Table S1, entry 20, ESI).

With the optimized reaction conditions in hand, we then explored the substrate scope to construct 3-iodo-2H-quinolizin-2-ones using I2 as electrophile and the results are summarized in Table 1. Various azacyclic ynones 1 were tolerated and the corresponding products 2 were delivered in moderate to excellent yields. Substrates 1b–1i with an alkyl, ether or halo group at the meta or para positions of the aryl groups could readily generate the corresponding products 2b–2i in 73% to 96% yields. Pleasingly, when we used 3.0 mmol of substrate 1a under the standard conditions, the desired product 2a could be given in 82% yield. Further investigation showed that naphthyl quinolizinone 2j was also afforded in near-quantitative yield. Heteroaromatic and aliphatic quinolizinones 2k, and 2m–2o were also synthesized, albeit in relatively lower yield due to the instability of the corresponding azacyclic ynones. Conversely, heteroaromatic quinolizinone 2l was not obtained. Then, substituents on the pyridine ring were further investigated, and the corresponding quinolizinones 2p–2s bearing methyl, bromo, and phenyl substituents could be furnished in moderate to excellent yields. Furthermore, the current methodology was also demonstrated on the pyridine analogues, affording isoquinoline and pyrazine derived products 2t and 2u. However, the pyrroline derived product 2v was not obtained. Finally, methylated quinolizinone 2w was also afforded in satisfactory yield.

Table 1 Substrate scopea,b
a Reaction conditions: 0.2 mmol 1, 0.5 mmol I2, 0.5 mol NaHCO3, 2.0 mL 1,4-dioxane, rt, 0.5 h. b Isolated yield. c 3.0 mmol of 1a was used.
image file: c9cc06250e-u1.tif


Subsequently, we explored the substrate scope to prepare 1,3-diiodo-2H-quinolizin-2-ones 3 using NIS as electrophile. A variety of azacyclic ynones 1 were studied and the results are shown in Table 2. To our delight, substrates 1b–1i with electron-donating or electron-withdrawing groups at the meta or para positions of the aryl groups (R1) were well tolerated, and the corresponding quinolizinones 3b–3i were obtained in good to excellent yield. Notably, the yield of product 3a could reach 81% when 3.0 mmol of substrate 1a was used. The naphthyl quinolizinone 3j was well amenable to this cyclization reaction, and it was obtained in 90% yield. Substrates 1k–1o with heterocyclic and alkyl groups were also tolerated, affording the desired products 3k–3o in 37% to 72% yield. In addition, the pyridine ring anchoring the different substituents was then tested. The experimental results revealed that the position of substituents on the pyridine ring has an obvious influence on reactivity. The less steric substrates 1p–1q also smoothly delivered the corresponding products 3p–3q in good to excellent yield. Conversely, the more steric substrates 1r–1s easily underwent cyclization reactions to generate products 2r–2s in excellent yield under standard conditions. When 3.0 equiv. of NIS was used, substrates 1r–1s could be transformed into the desired products 3r–3s at 60 °C after 24 h. Notably, when the pyridine system was changed into other heteroaromatic rings, such as isoquinoline and pyrazine, the main products 2t–2u were obtained under standard conditions. The desired products 3t–3u were smoothly delivered in the presence of 3.0 equiv. of NIS at 60 °C after 24 h. Fortunately, the desired product 3v was afforded in 91% yield under standard conditions. When the methyl substrate 1w reacted with NIS, the quinolizinone 2w was expectedly obtained in 62% yield. Finally, this electrophilic cyclization was suitable for NBS (N-bromosuccinimide) to deliver the product 3x, but not for NCS (N-chlorosuccinimide) as electrophile.

Table 2 Substrate scopea,b
a Reaction conditions: 0.2 mmol 1, 0.5 mmol NIS, 2.0 mL DCE, rt, 2 h. b Isolated yield. c 3.0 mmol of 1a. d 0.6 mmol NIS, 60 °C, 24 h. e 0.5 mmol NBS as electrophile. f 0.5 mmol NCS as electrophile.
image file: c9cc06250e-u2.tif


To further test the synthetic utility of the current methodology, some chemical transformations were conducted (Scheme 2). Products 2 and 3 with highly active C–I bonds could be decorated to synthesize functional chemicals by applying palladium catalysts. As expected, the products 4 and 5 were obtained via Suzuki reactions with good yields (Scheme 2a and b). Additionally, the iodobromination product 6 with C–Br and C–I bonds was obtained in 94% yield by the reaction of 2a with NBS.


image file: c9cc06250e-s2.tif
Scheme 2 Further chemical transformations of products 2a and 3a.

To better shed light on the mechanism, some control experiments were conducted (Scheme 3). We found that the product 7 was not obtained in the absence of NIS or I2 (Scheme 3a). This experimental result indicated that the electrophiles are indispensable for this cyclization reaction. Additionally, the 3-iodo-2H-quinolizin-2-one 2a smoothly reacted with NIS to give 3a in 92% yield (Scheme 3b). This result suggested that products 3 could be afforded from products 2. Additionally, the reaction of substrate 1 with NIS was monitored by 1H NMR, and the corresponding reaction intermediates were observed (see Fig. S2 in the ESI for details).


image file: c9cc06250e-s3.tif
Scheme 3 Control experiments.

Based on the present results and previous literature,6,7 a plausible mechanism for the divergent preparation of 3-iodo-2H-quinolizin-2-ones and 1,3-diiodo-2H-quinolizin-2-ones from azacyclic ynones 1 is depicted in Scheme 4. Firstly, the triple bond of substrates 1 or the intermediate A (R = I) was activated by the electrophile I2 or NIS, affording the corresponding iodonium intermediate B or D. Next, the pyridinium species C or E were formed by nucleophilic attack from the pyridine lone pair. Finally, deprotonation of the intermediate C or E (R = H) proceeded to afford the desired 3-iodo-2H-quinolizin-2-ones 2, which were further transformed into 1,3-diiodo-2H-quinolizin-2-ones 3 in the presence of NIS. Similarly, deprotonation of the intermediate E (R = I) could directly afford the desired 1,3-diiodo-2H-quinolizin-2-ones 3.


image file: c9cc06250e-s4.tif
Scheme 4 Plausible mechanism.

In summary, we have developed a novel and efficient strategy for the divergent preparation of 3-iodo-2H-quinolizin-2-ones and 1,3-diiodo-2H-quinolizin-2-ones from azacyclic ynones in moderate to excellent yields under metal-free, room temperature conditions in air. Moreover, the current method is characterized by high regioselectivity, broad substrate scope and easy operation. The plausible mechanism was proposed and supported by some control experiments. Notably, due to the existence of the highly active C–I bond, the Pd-catalyzed Suzuki coupling reaction was studied. Further applications of this method for constructing more complex natural products and pharmaceuticals are still ongoing in our laboratory.

This work was financially supported by the National Natural Science Foundation of China (no. U1504205), 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) S. M. Weinreb, Chem. Rev., 2006, 106, 2531 CrossRef CAS PubMed; (b) J. P. Michael, Nat. Prod. Rep., 2008, 25, 139 RSC; (c) B. Jasiewicz and T. Pospieszny, Mini-Rev. Org. Chem., 2013, 10, 217 CrossRef CAS; (d) N. Veerasamy and R. G. Carter, Tetrahedron, 2016, 72, 4989 CrossRef CAS.
  2. For selected references, see: (a) D. T. Amos, A. R. Renslo and R. L. Danheiser, J. Am. Chem. Soc., 2003, 125, 4970 CrossRef CAS PubMed; (b) S. S. Kinderman, R. de Gelder, J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra and F. P. J. T. Rutjes, J. Am. Chem. Soc., 2004, 126, 4100 CrossRef CAS PubMed; (c) K. M. Maloney and R. L. Danheiser, Org. Lett., 2005, 7, 3115 CrossRef CAS PubMed; (d) S. Yu, W. Zhu and D. Ma, J. Org. Chem., 2005, 70, 7364 CrossRef CAS PubMed; (e) D. Yang and G. C. Micalizio, J. Am. Chem. Soc., 2009, 131, 17548 CrossRef CAS PubMed; (f) G. Bélanger, G. O’Brien and R. Larouche-Gauthier, Org. Lett., 2011, 13, 4268 CrossRef PubMed; (g) Y. Tan, Y.-J. Chen, H. Lin, H.-L. Luan, X.-W. Sun, X.-D. Yang and G.-Q. Lin, Chem. Commun., 2014, 50, 15913 RSC; (h) S. G. Davies, A. M. Fletcher, E. M. Foster, I. T. T. Houlsby, P. M. Roberts, T. M. Schofield and J. E. Thomson, Chem. Commun., 2014, 50, 8309 RSC; (i) W. P. Unsworth, G. Coulthard, C. Kitsiou and R. J. K. Taylor, J. Org. Chem., 2014, 79, 1368 CrossRef CAS PubMed; (j) H. Chen, T. Xiao, L. Li, D. Anand, Y. He and L. Zhou, Adv. Synth. Catal., 2017, 359, 3642 CrossRef CAS; (k) Y. Tan, E.-L. Feng, Q.-S. Sun, H. Lin, X. Sun, G.-Q. Lin and X.-W. Sun, Org. Biomol. Chem., 2017, 15, 778 RSC.
  3. G. Y. Wang, L. G. Zhang, X. M. Wu, D. Das, D. Ruhrmund, L. Hooi, S. Misialek, P. T. R. Rajagopalan, B. O. Buckman, K. Kossen, S. D. Seiwert and L. Beigelman, Bioorg. Med. Chem. Lett., 2009, 19, 4484 CrossRef CAS PubMed.
  4. R. M. Tynebor, M.-H. Chen, S. R. Natarajan, E. A. O’Neill, J. E. Thompson, C. E. Fitzgerald, S. J. O’Keefe and J. B. Doherty, Bioorg. Med. Chem. Lett., 2010, 20, 2765 CrossRef CAS PubMed.
  5. (a) V. Boekelheide and J. P. Lodge, J. Am. Chem. Soc., 1951, 73, 3681 CrossRef CAS; (b) A. Fozard and G. Jones, J. Chem. Soc., 1964, 2760 RSC; (c) R. M. Acheson and J. Woollard, J. Chem. Soc., Perkin Trans. 1, 1975, 446 RSC; (d) A. R. Katritzky, J. W. Rogers, R. M. Witek and S. K. Nair, ARKIVOC, 2004, viii, 52 Search PubMed; (e) X. Fan, Y. He, X. Zhang and J. Wang, Green Chem., 2014, 16, 1393 RSC.
  6. (a) S. R. Natarajan, M.-H. Chen, S. T. Heller, R. M. Tynebor, E. M. Crawford, C. Minxiang, H. Kaizheng, J. Dong, B. Hu, W. Hao and S.-H. Chen, Tetrahedron Lett., 2006, 47, 5063 CrossRef CAS; (b) M. J. James, N. D. Grant, P. O’Brien, R. J. K. Taylor and W. P. Unsworth, Org. Lett., 2016, 18, 6256 CrossRef CAS PubMed; (c) X.-L. Min, C. Sun and Y. He, Org. Lett., 2019, 21, 724 CrossRef CAS PubMed.
  7. For selected references, see: (a) X. X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2005, 127, 12230 CrossRef CAS PubMed; (b) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil and Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 4764 CrossRef CAS PubMed; (c) C. W. Li, C. I. Wang, H. Y. Liao, R. Chaudhuri and R. S. Liu, J. Org. Chem., 2007, 72, 9203 CrossRef CAS PubMed; (d) Y. Yamamoto, I. D. Gridnev, N. T. Patild and T. Jin, Chem. Commun., 2009, 5075 RSC; (e) T. Dohi, D. Kato, R. Hyodo, D. Yamashita, M. Shiro and Y. Kita, Angew. Chem., Int. Ed., 2011, 50, 3784 CrossRef CAS PubMed; (f) G. Bharathiraja, S. Sakthivel, M. Sengoden and T. Punniyamurthy, Org. Lett., 2013, 15, 4996 CrossRef CAS PubMed; (g) Y. Chen, X. C. Liu, M. Lee, C. L. Huang, I. Inoyatov, Z. W. Chen, A. C. Perl and W. H. Hersh, Chem. – Eur. J., 2013, 19, 9795 CrossRef CAS PubMed; (h) Y. Chen, C. L. Huang, X. C. Liu, E. Perl, Z. W. Chen, J. Namgung, G. Subramaniam, G. Zhang and W. H. Hersh, J. Org. Chem., 2014, 79, 3452 CrossRef CAS PubMed; (i) R. Yan, X. Li, X. Yang, X. Kang, L. Xiang and G. Huang, Chem. Commun., 2015, 51, 2573 RSC; (j) X.-W. Liang, C. Zheng and S.-L. You, Chem. – Eur. J., 2016, 22, 11918 CrossRef CAS PubMed; (k) C. Huang, Y. Zeng, H. Cheng, A. Hu, L. Liu, Y. Xiao and J. Zhang, Org. Lett., 2017, 19, 4968 CrossRef CAS PubMed; (l) P. Fedoseev, G. Coppola, G. M. Ojeda and E. V. Van der Eycken, Chem. Commun., 2018, 54, 3625 RSC.
  8. (a) Y.-B. Wang, Y.-M. Wang, W.-Z. Zhang and X.-B. Lu, J. Am. Chem. Soc., 2013, 135, 11996 CrossRef CAS PubMed; (b) Y.-B. Wang, D.-S. Sun, H. Zhou, W.-Z. Zhang and X.-B. Lu, Green Chem., 2014, 16, 2266 RSC; (c) S. Zhang, X.-T. Bai, D.-Y. Chen, P. Chen, Q.-Q. Zhang and Y.-B. Wang, RSC Adv., 2017, 7, 31142 RSC; (d) X.-T. Bai, Q.-Q. Zhang, S. Zhang, D.-Y. Chen, J.-Y. Fu, J.-Y. Zhu, Y.-B. Wang and Y.-T. Tang, Eur. J. Org. Chem., 2018, 1581 CrossRef CAS; (e) L.-L. Chen, J.-W. Zhang, W.-W. Yang, P. Chen, D.-Y. Chen and Y.-B. Wang, Org. Biomol. Chem., 2019, 17, 3003 RSC.
  9. (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.

Footnote

Electronic supplementary information (ESI) available. CCDC 1940902 and 1940903. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc06250e

This journal is © The Royal Society of Chemistry 2019