C–N Bond Formation: Metal-Free Reactions of 1,4

Letter pubs.acs.org/OrgLett

Cascade CO/CC/C−N Bond Formation: Metal-Free Reactions of 1,4-Diynes and 1‑En-4-yn-3-ones with Isoquinoline and Quinoline N‑Oxides Bing Zhang,†,§ Long Huang,‡,§ Shiwei Yin,† Xuetong Li,† Tao Xu,† Biyang Zhuang,† Tao Wang,*,† Zunting Zhang,† and A. Stephen K. Hashmi‡ †

School of Chemistry and Chemical Engineering, Shaanxi Normal University, No.620 West Chang’an Avenue, Xi’an 710119, China Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany

‡

S Supporting Information *

ABSTRACT: The metal-free reactions of 1,4-diynes and 1-en-4-yn-3-ones with isoquinoline and quinoline N-oxides are developed, resulting in the formation of 3,4-dihydro-2H-pyrido[2,1-a]isoquinolines and 2,3-dihydro-1H-pyrido[1,2-a]quinolines via cascade CO/CC/C−N bond formation. It is the first report in which in the alkyne oxidation by N-oxides both the oxygen atom of N-oxides and the nitrogen atom are involved in a second C−heteroatom bond formation. The reactions showed a broad substrate scope and functional group tolerance. Furthermore, the products were found to display green-blue fluorescence in DMSO with fluorescence quantum yields up to 0.59.

T

respectively.8,9 In analogy to most cases in metal catalysis, pyridine N-oxides served only as an oxygen donor in the Brønsted acid promoted/catalyzed reactions, resulting in the formation of pyridine as a byproduct. Maulide and co-workers recently developed the catalyst-free oxyarylation of electron-poor alkynes with pyridine and quinoline N-oxides (Scheme 1d). CO and C−C bonds were formed in this reaction, leading to metasubstituted pyridines and quinolines in which N-oxides served as both oxygen and aryl sources.10 Ji and co-workers reported similar results: a new CC bond was formed at the orthoposition of the quinoline.11 Recent developments allowed atomeconomic transformations. However, the molecular complexity of the products left much to be explored. Herein, we report metalfree reactions of 1,4-diynes and 1-en-4-yn-3-ones with isoquinoline or quinoline N-oxide, affording 3,4-dihydro-2H-pyrido[2,1a]isoquinolines or 2,3-dihydro-1H-pyrido[1,2-a]quinolines by cascade CO/CC/C−N bond formation (Scheme 1e). These products represent interesting targets; pyrido[2,1-a]isoquinoline and pyrido[1,2-a]quinoline skeletons are widely found in biologically active alkaloids such as protoemetinol, psychotrine, emetine, and tubulosine.12 Furthermore, the distinct fluorescence properties of the products are also disclosed.

he reaction of alkynes with N-oxides has attracted significant interest because it enables diverse, synthetic highly useful transformations. The reaction can be initiated by metal catalysis, Brønsted acid catalysis, and even catalyst-free conditions. Scheme 1 shows typical examples of such transformations. In 2010, Zhang reported the first gold-catalyzed1 oxidation of alkynes by the use of pyridine N-oxides as an oxygen donor.2 Following this work, copper,3 rhodium,4 and zinc salts5 were also developed as catalysts for this transformation (Scheme 1a). However, in most cases, after delivering an oxygen atom to the alkyne, pyridine was formed as a byproduct. In 2014, Li6a and Chang6b have independently developed the redox-neutral coupling of quinoline N-oxide with internal alkynes by the use of a rhodium(III) catalyst in which the quinoline N-oxide acted as both oxygen source and aryl donor. In 2016, Sundararaju and coworkers also achieved this transformation by the use of a cobalt(III) catalyst (Scheme 1b).6c Brønsted acids were also employed to promote this type of reaction (Scheme 1c). In 2012, Gong and co-workers reported the MsOH-promoted oxidation of alkynes by pyridine N-oxides under metal-free conditions.7 However, stoichiometric amounts of MsOH were required for this transformation. In 2013 and 2017, Hashmi and Shin achieved the intra- and intermolecular oxygenative C−C coupling of alkynes with arenes by use of pyridine N-oxides as oxygen donor in the presence of catalytic amounts of Brønsted acid, © XXXX American Chemical Society

Received: June 30, 2017

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DOI: 10.1021/acs.orglett.7b01996 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 2. Scope with Respect to 1,4-Diynes and N-Oxidesa

Scheme 1. Alkyne Oxidation by N-Oxides

Initially, we investigated the reaction of N-(1,5-diphenylpenta1,4-diyn-3-yl)-4-methylbenzenesulfonamide (1a) with isoquinoline N-oxide (2a). In 2014, Hashmi and co-workers reported the formation of N-(furan-3-ylmethylene)benzenesulfonamides from the same reactants in the presence of a gold(I) catalyst.13 To our delight, when 1a and 2a were stirred in the presence of 5 mol % of DABCO (1,4-diazabicyclooctane) in dichloromethane at room temperature for 1.5 h, a highly fluorescent product 4a was obtained in 89% yield. In a further investigation, it was found that when the reaction was carried out in acetonitrile in the presence of 5 mol % of triethylamine, the reaction gave the best result (eq 1, 94%; for more details on optimization of the reaction conditions, see Table S1, Supporting Information).

a

Unless otherwise noted, the reaction was conducted with 1 (0.30 mmol) and 2 (0.36 mmol) in CH3CN (3 mL) for 0.5 h at rt; the yields given are yields of isolated products. bThe reaction was carried out in CH3CN for 12 h at 100 °C. cThe ratio was determined by 1H NMR analysis of the crude reaction mixture.

were obtained in a 6:1 ratio in 83% total yield. The structure of 4m was confirmed by a single-crystal X-ray structure analysis.14 A tert-butyl-substituted product 4n was obtained regioselectived in 57% yield as a single isomer, while n-butyl-substituted products 4o and 4o′ were obtained as two isomers in 40% and 27% yields, respectively. The structures of the isomers were assigned by 1H NMR based upon the differences in chemical shifts and the splitting of H(a) and H(b) (see 4o and 4o′), together with the differences in chemical shifts of 13C NMR of the carbonyl group. Apart from isoquinoline N-oxide (2a), quinoline N-oxides (2b− f) and pyridine N-oxides were examined. In analogy to isoquinoline N-oxide, quinoline N-oxides worked well, giving 2,3-dihydro-1H-pyrido[1,2-a]quinolines (5a−d) in good to excellent yields. When 8-methylquinoline N-oxide was subjected to the standard conditions, a quinoline derivative 6a was formed in 92% yield.14 This might be explained by the steric hindrance of the methyl group on the 8-position. When pyridine N-oxides were subjected to the standard conditions, no reactions were observed. In the initial screening, we found that when 1a was treated with 5 mol % of triethylamine in the absence of 2a, a isomerized product 3a was formed in quantitative yield (eq 2). A further investigation revealed that 3a can react with 2a under base-free conditions to afford 4a in excellent yield (eq 3). This result indicated that the base added in the reaction only catalyzed the isomerization of 1a to 3a, which further reacted with 2a under catalyst-free conditions to give the final product 4a. Based on this result, we envisioned that 1-en-4-yn-3-one derivatives 7 could

With the optimized reaction conditions in hand, we evaluated the substrate scope of this transformation (Scheme 2). Symmetrical starting materials bearing substituted phenyl groups were examined first. Generally, the reaction delivered the corresponding products 4 in good to excellent yields (4a−e, 4g−h). Only when a strong electron-withdrawing group (CF3) was installed, the reaction afforded the corresponding product 4f in moderate yield (69%). A thiophene-2-yl-substituted product 4i was also obtained in 78% yield, while a thiophene-3-yl-substituted product 4j was obtained in 93% yield. Aliphatic starting materials also worked smoothly, delivering the corresponding products in good yields; however, a high temperature was required. For instance, heating 1k and 1l with 2a to 100 °C in acetonitrile for 12 h gave the n-butyl-substituted product 4k and the cyclopropylsubstituted product 4l in 46% and 51% yield, respectively. Unsymmetrical starting materials were also evaluated to react with 2a. When a substrate bearing a strong electron-donating group (MeO−) and a strong electron-withdrawing group (CF3−) was subjected to the standard conditions, 4m and 4m′ B

DOI: 10.1021/acs.orglett.7b01996 Org. Lett. XXXX, XXX, XXX−XXX

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those with electron-donating groups (8b,c and 8h−j, 72−81%). With a thiophene-2-yl group, 8k was obtained in excellent yield (93%), while a thiophene-3-yl-substituted product 8l was obtained in moderate yield (41%). The formation of an unknown byproduct was the main reason accounting for the low yield of 8l. Compound 8m bearing a 1-naphthyl group was obtained in 65% yield. The n-butyl-substituted product 8n and the cyclopropylsubstituted product 8p were obtained in 48% and 55% yield, respectively. It is worth noting that the substrate bearing a TMS group on the alkyne terminal delivered 8o in 52% yield, in which the TMS was removed. The influence of the group R2 on the alkene was also examined. The reaction gave the corresponding products in good yields for substituted phenyl groups (8q−s, 62− 76%), an aliphatic group (8t, 71%) or a heteroaromatic group (8u, 61%). Compound 8v was obtained in 89% yield, which further indicated the versatility of the starting material 7. Quinoline N-oxides were examined as well, which gave 1Hpyrido[1,2-a]quinolin-3(2H)-ones in moderate to good yields (9a−d).14 Based on the results from eq 2, eq 3 and the formation of 6a, in combination with literature reports,10,11 a plausible mechanism for the formation of 3,4-dihydro-2H-pyrido[2,1-a]isoquinolines from 1 and 2 is suggested in Scheme 4 using the reaction of 1a

also be reacted with isoquinoline and quinoline N-oxides to give polycyclic products. To prove our hypothesis, (E)-1,5diphenylpent-1-en-4-yn-3-one (7a) was prepared. Delightedly, when 7a reacted with 2a in acetonitrile at 100 °C for 12 h, 1benzoyl-4-phenyl-3,4-dihydro-2H-pyrido[2,1-a]isoquinolin-2one (8a) was obtained in 85% yield (eq 4). This transformation is quite interesting because it enables the formation of 3,4-dihydro2H-pyrido[2,1-a]isoquinolines and 2,3-dihydro-1H-pyrido[1,2a]quinolines from 1-en-4-yn-3-ones without experiencing regioselectivity issues when the alkyne terminus and the alkene terminus carry different substituents. In addition, an R3 substituent is installed, which further enriches the diversity of the products. The attempt to achieve this transformation from 1,5-diphenylpenta-1,4-diyn-3-ol (10a) and 2a failed due to the decomposition of 10a under basic conditions (eq 5). The scope with regard to 1-en-4-yn-3-one derivatives 7 was also investigated (Scheme 3). First the substituent on the alkyne terminal (R1) was evaluated. With substituted phenyl groups, the substrates bearing electron-withdrawing groups gave the corresponding products in higher yields (8d−g, 76−93%) than

Scheme 4. Plausible Mechanism

Scheme 3. Scope of 1-En-4-yn-3-ones and N-Oxidesa

with 2a as an example. The alkyne in 1a is not able to directly react with 2a. In the presence of a catalytic amount of base, 1a is tautomerized15 to 3a, and then the alkyne is electron deficient. This activated intermediate reacts with 2a to form intermediate C via a [3 + 2] cycloaddition. The subsequent ring opening of isoxazole ring and the 1,2-proton shift afford intermediate D, which further undergoes a 1,4-addition of amine to α,βunsaturated imine delivering intermediate E. After a proton transfer from the ammonium substructure to the TsN − substructure and a tautomerization of the enamine to the conjugated imine, 4a is finally formed. The tautomerization of intermediate D to G provides an alternative pathway, in which F is directly formed from G via a 6π-electrocyclization. The reaction fails with pyridine N-oxides, as in their case the full aromatic stabilization energy will be lost, which obviously raises the barrier of activation significantly. Quinoline and isoquinoline N-oxides work well in this transformation because they do not suffer from a full dearomatization.16 Interestingly, the obtained nitrogen-containing polycyclic products showed distinct fluorescence properties in DMSO

a

Unless otherwise noted, the reaction was conducted with 7 (0.30 mmol) and 2 (0.36 mmol) in CH3CN (3 mL) for 12 h at 100 °C; the yields given are yields of isolated products. C

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(f) Zhang, L. Acc. Chem. Res. 2014, 47, 877. (g) Huple, D. B.; Ghorpade, S.; Liu, R.-S. Adv. Synth. Catal. 2016, 358, 1348. (h) Pan, F.; Shu, C.; Ye, L.-W. Org. Biomol. Chem. 2016, 14, 9456. (i) Jia, M.; Bandini, M. ACS Catal. 2015, 5, 1638. (j) Xie, J.; Pan, C.; Abdukader, A.; Zhu, C. Chem. Soc. Rev. 2014, 43, 5245. (k) Fürstner, A. Acc. Chem. Res. 2014, 47, 925. (l) Yang, W.; Hashmi, A. S. K. Chem. Soc. Rev. 2014, 43, 2941. (m) Fensterbank, L.; Malacria, M. Acc. Chem. Res. 2014, 47, 953. (n) Liu, L.-P.; Hammond, G. B. Chem. Soc. Rev. 2012, 41, 3129. (o) Garayalde, D.; Nevado, C. ACS Catal. 2012, 2, 1462. (p) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (q) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358. (r) Corma, A.; Leyva-Pérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (s) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910. (2) (a) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (b) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (c) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070. (d) Wang, T.; Shi, S.; Hansmann, M. M.; Rettenmeier, E.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2014, 53, 3715. (e) Wang, T.; Shi, S.; Rudolph, M.; Hashmi, A. S. K. Adv. Synth. Catal. 2014, 356, 2337. (f) Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2011, 50, 6911. (g) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040. (h) Yeom, H.-S.; Lee, Y.; Jeong, J.; So, E.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2010, 49, 1611. (i) Chen, M.; Chen, Y.; Sun, N.; Zhao, J.; Liu, Y.; Li, Y. Angew. Chem., Int. Ed. 2015, 54, 1200. (j) Zhao, J.; Liu, J.; Xie, X.; Li, S.; Liu, Y. Org. Lett. 2015, 17, 5926. (k) Qian, D.; Hu, H.; Liu, F.; Tang, B.; Ye, W.; Wang, Y.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 13751. (3) Gronnier, C.; Kramer, S.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2012, 134, 828. (4) (a) Liu, R.; Winston-McPherson, G. N.; Yang, Z.-Y.; Zhou, X.; Song, W.; Guzei, I. A.; Xu, X.; Tang, W. J. Am. Chem. Soc. 2013, 135, 8201. (b) Kim, I.; Lee, C. Angew. Chem., Int. Ed. 2013, 52, 10023. (c) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007, 46, 8872. (5) (a) Li, L.; Zhou, B.; Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.; Ye, L.W. Angew. Chem., Int. Ed. 2015, 54, 8245. (b) Pan, F.; Shu, C.; Ping, Y.-F.; Pan, Y.-F.; Ruan, P.-P.; Fei, Q.-R.; Ye, L.-W. J. Org. Chem. 2015, 80, 10009. (c) Zhou, B.; Li, L.; Ye, L.-W. Synlett 2016, 27, 493. (6) (a) Zhang, X.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2014, 53, 10794. (b) Sharma, U.; Park, Y.; Chang, S. J. Org. Chem. 2014, 79, 9899. (c) Barsu, N.; Sen, M.; Premkumar, J. R.; Sundararaju, B. Chem. Commun. 2016, 52, 1338. (7) Chen, D.-F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51, 12307. (8) Graf, K.; Rühl, C. L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013, 52, 12727. (9) Patil, D. V.; Kim, S. W.; Nguyen, Q. H.; Kim, H.; Wang, S.; Hoang, T.; Shin, S. Angew. Chem., Int. Ed. 2017, 56, 3670. (10) Chen, X.; Ruider, S. A.; Hartmann, R. W.; González, L.; Maulide, N. Angew. Chem., Int. Ed. 2016, 55, 15424. (11) (a) Chen, Z.-S.; Yang, F.; Ling, H.; Li, M.; Gao, J.-M.; Ji, K. Org. Lett. 2016, 18, 5828. Liang and co-workers reported a similar result by the use of Bi(OTf)3 as catalyst; see: (b) Han, Y.-P.; Li, X.-S.; Zhu, X.-Y.; Li, M.; Zhou, L.; Song, X.-R.; Liang, Y.-M. J. Org. Chem. 2017, 82, 1697. (12) (a) Chang, J.-K.; Chang, B.-R.; Chuang, Y.-H.; Chang, N.-C. Tetrahedron 2008, 64, 9685. (b) Battersby, A. R.; Kapil, R. S.; Bhakuni, B. S.; Popli, S. P.; Merchant, J. R.; Salgar, S. S. Tetrahedron Lett. 1966, 7, 4965. (13) Wang, T.; Huang, L.; Shi, S.; Rudolph, M.; Hashmi, A. S. K. Chem. Eur. J. 2014, 20, 14868. (14) CCDC 1547312 (6a), CCDC 1547313 (4m), and CCDC 1547318 (9c) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/ cif. (15) Wang, Y.-H.; Liu, H.; Zhu, L.-L.; Li, X.-X.; Chen, Z. Adv. Synth. Catal. 2011, 353, 707. (16) (a) You, S.-L., Ed. Asymmetric Dearomatization Reactions; Wiley: Weinheim, 2016.

with the emission maxima range from 505 to 540 nm (for details, see the SI). Fluorescence quantum yields of compounds 4 and 5 differ from 0.59 for 4i to 0.01 for 4f (for details, please see SI). However, 3,4-dihydro-2H-pyrido[2,1-a]isoquinolin-2-ones 8 and 1H-pyrido[1,2-a]quinolin-3(2H)-ones 9 exhibited rather low fluorescence quantum yields (Φ < 0.1). In conclusion, we have reported the metal-free reactions of 1,4diynes and 1-en-4-yn-3-ones with isoquinoline and quinoline Noxides. The former reaction took place at room temperature in the presence of catalytic amount of base, while the later one occurred under catalyst-free conditions. 3,4-Dihydro-2H-pyrido[2,1-a]isoquinolines and 2,3-dihydro-1H-pyrido[1,2-a]quinolines were obtained via a cascade CO/CC/C−N bond formation. To the best of our knowledge, this is the first report that the nitrogen atom of N-oxides is involved in the C−N bond formation in alkyne oxidation by N-oxides, which enriches the diversity of the transformation and quickly increases the molecular complexity. Mechanistic investigation revealed that an activated alkyne moiety is essential. Furthermore, the products displayed green-blue fluorescence in DMSO solution with fluorescence quantum yields up to 0.59 (4i). The importance of the products in natural products, the easy accessibility of the starting materials, and the mild reaction conditions combined with the distinct fluorescence properties of the products define the high potential of this reaction for both synthetic chemistry and material science.

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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.7b01996. Experimental procedures and analytical data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shiwei Yin: 0000-0002-4389-9509 Tao Wang: 0000-0002-1494-5297 Zunting Zhang: 0000-0003-0806-2452 A. Stephen K. Hashmi: 0000-0002-6720-8602 Author Contributions §

B.Z. and L.H. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the National Natural Science Foundation of China (21502110, 21542002) and the Fundamental Research Funds for the Central Universities (GK201703022) is greatly appreciated. We thank Prof. Dr. Rui Cao (Shaanxi Normal University) and Dr. Zongyao Zhang (Renmin University of China) for crystallographic investigation on 6a.

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REFERENCES

(1) (a) Asiri, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 4471. (b) Liu, L.; Zhang, J. Chem. Soc. Rev. 2016, 45, 506. (c) Qian, D.; Zhang, J. Chem. Soc. Rev. 2015, 44, 677. (d) Yeom, H.-S.; Shin, S. Acc. Chem. Res. 2014, 47, 966. (e) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226. D

DOI: 10.1021/acs.orglett.7b01996 Org. Lett. XXXX, XXX, XXX−XXX