[3+ 3] Cycloaddition of in Situ Formed Azaoxyallyl Cations with 2

May 9, 2017 - Reddy , B. V. S.; Ganesh , A. V.; Vani , M.; Murthy , T. R.; Kalivendi , S. V.; Yadav , J. S. Bioorg. Med. Chem. Lett. 2014, 24, 4501 DO...
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[3 + 3] Cycloaddition of in Situ Formed Azaoxyallyl Cations with 2‑Alkenylindoles: An Approach to Tetrahydro-β-carbolinones Kaifan Zhang,† Xiaoying Xu,† Jiuan Zheng,† Hequan Yao,† Yue Huang,*,‡ and Aijun Lin*,† †

State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China ‡ Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China S Supporting Information *

ABSTRACT: A novel [3 + 3] cycloaddition between in situ formed azaoxyallyl cations and 2-alkenylindoles has been developed. This concise method allows the efficient construction of a series of tetrahydro-β-carbolinones in good yields under mild conditions. Gram-scale experiments and further derivatization of tetrahydro-β-carbolinones highlighted the potential utility of our method.

T

Scheme 1. Methods for the Synthesis of Tetrahydro-βcarbolinones

etrahydro-β-carbolinone structural motifs have been identified as high-profile skeletons in a wide range of indole alkaloids with potent antitumor activity,1 such as cladoniamides F and G and ophiorrhisides A and B (Figure 1). On account of their prominent bioactivities and medicinal

Figure 1. Selected examples of natural products and bioactive compounds containing a tetrahydro-β-carbolinone framework.

value, the exploration of efficient methods to build such frameworks has attracted widespread research interest.2 Representative methods include the three-component Ugi reaction (Scheme 1a),3 zinc-catalyzed intramolecular alkyne oxidation/C−H functionalization (Scheme 1b),4 and goldcatalyzed intramolecular hydro-heteroarylation of acrylamides (Scheme 1c).5 Although the previous approaches were of interest in achieving tetrahydro-β-carbolinones, multistep processes, metal catalysts, extra oxidants, and/or restricted substrate scopes remained to be addressed for these methods to be generally applicable. Accordingly, the development of efficient methods with easily acquired materials under mild conditions is still highly desirable. Since the seminal discovery of cycloaddition involving in situ formed azaoxyallyl cations from α-halohydroxamates reported by Jeffrey,6 azaoxyallyl cations represented ideal synthons on © 2017 American Chemical Society

which to develop new nitrogen heterocycles.7 Recently, we realized a [3 + 2] cycloaddition reaction between azaoxyallyl cations and aldehydes, leading to the synthesis of oxazolidin-4ones in excellent yields.8 In view of our continuous interest in constructing functional indoles,9 herein we report our results on the synthesis of tetrahydro-β-carbolinones through [3 + 3] cycloaddition between in situ formed azaoxyallyl cations and 2alkenylindoles10 under metal-free conditions (Scheme 1d). We commenced our feasibility studies with dimethyl 2-((1methyl-1H-indol-2-yl)methylene)malonate (1a) and N-(benzyloxy)-2-bromo-2-methylpropanamide (2a) as the pilot subReceived: March 28, 2017 Published: May 9, 2017 2596

DOI: 10.1021/acs.orglett.7b00914 Org. Lett. 2017, 19, 2596−2599

Letter

Organic Letters Scheme 2. Substrate Scope of 2-Alkenylindolesa,b

strates. Impressively, the strong hydrogen-bond-donating and sterically bulky solvent hexafluoroisopropanol (HFIP) was effective in achieving the reaction, providing the lactamization product 3aa in 50% yield (Table 1, entry 5), while 2,2,2Table 1. Optimization of Reaction Conditionsa

entry

base

solvent

time (h)

yieldb,c (%)

1 2 3 4 5 6 7 8 9 10d 11e 12f 13g 14h 15

Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 NaOH Et3N KHCO3 Cs2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3

TFE TFP CH3CN DCM HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

12 12 12 12 3 3 3 3 3 3 3 3 3 3 3

nr nr nr nr 50 33 39 28 18 66 69 77 84 86 nr

a

Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), base (2.0 equiv) in solvent (1.0 mL) for 3 h at room temperature. bIsolated yields. cnr = no reaction. d1.2 equiv of 2a was used. e1.5 equiv of 2a was used. f 2.0 equiv of 2a was used. g3.0 equiv of Na2CO3 was used. h4.0 equiv of Na2CO3 was used.

trifuoroethanol (TFE), 2,2,3,3-tetrafluoropropanol (TFP), CH3CN, and DCM rendered no conversion (Table 1, entries 1−4). Other bases including inorganic and organic bases such as NaOH, Et3N, KHCO3, and Cs2CO3 failed to enhance the yields (Table 1, entries 6−9). Increasing the loading amount of 2a and Na2CO3 could lead to the improvement of 3aa (Table 1, entries 10−13). The optimal reaction conditions were obtained when 2.0 equiv of 2a and 4.0 equiv of Na2CO3 were employed with the complete conversion of 1a (Table 1, entry 14). No desired product was detected without base (Table 1, entry 15). With the optimized reaction conditions established, the substrate scope of the reaction with respect to the 2alkenylindole moiety was examined, and the results are summarized in Scheme 2. The reactions were well compatible with 2-alkenylindoles bearing methyl and methoxyl groups at the C-5 position, affording 3ba and 3ca in 94% and 87% yields. When an indole framework bearing a chloro substituent at the C-5 position was used, 3da was obtained in 41% yield with iminolactonization product 4da (42% yield) under standard conditions. The yield of 3da could be further improved to 76% by treatment with trifluoroacetic acid (TFA) as an additive after the complete conversion of 1d (see the SI for details). Steric hindrance retarded the reaction and 3ha was achieved in moderate yield with a methyl group at the C-4 position. 2Alkenylindoles 1 with various N-substituents, such as ethyl, allyl, and benzyl groups, underwent smooth reactions to provide 3ka−ma in 72−91% yields under the optimized conditions. Satisfactorily, switching the Michael acceptors from diester groups to monoester groups, 3na−pa could be realized

a

Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Na2CO3 (0.8 mmol) in HFIP (1.0 mL) for 3 h at room temperature. bIsolated yields. c2a (0.6 mmol), Na2CO3 (1.2 mmol). dTFA (1.4 mmol) was added until 2-alkenylindoles were completely consumed and then stirred at room temperature for another 3 h. e2a (0.3 mmol), Na2CO3 (0.6 mmol).

in 90−95% yields. X-ray crystallography of 3pa unambiguously determined its configuration as shown in Figure 2.11 Replacing the monoester group with ketone carbonyl groups resulted the cycloaddition of 1q and 1r in 91% and 96% yields. The reaction could also endure nitro and cyano groups, which are valuable and versatile precursors to an array of functional compounds, leading to 3sa and 3ta in 63% and 94% yield, respectively.

Figure 2. X-ray structure of product 3pa. Hydrogen atoms are omitted for clarity. 2597

DOI: 10.1021/acs.orglett.7b00914 Org. Lett. 2017, 19, 2596−2599

Letter

Organic Letters After checking the generality of 2-alkenylindoles 1, we then switched our attention to the reactivity of α-halohydroxamates 2, and the results are summarized in Scheme 3. Substrates with

Scheme 4. Further Study on [3 + 3] Cycloaddition Reaction between in Situ Formed Azaoxyallyl Cations and 2Alkenylindoles

Scheme 3. Substrate Scope of α-Halohydroxamatesa,b

involved.7a,8b,12c To further understand the mechanistic details of this [3 + 3] cycloaddition reaction, a control experiment was carried out (Scheme 5a). When the iminolactonization cycloadduct 4da was treated with 2.0 equiv TFA, lactamization cycloadduct 3da could be achieved in 73% yield. Scheme 5. Mechanism Study a

Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Na2CO3 (0.8 mmol) in HFIP (1.0 mL) for 3 h at room temperature. bIsolated yields. cTFA (1.0 mmol) was added until 2-alkenylindoles was completely consumed and stirred at room temperature for another 3 h. d dr = Diastereoisomeric ratio. eX = Cl, f2 (0.3 mmol), Na2CO3 (0.6 mmol). g60 °C. hK2CO3 (0.6 mmol) as base.

various protecting groups on the nitrogen atom such as methoxy, ethoxy, isopropoxy, tert-butoxy, and allyloxy groups behaved well, furnishing 3ab−af in 63−91% yields. Cyclohexylsubstituted hydroxamate 2g performed smoothly in the reaction to give 3ag in 83% yield. When α-halohydroxamates bearing a monoaryl group were tested, 3nh−nj were prepared in 54−57% yields (dr >20:1). The relative configuration of 3nj was determined by single-crystal X-ray analysis (see the SI for details).11 Additionally, α-halohydroxamates 2 with a monoalkyl group delivered 3qk in 79% (dr = 2.3:1) and 3ql in 91% (dr = 3.0:1) yields at elevated temperature. In order to showcase the robustness and practicality of this cycloaddition reaction, we carried out gram-scale experiments. As illustrated in Scheme 4a, 3na and 3pa could be isolated in 1.13 g (90%) and 1.27 g (85%) yields under the optimized conditions. Cleavage of the N−O bond of 3pa could be readily achieved through refluxing with Mo(CO)6 in a MeCN/H2O mixture solvent, and N-unprotected tetrahydro-β-carbolinone 5pa was obtained in 94% yield (Scheme 4b). The nitro group of cycloadduct 3sa could be converted to a primary amine in the presence of sodium borohydride and nickel catalyst. The tert-butoxycarbonyl (Boc) group protected product 6sa was obtained in 67% yield through a two-step route (Scheme 4c).10a Since both lactamization products and iminolactonization products could be detected in some reaction processes, we speculated that an O-addition pathway was likely to

On the basis of the above control experiment and previous reports,6−8,12 a plausible mechanism was proposed as shown in Scheme 5b. Under weakly basic conditions, α-halohydroxamate 2a in situ generates azaoxyallyl cation A. The ensuing cycloaddition of 2-alkenylindole 1 and azaoxyallyl cation A could occur through two possible pathways. In pathway a, the nitrogen atom as nucleophile delivers the N-cyclization product 3. In pathway b, O-addition to the Michael acceptors produces intermediate 4. Eventually, the generated O-alkylated intermediate 4 could rearrange to form tetrahydro-β-carbolinone 3. As observed in our experiments, some O-cyclization product, such as 4da, is stable enough to be isolated under standard conditions. Treatment of such reactions with TFA could 2598

DOI: 10.1021/acs.orglett.7b00914 Org. Lett. 2017, 19, 2596−2599

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Organic Letters

Jeffrey, C. S. Synthesis 2013, 45, 1825. (c) Barnes, K. L.; Koster, A. K.; Jeffrey, C. S. Tetrahedron Lett. 2014, 55, 4690. (d) Acharya, A.; Anumandla, D.; Jeffrey, C. S. J. Am. Chem. Soc. 2015, 137, 14858. (e) Acharya, A.; Eickhoff, J. A.; Chen, K.; Catalano, V. J.; Jeffrey, C. S. Org. Chem. Front. 2016, 3, 330. (7) (a) DiPoto, M. C.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2015, 137, 14861. (b) Ji, W.; Yao, L.; Liao, X. Org. Lett. 2016, 18, 628. (c) Li, C.; Jiang, K.; Ouyang, Q.; Liu, T.-Y.; Chen, Y.-C. Org. Lett. 2016, 18, 2738. (d) An, Y.; Xia, H.; Wu, J. Chem. Commun. 2016, 52, 10415. (e) Ji, W.; Liu, Y. A.; Liao, X. Angew. Chem., Int. Ed. 2016, 55, 13286. (f) Zhao, H.-W.; Zhao, Y.-D.; Liu, Y.-Y.; Zhao, L.-J.; Feng, N.-N.; Pang, H.-L.; Chen, X.-Q.; Song, X.-Q.; Du, J. RSC Adv. 2017, 7, 12916. (g) Lin, W.; Zhan, G.; Shi, M.; Du, W.; Chen, Y. Chin. J. Chem. 2017, DOI: 10.1002/cjoc.201600864. (8) (a) Zhang, K.; Yang, C.; Yao, H.; Lin, A. Org. Lett. 2016, 18, 4618. For similar works, see: (b) Acharya, A.; Montes, K.; Jeffrey, C. S. Org. Lett. 2016, 18, 6082. (c) Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Org. Chem. Front. 2017, 4, 91. (9) For selected examples on the synthesis of indoles and indolines in our group, see: (a) Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X. Org. Lett. 2012, 14, 2066. (b) Jiang, H.; Gao, S.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Adv. Synth. Catal. 2016, 358, 188. (c) Gao, S.; Yang, C.; Huang, Y.; Zhao, L.; Wu, X.; Yao, H.; Lin, A. Org. Biomol. Chem. 2016, 14, 840. (d) Gao, S.; Wu, Z.; Fang, X.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 3906. (e) Guo, S.; Yuan, K.; Gu, M.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 5236. (f) Fang, X.; Gao, S.; Wu, Z.; Yao, H.; Lin, A. Org. Chem. Front. 2017, 4, 292. (10) (a) Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C. C. J.; Merkens, C.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 13562. (b) Talukdar, R.; Tiwari, D. P.; Saha, A.; Ghorai, M. K. Org. Lett. 2014, 16, 3954. (c) Su, T.; Han, X.; Lu, X. Tetrahedron Lett. 2014, 55, 27. (d) Sha, F.; Tao, Y.; Tang, C.-Y.; Zhang, F.; Wu, X.-Y. J. Org. Chem. 2015, 80, 8122. (e) Raji Reddy, C.; Rani Valleti, R.; Dilipkumar, U. Chem. - Eur. J. 2016, 22, 2501. (f) Yang, W.-L.; Li, C.-Y.; Qin, W.-J.; Tang, F.-F.; Yu, X.; Deng, W.-P. ACS Catal. 2016, 6, 5685. (g) Sayyad, M.; Wani, I. A.; Babu, R.; Nanaji, Y.; Ghorai, M. K. J. Org. Chem. 2017, 82, 2364. (11) Crystallographic data for 3pa and 3nj have been deposited with the Cambridge Crystallographic Data Centre as deposition nos. CCDC 1539525 and 1546162. Detailed information can be found in the Supporting Information. (12) For selected examples employing oxyallyl cations, see: (a) Tang, Q.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14, 1922. (b) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C. Chem. Sci. 2013, 4, 3075. (c) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288. (d) Liu, C.; Oblak, E. Z.; Vander Wal, M. N.; Dilger, A. K.; Almstead, D. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 2134. For selected examples employing diazaoxyallyl cations, see: (e) Jeffrey, C. S.; Anumandla, D.; Carson, C. R. Org. Lett. 2012, 14, 5764. (f) Anumandla, D.; Littlefield, R.; Jeffrey, C. S. Org. Lett. 2014, 16, 5112. (g) Anumandla, D.; Acharya, A.; Jeffrey, C. S. Org. Lett. 2016, 18, 476.

accelerate the conversion of O-cyclization product 4 to Ncyclization product 3. In summary, we have realized a novel [3 + 3] cycloaddition reaction between in situ formed azaoxyallyl cations and 2alkenylindoles. This procedure provided an efficient route to synthesize tetrahydro-β-carbolinones in good yields under mild reaction conditions, exhibiting good functional group tolerance and gram-scale ability. Underlining the utility of our reaction, the product could be further converted to some functional molecules with potential bioactivity. Further applications of this methodology to the construction of natural products and pharmaceutical molecules are currently underway in our laboratory.

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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.7b00914. 1 H and 13C NMR spectra for all new compounds (PDF) X-ray crystallographic data for 3pa (CIF) X-ray crystallographic data for 3nj (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hequan Yao: 0000-0003-4865-820X Aijun Lin: 0000-0001-5786-4537 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous financial support from the National Natural Science Foundation of China (NSFC21502232), the Natural Science Foundation of Jiangsu Province (BK20140655), and the Foundation of State Key Laboratory of Natural Medicines (ZZYQ201605) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b00914 Org. Lett. 2017, 19, 2596−2599