Diastereoselective Synthesis of Tetrahydroquinolines via [4 + 2

Letter Cite This: Org. Lett. 2018, 20, 5995−5998

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Diastereoselective Synthesis of Tetrahydroquinolines via [4 + 2] Annulation between in Situ Generated p‑Quinone Methides and Nitroalkenes Junwei Wang,§ Xiang Pan,§ Jian Liu, Lin Zhao, Ying Zhi, Kun Zhao,* and Lihong Hu*

Org. Lett. 2018.20:5995-5998. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/05/18. For personal use only.

Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China S Supporting Information *

ABSTRACT: A formal [4 + 2] annulation reaction between in situ generated p-quinone methides and nitroalkenes via an aza-Michael/1,6-conjugate addition reaction sequence has been developed in which manganese dioxide is used as the oxidant to promote in situ formation of o-tosylaminophenylsubstituted p-QMs. Under mild conditions, this unprecedented cascade reaction readily occurs in good yield, providing straightforward access to a series of 4-aryl-substituted tetrahydroquinolines.

I

n recent years, p-quinone methides (p-QMs) have been considered highly active and versatile intermediates in organic synthesis.1 Since the seminal reports by Fan2 and Jørgensen,3 p-QMs have successfully served as vinylogous Michael acceptors in a large number of 1,6-conjugate addition reactions.4,5 Meanwhile, applications of p-QMs in domino reactions have also been disclosed by several research groups. For instance, annulation reactions based on simple p-QMs and vinyl p-QMs have been reported by Yao, Fan, Zhao, and Waser, allowing the synthesis of spirocyclohexadienones.6 In 2016, Enders and co-workers first demonstrated an organocatalytic domino oxa-Michael/1,6-addtion reaction between o-hydroxyphenyl-substituted p-QMs and isatin-derived enoates,7 and after that the use of hydroxy-substituted p-QMs in [4 + 2]annulation and [4 + 1]-annulation reactions was also extensively investigated.8 Very recently, the Lin and Yao group has reported the annulation reaction of o-alkynylphenyl-substituted p-QMs to access spiro[4,5]deca-6,9-dien-8-ones.9 In spite of the numerous advances mentioned above, there are still unmet challenges in the chemistry of p-quinone methides. First, almost all of the previous reports are based on using presynthesized p-QMs, and reports involving in situ formation of p-QMs are rare (Figure 1a).10,5b The Sun group developed an elegant strategy wherein p-quinone methides could be formed in situ under acid conditions. Second, the installation of a proper nucleophilic group onto the aromatic ring of p-QMs has so far proven elusive. To date, the installed nucleophilic group was limited to the hydroxyl group (Figure 1b). In order to address the aforementioned challenges, we envisioned that the use of a suitable oxidation reagent would convert precursors 1 into p-QM intermediates I, which could immediately undergo a subsequent domino reaction (Figure 1c). In addition, the 4-arylsubstituted tetrahydroquinoline skeleton is a very important structural unit that is ubiquitous in small molecules of medicinal interest,11 exhibiting antitumoral and antibacterial activities (Scheme 1, top).12 We envisaged that tetrahydroquinolines © 2018 American Chemical Society

Figure 1. Reports based on p-quinone methides (a and b) and our in situ generation strategy (c).

3 could be assembled efficiently through the union of compounds 1 and nitroalkenes 2 via a cascade reaction13 containing the in situ formation of p-quinone methides and an aza-Michael/1,6-conjugate addition sequence (Scheme 1, middle).14 Herein, we reported cascade C−H oxidation/azaMichael/1,6-addition reactions for the efficient synthesis of 4-aryl-substituted tetrahydroquinolines. To test the feasibility of our design, we developed a method to synthesize a sires of p-QMs precursor 1a (Scheme 1, bottom).15 With compound 1a in hand, nitrostyrene (2a) was selected as another reaction partner in view of its good reactivity.16 Crucial for the success of this reaction is the use of a suitable oxidant that Received: July 6, 2018 Published: September 20, 2018 5995

DOI: 10.1021/acs.orglett.8b02127 Org. Lett. 2018, 20, 5995−5998

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Organic Letters Scheme 1. Selected Biologically Active Compounds Featuring 4-Aryl-Substituted Tetrahydroquinoline Moieties and Our Reaction Design

Scheme 2. Substrate Scope for the Synthesis of 4-Aryl-Substituted Tetrahydroquinoline.a

Table 1. Reaction Condition Optimization Studiesa

entry

base

oxidant

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Et3N Et3N Et3N Et3N Et3N DBU i Pr2NH Na2CO3 K2CO3 K3PO4 i Pr2NH i Pr2NH i Pr2NH i Pr2NH i Pr2NH i Pr2NH

MnO2 Ag2CO3 Ag2O DDQ PhI(OAc)2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene CH3CN EtOAc CHCl3 Et2O THF

61 49 trace trace trace 75 91 (85)c trace 30 10 50 70 12 60 40 25

a

All reactions were conducted with 1a (0.12 mmol), 2a (0.10 mmol), base (0.2 equiv), and oxidant (2.0 equiv), while 5.0 equiv of MnO2 was used, solvent (1.0 mL), room temperature, 24 h. bDetermined by 1 H NMR using 1,3,5-trimethoxybenzene as an internal standard; dr >20:1. cIsolated yield in parentheses.

All reactions were conducted with 1a (0.12 mmol), 2a (0.10 mmol), Pr2NH (0.2 equiv), MnO2 (5.0 equiv), CH2Cl2 (1.0 mL), room temperature, 24 h. Yields are those of isolated products 3 after column chromatography. The diastereomeric ratio was determined by 1 H NMR and all of them were higher than 20:1. bIsolated yield of reaction on 1 mmol scale.

can promote in situ generation of the p-quinone methides. Therefore, our attention was initially turned to the screening of

oxidants. To our delight, when MnO2 was used as the oxidant, the desired product 3a was afforded in 61% yield and Ag2CO3

a

i

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DOI: 10.1021/acs.orglett.8b02127 Org. Lett. 2018, 20, 5995−5998

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the replacement of the tert-butyl groups by a methyl substituent influenced the efficiency of this reaction, and the corresponding product 3t was formed in 32% yield. Moreover, the structure and relative configuration of tetrahydroquinolines 3a were determined on the basis of HRMS and NMR spectroscopy as well as single-crystal X-ray analysis. One limitation of the existing methodology is that replacing sulfonyl projecting groups with butyloxycarbonyl, benzyloxycarbonyl, or acyl groups failed to deliver the desired products. Finally, we truned our attention to exploring the enantioselective version of this reaction (Scheme 3). Several widely used thiourea and squaramide catalysts17 were examined, and compound 3a was isolated with moderate enantioselectivity (79.5:20.5 er) when thiourea C was employed. In summary, we have developed a formal [4 + 2] annulation reaction between in situ formed p-quinone methides and nitroalkenes. This cascade reaction contains manganese dioxide mediated C−H oxidation for the in situ formation of o-tosylaminophenyl-p-QMs and an aza-Michael/1,6-conjugate addition sequence. Meanwhile, the feasibility for asymmetric access to such tetrahydroquinolines has also been briefly explored by employing chiral bifunctional organocatalyst. Currently, further applications of these o-tosylaminophenyl-p-QMs in domino transformations are ongoing in our laboratory.

provided a comparable yield (Table 1, entries 1 and 2). However, other oxidants (e.g., Ag2O, DDQ, PhI(OAc)2) have proven to be inefficient for this transformation (entries 3−5). Striving for higher efficiency of this reaction, the effect of base was examined, and we found that the organic base iPr2NH performed best, offering 3a in the best yield (Table 1, entries 6−10). Once oxidant and base were found, a series of solvents were further investigated, but the use of other solvents failed to improve the yield (entries 11−16). After establishing the optimal reaction conditions, we sought to investigate the generality of this reaction. First, the scope of the nitroalkenes part was examined (Scheme 2, 3a−l). We were pleased to discover that a wide range of nitroalkenes reacted with 1a to deliver the expected products in 59−85% yields. In detail, substrates bearing electron-neutral (R = H), electron-donating (R = OMe), or electron-withdrawing (R = F, NO2, Cl) groups at the C2 or C4 position of the benzene ring easily underwent this cascade reaction to provide the desired tetrahydroquinolines 3a−f in high yields. In addition, the disubstituted nitroalkenes were suitable substrates, and the corresponding products (3g−j) were synthesized with good results (63−85% yields). Moreover, it turned out that under the optical conditions nitroalkenes containing naphthyl and thienyl moieties also could readily be processed to afford products 3k and 3l in 81% and 68% yields, respectively. Subsequently, the substrate scope of this reaction was evaluated further by varying the reaction partner 1. In general, a series of p-QMs precursors 1, bearing different substituents on the benzene ring or on the nitrogen atom could be smoothly converted into the expected products (3m−s) in 70−78% yields with excellent diastereoselectivities. Furthermore, we found that

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02127. Detailed experimental procedures, characterization of new compounds, and copies of NMR spectra (PDF)

Scheme 3. Attempt to Prepare Chiral 3aa

Accession Codes

CCDC 1852716 (3a) 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.

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AUTHOR INFORMATION

Corresponding Authors

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

Kun Zhao: 0000-0002-5623-4258 Author Contributions §

J.W. and X.P. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant Nos. 81473110, 81773596, and 81703342), the National Natural Science Foundation of Jiangsu Higher Education Institutions (Grant No. 17KJA360004), the Outstanding Scientific and Technological Innovation Team Program of Jiangsu Higher Education Institutions, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

a Reaction conditions: 1a (0.12 mmol), 2a (0.10 mmol), A−E (10 mol %), MnO2 (5.0 equiv), CH2Cl2 (1.0 mL), room temperature, 24 h. Yield of isolated product 3a. The diastereomeric ratio was determined by 1H NMR, and er was determined by HPLC using a chiral stationary phase.

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DOI: 10.1021/acs.orglett.8b02127 Org. Lett. 2018, 20, 5995−5998