Bifunctional Thiourea-Catalyzed Asymmetric Inverse-Electron

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Bifunctional Thiourea-Catalyzed Asymmetric Inverse-ElectronDemand Diels−Alder Reaction of Allyl Ketones and Vinyl 1,2Diketones via Dienolate Intermediate Xinglong Li,†,¶ Xiangwen Kong,†,¶ Shuang Yang,*,† Miao Meng,§ Xinyue Zhan,‡ Min Zeng,‡ and Xinqiang Fang*,†

Org. Lett. Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 03/13/19. For personal use only.

†

State Key Laboratory of Structural Chemistry, and Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, Fuzhou 350100, China ‡ College of Chemistry, Fuzhou University, Fuzhou 350116, China § Department of Chemistry, Jinan University, Guangzhou 510632, China S Supporting Information *

ABSTRACT: Inverse-electron-demand Diels−Alder reactions have attracted intense research focus. However, enolate and enamine are the most employed intermediates to realize such transformation, and the use of dienolate intermediate remains elusive. Reported herein is the asymmetric inverse-electron-demand oxa-Diels−Alder reaction between allyl ketones and alkenyl 1,2-diketones using a bifunctional thiourea catalyst. The reaction afforded various highly functionalized dihydropyrans with good to excellent enantioselectivities under mild conditions, and further novel transformations on the products have also been realized. Herein we report the first enantioselective inverse-electrondemand oxa-Diels−Alder reaction using dienolate as the key intermediate. A bifunctional thiourea catalyst was used, and the reaction afforded a series of enantiopure dihydropyrans with three consecutive stereocenters (Scheme 1e). Compared to Chen’s dienamine chemistry,6 this work tolerated allyl ketones with internal alkene units, and the products were all formed with three stereocenters and different diastereoselectivities, indicating the sharp difference of dienolate chemistry compared to the dienamine one. Noteworthy is that during the preparation of this manuscript, Hong and co-workers reported a [2 + 2] annulation of vinylogous ketone enolates with nitroalkenes.7 Herein we report our results. As shown in Table 1, we selected phenyl allyl ketone 1a and diketone 2a as the model substrates to survey the reaction under a series of amine-thiourea catalysts. We were pleased to find that catalyst A8a−f resulted in the corresponding Diels− Alder reaction product 3a in moderate 65% yield with excellent 95% ee (Table 1, entry 1). The diastereomeric catalyst B8a−f led to a lower yield of 3a with inferior 79% ee (Table 1, entry 2). Then we checked the catalyst C,8g which is derived from

C

atalytic asymmetric inverse-electron-demand Diels− Alder reactions between easily available chemicals enable the concise construction of six-membered rings under mild conditions.1 During the past decade, a series of substrates or intermediates, such as alkenes, enol ethers, indoles, enamines, and enolates have been successfully exploited to undergo such type of annulation reactions, delivering various chiral cyclohexenes or six-membered heterocycles, which enriched the toolbox of organic chemists for further studies (Scheme 1a).2 In sharp contrast, dienolate species have been not used in such type of Diels−Alder reactions, owing to the challenges from the competitive enolate reaction, and the difficulties in realizing high diastereo- and enantioselectivities via a remote control fashion (Scheme 1b).3 On the other side, allyl ketones are a class of important synthons that have been widely used in a range of asymmetric reactions,4 such as α- or γ-selective aldol reactions or Michael additions (Scheme 1c).5 However, Diels−Alder reactions at the β,γ-alkene moiety of allyl ketones are still underdeveloped. In this context, the Chen group reported an elegant highly enantioselective annulation using allyl ketones and cyanosubstituted enones via chiral primary amine-mediated dienamine intermediate (Scheme 1d).6 However, in most cases, the substrates were terminal alkenes and resulted in products with two stereocenters. © XXXX American Chemical Society

Received: January 4, 2019

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DOI: 10.1021/acs.orglett.9b00035 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

did not give a satisfied result (Table 1, entry 4), and catalyst E8i led to 3a with 88% ee (Table 1, entry 5). At this stage, we put our efforts to increase the yield using A catalyst. While increasing the temperature in toluene did not promote the yield (Table 1, entry 6), we surveyed a series of different solvents. The reactions in CH2Cl2 and CHCl3 both gave excellent enantioselectivites, but 3a was obtained in 58% and 60% yields, respectively (Table 1, entries 7 and 8). A diminished ee value was detected when DCE was used as the solvent (Table 1, entry 9), and THF and 1,4-dioxane retarded the reaction significantly (Table 1, entries 10 and 11). Delightfully, we found that Et2O was a good choice of solvent considering both the yield and ee value of 3a (Table 1, entry 12). Further variations of reaction parameters such as increasing the amount of 1a or the catalyst loading did not show better results (Table 1, entries 13 and 14), and lowering the reaction temperature afforded less yield of 3a (Table 1, entry 15). For comparison, the reaction cannot occur without the presence of catalyst (Table 1, entry 16). Noteworthy is that in all cases, 3a was formed as a single diastereoisomer. Having obtained the optimal conditions, we then commenced to test the generality and limitation of this reaction. First, we tested a series of substrates with aryl substituents. As demonstrated in Scheme 2, we found that the introduction of both electron-donating and electron-withdrawing groups into the phenyl rings at the allyl moieties had little effect on the results, delivering the corresponding dihydropyrans with excellent enantioselectivities (Scheme 2, 3b and 3c). Then substrates with methyl or chloro substituents at the phenyl ketone units were also examined and no obvious influence on the outcomes was detected (Scheme 2, 3d and 3e). Furthermore, we checked the scope of vinyl diketone substrates, and the results showed that variations on the vinyl aryl rings were tolerated, despite the different electronic properties and substitution patterns (Scheme 2, 3f, 3g, and 3h). The replacement of a vinyl phenyl group with vinyl furan ring did not retard the reaction, affording 3i in 97% ee (Scheme 2, 3i). The introduction of 4-Cl or 2-OMe groups into the phenyl ketone sections of diketone substrates resulted in no erosion of both yields and ee values (Scheme 2, 3j and 3k). Additionally, variations on both aryl rings of allyl ketones or vinyl diketones showed limited impact on the results (Scheme 2, 3l and 3m), and the introduction of three or four different substituents into the phenyl rings of the substrates also proved compatible (Scheme 2, 3n and 3o). The absolute configuration of the annulation products was determined via the single crystal X-ray structure analysis of 3e, and other products were assigned by analogy (Figure 1). Having tested a range of substrates with differently substituted aryl rings, we then turned our attention to allyl ketones and vinyl diketones with aliphatic groups. Allyl methyl ketone was observed to undergo the annulation reaction under the standard conditions, albeit with lower yield and enantioselectivity (Scheme 3, 3p). However, tBu/allyl ketone worked well to produce 3q with 90% ee (Scheme 3, 3q). Methyl-substituted vinyl diketone was also viable, and the corresponding product 3r was generated in moderate yield with 95% ee (Scheme 3, 3r). The replacement of a phenyl group at the ketone moiety of diketone substrate proved possible, with excellent yield and enantioselectivity obtained (Scheme 3, 3s). Moreover, simultaneous introduction of a methyl group into both ketone units of the two reaction partners afforded 3t in 45% yield with 81% ee (Scheme 3, 3t).

Scheme 1. Research Background

Table 1. Reaction Condition Optimizationa

entry

catalyst

solvent, temp

yield (%)

ee (%)

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

A B C D E A A A A A A A A A A none

toluene, rt toluene, rt toluene, rt toluene, rt toluene, rt toluene, 30 °C CH2Cl2, rt CHCl3, rt DCE, rt THF, rt 1,4-dioxane, rt Et2O, rt Et2O, rt Et2O, rt Et2O, 0 °C Et2O, rt

65 50 45 33 65 55 58 60 40 trace trace 84 70 81 60 0

95 79 80 11 88 94 97 96 79

99 94 98 96

a Reaction conditions: 1a (0.13 mmol), 2a (0.1 mmol), catalyst (10 mol %), solvent (1.0 mL), 20 h, under argon protection. All isolated yields were based on 2a; dr was determined via the 1H NMR analysis of the reaction mixtures; ee values were determined via HPLC analysis on a chiral stationary phase. b1a (0.15 mmol) was used. c Catalyst (20 mol %) was used.

cyclobutene-1,2-dione, and a similar outcome with that from catalyst B was obtained (Table 1, entry 3). Tertiary amine D8h B


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Organic Letters Scheme 2. Scope of Substrates with Aryl Substituentsa

Scheme 3. Scope of Substrates with Aliphatic Substituentsa

a

All reactions were run on a 0.1 mmol scale, 20 h; all yields were determined by isolating desired products by column chromatography; dr was determined via the 1H NMR analysis of the crude reaction mixtures; ee values were determined via HPLC analysis on a chiral stationary phase. b4.2:1 dr. c2.7:1 dr.

Scheme 4. Evaluation of Other Enone Substrates and Control Experiment

a

All reactions were run on a 0.1 mmol scale, 20 h; all yields were determined by isolating desired products by column chromatography; dr was determined via the 1H NMR analysis of the crude reaction mixtures; ee values were determined via HPLC analysis on a chiral stationary phase.

conditions used by Chen and co-workers,6 but no reaction occurred in our reaction system, indicating that different activation mode was involved in this work (Scheme 4, eq 2). Furthermore, we also surveyed the reaction of (E)-3-methyl1,4-diphenylbut-3-en-1-one (1aa) or 1-phenylbut-3-en-1-one (1ab) with diketone 2a, but no reaction happened and only isomerizations of 1aa and 1ab were detected (Scheme 4, eq 3). To our pleasure, enone 1ac could undergo annulation with 2a, delivering 3a in 40% yield without affecting the stereoselectivities (Scheme 4, eq 4), and the optimal conditions can

Figure 1. Single crystal X-ray structure of 3e.

Similarly, 3u was also formed with excellent 90% ee (Scheme 3, 3u). The aliphatic allylic ketone could also afford the corresponding product 3v but in 35% yield with 2.7:1 dr and 60% ee (Scheme 3, 3v). No reaction between 1a and chalcone 2aa was observed under the standard conditions, showing the relatively higher reactivity of 2a (Scheme 4, eq 1). We also tested the optimal C


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Organic Letters also facilitate the reaction between allyl ketone 1a and β,γunsaturated α-ketoester 2ab, furnishing 3ab with excellent 98% ee (Scheme 4, eq 5). The diverse functional groups within the products enable facile and valuable further transformations. For instance, the oxidation of 3a by m-CPBA allowed access to substituted tetrahydropyran 4a in moderate yield,9 and the following reaction using DMP/NaHCO3 afforded fully substituted lactone 5a in 60% yield with 95% ee, probably through a rearrangement.10 Moreover, the selective reduction of the unsaturated ketone moiety of 3a under copper catalysis using PhSiH3 led to the formation of 6a with 90% ee (Scheme 5).

ORCID

Xinqiang Fang: 0000-0001-8217-7106 Author Contributions ¶

X.L. and X.K. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Natural Science Foundation of China (Grants 21871260 and 21502192), the strategic priority research program of the Chinese Academy of Sciences (XDB20000000), the Chinese Recruitment Program of Global Experts, Fujian Natural Science Foundation (2018J05035), and China Postdoctoral Science Foundation (2018M630734).

Scheme 5. Derivatizations of Product 3a

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(1) For selected reviews, see (a) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res. 2012, 45, 1491−1500. (b) Pellissier, H. Tetrahedron 2009, 65, 2839−2877. (c) Xie, M.; Lin, L.; Feng, X. Chem. Rec. 2017, 17, 1184−1202. (2) For selected examples of catalytic asymmetric inverse-electrondemand hetero-Diels−Alder reactions, see (a) Wang, B.; Feng, X. M.; Huang, Y. Z.; Liu, H.; Cui, X.; Jiang, Y. Z. J. Org. Chem. 2002, 67, 2175−2182. (b) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y. Z.; Feng, X. M.; Zhang, G. L. Org. Lett. 2004, 6, 2185−2188. (c) Lv, H.; Chen, X.-Y.; Sun, L.-H.; Ye, S. J. Org. Chem. 2010, 75, 6973−6976. (d) Zhang, Y.R.; Lv, H.; Zhou, D.; Ye, S. Chem. - Eur. J. 2008, 14, 8473−8476. (e) Wang, F.; Li, Z.; Wang, J.; Li, X.; Cheng, J.-P. J. Org. Chem. 2015, 80, 5279−5286. (f) Shang, D. J.; Xin, J. G.; Liu, Y. L.; Zhou, X.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2008, 73, 630−637. (g) Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng, X. M. Angew. Chem., Int. Ed. 2008, 47, 1308−1311. (h) Lin, L. L.; Chen, Z. L.; Yang, X.; Liu, X. H.; Feng, X. M. Org. Lett. 2008, 10, 1311−1314. (i) Lin, L. L.; Kuang, Y. L.; Liu, X. H.; Feng, X. M. Org. Lett. 2011, 13, 3868−3871. (j) Eschenbrenner-Lux, V.; Küchler, P.; Ziegler, S.; Kumar, K.; Waldmann, H. Angew. Chem., Int. Ed. 2014, 53, 2134−2137. (k) Zheng, H. F.; Liu, X. H.; Xu, C. R.; Xia, Y.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2015, 54, 10958−10962. (3) For reports using α,β-unsaturated aldehyde to realize Diels− Alder reaction via remote activation, see (a) Albrecht, Ł.; Dickmeiss, G.; Weise, C. F.; Rodríguez-Escrich, C.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2012, 51, 13109−13113. (b) Weise, C. F.; Lauridsen, V. H.; Rambo, R. S.; Iversen, E. H.; Olsen, M.-L.; Jørgensen, K. A. J. Org. Chem. 2014, 79, 3537−3546. (4) For selected reviews, see (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (b) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682−4698. (c) Pansare, S. V.; Paul, E. K. Chem. - Eur. J. 2011, 17, 8770−8779. (d) Bisai, V. Synthesis 2012, 44, 1453−1463. (e) Yin, Y.; Jiang, Z. ChemCatChem 2017, 9, 4306−4318. (f) Chinchilla, R.; Nájera, C. Chem. Rev. 2000, 100, 1891−1928. (g) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076−3154. (h) Schneider, C.; Abels, F. Org. Biomol. Chem. 2014, 12, 3531−3543. (5) (a) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Angew. Chem., Int. Ed. 2013, 52, 6666−6670. (b) Bai, X.; Zeng, G.; Shao, T.; Jiang, Z. Angew. Chem., Int. Ed. 2017, 56, 3684−3688. (c) Jing, Z.; Bai, X.; Chen, W.; Zhang, G.; Zhu, B.; Jiang, Z. Org. Lett. 2016, 18, 260−263. (d) Gu, Y.; Wang, Y.; Yu, T.Y.; Liang, Y.-M.; Xu, P.-F. Angew. Chem., Int. Ed. 2014, 53, 14128− 14131. (e) Zhan, G.; He, Q.; Yuan, X.; Chen, Y.-C. Org. Lett. 2014, 16, 6000−6003. (f) Jia, Z.-L.; Wang, Y.; Zhao, C.-G.; Zhang, X.-H.; Xu, P.-F. Org. Lett. 2017, 19, 2130−2133. (g) Trenner, J.; Depken, C.; Weber, T.; Breder, A. Angew. Chem., Int. Ed. 2013, 52, 8952−8956. (h) Tong, G.; Zhu, B.; Lee, R.; Yang, W.; Tan, D.; Yang, C.; Han, Z.; Yan, L.; Huang, K.-W.; Jiang, Z. J. Org. Chem. 2013, 78, 5067−5072.

In conclusion, we have developed the first dienolatemediated asymmetric inverse-electron-demand oxa-Diels− Alder reaction using allyl ketones and alkenyl 1,2-diketones. A cinchona alkaloid-based thiourea catalyst was employed to facilitate the process. Substrates with both aromatic and aliphatic substituents were tolerated, affording a variety of dihydropyrans bearing three consecutive stereocenters with good to excellent enantioselectivities. Different diastereoselectivity of the cyclization reaction was observed compared to the known report. Furthermore, valuable compounds with different skeletons were delivered through simple further transformations on the products.

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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.9b00035. Experimental procedures, spectroscopic data for all new compounds, and crystallographic data for 3e and 5a (PDF) Accession Codes

CCDC 1858718 and 1873480 contain 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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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

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


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Bifunctional Thiourea-Catalyzed Asymmetric Inverse-Electron

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