Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium/N‑Heterocyclic Carbene (NHC)-Catalyzed Asymmetric [3 + 2] Cycloaddition Reaction of Vinyl Epoxides with Allenic Amides Wan-Ying Wang,†,∥ Jing-Yu Wu,†,∥ Qing-Rong Liu,†,∥ Xiu-Yan Liu,† Chang-Hua Ding,*,†,‡ and Xue-Long Hou*,†,§
Downloaded via UNIV OF SOUTH DAKOTA on August 6, 2018 at 15:30:52 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China § Shanghai−Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China S Supporting Information *
ABSTRACT: Allenic amides are successfully developed as dipolarophiles to react with vinyl epoxides under Pd-catalysis. The chiral NHC showed its unique role as the ligand in this asymmetric [3 + 2] cycloaddition. Chiral tetrahydrofurans bearing three functional groups (monosubstituted alkene, tetrasubstituted enolether, and amide) and vicinal tertiary and quaternary stereocenters were obtained in high yields with high diastereo- and enantioselectivities. Upon study, it was found that α-allenic amides could serve as the reactants to react with vinyl epoxides in the presence of a Pd-catalyst when a chiral N-heterocyclic carbene (NHC) was used as the ligand, affording the corresponding 2-methylene tetrahydrofurans as the cycloadducts. In this letter, we report our preliminary study of this Pd/NHC-catalyzed asymmetric [3 + 2] cycloaddition of vinyl epoxides with α-allenic amides. We commenced our study with the reaction of α-allenic amide 1a and vinyl epoxide 2a in the presence of Pd(PPh3)4 in THF, which afforded the cycloadduct 3a in 69% yield (entry 1, Table 1). Preliminary examination of the ligand effect on the reaction indicated that bidentate ligands such as (R)-BINAP, (S)-tert-BuPHOX, and 2,2′-bipyridine proved to be inactive for the cycloaddition reaction, while the use of a monodentate chiral phosphine L112 afforded product 3a in 20% yield with 35% ee (entry 2). However, further studies with ligand L1 under different conditions did not improve the yield and enantioselectivity of product 3a. Considering that chiral NHC has emerged as a type of promising monodentate chiral ligand for transition-metal-catalyzed asymmetric reactions,13 several chiral NHC precursors were investigated. The utility of NHC precursor L214 furnished product 3a in 18% yield with 25% enantio excess (entry 3). The use of L315 resulted in a 17%
A
transition-metal-catalyzed intermolecular [3 + 2] cycloaddition reaction of vinyl epoxides and electron-deficient alkenes as an efficient approach to synthesize substituted tetrahydrofurans has received much attention from synthetic chemists.1 Early examples focused on the use of activated alkenes bearing two activators as the reactant in the presence of an achiral ligand.2 Recently, the catalytic asymmetric version of the reaction has witnessed rapid advancements. To date, not only the electron-deficient alkenes with two activators3 but also some other activated alkenes and their analogues, such as nitro alkenes,4 p-quinone methides,5 α,β-unsaturated ketones,6 and nitro substituted heteroaromatics,7 have been used successfully in the reaction, affording the corresponding cycloadducts with high diastereo- and enantioselectivities.8,9 Although significant achievements have been made, the dipolarophiles used in the reactions have still been limited to those electron-deficient alkenes and some heteroatom-containing cumulenes; thus, the development of a new kind of moiety for asymmetric [3 + 2] cycloaddition reaction remains to be explored. In the course of our research on this transition-metal-catalyzed asymmetric cycloaddition,4,6,10 we have realized the Pd-catalyzed asymmetric [3 + 2] cycloaddition of vinyl epoxides by using nitoralkenes4 and α,β-unsaturated ketones.6 We envisioned that because allenes can be attacked by the nucleophiles,11 they might be used as the electron-deficient alkenes. The exo-cyclic double bond of the resulting product should afford an additional functional group useful in further transformation. © XXXX American Chemical Society
Received: June 17, 2018
A
DOI: 10.1021/acs.orglett.8b01886 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
After establishing the optimized reaction conditions, the substrate scope of the Pd-catalyzed cycloaddition reaction of vinyl epoxide 2a with different α-allenic amides 1 was explored (Scheme 1). Replacing the methyl group of α-allenic amide 1a
Table 1. Impact of the Reaction Parameters on the Pd-Catalyzed [3 + 2] Cycloaddition Reaction of α-Allenic Amide 1a and Vinyl Epoxide 2aa
Scheme 1. Substrate Scope of the Pd/NHC-Catalyzed [3 + 2] Cycloaddition Reaction of α-Allenic Amides 1 and Vinyl Epoxide 2aa
entry
L
solvent
t (°C)
yield (%)b
drc
eed
e
− L1 L2 L3 L4 L5 L6 L7 L8 L9 L9 L9 L9 L9 L9 L9 L9
THF THF THF THF THF THF THF THF THF THF DME TBME dioxane toluene toluene toluene THF
30 30 30 30 30 30 30 30 30 30 30 30 30 30 50 15 15
69 20 18 17 29 37 45 70 61 90 63 92 14 91 55 93 89
− − − − − 3/1 20/1 10/1 20/1 20/1 20/1 20/1 20/1 20/1 20/1 20/1 20/1
− 35 25 45 0 37 70 70 14 90 90 90 88 91 89 93 91
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
a Molar ratio of 1/2a/t-BuOK/[Pd(η3-C3H5)Cl]2/L9 = 100/500/20/ 5/11; THF as solvent at 30 °C for products 3h−3m; Isolated yield; dr determined by 1H NMR; ee determined by chiral HPLC.
a
Molar ratio of 1a/2a/t-BuOK/[Pd(η3-C3H5)Cl]2/ligand = 100/ 500/20/5/11. bIsolated yield. cDetermined by 1H NMR. dDetermined by chiral HPLC. e5.0 mol % Pd(PPh3)4 used as the catalyst.
with ethyl led to the corresponding product 3b in 62% yield with 20/1 dr and 86% ee (3b vs 3c), indicating that the steric hindrance of the substituents of α-allenic amides 1 may exert significant impact on the reaction. α-Allenic amides 1 bearing six- and seven-membered ring substituents were well-tolerated and provided the corresponding products in excellent yields with excellent diastereo- and enantioselectivities, with a yield of 95%, dr of 20/1, and ee of 93% for 3c, and a yield of 97%, dr of 20/1, and ee of 90% for 3d. However, five-membered ring substituted α-allenic amide 1e afforded the corresponding product 3e in high yield (81%) and dr (20/1) but with low enantioselectivity (43%). Notably, the reaction of 4-oxocyclohexyl substituted α-allenic amide 1f proceeded efficiently also to afford product 3f in 77% yield with 20/1 dr and 92% ee, demonstrating the good functional group tolerance of the protocol and the beneficial introduction of an additional carbonyl group in the product for further derivatization. Also, a heterocycloalkyl substituted α-allenic amide was a competent reactant for this cycloaddition reaction leading to product 3g in quantitative yield with excellent stereoselectivities. Additionally, α-allenic amides 1 with an aryl group having methyl, methoxyl, and halogen substituents at the p- or m-positions reacted smoothly with vinyl epoxide 2a to furnish cycloaddition products 3h−l (49−64% yields 20/1 dr; >90% ee). However, the reaction of α-allenic amide with an ortho-fluorine
yield with 45% ee (entry 4), while racemic product 3a was afforded in the case of using L416 (entry 5). Product 3a was obtained in 37% yield with 3:1 dr and 37% ee when a commercially available NHC ligand precursor L517 was used (entry 6). Switching the counteranion of L5 from iodide to tetrafluoroborate led to a higher yield of 3a (45%) with significantly improved diastereo- and enantioselectivity (20/1 dr; 70% ee; entry 7 vs entry 6). The yield of 3a increased further to 70% by using L7 bearing a triflate as the counteranion (entry 8). Then two NHC precursors L8 and L913d with a triflate anion were screened (entries 9 and 10). Delightfully, employing L9 as the NHC precursor provided 3a in 90% yield with a dr of 20/1 and ee value of 90% (entry 10). Of the solvents screened (entries 11−14), tert-butyl methyl ether (TBME) and toluene delivered almost the same yield as well as diastereo- and enantioselectivities as THF (entries 12 and 14 vs entry 10), while DME and dioxane gave low yields (entries 11 and 13). Elevating the reaction temperature from 30 to 50 °C was not beneficial for the yield of 3a (entry 15 vs entry 14), while lowering the temperature to 15 °C resulted in the ee value of 3a increasing slightly to 93% (entry 16) and 91% (entry 17), respectively (for more optimization of reaction conditions, see Supporting Information (SI)). B
DOI: 10.1021/acs.orglett.8b01886 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters substituent on the phenyl ring led to product 3m with a dramatic decrease of diastereoselectivity (4/1 dr), indicating again that the reaction was significantly impacted by the steric effect of the substituents. The substituents on the amide nitrogen atom of α-allenic amides 1 could be a methyl and substituted aryl group, as exemplified with the products (3n and 3o). No kinetic resolution phenomenon was observed for the cycloaddition of allene 1l and vinyl epoxide 2a as the product 3l was obtained in 50% yield with 20/1 dr and 90% ee while allene 1l was recovered in 35% yield with 0% ee by stopping the reaction after 2 days. The cis stereochemistry between 3-amide and 4-vinyl groups of products 3h and 3i has been assigned on the basis of 1H NMR NOE experiments. The configuration of the tetrasubstituted enol ether group of products 3h and 3i was also determined through 1H NMR NOE experiments (for details, see SI).
■
Screening data, experimental procedures, NMR and HPLC spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Chang-Hua Ding: 0000-0002-4628-4016 Xue-Long Hou: 0000-0003-4396-3184 Author Contributions ∥
W.-Y.W., J.-Y.W., and Q.-R.L. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Financial support was received from the National Natural Science Foundation of China (21772215, 21472214, and 21532010), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20030100), the Chinese Academy of Sciences, the Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong.
■
Two vinyl epoxides 2b and 2c were subjected to a reaction with α-allenic amide 1a (eqs 1 and 2). Although the diastereoand enantioselectivities remained high, the yield decreased dramatically due to the low conversion of α-allenic amide 1a. Under the optimized reaction conditions, no reaction was observed or allenic amides were decomposed when 4-unsubstituted, 4-monosubstituted, 4,4-diphenyl, 1,4,4-trisubstituted, and N,N-diethyl allenic amides 1, and α-allenic ester were used as the reactants (for details, see SI). 2-(But-1-en2-yl)oxirane and vinyl aziridine also proved to be unreactive for the cycloaddition (for details, see SI). The beneficiality of the presence of the exocyclic double bond was demonstrated by the oxidation of product 3a with m-CPBA, which selectively converted the exocyclic tetra-substituted enol ether into the corresponding epoxide 4 in 68% yield (eq 3). In summary, we have successfully revealed that α-allenic amides are suitable dipolarophiles to react with vinyl epoxides under Pd-catalysis, and the chiral NHC is a unique ligand in this asymmetric [3 + 2] cycloaddition. Chiral tetrahydrofurans bearing three functional groups (monosubstituted alkene, tetrasubstituted enolether, and amide) and vicinal tertiary and quaternary stereocenters were obtained in high yields with high diastereo- and enantioselectivities. Current efforts are directed toward the extension of the methods to other types of substrates.
■
REFERENCES
(1) (a) Olofsson, B.; Somfai, P. Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006; pp 315−347. (b) Pineschi, M.; Bertolini, F.; Di Bussolo, V.; Crotti, P. Curr. Org. Synth. 2009, 6, 290−324. (c) He, J.; Ling, J.; Chiu, P. Chem. Rev. 2014, 114, 8037−8128. (d) De, N.; Yoo, E. ACS Catal. 2018, 8, 48−58. (2) (a) Shim, J.-G.; Yamamoto, Y. J. Org. Chem. 1998, 63, 3067− 3071. (b) Sekido, M.; Aoyagi, K.; Nakamura, H.; Kabuto, C.; Yamamoto, Y. J. Org. Chem. 2001, 66, 7142−7147. (c) Sako, S.; Kurahashi, T.; Matsubara, S. Chem. Lett. 2011, 40, 808−809. (3) Khan, A.; Yang, L.; Xu, J.; Jin, L. Y.; Zhang, Y. J. Angew. Chem., Int. Ed. 2014, 53, 11257−11260. (4) Wu, W.-Q.; Ding, C.-H.; Hou, X.-L. Synlett 2012, 23, 1035− 1038. (5) Ma, C.; Huang, Y.; Zhao, Y. ACS Catal. 2016, 6, 6408−6412. (6) Suo, J.-J.; Du, J.; Liu, Q.-R.; Chen, D.; Ding, C.-H.; Peng, Q.; Hou, X.-L. Org. Lett. 2017, 19, 6658−6661. (7) (a) Cheng, Q.; Zhang, H.-J.; Yue, W.-J.; You, S.-L. Chem. 2017, 3, 428−436. (b) Cheng, Q.; Zhang, F.; Cai, Y.; Guo, Y.-L.; You, S.-L. Angew. Chem., Int. Ed. 2018, 57, 2134−2138. (8) Examples of [3 + 2] cycloaddition of vinyl epoxides and their analogues with imines, aldehydes, and isocyanates: (a) Liu, Z.; Feng, X.; Du, H. Org. Lett. 2012, 14, 3154−3157. (b) Khan, A.; Zheng, R.; Kan, Y.; Ye, J.; Xing, J.; Zhang, Y. J. Angew. Chem., Int. Ed. 2014, 53, 6439−6442. (c) Yang, L.; Khan, A.; Zheng, R.; Jin, L. Y.; Zhang, Y. J. Org. Lett. 2015, 17, 6230−6233. (d) Khan, A.; Zhang, Y. J. Synlett 2015, 26, 853−860. (e) Khan, A.; Xing, J.; Zhao, J.; Kan, Y.; Zhang, W.; Zhang, Y. Chem. - Eur. J. 2015, 21, 120−124. (9) Examples for [5 + 4] and [4 + 2] cycloaddition: (a) Yang, L.-C.; Rong, Z.-Q.; Wang, Y.-N.; Tan, Z. Y.; Wang, M.; Zhao, Y. Angew. Chem., Int. Ed. 2017, 56, 2927−2931. (b) Rong, Z.-Q.; Yang, L.-C.; Liu, S.; Yu, Z.; Wang, Y.-N.; Tan, Z. Y.; Huang, R.-Z.; Lan, Y.; Zhao, Y. J. Am. Chem. Soc. 2017, 139, 15304−15307. (c) Yang, L.-C.; Tan, Z. Y.; Rong, Z.-Q.; Liu, R.; Wang, Y.-N.; Zhao, Y. Angew. Chem., Int. Ed. 2018, 57, 7860−7864. (10) (a) Xu, C.-F.; Zheng, B.-H.; Suo, J.-J.; Ding, C.-H.; Hou, X.-L. Angew. Chem., Int. Ed. 2015, 54, 1604−1607. (b) Suo, J.-J.; Liu, W.; Du, J.; Ding, C.-H.; Hou, X.-L. Chem. - Asian J. 2018, 13, 959−963. (11) (a) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2. (b) Yu, S.; Ma, S.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01886. C
DOI: 10.1021/acs.orglett.8b01886 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Angew. Chem., Int. Ed. 2012, 51, 3074−3112. (c) Ye, J.; Ma, S. Acc. Chem. Res. 2014, 47, 989−1000. (d) Alonso, J. M.; Quirós, M. a. T.; Muñoz, M. a. P. Org. Chem. Front. 2016, 3, 1186−1204. (12) Uozumi, Y.; Suzuki, N.; Ogiwara, A.; Hayashi, T. Tetrahedron 1994, 50, 4293−4302. (13) Reviews: (a) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619−636. (b) Janssen-Muller, D.; Schlepphorst, C.; Glorius, F. Chem. Soc. Rev. 2017, 46, 4845−4854. Selected examples: (c) Kumar, R.; Tokura, H.; Nishimura, A.; Mori, T.; Hoshimoto, Y.; Ohashi, M.; Ogoshi, S. Org. Lett. 2015, 17, 6018− 6021. (d) Wang, H.; Lu, G.; Sormunen, G. J.; Malik, H. A.; Liu, P.; Montgomery, J. J. Am. Chem. Soc. 2017, 139, 9317−9324. (e) Cai, Y.; Yang, X.-T.; Zhang, S.-Q.; Li, F.; Li, Y.-Q.; Ruan, L.-X.; Hong, X.; Shi, S.-L. Angew. Chem., Int. Ed. 2018, 57, 1376−1380. (f) Diesel, J.; Finogenova, A. M.; Cramer, N. J. Am. Chem. Soc. 2018, 140, 4489− 4493. (14) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett. 2009, 11, 3934−3937. (15) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704−2705. (16) Matsumoto, Y.; Yamada, K.-I.; Tomioka, K. J. Org. Chem. 2008, 73, 4578−4581. (17) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, P. Angew. Chem., Int. Ed. 2011, 50, 7438−7441.
D
DOI: 10.1021/acs.orglett.8b01886 Org. Lett. XXXX, XXX, XXX−XXX
