Highly Enantioselective [5 + 2] Annulations through Cooperative N

Communication Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Highly Enantioselective [5 + 2] Annulations through Cooperative N‑Heterocyclic Carbene (NHC) Organocatalysis and Palladium Catalysis Santanu Singha, Tuhin Patra, Constantin G. Daniliuc, and Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraβe 40, 48149 Münster, Germany S Supporting Information *

Scheme 1. NHC/Pd Dual Catalytic Enantioselective Annulation Strategy

ABSTRACT: The highly enantioselective [5 + 2] annulation of enals with vinylethylene carbonates through a cooperative N-heterocyclic carbene (NHC)/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the NHC organocatalyst to the active Pd catalyst. The complementary and matched combination of the chiral NHC catalyst and chiral phosphine ligand promotes high levels of both reactivity and enantioselectivity (mostly ≥99% ee). N-Heterocyclic carbene (NHC) organocatalysis is a powerful tool for the construction of complex chiral molecules from simple and readily available starting materials.1 However, NHC organocatalysis is typically limited to established substrate classes and reaction partners. The incorporation of a second cooperative catalyst could alleviate this limitation by enabling a diverse range of new reaction partners to be used and thus to provide access to fundamentally new transformations. Although there have been reports using NHCs with a second activation mode to promote elusive reactivity,2 most of these studies are limited to the incorporation of a cooperative Lewis acid3 or Brønsted acid catalyst.4 The use of a transition metal (TM) with an NHC organocatalysis in a cooperative fashion is still very rare,5 primarily because the organocatalyst carbene has a strong affinity to bind with the TM,6 which typically results in the destruction of their desired individual reactivity. With this taken into consideration, the design of a dual catalytic system where both TM catalyst and NHC catalyst will work in synergy remains a formidable challenge. Recent pioneering studies from the group of Scheidt7 to synthesize allylated dihydrocoumarins in an intramolecular and racemic fashion (Scheme 1A), followed by the report from our group on enantioselective and intermolecular [4 + 3] annulation reactions8 (Scheme 1B), are among the very first examples of dual catalytic systems involving a palladium catalyst and an NHC organocatalyst. Detailed mechanistic studies on the latter system revealed that the NHC, besides its role as an organocatalyst, also fortuitously acts as a ligand on the active metal catalyst (formation of a mixed ligand metal complex, Scheme 1B).8b In this context, we questioned whether it was possible to develop a dual catalytic system where the ligation of NHC to the TM is prevented and the NHC is only operative in the organocatalytic cycle. This would significantly aid the development of new enantioselective transformations by allowing the fine-tuning of both catalytic systems. Based on this strategy, we report herein the first © XXXX American Chemical Society

example of such NHC/TM cooperativity to generate challenging ε-caprolactones in a highly enantioselective fashion. To date, synthesis of seven-membered rings or higher, especially in an enantioselective fashion,9 is a considerable challenge in organic synthesis due to both unfavorable entropy effects and transannular interactions.10 Here, we envisioned that an annulation between a transition metal activated electrophile and an NHC bound nucleophile would enable the synthesis of these challenging products with high levels of enantioselectivity. To validate this idea, we sought to use a substituted vinylethylene carbonate (VEC) for the formation of an electrophilic π-allyl-palladium intermediate (I) upon Pdmediated decarboxylation.11,12 Meanwhile, an α,β-unsaturated aldehyde in combination with NHC would form a homoenolate (II) or enolate intermediate (III),13 which could nucleophilically attack this π-allyl-palladium species (I) and subsequently cyclize to form either an eight- or seven-membered lactone product respectively (Scheme 1C). Received: January 23, 2018 Published: February 22, 2018 A

DOI: 10.1021/jacs.8b00868 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

Table 2. Scope of [5 + 2] Annulation Reactiona

Our studies began by the reaction of phenyl vinylethylene carbonate (1a), trans-cinnamaldehyde (2a) with NHC precatalyst 4a and monodentate PPh3, from which no product was detected (Table 1, entry 1). Realizing that NHC 4a could Table 1. Reaction Optimizationa

entry precat. 1e,f 2e 3e 4 5 6 7

4a 4a 4a 4a 4a 4a 4b

phosphine

base

yield 3aa (%)b

ratio 3aa:5aac

ee (%)d

PPh3 L1 L2 L2 L3 L3 L3

K2CO3 K2CO3 K2CO3 NMPi NMPi DBU NMPi

− 20 55 70 76 − 18

− 1:2 6:1 14:1 22:1 − >20:1

− 98 >99 >99 >99 − 94

a

Conditions: 1a (0.1 mmol), 2a (0.15 mmol). bYields determined by H NMR using CH2Br2 as internal standard. cDetermined by 1H NMR. dDetermined by HPLC using a chiral column. NMPi = NMethylpiperidine. rt = room temperature. eEt2O as solvent. f12 mol % PPh3. 1

easily compete with the weakly coordinating PPh3 for ligation to Pd,7 we switched to a more strongly chelating bidentate ligand L1, which resulted in the formation of the desired [5 + 2] annulation product (3aa) in 20% yield and with excellent ee (entry 2). Interestingly, as 3aa also contains an allylic carboxylate linkage, the γ-lactone 5aa (cis/trans = 1.4:1) was also formed under the reaction conditions via a Pd catalyzed allylic rearrangement of 3aa. In order to suppress the formation of 5aa, a variety of other bidentate phosphine ligands were examined and (R)-BINAP (L2) was found to improve the ratio of 3aa:5aa to 6:1, increasing the yield of 3aa to 55% (>99% ee). Furthermore, the use of the weak amine base N-methylpiperidine and toluene as solvent improved the yield of 3aa to 70% (entry 4). Finally, using more bulky and electron-rich ligand (R)-Tol-BINAP (L3) afforded the desired product 3aa in 76% yield (entry 5). The use of stronger bases, such as DBU (known to favor homoenolate reactivity),13f completely inhibited the reaction (no trace of seven- or eight-membered lactone) (entry 6). Interestingly, when the reaction was carried out with achiral NHC 4b and chiral phosphine L3, the product 3aa was formed in 18% yield but with very good enantioselectivity (94% ee, entry 7). To the best of our knowledge, this is the first example of a highly enantioselective reaction performed using an achiral NHC in combination with a second chiral catalyst.3a,4a With the optimized conditions in hand, the scope with respect to the VEC was examined. A range of VECs containing electron-donating as well as electron-withdrawing groups at the para-position of the phenyl ring (R2) performed well in this reaction to deliver the corresponding annulated products (Table 2, 3aa−3ia) in good yield and with excellent

a Conditions: 1 (0.2 mmol), 2 (0.3 mmol), Toluene (0.1 M), rt, 10− 12 h (ratio of 3:5cis after isolation mentioned in parentheses as cis isomer of γ-lactone formed an inseparable mixture with sevenmembered lactone product). bAt 15 °C for 15 h. cEnal 2e (0.8 mmol).

enantioselectivity (mostly >99% ee). The absolute configuration of 3aa was unambiguously confirmed by single-crystal X-ray diffraction analysis. Substitution at the meta-position as well as dioxolane fused phenyl ring were well tolerated (3ja and 3ka). Polyaromatic and heteroaryl substituted VECs were also compatible (3la−3oa). A styryl substituted VEC was used to afford lactone (3pa) in 67% yield and with >99% ee. Notably, secondary alkyl substituted vinyl carbonate was tolerated to give lactone (3qa) in 62% yield and with excellent ee (99%). Alkyl substituents on both enal and VEC were also tolerated to afford the product (3qb) in good yield and with high enantioselectivity (99% ee). Finally, primary alkyl groups were also compatible, as demonstrated with the synthesis of lactone product (3rb) in high ee (99%) although in diminished yield (30%). Next, the generality of the enal in this annulation reaction was examined. Simple aliphatic enals with different alkyl groups at the β-position were well tolerated, providing the corresponding products (3mb−3md) in very high yields and with high enantioselectivity. Gratifyingly acrolein was also a viable substrate, affording the product (3me) in moderate yield (52%) with excellent enantioselectivity (>99%). For aryl enals, electron-donating (OMe) as well as electron-withdrawing B


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BINAP instead of (R)-BINAP, from which we observed only slight conversion of 2a and the formation of product 3aa in just

groups (F, Cl) on the phenyl ring were well suited to deliver lactone products (3mf−3mh) in good yields and in all cases with excellent enantioselectivity. In order to gain insight about the active palladium species involved in this reaction, we first independently synthesized [((R)-BINAP)Pd(η3-allyl)]BF4 (6) and [(NHC 4a)Pd(η3allyl)]Cl (8) complexes. When we carried out ESI-MS analysis of the crude reaction solution obtained by mixing VEC 1a with complex 6, we observed the corresponding π-allyl-palladium intermediate 7 in the mass spectrum (Scheme 2A). In contrast,

5% yield (55% ee, eq 1). However, when rac-BINAP was used, 3aa was obtained in an improved 50% yield and with 98% ee, which strongly indicates that (R)-BINAP is the matched and most active ligand in this reaction. All these results suggest that there is a strong match−mismatch scenario. Furthermore, we have already shown during the optimization studies that both NHC and phosphine contribute toward the enantioselectivity, as it can be controlled by using either a chiral NHC catalyst with an achiral phosphine (Table 1, entry 2) or a chiral phosphine with an achiral NHC (Table 1, entry 7). Based on these preliminary mechanistic investigations, we assume that the reaction begins with the formation of the extended Breslow (or homoenolate) intermediate A (Figure 1),

Scheme 2. Mechanistic Studies

by mixing complex 8 and carbonate 1a, no mass of the corresponding allyl-palladium species 9 was observed, indicating the incompetency of complex 8 in decarboxylation of 1a. When complex 8, (R)-BINAP (L2), and VEC 1a were mixed, again the mass of 7 was observed along with the mass of complex 6 and free NHC but no mass peak corresponding to the allyl-Pd intermediate (generated upon decarboxylation of 1a) with mixed ligands (both NHC and (R)-BINAP) was observed.14 The reaction could also be performed with a catalytic amount of complex 6 and NHC 4a to afford lactone 3aa in 70% yield (>99% ee), thus proving the catalytic competency of complex 6 (Scheme 2B). When the experiment was repeated with complex 8 and L2, 3aa was obtained in 22% yield (>99% ee); this diminished yield is probably because of the lower levels of free NHC generated by slow ligand exchange from complex 8 by L2. In support of this, when 10 mol % of precatalyst 4a was added under otherwise identical conditions, the yield of 3aa was indeed increased to 68% (>99% ee). The above-mentioned studies indicate that the [((R)BINAP)Pd] complex is likely to be the active metal catalyst in this reaction. To further validate our hypothesis that the NHC is not ligating Pd, we searched for nonlinear effects8b using NHC 4a and an achiral bidentate phosphine L1, and as per our expectation, we did not observe any nonlinear effect in the reaction.14 Next, we demonstrated the importance of matching both the chiral NHC (4a) with the chiral phosphine (L2) for enantioinduction. First, we performed the reaction with (S)-

Figure 1. Proposed dual catalytic cycle.

Scheme 3. Diversification of 3aaa

Conditions: (i) Pd2(dba)3 (2 mol %), L1 (5 mol %), Toluene, 50 °C, 12 h; (ii) DIBAL-H (3.0 equiv), CH2Cl2, rt, 2 h; (iii) mCPBA (1.8 equiv), CH2Cl2, rt, 24 h; (iv) 10% Pd/C, H2 (1 bar), EtOAc, rt, 30 min. a

followed by facile β-protonation to form the (Z)-enol intermediate B with the top face blocked by the substituents on NHC. In another cycle, upon Pd-mediated decarboxylation, VEC 1a forms the intermediate C whose bottom face is shielded by the phosphine.12c Finally, nucleophilic attack from enol B to the terminal position of the Pd-π-allyl moiety of C (via hydrogen bonded transition state D),14 followed by C


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137, 5891. For a concise review, see: (g) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (3) (a) Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345. (b) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat. Chem. 2010, 2, 766. (c) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080. (d) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810. (4) (a) Zhao, X.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 12466. (b) Xu, J.; Chen, X.; Wang, M.; Zheng, P.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2015, 54, 5161. (c) Chen, D. F.; Rovis, T. Synthesis 2017, 49, 293. (5) For TM and NHC compatibility, see: (a) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243. (b) Namitharan, K.; Zhu, T.; Cheng, J.; Zheng, P.; Li, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Nat. Commun. 2014, 5, 3982. (6) (a) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40, 5151. (b) Janssen-Müller, D.; Schlepphorst, C.; Glorius, F. Chem. Soc. Rev. 2017, 46, 4845. (7) Liu, K.; Hovey, M. T.; Scheidt, K. A. Chem. Sci. 2014, 5, 4026. (8) (a) Guo, C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2016, 138, 7840. (b) Guo, C.; JanssenMüller, D.; Fleige, M.; Lerchen, A.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 4443. (9) For selected recent examples, see: (a) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Chem. Sci. 2013, 4, 97. (b) Xu, H.; Hu, J.-L.; Wang, L.; Liao, S.; Tang, Y. J. Am. Chem. Soc. 2015, 137, 8006. (c) Huang, L.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2016, 138, 5793. (d) 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. (e) Wang, Y.-N.; Yang, L.-C.; Rong, Z.-Q.; Liu, T.-L.; Liu, R.; Zhao, Y. Angew. Chem., Int. Ed. 2018, 57, 1596. (10) Modern Physical Organic Chemistry; Anslyn, E. V., Dougherty, D. A., Eds.; Higher Education Press: Beijing, 2009. (11) (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (b) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258. (c) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (12) (a) Quan, M.; Butt, N.; Shen, J.; Shen, K.; Liu, D.; Zhang, W. Org. Biomol. Chem. 2013, 11, 7412. (b) Khan, A.; Zheng, R.; Kan, Y.; Ye, J.; Xing, J.; Zhang, Y. J. Angew. Chem., Int. Ed. 2014, 53, 6439. (c) Khan, A.; Xing, J.; Zhao, J.; Kan, Y.; Zhang, W.; Zhang, Y. J. Chem. - Eur. J. 2015, 21, 120. (d) Guo, W.; Martínez-Rodríguez, L.; Kuniyil, R.; Martin, E.; Escudero-Adán, E. C.; Maseras, F.; Kleij, A. W. J. Am. Chem. Soc. 2016, 138, 11970. (e) Guo, W.; Martínez-Rodríguez, L.; Martin, E.; Escudero-Adán, E. C.; Kleij, A. W. Angew. Chem., Int. Ed. 2016, 55, 11037. (f) Khan, A.; Khan, S.; Khan, I.; Zhao, C.; Mao, Y.; Chen, Y.; Zhang, Y. J. J. Am. Chem. Soc. 2017, 139, 10733. (13) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370. (c) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. (d) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873. (e) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (f) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20661. (g) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett. 2011, 13, 4708. (h) McCusker, E. O. B.; Scheidt, K. A. Angew. Chem., Int. Ed. 2013, 52, 13616. (i) Guo, C.; Fleige, M.; JanssenMüller, D.; Daniliuc, C. G.; Glorius, F. Nat. Chem. 2015, 7, 842. (14) See Supporting Information.

cyclization, delivers 3aa and regenerates the free NHC and Pd catalysts. The potential synthetic utility of this protocol was then demonstrated through the facile diversification of optically active lactone 3aa (Scheme 3). In all cases, no loss of enantiomeric excess was observed. In conclusion, we have developed the first highly enantioselective [5 + 2] annulation of an NHC enolate and a π-allyl-palladium intermediate via a dual catalytic process. Mechanistic studies revealed that use of a bidentate phosphine ligand was crucial to prevent the binding of NHC to the transition metal and thereby the success of this transformation. Overall, we hope that this study will aid the development of dual catalytic systems based on transition metal catalysis/ organocatalysis and enable the discovery of new asymmetric transformations.

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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/jacs.8b00868. Experimental procedures, spectroscopic data, and crystallographic data (CCDC 1588167) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Frank Glorius: 0000-0002-0648-956X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous financial support by the Deutsche Forschungsgemeinschaft (Leibniz Award) and the Alexander von Humbolt Foundation (T.P.) is gratefully acknowledged. We thank Tobias Knecht, Dr. Zackaria Nairoukh, Dr. Michael J. James, Adrian Tlahuext-Aca, and Dr. Mirco Fleige (all University of Münster) for helpful discussions.

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REFERENCES

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Highly Enantioselective [5 + 2] Annulations through Cooperative N

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