Letter Cite This: Org. Lett. 2018, 20, 1304−1307
pubs.acs.org/OrgLett
α‑Functionalization of 2‑Vinylpyridines via a Chiral Phosphine Catalyzed Enantioselective Cross Rauhut−Currier Reaction Cong Qin,† Yonghai Liu,† Yang Yu,† Yiwei Fu,† Hao Li,*,† and Wei Wang*,†,‡ †
State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China ‡ Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States S Supporting Information *
ABSTRACT: Herein, 2-vinylpyridines as a new type of electron-poor system for the asymmetric cross Rauhut−Currier reaction are reported. 2-Vinylpyridines are chemo- and enantioselectively activated by a newly designed chiral phosphine catalyst. The new reaction provides a powerful synthetic tool for accessing structurally diverse, highly valued chiral pyridine building blocks in good yields and with high enantioselectivities. Preliminary mechanistic studies reveal that two NH protons in the catalyst are critical for the synergistic activation of the substrates and governing the stereoselectivity of this reaction. Shi and co-workers reported the first enantioselective intermolecular R−C reaction catalyzed by quinidine-derived βisocupreidine (β-ICD).16 Breakthroughs of the field come from the works of Huang17 and Zhao and Zhang,18 respectively, by employing chiral phosphines19 as effective promoters (Scheme 1, eq 2 and 3). It is noted that, in these studies, highly active allenoates and vinyl ketones are essentially used. Clearly, the challenge of the field is the identification of new Michael receptors to expand the scope of the asymmetric R−C reaction beyond allenoates and vinyl ketones. Herein, we report 2-vinylpyridines as a new class of Michael receptor for an organocatalytic enantioselective cross R−C reaction. A newly designed chiral phosphine is developed as effective promoter for the chemo- and enantioselective activation of 2-vinylpyridines in the cross R−C reaction with 3-aroyl acrylates and 2-ene-1,4diones (Scheme 1, eq 4). On the basis of our recent studies of functionalization of pyridines,20 we observed 2-vinylpyridines as effective Michael receptor in conjugate addition reaction.6 In particular, it engaged in an unusual triethylphosphine promoted 3-component MBH reaction.21 We conceived that 2-vinylpyridines bearing electronwithdrawing groups (EWGs) could serve as electron-demanding Michael receptors for the effective enantioselective cross R−C reactions in the presence of a chiral phosphine catalyst. The validation of the working hypothesis began with a model reaction between 3-aroyl acrylate 1a (0.1 mmol) and 5-nitro-2vinylpyridine 2a (0.2 mmol) catalyzed by chiral phosphine
A
mong the heteroarenes, pyridines perhaps are the most sought structure in synthesis and medicinal chemistry. They are the most widespread molecules found in FDA-approved drugs that contain a nitrogen heterocycle.1 Furthermore, they are also ubiquitously distributed in numerous natural products, bioactive synthetic substances, and agrochemicals1,2 and widely employed as ligands in catalysis and molecular recognition.3 Therefore, strategies enabling the facile functionalization of the privileged structure will leverage new broad-ranging synthetic and biological applications.4 Direct elaboration of readily accessible vinylpyridines is a viable strategy for the synthesis of highly functionalized pyridines.5 In this context, significant advances have been made on β-functionalization of vinylpyridines by nucleophilic addition to the electrophilic β-position but generally in a nonasymmetric fashion. Recently, we developed a chiral amine and Brønsted acid co-catalyzed enantioselective conjugate addition of aldehydes into 4-vinylpyridines (Scheme 1, eq 1).6 In sharp contrast, the α-functionalization of the class of the substances is extremely rare. To the best of our knowledge, only two cases by employing transition metal promoted asymmetric reductive coupling reactions were recently reported by Krische and Lam, respectively.7 The Rauhut−Currier (R−C) reaction,8 also known as the vinylogous Morita−Baylis−Hillman (MBH) reaction, is a useful strategy for the α-functionalization of α,β-unsaturated systems.9 However, cross R−C reactions involving two different types of Michael receptors present significant challenges due to low substrate reactivity and poor control of chemo- and stereoselectivity.9−14 Furthermore, although the nonasymmetric cross success of achieving the enantioselective version is very limited,15 © 2018 American Chemical Society
Received: January 2, 2018 Published: February 16, 2018 1304
DOI: 10.1021/acs.orglett.8b00008 Org. Lett. 2018, 20, 1304−1307
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 1. Vinylpyridines as New Michael Receptors in Organocatalysis and Organocatalytic Enantioselective CrossR−C Reactions
catalysts at rt (Table 1). Although desired product 3a was obtained in 86% yield catalyzed by I, a facilitator used by Zhang in intramolecular R−C reaction,15b no enantioselectivity was observed (entry 1). When the reaction temperature was performed at 0 and −20 °C, the ee value was improved to 26% and 32%, respectively (entries 2 and 3). Modification of the chiral catalyst by removing the tBuSO moiety gave chiral phosphine catalysts II−III, which delivered the products in moderate yields and a little higher enantioselectivities respectively (entries 4 and 5, 32−44% ee). It was found that catalyst IV bearing bulky OTIP at the ortho-position of the phenyl group was beneficial to the enantioselectivity (entry 5). Therefore, Zhang’s chiral sulfinamide phosphine (S, RS)-W1 V18 used in an enantioselective intermolecular C−R reaction was probed and gave higher enantioselectivity (entry 7, 58% ee). The results suggested that the bulky side chain on phenyl ring is important for improvement of enantioselectivity. In addition, two H-bond donors may be necessary for the interaction with both substrates simultaneously to achieve better enantioselectivity. Several new β-amidephosphine catalysts by installing bulky Boc- or Fmoc- protected chiral natural amino acids (VI−X) were designed, synthesized, and evaluated for this reaction, accordingly (entries 8−12). To our delight, catalysts VII−IX showed a remarkable improvement in enantioselectivity (entries 9−11). Catalyst X with a more bulkier aryl substituent on the side chain afforded the product with poorer yield and enantioselectivity (entry 12). Based on these outcomes, we chose catalyst IX as the terminal catalyst. The enantioselectivity was improved to 83% ee when the reaction was conducted at −30 °C (entry 13). Survey of the solvents revealed that dichloromethane (DCM) was the choice in terms of enantioselectivity (entry 14).22 Further lowering the reaction temperature to −40 °C delivered the product in 70% yield with 90% ee with 20 mol % catalyst loading (entry 15). With the optimal reaction conditions in hand, the scope of the intermolecular cross R−C reaction was probed subsequently
entry
cat.
solvent
temp (°C)
time (h)
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15d
I I I II III IV V VI VII VIII IX X IX IX IX
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 CH2Cl2
25 0 −20 −20 −20 −20 −20 −20 −20 −20 −20 −20 −30 −30 −40
4 4 8 8 8 8 8 8 8 15 15 15 26 26 36
86 76 64 62 66 60 60 55 58 73 71 59 68 67 70
26 32 40 44 50 58 62 73 78 80 71 83 85 90
a Unless otherwise specified, all reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol), and IX (10 mol %) in 0.5 mL of solvent. b Isolated yields. cDetermined by HPLC analysis using a chiral stationary phase. dIX (20 mol %) was used.
(Scheme 2). The substituents bearing electron-neutral, electronwithdrawing groups (EWGs), and electron-donating groups (EDGs) on the phenyl rings of 3-aroyl acrylates 1a−e were well tolerated and gave the desired products in good yields (67−71%) and with good enantioselectivities (85−90% ee, 3a−e). It is noteworthy that the sterically demanding substrate bearing an ortho-substituted aromatic group gave the R−C product 3f with higher enantioselectivity (92% ee). A good performance for fused aromatic naphthyl- and heteroaromatic thienyl substrates was observed by affording the corresponding products 3g−h in 71−75% yields and with good enantioselectivities. Furthermore, the aliphatic cyclohexanyl 1i also worked smoothly with the protocol. It appears that the size of the ester has limited effect on the process (3j−l). Notably, in addition to 3-aroyl acrylates, the process also is applicable to 2-ene-1,4-diones. As shown in the synthesis of 3m−o, good yields and excellent enantioselectivities (94−96% ee) were achieved. In addition to 5-nitro-2-vinylpyridine, we found 5-CN-2vinylpyridine 2b was an active reactant for the process at −20 °C by delivering the corresponding product 3p with a moderate yield (46%) but high ee (90%, Scheme 3). Furthermore, introducing additional substituents into the framework enabled to work smoothly. 3-Methyl-5-cyano-2-vinylpyridine 2c afforded the product 3q with 95% ee when the reaction was carried out at −30 °C. As expected, higher active 5-CN-6-chlorovinylpyridine 2d and 5-CN-6-chloro-4-methyl vinylpyridine 2e gave the products 3r and 3t in significantly higher yield. Moreover, these 2-vinylpyridines could also react with other 3-aroyl 1305
DOI: 10.1021/acs.orglett.8b00008 Org. Lett. 2018, 20, 1304−1307
Letter
Organic Letters Scheme 2. Scope of 3-Aroyl Acrylates and 2-Ene-1,4-dionesa
ously to be S by the single-crystal X-ray diffraction analysis of 3w (see the Supporting Information). The R−C products bearing a newly formed electron-deficient CC bond can serve as useful handles for further synthetic elaboration. As showcased with 3a, it is an effective Michael acceptor for a conjugate addition reaction with a thiophenol to give the adduct 6 in high yield and with good diastereoselectivity (Scheme 4). Moreover, the CC double bond can work as a Scheme 4. Further Functionalization of the ElectronDeficient 2-Vinylpyridine CC Double Bond
Michael receptor for the second cross R−C reaction with 2a chemoselectively under the mild conditions by delivering bispyridine product 7. It can also undergo a palladium-catalyzed Heck with iodobenzene to give more complex pyridine 8. It is noted that these reactions gave the corresponding chiral products with very limited erosion of the enantioselectivity. A transition state (TS) is proposed for the observed absolute (R) configuration of the chiral R−C products (Scheme 5). The
a Unless otherwise specified, all reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol), and IX (20 mol %) in DCM (0.5 mL) at −40 °C. Isolated yields and ee determined by chiral HPLC analysis. bThe reaction was stirred for 42 h. cThe reaction was stirred for 45 h.
Scheme 3. Scope of 2-Vinylpyridinesa
Scheme 5. Proposed Transition State
a
Unless otherwise specified, all reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol), and IX (20 mol %) in DCM (0.5 mL) at −40 °C. Isolated yields and ee determined by chiral HPLC analysis. bThe reaction was stirred for 48 h. cThe reaction was stirred at −20 °C. d The reaction was stirred at −30 °C. eThe reaction was stirred at −10 °C.
zwitterionic intermediate A is formed from the chemoselective conjugate addition of side chain phosphine of the catalyst IX to 5nitro-2-vinylpyridine 2a. Its formation is supported by the evidence of the 31P NMR experiment of catalyst IX reacting with 2a, in which two newly formed 31P peaks are observed (Figure S1, SI). Although the function of the second phosphine moiety remains determined, we believe its steric hindrance plays a certain role in the influence of enantioselectivity. In addition, the “N” of the 2-vinylpyridine is critical for the enhanced activation of the CC double bond for the phosphine conjugate addition and the stabilization of the intermediate A by a H-bonding with the amide of the catalyst IX. The activation model could explain the results of no reaction occurred with the regioisomer 5-nitro4-vinylpyridine. Moreover, the block of the hydrogen bond donor (e.g., catalyst IX′) led to no reaction either (Scheme 5). In the proposed TS, the second H-bond interaction between the (R) Fmoc NH of catalyst IX and carbonyl moiety of 1a activates
acrylates (e.g., 3t) and 2-ene-1,4-diones (e.g., 3u−3w) at elevated temperature. The substrate limitation associated with 2-vinylpyridines is also realized. No reaction occurred with the weaker EWG such as trifluoromethyl or acetyl groups introduced into the 2-vinylpyridine scaffold. Furthermore, no reaction was observed with 4-vinylpyridines. These reflect the highly electronic demanding requirement and the positioning of the “N” for optimal activation by the catalyst for the process and an important challenge for the discovery of suitable Michael receptors for new cross R−C reactions. The absolute configuration of the R-C products was determined unambigu1306
DOI: 10.1021/acs.orglett.8b00008 Org. Lett. 2018, 20, 1304−1307
Letter
Organic Letters
(5) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. In Organic Reactions; Adams, R., Ed.; Wiley: New York, 1959; Vol. 10, p 179. (b) Giam, C. S. In Pyridine and Its Derivatives; Abramovitch, R. A., Ed.; Wiley: New York, 1974, Suppl part 3, p 112. (c) Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 4, pp 10 and 77. (d) Klumpp, D. A. Synlett 2012, 23, 1590. (6) Wang, S.; Li, X.; Liu, H.; Xu, L.; Zhuang, J.; Li, J.; Li, H.; Wang, W. J. Am. Chem. Soc. 2015, 137, 2303. (7) (a) Komanduri, V.; Grant, C. D.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 12592−12593. (b) Saxena, A.; Choi, B.; Lam, H. W. J. Am. Chem. Soc. 2012, 134, 8428. (8) Rauhut, M. M.; Currier, H. U. S. Patent 3074999, 1963; Chem. Abstr. 1963, 58, 11224a. (9) For recent reviews on the R−C reaction, see: (a) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035−1050. (b) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213−6226. (c) Chandra Bharadwaj, K. RSC Adv. 2015, 5, 75923−75946. (10) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 7758. (11) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394. (12) Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.; Sasai, H. Angew. Chem., Int. Ed. 2012, 51, 5423. (13) For selected examples of intramolecular R−C reactions, see: (a) Thalji, R. K.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 16778− 16779. (b) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168−10169. (c) Krafft, M. E.; Haxell, T. F. N.; Seibert, K. A.; Abboud, K. A. J. Am. Chem. Soc. 2006, 128, 4174−4175. (14) For selected examples of intermolecular R−C reactions, see: (a) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10, 2449. (b) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. ACS Catal. 2017, 7, 2805. (c) Shi, Z.; Yu, P.; Loh, T.-P.; Zhong, G. Angew. Chem., Int. Ed. 2012, 51, 7825. (d) Shi, Z.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52, 8584. (e) Gao, Y.; Xu, Q.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2017, 359, 1663. (f) Zhang, X.; Gan, K.; Liu, X.; Deng, Y.; Wang, F.; Yu, K.; Zhang, J.; Fan, C. Org. Lett. 2017, 19, 3207. (15) Examples of intramolecular asymmetric R−C reaction: (a) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256. (b) Su, X.; Zhou, W.; Li, Y.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 6874. (c) Yao, W.; Dou, X.; Wen, S.; Wu, J.; Vittal, J. J.; Lu, Y. Nat. Commun. 2016, 7, 13024. (16) Zhao, Q.; Pei, C.; Guan, X.; Shi, M. Adv. Synth. Catal. 2011, 353, 1973. (17) Dong, X.; Liang, L.; Li, E.; Huang, Y. Angew. Chem., Int. Ed. 2015, 54, 1621. (18) Zhou, W.; Su, X.; Tao, M.; Zhu, C.; Zhao, Q.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 14853. (19) For reviews related to chiral phosphine catalysis, see: (a) Ye, L.W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (b) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. (c) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. (d) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (e) Li, W.; Zhang, J. Chem. Soc. Rev. 2016, 45, 1657. (20) (a) Li, T.; Zhu, J.; Wu, D.; Li, X.; Wang, S.; Li, H.; Li, J.; Wang, W. Chem. - Eur. J. 2013, 19, 9147. (b) Li, X.; Wang, S.; Li, T.; Li, J.; Li, H.; Wang, W. Org. Lett. 2013, 15, 5634. (c) Yu, Y.; Liu, Y.; Liu, A.; Xie, H.; Li, H.; Wang, W. Org. Biomol. Chem. 2016, 14, 7455. (d) Li, H.; Li, X.; Yu, Y.; Li, J.; Liu, Y.; Li, H.; Wang, W. Org. Lett. 2017, 19, 2010. (e) Li, J.; Qin, C.; Yu, Y.; Fan, H.; Fu, Y.; Li, H.; Wang, W. Adv. Synth. Catal. 2017, 359, 2191. (21) Chen, J.; Li, J.; Wang, J.; Li, H.; Wang, W.; Guo, Y. Org. Lett. 2015, 17, 2214. (22) For details of the solvent screening, see the SI.
synergistically and importantly positions the ketone moiety in backside while (S) amide H bond and chiral phosphine direct the pyridine in front side for the Re face attack to give the observed (R) product under the steric effect of the aryl tethered PPh2 group. In summary, we have developed 2-vinylpyridines as a new type of activated alkene for enantioselective intermolecular cross R− C reactions with 3-aroyl acrylates and 2-ene-1,4-diones. The novel chiral phosphine catalysts containing amino acids were designed to catalyze the cross asymmetric R−C reactions. The process affords a new approach to synthetically valued chiral pyridine building blocks. The studies expand the scope of the challenging enantioselective intermolecular cross R−C reactions. Further efforts aimed at the expansion of this novel activated alkene chemistry to other transformations are currently underway in our laboratories.
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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.8b00008. Experimental details and spectroscopic data (PDF) Accession Codes
CCDC 1585391 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 data_
[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
Wei Wang: 0000-0001-6043-0860 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 (21572055, 21738002, and 21572054), the program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the Fundamental Research Funds for the Central Universities.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00008 Org. Lett. 2018, 20, 1304−1307
