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Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation-Binding Salen Nickel Complexes

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Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation-Binding Salen Nickel Complexes AngewandteA Journal of the Gesellschaft Deutscher Chemiker International Edition Chemie www.angewandte.org Accepted Article Title: Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation-Binding Salen Nickel Complexes. Authors: Dongseong Park, Carina I. Jette, Jiyun Kim, Woo-ok Jung, Yongmin Lee, Jongwoo Park, Seungyoon Kang, Min Su Han, Brian Stoltz, and Sukwon Hong This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913057 Angew. Chem. 10.1002/ange.201913057 Link to VoR: http://dx.doi.org/10.1002/anie.201913057 http://dx.doi.org/10.1002/ange.201913057 Angewandte Chemie International Edition 10.1002/anie.201913057 COMMUNICATION Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation-Binding Salen Nickel Complexes. Dongseong Park, 1,# Carina I. Jette, 2,# Jiyun Kim, 1,# Woo-Ok Jung, 1 Yongmin Lee, 3 Jongwoo Park, 4 Seungyoon Kang, 1 Min Su Han, 1 Brian M. Stoltz, 2,* and Sukwon Hong1,3,* Abstract: Cation-binding salen nickel catalysts were developed for A. Examples of bioactive compounds containing a chiral trifluorocarbinol the enantioselective alkynylation of trifluoromethyl ketones in high MeO HO CF H 3 F C N O yield (up to 99%) and high enantioselectivity (up to 97% ee). The 3 CONH Cl * 2 O CF3 reaction proceeds with substoichiometric quantities of base (10-20 N Ph H N O mol% KOt-Bu) and open to air. In the case of trifluoromethyl vinyl H Efavirenz CJ-17493 Anticonvulsant ketones, excellent chemo-selectivity was observed, generating 1,2- HIV reverse transcriptase inhibitor NK-1 receptor agonist addition products exclusively over 1,4-addition products. UV-vis B. Previous reports of asymmetric alkynylation of trifluoromethyl ketones: H HO CF3 analysis revealed the pendant oligo-ether group of the catalyst O Catalyst, Base + + Ph strongly binds to the potassium cation (K ) with 1:1 binding Ph CF3 Ph 5 -1 Ph stoichiometry (Ka = 6.6 × 10 M ). Shibasaki, 2007 Ma, 2011 Mashima, 2016 Meggers, 2017 Ar OMe N N Me Fluorinated organic compounds have proven to be O O OH O C N N N N Ph Ph AcO Mes N N Cu N N N Ru exceptionally useful in many areas of organic chemistry, N Rh Mes N OTf N Ph Ph N iPr H2O OAc Bn C 1 N N Me including materials, agrochemicals, and pharmaceuticals. In 20 mol % 20 mol % Ti(Oi-Pr)4 (2 equiv) Ar particular, chiral trifluoromethyl substituted tertiary alcohols and KOt-Bu (20 mol %) BaF2 (20 mol %) 5 mol % 0.5 mol % Me2Zn (3 equiv) related derivatives are important structural motifs present in a Et3N (20 mol %) 2 66% yield, 52% ee 89% yield, 91% ee 75% yield, 88% ee 97% yield, 99% ee number of bioactive compounds. Of particular importance is C. This research: Ni-catalyzed enantioselective alkynylation via bifunctional catalysis: Efavirenz, a frequently prescribed HIV reverse transcriptase Manuscript inhibitor (Figure 1a).3 One attractive strategy for the synthesis of such stereocenters is the asymmetric alkynylation of O H L7-Ni (5 mol %) HO CF3 Br N N Br KOt-Bu (10-20 mol %) Ni trifluoromethyl ketones, as this type of reaction may be catalytic R1 CF3 + R1 O O 4Å MS, THF R R 2 in base, resulting in eXceptionally mild reaction conditions. 2 25-40 °C, 24 h O K O Furthermore, the newly installed alkyne functional handle may R1= aryl vinyl up to 98% yield R2= aryl, cyclopropyl and 97% ee O O > 30 examples be easily converted to a diverse array of functional groups. Me Me L7-Ni + KOt-Bu Figure 1. Enantioselective addition of terminal alkynes to trifluoromethyl ketones. 1. Dongseong Park, Jiyun Kim, Woo-ok Jung, Seungyong Kang, Min 4a Since Carreira’s pioneering report, several catalysts have Su Han, Sukwon Hong Department of Chemistry, Gwangju Institute of Science and been developed for the enantioselective alkynylation of Technology (gIST), 123 Cheomdan-gwagiro, Buk-gu, gwangju aldehydes,4 imines,5 and alkyl ketones.6 In contrast, there are 61005, Republic of Korea fewer reports on the enantioselective alkynylation of E-mail: [email protected] 7,8 2. Carina I. Jette, Brian M. Stoltz trifluoromethyl ketones, as the high reactivity of these electron- Warren And Katharine Schlinger Laboratory for Chemistry and deficient electrophiles has led to significant challenges Chemical Engineering, California Institute of Technology, associated with facial selectivity. Although there have been Pasadena CA 91125 (USA) E-mail: [email protected] some reports on the enantioselective variant of this 3. Yongmin Lee, Sukwon Hong transformation, they all suffer from significant drawbacks, such Accepted School of Materials Science and Engineering, gwangju Institute of as high temperatures,7a large eXcesses of eXpensive Science and Technology (gIST), 123 Cheomdang-gwagiro Buk-gu, 7b,d Gwangju 61005, Republic of Korea reagents, or the use of precious, second-row transition metals 4. Jongwoo Park as catalysts (Figure 1b).7c,h-k Department of Chemistry, University of Florida, P.O.BoX 117200, In an effort to develop a more sustainable method for the Gainesville, FL 32611–7200 (USA) Current Address: Process R&D Center, SK biotek, 325 EXporo, enantioselective alkynylation of trifluoromethyl ketones, we Yuseong-gu, Daejeon, 34124, Republic of Korea turned our attention to the development of a cooperative catalyst involving a Lewis acid and Brønsted base (Figure 1c).9 The use # D.P., C.I.J., and J.K. all contributed equally to this work. of a single catalytic species to activate and bring together both Supporting information for this article is given via a link at the end of the nucleophile and electrophile could lead to a well-defined the document. environment for the reactive intermediates, which could enable This article is protected by copyright. All rights reserved. Angewandte Chemie International Edition 10.1002/anie.201913057 COMMUNICATION Table 1. Optimization of Reaction Conditionsa butyl substituent at this position completely shut down the reaction (entry 4, L4). We found Ni(II) to be the optimal Lewis H Catalyst (5 mol %) O F3C OH Base (20 mol %) Acid; switching to Co or Zn led to a significant drop in ee, and Pd CF3 Ph led to complete loss of reactivity (entries 5-7). Ph 4Å MS, THF (0.48 M) Temp, 24 h NeXt, we assessed the importance of the counter-ion on the 1a 2a 3aa tert-butoxide base. The highest enantioselectivity and yield was 1 equiv 4 equiv observed with KOt-Bu; both LiOt-Bu and NaOt-Bu led to a slight Entry Metal Ligand Base Temp (°C) Yield (%)b % eec reduction in yield and ee (entry 1 vs entries 8 and 9). When the 1 Ni L1 KOt-Bu 50 97 84 reaction temperature was lowered from 50 °C to 25 °C, the ee 2 Ni L2 KOt-Bu 50 48 82 was increased to 89% ee (entry 10). Lowering the temperature 3 Ni L3 50 86 86 KOt-Bu even further to –10 °C, however, led to the complete loss of 4 Ni L4 KOt-Bu 50 – – reactivity (entry 11). 5 50 91 49 Co L1 KOt-Bu Having investigated all other parameters, we returned 6 Zn L1 KOt-Bu 50 64 77 7 Pd L1 KOt-Bu 50 – – to our ligand, focusing on eXamining the effect of different steric and electronic modifications on the backbone. We found that the 8 Ni L1 LiOt-Bu 50 86 78 9 Ni L1 NaOt-Bu 50 83 85 binapthyl backbone was crucial for reactivity: when a ligand 10 Ni L1 KOt-Bu 25 93 89 possessing a cyclohexyl backbone was used instead, no product 11 Ni L1 KOt-Bu –10 – – was observed (entry 12). In agreement with the work of Wang 12 Ni L5 KOt-Bu 50 – – and co-workers13 we found that the introduction of bromide 13 Ni L6 KOt-Bu 50 97 88 substituents on the salicyl arenes led to a slight improvement in 14 Ni L7 KOt-Bu 50 95 91 15 Ni L7 KOt-Bu 25 93 93 the ee (entries 13 and 14). Using the 6-Bromo-Salen ligand (L7), the product was obtained in 93% yield and 93% ee at 25 °C under air (entry 15). N N a 3 Table 2: Substrate Scope with Aryl Trifluoromethyl Ketones M R N N R3 H O O M L7-Ni (5 mol %) N N O HO CF 2 KOt-Bu (20 mol %) 3 R O O R2 + M R CF O O 1 3 R1 O O R2 O O 4Å MS, THF (0.48M) R2 25 °C, 24 h O O 1a-h 2a-h 3 R1 R1 Me Me O O 1 equiv 4 equiv Me Me L1: R = O-CH CH O-CH 1 2 2 3 HO CF3 HO CF3 HO CF3 HO CF3 L2: R1 = O-CH3 L6: R2 = Br, R3 = H Manuscript L5 L3: R1 = O-[CH2CH2O]2-CH3 L7: R2 = H, R3 = Br L4: R = t-Bu Ph Ph Ph Ph 1 F Cl Br 3aa 3ba 3ca 3da a 93% yield 93% yield 94% yield 97% yield Reactions were performed on a 0.242 mmol scale. See Supporting Information for 93% ee 91% ee 89% ee 89% ee catalyst synthesis.
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