Enantioselective 1,2-Difunctionalization of 1,3-Butadiene by

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Enantioselective 1,2-Difunctionalization of 1,3-Butadiene by Sequential Alkylation and Carbonyl Allylation Yang Xiong and Guozhu Zhang* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China S Supporting Information *

ruthenium(II) and chiral phosphoric acid catalysis.10 Gong and co-workers developed an efficient 1,4-aryl hydroxylalkylation of dienes.11 During our study of chromium-catalyzed carbonyl allylation with functionalized carbohalides,12 we were inspired by Takai’s stoichiometric chromium-mediated three-component coupling of 1,3-diene with t-butyl or isopropyl iodide, and aldehyde.13 This proposed reaction mechanism has an active alkylated allyl radical that is quickly reduced by Cr(II) to give a stable metalassociated allylic anion that undergo carbonyl allylation. However, the potential of this elegant methodology is not fully understood, and the inertness of the primary alkyl halides, moderate diastereoselectivity, and lack of enantioselectivity motivate this work. We anticipated that a catalytic and enantioselective three-component coupling involving 1,3butadiene, an alkyl halide, and aldehyde might be viable for a Co/Cr bimetallic catalysis system via a suitable chiral ligand similar to the Cr/Ni-catalyzed (Nozaki−Hiyama−Kishi) reaction.12a,14 Herein, we describe our preliminary results detailing the successful implementation of this idea. A variety of alkyl halides and aldehydes participated in this threecomponent coupling; manganese is the only stoichiometric metallic reagent (Figure 1).15

ABSTRACT: A highly enantioselective three-component coupling of 1,3-butadiene with a variety of fluorinated or nonfluorinated alkyl halides and aldehydes has been achieved relying on a Cr/Co bimetallic catalysis system. The strategy established here facilitates straightforward introduction of the privileged fluoro functionalities into homoallylic alcohols from bulk feedstock materials in a highly anti-diastereo and enantioselective manner.

T

he 1,3-butadiene is a feedstock with an annual production scale of >10 million tons from petroleum cracking. The conversion of 1,3-butadiene to value-added fine chemicals is an attractive process from economic and environmental perspectives.1 The past decade has seen rapid developments in the stepwise 1,2- or 1,4-difunctionalization of 1,3-dienes through ionic allyl metal species.2 However, the radical-triggered carbon−carbon bond formation involving 1,3-butadiene remains challenging. Indeed, only a few examples have been reported likely because the resulting allyl radical intermediate is highly reactive evoking formidable selectivity.3 The introduction of fluorine atoms into organic molecules often leads to dramatic changes in their solubility, metabolic stability, and bioavailability.4 Because of these desirable properties, fluoroalkylated compounds are widely used in materials science, agro-chemistry, and medicinal chemistry.5 Thus, efficient and general methodologies for the synthesis of fluoroalkylated organic molecules are urgently needed. Versus general electrophilic and nucleophilic fluorinating reagents, radical nature perfluoroalkyl halides and related compounds are much less costly and more suitable for largescale synthesis.6 Despite the fact that the metal-catalyzed addition of perfluoroalkyl iodide and CF3I to alkene and alkyne has been documented,7 the relevant 1,2-fluoroalkylation of 1,3dienes from fluorinated alkyl halide have not been reported, and enantioselectivity is still unresolved. Stereoselective carbonyl allylation is one of the most useful classes of transformations, and it results in homoallylic alcohols that are valuable building blocks for organic synthesis.8 The development of enantioselective methods to construct homoallylic alcohols from cheap starting materials in an affordable approach that has attracted broad research interests.9 Recently, Krische and co-workers established the highly atomeconomic C−H crotylation of primary alcohols by hydrohydroxylakylation of 1,3-butadiene enabled by a combined © 2018 American Chemical Society

Figure 1. Catalytic and asymmetric three-component alkylation and allylation.

The reaction between dihydrocinnamaldehyde, 1,3-butadiene, and trifluoromethyl iodide was chosen as a model reaction. First, a standard setup involving a proton sponge (PS) as the base in the complexation step, TMSCl as the dissociation agent, Mn as the reducing reagent and CoPc (cobalt phthalocyanine)/CrCl2 were selected to test the reaction in the absence of any chiral ligands at room temperature. To our delight, the desired homoallylic alcohol was formed in good Received: December 1, 2017 Published: February 8, 2018 2735

DOI: 10.1021/jacs.7b12760 J. Am. Chem. Soc. 2018, 140, 2735−2738

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Journal of the American Chemical Society

reaction scale could be increased to 1 mmol with no loss in efficiency (Table 1, entry 16). After the optimal reaction conditions were established, the substrate scope with respect to aldehydes and alkyl halides was investigated (Figure 2). Coupling CF3I with the heptaldehyde proceeded smoothly, and the corresponding 4b was isolated in high yield with an excellent enantiomeric ratio (90% ee). Benzaldehyde was a good substrate as well albeit with mediocre dr (4c). We next turned our attention to 1,1,1-trifluoro-2-iodoethane. To our delight, the corresponding products (4d, 4e) derived from aliphatic aldehydes were obtained in good yields with decent stereoselectivites (up to 10:1 dr and 92.5% ee). The aldehydes with protected hetero atoms (O and N) were successfully engaged in the three-component coupling (4f, 4g), and the aromatic aldehydes provide coupling products in comparable yields but with better selectivity (4h−4k). The generality of this three-component coupling reaction was further proved by successful expansion to trifluoropropyl iodide, which led to β-1,1,1-trifluoropropyl homoallylic alcohols. Two representative aliphatic aldehydes were suitable substrates for clean reactions that provide the corresponding 4l, 4m in good yields with high stereoselectivity. Difluoromethylene (CF2) is an important bioisostere of the oxygen or a carbonyl group. It increases the dipole moment and acidity of neighboring groups often resulting in conformational changes.18 We used the commercially available 1,1-difluoro-2iodoethane as the difluoromethylating reagent, and we tested three-component coupling with two representative aliphatic aldehydes. To our delight, those reactions proceeded smoothly to give the corresponding difluoromethylated homoallylic alcohols (4n−4o) in moderate yields with excellent ee (up to 95%). The easily available (2-bromo-2,2-difluoroethoxy)(tertbutyl)dimethylsilane was also a good difluoroalkylating reagent leading to highly functionalized 4p and 4q in even better isolated yields with excellent stereoselectivities. The bimetallic-catalyzed method was further applied to monofluoromethylation and polyfluoroalkylation. The 1-fluoro2-iodoethane was transformed with two aliphatic aldehydes to the corresponding products (4r, 4s) in moderate yields with high ee. The three-component addition of perfluoroalkyl iodides including C2F5I, C3F7I, and C4F9I with aliphatic and aryl aldehydes performed well and produced the perfluoalkylated homoallylic alcohols 4t−4x in good yields with excellent drs and ees. In further substrate scope studies, several representative nonfluoro-substituted halides including iodoethane, 2-isopropyl iodide, iodocyclohexane, tert-butyl iodide were shown to be good substrates as well (4y−4ab). Moderate to good yields and excellent drs and ees were obtained. Beside 1,3-butadiene, isoprene was also a good coupling partner; under the standard asymmetric catalysis, a 3.3/1 regio selectivity, over 15/1 dr for each regioisomer and 98% ee for the major isomer have been achieved (4ac). Homoallylic alcohols are valuable intermediates in organic synthesis, and they can participate in a wide range of transformations at carbon−carbon double bonds or hydroxyl groups. Two short transformations were selected to demonstrate the potential application of our methodology by transferring the fluoro functional group into relatively complex molecules (Scheme 1). Product 4d (92.5% ee) underwent facile hydroboration and oxidation to deliver diol 5 in 75% yield.19 Treatment of 4d with acryloyl chloride was followed by ring

yield with moderate dr ratio (Table 1, entry 2). This result prompted us to examine chiral chromium ligands to achieve the asymmetric variant of this reaction. Table 1. Evaluation of Chiral Ligands and Other Reaction Parameters

Entrya

Deviation

Yieldb (%)

drc

ee(%)d

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

none Without ligand L1 L2 L3 L4 L5 L6 L7 0 °C instead of −10 °C Without CoPc NiCl2 instead of CoPc 5% CrCl2, 7% L1 CrCl3,f ZrCp2Cl2 instead of TMSCl 1 mmol of aldehyde

80 68 80 80 75 70 80 60 72 81 20 50 78 64 81 79

15:1 6:1 10:1 10:1 10:1 10:1 10:1 8:1 10:1 15:1 10:1 10:1 10:1 15:1 15:1 15:1

94 − 90 86 88 76 89 −5 74 93 92 80 85 88 95 94

a The reaction conditions were aldehyde (0.2 mmol), CF3I (0.6 mmol), 1,3-butadiene (0.6 mmol), CrCl2 (5 mol %), ligand (10 mol %), PS (10 mol %) CoPc (0.25 mol %), Mn (2 equiv), TMSCl (1 equiv) at −10 °C unless noted otherwise. bIsolated yield. cDetermined by 1HNMR analysis. dDetermined by chiral HPLC analysis, the absolute configuration was assigned by comparison with reported example; see Supporting Information for further details. eThe reactions were carried out at room temperature. f1 equiv of Mn was added for the complex formation; complexation took 8 h.

Extensive ligand screening and reaction optimization centered on the carbazole-based bisoxazoline ligands (Nakada ligand). Ligand L1 was optimal (Table 1, entries 3−8). Known diphenylamine bis(oxazoline) L7 was also examined and gave moderate stereo control (Table 1, entry 9).16 Lowering the temperature to 0 °C further improved the enantioselectivity to 93% ee (Table 1, entry 10). Finally, chiral ligand L1 gave 80% yield and a 94% ee when the reaction was performed at −10 °C. The impact of various deviations from the standard reaction conditions deserves mention. Solvent screening revealed that THF gave the best result. The yield of 4a decreased without CoPc presumably because CrCl2 could not reduce the CF3I efficiently (Table 1, entry 11) to initiate the radical addition. NiCl2 gave slightly decreased yield and ee (Table 1, entry 12). Cheaper and more easily handled CrCl3 could also be used directly (Table 1, entry 13). As a Cr−O dissociation reagent, ZrCp2Cl217 performed slightly better than TMSCl,15 but TMSCl was used in further studies for economic and environmental reasons (Table 1, entry 15). Notably, the 2736

DOI: 10.1021/jacs.7b12760 J. Am. Chem. Soc. 2018, 140, 2735−2738

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Figure 2. Substrate scope studies; all reactions carried out at 0.2 mmol scale under the standard conditions except for 4d, 4i, 4j which were prepared in 0.4 mmol scale, 4k (r.t., 24 h) in gram scale. ZrCp2Cl2 was used for making 4p and 4q.

generate fluorinated π-allyl radical species.21 The allyl radical was trapped by Cr(II). Subsequent isomerization2f followed by carbonyl allylation delivers the final product. The chiral ligand efficiently controls the stereoselectivity of the asymmetric carbonyl allylation through a close transition structure.12,14 Manganese serves as the reduction agent and renders both Co and Cr catalytic. In summary, we demonstrate enantioselective alkylation and hydroxyalkylation of feedstock 1,3-butadiene through a radical pathway for the first time. The Cr/Co bimetallic catalysis allows the compatibility of a broad range of functionalized alkyl halides and aldehydes under mild reaction conditions. This protocol will likely be useful in drug discovery and materials science because of the utility of homoallylic alcohols, the significance of fluorinated alkyl functionalities, the affordability of the starting materials, and ease of operation.

Scheme 1. Transformations of Fluorinated Homoallylic Alcohols

closing metathesis to produce dihydropyranone 6 in good yield.20 On the basis of the literature and these findings, we proposed a reaction mechanism (Figure 3). The CoPc initiates the formation of alkyl radical, which adds onto the 1,3-butadiene to

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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/jacs.7b12760. Experimental details (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Guozhu Zhang: 0000-0002-2222-6305

Figure 3. Proposed reaction mechanism. 2737

DOI: 10.1021/jacs.7b12760 J. Am. Chem. Soc. 2018, 140, 2735−2738

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Dedicated to Professor Yoshito Kishi on the occasion of his 80th birthday. We are grateful to NSFC-21772218, 21421091, XDB20000000, the “Thousand Plan” Youth program, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

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DOI: 10.1021/jacs.7b12760 J. Am. Chem. Soc. 2018, 140, 2735−2738