Asymmetric Borylative Propargylation of Ketones Catalyzed by a

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Asymmetric Borylative Propargylation of Ketones Catalyzed by a Copper(I) Complex Xu-Cheng Gan and Liang Yin* CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

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S Supporting Information *

ABSTRACT: A copper(I)-catalyzed asymmetric borylative propargylation of simple ketones was disclosed. Additive NaBARF was found to be pivotal to achieve excellent enantioselectivity. This reaction enjoyed advantages of broad substrate scope, good tolerance of functional groups, high diastereo- and enantioselectivities, and reaction robustness. The borylative product served as a suitable cross-coupling partner in a palladium-catalyzed Suzuki−Miyaura reaction. Finally, the synthetic utility of the methodology was showcased by the asymmetric synthesis of a chiral piperidine derivative.

C

good to excellent enantioselectivity with allenylboronate (Scheme 1a).4g Later, the catalytic asymmetric propargylation of ketones was enabled by a copper(I) catalyst with propargylboronate bearing a bulky TMS group on the other side of the alkyne moiety,6c by a silver catalyst with allenylboronate,6e and by a zinc catalyst with allenylboronate (Scheme 1a).6f Moreover, the asymmetric propargylation of

atalytic asymmetric addition of nucleophiles to ketones is one of most direct methods to access the optically active tertiary alcohols, which are prevalent structure units in biologically active compounds.1 However, simple ketones (unactivated) are inert in the presence of relatively weak nucleophiles, which greatly limits the application of ketones in organic synthesis. Moreover, compared to aldehydes, it is more difficult to discriminate between the two non-hydrogen substituents on the carbonyl group and thus to achieve effective enantiofacial control, which renders the asymmetric catalysis with ketones as the electrophiles less efficient. Therefore, developing effective asymmetric catalysis with simple ketones is a challenge and thus highly desirable in organic synthesis.1 The classical methods for the catalytic asymmetric nucleophilic addition to simple ketones employ various preformed metal reagents, such as alkyl or aryl metal reagents (such as Grignard reagent),1b,2 silyl enolates,3 allyl metal species,4 metal acetylides, 5 allenyl or propargyl metal species,4g,6 and other metallic nucleophiles.7 An atomeconomical method is the catalytic asymmetric addition to ketones with nucleophiles generated through deprotonation.8,9 Another efficient method is the asymmetric addition to ketones with a catalytic amount of nucleophiles generated in situ through reactions other than deprotonation, which generally allows the generation of multiple stereogenic carbon centers.10 Among the various catalytic asymmetric addition to ketones, the propargylation has received significant and continuous attention from the chemical community in recent decades due to the exceptionally versatile application of the chiral homopropargyl alcohols in organic synthesis.11 In 2010, Shibasaki and Kanai disclosed an example of copper(I)-catalyzed asymmetric propargylation of ketones in © XXXX American Chemical Society

Scheme 1. Prior Reactions in the Metal-Catalyzed Asymmetric Propargylation of Ketones and Our Reaction

Received: December 7, 2018

A

DOI: 10.1021/acs.orglett.8b03912 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of the Reaction Conditionsa

ketones of allenylboronate with an organocatalyst was achieved with the assistance of microwave heating.6d In 2011, the Sigman group reported an asymmetric propargylation of ketones with a chiral chromium catalyst by following the Nozaki−Hiyama−Kishi reaction protocol (Scheme 1b).6b Interestingly, the ligand class was designed and optimized by applying three-dimensional free energy relationships correlating steric and electronic effects. 1,3-Enynes found broad synthetic application in organic synthesis.12 They were also utilized in the catalytic asymmetric propargylation of carbonyl compounds. In 2008, Krische uncovered the first example of ruthenium-catalyzed propargylation of aldehydes with 1,3-enynes.13a The parent alcohols of aldehydes can be direct employed by using a transfer hydrogenative C−C coupling strategy. The low diastereoselectivity was further improved by modification of the structure of 1,3-enynes.13b The Krische group also successfully developed a catalytic asymmetric version of the reductive propargylation of aldehyde (or the parent alcohols) with an iridium catalyst in excellent diastereo- and enantioselectivities.13c The scope of 1,3-enynes was further expanded to 2methyl-1,3-enynes by switching the chiral iridium catalyst to a chiral ruthenium catalyst, which led to an array of chiral homopropargyl alcohols containing a gem-dimethyl moiety in excellent enantioselectivity.13e Moreover, 1,3-enynes were employed in the copper(I)-catalyzed asymmetric borylative propargylation of aldehydes by the Hoveyda group.13d In 2016, the Buchwald group developed a copper(I)catalyzed asymmetric reductive propargylation of ketones with 1,3-enynes and (dimethoxy)methylsilane (Scheme 1c).14 The chiral allenylcopper(I) species I were generated by the asymmetric reduction of 1,3-enynes with Cu*H. The allenylcopper(I) species II containing a C-BPin unit could be generated in situ through asymmetric borylation of 1,3enynes with Cu*BPin (Scheme 1d).13d Such a C-BPin moiety would serve as a synthetic handle for further structure elaboration.15 Previously, we reported the catalytic asymmetric addition of such species to fluoroalkyl ketones (activated ketones without acidic α-protons).16 Herein, we report a copper(I)-catalyzed asymmetric three-component reaction of simple ketones (unactivated ketones with acidic α-protons), 1,3-enynes and (BPin)2, which generated chiral homopropargyl alcohols in good to excellent yields with good to excellent stereoselectivity. It should be noted that NaBARF, an additive, was found to be indispensable to achieve excellent enantioselectivity. The three-component reaction of 1,3-enyne (1a), (BPin)2 (2), and acetophenone (3a) was investigated as a model reaction for the optimization of reaction conditions (Table 1). In the presence of 10 mol % of Cu(CH3CN)4PF6, 12 mol % of (R)-BINAP, and 1.5 equiv of LiOtBu, product 4a was obtained in 21% yield with >20/1 dr and 73% ee after oxidation of the C-BPin moiety (entry 1). (R)-SEGPHOS, (R)-DIFLUORPHOS, (R)-DTBM-SEGPHOS, and (R,R)-QUINOXP* did not give improved reaction results (entries 2−5). Ferroceneimbedded ligands, including (S)-(R)-PPFA, (R)-(S)-JOSIPHOS, and (R,RP)-TANIAPHOS, were not effective in the model reaction either (entries 6−8). P,N-Bidentate (S)-iPrPHOX and monodentate (Sa,Sc,Sc)-Feringa ligand were not suitable (entries 9 and 10). Fortunately, the reaction with (R,R)-Ph-BPE gave improved yield with moderate diastereoand enantioselectivities (entry 11). Considering the profound effect of the base on the asymmetric reaction with (BPin)2,16,17

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

total yieldb (%)

drc

eec (%)

>20/1 >20/1 >20/1

−73d −59d −46d

24 42 24 21

>20/1 >20/1 >20/1 >20/1

−39d 19 0 −17d

LiOtBu LiOtBu

18 15

5/1 >20/1

−22d 15

LiOtBu KOtBu KOMe KOMe KOMe

46 48 51 51 89

8/1 >20/1 >20/1 >20/1 >20/1

53 75 82 95 93

ligand

base

(R)-BINAP (R)-SEGPHOS (R)DIFLUORPHOS (R)-DTBMSEGPHOS (R,R)-QUINOXP* (S)-(R)-PPFA (R)-(S)-JOSIPHOS (R,Rp)TANIAPHOS (S)-iPr-PHOX (Sa,Sc,Sc)-Feringa ligand (R,R)-Ph-BPE (R,R)-Ph-BPE (R,R)-Ph-BPE (R,R)-Ph-BPE (R,R)-Ph-BPE

LiOtBu LiOtBu LiOtBu

21 20 22

LiOtBu

trace

LiOtBu LiOtBu LiOtBu LiOtBu

a 1a, 0.10 mmol; 2, 0.15 mmol; 3a, 0.20 mmol. bDetermined by 1H NMR analysis of reaction crude mixture using Cl2CHCHCl2 as an internal standard. cDetermined by chiral-stationary-phase HPLC analysis. dEnt-4a was obtained. e24 mol % ligand. f12 mol % NaBARF. g5 mol % Cu(CH3CN)4PF6, 6 mol % (R,R)-Ph-BPE, 6 mol % NaBARF, 1.0 equiv 1a, 2.5 euiv 2, 2.5 equiv 3a and 2.0 equiv KOMe were employed.

various bases were studied (for details, see the SI). KOtBu led to 4a in improved stereoselectivity (entry 12). KOMe was found to be the best base in terms of both yield and stereoselectivity (entry 13). The addition of 12 mol % NaBARF, which led to the generation of ionic [(R,R)-PhBPE-Cu]+BARF− complex in situ,18 further improved the enantioselectivity of 4a from 82% to 95% (entry 14). The yield was improved by increasing the amounts of 2, 3a, and KOMe with maintained stereoselectivity in the presence of 5 mol % of copper(I) catalyst (entry 15). Under the optimized reaction conditions, the substrate scope of ketones was evaluated (Scheme 2). As for parasubstituted acetophenones, both electron-withdrawing groups and electron-donating groups were well tolerated (4aa−ak). A variety of homopropargyl alcohols were isolated in good to excellent yields with both excellent diastereo- and enantioselectivities. Moreover, the reaction results were not affected by the position of substituents on the phenyl ring (4al−an). It is particularly noteworthy that various functional groups, such as sulfone (4ac), cyano (4ad and 4am), ester (4ae), bromo (4ah and 4al), and alkoxyl (4ai, 4ak and 4an), were not touched. 2B


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Organic Letters Scheme 2. Substrate Scope of Ketonesa

Scheme 3. Substrate Scope of 1,3-Enynesa

a

1a, 0.20 mmol; 2, 0.50 mmol; 3a, 0.50 mmol. Isolated yield reported. Diastereoselectivity and enantioselectivity determined by chiralstationary-phase HPLC analysis. bdr = 5/1. cdr = 3/1.

a

1a, 0.20 mmol; 2, 0.50 mmol; 3a, 0.50 mmol. Isolated yield reported. Diastereoselectivity and enantioselectivity determined by chiralstationary-phase HPLC analysis. bdr = 8/1.

coupled with (BPin)2 and acetophenone efficiently to furnish the products 4ha−oa uniformly in good yields with excellent both diastereo- and enantioselectivities. It is particularly noteworthy that an array of functional groups, such as TBSether (4ia and 4ja), benzyl ether (4ka), ester (4la), tosylate (4ma), sulfonamide (4na), and alkyl chloride (4oa), which can undergo further transformations for structure elaboration, was well tolerated under the present catalytic system. Moreover, it was fortunate to discover that propiophenone (3y), 1-phenyl1-pentanone (3z), 4-phenyl-2-butanone (3aa), and 2-butanone (3ab) were applicable, leading to 4ky, 4kz, 4haa, and 4hab in moderate yields with moderate diastereoselectivity and excellent enantioselectivity. The absolute configurations of these products were assigned temporarily according to the Xray structure of 4ac by analogy. The asymmetric borylative propargylation of ketones could be followed by a Suzuki−Miyaura cross-coupling as shown in Scheme 4. In the presence of 5 mol % of Pd(OAc)2, 10 mol % of Ru-Phos, and 3.0 equiv of Cs2CO3, product 5 was obtained in 73% yield with >20/1 dr and 94% ee. Furthermore, the hydroxyl group in product 4aa was successfully employed as a synthetic handle to introduce functional groups. For example, SN2 reaction with NaN3 afforded product 6 in 70% yield for two steps and SN2 reaction with NaSPh furnished product 7 in 75% yield for two steps (Scheme 4). A C−O bond-forming reaction catalyzed by a copper(I)−diamine complex was also achieved successfully. Product 4al was transformed to chiral tetrahydropyran derivative 8 in 66% yield (Scheme 4). Piperidines with two continuous stereogenic carbon centers (13) were reported to exhibit good analgesic activity.19 The two continuous chiral carbon centers could be accessed by the present methodology. As shown in Scheme 5, in the presence of 0.5 mol % of Cu(CH3CN)4PF6 and 0.6 mol % of (R,R)-Ph-

Acetonaphthone was also a competent substrate to give the product (4ao) in excellent results. Heterocycles are attractive structural units due to their vast presence in pharmaceutically active compounds. However, the heterocycles would potentially coordinate to metal center, which may deactivate the metal catalyst and lead to decreased yield and stereoselectivity. Fortunately, a pyrazole motif in acetophenone did not have a bad effect on both the yield and stereoselectivty (4ap). Moreover, both electron-deficient and electron-rich pyridinyl were not harmful to the reaction results (4aq and 4ar). 2-Acetylbenzo[b]thiophene was also an acceptable substrate (4as). Moreover, α,β-unsaturated ketone showed activity comparable to that of acetophenone (4at). α,β,γ,δ-Unsaturated ketone led to product 4au in moderate yield, possibly due to the side reactions caused by the polyunsaturated carbon−carbon double bonds. More importantly, the present reaction conditions were successfully extended to functionalized acetophenones, such as α-fluoro-, α,α-difluoro-, and α-chloroacetophenones (3v−x). Among these products (4av−ax), 4aw was remarkable as further transformations were enabled by the synthetically versatile alkyl chloride motif. The absolute configuration of 4ac was determined through X-ray crystallography analysis of its single crystals. The absolute configurations of other products were tentatively deduced by analogy. Then the scope of 1,3-enynes was investigated (Scheme 3). Several 1,3-enynes bearing aromatic or heteroaromatic substituents reacted with (BPin)2 and acetophenone smoothly to give the corresponding homopropargyl alcohols uniformly in good to excellent yields with excellent stereoselectivity (4aa−ga). Furthermore, a number of aliphatic 1,3-enynes C


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Organic Letters

ology and application of it in the asymmetric synthesis of natural products are currently on going in our laboratory.

Scheme 4. Transformations of the Products

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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.8b03912. Experimental procedures, X-ray diffraction data for 4ac, and spectroscopic data for all new compounds, including 1 H, 19F, and 13C NMR spectra and HPLC charts (PDF) Accession Codes

CCDC 1871853 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Scheme 5. Synthetic Application of Present Methodology

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Liang Yin: 0000-0001-9604-5198 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the “Thousand Youth Talents Plan”, the National Natural Science Foundation of China (Nos. 21672235 and 21871287), and the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000). Mr. Xian-Liang Wang (a joint graduate student at Shanghai University and Shanghai Institute of Organic Chemistry) is acknowledged for checking of the reproducibility of some experiments.

BPE, the gram-scale reaction of 3w proceeded in equal efficiency as the reaction with 5 mol % of copper(I) catalyst. The SN2 substitution of primary alkyl chloride with NaCN produced 9 in 84% yield. The full saturation of alkyne moiety and the reduction of the cyano group generated 10 in 82% yield. The selective conversion of primary alcohol to mesylate and the subsequent cyclization produced 11 in 83% yield for two steps. Transformation of the N-Boc moiety to the N-Me moiety and the following esterification afforded 12 in 74% yield for two steps. Clearly, our methodology provides a general synthetic approach for preparing chiral trans-13 with various substituents at C3-position. In conclusion, a copper(I)-catalyzed asymmetric borylative propargylation of simple ketones was achieved in good to excellent diastereoselectivity and excellent enantioselectivity. The reaction enjoys broad substrate scope for both ketones and 1,3-enynes. A broad range of functional groups, such as trifluoromethyl, sulfone, nitrile, ester, trifluoromethoxyl, alkoxyl, heterocycles, 1,3-diene, alkyl chloride, difluoromethyl, dimethyl amino, TBS ether, benzyloxy, tosylate, and tosylate amide, was well tolerated under the present reaction conditions. The borylated product was successfully employed in the following Suzuki−Miyaura cross-coupling reaction. Furthermore, the hydroxyl group in the final product served as a synthetic handle for the introduction of functional groups. Finally, the present methodology was applied in the asymmetric synthesis of a chiral piperidine derivative with potential analgesic activity. Further expansion of the method-

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Asymmetric Borylative Propargylation of Ketones Catalyzed by a

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