Authors: Fu‐Peng Wu | Jens Holz | Yang Yuan | Xiao‐Feng Wu
Source: CCS Chemistry (article, 2020-11-13)
Field: Chemistry — Organic Chemistry

Copper-Catalyzed Carbonylative Synthesis of β-Boryl Amides via Boroamidation of Alkenes Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2021Copper-Catalyzed Carbonylative Synthesis of β-Boryl Amides via Boroamidation of Alkenes Fu-Peng Wu, Jens Holz, Yang Yuan and Xiao-Feng Wu Fu-Peng Wu Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Rostock 18059 , Jens Holz Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Rostock 18059 , Yang Yuan Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Rostock 18059 and Xiao-Feng Wu *Corresponding author: E-mail Address: [email protected] E-mail Address: [email protected] Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Rostock 18059 Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023 https://doi.org/10.31635/ccschem.020.202000579 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail β-Boryl amide is a class of high value intermediates in organic chemistry. In this work, a copper-catalyzed carbonylative boroamidation of olefins toward the synthesize of β-boryl amides has been developed. Several new chemical bonds were constructed in this transformation. A wide range of β-boryl amides were produced in excellent regioselectivity and good to excellent yields. Ethylene gas can be successfully transformed under the same standard conditions as well. Notably, with the use of a chiral ligand, the first example of enantioselective carbonylative boroamidation of alkenes was realized. In addition, Piposulfan and Pipobroman, antineoplastic medicines, were prepared by this methodology in a straightforward manner. Download figure Download PowerPoint Introduction Amides are one of the most important moieties that exist in a wide range of organic intermediates, pharmaceuticals, advanced materials, and biologically active compounds.1 In particular, among all the amides, β-boryl amides have attracted growing attention as potent building blocks that provide an exceptional platform for further transformations (Scheme 1a). Due to the accepted importance, several synthetic methodologies have been established toward their synthesis. The conventional method to produce β-boryl amides is based on hydroboration of enamides. However, due to the electronic effect, α-boryl amides are more easily formed.2 To date, this challenge has been overcome and several transition metal-catalyzed hydroborations of α,β-unsaturated amides to produce β-boryl amides were developed by different research groups independently, including asymmetric versions (Scheme 1b).3–6 More recently, copper-catalyzed synthesis of β-boryl amides by borylative carboxamidation of styrenes with aryl isocyanates was achieved.7,8 Despite the impressive achievements, carbonylative boroamidation has not yet been developed, which is an attractive option for the synthetic community.9–11 By boroamidation, the powerful amide and alkyl boronate group can be effectively installed. Therefore, developing a new strategy of carbonylative boroamidation toward the preparation of β-boryl amides is highly desirable. Scheme 1 | (a–d) Strategies for β-boryl amide preparation and their importance. Download figure Download PowerPoint Transition metal-catalyzed borofunctionalization of olefins has been accepted as an irreplaceable tool in synthetic organic chemistry, which can add one boron and another unique group across the double bond to increase the molecular complexity and give functionalized organoboron compounds.12,13 To date, many catalytic procedures for the borofunctionalization of olefins, including enantioselective versions, have been developed, such as hydroboration,14–18 carboboration,19–21 borylacylation,22–24 aminoboration,25–27 and several others.28–36 However, asymmetric carbonylative borofunctionalization is very limited due to the interactions between carbon monoxide, boron, ligand, and transition metal (Scheme 1c).37–40 As our research interest continues on carbonylative borofunctionalization of alkenes,41–43 we found the β-borylalkylcopper intermediate, generated from the addition of LCu-Bpin species to olefins, is stable under CO atmosphere. Thus, we hypothesized that the β-borylalkylcopper intermediate is weakly affected by CO coordination and stereospecific transformation could be realized in the presence of a chiral bidentate ligand.44–48 Then β-boryl amides can be produced sterospecifically after carbonylative coupling with electrophilic reagents.49–51 In this work, we present our new results on carbonylative boroamidation of olefins. With copper as the catalyst, various alkenes and even ethylene gas smoothly react with excellent regioselectivity to produce the desired β-boryl amides in high yields. By using (S,S)-QuinoxP* as the ligand, an enantioselective carbonylative boroamidation was developed for the first time. Many chiral β-boryl amides were produced with unprecedented levels of regioselectivity and enantioselectivity (Scheme 1d). Experimental Section Unless otherwise noted, all reactions were carried out under a carbon monoxide or nitrogen atmosphere. Alkenes and hydroxylamine were synthesized per existing methods. The reagents were purchased from Sigma-Aldrich (Darmstadt, Germany), TCI (Eschborn, Germany), ABCR (Karlsruhe, Baden-Württemberg, Germany), and Acros (Geel, Belgium), and used without purification. All solvents were dried by standard techniques and distilled prior to use. Column chromatography was performed on silica gel (200–300 mesh) using n-pentane (bp. 36.1 °C), dichloromethane, and ethyl acetate as eluent. All NMR spectra were recorded at ambient temperature using Bruker Advance III HD 300 NMR (1H, 300 MHz; 13C{1H}, 75 MHz; 11B, 96 MHz) and Bruker ARX 400 NMR spectrometers (1H, 400 MHz; 13C{1H}, 101 MHz). 1H NMR chemical shifts are reported relative to TMS and were referenced via residual proton resonances of the corresponding deuterated solvent (CDCl3: 7.26 ppm), whereas 13C{1H} NMR spectra are reported relative to TMS via the carbon signals of the deuterated solvent (CDCl3: 77.0 ppm). Data for 1H are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, and br = broad), coupling constant (Hz), and integration. All 13C NMR spectra were broad-band 1H decoupled. However, signals for the carbon attached to boron, C(alkyl)-B, are usually too broad to observe in the 13C{1H} NMR spectra. Coupling constants are reported to 0.5 or 1 Hz accuracy. Gas chromatography (GC) analyses were performed on an Agilent HP-7890A instrument with a FID detector and HP-5 capillary column (polydimethylsiloxane with 5% phenyl groups, 30 m, 0.32 mm i.d., 0.25 μm film thickness) using argon as carrier gas. For chiral HPLC analysis, an Agilent 1100 series device was used. High-resolution mass spectra (HRMS) were recorded on an Agilent 6210 system. For chiral HPLC analysis, an Agilent 1100 series device was used. X-ray diffraction data for 9a were collected on a Bruker Kappa APEX II Duo diffractometer. The structures were solved by direct methods (SHELXS-97) and refined by full-matrix least-squares procedures on F2 (SHELXL-2014). XP (XPREP, Bruker AXS) and diamond were used for graphical representations. Because of the high toxicity of carbon monoxide, all the reactions should be performed in a mini reactor. The laboratory should be well equipped with a CO detector and alarm system. General procedure for carbonylative boroamidation with alkene A 4 mL screw-cap vial was charged with CuCl (1.9 mg, 10 mol %), Xantphos (11.6 mg, 10 mol %), B2pin2 (76.2 mg, 1.5 equiv), LiOMe (11.4 mg, 1.5 equiv), hydroxylamine (1.25 equiv), and an oven-dried stir bar. The vial was closed with a Teflon septum and cap and connected to the argon atmosphere via a needle. After THF (0.5 mL) and alkene (0.2 mmol) were added with a syringe under argon atmosphere, the vial was moved to an alloy plate and put into a Parr 4560 series mini reactor (300 mL) under argon atmosphere. At room temperature, the mini reactor was flushed with CO three times and charged with 10 bar CO. The mini reactor was placed on a heating plate equipped with a magnetic stirrer and an aluminum block. The reaction mixture was heated to 60 °C for 18 h. The reaction was then quenched upon addition of water (5 mL), and the mixture was extracted with DCM (5 mL). The combined organic layer was dried using Na2SO4 and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the corresponding product. General procedure for carbonylative boroamidation with ethylene A 4 mL screw-cap vial was charged with CuCl (1.9 mg, 10 mol %), Xantphos (11.6 mg, 10 mol %), B2pin2 (76.2 mg, 1.5 equiv), LiOMe (11.4 mg, 1.5 equiv), hydroxylamine (1.0 equiv), and an oven-dried stir bar. The vial was closed with a Teflon septum and cap and connected to the argon atmosphere via a needle. After THF (0.5 mL) was added with a syringe under argon atmosphere, the vial was moved to an alloy plate and put into a Parr 4560 series mini reactor (300 mL) under argon atmosphere. At room temperature, the mini reactor was flushed with ethylene three times. Then, the mini reactor was charged with 2 bar ethylene and 10 bar CO. The mini reactor was placed on a heating plate equipped with a magnetic stirrer and an aluminum block. The reaction mixture was heated to 60 °C for 18 h. The reaction was then quenched upon addition of water (5 mL), and the mixture was extracted with DCM (5 mL). The combined organic layer was dried using Na2SO4 and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the corresponding product. General procedure for enantioselective carbonylative boroamidation with styrene A 4 mL screw-cap vial was charged with CuCl (1.9 mg, 10 mol %), (S,S)-QuimoxP* (6.7 mg, 10 mol %), B2pin2 (76.2 mg, 1.5 equiv), LiOMe (11.4 mg, 1.5 equiv), hydroxylamine (1.25 equiv), and an oven-dried stir bar. The vial was closed with a Teflon septum and cap and connected to the argon atmosphere via a needle. After THF (0.5 mL) and styrene (0.2 mmol) were added with a syringe under argon atmosphere, the vial was moved to an alloy plate and put into a Parr 4560 series mini reactor (300 mL) under argon atmosphere. At room temperature, the mini reactor was flushed with CO three times and charged with 10 bar CO. The mini reactor was placed on a heating plate equipped with a magnetic stirrer and an aluminum block. The reaction mixture was heated to 60 °C for 18 h. The reaction was then quenched upon addition of water (5 mL), and the mixture was extracted with DCM (5 mL). The combined organic layer was dried using Na2SO4 and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the corresponding product. Results and Discussion We began our studies by reacting 4-phenyl-1-butene 1 with 1-(benzoyloxy) piperidine 2 and B2pin2, catalyzed by the CuCl/Xantphos system under 10 bar CO. To our delight, the desired β-boryl amide 3a was successfully obtained in 89% yield (Table 1, entry 1), with a small amount of regioisomeric product 3a′ (97:3). Low or no desired β-boryl amide 3a product was produced when bases were varied (Table 1, entries 2–4; for more details see Supporting Information Table S1–S5). In the testing of different copper catalysts, the copper catalysts with an NHC ligand such as IPr, IMes, and MeIPr or other ligand showed decreased catalytic activity (Table 1, entries 5–9). Bisphosphine ligands with varied bite angles were screened as well. From our obtained results, we found only Xantphos exclusively promoted the targeted transformation, and the other Xantphos-type ligands such as Homoxantphos, Sixantphos, N-Xantphos, and tBu-Xantphos gave no positive effect on the reaction outcome (Table 1, entry 12).44–48 Additionally, no reaction occurred without phosphine ligand (Table 1, entry 13). After fine-tuning the loadings of 2 and B2pin2 and LiOMe, 94% yield of the target product 3a can be formed, with 75% isolated yield. It is also worth noting that part of the product decomposed during the purification process (column chromatography). Notably, 45% yield of 3a can still be obtained under atmospheric pressure of CO (Table 1, entry 15). Table 1 | Optimization of the Reaction Conditionsa Entry [Cu] Ligand Base Yield (%) Regioisomeric Ratio 1 CuCl L1 LiOMe 89 97:3 2 CuCl L1 NaOMe 0 NR 3 CuCl L1 LiOtBu 36 96:4 4 CuCl L1 TMSONa 13 96:4 5 (CuOTf)2C6H6 L1 LiOMe 89 97:3 6 IPrCuCl L1 LiOMe 64 96:4 7 IPrCuCl None LiOMe 0 NR 8 MeIPrCuCl L1 LiOMe 59 97:3 9 IMesCuCl L1 LiOMe 12 96:4 10 CuCl DPEphos LiOMe 16 94:6 11 CuCl dppp LiOMe 9 92:8 12 CuCl L2- L5 LiOMe <5 NR 13 CuCl None LiOMe 0 NR 14b,c CuCl L1 LiOMe 94 (75) 97:3 15b,d CuCl L1 LiOMe 45 98:2 aStandard conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.2 mmol, 1.0 equiv), B2pin2 (0.3 mmol, 1.5 equiv), CuCl (10 mol %), L1 (10 mol %), LiOMe (0.3 mmol, 1.5 equiv), CO (10 bar), THF (0.4 M), stirred at 60 °C for 18 h, yields were determined by GC analysis using hexadecane as the internal standard. NR: No reaction. b 2a (0.25 mmol, 1.25 equiv). cIsolated yield. dCO (1 bar). Subsequently, the scope of alkenes was investigated for this carbonylative boroamidation with hydroxylamines under our standard conditions (Table 1, entry 14). As illustrated in Table 2, unactivated alkenes bearing various functional groups, including esters, sulfide, ethers, thiophene, furan, indole, C–C double bonds, and so on, were all successfully converted and gave the desired β-boryl amides in good to excellent yields with extraordinary regioisomeric ratio (rr > 20:1). Homoallylbenzenes with electron-donating ( 3b and 3c) substituents were transformed efficiently as well. Long alkyl chain ( 3d) or cycloheptane group ( 3e)-substituted olefins were also competent olefinic coupling partners here (54–64% yields). Various heteroatom-containing aliphatic olefins (O, S, Si, and 3f– 3l) underwent the desired carbonylative boroamidation in an effective manner; good yields of the final products were isolated (66–87% yields). Furthermore, functionalized thiophene, furan, and indole were also appropriate substrates in this procedure; the corresponding products were produced in high yields ( 3m– 3o). In addition, ester-containing olefins ( 3o and 3p) were compatible with this transformation too. Notably, the reaction occurs preferentially at terminal alkenes when the tested olefin contains multiple types of C–C double bonds ( 3r– 3u). Similarly, monoboroamidation product ( 3v) was obtained in 55% yield when the substrate contained two C–C double bonds. Styrene was also tested under our standard conditions and produced 33% yield of the desired β-boryl amide ( 3x). In the case of (E)-prop-1-en-1-ylbenzene, 25% yield of the corresponding product 3y can be isolated. Table 2 | Reaction Scopes: Testing of Alkenes and Hydroxylaminesa aStandard conditions: alkene (0.2 mmol, 1.0 equiv), hydroxylamine (0.25 mmol, 1.25 equiv), B2pin2 (0.3 mmol, 1.5 equiv), CuCl (10 mol %), Xantphos (10 mol %), LiOMe (0.3 mmol, 1.5 equiv), CO (10 bar), THF (0.25 M), stirred at 60 °C for 18 h, isolated yield. Subsequently, various hydroxylamines were evaluated for this carbonylative boroamidation. Cyclic amines including morpholine ( 4a), piperidine ( 4b and 4e), protected piperidone ( 4c), piperazine ( 4d), and tetrahydroisoquinoline ( 4f) were all well-tolerated in this transformation. Furthermore, diethyl- and dibenzyl-substituted hydroxylamine ( 4g and 4h) also showed excellent reactivity with excellent yields achieved (81–88% yields). Good yields of the target products can be produced as well from the other hydroxylamines substituted with primary carbon, secondary carbon, cyclohexyl, or furan ( 4i–4l). In all these cases, excellent regiocontrol (rr > 20:1) was observed. Remarkably, this carbonylative boroamidation can also be applied to more complex alkenes and hydroxylamines such as estrogen ( 5a), vitamin ( 5b), Paroexetine ( 5c), and the β-amino acid ester ( 5d) to give the target products in high yields and diastereoselectivity (dr > 20:1) (Table 3). Table 3 | Reaction Scopes: Testing of Ethylene Gas With the success of carbonylative boroamidation of alkenes, we further investigated this reaction with ethylene gas, which is the simplest olefin and an important building block in organic synthesis and the chemical industry. To our delight, when ethylene (2 bar) was treated with 1-(benzoyloxy)piperidine 2 under our standard conditions, the desired product 6a was produced in good yield. Subsequently, various hydroxylamines were applied to the reaction with ethylene, and the desired β-boryl amides were isolated in moderate to excellent yields ( 6d and 6e). The boron atom in these carbonylative boroamidation products provides an exceptional platform for further modifications. As shown in Scheme 2, a large-scale reaction was successful to give the target product 4g in 87% yield. Suzuki–Miyaura coupling was achieved as well and delivered the desired product 7a in 77% yield. β-Hydroxyl amide 7b was produced in 90% yield by oxidation of the parent β-boryl amide. Besides the installation of allyl group 7c, the C–B bond was easily converted into a C–N bond in 72% yield 7d as well (Scheme 2a). Notably, the drug Piposulfan precursor 8a was easily obtained under the standard condition with ethylene as the starting material. Then, in a straightforward manner, Piposulfan 8b, which was used for the treatment of neoplasm, was readily prepared by oxidation and protection. Similarly, 8b was converted into Pipobroman 8c with one additional bromination step (Scheme 2b). Scheme 2 | (a) Large-scale reaction and transformations of organoboranes. (b) Molecular synthesis of drugs Piposulfan and Pipobroman. Download figure Download PowerPoint To understand the reaction details, control experiments with several radical trapping reagents were carried out (Scheme 3a). Under the standard conditions, 2 equiv of radical inhibitors were added; the reaction outcomes were influenced, but the target product was still produced. Hence, we conclude that a radical intermediate is not involved in this reaction, which is consistent with literature reports.52–54 Subsequently, hydroxylamine 2 reacts with CO, and no R2NCO-OBz was detected, which excludes an anhydride intermediate (Scheme 3b). Scheme 3 | (a and b) Control experiments. Download figure Download PowerPoint The most likely reaction pathway is proposed according to our results (Scheme 4). First, the Cu(I) catalyst reacted with LiOMe and B2pin2 to give the (L)CuBpin complex.55 Subsequently, (L)CuBpin insertion into alkene generates the β-borylalkylcopper I, which, followed by CO coordination, provides the Cu complex II. After oxidative addition with hydroxylamine, the complex III formed, which underwent CO insertion to give the complex IV. The oxidative addition of β-borylalkylcopper I with hydroxylamine prior to CO coordination is possible as well. Finally, the desired product 3 could be obtained after reductive elimination and simultaneous regeneration of (L)CuOMe for the next catalytic cycle. In the catalytic cycle, we proposed the oxidative addition step occurs faster than the CO insertion step, for two reasons: (1) the oxidative addition step needs a relatively electron rich metal center; an acyl copper intermediate from CO insertion is electron poor. (2) An acyl copper intermediate is less stable than an alkyl copper complex and tends to undergo reductive elimination or decomposition.56 Scheme 4 | Proposed reaction mechanism. Download figure Download PowerPoint Finally, we set out to develop an enantioselective carbonylative boroamidation of alkenes (Table 4). 4-Phenyl-1-butene 1 and 1-(benzoyloxy) piperidine 2 were selected as the model coupling partners. Chiral Xantphos-type ligands ( L1* and L2*) were tested initially, moderated yields of 3aa were obtained with low enantioselectivity. No product could be detected with (R)-DTBM-SegPhos ( L4*), (R,R,R)-(+)-Ph-SKP ( L5*), or (R,S)-Josiphos ( L6*) as the ligand. An improvement in enantioselectivity (76% ee) for 3aa was obtained when switching to (R,R)-QuinoxP* ( L7*). Subsequently, a ligand class belonging to the same analogue was examined ( L8*– L11*), and 3aa was generated in 40% yield and 76% ee with (S,S)-BenzP* L8*. However, further evaluation of other ligands did not further improve the enantioselectivity for 3aa (for a full scope, see Supporting Information). To our delight, (E)-prop-1-en-1-ylbenzene 1′ was demonstrated a better model partner in this reaction system, which provides 61% yield and 83% ee for 9a. Furthermore, (S,S)-QuinoxP* ( L12*) proved to be superior to the other tested ligands ( L9* and L10*) and delivered 9a in 82% yield and 91% ee. Table 4 | Ligands Surveya aStandard conditions: olefin (0.2 mmol, 1.0 equiv), 2 (0.25 mmol, 1.25 equiv), B2pin2 (0.3 mmol, 1.5 equiv), CuCl (10 mol %), chiral ligand (10 mol %), LiOMe (0.3 mmol, 1.5 equiv), CO (10 bar), THF (0.25 M), stirred at 60 °C for 18 h. Yields are determined by GC analysis using hexadecane as internal standard. Regioisomeric ratio (rr) was determined by GC-MS. Diastereomeric ratio (dr) was determined by 1H NMR. Enantiomeric excess (ee) was determined by chiral-phase HPLC. Subsequently, the substrate testing of this enantioselective carbonylative boroamidation of olefins was examined with L12* as the ligand (Table 5). Morpholine, cycloheptyl cyclohexylbezyl, and dibenzyl-substituted hydroxylamine ( 9b– 9f) were effectively transformed into the target products with excellent diastereoselectivities (dr > 99:1) and enantioselectivities (85–95% ee). Dihydronaphthalene, indene, and styrenes also well in this process to the desired products ( ee). Finally, was and ee of the corresponding product ( was For the products and we the two groups are on the same of the double bond but to their Table 5 | Carbonylative Boroamidation aStandard conditions: olefin (0.2 mmol, 1.0 equiv), 2 (0.25 mmol, 1.25 equiv), B2pin2 (0.3 mmol, 1.5 equiv), CuCl (10 mol %), (S,S)-QuinoxP* (10 mol %), LiOMe (0.3 mmol, 1.5 equiv), CO (10 bar), THF (0.25 M), stirred at for 18 h, isolated yield. Regioisomeric ratio (rr) was determined by GC-MS. Diastereomeric ratio (dr) was determined by 1H NMR. Enantiomeric excess (ee) was determined by chiral-phase HPLC. of 9a without to and of A new strategy of copper-catalyzed carbonylative boroamidation of olefins has been By using hydroxylamines as the electrophilic various alkenes reacted successfully and gave the desired β-boryl amides in good to excellent yields. Ethylene gas can be successfully transformed as well. Notably, by using (S,S)-QuinoxP* as the ligand, the first example of an enantioselective carbonylative boroamidation was In addition, Piposulfan and Pipobroman, antineoplastic medicines, can also be prepared by this methodology in a straightforward manner. 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CO and of of Synthesis of and by and for the Reaction of Alkenes a of to Information Chinese Chemical the Chinese for and the of for at the of Rostock for their excellent The also for the X-ray times Amide ; Chemistry ; Catalysis ; Medicinal chemistry ; Organic chemistry Organoboron and organosilicon chemistry ; Asymmetric Hydrogenation and Catalysis ; Catalytic Cross-Coupling Reactions