Ruthenium-Catalyzed C−H Allylation of Alkenes with Allyl Alcohols via

Sep 13, 2018 - A robust Ru(II)-catalyzed C−H allylation of electron-deficient alkenes with allyl alcohols in aqueous solution is reported. This meth...
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Ruthenium-Catalyzed C−H Allylation of Alkenes with Allyl Alcohols via C−H Bond Activation in Aqueous Solution Xiaowei Wu† and Haitao Ji*,†,‡ †

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612-9416, United States ‡ Departments of Oncologic Sciences and Chemistry, University of South Florida, Tampa, Florida 33612, United States

J. Org. Chem. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/23/18. For personal use only.

S Supporting Information *

ABSTRACT: A robust Ru(II)-catalyzed C−H allylation of electron-deficient alkenes with allyl alcohols in aqueous solution is reported. This method provides a straightforward and efficient access to the synthetically useful 1,4-diene skeletons. With the assistance of the N-methoxycarbamoyl directing group, this allylation reaction features a broad substrate scope with good functional group tolerance, excellent regio- and stereoselectivity, absence of metal oxidants, water-tolerant solvents, and mild reaction conditions. The mechanistic studies indicate that the process of the reversible C−H bond ruthenation is assisted by acetate, and the rate-determining step is unlikely to be the step of C−H bond cleavage.

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INTRODUCTION The linear and branched allyl moieties are ubiquitous in biologically active compounds and natural products and are the important synthons for the versatile transformation into many useful functional groups. Allylation is one of the most important reactions in organic synthesis.1−10 Although a variety of methods have been developed to introduce the allyl moiety, such as nucleophilic substitution, transmetalation of aryl metal compounds to allyl electrophiles, Friedel−Crafts allylation, and Tsuji−Trost allylation,11−17 these methods usually suffer from the limited substrate scope, the competing formation of the undesired byproducts, harsh reaction conditions, and prefunctionalized substrates. Over the past decades, the direct C−H bond functionalization via transition metal-catalyzed reactions has emerged as a powerful approach for the synthesis of organic compounds.18−27 In this context, transition metal-catalyzed direct C−H allylation reactions with varieties of allylation reagents have attracted much attention in consideration of synthetic efficiency and atom economy.28 In recent years, transition metal-catalyzed direct C−H allylation reactions with diverse allylic surrogates (such as allyl acetates, allyl carbonates, allyl halides, allyl phosphonates, vinyl oxiranes, allenes, etc.) have been successfully developed (Scheme 1, eq 1). For instance, Ma and Cramer separately disclosed the early examples of Rh(III)-catalyzed C−H allylation reactions of N-methoxybenzamides with polysubstituted allenes.29,30 Subsequently, Glorius, Loh, Li, Wang, and © XXXX American Chemical Society

Scheme 1. Transition Metal-Catalyzed C−H Allylation Reactions

other groups reported Rh(III)-catalyzed C−H allylation with various preactivated allyl alcohol derivatives (such as allyl acetates, allyl carbonates, etc.).31−41 Ru(II)-catalyzed C−H allylation reactions have been developed by Goossen, Kim, Kapur, and others.42−49 Direct C−H allylation reactions with allylation reagents by Cp*Co(III) or Mn(I) catalysis were Received: August 8, 2018 Published: September 13, 2018 A

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

entry

cat.

solvent

base

3a yield (%)b

E/Z ratioc

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

[Cp*RhCl2]2 [RuCl2(p-cymene)]2 [Cp*IrCl2]2 [Cp*Co(CH3CN)3](SbF6)2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 [RuCl2(p-cymene)]2 − [RuCl2(p-cymene)]2

DCM DCM DCM DCM toluene THF MeOH EtOH H2O MeOH MeOH MeOH MeOH/H2O MeOH/H2O MeOH MeOH

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc K2CO3 CsOAc Na2CO3 CsOAc CsOAc CsOAc −

0 50 0 0 33 0 67 61 54 0 72(70) 0 73(68) 29 0 0

− >25:1 − − − − >25:1 >25:1 >25:1 − >25:1 − >25:1 >25:1 − −

a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol %), base (1 equiv) in 2 mL of solvent at 50 °C, Ar atmosphere. bNMR yields were calculated using CH2Br2 as an internal standard, and the isolated yields are reported in parentheses. cDetermined by 1H NMR using the crude reaction mixtures. dMeOH/H2O = 1/1, v/v. eThe reaction was performed at room temperature. fNo [RuCl2(p-cymene)]2. gNo CsOAc.

disclosed by Glorius, Ackermann, and others.50−56 In addition, Kanai and Matsunaga reported simple allyl alcohols as allylation reagents for C−H allylation under Cp*Co(III) catalysis, which proceeded through the β-hydroxide elimination pathway (Scheme 1, eq 2).57,58 Despite remarkable progress in the area of transition metal-catalyzed C−H allylation, most reactions require preactivated allyl alcohol derivatives (such as allyl carbonates, allyl acetates, etc.) as the coupling partners, high reaction temperatures, anhydrous organic solvents, and stoichiometric amounts of metal oxidants. In this context, the development of robust transition metal-catalyzed C−H functionalization in water-tolerant medium under metal oxidant-free and mild reaction conditions is highly desirable. To the best of our knowledge, only two examples of C−H allylation of (hetero)arenes by Rh(III) and Mn(I) catalysis using allenes and vinyl dioxolanones as the allylation reagents in aqueous solvent were reported by Ma and Ackermann, respectively.29,56 In consideration of the limited examples of utilizing simple allyl alcohols as allylation reagents45,47,49,57,58 and the low reactivity of olefins,59,60 the example of transition metal-catalyzed C−H allylation of alkenes with unactivated allyl alcohols via C−H activation in aqueous solvent remains unexplored. Herein, we reported a robust Ru(II)-catalyzed C−H allylation of acrylamides with allyl alcohols in aqueous solution. With the assistance of the Nmethoxycarbamoyl directing group, this transformation features a broad substrate scope with high functional group tolerance, high regio- and stereoselectivity, absence of metal oxidants, water-tolerant solvents, and mild conditions.

transition metal catalysts in the presence of NaOAc and dichloromethane (DCM) at 50 °C (entries 1−4). The results indicated that the reaction did not take place when [Cp*RhCl2]2, [Cp*IrCl2]2, or [Cp*Co(CH3CN)3](SbF6)2 was used as the catalyst. In contrast, the reaction afforded the skipped diene 3a in 50% yield with excellent stereoselectivity (E/Z > 25:1) when [RuCl2(p-cymene)]2 was employed as the catalyst. The Z-configuration of one alkene group of product 3a (labeled as a in Table 1) was determined by the NOESY NMR spectrum (see the Supporting Information). The E-configuration of the other alkene group of product 3a (labeled as b in Table 1) was determined by the coupling constant of its alkene protons. Subsequently, several solvents were screened (entries 5−9); we found that the yield was decreased to 33% when the reaction was conducted in toluene. The reaction did not proceed to provide the desired product when performed in THF. To our delight, the reaction afforded the desired product in good yield with excellent stereoselectivity when MeOH or EtOH was employed as the solvent. Notably, the reaction proceeded smoothly in water. The studies on the different bases concluded that K2CO3 and Na2CO3 yielded no product (entries 10 and 12). When CsOAc was used as the base, the yield of product reached 72% (entry 11). To explore the efficiency of this reaction in aqueous solution, we performed the coupling reaction in methanol− water (1:1, v/v), which offered the 1,4-diene product in good isolated yield with excellent stereoselectivity (entry 13), demonstrating the robustness of this new synthetic method. When the reaction was conducted at room temperature, the yield of product was only 29% (entry 14). Additionally, this reaction did not provide the desired product without the catalyst [RuCl2(p-cymene)]2 or the base CsOAc (entries 15 and 16). Since similar efficiency was observed when methanol or methanol−water (1:1, v/v) was used as the solvent, we

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RESULTS AND DISCUSSION We initiated our studies by choosing the coupling reaction between N-methoxy-2-phenylacrylamide (1a) and allyl alcohol (2a) as the model reaction. First, we investigated a variety of B

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Next, the scope of allyl alcohols as coupling partners was explored (Table 3). In general, the coupling reaction with

decided to explore the substrate scope by using the aqueous solution to develop this method. With the optimized conditions in hand, we began to explore the scope of the reaction. As shown in Table 2, a variety of

Table 3. Scope of Allyl Alcoholsa,b

Table 2. Scope of Alkenesa,b

a

Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [RuCl2(pcymene)]2 (5 mol %), CsOAc (1 equiv) in 2 mL of MeOH/H2O (1/ 1, v/v) at 50 °C, Ar atmosphere, 12 h. The E/Z ratios of all products are >25:1 unless otherwise noted. bIsolated yields are reported.

a

Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [{RuCl2(pcymene)}2] (5 mol %), CsOAc (1 equiv) in 2 mL of MeOH/H2O (1/1, v/v) at 50 °C, Ar atmosphere, 12 h. The E/Z ratios of all products are >25:1 unless otherwise noted. bIsolated yields are reported. cThe corresponding allylic methyl carbonate was used. d [Cp*RhCl2]2 (5 mol %), CsOAc (1 equiv) in 2 mL of MeOH at 50 °C, Ar atmosphere, 12 h.

acrylamides bearing electron-donating and electron-withdrawing groups were compatible with the reaction, which provided the corresponding allylation products smoothly in moderate to good yields with excellent stereoselectivity. For example, when halogen (such as fluorine and chlorine) and trifluoromethyl groups were introduced to the para position of the benzene ring of acrylamides, the reaction afforded the desired products smoothly in moderate to good yields (3b, 3c, and 3d, respectively). When electron-donating groups, such as methyl, methoxyl, and tert-butyl groups, were introduced to the C-4 position of the phenyl group, the reaction also offered the products in good yields with excellent stereoselectivity (3e− 3h). Further, the desired 1,4-diene products were obtained smoothly (3i−3l) when α,β-disubstituted acrylamide substrates (such as cyclic olefins and α,β-dimethyl acrylamide) were used in this reaction, highlighting the broad scope of alkene substrates. It should be noted that the substitution at the α position of acrylamides is essential for the reaction. The β-monosubstituted or α,β-unsubstituted acrylamides did not offer the desired products.

various allyl alcohols or their methyl carbonates afforded the corresponding 1,4-diene derivatives in good to excellent yields (3m−3y). The desired products were obtained in good yields with excellent stereoselectivity regardless of electron-withdrawing (such as fluorine, chlorine, bromine, and trifluoromethyl groups) or electron-donating groups (such as methyl and methoxyl groups) attaching to the benzene ring of allyl alcohols (3m−3r). The naphthyl or thiophenyl group substituted allyl alcohols also underwent the coupling process smoothly with satisfactory yields and stereoselectivity (3s and 3t). Unfortunately, the reaction did not take place with prop-2en-1-ol, but the desired product was obtained in good yield when its methyl carbonate was employed as the coupling partner under the standard reaction conditions (3u). A similar result was observed when crotyl alcohol was investigated under the standard reaction conditions (3v). Further, it is worth C

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 2. Gram-Scale and Transformation Reactions

noting that the use of 2-methylprop-2-en-1-ol (or its methyl carbonate), hept-1-en-3-ol (or its methyl carbonate), and cyclohex-2-en-1-ol (or its methyl carbonate) did not provide the desired products under ruthenium catalysis (3w−3y). However, the corresponding 1,4-diene products were obtained in good yields when using the corresponding allylic methyl carbonates as the coupling partners under rhodium catalysis (3w−3y). To further evaluate the efficiency and potential applications of this method, a scale-up experiment and a product transformation reaction were carried out (Scheme 2). The result of the gram-scale reaction showed that product 3a was obtained in good yield (Scheme 2a). The epoxidation of the isolated alkene double bond of 3a by 3-chloroperbenzoic acid (m-CPBA) and then the intramolecular epoxide ring opening reaction offered the dihydropyridinone derivative 4a in 63% yield (Scheme 2b). Deuterium-labeling experiments were carried out to gain insight in the mechanism of this catalytic reaction (Scheme 3). First, we performed the reaction in the presence of ruthenium catalyst, CsOAc, and the excess amount of methanol-d4, but allyl alcohol 2a. Approximately 49% deuteration was observed at the β-position of the acrylamide (see the Supporting Information). It suggests that the step of the C−H cleavage might be reversible under the reaction conditions. Second, the above reaction was carried out in the absence of CsOAc, and the result showed that no obvious deuterium incorporated at the β-position of the acrylamide, indicating that CsOAc plays a critical role in the step of C−H cleavage. Third, performing the reaction with allyl alcohol 2a resulted in no obvious deuteration at the β-position. These results suggest that the reversible step of ruthenation should be assisted by acetate ion. This result is consistent with the previous observation on ruthenium-catalyzed C−H functionalization.61,62 Further, we performed the coupling reaction with the deuterated substrates 1a-D and 2a-D, respectively. Both reactions afforded the deuterated 1,4-diene derivatives smoothly. What’s more, the kinetic isotope effect (KIE) experiments were conducted (Scheme 3b).63 The intermolecular competition reaction of 1a and deuterium-labeled 1a-D with allyl alcohol 2a was carried out under standard reaction conditions, which resulted in the kinetic isotope effect (kH/kD) of 1.13. The parallel reactions led to a KIE value of 1.3. These data indicated that the C−H bond cleavage was unlikely the rate-determining step. A plausible reaction pathway was proposed based on the results of the preliminary mechanistic experiments and the

Scheme 3. Mechanism Studies

previous reports45,57,58 (Scheme 4). First, the active ruthenium catalyst was generated through a ligand exchange between the D

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

by following the procedures as described in the literature. 2j, 2k, 2l, and 2n were commercial materials. General Procedure for the Synthesis and Characterization of 3a−3v. Representative procedure for synthesis of 3a: A reaction tube was charged with N-methoxy-2-phenylacrylamide 1a (36.0 mg, 0.2 mmol, 1 equiv), allylic alcohol 2a (0.4 mmol, 2 equiv), [RuCl2(pcymene)]2 (0.01 mmol, 0.05 equiv), CsOAc (0.2 mmol, 1 equiv), and 2 mL of MeOH/H2O (1/1, v/v). The mixture was heated at 50 °C for 12 h under Ar atmosphere. The resulting mixture was diluted with dichloromethane and washed by water. The combined organic layers were dried with Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (hexanes/EA = 4/1−2/1, v/v) to give the desired product 3a (68% yield, 40.5 mg). (2Z,5E)-N-Methoxy-2,6-diphenylhexa-2,5-dienamide (3a). Following the general procedure, 3a was obtained as colorless oil in 68% yield, 40.5 mg. 1H NMR (400 MHz, CDCl3) δ 8.27 (br, 1H), 7.41−7.29 (m, 9H), 7.25−7.19 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.33−6.18 (m, 2H), 3.87 (s, 3H), 3.31 (t, J = 6.9 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 137.3, 136.7, 135.5, 133.5, 131.7, 128.9, 128.7, 128.4, 127.5, 127.2, 126.6, 126.3, 64.8, 33.4 ppm. HRMS (ESI) m/z: calculated for C19H20NO2+ [M + H]+: 294.1494, found: 294.1491. (2Z,5E)-2-(4-Fluorophenyl)-N-methoxy-6-phenylhexa-2,5-dienamide (3b). Following the general procedure, 3b was obtained as colorless oil in 40% yield, 25.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.29 (br, 1H), 7.40−7.28 (m, 6H), 7.24−7.20 (m, 1H), 7.05−7.00 (m, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.26 (dt, J = 15.9, 6.6 Hz, 1H), 6.15 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H) ppm. 13 C NMR (126 MHz, CDCl3) δ 166.2, 162.9 (d, J = 247.2 Hz), 137.2, 134.6, 133.1, 132.7 (d, J = 3.3 Hz), 131.8, 128.7, 128.3 (d, J = 7.6 Hz), 127.6, 127.0, 126.3, 115.9 (d, J = 21.7 Hz), 64.8, 33.4 ppm. 19F NMR (471 MHz, CDCl3) δ −113.34 ppm. HRMS (ESI) m/z: calculated for C19H19NO2F+ [M + H]+: 312.1400, found: 312.1410. (2Z,5E)-2-(4-Chlorophenyl)-N-methoxy-6-phenylhexa-2,5-dienamide (3c). Following the general procedure, 3c was obtained as colorless oil in 63% yield, 42.1 mg. 1H NMR (500 MHz, CDCl3) δ 8.23 (br, 1H), 7.39−7.28 (m, 8H), 7.24−7.20 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.29−6.18 (m, 2H), 3.87 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.1, 137.2, 135.0, 134.6, 134.4, 133.5, 131.9, 129.1, 128.7, 127.8, 127.6, 126.8, 126.3, 64.9, 33.5 ppm. HRMS (ESI) m/z: calculated for C19H19NO2Cl+ [M + H]+: 328.1104, found: 328.1093. (2Z,5E)-N-Methoxy-6-phenyl-2-(4-(trifluoromethyl)phenyl)hexa2,5-dienamide (3d). Following the general procedure, 3d was obtained as colorless oil in 70% yield, 51.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.26 (br, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.37−7.27 (m, 4H), 7.25−7.21 (m, 1H), 6.49 (d, J = 15.9 Hz, 1H), 6.34−6.21 (m, 2H), 3.88 (s, 3H), 3.32 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 165.7, 140.0, 137.1, 135.0, 134.7, 132.1, 128.8, 127.7, 126.8, 126.5, 126.3, 125.9, 125.9, 125.9, 64.9, 33.5 ppm. 19F NMR (471 MHz, CDCl3) δ −62.70 ppm. HRMS (ESI) m/z: calculated for C20H19NO2F3+ [M + H]+: 362.1368, found: 362.1363. (2Z,5E)-N-Methoxy-6-phenyl-2-(p-tolyl)hexa-2,5-dienamide (3e). Following the general procedure, 3e was obtained as colorless oil in 81% yield, 51.2 mg. 1H NMR (500 MHz, CDCl3) δ 8.25 (br, 1H), 7.38−7.33 (m, 2H), 7.33−7.27 (m, 4H), 7.25−7.19 (m, 1H), 7.17− 7.13 (m, 2H), 6.48 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 15.8, 6.6 Hz, 1H), 6.17 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.30 (t, J = 6.6 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.6, 138.4, 137.4, 135.4, 133.8, 132.6, 131.6, 129.6, 128.7, 127.5, 127.4, 126.5, 126.3, 64.8, 33.4, 21.3 ppm. HRMS (ESI) m/z: calculated for C20H22NO2+ [M + H]+: 308.1651, found: 308.1645. (2Z,5E)-N-Methoxy-2-(4-methoxyphenyl)-6-phenylhexa-2,5-dienamide (3f). Following the general procedure, 3f was obtained as colorless oil in 66% yield, 43.3 mg. 1H NMR (500 MHz, CDCl3) δ 8.22 (br, 1H), 7.37−7.27 (m, 6H), 7.24−7.19 (m, 1H), 6.91−6.84 (m, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.27 (dt, J = 15.9, 6.5 Hz, 1H), 6.11 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.7, 159.8, 137.4, 135.0,

Scheme 4. Proposed Catalytic Cycle

[RuCl2(p-cymene)]2 catalyst and cesium acetate. Then, the Nmethoxycarbamoyl group directed C−H activation of acrylamide 1 by the active catalyst that was formed in situ gave the five-membered ruthenacycle I via acetate assistance. The C−H bond cleavage is probably reversible and not the ratedetermining step. Subsequently, coordination and insertion of olefin 2 afforded intermediate II, which underwent βhydroxide elimination to generate product 3 and H2O. Finally, the regeneration of the active catalyst with the assistance of AcOH completed the catalytic cycle.

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CONCLUSION In summary, we have developed a robust ruthenium-catalyzed C−H allylation of acrylamides with the easily available allyl alcohols in aqueous solution. This method provides access to the synthetically useful, regio- and stereoselective 1,4-diene derivatives in moderate to good yields. Additionally, this reaction features a broad substrate scope, absence of metal oxidants, good functional-groups compatibility, gram-scale synthesis, and mild reaction conditions. The mechanistic studies suggest that the C−H bond cleavage is unlikely involved in the rate-determining step.

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EXPERIMENTAL SECTION

General Information. Unless otherwise specified, the reagents (chemicals) were purchased from commercial sources and used without further purification. Analytical thin layer chromatography (TLC) was HSGF 254 (0.15−0.2 mm thickness). All products were characterized by their NMR and MS spectra. 1H, 19F, and 13C NMR spectra were recorded on a 400 or 500 MHz instrument. Chemical shifts were reported as values in parts per million (ppm), and the reference resonance peaks were set at 7.26 ppm for CDCl3 to collect the 1H NMR spectra and 77.16 ppm (CDCl3) to collect the 13C NMR spectra. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd), and broad (br). High-resolution mass spectra (HRMS) were measured on Micromass Ultra Q-TOF spectrometer. The following substrates were prepared according to the literature methods: Nmethoxy acrylamides 1 were prepared by the procedure reported in the literature.64,65 Allyl alcohols and their derivatives 2a,66 2b,66 2c,67 2d,66 2e,68 2f,66 2g,66 2h,66 2i,69 2k′,70 and 2m71 were also prepared E

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Hz), 136.6, 135.5, 133.5, 130.5, 128.9, 128.4, 127.7 (d, J = 7.9 Hz), 126.9 (d, J = 1.7 Hz), 126.6, 115.6 (d, J = 21.6 Hz), 64.8, 33.3 ppm. HRMS (ESI) m/z: calculated for C19H19NO2F+ [M + H]+: 312.1400, found: 312.1397. (2Z,5E)-6-(4-Chlorophenyl)-N-methoxy-2-phenylhexa-2,5-dienamide (3n). Following the general procedure, 3n was obtained as colorless oil in 57% yield, 38.0 mg. 1H NMR (400 MHz, CDCl3) δ 8.34 (br, 1H), 7.41−7.26 (m, 9H), 6.43 (d, J = 15.9 Hz, 1H), 6.28− 6.16 (m, 2H), 3.85 (s, 3H), 3.30 (t, J = 7.1 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 136.6, 135.8, 135.6, 133.4, 133.1, 130.5, 129.0, 128.8, 128.5, 127.9, 127.5, 126.7, 64.8, 33.4 ppm. HRMS (ESI) m/z: calculated for C19H19NO2Cl+ [M + H]+: 328.1104, found: 328.1097. (2Z,5E)-6-(4-Bromophenyl)-N-methoxy-2-phenylhexa-2,5-dienamide (3o). Following the general procedure, 3o was obtained as colorless oil in 63% yield, 47.6 mg. 1H NMR (500 MHz, CDCl3) δ 8.25 (br, 1H), 7.44−7.31 (m, 8H), 7.23−7.20 (m, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.26 (dt, J = 15.8, 6.6 Hz, 1H), 6.21−6.16 (m, 1H), 3.86 (s, 3H), 3.30 (t, J = 6.6 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 136.6, 136.3, 135.6, 133.4, 131.8, 130.6, 129.0, 128.5, 128.0, 127.8, 126.7, 121.2, 64.8, 33.4 ppm. HRMS (ESI) m/z: calculated for C19H19NO2Br+ [M + H]+: 372.0599, found: 372.0601. (2Z,5E)-N-methoxy-2-phenyl-6-(4-(trifluoromethyl)phenyl)hexa2,5-dienamide (3p). Following the general procedure, 3p was obtained as colorless oil in 62% yield, 45.7 mg. 1H NMR (500 MHz, CDCl3) δ 8.15 (br, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.42−7.28 (m, 5H), 6.52 (d, J = 16.0 Hz, 1H), 6.38 (dt, J = 15.9, 6.5 Hz, 1H), 6.20 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.37 (t, J = 6.3 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 162.9, 141.1, 136.9, 136.1, 133.6, 130.7, 130.3, 129.3, 128.8, 127.0, 126.7, 125.9 (q, J = 3.8 Hz), 125.7, 65.1, 33.7 ppm. 19F NMR (471 MHz, CDCl3) δ −62.48 ppm. HRMS (ESI) m/z: calculated for C20H19NO2F3+ [M + H]+: 362.1368, found: 362.1357. (2Z,5E)-N-Methoxy-2-phenyl-6-(p-tolyl)hexa-2,5-dienamide (3q). Following the general procedure, 3q was obtained as colorless oil in 73% yield, 45.5 mg. 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.43−7.30 (m, 6H), 7.25−7.22 (m, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.45 (d, J = 15.9 Hz, 1H), 6.27−6.15 (m, 2H), 3.87 (s, 3H), 3.30 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.5, 137.3, 136.7, 135.4, 134.5, 133.6, 131.5, 129.4, 128.9, 128.4, 126.6, 126.2, 126.1, 64.8, 33.4, 21.3 ppm. HRMS (ESI) m/z: calculated for C20H22NO2+ [M + H]+: 308.1651, found: 308.1647. (2Z,5E)-N-Methoxy-6-(4-methoxyphenyl)-2-phenylhexa-2,5-dienamide (3r). Following the general procedure, 3r was obtained as colorless oil in 71% yield, 46.4 mg. 1H NMR (400 MHz, CDCl3) δ 8.37 (br, 1H), 7.42−7.27 (m, 7H), 6.88−6.80 (m, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.24−6.07 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.27 (t, J = 7.1 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.5, 159.2, 136.7, 135.3, 133.6, 131.1, 130.1, 128.9, 128.4, 127.4, 126.6, 124.9, 114.1, 64.8, 55.4, 33.4 ppm. HRMS (ESI) m/z: calculated for C20H22NO3+ [M + H]+: 324.1600, found: 324.1608. (2Z,5E)-N-Methoxy-6-(naphthalen-2-yl)-2-phenylhexa-2,5-dienamide (3s). Following the general procedure, 3s was obtained as colorless oil in 90% yield, 63.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.23 (br, 1H), 7.81−7.75 (m, 3H), 7.70 (s, 1H), 7.58 (dd, J = 8.6, 1.7 Hz, 1H), 7.47−7.40 (m, 4H), 7.39−7.30 (m, 3H), 6.65 (d, J = 15.9 Hz, 1H), 6.41 (dt, J = 15.8, 6.6 Hz, 1H), 6.26 (t, J = 7.8 Hz, 1H), 3.88 (s, 3H), 3.38 (t, J = 6.7 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.5, 136.7, 135.6, 134.8, 133.8, 133.6, 133.0, 131.8, 129.0, 128.5, 128.3, 128.1, 127.8, 127.6, 126.7, 126.4, 126.0, 125.9, 123.6, 64.9, 33.5 ppm. HRMS (ESI) m/z: calculated for C23H22NO2+ [M + H]+: 344.1651, found: 344.1644. (2Z,5E)-N-Methoxy-2-phenyl-6-(thiophen-2-yl)hexa-2,5-dienamide (3t). Following the general procedure, 3t was obtained as colorless oil in 61% yield, 37.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.25 (br, 1H), 7.43−7.28 (m, 5H), 7.12 (d, J = 5.0 Hz, 1H), 6.98− 6.89 (m, 2H), 6.61 (d, J = 15.7 Hz, 1H), 6.18 (t, J = 7.8 Hz, 1H), 6.11 (dt, J = 15.7, 6.6 Hz, 1H), 3.86 (s, 3H), 3.28 (t, J = 6.8 Hz, 2H) ppm. 13 C NMR (126 MHz, CDCl3) δ 166.3, 142.4, 136.6, 135.6, 133.2, 128.9, 128.5, 127.4, 126.9, 126.7, 125.2, 124.9, 124.0, 64.8, 33.2 ppm.

131.6, 131.5, 129.2, 128.7, 127.9, 127.47, 127.45, 126.3, 114.3, 64.8, 55.5, 33.4 ppm. HRMS (ESI) m/z: calculated for C20H22NO3+ [M + H]+: 324.1600, found: 324.1591. (2Z,5E)-N-Methoxy-2-(3-methoxyphenyl)-6-phenylhexa-2,5-dienamide (3g). Following the general procedure, 3g was obtained as colorless oil in 58% yield, 38.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.28 (br, 1H), 7.37−7.34 (m, 2H), 7.33−7.26 (m, 3H), 7.24−7.19 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.94 (br, 1H), 6.88−6.80 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.32−6.16 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.3, 160.0, 138.1, 137.3, 135.3, 133.8, 131.7, 130.0, 128.7, 127.5, 127.1, 126.3, 119.1, 114.0, 112.2, 64.8, 55.5, 33.4 ppm. HRMS (ESI) m/z: calculated for C20H22NO3+ [M + H]+: 324.1600, found: 324.1595. (2Z,5E)-2-(4-(tert-Butyl)phenyl)-N-methoxy-6-phenylhexa-2,5-dienamide (3h). Following the general procedure, 3h was obtained as colorless oil in 65% yield, 46.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.20 (br, 1H), 7.39−7.28 (m, 8H), 7.24−7.19 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.28 (dt, J = 15.9, 6.5 Hz, 1H), 6.19 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 1.32 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.6, 151.6, 137.4, 135.3, 133.8, 132.8, 131.5, 128.7, 127.5, 127.4, 126.4, 126.3, 125.9, 64.8, 34.8, 33.4, 31.4 ppm. HRMS (ESI) m/z: calculated for C23H28NO2+ [M + H]+: 350.2120, found: 350.2111. 2-Cinnamyl-N-methoxycyclohex-1-ene-1-carboxamide (3i). Following the general procedure, 3i was obtained as colorless oil in 71% yield, 40.2 mg. 1H NMR (500 MHz, CDCl3) δ 8.18 (br, 1H), 7.38− 7.28 (m, 4H), 7.24−7.20 (m, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.21 (dt, J = 15.8, 6.7 Hz, 1H), 3.81 (s, 3H), 3.03 (d, J = 6.6 Hz, 2H), 2.30−2.23 (m, 2H), 2.15−2.06 (m, 2H), 1.71−1.61 (m, 4H) ppm. 13 C NMR (126 MHz, CDCl3) δ 170.0, 137.2, 131.6, 128.7, 127.90, 127.87, 127.5, 126.3, 64.7, 38.6, 29.3, 27.1, 22.4, 22.2 ppm. HRMS (ESI) m/z: calculated for C17H22NO2+ [M + H]+: 272.1651, found: 272.1638. 2-Cinnamyl-N-methoxycyclopent-1-ene-1-carboxamide (3j). Following the general procedure, a mixture of stereoisomers (E/Z = 16:1) was obtained as colorless oil in 60% yield, 31.7 mg. Spectral data for the major isomer (E): 1H NMR (500 MHz, CDCl3) δ 8.12 (br, 1H), 7.36−7.33 (m, 2H), 7.31−7.27 (m, 2H), 7.23−7.18 (m, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.24 (dt, J = 15.8, 7.0 Hz, 1H), 3.82 (s, 3H), 3.48 (d, J = 6.9 Hz, 2H), 2.60−2.48 (m, 4H), 1.93−1.85 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 154.1, 137.5, 131.7, 128.7, 127.3, 126.8, 126.3, 64.8, 37.7, 33.7, 33.5, 21.9 ppm. HRMS (ESI) m/ z: calculated for C16H20NO2+ [M + H]+: 258.1494, found: 258.1490. 5-Cinnamyl-N-Methoxy-3,4-dihydro-2H-pyran-6-carboxamide (3k). Following the general procedure, 3k was obtained as colorless oil in 70% yield, 39.0 mg. 1H NMR (500 MHz, CDCl3) δ 9.01 (br, 1H), 7.38−7.32 (m, 2H), 7.30−7.26 (m, 2H), 7.22−7.11 (m, 1H), 6.44 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 15.8, 7.1 Hz, 1H), 3.99−3.91 (m, 2H), 3.81 (s, 3H), 3.47 (d, J = 7.0 Hz, 2H), 2.18 (t, J = 6.5 Hz, 2H), 1.90− 1.77 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 161.9, 139.4, 137.8, 131.1, 128.6, 128.4, 127.1, 126.2, 122.6, 65.9, 64.6, 35.6, 26.1, 22.3. HRMS (ESI) m/z: calculated for C16H20NO3+ [M + H]+: 274.1443, found: 274.1434. (2Z,5E)-N-Methoxy-2,3-dimethyl-6-phenylhexa-2,5-dienamide (3l). Following the general procedure, 3l was obtained as colorless oil in 56% yield, 28.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.16 (br, 1H), 7.38−7.33 (m, 2H), 7.33−7.28 (m, 2H), 7.25−7.19 (m, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.21 (dt, J = 15.8, 6.6 Hz, 1H), 3.81 (s, 3H), 3.05 (d, J = 6.5 Hz, 2H), 1.89−1.86 (m, 3H), 1.78−1.74 (m, 3H) ppm. 13 C NMR (126 MHz, CDCl3) δ 169.9, 137.2, 136.7, 131.7, 128.7, 127.7, 127.5, 126.3, 125.7, 64.7, 39.7, 18.3, 16.4 ppm. HRMS (ESI) m/z: calculated for C15H20NO2+ [M + H]+: 246.1494, found: 246.1478. (2Z,5E)-6-(4-Fluorophenyl)-N-ethoxy-2-phenylhexa-2,5-dienamide (3m). Following the general procedure, 3m was obtained as colorless oil in 59% yield, 37.3 mg. 1H NMR (500 MHz, CDCl3) δ 8.32 (br, 1H), 7.43−7.28 (m, 8H), 7.01−6.95 (m, 2H), 6.44 (d, J = 15.9 Hz, 1H), 6.22−6.14 (m, 2H), 3.86 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 162.3 (d, J = 246.4 F

DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry HRMS (ESI) m/z: calculated for C17H18NSO2+ [M + H]+: 300.1058, found: 300.1050. (Z)-N-Methoxy-2-phenylhexa-2,5-dienamide (3u). Following the general procedure, 3u was obtained as colorless oil in 80% yield, 35.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.21 (br, 1H), 7.40−7.29 (m, 5H), 6.16 (t, J = 7.8 Hz, 1H), 5.96−5.86 (m, 1H), 5.18−5.06 (m, 2H), 3.86 (s, 3H), 3.19−3.01 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 136.7, 135.8, 133.2, 128.9, 128.8, 128.4, 126.6, 116.4, 64.8, 34.1 ppm. HRMS (ESI) m/z: calculated for C13H16NO2+ [M + H]+: 218.1181, found: 218.1178. (Z)-N-Methoxy-4-methyl-2-phenylhexa-2,5-dienamide (3v). Following the general procedure, 3v was obtained as colorless oil in 64% yield, 30.2 mg. 1H NMR (500 MHz, CDCl3) δ 8.26 (br, 1H), 7.41− 7.37 (m, 2H), 7.36−7.27 (m, 3H), 5.95 (d, J = 10.2 Hz, 1H), 5.91− 5.83 (m, 1H), 5.12−5.03 (m, 2H), 3.85 (s, 3H), 3.51−3.36 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.5, 141.9, 138.5, 136.6, 133.8, 128.9, 128.3, 126.5, 114.0, 64.7, 38.4, 20.7 ppm. HRMS (ESI) m/z: calculated for C14H18NO2+ [M + H]+:232.1338, found:232.1321. General Procedure for the Synthesis and Characterization of 3w−3y. Representative procedure for synthesis of 3w: A reaction tube was charged with N-methoxy-2-phenylacrylamide 1a (36.0 mg, 0.2 mmol, 1 equiv), allylic alcohol 2l (0.4 mmol, 2 equiv), [Cp*RhCl2]2 (0.01 mmol, 0.05 equiv), CsOAc (0.2 mmol, 1 equiv), and 2 mL of MeOH. The mixture was heated at 50 °C for 12 h under Ar atmosphere. The resulting mixture was diluted with dichloromethane and washed by water. The combined organic layers were dried with Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (hexanes/EA = 4/1−2/1, v/v) to give the desired product 3w (59% yield, 27.9 mg). (Z)-N-Methoxy-5-methyl-2-phenylhexa-2,5-dienamide (3w). Following the general procedure, 3w was obtained as colorless oil in 59% yield, 27.9 mg. 1H NMR (500 MHz, CDCl3) δ 8.25 (br, 1H), 7.42− 7.39 (m, 2H), 7.36−7.29 (m, 3H), 6.21 (t, J = 7.9 Hz, 1H), 4.84 (s, 1H), 4.78 (s, 1H), 3.85 (s, 3H), 3.07 (d, J = 7.8 Hz, 2H), 1.88−1.76 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 166.5, 144.4, 136.7, 136.1, 132.9, 128.9, 128.4, 126.5, 111.6, 64.8, 38.0, 23.1 ppm. HRMS (ESI) m/z: calculated for C14H18NO2+ [M + H]+: 232.1338, found: 232.1317. (2Z,5E)-N-Methoxy-2-phenylnona-2,5-dienamide (3x). Following the general procedure, a mixture of stereoisomers (E/Z = 3:1) was obtained as colorless oil in 85% yield, 45.0 mg. Spectral data for the major isomer (E): 1H NMR (500 MHz, CDCl3) δ 8.24 (br, 1H), 7.39−7.29 (m, 5H), 6.14 (t, J = 7.9 Hz, 1H), 5.54−5.47 (m, 2H), 3.86 (s, 3H), 3.11−2.98 (m, 2H), 2.03−1.96 (m, 2H), 1.43−1.35 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.7, 136.8, 135.0, 134.2, 132.7, 129.0, 128.3, 127.2, 126.6, 64.9, 34.9, 29.6, 22.8, 13.9 ppm. HRMS (ESI) m/z: calculated for C16H22NO2+ [M + H]+: 260.1651, found: 260.1644. (Z)-3-(Cyclohex-2-en-1-yl)-N-methoxy-2-phenylacrylamide (3y). Following the general procedure, 3y was obtained as colorless oil in 67% yield, 35.0 mg. 1H NMR (500 MHz, CDCl3) δ 8.15 (br, 1H), 7.39−7.36 (m, 2H), 7.35−7.27 (m, 3H), 5.98 (d, J = 10.5 Hz, 1H), 5.83−5.78 (m, 1H), 5.57−5.52 (m, 1H), 3.86 (s, 3H), 3.39−3.30 (m, 1H), 2.09−1.98 (m, 2H), 1.96−1.87 (m, 1H), 1.83−1.75 (m, 1H), 1.69−1.59 (m, 1H), 1.52−1.45 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 166.7, 140.0, 136.7, 133.6, 129.0, 128.9, 128.7, 128.2, 126.5, 64.8, 36.5, 29.3, 24.9, 20.7. HRMS (ESI) m/z: calculated for C16H20NO2+ [M + H]+: 258.1494, found: 258.1482. The Gram-Scale Reaction To Prepare 3a. To a 100 mL roundbottom flask was charged N-methoxy-2-phenylacrylamide 1a (1.0 g, 5.64 mmol, 1 equiv), allylic alcohol 2a (1.51 g, 11.29 mmol, 2 equiv), [RuCl2(p-cymene)]2 (172.8 mg, 0.28 mmol, 0.05 equiv), CsOAc (1.08 g, 5.64 mmol, 1 equiv), and 50 mL of (MeOH/H2O = 1/1, v/ v). The mixture was heated at 50 °C for 12 h under Ar atmosphere. The resulting mixture was diluted with dichloromethane and washed by water. The combined organic layers were dried with Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (hexanes/EA = 4/1−2/1, v/v) to give the desired product 3a (57% yield, 0.946 g).

Epoxidation and Subsequent Cyclization of 3a. To a solution of 3a (60.0 mg, 1 equiv) in CH2Cl2 (5 mL) was added 3chloroperbenzoic acid (52.9 mg, 1.5 equiv), and the mixture was allowed to stirred overnight at room temperature. Then, the resulting mixture was diluted with dichloromethane and washed by water. The combined organic layers were dried with Na 2 SO 4, filtered, concentrated, and purified by column chromatography on silica gel (hexanes/EA = 4/1−2/1, v/v) to give the product 4a as colorless oil (63% yield, 40.0 mg). 1H NMR (500 MHz, CDCl3) δ 9.49 (br, 1H), 7.37−7.33 (m, 2H), 7.29−7.23 (m, 6H), 7.19−7.16 (m, 2H), 6.08 (t, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.73 (d, J = 1.7 Hz, 1H), 3.20−3.13 (m, 1H), 2.95−2.85 (m, 1H), 2.58−2.50 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 165.9, 138.9, 136.5, 136.3, 128.8, 128.69, 128.65, 128.5, 126.7, 126.6, 125.8, 64.6, 61.8, 58.6, 31.8 ppm. HRMS (ESI) m/z: calculated for C19H20NO3+ [M + H]+: 310.1443, found: 310.1435.

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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.joc.8b02063.

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Procedures for the synthesis of 1 derivatives and deuterium-labeling experiments; the NOSEY spectrum for 3a; copies of 1H and 13C NMR spectral data (PDF)

AUTHOR INFORMATION

Corresponding Author

*Phone: 813-745-8070. Fax: 813-745-4506. E-mail: Haitao.Ji@ moffitt.org. ORCID

Haitao Ji: 0000-0001-5526-4503 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The H. Lee Moffitt Cancer Center & Research Institute is a NCI-designated Comprehensive Cancer Center, supported under NIH grant P30-CA76292. We thank Cheng Mo for recollecting the mass spectrometry data for some compounds.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.8b02063 J. Org. Chem. XXXX, XXX, XXX−XXX