Chemoselective SN2′ Allylations of Detrifluoroacetylatively In Situ

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Note Cite This: J. Org. Chem. 2017, 82, 13663−13670

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Chemoselective SN2′ Allylations of Detrifluoroacetylatively In Situ Generated 3‑Fluoroindolin-2-one-Derived Tertiary Enolates with Morita−Baylis−Hillman Carbonates Yi Zhu,† Haibo Mei,†,‡ Jianlin Han,*,† Vadim A. Soloshonok,*,‡,§ Jie Zhou,*,† and Yi Pan† †

School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Nanjing University, Nanjing 210093, China ‡ Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, San Sebastián 20018, Spain § IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, Bilbao 48011, Spain S Supporting Information *

ABSTRACT: The first example of the SN2′ reaction type of the detrifluoroacetylatively in situ generated tertiary fluoroenolates in the uncatalyzed reactions with Morita−Baylis− Hillman derivatives has been described. The SN2′ substitution takes place in a highly chemoselective manner as no corresponding SN2 products were observed in the reaction mixtures. Due to the excellent stereochemical outcome, the reactions seem to have an apparent synthetic value for the preparation of structurally new fluorinated oxindoles. wing to innovative applications of fluorinated compounds in the broad areas of pharmaceuticals,1 agrochemicals,2 and modern materials,3 the synthesis of structurally and functionally diverse molecules containing fluorine has been the focus of intensive research efforts.4 While the so-called “final stage fluorination”5 has certain potential merit, the current industrial production1,2,6 relies virtually solely on the fluorinated building-blocks strategy, which was shown to be a methodologically flexible approach to structurally complex compounds of medicinal importance.7 In this regard, fluorinebearing enol intermediates are quite useful structural units demonstrating adaptable reactivity and molecular diversity.8 The most recent advance in this area is the discovery9 of the detrifluoroacetylative approach for the in situ generation of fluoro-enolates 1 (Scheme 1).10 Many research groups have actively studied the chemistry of these new species 1, reporting the corresponding halogenation,11 aldol,12 Mannich,13 and Michael addition reactions.14 Thus, quite surprisingly, the

O

alkylation of enolates 1 still remains the most elusive type of reactivity, presenting an inspiring research target. In this regard, we decided to explore the nucleophilic properties of enolates 1 in the reactions with Morita−Baylis−Hillman derivatives 2. The chemistry of Morita−Baylis−Hillman derivatives is one of the most prolific areas of research.15 Their easy synthetic availability and reaction versatility render them valuable intermediates for the practical preparation of various biologically relevant compounds, in particular, pyrimidones, azetidinones, α-alkylidene-β-lactams, mikanecic acids, frontalines, α-methylene-γ-butyrolactones, ilmofosines, pyrrolidines, quinolones, diazacyclophanes, isoxazolines, sarkomycines, indolizines, nuciferoles, trimethoprimes, chromanones, and pyrazolones.15,16 However, the research in the area of Morita−Baylis−Hillman adducts is virtually completely focused on the application of various catalysts17,18 to activate the allylic system in derivatives 2. Being motivated rather by fundamental issues of the innate reactivity of the in situ generated enolates 1, then applicatory chemistry, we decided to study the reactions of 1 with derivatives 2 under catalyst-free conditions. The novelty of this task is that, to the best of our knowledge, there have been no reports on the uncatalyzed reactions between tertiary enolates and Morita−Baylis−Hillman adducts. Furthermore, the available literature data indicate19 that only relatively strong and sterically unhindered nucleophiles are capable of reacting with Morita−Baylis−Hillman derivatives under catalyst-free conditions, suggesting that the corresponding reactions with

Scheme 1. In Situ Detrifluoroacetylative Generation and Reactivity of Enolates 1

Received: September 23, 2017 Published: November 27, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

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

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

base DMAP DABCO Et3N DIPEA NaOtBu DBU DBN MTBDe TBDf TMGg TMG TMG TMG TMG TMG TMG TMG TMG

solvent THF THF THF THF THF THF THF THF THF THF MTBE toluene CH3CN DMF 1,4-dioxane THF THF THF

t (h)

E/Zb

yield (%)c

12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 1 5

d

0 0 50 24 45 70 62 56 48 90 10 12 9 8 10 72h 82 88

nd ndd 88/12 80/20 88/12 91/9 82/18 86/14 85/15 91/9 93/7 95/5 84/16 69/31 96/4 92/8 91/9 92/8

a

Reaction conditions: diol 1a (0.12 mmol), 2a (0.12 mmol), LiBr (3.0 equiv), base (3.0 equiv), solvent (2.0 mL), rt. bDetermined by NMR analysis. Isolated yields. dNot determined. eMTBD = 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. fTBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene. gTMG = 1,1,3,3-tetramethyl guanidine. h0 °C. c

(entry 1) and DABCO (entry 2) was unsuccessful as we did not observe the formation of the requisite enolate. However, triethylamine (entry 3), Hünig’s base (DIPEA) (entry 4), and NaOtBu (entry 5) allowed for the reaction to proceed. The analysis of the reaction mixture revealed that only one product, 8a, resulting via the corresponding SN2′ substitution, was detected in the reaction mixture. With this breakthrough in reactivity, we decided to focus next on non-nucleophilic bases to completely exclude any possible interactions between the base and the Morita−Baylis−Hillman carbonate 7a. The reactions conducted with DBU (entry 6) and DBN (entry 7) somehow gave different results, indicating that not just basicity by structural features are important for the stereochemical outcome. Thus, the application of DBU resulted in a better yield as well as a Z/E ratio of product 8a (entry 6 vs 7). Next a series of reactions were conducted using guanidine derivatives, such as 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) (entry 8), triazabicyclodecene (TBD) (entry 9), and 1,1,3,3tetramethylguanidine (TMG) (entry 10). Among these three guanidines, the latter, TMG, gave the best result in terms of the yield and geometric stereoselectivity. Thus, as shown in entry 10, the SN2′ product 8 was isolated with 90% yield as a 91/9 mixture of E- and Z-stereoisomers. Building on these results, we explored various solvents with the aim to further improve the reaction performance. However, a series of the reactions conducted in methyl tert-butyl ether (entry 11), toluene (entry 12), acetonitrile (entry 13), DMF (entry 14), and 1,4-dioxane (entry 15) showed a generally sluggish progress, affording product 8a with a low chemical yield. It should be noted that, in all of these cases, despite the subdued reactivity, the corresponding product of the possible SN2 substitution was not observed. Another interesting observation was that the

tertiary enolates are rather unlikely. Herein we report that detrifluoroacetylatively in situ generated fluoro-enolates 1 highly chemo-selectively react with Morita−Baylis−Hillman derivatives 2 via the virtually exclusively SN2′ mechanism. Moreover, the corresponding SN2′ products 4 are obtained with excellent (typical 87%) yields and a high (typically 90/10) (E)geometric selectivity. Taking into account that the indole heterocyclic system is a well-established pharmacophore unit in drug design,20,21 for the discovery stage in this research project, we selected 3-fluoro-2oxindole-derived enolates 6a (Table 1) as model tertiary nucleophiles. As the Morita−Baylis−Hillman derivative, we selected carbonate 7a, based on its availability and enhanced reactivity, as compared with the corresponding acetates. As shown in the scheme of Table 1, the starting enolate precursor, 3-(1,1-dihydroxy-2,2,2-trifluoroethyl)-substituted 3fluoro-2-oxindole 5a, is treated with a base to generate the in situ corresponding enolate 6a with a simultaneous release of a molecule of trifluoroacetic acid. A series of the preliminary experiments revealed that the application of lithium salts, in particular LiBr in THF, is absolutely critical for this process. As shown previously,12−14 LiBr, most likely, stabilizes the in situ formed enolate. For example, the reactions conducted in the absence of LiBr did not take place at all.14b Moreover, we attempted to use LiClO4 in the place of LiBr; though successful, it afforded the target products with lower chemical yields and a lower diastereoselectivity.14b Furthermore, the optimization of the stoichiometry, ranging from 0.5 to 4 equiv of LiBr,14b revealed that a 3 mol amount provides an optimal stereochemical outcome. However, the nature of the base, used in an equimolar amount with LiBr, turned out to also play a very important role. For example, the application of DMAP 13664

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

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The Journal of Organic Chemistry Scheme 2. Structural Generality Study of the SN2′ Reactions between 1 and 2

nitro-containing products 8f,k were prepared with a greater than average proportion of the minor (Z)-isomer. Interestingly, the position of the nitro group on the aromatic ring had virtually no effect on the reaction outcome. Another nontypical result was observed in the reaction of the disubstituted ortho-/ meta-di-chloro derivative. Thus, product 8l was isolated with 95% yield as an individual stereopure (E)-isomer. In the second series of the reactions, we investigated the effect of substitution on the aromatic ring of the enolate precursors 5. In this case, the number of examples is limited due to some restrictions in the availability of the starting compounds for the preparation of hydrates 5. Nevertheless, the examples 8m−r presented in Scheme 2 demonstrate that the corresponding derivatives bearing halogen atoms, trifluoromethyl or methyl groups in position 5 or 6 of the heterocyclic moiety, show quite typical reaction outcomes ranging from 92 to 83% chemical yields and 96/4 to 90/10 geometric selectivity. Finally, to briefly access yet another dimension of the structural generality, we prepared compound 8r derived from the corresponding Morita−Baylis− Hillman carbonate bearing a CN group in the place of an alkoxy-carbonyl function. This relatively drastic structural

reactions conducted in toluene (entry 12) and 1,4-dioxane (entry 15) resulted in a noticeably greater geometric selectivity, of about 95/5, giving preference for the (E)-isomer, the same as observed in THF. Finally, the reaction time and temperature were examined as shown in entries 16−18. However, no significant effect of these factors was found. Compound (E)-8a was prepared in a stereochemically pure form by column chromatography, and its configuration was determined by the crystallographic analysis (see Supporting Information). Using the optimized reaction conditions, we were in a position to explore the structural generality of this new SN2′ reactivity of the detrifluoroacetylatively in situ generated 3fluoro-2-oxindole enolates 1. The major results are collected in Scheme 2. First, we investigated the reactions of Morita− Baylis−Hillman carbonates 2 bearing various substituents on the aromatic ring. For example, products containing unsubstituted phenyl 8d, halogen substituted in para-8a−c, meta8g,h, and ortho-8i, bearing electron-donating methyl 8e,j, and electron-withdrawing nitro groups 8f,k, in para- and metapositions, were obtained in generally excellent chemical yields and geometric selectivity. Nevertheless, one can notice that the 13665

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

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The Journal of Organic Chemistry

A solution of the trifluoromethylated intermediate (5 mmol) in acetonitrile (20 mL) was treated with Selectfluor (6 mmol) at room temperature. After 24 h, the reaction was diluted with ethyl acetate (20 mL) and filtered through Celite. The residue was washed with H2O (2 × 20 mL) and a brine solution (1 × 20 mL) and dried with anhydrous Na2SO4. The solvent was removed to give the products, β-keto-amides-hydrates 5, without further purification. 3-Fluoro-1-methyl-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)indolin-2-one (5a): 1H NMR (400 MHz, CDCl3) δ 7.69−7.60 (m, 1H), 7.48 (tdd, J = 7.8, 2.1, 1.3 Hz, 1H), 7.22−7.13 (m, 1H), 6.93 (dd, J = 7.9, 1.1 Hz, 1H), 5.15 (d, J = 10.2 Hz, 2H), 3.26 (s, 3H). 3,5-Difluoro-1-methyl-3-(2,2,2-trifluoro-1,1dihydroxyethyl)indolin-2-one (5b): 1H NMR (400 MHz, CDCl3) δ 7.43−7.36 (m, 1H), 7.24−7.13 (m, 1H), 6.88 (ddd, J = 8.6, 4.0, 1.3 Hz, 1H), 5.12 (s, 2H), 3.26 (s, 3H). 5-Chloro-3-fluoro-1-methyl-3-(2,2,2-trifluoro-1,1dihydroxyethyl)indolin-2-one (5c): 1H NMR (400 MHz, DMSO) δ 7.97 (d, J = 73.2 Hz, 2H), 7.55 (dd, J = 7.6, 1.9 Hz, 2H), 7.18−6.96 (m, 1H), 3.11 (s, 3H). 5-Bromo-3-fluoro-1-methyl-3-(2,2,2-trifluoro-1,1dihydroxyethyl)indolin-2-one (5d): 1H NMR (400 MHz, DMSO) δ 8.00 (d, J = 69.0 Hz, 2H), 7.73−7.50 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 3.11 (s, 3H). 3-Fluoro-1-methyl-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)5-(trifluoromethyl)indolin-2-one (5e): 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 6.94 (dd, J = 8.5, 1.2 Hz, 1H), 4.99 (s, 2H), 3.27 (s, 3H). 6-Chloro-3-fluoro-1-methyl-3-(2,2,2-trifluoro-1,1dihydroxyethyl)indolin-2-one (5f): 1H NMR (400 MHz, DMSO) δ 8.02−7.75 (m, 2H), 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (t, J = 1.5 Hz, 1H), 7.16 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 3.12 (s, 3H). 3-Fluoro-1,5-dimethyl-3-(2,2,2-trifluoro-1,1dihydroxyethyl)indolin-2-one (5g): 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.28 (s, 1H), 6.82 (dd, J = 8.0, 1.2 Hz, 1H), 5.15 (d, J = 30.3 Hz, 2H), 3.24 (s, 3H), 2.36 (s, 3H). The Morita−Baylis−Hillman carbonate substrates 7 were prepared according to the previous methods without any changes.23 General Procedure for the SN2′ Reaction between 1 and 2. The mixture of 3-(1,1-dihydroxy-2,2,2-trifluoroethyl)substituted 3-fluoro-2-oxindole 5 (0.10 mol) and 7 (0.12 mmol) were dissolved in 1.0 mL of THF and stirred at room temperature for 5 min. Then, TMG (37.6 μL, 0.3 mmol, 3.0 equiv) dissolved in 1.0 mL of THF was added dropwise, and the mixture was stirred at this temperature until complete consumption of the starting material (monitored by TLC). Finally, the reaction was quenched with saturated aqueous NH4Cl (2.0 mL), followed by H2O (6.0 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The organic phase was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc = 10:1 to 5:1) to afford products 8. Methyl (E)-3-(4-Bromophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8a): white solid, mp 136−138 °C, 37.5 mg (90% yield); E/Z = 91/9; 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.43−7.32 (m, 5H), 7.29−7.21 (m, 1H), 7.02 (tt, J = 7.6, 0.9 Hz, 1H), 6.83 (dd, J = 7.9, 1.3 Hz, 1H), 3.65 (s, 3H), 3.46 (ddd, J = 20.9, 14.8, 0.7 Hz, 1H), 3.31 (ddd, J = 21.8, 14.7, 0.7 Hz, 1H), 3.17 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.21 (s, 1F); 13C NMR (126 MHz,

change did not influence the reaction performance in any noticeable way, as product 8s was isolated with 93% yield and 89/11 geometric purity. Furthermore, we demonstrated that the present method can also be used for the reactions of the aliphatic Morita−Baylis−Hillman carbonate. For example, compound 8t was prepared with 85% yield as a 94/6 mixture of the corresponding diastereomers. However, our attempts to extend this approach to some other types of detrifluoroacetylatively generated enolates were unsuccessful.14b Once again, it should be emphasized that no products resulting from the possibly competing SN2 process were ever observed in the reaction mixtures. As the closing objective in this research project, we attempted to provide the mechanistic rationale that the results obtained. As one can see from Figure 1, three possible

Figure 1. Possible transition states TS-A and B in the reactions understudy.

transition states can be constructed to account for the formation of products 8. Considering the transition states A and B, one might agree that TS-A appears to be the most probable, providing for the unidirectional flow of electrons and avoiding any repulsive electrostatic interactions between the polarized/charged functional groups. Furthermore, TS-A can be additionally stabilized via the attractive parallel displaced type of aromatic interactions22 between phenyl rings of the tertiary enolate and the Morita−Baylis−Hillman carbonate. This feature is of particular importance as it can be used to account for the observed effect of the aromatic substitution of the stereochemical outcome. By contrast, TS-B and C could hardly explain the observed experimental data. In conclusion, we disclose the first example of the SN2′ reactivity of the detrifluoroacetylatively in situ generated tertiary fluoro-enolates in the uncatalyzed reactions with Morita−Baylis−Hillman carbonates. We found that the corresponding substitution reactions readily occur at ambient temperatures in the presence of LiBr and a non-nucleophilic base. Excellent chemical yields, high geometric selectivity, and structural generality all bode well with great synthetic value of these reactions for the preparation of novel fluorine-containing compounds.

■

EXPERIMENT SECTION General Procedures for the Synthesis of β-Ketoamides-hydrates 5. 13a To a stirred solution of sodium hydride (20 mmol) in diethyl ether (20 mL) was added dropwise the solution of trifluoromethyl ethyl acetate (10.5 mmol) and oxindoles (10 mmol) in diethyl ether (20 mL), and the mixture stirred for 24 h at room temperature. Then the resulting mixture was diluted with a 1 M HCl solution (pH = 3) and extracted with ether. The combined organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude trifluoromethylated intermediate, which was purified by recrystallization. 13666

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

Note

The Journal of Organic Chemistry CDCl3) δ 172.5 (d, J = 22.0 Hz), 168.5, 143.7 (d, J = 5.6 Hz), 141.9, 134.9, 133.2, 131.2 (d, J = 2.8 Hz), 130.7 (d, J = 3.0 Hz), 128.8, 126.6 (d, J = 2.5 Hz), 125.6 (d, J = 19.0 Hz), 124.9, 122.9 (d, J = 2.6 Hz), 108.7, 92.6 (d, J = 191.4 Hz), 52.2, 33.1 (d, J = 28.4 Hz), 26.3; IR (cm−1) 2950, 1716, 1614, 1470, 1354, 1101; HRMS (ESI-TOF) calcd for [C20H17BrFNO3 + Na]+ 440.0274, found 440.0273. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-(4-fluorophenyl)acrylate (8b): white solid, mp 78−80 °C, 31.4 mg (88% yield); E/Z = 92/8; 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.52−7.44 (m, 2H), 7.38 (tt, J = 7.8, 1.5 Hz, 1H), 7.28−7.26 (m, 1H), 7.10 (t, J = 8.7 Hz, 2H), 7.04 (tt, J = 7.6, 0.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H), 3.57−3.45 (m, 1H), 3.39−3.29 (m, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −111.56 (s, 1F), −157.19 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.5 (d, J = 22.1 Hz), 168.6, 162.9 (d, J = 249.9 Hz), 143.7 (d, J = 5.5 Hz), 142.1, 131.4 (dd, J = 8.3, 3.2 Hz), 131.2 (d, J = 2.8 Hz), 130.8 (d, J = 3.3 Hz), 126.0−125.3 (m), 124.9, 122.8 (d, J = 2.7 Hz), 115.7 (d, J = 21.5 Hz), 108.7, 92.7 (d, J = 191.3 Hz), 52.1, 32.9 (d, J = 28.4 Hz), 26.3; IR (cm−1) 2928, 1735, 1615, 1507, 1472, 1375, 1110; HRMS (ESI-TOF) calcd for [C20H17F2NO3 + Na]+ 380.1074, found 380.1076. Methyl (E)-3-(4-Chlorophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8c): white solid, mp 110−112 °C, 34.3 mg (92% yield); E/Z = 92/8; 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.45−7.34 (m, 5H), 7.30−7.23 (m, 1H), 7.04 (tt, J = 7.6, 0.9 Hz, 1H), 6.85 (dd, J = 7.9, 1.3 Hz, 1H), 3.66 (s, 3H), 3.48 (ddd, J = 20.9, 14.8, 0.7 Hz, 1H), 3.33 (ddd, J = 21.8, 14.7, 0.7 Hz, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.19 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.4 (d, J = 22.0 Hz), 168.5, 143.7 (d, J = 5.6 Hz), 141.8, 134.9, 133.2, 131.2 (d, J = 2.8 Hz), 130.7 (d, J = 3.0 Hz), 128.8, 126.6 (d, J = 2.5 Hz), 125.5 (d, J = 19.0 Hz), 124.9, 122.9 (d, J = 2.6 Hz), 108.7, 92.6 (d, J = 191.4 Hz), 52.2, 33.0 (d, J = 28.4 Hz), 26.3; IR (cm−1) 2920, 1718, 1615, 1468, 1325, 1090; HRMS (ESI-TOF) calcd for [C20H17ClFNO3 + Na]+ 396.0779, found 396.0777. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-phenyl acrylate (8d): white solid, mp 100−102 °C, 30.2 mg (89% yield); E/Z = 93/7; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.46−7.34 (m, 6H), 7.26 (dt, J = 7.3, 1.6 Hz, 1H), 7.06−6.98 (m, 1H), 6.84 (dd, J = 7.8, 1.3 Hz, 1H), 3.66 (s, 3H), 3.60−3.48 (dd, J = 20.9, 14.8 Hz, 1H), 3.39 (dd, J = 20.9, 14.7 Hz, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −156.64 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.6 (d, J = 21.9 Hz), 168.7, 143.7 (d, J = 5.6 Hz), 143.2, 134.8, 131.1 (d, J = 2.8 Hz), 129.3 (d, J = 2.7 Hz), 128.9, 128.6, 126.1 (d, J = 3.1 Hz), 125.6 (d, J = 18.9 Hz), 125.0, 122.8 (d, J = 2.6 Hz), 108.6, 92.7 (d, J = 190.8 Hz), 52.1, 32.9 (d, J = 29.0 Hz), 26.3; IR (cm−1) 2922, 1723, 1613, 1470, 1373, 1176, 1092; HRMS (ESI-TOF) calcd for [C20H18FNO3 + Na]+ 362.1168, found 362.1166. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-(p-tolyl)acrylate (8e): white solid, mp 82−84 °C, 28.6 mg (81% yield); E/Z = 94/6; 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.43−7.32 (m, 3H), 7.30−7.25 (m, 1H), 7.22 (d, J = 7.9 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H), 3.57 (dd, J = 20.9, 14.8 Hz, 1H), 3.39 (dd, J = 21.4, 14.9 Hz, 1H), 3.19 (s, 3H), 2.39 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −156.60 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.7 (d, J = 22.1 Hz), 168.8, 143.7 (d, J = 5.8 Hz), 143.3, 139.2, 131.9, 131.1 (d, J = 2.8 Hz), 129.5 (d, J = 2.8

Hz), 129.3, 125.6 (d, J = 19.1 Hz), 125.1, 122.8 (d, J = 2.6 Hz), 108.6, 92.8 (d, J = 190.8 Hz), 52.0, 33.0 (d, J = 28.8 Hz), 26.3, 21.4; IR (cm−1) 2921, 1718, 1615, 1466, 1375, 1198, 1090; HRMS (ESI-TOF) calcd for [C21H20FNO3 + Na]+ 376.1325, found 376.1320. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-(4-nitrophenyl)acrylate (8f): white solid, mp 106− 108 °C, 32.3 mg (84% yield); E/Z = 86/14; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.40 (tt, J = 7.8, 1.5 Hz, 2H), 7.28−7.25 (m, 1H), 7.12−7.02 (m, 1H), 6.91−6.82 (m, 1H), 3.71 (s, 3H), 3.48−3.37 (ddd, J = 21.2, 14.6, 0.8 Hz, 1H), 3.32 (ddd, J = 21.3, 14.6, 0.7 Hz, 1H), 3.19 (s, 1H); 19F NMR (471 MHz, CDCl3) δ −157.43 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.1 (d, J = 21.8 Hz), 167.9, 147.6, 143.6 (d, J = 5.5 Hz), 141.4, 140.4, 131.4 (d, J = 2.7 Hz), 130.0 (d, J = 3.3 Hz), 129.4 (d, J = 2.3 Hz), 125.4 (d, J = 18.9 Hz), 123.8, 123.0 (d, J = 2.5 Hz), 108.9, 92.3 (d, J = 192.1 Hz), 52.4, 33.1 (d, J = 28.4 Hz), 26.3; IR (cm−1) 2950, 1714, 1613, 1515, 1470, 1341, 1094; HRMS (ESI-TOF) calcd for [C20H17FN2O5 + Na]+ 407.1019, found 407.1018. Methyl (E)-3-(3-Bromophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8g): white solid, mp 143−145 °C, 33.4 mg (80% yield); E/Z = 89/11; 1H NMR (500 MHz, CDCl3) δ 7.74 (s, 1H), 7.48 (dt, J = 8.1, 1.3 Hz, 1H), 7.44− 7.33 (m, 3H), 7.32−7.24 (m, 2H), 7.08−6.98 (m, 1H), 6.85 (d, J = 7.9 Hz, 1H), 3.71 (s, 3H), 3.47 (dd, J = 21.0, 14.7 Hz, 1H), 3.32 (ddd, J = 21.1, 14.7, 0.7 Hz, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.53 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.4 (d, J = 22.0 Hz), 168.3, 143.7 (d, J = 5.7 Hz), 141.3, 136.8, 131.9 (d, J = 2.4 Hz), 131.7, 131.3 (d, J = 2.8 Hz), 130.1, 127.7 (d, J = 3.3 Hz), 127.6 (d, J = 2.9 Hz), 125.4 (d, J = 19.1 Hz), 124.9, 122.9 (d, J = 2.7 Hz), 122.6, 108.7, 92.5 (d, J = 191.9 Hz), 52.3, 33.0 (d, J = 28.5 Hz), 26.3; IR (cm−1) 2922, 1727, 1612, 1559, 1470, 1354, 1181, 1086; HRMS (ESI-TOF) calcd for [C20H17BrFNO3 + Na]+ 440.0274, found 440.0275. Methyl (E)-3-(3-Chlorophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8h): white solid, mp 66−68 °C, 30.6 mg (82% yield); E/Z = 88/12; 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.38 (tt, J = 7.8, 1.5 Hz, 1H), 7.34−7.30 (m, 3H), 7.29−7.23 (m, 2H), 7.04 (tt, J = 7.6, 0.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.70 (s, 3H), 3.53−3.41 (m, 1H), 3.39−3.27 (m, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.44 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.4 (d, J = 22.0 Hz), 168.3, 143.7 (d, J = 5.5 Hz), 141.4, 136.6, 134.4, 131.2 (d, J = 2.8 Hz), 129.8, 129.1 (d, J = 2.5 Hz), 128.8, 127.6 (d, J = 2.8 Hz), 127.2 (d, J = 3.0 Hz), 125.4 (d, J = 19.0 Hz), 124.9, 122.9 (d, J = 2.5 Hz), 108.7, 92.5 (d, J = 191.6 Hz), 52.2, 33.0 (d, J = 28.5 Hz), 26.3; IR (cm−1) 2922, 1735, 1616, 1470, 1375, 1109, 1008; HRMS (ESI-TOF) calcd for [C20H17ClFNO3 + Na]+ 396.0779, found 396.0777. Methyl (E)-3-(2-Bromophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8i): white solid, mp 60−62 °C, 37.9 mg (91% yield); E/Z = 96/4; 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.45−7.33 (m, 4H), 7.27 (dt, J = 7.5, 1.6 Hz, 1H), 7.10−6.96 (m, 1H), 6.85 (dd, J = 7.9, 1.2 Hz, 1H), 3.66 (s, 3H), 3.48 (ddd, J = 20.9, 14.8, 0.7 Hz, 1H), 3.39−3.26 (m, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.19 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.4 (d, J = 22.0 Hz), 168.4, 143.7 (d, J = 5.6 Hz), 141.8, 134.9, 133.2, 131.2 (d, J = 2.8 Hz), 130.7 (d, J = 3.0 Hz), 128.8, 126.6 (d, J = 2.5 Hz), 125.6 (d, J = 19.0 Hz), 124.9, 122.9 (d, J = 2.6 Hz), 108.7, 92.6 (d, J = 191.4 Hz), 52.2, 33.0 (d, J = 28.4 Hz), 26.3; 13667

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

Note

The Journal of Organic Chemistry IR (cm−1) 2924, 1735, 1616, 1470, 1375, 1107, 1023; HRMS (ESI-TOF) calcd for [C20H17BrFNO3 + Na]+ 440.0274, found 440.0270. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-(m-tolyl)acrylate (8j): white solid, mp 82−84 °C, 32.1 mg (91% yield); E/Z = 95/5; 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.43−7.35 (m, 1H), 7.32−7.22 (m, 3H), 7.20−7.13 (m, 2H), 7.02 (tt, J = 7.6, 0.9 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.67 (s, 3H), 3.56 (dd, J = 20.7, 14.7 Hz, 1H), 3.37 (ddd, J = 21.3, 14.8, 0.8 Hz, 1H), 3.19 (s, 1H), 2.36 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −156.61 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.7 (d, J = 21.9 Hz), 168.7, 143.7 (d, J = 5.7 Hz), 143.3, 138.1, 134.7, 131.1 (d, J = 2.8 Hz), 130.0 (d, J = 2.3 Hz), 129.6, 128.5, 126.3 (d, J = 2.7 Hz), 125.9 (d, J = 3.2 Hz), 125.6 (d, J = 18.9 Hz), 125.1, 122.8 (d, J = 2.6 Hz), 108.5, 92.7 (d, J = 191.0 Hz), 52.1, 33.0 (d, J = 28.9 Hz), 29.7, 26.3, 21.4; IR (cm−1) 2920, 1735, 1616, 1470, 1375, 1108, 1008; HRMS (ESI-TOF) calcd for [C21H20FNO3 + Na]+ 376.1325, found 376.1322. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-3-(3-nitrophenyl)acrylate (8k): white solid, mp 83− 85 °C, 30.7 mg (80% yield); E/Z = 85/15; 1H NMR (500 MHz, CDCl3) δ 8.23−8.14 (m, 2H), 7.84 (s, 1H), 7.80−7.75 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.42−7.36 (m, 1H), 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.09−7.00 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.51−3.39 (m, 1H), 3.34 (dd, J = 20.9, 14.7 Hz, 1H), 3.20 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −155.75 (s, 1F) (Z), −157.92 (s, 1F) (E); 13C NMR (126 MHz, CDCl3) δ 172.1 (d, J = 21.9 Hz), 168.0, 148.3, 143.7 (d, J = 5.3 Hz), 140.0, 137.6, 136.4, 135.1 (d, J = 2.9 Hz), 134.1, 131.4 (d, J = 2.8 Hz), 129.6, 129.3−128.6 (m), 125.6, 125.2 (d, J = 19.1 Hz), 124.8, 123.7 (d, J = 2.9 Hz), 123.4, 123.2−122.9 (m), 108.9, 92.4 (d, J = 192.4 Hz), 52.4, 33.0 (d, J = 28.4 Hz), 26.3; IR (cm−1) 2920, 1731, 1615, 1528, 1470, 1351, 1095; HRMS (ESI-TOF) calcd for [C20H17FN2O5 + Na]+ 407.1019, found 407.1017. Methyl (E)-3-(2,3-Dichlorophenyl)-2-((3-fluoro-1-methyl-2oxoindolin-3-yl)methyl)acrylate (8l): white solid, mp 133−135 °C, 38.7 mg (95% yield); E/Z = 99/1; 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.51−7.46 (m, 1H), 7.40−7.34 (m, 1H), 7.34−7.30 (m, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.24−7.21 (m, 1H), 3.68 (s, 3H), 3.49−3.38 (m, 1H), 3.34 (ddd, J = 17.6, 14.3, 0.8 Hz, 1H), 3.14 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −153.95 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.2 (d, J = 21.6 Hz), 167.7, 143.9 (d, J = 5.6 Hz), 139.8, 135.7, 133.4, 132.0, 131.3 (d, J = 2.9 Hz), 130.5, 128.5 (d, J = 4.7 Hz), 128.2 (d, J = 3.6 Hz), 127.4, 125.1, 124.9 (d, J = 18.9 Hz), 122.8 (d, J = 2.6 Hz), 108.6, 92.2 (d, J = 190.6 Hz), 52.3, 32.3 (d, J = 30.5 Hz), 26.23; IR (cm−1) 2922, 1733, 1612, 1431, 1280, 1101; HRMS (ESI-TOF) calcd for [C 20 H 16 C l2 FNO 3 + Na] + 430.0389, found 430.0387. Methyl (E)-3-(4-Bromophenyl)-2-((3,5-difluoro-1-methyl-2oxoindolin-3-yl)methyl)acrylate (8m): white solid, mp 69−71 °C, 37.8 mg (87% yield); E/Z = 92/8; 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.60−7.51 (m, 2H), 7.36−7.30 (m, 2H), 7.08 (tdd, J = 8.8, 2.6, 1.6 Hz, 1H), 7.00 (dt, J = 7.5, 2.2 Hz, 1H), 6.77 (ddd, J = 8.5, 4.0, 1.3 Hz, 1H), 3.71 (s, 3H), 3.47 (ddd, J = 20.5, 14.7, 0.7 Hz, 1H), 3.33 (ddd, J = 21.6, 14.8, 0.7 Hz, 1H), 3.18 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −119.53 (s, 1F), −157.62 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.1 (d, J = 21.8 Hz), 168.3, 159.0 (dd, J = 242.7, 3.0 Hz), 142.2, 139.6 (dd, J = 5.5, 2.2 Hz), 133.5, 131.9, 130.8 (d, J = 3.1 Hz), 126.9 (d, J = 7.9 Hz), 126.2 (d, J = 2.9 Hz),

123.3, 117.4 (dd, J = 23.6, 2.7 Hz), 113.2 (d, J = 25.4 Hz), 109.4 (d, J = 8.0 Hz), 92.4 (d, J = 193.3 Hz), 52.3, 32.8 (d, J = 28.4 Hz), 26.4; IR (cm−1) 2922, 1735, 1627, 1494, 1366, 1105, 1008; HRMS (ESI-TOF) calcd for [C20H16BrF2NO3 + Na]+ 458.0179, found 458.0181. Methyl (E)-3-(4-Bromophenyl)-2-((5-chloro-3-fluoro-1methyl-2-oxoindolin-3-yl)methyl)acrylate (8n): white solid, mp 134−136 °C, 40.1 mg (89% yield); E/Z = 95/5; 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.61−7.48 (m, 2H), 7.40− 7.30 (m, 3H), 7.19 (t, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.4, 1.3 Hz, 1H), 3.72 (s, 3H), 3.47 (ddd, J = 19.9, 14.7, 0.7 Hz, 1H), 3.33 (ddd, J = 21.5, 14.6, 0.7 Hz, 1H), 3.17 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.69 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 171.9 (d, J = 21.9 Hz), 168.3, 142.4, 142.2 (d, J = 5.4 Hz), 133.5, 131.9, 131.0 (d, J = 2.7 Hz), 130.8 (d, J = 3.0 Hz), 128.3 (d, J = 2.8 Hz), 126.9 (d, J = 19.1 Hz), 126.1 (d, J = 3.2 Hz), 125.4, 123.4, 109.7, 92.2 (d, J = 193.1 Hz), 52.3, 32.7 (d, J = 28.4 Hz), 26.4; IR (cm−1) 2920, 1702, 1612, 1489, 1433, 1177, 1077; HRMS (ESI-TOF) calcd for [C20H16BrClFNO3 + Na]+ 473.9884, found 473.9879. Methyl (E)-2-((5-Bromo-3-fluoro-1-methyl-2-oxoindolin-3yl)methyl)-3-(4-bromophenyl)acrylate (8o): white solid, mp 158−160 °C, 45.5 mg (92% yield); E/Z = 95/5; 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.62−7.51 (m, 2H), 7.49 (dd, J = 8.3, 1.8 Hz, 1H), 7.37−7.30 (m, 3H), 6.72 (dd, J = 8.3, 1.2 Hz, 1H), 3.72 (d, J = 1.1 Hz, 3H), 3.60−3.40 (m, 1H), 3.38−3.25 (m, 1H), 3.16 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.61 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 171.8 (d, J = 21.8 Hz), 168.3, 142.7 (d, J = 5.4 Hz), 142.4, 133.9 (d, J = 2.7 Hz), 133.5, 131.9, 130.8 (d, J = 3.0 Hz), 128.1, 127.2 (d, J = 19.1 Hz), 126.1 (d, J = 3.2 Hz), 123.4, 115.4 (d, J = 3.0 Hz), 110.2, 92.2 (d, J = 193.5 Hz), 52.4, 32.7 (d, J = 28.5 Hz), 26.4; IR (cm−1) 2920, 1701, 1608, 1489, 1006; HRMS (ESI-TOF) calcd for [C20H16Br2FNO3 + Na]+ 517.9379, found 517.9376. Methyl (E)-3-(4-Bromophenyl)-2-((3-fluoro-1-methyl-2oxo-5-(trifluoromethyl)indolin-3-yl)methyl)acrylate (8p): white solid, mp 101−103 °C, 42.2 mg (87% yield); E/Z = 96/4; 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.26 (ddd, J = 8.7, 1.7, 0.8 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.5, 1.2 Hz, 1H), 3.70 (s, 3H), 3.50 (ddd, J = 20.6, 14.8, 0.8 Hz, 1H), 3.42− 3.27 (m, 1H), 3.19 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −58.35 (s, 3F), −157.11 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.1 (d, J = 21.8 Hz), 168.1, 144.7, 142.4, 142.3 (d, J = 5.4 Hz), 133.5, 131.9, 130.8 (d, J = 3.1 Hz), 126.8 (d, J = 19.1 Hz), 126.0 (d, J = 2.7 Hz), 124.3 (d, J = 2.4 Hz), 123.5, 121.5, 119.4, 119.0, 109.3, 91.4, 52.2, 32.8 (d, J = 28.5 Hz), 26.5; IR (cm−1) 2920, 1735, 1623, 1491, 1367, 1153, 1097; HRMS (ESI-TOF) calcd for [C21H16BrF4NO3 + K]+ 523.9887, found 523.9885. Methyl (E)-3-(4-Bromophenyl)-2-((6-chloro-3-fluoro-1methyl-2-oxoindolin-3-yl)methyl)acrylate (8q): white solid, mp 169−171 °C, 37.4 mg (83% yield); E/Z = 92/8; 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.16 (dd, J = 7.9, 2.0 Hz, 1H), 7.01 (ddd, J = 7.9, 1.9, 0.8 Hz, 1H), 6.85 (t, J = 1.5 Hz, 1H), 3.69 (s, 3H), 3.52−3.41 (m, 1H), 3.33 (ddd, J = 20.9, 14.8, 0.7 Hz, 1H), 3.17 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −155.96 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.3 (d, J = 22.0 Hz), 168.3, 145.0 (d, J = 5.4 Hz), 142.2, 137.3, 133.5, 131.9, 130.8 (d, J = 3.1 Hz), 126.3 (d, J = 3.0 Hz), 125.9, 123.8 (d, J = 19.1 Hz), 123.4, 122.7 (d, J = 2.6 Hz), 109.5, 92.0 (d, J = 191.9 Hz), 52.3, 32.8 (d, J = 28.9 Hz), 26.4; IR (cm−1) 2922, 1718, 1610, 13668

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

Note

The Journal of Organic Chemistry ORCID

1431, 1377, 1370, 1111; HRMS (ESI-TOF) calcd for [C20H16BrClFNO3 + Na]+ 473.9884, found 473.9885. Methyl (E)-3-(4-Bromophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylate (8r): white solid, mp 137−139 °C, 36.6 mg (85% yield); E/Z = 90/10; 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 7.9, 2.1 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.73 (dd, J = 7.9, 1.2 Hz, 1H), 3.68 (s, 3H), 3.46 (dd, J = 20.6, 14.7 Hz, 1H), 3.32 (dd, J = 21.5, 14.7 Hz, 1H), 3.16 (s, 3H), 2.30 (s, 3H); 19F NMR (471 MHz, CDCl3) δ −157.31 (s, 1F); 13C NMR (126 MHz, CDCl3) δ 172.3 (d, J = 22.0 Hz), 168.5, 141.8, 141.2 (d, J = 5.7 Hz), 133.7, 132.5 (d, J = 2.7 Hz), 131.8, 131.4 (d, J = 2.9 Hz), 130.9 (d, J = 3.0 Hz), 126.8 (d, J = 2.8 Hz), 125.6, 125.4, 123.2, 108.44, 92.8 (d, J = 191.5 Hz), 52.1, 33.0 (d, J = 28.6 Hz), 26.3, 21.0; IR (cm−1) 2920, 1703, 1615, 1491, 1437, 1366, 1355, 1101; HRMS (ESI-TOF) calcd for [C21H19BrFNO3 + Na]+ 454.0430, found 454.0432. (E)-3-(4-Bromophenyl)-2-((3-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)acrylonitrile (8s): white solid, mp 101−103 °C, 35.7 mg (93% yield); E/Z = 89/11; 1H NMR (500 MHz, CDCl3) δ 7.72−7.63 (m, 2H), 7.54 (dt, J = 7.4, 1.6 Hz, 1H), 7.44−7.36 (m, 3H), 7.24−7.16 (m, 1H), 7.13−7.02 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 3.31 (ddd, J = 13.8, 10.7, 1.0 Hz, 1H), 3.20 (s, 3H), 3.19−3.08 (m, 1H); 19F NMR (471 MHz, CDCl3) δ −154.05 (s, 1F) (Z), −154.84 (s, 1F) (E); 13C NMR (126 MHz, CDCl3) δ 171.6 (d, J = 20.9 Hz), 149.6, 144.0 (d, J = 5.2 Hz), 133.1, 132.0 (d, J = 2.9 Hz), 130.8, 129.8, 128.9 (d, J = 3.1 Hz), 125.8, 123.9 (d, J = 18.9 Hz), 123.6 (d, J = 2.6 Hz), 118.0, 109.0, 102.0 (d, J = 9.0 Hz), 91.9 (d, J = 192.8 Hz), 40.4 (d, J = 30.8 Hz), 26.4; IR (cm−1) 3362, 2920, 2212, 1729, 1615, 1470, 1375, 1094; HRMS (ESI-TOF) calcd for [C19H15FN2O + Na]+ 329.1066, found 329.1065. Methyl (E)-2-((3-Fluoro-1-methyl-2-oxoindolin-3-yl)methyl)but-2-enoate (8t): white solid, mp 96−98 °C, 23.6 mg (85% yield); E/Z = 94/6; 1H NMR (400 MHz, CDCl3) δ 7.40−7.28 (m, 2H), 7.11−6.99 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 3.54 (s, 3H), 3.32 (dd, J = 17.8, 14.4 Hz, 1H), 3.18 (s, 3H), 3.11 (dd, J = 23.1, 14.4 Hz, 1H), 1.89 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3) δ −156.86 (s, 1F) (Z), −158.51 (s, 1F) (E); 13C NMR (101 MHz, CDCl3) δ 172.8 (d, J = 21.8 Hz), 167.9, 143.6 (d, J = 5.8 Hz), 142.9, 142.7, 131.1 (d, J = 3.0 Hz), 125.8 (d, J = 3.7 Hz), 125.1, 122.7 (d, J = 2.7 Hz), 108.6, 92.7 (d, J = 191.4 Hz), 51.7, 31.7 (d, J = 29.1 Hz), 26.3, 15.1 (d, J = 2.6 Hz); IR (cm−1) 1735, 1615, 1436, 1269, 1097, 752; HRMS (ESI-TOF) calcd for [C15H16FNO3 + Na]+ 300.1012, found 300.1009.

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Jianlin Han: 0000-0002-3817-0764 Vadim A. Soloshonok: 0000-0003-0681-4526 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 21472082). The support from the Collaborative Innovation Center of Solid-State Lighting and Energy-Saving Electronics, Jiangsu 333 program (for Pan), IKERBASQUE, Basque Foundation for Science (for Soloshonok), Shenzhen Virtual University Park, and Changzhou Jin-Feng-Huang program (for Pan) are also acknowledged.

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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.7b02409. Control experiments, reaction of linear hydrates and the aliphatic MBH substrate, full spectroscopic data for compounds 8, copies of 1H and 13C NMR spectra, and X-ray single-crystal analysis of 8a (PDF) Crystal data for 8a (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. 13669

DOI: 10.1021/acs.joc.7b02409 J. Org. Chem. 2017, 82, 13663−13670

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