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Enantioselective Synthesis of 1,3-Disubstituted 1,3Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o‑Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid Xing Yang,‡ Shuai Pang,‡ Feng Cheng, Yue Zhang, Ya-Wei Lin, Quan Yuan, Fang-Lin Zhang, and Yi-Yong Huang* Department of Chemistry, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, P.R. China S Supporting Information *

ABSTRACT: The first chiral Brønsted acid-catalyzed asymmetric cascade allylboration/oxo-Michael reaction between o-formyl chalcones and allylboronate has been successfully discovered, which afforded chiral 1,3-disubstituted 1,3-dihydroisobenzofurans with a yield, diastereoselective ratio (dr) and enantioselective excess (ee) up to 94%, 2.5:1, and 98%, respectively. In addition, 2,3-dienylboronic pinacol ester was also applied into this cascade reaction with good catalytic results.

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INTRODUCTION

minomethyl-3-phenylphthalan (II) exhibit antihistaminic activity.2 The 1,3-dihydrobenzo[c]furan analogue of d4T (III) has an anti-HIV activity.3 In addition, the σ1 receptor ligand (IV) comprising the same key motif was selected as an 18F-labeled radiotracer for noninvasive imaging of the central σ1 receptor protein.4 Therefore, the development of efficient synthetic methods to construct chiral 1,3-disubstituted 1,3-dihydroisobenzofurans represents a significant task for organic chemists. Despite achieving the catalytic enantioselective synthesis of chiral 1-disubstituted 1,3-dihydroisobenzofurans (Scheme 1a)5 and racemic synthesis of 1,3-disubstituted 1,3-dihydroisobenzofurans (Scheme 1b),6 the asymmetric synthesis of chiral 1,3disubstituted 1,3-dihydroisobenzofurans in a catalytic manner has not been explored and remains highly desirable. The chiral phosphoric acid (CPA)-catalyzed asymmetric reactions of unsaturated organoboronate reagents with aldehydes for chiral secondary alcohols have reached tremendous development in the past few years.7 In 2010, the Antilla group discovered a CPA-catalyzed enantioselective allylboration of aldehydes.7e Thereafter, a catalytic asymmetric allenylboration of aldehydes enabled by a CPA was disclosed by the Antilla group7f and Roush group.7g In 2015, our group

Chiral 1,3-disubstituted 1,3-dihydroisobenzofuran skeletons are frequently found in biologically and pharmaceutically active compounds. As shown in Figure 1, compound I as a melanocortin subtype-4 receptor (MC4R) agonist shows good efficacy in lowering the food intake and body weight in rodents.1 Both the cis- and trans-isomers of l-N,N-dimethyla-

Figure 1. Selected important molecules containing a 1,3-disubstituted 1,3-dihydroisobenzofuran scaffold. © 2017 American Chemical Society

Received: July 25, 2017 Published: September 8, 2017 10388

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry Scheme 1. Cascade Strategies for the Synthesis of 1,3-Dihydroisobenzofurans

Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

additive

solvent

T/°C

yield/%b

drc (cis/trans)

ee/%d (cis/trans)

e

(R)-4a (R)-4a (R)-4a (R)-4a (R)-4a (R)-4b (R)-4c (R)-4a (R)-4a (R)-4a (R)-4a

4 Å MS 4 Å MS 4 Å MS 4 Å MS none none none i PrOH i PrOH i PrOH i PrOH

toluene CH2Cl2 PhCF3 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4

rt rt rt rt rt rt rt rt 0 to rt −10 to rt −20 to rt

58 48 57 65 63 58 83 94 93 92 92

1.9:1 1.4:1 1.5:1 1.8:1 3.2:1 1.1:1 2.2:1 1.7:1 1.5:1 1.4:1 1.4:1

71/52 26/17 70/69 85/76 95/72 25/11 81/75 90/85 92/88 94/88 94/90

1 2e 3e 4e 5 6 7 8f 9f 10f 11f a

Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), catalyst (5 mol %), solvent (0.5 mL). bCombined isolated yield of cis- and trans-isomers. Determined by 1H NMR analysis of the crude products. dDetermined by chiral HPLC. e50 mg 4 Å MS. fThe reaction mixture was stirred at the corresponding temperature for 12 h, followed by the addition of iPrOH (1.0 equiv), and then stirred at rt for 24 h. c

tion of o-formyl chalcones was envisaged (Scheme 1c). Since CPA has been widely used in catalytic asymmetric oxo-Michael reactions,11 we hoped that the second step of the intramolecular asymmetric oxo-Michael reaction in our study could also be well controlled by a CPA catalyst.12

developed a CPA-catalyzed enantioselective dienylboration reaction between 2,3-dienylboronic ester and aldehydes.8 Furthermore, cascade reactions9 initiated by such type of addition reactions to obtain complex molecules have also been documented. For example, in 2013, Fustero and co-workers exemplified a cascade CPA-catalyzed allylboration/ring-closing metathesis reaction of o-vinylbenzaldehydes to build benzo- and heteroarene-fused cyclic homoallylic alcohols.10a In 2016, they further applied the same strategy to get ω-alkynyl homoallylic and homopropargylic alcohols, thus facilitating the construction of other complex scaffolds.10b Toward overcoming the difficulties of creating chiral 1,3-disubstituted 1,3-dihydroisobenzofurans, the unprecedented chiral phosphoric acidcatalyzed cascade asymmetric allylboration/oxo-Michael reac-

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RESULTS AND DISCUSSION

To begin the research, o-formyl chalcone 1a was synthesized and chosen as one of the model substrates for optimizing the reaction conditions. Since the BINOL-derived chiral phosphoric acid (R)-4a bearing 2,4,6-trisisopropyl substitutents has shown excellent performance in the asymmetric allylboration of aldehydes, (R)-4a was chosen as the first choice in this study 10389

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry

Table 2. Scope of the External Aryl Group of the o-Formyl Chalconesa

(Table 1). The reaction between 1a and allylboronate 2 was carried out in the presence of 4 Å molecular sieves (MS) in toluene at rt. As expected, chiral 1,3-disubstituted 1,3dihydroisobenzofuran 3a was isolated in 58% yield with 1.9:1 dr and moderate enantioselectivity (Table 1, entry 1). cis-3a and trans-3a were determined by NOESY NMR analysis (see Supporting Information), and the diastereochemistry of other 1,3-dihydroisobenzofurans were assigned by analogy. Through a process of solvent screening, CCl4 proved to be the most suitable solvent in view of yield and stereoselectivity (entry 4). In the absence of 4 Å MS, no improvement of yield, albeit a slightly higher level of stereoselectivity, was observed (entry 5). Two other chiral Brønsted acids, (R)-4b and (R)-4c, did not improve the catalytic results (entries 6 and 7). It is noteworthy that the moderate yields in the above cases resulted from the incomplete conversion of the allylboration intermediate formed in the first step. Since protonic additives could accelerate the intramolecular oxo-Michael reaction by converting the alkoxyboronate intermediate into the corresponding alcohol, i PrOH (1.0 equiv) was added after the initial allylboration was completed. The yield of the final product was significantly improved to 93% yield, albeit the diastereoselective ratio decreased slightly (entry 8 vs entry 5). Other protonic additives, such as MeOH, EtOH, tBuOH, and H2O, did not give superior results (see Supporting Information). Further investigation of the temperature indicated that the allylboration reaction in CCl4 at −20 °C for 12 h and the following oxoMichael reaction containing the iPrOH additive at rt for 24 h gave the best result (entry 11). Although the diastereoselectivity is not so satisfactory, the diastereoisomers could be easily separated by column chromatography. Under the optimized reaction conditions, a variety of oformyl chalcones with substituents at the external aryl group were found to be suitable for this cascade reaction, affording the chiral 1,3-disubstituted 1,3-dihydroisobenzofurans in high yields (87−94% yield) with 1.0:1−1.7:1 dr and high enantioselectivities (90−98% ee for cis-isomers and 85−96% ee for trans-isomers). External aryls with electron-donating groups and halogen groups at the para position were all tolerated (entries 2−6, Table 2), and the corresponding products 3b−f were obtained in high yields (89−94% yield) with excellent enantioselectivities (90−98% ee for cis-isomers and 86−95% ee for trans-isomers). However, the electronwithdrawing group (CF3) at the same position resulted in a relatively lower reactivity (entry 7). Aryls with halogen groups (F and Br) embedded at the 3-position had no obvious influence on the catalytic results (entries 8 and 9). When a strong electron-withdrawing group (NO2) was introduced at the 3-position of the external aryl group, good results could be achieved by adjusting the temperature and extending the reaction time (entry 10). The absolute configuration of trans-3j was established by X-ray crystallographic analysis (Figure 2).13 A substrate with a 3,4-F2-substituted aryl group provided the desired product in 93% yield with good enantioselectivities (entry 11). When a methyl group was introduced at the 2position, the adduct 3l was formed in a similar level of result (entry 12). Moreover, 1-naphthyl-substituted o-formyl chalcone was examined for its high yield and satisfactory enantioinduction (entry 13). Notably, heteroaryl-substituted o-formyl chalcones (2-furyl and 2-thienyl) were applied to this cascade reaction, delivering the desired product in comparable results (entries 14 and 15).

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

R

product

yield/%b

drc (cis/trans)

ee/%d (cis/trans)

Ph (1a) 4-MeC6H4 (1b) 4-MeOC6H4 (1c) 4-FC6H4(1d) 4-ClC6H4 (1e) 4-BrC6H4 (1f) 4-CF3C6H4(1g) 3-FC6H4(1h) 3-BrC6H4 (1i) 3-NO2C6H4 (1j) 3,4-F2C6H4 (1k) 2-MeC6H4 (1l) 1-naphthyl (1m) 2-furyl (1n) 2-thienyl (1o)

3a 3b 3c

92 92 89

1.4:1 1.6:1 1.3:1

94/90 92/88 90/86

3d 3e 3f 3g 3h 3i 3j

94 92 93 88 92 89 92

1.6:1 1.6:1 1.7:1 1.4:1 1.3:1 1.2:1 1.0:1

98/94 97/94 97/95 95/96 96/94 95/85 90/98

3k 3l 3m

93 87 92

1.1:1 1.5:1 1.5:1

95/87 90/87 98/88

3n 3o

94 93

1.0:1 1.2:1

90/92 95/92

a

Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), catalyst (5 mol %), solvent (0.5 mL). bCombined isolated yield of cis- and transisomers. cDetermined by 1H NMR analysis of the crude products. d Determined by chiral HPLC. eThe allylboration step was carried out at −20 °C for 24 h, then at rt for 12 h.

Figure 2. Determination of the absolute stereochemistry of trans-3j by X-ray crystallography.

Next, the scope of the internal aryl group of o-formyl chalcones was examined under the standard conditions. oFormyl chalcones with F and Cl at the 5-position could be converted into the corresponding products with comparable results (Table 3, entries 2 and 3), while inferior enantioselectivity was accessed with 5-methoxyl-substituted o-formyl chalcone (entry 4). The electronic nature of the 4-position substituent has little effect on yield and enantioselectivity, but a slightly higher diastereoselectivity was observed in several cases (entries 5, 6, and 8). Moreover, o-formyl chalcones with a fluoro-group at the 3-position of the internal aryl was studied, and the adduct 3w was obtained with good results (entry 9). It should be noted that the cis- and trans-isomers in all cases in Tables 2 and 3 could be separated by column chromatography. In addition, we focused on the asymmetric cascade reaction between o-formyl chalcone 1a and 2,3-dienylboronic pinacol ester 5 (Scheme 2). We were pleased to find that 2,3dienylboronic ester 5 was also applicable to such a type of 10390

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry Table 3. Scope of the Internal Aryl Group of the o-Formyl Chalconesa

entry

R

product

yield/%b

drc (cis/trans)

ee/%d (cis/trans)

1 2 3 4 5e 6 7f 8 9g

H (1a) 5-F (1p) 5-Cl (1q) 5-MeO (1r) 4-F (1s) 4-Me (1t) 4-MeO (1u) 4-CF3 (1v) 3-F (1w)

3a 3p 3q 3r 3s 3t 3u 3v 3w

92 93 93 94 89 90 90 92 87

1.4:1 1.4:1 1.1:1 1.4:1 2.5:1 2.0:1 1.4:1 2.5:1 1.1:1

94/90 95/96 96/96 87/80 95/80 90/86 92/88 91/90 87/91

reactions were monitored by TLC. TLC analysis was performed by illumination with a UV lamp (254 nm). All flash chromatography was packed with silica gel as the stationary phase. 1H NMR (500 MHz) spectra were recorded on a Bruker Avance 500 instrument, and chemical shifts (δ) were reported in ppm downfield from internal TMS with the solvent resonance as the internal standard (CDCl3, δ = 7.26 ppm). 13C NMR (126 MHz) spectra were recorded on a Bruker Avance 500 instrument, and chemical shifts were reported in ppm downfield from TMS with the solvent resonance as the internal standard (CDCl3, δ = 77.2 ppm). 19F NMR (471 MHz) spectra were recorded on a Bruker Avance 500 instrument. Coupling constants (J) were measured in hertz (Hz). Optical rotations were measured on a SGWR-533 automatic polarimeter. Infrared spectra were recorded on a NICOLET FT/IR-200 spectrometer. High-resolution MS (ESIorbitrap) were obtained on a Thermo Fisher Q Exactive mass spectrometer. General Procedure for the Asymmetric Cascade Reaction. To an oven-dried 2 mL test tube with a stir bar were added (R)-4a catalyst (5 mol %) and o-formy chalcone 1 (0.1 mmol). In a nitrogen atmosphere, an anhydrous solvent (0.4 mL) was added, and the reaction mixture was then cooled to −20 ° C, followed by the addition of a solution of allyl- or homoallenylboronate pinacol ester (0.12 mmol) in CCl4 (0.1 mL) over 10 min. The mixture was stirred for the time indicated in the text to consume o-formy chalcone, followed by the addition of iPrOH (1.0 equiv), and the reaction mixture was then stirred at rt for another 24 h. Finally the reaction mixture was directly subjected to the preparative thin-layer chromatography (PE/DCM = 1:2). Characterization Data of the Catalytic Adducts. 2-((1R,3S)-3Allyl-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (cis-3a). Yellow solid, mp = 60.4−61.8 °C, 25.6 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.4:1, ee = 94%. The enantiomeric purity was determined by HPLC (Chiracel OJH column, n-hexane/i-PrOH = 99.5/0.5, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 13.5 min, tmajor = 14.6 min). [α]25 D = +41.1 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.33−7.17 (m, 4H), 5.88−5.74 (m, 2H), 5.29 (t, J = 5.4 Hz, 1H), 5.12−5.07 (m, 2H), 3.56 (dd, J = 16.5, 7.1 Hz, 1H), 3.33 (dd, J = 16.5, 5.3 Hz, 1H), 2.70−2.61 (m, 1H), 2.61−2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 198.0, 142.0, 141.7, 137.2, 134.1, 133.2, 128.6, 128.4, 127.8, 127.7, 121.5, 121.4, 117.7, 82.6, 79.3, 46.6, 41.0. IR (KBr): 3071, 2925, 1764, 1680, 1597, 1357, 1287, 1211, 916, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H18O2Na, 301.1204; found, 301.1199. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (trans-3a). Yellow oil, dr = 1.4:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/iPrOH = 99.5:0.5, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 18.2 1 min, tmajor = 28.1 min). [α]25 D = −29.0 (c 0.6, CHCl3). H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.33−7.22 (m, 3H), 7.20 (d, J = 6.5 Hz, 1H), 5.93 (td, J = 6.2, 2.3 Hz, 1H), 5.89−5.77 (m, 1H), 5.35 (td, J = 5.5, 2.3 Hz, 1H), 5.10 (dd, J = 21.2, 13.7 Hz, 2H), 3.55 (dd, J = 16.7, 6.5 Hz, 1H), 3.31 (dd, J = 16.7, 6.0 Hz, 1H), 2.63−2.51 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.9, 141.9, 141.7, 137.1, 133.9, 133.2, 128.6, 128.3, 127.7, 127.6, 121.7, 121.4, 117.8, 82.3, 79.4, 45.9, 40.9. IR (KBr): 3070, 2924, 1765, 1680, 1597, 1449, 1288, 1211, 979, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H18O2Na, 301.1204; found, 301.1197. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(p-tolyl)ethanone (cis-3b). Yellow solid, mp = 66.8−67.8 °C, 26.9 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.6:1, ee = 92%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 10.1 min, tmajor = 11.1 min). [α]25 D = +30.1 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 7.9 Hz, 2H), 7.29−7.19 (m, 7H), 5.89−5.75 (m, 2H), 5.28 (t, J = 5.4 Hz, 1H), 5.13−5.07 (m, 2H), 3.54 (dd, J = 16.4, 7.0 Hz, 1H), 3.29 (dd, J = 16.4, 5.3 Hz, 1H), 2.72−2.61 (m, 1H), 2.61−2.50 (m, 1H), 2.41 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 197.6, 144.1, 142.1, 141.7, 134.7,

a

Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), catalyst (5 mol %), solvent (0.5 mL). bCombined isolated yield of cis- and transisomers. cDetermined by 1H NMR analysis of the crude products. d Determined by chiral HPLC. eThe allylboration step was carried out at −20 °C for 24 h, then at rt for 2 h. fAfter the addition of iPrOH (1.0 equiv) and CH2Cl2 (0.2 mL), the reaction mixture was stirred at rt for 36 h. gAfter the addition of iPrOH (1.0 equiv), the reaction mixture was stirred at rt for 36 h.

Scheme 2. Chiral Phosphoric Acid-Catalyzed Cascade Homoallenylboration/Oxo-Michael Reaction

asymmetric transformation. When 1.5 equiv of 5 was used, the corresponding enantioenriched 1,3-disubstituted 1,3-dihydroisobenzofuran 6 with the 1,3-dienyl substituent was successfully isolated in 92% yield with 1.8:1 dr and 93% ee for the cis-isomer and 89% ee for the trans-isomer under the standard conditions. In conclusion, we have developed an unprecedented asymmetric cascade allylboration/oxo-Michael reaction of oformyl chalcones in the presence of a chiral phosphoric acid catalyst. This synthetic strategy offers an efficient access to a broad range of enantiomerically enriched 1,3-disubstituted 1,3dihydroisobenzofurans. Both the cis- and trans-isomers were obtained in good yields with high enantioselectivities. In addition, 2,3-dienylboronic pinacol ester has also been applied into this cascade reaction. To the best of our knowledge, it represents the first catalytic asymmetric route to optically pure 1,3-disubstituted 1,3-dihydroisobenzofurans. Further studies on other cascade reactions initiated by the chiral phosphoric acidcatalyzed allyl- or homoallenyl-borations are under way in our laboratory.

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EXPERIMENTAL SECTION

General Information. All reactions and manipulations involving air-sensitive compounds were performed using standard Schlenk techniques. Anhydrous toluene, Et2O, and THF were distilled from sodium benzophenone ketyl. Anhydrous CH2Cl2, CHCl3, and CCl4 were distilled from CaH2 under an atmosphere of nitrogen. o-Formyl chalcones were prepared according to the literature procedure.14 All 10391

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry

H NMR (500 MHz, CDCl3): δ 8.00 (dd, J = 8.3, 5.6 Hz, 2H), 7.36− 7.22 (m, 3H), 7.20 (d, J = 6.9 Hz, 1H), 7.12 (t, J = 8.5 Hz, 2H), 5.90 (t, J = 5.0 Hz, 1H), 5.87−5.79 (m, 1H), 5.35 (s, 1H), 5.10 (dd, J = 20.6, 13.7 Hz, 2H), 3.51 (dd, J = 16.5, 6.6 Hz, 1H), 3.27 (dd, J = 16.5, 5.7 Hz, 1H), 2.69−2.46 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.4, 165.8 (d, J = 255.4 Hz), 141.7, 141.6, 133.8, 133.6, 133.5, 130.97 (d, J = 9.3 Hz), 127.8 (d, J = 3.0 Hz), 121.7, 121.4, 117.9, 115.7 (d, J = 22.1 Hz), 82.4, 79.4, 45.8, 40.8. 19F NMR (471 MHz, CDCl3): δ −104.91 to −105.07 (m, 1F). IR (KBr): 3075, 2924, 1764, 1680, 1596, 1357, 1156, 1042, 981, 839 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1103. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4chlorophenyl)ethanone (cis-3e). Yellow solid, mp = 67.1−68.2 °C, 28.7 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.6:1, ee = 97%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 12.6 min, tmajor = 1 15.4 min). [α]25 D = +21.0 (c 0.9, CHCl3). H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.32− 7.26 (m, 2H), 7.21 (t, J = 7.7 Hz, 2H), 5.85−5.72 (m, 2H), 5.28 (t, J = 5.5 Hz, 1H), 5.13−5.07 (m, 2H), 3.51 (dd, J = 16.3, 7.3 Hz, 1H), 3.29 (dd, J = 16.3, 5.0 Hz, 1H), 2.70−2.60 (m, 1H), 2.60−2.48 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 196.9, 141.7, 141.6, 139.7, 135.5, 134.0, 129.9, 128.9, 127.9, 127.8, 121.5, 121.4, 117.8, 82.6, 79.3, 46.5, 40.9. IR (KBr): 3074, 2925, 1765, 1681, 1588, 1399, 1210, 1012, 981, 751 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17ClO2Na, 335.0815; found, 335.0807. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4chlorophenyl)ethanone (trans-3e). Yellow oil, dr = 1.6:1, ee = 94%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 20.4 min, tminor = 28.4 min). [α]25 D = −21.2 (c 0.6, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.32−7.15 (m, 4H), 5.89 (td, J = 6.3, 2.3 Hz, 1H), 5.86− 5.78 (m, 1H), 5.35−5.33 (m, 1H), 5.09 (dd, J = 19.6, 13.7 Hz, 2H), 3.49 (dd, J = 16.5, 6.7 Hz, 1H), 3.27 (dd, J = 16.5, 5.7 Hz, 1H), 2.62− 2.50 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.8, 141.7, 141.6, 139.7, 135.5, 133.8, 129.7, 128.9, 127.8, 127.7, 121.6, 121.5, 117.9, 82.4, 79.3, 45.9, 40.8. IR (KBr): 3074, 2924, 1765, 1681, 1588, 1399, 1209, 1011, 980, 753 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17ClO2Na, 335.0815; found, 335.0808. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4bromophenyl)ethanone (cis-3f). Yellow solid, mp = 69.7−70.8 °C, 33.1 mg, 93% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.7:1, ee = 97%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 10.7 min, tmajor = 1 13.3 min). [α]25 D = +22.1 (c 0.6, CHCl3). H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.30− 7.20 (m, 4H), 5.86−5.72 (m, 2H), 5.28 (t, J = 5.6 Hz, 1H), 5.12−5.07 (m, 2H), 3.51 (dd, J = 16.3, 7.3 Hz, 1H), 3.28 (dd, J = 16.3, 4.9 Hz, 1H), 2.70−2.59 (m, 1H), 2.59−2.49 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.1, 141.7, 141.6, 135.9, 134.0, 131.9, 130.0, 128.5 (2C), 127.9, 127.8, 121.4, 117.8, 82.6, 79.3, 46.4, 40.9. IR (KBr): 3074, 2924, 1768, 1681, 1588, 1399, 1207, 1091, 982, 750 cm−1. HRMS (ESI) m/ z: [M + Na]+ calcd for C19H17BrO2Na, 379.0310; found, 379.0304. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4bromophenyl)ethanone (trans-3f). Yellow oil, dr = 1.7:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 15.4 min, tminor = 21.7 min). [α]25 D = −7.6 (c 0.6, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.32−7.16 (m, 4H), 5.90 (s, 1H), 5.87−5.74 (m, 1H), 5.34 (s, 1H), 5.09 (dd, J = 20.0, 13.7 Hz, 2H), 3.50 (dd, J = 16.5, 6.7 Hz, 1H), 3.27 (dd, J = 16.5, 5.7 Hz, 1H), 2.64−2.45 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.8, 141.7, 141.6, 139.7, 135.4, 133.8, 129.7, 128.9, 127.8, 127.7, 121.6, 121.5, 117.9, 82.4, 79.3, 45.9, 40.8. IR (KBr): 3074, 2923, 1768, 1681, 1588, 1399, 1207, 1091, 982, 753 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17BrO2Na, 379.0310; found, 379.0303. 1

134.1, 129.3, 128.5, 127.7 (2C), 121.6, 121.4, 117.7, 82.5, 79.3, 46.4, 41.0, 21.7. IR (KBr): 3074, 2894, 1767, 1605, 1359, 1289, 1207, 1177, 992, 757 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1354. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(p-tolyl)ethanone (trans-3b). Yellow oil, dr = 1.6:1, ee = 88%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 13.8 min, tmajor = 15.8 min). [α]25 D = −36.7 (c 0.6, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.90 (d, J = 8.1 Hz, 2H), 7.32−7.19 (m, 6H), 5.97−5.92 (m, 1H), 5.92−5.80 (m, 1H), 5.38 (s, 1H), 5.12 (dd, J = 21.5, 13.7 Hz, 2H), 3.55 (dd, J = 16.6, 6.4 Hz, 1H), 3.30 (dd, J = 16.6, 6.1 Hz, 1H), 2.68−2.51 (m, 2H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 197.5, 144.0, 142.0, 141.7, 134.7, 133.9, 129.3, 128.4, 127.7, 127.6, 121.8, 121.4, 117.8, 82.3, 79.4, 45.8, 40.9, 21.7. IR (KBr): 3076, 2895, 1765, 1605, 1359, 1288, 1207, 1176, 995, 754 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1355. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4methoxyphenyl)ethanone (cis-3c). Yellow solid, mp = 52.9−53.8 °C, 27.4 mg, 89% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.3:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 24.9 min, tmajor = 1 29.5 min). [α]25 D = +66.3 (c 0.6, CHCl3). H NMR (500 MHz, CDCl3): δ 7.99 (d, J = 8.9 Hz, 2H), 7.34−7.12 (m, 4H), 6.94 (d, J = 8.9 Hz, 2H), 5.89−5.74 (m, 2H), 5.28 (t, J = 5.4 Hz, 1H), 5.11 (dd, J = 24.1, 6.4 Hz, 2H), 3.87 (s, 3H), 3.52 (dd, J = 16.2, 7.1 Hz, 1H), 3.26 (dd, J = 16.2, 5.4 Hz, 1H), 2.72−2.59 (m, 1H), 2.59−2.49 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 196.5, 163.6, 142.1, 141.7, 134.1, 130.7, 130.6, 130.4, 127.7, 121.6, 121.4, 117.7, 113.7, 82.5, 79.5, 55.5, 46.2, 41.0. IR (KBr): 3074, 2929, 1670, 1597, 1358, 1256, 1167, 1027, 981, 752 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1303. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4methoxyphenyl)ethanone (trans-3c). Yellow solid, mp = 56.7−57.8 °C, dr = 1.3:1, ee = 86%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 36.3 min, tmajor = 42.9 min). [α]25 D = −25.7 (c 0.6, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 8.8 Hz, 2H), 7.31−7.14 (m, 4H), 6.92 (d, J = 8.8 Hz, 2H), 5.94−5.88 (m, 1H), 5.88−5.77 (m, 1H), 5.35 (s, 1H), 5.16−5.03 (m, 2H), 3.86 (s, 3H), 3.49 (dd, J = 16.4, 6.4 Hz, 1H), 3.25 (dd, J = 16.4, 6.1 Hz, 1H), 2.66−2.47 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.4, 163.6, 142.0, 141.7, 133.9, 130.6, 130.3, 127.7, 127.6, 121.8, 121.4, 117.8, 113.7, 82.3, 79.5, 55.5, 45.6, 40.9. IR (KBr): 3074, 2922, 1670, 1597, 1358, 1257, 1167, 1027, 981, 754 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1304. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4fluorophenyl)ethanone (cis-3d). Yellow solid, mp = 38.3−39.4 °C, 27.8 mg, 94% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.6:1, ee = 98%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 11.7 min, tmajor = 1 13.6 min). [α]25 D = +45.4 (c 0.9, CHCl3). H NMR (500 MHz, CDCl3): δ 8.11−7.98 (m, 2H), 7.35−7.18 (m, 5H), 7.13 (t, J = 8.6 Hz, 2H), 5.84−5.76 (m, 2H), 5.28 (t, J = 5.3 Hz, 1H), 5.12−5.07 (m, 2H), 3.52 (dd, J = 16.2, 7.3 Hz, 1H), 3.29 (dd, J = 16.2, 5.1 Hz, 1H), 2.70− 2.61 (m, 1H), 2.60−2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 196.5, 165.9 (d, J = 255.8 Hz), 141.7, 141.6, 134.1, 133.7, 133.6, 131.1 (d, J = 9.3 Hz), 127.8 (d, J = 9.5 Hz), 121.5, 121.4, 117.8, 115.6 (d, J = 21.9 Hz), 82.6, 79.4, 46.4, 41.0. 19F NMR (471 MHz, CDCl3): δ −105.0 (d, J = 5.3 Hz, 1F). IR (KBr): 3075, 2925, 1765, 1680, 1596, 1357, 1156, 1042, 982, 839 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1105. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4fluorophenyl)ethanone (trans-3d). Yellow oil, dr = 1.6:1, ee = 94%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 14.0 min, tmajor = 16.1 min). [α]25 D = −3.9 (c 0.7, CHCl3). 10392

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4(trifluoromethyl)phenyl)ethanone (cis-3g). Yellow oil, 30.5 mg, 88% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.4:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 9.0 min, tmajor = 11.0 min). [α]25 D = +23.7 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.38−7.13 (m, 4H), 5.89−5.69 (m, 2H), 5.29 (t, J = 5.2 Hz, 1H), 5.12−5.07 (m, 2H), 3.56 (dd, J = 16.3, 7.4 Hz, 1H), 3.34 (dd, J = 16.3, 4.8 Hz, 1H), 2.69−2.59 (m, 1H), 2.59−2.47 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.3, 141.6, 141.5, 139.9, 134.5 (q, J = 32.8 Hz), 134.0, 128.8, 128.0, 127.8, 125.7 (q, J = 3.8 Hz), 123.6 (q, J = 273.2 Hz), 121.5, 121.4, 117.8, 82.7, 79.3, 46.7, 40.9. 19 F NMR (471 MHz, CDCl3): δ −63.1 (s, 3F). IR (KBr): 2925, 2855, 1765, 1689, 1410, 1323, 1167, 1065, 983, 756 cm−1. HRMS (ESI) m/ z: [M + Na]+ calcd for C20H17F3O2Na, 369.1078; found, 369.1070. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(4(trifluoromethyl)phenyl)ethanone (trans-3g). Yellow oil, dr = 1.4:1, ee = 96%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 11.9, tminor = 19.6 min). [α]25 D = −6.0 (c 0.8 CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.33−7.18 (m, 4H), 5.92−5.89 (m, 1H), 5.86−5.78 (m, 1H), 5.35 (s, 1H), 5.09 (dd, J = 19.0, 13.8 Hz, 2H), 3.54 (dd, J = 16.6, 6.7 Hz, 1H), 3.32 (dd, J = 16.6, 5.6 Hz, 1H), 2.62− 2.50 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.1, 141.6, 141.5, 139.8, 134.5 (q, J = 32.7 Hz), 133.7, 128.7, 127.9, 127.8, 125.68 (q, J = 3.7 Hz), 123.6 (q, J = 272.9 Hz), 121.6, 121.5, 117.9, 82.5, 79.3, 46.2, 40.8. 19F NMR (471 MHz, CDCl3): δ −63.1 (s, 3F). IR (KBr): 3077, 2926, 1765, 1689, 1410, 1322, 1167, 1065, 981, 755 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H17F3O2Na, 369.1078; found, 369.1070. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3fluorophenyl)ethanone (cis-3h). Yellow solid, mp = 53.3−54.4 °C, 27.2 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.3:1, ee = 96%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 9.5 min, tmajor = 10.9 1 min). [α]25 D = +31.7 (c 0.8, CHCl3). H NMR (500 MHz, CDCl3): δ 7.78 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.47−7.43 (m, 1H), 7.31−7.20 (m, 5H), 5.88−5.71 (m, 2H), 5.29 (t, J = 5.3 Hz, 1H), 5.13−5.07 (m, 2H), 3.52 (dd, J = 16.4, 7.3 Hz, 1H), 3.30 (dd, J = 16.4, 4.9 Hz, 1H), 2.70−2.59 (m, 1H), 2.59−2.48 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 196.9 (d, J = 2.0 Hz), 162.9 (d, J = 248.2 Hz), 141.7, 141.6, 139.3 (d, J = 6.1 Hz), 134.0, 130.23 (d, J = 7.6 Hz), 127.9, 127.8, 124.2 (d, J = 3.0 Hz), 121.4, 120.3, 120.2, 117.8, 115.2 (d, J = 22.4 Hz), 82.6, 79.3, 46.6, 40.9. 19F NMR (471 MHz, CDCl3): δ −111.83 to −111.93 (m, 1F). IR (KBr): 3075, 2925, 1767, 1685, 1588, 1442, 1240, 1150, 988, 681 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1105. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3fluorophenyl)ethanone (trans-3h). Yellow oil, dr = 1.3:1, ee = 94%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 11.9 min, tminor = 15.8 min). [α]25 D = −20.0 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.46−7.41 (m, 1H), 7.33−7.16 (m, 5H), 5.90 (t, J = 4.9 Hz, 1H), 5.87−5.75 (m, 1H), 5.35 (s, 1H), 5.10 (dd, J = 20.4, 13.7 Hz, 2H), 3.51 (dd, J = 16.7, 6.6 Hz, 1H), 3.28 (dd, J = 16.7, 5.7 Hz, 1H), 2.65−2.46 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.7 (d, J = 2.0 Hz), 162.9 (d, J = 249.5 Hz), 141.6, 139.2 (d, J = 6.1 Hz), 133.8, 130.3 (d, J = 7.6 Hz), 127.8, 127.7, 124.1 (d, J = 3.0 Hz), 121.6, 121.5, 120.3, 120.2, 117.9, 115.0 (d, J = 22.4 Hz), 82.4, 79.3, 46.1, 40.8. 19F NMR (471 MHz, CDCl3): δ −111.78 to −111.83 (m, 1F). IR (KBr): 3075, 2924, 1766, 1685, 1588, 1442, 1240, 1150, 1042, 752 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1103. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3bromophenyl)ethanone (cis-3i). Yellow oil, 31.7 mg, 89% yield (combined weight and isolated yield of cis- and trans-isomers), dr =

1.2:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 10.9 min, tmajor = 12.4 min). [α]25 D = +19.8 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.40−7.15 (m, 5H), 5.92−5.71 (m, 2H), 5.28 (t, J = 5.4 Hz, 1H), 5.13−5.08 (m, 2H), 3.51 (dd, J = 16.3, 7.4 Hz, 1H), 3.29 (dd, J = 16.3, 4.9 Hz, 1H), 2.71−2.61 (m, 1H), 2.61−2.47 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 196.8, 141.6 (2C), 138.9, 136.1, 134.0, 131.5, 130.2, 127.8, 127.7, 127.0, 123.0, 121.5, 121.4, 117.9, 82.7, 79.2, 46.5, 40.9. IR (KBr): 3073, 2924, 1766, 1684, 1590, 1419, 1288, 1198, 1043, 678 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17BrO2Na, 379.0310; found, 379.0302. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3bromophenyl)ethanone (trans-3i). Yellow oil, dr = 1.2:1, ee = 85%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 12.6 min, tmajor = 15.2 min). [α]25 D = −17.0 (c 0.5, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.35−7.19 (m, 5H), 5.89 (t, J = 5.5 Hz, 1H), 5.88−5.75 (m, 1H), 5.35 (s, 1H), 5.10 (dd, J = 20.3, 13.7 Hz, 2H), 3.50 (dd, J = 16.6, 6.7 Hz, 1H), 3.27 (dd, J = 16.6, 5.7 Hz, 1H), 2.67− 2.48 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.6, 141.6, 141.5, 138.8, 136.1, 133.8, 131.4, 130.2, 127.8, 127.7, 126.8, 123.0, 121.5, 121.4, 117.9, 82.4, 79.2, 46.0, 40.8. IR (KBr): 3073, 2922, 1764, 1684, 1565, 1420, 1289, 1200, 983, 678 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17BrO2Na, 379.0310; found, 379.0303. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3nitrophenyl)ethanone (cis-3j). Yellow oil, 29.7 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.0:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 12.8 min, tminor = 19.9 min). [α]25 D = +7.4 (c 0.8, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.83 (s, 1H), 8.43 (d, J = 7.4 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.41−7.14 (m, 4H), 5.83−5.72 (m, 2H), 5.29 (t, J = 5.3 Hz, 1H), 5.11−5.06 (m, 2H), 3.59 (dd, J = 16.1, 7.7 Hz, 1H), 3.37 (dd, J = 16.0, 4.5 Hz, 1H), 2.71−2.61 (m, 1H), 2.61−2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 196.1, 148.4, 141.6, 141.3, 138.5, 134.0, 133.9, 129.8, 128.1, 127.9, 127.5, 123.5, 121.5, 121.3, 117.8, 82.8, 79.3, 46.6, 40.8. IR (KBr): 3078, 2923, 1688, 1613, 1529, 1348, 1207, 1043, 914, 734 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17NO4Na, 346.1055; found, 346.1050. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3nitrophenyl)ethanone (trans-3j). Yellow solid, mp = 68.5−69.7 °C, dr = 1.0:1, ee = 98%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 14.4 min, tminor = 19.7 min). [α]25 D = +19.5 (c 0.4, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.69−7.66 (m, J = 5.6 Hz, 1H), 7.34−7.17 (m, 4H), 5.91 (s, 1H), 5.85−5.77 (m, 1H), 5.37 (s, 1H), 5.09 (dd, J = 20.3, 13.7 Hz, 2H), 3.57 (dd, J = 16.3, 7.2 Hz, 1H), 3.34 (dd, J = 16.3, 5.1 Hz, 1H), 2.63−2.47 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 196.0, 148.4, 141.6, 141.2, 138.4, 133.9, 133.7, 129.9, 128.0, 127.8, 127.5, 123.4, 121.6, 121.5, 117.9, 82.6, 79.3, 46.2, 40.8. IR (KBr): 3078, 2922, 1689, 1612, 1528, 1347, 1206, 1043, 919, 735 cm −1 . HRMS (ESI) m/z: [M + Na] + calcd for C19H17NO4Na, 346.1055; found, 346.1050. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3,4difluorophenyl)ethanone (cis-3k). Yellow oil, 29.2 mg, 93% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.1:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 10.0 min, tmajor = 12.3 min). [α]25 D = +20.2 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.91−7.76 (m, 2H), 7.36−7.17 (m, 5H), 5.84−5.72 (m, 2H), 5.29 (t, J = 5.4 Hz, 1H), 5.13−5.08 (m, 2H), 3.48 (dd, J = 16.1, 7.5 Hz, 1H), 3.30−3.22 (m, 1H), 2.72−2.61 (m, 1H), 2.59−2.51 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 195.7, 153.2 (dd, J = 257.2, 13.1 Hz), 150.4 (dd, J = 252.3, 13.1 Hz), 141.6 (d, J = 8.1 Hz), 134.3, 133.9, 128.0, 127.8, 125.5 (dd, J = 7.4, 3.5 Hz), 121.5, 121.4, 117.9 (d, J = 1.8 Hz), 117.8, 117.7 (d, J = 10393

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry 1.8 Hz), 117.4 (d, J = 17.9 Hz), 82.7, 79.3, 46.4, 40.9. 19F NMR (471 MHz, CDCl3): δ −129.54 to −129.62 (m, 1F), −136.03 to −136.23 (m, 1F). IR (KBr): 3076, 2922, 1765, 1685, 1610, 1515, 1430, 1277, 990, 754 cm −1 . HRMS (ESI) m/z: [M + Na] + calcd for C19H16F2O2Na, 337.1016; found, 337.1008. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(3,4difluorophenyl)ethanone (trans-3k). Yellow oil, dr = 1.1:1, ee = 87%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 12.8 min, tmajor = 13.9 min). [α]25 D = −11.7 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.85−7.78 (m, 1H), 7.77−7.71 (m, 1H), 7.33−7.16 (m, 5H), 5.91−5.74 (m, 2H), 5.38−5.31 (m, 1H), 5.15−5.04 (m, 2H), 3.47 (dd, J = 16.4, 6.8 Hz, 1H), 3.25 (dd, J = 16.5, 5.5 Hz, 1H), 2.64−2.47 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 195.5, 153.8 (dd, J = 257.5, 13.1 Hz), 150.5 (dd, J = 251.5, 13.0 Hz), 141.53 (d, J = 18.8 Hz), 134.3, 133.7, 127.9, 127.8, 125.38 (dd, J = 7.4, 3.6 Hz), 121.6, 121.5, 117.9, 117.7 (d, J = 1.8 Hz), 117.6 (d, J = 1.8 Hz), 117.5 (d, J = 18.0 Hz), 82.5, 79.3, 45.8, 40.8. 19F NMR (471 MHz, CDCl3): δ −129.34 to −129.62 (m, 1F), −135.93 to −136.11 (m, 1F). IR (KBr): 3076, 2924, 1765, 1685, 1609, 1515, 1429, 1277, 990, 754 cm −1 . HRMS (ESI) m/z: [M + Na] + calcd for C19H16F2O2Na, 337.1016; found, 337.1007. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(o-tolyl)ethanone (cis-3l). Yellow oil, 25.4 mg, 87% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.5:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 11.9 min, tmajor = 17.4 min). [α]25 D = +16.0 (c 0.8, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.32−7.13 (m, 6H), 5.89−5.72 (m, 2H), 5.27 (t, J = 5.5 Hz, 1H), 5.11−5.06 (m, 2H), 3.44 (dd, J = 16.3, 7.6 Hz, 1H), 3.28 (dd, J = 16.3, 4.8 Hz, 1H), 2.69−2.59 (m, 1H), 2.59−2.47 (m, 4H). 13 C NMR (126 MHz, CDCl3): δ 201.9, 141.9, 141.7, 138.3, 138.0, 134.1, 131.9, 131.4, 128.9, 127.8, 127.7, 125.6, 121.4, 121.5, 117.7, 82.6, 79.5, 49.4, 41.1, 21.3. IR (KBr): 3073, 2925, 1681, 1457, 1355, 1040, 978, 914, 798, 606 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1356. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(o-tolyl)ethanone (trans-3l). Yellow oil, dr = 1.5:1, ee = 87%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 9.6 min, tmajor = 10.3 min). [α]25 D = −10.0 (c 0.6, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.32−7.13 (m, 6H), 5.88−5.79 (m, 2H), 5.30 (s, 1H), 5.09 (dd, J = 21.0, 13.7 Hz, 2H), 3.43 (dd, J = 16.4, 6.8 Hz, 1H), 3.26 (dd, J = 16.4, 5.6 Hz, 1H), 2.67−2.45 (m, 5H). 13C NMR (126 MHz, CDCl3): δ 201.9, 141.8, 141.7, 138.4, 137.9, 133.9, 131.9, 131.4, 128.8, 127.7, 127.6, 125.6, 121.6, 121.5, 117.7, 82.3, 79.6, 48.7, 40.9, 21.3. IR (KBr): 3073, 2921, 1680, 1458, 1354, 1038, 976, 915, 802, 610 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1356. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(naphthalen1-yl)ethanone (cis-3m). Yellow oil, 30.2 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.5:1, ee = 98%. The enantiomeric purity was determined by HPLC (Chiracel OJH column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 21.3 min, tmajor = 22.7 min). [α]25 D = +4.4 (c 1.0, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 8.70 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.30−7.25 (m, 3H), 7.23−7.16 (m, 1H), 5.92−5.87 (m, 1H), 5.87− 5.75 (m, 1H), 5.32−5.26 (m, 1H), 5.12−5.01 (m, 2H), 3.60 (dd, J = 16.1, 7.7 Hz, 1H), 3.44 (dd, J = 16.2, 4.7 Hz, 1H), 2.70−2.59 (m, 1H), 2.58−2.48 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 202.1, 141.8, 141.7, 136.1, 134.1, 134.0, 132.8, 130.2, 128.4, 128.2, 128.0, 127.8, 127.7, 126.5, 125.9, 124.3, 121.5, 121.4, 117.7, 82.6, 79.7, 50.0, 41.1. IR (KBr): 3046, 2923, 1676, 1507, 1459, 1354, 1286, 1170, 1043, 750 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C23H20O2Na, 351.1361; found, 351.1354.

2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(naphthalen1-yl)ethanone (trans-3m). Yellow oil, dr = 1.5:1, ee = 88%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 12.0 min, tminor = 19.5 min). [α]25 D = −3.3 (c 0.8, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 8.67 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.92−7.83 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.32−7.24 (m, 3H), 7.21−7.15 (m, 1H), 5.97 (t, J = 5.0 Hz, 1H), 5.88−5.75 (m, 1H), 5.33 (s, 1H), 5.09 (dd, J = 21.6, 13.6 Hz, 2H), 3.60 (dd, J = 16.2, 6.8 Hz, 1H), 3.42 (dd, J = 16.2, 5.6 Hz, 1H), 2.66−2.47 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 202.0, 141.8, 141.7, 135.9, 133.9, 133.8, 132.8, 130.2, 128.4, 128.1, 128.0, 127.8, 127.7, 126.5, 125.9, 124.3, 121.6, 121.5, 117.7, 82.4, 79.8, 49.2, 40.8. IR (KBr): 3047, 2922, 1676, 1507, 1459, 1351, 1286, 1171, 1041, 754 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C23H20O2Na, 351.1361; found, 351.1354. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(furan-2-yl)ethanone (cis-3n). Yellow oil, 25.2 mg, 94% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.0:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 98:2, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 13.7 min, tmajor = 15.2 min). [α]25 D = +10.1 (c 0.8, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.60 (s, 1H), 7.38−7.07 (m, 5H), 6.64−6.45 (m, 1H), 5.95−5.70 (m, 2H), 5.27 (t, J = 5.4 Hz, 1H), 5.12−5.07 (m, 2H), 3.38 (dd, J = 15.7, 7.6 Hz, 1H), 3.20 (dd, J = 15.7, 5.0 Hz, 1H), 2.69−2.59 (m, 1H), 2.59−2.45 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 186.7, 153.0, 146.7, 141.7, 141.6, 134.1, 127.8, 127.7, 121.4, 121.3, 117.9, 117.7, 112.3, 82.7, 79.2, 46.5, 41.1. IR (KBr): 2921, 2852, 1670, 1567, 1394, 1301, 1234, 1043, 915, 693 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H16O3Na, 291.0997; found, 291.0993. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(furan-2-yl)ethanone (trans-3n). Yellow solid, mp = 74.2−75.0 °C, dr = 1.0:1, ee = 92%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 8.3 min, tminor = 13.9 min). [α]25 D = +25.7 (c 0.8, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.58 (s, 1H), 7.37−7.13 (m, 5H), 6.54−6.53 (m, 1H), 5.93−5.70 (m, 2H), 5.36 (s, 1H), 5.08 (dd, J = 21.0, 13.7 Hz, 2H), 3.37 (dd, J = 15.8, 7.1 Hz, 1H), 3.15 (dd, J = 15.8, 5.6 Hz, 1H), 2.61−2.49 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 186.7, 152.9, 146.6, 141.7, 141.6, 133.8, 127.8, 127.7, 121.5, 121.4, 117.8, 117.7, 112.3, 82.4, 79.2, 45.8, 40.8. IR (KBr): 2923, 2853, 1672, 1653, 1566, 1467, 1394, 1041, 918, 754 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H16O3Na, 291.0997; found, 291.0991. 2-((1R,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(thiophen-2yl)ethanone (cis-3o). Yellow oil, 26.4 mg, 93% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.2:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 19.7 min, tmajor = 23.4 min). [α]25 D = +30.1 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.34−7.17 (m, 5H), 7.13 (t, J = 4.3 Hz, 1H), 5.86−5.73 (m, 2H), 5.28 (t, J = 5.4 Hz, 1H), 5.13−5.08 (m, 2H), 3.46 (dd, J = 15.7, 7.4 Hz, 1H), 3.26 (dd, J = 15.7, 5.1 Hz, 1H), 2.72−2.60 (m, 1H), 2.60−2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 190.7, 144.7, 141.6, 141.5, 134.1, 134.0, 132.7, 128.1, 127.8, 127.7, 121.5, 121.4, 117.8, 82.6, 79.4, 47.3, 41.0. IR (KBr): 3075, 2923, 1653, 1518, 1414, 1293, 1213, 1042, 914, 722 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H16O2SNa, 307.0769; found, 307.0763. 2-((1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl)-1-(thiophen-2yl)ethanone (trans-3o). Yellow oil, dr = 1.2:1, ee = 92%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 15.0 min, tminor = 13.3 min). [α]25 D = +6.7 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.30−7.19 (m, 4H), 7.12 (t, J = 4.3 Hz, 1H), 5.88 (t, J = 6.2 Hz, 1H), 5.85−5.78 (m, 1H), 5.36 (s, 1H), 5.09 (dd, J = 20.9, 13.7 Hz, 2H), 3.46 (dd, J = 15.9, 6.8 Hz, 1H), 3.23 (dd, J = 15.9, 5.8 Hz, 1H), 2.62−2.50 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 190.6, 144.6, 141.6, 141.5, 134.0, 133.8, 132.5, 128.2, 127.8, 127.7, 121.7, 10394

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry

2-((1R,3S)-3-Allyl-5-methoxy-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (cis-3r). Yellow solid, mp = 74.2−75.0 °C, 29.0 mg, 94% yield (combined weight and isolated yield of cis- and transisomers), dr = 1.4:1, ee = 87%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 11.1 min, tmajor = 1 13.4 min). [α]25 D = +32.9 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 5.88−5.71 (m, 2H), 5.23 (t, J = 5.4 Hz, 1H), 5.14−5.08 (m, 2H), 3.81 (s, 3H), 3.54 (dd, J = 16.4, 6.9 Hz, 1H), 3.29 (dd, J = 16.4, 5.4 Hz, 1H), 2.68−2.58 (m, 1H), 2.58−2.49 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 198.2, 159.8, 143.4, 137.2, 134.1 (2C), 133.2, 128.6, 128.4, 122.3, 117.8, 113.7, 106.7, 82.4, 79.1, 55.6, 46.8, 41.0. IR (KBr): 3069, 2925, 1680, 1492, 1269, 1206, 1110, 1028, 982, 916, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1305. 2-((1S,3S)-3-Allyl-5-methoxy-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (trans-3r). Yellow oil, dr = 1.4:1, ee = 80%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 11.0 min, tminor = 15.4 min). [α]25 D = −13.8 (c 0.8, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 8.3 Hz, 1H), 6.91− 6.75 (m, 1H), 6.71 (s, 1H), 5.96−5.74 (m, 2H), 5.30 (s, 1H), 5.10 (dd, J = 23.2, 13.7 Hz, 2H), 3.80 (s, 3H), 3.52 (dd, J = 16.6, 6.2 Hz, 1H), 3.28 (dd, J = 16.6, 6.2 Hz, 1H), 2.65−2.46 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 198.1, 159.7, 143.4, 137.1, 134.0, 133.9, 133.2, 128.6, 128.3, 122.6, 117.8, 113.7, 106.8, 82.2, 79.1, 55.5, 46.1, 40.8. IR (KBr): 3069, 2923, 1680, 1492, 1265, 1205, 1109, 998, 982, 753, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1304. 2-((1R,3S)-3-Allyl-6-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (cis-3s). Yellow solid, mp = 47.1−48.2 °C, 26.4 mg, 89% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 2.5:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 12.2 min, tmajor = 16.5 min). [α]25 D = −49.8 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.13 (dd, J = 8.0, 5.0 Hz, 1H), 6.97 (dd, J = 18.2, 8.5 Hz, 2H), 5.85−5.73 (m, 2H), 5.24 (t, J = 5.1 Hz, 1H), 5.10 (dd, J = 13.6, 7.4 Hz, 2H), 3.58 (dd, J = 16.8, 6.6 Hz, 1H), 3.31 (dd, J = 16.8, 5.8 Hz, 1H), 2.68−2.58 (m, 1H), 2.58− 2.49 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.7, 162.8 (d, J = 254.4 Hz), 144.3 (d, J = 8.2 Hz), 137.1 (d, J = 2.2 Hz), 137.0, 133.8, 133.4, 128.6, 128.3, 122.6 (d, J = 8.9 Hz), 118.0, 114.9 (d, J = 23.1 Hz), 109.0 (d, J = 23.9 Hz), 82.1, 78.9, 46.3, 41.0. 19F NMR (471 MHz, CDCl3): δ −115.02 to −115.07 (m, 1F). IR (KBr): 3070, 2923, 1681, 1599, 1486, 1357, 1254, 1047, 983, 761, 688 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1104. 2-((1S,3S)-3-Allyl-6-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (trans-3s). Yellow solid, mp = 46.1−47.0 °C, dr = 2.5:1, ee = 80%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tmajor = 12.3 min, tminor = 17.8 min). [α]25 D = −7.1 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.13 (dd, J = 8.8, 4.8 Hz, 1H), 6.97 (t, J = 7.3 Hz, 2H), 5.88 (s, 1H), 5.86−5.78 (m, 1H), 5.31 (s, 1H), 5.13−5.08 (m, 2H), 3.57 (dd, J = 16.9, 6.0 Hz, 1H), 3.30 (dd, J = 16.9, 6.5 Hz, 1H), 2.62−2.48 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.6, 162.7 (d, J = 245.2 Hz), 144.2 (d, J = 8.3 Hz), 137.1, 136.9, 133.6, 133.4, 128.7, 128.2, 122.6 (d, J = 8.9 Hz), 118.1, 114.9 (d, J = 23.2 Hz), 109.2 (d, J = 23.9 Hz), 81.9, 79.0, 45.6, 40.9. 19F NMR (471 MHz, CDCl3): δ −115.02 to −115.07 (m, 1F). IR (KBr): 3071, 2922, 1680, 1598, 1479, 1357, 1255, 1048, 982, 762, 688 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1105. 2-((1R,3S)-3-Allyl-6-methyl-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (cis-3t). Yellow solid, mp = 65.0−66.2 °C, 26.3 mg, 90% yield (combined weight and isolated yield of cis- and trans-

121.4, 117.8, 82.4, 79.4, 46.6, 40.8. IR (KBr): 3075, 2923, 1654, 1518, 1414, 1291, 1213, 1041, 915, 751 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H16O2SNa, 307.0769; found, 307.0763. 2-((1R,3S)-3-Allyl-5-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (cis-3p). Yellow oil, 27.5 mg, 93% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.4:1, ee = 95%. The enantiomeric purity was determined by HPLC (Chiracel OD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 9.8 min, tmajor = 10.9 min). [α]25 D = +34.8 (c 0.7, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.04−7.97 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.18 (dd, J = 8.0, 5.1 Hz, 1H), 6.96 (dd, J = 12.3, 4.9 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.85− 5.73 (m, 2H), 5.24 (t, J = 5.2 Hz, 1H), 5.16−5.07 (m, 2H), 3.56 (dd, J = 16.6, 6.6 Hz, 1H), 3.31 (dd, J = 16.6, 5.7 Hz, 1H), 2.66−2.58 (m, 1H), 2.58−2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.9, 162.8 (d, J = 245.7 Hz), 144.0 (d, J = 8.1 Hz), 137.5, 137.1, 133.6, 133.3, 128.6, 128.4, 123.0 (d, J = 8.9 Hz), 118.1, 114.9 (d, J = 23.1 Hz), 108.6 (d, J = 23.6 Hz), 82.1 (d, J = 2.6 Hz), 79.0, 46.5, 40.8. 19F NMR (471 MHz, CDCl3): δ −115.04 to −115.09 (m, 1F). IR (KBr): 3070, 2919, 1771, 1680, 1599, 1488, 1354, 1258, 1047, 818, 688 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1103. 2-((1S,3S)-3-Allyl-5-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (trans-3p). Yellow oil, dr = 1.4:1, ee = 96%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 13.7 min, tmajor = 17.5 min). [α]25 D = −33.8 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.20 (dd, J = 8.2, 5.0 Hz, 1H), 7.00−6.91 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.86 (d, J = 7.8 Hz, 1H), 5.84−5.77 (m, 1H), 5.31 (s, 1H), 5.14−5.06 (m, 2H), 3.55 (dd, J = 16.8, 6.1 Hz, 1H), 3.29 (dd, J = 16.8, 6.4 Hz, 1H), 2.64−2.47 (m, 2H). 13 C NMR (126 MHz, CDCl3): δ 197.8, 162.8 (d, J = 245.6 Hz), 144.0 (d, J = 8.1 Hz), 137.4 (d, J = 2.2 Hz), 137.0, 133.4, 133.3, 128.6, 128.3, 123.2 (d, J = 9.0 Hz), 118.2, 114.9 (d, J = 23.1 Hz), 108.6 (d, J = 23.6 Hz), 82.0 (d, J = 2.6 Hz), 79.0, 45.9, 40.6. 19F NMR (471 MHz, CDCl3): δ −115.08 to −115.13 (m, 1F). IR (KBr): 3069, 2923, 1772, 1680, 1598, 1488, 1352, 1255, 1046, 921, 688 cm−1. HRMS (ESI) m/ z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1104. 2-((1R,3S)-3-Allyl-5-chloro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (cis-3q). Yellow oil, 29.0 mg, 93% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.1:1, ee = 96%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 13.5 min, tmajor = 22.6 min). [α]25 D = +61.2 (c 0.8, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.99 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.29−7.21 (m, 1H), 7.17 (d, J = 7.0 Hz, 2H), 5.83−5.75 (m, 2H), 5.24 (t, J = 5.4 Hz, 1H), 5.12 (dd, J = 13.5, 8.5 Hz, 2H), 3.56 (dd, J = 16.7, 6.6 Hz, 1H), 3.31 (dd, J = 16.7, 5.8 Hz, 1H), 2.69−2.58 (m, 1H), 2.58−2.48 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 197.8, 143.8, 140.6, 137.0, 133.7, 133.5, 133.4, 128.7, 128.4, 128.0, 122.9, 121.7, 118.2, 82.1, 79.0, 46.3, 40.7. IR (KBr): 3071, 2921, 1681, 1541, 1448, 1347, 1209, 1046, 983, 819, 689 cm −1 . HRMS (ESI) m/z: [M + Na] + calcd for C19H17ClO2Na, 335.0815; found, 335.0808. 2-((1S,3S)-3-Allyl-5-chloro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (trans-3q). Yellow oil, dr = 1.1:1, ee = 96%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 14.9 min, tminor = 21.5 min). [α]25 D = +6.7 (c 0.8, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.25−7.14 (m, 3H), 5.91−5.85 (m, 1H), 5.84−5.77 (m, 1H), 5.31 (s, 1H), 5.15−5.09 (m, 2H), 3.55 (dd, J = 16.8, 6.0 Hz, 1H), 3.29 (dd, J = 16.9, 6.5 Hz, 1H), 2.63−2.47 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.7, 143.8, 140.5, 136.9, 133.6, 133.4, 133.3, 128.7, 128.2, 128.0, 123.1, 121.7, 118.3, 81.9, 79.1, 45.7, 40.6. IR (KBr): 3071, 2921, 1680, 1541, 1448, 1347, 1209, 1047, 982, 819, 688 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17ClO2Na, 335.0815; found, 335.0808. 10395

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry

1H), 3.36 (dd, J = 16.9, 5.5 Hz, 1H), 2.72−2.63 (m, 1H), 2.63−2.54 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.5, 145.7, 143.0, 136.9, 133.4, 133.3, 130.5 (q, J = 32.3 Hz), 128.7, 128.3, 125.2 (q, J = 3.7 Hz), 124.2 (q, J = 272.5 Hz), 121.9, 118.9 (d, J = 3.9 Hz), 118.3, 82.3, 79.0, 46.2, 40.6. 19F NMR (471 MHz, CDCl3): δ −62.0 (s, 3F). IR (KBr): 3069, 2918, 1773, 1682, 1449, 1324, 1162, 1065, 981, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H17F3O2Na, 369.1078; found, 369.1072. 2-((1S,3S)-3-Allyl-6-(trifluoromethyl)-1,3-dihydroisobenzofuran1-yl)-1-phenylethanone (trans-3v). Yellow oil, dr = 2.5:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 14.2 min, tminor = 16.3 min). [α]25 D = −4.3 (c 0.5, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.4 Hz, 2H), 7.59−7.54 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H), 5.86−5.77 (m, 1H), 5.39 (s, 1H), 5.11 (t, J = 12.9 Hz, 2H), 3.59 (dd, J = 17.0, 6.2 Hz, 1H), 3.34 (dd, J = 17.0, 6.2 Hz, 1H), 2.68−2.49 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.4, 145.7, 142.9, 136.9, 133.4, 133.2, 130.4 (q, J = 32.1 Hz), 128.7, 128.2, 125.2 (q, J = 3.8 Hz), 124.1 (q, J = 272.9 Hz), 121.9, 119.1 (q, J = 3.8 Hz), 118.4, 82.1, 79.1, 45.6, 40.6. 19F NMR (471 MHz, CDCl3): δ −62.0 (s, 3F). IR (KBr): 3068, 2926, 1773, 1682, 1449, 1324, 1162, 1064, 980, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H17F3O2Na, 369.1078; found, 369.1073. 2-((1R,3S)-3-Allyl-7-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (cis-3w). Yellow oil, 25.8 mg, 87% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 1.1:1, ee = 87%. The enantiomeric purity was determined by HPLC (Chiracel OJH column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 18.5 min, tminor = 30.7 min). [α]25 D = −21.6 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.1 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.35−7.20 (m, 1H), 6.97 (dd, J = 11.3, 8.2 Hz, 2H), 5.98 (d, J = 8.8 Hz, 1H), 5.87−5.65 (m, 1H), 5.30 (t, J = 5.3 Hz, 1H), 5.05 (d, J = 12.8 Hz, 2H), 3.62 (dd, J = 16.3, 1.8 Hz, 1H), 3.44 (dd, J = 16.2, 8.9 Hz, 1H), 2.65−2.57 (m, 1H), 2.57− 2.50 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 197.4, 157.3 (d, J = 248.0 Hz), 145.4 (d, J = 4.6 Hz), 137.3, 133.6, 133.1, 130.2 (d, J = 6.8 Hz), 128.6, 128.4, 127.8 (d, J = 17.1 Hz), 118.1, 117.3 (d, J = 3.5 Hz), 114.5 (d, J = 20.3 Hz), 83.3, 77.8 (d, J = 3.0 Hz), 44.6, 40.8. 19F NMR (471 MHz, CDCl3): δ −119.62 to −119.65 (m, 1F). IR (KBr): 3072, 2923, 1773, 1684, 1474, 1374, 1279, 1245, 1019, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1104. 2-((1S,3S)-3-Allyl-7-fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethanone (trans-3w). Yellow oil, dr = 1.1:1, ee = 91%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 1 nm, tminor = 7.8 min, tmajor = 9.7 min). [α]25 D = +45.3 (c 0.7, CHCl3). H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 7.9 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.28 (dd, J = 12.2, 7.2 Hz, 1H), 6.96 (dd, J = 16.6, 8.1 Hz, 2H), 6.12−6.00 (m, 1H), 5.86−5.59 (m, 1H), 5.37 (s, 1H), 5.11−5.05 (m, 2H), 3.52 (dd, J = 16.2, 3.0 Hz, 1H), 3.41 (dd, J = 16.3, 8.3 Hz, 1H), 2.65−2.46 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 197.3, 157.1 (d, J = 247.8 Hz), 145.5 (d, J = 4.6 Hz), 137.1, 133.3, 133.1, 130.1 (d, J = 6.7 Hz), 128.6, 128.4, 127.9 (d, J = 17.5 Hz), 118.1, 117.3 (d, J = 3.5 Hz), 114.4 (d, J = 20.0 Hz), 83.0, 77.8 (d, J = 2.7 Hz), 44.0, 40.5. 19F NMR (471 MHz, CDCl3): δ −119.25 to −119.28 (m, 1F). IR (KBr): 3072, 2924, 1774, 1685, 1474, 1373, 1277, 1245, 985, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17FO2Na, 319.1110; found, 319.1102. 2-((1R,3S)-3-(Buta-1,3-dien-2-yl)-1,3-dihydroisobenzofuran-1-yl)1-phenylethanone (6). Yellow oil (mixture of diastereomers), 26.7 mg, 92% yield (combined weight and isolated yield of cis- and transisomers), dr = 1.8:1, cis-6 ee = 93%; trans-6 ee = 89%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, cis-6 tminor = 15.7 min, tmajor = 17.9 min; trans-6 tminor = 24.1 min, 1 tmajor = 29.6 min). [α]25 D = −49.2 (c 1.0, CHCl3). cis-6 H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.8 Hz, 2H), 7.58−7.56 (m, 1H), 7.48− 7.45 (m, 2H), 7.28−7.19 (m, 4H), 6.35−6.30 (m, 1H), 5.90 (t, J = 6.1

isomers), dr = 2.0:1, ee = 90%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tminor = 12.0 min, tmajor = 1 20.4 min). [α]25 D = +11.0 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.09 (q, J = 7.8 Hz, 2H), 7.04 (s, 1H), 5.85−5.77 (m, 2H), 5.25 (t, J = 5.3 Hz, 1H), 5.12−5.06 (m, 2H), 3.55 (dd, J = 16.5, 7.1 Hz, 1H), 3.32 (dd, J = 16.5, 5.2 Hz, 1H), 2.66−2.58 (m, 1H), 2.58−2.49 (m, 1H), 2.36 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 198.1, 142.3, 138.9, 137.6, 137.2, 134.2, 133.2, 128.6, 128.5, 128.4, 122.0, 121.1, 117.6, 82.4, 79.1, 46.6, 41.1, 21.3. IR (KBr): 3067, 2922, 1766, 1681, 1448, 1357, 1288, 1207, 1047, 981, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1355. 2-((1S,3S)-3-Allyl-6-methyl-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (trans-3t). Yellow oil, dr = 2.0:1, ee = 86%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 12.5 min, tminor = 16.7 min). [α]25 D = +2.5 (c 0.5, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.50−7.42 (m, 2H), 7.10−7.05 (m, 3H), 5.92−5.76 (m, 2H), 5.32 (s, 1H), 5.09 (dd, J = 21.5, 13.7 Hz, 2H), 3.53 (dd, J = 16.7, 6.5 Hz, 1H), 3.30 (dd, J = 16.7, 5.9 Hz, 1H), 2.60−2.47 (m, 2H), 2.34 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 198.0, 142.2, 138.8, 137.6, 137.1, 134.0, 133.2, 128.6, 128.5, 128.3, 122.2, 121.1, 117.7, 82.2, 79.2, 46.0, 41.0, 21.3. IR (KBr): 3067, 2919, 1767, 1681, 1448, 1361, 1207, 1046, 981, 915, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O2Na, 315.1361; found, 315.1355. 2-((1R,3S)-3-Allyl-6-methoxy-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (cis-3u). Yellow solid, mp = 57.9−59.2 °C, 27.7 mg, 90% yield (combined weight and isolated yield of cis- and transisomers), dr = 1.4:1, ee = 92%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 10.3 min, tminor = 1 12.2 min). [α]25 D = +8.8 (c 0.9, CHCl3). H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.84 (dd, J = 8.3, 1.4 Hz, 1H), 6.76 (s, 1H), 5.87−5.73 (m, 2H), 5.23 (t, J = 5.3 Hz, 1H), 5.12−5.07 (m, 2H), 3.78 (s, 3H), 3.56 (dd, J = 16.5, 7.0 Hz, 1H), 3.31 (dd, J = 16.5, 5.4 Hz, 1H), 2.66−2.57 (m, 1H), 2.57−2.48 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 198.1, 159.8, 143.6, 137.2, 134.2, 133.8, 133.2, 128.6, 128.4, 122.1, 117.7, 114.1, 106.7, 82.3, 79.2, 55.5, 46.6, 41.3. IR (KBr): 3068, 2928, 1761, 1680, 1448, 1288, 1207, 1027, 982, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1301. 2-((1S,3S)-3-Allyl-6-methoxy-1,3-dihydroisobenzofuran-1-yl)-1phenylethanone (trans-3u). Yellow oil, dr = 1.4:1, ee = 88%. The enantiomeric purity was determined by HPLC (Chiracel AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm, tmajor = 8.8 min, tminor = 11.9 min). [α]25 D = +22.5 (c 0.7, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.78 (s, 1H), 5.92−5.76 (m, 2H), 5.30 (s, 1H), 5.09 (dd, J = 18.9, 13.8 Hz, 2H), 3.77 (s, 3H), 3.54 (dd, J = 16.7, 6.4 Hz, 1H), 3.29 (dd, J = 16.7, 6.1 Hz, 1H), 2.60−2.45 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 198.0, 159.7, 143.6, 137.1, 134.0, 133.7, 133.2, 128.6, 128.3, 122.1, 117.7, 114.1, 106.8, 82.0, 79.2, 55.5, 45.9, 41.1. IR (KBr): 3068, 2924, 1760, 1680, 1448, 1288, 1205, 1027, 980, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H20O3Na, 331.1310; found, 331.1301. 2-((1R,3S)-3-Allyl-6-(trifluoromethyl)-1,3-dihydroisobenzofuran1-yl)-1-phenylethanone (cis-3v). Yellow oil, 31.8 mg, 92% yield (combined weight and isolated yield of cis- and trans-isomers), dr = 2.5:1, ee = 91%. The enantiomeric purity was determined by HPLC (Chiracel OJ-H column, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/ min, λ = 254 nm, tminor = 12.2 min, tmajor = 14.5 min). [α]25 D = +41.2 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.9 Hz, 2H), 7.58 (dd, J = 14.2, 7.5 Hz, 2H), 7.49 (dd, J = 16.9, 9.4 Hz, 3H), 7.31 (d, J = 7.9 Hz, 1H), 5.86 (t, J = 5.9 Hz, 1H), 5.83−5.75 (m, 1H), 5.32 (s, 1H), 5.11 (dd, J = 13.3, 7.9 Hz, 2H), 3.61 (dd, J = 16.9, 6.7 Hz, 10396

DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397

Article

The Journal of Organic Chemistry Hz, 1H), 5.85 (s, 1H), 5.45 (d, J = 17.7 Hz, 1H), 5.31−5.25 (m, 2H), 5.17−5.12 (m, 1H), 3.67−3.62 (m, 1H), 3.41−3.36 (m, 1H). trans-6 1 H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 7.8 Hz, 2H), 7.58−7.56 (m, 1H), 7.48−7.45 (m, 2H), 7.28−7.19 (m, 4H), 6.32−6.26 (m, 1H), 6.03 (t, J = 6.1 Hz, 1H), 5.95 (s, 1H), 5.40 (d, J = 17.7 Hz, 1H), 5.26− 5.22 (m, 2H), 5.17−5.12 (m, 1H), 3.63−3.58 (m, 1H), 3.39−3.34 (m, 1H). cis-6 13C NMR (126 MHz, CDCl3): δ 197.8, 146.0, 142.0, 141.1, 137.0, 135.8, 133.3, 128.6, 128.4, 127.9, 127.8, 122.1, 121.5, 116.4, 115.6, 83.5, 79.4, 46.0. trans-6 13C NMR (126 MHz, CDCl3): δ 197.8, 146.1, 141.7, 140.7, 137.1, 135.5, 133.2, 128.3, 128.0, 127.9, 127.8, 122.0, 121.8, 116.0, 115.5, 83.6, 80.0, 45.8. IR (KBr): 3074, 2924, 1773, 1684, 1634, 1574, 1473, 1319, 1259, 1132, 954, 689 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H18O2Na, 313.1204; found, 313.1199.

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Antilla, J. C. J. Am. Chem. Soc. 2010, 132, 11884. (f) Jain, P.; Wang, H.; Houk, K. N.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51, 1391. (g) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 10947. (8) Huang, Y.-Y.; Yang, X.; Lv, Z.-C.; Cai, C.; Kai, C.; Pei, Y.; Feng, Y. Angew. Chem., Int. Ed. 2015, 54, 7299. (9) For selected reviews on cascade catalysis, see: (a) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (b) de Meijere, A.; von Zezschwitz, P.; Bräse, S. Acc. Chem. Res. 2005, 38, 413. (c) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754. (d) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (e) Park, J.; Hong, S. Chem. Soc. Rev. 2012, 41, 6931. (f) Pellissier, H. Chem. Rev. 2013, 113, 442. (g) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (10) (a) Fustero, S.; Rodríguez, E.; Lázaro, R.; Herrera, L.; Catalán, S.; Barrio, P. Adv. Synth. Catal. 2013, 355, 1058. (b) Rodríguez, E.; Grayson, M. N.; Asensio, A.; Barrio, P.; Houk, K. N.; Fustero, S. ACS Catal. 2016, 6, 2506. (11) For selected examples of chiral phosphoric acid-catalyzed intramolecular oxo-Michael reactions, see: (a) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056. (b) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554. For reviews on oxo-Michael reactions, see: (c) Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5, 1499. (d) Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2008, 37, 1218. (e) Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2012, 41, 988. (12) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (13) CCDC 1552189 (trans-3j) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. (14) (a) Jiang, J.; Guan, X.-Y.; Liu, S.-Y.; Ren, B.-Y.; Ma, X.-C.; Guo, X.; Lv, F.-P.; Wu, X.; Hu, W.-H. Angew. Chem., Int. Ed. 2013, 52, 1539. (b) Qian, H.; Zhao, W.-X.; Sung, H.; Williams, I.; Sun, J.-W. Chem. Commun. 2013, 49, 4361 and references 5 and 6..

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01856. Additional experiments, copies of NMR spectra for all new products, HPLC charts, and X-ray data for compound trans-3j(PDF) Crystal data for compound trans-3j (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yi-Yong Huang: 0000-0001-6209-8304 Author Contributions ‡

X. Yang and S. Pang contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully thank the financial support of this investigation by the National Natural Science Foundation of China (21573169 and 21772151) and the Fundamental Research Funds for the Central Universities (WUT: 2016-IB-007 and 2016-YB-007).

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REFERENCES

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DOI: 10.1021/acs.joc.7b01856 J. Org. Chem. 2017, 82, 10388−10397