HETEROCYCLES

Paper | Special issue | Vol. 77, No. 2, 2009, pp. 1285-1296
Received, 13th September, 2008, Accepted, 3rd October, 2008, Published online, 6th October, 2008.
DOI: 10.3987/COM-08-S(F)114

■ Synthesis of Isochromanes and Isothiochromanes Bearing Fluorinated One-Carbon Units via Intramolecular Cyclizations of ortho-Substituted α-(Trifluoromethyl)styrenes

Junji Ichikawa,* Masahiro Ikeda, and Masahiro Hattori

Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki 305-0006, Japan

Abstract

α-(Trifluoromethyl)styrenes bearing a nucleophilic oxygen or sulfur atom tethered by a methylene or methyne unit at the ortho carbon were prepared by the coupling reaction of 2-bromo-3,3,3-trifluoropropene with aryl iodides via (3,3,3-trifluoroprop-1-en-2-yl)boronic acid. The styrenes thus obtained readily undergo an intramolecular nucleophilic addition or substitution (S_N2’-type) of the oxygen and sulfur under basic conditions, leading to 4-trifluoromethyl- or 4-difluoromethylene-substituted isochromanes and isothiochromanes, respectively.

INTRODUCTION
Isochromane (3,4-dihydro-1H-2-benzopyran)1 and isothiochromane (3,4-dihydro-1H-2-benzothiopyran)2 derivatives constitute an important class of natural and synthetic compounds. Because they exhibit a wide variety of biological activities, iso(thio)chromane skeletons are frequently found in the structures of drugs and drug candidates. Moreover, they are structural analogues of tetrahydroisoquinolines, which are widespread in the alkaloid family.3 Hence, there have been many reports on the use of iso(thio)chromanes as starting materials or intermediates for the synthesis of medicinal and agrochemical agents.4
While the synthesis of iso(thio)chromanes has been extensively studied,1,2,5 a quite limited number of reports have appeared on the synthesis of their partially fluorinated counterparts.6 The introduction of fluorocarbon substituents into heterocycles has come into wide use as one of the most efficient methods for modification of biological activity, as well as of physical and chemical properties.7,8 In particular, the incorporation of a trifluoromethyl (CF3) group into organic molecules increases lipophilicity and affects electron density.9 An exo-difluoromethylene (=CF2) group acts as a reactive site toward nucleophiles,10,11 and its reduction provides a difluoromethyl (CHF2) group,12 which raises lipophilicity and functions as a hydrogen-bond donor without nucleophilicity.13 Thus, the development of a synthetic method for iso(thio)chromanes with these fluorinated one-carbon units is a highly desirable goal.
α-(Trifluoromethyl)styrenes are susceptible to nucleophilic attack, because of the electron-withdrawing trifluoromethyl group. Utilizing this reactivity, we have recently found that the (trifluoromethyl)styrenes with a nitrogen functionality readily undergo an intramolecular addition or SN2′-type reaction, depending on conditions with or without a proton source. These reactions provided quinoline and isoquinoline derivatives bearing a fluorinated one-carbon unit such as a CF3, CHF2, or =CF2 group.14
In a continuation of our research on the cyclizations of 2-trifluoromethyl-1-alkenes,14,15 we sought to apply the intramolecular addition and substitution concept to the construction of 6-membered oxygen- or sulfur-containing heterocycles, isochromane and isothiochromane derivatives. On the basis of these considerations, α-(trifluoromethyl)styrene derivatives were designed to bear a nucleophilic oxygen or a sulfur atom tethered by a methylene or methyne unit at the ortho carbon. They were subjected to the ring-forming reactions in a 6-endo-trig fashion under basic conditions. Herein we wish to report the results of our studies on the synthesis of 4-trifluoromethyl- or 4-difluoromethylene-substituted isochromanes and isothiochromanes.

RESULTS AND DISCUSSION
Preparation of α-(Trifluoromethyl)styrenes Bearing a Nucleophilic Oxygen or Sulfur Atom
The cyclization precursors, o-substituted -(trifluoromethyl)styrenes, were easily prepared by the Suzuki–Miyaura cross-coupling reaction of aryl iodides with (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (2) that was prepared from 2-bromo-3,3,3-trifluoropropene (1), according to a modified literature procedure (Scheme 1).14a,16 (Trifluoromethyl)styrene 3a bearing a hydroxymethyl group at the ortho position, precursors of isochromanes, was successfully obtained in 88% yield via the coupling of 2 with o-iodobenzyl alcohol (Scheme 1, route A). Alcohols 3 were also obtained via another route, which allows the introduction of a substituent (R) on the benzylic carbon (route B). The coupling of 2 with o-iodobenzaldehyde afforded (trifluoromethyl)styrene 4 bearing an o-formyl group in 81% yield. The addition of nucleophiles such as Grignard reagents to 4 selectively occurred at the formyl carbon to provide 3b and 3c.
As sulfur-containing substrates for the synthesis of isothiochromanes, thioacetates 6 were readily prepared from alcohols 3 via the corresponding mesylates 5 by the introduction of an acetylthio (AcS) group at the benzylic position on treatment with the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) salt of ethanethioic S-acid (Scheme 1, route C).

Cyclization of α-(Trifluoromethyl)styrenes Bearing a Nucleophilic Oxygen or Sulfur Atom
We first examined the cyclization of (trifluoromethyl)styrenes 3 with a nucleophilic oxygen as precursors of isochromanes. Intramolecular addition of 3a was attempted under basic conditions with a proton source to trap the intermediary trifluoromethylated carbanion. Treatment of 3a with KOH (1.5 equiv) in ethylene glycol (ethane-1,2-diol) gave the desired cyclic product 7a in 37% yield, whereas the addition was more successfully effected by the use of DBU (1.1 equiv) in diglyme [bis(2-methoxyethyl) ether] at 120 °C (Table 1, Entry 1), where the hydroxy group of 3a and/or DBU•H+ acted as a proton donor. 4-Trifluoromethylated isochromane 7a was obtained in 82% yield without formation of a substitution product 8a (vide infra). In the case of secondary alcohols 3b,c, ring closure also occurred under similar conditions, leading to 1,4-disubstituted isochromanes 7b,c in 72 and 86% yields with 87:13 and 57:43 diastereomer ratios, respectively (Entries 2 and 3).
Chromane precursors 3 were next subjected to basic conditions in the absence of a proton source to attempt intramolecular substitution, leading to 4-difluoromethylenated isochromanes 8. Treatment with NaH in dimethylformamide (DMF) mainly caused decomposition of 3a and afforded the expected SN2′-type product 8a only in 10% yield along with 7a in 20% yield. After screening of basic conditions, we found that treatment with K3PO4 (2.0 equiv) in DMF improved the yield of 8a to 38% with the accompanying formation of 7a in 11% yield (Entry 4).

We then tried the cyclizations via addition or substitution using sulfur nucleophiles, which would provide isothiochromanes. When thioacetates 6a,b were treated with K2CO3 (1.1 equiv) in MeOH, the deacetylation of 6 occurred to generate the corresponding thiolates, whose intramolecular addition readily proceeded in the presence of a proton source. The desired products, 4-trifluoromethylated isothiochromanes 9a,b were obtained in 92% yield and 80% yield with 57:43 diastereomer ratio, respectively (Table 2, Entries 1 and 2). In contrast, treatment of 6a,b with sodium methoxide (2.0–3.0 equiv) in tetrahydrofuran (THF) promoted deacetylation followed by SN2′-type reaction instead of addition, which is due to the aprotic conditions. The two successive processes provided 4-difluoromethylenated isothiochromanes 10a,b in 76% and 73% yields, respectively (Entries 3 and 4).

In conclusion, the above results show that our intramolecular addition and substitution concept in 2-trifluoromethyl-1-alkenes can be successfully applied to the construction of 6-membered oxygen- or sulfur-containig heterocycles as well as nitrogen-containing heterocycles. o-Substituted α-(trifluoromethyl)styrenes, prepared from 2-bromo-3,3,3-trifluoro-1-propene and aryl iodides, readily undergo 6-endo ring closure via addition or substitution, depending on the reaction conditions. These reactions provide a facile method for the construction of selectively trifluoromethylated and difluoromethylenated benzo(thio)pyran frameworks.

EXPERIMENTAL
IR spectra were recorded by ATR (attenuated total reflectance) method. NMR spectra were recorded in CDCl3 at 500 MHz (1H NMR), 126 MHz (13C NMR), and 470 MHz (19F NMR). Chemical shift values were given in ppm relative to internal Me4Si (for 1H NMR: δ 0.00), CDCl3 (for 13C NMR: δ 77.0), and C6F6 (for 19F NMR: δF 0.0). Column chromatography and preparative thin-layer chromatography (PTLC) were performed on silica gel. Unless otherwise noted, all reactions were conducted under nitrogen. Toluene, DMF, CH2Cl2, THF, and diethyl ether (Et2O) were dried by passing over a column of activated alumina (A-2, Purity) followed by a column of Q-5 scavenger (Engelhard). MeOH was distilled from Mg, and stored over molecular sieves 3Å. Ethylene glycol and diglyme were distilled from MgSO4 and CaH2, respectively, and then stored over molecular sieves 4Å.

[2-(3,3,3-Trifluoroprop-1-en-2-yl)phenyl]methanol (3a): To a magnesium turnings (571 mg, 23.4 mmol) and trimethylborate (6.51 mL, 58.5 mmol) in THF (40 mL) was added 2-bromo-3,3,3-trifluoropropene (2.00 mL, 19.5 mmol) in THF (5 mL) over 1 h at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with HCl (20 mL of 6 M aqueous solution), and organic materials were extracted three times each with Et2O. The combined extracts were washed with brine and then dried over MgSO4. Removal of the solvent under reduced pressure gave the residue, crude 1-(trifluoromethyl)vinylboronic acid (2) [19F NMR (CDCl3) δF 98.3 (s)], which was immediately used without purification in the following palladium-catalyzed coupling reaction with iodoarenes. The mixture of the crude boronic acid 2, 2-iodophenylmethanol (2.62 g, 11.2 mmol), sodium carbonate (12 mL of 1.0 M aqueous solution), Pd(PPh3)4 (259 mg, 0.224 mmol) in toluene–MeOH (140 mL, 5:1) was stirred at 70 °C for 16 h. The reaction was quenched with phosphate buffer (pH 7). The mixture was extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane­–AcOEt 3:1) to give 3a (2.00 g, 88%) as a colorless oil. 1H NMR (500 MHz, CDCl3, δ): 4.67 (s, 2H), 5.60 (q, JHF = 1.2 Hz, 1H), 6.15 (q, JHF = 1.4 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 7.6, 7.6 Hz, 1H), 7.43 (dd, J = 7.6, 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 62.7, 122.8 (q, JCF = 274 Hz), 123.5 (q, JCF = 5 Hz), 127.5, 128.4, 129.3, 129.8, 132.4, 136.9 (q, JCF = 31 Hz), 139.4. 19F NMR (470 MHz, CDCl3, δF): 94.7 (s). IR (neat): 3330, 1342, 1217, 1169, 1115, 1072, 769 cm-1. Anal. Calcd for C10H9OF3: C, 59.41; H, 4.49. Found: C, 59.2; H, 4.58.
2-(3,3,3-Trifluoroprop-1-en-2-yl)benzaldehyde (4): Compound 4 was prepared by the method described for 3a. Purification by column chromatography (hexane–AcOEt 5:1) gave 4 (81%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 5.62 (q, JHF = 1.3 Hz, 1H), 6.29 (q, JHF = 1.3 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.6, 7.6 Hz, 1H), 7.63 (dd, J = 7.6, 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 10.1 (s, 1H). 13C NMR (126 MHz, CDCl3, δ): 122.4 (q, JCF = 274 Hz), 125.1 (q, JCF = 5 Hz), 128.4, 129.5, 130.7, 133.6, 134.8, 135.4 (q, JCF = 32 Hz), 136.6, 190.8. 19F NMR (470 MHz, CDCl3, δF): 94.8 (s). IR (neat): 2858, 1701, 1599, 1346, 1173, 1126, 962 cm-1. Anal. Calcd for C10H7OF3: C, 60.01; H, 3.53. Found: C, 60.03; H, 3.66.
1-[2-(3,3,3-Trifluoroprop-1-en-2-yl)phenyl]pentan-1-ol (3b): To a solution of 4 (1.02 g, 5.09 mmol) in Et2O (45 ml) was added butylmagnesium bromide (3.06 ml, 2.0 M in Et2O, 6.12 mmol) at –78 °C. The reaction mixture was stirred at –78 °C for 30 min and at rt for an additional 3 h. Then, phosphate buffer (pH 7) was added to quench the reaction. Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane–AcOEt 3:1) to give 3b (1.12 g, 85%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 0.88 (t, J = 7.2 Hz, 3H), 1.21–1.45 (m, 4H), 1.62–1.69 (m, 1H), 1.76–1.83 (m, 2H), 4.79 (dd, J = 8.3, 5.0 Hz, 1H), 5.52 (q, JHF = 1.2 Hz, 1H), 6.14 (q, JHF = 1.4 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.28 (dd, J = 7.6, 7.6 Hz, 1H), 7.43 (dd, J = 7.6, 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 13.9, 22.5, 28.2, 38.3, 70.6, 122.8 (q, JCF = 274 Hz), 123.5 (q, JCF = 5 Hz), 126.2, 127.2, 129.5, 129.8, 131.8, 137.5 (q, JCF = 31 Hz), 143.8. 19F NMR (470 MHz, CDCl3, δF): 94.5 (s). IR (neat): 2933, 2862, 1340, 1167, 1124, 1095, 953, 762, 631 cm-1. Anal. Calcd for C14H17OF3: C, 65.10; H, 6.63. Found: C, 65.45; H, 7.00.
Phenyl[2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl]methanol (3c): Compound 3c was prepared by the method described for 3b. Purification by column chromatography (hexane–AcOEt 5:1) gave 4 (91%) as a white solid. 1H NMR (500 MHz, CDCl3, δ): 2.12 (d, J = 3.8 Hz, 1H), 5.42 (q, JHF = 1.1 Hz, 1H), 5.98 (d, J = 3.8 Hz, 1H), 6.12 (q, JHF = 1.4 Hz, 1H), 7.24–7.28 (m, 2H), 7.29–7.35 (m, 5H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 72.5, 122.9 (q, JCF = 274 Hz), 124.2 (q, JCF = 5 Hz), 126.6, 127.5, 127.5, 127.9, 128.4, 129.4, 129.9, 132.5, 136.9 (q, JCF = 31 Hz), 142.5, 143.4. 19F NMR (470 MHz, CDCl3, δF): 94.7 (s). IR (neat): 3334, 2921, 1342, 1403, 1169, 1122, 1016, 700 cm-1. Anal. Calcd for C16H13OF3: C, 69.06; H, 4.71. Found: C, 68.92; H, 4.78.
S-[2-(3,3,3-Trifluoroprop-1-en-2-yl)phenyl]methyl ethanethioate (6a): Compound 6a was prepared by the method described for 6b (vide infra). Purification by PTLC (hexane–AcOEt 5:1) gave 6a (85%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 2.34 (s, 3H), 4.13 (s, 2H), 5.59 (q, JHF = 1.3 Hz, 1H), 6.17 (q, JHF = 1.4 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.27 (dd, J = 7.6, 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 30.2, 30.8, 122.8 (q, JCF = 274 Hz), 123.9 (q, JCF = 5 Hz), 127.2, 129.4, 130.0, 130.3, 133.3, 136.5, 137.0 (q, JCF = 31 Hz), 194.8. 19F NMR (470 MHz, CDCl3, δF): 94.6 (s). IR (neat): 2252, 1684, 1344, 1203, 1132, 903, 721, 650 cm-1. Anal. Calcd for C12H11OF3S: C, 55.38; H, 4.26. Found: C, 55.49; H, 4.43.
S-1-[2-(3,3,3-Trifluoroprop-1-en-2-yl)phenyl]pentyl ethanethioate (6b): To a solution of 3b (615 mg, 2.38 mmol) and triethylamine (0.50 mL, 3.6 mmol) in CH2Cl2 (11 ml) was added methanesulfonyl chloride (0.22 mL, 2.9 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 2 h, saturated aqueous NH4Cl was added to quench the reaction. The organic layer was washed with brine and dried over MgSO4. Removal of the solvent under reduced pressure gave the residue, crude mesylate 5b, which was used without purification in the following substitution reaction with ethanethioic S-acid. To a solution of DBU (1.04 mL, 7.0 mmol) in DMF (3.3 ml) was added ethanethioic S-acid (0.50 mL, 7.1 mmol) dropwise at rt. The crude mesylate 5b in DMF (6.6 ml) was added, and the mixture was stirred at rt for 20 h. The reaction was quenched with saturated aqueous NH4Cl. After water was added, organic materials were extracted with AcOEt three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane–AcOEt 5:1) to give 6b (600 mg, 82%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 0.84 (t, J = 7.2 Hz, 3H), 1.16–1.18 (m, 1H), 1.26–1.31 (m, 3 H), 1.87–1.93 (m, 2H), 2.28 (s, 3H), 4.76 (t, J = 7.6 Hz, 1H), 5.59 (q, JHF = 1.1 Hz, 1H), 6.19 (q, JHF = 1.3 Hz, 1H), 7.22–7.27 (m, 2H), 7.36–7.37 (m, 2H). 13C NMR (126 MHz, CDCl3, δ): 13.8, 22.4, 29.4, 30.3, 37.1, 44.6, 122.9 (q, JCF = 274 Hz), 124.1 (q, JCF = 5 Hz), 126.8, 127.8, 129.3, 130.0, 132.6, 136.6 (q, JCF = 31 Hz), 140.6, 194.2. 19F NMR (470 MHz, CDCl3, δF): 95.0 (s). IR (neat): 2931, 2862, 1691, 1402, 1342, 1201, 1167, 1092, 1068, 953, 629 cm-1. Anal. Calcd for C16H19OF3S: C, 60.74; H, 6.05. Found: C, 60.51; H, 6.14.
4-Trifluoromethyl-3,4-dihydro-1H-2-benzopyran (7a): To a solution of 3a (51 mg, 0.25 mmol) in diglyme (2.5 mL) was added DBU (42 µL, 0.28 mmol). After the reaction mixture was heated at 120 °C for 48 h, phosphate buffer (pH 7) was added to quench the reaction. Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by PTLC (pentane–Et2O 5:1) to give 7a (42 mg, 82%) as a colorless crystal. 1H NMR (500 MHz, CDCl3, δ): 3.42 (qm, JHF = 9.3 Hz, 1H), 3.92 (dm, J = 12.3 Hz, 1H), 4.41 (dd, J = 12.3, 2.3 Hz, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.87 (d, J = 15.2 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.26 (dd, J = 7.6, 7.6 Hz, 1H), 7.32 (dd, J = 7.6, 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 41.1 (q, JCF = 26 Hz), 63.8 (q, JCF = 3 Hz), 67.7, 124.7, 126.1 (d, JCF = 1 Hz), 126.2 (q, JCF = 281 Hz), 126.8, 128.3, 130.2, 135.8. 19F NMR (470 MHz, CDCl3, δF): 93.7 (d, JFH = 9 Hz). IR (neat): 2871, 1734, 1495, 1456, 1350, 1269, 1230, 1153, 1108, 995, 912, 742 cm-1. Anal. Calcd for C10H9OF3: C, 59.41; H, 4.49. Found: C, 59.28; H, 4.54.
1-Butyl-4-trifluoromethyl-3,4-dihydro-1H-2-benzopyran (7b): Compound 7b was prepared by the method described for 7a. Purification by PTLC (pentane–Et2O 10:1) gave 7b (72%; 87:13 diastereomer ratio) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): (major) 0.90 (t, J = 7.2 Hz, 3H), 1.28–1.46 (m, 4H), 1.80–1.88 (m, 1H), 1.94–2.01 (m, 1H), 3.26 (qd, JHF = 9.2, 3.6 Hz, 1H), 3.83 (ddq, J = 12.3, 3.6, 1.8 Hz, 1H), 4.47 (d, J = 12.3 Hz, 1H), 4.74 (dd, J = 7.6, 2.7 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.23–7.26 (m, 1H), 7.32–7.35 (m, 2H); (minor) 0.94 (t, J = 7.2 Hz, 3H), 1.32–1.55 (m, 4H), 1.70–1.77 (m, 1H), 1.81–1.89 (m, 1H), 3.38–3.45 (m, 1H), 4.12 (d, J = 4.0 Hz, 2H), 4.79 (dd, J = 10.1, 3.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.23–7.26 (m, 1H), 7.31 (dd, J = 7.6, 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): (major) 14.0, 22.8, 26.8, 35.4, 41.8 (q, JCF = 26 Hz), 62.8 (q, JCF = 3 Hz), 76.3, 124.9, 126.2 (q, JCF = 281 Hz), 126.4, 126.9 (q, JCF = 2 Hz), 128.5, 130.5, 139.5; (minor) 14.0, 22.5, 28.1, 34.8, 41.5 (q, JCF = 26 Hz), 58.8 (q, JCF = 3 Hz), 75.0, 125.5, 126.3 (q, JCF = 281 Hz), 126.4 (q, JCF = 2 Hz), 126.6, 128.1, 129.6, 139.8. 19F NMR (470 MHz, CDCl3, δF): (major) 93.9 (d, JFH = 9 Hz); (minor) 93.8 (d, JFH = 9 Hz). IR (neat) 2956, 2931, 1250, 1155, 1119, 750, 620 cm-1. Anal. Calcd for C14H17OF3: C, 65.10; H, 6.63. Found: C, 65.02; H, 6.77.
1-Phenyl-4-trifluoromethyl-3,4-dihydro-1H-2-benzopyran (7c): Compound 7c was prepared by the method described for 7a. Purification by PTLC (pentane–Et2O 5:1) gave 7b (86%; 57:43 diastereomer ratio) as a colorless crystal. 1H NMR (500 MHz, CDCl3, δ): (major) 3.40 (qd, JHF = 9.1, 3.6 Hz, 1H), 4.07 (ddq, J = 12.4, 3.6, 1.8 Hz, 1H), 4.59 (d, J = 12.4 Hz, 1H), 5.66 (s, 1H), 6.79 (d, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.5, 7.5 Hz, 1H), 7.25 (dd, J = 7.5, 7.5 Hz, 1H), 7.34–7.37 (m, 5H), 7.39 (d, J = 7.5 Hz, 1H); (minor) 3.52–3.57 (m, 1H), 4.05–4.12 (m, 2H), 5.88 (s, 1H), 6.93 (d, J = 7.4 Hz, 1H), 7.19–7.22 (m, 2H), 7.27–7.38 (m, 5H), 7.47 (d, J = 7.4 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): (major) 41.5 (q, JCF = 26 Hz), 63.6 (q, JCF = 3 Hz), 80.5, 126.2 (q, JCF = 281 Hz), 126.4 (q, JCF = 2 Hz), 126.9, 127.1, 128.4, 128.5, 128.6, 128.9, 130.2, 138.9, 141.1; (minor) 41.3 (q, JCF = 26 Hz), 59.4 (q, JCF = 3 Hz), 77.8, 126.3 (q, JCF = 281 Hz), 127.2 (q, JCF = 2 Hz), 127.2, 127.5, 127.9, 128.3, 128.4, 129.1, 129.6, 137.1, 140.9. 19F NMR (470 MHz, CDCl3, δF): (major) 93.9 (d, JFH = 9 Hz); (minor) 93.8 (d, JFH = 9 Hz). IR (neat): 3064, 3031, 2870, 1455, 1355, 1243, 1155, 999, 747, 700 cm-1. Anal. Calcd for C16H13OF3: C, 69.06; H, 4.71. Found: C, 69.08; H, 4.94.
4-Difluoromethylene-3,4-dihydro-1H-2-benzopyran (8a): Compound 8a was prepared by the method described for 8c (vide infra). Purification by PTLC (pentane–Et2O 5:1) gave 8a (38%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 4.50 (dd, JHF = 2.7, 2.7 Hz, 2H), 4.79 (s, 2H), 7.05 (d, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.5, 7.5 Hz, 1H), 7.27 (dd, J = 7.5, 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 63.2 (dd, JCF = 4, 4 Hz), 68.9, 85.7 (dd, JCF = 20, 13 Hz), 124.7, 125.7 (d, JCF = 3 Hz), 126.6 (dd, JCF = 10, 5 Hz), 127.0 (dd, JCF = 2, 2 Hz), 127.3, 134.1 (dd, JCF = 5, 3 Hz), 152.3 (dd, JCF = 296, 291 Hz). 19F NMR (470 MHz, CDCl3, δF): 75.6 (d, JFF = 41 Hz, 1F), 75.5 (d, JFF = 41 Hz, 1F). IR (neat): 2958, 2846, 1722, 1329, 1261, 1236, 1086, 1053, 760, 737 cm-1. Anal. Calcd for C10H8OF2: C, 65.93; H, 4.43. Found: C, 66.07; H, 4.59.
4-Difluoromethylene-1-phenyl-3,4-dihydro-1H-2-benzopyran (8c): To a solution of 8c (53 mg, 0.19 mmol) in DMF (2.0 mL) was added K3PO4 (81 mg, 0.38 mmol) at rt. After the reaction mixture was stirred at 120 °C for 6 h, phosphate buffer (pH 7) was added to quench the reaction. Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by PTLC (pentane–Et2O 5:1) to give 8c (21 mg, 43%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 4.43 (ddd, J = 13.2 Hz, JHF = 3.6, 3.6 Hz, 1H), 4.63 (dd, J = 13.2 Hz, JHF = 2.6 Hz, 1H), 5.76 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 7.6, 7.6 Hz, 1H), 7.24–7.39 (m, 6H), 7.66 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 61.0 (dd, JCF = 4, 4 Hz), 80.0, 86.0 (dd, JCF = 24, 8 Hz), 126.4 (dd, JCF = 4, 2 Hz), 126.5 (dd, JCF = 14, 2 Hz), 126.9 (dd, JCF = 2, 2 Hz), 127.1, 127.5, 128.4, 128.5, 128.8, 136.5 (dd, JCF = 6, 2 Hz), 140.7, 152.2 (dd, JCF = 300, 287 Hz). 19F NMR (470 MHz, CDCl3, δF): 75.5 (d, JFF = 41 Hz, 1F), 75.9 (d, JFF = 41 Hz, 1F). IR (neat): 3066, 3032, 2927, 2854, 1732, 1718, 1238, 760, 700 cm-1. Anal. Calcd for C16H12OF2: C, 74.41; H, 4.68. Found: C, 74.42; H, 4.91.
4-Trifluoromethyl-3,4-dihydro-1H-2-benzothiopyran (9a): To a solution of 6a (44 mg, 0.17 mmol) in MeOH (1.7 mL) was added K2CO3 (26 mg, 0.19 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 4 h, phosphate buffer (pH 7) was added to quench the reaction. Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over MgSO4. After removal of the solvent under reduced pressure, the residue was purified by PTLC (pentane–Et2O 20:1) to give 7a (34 mg, 92%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 3.11 (dd, J = 13.6, 6.4 Hz, 1H), 3.17 (dd, J = 13.6, 5.8 Hz, 1H), 3.73–3.81 (m, 1H), 3.78 (s, 2H), 7.17–7.19 (m, 1H), 7.24–7.29 (m, 2H), 7.37–7.38 (m, 1H). 13C NMR (126 MHz, CDCl3, δ): 25.6 (q, JCF = 3 Hz), 30.0, 42.9 (q, JCF = 26 Hz), 126.4 (q, JCF = 282 Hz), 127.1, 127.9, 128.6, 129.5 (q, JCF = 1 Hz), 130.4 (q, JCF = 2 Hz), 136.1. 19F NMR (470 MHz, CDCl3, δF): 94.6 (d, JFH = 9 Hz). IR (neat): 3064, 2921, 1496, 1448, 1340, 1270, 1241, 1151, 1103, 950, 763, 739 cm-1. Anal. Calcd for C10H9F3S: C, 55.03; H, 4.16. Found: C, 55.17; H, 4.32.
1-Butyl-4-trifluoromethyl-3,4-dihydro-1H-2-benzothiopyran (9b): Compound 9b was prepared by the method described for 9a. Purification by PTLC (pentane–Et2O 30:1) gave 9b (80%; 57:43 diastereomer ratio) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 0.93 (t, J = 7.2 Hz, 1.8H), 0.94 (t, J = 7.2 Hz, 1.2H), 1.28–1.49 (m, 3H), 1.55–1.66 (m, 1H), 1.78–2.02 (m, 2H), 3.01 (dd, J = 14.1, 4.3 Hz, 0.6H), 3.05–3.14 (m, 0.8H), 3.20 (br dd, J = 14.1, 4.3 Hz, 0.6H), 3.65–3.85 (m, 2H), 7.18–7.31 (m, 3H), 7.34 (d, J = 7.6 Hz, 0.6H), 7.43 (d, J = 7.6 Hz, 0.4H). 13C NMR (126 MHz, CDCl3, δ): 14.0, 14.0, 22.2 (q, JCF = 3 Hz), 22.3 (q, JCF = 3 Hz), 22.3, 22.4, 29.9, 30.2, 35.0, 38.1, 41.9, 42.1, 42.4 (q, JCF = 26 Hz), 43.2 (q, JCF = 26 Hz), 126.3 (q, JCF = 282 Hz), 126.6 (q, JCF = 282 Hz), 126.6, 126.8, 127.5, 127.9, 128.0, 128.7 (q, JCF = 1 Hz), 128.8, 129.2 (q, JCF = 1 Hz), 129.8 (q, JCF = 2 Hz), 130.6 (q, JCF = 2 Hz), 140.2, 140.8. 19F NMR (470 MHz, CDCl3, δF): 95.4 (d, JFH = 9 Hz, 1.8F), 94.6 (d, JFH = 9 Hz, 1.2F). IR (neat): 3060, 3025, 2958, 2931, 1493, 1446, 1346, 1273, 1244, 1238, 1151, 1107 cm-1. Anal. Calcd for C14H17F3S: C, 61.29; H, 6.25. Found: C, 61.41; H, 6.43.
4-Difluoromethylene-3,4-dihydro-1H-2-benzothiopyran (10a): To a solution of 6a (56 mg, 0.22 mmol) in THF (2.2 mL) was added NaOMe (24 mg, 0.43 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and at rt for an additional 3 h. Then, phosphate buffer (pH 7) was added to quench the reaction. Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by PTLC (pentane–Et2O 20:1) to give 10a (32 mg, 76%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 3.53 (dd, JHF = 2.3, 2.3 Hz, 2H), 3.79 (s, 2H), 7.16 (d, J = 7.4 Hz, 1H), 7.21 (dd, J = 7.4, 7.4 Hz, 1H), 7.25 (dd, J = 7.4, 7.4 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H). 13C NMR (126 MHz, CDCl3, δ): 25.1 (dd, JCF = 2, 2 Hz), 30.8, 87.1 (dd, JCF = 23, 12 Hz), 127.0, 127.2, 127.9, 128.5 (dd, JCF = 11, 1 Hz), 129.2 (dd, JCF = 5, 4 Hz), 135.2 (d, JCF = 5 Hz), 152.9 (dd, JCF = 297, 287 Hz). 19F NMR (470 MHz, CDCl3, δF): 72.3 (d, JFF = 37 Hz, 1F), 75.1 (d, JFF = 37 Hz, 1F). IR (neat): 3064, 2910, 1712, 1489, 1326, 1228, 1112, 985, 756, 713 cm-1. Anal. Calcd for C10H8F2S: C, 60.59; H, 4.07. Found: C, 60.38; H, 4.15.
1-Butyl-4-difluoromethylene-3,4-dihydro-1H-2-benzothiopyran (10b): Compound 10b was prepared by the method described for 10a. Purification by PTLC (pentane–Et2O 30:1) gave 10b (73%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, δ): 0.91 (t, J = 7.1 Hz, 3H), 1.28–1.41 (m, 3H), 1.47–1.58 (m, 1H), 1.77–1.88 (m, 2H), 3.46 (ddd, JHF = 14.1, 2.4, 2.4 Hz, 1H), 3.63 (ddd, JHF = 14.1, 2.4, 2.4 Hz, 1H), 3.73 (t, J = 6.8 Hz, 1H), 7.15–7.18 (m, 1H), 7.21–7.27 (m, 2H), 7.43–7.47 (m, 1H). 13C NMR (126 MHz, CDCl3, δ): 13.9, 22.3, 22.5, 30.1, 36.5, 43.6, 86.9 (dd, JCF = 23, 13 Hz), 126.8, 127.1, 127.3, 128.7, 128.7 (d, JCF = 8 Hz), 140.5 (d, JCF = 5 Hz), 152.9 (dd, JCF = 296, 288 Hz). 19F NMR (470 MHz, CDCl3, δF): 71.3 (d, JFF = 37 Hz, 1F), 75.0 (d, JFF = 37 Hz, 1F). IR (neat): 3066, 2956, 2929, 2858, 1716, 1487, 1254, 1232, 1106, 980, 758cm-1. Anal. Calcd for C14H16F2S: C, 66.11; H, 6.34. Found: C, 66.10; H, 6.52.

ACKNOWLEDGEMENTS
We are grateful to Ono Pharmaceutical Co., Ltd. for financial support. We also thank Tosoh F-Tech, Inc. for a generous gift of 2-bromo-3,3,3-trifluoropropene.


This paper is dedicated to Professor Emeritus, Tohoku University, Keiichiro Fukumoto in celebration of his 75th birthday.

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