Iron-Catalyzed Synthesis of Sulfur-Containing Heterocycles - The

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Iron-Catalyzed Synthesis of Sulfur-Containing Heterocycles Cyril Bosset,† Gauthier Lefebvre,† Patrick Angibaud,‡ Ian Stansfield,‡ Lieven Meerpoel,§ Didier Berthelot,‡ Amandine Guérinot,*,† and Janine Cossy*,† †

Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231, ESPCI Paris, CNRS, PSL Research University, 10 rue Vauquelin 75231 Paris Cedex 05, France ‡ Janssen Research & Development, Oncology Discovery Chemistry, Campus de Maigremont CS 10615, 27106 Cedex, Val de Reuil, France § Janssen Research & Development, Janssen Pharmaceutica NV Turnhoutseweg 30, 2340 Beerse, Belgium S Supporting Information *

ABSTRACT: An iron-catalyzed synthesis of sulfur- and sulfone-containing heterocycles is reported. The method is based on the cyclization of readily available substrates and proceeded with high efficiency and diastereoselectivity. A variety of sulfur-containing heterocycles bearing moieties suitable for subsequent functionalization are prepared. Illustrative examples of such postcyclization modifications are also presented.

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INTRODUCTION Organosulfur heterocycles represent important motifs that have been employed in both the pharmaceutical field and as functional materials.1 In particular, sulfur-containing 1,4heterocycles are ubiquitous pharmacophores often found in biologically active natural products as well as in synthetic drug molecules. For example, the 1,4-oxathiane scaffold is encountered in muscarinic agonists,2 antifungal compounds,3 antitumoral agents (1, Figure 1),4 and antiasthma molecules (raphanuside, Figure 1).5

mediate the formation of these S-containing heterocycles. Nowadays, there is a growing need to develop nonexpensive, eco-friendly and powerful synthetic methods that could be turned into industrial processes. In this context, we recently directed our attention to the FeCl3-catalyzed construction of valuable building blocks incorporating heterocycles such as tetrahydropyrans and piperidines.16 These reactions are based on a FeCl3-catalyzed activation of an allylic alcohol followed by an intramolecular nucleophilic addition on the resulting carbocation (Scheme 1).17,18 It is noteworthy that the iron salt is also able to induce a reopening of the formed heterocycles, thus allowing them to reach high diastereoselectivity in favor of the most stable isomer under thermodynamic control. This method employs an iron salt that is both cheap and of relatively low toxicity as the key reagent. Furthermore, it is atom economical as only water is produced along with the desired product. Herein, we report the ironcatalyzed synthesis of a range of sulfur-containing 1,4heterocycles E from easily accessible precursors D (Scheme 1).

Figure 1. Sulfur-containing heterocycles in bioactive products.

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RESULTS AND DISCUSSION Initially, to avoid an eventual deactivation of the iron catalyst caused by the coordinating sulfur atom, we decided to focus on the synthesis of 1,4-oxathiane 4,4-dioxides. Most of the substrates of type D (X = O, SO2) could be easily prepared in two steps from dimethylsulfone and commercially available aldehydes.19 Gratifyingly, when 2a was treated with a catalytic amount of FeCl3·6H2O, after 7 h at 50 °C, the cyclized product 3a was isolated in high yield (94%) and with an excellent

Similarly, the 1,4-thiomorpholine moiety has been widely encountered in a variety of bioactive products including DPPIV inhibitors,6 anti-inflammatory drugs,7 antimycobacterial agents,8 and hypolipidemic compounds.9 Furthermore, because of their interesting biological properties, the S,S-dioxide derivatives of 1,4-oxathianes and 1,4-thiomorpholines are frequently targeted as well.10 As a consequence, a large range of synthetic methods has been developed to access these Scontaining heterocycles. In particular, 1,4-oxathianes could variously be prepared using a Mitsunobu reaction,11 a ring expansion,12 a reductive etherification13 or by functionalization of hydroxythiols.14,15 However, few of the reported methods are based on the use of catalytic quantities of reagent to © 2016 American Chemical Society

Received: July 28, 2016 Published: October 13, 2016 4020

DOI: 10.1021/acs.joc.6b01827 J. Org. Chem. 2017, 82, 4020−4036

The Journal of Organic Chemistry

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Table 1. Influence of the R1 Substituent on the Outcome of the Cyclization

Scheme 1. Iron-Catalyzed Cyclization To Access Heterocycles

diastereoselectivity in favor of the cis compound (dr >98:2) (Scheme 2).20 Scheme 2. Synthesis of the 1,4-Oxathiane 4,4-Dioxide 3a

Scheme 3. Synthesis of a Sulfonyl Benzopyran Analogue The influence of the R1 substituent (Scheme 1) on the outcome of the reaction was then investigated. When the phenyl group was replaced by an alkyl side chain (R1 = iPr, nC5H11), the cyclized cis products were formed in good yields and diastereoselectivities (Table 1, entries 1 and 2). The cis-1,4oxathiane 4,4-dioxide 3d bearing a terminal double bond was efficiently obtained from its precursor 2d under iron catalysis (Table 1, entry 3). Interestingly, the reaction conditions tolerate the presence of N-heteroaryl moieties, and when a 2chloropyridine was present, the cyclized product was isolated with a good yield of 73% as a cis isomer (Table 1, entry 4). Noteworthy, the transformation requires a longer reaction time, possibly due to a partial deactivation of the iron catalyst upon coordination to the nitrogen atom. A similar observation was made in the presence of a dichloropyrimidine moiety on the precursor (Table 1, entry 5). However, although a longer reaction time is required, it does not affect the yield of the transformation (93%). In contrast, diol 2g, which possesses an indole substituent, was transformed into its cyclized counterpart with a moderate yield of 49% (Table 1, entry 6) due to a partial degradation of the starting material and/or product. Interestingly, the sulfonyl benzopyran analogue 3h could be prepared from phenol 2h with a good yield of 85% (Scheme 3). A variety of diols possessing different R2 substituents were then examined. The phenyl was not essential to the transformation as a methyl group could be used instead. However, in this case, after 20 h at 50 °C, the diol 2i was totally transformed into a 56:44 mixture of cis- and trans-cyclic

compounds. An extended heating period at 110 °C in (CH2)2Cl2 proved necessary to reach full diastereoselectivity in favor of the most stable cis isomer (Table 2, entry 1). In the absence of a phenyl group at R2, the iron-catalyzed equilibration between the cis- and trans-sulfur-containing heterocycles seemed more difficult, thus requiring higher temperature. At 110 °C, a partial (E)/(Z)-isomerization of the double bond was observed. When a terminal double bond was present (R2 = H), even harsher conditions were needed, as after 6 h at 110 °C the two diastereomers were obtained as a 61:39 mixture. Further heating at 120 °C for 30 h led to a significant improvement in the diasteromeric ratio (83:17) in favor of the cis isomer (Table 2, entry 2). Surprisingly, diene 2k showed a very high reactivity and was fully converted into the cyclic product 3k after 20 h at rt, and only 30 min at 50 °C was necessary to reach essentially a complete diastereoselectivity in favor of the cis compound (dr >98:2) (Table 2, entry 3). In addition, the symmetrical diol 2l could be transformed into its corresponding cyclized product with a good yield of 88%. Once again, prolonged heating at 110 °C was necessary to reach an excellent diastereoselectivity in favor of the cis adduct (Scheme 4). 4021



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Table 2. Influence of the R2 Substituent on the Outcome of the Cyclization

Scheme 5. Access to 1,4-Thiomorpholine 4,4-Dioxides

See the Supporting Information for details. b20 h at 50 °C in CH2Cl2 (dr = 56:44) and then 20 h at 110 °C in (CH2)2Cl2. cE/Z = 88:12. d20 h at rt and then 30 min at 50 °C in CH2Cl2. a

Scheme 4. Cyclization of the Bis-benzylic Diol 2l

Scheme 6. Troublesome Reduction of 3d

Following the successful results with the 1,4-oxathiane 4,4dioxides, we turned our attention to the preparation of 1,4thiomorpholine 4,4-dioxides. However, in this instance, when the amino alcohol 4a was reacted with 5 mol % of FeCl3·6H2O, the cyclization delivered the expected product 5a (59%) as a 75:25 mixture of cis and trans isomers together with a small amount (10%) of a diene byproduct 6 (Scheme 5, eq 1), resulting from dehydration of the starting material. In addition, when the mixture of cis-5a and trans-5a was treated with FeCl3· 6H2O at 50 °C, after 20 h, no evolution of the diastereomeric ratio was noticed, and again, diene 6 was isolated in 33% yield (Scheme 5, eq 2).21 On the contrary, the aniline derivative 4b successfully furnished the corresponding 1,4-thiomorpholine dioxide 5b with a good yield of 79% (Scheme 5, eq 3). To access the 1,4-oxathiane scaffold, reduction of the S,Sdioxide 3d was attempted using an excess of DIBAL-H. However, after 4 days at 80 °C, no conversion of the starting material was observed (Scheme 6). Consequently, we decided to investigate the direct ironcatalyzed cyclization of diols of type D (Scheme 1) including a sulfur atom instead of a sulfone (Scheme 1). Gratifyingly, when 8a was reacted with 5 mol % of FeCl3·6H2O, the corresponding 1,4-oxathiane 9a was isolated with a good yield of 77% and an excellent diastereomeric ratio of 98:2 in favor of the cis product. Although unexpected, it appears that the potentially coordinating sulfur atom does not poison the iron catalyst. Similarly, diol 8b was efficiently transformed into the trans-2,5-disubstituted 1,4-oxathiane 9b. Once again, the major product formed corresponds to the thermodynamic product. Finally, when the phenol 8c was submitted to the iron-catalyzed cyclization, the reaction proceeded smoothly, delivering the benzoxathiane product in 86% yield (Scheme 7).

Scheme 7. Synthesis of 1,4-Oxathianes

The same approach was successfully adopted to synthesize the 1,4-thiomorpholine scaffold. Treatment of the sulfonamide 10a with FeCl3·6H2O afforded the 2,6-disubstituted thiomorpholine 11a with good yield (69%) and diastereoselectivity (dr 4022



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= 95:5).22 The aniline derivatives 10b and 10c were also efficiently converted to the corresponding benzothiomorpholines 11b and 11c, respectively (Scheme 8).

Scheme 9. Hypothetic Mechanism of the Cyclization

Scheme 8. Synthesis of 1,4-Thiomorpholines

The results observed during the iron-induced cyclization of diols 2i and 2l enabled us to highlight the underlying mechanism of the transformation. As previously described, diols 2i and 2l were fully converted into oxathianes 3i and 3l after 20 h at 50 °C, but a poor diastereoselectivity was measured at this stage in both cases. However, prolonged heating at 110 °C of the mixtures of cis and trans isomers of 3i and 3l in the presence of FeCl3·6H2O enabled us to dramatically improve the dr in favor of cis-3i and cis-3l, suggesting an opening/reclosure of the heterocycle.23 Such an opening/reclosure process could be supported by the recently reported iron-catalyzed C−O bond cleavage in allylic or benzylic ethers.24 With these results in hand and based on the iron-catalyzed alcohol activations reported in the literature, a mechanism involving the formation of a carbocation intermediate through iron-induced activation of the allylic alcohol in D could be hypothesized (Scheme 9).16,18 An intramolecular nucleophilic attack on the carbocation could then occur to form the heterocycle E in a nondiastereoselective fashion. In addition, the iron salt would be able to induce an opening of the heterocycle E to form carbocationic intermediate F. This would allow the establishment of a thermodynamic equilibrium between cis-E and trans-E, resulting in the major formation of the thermodynamically most stable isomer, depending on the position of the substituents on the ring (i.e., cis-2,6disubstituted 1,4-oxathiane or trans-2,5-disubstituted 1,4oxathiane in the case of compound 9b). The current method induces the presence of a double bond on one of the substituents of the sulfur heterocycle. This motif provides a moiety that can be exploited for further functionalization of the scaffold. For instance, an oxidative cleavage followed by a reduction were performed on 1,4oxathiane 4,4-dioxide 3a to furnish the primary alcohol 12, which in turn could be further functionalized. A crossmetathesis between 3i and methyl acrylate in the presence of the Grubbs−Hoveyda II catalyst (G−H II) produced the unsaturated ester 13 in 60% yield (Scheme 10). Interestingly, the 1,4-oxathiane dioxide 3j previously obtained as a mixture of cis and trans isomers (cis/trans = 78:22) appeared to be a good substrate in palladium-catalyzed Heck reactions. When 3j was reacted with 4-iodotoluene in the presence of a catalytic amount of Pd(OAc)2 and P(o-Tolyl)3,

Scheme 10. Functionalization of 1,4-Oxathiane 4,4-Dioxide

the Heck product 14 was obtained with a similar cis/trans ratio (82:18 versus 78:22). However, further treatment of alkene 14 with 5 mol % of FeCl3·6H2O enabled its isomerization, thus delivering the cis isomer as the sole product (Scheme 11). Surprisingly, when the Heck coupling was conducted on the 2-chloro-5-iodopyridine, the expected disubstituted alkene 15 was obtained with an excellent diasteroselectivity suggesting that an isomerization process was occurring under the reaction conditions. Finally, the dienyl boronate 17 could be formed from a Heck reaction between 3j and the vinyliodo-MIDA boronate 16 (MIDA = N-methyliminodiacetic acid).25 As previously discussed, an in situ isomerization afforded the cis product with excellent diastereoselectivity (Scheme 12).

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CONCLUSION In summary, an iron-catalyzed cyclization was developed to access a variety of sulfur-containing heterocycles. The reaction 4023



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KMnO4), followed by heating. Column chromatography was carried out under positive pressure using silica gel (Merck Kieselgel 60, 230− 400) and the indicated solvents [v/v; used without purification, including petroleum ether (boiling range 40−60 °C)]. 1H NMR spectra of samples were run at 400 MHz, and chemical shifts are given in ppm (δ) compared to the residual solvent signal, which was used as an internal reference (acetone-d6: δ = 2.05 ppm; CDCl3: δ = 7.26 ppm). Coupling constants (J) are given in Hertz (Hz), and the following abbreviations are used to describe the signal multiplicity: s (singlet), d (doublet), t (triplet), q (quadruplet), quint (quintuplet), m (multiplet), br (broad). 13C{1H} NMR spectra of samples were run at 100 MHz. Chemical shifts are given in ppm (δ) compared to the residual solvent signal, which was used as an internal reference (acetone-d6: δ = 29.84 ppm; CDCl3: δ = 77.16 ppm). Infrared (IR) spectra were recorded neat (IRFT), and wavenumbers are indicated in cm−1. Low-resolution mass spectra with electronic impact (MS-EI) were recorded on a gas chromatograph−mass spectrometer. Highresolution mass spectra (HRMS) were performed using ESI and a TOF mass analyzer. General Procedure 1: Synthesis of Hydroxysulfones. To a stirred solution of dimethylsulfone (1.0 equiv) in dry THF (0.1 M) at −78 °C was added dropwise n-BuLi (2.5 M in hexanes, 1.1 equiv). The reaction was stirred at −78 °C for 30 min, aldehyde (1.2 equiv) was added dropwise, and the mixture was stirred at −78 °C for 1.5 h. The reaction was quenched with ice, and a saturated aqueous solution of NH4Cl (40 mL) was added to the mixture. The phases were separated, and the aqueous layer was further extracted with EtOAc (2 × 40 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oily residue, which was purified by column chromatography to yield the desired alcohol. 2-(Methylsulfonyl)-1-phenylethanol (S1). Prepared according to general procedure 1 using dimethylsulfone (1.00 g, 10.62 mmol) and benzaldehyde. The crude product was purified by flash column chromatography (PE/EtOAc = 1:1) to give pure alcohol S1 (1.74 g, 82%) as a white solid. These data are in full accordance with those reported in the literature:26 Rf = 0.29 (PE/EtOAc = 1:1); mp 101−102 °C; IR (neat): 3431, 1601, 1494, 1457, 1390, 1359, 1309, 1274, 1233, 1161, 1121, 1080, 1060, 1027, 1001 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.41−7.30 (m, 5H), 5.32 (ddd, J = 10.3, 3.0, and 2.1 Hz, 1H), 3.44 (ddd, J = 14.8, 10.3, and 0.4 Hz, 1H), 3.14 (m, 1H), 3.07 (dd, J = 3.0 and 1.2 Hz, 1H), 3.03 (br s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 141.1, 129.1 (2C), 128.8, 125.8 (2C), 69.4, 62.5, 43.0; MS (EI) m/ z (rel intensity) 182 ([M − H2O]·+, 2), 121 ([M − SO2CH3]+, 12), 120 (100), 107 ([PhCHOH]+, 37), 105 (38), 103 ([M − H2O − SO2CH3] +, 29), 102 (14), 91 (19), 79 (50), 78 (29), 77 ([C6H5]+, 43), 51 (20). (E)-1-(Methylsulfonyl)-4-phenylbut-3-en-2-ol (S2). Prepared according to general procedure 1 using dimethylsulfone (1.00 g, 10.62 mmol) and cinnamaldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 1:1) to give pure alcohol S2 (1.79 g, 74%) as a white solid. These data are in full accordance with those reported in the literature:27 Rf = 0.30 (PE/EtOAc = 1:1); mp 110−111 °C; IR (neat) 3448, 1598, 1492, 1448, 1411, 1316, 1279, 1239, 1179, 1124, 1101, 1072, 1023 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.39−7.26 (m, 5H), 6.72 (dd, J = 15.9 and 1.0 Hz, 1H), 6.18 (dd, J = 15.9 and 6.6 Hz, 1H), 4.96 (m, 1H), 3.33 (dd, J = 14.5 and 10.0 Hz, 1H), 3.17 (br d, J = 14.7 Hz, 1H), 3.07 (br s, 3H), 2.86 (br d, J = 2.7 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 135.7, 132.4, 128.9 (2C), 128.5, 128.0, 126.8 (2C), 68.1, 60.7, 43.2; MS (EI) m/z (rel intensity) 208 ([M − H2O]·+, 6), 129 ([M − H2O − SO2CH3] +, 39), 128 (100), 127 (19), 115 (20), 102 (17), 91 (16), 77 ([C6H5]+, 24), 63 (22), 51 (27), 50 (10); HRMS (ESI) calcd for C11H14O3SNa [M + Na]+ 249.0556, found 249.0554. 2-(Methylsulfonyl)phenol (S3). To an ice-cold, stirred solution of 2-hydroxythioanisole (400 mg, 2.85 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added m-CPBA (77% purity, 3.20 g, 14.27 mmol, 5.0 equiv), and the mixture was stirred at rt for 18 h. The precipitate was removed by filtration, and the filtrate was evaporated under reduced pressure to give a beige solid, which was purified by flash column chromatography

Scheme 11. Heck/Isomerization Tandem Reaction on 3j

Scheme 12. Heck Reactions on 3j

generally proceeded with good yields and excellent diastereoselectivities in favor of the most stable compounds. The availability of the substrates, the use of the nonexpensive and relatively low toxicity iron catalyst FeCl3·6H2O, as well as the atom economy make the process interesting for synthetic purposes and industrial applications.

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EXPERIMENTAL SECTION

General Experimental Methods. All moisture and oxygensensitive reactions were carried out in oven-dried glassware under an argon atmosphere. THF, Et2O, and CH2Cl2 were dried using a solvent purification system. Acetone, petroleum ether (PE), pentane, and ethyl acetate (EtOAc) were used as received. Commercially available reagents were used as received. Reactions run at room temperature were performed between 20 and 25 °C. Solvent evaporations were conducted under reduced pressure at temperatures less than 45 °C. TLC was performed on silica gel plates visualized either with a UV lamp (254 nm) or using a staining solution (p-anisaldehyde or 4024



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1116, 1069, 1048, 1026 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38− 7.24 (m, 5H), 6.70 (dd, J = 15.8 and 1.1 Hz, 0.5H), 6.69 (dd, J = 15.8 and 1.1 Hz, 0.5H), 6.162 (dd, J = 16.0 and 6.4 Hz, 0.5H), 6.158 (dd, J = 16.0 and 6.4 Hz, 0.5H), 4.96 (m, 1H), 4.28 (m, 1H), 3.62−3.03 (m, 6H), 1.63−1.23 (m, 8H), 0.89 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ [135.83 and 135.81], [132.21 and 132.16], [128.824 (2C) and 128.816 (2C)], [128.43 and 128.42], [128.3 and 128.0], 126.8 (2C), [68.0 and 67.7], [66.8 and 66.5], [61.3 and 60.9], [60.7 and 60.3], [37.1 and 36.8], [31.61 and 31.59], [24.9 and 24.8], 22.6, [14.11 and 14.10]; HRMS (ESI) calcd for C17H26O4SNa [M + Na]+ 349.1444, found 349.1443. (E)-1-((2-Hydroxybut-3-en-1-yl)sulfonyl)-4-phenylbut-3-en-2-ol (2d). Prepared according to general procedure 2 using hydroxysulfone S2 (230 mg, 1.02 mmol) and acrolein. The crude product was purified by column chromatography (pentane/EtOAc = 1:1) to give pure diol 2d (115 mg, 40%) as a colorless oil as a 50:50 mixture of diastereomers: Rf = 0.32 (PE/EtOAc = 1:1); IR (neat) 3451, 1648, 1601, 1580, 1496, 1451, 1393, 1285, 1121, 1049, 991, 970, 934 cm−1; 1 H NMR (CDCl3, 400 MHz) δ 7.37−7.24 (m, 5H), 6.70 (dd, J = 15.8 and 1.1 Hz, 0.5H), 6.69 (dd, J = 15.8 and 1.0 Hz, 0.5H), 6.16 (dd, J = 15.9 and 6.3 Hz, 1H), 5.85 (ddd, J = 17.2, 10.3, and 5.7 Hz, 1H), 5.40 (br dtapp, J = 17.1 and 1.2 Hz, 0.5H), 5.39 (br dtapp, J = 17.3 and 1.2 Hz, 0.5H), 5.24 (br dtapp, J = 10.5 and 1.2 Hz, 0.5H), 5.23 (br dtapp, J = 10.4 and 1.2 Hz, 0.5H), 4.97 (m, 1H), 4.81 (m, 1H), 3.64 (dd, J = 14.8 and 10.1 Hz, 0.5H), 3.57 (dd, J = 14.8 and 10.2 Hz, 0.5H), 3.47 (dd, J = 14.6 and 9.9 Hz, 0.5H), 3.47 (br s, 0.5H), 3.39 (dd, J = 14.9 and 9.7 Hz, 0.5H), 3.36 (br s, 0.5H), 3.32 (dd, J = 14.6 and 2.5 Hz, 0.5H), 3.28−3.15 (m, 2.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [137.5 and 137.2], [135.9 and 135.8], [132.2 and 132.1], [128.82 (2C) and 128.81 (2C)], [128.41 and 128.39], [128.3 and 128.0], 126.8 (2C), [117.0 and 116.9], [68.02 and 68.01], 67.6, [60.9 and 60.7], [60.6 and 60.4]; MS (EI) m/z (rel intensity) 147 (13), 146 (100), 145 (39), 133 ([PhC2H2CHOH] +, 16), 131 (21), 130 (16), 129 (34), 128 (22), 127 (11), 117 (25), 116 (15), 115 (24), 105 (28), 104 ([PhC2H3]·+, 62), 103 (13), 91 (32), 77 ([C6H 5]+, 20), 55 (22); HRMS (ESI) calcd for C14H18O4SNa [M + Na]+ 305.0818, found 305.0816. (E)-1-((2-(2-Chloropyridin-3-yl)-2-hydroxyethyl)sulfonyl)-4-phenylbut-3-en-2-ol (2e). Prepared according to general procedure 2 using hydroxysulfone S2 (450 mg, 1.99 mmol) and 2-chloro-3pyridinecarboxaldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 1:1) to give pure diol 2e (506 mg, 69%) as a colorless wax as a 1:1 mixture of diastereomers: Rf = 0.33 (PE/EtOAc = 2:3); IR (neat) 3450, 1570, 1494, 1449, 1408, 1288, 1167, 1125, 1089, 1055, 968 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.26 (m, 1H), 8.01 (m, 1H), 7.35−7.23 (m, 6H), 6.68 (br d, J = 16.0 Hz, 1H), 6.17 (dd, J = 15.9 and 6.6 Hz, 0.5H), 6.16 (dd, J = 15.9 and 6.6 Hz, 0.5H), 5.62 (m, 1H), 4.99 (br qapp, J = 7.7 Hz, 1H), 4.62 (br d, J = 2.8 Hz, 0.5H), 4.51 (br d, J = 3.8 Hz, 0.5H), 3.81 (br s, 1H), 3.69−3.23 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ [149.10 and 149.07], [148.1 and 148.0], [137.03 and 137.01], [135.8 and 135.74], [135.73 and 135.5], [132.3 and 132.2], 128.8 (2C), [128.44 and 128.43], [128.2 and 128.0], [126.77 (2C) and 126.76 (2C)], [123.44 and 123.41], [68.0 and 67.7], [65.5 and 65.2], [60.9 and 60.6], [60.3 and 60.2]; HRMS (ESI) calcd for C17H18ClNO4SNa [M + Na]+ 390.0537, found 390.0540. (E)-1-((2-(4,6-Dichloropyrimidin-5-yl)-2-hydroxyethyl)sulfonyl)-4phenylbut-3-en-2-ol (2f). Prepared according to general procedure 2 using hydroxysulfone S2 (256 mg, 1.13 mmol) and 4,6-dichloropyrimidine-5-carboxaldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 1:1) to give pure diol 2f (120 mg, 26%) as a colorless wax as a 1:1 mixture of diastereomers: Rf = 0.63 and 0.71 (PE/EtOAc = 1:1); IR (neat) 3430, 1650, 1537, 1517, 1494, 1449, 1417, 1333, 1291, 1161, 1126, 1070 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 7.36−7.23 (m, 5H), 6.69 (br dd, J = 15.8 and 1.1 Hz, 0.5H), 6.68 (br dd, J = 15.8 and 1.1 Hz, 0.5H), 6.18 (dd, J = 15.9 and 6.7 Hz, 0.5H), 6.17 (dd, J = 15.9 and 6.7 Hz, 0.5H), 6.04 (ddd, J = 10.1, 5.0, and 2.3 Hz, 0.5H), 5.97 (ddd, J = 10.9, 7.2, and 2.3 Hz, 0.5H), 4.99 (m, 1H), 4.43 (dd, J = 14.7 and 10.9 Hz, 0.5H), 4.38 (d, J = 7.3 Hz, 0.5H), 4.33 (d, J = 5.4 Hz, 0.5H), 4.20 (dd, J = 14.7 and 10.3 Hz, 0.5H), 3.81 (dd, J = 14.8 and 10.3 Hz, 0.5H),

(pentane/EtOAc = 2:1) to yield sulfone S3 (400 mg, 81%) as a white solid. These data are in full accordance with those reported in the literature:28 Rf = 0.40 (PE/EtOAc = 1:1); mp 85−87 °C; IR (neat) 3535, 3491, 1640, 1590, 1496, 1453, 1409, 1361, 1307, 1274, 1219, 1162, 1139, 1126, 1065 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.81 (br s, 1H), 7.68 (dd, J = 8.2 and 1.7 Hz, 1H), 7.52 (ddd, J = 8.4, 7.3, and 1.7 Hz, 1H), 7.05−7.01 (m, 2H), 3.12 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 155.9, 136.6, 128.8, 122.9, 120.9, 119.2, 45.0; MS (EI) m/z (rel intensity) 172 ([M]·+, 95), 157 ([M − CH3]+, 59), 109 (96), 93 ([M − SO2CH3]+, 77), 81 (22), 65 (100), 64 (23), 63 (39), 53 (19). General Procedure 2: Synthesis of Diols 2a−l. To a stirred solution of hydroxysulfone S1−S3 (1.0 equiv) in dry THF (0.06 M) at −78 °C was added dropwise n-BuLi (2.5 M in hexanes, 2.3 equiv). The reaction was stirred at −78 °C for 1 h, aldehyde (1.3 equiv) was added dropwise, and the mixture was stirred at −78 °C for 2 h. The reaction was quenched with ice, and a saturated aqueous solution of NH4Cl (40 mL) was added to the mixture. The phases were separated, and the aqueous layer was further extracted with EtOAc (2 × 40 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oily residue that was purified by flash column chromatography to yield the desired diol. The diastereomeric ratio of the diols was determined by 1H NMR analysis. (E)-1-((2-Hydroxy-2-phenylethyl)sulfonyl)-4-phenylbut-3-en-2-ol (2a). Prepared according to general procedure 2 using hydroxysulfone S1 (160 mg, 0.80 mmol) and cinnamaldehyde. The crude product was purified by column chromatography (pentane/EtOAc = 3:2) to give pure diol 2a (244 mg, 92%) as a white solid as a 50:50 mixture of diastereomers: Rf = 0.27 (PE/EtOAc = 3:2); mp 104−106 °C; IR (neat) 3382, 1655, 1600, 1493, 1450, 1384, 1272, 1202, 1159, 1113, 1061, 1046, 990, 967 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38−7.25 (m, 10H), 6.70 (dd, J = 15.8 and 1.2 Hz, 0.5H), 6.69 (dd, J = 15.8 and 1.2 Hz, 0.5H), 6.161 (dd, J = 15.8 and 6.4 Hz, 0.5H), 6.158 (dd, J = 15.8 and 6.4 Hz, 0.5H), 5.36 (br d, J = 10.8 Hz, 1H), 4.97 (qapp, J = 7.5 Hz, 1H), 3.79 (dd, J = 14.7 and 10.6 Hz, 0.5H), 3.66 (dd, J = 14.6 and 10.1 Hz, 0.5H), 3.58 (m, 1H), 3.47 (dd, J = 14.7 and 9.6 Hz, 0.5H), 3.40−3.31 (m, 2H), 3.24−3.20 (m, 1.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [141.2 and 140.9], [135.83 and 135.82], [132.3 and 132.1], [129.1 (2C) and 129.0 (2C)], [128.83 (2C) and 128.82 (2C)], [128.7 and 128.6], 128.4, [128.3 and 128.0], [126.81 (2C) and 126.80 (2C)], [125.81 (2C) and 125.78 (2C)], [69.5 and 69.0], [68.1 and 67.7], [62.7 and 62.4], [60.8 and 60.3]; HRMS (ESI) calcd for C18H + 20O4SNa [M + Na] 355.0975, found 355.0971. (E)-1-((2-Hydroxy-3-methylbutyl)sulfonyl)-4-phenylbut-3-en-2-ol (2b). Prepared according to general procedure 2 using hydroxysulfone S2 (200 mg, 0.88 mmol) and isobutyraldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 2:1) to give pure diol 2b (195 mg, 74%) as a colorless oil as a 1:1 mixture of diastereomers: Rf = 0.31 (PE/EtOAc = 2:1); IR (neat) 3454, 1650, 1600, 1578, 1494, 1467, 1449, 1389, 1370, 1284, 1169, 1117, 1045, 1006, 968 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.36−7.22 (m, 5H), 6.68 (br d, J = 15.9 Hz, 0.5H), 6.67 (br d, J = 15.7 Hz, 0.5H), 6.15 (dd, J = 15.9 and 6.4 Hz, 0.5H), 6.14 (dd, J = 15.9 and 6.4 Hz, 0.5H), 4.94 (m, 1H), 4.06 (m, 1H), 3.72 (m, 0.5H), 3.62 (m, 1H), 3.51−3.41 (m, 1.5H), 3.34−3.09 (m, 3H), 1.74 (m, 1H), 0.93−0.90 (m, 6H); 13 C{1H} NMR (CDCl3, 100 MHz) δ [135.83 and 135.80], [132.0 and 131.9], [128.8 (2C) and 128.7 (2C)], [128.4 and 128.32], [128.31 and 128.2], 126.7 (2C), [71.2 and 70.7], [67.9 and 67.5], [60.6 and 60.2], [59.0 and 58.7], [33.8 and 33.7], 18.1, [17.2 and 17.1]; MS (EI) m/z (rel intensity) 131 (12), 130 ([PhC4H5]·+, 100), 129 (36), 128 (50), 127 (14), 115 (15), 91 (9), 77 (9), 69 (10); HRMS (ESI) calcd for C15H22O4SNa [M + Na]+ 321.1131, found 321.1129. (E)-1-((2-Hydroxy-4-phenylbut-3-en-1-yl)sulfonyl)heptan-2-ol (2c). Prepared according to general procedure 2 using hydroxysulfone S2 (200 mg, 0.88 mmol) and n-hexanal. The crude product was purified by flash column chromatography (pentane/EtOAc = 5:2) to give pure diol 2c (232 mg, 80%) as a white solid as a 1:1 mixture of diastereomers: Rf = 0.32 (PE/EtOAc = 5:2); mp 112−113 °C; IR (neat) 3387, 1599, 1493, 1449, 1391, 1356, 1334, 1278, 1205, 1178, 4025



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MHz) δ 7.39−7.29 (m, 5H), 5.82 (m, 1H), 5.49 (m, 1H), 5.35 (br dd, J = 10.4 and 1.3 Hz, 1H), 4.75 (m, 1H), 3.74 (dd, J = 14.8 and 10.6 Hz, 0.5H), 3.58−3.51 (m, 1.5H), 3.41−3.33 (m, 1.5H), 3.22 (br dqapp, J = 15.0 and 1.7 Hz, 1H), 3.12 (br dtapp, J = 14.5 and 1.7 Hz, 0.5H), 2.98 (br s, 0.5H), 2.81 (br s, 0.5H), 1.73−1.70 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ [141.3 and 141.0], [130.5 and 130.3], [129.4 and 129.3], [129.05 (2C) and 129.01 (2C)], [128.62 and 128.60], [125.79 (2C) and 125.77 (2C)], [69.3 and 68.9], [68.1 and 67.7], [62.7 and 62.4], [61.0 and 60.4], [17.76 and 17.75]; MS (EI) m/z (rel intensity) 121 (22), 120 (89), 107 ([PhCHOH]+, 19), 105 (55), 104 ([PhC2H3]·+, 100), 103 (32), 91 (17), 84 (30), 79 (26), 78 (24), 77 ([C6H5]+, 37), 71 ([C3H5CHOH]+, 15), 69 (54), 68 ([C5H8]·+, 39), 67 (27), 55 (11), 51 (12); HRMS (ESI) calcd for C13H18O4SNa [M + Na]+ 293.0818, found 293.0814. 1-((2-Hydroxy-2-phenylethyl)sulfonyl)but-3-en-2-ol (2j). Prepared according to general procedure 2 using hydroxysulfone S1 (230 mg, 1.15 mmol) and acrolein. The crude product was purified by flash column chromatography (PE/EtOAc = 1:1) to give a beige oil (278 mg), which is an inseparable mixture of desired diol 2j (75% by 1H NMR analysis), obtained as a 1:1 mixture of diastereomers, and unreacted hydroxysulfone S1 (25% by 1H NMR analysis): Rf = 0.29 (PE/EtOAc = 1:1); IR (neat) 3456, 1494, 1454, 1391, 1282, 1119, 1055 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.36−7.27 (m, 5H), 5.83 (ddd, J = 17.1, 10.4, and 5.7 Hz, 1H), 5.37 (br dtapp, J = 17.2 and 1.4 Hz, 0.5H), 5.36 (br dtapp, J = 17.2 and 1.4 Hz, 0.5H), 5.31 (br dd, J = 10.5 and 2.0 Hz, 0.5H), 5.29 (br dd, J = 10.5 and 2.0 Hz, 0.5H), 5.22 (br dtapp, J = 10.5 and 1.2 Hz, 0.5H), 5.21 (br dtapp, J = 10.5 and 1.2 Hz, 0.5H), 4.76 (m, 1H), 3.76 (br s, 0.5H), 3.74 (dd, J = 14.7 and 10.6 Hz, 1H), 3.65 (br s, 0.5H), 3.53 (br dd, J = 14.5 and 10.1 Hz, 1H), 3.34 (dd, J = 14.6 and 9.4 Hz, 1H), 3.28 (dd, J = 15.0 and 1.7 Hz, 0.5H), 3.22 (dd, J = 15.0 and 2.2 Hz, 0.5H), 3.14 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ [141.3 and 141.0], [137.5 and 137.2], [129.0 (2C) and 128.9 (2C)], [128.6 and 128.5], [125.79 (2C) and 125.77 (2C)], [116.9 and 116.8], [69.3 and 68.8], [67.9 and 67.5], [62.5 and 62.3], [60.5 and 60.1]; MS (EI) m/z (rel intensity) 174 (10), 121 (14), 120 (100), 107 ([PhCHOH]+, 24), 105 (36), 104 ([PhC 2H3]·+, 24), 103 (26), 91 (16), 79 (25), 78 (18), 77 ([C6H5]+, 23), 55 (16), 54 (12); HRMS (ESI) calcd for C12H16O 4SNa [M + Na]+ 279.0662, found 279.0664. (3E,5E)-1-((2-Hydroxy-2-phenylethyl)sulfonyl)hepta-3,5-dien-2-ol (2k). Prepared according to general procedure 2 using hydroxysulfone S1 (200 mg, 1.00 mmol) and (E,E)-2,4-hexadienal. The crude product was purified by flash column chromatography on neutralized silica gel (pentane/EtOAc = 2:1) to give diol 2k (190 mg, 64%) as a pale yellow oil as a 1:1 mixture of diastereomers (each diastereomer has 2 conformations s-trans and s-cis in a 90:10 ratio): Rf = 0.29 (PE/EtOAc = 2:1); IR (neat) 3459, 1660, 1494, 1452, 1390, 1284, 1201, 1158, 1118, 1052 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.37−7.28 (m, 5H), 6.64 (dddt, J = 14.8, 11.4, 4.2, and 1.2 Hz, 0.1H), 6.27 (br ddd, J = 14.8, 11.4, and 4.2 Hz, 0.9H), 5.99 (m, 1H), 5.77 (br dq, J = 15.2 and 6.7 Hz, 0.9H), 5.61 (m, 0.2H), 5.50 (br ddd, J = 15.3, 6.6, and 0.8 Hz, 0.9H), 5.32 (m, 1H), 4.85 (br q, J = 8.0 Hz, 0.1H), 4.78 (br q, J = 8.0 Hz, 0.9H), 3.75 (m, 0.5H), 3.68 (br s, 0.5, OH), 3.61−3.50 (m, 1.5H), 3.42−3.07 (m, 3.5H), 1.76 (br dd, J = 6.8 and 1.3 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ [141.3 and 141.0], [132.7 and 132.6], 132.2, 130.1, [129.00 (2C) and 128.97 (2C)], [128.9 and 128.55], 128.58, [125.80 (2C) and 125.78 (2C)], [69.3 and 68.8], [67.8 and 67.4], [62.6 and 62.4], [60.9 and 60.3], [18.3 and 13.6]; MS (EI) m/z (rel intensity) 110 (50), 105 (16), 104 ([PhC2H3]·+, 100), 103 (11), 97 (10), 95 (64), 91 (12), 79 (23), 77 ([C6H5]+, 28), 68 (41), 67 (12), 55 (15); HRMS (ESI) calcd for C15H20O4SNa [M + Na]+ 319.0975, found 319.0974. 2,2′-Sulfonylbis(1-phenylethanol) (2l). Prepared according to general procedure 2 using hydroxysulfone S1 (220 mg, 1.10 mmol) and benzaldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 2:1) to give pure diol 2l (221 mg, 66%) as a white solid as a 1:1 mixture of diastereomers: Rf = 0.25 (PE/ EtOAc = 2:1); mp 128−129 °C; IR (neat) 3372, 1494, 1457, 1279, 1243, 1196, 1167, 1118, 1083, 1052 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.41−7.31 (m, 10H), 5.40 (m, 1H), 5.37 (m, 1H), 3.77 (dd, J

3.54 (dd, J = 14.8 and 9.4 Hz, 0.5H), 3.49 (br d, J = 3.1 Hz, 0.5H), 3.45 (br d, J = 3.3 Hz, 0.5H), 3.38 (dd, J = 14.5 and 2.6 Hz, 0.5H), 3.32 (dd, J = 14.7 and 2.5 Hz, 0.5H), 3.19 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ [161.2 (2C) and 161.0 (2C)], [157.3 and 157.2], [135.6 and 135.5], [132.8 and 132.7], [130.7 and 130.5], [128.88 (2C) and 128.86 (2C)], [128.7 and 128.6], [127.8 and 127.7], [126.81 (2C) and 126.80 (2C)], [68.7 and 67.9], [65.5 and 64.7], [60.74 and 60.68], [57.8 and 57.7]; MS (EI) m/z (rel intensity) 146 (14), 131 (10), 129 (10), 115 (10), 105 (10), 104 ([PhC2H3]·+, 100); HRMS (ESI) calcd for C16H16Cl2N2O4SNa [M + Na]+ 425.0100, found 425.0100. (E)-1-((2-Hydroxy-2-(1-tosyl-1H-indol-3-yl)ethyl)sulfonyl)-4-phenylbut-3-en-2-ol (2g). Prepared according to general procedure 2 using hydroxysulfone S2 (450 mg, 1.99 mmol) and 1-tosyl-1H-indole3-carbaldehyde.29 The crude product was purified by flash column chromatography (PE/EtOAc = 3:2) to give pure diol 2g (598 mg, 57%) as a white solid as a 1:1 mixture of diastereomers: Rf = 0.28 and 0.34 (PE/EtOAc = 3:2); mp 144−146 °C; IR (neat) 3485, 1597, 1494, 1447, 1369, 1277, 1231, 1170, 1118, 1098, 1045 cm−1; 1H NMR ((CD3)2CO, 400 MHz) δ 8.00 (dtapp, J = 8.4 and 0.9 Hz, 0.5H), 7.99 (dtapp, J = 8.4 and 0.9 Hz, 0.5H), 7.91−7.86 (m, 2H), 7.81 (ddd, J = 7.9, 1.3, and 0.8 Hz, 0.5H), 7.78−7.75 (m, 1.5H), 7.47−7.44 (m, 2H), 7.39−7.32 (m, 5H), 7.29−7.22 (m, 2H), 6.76 (dd, J = 15.9 and 1.1 Hz, 0.5H), 6.74 (dd, J = 15.9 and 1.1 Hz, 0.5H), 6.39 (dd, J = 15.9 and 6.0 Hz, 0.5H), 6.38 (dd, J = 15.9 and 6.0 Hz, 0.5H), 5.60 (m, 1H), 5.08 (dd, J = 4.7 and 0.9 Hz, 0.5H), 5.01 (dd, J = 4.2 and 0.6 Hz, 0.5H), 4.93 (m, 1H), 4.84 (dd, J = 4.6 and 1.0 Hz, 0.5H), 4.77 (br d, J = 4.2 Hz, 0.5H), 4.15 (dd, J = 14.7 and 10.1 Hz, 0.5H), 3.85 (dd, J = 14.6 and 9.1 Hz, 0.5H), 3.82 (dd, J = 14.8 and 9.6 Hz, 0.5H), 3.62 (dd, J = 14.7 and 2.9 Hz, 0.5H), 3.52 (dd, J = 14.7 and 8.3 Hz, 0.5H), 3.45 (dd, J = 14.5 and 3.8 Hz, 0.5H), 3.40 (br dtapp, J = 14.5 and 2.0 Hz, 0.5H), 3.24 (m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H); 13C{1H} NMR ((CD3)2CO, 100 MHz) δ [146.42 and 146.41], [137.60 and 137.57], [136.3 and 136.2], [136.0 and 135.9], [131.33 and 131.30], [131.2 and 131.1], [131.0 (2C) and 130.9 (2C)], [129.53 and 129.494], [129.486 (2C) and 129.46 (2C)], [128.61 and 128.57], [127.84 (2C) and 127.83 (2C)], 127.4 (2C), [125.74 and 125.73], [125.3 and 125.1], [124.5 and 124.4], [124.17 and 124.16], [121.6 and 121.5], [114.5 and 114.4], [68.6 and 68.2], [63.8 and 63.4], [61.52 and 61.46], [61.4 and 61.1], [21.43 and 21.42]; HRMS (ESI) calcd for C27H27NO6S2Na [M + Na]+ 548.1172, found 548.1164 (E)-2-((2-Hydroxy-4-phenylbut-3-en-1-yl)sulfonyl)phenol (2h). Prepared according to general procedure 2 using hydroxysulfone S3 (250 mg, 1.45 mmol) and cinnamaldehyde. The crude product was purified by flash column chromatography (pentane/acetone = 2:1) to give pure diol 2h (348 mg, 79%) as an off-white powder: Rf = 0.33 (PE/acetone = 3:2); mp 138−139 °C; IR (neat) 3417, 1593, 1496, 1455, 1364, 1289, 1249, 1143, 1124, 1062, 1034 cm−1; 1H NMR ((CD3)2CO, 400 MHz) δ 7.80 (dd, J = 7.8, 1.7 Hz, 1H), 7.52 (dd, J = 8.4, 7.3, 1H), 7.37−7.34 (m, 2H), 7.32−7.28 (m, 2H), 7.23 (m, 1H), 7.05 (ddd, J = 8.3, 1.2, and 0.4 Hz, 1H), 7.03 (ddd, J = 7.8, 7.2, and 1.0 Hz, 1H), 6.63 (dd, J = 16.0 and 1.4 Hz, 1H), 6.27 (dd, J = 15.9 and 6.0 Hz, 1H), 4.79 (dddd, J = 7.4, 6.0, 5.0, and 1.5 Hz, 1H), 3.71 (dd, J = 14.3 and 7.2 Hz, 1H), 3.66 (dd, J = 14.5 and 5.0 Hz, 1H); 13C{1H} NMR ((CD3)2CO, 100 MHz) δ 156.7, 137.6, 136.4, 131.1, 131.0, 130.4, 129.3 (2C), 128.5, 127.3 (2C), 126.3, 120.7, 118.5, 67.9, 62.0; MS (EI) m/z (rel intensity) 286 ([M − H2O]·+, 9), 147 (16), 146 (100), 145 (44), 133 (25), 131 (31), 130 ([PhC4H5]·+, 34), 129 (88), 128 (82), 127 (20), 119 (14), 118 (10), 117 (35), 116 (21), 115 (41), 105 (43), 104 (18), 103 (17), 93 (10), 91 (46), 79 (12), 78 (12), 77 ([C6H5]+, 37), 65 (33), 63 (12), 55 (31), 51 (15); HRMS (ESI) calcd for C16H16O4SNa [M + Na]+ 327.0662, found 327.0662. (E)-1-((2-Hydroxy-2-phenylethyl)sulfonyl)pent-3-en-2-ol (2i). Prepared according to general procedure 2 using hydroxysulfone S1 (250 mg, 1.25 mmol) and crotonaldehyde. The crude product was purified by flash column chromatography (pentane/EtOAc = 2:1) to give pure diol 2i (225 mg, 67%) as a white solid as a 1:1 mixture of diastereomers: Rf = 0.40 (PE/EtOAc = 1:1); mp 76−77 °C; IR (neat) 3372, 1670, 1602, 1493, 1450, 1380, 1353, 1333, 1272, 1228, 1189, 1167, 1110, 1081, 1061, 1042, 1006 cm−1; 1H NMR (CDCl3, 400 4026



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1107, 1097, 1072, 1039, 1016 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.26 (m, 5H), 6.71 (dd, J = 16.1 and 1.1 Hz, 1H), 6.15 (dd, J = 16.0 and 6.2 Hz, 1H), 5.88 (ddd, J = 17.3, 10.6, and 5.6 Hz, 1H), 5.43 (ddd, J = 17.3, 1.4, and 0.9 Hz, 1H), 5.31 (br dtapp, J = 10.6 and 1.1 Hz, 1H), 4.69 (dddd, J = 11.1, 6.2, 2.1, and 1.5 Hz, 1H), 4.58 (m, 1H), 3.18−2.94 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 135.7, 134.7, 133.0, 128.8 (2C), 128.6, 126.8 (2C), 125.4, 118.0, 76.0, 75.9, 56.2, 55.9; MS (EI) m/z (rel intensity) 264 ([M]·+, 3), 146 (19), 131 (22), 130 (11), 129 (18), 128 (12), 115 (15), 105 (10), 104 ([PhC2H3] ·+, 100), 54 ([C4H6]·+, 20); HRMS (ESI) calcd for C14H16O3SNa [M + Na]+ 287.0712, found 287.0715. (E)-2-(2-Chloropyridin-3-yl)-6-styryl-1,4-oxathiane 4,4-Dioxide (3e). Prepared according to general procedure 3 using diol 2e (100 mg, 0.27 mmol). After 3 days, pure cis-3e was isolated (69 mg, 73%) as a colorless oil: Rf = 0.55 (PE/EtOAc = 1:1); IR (neat) 1582, 1566, 1495, 1450, 1416, 1377, 1340, 1305, 1270, 1242, 1201, 1169, 1131, 1056, 1032 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.40 (dd, J = 4.7 and 2.0 Hz, 1H), 7.98 (ddd, J = 7.8, 1.9, and 0.6 Hz, 1H), 7.41−7.27 (m, 6H), 6.74 (dd, J = 16.1 and 0.9 Hz, 1H), 6.20 (dd, J = 16.0 and 6.2 Hz, 1H), 5.40 (dd, J = 11.0 and 1.9 Hz, 1H), 4.86 (dddd, J = 10.8, 6.3, 2.1, and 1.3 Hz, 1H), 3.54 (ddd, J = 13.9, 3.5, and 1.9 Hz, 1H), 3.28 (ddd, J = 13.9, 3.5, and 2.3 Hz, 1H), 3.17 (dd, J = 13.9 and 10.7 Hz, 1H), 2.96 (dd, J = 13.9 and 11.2 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 149.7, 148.2, 136.4, 135.4, 133.5, 133.1, 128.8 (2C), 128.7, 126.8 (2C), 124.9, 123.2, 76.6, 73.8, 56.2, 55.7; MS (EI) m/z (rel intensity) 349 ([M]·+, 1), 146 (13), 140 (29), 139 (18), 131 (10), 129 (12), 115 (10), 105 (10), 104 (100); HRMS (ESI) calcd for C17H16ClNO3SNa [M + Na]+ 372.0432, found 372.0433. (E)-2-(4,6-Dichloropyrimidin-5-yl)-6-styryl-1,4-oxathiane 4,4-Dioxide (3f). Prepared according to general procedure 3 using diol 2f (70 mg, 0.17 mmol). After 48 h, pure cis-3f was isolated (62 mg, 93%) as a colorless oil: Rf = 0.71 (PE/EtOAc = 1:1); mp 171−172 °C; IR (neat) 1542, 1518, 1449, 1424, 1378, 1356, 1340, 1307, 1251, 1233, 1208, 1167, 1139, 1119, 1093, 1066, 1021, 1001 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 7.39−7.26 (m, 5H), 6.76 (dd, J = 15.9 and 0.8 Hz, 1H), 6.16 (dd, J = 16.0 and 6.2 Hz, 1H), 5.78 (dd, J = 11.8 and 2.2 Hz, 1H), 4.83 (m, 1H), 3.87 (dd, J = 13.7 and 12.0 Hz, 1H), 3.27 (ddd, J = 14.0, 3.4, and 2.4 Hz, 1H), 3.20 (dd, J = 14.1 and 10.8 Hz, 1H), 3.11 (ddd, J = 13.9, 3.3, and 2.3 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 161.3 (2C), 157.7, 135.3, 133.7, 128.84 (2C), 128.80, 128.1, 126.9 (2C), 124.4, 77.0, 73.0, 56.4, 52.2; MS (EI) m/z (rel intensity) 384 ([M]·+, 1), 146 (15), 131 (10), 129 (10), 115 (11), 105 (9), 104 ([PhC2H3]·+, 100); HRMS (ESI) calcd for C16H15Cl2N2O3S [M + H]+ 385.0175, found 385.0176. (E)-2-Styryl-6-(1-tosyl-1H-indol-3-yl)-1,4-oxathiane 4,4-Dioxide (3g). Prepared according to general procedure 3 using diol 2g (200 mg, 0.38 mmol). After 24 h, pure cis-3g was isolated (95 mg, 49%) as a colorless oil: Rf = 0.37 (PE/EtOAc = 5:2); IR (neat) 1597, 1494, 1447, 1367, 1299, 1242, 1214, 1172, 1133, 1118, 1099, 1085, 1055, 1033 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.01 (dtapp, J = 8.3 and 0.9 Hz, 1H), 7.81 (dtapp, J = 8.4 and 1.8 Hz, 2H), 7.63 (d, J = 0.7 Hz, 1H), 7.61 (dtapp, J = 8.0 and 1.0 Hz, 1H), 7.40−7.22 (m, 9H), 6.73 (br d, J = 16.2 Hz, 1H), 6.21 (dd, J = 16.0 and 6.3 Hz, 1H), 5.37 (m, 1H), 4.88 (m, 1H), 3.42−3.35 (m, 2H), 3.28 (br dapp, J = 13.9 Hz, 1H), 3.19 (dd, J = 13.9 and 11.0 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 145.4, 135.5, 135.2, 135.0, 133.2, 130.1 (2C), 128.8 (2C), 128.6, 127.9, 127.0 (2C), 126.8 (2C), 125.4, 125.3, 123.7, 123.4, 120.0, 119.9, 113.9, 76.6, 71.6, 56.4, 56.1, 21.7; MS (EI) m/z (rel intensity) 155 ([CH3C6H4SO2]+, 9), 91 ([CH3C6H4]+, 100), 65 (9); HRMS (ESI) calcd for C27H25NO5S2Na [M + Na]+ 530.1066, found 530.1061. (E)-2-Styryl-2,3-dihydrobenzo[b][1,4]oxathiine 4,4-dioxide (3h). Prepared according to general procedure 3 using diol 2h (90 mg, 0.30 mmol). After 6 h, pure 3h was isolated (72 mg, 85%) as a white solid. Rf = 0.42 (PE/acetone = 4:1); mp 145−146 °C; IR (neat) 1600, 1574, 1498, 1469, 1447, 1374, 1341, 1296, 1271, 1230, 1219, 1140, 1114, 1075, 1044, 1031, 991, 970 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (dd, J = 7.9 and 1.6 Hz, 1H), 7.50−7.43 (m, 3H), 7.40−7.31 (m, 3H), 7.14 (ddd, J = 8.0, 7.2, and 1.1 Hz, 1H), 7.07 (dd, J = 8.5 and 1.0 Hz, 1H), 6.87 (br d, J = 15.9 Hz, 1H), 6.32 (dd, J = 15.9 and 6.8 Hz, 1H),

= 14.6 and 10.5 Hz, 1H), 3.58 (br dd, J = 14.8 and 10.2 Hz, 1H), 3.38 (br dd, J = 14.6 and 1.8 Hz, 1H), 3.33 (br d, J = 2.5 Hz, 1H), 3.26 (br d, J = 14.8 Hz, 1H), 3.163 (d, J = 3.6 Hz, 0.5H), 3.161 (d, J = 3.6 Hz, 0.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [141.1 (2C) and 140.9 (2C)], [129.10 (4C) and 129.09 (4C)], [128.74 (2C) and 128.71 (2C)], [125.82 (4C) and 125.81 (4C)], [69.5 (2C) and 69.1 (2C)], [62.7 (2C) and 62.1 (2C)]; MS (EI) m/z (rel intensity) 121 (32), 120 (100), 107 ([PhCHOH]+, 18), 105 (69), 104 ([PhC2H 3]·+, 68), 103 (32), 91 (18), 79 (29), 78 (27), 77 ([C6H5]+, 43), 51 (14); HRMS (ESI) calcd for C16H18O4SNa [M + Na]+ 329.0818, found 329.0814. General Procedure 3: Iron-Catalyzed Cyclization of Diols 2a−l. To a stirred solution of diol 2 (1.0 equiv) in CH2Cl2 (0.15 M) was added powdered FeCl3·H2O (5 mol %), and the mixture was stirred at 50 °C in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 2:1), and the solvents were removed under reduced pressure to yield the corresponding heterocycle 3, which was not subjected to further purification. The diastereomeric ratio was determined by 1H NMR analysis and confirmed by GCMS analysis. (E)-2-Phenyl-6-styryl-1,4-oxathiane 4,4-Dioxide (3a). Prepared according to general procedure 3 using diol 2a (90 mg, 0.27 mmol). After 7 h, pure cis-3a was isolated (80 mg, 94%) as a white solid: Rf = 0.41 (CHCl3); mp 151−153 °C; IR (neat) 1495, 1451, 1304, 1241, 1209, 1156, 1129, 1098, 1057, 1030, 907 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.45−7.26 (m, 10H), 6.74 (dd, J = 16.0 and 1.1 Hz, 1H), 6.21 (dd, J = 16.0 and 6.1 Hz, 1H), 5.11 (dd, J = 10.7 and 2.6 Hz, 1H), 4.83 (dddd, J = 11.1, 6.1, 2.2, and 1.5 Hz, 1H), 3.29−3.11 (m, 4H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 138.5, 135.6, 133.0, 129.0 (2C), 128.9, 128.8 (2C), 128.5, 126.8 (2C), 125.9 (2C), 125.5, 77.4, 76.2, 57.7, 56.1; MS (EI) m/z (rel intensity) 314 ([M]·+, 1), 146 (5), 130 ([PhC4H5] ·+, 5), 129 (8), 128 (5), 115 (6), 105 (11), 104 ([PhC ·+ + 2H3] , 100), 103 (7), 78 (6), 77 ([C6H5] , 5); HRMS (ESI) calcd for + C18H18O3SNa [M + Na] 337.0869, found 337.0868. (E)-2-Isopropyl-6-styryl-1,4-oxathiane 4,4-Dioxide (3b). Prepared according to general procedure 3 using diol 2b (80 mg, 0.27 mmol). After 7 h, pure cis-3b was isolated (62 mg, 82%) as a white solid: Rf = 0.45 (CHCl3); mp 118−119 °C; IR (neat) 1601, 1578, 1499, 1471, 1450, 1382, 1359, 1329, 1289, 1271, 1252, 1206, 1190, 1162, 1135, 1119, 1097, 1074, 1049, 1036 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.26 (m, 5H), 6.68 (dd, J = 16.0 and 1.5 Hz, 1H), 6.13 (dd, J = 16.0 and 5.8 Hz, 1H), 4.60 (ddtapp, J = 11.2, 5.9, and 1.7 Hz, 1H), 3.78 (ddd, J = 11.3, 5.8, and 1.9 Hz, 1H), 3.15−2.87 (m, 4H), 1.90 (hex, J = 6.8 Hz, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 135.8, 132.3, 128.8 (2C), 128.4, 126.8 (2C), 125.9, 80.2, 75.7, 56.3, 54.0, 32.9, 18.13, 18.11; MS (EI) m/z (rel intensity) 280 ([M]·+, 3), 147 (44), 146 (33), 145 (18), 133 (10), 131 (15), 130 ([PhC4H5]·+, 26), 129 (65), 128 (29), 117 (18), 115 (30), 105 (34), 104 ([PhC2H3]·+, 100), 91 (19), 77 ([C6H5]+, 12), 70 ([C5H 10]·+, 12), 69 (78), 55 (30); HRMS (ESI) calcd for C15H20O3SNa [M + Na]+ 303.1025, found 303.1026. (E)-2-Pentyl-6-styryl-1,4-oxathiane 4,4-Dioxide (3c). Prepared according to general procedure 3 using diol 2c (80 mg, 0.25 mmol). After 7 h, pure cis-3c was isolated (67 mg, 89%) as a colorless oil: Rf = 0.39 (PE/CHCl3 = 1:3); IR (neat) 1600, 1495, 1450, 1357, 1305, 1251, 1234, 1204, 1129, 1073 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.25 (m, 5H), 6.68 (dd, J = 16.0 and 1.5 Hz, 1H), 6.13 (dd, J = 16.0 and 6.0 Hz, 1H), 4.61 (ddtapp, J = 11.2, 6.1, and 1.5 Hz, 1H), 4.02 (m, 1H), 3.15−2.85 (m, 4H), 1.73 (m, 1H), 1.60−1.26 (m, 7H), 0.90 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 135.8, 132.6, 128.8 (2C), 128.5, 126.8 (2C), 125.7, 75.8, 75.7, 56.34, 56.28, 35.4, 31.5, 24.8, 22.5, 14.1; MS (EI) m/z (rel intensity) 308 ([M]·+, 1), 293 ([M − CH3]+, 1), 147 (18), 146 (23), 145 (13), 131 (13), 130 ([PhC4H5]·+, 19), 129 (41), 128 (21), 117 (15), 115 (23), 105 (25), 104 ([PhC2H3]·+, 100), 91 (17), 55 (48); HRMS (ESI) calcd for C17H24O3SNa [M + Na]+ 331.1338, found 331.1339. (E)-2-Styryl-6-vinyl-1,4-oxathiane 4,4-Dioxide (3d). Prepared according to general procedure 3 using diol 2d (75 mg, 0.27 mmol). After 7 h, pure cis-3d was isolated (60 mg, 85%) as a white solid: Rf = 0.48 (PE/EtOAc = 3:1); mp 114−115 °C; IR (neat) 1645, 1578, 1497, 1449, 1407, 1384, 1331, 1290, 1239, 1211, 1166, 1123, 4027



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5.47 (dddd, J = 11.3, 6.7, 2.1, and 1.2 Hz, 1H), 3.56 (dd, J = 14.0 and 11.4 Hz, 1H), 3.48 (dd, J = 14.0 and 2.2 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 153.3, 135.2, 134.64, 134.56, 128.95, 128.88 (2C), 127.0 (2C), 125.6, 123.9, 123.8, 122.4, 119.0, 76.5, 54.3; MS (EI) m/z (rel intensity) 286 ([M]·+, 9), 131 (17), 130 ([PhC4H5]·+, 37), 129 (96), 128 (100), 127 (16), 117 (12), 115 (35); HRMS (ESI) calcd for C16H14O3SNa [M + Na]+ 309.0556, found 309.0555. 2-Phenyl-6-(prop-1-en-1-yl)-1,4-oxathiane 4,4-Dioxide (3i). To a stirred solution of diol 2i (85 mg, 0.31 mmol, 1.0 equiv) in CH2Cl2 (2.5 mL) was added powdered FeCl3·6H2O (4.2 mg, 0.016 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 20 h in a sealed vial. GC/MS analysis on the crude mixture showed a 56:44 mixture of cisand trans-3i. The solution was evaporated, the residue was taken up in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at 110 °C for 20 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 5:1), and the solvents were removed under reduced pressure to yield cis-3i (67 mg, 84%) as a white solid as a 88:12 mixture of E- and Z-alkenes: Rf = 0.49 (PE/EtOAc = 4:1); mp 128−129 °C; IR (neat) 1603, 1495, 1451, 1382, 1336, 1289, 1248, 1181, 1163, 1133, 1095, 1057, 1025 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.41−7.32 (m, 5H), 5.87 (dqd, J = 15.5, 6.5, and 1.1 Hz, 0.9H), 5.73 (dqd, J = 10.8, 7.0, and 1.3 Hz, 0.1H), 5.54 (ddq, J = 15.3, 6.5, and 1.7 Hz, 0.9H), 5.49 (ddq, J = 10.7, 7.9, and 1.8 Hz, 0.1H), 5.05 (dd, J = 11.0 and 2.7 Hz, 0.1H), 5.02 (dd, J = 10.8 and 2.5 Hz, 0.9H), 4.94 (m, 0.1H), 4.58 (m, 0.9H), 3.22−3.00 (m, 4H), 1.75−1.72 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.7 (E-3i), 138.6 (Z3i), 130.4 (E-3i), 129.5 (Z-3i), 129.04 (2C, E-3i), 129.03 (2C, Z-3i), 128.9 (E-3i and Z-3i), 127.9 (E-3i), 127.3 (Z-3i), 126.0 (2C, E-3i), 125.9 (2C, Z-3i), 77.4 (Z-3i), 77.3 (E-3i), 76.3 (E-3i), 72.3 (Z-3i), 57.78 (Z-3i), 57.77 (E-3i), 56.2 (E-3i), 55.9 (Z-3i), 17.9 (E-3i), 13.9 (Z-3i); MS (EI) m/z (rel intensity) 252 ([M]·+, 1), 120 (13), 107 (19), 105 (29), 104 ([PhC2H3]·+, 100), 103 (15), 78 (20), 77 (14), 69 (12), 68 ([C5 H8 ] ·+, 74), 67 (30); HRMS (ESI) calcd for C13H16O3SNa [M + Na]+ 275.0712, found 275.0717. 2-Phenyl-6-vinyl-1,4-oxathiane 4,4-Dioxide (3j). To a stirred solution of diol 2j (600 mg, 2.34 mmol, 1.0 equiv) in 1,2dichloroethane (12 mL) was added powdered FeCl3·6H2O (31.6 mg, 0.12 mmol, 0.05 equiv), and the mixture was stirred at 120 °C for 30 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 3:1), and the solvents were removed under reduced pressure to give a 83:17 mixture of cis-3j and trans-3j (436 mg, 78%) as a white solid: Rf = 0.59 and 0.47 (PE/EtOAc = 4:1); mp 102−103 °C; IR (neat) 1496, 1456, 1429, 1351, 1293, 1247, 1210, 1195, 1168, 1121, 1069, 1033 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.41−7.32 (m, 5H), 6.33 (ddd, J = 17.3, 10.7, and 5.6 Hz, 0.2H), 5.89 (ddd, J = 17.3, 10.7, and 5.6 Hz, 0.8H), 5.47 (ddd, J = 17.2, 1.7, and 1.0 Hz, 0.2H), 5.45 (ddd, J = 10.4, 1.7, and 1.0 Hz, 0.2H), 5.43 (ddd, J = 17.2, 1.5, and 1.0 Hz, 0.8H), 5.37 (dd, J = 9.9 and 2.6 Hz, 0.2H), 5.29 (bdtapp, J = 10.6 and 1.1 Hz, 0.8H), 5.04 (dd, J = 11.0 and 2.3 Hz, 0.8H), 4.99 (m, 0.2H), 4.64 (dddtapp, J = 11.1, 5.6, 1.9, and 1.3 Hz, 0.8H), 3.37 (m, 0.4H), 3.26−3.10 (m, 2.8H), 3.03 (dd, J = 13.9 and 11.2 Hz, 0.8H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.6 (cis-3j), 138.4 (trans-3j), 134.8 (cis-3j), 133.3 (trans-3j), 129.0 (2C, cis-3j and 2C, trans-3j), 128.90 (cis-3j), 128.86 (trans-3j), 126.1 (2C, trans-3j), 125.9 (2C, cis-3j), 120.3 (trans-3j), 117.9 (cis-3j), 77.3 (cis-3j), 76.1 (cis-3j), 73.2 (trans-3j), 71.5 (trans-3j), 57.8 (cis-3j), 57.4 (trans-3j), 55.8 (cis-3j), 53.8 (trans-3j); MS (EI) m/z (rel intensity) 238 ([M]·+, 1), 133 (11), 120 (25), 107 (13), 106 (10), 105 (100), 104 ([PhC2H3]·+, 56), 103 (18), 91 (21), 78 (32), 77 ([C6H5]+, 24), 68 (11), 67 (17), 55 (14), 54 ([C4H6]·+, 92), 51 (12); HRMS (ESI) calcd for C12H14O3SNa [M + Na]+ 261.0556, found 261.0559. 2-((1E,3E)-Penta-1,3-dien-1-yl)-6-phenyl-1,4-oxathiane 4,4-Dioxide (3k). To a stirred solution of diol 2k (40 mg, 0.14 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added powdered FeCl3·6H2O (1.8 mg, 0.007 mmol, 0.05 equiv), and the mixture was stirred at rt for 20 h then at 50 °C for 30 min in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 3:1), and the solvents were removed under reduced pressure to yield pure cis-3k (32 mg, 85%) as a white solid as a 90:10 mixture of conformers s-trans and s-cis: Rf = 0.71 (PE/EtOAc = 3:1); mp 125−127 °C; IR (neat) 1663, 1603,

1495, 1450, 1390, 1359, 1334, 1291, 1243, 1215, 1181, 1162, 1135, 1097, 1078, 1042, 1021 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.42− 7.32 (m, 5H), 6.68 (ddtapp, J = 15.4, 11.3, and 1.3 Hz, 0.1H), 6.31 (br dd, J = 15.4 and 10.5 Hz, 0.9H), 6.02 (m, 1H), 5.80 (br dq, J = 14.9 and 6.7 Hz, 0.9H), 5.65 (m, 0.2H), 5.55 (br ddd, J = 15.2, 6.1, and 0.6 Hz, 0.9H), 5.05 (dd, J = 10.5 and 2.5 Hz, 0.1H), 5.03 (dd, J = 11.0 and 2.4 Hz, 0.9H), 4.71 (m, 0.1H), 4.65 (br dd, J = 10.4 and 6.5 Hz, 0.9H), 3.23−3.10 (m, 3H), 3.04 (dd, J = 13.7 and 11.0 Hz, 1H), 1.77 (br dd, J = 6.8 and 1.3 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.61 (s-trans), 138.58 (s-cis), 133.5 (s-trans), 132.7 (s-trans), 130.1 (s-trans), 129.6 (s-cis), 129.03 (2C, s-cis), 129.01 (2C, s-trans), 128.90 (s-cis), 128.88 (s-trans), 128.4 (s-cis), 128.1 (s-cis), 127.8 (s-cis), 126.0 ( strans), 125.93 (2C, s-trans), 125.92 (2C, s-cis), 77.4 (s-cis), 77.3 (strans), 76.4 (s-cis), 76.1 (s-trans), 57.80 (s-cis), 57.77 (s-trans), 56.1 (strans and s-cis), 18.3 (s-trans), 13.6 (s-cis); MS (EI) m/z (rel intensity) 278 ([M]·+, 1), 110 (10), 105 (12), 104 ([PhC2H 3]·+, 100), 95 (11), 79 (15), 77 ([C6H5]+, 11), 68 (40); HRMS (ESI) calcd for C15H18O3SNa [M + Na]+ 301.0869, found 301.0871. 2,6-Diphenyl-1,4-oxathiane 4,4-Dioxide (3l). To a stirred solution of diol 2l (72 mg, 0.24 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added powdered FeCl3·6H2O (3.2 mg, 0.012 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 20 h in a sealed vial. GC/MS analyis on the crude mixture showed a mixture of cis- and trans-3l. The solution was evaporated, the residue was taken up in 1,2-dichloroethane (2 mL), and the mixture was stirred at 110 °C for 12 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 4:1), and the solvents were removed under reduced pressure to yield pure cis-3l (60 mg, 88%) as a white solid: Rf = 0.53 (PE/EtOAc = 4:1); mp 149−150 °C; IR (neat) 1603, 1496, 1453, 1385, 1336, 1296, 1245, 1213, 1172, 1130, 1089, 1069, 1037 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.44−7.33 (m, 10H), 5.18 (dd, J = 10.8 and 2.5 Hz, 2H), 3.34−3.20 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.6 (2C), 129.1 (4C), 128.9 (2C), 125.9 (4C), 77.6 (2C), 57.9 (2C); MS (EI) m/z (rel intensity) 120 (31), 105 (19), 104 ([PhC2H3]·+, 100), 103 (14), 78 (19), 77 ([C6H5] +, 12); HRMS (ESI) calcd for C16H16O 3SNa [M + Na]+ 311.0712, found 311.0712. (E)-N-(2-((2-Hydroxy-4-phenylbut-3-en-1-yl)sulfonyl)-1-phenylethyl)-4-methylbenzenesulfonamide (4a). To a stirred solution of hydroxysulfone S2 (255 mg, 1.13 mmol, 1.0 equiv) in dry THF (19 mL) at −78 °C was added dropwise n-BuLi (2.5 M in hexanes, 1.04 mL, 2.59 mmol, 2.3 equiv). The reaction was stirred at −78 °C for 1 h, 4-methyl-N-(phenylmethylidene)benzene-1-sulfonamide (380 mg, 1.47 mmol, 1.3 equiv) was added dropwise, and the mixture was stirred at −78 °C for 2 h. The reaction was quenched with ice, and a saturated aqueous solution of NH4Cl (10 mL) was added. The phases were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow solid that was purified by flash column chromatography (pentane/EtOAc = 2:1) to yield pure tosylamide 4a (88 mg, 16%) as a colorless oil as a 50:50 mixture of diastereomers: Rf = 0.47 (PE/EtOAc = 1:1); IR (neat) 3484, 3263, 1598, 1494, 1450, 1399, 1290, 1156, 1121, 1091, 1069, 968, 911 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.55 (br dtapp, J = 8.3 and 1.7 Hz, 1H), 7.53 (br dtapp, J = 8.3 and 1.9 Hz, 1H), 7.34−7.23 (m, 5H), 7.18−7.04 (m, 7H), 6.62 (dd, J = 15.9 and 1.2 Hz, 0.5H), 6.61 (dd, J = 15.9 and 1.1 Hz, 0.5H), 6.40 (br d, J = 7.7 Hz, 0.5H), 6.26 (br d, J = 6.2 Hz, 0.5H), 6.07 (dd, J = 15.9 and 6.6 Hz, 0.5H), 6.03 (dd, J = 15.8 and 6.6 Hz, 0.5H), 5.02 (ddd, J = 9.1, 7.7, and 3.9 Hz, 0.5H), 4.94 (ddd, J = 9.0, 6.0, and 5.0 Hz, 0.5H), 4.86 (m, 1H), 3.90 (dd, J = 15.0 and 9.0 Hz, 0.5H), 3.66 (dd, J = 14.7 and 8.8 Hz, 0.5H), 3.55 (dd, J = 14.8 and 5.2 Hz, 0.5H), 3.38−3.28 (m, 1.5H), 3.12 (br d, J = 3.5 Hz, 0.5H), 3.01−2.89 (m, 1.5H), 2.30 (s, 1.5H), 2.29 (s, 1.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [143.6 and 143.5], [138.2 and 138.0], [137.0 and 136.6], [135.82 and 135.76], [132.5 and 132.1], [129.53 (2C) and 129.50 (2C)], [128.9 (4C) and 128.8 (4C)], [128.42 and 128.39], [128.37 and 128.3], [128.0 and 127.9], [127.4 (2C) and 127.2 (2C)], [127.0 (2C) and 126.85 (2C)], [126.79 (2C) and 126.7 (2C)], [68.2 and 67.7], [60.6 and 60.3], [59.9 and 59.3], [53.7 and 53.5], [21.53 and 21.52]; HRMS (ESI) calcd for C25H27NO5S2Na [M + Na]+ 508.1223, found 508.1221. 4028



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−78 °C was added dropwise n-BuLi (2.5 M in hexanes, 811 μL, 2.03 mmol, 2.2 equiv). The reaction was stirred at −78 °C for 1 h, cinnamaldehyde (139 μL, 1.11 mmol, 1.2 equiv) was added dropwise, and the mixture was stirred at −78 °C for 2 h. The reaction was quenched with ice, and a saturated aqueous solution of NH4Cl (5 mL) was added to the mixture. The phases were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (pentane/acetone = 4:1) to yield pure alcohol 4b (383 mg, 91%) as a colorless oil: Rf = 0.14 (PE/ acetone = 1:1); mp 123−124 °C; IR (neat) 3512, 3253, 1732, 1595, 1485, 1456, 1410, 1344, 1306, 1275, 1161, 1140, 1122, 1090, 1065, 1042, 969, 912 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.11 (br s, 1H), 7.83−7.79 (m, 3H), 7.72 (br d, J = 8.5 Hz, 1H), 7.55 (br tapp, J = 7.8 Hz, 1H), 7.33−7.24 (m, 7H), 7.19 (br tapp, J = 7.8 Hz, 1H), 6.63 (dd, J = 15.8 and 1.5 Hz, 1H), 5.95 (dd, J = 15.9 and 6.1 Hz, 1H), 4.84 (m, 1H), 3.16 (dd, J = 14.6 and 9.2 Hz, 1H), 3.07 (dd, J = 14.4 and 2.5 Hz, 1H), 2.96 (br s, 1H), 2.29 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 144.8, 137.0, 136.6, 135.85, 135.83, 132.3, 130.8, 130.2 (2C), 128.8 (2C), 128.4, 127.43, 127.35 (2C), 126.8 (2C), 126.6, 124.4, 121.0, 67.1, 62.3, 21.6; HRMS (ESI) calcd for C23H23NO5S2Na [M + Na]+ 480.0910, found 480.0909. (E)-3-Phenyl-5-styryl-4-tosylthiomorpholine 1,1-Dioxide (5a). To a stirred solution of alcohol 4a (62 mg, 0.13 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL) was added powdered FeCl3·6H2O (1.7 mg, 0.006 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 18 h in a sealed vial. The reaction was cooled to rt, and the solvent was evaporated under reduced pressure to give an orange oily residue that was purified by flash column chromatography (pentane/EtOAc = 2:1) to yield a 75:25 mixture of cis-5a and trans-5a (35 mg, 59%) as a colorless oil and dehydrated compound 6 (6 mg, 10%) as a colorless oil as a 80:20 mixture of conformers s-trans-6 and s-cis-6. Because of these complex mixtures, 5a could not be fully characterized: Rf = 0.51 and 0.45 (PE/EtOAc = 2:1); 1H NMR (CDCl3, 400 MHz) δ 7.65 (br dtapp, J = 8.3 and 2.0 Hz, 0.5H, trans-5a), 7.43−7.26 (m, 6H, cis-5a and trans-5a), 7.24−7.11 (m, 6H, cis-5a and trans-5a), 7.00 (br dapp, J = 8.2 Hz, 1.5H, cis-5a), 6.68 (dd, J = 16.0 and 0.9 Hz, 0.8H, cis-5a), 6.58 (dd, J = 16.0 and 6.0 Hz, 0.8H, cis- 5a), 6.56 (br d, J = 15.8 Hz, 0.2H, trans-5a), 6.18 (dd, J = 15.9 and 7.8 Hz, 0.2H, trans-5a), 5.73 (t, J = 5.7 Hz, 0.2H, trans-5a), 5.52 (dd, J = 8.7 and 2.8 Hz, 0.8H, cis-5a), 5.35 (br dapp, J = 5.1 Hz, 0.8H, cis-5a), 5.29 (br qapp, J = 6.6 Hz, 0.2H, trans-5a), 4.25 (ddd, J = 14.1, 8.7, and 0.9 Hz, 0.8H, cis-5a), 4.02 (ddd, J = 14.7, 6.0, and 1.1 Hz, 0.2H, trans-5a), 3.63 (ddd, J = 14.3, 5.2, and 1.9 Hz, 0.7H, cis-5a), 3.51−3.43 (m, 1.5H, cis-5a), 3.36 (ddd, J = 14.6, 5.8, and 0.9 Hz, 0.2H, cis-5a), 3.30 (br dd, J = 14.9 and 5.7 Hz, 0.3H, trans-5a), 3.22 (br dd, J = 14.3 and 5.5 Hz, 0.3H, trans- 5a), 2.43 (s, 0.7H, trans-5a), 2.32 (s, 2.3H, cis-5a). 4-Methyl-N-(1-phenyl-2-(((1E,3E)-4-phenylbuta-1,3-dien-1-yl)sulfonyl)ethyl)benzenesulfonamide (6): Rf = 0.16 (PE/EtOAc = 2:1); IR (neat) 3270, 1625, 1598, 1495, 1450, 1401, 1329, 1305, 1159, 1122, 1092, 998, 915 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.61−7.57 (m, 2H, s-trans-6 and s-cis-6), 7.46−7.35 (m, 5H, s-trans- 6 and s-cis-6), 7.24−7.11 (m, 8H, s-trans-6 and s-cis-6), 6.93 (br d, J = 15.3 Hz, 1H, strans-6 and s-cis-6), 6.62 (ddd, J = 15.6, 11.1, and 0.5 Hz, 1H, s-trans-6 and s-cis-6), 5.94 (br dapp, J = 14.8 Hz, 1H, s-trans-6 and s-cis-6), 5.90 (d, J = 5.2 Hz, 0.8H, s-trans-6), 5.86 (d, J = 5.5 Hz, 0.2H, s-cis-6), 4.80 (br dtapp, J = 8.0 and 5.1 Hz, 1H, s-trans- 6 and s-cis-6), 3.54 (dd, J = 14.7 and 8.0 Hz, 0.8H, s-trans-6), 3.53 (dd, J = 14.8 and 7.6 Hz, 0.2H, s-cis-6), 3.31 (dd, J = 14.8 and 4.9 Hz, 0.8H, s-trans-6), 3.29 (dd, J = 14.7 and 5.3 Hz, 0.2H, s-cis-6), 2.38 (s, 2.4H, s-trans-6), 2.37 (s, 0.6H, s-cis-6); 13C{1H} NMR (CDCl3, 100 MHz) δ 145.5 (s-trans-6 and scis-6), 144.2 (s-trans-6 and s-cis-6), 143.7 (s-trans-6 and s-cis-6), 137.8 (s-trans-6 and s-cis-6), 136.8 (s-trans-6 and s-cis-6), 135.3 (s-trans-6 and s-cis-6), 130.1 (s-trans-6 and s-cis-6), 129.68 (2C, s-trans-6), 129.67 (2C, s-cis-6), 129.4 (2C, s-cis-6), 129.1 (2C, s-trans-6), 129.0 (2C, strans-6), 128.9 (2C, s-cis-6), 128.6 (s-trans-6 and s-cis-6), 127.7 (2C, strans-6 and s-cis-6), 127.5 (2C, s-trans-6), 127.4 (2C, s-cis-6), 127.0 (2C, s-trans-6 and s-cis-6), 126.2 (s-trans-6 and s-cis-6), 123.3 (s-trans-6 and s-cis-6), 60.7 (s-trans-6 and s-cis-6), 53.7 (s-trans-6), 53.6 (s-cis-6),

2-(Methylthio)aniline (S4). To a stirred solution of 2-aminothiophenol (1.72 mL, 15.98 mmol, 1.0 equiv) in MeOH (48 mL) was slowly added a solution of NaOH (767 mg, 19.17 mmol, 1.2 equiv) in H2O (16 mL), and the resulting mixture was stirred at rt for 10 min. MeI (1.19 mL, 19.17 mmol, 1.2 equiv) was added dropwise, and the solution was stirred at rt for 3 h. The reaction was concentrated under reduced pressure, the residue was taken up in CHCl3 (20 mL), and H2O (20 mL) was added. The phases were separated, and the aqueous layer was extracted with CHCl3 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (PE/EtOAc = 95:5) to yield thioether S4 (2.00 g, 90%) as a purple oil. These data are in full accordance with those reported in the literature:30 Rf = 0.47 (PE/ EtOAc = 9:1); IR (neat) 3443, 3346, 1604, 1478, 1447, 1299, 1251, 1157, 1084, 1025, 969 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.36 (dd, J = 8.0 and 1.5 Hz, 1H), 7.10 (ddd, J = 8.1, 7.2, and 1.5 Hz, 1H), 6.75−6.71 (m, 2H), 4.27 (bs, 2H), 2.37 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 147.2, 133.5, 129.0, 120.3, 118.8, 115.0, 17.8; MS (EI) m/z (rel intensity) 140 ([M + H]+, 9), 139 ([M]·+, 100), 124 ([M − CH3]+, 94), 106 (14), 97 (11), 80 (61), 65 (12). 4-Methyl-N-(2-(methylthio)phenyl)benzenesulfonamide (S5). To an ice-cold, stirred solution of aniline S4 (700 mg, 5.03 mmol, 1.0 equiv) and pyridine (1.22 mL, 15.08 mmol, 3.0 equiv) in CH2Cl2 (26 mL) was slowly added TsCl (1.05 g, 5.53 mmol, 1.1 equiv), and the mixture was refluxed for 18 h. The solution was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (20 mL), and a 1 M aqueous solution of HCl (20 mL) was added. The phases were separated and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a blue oil, which was purified by flash column chromatography (PE/ EtOAc = 6:1) to yield sulfonamide S5 (1.21 g, 82%) as a white solid. These data are in full accordance with those reported in the literature:31 Rf = 0.62 (PE/EtOAc = 4:1); mp 146−147 °C; IR (neat) 3271, 1595, 1493, 1472, 1435, 1385, 1325, 1305, 1273, 1212, 1184, 1156, 1089, 1070, 1041, 1019, 960, 940, 907 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.67 (br d, J = 8.3 Hz, 2H), 7.65 (br s, 1H), 7.60 (dd, J = 8.2 and 1.5 Hz, 1H), 7.36 (dd, J = 7.8 and 1.6 Hz, 1H), 7.24− 7.18 (m, 3H), 7.03 (tdapp, J = 7.6 and 1.4 Hz, 1H), 2.35 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 144.1, 137.4, 136.2, 133.4, 129.7 (2C), 129.0, 127.3 (3C), 125.2, 120.4, 21.6, 19.2; MS (EI) m/z (rel intensity) 293 ([M]·+, 26), 138 ([M − Ts]+, 67), 94 (100), 91 (16), 77 (10), 65 (19). 4-Methyl-N-(2-(methylsulfonyl)phenyl)benzenesulfonamide (S6). To an ice-cold, stirred solution of sulfide S5 (600 mg, 2.05 mmol, 1.0 equiv) in CH2Cl2 (36 mL) was added m-CPBA (77% purity, 1.01 g, 4.50 mmol, 2.2 equiv), and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with a saturated aqueous solution of Na2S2O3 (10 mL), and a saturated aqueous solution of Na2CO3 (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a white solid, which was purified by flash column chromatography (PE/EtOAc = 4:1) to yield sulfone S6 (425 mg, 64%) as a beige solid: Rf = 0.24 (PE/EtOAc = 4:1); mp 127−128 °C; IR (neat) 3245, 1595, 1579, 1485, 1456, 1407, 1339, 1303, 1267, 1222, 1188, 1158, 1124, 1087, 1067, 1044, 967, 913 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.15 (br s, 1H), 7.83−7.78 (m, 3H), 7.68 (dd, J = 8.4 and 1.1 Hz, 1H), 7.54 (ddd, J = 8.3, 7.3, and 1.6 Hz, 1H), 7.29 (br ddapp, J = 8.6 and 0.7 Hz, 2H), 7.20 (ddd, J = 7.8, 7.3, and 1.1 Hz, 1H), 2.86 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 144.8, 136.6, 136.5, 135.6, 130.1 (2C), 130.0, 127.3 (3C), 124.4, 120.7, 44.5, 21.7; MS (EI) m/z (rel intensity) 325 ([M]·+, 17), 155 ([CH3C6H4SO2]+, 36), 92 (10), 91 ([CH3C6H4]+, 100), 65 (22); HRMS (ESI) calcd for C14H16NO4S2 [M + H]+ 326.0515, found 326.0518. (E)-N-(2-((2-Hydroxy-4-phenylbut-3-en-1-yl)sulfonyl)phenyl)-4methylbenzenesulfonamide (4b). To a stirred solution of methylsulfone S6 (300 mg, 0.92 mmol, 1.0 equiv) in dry THF (20 mL) at 4029



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1738, 1468, 1434, 1374, 1234, 1131, 1025, 969, 942 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.87 (dqapp, J = 7.6 and 5.6 Hz, 1H), 2.69 (ddd, J = 13.9, 8.7, and 5.6 Hz, 1H), 2.64 (ddd, J = 13.9, 8.5, and 5.9 Hz, 1H), 2.06 (s, 3H), 1.72−1.56 (m, 2H), 1.37 (t, J = 8.6 Hz, 1H, SH), 1.34− 1.19 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.7, 74.8, 32.2, 28.2, 27.4, 22.6, 21.2, 14.0; MS (EI) m/z (rel intensity) 129 ([M − CH2SH]+, 6), 117 (13), 116 ([M − AcOH]·+, 100), 101 (12), 87 (35), 83 (56), 82 (68), 75 (19), 74 (59), 73 (40), 69 (28), 67 (46), 61 (13), 60 (58), 55 (49); HRMS (ESI) calcd for C8H16O2SNa [M + Na]+ 199.0763, found 199.0765. (E)-1-((4-Hydroxy-4-phenylbut-2-en-1-yl)thio)hexan-2-yl Acetate (S9). To a stirred solution of thiol S8 (78 mg, 0.44 mmol, 1.0 equiv) in EtOH (2.5 mL) was added a solution of NaOH (35 mg, 0.88 mmol, 2.0 equiv) in H2O (0.5 mL) and the resulting mixture was stirred at rt for 10 min. Allyl bromide S7 (100 mg, 0.44 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 2 h. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (15 mL), and H2O (15 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 5:2) to yield pure hydroxy acetate S9 (70 mg, 49%) as a colorless oil as a 1:1 mixture of diastereomers and pure diol 8a (23 mg, 19%) as a colorless oil as a 50:50 mixture of diastereomers: Rf = 0.46 (PE/EtOAc = 5:2); IR (neat) 3435, 1735, 1602, 1492, 1453, 1422, 1373, 1237, 1070, 1021, 967, 939, 913 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38−7.31 (m, 4H), 7.26 (m, 1H), 5.82−5.65 (m, 2H), 5.20 (m, 1H), 4.88 (m, 1H), 3.14 (br dapp, J = 6.8 Hz, 2H), 2.86 (br t, J = 3.4 Hz, 0.5H), 2.78 (br t, J = 3.8 Hz, 0.5H), 2.60 (dd, J = 14.1 and 6.4 Hz, 0.5H), 2.56−2.49 (m, 1.5H), 2.042 (s, 1.5H), 2.036 (s, 1.5H), 1.64 (m, 1H), 1.51 (m, 1H), 1.38−1.16 (m, 4H), 0.89 (t, J = 7.0 Hz, 1.5H), 0.88 (t, J = 7.1 Hz, 1.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [171.12 and 171.10], [143.02 and 142.96], [136.14 and 136.07], [128.57 (2C) and 128.56 (2C)], [127.64 and 127.62], [127.4 and 127.3], 126.2 (2C), [74.55 and 74.49], [73.5 and 72.9], [34.4 and 34.3], [34.1 and 33.6], [32.81 and 32.78], 27.5, 22.6, 21.3, 14.0; MS (EI) m/z (rel intensity) 304 ([M − H2O]·+, 23), 262 ([M − AcOH]·+, 9), 161 (15), 147 (13), 146 (73), 145 (33), 143 (12), 142 (11), 131 (14), 130 (38), 129 (61), 128 (27), 117 (31), 116 (31), 115 (22), 105 (100), 91 (26), 87 (11), 83 (28), 82 (19), 79 (10), 77 ([C6H5]+, 34), 60 (13), 55 (29); HRMS (ESI) calcd for C18H26O3SNa [M + Na]+ 345.1495, found 345.1493. (E)-1-((4-Hydroxy-4-phenylbut-2-en-1-yl)thio)hexan-2-ol (8a). To an ice-cold, stirred solution of hydroxy acetate S9 (65 mg, 0.20 mmol, 1.0 equiv) in MeOH (2 mL) was added a solution of LiOH (24 mg, 1.01 mmol, 5.0 equiv) in H2O (2 mL), and the resulting mixture was stirred at rt for 2 h. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give pure diol 8a (56 mg, 99%) as a colorless oil as a 1:1 mixture of diastereomers: Rf = 0.15 (PE/EtOAc = 5:2); IR (neat) 3357, 1492, 1453, 1414, 1220, 1069, 1006, 966, 914 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.37−7.25 (m, 5H), 5.76−5.73 (m, 2H), 5.20 (br sapp, 1H), 3.57 (br sapp, 1H), 3.18−3.09 (m, 2H), 2.67 (dd, J = 13.6 and 3.7 Hz, 0.5H), 2.62 (dd, J = 13.7 and 3.5 Hz, 0.5H), 2.55 (br s, 2H), 2.37 (dd, J = 13.7 and 8.7 Hz, 0.5H), 2.36 (dd, J = 13.7 and 8.5 Hz, 0.5H), 1.48−1.19 (m, 6H), 0.89 (t, J = 7.1 Hz, 1.5H), 0.88 (t, J = 7.0 Hz, 1.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [143.0 and 142.9], [135.9 and 135.8], 128.7 (2C), [127.87 and 127.86], [127.28 and 127.25], [126.23 (2C) and 126.19 (2C)], [74.54 and 74.49], [69.6 and 69.2], [38.7 and 38.5], [36.0 and 35.9], [33.7 and 33.4], [27.93 and 27.90], [22.79 and 22.78], [14.13 and 14.12]; MS (EI) m/z (rel intensity) 262 ([M − H2O]·+, 5), 146 (22), 145 (14), 131 (17), 130 ([PhC4H5]·+, 100), 129 (25), 128 (10), 117 (9), 115 (10), 105 (30), 91 (9), 77 ([C6H5]+, 14), 69 (9), 55 (9); HRMS (ESI) calcd for C16H24O2SNa [M + Na]+ 303.1389, found 303.1389.

21.68 (s-trans-6), 21.66 (s-cis-6); MS (EI) m/z (rel intensity) 296 (15), 278 (13), 261 (24), 229 (15), 180 (19), 142 (10), 141 (18), 129 (29), 128 (100), 127 (20), 117 (16), 115 (22), 103 (10), 102 (18), 91 (38), 77 (33), 51 (14); HRMS (ESI) calcd for C25H25NO4S2Na [M + Na]+ 490.1117, found 490.1113. (E)-3-Styryl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 1,1-Dioxide (5b). To a stirred solution of alcohol 4b (75 mg, 0.16 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added powdered FeCl3·6H2O (2.2 mg, 0.008 mmol, 0.05 equiv) and the mixture was stirred at 50 °C for 45 min in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 3:1), and the solvents were removed under reduced pressure to yield pure dihydrobenzothiazine 1,1-dioxide 5b (57 mg, 79%) as a colorless oil: Rf = 0.50 (PE/EtOAc = 3:2); IR (neat) 1592, 1494, 1471, 1445, 1402, 1354, 1305, 1240, 1164, 1145, 1088, 1071, 1030, 964 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.96 (ddd, J = 8.4, 1.1, and 0.4 Hz, 1H), 7.81 (ddd, J = 7.8, 1.6, and 0.4 Hz, 1H), 7.59 (ddd, J = 8.4, 7.4, and 1.7 Hz, 1H), 7.56 (br d, J = 8.3 Hz, 2H), 7.38 (ddd, J = 7.9, 7.4, and 1.1 Hz, 1H), 7.33−7.22 (m, 7H), 6.72 (dd, J = 15.8 and 1.6 Hz, 1H), 6.24 (dd, J = 15.8 and 6.2 Hz, 1H), 5.59 (qdapp, J = 6.3 and 1.5 Hz, 1H), 3.54 (dd, J = 14.2 and 6.0 Hz, 1H), 3.32 (dd, J = 14.3 and 6.7 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 145.1, 135.6, 135.2, 134.8, 134.2, 133.7, 133.3, 130.0 (2C), 128.7 (2C), 128.6, 127.8, 127.7 (2C), 127.0, 126.9 (2C), 124.6, 124.5, 57.2, 55.2, 21.8; HRMS (ESI) calcd for C23H22NO4S2 [M + H]+ 440.0985, found 440.0989. (E)-4-Bromo-1-phenylbut-2-en-1-ol (S7). To a stirred solution of ethyl 4-bromobut-2-enoate (0.357 μL, 2.59 mmol, 1.0 equiv) in dry CH2Cl2 (20 mL) at −78 °C was added dropwise a solution of DIBALH (1 M in toluene, 3.11 mL, 3.11 mmol, 1.2 equiv), and the resulting mixture was stirred at −78 °C for 1.5 h. The reaction was carefully quenched with a saturated aqueous solution of potassium sodium tartrate, the temperature was raised to rt, and the resulting suspension was stirred until two phases appeared. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give crude 4bromocrotonaldehyde as a pale yellow oil. To an ice-cold, stirred solution of 4-bromocrotonaldehyde in dry THF (20 mL) was added dropwise a solution of phenylmagnesium bromide (1 M in THF, 2.85 mL, 2.85 mmol, 1.1 equiv), and the resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 mL), and H2O (20 mL) was added. The phases were separated, and the aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oily residue that was purified by column chromatography (PE/EtOAc = 5:1) to yield alcohol S7 (210 mg, 36% over the two steps) as a colorless oil: Rf = 0.41 (PE/EtOAc = 4:1); IR (neat) 3383, 1601, 1492, 1452, 1204, 1070, 1016, 965, 917 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.28 (m, 5H), 6.03 (dtd, J = 15.2, 6.9, and 0.7 Hz, 1H), 5.96 (br dd, J = 15.1 and 5.4 Hz, 1H), 5.24 (br tapp, J = 4.5 Hz, 1H), 3.97 (br dapp, J = 6.9 Hz, 2H), 2.06 (br d, J = 3.8 Hz, 1H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 142.2, 137.0, 128.8 (2C), 128.2, 127.1, 126.4 (2C), 74.0, 32.0; MS (EI) m/z (rel intensity) 147 ([M − Br]+, 23), 129 (47), 128 (13), 105 (100), 91 (21), 79 (13), 77 ([C6H5]+, 41), 55 (11), 51 (15); HRMS (ESI) dehydration of the compound, detection of signals at 208.99 and 210.99 for [M − H2O + H]+. 1-Mercaptohexan-2-yl Acetate (S8). To an ice-cold, stirred mixture of thioacetic acid (778 μL, 10.94 mmol, 1.2 equiv), 1,2epoxyhexane (1.10 mL, 9.12 mmol, 1.0 equiv), Et3N (63 μL, 0.46 mmol, 0.05 equiv), and SiO2 (3.00 g, 49.93 mmol, 5.5 equiv) was added CH2Cl2 (3.0 mL), and the mixture was stirred at rt for 48 h. The reaction was diluted with CH2Cl2 (25 mL), water (25 mL) was added, the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (PE/EtOAc = 20:1) to yield thiol S8 (823 mg, 51%) as a colorless oil: Rf = 0.42 (PE/EtOAc = 20:1); IR (neat) 4030



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Methyl 2-(Acetylthio)-2-phenylacetate (S10). To an ice-cold, stirred solution of methyl mandelate (500 mg, 3.01 mmol, 1.0 equiv) and Et3N (460 μL, 3.31 mmol, 1.1 equiv) in CH2Cl2 (30 mL) was added dropwise MsCl (245 μL, 3.16 mmol, 1.05 equiv), and the mixture was stirred at 0 °C for 45 min. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give the expected mesylate (726 mg, 99%) as a white solid. To a stirred solution of the previously prepared mesylate (726 mg, 2.97 mmol, 1.0 equiv) in acetone (80 mL) was added potassium thioacetate (509 mg, 4.46 mmol, 1.5 equiv), and the mixture was vigorously stirred at rt for 3 h. The reaction was quenched with H2O (20 mL), and CH2Cl2 (40 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give thioester S10 (663 mg, 99%) as a brown oil. These data are in full accordance with those reported in the literature:32 Rf = 0.62 (PE/EtOAc = 3:1); IR (neat) 1739, 1692, 1585, 1497, 1454, 1434, 1354, 1282, 1216, 1190, 1154, 1132, 1105, 1076, 1007, 955 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.39−7.28 (m, 5H), 5.32 (s, 1H), 3.74 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 194.0, 170.6, 134.9, 129.1 (2C), 128.6, 128.5 (2C), 53.2, 51.2, 30.1; MS (EI) m/z (rel intensity) 224 ([M]·+, 1), 192 ([M − MeOH]·+, 63), 182 (59), 165 (10), 150 (41), 149 (10), 123 (100), 122 (18), 121 (58), 91 (11), 90 (14), 89 (13), 77 ([C6H5]+, 19). 2-Mercapto-2-phenylethanol (S11). To an ice-cold, stirred solution of ester S10 (400 mg, 1.78 mmol, 1.0 equiv) in dry Et2O (30 mL) was added dropwise a solution of DIBAL-H (1 M in THF, 7.1 mL, 7.1 mmol, 4.0 equiv), and the resulting mixture was stirred at rt for 3 h. The reaction was then cooled to 0 °C, a saturated aqueous solution of potassium sodium tartrate was carefully added, and the resulting suspension was stirred at rt until two phases appeared. The phases were separated, and the aqueous layer was extracted with Et2O (2 × 30 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a white oily residue, which was purified by flash column chromatography (PE/EtOAc = 5:2) to yield hydroxythiol S11 (185 mg, 67%) as a colorless oil. These data are in full accordance with those reported in the literature:33 Rf = 0.33 (PE/EtOAc = 5:2); IR (neat) 3248, 1600, 1492, 1453, 1189, 1054, 1019 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.37−7.25 (m, 5H), 4.08 (qapp, J = 7.0 Hz, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 2.24 (br s, 1H, OH), 1.97 (d, J = 6.9 Hz, 1H, SH); 13C{1H} NMR (CDCl3, 100 MHz) δ 140.6, 129.0 (2C), 127.9, 127.5 (2C), 68.4, 46.4; MS (EI) m/z (rel intensity) 154 ([M]·+, 13), 124 (17), 123 ([M − CH2OH]+, 100), 122 (53), 121 (18), 103 (21), 91 (29), 79 (8), 77 ([C6H5]+, 19), 65 (8), 51 (9). (E)-4-((2-Hydroxy-1-phenylethyl)thio)-1-phenylbut-2-en-1-ol (8b). To a stirred solution of thiol S11 (95 mg, 0.62 mmol, 1.1 equiv) in EtOH (3 mL) was added a solution of NaOH (45 mg, 1.12 mmol, 2.0 equiv) in H2O (0.6 mL), and the resulting mixture was stirred at rt for 10 min. Allyl bromide S7 (127 mg, 0.56 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 1.5 h. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 3:2) to yield thioether 8b (119 mg, 71%) as a colorless oil as a 1:1 mixture of diastereomers: Rf = 0.33 (PE/EtOAc = 3:2); IR (neat) 3347, 1600, 1491, 1452, 1415, 1193, 1054, 1011, 967, 910 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.39−7.20 (m, 10H), 5.74− 5.62 (m, 2H), 5.15 (br dapp, J = 4.0 Hz, 1H), 3.88 (m, 1H), 3.80 (br qapp, J = 5.6 Hz, 2H), 3.11 (m, 1H), 2.99 (m, 1H), 2.72 (br d, J = 3.0 Hz, 0.5H), 2.52 (br d, J = 3.1 Hz, 0.5H), 2.42 (br t, J = 6.2 Hz, 0.5H), 2.33 (br t, J = 6.4 Hz, 0.5H); 13C{1H} NMR (CDCl3, 100 MHz) δ [142.85 and 142.82], [139.6 and 139.5], [135.8 and 135.7], [128.81

(2C) and 128.79 (2C)], [128.69 (2C) and 128.68 (2C)], [128.35 (2C) and 128.30 (2C)], [127.9 and 127.8], [127.733 and 127.725], [127.3 and 127.2], [126.3 (2C) and 126.2 (2C)], [74.51 and 74.50], [65.80 and 65.78], [51.59 and 51.58], [32.9 and 32.8]; MS (EI) m/z (rel intensity) 282 ([M − H2O]·+, 4), 269 ([M − CH2OH]+, 13), 252 (12), 146 (53), 145 (13), 131 (15), 130 ([PhC4H5]·+, 98), 129 (32), 128 (10), 123 (100), 121 (22), 117 (11), 105 (49), 104 (18), 103 (27), 91 (34), 79 (11), 77 ([C6H5]+, 40); HRMS (ESI) calcd for C18H20O2SNa [M + Na]+ 323.1076, found 323.1075. (E)-2-((4-Hydroxy-4-phenylbut-2-en-1-yl)thio)phenol (8c). To a stirred solution of 2-mercaptophenol (55 μL, 0.53 mmol, 1.1 equiv) in EtOH (2.5 mL) was added a solution of NaOH (39 mg, 0.97 mmol, 2.0 equiv) in H2O (0.5 mL), and the resulting mixture was stirred at rt for 10 min. Allyl bromide S7 (110 mg, 0.48 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 1 h. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 4:1) to yield thioether 8c (61 mg, 46%) as a colorless oil: Rf = 0.22 (PE/EtOAc = 4:1); IR (neat) 3387, 1573, 1492, 1470, 1448, 1341, 1287, 1238, 1192, 1154, 1125, 1067, 1027, 1003, 965, 913 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38 (ddd, J = 7.8, 1.7, and 0.3 Hz, 1H), 7.34−7.30 (m, 2H), 7.29−7.20 (m, 4H), 6.95 (ddd, J = 8.2, 1.3, and 0.3 Hz, 1H), 6.82 (tdapp, J = 7.5 and 1.4 Hz, 1H), 6.70 (br s, 1H), 5.74 (dtd, J = 15.1, 7.5, and 1.2 Hz, 1H), 5.40 (ddt, J = 15.2, 6.5, and 1.1 Hz, 1H), 5.07 (br d, J = 6.5 Hz, 1H), 3.30 (br d, J = 7.6 Hz, 2H), 1.99 (br s, 1H); 13C{1H} NMR (CDCl 3, 100 MHz) δ 157.3, 142.3, 136.8, 136.2, 131.6, 128.6 (2C), 127.8, 126.29 (2C), 126.26, 120.9, 117.8, 114.9, 74.3, 38.5; MS (EI) m/z (rel intensity) 254 ([M − H2O]·+, 34), 130 (31), 129 (100), 128 (59), 127 (16), 126 (39), 115 (26), 105 (33), 97 (12), 91 (18), 77 ([C6H5]+, 33), 51 (12); HRMS (ESI) calcd for C16H16O2SNa [M + Na]+ 295.0763, found 295.0764. (E)-2-Butyl-6-styryl-1,4-oxathiane (9a). To a stirred solution of diol 8a (54 mg, 0.19 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added FeCl3·6H2O (2.6 mg, 0.01 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 3.5 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 8:1), and the solvents were removed under reduced pressure to yield cis-oxathiane 9a (39 mg, 77%) as a colorless oil: Rf = 0.38 (PE/CHCl3 = 4:1); IR (neat) 1599, 1494, 1449, 1413, 1378, 1321, 1227, 1170, 1139, 1107, 1063, 964, 910 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.37 (m, 2H), 7.31 (m, 2H), 7.23 (ttapp, J = 7.3 and 1.5 Hz, 1H), 6.62 (dd, J = 16.0 and 1.2 Hz, 1H), 6.18 (dd, J = 16.0 and 5.9 Hz, 1H), 4.31 (ddtapp, J = 10.7, 5.9, and 1.8 Hz, 1H), 3.68 (m, 1H), 2.69 (dd, J = 13.3 and 10.7 Hz, 1H), 2.56 (dd, J = 13.4 and 10.5 Hz, 1H), 2.42 (dtapp, J = 13.3 and 1.9 Hz, 1H), 2.34 (dtapp, J = 13.5 and 1.8 Hz, 1H), 1.63 (m, 1H), 1.53−1.29 (m, 5H), 0.91 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 136.7, 130.8, 129.5, 128.7 (2C), 127.9, 126.7 (2C), 79.2, 79.0, 36.4, 31.1, 30.8, 27.6, 22.8, 14.2; MS (EI) m/z (rel intensity) 262 ([M]·+, 21), 178 (44), 146 (10), 133 (80), 132 (37), 131 (93), 130 ([PhC4H5]·+, 74), 129 (44), 128 (32), 127 (10), 117 (10), 115 (39), 104 (32), 103 (17), 91 (13), 89 (18), 87 (13), 83 (20), 82 (100), 81 (13), 78 (12), 77 ([C6H5]+, 19), 67 (19), 56 (18), 55 (48); HRMS (ESI) calcd for C16H23OS [M + H]+ 263.1464, found 263.1467 (E)-5-Phenyl-2-styryl-1,4-oxathiane (9b). To a stirred solution of diol 8b (55 mg, 0.18 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added FeCl3·6H2O (2.5 mg, 0.009 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 4 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 8:1), and the solvents were removed under reduced pressure to yield trans-oxathiane 9b (41 mg, 79%, cis/trans = 4:96) as a colorless oil. Only the major diastereomer is described: Rf = 0.48 (PE/EtOAc = 9:1); IR (neat) 1655, 1599, 1491, 1450, 1411, 1354, 1293, 1165, 1115, 1087, 1073, 1044, 1024, 1000, 964, 913 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.44−7.25 (m, 10H), 6.70 (dd, J = 16.1 and 1.1 Hz, 1H), 6.23 (dd, J = 16.0 and 6.0 Hz, 1H), 4.36 (m, 1H), 4.33 (br dd, J = 11.5 and 3.4 Hz, 4031



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1333, 1271, 1213, 1186, 1157, 1090, 1061, 1036, 1017, 967, 909 cm−1; H NMR (CDCl3, 400 MHz) δ 7.91 (br s, 1H), 7.71 (br d, J = 8.4 Hz, 2H), 7.54 (br dd, J = 8.3 and 1.4 Hz, 1H), 7.34−7.15 (m, 9H), 6.92 (tdapp, J = 7.6 and 1.4 Hz, 1H), 5.67 (dtd, J = 15.0, 7.4, and 1.3 Hz, 1H), 5.23 (ddt, J = 15.0, 6.6, and 1.1 Hz, 1H), 5.04 (br d, J = 6.5 Hz, 1H), 3.14 (d, J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.22 (br d, J = 3.5 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 144.3, 142.3, 139.4, 136.9, 136.8, 136.3, 130.3, 129.8 (2C), 128.5 (2C), 127.7, 127.3 (2C), 126.2 (2C), 125.4, 124.5, 122.9, 119.1, 74.0, 38.5, 21.6; MS (EI) m/z (rel intensity) 407 ([M − H2O]·+, 30), 253 (19), 252 (100), 251 (18), 250 (21), 219 (12), 218 (14), 174 (12), 149 (10), 148 (49), 136 (46), 135 (15), 130 (12), 129 (20), 128 (16), 124 (54), 118 (12), 117 (46), 116 (13), 115 (57), 109 (13), 104 (10), 103 (11), 92 (10), 91 ([CH3C6H4]+, 95), 78 (11), 77 ([C6H5]+, 25), 65 (25), 51 (12); HRMS (ESI) calcd for C23H23NO3S2Na [M + Na]+ 448.1012, found 448.1013. (E)-((4-Bromo-1-phenylbut-2-en-1-yl)oxy)-tert-butyldimethylsilane (S13). To an ice-cold, stirred solution of alcohol S7 (350 mg, 1.54 mmol, 1.0 equiv) and imidazole (315 mg, 4.62 mmol, 3.0 equiv) in CH2Cl2 (12 mL) was added TBSCl (348 mg, 2.31 mmol, 1.5 equiv), and the mixture was stirred at rt for 4 h. A saturated aqueous solution of NH4Cl (15 mL) and H2O (15 mL) was added, the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (PE/ EtOAc = 9:1) to furnish pure silyl ether S13 (405 mg, 77%) as a colorless oil: Rf = 0.58 (PE/EtOAc = 8:1); IR (neat) 1697, 1600, 1492, 1471, 1451, 1361, 1253, 1204, 1101, 1057, 1027, 1005, 964, 939, 916 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.35−7.30 (m, 4H), 7.25 (m, 1H), 5.95 (dtd, J = 14.9, 7.6, and 1.0 Hz, 1H), 5.84 (ddt, J = 15.1, 5.6, and 0.7 Hz, 1H), 5.20 (br d, J = 5.6 Hz, 1H), 3.95 (br d, J = 7.4 Hz, 2H), 0.92 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 143.2, 138.6, 128.5 (2C), 127.4, 126.1 (2C), 125.3, 74.5, 32.5, 26.0 (3C), 18.5, −4.4, −4.7; MS (EI) m/z (rel intensity) 261 ([M − Br]+, 9), 130 (20), 129 (100), 128 (11), 115 (8), 75 (48), 73 (21); HRMS (ESI) compound not detected. (E)-2-((4-((tert-Butyldimethylsilyl)oxy)-4-phenylbut-2-en-1-yl)thio)aniline (S14). To a stirred solution of 2-aminothiophenol (57 μL, 0.53 mmol, 1.0 equiv) in EtOH (2.5 mL) was added a solution of NaOH (32 mg, 0.79 mmol, 1.5 equiv) in H2O (0.5 mL), and the resulting mixture was stirred at rt for 5 min. Allyl bromide S13 (180 mg, 0.53 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 30 min. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 7:1) to yield thioether S14 (147 mg, 72%) as an orange oil: Rf = 0.65 (PE/EtOAc = 7:1); IR (neat) 3466, 3364, 1607, 1480, 1450, 1391, 1362, 1308, 1254, 1219, 1198, 1159, 1104, 1051, 1028, 1007, 990, 966, 940 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.30−7.26 (m, 3H), 7.24−7.19 (m, 3H), 7.08 (ddd, J = 8.0, 7.3, and 1.6 Hz, 1H), 6.65 (ddd, J = 8.1, 1.4, and 0.3 Hz, 1H), 6.60 (ddd, J = 7.6, 7.2, and 1.4 Hz, 1H), 5.71 (dtd, J = 15.0, 7.4, and 1.3 Hz, 1H), 5.46 (ddt, J = 15.0, 5.9, and 1.1 Hz, 1H), 5.07 (br d, J = 6.0 Hz, 1H), 4.26 (br s, 2H, NH2), 3.34 (ddd, J = 7.4, 1.1, and 0.6 Hz, 2H), 0.89 (s, 9H), 0.03 (s, 3H), −0.04 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 148.6, 143.9, 136.8, 136.7, 130.0, 128.2 (2C), 127.1, 126.1 (2C), 125.2, 118.5, 117.2, 115.0, 75.0, 36.8, 26.0 (3C), 18.5, −4.4, −4.7; MS (EI) m/z (rel intensity) 261 (5), 221 (14), 183 (10), 164 (28), 130 (16), 129 (34), 124 (27), 115 (14), 80 (15), 75 (42), 73 (100); HRMS (ESI) calcd for C22H31NOSSiNa [M + Na]+ 408.1788, found 408.1787. (E)-tert-Butyl (2-((4-((tert-Butyldimethylsilyl)oxy)-4-phenylbut-2en-1-yl)thio)phenyl)carbamate (S15). To an ice-cold, stirred solution of aniline S14 (140 mg, 0.36 mmol, 1.0 equiv), DMAP (9 mg, 0.07 mmol, 0.2 equiv), and Et3N (101 μL, 0.73 mmol, 2.0 equiv) in CH2Cl2 (5 mL) was added Boc2O (159 mg, 0.73 mmol, 2.0 equiv), and the

1H), 4.11 (dd, J = 10.8 and 3.0 Hz, 1H), 3.94 (dd, J = 11.7 and 10.9 Hz, 1H), 3.00 (dd, J = 13.6 and 10.7 Hz, 1H), 2.65 (br dd, J = 13.6 and 2.3 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.0, 136.6, 131.5, 128.9 (2C), 128.7 (2C), 128.6, 128.164, 128.156 (2C), 128.0, 126.7 (2C), 78.0, 75.0, 44.3, 33.4; MS (EI) m/ z (rel intensity) 282 ([M]·+, 13), 131 (8), 130 ([PhC4H5]·+, 10), 129 (11), 105 (9), 104 ([PhC2H3]·+, 100), 103 (10), 91 (8), 78 (12), 77 ([C6H5]+, 9); HRMS (ESI) calcd for C18H19OS [M + H]+ 283.1151, found 283.1153. (E)-2-Styryl-2,3-dihydrobenzo[b][1,4]oxathiane (9c). To a stirred solution of diol 8c (45 mg, 0.17 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added powdered FeCl3·6H2O (2.2 mg, 0.008 mmol, 0.05 equiv), and the mixture was stirred at rt for 45 min. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 8:1), and the solvents were removed under reduced pressure to yield pure dihydrobenzooxathiine 9c (36 mg, 86%) as a white solid: Rf = 0.32 (PE/CHCl3 = 4:1); mp 99−100 °C; IR (neat) 1569, 1493, 1467, 1440, 1416, 1355, 1289, 1261, 1232, 1214, 1154, 1125, 1062, 970, 915 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.45−7.42 (m, 2H), 7.36 (ttapp, J = 7.4 and 1.8 Hz, 2H), 7.29 (ddtapp, J = 8.1, 6.3, and 1.5 Hz, 1H), 7.10 (ddapp, J = 7.8 and 1.5 Hz, 1H), 7.04 (dddapp, J = 8.3, 7.0, and 1.7 Hz, 1H), 6.93 (ddapp, J = 8.3 and 1.5 Hz, 1H), 6.89 (tdapp, J = 7.5 and 1.5 Hz, 1H), 6.78 (br d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0 and 6.4 Hz, 1H), 4.91 (dddd, J = 7.5, 6.4, 3.1, and 1.1 Hz, 1H), 3.15 (dd, J = 13.0 and 7.4 Hz, 1H), 3.10 (dd, J = 13.2 and 3.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 151.5, 136.2, 132.9, 128.8 (2C), 128.3, 127.4, 127.0, 126.8 (2C), 125.9, 121.6, 118.8, 117.3, 74.9, 30.3; MS (EI) m/z (rel intensity) 254 ([M]·+, 38), 221 (8), 137 (8), 130 ([PhC4H5]·+, 31), 129 (100), 128 (59), 127 (14), 126 (9), 115 (29), 77 ([C6H5]+, 8); HRMS (ESI) calcd for C16H15OS [M + H]+ 255.0838, found 255.0843. (E)-4-((2-Aminophenyl)thio)-1-phenylbut-2-en-1-ol (S12). To a stirred solution of 2-aminothiophenol (71 μL, 0.66 mmol, 1.0 equiv) in EtOH (3 mL) was added a solution of NaOH (53 mg, 1.32 mmol, 2.0 equiv) in H2O (0.5 mL), and the resulting mixture was stirred at rt for 10 min. Allyl bromide S7 (150 mg, 0.66 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 30 min. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 4:1) to yield thioether S12 (124 mg, 69%) as a yellow oil: Rf = 0.27 (PE/EtOAc = 4:1); IR (neat) 3347, 1604, 1477, 1448, 1306, 1219, 1157, 1069, 1004, 965 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.35−7.29 (m, 3H), 7.25 (m, 1H), 7.23−7.19 (m, 2H), 7.13 (ddd, J = 7.9, 7.3, and 1.6 Hz, 1H), 6.71 (ddd, J = 8.0, 1.3, and 0.4 Hz, 1H), 6.67 (ddd, J = 7.7, 7.2, and 1.3 Hz, 1H), 5.78 (dtd, J = 15.2, 7.5, and 1.3 Hz, 1H), 5.42 (ddt, J = 15.3, 6.7, and 1.0 Hz, 1H), 5.06 (br d, J = 6.8 Hz, 1H), 3.62 (br s, 3H, NH2 and OH), 3.34 (br dapp, J = 7.6 Hz, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 148.9, 142.6, 137.3, 135.2, 130.3, 128.5 (2C), 127.6, 127.4, 126.3 (2C), 118.9, 117.1, 115.3, 74.3, 37.2; MS (EI) m/z (rel intensity) 271 ([M]·+, 3), 164 (52), 136 (11), 129 (17), 128 (11), 127 (10), 126 (11), 125 (100), 124 (25), 105 (32), 93 (10), 91 (17), 80 (30), 77 ([C6H5]+, 34), 55 (10); HRMS (ESI) calcd for C16H17NOSNa [M + Na]+ 294.0923, found 294.0929. (E)-N-(2-((4-Hydroxy-4-phenylbut-2-en-1-yl)thio)phenyl)-4-methylbenzenesulfonamide (10b). To an ice-cold, stirred solution of aniline S12 (100 mg, 0.37 mmol, 1.0 equiv) and pyridine (59 μL, 0.74 mmol, 2.0 equiv) in CH2Cl2 (5 mL) was slowly added TsCl (77 mg, 0.41 mmol, 1.1 equiv), and the mixture was stirred at rt for 18 h. A saturated aqueous solution of NH4Cl (5 mL) and H2O (5 mL) was added, the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/acetone = 4:1) to yield sulfonamide 10b (96 mg, 61%) as a colorless oil: Rf = 0.35 (PE/acetone = 4:1); IR (neat) 3525, 3254, 1597, 1588, 1574, 1492, 1475, 1449, 1385,

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over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (PE/EtOAc = 6:1) to yield thioester S17 (127 mg, 25%) as a colorless oil: Rf = 0.29 (PE/EtOAc = 4:1); IR (neat) 3429, 1686, 1493, 1453, 1396, 1354, 1298, 1237, 1199, 1128, 1055, 1028, 1002, 956, 917 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.41−7.28 (m, 5H), 4.81 (br dtapp, J = 8.5 and 3.5 Hz, 1H), 3.32 (dd, J = 13.9 and 3.9 Hz, 1H), 3.11 (dd, J = 14.1 and 8.5 Hz, 1H), 2.72 (br s, 1H, OH), 2.36 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 196.6, 142.5, 128.6 (2C), 128.1, 125.9 (2C), 73.3, 38.1, 30.7; MS (EI) m/z (rel intensity) 137 (13), 136 ([M − AcOH]·+, 93), 135 (100), 134 (10), 104 ([PhC2H 3]·+, 90), 103 (49), 102 (13), 91 (72), 89 (10), 78 (59), 77 ([C6H5]+, 42), 65 (13), 63 (19), 52 (15), 51 (51), 50 (25); HRMS (ESI) calcd for C10H12O2SNa [M + Na]+ 219.0450, found 219.0450. S-(2-(4-Methylphenylsulfonamido)-2-phenylethyl) Ethanethioate (S18). To an ice-cold, stirred solution of alcohol S17 (220 mg, 1.12 mmol, 1.0 equiv), PPh3 (882 mg, 3.36 mmol, 3.0 equiv), and BocNHTs (760 mg, 2.80 mmol, 2.5 equiv) in THF (10 mL) was added DIAD (556 μL, 2.80 mmol, 2.5 equiv), and the mixture was stirred at rt for 18 h. Silica was added, and the reaction was concentrated under reduced pressure to give an orange powder, which was purified by column chromatography (pentane/EtOAc = 6:1) to yield the expected tert-butyl carbamate (266 mg, 53%) as a colorless oil. To an ice-cold, stirred solution of the previously prepared tert-butyl carbamate (266 mg, 0.59 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added TFA (659 μL, 8.88 mmol, 15.0 equiv), and the resulting mixture was refluxed for 4 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL), the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (pentane/EtOAc = 3:1) to yield sulfonamide S18 (91 mg, 44%) as a colorless oil: Rf = 0.25 (PE/EtOAc = 3:1); IR (neat) 3267, 1688, 1598, 1495, 1455, 1400, 1325, 1209, 1155, 1091, 1066, 1019, 933 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.58 (br dapp, J = 8.1 Hz, 2H), 7.22−7.18 (m, 3H), 7.16−7.13 (m, 4H), 5.50 (br d, J = 7.1 Hz, 1H), 4.47 (ddd, J = 8.9, 7.0, and 5.2 Hz, 1H), 3.21 (dd, J = 14.3 and 9.0 Hz, 1H), 3.08 (dd, J = 14.3 and 5.2 Hz, 1H), 2.36 (s, 3H), 2.25 (d, J = 0.6 Hz, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 196.3, 143.2, 139.7, 137.5, 129.4 (2C), 128.7 (2C), 128.0, 127.2 (2C), 126.6 (2C), 58.2, 35.7, 30.6, 21.6; MS (EI) m/z (rel intensity) 261 (16), 260 ([PhCHNHTs]+, 100), 155 ([CH3C6H4SO2]+, 65), 104 (9), 92 (8), 91 ([CH3C6H4]+, 88), 65 (13); HRMS (ESI) calcd for C17H19NO3S2Na [M + Na]+ 372.0699, found 372.0700. (E)-3-Phenyl-5-styryl-4-tosylthiomorpholine (11a). To an ice-cold, stirred solution of thioester S18 (81 mg, 0.23 mmol, 1.0 equiv) in MeOH (3 mL) was added a solution of LiOH (17 mg, 0.70 mmol, 3.0 equiv) in H2O (1 mL), and the resulting mixture was stirred at rt for 2 h. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and a saturated aqueous solution of NH4Cl (5 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give the expected thiol (71 mg, 100%) as a colorless oil. To a stirred solution of the previously prepared thiol (68 mg, 0.22 mmol, 1.0 equiv) in EtOH (2 mL) was added a solution of NaOH (13 mg, 0.33 mmol, 1.5 equiv) in H2O (0.5 mL), and the resulting mixture was stirred at rt for 10 min. Allyl bromide S7 (50 mg, 0.22 mmol, 1.0 equiv) was added, and the solution was stirred at rt for 30 min. The reaction was concentrated under reduced pressure, the residue was taken up in CH2Cl2 (10 mL), and H2O (10 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/EtOAc = 5:2) to yield thioether 10a (39 mg, 39%) as a colorless oil. To a stirred solution of alcohol 10a (33 mg, 0.07 mmol, 1.0 equiv) in CH2Cl2 (1.5

mixture was stirred at rt for 7 h. The reaction was quenched with a 1 M aqueous solution of HCl (5 mL), the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give an orange oil, which was purified by flash column chromatography (pentane/Et2O = 8:1) to yield tert-butyl carbamate S15 (18 mg, 10%) as a colorless oil and ethyl carbamate S16 (38 mg, 23%) as a colorless oil: Rf = 0.65 (PE/Et2O = 8:1); IR (neat) 3365, 1731, 1578, 1507, 1472, 1432, 1392, 1367, 1302, 1280, 1241, 1219, 1154, 1103, 1068, 1045, 1024, 1005, 989, 964, 940 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.10 (br d, J = 8.4 Hz, 1H), 7.76 (br s, 1H), 7.36 (br dd, J = 7.8 and 1.6 Hz, 1H), 7.30− 7.17 (m, 6H), 6.84 (tdapp, J = 7.6 and 1.5 Hz, 1H), 5.67 (dtd, J = 15.0, 7.3, and 1.5 Hz, 1H), 5.42 (ddt, J = 15.1, 5.7, and 1.1 Hz, 1H), 5.05 (br d, J = 5.9 Hz, 1H), 3.33 (br d, J = 7.6 Hz, 2H), 1.54 (s, 9H), 0.89 (s, 9H), 0.02 (s, 3H), −0.06 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 152.8, 143.6, 140.4, 137.7, 136.1, 129.9, 128.3 (2C), 127.1, 126.0 (2C), 124.0, 122.6, 120.7, 118.4, 80.7, 74.8, 38.1, 28.5 (3C), 26.0 (3C), 18.4, −4.5, −4.7; MS (EI) m/z (rel intensity) 281 (12), 280 (60), 144 (19), 131 (11), 130 (100), 129 (27), 115 (34), 104 (76), 91 (50); HRMS (ESI) calcd for C27H39NO3SSiNa [M + Na]+ 508.2312, found 508.2305. (E)-Ethyl (2-((4-((tert-butyldimethylsilyl)oxy)-4-phenylbut-2-en-1yl)thio)phenyl)carbamate (S16): Rf = 0.45 (PE/Et2O = 8:1); IR (neat) 3359, 1737, 1580, 1512, 1437, 1303, 1236, 1206, 1099, 1076, 1051, 965 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.13 (br d, J = 8.3 Hz, 1H), 7.92 (br s, 1H), 7.38 (ddd, J = 7.7, 1.6, and 0.4 Hz, 1H), 7.30− 7.16 (m, 6H), 6.87 (tdapp, J = 7.6 and 1.4 Hz, 1H), 5.67 (dtd, J = 15.1, 7.3, and 1.5 Hz, 1H), 5.42 (ddt, J = 15.1, 5.6, and 1.1 Hz, 1H), 5.05 (br d, J = 5.7 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.33 (br dd, J = 7.4 and 0.9 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.02 (s, 3H), −0.06 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 153.5, 143.6, 140.1, 137.8, 136.2, 130.0, 128.3 (2C), 127.2, 126.0 (2C), 123.9, 122.9, 120.8, 118.4, 74.8, 61.4, 38.2, 26.0 (3C), 18.4, 14.7, −4.6, −4.7; MS (EI) m/z (rel intensity) 400 ([M − tBu]+, 21), 208 (26), 150 (16), 130 (25), 129 (74), 128 (17), 121 (12), 115 (16), 75 (46), 73 (100); HRMS (ESI) calcd for C25H35NO3SSiNa [M + Na]+ 480.1999, found 480.1999. (E)-Ethyl (2-((4-Hydroxy-4-phenylbut-2-en-1-yl)thio)phenyl)carbamate (10c). To an ice-cold, stirred solution of silyl ether S16 (30 mg, 0.07 mmol, 1.0 equiv) in dry THF (2 mL) was added TBAF (1 M in THF, 131 μL, 0.13 mmol, 2.0 equiv), and the mixture was stirred at 0 °C for 2 h. The reaction was concentrated under reduced pressure to give a yellowish oily residue, which was purified by flash column chromatography (pentane/EtOAc = 4:1) to furnish alcohol 10c (13 mg, 58%) as a colorless oil: Rf = 0.26 (PE/EtOAc = 4:1); IR (neat) 3354, 1734, 1580, 1514, 1438, 1388, 1303, 1237, 1208, 1076, 1051, 968 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.08 (br d, J = 8.1 Hz, 1H), 7.88 (br s, 1H), 7.43 (br dd, J = 7.6, 1.6 Hz, 1H), 7.34−7.22 (m, 4H), 7.20−7.17 (m, 2H), 6.94 (btdapp, J = 7.6 and 1.4 Hz, 1H), 5.71 (br dtd, J = 15.1, 7.7, and 1.2 Hz, 1H), 5.38 (br dd, J = 15.2 and 6.2 Hz, 1H), 5.02 (br d, J = 6.3 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.33 (br d, J = 7.6 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.26 (br s, 1H, OH); 13 C{1H} NMR (CDCl3, 100 MHz) δ 153.8, 142.4, 140.6, 136.7, 136.5, 130.4, 128.6 (2C), 127.7, 126.3 (2C), 125.9, 123.3, 121.0, 119.0, 74.3, 61.6, 38.5, 14.7; MS (EI) m/z (rel intensity) 343 ([M]·+, 4), 326 (18), 325 ([M − H2O]·+, 82), 197 (32), 164 (10), 152 (17), 151 (69), 150 (18), 147 (13), 146 (42), 136 (20), 130 (21), 129 (69), 128 (33), 127 (15), 126 (14), 125 (100), 124 (93), 123 (13), 120 (11), 117 (16), 115 (18), 106 (10), 105 (84), 93 (13), 91 (36), 80 (26), 77 ([C6H5]+, 56), 55 (19), 51 (10); HRMS (ESI) calcd for C19H21NO3SNa [M + Na]+ 366.1134, found 366.1133. S-(2-Hydroxy-2-phenylethyl) Ethanethioate (S17). To an ice-cold, stirred mixture of thioacetic acid (187 μL, 2.62 mmol, 1.0 equiv), styrene oxide (300 μL, 2.62 mmol, 1.0 equiv), Et3N (18 μL, 0.13 mmol, 0.05 equiv), and SiO2 (1.31 g, 21.82 mmol, 8.3 equiv) was added CH2Cl2 (1.5 mL), and the mixture was stirred at rt for 20 min. The reaction was diluted with CH2Cl2 (15 mL), H2O (15 mL) was added, the phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The organic layers were combined, dried 4033



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mL) was added FeCl3·6H2O (1.0 mg, 0.004 mmol, 0.05 equiv), and the mixture was stirred at rt for 30 min. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 5:1), and the solvents were removed under reduced pressure to yield cis-thiomorpholine 11a (22 mg, 69%) as a colorless oil: Rf = 0.63 (PE/EtOAc = 5:1); IR (neat) 1673, 1599, 1495, 1448, 1329, 1244, 1153, 1091, 1049, 967, 915 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.44 (br d, J = 8.4 Hz, 2H), 7.36−7.23 (m, 10H), 7.04−7.00 (m, 2H), 6.46 (br d, J = 16.2 Hz, 1H), 6.38 (dd, J = 15.9 and 6.6 Hz, 1H), 5.55 (dd, J = 5.5 and 3.8 Hz, 1H), 4.74 (br tdapp, J = 7.1 and 3.0 Hz, 1H), 3.38 (dd, J = 13.9 and 5.5 Hz, 1H), 3.28 (dd, J = 13.9 and 3.6 Hz, 1H), 3.10 (dd, J = 13.3 and 7.4 Hz, 1H), 2.84 (dd, J = 13.3 and 3.1 Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 142.8, 140.0, 138.1, 136.3, 133.7, 129.2 (2C), 128.6 (2C), 128.5 (2C), 128.2, 128.0 (2C), 127.6, 127.3, 127.2 (2C), 126.7 (2C), 57.9, 57.5, 30.5, 28.8, 21.5; HRMS (ESI) calcd for C25H26NO2S2 [M + H]+ 436.1400, found 436.1401. (E)-3-Styryl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (11b). To a stirred solution of alcohol 10b (55 mg, 0.13 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added powdered FeCl3·6H2O (1.7 mg, 0.006 mmol, 0.05 equiv), and the mixture was stirred at rt for 10 min. The solution was then filtered through a pad of silica gel (pentane/acetone = 4:1), and the solvents were removed under reduced pressure to yield pure dihydrobenzothiazine 11b (43 mg, 82%) as a colorless oil: Rf = 0.39 (PE/acetone =4:1); IR (neat) 1597, 1494, 1471, 1439, 1348, 1305, 1215, 1185, 1162, 1089, 1064, 1029, 961, 908 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.76 (ddd, J = 8.0, 1.5, and 0.6 Hz, 1H), 7.47 (br d, J = 8.4 Hz, 2H), 7.29−7.19 (m, 7H), 7.16−7.05 (m, 3H), 6.69 (dd, J = 15.9 and 1.6 Hz, 1H), 6.06 (dd, J = 15.9 and 5.6 Hz, 1H), 5.41 (br qdapp, J = 5.1 and 1.7 Hz, 1H), 3.07 (dd, J = 12.8 and 5.1 Hz, 1H), 2.80 (dd, J = 12.8 and 4.5 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 144.0, 136.7, 136.3, 133.2, 132.4, 129.8 (2C), 129.5, 129.1, 128.6 (2C), 128.0, 127.4 (2C), 127.2, 126.7 (2C), 126.4, 125.9, 125.2, 55.0, 30.9, 21.7; MS (EI) m/z (rel intensity) 407 ([M]·+, 28), 253 (19), 252 ([M − Ts]+, 99), 251 (19), 250 (23), 219 (12), 218 (13), 174 (12), 149 (10), 148 (50), 136 (48), 135 (16), 130 ([PhC4H5]·+, 13), 129 (21), 128 (18), 124 (57), 118 (11), 117 (48), 116 (14), 115 (58), 109 (13), 104 (11), 103 (11), 92 (10), 91 ([CH3C6H4]+, 100), 78 (11), 77 ([C6H5]+, 26), 65 (27), 51 (11); HRMS (ESI) calcd for C23H22NO2S2 [M + H]+ 408.1087, found 408.1095. (E)-Ethyl 3-Styryl-2H-benzo[b][1,4]thiazine-4(3H)-carboxylate (11c). To a stirred solution of alcohol 10c (12 mg, 0.035 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added FeCl3·6H2O (0.5 mg, 0.002 mmol, 0.05 equiv), and the mixture was stirred at rt for 4 h. The solution was then filtered through a pad of silica gel (pentane/acetone = 4:1), and the solvents were removed under reduced pressure to yield pure dihydrobenzothiazine 11c (8 mg, 70%) as a pale yellow oil: Rf = 0.55 (PE/acetone = 3:1); IR (neat) 1696, 1569, 1476, 1443, 1395, 1374, 1311, 1280, 1266, 1231, 1169, 1135, 1088, 1042, 961, 907 cm−1; 1 H NMR (CDCl3, 400 MHz) δ 7.45 (dd, J = 8.1 and 1.1 Hz, 1H), 7.28−7.18 (m, 5H), 7.17 (ddd, J = 7.8, 1.6, and 0.4 Hz, 1H), 7.09 (ddd, J = 8.0, 7.3, and 1.8 Hz, 1H), 7.02 (tdapp, J = 7.6 and 1.5 Hz, 1H), 6.62 (dd, J = 15.9 and 1.5 Hz, 1H), 6.07 (dd, J = 15.9 and 6.2 Hz, 1H), 5.63 (br qdapp, J = 6.1 and 1.5 Hz, 1H), 4.31 (dq, J = 10.7 and 7.1 Hz, 1H), 4.19 (dq, J = 10.7 and 7.2 Hz, 1H), 3.47 (dd, J = 12.6 and 5.0 Hz, 1H), 3.03 (dd, J = 12.6 and 4.8 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 154.7, 136.5, 134.6, 132.9, 128.6 (2C), 128.3, 128.0, 127.9, 127.1, 126.6 (2C), 126.0, 125.2, 124.7, 62.5, 53.1, 33.4, 14.6; MS (EI) m/z (rel intensity) 326 (22), 325 ([M]·+, 100), 310 ([M − CH3]+, 31), 266 (15), 253 (14), 252 ([M − CO2Et]+, 73), 238 (21), 236 (14), 220 (10), 219 (14), 218 (13), 208 (12), 164 (10), 162 (10), 149 (12), 148 (33), 136 (72), 135 (20), 130 (29), 129 (86), 128 (45), 127 (12), 125 (19), 124 (27), 117 (18), 116 (10), 115 (46), 109 (11), 91 (32), 77 (19); HRMS (ESI) calcd for C19H20NO2S [M + H]+ 326.1209, found 326.1211. 2-(Hydroxymethyl)-6-phenyl-1,4-oxathiane 4,4-Dioxide (12). To a stirred solution of alkene 3a (158 mg, 0.50 mmol, 1.0 equiv) and NMO (88 mg, 0.75 mmol, 1.5 equiv) in H2O/t-BuOH (1:1, 4 mL) under argon was slowly added a solution of OsO4 (0.079 M in t‑BuOH, 127 μL, 0.01 mmol, 0.02 equiv), and the mixture was stirred

at rt for 18 h. The reaction was quenched with an aqueous solution of Na2S2O3 (5 mL), and EtOAc (8 mL) was added. The phases were separated, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give the diol (143 mg, 82%) as a beige solid. To a stirred solution of the previously prepared diol (112 mg, 0.32 mmol, 1.0 equiv) in THF/ buffer pH = 7 (1/1, 6 mL) was added NaIO4 (172 mg, 0.80 mmol, 2.5 equiv). The mixture was stirred at rt for 5.5 h before addition of EtOAc (10 mL) and H2O (10 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a yellow oil, which was purified by flash column chromatography (pentane/EtOAc = 1:2) to furnish the corresponding aldehyde (50 mg, 65%) as a colorless oil (some traces of the aldehyde hydrate were also observed). To an icecold, stirred solution of the previously prepared aldehyde (30 mg, 0.12 mmol, 1.0 equiv) in EtOH (3 mL) was added NaBH4 (14 mg, 0.37 mmol, 3.0 equiv), and the mixture was stirred at rt for 1.5 h. The solution was evaporated under reduced pressure, and the residue was taken up in CH2Cl2 (3 mL) and H2O (3 mL). The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 3 mL). The organic layers were combined, dried over MgSO4, and filtered, and the solvents were removed under reduced pressure to give a colorless oil, which was purified by column chromatography (pentane/EtOAc = 1:1) to yield alcohol 12 (28 mg, 93%) as a colorless oil: Rf = 0.41 (PE/EtOAc = 1:2); IR (neat) 3506, 1497, 1455, 1297, 1242, 1211, 1157, 1127, 1094, 1051, 1013 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.42−7.32 (m, 5H), 5.02 (dd, J = 9.9 and 3.5 Hz, 1H), 4.22 (m, 1H), 3.81 (ddd, J = 11.9, 6.6, and 3.7 Hz, 1H), 3.69 (dtapp, J = 11.9 and 5.7 Hz, 1H), 3.22−3.06 (m, 4H), 2.32 (t, J = 6.6 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.2, 129.12, 129.07 (2C), 126.0 (2C), 77.7, 76.8, 64.5, 57.6, 52.8; MS (EI) m/z (rel intensity) 242 ([M]·+, 1), 211 ([M − CH2OH]+, 2), 167 (18), 121 (96), 120 (32), 107 (32), 105 (51), 104 ([PhC2H3]·+, 100), 103 (41), 91 (28), 80 (11), 79 (32), 78 (32), 77 ([C6H5]+, 30), 65 (10), 57 (36), 51 (13); HRMS (ESI) calcd for C11H14O4SNa [M + Na]+ 265.0505, found 265.0509. Methyl 3-(4,4-Dioxido-6-phenyl-1,4-oxathian-2-yl)acrylate (13). To a stirred solution of 3i (55 mg, 0.22 mmol,1.0 equiv) and methyl acrylate (5.0 equiv) in dry CH2Cl2 (0.2 M) in a sealed tube under argon was added G−H II catalyst (10 mol %). The mixture was stirred at 50 °C for 24 h, cooled down to rt and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 5:1) to furnish ester 13 (39 mg, 60%) as a colorless oil as a 90:10 mixture of E- and Z-alkenes: Rf = 0.40 (PE/EtOAc = 4:1); IR (neat) 1720, 1667, 1610, 1512, 1497, 1454, 1437, 1339, 1303, 1280, 1245, 1198, 1170, 1130, 1103, 1054, 1034 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.43−7.33 (m, 5H), 6.86 (dd, J = 15.7 and 4.3 Hz, 0.9H), 6.29 (dd, J = 11.6 and 6.7 Hz, 0.1H), 6.22 (dd, J = 15.6 and 1.9 Hz, 0.9H), 5.92 (dd, J = 11.6 and 1.8 Hz, 0.1H), 5.66 (ddtapp, J = 11.1, 6.7, and 1.9 Hz, 0.1H), 5.07 (br dd, J = 11.0 and 2.4 Hz, 1H), 4.83 (ddtapp, J = 11.4, 4.3, and 1.9 Hz, 0.9H), 3.77 (s, 0.3H), 3.76 (s, 2.7H), 3.28−3.13 (m, 3H), 3.01 (dd, J = 13.4 and 11.3 Hz, 0.9H), 2.99 (dd, J = 13.4 and 11.3 Hz, 0.1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 166.1 (E-13), 165.6 (Z-13), 145.1 (Z13), 142.5 (E-13), 138.4 (Z-13), 138.0 (E-13), 129.11 (2C, E-13), 129.09 (E-13), 129.05 (2C, Z- 13), 129.00 (Z-13), 125.9 (2C, Z-13), 125.8 (2C, E-13), 122.7 (E-13), 121.0 (Z-13), 77.5 (E-13), 77.3 (Z13), 74.2 (E-13), 73.8 (Z-13), 57.89 (Z-13), 57.86 (E-13), 55.2 (E13), 54.3 (Z-13), 52.1 (E-13 and Z-13); MS (EI) m/z (rel intensity) 264 ([M − MeOH] ·+, 5), 236 ([M − HCO2Me]·+, 9), 129 (17), 128 (19), 120 (39), 113 (30), 112 (39), 111 (37), 105 (100), 104 ([PhC2H3]·+, 98), 103 (38), 97 (26), 91 (29), 82 (22), 81 (60), 79 (10), 78 (47), 77 ([C6H5]+, 32), 67 (18), 65 (11), 59 (10), 55 (13), 53 (37), 51 (17); HRMS (ESI) calcd for C14H16O5SNa [M + Na]+ 319.0611, found 319.0611. (E)-2-(4-Methylstyryl)-6-phenyl-1,4-oxathiane 4,4-Dioxide (14). To a stirred solution of 3j (cis/trans = 78:22, 82 mg, 0.34 mmol, 1.0 equiv), 4-iodotoluene (98 mg, 0.45 mmol, 1.3 equiv), Et3N (72 μL, 4034



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MHz) δ 169.1, 169.0, 142.1, 140.3, 134.7, 131.6, 129.4 (2C), 129.2, 127.1 (2C), 78.0, 76.3, 62.28, 62.27, 57.6, 56.0, 47.4; HRMS (ESI) calcd for C19H22BNO7SNa [M + Na]+ 442.1102, found 442.1104.

0.52 mmol, 1.5 equiv), and tri(o-tolyl)phosphine (21 mg, 0.07 mmol, 0.2 equiv) in dry DMF (5 mL) was added Pd(OAc)2 (3.9 mg, 0.02 mmol, 0.05 equiv), and the mixture was stirred at 115 °C for 18 h in a sealed tube. The volatiles were evaporated under reduced pressure to give a black residue, which was purified by flash column chromatography (pentane/EtOAc = 5:1) to yield disubstituted alkene 14 (82 mg, 73%) as a white solid as a 82:18 cis/trans mixture. To a stirred solution of the mixture of cis-14 and trans-14 (cis/trans = 82:18, 62 mg, 0.19 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL) was added powdered FeCl3·6H2O (2.6 mg, 0.009 mmol, 0.05 equiv), and the mixture was stirred at 50 °C for 8 h in a sealed vial. The solution was then filtered through a pad of silica gel (pentane/EtOAc = 3:1), and the solvents were removed under reduced pressure to yield pure cis-14 (56 mg, 90%) as a white solid: Rf = 0.47 (PE/EtOAc = 4:1); mp 160− 161 °C; IR (neat) 1653, 1609, 1513, 1456, 1358, 1307, 1269, 1241, 1213, 1176, 1155, 1130, 1115, 1056, 1038, 989, 969, 917 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.44−7.35 (m, 5H), 7.29 (br d, J = 8.1 Hz, 2H), 7.15 (br d, J = 8.1 Hz, 2H), 6.70 (br d, J = 16.0 Hz, 1H), 6.15 (dd, J = 16.0 and 6.2 Hz, 1H), 5.10 (dd, J = 10.6 and 2.6 Hz, 1H), 4.81 (dddd, J = 11.0, 6.2, 2.2, and 1.4 Hz, 1H), 3.28−3.11 (m, 4H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.6 (2C), 133.0, 132.9, 129.5 (2C), 129.0 (2C), 128.9, 126.7 (2C), 126.0 (2C), 124.4, 77.4, 76.4, 57.8, 56.2, 21.4; MS (EI) m/z (rel intensity) 328 ([M]·+, 2), 145 (20), 131 (14), 129 (22), 128 (14), 119 (11), 118 (100), 117 (15), 115 (10), 105 (21), 104 ([PhC2H3]·+, 90), 91 (12), 78 (10); HRMS (ESI) calcd for C19H20O3SNa [M + Na]+ 351.1025, found 351.1026. (E)-2-(2-(6-Chloropyridin-3-yl)vinyl)-6-phenyl-1,4-oxathiane 4,4Dioxide (15). To a stirred solution of 3j (cis/trans = 83:17, 100 mg, 0.42 mmol, 1.0 equiv), 2-chloro-5-iodopyridine (201 mg, 0.84 mmol, 2.0 equiv), Et3N (146 μL, 1.05 mmol, 2.5 equiv), and tri(otolyl)phosphine (26 mg, 0.08 mmol, 0.2 equiv) in dry DMF (5 mL) was added Pd(OAc)2 (4.7 mg, 0.02 mmol, 0.05 equiv), and the mixture was stirred at 115 °C for 18 h in a sealed tube. The volatiles were evaporated under reduced pressure to give a black residue, which was purified by flash column chromatography (pentane/acetone = 4:1) to yield disubstituted alkene 15 (104 mg, 71%) as a yellow solid isolated as a pure cis-isomer: Rf = 0.41 (PE/EtOAc = 5:2); mp 143− 144 °C; IR (neat) 1583, 1558, 1496, 1459, 1374, 1338, 1302, 1243, 1211, 1129, 1097, 1055, 1023, 969, 909 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.36 (br d, J = 2.5 Hz, 1H), 7.67 (ddd, J = 8.3, 2.6, and 0.4 Hz, 1H), 7.43−7.34 (m, 5H), 7.29 (br dt, J = 8.3 and 0.5 Hz, 1H), 6.71 (br dd, J = 16.0 and 1.1 Hz, 1H), 6.25 (dd, J = 16.1 and 5.6 Hz, 1H), 5.09 (br dd, J = 10.4 and 2.6 Hz, 1H), 4.84 (ddtapp, J = 11.2, 5.6, and 1.7 Hz, 1H), 3.28−3.09 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 151.0, 148.3, 138.2, 135.9, 130.4, 129.09 (2C), 129.08, 128.4, 127.9, 125.9 (2C), 124.4, 77.6, 75.7, 57.7, 55.8; MS (EI) m/z (rel intensity) 349 ([M]·+, 1), 139 (16), 105 (13), 104 ([PhC2H3]·+, 100), 103 (10), 78 (10), 77 ([C6H5]+, 9); HRMS (ESI) calcd for C17H17ClNO3S [M + H]+ 350.0612, found 350.0613. 2-((1E,3E)-4-(4,4-Dioxido-6-phenyl-1,4-oxathian-2-yl)buta-1,3dien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (17). To a stirred solution of 3j (cis/trans = 83:17, 190 mg, 0.80 mmol, 1.4 equiv), (E)-2-(2-iodovinyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8dione 16 (176 mg, 0.57 mmol, 1.0 equiv), and silver acetate (143 mg, 0.85 mmol, 1.5 equiv) in dry acetonitrile (4 mL) was added Pd(OAc)2 (6.4 mg, 0.03 mmol, 0.05 equiv), and the mixture was stirred at 80 °C for 16 h in a sealed tube. The volatiles were evaporated under reduced pressure to give a black residue, which was purified by flash column chromatography (pentane/acetone = 2:3) to yield diene 17 (155 mg, 65%) as a white solid isolated as a pure cis-isomer together with some minor unidentified impurities: Rf = 0.55 (PE/ acetone =2:3); mp 240−242 °C; IR (neat) 1759, 1604, 1495, 1456, 1338, 1285, 1244, 1218, 1154, 1129, 1106, 1087, 1053, 1027, 1005, 954 cm−1; 1H NMR ((CD3)2CO, 400 MHz) δ 7.52−7.48 (m, 2H), 7.43−7.32 (m, 3H), 6.60 (br dd, J = 17.1 and 10.5 Hz, 1H), 6.50 (br ddd, J = 15.0, 10.5, and 1.1 Hz, 1H), 5.87 (br dd, J = 15.0 and 5.7 Hz, 1H), 5.79 (br d, J = 17.0 Hz, 1H), 5.04 (br tapp, J = 6.6 Hz, 1H), 4.69 (ddtapp, J = 11.2, 5.7, and 1.4 Hz, 1H), 4.22 (d, J = 16.8 Hz, 2H), 4.03 (ddapp, J = 16.8 and 1.3 Hz, 2H), 3.31−3.24 (m, 3H), 3.16 (dd, J = 13.6 and 11.1 Hz, 1H), 2.98 (s, 3H); 13C{1H} NMR ((CD3)2CO, 100

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01827. 1 H and 13C{1H} NMR spectra for substrates and products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: 33 140794429. *E-mail: [email protected]. Tel: 33 140794429. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Janssen Research & Development is gratefully acknowledged for financial support (C.B.) and fruitful discussions. REFERENCES

(1) (a) Metzner, P.; Thuillier, A. In Sulfur Reagents in Organic Synthesis; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic Press: London, 1994. (b) Bichler, P.; Love, J. In Topics of Organometallic Chemistry; Vigalok, A., Ed.; Springer: Heidelberg, 2010; Vol. 31, p 39. (2) Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Bruni, B.; Buccioni, M.; Carrieri, A.; Ciattini, S. Bioorg. Med. Chem. 2007, 15, 886. (3) Miyauchi, H.; Tanio, T.; Ohashi, N. Bioorg. Med. Chem. Lett. 1996, 6, 2377. (4) Hronowski, L. J. J.; Szarek, W. A. J. Med. Chem. 1982, 25, 522. (5) Yang, F.; Lian, G.; Yu, B. Carbohydr. Res. 2010, 345, 309. (6) Han, B.; Liu, J. L.; Huan, Y.; Li, P.; Wu, Q.; Lin, Z. Y.; Shen, Z. F.; Yin, D. L.; Huang, H. H. Chin. Chem. Lett. 2012, 23, 297. (7) Theodosis-Nobelos, P.; Kourti, M.; Gavalas, A.; Rekka, E. A. Bioorg. Med. Chem. Lett. 2016, 26, 910. (8) Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F. Bioorg. Med. Chem. 2003, 11, 515. (9) Tooulia, K.-K.; Theodosis-Nobelos, P.; Rekka, E. A. Arch. Pharm. 2015, 348, 629. (10) See, for example: (a) Sasaki, T.; Takahashi, T.; Nagase, T.; Mizutani, T.; Ito, S.; Mitobe, Y.; Miyamoto, Y.; Kanesaka, M.; Yoshimoto, R.; Tanaka, T.; Takenaga, N.; Tokita, S.; Sato, N. Bioorg. Med. Chem. Lett. 2009, 19, 4232. (b) Menichetti, S.; Aversa, M. C.; Cimino, F.; Contini, A.; Viglianisi, C.; Tomaino, A. Org. Biomol. Chem. 2005, 3, 3066. (c) Regueiro-Ren, A.; Liu, Z.; Chen, Y.; Sin, N.; Sit, S.Y.; Swidorski, J. J.; Chen, J.; Venables, B. L.; Zhu, J.; Nowicka-Sans, B.; Protack, T.; Lin, Z.; Terry, B.; Samanta, H.; Zhang, S.; Li, Z.; Beno, B. R.; Huang, X. S.; Rahematpura, S.; Parker, D. D.; Haskell, R.; Jenkins, S.; Santone, K. S.; Cockett, M. I.; Krystal, M.; Meanwell, N. A.; Hanumegowda, U.; Dicker, I. B. ACS Med. Chem. Lett. 2016, 7, 568. (d) Dininno, F. P.; Seongkon, K.; Wu, J. Y. Estrogen Receptor Modulators. WO0232373 (A2), 2002. (e) Dininno, F. P.; Hammond, M. L. Estrogen Receptor Modulators. US2003225132 (A1), 2003. (f) Sasaki, T.; Nagaaki, S.; Takahashi, T.; Mizutani, T. Novel Benzoxathiin Derivative. EP1944301 (A1), 2008. (11) (a) Paul, N.; Kaladevi, S.; Beneto, A. J.; Muthusubramanian, S.; Bhuvanesh, N. Tetrahedron 2012, 68, 6892. (12) (a) Ioannou, M.; Porter, M. J.; Saez, F. Tetrahedron 2005, 61, 43. (b) Stepakov, A. V.; Molchanov, A. P.; Magull, J.; Vidović, D.; Starova, G. L.; Kopf, R. Tetrahedron 2006, 62, 3610. (13) Gharpure, S. J.; Anuradha, D.; Prasad, J. V. K.; Rao, P. S. Eur. J. Org. Chem. 2015, 2015, 86. 4035



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(14) (a) Aggarwal, V. K.; Ford, J. G.; Jones, R. V. H.; Fieldhouse, R. Tetrahedron: Asymmetry 1998, 9, 1801. (b) Frieze, D. M.; Hughes, P. F.; Merrill, R. L.; Evans, S. A., Jr. J. Org. Chem. 1977, 42, 2206. (c) Blanchard, P.; Cappon, A.; Levillain, E.; Nicolas, Y.; Frère, P.; Roncali, J. Org. Lett. 2002, 4, 607. (d) Evans, S. A., Jr.; Goldsmith, B.; Merrill, R. L.; Williams, R. E. J. Org. Chem. 1977, 42, 438. (15) Selected examples of thiomorpholine synthesis: (a) Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel, D.; García-Valverde, M. Tetrahedron Lett. 2002, 43, 8591. (b) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.; Gallagher, T. Org. Lett. 2003, 5, 811. (c) Bera, S.; Panda, G. ACS Comb. Sci. 2012, 14, 1. (d) Vo, C.-V. T.; Mikutis, G.; Bode, J. W. Angew. Chem., Int. Ed. 2013, 52, 1705. (e) Luescher, M. U.; Bode, J. W. Angew. Chem., Int. Ed. 2015, 54, 10884. (f) Samzadeh-Kermani, A. Synlett 2014, 25, 1839. (16) (a) Guérinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808. (b) Guérinot, A.; Serra-Muns, A.; Bensoussan, C.; Reymond, S.; Cossy, J. Tetrahedron 2011, 67, 5024. (c) Cornil, J.; Guérinot, A.; Reymond, S.; Cossy, J. J. Org. Chem. 2013, 78, 10273. (d) Cornil, J.; Gonnard, L.; Guérinot, A.; Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2014, 2014, 4958. (e) Cornil, J.; Gonnard, L.; Bensoussan, C.; Serra-Muns, A.; Gnamm, C.; Commandeur, C.; Commandeur, M.; Reymond, S.; Guérinot, A.; Cossy, J. Acc. Chem. Res. 2015, 48, 761. (17) For selected reviews on alcohol proelectrophiles, see: (a) Ayers, B. J.; Chan, P. W. H. Synlett 2015, 26, 1305. (b) Muzart, J. Tetrahedron 2008, 64, 5815. (c) Bandini, M.; Tragni, M. Org. Biomol. Chem. 2009, 7, 1501. (d) Muzart, J. Eur. J. Org. Chem. 2007, 2007, 3077. (e) Tamaru, Y. Eur. J. Org. Chem. 2005, 2005, 2647. (f) Kabalka, G. W.; Yao, M.-L. Curr. Org. Synth. 2008, 5, 28. (18) Selected examples of iron-catalyzed alcohol activation: (a) Trillo, P.; Baeza, A.; Nájera, C. Eur. J. Org. Chem. 2012, 2012, 2929. (b) Sharma, G. V. M; Kumar, K. R.; Sreenivas, P.; Krishna, P. R.; Chorghade, M. S. Tetrahedron: Asymmetry 2002, 13, 687. (c) Zhan, S.P.; Yu, J.-L.; Liu, H.-J.; Cui, Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-L. J. Org. Chem. 2006, 71, 8298. (d) Han, J.; Cui, Z.; Wang, J.; Liu, Z. Synth. Commun. 2010, 40, 2042. (19) See the Supporting Information for details. (20) When the cyclization of 2a into 3a was performed with 5 mol % of HCl (2 M in Et2O) at 50 °C for 7 h, a low conversion of 10% was obtained and no diastereoselectivity was observed for 3a, thus underlining the importance of the iron catalyst. (21) Because of this side reaction, 5a could not be isolated cleanly. (22) The position of the alcohol and the double bond was inverted because of synthetic issues and had no influence on the outcome of the cyclization. (23) A similar improvement of the dr through reaction time was observed for the iron-mediated synthesis of functionalized tetrahydropyrans: Bosset, C.; Angibaud, P.; Stanfield, I.; Meerpoel, L.; Berthelot, D.; Guérinot, A.; Cossy, J. J. Org. Chem. 2015, 80, 12509. (24) Fan, X.; Cui, X.-M.; Guan, Y.-H.; Fu, L.-A.; Lv, H.; Guo, K.; Zhu, H.-B. Eur. J. Org. Chem. 2014, 2014, 498. (25) Cornil, J.; Echeverria, P.-E.; Phansavath, P.; RatovelomananaVidal, V.; Guérinot, A.; Cossy, J. Org. Lett. 2015, 17, 948. (26) Gao, X.; Pan, X.; Gao, J.; Huang, H.; Yuan, G.; Li, Y. Chem. Commun. 2015, 51, 210. (27) Baliah, V.; Shanmuganathan, Sp. J. Org. Chem. 1958, 23, 1233. (28) Pedersen, A. O.; Schroll, G.; Lawesson, S.-O. Tetrahedron 1970, 26, 4449. (29) Yang, L.; Deng, G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9, 1387. (30) Hari, D. P.; Hering, T.; König, B. Org. Lett. 2012, 14, 5334. (31) Andersen, K. K.; Chumpradit, S.; McIntyre, D. J. J. Org. Chem. 1988, 53, 4667. (32) Yao, W.; Liao, M.; Zhang, X.; Xu, H.; Wang, J. Eur. J. Org. Chem. 2003, 2003, 1784. (33) Lamb, B. M.; Barbas, C. F., III. Chem. Commun. 2015, 51, 3196.

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Iron-Catalyzed Synthesis of Sulfur-Containing Heterocycles - The

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