Stereocontrolled Synthesis of 3-Sulfonyl Chroman ... - ACS Publications

May 23, 2018 - Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. ‡. Department of Medical Research...
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Stereocontrolled Synthesis of 3‑Sulfonyl Chroman-4-ols Meng-Yang Chang*,†,‡ and Yu-Lin Tsai† †

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

‡

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ABSTRACT: The stereocontrolled reduction of 3-sulfonyl chromen-4-ones by two synthetic methods, NaBH4/LiCl and Pd/C/ H2, provides two kinds of 3-sulfonyl chroman-4-ols with three contiguous chiral centers under different reaction conditions. The use of various reaction conditions is investigated for efficient transformation. 2-Substituted benzopyran-4-ones, e.g., chromones and flavones, represent a key class of naturally occurring oxygen-containing heterocyclic compounds that are responsible for the flavors in fruits, seeds, and organisms.1 These natural components possess various biological activities including those with antitumor, antibacterial, and antioxidant properties.2 There are numerous synthetic reports on the preparation of chromonoid and flavonoid core structures along with their related derivatives.3 Among these synthetic applications toward the benzopyan-containing molecules, stereoselective reduction reactions of chromones and flavones or chroman-4-ones and flavan-4-ones to chroman-4-ols and flavan-4-ols have seen a growing interest by different routes, including hydrogenation over catalysts, e.g., palladium, platinum, and their complexes, catalytic transfer hydrogenation, 1,2- or 1,4-addition by boroncontaining hydrides and complex aluminum-based hydrides, and some special routes.4 Additionally, the core skeletons of chroman-4-ols and flavan-4-ols have been found in many natural products, such as luteoforol, apiforol, and abacopterins A−D.5 Recently, other significant efforts were also demonstrated to provide different synthetic pathways (Scheme 1) involving (1) a Co(II) complex-catalyzed tandem 1,4/1,2-reduction of flavones to flavan-4-ols in the presence of NaBH4,6a (2) a facile and efficient conversion of 2-polyfluoroalkyl chromones to chroman-4-ols via NaBH4-mediated direct domino 1,4/1,2reduction,6b (3) various yeast strain-assisted chemoenzymatic transformations from flavan-4-ones to flavan-4-ols,6c (4) a Ru(II)-catalyzed hydrogenation of flavones and chromones to chroman-4-ols and flavan-4-ols with several N-heterocyclic carbines (NHCs),6d and (5) a Ti(IV)−BINOL complex catalyzed by intermolecular annulation of salicylaldehydes and tertiary anamides.6e Among the existing popular preparations toward chromen-4-ols and flavan-4-ols, however, the major attention is still focused on the reduction approach with some special conditions due to the reduction of 2-substituted benzopyran-4-ones to the corresponding 2-substituted dihydro-2H-benzopyran-4-ols being more difficult than that of their © 2018 American Chemical Society

Scheme 1. Reduction Route toward 2-Substituted Dihydro2H-benzopyran-4-ols

dihydro-2H-benzopyran-4-ones derivatives.6b In fact, to the best of our knowledge, so far, no sulfonyl-conjugated substituent on the core structure has been reported for the family of 2-substituted dihydro-2H-benzopyran-4-ols, and little data are available on the synthesis of sulfonyl-containing benzopyran-4-ones.7 Owing to specific chemoselectivity, multifunctionalized properties and diversified bioactivity, the installation of a sulfonyl moiety to a key core skeleton has long held a respected position in synthetic chemistry, material science, and pharmaceutical fields. As a result of recent findings, new methods to investigate their preparation are needed. In an ongoing effort to emphasize the synthesis of sulfonyl skeletons,8 herein, we present a facile and efficient synthesis of 3-sulfonyl chromen-4-ols with three contiguous chiral centers (Scheme 2). According to our preliminary report,8a the starting material, 3-sulfonyl chromen-4-ones 3, was afforded from a Cu(OAc)2-promoted one-pot (4+2) annulation of sulfonylacetylenes 1 with salicyclic acids 2 in the presence of BOP and DMAP in MeNO2 at reflux in moderate to good yields. Received: April 25, 2018 Published: May 23, 2018 6798

DOI: 10.1021/acs.joc.8b01043 J. Org. Chem. 2018, 83, 6798−6804

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The Journal of Organic Chemistry

temperature-dependent with higher yields obtained at 0 °C. Elongating the time (1 → 3 h), the yield of 4a was maintained (89%, entry 8). Next, the solvent system was examined; a cosolvent of MeOH and THF (v/v = 1/1) could increase the yield to 91% (entry 9). Changing the reactant from NaBH4 to NaCNBH3, a lower yield (82%) of 4a was observed (entry 10). From these results, we found that the formation of 5a could be controlled selectively by the reaction temperature. Subsequently, two aluminum-containing reductants were studied, LiAlH4 and DIBALH. However, neither of them obtained higher yields of 4a than boron-containing reductants (entries 11−12). Among the complex mixture, 4a was produced at only 30% and 40% yields, respectively. From these observations, we concluded that entry 9 provided optimal conditions for a onepot domino 1,4-/1,2-reduction of 3-sulfonyl chromen-4-ones 3. Generally, we found that the addition of LiCl (2.1 equiv), lower temperature (0 °C), and co-solvent (MeOH and THF) could improve the ratio of 4a and 5a efficiently under NaBH4mediated reduction conditions. The stereochemical structures of 4a and 5a were determined by single-crystal X-ray crystallography.9 On the basis of our experimental results, a plausible mechanism for the formation of 4a and 5a is illustrated in Scheme 3. Initially, a borohydride anion (BH4−) chelates with

Scheme 2. Our Route of 3-Sulfonyl Chromen-4-ols

On the basis of previous reports,6a,b the initial study commenced with the treatment of the model substrate 3a (Ar = Ph, R = Tol, R’ = Me, 1.0 mmol) with a 1.1 equiv of NaBH4 in MeOH at 25 °C for 1 h (Table 1, entry 1). However, the reduction conditions provided 4a at an 80% yield along with a 13% yield of 5a. In comparison with works of both Chauhan6a and Sosnovskikh,6b the substrate 3a was converted easily into 4a and 5a during a sequential 1,4- and 1,2-reduction process. A possible reason is that the 3-sulfonyl substituent having an additional electron-withdrawing factor could enhance the electronic effect of the 2-carbon such that the hydride attacks this position easily in the absence of catalysts. Sosnovskikh et al. also demonstrated that polyfluoroalkyl groups with an electron-withdrawing effect could activate the 2-carbon position to allow the domino reduction to proceed easily under catalyst-free conditions.6b The phenomenon is similar to our results. With these results in mind, the optimal reduction condition was examined next. The stoichiometric amount of NaBH4 was decreased to 1.1 equiv, and a slightly lower yield (72%) of 4a was provided (entry 2). Controlling NaBH4 as the reactant, we surveyed the effect of the additives on the reduction. By the addition of LiCl, 2.1 equiv of LiCl provided a better yield of 4a than 1.1 equiv of LiCl (entries 3−4). We believe that the in situ-formed LiBH4 (from the combination of NaBH4 and LiCl) was a stronger reactant than NaBH4, such that it could enhance the reactivity and increase the yield of 4a. Changing the additives to KCl and CeCl3 (entries 5−6), the isolated yields of 4a (75% and 68%) were lower than LiCl (85%). Furthermore, reaction temperature screening was performed (entry 7). Gratifyingly, when the reaction was treated with an ice bath, the yield of 4a was enhanced to 87%, and only trace amounts of 5a were observed. It was obvious that the reaction was highly

Scheme 3. Plausible Mechanism

Table 1. Reaction Conditionsa

yield (%)b entry

reductant (equiv)

1 2 3 4 5 6 7 8 9 10 11 12

NaBH4 (2.1) NaBH4 (1.1) NaBH4 (2.1) NaBH4 (2.1) NaBH4 (2.1) NaBH4 (2.1) NaBH4 (2.1) NaBH4 (2.1) NaBH4 (2.1) NaCNBH3 (2.1) LiAlH4 (2.1)e DIBALH (2.1)e

additive (equiv) c c

LiCl (1.1) LiCl (2.1) KCl (2.1) CeCl3 (2.1) LiCl (2.1) LiCl (2.1) LiCl (2.1) LiCl (2.1) c c

temp (°C)

solvent (mL)

time (h)

4a

5a

25 25 25 25 25 25 0 0 0 0 0 0

MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH/THF (1/1) MeOH/THF (1/1) THF THF

1 1 1 1 1 1 1 3 3 3 3 3

80 72 76 85 75 68 87 89 91 82 30 40

13 12 12 9 15 12 trace trace d d

8 8

a

The reactions were run on a 1.0 mmol scale with 3a, solvent (8 mL). bIsolated yields. cNo addition. dNo detection. eComplex mixture was isolated as major products. 6799

DOI: 10.1021/acs.joc.8b01043 J. Org. Chem. 2018, 83, 6798−6804

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The Journal of Organic Chemistry

conditions using the shaker hydrogenation apparatus, we exclusively obtained the corresponding sole isomer 5a in a good yield (95%). Encouraged by this result, we tested Pd/Ccatalyzed hydrogenation conditions, including pressure, temperature, reaction solvent, and time, as shown in Table 3.

the oxygen atom (O-1) of 3a to yield A. By an intramolecular hydride (red)-mediated 1,4-addition of A, B1 and B2 are afforded via the C(sp2)-H bond formation. The product mixture of the inseparated B1 and B2 could be isolated for demonstration. For the relative orientation between the sulfonyl and methyl groups, B1, with a lower repulsion, exhibits a more stable trans-configuration than B2 with a stronger steric hindrance, such that B1 is preferred for generation. Following the involvement of another BH4−, the chelation of the carbonyl group leads to C1 and C2. Owing to the steric effect of the bulky sulfonyl group, the chelation should be orientated as the opposite face. After the hydride (blue) attacks the carbonyl group (C-4) on C1 and C2, both 4a and 5a are formed via an intramolecular 1,2-addition. From the possible mechanism, we found that the stoichiometric amounts of NaBH4/LiCl required at least two equivalents, such that a one-pot reaction provided a better yield (91%) of 4a under ice bath (0 °C) conditions. To study the scope and limitations of this approach, 3a−3n were reacted with a combination of NaBH4 and LiCl to afford diversified 4, as shown in Table 2. With optimal conditions

Table 3. Reaction Conditionsa

entry

pressure (atm)

temp (°C)

solvent

time (h)

yield (%)b

1 2 3 4 5 6 7

2 1 2.5 2 2 2 2

25 25 25 80 25 25 25

DME DME DME DME dioxane DME DME

20 20 20 20 20 10 30

95

a b

a

Table 2. Synthesis of 4

entry

3, Ar = , R = , R’ =

4, (%)b

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

3a, Ph, Tol, Me 3b, 4-BrC6H3, Tol, Me 3c, 4-ClC6H3, Tol, Me 3d, Ph, 4-FC6H4, Me 3e, 5-MeOC6H3, Tol, Me 3f, Ph, 3-MeC6H4, Me 3g, Ph, 4-nBuC6H4, Me 3h, Ph, 4-iPrC6H4, Me 3i, Ph, 4-tBuC6H4, Me 3j, Ph, 4-EtC6H4, Me 3k, Ph, Tol, Et 3l, 4-FC6H3, Tol, Me 3m, Ph, 4-MeOC6H4, Me 3n, Ph, Me, Me

4a, 91 4b, 86 4c, 85 4d, 79 4e, 82 4f, 84 4g, 86 4h, 83 4i, 85 4j, 84 4k, 86 4l, 80 4m, 84 4n, 86

c

90 92 81 84 94

The reactions were run on a 1.0 mmol scale with 3a, solvent (8 mL). Isolated yields. cNo detection.

When we submitted 3a to the hydrogenation process at 1 atm, however, only the starting material 3a was recovered, and no desired 5a was obtained (entry 2). By increasing the pressure (2 → 2.5 atm), the yield of 5a was decreased slightly (90%, entry 3). A higher temperature (80 °C) was tested, but the yield was maintained (92%, entry 4). Then, after the solvent was changed from DME to dioxane, we found that cyclic ether did not improve the yield (81%, entry 5). Furthermore, by diminishing (10 h) and elongating (30 h) the reaction time, the results showed that 20 h provided better yields (entries 6−7). In comparison with the above hydrogenation conditions, we envisioned that the hydrogenation pressure was a key factor for the formation of 5a. With the optimal conditions in hand (Table 3, entry 4), one-pot hydrogenation of 3a−3c and 3f− 3m was studied. In Table 4, entries 1−12, efficient formation of 5a−5c and 5f−5m showed that the substituents (Ar, R, and R’) did not affect the yield (80%−95%). In particular, when 3b was applied under the conditions listed in Table 3, entry 4 (80 °C,

a

Reactions were run on a 1.0 mmol scale with 3, NaBH4 (80 mg, 2.1 equiv), LiCl (2.1 equiv), MeOH/THF (8 mL, v/v = 1/1), 3 h, and 0 °C. bIsolated yields.

Table 4. Synthesis of 5a

established (Table 1, entry 9) and a plausible mechanism proposed (Scheme 3), we found that this route allowed for a direct one-pot reduction under mild conditions in moderate to good yields (79−91%). Among entries 1−14, efficient formations of 4a−4n showed that the substituents (Ar, R, and R’) did not affect the yield. For the electronic nature of the aryl substituents (Ar) of 3, not only electron-neutral but electron-withdrawing and electron-donating groups were appropriate. For the sulfonyl substituents (R) of 3, both aliphatic and aromatic groups were well-tolerated. However, for the R’ substituents of 3, only aliphatic groups (Me and Et) could be well-applied. On the other hand, attempts to afford skeleton 5 as the major product were examined next. On the basis of the three contiguous cis-configured stereocenters, we commenced our study with the hydrogenation of 3a. Fortunately, when we applied the Pd/C (10%) catalyst for the hydrogenation of 3a in DME at 25 °C for 20 h under 2 atm

entry

3, Ar = , R = , R’ =

5, (%)b

1 2 3 4 5 6 7 8 9 10 11 12

3a, Ph, Tol, Me 3b, 4-BrC6H3, Tol, Me 3c, 4-ClC6H3, Tol, Me 3e, 5-MeOC6H3, Tol, Me 3f, Ph, 3-MeC6H4, Me 3g, Ph, 4-nBuC6H4, Me 3h, Ph, 4-iPrC6H4, Me 3i, Ph, 4-tBuC6H4, Me 3j, Ph, 4-EtC6H4, Me 3k, Ph, Tol, Et 3l, 4-FC6H3, Tol, Me 3m, Ph, 4-MeOC6H4, Me

5a, 95 5b, 83 5c, 83 5e, 84 5f, 90 5g, 86 5h, 90 5i, 87 5j, 82 5k, 84 5l, 80 5m, 85

a

Reactions were run on a 1.0 mmol scale with 3, Pd/C (10%, 30 mg), H2 (2 atm), DME (8 mL), 20 h, and 25 °C. bIsolated yields. 6800

DOI: 10.1021/acs.joc.8b01043 J. Org. Chem. 2018, 83, 6798−6804

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The Journal of Organic Chemistry

136.2, 130.3, 129.9 (2×), 129.5, 128.6 (2×), 121.9, 121.0, 116.7, 67.9, 67.5, 63.9, 21.5, 20.1. Single-crystal X-ray diagram: The crystal of compound 4a was grown by slow diffusion of EtOAc into a solution of compound 4a in CH2Cl2 to yield colorless prisms. The compound crystallized in the monoclinic crystal system, space group P 21/c, a = 9.4156(7) Å, b = 16.2735(13) Å, c = 10.0456(8) Å, V = 1515.5(2) Å3, Z = 4, dcalcd= 1.395 g/cm3, F(000) = 672, 2θ range of 2.197−26.505°, and R indices (all data) R1 = 0.0411 and wR2 = 0.0852. 6-Bromo-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (4b). Yield = 86% (341 mg). Colorless solid. mp = 154−155 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18BrO4S, 397.0109; found, 397.0110. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 2.8 Hz, 1H), 7.27−7.24 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.88−4.85 (m, 1H), 4.82 (d, J = 3.2 Hz, 1H), 3.38 (dd, J = 3.2, 9.2 Hz, 1H), 2.46 (s, 3H), 2.30 (br, s, 1H), 1.62 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 152.3, 145.5, 135.9, 133.1, 131.9, 129.9 (2×), 128.6 (2×), 123.8, 118.6, 112.9, 67.9, 67.4, 63.5, 21.7, 20.0. 6-Chloro-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (4c). Yield = 85% (299 mg). Colorless solid. mp = 144−145 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18ClO4S, 353.0614; found, 353.0612. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 2.8 Hz, 1H), 7.13 (dd, J = 2.4, 8.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.90−4.86 (m, 1H), 4.83 (br s, 1H), 3.38 (dd, J = 3.2, 9.2 Hz, 1H), 3.37 (br, s, 1H), 2.47 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.8, 145.6, 136.0, 130.3, 130.1 (2×), 128.9, 128.6 (2×), 125.8, 123.2, 118.2, 68.0, 67.5, 63.6, 21.7, 20.1. 3-(4-Fluorobenzenesulfonyl)-2-methylchroman-4-ol (4d). Yield = 79% (254 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H16FO4S, 323.0753; found, 323.0752. 1H NMR (400 MHz, CDCl3, δ): 8.00−7.95 (m, 2H), 7.26−7.16 (m, 4H), 6.91 (dt, J = 1.6, 7.6 Hz, 1H), 6.76 (dd, J = 0.4, 8.0 Hz, 1H), 4.90−4.83 (m, 2H), 3.44 (dd, J = 3.2, 9.6 Hz, 1H), 3.09 (br, d, J = 4.4 Hz, 1H), 1.65 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 166.0 (d, J = 256.2 Hz), 153.0, 135.1, 131.8 (d, J = 9.8 Hz, 2×), 130.5, 129.2, 121.7, 121.2, 116.8, 116.5 (d, J = 22.7 Hz, 2×), 68.2, 67.6, 63.8, 20.1. 7-Methoxy-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (4e). Yield = 82% (285 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O5S, 349.1110; found, 349.1112. 1H NMR (400 MHz, CDCl3, δ): 7.83 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 2.4, 8.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 4.87−4.83 (m, 1H), 4.80 (br, s, 1H), 3.73 (s, 3H), 3.37 (dd, J = 3.2, 9.6 Hz, 1H), 3.09 (br, s, 1H), 2.46 (s, 3H), 1.64 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 161.3, 154.4, 145.2, 136.3, 130.3, 129.9 (2×), 128.6 (2×), 114.4, 108.4, 100.9, 68.1, 67.5, 63.6, 55.3, 21.6, 20.1. 2-Methyl-3-(toluene-3-sulfonyl)chroman-4-ol (4f). Yield = 84% (267 mg). Colorless solid. mp = 128−129 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O4S, 319.1004; found, 319.1002. 1H NMR (400 MHz, CDCl3, δ): 7.77−7.74 (m, 2H), 7.50−7.44 (m, 2H), 7.22−7.18 (m, 2H), 6.91 (dt, J = 1.2, 7.6 Hz, 1H), 6.79 (dd, J = 1.2, 7.6 Hz, 1H), 4.93−4.86 (m, 2H), 4.88 (br, s, 1H), 3.44 (dd, J = 2.8, 9.2 Hz, 1H), 2.45 (s, 3H), 1.65 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 153.3, 139.7, 139.1, 135.0, 130.4, 129.5, 129.1, 128.7, 125.6, 121.8, 121.0, 116.7, 67.8, 67.5, 63.9, 21.4, 20.1. 3-(4-n-Butylbenzenesulfonyl)-2-methylchroman-4-ol (4g). Yield = 86% (310 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C20H25O4S, 361.1474; found, 361.1474. 1H NMR (400 MHz, CDCl3, δ): 7.84 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.21− 7.16 (m, 2H), 6.90 (dt, J = 1.2, 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.92−4.85 (m, 2H), 3.41 (dd, J = 2.8, 9.6 Hz, 1H), 3.30 (br, s, 1H), 2.71 (t, J = 7.6 Hz, 2H), 1.67−1.59 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.43−1.32 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 153.2, 150.2, 136.3, 130.3, 129.4, 129.2 (2×), 128.6 (2×), 124.9, 121.0, 116.7, 67.9, 67.5, 63.9, 35.6, 33.0, 22.2, 20.1, 13.8.

20 h), only 80% of debromo product 5a was produced, and no isolation of 5b was observed. On the basis of the results, a plausible mechanism for the formation of 5a is illustrated in Scheme 4. By in situ Scheme 4. Plausible Mechanism

coordination of the six-membered ring, palladium chelates with the carbonyl and sulfonyl group of 3a to afford I.10 Sequentially, a double syn-addition of the enone moiety on I with hydrogen (2 equiv) generates 5a under 2 atm conditions. In summary, we have developed two facile routes for the stereocontrolled reduction of 3-sulfonyl chromen-4-ones 3 under NaBH4/LiCl and Pd/C/H2 reaction conditions. Two efficient cascade 1,4/1,2-reduction processes provide two kinds of 3-sulfonyl chroman-4-ols 4 and 5 with three contiguous chiral centers based on cis-trans (for 4) and cis-cis (for 5) conformations. Related plausible mechanisms have been proposed. The structures of the key products were confirmed by X-ray crystallography. The uses of various reaction conditions were investigated for efficient transformation. Further investigations regarding the synthetic application of sulfonyl chroman-4-ols will be conducted and published in due course.

■

EXPERIMENTAL SECTION

General Methods. All reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Hydrogenation reactions were proceeded by the use of a nonreactant borosilicate glass vessel and the Parr shaker-type hydrogenators. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm), and the coupling constants (J) are given in Hertz. High-resolution mass spectra (HRMS) were measured with a mass spectrometer (Finnigan/Thermo Quest MAT 95XL). X-ray crystal structures were obtained with an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were carried out with a Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid Analyzer, or Elementar Vario EL III instrument. General Synthetic Route for the Synthesis of Skeleton 4. NaBH4 (80 mg, 2.1 mmol) was added to a solution of 3 (1.0 mmol) and LiCl (90 mg, 2.1 mmol) in a co-solvent of MeOH and THF (8 mL, v/v = 1/1) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was warmed to rt, and the solvent was concentrated. The residue was diluted with water (10 mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford the crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1−4/1) afforded 4. 2-Methyl-3-(toluene-4-sulfonyl)chroman-4-ol (4a). Yield = 91% (289 mg). Colorless solid. mp = 155−156 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O4S, 319.1004; found, 319.1002. 1H NMR (400 MHz, CDCl3, δ): 7.84 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.21−7.18 (m, 2H), 6.89 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.89−4.85 (m, 2H), 3.40 (dd, J = 2.8, 9.6 Hz, 1H), 3.25 (br, s, 1H), 2.46 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 153.2, 145.3, 6801

DOI: 10.1021/acs.joc.8b01043 J. Org. Chem. 2018, 83, 6798−6804

Note

The Journal of Organic Chemistry 3-(4-Isopropylbenzenesulfonyl)-2-methylchroman-4-ol (4h). Yield = 83% (287 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H23O4S, 347.1317; found, 347.1318. 1H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.21 (dd, J = 1.6, 8.0 Hz, 1H), 7.17 (dt, J = 1.6, 8.0 Hz, 1H), 6.90 (dt, J = 1.2, 7.6 Hz, 1H), 6.76 (dd, J = 0.8, 8.4 Hz, 1H), 4.91−4.88 (m, 2H), 3.42 (dd, J = 2.8, 9.2 Hz, 1H), 3.32 (d, J = 3.6 Hz, 1H), 3.02− 2.97 (m, 1H), 1.65 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3, δ): 155.9, 153.2, 136.4, 130.3, 129.4, 128.7 (2×), 127.3 (2×), 121.8, 121.0, 116.7, 67.8, 67.6, 63.9, 34.2, 23.54, 23.53, 20.1. 3-(4-t-Butylbenzenesulfonyl)-2-methylchroman-4-ol (4i). Yield = 85% (306 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C20H25O4S, 361.1474; found, 361.1474. 1H NMR (400 MHz, CDCl3, δ): 7.86 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.23− 7.16 (m, 2H), 6.90 (dt, J = 0.4, 7.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.94−4.87 (m, 2H), 3.42 (dd, J = 2.8, 9.6 Hz, 1H), 3.31 (br, s, 1H), 1.66 (d, J = 6.0 Hz, 3H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3, δ): 158.2, 153.2, 136.0, 130.3, 129.4, 128.4 (2×), 126.3 (2×), 121.8, 121.0, 116.7, 67.8, 67.6, 63.9, 35.2, 31.0 (3×), 20.2. 3-(4-Ethylbenzenesulfonyl)-2-methylchroman-4-ol (4j). Yield = 84% (279 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O4S, 333.1161; found, 333.1162. 1H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.21− 7.16 (m, 2H), 6.89 (dt, J = 0.8, 7.6 Hz, 1H), 6.78 (dd, J = 0.8, 8.0 Hz, 1H), 4.92−4.84 (m, 2H), 3.41 (dd, J = 2.8, 9.6 Hz, 1H), 3.29 (br, s, 1H), 2.75 (q, J = 7.6 Hz, 2H), 1.64 (d, J = 6.4 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 153.2, 151.3, 136.3, 130.3, 129.4, 128.71 (2×), 128.67 (2×), 121.8, 121.0, 116.7, 67.8, 67.5, 63.9, 28.9, 20.1, 15.0. 2-Ethyl-3-(toluene-4-sulfonyl)chroman-4-ol (4k). Yield = 86% (286 mg). Colorless solid. mp = 127−128 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O4S, 333.1161; found, 333.1162. 1H NMR (400 MHz, CDCl3, δ): 7.80 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22−7.15 (m, 2H), 6.89 (dt, J = 0.8, 7.6 Hz, 1H), 6.74 (dd, J = 0.8, 8.0 Hz, 1H), 4.88 (br, t, J = 3.6 Hz, 1H), 4.75 (dt, J = 3.6, 8.0 Hz, 1H), 3.51 (dd, J = 2.8, 8.4 Hz, 1H), 3.36 (d, J = 4.8 Hz, 1H), 2.45 (s, 3H), 2.18−2.08 (m, 1H), 1.91−1.80 (m, 1H), 1.04 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 153.1, 145.2, 136.0, 130.2, 129.8 (2×), 128.9, 128.6 (2×), 121.9, 120.9, 116.7, 72.1, 65.8, 64.0, 26.4, 21.6, 9.1. 6-Fluoro-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (4l). Yield = 80% (269 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18FO4S, 337.0910; found, 337.0910. 1H NMR (400 MHz, CDCl3, δ): 7.82−7.79 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.95− 6.86 (m, 2H), 6.70 (dd, J = 4.8, 8.8 Hz, 1H), 4.89−4.82 (m, 2H), 3.45−3.39 (m, 2H), 2.46 (s, 3H), 1.61 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 156.9 (d, J = 238.8 Hz), 149.2, 145.5, 136.0, 129.9 (2×), 128.6 (2×), 122.7 (d, J = 7.6 Hz), 117.9 (d, J = 8.3 Hz), 117.2 (d, J = 23.5 Hz), 115.1 (d, J = 22.7 Hz), 67.9, 67.6, 63.7, 21.7, 20.1. 3-(4-Methoxybenzenesulfonyl)-2-methylchroman-4-ol (4m). Yield = 84% (281 mg). Colorless solid. mp = 139−140 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O5S, 335.0953; found, 335.0952. 1H NMR (400 MHz, CDCl3, δ): 7.87 (d, J = 8.8 Hz, 2H), 7.21−7.16 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.89 (dt, J = 1.2, 7.6 Hz, 1H), 6.77 (dd, J = 0.8, 8.4 Hz, 1H), 4.89−4.82 (m, 2H), 3.89 (s, 3H), 3.38 (dd, J = 2.8, 9.2 Hz, 1H), 3.30 (br, s, 1H), 1.65 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 164.0, 153.2, 130.9 (2×), 130.4, 130.3, 129.4, 121.9, 121.0, 116.7, 114.4 (2×), 68.0, 67.5, 63.9, 55.7, 20.1. 3-Methanesulfonyl-2-methylchroman-4-ol (4n). Yield = 86% (208 mg). Colorless solid. mp = 182−183 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C11H15O4S, 243.0691; found, 243.0692. 1H NMR (400 MHz, CDCl3, δ): 7.49 (dd, J = 1.2, 8.0 Hz, 1H), 7.25 (dt, J = 1.6, 8.0 Hz, 1H), 7.04 (dt, J = 1.2, 8.4 Hz, 1H), 6.85 (dd, J = 1.2, 8.4 Hz, 1H), 5.32 (t, J = 6.4 Hz, 1H), 4.87−4.81 (m, 1H), 4.02 (d, J = 6.4 Hz, 1H), 3.63−3.61 (m, 1H), 2.94 (d, J = 0.4 Hz, 3H), 1.75 (d, J = 6.4 Hz, 3H).

C NMR (100 MHz, CDCl3, δ): 152.3, 130.2, 128.5, 122.4, 121.9, 116.9, 70.4, 65.2, 64.5, 43.4, 18.0. 2-Methyl-3-(toluene-4-sulfonyl)chroman-4-one (B1/B2). NaBH4 (42 mg, 1.1 mmol) was added to a solution of 3a (314 mg, 1.0 mmol) and LiCl (47 mg, 1.1 mmol) in a co-solvent of MeOH and THF (8 mL, v/v = 1/1) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was warmed to rt, and the solvent was concentrated. The residue was diluted with water (10 mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford the crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1−4/1) afforded a mixture of B1 and B2 (two isomers, ratio >10:1). Yield = 82% (259 mg). Colorless solid. mp = 59−61 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H17O4S, 317.0848; found, 317.0846. For the major trans-isomer: 1H NMR (400 MHz, CDCl3, δ): 7.76 (ddd, J = 0.4, 1.6, 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.43 (ddd, J = 1.6, 7.2, 8.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.94 (dt, J = 1.2, 8.4 Hz, 1H), 6.79 (dd, J = 0.4, 8.4 Hz, 1H), 5.61 (dq, J = 1.2, 6.8 Hz, 1H), 3.82 (d, J = 1.6 Hz, 1H), 2.35 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 182.6, 158.2, 145.5, 137.2, 134.3, 129.4 (2×), 129.2 (2×), 126.8, 121.5, 119.8, 118.5, 73.6, 71.9, 21.6, 18.4. General Synthetic Route for the Synthesis of Skeleton 5. Pd/ C (10%, 30 mg) was added to a solution of 3 (1.0 mmol) in DME (8 mL) at 25 °C in a nonreactant borosilicate glass vessel under the shaker hydrogenation apparatus. Hydrogen gas was installed to the reaction mixture at 25 °C. The pressure was increased to 2 atm. The reaction mixture was stirred at 25 °C for 20 h. The pressure was decreased to 1 atm, and the solvent was concentrated. The residue was diluted with water (10 mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford the crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1−4/ 1) afforded 5. 2-Methyl-3-(toluene-4-sulfonyl)chroman-4-ol (5a). Yield = 95% (302 mg). Colorless solid. mp = 137−138 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O4S, 319.1004; found, 319.1002. 1H NMR (400 MHz, CDCl3, δ): 7.83 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.29−7.27 (m, 1H), 7.20−7.16 (m, 1H), 6.95−6.91 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 3.2 Hz, 1H), 5.00−4.94 (m, 1H), 3.67 (t, J = 3.2 Hz, 1H), 3.61 (br, s, 1H), 2.46 (s, 3H), 1.78 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.3, 145.7, 135.5, 130.2, 130.1 (2×), 129.9, 128.3 (2×), 121.5, 121.3, 117.5, 68.6, 64.8, 63.1, 21.6, 17.2. Singlecrystal X-ray diagram: The crystal of compound 5a was grown by slow diffusion of EtOAc into a solution of compound 5a in CH2Cl2 to yield colorless prisms. The compound crystallized in the monoclinic crystal system, space group P 21/c, a = 15.4645(14) Å, b = 18.3380(16) Å, c = 5.4053(4) Å, V = 1530.4(2) Å3, Z = 4, dcalcd= 1.382 g/cm3, F(000) = 672, 2θ range 1.319−26.472°, and R indices (all data) R1 = 0.0716 and wR2 = 0.1573. 6-Bromo-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (5b). Yield = 83% (329 mg). Colorless solid. mp = 150−151 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18BrO4S, 397.0109; found, 397.0110. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 2.4, 8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.97−4.92 (m, 2H), 4.23 (br, s, 1H), 3.63 (t, J = 3.6 Hz, 1H), 2.46 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 150.6, 145.9, 135.4, 133.0, 132.4, 130.1 (2×), 128.4 (2×), 123.5, 119.3, 113.3, 69.1, 64.4, 63.0, 21.7, 17.2. 6-Chloro-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (5c). Yield = 83% (292 mg). Colorless solid. mp = 139−140 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18ClO4S, 353.0614; found, 353.0611. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 2.8, 8.4 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.97−4.93 (m, 2H), 4.20 (br, s, 1H), 3.63 (t, J = 3.6 Hz, 1H), 2.46 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H). 13C NMR (100 13

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DOI: 10.1021/acs.joc.8b01043 J. Org. Chem. 2018, 83, 6798−6804

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The Journal of Organic Chemistry MHz, CDCl3, δ): 150.0, 145.9, 135.4, 130.1 (3×), 129.4, 128.4 (2×), 126.1, 123.0, 118.8, 69.1, 64.4, 63.0, 21.7, 17.2. 7-Methoxy-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (5e). Yield = 84% (292 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O5S, 349.1110; found, 349.1112. 1H NMR (400 MHz, CDCl3, δ): 7.82 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (d, J = 2.4 Hz, 1H), 4.99−4.93 (m, 2H), 4.07 (br, s, 1H), 3.73 (s, 3H), 3.64 (t, J = 3.2 Hz, 1H), 2.46 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 161.2, 152.3, 145.6, 135.5, 130.7, 130.1 (2×), 128.3 (2×), 114.0, 108.5, 101.7, 68.7, 64.8, 62.7, 55.3, 21.6, 17.3. 2-Methyl-3-(toluene-3-sulfonyl)chroman-4-ol (5f). Yield = 90% (286 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O4S, 319.1004; found, 319.1003. 1H NMR (400 MHz, CDCl3, δ): 7.78−7.74 (m, 1H), 7.73 (s, 1H), 7.50−7.49 (m, 2H), 7.30 (dd, J = 1.2, 8.4 Hz, 1H), 7.18 (dt, J = 1.6, 8.8 Hz, 1H), 6.93 (dt, J = 1.6, 8.4 Hz, 1H), 6.75 (dd, J = 1.2, 8.4 Hz, 1H), 5.03−4.99 (m, 1H), 4.98−4.95 (m, 1H), 4.17 (br, s, 1H), 3.70 (s, J = 7.6 Hz, 1H), 2.45 (s, 3H), 1.79 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.3, 140.0, 138.4, 135.2, 130.3, 129.9, 129.3, 128.5, 125.5, 121.5, 121.3, 117.5, 68.6, 64.7, 63.1, 21.3, 17.3. 3-(4-n-Butylbenzenesulfonyl)-2-methylchroman-4-ol (5g). Yield = 86% (310 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C20H25O4S, 361.1474; found, 361.1475. 1H NMR (400 MHz, CDCl3, δ): 7.84 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (dd, J = 1.6, 7.6 Hz, 1H), 7.17 (dt, J = 1.6, 7.6 Hz, 1H), 6.93 (dt, J = 1.2, 7.6 Hz, 1H), 6.74 (dd, J = 0.8, 8.4 Hz, 1H), 5.03 (s, 1H), 5.01−4.94 (m, 1H), 4.21 (d, J = 2.8 Hz, 1H), 3.69 (t, J = 4.0 Hz, 1H), 2.70 (t, J = 7.6 Hz, 2H), 1.79 (d, J = 6.8 Hz, 3H), 1.69−1.58 (m, 2H), 1.41−1.34 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.3, 150.5, 135.6, 130.2, 129.9, 129.5 (2×), 128.4 (2×), 121.5, 121.3, 117.4, 68.7, 64.7, 63.1, 35.6, 33.0, 22.2, 17.3, 13.8. 3-(4-Isopropylbenzenesulfonyl)-2-methylchroman-4-ol (5h). Yield = 90% (311 mg). Colorless solid. mp = 125−126 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H23O4S, 347.1317; found, 347.1318. 1H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 1.6, 8.0 Hz, 1H), 7.16 (dt, J = 1.6, 8.0 Hz, 1H), 6.93 (dt, J = 1.2, 7.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 5.04 (s, 1H), 5.01− 4.94 (m, 1H), 4.23 (d, J = 2.4 Hz, 1H), 3.68 (t, J = 3.6 Hz, 1H), 3.04− 2.97 (m, 1H), 1.80 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3, δ): 156.2, 151.3, 135.7, 130.2, 129.8, 128.5 (2×), 127.6 (2×), 121.5, 121.3, 117.4, 68.7, 64.7, 63.2, 34.3, 23.54, 23.50, 17.3. 3-(4-t-Butylbenzenesulfonyl)-2-methylchroman-4-ol (5i). Yield = 87% (313 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C20H25O4S, 361.1474; found, 361.1475. 1H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 1.6, 8.0 Hz, 1H), 7.16 (dt, J = 1.6, 8.0 Hz, 1H), 6.93 (dt, J = 1.2, 7.6 Hz, 1H), 6.71 (dd, J = 1.2, 8.0 Hz, 1H), 5.05 (s, 1H), 5.00−4.94 (m, 1H), 4.23 (s, 1H), 3.68 (t, J = 3.6 Hz, 1H), 1.80 (d, J = 6.8 Hz, 3H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3, δ): 158.6, 151.4, 135.4, 130.2, 129.8, 128.3 (2×), 126.5 (2×), 121.5, 121.3, 117.4, 68.8, 64.7, 63.2, 35.4, 31.0 (3×), 17.3. 3-(4-Ethylbenzenesulfonyl)-2-methylchroman-4-ol (5j). Yield = 82% (272 mg). Colorless solid. mp = 141−142 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O4S, 333.1161; found, 333.1162. 1H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (dd, J = 1.6, 8.0 Hz, 1H), 7.17 (dt, J = 1.2, 7.6 Hz, 1H), 6.92 (dt, J = 1.2, 7.6 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.04 (d, J = 3.2 Hz, 1H), 5.00−4.94 (m, 1H), 3.90 (br, s, 1H), 3.68 (t, J = 3.6 Hz, 1H), 2.74 (q, J = 7.6 Hz, 2H), 1.79 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.7, 151.3, 135.6, 130.1, 129.8, 128.9 (2×), 128.4 (2×), 121.5, 121.2, 117.4, 68.6, 64.7, 63.1, 28.9, 17.2, 15.0. 2-Ethyl-3-(toluene-4-sulfonyl)chroman-4-ol (5k). Yield = 84% (279 mg). Colorless solid. mp = 152−153 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H21O4S, 333.1161; found, 333.1163. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 1.6,

7.6 Hz, 1H), 7.17 (dt, J = 1.2, 7.6 Hz, 1H), 6.93 (dt, J = 1.2, 7.6 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.00 (d, J = 3.2 Hz, 1H), 4.67−4.63 (m, 1H), 4.20 (br, s, 1H), 3.73 (t, J = 3.6 Hz, 1H), 2.45 (s, 3H), 2.39−2.27 (m, 1H), 2.18−2.08 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 151.3, 145.6, 135.6, 130.1, 130.0 (2×), 129.7, 128.4 (2×), 122.0, 121.3, 117.5, 74.6, 64.7, 63.1, 23.8, 21.6, 11.3. 6-Fluoro-2-methyl-3-(toluene-4-sulfonyl)chroman-4-ol (5l). Yield = 80% (269 mg). Colorless solid. mp = 156−157 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H18FO4S, 337.0910; found, 337.0912. 1H NMR (400 MHz, CDCl3, δ): 7.80 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 2.8, 8.4 Hz, 1H), 6.86 (dt, J = 3.6, 9.2 Hz, 1H), 6.65 (dd, J = 4.4, 9.2 Hz, 1H), 4.99 (d, J = 3.6 Hz, 1H), 4.94−4.87 (m, 1H), 4.31 (br, s, 1H), 3.65 (t, J = 3.6 Hz, 1H), 2.45 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3, δ): 157.2 (d, J = 238.0 Hz), 147.4 (d, J = 2.3 Hz), 145.8, 135.4, 130.0 (2×), 128.4 (2×), 122.6 (d, J = 6.8 Hz), 118.5 (d, J = 7.6 Hz), 117.1 (d, J = 22.7 Hz), 115.4 (d, J = 22.7 Hz), 69.0, 64.5, 63.2, 21.6, 17.1. 3-(4-Methoxybenzenesulfonyl)-2-methylchroman-4-ol (5m). Yield = 85% (284 mg). Colorless gum. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H19O5S, 335.0953; found, 335.0956. 1H NMR (400 MHz, CDCl3, δ): 7.86 (d, J = 9.2 Hz, 2H), 7.28 (dd, J = 1.6, 7.6 Hz, 1H), 7.17 (dt, J = 1.6, 7.6 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 6.93 (dt, J = 1.2, 7.6 Hz, 1H), 6.73 (dd, J = 0.8, 8.4 Hz, 1H), 5.02 (d, J = 3.2 Hz, 1H), 4.99−4.93 (m, 1H), 4.50 (br, s, 1H), 3.88 (s, 3H), 3.66 (t, J = 3.6 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 164.3, 151.3, 130.6 (2×), 130.1, 129.8, 129.7, 121.5, 121.3, 117.4, 114.6 (2×), 68.7, 64.8, 63.1, 55.8, 17.3.

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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.8b01043. X-ray crystallographic analysis data for compounds 4a and 5a (CIF) Scanned photocopies of NMR spectral data for all of the compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Meng-Yang Chang: 0000-0002-1983-8570 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the Ministry of Science and Technology of the Republic of China for financial support (MOST 106-2628-M-037-001-MY3).

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REFERENCES

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