Aldol Reaction of N-tert-Butanesulfinyl Imidates under Basic

Sep 19, 2017 - Diastereoselective aldol reaction of N-tert-butanesulfinyl imidates under typical hard enolization conditions is reported. Potassium bi...
0 downloads 16 Views 664KB Size
Download PDF
Note pubs.acs.org/joc

Cite This: J. Org. Chem. 2017, 82, 11253-11261

Aldol Reaction of N-tert-Butanesulfinyl Imidates under Basic Conditions for Diastereoselective Synthesis of anti-Aldols Chun-Tian Li,†,‡ Hui Liu,† Yan-Jun Xu,† and Chong-Dao Lu*,† †

Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China ‡ University of the Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: Diastereoselective aldol reaction of N-tert-butanesulfinyl imidates under typical hard enolization conditions is reported. Potassium bis(trimethylsilyl)amide (KHMDS) effectively promotes the aldol reaction of α-aryl- and α-alkyl-substituted imidates, providing anti-aldol adducts in high yields with good to excellent diastereoselectivities. In the case of α-aryl imidates, high conversion depends on adding trimethylsilyl chloride (TMSCl) to the reaction mixture. In the presence of a suitable Lewis acid, cyclohexanone is a good electrophile in the aldol reaction of imidates.

T

while also suppressing the reversibility of aldolization. The synthetic applications of this reaction are limited by the fact that, under soft enolization conditions, only α-aryl or α-chloro imidates are suitable substrates. The lack of α-alkyl N-tBS imidate reactivity under these conditions may be because the αproton of imidates is less acidic than that of α-aryl and α-chloro counterparts. In principle, this problem could be solved by resorting to hard enolization conditions.14 However, preliminary investigations by Poisson and co-workers have shown that, in the presence of a range of strong bases or additives, reaction of αphenyl N-tBS imidates with benzaldehyde leads to low conversion (20%), degradation, or no reaction.8 Despite these negative results, we wanted to test the possibility of aldol reaction of N-tert-butanesulfinyl imidates in the presence of strong base (Scheme 1b). We reasoned that this approach could be successful, based on our report that strong bases can initiate diastereoselective nucleophilic addition of N-tBS imidates to nitrosoarenes,12b which can be considered as an N-nitroso aldol reaction and therefore quite similar to the typical aldol reaction. Here we describe our efforts in this regard, and we show that, under typical hard enolization conditions, α-aryl- and α-alkylsubstituted imidates undergo aldol addition with aldehydes to provide anti-aldol adducts in good yields and stereoselectivities. We began our studies by deprotonating α-methyl N-tBS imidate 1a at −78 °C in the presence of sodium bis(trimethylsilyl)amide (NaHMDS), which we previously found to be the best base for alkylation9 and electrophilic αhydroxyamination12b of N-tBS imidates. Benzaldehyde was introduced into the deprotonated 1a, which caused complete

he aldol reaction is a fundamental transformation in organic synthesis for stereoselective construction of C−C bonds, giving β-hydroxy carbonyl compounds.1a,b For example, it allows efficient preparation of hydroxyl-containing natural compounds such as polyketides.1c Evans and co-workers showed in 1981 that chiral enolates of acyl oxazolidinones can successfully intercept aldehydes with exceptional pi-face selectivities.2 Since then, the use of chiral enolates3 to access enantiopure aldol adducts has been an important tool in organic synthesis. Indeed, recent years have seen tremendous progress in the use of chiral amines4 and chiral metal complexes5 as aldol catalysts to realize asymmetric nucleophilic addition of carbonyl compounds to aldehydes. It is well-known that asymmetric aldol reactions can be carried out using the well-established Evans oxazolidinones as chiral auxiliary, as well as their thio analogues derived from natural and unnatural amino acids or amino alcohols.6 Recently, asymmetric aldol reactions have also been achieved using Ntert-butylsulfinyl (N-tBS) imidates as chiral amide7 equivalents (Scheme 1a).8 Aldol reactions of N-sulfinyl imidates9−13 require titanium as the Lewis acid, which leads to formation of the reactive aza-enolate in the presence of tertiary amine, Scheme 1. Aldol Reaction of N-tert-Butanesulfinyl Imidates

Received: August 7, 2017 Published: September 19, 2017 © 2017 American Chemical Society

11253

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry

the product 3ba in 84% yield with excellent diastereoselectivity (entry 14). With these optimized conditions in hand, we examined the scope of aldol addition involving α-alkyl N-tBS imidates (Table 2). The α-methyl imidate 1a underwent aldol addition to various aryl aldehydes, including electron-rich, -poor, and -neutral aromatic aldehydes (entries 1−9) and heteroaromatic aldehydes (entries 10−12). The least efficient substrate was pnitrobenzaldehyde 2c (entry 3), which produced the adduct 3ac in 57% yield and 6:1 dr. We were able to scale up the aldol reaction of 1a and 2e to 1 g, obtaining 3ae in 79% yield with excellent diastereoselectivity (entry 5).18 The addition reaction worked for o-, m-, and p-substituted benzaldehydes, which gave the corresponding products 3ag−ai in high yields with excellent diastereoselectivities (entries 7−9). X-ray diffraction studies of 3ah crystals permitted its stereochemical assignment as (RS,2R)-2,3-anti.19 Another suitable substrate was α,β-unsaturated aldehyde 2m (entry 13), which underwent aldol addition with ent-1a to give adduct ent-3am. This adduct can be considered the equivalent of the anti-aldol in Crimmins’s formal synthesis of (+)-sorangicin A.20 Reaction of pivaldehyde gave the corresponding aldol product. When the reaction was quenched with a saturated solution of NH4Cl, the functional group of N-tBS imidate simultaneously hydrolyzed to N-acetyl tert-butanesulfinamide (or N-tBS amide, entry 14). We failed in our attempts to extend the reaction to enolizable aldehydes such as isovaleraldehyde under standard conditions; in these cases, we obtained complicated mixtures. No improvement was achieved when isovaleraldehyde was added to the reaction mixture that was generated from combination of 1a with KHMDS. Adding MgBr2 to the reaction mixture before the introduction of isovaleraldehyde led to isolable adducts, but three diastereomers were found in approximately equal molar amounts. A range of α-alkyl-substituted N-tBS imidates were investigated for their ability to add to benzaldehyde. Good yields and excellent diastereoselectivities were obtained in most cases (entries 14−22). In several cases, TMSCl was introduced to the reaction mixture to ensure high conversion (entries 17− 20). The aldol reaction of α-unsubstituted imidate 1k occurred, giving acetate aldol21 adduct 3ka in an unoptimized yield of 54% (entry 23). The β-elimination byproduct derived from 3ka was also obtained (13% yield). Next, the reaction scope of α-aryl N-tBS imidates was examined using the KHMDS/TMSCl protocol. Various β-arylsubstituted β-hydroxy-α-aryl N-tBS imidates were synthesized in high yields with excellent diastereoselectivities (Table 3, entries 1−10, 13−17). In the presence of MgBr2, aldol coupling of pivaldehyde or isovaleraldehyde with imidate 1b was feasible, giving 3bn or 3bo in moderate yields (entries 11 and 12), albeit with decreased dr in the case of isovaleraldehyde (entry 12). The proton and carbon NMR spectroscopic data and specific rotations of our anti-aldol adducts 3ba, 3bc−d, 3bi−k, 3bn, 3oa, and 3pa were in agreement with those reported by Poisson and co-workers.8 We extended the aldol reaction of N-tBS imidates to cyclohexanone by adding a suitable Lewis acid (Scheme 2). Nucleophilic addition of α-methyl and α-phenyl imidates 1a and 1b to cyclohexanone provided the corresponding adducts 5 and 6 with excellent diasteroselectivities. The configuration of 6 was assigned as (RS,2R) by X-ray crystallography.19 In summary, we have described an effective aldol reaction of N-tert-butanesulfinyl imidates under basic conditions. Using

consumption of 1a and gave the desired aldol product 3aa with moderate diastereoselectivity (∼6:1 dr; Table 1, entry 1).15 Table 1. Initial Optimization of Aldol Addition of N-tertButanesulfinyl Imidatesa

entry d

1 2d 3d 4d 5e 6e 7e 8e 9e,f 10e,g 11e,g 12d,g 13d,g e,f,h

14

base (equiv)/additive (equiv)

product, conv,b % (yield, %)c

drb

NaHMDS (1.5) LiHMDS (1.5) KHMDS (1.5) KHMDS (1.1) KHMDS (1.1) KHMDS (1.1) LiHMDS (1.1) NaHMDS (1.1) KHMDS (1.1) KHMDS (1.1) KHMDS (1.1) /BF3·Et2O (5.0) KHMDS (1.1)/ZnBr2 (3.0) KHMDS (1.1)/MgBr2· Et2O (4.0) KHMDS (1.1)/TMSCl (2.0)

3aa, 100 3aa, 100 3aa, 100 3aa, 100 (80) 3aa, 100 (93) 3ba, 75 3ba, 50 3ba, 52 3ba, 81 3ba, 91 3ba, 96

6:1:0:0 3:1:0:0 >20:1:0:0 >20:1:0:0 >20:1:0:0 25:1:20:1 >20:1 25:1 20:1 24:1 >20:1 16:1 >20:1 >20:1 21:1 >20:1 20:1 >20:1 >20:1 >20:1 16:1 >20:1 10:1

Reaction conditions: 1 (0.30 mmol), 2 (0.39 mmol), and KHMDS (0.33 mmol) in anhydrous THF (3.0 mL) under argon at −78 °C, unless otherwise noted. bIsolated yield after silica gel chromatography. cDetermined by 1H NMR spectroscopy of the crude reaction mixture; dr = major isomer:minor isomer. dReaction on 1 g scale. eThe (SS)-enantiomer was used. fThe N-tBS amide derived from hydrolysis of N-tBS imidate was obtained. gTMSCl was used to ensure high conversion. a

imidates 1e−j were prepared according to the method developed by Qin.11a General Procedure for the Preparation of 3aa−am, 3ca−da, and 3ia−ka. To a solution of 1 (0.4 mmol, 1.0 equiv) and 2 (0.52 mmol, 1.3 equiv) in 2.0 mL of THF was added KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv) at −78 °C. The resulting mixture was maintained at −78 °C for 4.5−5 h until the absence of starting material via TLC analysis and quenched with saturated NH4Cl (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford 3aa−an, 3ca, 3da, 3ka. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3phenylpropanimidate (3aa). 1a (57.4 mg, 0.30 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.66 mL, 0.33 mmol, 1.1 equiv), and benzaldehyde 2a (41.4 mg, 0.39 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3aa as 1 yellow oil: 82.9 mg, 93% yield; [α]25 D −113 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.29−7.25 (m, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.37 (t, J = 9.2 Hz, 1H), 3.84 (s, 3H), 3.61−3.53 (m, 1H), 1.29 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 176.7, 144.5, 128.7, 127.8, 127.4, 77.1, 56.6, 54.1, 47.3, 22.0, 14.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H24NO3S 298.1471, found 298.1469. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-(4-methoxyphenyl)-2-methylpropanimidate (3ab). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2b (72.2 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ab as

KHMDS base, we achieved diastereoselective synthesis of antialdols from both α-alkyl- and α-aryl-substituted N-tBS imidates under typical hard enolization conditions.

■

EXPERIMENTAL SECTION

General Experimental Details. All reactions were performed under an argon atmosphere in flame-dried glassware with magnetic stirring. Purification of the reaction products was carried out by flash column chromatography using 200−300 mesh silica gel. Visualization on TLC (analytical thin layer chromatography) was achieved by the use of UV light (254 nm) and treatment with aqueous ceric ammonium molybdate staining followed by heating. High-resolution mass spectra (HRMS) were recorded using electron spray ionization with a time-of-flight mass analyzer (ESI-TOF) or using electron spray ionization with an orbitrap mass analyzer (ESI-LTQ-Orbitrap or ESIQ-Orbitrap). Proton and carbon magnetic resonance spectra (1H NMR and 13C NMR) were recorded on a 400 or 600 MHz (1H NMR at 400 or 600 MHz and 13C NMR at 100 or 150 MHz) spectrometer with solvent resonance as the internal standard (1H NMR, CDCl3 at 7.26 ppm, C6D6 at 7.16 ppm; 13C NMR, CDCl3 at 77.16 ppm, C6D6 at 128.1 ppm). 1H NMR data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s) in Hz, and integration. Materials. THF was distilled from sodium/benzophenone. N-tertButylsulfinyl imidates of 1a−d and 1l−p were prepared by known methods from tert-butylsulfinamide according to the reported procedure from Ellman9c and De Kimpe.9a N-tert-Butylsulfinyl 11255

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry Table 3. Aldol Reaction of α-Phenyl N-tBS Imidatesa,b

entry

imidate (Ar)

aldehydes (R′)

product

yield (%)c

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

1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1b (Ph) 1l (4-MeC6H4) 1m (3-MeC6H4) 1n (2-MeC6H4) 1o (4-MeOC6H4) 1p (4-FC6H4)

2a (Ph) 2b (4-MeOC6H4) 2c (4-NO2C6H4) 2d (4-FC6H4) 2g (4-MeC6H4) 2h (3-MeC6H4) 2i (2-MeC6H4) 2j (2-furyl) 2k (2-thienyl) 2l (2-pyridyl) 2n (tBu) 2o (Me2CHCH2) 2a (Ph) 2a (Ph) 2a (Ph) 2a (Ph) 2a (Ph)

3ba 3bb 3bc 3bd 3bg 3bh 3bi 3bj 3bk 3bl 3bn 3bo 3la 3ma 3na 3oa 3pa

84 62 88 85d 85 89 85 87 83 83 62 68f 84 92 97 96 81

chromatography (petroleum/ethyl acetate = 5:1) afforded 3ad as a 1 colorless liquid: 111 mg, 88% yield; [α]25 D −105 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.4 Hz, 5.6 Hz, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.06 (d, J = 10.0 Hz, 1H), 4.35 (t, J = 10.0 Hz, 1H), 3.84 (s, 3H), 3.56−3.49 (m, 1H), 1.27 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 162.5 (d, JC−F = 244.1 Hz), 139.2 (d, JC−F = 3.2 Hz), 128.6 (d, JC−F = 8.2 Hz), 115.4 (d, JC−F = 21.3 Hz), 76.0, 57.1, 54.7, 46.8, 22.1, 14.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22FNNaO3S 338.1197, found 338.1192. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(4-chlorophenyl)-3-hydroxy-2-methylpropanimidate (3ae). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2e (74.6 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ae as a 1 colorless liquid: 112.4 mg, 85% yield; [α]25 D −120 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.35−7.29 (m, 4H), 5.12 (d, J = 10.0 Hz, 1H), 4.34 (t, J = 10.0 Hz, 1H), 3.83 (s, 3H), 3.55−3.47 (m, 1H), 1.28 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.1, 141.9, 133.6, 128.7, 128.4, 76.0, 57.1, 54.8, 46.7, 22.1, 14.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22ClNNaO3S 354.0901, found 354.0907. Methyl (2R,3S)-3-(4-Bromophenyl)-N-((R)-tert-butylsulfinyl)-3-hydroxy-2-methylpropanimidate (3af). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2f (98.2 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3af as a 1 yellow oil: 135.4 mg, 90% yield; [α]25 D −20 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.33 (t, J = 10.4 Hz, 1H), 3.83 (s, 3H), 3.54−3.47 (m, 1H), 1.28 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.1, 142.5, 131.7, 128.8, 121.8, 76.1, 57.1, 54.8, 46.7, 22.1, 14.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22BrNNaO3S 398.0396, found 398.0393. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3-(ptolyl)propanimidate (3ag). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2g (63.7 mg, 97%, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded of 3ag as a 1 yellow oil: 105.5 mg, 85% yield; [α]25 D −75 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.87 (d, J = 10.4 Hz, 1H), 4.34 (t, J = 10.0 Hz, 1H), 3.84 (s, 3H), 3.60−3.53 (m, 1H), 2.33 (s, 3H), 1.29 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7, 140.3, 137.5, 129.3, 126.9, 76.5, 57.0, 54.7, 46.7, 22.1, 21.3, 14.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H25NNaO3S 334.1447, found 334.1452. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3(m-tolyl)propanimidate (3ah). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2h (63.7 mg, 98%, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ah as a white solid: 110.7 mg, 90% yield; mp 124.2−125.7 °C; [α]25 D −112 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.25−7.18 (m, 3H), 7.08 (d, J = 6.8 Hz, 1H), 4.91 (d, J = 10.0 Hz, 1H), 4.35 (t, J = 10.0 Hz, 1H), 3.84 (s, 3H), 3.61−3.54 (m, 1H), 2.36 (s, 3H), 1.29 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.6, 143.2, 138.2, 128.7, 128.4, 127.5, 124.1, 76.7, 57.0, 54.7, 46.5, 22.1, 21.6, 14.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H26NO3S 312.1628, found 312.1630. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3-(otolyl)propanimidate (3ai). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2i (63.7 mg, 98%, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ai as a 1 colorless oil: 103.6 mg, 83% yield; [α]25 D −55 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.27−7.23 (m, 1H), 7.17−7.10 (m, 2H), 4.84−4.77 (m, 2H), 3.85 (s, 3H), 3.74−3.67 (m, 1H), 2.40 (s, 3H), 1.29 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.4, 141.6, 135.7, 130.3, 127.5, 126.9, 126.0, 71.4, 57.0, 54.7, 46.9, 22.1, 19.8, 13.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H25NNaO3S 334.1447, found 334.1453.

a

Reaction conditions: 1 (0.30 mmol), 2 (0.60 mmol), and KHMDS (0.33 mmol) in anhydrous THF (3.0 mL) under argon at −78 °C for 1 h followed by addition of TMSCl (0.60 mmol), unless otherwise noted. bDiastereoselective ratio was determined by 1H NMR analysis of the crude reaction mixture (dr = major isomer:∑minor isomers) and was >20:1 unless otherwise noted. cIsolated yield after silica gel chromatography. dReaction on 1 g scale. eLewis acid (MgBr2·Et2O, 2.0 equiv) was used. f3:1:0:0 dr.

Scheme 2. Addition of N-tBS Imidates to Cyclohexanone

1 colorless oil: 118.7 mg, 91% yield; [α]25 D −65 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.85 (d, J = 10.0 Hz, 1H), 4.33 (t, J = 10.0 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.58−3.51 (m, 1H), 1.28 (s, 9H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7, 159.3, 135.5, 128.0, 114.0, 76.2, 56.9, 55.4, 54.6, 46.8, 22.1, 14.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H25NNaO4S 350.1397, found 350.1399. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3-(4nitrophenyl)propanimidate (3ac). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2c (78.5 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ac as a yellow solid: 78.5 mg, 91% yield; mp 87.5−89.2 °C; [α]25 D −89 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 5.47 (d, J = 10.4 Hz, 1H), 4.70 (t, J = 10.0 Hz, 1H), 3.86 (s, 3H), 3.57−3.52 (m, 1H), 1.30 (s, 9H), 0.97 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 150.8, 147.7, 128.0, 123.9, 75.8, 57.3, 54.9, 46.5, 22.1, 14.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22N2NaO5S 365.1142, found 365.1146. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(4-fluorophenyl)-3-hydroxy-2-methylpropanimidate (3ad). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2d (64.5 mg, 0.52 mmol, 1.3 equiv) were used. Column

11256

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry

(400 MHz, CDCl3) δ 7.40 (d, J = 6.8 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.29−7.25 (m, 1H), 4.85 (d, J = 10.4 Hz, 1H), 4.40 (t, J = 10.0 Hz, 1H), 3.85 (s, 3H), 3.59−3.53 (m, 1H), 1.68−1.59 (m, 1H), 1.29 (s, 9H), 1.26−0.90 (m, 3H), 0.77 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.4, 143.6, 128.6, 127.9, 127.0, 75.7, 56.8, 54.6, 53.0, 31.2, 22.1, 20.8, 13.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H27NNaO3S 348.1604, found 348.1609. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-((S)-hydroxy(phenyl)methyl)pent-4-enimidate (3ia). 1i (97.8 mg, 0.45 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 1.0 mL, 0.50 mmol, 1.1 equiv), and aldehyde 2a (62.1 mg, 0.59 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ia as 1 colorless oil: 122.7 mg, 84%; [α]25 D −99 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.43−7.40 (m, 2H), 7.37−7.33 (m, 2H), 7.30− 7.27 (m, 1H), 5.61−5.50 (m, 1H), 4.97−4.92 (m, 1H), 4.43 (t, J = 10.0 Hz, 1H), 3.83 (s, 3H), 3.69−3.62 (m, 1H), 2.40−2.31 (m, 1H), 1.81−1.74 (m, 1H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.2, 143.2, 134.8, 128.7, 128.0, 127.0, 116.9, 75.4, 57.0, 54.6, 52.7, 33.5, 22.1; HRMS (ESI-TOF) m/z [M + Na] + calcd for C17H25NNaO3S 346.1447, found 346.1448. Methyl (R)-5-((tert-Butyldimethylsilyl)oxy)-N-((R)-tert-butylsulfinyl)-2-((S)-hydroxy(phenyl)methyl)pentanimidate (3ja). 1j (21.3 mg, 0.06 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 134 μL, 0.067 mmol, 1.1 equiv), and aldehyde 2a (8.4 mg, 0.08 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ja as colorless oil: 22.3 mg, 80%; [α]25 D −102 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.41−7.39 (m, 2H), 7.35− 7.31 (m, 2H), 7.28−7.24 (m, 1H), 4.90 (d, J = 10.4 Hz, 1H), 4.40 (t, J = 10.0 Hz, 1H), 3.85 (s, 3H), 3.55−3.42 (m, 3H), 1.69−1.62 (m, 1H), 1.45−1.36 (m, 1H), 1.29 (s, 9H), 1.28−1.23 (m, 1H), 1.13−1.04 (m, 1H), 0.80 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2, 143.5, 128.6, 127.9, 127.0, 75.8, 62.5, 57.0, 54.7, 53.0, 30.8, 26.0, 25.6, 22.1, 18.4, − 5.2; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C23H42NO4SSi 456.2598, found 456.2596. Methyl (S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenylpropanimidate (3ka). 1k (71.0 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aryl aldehyde 2a (55.2 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ka as a white solid: 62 mg, 1 55%; mp 65.5−66.7 °C; [α]25 D −89 (c 0.295, MeOH); H NMR (400 MHz, CDCl3) δ 7.43−7.41 (m, 2H), 7.36−7.32 (m, 2H), 7.28−7.23 (m, 1H), 5.03 (d, J = 8.4 Hz, 1H), 4.95−4.90 (m, 1H), 3.82 (s, 3H), 3.25 (dd, J = 13.2, 10.8 Hz, 1H), 2.79 (dd, J = 12.8, 3.6 Hz, 1H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.2, 144.6, 128.6, 127.6, 125.6, 70.4, 57.2, 54.7, 43.8, 22.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H21NNaO3S 306.1134, found 306.1128. General Procedure for the Preparation of Product 3an and 3ea−ha. To a solution of 1 (0.4 mmol, 1.0 equiv) and 2 (0.52 mmol, 1.3 equiv) in 2.0 mL of THF was added KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv) at −78 °C. After the resulting solution was maintained at −78 °C for 4.5−5 h, TMSCl (69 μL, 0.8 mmol, 2.0 equiv) was added to the solution via syringe. When complete consumption of imidate 1 was observed via TLC analysis, the reaction was quenched with HF (0.3 mL, diluted with 3 mL of water) and the resulting solution was stirred at room temperature until the absence of silyl ether via TLC analysis. The aqueous layer was extracted with 15 mL (×3) of EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography to afford products 3an and 3ea−ha. (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3-phenylpropanamide (3an). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), aldehyde 2n (46.7 mg, 96%, 0.52 mmol, 1.3 equiv), and TMSCl (69 μL, 0.8 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3an as a white solid: 57.2 mg, 54%; mp 160.8−162.0 1 °C; [α]25 D −64 (c 0.125, MeOH); H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 3.39 (br s, 1H), 3.41−3.31 (m, 1H), 2.75 (d, J = 5.6 Hz, 1H), 1.37 (d, J = 7.6 Hz, 3H), 1.26 (s, 9H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.9, 82.6, 56.7, 42.5, 36.2, 26.4, 22.3, 19.3; HRMS

Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(furan-2-yl)-3-hydroxy2-methylpropanimidate (3aj). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2j (43.4 μL, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3aj as a 1 colorless oil: 88.4 mg, 77% yield; [α]25 D −96 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 6.31−6.29 (m, 2H), 4.80 (d, J = 10.4 Hz, 1H), 4.44 (t, J = 10.4 Hz, 1H), 3.88−3.82 (m, 1H), 3.82 (s, 3H), 1.26 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7, 155.2, 142.4, 110.2, 107.5, 69.6, 57.0, 54.7, 44.1, 22.1, 14.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H21NNaO4S 310.1083, found 310.1088. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3(thiophen-2-yl)propanimidate (3ak). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2k (58.3 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ak as a 1 yellow oil: 106 mg, 87% yield; [α]25 D −74 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.24−7.23 (m, 1H), 7.04−7.03 (m, 1H), 6.95− 6.93 (m, 1H), 4.96 (d, J = 10.0 Hz, 1H), 4.66 (t, J = 10.0 Hz, 1H), 3.82 (s, 3H), 3.70−3.63 (m, 1H),1.27 (s, 9H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7, 147.2, 126.7, 125.0, 125.0, 72.0, 57.0, 54.7, 47.1, 22.1, 14.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H21NNaO3S2 326.0855, found 326.0857. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-3(pyridin-2-yl)propanimidate (3al). 1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2l (56.8 mg, 98%, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3al 1 as a orange oil: 106.4 mg, 89% yield; [α]25 D −76 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 8.59−8.57 (m, 1H), 7.68 (td, J = 7.6, 1.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.20−7.17 (m, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.57 (t, J = 10.0 Hz, 1H), 3.84 (s, 3H), 3.80−3.72 (m, 1H), 1.27 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 161.9, 149.1, 136.8, 122.8, 121.8, 56.8, 54.7, 45.6, 22.1, 14.2; HRMS (ESI-TOF) m/z [M + Na] + calcd for C14H22N2NaO3S 321.1243, found 321.1240. Methyl (2S,3S)-N-((S)-tert-Butylsulfinyl)-3-hydroxy-2-methyl-5phenylpent-4-enimidate (ent-3am). ent-1a (76.5 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2m (65.6 μL, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3am as a yellow oil: 109.7 mg, 84% yield; [α]25 D +17 (c 0.25, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.19 (dd, J = 15.6 Hz, 7.6 Hz, 1H), 4.37 (d, J = 10.0 Hz, 1H), 4.07−4.00 (m, 1H), 3.82 (s, 3H), 3.41−3.37 (m, 1H), 1.27 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.5, 136.8, 132.1, 130.7, 128.6, 127.8, 126.7, 74.9, 56.8, 54.7, 45.3, 22.1, 14.6; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C17H26NO3S 324.1628, found 324.1627. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-((S)-hydroxy(phenyl)methyl)butanimidate (3ca). 1c (82.1 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2a (55.2 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3ca as a 1 colorless oil: 110 mg, 88% yield; [α]25 D −150 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 6.8 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.28−7.24 (m, 1H), 4.87 (d, J = 10.0 Hz, 1H), 4.40 (t, J = 10.4 Hz, 1H), 3.85 (s, 3H), 3.49−3.42 (m, 1H), 1.67−1.56 (m, 1H), 1.29 (s, 9H), 1.10−1.00 (m, 1H), 0.75 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 143.6, 128.6, 127.8, 126.9, 75.6, 56.8, 55.1, 54.6, 22.5, 22.1, 12.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H25NNaO3S 334.1447, found 334.1443. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-((S)-hydroxy(phenyl)methyl)pentanimidate (3da). 1d (87.8 mg, 0.40 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.88 mL, 0.44 mmol, 1.1 equiv), and aldehyde 2a (55.2 mg, 0.52 mmol, 1.3 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3da as a 1 colorless oil: 117.3 mg 90%; [α]25 D −60 (c 0.25, MeOH); H NMR 11257

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C12H26NO3S 264.1628, found 264.1627. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-((S)-hydroxy(phenyl)methyl)-5-methylhexanimidate (3ea). 1e (54.8 mg, 0.22 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.24 mL, 0.48 mmol, 1.1 equiv), aldehyde 2a (30.6 mg, 0.29 mmol, 1.3 equiv), and TMSCl (48.2 μL, 0.44 mmol, 2.0 equiv) were used to afford 3ea as yellow oil: 72.1 mg, 1 92%; [α]25 D −121 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.29−7.27 (m, 1H), 4.85 (d, J = 10.4 Hz, 1H), 4.40 (t, J = 10.0 Hz, 1H), 3.85 (s, 3H), 3.54−3.48 (m, 1H), 1.67−1.58 (m, 1H), 1.46−1.35 (m, 1H), 1.30 (s, 9H), 1.03−0.94 (m, 3H), 0.73 (dd, J = 13.6, 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 143.6, 128.6, 127.9, 127.0, 75.8, 56.9, 54.6, 53.2, 36.6, 27.8, 27.0, 23.0, 22.1, 22.0; HRMS (ESI-LTQOrbitrap) m/z [M + H]+ calcd for C19H32NO3S 354.2097, found 354.2104. Methyl (2R,3S)-2-Benzyl-N-((R)-tert-butylsulfinyl)-3-hydroxy-3phenylpropanimidate (3fa). 1f (75.1 mg, 0.28 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.62 mL, 0.31 mmol, 1.1 equiv), aldehyde 2a (38.6 mg, 0.36 mmol, 1.3 equiv), and TMSCl (48.4 μL, 0.56 mmol, 2.0 equiv) were used to afford 3fa as white solid: 96.3 mg, 92%; mp 1 94.1−95.2 °C; [α]25 D −135 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 6.8 Hz, 2H), 7.13 (t, J = 7.2 Hz, 2H), 7.00 (d, J = 7.2 Hz, 1H), 4.86 (d, J = 10.4 Hz, 1H), 4.56 (t, J = 9.6 Hz, 1H), 4.00−3.93 (m, 1H), 3.75 (s, 3H), 2.84 (dd, J = 13.6 Hz, 12.0 Hz, 1H), 2.38 (dd, J = 13.2 Hz, 4.0 Hz, 1H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.9, 143.2, 138.7, 128.8, 128.5, 128.5, 128.2, 127.0, 126.5, 75.5, 56.7, 54.8, 54.4, 35.5, 22.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H28NO3S 374.1784, found 374.1777. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenyl-2(thiophen-2-ylmethyl)propanimidate (3ga). 1g (48.4 mg, 0.177 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.40 mL, 0.20 mmol, 1.1 equiv), aldehyde 2a (24.4 mg, 0.23 mmol, 1.3 equiv), and TMSCl (31.0 μL, 0.35 mmol, 2.0 equiv) were used to afford 3ga as colorless 1 oil: 63.3 mg, 94%; [α]25 D −108 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.48−7.46 (m, 2H), 7.40−7.37 (m, 2H), 7.33−7.29 (m, 1H), 7.06 (dd, J = 4.8 Hz, 1.2 Hz), 6.84 (q, J = 5.2 Hz, 3.6 Hz, 1H), 6.66−6.65 (m, 1H), 5.00 (d, J = 10.0 Hz, 1H), 4.51 (t, J = 10.0 Hz, 1H), 3.98−3.92 (m, 1H), 3.81 (s, 3H), 3.15 (dd, J = 14.8 Hz, 12.0 Hz, 1H), 2.54−2.49 (m, 1H), 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.3, 143.0, 141.0, 128.9, 128.2, 127.0, 126.9, 125.1, 123.8, 75.3, 57.0, 55.1, 54.6, 29.7, 22.0; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C19H26NO3S2 380.1349, found 380.1343. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenyl-2(pyridin-2-ylmethyl)propanimidate (3ha). 1h (53.7 mg, 0.20 mmol, 1.0 equiv), KHMDS (0.5 M in toluene, 0.44 mL, 0.22 mmol, 1.1 equiv), aldehyde 2a (27.6 mg, 0.26 mmol, 1.3 equiv), and TMSCl (35.0 μL, 0.40 mmol, 2.0 equiv) to afford 3ha as colorless oil: 61 mg, 1 81%; [α]25 D −120 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 4.8 Hz, 1H), 7.51−7.47 (m, 3H), 7.35 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.03 (dd, J = 7.2 Hz, 5.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.10 (br s, 1H), 4.57 (d, J = 10.0 Hz, 1H), 4.28−4.22 (m, 1H), 3.71 (s, 3H), 3.10 (dd, J = 14.8 Hz, 11.2 Hz, 1H), 2.56 (dd, J = 14.4 Hz, 4.0 Hz, 1H), 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.2, 158.6, 149.2, 143.1, 136.2, 128.7, 128.0, 127.1, 122.8, 121.4, 75.5, 56.6, 54.5, 51.9, 37.5, 22.1; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C20H27N2O3S 375.1737, found 375.1732. General Procedure for the Preparation of Products 3ba−bd, 3bg−bl, 3bn−bo, and 3la−pa. To a solution of 1 (0.3 mmol, 1.0 equiv) and 2 (0.6 mmol, 2.0 equiv) in 2.0 mL of THF was added KHMDS (0.5 M in toluene, 0.66 mL, 0.33 mmol, 1.1 equiv) under −78 °C. After the resulting solution was maintained at −78 °C for 1.0 h, TMSCl (52 μL, 0.6 mmol, 2.0 equiv) was added to the solution. When complete consumption of imidate 1 was observed via TLC analysis, the reaction was quenched with HF (0.3 mL, diluted with 3 mL of water) and the resulting solution was stirred at room temperature until the absence of silyl ether via TLC analysis. The aqueous layer was extracted with 15 mL (×3) of EtOAc. The combined organic layers were washed with saturated sodium

bicarbonate aqueous and dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford products 3ba−bd, 3bg−bl, 3bn−bo, and 3la−pa. Methyl (2R,3R)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2,3-diphenylpropanimidate (3ba). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2a (0.6 mmol, 63.7 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 90.6 mg (84%) of 3ba as a white solid: 90.6 mg, 84%; 8 22 [α]25 D −215 (c 1.0, CHCl3) [lit. [α]D −209 (c 1.0, CHCl3)]. The proton and carbon NMR spectra of 3ba are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-(4-methoxyphenyl)-2-phenylpropanimidate (3bb). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2b (0.6 mmol, 83.4 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bb as a yellow solid: 72.8 mg, 62%; mp 118.6−119.7 1 °C; [α]25 D −90 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.24− 7.16 (m, 5H), 7.14−710 (m, 2H), 6.70−6.67 (m, 2H), 5.04 (t, J = 9.6 Hz, 1H), 4.86 (d, J = 10.4 Hz, 1H), 4.27 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.3, 159.0, 135.5, 134.6, 129.9, 128.5, 127.9, 127.7, 113.7, 75.4, 58.7, 56.9, 55.3, 55.0, 22.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H27NNaO4S 412.1553, found 412.1559. Methyl(2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-(4-nitrophenyl)-2-phenylpropanimidate (3bc). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2c (0.6 mmol, 92.5 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bc as a yellow solid: 106.3 mg, 88%; [α]25 D −181.6 (c 1.0, CHCl3) [lit.8 [α]22 D −174.5 (c 1.0, CHCl3)]. The proton and carbon NMR spectra of 3bc are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(4-fluorophenyl)-3-hydroxy-2-phenylpropanimidate (3bd). 1b (1.0 g, 3.95 mmol, 1.0 equiv), 2d (1.48 g, 7.90 mmol, 2.0 equiv), KHMDS (0.5 M in toluene, 8.69 mL, 4.35 mmol, 1.1 equiv), and TMSCl (683 μL, 7.9 mmol, 2.0 equiv) were used to afford product 3bd as a white solid: 1.26 g (85%); 8 22 [α]25 D −195.0 (c 1.0, CHCl3) [lit. [α]D −193.7 (c 1.0, CHCl3)]. The proton and carbon NMR spectra of 3bd are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-phenyl-3-(ptolyl)propanimidate (3bg). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2g (0.6 mmol, 74.3 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bg as a white solid: 95.2 mg, 85%; mp 126.1−127.4 °C; 1 [α]25 D −91 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.25−7.16 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.05 (t, J = 10.0 Hz, 1H), 4.88 (d, J = 10.4 Hz, 1H), 4.30 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 2.22 (s, 3H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.3, 139.3, 137.2, 135.5, 129.9, 128.9, 128.4, 127.7, 126.6, 75.6, 58.6, 56.9, 55.0, 22.1, 21.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H27NNaO3S 396.1604, found 396.1601. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-phenyl-3(m-tolyl)propanimidate (3bh). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2h (0.6 mmol, 74.3 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bh as a white solid: 99.7 mg, 89%; mp 102.8−103.9 °C; 1 [α]25 D −74 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.24−7.16 (m, 5H), 7.05−6.92 (m, 4H), 5.05 (d, J = 10.4 Hz, 1H), 4.88 (d, J = 10.4 Hz, 1H), 4.29 (br s, 1H), 3.87 (s, 3H), 2.21 (s, 3H), 1.26 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 174.2, 142.1, 137.8, 135.4, 129.9, 128.5, 128.4, 128.1, 127.7, 127.4, 123.9, 75.9, 58.4, 56.9, 55.0, 22.1, 21.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H27NNaO3S 396.1604, found 396.1606. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-phenyl-3-(otolyl)propanimidate (3bi). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2i (0.6 11258

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry

(d, J = 10.4 Hz, 1H), 4.44 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.25 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.5, 142.4, 137.4, 132.2, 129.7, 129.1, 128.2, 127.6, 126.8, 75.8, 58.2, 56.8, 55.0, 22.1, 21.2; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C21H28NO3S 374.1784, found 374.1781. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenyl-2(m-tolyl)propanimidate (3ma). 1m (0.2 mmol, 53.5 mg, 1.0 equiv), 2a (0.4 mmol, 42.4 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.22 mmol, 0.44 mL, 1.1 equiv), and TMSCl (35 μL, 0.4 mmol, 2.0 equiv) were used to afford 3am as colorless oil: 68.6 mg, 91%; [α]25 D −99 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.22−6.97 (m, 9H), 5.07 (t, J = 10.0 Hz, 1H), 4.85 (d, J = 10.4 Hz, 1H), 4.40 (d, J = 9.6 Hz,1H), 3.87 (s, 3H), 2.24 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.4, 142.4, 138.0, 135.2, 130.6, 128.5, 128.3, 128.2, 127.6, 126.8, 126.8, 75.7, 58.6, 56.9, 55.0, 22.1, 21.5; HRMS (ESILTQ-Orbitrap) m/z [M + H]+ calcd for C21H28NO3S 374.1784, found 374.1781. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenyl-2-(otolyl)propanimidate (3na). 1n (0.2 mmol, 53.5 mg, 1.0 equiv), 2a (0.4 mmol, 42.4 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.22 mmol, 0.44 mL, 1.1 equiv), and TMSCl (35 μL, 0.4 mmol, 2.0 equiv) were used to afford 3na as white solid: 72.2 mg, 97%; mp 131.2−132.7 1 °C; [α]25 D −19 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.22−7.05 (m, 7H), 6.94 (d, J = 7.6 Hz, 1H), 5.17−5.07 (m, 2H), 4.62 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H), 2.04 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.2, 142.3, 137.0, 133.8, 130.3, 129.6, 128.1, 127.6, 127.5, 126.6, 126.0, 76.0, 57.1, 55.2, 53.4, 22.1, 20.2; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C21H28NO3S 374.1784, found 374.1776. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-(4-methoxyphenyl)-3-phenylpropanimidate (3oa). 1o (0.3 mmol, 85.1 mg, 1.0 equiv), 2a (0.6 mmol, 63.7 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3oa as a white solid: 112.5 mg, 97%; [α]25 D −183.1 (c 0.35, CHCl3) [lit.8 [α]22 D −41.2 (c 0.67, CHCl3)]. The proton and carbon NMR spectra of 3oa are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-2-(4-fluorophenyl)-3-hydroxy-3-phenylpropanimidate (3pa). 1p (0.3 mmol, 81.4 mg, 1.0 equiv), 2a (0.6 mmol, 63.7 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3pa as a white solid: 91.6 mg, 81%; [α]25 D −203.5 (c 1.0, CHCl3) [lit.8 [α]22 D −162.7 (c 1.0, CHCl3)]. The proton and carbon NMR spectra of 3pa are consistent with those reported (see the Supporting Information).8 Procedure for the Preparation of Product 5. KHMDS (0.5 M in THF, 0.44 mL, 0.22 mmol, 1.1 equiv) was added dropwise to a stirring solution of 1a (38.3 mg, 0.2 mmol, 1.0 equiv) in 1.0 mL of THF at −78 °C. After the solution was maintained at −78 °C for 45 min, a solution of MgBr2·Et2O (103.3 mg, 0.40 mmol, 2.0 equiv) in 1.0 mL of THF was added. After 20 min, cyclohexanone (62.2 μL, 0.6 mmol, 3.0 equiv) in 1.0 mL of THF was added to the solution. After the resulting solution was maintained at −78 °C for 5.0 h, the reaction was quenched with saturated NH4Cl (5 mL). The aqueous layer was extracted with 5 mL (×3) of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (petroleum/ethyl acetate = 5:1) to afford product 5. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-(1-hydroxycyclohexyl)propanimidate (5). 5: colorless oil; 28.8 mg, 50%; [α]25 D −20 (c 0.25, MeOH); 1H NMR (400 MHz, C6D6) δ 4.12 (d, J = 2.0 Hz, 1H), 3.48 (dd, J = 14.0 Hz, 7.2 Hz, 1H), 3.28 (s, 3H), 2.09−1.89 (m, 3H), 1.66−1.46 (m, 5H), 1.32−1.24 (m, 1H), 1.12 (s, 9H), 1.08−1.01 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 176.2, 71.3, 56.5, 53.6, 50.1, 37.7, 32.2, 26.4, 22.4, 22.1, 22.0, 12.8; HRMS (ESI-LTQ) m/z [M + Na]+ calcd for C14H27NNaO3S 312.1604, found 312.1600.

mmol, 74.3 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bi as a white solid: 95.2 mg, 89%; [α]25 D −219.6 (c 0.44, CHCl3) [lit.8 [α]22 D −195.5 (c 1.0, CHCl3)]. The proton and carbon NMR spectra of 3bi are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(furan-2-yl)-3-hydroxy2-phenylpropanimidate (3bj). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2j (0.6 mmol, 58.2 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bj as a white solid: 91.2 mg, 87%; [α]25 D −277.9 (c 0.51, CHCl3) [lit.8 [α]22 D −323.2 (c 0.5, CHCl3)]. The proton and carbon NMR spectra of 3bj are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-phenyl-3(thiophen-2-yl)propanimidate (3bk). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2k (0.6 mmol, 68.6 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bk as a white solid: 90.4 mg, 83%; [α]25 D −227.6 (c 0.5, CHCl3) [lit.8 [α]22 D −284.4 (c 0.5, CHCl3)]. The proton and carbon NMR spectra of 3bk are consistent with those reported (see the Supporting Information).8 Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-2-phenyl-3(pyridin-2-yl)propanimidate (3bl). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2l (0.6 mmol, 65.6 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ ethyl acetate = 5:1) afforded 3bl as a white solid: 89.8 mg, 83%; mp 1 72.0−73.2 °C; [α]25 D −66 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.8 Hz,1H), 7.37−7.33 (m, 1H), 7.24−7.18 (m, 5H), 7.07−7.04 (m, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.22−5.18 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.72 (d, J = 9.6 Hz 1H), 3.90 (s, 3H), 1.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.2, 159.4, 149.1, 135.9, 135.4, 129.5, 128.6, 127.8, 122.8, 122.1, 75.3, 57.1, 56.7, 54.9, 22.1; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C19H25N2O3S 361.1580, found 361.1578. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-4,4-dimethyl2-phenylpentanimidate (3bn). 1b (0.3 mmol, 76 mg, 1.0 equiv), 2n (0.9 mmol, 97.8 μL, 3.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and MgBr2·Et2O (154.9 mg, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3bn as a white solid: 63.4 mg, 62%; [α]25 D −256.2 (c 0.5, CHCl3) [lit.8 [α]22 D −273.2 (c 0.5, CHCl3)]. The proton and carbon NMR spectra of 3bn are consistent with those reported (see the Supporting Information).8 Methyl (2R,3R)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-5-methyl-2phenylhexanimidate (3bo). 1b (0.2 mmol, 50.7 mg, 1.0 equiv), 2o (0.6 mmol, 64.3 μL, 3.0 equiv), KHMDS (0.5 M in toluene, 0.22 mmol, 0.44 mL, 1.1 equiv), TMSCl (52 μL, 0.6 mmol, 2.0 equiv), and MgBr2.Et2O (103.3 mg, 0.4 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 46.1 mg 1 (83%) of 3bo as a colorless oil: [α]25 D −62 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.35−7.28 (m, 5H), 4.47 (d, J = 10.0 Hz, 1H), 4.17−4.11 (m, 1H), 3.77 (s, 3H), 1.94−1.85 (m, 1H), 1.33−1.25 (m, 2H), 1.23 (s, 9H), 1.05−0.99 (m, 1H), 0.80 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 174.6, 136.4, 129.5, 128.7, 127.8, 71.0, 58.2, 56.7, 54.9, 45.3, 24.5, 23.9, 22.0, 21.3; HRMS (ESI-LTQOrbitrap) m/z [M + H]+ calcd for C18H30NO3S 340.1941, found 340.1941. Methyl (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-hydroxy-3-phenyl-2-(ptolyl)propanimidate (3la). 1l (0.3 mmol, 80.2 mg, 1.0 equiv), 2a (0.6 mmol, 63.7 mg, 2.0 equiv), KHMDS (0.5 M in toluene, 0.33 mmol, 0.66 mL, 1.1 equiv), and TMSCl (52 μL, 0.6 mmol, 2.0 equiv) were used. Column chromatography (petroleum/ethyl acetate = 5:1) afforded 3la as a white solid: 94.3 mg, 84%; mp 124.1−125.3 °C; 1 [α]25 D −101 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.23− 7.11 (m, 7H), 6.99 (d, J = 8.0 Hz, 2H), 5.06 (t, J = 9.6 Hz, 1H), 4.85 11259

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry Procedure for the Preparation of Product 6. KHMDS (0.5 M in THF, 0.44 mL, 0.22 mmol, 1.1 equiv) was added dropwise to a stirring solution of 1b (50.7 mg, 0.2 mmol, 1.0 equiv) in 1.0 mL of dry THF at −78 °C. After the solution was maintained at −78 °C for 45 min, a solution of ZnBr2 (90.1 mg, 0.4 mmol, 2.0 equiv) and cyclohexanone (62.2 μL, 0.6 mmol, 3.0 equiv) in 2.0 mL of dry THF was added. After the resulting solution was maintained at −78 °C for 5.0 h, the reaction was quenched with saturated NH4Cl (5 mL). The aqueous layer was extracted with 5 mL (×3) of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (petroleum/ethyl acetate = 3:1) to afford product 6. Methyl (R)-N-((R)-tert-Butylsulfinyl)-2-(1-hydroxycyclohexyl)-2phenylacetimidate (6). 6: colorless oil; 60.7 mg, 86%; [α]25 D −94 (c 0.25, MeOH); 1H NMR (400 MHz, C6D6) δ 7.47−7.45 (m, 2H), 7.32−7.25 (m, 3H), 4.64 (s, 1H), 3.86 (s, 3H), 2.90 (s, 1H), 1.72− 1.18 (m, 10H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.7, 135.0, 130.6, 128.4, 127.7, 72.7, 58.9, 56.5, 54.6, 37.9, 34.6, 25.6, 22.0, 21.9, 21.7; HRMS (ESI-LTQ-Orbitrap) m/z [M + H]+ calcd for C19H30NO3S 352.1941, found 352.1936. (R)-N-((2S,3S)-3-(4-Chlorophenyl)-3-hydroxy-2-methylpropyl)-2methylpropane-2-sulfinamide (7). To a stirred solution of 3ae (20 mg, 0.06 mmol, 1.0 equiv) in THF (1.0 mL) at 0 °C was added dropwise DIBAL-H (1.0 M in pentane 0.15 mmol, 2.5 equiv). The resultant solution was stirred for 1 h at 0 °C before being quenched with MeOH. Water (5 mL) was added and the organic layer separated. The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield a pale yellow oil. The crude product was purified by column chromatography (dichloromethane/ethyl acetate = 1:2) to give the title compound 7 (18.2 mg, 100%) as a white solid: mp 81.7−82.4 °C; 1 [α]25 D −70 (MeOH, c = 0.29); H NMR (600 MHz, CDCl3) δ 7.26− 7.20 (m, 4H), 4.37 (d, J = 8.4 Hz, 1H), 3.91 (t, J = 6.0 Hz, 1H), 3.33− 3.29 (m, 1H), 3.17−3.13 (m, 1H), 2.11−2.05 (m, 1H), 1.17 (s, 9H), 0.67 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 141.9, 133.4, 128.6, 128.1, 78.4, 55.9, 50.6, 41.1, 22.7, 15.2; HRMS (ESI QOrbitrap) m/z [M + Na]+ calcd for C14H22ClNNaO2S 326.0952, found 326.0950. (2R,3S)-N-((R)-tert-Butylsulfinyl)-3-(4-chlorophenyl)-3-hydroxy-2methylpropanamide (8). To a stirred solution of 3ae (0.194 mmol, 20 mg, 1.0 equiv) in 3.0 mL of THF was added H2SO4 (1.0 M, 3 mL). The solution was allowed to stir at rt until the absence of starting material. Then, the reaction mixture was extracted with 5 mL (×3) of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Column chromatography (petroleum/ethyl acetate = 1:1) afforded 8 (33 mg, 53%) as a colorless oil: [α]25 D −54 (MeOH, c = 0.1); 1H NMR (600 MHz, CDCl3) δ 8.27 (br s, 1H), 7.33−7.32 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.68 (t, J = 6.0 Hz, 1H), 3.38 (d, J = 4.8 Hz, 1H), 2.78 (br s, 1H), 1.19 (s, 9H), 1.09 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 175.9, 140.5, 134.0, 128.9, 127.9, 75.8, 57.4, 48.3, 22.0, 14.8; HRMS (ESI Q-Orbitrap) m/z [M + Na]+ calcd for C14H20ClNNaO3S 340.0745, found 340.0742.

■

ORCID

Chong-Dao Lu: 0000-0001-8968-0134 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (U1403301, 21572262, and 21372255), the Recruitment Program of Global Experts (Xinjiang Program), and the Director Foundation of XTIPC (2015RC014).

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01982. 1 H and 13C NMR spectra and X-ray crystal structures of 3ah and 6 (PDF) X-ray crystallographic data for 3ah (CIF) X-ray crystallographic data for 6 (CIF)

■

REFERENCES

(1) (a) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, Germany, 2004. (b) Mahrwald, R. Modern Methods in Stereoselective Aldol Reactions; Wiley-VCH: Weinheim, Germany, 2013. (c) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506− 7525. (2) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127−2129. (3) For a review of asymmetric enolate methodology, see: (a) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917−947. For recent advances in chiral lithium enolates derived from carboxylic acids with chiral lithium amides as noncovalent auxiliaries, see: (b) Yu, K.; Lu, P.; Jackson, J. J.; Nguyen, T. D.; Alvarado, J.; Stivala, C. E.; Ma, Y.; Mack, K. A.; Hayton, T. W.; Collum, D. B.; Zakarian, A. J. Am. Chem. Soc. 2017, 139, 527−533. (4) For earlier examples of chiral amine-catalyzed direct aldol reactions: see: (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395−2396. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260−5267. (c) Bùgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002, 620−621. (d) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798−6799. (e) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262−5263. (5) For earlier examples of chiral metal complex-catalyzed direct aldol reactions: see: (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871−1873. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168−4178. (c) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003−12004. (d) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706−8707. (6) Shamszad, M.; Crimmins, M. T. Amino Acid Derived Heterocyclic Chiral Auxiliaries: The use of Oxazolidinones, Oxazolidinethiones, Thiazolidinethiones, and Imidazolidinones. In Comprehensive Chirality; Elsevier Ltd, 2012; Vol. 3, pp 19−41. (7) For 1,4-reductive aldol reactions of α,β-unsaturated amides, see: (a) Nuhant, P.; Allais, C.; Roush, W. R. Angew. Chem., Int. Ed. 2013, 52, 8703−8707. (b) Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R. Angew. Chem., Int. Ed. 2013, 52, 12888−12891. For recent examples of direct catalytic asymmetric aldol reactions of α-alkylamides, see: (c) Liu, Z.; Takeuchi, T.; Pluta, R.; Arteaga, F. A.; Kumagai, N.; Shibasaki, M. Org. Lett. 2017, 19, 710−713. (8) For aldol reactions of N-sulfonyl imidates in the presence of TiCl2(OiPr)2/NEt3, see: Bartrum, H. E.; Viceriat, A.; Carret, S.; Poisson, J.-F. Org. Lett. 2014, 16, 1972−1975. (9) For synthetic applications of N-tert-butylsulfinyl imidates in alkylation reactions, see: (a) Colpaert, F.; Mangelinckx, S.; Verniest, G.; De Kimpe, N. J. Org. Chem. 2009, 74, 3792−3797. (b) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2011, 76, 234−244. (c) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652−15653. For other transformations involving nucleophilic addition of N-tertbutylsulfinyl imidates, see refs 10−12. (10) For Mannich reaction, see: (a) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. Org. Lett. 2010, 12, 1904−1907. (b) Colpaert, F.; Mangelinckx, S.; De Brabandere, S.; De Kimpe, N. J. Org. Chem.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] 11260

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261

Note

The Journal of Organic Chemistry 2011, 76, 2204−2213. (c) Semina, E.; Colpaert, F.; Van Hecke, K.; De Kimpe, N.; Mangelinckx, S. Eur. J. Org. Chem. 2015, 2015, 4847−4859. (11) For 1,4-addition reaction, see: (a) Wang, J.; Zhou, Y.; Zhang, L.; Li, Z.; Chen, X. J.; Liu, H. Org. Lett. 2013, 15, 1508−1511. (b) Wang, H.-J.; Tang, P.; Zhou, Q.-L.; Zhang, D.; Chen, Z.-T.; Huang, H.-X.; Qin, Y. J. Org. Chem. 2015, 80, 2494−2502. (c) Huang, H.-X.; Wang, H.-J.; Tan, L.; Wang, S.-Q.; Tang, P.; Song, H.; Liu, X.-Y.; Qin, Y. J. Org. Chem. 2016, 81, 10506−10516. (12) For 1,2-addition reactions with aldehydes or nitrosoarenes, see: (a) Huang, W.; Liu, H.; Lu, C.-D.; Xu, Y.-J. Chem. Commun. 2016, 52, 13592−13595. (b) Ma, P.-J.; Liu, H.; Lu, C.-D.; Xu, Y.-J. Org. Lett. 2017, 19, 670−673 and ref 8.. (13) For reviews on using tert-butanesulfinamide as chiral auxiliary, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984−995. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162−1186. (c) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600−3740. (d) Dong, H.-Q.; Xu, M.-H.; Feng, C.-G.; Sun, X.-W.; Lin, G.-Q. Org. Chem. Front. 2015, 2, 73−89. (14) For aldol reactions of N-sulfinyl ketimines with aldehydes under stong basic conditions, see: (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518−6519. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276−11282. (c) Priede, M.; Kazak, M.; Kalnins, T.; Shubin, K.; Suna, E. J. Org. Chem. 2014, 79, 3715−3724. For strong base-initiated aldol-Tishchenko reaction of Nsulfinyl ketimines with aldehydes, see: (d) Foley, V. M.; McSweeney, C. M.; Eccles, K. S.; Lawrence, S. E.; McGlacken, G. P. Org. Lett. 2015, 17, 5642−5645. (15) The Rf value of starting material 1a is nearly identical to that of its aldol product 3aa. (16) For earlier examples of TMSCl in aldol reactions, see: (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392−393. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127−1130. (17) Quenching the reaction with NaHCO3 solution rather than aqueous HF gave a mixture of silylated and nonsilylated products. (18) Transformations of the N-tBS imidate functional group to NtBS amine and N-tBS amide were illustrated by reduction of the aldol adduct 3ae to the corresponding amine 7 (100% yield) using DIBALH and hydrolysis of 3ae to the corresponding amide 8 (53% yield) using H2SO4 solution. For details, see the Experimental Section. (19) For the X-ray structure of compounds 3ah and 6, see the Supporting Information. (20) (a) Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223− 4225. (b) Crimmins, M. T.; Haley, M. W.; O’Bryan, E. A. Org. Lett. 2011, 13, 4712−4715. (21) For reviews of stereoselective acetate aldol reactions from metal enolates, see: Ariza, X.; Garcia, J.; Romea, P.; Urpi, F. Synthesis 2011, 2011, 2175−2191.

11261

DOI: 10.1021/acs.joc.7b01982 J. Org. Chem. 2017, 82, 11253−11261