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Generalized access to fluorinated β-keto amino compounds through asymmetric additions of α,α-difluoroenolates to CF3-sulfinylimine† Chen Xie,a Lingmin Wu,a Haibo Mei,a Vadim A. Soloshonok,b,c Jianlin Han*a,d and Yi Pana CF3-containing chiral imines readily react with α,α-difluoroenolates affording a novel type of β-keto-
Received 25th July 2014, Accepted 12th August 2014
amino compounds featuring the R-CO-CF2-CH(NH2)-CF3 moiety. The reactions feature exceptional generality allowing preparation of various aromatic, hetero-aromatic and aliphatic derivatives in high
DOI: 10.1039/c4ob01575d
yields and diastereoselectivity. The products are configurationally stable and can be transformed to more
www.rsc.org/obc
functionalized complex compounds.
Introduction Fluorine-containing compounds constitute the fastest growing sector of the pharmaceutical and agrochemical industries.1 Thus, the recent decade has witnessed an unprecedented 20% growth in the number of marketed fluorine-containing drugs.2 Therefore, the development of new methods for the preparation of fluoroorganic compounds as well as the discovery of new fluorinated structural units play a paramount role in shaping up the future generations of more potent and selective drugs.1,2 In this regard, the Colby group has made an important discovery3 demonstrating that α,α-difluoroenolates 1 (Scheme 1) can be generated in situ via Et3N induced haloform-type reaction4 of pentafluoro-β-di-ketone hydrate 2. Trimethylsilyl ethers of 1 are extremely valuable intermediates for installation of the difluoromethylene group5 and their chemistry has been intensively studied. Compared to the literature methods,6 using specially prepared esters of 1, Colby’s approach has a clear advantage, as unprotected enolate 1 can be easily generated under the operationally convenient conditions7 and has an apparent potential for large scale applications. On the other hand, the chemistry of a protection free a School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China. E-mail: [email protected]; Fax: +86-25-83686133; Tel: +86-25-83686133 b Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain c IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain d Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China † Electronic supplementary information (ESI) available: Experimental procedures, full spectroscopic data for compounds 9–12 and copies of 1H NMR and 13 C NMR spectra. CCDC 972034. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01575d
7836 | Org. Biomol. Chem., 2014, 12, 7836–7843
Scheme 1
Generation and reactions of α,α-difluoroenolates 1.
enolate 1 still remains virtually unstudied. Thus, there are only four reports by Colby4,8 and Wolf9,10 groups describing aldol additions and halogenation of the in situ generated α,α-difluoroenolates 1.
Results and discussion Taking into consideration that α,α-difluoro-β-amino-ketones of structure 5 have even greater pharmaceutical potential1,2,6,11 as compared with derivatives 3, one may presume that Mannichtype addition reactions between enolate 1 and the corresponding imines may offer an advanced preparation of amino compounds 5. We report that the Mannich-type reactions of enolate 1 with (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine easily take place under operationally convenient conditions leading to compounds 5 (R′ = CF3) with excellent chemical yields and stereoselectivity. We demonstrate remarkable configurational stability of derivatives 5 as well as their deprotection and transformation to more functionally complex derivatives such as β-amino acids.
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Table 1
Paper
Optimization of reaction conditionsa
Entry
Base
Additive
Solvent
T (°C)
t (h)
Yieldb (%)
drc
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Et3N LiOH NaOH KOH Cs2CO3 CF3COOLi tBuOLi Et3N DABCO DBU DABCO DBU Et3N Et3N Et3N Et3N Et3N Et3N
LiBr No No No No No No No No No LiBr LiBr LiBr LiBr LiBr LiBr LiBr LiBr
THF THF THF THF THF THF THF THF THF THF THF THF DMF DCM CH3CN CH3OH Toluene THF
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 0
0.5 4 4 4 4 12 1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
91 22 14 13 6 0 48 0 0 8 85 77 11 10 65 0 8 95
95 : 5 96 : 4 97 : 3 97 : 3 99 : 1 — 94 : 6 — — 99 : 1 95 : 5 94 : 6 97 : 3 83 : 17 90 : 10 — 83 : 17 99 : 1
a
Reaction conditions: CF3-sulfinylimine 6 (0.6 mmol), 7a (0.5 mmol), base, solvent (5 mL), additive (1.5 mmol). b Isolated yields. c Determined by F NMR.
19
Drawing inspiration from the success of CF3-containing N-tert-butanesulfinyl-imines in the asymmetric synthesis of biologically relevant amino compounds,12 and Wolf group’s results on the reactions of trifluoromethyl ketones (CF3CO-R)10 with α,α-difluoroenolates 1, we focused our study on the addition reaction between enolates 1 and chiral CF3-sulfinylimine 6 (Table 1). Gratifyingly, the reaction between the precursor of α,α-difluoroenolate 1a, ketone 7a, and imine 6 occurred very cleanly affording the product 8a in 91% yield and 95 : 5 dr (Table 1, entry 1). This result was an important breakthrough indicating that practical access to a novel family of fluorinated compounds of type 8 having high pharmaceutical potential is a synthetic reality. With these exciting results in hand, we next looked into studying all aspects of the reaction conditions to further increase the synthetic value of this reaction. Our first goal was to establish the role of the counterion in stabilization vs. reactivity of the free α,α-difluoroenolate 1a. To this end we conducted a series of reactions of 7a with imine 6 in the presence of various inorganic bases and without the use of LiBr as an additive. The experiments using LiOH, NaOH, KOH and Cs2CO3 (entries 2–5) have revealed a very important trend. First of all, the chemical yield of the target product 8a in these reactions was dramatically lower as compared with the standard conditions using LiBr as an additive (entries 2–4 vs. 1). Second, the yield was also gradually decreasing along the series, from 22% in the LiOH promoted reaction (entry 2) to only 6% in the case Cs2CO3 was used as the base (entry 5). These experimental data strongly indicated the paramount role of the Li as a counterion in stabilization of the in situ formed α,α-difluoroenolate 1a. Surprisingly, the diastereo-
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selectivity was also gradually changing but in the opposite direction from 96 : 4 dr for LiOH (entry 2) to 99 : 1 dr in the Cs2CO3 used reaction (entry 5). It should be noted that the important role of Li was also observed by Wolf10 in the corresponding aldol addition reactions. Two additional experiments were conducted to see the role of Li in connection with the strength of the Li-derived base. As shown in entries 6 and 7, no reaction was observed in the case of the very weak base CF3COOLi (entry 6) while t-BuOLi promoted reaction gave the product 8a in 48% yield and 94 : 6 dr (entry 7). Following this trend we conducted a series of reactions using different organic bases (entries 8–10). Again, quite surprisingly, without LiBr as the additive, Et3N (entry 8) and DABCO (entry 9) promoted reactions failed to produce the product 8a while in the case of DBU (entry 10) the reaction did take place, but resulted in a low isolated yield of 8a. These data clearly indicated the importance of LiBr as an additive in these reactions. Therefore, we have repeated the additions using DABCO and DBU conducted in the presence of LiBr. As one can see from entries 11 and 12, the LiBr had quite a dramatic effect on the outcome of these reactions as the product 8a was isolated in reasonably good yield and diastereoselectivity. However still, the use of Et3N gave better stereochemical outcome (entries 11, 12 vs. 1) Finally, we decided to study the role of the reaction solvent and conducted a series of experiments using Et3N as a base along with LiBr as an additive. The results were rather disappointing (entries 13–17) pointing to THF as the solvent of choice, most likely for stabilization and reactivity of the α,α-difluoroenolate 1a. While all these results were of great exploratory value they did not allow us to improve the stereochemical outcome obtained under standard Colby conditions (entry 1).
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Table 2
Organic & Biomolecular Chemistry Generality of the asymmetric Mannich additionsa
Entry
R
Product
Yieldb (%)
drc
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
C6H5 2-CH3-C6H4 2-Cl-C6H4 2-Br-C6H4 3-MeO-C6H4 3-Cl-C6H4 3-Br-C6H4 4-Me-C6H4 4-MeO-C6H4 4-F-C6H4 4-Cl-C6H4 4-Br-C6H4 4-CN-C6H4 2-Naphthyl 2-Thienyl t-Bu
10a 10b 10c 10d 10e 10f 10g 10h 10i 10j 10k 10l 10m 10n 10o 10p
95 91 88 89 93 92 92 94 95 91 93 93 88 98 98 83
99 : 1 99 : 1 99 : 1 98 : 2 99 : 1 99 : 1 98 : 2 99 : 1 >99 : 1 99 : 1 99 : 1 99 : 1 97 : 3 99 : 1 >99 : 1 >99 : 1
Fig. 1
ORTEP structure of compound 9t (CCDC number 972034).
Reaction conditions: 9 (0.5 mmol), sulfinylimine 6 (0.6 mmol), LiBr (1.5 mmol), triethylamine (1.0 mmol), THF (5 mL), rt, 30 min. b Isolated yields. c Isomer ratio was determined by 19F NMR on crude reaction mixtures.
Fig. 2
Suggested mechanism and transition states.
a
As the last resort, we decided to see the role of the reaction temperature. Gratifyingly, the reaction conducted at 0 °C (entry 18) afforded the target product 8a in noticeably increased amount, both chemical yield (95%) and diastereoselectivity (99 : 1 dr) (entry 18 vs. 1). With these results in hand, we were in a position to take on the most important goal of this study, the exploration of generality of these reactions. One may agree that the results summarized in Table 2 are truly remarkable leading to only one conclusion – the extraordinary generality of these reactions as well as their synthetic value in preparation of this new family of fluorinate β-keto-amines of high pharmaceutical potential. Thus, the isolated yields of products 10a–p were in the range between 83 and 98% and the diastereoselectivity between 98 : 2 and >99 : 1 dr, revealing absolutely no noticeable trend of the position or electronic nature of the substituent on the phenyl ring in substrates 9 on the stereochemical outcome. One may agree that the observed range in yields and diastereoselectivity might be rather the function of physicochemical properties of various compounds isolated on relatively small scale than the structural limitation of these reactions. Importantly, the heterocyclic and aliphatic substrates 9o and 9p gave the corresponding products 10o and 10p with perfect (>99 : 1 dr) diastereoselectivity (entries 15, 16). Taking advantage of the high crystallinity of compound 10o we performed its crystallographic study revealing the (Ss)(S) absolute configuration of product 10o (Fig. 1). Stereochemistry of all other derivatives 10a–p was assigned accordingly based on spectral as well as chiroptical properties of compounds 10a–p.
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Knowing the absolute configuration of reaction products we were in position to propose a plausible mechanism of the reactions under study. As shown in Fig. 2, we believe that a highly organized, chair-like transition state A cannot be formed as the groups R and CF3 are in close proximity to each other and therefore would be engaged in steric repulsive interactions. On the other hand, in the transition state B these groups are pointing in different directions and experiencing the least possible steric interactions with other substituents. Consequently, in our opinion, the transition state B is the most plausible and can account for the observed extraordinary generality of the reactions. Another, very important issue we felt should be addressed is the configurational stability of the compounds under study. Considering electron-withdrawing properties of the CF3 and CF2 groups,13 one may expect that the stereogenic CH(NH2) carbon might be reasonably acidic and therefore configurationally unstable in the presence of bases.14 To briefly assess this issue, we conducted a series of experiments monitoring the stability of compound 10a. We found that at ambient temperatures derivative 10a is indefinitely (7 days monitoring, see ESI†) stable in CHCl3, DMSO, benzene and CH3OH solutions (c = 0.01 mol L−1). The same experiments conducted in the presence of very large amounts (100 equiv.) of Et3N and DABCO also did not show any sign of decomposition or epimerization of the stereogenic center. However, exposure of compound 10a to 100 equiv. of DBU led to its decomposition.15,16 As the final objectives of this study, we decided to have some preliminary results on the chemistry of the products 10, their deprotection and useful chemical transformations. As shown in Scheme 2, the sulfinyl group in product 10i can be
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General information
Scheme 2
Removal of the sulfinyl group.
Scheme 3
Baeyer–Villiger oxidation of product 10i.
Scheme 4
Reduction of 10i with DIBAL.
easily removed under the standard conditions17 to furnish unprotected, free amine 11 in a good 88% yield. Of particular interest is the structural transformation of the compound 10i into the first representative example 12 of a new family of fluorinated β-amino acids (Scheme 3). Thus, under very mild conditions of Baeyer–Villiger oxidation product 12 was isolated in 83% yield. Finally, we briefly explored the chemistry and stereoselectivity of the carbonyl group reduction in compound 10i. As one can see from Scheme 4, using the DIBAL derivative 10i was cleanly transformed into 13 with good chemical yield (94%) and high, for this type of reactions, diastereoselectivity. Based on the literature precedent9 and spectroscopic properties of compound 13 the configuration of the newly created stereogenic center can be assigned as (R).
Conclusions To conclude, we have discovered that CF3-containing chiral N-tert-butanesulfinyl-imines cleanly react with in situ generated α,α-difluoroenolates giving rise to previously unknown type of β-keto-amino compounds possessing the R-CO-CF2-CH(NH2)CF3 moiety. These reactions feature remarkable generality allowing preparation of series of aromatic, hetero-aromatic and aliphatic derivatives in high yields and diastereoselectivity. Of particular scientific and synthetic value is that the resulting products are configurationally stable and can be easily deprotected and transformed to more functionally complex compounds such as β-amino acids. Systematic studies of the chemistry and chiroptical properties of these new compounds are currently underway in our laboratories.
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All commercial reagents and solvents were used without additional purification unless otherwise specified. CF3-sulfinylimine 6 was obtained from Accela ChemBio Co., Ltd. Pentafluoro-β-di-ketone hydrates 9 were synthesized according to literature.3,18 All experiments were monitored by thin layer chromatography (TLC). TLC was performed on pre-coated silica gel plates. Column chromatography was performed using silica gel 60 (300–400 mesh). 1H NMR (400 MHz), 13C NMR (101 MHz) and 19F NMR (376 MHz) spectra were obtained on a Bruker AVANCE III-400 spectrometer. Chemical shifts are reported in ppm (δ) relative to internal tetramethylsilane (TMS, δ 0.0 ppm) or with the solvent reference relative to TMS employed as the internal standard (CDCl3, δ 7.26 ppm). Data are reported as follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)], coupling constants [Hz], integration). Melting points are uncorrected. Values of optical rotation were measured on a Rudolph Automatic Polarimeter A21101. Infrared spectra were obtained on Bruker Vector 22 in KBr pellets. HRMS were recorded on a LTQ-Orbitrap XL (Thermofisher, USA). Procedure for the asymmetric addition of α,α-difluoroenolates to CF3-sulfinylimine To a solution of pentafluoro-β-di-ketone hydrates 9 (0.5 mmol), CF3-sulfinylimine 6 (120.7 mg, 0.6 mmol, 1.2 equiv.), and LiBr (130.3 mg, 1.5 mmol, 3.0 equiv.) in THF (5 mL) cooled in an ice-water bath was added Et3N (101.2 mg, 1.0 mmol, 2.0 equiv.) dropwise. After 30 min, the reaction was quenched with saturated aqueous NH4Cl (5 mL) followed by H2O (20 mL) and the mixture was brought to room temperature. The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H2O (2 × 50 mL) and brine solution (1 × 50 mL) and dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography to afford the corresponding products 10. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-phenylbutan2-yl)propane-2-sulfinamide (10a) Colorless oil (169.1 mg, 95% yield, 99 : 1 dr), [α]25 D +4.09 (c = 2.01, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.05–7.97 (m, 2H), 7.67–7.61 (m, 1H), 7.48 (t, J = 7.9 Hz, 2H), 4.90–4.74 (m, 1H), 4.08 (d, J = 10.9 Hz, 1H), 1.13 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.2 (dd, J = 29.8, 28.2 Hz), 135.2, 131.3 (t, J = 2.6 Hz), 130.1 (t, J = 3.3 Hz), 129.0, 122.8 (q, J = 284.5 Hz), 115.0 (t, J = 264.5 Hz), 60.5–59.0 (m), 57.8, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.1, 7.8 Hz, 3F), −104.6 (dq, J = 297.1, 13.1 Hz, 1F), −109.4 (dq, J = 297.2, 7.7 Hz, 1F). IR (KBr): ν = 2962, 2930, 1703, 1599, 1450, 1265, 1205, 1183, 1160, 1091, 1067, 882, 723, 688, 650 cm−1. HRMS [M + Na+]: calcd for C14H16F5NO2SNa+: 380.0714, found: 380.0715.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-(o-tolyl)butan2-yl)propane-2-sulfinamide (10b) Colorless oil (169.9 mg, 91% yield, 99 : 1 dr), [α]25 D +17.48 (c = 2.79, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.81 (d, J = 7.8 Hz, 1H), 7.51–7.43 (m, 1H), 7.35–7.26 (m, 2H), 4.95–4.79 (m, 1H), 4.09 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 1.23 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 190.2 (t, J = 28.3 Hz), 141.0, 133.4, 132.4, 130.9 (t, J = 2.1 Hz), 129.8 (t, J = 5.9 Hz), 125.7, 122.8 (qd, J = 284.0, 2.6 Hz), 114.5 (t, J = 264.5 Hz), 60.6–59.0 (m), 57.9, 22.4, 20.9; 19F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 11.5, 7.5 Hz, 3F), −104.8 (dq, J = 296.0, 7.5 Hz, 1F), −107.2 (dq, J = 296.0, 11.5 Hz, 1F). IR (KBr): ν = 3196, 2963, 1706, 1459, 1343, 1295, 1263, 1184, 1161, 1141, 1096, 883, 857, 740, 651 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO2SNa+: 394.0871, found: 394.0870. (S)-N-((S)-4-(2-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10c) Colorless oil (173.4 mg, 88% yield, 99 : 1 dr), [α]25 D +13.28 (c = 1.61, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.63 (d, J = 7.7 Hz, 1H), 7.49–7.45 (m, 2H), 7.38–7.31 (m, 1H), 4.91–4.74 (m, 1H), 4.14 (d, J = 10.7 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 189.0 (t, J = 30.4 Hz), 133.7, 133.4, 131.6 (t, J = 1.9 Hz), 131.4, 130.1 (t, J = 4.1 Hz), 126.7, 122.7 (qd, J = 284.3, 1.9 Hz), 113.8 (t, J = 264.5 Hz), 60.3–58.7 (m), 57.9, 22.4; 19 F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 11.5, 7.8 Hz, 3F), −106.8 (dq, J = 296.9, 7.8 Hz, 1F), −108.0 (dq, J = 297.0, 11.6 Hz, 1F). IR (KBr): ν = 3183, 2962, 2928, 1721, 1589, 1474, 1437, 1290, 1261, 1221, 1187, 1162, 1114, 1077, 1051, 883, 750, 646 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0329. (S)-N-((S)-4-(2-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10d) Colorless oil (195.8 mg, 89% yield, 98 : 2 dr), [α]25 D +9.02 (c = 2.22, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.70–7.60 (m, 2H), 7.42–7.34 (m, 2H), 4.89–4.72 (m, 1H), 4.15 (d, J = 10.7 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 189.3 (t, J = 30.3 Hz), 134.8, 133.7, 133.3, 130.1 (t, J = 4.4 Hz), 127.1, 122.7 (qd, J = 284.2, 2.0 Hz), 121.3, 113.7 (t, J = 264.7 Hz), 60.5–58.7 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 11.7, 7.7 Hz, 3F), −106.0 (dq, J = 297.9, 7.6 Hz, 1F), −107.6 (dq, J = 298.1, 11.7 Hz, 1F). IR (KBr): ν = 3188, 2962, 1722, 1289, 1262, 1219, 1187, 1162, 1112, 1072, 882, 747, 644 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 459.9819, found: 459.9817. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(3-methoxyphenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10e) Colorless oil (181.2 mg, 93% yield, 99 : 1 dr), [α]25 D −0.07 (c = 2.87, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.64 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.3, 2.6 Hz, 1H), 4.90–4.74 (m, 1H), 4.00 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 1.16 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.0 (dd, J = 29.5, 28.3 Hz), 160.0, 132.5 (t, J = 2.6 Hz), 130.1, 122.8 (q,
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Organic & Biomolecular Chemistry
J = 284.4 Hz), 122.6 (t, J = 4.0 Hz), 121.7, 115.0 (t, J = 264.3 Hz), 114.4 (t, J = 2.3 Hz), 60.7–59.1 (m), 57.9, 55.6, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.9 Hz, 3F), −104.6 (dq, J = 296.7, 13.0 Hz, 1F), −109.1 (dq, J = 296.7, 7.6 Hz, 1F). IR (KBr): ν = 3190, 2962, 1704, 1599, 1582, 1284, 1264, 1238, 1181, 1157, 1086, 882, 752, 683 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO3SNa+: 410.0820, found: 410.0819. (S)-N-((S)-4-(3-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10f ) White solid (181.1 mg, 92% yield, 99 : 1 dr), mp: 66–67 °C, 1 [α]25 D +4.60 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.99 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.64 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 4.89–4.74 (m, 1H), 4.01 (d, J = 10.7 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.3 (dd, J = 30.2, 29.1 Hz), 135.5, 135.2, 132.8 (t, J = 2.7 Hz), 130.5, 130.0 (t, J = 3.1 Hz), 128.2 (t, J = 4.0 Hz), 122.8 (q, J = 284.9 Hz), 114.9 (t, J = 264.3 Hz), 60.4–58.9 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −105.0 (dq, J = 299.7, 13.0 Hz, 1F), −109.0 (dq, J = 299.7, 7.6 Hz, 1F). IR (KBr): ν = 3196, 2963, 1711, 1264, 1220, 1186, 1162, 1119, 1086, 882, 752, 678 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0324. (S)-N-((S)-4-(3-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10g) White solid (200.5 mg, 92% yield, 98 : 2 dr), mp: 54–56 °C, 1 [α]25 D +4.45 (c = 0.99, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.13 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 4.88–4.73 (m, 1H), 4.05 (d, J = 10.7 Hz, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.2 (t, J = 29.7 Hz), 138.0, 133.0 (t, J = 2.7 Hz), 132.9 (t, J = 3.1 Hz), 130.6, 128.6 (t, J = 3.7 Hz), 123.3, 122.7 (q, J = 284.3 Hz), 114.9 (t, J = 264.1 Hz), 60.5–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.0, 7.6 Hz, 3F), −104.9 (dq, J = 299.6, 13.0 Hz, 1F), −109.0 (dq, J = 299.6, 7.6 Hz, 1F). IR (KBr): ν = 3177, 2962, 2929, 1710, 1565, 1474, 1366, 1348, 1265, 1186, 1161, 1117, 1075, 887, 749, 678, 661 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 459.9819, found: 459.9819. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-( p-tolyl)butan2-yl)propane-2-sulfinamide (10h) Colorless oil (175.5 mg, 94% yield, 99 : 1 dr), [α]25 D +1.30 (c = 2.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.90 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.88–4.72 (m, 1H), 4.07 (d, J = 10.6 Hz, 1H), 2.39 (s, 3H), 1.12 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.6 (dd, J = 29.4, 28.0 Hz), 146.6, 130.2 (t, J = 3.1 Hz), 129.7, 128.7 (t, J = 2.5 Hz), 122.8 (q, J = 284.3 Hz), 115.1 (t, J = 264.3 Hz), 60.5–58.9 (m), 57.7, 22.3, 21.8; 19F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 13.2, 7.8 Hz, 3F), −104.5 (dq, J = 295.7, 13.2 Hz, 1F), −109.6 (dq, J = 295.8, 7.7 Hz, 1F). IR (KBr): ν = 1698, 1607, 1265, 1203, 1181, 1161, 1128, 1103, 1064, 750, 667 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO2SNa+: 394.0871, found: 394.0874.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(4-methoxyphenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10i) White solid (184.9 mg, 95% yield, >99 : 1 dr), mp: 104–105 °C, 1 [α]25 D −1.87 (c = 1.07, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.03 (d, J = 8.9 Hz, 2H), 6.99–6.94 (m, 2H), 4.89–4.72 (m, 1H), 4.02 (d, J = 10.8 Hz, 1H), 3.88 (s, 3H), 1.14 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 185.3 (t, J = 28.4 Hz), 165.2, 132.8 (t, J = 3.5 Hz), 124.1 (t, J = 2.6 Hz), 122.9 (q, J = 284.3 Hz), 115.3 (t, J = 264.5 Hz), 114.4, 60.7–59.2 (m), 57.8, 55.7, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 8.0 Hz, 3F), −104.0 (dq, J = 295.2, 13.1 Hz, 1F), −109.0 (dq, J = 295.2, 8.0 Hz, 1F). IR (KBr): ν = 1693, 1601, 1267, 1178, 1160, 1101, 848 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO3SNa+: 410.0820, found: 410.0820. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(4-fluorophenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10j) Colorless oil (170.3 mg, 91% yield, 99 : 1 dr), [α]25 D +4.44 (c = 2.07, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.07 (dd, J = 8.8, 5.4 Hz, 2H), 7.19–7.12 (m, 2H), 4.88–4.73 (m, 1H), 4.09 (d, J = 10.7 Hz, 1H), 1.13 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 185.7 (dd, J = 29.7, 28.8 Hz), 166.9 (d, J = 259.2 Hz), 133.3–133.0 (m), 127.8 (q, J = 2.7 Hz), 122.8 (q, J = 284.3 Hz), 116.5 (d, J = 22.1 Hz), 115.1 (t, J = 264.3 Hz), 60.5–58.8 (m), 57.8, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.1, 7.7 Hz, 3F), −100.5 (s, 1F), −104.7 (dq, J = 298.0, 13.1 Hz, 1F), −108.9 (dq, J = 298.0, 7.7 Hz, 1F). IR (KBr): ν = 3184, 2963, 2930, 1704, 1600, 1509, 1302, 1265, 1246, 1222, 1185, 1163, 1109, 1086, 1066, 883, 855, 838 cm−1. HRMS [M + Na+]: calcd for C14H15F6NO2SNa+: 398.0620, found: 398.0621. (S)-N-((S)-4-(4-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10k) Colorless oil (181.2 mg, 93% yield, 99 : 1 dr), [α]25 D +2.61 (c = 0.92, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.98 (d, J = 8.6 Hz, 2H), 7.52–7.47 (m, 2H), 4.90–4.73 (m, 1H), 4.01 (d, J = 10.7 Hz, 1H), 1.16 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.2 (dd, J = 30.0, 28.9 Hz), 142.1, 131.5 (t, J = 3.5 Hz), 129.6 (t, J = 2.8 Hz), 129.6, 122.8 (q, J = 284.6 Hz), 115.0 (t, J = 264.3 Hz), 60.5–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −104.8 (dq, J = 298.9, 13.0 Hz, 1F), −109.0 (dq, J = 298.9, 7.7 Hz, 1F). IR (KBr): ν = 3184, 2963, 2929, 1706, 1589, 1266, 1205, 1183, 1162, 1115, 1093, 1065, 1015, 883, 849, 806, 759 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0324. (S)-N-((S)-4-(4-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10l) White solid (201.4 mg, 93% yield, 99 : 1 dr), mp: 80–81 °C, 1 [α]25 D +5.84 (c = 0.99, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.89 (d, J = 8.6 Hz, 2H), 7.68–7.63 (m, 2H), 4.89–4.73 (m, 1H), 4.02 (d, J = 10.7 Hz, 1H), 1.15 (s, 9 H); 13C NMR (CDCl3, 101 MHz): δ = 186.5 (t, J = 29.5 Hz), 132.5, 131.5 (t, J = 3.4 Hz), 131.0, 130.1 (t, J = 2.7 Hz), 122.8 (q, J = 284.2 Hz), 115.0 (t, J = 264.2 Hz), 60.4–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3,
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376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −104.9 (dq, J = 298.7, 13.0 Hz, 1F), −109.0 (dq, J = 298.7, 7.6 Hz, 1F). IR (KBr): ν = 3173, 2963, 2929, 2872, 1706, 1585, 1400, 1366, 1348, 1311, 1267, 1184, 1162, 1114, 1075, 1012, 923, 884, 852, 806, 756, 649 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 457.9819, found: 457.9818. (S)-N-((S)-4-(4-Cyanophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10m) Colorless oil (168.1 mg, 88% yield, 97 : 3 dr), [α]25 D +13.50 (c = 3.20, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.12 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 4.87–4.76 (m, 1H), 4.12 (d, J = 10.6 Hz, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.5 (t, J = 30.2 Hz), 134.4 (t, J = 2.6 Hz), 132.8, 130.4 (t, J = 3.3 Hz), 122.7 (q, J = 284.2 Hz), 118.3, 117.4, 114.8 (t, J = 267.1 Hz), 60.1–58.5 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.0, 7.4 Hz, 3F), −105.3 (dq, J = 300.9, 12.9 Hz, 1F), −109.0 (dq, J = 301.3, 7.5 Hz, 1F). IR (KBr): ν = 3203, 2980, 2966, 2931, 2233, 1716, 1266, 1223, 1180, 1162, 1094, 1064, 1020, 884, 856, 816, 770, 665 cm−1. HRMS [M + Na+]: calcd for C15H15F5N2O2SNa+: 405.0667, found: 405.0668. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(naphthalen-2-yl)4-oxobutan-2-yl)propane-2-sulfinamide (10n) Colorless oil (199.3 mg, 98% yield, 99 : 1 dr), [α]25 D +5.63 (c = 1.88, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.65 (s, 1H), 8.03–7.95 (m, 2H), 7.93–7.84 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 5.01–4.85 (m, 1H), 4.15 (d, J = 10.7 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.0 (t, J = 28.8 Hz), 136.3, 133.0 (t, J = 4.3 Hz), 132.2, 130.2, 130.0, 129.0, 128.5 (d, J = 2.3 Hz), 127.9, 127.4, 124.3, 122.9 (q, J = 284.3 Hz), 115.3 (t, J = 264.5 Hz), 60.6–59.1 (m), 57.8, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.1, 7.8 Hz, 3F), −103.9 (dq, J = 296.3, 13.1 Hz, 1F), −108.7 (dq, J = 296.3, 7.5 Hz, 1F). IR (KBr): ν = 3195, 2961, 2928, 1698, 1627, 1597, 1469, 1366, 1346, 1288, 1264, 1239, 1182, 1159, 1126, 1093, 871, 827, 794, 778, 761, 669, 474 cm−1. HRMS [M + Na+]: calcd for C18H18F5NO2SNa+: 430.0871, found: 430.0871. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-(thiophen2-yl)butan-2-yl)propane-2-sulfinamide (10o) White solid (178.4 mg, 98% yield, >99 : 1 dr), mp: 77–78 °C, 1 [α]25 D −21.05 (c = 0.30, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.07–8.01 (m, 1H), 7.87 (dd, J = 4.9, 1.0 Hz, 1H), 7.22 (dd, J = 4.9, 4.0 Hz, 1H), 4.83–4.67 (m, 1H), 4.00 (d, J = 10.8 Hz, 1H), 1.12 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 180.3 (dd, J = 30.3, 28.4 Hz), 138.1, 137.4 (dd, J = 3.4, 2.1 Hz), 136.5 (dd, J = 7.4, 4.1 Hz), 129.3, 122.7 (qd, J = 284.4, 1.1 Hz), 114.8 (t, J = 263.6 Hz), 60.7–59.1 (m), 57.9, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −69.2 (dd, J = 13.0, 7.8 Hz, 3F), −105.3 (dq, J = 284.3, 13.0 Hz, 1F), −112.1 (dq, J = 284.3, 7.8 Hz, 1F). IR (KBr): ν = 2962, 1671, 1411, 1290, 1263, 1205, 1183, 1160, 1117, 1086, 1043, 884, 736, 648 cm−1. HRMS [M + Na+]: calcd for C12H14F5NO2S2Na+: 386.0278, found: 386.0279.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-5,5-dimethyl4-oxohexan-2-yl)propane-2-sulfinamide (10p) Colorless oil (140.9 mg, 83% yield, >99 : 1 dr), [α]25 D +14.99 (c = 0.89, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 4.76–4.60 (m, 1H), 3.92 (d, J = 10.8 Hz, 1H), 1.25 (s, 9H), 1.20 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 202.4 (t, J = 26.7 Hz), 122.8 (qd, J = 284.1, 3.3 Hz), 115.3 (t, J = 266.3 Hz), 60.2–59.1 (m), 57.9, 43.9 (t, J = 2.5 Hz), 25.9 (t, J = 2.1 Hz), 22.4; 19F NMR (CDCl3, 376 MHz): δ = −69.3 (dd, J = 11.6, 7.5 Hz, 3F), −106.9 (dq, J = 299.2, 7.4 Hz, 1F), −108.4 (dq, J = 299.2, 11.6 Hz, 1F). IR (KBr): ν = 3188, 2975, 2937, 2877, 1728, 1482, 1368, 1342, 1267, 1235, 1203, 1170, 1150, 1136, 1119, 1078, 884, 864, 666 cm−1. HRMS [M + Na+]: calcd for C12H20F5NO2SNa+: 360.1027, found: 360.1027. Procedure for the deprotection of 10i to afford the free amine 11 10i (193.7 mg, 0.5 mmol) and MeOH (5 mL) were placed in a 25 mL round-bottom flask and aq. HCl (36%, 1 mL) was added dropwise. The reaction was stirred at room temperature for 24 h, during which the cleavage was monitored by TLC. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (1.52 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 h, then H2O (10 mL) was added. The organic layer was taken, washed with H2O (2 × 10 mL), dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography (hexanes– EtOAc = 2 : 1) to afford the corresponding deprotection product 11 as a white solid in 88% isolated yield. (S)-3-Amino-2,2,4,4,4-pentafluoro-1-(4-methoxyphenyl)butan1-one (11) White solid (124.8 mg, 88% yield), mp: 67–68 °C, [α]25 D +4.00 (c = 1.05, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.09 (d, J = 9.0 Hz, 2H), 7.01–6.94 (m, 2H), 4.33–4.18 (m, 1H), 3.90 (s, 3H), 1.72 (s, 2H); 13C NMR (CDCl3, 101 MHz): δ = 186.4 (t, J = 28.7 Hz), 165.0, 132.9 (t, J = 3.6 Hz), 124.7 (t, J = 2.3 Hz), 124.1 (q, J = 283.1 Hz), 116.1 (t, J = 262.3 Hz), 114.3, 55.8, 55.5–54.9 (m); 19F NMR (CDCl3, 376 MHz): δ = −72.0 (dd, J = 13.7, 7.4 Hz, 3F), −106.9 (dq, J = 289.6, 13.7 Hz, 1F), −113.8 (dq, J = 289.6, 7.4 Hz, 1F). IR (KBr): ν = 3429, 3356, 1698, 1604, 1514, 1364, 1263, 1219, 1178, 1166, 1147, 1115, 1091, 1067, 1020, 934, 859, 834, 783, 751, 682, 615, 584, 549 cm−1. HRMS [M + H+]: calcd for C11H11F5NO2+: 284.0704, found: 284.0703. Procedure for the Baeyer–Villiger oxidation of 10i to afford the product 12 To a solution of 10i (193.7 mg, 0.5 mmol) in 10 mL of CH2Cl2 cooled in an ice-water bath was added m-CPBA (431.4 mg, 2.5 mmol, 5.0 equiv.). The reaction was performed at 0 °C for 2 h followed by dilution with CH2Cl2 (20 mL) and extraction with aqueous NaHCO3 (20 mL). The organic layer was taken, washed with H2O (2 × 20 mL), dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product,
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Organic & Biomolecular Chemistry
which was purified by column chromatography (hexanes– EtOAc = 4 : 1) to afford the corresponding Baeyer–Villiger oxidation product 12 as a colorless oil in 83% isolated yield. (S)-4-Methoxyphenyl 3-(1,1-dimethylethylsulfonamido)2,2,4,4,4-pentafluorobutanoate (12) Colorless oil (173.8 mg, 83% yield), [α]25 D −14.20 (c = 0.34, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.14–7.08 (m, 2H), 6.95–6.90 (m, 2H), 5.02–4.77 (m, 2H), 3.82 (s, 3H), 1.47 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 160.2 (t, J = 31.3 Hz), 158.2, 143.0, 122.3 (qd, J = 283.3, 5.7 Hz), 121.6, 114.8, 111.2 (t, J = 259.6 Hz), 61.7, 58.5–56.9 (m), 55.7, 24.1; 19F NMR (CDCl3, 376 MHz): δ = −70.0 (dd, J = 10.6, 7.0 Hz, 3F), −108.8 (dq, J = 271.8, 6.9 Hz, 1F), −114.5 (dq, J = 271.6, 10.6 Hz, 1F). IR (KBr): ν = 3280, 1779, 1511, 1467, 1351, 1322, 1288, 1266, 1256, 1217, 1192, 1165, 1134, 1124, 1095, 1045, 905, 864, 826, 810, 719, 710, 665, 530, 520 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO5SNa+: 442.0718, found: 442.0720. Procedure for the DIBAL-H reduction of 10i to afford the product 13 A solution of 10i (193.7 mg, 0.5 mmol) in 5 mL of anhydrous THF was cooled to −78 °C. Then, 1.5 mL of DIBAL-H (1.0 M in THF, 1.5 mmol, 3.0 equiv.) was added dropwise, and the mixture was stirred at this temperature for 2 h. After completion of the reaction, several drops of 3.0 M HCl solution were added and the mixture was stirred at room temperature for 15 min, then H2O (20 mL) was added. The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H2O (2 × 50 mL) and brine solution (1 × 50 mL) and dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography (hexanes–EtOAc = 2 : 1) to afford the corresponding product 13 as a white solid in 94% isolated yield with 15 : 1 dr. (S)-2-Methyl-N-((2S)-1,1,1,3,3-pentafluoro-4-hydroxy-4-(4methoxyphenyl)butan-2-yl)propane-2-sulfinamide (13) White solid (182.3 mg, 94% yield, 15 : 1 dr), mp: 158–159 °C. 1 H NMR (CDCl3, 400 MHz): δ = 7.35 (d, J = 8.6 Hz, 2H), 6.94–6.89 (m, 2H), 5.00 (dd, J = 22.4, 2.4 Hz, 1H), 4.55–4.40 (m, 2H), 3.81 (s, 3H), 1.28 (s, 9H); 13C NMR (MeOD, 101 MHz): δ = 161.5, 130.7, 129.6, 125.2 (q, J = 284.2 Hz), 120.9 (t, J = 253.8 Hz), 114.5, 72.4 (dd, J = 32.7, 22.5 Hz), 61.2–60.2 (m), 59.0, 55.7, 23.1; 19F NMR (CDCl3, 376 MHz): δ = −68.7 (dd, J = 15.3, 9.9 Hz, 3F), −114.8 (d, J = 265.2 Hz, 1F), −120.4 (dq, J = 265.0, 15.2 Hz, 1F). IR (KBr): ν = 3355, 3269, 1614, 1516, 1337, 1307, 1259, 1249, 1226, 1167, 1132, 1048, 1031, 888, 847, 787, 756, 671 cm−1. HRMS [M + Na+]: calcd for C15H20F5NO3SNa+: 412.0976, found: 412.0981.
Acknowledgements We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 21102071)
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and the Fundamental Research Funds for the Central Universities (no. 1107020522 and no. 1082020502). The Jiangsu 333 program (for Pan) is also acknowledged.
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Notes and references 1 (a) C. Isanbor and D. O’Hagan, J. Fluorine Chem., 2006, 127, 303; (b) J. P. Begue and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127, 992; (c) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013; (d) D. O’Hagan, J. Fluorine Chem., 2010, 131, 1071. 2 J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432. 3 C. Han, E. H. Kim and D. A. Colby, J. Am. Chem. Soc., 2011, 133, 5802. 4 H. Ohkura, D. O. Berbasov and V. A. Soloshonok, Tetrahedron, 2003, 59, 1647. 5 G. K. S. Prakash, J. Hu, T. Mathew and G. A. Olah, Angew. Chem., Int. Ed., 2003, 42, 5216. 6 (a) G. Takikawa, K. Toma and K. Uneyama, Tetrahedron Lett., 2006, 47, 6509; (b) H. Amii, T. Kobayashi, H. Terasawa and K. Uneyama, Org. Lett., 2001, 3, 3103; (c) S. Jonet, F. Cherouvrier, T. Brigaud and C. Portella, Eur. J. Org. Chem., 2005, 4304. 7 For examples of OCC, see: (a) D. Boyall, D. E. Frantz and E. M. Carreira, Org. Lett., 2002, 4, 2605; (b) T. K. Ellis, C. H. Martin, G. M. Tsai, H. Ueki and V. A. Soloshonok, J. Org. Chem., 2003, 68, 6208. 8 J. P. John and D. A. Colby, J. Org. Chem., 2011, 76, 9163. 9 P. Zhang and C. Wolf, Angew. Chem., Int. Ed., 2013, 52, 7869. 10 P. Zhang and C. Wolf, J. Org. Chem., 2012, 77, 8840. 11 (a) V. A. Soloshonok, H. Ohkura, A. Sorochinsky, N. Voloshin, A. Markovsky, M. Belik and T. Yamazaki, Tetrahedron Lett., 2002, 43, 5445; (b) W. Kashikura, K. Mori and T. Akiyama, Org. Lett., 2011, 13, 1860; (c) Z. L. Yuan, Y. Wei and M. Shi, Tetrahedron, 2010, 66, 7361; (d) X. Fang, X. Yang, M. Zhao, Q. Di, X. Wang and F. Wu, J. Fluorine Chem., 2009, 130, 974.
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12 (a) H. Mei, Y. Xiong, J. Han and Y. Pan, Org. Biomol. Chem., 2011, 9, 1402; (b) N. Shibata, T. Nishimine, N. Shibata, E. Tokunaga, K. Kawada, T. Kagawa, A. E. Sorochinsky and V. A. Soloshonok, Chem. Commun., 2012, 48, 4124; (c) K. V. Turcheniuk, K. O. Poliashko, V. P. Kukhar, A. B. Rozhenko, V. A. Soloshonok and A. E. Sorochinsky, Chem. Commun., 2012, 48, 11519; (d) G. V. Röschenthaler, V. P. Kukhar, I. B. Kulik, M. Y. Belik, A. E. Sorochinsky, E. B. Rusanov and V. A. Soloshonok, Tetrahedron Lett., 2012, 53, 539; (e) C. Xie, H. Mei, L. Wu, V. A. Soloshonok, J. Han and Y. Pan, RSC Adv., 2014, 4, 4763; (f) C. Xie, H. B. Mei, L. M. Wu, V. A. Soloshonok, J. L. Han and Y. Pan, Eur. J. Org. Chem., 2014, 1445; (g) M. V. Shevchuk, V. P. Kukhar, G. V. Roeschenthaler, B. S. Bassil, K. Kawada, V. A. Soloshonok and A. E. Sorochinsky, RSC Adv., 2013, 3, 6479; (h) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010, 110, 3600; (i) H. Mei, C. Xie, L. Wu, V. A. Soloshonok, J. Han and Y. Pan, Org. Biomol. Chem., 2013, 11, 8018; ( j) H. Mei, Y. Xiong, C. Xie, V. A. Soloshonok, J. Han and Y. Pan, Org. Biomol. Chem., 2014, 12, 2108. 13 (a) V. A. Soloshonok and T. Hayashi, Tetrahedron: Asymmetry, 1994, 5, 1091; (b) H. Ohkura, D. O. Berbasov and V. A. Soloshonok, Tetrahedron, 2003, 59, 1647. 14 S. V. Kobzev, V. A. Soloshonok, S. V. Galushko, Y. L. Yagupolskii and V. P. Kukhar, Zh. Obshch. Khim., 1989, 59, 909. 15 (a) V. A. Soloshonok, H. Ohkura and M. Yasumoto, J. Fluorine Chem., 2006, 127, 924; (b) V. A. Soloshonok, H. Ohkura and M. Yasumoto, J. Fluorine Chem., 2006, 127, 930. 16 There is some similarity in the stability of 10a with the highly acidic stereogenic center in CF3–CH(Ph)(NvCH– Ph), see: V. A. Soloshonok and M. Yasumoto, J. Fluorine Chem., 2007, 128, 170. 17 J. Han, A. E. Sorochinsky, T. Ono and V. A. Soloshonok, Curr. Org. Synth., 2011, 8, 281. 18 I. Saidalimu, X. Fang, X. P. He, J. Liang, X. Yang and F. Wu, Angew. Chem., Int. Ed., 2013, 52, 5566.
Org. Biomol. Chem., 2014, 12, 7836–7843 | 7843
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PAPER
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Generalized access to fluorinated β-keto amino compounds through asymmetric additions of α,α-difluoroenolates to CF3-sulfinylimine† Chen Xie,a Lingmin Wu,a Haibo Mei,a Vadim A. Soloshonok,b,c Jianlin Han*a,d and Yi Pana CF3-containing chiral imines readily react with α,α-difluoroenolates affording a novel type of β-keto-
Received 25th July 2014, Accepted 12th August 2014
amino compounds featuring the R-CO-CF2-CH(NH2)-CF3 moiety. The reactions feature exceptional generality allowing preparation of various aromatic, hetero-aromatic and aliphatic derivatives in high
DOI: 10.1039/c4ob01575d
yields and diastereoselectivity. The products are configurationally stable and can be transformed to more
www.rsc.org/obc
functionalized complex compounds.
Introduction Fluorine-containing compounds constitute the fastest growing sector of the pharmaceutical and agrochemical industries.1 Thus, the recent decade has witnessed an unprecedented 20% growth in the number of marketed fluorine-containing drugs.2 Therefore, the development of new methods for the preparation of fluoroorganic compounds as well as the discovery of new fluorinated structural units play a paramount role in shaping up the future generations of more potent and selective drugs.1,2 In this regard, the Colby group has made an important discovery3 demonstrating that α,α-difluoroenolates 1 (Scheme 1) can be generated in situ via Et3N induced haloform-type reaction4 of pentafluoro-β-di-ketone hydrate 2. Trimethylsilyl ethers of 1 are extremely valuable intermediates for installation of the difluoromethylene group5 and their chemistry has been intensively studied. Compared to the literature methods,6 using specially prepared esters of 1, Colby’s approach has a clear advantage, as unprotected enolate 1 can be easily generated under the operationally convenient conditions7 and has an apparent potential for large scale applications. On the other hand, the chemistry of a protection free a School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China. E-mail: [email protected]; Fax: +86-25-83686133; Tel: +86-25-83686133 b Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain c IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain d Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China † Electronic supplementary information (ESI) available: Experimental procedures, full spectroscopic data for compounds 9–12 and copies of 1H NMR and 13 C NMR spectra. CCDC 972034. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01575d
7836 | Org. Biomol. Chem., 2014, 12, 7836–7843
Scheme 1
Generation and reactions of α,α-difluoroenolates 1.
enolate 1 still remains virtually unstudied. Thus, there are only four reports by Colby4,8 and Wolf9,10 groups describing aldol additions and halogenation of the in situ generated α,α-difluoroenolates 1.
Results and discussion Taking into consideration that α,α-difluoro-β-amino-ketones of structure 5 have even greater pharmaceutical potential1,2,6,11 as compared with derivatives 3, one may presume that Mannichtype addition reactions between enolate 1 and the corresponding imines may offer an advanced preparation of amino compounds 5. We report that the Mannich-type reactions of enolate 1 with (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine easily take place under operationally convenient conditions leading to compounds 5 (R′ = CF3) with excellent chemical yields and stereoselectivity. We demonstrate remarkable configurational stability of derivatives 5 as well as their deprotection and transformation to more functionally complex derivatives such as β-amino acids.
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Table 1
Paper
Optimization of reaction conditionsa
Entry
Base
Additive
Solvent
T (°C)
t (h)
Yieldb (%)
drc
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Et3N LiOH NaOH KOH Cs2CO3 CF3COOLi tBuOLi Et3N DABCO DBU DABCO DBU Et3N Et3N Et3N Et3N Et3N Et3N
LiBr No No No No No No No No No LiBr LiBr LiBr LiBr LiBr LiBr LiBr LiBr
THF THF THF THF THF THF THF THF THF THF THF THF DMF DCM CH3CN CH3OH Toluene THF
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 0
0.5 4 4 4 4 12 1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
91 22 14 13 6 0 48 0 0 8 85 77 11 10 65 0 8 95
95 : 5 96 : 4 97 : 3 97 : 3 99 : 1 — 94 : 6 — — 99 : 1 95 : 5 94 : 6 97 : 3 83 : 17 90 : 10 — 83 : 17 99 : 1
a
Reaction conditions: CF3-sulfinylimine 6 (0.6 mmol), 7a (0.5 mmol), base, solvent (5 mL), additive (1.5 mmol). b Isolated yields. c Determined by F NMR.
19
Drawing inspiration from the success of CF3-containing N-tert-butanesulfinyl-imines in the asymmetric synthesis of biologically relevant amino compounds,12 and Wolf group’s results on the reactions of trifluoromethyl ketones (CF3CO-R)10 with α,α-difluoroenolates 1, we focused our study on the addition reaction between enolates 1 and chiral CF3-sulfinylimine 6 (Table 1). Gratifyingly, the reaction between the precursor of α,α-difluoroenolate 1a, ketone 7a, and imine 6 occurred very cleanly affording the product 8a in 91% yield and 95 : 5 dr (Table 1, entry 1). This result was an important breakthrough indicating that practical access to a novel family of fluorinated compounds of type 8 having high pharmaceutical potential is a synthetic reality. With these exciting results in hand, we next looked into studying all aspects of the reaction conditions to further increase the synthetic value of this reaction. Our first goal was to establish the role of the counterion in stabilization vs. reactivity of the free α,α-difluoroenolate 1a. To this end we conducted a series of reactions of 7a with imine 6 in the presence of various inorganic bases and without the use of LiBr as an additive. The experiments using LiOH, NaOH, KOH and Cs2CO3 (entries 2–5) have revealed a very important trend. First of all, the chemical yield of the target product 8a in these reactions was dramatically lower as compared with the standard conditions using LiBr as an additive (entries 2–4 vs. 1). Second, the yield was also gradually decreasing along the series, from 22% in the LiOH promoted reaction (entry 2) to only 6% in the case Cs2CO3 was used as the base (entry 5). These experimental data strongly indicated the paramount role of the Li as a counterion in stabilization of the in situ formed α,α-difluoroenolate 1a. Surprisingly, the diastereo-
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selectivity was also gradually changing but in the opposite direction from 96 : 4 dr for LiOH (entry 2) to 99 : 1 dr in the Cs2CO3 used reaction (entry 5). It should be noted that the important role of Li was also observed by Wolf10 in the corresponding aldol addition reactions. Two additional experiments were conducted to see the role of Li in connection with the strength of the Li-derived base. As shown in entries 6 and 7, no reaction was observed in the case of the very weak base CF3COOLi (entry 6) while t-BuOLi promoted reaction gave the product 8a in 48% yield and 94 : 6 dr (entry 7). Following this trend we conducted a series of reactions using different organic bases (entries 8–10). Again, quite surprisingly, without LiBr as the additive, Et3N (entry 8) and DABCO (entry 9) promoted reactions failed to produce the product 8a while in the case of DBU (entry 10) the reaction did take place, but resulted in a low isolated yield of 8a. These data clearly indicated the importance of LiBr as an additive in these reactions. Therefore, we have repeated the additions using DABCO and DBU conducted in the presence of LiBr. As one can see from entries 11 and 12, the LiBr had quite a dramatic effect on the outcome of these reactions as the product 8a was isolated in reasonably good yield and diastereoselectivity. However still, the use of Et3N gave better stereochemical outcome (entries 11, 12 vs. 1) Finally, we decided to study the role of the reaction solvent and conducted a series of experiments using Et3N as a base along with LiBr as an additive. The results were rather disappointing (entries 13–17) pointing to THF as the solvent of choice, most likely for stabilization and reactivity of the α,α-difluoroenolate 1a. While all these results were of great exploratory value they did not allow us to improve the stereochemical outcome obtained under standard Colby conditions (entry 1).
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Table 2
Organic & Biomolecular Chemistry Generality of the asymmetric Mannich additionsa
Entry
R
Product
Yieldb (%)
drc
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
C6H5 2-CH3-C6H4 2-Cl-C6H4 2-Br-C6H4 3-MeO-C6H4 3-Cl-C6H4 3-Br-C6H4 4-Me-C6H4 4-MeO-C6H4 4-F-C6H4 4-Cl-C6H4 4-Br-C6H4 4-CN-C6H4 2-Naphthyl 2-Thienyl t-Bu
10a 10b 10c 10d 10e 10f 10g 10h 10i 10j 10k 10l 10m 10n 10o 10p
95 91 88 89 93 92 92 94 95 91 93 93 88 98 98 83
99 : 1 99 : 1 99 : 1 98 : 2 99 : 1 99 : 1 98 : 2 99 : 1 >99 : 1 99 : 1 99 : 1 99 : 1 97 : 3 99 : 1 >99 : 1 >99 : 1
Fig. 1
ORTEP structure of compound 9t (CCDC number 972034).
Reaction conditions: 9 (0.5 mmol), sulfinylimine 6 (0.6 mmol), LiBr (1.5 mmol), triethylamine (1.0 mmol), THF (5 mL), rt, 30 min. b Isolated yields. c Isomer ratio was determined by 19F NMR on crude reaction mixtures.
Fig. 2
Suggested mechanism and transition states.
a
As the last resort, we decided to see the role of the reaction temperature. Gratifyingly, the reaction conducted at 0 °C (entry 18) afforded the target product 8a in noticeably increased amount, both chemical yield (95%) and diastereoselectivity (99 : 1 dr) (entry 18 vs. 1). With these results in hand, we were in a position to take on the most important goal of this study, the exploration of generality of these reactions. One may agree that the results summarized in Table 2 are truly remarkable leading to only one conclusion – the extraordinary generality of these reactions as well as their synthetic value in preparation of this new family of fluorinate β-keto-amines of high pharmaceutical potential. Thus, the isolated yields of products 10a–p were in the range between 83 and 98% and the diastereoselectivity between 98 : 2 and >99 : 1 dr, revealing absolutely no noticeable trend of the position or electronic nature of the substituent on the phenyl ring in substrates 9 on the stereochemical outcome. One may agree that the observed range in yields and diastereoselectivity might be rather the function of physicochemical properties of various compounds isolated on relatively small scale than the structural limitation of these reactions. Importantly, the heterocyclic and aliphatic substrates 9o and 9p gave the corresponding products 10o and 10p with perfect (>99 : 1 dr) diastereoselectivity (entries 15, 16). Taking advantage of the high crystallinity of compound 10o we performed its crystallographic study revealing the (Ss)(S) absolute configuration of product 10o (Fig. 1). Stereochemistry of all other derivatives 10a–p was assigned accordingly based on spectral as well as chiroptical properties of compounds 10a–p.
7838 | Org. Biomol. Chem., 2014, 12, 7836–7843
Knowing the absolute configuration of reaction products we were in position to propose a plausible mechanism of the reactions under study. As shown in Fig. 2, we believe that a highly organized, chair-like transition state A cannot be formed as the groups R and CF3 are in close proximity to each other and therefore would be engaged in steric repulsive interactions. On the other hand, in the transition state B these groups are pointing in different directions and experiencing the least possible steric interactions with other substituents. Consequently, in our opinion, the transition state B is the most plausible and can account for the observed extraordinary generality of the reactions. Another, very important issue we felt should be addressed is the configurational stability of the compounds under study. Considering electron-withdrawing properties of the CF3 and CF2 groups,13 one may expect that the stereogenic CH(NH2) carbon might be reasonably acidic and therefore configurationally unstable in the presence of bases.14 To briefly assess this issue, we conducted a series of experiments monitoring the stability of compound 10a. We found that at ambient temperatures derivative 10a is indefinitely (7 days monitoring, see ESI†) stable in CHCl3, DMSO, benzene and CH3OH solutions (c = 0.01 mol L−1). The same experiments conducted in the presence of very large amounts (100 equiv.) of Et3N and DABCO also did not show any sign of decomposition or epimerization of the stereogenic center. However, exposure of compound 10a to 100 equiv. of DBU led to its decomposition.15,16 As the final objectives of this study, we decided to have some preliminary results on the chemistry of the products 10, their deprotection and useful chemical transformations. As shown in Scheme 2, the sulfinyl group in product 10i can be
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General information
Scheme 2
Removal of the sulfinyl group.
Scheme 3
Baeyer–Villiger oxidation of product 10i.
Scheme 4
Reduction of 10i with DIBAL.
easily removed under the standard conditions17 to furnish unprotected, free amine 11 in a good 88% yield. Of particular interest is the structural transformation of the compound 10i into the first representative example 12 of a new family of fluorinated β-amino acids (Scheme 3). Thus, under very mild conditions of Baeyer–Villiger oxidation product 12 was isolated in 83% yield. Finally, we briefly explored the chemistry and stereoselectivity of the carbonyl group reduction in compound 10i. As one can see from Scheme 4, using the DIBAL derivative 10i was cleanly transformed into 13 with good chemical yield (94%) and high, for this type of reactions, diastereoselectivity. Based on the literature precedent9 and spectroscopic properties of compound 13 the configuration of the newly created stereogenic center can be assigned as (R).
Conclusions To conclude, we have discovered that CF3-containing chiral N-tert-butanesulfinyl-imines cleanly react with in situ generated α,α-difluoroenolates giving rise to previously unknown type of β-keto-amino compounds possessing the R-CO-CF2-CH(NH2)CF3 moiety. These reactions feature remarkable generality allowing preparation of series of aromatic, hetero-aromatic and aliphatic derivatives in high yields and diastereoselectivity. Of particular scientific and synthetic value is that the resulting products are configurationally stable and can be easily deprotected and transformed to more functionally complex compounds such as β-amino acids. Systematic studies of the chemistry and chiroptical properties of these new compounds are currently underway in our laboratories.
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All commercial reagents and solvents were used without additional purification unless otherwise specified. CF3-sulfinylimine 6 was obtained from Accela ChemBio Co., Ltd. Pentafluoro-β-di-ketone hydrates 9 were synthesized according to literature.3,18 All experiments were monitored by thin layer chromatography (TLC). TLC was performed on pre-coated silica gel plates. Column chromatography was performed using silica gel 60 (300–400 mesh). 1H NMR (400 MHz), 13C NMR (101 MHz) and 19F NMR (376 MHz) spectra were obtained on a Bruker AVANCE III-400 spectrometer. Chemical shifts are reported in ppm (δ) relative to internal tetramethylsilane (TMS, δ 0.0 ppm) or with the solvent reference relative to TMS employed as the internal standard (CDCl3, δ 7.26 ppm). Data are reported as follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)], coupling constants [Hz], integration). Melting points are uncorrected. Values of optical rotation were measured on a Rudolph Automatic Polarimeter A21101. Infrared spectra were obtained on Bruker Vector 22 in KBr pellets. HRMS were recorded on a LTQ-Orbitrap XL (Thermofisher, USA). Procedure for the asymmetric addition of α,α-difluoroenolates to CF3-sulfinylimine To a solution of pentafluoro-β-di-ketone hydrates 9 (0.5 mmol), CF3-sulfinylimine 6 (120.7 mg, 0.6 mmol, 1.2 equiv.), and LiBr (130.3 mg, 1.5 mmol, 3.0 equiv.) in THF (5 mL) cooled in an ice-water bath was added Et3N (101.2 mg, 1.0 mmol, 2.0 equiv.) dropwise. After 30 min, the reaction was quenched with saturated aqueous NH4Cl (5 mL) followed by H2O (20 mL) and the mixture was brought to room temperature. The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H2O (2 × 50 mL) and brine solution (1 × 50 mL) and dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography to afford the corresponding products 10. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-phenylbutan2-yl)propane-2-sulfinamide (10a) Colorless oil (169.1 mg, 95% yield, 99 : 1 dr), [α]25 D +4.09 (c = 2.01, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.05–7.97 (m, 2H), 7.67–7.61 (m, 1H), 7.48 (t, J = 7.9 Hz, 2H), 4.90–4.74 (m, 1H), 4.08 (d, J = 10.9 Hz, 1H), 1.13 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.2 (dd, J = 29.8, 28.2 Hz), 135.2, 131.3 (t, J = 2.6 Hz), 130.1 (t, J = 3.3 Hz), 129.0, 122.8 (q, J = 284.5 Hz), 115.0 (t, J = 264.5 Hz), 60.5–59.0 (m), 57.8, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.1, 7.8 Hz, 3F), −104.6 (dq, J = 297.1, 13.1 Hz, 1F), −109.4 (dq, J = 297.2, 7.7 Hz, 1F). IR (KBr): ν = 2962, 2930, 1703, 1599, 1450, 1265, 1205, 1183, 1160, 1091, 1067, 882, 723, 688, 650 cm−1. HRMS [M + Na+]: calcd for C14H16F5NO2SNa+: 380.0714, found: 380.0715.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-(o-tolyl)butan2-yl)propane-2-sulfinamide (10b) Colorless oil (169.9 mg, 91% yield, 99 : 1 dr), [α]25 D +17.48 (c = 2.79, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.81 (d, J = 7.8 Hz, 1H), 7.51–7.43 (m, 1H), 7.35–7.26 (m, 2H), 4.95–4.79 (m, 1H), 4.09 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 1.23 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 190.2 (t, J = 28.3 Hz), 141.0, 133.4, 132.4, 130.9 (t, J = 2.1 Hz), 129.8 (t, J = 5.9 Hz), 125.7, 122.8 (qd, J = 284.0, 2.6 Hz), 114.5 (t, J = 264.5 Hz), 60.6–59.0 (m), 57.9, 22.4, 20.9; 19F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 11.5, 7.5 Hz, 3F), −104.8 (dq, J = 296.0, 7.5 Hz, 1F), −107.2 (dq, J = 296.0, 11.5 Hz, 1F). IR (KBr): ν = 3196, 2963, 1706, 1459, 1343, 1295, 1263, 1184, 1161, 1141, 1096, 883, 857, 740, 651 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO2SNa+: 394.0871, found: 394.0870. (S)-N-((S)-4-(2-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10c) Colorless oil (173.4 mg, 88% yield, 99 : 1 dr), [α]25 D +13.28 (c = 1.61, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.63 (d, J = 7.7 Hz, 1H), 7.49–7.45 (m, 2H), 7.38–7.31 (m, 1H), 4.91–4.74 (m, 1H), 4.14 (d, J = 10.7 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 189.0 (t, J = 30.4 Hz), 133.7, 133.4, 131.6 (t, J = 1.9 Hz), 131.4, 130.1 (t, J = 4.1 Hz), 126.7, 122.7 (qd, J = 284.3, 1.9 Hz), 113.8 (t, J = 264.5 Hz), 60.3–58.7 (m), 57.9, 22.4; 19 F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 11.5, 7.8 Hz, 3F), −106.8 (dq, J = 296.9, 7.8 Hz, 1F), −108.0 (dq, J = 297.0, 11.6 Hz, 1F). IR (KBr): ν = 3183, 2962, 2928, 1721, 1589, 1474, 1437, 1290, 1261, 1221, 1187, 1162, 1114, 1077, 1051, 883, 750, 646 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0329. (S)-N-((S)-4-(2-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10d) Colorless oil (195.8 mg, 89% yield, 98 : 2 dr), [α]25 D +9.02 (c = 2.22, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.70–7.60 (m, 2H), 7.42–7.34 (m, 2H), 4.89–4.72 (m, 1H), 4.15 (d, J = 10.7 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 189.3 (t, J = 30.3 Hz), 134.8, 133.7, 133.3, 130.1 (t, J = 4.4 Hz), 127.1, 122.7 (qd, J = 284.2, 2.0 Hz), 121.3, 113.7 (t, J = 264.7 Hz), 60.5–58.7 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 11.7, 7.7 Hz, 3F), −106.0 (dq, J = 297.9, 7.6 Hz, 1F), −107.6 (dq, J = 298.1, 11.7 Hz, 1F). IR (KBr): ν = 3188, 2962, 1722, 1289, 1262, 1219, 1187, 1162, 1112, 1072, 882, 747, 644 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 459.9819, found: 459.9817. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(3-methoxyphenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10e) Colorless oil (181.2 mg, 93% yield, 99 : 1 dr), [α]25 D −0.07 (c = 2.87, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.64 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.3, 2.6 Hz, 1H), 4.90–4.74 (m, 1H), 4.00 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 1.16 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.0 (dd, J = 29.5, 28.3 Hz), 160.0, 132.5 (t, J = 2.6 Hz), 130.1, 122.8 (q,
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Organic & Biomolecular Chemistry
J = 284.4 Hz), 122.6 (t, J = 4.0 Hz), 121.7, 115.0 (t, J = 264.3 Hz), 114.4 (t, J = 2.3 Hz), 60.7–59.1 (m), 57.9, 55.6, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.9 Hz, 3F), −104.6 (dq, J = 296.7, 13.0 Hz, 1F), −109.1 (dq, J = 296.7, 7.6 Hz, 1F). IR (KBr): ν = 3190, 2962, 1704, 1599, 1582, 1284, 1264, 1238, 1181, 1157, 1086, 882, 752, 683 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO3SNa+: 410.0820, found: 410.0819. (S)-N-((S)-4-(3-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10f ) White solid (181.1 mg, 92% yield, 99 : 1 dr), mp: 66–67 °C, 1 [α]25 D +4.60 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.99 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.64 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 4.89–4.74 (m, 1H), 4.01 (d, J = 10.7 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.3 (dd, J = 30.2, 29.1 Hz), 135.5, 135.2, 132.8 (t, J = 2.7 Hz), 130.5, 130.0 (t, J = 3.1 Hz), 128.2 (t, J = 4.0 Hz), 122.8 (q, J = 284.9 Hz), 114.9 (t, J = 264.3 Hz), 60.4–58.9 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −105.0 (dq, J = 299.7, 13.0 Hz, 1F), −109.0 (dq, J = 299.7, 7.6 Hz, 1F). IR (KBr): ν = 3196, 2963, 1711, 1264, 1220, 1186, 1162, 1119, 1086, 882, 752, 678 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0324. (S)-N-((S)-4-(3-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10g) White solid (200.5 mg, 92% yield, 98 : 2 dr), mp: 54–56 °C, 1 [α]25 D +4.45 (c = 0.99, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.13 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 4.88–4.73 (m, 1H), 4.05 (d, J = 10.7 Hz, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.2 (t, J = 29.7 Hz), 138.0, 133.0 (t, J = 2.7 Hz), 132.9 (t, J = 3.1 Hz), 130.6, 128.6 (t, J = 3.7 Hz), 123.3, 122.7 (q, J = 284.3 Hz), 114.9 (t, J = 264.1 Hz), 60.5–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.0, 7.6 Hz, 3F), −104.9 (dq, J = 299.6, 13.0 Hz, 1F), −109.0 (dq, J = 299.6, 7.6 Hz, 1F). IR (KBr): ν = 3177, 2962, 2929, 1710, 1565, 1474, 1366, 1348, 1265, 1186, 1161, 1117, 1075, 887, 749, 678, 661 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 459.9819, found: 459.9819. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-( p-tolyl)butan2-yl)propane-2-sulfinamide (10h) Colorless oil (175.5 mg, 94% yield, 99 : 1 dr), [α]25 D +1.30 (c = 2.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.90 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.88–4.72 (m, 1H), 4.07 (d, J = 10.6 Hz, 1H), 2.39 (s, 3H), 1.12 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.6 (dd, J = 29.4, 28.0 Hz), 146.6, 130.2 (t, J = 3.1 Hz), 129.7, 128.7 (t, J = 2.5 Hz), 122.8 (q, J = 284.3 Hz), 115.1 (t, J = 264.3 Hz), 60.5–58.9 (m), 57.7, 22.3, 21.8; 19F NMR (CDCl3, 376 MHz): δ = −69.0 (dd, J = 13.2, 7.8 Hz, 3F), −104.5 (dq, J = 295.7, 13.2 Hz, 1F), −109.6 (dq, J = 295.8, 7.7 Hz, 1F). IR (KBr): ν = 1698, 1607, 1265, 1203, 1181, 1161, 1128, 1103, 1064, 750, 667 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO2SNa+: 394.0871, found: 394.0874.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(4-methoxyphenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10i) White solid (184.9 mg, 95% yield, >99 : 1 dr), mp: 104–105 °C, 1 [α]25 D −1.87 (c = 1.07, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.03 (d, J = 8.9 Hz, 2H), 6.99–6.94 (m, 2H), 4.89–4.72 (m, 1H), 4.02 (d, J = 10.8 Hz, 1H), 3.88 (s, 3H), 1.14 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 185.3 (t, J = 28.4 Hz), 165.2, 132.8 (t, J = 3.5 Hz), 124.1 (t, J = 2.6 Hz), 122.9 (q, J = 284.3 Hz), 115.3 (t, J = 264.5 Hz), 114.4, 60.7–59.2 (m), 57.8, 55.7, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 8.0 Hz, 3F), −104.0 (dq, J = 295.2, 13.1 Hz, 1F), −109.0 (dq, J = 295.2, 8.0 Hz, 1F). IR (KBr): ν = 1693, 1601, 1267, 1178, 1160, 1101, 848 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO3SNa+: 410.0820, found: 410.0820. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(4-fluorophenyl)4-oxobutan-2-yl)propane-2-sulfinamide (10j) Colorless oil (170.3 mg, 91% yield, 99 : 1 dr), [α]25 D +4.44 (c = 2.07, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.07 (dd, J = 8.8, 5.4 Hz, 2H), 7.19–7.12 (m, 2H), 4.88–4.73 (m, 1H), 4.09 (d, J = 10.7 Hz, 1H), 1.13 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 185.7 (dd, J = 29.7, 28.8 Hz), 166.9 (d, J = 259.2 Hz), 133.3–133.0 (m), 127.8 (q, J = 2.7 Hz), 122.8 (q, J = 284.3 Hz), 116.5 (d, J = 22.1 Hz), 115.1 (t, J = 264.3 Hz), 60.5–58.8 (m), 57.8, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.1, 7.7 Hz, 3F), −100.5 (s, 1F), −104.7 (dq, J = 298.0, 13.1 Hz, 1F), −108.9 (dq, J = 298.0, 7.7 Hz, 1F). IR (KBr): ν = 3184, 2963, 2930, 1704, 1600, 1509, 1302, 1265, 1246, 1222, 1185, 1163, 1109, 1086, 1066, 883, 855, 838 cm−1. HRMS [M + Na+]: calcd for C14H15F6NO2SNa+: 398.0620, found: 398.0621. (S)-N-((S)-4-(4-Chlorophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10k) Colorless oil (181.2 mg, 93% yield, 99 : 1 dr), [α]25 D +2.61 (c = 0.92, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.98 (d, J = 8.6 Hz, 2H), 7.52–7.47 (m, 2H), 4.90–4.73 (m, 1H), 4.01 (d, J = 10.7 Hz, 1H), 1.16 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.2 (dd, J = 30.0, 28.9 Hz), 142.1, 131.5 (t, J = 3.5 Hz), 129.6 (t, J = 2.8 Hz), 129.6, 122.8 (q, J = 284.6 Hz), 115.0 (t, J = 264.3 Hz), 60.5–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −104.8 (dq, J = 298.9, 13.0 Hz, 1F), −109.0 (dq, J = 298.9, 7.7 Hz, 1F). IR (KBr): ν = 3184, 2963, 2929, 1706, 1589, 1266, 1205, 1183, 1162, 1115, 1093, 1065, 1015, 883, 849, 806, 759 cm−1. HRMS [M + Na+]: calcd for C14H15ClF5NO2SNa+: 414.0324, found: 414.0324. (S)-N-((S)-4-(4-Bromophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10l) White solid (201.4 mg, 93% yield, 99 : 1 dr), mp: 80–81 °C, 1 [α]25 D +5.84 (c = 0.99, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.89 (d, J = 8.6 Hz, 2H), 7.68–7.63 (m, 2H), 4.89–4.73 (m, 1H), 4.02 (d, J = 10.7 Hz, 1H), 1.15 (s, 9 H); 13C NMR (CDCl3, 101 MHz): δ = 186.5 (t, J = 29.5 Hz), 132.5, 131.5 (t, J = 3.4 Hz), 131.0, 130.1 (t, J = 2.7 Hz), 122.8 (q, J = 284.2 Hz), 115.0 (t, J = 264.2 Hz), 60.4–58.8 (m), 57.9, 22.4; 19F NMR (CDCl3,
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376 MHz): δ = −68.9 (dd, J = 13.0, 7.7 Hz, 3F), −104.9 (dq, J = 298.7, 13.0 Hz, 1F), −109.0 (dq, J = 298.7, 7.6 Hz, 1F). IR (KBr): ν = 3173, 2963, 2929, 2872, 1706, 1585, 1400, 1366, 1348, 1311, 1267, 1184, 1162, 1114, 1075, 1012, 923, 884, 852, 806, 756, 649 cm−1. HRMS [M + Na+]: calcd for C14H15BrF5NO2SNa+: 457.9819, found: 457.9818. (S)-N-((S)-4-(4-Cyanophenyl)-1,1,1,3,3-pentafluoro-4-oxobutan2-yl)-2-methylpropane-2-sulfinamide (10m) Colorless oil (168.1 mg, 88% yield, 97 : 3 dr), [α]25 D +13.50 (c = 3.20, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.12 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 4.87–4.76 (m, 1H), 4.12 (d, J = 10.6 Hz, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 186.5 (t, J = 30.2 Hz), 134.4 (t, J = 2.6 Hz), 132.8, 130.4 (t, J = 3.3 Hz), 122.7 (q, J = 284.2 Hz), 118.3, 117.4, 114.8 (t, J = 267.1 Hz), 60.1–58.5 (m), 57.9, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.0, 7.4 Hz, 3F), −105.3 (dq, J = 300.9, 12.9 Hz, 1F), −109.0 (dq, J = 301.3, 7.5 Hz, 1F). IR (KBr): ν = 3203, 2980, 2966, 2931, 2233, 1716, 1266, 1223, 1180, 1162, 1094, 1064, 1020, 884, 856, 816, 770, 665 cm−1. HRMS [M + Na+]: calcd for C15H15F5N2O2SNa+: 405.0667, found: 405.0668. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-(naphthalen-2-yl)4-oxobutan-2-yl)propane-2-sulfinamide (10n) Colorless oil (199.3 mg, 98% yield, 99 : 1 dr), [α]25 D +5.63 (c = 1.88, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.65 (s, 1H), 8.03–7.95 (m, 2H), 7.93–7.84 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 5.01–4.85 (m, 1H), 4.15 (d, J = 10.7 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 187.0 (t, J = 28.8 Hz), 136.3, 133.0 (t, J = 4.3 Hz), 132.2, 130.2, 130.0, 129.0, 128.5 (d, J = 2.3 Hz), 127.9, 127.4, 124.3, 122.9 (q, J = 284.3 Hz), 115.3 (t, J = 264.5 Hz), 60.6–59.1 (m), 57.8, 22.4; 19F NMR (CDCl3, 376 MHz): δ = −68.8 (dd, J = 13.1, 7.8 Hz, 3F), −103.9 (dq, J = 296.3, 13.1 Hz, 1F), −108.7 (dq, J = 296.3, 7.5 Hz, 1F). IR (KBr): ν = 3195, 2961, 2928, 1698, 1627, 1597, 1469, 1366, 1346, 1288, 1264, 1239, 1182, 1159, 1126, 1093, 871, 827, 794, 778, 761, 669, 474 cm−1. HRMS [M + Na+]: calcd for C18H18F5NO2SNa+: 430.0871, found: 430.0871. (S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-4-oxo-4-(thiophen2-yl)butan-2-yl)propane-2-sulfinamide (10o) White solid (178.4 mg, 98% yield, >99 : 1 dr), mp: 77–78 °C, 1 [α]25 D −21.05 (c = 0.30, CHCl3). H NMR (CDCl3, 400 MHz): δ = 8.07–8.01 (m, 1H), 7.87 (dd, J = 4.9, 1.0 Hz, 1H), 7.22 (dd, J = 4.9, 4.0 Hz, 1H), 4.83–4.67 (m, 1H), 4.00 (d, J = 10.8 Hz, 1H), 1.12 (s, 9H); 13C NMR (CDCl3, 101 MHz): δ = 180.3 (dd, J = 30.3, 28.4 Hz), 138.1, 137.4 (dd, J = 3.4, 2.1 Hz), 136.5 (dd, J = 7.4, 4.1 Hz), 129.3, 122.7 (qd, J = 284.4, 1.1 Hz), 114.8 (t, J = 263.6 Hz), 60.7–59.1 (m), 57.9, 22.3; 19F NMR (CDCl3, 376 MHz): δ = −69.2 (dd, J = 13.0, 7.8 Hz, 3F), −105.3 (dq, J = 284.3, 13.0 Hz, 1F), −112.1 (dq, J = 284.3, 7.8 Hz, 1F). IR (KBr): ν = 2962, 1671, 1411, 1290, 1263, 1205, 1183, 1160, 1117, 1086, 1043, 884, 736, 648 cm−1. HRMS [M + Na+]: calcd for C12H14F5NO2S2Na+: 386.0278, found: 386.0279.
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(S)-2-Methyl-N-((S)-1,1,1,3,3-pentafluoro-5,5-dimethyl4-oxohexan-2-yl)propane-2-sulfinamide (10p) Colorless oil (140.9 mg, 83% yield, >99 : 1 dr), [α]25 D +14.99 (c = 0.89, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 4.76–4.60 (m, 1H), 3.92 (d, J = 10.8 Hz, 1H), 1.25 (s, 9H), 1.20 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 202.4 (t, J = 26.7 Hz), 122.8 (qd, J = 284.1, 3.3 Hz), 115.3 (t, J = 266.3 Hz), 60.2–59.1 (m), 57.9, 43.9 (t, J = 2.5 Hz), 25.9 (t, J = 2.1 Hz), 22.4; 19F NMR (CDCl3, 376 MHz): δ = −69.3 (dd, J = 11.6, 7.5 Hz, 3F), −106.9 (dq, J = 299.2, 7.4 Hz, 1F), −108.4 (dq, J = 299.2, 11.6 Hz, 1F). IR (KBr): ν = 3188, 2975, 2937, 2877, 1728, 1482, 1368, 1342, 1267, 1235, 1203, 1170, 1150, 1136, 1119, 1078, 884, 864, 666 cm−1. HRMS [M + Na+]: calcd for C12H20F5NO2SNa+: 360.1027, found: 360.1027. Procedure for the deprotection of 10i to afford the free amine 11 10i (193.7 mg, 0.5 mmol) and MeOH (5 mL) were placed in a 25 mL round-bottom flask and aq. HCl (36%, 1 mL) was added dropwise. The reaction was stirred at room temperature for 24 h, during which the cleavage was monitored by TLC. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (1.52 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 h, then H2O (10 mL) was added. The organic layer was taken, washed with H2O (2 × 10 mL), dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography (hexanes– EtOAc = 2 : 1) to afford the corresponding deprotection product 11 as a white solid in 88% isolated yield. (S)-3-Amino-2,2,4,4,4-pentafluoro-1-(4-methoxyphenyl)butan1-one (11) White solid (124.8 mg, 88% yield), mp: 67–68 °C, [α]25 D +4.00 (c = 1.05, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.09 (d, J = 9.0 Hz, 2H), 7.01–6.94 (m, 2H), 4.33–4.18 (m, 1H), 3.90 (s, 3H), 1.72 (s, 2H); 13C NMR (CDCl3, 101 MHz): δ = 186.4 (t, J = 28.7 Hz), 165.0, 132.9 (t, J = 3.6 Hz), 124.7 (t, J = 2.3 Hz), 124.1 (q, J = 283.1 Hz), 116.1 (t, J = 262.3 Hz), 114.3, 55.8, 55.5–54.9 (m); 19F NMR (CDCl3, 376 MHz): δ = −72.0 (dd, J = 13.7, 7.4 Hz, 3F), −106.9 (dq, J = 289.6, 13.7 Hz, 1F), −113.8 (dq, J = 289.6, 7.4 Hz, 1F). IR (KBr): ν = 3429, 3356, 1698, 1604, 1514, 1364, 1263, 1219, 1178, 1166, 1147, 1115, 1091, 1067, 1020, 934, 859, 834, 783, 751, 682, 615, 584, 549 cm−1. HRMS [M + H+]: calcd for C11H11F5NO2+: 284.0704, found: 284.0703. Procedure for the Baeyer–Villiger oxidation of 10i to afford the product 12 To a solution of 10i (193.7 mg, 0.5 mmol) in 10 mL of CH2Cl2 cooled in an ice-water bath was added m-CPBA (431.4 mg, 2.5 mmol, 5.0 equiv.). The reaction was performed at 0 °C for 2 h followed by dilution with CH2Cl2 (20 mL) and extraction with aqueous NaHCO3 (20 mL). The organic layer was taken, washed with H2O (2 × 20 mL), dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product,
7842 | Org. Biomol. Chem., 2014, 12, 7836–7843
Organic & Biomolecular Chemistry
which was purified by column chromatography (hexanes– EtOAc = 4 : 1) to afford the corresponding Baeyer–Villiger oxidation product 12 as a colorless oil in 83% isolated yield. (S)-4-Methoxyphenyl 3-(1,1-dimethylethylsulfonamido)2,2,4,4,4-pentafluorobutanoate (12) Colorless oil (173.8 mg, 83% yield), [α]25 D −14.20 (c = 0.34, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.14–7.08 (m, 2H), 6.95–6.90 (m, 2H), 5.02–4.77 (m, 2H), 3.82 (s, 3H), 1.47 (s, 9H); 13 C NMR (CDCl3, 101 MHz): δ = 160.2 (t, J = 31.3 Hz), 158.2, 143.0, 122.3 (qd, J = 283.3, 5.7 Hz), 121.6, 114.8, 111.2 (t, J = 259.6 Hz), 61.7, 58.5–56.9 (m), 55.7, 24.1; 19F NMR (CDCl3, 376 MHz): δ = −70.0 (dd, J = 10.6, 7.0 Hz, 3F), −108.8 (dq, J = 271.8, 6.9 Hz, 1F), −114.5 (dq, J = 271.6, 10.6 Hz, 1F). IR (KBr): ν = 3280, 1779, 1511, 1467, 1351, 1322, 1288, 1266, 1256, 1217, 1192, 1165, 1134, 1124, 1095, 1045, 905, 864, 826, 810, 719, 710, 665, 530, 520 cm−1. HRMS [M + Na+]: calcd for C15H18F5NO5SNa+: 442.0718, found: 442.0720. Procedure for the DIBAL-H reduction of 10i to afford the product 13 A solution of 10i (193.7 mg, 0.5 mmol) in 5 mL of anhydrous THF was cooled to −78 °C. Then, 1.5 mL of DIBAL-H (1.0 M in THF, 1.5 mmol, 3.0 equiv.) was added dropwise, and the mixture was stirred at this temperature for 2 h. After completion of the reaction, several drops of 3.0 M HCl solution were added and the mixture was stirred at room temperature for 15 min, then H2O (20 mL) was added. The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H2O (2 × 50 mL) and brine solution (1 × 50 mL) and dried with anhydrous Na2SO4, filtered and the solvent was removed to give the crude product, which was purified by column chromatography (hexanes–EtOAc = 2 : 1) to afford the corresponding product 13 as a white solid in 94% isolated yield with 15 : 1 dr. (S)-2-Methyl-N-((2S)-1,1,1,3,3-pentafluoro-4-hydroxy-4-(4methoxyphenyl)butan-2-yl)propane-2-sulfinamide (13) White solid (182.3 mg, 94% yield, 15 : 1 dr), mp: 158–159 °C. 1 H NMR (CDCl3, 400 MHz): δ = 7.35 (d, J = 8.6 Hz, 2H), 6.94–6.89 (m, 2H), 5.00 (dd, J = 22.4, 2.4 Hz, 1H), 4.55–4.40 (m, 2H), 3.81 (s, 3H), 1.28 (s, 9H); 13C NMR (MeOD, 101 MHz): δ = 161.5, 130.7, 129.6, 125.2 (q, J = 284.2 Hz), 120.9 (t, J = 253.8 Hz), 114.5, 72.4 (dd, J = 32.7, 22.5 Hz), 61.2–60.2 (m), 59.0, 55.7, 23.1; 19F NMR (CDCl3, 376 MHz): δ = −68.7 (dd, J = 15.3, 9.9 Hz, 3F), −114.8 (d, J = 265.2 Hz, 1F), −120.4 (dq, J = 265.0, 15.2 Hz, 1F). IR (KBr): ν = 3355, 3269, 1614, 1516, 1337, 1307, 1259, 1249, 1226, 1167, 1132, 1048, 1031, 888, 847, 787, 756, 671 cm−1. HRMS [M + Na+]: calcd for C15H20F5NO3SNa+: 412.0976, found: 412.0981.
Acknowledgements We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 21102071)
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and the Fundamental Research Funds for the Central Universities (no. 1107020522 and no. 1082020502). The Jiangsu 333 program (for Pan) is also acknowledged.
Published on 13 August 2014. Downloaded by Yale University Library on 01/10/2014 15:18:52.
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