Synthesis of β-Ketosulfonamides Derived from Amino Acids and Their

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Cite This: J. Org. Chem. 2017, 82, 11157-11165

Synthesis of β‑Ketosulfonamides Derived from Amino Acids and Their Conversion to β‑Keto-α,α-difluorosulfonamides via Electrophilic Fluorination Jacob Soley,† Edmond Chiu,† Ryan Chung,‡ Jeremy Green,§ Jason E. Hein,‡ and Scott D. Taylor*,† †

Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada § Vertex Pharmaceuticals, 50 Northern Avenue, Boston, Massachusetts 02210, United States ‡

S Supporting Information *

ABSTRACT: β-Ketosulfonamides derived from Boc or Cbzprotected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating N-allyl, N-alkyl methanesulfonamides with n-BuLi, followed by reaction of the resulting carbanion with methyl esters of N-protected L-amino acids. The analogous reaction using the dianion derived from an N-alkyl methanesulfonamide proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15−60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be removed in good yield using cat. Pd(PPh)3)4 and dimethyl barbituric acid. When the fluorination reaction was performed with Cs2CO3 as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while βketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides.

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INTRODUCTION

As part of a research program on the development of inhibitors of medicinally significant proteases, we wished to prepare a series of N-ethyl or, preferably, N-methyl β-keto-α,αdifluorosulfonamides derived from hydrophobic amino acids. Here we report the synthesis of β-ketosulfonamides (3) (Figure 2) derived from α-amino acids by reaction of monoanions of N-

β-Keto-α,α-difluoro esters, amides, and phosphonates have been the subjects of study for many years mainly due to their applications as probes and inhibitors of enzymes. For example, certain β-keto-α,α-difluoroamides have been shown to be up to 1000 times more potent inhibitors of serine proteases, such as pepsin,2a renin,2b elastase,2c and chymase,2d than their nonfluorinated counterparts. Studies indicate that β-keto-α,αdifluoroamides inhibit these enzymes by forming covalent adducts with active site residues.2c Surprisingly, only a single report has appeared that has described the synthesis and in vitro biological activity of a βketo-α,α-difluorosulfonamide.4 In 2007, Vannada et al. reported the synthesis of compound 1 (Figure 1), a hydrolytically stable analog of compound 2, which is a highly potent inhibitor of MtbA, an enzyme involved in the biosynthesis of mycobactins in Mycobacterium tuberculosis. 1

2

3

Figure 2. Compounds prepared in this study.

alkyl, N-allylmethanesulfonamides with N-protected amino acid methyl esters. These β-ketosulfonamides were converted into the corresponding β-keto-α,α-difluorosulfonamides (4) (Figure 2) by electrophilic fluorination of 3 using Selectfluor in the presence of CsF. We also report that when the fluorination reaction was performed using Cs2CO3, compounds of type 5 were obtained as the dominant products, and the formation of these compounds was dependent upon the side chain of the amino acid.

Figure 1. Compound 1, a hydrolytically stable analog of MtbA inhibitor 2. © 2017 American Chemical Society

Received: August 29, 2017 Published: October 11, 2017 11157

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry Scheme 1. Synthesis of β-ketosulfonamides 9−11

Table 1. Formation of β-Ketosulfonamides from N,N-Disubstituted Methanesulfonamides and N-Protected Amino Acid Methyl Esters

entry 1 2 3 4 5 6 7 8 9 a

sulfonamide 7 12 12 12 12 12 12 12 12

amino acid ester 2

product

3

8 (R = CH2CH2Ph, R = Boc) 13 (R2 = CH(CH3)2, R3 = Boc) 14 (R2 = CH2Ph, R3 = Boc) 15 (R2 = CH3, R3 = Boc) 16 (R2 = CH2CH2SCH3, R3 = Boc) 17 (R2 = CH(CH3)2, R3 = Z) 18 (R2 = CH(CH3)CH2CH3, R3 = Z) 19 (R2 = CH2CH(CH3)2, R3 = Z) 20 (R2 = CH2Ph(p-OtBu), R3 = Z)

11 21 22 23 24 25 26 27 28

yield (%) 92 97 93 84 74 65 71 83 68

era >99:1 >99:1 NDb 99:1 96:4 99:1 NDb NDb NDb

Enantiomeric ratio (er) determined using chiral HPLC. bND = not determined.

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RESULTS AND DISCUSSION

The low yields that were obtained using the dianion approach prompted us to examine whether the reaction of a monoanion of an N,N-dialkyl methanesulfonamide with methyl esters of N-protected amino acids would provide βketosulfonamides in higher yield. We chose N-allyl, Nethylmethanesulfonamide (7, Scheme 1) as a model substrate for these studies anticipating that the allyl group could be removed later via a Tsuji−Trost reaction without affecting the N-protecting group on the amino acid portion of the product. Hence, 3.2 equiv of the monoanion of 7, generated using nBuLi at −78 °C, was reacted with 8 at −78 °C. After 1 h, TLC indicated that the reaction was complete, and compound 11 was isolated in a 92% yield. This process also worked well using N-methyl, N-allylmethanesulfonamide (12) and other methyl esters of Boc- and Z-protected amino acids (Table 1), though the reactions with the Z derivatives proceeded in slightly lower yields. However, sulfonamide 12 and products 25, 26, and 28 exhibited very similar mobility on silica gel making purification by chromatography challenging, contributing to the slightly lower yields for these three compounds. We were able to determine the enantiomeric ratios (er) of some of the compounds in Table 1 using chiral HPLC which were found to be between 96:4 and 99:1. Compound 1 was prepared by Vannada et al.4 in an 87% yield by subjecting a nonfluorinated, protected β-ketosulfona-

We initially envisaged preparing compounds of type 3 by reacting the dianion of N-alkyl-methanesulfonamides with the methyl esters of N-protected amino acids (Scheme 1), as this approach to β-ketosulfonamides has been reported to be successful when employing a methyl ester of a benzoic acid derivative as the electrophile.4 N-Ethylmethanesulfonamide (6) and L-Boc-hPheOMe (8) were employed as model substrates. The conditions developed by Thompson et al.5 were used for dianion formation except the literature procedure was modified to account for the additional carbamate proton in 8. Thus, sulfonamide 6 in THF was subjected to 2.2 equiv LDA at −78 °C, then allowed to warm to −30 °C over 45 min, and then cooled to −78 °C. A 3-fold molar excess of this mixture was reacted with 8 at −78 °C in THF, and the mixture was allowed to warm to rt and reacted for 8 h. After workup, βketosulfonamide 9 was obtained in a 19% yield. When 4.2 equiv of the dianion was used, compound 9 was obtained in a 30% yield. Using more than 4.2 equiv of the dianion, generated using LDA or n-BuLi, or maintaining the reaction at −78 or −30 °C or generating the dianion at 0 °C followed by its reaction with 8 at 0 °C resulted in similar or lower yields of 9. In contrast, the reaction of the dianion of 6 with methylbenzoate gave compound 10 in a 90% yield (Scheme 1). 11158

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry Scheme 2. Conditions Examined for the Fluorination of 21

Table 2. Formation of β-Keto-α,α-difluorosulfonamides from β-Ketosulfonamides

a

entry

R1

R2

R3

R4

base

product

yield (%)

1 2 3 4 5 6 7 8 9 10

Me Me Et Et Me Me Me Me Me Me

allyl allyl allyl H allyl allyl allyl allyl allyl allyl

Boc Z Boc Boc Boc Boc Z Z Z Boc

CH(CH3)2 CH(CH3)2 CH2CH2Ph CH2CH2Ph CH2Ph CH3 CH(CH3)CH2CH3 CH2CH(CH3)2 CH2Ph(p-OtBu) CH2CH2SCH3

CsF CsF CsF TBAF CsF CsF CsF CsF CsF CsF

30 32 33 34 35 36 37 38 39 40

84 93 85 74a 84 76 90 82 74 0

68% yield using CsF.

mide precursor to 1.6 equiv NaH in dry THF at 0 °C for 20 min followed by cannulation of the mixture into a solution of 2 equiv of Selectfluor in CH3CN at −10 °C and allowing the mixture to warm to 0 °C over 2 h. We examined these conditions for fluorinating compound 21 except the number of equiv of NaH and Selectfluor was increased to account for the carbamate proton in 21. The reaction proved to be surprisingly sluggish, and, after 24 h, unreacted 21 still remained. Upon workup, the monofluorinated product 29 (Scheme 2) was obtained in a 70% yield, while the difluorinated compound 30 was obtained in only 5% yield. Efforts to improve the yield of 30 focused on examining alternative bases and solvents for the fluorination reaction. We reasoned that the fluorination reaction should not require a strong base such as NaH, as we estimated the pKa of the αprotons in 21 to be 10−12.6 Thus, compound 21 was subjected to 2.5 equiv of either DBU, Cs2CO3, CsF, or TBAF in dry MeOH, CH3CN, or DMF for 15 min followed by the addition of 3 equiv Selectfluor, and the reaction was monitored by 19FNMR and TLC. Reactions performed using DBU as base proceeded sluggishly, and, after 24 h, the mixture consisted of mainly unreacted starting material and monofluorinated compound 29 (δf ≈ −184 ppm), and only a small amount of the difluorinated compound 30 (δF ≈ −107 ppm) was formed. With Cs2CO3 as base and DMF or CH3CN as solvent, all of 21 was consumed after 15−30 min, and 19F-NMR revealed the presence of mainly compound 30 along with a variety of unidentified impurities as evidenced by a significant number of small peaks between −104 and −150 ppm. Among these impurity peaks in the 19F-NMR spectrum was a doublet at approximately −122 ppm corresponding to compound 31 (Figure 3).7 The formation of 31 indicates that fragmentation of the C−C bond between the carbonyl and CF2 groups in 30 was occurring.8 The reaction in MeOH was slightly slower but cleaner, and after 1 h no starting sulfonamide remained, and 19 F-NMR revealed mainly product 30 along with about 10% compound 29 as well as a small amount of impurities including compound 31.

Figure 3. A byproduct formed during the electrophilic fluorination of β-ketosulfonamides.

With CsF or TBAF as base, the reaction proceeded sluggishly in CH3CN or MeOH. However, in DMF, all of 21 was consumed within 15 min (for TBAF) or 60 min (with CsF), and a mixture of 29 and 30 was obtained with 30 accounting for approximately 75% of the product and very few impurities were present. Since the reaction products remained unchanged after 2 h, we performed the reaction in DMF again except the amount of CsF or TBAF and Selectfluor was increased to 4 equiv. Under these conditions, all of 21 was consumed within 15 min using TBAF or within 45 min using CsF, though the CsF reaction gave the difluorinated 30 almost exclusively. After aqueous workup and chromatographic purification, compound 30 was obtained in a 78% yield using TBAF and an 84% yield using CsF. These conditions were applied to other βketosulfonamides (Table 2). All of the β-keto-α,α-difluorosulfonamides were obtained in good yield with the exception of the methionine derivative 24 which gave a complex mixture of products probably due to a reaction between the sulfide moiety and Selectfluor.9 It was also found that the fluorination reaction could be carried out on the crude substrates with only a slight reduction in yield. For example, fluorination of crude 25 and 26 (obtained after aqueous workup followed by drying (Na2SO4), filtration, and subjecting the residue to high vacuum for several hours) using our usual procedure gave compounds 32 and 37 in yields of 86%. In contrast to compounds 25 and 26, compounds 32 and 37 were easily separated from sulfonamide 12 by column chromatography. Fluorination of the unprotected sulfonamide 9 (entry 4) was also accomplished in good yield, though it was found that the reaction proceeded in higher yield using TBAF as opposed to CsF. 11159

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

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The Journal of Organic Chemistry Removal of the allyl group from the β-keto-α,α-difluorosulfonamides was examined using compounds 30 and 35. Little or no deallylation occurred using 2.5−10 equiv of either N-methylbarbituric acid (NMBA), morpholine, or benzenesulfinic acid in the presence of 10 mol % Pd(PPh3)4 in methylene chloride either a room temperature or reflux. Nevertheless, deallylation was achieved using 10 mol % Pd(PPh3)4, 5 equiv of DMBA, and dry CH3CN in a Schlenk tube at 100 °C for 24 h (Scheme 3) to give compounds 41 and 42 in yields of 81% and

using 4 equiv of Cs2CO3 and 4 equiv of Selectfluor at room temperature for 30−60 min, 19F-NMR spectra of the reaction mixtures indicated that the desired difluorinated compounds (30, 32, 37, and 38) were the dominant products, though various unidentified byproducts, as well as compound 31, were also formed. However, when these conditions were applied to β-ketosulfonamides derived from hPhe (11), Phe (22), Ala (23), and Tyr (28), the expected difluorinated products (33, 35, 36, and 39) were not the major products. In the case of tyrosine derivative 28, a complex mixture of products was obtained. However, with substrates 11, 22, and 23, compounds 44−46 were the major products,13 which were isolated in yields of 35−64% (Scheme 5).

Scheme 3. Deallylation of Compounds 30 and 35

Scheme 5. Products Formed When the Fluorination Reaction Is Performed on Compounds 11, 22, and 23, Using 4 equiv of Cs2CO3 76%, respectively.10 The er of compounds 30 and 32 were found to be 99:1. However, the er of compound 41 was determined to be 3:2, indicating that considerable loss of stereochemical integrity occurred during deallylation. In the 13C NMR spectra of the β-keto-α,α-difluorosulfonamides described in Table 2 and Scheme 3, the carbonyl carbon appears as a triplet at approximately 195 ppm (J = 24.3 Hz) in CDCl3 and DMSO-d6. This indicates that these compounds exist mainly in their keto form and not as their hydrates in these solvents, as the hydrated carbon would have appeared much further upfield.11 The 19F-NMR spectra of these compounds, in CDCl3 or DMSO-d6 at room temperature, show a large AB quartet centered at approximately −108 ppm. For some of the compounds, smaller AB quartets that have chemical shifts very similar to the large AB quartet are also apparent. For example, with compound 41, a small AB quartet accounts for approximately 15% of the total peak area in DMSO-d6 at room temperature. The 19F-NMR spectra of compound 41 in DMSO-d6 and DMSO-d6/12% D2O are identical suggesting that the hydrate is not responsible for the minor AB quartet.12 At 80 °C in DMSO-d6, only a single AB quartet is evident in the 19F-NMR spectrum suggesting that the minor quartets observed at room temperature are due to rotamers. Although the 1H- or 13C NMR spectra of 41 in DMSO-d6 do not reveal the presence of multiple conformers in solution, we are unable to offer any other explanation, other than the presence of rotamers, to account for the additional peaks in the 19F-NMR spectrum. During the fluorination of tyrosine derivative 28, using the conditions described above in Table 2, a small amount of compound 43 was isolated in addition to compound 39 (Scheme 4). When the reaction was allowed to proceed for 10 h, compounds 39 and 43 were isolated in yields of 34% and 31%, respectively. Letting the reaction proceed for 24 h resulted in lower yields for both products. When the fluorination reaction was performed on βketosulfonamides derived from Val, Leu. and Ile (21, 25−27)

Unlike the products listed in Table 2, compounds 44−46 exist exclusively as their hydrates in CDCl3 as evidenced by the lack of a triplet at 195 ppm and the presence of a triplet at 79 ppm (J = 20.2 Hz) in their 13C NMR spectra. Thus, the electron-withdrawing CN moiety destabilizes the adjacent carbonyl group which promotes formation of the hydrate. Possible mechanisms for the formation of compounds 43− 46 are presented in Scheme 6. We propose that upon difluorination of the α-carbon, the C−H proton adjacent to the β-carbonyl becomes more acidic and can be removed by Cs2CO3 (or CsF in the case of the tyrosine derivative 39) to give intermediate 47 (pathway 1). Fluorination of 47 produces compound 48 which undergoes elimination of fluoride to give imine 49. Compound 49 can tautomerize to the conjugated ketone 50, or, if tautomerization is not favorable, it will form hydrate 51. An alternative mechanism can also be envisaged where removal of the N−H proton occurs after difluorination of the methylene carbon to give amide 52. Fluorination of 52 on the Boc-protected nitrogen provides compound 53 (pathway 2). Elimination of fluoride from 53 gives compound 49. The observation that compounds of type 50 or 51 were not obtained when the fluorination reaction was performed on βketosulfonamides derived from Val, Leu, and Ile suggests to us that pathway 1 may be the more plausible pathway as fluorination of intermediate 47 may be difficult with the more sterically demanding Val, Leu, and Ile derivatives. One would expect that the steric effect of the side chain would have less impact on the fluorination of intermediate 52. The driving force behind the formation of tautomerized product 43 is most likely the formation of a conjugated system that allows delocalization of the lone pair of electrons of the phenolic oxygen into the carbonyl (Figure 4). Unlike compounds 44−46, compound 43 does not exist as its hydrate partly because electron delocalization into the carbonyl group makes the carbonyl carbon less electropositive than the corresponding carbon in compounds 44−46.

Scheme 4. Formation of Compound 43

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DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry Scheme 6. Possible Mechanisms for the Formation of Compounds of Type 50 and 51

All 13C NMR spectra were proton decoupled. Chemical shifts (δ) for 1H NMR spectra run in CDCl3 are reported in ppm relative to the standard tetramethylsilane (TMS). Chemical shifts for 13C NMR spectra run in CDCl3 are reported in ppm relative to the solvent residual carbon (δ 77.0 for central peak). Chemical shifts (δ) for 19F NMR spectra run in CDCl3 or DMSO-d6 are reported in ppm relative to CFCl3 (δ 0.0, external standard). Chemical shifts (δ) for 1H NMR spectra run in or DMSO-d6/D2O mixtures are reported in ppm relative to DMSO residual solvent protons (δ 2.5). Chemical shifts for 13C NMR spectra run in DMSO-d6 or DMSO-d6/D2O mixtures are reported in ppm relative to the solvent residual carbon (δ 39.5). The samples for high-resolution positive ion electrospray ionization mass spectrometry (HRMS-ESI+) (ion trap) were prepared in 1:1 CH3CN/ H2O + 0.2% formic acid. Chiral HPLC analyses were performed using a Chiralpak AS-RH column (250 × 4.6 mm) with CH3CN/0.1%TFA in H2O as eluent. N-Allyl-N-ethylmethanesulfonamide (7). To a solution of Nethylmethanesulfonamide (6, 1.00 g, 9.16 mmol, 1 equiv) in dry acetone (10 mL) were added allyl bromide (0.79 mL, 9.16 mmol, 1 equiv) and anhydrous K2CO3 (2.53 g, 18.3 mmol, 2 equiv), and the mixture stirred for 24 h. After 24 h another 0.25 equiv of ally bromide was added, and the mixture stirred for an additional 6 h. Water (30 mL) was added, and the solution extracted with CH2Cl2 (3 × 30 mL)). The organic layer was dried (Na2SO4) and concentrated. Purification by FC (flash chromatography) (20% EtOAc, 80% hexane) gave compound 7 as a colorless liquid (0.89 g, 60% yield). 1H NMR (300 MHz, CDCl3): δ 5.68−5.85 (1H, m), 5.23 (1H, dd, J = 1.2, 17.1 Hz), 5.18 (1H, dd, J = 1.2, 11.2 Hz), 3.77 (2H, d, J = 6.1 Hz), 3.21 (2 H, q, J = 7.3 Hz), 2.79 (3H, s), 1.12 (3H, t, J = 7.3 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 133.0, 118.9, 49.3, 41.7, 39.3, 13.8; HRMS-ESI+ (m/z) calcd for C6H14NO2S (M + H)+, 164.07398; found, 164.07394. tert-Butyl (1-(N-Ethylsulfamoyl)-2-oxo-5-phenylpentan-3-yl)carbamate (9). To a flame-dried round-bottom flask under Ar was added dry diisopropyl amine (0.68 mL, 4.9 mmol, 9.8 equiv). The mixture was cooled to −78 °C, and then n-BuLi (2.78 mL of a 1.6 M solution in hexane, 4.45 mmol, 8.9 equiv) was added. After being stirred for 10 min at 0 °C, this solution was cooled to −78 °C and treated with sulfonamide 6 (0.198 mL, 2.10 mmol, 4.2 equiv) in dry THF (4 mL), added over a period of 10 min. The reaction mixture was allowed to warm −30 °C over a period of 45 min and was then cooled to −78 °C and treated with a solution of Boc-hPheOMe (8, 0.146 g, 0.500 mmol) in dry THF (4 mL) added in a fast stream. The solution was allowed to warm to rt and followed by TLC. After 8 h the mixture was cooled to 0 °C and quenched with sat. aqueous NH4Cl. The mixture was extracted with ether (3 × 20 mL). The combined organic extracts were washed with brine and water, dried (Na2SO4), filtered, and concentrated in vacuo to give a yellow oil. Purification using FC

Figure 4. Delocalization of the lone pair of electrons of the phenolic oxygen into the carbonyl group in compound 43.

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CONCLUSION A series of β-ketosulfonamides derived from amino acids were prepared in good yield by reacting the monoanion of N-alkyl, N-allylmethanesulfonamides with N-protected amino acid methyl esters. The corresponding reaction with the dianion of N-ethylmethanesulfonamide proceeded in much lower yield. The β-ketosulfonamides were converted into the corresponding β-keto-α,α-difluorosulfonamides by electrophilic fluorination using Selectfluor in the presence of CsF. The allyl protecting group can be removed in good yield using cat. Pd(PPh)3)4 and dimethyl barbituric acid; however, significant racemization occurred during deallylation. When the fluorination reaction was performed with Cs2CO3 as base, β-ketosulfonamides derived from Val, Leu, or Ile gave the expected β-keto-α,αdifluorosulfonamides, while β-ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,αdifluorosulfonamides. Studies to incorporate the β-keto-α,αdifluorosulfonamides into peptides and the biological properties of the resulting peptides are in progress.

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EXPERIMENTAL SECTION

General. All reagents and solvents were purchased from commercial suppliers and used without purification unless stated otherwise. Methyl esters of the Boc or Z-protected amino acids were either purchased or prepared via reaction of the corresponding Boc or Z-protected amino acids with SOCl2 in dry MeOH14 or via reaction of their cesium salts with methyl iodide in dry DMF.15 Dimethylformamide (DMF) was distilled from calcium hydride under reduced pressure and stored over activated 4 Å molecular sieves. Tetrahydrofuran (THF) was distilled from sodium metal in the presence of benzophenone under nitrogen. Acetonitrile was distilled from calcium hydride (CaH2) under nitrogen. Diisopropylamine was distilled from sodium metal. Methanol was distilled from Mg turnings and stored over activated 4 Å molecular sieves. 11161

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry

(d, 1H, J = 8.6 Hz), 4.29 (1H, dd, J = 4.6, 8.8 Hz), 4.23 (1H, d, J = 14.3 Hz), 4.03 (1H, d, J = 14.3 Hz), 3.78 (2H, d, J = 6.1 Hz), 2.83 (1H, s), 2.35−2.26 (1H, m), 1.42 (9H, s), 0.99 (3H, d, J = 6.8 Hz), 0.81 (3H, s, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 199.0, 155.9, 132.5, 119.2, 80.3, 65.1, 58.1, 53.1, 34.5, 28.6, 28.2, 19.8, 16.8; HRMS-ESI+ (m/z) calcd for C11H21N2O5S (M − C4H9 + 2H)+, 293.1166; found, 293.1164. tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-3-oxo-1-phenylbutan2-yl)carbamate (22). Obtained as an amorphous white solid (0.370, 93% yield) after FC (25% EtOAc, 75% hexane) from ester 14 (0.279, 1.00 mmol) and sulfonamide 12 (0.521 g, 3.2 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.46−7.21 (3H, m), 7.17 (2H, d, J = 6.6 Hz), 5.82−5.69 (1H, m), 5.26 (1H, d, J = 18.5 Hz), 5.24 (1H, d, J = 9.5 Hz), 5.10 (1H, d, J = 6.9 Hz), 4.53−4.46 (1H, m), 4.17 (1H, d, J = 13.8 Hz), 4.03 (1H, d, J = 13.8 Hz), 3.74 (2H, d, J = 5.8 Hz), 3.20 (1H, dd, J = 5.8, 14.4 Hz), 2.90 (1H, d, J = 9.0, 14.3 Hz), 2.18 (3H, s), 1.37 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.8, 155.5, 136.3, 132.4, 129.3, 128.8, 127.1, 119.3, 80.2, 61.3, 57.9, 53.1, 36.4, 34.4, 28.2; HRMS-ESI+ (m/z) calcd for C19H29N2O5S (M + H)+, 397.1792; found, 397.1787 tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-3-oxobutan-2-yl)carbamate (23). Obtained as an amorphous white solid (0.658, 84% yield) after FC (10% EtOAc, 90% benzene) from ester 15 (0.500 g, 2.46 mmol) and sulfonamide 12 (1.28 g, 8.61 mmol). 1H NMR (CDCl3, 300 MHz): 5.56−5.81 (m, 1H), 5.15−5.32 (m, 3H), 4.19− 4.35 (m, 2H), 4.06 (one-half of a doublet of doublets, 1H, J = 13.9 Hz), 3.74 (d, 2H, J = 5.6 Hz), 2.80 (s, 3H), 1.39 (s, 9H), 1.33 (d, 3H, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): 199.7, 155.3, 132.3, 119.1, 80.2, 57.1, 55.9, 53.0, 34.3, 28.1, 16.3; HRMS-ESI+ (m/z) calcd for C13H25N2O5S (M + H)+, 321.1475; found, 321.1479. tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-5-(methylthio)-2-oxopentan-3-yl)carbamate (24). Obtained as an amorphous white solid (1.12 g, 74% yield) after FC (33% EtOAc, 67% hexane) from ester 16 (0.970 g, 3.68 mmol) and sulfonamide 12 (1.90 g, 12.8 mmol). 1H NMR (CDCl3, 300 MHz): 5.8−5.65 (m, 1H), 5.41 (d, 1H, J = 7.4 Hz), 5.24 (1H, d, J = 16.4 Hz), 5.19 (1H, d, J = 9.5 Hz), 4.32−4.44 (1H, m), 4.21 (1H, d, J = 13.8 Hz), 4.08 (1H, d, J = 13.8 Hz), 3.73 (d, 1H, J = 5.8 Hz), 2.79 (s, 3H), 2.45−2.55 (m, 2H), 2.10−2.23 (1H, m), 2.03 (3H, s), 1.77−1.90 (m, 1H), 1.39 (s, 9H); 13C{1H} NMR (CDCl3, 75 MHz): 199.0, 155.6, 132.3, 119.3, 80.5, 59.4, 57.5, 53.0, 34.4, 30.1, 29.7, 28.2, 15.4; HRMS-ESI + (m/z) calcd for C15H32N3O5S2 (M + NH4)+, 398.1778; found, 398.1773. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxopentan-3yl)carbamate (25). Obtained as an amorphous white solid (1.12 g, 65% yield) after FC (30% EtOAc, 70% hexane) from ester 17 (2.00 g, 8.02 mmol) and sulfonamide 12 (4.18 g, 28.0 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.31 (5H, s), 5.77−5.68 (1H, m), 5.52 (1H, d, J = 9.0 Hz), 5.27−5.19 (2H, m), 5.09 (2H, s), 4.40 (1H, dd, J = 4.2, 9.0 Hz), 4.21 (1H, s, J = 13.8 Hz), 4.02 (1H, d, J = 13.8 Hz), 3.75 (3H, d, J = 5.8 Hz), 2.79 (3H, s), 2.34−2.27 (1H, m), 0.99 (3H, d, J = 6.9 Hz) 0.80 (3H, d, J = 6.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.6, 156.5, 136.1, 132.4, 128.6, 128.3, 128.1, 119.2, 67.2, 65.5, 58.2, 53.0, 34.3, 28.8, 19.8, 16.7; HRMS-ESI+ (m/z) calcd for C18H27N2O5S (M + H)+, 383.1635; found, 383.1627. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxohexan-3yl)carbamate (26). Obtained as an amorphous white solid (1.00 g, 71% yield) after FC (33% EtOAc, 67% hexane) from ester 18 (1.00 g, 3.57 mmol) and sulfonamide 12 (1.87 g, 12.5 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.34 (5H, s), 5.85−5.69 (1H, m), 5.37 (1H, bd, J = 9.0 Hz), 5.27 (1H, d, J = 17.5 Hz), 5.25 (1H, d, J = 9.5 Hz), 5.11, (2H, s), 4.42 (1H, dd, J = 4.2, 9.0), 4.22 (1H, d, J = 14.3 Hz), 4.02 (1H, d, J = 14.3 Hz), 3.78 (2H, d, J = 5.8 Hz), 2.82 (3H, s), 1.40−1.25 (1H, m), 1.16−1.00 (1H, m), 1.00 (3H, d, J = 6.4 Hz), 0.89 (3H, t, J = 7.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.6, 156.4, 136.1, 132.4, 128.6, 128.3, 128.1, 119.3, 67.2, 65.4, 58.4, 35.6, 34.3, 24.1, 16.1, 11.5; HRMS-ESI+ (m/z) calcd for C19H29N2O5S (M + H)+, 397.1792; found, 397.1785. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-5-methyl-2-oxohexan-3yl)carbamate (27). Obtained as an amorphous white solid (0.330 g, 83% yield) after FC (25% EtOAc, 75% hexane) from ester 19 (0.279 g,

(30% EtOAc, 70% hexane) provided compound 9 as an amorphous white solid (0.057 g, 30% yield). 1H NMR (CDCl3, 300 MHz): δ 7.29−7.08 (5H, m), 5.22 (1H, bt), 5.13 (1H, d, J = 7.1 Hz), 4.43−4.31 (1H, m), 4.28 (1H, d, J = 14.4 Hz), 4.01 (1H, d, J = 14.4 Hz), 3.11 (2H, overlapping dq, J = 6.8 Hz), 2.25−2.10 (1H, m), 1.88−1.71 (1H, m), 1.44 (9H, s), 1.18 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 200.1, 155.9, 140.2, 128.6, 128.4, 126.4, 80.8, 59.6, 58.2, 38.7, 31.8, 31.6, 28.3, 15.2; HRMS-ESI+ (m/z) calcd for C18H32N3O5S (M + NH4)+, 402.2057; found, 402.2051. N-Ethyl-2-oxo-2-phenylethane-1-sulfonamide (10). To a flamedried flask under Ar was added dry diisopropylamine (0.770 mL, 5.50 mmol, 3.3 equiv) and THF (6 mL) and then cooled to 0 °C. n-BuLi (1.6 M in hexane, 3.25 mL, 5.20 mmol, 3.1 equiv) was added, and the mixture stirred at 0 °C for 30 min. A solution of sulfonamide 6 (0.200 g, 1.67 mmol, 1 equiv) in THF (6 mL) was added, and the mixture was stirred for 1 h at 0 °C. A solution of methyl benzoate (0.231 mL, 1.84 mmol, 1.1 equiv) in THF (2 mL) was added, and the mixture stirred for 1 h at 0 °C. The reaction was quenched with sat. aqueous NH4Cl (15 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a pale yellow solid. Purification using FC (75% EtOAc, 25% hexane) provided compound 10 as an amorphous white solid (0.340 g, 90% yield). 1H NMR (CDCl3, 300 MHz): δ 7.96 (2H, d, J = 8.3 Hz), 7.62 (1H, t, J = 6.8 Hz), 7.48 (2H, overlapping dd, J = 7.3 Hz), 4.94 (1H, bt, J = 5.4 Hz), 4.42 (2H, s), 3.27−3.14 (2H, m), 1.21 (3H, t, J = 7.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 190.2, 135.6, 134.5, 129.0, 57.3, 38.8, 15.3; HRMS-ESI+ (m/z) calcd for C10H14NO3S (M + H)+, 228.06890; found, 228.0688. N-allyl-N-methylmethanesulfonamide (12). To a solution of Nmethylmethanesulfonamide (10.9 g, 100 mmol, 1 equiv) in dry DMF (50 mL) was added allyl bromide (11.2 mL, 130 mmol, 1.3 equiv) and anhydrous K2CO3 (27.6 g, 200 mmol, 1 equiv). The mixture was stirred for 18 h. Water was added (100 mL), and the mixture was extracted with Et2O (3 × 150 mL). The organic layer was washed with water (3 × 100 mL), sat. brine (1 × 100 mL), then concentrated by rotary evaporation. The resulting yellow liquid was purified by vacuum distillation to give sulfonamide 12 as a colorless liquid (13.3 g, 89% yield). Bp. = 67−70 °C (0.30 mmHg). The 1H NMR spectrum was identical to that reported in the literature.16 1H NMR (300 MHz, CDCl3): δ 5.74−5.89 (m, 1H), 5.27 (1H, dd, J = 1.6, 17.0 Hz), 5.24 (1H, dd, J = 1.6, 10.1 Hz), 3.72 (2H, d, J = 6.3 Hz), 2.79 (3H, s). General Procedure for Preparing β-Ketosulfonamides 11 and 21−28. To a solution of sulfonamide 7 or 12 (3.2 equiv) in dry THF (5.7 mL/mmol) at −78 °C was added n-BuLi (1.6 M solution in in hexane, 3.5 equiv) dropwise over 2 min. The mixture was stirred at −78 °C for 45 min. A solution of the protected amino acid (1.0 equiv) in dry THF (5 mL/mmol) was added over 10 min. The mixture was stirred at −78 °C for 1 h. A sat. aqueous solution of NH4Cl was added, and the mixture extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by FC (EtOAc, hexane or EtOAc, benzene) gave pure 11 and 21−28. In most instances unreacted sulfonamide 7 or 12 could be isolated and reused. tert-Butyl (1-(N-Allyl-N-ethylsulfamoyl)-2-oxo-5-phenylpentan-3yl)carbamate (11). Prepared as an amorphous white solid (0.189 g, 92% yield) after FC (20% EtOAc, 80% hexane) from ester 8 (0.146 g, 0.500 mmol) and sulfonamide 7 (0.261 g, 1.60 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32−7.14 (5H, m), 5.38−5.25 (1H, m), 5.30− 5.20 (3H, m), 4.35−4.27 (1H, m), 4.25 (1H, d, J = 13.7 Hz), 3.95 (1H, d, J = 13.7 Hz), 3.83 (1H, d, J = 6.1 Hz), 3.27 (2H, q, J = 7.1 Hz), 2.71−2.64 (1H, m), 2.33−2.20 (1H, m), 1.94−1.80 (1H, m), 1.45 (9H, s), 1.16 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 199.2, 155.6, 140.6, 133.1, 128.6, 128.5, 126.3, 119.0, 80.4, 60.0, 59.2, 50.1, 42.6, 32.2, 31.7, 28.3, 14.0; HRMS-ESI+ (m/z) calcd for C21H36N3O5S (M + NH4)+, 442.2370; found, 442.2365. tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxopentan3-yl)carbamate (21). Obtained as an amorphous white solid (1.45 g, 97% yield) after FC (25% EtOAc, 75% hexane) from ester 13 (1.00 g, 4.32 mmol) and sulfonamide 12 (2.25 g, 15.1 mmol). 1H NMR (CDCl3, 300 MHz): δ 5.83−5.72 (1H, m), 5.29−5.21 (2H, m), 5.19 11162

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry 1.00 mmol) and sulfonamide 12 (0.521 g, 3.00 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32 (5H, s), 5.79−5.65 (1H, m), 5.25 (1H, d, J = 17.8 Hz), 5.23 (1H, d, J = 9.9 Hz), 5.10 (2H, s), 4.42 (1H, m), 4.25 (1H, d, J = 13.7 Hz), 4.02 (1H, d, J = 13.7 Hz), 3.75 (2H, d, J = 5.6 Hz); 2.79 (3H, s), 1.74−1.61 (2H, m), 1.45 (1H, m), 0.92 (6H, d, J = 3.2 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 199.7, 156.3, 136.1, 132.4, 128.6, 128.3, 128.1, 119.3, 67.2, 59.3, 57.5, 53.0, 39.3, 34.4, 24.8, 23.2, 21.3; HRMS-ESI+ (m/z) calcd for C19H32N3O5S (M + NH4)+,414.2057; found, 414.2048. Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)3-oxobutan-2-yl)carbamate (28). Obtained as an amorphous white solid (0.887 g, 68% yield) after FC (33% EtOAc, 67% hexane) from ester 20 (1.0 g, 2.59 mmol) and sulfonamide 12 (1.23 g, 8.29 mmol). 1 H NMR (CDCl3, 300 MHz): δ 7.38−7.24 (5H, m), 7,.02 (2H, d, J = 8.3 Hz), 6.89 (2H, d, J = 8.3 Hz), 5.82−5.67 (1H, m), 5.53 (1H, d, J = 7.3 Hz), 5.25 (1H, d, J = 17.1 Hz), 5.23 (1H, d, J = 9.5 Hz), 5.15 (2H, s), 4.64−4.55 (1H, m), 4.13 (1H, d, J = 13.9 Hz), 4.00 (1H, d, J = 13.9 Hz), 3.72 (2H, d, J = 5.9 Hz), 3.15 (1H, dd, J = 5.6, 14.2 Hz), 2.91 (1H, dd, J = 8.3, 14.2 Hz), 2.27 (3H, s), 1.30 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.4, 156.0, 154.5, 136.0, 132.2, 130.6, 129.7, 128.6, 128.3, 128.1, 124.4, 119.3, 78.5, 67.2, 61.7, 58.1, 53.0, 35.8, 34.3, 28.8; HRMS-ESI+ (m/z) calcd for C26H38N3O6S (M + NH4)+, 520.2476; found, 520.2467. tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-1-fluoro-4-methyl-2-oxopentan-3-yl)carbamate (29). NaH (60% dispersion in mineral oil, 0.030 g, 0.746 mmol, 2.6 equiv) was suspended in dry hexane (5 mL) under argon atmosphere. This was allowed to settle, and the hexane was removed by syringe. Residual hexane was removed by resuspending in dry THF (5 mL), allowing the mixture to settle, removing THF by syringe twice, and then suspending the resulting solid in dry THF (5 mL). This mixture was cooled to 0 °C, and compound 21 (0.100 g, 0.287 mmol, 1 equiv) was added and stirred for 20 min. After 20 min the mixture was cannulated into a flask containing Selectfluor (0.305 g, 0.862 mmol, 3.0 equiv) in acetonitrile (5 mL) under argon atmosphere at −10 °C with stirring. This mixture was allowed to warm to room temperature overnight (20 h), then quenched with water (50 mL), and extracted three times with diethyl ether (50 mL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated. Purification using FC (15% EtOAc, 85% hexane then 35% EtOAc, 65% hexane) provided compound 29 as a colorless oil (mixture of diastereomers, 0.074 g, 70% yield). 1H NMR (CDCl3, 500 MHz): δ 5.80 (d, 2H, J = 48 Hz), 5.76−5.85 (m, 2H), 5.29−5.33 (m, 4H), 5.20 (d, 1H, J = 8.5 Hz), 5.05 (d, 1H, 8.7 Hz), 4.71 (d, 1H, J = 8.9 Hz), 4.63 (dd, 1H, J = 6.2 Hz, 6.5 Hz), 3.95 (dd, 2H, J = 5.7 Hz, 15 Hz), 3.81−3.89 (m, 2H), 2.94 (s, 3H), 2.93 (s, 3H), 2.43 (bs, 1H), 2.21−2.26 (m, 1H), 1.45 (s, 18H), 1.05 (d, 3H, J = 6.7 Hz), 1.02 (d, 3H, J = 6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz), 0.83 (d, 3H, J = 6.7 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.3 (d, J = 19.0 Hz), 197.4 (d, J = 19.9 Hz), 155.7, 155.6, 132.0, 131.9, 119.8, 119.7, 100.1 (d, J = 71.0 Hz), 98.1 (d, J = 70.1 Hz), 80.4, 80.4, 62.6, 61.1, 53.4, 53.3, 34.8, 34.8, 28.9, 28.7, 28.2, 19.9, 19.8, 16.8, 16.3; 19F NMR (CDCl3, 282 Hz): δ −184.4 (d, 1F, J = 47.9 Hz), −185.5 (d, 1F, J = 50.8 Hz); HRMS-ESI+ (m/z) calcd for C15H28FN2O5S+: 367.1698 found: 367.1697. General Procedure for Preparing β-Keto-α,α-difluorosulfonamides 30 and 32−40. To a solution of the β-ketosulfonamides in dry DMF (0.04 mL/mg β-ketosulfonamide) was added 4 equiv CsF (for N-allyl-β-ketosulfonamides) or 4 equiv TBAF (1 M in THF, for 28), and the mixture stirred for 15 min. Four equiv of Selectfluor was added, and the mixture stirred for 30−60 min. The mixture was diluted with water then extracted with Et2O (3×). The combined organic layers were washed with saturated brine, then dried (Na2SO4), and concentrated by rotary evaporation. FC of the residue (EtOAc, hexane or EtOAc, benzene) provided the purified products. tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl2-oxopentan-3-yl)carbamate (30). Obtained as a colorless liquid (0.926 g, 84% yield) after FC (20% EtOAc, 80% hexane) from compound 21 (1.00 g, 2.87 mmol). 1H NMR (CDCl3, 300 MHz): δ 5.83−5.71 (1H, m), 5.32 (d, J = 14.7 Hz), 5.06 (1H, d, J = 9.3 Hz), 4.83 (1H, d, J = 9.3 Hz), 3.95 (1H, bs), 2.42−2.34 (1H, m), 1.45 (9H,

s), 1.06 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.4 (t, J = 26.3 Hz), 155.3, 131.8, 120.2, 115.6 (t, J = 297.6), 80.3, 61.0, 53.7, 35.0, 28.9, 28.1, 19.9, 16.0; 19F NMR (CDCl3, 282 MHz): δ −106.5 (d, J = 246.6 Hz), −106.9 (d, J = 246.6 Hz), −108.0 (d, J = 246.6 Hz), −108.8 (d, J = 246.6 Hz); HRMS-ESI+ (m/z) calcd for C15H27F2N2O5S (M + H)+, 385.1603; found, 385.1603. N-Allyl-1,1-difluoro-N-methylmethanesulfonamide (31). To a solution of sulfonamide 12 (2.1 mL, 15.7 mmol, 2 equiv) in dry THF (50 mL) in a flame-dried round-bottom flask under argon at −78 °C was added n-BuLi (2.5 M in hexanes, 6.30 mL, 15.7 mmol, 2 equiv) dropwise, and the mixture was stirred for 40 min. Methylbenzoate (0.93 mL, 7.30 mmol, 1 equiv) was added, and the resulting yellow solution stirred for 2 h at −78 °C and then quenched with sat. aqueous NH4Cl (10 mL). Water (50 mL) was added, and then the mixture was extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo. Purification by FC (10% EtOAc, 90% hexane then 30% EtOAc, 70% hexane) yielded N-allyl-N-methyl-2-oxo-2-phenylethane-1-sulfonamide as a colorless oil (1.43g, 77%). 1H NMR (CDCl3, 300 MHz): δ 8.03 (d, 2H, J = 8.3 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.51 (t, 2H, J = 7.82 Hz), 5.70−5.84 (m, 1H), 5.25−5.31 (m, 2H), 4.59 (s, 3H), 3.78 (d, 2H, J = 6.4 Hz), 2.87 (s, 3H); 13C{1H} NMR (CDCl3, 75 MHz): δ 189.5, 135.8, 134.4, 132.6, 129.4, 128.9, 119.1, 57.8, 53.3, 34.6; HRMSESI (m/z) calcd for C12H16NO3S (M + H)+, 254.0845; found, 254.0844. To a solution of CsF (0.607 g, 4 mmol, 4 equiv) in dry DMF (12 mL) was added N-allyl-N-methyl-2-oxo-2-phenylethane-1sulfonamide (0.253 g, 1 mmol, 1 equiv) and Selectfluor (1.42 g, 4 mmol, 4 equiv). The resulting mixture was stirred at room temperature overnight, then aqueous sodium hydroxide (6 M, 10 mL) was added, and the mixture was stirred 15 min. The reaction was diluted with water (50 mL) and extracted three times with diethyl ether (30 mL). The combined organic layers were washed three times with water (50 mL), then dried (Na2SO4), filtered, and concentrated in vacuo. Purification by FC (5% Et2O, 95% pentane then 10% Et2O, 90% pentane) yielded compound 31 as a colorless oil (0.118 g, 63%). 1H NMR (CDCl3, 300 MHz): δ 6.18 (t, 1H, J = 53.8 Hz), 5.70−5.84 (m, 1H), 5.26−5.31 (m, 2H), 3.91 (d, 2H, J = 6.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 132.0, 119.9, 114.7 (t, J = 278 Hz), 53.2, 34.7; 19 F NMR (CDCl3, 282 MHz) δ 121.7 (d, 2F, J = 53.4 Hz); HRMS-ESI (m/z) calcd for C5H9F2LiNO2S (M + H)+, 192.0477; found, 192.0477. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl-2oxopentan-3-yl)carbamate (32). Obtained as a colorless liquid (0.511 g, 93% yield) after FC (30% EtOAc, 70% hexane) from compound 25 (0.500 g, 1.31 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.35 (5H, s), 5.84−5.70 (1H, m), 5.32−5.27 (3H, m), 5.11 (2H, s), 4.92 (1H, dd, J = 3.7, 9.3 Hz), 3.92 (2H, bs), 2.96 (3H, s), 2.43−2.33 (1H, m), 1.05 (3H, d, J = 6.6 Hz), 0.82 (3H, d, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.0 (t, J = 24.7 Hz), 156.0, 136.0, 131.7, 128.6, 128.3, 128.2, 120.3, 119.6 (t, J = 297 Hz), 67.4, 61.5, 53.7, 35.0, 29.1, 19.9, 16.0; 19F NMR (CDCl3, 282 MHz): δ −106.6 (d, J = 246.6 Hz), −107.3 (d, J = 244.8 Hz), −108.1 (d, J = 246.6 Hz), −108.5 (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for C18H25F2N2O5S (M + H)+, 419.1447; found, 419.1446. tert-Butyl (1-(N-Allyl-N-ethylsulfamoyl)-1,1-difluoro-2-oxo-5-phenylpentan-3-yl)carbamate (33). Obtained as a colorless oil (0.185 g, 85% yield) after FC (20% EtOAc, 80% hexane) from compound 11 (0.200 g, 0.471 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.28−7.16 (5H, m), 5.87−5.70 (1H, m), 5.29 (1H, d, J = 17.8 Hz), 5.27 (1H, d, J = 8.3 Hz), 5.16 (1H, d, J = 6.6 Hz), 4.88 (1H, m), 3.96 (2H, bd, J = 5.4 Hz), 3.42 (1H, dd, J = 6.6, 7.1 Hz), 2.80−2.60 (2H, m), 2.36−2.20 (1H, m), 1.94−1.79 (1H, m), 1.44 (9H, s), 1.19 (3H, t, J = 7.1 Hz); 13 C{1H} NMR (CDCl3, 75 MHz): δ 195.2 (t, J = 24.8 Hz), 155.0, 140.3, 132.5, 128.6, 128.5, 126.3, 120.0, 115.3 (t, J = 297.1 Hz), 80.5, 56.2, 50.4, 42.9, 32.6, 31.5, 28.2, 13.8; 19F NMR (CDCl3, 282 MHz): −107.3 (d, J = 244.8 Hz), −107.4, (d, J = 243.1 Hz), −108.6 (d, J = 243.1 Hz), −108.9 (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for C21H31F2N2O5S (M + H)+, 461.1916; found, 461.1917. tert-Butyl (1-(N-Ethylsulfamoyl)-1,1-difluoro-2-oxo-5-phenylpentan-3-yl)carbamate (34). Obtained as a white solid (0.078 g, 74% 11163

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165

Article

The Journal of Organic Chemistry

182.2 (t, J = 22.7 Hz), 159.0, 154.0, 140.6, 135.9, 132.7, 131.8, 128.5, 128.3, 127.0, 126.7, 122.8, 120.1, 117.6 (t, J = 295.4 Hz), 79.7, 67.7, 53.8, 35.1, 28.9; 19F-NMR (CDCl3, 282 MHz): δ −107.3 (d, J = 244.8 Hz); −108.4 (J = 244.8 Hz), −108.6 (d, J = 248.3 Hz); HRMS-ESI+ (m/z) calcd for C26H33F2N2O6S (M + H)+, 539.2022; found, 539.2023. General Procedure for the Deallylation of Compounds 30 and 35. To a solution of 30 or 35 and DMBA (5 equiv) in dry acetonitrile (0.05 mL/mg 30 or 35) in a pressure tube was added Pd(PPh3)4 (0.1 equiv). The mixture was heated to 100 °C for 24 h. After cooling, the mixture was diluted with EtOAc and washed with sat. NaHCO3 (3×), water (1×), and sat. brine (1×), dried (Na2SO4), and concentrated by rotary evaporation. The residue was purified by FC (EtOAc, hexane). tert-Butyl (1,1-Difluoro-4-methyl-1-(N-methylsulfamoyl)-2-oxopentan-3-yl)carbamate (41). Prepared via deallylation of compound 30 (050 g, 0.142 mmol) using the general procedure. Obtained as a white amorphous solid (0.042 g, 75% yield) after FC (20% EtOAc, 80% hexane). 1H NMR (CDCl3, 300 MHz): δ 6.02 (1H, bs), 4.98 (1H, d, J = 8.6 Hz), 4.73 (1H, dd, J = 2.9, 7.6 Hz), 2.92 (3H, d, J = 3.9 Hz), 2.43−2.31 (1H, m), 1.42 (9H, s), 1.08 (3H, d, J = 6.6 Hz), 0.85 (3H, d, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.5 (t, J = 22.7 Hz), 156.1, 115.2 (t, J = 297.0 Hz), 81.2, 61.4, 30.1, 28.6, 28.1, 19.9, 16.1; 19F NMR (CDCl3, 282 MHz): δ −107.3 (d, J = 246.6 Hz), −108.6 (d, J = 246.6 Hz); 19F NMR (DMSO-d6, 282 MHz, 23 °C): δ −105.8 (d, J = 249.6 Hz), −106.0 (d, J = 245.0 Hz), −110.2 (d, J = 246.1 Hz), −110.8 (d, J = 245.3 Hz); 19F NMR (DMSO-d6, 282 MHz, 80 °C): δ −105.5 (d, J = 148.0 Hz), −108.8 (d, J = 148.0 Hz); HRMSESI+ (m/z) calcd for C12H23F2N2O5S (M + H)+, 345.1290; found, 345.1290. tert-Butyl (4,4-Difluoro-4-(N-methylsulfamoyl)-3-oxo-1-phenylbutan-2-yl)carbamate (42). Prepared via deallylation of compound 35 (0.050 g, 0.140 mmol) using the general procedure. Obtained as a white amorphous solid (0.041 g, 75% yield) after FC (30% EtOAc, 70% hexane). Crystals used for X-ray crystallography were obtained by recrystallization from heptane (mp = 113−115 °C) 1H NMR (CDCl3, 300 MHz): δ 7.36−7.24 (3H, m), 7.16 (2H, d, J = 6.8 Hz), 6.10 (1H, bs), 5.10−5.01 (1H, m), 4.92 (1H, d, J = 6.3 Hz), 3.30 (1H, dd, J = 3.4, 17.1 Hz), 2.94−2.77 (4H, m), 1.36 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.1 (t, J = 23.2 Hz), 155.6, 134.4, 129.2, 129.0, 127.6, 115.5 (t, J = 298.1 Hz), 83.4, 57.6, 36.0, 30.0, 28.1; 19F NMR (CDCl3, 282 MHz): δ −106.8 (d, J = 246.6 Hz), −108.2 (d, J = 246.6 Hz); HRMS-ESI+ (m/z) calcd for C16H23F2N2O5S (M + H)+, 393.1290; found, 393.1290. Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)4,4-difluoro-3-oxobut-1-en-2-yl)carbamate (43). Prepared using the same procedure described for compound 39 except the reaction was conducted for 10 h. Obtained as an amorphous white solid (0.040 g, 31% yield) after FC (5% EtOAc, 95% benzene) from compound 28 (0.100 g, 0.231 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.60 (s, 1H), 7.56 (2H, d, J = 8.7 Hz), 7.31 (5H, bs), 6.94 (2H, d, J = 8.7 Hz), 6.52 (1H, bs), 5.82−5.70 (1H, m), 5.28 (1H, dd, J = 1.0, 17.5 Hz), 5.27 (1H, dd, J = 1.0, 11.1 Hz), 5.13 (2H, bs), 3.92 (2H, bs), 2.96 (3H, s), 1.39 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 182.2 (t, J = 22.7 Hz), 159.0, 154.0, 140.6, 135.9, 132.7, 131.8, 128.5, 128.3, 127.0, 126.7, 122.8, 120.1, 117.6 (t, J = 295.4 Hz), 79.7, 67.7, 53.8, 35.1, 28.9; 19 F NMR (CDCl3, 282 MHz): δ −101.9; HRMS-ESI+ (m/z) calcd for C26H31F2N2O6S (M + H)+, 537.1865; found, 537.1865. General Procedure for the Preparation of Compounds 44− 46. These compounds were prepared using the general procedure described above for the synthesis of β-keto-α,α-difluorosulfonamides 32, 33, and 35-44 except 4 equiv of Cs2CO3 was used, and the reactions were allowed to stir for 30−60 min after the addition of Selectfluor. tert-Butyl (E)-(1-(N-Allyl-N-ethylsulfamoyl)-1,1-difluoro-2,2-dihydroxy-5-phenylpentan-3-ylidene)carbamate (44). Obtained as an amorphous white solid (0.036 g, 64% yield) after FC (20% EtOAc, 80% hexane) from compound 11 (0.050 g, 0.118 mmol). 1H NMR (CDCl3, 300 MHz): δ 8.76 (1H, s), 7.32−7.16 (5H, m), 5.88−5.71 (1H, m), 5.31 (1H, d, J = 17.3 Hz), 5.30 (1H, d, J = 7.7 Hz), 4.28 (1H,

yield) after FC (15% EtOAc, 85% hexane) from compound 9 (0.096 g, 0.250 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.38−7.10 (5H, m), 6.19 (1H, s), 5.05 (1H, d, J = 7.6 Hz), 4.78−4.73 (1H, bt, J = 7.1 Hz), 3.35−3.10 (2H, m), 2.84−2.61 (2H, m), 2.32−2.18 (1H, m), 1.89− 1.71 (1H, m), 1.43 (9H, s), 1.43 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.8 (t, J = 23.7 Hz), 155.9, 139.5, 128.7, 128.4, 126.6, 115.3 (t, J = 299.1 Hz), 81.5, 56.5, 39.3, 31.8, 28.1, 15.5; 19F NMR (CDCl3, 282 MHz): −108.3 (d, J = 244.8 Hz), −109.4, (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for C18H30F2N3O5S (M + NH4)+, 438.1869; found, 438.1862. tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3-oxo-1phenylbutan-2-yl)carbamate (35). Obtained as a pale yellow amorphous solid (0.724 g, 84% yield) after FC (15% EtOAc, 85% hexane) from compound 22 (0.800 g, 2.00 mmol).1H NMR (CDCl3, 300 MHz): δ 7.36−7.24 (3H, m), 7.16 (2H, d, J = 6.8 Hz), 5.83−5.73 (1H, m), 5.29 (2H, d, J = 13.2 Hz), 5.12−4.85 (2H, m), 3.92 (2H, bs), 3.30 (1H, bd, J = 13.9 Hz), 2.97 (3H, s), 3.00−2.79 (1H, m), 1.53 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 194.5 (t, J = 24.3 Hz), 154.7, 135.1, 131.7, 129.4, 128.7, 127.2, 120.2, 115.8 (t, J = 297.6 Hz), 80.5, 57.0, 53.7, 36.5, 35.0, 28.1; 19F NMR (CDCl3, 282 MHz): δ −107.1 (d, J = 244.8 Hz), −107.2 (d, J = 244.8 Hz), −108.1 (d, J = 244.8 Hz), −108.3 (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for C15H19F2N2O5S (M − (CH3)3 + 2H)+, 377.0977; found, 377.0976. tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3-oxobutan-2-yl)carbamate (36). Obtained as a white solid (0.131 g, 76% yield) after FC (20% EtOAc, 80% benzene) from compound 23 (0.155 g, 0.484 mmol). 1H NMR (CDCl3, 300 MHz): δ 5.80−5.68 (1H, m), 5.29 (1H, d, J = 15.7 Hz), 5.28 (1H, d, J = 11.2 Hz), 5.09 (1H, s), 4.81 (1H, dq, J = 7.0, 7.0 Hz), 3.90 (2H, bs), 2.95 (3H, s), 1.41 (s, 1.5H, one-half of the doublet corresponding to CH-CH3), 1.39 (12H, s, 9H from (CH3)3-C overlapping with one-half of the doublet corresponding to CH-CH3); 13C{1H} NMR (CDCl3, 75 MHz): δ 196.0 (t, J = 24.3 Hz), 154.7, 131.8, 120.2, 115.7 (t, J = 297.1 Hz), 80.4, 53.7, 52.3, 35.0, 28.2, 17.1; 19F NMR (CDCl3, 282 MHz): δ −106.3, (d, J = 251.7 Hz), −106.7 (d, J = 246.6 Hz), −108.2 (d, J = 246.6 Hz), −108.8 (d, J = 253.5 Hz); HRMS-ESI+ (m/z) calcd for C9H15F2N2O5S (M - (CH3)3 + 2H)+, 301.0662; found, 301.0663. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl-2oxohexan-3-yl)carbamate (37). Obtained as a colorless oil (0.196 g, 90% yield) after FC (15% EtOAc, 85% hexane) from compound 26 (0.200 g, 0.504 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.33 (5H, s), 5.80−5.71 (1H, m), 5.40−5.25 (3H, m), 5.10 (2H, s), 4.90 (1H, dd, J = 4.4, 9.3 Hz), 3.91 (1H, bs), 2.95 (3H, s), 2.10 (1H, bs), 1.38−1.21 (1H, m), 1.06−0.95 (4H, m), 0.86 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.1 (t, J = 24.3 Hz), 156.0, 136.1, 131.8, 128.6, 128.3, 128.2, 120.2, 115.7 (t, J = 297.1 Hz), 67.3, 61.7, 53.7, 35.7, 35.0, 23.3, 16.2, 11.3; 19F NMR (CDCl3, 282 MHz): −106.2 (d, J = 246.6 Hz), −106.9 (d, J = 246.6 Hz), −108.1 (d, J = 246.6 Hz), −108.3 (d, J = 246.6 Hz); HRMS-ESI+ (m/z) calcd for C19H27F2N2O5S (M + H)+, 433.1603; found, 433.1604. Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-5-methyl-2oxohexan-3-yl)carbamate (38). Obtained as a colorless oil (0.180 g, 82% yield) after FC (15% EtOAc, 85% hexane) from compound 27 (0.200 g, 0.504 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32 (5H, s), 5.87−5.69 (1H, m), 5.38−5.25 (3H, m), 5.10 (2H, s), 5.03−4.18 (1H, m), 3.91 (2H, bs), 2.95 (3H, s), 1.84−1.60 (2H, m), 1.49−1.30 (1H, m), 0.98 (3H, d, J = 5.4 Hz), 0.93 (3H, d, J = 5.6 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.6, (t, J = 23.7 Hz), 155.6, 135.9, 131.7, 128.4, 128.1, 128.0, 120.1, 115.7, (t, J = 297.1, Hz), 67.1, 55.3, 53.6, 39.6, 34.9, 24.8, 23.1, 20.9; 19F NMR (CDCl3, 282 MHz): −106.8 (d, J = 246.6 Hz), −107.6, (d, J = 246.6 Hz), HRMS-ESI+ (m/z) calcd for C19H27F2N2O5S (M + H)+, 433.1603; found, 433.1603. Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)4,4-difluoro-3-oxobutan-2-yl)carbamate (39). Obtained as a pale yellow semisolid (0.040 g, 74% yield) after FC (5% EtOAc, 95% benzene then 10% EtOAc, 90% benzene) from compound 28 (0.050 g, 0.100 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.24−7.38 (m, 5H), 7.02 (2H, d, J = 8.3 Hz), 5.82−5.70 (1H, m), 5.05−5.35 (1H, m), 3.92 (2H, bs), 3.28 (1H, dd, J = 4.9, 14.7 Hz), 2.97 (3H, s), 2.88 (1H, dd, J = 7.8, 14.4 Hz), 1.32 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 11164

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s), 4.10−3.90 (1H, m), 3.53−3.36 (1H, m), 3.90−3.75 (1H, m), 2.66− 2.52 (2H, m), 2.41−2.38 (1H, m), 1.55 (9H, s), 1.20 (3H, t, J = 7.0 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 165.3, 148.5, 140.1, 132.2, 128.5, 128.4, 126.2, 120.7 (t, J = 296.5 Hz), 119.9, 83.1, 79.5 (t, J = 21.6 Hz), 50.2, 42.8, 34.8, 28.8, 27.9, 13.6; 19F NMR (CDCl3, 282 MHz): δ −107.2 (d, J = 243.1 Hz), −108.1 (d, J = 243.1 Hz); HRMSESI+ (m/z) calcd for C21H30F2N2O6NaS (M + Na)+, 499.1685; found, 499.1686. tert-Butyl (E)-(4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3,3-dihydroxy-1-phenylbutan-2-ylidene)carbamate (45). Obtained as an amorphous white solid (0.025 g, 45% yield) after FC (25% EtOAc, 75% hexane) from compound 22 (0.050 g, 0.126 mmol). 1H NMR (CDCl3, 300 MHz): δ 8.35 (1H, s), 7.40−7.21 (5H, m), 5.89−5.73 (1H, m), 5.34 (2H, two overlapping doublets with J ∼ 11.5 Hz), 4.2− 3.7 (1H, bs), 3.98 (2H, s), 3.62 (1H, d, J = 14.1 Hz), 3.36 (2H, d, J = 14.1 Hz), 3.02 (3H, s), 1.44 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 165.3, 148.2, 132.1, 131.7, 130.7, 128.7, 127.7, 121.7 (t, J = 297.1 Hz), 120.2, 82.80, 79.5 (t, J = 26.2 Hz), 53.6, 38.6, 35.0, 27.8; 19 F NMR (CDCl3, 282 MHz): δ −105.7; HRMS-ESI+ (m/z) calcd for C15H19F2N2O6S(M − C4H9 + 2H)+, 393.0926; found, 393.0933. tert-Butyl (E)-(4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3,3-dihydroxybutan-2-ylidene)carbamate (46). Obtained as an amorphous white solid (0.041 g, 35% yield) after FC (30% EtOAc, 70% hexane) from compound 23 (0.100 g, 0.312 mmol). 1H NMR (CDCl3, 300 MHz): δ 8.70 (1H, bs), 5.82−5.69 (1H, m), 5.28 (2H, bd, J = 13.4 Hz), 4.37 (1H, s), 3.92 (1H, bs), 2.95 (3H, s), 1.73 (3H, s), 1.48 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 160.5, 148.7, 131.7, 121.7 (t, J = 295.1 Hz), 120.1, 83.1, 76.8 (t, J = 21.7 Hz), 53.6, 34.9, 27.9, 21.0; 19 F NMR (CDCl3, 282 MHz): δ −106.3 (bd, J = 243.3 Hz), −107.4 (d, J = 243.1 Hz); HRMS-ESI+ (m/z) calcd for C13H22F2N2O6LiS (M + Li)+, 379.1321; found, 379.1320.

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REFERENCES

(1) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J. Med. Chem. 1990, 33, 394−407. (2) (a) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24, 1813−1817. (b) Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S. R.; Thomasco, L. M. J. Med. Chem. 1985, 28, 1553−1555. (c) Takahashi, L. H.; Radhakrishnan, R.; Rosenfield, R. E.; Meyer, E. F.; Trainor, D. J. Am. Chem. Soc. 1989, 111, 3368−3374. (d) Eda, M.; Ashimori, A.; Akahoshi, F.; Yoshimura, T.; Inoue, Y.; Fukaya, C.; Nakajima, M.; Fukuyama, H.; Imada, T.; Nakarnura, N. Bioorg. Med. Chem. Lett. 1998, 8, 919−924. (3) (a) Cox, R. J.; Gibson, J. S.; Martin, M. B. M. ChemBioChem 2002, 3, 874−886. (b) Cox, R. J.; Gibson, J. S.; Hadfield, A. T. ChemBioChem 2005, 6, 2255−2260. (c) Ladame, S.; Willson, M.; Perie, J. Eur. J. Org. Chem. 2002, 2002, 2640−2648. (d) Kobzar, O. L.; Shevchuk, M. V.; Lyashenko, A. N.; Tanchuk, V. Y.; Romanenko, V. D.; Kobelev, S. M.; Averin, A. D.; Beletskaya, I. P.; Vovk, A. I.; Kukhar, V. P. Org. Biomol. Chem. 2015, 13, 7437−7444. (e) Derbanne, M.; Zulauf, A.; Le Goff, S.; Pfund, E.; Sadoun, M.; Pham, T.-H.; Lequeux, T. Org. Process Res. Dev. 2014, 18, 1010−1019. (4) Vannada, J.; Bennett, B. M.; Wilson, D. J.; Boshoff, H. I.; Barry, B. E.; Aldrich, C. C. Org. Lett. 2006, 8, 4707−4710. (5) Thompson, M. E. J. Org. Chem. 1984, 49, 1700−1703. (6) Bunting, J. W.; Kanter, J. P. J. Am. Chem. Soc. 1993, 115, 11705− 11715. (7) Compound 31 was identified by synthesis of an authentic sample. See the SI. (8) Ladame et al. (ref 3c) have reported that β-keto-α,αdifluorophosphonates readily undergo C−C bond fragmentation between the carbonyl and CF2 carbons under basic conditions. Their studies indicate that the decomposition reaction afforded :CF2, a highly reactive carbene. The formation of :CF2 may account for the significant number of small peaks that appear between −104 and −150 ppm in the 19F-NMR spectra during some of the reactions described here. (9) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212 We also attempted the fluorination of the methionine derivative (compound 24) using our usual conditions except N-fluorobenzenesulfonimide (NFSi) was used in place of Selectfluor. No reaction had occurred after 8 h.. (10) The X-ray structure of compound 42 was obtained (see the SI). (11) Ni, C.; Zhang, L.; Hu, J. J. J. Org. Chem. 2009, 74, 3767. (12) It is possible that these compounds would exist, either in part or entirely, as their hydrates in a purely aqueous environment. The low solubility of these compounds in aqueous solution prevented us from determining this. (13) Compound 31 as well as other minor unidentified impurities were also evident in the 19F NMR spectra of the crude reaction mixture. (14) Siedel, W.; Sturm, K.; Geiger, R. Chem. Ber. 1963, 96, 1436− 1439. (15) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha, I. D.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1977, 42, 1286−1290. (16) King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F. J. Am. Chem. Soc. 1992, 114, 3028−3033.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02179.

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Article

X-ray crystal structure of compound 42 (CIF) Spectral data ( 1 H, 13 C, 19 F-NMR) for all new compounds, 19F-NMR spectra of compound 41 at 80 °C (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ryan Chung: 0000-0001-7242-1195 Jeremy Green: 0000-0003-4544-6412 Jason E. Hein: 0000-0002-4345-3005 Scott D. Taylor: 0000-0001-5449-5940 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant to S.D.T. (RGPIN-2017-04233) and an NSERC Engage Grant (EGP-437470-2012) to S.D.T. and Vertex Pharmaceuticals. J.S. thanks NSERC for a postgraduate scholarship. We thank Luc Farmer, Simon Giroux, and Dylan Jacobs of Vertex Pharmaceuticals for helpful discussions during the early stages of this work. We also thank Luke Vanderzwet for assitance during the early stages of this work. 11165

DOI: 10.1021/acs.joc.7b02179 J. Org. Chem. 2017, 82, 11157−11165