Preparation of Enantiomerically Pure Perfluorobutanesulfinamide and Its Application to the Asymmetric Synthesis of \xce\xb1-Amino Acids
A high yielding and practical two-step synthesis of enantiomerically pure perfluorobutanesulfinamide from Senanayake\xe2\x80\x99s 2-aminoindanol-derived sulfinyl transfer reagent was developed and carried out on multi-gram scale. Straightforward condensation of this sulfinamide with ethyl glyoxylate provided the N-perfluorobutanesulfinyl imino ester. The utility of this activated N-sulfinyl imino ester was demonstrated for reactions that either gave no product or very low yields with the corresponding less electrophilic N-tert-butanesulfinyl derivative. Specifically, the Rh(III)-catalyzed C-H bond addition of aromatic compounds to the N-perfluorobutanesulfinyl imino ester provided arylglycines with very high diastereoselectivities for a range of directing groups including pyrrolidine amide, azo, sulfoximine, 1-pyrazole and 1,2,3-triazole functionality. Thermal asymmetric aza-Diels Alder reactions also proceeded in good yields and with high selectivity, including for the substituted dienes (E)-1,3-pentadiene and (2E, 4E)-2,4-hexadiene.
INTRODUCTION<!>RESULTS AND DISCUSSION<!>CONCLUSIONS<!>General Information<!>(1S,2R)-1-(2,4,6-trimethylbenzenesulfonamido)-2,3-dihydro-1H-inden-2-yl-(S)-nonafluorobutane-1-sulfinate (6)<!>(S)-Perfluorobutanesulfinamide (8)<!>Recovery of N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2,4,6-trimethylbenzenesulfonamide (7)<!>(S,E)-Ethyl-2-(((perfluorobutyl)sulfinyl)imino)acetate (9)<!>General Procedure for Synthesis of 1-Benzyl-4-Aryl-1H-1,2,3-Triazoles<!>1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (10k)<!>1-Benzyl-4-(p-tolyl)-1H-1,2,3-triazole (10l)<!>1-Benzyl-4-(m-tolyl)-1H-1,2,3-triazole (10m)<!>Synthesis and Characterization of Arylglycines 11a\xe2\x80\x9311c<!>Ethyl (S)-2-(4-chlorobenzamido)-2-(2-(pyrrolidine-1-carbonyl)phenyl)acetate (11a-amide)<!>Procedure for Synthesis of Ethyl (S)-2-(2-((1-oxidotetrahydrothiophen-1-ylidene)carbamoyl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11d)<!>General Procedure for Synthesis of Arylglycines 11e\xe2\x80\x9311i<!>Ethyl (S)-2-(2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11e)<!>Ethyl (S)-2-(5-methyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11f)<!>Ethyl (S)-2-(5-methoxy-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11g)<!>Ethyl (S)-2-(5-acetyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11h)<!>Ethyl (S)-2-(4-methyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11i)<!>General Procedure for the Synthesis of Arylglycines 11j\xe2\x80\x9311m<!>Ethyl (S)-2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11j)<!>Ethyl (S)-2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-methoxyphenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11k)<!>Ethyl (S)-2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-methylphenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11l)<!>Ethyl (S)-2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylphenyl)-2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11m)<!>General Procedure for the aza-Diels-Alder reaction<!>Ethyl (S)-4-methyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (15a)<!>Ethyl (S)-4,5-dimethyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (15b)<!>Ethyl (2S,3S,6R)-3,6-dimethyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (15c)<!>Ethyl (2S,6R)-6-methyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (15d)
<p>α-Amino acids were one of the first classes of compounds to be targeted for asymmetric synthesis due to their pervasive biological roles,1 and their asymmetric syntheses continue to be important to numerous drug discovery and chemical biology applications.2 In this regard, N-tert-butanesulfinyl imino esters have proven to be extremely versatile intermediates for the asymmetric synthesis of α-amino acids.3 The addition of a variety of organometallic reagents proceeds with high diastereoselectivities, including lithium,4 magnesium,5 indium,6 and zinc7 reagents, and through the use of transition metal-catalysts, also organoboron reagents.8 Transition metal catalysts have also been applied to the addition of allyl alcohols via isomerization pathways9 and for the hydrogen-mediated reductive coupling of alkynes.10 Stabilized anions such as enolates11 and nitronate12 anions also have been added with good selectivities. Moreover, Lewis acids have been employed to catalyze Friedel-Craft reactions with electron-rich aromatic13 and heteroaromatic compounds,14 Mannich-type additions of silyl enol ethers,15 and aza-Diels Alder cycloadditions with dienes.16</p><p>However, for some reactions of N-tert-butanesulfinyl imino esters, little to no conversion to the desired addition prod-ucts was observed because the imines were not sufficiently electrophilic.16a,17 In seminal work Liu and coworkers have reported on the preparation of enantiomerically pure perfluoroalkanesulfinamides and on their conversion to N-perfluoroalkanesulfinyl aldimines. They have further shown that these more electrophilic imines can be effective substrates for the addition of a number of nucleophiles.18</p><p>Herein, we describe a practical two-step synthesis of perfluorobutanesulfinamide from Senanayake's 2-aminoindanol-derived sulfinyl transfer reagent in good overall yield and high enantiopurity.19 Condensation with ethyl glyoxylate to provide the corresponding N-perfluorobutanesulfinyl imino ester is also described. We further report that the enhanced electrophilicity of this N-perfluorobutanesulfinyl imino ester enables transformations to be performed that are shown not to proceed with the corresponding N-tert-butanesulfinyl imino ester. Specifically, Rh(III)-catalyzed, highly diastereoselective addition of aromatic C-H bonds enables the asymmetric synthesis of arylglycines, a class of compounds present in many drugs including glycopeptide antibiotics such as vancomycin, many β-lactam antibiotics such as cefprozil, and the cardio-vascular agent Plavix.20 Moreover, the asymmetric synthesis of pipecolic acid derivatives has been accomplished by thermal aza-Diels–Alder cycloaddition reactions with substituted dienes, including those that have been reported to give low cycloaddition yields for the corresponding N-tert-butanesulfinyl imino ester.16a The pharmaceutical relevance of these aza-Diels Alder reactions is highlighted by the AIDs drug Saquinavir and the blockbuster HCV drug Ledipasvir each of which incorporates a pipecolic acid derivative.20</p><!><p>An effective route to enantiomerically pure perfluoroalkanesulfinamides has been developed,21 but significant quantities of material are difficult to access due to the multi-step sequence that includes several purification steps. For this reason, we investigated alternative methods for the preparation of perfluorobutanesulfinamide. The most practical and by far the most extensively used method for the asymmetric synthesis of the more commonly used tert-butanesulfinamide is catalytic enantioselective oxidation of inexpensive tert-butyl disulfide followed by addition of LiNH2.22 Unfortunately, this approach is not relevant to the synthesis of perfluoralkanesulfinamides because the corresponding disulfides are not commercially available and are inconvenient to prepare. The chiral sulfinyl transfer auxiliary approach developed by Senanayake and coworkers is an alternative general and efficient method for the preparation of a broad range of enantiomerically pure sulfinamides (Scheme 1).19 Addition of a Grignard reagent to the sulfinyl transfer reagent 1 proceeds with inversion of stereochemistry to give sulfinate ester 2. Treatment of 2 with an amide nucleophile then provides sulfinamide 3 and the chiral auxiliary 4, which then can be recycled back to the sulfinyl transfer reagent 1 by reaction with thionyl chloride.</p><p>The key challenge to applying this approach to the perfluoroalkansulfamides is the well-documented instability of perfluoroalkyl Grignard reagents, which unless maintained at low temperature rapidly decompose through facile elimination of fluoride.23 We therefore investigated the preparation and reaction of the perfluorobutyl Grignard reagent by transmetalation of perfluorobutyl iodide with ethylmagnesium bromide at −78 °C followed by slow addition of a THF solution of the pre-cooled 2-aminoindanol-derived sulfinyl transfer reagent 5 (Table 1). A slight excess of perfluorobutyl iodide relative to ethylmagnesium bromide was employed to prevent competitive formation of the undesired ethanesulfinate ester byproduct. Moreover, exactly one equiv of the Grignard reagent was used to prevent overaddition of the Grignard reagent to the desired sulfinate ester product 6, which would give a sulfoxide byproduct. The duration of the transmetalation step was evaluated at both 30 and 60 min (entries 1 and 2), with 60 min providing the highest yield (entry 2). To minimize reagent waste, the stoichiometry of the perfluorobutyl iodide was lowered to 1.05 equiv without any reduction in yield (entry 3). Additionally, the reaction can be conducted at a higher concentration, which is preferable when performed on larger scales (entry 4). The solubility of sulfinyl transfer reagent 5 prevented a concentration higher than 0.3 M from being used. The only observed impurity was a small amount of byproduct 7, which has no detrimental effects on the subsequent step of the synthesis (vide infra). Therefore, the crude material obtained after extractive isolation was employed in the next step without further purification.</p><p>Various amine nucleophiles were next evaluated for cleavage of 6 to provide the sulfinamide product 8 (Table 2). Initially, we speculated that the electron withdrawing perfluorobutyl group might render sulfinate ester 6 sufficiently reactive for cleavage with the most practical and inexpensive source of ammonia, ammonium hydroxide. However, when 6 was treated with excess ammonium hydroxide either neat or with THF as a cosolvent, no reaction was observed at rt (entry 1). While complete consumption of the sulfinate ester 6 could be achieved by heating in a sealed tube, and though the alcohol byproduct 7 was detected, none of the desired sulfinamide 8 was observed (entry 2). The absence of sulfinamide 8 could in part be due to preferential saponification of 6 under the reaction conditions. However, control experiments also established that 8 was not stable to concentrated NH4OH even at rt. LiHMDS is one of the most commonly used nucleophiles for sulfinate ester cleavage19 and was next investigated. Addition of 5 equiv of LHMDS provided sulfinamide 8 in 59% yield after chromatography (entry 3). Only two equivalents of base are required, one equivalent to serve as a nucleophile and the second equivalent to deprotonate the sulfonamide group in 6. Unfortunately, attempts to reduce the amount of LiHMDS to either 2.0 or 3.0 equiv led to diminished yields (entries 4 and 5, respectively). In contrast, addition of 5 equiv of NaHMDS in place of LiHMDS resulted in a higher the yield of 8 (entry 6). Furthermore, decreasing the amount of NaHMDS to 3.0 equiv did not significantly affect the reaction yield (entry 7). Because at least 2 equiv of this strong base are needed, further reduction in the number of equivalents of base were not investigated. The more costly KHMDS also gave a slightly lower yield than NaHMDS under identical reaction conditions (entry 8). Finally, addition of NaHMDS at double the reaction concentration provided pure sulfinamide 8 in the same yield as observed at the lower concentration (entry 9).</p><p>With optimal conditions identified for the preparation and cleavage of sulfinate ester 6, perfluorobutanesulfinamide (8) was next prepared on multigram scale from sulfinyl transfer reagent 5 in a two-step sequence (Scheme 2). Sulfinamide 8 was isolated in 67% overall yield for the two steps with the sole purification being straightforward chromatographic separation from the by-product 7 and its O-TMS ether. Importantly, sulfinamide 8 was obtained in 99% ee as determined by chiral HPLC analysis. Chiral auxiliary 7 also can be recovered in pure form in 76% overall yield from 5 by treating the mixture of 7 and its silyl ether with Bu4NF followed by extractive isolation and recrystallization.</p><p>We next focused on the preparation of N-perfluorobutanesulfinyl imino ester 9 as a versatile intermediate for the asymmetric synthesis of α-amino acids. Condensation of 8 with ethyl glyoxylate was performed with molecular sieves as the dehydrating reagent (eq 1). Although N-sulfinyl imino ester 9 is not stable to column chromatography, it is sufficiently pure that it can be directly used in subsequent reactions after filtration to remove the sieves followed by concentration.</p><p>Recently we reported on the first asymmetric addition of C–H bonds to N-perfluorobutanesulfinyl imines.17a This study included the asymmetric syntheses of the three arylglycines 11a–c by Rh(III)-catalyzed C-H bond addition to perfluorobutanesulfinyl imine 9 (Table 3). Here an expanded set of directing groups and compatibility with different functionality and substitution patterns has been demonstrated (11d–11m). All Rh(III)-catalyzed C–H bond additions were performed at ≤ 60 °C because rapid decomposition of perfluorobutanesulfinyl imino ester 9 occurs at higher temperatures. A number of directing groups proved to be effective for this reaction. In addition to the previously reported benzamide (11a) and azo (11b and c) directing groups, sulfoximine (11d), pyrazoles (11e–i) and 1,2,3-triazoles (11j–m) also were shown to be effective. Good scope was also observed for substitution on the arene ring with electron deficient and reactive keto functionality (11h) and electron donating groups (11f, 11g, 11i, and 11k–11m). The desired products were obtained in moderate to good yield, and in all cases with excellent diastereoselectivities as rigorously determined by HPLC analysis using an authentic mixture of diastereomer standards.24</p><p>The absolute configuration of 11a was established by x-ray structure determination of its 4-chlorobenzamide derivative. The stereochemistry of all of the other addition products 11 were assigned by analogy. The sense of induction is consistent with the stereochemical model that we reported for C-H bond addition to aromatic imines (Figure 1). Enantiomeric rhodacycles A and B are based upon the x-ray structures of corresponding cationic rhodacycles derived from 2-phenylpyridine.25,26 The observed sense induction is obtained if the reaction occurs through C with the C4F9 substituent pointing away from the reaction center. This model is consistent with prior mechanistic studies on the addition of 2-phenylpyridine to N-sulfonyl and N-carbamoyl imines.27 The high diastereoselectivity requires equilibration between enantiomeric rhodacycles A and B either before or after coordination of N-sulfinyl iminoester 9.</p><p>We and others had previously reported that Rh(III)-catalyzed C-H bond additions to N-tert-butanesulfinyl benzaldimine were unsuccessful,17 in contrast to the additions to the corresponding N-perfluorobutanesulfinyl derivative.17a However, because the carboxy group of N-sulfinyl imino esters activates the imine for addition, as a further control we now also have evaluated Rh(III)-catalyzed C–H bond additions to tert-butanesulfinyl imino ester 12 (Scheme 3). The desired addition products were not obtained for either the amide or sulfoximine directing groups. At 50 °C no reaction was observed, and upon incremental heating up to 120 °C only decomposition occurred.</p><p>As shown in eq 2, the N-perfluorobutanesulfinyl group readily can be cleaved by treatment with HCl in CH2Cl2 at rt to provide the hydrochloride salt 13b in high yield and without any loss in stereochemical purity.17a</p><p>Gautun and coworkers have previously reported highly diastereoselective aza-Diels Alder reaction of tert-butanesulfinyl imino ester 12 with dienes with TMSOTf as a Lewis acid catalyst.16 While cycloaddition with unhindered dienes proceeded in high yields and with high selectivity, for more hindered diene substrates the aza-Diels Alder products were obtained in very low yields (eq 3).</p><p>The synthetic utility of N-perfluorobutanesulfinyl imino ester 9 was therefore evaluated for aza-Diels Alder reactions (Table 4). When TMSOTf or BF3·Et2O were employed as Lewis acids for cycloaddition of 9 with 2-methylbutadiene (14a) under the conditions previously reported for the aza-Diels–Alder reaction of N-tert-butanesulfinyl imino ester 12,16 no desired product was obtained due to the rapid decomposition of 9 (entries 1 and 2, respectively). However, when the reaction solution was heated to 50 °C without a Lewis acid catalyst good conversion to the desired cycloaddition product 15a was observed (entry 3). The higher boiling point solvent 1,2-dichloroethane (DCE) resulted in higher conversion (entry 4), and increasing the reaction concentration to 1.0 M led to a higher yield of 15a with almost complete consumption of starting material 9 (entry 5). Increasing the temperature above 50 °C resulted in a lower yield due to competitive decomposition of imino ester 9 (entry 6). The reaction also proceeded at 2.0 M (entry 7) and even without solvent (entry 8).</p><p>The thermal aza-Diels Alder reaction of the corresponding N-tert-butanesulfinyl imino ester 12 was also evaluated for comparison purposes (eq 4). At 50 °C no reaction occurred, and incremental heating up to 120 °C only resulted in the decomposition of imine 12.</p><p>The thermal aza-Diels Alder reaction for the N-perfluorobutanesulfinyl imino ester 9 was next evaluated for several dienes (Table 5). For the reactive dienes 2-methylbutadiene and 2,3-dimethylbutadiene the aza-Diels Alder products 15a and 15b were obtained in high yields and with very high diastereoselectivity. However, it should be noted that for these dienes, the TMSOTF catalyzed aza-Diels Alder reaction with tert-butanesulfinyl imino ester 12 had previously been shown to be efficient.16 Much more significantly, the reaction also proceeded in good yields and selectivity for the less reactive dienes (E)-1,3-pentadiene and (2E, 4E)-2,4-hexadiene to give 15c and 15d. For these dienes Lewis acid catalyzed addition to tert-butanesulfinyl imino ester 12 had previously been shown to proceed in very low yields (see eq 3).16a The absolute con-figuration of the pipecolic acid derivative 15d was rigorously determined by x-ray crystal structure analysis and the remainder of the products were assigned by analogy.</p><!><p>In conclusion, a high yielding and practical two-step synthesis of enantiomerically pure perfluorobutanesulfinamide from Senanayake's 2-aminoindanol-derived sulfinyl transfer reagent was developed and carried out on multi-gram scale. Straightforward preparation of the N-perfluorobutanesulfinyl imine from ethyl glyoxylate also proceeded cleanly and in high yield. The enhanced reactivity of the N-perfluorobutanesulfinyl imino ester allowed for the Rh(III)-catalyzed addition of aryl C–H bonds using a wide range of directing groups to provide arylglycines in moderate to good yields and with high diastereoselectivity. We further demonstrated the utility of the N-perfluorobutanesulfinyl imino ester for the asymmetric synthesis of pipecolic acid derivatives via aza-Diels–Alder reaction. We anticipate that N-perfluorobutanesulfinyl imino esters may prove effective when the corresponding less electrophilic N-tert-butanesulfinyl imino esters are determined to have insufficient reactivity.</p><!><p>Unless noted, all catalytic reactions were set up inside a nitrogen filled glovebox using oven-dried (150 °C) glassware that was evacuated hot prior to use. Unless otherwise indicated, all reagents and starting materials were obtained from commercial suppliers and used without further purification. Heating in addition to work-up and isolation of the products of the reactions were performed on the bench-top using standard techniques. Tetrahydrofuran and diethyl ether were purified by passage through activated alumina using a solvent purification system. [Cp*RhCl2]2,28 AgB(C6F5)4,29 benzoylpyrrolidine,30 azobenzenes,31 sulfoximine,32
N-aryl-1H-pyrazoles,33 and 1-benzyl-4-phenyl-1H-1,2,3-triazoles34 were synthesized according to published procedures. 1,2-Dichloroethane (DCE) was deoxygenated by sparging with nitrogen gas followed by storage over activated 3 Å molecular sieves for 48 h prior to use. Ethylmagnesium bromide was titrated35 before use, and the oxathiazolidine oxide chiral sulfinyl transfer auxiliary (5) was prepared according to a published procedure.36 Ethyl glyoxalate was prepared following a published procedure.37 Flash-column chrom atography was performed with 230–400 mesh silica gel. The products were visualized on TLC either by UV or staining with KMnO4. Normal phase chromatography was performed on 230–240 mesh silica gel or preparative thin-layer chromatography plates (1 mm SiO2, 20 × 20 cm). Reverse phase chromatography was performed with C18 columns using an automated purification system. 1H, 13C{1H}, and 19F NMR characterization data were collected at ambient temperature, and chemical shifts are reported in parts per million relative to CDCl3 (1H NMR; 7.26 ppm, 13C{1H} NMR; 77.16 ppm) or MeOD (1H NMR; pentet, 3.31 ppm). Only partial data are provided for IR spectra. Melting points are reported uncorrected. High resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI) on a time-of-flight (TOF) mass spectrometer. Enantiomeric excess or diastereomeric ratio were determined using an HPLC (1.0 mL/min flow rate) equipped with a multiwavelength detector and a Chiralpak IB column or an Microsorb 100-5 Si 250 × 4.6mm silica column, respectively.</p><!><p>A flame dried 250 mL three-necked round bottom flask cooled under nitrogen was equipped with a magnetic stir bar and rubber septa. The flask was flushed with nitrogen for 10 min and then charged with diethyl ether (48 mL) before it was cooled to −78 °C using a dry ice-acetone bath. The flask was then charged with nonafluoro-1-iodobutane (5.74 mL, 33.4 mmol, 1.05 equiv) before ethylmagnesium bromide (12.0 mL, 2.65 M in ether, 31.8 mmol, 1.00 equiv) was added drop-wise with stirring via syringe over 5 min. After the addition, the flask was covered with aluminum foil to protect it from light, and the Grignard mixture was stirred for 1 h at −78 °C. While the Grignard mixture was being stirred, a separate one-necked oven dried 100 mL round bottom flask was charged with oxathiazolidine oxide36 (12.0 g, 31.8 mmol, 1.00 equiv) and 45 mL of anhydrous THF, and the resulting mixture was heated to 50 °C until complete dissolution had occurred. The resulting THF solution was cooled to −78 °C with a dry ice-acetone bath before it was transferred via cannula to the 250 mL flask containing the Grignard reagent (1 h after ethylmagnesium bromide addition). The resulting reaction mixture in the 250 mL flask was stirred at −78 °C for 1 h before the reaction was quenched by addition of 15.5 mL of 4.1 M acetic acid in THF (2 equiv) over 5 min. The solution was allowed to warm to rt over ~30 min, and then the mixture was transferred to a separatory funnel. Additional deionized water (60 mL) was added, and the aqueous layer was separated and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was shaken with saturated aqueous Na2S2O3 solution (30 mL) until the orange color disappeared. The organic layer was then washed with brine (30 mL), dried over sodium sulfate and concentrated to dryness under reduced pressure to afford crude product 6 (17.3 g, 91% yield) as an off-white solid. The crude product was determined to be of sufficient purity by 1H NMR and was used directly in the subsequent step. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 1H), 7.24 – 7.20 (m, 2H), 7.18 – 7.14 (m, 1H), 7.01 (s, 2H), 5.26 – 5.20 (m, 2H), 5.00 (dd, J = 10.5, 4.3 Hz, 1H), 3.27 – 3.09 (m, 2H), 2.73 (s, 6H), 2.32 (s, 3H).</p><!><p>To a flame dried three necked 250 mL indented style (Morton) round bottom flask equipped with magnetic stir bar and cooled under nitrogen was added 17.3 g of crude perfluorobutanesulfinate ester 7. The flask was then fitted with an oven-dried 125 mL addition funnel and rubber septa before flushing with nitrogen for 10 min. Anhydrous THF (53 mL) was then added via syringe with stirring until all the solids had dissolved to give a clear solution. The solution of 7 in THF was cooled to −78 °C using a dry ice-acetone bath before 43.4 mL (86.9 mmol, 3 equiv assuming that crude 7 was 100% pure) of a 2.0 M solution of NaHMDS in THF was added dropwise via an addition funnel over 10 min. The resulting reaction mixture was stirred for 3.5 h at −78 °C before it was quenched by dropwise addition of a saturated aqueous NH4Cl solution (50 mL). After allowing to warm to rt over ~30 min, the biphasic mixture was stirred at room temperature for 16 h before being transferred to a separatory funnel. The aqueous layer was separated and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a dark red-brown oil. Purification by flash column chromatography with 10% MTBE in CH2Cl2 as eluent (8 has an Rf value of 0.31) afforded the product 8 (6.0 g, 67% yield over two steps) as an off-white solid that was determined to be of >99%ee as determined by chiral HPLC analysis (Chiralpak IB, EtOH/hexanes 10:90, 1.0 mL/min. 230 nm) of 8: tR = 7.4 min (S) and 11.4 min (R); mp 73–75 °C [lit. 64–66 °C].11 The analytical data for this compound are consistent with previously reported data.18d IR (film): 3349, 1264, 1205, 1136, 1021, 731, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 119.4 – 107.7 (m); 19F NMR (376 MHz, CDCl3) δ −80.82 (tt, J = 9.8, 2.3 Hz, 3F), −121.43 to −121.72 (m, 2F), −121.08 to −122.05 (m, 1F), −122.50 to −123.32 (m, 1F), −126.12 to −126.25 (m, 2F); [α]D20 = −16.2 (c 0.46, CH3OH); Anal. Calcd for C4H2F9NOS: C, 16.97; H, 0.71; N, 4.95. Found: C, 17.09; H, 0.71; N, 5.34.</p><!><p>From the column chromatography purification of 8, fractions that contain 7 (Rf = 0.59, 10% MTBE in CH2Cl2) or its O-TMS ether (Rf = 0.90, 10% MTBE in CH2Cl2) were combined and concentrated to give 12.0 g of dark red-brown oil. The material was transferred to a one-necked 250 mL round bottom flask using 100 mL of THF to solubilize the material and assist with transfer. To the stirred solution at ambient temperature was then added 30 mL of 1 M TBAF solution in THF. After being stirred at ambient temperature for 1 h, the mixture was transferred to a 250 mL separatory funnel. Additional ethyl acetate (50 mL) and deionized water (50 mL) were used to assist transfer. The aqueous layer was separated and further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with deionized water (2 × 30 mL) and saturated aqueous NaCl solution (30 mL) and then dried over sodium sulfate. The drying agent was removed by vacuum filtration, and the filtrate was concentrated to dryness via rotary evaporator before it was triturated with 50 mL of hexanes and vacuum filtered through a Buchner funnel equipped with a filter paper to afford 10.0 g of a light brown solid material, which was diluted with 40 mL of ethyl acetate in a 250 mL Erlenmeyer flask. The mixture was heated to 50 °C with swirling to dissolve all the material, and then 80 mL of hexanes was layered on top and the flask covered with aluminum foil. The flask was stored at −20 °C overnight (16 h). The crystalline product was isolated by vacuum filtration using a Buchner funnel equipped with a filter paper. The crystalline solid was crushed to powder using a porcelain mortar and pestle before it is dried under high vacuum to provide 8.0 g (76% recovery from 5) of 7 as an off-white solid; mp 148–150 °C [lit. 149–150 °C].36 The analytical data for this compound are consistent with previously reported data.36 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.10 (m, 4H), 7.01 (s, 2H), 5.33 (d, J = 9.5 Hz, 1H), 4.63 (dd, J = 9.5, 4.8 Hz, 1H), 4.44 – 4.39 (m, 1H), 3.09 (dd, J = 16.8, 5.1 Hz, 1H), 2.92 (d, J = 16.5 Hz, 1H), 2.72 (s, 6H), 2.33 (s, 3H), 2.17 (d, J = 4.9 Hz, 1H).</p><!><p>To a 20 mL screw top scintillation vial equipped with magnetic stir bar and flushed with nitrogen was weighed out distilled ethyl glyoxalate (108.2 mg, 1.06 mmol, 1.0 equiv) before addition of anhydrous CH2Cl2 (3.5 mL, [sulfinyl imino ester] = 0.30 M). To the solution was added 3 Å molecular sieves and (S)-nonafluorobutanesulfinamide (300 mg, 1.06 mmol, 1.0 equiv) before the vial was capped. The resulting mixture was stirred at room temperature over 4 d with the reaction conversion monitored by 1H NMR. After complete conversion was observed, the resulting mixture was filtered through a fine glass frit funnel to remove the molecular sieves and the flask and funnel were washed with additional CH2Cl2. The combined filtrate was concentrated under reduced pressure to give crude product 9 (322 mg, 83% yield) as a clear yellow-orange liquid which was of sufficient purity to be used in subsequent transformations. The analytical data for this compound are consistent with previously reported data.17a 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).</p><!><p>The following procedure was adapted from the literature.34a In a 20 mL scintillation vial equipped with a magnetic stir bar was added the indicated benzyl bromide (4.40 mmol, 1.1 equiv) to a stirred solution of DMF-H2O (10 mL; 4:1). Following this, CuSO4·5H2O (499 mg, 2.00 mmol, 0.5 equiv), sodium azide (312 mg, 4.80 mmol, 1.2 equiv), L-ascorbic acid (705 mg, 4.00 mmol, 1.0 equiv), and sodium carbonate (424 mg, 4.00 mmol, 1.0 equiv) were added. After the solution was stirred for 5 min, the indicated ethynylarene was added (4.00 mmol, 1.0 equiv), and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was transferred to a stirred 0.1 M solution of EDTA (disodium salt, dihydrate) in DI water (100 mL), followed by the addition of 100 mL NH4OH (28–30% v/v). The resulting mixture was then stirred vigorously at 1200 rpm for 30 min before being diluted with CH2Cl2 (200 mL) and transferred to a separatory funnel. The mixture was extracted with CH2Cl2 (2 × 50 mL), and the combined organic layers were washed with DI water (50 mL) and brine (50 mL), dried with MgSO4, and concentrated under reduced pressure. Purification by flash column chromatography with EtOAc/hexanes afforded the 1-benzyl-4-aryl-1H-1,2,3-triazole.</p><!><p>The general procedure was followed with benzyl bromide (753 mg, 4.40 mmol, 1.1 equiv) and 4-ethynylanisole (529 mg, 4.00 mmol, 1.0 equiv). Purification by flash column chromatography (10%–30% EtOAc in hexanes gradient) afforded the product (10k) (729 mg, 69% yield) as an off-white solid. mp: 142–143 °C [lit.34b 141–142 °C]. The analytical data for this compound are consistent with previously reported data.34b</p><!><p>The general procedure was followed with benzyl bromide (753 mg, 4.40 mmol, 1.1 equiv) and 4-ethynyltoluene (465 mg, 4.00 mmol, 1.0 equiv). Purification by flash column chromatography (10%–20% EtOAc in hexanes gradient) afforded the product (893 mg, 90% yield) as a white solid. mp: 152–154 °C [lit.34b 150–152 °C]. The analytical data for this compound are consistent with previously reported data.34b</p><!><p>The general procedure was followed with benzyl bromide (753 mg, 4.40 mmol, 1.1 equiv) and 3-ethynyltoluene (465 mg, 4.00 mmol, 1.0 equiv). Purification by flash column chromatography (10%–25% EtOAc in hexanes gradient) afforded the product (758 mg, 76% yield) as a white solid. 146–147 °C [lit.34c 144–146 °C]. The analytical data for this compound are consistent with previously reported data.34c</p><!><p>Synthetic procedures, full analytical characterization and NMR spectra were previously reported for arylglycines 11a–c.17a</p><!><p>To a flame dried 1 dram vial equipped with a magnetic stir bar was added 11a (60 mg, 0.11 mmol, 1 equiv). Anhydrous CH2Cl2 (1 mL) was added, and the solution was cooled to 0 °C with an ice bath followed by dropwise addition of 4M HCl in dioxane (0.14 mL, 0.55 mmol, 5 equiv). The mixture was stirred at 0 °C for 2 h and then concentrated to dryness under reduced pressure. The resulting solid residue was dissolved in anhydrous CH2Cl2 (1 mL) and Et3N (0.038 mL, 0.28 mmol, 2.5 equiv) was added. After cooling the mixture to 0 °C with an ice bath, a solution of benzoyl chloride (20.3 mg, 0.12 mmol, 1.05 equiv) in anhydrous CH2Cl2 (1 mL) was added slowly dropwise. The reaction mixture was warmed up slowly to room temperature and stirred for 2 h before concentrating to dryness under reduced pressure. Purification by flash column chromatography (50% EtOAc in hexanes) afforded the product 11a-amide (39.5 mg, 86% yield) as an off-white solid; mp 118–120 °C. IR (film): 3286, 1743, 1660, 1614, 1594, 1521, 1479, 1432, 1338, 1320, 1206, 1180, 1091, 1014, 847, 732 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.45 – 7.31 (m, 5H), 6.02 (d, J = 8.8 Hz, 1H), 4.24 – 4.02 (m, 2H), 3.64 – 3.53 (m, 2H), 3.38 – 3.29 (m, 1H), 3.26 – 3.19 (m, 1H), 2.02 – 1.77 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.7, 170.5, 165.3, 137.9, 136.0, 134.7, 132.3, 132.0, 130.4, 129.0, 128.8, 128.3, 127.7, 61.9, 56.9, 49.7, 46.2, 26.3, 24.7, 14.3; [α]D20 = +39.0 (c 0.32, CH3OH); HRMS (ESI/[M+H]+) calcd. for C22H23ClN2O4: 415.1419. Found 415.1390.</p><p>X-ray quality crystals of the 11a-amide were obtained according to the following procedure: In a flame dried 1 dram vial, 10 mg of 11a-amide was dissolved in 1.0 mL of Et2O with heating. The 1 dram vial containing the solution of 11a-amide in Et2O was placed inside a 20 mL scintillation vial filled with 5 mL of pentane. The scintillation vial was sealed and allowed to sit at room temperature for 2 days after which single crystals formed.</p><!><p>In a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) was weighed out into a 1 mL conical screw-capped vial followed by benzoylsulfoximine 10d (50.2 mg, 0.225 mmol, 1.5 equiv), [Cp*RhCl2]2 (9.3 mg, 0.015 mmol, 10 mol %), and AgB(C6F5)4(Et2O)2 (56.1 mg, 0.06 mmol, 40 mol %). To this mixture was added DCE (0.200 mL, [sulfinyl imine] = 0.750 M) and a triangular magnetic stir bar before the vial was sealed with a cap containing a PTFE septum and was removed from the glovebox. The reaction mixture was stirred at ambient temperature for 24 h before it was filtered through a plug of Celite in a pipette with CH2Cl2 (4 mL). The filtrate was then concentrated and subjected to purification by flash column chromatography on silica gel to afford the product 11d (45.1 mg, 55% yield) as a yellow oil. IR (film): 1739, 1612, 1595, 1573, 1309, 1196, 1093, 746, 723, 692 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.66 (d, J = 7.4 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.81 – 3.73 (m, 1H), 3.72 – 3.64 (m, 1H), 3.41 – 3.31 (m, 2H), 2.42 – 2.32 (m, 2H), 2.35 – 2.22 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 176.8, 170.3, 136.7, 134.4, 132.2, 131.8, 131.1, 128.9, 120.5 – 106.3 (m), 62.3, 59.9, 53.1, 52.7, 23.9, 23.7, 14.1; 19F NMR (376 MHz, CDCl3) δ −80.86 (t, J = 9.7 Hz, 3F), −117.84 (dt, J = 249.1, 13.1 Hz, 1F), −121.64 to −121.91 (m, 2F), −122.44 to −123.39 (m, 1F), −126.12 to −126.35 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C19H19F9N2O5S2: 591.0664. Found 591.0659.</p><!><p>In a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv), the indicated 1-aryl-1H-pyrazole (10e–10i)33 (0.300 mmol, 2.0 equiv), [Cp*RhCl2]2 (9.3 mg, 0.015 mmol, 0.10 equiv), and AgB(C6F5)4 (62.0 mg, 0.060 mmol, 0.40 equiv, 23.8 %w/w toluene) were added to a 0.5–2.0 mL microwave vial equipped with a triangular magnetic stir bar followed by the addition of 1,2-dichloroethane (200 μL, [sulfinyl imine] = 0.75 M). The vial was sealed and removed from the glovebox. The reaction vial was then placed in a temperature-controlled oil bath preset to 50 °C and was stirred for 24 h. The vial was removed from the oil bath and cooled to ambient temperature before the reaction vessel was unsealed. The crude mixture was purified directly by silica gel chromatography.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-phenyl-1H-pyrazole (43.3 mg, 0.300 mmol, 2.0 equiv). Purification by flash column chromatography (10%–20% EtOAc in hexanes gradient) afforded the product 11e (52.0 mg, 68% yield) as a light yellow oil. IR (film): 1739, 1521, 1396, 1351, 1195, 1138, 1099, 1015, 941, 864, 758, 723, 692, 619, 577, 515, 428 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.51–7.40 (m, 4H), 7.33 (dd, J = 7.4, 1.8 Hz, 1H), 6.47 (t, J = 1.9 Hz, 1H), 5.45 (d, J = 9.0 Hz, 1H), 4.00–3.87 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.1, 141.2, 138.7, 132.7, 132.2, 130.7, 130.0, 129.0, 125.4, 120.4–106.5 (m), 107.8, 62.4, 58.0, 13.9; 19F NMR (376 MHz, CDCl3): δ −81.81 (t, J = 9.5 Hz, 3F), −117.51 (dt, J = 249.0, 12.7 Hz, 1F), −122.69 to −122.85 (m, 2F), −124.30 (dt, J = 249.0, 12.7 Hz, 1F), −126.29 to −128.07 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C17H15F9N3O3S: 512.0685. Found 512.0684.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-(p-tolyl)-1H-pyrazole6a (47.5 mg, 0.300 mmol, 2.0 equiv). Purification by flash column chromatography (10%–20% EtOAc in hexanes gradient) afforded the product 11f (59.6 mg, 76% yield) as a light yellow oil. IR (film): 1738, 1522, 1396, 1351, 1195, 1138, 1099, 1024, 942, 862, 822, 746, 722, 692, 620, 576, 519, 436 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.30 (s, 1H), 7.26–7.23 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 3.98–3.87 (m, 2H), 2.40 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.1, 140.9, 139.2, 136.3, 132.6, 132.6, 130.7, 130.5, 125.4, 120.4–106.4 (m), 107.6, 62.3, 57.6, 21.0, 13.9; 19F NMR (376 MHz, CDCl3): δ −81.86 (tt, J = 9.6, 2.4 Hz, 3F), −117.34 (dt, J = 248.9, 12.9 Hz, 1F), −122.75 to −122.90 (m, 2F), −124.57 (dt, J = 248.9k, 11.6 Hz, 1F), −126.32 to −128.10 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C18H17F9N3O3S: 526.0841. Found 526.0840.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-(4-methoxyphenyl)-1H-pyrazole33a (52.3 mg, 0.300 mmol, 2.0 equiv). Purification by preparative thin-layer silica gel chromatography using 25% EtOAc/hexanes afforded the product 11g (38.3 mg, 47% yield) as a light yellow oil. IR (film): 1740, 1523, 1196, 1138, 1043, 1018, 943, 864, 816, 746, 723, 692, 613, 435 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.7, 2.8 Hz, 1H), 6.43 (t, J = 2.2 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H), 4.00–3.88 (m, 2H), 3.85 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 168.9, 159.7, 140.8, 134.4, 131.9, 131.0, 127.2, 116.7, 115.0, 120.4–106.4 (m), 107.4, 62.4, 57.3, 55.8, 13.9; 19F NMR (471 MHz, CDCl3): δ −81.87 (t, J = 9.5 Hz, 3F), −117.38 (dt, J = 249.2, 13.2 Hz, 1F), −122.71 to −122.88 (m, 2F), −124.49 (ad, J = 249.2, 1F), −126.48 to −127.98 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C18H17F9N3O4S: 542.0791. Found 542.0790.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one33b (55.9 mg, 0.300 mmol, 2.0 equiv). Purification by preparative thin-layer silica gel chromatography using 25% EtOAc/hexanes afforded the product 11h (50.6 mg, 61% yield) as a light yellow waxy solid. IR (film): 1726, 1697, 1607, 1524, 1395, 1191, 1137, 1033, 943, 759, 746, 722, 692, 613, 514, 457 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.08 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 8.2, 2.0 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 9.1 Hz, 1H), 6.51 (t, J = 2.2 Hz, 1H), 5.58 (d, J = 9.1 Hz, 1H), 4.00–3.88 (m, 2H), 2.63 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 196.3, 168.7, 141.9, 141.8, 136.6, 132.9, 132.3, 130.5, 129.8, 124.8, 120.3–106.4 (m), 108.6, 62.5, 58.3, 26.8, 13.9; 19F NMR (471 MHz, CDCl3): δ −82.10 (t, J = 9.5 Hz, 3F), −117.80 (dt, J = 248.9, 13.5 Hz, 1F), −122.93 to −123.09 (m, 2F), −124.53 (ad, J = 248.9 Hz, 1F), −126.72 to −128.91 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C19H17F9N3O4S: 554.0791. Found 554.0793.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-(m-tolyl)-1H-pyrazole33a (47.5 mg, 0.300 mmol, 2.0 equiv). Purification by flash column chromatography (10%–20% EtOAc in hexanes gradient) afforded the product 11i (60.1 mg, 76% yield) as a light yellow oil. IR (film): 1738, 1519, 1394, 1351, 1194, 1138, 1101, 1014, 955, 859, 746, 722, 692, 619, 580, 437 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.71 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.38–7.35 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 6.46 (t, J = 2.2 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 3.98–3.88 (m, 2H), 2.40 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.2, 141.1, 140.4, 138.5, 131.9, 130.6, 129.7, 129.6, 126.1, 120.4–106.4 (m), 107.6, 62.3, 57.6, 21.1, 14.0; 19F NMR (376 MHz, CDCl3): δ −81.87 (tt, J = 9.4, 2.6 Hz, 3F), −117.57 (dt, J = 249.1, 13.0 Hz, 1F), −122.72 to −122.89 (m, 2F), −124.33 (dt, J = 249.1, 12.2 Hz, 1F), −126.33 to −128.10 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C18H17F9N3O3S: 526.0841. Found 526.0842.</p><!><p>In a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv), the indicated 1-benzyl-4-aryl-1H-1,2,3-triazole (10j–10m)34 (0.300 mmol, 2.0 equiv), [Cp*RhCl2]2 (9.3 mg, 0.015 mmol, 0.10 equiv), AgB(C6F5)4 (62.0 mg, 0.060 mmol, 0.40 equiv, 23.8 %w/w toluene), and AgOAc (5.0 mg, 0.030 mmol, 0.20 equiv) were added to a 0.5–2.0 mL microwave vial equipped with a triangular magnetic stir bar followed by the addition of 1,2-dichloroethane (200 μL, [sulfinyl imine] = 0.75 M). The vial was sealed and removed from the glovebox. The reaction vial was then placed in a temperature-controlled oil bath preset to 50 °C. After the solution was stirred for 24 h, the vial was removed from the oil bath and cooled to ambient temperature before the reaction vessel was unsealed. The crude mixture was purified directly by chromatography.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-phenyl-1H-1,2,3-triazole34a (70.6 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel chromatography using 50% Et2O/pentane provided the first step of the purification process. Pure product was then obtained by C18 reverse phase column chromatography with loading of the isolated material onto the column as a solution in 1 mL of DMSO. Reverse phase purification was performed with 15.5 g of reverse phase media and a 95 column volume gradient from 10–65% CH3CN:H2O containing 0.1% TFA. Fractions containing product were combined and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and concentrated to afford the product 11j (52.1 mg, 58% yield) as a colorless oil. IR (film): 1738, 1352, 1196, 1138, 1014, 763, 721, 692, 581 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.67 (s, 1H), 7.42–7.28 (m, 10H), 5.78 (d, J = 8.0 Hz, 1H), 5.59 (d, J = 14.8 Hz, 1H), 5.55 (d, J = 14.8 Hz, 1H), 4.01–3.92 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.9, 147.4, 135.4, 134.4, 130.4, 130.1, 129.3, 129.3, 129.1, 129.1, 128.3, 122.0, 120.4–106.2 (m), 62.1, 58.6, 54.5, 13.8; 19F NMR (471 MHz, CDCl3): δ −81.88 (t, J = 9.5 Hz, 3F), −117.99 (dt, J = 249.0, 12.6 Hz, 1F), −122.03 to −123.54 (m, 2F), −123.56 (ad, J = 249.0 Hz, 1F), −126.52 to −127.93 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C23H20F9N4O3S: 603.1107. Found 603.1108.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (79.6 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel chromatography using 50% Et2O/pentane provided the first step in the purification process. Pure product was then obtained by C18 reverse phase column chromatography with loading of the isolated material onto the column as a solution in 1 mL of DMSO. Reverse phase purification was performed with 15.5 g of reverse phase media and an 80 column volume gradient from 10–70% CH3CN:H2O containing 0.1% TFA. Fractions containing product were combined and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and concentrated to afford the product 11k (53.0 mg, 56% yield) as a yellow oil. IR (film): 1738, 1615, 1493, 1459, 1351, 1196, 1138, 864, 814, 746, 721, 693, 580 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.41–7.30 (m, 7H), 6.93 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.6, 2.6 Hz, 1H), 5.73 (d, J = 7.9 Hz, 1H), 5.58 (d, J = 14.9 Hz, 1H), 5.53 (d, J = 14.9 Hz, 1H), 4.01–3.93 (m, 2H), 3.81 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.8, 160.0, 147.3, 136.8, 134.4, 131.5, 129.3, 129.0, 128.3, 121.8, 121.5, 115.6, 114.7, 120.4–106.4 (m), 62.2, 58.4, 55.5, 54.5, 13.8; 19F NMR (376 MHz, CDCl3): δ −81.85 (t, J = 9.6 Hz, 3F), −117.85 (dt, J = 249.0, 13.0 Hz, 1F), −121.83 to −123.66 (m, 2F), −123.74 (ad, J = 249.0 Hz, 1F), −126.35 to −128.08 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C24H22F9N4O4S: 633.1213. Found 633.1214.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(p-tolyl)-1H-1,2,3-triazole (74.8 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel chromatography using 50% Et2O/pentane provided the first step in the purification process. Pure product was then obtained by C18 reverse phase column chromatography with loading of the isolated material onto the column as a solution in 1 mL of DMSO. Reverse phase purification was performed with 15.5 g of reverse phase media and a 70 column volume gradient from 10–60% CH3CN:H2O containing 0.1% TFA. Fractions containing product were combined and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and concentrated to afford the product 11l (48.3 mg, 52% yield) as a colorless oil. IR (film): 1739, 1459, 1351, 1232, 1197, 1138, 1015, 820, 721, 692, 578 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.41–7.28 (m, 7H), 7.22 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.73 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 14.8 Hz, 1H), 5.53 (d, J = 14.8 Hz, 1H), 4.02–3.91 (m, 2H), 2.36 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 170.0, 147.5, 139.4, 135.2, 134.4, 131.2, 130.0, 129.9, 129.3, 129.0, 128.3, 126.4, 121.7, 120.4–106.2 (m), 62.1, 58.5, 54.5, 21.2, 13.8; 19F NMR (376 MHz, CDCl3): δ −81.86 (t, J = 9.6 Hz, 3F), −117.83 (dt, J = 248.9, 12.6 Hz, 1F), −121.89 to −123.71 (m, 2F), −123.80 (ad, J = 248.9 Hz, 1F), −126.36 to −128.09 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C24H22F9N4O3S: 617.1263. Found 617.1261.</p><!><p>The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(m-tolyl)-1H-1,2,3-triazole (74.8 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel chromatography using 50% Et2O/pentane provided the first step in the purification process. Pure product was then obtained by C18 reverse phase column chromatography with loading of the isolated material onto the column as a solution in 1 mL of DMSO. Reverse phase purification was performed with 15.5 g of reverse phase media and a 75 column volume gradient from 10–60% CH3CN:H2O containing 0.1% TFA. Fractions containing product were combined and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and concentrated to afford the product 11m (49.1 mg, 53% yield) as a colorless waxy solid. IR (film): 1739, 1459, 1352, 1197, 1138, 1014, 862, 819, 786, 746, 721, 692, 575 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.42–7.37 (m, 3H), 7.34–7.28 (m, 3H), 7.24 (d, J = 1.8 Hz, 1H), 7.20–7.17 (m, 2H), 5.73 (d, J = 7.9 Hz, 1H), 5.59 (d, J = 14.8 Hz, 1H), 5.55 (d, J = 14.8 Hz, 1H), 4.02–3.94 (m, 2H), 2.34 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 170.1, 147.5, 139.1, 134.4, 132.4, 130.8, 130.3, 130.0, 129.3, 129.1, 129.1, 128.3, 121.9, 120.4–106.4 (m), 62.1, 58.3, 54.6, 21.1, 13.8; 19F NMR (376 MHz, CDCl3): δ −81.84 (t, J = 9.5 Hz, 3F), −117.91 (dt, J = 249.2, 13.3 Hz, 1F), −121.84 to −123.69 (m, 2F), −123.59 (ad, J = 249.2 Hz, 1F), −126.34 to −128.07 (m, 2F); HRMS (ESI/[M+H]+) calcd. for C24H22F9N4O3S: 617.1263. Found 617.1260.</p><!><p>In a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (183.6 mg, 0.50 mmol, 1.0 equiv) was weighed out into a 1 mL conical screw-capped vial. DCE (0.20 mL, [sulfinyl imine] = 1.0 M) and a triangular magnetic stir bar were then added. The vial was sealed with a screw top cap containing a PTFE septum and was removed from the glovebox. The cap was removed and the corresponding diene (14a–14d) (2.5 mmol, 5.0 equiv) was added by syringe before the vial was sealed again with the cap. The vial was then heated in a temperature-controlled aluminum-heating block set at 50 °C and was stirred for 16 h, the vial was removed from the heating block and allowed to cool to ambient temperature. Excess diene and solvent were removed under reduced pressure, and the remaining crude material was purified by silica gel flash column chromatography.</p><!><p>The general procedure using isoprene 14a (0.25 mL, 2.5 mmol, 5.0 equiv) was followed. Purification by flash column chromatography (10% EtOAc in hexanes) afforded the product 15a (154 mg, 71% yield) as a colorless oil. IR (film): 2920, 1740, 1350, 1196, 1138, 1112, 1009, 921, 746, 721, 691 cm−1; 1H NMR (600 MHz, CDCl3) δ 5.42 – 5.37 (m, 1H), 4.57 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.00 (d, J = 17.5 Hz, 1H), 3.82 (d, J = 17.1 Hz, 1H), 2.51 – 2.45 (m, 2H), 1.72 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.1, 131.4, 116.6, 120.6 – 106.3 (m), 62.0, 52.6, 42.9, 32.2, 23.5, 14.2; 19F NMR (376 MHz, CDCl3) δ −80.88 (t, J = 9.5 Hz, 3F), −114.90 (dt, J = 248.3, 12.9 Hz, 1F), −120.58 to −123.54 (m, 3F), −125.27 to −127.14 (m, 2F); HRMS (ESI/[M+Na]+) calcd. for C13H14F9NO3S: 458.0443. Found 458.0447.</p><!><p>The general procedure using dimethylbutadiene 14b (0.29 mL, 2.5 mmol, 5.0 equiv) was followed. Purification by flash column chromatography (10% EtOAc in hexanes) afforded the product 15b (182 mg, 81% yield) as colorless oil. IR (film): 2917, 1742, 1350, 1232, 1196, 1134, 1009, 998, 746, 721, 690 cm−1; 1H NMR (600 MHz, CDCl3) δ 4.51 (s, 1H), 4.19 (qd, J = 7.1, 2.3 Hz, 2H), 3.89 (d, J = 16.5 Hz, 1H), 3.59 (d, J = 16.6 Hz, 1H), 2.52 – 2.41 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.0, 123.1, 121.6, 120.7 – 106.0 (m), 61.6, 52.5, 46.2, 33.0, 18.7, 15.9, 14.0; 19F NMR (376 MHz, CDCl3) δ −80.85 (t, J = 9.5 Hz, 3F), −114.85 (dt, J = 248.6, 12.7 Hz, 1F), −121.46 to −123.53 (m, 3F), −125.28 to −127.13 (m, 2F); HRMS (ESI/[M+Na]+) calcd. for C14H16F9NO3S: 472.0599. Found 472.0598.</p><!><p>The general procedure using 2,4-hexadiene 14c (0.29 mL, 2.5 mmol, 5.0 equiv) was followed. Purification by flash column chromatography (10% EtOAc in hexanes) afforded the product 15c (154 mg, 69% yield) as a colorless oil. IR (film): 2978, 1749, 1233, 1189, 1137, 1110, 1018, 997, 746, 722, 692 cm−1; 1H NMR (600 MHz, CDCl3) δ 5.71 (ddd, J = 10.4, 5.5, 2.0 Hz, 1H), 5.57 – 5.51 (m, 1H), 4.60 – 4.54 (m, 1H), 4.49 (s, 1H), 4.24 – 4.12 (m, 2H), 2.78 (p, J = 5.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.2, 129.6, 128.3, 121.7 – 106.1 (m), 61.5, 54.0, 50.8, 32.7, 20.2, 19.8, 14.1; 19F NMR (376 MHz, CDCl3) δ −80.88 (t, J = 9.6 Hz, 3F), −108.89 to −115.20 (m, 1F), −122.28 to −122.42 (m, 2F), −125.14 to −127.34 (m, 3F); HRMS (ESI/[M+Na]+) calcd. for C14H16F9NO3S: 472.0599. Found 472.0591.</p><!><p>The general procedure using 1,3-pentadiene 14d (0.25 mL, 2.5 mmol, 5.0 equiv) was followed. Purification by flash column chromatography (10% EtOAc in hexanes) afforded the product 15d (141 mg, 65% yield) as a colorless oil and as inseparable exo/endo diastereomeric mixture (dr = 8/1, 1H NMR). IR (film): 2987, 1742, 1350, 1191, 1136, 1109, 1007, 746, 721, 691 cm−1; 1H NMR (600 MHz, CDCl3) major isomer only δ 5.80 – 5.73 (m, 1H), 5.65 – 5.58 (m, 1H), 4.76 (s, 1H), 4.56 – 4.50 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.61 – 2.55 (m, 1H), 2.51 – 2.45 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3, selected signals) δ 170.0, 130.5, 122.9, 121.1 – 106.2 (m), 61.7, 50.1, 28.6, 23.4 19.8, 14.1; 19F NMR (376 MHz, CDCl3) δ −80.86 (t, J = 9.5 Hz, 3F), −110.20 to −115.41 (m, 1F), −122.29 (app. q, J = 9.6 Hz, 2F), −125.10 to −127.46 (m, 3F); HRMS (ESI/[M+Na]+) calcd. for C13H14F9NO3S: 458.0443. Found 458.0438. HPLC (Microsorb 100-5 Si, EtOH/hexanes. 2:98, 1.0 mL/min. 230 nm) of 15d: tR = 4.78 (minor) and 5.05 min (major). A 1:1 mixture of endo/exo diastereomers of 15d was obtained by collecting enriched fractions (tR = 4.7 to 5.0 min). The enriched fractions from multiple runs were combined and concentrated to give 2.0 mg of the 1:1 mixture (15d-mix). Relative configurations were determined from 2D NOE experiments of 15d-mix.</p><p>The absolute configuration of the major exo diastereomer was determined by sulfinyl group cleavage and then X-ray structural analysis of the 2,4,6-trinitrobenzenesulfonate salt of the resulting amine. To a flame dried 1 dram vial equipped with a magnetic stir bar was added 15d (31.7 mg, 0.073 mmol, 1 equiv) followed by 2M HCl in Et2O (0.36 mL, 0.73 mmol, 10 equiv). The mixture was stirred and heated to 50 °C for 8 h and then concentrated to dryness under reduced pressure. The concentrate was dissolved in 10 mL of 0.1M aqueous HCl, transferred to separatory funnel and washed with Et2O (1 × 5 mL) before aqueous Na2CO3(sat) was added with stirring until a pH of 10–11 was reached. The basic aqueous layer was extracted with Et2O (3 × 10 mL), and the combined organic layer was dried over MgSO4 and concentrated under reduced pressure to afford the free amine (6.7 mg. 54% yield. To 4.8 mg of the unpurified free amine in a 1 dram vial was added 7.5 mg (0.9 equiv) of 2,4,6-trinitrobenzenesulfonic acid followed by 0.5 mL of toluene, which resulted in a cloudy mixture. To this cloudy mixture was added methanol dropwise with swirling until the solution turned clear (10 drops). The clear solution was transferred into a NMR tube and layered with 1.0 mL of HPLC grade hexanes. The NMR tube was allowed to sit at ambient temperature for 3 days after which single crystals were formed.</p>