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4‑Cyanobenzenesulfonamides: Amine Synthesis and Protecting Strategy To Compliment the Nosyl Group Michael A. Schmidt,*,† Ryjul W. Stokes,† Merrill L. Davies,‡ and Frederick Roberts‡ †
Chemical & Synthetic Development, Technologies Group, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick New Jersey 08903, United States ‡ Chemical & Synthetic Development, Special Analytical Support, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick New Jersey 08903, United States S Supporting Information *
ABSTRACT: 4-Cyanobenzenesulfonamides of secondary amines were found to cleave to the parent amine cleanly under the action of thiol and base. This feature readily lends itself to the use of this motif as an amine protecting/activating group within a broader context of amine synthesis. The crystalline sulfonamides could be further elaborated by alkylation and arylation similarly to nitrobenzenesulfonamides. The sulfonamides could withstand conditions that functionalize nitroarenes, such as reductions and vicarious nucleophilic substitution reactions.
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INTRODUCTION In the course of a recent project, we desired a synthetic strategy with stable, predominately crystalline intermediates. This feature could allow for efficient, large-scale purification of compounds via crystallization rather than tedious chromatography and also allow for easy handling, transport, and storage of intermediates in the synthetic route. A p-toluenesulfonamide derivative met these criteria; however, it proved too stable to be easily cleaved, jeopardizing more sensitive functional groups.1 Many derivatives with easily cleavable sulfonamide groups (e.g., SES, 9-anthracenylsulfonyl) were oils and/or unstable to downstream chemistry, and oftentimes the corresponding sulfonyl chloride was expensive and/or not readily available. The easily cleavable nosyl group, pioneered by Fukuyama,2 was not strategic, as there was nitro-specific chemistry in the sequence. Screening a wide variety of readily available, potentially easily removable sulfonamides, we found that both 2- and 4-cyanobenzenesulfonamides (abbreviated herein as 2Cs and 4-Cs, respectively) could be cleaved with thiolate anions, similarly to the nosyl group. We chose to focus more on the 4-Cs over the 2-Cs as the compounds were, on average, more crystalline. Herein, we describe the applicability of 4cyanobenzenesulfonamides in complex amine synthesis and as a protecting group.
recrystallization, if desired, from toluene and hexane affords 4-CsCl as sandy, light beige crystals (mp 108−109 °C). The sulfonic acid was never detected in large amounts by HPLC analysis, and what little was detected remains mostly in the filter cake during the initial filtration. However, the uncertainty in the ionization state of this impurity in the commercial lot (e.g., free acid or an unknown salt form) led us to examine a more general solution to remove it using an aqueous wash. We found it is possible to wash the impurities away with a 1 M, pH = 7 aqueous sodium phosphate buffer without any significant reaction with the sulfonyl chloride. A variety of amines were sulfonylated under two mild, general conditions (Table 1). The choice of the condition depended on the amine (aryl or alkyl). For anilines, the optimal conditions were 2,6-lutidine as a base and dichloromethane as the solvent. In the case of p-bromoaniline, we found the use of stronger bases such as triethylamine could lead to double sulfonylation owing to the acidity of the product 2.4 This disulfonylated compound did not act as a Cs-transfer reagent, even after addition of DMAP (10 mol %). The deactivated Nmethylnitroaniline required pyridine as a base and 1,2dichloroethane at 60 °C for 24 h to reach completion to form 3. Upon aqueous workup, many sulfonylated anilines precipitated from the organic layer. Exchanging the solvent for tetrahydrofuran before water addition solubilized the products and allowed for a much easier aqueous workup. Interestingly, performing the sulfonylation of the anilines in tetrahydrofuran was prohibitively slow. For most primary and secondary alkyl amines, the sulfonamide is synthesized cleanly with triethylamine in tetrahydrofuran. These reactions were run at approximately 0−5 °C to mitigate the exotherm of the reaction. In the case of the serine amino acid derivative leading to
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RESULTS AND DISCUSSION A convenient source of the 4-Cs group is the commercially available sulfonyl chloride. We found, however, that certain commercial lots contained significant amounts (up to 13 wt % by quantitative NMR analysis) of insoluble, NMR- and HPLCsilent solids, likely stemming from the reagent preparation.3 To remedy this, we developed a purification protocol to improve the quality of the reagent. The crude sulfonyl chloride is stirred in warm toluene and filtered warm to remove insoluble impurities, and then the solvent is removed. A further © 2017 American Chemical Society
Received: March 14, 2017 Published: April 14, 2017 4550
DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
The Journal of Organic Chemistry
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Table 1. Sulfonylation of Amines with 4-CsCl
a
Table 2. Derivatization of 4-Cyanobezenesulfonamides
See the Experimental Section for exact conditions.
product 9, we found the inverse, dropwise addition of the trimethylamine last minimized the self-oligomerization of the free amino ester, observed to a minor extent (∼5%) otherwise. The resulting sulfonamides were capable of being further functionalized under conditions comparable to nitrobenzenesulfonamides (Table 2).2 For example, the sulfonamides could be alkylated under Mitsunobu conditions (Table 2, entries 1− 3). The optimal conditions were triphenylphosphine (1.25 to 2.00 equiv) with DEAD or DIAD (1.25 to 2.00 equiv). With ADDP, the competing side reaction to form 2,5-dipiperdin-1-yl1,3,4-oxadiazole was observed in significant amounts. Sulfonamide 4 could be converted to PMB derivative 10 with predominant inversion (96.8 to 3.2 er), and the serine derivative could be converted to the highly crystalline aziridine 11. Interestingly, in the case of the aryl sulfonamide 2, the stabilized ylide 2-(triphenyl-λ5-phosphanylidene)acetonitrile could function as a dehydrating agent (1.50 equiv, 90 °C, 2 h) in a fashion similar to the work of Tsunoda.5 This particular ylide reagent worked well only for the aryl sulfonamide; the alkyl sulfonamides (e.g., 5) are likely not acidic enough to participate as efficiently.4 Standard alkylation conditions (2.00 equiv of electrophile, 2.00 equiv of potassium carbonate, 5.00 mL/g DMF) could also be used to propargylate the indoyl sulfonamide 7 (Table 2, entry 4) or alkylate the sulfonamide 8 (Table 2, entry 5) without epimerization (99.9 to 0.1 er). Arylation of the sulfonamides can be achieved using a direct SNAr of 5 with the appropriately activated 1-fluoro-2-nitrobenzene (1.50 equiv) with potassium carbonate (2.00 equiv) in DMF at 100 °C (Table 2, entry 6). Additionally, arylation can also be achieved by a Chan−Evans−Lam coupling,6 as exemplified by 15 (Table 2, entry 7). The cleavage of a secondary sulfonamide occurred analogously to the nosyl group and was initially observed using 10.0 equiv of 1-dodecanethiol and 9.5 equiv of cesium carbonate in dimethyl sulfoxide at room temperature.7 While this reaction was clean and rapid, we sought to identify an
a
See the Experimental Section for exact conditions.
alternative base and solvent pair that would be more economical and practical to use. To that end we screened a variety of additional solvents (methanol, toluene, acetonitrile, tetrahydrofuran, and dimethylformamide) and bases (cesium carbonate, potassium carbonate, potassium hydroxide, trimethylamine, Hunig’s base, and DBU). From this screen, we identified that base strength and base solubility were important parameters that affected the rate of the deprotection, with the stronger, soluble base DBU being optimal. Subtle solvent effects also impacted the rate. While the cleavage of 1 in toluene took nearly 24 h, the reaction was complete in 11 h in fluorobenzene, 7 h in trifluorotoluene, and 3 h in nitrobenzene. Ultimately, DMF provided the fastest rate and allowed the reduction of the thiol to 5.00 equiv and the DBU to 4.75 equiv. Heating the reactions to 50 or 60 °C generally provided more byproducts. Other mercaptans were not effective, such as 2mercaptoacetic acid (multiple byproducts) and p-thiocresol (no reaction). Commercial, HPLC-grade DMF was used which had a typical water content of 47−370 ppm by Karl Fischer titration. To test the tolerability of the reaction toward water, the deprotection of 12 was studied with varying levels of water in the DMF solvent. DMF with a water content of 360 ppm, 0.1622 and 0.7557 wt %, had a nearly identical rate and purity profile. There was a slight depression in rate at the highest level of water. As expected, the combination of the thiol and base in 4551
DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
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Gratifyingly, nitro sulfonamide 3 could be functionalized selectively at the nitro group under certain cases without attack at the nitrile of the sulfonamide. For example, the nitro group in 3 was reduced to an amino group, 24 with zinc, and isobutyric acid in 90% yield. In addition, 3 could be functionalized using a vicarious nucleophilic substitution reaction with chloromethyl phenylsulfone in good yield (92%).11 Treatment of 1 with 3.00 equiv of 10 M aqueous sodium hydroxide in tetrahydrofuran at 50 °C for 24 h afforded no reaction, as did treatment of 1 with 3.00 equiv of hydrazine in tetrahydrofuran at 50 °C for 24 h. Interestingly, treatment of 1 with 3.00 equiv of 50 wt % aqueous hydroxylamine (Figure 1, eq 4) at 50 °C for 5 h had completely converted 1 to two products identified by LCMS as the amidoxime 26 (hydroxylamine addition) and the primary amide 27 (water addition) in an ∼60:40 ratio. The high level of the hydrolysis product may be explained by O-attack of hydroxylamine, potentially though the tautomer, ammonia oxide, followed by hydrolysis of this activated imidate, a mode of reactivity proposed for hydroxylamine-mediated ester hydrolysis.12 A sulfonamide 29 (Figure 1, eq 5), prepared either from the sulfonylation of alanine derivative 28 (97% yield) to give the corresponding sulfonamide 30 (not shown), then alkylation (97% yield, 99.5 to 0.5 er), or through the Mitsunobu reaction of 4 with tertbutyl D-lactate (86% yield, 99.8 to 0.2 er) was found to undergo the deprotection to 31 in 80% yield; however, we isolated 11% of a tertiary amine product 32, resulting from the migration of the sulfonamide aryl group to the α-carbon of the amino acid. The rearrangement is known in the case of the nosyl group and other electron-deficient sulfonamides of amino esters (including 4-Cs).13 The resulting two products 31 and 32, however, were found to have low enantiopurity (∼60 to 40 er for 31 and racemic for 32). A control deprotection experiment8 without addition of thiol revealed that DBU is competent in racemizing 29 within 2 h; however, with cesium carbonate, the rate is much slower (91 to 9 er after 24 h). Replacing the DBU with cesium carbonate in the deprotection of 29, however, afforded both 31 and 32 in similar yields (80% and 6%, respectively) but only slightly better enantiopurity (∼69 to 31 er for 31 and 57 to 43 er for 32, the absolute stereochemistry was not determined, assigned to R by analogy to ref 13), indicating the possibility that the thiolate anion is additionally responsible for the erosion. Replacing 1-dodecanethiol with tert-dodecanethiol afforded predominately 32 (73.2 to 26.8 er crude) and only a trace of 31. The use of the polysulfide, sodium tetrasulfide was ineffective (trace product). In conclusion, we have explored the use of a 4cyanobenzenesulfonyl group to protect amines and enable further nitrogen functionalization in a manner analogous to that of the nosyl group. 4-Cyanobenzenesulfonamides could be alkylated with alkyl halides or through a Mitsunobu reaction with inversion. Additionally, the sulfonamides can be arylated through a direct SNAr of an appropriately activated arene or with arylboronic acids through a Chan−Evans−Lam coupling. We have shown that, while the deprotection of the 4-Cs group is slower than the nosyl group, it can be removed efficiently with dodecanethiol and DBU. The thiol was air sensitive under the deprotection conditions; however, a nitrogen sparge can effectively halt the oxidation. We’ve demonstrated that the 4cyanobenzenesulfonamide group can survive nitro-specific functional group manipulations such as a zinc reduction and a vicarious nucleophilic substitution reaction. Lastly, a brief examination of the stability of the sulfonamide nitrile group to
DMF was sensitive to air and if present would lead to oxidative dimerization of the thiol to the disulfide, which would precipitate from solution. A control experiment revealed that sparging a solution of the thiol in DMF with nitrogen for a minimum of 20 min prior to the introduction of the base eliminated the oxidation.8 Thus, the optimium protocol for deprotection was sparging a solution of the substrate and dodecanethiol (5.00 equiv) in DMF (10 mL/g) for 20 min followed by the addition of DBU (4.75 equiv) and stirring under nitrogen. For small-scale experiments (99.9:0.1 er by chiral HPLC analysis. Sample prep: 4.0 mg/mL in 2-propanol. Column: Phenomenex Lux Cellulose-3 (3 μm, 4.6 × 150 mm). Column temperature: 30 °C. Detector wavelength: 230 nm. Injection volume: 10 μL. Flow rate: 1.2 mL/min. Mobile phase “A”: 0.05 vol % diethylamine in heptane. Mobile phase “B”: 0.05 vol % diethylamine in ethanol. Gradient: t = 0 min: 3% “B”, t = 2 min: 3% “B”, t = 20 min: 20% “B”, t = 24 min: 20% “B”. 21: 5.61 min, ent-21: 6.27 min. 1H 4557
DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
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NMR (CDCl3, 400 MHz): δ 7.35−7.37 (m, 4H), 7.25−7.29 (m, 1H), 7.21 (app d, J = 8.6 Hz, 2H), 6.86 (app d, J = 8.6 Hz, 2H), 3.79−3.83 (m, 4H), 3.60 (d, J = 12.9 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H), 1.57 (br s, 1H), 1.37 (d, J = 6.6 Hz, 3H). [α]D20: −47.87 (c = 8.0 mg/mL, chloroform). tert-Butyl (4-Methoxybenzyl)carbamate (23). To a solution of sulfonamide 4 (1.00 g, 3.31 mmol, 1.00 equiv) and 4-N,Ndimethylaminopyridine (40.8 mg, 0.33 mmol, 0.10 equiv) in dichloromethane (7.50 mL) was added di-tert-butyl dicarbonate (893 mg, 3.97 mmol, 1.20 equiv), and the solution was stirred. Moderate off-gassing was observed and the reaction reached completion (Rf 22 (30% ethyl acetate in hexanes): 0.50) after 1 h. The solution was concentrated in vacuo, then the clear syrup was dissolved in dimethylformamide (water content by Karl Fischer titration: 369.286 ppm, 10.00 mL), and 1-dodecanethiol (3.96 mL, 16.5 mmol, 5.00 equiv) was added. The mixture was sparged with nitrogen for 20 min before addition of DBU (2.36 mL, 15.7 mmol, 4.75 equiv). The light orange solution was stirred for 2 h, poured into water (20 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford an oil. The residue was purified flash column chromatography over silica gel (0−30% ethyl acetate in hexanes gradient) to afford the desired product 23 as a clear oil that slowly solidified (733 mg, 93%). The spectral data matched a literature report.19 1H NMR (CDCl3, 400 MHz): δ 7.21 (d, J = 8.3 Hz, 2H), 6.87 (app d, J = 8.6 Hz, 2H), 4.78 (br s, 1H), 4.25 (br d, J = 5.3 Hz, 2H), 3.80 (s, 3H), 1.47 (s, 9H). N-(4-Aminophenyl)-4-cyano-N-methylbenzenesulfonamide (24). To a suspension of the sulfonamide 3 (1.00 g, 3.15 mmol, 1.00 equiv) and washed zinc20 (2.06 g, 31.52 mmol, 10.00 equiv) in dichloromethane (20.0 mL) was slowly added isobutyric acid (2.92 mL, 31.52 mmol, 10.00 equiv) at a rate such that the internal temperature did not exceed 30 °C (∼15 min) using an ice−water bath to regulate the temperature. Upon complete addition, the slurry was stirred for 30 min, and then the solids were filtered and washed with dichloromethane (2 × 10 mL). The combined dichloromethane streams were added into a saturated aqueous solution of sodium bicarbonate (75 mL). The layers were split, and the aqueous layer was extracted with dichloromethane (2 × 25 mL). The combined organic layers were washed with water (25 mL), and then a saturated, aqueous solution of brine (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow foam. The residue was purified by flash column chromatography over silica gel (25 to 50% ethyl acetate in hexanes) to afford the product as off white crystals (810 mg, 90%). Rf (50% ethyl acetate in hexanes) 0.38. Mp (ethyl acetate/hexane): 165−166 °C. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (app d, J = 8.6 Hz, 2H), 7.67 (app d, J = 8.6 Hz, 2H), 6.67 (app d, J = 8.8 Hz, 2H), 6.45 (app d, J = 8.8 Hz, 2H), 5.27 (br s, 2H), 3.07 (s, 3H). 13C NMR (DMSO-d6, 100.6 Hz): δ 148.4, 140.5, 113.2, 128.3, 128.2, 127.6, 117.7, 115.4, 113.7, 38.6. IR (KBr) (cm−1): 3457 (br m), 3368 (br m), 2241 (m), 1647 (s), 1514 (s). HRMS (ESI) (m/z): calcd for C14H14O2N3S [M + H]+ 288.08012, found 288.08126. 4-Cyano-N-methyl-N-(4-nitro-3-((phenylsulfonyl)methyl)phenyl)benzenesulfonamide (25). To an oven-dried flask were added the sulfonamide 3 (1.00 g, 3.15 mmol, 1.00 equiv) and chloromethyl phenyl sulfone (774 mg, 3.94 mmol, 1.25 equiv). Tetrahydrofuran (15.0 mL, water content by Karl Fischer titration: 33.4481 ppm) was added, and the mixture was stirred under nitrogen until a homogeneous solution formed (approximately 2−3 min.). The solution was cooled to an internal temperature of −50 °C with a dry ice−acetone bath, and a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 7.88 mL, 7.88 mmol, 2.50 equiv) was added dropwise, maintaining the internal temperature at −50 °C (approximately 10 min). Immediately upon addition of the base, an intense violet color developed. After addition, the deep violet solution is was stirred at an internal temperature of −50 °C for 1.5 h, a solution of acetic acid (542 μL, 9.45 mmol, 3.00 equiv) in tetrahydrofuran (5.00 mL) was added dropwise, maintaining an internal temperature of −50 °C (approximately 5 min), and then the mixture was allowed to warm to room temperature. At approximately −38 °C, the violet color
disappeared. The reaction mixture was poured into a pH = 7 aqueous, sodium phosphate buffer (1.0 M, 50 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 25 mL), and the combined organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a tan gel. The residue was purified by flash column chromatography over silica gel (0−5% ethyl acetate in dichloromethane) to afford the product as a white powder (1.36 g, 92%). Rf (5% ethyl acetate in dichloromethane) 0.48. Mp (ethyl acetate/dichloromethane): 170−172 °C. 1H NMR (DMSO-d6, 400 MHz): δ 8.10 (app d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.70− 7.76 (m, 3H), 7.58−7.63 (m, 4H), 7.46 (dd, J = 8.8, 2.5 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 3.09 (s, 3H). 13C NMR (DMSO-d6, 100.6 MHz): δ 147.0, 144.3, 139.4, 137.6, 134.3, 133.7, 130.6, 129.5, 128.0, 127.9, 126.6, 126.5, 124.0, 117.5, 116.2, 56.9, 37.4. IR (KBr) (cm−1): 2238 (m), 1521 (s), 1364 (s), 1183 (s), 1153 (s). HRMS (ESI) (m/z): calcd for C21H21O6N4S [M + NH4]+ 489.08970, found 489.09079. (+)-tert-Butyl (4-Cyanophenylsulfonyl)-L-alaninate (30). A mixture of L-alanine tert-butyl ester hydrochloride (5.00 g, 27.0 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was cooled to an internal temperature of 4.5 °C with an ice−water bath, and triethylamine (8.35 mL, 59.3 mmol, 2.20 equiv) was added. The slurry was cooled to an internal temperature of 2.2 °C, and 4cyanobenzensulfonyl chloride (5.66 g, 27.5 mmol, 1.02 equiv) was added in portions over 30 min, maintaining an internal temperature below 5.0 °C. The slurry was warmed to room temperature and stirred for 1 h. The reaction mixture was poured into water (50 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a tan oil. The residue was purified by flash column chromatography over silica gel (5 to 40% ethyl acetate in hexanes gradient) to afford the product as a thick oil that crystallized upon standing (8.15 g, 97%). The product was found to have a chiral purity of 99.9:0.1 er by chiral HPLC analysis. Sample prep: 2.0 mg/mL in 2-propanol. Column: Chiralpak AZ-3R (3 μm, 4.6 × 150 mm). Column temperature: 30 °C. Detector wavelength: 254 nm. Injection volume: 10 μL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05 vol % trifluoroacetic acid in acetonitrile/water (5:95 vol %). Mobile phase “B”: 0.05 vol % trifluoroacetic acid in acetonitrile/water (95:5 vol %). Gradient: t = 0 min: 0% “B”, t = 25 min: 100% “B”, t = 30 min: 100% “B”. 30: 14.17 min, ent-30: 15.76 min. Rf (30% ethyl acetate in hexanes): 0.46. Mp (ethyl acetate/hexanes): 88−89 °C. 1H NMR (DMSO-d6, 400 MHz): δ 8.57 (d, J = 8.8 Hz, 1H), 8.07 (app d, J = 8.8 Hz, 2H), 7.94 (app d, J = 8.6 Hz, 2H), 3.81 (dq, J = 8.6, 7.3 Hz, 1H), 1.24 (s, 9H), 1.18 (d, J = 7.3 Hz, 3H). 13C NMR (DMSO-d6, 100.6 Hz): δ 170.5, 145.4, 133.2, 127.3, 117.7, 114.7, 80.9, 51.8, 27.3, 18.5. [α]D20: +27.12 (c = 8.61 mg/ mL, dichloroethane). IR (KBr) (cm−1): 3270 (br s), 2233 (m), 1723 (s), 1316 (s), 1120 (s), 838 (m). HRMS (ESI) (m/z): calcd for C14H17O4N2S [M − H]− 309.09035, found 309.08994. (−)-tert-Butyl N-(4-Cyanophenylsulfonyl)-N-(4-methoxybenzyl)-L-alaninate (29) (via Mitsunobu Reaction). A solution of PMB sulfonamide 4 (1.00 g, 3.31 mmol, 1.00 equiv), (+)-tert-butyl Dlactate (732 mg, 4.96 mmol, 1.50 equiv), and triphenylphosphine (1.30 g, 4.96 mmol, 1.50 equiv) in dichloromethane (10.0 mL) was cooled to an internal temperature of 1.1 °C with an ice−water bath, and a solution of diethyl azodicarboxylate (40 wt % in toluene, 2.26 mL, 4.96 mmol, 1.50 equiv) was added slowly, maintaining the internal temperature below 5 °C (30 min). The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was purified directly by flash column chromatography (0 to 25% ethyl acetate in hexanes gradient) to afford the product as a thick, clear gel (1.22 g, 86%). The gel slowly crystallized (∼1 mo). Alternatively, the gel could be dissolved with heating in a 1:2 v/v solution of tetrahydrofuran in hexanes (9 mL), and upon concentration the product was observed to crystallize. The product was found to have a chiral purity of 99.8:0.2 er by chiral HPLC analysis after chromatography before crystallization. Sample prep: 2.0 mg/mL in 2-propanol. Column: Phenomenex Lux 4558
DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
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Cellulose-3 (3 μm, 4.6 × 150 mm). Column temperature: 25 °C. Detector wavelength: 254 nm. Injection volume: 5 μL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05 vol % trifluoroacetic acid in acetonitrile/water (5:95 vol %). Mobile phase “B”: 0.05 vol % trifluoroacetic acid in acetonitrile:water (95:5 vol %). Gradient: t = 0 min: 0% “B”, t = 25 min: 100% “B”, t = 30 min: 100% “B”. 29: 17.61 min, ent-29: 18.47 min. Rf (20% ethyl acetate in hexanes): 0.33. Mp (tetrahydrofuran/hexanes): 92−95 °C. 1H NMR (DMSO-d6, 400 MHz): δ 8.06 (app d, J = 8.6 Hz, 2H), 7.98 (app d, J = 8.6 Hz, 2H), 7.21 (app d, J = 8.8 Hz, 2H), 6.86 (app d, J = 8.8 Hz, 2H), 4.59 (d, J = 16.2 Hz, 1H), 4.52 (q, J = 7.3 Hz, 1H), 4.22 (d, J = 16.2 Hz, 1H), 3.73 (s, 3H), 1.24 (s, 9H), 1.16 (d, J = 7.3 Hz, 3H). 13C NMR (DMSO-d6, 100.6 Hz): δ 169.2, 158.6, 144.1, 133.3, 129.2, 129.1, 127.8, 117.6, 115.1, 113.6, 81.3, 56.0, 55.0, 48.6, 27.3, 16.8. [α]D20: 41.58 (c = 8.58 mg/mL, chloroform). IR (thin film) (cm−1): 2235 (m), 1736 (s), 1515 (m), 1341 (m), 1148 (s). HRMS (ESI) (m/z): calcd for C22H26O5N2NaS [M + Na]+ 453.14546, found 453.14651. (−)-tert-Butyl N-(4-Cyanophenylsulfonyl)-N-(4-methoxybenzyl)-L-alaninate (29) (via Alkylation). To a vigorously stirring suspension of sulfonamide 30 (99.9 to 0.1 er, 1.00 g, 3.22 mmol, 1.00 equiv) and potassium carbonate (899 mg, 6.44 mmol, 2.00 equiv) in dimethylformamide (water content by Karl Fischer titration: 44.6623 ppm, 5.00 mL) was added p-methoxybenzyl chloride (892 μL, 6.44 mmol, 2.00 equiv). The slurry was heated to an internal temperature of 60 °C under nitrogen and was stirred for 4.5 h. The mixture was cooled to room temperature and partitioned between water (10 mL) and ethyl acetate (10 mL). The layers were split, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with a saturated, aqueous solution of brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear oil. The crude residue was purified by flash chromatography over silica gel (0 to 25% ethyl acetate in hexanes gradient) to afford the product as a thick gel that slowly solidified (1.34 g, 97%). The product was found to have a chiral purity of 99.5:0.5 er by chiral HPLC analysis. For characterization data and chiral method, see above. tert-Butyl N-(4-Methoxybenzyl)alaninate (31). A solution of sulfonamide (29 from the Mitsunobu reaction, 200 mg, 0.465 mmol, 1.00 equiv) and 1-dodecanethiol (1.11 mL, 4.65 mmol, 10.00 equiv) in dimethylformamide (water content by Karl Fischer titration: 46.4896 ppm, 2.00 mL) was sparged with nitrogen for 20 min before addition of DBU (349 μL, 2.32 mmol, 5.00 equiv). The solution became a light yellow color and was stirred for 23 h under nitrogen. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with a saturated aqueous solution of brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford an oil. The residue was purified flash column chromatography over silica gel (0−50% ethyl acetate in hexanes gradient) to afford the desired product 31 as a clear oil (98.1 mg, 80%). The product21 was found to have a chiral purity of approximately 60:40 er by chiral HPLC analysis. Sample prep: 4.0 mg/mL in methanol. Column: Chiralpak ID-3 (3 μm, 4.6 × 150 mm). Column temperature: 40 °C. Detector wavelength: 220 nm. Injection volume: 5 μL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.01 M ammonium acetate in acetonitrile/water (5:95 vol %). Mobile phase “B”: 0.01 M ammonium acetate in acetonitrile/water (95:5 vol %). Gradient: t = 0 min: 0% “B”, t = 20 min: 50% “B”, t = 24 min: 50% “B”. (S)-31: 17.89 min, (R)-31: 18.35 min. Rf (50% ethyl acetate in hexanes): 0.54. 1H NMR (DMSO-d6, 400 MHz): δ 7.20 (app d, J = 8.6 Hz, 2H), 6.86 (app d, J = 8.6 Hz, 2H), 3.72 (s, 3H), 3.64 (d, J = 12.9 Hz, 1H), 3.50 (d, J = 12.9 Hz, 1H), 3.07 (q, J = 6.7 Hz, 1H), 2.18 (br s, 1H), 1.42 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR (DMSO-d6, 100.6 Hz): δ 174.5, 158.1, 132.2, 129.1, 113.5, 79.9, 55.9, 55.0, 50.2, 27.7, 18.9. IR21 (KBr) (cm−1): 2933 (br s), 2272 (m), 1744 (s), 1519 (s), 1255 (s), 815 (m). HRMS (ESI) (m/z): calcd for C15H24O3N [M + H]+ 266.17507, found 266.17599. tert-Butyl 2-(4-Cyanophenyl)-2-((4-methoxybenzyl)amino)propanoate (32). The arylated product 32 was also isolated as a white solid (18.2 mg, 11%). The product was found to be racemic by chiral HPLC analysis. Sample prep: 2.0 mg/mL in methanol. Column: Chiralpak IG (5 μm, 4.6 × 150 mm). Column temperature: 30 °C.
Detector wavelength: 220 nm. Injection volume: 10 μL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.01 M ammonium acetate in acetonitrile/water (5:95 vol %). Mobile phase “B”: 0.01 M ammonium acetate in acetonitrile/water (95:5 vol %). Gradient: t = 0 min: 0% “B”, t = 30 min: 100% “B”, t = 37 min: 100% “B”. Ent-1−32: 23.31 min, Ent-2−32: 24.28 min. Rf (50% ethyl acetate in hexanes): 0.90. Mp (ethyl acetate/hexanes): 70−73 °C. 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.73 (s, 3H), 3.54 (dd, J = 12.5, 8.0 Hz, 1H), 3.43 (dd, J = 12.6, 6.3 Hz, 1H), 2.70 (br t, J = 7.2 Hz, 1H), 1.55 (s, 3H), 1.40 (s, 9H). 13C NMR (DMSO-d6, 100.6 Hz): δ 172.7, 158.2, 149.3, 132.6, 132.2, 129.0, 127.0, 118.7, 113.6, 110.0, 81.2, 65.6, 55.0, 46.8, 27.5, 24.8. IR (thin film) (cm−1): 3337 (br w), 2229 (m), 1725 (s), 1514 (s), 1250 (s). HRMS (ESI) (m/z): calcd for C22H27O3N2 [M + H]+ 367.20162, found 367.20245.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00608. Quality assessment of commercial 4-cyanobenzenesulfonyl chloride; air oxidation studies of 1-dodecanethiol; racemization study of 29; chiral HPLC, 1H NMR, and 13 C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Michael A. Schmidt: 0000-0002-4880-2083 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to thank Dr. Robert Waltermire and Dr. David Kronenthal for supporting the Bristol-Myers Squibb Undergraduate Summer Internship for R.W.S. We thank Dr. Adrian Ortiz for reviewing the manuscript. We thank Gottfried Wenke for pKa determinations, Larisa Zueva and Tianhong Zhang for IR and OR determinations, and Jon Marshall for HRMS support. We are grateful to Dr. Sloan Ayers for assistance in obtaining a NOESY spectra.
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REFERENCES
(1) (a) Kocieński, P. J. Protecting Groups; Georg Thieme Verlag: Stuttgart, 1994. (b) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, 2004. See also: (c) Searles, S.; Nukina, S. Chem. Rev. 1959, 59, 1077. (2) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353 and references cited therein. (3) From a modified Sandmeyer reaction: (a) Mansfeld, M.; Pařík; Ludwig, M. Collect. Czech. Chem. Commun. 2004, 69, 1479. (b) Hogan, P. J.; Cox, B. G. Org. Process Res. Dev. 2009, 13, 875. (c) Malet-Sanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324. From a metal−halogen exchange/SO2 trap/oxidative chlorination: (d) Hamada, T.; Yonemitsu, O. Synthesis 1986, 1986, 852. (e) Pandya, R.; Murashima, T.; Tedeschi, L.; Barrett, A. G. M. J. Org. Chem. 2003, 68, 8274. From the reaction of p-sulfonaminobenzoic acid with PCl5: (f) Ishifuku, K.; Sakurai, H.; Okamoto, H.; Satoh, S. Yakugaku Zasshi 1949, 69, 417. (g) Trave, R. Farmaco 1960, 15, 474. From oxidative chlorination of 4-(methylthio)benzonitrile: (h) Karino, H.; Goda, H.; Sakamoto, J.; Yoshida, K.; Nishiguchi, H. Patent WO 9633167 1996. 4559
DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
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(4) The aqueous pKa of 2 was measured to be 7.0, similar to that of the 4-nitrobenzenesulfonamide of p-bromoaniline, which was measured to be 6.9. The pKa alkyl sulfonamide 5 was measured to be 10.9. (5) (a) Tsunoda, T.; Ozaki, F.; Itô, S. Tetrahedron Lett. 1994, 35, 5081. (b) Tsunoda, T.; Nagaku, M.; Nagino, C.; Kawamura, Y.; Ozaki, F.; Hioki, H.; Itô, S. Tetrahedron Lett. 1995, 36, 2531. (c) Tsunoda, T.; Yamamoto, H.; Goda, K.; Itô, S. Tetrahedron Lett. 1996, 37, 2457. (d) Tsunoda, T.; Nagino, C.; Oguri, M.; Itô, S. Tetrahedron Lett. 1996, 37, 2459. (6) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-p.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (7) 4-Dodecylthiobenzonitrile was isolated as a byproduct, and the structure was confirmed by comparison of the 1H NMR spectrum with a literature report. Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 2357. (8) See the Supporting Information for details. (9) (a) Terrier, F. Chem. Rev. 1982, 82, 77. (b) Artamkina, G. A.; Egorov, M. P.; Beletskaya, I. P. Chem. Rev. 1982, 82, 427. See also ref 2. (10) Temperini, A.; Annesi, D.; Testaferri, L.; Tiecco, M. Tetrahedron Lett. 2010, 51, 5368. (11) Mąkosza, M. Synthesis 2011, 2011, 2341. (12) (a) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4581. (b) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4585. (c) Silva, C. M.; Dias, I. C.; Pliego, J. R. Org. Biomol. Chem. 2015, 13, 6217. (13) (a) Wilson, M. W.; Ault-Justus, S. E.; Hodges, J. C.; Rubin, J. R. Tetrahedron 1999, 55, 1647. (b) Lupi, V.; Penso, M.; Foschi, F.; Gassa, F.; Mihali, V.; Tagliabue, A. Chem. Commun. 2009, 5012. (c) Foschi, F.; Landini, D.; Lupi, V.; Mihali, V.; Penso, M.; Pilati, T.; Tagliabue, A. Chem. - Eur. J. 2010, 16, 10667. (14) Hu, D. X.; Grice, P.; Ley, S. V. J. Org. Chem. 2012, 77, 5198. (15) A 28−30 wt % aqueous solution of ammonium hydroxide was extracted with an equal volume of dichloromethane. The dichloromethane layer was dried over sodium sulfate and then filtered with gentle suction. (16) Jiao, J.; Zhang, X.-R.; Chang, N.-H.; Wang, J.; Wei, J.-F.; Shi, X.Y.; Chen, Z.-G. J. Org. Chem. 2011, 76, 1180. (17) Li, H.; Achard, M.; Bruneau, C.; Sortais, J.-B.; Darcel, C. RSC Adv. 2014, 4, 25892. (18) Pan, H.-J.; Zhang, Y.; Shan, C.; Yu, Z.; Lan, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2016, 55, 9615. (19) Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956. (20) The zinc was washed according to: Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 6th ed.; Elsevier: Oxford, 2009; p 503. Crude zinc powder was slurried with an aqueous solution of 2 wt % hydrochloric acid (2.5 mL/g Zn) for 1 min and then filtered; this process was repeated once more. The zinc was washed with water (3 × 0.85 mL/g Zn), then ethanol (2 × 1.67 mL/g Zn), then methyl tert-butyl ether (1.67 mL/g Zn). Between each wash, the solids were collected by filtration and slurried in the subsequent wash for ∼0.5−1 min. The lumpy gray powder was crushed and dried in vacuo to constant weight prior to use. (21) The chiral data and IR spectrum were obtained on the HCl salt as solutions of the freebase appeared to degrade over time. The amine was dissolved in MTBE (10 mL/g), and 1.0 equiv of HCl (4 M HCl in dioxane) was added. The slurry was stirred for 15 min, and then the solvents were concentrated in vacuo. The white powder was suspended in MTBE (5 mL/g) and filtered.
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DOI: 10.1021/acs.joc.7b00608 J. Org. Chem. 2017, 82, 4550−4560
