The Synthesis of Trifluoromethyl-sulfonimidamides from Sulfinamides

Aug 15, 2017 - *E-mail: [email protected]., *E-mail: [email protected]. ... Thomas Q. Davies , Adrian Hall , Michael C. Willis. Angewandte Chemi...
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The Synthesis of Trifluoromethyl-sulfonimidamides from Sulfinamides Charlotte S. Richards-Taylor,† Carolina Martínez-Lamenca,*,† Joseph E. Leenaerts,† Andres A. Trabanco,‡ and Daniel Oehlrich*,† †

Neuroscience Medicinal Chemistry, Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium Neuroscience Medicinal Chemistry, Janssen Research & Development, C/Jarama 75A, 45007 Toledo, Spain

‡

S Supporting Information *

ABSTRACT: A general synthesis of CF3-sulfonimidamides from sulfinamides under both batch and continuous flow conditions is described. The reaction proceeds via a sulfonimidoyl fluoride intermediate. A reaction scope showing good group variation on the substituents of both nitrogen atoms is also presented.

S

around 20% of marketed pharmaceuticals contain at least one fluorine atom.9 In the continuous search for structurally novel drug-like motifs, we became interested in the possibility of installing a trifluoromethyl substituent on the sulfur atom of SIAs. We anticipated that the large volume and strong electronwithdrawing capability of the CF3 group would confer unique properties to the SIA function. The number of synthesis routes to prepare SIAs is very limited.10 To the best of our knowledge, the synthesis of CF3SIAs has only been disclosed once by Garlyauskayte et al. However, their discloure specifically targets N-(trifluoromethylsulfonyl)trifluoromethanesulfonimidamides, proceeding via a fluoride intermediate.11 The majority of syntheses of SIAs proceed via formation of a sulfonimidoyl chloride which then undergoes a nucleophilic substitution reaction with an amine to afford the SIA function (Scheme 2a).12 One limitation of these routes is the accessibility and handling of the hydrolytically unstable sulfonimidoyl chloride intermediate.13 The oxidative

ulfonimidamides (SIAs) are the aza-analogs of sulfonamides, in which an oxygen atom, is replaced by a nitrogen. This single atom modification results in the formation of a stereogenic sulfur atom and creates a novel handle for chemical diversity. SIAs were first described in the early 1960s1 and since then have found multiple applications in organic chemistry as reagents,2 chiral organocatalysts,3 and chiral ligands in asymmetric metal catalysis.4 The use and exploration of novel sulfur-containing bioisosteres has recently started to gain favor within the medicinal chemist community.5 In this context, SIAs have proven to function as bioisosteric replacements of sulfonamides and carboxylic acids in drug discovery programs. In a recent example, Arvidsson and co-workers reported the bioisosteric replacement of the sulfonamide group in Begacestat, a known γ-secretase inhibitor (Scheme 1a).6 Aryl substituted cyclic SIAs have been described as nonplanar bioisosteric replacements for carboxylic acids with improved permeability and reduced efflux liability (Scheme 1b).7 Fluorine substitution has proven to be a useful strategy in medicinal chemistry programs to improve the physicochemical and pharmacokinetic profile of lead molecules.8 For this reason,

Scheme 2. Preparation of SIAs

Scheme 1. SIAs as Sulfonamide and Carboxylic Acid Bioisosteres

Received: June 30, 2017 Published: August 15, 2017 © 2017 American Chemical Society

9898

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

Note

The Journal of Organic Chemistry

(Table 1, entries 4, 6). Potassium fluoride with catalytic 18crown-6 underperformed AgF, leading to 70% conversion to 2a (Table 1, entry 5). Finally, the use of TBAF resulted in 100% conversion to 2a after 16 h (Table 1, entry 7). An identical result was also obtained in just 30 min probing the suitability of this fluorine source for further reaction optimization. Interestingly, the number of equivalents of both NCS and TBAF could be reduced to 1.1 equiv while still maintaining the conversion to 2a (Table 1, entry 9) albeit with a slightly lower conversion to 3a. Additionally, when the amount of amine was reduced to 2 equiv, the sulfonimidamide 3a was observed in 73% conversion together with 16% of the corresponding sulfonamide, the oxidation product of 1a (Table 1, entry 10). Pleasingly, when the crude reaction mixture after step 1 was concentrated in vacuo, prior to the addition of 2 equiv of amine the conversion to 3a was 97% and the product could be isolated in 80% yield (Table 1, entry 11). In a parallel effort to reduce the quantities of amine required, the addition of possible cobases was explored. The use of nonnucleophilic bases for the in situ trapping of the HF formed was unsuccessful, resulting in a lower conversion to 3a and promotion in the formation of the sulfonamide byproduct. This predisposition of sulfonimidoyl fluorides to form sulfonamides under basic conditions has previously been observed by Gnamm et al.11 Interestingly, the sulfonimidoyl fluoride 2a is not susceptible to hydrolysis even after 16 h and can be easily purified by column chromatography. With the optimized conditions in hand (Table 1, entry 11), the scope of the reaction was explored. Thus, a range of diverse sulfinamides (1a−1g)16 successfully underwent the two-step transformation to form the corresponding SIAs 3a−g (Scheme 3) with satisfactory isolated yields (75−89%). Of note is that

chlorination of CF3-sulfinamides to form the sulfonimidoyl chloride, the required intermediate for our purpose, was reported to be unsuccessful by the group of Bolm (Scheme 2b).14 We hypothesized that the in situ generation of the more stable sulfonimidoyl fluoride and subsequent reaction with an amine could render the targeted compounds, and herein we describe our methodology for the synthesis of CF 3 sulfonimidamides (Scheme 2c). To verify our hypothesis, sulfinamide 1a and pyrrolidine were chosen as model substrates (Table 1). Our initial reaction Table 1. Evaluation of Conditions for the Preparation of CF3-SIAsa,b

NCS (equiv)

[F] (equiv)

1 2 3

2.1 2.1 −

4 5f 6 7

2.1 2.1 2.1 2.1

8

2.1

9

1.1

10

1.1

11g

1.1

AgF, 2.1 − TBAF, 2.0 NaF, 5.0 KF, 2.0 NFSI, 2.1 TBAF, 2.1 TBAF, 2.1 TBAF, 1.1 TBAF, 1.1c TBAF, 1.1

entry

t (h)

2a, conv.c (%)

amine (equiv)

3,a conv.c,d (%)

16 16 16

100 − NRe

10 10 10

98 (81) − −

16 16 16 16

NRe 70 NRe 100

− − − 10

− − − 99

0.5

100

10

100

0.5

100

10

90

0.5

100

2

73

0.5

100

2

97 (80)

Scheme 3. Sulfinamide Scopea

a

Experiments carried out with 0.17 mmol of 1a at 0.2 M concentration. b[F]: fluorine source. cConversion determined by 19F NMR of the crude reaction mixture. dIsolated yield in parentheses. e NR: no reaction. fExperiment carried out with 18-crown-6 (0.02 equiv). gReaction crude was evaporated to dryness before the addition of pyrrolidine.

conditions involved treatment of 1a with 2.1 equiv of NCS followed by 2.1 equiv of AgF at room temperature in MeCN, which led to complete conversion to the sulfonimidoyl fluoride 2a after 16 h. Subsequent addition of pyrrolidine afforded product 3a in 81% isolated yield (Table 1, entry 1). When the reaction was run in the absence of the F-source (Table 1, entry 2), no sulfonimidoyl chloride was detected and only degradation products were observed after addition of pyrrolidine, which is in line with literature reports from the group of Bolm.14 Additionally when the reaction was run in the presence of 2.0 equiv of TBAF but without NCS, the starting material was recovered (Table 1, entry 3). These observations suggest that the mechanism involves the initial formation of a highly unstable sulfonimidoyl chloride that then undergoes rapid in situ trans-halogenation to afford the corresponding and more stable sulfonimidoyl fluoride 2a.15 In order to improve the initial reaction conditions a set of fluorinating agents were explored (Table 1, entries 4−7). Unfortunately, on treatment with NaF or N-fluorobenzenesulfonimide (NFSI), sulfonimidoyl fluoride 2a was not formed

a

Reaction conditions: (i) NCS (1.1 equiv), TBAF (1.1 equiv), MeCN, 0 °C to rt, 30 min, the evaporation to dryness; (ii) pyrrolidine (2 equiv), MeCN, rt, 2 h.

both aliphatic (3a−c) and aromatic (3d−g) substituents were equally tolerated on the sulfur atom and that the reaction was not noticeably impeded by the sterics of the sulfinamide, as demonstrated by the good yields obtained with the αmethylbenzyl (3b) and mesityl (3e) groups. Interestingly, both electron-donating (3d,e) and electron-withdrawing (3f) groups are compatible with the reaction. The reaction was even tolerant of heterocyclic sulfinamides, and pyrimidine−CF3-SIA 3g was synthesized in 87% yield. 9899

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

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The Journal of Organic Chemistry A study to determine the scope of amines was done, and the initial result are shown in Scheme 4. The primary CF3-SIA 3h

Table 2. Optimization of Continuous Flow Reaction Conditionsa

Scheme 4. Amine Scopea

a

Reaction conditions: (i) NCS (1.1 equiv), TBAF (1 M in THF) (1.1 equiv), 0 °C to rt, MeCN; (ii) amine (2 equiv), MeCN, rt, 2 h. b Ammonia (gas). c8 equiv of amine used. dConversion determined by 19 F NMR.

entry

setup

[F]

2a, conv. (%)b

1 2 3 4d 5d

A A A B B

TBAF TBAF TBAF FP FP

100 60 80 100 60

T (°C)

3a, yield (%)b

rt 38

NRc

rt 97 (73)

NRc

a Reaction conditions: 1a (1 equiv), NCS (1.1 equiv), pyrrolidine (2 equiv), MeCN. bConversion monitored by 19F NMR; isolated yield in parentheses. cNR: no reaction. dNCS (1.5 equiv).

was obtained in 57% yield when ammonia gas was used as a source of nitrogen. Previous attempts using ammonium hydroxide resulted in no more than 18% conversion to the desired product, the mass balance being the corresponding sulfonamide. In general primary aliphatic amines led to the corresponding CF3-SIAs in good to moderate yields (3i, 3l, and 3m). In the case of secondary amines there seemed to be a steric limitation on the amine. Thus, small aliphatic secondary amines such as dimethyl amine, azetidine, and pyrrolidine formed the corresponding SIAs (3j, 3a, and 3k) in high yields, whereas the bulkier N-methyl-4-methoxybenzylamine only gave 15% conversion to the corresponding product 3n. Methylhydrazine was found to be unreactive under these reaction conditions, and no further attempts at optimization were performed. Interestingly, in cases where the NRR′ group has at least one proton, the SIA can undergo tautomerization, which offers dual hydrogen bond donor/acceptor properties and leads to additional flexibility within the receptor or targeted recognition point. To avoid the need to concentrate the reaction mixture in vacuo prior to the addition of amine, and in order to take advantage of the efficient mixing properties of flow chemistry, a two-flow microchip reactor protocol was explored, and the results obtained are shown in Table 2. Pleasingly, the initial attempt using TBAF as the fluorinating reagent resulted in full conversion to the sulfonimidoyl fluoride 2a, but on treatment with pyrrolidine no SIA 3a was detected (Table 2, entry 1). To promote the amine incorporation, the temperature of the second step was increased to 60 °C, which resulted in a suboptimal 38% yield of CF3-SIA 3a, in combination with unreacted sulfonimidoyl fluoride 2a and sulfonamide byproduct (Table 2, entry 2). Attempts to further increase the temperature resulted in extensive product degradation (Table 2, entry 3). Nevertheless, the use of flow chemistry opened the opportunity to exchange TBAF by a resin equivalent and remove the threat of possible side product formation by having an excess of TBAF in the system. Thus, when the fluoropolymer (FP) Amberlite IRA 900 F−-form was used as a fluorine source, full conversion to the sulfonimidoyl fluoride

2a was observed, but again no SIA 3a was detected when the second step was performed at room temperature (Table 2, entry 4). Pleasingly, 97% conversion to the desired product was achieved when the temperature of the second step was increased to 60 °C (Table 2, entry 5). Although the isolated yield of 73% is slightly inferior to the batch setup, this protocol avoids the need for concentration after the first step. The use of this FP in batch conditions required 3 h to achieve complete conversion to the sulfonimidoyl fluoride 2a compared to the 30 min reaction time when using TBAF, and furthermore, addition of the amine resulted in a decreased 70% conversion to the sulfonimidamide product 3a. Previously reported substitution reactions using organolithium reagents on sulfonimidoyl fluorides14 triggered us to explore their analogous reactivity on CF3-sulfonimidoyl fluorides with the aim to synthesize CF3-susbtituted sulfoximines. Interestingly, the treatment of CF3-sulfonimidoyl fluoride 2a with methyl-lithium gave CF3-sulfoximine 5a in 43% yield (Scheme 5). To the best of our knowledge this is the Scheme 5. Synthesis of CF3-Sulfoximine 5a

first preparation of an N-alkyl-S-alkyl-trifluoromethyl-sulfoximine and could serve as the basis of a novel synthetic methodology for the synthesis of aliphatic CF3-sulfoximines. In conclusion, we have developed an efficient method for the preparation of CF3-sulfonimidamides from the corresponding sulfinamides. The reaction occurs via a CF3-sulfonimidoyl fluoride intermediate formed in situ from the corresponding highly unstable CF3-sulfonimidoyl chloride. An initial reaction scope showing good group variation on the substituents of both nitrogen atoms has also been presented. This methodology has also been extended to show utility of CF3-sulfonimidoyl 9900

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

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The Journal of Organic Chemistry fluorides in the synthesis of aliphatic CF3-sulfoximines. This convenient procedure affords access to a synthetically challenging functional group and will ease its addition to the medicinal chemists’ toolbox as well as to the wider chemistry community.

■

q, J = 333.0), 54.5 (1C), 43.1 (1C), 35.4 (1C), 35.3 (1C), 32.9 (1C), 32.8 (1C); 19F NMR (377 MHz, CDCl3) −81.6 (s); HRMS (ESITOF) m/z: [M + H]+ calcd for [C13H17F3NOS], 292.0982; found, 292.0980. 1,1,1-Trifluoro-N-(1-phenylethyl)methanesulfinamide (1b). Prepared following Procedure A using α-methylbenzylamine (645 μL, 5.0 mmol). Column chromatography (80 g silica, 0−15% EtOAc in heptane) yielded 1b (762 mg, 32%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.43−7.29 (5H, m), 4.77−4.53 (2H, m), 1.63 (3H, overlapping d, J = 7.0); 13C NMR (101 MHz, CDCl3) 142.0 (1C), 141.5 (1C), 129.0 (2C), 128.9 (2C), 128.3 (1C), 128.2 (1C), 126.6 (2C), 126.3 (2C), 123,6 (2C, q, J = 333.0), 54.5 (1C), 54.3 (1C), 24.2 (1C), 23.7 (1C); 19F NMR (377 MHz, CDCl3) −81.2 (br. s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C9H11F3NOS], 238.0513; found, 238.0511. N-Benzyl-1,1,1-trifluoromethanesulfinamide (1c). Prepared following Procedure A using benzylamine (546 μL, 5.0 mmol). Column chromatography (40 g silica, 0−50% EtOAc in heptane) yielded 1c (762 mg, 32%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.31− 7.42 (5H, m), 4.64 (1H, br s), 4.5 (dd, J = 13.9, 6.2, 1H), 4.34 (dd, J = 13.9, 5.3, 1H); 13C NMR (101 MHz, CDCl3) 136.5 (1C), 128.9 (2C), 128.1 (2C), 125.3 (1C), 122.0 (1C), 46.4 (1C). 19F NMR (377 MHz, CDCl3) −79.9 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C8H9F3NOS], 224.0356; found, 224.0354. 1,1,1-Trifluoro-N-(p-tolyl)methanesulfinamide (1d). Prepared following Procedure A using p-toluidine (535 mg, 5.0 mmol). Column chromatography (80 g silica, 0−30% EtOAc in heptane) yielded 1d (914 mg, 41%) as a white solid; mp 81.7 °C; 1H NMR (400 MHz, CDCl3) 7.17 (2H, d, J = 8.0), 7.05−7.00 (2H, m), 6.15 (1H, br s), 2.35 (3H, s); 13C NMR (101 MHz, CDCl3) 135.7 (1C), 135.2 (1C), 130.4 (2C), 123.6 (1C, q, J = 334.0), 121.3 (2C), 20.8 (1C); 19F NMR (377 MHz, CDCl3) −81.2 (s); HRMS (ESI-TOF) m/z: [M − H]− calcd for [C8H7F3NOS], 222.0200; found, 222.0203. 1,1,1-Trifluoro-N-(2,4,6-trimethylphenyl)methanesulfinamide (1e). Prepared following Procedure A using 2,4,6-trimethylaniline (702 μL, 5.0 mmol). Column chromatography (80 g silica, 0−30% EtOAc in heptane) yielded 1e (1.73 g, 69%) as a white solid; mp 77.5 °C; 1H NMR (400 MHz, CDCl3) 6.93 (2H, s), 5.79 (1H, br. s), 2.32 (6H, s), 2.29 (3H, s); 13C NMR (101 MHz, CDCl3) 137.5 (1C), 134.8 (2C), 131.6 (1C), 129.8 (2C), 123.9 (1C, q, J = 331.0), 20.8 (1C), 18.7 (2C); 19F NMR (377 MHz, CDCl3) −81.2 (s); HRMS (ESI-TOF) m/ z: [M − H]− calcd for [C10H11F3NOS], 252.0513; found, 250.0514. N-(4-Bromophenyl)-1,1,1-trifluoro-methanesulfinamide (1f). Prepared following Procedure A using 2-aminopyrimidine (1.56 g, 10.0 mmol). Column chromatography (80 g silica, 0−30% EtOAc in heptane) yielded 1f (194 mg, 69%) as a white solid; mp 96.6 °C; 1H NMR (400 MHz, CDCl3) 7.44−7.53 (2H, m), 6.99−7.02 (2H, m,), 6.49 (1H, br s); 13C NMR (101 MHz, CDCl3) 137.1 (1C), 132.8 (2C), 125.2 (1C, q, J = 335.0), 122.1 (1C); 19F NMR (377 MHz, CDCl3) −80.7 (s); HRMS (ESI-TOF) m/z: [M − H]− calcd for [C7H4BrF3NOS], 285.9149; found, 285.9149. 1,1,1-Trifluoro-N-pyrimidin-2-yl-methanesulfinamide (1g). Prepared following Procedure A using 2-aminopyrimidine (1.56 mg, 10.0 mmol). Column chromatography (80 g silica, 0−30% EtOAc in heptane) yielded 1g (731 mg, 69%) as a white solid; mp 115.2 °C; 1H NMR (400 MHz, CDCl3) 9.79 (1H, br. s), 8.59 (2H, d, J = 5.0), 7.08 (1H, t, J = 5.0); 13C NMR (101 MHz, CDCl3) 158.8 (1C), 158.6 (2C), 124.2 (1C, q, J = 335.0), 116.5 (1C); 19F NMR (377 MHz, CDCl3) −80.4 (s); HRMS (ESI-TOF) m/z: [M − H]− calcd for [C5H3F3N3OS], 209.9948; found, 209.9950. 1,1,1-Trifluoro-N-((1r,4r)-4-phenylcyclohexyl)methane-sulfonimidoyl fluoride-sulfane (2a). To a stirred solution of 1a (100 mg, 0.34 mmol) and NCS (50 mg, 0.39 mmol) in MeCN (1.80 mL) was added TBAF (1 M in THF) (377 μL, 0.39 mmol) at 0 °C. The reaction mixture was allowed to warm to rt over 30 min. Then the reaction mixture was reduced in vacuo. Column chromatography (12 g silica, heptane) yielded 2a (95 mg, 89%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.34−7.28 (2H, m), 7.25−7.18 (3H, m), 3.75 (1H, tdt, J = 11.5, 7.5, 4.0), 2.55 (1H, tt, J = 12.0, 3.5), 2.24−2.13 (2H, m), 2.03−1.95 (2H, m), 1.79−1.52 (4H, m); 13C NMR (101 MHz,

EXPERIMENTAL SECTION

General Experimental. The 1H, 19F, and 13C NMR spectra were recorded on a Bruker Avance-400, -377, and -101 MHz spectrometer, respectively. 19F NMR spectra were referenced to C6F6 (δ −164.90 ppm). Chemical shifts are given in ppm (δ). Coupling constants (J) are given in hertz (Hz). The letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, respectively. The letters br indicate that the signal is broad. Melting points were measured with differential scanning calorimetry on a Mettler-Toledo-DCS823. The reactions were monitored with the aid of thin-layer chromatography (TLC) on 0.25 mm precoated silica gel plates. Visualization was carried out with UV light or potassium permanganate stains. Column chromatography was performed with the indicated solvents on silica gel 60 (particle size 0.040−0.063 mm). High resolution mass spectra were recorded on a QToF mass spectrometer configured with an electrospray ionization source, maintained at 140 °C, using nitrogen as the nebulizer gas, argon as collision gas, and a Lockmass device for mass calibration using Leucine-Enkephaline as the standard substance. Spectra were acquired either in positive or in negative ionization mode, by scanning from 50 to 1200 Da in 0.1 s. In positive mode the capillary needle voltage was either 0.5 or 2.0 kV. In negative mode the capillary needle voltage was 2.0 kV. Cone voltage was 25 V in both ionization modes. N-Chlorosuccinimide (NCS) was recrystallized from warm acetic acid and then washed with acetic acid and heptane. All other reagents and solvents were used directly as received. The sulfinamides N-(4-bromophenyl)trifluoromethane-sulfinamide and N-benzyltrifluoromethane-sulfinamide were prepared according to a literature procedure.17 The trans-4-phenylcyclohexanamine was prepared according to a literature procedure.18 General Procedures. Procedure A: Synthesis of Sulfinamides. To a solution of sodium trifluoromethane-sulfinate (1.56 g, 10.0 mmol) in EtOAc (10 mL) was added phosphorus oxychloride (470 μL, 5.0 mmol) at room temperature. The resulting mixture was stirred for 5 min, and then aryl amine (5.0 mmol) was added portionwise. The reaction mixture was stirred for an additional 30 min. The reaction mixture was then washed with brine (20 mL) and extracted with ethyl acetate (20 mL). The combined ethyl acetate fractions were dried over MgSO4, filtered, and reduced in vacuo. Purification by column chromatography yielded the desired product. Procedure B: Synthesis of Trifluoromethylsulfonimid-amides. To a stirred solution of sulfinamide (0.34 mmol) and NCS (50 mg, 0.39 mmol) in MeCN (1.80 mL) was added TBAF (1 M in THF) (377 μL, 0.39 mmol) at 0 °C. The reaction mixture was allowed to warm to rt over 30 min. Then the reaction mixture was concentrated to dryness in vacuo. MeCN (0.90 mL) and amine (2−8 equiv) were added, and the reaction mixture was stirred for 2 h at room temperature unless otherwise stated. Then the reaction mixture was reduced in vacuo. Purification by column chromatography yielded the desired product. 1,1,1-Trifluoro-N-(4-phenyl-cyclohexyl)-methanesulfin-amide19 (1a). To a solution of sodium trifluoromethanesulfinate (8.90 g, 57.1 mmol) in EtOAc (57 mL) was added phosphoryl chloride (2.7 mL, 28.6 mmol) at rt. The resulting mixture was stirred for 5 min, then trans-4-phenylcyclohexanamine (5.00 g, 28.5 mmol) was added portionwise, and then DIPEA (4.9 mL, 28.5 mmol) was added dropwise. The reaction mixture was stirred at rt for 30 min. The reaction mixture was then washed with brine, extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (330 g silica, 0−10% EtOAc in heptane) yielded 1a (4.7 g, 57%) as a white solid; mp 108.3 °C; 1H NMR (400 MHz, CDCl3) 7.33−7.28 (2H, m), 7.25−7.18 (3H, m), 4.26 (1H, br d, J = 7.0), 3.51−3.42 (1 H, m), 2.52 (1H, tt, J = 12.0, 3.5), 2.25−2.17 (2H, m), 2.05−1.96 (2H, m), 1.66−1.43 (4H, m); 13C NMR (101 MHz, CDCl3) 145.8 (1C), 128.5 (2C), 126.7 (2C), 126.3 (1C), 123.6 (1C, 9901

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

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The Journal of Organic Chemistry

(101 MHz, CDCl3) 140.3 (1C), 132.2 (2C), 125.1 (2C), 120.7 (1C, q, J = 327.0), 160.1 (1C), 49.1 (2C), 25.9 (2C); 19F NMR (377 MHz, CDCl3) −76.3 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C11H13BrF3N2OS]: 356.9884; found, 356.9881. 2-((Oxo(pyrrolidin-1-yl)(trifluoromethyl)-l6-sulfanylidene)amino)-pyrimidine (3g). Prepared following Procedure B using 1g (72 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). The reaction mixture was washed with 1 M NaOH, and the organic layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3g (84 mg, yield 87%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 8.51 (2H, d, J = 5.0), 6.91 (1H, t, J = 5.0), 3.70−3.60 (2H, m), 3.50−3.40 (2H, m), 2.06−1.92 (4H, m); 13C NMR (101 MHz, CDCl3) 158.6 (1C), 121.8 (1C), 115.4 (1C), 49.3 (2C), 29.5 (1C), 25.8 (1C); 19F NMR (377 MHz, CDCl3) −78.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C9H12F3N4OS], 281.0683; found, 281.0695. 1,1,1-Trifluoro-N-((1r,4r)-4-phenylcyclohexyl)methanesulfon-imidamide (3h). Prepared following Procedure B by using 1a (100 mg, 0.34 mmol) and bubbling ammonia gas through the reaction mixture using an ammonia gas filled balloon. The reaction mixture was washed with 1 M NaOH, and the organic layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (12 g silica, 0− 30% EtOAc in heptane) yielded 3h (60 mg, 57%) as a white solid; mp 130.6 °C; 1H NMR (400 MHz, DMSO-d6) 8.11 (1H, br. s), 7.29− 7.14 (5H, m), 5.79 (1H, br. s), 3.39−3.31 (1H, m), 2.47−2.38 (1H, m), 2.01−1.87 (2H, m), 1.84−1.75 (2H, m), 1.57−1.40 (4H, m); 13C NMR (101 MHz, CDCl3) 145.8 (1C), 128.5 (2C), 126.7 (2C), 126.3 (1C), 120.6 (1C, q, J = 325.0), 54.3 (1C), 43.0 (1C), 35.2 (1C), 34.7 (1C), 32.9(8) (1C), 32.9(5) (1C); 19F NMR (377 MHz, CDCl3) −81.4 (s); HRMS (ESI-TOF) m/z: [M + H] + calcd for [C13H18F3N2OS], 307.1091; found, 307.1090. N-[N-(4-Phenylcyclohexyl)-S-(trifluoromethyl)sulfon-imidoyl]methanamine (3i). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and methylamine (2 M in THF) (1.37 mL, 2.75 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3i as a white solid (106 mg, 95%); mp 77.0 °C; 1H NMR (400 MHz, CDCl3) 7.33−7.26 (2H, m), 7.23−7.18 (3H, m), 4.66 (1H, s), 3.55−3.45 (1H, m), 2.95−2.91 (3H, m), 2.55−2.45 (1H, m), 2.18−2.05 (2H, m), 2.00−1.90 (2H, m), 1.63−1.47 (4H, m); 13C NMR (101 MHz, CDCl3) 146.5 (1C), 128.4 (2C), 126.7 (2C), 126.1 (1C), 120.6 (1C, q, J = 327.0), 53.5 (1C), 43.2 (1C), 36.4 (1C), 35.7 (1C), 33.1 (2C), 29.5 (1C); 19F NMR (377 MHz, CDCl3) −86.7 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C14H20F3N2OS], 321.1248; found, 321.1252. N-Methyl-N-[N-(4-phenylcyclohexyl)-S-(trifluoromethyl)sulfonimidoyl]methanamine (3j). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and dimethylamine (2 M in THF) (1.37 mL, 2.75 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3j (70 mg, 60%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.32−7.26 (2H, m), 7.23−7.17 (3H, m), 3.48−3.39 (1H, m), 3.05 (6H, q, J = 1.5), 2.56−2.47 (1H, m), 2.12− 2.02 (2H, m), 1.97−1.88 (2H, m), 1.67−1.48 (4H, m); 13C NMR (101 MHz, CDCl3) 146.9 (1C), 128.3 (2C), 126.7 (2C), 126.0 (1C), 120.8 (1C, q, J = 328.0), 53.2 (1C), 43.3 (1C), 38.5 (2C), 36.6 (1C), 36.4 (1C), 33.2 (1C), 33.1 (1C); 19F NMR (377 MHz, CDCl3) −76.1 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C15H22F3N2OS], 335.1404; found, 335.1404. 1-(N((1r,4r)-4-Phenylcyclohexyl)-S-(trifluoromethyl)-sulfonimidoyl)azetidine (3k). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and azetidine (46 μL, 0.69 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3k (98 mg, 82%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.33− 7.26 (2H, m), 7.23−7.17 (3H, m), 4.19−4.10 (4H, m), 3.51−3.41 (1H, m), 2.55−2.45 (1H, m), 2.31 (2H, quin, J = 8.0), 2.07−1.88 (4H, m), 1.64−1.49 (4H, m); 13C NMR (101 MHz, CDCl3) 146.9 (1C), 128.3 (2C), 126.8 (2C), 126.0 (1C), 121.0 (1C, q, J = 329.0), 53.2 (1C), 51.8 (2C), 43.3 (1C), 36.9 (1C), 36.4 (1C), 33.2 (1C), 33.1 (1C), 14.9 (1C); 19F NMR (377 MHz, CDCl3) −76.2 (s); HRMS

CDCl3) 146.1 (1C), 128.4 (2C), 126.7 (2C), 126.2 (1C), 117.9 (1C, qd, J = 318.0, 67.0), 56.0 (1C, d, J = 4.0), 43.0 (1C), 35.7 (1C, 4.0), 35.5 (1C, d, J = 5.5), 32.7 (2C, J = 1.5); 19F NMR (377 MHz, CDCl3) −65.1 (1F, qd, J = 17.0, 7.5), −79.8 (3F, d, J = 17.0); HRMS (ESITOF) m/z: [M + H]+ calcd for [C13H15F4NOS], 309.0811; found, no ionization. 1-(N-((1r,4r)-4-Phenylcyclohexyl)-S-(trifluoromethyl)-sulfonimidoyl)pyrrolidine (3a). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3a (99 mg, 80%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.32− 7.27 (2H, m), 7.24−7.17 (3H, m), 3.55−3.42 (5H, m), 2.57−2.46 (1H, m), 2.11−1.88 (8H, m), 1.66−1.50 (4H, m); 13C NMR (101 MHz, CDCl3) 146.9 (1C), 128.3 (2C), 126.7 (2C), 126.0 (1C), 121.2 (1C, q, J = 330.0), 53.2 (1C), 48.9 (2C), 43.4 (1C), 36.7 (1C), 36.6 (1C), 33.2 (1C), 33.1 (1C), 25.9 (2C); 19F NMR (377 MHz, CDCl3) −75.9 (s); HRMS (ESI-TOF) m/z: [M + H] + calcd for [C17H24F3N2OS], 361.1561; found, 361.1558. 1-(N-(1-Phenylethyl)-S-(trifluoromethyl)sulfon-imidoyl)-pyrrolidine (3b). Prepared following Procedure B using 1b (81 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3b (79 mg, 75%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.44−7.38 (4H, m), 7.36− 7.29 (4H, m), 7.26−7.20 (2H, m), 4.77 (2H, q, J = 6.5), 3.55−3.48 (4H, m), 3.43−3.34 (2H, m), 3.31−3.22 (2H, m), 2.00−1.91 (4H, m), 1.88−1.83 (4H, m), 1.54 (3H, d, J = 2.0), 1.52 (3H, d, J = 2.0); 13C NMR (101 MHz, CDCl3) 145.9(8) (1C, s), 145.9(1) (1C, s), 128.2(3) (2C), 128.1(5) (2C), 126.7(1) (1C), 126.6(5) (1C), 125.9(3) (2C), 125.8(5) (2C), 121.4 (1C, q, J = 331.0), 120.9 (1C, q, J = 331.0), 53.3 (1C, s), 52.7 (1C, s), 48.9 (2C, s), 48.8 (2C, s), 27.5 (1C, s), 27.4 (1C, s), 25.9 (2C, s), 25.8 (2C, s); 19F NMR (377 MHz, CDCl3) −75.3 (s), −76.5 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C13H18F3N2OS], 307.1091; found, 307.1083/307.1089. 1-(N-Benzyl-S-(trifluoromethyl)sulfonimidoyl)pyrrolidine (3c). Prepared following Procedure B using 1c (77 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3c (82 mg, 82%) as a colorless oil; 1 H NMR (400 MHz, CDCl3) 7.41−7.30 (4H, m), 7.27−7.21 (1H, m), 4.48−4.39 (2H, m), 3.54−3.40 (4H, m), 1.99−1.90 (4H, m); 13C NMR (101 MHz, CDCl3) 140.0 (1C), 128.3 (2C), 127.1 (2C), 126.8 (1C), 121.2 (1C, q, J = 328.0), 48.8 (2C), 45.7 (1C), 25.9 (2C); 19F NMR (377 MHz, CDCl3) −75.7 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for [C12H16F3N2OS], 293.0935; found, 293.0935. 1-(N-(p-Tolyl)-S-(trifluoromethyl)sulfon-imidoyl)-pyrrolidine (3d). Prepared following Procedure B using 1d (77 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3d (88 mg, 88%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) 7.08−6.97 (4H, m), 3.60−3.44 (4H, m), 2.30 (3H, s), 1.99−1.91 (4H, m); 13C NMR (101 MHz, CDCl3) 138.3 (1C), 132.6 (1C), 129.8 (2C), 123.3 (2C), 120.8 (1C, q, J = 329), 49.0 (2C) 25.9 (2C), 20.8 (1C); 19F NMR (377 MHz, CDCl3) −76.4 (s); HRMS (ESI-TOF) m/z: [M + H] + calcd for [C12H16F3N2OS], 293.0935; found, 293.0936. 1-(N-Mesityl-S-(trifluoromethyl)sulfonimidoyl)pyrrolidine (3e). Prepared following Procedure B using 1e (86 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3e (87 mg, 79%) as a colorless oil; 1 H NMR (400 MHz, CDCl3) 6.83 (2H, s), 3.59−3.50 (2H, m), 3.47− 3.39 (2H, m), 2.31 (6H, s), 2.24 (3H, s), 1.94 (4H, dt, J = 6.5, 3.5); 13 C NMR (101 MHz, CDCl3) 135.7 (1C, s), 132.6 (1C, s), 131.9 (1C, s), 129.0 (2C, s), 121.4 (1C, q, J = 330.0), 119.8 (1C, s), 48.6 (2C, s), 25.9 (2C, s), 20.6 (1C, s), 19.8 (2C, s); 19F NMR (377 MHz, CDCl3) −76.0 (s); HRMS (ESI-TOF) m/z: [M + H] + calcd for [C14H20F3N2OS], 321.1248; found, 321.1245. 1-(N-(4-Bromophenyl)-S-(trifluoromethyl)sulfonimidoyl)-pyrrolidine (3f). Prepared following Procedure B using 1f (99 mg, 0.34 mmol) and pyrrolidine (57 μL, 0.69 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3f (109 mg, 89%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.39−7.32 (2H, m), 7.01− 6.95 (2H, m), 3.60−3.42 (4H, m), 2.02−1.92 (4H, m); 13C NMR 9902

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

Note

The Journal of Organic Chemistry (ESI-TOF) m/z: [M + H]+ calcd for [C16H22F3N2OS]: 347.1404; found, 347.1401. N-Allyl-1,1,1-trifluoro-N′-((1r,4r)-4-phenylcyclohexyl)-methanesulfonimidamide (3l). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and allylamine (229 μL, 2.75 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3l (104 mg, 87%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 7.33− 7.28 (2H, m), 7.23−7.18 (3H, m), 5.92 (1H, ddt, J = 17.0, 10.5, 5.5), 5.32 (1H, dq, J = 17.0, 1.5), 5.19 (1H, dq, J = 10.0, 1.5), 4.59−4.48 (1H, m), 3.93−3.83 (2H, m), 3.57−3.46 (1H, m), 2.54−2.45 (1H, m), 2.20−2.07 (2H, m), 2.01−1.90 (2H, m), 1.64−1.44 (4H, m); 13C NMR (101 MHz, CDCl3) 146.3 (1C), 134.7 (1C), 128.4 (2C), 126.7 (2C), 126.2 (1C), 120.4 (1C, q, J = 326.0), 116.5 (1C), 53.7 (1C), 45.6 (1C), 43.2 (1C), 36.1 (1C), 35.5 (1C), 33.0(7) (1C), 33.0(5) (1C); 19F NMR (377 MHz, CDCl3) −79.1 (s); HRMS (ESI-TOF) m/ z: [M + H]+ calcd for [C16H22F3N2OS], 347.1404; found, 347.1404. N-[N-(4-Phenylcyclohexyl)-S-(trifluoromethyl)sulfon-imidoyl]prop-2-yn-1-amine (3m). Prepared following Procedure B using 1a (100 mg, 0.34 mmol) and propargylamine (176 μL, 2.75 mmol). Column chromatography (12 g silica, 0−30% EtOAc in heptane) yielded 3m (79 mg, 66%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.33−7.28 (2H, m), 7.23−7.18 (3H, m), 4.55 (1H, s), 4.10− 3.97 (2H, m), 3.60−3.51 (1H, m), 2.50 (1H, tt, J = 12.0, 3.5), 2.34 (1H, t, J = 2.5), 2.25−2.14 (2H, m), 2.02−1.93 (2H, m), 1.65−1.43 (4H, m); 13C NMR (101 MHz, CDCl3) 146.1 (1C), 128.5 (2C), 126.7 (2C), 126.2 (1C), 120.0 (1C, q, J = 324.0), 71.8 (2C), 54.1, (1C), 43.1 (1C), 35.7 (1C), 34.9 (1C), 33.0 (1C), 33.0 (1C), 32.1 (1C); 19F NMR (377 MHz, CDCl3) −79.6 (s); HRMS (ESI-TOF) m/ z: [M + H]+ calcd for [C16H20F3N2OS], 345.1248; found, 345.1255. Methyl(((1r,4r)-4-phenylcyclohexyl)imino)(trifluoro-methyl)-l6sulfanone (5a). Sulfonimidoyl fluoride 2a (40 mg, 0.13 mmol) was dissolved in THF (0.65 mL, 7.95 mmol), and the solution was cooled to −78 °C. MeLi (1.6 M in THF) (162 μL, 0.26 mmol) was added dropwise, and the mixture was stirred for 15 min before being poured into an equivalent volume of sat. aq. ammonium chloride. The organic layer was separated, and the aqueous layer was extracted several times with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (12 g, silica, 0−10% EtOAc in heptane) yielded 5a (17 mg, 43%) as a white solid; mp 66.5 °C; 1H NMR (400 MHz, CDCl3) 7.33−7.26 (2H, m), 7.23−7.17 (3H, m), 3.54−3.43 (1H, m), 3.06−3.03 (3H, m), 2.55− 2.44 (1H, m), 2.09−1.87 (4H, m), 1.62−1.44 (4H, m). 13C NMR (101 MHz, CDCl3) 146.8 (1C, s), 128.3 (2C, s), 126.8 (2C, s), 126.0 (1C, s), 121.4(1C, q, J = 338.0), 53.7 (1C), 43.3 (1C), 38.2 (1C), 37.3 (1C), 35.5 (1C), 33.1 (1C), 33.0 (1C); 19F NMR (377 MHz, CDCl3) −78.6 (s); HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H19F3NOS, 306.1139; found, 306.1141. Flow Assisted Synthesis of 1-(N-((1r,4r)-4-Phenylcyclohexyl)-S(trifluoromethyl)sulfonimidoyl)-pyrrolidine (3a). Three solutions in dry MeCN were prepared: sulfinamide (0.14 mmol, 0.38 M, 1 equiv), NCS (0.21 mmol, 0.57 M, 1.5 equiv), and pyrrolidine (0.28 mmol, 0.77 M, 2 equiv). One syringe pump was used to feed the NCS and sulfinamide solutions through two capillary tubings. Each of the solutions was pumped at 25 μL/min. The two liquid flows were fed into a microchip reactor. The exiting capillary tubing was then passed through an Omnifit column containing 600 mg of fluoride on polymer support which was packed manually. The exiting capillary tubing was connected to the second microchip reactor where the pyrrolidine solution was also added by another syringe pump. This reactor was submerged in an oil bath set at 60 °C. The pyrrolidine solution was pumped at 50 μL/min. Upon exiting the reactor, the reaction mixture was collected in a flask and then reduced in vacuo. Column chromatography (12 g silica, 0−10% EtOAc in heptane) yielded 3a (36 mg, 73%) as a colorless oil. Physical and spectra data were in accordance with batch synthesis.

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H, 13C, and 19F NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Andres A. Trabanco: 0000-0002-4225-758X Daniel Oehlrich: 0000-0002-3392-1952 Notes

The authors declare no competing financial interest.

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REFERENCES

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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.7b01628. 9903

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904

Note

The Journal of Organic Chemistry (16) (17) (18) 5210. (19) 7250.

Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112. Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112. Dong, L.; Aleem, S.; Fink, C. A. Tetrahedron Lett. 2010, 51, Billard, T.; Greiner, A.; Langlois, B. R. Tetrahedron 1999, 55,

9904

DOI: 10.1021/acs.joc.7b01628 J. Org. Chem. 2017, 82, 9898−9904