A convenient synthetic route to sulfonimidamides from sulfonamides

Transcription

1 Electronic upplementary Material (EI) for RC Advances. This journal is The Royal ociety of Chemistry upporting Information Article Title: A convenient synthetic route to sulfonimidamides from sulfonamides Authors: Yantao Chen,* and James Gibson Contents creening of stability of a, a, and b... Experimental section... General... Preparation of Ph P [] :... -(tert-butyldimethylsilyl)--methylbenzenesulfonamide ():... -(tert-butyldimethylsilyl)methanesulfonamide ():... Typical procedure A: sulfonimidamides a-j from, and a-f from... Typical procedure B: sulfonimidamides a-i from... H MR and C MR:... Chiral separation of j on prep. chiral HPLC...0 otes and references:...

2 creening of stability of a, a, and b R HTB R= Tol R= Me Ph P (. eq) Et (. eq) CH, 0 o C, min TB R a R= Tol a R= Me HTM Ph P (. eq) Et (. eq) CH, 0 o C, min TM = (Me) i- TM b cheme Formation of sulfonimidoyl chlorides a, a and b silyl sulfonimidoyl chlorides a, a and b were formed in min and under other conditions (cheme ). Then the reaction mixture was monitored with H MR using hexamethylbenzene as an internal standard, and yields were recorded over time (Figure ). Figure Yield of ulfonimidoyl Chloride against Time The stability of a and a was independent of temperature, only a modest reduction in yield was observed due to slow hydrolysis. The stability of b was temperature dependent, it decomposed rapidly at room temperature, with only trace amounts of b (<%) present after h. Therefore, TB-protected sulfonamides were used for the synthesis of sulfonimidamides a-k and a-f.

3 Experimental section General. Unless otherwise noted all materials and reagents were obtained from commercial sources and used without further purification. All solvents used in moisture sensitive reactions were of commercial anhydrous grade. Melting points were measured on a Büchi apparatus without correction. uclear magnetic resonance (MR) spectra were recorded on Brucker 00 Ultrashield and 00 Ultrashield MR spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and are referenced to the solvent, for H MR (CD δ =., DM-d δ =.0 ppm) and C MR (CD δ = δ.0, DM-d δ =.0). Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broad resonance. Liquid chromatography mass spectrometry (LCM) traces were recorded on a Waters Acquity UPLC instrument. High performance liquid chromatography (HPLC) was performed on a Kromasil C8 column ( μm, 0x0 ID mm). upercritical Fluid Chromatography (FC) was performed on a Chiralpak IA column ( μm, 0x ID mm). Automated flash chromatography was performed on Biotage and Grace Reveleris X machines. A Waters XBridge column with C8 packing material has been used for high resolution mass spectra (HRM) experiments. HRM results were recorded for all final compounds, on a Waters LCT spectrometer fitted with an electrospray (EI) ion source. All final compounds were assessed as being >% pure by MR, and to be the correct mass by HRM. Compound names were generated using structure to name function in ChemDraw Ultra.0.

4 Preparation of Ph P [] : P C 0 o C, h P A solution of triphenylphosphine ( equiv) and hexachloroethane ( equiv) in dry CH (.0-.0 ml) under a atmosphere was heated to 0 C with stirring for h, a suspension formed upon heating. An extended reaction time was used to ensure complete conversion. The title compound was not isolated, the slurry containing the title compound was used directly for further transformations, a quantitative yield was assumed. -(tert-butyldimethylsilyl)--methylbenzenesulfonamide (): H i To a stirred suspension of -methylbenzenesulfonamide (. g, mmol) in dry THF (0 ml) was added triethylamine (. ml, mmol) under at C to give a clear solution. The mixture was cooled to 0 C and a solution of tert-butyldimethylsilyl chloride (. g, mmol) in toluene ( ml) was added cautiously over 0 min. The mixture warmed to C and stirred for h, then warmed to 0 C and stirred vigorously for 8 h (conversion was monitored by H MR, a longer reaction time was used to ensure complete conversion and simplify purification). The resulting suspension was cooled to C and the solid was removed by filtration and washed with Et ( x ml). The filtrate and washings were combined and the solvent was removed under reduced pressure overnight to obtain a crude solid (. g, %), which was mixed with Et (0 ml) and THF (0 ml) and stirred at C for 0 min to give a suspension. The insoluble material was removed by filtration and the solvent was removed under reduced pressure to give a solid, which was held under reduced pressure for days, affording the title compound; (. g, % yield); mp: C; H MR (00 MHz, CD ) δ..8 (m, H),.. (m, H),. (s, H),. (s, H), 0.8

5 (s, H), 0. (s, H); C MR ( MHz, CD ) δ.8,.,.,.,.,.,., -.; HRM (EI+) calcd for [M + H] + C H i + : 8., found 8.. -(tert-butyldimethylsilyl)methanesulfonamide (): To a solution of methanesulfonamide (0. g,.8 mmol) dry THF ( ml) was added triethylamine (. ml,. mmol) with stirring H i at C. A solution of tert-butyldimethylsilyl chloride (. g,.8 mmol) in dry toluene ( ml) was added over min, a suspension formed. The mixture was stirred for h at C. The resulting suspension was filtered and the solid was washed with Et ( ml), a precipitate formed in the filtrate. Et ( ml) was added to the filtrate and the mixture was allowed to stand for min then filtered to obtain a clear solution. The solvent was removed under reduced pressure and the resulting solid was held under vacuum for h to give the title compound as a colourless solid; (.8 g, % yield); mp: C; H MR (00 MHz, DM-d ) δ.0 (s, H),. (s, H), 0.8 (s, H), 0. (s, H); C MR ( MHz, DM-d ) δ.0,.,., -.; HRM (EI+) calcd for [M + H] + C H i + :.08, found.0. Typical procedure A: sulfonimidamides a-j from, and a-f from R R= Tol R= Me HTB Ph P (. eq) Et (. eq) CH, 0 o C, min R TB a, R = Tol a, R = Me R R H 0 o C, 0 min rt, 0 min - d TB H +, H R R R RT -0 min a, R = Tol, R =R =H a-e, R = Me R H R R b-k, R = Tol f, R = Me To a stirred suspension of Ph P ( mg,. mmol) in dry CH (.0 ml) under a atmosphere, was added triethylamine (0. ml,.0 mmol). The mixture was stirred for min at room temperature, a yellow suspension immediately formed. The reaction mixture was cooled to 0 o C and a solution of (.00 mmol) in dry CH (0. ml) was added. The reaction mixture was stirred for min at 0 o C, after min a clear solution formed. o

6 attempt was made to isolate the sulfonimidoyl chloride intermediate. To the reaction mixture was added a solution of amine (.0 mmol) in dry CH (.0 ml) in one portion. The mixture was stirred at 0 o C for 0 min then warmed to room temperature (longer reaction times were used if required, conversion to sulfonimidamide was judged by LCM). If a suspension formed, the solids were removed by filtration. The solvent was removed under reduced pressure to give a crude residue which was dissolved in acetonitrile (ca. ml). The compound was deprotected under acidic conditions and the mixture was stirred at room temperature for min to. h (conversion was judged by LCM). The solvent was removed under reduced pressure to give an oil residue which was purified by HPLC or automated flash chromatography. -(tert-butyldimethylsilyl)--methylbenzenesulfonamide (a): Ammonia gas was introduced to the reaction mixture of in-situ formed a. i H Flash chromatography using a gradient of EtAc ( 0%) in heptane over CV as mobile phase afforded a colourless solid; (0.8 g, 8% yield); mp: C; H MR (00 MHz, DM-d ) δ..8 (m, H),.. (m, H),. (s, H),. (s, H), 0.8 (s, H), 0.00 (s, H), -0.0 (s, H); C MR ( MHz, DM-d ) δ., 0., 8.,.,.0,.8,.8, -., -.; HRM (EI+) calcd for [M + H] + C H i + : 8., found: 8.. -Methylbenzenesulfonimidamide (b): H H To a solution of '-(tert-butyldimethylsilyl)--methylbenzenesulfonimidamide ( mg, 0.0 mmol) (a) in diethyl ether (.8 ml) was added H in,-dioxane ( M, 0.00 ml,. mmol), a precipitate formed. The mixture was stirred at room temperature for min. The ethereal suspension was extracted with water (

7 ml) then aqueous hydrochloric acid ( M, ml). The aqueous extracts were pooled and basified to ph by addition of aqueous ammonium hydroxide (% wt,.0 ml). The aqueous phase was extracted with EtAc ( x ml). The organic extracts were combined, dried over anhydrous Ca and filtered. The solvent was removed under reduced pressure to give the title compound as a white crystalline solid; ( mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ. (d, J = 8. Hz, H),.0 (d, J = 8.0 Hz, H),. (br s, H),. (s, H), (one very broad peak at. ppm and one proton not visible); C MR ( MHz, DM-d ) δ., 0.8, 8.8,.,.8; HRM (EI+) calcd for [M + H] + C H + :.0, found:.00.,-dimethylbenzenesulfonimidamide (c): H H A solution of MeH in EtH (% wt) (0. ml,.00 mmol) was added to the mixture of in-situ formed a. Deprotection conditions: formic acid (0. ml,.0 mmol), water (0.0 ml,.0 mmol), 0 min. HPLC using a gradient of acetonitrile (-0%) in H /H (0: 0.) as the mobile phase gave as a colourless solid; ( mg, % yield); mp: 8 8 C; H MR (00 MHz, DM-d ) δ.. (m, H),..8 (m, H),.0 (s, H),.0 (s, H),. (s, H),. (s, H); C MR ( MHz, DM-d ) δ., 8.,.0,.,.,.8; HRM (EI+) calcd for [M + H] + C 8 H + : 8.08, found 8.0.,,-Trimethylbenzenesulfonimidamide (d): H A solution of (Me) H in THF (M) (.0 ml,.00 mmol) was added to the mixture of in-situ formed a. Deprotection conditions: formic acid (.00 ml,. mmol), water (.00 ml,. mmol), h. HPLC using a gradient of acetonitrile (-0%) in H /H (0: 0.) as the mobile phase gave a colourless solid; ( mg, 80% yield); mp: 8 8 C; H MR (00 MHz, DM-d )

8 8 δ.. (m, H),. (d, J =. Hz, H),. (s, H),. (s, H),. (s, H); C MR ( MHz, DM-d ) δ.,.,.,.8, 8.,.; M (EI+) calcd for [M + H] + C H + :.00, found.0. -(-Methylphenylsulfonimidoyl)morpholine [] (e): H Morpholine (0. ml,.00 mmol) was added to the mixture of in-situ formed a. Deprotection conditions: formic acid (.00 ml,. mmol), water (.00 ml,. mmol), h. HPLC using a gradient of acetonitrile (0 0%) in H /HC H (0: 0.) as the mobile phase afforded a colourless solid; (8 mg, 8% yield); mp: 8 C; H MR (00 MHz, DM-d ) δ.. (m, H),. (d, J =. Hz, H),. (s, H),. (t, J =.,. Hz, H),..8 (m, H),. (s, H); C MR ( MHz, DM-d) δ.,.,.,.,.,.,.; HRM (EI+) calcd for [M + H] + C H + :., found.. '-(-Chlorophenyl)--methylbenzenesulfonimidamide (f): A solution of -chloroaniline (8 mg,.00 mmol) in dry CH (.0 ml) was added to the mixture of in-situ formed a. Deprotection conditions: acetic H acid (.0 ml,. mmol), water (.0 ml, 8. mmol), h. HPLC using a gradient of acetonitrile ( %) in H /HC H (0: 0.) as the mobile phase gave a colourless solid; ( mg, 0% yield); mp: 8 0 C; H MR (00 MHz, DM-d ) δ.80 (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (s, H),..8 (m, H),. (d, J = 8. Hz, H),. (s, H); C MR ( MHz, DM-d ) δ.,., 0.8,., 8.,.,.,.; HRM (EI+) calcd for [M + H] + C H + : 8.0, found 8.00.

9 '-(-Bromophenyl)--methylbenzenesulfonimidamide (g): Br H A solution of -bromoaniline (0. g,.00 mmol) in dry CH (.0 ml) was added to the mixture of in-situ formed a. Deprotection conditions: H in dioxane ( M) (.00 ml, 8.00 mmol), min. HPLC using a gradient of acetonitrile (0 %) in H /H (0: 0.) as the mobile phase gave a colourless solid; ( mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ.80 (d, J = 8. Hz, H),. (d, J = 8. Hz, H),.8 (d, J = 8. Hz, H),. (br s, H),. (d, J = 8. Hz, H),. (s, H); C MR ( MHz, DM-d ) δ.0,.0, 0.8,.,.,.,.,.,.; M (EI+) calcd for [M + H] + C H Br + :.00, found.80. -(-Bromobenzyl)--methylbenzenesulfonimidamide (h): H H A solution of (-bromophenyl)methanamine (8 mg,.00 mmol) in dry CH (.0 ml) was added to the mixture of in-situ Br formed a. Deprotection conditions: formic acid (0. ml,.0 mmol), water (0.0 ml,.0 mmol), 0 min. FC using % EtH in C ( bar) as the mobile phase gave a light pink solid; ( mg, % yield); mp: 0 C; H MR (00 MHz, DM-d ) δ. (d, J = 8. Hz, H),.. (m, H),. (br s, H)*,. (d, J = 8.0 Hz, H),. (d, J = 8.0 Hz, H),. (br s, H),.0 (s, H),. (s, H); C MR ( MHz, DM-d )., 0.0, 8., 0.8,.,.,.,.,.,.; HRM (EI+) calcd for [M + H] + C H Br + :.0, found.08. (*ote: broad overlap with aromatic region). -(-Bromophenethyl)--methylbenzenesulfonimidamide (i):

10 H H Br A solution of -(-bromophenyl)ethanamine (0. ml,.00 mmol) in dry CH (.0 ml) was added to the mixture of insitu formed a. Deprotection conditions: formic acid (0. ml,.0 mmol), water (0.0 ml,.0 mmol), 0 min. FC using % EtH in C ( bar) as the mobile phase gave a pink solid; ( mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ.8 (d, J = 8. Hz, H),.. (m, H),. (d, J = 8.0 Hz, H),. (d, J = 8. Hz, H),.0 (br s, H),. (br s, H),.0 (t, J =.8 Hz, H),. (t, J =. Hz, H),.0 (s, H); C MR ( MHz, DM-d ) δ.,., 8.,.0, 0.,.0,.,.,.,.8; HRM (EI+) calcd for [M + H] + C H 8 Br + :.0, found.0. -(p-toluenesulfonyl)-p-toluenesulfonimidamide (j): H A suspension of -methylbenzenesulfonamide (.88 g,. mmol) in dry CH ( ml) was added to the mixture of in-situ formed a (. mmol). The mixture was stirred at room temperature for 8 h, a clear yellow solution formed. Deprotection conditions: formic acid (.00 ml,.0 mmol), water (.00 ml,. mmol), h. HPLC using a gradient of acetonitrile (0 0%) in H /HC H (0: 0.) as the mobile phase gave a colourless solid; ( mg, % yield); mp: 0 C (-enantiomer was prepared by Liang using different chemistry approach; [] mp: -. C); H MR (00 MHz, DMd ) δ 8.0 (s, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),.8 (s, H),. (s, H); HRM (EI+) calcd for [M + H] + C H + :.08, found.00. Preparative separation of racemic material j:

11 Conditions: Chiralpak IC, 0 x mm, µm size, Heptane/EtH/TEA 0/0/0. as mobile phase, 8 ml/min flow, rt, nm, min run. Enantiomer : (-)--(p-toluenesulfonyl)-p-toluenesulfonimidamide ()-j Retention time:.8 min, ee >.%, [α] D - (c 0., acetone) (Lit. [α] D - (c 0., acetone). Enantiomer : (+)--(p-toluenesulfonyl)-p-toluenesulfonimidamide (R)-j Retention time:.8 min, ee =.%, [α] D + (c 0., acetone) ( not reported in lit.) -Methyl-'-(thiazol--yl)benzenesulfonimidamide (k): A suspension of thiazol--amine (00 mg,.00 mmol) in dry THF (.00 ml) was added to the mixture of in-situ formed a. Deprotection H conditions: formic acid (.00 ml,. mmol), water (.00 ml,. mmol), 0 min. HPLC using a gradient of acetonitrile (0 0%) in H /HC H (0: 0.) as the mobile phase gave a faint yellow oil, which was solidified during storage at rt; (8 mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ.8 (d, J = 8. Hz, H),. (s, H),.8 (d, J = 8.0 Hz, H),. (d, J =.8 Hz, H),.8 (d, J =.8 Hz, H),. (s, H); C MR ( MHz, DM-d ) δ.,.,., 8.,.,.8,.8,.; HRM (EI+) calcd for [M + H] + C H + :.0, found.0. '-(tert-butyldimethylsilyl)methanesulfonimidamide (a): Ammonia gas was introduced to the reaction mixture of in-situ formed a. i H Flash chromatography using a gradient of EtAc ( %) in heptane over CV as mobile phase afforded a colourless solid; (0. g, % yield); mp: 8 C; H MR (00 MHz, DM-d ) δ.8 (s, H),. (s, H), 0.8 (s,

12 H), 0.0 (s, H), 0.0 (s, H); C MR ( MHz, DM-d ) δ 8.,.,., -.; HRM (EI+): not available (weal UV). '-(tert-butyldimethylsilyl)--ethylmethanesulfonimidamide (b): A solution of EtH in THF ( M) (.0 ml,.0 mmol) was added to the i H reaction mixture of in-situ formed a. Automated flash chromatography on a Biotage KP-IL g column using a gradient of EtAc ( 80%) in heptane over CV gave a colourless oil; ( mg, % yield); H MR (00 MHz, DM-d ) δ. (t, J =. Hz, H),.8. (m, H),.8 (s, H),.0 (t, J =. Hz, H), 0.8 (s, H), 0.0 (s, H), 0.0 (s, H); C MR ( MHz, DM-d ) δ., 8.0,.0,.,., -., -.; HRM (EI+) calcd for [M + H] + C H i + :., found.. -{-[tert-butyl(dimethyl)silyl]--methylsulfonimidoyl}morpholine a (c): i Morpholine (0. ml,.00 mmol) was added to the reaction mixture of insitu formed a. Automated flash chromatography on a Biotage KP-IL g column using a gradient of EtAc ( 80%) in heptane over CV gave a colourless oil; (8 mg, % yield); H MR (00 MHz, DM-d ) δ.8.8 (m, H),.0 (t, J =. Hz, H),. (s, H), 0.8 (s, H), 0.0 (s, H), 0.0 (s, H); C MR ( MHz, DM-d ) δ.,.,.0,.,., -.; HRM (EI+) calcd for [M + H] + C H i + :., found.80. ( a structure name was generated using ACD name because ChemDraw does not work for it.) '-(-Bromophenyl)methanesulfonimidamide (d): H H Br A solution of -bromoaniline ( mg,.00 mmol) in dry CH (.0 ml) was added to the reaction mixture of in-situ formed a. Deprotection conditions: formic acid (.00 ml,. mmol), water (.00 ml,. mmol), 0 min. HPLC

13 using a gradient of acetonitrile ( %) in H /H (0: 0.) as the mobile phase gave a colourless solid; (0 mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ.0 (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (s, H),. (s, H); C MR ( MHz, DM-d ) δ.,.,.,.,.; HRM (EI+) calcd for [M + H] + C H Br + : 8., found (-Bromophenethyl)methanesulfonimidamide (e): H H Br -(-Bromophenyl)ethanamine (0. ml,.00 mmol) was added to the reaction mixture of in-situ formed a. Deprotection conditions: H in dioxane (M) (.00 ml,.00 mmol), min. HPLC using a gradient of acetonitrile (0 0%) in H /H (0: 0.) as the mobile phase gave a colourless solid; ( mg, 8% yield); mp: 8 8 C; H MR (00 MHz, DM-d ) δ.. (m, H),. (d, J = 8. Hz, H),. (br s, H),. (br s, H),. (tq, J =.,.,. Hz, H),.8 (s, H),. (t, H); C MR ( MHz, DM-d ) δ 8.,.,.,.,.,.; (ne broad C peak (δ.) accounts for an average of aromatic carbon environments, confirmed by HQC); HRM (EI+) calcd for [M + H] + C H Br + :.00, found.000. Methanesulfonimidamide (f):

14 H H '-(tert-butyldimethylsilyl)methanesulfonimidamide (a) ( mg, 0. mmol) was dissolved in FA (. ml) and water (0. ml). The mixture was stirred at RT for 0 min. The solvents were removed under reduced pressure to give an oil residue, which was treated with i-prh and TBME to give the title product as a white crystalline solid; (0 mg, 8% yield); mp: 0 C; H MR (00 MHz, DM-d ) δ. (br s, H),. (s, H); (only one proton was integrated at. ppm); C MR ( MHz, DM-d ) δ.; HRM (EI+) calcd for [M + H] + CH + :.0, found.08. Typical procedure B: sulfonimidamides a-i from H mmol Ph P (. eq) Et (. eq) CH o C, h H R RT, 0 min R H a a-i To a stirred suspension of Ph P ( mg,. mmol) in dry CH (.0 ml) under a atmosphere (prepared according to general procedure A), was added triethylamine (0. ml,.0 mmol). The mixture was stirred for min at room temperature, a yellow suspension immediately formed. A solution of (8 mg,.00 mmol) in dry CH (0. ml) was added. The reaction mixture was stirred for min at room temperature, a light brown solution formed. The reaction mixture was warmed to o C and stirred for hours, the solution darkened with time. o attempt was made to isolate a. The reaction mixture was added slowly via syringe to a solution of amine ( mmol) in dry CH (.0 ml). The mixture was stirred for 0 min at room temperature. If a suspension formed, the solids were removed by filtration. The solvent was removed under reduced pressure and the residue was purified by HPLC, FC, or automated flash chromatography.

15 '-(-Chlorophenyl)-,-dimethylbenzenesulfonimidamide (a): H A solution of methylamine in EtH (% wt) (0. ml,.00 mmol) diluted with dry CH (.0 ml) was added to the reaction mixture of insitu formed a. Automated flash chromatography using heptane/isopropyl alcohol (8:) as the mobile phase gave a colourless solid; ( mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ.8 (d, J = 8. Hz, H),.0 (d, J = 8.0 Hz, H),.0 (m, H),.. (m, H),.00.0 (m, H),.8 (s, H),. (d, J =. Hz, H); C MR ( MHz, DM-d ) δ.,.,.0,., 8.,.,.8,., 8.,.0; HRM (EI+) calcd for [M + H] + C H + :.0, found.08. '-(-chlorophenyl)-,,-trimethylbenzenesulfonimidamide (b): A solution of (Me) H in THF ( M) (. ml,.00 mmol) was added to the reaction mixture of in-situ formed a. HPLC using a gradient of 0-0% acetonitrile in H/AC/H //0. buffer gave as an off-white solid; ( mg, % yield); mp: 8 8 C; H MR (00 MHz, CD ) δ.8 (d, J = 8.0 Hz, H),. (d, J = 8.0 Hz, H),.. (m, H),. (s, H),. (s, H); C MR ( MHz, CD ) δ.,.8,.,.,., 8.,.,., 8.,.; mp: C; HRM (EI+) calcd for [M + H] + C H 8 + : 0.088, found [-(-Chlorophenyl)--(-methylphenyl)sulfonimidoyl]morpholine a (c): [] A solution of morpholine (0. ml,.00 mmol) in dry CH (.0 ml) was added to the reaction mixture of in-situ formed a. HPLC using a

16 gradient of acetonitrile ( 0%) in water/ formic acid (0: 0.) as the mobile phase gave as a colourless oil which partially solidified upon standing; (8 mg, % yield); H MR (00 MHz, DM-d ) δ. (d, J = 8. Hz, H),.8 (d, J = 8.0 Hz, H),.. (m, H),.. (m, H),.. (m, H),.8. (m, H),. (s, H); C MR ( MHz, DM-d ) δ.,.,.,.8, 8.,.,.,.8,.,.,.0; HRM (EI+) calcd for [M + H] + C H + :.0, found.0. ( a structure name was generated using ACD name because ChemDraw does not work for it.) '-(-chlorophenyl)--(-(-hydroxyethoxy)ethyl)--methylbenzenesulfonimidamide (d): -(-aminoethoxy)ethanol (. mg, 0.0 mmol) was added to the H reaction mixture of in-situ formed a. HPLC using a gradient of H acetonitrile ( 0%) in H / H (0: 0.) as the mobile phase gave as a yellow oil; (.0 mg, % yield); H MR (00 MHz, DM-d) δ.8 (d, J = 8. Hz, H),. (s, H),. (d, J = 8. Hz, H),.. (m, H),.0.0 (m, H),. (t, J =.,. Hz, H),.0 (q, J =.,.,. Hz, H),.. (m, H),.8 (s, H),.8 (s, H); C MR ( MHz, DM-d ) δ.8,.,.,., 8.,.,.8,.,.0, 8., 0.,.,.0; HRM (EI+) calcd for [M + H] + C H + :., found..,'-bis(-chlorophenyl)--methylbenzenesulfonimidamide (e): A solution of -chloroaniline ( mg,. mmol) in dry CH (.0 ml) was added to the reaction mixture of in-situ formed a. H HPLC using a gradient of acetonitrile ( 0%) in H / H (0: 0.) as the mobile phase gave a colourless solid; (.0 mg,

17 8% yield); mp: C; H MR (00 MHz, CD ) δ.8 (d, J = 8., H),. (d, J = 8., H),.. (m, H),.0.0 (m, H),. (s, H); C MR ( MHz, CD ) δ.0,.0,.8,.,., 8.,.,.,.; H MR (00 MHz, DMd ) δ.8 (s, H),.8 (d, J = 8. Hz, H),. (d, J = 8. Hz, H),.. (m, H),.0. (m, H),. (s, H); C MR ( MHz, DM-d ) δ.,.,.,.8,.0,.,.,.,.0; HRM (EI+) calcd for [M + H] + C H + :.0, found.0. (ote: In CD the H resonance was not observed, possibly because it is readily exchangeable). -(-Bromophenyl)-'-(-chlorophenyl)--methylbenzenesulfonimidamide (f): H Br A solution of -bromoaniline ( mg,.00 mmol) in dry CH (.0 ml) was added to the reaction mixture of in-situ formed a. FC using % EtH in C ( bar) as the mobile phase gave a light brown solid; ( mg, % yield); mp: 8 C (decomposed); H MR (00 MHz, DM-d ) δ. (s, H),.8 (d, J = 8. Hz, H),.. (m, H),. (d, J = 8. Hz, H),. (br s, H),. (s, H); C MR ( MHz, DM-d ) δ.,.8,.,.,.8,., 8.,.,.0,.,.,.,.; HRM (EI+) calcd for [M + H] + C H Br +., found.8. '-(-chlorophenyl)--(-methoxyphenyl)--methylbenzenesulfonimidamide (g):

18 8 A solution of -methoxyaniline (. mg, 0.0 mmol) in dry H CH (.0 ml) was added to the reaction mixture of in-situ formed a. HPLC using a gradient of acetonitrile ( 0%) in H / H (0: 0.) as the mobile phase gave an off-white solid; (. mg, % yield); mp: 0 C; H MR (00 MHz, DM-d) δ. (s, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (d, J = 8. Hz, H),. (s, H),. (d, J = 8. Hz, H),. (s, H),. (s, H); C MR ( MHz, DM-d) δ.,.,., 8.8,.,.,.,.,.; HRM (EI+) calcd for [M + H] + C H l + 8.0, found (-Bromobenzyl)-'-(-chlorophenyl)--methylbenzenesulfonimidamide (h): A solution of (-bromophenyl)methanamine (8 mg,.00 mmol) in dry CH (.0 ml) was added to the reaction mixture of insitu formed a. HPLC using Heptane/EtH/TEA (0:0:0.) as H the mobile phase gave a light pink solid; (8 mg, % yield); mp: C; H MR (00 MHz, DM-d ) δ. (t, J = Br.0 Hz, H),..8 (m, H),.. (m, H),.. (m, H),.0. (m, H),. (d, J =.0 Hz, H),.8 (s, H); C MR ( MHz, DMd ) δ.,.,.,., 0.,.8,., 8.,.,.,.,.,.,.; HRM (EI+) calcd for [M + H] + C H Br + :.000, found.00. -(-Bromophenethyl)-'-(-chlorophenyl)--methylbenzenesulfonimidamide (i): A solution of -(-bromophenyl)ethanamine (00 mg,.00 H Br mmol) in dry CH (.0 ml) was added to the reaction mixture of in-situ formed a. HPLC using % EtH/TEA

19 (0: 0.) in C ( bar) as the mobile phase. The title compound was obtained as a colourless solid; ( mg, % yield); mp: 8 C; H MR (00 MHz, DM-d ) δ..8 (m, H),. (s, H),.. (m, H),..8 (m, H),.0 (d, J = 8. Hz, H),..8 (m, H),. (d, J =. Hz, H),. (t, J =.0 Hz, H),.8 (s, H); C MR ( MHz, DM-d ) δ.8,., 8.,.,.0, 0.,., 8.,.0,.,.,.,.8,.,.0; HRM (EI+) calcd for [M + H] + C H Br + :.0, found.0.

20 H MR and C MR: Compound Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: CD 8 H i C H C H C H C H C H 8 A (m). B (m). C (s). D (s). E (s) 0.8 F (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: CD H i C H C H C H C H C H

21 Compound

22 Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM A (s).08 B (s). C (s) 0. D (s) 0. H i C H C H C H C H Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H i C H C H C H C H Compound a

23 Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM plitting of i-me Protons F (s) 0.00 G (s) -0.0 G (s) -0.0 A (m). B (m). C (s). D (s). E (s) 0.8 F (s) i C H C H 8 H Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM i C H C H 8 H plitting of i-me Carbons

24 Compound b Frequency:.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H 8 H A (d). B (d).0 C (s). D (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H 8 H

25 Compound c Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H 8 H C H D (m). B (s). C (m). E (s).0 F (s).0 A (s). A (s). B (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H 8 H C H

26 Compound d Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 H C H B (d). D (s). A (m). C (s). G (s). A (m). B (d) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H C H

27 Compound e Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 H B (d). F (s). A (m). C (s). D (t). E (m) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H

28 8 Compound f Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM A (d).80 C (s). B (d). D (m). E (d). F (s). 8 C (s). A (d).80 B (d). D (m). E (d). 8 H Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H

29 Compound g Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM Br 8 8 H A (d).80 C (br). B (d). D (d).8 E (d). F (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM Br 8 8 H

30 0 Compound h Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H 8 H 8 Br A (d). B (m). C (d). D (d). G (d). E (s).0 F (s). B (m). C (d). D (d) H verlap Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H 8 H 8 Br

31 Compound i Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H 8 H 8 Br B (m). H (t). A (d).8 C (d). E (br).0 F (br). G (t).0 I (s).0 D (d) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H 8 H 8 Br

32 Compound j Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H 8 8 C H A (s) 8.0 B (d). C (d). E (d). G (s). F (s).8 D (d). F (s).8 G (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H 8 8 C H

33

34 Compound k Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 H B (s). D (d). A (d).8 C (d).8 E (d).8 G (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM H

35 Compound a Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 i C H C H H A (s).8 B (s). C (s) 0.8 E (s) 0.0 D (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM i C H C H H

36 Compound b Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM C H H C C H C H i 8 H C H A (t). C (s).8 B (m). D (t).0 E (s) 0.8 G (s) 0.0 F (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM C H H C C H C H i 8 H C H

37 Compound c

38 8 Compound d Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM Br 8 B (d). H A (d).0 C (s). D (s). A (d).0 B (d). C (s) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: DM Br 8 H

39

40 0 Compound e Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM H H Br 8 B (d). E (tq). G (t). A (m). C (s). D (s). F (s).8 G (t). E (tq). F (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H H Br

41 Frequency: 00.MHz (nmr) Experiment ame: HQC_night #cans: 8 olvent: DM H H Br f (ppm) ne C peak accounts for two aromatic carbon environments, it correlates to two H aromatic resonances as demonstrated by HQC

42 Compound f

43 Compound a Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 E (m).0 8 H Me A (d).8 C (m).0 B (d).0 D (m). C (m).0 G (d). F (s) F (s).8 G (d). A (d).8 B (d).0 D (m). E (m) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H C H

44 Compound b

45 Compound c Frequency: 00.MHz (nmr) pinner: Experiment ame: Proton_day olvent: DM 8 8 A (d). B (d).8 C (m). D (m). E (m). F (m).8 G (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM

46 Compound d

47 Compound e (CD as solvent, the H peak is very broad) Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: CD H 8 A (d).8 C (m). B (d). F (s). 8 D (m).0 C (m). A (d).8 B (d). D (m) Frequency:.MHz (nmr) Experiment ame: Carbon_day #cans: olvent: CD H

48 Compound e (DM-d as solvent) 8

49 Compound f Frequency: 00.MHz (nmr) Experiment ame: Proton_day #cans: olvent: DM 8 D (d). 8 H Br A (s). B (d).8 C (m). F (s). E (br). D (d). B (d).8 C (m). E (br) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H Br

50 Compound g 0

51 Compound h

52 Frequency: 00.MHz (nmr) Experiment ame: Proton_night #cans: 8 olvent: DM 8 A (t). B (m).80 C (m). D (m). E (m).0 8 H Br A (t). B (m).80 C (m). D (m). E (m).0 F (d) H (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H Br Compound i

53 Frequency: 00.MHz (nmr) Experiment ame: Proton_night #cans: 8 olvent: DM 8 8 H B (s). A (m) Br. C (m).8 E (d).0 D (m). F (m). G (d). H (t). I (s) Frequency:.MHz (nmr) Experiment ame: Carbon_night #cans: 000 olvent: DM H Br

54 Chiral separation of j on prep. chiral HPLC Enantiomer :

55 Enantiomer : otes and references: [] A. K. Roy, J. Am. Chem. oc.,, 8-0. [] G. C. andi,. R. Kota, T. Govender, H. G. Kruger, P. I. Arvidsson, Tetrahedron, 0, 8-. [] C. Liang, F. Collet, F. Robert-Peillard, P. Mueller, R. H. Dodd, P. Dauban, J. Am. Chem. oc. 08, 0,.