Modular Sulfondiimine Synthesis Using a Stable Sulfinylamine Reagent

Sulfondiimines—the double aza-analogues of sulfones—hold significant potential as leads in discovery chemistry, yet their application in this arena has been held back by the scarcity of appropriate synthetic routes. Existing methods employ sulfides as substrates, and rely on consecutive imination reactions using the hazardous reagent O-mesitylenesulfonyl hydroxylamine. Here we report a method for sulfondiimine synthesis that does not begin with a sulfide or a thiol, and instead employs two Grignard reagents and a bespoke sulfinylamine (R—N=S=O) reagent as starting materials. Lewis acid-mediated assembly of these three components provides efficient access to a series of sulfilimine intermediates. A novel rhodium-catalyzed imination of these electron-rich sulfilimines then delivers a varied range of sulfondiimines featuring orthogonal N-functionalization. Conditions for the selective manipulation of both N-atoms of the sulfondiimines are reported, allowing access to a broad range of mono- and difunctionalized products. The oxidation of the sulfilimine intermediates is also described, and provides a complementary route to sulfoximines.


Preparation of diaryl sulfilimine
N-Sulfinyl-tert-octylamine 1 (370 mg, 2.11 mmol, 1.05 equiv.) was dissolved in anhydrous THF (4.0 mL) in an oven-dried 25 mL round bottom flask. The mixture was cooled to -78 °C before the addition of TMSOTf (440 mg, 1.98 mmol, 1.0 equiv.). 4-Chlorophenylmagnesium bromide (2.25 mL, 0.88 M in 2-methyltetrahydrofuran, 1.98 mmol, 1.0 equiv.) was added dropwise after 1 min. The reaction was stirred at -78 °C for 2 min and then the temperature was increased to -30 °C. Then the organolithium reagent was by syringe. The mixture was stirred at -30 °C for 10 min, then warmed to room temperature and stirred for 1.5 h. The reaction was subsequently quenched with sat. aq. tetrasodium EDTA solution. Ethyl acetate (60 mL) was then added and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (2 × 30 mL). The combined extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.

Preparation of organolithium reagent
Benzofuran (317 mg, 2.69 mmol, 1.5 equiv.) and THF (5.0 mL) were added to an oven-dried reaction tube. The reaction was cooled to 0 °C. n-Butyllithium (1.20 mL, 2.24 M in hexanes, 2.69 mmol, 1.5 equiv.) was added dropwise and the mixture stirred at the room temperature for 1 h.  and THF (2.0 mL) were added to an oven-dried reaction tube and were cooled to -78 °C.

Preparation of diaryl sulfilimine
n-Butyllithium (0.48 mL, 2.24 M in hexanes, 1.1 mmol, 1.3 equiv.) was added dropwise and the mixture was stirred at the same temperature for 40 min.
Two portions of PhI=NNs (2 × 137 mg, 0.678 mmol, 3.0 equiv.) were subsequently added at the 8 th and 16 th hour. The reaction mixture was then transferred to a 100 mL round bottom flask, to separate from the 4 Å MS, washing the vial several times with CH 2 Cl 2 . The solvent was then removed under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate 6:1 to 4:1) to afford sulfondiimine 4a as a light yellow solid (55 mg, 44%).
Methylmagnesium bromide (0.67 mL, 3.0 M in diethyl ether, 2.0 mmol, 1.5 equiv.) was then added quickly. The mixture was stirred at -30 °C for 10 min. Then the reaction was quenched with sat. aq.
tetrasodium EDTA solution (100 mL) and poured into a 250 mL separating funnel. Ethyl acetate (80 mL) was then added and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (2 × 40 mL). The combined extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude sulfilimine was dissolved in a mixture S15 of diethyl ether (15 mL) and petroleum ether (5 mL) and acidified by an 1 M aq. solution of 4-toluenesulfonic acid (35 mL). The organic layer was discarded. The aqueous phase was washed once with a mixture of diethyl ether (5 mL) and petroleum ether (15 mL). The aqueous phase was then extracted with CH 2 Cl 2 (3 × 40 mL), combined CH 2 Cl 2 extracts dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the 4-toluenesulfonic acid-sulfilimine salt 3ba (c. 85% yield). The sulfilimine salt 3ba was then dissolved in CH 2 Cl 2 (50 mL) and treated with 1 M aq. NaOH (50 mL). The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (2 × 50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford sulfilimine 3b as a light yellow oil (300 mg, 83%).

Notes:
1. The reaction can be warmed from -78 °C to -30 °C through an addition of acetone to the dry ice-acetone bath over 5 min, or a quick replacement of the dry ice-acetone bath with an acetone bath at -30 °C 2. Solvents were removed in a rotary evaporator below 30 °C due to instability of the sulfilimine 3b at high temperatures.
3. After performing an acid-base workup as mentioned above, crude S-aryl-S-alkyl and S,S-dialkyl sulfilimines were used without further purification in the next step. For long-term storage, 4-toluenesulfonic acid salt would be preferred over the neutral sulfilimine due to enhanced stability.
4. EDTA solution is used to complex the magnesium salts present in the Grignard reagents, which otherwise emulsions may be formed and complicate the aqueous work-up if only water is used instead.
5. The S-aryl-S-alkyl and S,S-dialkyl sulfilimines are typically very polar and appear to be strongly basic, which often stay on the baseline of the TLC plate even when ethyl acetate is used as the eluent. When mixtures of ethyl acetate and methanol were used, the sulfilimine may travel further up the TLC plate but "streaking" is often observed. For sulfilimine 3b, 3:1 petrol/ethyl acetate can be used to observe the by-products (which are removed during the diethyl ether/petroleum ether washes).

Notes:
1. The reaction was run under air.
2. The reaction is run for 24 hours as standard as some S,S-diaryl substrates need extended reaction times, but it may be finished sooner for S-aryl-S-alkyl and S,S-dialkyl substrates.
3. The protected sulfondiimines are stable towards air and moisture and do not need any special care to be taken when handling them.

S27
Sulfilimine prepared according to General Procedure C using N-sulfinyl-

General Procedure E for Aryl-Alkyl and Dialkyl Sulfoximine Synthesis
S30 N-Sulfinyl-tert-octylamine 1 (248 mg, 1.42 mmol, 1.05 equiv.) was dissolved in anhydrous THF and the organic layer was then discarded. The aqueous phase was washed once with a mixture of diethyl ether (5 mL) and petroleum ether (15 mL). The aqueous phase was then extracted with CH 2 Cl 2 (3 × 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to afford the 4-toluenesulfonic acid-sulfilimine salt 3ba (c. 85% yield). The sulfilimine salt was then dissolved in CH 2 Cl 2 (50 mL) and treated with 1M aq. NaOH solution (50 mL). The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (2 × 50 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford sulfilimine 3b as a light yellow oil (301 mg, 82%).
(Please see notes on General Procedure C for further guidance.) Sulfilimine 3b (301 mg, 1.12 mmol, 1.0 equiv.) was dissolved in anhydrous MeCN (6.0 mL) in an oven-dried 50 mL round bottom flask. Then the mixture was heated to 40 °C before TPAP (20 mg, 0.057 mmol, 5.0 mol%) was added, then NMO (787 mg, 6.73 mmol, 6.0 equiv.) was added. The reaction was stirred at 40 °C for 24 h until completion of the reaction (TLC). The reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 5:1 to 3:1) to afford sulfoximine 5a as a colourless oil (315 mg, 99%).