Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions

Abstract

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key-step in the preparation of certain ATR kinase inhibitors. Reactions with NaN 3 or TMSN 3 and concentrated sulfuric acid under literature conditions provided slow reactions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C.The imidation reaction using TMSN 3 as reagent was successfully performed in a flow reactor utilizing CH 2 Cl 2 /H 2 SO 4 biphasic conditions. The mixture was subsequently quenched in-line with H 2 O. Phase separation, neutralization and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

Synthesis of NH‐Sulfoximines by Using Recyclable Hypervalent Iodine(III) Reagents under Aqueous Micellar Conditions

“…foximines in flow reactors, with av iew to efficient and safe industrial application [10] (Scheme 1b). Similar continuous-flow strategies were also reportedf or the syntheses of N-protected sulfoximines [11] and pharmaceutically relevant morpholinopyrimidines with as ulfoximine moiety [12] by the groups of Lebel and Kappe,r espectively.N otwithstanding the enormous progress made for preparing sulfoximines, andw ith respectt o large-scale manufacturing, sustainability,a nd environmentally friendly process development, it would be desirable to perform the reactions in water [13] and recycle the excess oxidants. However,c ommonly used hypervalent iodine(III) compounds, such as PhI(OAc) 2 and PhI(OCOCF 3 ) 2 ,h ave low solubility in water and are difficult to recycle.…”

“…Following these pioneering works, Luisi and co‐workers then developed a convenient, mild, and green synthesis of NH‐sulfoximines in flow reactors, with a view to efficient and safe industrial application (Scheme b). Similar continuous‐flow strategies were also reported for the syntheses of N ‐protected sulfoximines and pharmaceutically relevant morpholinopyrimidines with a sulfoximine moiety by the groups of Lebel and Kappe, respectively. Notwithstanding the enormous progress made for preparing sulfoximines, and with respect to large‐scale manufacturing, sustainability, and environmentally friendly process development, it would be desirable to perform the reactions in water and recycle the excess oxidants.…”

Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers

“…Methods to achieve this have involved harsh and explosive or unstable reagents such as azides, 15 O--mesitylenesulfonylhydroxylamine (MSH) or O--(2,4--dinitrophenyl)--hydroxylamine (DPH), 16 and technological advances have been exploited to facilitate use of these reagents. 17 Richards reported the use of DPH with Rh catalysts for the direct preparation of NH--sulfoximines from sulfoxides under mild conditions. 18 We recently reported a new convenient process for direct NH transfer to sulfoxides using 21 To date there are no methods to promote selective N--and O--transfer in the same reaction to generate NH--sulfoximines from sulfides, and a convenient method to achieve this would be highly desirable.…”

Three‐Dimensional Heterocycles by Iron‐Catalyzed Ring‐Closing Sulfoxide Imidation

“…[8] Its use in catalyzed nitrene transfer reactions has led to convenient methods for C À H bond aminations. [10][11][12][13] We [14] and others [12b, 15] used combinations of iron catalysis and organoazides in sulfur imidations. [10][11][12][13] We [14] and others [12b, 15] used combinations of iron catalysis and organoazides in sulfur imidations.…”

“…[9] In many cases,o rganoazides have been applied as nitrene precursors,w hich is attractive because molecular nitrogen is the only byproduct being released during substrate activation. [10][11][12][13] We [14] and others [12b, 15] used combinations of iron catalysis and organoazides in sulfur imidations. [16] As ar esult, sulfilimines and sulfoximines were obtained, which proved interesting for asymmetric synthesis [17] and applications in crop protection and medicinal chemistry.…”