Synthesis of aryl benzyl NH-sulfoximines

Efficient synthesis and characterisation of a series of aryl benzyl NH-sulfoximines are described. While N-protected versions of aryl benzyl sulfoximines have been previously described, reports of their deprotection are very limited, presumably due to lability under the typically harsh deprotection conditions which can be employed with the less reactive aryl alkyl derivatives. Use of N-cyanosulfoximines as key intermediates overcomes these difficulties leading to an effective synthetic route to these compounds.     

The stereochemistry of isoquinoline Reissert compounds: a unique platform for observation of steric and electronic interactions

Isoquinoline Reissert compounds (2-acyl-1,2-dihydroisoquinaldonitriles) with either 3-H (1) or 3-CH₃ (2) substituents and various N-acyl groups have been examined in detail by ¹H and ¹³C NMR spectroscopy and X-ray crystallography. In all cases the trans amide conformation, with reference to the carbonyl oxygen and the 3-position of the isoquinoline ring, predominates in solution. In the solid state the nitrile moieties are pseudo-axial and the amides exist almost exclusively in the trans form, except for the case of 2-isobutyryl-3-methyl-1,2-dihydroisoquinaldonitrile (2c), which exists exclusively as the cis amide form in the solid state. In N-aroyl 3-CH₃ compounds with two ortho-aroyl substituents both amide isomerism and hindered aryl/carbonyl rotation are observed by ¹H NMR spectroscopy. In other N-aroyl derivatives only hindered aryl/carbonyl rotations are observed by NMR and in N-alkanoyl compounds amide isomerism is observable only at very low temperatures. X-ray crystallography reveals the two rotamers in the solid state in four cases of ortho-substituted benzoyl compounds; with one exception, the rotamer with the larger ortho-aroyl substituent syn to the pseudo-axial cyano group is favored. Unusual solubility and reactivity patterns observed with these compounds are rationalized in terms of the interplay between steric and electronic factors.     

Efficient copper-induced coupling between NH-fluoroalkylated sulfoximines and aryl iodides or bromides

A high yielding, simple, and flexible copper-based system for N-arylation of fluorinated sulfoximines is reported. Best results were achieved using copper iodide in combination with DMEDA and Cs₂CO₃ to provide a wide range of N-arylated perfluoroalkylated sulfoximines. These conditions tolerate a great number of substituents on either aromatic cycle, including heteroaromatic rings, for the N-functionalization.     

Metal-free imination of sulfoxides and sulfides

Using a nitrogen transfer agent obtained in situ by mixing of NsNH₂ and PhI(OAc)₂, various N-nosyl sulfoximines and N-nosyl sulfilimines have been prepared under metal-free conditions starting from the corresponding sulfoxides and sulfides, respectively.     

General synthetic strategies towards N-alkyl sulfoximine building blocks for medicinal chemistry and the use of dimethylsulfoximine as a versatile precursor

The sulfoximine group has great potential as a substituent in drug discovery, as evidenced by two new clinical candidates, and can be viewed as an isosteric alternative to the commonly used sulfone. Our aim was to improve the accessibility of this group by synthesising a diverse range of S-alkyl and N-alkyl sulfoximine building blocks with procedures that are applicable on a practical scale (>10 g). In particular, synthesis of the less well exploited N-alkyl sulfoximines and the use of dimethylsulfoximine as a versatile, commercially available precursor is discussed.     

Reaction of some N-substituted 1,4-benzoquinone imines with sodium arenesulfinates

N-Arylsulfonyl, N-aroyl, and N-[arylsulfonylimino(phenyl)methyl] derivatives of 1,4-benzoquinone imine reacted with sodium arenesulfinates to give 1,4-, 1,6-, and 6,1-addition products which were formed according to two concurrent paths: direct nucleophilic addition of arenesulfinate anion to neutral quinone imine molecule and radical ion addition of arenesulfinate radical to radical anion derived from quinone imine.     

Copper-catalyzed denitrogenative N-arylation of sulfoximines and sulfonamides with arylhydrazines

A Cu-mediated ligand-free arylation of NH-sulfoximines and sulfonamides by arylhydrazine hydrochlorides was herein demonstrated. The oxidative transformation provided an easy access towards N-aryl sulfoximines and sulfonamides in high yields (up to 93% yields) with broad functional groups tolerance (up to 36 examples). The protocol was proposed to take place through the free radical pathway based on the results of control reactions and EPR analysis.     

Reactions of N-substituted 2,6(3,5)-dialkyl-1,4-benzoquinone imines with arenesulfinic acids

The regioselectivity in the reactions of N-arylsulfonyl-2,6-dialkyl-1,4-benzoquinone imines with arenesulfinic acids (1,6-, 6,1-, or 6,3-addition) is determined by steric factor, while in the reactions of N-aroyl-1,4-benzoquinone imines electronic effect of substituents in the quinoid ring is crucial. The reactions of N-arylsulfonyl-3,5-dimethyl-1,4-benzoquinone imines with arenesulfinic acids follow mainly the 1,4-addition pattern. N-(N-Arylsulfonylbenzimidoyl)-1,4-benzoquinone imines are capable of reacting in a way similar to both N-arylsulfonyl and N-aroyl derivatives.     

Synthesis of 1,5-P,N-phosphino-sulfoximines through phospha-Michael reaction of alkenyl sulfoximines and their evaluation as ligands in palladium-catalyzed allylic alkylation

We describe a modular synthesis of cyclic and acyclic 1,5-P,N-phosphino-sulfoximines by using a phospha-Michael reaction of the corresponding alkenyl sulfoximines with HPPh₂/KOtBu as key step, which proceeds with medium diastereoselectivity. The palladium-catalyzed allylic alkylation of racemic 1,3-diphenyl allyl acetate with malonate in the presence of a S_SR_CR_C-configured N-benzyl-substituted cyclic phosphino-sulfoximine gave the corresponding alkene with 97% ee in 98% yield. A comparative study of N-substituted phosphino-sulfoximines showed the selectivity of the Pd(0)-catalyst to be dependent not only on the chiral backbone of the ligand but also on the N-substituent and configuration of the sulfoximine group.     

Photoredox mediated CN cross coupling of sulfoximines with aryl iodides

A new photoredox-catalyzed CN coupling reaction of sulfoximines with aryl halides has been developed for a general N-arylation of sulfoximines. The reactions proceed in the presence of visible light with high levels of chemoselectivity and a wide range of functionality is tolerated. There is a rapidly increasing interest in sulfoximines as pharmacophores in drug discovery and this new method offers potential in terms of high functional group tolerance and late-stage functionalization of compounds.     

Synthesis of Chiral Sulfoximines via Iridium-Catalyzed Regio- and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand

Transition metal-catalyzed enantioselective C−H activation of prochiral sulfoximines for non-annulated products remains a formidable challenge. We herein report iridium-catalyzed enantioselective C−H borylation of N-silyl diaryl sulfoximines using a well-designed chiral bidentate boryl ligand with a bulky side arm. This method is capable of accommodating a broad range of substrates under mild reaction conditions, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative-scale C−H borylation for diverse downstream transformations, including the synthesis of chiral version of bioactive molecules. Computational studies showed that the bulky side arm of the ligand confers high regio- and enantioselectivity through steric effect.     

Stereochemistry of alkylated isoquinoline Reissert compounds

A series of alkylated isoquinoline Reissert compounds (2-acyl-1-alkyl-1,2-dihydroisoquinoline-1-nitriles) with either 3-H (3) or 3-CH₃ (4) substituents was examined by ¹H, ¹³C, and ¹⁹F NMR spectroscopies and X-ray crystallography. In all cases the trans-amide conformation, with reference to the carbonyl oxygen and the 3-position of the isoquinoline ring, exists exclusively in the solid state, and predominates in solution. As expected the 1-alkyl groups (isopropyl, isobutyl, benzyl) are nearly pseudo-axial or axial in all cases. In N-aroyl compounds the larger ortho-aroyl substituent lies syn to the 1-alkyl moiety in nine of the 11 cases, as revealed by X-ray crystallographic studies. In solution NMR results show that atropisomerism about the Ar/CO bond is usually rapid at room temperature, but slow at −50 °C and usually favors the syn isomer. CH?π interactions of the 3-methyl protons of 4 with the N-aroyl moieties appear to influence the atropisomerism.     

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described_. The CCR generally requires dual Ni catalysis and MgBr₂ promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr₂ in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl₂ as a precatalyst and MgBr₂ with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh₃)₂Cl₂ as a precatalyst and ZnPh₂ does not require salt promotion and is stereoretentive. The reaction with Zn(CH₂SiMe₃)₂, however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh₃)₂Cl₂. Ni-Catalyzed and MgBr₂-promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh₂ and Zn(CH₂SiMe₃)₂ is stereoretentive with Ni(dppp)Cl₂ and Ni(PPh₃)₂Cl₂. CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.     

1,2‐Thiazines: One‐Pot Syntheses Utilizing Mono and Diaza Analogs of Sulfones

A one‐pot Michael addition/cyclization/condensation reaction sequence for the regioselective synthesis of 1,2‐thiazines, starting from propargyl ketones and NH‐sulfoximines or NH‐sulfondiimines, has been developed. Under mild and operationally simple reaction conditions previously unprecedented 1,2‐thiazine 1‐imide and 1‐oxide derivatives are formed in good to excellent yields. The products represent heterocyclic building blocks, readily modifiable by a regioselective C?H bond functionalization, classical cross‐coupling reactions, and deprotection.     

BINOL-derived N-phosphino sulfoximines as ligands for asymmetric catalysis

BINOL-derived N-phosphino sulfoximines have been prepared for the first time and tested as ligands in asymmetric transition metal catalysis. Up to 99% ee was achieved in the Rh-catalyzed asymmetric hydrogenation of functionalized olefins and up to 66% ee in the Pd-catalyzed allylic alkylation.     

A versatile route to benzocanthinones

Benzocanthinone (1) and five analogs (10, 12-15) were prepared by radical-induced cyclizations of halo N-aroyl derivatives of β-carboline and carbazole.     

Sulfonimidamide as a directing agent for Pd-catalyzed regioselective oxidative C–H acyloxylation of arenes

In this report, we describe the utilization of sulfonimidamide (SIA) as a novel directing group for a Pd-catalyzed regioselective oxidative C–H acyloxylation of aryl group of N-aroyl part of SIA in moderate to good yields in the presence of (Diacetoxyiodo)benzene (PhI(OAc)₂) as an oxidizing agent and alkanoic acid as solvent. The solvent alkanoic acid is found to be the source of acyloxylation.     

An expedient route to highly functionalized 2H-chromene-2-thiones via ring annulation of β-oxodithioesters catalyzed by InCl3 under solvent-free conditions

A convenient and one-pot synthesis of 3-aroyl/heteroaroyl-2H-chromene-2-thiones and benzo[f]2H-chromene-2-thiones has been developed by the condensation of β-oxodithioesters and salicylaldehydes/α-hydroxynaphthaldehydes in the presence of indium trichloride under solvent-free conditions. The reaction is operationally facile, readily scalable, and offers rapid entry into differentially substituted chromene-2-thione scaffolds.     

Synthesis of Enantiopure Benzo Fused Cyclic Sulfoximines Through Stereoselective [3+2] Cycloaddition between N-tert-Butanesulfinyl [(2-Pyridyl)sulfonyl]-difluoromethyl Ketimines and Arynes

The previously developed stereoselective [3+2] cycloaddition between N-tert-butanesulfinyl ketimines and arynes has been extended to the synthesis of enantiopure [(2-pyridyl)sulfonyl]difluoromethylated cyclic sulfoximines. The use of 2-PySO₂CF₂ as the facilitating group offers new opportunities for the elaboration of the [3+2] cycloaddition products by virtue of the diverse relativity of 2-pyridyl sulfones.     

Batch and Continuous-Flow Iron(II)-Catalyzed Synthesis of Sulfilimines and Sulfoximines using N-Mesyloxycarbamates

The synthesis of sulfilimines and sulfoximines with N-mesyloxycarbamates in presence of catalytic iron(II) chloride hydrate is described. The use of 1-butylimidazole as a base proved instrumental in enabling a homogeneous reaction mixture compatible with continuous flow processes. The amination is applicable to a wide range of substrates, and affords the desired product in good to excellent yields within 1 to 60 minutes.