SuFEx Chemistry of Thionyl Tetrafluoride (SOF4) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides,Sulfoximines, Sulfonimidamides,and Sulfonimidates

Thionyl tetrafluoride (SOF₄) is a valuable connective gas for sulfur fluoride exchange (SuFEx) click chemistry that enables multidimensional linkages to be created via sulfur–oxygen and sulfur–nitrogen bonds. Herein, we expand the available SuFEx chemistry of SOF₄ to include organolithium nucleophiles, and demonstrate, for the first time, the controlled projection of sulfur–carbon links at the sulfur center of SOF₄‐derived iminosulfur oxydifluorides (R¹?N=SOF₂). This method provides rapid and modular access to sulfonimidoyl fluorides (R¹?N=SOFR²), another array of versatile SuFEx connectors with readily tunable reactivity of the S?F handle. Divergent connections derived from these valuable sulfonimidoyl fluoride units are also demonstrated, including the synthesis of sulfoximines, sulfonimidamides, and sulfonimidates.     

SuFEx Chemistry of Thionyl Tetrafluoride (SOF4) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides,Sulfoximines, Sulfonimidamides,and Sulfonimidates

Thionyl tetrafluoride (SOF₄) is a valuable connective gas for sulfur fluoride exchange (SuFEx) click chemistry that enables multidimensional linkages to be created via sulfur–oxygen and sulfur–nitrogen bonds. Herein, we expand the available SuFEx chemistry of SOF₄ to include organolithium nucleophiles, and demonstrate, for the first time, the controlled projection of sulfur–carbon links at the sulfur center of SOF₄‐derived iminosulfur oxydifluorides (R¹−N=SOF₂). This method provides rapid and modular access to sulfonimidoyl fluorides (R¹−N=SOFR²), another array of versatile SuFEx connectors with readily tunable reactivity of the S−F handle. Divergent connections derived from these valuable sulfonimidoyl fluoride units are also demonstrated, including the synthesis of sulfoximines, sulfonimidamides, and sulfonimidates.     

Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub

Sulfur(VI) fluoride exchange (SuFEx) is a new family of click chemistry based transformations that enable the synthesis of covalently linked modules via S^VI hubs. Here we report thionyl tetrafluoride (SOF₄) as the first multidimensional SuFEx connector. SOF₄ sits between the commercially mass‐produced gases SF₆ and SO₂F₂, and like them, is readily synthesized on scale. Under SuFEx catalysis conditions, SOF₄ reliably seeks out primary amino groups [R‐ NH₂ ] and becomes permanently anchored via a tetrahedral iminosulfur(VI) link: R−N=(O=)S(F)₂. The pendant, prochiral difluoride groups R−N=(O=) SF₂ , in turn, offer two further SuFExable handles, which can be sequentially exchanged to create 3‐dimensional covalent departure vectors from the tetrahedral sulfur(VI) hub.     

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

SuFEx is a new‐generation click chemistry transformation that exploits the unique properties of S?F bonds and their ability to undergo near‐perfect reactions with nucleophiles. We report here the first SuFEx‐based procedure for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new process involves rapid S?F exchange with trifluoromethyltrimethylsilane (TMSCF₃) upon activation by potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative mechanism is proposed involving nucleophilic displacement of S?F by the trifluoromethyl anion via a five‐coordinate intermediate. The utility of late‐stage SuFEx trifluoromethylation is demonstrated through the synthesis and selective anticancer properties of a bis(trifluoromethyl)sulfur oxyimine.     

Visible‐Light‐Induced Selective Photocatalytic Aerobic Oxidation of Amines into Imines on TiO2

Imines are important intermediates for the synthesis of fine chemicals, pharmaceuticals, and agricultural chemicals. Selective oxidation of amines into their corresponding imines with dioxygen is one of the most‐fundamental chemical transformations. Herein, we report the oxidation of a series of benzylic amines into their corresponding imines with atmospheric dioxygen as the oxidant on a surface of anatase TiO₂ under visible‐light irradiation (λ>420 nm). The visible‐light response of this system was caused by the formation of a surface complex through the adsorption of a benzylic amine onto the surface of TiO₂. From the analysis of products of specially designed benzylic amines, we demonstrated that a highly selective oxygenation reaction proceeds via an oxygen‐transfer mechanism to afford the corresponding carbonyl compound, whose further condensation with an amine would generate the final imine product. We found that when primary benzylic amines (13 examples), were chosen as the substrates, moderate to excellent selectivities for the imine products were achieved (ca. 38–94 %) in moderate to excellent conversion rates (ca. 44–95 %). When secondary benzylic amines (15 examples) were chosen as the substrates, both the corresponding imines and aldehydes were detected as the main products with moderate to high conversion rates (ca. 18–100 %) and lower selectivities for the imine products (ca. 14–69 %). When tribenzylamine was chosen as the substrate, imine (27 %), dibenzylamine (24 %), and benzaldehyde products (39 %) were obtained in a conversion of 50 %. This report can be viewed as a prototypical system for the activation of C? H bonds adjacent to heteroatoms such as N, O, and S atoms, and oxofuctionalization with air or dioxygen as the terminal oxidant under visible‐light irradiation using TiO₂ as the photocatalyst.     

Selective Functionalization of Aminoheterocycles by a Pyrylium Salt

The functionalization of aminoheterocycles by using a pyrylium tetrafluoroborate reagent (Pyry‐BF₄) is presented. This reagent efficiently condenses with a great variety of heterocyclic amines and primes the C?N bond for nucleophilic aromatic substitution. More than 60 examples for the formation of C?O, C?N, C?S, or C?SO₂R bonds are disclosed herein. In contrast to C?N activation through diazotization and polyalkylation, this method is characterized by its mild conditions and impressive functional‐group tolerance. In addition to small‐molecule derivatization, Pyry‐BF₄ allows the introduction of functional groups in a late‐stage fashion to furnish highly functionalized structures.     

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Diversity Oriented Clicking (DOC) is a unified click‐approach for the modular synthesis of lead‐like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving “diversity with ease”, by combining classic C?C π‐bond click chemistry with recent developments in connective SuFEx‐technologies. We showcase 2‐S ubstituted‐A lkynyl‐1‐S ulfonyl F luorides (SASFs) as a new class of connective hub in concert with a diverse selection of click‐cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click‐library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3‐ and 1,5‐dipoles; while reaction with cyclic dienes yields several three‐dimensional bicyclic Diels–Alder adducts. Growing the library to 278 discrete compounds through late‐stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well‐plates—demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.     

Distal Allylic/Benzylic C−H Functionalization of Silyl Ethers Using Donor/Acceptor Rhodium(II) Carbenes

Regio‐ and stereoselective distal allylic/benzylic C?H functionalization of allyl and benzyl silyl ethers was achieved using rhodium(II) carbenes derived from N‐sulfonyltriazoles and aryldiazoacetates as carbene precursors. The bulky rhodium carbenes led to highly site‐selective functionalization of less activated allylic and benzylic C?H bonds even in the presence of electronically preferred C?H bonds located α to oxygen. The dirhodium catalyst Rh₂(S‐NTTL)₄ is the most effective chiral catalyst for triazole‐derived carbene transformations, whereas Rh₂(S‐TPPTTL)₄ works best for carbenes derived from aryldiazoacetates. The reactions afford a variety of δ‐functionalized allyl silyl ethers with high diastereo‐ and enantioselectivity. The utility of the present method was demonstrated by its application to the synthesis of a 3,4‐disubstituted l ‐proline scaffold.     

Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope,Enantioselectivity, and Mechanism

SuFEx reactions, in which an S?F moiety reacts with a silyl‐protected phenol, have been developed as powerful click reactions. In the current paper we open up the potential of SuFEx reactions as enantioselective reactions, analyze the role of Si and outline the mechanism of this reaction. As a result, fast, high‐yielding, “Si‐free” and enantiospecific SuFEx reactions of sulfonimidoyl fluorides have been developed, and their mechanism shown, by both experimental and theoretical methods, to yield chiral products.     

The diiodine basicity scale: toward a general halogen-bond basicity scale

The new diiodine basicity scale pK_BI2 is quasi‐orthogonal to most known Lewis basicity scales (hydrogen‐bond, dative‐bond and cation basicity scales). The diiodine basicity falls in the sequence N>P≈Se>S>I≈O>Br>Cl>F for the iodine‐bond acceptor atomic site and SbO≈NO≈AsO>SeO>PO>SO>C?O>? O? >SO₂ or PS?? S? >C?S?N?C?S for the functionality of oxygen or sulfur bases. Substituent effects are quantified through linear free energy relationships, which allow the calculation of individual complexation constants for each site of polybases and thus the classification of aromatic ethers as carbon π bases and of aromatic amines, thioethers and selenoethers as N, S and Se bases, respectively. The pK_BI2 values of nBu₃N⁺‐N^?C≡N, 2‐aminopyridine and 1,10‐phenanthroline reveal a superbasic nitrile, a hydrogen‐bond‐assisted iodine bond and a two‐centre iodine bond, respectively. The diiodine basicity scale is a general inorganic but family‐dependent organic halogen‐bond basicity scale because organic halogen‐bond donors such as IC≡N and ICF₃ have a stronger electrostatic character than I₂. The family independence can be restored by the addition of an electrostatic parameter, either the experimental pK_BHX hydrogen‐bond basicity scale or the computed minimum electrostatic potential.     

Zinc‐catalyzed transformation of diarylphosphoryl azides to diarylphosphate esters and amides

We have developed a facile and efficient procedure for the synthesis of diarylphosphate esters and amides. Using Zn(acac)₂ as the catalyst, the reaction of diarylphosphoryl azides with aliphatic alcohols and phenols through an unusual P?N bond cleavage provided a number of diarylphosphate esters in good yields (22 examples, up to 94%). Additionally, various diarylphosphate amides were obtained from the corresponding amines in excellent yields as well (8 examples, up to 96%).     

A 1:1 molecular complex of bis(4‐aminophenyl) disulfide and 4‐aminothiophenol

The centrosymmetric crystal structure of the title complex, C₁₂H₁₂N₂S₂·C₆H₇NS, is built up of dimers of the constituent mol­ecules and stabilized by a herring‐bone geometry between the phenyl rings. The structure reveals an N—H?N—H?N—H?S co‐operative hydrogen‐bonded chain, and C—H?S and N—H?π hydrogen bonds. The S—H group forms an uncommon S—H?π interaction.     

An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

A new enantioselective palladium(II)‐catalyzed benzylic C?H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ‐C?H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL) phosphoric acid ligand, Cs₂CO₃, and solvent‐free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C?H palladation step.     

Barium‐Mediated Cross‐Dehydrocoupling of Hydrosilanes with Amines: A Theoretical and Experimental Approach

Alkaline‐earth (most prominently barium) complexes of the type [Ae{N(SiMe₃)₂}₂?(THF)_x] and [{N^N}Ae{N(SiMe₃)₂}?(THF)_x] are very active and productive precatalysts (TON=396, TOF up to 3600 h^?1; Ca相似文献   

Catalytic Reductive N‐Alkylations Using CO2 and Carboxylic Acid Derivatives: Recent Progress and Developments

N‐Alkylamines are key intermediates in the synthesis of fine chemicals, dyes, and natural products, and hence are highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient procedures for their production continues to attract the interest of both academic and industrial chemists. Reductive procedures such as reductive amination or N‐alkylation through hydrogen autotransfer by employing carbonyl compounds or alcohols as alkylating agents have prevailed for the synthesis of amines. In the last few years, carboxylic/carbonic acid derivatives and CO₂ have been introduced as alternative and convenient alkylating sources. The safety, easy accessibility, and high stability of these reagents makes the development of new reductive transformations with them as N‐alkylating agents a useful alternative to existing procedures. In this Review, we summarize reported examples of one‐pot reductive N‐alkylation methods that use carboxylic/carbonic acid derivatives or CO₂ as alkylating agents.     

Palladium‐Catalyzed Asymmetric Amination of Allenyl Phosphates: Enantioselective Synthesis of Allenes with an Additional Unsaturated Unit

A highly enantioselective Pd‐catalyzed amination of allenyl phosphates generating 2,3‐allenyl amines with central chirality has been developed. Under the optimized conditions, chiral 2,3‐allenyl amines with or without (an) additional C? C double or triple bond(s) have been prepared at 0 °C with up to 90 % yield and 94 % ee by identifying (R)‐3,4,5‐(MeO)₃‐MeOBIPHEP as the ligand.     

Reactions of Chlorosulfanyl Derivatives of Cyclobutanones with Different Nucleophiles

The reactions of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 2 ) with N, O, S, and P nucleophiles occur by substitution of Cl at the S‐atom. Whereas, in the cases of secondary amines, alkanols, phenols, thiols, thiophenols, and di‐ and trialkyl phosphates, the initially formed substitution products were obtained, the corresponding products with allyl and propargyl alcohols undergo a [2,3]‐sigmatropic rearrangement to give allyl and allenyl sulfoxides, respectively. Analogous substitution reactions were observed when 3‐chloro‐3‐(chlorodisulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 3 ) was treated with N, O, and S nucleophiles. The reaction of 3 with Et₃P led to an unexpected product via cleavage of the S? S bond (cf. Scheme 13). In the reactions of 2 with primary amines and H₂O, the substitution products react further via elimination of HCl to yield the corresponding thiocarbonyl S‐imides and the thiocarbonyl S‐oxide, respectively. Whereas the latter could be isolated, the former were not stable but could be intercepted by MeOH (Scheme 4) or adamantanethione (Scheme 5). The structures of some of the substitution products were established by X‐ray crystallography.     

Electron predators are hydrogen atom traps. Effects of aryl groups on N—Cα bond dissociations of peptide radicals

Effects of substituted aryl groups on dissociations of peptide aminoketyl radicals were studied computationally for model tetrapeptide intermediates GXD^?G where X was a cysteine residue that was derivatized by S‐(3‐nitrobenzyl), S‐(3‐cyanobenzyl), S‐(3,5‐dicyanobenzyl), S‐(2,3,4,5,6‐pentafluorobenzyl), and S‐benzyl groups. The aminoketyl radical was placed within the Asp amide group. Aminoketyl radicals having the S‐(3‐nitrobenzyl) group were found to undergo spontaneous and highly exothermic migration of the hydroxyl hydrogen atom onto the nitro group in conformers allowing interaction between these groups. Competing reaction channels were investigated for aminoketyl radicals having the S‐(3‐cyanobenzyl) and S‐(3,5‐dicyanobenzyl) groups, e.g. H‐atom migration to the C and N atoms of the C≡N group, migration to the C‐4 position of the phenyl ring, and dissociation of the radical‐activated N? C_α bond between the Asp and Gly residues. RRKM kinetic analysis on the combined B3LYP and ROMP2/6‐311++G(2d,p) potential energy surface indicated > 99% H‐atom transfer to the C≡N group forming a stable iminyl intermediate. The N? C_α bond dissociation was negligible. In contrast, peptides with the S‐(2,3,4,5,6‐pentafluorobenzyl) and S‐benzyl groups showed preferential N? C_α bond dissociation that outcompeted H‐atom migration to the C‐4 position and fluorine substituents in the phenyl ring. These computational results are used to suggest an alternative mechanism for the quenching effect on electron‐based peptide backbone dissociations of benzyl groups with electron‐withdrawing substitutents, as reported recently. Copyright © 2010 John Wiley & Sons, Ltd.     

KF/Al2O3‐Mediated N‐Alkylation of Amines and Nitrogen Heterocycles and S‐Alkylation of Thiols

KF/Al₂O₃ efficiently catalyzes N‐alkylation of heterocyclic, primary, and secondary amines and S‐alkylation of thiols with a variety of alkyl halides. The N‐alkylation and S‐alkylation adducts were produced in good to excellent yields and in short times.     

2,2‐Bis(ethoxycarbonyl)vinyl (BECV) as a Versatile Amine Protecting Group for Selective Functional‐Group Transformations

A 2,2‐Bis(ethoxycarbonyl) vinyl‐ (BECV) group was used for the selective protection of amines at room temperature in the presence of potentially interfering functional groups such as OH, SH, COOH as well as other NH₂ groups. Several functional group transformations such as esterification, O‐alkylation, O‐acylation, N‐alkylation, N‐acylation, S‐alkylation can selectively be carried out in the presence of the BECV group. The selective deprotection of the BECV group was achieved in a short time using ethylenediamine at room temperature while several other functional groups such as benzoate, aliphatic esters, amides and ethers remain intact. The BECV group shows orthogonal stability against the common protecting groups such as Fmoc, Cbz and Boc.