N-tosyl Hydrazones Research Articles

N‐Tosylhydrazones as [N,N] Synthons in Heterocyclic Chemistry: Synthesis of 3,5‐Disubstituted N‐Alkenyl‐1H‐pyrazoles

AbstractA new mode of reactivity of N‐sulfonylhydrazones towards alkynes is described: ketone‐derived N‐tosylhydrazones (NTHs) bearing α‐H atoms behave as [NN] synthons in their reactions with alkoxy alkynyl Fischer carbene complexes (FCCs) and only the two N atoms are incorporated into the newly formed pyrazole ring. The scope of the reaction, leading to 5‐methoxy‐N‐alkenyl pyrazoles, proved to be wide regarding both partners; thus, a variety of aryl and primary, secondary, and tertiary alkyl substituents are tolerated within the FCC, while aryl alkyl NTHs, symmetric and asymmetric dialkyl NTHs and NTHs derived of cyclic ketones can be also employed. In addition, the reaction can be performed at large scale and applied for late‐stage diversification of natural products. A reasonable reaction mechanism is also proposed, which is supported by deuteration experiments and DFT calculations.

N-Heterocyclic Carbene-Catalyzed Facile Synthesis of Phthalidyl Sulfonohydrazones: Density Functional Theory Mechanistic Insights and Docking Interactions.

N-heterocyclic carbene catalysis reaction protocol is disclosed for the synthesis of phthalidyl sulfonohydrazones. A broad range of N-tosyl hydrazones react effectively with phthalaldehyde derivatives under open-air conditions, enabling the formation of a new C-N bond via an oxidative path. The reaction proceeds under mild reaction conditions with broad substrate scopes, wide functional group tolerance, and good to excellent yields. The mechanistic pathway is studied successfully using control experiments, competitive reactions, ESI-MS spectral analyses of the reaction mixture, and computational study by density functional theory. The potential use of one of the phthalidyl sulfonohydrazone derivatives as the inhibitor of β-ketoacyl acyl carrier protein synthase I of Escherichia coli is investigated using molecular docking.

Convenient access to amidines by mesoionic singlet palladium carbene catalyzed hydrazone-isocyanide-amine (HIA) coupling: Scope and mechanistic insights

Facile synthesis of amidines 5(a-j), 6(a-g) and 7(a-j) by the tandem three-component coupling of N-tosylhydrazones, isocyanides and amines catalysed by the molecular binuclear Pd mesoionic singlet carbene complexes namely, [(R)-1,1′-(C10H6)2–2,2′-(OCH2(1-CH2Ph-3-R-1,2,3-triazol-5-ylidene))2]Pd2I4(NC5H5)2 [R = Me (4a) and Et (4b)] was achieved in good to excellent yields of ca. 51–97% at a low catalyst loading of 0.5 mol% in 6 h of the reaction time. A large opportunity for the utility of this coupling reaction was evident from its broader substrate scope arising from the use of a wide range of N-tosyl hydrazones, amines, and aromatic as well as aliphatic isocyanides. Combined experimental and computational studies performed on the representative substrates namely, PhCHNNHTs, 2,6-Me2C6H3NC, and morpholine indicated that the catalysis proceeded via the formation of palladium (0) active species [(R)-1,1′-(C10H6)2–2,2′-(OCH2(1-CH2Ph-3-R-1,2,3-triazol-5-ylidene))2]Pd2(2,6-Me2C6H3NC)2 [R = Me (B1), Et (B2)] alongside the generation of a ketenimine intermediate 2,6-Me2C6H3NCCHPh in the tricomponent coupling reaction. The dinitrogen elimination from the metal-coordinated diazo intermediate represents the rate-determining step of the reaction. The mechanistic revelations brought forth in this study hold promising potential for enriching our understanding of multi-component reactions leading to amidines enabled by transition metal catalysts.

N-Heterocyclic Carbene-Catalyzed Aza-Michael-Mannich-Lactamization Cascade for the Enantioselective Synthesis of Pyrazoloquinolin-3-ones.

The enantioselective synthesis of functionalized pyrazoloquinolin-3-ones via N-heterocyclic carbene-catalyzed cascade reaction of α-bromoenals with 2-aminoaryl N-tosyl hydrazones is reported. The in situ-generated α,β-unsaturated acylazoliums underwent an aza-Michael-Mannich-lactamization sequence to afford the tricyclic products bearing three contiguous stereocenters, including a sterically demanding quaternary stereocenter with high enantioselectivity. The unprotected amine-triggered aza-Michael pathway over the competing amidation pathway is noteworthy.

Copper-catalyzed tandem cyclization/arylation of α,β-alkynic hydrazones with diaryliodonium salts: synthesis of N-arylpyrazoles.

A copper-catalyzed efficient method for the synthesis of a diverse variety of substituted N-aryl pyrazoles from readily available α,β-alkynic N-tosyl hydrazones and diaryliodonium triflates is realized. This one-pot multi-step methodology features a broad scope with good yields, scalability, and appreciable functional group tolerance. Detailed control experiments reveal that the reaction proceeds through tandem cyclization/deprotection/arylation events where the copper catalyst plays a distinct role.

Pd-Catalyzed Coupling of N-Tosylhydrazones with Benzylic Phosphates: Toward the Synthesis of Di- or Tri-Substituted Alkenes

This study shows that various di- and tri-substituted alkenes with high chemoselectivity were obtained in good to high yields by coupling N-tosylhydrazones (NTHs) with benzylic phosphates as electrophilic partners. The obtained new catalytic system consisted of PdCl2(CH3CN)2/dppp, LiOtBu as a base, and cyclopentyl methyl ether as a green solvent. In addition, we performed a gram-scale transformation using NTH derivatives and benzylic phosphates having a C sp2-Cl bond. The latter was used as a starting point for further postfunctionalization of the key intermediates.

Copper-catalyzed sulfonylation of N-tosylhydrazones followed by a one-pot C-N bond formation.

A new methodology to synthesize sulfonyl-N-phenylaniline derivatives via the trapping of bromo-sulfone derivatives generated from N-tosylhydrazones (NTHs) with amines is described. The reaction proved successful for a wide range of NTHs and amines and tolerated various functional groups on either coupling partner (35 examples). The mechanism was studied, and we showed that the sulfone formation does not follow a radical pathway.

Ferrocene containing N-tosyl hydrazones as optical and electrochemical sensors for Hg2+, Cu2+ and F− ions

Ferrocene containing N-tosyl hydrazones as selective and sensitive optical and electrochemical chemosensors were synthesized and characterized by 1H NMR, 13C NMR, ESI-MS and X-ray analysis. The cation and anion binding studies were carried out using various techniques including electrochemistry, UV–vis and 1H NMR spectroscopy. Chemosensors 2a and 2b have shown excellent selective recognition toward Hg2+, Cu2+ and F− through optical and electrochemical signals. The color of 2a and 2b in solution changed visibly from pale yellow to red upon addition of Hg2+ion, while the color of solution changed from pale yellow to yellow green upon addition of Cu2+, which can be easily detected by the naked eye.

Palladium-catalyzed cascade reactions of alkene-tethered carbamoyl chlorides with N-tosyl hydrazones: synthesis of alkene-functionalized oxindoles.

A palladium-catalyzed cascade reaction of alkene-tethered carbamoyl chlorides with N-tosyl hydrazones is described. It provided a new way to synthesize various alkene-functionalized oxindoles bearing an all-carbon quaternary center. The olefin moieties could serve as versatile handles for further elaboration. This transformation was highly efficient and showed good functional group tolerance.

Asymmetric Copper-Catalyzed C(sp)–H Bond Insertion of Carbenoids Derived from N-Tosylhydrazones

A chiral copper(I)–phosphoramidite complex efficiently catalyzed the asymmetric insertion of the carbenoids derived from N-tosyl hydrazones into alkyne C–H bonds to give the corresponding chiral alkynylated products in up to 77% yield and with up to 74% ee.

Palladium-catalyzed heck-type cascade cyclization of (Z)-1-iodo-1,6-dienes with N-tosyl hydrazones.

A palladium-catalyzed heck-type cascade cyclization of (Z)-1-iodo-1,6-dienes with N-tosyl hydrazones is reported. The alkylpalladium intermediate coupled with the diazo compound, generating the second alkylpalladium species bearing two β-H, which generated a terminal alkene as the major products in the anti-Zaitsev way via the highly regioselective β-H elimination. It provided a new way to synthesize tetrahydropyridine derivatives bearing a terminal alkene.

One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines.

A new, three-step, telescoped reaction sequence for the regioselective conversion of N-tosyl hydrazones and aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines is described. The process involves an efficient nucleophilic ring opening of the aziridine, giving access to a wide range of aminohydrazones, isolated with excellent yields. A "one-pot" procedure, combining the ring opening with a cyclization and an oxidation step, allows the preparation of diversified triazines in good yields.

Catalytic 1,2-dihydronaphthalene and E-aryl-diene synthesis via CoIII-Carbene radical and o-quinodimethane intermediates.

Catalytic synthesis of substituted 1,2-dihydronaphthalenes via metalloradical activation of o-styryl N-tosyl hydrazones ((E)-2-(prop-1-en-1-yl)benzene-N-tosyl hydrazones) is presented, taking advantage of the intrinsic reactivity of a cobalt(iii)-carbene radical intermediate. The method has been successfully applied to a broad range of substrates with various R1 substituents at the aromatic ring, producing the desired ring products in good to excellent isolated yields for substrates with an R2 = COOEt substituent at the vinylic position (∼70-90%). Changing the R2 moiety from an ester to other substituents has a surprisingly large influence on the (isolated) yields. This behaviour is unexpected for a radical rebound ring-closure mechanism, and points to a mechanism proceeding via ortho-quinodimethane (o-QDM) intermediates. Furthermore, substrates with an alkyl substituent on the allylic position reacted to form E-aryl-dienes in excellent yields, rather than the expected 1,2-dihydronaphthalenes. This result, combined with the outcome of supporting DFT calculations, strongly points to the release of reactive o-QDM intermediates from the metal centre in all cases, which either undergo a 6π-cyclisation step to form the 1,2-dihydronaphthalenes, or a [1,7]-hydride shift to produce the E-aryl-dienes. Trapping experiments using TEMPO confirm the involvement of cobalt(iii)-carbene radical intermediates. EPR spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) confirm the radical nature of the catalytic reaction.

Two N-Tosyl Hydrazones Joined Together by the Hand of Sulfur

Two N-Tosyl Hydrazones Joined Together by the Hand of Sulfur

ChemInform Abstract: CoIII—Carbene Radical Approach to Substituted 1H‐Indenes.

ChemInformVolume 47, Issue 51 Isocyclic Compounds ChemInform Abstract: CoIII—Carbene Radical Approach to Substituted 1H-Indenes. Braja Gopal Das, Braja Gopal Das Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorAndrei Chirila, Andrei Chirila Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorMoniek Tromp, Moniek Tromp Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorJoost N. H. Reek, Joost N. H. Reek Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorBas de Bruin, Bas de Bruin Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this author Braja Gopal Das, Braja Gopal Das Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorAndrei Chirila, Andrei Chirila Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorMoniek Tromp, Moniek Tromp Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorJoost N. H. Reek, Joost N. H. Reek Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this authorBas de Bruin, Bas de Bruin Van′t Hoff Inst. Mol. Sci., Univ. Amsterdam, NL-1098 XH Amsterdam, Neth.Search for more papers by this author First published: 05 December 2016 https://doi.org/10.1002/chin.201651103Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue51December, 2016 RelatedInformation

Multicomponent Coupling Reactions of Two N-Tosyl Hydrazones and Elemental Sulfur: Selective Denitrogenation Pathway toward Unsymmetric 2,5-Disubstituted 1,3,4-Thiadiazoles.

A copper-mediated, three-component reaction between two different N-Ts hydrazones and elemental sulfur was developed, leading to a series of unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles in moderate yields with good functional group compatibility. This procedure features the employment of elemental sulfur and the selective denitrogenation between aryl and alkyl aldehyde N-tosyl hydrazones, allowing rapid access to unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles frameworks with chemical diversity and complexity.

Co(III)-Carbene Radical Approach to Substituted 1H-Indenes.

A new strategy for the catalytic synthesis of substituted 1H-indenes via metalloradical activation of o-cinnamyl N-tosyl hydrazones is presented, taking advantage of the intrinsic reactivity of a Co(III) carbene radical intermediate. The reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of functionalized 1H-indene derivatives. The cheap and easy to prepare low spin cobalt(II) complex [Co(II)(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene) proved to be the most active catalyst among those investigated, which demonstrates catalytic carbene radical reactivity for a nonporphyrin cobalt(II) complex, and for the first time catalytic activity of [Co(II)(MeTAA)] in general. The methodology has been successfully applied to a broad range of substrates, producing 1H-indenes in good to excellent yields. The metallo-radical catalyzed indene synthesis in this paper represents a unique example of a net (formal) intramolecular carbene insertion reaction into a vinylic C(sp(2))-H bond, made possible by a controlled radical ring-closure process of the carbene radical intermediate involved. The mechanism was investigated computationally, and the results were confirmed by a series of supporting experimental reactions. Density functional theory calculations reveal a stepwise process involving activation of the diazo compound leading to formation of a Co(III)-carbene radical, followed by radical ring-closure to produce an indanyl/benzyl radical intermediate. Subsequent indene product elimination involving a 1,2-hydrogen transfer step regenerates the catalyst. Trapping experiments using 2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) radical or dibenzoylperoxide (DBPO) confirm the involvement of cobalt(III) carbene radical intermediates. Electron paramagnetic resonance spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) reveal the radical nature of the reaction.

ChemInform Abstract: Palladium‐Catalyzed Three‐Component Reaction of N‐Tosyl Hydrazones, Isonitriles and Amines Leading to Amidines.

A palladium-catalyzed three-component reaction between N-tosyl hydrazones, aryl isonitriles and amines was developed, leading to amidines in moderate to good yields. This procedure features the rapid construction of amidine frameworks with high diversity and complexity. Ketenimines serve as intermediates, which encounter nucleophilic attack by amines to produce amidines.

Palladium-catalyzed three-component reaction of N-tosyl hydrazones, isonitriles and amines leading to amidines

A palladium-catalyzed three-component reaction between N-tosyl hydrazones, aryl isonitriles and amines was developed, leading to amidines in moderate to good yields. This procedure features the rapid construction of amidine frameworks with high diversity and complexity. Ketenimines serve as intermediates, which encounter nucleophilic attack by amines to produce amidines.

Copper-catalyzed aerobic oxidative transformation of ketone-derived N-tosyl hydrazones: an entry to alkynes.

A novel strategy involving Cu-catalyzed oxidative transformation of ketone-derived hydrazone moiety to various synthetic valuable internal alkynes and diynes has been developed. This method features inexpensive metal catalyst, green oxidant, good functional group tolerance, high regioselectivity and readily available starting materials. Oxidative deprotonation reactions were carried out to form internal alkynes and symmetrical diynes. Cross-coupling reactions of hydrazones with halides and terminal alkynes were performed to afford functionalized alkynes and unsymmetrical conjugated diynes. A mechanism proceeding through a Cu-carbene intermediate is proposed for the CC triple bond formation.