hydroxylamine-O-sulfonic Acid Research Articles

Development of a 2nd Generation Process for 3‐Ethyl‐4‐Hydroxy‐5‐Methylbenzonitrile – A Key Building Block of S1P1 Receptor Modulator Cenerimod – through a Non‐Classical Nitrile Formation Using Hydroxylamine‐O‐sulfonic Acid (HOSA)

AbstractA new, improved 2nd generation route for the synthesis of 3‐ethyl‐4‐hydroxy‐5‐methylbenzonitrile has been developed. The original route started from 2‐ethyl‐6‐methylaniline, which was converted by a classical sequence of para‐bromination, cyanation and Sandmeyer hydroxylation into the desired phenol. This route was used on multi‐kg scale and delivered the product with the desired purity. However, the route was not ideal, as it featured safety critical steps (cyanation), employed undesirable solvents (DMF), included laborious workup and isolation procedures, and suffered from a low overall yield (40–45 %) and suboptimal green metrics (PMI: 210). We envisioned a new, non‐classical approach to the product by introducing the nitrile through a para‐selective formylation, followed by transformation of the intermediate aldehyde into the nitrile with hydroxylamine‐O‐sulfonic acid (HOSA). The new sequence of Sandmeyer hydroxylation, Duff formylation and HOSA‐promoted nitrile formation was thoroughly optimized and finally scaled up to 400 g. This novel 3‐step sequence delivered 3‐ethyl‐4‐hydroxy‐5‐methylbenzonitrile in 69 % overall yield with excellent purity (99.3 % a/a) and a vastly improved PMI of 81.

Development of a Scalable Electrophilic Amination Protocol for the Multi-kg Production of 5-Methyl-2-pyridinesulfonamide: A Regulatory Starting Material of Endothelin Receptor Antagonist Clazosentan

5-Methyl-2-pyridinesulfonamide is a regulatory starting material of endothelin receptor antagonist clazosentan. The original route to the key sulfonamide relied on the textbook conversion of the corresponding thiophenol to the intermediate sulfonyl chloride followed by its quenching with aqueous ammonia. However, this route suffered from a wide range of issues such as a low overall yield (29%), challenging aqueous workups and isolations, and the formation of a genotoxic benzyl chloride impurity. Therefore, we developed a conceptually novel production route for 5-methyl-2-pyridinesulfonamide. The new process relied on selectively oxidizing the thiophenol to the intermediate sulfinate salt followed by an electrophilic amination of the nucleophilic sulfinate sulfur-atom with hydroxylamine-O-sulfonic acid (HOSA). This oxidation/electrophilic amination sequence worked as a “one-pot” procedure by simply adding HOSA to the reaction mixture after complete oxidation of the thiophenol with 70% aq. t-BuOOH. The process was extensively optimized with regard to the oxidation step, increasing the stability of HOSA in the reaction mixture, and the final isolation of 5-methyl-2-pyridinesulfonamide. The new process was performed on a 22 kg scale, delivering the desired product as a white solid in 69% overall yield and excellent purity (>99.9% a/a).

Cu-α-diimine Compounds Encapsulated in Porous Materials as Catalysts for Electrophilic Amination of Aromatic C-H Bonds.

Electrophilic amination has emerged as a more environmentally benign approach to construct arene C-N bonds. However, heterogeneous catalysts remain largely unexplored in this area, even though their use could facilitate product purification and catalyst recovery. Here we investigate strategies to heterogenize a Cu(2,2'-bipyridine) catalyst for the amination of arenes lacking a directing group with hydroxylamine-O-sulfonic acid (HOSA). Besides immobilization of Cu on a metal-organic framework (MOF) or covalent organic framework (COF) with embedded 2,2'-bipyridines, a ship-in-a-bottle approach was followed in which the Cu complex is encapsulated in the pores of a zeolite. Recyclability and hot centrifugation tests show that zeolite Beta-entrapped CuII(2,2'-bipyridine) is superior in terms of stability. With N-methylmorpholine as a weakly coordinating, weak base, simple arenes, such as mesitylene, could be aminated with yields up to 59%, corresponding to a catalyst TON of 24. The zeolite could be used in three consecutive runs without a decrease in activity. Characterization of the catalyst by EPR and XAS showed that the active catalytic complex consisted of a site-isolated CuII species with one 2,2'-bipyridine ligand.

Synthesis of Unsymmetrical 1,1’‐Bibenzimidazoles via an N‐Amination Reaction Forming the Key N‐N Bond

AbstractThe novel synthesis of unsymmetrical 1,1’‐bibenzimidazoles is described. The key N−N bond was introduced on 1H‐benzimidazole or 1H‐benzimidazole‐2‐sulfonic acid by N‐amination with hydroxylamine‐O‐sulfonic acid (HASA). The precursors, 1‐[(2‐nitrophenyl)amino]‐1H‐benzimidazoles, were prepared by nucleophilic aromatic substitution of 1‐fluoro‐2‐nitrobenzene with 1H‐benzimidazole‐1‐amines. The synthesis was demonstrated on 11 novel 1,1’‐bibenzimidazoles, which were prepared in the final step by one‐pot reduction/cyclization with DMF or DMA acetals under mild acidic conditions in good overall yields.

Site-selective amination and/or nitrilation via metal-free C(sp2)-C(sp3) cleavage of benzylic and allylic alcohols.

Benzylic/allylic alcohols are converted via site-selective C(sp2)–C(sp3) cleavage to value-added nitrogenous motifs, viz., anilines and/or nitriles as well as N-heterocycles, utilizing commercial hydroxylamine-O-sulfonic acid (HOSA) and Et3N in an operationally simple, one-pot process. Notably, cyclic benzylic/allylic alcohols undergo bis-functionalization with attendant increases in architectural complexity and step-economy.

Synthesis of semi-saturated polycyclic 1,2,4-triazoles from lactams

A two-step method for the preparation of annulated 1,2,4-triazoles has been developed via the hydroxylamine-O-sulfonic acid (HOSA)-mediated N-amination of readily available lactams followed by condensation with ethyl 2-ethoxy-2-iminoacetate. Various annulated ring sizes can be incorporated into the resulting polycyclic triazoles.

An Approximate Analytical Solution Of Nonlinear Equations In N-Aminopiperidine Synthesis: New Approach Of Homotopy Perturbation Method)

the synthesis of N-aminopiperidine (NAPP) using hydroxylamine-O-sulfonic acid (HOSA) is based on system of nonlinear rate equations. The new approach to homotopy perturbation method is applied to solve the nonlinear equations. A simple analytical expression for concentrations of hydroxylamine-O-sulfonique acid (HOSA), piperidine (PP), N-aminopiperidine (NAPP), sodium hydroxide (NaOH) and diazene (N2H2) along with NAPP yield is obtained and is compared with numerical result. Satisfactory agreement is obtained in the comparison of approximate analytical solution and numerical simulation. The obtained analytical result of NAPP yield is compared with the experimental results. The influence of reagents ratio p and rate constants ratio r on yield has been discussed.

Chemiluminescence assay for Listeria monocytogenes based on Cu/Co/Ni ternary nanocatalyst coupled with penicillin as generic capturing agent.

Bacterial pathogen control is important in seafood production. In this study, a Cu/Co/Ni ternary nanoalloy (Cu/Co/Ni TNA) was synthesized using the oleylamine reducing method. It was found that Cu/Co/Ni TNA greatly enhanced the chemiluminescence (CL) signal of the hydroxylamine-O-sulfonic acid (HOSA)-luminol system. The CL properties of Cu/Co/Ni TNA were investigated systemically. The possible CL mechanism also was intensively investigated. Based on the enhanced CL phenomenon of Cu/Co/Ni TNA, a Cu/Co/Ni TNA, penicillin, and anti-L. monocytogenes (Listeria monocytogenes) antibody-based sandwich complex assay for detection of L. monocytogenes was established. In this sandwich CL assay, penicillin was employed to capture and enrich pathogenic bacteria with penicillin-binding proteins (PBPs) while anti-L. monocytogenes antibody was adopted as the specific recognition molecule to recognize L. monocytogenes. L. monocytogenes was detected sensitively based on this new Cu/Co/Ni TNA-HOSA-luminol CL system. The CL intensity was proportional to the L. monocytogenes concentration ranging from 2.0 × 102 CFU ml-1 to 3.0 × 107 CFU ml-1 and the limit of detection wa 70 CFU ml-1 . The reliability and potential applications of our method was verified by comparison with official methods and recovery tests in environment and food samples.

Zinc(II)-Catalyzed Synthesis of Secondary Amides from Ketones via Beckmann Rearrangement Using Hydroxylamine-O-sulfonic Acid in Aqueous Media

A zinc(II)-catalyzed single-step protocol for the Beckmann rearrangement using hydroxylamine-O-sulfonic acid (HOSA) as the nitrogen source in water was developed. This direct method efficiently produces secondary amides under open atmosphere in a pure form after basic aqueous workup. It is environmentally benign and operationally simple.

Hydroxylamine‐O‐Sulfonic Acid (HOSA) as a Redox‐Neutral Directing Group: Rhodium Catalyzed, Additive Free, One‐Pot Synthesis of Isoquinolines from Arylketones

A new application of hydroxylamine‐O‐sulfonic acid (HOSA) has been discovered whereby aromatic ketones react with HOSA and alkynes to form isoquinolines in the presence of a RhIII catalyst. This C–H/N–O annulation methodology gives excellent yields even without any silver additive, acid/base or metal oxidant. This is the first report wherein a directing group is simultaneously forming in situ, acting as acid additive, and also as an internal oxidant.

Cu(OTf)2-catalyzed Beckmann Rearrangement of Ketones Using Hydroxylamine-O-sulfonic Acid (HOSA).

The Beckmann Rearrangement (BKR) of ketones to secondary amides often requires harsh reaction conditions that limit its practicality and scope. Herein, we describe the Cu(OTf)2-catalyzed BKR of ketones under mild reaction conditions using hydroxylamine-O-sulfonic acid (HOSA), a commercial water soluble aminating agent. This method is compatible with most functional groups and directly provides the desired amides in good to excellent yields.

Synthesis of 9-Substituted 2-Alkyl(aryl)imidazo-[1,2-a]benzimidazole-3-carbonitriles

A one-pot preparative synthesis of 9-substituted 2-alkyl(aryl)imidazo[1,2-a]benzimidazole-3-carbonitriles from the corresponding 3-carbaldehydes and hydroxylamine O-sulfonic acid has been developed.

Mismatched catalytic hairpin assembly coupling hydroxylamine-O-sulfonic acid as oxide for DNA assay

Catalytic hairpin assembly (CHA) is an enzyme-free amplification method that it has been proved to be useful in signal amplification. In this work, hydroxylamine-O-sulfonic acid (HOSA) is used as an oxide for LumAuNPs chemiluminescence (CL) in mismatched catalytic hairpin assembly (MCHA) for the first time. Functionally, this system consists of two hairpin species, the biotin-labeled hairpin H1 and LumAuNPs-labeled hairpin H2, which are stable and unable to hybridize in the absence of target DNA. However, the MCHA is initiated in the presence of target DNA, which regenerates the target DNA to catalyze another new cyclic reuse and leads to the formation of numerous H1-H2 complexes. In this case, HOSA serves as an oxidizing agent reacted with LumAuNPs, which can generate strong CL. In this fascinating hairpin assembly amplification strategy, mismatched base sequences are designed in hairpin H2 to decrease nonspecific CHA products, which reduce the background signal significantly. Under the optimal experimental conditions, this approach shows high selectivity even toward single-base mismatch and improves sensitivity greatly for target DNA with a linear range of 2.5 fM–1 pM, achieving a detection limit as low as 0.8 fM. The developed method holds a great promise for further applications in early clinical diagnosis and therapy.

ChemInform Abstract: Diastereoselective Synthesis of Substituted Diaziridines from Simple Ketones and Aldehydes.

Diastereopure substituted diaziridines from simple ketones, aldehydes and amines are here reported. These important chemical scaffolds are obtained in the presence of a weak inorganic base and hydroxylamine O-sulfonic acid (HOSA). This method introduces three stereocenters in one step to provide a wide variety of substituted diaziridines with high yields and diastereoselectivities.

Diastereoselective synthesis of substituted diaziridines from simple ketones and aldehydes.

Diastereopure substituted diaziridines from simple ketones, aldehydes and amines are here reported. These important chemical scaffolds are obtained in the presence of a weak inorganic base and hydroxylamine O-sulfonic acid (HOSA). This method introduces three stereocenters in one step to provide a wide variety of substituted diaziridines with high yields and diastereoselectivities.

Synthesis and molecular structure of (Z)-1H-purin-6-ylideneaminooxysulfonic acid: a possible secondary metabolite of adenine

Abstract The reaction of 6-chloropurine (1) with fourfold excess of hydroxylamine-O-sulfonic acid (HOSA) provided (Z)-1H-purin-6-ylideneaminooxysulfonic acid (2) which can be regarded as a secondary metabolite of ultimate mutagen 6-hydroxylaminopurine (6-HAP). A similar reaction of 1 with twofold excess of HOSA gave a mixture of the substrate and the betaine product which co-crystallized from DMF-methanol-water in the form of complex 3 that proved to be a 1:1 complex 1·2 with offset face-to-face π-stacking interactions between purine rings.

Amination of energetic anions: high-performing energetic materials

The new energetic materials 2-amino-5-nitrotetrazole (ANT, 1), 1-amino-3,4-dinitro-1,2,4-triazole (ADNT, 2), and both 1,1'-diamino-5,5'-bistetrazole and 1,2'-diamino-5,5'-bistetrazole (11DABT, 3 and 12DABT, 4) have been prepared by the amination of the parent anion with O-tosylhydroxylamine. The 5-H-tetrazolate anion has also been aminated using hydroxylamine O-sulfonic acid to both 1-aminotetrazole and 2-aminotetrazole (1AT, 5 and 2AT, 6). The prepared materials have been characterized chemically (XRD (1-4, 6·AtNO(2), 8), multinuclear NMR, IR, Raman) and as explosives (mechanical and electrostatic sensitivity) and their explosive performances calculated using the EXPLO5 computer code. The prepared N-amino energetic materials, which can also be used as new ligands for high energy-capacity transition metal complexes, exhibit high explosive performances (in the range of hexogen and octogen) and a range of sensitivities from low to extremely high.

Synthesis of aza-aromatic hydroxylamine- O-sulfonates and their application to tandem nucleophilic addition–electrophilic 5- endo- trig cyclization

Hydroxylamine- O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine- O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition–electrophilic 5- endo- trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G ∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine- O-sulfonates and N-(5-methoxy-2 H-[1,2,4]thiadiazolo[2,3- a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2 H-[1,2,4]thiadiazolo[3,2- a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC 50 in the range 1.47–2.97 μM).

Insights into regioselective oxy (-O-) and imino (-NH-) group insertions of 3-nortricyclanone.

Lactam 4-azatricyclo[3.2.1.0(2,7)]octan-3-one (16a) was proven to be formed in a previously reported reaction that claimed production of lactam 3-azatricyclo[3.2.1.0(2,7)]octan-4-one (17a). In a related reaction, bicyclo[3.1.0]hex-2-ene-endo-6-carbonitrile (15), lactam (16a), and novel hydroxycarbonitriles 19-21 were selectively formed when 3-nortricyclanone (1) was treated with aqueous hydroxylamine-O-sulfonic acid (HOSA). Since nitrile 15 neither hydrolyzed nor underwent intramolecular Ritter reaction under these conditions, mechanisms involving Beckmann rearrangement of 3 to nitrilium ion 9 (normal) and Beckmann fragmentation of 3 to cation 8 (abnormal) were investigated using semiempirical calculations. When alkaline HOSA was employed, lactams 16a and 17a were formed in a 1:2 ratio, perhaps via oxaziridine 6a. A similar selectivity was observed using an NH(3)/NaOCl reagent solution, which afforded lactone 4-oxatricyclo[3.2.1.0(2,7)]octan-3-one (16b) in addition to both lactams. Consequently, the Baeyer-Villiger oxidation of 1 with NaOCl gave 16b exclusively. Finally, the Schmidt reaction of ketone 1 gave only the lactam 17a, via cyclopropyl migration, and the same fragmentation products obtained from the acidic HOSA reaction. Migration selectivities are rationalized in terms of nucleofugacity, electronic effects, cyclopropyl regulation, and MO theory.

Enantioselective Synthesis of Brinzolamide (AL-4862), a New Topical Carbonic Anhydrase Inhibitor. The “DCAT Route” to Thiophenesulfonamides

A large scale synthesis of the topical carbonic anhydrase inhibitors AL-4623A (13a·HCl) and AL-4862 (13b) from 3-acetyl-2,5-dichlorothiophene (“DCAT”, 1) is described. Reaction of 1 with NaSBn gave thioether 2, which was converted via sulfenyl chloride 3 and sulfenamide 5 to sulfonamide 6. Bromination of 6 gave bromo ketone 7, which upon reduction with (+)-B-chlorodiisopinocampheylborane and cyclization of the resulting bromohydrin produced S thieno[3,2-e]-1,2-thiazine 8a (96% ee) after chromatography. Treatment of 8a in THF with n-BuLi at −70 °C resulted in Li−Cl exchange. Reaction of the thienyllithium with SO2 and hydroxylamine O-sulfonic acid afforded bis-sulfonamide 11a. Protection of 11a as the acetimidate 12a, followed by tosylation and amination, gave R amine 13a. The synthesis of 13b proceeded via primary sulfonamide 16, which was brominated, reduced, and cyclized to give S thieno[3,2-e]-1,2-thiazine 18 (>98% ee). By virtue of the ionizable NH, 18 was separable from reduction byproducts by base e...