Regio- and Enantioselective Synthesis of 1,2-Diamines by Formal Hydroamination of Enamines: Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis-Piperazines as a Privileged Scaffold.

We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the "click-type" synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1'-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.

Asymmetric Synthesis of Axially Chiral N, N-1,2-Pentatomic Heterobiaryl Diamines by an Organocatalytic Arylation Reaction.

The utilization of axially chiral biaryl diamines has been widely acknowledged as highly advantageous structures for the advancement of chiral catalysts and ligands. This highlights their extensive range of applications in asymmetric catalysis and synthesis. Herein, we devised a direct arylation reactions of 5-aminopyrazoles with azonaphthalenes, utilizing chiral phosphoric acid as the catalyst. This method delivers structurally novel atroposelective N, N-1,2-azole heteroaryl diamines with high yields (up to >98%) and good to excellent enantiomeric ratios while exhibiting a wide range of substrate compatibility.

Efficient recycling pathway of bio-based composite polyurethane foams via sustainable diamine.

Aminolysis is widely recognized as a valuable chemical route for depolymerizing polymeric materials containing ester, amide, or urethane functional groups, including polyurethane foams. Bio-based polyurethane foams, pristine and reinforced with 40 wt% of sustainable fillers, were depolymerized in the presence of bio-derived butane-1,4-diamine, BDA. A process comparison was made using fossil-derived ethane-1,2-diamine, EDA, by varying amine/polyurethane ratio (F/A, 1:1 and 1:0.6). The obtained depolymerized systems were analyzed by FTIR and NMR characterizations to understand the effect of both diamines on the degradation pathway. The use of bio-based BDA seemed to be more effective with respect to conventional EDA, owing to its stronger basicity (and thus higher nucleophilicity), corresponding to faster depolymerization rates. BDA-based depolymerized systems were then employed to prepare second-generation bio-based composite polyurethane foams by partial replacement of isocyanate components (20 wt%). The morphological, mechanical, and thermal conductivity properties of the second-generation polyurethane foams were evaluated. The best performances (σ10 %=71 ± 9 kPa, λ = 0.042 ± 0.015 W∙ m-1 ∙K-1) were attained by employing the lowest F/A ratio (1:0.6); this demonstrates their potential application in different sectors such as packaging or construction, fulfilling the paradigm of the circular economy.

Repurposing antiparasitic N,N'-aliphatic diamine derivatives as promising antimycobacterial agents.

In previous studies, we demonstrated the potent activity of a library of 25 N,N'-disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against Mycobacterium tuberculosis H37Rv and M. avium, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against M. smegmatis, a non-pathogenic species, and the non-tuberculosis mycobacteria M. abscessus, M. kansasii, and M. fortuitum. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against M. tuberculosis (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against M. smegmatis, M. kansasii, and M. fortuitum (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web-based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.

Risk assessment-based verification of the CertiPURTM limit values for toluene diamine and methylene dianiline in flexible polyurethane foam.

Flexible polyurethane foams (PUF) are used in many consumer products. PUF may contain trace levels of aromatic diamine impurities that could represent a potential health risk. The risk associated with sleeping on a PUF mattress was evaluated. Toxicity benchmarks for sensitization and non-cancer endpoints were derived from the respective points-of-departure using standard assessment factors. For the cancer endpoints, toxicity benchmarks were derived from the 25th-percentile values of animal studies. Recently published emission and migration data allowed to link exposure with the CertiPURTM voluntary quality limits of ≤5 mg.kg-1 for 2,4-toluene diamine and 4,4'-methylene dianiline in PUF. Using conservative exposure scenarios, lifetime-average daily internal doses from the combined inhalation and dermal exposures were calculated. Margins of safety for non-cancer and sensitization endpoints were >104. The theoretical excess cancer risk was ≤1.5 × 10-7. It is concluded that sleeping on a mattress that satisfies the CertiPUR limit value does not pose undue risk to consumers.

Ringing the Changes: Effects of Heterocyclic Ring Size on Stereoselectivity in [(η5-C5Me5)RhCl], [(η5-C5Me5)IrCl] and [Ru(η6-cymene)Cl] Complexes of Chiral 3-Amino-1-Azacycles.

Ring size-dependent diastereoselective coordination of unsymmetrical diamines containing one azacyclic nitrogen and one exocyclic nitrogen to [(η5-C5Me5)MCl]+ cores where M = Rh, Ir and [Ru(η6-cymene)Cl]+ is reported herein. Total stereoselectivity was observed with the six- and seven-membered azacycles, whereas the five-derivative proved poorly selective. All complexes were active for transfer hydrogenation but showed no enantioselectivity with prochiral ketones.

Enzymatic Desymmetrisation of Prochiral meso-1,2-Disubstituted-1,2-Diaminoethane for the Synthesis of Key Enantioenriched (-)-Nutlin-3 Precursor.

Herein we present the biocatalysed preparation of a mono-N-carbamate-protected precursor of antitumoral Nutlin-3a through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl, diethyl and dimethyl carbonates. The reactions were conducted at different temperatures, for different reaction times and with variable co-solvent systems to evaluate the effects on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) when conducting the reaction solventless at 75 °C.

Coordination Polymer Based on a Triangular Carboxylate Core {Fe(µ3-O)(µ-O2CR)6} and an Aliphatic Diamine.

Interaction of the pre-organized complex of iron(II) trimethylacetate and 1,10-phenanthroline (phen) [Fe2(piv)4(phen)2] (1) (piv = (Me)3CCO2-)) with 1,6-diaminohexane (dahx) in anhydrous acetonitrile yielded a 1D coordination polymer [Fe3O(piv)6(dahx)1.5]n (2) and an organic salt of pivalic acid (H2dahx)(piv)2 (3). The structure of the obtained compounds was determined by single-crystal X-ray diffraction analysis. The phase purity of the complexes was determined by powder X-ray diffraction analysis. According to the single-crystal X-ray analysis, coordination polymer 2 is formed due to the binding of a triangular carboxylate core {Fe3(µ3-O)(µ-piv)6} with an aliphatic diamine ligand. Thermal behavior was investigated for compounds 1 and 2 in an argon atmosphere.

Direct Asymmetric Synthesis of α-Aminoimines from 1,2-Bis-N-Sulfinylimines by Using Allyl Boronic Acids.

A unique direct asymmetric synthesis of α-aminoimines is realized, through rapid and exclusive mono-allylation of chiral bis-N-sulfinylimines using allylboronic acids. The highly selective allylation was possible as electrophilic imine functional group in the product α-aminoimines remained unreactive towards allyl boronic acid nucleophiles. Notably, by varying the geometry and chiral auxiliary, all four isomers of the α-aminoimines were accessed from readily available precursors. A range of allyl nucleophiles, which are tricky to generate by other means possessing highly reactive functional groups also took part in this reaction, expanding the scope further. The applicability of the products α-aminoimines were further demonstrated by accessing a range of structurally diverse chiral cyclic and acyclic 1,2-diamines bearing adjacent stereocenters through addition of a second nucleophile or Prins-type cyclization by exploiting the nucleophilicity of the tethered alkene moiety. Moreover, the leaving group aptitude of sulfinyl auxiliary attached to imine, was exploited to access valuable chiral α-aminonitriles under thermal conditions without employing any reagents. Detailed DFT calculation revealed a chair-like transition state, arising from corresponding allylboroxine species, likely operating for the allylboration reaction across imine.

Recombinant human diamine oxidase prevents hemodynamic effects of continuous histamine infusion in guinea pigs.

OBJECTIVE: To test whether recombinant human diamine oxidase (rhDAO) with a mutated heparin-binding motif (mHBM), which shows an increased alpha-distribution half-life, prevents histamine-induced hemodynamic effects. MATERIAL: Thirty-eight female guinea pigs were either pretreated with rhDOA_mHBM or buffer. TREATMENT AND METHODS: Guinea pigs received a continuous infusion of histamine. Heart rate (HR), body core temperature and mean arterial pressure (MAP) were measured and blood was collected. RESULTS: Continuous intravenous infusion of 8 µg/kg/min histamine increased mean peak plasma histamine levels from 5 (± 0.3 SEM) to 28 ng/mL (± 4.9 SEM) after 30 min but had no effect on oxygen saturation. Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean HR (p = 0.008), histamine plasma concentrations (p = 0.002), and higher body core temperatures at the end of the histamine challenge (p = 0.02) compared to controls. Cessation of histamine infusion led to a rebound increase in MAP, but this hemodynamic instability was prevented by rhDAO_mHBM. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p = 0.004) and 1-Methylhistamine (p < 0.0001) concentrations compared to controls. CONCLUSIONS: Prophylactic infusion of rhDAO_mHBM prevents hemodynamic effects in a guinea pig model of continuous histamine infusion. These findings might help in the translation from animals to humans and in the selection of the optimal dosing of rhDAO_mHBM during human histamine challenge studies.

Emission and time-resolved migration rates of aromatic diamines from two flexible polyurethane foams.

Performing risk assessments (RA) on household use of flexible polyurethane (PU) foams requires access to reliable data about emission and migration of potential diamine impurities. A toluene diisocyanate (TDI) and a methylene diphenyl diisocyanate (MDI) based foam were thermally treated to enable measurements on samples with defined concentrations of the corresponding diamines, toluene diamine (TDA), and methylene dianiline (MDA). The thermally treated foams used for emission testing contained up to 15 mg.kg-1 of TDA and 27 mg.kg-1 of MDA. Those used for migration testing contained 5.1 mg.kg-1 of TDA and 14.1 mg.kg-1 of MDA. Stability of the thermally generated diamines was sufficient for testing over a 37-day period. Analytical techniques that did not decompose the polymer matrix were applied. Emission rates for TDA and MDA isomers were less than the limit of quantitation (LOQ) of 0.008-0.07 µg.m-2.h-1. Migration was studied using samples of the same thermally treated foams over a 35-day period. Quantifiable migration of MDA from the MDI-based foam was only observed on Days 1 and 2. From Day 3 onward, migration rates were less than the LOQ. Quantifiable migration of TDA from the TDI-based foam rapidly decreased with time and was only observed on Days 1 thru 3. From Day 4 onward, migration rates were less than the LOQ. Theoretically, the migration rate should be inversely proportional to the square root of time (t) as t-0.5. This relationship was confirmed by the experimental data and enables extrapolating migration values to more extended time periods to conduct RAs.

Sampling chamber with minimal wall surface for simultaneous emission testing of diisocyanates and diamines from polyurethane products.

A sampling chamber was developed for emission testing of diisocyanates, methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), and corresponding diamines, methylene diphenyl diamine (MDA), and toluene diamine (TDA) from polyurethane (PU) product surfaces. In addition, a methodology for validation of the sampling chamber was presented, based on the introduction of generated standard atmospheres of the different diisocyanates and diamines to the sampling chamber system. Sampling of diisocyanates and diamines was performed on a circular glass fiber filter (150 mm diameter) impregnated with dihexyl amine (DHA) and acetic acid (AA) positioned inside a cylindrical stainless steel sampling chamber. The diisocyanates were immediately derivatized to DHA derivatives, and the amines were derivatized in a subsequent work-up procedure with ethyl chloroformate (ECF). The design of the sampling chamber and the presented methodology allowed for simultaneous sampling and analysis of diisocyanates and diamines of emission from a large surface area with minimal interior wall interaction in the sampling chamber. Performance characteristics of the sampling chamber for different sampling times and air humidity were obtained by determining collected amounts of the diisocyanates and diamines in the different parts of the sampling chamber. The repeatability of the collected amount on the impregnated filters in the sampling chamber was 15% with an overall recovery for 8 h of sampling in the range of 61% to 96%. The performance of the sampling chamber was not affected by air humidity (5%-75% RH), and no breakthrough during sampling was observed. LC-MS/MS determinations allowed for emission testing of diisocyanates and diamines on product surfaces as low as 10-30 ng m-2 h-1.

New Fluorine-Containing Diamine Monomers for Potentially Improved Polyimides.

Two new fluorine-containing diamine monomers were designed with the goal of reducing charge transfer complex (CTC) interactions between neighboring chains in polyimides (i.e., high transparency/low color) while hopefully maintaining the well-known thermal stability and flexibility generally associated with polyimides. The proposed diamines have been prepared through (1) the functionalization of 1,3-bis[(pentafluorobenzyl)oxy]benzene with 4-aminophenol and (2) the addition of 2-chloro-5-nitrobenzotrifluoride to 4,4'-bicyclohexanol followed by reduction of the resulting dinitro compound. The new compounds have been characterized by multinuclear NMR and IR spectroscopy and high-resolution liquid chromatography-mass spectrometry as well as single-crystal X-ray diffraction on the new diamine prepared from 4,4'-bicyclohexanol. Not only was the structure of the proposed new diamine confirmed, but another interesting example of hydrogen bonding between an N-H proton and the π-system of an aromatic ring was observed and documented. Initial polymerizations have been carried out via the two-step imidization process.

Synthesis of Six-Membered N-Heterocyclic Carbene Precursors Based on Camphor.

The endo- and exo-N-heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1S)-(+)-ketopinic acid. The obtained N-heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.

Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of ß-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of ß-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.

Transforming Inert Cycloalkanes into α,ω-Diamines by Designed Enzymatic Cascade Catalysis.

Aliphatic α,ω-diamines (DAs) are important monomer precursors that are industrially produced by energy-intensive, multistage chemical reactions that are harmful to the environment. Therefore, the development of sustainable green DA synthetic routes is highly desired. Herein, we report an efficient one-pot in vivo biocatalytic cascade for the transformation of cycloalkanes into DAs with the aid of advanced techniques, including the RetroBioCat tool for biocatalytic route design, enzyme mining for finding appropriate enzymes and microbial consortia construction for efficient pathway assembly. As a result, DAs were successfully produced by the designed microbial consortia-based biocatalytic system. In particular, the highest biosynthesis productivity record of 1,6-hexanediamine was achieved when using either cyclohexanol or cyclohexane as a substrate. Thus, the developed biocatalytic process provides a promising alternative to the dominant industrial process for manufacturing DAs.

Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines via Reductive Coupling of Ketimines Templated by Chiral Diborons.

We herein describe the chiral diboron-templated asymmetric homocoupling of aryl alkyl ketimines, providing for the first time a series of chiral vicinal tetrasubstituted diamines with excellent ee values and good to high yields. The powerful and efficient diboron-participated [3,3]-sigmatropic rearrangement is successfully demonstrated by the homocoupling of a variety of ketimines thanks to the rational design and engineering of chiral diborons. Systematic DFT studies suggest that two chiral diborons adopt different conformational assembling strategies to couple the diboron template with ketimine substrates in their tight concerted transition states to ensure the excellent enantioselectivities. The synthetic value of chiral vicinal tetrasubstituted diamines is demonstrated by the asymmetric α-bromination of aliphatic aldehydes by employing a chiral vicinal tetrasubstituted diamine-based organocatalyst.

Iridium(III)-Catalyzed Intermolecular C(sp3 )-H Amidation for the Synthesis of Chiral 1,2-Diamines.

Chiral 1,2-diamines are privileged scaffolds among bioactive natural products, active pharmaceutical ingredients, ligands for transition-metal-based asymmetric catalysis and organocatalysts. Despite this interest, the construction of chiral 1,2-diamine motifs still remains a challenge. To address this, an iridium(III)-catalyzed intermolecular C(sp3 )-H amidation reaction was developed. This method relies on the design of a new, cheap and cleavable exo-protecting/directing group derived from camphorsulfonic acid, which is directly installed from easily accessible precursors, and furnishes scalemic free 1,2-diamines upon cleavage of both nitrogen substituents. It was found applicable to both α-secondary and α-tertiary-1,2-diamines, for which a two-step protocol involving intermolecular olefin hydroamination and C(sp3 )-H amidation was developed. Kinetic and computational studies provided insights into the observed reactivity difference between pairs of diastereoisomeric substrates.

Enantioselective 1,3-Dipolar Cycloaddition Using (Z)-α-Amidonitroalkenes as a Key Step to the Access to Chiral cis-3,4-Diaminopyrrolidines.

The enantioselective 1,3-dipolar cycloaddition between imino esters and (Z)-nitroalkenes bearing a masked amino group in the ß-position was studied using several chiral ligands and silver salts. The optimized reaction conditions were directly applied to the study of the scope of the reaction. The determination of the absolute configuration was evaluated using NMR experiments and electronic circular dichroism (ECD). The reduction and hydrolysis of both groups was performed to generate in an excellent enantiomeric ratio the corresponding cis-2,3-diaminoprolinate.

Determination of Residual Diisocyanates and Related Diamines in Biodegradable Mulch Films Using N-Ethoxycarbonylation Derivatization and GC-MS.

Diisocyanates are highly reactive compounds with two functional isocyanate groups. The exposure of diisocyanates is associated with severely adverse health effects, such as asthma, inflammation in the respiratory tract, and cancer. The hydrolysis product from diisocyanates to related diamines is also a potential carcinogen. Here, we developed an effective, accurate, and precise method for simultaneous determination of residual diisocyanates and related diamines in biodegradable mulch films, based on N-ethoxycarbonylation derivatization and gas chromatography-mass spectrometry. The method development included the optimization of ultrasonic hydrolysis and extraction, screening of N-ethoxycarbonylation conditions with ethyl chloroformate, evaluation of the diamines degradation, and analysis of the fragmentation mechanisms. Under the optimum experimental conditions, good linearity was observed with R2 > 0.999. The extraction recoveries were found in the range of 93.9−101.2% with repeatabilities and reproducibilities in 0.89−8.12% and 2.12−10.56%, respectively. The limits of detection ranged from 0.0025 to 0.057 µg/mL. The developed method was applied to commercial polybutylene adipate co-terephthalate (PBAT) biodegradable mulch film samples for analysis of the diverse residual diisocyanates and related diamine additives. The components varied greatly among the sample from different origin. Overall, this study provides a reliable method for assessing safety in biodegradable mulch films.