Reaction of 1,2‐Dialkyldiaziridines and 1,2,3‐Trialkyldiaziridines with Methyl Propiolate in Ionic Liquids and in Organic Solvents

An interaction of 1,2‐dialkyldiaziridine and 1,2,3‐trialkyldiaziridine with methyl propiolate was studied both in organic solvent (MeCN, CH₂Cl₂, C₆H₆) and in ionic liquids. Earlier unknown linear structures, in which three molecules of methyl propiolate were suited to one diaziridine molecule (adducts 1 : 3), were obtained in MeCN. The diaziridine ring expansion products 1,2,3,4‐tetrahydropyrimidine derivatives (adducts 1 : 2) and, along with them in some cases, the same linear structures were obtained in ionic liquids. A mechanism of reactions found was offered. The regioselectivity of reactions was supposed to determine by the structure of substituents in initial diaziridines. This conclusion was supported by quantum chemical calculations.     

Mass spectrometry of diaziridines: 1—Rearrangements of the molecular ion of 1-benzyl-3,3-dimethyldiaziridine and identification of some daughter ions using collisional activation

Intense rearrangement processes involving migrations of hydrogen atoms and the phenyl group were observed in the electron impact induced fragmentation of 1-benzyl-3,3-dimethyldiaziridine. The following ions are observed: (i) m/z 146: a two-step fragmentation involving hydrogen transfer followed by loss of NH₂; (ii) m/z 119: C—N¹ bond fission followed by a 1–4 phenyl shift and loss of CH₃N₂; (iii) m/z 106: a process involving reciprocal hydrogen migration between the methyl and benzylic methylene groups; (iv) m/z 58: hydrogen transfer from benzylic methylene and subsequent loss of PhCHN. The origin of these ions has been confirmed by measurements of metastable transitions in 1-benzyl-3,3-dimethyldiaziridine, and on specifically deuterated and substituted diaziridines. The structure of the ions at m/z 119 and m/z 106 has been deduced by means of collisional activation spectrometry.     

Glycosylidene Carbenes,Part 30 , Crystal Structure of a Glucose‐Derived N,N‐Unsubstituted Alkoxydiaziridine

The crystal structure of 1,5‐anhydro‐2,3,4,6‐tetra‐O‐benzyl‐1‐hydrazi‐D ‐glucitol ( 2 ) is reported and compared with the structures of other diaziridines. It is the first crystal structure of an N,N‐unsubstituted diaziridine, noncoordinated at the N‐atom, and the first crystal structure of a C‐alkoxy‐diaziridine. Although there is considerable shortening of the C(5)O−C(1) bond, there is no asymmetry in the C(1)−N bond length, the C(5)O, C(1), C(2) plane bisecting the N−N bond. The C(1)−N bonds appear to be slightly shorter and the N−N bond longer than the average for diaziridines, although the structural data for diaziridines do not lend themselves to unequivocal interpretation.     

3-Cyclopropyl-1,2-dimethyldiaziridine: synthesis and study of molecular structure by gas electron diffraction method

The molecular structure and conformational behavior of 3-cyclopropyl-1,2-dimethyldiaziridine have been for the first time experimentally studied by gas-phase electron diffraction and quantum chemical calculations. The two most stable conformers at 298 K possess anti and gauche mutual ring orientation (with prevalence of the anti conformer) whereas only one anti conformer is observed in solution. The determined structural parameters of gaseous 3-cyclopropyl-1,2-dimethyldiaziridine have been compared with those for 3,3-bidiaziridine structural analogues in the crystal phase. The simple and convenient procedure for the synthesis of 3-cyclopropyl-1,2-dimethyldiaziridine comprising cyclopropane and diaziridine rings in one molecule was developed. The standard enthalpy of formation of 3-cyclopropyl-1,2-dimethyldiaziridine in the gas phase was calculated using Gaussian-4 theory, yielding value of 281.9?±?5.0 kJ/mol.     

First synthesis of 1,5-diazabicyclo[3.1.0]hexane complexes with cadmium salts

Complexes of bicyclic diaziridines 6,6′-bi(1,5-diazabicyclo[3.1.0]hexane) (L ¹ ) and 6-(4-methoxyphenyl)-1,5-diazabicyclo[3.1.0]hexane (L ² ) with the salts Cd(NO₃)₂ · 4H₂O and Cd(ClO₄)₂ · 6H₂O have been synthesized. The fact of complexation has been established by cyclic voltammetry. The crystal structure of complex L ¹ with Cd(NO₃)₂ (the coordination number of cadmium is 8) has been studied by X-ray diffraction.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen atoms—XX: The NMR spectra and stereochemistry of some hexahydropyrido[2, 1-c] [1, 4] oxazin-3(4H)-ones and related compounds

A series of substituted hexahydropyrido [2,1-c] [1,4] oxazin-3(4H)-ones has been synthesised, and the configurations of these bicyclic lactones assigned utilising chemical and spectral data. All the compounds adopt trans-fused conformations and the conformation of the lactone ring is discussed with reference to the magnitude of the geminal coupling constant of the N? CH₂? C(O)? O protons, and the vicinal couplings between the angular proton and the methylene protons adjacent to the ring oxygen atom. The lactone ring conformation is shown to differ slightly from the half chair conformation described for some monocyclic δ -lactones. The synthesis and NMR spectra of some related compounds possessing the bridgehead N? CH₂? C(O)? O system are discussed and these compounds are also shown to adopt a trans-fused ring conformation.     

Diastereoselective synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes

A general method was developed for the synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes via intramolecular aminomethylation of the NH group of the diaziridine ring by the reactions of 3-aminomethyl-1,3-dimethyldiaziridine with aliphatic, aromatic, and heteroaromatic carbonyl compounds. These reactions with aldehydes proceeded diastereoselectively to form mixtures of two racemates, viz., 1R*,2R*,5R*,6R* and 1R*,2S*,5R*,6R*, in a ratio of (3—20) : 1, the predominant diastereomer being isolated in all cases. The reactions with symmetrical ketones gave rise exclusively to the (1R*,5R*,6R*) racemate. The predominant diastereomer 1R*,2R*,5R*,6R*-2-(2-bromothien-5-yl)-1,3,6-triazabicyclo[3.1.0]hexane crystallized as a conglomerate. The structure of one of its enantiomers was established by X-ray diffraction analysis.     

New Trends in Diaziridine Formation and Transformation (a Review)

This review focuses on diaziridine, a high strained three-membered heterocycle with two nitrogen atoms that plays an important role as one of the most important precursors of diazirine photoaffinity probes, as well as their formation and transformation. Recent research trends can be grouped into three categories, based on whether they have examined non-substituted, N-monosubstituted, or N,N-disubstituted diaziridines. The discussion expands on the conventional methods for recent applications, the current spread of studies, and the unconventional synthesis approaches arising over the last decade of publications.     

Preparative separations and racemizations of enantiomeric diaziridines

Preparative separations or enrichments of enantiomers of diaziridines 1, 2, and 5 were achieved by liquid chromatography on triacetylcellulose, (+)-1 and (+)-2 being isolated almost pure (Table 1). Enantiomeric purities were determined by ¹H NMR in the presence of the optically active auxiliary compound (+)-Eu(hfbc)₃. The barriers to nitrogen inversion in 1 and 4 were determined and its lower limit in the nitrogen unsubstituted diaziridine 3 was estimated.     

Highly Diastereo‐ and Enantioselective Aziridination of α,β‐Unsaturated Amides with Diaziridine and Mechanistic Consideration on Its Stereochemistry

During studies of aziridination of α,β‐unsaturated amides with diaziridine, we found that we could prepare both the cis‐ and trans‐aziridinecarboxamides by choosing an appropriately substituted diaziridine. While 3‐monosubstituted diaziridine 2 was suitable for the trans‐selective aziridination, employment of 3,3‐dialkyldiaziridine 1 resulted in the formation of cis‐aziridine carboxamides, irrespective of the geometry of the substrate (Scheme 1 and Tables 1 and 2). To elucidate the unique nonstereospecificity and to expand these aziridinations to asymmetric ones, several optically active diaziridines were newly prepared. Aziridination with an optically active 3‐monosubstituted diaziridine, 3‐cyclohexyl‐1‐[(1R)‐1‐phenylethyl]diaziridine 16 , proceeded smoothly with high trans‐selectivity as well as excellent enantioselectivity (up to 98% ee; see Table 3). On the other hand, highly enantioselective cis‐aziridination was achieved (>99% ee) with optically active 3,3‐dimethyl‐1‐[(1R)‐1‐phenylethyl]diaziridine 15 , though the yield was low (4%). This aziridination was considered to proceed stepwise by way of the enolate intermediate (Scheme 2). Careful inspection of the stereochemistry and its solvent‐dependence suggested that the diastereoselection of the reaction was kinetically controlled: the 1,4‐addition of N‐lithiated diaziridine was a crucial step for determination of the stereochemical course of the aziridination (Figs. 2–4).     

Glycosylidene Carbenes. Part 31

The diastereoselectivity of the addition of NH₃ and MeNH₂ to glyconolactone oxime sulfonates and the structures of the resulting N‐unsubstituted and N‐methylated glycosylidene diaziridines were The ¹⁵N‐labelled glucono‐ and galactono‐1,5‐lactone oxime mesylates 1* and 9* add NH₃ mostly axially (>3 : 1; Scheme 4), while the ¹⁵N‐labelled mannono‐1,5‐lactone oxime sulfonate 19* adds NH₃ mostly equatorially (9 : 1; Scheme 7). The ¹⁵N‐labelled mannono‐1,4‐lactone oxime sulfonate 30* adds NH₃ mostly from the exo side (>4 : 1; Scheme 9). The configuration of the N‐methylated pyranosylidene diaziridines 17, 18, 28 , and 29 suggests that MeNH₂ adds to 1, 9, 19 , and 23 mostly to exclusively from the equatorial direction (>7 : 3; Schemes 5 and 8). The mannono‐1,4‐lactone oxime sulfonate 30 adds MeNH₂ mostly from the exo side (85 : 15; Scheme 10), while the ribo analogue 37 adds MeNH₂ mostly from the endo side (4 : 1; Scheme 10). Analysis of the preferred and of the reactive conformers of the tetrahedral intermediates suggests that the addition of the amine to lactone oxime sulfonates is kinetically controlled. The diastereoselectivity of the diaziridine formation is rationalized as the result of the competing influences of intramolecular H‐bonding during addition of the amines, steric interactions (addition of MeNH₂), and the kinetic anomeric effect. The diaziridines obtained from 2,3,5‐tri‐O‐benzyl‐D ‐ribono‐ and ‐D ‐arabinono‐1,4‐lactone oxime methanesulfonate ( 42 and 48 ; Scheme 11) decomposed readily to mixtures of 1,4‐dihydro‐1,2,4,5‐tetrazines, pentono‐1,4‐lactones, and pentonamides. The N‐unsubstituted gluco‐ and galactopyranosylidene diaziridines 2, 4, 6, 8 , and 10 are mixtures of two trans‐substituted isomers ( S / R ca. 19 : 1, Scheme 2). The main, (S,S)‐configured isomers S are stabilised by a weak intramolecular H‐bond from the pseudoaxial NH to RO? C(2). The diaziridines 12 , derived from GlcNAc, cannot form such a H‐bond; the (R,R)‐isomer dominates ( R / S 85 : 15; Scheme 3). The 2,3‐di‐O‐benzyl‐D ‐mannopyranosylidene diaziridines 20 and 22 adopt a ⁴C₁ conformation, which does not allow an intramolecular H‐bond; they are nearly 1 : 1 mixtures of R and S diastereoisomers, whereas the ^OH₅ conformation of the 2,3:5,6‐di‐O‐isopropylidene‐D ‐mannopyranosylidene diaziridines 24 is compatible with a weak H‐bond from the equatorial NH to O? C(2); the (R,R)‐isomer is favoured ( R / S ≥7 : 3; Scheme 6). The mannofuranosylidene diaziridine 31 completely prefers the (R,R)‐configuration (Scheme 9).     

Glycosylidene Carbenes. Part 32

Acylation and sulfonylation of the N,N′‐unsubstituted glucosylidenespirodiaziridines 1A / 1B 95 : 5 with Ac₂O, BzCl, FmocCl, TsCl, (naphthalen‐2‐yl)sulfonyl, and (2,4,6‐triisopropylphenyl)sulfonyl chloride, and concomitant rearrangement gave the acylated and sulfonylated gluconolactone hydrazones 2B – 2G in 40–83% yield (Scheme 2). Similarly, the galacto and manno analogues 3A / 3B 95 : 5 and 5A / 5B 55 : 45 and the mannofuransoylidene‐diaziridine 30 were acetylated and tosylated to give 4A, 4B, 6, 31A , and 31B (55–73% yield; Schemes 2 and 5). ¹⁵N‐Labelling of 11A / 11B and 14A / 14B showed that the pseudoequatorial NH of the gluco diaziridines 1 and the pseudoaxial NH of the galacto diaziridines 3 were preferentially acetylated and tosylated (Scheme 3). Sulfonylation of the N‐methylated diaziridines 19A / 19B 72 : 28, 22A / 22B 85 : 15, 25A / 25B 85 : 15, 28A / 28B 80 : 20, and 33A / 33B / 33C / 33D 76 : 4 : 12 : 8 yielded the N‐methyl‐N‐tosylglyconolactone hydrazones 20, 23, 26, 29 , and 34 (44–66%; Schemes 4 and 5). The methylated N‐atom of the diaziridines proved more reactive, irrespective of the configuration at C(2) and C(4). The products were readily hydrolysed to glyconolactones.     

An electron diffraction study of 3-methyldiaziridine and 1,2-dimethyldiaziridine

The structures of the title compounds, diaziridines, (the first to be studied in the gas phase) have been determined by electron diffraction. The following principal structural parameters were obtained with the estimated standard deviations parenthesized: 3-methyldiaziridine, N-C = 1.489(9) Å, N-N = 1.444(13) Å, C-C = 1.505(16) Å, C-H = 1.107(5) Å, α =∠ (C-C, NCN) = 61.3° (0.9); 1,2-dimethyldiaziridine, (parameters of the cycle CN₂ were assumed from the previous molecule), N-C (methyl) = 1.445(3) Å, C-H = 1.108(9) Å, ∠ C-N-Me = 112.0° (0.5), the two methyl groups are in the trans position. Vibrational amplitudes were also determined for all important distances.     

Nucleophile‐Dependent Regio‐ and Stereoselective Ring Opening of 1‐Azoniabicyclo[3.1.0]hexane Tosylate

1‐[(1R)‐(1‐Phenylethyl)]‐1‐azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2‐(3‐hydroxypropyl)aziridine upon reaction with p‐toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH₃CN to afford either piperidines or pyrrolidines through regio‐ and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring‐opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.     

Stereoselective synthesis of syn β-hydroxy cycloalkane carboxylates: transfer hydrogenation of cyclic β-keto esters via dynamic kinetic resolution

The transfer hydrogenation of bicyclic and monocyclic β-keto esters using HCO₂H/Et₃N as the hydrogen source and TsDPEN-based Ru(II) catalysts proceeds with dynamic kinetic resolution to afford the corresponding cyclic β-hydroxy esters with moderate to excellent levels of diastereo- and enantioselectivities. The mild reaction conditions used make possible to preserve in most cases the syn relative configuration of the products, providing a complementary tool to known approaches to the synthesis of anti isomers.     

Dibromomethane as one-carbon source in organic synthesis: total synthesis of (±)- and (−)-methylenolactocin

A general method was developed to construct monocyclic α-methylene-γ-butyrolactone moiety. The key step is to introduce the α-methylene group by the ozonolysis of mono-substituted alkenes followed by reacting with a preheated mixture of CH₂Br₂-Et₂NH. Application of this key step in the total synthesis of the (±)- and (−)-methylenolactocin was described.     

Asymmetrical nonbridgehead nitrogen—XXIII: Chiral 3,3-bis(trifluoromethyl)diaziridines

By means of the reaction of O-tosyloxime 1a with propargyl amine, esters of glycine and (S)-α-alanine, β-acetoxyethyl amine and β-dimethylaminoethyl amine functionally substituted 3,3-bis(trifluoromethyl)diaziridines 2a–g have been obtained. In the reactions with more bulky amines, (S)-phenylalanine Et ester, (R, S)-α-phenylethyl amine and t-butyl amine, 1a acts as a tosylating reagent. The ester group in diaziridine 2e is readily saponified by alcoholic alkali, whereas diaziridine 2c is rearranged in these conditions with ring-expansion. Complete asymmetric transformation has been found to take place on the formation of the solid phase of diastereomers 2d and 2j, and a closed cycle of diastereomeric transformations has been accomplished. Diaziridine 2g with chiral centres only at the nitrogen atoms has been obtained with the optical purity of 85.5% by resolution via salt 5c with d-(+)-camphor-3-carboxylic acid. The absolute configuration of (+)-2g and its quaternary salt, (+)-2h, has been determined from CD spectra. Optically active (?)-2h salt (optical purity 2.0%) has been also obtained by asymmetric synthesis on the basis of 1–10-camphorsulphonyl oxime 1b. From the kinetics of 2g, h racemization and 2d, e, i, j, k epimerization the energy parameters of the inversion of N atoms in 3,3-bis (trifluoromethyl)diaziridines have been determined.     

Novel features of iron-mediated radical reactions: an unusual mode of silyloxycyclopropane fission, and a new method for radical chain termination using CH2I2

Fe(NO₃)₃ mediated radical reactions of silyloxycyclopropanes derived from a range of bicyclic ketones are described, and include examples that undergo an unexpected regiochemical mode of cyclopropane cleavage. The inclusion of CH₂I₂ in such reactions allows the synthesis of iodinated products.     

Preferential Adsorption of Ethylene Oxide on Fe and Chlorine on Ni Enabled Scalable Electrosynthesis of Ethylene Chlorohydrin

Industrial manufacturing of ethylene chlorohydrin (ECH) critically requires excess corrosive hydrochloric acid or hypochlorous acid with dealing with massive by-products and wastes. Here we report a green and efficient electrosynthesis of ECH from ethylene oxide (EO) with NaCl over a NiFe₂O₄ nanosheet anode. Theoretical results suggest that EO and Cl preferentially adsorb on Fe and Ni sites, respectively, collaboratively promoting the ECH synthesis. A Cl radical-mediated ring-opening process is proposed and confirmed, and the key Cl and carbon radical species are identified by high-resolution mass spectrometry. This strategy can enable scalable electrosynthesis of 185.1 mmol of ECH in 1 h with 92.5 % yield at a 55 mA cm⁻² current density. Furthermore, a series of other chloro- and bromoethanols with good to high yields and paired synthesis of ECH and 4-amino-3,6-dichloropyridine-2-carboxylicacid via respectively loading and unloading Cl are achieved, showing the promising potential of this strategy.     

Electrochemical oxidation of tetramethoxy precursor as a key step for the synthesis of coenzyme Q10

The feasibility of electrosynthesis of coenzyme Q₁₀ (1) by electrooxidation of tetramethoxy precursor (2) has been investigated at carbon, Pt and BDD anodes in a divided cell. The process strongly depends on the applied potential, anode material and water content of the solvent. At carbon anodes in CH₃CN/CH₂Cl₂ + 0.15 M Bu₄NBF₄ at proper operative conditions high faradic efficiency (>60%) and excellent selectivity (95–97%) of the target product were obtained.