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The development of a biomass-based polymer platform has become increasingly important to address environmental problems. In the present study, we present a furan-based polymer platform, furandiacyl...

Inspired by the potent polycyclic xanthone antibiotic lysolipin I, a general study on asymmetric dihydroxylation reactions of variously substituted isoquinolinones was performed. Different isoquinolinones were efficiently prepared, either by a Pomeranz–Fritsch type condensation or a Curtius rearrangement. Under a broad variety of conventional oxygenation procedures, they proved very unreactive. However, either by suitable substitution of the appending aromatic ring or more forcing conditions a dihydroxylation could finally be performed, which allowed the synthesis of the EF-ring of lysolipin I.

Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.

As pure compounds, small carbonyl azides enjoy a bad reputation, due to the high explosive sensitivity and instability they demonstrate. Consequently, most reported examples have only been poorly characterized. The compounds oxalyl diazide (1), carbamoyl azide (2), as well as N,N'-bis(azidocarbonyl)hydrazine (3) were obtained by performing a diazotation reaction on the corresponding hydrazo precursor. Carbamoyl azide (2) could also be obtained from oxalyl diazide via Curtius rearrangement to the reactive isocyanate, followed by reaction with water. Further, different trapping reactions of the isocyanate with hydroxyl (methanol, oxetan-3-ol) and amino (2-amino-5H-tetrazole) functions are described. All products were extensively analyzed using IR, EA, DTA and multinuclear NMR spectroscopy, and the crystal structures elucidated using single crystal X-ray diffraction. In addition, the sensitivities toward friction and impact were determined and the energetic performances of the carbonyl azides were calculated using the EXPLO5 code.

Aim. To develop convenient approaches to the synthesis of 6-amino- and 6-oxoimidazo[4,5-b]pyrazolo[3,4-e]pyridines as promising biologically active scaffolds.Results and discussion. It has been found that cyclocondensation of N-Boc-4-aminopyrazole-5-carbaldehydes with creatinine can be used as an effective method for obtaining 6-aminoimidazo[4,5-b]pyrazolo[3,4-e]pyridines previously unknown. For the synthesis of their 6-oxoanalogs, the reaction of 5-aminopyrazolo[4,3-b]pyridine-6-carboxylic acids used in a modifed Curtius rearrangement with diphenylphosphorylazide was successful. This method was implemented through the stage of the intermediate aminoisocyanates formation.Experimental part. The reaction of N-Boc-4-aminopyrazole-5-carbaldehydes with creatinine in the presence of pyrrolidine as a catalyst in refluxing acetic acid allowed to obtain 6-aminoimidazo[4,5-b]pirazolo[3,4-e]pyridines with the yields of 54 – 70 %. The structure of the compounds synthesized was proven by spectral measurements. In the 1H NMR spectra there were singlets of H-3 (7.63 – 7.88 ppm) and H-8 (7.87 – 8.26 ppm) protons, as well as broad singlets of the NH2 group in the range of 7.05 – 7.21 ppm. Heating of 5-aminopyrazolo[4,3-b]pyridine-6-carboxylic acids with triethylamine and diphenylphosphorylazide in dioxane for 6 hours gave 1-substituted imidazo[4,5-b]pyrazolo[3,4-е]pyridine-6(5Н)-ones with the yields of 67 – 80 %. The IR-spectra of the compounds synthesized were characterized by the absorption bands of the C=O (1705 – 1708 cm-1) and NH (3275 – 3281 cm-1) groups. 1H NMR-spectra were characterized by singlets of H-3 and H-8 protons in the intervals of 7.43 – 8.08 ppm and 7.92 – 8.32 ppm respectively, as well as by two broad singlets of NH-protons in the ranges of 10.90 – 11.12 ppm and 11.25 – 11.37 ppm.Conclusions. Effective approaches to the synthesis of new promising heterocyclic systems of 6-amino- and6-oxoimidazo[4,5-b]pirazolo[3,4-e]pyridines have been developed. Cyclocondensations of N-Boc-4-aminopyrazole-5-carbaldehydes with creatinine and 5-aminopyrazolo[4,3-b]pyridine-6-carboxylic acids with diphenylphosphorylazide have been proven to be convenient ways to obtain these compounds with good yields.Key words: N-Boc-4-aminopyrazole-5-carbaldehyde; creatinine; 5-aminopyrazolo[4,3-b]pyridine-6-carboxylic acid; diphenylphosphorylazide; 6-amino(oxo)imidazo[4,5-b]pyrazolo[3,4-e]pyridines;cyclocondensation

A diverse range of ureas, N-acylureas, carbamates, and thiocarbamates has been synthesized in good to excellent yields by reacting N-acylbenzotriazoles individually with amines or amides or phenols or thiols in the presence of diphenylphosphoryl azide (DPPA) as a suitable azide donor in anhydrous toluene at 110 °C for 3–4 hours. In this route, DPPA was found to be a good alternative to trimethylsilyl azide and sodium azide for the azide donor in Curtius degradation. The high reaction yields, one-pot and metal-free conditions, straightforward nature, easy handling, use of readily available reagents, and in many cases avoidance of column chromatography are the notable features of the devised protocol.

A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries.

A palladium-catalyzed three-component carbonylative reaction for the synthesis of 3H-1,2,4-triazol-3-ones from hydrazonoyl chlorides and NaN3 has been achieved. The reaction presumably proceeds through a cascade carbonylation, acyl azide formation, Curtius rearrangement, and intramolecular nucleophilic addition sequence. A wide variety of structurally diverse 3H-1,2,4-triazol-3-ones were constructed in moderate to excellent yields. Benzene-1,3,5-triyl triformate (TFBen) was applied as a solid and convenient CO surrogate.

Background and Objective: Due to the well-documented anti-proliferative activity of 2-thiohydantoin incorporated with pyrazole, oxadiazole, quinazoline, urea, β-naphthyl carbamate and Schiff bases, they are noteworthy in pharmaceutical chemistry. Methods: An efficient approach for the synthesis of a novel series of 2-thiohydantoin derivatives incorporated with pyrazole and oxadiazole has proceeded via the reaction of the acyl hydrazide with chalcones and/or triethyl orthoformate. Schiff bases were synthesized by the reaction of the acyl hydrazide with different aromatic aldehydes. Moreover, Curtius rearrangement was applied to the acyl azide to obtain the urea derivative, quinazoline derivative, and carbamate derivative. Results: The synthesized compounds structures were discussed and confirmed depending on their spectral data. The anticancer activity of these heterocyclic compounds was evaluated against the breast cancer cell line (MCF-7), where they showed variable activity. Compound 5d found to have a superior anticancer activity, where it has (IC50 = 2.07 ± 0.13 μg/mL) in comparison with the reference drug doxorubicin that has (IC50 = 2.79 ± 0.07 μg / mL). Then compound 5d subjected to further studies such as cell cycle analysis and apoptosis. Apoptosis was confirmed by the upregulation of Bax, downregulation of Bcl-2, and the increase of the caspase 3/7percentage. Conclusion: Insertion of pyrazole, oxadiazole and, quinazoline moieties with 2-thiohydantoin moiety led to the enhancement of its anti-proliferative activity. Hence they can be used as anticancer agents.

The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.

Aim . To develop a convenient synthetic approach for the preparation of multigram amounts of 2,2-difluoro-γ-aminobutyric acid, which is pharmacologically promising analog of γ-aminobutyric acid (GABA). Results and discussion . α,α-Difluoro-γ-aminobutyric acid (2,2-difluoro-GABA, 53 g) has been synthesized using the reaction of ethyl bromodifluoroacetate (EBDFA) addition to benzyl acrylate in the presence of copper as a key stage. Experimental part . The reaction of EBDFA with benzyl acrylate in the presence of copper and tetramethylethylenediamine (TMEDA) was carried out; the resulting product was transformed to the target α,α-difluoro-γ-aminobutyric acid (in the form of hydrochloride) by consecutive debenzylation, Curtius rearrangement and treatment with hydrochloric acid to remove protecting groups. The synthesis was scaled up for the preparation of 53 g of α,α-difluoro-γ-aminobutyric acid. The ethyl ester of α,α-difluoro-γ-aminobutyric acid was also prepared and further transformed to 3,3-difluoropyrrolidine-2-one. The structure of the compounds synthesized was confirmed by 1 Н, 13 C and 19 F NMR spectroscopy, mass spectrometry and elemental analysis. Conclusions . It has been shown that the synthetic approach developed can be used for the preparation of α,α-difluoro-γ-aminobutyric acid in multigram amounts. The pathway is much more convenient, cheaper and safer compared to the method earlier described. Received: 30.07.2020 Revised: 19.08.2020 Accepted: 27.08.2020

A practical and highly efficient protocol for the production of Autotaxin (ATX) inhibitor Ziritaxestat (1) was described. The procedure began with a catalyst-free bicomponent cyclization for the co...

A one-pot transformation of biaryl dicarboxylic acids to (NH)-phenanthridinone derivatives based on a Curtius rearrangement and subsequent basic hydrolysis was developed. This method is also applicable for the preparation of optically active amide-functionalized [7]helicene-like molecules. Furthermore, aza[5]helicene derivatives with a phosphate moiety were isolated as a product of the Curtius rearrangement step in the case of substrates that bear chalcogen atoms. The stereostructures of these products, revealed by X-ray diffraction analysis, suggested that chalcogen-bonding and pnictogen-bonding interactions might contribute to their stabilization. The configurational stability of the helicene-like molecules and their chiroptical properties were further investigated.

A new variant of the intramolecular Diels-Alder oxazole (IMDAO) cycloaddition that provides direct access to 6-azaindoles was developed. The IMDAO reaction was applied in a total synthesis of the aminophenylpyrrole-derived alkaloid marinoquinoline A, also featuring the use of a Curtius reaction for preparation of a 5-aminooxazole, a propargylic C,H-bond insertion, an in situ alkyne-allene isomerization, and a ruthenium-catalyzed cycloisomerization for benzene ring annulation to the 6-azaindole.

2H-Azirine-2-carbonyl azides, new reactive heterocyclic building blocks, were synthesized in high yield by the reaction of sodium azide with 2H-azirine-2-carbonyl chlorides, generated by the Fe(II)-catalyzed isomerization of 5-chloroisoxazoles. 2-(Azidocarbonyl)-1H-pyrroles, prepared by the Ni(II)-catalyzed reaction of 2-(azidocarbonyl)-2H-azirines with 1,3-diketones, easily undergo the Curtius rearrangement in boiling tBuOH to give Boc-protected α-aminopyrroles in high yield. Heating of 2-(azidocarbonyl)-1H-pyrroles for a short time in inert solvents leads to the high-yield formation of benzo- and hetero-fused 1H-pyrrolo[2,3-b]pyridin-6(7H)-ones, which are formed via a 6π electrocyclization involving the vicinal aryl or hetaryl substituent and the N═C bond of isocyanate, generated by the Curtius rearrangement of the azidocarbonyl group. The Pd-catalyzed cross-coupling reaction of 1-acetyl-2-methyl-3H-pyrrolo[2,3-c]isoquinolin-5-yl triflate, easily prepared from the corresponding pyrroloisoquinolone, leads to variously 5-substituted 3H-pyrrolo[2,3-c]isoquinolines in excellent yields.

A transition-metal-free deoxygenative C-H amination reaction of azine-N-oxides with acyl azides is described. The initial formation of an isocyanate from the starting acyl azide via a Curtius rearrangement can trigger a [3 + 2] dipolar cycloaddition of polar N-oxide fragments to generate the aminated azine derivative. The applicability of this method is highlighted by the late-stage and sequential amination reactions of complex bioactive compounds, including quinidine and fasudil. Moreover, the direct transformation of aminated azines into various bioactive N-heterocycles illustrates the significance of this newly developed protocol.

SB-203207 is an altemicidin-type alkaloid that potently inhibits isoleucyl tRNA synthetase activity. Its main structural feature is a hexahydro-6-azaindene framework containing a unique β-hydroxy α,α-disubstituted α-amino acid moiety on the cyclopentane portion. Herein we have established a method for constructing the four contiguous nitrogen-containing stereogenic centers of SB-203207 by using as key steps the stereoselective alkylation of bowl-shaped tricyclic lactone to construct a quaternary carbon at C1, the stereoselective hydroboration-oxidation reaction to install the C2 hydroxy group, and the Curtius rearrangement to introduce a nitrogen atom onto the C1 quaternary carbon.

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper-catalyzed three-component reaction of aryl acetylenes, amines, and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO2 as the only byproduct. Transformation of the dioxazolones on the Cu catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu-C bond rather than undergoing an undesired Curtius rearrangement. For nonaromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 min. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple copper(I) iodide (CuI) as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol The herein reported procedure not only provides a new, practical, and direct route to N-acyl amidines but also represents a new type of C-N bond formation.

A synthetic approach is described for the transformation of R-(-)-carvone to methyl (2Z,5S,6E)-5-[(tert-butoxycarbonyl)amino]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)hepta-2,6-dienoate, the key building block for the convergent synthesis of the known antitumor macrolactam ixabepilone. The synthetic sequence includes 10 stages, where the key stage is Curtius rearrangement. Optimal conditions have been found for that rearrangement.

The good leaving tendency of the benzotriazole moiety has been exploited for the synthesis of symmetric, unsymmetric, N-acyl, and cyclic ureas in good yields from N-acylbenzotriazoles by treating the latter with various amines in the presence of TMSN3/Et3N in a sealed tube. The salient features of the devised protocol includes the high-yield, mild, metal-free, one-pot reaction conditions, and short reaction time. Furthermore, in many cases, no column chromatography is required for the purification.

Synthesis of two naturally occurring anthraquinones, Barleriaquinone-I (BQ-I) and Barleriaquinone-II (BQ-II) is achieved from commercially available naphthalene-1,5-diol. The anthraquinone core is constructed by utilizing simultaneous Heck and cross coupling reaction as the key step.

Herein, we describe the synthesis of novel piperidinyl thieno tetrahydroisoquinolines attached or fused to other new heterocycles. The diazotization of the previously synthesized pyrrolyl carbohydrazide 1 followed by several reactions with ethanol, aniline and heterocyclization after boiling in dry xylene under Curtius rearrangement conditions yielded the corresponding carbamate, phenyl urea and pyrazino derivatives 3–5. Furthermore, the condensation of 1 with various aromatic aldehydes and ethyl acetoacetate afforded the consistent Schiff's bases 6a-c and 7. The ring closure of the ethyl butanoate ester 7 furnished pyrazolyl compound 8 after heating in an ethanolic sodium ethoxide solution. Moreover, the nucleophilic addition of the carbohydrazide 1 to carbon disulfide in pyridine produced oxadiazolyl thione 9 which was reacted with ethyl chloroacetate to give ethyl sulfanyl acetate ester 10. The assignments of the chemical structures of these new heterocycles were confirmed by using elemental and spectral analysis. Alternatively, selected compounds were examined for antibacterial and antifungal screening. The results revealed highly promising influences against the nominated pathogenic strains.

The complete theoretical study of thermal Curtius rearrangement of syn-syn and syn-anti conformers of oxalyl diazide, in the gas phase and in solution has been established for the first time. The inexplicit solvent effect was taken into account via the self-consistent reaction field (SCRF) method. The gas and solution phases of all optimized geometries of the mentioned conformers associated with the Curtius rearrangement along the concerted and stepwise pathways were reported using the polarized continuum model and non-electrostatic terms from the SMD universal solvation model. The Curtius rearrangement of syn-syn and syn-anti conformers was taken place via concerted and stepwise pathways, respectively. The syn-syn conformer of oxalyl diazide is more stable than the syn-anti conformer in the gas phase and solution, and rearranged to syn-carbonyl azide isocyanate via an exergonic concerted mechanism with a single transition state. Nevertheless, the rearrangement of syn-anti conformer occurred through the two transition states and an intermediate, which the first and second steps are endergonic and exergonic, respectively. Theoretical results point out that the concerted pathway is predominant with 102-106 and 104-105 times faster than the stepwise mechanism in gas phase and solution, respectively. Topological analysis of the electron localization function at the B3LYP/6–311++G (2d,d,p) level of theory indicate that the catastrophe sequence 1-6-C†TSC†F C†C-0 begins with the N4–N5 bond breaking, elimination of nitrogen molecule and increasing of non-bonding monosynaptic attractor on N4 atom, and then changing of topological signature of C2–N4 bond, breaking of C1–C2 bond, and formation of pseudo-radical centers on C1 and C2 atoms. Subsequently, annihilation of pseudo-radical centers on the C1 atom, change of topological signature of C2–N4 and formation of C1–N4 bond were executed. The obtained results of ELF calculations show that the reaction takes place via a concerted mechanism but highly asynchronous process.

Due to reasons of sustainability and conservation of resources, polyurethane (PU)-based systems with preferably neutral carbon footprints are in increased focus of research and development. The proper design and development of bio-based polyols are of particular interest since such polyols may have special property profiles that allow the novel products to enter new applications. Sophorolipids (SL) represent a bio-based toolbox for polyol building blocks to yield diverse chemical products. For a reasonable evaluation of the potential for PU chemistry, however, further investigations in terms of synthesis, derivatization, reproducibility, and reactivity towards isocyanates are required. It was demonstrated that SL can act as crosslinker or as plasticizer in PU systems depending on employed stoichiometry. (ω-1)-hydroxyl fatty acids can be derived from SL and converted successively to polyester polyols and PU. Additionally, (ω-1)-hydroxyl fatty acid azides can be prepared indirectly from SL and converted to A/B type PU by Curtius rearrangement.

Various ligation processes have recently become a powerful tool in synthetic polymer chemistry. Herein, the use of a new photochemical ligation process as a versatile approach for the cross-linking polymerization, functionalization of polymer chain ends, and surface modification of various materials such as silica and graphene oxide, is demonstrated. The process is based on the formation of urethane linkages by the reaction of photochemically in situ generated isocyanates from benzoyl azides with hydroxyl moieties in the presence of organobase, bicyclo[2.2.2]-1,4-diazaoctane (DABCO) under ambient conditions. The intermediates and obtained materials are characterized by NMR, FTIR, TGA, and TEM analyses. It is believed that this simple and efficient ligation process will expand future applications to fabricate complex macromolecular structures, biomaterials, and gels.

Dendritic materials possessing urethane linkage are surprisingly more stable than similar structures having functional groups such as ether, ester, amide, or carbosilane. This generates profound interest in dendritic polyurethanes. Construction of a well-defined polyurethane dendrimer is, however, challenging because of isocyanates' high reactivity. As a model of our ongoing dendrimer-research, herein, we report a protecting group-free one-pot multicomponent Curtius reaction to furnish a robust and versatile AB2-type dendron, which ensures late-stage modification of both the dendron and dendritic macromolecule yielding a surface functionalized polyurethane dendrimer. While 5-hydroxyisophthalic acid, 11-bromoundecanol, and 4-penten-1-ol were utilized in the construction of the dendron, thiol-ene click chemistry was employed for the late-stage modification. Novel dendrons and dendrimers synthesized were characterized by NMR (1D and 2D) and high-resolution MALDI-TOF analysis. This strategy allows an easy late-stage modification of dendritic macromolecules and is highly useful in the synthesis of both symmetrical and unsymmetrical dendrimers (Janus dendrimers).

A stereodivergent strategy has been devised to access the diene motif found in biologically active compounds from the Piperaceae family. Herein the first total syntheses of 2E,4E configured piperchabamide E (2) and its enantiomer (ent-2), as well as 2E,4Z configured scutifoliamide B (3), are narrated. The mainstay in the adopted approach is the gram-scale conversion of quaternized pyridine in a practical three-step sequence to access isomerically pure conjugated bromodiene esters 2E,4E8 and 2E,4Z9 by differential crystallization. Even though the developed oxidation protocol forms the basis of the entailed divergent strategy, the geometrical integrity of the involved bromodiene motive can be controlled by the choice of solvent. Thus, while oxidation of pure bromodienal 2E,4Z7 in methanol yields equal amounts of bromodiene esters 2E,4E8 and 2E,4Z9, only bromodiene ester 2E,4Z10 is formed in isopropanol. Subseqently, capitalizing on a stereoretentive Suzuki cross-coupling and direct amidation of the corresponding esters, the featured natural products can be accessed in five and six steps, respectively. The somewhat surprising (R)-configured amine portion, which has been assigned to piperchabamide E (2), is facilitated by a Curtius rearrangement. Following this, the actual amine portion is shown to be (S)-configured.

Transition-metal-catalyzed sp2 C-N bond formation is a reliable method for the synthesis of aryl amines. Catalytic sp3 C-N formation reactions have been reported occasionally, and methods that can realize both sp2 and sp3 C-N formation are relatively unexplored. Herein, we address this challenge with a method of catalytic decarboxylative C-N formation that proceeds through a cascade carboxylic acid activation, acyl azide formation, Curtius rearrangement and nucleophilic addition reaction. The reaction uses naturally abundant organic carboxylic acids as carbon sources, readily prepared azidoformates as the nitrogen sources, and 4-dimethylaminopyridine (DMAP) and Cu(OAc)2 as catalysts with as low as 0.1 mol % loading, providing protected alkyl, alkenyl and aryl amines in high yields with gaseous N2 and CO2 as the only byproducts. Examples are demonstrated of the late-stage functionalization of natural products and drug molecules, stereospecific synthesis of useful α-chiral alkyl amines, and rapid construction of different ureas and primary amines.

The transformation of acyl azide derivatives into N-methylamines was developed using methanol as the C1 source via the one-pot Curtius rearrangement and borrowing hydrogen methodology. Following this protocol, various functionalised N-methylated amines were synthesized using the (NNN)Ru(II) complex from carboxylic acids via an acyl azide intermediate. Several kinetic studies and DFT calculations were carried out to support the mechanism and also to determine the role of the Ru(II) complex and base in this transformation.

Two asymmetrically substituted cobaltocenium carb­oxy­lic acid compounds were synthesized and their crystal structures determined. Both crystallize as hydrates and exhibit an extended hydrogen-bonding network., 1′-Amino­cobaltocenium-1-carb­oxy­lic acid chloride, [Co(C5H6N)(C6H5O2)]Cl·H2O, (3), and its azo derivative 1′-[2-(1-amino-2,6-dimethylphenyl)diazen-1-yl]cobaltocenium-1-carb­oxy­lic acid hexa­fluorido­phosphate, [Co(C13H14N3)(C6H5O2)]PF6·H2O (5) were obtained from cobaltocenium-1,1′-di­carb­oxy­lic acid hexa­fluorido­phosphate by converting one carboxyl group to its chloro­carboxyl derivative followed by chloride/azide exchange, Curtius rearrangement, diazo­tiation and azo coupling with 2,6-di­methyl­aniline. Both title compounds crystallize as their monohydrates. In the crystal structure of 3, both functional groups lie in the same direction, with the Cp rings being nearly eclipsed, and participate in an extended hydrogen-bonded supra­molecular network including the counter-ion and the water mol­ecule of crystallization. Although the functional groups in 5 are somewhat further apart, bearing a greater torsion angle with the Cp rings now staggered, a similar supra­molecular network is observed with not only the carb­oxy­lic acid and azo groups, but also with the more remote amino group participating in a hydrogen-bonded network, again including the counter-ion and the water mol­ecule. The hexa­fluorido­phosphate ion shows positional disorder. Compound 3 was refined as an inversion twin. In 5, each of the six F atoms is disordered over two sets of sites in a 1:1 ratio.

A six-step semisynthetic approach towards chiral nonracemic pyrrolo-allocolchicinoids starting from naturally occurring colchicine was developed. The synthetic scheme includes an electrocyclic tropolone ring contraction to afford allocolchicinic acid followed by the Curtius reaction, giving the corresponding aniline. The Sandmeyer reaction and copper-mediated hydrazination gave hydrazine-substituted allocolchicine. This was introduced into the Fischer indole synthesis, affording libraries of regioisomeric indole-based allocolchicine congeners.

Sulfonyl azide isocyanate, (OCN)S(O)2N3, was prepared and characterized by IR (gas, matrix-isolation), Raman (liquid), and UV-vis spectroscopy. Upon flash vacuum pyrolysis (FVP) at ca. 1000 K, gaseous (OCN)S(O)2N3 decomposes completely and yields fragments N2, SO2, SO3, NCN, N3, NCO, CO, CN, and NO. In contrast, the azide splits off N2 and furnishes a transient triplet sulfonyl nitrene intermediate (OCN)S(O)2N upon a 266 nm laser irradiation in solid Ne-matrix at 2.8 K. Subsequent photolysis of the nitrene with visible light (λ = 380-450 nm) results in oxygen-shifted Curtius rearrangement to a novel nitroso sulfoxide (OCN)S(O)NO. For comparison, the photodecomposition of the closely related sulfonyl diazide O2S(N3)2 in a solid Ar matrix was also studied. Upon an ArF excimer laser (193 nm) photolysis, O2S(N3)2 decomposes and yields N2, SO2, and OSNNO via the intermediacy of an elusive sufonyl nitrene N3S(O)2N. Further visible light irradiation (λ > 395 nm) leads to depletion of N3S(O)2N and OSNNO and concomitant formation of SO2 and N2. The identification of the intermediates in cryogenic matrixes by IR spectroscopy was supported by 15N-labeling experiments and quantum chemical calculations. The mechanism for the decomposition of both sulfonyl azides (OCN)S(O)2N3 and O2S(N3)2 was discussed on the basis of the observed intermediates and the calculated potential energy profiles.

Polyurethane (PU) is a most commonly used polymer for various application such as rigid and flexible foams, coatings etc. Also another class known as biodegradable PUs are used in specialized medical fields like soft-tissue engineering, regenerative medicine and also drug delivery systems, However, the degradation of the polyurethanes derived traditionally from general diisocyanates like 4,40-methylene diphenyl diisocyanate and toluene diisocyanate gives toxic products. Therefore, it is imperative to find an alternative route for the synthesis of PU which involves least or no toxic reagents. The consequently formed products are named non-isocyanate polyurethanes (NIPU). Recently, few alternative synthesis methods have been suggested by many researchers like a synthesis of polyhydroxyurethanes by polyaddition of diamines with cyclic carbonates. Such methods use functionalized vegetable oil as a biocompatible monomer which has led to a new range of biodegradable, renewable and sustainable source for NIPUs. Use of cyclocarbonates class of compounds has shown potential in the preparation of green PUs. Self-polycondensation reactions between AB-type fatty monomers bearing acyl azide and hydroxyl functionalities will take part. Here, the isocyanate group formation takes place in situ via Curtius rearrangement. The only disadvantage of this method is that the acyl azide groups are obtained by the harmful reaction of sodium azide with carboxylic acids. Bio-renewable sources represent a rich source of precursors for the synthesis of polyols and polyisocyanates. Many such sustainable routes for the synthesis of NIPUs reported in the literature are presented in the following article.

A linear 14-step sequence was developed for the synthesis of an oxaspirocyclic cyclopentane-based candidate drug 1 containing four chiral centers. Compared with the first-generation synthesis with an overall yield of 0.7%, which also included several chromatographic purifications, the large-scale approach furnished >800 g of API 1 in 19% overall yield, and chromatography was avoided in all but two steps. The major achievements were the development of a Curtius rearrangement where hazards were minimized, a robust and safer dose-controlled allylzinc addition to a ketone, and a selective monohydrolysis of a diester.

The approach presented here is an unprecedented insight into the understanding of kinetics and molecular mechanism of thermal Curtius rearrangement of 3-oxocyclobutane-1-carbonyl azide. Curtius rearrangement can proceed via concerted and stepwise mechanisms. The CBS-QB3 and CBS-APNO composite methods indicated that concerted pathway is dominant and 104–105 times faster than stepwise path. The bonding evolution theory analysis at the B3LYP/6-311G(d,p) revealed that the reaction via concerted pathway can be described with catastrophe sequence 9-CF†C†TSFC†FC†C-0 by the following chemical events: (a) change of topological signature of N2 N3 bond; (b) increasing the number of non-bonding monosynaptic attractor on N1 atom; (c) breaking of N1 N2 bond and extrusion of nitrogen molecule; (d) decreasing the number of non-bonding monosynaptic attractors on N1 atom; (e) breaking of C4 C5 bond and formation of pseudoradical centers on the C4 and C5 atoms; (f) annihilation of pseudoradical center on the C5 atom; (g) change of topological signature of N1 C5 bond; and (h) formation of N1 C4 bond. Along the reaction course electron flow redistribution is asynchronous and bond breaking/forming do not takes place simultaneously demonstrating that the reaction is concerted yet highly asynchronous process.

Carbon–nitrogen bond formation is one of the most important reactions in organic chemistry. Various synthetic strategies for the generation of C–N bonds are described in the literature. For example, primary amines can be easily synthesized by the thermal decomposition of an acyl azide to an isocyanate, i.e. the Curtis rearrangement, followed by hydrolysis; the Curtius rearrangement has been used extensively. Furthermore, the advantage of the Curtius rearrangement is the isolation of acyl azides as well as the corresponding isocyanates. The isocyanates can be converted into various nitrogen-containing compounds upon reaction with various nucleophiles that can be used as important synthons for cyclization, in other words, for the synthesis of heterocycles. Therefore, this review demonstrates the importance of acyl azides not only in the synthesis acyclic systems, but also in the synthesis of various nitrogen-containing heterocycles.1 Introduction2 Synthesis of Acyl Azides2.1 Acyl Azides from Carboxylic Acid Derivatives2.2 Acyl Azides by Direct Transformation of Carboxylic Acids2.3 Acyl Azides from Aldehydes2.4 Carbamoyl Azides from Haloarenes, Sodium Azide, and N-Formylsaccharin3 Mechanism of Formation of Isocyanates4 Synthesis of Diacyl Azides5 Synthetic Applications5.1 Synthesis of Pyrimidinone Derivatives5.2 Dihydropyrimidinone and Isoquinolinone Derivatives5.3 Synthesis of Tetrahydroisoquinoline Skeleton5.4 Synthesis of Five-Membered Heterocycles5.5 Heterocycles Synthesized Starting from Homophthalic acid5.6 Heterocycles Synthesized from 2-(Ethoxycarbonyl)nicotinic Acid5.7 Formation of Aza-spiro Compounds5.8 Parham-Type Cyclization5.9 Diazepinone Derivatives5.10 Synthesis of Pyridine Derivatives5.11 Synthesis of Indole Derivatives6 Miscellaneous7 Conclusion

International audience; The shortest synthesis of N-protected 1′-aminoferrocene-1-carboxylic acid from readily available ferrocene-1,1′-dicarboxylic acid is reported. 1′-Azidocarbonylferrocene-1-carboxylic acid was first obtained by reaction of the latter with diphenylphosphoryl azide. It was then converted into four amino acids by a Curtius rearrangement conducted in the presence of tert-butanol, benzyl alcohol, 9-fluorenemethanol or allyl alcohol. The benzyl and allyl carbamate derivatives are reported and characterized for the first time. The four corresponding new succinimidyl activated esters were also prepared and their usefulness was demonstrated in peptide coupling. Various structures were elucidated by X-ray crystallography, including 1′-azidocarbonylferrocene-1-carboxylic acid and 1,1′-diazidocarbonylferrocene. © 2018 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Upon either photolysis or pyrolysis, carbonyl azide can eliminate molecular nitrogen along with the formation of isocyanate. Though two different pathways (namely stepwise versus concerted) have been proposed, the detailed decomposition mechanism is still elusive to date. Herein, we have employed combined electronic structure calculations and nonadiabatic dynamics simulations to study the radiationless deactivation and rearrangement mechanisms of FC(O)N3 in the S3, S2, S1, and S0 states in an argon matrix. On the basis of QM(CASPT2)/MM calculations, we found that, upon 193 nm irradiation, the excited-state decay of FC(O)N3 from the S3 state via S2 and S1 to the S0 state is an ultrafast process and could be completed within 100 fs, and a subsequent Curtius rearrangement occurs in the period of ∼300 fs; the elimination of N2 and the formation of fluorocarbonyl nitrene FC(O)N could take place in both S1 and S0 states rather than in higher excited states; the isomerization from FC(O)N to FNCO involves a stepwise mechanism and could only be found in the S0 state. This mechanistic scenario has been verified by both electronic structure calculations and full-dimensional trajectory-based “on the fly” QM(CASPT2)/MM nonadiabatic dynamics simulations. Finally, the currently calculated results provide important mechanistic insights for similar carbonyl azides.

Levopimaric acid, a readily available starting material, was used in efficient syntheses of new enantiopure diamines and Schiff bases with good yields. The synthetic procedure is based on the fumaropimaric acid monomethyl ester conversion into the optically pure trans-1,2-diamine via a Curtius rearrangement. New diamines were studied as ligands in the copper-catalyzed asymmetric Henry reaction.

Commercial route definition for a glucokinase activator called for a reevaluation of the synthesis and processes used to access multikilogram quantities of 2-amino-5-methylpyrazine. After consideration of different options, a variation of the Curtius rearrangement used by the medicinal chemistry route was selected for further development. The formation of an acyl azide for the Curtius rearrangement required a process safety control strategy to be put in place. The process developed was used to successfully deliver multikilogram quantities of 2-amino-5-methylpyrazine in an overall yield of 68%, starting from 5-methylpyrazine-2-carboxylic acid.

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC 50

The decomposition of phenyl azidoformate, PhOC(O)N3, was studied by combining matrix isolation spectroscopy and quantum chemical calculations. Upon UV laser photolysis (193 and 266 nm), the azide isolated in cryogenic noble gas matrices (Ne and Ar, 2.8 K) decomposes into N2 and a novel oxycarbonylnitrene PhOC(O)N, which was identified by matrix-isolation IR spectroscopy (with 15N labeling) and EPR spectroscopy (|D/hc| = 1.620 cm–1 and |E/hc| = 0.024 cm–1). Subsequent visible-light irradiation (532 nm) causes rearrangement of the nitrene into phenoxy isocyanate PhONCO with complex secondary fragmentation (PhO· + ·NCO) and radical recombination species in matrices. The observation of PhONCO provides solid evidence for the Curtius rearrangement of phenyl azidoformate. In sharp contrast, flash vacuum pyrolysis (FVP) of PhOC(O)N3 at 550 K yields N2 and exclusively the intramolecular C–H amination product 3H-benzooxazol-2-one. FVP at higher temperature (700 K) leads to further dissociation into CO2, HNCO, and r...

We describe the synthesis of a novel class of compounds, 1,2-dihydrofuro[3,4-d]pyrimidines (15, 16, 18, 20) starting from dimethyl furan-3,4-dicarboxylate 6. Synthesis of these compounds consist of two basic parts: Formation of 4-(2-azido-2-oxoethyl)furan-3-carbonyl azide 11 by eight organic reactions and formation of final products by intramolecular cyclization after two selective Curtius rearrangements of acyl azides 11.

3-Methylenecyclobutanecarboxylic acid and its methyl ester were used as the starting compounds for the synthesis of new spiro[2.3]hexane amino acids, the conformationally rigid analogs of γ-aminobutyric acid, namely, 5-aminospiro[2.3]hexanecarboxylic and 5-amino-spiro[2.3]hexanephosphonic acids, promising modulators of GABAergic cascades in the human central nervous system. The methods developed for the synthesis of the target amino acids are based on the reactions of catalytic [1+2] cycloaddition of diazoacetic and diazophosphonic esters to 3-substituted methylenecyclobutanes, as well as on a modified Curtius reaction for the transformation of a carboxy group to the amine one.

The Schmidt reaction is the acid-catalyzed analogue of the Curtius reaction and is extensively used in organic synthesis. In this work, the mechanism of this reaction has been explored using DFT calculations at the B3LYP/6-311+G(d,p) level. Protonated formyl azide may undergo rearrangement to the product, protonated isocyanic acid, with simultaneous extrusion of molecular nitrogen (concerted mechanism), or undergo rearrangement to the anti conformer, followed by removal of nitrogen to form the nitrenium ion, which then rearranges to the final product, protonated isocyanic acid (step-wise mechanism). Like the Curtius reaction, it is found that the concerted pathway is definitely preferred. The key role of acidification in decreasing the overall energy barrier is more highlighted in case of phenyl substitution, with negligible effect on the lower homologues. For methoxy and amine substituents, there is very little difference in the activation energies of the concerted and step-wise reactions, with the former being still slightly preferred. Unlike the parent compound, the rearrangement of substituted nitrenium ion in some cases involves side reactions like C-H insertion and cyclization.

Difluoroacetyl azide, CHF 2 C(O)N 3 , has been synthesized and characterized. The azide decomposes slowly at room temperature (300 K) into N 2 and difluoromethyl isocyanate CHF 2 NCO, which has also been isolated as neat substance and fully characterized. The elusive nitrene intermediate CHF 2 C(O)N in the stepwise Curtius-rearrangement of the azide is tentatively identified by IR spectroscopy during the 193 nm laser photolysis of the azide in solid Ne matrix at 2.8 K. Unexpectedly, flash vacuum pyrolysis (FVP) of CHF 2 C(O)N 3 at 500 K yields a novel carbonyl isocyanide FC(O)NC with N 2 , HF, FCN, CO, and traces of CHF 2 NCO. Subsequent irradiation (193 nm) of the pyrolysis products results in the rearrangement of FC(O)NC to FC(O)CN. According to the quantum chemical calculations (B3LYP and CCSD(T)), the azide CHF 2 C(O)N 3 prefers concerted Curtius rearrangement with minor contribution of the stepwise decomposition. The thermally generated CHF 2 NCO eliminates HF and forms FC(O)NC solely under the pyrolysis conditions, whereas, no HF-elimination occurs to isolated CHF 2 NCO even at 1000 K due to a formidable activation barrier.

One-step preparation method was developed for adamantyl-containing isocyanates obtained by Curtius reaction from adamantanecarboxylic and acetic acids. Synthesis of isocyanate was performed without the isolation of intermediate acid chloride which solution was added to sodium azide in boiling toluene. In the reactor the acid azide formation and its rearrangement in isocyanate occurred simultaneously. Yields of target products were 83–94% with respect to the acid.