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An orthogonal agent having both alcohol and acylazide groups was used to construct novel polyurethanes by a simple synthetic process. Ring‐opening polymerization (ROP) of δ‐valerolactone from the orthogonal agent afforded a crystalline polymer having acylazide initiation end, while that of δ‐decanolactone resulted in an amorphous polymer. Since acylazide groups undergo thermally induced Curtius rearrangements to yield isocyanate groups, simple heating of above polymers gave macromonomers having both an isocyanate initiation end and an alcohol termination end, which afforded corresponding polyurethane by self‐polyaddition in a bulk condition without any additives. Meanwhile, kinetic analysis of the Curtius rearrangement revealed that a quantitative conversion was reached within a short reaction time, for example at 110°C for 30 min, or at 100°C for 1 h. Moreover, obtained polyurethane species showed unique self‐immolative type thermal degradation behavior. Considering the above, this orthogonal agent turned out to be useful to construct various polyurethane structures by a facile synthetic process, which would contribute to precise polymer synthesis and sequence defined polymer synthesis. [ABSTRACT FROM AUTHOR]

Nicotinic acid derivatives have a wide range of biological activity and are widely used in medical practice as first-line drugs for the treatment of tuberculosis [1], pulmonary arterial hypertension [2], vitamin B6- dependent epilepsy [3], inhibitors of blood clotting factor IXa [4, 5], human immunodeficiency virus inhibitor [6,7], etc. It should be noted that the pyridine cycle is part of many vital organic compounds, which determines it's one of the dominant roles among heterocycles. Therefore, the development of convenient preparative methods for the synthesis of new nicotinic acid derivatives is an urgent task, since these compounds are of practical and theoretical interest. The purpose of this work is the targeted synthesis of nicotinic acid azide and its further modification in order to obtain new pharmacologically active compounds. In this work, the synthesis of nicotinic acid azide was carried out by the interaction of sodium nitrite with nicotinic hydrazide with a yield of 99%. The interaction of nicotinic acid azide with alcohols (isopropyl and butyl alcohols) and a secondary amine (cytisine alkaloid) has been studied. It has been shown that when heated in a dry benzene medium, nicotinic acid azide undergoes a Curcius rearrangement to form isocyanate, which reacts in situ with alcohols and the alkaloid cytisine to form the corresponding urethanes and urea. In order to synthesize 1,2,3-triazole derivatives, the interaction of nicotinic acid azide with terminal acetylene - prop-2-inyl ether of 3-tert-butyl-5-ethyl-2-hydroxybenzoic acid was carried out in a DMFA and heated (70-80 °C) in the presence of copper sulfate CuSO4×5H2O and sodium ascorbate (NaAsc). It was found that as a result of the reaction, not the expected 1,2,3-triazole compound is formed, but 3-aminopyridine and the initial acetylene compound. It is shown that when heated, the azide decomposes to form an intermediate particle, nitrene, and the subsequent migration of the pyridyl radical to the nitrogen atom (Curtius rearrangement) leads to isocyanate. As a result of hydration of isocyanate and subsequent decarboxylation of the resulting carbamic acid, 3-aminopyridine is obtained. Conclusion. The synthesis of nicotinoylazide was carried out by the interaction of sodium nitrite with nicotinic acid hydrazide. The interaction of nicotinic acid azide with terminal acetylen - prop-2-vinyl ester of 3-tert-butyl-5-ethyl-2-hydroxybenzoic acid did not lead to the formation of the expected 1,2,3-triazole compound. It was found that the initial azide undergoes Curcius rearrangement upon heating in situ with the formation of corresponding urethanes and urea. The structure of the synthesized compounds was confirmed by NMR 1H and 13C spectroscopy, as well as data from the two-dimensional spectra COZY (1H-1H) and HMQC (1H-13C). [ABSTRACT FROM AUTHOR]

The oxidative formation of N−N bonds from primary amides has been recently reported and then retracted in the journal Nature Communications by Kathiravan, Nicholls, and co‐authors, utilizing a hypervalent iodane reagent. Unfortunately, the authors failed to recognize the Curtius reaction taking place under the described reaction conditions. Thus, the claimed N−N coupling products were not formed. Instead, the Curtius rearrangement urea coupling products were obtained. We demonstrate this herein by means of NMR and x‐ray analysis, as well as with the support of an alternative synthetic route. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in the DNA repair pathway. Inhibitors of these enzymes belong to a new type of anticancer drugs that selectively kill cancer cells by targeting the homologous recombination genetic defects. This study presents a new synthetic approach to PARP inhibitors containing a 4-trifluoromethyl substituted 3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione scaffold. The method is based on a practical one-step cyclocondensation of 2-(2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl)acetic acid derivatives via the Curtius rearrangement of the corresponding acyl azides formed in situ upon the treatment with diphenylphosphoryl azide. The resulting products have been found to possess a potent inhibitory effect on PARP-1 and PARP-2 isoforms of poly(ADP-ribose) polymerases. The structure–activity analysis has revealed that the N1-aryl substituent is crucial to the selectivity and high potency towards PARP-2, and that the p-fluorobenzyl group is the optimal group for the non-selective and potent PARP-1 and PARP-2 inhibition.

The functionalization of 4-(diethoxyphosphoryl)-4,7-dihydro-5H-thiopyrano[3,4-b]furan was carried out at the position 5 of thiopyran fragment. Alkaline hydrolysis of ethyl-4-(diethoxyphosphoryl)-4,7-dihydro-5H-thiopyrano[3,4-b]furan-5-carboxylate proceeds selectively at the ester group. The acid formed, when treated with thionyl chloride, gives the corresponding acid chloride. The latter was used for the acylation of glycine, α- and β-alanine esters. Acid chloride under the conditions of phase transfer catalysis forms acyl azide, which under mild conditions rearranges to isocyanate. The latter compound reacts with primary amines to form ureas, and with amino acid esters—the ureide esters. Reduction of the acid chloride with sodium borohydride leads to the corresponding alcohol. The chloride obtained from it reacts with sodium azide and iodide to form the usual products of nucleophilic substitution, and with potassium thiocyanate it gives thiocyanate. Iodide reacts with triethyl phosphite to form the corresponding phosphonate. The oxidation of alcohol with Collins reagent and the acetic anhydride–DSMO system was studied. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in the DNA repair pathway. Inhibitors of these enzymes belong to a new type of anticancer drugs that selectively kill cancer cells by targeting the homologous recombination genetic defects. This study presents a new synthetic approach to PARP inhibitors containing a 4-trifluoromethyl substituted 3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione scaffold. The method is based on a practical one-step cyclocondensation of 2-(2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl)acetic acid derivatives via the Curtius rearrangement of the corresponding acyl azides formed in situ upon the treatment with diphenylphosphoryl azide. The resulting products have been found to possess a potent inhibitory effect on PARP-1 and PARP-2 isoforms of poly(ADP-ribose) polymerases. The structure–activity analysis has revealed that the N1-aryl substituent is crucial to the selectivity and high potency towards PARP-2, and that the p-fluorobenzyl group is the optimal group for the non-selective and potent PARP-1 and PARP-2 inhibition [ABSTRACT FROM AUTHOR]

One-pot combination of Curtius rearrangement and radical polymerization of an acrylamide derivative bearing carbonyl azide group (ACA) was investigated to provide polyacrylamide bearing side-chain isocyanate groups. The one-pot Curtius rearrangement and radical polymerization successfully proceeded at a low monomer concentration (0.05 mol/L) to avoid cross-linking between the side-chain isocyanate groups. The one-pot conversion of the in situ generated isocyanate groups into the urethane groups succeeded by the excess amount of alcohol to be reacted (100 equivalents to ACA). The one-pot reaction in the presence of various alcohols (methanol, ethanol, propanol, and butanol) proceeded smoothly to provide the polyacrylamide bearing various urethane moieties with number average molecular weights (Mn = 1200 ~ 1600) in 63–96% yields. [ABSTRACT FROM AUTHOR]

An efficient method was developed for the one-pot synthesis of novel series of urea derivatives from 4-(4-aminophenyl)-3-morpholinone via in situ generated isocyanate through continuous-flow system. All the compounds were docked against DNA gyrase enzyme and antimicrobial and antifungal activities were investigated. [ABSTRACT FROM AUTHOR]

A novel compound N-benzyl-2-oxo-1,2-dihydrofuro [3,4-d]pyrimidine-3(4H)-carboxamide (DHFP) was synthesized by addition, rearrangement, and intramolecular cyclization reactions. The three-dimensional geometry of DHFP has been determined by density functional theory calculations in the gas phase. Thus, the geometrical properties of DHFP such as the bond lengths, bond angles, and dihedral bond angles have been determined in the optimized molecular configuration. Also, the HOMO-LUMO energies were calculated. The charge distribution of the DHFP has been calculated by Natural Population Analysis (NPA) approach. NMR and FTIR spectra were calculated and compared with their experimental corresponding to confirm the synthesis of the DHFP. The anticancer activities of the DHFP were also determined on human colon cancer (HT29) and prostate cancer (DU145) cell lines. Molecular docking studies of the DHFP with EGFR tyrosine kinase, which is responsible for cancer cell proliferation and growth, were performed and it was observed that docking interaction took place. The DHFP has the potential to be a drug, as it is determined that DHFP obeys Lipinski's five rules, can cross the blood-brain barrier, and can be rapidly absorbed from the gastrointestinal wall.

We develop a tandem protocol to synthesize unsymmetrical sulfoximine‐based urea via Curtius rearrangement. The aliphatic/aromatic acid in the presence of diphenylphosphorylazide (DPPA) undergo Curtius rearrangement, and subsequent nucleophilic attack with sulfoximine provides corresponding urea derivative in very good to excellent yield. The protocol is equally applicable for gram‐scale synthesis. The direct use of cheap, easy handling, commercially available aliphatic/aromatic acids are the main advantages of this method. Additionally, we synthesize the sulfoximine analogue of key biologically active compounds, such as tolbutamide, chlorpropamide, and oncolytic sulfonyl urea. [ABSTRACT FROM AUTHOR]

In the reaction of 2H-azirine-2-carbonyl azides with vinyldiazoacetates at ambient temperatures in the absence of an effective oxidant, a competition takes place between the rearrangement of the azidohydrin intermediate of the Schmidt reaction, leading to pyridine-3-isocyanate, and the decomposition of the intermediate to form deaminated pyridine and cyanic acid. The driving force behind both processes is the elimination of a nitrogen molecule. In the presence of an effective oxidizing agent in the reaction medium, the main process is the Curtius rearrangement of the pyridinecarbonyl azide intermediate, leading to pyridine-3-isocyanate. [ABSTRACT FROM AUTHOR]

[Display omitted] Efficient preparative procedures for the synthesis of 2,3-disubstituted 5,6,7,8-tetraalkoxyquinolines starting from tetraalkoxybenzaldehydes are reported. The latter are available from plant (polyalkoxy)(allyl)benzenes, secondary metabolites of parsley and dill seeds. [ABSTRACT FROM AUTHOR]

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.

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 1Н, 13C and 19F 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.

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. [ABSTRACT FROM AUTHOR]

The ring contraction‐lactamisation of anhydrides upon reaction with trimethylsilylazide in the presence of an amine catalyst has been studied. Under controlled conditions, 5,‐ 6‐ and 8‐membered ring lactams can be generated from cyclic anhydrides in an operationally simple procedure. In the case of γ‐lactams, the methodology allows for the synthesis of challenging systems incompatible with the usual disconnection involving an amine and an activated carbonyl group. The synthesis of simple larger ring lactams is hampered by inaccessible monomeric cyclic anhydride precursors ‐ a problem which can be circumvented through rigidification. Succinic anhydrides make N‐carboxyanhydrides of use in polymer chemistry and as β‐peptide precursors. [ABSTRACT FROM AUTHOR]

Unprecedented reversal in regioselectivity during methanolysis of anhydrides due to the change in substitution pattern of fluorine in the phenyl moiety, and the formation of nitrene intercepted intermediates during Curtius rearrangement of the acids were the major impediments for discovering bioactive molecules in beta amyloid cleaving enzyme‐1 (BACE1) program. Solutions to these synthetic challenges, and our investigation into this unexpected change in reactivity are discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The 2-(alkylcarbonyl)benzoic acids obtained by esterification of phthalic anhydride are converted into azide derivatives: alkyl 2-[(azidocarbonyl)amino]benzoates and to ureas: dialkyl 2,2′-[carbonyl bis (azanediyl)]dibenzoates. These transformations were carried out using classical Curtius rearrangement conditions in the presence of diphenylphosphoryl azide (DPPA) in a basic medium, followed by hydrolysis. Subsequently, a final condensation reaction of these urea derivatives enabled us to obtain, for the first time, the new alkyl derivatives, alkyl 2-[2,4-dioxo-1,2-dihydroquinazolin-3(4 H)-yl]benzoates. All the new compounds obtained in satisfactory yields were characterized by1 H and13 C NMR, and by X-ray crystallographic analysis. [ABSTRACT FROM AUTHOR]

Direct conversion of carboxylic acids to ureas, carbamates, and thiocarbamates in a single pot via Curtius rearrangement is accomplished. One recently established coupling reagent, Ethyl‐2‐cyano‐2‐(2‐nitrophenylsulfonyloximino)acetate (ortho‐NosylOXY, I), is successfully used for the racemization free synthesis of ureas, di‐peptidyl ureas, and carbamates with moderate to good yield (82–69%). This single‐pot hassle‐free procedure works with a diverse range of N‐protecting groups Fmoc, Boc, and Cbz. Various amine, including aromatic, methyl esters of amino acids, t‐butylamine, alcohols, and thiols, are used as nucleophiles. A detailed NMR‐based mechanism study is incorporated here. Racemization suppression, easy removal of by‐products, and less waste generation make this methodology useful. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A convenient, safe, and effective synthetic protocol for the synthesis of chiral β-homoglutamic acid was described. The strategy started from 3-cyclohexenecarboxylic acid, followed by three steps classic reaction including Curtius Rearrangement, oxidative cleavage of alkene, and debenzylation by catalytic hydrogenation. The chiral β-homoglutamic acid was prepared with a high yield and high enantiomeric excess. [ABSTRACT FROM AUTHOR]

Three new functional 2‐substituted 1,3‐dinitroimidazolidines were synthesized herein. A synthetic strategy is suggested for structurally different α,α‐dinitraminocarboxylic acids via condensation of glyoxylic acid ethyl ester with amine or amide derivatives. Alkali‐ and acid‐catalyzed hydrolyses of ethyl 1,3‐dinitroimidazolidine‐2‐carboxylate were studied. A series of hydrolysis products were isolated. The Curtius rearrangement of 1,3‐dinitroimidazolidine‐2‐carboxylic acid to 2‐isocyanato‐1,3‐dinitroimidazolidine was carried out. Hydrolyses of 1,3‐dinitroimidazolidine‐2‐carbonyl azide and 2‐isocyanato‐1,3‐dinitroimidazolidine were studied. 1,3‐Dinitroimidazolidine‐2‐amine was captured as 1,3‐bis(1,3‐dinitroimidazolidin‐2‐yl)urea. [ABSTRACT FROM AUTHOR]

The Curtius rearrangement reaction is studied by using quantum theory of atoms in molecules (QTAIM) analysis of the electron density and the interacting quantum atoms (IQA) formalism. Although the rearrangements take place in one stage, two phases are distinguished when the rearranged atom is H: the first one corresponds to the separation of N2, and the second one to the N‐H/C‐H bond rearrangement. The transition state (TS) for the reaction does not represent an intermediate between reagent and product for the migration but for the isolation of the N2 molecule. When the migration is undergone by a fluorine atom, no electronic phases can be distinguished and the process is really concerted. As the migration happens closer to the TS, the TS is more similar to the product. The IQA analysis reveals different electron density evolutions for H and F migrations, and the scarce relevance (in terms of energy) of the point where BCPs appear or disappear. [ABSTRACT FROM AUTHOR]

A metal‐free, versatile triple‐bond directed approach for the decarbonylative C−H amination of ortho‐alkynyl quinoline/pyridine aldehydes using N‐fluorobenzenesulfonimide as nitrogen source under mild reaction conditions has been described. The designed reaction strategy was triggered by trapping of fluorine by base with subsequent attack of bis(phenylsulfonyl)‐λ2‐azane on the carbonyl carbon of a heterocycle, which was gradually converted into the corresponding amine through a Curtius type rearrangement. This protocol provides a one‐step approach for the conversion of aldehydes into amines in good yields. The synthesized amines were successfully transformed into biologically important pyrroloquinolines/pyridines. [ABSTRACT FROM AUTHOR]

Pd‐catalyzed synthesis of urea derivatives from aryl iodides and different aliphatic and aromatic amines using sodium azide and chromium hexacarbonyl is described. In this process, carbonylation of aryl iodides, Curtius rearrangement of aroyl azides, and nucleophilic addition of amines sequentially occur to afford the products in good to excellent yields. This protocol is operationally simple and displays a broad substrates scope. [ABSTRACT FROM AUTHOR]

A palladium‐catalyzed domino method for the direct synthesis of carbamates and ureas has been developed by using readily available and economical starting materials (aryl halide, carbon monoxide, sodium azide, amines and alcohols) in a one‐pot approach. The domino process underwent carbonylation, Curtius rearrangement, and nucleophilic addition. This protocol provides a step‐economical and highly efficient reaction to access the wide range of valuable carbamates, symmetrical and unsymmetrical ureas with high yields under remarkable mild reaction conditions that are important factors in pharmaceutical science, biochemistry and agricultural industries. Furthermore, the magnetically recoverable nanocatalyst (Fe3O4@SiO2/Pd(II)) can be conveniently and swiftly recycled using external magnet and reused at least for seven times without noticeable loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

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 /Et3 N 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Some new isoxazole derivatives 3a-d were synthesized via the reaction of 3-(dimethylamino)-1-(5-methyl-1-(3-nitrophenyl)-1^-1,2,3-triazol-4-yl)prop-2-en-1-one (1) with different hydroximoyl chlorides derivatives 2a-d. From these new isoxazoles 3a-d a new series of isoxazolopyridazines 4a-d was derived using hydrazine hydrate. In addition, enaminone 1 was reacted with ethyl acetoacetate to afford the corresponding ester derivative 6, the latter was submitted to react with different chemical reagents to obtain a variety of bioac-tive substituted pyridine derivatives. The azido derivative 14, was used as the key molecule for the synthesis of new urea and aryl carbamate derivatives upon its reaction with different amines and phenol through Curtius rearrangement. The chemical compositions of all the new compounds were investigated from their spectral and microanalytical data. The synthesized compounds were tested for their pharmacological potency as, anti-hepatic cancer and anti-microbial agents. Most of the tested compounds showed good anti-hepatic cancer results comparing with the standard drug doxorubicin especially when their toxic effects on the normal cell lines were studied. Referring to the anti-microbial test most of the compounds showed strong effects. [ABSTRACT FROM AUTHOR]

• The more stable syn-syn conformer of MA than the syn-anti conformer. • The preferred one-step process of Curtius rearrangement of syn-syn -MA comparing with the two-step concerted mechanism. • Eight structural stability domains and seven catastrophes of the cusp and fold types to achieve Curtius rearrangement of syn-syn -MA. • Ninet structural stability domains and eight catastrophes of the cusp and fold types to achieve Curtius rearrangement of syn-ICA. • The concerted Curtius rearrangement of syn-syn -MA and syn -ICA are highly asynchronous processes with the absolute asynchronicity of 0.801 and 0.763, respectively. An innovative and comprehensive theoretical investigation was conducted to examine the thermal Curtius rearrangement of malonyl azide in its syn–syn and syn–anti conformations, taking into account both the concerted and stepwise pathways. This study covered analyses performed in gaseous environments and a range of solvents. In both the gas phase and different solvents, the syn–syn conformation of malonyl azide proves to be more stable than the syn–anti conformation with a stability difference ranging from 4.15 to 4.99 kcal mol−1. It undergoes an exergonic concerted process with a single transition state, leading to the formation of syn –2–isocyanatoacetyl azide. Furthermore, syn –2–isocyanatoacetyl azide can be converted into methylene diisocyanate via a concerted pathway. In contrast, the rearrangement of the syn–anti conformation involves two transition states and an intermediate. The initial step is endergonic, followed by an exergonic subsequent step. The calculated ΔG values for the conversion of syn–syn –MA to syn –ICA and syn –ICA to MDI in the gas phase, determined at the CBS–QB3 level of theory, are –62.91 and –64.67 kcal mol−1, respectively. Meanwhile, the Gibbs free energies for the first and second steps of the rearrangement of syn-anti conformation are 10.51 and –77.98 kcal mol−1, respectively. Theoretical results indicate the dominance of the concerted pathway, surpassing the stepwise mechanism by roughly 104–106 and 104 times in both the gas phase and various solvents, respectively. Analyzing the electron localization function using the B3LYP/6–311++G(2d,d,p) level of theory unveils the catastrophe sequences for syn–syn malonyl azide and syn –2–isocyanatoacetyl azide structures, denoted as 8–CF†C†TSF†C†C†C and 9–CF†C†TSFC†FC†C-0 , respectively. The Curtius rearrangement of the syn–syn malonyl azide conformer commences with the transformation of two valence bonding disynaptic attractors, where V 1,2 (N 2 ,N 3) merges into a single disynaptic attractor. This is followed by the division of the non–bonding monosynaptic attractor V(N 1) into two non–bonding monosynaptic attractors. Subsequently, the N 1 –N 2 bond breaks, eliminating a nitrogen molecule and altering the topological signature of C 1 –N 1. This transformation leads to the consolidation of the pair of non–bonding monosynaptic attractors V 1,2 (N 1) into a single non–bonding monosynaptic attractor V(N 1). Then, the C 1 –C 2 bond breaks, resulting in the formation of pseudo–radical centers on the C 1 and C 2 atoms. Following this, a transformation in the topological signature of C 1 –N 1 occurs, leading to the elimination of pseudo–radical centers on the C 1 atom and the formation of a C 2 –N 1 bond. The results of ELF calculations indicate that the Curtius rearrangement of syn -ICA follows a method similar to that of syn-syn. The results indicate that the reaction follows a concerted mechanism but is highly asynchronous, with absolute asynchronicity indices of 0.801 and 0.763 for the Curtius rearrangement of syn -syn-MA and syn -ICA, respectively. [ABSTRACT FROM AUTHOR]

In this paper, the H-shift, Curtius rearrangement and intersystem crossing (ISC) processes of singlet methoxysulfonyl nitrene CH 3 OS(O) 2 N have been investigated theoretically without and with one water molecule to explore the role of water to play in the title reaction. The calculation results demonstrate that the introduction of one water molecule is effective in stabilizing the transition states and reducing the barrier heights of the reactions compared to the isolated reactant, and the formations of singlet HNSO 2  + HCHO and CH 3 ON + SO 2 are the most feasible product pathways both in the absence and presence of one water molecule. [ABSTRACT FROM AUTHOR]

Abstract: A palladium‐catalyzed carbonylative procedure for the synthesis of unsymmetrical ureas has been developed. This one‐pot one‐step cascade procedure is consisted by three individual processes: carbonylation, Curtius rearrangement, and nucleophilic addition. A series of unsymmetrical ureas were prepared from easily available aryl iodides and amines in moderate to excellent yields. This procedure provides a convenient and practical approach for unsymmetrical urea synthesis. [ABSTRACT FROM AUTHOR]

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 10 4 –10 5 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 † TS FC † FC † C-0 by the following chemical events: (a) change of topological signature of N 2 N 3 bond; (b) increasing the number of non-bonding monosynaptic attractor on N 1 atom; (c) breaking of N 1 N 2 bond and extrusion of nitrogen molecule; (d) decreasing the number of non-bonding monosynaptic attractors on N 1 atom; (e) breaking of C 4 C 5 bond and formation of pseudoradical centers on the C 4 and C 5 atoms; (f) annihilation of pseudoradical center on the C 5 atom; (g) change of topological signature of N 1 C 5 bond; and (h) formation of N 1 C 4 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. [ABSTRACT FROM AUTHOR]

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 Introduction 2 Synthesis of Acyl Azides 2.1 Acyl Azides from Carboxylic Acid Derivatives 2.2 Acyl Azides by Direct Transformation of Carboxylic Acids 2.3 Acyl Azides from Aldehydes 2.4 Carbamoyl Azides from Haloarenes, Sodium Azide, and N-Formylsaccharin 3 Mechanism of Formation of Isocyanates 4 Synthesis of Diacyl Azides 5 Synthetic Applications 5.1 Synthesis of Pyrimidinone Derivatives 5.2 Dihydropyrimidinone and Isoquinolinone Derivatives 5.3 Synthesis of Tetrahydroisoquinoline Skeleton 5.4 Synthesis of Five-Membered Heterocycles 5.5 Heterocycles Synthesized Starting from Homophthalic acid 5.6 Heterocycles Synthesized from 2-(Ethoxycarbonyl)nicotinic Acid 5.7 Formation of Aza-spiro Compounds 5.8 Parham-Type Cyclization 5.9 Diazepinone Derivatives 5.10 Synthesis of Pyridine Derivatives 5.11 Synthesis of Indole Derivatives 6 Miscellaneous 7 Conclusion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out. [ABSTRACT FROM AUTHOR]

Green synthesis of nano MgO particles and their application in the formylation of isocyanates of iV-Fmoc/Cbz/Boc protected amino acids were reported. Nano magnesium oxide catalysed reaction of isocyanate with 96% formic acid was established to obtain formamides. For this, the carboxyl group of protected amino acids was activated via mixed anhydride method and treated with NaNß. The formed azides were converted into their isocyanates through Curtius rearrangement and treated with HCOOH and catalytic amount of nano MgO. The advantages of this method were being remarkably simple and attaining economically low-cost nano metal oxide under milder reaction conditions. Most importantly, MgO could be easily separated and other basic impurities were removed through a simple work-up. This protocol showed high efficiency in catalysing the transformation in a greener fashion. The molecular docking study of the synthesized compounds was performed against the macromolecules sortase-A and glucosamine 6-phosphate synthase to understand the binding interactions. The results of in vitro antibacterial activities of the synthesized compounds were supported by docking analysis. [ABSTRACT FROM AUTHOR]

The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical. [ABSTRACT FROM AUTHOR]

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 . [ABSTRACT FROM AUTHOR]

The regio- and stereoselective synthesis of a new synthon, trans -3,8-dioxatricyclo[3.2.1.0 2,4 ]octane-6,7-diamine, from 7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate is reported. Transformation of the acid functionalities to acyl azides followed by Curtius rearrangement gave the corresponding trans -diisocyanate, which was reacted with HCl to produce a trans -diamino compound that is a potentially important synthon for the versatile synthesis of aminocyclitols. [ABSTRACT FROM AUTHOR]

A highly efficient synthesis of unsymmetrical sulfoximine ureas is developed. The reaction unites simple NH-sulfoximines and acyl azides by a formal Curtius rearrangement as the key step. This reaction could be easily scaled up to gram scale and omits the generation of hazardous byproducts, thus allowing a practical and environmentally benign path for the synthesis of medicinally important sulfonimidoyl unsymmetrical ureas. [ABSTRACT FROM AUTHOR]

A series of new bio-based aromatic diisocyanates, namely bis(4-isocyanato-2-methoxyphenoxy)alkane and bis(4-isocyanato-2,6-dimethoxyphenoxy)alkane, were synthesized starting from lignin-derived phenolic acids, namely vanillic acid and syringic acid, via the Curtius rearrangement. The diisocyanates were employed to synthesize poly(ether urethane)s by reacting them with potentially bio-based aliphatic diols, namely 1,10-decanediol and 1,12-dodecanediol. The chemical structures of diisocyanates and poly(ether urethane)s were confirmed using Fourier transform infrared, 1H NMR and 13C NMR spectroscopy. Inherent viscosities and number-average molecular weights of the poly(ether urethane)s were in the ranges 0.58-0.68 dL g−1 and 32 100-58 500 g mol−1, respectively, indicating the formation of reasonably high molecular weight polymers. The poly(ether urethane)s exhibited 10% weight loss in the temperature range 304-308 °C. The glass transition temperatures of the poly(ether urethane)s were in the range 49-74 °C and were dependent both on the number of methylene units in the diols and on the number of methoxy substituents on the aromatic rings of the diisocyanate component. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]