Phosphoryl Azide Research Articles

Synthesis of New 4,5-Dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine–Derived Ureas and Their Anticancer Activity

A new series of 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticancer activity. N-1-(5-Methylisoxazol-4-yl/4-fluoro-2,3-dihydro-1H-inden-1-yl/aryl)-N’-3-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl) urea derivatives were accomplished in good yields by the reaction of 4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine with 3-(3-chloro-5-fluoro-2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylic acid, 4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid, and various simple aromatic carboxylic acids in the presence of diphenyl phosphoryl azide (DPPA). All the newly synthesized title compounds were characterized by elemental and spectral data. Furthermore, anticancer activity was screened for the title compounds (12a–j) in vitro against human neuroblastoma cell lines (SK N SH) and human colon carcinoma cell lines (COLO 205) by using the MTT cell viability method. A few of them (12a and 12b) possess significant cytotoxicity, and some other compounds 12d-f and 12j displayed moderate cytotoxicity against both cell lines.

Synthesis of phosphoramidates: a facile approach based on the C-N bond formation via Ir-catalyzed direct C-H amidation.

A new synthetic route to phosphoramidates by intermolecular C-H amidation is presented. Substrates with assorted directing groups were activated by an iridium-based catalyst system and reacted with a number of phosphoryl azides, executing efficient phosphoramidate synthesis via C-N bond formations.

Iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide.

An iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide as the amino source is described. The direct C-H phosphoramidation of arenes bearing pyridinyl, pyrazoyl, and quinolinyl as the directing group has good functional group tolerance and occurs smoothly under mild conditions, providing N-aryl phosphoramidates in good yields.

Synthesis of chiral N-phosphoryl aziridines through enantioselective aziridination of alkenes with phosphoryl azide via Co(II)-based metalloradical catalysis.

The Co(II) complex of a new D2-symmetric chiral porphyrin 3,5-DiMes-QingPhyrin, [Co(P6)], can catalyze asymmetric aziridination of alkenes with bis(2,2,2-trichloroethyl)phosphoryl azide (TcepN3) as a nitrene source. This new Co(II)-based metalloradical aziridination is suitable for different aromatic olefins, producing the corresponding N-phosphorylaziridines in good to excellent yields (up to 99%) with moderate to high enantioselectivities (up to 85% ee). In addition to mild reaction conditions and generation of N2 as the only byproduct, this new metalloradical catalytic system is highlighted with a practical protocol that operates under neutral and non-oxidative conditions.

ChemInform Abstract: Cu‐Catalyzed Tandem Reactions of Fluorinated Alkynes with Sulfonyl Azides en Route to 2‐Trifluoromethylquinolines.

AbstractThe copper‐catalyzed reaction of alkyne (I) with phosphoryl azide (II) affords the desired phosphoramidate (III) under mild reaction conditions.

Copper-Catalyzed Reaction of Ketenimine and in Situ Generated Immonium Ion: Access to α,β-Unsaturated Amidines

A Cu-catalyzed three-component reaction of alkyne, azides (sulfonyl or phosphoryl azides), and N,N-dialkyloxyformamide dialkyl acetal via electrophilic addition of immonium ion to copper ketenimine is reported. This new protocol for the preparation of α,β-unsaturated amidine derivatives appears to offer high yield, mild conditions, and wide substrate scope. The reaction might involve the processes of copper ketenimine intermediate formation, electrophilic addition, and isomerization.

Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and scope

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.

ChemInform Abstract: [RuIV(F20‐TPP)Cl2] Efficiently Catalyzed Inter‐ and Intra‐Molecular Nitrene Insertion into sp3 C—H Bonds of Hydrocarbons Using Phosphoryl Azides as Nitrene Sources.

ChemInform Abstract: [Ru^IV(F₂₀‐TPP)Cl₂] Efficiently Catalyzed Inter‐ and Intra‐Molecular Nitrene Insertion into sp³ C—H Bonds of Hydrocarbons Using Phosphoryl Azides as Nitrene Sources.

Effective Synthesis of Chiral N‐Fluoroaryl Aziridines through Enantioselective Aziridination of Alkenes with Fluoroaryl Azides

Catalytic aziridination of alkenes with nitrene sources via “C2+N1” addition represents a general approach for the direct synthesis of aziridines, the smallest three-membered N-heterocycles.[1] The enantioselective version of this catalytic process allows for efficient access to chiral nonracemic aziridines, which are versatile synthetic intermediates in asymmetric synthesis.[1-2] Several classes of transition metal-based chiral catalysts, such as Mn, Fe, Cu, Rh and Co complexes, have been found effective in catalyzing asymmetric olefin aziridination with different nitrene sources.[1,3] Besides iminoiodanes and haloamines, organic azides have been actively pursued as alternative nitrene sources for metal-catalyzed aziridination as they enjoy several advantages.[3] While sulfonyl and phosphoryl azides have been effectively employed for metal-catalyzed asymmetric aziridination,[4] catalytic processes based on the use of other types of azides, such as aryl azides, have been less developed. In addition to generating environmentally friendly nitrogen gas as the only byproduct, asymmetric catalytic aziridination with readily available aryl azides provides an attractive approach for the synthesis of valuable N-aryl aziridines through direct introduction of N-aryl groups concurrently with the ring formation.[5,6] This would avoid two additional steps of deprotection and N-arylation when other types of nitrene sources are used for preparing N-aryl aziridines.[7] However, few catalytic systems have been shown to be effective for asymmetric olefin aziridination with aryl azides.[4d,6]

Organization of collagen in the presence of diphenyl phosphoryl azide (DPPA): An in vitro study

Collagen, an important fibrous protein and its stability is closely related to organizational order. In this work, organization of collagen in the presence of diphenyl phosphoryl azide (DPPA) was studied using circular dichroic spectroscopy, stress–strain characteristics and fibrillogenesis. The reconstituted collagen fibrils in the presence of DPPA were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and polarizing light microscopy. CD spectra show that the secondary structure of the collagen molecule is preserved when the concentrations of DPPA is less than 0.018μM. The Increase in shearing stress with shearing speed is 5–8% higher in the presence of DPPA may be due to the rigidity of the collagen chains. DPPA facilitates self assembly processes, thinner fibrils are seen in polarizing light microscopy and seem to favor the molecular and phase structure of collagen. Thermal stability of collagen in the presence of DPPA ensured the integrity and stabilization of reconstituted collagen fibrillar matrices. Collagen fibrils have higher denaturation enthalpy 15J/gm at 0.5μM (DPPA) when compared to 10.5J/gm for native collagen fibrils which is an indication of more stable fibrils. As a result, the reconstituted collagen fibrils in the presence of DPPA brought about the stabilization of the secondary structure of collagen molecules at lower concentrations of DPPA.

RuIV(F20-TPP)Cl2] efficiently catalysed inter- and intra-molecular nitrene insertion into sp3 C–H bonds of hydrocarbons using phosphoryl azides as nitrene sources

[Ru(IV)(F20-TPP)Cl2][H2(F20-TPP) = meso-tetrakis(pentafluorophenyl)porphyrin] is an active catalyst for both inter- and intra-molecular nitrene insertion into sp(3) C-H bonds of hydrocarbons in good to high product yields using phosphoryl azides as nitrene sources.

Mechanistic insights into the hydrolysis of organophosphorus compounds by paraoxonase-1: exploring the limits of substrate tolerance in a promiscuous enzyme

We designed, synthesized and screened a library of analogs of the organophosphate pesticide metabolite paraoxon against a recombinant variant of human serum paraoxonase-1. Alterations of both the aryloxy leaving group and the retained alkyl chains of paraoxon analogs resulted in substantial changes to binding and hydrolysis, as measured directly by spectrophotometric methods or in competition experiments with paraoxon. Increases or decreases in the steric bulk of the retained groups generally reduced the rate of hydrolysis, while modifications of the leaving group modulated both binding and turnover. Studies on the hydrolysis of phosphoryl azide analogs as well as amino-modified paraoxon analogs, the former being developed as photo-affinity labels, found enhanced tolerance of structural modifications, when compared with O-alkyl substituted molecules. Results from computational modeling predict a predominant active site binding mode for these molecules which is consistent with several proposed catalytic mechanisms in the literature, and from which a molecular-level explanation of the experimental trends is attempted. Overall, the results of this study suggest that while paraoxonase-1 is a promiscuous enzyme, there are substantial constraints in the active site pocket, which may relate to both the leaving group and the retained portion of paraoxon analogs.

ChemInform Abstract: Ruthenium(IV) Porphyrin Catalyzed Phosphoramidation of Aldehydes with Phosphoryl Azides as a Nitrene Source.

AbstractThe reaction works with alkyl phosphoryl azides as well and can be scaled up.

Ruthenium(iv) porphyrin catalyzed phosphoramidation of aldehydes with phosphoryl azides as a nitrene source

[Ru(IV)(por)Cl(2)] (por = porphyrin dianion) can efficiently catalyze nitrene insertion into aldehyde C-H bonds with phosphoryl azides as a nitrene source to give N-acylphosphoramidates in good to high yields.

Synthesis of an NDPK Phosphocarrier Domain Peptide Containing a Novel Triazolylalanine Analogue of Phosphohistidine Using Click Chemistry

Click phosphorylation of a propargylated unprotected peptide and phosphoryl azide using chaotrope-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition enabled a high-yielding and rapid synthesis of a nucleoside diphosphate kinase (NDPK) phosphocarrier domain. The synthesis showcases a valuable synthetic platform for the synthesis of biologically relevant phosphopeptide analogues.

Synthesis and Derivatization of the Bis(amido)‐λ3‐cyclodiphosphazanes cis‐[R′(H)NP(μ‐NR)]2, Including a Rare Example, trans‐[tBu(H)N(Se)P(μ‐NCy)]2, Showing Intermolecular Se···H–O Hydrogen Bonding

AbstractThe reaction of PCl3 with CyNH2 in a 1:3 ratio affordedthe dichloro‐λ3‐cyclodiphosphazane, cis‐[ClP(μ‐NCy)]2 (2), whereas the corresponding 1:5 reaction gave the bis(amido)‐λ3‐cyclodiphosphazane cis‐[Cy(H)NP(μ‐NCy)]2 (3) in quantitative yield. The dichloro derivative 2 was converted into 3 by reacting 2 with four equivalents of CyNH2. The mixed (amido)derivatives cis‐[tBu(H)NP(μ‐NCy)]2 (4) and cis‐[Cy(H)NP(μ‐NtBu)]2 (5) were prepared from the reaction of cis‐[ClP(μ‐NCy)]2 (2) and cis‐[ClP(μ‐NtBu)]2 (1a) with a fourfold excess of the respective primary amines. The oxidation of the bis(amido)‐λ3‐cyclodiphosphazanes 3–5 with two equivalents of H2O2/H2O, S8, and Se8 produced the bis(oxo) [R′(H)N(O)P(μ‐NR)]2 [R = R′ = Cy (6); R = tBu, R′ = Cy (7); R = Cy, R′ = tBu (8)], bis(sulfide) [R′(H)N(S)P(μ‐NR)]2 [R = R′ = Cy (9); R = tBu, R′ = Cy (10); R = Cy, R′ = tBu (11)], and bis(selenide) [R′(H)N(Se)P(μ‐NR)]2 [R = R′ = Cy (12); R = tBu, R′ = Cy (13); R = Cy, R′ = tBu (14)] derivatives, respectively. The reaction of cis‐[R(H)NP(μ‐NtBu)]2 with two equivalents of phosphoryl azide, [N3P(O)(OPh)2], afforded the corresponding bis(iminophosphoryl) derivatives, cis‐{R(H)N[(OPh)2P(O)N]P(μ‐NtBu)}2 [R = tBu (15), R = Ph (16), R = Cy (17)]. The solid‐state structures for 11, 12, 13, and 15 were determined by single‐crystal X‐ray diffraction studies. Interestingly, the bis(selenide) derivative [tBu(H)N(Se)P(μ‐NCy)]2 13 turned out be a trans isomer in the solid state, whereas the other cyclodiphosphazane derivatives exhibited the cis geometry. Compounds 13 and 15 crystallized along with a water molecule that facilitated the intermolecular Se···H–O and N···H–O hydrogen bonding, respectively, to form a linear 1D hydrogen bonding network.

Ultrafast Spectroscopy and Computational Study of the Photochemistry of Diphenylphosphoryl Azide: Direct Spectroscopic Observation of a Singlet Phosphorylnitrene

The photochemistry of diphenylphosphoryl azide was studied by femtosecond transient absorption spectroscopy, by chemical analysis of light-induced reaction products, and by RI-CC2/TZVP and TD-B3LYP/TZVP computational methods. Theoretical methods predicted two possible mechanisms for singlet diphenylphosphorylnitrene formation from the photoexcited phosphoryl azide. (i) Energy transfer from the (π,π*) singlet excited state, localized on a phenyl ring, to the azide moiety, thereby leading to the formation of the singlet excited azide, which subsequently loses molecular nitrogen to form the singlet diphenylphosphorylnitrene. (ii) Direct irradiation of the azide moiety to form an excited singlet state of the azide, which in turn loses molecular nitrogen to form the singlet diphenylphosphorylnitrene. Two transient species were observed upon ultrafast photolysis (260 nm) of diphenylphosphoryl azide. The first transient absorption, centered at 430 nm (lifetime (τ) ∼ 28 ps), was assigned to a (π,π*) singlet S(1) excited state localized on a phenyl ring, and the second transient observed at 525 nm (τ ∼ 480 ps) was assigned to singlet diphenylphosphorylnitrene. Experimental and computational results obtained from the study of diphenyl phosphoramidate, along with the results obtained with diphenylphosphoryl azide, supported the mechanism of energy transfer from the singlet excited phenyl ring to the azide moiety, followed by nitrogen extrusion to form the singlet phosphorylnitrene. Ultrafast time-resolved studies performed on diphenylphosphoryl azide with the singlet nitrene quencher, tris(trimethylsilyl)silane, confirmed the spectroscopic assignment of singlet diphenylphosphorylnitrene to the 525 nm absorption band.

Synthesis of Cyclophosphoramidates by Intramolecular C-H Amination

Reported is a synthesis of six- and seven-membered cyclophosphoramidates by ­cobalt(II)-catalyzed intramolecular C-H amination effected by phosphoryl azides. A previously ­reported method for intramolecular amination of carbonyl azides catalyzed by commercially available [Co(TPP)] (TPP: tetraphenylporphyrin) (J. V. Ruppel, R. M. Kamble, X. P. Zhang Org. Lett. 2007, 9, 4889) was found to be ineffective for phosphoryl azide substrates. The success of [Co(II)(Por)] A may be the result of hydrogen-bond interaction between P=O and NH which activates the catalysis.

Cobalt(II)-Catalyzed Intramolecular C−H Amination with Phosphoryl Azides: Formation of 6- and 7-Membered Cyclophosphoramidates

A highly effective Co(II)-based system has been developed for catalytic intramolecular C-H amination with phosphoryl azides without the need of terminal oxidant or other additives, resulting in the high-yielding production of cyclophosphoramidates with nitrogen gas as the byproduct. Additional features of this new catalytic system include the amination of primary C-H bonds and formation of 7-membered-ring structures.

Utility of Ammonium Salts for the Synthesis of Amidines

Reported is a copper-catalyzed, three-component coupling reaction of terminal alkynes, sulfonyl or phosphoryl azides and ammonium salts to give N-unprotected amidines. The derived amidines with a 2-bromosulfonyl moiety were efficiently cyclized by a copper-catalyzed ­intramolecular arylation to afford 2H-1,2,4-benzo-thiadiazine-1,1-dioxides. The reaction is carried out under very mild (room temperature), simple (inert atmosphere is not required) conditions using inexpensive ammonium salt or aqueous ammonia reagents. The synthesis of amidines proceeds mostly in good yields, except for using a phosphoryl azide (39% yield). The cyclization also proceeds in good yields as well as a one-pot version of the reaction. The substrate scope was well studied but the one-pot reaction was not well tested (one substrate).