Phosphorus Heterocycles Research Articles

Chemoselective Synthesis of Fused Phosphorus Compound with 2-Hydropyrimidine-2-Thione Derivatives in Mixture of Water/Acetone as a Green Solvent

3,4-Dihydropyrimidin-2(1H)-thione derivatives undergo a chemoselective reaction with dialkylacetylenedicarboxylate in the presence of triphenylphosphine lead to the corresponding stable heterocyclic phosphorus ylides in good yield. In this method, a mixture of water/acetone as a green solvent was used. [Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the following free supplemental files: Additional figures]

Formation of phosphorus heterocycles using a cationic electrophilic phosphinidene complex

The electrophilic terminal aminophosphinidene complex [CpFe(CO)2P{N-i-Pr2}][X] (Cp = cyclopentadienyl, i-Pr = isopropyl, X = AlCl4 or NaBPh4), generated from [CpFe(CO)2{P(Cl)N-i-Pr2}] by chloride abstraction, reacts with alkynes and alkenes via (1 + 2) cycloaddition to form phosphirenes and phosphiranes respectively. Conjugated alkenes react with [CpFe(CO)2P{N-i-Pr2}]+ to form phosphirane intermediates, which then rearrange to 3-phospholenes. The phosphinidene complex reacts with benzylideneacetone to give an oxo-3-phospholene complex. Azobenzene reacts with [CpFe(CO)2P{N-i-Pr2}]+ to form a benzodiazophosphole via C–H activation. Addition of HCl or HBF4·Et2O to the iron diphenylphosphirene complex and iron benzodiazophosphole complex results in P–N bond cleavage, yielding the respective chlorophosphorus heterocyclic complexes. The heterocycles can be removed from the metal complexes to make metal free phosphorus heterocycles by addition of trimethyl- or triethylphosphine.

Synthesis and Spectral Characterization of Some Novel Phosphonyl‐ and Phosphoryl Pyrazole Compounds

ABSTRACT1,3‐Diphenyl‐1H‐pyrazole‐4‐carbaldehyde (1) reacted with aniline, 2‐substituted anilines, and P,P‐dimethylphosphinic hydrazide in the presence of diethyl phosphite to give acyclic α‐aminophosphonate 2, cyclic α‐aminophosphonates 4–6, and α‐hydrazinophosphonate 7, respectively. Also, treatment of aldehyde 1 with cyanoaceto‐hydrazide, acetophenone, and malononitrile afforded the condensation products 8, 16, and 21, respectively, which in turn, reacted with diethyl phosphite and P,P‐dimethylphosphinic hydrazide. The reaction of diethyl phosphite with the hydrazone 8 and chalcone 16 yielded the novel phosphorus heterocycles 13 and 18, respectively, while its reaction with the dicyanoarylidene 21 produced the dicyanopyrazolyl phosphonate 22. On the other hand, treatment of the hydrazone 8 with P,P‐dimethylphosphinic hydrazide gave the unexpected P,P‐dimethylphosphinic hydrazone 15, which reacted with diethyl phosphite forming α‐hydrazinophosphonate 7. Furthermore, the interesting N‐phosphoryl pyrazoles 20 and 24 were resulted in good yield via cycloaddition of P,P‐dimethylphosphinic hydrazide to the chalcone 16 and dicyanoarylidene 21, respectively. Structures of all newly synthesized compounds were confirmed by considering the data of IR spectroscopy, MS, and 1H‐, 13C‐, and 31P‐NMR spectroscopy, as well as that of elemental analyses.

Cyclometalation of Aryl-Substituted Phosphinines through CH-Bond Activation: A Mechanistic Investigation

A series of 2,4,6-triarylphosphinines were prepared and investigated in the base-assisted cyclometalation reaction using [Cp*IrCl2]2 (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl) as the metal precursor. Insight in the mechanism of the C-H bond activation of phosphinines as well as in the regioselectivity of the reaction was obtained by time-dependent (31)P{(1)H} NMR spectroscopy. At room temperature, 2,4,6-triarylphosphinines instantaneously open the Ir-dimer and coordinate in an η(1)-fashion to the metal center. Upon heating, a dissociation step towards free ligand and an Ir-acetate species is observed and proven to be a first-order reaction with an activation energy of ΔEA = 56.6 kJ mol(-1) found for 2,4,6-triphenylphosphinine. Electron-donating substituents on the ortho-phenyl groups of the phosphorus heterocycle facilitate the subsequent cyclometalation reaction, indicating an electrophilic C-H activation mechanism. The cyclometalation reaction turned out to be very sensitive to steric effects as even small substituents can have a large effect on the regioselectivity of the reaction. The cyclometalated products were characterized by means of NMR spectroscopy and in several cases by single-crystal X-ray diffraction. Based on the observed trends during the mechanistic investigation, a concerted base-assisted metalation-deprotonation (CMD) mechanism, which is electrophilic in nature, is proposed.

Bulky Phosphinines: From a Molecular Design to an Application in Homogeneous Catalysis

The design and preparation of an asymmetrically substituted and bulky phosphinine was achieved by introducing sterically demanding substituents into specific positions of a rigid phosphorus-heterocyclic framework. Compound 5 shows, at the same time, axial chirality and a sufficiently high energy barrier for internal rotation to prevent enantiomerization. Both enantiomers of 5 were isolated by means of chiral analytical HPLC, and their absolute configurations could be assigned by combining experimental data and DFT calculations. Despite its substitution pattern, 5 can still coordinate to transition-metal centers through the lone pair of electrons on the phosphorus atom. Rapid C-H activation on the adjacent aryl substituent at the 2-position of the phosphorus heterocycle was achieved by using [{Cp*IrCl2}2] (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) as a metal precursor. A racemic mixture of 5 was applied as a π-accepting low-coordinate phosphorus ligand in the Rh-catalyzed hydroformylation of trans-2-octene, which showed a clear preference for the formation of 2-methyloctanal.

New Chiral Zwitterionic Phosphorus Heterocycles: Synthesis, Structure, Properties and Application as Chiral Solvating Agents

A family of new chiral zwitterionic phosphorus-containing heterocycles (zPHC) have been derived from methylene-bridged bis(imidazolines). These structures were unambiguously determined, including single-crystal XRD analysis for two compounds. The stability, acid/base and electronic properties of these dipolar phosphorus heterocycles were subsequently investigated. zPHCs can be successfully employed as a new class of chiral solvating agents for the enantiodifferentiation of chiral carboxylic and sulfonic acids by NMR spectroscopy. The stoichiometry and binding constants for the donor-acceptor complexes formed were established by NMR titration methods.

2‐(2′‐Pyridyl)‐4,6‐diphenylphosphinine versus 2‐(2′‐Pyridyl)‐4,6‐diphenylpyridine: Synthesis, Characterization, and Reactivity of Cationic RhIII and IrIII Complexes Based on Aromatic Phosphorus Heterocycles

The bidentate P,N hybrid ligand 1 allows access for the first time to novel cationic phosphinine-based Rh(III) and Ir(III) complexes, broadening significantly the scope of low-coordinate aromatic phosphorus heterocycles for potential applications. The coordination chemistry of 1 towards Rh(III) and Ir(III) was investigated and compared with the analogous 2,2'-bipyridine derivative, 2-(2'-pyridyl)-4,6-diphenylpyridine (2), which showed significant differences. The molecular structures of [RhCl(Cp*)(1)]Cl and [IrCl(Cp*)(1)]Cl (Cp*=pentamethylcyclopentadienyl) were determined by means of X-ray diffraction and confirm the mononuclear nature of the λ(3) -phosphinine-Rh(III) and Ir(III) complexes. In contrast, a different reactivity and coordination behavior was found for the nitrogen analogue 2, especially towards Rh(III) as a bimetallic ion pair [RhCl(Cp*)(2)](+) [RhCl3 (Cp*)](-) is formed rather than a mononuclear coordination compound. [RhCl(Cp*)(1)]Cl and [IrCl(Cp*)(1)]Cl react with water regio- and diastereoselectively at the external PC double bond, leading exclusively to the anti-addition products [MCl(Cp*)(1H⋅OH)]Cl as confirmed by X-ray crystal-structure determination.

Resolution of 5- and 6-Membered P-Heterocycles: Racemic and Optically Active Platinum(II)-3-Phospholene Complexes

Methods were developed for the resolution of several five- and six-membered phosphorus heterocycles (1c-e, 2, 4). It was investigated if the optical activity is preserved during the 1a→2→3→4 reaction sequence. Racemic and optically active 1b-e 3-phospholene 1-oxides were converted to the corresponding platinum-complexes (10b-e), which are potential catalysts.

Developments in the Coordination Chemistry of Phosphinines

AbstractThis microreview describes progress in the development and coordination chemistry of donor‐functionalized phosphinines – the phosphorus analogues of pyridines – that has been made during the last five years. The stepwise assembly of 2,4,6‐triarylphosphinines starting from functionalized benzaldehyde and acetophenone derivatives allows the incorporation of additional substituents into specific positions of the aromatic phosphorus heterocycle. This strategy can be used to synthesize chelating phosphinines, which is an essential aspect especially for the preparation of phosphinine‐based transition metal complexes containing metal centres in medium‐to‐high oxidation states. Access to such coordination compounds used to be very difficult because monodentate phosphinines cannot be used for this purpose, due to their weak σ‐donor properties but strong π‐accepting capacities. Moreover, metal complexes of less highly substituted phosphinines turned out to be extremely sensitive to nucleophilic attack, making their straightforward synthesis, characterization and application rather unattractive. The recent strategies in this area facilitate synthetic access to a completely new set of phosphinine‐metal complexes for the first time, leading to a much broader scope for potential applications. New developments in the areas of homogeneous catalysis and materials sciences can consequently be foreseen in the near future.

A Non-Karplus Effect: Evidence from Phosphorus Heterocycles and DFT Calculations of the Dependence of Vicinal Phosphorus–Hydrogen NMR Coupling Constants on Lone-Pair Conformation

In contrast to literature reports of a Karplus-type curve that correlates (3)J(PH) with phosphorus-hydrogen dihedral angle, a recently reported glycine-derived 1,3,2-oxazaphospholidine (7c) has two hydrogen atoms on the ring with identical PNCH dihedral angles but measured coupling constants of ∼6 and 1.5 Hz. DFT calculations were in accord with these values and suggested that the smaller coupling constant is negative. Experimental evidence of the opposite signs of these coupling constants was obtained by analysis of the ABX NMR spectrum of the new glycine-derived N-p-toluenesulfonyl phosphorus heterocycle 6c. DFT calculations on 6c and on Me(2)NPCl(2) and t-BuPCl(2) were also in accord with NMR data and allowed confirmation of unusual features including a lone pair effect on (3)J(PH), the negative coupling constant, temperature-dependent chemical shifts due to rotation about the sulfonamide S-N bond, and vicinal phosphorus-hydrogen coupling constants over 40 Hz. Calculation of phosphorus-hydrogen coupling constants both as a function of PYCH dihedral angle θ (Y = O, N, C) and lone pair-PYC dihedral angle ω shows similar θ,ω surfaces for (3)J(PH) with a range of (3)J(PH) from -4.4 to +51 Hz and demonstrates the large non-Karplus effect of lone-pair conformation on vicinal phosphorus-hydrogen coupling constants.

ChemInform Abstract: Acid/Base‐Catalyzed Cyclization of O‐Alkynylphenylphosphonic Acid Monoesters and (O‐Hydroxyphenyl)ethynylphosphinates.

AbstractThe first examples of the synthesis of phosphorus heterocycles via acid‐ or base‐catalyzed intramolecular cyclization reactions of title alkynes are given.

Synthesis of tetraethyl (2-benzyl-3-oxoisoindolyl-1,1-diyl)-bisphosphonate and its properties

The reaction of o-phthalyl chloride with sodium diethylphosphite affords a cyclic bisphosphonate, 3,3-bis(diethylphosphono)-1(3H)-isobenzofuranone. The reaction of 1(3H)-isobenzofuranone with potassium carbonate proceeds through the ring opening and elimination of one phosphonate group to give acyclic α-ketophosphonate. At the same time, the reaction of bisphosphonate with the concentrated hydrochloric acid does not lead to the ring opening but gives bisphosphonic acid in a good yield. 3,3-Bis(diethylphosphono)-1(3H)-isobenzofuranone reacts with benzylamine in the presence of triethylamine with the replacement of endocyclic oxygen atom by benzylamino group, which leads to the formation of the corresponding bisphosphonate phthalimide, the first representative of a new type of bisphosphonates and phosphorus heterocycles.

Acid/base‐catalyzed cyclization of O‐alkynylphenylphosphonic acid monoesters and (O‐hydroxyphenyl)ethynylphosphinates

AbstractIn this work, we found that acids (i.e., HCl and NaHSO3) rather than bases could catalyze the cyclization of o‐alkynylphenylphosphonic acid monoesters at slow rates and give phosphaisocoumarins in low to medium yields, whereas the cyclization of (o‐hydroxyphenyl)ethynylphosphinates proceeded very smoothly under basic conditions rather than acidic conditions, and a series of phosphachromones could be prepared in excellent yields at room temperature using K2CO3 as catalyst. This is the first example of the synthesis of phosphorus heterocycles via acid/base‐catalyzed intramolecular cyclization of alkynes. Possible mechanisms were discussed. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:649–652, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20728

Symmetrical spiro-phosphoroheterocycles from the selenation of carbohydrazides

2,4-Bis(phenyl)-1,3-diselenadiphosphetane-2,4-diselenide (Woollins’ reagent) reacts with benzoic hydrazides in refluxing toluene to give new symmetrical spiro heterocycles in 48–76% isolated yields. However, under identical conditions, treating Woollins’ reagent with thiophene-2-carbohydrazide leads to an additional product, 1,3,4-selenadiazole (27% yield) together with the spiro phosphorus heterocycle in 44% yield. Three representative X-ray structures are reported.

Preparation of Phospha Sugar Analogues and Their Evaluation as Novel Molecular Targeting Anticancer Agents

Phospha sugars were prepared by a novel synthetic route starting from phosphorus heterocyclic compounds, 2-phospholenes. The anhydro- and deoxy-phospha sugar derivatives have been revealed to have potential anticancer activities against human leukemia of K562 and U937 cell lines. In this article, deoxybromophospha sugars with different numbers of bromo substituents were prepared, and their anticancer activities were evaluated by MTT method. The order of the activities depending on the number of bromo substituent was first revealed, and trideoxytribromotetrofuranose type phospha sugar [2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (4: TBMPPAO)] was the most active among these phospha sugars prepared. Diasteromers of dideoxydibromotetrofuranose-type phospha sugar [2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2: DBMPPAO)] were separated into four components, and the structure as well as the character of each component was assigned by spectral and chromatographic data as well as by MTT method.The deoxybromophospha sugars have higher antileukemia activity than Gleevec against U937 cells.

Theoretical Conformational Analysis of Cyclic Organophosphorus and Organosilicon Compounds

The structure of some six- and eight-membered phosphorus and silicon heterocycles was established by the method of dipole moments and density functional theory calculations. There are two necessary conditions for the feasibility of the transannular interaction in these heterocycles: (1) the favorable disposition of the donor and acceptor centers in a molecule and (2) the presence of the substituents with the considerable polarizing effect at the heteroatom.

PdII and PtII Complexes of 2‐(2′‐Pyridyl)‐4,6‐diphenylphosphinine: Synthesis, Structure, and Reactivity

The coordination chemistry of the bidentate P,N hybrid ligand 2-(2'-pyridyl)-4,6-diphenylphosphinine (1) towards Pd(II) and Pt(II) has been investigated. The molecular structures of the complexes [PdCl(2)(1)] and [PtCl(2)(1)] were determined by X-ray diffraction, representing the first crystallographically characterized λ(3)-phosphinine-Pd(II) and -Pt(II) complexes. Both complexes reacted with methanol at the P=C double bond at an elevated temperature, leading to the corresponding products [MCl(2)(1H·OCH(3))]. The molecular structure of [PdCl(2)(1H·OCH(3))] was determined crystallographically and revealed that the reaction with methanol proceeds selectively by syn addition and exclusively to one of the P=C double bonds. Strikingly, the reaction of [PdCl(2)(1H·OCH(3))] with the chelating diphosphine DPEphos at room temperature in CH(2)Cl(2) led quantitatively to [PdCl(2)(DPEphos)] and phosphinine 1 by elimination of CH(3)OH and rearomatization of the phosphorus heterocycle.

ChemInform Abstract: Preparation and Characterization of Novel 4‐Bromo‐3,4‐dimethyl‐1‐phenyl‐2‐phospholene 1‐Oxide and the Analogous Phosphorus Heterocycles or Phospha Sugars.

AbstractSome new 4‐bromo‐2‐phospholene 1‐oxides (IV) are synthesized by allylic radical bromination of 2‐phospholene oxides (III).

Preparation and Characterization of Phospha Sugar Analogues, 2,3-Dibromo-3-methyl-1- phenylphospholane 1-Oxide Derivatives, as Novel Anticancer Agents

The synthesis of new phospha sugar analogues or phosphorus heterocycles and their biological activities as novel anticancer agents are reported in this article. A 1,2-dibromo-1,2-dideoxy phospha sugar derivative, 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2), was prepared from 1-phenyl-3-methyl-2-phospholene 1-oxide (1), and the yield and ratio of diastereomers 2a to 2d were changed by a catalyst such as manganese(IV) oxide and manganese(II) bromide. The antitumor activities of the mixture of dibromides 2 and the separated diastereomeric components 2a to 2d of the dibromides were evaluated by MTT in vitro method against the human leukemia cell lines of K562 and U937. The results showed that all of the diastereomers 2a to 2d as well as the diastereomer mixture exert excellent anticancer activity, and moreover, among them, diastereomer 2d showed the highest antitumor activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

ChemInform Abstract: Synthesis and Bio‐Activity of Alkyl/Aryl [2‐(1,2,4,5‐Tetrahydro‐3‐sulfanylene/selenylene naphtha[1,8][1,5,3]diazaphosphocin‐3‐yl)methyl amino acid esters

AbstractThe synthesis of the eight‐membered phosphorus heterocyclic compounds (VI) and (VIII) is accomplished in three steps involving the cyclization of diaminonaphthalene (I) with tris(bromomethyl)phosphine (II), conversion of the naphthodiazaphosphocine (III) (no yield given) to the corresponding sulfide (IV) and selenide (VII), and reaction of the latter compounds with amino acid esters (V).