Preparation of Optically Active Six‐Membered P‐Heterocycles: A 3‐Phosphabicyclo[3.1.0] hexane 3‐oxide,a 1,2‐Dihydrophosphinine 1‐oxide,and a 1,2,3,6‐Tetrahydrophosphinine 1‐oxide

The earlier described a 3‐methyl‐1‐phenyl‐3‐phospholene 1‐oxide ( 1 ) → 6,6‐dichloro‐1‐methyl‐3‐phenyl‐3‐phosphabicyclo[3.1.0]hexane 3‐oxide ( 2 ) → 4‐chloro‐1‐phenyl‐1,2‐dihydrophosphinine 1‐oxide ( 3 ) → 4‐chloro‐5‐methyl‐1‐phenyl‐1,2,3,6‐tetrahydrophosphinine 1‐oxide ( 4 ) reaction sequence was investigated from the point of view of preparing optically active intermediates/products ( 2–4 ). In principle, both the resolution of the corresponding racemic products and the transformation of the optically active starting materials are suitable approaches for the preparation of optically active six‐membered P‐heterocycles ( 2–4 ). Racemization occurred during the dichlorocyclopropanation reaction of (S)‐3‐methyl‐1‐phenyl‐3‐phospholene 1‐oxide ((S)‐ 1 ), but the thermolytic ring opening of (−)‐ 2, and the selective reduction of α,β‐double bond of (−)‐ 3 did not cause the loss of optical activity. First in the literature, the resolution of a 3‐phosphabicyclo[3.1.0]hexane 3‐oxide ( 2 ) and a 1,2,3,6‐tetrahydrophosphinine 1‐oxide ( 4 ) was elaborated. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:179–186, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21080     

The Synthesis of 3‐Phosphabicyclo[3.1.0]‐ hexane 3‐Oxides and 1,2‐Dihydrophosphinine 1‐Oxides with Lipophilic P‐Alkoxy Substituents by Ring Enlargement

A series of 1‐alkoxy‐3‐phospholene 1‐oxides available from the microwave‐assisted direct esterification of 1‐hydroxy‐3‐phospholene oxide was converted to the two diastereomers of 6,6‐dichloro‐3‐phosphabicyclo[3.1.0]hexane 3‐oxides by the addition of dichlorocarbene to the double bond. Thermolysis of the 3‐phospholene oxide–dichlorocarbene adducts afforded the corresponding 1,2‐dihydrophosphinine 1‐oxides as a ca. 3:1 mixture of two double bond isomers. Relative stability of the isomers of the intermediates and the products and their stereostructures were evaluated by B3LYP/6‐31G(d,p) calculations.     

The synthesis of optically active P‐heterocycles

Optically active 1‐alkoxy‐ and 1‐amino‐3‐phospholene oxides were synthesized by the reaction of the corresponding 1‐chloro‐3‐phospholene oxides with (1R,2S,5R)‐(–)menthol and (S)‐(–)‐α‐phenylethylamine. The 3‐methyl‐3‐phospholene oxides were subjected to dichlorocyclopropanation under liquid–liquid phase transfer catalytic conditions to afford the 3‐phosphabicyclo[3.1.0]hexane 3‐oxides as a mixture of four diastereomers. Thermolysis of the menthyl‐phosphabicyclohexane oxides led to the corresponding 1,2‐dihydrophosphinine oxide as a diastereomeric mixture of two double‐bond isomers. As a result of additional steps, the dichlorocarbene addition reaction of the 1‐menthyl‐3,4‐dimethyl‐3‐phospholene oxide resulted in eventually, the formation of a 4‐dichloromethylene‐1,4‐dihydrophosphinine oxide. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:271–277, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20599     

The synthesis of six‐membered P‐heterocycles with sterically demanding substituent on the phosphorus atom

The ring enlargement of 1‐(2,4,6‐trialkylphenyl)2,5‐dihydro‐1H‐phosphole oxides ( 1 ) via 6,6‐dichloro‐3‐Phosphabicyclo[3.1.0]hexanes ( 2 ) afforded the double‐bond isomers of 1,2‐dihydrophosphinine oxides ( 3 ). Catalytic hydrogenation of the isomeric 1‐(di‐tert‐butyltolyl)‐1,2‐dihydrophosphinine oxides ( 3a ) gave the diastereomers of phosphinane oxide ( 4 ), while that of the 1‐(tri‐isopropylphenyl) isomers ( 5 ) led predominantly to phospholane oxides ( 6 ) formed by ring contraction. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:528–533, 2001     

Fragmentation‐related phosphinylations using 2‐aryl‐2‐phosphabicyclo[2.2.2]oct‐ 5‐ene‐ and ‐octa‐5,7‐diene 2‐oxides

A series of new P‐methylphenyl P‐heterocycles are introduced. The para and ortho substituted 2,5‐dihydro‐1H‐phosphole oxides ( 1a and 1b ) were converted to the double‐bond isomers ( A and B ) of 1,2‐dihydrophosphinine oxides ( 3a and 3b ) via the corresponding phosphabicyclo[3.1.0]hexane oxides ( 2a or 2b ). Isomeric mixture ( A and B ) of the dihydrophosphinine oxides ( 3a and 3b ) gave, in turn, the isomers ( A and B ) of phosphabicyclo[2.2.2]oct‐5‐enes ( 4a and 4b ) or a phosphabicyclo[2.2.2]octa‐5,7‐diene ( 5 ) in Diels‐Alder reaction with dienophiles. The bridged P‐heterocycles ( 4 and 5 ) were useful in the photo‐ or thermoinduced fragmentation‐related phosphinylation of hydroxy compounds and amines. The new precursors ( 4a and 4b ) were applied in mechanistic investigations. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:443–451, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10176     

New P‐ligands: 3‐(ethyl‐phenylphosphinato‐) 1,2,3,6‐tetrahydro‐ and 1,2,3,4,5,6‐hexahydrophosphinine derivatives

The trimethylaluminum‐mediated Michael addition of ethyl phenyl‐H‐phosphinate to 1,2‐dihydrophosphinine oxides ( 1A ) yielded 3‐(EtOPhP(O))‐1,2,3,6‐tetrahydrophosphinine oxides ( 4 ) in a selective manner, as a mixture of only two diastereomers. In the above type of reactions (e.g., in that of 1Aa and Ph₂P(O)H), Me₃Al could not be substituted by microwave irradiation due to low efficiency. Catalytic hydrogenation of the Michael adducts ( 4 ) led to 3‐(EtOPhP(O)‐1,2,3,4,5,6‐hexahydrophosphinine oxides 5 , in the case of P‐phenyl substituent ( 5a ), as a mixture of only two diastereomers, while in the instance of the P‐ethoxy derivative ( 5b ), as a mixture of four isomers. Stereostructure of the products ( 5 ) was substantiated on the basis of analogies and stereospecific NMR couplings. The predominant conformations of compounds 4a , 4b , 5a , and 5b‐1 were determined by HF/6‐31G* calculations. Reduction of P(1)–Ph heterocycles 4a and 5a by phenylsilane resulted in monodeoxygenation to afford P‐ligands 6 and 8 , respectively, that were protected as the corresponding phosphine boranes ( 7 and 9 , respectively). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:747–753, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20365     

A new family of platinum(II) complexes incorporating five‐ and six‐membered cyclic phosphine ligands

New platinum complexes of the type cis‐Pt(L)₂Cl₂ have been synthesized from five‐ and six‐membered cyclic phosphines, which were prepared after deoxygenating a series of phosphine oxides (3‐phospholene oxides, phospholane oxides, a 1,4‐dihydrophosphinine oxide, and a 1,2,3,6‐tetrahydrophosphinine oxide). The complexes were characterized by NMR and mass spectral data, and their stereostructures were elucidated by B3LYP/6‐31G(d)‐LANL2DZ ECP calculations. The phosphine intermediates were characterized as the corresponding phosphine‐boranes. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:63–70, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20579     

Synthesis and X‐ray study of cis and trans isomers of 6‐cyano‐2‐oxa‐10‐thia‐1‐phosphabicyclo[4.4.0]decane‐1‐oxide

Intramolecular cyclization of bis(3‐chloropropyl)‐diethoxythiophosphorylacetonitrile 7, taking place under distillation in vacuo, yields 6‐cyano‐2‐oxa‐10‐thia‐1‐phosphabicyclo[4.4.0]decane‐1‐oxide 10 as a mixture of cis and trans isomers in a 2.3:1 ratio. The isomers were separated chromatographically. For both isomers, single crystals with nonequivalent enantiomeric ratios were obtained under crystallization. The structures of both isomers of bicyclophostone 10 are confirmed by X‐ray study of single crystals. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:163–170, 2000     

Phospha‐michael reactions involving p‐heterocyclic nucleophiles

P‐heterocyclic γ‐ketophosphonates were synthesized by the Michael reaction of methyl vinyl ketone with dibenzo‐1,2‐oxaphosphorine 2‐oxide, 1,3,2‐dioxaphosphorine 2‐oxide and benzo‐1,3,2‐dioxaphospholane 2‐oxide, respectively. In the first two cases, 50% of 1,8‐diazabicyclo[5.4.0[undec‐7‐ene had to be used that was also required in the addition of dibenzooxaphosphorine oxide to cyclohexenone to result in the formation of the corresponding γ‐ketophosphonate. The addition of dibenzooxaphosphorine oxide to less reactive 1,2‐dihydrophosphinine oxide was accomplished after activation by an equimolar amount of trimethylaluminum to afford a 3‐P(O)<‐1,2,3,6‐tetrahydrophosphinine oxide, which was subjected to catalytic hydrogenation to provide the corresponding 1,2,3,4,5,6‐hexahydrophosphinine oxide. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:288–292, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20421     

2‐Ethyl‐2‐phosphabicyclo[2.2.2]oct‐7‐ene derivatives: Synthesis and use in fragmentation‐related phosphorylations

A 2‐phosphabicyclo[2.2.2]oct‐7‐ene oxide ( 2 ) and a 2‐phosphabicyclo[2.2.2]octa‐5,7‐diene oxide ( 3 ) with ethyl substituent on the phosphorus atom was synthesized and their fragmentation properties were studied. The phosphabicyclooctadiene oxide ( 3 ) could be utilized in both the UV light‐mediated phosphorylation of simple alcohols and in the thermoinduced phosphorylation of hydroquinone giving an easy access to P‐ethylphosphinates (e.g., 4 and 6 ). The phosphabicyclooctene oxide ( 2 ) was, however, not useful in photoinduced phosphorylations; under such conditions the precursor ( 2 ) underwent dechlorination to afford 5 . © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:196–199, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20093     

3‐P⩵O‐Functionalized Phospholane 1‐Oxides by the Michael Reaction of 1‐Phenyl‐2‐phospholene 1‐Oxide and Dialkyl Phosphites,H‐Phosphinates,or Diphenylphosphine Oxide

The addition of dialkyl phosphites, H‐phosphinates, and diphenylphosphine oxide on the β carbon atom of the not too reactive double bond of 1‐phenyl‐2‐phospholene 1‐oxide was carried out in two ways. According to the first approach (A), the P‐reagents were activated by trimethylaluminum prior to the Michael addition. The second method (B) involved the microwave(MW)‐assisted solventless reaction of the P‐species with the phospholene oxide. In general, method A was more efficient and more selective than route B. However, the addition of dialkyl phosphites and diphenylphosphine oxide could also be accomplished well under MW conditions. The disadvantage of the MW‐assisted approach is that the Michael adducts are formed as a mixture of isomers. The 3‐P⩵O‐phospholane oxides are novel products, and among these, the bis(phosphine oxide) is the precursor of the bidentate P‐ligand LuPhos.     

Crystallographic characterization of a stable 7‐phosphanorbornadiene‐7‐oxide: 2,3‐benzo‐1,4,5,6,7‐pentaphenyl‐7‐phosphabicyclo[2.2.1] hepta‐2,5‐diene‐7‐oxide

The stable 7‐phosphanorbornadiene derivative, 2,3‐benzo‐1,4,5,6,7‐pentaphenyl‐7‐phosphabicyclo[2.2.1]hepta‐2,5‐diene‐7‐oxide ( 1 ) was synthesized in 45% yield via the Diels‐Alder reaction of pentaphenylphosphole oxide and benzyne. The reaction occurs specifically to give a single isomer, which was characterized by use of X‐ray crystallography and ³¹P NMR spectroscopy. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:182–186, 2000     

Synthesis,Characterization, and Application of Platinum(II) Complexes Incorporating Racemic and Optically Active 4‐Chloro‐5‐Methyl‐1‐Phenyl‐1,2,3,6‐Tetrahydrophosphinine Ligand

An efficient resolution method was elaborated for the preparation of (+)‐4‐chloro‐5‐methyl‐1‐phenyl‐1,2,3,6‐tetrahydrophosphinine oxide using the acidic Ca²⁺ salt of (–)‐O,O‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid. Crystal structure of the diastereomeric complex was evaluated by single crystal X‐ray analysis. Beside this, the absolute P‐configuration was also determined by a circular dichroism (CD) spectroscopic study including theoretical calculations. The tetrahydrophosphinine oxide was then converted to the corresponding platinum complex whose stereostructure was investigated by high‐level quantum chemical calculations. The Pt complex was tested as a catalyst in the hydroformylation of styrene.     

An efficient synthesis and crystal structure of novel 1‐oxo‐2‐propyl‐4‐(substituted)phenylimino‐1,2,3,4,5,6,7,8‐octahydro[1,4,3]thiazaphosphorino[4,3‐a][1,3,2]benzodiazaphosphorine 3‐oxides

A series of 1‐oxo‐2‐propyl‐4‐(substituted)phenylimino‐1,2,3,4,5,6,7,8‐octahydro‐[1,4,3]thiazaphosphorino[4,3‐a][1,3,2]benzodiazaphosphorine 3‐oxides ( 5a–g ) has been synthesized in excellent yields via the reaction of 1‐(2‐bromoethyl)‐2,3‐dihydro‐3‐propyl‐1,3,2‐benzodiazaphosphorin‐4(1H)‐one 2‐oxide with (substituted) phenyl isothiocyanates, which contain the proximate imino and phosphoryl groups in the fused heterocycle. The structures of all of the new compounds were confirmed by spectroscopic methods and microanalyses. The results from X‐ray crystallography analysis of 5a showed that the proximate imino and phosphoryl groups are not coplanar due to their being jointly located in the fused heterocycle, thus having ring tension, and this then destroys the conjugation between the CN and the PO moieties. As a result, the length of the P C bond, measured as 1.8285(18) Å, is just the same as that of a P C bond not involved in conjugation (1.80–1.85 Å). Also, the C(1), C(2), S(1), C(3), P(1), and N(2) atoms of the [1,4,3]thiazaphosphorino moiety exist preferably in the boat conformation. The coplanar C(1), N(2), C(3), and S(1) atoms, within an average deviation of 0.0564 Å, form the ground floor of the boat conformation, whereas, the P(1) and C(2) atoms are on the same side of the coplanar structure with the distance of 0.7729 Å and 0.7621 Å, respectively. On the other hand, around the CN double bond, the P(1) C(3) bond and the N(1) C(11) bond are in a trans relationship because of the repulsive action of the n‐propyl group in the 2‐position of the title compound. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:599–610, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10041     

A theoretical study on the conformation of 3‐phosphinoxido‐ and 3‐phosphono‐1,2,3,4,5,6‐hexahydrophosphinine 1‐oxides

The title compounds ( 2 and 4 ) obtained by the diastereoselective hydrogenation of the corresponding 1,2,3,6‐tetrahydrophosphinine oxides ( 1 and 3 ) were subjected to a detailed quantum chemical study. The possible chair conformers were calculated at the HF/6‐31G* level of theory, according to which, the 1‐phenyl‐3‐P(O)Y₂‐substituted products ( 2 ) exist in the trans₁ form, in which all substituents are equatorial. At the same time, the 1‐ethoxy‐3‐dialkylphosphono compounds ( 4 ) adopt the cis conformations, in which the 1‐ethoxy group is axial and the 3‐P(O)(OR)₂ moiety is equatorial. The major diastereomer ( 4–1 ) is cis₃, in which the 5‐methyl group is axial, while the minor one is cis₁ with an equatorial methyl substituent. It is noteworthy that the rotational position of the exocyclic P(O)Z₂ function affected the energy content of the chair conformer to a high extent. The possibility of the involvement of the twist conformers was also considered. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:520–524, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20148     

2,4‐Dioxa‐7‐aza‐, 2,4‐Dioxa‐8‐aza‐, and 2,4‐Dioxa‐9‐aza‐3‐phosphadecalins as Rigid Acetylcholine Mimetics: Syntheses and Characterization

Phosphorylation of suitable piperidine precursors yielded a series of novel decalin‐type O,N,P‐heterocycles. The title compounds, P(3)‐axially and P(3)‐equatorially X‐substituted, cis‐ and trans‐configurated 2,4‐dioxa‐7‐aza‐, 2,4‐dioxa‐8‐aza‐, and 2,4‐dioxa‐9‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides (X=Cl, F, 4‐nitrophenoxy, and 2,4‐dinitrophenoxy), are configuratively fixed and conformationally constrained P‐analogues of acetylcholine and as such represent acetylcholine (7‐aza and 9‐aza isomers) or γ‐homo‐acetylcholine mimetics (8‐aza isomers). Being irreversible inhibitors of acetylcholinesterase (AChE), the compounds are considered to be suitable probes for the investigation of the stereochemical course of the inhibition reaction by ³¹P‐NMR spectroscopy. Moreover, the design of these mimetics will enable studies of molecular interactions with AChE, in particular, the recognition conformation of acetylcholine.     

Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐oxides (=9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=7‐benzyl‐2‐fluorohexahydro‐4H‐1,3,2‐dioxaphosphorino[4,5‐c]pyridine 2‐oxides) were prepared (ee >99%) and fully characterized (Schemes 2 and 4). The absolute configurations were deduced from that of their precursors, the enantiomerically pure ethyl 1‐benzyl‐3‐hydroxypiperidine‐4‐carboxylates and 1‐benzyl‐3‐hydroxypiperidine‐4‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, the title compounds represent acetylcholine mimetics and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are moderate irreversible inhibitors of the enzyme.     

Synthesis and antimicrobial activity of 5,5′‐dimethyl‐2‐oxido‐[1,3,2]‐dioxaphos‐phorinane‐2‐yl‐amino carboxylates

Synthesis of several 5,5‐dimethyl‐2‐oxido‐[1,3,2]‐dioxaphosphorinane‐2‐yl‐amino carboxylates ( 4a–j ) was accomplished through a two‐step process. This involves prior preparation of the intermediate monochloride ( 2 ), 2‐chloro‐5,5‐dimethyl [1,3,2]dioxaphosphorinane‐2‐oxide and its subsequent reaction with various amino acid esters ( 3a–j ) in dry tetrahydrofuran in the presence of triethyl amine at room temperature. They were characterized by elemental analysis, IR, ¹H, ¹³C, ³¹P NMR, and mass spectral data. Their antifungal and antibacterial activity is also evaluated. Majority of these compounds exhibited moderate antimicrobial activity in the assay. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:256–260, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20426     

Synthesis,spectral, and antimicrobial studies of 1‐butyl‐3‐substituted‐4‐(2‐aryl‐1H‐indol‐3‐yl)‐2‐azetidinones

Ketene generated from acetyl chloride or chloroacetyl chloride adds on indolyl Schiff's base double bond to afford 1‐butyl‐3‐substituted‐4‐(2‐aryl‐1H‐indol‐3‐yl)‐2‐azetidinones in THF. The reaction proceeds stereospecifically via concerted trans [2+2] cycloaddition. The synthesized compounds have been characterized by elemental analyses and spectral data (IR, PMR, and mass). All synthesized compounds have been evaluated for antibacterial and antifungal activities, and 4g to 4l have shown promising results. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:494–501, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20052     

Synthesis of cyclic aminomethylphosphonates and aminomethyl‐arylphosphinic acids by an efficient microwave‐mediated phospha‐mannich approach

Microwave‐assisted condensation of 1,3,‐2‐dioxaphosphinane 2‐oxide ( 1 ), paraformaldehyde and secondary amines including 5‐ and 6‐membered N‐heterocycles at 55°C gave cyclic aminomethylphosphonates ( 2 ), whereas an analogous reaction involving dibenzo[c.e][1,2]oxaphosphinane 2‐oxide ( 3 ) resulted in the corresponding aminomethyl‐2‐(2′‐hydroxybiphenyl)phosphinic acids ( 4 ) as a consequence of a hydrolytic ring opening following the condensation. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:207–210, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20387