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     

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.     

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     

A new P‐heterocyclic family: A variety of six‐membered and bridged P‐heterocycles with 1‐benzyl substituent

The ring enlargement of 1‐benzyl‐2,5‐dihydro‐1H‐phosphole oxide ( 1 ) via the corresponding 2‐phosphabicyclo[3.1.0]hexane 2‐oxide ( 2 ) afforded, depending on the conditions, the double bond isomers ( A and B ) of 1,2‐dihydrophosphinine oxide 4 or that of 3‐substituted 1,2,3,6‐tetrahydrophosphinine oxides 5 and 6 . Dihydrophosphinine oxides ( 4 ) were suitable starting materials for 1,2,3,4,5,6‐hexahydrophosphinine oxide 7 and 1,2,3,6‐tetrahydrophosphinine oxide 8 obtained by reductive approaches and for the double bond isomers ( A and B ) of 2‐phosphabicyclo[2.2.2]octadiene 2‐oxide 9 and phosphabicyclooctene oxide 10 prepared in Diels–Alder cycloaddition. Precursor 9 was utilized in the fragmentation‐related phosphorylation of alcohols. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:28–34, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20363     

Synthesis and use of borane and platinum(II) complexes of 3‐diphenylphosphino‐1‐ phenylphospholane (LuPhos)

3‐Diphenylphosphinoyl‐1‐phenylphospholane 1‐oxide ( 2 ) obtained by the Michael addition of diphenylphosphine oxide to the double‐bond of 1‐phenyl‐2‐phospholene 1‐oxide ( 1 ) was subjected to double deoxygenation to afford the corresponding bisphosphine ( 3 , LuPhos) that was converted to bis(phosphine borane) 4 and to cis chelate platinum(II) complex 6 . A mixed phosphine oxide–phosphine borane 5 was also prepared. Stereostructures of the bidentate P‐ligand 3 and the ring platinum(II) complex ( 6 ) were evaluated by quantum chemical calculations. Complex 6 used as a catalyst showed modest activity, but unusual regioselectivity in the hydroformylation of styrene and its 4‐substituted analogues. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:730–736, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20741     

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     

Convenient synthesis of 1-alkoxy-1,2-dihydrophosphinine 1-oxides by ring enlargement

The addition of dichlorocarbene to the double bond of 1-alkoxy-dihydrophosphole oxides and subsequent thermolysis of the adduct so obtained affords mixtures of the two double bond isomers of alkoxy-dihydrophosphinine oxides, if the latter step is carried out in the presence of triethylamine. Experimental data support the involvement of a cationic intermediate during the opening of the cyclopropane ring. A simplified procedure for the preparation of the starting dihydrophospholes is also presented.     

The Deoxygenation of Phosphine Oxides under Green Chemical Conditions

The deoxygenation of a few diaryl‐phenylphosphine oxides, dimethyl‐phenylphosphine oxide, and 3‐methyl‐1‐phenyl‐3‐phospholene 1‐oxide was studied by phenylsilane, tetramethyldisiloxane (TMDS), and polymethylhydrosiloxane (PMHS) under conventional or microwave (MW) heating, in toluene or in the absence of any solvent at different temperatures. It was found that the deoxygenation with TMDS or PMHS under MW and solvent‐free conditions may be the method of choice and provides a green chemical approach.     

Convenient synthesis of 1-alkoxy-di- and tetrahydrophosphinine 1-oxides by ring enlargement

The double bond of the P-alkoxy 3,4-dimethyl-2,5-dihydro-1H-phosphole 1-oxides reacts easily with dichlorocarbene to give two diastereomers of an unstable adduct useful in the synthesis of ring expanded products, such as 1,2-dihydrophosphinine oxides or 1,2,3,6-tetrahydrophosphinine oxides. The former can be prepared by thermolysis of the adducts, while the latter are obtained by cyclopropane ring opening effected by silver nitrate in an alcoholic solvent. The preparation of the double-bond isomers of 1-alkoxy-tetrahydrophosphinine oxides containing only one methyl substituent in the ring is also described. The reaction of dihydro-1H-phosphole oxides with dichlorocarbene can be modified to give P-alkoxy 1,4-dihydrophosphinine oxides in an unexpected reaction.     

A Case Study on the Resolution of the 1‐i‐Butyl‐3‐methyl‐3‐phospholene 1‐Oxide via Diastereomeric Complex Formation Using TADDOL Derivatives and via Diastereomeric Coordination Complexes Formed from the Calcium Salts of O,O′‐Diaroyl‐(2R,3R)‐tartaric Acids

The resolution of 1‐i‐butyl‐3‐methyl‐3‐phospholene 1‐oxide was studied applying TADDOL [(−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane], spiro‐TADDOL [(−)‐(2R,3R)‐α,α,α′,α′‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol], or the acidic and neutral Ca²⁺ salts of (−)‐O,O′‐dibenzoyl‐ and (−)‐O,O′‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid as the resolving agent. The absolute configuration of the P‐asymmetric center was determined by circular dichroism spectroscopy and related quantum chemical calculations. In one instance, the single crystal of the diastereomeric complex incorporating i‐butyl‐3‐phospholene oxide and spiro‐TADDOL was subjected to X‐ray analysis, which suggested a feasible hypothesis for the efficiency of the resolution process under discussion that may be an example for the “solvent‐inhibited” resolution.     

Preparation of 3‐(10′‐halo‐9′‐anthracenyl) isoxazolecarboxylic esters

The 10‐halo (Cl or Br) anthracene‐9‐nitrile oxides (1a,b) were obtained directly from the treatment of 9‐anthracenylaldoxime with N‐halosuccinimide (NCS or NBS) in DMF. The 3‐(10′‐halo‐9′‐anthracenyl)‐5‐isoxazolecarboxylic esters ( 5a,b and 6a,b ) were prepared via 1 ,3‐dipolar cycloaddition between the obtained nitrile oxides 1a (or 1b ) and two different dipolarophiles: ethyl β‐pyrrolidinocrotonate (an enamine of ethyl acetoacetate) or dimethyl acetylenedicarbox‐ylate (DMAD) respectively. The 10 (or 10′)‐ position of the anthracene in either anthracene‐9‐nitrile oxide or 3‐(9′‐anthracenyl) isoxazole molecules (3,4) is readily halogenated by N‐halosuc‐cinimide in DMF. X‐ray studies showed that 5a possesses two aromatic ring systems that lie at 74.4° from coplanarity. The bond linking the two ring systems is 1.4893(18) Å, indicating only partial conjugation between the two ring systems. The crystal lattice showed unique head‐to‐tail intermolecular stacking of anthracene rings.     

A New Monomer for π‐Conjugated Polymers — Synthesis and Characterization of Bis((Z)‐5‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole‐4‐yl)monosulfane

Bis((Z)‐5‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole‐4‐yl)monosulfane ( 6 ), a molecule consisting of two diphenyldithiafulvene units connected by a sulfur bridge, was synthesized by the selective lithiation of (Z)‐4‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole ( 7a ) at the endocyclic double bond and by subsequent reaction of the lithiated intermediate with bis(phenylsulfonyl)sulfane. Since this reaction sequence proceeded with retention of configuration, of three possible isomers (E, E, Z, E, and Z, Z) only the Z, Z form was obtained. On the basis of the X‐ray structure analysis and the NMR‐spectroscopic characterization of 6 supplemented by the NMR parameters of (E)‐ and (Z)‐4‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole, it was demonstrated that two characteristic ⁵J coupling constants of the proton at the exocyclic double bond indicate the configuration (Z or E) of disubstituted dithiafuvene derivatives.     

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     

P-Substituted 3-phosphabicyclo [3.1.0] hexane 3-oxides from diastereoselective substitution at phosphorus

Preparation of P-amino-3-phosphabicyclo[3.1.0]-hexane 3-oxides either by addition of dichlorocarbene to the double bond of 1-amino-2,5-dihydro-1H-phosphole 1-oxides or by substitution of the P-chloro derivative of the bicyclic system was accomplished. Two different diastereomers are obtained by the two approaches; their ¹³C NMR spectra were interpreted on the basis of the P-ethoxy isomers, whose structures were confirmed by X-ray analysis. The P-hydroxy adduct was also prepared, and it was found that intermolecular O H … O hydrogen bonding connects the molecules together in the solid phase. This effect eliminates the possibility of diastereoisomerism, as was also observed in the case of P-hydroxy tetrahydrophosphinine oxides. Thermolysis of the P-hydroxy adduct is a better way to synthesize 1-hydroxy-1,2-dihydrophosphinine oxides than by hydrolysis of the phosphinic chlorides.     

Microwave‐Assisted Direct Esterification of Cyclic Phosphinic Acids

It is known that phosphinic acids do not undergo direct esterification under conventional conditions. However, the reaction may take place on microwave irradiation. 1‐Hydroxy‐3‐phospholene 1‐oxides, 1‐hydroxy‐phospholane 1‐oxides, and a 1‐hydroxy‐1,2,3,4,5,6‐hexahydrophosphinine 1‐oxide were esterified with n‐pentanol, i‐pentanol, n‐octanol, and i‐octanol(2‐ethylhexanol). The phosphinates prepared in 50%–94% yield are all new compounds, and a number of them are useful intermediates.     

Regioselective Synthesis of β‐Aryl‐ and β‐Amino‐Substituted Aliphatic Esters by Rhodium‐Catalyzed Tandem Double‐Bond Migration/Conjugate Addition

Rhodium–phosphite catalysts were found to effectively mediate double‐bond migrations within unsaturated esters. Once the double‐bond is in conjugation with the carboxylate group, they also catalyze the Michael addition of carbon and nitrogen nucleophiles. In the presence of these catalysts, unsaturated carboxylates enter a dynamic equilibrium of positional and geometrical double‐bond isomers. The conjugated species are continuously removed through 1,4‐additions with formation of β‐amino esters or β‐arylated products, depending on the nucleophile employed. The applicability of both protocols to a range of substrates, such as fatty esters of different chain lengths and double‐bond positions, and several nucleophiles including arylborates and primary and secondary amines, is demonstrated.     

Unexpected Course of the Reaction of 2‐Unsubstituted 1H‐Imidazole 3‐Oxides with Ethyl Acrylate

The attempted ethenylation at C(2) of 2‐unsubstituted 1H‐imidazole N‐oxides with ethyl acrylate (=prop‐2‐enoate) in the presence of Pd(OAc)₂ does not occur. In contrast to the other aromatic N‐oxides, the [2+3] cycloaddition of imidazole N‐oxides predominates, and 3‐hydroxyacrylates, isomeric with the cycloadducts, are key products for the subsequent reaction. The final products were identified as dehydrated 2+1 adducts of 1H‐imidazole N‐oxide and ethyl acrylate. The role of the catalyst is limited to the dehydration of the intermediate 3‐hydroxypropanoates to give 1H‐imidazol‐2‐yl‐substituted acrylates.     

α‐Aminophosphonates and α‐Aminophosphine Oxides by the Microwave‐Assisted Kabachnik–Fields Reactions of 3‐Amino‐6‐methyl‐2 H‐pyran‐2‐ones

The microwave‐assisted Kabachnik–Fields reaction of a series of 3‐amino‐6‐methyl‐2H‐pyran‐2‐ones, paraformaldehyde, and dialkyl phosphites or diphenylphosphine oxide led to α‐aminophosphonates or α‐aminophosphine oxides, respectively. The α‑aminophosphonates were obtained under solvent‐free conditions, whereas the α‑aminophosphine oxides in acetonitrile. The novel products were characterized by NMR and mass spectral data. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:221–225, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21086     

3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Rigid Acetylcholine Mimetics: Conformational Analysis and Direct Evidence of the Anomeric Effect

Conformational analyses of the P(3)‐axially and P(3)‐equatorially F‐substituted (±)‐cis‐ and (±)‐trans‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides) were performed. The results are based on independent studies in both solution and the solid state by ¹H‐ and ³¹P‐NMR experiments and computational and X‐ray crystallographic data. As expected, the axial epimers adopt neat double‐chair conformations in solution and in the crystal. Due to the anomeric effect of the electron withdrawing F‐substituent, the 2,4‐dioxa‐3‐phospha moiety in the equatorial epimers adopts a mixture of conformations in solution, mainly chair and twist‐boat; whereas a neat twist‐boat (trans‐isomer) and the unusual envelope conformation (cis‐isomer) were detected in the solid state. This is the first report of a straight visualization of these conformations and the impact of the anomeric effect in such systems.     

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