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The addition of phosphorous acid on the C=O group of substituted benzaldehydes in the presence of hydrochloric acid in water affords a mixture of the corresponding α - chlorophosphonic acid and α-hydroxyphosphonic acid. The selectivity towards the α-chloro derivatives may be increased to 92% by the excess of HCl applying forcing conditions. α- Hydroxyphosphonic acids may be synthesized better in yields of 83-92% by the hydrolysis of the corresponding dimethyl α-hydroxyphosphonates. α-Chlorophosphonic acids may also be obtained in yields of 66-79% from α -hydroxyphosphonic esters by reaction with thionyl chloride followed by hydrolysis. The α -chlorophosphonic acids and esters are useful intermediates for other phosphonic derivatives.

The possible combinations and connections of microwave (MW) and catalysts are discussed. MW-assisted reactions, such as the direct esterification or the alkylating esterification of phosphinic acid...

Background: The synthesis of high value risedronic acid is not fully resolved, as, for the time being, the best method based on the preparation from 3-pyridylcarboxylic acid by reaction with phosphorus trichloride in methanesulfonic acid gives risedronic acid in a good yield, but in an unpure form. Methods: Alternative protocols realizing the synthesis in sulfolane as the solvent and/or in the presence of suitable IL additive were developed to obtain the target dronic acid in a pure form. Results & Conclusion: Using phosphorus trichloride and phosphorous acid in two equivalents quantities together with 0.6 equivalents of [bmim][BF4] without any solvent, the method afforded the target dronic acid in a yield of 66% in a pure form.

The reaction of 1H-imidazol-1-ylacetic acid and two equivalents of phosphorus trichloride/phosphorous acid at 75 °C in sulfolane, or in the presence of catalytic amounts of [bmim][BF4] afforded zoledronic acid in yields up to 75%. The joint use of the ionic liquid additive and sulfolane as the solvent was synergetic affording highly valuable zoledronic acid in a record yield of 93%.

Several new trans-dihydronarciclasine analogues were stereo­selectively synthesised by applying our feasible and efficient process developed recently. These new phenanthridone alkaloid derivatives were obtained in both racemic and optically active forms. During their enantioselective syntheses, high selectivities (up to 99% ee) were achieved by using (8S,9S)-9-amino(9-deoxy)epiquinine as an organocatalyst. The modifications, the introduction of ethoxy or methoxy groups, were made in ring A of the phenanthridone scaffold.

Determination of the proton dissociation constants of several arylphosphonic acid derivatives was carried out to investigate the accuracy of the Hammett equations available for this family of compounds. For the measurement of the pKa values modern, accurate methods, such as the differential potentiometric titration and NMR-pH titration were used. We found our results significantly different from the pKa values reported before (pKa1: MAE = 0.16 pKa2: MAE=0.59). Based on our recently measured pKa values, refined Hammett equations were determined that might be used for predicting highly accurate ionization constants of newly synthesized compounds (pKa1=1.70-0.894σ, pKa2=6.92-0.934σ).

The microwave (MW) technique has become an important tool also in the organophosphorus field of organic chemistry. On the one hand, otherwise reluctant reactions, such as the esterification of P-acids, may be enhanced by the effect of MW, while on the other hand, catalysts may be omitted, or catalyst systems may be simplified on MW irradiation. This later group includes the Kabachnik–Fields reactions, alkylation of active methylene-containing compounds, O-alkylations, deoxygenations, as well as the Hirao reaction. It is also the purpose of this review to elucidate the scope and limitations of the MW tool, to interpret the MW effects, and to model the distribution of local overheatings and their beneficial effect.1 Introduction2 The Esterification of Phosphinic Acids2.1 Synthetic Results2.2 Scope and Limitation of the Application of MWs2.3 Modelling the Distribution of the Local Overheatings and Predicting­ Their Effect3 The Simplification of Catalytic Systems3.1 Replacement of the Catalyst by MW Irradiation3.1.1 The Kabachnik–Fields Reaction3.1.2 Solid–Liquid Phase Alkylation of Active Methylene-Containing Compounds3.1.3 Solid–Liquid Phase Alkylation of Phosphinic Acids3.1.4 The Deoxygenation of Phosphine Oxides3.2 The Hirao Reaction without Added P-Ligands4 Conclusions

A monoaza-15-crown-5 lariat ether derived from d -glucose 1 has been applied as a chiral phase-transfer catalyst in the Michael addition of diethyl, dimethyl, diisopropyl and dibenzyl malonates to enones under mild conditions to afford the adducts with good to excellent enantioselectivities. In the reaction of diethyl malonate with substituted trans-chalcone, the adducts with in enantioselectivities up to 89% ee. Among the reactions of substituted diethyl malonates, those of diethyl acetoxymalonate gave the best results (96% ee). The effect of the substituents of the chalcone was also investigated in reactions with diethyl acetoxymalonate. Among the chalcones substituted on the β-aryl, the para-substituted compounds resulted in the highest enantioselectivities (88–97% ee). The substituents on the benzoyl aryl of chalcone caused a decrease in the enantioselectivity compared to the unsubstituted case. The adducts with furyl or thiophenyl substituents were formed with >99% ee. The glucose-based catalyst also proved to be effective in the cases of diisopropyl and dibenzyl acetoxymalonates (including ees up to 99% ee). The reactions of diethyl acetoxymalonate with cyclic enones gave the corresponding Michael adducts with enantioselectivities up to 83%. The absolute configuration of one of the new Michael adducts was determined by CD spectroscopy.

Application of the microwave (MW) technique offers many advantages in organophosphorus syntheses. Reluctant reactions may take place on MW irradiation. In most cases, MWs make the reactions more efficient in respect of rate, selectivity and yield. The benefits are shown via representative examples. MW irradiation may replace a catalyst, or simplify catalytic systems. The synthesis of catalysts incorporating heterocyclic P-ligands is also discussed. Where it was relevant, structural chemical details were also provided.

The microwave (MW) technique become an important tool in organophosphorus chemistry. On the one hand, otherwise reluctant reactions, such as the Diels–Alder cycloadditions, inverse Wittig-type reac...

The oxidative P-C coupling is a special method for the preparation of phosphinoylated substrates. This reaction was utilized to make available a wide range of compounds, including N-, P- and O-heterocycles and is expected to spread in the future. In this chapter, we give an overview of this relatively new approach to reveal the potential of the oxidative P-C coupling serving as a “green” method. The oxidative approach was regarded in a broader sense.

Two new pyridine-based asymmetric bifunctional organocatalysts containing one or two camphorsulfonamide units were synthesized. Asymmetric Michael addition of pentane-2,4-dione to β-nitrostyrene was catalyzed by these organocatalysts. During our experiments, influence of the solvent and temperature on the yield and enantioselectivity was studied. Using monocamphorsulfonamide derivative the S enantiomer of the corresponding Michael adduct was gained with moderate yield (up to 51 %) and low enantiomeric excess (up to 18 %). Organic solvent nanofiltration was successfully applied for the recovery of these organocatalysts. Furthermore, pyridine camphorsulfonamide was reduced to its piperidine derivative. Using piperidine monosulfonamide derivative racemic Michael adduct was obtained with excellent yield (up to 89 %). Beside its organocatalytic relevance, piperidine monosulfonamide derivative may also possess biological activity.

Some new trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety were stereoselectively synthesised using our feasible and efficient method developed recently. These new phenanthridone alkaloid analogues were obtained in both racemic and optically active forms. High enantioselectivities (up to 99% ee) were achieved by applying (8S,9S)-9-amino(9-deoxy)epiquinine as an organocatalyst. Due to a side reaction, various methoxyphenanthridine regioisomers were also prepared which afforded further synthetic trans-dihydronarciclasine analogues modified in the ring A of the phenanthridone scaffold. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00706-018-2287-7) contains supplementary material, which is available to authorized users.

New chiral monoaza-15-crown-5 type macrocycles annelated to methyl 4,6-O-benzylidene-α-D-galactopyranoside have been synthesized. These crown ethers proved to be efficient catalysts in a few asymmetric reactions under mild phase transfer catalytic conditions. Michael adducts were formed with good to excellent enantioselectivities, so the addition of diethyl acetamidomalonate to β-nitrostyrene took place with up to 92% ee, while the reaction of diethyl acetoxymalonate with chalcones proceeded with up to 99% ee. Using diethyl bromomalonate as the nucleophile, the chiral cyclopropane derivatives were formed in up to 99% ee with the addition to chalcone, in up to 78% ee in the reaction with benzylidene malononitrile, and in up to 76% ee in the reaction with 2-benzylidene-1,3-diphenyl-1,3-propanedione applying α-D-galactoside-based crown ethers as the catalysts. In the Michael addition, the substituents of the chalcone had a considerable impact on the outcome of the reactions. Quantum chemical calculations have also been employed to evaluate the origin of the stereoselectivities.

The basic method for the synthesis of dronic acid derivatives (etidronate, fenidronate, pamidronate, alendronate, ibandronate, zoledronic acid, and risedronic acid) starting from the corresponding carboxylic acid, phosphorus trichloride and phosphorous acid is surveyed. The focus is on the optimized syntheses elaborated by us using only 3.2 equivalents of phosphorus trichloride as the P-reagent in methanesulfonic acid as the solvent.

The chiral monoaza-15-crown-5 lariat ether annelated to methyl-4,6-O-benzylidene-α- d -glucopyranoside has been applied as a phase-transfer catalyst in several Michael addition reactions under mild conditions affording the adducts with good to excellent enantioselectivities. In the addition of α-substituted diethyl malonates to trans-chalcones, the substituents of the reactants had a significant impact on the yield and enantioselectivity. Among the reactions of substituted diethyl malonates, that of diethyl-2-acetoxymalonate gave the best results (up to 97% ee). New phase-transfer-catalyzed cyclopropanation reactions (MIRC reactions) of a few enones were also developed using diethyl 2-bromomalonate as the nucleophile. The corresponding chiral cyclopropane derivatives were formed with enantioselectivities up to 92% from 2-benzylidenemalononitrile starting materials, in up to 60% enantiomeric excess using 2-benzylidene-1,3-diphenyl-1,3-propanediones, and in up to 88% optical purity applying trans-chalcones as the starting materials.

The solid–liquid phase C-alkylation of active methylene containing compounds with C=O or P=O functions under phase transfer catalysis or microwave conditions has been summarized in this minireview. The mono- and dialkylation of the methylene containing derivatives was investigated under microwave (MW) conditions. It was found that in many cases, there was no need to use phase transfer catalyst under MW conditions. Moreover, most of the reactions were carried out without any solvent. These results mean a serious green chemical advantage.

The use of the microwave (MW) technique has many advan­tages in organophosphorus chemistry. MW irradiation may replace a catalyst, or simplify a catalytic system. New reactions may also become possible under MW irradiation. In most cases, microwaves just make the reactions more efficient in respect of rate, selectivity and yield. The benefits are shown via representative examples. In another field, our methods developed for the resolution of cyclic phosphine oxides and phosphinates are summarized. After deoxygenation, the racemic or optically active P-heterocycles were used as P-ligands in platinum complexes that together with other derivatives are potential catalysts. The third topic embraces the optimization of the synthesis of dronic acids/dronates. Starting from the cor­responding carboxylic acids and using methanesulfonic acid as the solvent, 3 equivalents of phosphorus trichloride is enough as the P-reactant. Applying sulfolane as the solvent, the opti­mum set of reactants comprises 2 equivalents of phosphorus trichloride and phosphorous acid.

A few new d-mannitol-based monoaza-15-crown-5 type chiral lariat ethers and 18-crown-6 type macrocycles were synthesized. These crown compounds were used as phase transfer catalysts in asymmetric Michael addititons and in a Darzens condensation under mild conditions to afford the corresponding products in a few cases in good to excellent enantioselectivities. In the Michael addition of diethyl acetoxymalonate to trans-chalcone, in the addition of diethyl acetamidomalonate to s-nitrostyrene, in the reaction of diethyl bromomalonate with benzylidene malononitriles, in the cyclopropanation reaction of diethyl bromomalonate and 2-benzylidene-1,3-indandione, and in the Darzens condensation of α-chloroacetophenone with benzaldehyde, maximum enantioselectivities of 39%, 65%, 99%, 56%, and 62%, respectively, were obtained in the presence of the d-mannitol-based macrocycles as the catalysts.

A feasible and enantioselective total synthesis of (−)-trans-dihydronarciclasine [(−)-1], a highly biologically active alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael addition, in which an optically active nitropentanone [(−)-13] was obtained from a butenone derivative (12). Excellent enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst. The target molecule can be prepared in 13 steps from compound (−)-13. The total synthesis has provided a facile and first access to the ent-form of naturally occurring (+)-trans-dihydronarciclasine, a highly potent cytostatic alkaloid.

New, green methods have been elaborated for the syntheses of α-hydroxyphosphonates and α-hydroxymethylenebisphosphonic derivatives (HMBPs, dronates). α-Hydroxyphosphonates were prepared via the Pud...

The synthesis of pamidronic acid and sodium pamidronate dihydrate from β-alanine and P-reagents (phosphorus trichloride and phosphorous acid) was investigated at 75°C in different solvents, and the preparation was optimized. In sulfolane, the use of 2 equiv of phosphorus trichloride and phosphorous acid was found the optimum to lead to pamidronic acid in a yield of 63%. In methanesulfonic acid, 3.2 equiv of phosphorus trichloride was necessary without any phosphorous acid to give pamidronate dihydrate in the best yield (57%) after hydrolysis and pH adjustment. In the first case, the P-nucleophile may be (HO)2P–O–PCl–O–P(OH)2 or (HO)2P–O–PCl2, whereas in the second case, the P-reactant is probable Cl2P–O–S(O)2Me. It can be said that the mechanism proposed for the formation of pamidronic acid is highly influenced by the solvent used, as it determines the necessary P-reagent(s). Our results promote the “on purpose” planning of the synthesis of dronates.

According to literature, the synthesis of dronic acid derivatives from the corresponding carboxylic acids using phosphorus trichloride and phosphorous acid as the P-reactants is controversial, due to the wide range of molar ratios and diverse conditions. In this minireview, we summarize our results on the clarification of these problems. For example, with zoledronic acid and risedronic acid, we found that, using methanesulfonic acid (MSA) as the solvent, 3.2 equivalents of phosphorus trichloride was enough. Generalizing this optimized method, etidronate, fenidronate, ibandronate and alendronate were obtained in yields of 38%–57%, which is reasonable for valuable dronates, and in most cases, with high purities. Mechanistic aspects are also discussed.

To further broaden the methods for the heterogeneous phase alkylation of CH acidic compounds, the dialkylation of diethyl ethoxycarbonylmethylphosphonate was studied in the presence of Cs2CO3 under microwave and solvent-free conditions. It was found that after repeating the alkylations by the addition of newer portions of the alkylating agent and the base on a few occasions, the dialkylation was quite efficient. Even dialkyl derivatives with different alkyl groups could be synthesized. The presence of a phase-transfer catalyst was harmful, as prevented the formation of the dialkyl products.

The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus trichloride/ phosphorus acid in methanesulfonic acid was studied and optimized. We showed that it is enough to use 3.2 equivalents of the phosphorus trichloride and there is no need to apply phosphorus acid. In the two-step variation of the synthesis, the acetyl chloride was formed by the reaction of acetic acid with phosphorus trichloride, thionyl chloride or triphosgene, then the intermediate was converted to etidronate by reaction with 2.2 equivalents of phosphorus trichloride. The work-up included in all cases hydrolysis and pH adjustment.

Ibandronate and Alendronate/Alendronic acid were prepared by the reaction of the corresponding amino acids (N-methyl-Npentylalanine and �-aminobutyric acid) with 3.2 equivalents of phosphorus trichloride, in the absence of any phosphorous acid, in methanesulfonic acid at 75 °C for 12 h followed by hydrolysis, pH adjustment and purification. The first intermediate of the reaction sequence is the corresponding chloride (>N(CH2)nC(O)Cl) or mixed ester (>N(CH2)nC(O)OS(O) 2Me).

A novel xantphos analog diphosphine ligand, 9,9-dimethyl-4,5-bis(diphenylphosphinomethyl)-9H-xanthene (X(CP)2), with methylene groups inserted between the xanthene skeleton and the two diphenylphosphine units, has been synthesized. A two-coordinate and a three-coordinate gold(I) complex of the ligand, [Au2Cl2(X(CP)2)] and [AuCl(X(CP)2)], have been prepared and studied by X-ray diffraction, NMR and optical spectroscopy. In the solid state, [AuCl(X(CP)2)] adopts a highly ordered structure with a planar xanthene skeleton that faces another plane composed of two phenyl rings and the AuCl moiety. The structure of [Au2Cl2(X(CP)2)] is much less regular, the two P–Au–Cl vectors point to the opposite sides of the folded xanthene backbone. The exchange-broadened resonances in the NMR spectra of [AuCl(X(CP)2))] indicate that this complex exists as a mixture of various chemical species and/or conformers in solution. In contrast, the NMR spectra of [Au2Cl2(X(CP)2)] exclude any medium-range exchange processes. Aurophilic interactions are absent in both X(CP)2 complexes. X(CP)2, as well as its two gold complexes, is phosphorescent in the solid state; the complexes emit at higher wavelengths and with longer lifetimes than the free ligand.

The spread of microwave (MW) equipment has brought about a tremendous development in synthetic organic chemistry. This environmentally friendly methodology, associated often with solventless conditions, has also had a positive impact on organophosphorus chemistry, allowing new reactions to be carried out, or increasing the rate, selectivity and yield. In special cases, MW irradiation may replace phase transfer or other kinds of catalysts. Reactions, such as the derivatization of phosphinic acids, the inverse Wittig protocol, Diels– Alder cycloadditions, fragmentation-related phosphorylations, phospha-Michael additions, Kabachnik–Fields condensations, the addition of >P(O)H species to carbonyl compounds, substitution of

Twenty-five amides were synthesized in almost quantitative yields by microwave-assisted condensation of arylacetic acids and 2-aryl-ethylamines under solventless conditions. The N-arylethyl-arylacetylamides are intermediates of the corresponding isoquinoline derivates. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

A few new l-threitol-based lariat ethers incorporating a monoaza-15-crown-5 unit were synthesized starting from diethyl l-tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2-nitropropane to trans-chalcone, and the reaction of diethyl acetamidomalonate with β-nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee) values (99% ee) were measured in the case of 4-chloro- and 4-methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene-malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol-based crown ethers.

The syntheses of hydroxymethylenebisphosphonic acid derivatives (dronic acid derivatives) starting from the corresponding substituted acetic acids and P-reagents, mainly phosphorus trichloride and phosphorous acid are surveyed according to the solvents applied. The nature of the solvent is a critical point due to the heterogeneity of the reaction mixtures. This review sheds light on the optimum choice and ratio of the P-reactants, and on the optimum conditions.

A series of substituted diethyl arylphosphonates was synthesized by the microwave-assisted Arbuzov reaction of triethyl phosphite and aryl bromides in the presence of NiCl2 as the catalyst under solvent-free conditions in good yields. The resulting phosphonates were hydrolyzed to the corresponding arylphosphonic acids whose acidity was evaluated by physicochemical methods.

The reaction of diethyl ethoxycarbonylmethylphosphonate with a series of alkyl halides, under microwave (MW) and solventless conditions at 120°C, in the presence of Cs2CO3 and in the absence of a phase transfer catalyst afforded the corresponding monoalkylated products in yields of >70%. The thermal variant carried out in boiling acetonitrile was slow and led to incomplete conversions. In the MW method, the phase transfer catalyst is substituted by MW irradiation and there is no need for a solvent. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:241–246, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21009

The microwave (MW)-assisted addition of dialkyl phosphites to α-oxophosphonates was investigated and optimized under solventless conditions to provide the phenyl- and benzyl-hydroxy-methylenebisphosphonates efficiently by suppressing the rearrangement side reaction. Methyl-hydroxy-methylenebisphosphonates with mixed ester functionalities and an analogous diester-diacid were also synthesized. It was found that the α-oxophosphonates may also be converted to hydroxy-methylenebisphosphonates and/or rearranged products without using dialkyl phosphite as the reagent and with the careful exclusion of water, simply on standing at room temperature, on thermal treatment, or on MW irradiation. These novel reactions taking place via the controlled decomposition of the precursor and resulting in the intermediate formation of dialkyl phosphite were also studied in detail. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:640–648, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20727

A variety of reactions including esterifications, alkylations, additions, cycloadditions, fragmentations, and condensations were carried out under microwave MW-assisted and solventless conditions, occasionally in ionic liquids (ILs). In a few cases, MW was synergic with phase transfer catalysis or could substitute it. A variety of P(III) ligands were developed and converted to Pt(II) complexes that can be used as catalysts. Finally, phosphorylations and the Kabachnik–Fields reaction were monitored and optimized by an on-line method, in situ Fourier transform IR spectroscopy.

Optimum conditions for the solid–liquid phase alkylation of methylenebis(diphenylphosphine oxide) (MBDPPO) and ethyl cyanomethylphosphonate (ECMP) were explored studying the role of phase transfer catalysis and microwave (MW) irradiation, as well as the effect of the cation of the alkali carbonate. It was found that the alkylation of MBDPPO may be best accomplished in acetonitrile, in the presence of a quaternary ammonium salt and Cs2CO3, while that of ECMP in the absence of catalyst and solvent using K2CO3. MW irradiation was beneficial in both cases. During the alkylation of ECMP, by-products coming from the alcoholysis of the diethyl ester were also identified. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:174–179, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20673

Optimum conditions for the solid–liquid phase alkylation of tetraethyl methylenebisphosphonate are dependent on the nature of the alkyl halide. The benzylation with benzyl bromide takes place efficiently in boiling acetonitrile in the presence of potassium carbonate and a phase transfer catalyst. The ethylation with ethyl iodide was best accomplished under solventless microwave conditions in the presence of cesium carbonate and in the absence of an onium salt. The analogous propylation and butylation were complicated by the formation of mixed esters. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 22:11–, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20648

The reaction of 4-chlorophenol and 4-nitrophenol with diethyl chlorophosphate carried out in a liquid–liquid and solid–liquid two phase system, respectively, was monitored by in situ Fourier transform IR spectroscopy.

The solid–liquid phase alkylation of a variety of five-membered N-heterocycles (carbazole, imidazole, benzimidazole, and indole-3-carbaldehyde) was carried out under different conditions. The use of alkali carbonate in dimethylformamide or in MeCN (in the latter case, in the presence of a phase-transfer catalyst) is a suitable method to prepare the corresponding N-alkylated products in an efficient way. In most cases, the solventless, microwave-assisted reaction is an environmentally friendly alternative to traditional methods.

In situ Fourier transform IR spectroscopy has been found to be an appropriate tool for monitoring the title reaction resulting in the formation of diethyl phenylphosphate.