Hirao Reaction Research Articles

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Synthesis and Anticancer Activity of Phosphinoylated and Phosphonoylated N-Heterocycles Obtained by the Microwave-Assisted Palladium Acetate-Catalyzed Hirao Reaction.

A literature survey showed that different derivatives with the 9-phenyl-9H-carbazole or the dihydroindoline scaffold may be of biological activity including cytotoxic effect. Driven by this experience, P-functionalized derivatives of these N-heterocycles were synthesized. Three N-heterocycles, 9-(4-bromophenyl)-9H-carbazole, 3-bromo-9-phenyl-9H-carbazole and 1-(5-bromoindolin-1-yl)ethan-1-one, were coupled with dialkyl phosphites and diarylphosphine oxides using Pd(OAc)2 (10 %) as the catalyst precursor and triethylamine as the base in ethanol under microwave irradiation. The excess of the Y2 P(O)H reagent (Y=alkoxy, aryl) (30 %) served as the P-ligand in its trivalent tautomeric form (Y2 POH), hence there was no need for the usual P-ligands meaning cost and environmental burden. Hence, the presented method is a "green" approach that proved to be more efficient than the preparation by the traditional method. The products, dialkyl phosphonates and tertiary phosphine oxides obtained in 58-84 % yields were characterized, one of them also by single crystal X-ray analysis, and were subjected to in vitro biological activity evaluation. A (carbazol)yl-phenylphosphonate, an N-phenyl-(carbazol)yl-phosphonate, a (carbazol)yl-phenylphosphine oxide and an N-phenyl-(carbazol)ylphosphine oxide revealed a significant cytotoxic activity on A549 human non-small-cell lung carcinoma and MonoMac-6 acute monocytic leukemia cancer cells. The cytotoxic effect was significant as compared to that of the reference compounds.

Microwave-Assisted Palladium Acetate-Catalyzed C-P Cross-Coupling of Arylboronic Acids and >P(O)H Reagents in the Absence of the Usual Mono- and Bidentate P-Ligands: Mechanistic Insights.

A less-studied halogen-free variation of the Hirao reaction involving the coupling of arylboronic acids with >P(O)H reagents, such as diarylphosphine oxides, diethyl phosphite, and ethyl phenyl-H-phosphinate, was investigated in detail using Pd(OAc)2 as the catalyst precursor and applying some excess of the P-reagent to supply the ligand via its trivalent tautomeric (>P-OH) form. The optimum conditions (1.2 equiv of the P-reagent, 135-150 °C, and air) were explored for the synthesis of diaryl-phenylphosphine oxides, aryl-diphenylphosphine oxides, diethyl arylphosphonates, ethyl diphenylphosphinate, and two bisphosphinoyl derivatives. In the reaction of 4-chlorophenyl- or 3-chlorophenylboronic acid with Ph2P(O)H, triphenylphosphine oxide was also formed as a byproduct. Theoretical calculations suggested that the catalytic cycle of the P-C coupling of PhB(OH)2 with Ph2P(O)H is different from that of the usual cross-coupling reactions. It comprises the addition of a phenyl anion and then the tautomeric form >P-OH of the >P(O)H reagent to the Pd2+ catalyst complex. This is then followed by reductive elimination affording Ph3PO that is accompanied with the conversion of Pd2+ to Pd0. There is a need for a subsequent stoichiometric oxidation of Pd(0) by molecular oxygen. The spontaneous formation of the self-assembling ligands around the Pd2+ center from the >P(O)H reactant plays a crucial role in the mechanism and promotes the efficiency of the catalyst.

Highly efficient and well-defined phosphinous acid-ligated Pd(II) precatalysts for Hirao cross-coupling reaction.

We report the synthesis of a new palladium complex (1a) bearing two different P-donors, di(1-adamantyl)phosphinous acid and triphenylphosphine. A heteroleptic complex with a phosphinous acid ligand has rarely been reported. With phenyl bromide and di-p-tolylphosphine oxide as reagents, PPh3-stabilised 1a was proved to be a noteworthy Pd(II) precatalyst for carbon-phosphorus bond formation. 1a-catalysed Hirao coupling could be efficiently made in environmentally benign ethanol. Reacting for 10 to 120 minutes, aryl bromides equipped with electron-donating or electron-withdrawing groups were successfully catalysed. Nucleophile-sensitive 2-bromopyridine, 2-bromothiophene, and 4-bromobenzonitrile were applicable in toluene/ethylene glycol (EG) (9/1). 1a-catalyzed Hirao coupling was successfully applied to the synthesis of a host material in an organic light-emitting diode (OLED) and precursor of biarylphosphines. A mechanistic study regarding how plausible Pd(0) active species are generated was jointly investigated by means of DFT calculation, ESI mass spectroscopy, and experiment. Interestingly, we demonstrated a proof of concept that bulky di(1-adamantyl)phosphine oxide is a useful preligand and less bulky di-p-tolylphosphine oxide is the substrate in the Hirao coupling.

The Hirao Reaction: Palladium-Catalyzed Cross-Coupling of Dialkyl Phosphites with Aryl Halides

Key words C(sp2)–P bond formation - palladium catalysis - phosphonates

New data on the Hirao reaction; The use of Cu(II) salts as the catalyst precursor under microwave irradiation in the absence of added P‐ligands

After surveying the most important results described on the Pd(0)/Pd(II)- and Ni(II)-catalyzed P–C couplings of bromobenzene and diethyl phosphite or diphenylphosphine oxide, the simple Hirao reactions catalyzed by different Cu(II) salts were investigated. In these instances, the more reactive iodobenzene had to be used. CuSO4 and Cu(OAc)2 · H2O were found suitable catalyst precursors in case they were used together with two equiv. of triethylamine suggesting the role of the amine in the complexation. Theoretical calculations suggested that the corresponding Cu(I) species formed from the initial Cu(II) salt is involved in the catalytic cycle.

Ferrocenephosphonates: Copper-Promoted Synthesis and Further Functionalization

AbstractFerrocenephosphonates make up an important class of organometallic derivatives with a wide range of useful applications in organic synthesis and coordination chemistry. Here, an approach to ferrocenephosphonates based on a copper-promoted Hirao coupling is reported. Further functionalizations based on regioselective deprotolithiation and both Negishi and Suzuki–Miyaura cross-coupling reactions are also described to reach original derivatives.

New Data on the Hirao Reaction; the Use of Cu(Ii) Salts as the Catalyst Precursor Under Microwave Irradiation in the Absence of Added P-Ligands

New Data on the Hirao Reaction; the Use of Cu(Ii) Salts as the Catalyst Precursor Under Microwave Irradiation in the Absence of Added P-Ligands

Microwave assisted P–C coupling reactions without directly added P-ligands

Our group introduced a green protocol for the Pd(OAc)2- or NiCl2-catalyzed P–C coupling reaction of aryl halides and various > P(O)H-compounds under MW conditions without directly added P-ligands. The reactivity of a few aryl derivatives in the Pd(OAc)2-catalyzed Hirao reaction was also studied. An induction period was observed in the reaction of bromobenzene and diphenylphosphine oxide. Finally, the less known copper(I)-promoted P–C coupling reactions were investigated experimentally. The mechanism was explored by quantum chemical calculations.

Palladium anchored on a covalent organic framework as a heterogeneous catalyst for phosphorylation of aryl bromides

A simple azine‐linked covalent organic framework (COF) with high thermal and chemical stabilities has been prepared by using deep eutectic solvent (DES) as green media. The as‐synthesized COF was employed as heterogeneous ligand for immobilization of PdII. The obtained Pd‐supported COF nanoparticles catalyst (defined as Pd/TFPT‐Azine‐COF) was found to be an efficient heterogeneous catalyst for the Hirao reaction of aryl halides and dialkyl phosphites or diphenylphosphine oxide with excellent recyclability, reusability, and retention of crystallinity.

MW-Promoted Cu(I)-Catalyzed P–C Coupling Reactions without the Addition of Conventional Ligands; an Experimental and a Theoretical Study

An experimental and a theoretical study on the so far less investigated Cu(I) salt-catalyzed Hirao reaction of iodobenzene and diarylphosphine oxides (DAPOs) revealed that Cu(I)Br or Cu(I)Cl is the most efficient catalyst under microwave irradiation. The optimum conditions included 165 °C and a 1:2 molar ratio for DAPOs and triethylamine. The possible ligations of Cu(I) were studied in detail. Bisligated P---Cu(I)---P (A), P---Cu(I)---N (B) and N---Cu(I)---N (C) complexes were considered as the catalysts. Calculations on the mechanism suggested that complexes A and B may catalyze the P–C coupling, but the latter one is more advantageous both according to experiments and calculations pointing out the Cu(I) → Cu(III) conversion in the oxidative addition step. The P–C coupling cannot take place with PhBr, as in this case, the catalyst complex cannot be regenerated.

Nucleophilic H-Phosphites, H-Phosphinates, and H-Phosphine Oxides in Organic Reactions

AbstractP(O)–H compounds like H-phosphites, H-phosphinates, and H-phosphine oxides are widely used as nucleophiles. Herein, their reactions with unsaturated compounds, C–H activation, the Hirao reaction, P–C, P–S, P–O, P–N, and P–F couplings are thoroughly discussed and summarized. This review will focus on their reactions with alkenes, alkynes, enamides, propynoic acids, epoxide, arynes, arenes, quinones, isothiocyanates, diazo compounds, aldehydes, ketones, imines, pyridines, acid derivatives, carbocations, aryl halides, dibromoalkenes, disulfides, thiosulfates, sulfonyl chlorides, iodonium salts, amines, alcohols, and thiols.1 Introduction2 Addition to Alkenes/Alkynes3 Addition to Other Unsaturated Compounds4 Coupling with Carbocations5 Phosphorylation of Aryl C–H Bonds6 Hirao Reaction7 P–S, P–O, P–N, or P–F Coupling8 Conclusions

Diversity-Oriented Synthesis toward Aryl- and Phosphoryl-Functionalized Imidazo[1,2-a]pyridines.

We report herein an efficient synthesis of diversely polysubstituted imidazo[1,2-a]pyridines, a family of aza-heterocycles endowed with numerous biological properties, through a sequence involving two consecutive palladium-catalyzed cross-coupling reactions. First, we demonstrated that a Hirao coupling occurred straightforwardly in high yields at positions 3, 5, and 6 of imidazopyridine derivatives, giving access to a wide variety of substituted phosphonates, phosphinates, and phosphine oxides. In a second step, direct CH-arylation of phosphorylimidazopyridines with aryl halides was found to be effective and fully selective, leading to 3-aryl-substituted imidazopyridines in moderate to high yields depending on steric hindrance.

Focusing on the Catal. of the Pd- and Ni-Catalyzed Hirao Reactions.

The Hirao reaction involving the phosphinoylation or phosphonation of aryl halides by >P(O)H reagents is a P–C bond forming transformation belonging to the recently very hot topic of cross-couplings. The Pd- or Ni-catalyzed variations take place via the usual cycle including oxidative addition, ligand exchange, and reductive elimination. However, according to the literature, the nature of the transition metal catalysts is not unambiguous. In this feature article, the catalysts described for the Pd(OAc)2-promoted cases are summarized, and it is concluded that the “(HOY2P)2Pd(0)” species (Y = aryl, alkoxy) is the real catalyst. In our model, the excess of the >P(O)H reagent served as the P-ligand. During the less studied Ni(II)-catalyzed instances the “(HOY2P)(−OY2P)Ni(II)Cl−” form was found to enter the catalytic cycle. The newest conclusions involving the exact structure of the catalysts, and the mechanism for their formation explored by us were supported by our earlier experimental data and theoretical calculations.

Recent Advances in Microwave Promoted C-P Cross-coupling Reactions

: Organophosphorous compounds are of potential importance in diverse fields. They are often used as intermediates for making functionalized phosphine ligands as well as find vast applications in the areas of industrial, agricultural and biological chemistry. The microwave-assisted synthesis of C-P bonds has become increasingly popular because of its various advantages over conventional heating in the perspectives of green chemistry. : This review article has primarily focused on the synthesis of various organophosphorous molecules via microwave promoted C-P cross-coupling reactions under metal-catalyzed or metal–free conditions over the last two decades. The synthesis of phosphine ligands on 4,4′-bisquinolone structural framework, disubstituted phosphinic acid esters, vinyl phosphines, aryl- and vinylphosphonates, sugar and nucleoside phosphonates, aminobisphosphonates, triphenyl phosphines, water-soluble tertiary phosphine oxides and many other potentially useful organophosphorous compounds have been illustrated critically. The Hirao reaction, Michaelis-Arbuzov reaction and Sandmeyer type of reactions are generally involved in creating C-P bonds. The role of various metal catalysts, solvents, bases, additives and temperature in different literatures are carefully discussed.

A Study on the Reactivity of Monosubstituted Benzenes in the MW-Assisted Pd(OAc)2-catalyzed Hirao Reaction with Ph2P(O)H and (EtO)2P(O)H Reagents

The reactivity order of “iodobenzene > bromobenzene > phenyl trifluoromethanesulfonate” was established in microwave (MW)-assisted Pd(OAc)2-catalyzed P–C coupling reactions with diphenylphosphine oxide and diethyl phosphite, where the excess of the these >P(O)H reagents served as the reducing agent, and, via its tautomeric >P-OH form, also as the P-ligand. The P–C coupling of Ph2P(O)H with PhBr at 120 °C took place via an induction period, during which the active “P-Pd-P” catalyst was formed from the Pd(II) salt and the >P(O)H species. The lower reactivity of PhBr towards Ph2P(O)H could be promoted by the addition of 20% of KI to the reaction mixture at 120 °C, or utilizing 1 equivalent of KI after a pre-reaction with PhBr at 120-150 °C followed by the P–C coupling at 100 °C. The reactivity of PhOTf and a bromo analogue was compared in competitive couplings with Ph2P(O)H. Beyond this, the reactivity of Ph2P(O)H and (EtO)2P(O)H towards PhOTf was evaluated in another competitive experiment. Increasing the scale of the P–C coupling reaction of (EtO)2P(O)H with PhBr, the quantity for the components of the catalyst could be decreased.

Experimental and Theoretical Study on the “2,2′-Bipiridyl-Ni-Catalyzed” Hirao Reaction of >P(O)H Reagents and Halobenzenes: A Ni(0) → Ni(II) or a Ni(II) → Ni(IV) Mechanism?

It was found by us that the P–C coupling reaction of >P(O)H reagents with PhX (X = I and Br) in the presence of NiCl2/Zn as the precursors for the assumed Ni(0) complexant together with 2,2′-bipyridine as the ligand took place only with PhI at 50/70 °C. M06-2X/6-31G(d,p)//PCM(MeCN) calculations for the reaction of Ph2P(O)H and PhX revealed a favorable energetics only for the loss of iodide following the oxidative addition of PhI on the Ni(0) atom. However, the assumed transition states with Ni(II) formed after P-ligand uptake and deprotonation could not undergo reductive elimination meaning a “dead-end route”. Hence, it was assumed that the initial complexation of the remaining Ni2+ ions with 2,2′-bipyridine may move the P–C coupling forward via a Ni(II) → Ni(IV) transition. This route was also confirmed by calculations, and this mechanism was justified by preparative experiments carried out using NiCl2/bipyridine in the absence of Zn. Hence, the generally accepted Ni(0) → Ni(II) route was refuted by us, confirming the generality of the Ni(II) → N(IV) protocol, either in the presence of bipyridine, or using the excess of the >P(O)H reagent as the P-ligand. The results of the calculations on the complex forming ability of Ni(0) and Ni(II) with 2,2′-bipyridine or the P-reagents were in accord with our mechanistic proposition.

A surprising mechanism lacking the Ni(0) state during the Ni(II)-catalyzed P–C cross-coupling reaction performed in the absence of a reducing agent – An experimental and a theoretical study

Abstract The Hirao reaction, i.e. the P–C coupling between a bromoarene and a >P(O)H reagent performed in most cases in the presence of a Pd(0) complex incorporating a P-ligand may also be carried out applying a Ni(II) catalyst precursor with or without Zn or Mg as the reducing agent. The Ni catalysts may include P- or N-ligands. B3LYP/6-31G(d,p)//PCM(MeCN) quantum chemical calculations suggested that the mechanism of the NiX2 catalyzed (X=Cl or Br) P–C couplings performed in the absence of a reducing agent, and in the excess of the >P(O)H reagent serving as the P-ligand (via its tautomeric >POH form) is completely different from that of the Pd(OAc)2 promoted version, as no reduction of the Ni(II) occurs. In the two variations mentioned, the active catalyst is the dehydrobrominated species derived from primary complex [(HO)Y2P]2Ni(II)Br2, and the [(HO)Y2P]2Pd(0) complex itself, respectively. Both species undergo temporary oxidation (to “Ni(IV)” and “Pd(II)”, respectively) in the catalytic cycle. During the catalysis with “P2Ni(II)X2”, one of the P-ligands serves the >P(O)H function of the ArP(O)H < product. The consequence of this difference is that in the Ni(II)-catalyzed case, somewhat less >P(O)H-species is needed than in the Pd(0)-promoted instance. Applying 10 % of the Pd(OAc)2 or NiX2 precursor, the optimum quantity of the P-reagent is 1.3 equivalent and, in the first approach, 1.1 equivalent, respectively. Preparative experiments justified the new mechanism explored. The ligation of Ni(II) was also investigated by theoretical calculations. It was proved that the bis-complexation is the most favorable energetically as compared to the mono-, tri- and tetra-ligation.

Microwave-Assisted Hirao Reaction of Heteroaryl Bromides and >P(O)H Reagents Using Pd(OAc)2 as the Catalyst Precursor in the Absence of Added P-Ligands

Bromopyridines, bromotiophenes and 3-bromofuran were reacted with diphenylphosphine oxide or diethyl phosphite under microwave irradiation using Pd(OAc)2 as the catalyst precursor together with some excess of the >P(O)H reagent. Hence, there was no need for the usual mono- and bidentate P-ligands. The >P(O)-functionalized heterocycles were obtained in variable (55-95%) yields. The results of our “green” protocol were in most cases better than those of the literature methods.

New Developments on the Hirao Reactions, Especially from "Green" Point of View.

Background: The Hirao reaction discovered ca. 35 years ago is an important P–C coupling protocol between dialkyl phosphites and aryl halides in the presence of Pd(PPh3)4 as the catalyst and a base to provide aryl phosphonates. Then, the reaction was extended to other P-reagents, such as secondary phosphine oxides and H-phosphinates and to other aryl and hetaryl derivatives to afford also phosphinic esters and tertiary phosphine oxides. Instead of the Pd(PPh3)4 catalyst, Pd(OAc)2 and Ni-salts were also applied as catalyst precursors together with a number of mono- and bidentate P-ligands.Objective: In our review, we undertook to summarize the target reaction with a special stress on the developments attained in the last 6 years, hence this paper is an update of our earlier reviews in a similar topic.Conclusions: “Greener” syntheses aimed at utilizing phase transfer catalytic and microwave-assisted approaches, even under “P-ligand-free. or even solvent-free conditions are the up-to date versions of the classical Hirao reaction. The mechanism of the reaction is also in the focus these days.