Microwaves as “Co-Catalysts” or as Substitute for Catalysts in Organophosphorus Chemistry

The purpose of this review is to summarize the importance of microwave (MW) irradiation as a kind of catalyst in organophosphorus chemistry. Slow or reluctant reactions, such as the Diels-Alder cycloaddition or an inverse-Wittig type reaction, may be performed efficiently under MW irradiation. The direct esterification of phosphinic and phosphonic acids, which is practically impossible on conventional heating, may be realized under MW conditions. Ionic liquid additives may promote further esterifications. The opposite reaction, the hydrolysis of P-esters, has also relevance among the MW-assisted transformations. A typical case is when the catalysts are substituted by MWs, which is exemplified by the reduction of phosphine oxides, and by the Kabachnik–Fields condensation affording α-aminophosphonic derivatives. Finally, the Hirao P–C coupling reaction may serve as an example, when the catalyst may be simplified under MW conditions. All of the examples discussed fulfill the expectations of green chemistry.

The spread of the microwave (MW) technique opened a new chapter in organic chemistry in whole [1][2][3], and also in its specialized fields, such as heterocyclic [3][4][5] and organophosphorus chemistry [2,6]. MW irradiation makes possible more efficient syntheses in terms of reaction time, selectivity, and purity [1,2]. The role of MWs in organic syntheses provoked sharp disputes, however, today there is an agreement that thermal effects are responsible for the beneficial effect of MWs [7,8]. A widely accepted concept is that the efficiency of the MW irradiation is the consequence of the statistically occurring local overheating in the bulk of the mixture [9][10][11].
During our work, we laid the stress on green chemical aspects within organophosphorus chemistry [12]. This will be summarized in this review article. Besides developing efficient syntheses, we could enhance reluctant or slow reactions by applying the MW irradiation (1). It was another option to promote further certain MW-assisted reactions by performing them in the presence of an ionic liquid additive/catalyst (2). It is another possibility to substitute certain catalysts by MW irradiation (3). Last but not least, MWs may simplify catalytic systems/catalysts (4). In this paper, options (1)-(4) will be discussed in detail, placing the particular reactions into literature context.
In the novel inverse Wittig-type reactions, MW irradiation made possible reactions at 150 °C for 3 h that were rather reluctant on conventional heating. Hence, MW acted as a kind of catalyst. Scheme 3. The inverse Wittig-type reaction of P-aryl ring phosphine oxides with DMAD.
In the novel inverse Wittig-type reactions, MW irradiation made possible reactions at 150 °C for 3 h that were rather reluctant on conventional heating. Hence, MW acted as a kind of catalyst. Scheme 3. The inverse Wittig-type reaction of P-aryl ring phosphine oxides with DMAD.
In the above case, the nature of the 1,2-dihydrophosphinine oxide determined its reactivity towards DMAD. Moreover, both the Diels-Alder cycloaddition and the inverse-Scheme 2. The inverse Wittig-type reaction of a P-aryl 1,2-dihydrohosphine oxide with dimethyl acetylenedicarboxylate (DMAD).
In the novel inverse Wittig-type reactions, MW irradiation made possible reactions at 150 °C for 3 h that were rather reluctant on conventional heating. Hence, MW acted as a kind of catalyst. Scheme 3. The inverse Wittig-type reaction of P-aryl ring phosphine oxides with DMAD.
In the above case, the nature of the 1,2-dihydrophosphinine oxide determined its reactivity towards DMAD. Moreover, both the Diels-Alder cycloaddition and the inverse- In the novel inverse Wittig-type reactions, MW irradiation made possible reactions at 150 • C for 3 h that were rather reluctant on conventional heating. Hence, MW acted as a kind of catalyst.
In the above case, the nature of the 1,2-dihydrophosphinine oxide determined its reactivity towards DMAD. Moreover, both the Diels-Alder cycloaddition and the inverse-Wittig type reaction took place efficiently on MW irradiation without the application of any catalyst.

Microwave-Assisted, Ionic Liquid-Catalyzed Direct Esterification of P-Oxoacids That Is Otherwise Impossible under Thermal Conditions
Phosphinic and phosphonic acids cannot be involved in direct esterification under common conditions. Only a few examples are known for the direct esterification of P-acids. These reactions required forcing conditions and were not efficient [22][23][24][25][26]. However, it was found by us that the P-acids can be esterified on MW irradiation.
The esterification of 1-hydroxy-3-phospholene oxide (8) with a series of alcohols at 180-235 • C afforded the alkyl phosphinates (9) in yields of 71-95% (Scheme 4/B vs. A, Table 1/Entries 1, 3, 5, 7, 9 and 11) [27][28][29]. The esterifications were less efficient with volatile and sterically hindered alcohols. The relatively high temperature required means a limitation that may be overcome by applying ionic liquids (ILs) as catalysts. It was found that in the presence of 10% of [bmim][PF 6 ] as an additive, the esterifications took place at a lower temperature, and became faster and more efficient in shorter reaction times (Scheme 4/D, Table 1/Entries 2, 4, 6, 8, 10 and 12) [30]. The thermal direct esterifications were also somewhat promoted by the ionic liquid additive (Scheme 4/C). Wittig type reaction took place efficiently on MW irradiation without the application of any catalyst.

Microwave-Assisted, Ionic Liquid-Catalyzed Direct Esterification of P-Oxoacids That Is Otherwise Impossible under Thermal Conditions
Phosphinic and phosphonic acids cannot be involved in direct esterification under common conditions. Only a few examples are known for the direct esterification of Pacids. These reactions required forcing conditions and were not efficient [22][23][24][25][26]. However, it was found by us that the P-acids can be esterified on MW irradiation.
The esterification of the reactive phenyl-H-phosphinic acid (18) took place at a temperature of  • C to provide the phosphinates (19) in good (73-90%) yields [33]. The presence of [bmim][PF 6 ] had a beneficial effect on the outcome (Scheme 5/(1)) [34]. Methylphenylphosphinic acid (20), and what is more, the sterically hindered diphenylphosphinic acid (22), could also be efficiently esterified in the presence of an IL (Scheme 5/(2) and (3)) [34,35]. It is noteworthy that thiobutanol could also be used under MW-assistance to afford the corresponding thiophosphinates [36]; however, the direct amidations of phosphinic It is noteworthy that thiobutanol could also be used under MW-assistance to afford the corresponding thiophosphinates [36]; however, the direct amidations of phosphinic acids were reluctant even on MW irradiation [37].
Our next targets were the phosphonic acids. In the first approach, the alkyl phenyl-Hphosphinates (19) were oxidized, then the ester-acid were esterified. However, we could not be satisfied with the efficiency (Scheme 6) [38]. Scheme 5. MW-promoted direct esterification of different phenyl-phosphinic acids (18, 20, and 22).
It is noteworthy that thiobutanol could also be used under MW-assistance to afford the corresponding thiophosphinates [36]; however, the direct amidations of phosphinic acids were reluctant even on MW irradiation [37].
Our next targets were the phosphonic acids. In the first approach, the alkyl phenyl-H-phosphinates (19) were oxidized, then the ester-acid were esterified. However, we could not be satisfied with the efficiency (Scheme 6) [38]. Scheme 6. The preparation of dialkyl phenylphosphonates (25) via alkyl phenyl-H-phosphinates (19).
For this, the direct esterification of phenylphosphonic acid was studied in detail. We learned that the MW-assisted and IL-catalyzed protocol furnished the monoesters (27) in good selectivities and in acceptable yields (Table 3). At the same time, the diesterification to species 25 was not efficient (  [34,39]. Table 3. MW-promoted direct esterification of phenylphosphonic acid (26). Scheme 6. The preparation of dialkyl phenylphosphonates (25) via alkyl phenyl-H-phosphinates (19).
For this, the direct esterification of phenylphosphonic acid was studied in detail. We learned that the MW-assisted and IL-catalyzed protocol furnished the monoesters (27) in good selectivities and in acceptable yields (Table 3). At the same time, the diesterification to species 25 was not efficient (       As an alternative possibility, phenylphosphonic acid (26) was also subjected to alkylating esterifications using BuBr. These reactions were complete and selective for the diesterification only when BuBr was used in a 5-fold quantity at 120 • C (Table 5) [39].   In this way, phenylphosphonates with (two) different alkyl groups (28) could also be prepared ( Table 7). The isolated yields of products 28 were mostly around 70% [39].    In this way, phenylphosphonates with (two) different alkyl groups (28) could also be prepared ( Table 7). The isolated yields of products 28 were mostly around 70% [39]. In this way, phenylphosphonates with (two) different alkyl groups (28) could also be prepared ( Table 7). The isolated yields of products 28 were mostly around 70% [39].   In this way, phenylphosphonates with (two) different alkyl groups (28) could also be prepared ( Table 7). The isolated yields of products 28 were mostly around 70% [39].  [34,39], while the second HO function (as in 27) is converted to alkoxy by alkylation using an alkyl halogenide (Scheme 7) [39]. It follows from our results that the method of choice for the diesterification of phosphonic acid 26 is when the first HO group of the phosphonic acid (26) is esterified with alcohol under MW conditions [34,39], while the second HO function (as in 27) is converted to alkoxy by alkylation using an alkyl halogenide (Scheme 7) [39].

Scheme 7.
The new protocol elaborated for the synthesis of dialkyl phenylphosphonates.
It is noteworthy that the MW-assisted continuous flow esterification of a H-phosphinic acid was also elaborated [40].
The opposite reaction of esterification is hydrolysis that is of high importance also in the sphere of P-esters [43,44]. The hydrolysis of phosphinates and phosphonates is carried out, in most cases, under acidic conditions [45][46][47][48][49][50][51][52], but, among other possibilities, base-catalyzed cases also occur [53][54][55][56][57]. It was a new approach to perform the hydrolyses under MW irradiation. Alkyl diphenylphosphinates (29) were hydrolyzed at 180 • C in the presence of 10% of p-toluenesulfonic acid (PTSA) as the catalyst (Scheme 8) [58]. For the esters with n-alkyl substituents, completion of the hydrolysis required 1.5-2.2 h; however, with the i-propyl ester, the hydrolysis took place after 0.5 h. This latter experience is due to the realization of the A Al 1 mechanism. The acid (30) was isolated in yields of 94-97%. with n-alkyl substituents, completion of the hydrolysis required 1.5-2.2 h; however, with the i-propyl ester, the hydrolysis took place after 0.5 h. This latter experience is due to the realization of the AAl1 mechanism. The acid (30) was isolated in yields of 94-97%.

Scheme 8. MW-assisted hydrolysis of alkyl diphenylphosphinates (29).
A comparative thermal experiment afforded the phosphinic acid (30) in a lower conversion of 24%, indicating the beneficial effect of MWs. This is the consequence of the local overheating [27,28] and the better MW absorbing effect of PTSA.
In conclusion, MW irradiation made possible the otherwise impossible direct esterification of phosphinic acids, and the monoesterification of phosphonic acids. MW irradiation proved to be a useful tool in overcoming the enthalpy of activation barriers higher than 130 kJ mol -1 [27,28]. This is due to the beneficial effect of the statistically occurring local overheating [41,42]. On the other hand, the MWs were beneficial also in the acidcatalyzed hydrolysis of phosphinates.

Microwave as a Substitute for the Catalysts in the Deoxygenation of Phosphine Oxides
Besides the widely applied trichlorosilane (Cl3SiH) and phenylsilane (PhSiH3) [59,60], the use of the cheaper ethoxysilanes, (EtO)3SiH and (EtO)2MeSiH, as well as 1,1,3,3-tetramethyldisiloxane (TMDS) and polymethylhydrosiloxane, called also as methylpolysiloxane ([PMHS or MPS] represented by formula [-O-SiH(Me)-]n), offers alternative possibilities [61,62]. However, these silanes are of low reactivity. Beller et al. tested different acids as catalysts in the deoxygenation of triphenylphosphine oxide (31) with diethoxymethylsilane as the reductant (Table 8) [61]. No deoxygenation occurred in the lack of a catalyst. Adding 15 mol% of benzoic acid to the mixture, triphenylphosphine (32) was obtained in a yield of 6%. However, in the presence of the diphenyl ester of phosphoric acid as the catalyst, the yield of PPh3 was 75%. Moreover, it was observed that the use of a A comparative thermal experiment afforded the phosphinic acid (30) in a lower conversion of 24%, indicating the beneficial effect of MWs. This is the consequence of the local overheating [27,28] and the better MW absorbing effect of PTSA.
In conclusion, MW irradiation made possible the otherwise impossible direct esterification of phosphinic acids, and the monoesterification of phosphonic acids. MW irradiation proved to be a useful tool in overcoming the enthalpy of activation barriers higher than 130 kJ mol -1 [27,28]. This is due to the beneficial effect of the statistically occurring local overheating [41,42]. On the other hand, the MWs were beneficial also in the acid-catalyzed hydrolysis of phosphinates.

Microwave as a Substitute for the Catalysts in the Deoxygenation of Phosphine Oxides
Besides the widely applied trichlorosilane (Cl 3 SiH) and phenylsilane (PhSiH 3 ) [59,60], the use of the cheaper ethoxysilanes, (EtO) 3 SiH and (EtO) 2 MeSiH, as well as 1,1,3,3tetramethyldisiloxane (TMDS) and polymethylhydrosiloxane, called also as methylpolysilox ane ([PMHS or MPS] represented by formula [-O-SiH(Me)-] n ), offers alternative possibilities [61,62]. However, these silanes are of low reactivity. Beller et al. tested different acids as catalysts in the deoxygenation of triphenylphosphine oxide (31) with diethoxymethylsilane as the reductant (Table 8) [61]. No deoxygenation occurred in the lack of a catalyst. Adding 15 mol% of benzoic acid to the mixture, triphenylphosphine (32) was obtained in a yield of 6%. However, in the presence of the diphenyl ester of phosphoric acid as the catalyst, the yield of PPh 3 was 75%. Moreover, it was observed that the use of a P-ester-acid catalyst with an electron-withdrawing substituent in the phenyl ring led to the quantitative reduction.  Catalyst Different tertiary phosphine oxides (33) were reduced to the respective phosphines (34) using (EtO)3SiH in the presence of titanium(IV) isopropoxide as the catalyst ( Table 9). The deoxygenations were performed in tetrahydrofuran (THF). On heating at 67 °C, the completion required 1 h, if the silane was applied in a 3-fold excess [62]. The reduction of aryl-diphenylphosphine oxides with (EtO)3SiH in the presence of Ti(O i Pr)4 in benzene at reflux provided the corresponding phosphine in 90% yield after a reaction time of 30 min [63].
The deoxygenation of triphenylphosphine oxide (31) was also elaborated using TMDS in the presence of catalysts. Copper(II) triflate was a suitable promoter in the reduction of the P=O unit at 100 °C in PhMe [64]. Without a catalyst, even measuring in TMDS in a 12 equivalents' quantity, no reduction occurred. The use of 15 mol% of the (PhO)2P(O)OH in boiling PhMe also promoted deoxygenation [61]. Using 10 mol% of Ti(O i Pr)4 at 100 °C, triphenylphosphine (32) was formed in a conversion of 86%. In the presence of 1% of InBr3 as the catalyst, the reduction was quantitative at 100 °C [65] (Table  10).
Different tertiary phosphine oxides (33) were reduced to the respective phosphines (34) using (EtO) 3 SiH in the presence of titanium(IV) isopropoxide as the catalyst ( Table 9). The deoxygenations were performed in tetrahydrofuran (THF). On heating at 67 • C, the completion required 1 h, if the silane was applied in a 3-fold excess [62].  Catalyst Different tertiary phosphine oxides (33) were reduced to the respective phosphines (34) using (EtO)3SiH in the presence of titanium(IV) isopropoxide as the catalyst ( Table 9). The deoxygenations were performed in tetrahydrofuran (THF). On heating at 67 °C, the completion required 1 h, if the silane was applied in a 3-fold excess [62]. The reduction of aryl-diphenylphosphine oxides with (EtO)3SiH in the presence of Ti(O i Pr)4 in benzene at reflux provided the corresponding phosphine in 90% yield after a reaction time of 30 min [63].
The deoxygenation of triphenylphosphine oxide (31) was also elaborated using TMDS in the presence of catalysts. Copper(II) triflate was a suitable promoter in the reduction of the P=O unit at 100 °C in PhMe [64]. Without a catalyst, even measuring in TMDS in a 12 equivalents' quantity, no reduction occurred. The use of 15 mol% of the (PhO)2P(O)OH in boiling PhMe also promoted deoxygenation [61]. Using 10 mol% of Ti(O i Pr)4 at 100 °C, triphenylphosphine (32) was formed in a conversion of 86%. In the presence of 1% of InBr3 as the catalyst, the reduction was quantitative at 100 °C [65] (Table  10). The reduction of aryl-diphenylphosphine oxides with (EtO) 3 SiH in the presence of Ti(O i Pr) 4 in benzene at reflux provided the corresponding phosphine in 90% yield after a reaction time of 30 min [63].
The deoxygenation of triphenylphosphine oxide (31) was also elaborated using TMDS in the presence of catalysts. Copper(II) triflate was a suitable promoter in the reduction of the P=O unit at 100 • C in PhMe [64]. Without a catalyst, even measuring in TMDS in a 12 equivalents' quantity, no reduction occurred. The use of 15 mol% of the (PhO) 2 P(O)OH in boiling PhMe also promoted deoxygenation [61]. Using 10 mol% of Ti(O i Pr) 4 at 100 • C, triphenylphosphine (32) was formed in a conversion of 86%. In the presence of 1% of InBr 3 as the catalyst, the reduction was quantitative at 100 • C [65] (Table 10). It is noteworthy that there is no need for any catalyst if the reduction of triphenylphosphine oxide (31) with TMDS is performed in a solvent-free manner under MW irradiation. After treatment at 200 °C for 6.5 h, the reduction was quantitative. On conventional heating at 175 °C, there was a need for a 1-day reaction time. As the reduction takes place in the absence of catalyst, the MW-assisted approach may be regarded as a "green" protocol (Table 11) [66,67]. Practically, MW irradiation substituted the catalyst. The reduction of ring phosphine oxides, such as 3-methyl-1-phenyl-2-phospholene oxide (35a), was performed using TMDS together with InBr3 as the catalyst in PhMe at 100 °C [65]. The deoxygenation also took place in the absence of catalyst in PhMe at reflux [68]. The solvent-and catalyst-free reduction of 1-phenyl-3-phospholene oxide 35b was complete after a shorter reaction time in both the thermal and MW-promoted variations (Table 12) [66]. The next user-friendly silane, PMHS can be used in the deoxygenation of triphenylphosphine oxide (31). At 290 °C in the absence of any solvent, triphenylphosphine (32) was isolated in an 86% yield [69]. It is a disadvantage that the application of PMHS It is noteworthy that there is no need for any catalyst if the reduction of triphenylphosphine oxide (31) with TMDS is performed in a solvent-free manner under MW irradiation. After treatment at 200 • C for 6.5 h, the reduction was quantitative. On conventional heating at 175 • C, there was a need for a 1-day reaction time. As the reduction takes place in the absence of catalyst, the MW-assisted approach may be regarded as a "green" protocol (Table 11) [66,67]. Practically, MW irradiation substituted the catalyst. It is noteworthy that there is no need for any catalyst if the reduction of triphenylphosphine oxide (31) with TMDS is performed in a solvent-free manner under MW irradiation. After treatment at 200 °C for 6.5 h, the reduction was quantitative. On conventional heating at 175 °C, there was a need for a 1-day reaction time. As the reduction takes place in the absence of catalyst, the MW-assisted approach may be regarded as a "green" protocol (Table 11) [66,67]. Practically, MW irradiation substituted the catalyst. The reduction of ring phosphine oxides, such as 3-methyl-1-phenyl-2-phospholene oxide (35a), was performed using TMDS together with InBr3 as the catalyst in PhMe at 100 °C [65]. The deoxygenation also took place in the absence of catalyst in PhMe at reflux [68]. The solvent-and catalyst-free reduction of 1-phenyl-3-phospholene oxide 35b was complete after a shorter reaction time in both the thermal and MW-promoted variations (Table 12) [66]. The next user-friendly silane, PMHS can be used in the deoxygenation of triphenylphosphine oxide (31). At 290 °C in the absence of any solvent, triphenylphosphine (32) was isolated in an 86% yield [69]. It is a disadvantage that the application of PMHS The reduction of ring phosphine oxides, such as 3-methyl-1-phenyl-2-phospholene oxide (35a), was performed using TMDS together with InBr 3 as the catalyst in PhMe at 100 • C [65]. The deoxygenation also took place in the absence of catalyst in PhMe at reflux [68]. The solvent-and catalyst-free reduction of 1-phenyl-3-phospholene oxide 35b was complete after a shorter reaction time in both the thermal and MW-promoted variations (Table 12) [66]. It is noteworthy that there is no need for any catalyst if the reduction of triphenylphosphine oxide (31) with TMDS is performed in a solvent-free manner under MW irradiation. After treatment at 200 °C for 6.5 h, the reduction was quantitative. On conventional heating at 175 °C, there was a need for a 1-day reaction time. As the reduction takes place in the absence of catalyst, the MW-assisted approach may be regarded as a "green" protocol (Table 11) [66,67]. Practically, MW irradiation substituted the catalyst. The reduction of ring phosphine oxides, such as 3-methyl-1-phenyl-2-phospholene oxide (35a), was performed using TMDS together with InBr3 as the catalyst in PhMe at 100 °C [65]. The deoxygenation also took place in the absence of catalyst in PhMe at reflux [68]. The solvent-and catalyst-free reduction of 1-phenyl-3-phospholene oxide 35b was complete after a shorter reaction time in both the thermal and MW-promoted variations (Table 12) [66]. The next user-friendly silane, PMHS can be used in the deoxygenation of triphenylphosphine oxide (31). At 290 °C in the absence of any solvent, triphenylphosphine (32) was isolated in an 86% yield [69]. It is a disadvantage that the application of PMHS The next user-friendly silane, PMHS can be used in the deoxygenation of triphenylphosphine oxide (31). At 290 • C in the absence of any solvent, triphenylphosphine (32) was isolated in an 86% yield [69]. It is a disadvantage that the application of PMHS requires a relatively high temperature. Applying the reducing agent in a 12 equivalents' quantity at 100 • C in PhMe, no reduction took place after 2 h. At the same time, applying Cu(OTf) 2 as the promoter at 100 • C for 15 h, the deoxygenation took place [64]. Applying 15 mol% of (PhO) 2 P(O)OH as the catalyst at reflux for 1 day, the conversion was incomplete, and the phosphine (32) was obtained in a 35% yield [62]. Applying PMHS at a temperature of 175 • C on conventional heating in the absence of any catalyst and solvent, completion of the reduction required 17 h. In the MW-promoted version, 8 h was enough for an almost quantitative outcome (Table 13). Table 13. Deoxygenation of triphenylphosphine oxide with polymethylhydrosiloxane (PMHS).
Molecules 2021, 26, x FOR PEER REVIEW requires a relatively high temperature. Applying the reducing agent in a 12 equivale quantity at 100 °C in PhMe, no reduction took place after 2 h. At the same time, appl Cu(OTf)2 as the promoter at 100 °C for 15 h, the deoxygenation took place [64]. Appl 15 mol% of (PhO)2P(O)OH as the catalyst at reflux for 1 day, the conversion was inc plete, and the phosphine (32) was obtained in a 35% yield [62]. Applying PMHS at a perature of 175 °C on conventional heating in the absence of any catalyst and solv completion of the reduction required 17 h. In the MW-promoted version, 8 h was eno for an almost quantitative outcome (Table 13). The first deoxygenation of 1-phenyl-2-phospholene oxide 35a with PMHS was formed in the absence of any solvent at 250 °C [69]. Then, this transformation was car out in PhMe at reflux 6 h [68]. The deoxygenation of 1-phenyl-3-phospholene oxide was also investigated under thermal and MW-promoted, in most cases, solvent-free ditions. These deoxygenations were complete at 110 °C after 4 and 2 h, respectively (T 14) [66,67]. The outcome of the deoxygenation of the dimethylphospholene oxide 35c better in PhMe at reflux. Optimum conditions for the reduction of 1-alkyl-3-methyl-3-phospholene 1-ox by PhSiH3, TMDS, and PMHS were also evaluated [70]. The first deoxygenation of 1-phenyl-2-phospholene oxide 35a with PMHS was performed in the absence of any solvent at 250 • C [69]. Then, this transformation was carried out in PhMe at reflux 6 h [68]. The deoxygenation of 1-phenyl-3-phospholene oxide 35b was also investigated under thermal and MW-promoted, in most cases, solvent-free conditions. These deoxygenations were complete at 110 • C after 4 and 2 h, respectively (Table 14) [66,67]. The outcome of the deoxygenation of the dimethylphospholene oxide 35c was better in PhMe at reflux.  [64]. Applying 15 mol% of (PhO)2P(O)OH as the catalyst at reflux for 1 day, the conversion was incomplete, and the phosphine (32) was obtained in a 35% yield [62]. Applying PMHS at a temperature of 175 °C on conventional heating in the absence of any catalyst and solvent, completion of the reduction required 17 h. In the MW-promoted version, 8 h was enough for an almost quantitative outcome (Table 13). The first deoxygenation of 1-phenyl-2-phospholene oxide 35a with PMHS was performed in the absence of any solvent at 250 °C [69]. Then, this transformation was carried out in PhMe at reflux 6 h [68]. The deoxygenation of 1-phenyl-3-phospholene oxide 35b was also investigated under thermal and MW-promoted, in most cases, solvent-free conditions. These deoxygenations were complete at 110 °C after 4 and 2 h, respectively (Table  14) [66,67]. The outcome of the deoxygenation of the dimethylphospholene oxide 35c was better in PhMe at reflux. Optimum conditions for the reduction of 1-alkyl-3-methyl-3-phospholene 1-oxides by PhSiH3, TMDS, and PMHS were also evaluated [70]. Optimum conditions for the reduction of 1-alkyl-3-methyl-3-phospholene 1-oxides by PhSiH 3 , TMDS, and PMHS were also evaluated [70].
TMDS and PMHS are user-friendly and low-cost reducing agents. The lower reactivity can be compensated by a solvent-free and MW-assisted protocol. MWs can be regarded as a kind of promoter substituting efficient catalysts.
Primary amines are suitable components for bis(Kabachnik-Fields) condensations [92]. In these distances, alkyl or arylamines were reacted with two equivalents of the formaldehyde and the >P(O)H reagents to afford the bis(Z 1 Z 2 P(O)CH2)amines (38) (Scheme 10) [93][94][95]. Most of the reactions could be carried out in a solvent-free manner.
Primary amines are suitable components for bis(Kabachnik-Fields) condensations [92]. In these distances, alkyl or arylamines were reacted with two equivalents of the formaldehyde and the >P(O)H reagents to afford the bis(Z 1 Z 2 P(O)CH2)amines (38) (Scheme 10) [93][94][95]. Most of the reactions could be carried out in a solvent-free manner.
The α-aminophosphonates may be formed via imine of α-hydroxyphosphonate intermediates [72,92,99,100]. α-Hydroxyphosphonates may be formed in a reversible manner from the corresponding oxo compound and dialkyl phosphite [101,102]. It was a somewhat surprising experience that the α-hydroxyphosphonates could be converted to the respective α-aminophosphonates by reaction with primary amines under MW conditions. This was promoted by a favorable adjacent group effect [103,104].
In summary, a wide range of mono-and bis Kabachnik-Fields reactions were carried out under MW-assisted and catalyst-free conditions, and mostly in a solvent-free manner.
Moreover, the work-up needed a considerable quantity of solvents. Hence, thes methods cannot be regarded as green. The author of this review together with co-worker developed an indeed environmentally-friendly method by crystallizing the products from the mixtures [116].
Moreover, the work-up needed a considerable quantity of solvents. Hence, these methods cannot be regarded as green. The author of this review together with co-workers developed an indeed environmentally-friendly method by crystallizing the products from the mixtures [116].
"Greener" and more efficient protocols were developed for the Hirao reaction in the last twenty years. The MW technique also proved to be useful in the Hirao reactions. The first MW-assisted P-C coupling took place between aryl halides/triflates and diethyl phosphite in the presence of bis(triphenylphosphine)palladium dichloride, triethylamine, and triethylsilane as the reductant (Scheme 13) [149]. The Hirao reaction was performed in a domestic microwave device. first MW-assisted P-C coupling took place between aryl halides/triflates and diethyl phosphite in the presence of bis(triphenylphosphine)palladium dichloride, triethylamine, and triethylsilane as the reductant (Scheme 13) [149]. The Hirao reaction was performed in a domestic microwave device.
Scheme 13. The first P-C coupling realized on MW irradiation.
The MW-assisted Hirao reaction of dialkyl phosphites with aryl and vinyl halides/triflates was also studied in the presence of Pd(PPh3)4 [150]. The best results (72-96%) were obtained using Cs2CO3 in THF. The MW protocol was also applied in the synthesis of Pfunctionalized 11β-aryl-substituted steroids (43) that are progesterone receptor antagonists (Scheme 14) [151].

Scheme 14.
The derivation of 11β-aryl-substituted steroids with the help of the Hirao reaction.
A few arylboronic acids and arylfluoroborates were coupled with dialkyl phosphites using the Pd(OAc)2 or Pd(O2CCF3)2/dmphen catalyst combination, and p-benzoquinone in the absence of a base [152]. The authors assumed the role of the reoxidant in the catalytic cycle. The author of this review believes that the application of an oxidant in the P-C coupling is mistaken. Instead, a reductive agent may be useful. A new cyclodiphosphazanecontaining Pd catalyst was tested in the preparation of triarylphosphine oxides from aril bromides and diphenylphosphine oxide [153]. The use of this exotic promoter and Cs2CO3 Scheme 13. The first P-C coupling realized on MW irradiation.
The MW-assisted Hirao reaction of dialkyl phosphites with aryl and vinyl halides/ triflates was also studied in the presence of Pd(PPh 3 ) 4 [150]. The best results (72-96%) were obtained using Cs 2 CO 3 in THF. The MW protocol was also applied in the synthesis of Pfunctionalized 11β-aryl-substituted steroids (43) that are progesterone receptor antagonists (Scheme 14) [151]. first MW-assisted P-C coupling took place between aryl halides/triflates and diethyl phosphite in the presence of bis(triphenylphosphine)palladium dichloride, triethylamine, and triethylsilane as the reductant (Scheme 13) [149]. The Hirao reaction was performed in a domestic microwave device.
Scheme 13. The first P-C coupling realized on MW irradiation.
The MW-assisted Hirao reaction of dialkyl phosphites with aryl and vinyl halides/triflates was also studied in the presence of Pd(PPh3)4 [150]. The best results (72-96%) were obtained using Cs2CO3 in THF. The MW protocol was also applied in the synthesis of Pfunctionalized 11β-aryl-substituted steroids (43) that are progesterone receptor antagonists (Scheme 14) [151].

Scheme 14.
The derivation of 11β-aryl-substituted steroids with the help of the Hirao reaction.
A few arylboronic acids and arylfluoroborates were coupled with dialkyl phosphites using the Pd(OAc)2 or Pd(O2CCF3)2/dmphen catalyst combination, and p-benzoquinone in the absence of a base [152]. The authors assumed the role of the reoxidant in the catalytic cycle. The author of this review believes that the application of an oxidant in the P-C coupling is mistaken. Instead, a reductive agent may be useful. A new cyclodiphosphazanecontaining Pd catalyst was tested in the preparation of triarylphosphine oxides from aril bromides and diphenylphosphine oxide [153]. The use of this exotic promoter and Cs2CO3 A few arylboronic acids and arylfluoroborates were coupled with dialkyl phosphites using the Pd(OAc) 2 or Pd(O 2 CCF 3 ) 2 /dmphen catalyst combination, and p-benzoquinone in the absence of a base [152]. The authors assumed the role of the reoxidant in the catalytic cycle. The author of this review believes that the application of an oxidant in the P-C coupling is mistaken. Instead, a reductive agent may be useful. A new cyclodiphosphazanecontaining Pd catalyst was tested in the preparation of triarylphosphine oxides from aril bromides and diphenylphosphine oxide [153]. The use of this exotic promoter and Cs 2 CO 3 as a base in acetonitrile under MW irradiation gave Ph 3 P=O in yields of 46-95%. It is noteworthy that the coupling of iodo-and bromobenzoic acids with diphenylphosphine oxide could be performed in water using Pd/C catalyst under MW conditions (Scheme 15) [154]. In this case, the tetrabutylammonium bromide additive had no influence on the outcome.

Scheme 14.
The derivation of 11β-aryl-substituted steroids with the help of the Hirao reaction.
A few arylboronic acids and arylfluoroborates were coupled with dialkyl phosphites using the Pd(OAc)2 or Pd(O2CCF3)2/dmphen catalyst combination, and p-benzoquinone in the absence of a base [152]. The authors assumed the role of the reoxidant in the catalytic cycle. The author of this review believes that the application of an oxidant in the P-C coupling is mistaken. Instead, a reductive agent may be useful. A new cyclodiphosphazanecontaining Pd catalyst was tested in the preparation of triarylphosphine oxides from aril bromides and diphenylphosphine oxide [153]. The use of this exotic promoter and Cs2CO3 as a base in acetonitrile under MW irradiation gave Ph3P=O in yields of 46-95%. It is noteworthy that the coupling of iodo-and bromobenzoic acids with diphenylphosphine oxide could be performed in water using Pd/C catalyst under MW conditions (Scheme 15) [154]. In this case, the tetrabutylammonium bromide additive had no influence on the outcome.

Scheme 15.
Hirao reaction in water using Pd/C on MW irradiation. Scheme 15. Hirao reaction in water using Pd/C on MW irradiation. It was recognized by the Keglevich group that the Hirao cross-couplings may take place in the presence of Pd(OAc) 2 without the addition of the usual P-ligands under solventfree and MW-assisted conditions (Scheme 16) [155]. The reaction of bromobenzene and 1.5 equivalents of the dialkyl phosphites, phenyl-H-phosphinates, and diphenylphosphine oxide was carried out in the presence of 5% of Pd(OAc) 2 and 1.1 equivalents of triethylamine. The relevance of the MW technique was pointed out by comparative thermal experiments. The conversion was almost complete at 120 • C, but the best results were obtained at 150 • C. It was recognized by the Keglevich group that the Hirao cross-couplings may take place in the presence of Pd(OAc)2 without the addition of the usual P-ligands under solvent-free and MW-assisted conditions (Scheme 16) [155]. The reaction of bromobenzene and 1.5 equivalents of the dialkyl phosphites, phenyl-H-phosphinates, and diphenylphosphine oxide was carried out in the presence of 5% of Pd(OAc)2 and 1.1 equivalents of triethylamine. The relevance of the MW technique was pointed out by comparative thermal experiments. The conversion was almost complete at 120 °C, but the best results were obtained at 150 °C. Scheme 16. MW-promoted P-C couplings applying Pd(OAc)2 without added P-ligands.
In the next stage, the Pd(OAc)2-promoted "P-ligand-free" Hirao reactions were extended to different bromoarenes (Table 15) [156]. The experience was that both electronreleasing and electron-withdrawing substituents decreased the reactivity, as in these instances, higher temperatures (175-200 °C) were necessary to obtain the aryl phosphonates in acceptable yields (69-92%) ( Table 15). The reactions of the methoxy-and alkyl-substituted bromoarenes with a decreased reactivity required, in most cases, a temperature of 200 °C, and the application of 10% of the Pd(OAc)2 catalyst.  In the next stage, the Pd(OAc) 2 -promoted "P-ligand-free" Hirao reactions were extended to different bromoarenes (Table 15) [156]. The experience was that both electronreleasing and electron-withdrawing substituents decreased the reactivity, as in these instances, higher temperatures (175-200 • C) were necessary to obtain the aryl phosphonates in acceptable yields (69-92%) ( Table 15). The reactions of the methoxy-and alkylsubstituted bromoarenes with a decreased reactivity required, in most cases, a temperature of 200 • C, and the application of 10% of the Pd(OAc) 2 catalyst. Recently, Hirao et al. have publised another "P-ligand-free" reaction (Scheme 17) [157]. According to this, diethyl phosphite was coupled with 2-nitro-5-bromoanisole applying Pd(OAc) 2 as the catalyst and Na 2 CO 3 in xylene at 120 • C to furnish the respective aryl phosphonate (47)  Recently, Hirao et al. have publised another "P-ligand-free" reaction (Scheme 17) [157]. According to this, diethyl phosphite was coupled with 2-nitro-5-bromoanisole applying Pd(OAc)2 as the catalyst and Na2CO3 in xylene at 120 °C to furnish the respective aryl phosphonate (47) in a yield of 69% after 24 h. Scheme 17. An additional Pd(OAc)2-catalyzed "P-ligand-free" P-C coupling.
Xiao and his co-workers described the Pd-catalyzed cross-coupling of an arylsulfinate salt with dialkyl phosphites applying PdCl2 without the usual P-ligands in DMF-DMSO [158]. The arylphosphonates were prepared in good yields using silver carbonate as the oxidant under MW irradiation. Here, it is noted again that there is no need for an oxidant during the P-C coupling. The Pd(OAc)2-promoted "P-ligand-free" protocol was extended to the Hirao reaction of heteroaryl bromides [159], and the reactivity of the substrates was studied in detail [160].
Moreover, the mechanism of the Pd-catalyzed Hirao reactions carried out using the P-reactant in excess was investigated experimentally and by quantum chemical calculations [161]. It was found that if Pd(OAc)2 is applied in a quantity of 10%, the >P(O)H reactant should be used in a quantity of 1.3 equivalents. 10% of the P-species reduces Pd(II) to Pd(0), while 20% covers the P-ligand that is the trivalent tautomeric form (>P-OH) of the >P(O)H reagent. The whole catalytic cycle involving oxidative addition, ligand exchange, and reductive elimination was adapted to our model, and the elemental steps were refined [161]. The formation of the "PdP2" catalyst and its activity were investigated under a separate cover [162]. It turned out that the Ar2POH ligands with 2-MePh or 3,5-diMePh substituents are more advantageous than the Ph one, as the steric hindrance prevents the tricoordination of the Pd [162].
It was also found that NiCl2 may also be a suitable catalyst in the P-C coupling of bromobenzene and a series of >P(O)H reagents (Scheme 18) [163]. The experiments were Scheme 17. An additional Pd(OAc) 2 -catalyzed "P-ligand-free" P-C coupling.
Xiao and his co-workers described the Pd-catalyzed cross-coupling of an arylsulfinate salt with dialkyl phosphites applying PdCl 2 without the usual P-ligands in DMF-DMSO [158]. The arylphosphonates were prepared in good yields using silver carbonate as the oxidant under MW irradiation. Here, it is noted again that there is no need for an oxidant during the P-C coupling. The Pd(OAc) 2 -promoted "P-ligand-free" protocol was extended to the Hirao reaction of heteroaryl bromides [159], and the reactivity of the substrates was studied in detail [160].
Moreover, the mechanism of the Pd-catalyzed Hirao reactions carried out using the P-reactant in excess was investigated experimentally and by quantum chemical calculations [161]. It was found that if Pd(OAc) 2 is applied in a quantity of 10%, the >P(O)H reactant should be used in a quantity of 1.3 equivalents. 10% of the P-species reduces Pd(II) to Pd(0), while 20% covers the P-ligand that is the trivalent tautomeric form (>P-OH) of the >P(O)H reagent. The whole catalytic cycle involving oxidative addition, ligand exchange, and reductive elimination was adapted to our model, and the elemental steps were refined [161]. The formation of the "PdP 2 " catalyst and its activity were investigated under a separate cover [162]. It turned out that the Ar 2 POH ligands with 2-MePh or 3,5-diMePh substituents are more advantageous than the Ph one, as the steric hindrance prevents the tricoordination of the Pd [162].
It was also found that NiCl 2 may also be a suitable catalyst in the P-C coupling of bromobenzene and a series of >P(O)H reagents (Scheme 18) [163]. The experiments were carried out at 150 • C on MW irradiation. Using 1.5 equivalents of NEt 3 in a solvent-free manner, completion of the reaction of diethyl phosphite and bromobenzene required 2 h, and the diethyl phenylphosphonate was isolated in a 67% yield. The use of K 2 CO 3 in acetonitrile was more advantageous: in the presence of 5% NiCl 2 , after a reaction time of 45 min the yield of the corresponding product was 92%. Applying phenyl-H-phosphinates, the diphenylphosphinates were isolated in yields of 84-89%. Diphenylphosphine oxide and other aryl-substituted secondary phosphine oxides served as additional reagents in the "P-ligand-free" P-C couplings under discussion. The NiCl2-catalyzed phosphonylation of a series of bromoarenes gave similar results as those in the presence of Pd(OAc)2. However, the scope of the aryl bromides was more limited (Scheme 19) [163].
The nature of the Ni-catalyst, its formation, and the mechanism of the NiCl2-catalyzed P-C coupling reactions was also studied experimentally and by theoretical calculations [163]. It was found that in these cases, a Ni(II)(PY2OH)2 type catalyst is formed, and Ni(II) is converted to Ni(IV) in the oxidative addition step. This surprising finding was also proved to be true for earlier Ni-catalyzed instances [164] carried out originally in the presence of Zn or Mg reductants [165][166][167]. Hence, the Ni(II)  Ni(IV) conversion may be of more general value instead of the earlier assumed Ni(0)  Ni(II) protocol [168].
Both the Pd-and the Ni-catalyzed protocols elaborated by the Keglevich group are suitable for the coupling of bromoarenes and different >P(O)H reagents. Considering the conditions, costs, and toxicity, one can conclude that the application of Pd(OAc)2 is more attractive, but the use of NiCl2 may be a good alternative as well. The recent developments and extensions of the P-C coupling reactions open a new horizon since there is no need to add sensitive and expensive P-ligands.
A catalyst-free method was developed for the P-C coupling of halobezoic acids and secondary phosphine oxides in water as the medium (Scheme 20) [169]. 4-Iodo-, 3-bromo-, and 4-bromobenzoic acids were coupled with diaryl phosphine oxides under MW conditions at 180 °C for 1-6 h in the presence of K2CO3. The only limitation of this "green" P-Scheme 18. Hirao reactions applying NiCl 2 as the catalyst without added P-ligands.
The NiCl 2 -catalyzed phosphonylation of a series of bromoarenes gave similar results as those in the presence of Pd(OAc) 2 . However, the scope of the aryl bromides was more limited (Scheme 19) [163]. The NiCl2-catalyzed phosphonylation of a series of bromoarenes gave similar results as those in the presence of Pd(OAc)2. However, the scope of the aryl bromides was more limited (Scheme 19) [163].
The nature of the Ni-catalyst, its formation, and the mechanism of the NiCl2-catalyzed P-C coupling reactions was also studied experimentally and by theoretical calculations [163]. It was found that in these cases, a Ni(II)(PY2OH)2 type catalyst is formed, and Ni(II) is converted to Ni(IV) in the oxidative addition step. This surprising finding was also proved to be true for earlier Ni-catalyzed instances [164] carried out originally in the presence of Zn or Mg reductants [165][166][167]. Hence, the Ni(II)  Ni(IV) conversion may be of more general value instead of the earlier assumed Ni(0)  Ni(II) protocol [168].
Both the Pd-and the Ni-catalyzed protocols elaborated by the Keglevich group are suitable for the coupling of bromoarenes and different >P(O)H reagents. Considering the conditions, costs, and toxicity, one can conclude that the application of Pd(OAc)2 is more attractive, but the use of NiCl2 may be a good alternative as well. The recent developments and extensions of the P-C coupling reactions open a new horizon since there is no need to add sensitive and expensive P-ligands.
A catalyst-free method was developed for the P-C coupling of halobezoic acids and secondary phosphine oxides in water as the medium (Scheme 20) [169]. 4-Iodo-, 3-bromo-, and 4-bromobenzoic acids were coupled with diaryl phosphine oxides under MW conditions at 180 °C for 1-6 h in the presence of K2CO3. The only limitation of this "green" P-C coupling reaction is the low water-solubility of the P-reagents. The nature of the Ni-catalyst, its formation, and the mechanism of the NiCl 2 -catalyzed P-C coupling reactions was also studied experimentally and by theoretical calculations [163]. It was found that in these cases, a Ni(II)(PY 2 OH) 2 type catalyst is formed, and Ni(II) is converted to Ni(IV) in the oxidative addition step. This surprising finding was also proved to be true for earlier Ni-catalyzed instances [164] carried out originally in the presence of Zn or Mg reductants [165][166][167]. Hence, the Ni(II) → Ni(IV) conversion may be of more general value instead of the earlier assumed Ni(0) → Ni(II) protocol [168].
Both the Pd-and the Ni-catalyzed protocols elaborated by the Keglevich group are suitable for the coupling of bromoarenes and different >P(O)H reagents. Considering the conditions, costs, and toxicity, one can conclude that the application of Pd(OAc) 2 is more attractive, but the use of NiCl 2 may be a good alternative as well. The recent developments and extensions of the P-C coupling reactions open a new horizon since there is no need to add sensitive and expensive P-ligands.
A catalyst-free method was developed for the P-C coupling of halobezoic acids and secondary phosphine oxides in water as the medium (Scheme 20) [169]. 4-Iodo-, 3bromo-, and 4-bromobenzoic acids were coupled with diaryl phosphine oxides under MW conditions at 180 • C for 1-6 h in the presence of K 2 CO 3 . The only limitation of this "green" P-C coupling reaction is the low water-solubility of the P-reagents.
Both the Pd-and the Ni-catalyzed protocols elaborated by the Keglevich group are suitable for the coupling of bromoarenes and different >P(O)H reagents. Considering the conditions, costs, and toxicity, one can conclude that the application of Pd(OAc)2 is more attractive, but the use of NiCl2 may be a good alternative as well. The recent developments and extensions of the P-C coupling reactions open a new horizon since there is no need to add sensitive and expensive P-ligands.
A catalyst-free method was developed for the P-C coupling of halobezoic acids and secondary phosphine oxides in water as the medium (Scheme 20) [169]. 4-Iodo-, 3-bromo-, and 4-bromobenzoic acids were coupled with diaryl phosphine oxides under MW conditions at 180 °C for 1-6 h in the presence of K2CO3. The only limitation of this "green" P-C coupling reaction is the low water-solubility of the P-reagents. Scheme 20. A catalyst-free Hirao reaction in aqueous medium.
In summary, the Hirao reaction utilizing a series of suitably substituted aryl derivatives and different >P(O)H reagents along with a Pd or Ni catalyst provides arylphosphonates, tertiary phosphine oxides, and related compounds that may be useful intermediates in synthetic organic chemistry. The chemistry discussed hides interesting green chemical aspects, such as MW activation, solvent-and catalyst-free protocols, as well as mechanistic delicates.
Funding: This project was supported by the National Research, Development and Innovation Office (K119202 and K134318).

Data Availability Statement:
The data presented in this study are available in the references.