Or As Substitute for Catalysts in Organophosphorus Chemistry

molecules

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

György Keglevich

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected]

Abstract: 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.

Keywords: microwave; organophosphorus chemistry; catalyst; catalyst- and solvent-free; green chemistry

The spread of the microwave (MW) technique opened a new chapter in organic Citation: Keglevich, G. Microwaves chemistry in whole [1–3], and also in its specialized fields, such as heterocyclic [3–5] and as “Co-Catalysts” or as Substitute for organophosphorus chemistry [2,6]. MW irradiation makes possible more efficient syntheses Catalysts in Organophosphorus in terms of reaction time, selectivity, and purity [1,2]. The role of MWs in organic syntheses Chemistry. Molecules 2021, 26, 1196. provoked sharp disputes, however, today there is an agreement that thermal effects are https://doi.org/10.3390/ molecules26041196 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

Academic Editor: Cesar Mateo overheating in the bulk of the mixture [9–11]. During our work, we laid the stress on green chemical aspects within organophos- Received: 10 February 2021 phorus chemistry [12]. This will be summarized in this review article. Besides developing Accepted: 19 February 2021 efﬁcient syntheses, we could enhance reluctant or slow reactions by applying the MW Published: 23 February 2021 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 Publisher’s Note: MDPI stays neutral possibility to substitute certain catalysts by MW irradiation (3). Last but not least, MWs with regard to jurisdictional claims in may simplify catalytic systems/catalysts (4). In this paper, options (1)–(4) will be discussed published maps and institutional afﬁl- in detail, placing the particular reactions into literature context. iations. 1. Microwave Irradiation Allowing the Inverse-Wittig Type Reaction That Is Reluctant on Conventional Heating The Diels–Alder reaction of 1-phenyl-1,2-dihydrophosphinine oxide 1 with dienophiles,

Copyright: © 2021 by the author. like N-phenylmaleimide and dimethyl acetylenedicarboxylate (DMAD), resulted in the Licensee MDPI, Basel, Switzerland. formation of the respective phosphabicyclo[2.2.2]octene derivatives (2) and (3). The mi- This article is an open access article crowave (MW) technique was useful in shortening the reaction times and making the distributed under the terms and syntheses efﬁcient. The MW-promoted reactions were 25 times faster than the thermal conditions of the Creative Commons variations (Scheme1)[13]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Molecules 2021, 26, 1196. https://doi.org/10.3390/molecules26041196 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 24

Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEW 2 of 24 syntheses efficient. The MW-promoted reactions were 25 times faster than the thermal variations (Scheme 1) [13].

Molecules 2021, 26, 1196 2 of 23 syntheses efficient. The MW-promoted reactions were 25 times faster than the thermal variations (Scheme 1) [13].

Scheme 1. [4 + 2]Cycloadditions of a 1,2-dihydrophosphinine oxide (1) with dienophiles.

However, the 1-(2,4,6-triisopropylphenyl-1,2-dihydrophosphinine) oxide (4) [14] un- SchemeSderwentcheme 1. an [4 + inverse 2]Cycloadditions 2]Cycloadditions-Wittig type of atransformation 1,2 1,2-dihydrophosphinine-dihydrophosphinine in reaction oxide with (1) with DMAD dienophiles. to afford the corresponding β-oxophosphorane 5 (Scheme 2) [15,16]. However, the 1-(2,4,6-triisopropylphenyl-1,2-dihydrophosphinine)1-(2,4,6-triisopropylphenyl-1,2-dihydrophosphinine) oxide ( 4))[ [1144] un- derwent an an inverse inverse-Wittig-Wittig type type transformation transformation in inreaction reaction with with DMAD DMAD to afford to afford the cor- the correspondingresponding β-oxophosphoraneβ-oxophosphorane 5 (Scheme5 (Scheme 2) [12)[5,1156,].16 ].

Scheme 2. The inverse Wittig-type reaction of a P-aryl 1,2-dihydrohosphine oxide with dimethyl acetylenedicarboxylate (DMAD).

SchemeSchemeThen, 2. TheThe the inverse inverse new protocol Wittig Wittig-type-type seemed reaction reaction to beof of aofa P P-aryla-aryl more 1,2 1,2-dihydrohosphine general-dihydro valuehosphine [17 oxide]. oxideThe with use with ofdimethyl dimethyl the MW acetylenedicarboxylatetechnique was advantageous (DMAD).(DMAD). not only in the inverse Wittig-type reaction of 2,4,6-triisopropylphenyl-3-phospholene oxide but also in the reaction of 2,4,6-triiso- propylphenylphospholaneThen, the the new new protocol protocol seemed oxide seemed and to to be 2,4,6 be of ofa- triisopropylphenylmore a more general general value value- 1,2[17-].dihydrophosphinine [17 The]. Theuse of use the of MW the MWtechniqueoxide technique (all representedwas advantageous was advantageous by formula not only6) not to affordin only thein inverseβ- theoxophosphoranes inverse Wittig Wittig-type-type reaction7 (Scheme reaction of 3)2,4,6 [1 of8-,1triiso- 2,4,6-9]. triisopropylphenyl-3-phospholenepropylphenylIn the novel-3-phospholen inverse Wittige oxide-type oxide reactions, but also also inMW the in irradiation reaction the reactionof made 2,4,6-triisopropylphenyl possible of 2,4,6 reactions-triiso- phospholanepropylphenylphospholaneat 150 °C for 3 oxide h that and were 2,4,6-triisopropylphenyl-1,2-dihydrophosphinine rather oxide reluctant and 2,4,6 on-triisopropylphenyl conventional heating.-1,2- dihydrophosphinineHence, oxide MW (all acted repre- as sentedoxidea kind (all byof catalyst.represented formula 6) to by afford formulaβ-oxophosphoranes 6) to afford β-oxophosphoranes7 (Scheme3)[18 7,19 (Scheme]. 3) [18,19]. 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.

SchemeScheme 3.3. TheThe inverseinverse Wittig-typeWittig-type reactionreaction ofof P-arylP-aryl ringring phosphinephosphine oxidesoxides withwith DMAD.DMAD.

InTheoretical the novel calculations inverse Wittig-type suggested reactions, a mechanism MW irradiation involving madean oxaphosphete possible reactions interme- at ◦ 150SdiatechemeC [20for 3., 21The 3]. h inverse that were Wittig rather-typereluctant reaction of on P-ary conventionall ring phosphine heating. oxides Hence, with DMAD. MW acted as a kindIn of catalyst.the above case, the nature of the 1,2-dihydrophosphinine oxide determined its re- activityTheoretical towards calculationsDMAD. Moreover, suggested both a mechanism the Diels–Alder involving cycloaddition an oxaphosphete and the interme- inverse- diate [20,,21].]. In the the above above case, case, the the nature nature of of the the 1,2 1,2-dihydrophosphinine-dihydrophosphinine oxide oxide determined determined its re- its reactivity towards DMAD. Moreover, both the Diels–Alder cycloaddition and the inverse- activity 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.

Molecules 2021, 26, x FOR PEER REVIEW 3 of 24

Molecules 2021, 26, 1196 Wittig type reaction took place efficiently on MW irradiation without the application3 of of 23 any catalyst.

2. Microwave Microwave-Assisted,-Assisted, Ionic Liquid Liquid-Catalyzed-Catalyzed Direct Esterification Esterification of P-OxoacidsP-Oxoacids TThathat I Iss Otherwise Impossi Impossibleble under Thermal Conditions PPhosphinichosphinic and and phosphonic acids cannot be involved in direct esterificationesterification under common conditions.conditions. OnlyOnly a a few few examples examples are are known known for for the the direct direct esterification esterification of P-acids. of P- acids.These reactionsThese reactions required required forcing conditionsforcing conditions and were and not were efficient not [ 22efficient–26]. However, [22–26]. itHow- was ever,found it bywas us found that the by P-acids us that canthe beP-acids esterified can be on esterified MW irradiation. on MW irradiation. The esterification esterification of 1 1-hydroxy-3-phospholene-hydroxy-3-phospholene oxide oxide ( (88)) with with a series of alcohols at 180180–235–235 °C◦C afforded the alkyl phosphinates (9)) inin yieldsyields ofof 71–95%71–95% (Scheme(Scheme4 /B4/B vs.vs. A,A, Table1 1/Entries/Entries 1, 1, 3, 3, 5, 5, 7, 7, 9 9and and 11) 11) [2 [7–2729–].29 The]. The esterifications esterifications were were less lessefficient efficient with with vol- atilevolatile and and sterically sterically hindered hindered alcohols. alcohols. The The relatively relatively high high temperature temperature required required means a limitationlimitation that that may be overcome by applying ionic liquids (ILs) as catalysts.catalysts. It was found thatthat in in the the presence presence of of 10% 10% of of [bmim][PF [bmim][PF6]6 as] as an an additive, additive, the the esterifications esterifications took took place place at aat lower a lower temperature, temperature, and and became became faster faster and and more more efficient efficient in in shorter shorter reaction times (Scheme 44/D,/D , Table Table 11/Entries/Entries 2, 4, 6, 8, 1010 andand 12)12) [[30]. The thermal direct esterificationsesterifications were also somewhat promoted by the ionic liquid additive (Scheme4 4/C)./C).

SSchemecheme 4 4.. TheThe MW MW-assisted-assisted catalytic direct esterification esteriﬁcation 1-hydroxy-3-methyl-3-phospholene1-hydroxy-3-methyl-3-phospholene 1-oxide1-oxide ((88).).

TableTable 1. 1. EsteriﬁcationEsterificationEsterification with with other other alcohols. alcoholsalcohols..

Me Me T / 215.5 bar / t + ROH P [bmim][PF6] P O OH O OR 9 8 ◦ Conversion EntryEntry R R [bmim][PF [bmim][PF66]T(] T (°C)C) t (h) t (h) Conversion (%) Yield (%) (%) Entry R [bmim][PF6] T (°C) t (h) Conversion(%) (%) Yield (%) 11 PrPr –– 180180 44 4040 3030 1 Pr – 180 4 40 30 22 PrPr Pr 10%10% 10% 180180 180 33 39898 98 68 68 33 PentPent Pent –– – 220220 220 2.52.5 2.5100100 100 82 82 44 PentPent Pent 10%10% 10% 180180 180 0.50.5 0.5100100 100 94 94 i 55 iPentiPentPent ––– 235235 235 33 3100100 100 ** *76 76 6 iPent 10% 180 0.5 100 95 66 iPentiPent 10%10% 180180 0.50.5 100100 9595 7 Oct – 220 2 95 * 71 778 OctOct Oct 10%–– 220220 180 22 0.339595 100 ** 71 8571 889 OctOctiOct 10%10%– 180180 220 0.330.33 1100100 100 85 7685 9109 iOctiOctiOct 10%–– 220220 180 11 0.33100100 100 76 8476 101011 DodecyliOctiOct 10%10% – 180180 230 0.330.33 2100100 100 84 9584 12 Dodecyl 10% 180 0.33 100 94 1111 DodecylDodecyl –– 230230 22 100100 9595 * Estimated value. 1212 DodecylDodecyl 10%10% 180180 0.330.33 100100 9494 * Estimated value. Then, the MW-promoted IL-catalyzed direct esteriﬁcations were extended to other ring phosphinic acids, like 1-hydroxy-3,4-dimethyl-3-phospholene oxide (10), 1-hydroxy- Table 2. Extension of the MW‐assisted IL‐catalyzed direct esterification to other cyclic phosphinic acids.

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MoleculesMolecules 20212021, 26,, 26x FOR, 1196 PEER REVIEW 2 of4 of 7 23

Model Reaction [bmim][PF6] T (°C) t (h) Yield (%) Molecules 2021, 26, x FOR PEER REVIEW 2 of 7

– 235 3 67 Model Reaction 12 14 [bmim][PF6] T (°C) t (h) Yield (%) Molecules 2021, 26, x FOR PEER REVIEWphospholane oxides ( and ), as well as, a 1-hydroxy-1,2,3,4,5,6-hexahydrophosphinine2 of 7 oxide (16) (Table2)[29–31]. Model Reaction [bmim][PF– 6] T235 (°C) t (h)3 Yield67 (%) Table 2. Extension of the MW-assisted IL-catalyzed direct esteriﬁcation10% to other200 cyclic phosphinic1 acids. 72 – 235 3 67 Model Reaction [bmim][PF6] T ◦(°C) t (h) Yield (%) Model Reaction [bmim][PF6]T( C) t (h) Yield (%) 10% 200 1 72 –– 235235 33 67 67 – 235 3 79 10% 200 1 72

– 235 3 79 10%10% 200200 11 72 72 10% 220 1 89 –– 235235 3 79 79

10% 220 1 89 – 235 3 79 – 235 5 60 10%10% 220220 1 89 89

–– 235235 5 60 60 10% 220 1 89 10% 220 2 84 – 235 5 60

10%10% 220220 2 84 84 – 235 5 60 – 220 4 31 –10% 220220 42 84 31

– 220 4 31 10% 220 2 84 10% 200 2 42 10% 200 2 42 – 220 4 31

10% 200 2 42 Using IL-catalysis, even phenols could– be the reactants220 in the MW-assisted4 31 esterifica- Table 3.tion MW of‐promoted cyclic phosphinic direct esterification acids [32 of]. phenylphosphonic10% 200acid (26). 2 42 The esterification of the reactive phenyl-H-phosphinic acid (18) took place at a tem- ◦ Table 3. perature MW‐promoted of 160–190 direct esterificationC to provide of the phenylphosphonic10% phosphinates ( 19acid200) in (26 good). (73–90%)2 yields42 [ 33]. The presence of [bmim][PF6 ] had a beneficial effect on the outcome (Scheme5/(1)) [ 34]. Methyl- Table 3. phenylphosphinic MW‐promoted direct acid esterification (20), and what of phenylphosphonic is more, the sterically acid (26 hindered). diphenylphosphinic Molecules 2021, 26, x FOR PEER REVIEW 5 of 24 acid (22), could also be efficiently esterified in the presence of an IL (Scheme5/(2) and Table 3.(3)) MW [34‐promoted,35]. direct esterification of phenylphosphonic acid (26).

CompositionMW R T (°C) t (h) Conversion (%) Yield of the Monoester (%) O Monoester140 °C / (%)16 bar Diester30 min (%) O P + ROH P (1) [bmim][PFComposition] (10%) BuR T180 (°C) t0.75 (h) ConversionH 100OH (15(%) equiv.) 95 6 5 YieldH ofOR the Monoester82 (%) Et 165 8 18 82 Monoester94 (%)i Diester6 (%) 19 70 R = Et,Composition Bu, Bu, Pent, Oct OctBuR T180 (°C) t0.75 (h) Conversion100 (%) 9596 54 Yield88 94% of the Monoester8290 (%) Et 165 8 82 Monoester94 (%) Diester6 (%) 70 MW Bu 180 0.75 O100 95Composition 5 O 82 OctR T180 (°C) 0.75t (h)Table 4.Conversion MW‐100promoted (%) direct esterification180 96°C / 14 bar of phenylphosphonic0.33/2 4h Yieldmonoesters of the (27 90Monoester). (%) Et 165 8 P 82OH + ROH Monoester94 (%) Diester6 (%) P OR 70(2) [bmim][PF ] (10%) OctBu 180180 0.750.75Table 4. MWMe‐100100promoted direct esterification9695 of6 phenylphosphonic45 monoestersMe (279082). Et 165 8 20 82 94 R = Bu, Oct 6 21 70 73 92% Oct 180 0.75Table 4. MW‐100promoted direct esterification96 of phenylphosphonic4 monoesters (2790).

MW Table 4. MW‐promoted direct esterification of phenylphosphonic monoesters (27). O 200 °C / 16 bar 2 h O P + ROH P (3) R OH (15 equiv.) T[bmim][PF (°C) 6] (10%) t (h) OR Conversion (%)

Bu 220 6 45 22OctR RT = 235(°C) Bu, Pent, iPent, Oct t (h)3 23 Conversion72 (%)

Bu 220 6 65 95% 45 R T (°C) t (h) Conversion (%) SchemeSchemeOct 5.5. MW-promotedMW -promoted directdirect235 esteriﬁcationesterification ofof differentdifferent phenyl-phosphinic3phenyl -phosphinic acidsacids72 (18(18 ,,20 20,, and and22 ). 22). Bu 220 6 45

OctR T235 (°C) t 3(h) Conversion72 (%) It isBu noteworthy that thiobutanol220 could also be used6 under MW-assistance45 to afford

the correspondingOct thiophosphinates235 [36]; however, 3the direct amidations72 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 (Table 4). [Bmim][PF6] was somewhat less efficient than [bmim][BF4] [34,39].

Table 3. MW-promoted direct esterification of phenylphosphonic acid (26).

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MW O 140 °C / 16 bar 30 min O P + ROH P (1) [bmim][PF ] (10%) H OH (15 equiv.) 6 H OR 18 R = Et, Bu, iBu, Pent, Oct 19 88 94%

MW O O 180 °C / 14 bar 0.33/2 h P OH + ROH P OR (2) [bmim][PF ] (10%) MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW Me 6 Me 22 ofof 77

20 R = Bu, Oct 21 73 92%

ModelModel ReactionReaction MW[bmim][PF[bmim][PF66]] TT (°C)(°C) tt (h)(h) YieldYield (%)(%) O 200 °C / 16 bar 2 h O P + ROH –– 235235 P 33 (3) 6767 OH (15 equiv.) [bmim][PF6] (10%) OR

22 R = Bu, Pent, iPent, Oct 23 10%10% 200200 11 7272 65 95% Molecules 2021, 26, 1196 5 of 23 Scheme 5. MW-promoted direct esterification of different phenyl-phosphinic acids (18, 20, and 22 ). –– 235235 33 7979 It is noteworthynoteworthy that thiobutanol could also be used under MW-assistanceMW-assistance to afford the corresponding thiophosphinates [3 [366]];; however, the directdirect amidationsamidations ofof phosphinicphosphinic acids were reluctant even on MWMW irradiationirradiation10%10% [[3377].]. 220220 11 8989 Our next targetstargets werewere thethe phosphonic phosphonic acids. acids. In In the the ﬁrst first approach, approach the, the alkyl alkyl phenyl- phenylH-

phosphinatesH -phosphinates (19 ()19 were) were oxidized, oxidized, then then the ester-acid the ester- wereacid were esterified. esterified. However, However, we could we not be satisfied with the efficiency (Scheme6)[38]. could not be satisfied with the efficiency (Scheme–– 6) [38].235235 55 6060

10%10% 220220 22 8484

SchemeScheme 6. The preparationpreparationof of dialkyl dialkyl phenylphosphonates phenylphosphonates–– (25 (25)220 via220) via alkyl alkyl phenyl- phenyl44 H--phosphinatesH-phosphinates3131 (19 ). (19). For this, the direct esteriﬁcation of phenylphosphonic acid was studied in detail. We learnedFor thatthis, the the MW-assisted direct esterification and IL-catalyzed of phenylphosphonic protocol furnished acid was the studied monoesters in detail. (27 )We in goodlearned selectivities that the MW and-assisted in acceptable and IL yields-catalyzed10%10% (Table protocol3). At the200200 furnished same time, the22 the monoesters diesteriﬁcation4242 ( 27) in

togood species selectivities25 was and not in efﬁcient acceptable (Table yields4). [Bmim][PF (Table 3). At6] wasthe same somewhat time, the less diesterification efﬁcient than

[bmim][BFto species 254][ 34was,39 not]. efficient (Table 4). [Bmim][PF6] was somewhat less efficient than TableTable[bmim][BF 3.3. MWMW‐‐promotedpromoted4] [34,3 9 directdirect]. esterificationesterification ofof phenylphosphonicphenylphosphonic acidacid ((2626).). Table 3. MW-promoted direct esteriﬁcation of phenylphosphonic acid (26). Table 3. MW-promoted direct esterification of phenylphosphonic acid (26).

Yield of the ◦ ConversionCompositionComposition Composition R T (°C) t (h) R ConversionT( C) (%)t (h) Yield of the MonoesterMonoester (%) R T (°C) t (h) Conversion (%) (%) Monoester (%)Yield Diester of (%) the Monoester (%) MonoesterMonoester (%)(%) DiesterDiester (%)(%) (%) BuBu 180180 0.750.75 Bu 180100100 0.75 1009595 9555 58282 82 EtEt 165165 88 Et 1658282 89494 82 9466 67070 70 Oct 180 0.75 100 96 4 90 OctOct 180180 0.750.75 100100 9696 44 9090

TableTable 4. 4.4. MW-promoted MWMW‐‐promotedpromoted direct directdirect esteriﬁcation esterificationesterification of ofof phenylphosphonic phenylphosphonicphenylphosphonic monoesters monoestersmonoesters ( 27((2727).).).

RT(◦C) t (h) Conversion (%) RR TT (°C)(°C) tt (h)(h) ConversionConversion (%)(%) Bu 220 6 45 BuBu 220220 66 4545 Oct 235 3 72 OctOct 235235 33 7272

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 (Table5)[39]. Molecules 2021, 26, x FOR PEER REVIEW 3 of 7

Molecules 2021, 26, x FOR PEER REVIEW 3 of 7 Molecules Molecules 20212021,, 2626,, 1196x FOR PEER REVIEW 63 of of 23 7

Table 5. Alkylating esterification of phenylphosphonic acid (26). Table 5. Alkylating esterification of phenylphosphonic acid (26). Table 5. Alkylating esterification of phenylphosphonic acid (26). Table 5. Alkylating esteriﬁcation of phenylphosphonic acid (26).

Composition BuBr (Equiv.) T (°C) t (h) Conversion (%) MonoesterCompositionComposition (%) Diester (%) BuBrBuBr (Equiv.) (Equiv.) TT( (°C)◦C) t (h)t (h) Conversion Conversion (%) (%) Composition BuBr (Equiv.)1 T 100(°C) t (h)2 Conversion62 (%) Monoester61 (%) Diester39 (%) MonoesterMonoester (%) (%) Diester Diester (%) 2.21 100 24 6295 6132 3968 11 100 100 2 262 6261 61 39 39 2.25 100120 4 10095 3217 8368 * 2.22.2 100 100 4 495 9532 32 68 68 * The diester55 was prepared120 120 in a yield4 4 of 69%. 100 100 17 17 83 83 * 5 120 4 100 17 83 * ** TheThe diester diester was was prepared prepared in a in yield a yield of 69%. of 69%. * The Atdiester the samewas prepared time, the in monoalkyl a yield of 69%. phenylphosphonates (27) could be esterified further in reactionAt the withsame alkyl time, halides the monoalkyl under MW phenylphosphonates irradiation (Table ( 276)27 )[39]. could be esterified further At the same time, the monoalkyl phenylphosphonates ((27)) could be esteriﬁedesterified furtherfurther in reaction withwith alkylalkyl halideshalides underunder MWMW irradiationirradiation (Table(Table6 )[6) 39[39].]. inTable reaction 6. Alkylation with alkyl of phenylphosphonic halides under MW monoesters irradiation (27)—synthesis (Table 6) [39]. of dialkyl phenylphospho‐ Tablenates ( 6.6.25 Alkylation). of of phenylphosphonic phenylphosphonic monoesters monoesters (27 (27)—synthesis)—synthesis of of dialkyl dialkyl phenylphospho phenylphospho-‐ natesTable ( 6.25 Alkylation). of phenylphosphonic monoesters (27)—synthesis of dialkyl phenylphospho‐ nates (25).).

R RX T (°C) t (h) Yield (%) R RX T (◦C) t (h) Yield (%) BuR BuBrRX T85 (°C) * t 0.5(h) Yield80 (%) R RX T (°C) t (h) Yield (%) BuEt BuBuBrEtI BuBr8585 * 85 *0.5 0.5 808092 Bu EtBuBr EtI85 * 850.5 0.5 9280 OctEt OctBrEtI 10085 0.51 9272 Et OctEtI OctBr85 1000.5 1 7292 * TheOct yield of the comparativeOctBr thermal100 experiment was 57%. 1 72 * TheOct yield of the comparativeOctBr thermal experiment100 was 57%. 1 72 * The yield of the comparative thermal experiment was 57%. * The Inyield this of way, the comparative phenylphosphonates thermal experiment with (two) was different57%. alkyl groups (28) could also be In this way, phenylphosphonates with (two) different alkyl groups (28) could also be preparedIn this (Table way, 7).phenylphosphonates The isolated yields with of products (two) different 28 were alkyl mostly groups around (28 )70% could [39]. also be preparedIn this (Table way,7 ).phenylphosphonates The isolated yields of with products (two) different28 were alkyl mostly groups around (28 70%) could [39 ].also be prepared (Table 7). The isolated yields of products 28 were mostly around 70% [39]. preparedTable 7. The (Table preparation 7). The of isolated phenylphosphonates yields of products (28) with 28 differentwere mostly alkyl groups.around 70% [39]. Table 7. The preparation of phenylphosphonates (28) with different alkyl groups. Table 7. The preparation of phenylphosphonates (28) with different alkyl groups. Table 7. The preparation of phenylphosphonates (28) with different alkyl groups.

R R’X Yield of the “Mixed” Ester (%) R R’X Yield of the “Mixed” Ester (%) BuR Bu R’XEtI EtIYield of the “Mixed”71 71Ester (%) R R’X n Yield of the “Mixed” Ester (%) BuBu nPrBrEtI PrBr7168 68 BuBu EtI iPrBr 71 48 Bu niPrBr 6848 BuEt nPrBr nPrBr68 72 BuEt inPrBrPrBr i 4872 BuEt iPrBr PrBr 48 54 Et Et niPrBr BuBr7254 72 Et nPrBr 72 Et iBuBrPrBr 5472 Et iPrBr 54 Et BuBr 72 It followsEt from our resultsBuBr that the method of choice for the72 diesterification of phosphonic acid 26 is when the first HO group of the phosphonic acid (26) is esterified with

Molecules 2021, 26, x FOR PEER REVIEW 7 of 24

R RX T (°C) t (h) Yield (%) Bu BuBr 85 * 0.5 80 Et EtI 85 0.5 92 Oct OctBr 100 1 72 * The yield of the comparative thermal experiment was 57%.

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].

Table 7. The preparation of phenylphosphonates (28) with different alkyl groups.

R R’X Yield of the “Mixed” Ester (%) Bu EtI 71 Bu nPrBr 68 Bu iPrBr 48 Et nPrBr 72 Et iPrBr 54

Molecules 2021, 26, 1196 Et BuBr 72 7 of 23

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 [[3344,,3399],], whilewhile thethe secondsecond HOHO functionfunction (as(as inin 2727)) isis convertedconverted to alkoxy by alkylation usingusing anan alkylalkyl halogenidehalogenide (Scheme(Scheme7 7))[ 39[39].].

SchemeScheme 7. The new protocol elaborated for the synthesis ofof dialkyldialkyl phenylphosphonates.phenylphosphonates.

It isis noteworthy noteworthy that that the the MW-assisted MW-assisted continuous continuous flow flow esterification esterification of a Hof-phosphinic a H-phos- acidphinic was acid also was elaborated also elaborated [40]. [40]. We werewere successfulsuccessful inin modelingmodeling thethe rate-enhancingrate-enhancing effecteffect ofof MWs.MWs. TheThe esterificationesterification of phenyl-phenyl-H-phosphinic-phosphinic acid andand 1-hydroxy-3-methyl-3-phospholene1-hydroxy-3-methyl-3-phospholene 1-oxide1-oxide served asas the model reactions [[4141,,4242].]. The opposite reaction reaction of of esterification esterification is is hydrolysis hydrolysis that that is isof of high high importance importance also also in inthe the sphere sphere of P of-esters P-esters [43,4 [443]., 44The]. hydrolysis The hydrolysis of phosphinates of phosphinates and phosphonates and phosphonates is carried is carried out, in most cases, under acidic conditions [45–52], but, among other possibilities, Molecules 2021, 26, x FOR PEER REVIEWout, in most cases, under acidic conditions [45–52], but, among other possibilities,8 baseof 24- base-catalyzedcatalyzed cases casesalso occur alsooccur [53–57 [53]. It–57 was]. It a wasnew aapproach new approach to perform to perform the hydrolyses the hydrolyses under under MW irradiation. Alkyl diphenylphosphinates (29) were hydrolyzed at 180 ◦C in the MW irradiation. Alkyl diphenylphosphinates (29) were hydrolyzed at 180 °C in the pres- presence of 10% of p-toluenesulfonic acid (PTSA) as the catalyst (Scheme8)[ 58]. For the ence of 10% of p-toluenesulfonic acid (PTSA) as the catalyst (Scheme 8) [58]. For the esters esterswith n with-alkyln -alkylsubstituents, substituents, completion completion of the ofhydrolysis the hydrolysis required required 1.5–2.2 1.5–2.2 h; however, h; however, with withthe i- thepropyli-propyl ester, ester, the hydrolysis the hydrolysis took took place place after after 0.5 h. 0.5 This h. This latter latter experience experience is due is due to the to therealization realization of the of theAAl1 A mechanism.Al1 mechanism. The Theacid acid(30) (was30) wasisolated isolated in yields in yields of 94 of–97%. 94–97%.

SchemeScheme 8. MWMW-assisted-assisted hydrolysis ofof alkyl diphenylphosphinatesdiphenylphosphinates ((2929).).

A comparative comparative thermal thermal experiment experiment afforded afforded the the phosphinic phosphinic acid acid (30) ( 30in )a inlower a lower con- conversionversion of 24% of 24%,, indicating indicating the beneficial the beneficial effect effect of MWs. of MWs. This Thisis the is consequence the consequence of the of local the localoverheating overheating [27,28 [27] and,28] the and better the better MW absorbing MW absorbing effect effect of PTSA. of PTSA. In conclusion, MWMW irradiationirradiation mademade possiblepossible thethe otherwiseotherwise impossible impossible direct direct esterifi- esteri- cationfication of of phosphinic phosphinic acids, acids, and and the the monoesterification monoesterification of phosphonic of phosphonic acids. acids. MW MW irradiation irradi- provedation proved to be ato useful be a useful tool in tool overcoming in overcoming the enthalpy the enthalpy of activation of activation barriers barriers higher higher than –1 130than kJ 130 mol kJ mol[27,–281 [2].7 This,28]. isThis due is todue the to beneficial the beneficial effect effect of the of statistically the statistically occurring occurring local overheatinglocal overheati [41ng,42 ].[41 On,42 the]. On other the hand,other thehand, MWs the were MWs beneficial were beneficial also in the also acid-catalyzed in the acid- hydrolysiscatalyzed hydrolysis of phosphinates. of phosphinates. 3. Microwave as a Substitute for the Catalysts in the Deoxygenation of Phosphine3. Microwave Oxides as a Substitute for the Catalysts in the Deoxygenation of Phosphine Ox- ides Besides the widely applied trichlorosilane (Cl3SiH) and phenylsilane (PhSiH3)[59,60], 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- tetramethyldisiloxanethe use of the cheaper (TMDS) ethoxysilanes, and polymethylhydrosiloxane, (EtO)3SiH and (EtO)2MeSiH, called as also well as methylpolysiloxas 1,1,3,3-tetramethyldisiloxane (TMDS) and polymethylhydrosiloxane, called also as methylpolysilox- ane ([PMHS or MPS] represented by formula [–O–SiH(Me)–]n), offers alternative possibili- tiesane [([PMHS61,62]. However, or MPS] represented these silanes by are formula of low reactivity. [–O–SiH(Me) Beller–]n et), al.offers tested alternative different possibil- acids as catalystsities [61,62 in]. the However, deoxygenation these silanes of triphenylphosphine are of low reactivity oxide. Beller (31) withet al. diethoxymethylsilanetested different acids as the catalysts reductant in the (Table deoxygena8)[ 61]. Notion deoxygenation of triphenylphosphine occurred in oxide the lack (31 of) witha catalyst. diethoxyme- Adding thylsilane 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 P-ester-acid catalyst with an electron-withdrawing substituent in the phenyl ring led to the quantitative reduction.

Table 8. Deoxygenation of triphenylphosphine oxide (31) using (EtO)2MeSiH with acid catalysts.

Catalyst Yield (%) – <1 PhCOOH 6 (PhO)2P(O)OH 75 (4-NO2C6H4O)2P(O)OH >99 (4-CF3C6H4O)2P(O)OH >99

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).

Molecules 2021, 26, 1196 8 of 23

15 mol% of benzoic acid to the mixture, triphenylphosphine (32) was obtained in a yield of

Molecules 2021,, 26,, x FOR PEER REVIEW6%. However, in the presence of the diphenyl ester of phosphoric acid as the catalyst,4 the of 7

yield of PPh3 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.

Table 8. Deoxygenation of triphenylphosphine oxide (31) using (EtO)2MeSiH with acid catalysts. Table 8. Deoxygenation of triphenylphosphine oxide (31) using (EtO)2MeSiH with acid catalysts.

Catalyst Yield (%) Catalyst Yield (%) – <1 PhCOOH– <16 PhCOOH 6 (PhO)2P(O)OH 75 (PhO)2P(O)OH 75 2 6 4 2 (4(4-NO‐NO22CC66HH44O)O)22P(O)OHP(O)OH >99>99 (4-CF(4‐CF33CC66HH44O)O)22P(O)OHP(O)OH >99>99

Different tertiary phosphine oxides (33)) werewere reducedreduced toto thethe respectiverespective phosphinesphosphines (34) using (EtO)3SiH in the presence of titanium(IV) isopropoxide as the catalyst (Table 9). (34) using (EtO)3SiH in the presence of titanium(IV) isopropoxide as the catalyst (Table9). The deoxygenationsdeoxygenations were performedperformed in tetrahydrofuran (THF). OnOn heatingheating atat 6767 ◦°C,C, thethe completion required 11 h,h, ifif thethe silanesilane waswas appliedapplied inin aa 3-fold3‐fold excessexcess [[62].62].

Table 9.9. ReductionsReductions withwith triethoxysilane.triethoxysilane.

R Yield (%) R Yield (%) Ph 85 Ph 85 CH2CH2P(O)Ph2 90 CH2CH2P(O)Ph2 90 MeMe 9999 EtEt 9595 iPriiPr 8181 i PriiPr 4141 Bn 98 Bn 98 CH2Bn 83 CH2Bn 83

The reduction of aryl-diphenylphosphine oxides with (EtO) SiH in the presence of The reduction of aryl‐diphenylphosphine oxides with (EtO)3SiH in the presence of i Ti(O iPr) in benzene at reﬂux provided the corresponding phosphine in 90% yield after a Ti(OiPr)4 in benzene at reflux provided the corresponding phosphine in 90% yield after a reaction timetime of 3030 minmin [[63].63]. The deoxygenationdeoxygenation of of triphenylphosphine triphenylphosphine oxide oxide (31 )( was31) alsowas elaboratedalso elaborated using TMDSusing inTMDS the presence in the presence of catalysts. of catalysts. Copper(II) Copper(II) triﬂate triflate was a suitablewas a suitable promoter promoter in the reduction in the re‐ of the P=O unit at 100 ◦C in PhMe [64]. Without a catalyst, even measuring in TMDS in a duction of the P=O unit at 100 °C in PhMe [64]. Without a catalyst, even measuring in 12 equivalents’ quantity, no reduction occurred. The use of 15 mol% of the (PhO)2P(O)OH TMDS in a 12 equivalents’ quantity, no reduction occurred. The use of 15i mol% of ◦the in boiling PhMe also promoted deoxygenation [61]. Using 10 mol% of Ti(O Pr)4 at 100 C, (PhO)2P(O)OH in boiling PhMe also promoted deoxygenation [61]. Using 10 mol% of triphenylphosphinei (32) was formed in a conversion of 86%. In the presence of 1% of InBr3 Ti(OiPr)4 at 100 °C, triphenylphosphine (32) was formed in a conversion of 86%. In the as the catalyst, the reduction was quantitative at 100 ◦C[65] (Table 10). presence of 1% of InBr3 as the catalyst, the reduction was quantitative at 100 °C [65] (Table 10).

Table 10. The catalytic deoxygenation of triphenylphosphine oxide (31) applying 1,1,3,3‐tetrame‐ thyldisiloxane (TMDS) as the reducing agent.

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Molecules 2021, 26, x FOR PEER REVIEW 5 of 7 Table 10. The catalytic deoxygenation of triphenylphosphine oxide (31) applying 1,1,3,3- tetramethyldisiloxane (TMDS) as the reducing agent.

Equivalent of TMDS Catalyst (mol%) T (°C) t (h) Conversion (%) Equivalent of TMDS Catalyst (mol%) T (°C) t (h) Conversion (%) Equivalent12 of TMDS Catalyst (mol%)– T (◦C)100 t (h)2 Conversion<1 (%) Equivalent12 of TMDS Catalyst– (mol%) T100 (°C) t (h)2 Conversion<1 (%) 3 Cu(OTf)2 (10) 100 15 96 12 – 100 2 <1 123 Cu(OTf)– 2 (10) 100 152 <196 3 (PhO)2P(O)OH (15) 110 24 62 3 Cu(OTf)2 (10) 100 15 96 3 (PhO)Cu(OTf)2P(O)OHi 2 (10) (15) 100110 1524 9662 31.2 (PhO)Ti(O2P(O)OHPr)4 (10) (15) 110100 2424 6286 1.23 (PhO)Ti(Oi2P(O)OHiPr)4 (10) (15) 100110 24 8662 1.23 Ti(OInBrPr)4 3(10) (1) 100100 2418 86>99 i 1.233 Ti(O InBrInBr3Pr)(1)3 (1)4 (10) 100100 182418 >99>9986 It is noteworthy3 that thereInBr is 3no (1) need for any100 catalyst18 if the reduction>99 of tri‐ phenylphosphineItIt isis noteworthy noteworthy oxide that that ( there31 ) therewith is no TMDSis need no is forneed performed any for catalyst any in catalysta if solvent the reduction if‐free the manner ofreduction triphenylphos- under of MWtri‐ phinephenylphosphineirradiation.It oxide is noteworthy (After31) with treatmentoxide TMDS that (31) attherewith is 200 performed TMDS °Cis forno is6.5need in performed h, a solvent-free thefor reduction any in acatalyst solvent manner was quantitative.‐iffree under the manner reduction MW On irradiation.under conven of MW tri‐‐ Afterirradiation.phenylphosphinetional treatment heating After at at 175treatment 200 oxide °C,◦C (there for31) at 6.5with 200was h, TMDS the°C a need for reduction is6.5 for performed h, a the 1 was‐day reduction quantitative. reaction in a solvent was time. quantitative. On‐free As conventional mannerthe reduction On under conven heating takesMW‐ atirradiation.tionalplace 175 in◦heatingC, the there After absence at was 175 treatment a°C,of need catalyst, there forat was200 a the 1-day °Ca MWneed for reaction 6.5‐ assistedfor h, a the1‐ time.day approachreduction reaction As the maywas reductiontime. quantitative.be As regarded the takes reduction place asOn a conven“green” in takes the‐ absenceplacetionalprotocol inheating the of (Table catalyst, absence at 11) 175 [66,67]. theof°C, catalyst, there MW-assisted Practically, was the a MWneed approach MW‐assisted for irradiation a 1‐day may approach reaction be substituted regarded may time. be asAsregardedthe athe catalyst. “green” reduction as a protocol “green” takes (Tableprotocolplace in11 the)[(Table66 absence,67 ].11) Practically, [66,67]. of catalyst, Practically, MW the irradiation MW MW‐assisted irradiation substituted approach substituted the may catalyst. be theregarded catalyst. as a “green” protocolTable 11. (TableDeoxygenation 11) [66,67]. of triphenylphosphine Practically, MW irradiationoxide (31) using substituted TMDS in the the catalyst. absence of catalysts. TableTable 11. 11. DeoxygenationDeoxygenation ofof triphenylphosphinetriphenylphosphine oxide oxide ( (3131)) using using TMDS TMDS in in the the absence absence of of catalysts. catalysts. Table 11. Deoxygenation of triphenylphosphine oxide (31) using TMDS in the absence of catalysts.

Equivalent of TMDS Mode of Heating ◦T (°C) t (h) Conversion (%) Equivalent of TMDS Mode of Heating T ( C) t (h) Conversion (%) Equivalent2 of TMDS Mode of Heating T 175(°C) t (h)24 Conversion92 (%) Equivalent22 of TMDS Mode ∆of Heating 175T175 (°C) 24t 24(h) Conversion 9292 (%) 22 MWMW 200200 6.56.5 100100 2 MW 200175 6.524 10092 The reduction2 of ring phosphineMW oxides, such as200 3‐ methyl6.5‐1‐ phenyl‐2‐phospholene100 The reduction of ring phosphine oxides, such as 3-methyl-1-phenyl-2-phospholene oxideThe (35a reduction), was performed of ring phosphine using TMDS oxides, together such with as 3InBr‐methyl3 as the‐1‐ phenylcatalyst‐2 in‐phospholene PhMe at 100 oxide (35a), was performed using TMDS together with InBr as the catalyst in PhMe at oxide°C [65].The (35a Thereduction), was deoxygenation performed of ring phosphineusing also TMDStook oxides,place together in such the with absenceas InBr3‐methyl3 asof3 thecatalyst‐1‐ catalystphenyl in ‐ PhMe2in‐phospholene PhMe at atreflux 100 100 ◦C[65]. The deoxygenation also took place in the absence of catalyst in PhMe at oxide°C[68]. [65]. The (35a The solvent), was deoxygenation performed‐ and catalyst using also‐free tookTMDS reduction place together in ofthe with1 ‐absencephenyl InBr‐3 ofas‐phospholene catalystthe catalyst in PhMe inoxide PhMe at35b refluxat was100 reﬂux [68]. The solvent- and catalyst-free reduction of 1-phenyl-3-phospholene oxide 35b [68].°Ccomplete [65]. The The solventafter deoxygenation a ‐ shorterand catalyst reaction also‐free tooktime reduction placein both in of thethe 1 ‐ thermalphenylabsence‐ 3 andof‐phospholene catalyst MW‐promoted in PhMeoxide variations at35b reflux was was complete after a shorter reaction time in both the thermal and MW-promoted variations complete[68].(Table The 12) solventafter [66]. a shorter‐ and catalyst reaction‐free time reduction in both ofthe 1 thermal‐phenyl‐ and3‐phospholene MW‐promoted oxide variations 35b was (Tablecomplete(Table 1212))[ after [66].66]. a shorter reaction time in both the thermal and MW‐promoted variations Table(Table 12. 12) Deoxygenation [66]. of phospholene oxides (35) applying TMDS. TableTable 12. 12. DeoxygenationDeoxygenation ofof phospholenephospholene oxides oxides ( (3535)) applying applying TMDS. TMDS. Table 12. Deoxygenation of phospholene oxides (35) applying TMDS.

Equivalent of Catalyst Mode of Conversion P=O Equivalent of Catalyst Solvent Mode of T(◦C) t (h) Conversion P=O EquivalentTMDS of Catalyst(mol%) Solvent ModeHeating of T (°C) t (h) Conversion(%) P=O TMDS (mol%) Solvent Heating T (°C) t (h) (%) a EquivalentTMDS3 of InBrCatalyst(mol%)3 (1) PhMe ModeHeating∆ of 100 40Conversion(%) 95 a 3  aP=O 23 InBr – (1) Solvent PhMePhMe ∆ T110 100(°C) t 8(h)40 8295 a TMDS3 InBr(mol%)3 (1) PhMe Heating 100 40 (%)95 b a 22 –– PhMe – ∆ 110110 58 10082 b ab 2232 InBr –––3 (1) PhMe –– MW 110110100110 40 385 1001008295 bab 22 –– PhMe–– MW 110110 583 10010082 b 2 – – MW 110 35 100 b 2 The– next user‐friendly– silane,MW PMHS can be110 used in the 3deoxygenation 100 of tri‐ phenylphosphineThe next user oxide‐friendly (31). Atsilane, 290 °CPMHS in the can absence be used of any in solvent, the deoxygenation triphenylphosphine of tri‐ phenylphosphine(32) Thewas isolatednext user inoxide‐ friendlyan 86%(31). yieldAtsilane, 290 [69]. °CPMHS inIt isthe a canabsencedisadvantage be used of any inthat solvent, the the deoxygenation application triphenylphosphine of ofPMHS tri‐ (phenylphosphine32) was isolated inoxide an 86% (31). yield At 290 [69]. °C Itin is the a disadvantageabsence of any that solvent, the application triphenylphosphine of PMHS (32) was isolated in an 86% yield [69]. It is a disadvantage that the application of PMHS

Molecules 2021, 26, 1196 10 of 23 Molecules 2021, 26, x FOR PEER REVIEW 6 of 7

Molecules 2021, 26, x FOR PEER REVIEW 6 of 7 The next user-friendly silane, PMHS can be used in the deoxygenation of triph- requiresenylphosphine a relatively oxide high (31 temperature.). At 290 ◦C in Applying the absence the ofreducing any solvent, agent triphenylphosphine in a 12 equivalents’ (32 ) quantitywas isolated at 100 in°C an in 86% PhMe, yield no [ 69reduction]. It is a disadvantagetook place after that 2 theh. At application the same oftime, PMHS applying requires requires a relatively high temperature. Applying the reducing agent in a 12 equivalents’ Cu(OTf)a relatively2 as the high promoter temperature. at 100 Applying°C for 15 h, the the reducing deoxygenation agent in took a 12 equivalents’place [64]. Applying quantity at ◦ quantity at 100 °C in PhMe, no reduction took place after 2 h. At the same time, applying 15 100mol%C of in (PhO) PhMe,2P(O)OH no reduction as the took catalyst place at after reflux 2 h.for At 1 theday, same the conversion time, applying was Cu(OTf)incom‐ 2 Cu(OTf)2 as the promoter at 100 °C for 15 h, the deoxygenation took place [64]. Applying plete,as the and promoter the phosphine at 100 (◦32C) for was 15 obtained h, the deoxygenation in a 35% yield took [62]. place Applying [64]. ApplyingPMHS at a 15 tem mol%‐ 15 mol% of (PhO)2P(O)OH as the catalyst at reflux for 1 day, the conversion was incom‐ peratureof (PhO) of2 175P(O)OH °C on as conventional the catalyst at heating reﬂux forin the 1 day, absence the conversion of any catalyst was incomplete, and solvent, and completionthe phosphine of theplete, ( reduction32) and was the obtained required phosphine in 17 a 35% h.(32 In) yield wasthe MWobtained [62].‐promoted Applying in a 35% version, PMHS yield at [62].8 ah temperaturewas Applying enough PMHS of at a tem‐ for175 an almost◦C on conventional quantitativeperature of outcome heating 175 °C inon (Table the conventional absence 13). of anyheating catalyst in the and absence solvent, of completion any catalyst of and solvent, the reductioncompletion required 17 of h. the In reduction the MW-promoted required 17 version, h. In the 8 h MW was‐promoted enough for version, an almost 8 h was enough Table 13. Deoxygenationquantitative of triphenylphosphine outcomefor an almost (Table quantitative oxide13). with polymethylhydrosiloxane outcome (Table 13). (PMHS).

Table 13. DeoxygenationTable 13. Deoxygenation of triphenylphosphine of triphenylphosphine oxide with polymethylhydrosiloxane oxide with polymethylhydrosiloxane (PMHS). (PMHS).

Equivalent of PMHS Catalyst (mol%) Mode of Heating Solvent T (°C) t (h) Yield (%) Equivalent5 of PMHS Catalyst– (mol%) Mode of Heating Solvent– 290 T (◦ C) t2 (h) Yield86 (%) Equivalent of PMHS Catalyst (mol%) Mode of Heating Solvent T (°C) t (h) Yield (%) 12 –  PhMe 100 2 0 55 – – ∆  – 290– 2290 86 2 86 6 12Cu(OTf) – 2 (10) ∆ PhMePhMe 100 100 15 2 88 0 12 –  PhMe 100 2 0 4 6(PhO) Cu(OTf)2P(O)OH2 (10) (15) ∆ PhMePhMe 110 100 24 15 35 88 6 Cu(OTf)2 (10)  PhMe 100 15 88 2 4 (PhO)2P(O)OH– (15) ∆ PhMe– 175 110 17 24 87 35 24 – (PhO)2P(O)OH ∆(15)  – 175PhMe 17110 8724 35 2 – MW – 175 8 90 22 –– MW – 175– 8175 9017 87 2 The first deoxygenation– of 1‐phenyl‐2‐MWphospholene oxide– 35a with PMHS175 was per8 ‐ 90 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 outformed in PhMe in theat reflux absenceThe 6 hfirst of [68]. any deoxygenation The solvent deoxygenation at 250 of C[1‐phenyl69 of]. 1 Then,‐phenyl‐2‐phospholene this‐3 transformation‐phospholene oxide 35aoxide was with carried 35b PMHS was per‐ wasout also in investigated PhMeformed at reflux under in the 6 hthermal absence [68]. The and of any deoxygenationMW solvent‐promoted, at 250 of in °C 1-phenyl-3-phospholenemost [69]. cases, Then, solvent this transformation‐free con oxide‐ was carried 35b was also investigated under thermal and MW-promoted, in most cases, solvent-free ditions. These deoxygenationsout in PhMe at werereflux complete 6 h [68]. at The 110 deoxygenation °C after 4 and 2of h, 1 respectively‐phenyl‐3‐phospholene (Table oxide 35b conditions. These deoxygenations were complete at 110 ◦C after 4 and 2 h, respectively 14) [66,67]. The wasoutcome also investigatedof the deoxygenation under thermal of the anddimethylphospholene MW‐promoted, in oxidemost cases,35c was solvent ‐free con‐ (Table 14) [66,67]. The outcome of the deoxygenation of the dimethylphospholene oxide better in PhMe ditions.at reflux. These deoxygenations were complete at 110 °C after 4 and 2 h, respectively (Table 35c was better14) in [66,67]. PhMe atThe reflux. outcome of the deoxygenation of the dimethylphospholene oxide 35c was better in PhMe at reflux. TableTable 14. 14. TheThe deoxygenation deoxygenation of a of series a series of phospholene of phospholene oxides oxides using using PMHS. PMHS. Table 14. The deoxygenation of a series of phospholene oxides using PMHS.

Phosphine Oxide Silane (Equiv.) Mode of Heating Solvent T (◦C) t (h) Yield (%) Phosphine Oxide Silane (Equiv.) Mode of Heating Solvent T (°C) t (h) Yield (%) aa 5 5 ∆ – –250 250 2 288 88 a Phosphine Oxide2 Silane (Equiv.)∆ Mode of HeatingPhMe Solvent 110 T 6 (°C) t 85 (h) Yield (%) a 2  PhMe 110 6 85 b a 2 5 ∆  – 110– 4250 912 88 b 2  – 110 4 91 b a 22 MW –PhMe 110 2110 926 85 bc 5 2 MW∆ – –110 250 2 –92 35 b 2  – 110 4 91 cc 2 5 ∆ PhMe– 250 110 – 635 92 b 2 MW – 110 2 92 c 2  PhMe 110 6 92 c 5  – 250 – 35 Optimum conditions for the reduction of 1-alkyl-3-methyl-3-phospholene 1-oxides by c 2  PhMe 110 6 92 PhSiHOptimum3, TMDS, conditions and PMHS for werethe reduction also evaluated of 1‐alkyl [70].‐3‐methyl‐3‐phospholene 1‐oxides by PhSiHTMDS3, TMDS, and PMHSand PMHS are user-friendly were also evaluated and low-cost [70]. reducing agents. The lower reactivity Optimum conditions for the reduction of 1‐alkyl‐3‐methyl‐3‐phospholene 1‐oxides can be compensated by a solvent-free and MW-assisted protocol. MWs can be regarded as by PhSiH3, TMDS, and PMHS were also evaluated [70]. Tablea kind 15. MW of promoter‐assisted Hirao substituting reaction efﬁcientof bromoarenes catalysts. and diethyl phosphite applying Pd(OAc)2 as the catalyst precursor. Table 15. MW‐assisted Hirao reaction of bromoarenes and diethyl phosphite applying Pd(OAc)2 as the catalyst precursor.

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4. Microwave as a Substitute for Catalysts in the Kabachnik–Fields Reaction α-Aminophosphonic acids, the P-analogues of α-amino acids, are of importance due to their potential biological activity, which is the consequence of their enzyme in- hibitory properties [71]. The major method for the synthesis of α-aminophosphonates is the Kabachnik–Fields condensation of amines, aldehydes or ketones, and dialkyl phosphites [72,73]. α-Aminophosphonates (37, Y = RO) and α-aminophosphine oxides (37, Y = Ph) were synthesized by the solvent- and catalyst-free MW-assisted phospha-Mannich reaction of primary amines, oxo compounds, and dialkyl phosphites or diphenylphosphine oxide. Earlier preparations utilized special catalysts, such as, tetra-tert-butyl-substituted phthalocyanine—AlCl3 complex [74], magnesium perchlorate [75], metal triflates (M(OTf)n, M = Li, Mg, Al, Cu and Ce) [76], indium(III) triflate [77], bismuth(I) nitrate [78], samarium(II) iodide [79], ceric ammonium nitrate (CAN) [80], indium(III) chloride [81], and Molecules 2021, 26, x FOR PEER REVIEWa variety of lanthanide (Yb, Sm, Sc, La) triflates [82], which mean cost and environmen-12 of 24 Molecules 2021, 26, x FOR PEER REVIEW 12 of 24 tal burden. It was found that under MW conditions, there is no need for any catalyst (Scheme9)[83].

Scheme 9. MW-assisted phospha-Mannich condensations. SchemeScheme 9.9. MW-assistedMW-assisted phospha-Mannichphospha-Mannich condensations.condensations. Starting from heterocyclic amines: pyrrolidine, piperidine, morpholine and pipera- Starting from heterocyclic amines: pyrrolidine, piperidine, morpholine and piperazine zine derivativesStarting from or heterocyclicheterocyclic >P(O)Hamines :species pyrrolidine,, N-heterocyclic piperidine, [8 4morpholine] and P-heterocyclic and pipera- [85] derivatives or heterocyclic >P(O)H species, N-heterocyclic [84] and P-heterocyclic [85] α- αzine-aminophosphonates derivatives or heterocyclic were obtained >P(O)H .species 3-Amino, N-heterocyclic-6-methyl-2H [8-pyran4] and- 2P--onesheterocyclic were also[85] aminophosphonates were obtained. 3-Amino-6-methyl-2H-pyran-2-ones were also suitable suitableα-aminophosphonates amino derivatives were in Kabachnik obtained. – 3Fields-Amino reaction-6-methyl with-2H formaldehyde-pyran-2-ones andwere dialkyl also amino derivatives in Kabachnik–Fields reaction with formaldehyde and dialkyl phosphites phosphitessuitable amino or diphenylphosphine derivatives in Kabachnik oxide [8–Fields6]. As specialreaction cases, with α formaldehyde-aminophosphonates and dialkyl with or diphenylphosphine oxide [86]. As special cases, α-aminophosphonates with different differentphosphites alkoxy or diphenylphosphine groups [87], α-aminophosphinates oxide [86]. As special [88 cases,], and α α-aminophosphonates-aminophoshonates with alkoxy groups [87], α-aminophosphinates [88], and α-aminophoshonates with sterically stericadifferentlly alkoxydemanding groups α- aryl[87], substituents α-aminophosphinates [89] were also[88], synthesized and α-aminophoshonates under MW-assisted with demandingsterically demandingα-aryl substituents α-aryl substituents [89] were also[89] synthesizedwere also synthesized under MW-assisted under MW conditions.-assisted Moreover,conditions. carboxylicMoreover, amidescarboxylic could amides also becould used also under be used solvolytic under conditionssolvolytic conditions [90]. It is [conditions.90]. It is noteworthy Moreover, that carboxylic the phospha amides-Mannich could also reactions be used may under also solvolytic be performed conditions in the noteworthy[90]. It is noteworthy that the phospha-Mannich that the phospha reactions-Mannich may reactions also be may performed also be inperformed the presence in the of presence® of the T3P® activating agent [91]. thepresence T3P activatingof the T3P® agent activating [91]. agent [91]. PrimaryPrimary amines amines are are suitable suitable components components for for bis(Kabachnik–Fields) bis(Kabachnik–Fields) condensations condensations [92]. [92]. PrimaryIn these distances amines are, alkyl suitable or arylamines components were for reacted bis(Kabachnik with two– equivalentsFields) condensations of the for- In[92 these]. In distances,these distances alkyl or, alkyl arylamines or arylamines were reacted were withreacted two with equivalents two equivalents of the formaldehyde of the formaldehyde and the >P(O)H reagents to afford1 2 the bis(Z1Z2P(O)CH2)amines (38) (Scheme and the >P(O)H reagents to afford the bis(Z Z P(O)CH2)amines (38) (Scheme 10) [93–95]. maldehyde and the >P(O)H reagents to afford the bis(Z1Z2P(O)CH2)amines (38) (Scheme Most10) [9 of3–9 the5]. reactionsMost of the could reactions be carried could out be in carried a solvent-free out in a manner. solvent-free manner. 10) [93–95]. Most of the reactions could be carried out in a solvent-free manner.

SchemeScheme 10.10. The bis(phospha-Mannich)bis(phospha-Mannich) reaction.reaction. Scheme 10. The bis(phospha-Mannich) reaction. 1 2 TheThe bisphosphinoyl derivatives derivatives ( (3838,,Z Z1 == Z Z2 = Ph)= Ph) were were transformed transformed after after double double--de- 1 2 deoxygenationoxygenationThe bisphosphinoyl to tobis(phosphines) bis(phosphines) derivatives that that (were38, wereZ useful = Z useful = inPh) the inwere synthesis the transformed synthesis of ring of after platinum ring double platinum com--de- complexesplexesoxygenation [94–9 [946 to] –α 96bis(phosphines)-, ]β-α and-, β -γ- andaminoγ -aminothat acids were (or acids esters)useful (or werein esters) the also synthesis were utilized also of in utilizedring the doubleplatinum in the Kabach- com- dou- blenikplexes– Kabachnik–FieldsFields [94– condensation96] α-, β- and condensation toγ- furnishamino acids the to bi furnish(ors(phosphono esters) the were bis(phosphono-- or also phosphinoyl) utilized or in phosphinoyl) theproducts double [9 Kabach-7,9 prod-8]. uctsnik–Fields [The97,98 α ].-condensationaminophosphonates to furnish may the bebis(phosphono formed via imine- or phosphinoyl) of α-hydroxyphosphonate products [97,98]. in- termediatesThe α-aminophosphonates [72,92,99,100]. α-Hydroxyphosphonates may be formed via iminemay be of formed α-hydroxyphosphonate in a reversible man- in- nertermediates from the [corresponding72,92,99,100]. α oxo-Hydroxyphosphonates compound and dialkyl may phosphite be formed [101 in,102 a reversible]. It was a some- man- whatner from surprising the corresponding experience oxo that compound the α-hydroxyphosphonates and dialkyl phosphite could [101 be,102 converted]. It was a some-to the respectivewhat surprising α-aminophosphonates experience that theby reactionα-hydroxyphosphonates with primary amines could under be converted MW conditions. to the Thisrespective was promoted α-aminophosphonates by a favorable by adjacent reaction group with primaryeffect [10 amines3,104]. under MW conditions. This Inwas summary, promoted a wideby a favorablerange of mono adjacent- and group bis Kabachnik effect [10–3Fields,104]. reactions were carried out underIn summary, MW-assisted a wide and range catalyst of mono-free- andconditions, bis Kabachnik and mostly–Fields in areactions solvent- freewere manner. carried out underα-Aryl MW-α-hydroxyphosponates-assisted and catalyst -[10free5 ]conditions, mentioned an aboved mostly as intermediates in a solvent-free in the manner. phospha-Mannichα-Aryl-α - condensationshydroxyphosponates, along [10 with5] mentioned α-aryl-α-hydroxyphosphine above as intermediates oxides in ( 39the), phos- were synthesizedpha-Mannich in condensationsa catalytic and, solvent along with-free αMW-aryl-assisted-α-hydroxyphosphine Pudovik reaction oxides compris (39),ing were the additionsynthesized of >P(O)H in a catalytic species and to solventaryl aldehydes-free MW (Scheme-assisted 1 1Pudov) [106].ik reaction comprising the addition of >P(O)H species to aryl aldehydes (Scheme 11) [106].

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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. α-Aryl-α-hydroxyphosponates [105] mentioned above as intermediates in the phospha- Mannich condensations, along with α-aryl-α-hydroxyphosphine oxides (39), were synthe- Molecules 2021, 26, x FOR PEER REVIEW 13 of 24 sized in a catalytic and solvent-free MW-assisted Pudovik reaction comprising the addition of >P(O)H species to aryl aldehydes (Scheme 11)[106].

SchemeScheme 11. 11MW-promoted. MW-promoted synthesis synthesis of α -hydroxyphosphonatesof α-hydroxyphosphonates and α-hydroxyphosphine and α-hydroxyphosphine oxides oxides byby thethe Pudovik Pudovik reaction. reaction.

α DialkylDialkyl phosphites phosphites could could also also be reactedbe reacted with with-ketophosphonates α-ketophosphonates to result to in result the in the formation of dronate analogue α-hydroxybisphosphonates in the presence of diethylamine formation of dronate analogue α-hydroxybisphosphonates in the presence of diethyla- and in the absence of any solvent [107,108]. mineIt and was in found the absence that the Pudovikof any solvent reaction [10 may7,10 also8]. be realized at room temperature in a solvent-freeIt was found manner. that the However, Pudovik these reaction methods may required also be realized special catalysts, at room suchtemperature as in piperazinea solvent- [free109], manner. magnesium However, chloride/3 these equivalents methods of required triehylamine special [110 ],catalysts, barium hydrox- such as piper- ideazine [111 [10], sodium9], magnesium carbonate chloride/3 [112], potassium equivalents phosphate of [triehylamine113], sodium-modified [110], barium fluoroap- hydroxide atite[111 [],114 sodium], and silica-supportedcarbonate [112], tungstic potassium acid [phosphate115]. [113], sodium-modified fluoroapatite [114Moreover,], and silica the-supported work-up neededtungstic a considerableacid [115]. quantity of solvents. Hence, these methodsMoreover, cannot be the regarded work- asup green. needed The aauthor considerable of this review quantity together of with solvents. co-workers Hence, these developed an indeed environmentally-friendly method by crystallizing the products from methods cannot be regarded as green. The author of this review together with co-workers the mixtures [116]. developed an indeed environmentally-friendly method by crystallizing the products from 5.the Microwave mixtures Irradiation[116]. Allowing the Simplification of the Catalysts in the Hirao Reaction 5. MicrowaveThe Hirao reactionIrradiation of aryl, Allowing heteroaryl, the andSimplification vinyl halogenides of the (or Catalysts other derivatives) in the Hirao withReaction dialkyl phosphites, alkyl H-phosphinates, and secondary phosphine oxides is an important method for the synthesis of phosphonates, phosphinates, and phosphine oxides, respectivelyThe Hirao [117– 119reaction]. The originalof aryl, Hiraoheteroaryl P–C coupling, and vinyl aimed halogenides at the synthesis (or of other arylphos- derivatives) phonateswith dialkyl reacting phosphites, aryl- and alkyl vinyl H halogenides-phosphinates with, dialkyland secondary phosphites phosphine in the presence oxides of is an im- tetrakis(triphenylphosphine)palladiumportant method for the synthesis of (Schemephosphonates, 12)[120– phosphinates122]. The P–C coupling, and phosphine reaction oxides, wasrespectively then extended [117– to11 other9]. The substrates original [123 Hirao–135] thatP–C was coupling followed aimed by further at the variations synthesis of ar- involvingylphosphonates different reacting >P(O)H aryl reagents,- and Pd(II)-,vinyl halogenides or other metal with (Ni(II) dialkyl and phosphites Cu(II)) salts in as the pres- catalystence of precursorstetrakis(triphenylphosphine)palladium together with mono- and bidentate (Scheme P-ligands, 12) bases[120–1 (mostly22]. The amines) P–C coupling andreaction solvents. was then extended to other substrates [123–135] that was followed by further variations involving different >P(O)H reagents, Pd(II)-, or other metal (Ni(II) and Cu(II)) salts as catalyst precursors together with mono- and bidentate P-ligands, bases (mostly amines) and solvents.

Scheme 12. The classical P–C coupling reactions.

Instead of Pd(PPh3)4, the application of Pd salts together with P-ligands was spread. In such cases, the Pd(0) catalyst is formed in situ from the components. From among the Pd salts, Pd(OAc)2 is the most suitable. The Pd(OAc)2/P-ligand combination was often utilized in the preparation of arylphosphonates, and this approach was more suitable than the classical Pd(PPh3)4 catalyst [136–148]. PPh3, dppp, dppb, dppe, dppf, and BINAP (2,2′- bis(diphenylphosphino)-1,1′-binaphthyl were the typical P-ligands applied. “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

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Scheme 11. MW-promoted synthesis of α-hydroxyphosphonates and α-hydroxyphosphine oxides by the Pudovik reaction.

Dialkyl phosphites could also be reacted with α-ketophosphonates to result in the formation of dronate analogue α-hydroxybisphosphonates in the presence of diethylamine and in the absence of any solvent [107,108]. It was found that the Pudovik reaction may also be realized at room temperature in a solvent-free manner. However, these methods required special catalysts, such as piperazine [109], magnesium chloride/3 equivalents of triehylamine [110], barium hydroxide [111], sodium carbonate [112], potassium phosphate [113], sodium-modified fluoroapatite [114], and silica-supported tungstic acid [115]. 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].

5. Microwave Irradiation Allowing the Simplification of the Catalysts in the Hirao Reaction The Hirao reaction of aryl, heteroaryl, and vinyl halogenides (or other derivatives) with dialkyl phosphites, alkyl H-phosphinates, and secondary phosphine oxides is an important method for the synthesis of phosphonates, phosphinates, and phosphine oxides, respectively [117–119]. The original Hirao P–C coupling aimed at the synthesis of arylphosphonates reacting aryl- and vinyl halogenides with dialkyl phosphites in the presence of tetrakis(triphenylphosphine)palladium (Scheme 12) [120–122]. The P–C coupling reaction was then extended to other substrates [123–135] that was followed by further variations involving different >P(O)H reagents, Pd(II)-, or other metal (Ni(II) and Cu(II)) Molecules 2021, 26, 1196 salts as catalyst precursors together with mono- and bidentate P-ligands, 13bases of 23 (mostly amines) and solvents.

SchemeScheme 12. 12The. The classical classical P–C P– couplingC coupling reactions. reactions.

Instead of Pd(PPh3)4, the application of Pd salts together with P-ligands was spread. Instead of Pd(PPh3)4, the application of Pd salts together with P-ligands was spread. In such cases, the Pd(0) catalyst is formed in situ from the components. From among the In such cases, the Pd(0) catalyst is formed in situ from the components. From among the Pd salts, Pd(OAc)2 is the most suitable. The Pd(OAc)2/P-ligand combination was often utilizedPd salts, in Pd(OAc) the preparation2 is the of most arylphosphonates, suitable. The andPd(OAc) this approach2/P-ligand was combination more suitable was than often uti- Molecules 2021, 26, x FOR PEER REVIEWthelized classical in the Pd(PPhpreparation3)4 catalyst of arylphosphonates, [136–148]. PPh3, dppp, and this dppb, approach dppe, dppf, was andmore BINAP14 suitableof 24 than Molecules 2021, 26, x FOR PEER REVIEW0 0 14 of 24 (2,2the -bis(diphenylphosphino)-1,1classical Pd(PPh3)4 catalyst-binaphthyl [136–148]. werePPh3 the, dppp, typical dppb, P-ligands dppe, applied. dppf, and BINAP (2,2′- bis(diphenylphosphino)“Greener” and more efficient-1,1′-binaphthyl protocols were were developed the typical for P the-ligands Hirao reactionapplied. in the last twenty years. The MW technique also proved to be useful in the Hirao reactions. first MW“Greener”-assisted andP–C couplingmore efficient took place protocols between were aryl developedhalides/triflates for theand Hiraodiethyl reaction phos- in the Thefirst firstMW MW-assisted-assisted P–C P–Ccoupling coupling took took place place between between aryl halides/triflates aryl halides/triflates and diethyl and diethyl phos- phitelast twenty in the presence years. The of bis(triphenylphosphine)palladium MW technique also proved to be dichloride, useful in triethylamine, the Hirao reactions and . The phosphitephite in the in presence the presence of bis(triphenylphosphine)palladium of bis(triphenylphosphine)palladium dichloride, dichloride, triethylamine, triethylamine, and triethylsilane as the reductant (Scheme 13) [149]. The Hirao reaction was performed in a andtrieth triethylsilaneylsilane as the as thereduc reductanttant (Scheme (Scheme 13 )13 [14)[9149]. The]. The Hirao Hirao reaction reaction was was performed performed in in a domestic microwave device. adomestic domestic microwave microwave device device..

Scheme 13. The first P–C coupling realized on MW irradiation. SchemeScheme 13.13. TheThe ﬁrstfirst P–CP–C couplingcoupling realizedrealized onon MWMW irradiation.irradiation.

TheThe MW MW-assistedMW--assistedassisted HiraoHirao reactionreaction reaction ofof of dialkyldialkyl dialkyl phosphitesphosphites phosphites withwith with arylaryl aryl andand and vinylvinyl vinyl halides/tri-halides/tri- halides/ triﬂatesflates was was also also studi studieded in in the the presence presence o off Pd(PPh Pd(PPh3))4 [1[15050].]. The The best best results results (72 (72–96%)–96%) were flates was also studied in the presence of Pd(PPh3)44 [150]. The best results (72–96%) were obtained using Cs2COCO3 inin THF. THF. The The MW MW protocol was also applied in the synthesis of P P-- obtained using Cs22CO3 in THF. The MW protocol was also applied in the synthesis of P- β functionalizedfunctionalized 11 11β11β-aryl-substituted--arylaryl--substitutedsubstituted steroids ststeroidseroids (43 ((4343) that)) thatthat are areare progesterone progesteroneprogesterone receptor receptorreceptor antagonists antago-antago- (Scheme 14)[151]. nistsnists (Scheme(Scheme 1414)) [[115511].].

Scheme 14. The derivation of 11ββ-aryl-substituted steroids with the help of the Hirao reaction. SchemeScheme 14.14. TheThe derivationderivation ofof 1111β-aryl-substituted-aryl-substituted steroidssteroids withwith thethe helphelp ofof thethe HiraoHirao reaction.reaction.

AA fewfew arylboronicarylboronic acidsacids andand arylfluoroboratesarylfluoroborates werewere couplcoupleded withwith dialkyldialkyl phosphitesphosphites using the Pd(OAc)2 or Pd(O2CCF3)2/dmphen catalyst combination, and p-benzoquinone in using the Pd(OAc)2 or Pd(O2CCF3)2/dmphen catalyst combination, and p-benzoquinone in thethe absenceabsence ofof aa basebase [[115252].]. TheThe authorsauthors assumedassumed thethe rolerole ofof thethe reoxidantreoxidant inin thethe catalyticcatalytic cyclecycle.. TheThe authorauthor ofof thisthis reviewreview believebelievess thatthat thethe applicationapplication ofof anan oxidantoxidant inin thethe PP––CC cou-couplingpling isis mistaken.mistaken. Instead,Instead, aa reductivereductive agentagent maymay bebe usefuluseful.. AA newnew cyclodiphosphazanecyclodiphosphazane-- containingcontaining PdPd catalystcatalyst waswas testedtested inin thethe preparationpreparation ofof triarylphosphinetriarylphosphine oxidesoxides fromfrom arilaril bromides and diphenylphosphine oxide [153]. The use of this exotic promoter and Cs2CO3 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 note- as a base in acetonitrile under MW irradiation gave Ph3P=O in yields of 46–95%. It is note- worthyworthy thatthat thethe couplingcoupling ofof iodoiodo-- andand bromobenzoicbromobenzoic acidsacids withwith diphenylphodiphenylphosphinesphine oxideoxide couldcould bebe performedperformed inin waterwater ususinging Pd/CPd/C catalystcatalyst underunder MWMW conditionsconditions (Scheme(Scheme 1515)) [[151544].]. InIn thisthis casecase,, thethe tetrabutylammoniumtetrabutylammonium bromidebromide additiveadditive hadhad nono influenceinfluence onon thethe outcomeoutcome..

Scheme 15. Hirao reaction in water using Pd/C on MW irradiation. Scheme 15. Hirao reaction in water using Pd/C on MW irradiation.

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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 P- functionalized 11β-aryl-substituted steroids (43) that are progesterone receptor antagonists (Scheme 14) [151].

Molecules 2021, 26, 1196 14 of 23 Scheme 14. The derivation of 11β-aryl-substituted steroids with the help of the Hirao reaction.

A few arylboronic acids and arylﬂuoroboratesarylfluoroborates werewere coupledcoupled withwith dialkyldialkyl phosphitesphosphites usingusing the Pd(OAc)2 oror Pd(O Pd(O22CCFCCF33)2)/dmphen2/dmphen catalyst catalyst combination combination,, and and p-benzoquinonep-benzoquinone in inthe the absence absence of ofa base a base [1 [52152]. ].The The authors authors assumed assumed the the role role of of the the reoxidant reoxidant in the catalyticcatalytic cycle.cycle. The The author author of of this this review review believe believess that that the the application application of an of oxidant an oxidant in the in P the–C P–Ccou- couplingpling is mistaken. is mistaken. Instead, Instead, a reductive a reductive agent agent may may be be useful useful.. A A new new cyclodiphosphazane cyclodiphosphazane-- containing Pd catalyst waswas testedtested inin thethe preparationpreparation ofof triarylphosphinetriarylphosphine oxidesoxides fromfrom arilaril bromides andand diphenylphosphinediphenylphosphine oxide oxide [ 153[153].]. The The use use of of thisthis exoticexotic promoterpromoter and and Cs Cs22COCO33 as a base in acetonitrile underunder MWMW irradiationirradiation gavegave PhPh33P=OP=O in yields of 46–95%.46–95%. It is note- worthyworthy thatthat thethe coupling ofof iodo-iodo- and bromobenzoic acids with diphenylphosphinediphenylphosphine oxideoxide could bebe performed inin waterwater usingusing Pd/CPd/C catalyst catalyst under MW conditions (Scheme 15)[) [151544].]. InIn thisthis case,case, the tetrabutylammonium bromide additive had no inﬂuenceinfluence on the outcome.outcome.

Molecules 2021, 26, x FOR PEER REVIEW 15 of 24

SchemeScheme 15.15. Hirao reaction inin water usingusing Pd/CPd/C on on MW MW irradiation irradiation..

ItIt waswas recognized recognized by by the theKeglevich Keglevichgroup group that that the Hiraothe Hirao cross-couplings cross-couplings may takemay place take place in the presence of Pd(OAc)2 without the addition of the usual P-ligands under sol- in the presence of Pd(OAc)2 without the addition of the usual P-ligands under solvent- freevent and-free MW-assisted and MW-assisted conditions conditions (Scheme (Scheme 16)[155 16)]. [15 The5]. reactionThe reaction of bromobenzene of bromobenzene and 1.5and equivalents 1.5 equivalents of the dialkyl of the phosphites, dialkyl phosphites, phenyl-H-phosphinates, phenyl-H-phosphinates and diphenylphosphine, and diphe- oxidenylphosphine was carried oxide out was in carried the presence out in the of 5% presence of Pd(OAc) of 5%2 ofand Pd(OAc) 1.1 equivalents2 and 1.1 equivalents of triethylamine.of triethylamine. The relevance The relevance of the MW of techniquethe MW technique was pointed was outpointed by comparative out by comparative thermal experiments.thermal experiments. The conversion The conversion was almost was almost complete complete at 120 ◦atC, 120 but °C, the but best the results best results were obtainedwere obtained at 150 at◦C. 150 °C.

SchemeScheme 16.16. MW-promotedMW-promoted P–CP–C couplingscouplings applyingapplying Pd(OAc)Pd(OAc)22 without addedadded P-ligands.P-ligands.

InIn thethe nextnext stage,stage, thethe Pd(OAc)Pd(OAc)22-promoted-promoted “P-ligand-free”“P-ligand-free” Hirao reactions were ex- tendedtended toto differentdifferent bromoarenesbromoarenes (Table 1515)[) [151566].]. TheThe experienceexperience was thatthat bothboth electron-electron- releasingreleasing andand electron-withdrawingelectron-withdrawing substituents decreased the reactivity, as in these in- ◦ stances,stances, higher higher temperatures temperatures (175 (175–200–200 °C)C) were were necessary necessary to obtain to obtain the thearyl arylphosphonates phospho- natesin acceptable in acceptable yieldsyields (69–92%) (69–92%) (Table (Table 15). The 15 ).reactions The reactions of the ofmethoxy the methoxy-- and alkyl and-substi- alkyl- substitutedtuted bromoarenes bromoarenes with witha decreased a decreased reactivity reactivity required, required, in most in most cases, cases, a temperature a temperature of ◦ of200 200 °C, C,and and the the application application of of10% 10% of ofthe the Pd(OAc) Pd(OAc)2 catalyst.2 catalyst.

Table 15. MW-assisted Hirao reaction of bromoarenes and diethyl phosphite applying Pd(OAc)2 as the catalyst precursor.

Y Pd(OAc)2 (%) T (°C) t (min) Conversion (%) Yield (46) (%) H 5 150 5 99 93 4-MeO 10 200 2 80 69 3-MeO 10 200 2 93 79 4-Pr 10 200 2 86 71 4-Et 10 175 15 93 85 4-Me 10 175 10 86 73 4-Cl 10 175 10 95 83 3-Cl 10 175 10 95 87 4-F 5 175 5 99 91 3-F 5 175 10 100 88 4-CO2Et 5 175 15 100 89 3-CO2Et 10 200 2 93 81 4-C(O)Me 5 175 5 96 71 3-C(O)Me 10 175 5 100 92

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Table 15. MW-assisted Hirao reaction of bromoarenes and diethyl phosphite applying Pd(OAc)2 as the catalyst precursor.

◦ Y Pd(OAc)2 (%) T ( C) t (min) Conversion (%) Yield (46) (%) Y Pd(OAc)2 (%) T (°C) t (min) Conversion (%) Yield (46) (%) H 5 5 150 150 5 5 99 99 93 4-MeO 10 200 2 80 69 4‐MeO 10 200 2 80 69 3-MeO 10 200 2 93 79 3‐4-PrMeO 10 10 200 200 2 2 93 86 7179 44-Et‐Pr 10 10 200 175 2 15 86 93 8571 4-Me4‐Et 10 10 175 175 15 10 93 86 7385 44-Cl‐Me 10 10 175 175 10 10 86 95 8373 3-Cl 10 175 10 95 87 44-F‐Cl 10 5 175 175 10 5 95 99 9183 33-F‐Cl 10 5 175 175 10 10 95 100 8887 4-CO4‐F2 Et5 5 175 175 5 15 99 100 8991 3-CO3‐F2 Et5 10 175 200 10 2 100 93 8188 Molecules 2021, 26, x FOR PEER REVIEW4-C(O)Me 5 175 5 96 71 16 of 24

3-C(O)Me4‐CO2Et 5 10 175 175 15 5 100 100 9289 3‐CO2Et 10 200 2 93 81 4‐C(O)Me 5 175 5 96 71 Recently, Hirao Hirao et et al. al. have have publised publised another another “P-ligand-free” “P-ligand-free” reaction reac (Schemetion (Scheme 17)[157 17].) 3‐C(O)Me 10 175 5 100 92 According[157]. According to this, to diethyl this, diethyl phosphite phosphite was coupled was coupled with 2-nitro-5-bromoanisole with 2-nitro-5-bromoanisole applying ap- ◦ Pd(OAc)plying Pd(OAc)2 as the2 catalystas the catalyst and Na and2CO Na3 in2CO xylene3 in xylene at 120 at C120 to °C furnish to furnish the respective the respective aryl phosphonatearyl phosphonate (47) in(47 a) yieldin a yield of 69% of 69% after after 24 h. 24 h.

SchemeScheme 17.17. An additional Pd(OAc)2--catalyzedcatalyzed “P “P-ligand-free”-ligand-free” P P–C–C coupling coupling..

Xiao and and his his co-workers co-workers described described the the Pd-catalyzed Pd-catalyzed cross-coupling cross-coupling of an of arylsulﬁ- an aryl- natesulfinate salt salt with with dialkyl dialkyl phosphites phosphites applying applying PdCl PdCl2 without2 without the the usual usual P-ligands P-ligands inin DMF–DMF– DMSO [158158]. The arylphosphonates were preparedprepared in good yields usingusing silversilver carbonatecarbonate as the oxidant under under MW MW irradiation. irradiation. Here Here,, it itis isnote notedd again again that that there there is no is noneed need for foran anoxidant oxidant during during the theP–C P–C coupling coupling.. TheThe Pd(OAc) Pd(OAc)2-promot2-promoteded “P-ligand “P-ligand-free”-free” protocol protocol was wasextended extended to the to Hirao the Hirao reaction reaction of heteroaryl of heteroaryl bromides bromides [159], [159 and], the and reactivity the reactivity of the of sub- the substratesstrates was was studied studied in detail in detail [160 [160]. ]. Moreover,Moreover, the mechanismmechanism of thethe Pd-catalyzedPd-catalyzed HiraoHirao reactionsreactions carried outout usingusing thethe P-reactantP-reactant in excess was investigated experimentally and by quantum chemical calculations [161]. It was found that if Pd(OAc) is applied in a quantity of 10%, the >P(O)H tions [161]. It was found that if Pd(OAc)2 is2 applied in a quantity of 10%, the >P(O)H reac- reactanttant should should be used be used in a inquantity a quantity of 1.3 of 1.3equivalents. equivalents. 10% 10% of the of theP-species P-species reduces reduces Pd(II) Pd(II) to toPd(0), Pd(0), while while 20% 20% covers covers the the P-ligand P-ligand that that is the is the trivalent trivalent tautomeric tautomeric form form (>P (>P–OH)–OH) of the of the>P(O)H >P(O)H reagent. reagent. The whole The whole catalytic catalytic cycle involving cycle involving oxidative oxidative addition, addition, ligand ligandexchange, ex- change,and reductive and reductive elimination elimination was adapted was adapted to our model, to our and model, the andelemental the elemental steps were steps refined were reﬁned [161]. The formation of the “PdP2” catalyst and its activity were investigated under [161]. The formation of the “PdP2” catalyst and its activity were investigated under a sep- a separate cover [162]. It turned out that the Ar2POH ligands with 2-MePh or 3,5-diMePh arate 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 carried out at 150 °C on MW irradiation. Using 1.5 equivalents of NEt3 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 K2CO3 in acetonitrile was more advantageous: in the presence of 5% NiCl2, 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.

Molecules 2021, 26, 1196 16 of 23

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 ◦ carried out at 150 C on MW irradiation. Using 1.5 equivalents of NEt3 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 K2CO3 in acetonitrile was more advantageous: in the presence of 5% NiCl2, 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 Molecules 2021, 26, x FOR PEER REVIEW 17 of 24 and other aryl-substituted secondary phosphine oxides served as additional reagents in the “P-ligand-free” P–C couplings under discussion.

Scheme 18. Hirao reactions applying NiCl2 as the catalyst without added P-ligands. SchemeScheme 18.18. HiraoHirao reactionsreactions applyingapplying NiClNiCl22 as the catalyst without addedadded P-ligands.P-ligands.

TheThe NiClNiCl22--catalyzedcatalyzed phosphonylation ofof aa seriesseries ofof bromoarenesbromoarenes gavegave similarsimilar resultsresults asas thosethose inin thethe presencepresence ofof Pd(OAc)Pd(OAc)22.. However, thethe scopescope ofof thethe arylaryl bromidesbromides waswas moremore limitedlimited (Scheme(Scheme 1919)[) [163163].].

SchemeScheme 19.19. NiClNiCl22--catalyzedcatalyzed P P–C–C couplings of bromoarenes withwith diethyldiethyl phosphite.phosphite.

TheThe naturenature of of the the Ni-catalyst, Ni-catalyst, its its formation, formation, and and the the mechanism mechanism of the of NiCl the 2NiCl-catalyzed2-cata- P–Clyzed coupling P–C coupling reactions reactions was also was studied also studied experimentally experimentally and by theoretical and by theoretical calculations calcula- [163]. It was found that in these cases, a Ni(II)(PY OH) type catalyst is formed, and Ni(II) is tions [163]. It was found that in these cases, a2 Ni(II)(PY2 2OH)2 type catalyst is formed, and convertedNi(II) is converted to Ni(IV) into theNi(IV) oxidative in the additionoxidative step. addition This surprising step. This ﬁnding surprising was finding also proved was toalso be proved true for to earlier be true Ni-catalyzed for earlier Ni instances-catalyzed [164 instances] carried [16 out4] originally carried out in originally the presence in the of → Znpresence or Mg of reductants Zn or Mg [reductants165–167]. Hence,[165–16 the7]. Hence, Ni(II) theNi(IV) Ni(II)  conversion Ni(IV) conversion may be of may more be → generalof more valuegeneral instead value of instead the earlier of the assumed earlier assumed Ni(0) Ni(II)Ni(0)  protocol Ni(II) protocol [168]. [168]. Both the Pd- and the Ni-catalyzed protocols elaborated by the Keglevich group are 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 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 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 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 and extensions of the P–C coupling reactions open a new horizon since there is no need add sensitive and expensive P-ligands. 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.

Molecules 2021, 26, x FOR PEER REVIEW 17 of 24

Scheme 18. Hirao reactions applying NiCl2 as the catalyst without added P-ligands.

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].

Scheme 19. NiCl2-catalyzed P–C couplings of bromoarenes with diethyl phosphite.

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 [165–167]. 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 Molecules 2021, 26, 1196 17 of 23 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. AA catalyst-freecatalyst-free method method was was developed developed for for the the P– P–CC coupling coupling of halobezoic of halobezoic acids acids and andsecondary secondary phosphine phosphine oxides oxides in water in water as the as medium the medium (Scheme (Scheme 20) [16 209].)[ 4-169Iodo].- 4-Iodo-,, 3-bromo 3-- bromo-,, and 4-bromobenzoic and 4-bromobenzoic acids were acids coupl wereed coupled with diaryl with diaryl phosphine phosphine oxides oxides under under MW MWcon- ◦ conditionsditions at 180 at 180 °C forC for1–6 1–6 h in h the in thepresence presence of K of2CO K2CO3. The3. The only only limitation limitation of this of this “green “green”” P– P–CC coupling coupling reaction reaction is isthe the low low water water-solubility-solubility of ofthe the P- P-reagents.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. Acknowledgments: G.K. is grateful to all co-authors appearing in the cited references. Conflicts of Interest: The authors declare no conflict of interest.

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