Next Article in Journal
Highly Active Rutile TiO2 for Photocatalysis under Violet Light Irradiation at 405 nm
Next Article in Special Issue
Self-Supported Polymeric Ruthenium Complexes as Olefin Metathesis Catalysts in Synthesis of Heterocyclic Compounds
Previous Article in Journal
Chloride-Enhanced Removal of Ammonia Nitrogen and Organic Matter from Landfill Leachate by a Microwave/Peroxymonosulfate System
Previous Article in Special Issue
β-Amino Acid Organocatalysts in the Asymmetric Michael Addition of Isobutyraldehyde to N-Substituted Maleimides
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Pd-Catalyzed Hirao P–C Coupling Reactions with Dihalogenobenzenes without the Usual P-Ligands under MW Conditions

1
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
2
Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, 1521 Budapest, Hungary
3
MS Proteomics Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(10), 1080; https://doi.org/10.3390/catal12101080
Submission received: 1 September 2022 / Revised: 14 September 2022 / Accepted: 15 September 2022 / Published: 20 September 2022
(This article belongs to the Special Issue Catalysis in Heterocyclic and Organometallic Synthesis II)

Abstract

:
A literature survey of the P–C coupling reactions of 1,4-and 1,2-bromo-iodobenzenes with diphenylphosphine oxide or diethyl phosphite under different conditions comprising Pd-, Ni-, or Cu-catalysis revealed that, depending on the experimental details, the yields of the corresponding >P(O)-bromobenzenes were rather diverse and occasionally contradicting. Therefore, the reactivity of a series of 1,4-, 1,3- and 1,2-dibromo- and bromo-iodobenzenes with the above mentioned P-reagents was evaluated under the “P-ligand-free” microwave (MW)-assisted conditions elaborated by us. Starting from dibromobenzenes and iodo-bromoarenes, practical and competent syntheses were developed for phosphonoyl- and phosphinoyl-bromoarenes, and, in a few instances, for arenes with two P-functions. The cheaper dibromobenzenes may be substituted for the bromo-iodo derivatives. In all, 12 products were prepared in yields of 45–82%. They were fully characterized. The method described does not require the use of traditional P-ligands.

Graphical Abstract

1. Introduction

For the preparation of dialkyl arylphosphonates, the Hirao reaction comprising the P–C coupling between a dialkyl phosphite and an aryl or vinyl halide (mostly bromide) using palladium-tetrakistriphenylphosphine as the catalyst and triethylamine as the base in different solvents is a convenient method [1,2,3,4,5,6,7,8]. The original procedure was followed using variations applying in situ formed Pd catalysts from suitable precursors (e.g. Pd(OAc)2 and PdCl2) and added mono- or bidentate P-ligands. The reaction model was extended to H-phosphinates and secondary phosphine oxides using different arenes [9,10,11,12,13,14,15]. Keglevich et al. developed a microwave-assisted method in which the excess of the >P(O)H reagent served as the P-ligand, via its trivalent tautomeric form, to Pd [16,17,18,19,20]. Hence, there was no need to apply traditional P-ligands decreasing both the cost and the environmental burden.
The data accumulated on the P–C coupling reaction of bromo-iodobenzenes are summarized in Table 1. 1-Bromo-4-iodobenzene was reacted with diphenylphosphine oxide and diethyl phosphite, applying palladium-tetrakistriphenylphosphine as the catalyst. In the two cases, the base, solvent and the temperature were NEt3/PhMe/110 °C and Cs2CO3/THF/120 °C, respectively (Table 1, entries 1 and 2). The latter experiment was performed on MW irradiation. The 4-bromophenylphosphine oxide (I, Y = Ph) and 4-bromophenylphosphonate (I, Y = EtO) were obtained in a yield of 85% and 19%, respectively [21,22]. The latter product could be better prepared from the reaction of 4-bromo-iodobenzene with (EtO)2P(O)H using Pd(OAc)2/dppf catalyst with NEt3 in THF at 68 °C in the presence of KOAc as the additive. The phosphonate (I, Y = EtO) was obtained in a somewhat higher yield of 48% (Table 1, entry 3) [15,23].
1-Bromo-2-iodobenzene was also used in Hirao P–C coupling. The reaction with Ph2P(O)H was performed using Pd(dba)2/dppp and Pd2(dba)3/dppp and DIPEA in PhMe at 120 °C or 90 °C to afford the corresponding 2-bromophenylphosphine oxide (I, Y = Ph) in yields of 65 and 64%, respectively (Table 1, entries 4 and 5) [24,25], while the coupling with (EtO)2P(O)H was realized applying Pd(OAc)2/PPh3 and DIPEA in EtOH at reflux. The 2-bromophenylphosphonate (I, Y = EtO) was obtained in 74% yield (Table 1, entry 6) [26]. The relatively good yields are somewhat surprising, if the steric hindrance in the initial dihalogenobenzene is considered. Although we applied the same reaction conditions (Pd(OAc)2/PPh3, DIPEA, EtOH, reflux) [26], the results of the experiment shown under entry 6 of Table 1 could not be reproduced. Practically, no 2-bromo-diethylphosphonoylbenzene was formed.
The above dihalogenobenzene → P(O)H reactions were also carried out utilizing Ni- and Cu-catalysts. Regarding the application of the NiCl2/2,2’-bipyridyl catalyst in the P–C coupling of 1,4-dibromobenzene or 4-bromo-iodobenzene and Ph2P(O)H, Zn was also added in the reaction mixture [27]. In these cases, the bisphosphinoyl species was the target. However, we proved in another study, that the addition of a metal reducing agent into a Ni-catalyzed Hirao reaction causes problems instead of promoting the P–C coupling [28]. Consequently, the 75–88% yields reported may be questioned [27]. In another variation, 4-bromo-iodobenzene was reacted with Ph2P(O)H using Ni(cod)2/dtbbpy along with Ru(bpy)3Cl2 as the co-catalyst and Cs2CO3 as the base in MeOH at 23 °C on blue-LED irradiation to give the corresponding diphenyl-arylphosphine oxide in an 81% yield (Table 1, entry 7) [29].
The coupling of 1-bromo-2-halogenobenzenes with Ph2P(O)H using CuI/α-phenylethylamine in the presence of K2CO3 in toluene at 110 °C was also investigated [30]. Under such conditions, starting from 1,2-dibromobenzene, no formation of the expected bis(phosphinoyl) product was observed. However, applying 1-bromo-2-iodobenzene along with one equivalent of Ph2P(O)H, the bis(phosphinoyl) product was isolated in a yield of 43% [30]. A similar reaction of 1-bromo-2-iodobenzene with (EtO)2P(O)H in the presence of CuI applied along with different N-ligands and Cs2CO3 in toluene at 110 °C afforded the 4-bromophenylphosphonate (I, Y = EtO) in up to an 85% yield (Table 1, entries 8 and 9) [31,32].
It may be seen that applying the classical catalyst Pd(PPh3)4, 1-bromo-4-iodobenzene could be efficiently converted to the 4-bromophenyl-diphenylphosphine oxide. However, the yield of the 4-bromophenylphosphonate was low, even when using Pd(OAc)2/dppf as the catalyst. The latter species was obtained in better yields applying a Cu catalyst with N-ligands. Surprisingly, the 2-bromophenyl-phosphine oxide and phosphonate were isolated in rather good (64–74%) yields using different Pd/phosphine catalysts starting with 1-bromo-2-iodobenzene. In any case, the outcome of the P–C coupled products was variable. We wished to evaluate how the different bromo-halogenobenzenes including dibromo derivatives may be converted to phosphine oxides and phosphonates applying the MW-assisted “P-ligand-free” approach developed previously by us [17,18]. On the other hand, our purpose was to synthesize bromophenyl-phosphine oxides and phosphonates, suitable starting materials in Arbuzov reactions and Suzuki cross couplings.
Table 1. P–C coupling reactions of bromo-iodobenzenes in the presence of different catalysts/precursors – a literature survey.
Table 1. P–C coupling reactions of bromo-iodobenzenes in the presence of different catalysts/precursors – a literature survey.
Catalysts 12 01080 i001
EntryArX1X2P-ReagentCatalyst (Precursor)/LigandAdditional ConditionsBaseSolventT (°C)Isolated Yield (%)Ref.
11-Br-4-IC6H4Ph2P(O)HPd(PPh3)4NEt3PhMe11085[21]
21-Br-4-IC6H4(EtO)2P(O)HPd(PPh3)4MWCs2CO3THF12019[22]
31-Br-4-IC6H4(EtO)2P(O)HPd(OAc)2/dppfKOAc additiveNEt3THF6848[15,23]
41-Br-2-IC6H4Ph2P(O)HPd(dba)2/dpppDIPEAPhMe12065[24]
51-Br-2-IC6H4Ph2P(O)HPd2(dba)3/dpppDIPEAPhMe9064[25]
61-Br-2-IC6H4(EtO)2P(O)HPd(OAc)2/PPh3DIPEAEtOHreflux74[26]
71-Br-4-IC6H4,Ph2P(O)HNi(cod)2/dtbbpy, Ru(bpy)3Cl2·6H2Oblue LEDCs2CO3MeOH2681[29]
81-Br-4-IC6H4(EtO)2P(O)HCuI/phenCs2CO3PhMe10084[31]
91-Br-4-IC6H4(EtO)2P(O)HCuI/proline or pipecolonic acidCs2CO3PhMe11086/85 [32]

2. Results and Discussion

First, the reaction of 1,4-dibromobenzene with diphenylphosphine oxide was investigated in the presence of 5 mol% Pd(OAc)2, and 1.1 equivalents of triethylamine in ethanol as the solvent under on microwave irradiation. According to our earlier protocol, the Ph2P(O)H was measured in a 1.15 equivalents quantity to ensure the P-ligand and the reducing agent for the Pd(0)→Pd(II) transition [18]. After an irridation at 120 °C for 30 min, the mixture contained 85% of the expected 4-bromo(phenyl-diphenylphosphine oxide 1a, 6% of the bisphosphinoyl compound 2a along with 7% of (EtO)Ph2P(O) and 2% of Ph3P(O) by-products (Table 2, entry 1). Preparative yield of the target product was 63% after chromatography. Repeating the reaction applying 2.15 equivalents of the P-reagent and 1 h reaction time, the mixture comprised 15% of monophosphinoylarene 1a, 41% of bisphosphinoylbenzene 2a, 16% of (EtO)Ph2P(O) and 26% of Ph3P(O) beside 2% of the unreacted starting material (Ph2P(O)H) (Table 2, entry 2). One can see that the latter reaction was not selective. Changing for diethyl phosphite, after an irradiation at 120 °C for 1 h, the diethylphosphonoylarene 1b was present in 69% together with 18% of bis(diethylphosphono)benzene 2b and 12% of (EtO)2PhP(O) (Table 2, entry 3). The desired product 1b was obtained in a yield of 48% after chromatography.
The experiments with the 4-bromo-iodobenzene were performed in a similar manner; however, the formation of 4-bromophenyl-diphenylphosphine oxide (1a) and diethylphosphono-bromobenzene (1b) was more selective at 120 °C as in the previous cases (see Table 2, entries 1 and 3) indicated by their proportions of 97% and 88%, respectively (Table 3, entries 2 and 4). The coupling with Ph2P(O)H led to similar results after an irradiation at 100 °C for 1 h (Table 3, entry 1). Using 2.15 equivalents of the secondary phosphine oxide, the selectivity was similar to the reaction with 1,4-dibromobenzene (19% of 1a, and 42% of 2a were formed) (Table 3, entry 3). At the same time, in reaction with two equivalents of (EtO)2P(O)H, the coupling was significantly more selective, as indicated by the 87:13 ratio of products 2b and 1b. It is noteworthy that the latter conversion took place without any side reaction (Table 3, entry 5).
The application of 1,4-dibromobenzene as the starting material provided products 1a and 1b in lower yields as compared to the cases starting from 4-bromo-1-iodobenezene. Our method afforded aryldiphenylphosphine oxide (1a) in a somewhat lower yield (63–75%) than that obtained using the literature method (85%) [21]. However, the phosphonoarene 1b was obtained in a higher yield (63%) as compared to the outcomes (19 and 48%) reported [15,22,23].
Changing for 1,3-dibromobenzene and using Ph2P(O)H under the conditions applied above, 3-bromophenyl-diphenylphosphine oxide 3a was formed in a similar selectivity as the para analogue 1a (Table 4, entry 1). At the same time, applying 2.15 equivalents of the P-reagent, the bisphosphinoylbenzene (4a) was formed in a selectivity of 92% (Table 4, entry 2). Products 3a and 4a were isolated in a 68% and 75% yield, respectively, after chromatography. The reaction of the dibromobenzene and 1.15 equivalents of Ph2P(O)H (Table 4, entry 1) was repeated on a 3-fold scale. In this case, the yield of compound 3a increased to 76%. The coupling of 1,3-dibromobenzene with 1.15 equivalents of diethyl phosphite was not especially selective, either at 120 °C/1 h in EtOH, or at 150 °C/30 min (solvent-free), as the ratio of species 3b and 4b was 57:27 and 63:24, respectively (Table 4, entries 3 and 4). Diethylphosphono-bromobenzene (3b) was obtained in a 45% yield after purification. The P–C coupling with Ph2P(O)H seemed to be easier and more selective than that with (EtO)2P(O)H.
Repeating the reactions with 3-bromo-iodobenzene, all reactions were more selective, if not completely selective. The bromophenyl-diphenylphosphine oxide 3a was present in the reaction mixture in 94–95%, regardless of whether 100 °C/1 h or 120 °C/30 min was applied (Table 5, entries 1 and 2). Product 3a was isolated in 78 and 75% yields. Measuring in 2.15 equivalents of Ph2P(O)H, after irradiation at 120 °C for 35 min, the proportion of bisphosphinoylbenzene 4a was 88%, which could be isolated in a yield of 70% (Table 5, entry 3). The diethylphosphono-bromobenzene 3b synthesized at 120 °C/30 min was present in 81% in the crude mixture, which could be prepared in a 66% yield (Table 5, entry 4).
The MW-assisted “P-ligand-free” Hirao reaction is a good choice for the preparation of 3-bromophenyl-P(O)Y2 products 3a and 3b. 1,3-Dibromobenzene is also a suitable starting material, however, the 1-iodo-3-bromobenzene for more efficient preparations. The latter could also be converted to the bis-phosphinoyl derivative (4a).
3-Chloro-bromobenzene could also be applied to prepare the corresponding 1-phosphinoyl- and 1-phosphonoyl-3-chlorobenzenes 5a and 5b, respectively, in a selective manner (Table 6, entries 1 and 2). However, longer reaction times were necessary at 120 °C as compared to the cases, in which 3-bromo-1-iodobenzene was used as the starting material.
The coupling of 1,2-dibromobenzene with 1.15 equivalents of diphenylphosphine oxide in the presence of 5 mol% of Pd(OAc)2 and 1.1 equivalents triethylamine in ethanol as the solvent at 150 °C on MW irradiation was rather inefficient. As can be seen from Table 7, entry 1, the 2-bromo-phosphinoylbenzene (6a) was formed in 20%, while the di(Ph2P(O))-product (7a) was also present in a comparable proportion (19%). The remaining part covered 48% of triphenylphosphine oxide (48%) formed on debromination, and phenylphosphinic acid coming from the oxidation of Ph2P(O)H. An increase in the quantity of the catalyst precursor from 5 to 10 mol% and that of the P-species from 1.15 to 1.3 favored the formation of Ph3P(O) (58%), otherwise there was no significant change except that some ethyl diphenylphosphinate also appeared in the mixture (Table 7, entry 2).
The reaction with diethyl phosphite using 5 mol% of Pd(OAc)2, 1.15 equivalents of the P-reagent and triethylamine in ethanol at 150 °C resulted in a mixture comprising 30% of 2-bromo-diethylphosphonoylbenzene (6b) along with 66% of diethyl phenylphosphonate (Table 7, entry 3). However, in a solvent-free manner, the side-reaction could be suppressed, although the conversion was not complete (Table 7, entry 4). The best run occurred, when 10 mol% of the catalyst precursor was used along with 1.3 equivalents of (EtO)2P(O)H in the absence of ethanol for a longer irradiation time of 45 min (Table 7, entry 5). The bromophenylphosphonate (6b) could be isolated in 60% yield after chromatography. It can be noted that although 1,2-dibromobenzene is a sterically hindered substrate, its monophosphonoylation is possible.
The similar reactions of bromo-2-iodobenzene with Ph2P(O)H and (EtO)2P(O)H reagents were more clear-cut. The coupling with Ph2P(O)H at 150 °C in ethanol took place so that the desired product 6a was present in 65/66% portions in the mixture, and was prepared in a yield of 45%. The remaining part comprised ~10% of ethyl diphenylphosphinate, ~11% of Ph3P(O) and 15/12% of Ph2P(O)OH (Table 8, entries 1 and 2). Ph3P(O) may have formed from 6a by debromination. In another experiment, we applied 2.15 equivalents of Ph2P(O) in order to synthesize bis-P(O)Ph2 compound 7a. After a reaction time of 1 h, the mixture comprised ~50% of the target product 7a, along with ~10% of (EtO)Ph2P(O) and 40% of Ph3P(O). Due to the side-reactions, this approach is not efficient.
It is noteworthy that the P–C coupling with (EtO)2P(O)H was again more selective in the solvent-free variation. Performing the model reaction in ethanol, the proportion of arylphosphonate 6b was only 36%, but in the absence of any solvent, the resulting mixture contained 91% of the target compound (6b) along with 9% of diethyl phenylphoshonate (Table 8, entries 3 and 4). Using a smaller amount of catalyst precursor and P-ligand, the conversion was not so efficient (Table 8, entry 5).
In order to prepare a mixed derivative, 4-bromophenyl-diphenylphosphine oxide 1a was reacted with 1.15 equivalents of (EtO)2P(O)H in the presence of 5 mol% of Pd(OAc)2 and 1.1 equivalents of NEt3 in EtOH at 150 °C under MW irradiation. The useful conversion of ca. 80% allowed a 51% isolated yield of 4-diethylphosphonoylphenyl-diphenylphosphine oxide 8 after chromatography (Scheme 1).
Finally, 3-bromophenyl-diphenylphosphine oxide (3a) was reacted with 1.15 equivalents of Ph2P(O)H and (EtO)2P(O)H under optimum conditions (5 mol% Pd(OAc)2, 1.1 equivalents NEt3 in EtOH at 150 °C), involving MW assistance. Although the formation of a few by-products was inevitable, the efficiency was quite good. Products 4a and 9 were obtained in yields of 67% and 64%, respectively (Table 9, entries 1 and 2).
The mono >P(O)Ar products (1a, 1b, 3a, 5a, 5b, 6a and 6b), as well as the bis (>P(O))arene derivatives (2b, 4a, 8, and 9) were fully characterized by 31P, 13C, 1H NMR spectral data along HRMS. The pulse programs of one-dimensional (1H, 13C and DEPTQ) and two-dimensional (1H,1H-COSY, 1H,13C-HSQC, 1H,13C-HMBC and 1H,1H-ROESY) measurements were utilized during the structure elucidation of compounds 4a, 6a, 8 and 9. The starting points of signal assignment were easily identifiable units of molecules: the methyl and methylene groups of the ethoxy moiety, and the triplet para hydrogens of the P(Ph)2 unit. The remainder of the molecular structures was elucidated using the same NMR methods mentioned above, e.g.: COSY cross-peak between ortho and para hydrogens of the P(Ph)2 unit, ROESY correlation of methylene hydrogens to some hydrogens of the disubstituted benzene ring, and the quaternary atoms by their HMBC correlations to hydrogens of own aromatic rings.
In summary, 12 compounds were synthesized, of which 3 (5a, 8 and 9) are new derivatives. Compound 3a was mentioned in a patent, however, no spectral characterization was provided [34]. 31P, 13C and 1H NMR spectra can be found in the Supplementary Materials section.

3. Experimental

3.1. General Information

The reactions were carried out in a CEM® Discover Model SP (300 W) focused microwave reactor (Buckingham, UK) equipped with a stirrer and a pressure controller using 80–100 W irradiation under isothermal conditions. The reaction mixtures were irradiated in sealed borosilicate glass vessels (with a volume of 10 mL) available from the supplier of CEM®. The reaction temperature was monitored by an external IR sensor.
The 31P, 13C and 1H NMR spectra were taken in CDCl3 solution on a Bruker Avance 300/Avance 500 spectrometer (Rheinstetten, Germany) operating at 121.5/202.4, 75.5/125.7 and 300 / 500 MHz, respectively. The 31P chemical shifts are downfield relative to H3PO4, while the 13C and 1H chemical shifts are downfield relative to TMS. The couplings are given in Hz. The exact mass measurements were performed using an Agilent 6545 Q-TOF mass spectrometer (Santa Clara, CA, USA) in high resolution, positive electrospray mode. The chemicals were purchased from Sigma-Aldrich (Louis, MO, United States).

3.2. Procedures for the P–C Coupling of 1,4- or 1,3-Dibromobenzene and Diphenylphosphine Oxide or Diethyl Phosphite (Table 2, Entries 1 and 3; Table 4, Entries 1, 2 and 4)

To 0.022 mmol of the Pd(OAc)2 catalyst (4.8 mg) in 1 mL of ethanol or without any solvent were added 0.43 mmol of dibromobenzene [1,4-dibromobenzene: 0.10 g or 1,3-dibromobenzene: 0.052 mL], 0.49 mmol (0.10 g) or 0.92 mmol (0.19 g) of diphenylphosphine oxide or 0.49 mmol (0.063 mL) of diethyl phosphite, and 0.47 mmol (0.066 mL) or 0.95 mmol (0.13 mL) of triethylamine. Then, the mixture was irradiated in a closed vial in the MW reactor at 120 °C or 150 °C for the times shown in Table 2, entry 1 and Table 4, entries 1 and 2, or Table 2, entry 3 and Table 4, entry 4. The reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after evaporation was passed through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluent. The crude product was analyzed by 31P NMR spectroscopy, then it was purified by column chromatography (silica gel, and hexane–acetone 6:4 as the eluent) to afford compounds 1a, 3a and 4a (Table 2, entry 1 and Table 4, entries 1 and 2), or phosphonates 1b and 3b (Table 2, entry 3 and Table 4, entry 4).

3.3. Procedures for the P–C Coupling of 4-Bromo- or 3-Bromo-Iodobenzenes and Diphenylphosphine Oxide or Diethyl Phosphite (Table 3, Entries 2, 4 and 5; Table 5, Entries 1, 3 and 4)

To 0.022 mmol of the Pd(OAc)2 catalyst (4.8 mg) in 1 mL of ethanol or without any solvent were added 0.43 mmol of bromo-iodobenzenes [4-bromo-iodobenzene: 0.12 g, or 3-bromo-iodobenzene: 0.055 mL], 0.49 mmol (0.10 g) or 0.92 mmol (0.19 g) of diphenylphosphine oxide or 0.49 mmol (0.063 mL) or 0.99 mmol (0,13 mL) of diethyl phosphite, and 0.47 mmol (0.066 mL) or 0.95 mmol (0.13 mL) of triethylamine. Then, the mixture was irradiated in a closed vial in the MW reactor at 100 or 120 °C for 25–30 min (Table 3, entry 2 and Table 5, entries 1 and 3, or Table 3, entries 4 and 5, and Table 5, entry 4). The work-up and analysis along with the purification was done as described under 3.2 to furnish compounds 1a, 3a and 4a (Table 3, entry 2 and Table 5, entries 1 and 3), or phosphonates 1b, 2b and 3b (Table 3, entries 4 and 5, and Table 5, entry 4).

3.4. Procedure for the P–C Coupling of 3-Chloro-Bromobenzene and Diphenylpshosphine Oxide or Diethyl Phosphite (Table 6, Entry 1 and 2)

To 0.022 mmol of the Pd(OAc)2 catalyst (4.8 mg) in 1 mL of ethanol were added 0.43 mmol (0.051 mL) 3-chloro-bromobenzene, 0.49 mmol of >P(O)H-reagent [diphenylphosphine oxide: 0.10 g, or diethyl phosphite: 0.063 mL], and 0.47 mmol (0.066 mL) of triethylamine. Then, the mixture was irradiated in a closed vial in the MW reactor at 120 °C for 60 or 45 min. 3 mL of EtOH was added to the mixture, it was filtrated, and the residue obtained after evaporation was passed through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluent. The crude product was purified by column chromatography (silica gel, and dichloromethane–methanol 96:4 or ethyl acetate as the eluent) to give 0.11 g (80%) of product 5a or 0.088 g (82%) of product 5b.

3.5. The Preparation of Diethyl 2-Bromophenylphosphonate 6b (Table 8, Entry 4)

To 0.043 mmol of the Pd(OAc)2 catalyst (9.6 mg) were added 0.43 mmol (0.055 mL) of 2-bromo-iodobenzene, 0.56 mmol (0.072 mL) of diethyl phosphite, and 0.47 mmol (0.066 mL) of triethylamine. Then, the mixture was irradiated in a closed vial in the MW reactor at 150 °C for 45 min. The crude reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after concentration was passed through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluent. The crude product was analyzed by 31P NMR spectroscopy, and then it was purified by column chromatography (silica gel, and ethyl acetate as the eluent) to give phosphonate 6b in a yield of 75% (0.12 g).

3.6. The Synthesis of 4-Diethylphosphonoylphenyl-Diphenylphosphine Oxide 8 (Scheme 1)

To a MW glass vessel were added 0.021 mmol of the Pd(OAc)2 catalyst (4.7 mg), 0.42 mmol of (4-bromophenyl)-diphenylphosphine oxide 1a (0.15 g), 0.48 mmol (0.062 mL) of diethyl phosphite, 0.46 mmol (0.064 mL) of triethylamine and 1 mL of ethanol. The mixture was irradiated in a closed vial in the MW reactor at 150 °C for 30 min. The reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after concentration was passed through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluent. The crude product was analyzed by 31P NMR spectroscopy, and then it was purified by column chromatography (silica gel, and dichloromethane–methanol 97:3 as the eluent) to give 4-diethylphosphonoylphenyl-diphenylphosphine oxide 8 in a yield of 51% (0.09 g).

3.7. The Procedure for the P–C Coupling of 3-Bromophenyl-Diphenylphosphine Oxide 3a with Diphenylphosphine Oxide and Diethyl Phosphite (Table 9, Entry 1 and 2)

To a MW glass vessel were added 0.021 mmol of the Pd(OAc)2 catalyst (4.7 mg), 0.42 mmol of (3-bromophenyl)-diphenylphosphine oxide 3a (0.15 g), 0.48 mmol of >P(O)H-reagent [0.097 g of diphenylphosphine oxide or 0.062 mL of diethyl phosphite], 0.46 mmol (0.064 mL) of triethylamine and 1 mL of ethanol. Then, the mixture was irradiated in a closed vial in the MW reactor at 150 °C for 30 min. The reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after concentration was passed through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluent. The crude product was analyzed by 31P NMR spectroscopy, and then it was purified by column chromatography (silica gel, and dichloromethane–methanol 97:3 as the eluent) to give 0.13 g (67%) of 1,3-phenylenebis(diphenylphosphine oxide) 4a or 0.11 g (64%) of 3-diethylphosphonoylphenyl-diphenylphosphine oxide 9.

3.8. Spectral Data for the Compounds Isolated

  • (4-Bromophenyl)-diphenylphosphine Oxide (1a) (Table 2, Entry 1 and Table 3, Entry 2). Appearance: white crystals, mp. 157–158 °C; 31P NMR (CDCl3, 202.4 MHz) δ 28.5, δP [29] (CDCl3, 162 MHz) 25.2, δP [35] (CDCl3, 162 MHz) 28.7; 13C NMR (CDCl3, 125.7 MHz) δ 133.6 (d, J = 10.6, C2)a, 132.2 (d, J = 2.8, C4′), 132.1 (d, J = 104.9, C1′), 132.0 (d, J = 9.9, C2′)b, 131.84 (d, J = 12.5, C3)a, 131.76 (d, J = 104.3, C1), 128.7 (d, J = 12.2, C3′)b, 127.2 (d, J = 3.4, C4), a,b may be reversed, δC [29] (CDCl3, 100 MHz) 133.5 (d, J = 10.5), 132.1 (d, J = 2.8), 131.9 (d, J = 104.4), 131.9 (d, J = 10.0), 131.7 (d, J = 12.4), 131.6 (d, J = 107.1), 128.6 (d, J = 12.1), 128.1 (d, J = 3.4), δC [35] (CDCl3, 100 MHz) 133.6 (d, J = 10.6), 132.1 (d, J = 2.7), 132.0 (d, J = 10.0), 131.9 (d, J = 104.6), 131.8 (d, J = 12.4), 131.3 (d, J = 45.6), 128.6 (d, J = 12.2), 127.2 (d, J = 3.3); 1H NMR (CDCl3, 500 MHz) δ 7.66–7.59 (m, 6H), 7.57–7.51 (m, 4H), 7.48–7.45 (m, 4H), δH [29] (CDCl3, 600 MHz) 7.72–7.59 (m, 6H), 7.58–7.52 (m, 4H), 7.49–7.46 (m, 4H), δH [35] (CDCl3, 400 MHz) 7.68–7.65 (m, 3H), 7.63–7.62 (m, 2H), 7.60–7.58 (m, 2H), 7.56–7.51 (m, 4H), 7.49–7.47 (m, 3H); [M + H]+ = 357.0045 C18H15OPBr requires 357.0044.
  • Diethyl 4-Bromophenylphosphonate (1b) (Table 2, Entry 3 and Table 3, Entry 4). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 17.8, δP [32] (CDCl3, 121 MHz) 18.3, δP [36] (CDCl3, 121 MHz) δ 16.7; 13C NMR (CDCl3, 125.7 MHz) δ 133.3 (d, J = 10.7, C2)a, 131.8 (d, J = 15.5, C3)a, 127.54 (d, J = 190.5, C1), 127.53 (d, J = 4.2, C4), 62.3, (d, J = 5.5,CH2), 16.3 (d, J = 6.4, CH3), a may be reversed, δC [32] (CDCl3, 75 MHz) 133.4, 133.3, 132.0, 131.8, 127.7 (J = 188.59), 127.6, 62.4 (J = 5.02), 16.3 (J = 6.46), δC [36] (CDCl3, 75 MHz) 133.3 (J = 10.1), 131.7 (J = 16.5), 129.8 (J = 185.0), 127.5 (J = 3.9), 61.8 (J = 5.7), 16.3 (J = 5.7); 1H NMR (CDCl3, 500 MHz) δ 7.72–7.68 (m, 2H), 7.65–7.62 (m, 2H), 4.21–4.06 (m, 4H, CH2), 1.34 (t, J = 7.0, 6H, CH3), δH [32] (CDCl3, 300 MHz) 7.60–7.72 (m, 4H), 4.10–4.20 (m, 4H), 1.32 (t, J = 7.2, 6H), δH [36] (CDCl3, 300 MHz) 7.62 (d, J = 8.94, 2H), 7.20 (d, J = 8.94, 2H), 3.84–3.86 (m, 4H), 1.17 (t, J = 7.2, 6H); [M + H]+ = 292.9939 C10H15O3PBr requires 292.9942.
  • Tetraethyl 1,4-Phenylenebisphosphonate (2b) (Table 3, Entry 5). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 16.8, δP [37] (121 MHz, CDCl3) 17.5; 13C NMR (CDCl3, 125 MHz) δ 132.9 (dd, J1 = 189.9, J2 = 2.7, C1), 131.7–131.5 (m, C2), 62.5 (d, J = 5.4, CH2), 16.3 (d, J = 6.4, CH3), δC [37] (75 MHz, CDCl3) 134.1 (d, J = 3.1), 131.8–131.4 (m), 63.3–62.3 (m), 16.5–16.2 (m); 1H NMR (CDCl3, 500 MHz) δ 7.95–7.91 (m, 4H), 4.24–4.09 (m, 8H, CH2), 1.36 (t, J = 7.1, 12H, CH3), δH [37] (300 MHz, CDCl3) 7.97–7.84 (m, 4H), 4.24–4.01 (m, 8H), 1.39–1.28 (m, 12H); [M + H]+ = 351.1121 C14H25O6P2 requires 351.1126.
  • 3-Bromophenyl-diphenylphosphine Oxide (3a) (Table 4, Entry 1 and Table 5, Entry 1). Appearance: white crystals, mp. 92–93 °C; 31P NMR (CDCl3, 202.4 MHz) δ 28.0; 13C NMR (CDCl3, 125.7 MHz) δ 135.4 (d, J = 100.8, C1), 135.0 (d, J = 2.5, C4), 134.6 (d, J = 10.5, C2), 132.3 (d, J = 2.8, C4′), 132.0 (d, J = 10.0, C2′)a, 131.8 (d, J = 105.0, C1′), 130.5 (d, J = 9.5, C6), 130.2 (d, J = 12.6, C5), 128.7 (d, J = 12.3, C3′)a, 123.2 (d, J = 15.2, C3), a may be reversed; 1H NMR (CDCl3, 500 MHz) δ 7.84–7.81 (m, 1H), 7.69–7.64 (m, 5H), 7.60–7.56 (m, 3H), 7.51–7.47 (m, 4H), 7.36–7.32 (m, 1H); [M + H]+ = 357.0046 C18H15OPBr requires 357.0044.
  • 1,3-Phenylenebis(diphenylphosphine Oxide) (4a) (Table 5, Entry 3). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 28.5, δP [27] (CDCl3,162 MHz) 30.5; 13C NMR (CDCl3, 125.7 MHz) δ 135.5 (dd, J1 = 10.1, J2 = 3.1, C3), 135.4 (t, J = 11.2, C1), 133.6 (dd, J1 = 101.8, J2 = 10.7, C2), 132.2 (d, J = 2.3, C4′)a, 131.95 (d, J = 10.2, C2′)a, 131.7 (d, J = 105.1, C1′), 128.95 (t, J = 11.3, C4), 128.6 (d, J = 12.5, C3′)a, a may be reversed, δC [27] (CDCl3, 100 MHz) 135.2–135.4 (m, 2C), 135.1, 133.5 (dd, J1 = 101.7, J2 = 10.7), 132.0, 131.8 (d, J = 10.3), 131.5 (d, J = 104.9), 128.8 (t, J = 11.2), 128.4 (d, J = 12.6), 127.1; 1H NMR (CDCl3, 500 MHz) δ 7.96 (ddm, J1 = 12.5, J2 = 7.7, 2H), 7.69 (tt, J1 = 11.7, J2 = 1.5, 1H), 7.62 (tt, J1 = 7.7, J2 = 2.5, 1H), 7.58 (dd, J1 = 12.1, J2 = 7.9, 8H), 7.53 (t, J = 7.4, 4H), 7.41 (td, J1 = 7.7, J2 = 2.8, 8H), δH [27] (CDCl3, 400 MHz) 7.93–7.98 (m, 2H), 7.71 (t, J = 11.7, 1H), 7.50–7.63 (m, 13H), 7.38–7.43 (m, 8H); [M + H]+ = 479.1327 C30H25O2P2 requires 479.1330.
  • Diethyl 3-Bromophenylphosphonate (3b) (Table 4, Entry 4 and Table 5, Entry 4). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 16.2; 13C NMR (CDCl3, 125.7 MHz) δ 135.6 (d, J = 2.8, C4), 134.7 (d, J = 10.7, C2)a, 131.2 (d, J = 187.3, C1), 130.4 (d, J = 6.0, C6), 130.3 (d, J = 12.8, C5)a, 123.0 (d, J = 19.7, C3), 62.6 (d, J = 5.5, CH2), 16.5 (d, J = 6.4, CH3), a may be reversed, δC [33] (101 MHz, CDCl3) 135.4 (d, J = 3.0), 134.5 (d, J = 10.6), 131.1 (d, J = 186), 130.2 (d, J = 4.9), 130.1 (d, J = 11.7), 122.9 (d, J = 19.8), 62.4 (d, J = 5.5), 16.3 (d, J = 6.4); 1H NMR (CDCl3, 500 MHz) δ 7.98–7.95 (m, 1H), 7.79–7.74 (m, 1H), 7.71–7.69 (m, 1H), 7.39–7.35 (m, 1H), 4.23–4.08 (m, 4H, CH2), 1.36 (t, J = 7.1, 6H, CH3), δH [33] (400 MHz, CDCl3) 7.93 (d, J = 13.6, 1H), 7.72 (dd, J1 = 12.9, J2 = 7.6, 1H), 7.66 (d, J = 8.0, 1H), 7.33 (td, J1 = 7.8, J2 = 4.8, 1H), 4.21–4.00 (m, 4H), 1.32 (t, J = 7.1, 6H); [M + H]+ = 292.9937 C10H15O3PBr requires 292.9942.
  • Diphenyl-3-chlorophenylphosphine Oxide (5a) (Table 6, Entry 1). Appearance: white crystals, mp. 75–76 °C; 31P NMR (CDCl3, 202.4 MHz) δ 28.1; 13C NMR (CDCl3, 125.7 MHz) δ 135.1 (d, J = 101.3, C1), 135.0 (d, J = 15.6, C3), 132.3 (d, J = 2.8, C4′), 132.1 (d, J = 2.7, C4), 132.0 (d, J = 10.0, C2′)a, 131.84 (d, J = 10.7, C2)b, 131.82 (d, J = 105.1, C1′), 130.1 (d, J = 9.5, C6)b, 129.9 (d, J = 12.9, C5), 128.7 (d, J = 12.3, C3′)a, a,b may be reversed; 1H NMR (CDCl3, 500 MHz) δ 7.68–7.64 (m, 5H), 7.59–7.55 (m, 3H), 7.53–7.47 (m, 5H), 7.43–7.39 (m, 1H); [M + H]+ = 313.0547 C18H15OPCl requires 313.0549.
  • Diethyl 3-Chlorophenylphosphonate (5b) (Table 6, Entry 2). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 16.5, δP [17] (CDCl3) 17.5; 13C NMR (CDCl3, 125.7 MHz) δ 134.8 (d, J = 20.3, C3), 132.5 (d, J = 3.0, C4), 131.6 (d, J = 10.7, C2)a, 130.8 (d, J = 187.8, C1), 129.9 (d, J = 16.5, C5), 129.8 (d, J = 9.2, C6)a, 62.4 (d, J = 5.5, CH2), 16.3 (d, J = 6.4, CH3), a may be reversed, δC [17] (CDCl3) 134.7 (d, J = 20.3, C2), 132.4 (d, J = 3.0, C4), 131.6 (d, J = 10.7, C3), 130.7 (d, J = 187.9, C1), 129.74 (d, J = 16.3, C6), 129.69 (d, J = 9.2, C5), 62.3 (d, J = 5.5, CH2), 16.2 (d, J = 6.4, CH3); 1H NMR (CDCl3, 500 MHz) δ 7.83–7.68 (m, 2H), 7.56–7.53 (m, 1H), 7.46–7.39 (m, 1H), 4.25–4.05 (m, 4H, CH2), 1.36 (t, J = 7.1, 6H, CH3), δH [17] (CDCl3) 7.81–7.59 (m, 2H, ArH), 7.51–7.43 (m, 1H, ArH), 7.40–7.31 (m, 1H, ArH), 4.20–3.96 (m, 4H, OCH2), 1.30 (t, J = 7.1, 6H, CH3); [M + H]+ = 249.0448 C10H15O3PCl requires 249.0447.
  • (2-Bromophenyl)-diphenylphosphine Oxide (6a) (Table 8, Entry 1). Appearance: white crystals; 31P NMR (CDCl3, 202.4 MHz) δ 30.5, δP [25] (CDCl3, 200 MHz) 30.6, δP [24] (CDCl3, 162 MHz) 32.2; 13C NMR (CDCl3, 125.7 MHz) δ 136.0 (d, J = 10.5, C3)a, 134.9, (d, J = 7.5, C6)a, 133.4 (d, J = 2.4, C4), 133.0 (d, J = 104.6, C1), 132.1 (d, J = 10.0, C2′)b, 132.0 (d, J = 2.8, C4′), 131.7 (d, J = 108.0, C1′), 128.6 (d, J = 12.5, C3′)b, 127.0 (d, J = 11.1, C5)a 126.9 (d, J = 4.7, C2), a,b may be reversed, δC [25] (CDCl3, 75 MHz) 136.1 (d, J = 10.4), 135.0 (d, J = 7.7), 133.6 (d, J = 2.2), 133.2 (d, J = 104.3), 132.3 (d, J = 9.9), 132.1 (d, J = 2.7), 131.9 (d, J = 107.6), 128.7 (d, J = 12.6), 127.1 (d, J = 11.5), 127.1 (d, J = 4.9), δC [24] (CDCl3, 100 MHz) 136.3 (d, J = 10.4), 135.2 (d, J = 8.0), 133.7 (d, J = 2.4), 133.5 (d, J = 104.7), 132.5 (d, J = 9.6), 132.3 (d, J = 2.4), 132.2 (d, J = 107.9), 128.9 (d, J = 12.0), 127.3 (d, J = 11.2), 127.3; 1H NMR (CDCl3, 500 MHz) δ 7.74–7.71 (m, 4H), 7.70–7.67 (m, 1H), 7.59–7.55 (m, 2H), 7.50–7.46 (m, 4H), 7.41–7.32 (m, 3H,) δH [25] (CDCl3, 500 MHz) 7.75–7.65 (m, 5H), 7.58–7.53 (m, 2H), 7.60–7.45 (m, 4H), 7.41–7.30 (m, 3H), δH [24] (CDCl3, 400 MHz) 7.75–7.65 (m, 5H), 7.58–7.31 (m, 9H); [M + H]+ = 357.0045 C18H15OPBr requires 357.0044.
  • Diethyl 2-Bromophenylphosphonate (6b) (Table 8, Entry 4). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 14.8, δP [26] (CDCl3, 121 MHz) 15.4; 13C NMR (CDCl3, 125.7 MHz) δ 136.3 (d, J = 8.3, C6)a, 134.3 (d, J = 11.2, C3)a, 133.6 (d, J = 2.7, C4), 129.5 (d, J = 192.0, C1), 126.9 (d, J = 13.6, C5)a, 125.2 (d, J = 3.8, C2), 62.6 (d, J = 5.6, CH2), 16.3 (d, J = 6.5, CH3), a may be reversed, δC [26] (CDCl3, 75 MHz) 136.2 (d, J = 8.3, Ar-CH), 133.5 (d, J = 2.7, Ar-CH), 129.3 (d, J = 192.0, Ar-qC), 126.8 (d, J = 13.6, Ar-CH), 125.1 (d, J = 3.9, Ar-qC), 62.5 (d, J = 5.6 OCH2CH3), 16.2 (d, J = 6.6 OCH2CH3); 1H NMR (CDCl3, 500 MHz) δ 8.07–8.02 (m, 1H), 7.71–7.68 (m, 1H), 7.45–7.38 (m, 2H), 4.27–4.12 (m, 4H, CH2), 1.39 (t, J = 7.1, 6H, CH3), δH [26] (CDCl3, 300 MHz) 8.05–7.96 (m, 1H, ArH), 7.70–7.62 (m, 1H, ArH), 7.43–7.33 (m, 2H, ArH), 4.28–4.04 (m, 4H, OCH2CH3), 1.35 (td, J1 = 7.1, J2 = 0.5) 6H, OCH2CH3); [M + Na]+ = 314.9761 C10H14O3PBrNa requires 314.9762.
  • 4-Diethylphosphonoylphenyl-diphenylphosphine Oxide (8) (Scheme 1). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 28.4 (m, P(C6H5)2), 16.8 (d; J = 3.7, P(OCH2CH3)2); 13C NMR (CDCl3, 125.7 MHz) δ 137.3 (dd, J1 = 100.5, J2 = 3.0, C1), 132.6 (dd, J1 = 186.9, J2 = 2.9, C4), 132.3 (d, J = 2.8, C4′), 132.1 (d, J = 10.0, C2′)a, 132.0 (dd, J = 14.9, J = 9.8, C2), 131.7 (d, J ~ 105, C1′), 131.6 (dd, J1 = 11.8, J2 = 10.0, C3), 128.7 (d, J = 12.2, C3′)a, 62.5 (d, J = 5.6, CH2), 16.4 (d, J = 6.4, CH3), a may be reversed; 1H NMR (CDCl3, 500 MHz) 7.90 (ddd, J1 = 12.8, J2 = 8.3, J3 = 2.5, 2H), 7.78 (ddd, J1 = 11.6, J2 = 8.1, J3 = 3.9, 2H), 7.67 (ddd, J1 = 12.1, J2 = 7.8, J3 = 1,3, 4H), 7.58 (tm, J = 7.5, 2H), 7.49 (td, J1 = 7.6, J2 = 2.9, 4H), 4.18 (m) 4.10 (m, 4H, CH2), 1.34 (t, J = 7.1, 6H, CH3); [M + H]+ = 415.1228 C22H25O4P2 requires 415.1228.
  • 3-Diethylphosphonoylphenyl-diphenylphosphine Oxide (9) (Table 9, Entry 2). Appearance: colorless oil; 31P NMR (CDCl3, 202.4 MHz) δ 28.3 (m, P(C6H5)2), 16.7 (d, J = 5.0, P(OCH2CH3)2); 13C NMR (CDCl3, 125.7 MHz) δ 135.8 (dd, J1 = 9.7, J2 = 2.8, C6), 135.2 (dd, J1 = 10.0, J2 = 2.6, C4), 135.0 (t, J = 10.6, C2), 133.6 (dd, J1 = 102.1, J2 = 13.7, C1), 132.3 (d, J = 2.9, C4′), 132.1 (d, J = 10.0, C2′)a, 132.0 (d, J = 104.8, C1′), 129.5 (dd, J1 = 188.6, J2 = 11.3, C3), 128.75 (dd, J1 = 14.2, J2 = 11.2, C), 128.7 (d, J = 12.3, C3′)a, 62.5 (d, J = 5.7, CH2), 16.3 (d, J = 6.4, CH3), a may be reversed; 1H NMR (CDCl3, 500 MHz) 8.06 (t, J = 12.6, 1H), 8.01 (ddq, J1 = 13.1, J2 = 7.7, J3 = 1.5, 1H), 7.89 (ddq, J1 = 11.7, J2 = 7.8, J3 = 1.5, 1H), 7.67 (ddd, J1 = 12.1, J2 = 8.0, J3 = 1.4, 4H), 7.59 (tt, J1b, J2 = 3.3, 1H), 7.57 (tq, J1 = 7.5, J2 = 1.5, 2H), 7.48 (td, J1 = 7.6, J2 = 2.9, 4H), 4.12 (m) 4.05 (m, 4H, CH2), 1.27 (t, J = 7.1, 6H, CH3), b the coupling could not be detected due to overlapping signals; [M + Na]+ = 437.1042 C22H24O4P2Na requires 437.1048.

4. Conclusions

A Hirao P–C cross coupling protocol using the excess of P-reagents as the P-ligands under MW irradiation was applied to the synthesis of bromophenylphosphine oxides and phosphonates in order to provide valuable starting materials for further transformations. A collection of 1,4-, 1,3- and 1,2-dibromobenzenes and the corresponding bromo-iodo derivatives were reacted with diphenylphosphine oxide and diethyl phosphite using Pd(OAc)2 as the catalyst precursor and an excess of the Y2P(O)H reagent (Y = Ph, EtO) as the P-ligand via its Y2POH tautomeric form. The bromophenylphosphine oxides and phosphonates, in most cases, could be obtained in reasonable yields, however, the reaction of the ortho-dihalogenobenzenes was reluctant. The bromo-iodobenzenes could be replaced by the cheaper dibromo derivatives. In a few cases, the bis(>P(O)-benzene) species were also prepared, either directly, or from the isolated mono(>P(O)-bromophenyl) derivative. In all, 12 products, of which 3 are new, were prepared and characterized.

Supplementary Materials

The supporting information including the 31P, 1H, and 13C NMR spectra of the products can be downloaded at: https://www.mdpi.com/article/10.3390/catal12101080/s1.

Author Contributions

Conceptualization, G.K.; methodology, B.H.; formal analysis, P.R.V., A.S. and L.D.; investigation, B.H. and N.Á.S.; data curation, A.S. and L.D.; writing—original draft preparation, G.K. and B.H.; writing—review and editing, G.K.; supervision, G.K.; project administration, G.K.; funding acquisition, G.K. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by the National Research, Development and Innovation Office (K134318).

Data Availability Statement

Not relevant.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Stereoselective synthesis of vinylphosphonate. Tetrahedron Lett. 1980, 21, 3595–3598. [Google Scholar] [CrossRef]
  2. Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T. Palladium-catalyzed new carbon-phosphorus bond formation. Bull. Chem. Soc. Jpn. 1982, 55, 909–913. [Google Scholar] [CrossRef]
  3. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. A Novel Synthesis of Dialkyl Arenephosphonates. Synthesis 1981, 1981, 56–57. [Google Scholar] [CrossRef]
  4. Lu, X.; Zhu, J. Palladium-catalyzed reaction of aryl polyfluoroalkanesulfonates with O,O-dialkyl phosphonates. Synthesis 1987, 1987, 726–727. [Google Scholar] [CrossRef]
  5. Holt, D.A.; Erb, J.M. Palladium-catalyzed phosphorylation of alkenyl triflates. Tetrahedron Lett. 1989, 30, 5393–5396. [Google Scholar] [CrossRef]
  6. Kazankova, M.A.; Trostyanskaya, I.G.; Lutsenko, S.V.; Beletskaya, I.P. Nickel- and palladium-catalyzed cross-coupling as a route to 1- and 2-alkoxy- or dialkylaminovinylphosphonates. Tetrahedron Lett. 1999, 40, 569–572. [Google Scholar] [CrossRef]
  7. Zhong, P.; Xiong, Z.X.; Huang, X. A facile regio- and stereocontrolled synthesis of (E)-vinylphosphonates VIA cross coupling of (E)-vinyl iodides with dialkyl phosphites. Synth. Commun. 2000, 30, 273–278. [Google Scholar] [CrossRef]
  8. Kobayashi, Y.; William, A.D. Palladium- and nickel-catalyzed coupling reactions of α-bromoalkenylphosphonates with arylboronic acids and lithium alkenylborates. Adv. Synth. Catal. 2004, 346, 1749–1757. [Google Scholar] [CrossRef]
  9. Jablonkai, E.; Keglevich, G. P–C bond formation by coupling reaction utilizing >P(O)H species as the reagents. Curr. Org. Synth. 2014, 11, 429–453. [Google Scholar] [CrossRef]
  10. Jablonkai, E.; Keglevich, G. Advances and new variations of the Hirao reaction. Org. Prep. Proc. Int. 2014, 46, 281–316. [Google Scholar] [CrossRef]
  11. Henyecz, R.; Keglevich, G. New developments on the Hirao reactions, especially from “green” point of view. Curr. Org. Synth. 2019, 16, 523–545. [Google Scholar] [CrossRef] [PubMed]
  12. Kalek, M.; Stawinski, J. Pd(0)-catalyzed phosphorus−carbon bond formation. Mechanistic and synthetic studies on the role of the palladium sources and anionic additives. Organometallics 2007, 26, 5840–5847. [Google Scholar] [CrossRef]
  13. Belabassi, Y.; Alzghari, S.; Montchamp, J.-L. Revisiting the Hirao cross-coupling: Improved synthesis of aryl and heteroaryl phosphonates. J. Organomet. Chem. 2008, 693, 3171–3178. [Google Scholar] [CrossRef] [PubMed]
  14. Deal, E.L.; Petit, C.; Montchamp, J.-L. Palladium-catalyzed cross-coupling of H-phosphinate esters with chloroarenes. Org. Lett. 2011, 13, 3270–3273. [Google Scholar] [CrossRef]
  15. Kalek, M.; Jezowska, M.; Stawinski, J. Preparation of arylphosphonates by palladium(0)-catalyzed cross-coupling in the presence of acetate additives: Synthetic and mechanistic studies. Adv. Synth. Catal. 2009, 351, 3207–3216. [Google Scholar] [CrossRef]
  16. Jablonkai, E.; Keglevich, G. P-ligand-free, microwave-assisted variation of the Hirao reaction under solvent-free conditions; the P–C coupling reaction of >P(O)H species and bromoarenes. Tetrahedron Lett. 2013, 54, 4185–4188. [Google Scholar] [CrossRef]
  17. Keglevich, G.; Jablonkai, E.; Balázs, L.B. A “green” variation of the Hirao reaction: The P–C coupling of diethyl phosphite, alkyl phenyl-H-phosphinates and secondary phosphine oxides with bromoarenes using a P-ligand-free Pd(OAc)2 catalyst under microwave and solvent-free conditions. RSC Adv. 2014, 4, 22808–22816. [Google Scholar] [CrossRef]
  18. Keglevich, G.; Henyecz, R.; Mucsi, Z.; Kiss, N.Z. The palladium acetate-catalyzed microwave-assisted Hirao reaction without an added phosphorus ligand as a “green” protocol: A quantum chemical study on the mechanism. Adv. Synth. Catal. 2017, 359, 4322–4331. [Google Scholar] [CrossRef]
  19. Henyecz, R.; Mucsi, Z.; Keglevich, G. Palladium-catalyzed microwave-assisted Hirao reaction utilizing the excess of the diarylphosphine oxide reagent as the P-ligand; a study on the activity and formation of the "PdP2" catalyst. Pure Appl. Chem. 2019, 91, 121–134. [Google Scholar] [CrossRef]
  20. Keglevich, G.; Henyecz, R.; Mucsi, Z. Focusing on the catalysts of the Pd- and Ni- catalyzed Hirao reactions. Molecules 2020, 25, 3897. [Google Scholar] [CrossRef]
  21. Ueoka, K.; Tanaka, D.; Arai, T.; Ichihashi, Y. Phosphine oxide derivative and light-emitting element provided with same. WO2014057873A1, 17 April 2014. [Google Scholar]
  22. Crawford, J.; Zak, M.; Kellar, T.; Cheng, Y.X.; Li, W.; Romero, A.F.; Gibbons, P.; Zhao, G.; Hamilton, G.; Goodacre, S.C. Pyrazole derivatives, compositions and therapeutic use thereof. WO2017191098A1, 9 November 2017. [Google Scholar]
  23. Marx, M.A.Z.; Lee, M.R.; Bobinski, T.P.; Burns, A.C.; Arora, N.; Christensen, J.G.; Ketcham, J.N. PRC2 inhibitors. WO2019152419A1, 8 August 2019. [Google Scholar]
  24. Baillie, C.; Xiao, J. Palladium-catalysed synthesis of biaryl phosphines. Tetrahedron 2004, 60, 4159–4168. [Google Scholar] [CrossRef]
  25. Zhang, Z.; Smal, V.; Retailleau, P.; Voituriez, A.; Frison, G.; Marinetti, A.; Guinchard, X. Tethered counterion-directed catalysis: Merging the chiral ion-pairing and bifunctional ligand strategies in enantioselective gold(I) catalysis. J. Am. Chem. Soc. 2020, 142, 3797–3805. [Google Scholar] [CrossRef]
  26. Bonnaventure, I.; Charette, A.B. Probing the importance of the hemilabile site of bis(phosphine) monoxide ligands in the copper-catalyzed addition of diethylzinc to N-phosphinoylimines: Discovery of new effective chiral ligands. J. Org. Chem. 2008, 73, 6330–6340. [Google Scholar] [CrossRef] [PubMed]
  27. Zhang, X.; Liu, H.; Hu, X.; Tang, G.; Zhu, J.; Zhao, Y. Ni(II)/Zn catalyzed reductive coupling of aryl halides with diphenylphosphine oxide in water. Org. Lett. 2011, 13, 3478–3481. [Google Scholar] [CrossRef] [PubMed]
  28. Keglevich, G.; Henyecz, R.; Mucsi, Z. Experimental and theoretical study on the “2,2′-bipiridyl-Ni-catalyzed” Hirao reaction of >P(O)H reagents and halobenzenes: A Ni(0) → Ni(II) or a Ni(II) → Ni(IV) mechanism? J. Org. Chem. 2020, 85, 14486–14495. [Google Scholar] [CrossRef]
  29. Xuan, J.; Zeng, T.T.; Chen, J.; Lu, L.Q.; Xiao, W.J. Room temperature C–P bond formation enabled by merging nickel catalysis and visible-light-induced photoredox catalysis. Chem. Eur. J. 2015, 21, 4962–4965. [Google Scholar] [CrossRef] [PubMed]
  30. Stankevic, M.; Wlodarczyk, A. Efficient copper(I)-catalyzed coupling of secondary phosphine oxides with aryl halides. Tetrahedron 2013, 69, 73–81. [Google Scholar] [CrossRef]
  31. Karlstedt, N.B.; Beletskaya, I.P. Copper-catalyzed cross-coupling of diethyl phosphonate with aryl iodides. Russ. J. Organ. Chem. 2011, 47, 1011–1014. [Google Scholar] [CrossRef]
  32. Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. Proline/pipecolinic acid-promoted copper-catalyzed P-arylation. J. Org. Chem. 2006, 71, 5020–5022. [Google Scholar] [CrossRef]
  33. Pan, L.; Kelley, A.S.; Cooke, V.M.; Deckert, M.M.; Laulhé, S. Transition-metal-free photoredox phosphonation of aryl C–N and C–X bonds in aqueous solvent mixtures. ACS Sustainable Chem. Eng. 2022, 10, 691–695. [Google Scholar] [CrossRef]
  34. Zöllner, M.; Rothe, C. Semiconducting material comprising a phosphine oxide matrix and metal salt. WO2015052284A1, 16 April 2015. [Google Scholar]
  35. Dong, J.; Liu, L.; Ji, X.; Shang, Q.; Liu, L.; Su, L.; Chen, B.; Kan, R.; Zhou, Y.; Yin, S.-F.; et al. General oxidative aryl C–P bond formation through palladium-catalyzed decarbonylative coupling of aroylhydrazides with P(O)H compounds. Org. Lett. 2019, 21, 3198–3203. [Google Scholar] [CrossRef] [PubMed]
  36. Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. A versatile and efficient ligand for copper-catalyzed formation of C–N, C–O, and P–C bonds: Pyrrolidine-2-phosphonnic acid phenyl monoester. Chem. Eur. J. 2006, 12, 3636–3646. [Google Scholar] [CrossRef] [PubMed]
  37. Shaikh, R.S.; Düsel, S.J.S.; Koenig, B. Visible-light photo-Arbuzov reaction of aryl bromides and trialkyl phosphites yielding aryl phosphonates. ACS Catal. 2016, 6, 8410–8414. [Google Scholar] [CrossRef]
Scheme 1. P–C coupling of 4-bromophenyl-(diphenylphosphine oxide) with (EtO)2P(O)H.
Scheme 1. P–C coupling of 4-bromophenyl-(diphenylphosphine oxide) with (EtO)2P(O)H.
Catalysts 12 01080 sch001
Table 2. P–C coupling reactions of 1,4-dibromobenzene.
Table 2. P–C coupling reactions of 1,4-dibromobenzene.
Catalysts 12 01080 i002
EntryYP-Reagent (equiv.)t
(min)
Conversion
(%) a
Product Composition (%) aIsolated Yield of 1 (%)
12Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)
1Ph (a)1.15301008567 (A)263 (1a)
2Ph (a)2.1560981541 b16 (A) c26 d
3EtO (b)1.1560996918 e12 (B) fn. r.48 (1b)
a Based on 31P NMR. b δP (CDCl3) 29.8, δP lit. [27] (CDCl3) 36.8; [M + H]+ = 479.1323 C30H25O2P2 requires 479.1330. c δP (CDCl3) 31.4, δP lit. [17] (CDCl3) 32.2; [M + H]+ = 247.0882, C14H16O2P requires 247.0888. d δP (CDCl3) 29.2, δP lit. [28] (CDCl3) 29.5; [M + H]+ = 279.0941, C18H16OP requires 279.0939. e δP (CDCl3) 16.9, δP lit. [33] (CDCl3) 16.8; [M + H]+ = 351.1121 C14H25O6P2 requires 351.1126. f δP (CDCl3) 18.8, δP lit. [32] (CDCl3) 19.4; [M + H]+ = 215.0827, C10H16O3P requires 215.0837. n. r.: not relevant.
Table 3. P–C coupling reactions of 4-bromo-iodobenzene.
Table 3. P–C coupling reactions of 4-bromo-iodobenzene.
Catalysts 12 01080 i003
EntryYP-Reagent
(equiv.)
T (°C)t (min)Conversion (%) aProduct Composition (%) aIsolated Yield of 1 (%)
12Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)
1Ph (a)1.15 b10060100962 (A)274 (1a)
2Ph (a)1.15 b12030100972 (A)175 (1a)
3Ph (a)2.15 b1206010019428 (A)31
4EtO (b)1.15 b12030988873 (B)n. r.63 (1b)
5EtO (b)2.3 c120301001387n. r.65 (2b)
a Based on 31P NMR. b In the presence of 5 mol% Pd(OAc)2 catalyst. c In the presence of 10 mol% Pd(OAc)2 catalyst. n. r.: not relevant.
Table 4. P–C coupling reactions of 1,3-dibromobenzene.
Table 4. P–C coupling reactions of 1,3-dibromobenzene.
Catalysts 12 01080 i004
EntryYP-Reagent (equiv.)T (°C)t (min)SolventConversion (%) aProduct Composition (%) aIsolated Yield (%)
34Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)
1Ph (a)1.1512025EtOH1008564 (A)568 (3a)
2Ph (a)2.1512030EtOH1002922 (A)475 (4a)
3EtO (b)1.1512060EtOH945727 b10 (B)n. r.
4EtO (b)1.1515030976324 b10 (B)n. r.45 (3b)
a Based on 31P NMR. b δP (CDCl3) 16.9; [M + H]+ = 351.1123 C14H25O6P2 requires 351.1126. n. r.: not relevant.
Table 5. P–C coupling reactions of 3-bromo-iodobenzene.
Table 5. P–C coupling reactions of 3-bromo-iodobenzene.
Catalysts 12 01080 i005
EntryYP-Reagent
(equiv.)
T (°C)t (min)SolventConversion
(%) a
Product Composition (%) aIsolated Yield (%)
34Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)
1Ph (a)1.1510060EtOH100941 (A)578 (3a)
2Ph (a)1.1512030EtOH1009531 (A)275 (3a)
3Ph (a)2.1512035EtOH97883 (A)670 (4a)
4EtO (b)1.15120309881134 (B)n. r.66 (3b)
a Based on 31P NMR. n. r.: not relevant.
Table 6. P–C coupling reactions of 3-chloro-bromobenzene.
Table 6. P–C coupling reactions of 3-chloro-bromobenzene.
Catalysts 12 01080 i006
EntryYt (min)Isolated Yield of 5 (%)
1Ph (a)6080 (5a)
2EtO (b)4582 (5b)
Table 7. P–C coupling reactions of 1,2-dibromobenzene.
Table 7. P–C coupling reactions of 1,2-dibromobenzene.
Catalysts 12 01080 i007
EntryYP-Reagent
(equiv.)
t
(min)
SolventConversion
(%) a
Product Composition (%) aIsolated Yield of 6 (%)
67Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)
1Ph (a)1.15 b60EtOH100 c2019 d48
2Ph (a)1.3 e60EtOH1002020 d2 (A)58
3EtO (b)1.15 b30EtOH963066 (B)n. r.
4EtO (b)1.15 b30816912 (B)n. r.41 (6b)
5EtO (b)1.3 e451007416 (B)n. r.60 (6b)
a Based on 31P NMR. b In the presence of 5 mol% Pd(OAc)2 catalyst. c 13% Ph2P(O)OH, δP (CDCl3) 28.2; [M + H]+ = 219.0568, C12H12O2P requires 219.0575. d δP (CDCl3) 31.4, [M + H]+ = 479.1329, C30H25O2P2 requires 479.1330. e In the presence of 10 mol% Pd(OAc)2 catalyst. n. r.: not relevant.
Table 8. P–C coupling reactions of 1-bromo-2-iodobenzene.
Table 8. P–C coupling reactions of 1-bromo-2-iodobenzene.
Catalysts 12 01080 i008
EntryYP-Reagent
(equiv.)
t (min)SolventConversion
(%) a
Product Composition (%) aIsolated Yield (%)
6Ph2(EtO)P(O) (A)
or
Ph(EtO)2P(O) (B)
Ph3P(O)Ph2P(O)OH
1Ph (a)1.15 b60EtOH100659 (A)1115 c45 (6a)
2Ph (a)1.3 d60EtOH1006611 (A)1112 c
3EtO (b)1.3 d45EtOH953636 (B)n. r.n. r.
4EtO (b)1.3 d45100919 (B)n. r.n. r.75 (6b)
5EtO (b)1.15 b30856916 (B)n. r.n. r.43 (6b)
a Based on 31P NMR. b In the presence of 5 mol% Pd(OAc)2 catalyst. c δP (CDCl3) 28.2; [M + H]+ = 219.0568, C12H12O2P requires 219.0575. d In the presence of 10 mol% Pd(OAc)2 catalyst. n. r.: not relevant.
Table 9. P–C coupling reactions of 3-bromophenyl(diphenylphosphine oxide) with Ph2P(O)H and (EtO)2P(O)H reagents.
Table 9. P–C coupling reactions of 3-bromophenyl(diphenylphosphine oxide) with Ph2P(O)H and (EtO)2P(O)H reagents.
Catalysts 12 01080 i009
EntryYProduct Composition (%) aIsolated Yield (%)
4a or 9(EtO)Ph2P(O)Ph3P(O)Ph2P(O)OH
1Ph (a)91 (4a)34267 (4a)
2EtO (b)87 (9)n. r.13n. r.64 (9)
a Based on 31P NMR. n. r.: not relevant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Huszár, B.; Varga, P.R.; Szűcs, N.Á.; Simon, A.; Drahos, L.; Keglevich, G. Pd-Catalyzed Hirao P–C Coupling Reactions with Dihalogenobenzenes without the Usual P-Ligands under MW Conditions. Catalysts 2022, 12, 1080. https://doi.org/10.3390/catal12101080

AMA Style

Huszár B, Varga PR, Szűcs NÁ, Simon A, Drahos L, Keglevich G. Pd-Catalyzed Hirao P–C Coupling Reactions with Dihalogenobenzenes without the Usual P-Ligands under MW Conditions. Catalysts. 2022; 12(10):1080. https://doi.org/10.3390/catal12101080

Chicago/Turabian Style

Huszár, Bianka, Petra Regina Varga, Nóra Á. Szűcs, András Simon, László Drahos, and György Keglevich. 2022. "Pd-Catalyzed Hirao P–C Coupling Reactions with Dihalogenobenzenes without the Usual P-Ligands under MW Conditions" Catalysts 12, no. 10: 1080. https://doi.org/10.3390/catal12101080

APA Style

Huszár, B., Varga, P. R., Szűcs, N. Á., Simon, A., Drahos, L., & Keglevich, G. (2022). Pd-Catalyzed Hirao P–C Coupling Reactions with Dihalogenobenzenes without the Usual P-Ligands under MW Conditions. Catalysts, 12(10), 1080. https://doi.org/10.3390/catal12101080

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop