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

Abstract

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

Introduction

A heteroatomic variation of the cross-coupling reactions is the C–P coupling discovered by Hirao in 1980.^1,2 Since then, this new reaction between bromoarenes and dialkyl phosphites or secondary phosphine oxides providing dialkyl arylphosphonates or tertiary phosphine oxides has become an important method.³⁻⁵ The original Pd(PPh₃)₄ catalyst was replaced by Pd(II) salts used together with mono- and bidentate P-ligands, and the scope of the reaction components was extended.^6,7 The mechanism was evaluated.^6,8 Efforts were made to perform the P–C coupling under green chemical conditions.^9,10 Later on, Ni- and Cu-catalyzed versions were also elaborated.^3,4,11,12

The Hirao reaction of arylboronic acids with different >P(O)H reagents is a less-studied field. The coupling of arylboronic acids with diphenylphosphine oxide, ethyl phenyl-H-phosphinate, and diethyl phosphite was best performed at 90 °C for 24 h applying Pd(OAc)₂/bis(diphenylphosphino)butane (dppb) as the catalyst system, K₂CO₃ as the base in 1,4-dioxane as the solvent with the use of air as an oxidant. The corresponding tertiary phosphine oxides, phosphinates, and phosphonates were obtained in 48–94% yields after a reaction time of 24 h.¹³ The second example for the Pd(II) salt-catalyzed case is the microwave (MW)-assisted reaction of arylboronic acids with diethyl phosphite in the presence of Pd(OAc)₂/2,9-dimethyl-1,10-phenantroline (dmphen) in dimethylformamide. After an irradiation at 100 °C for 20–30 min, the dialkyl arylphosphonates were obtained in yields of 51–90%. The couplings were promoted by the addition of p-benzoquinone as an oxidating agent.¹⁴ A series of pyridylboronic acids also underwent the coupling reaction with dialkyl phosphites at 100 °C, in this case, using PdCl₂/PPh₃ as the catalyst precursor in N-,N-dimethylacetamide, in the presence of Ag₂O as an additive. After a 2 h reaction time, the yields fell in the range of 51–95%.¹⁵ A NiBr₂/pyridine-catalyzed coupling of arylboronic acids and mainly diarylphosphine oxides carried out at 100 °C for 24 h in dichloroethane in the presence of K₂CO₃ furnished the corresponding triarylphosphine oxides in variable 5–99% yields.¹⁶ Last but not least, Cu₂O/1,10-phenantrolin (phen) and a special Cu(II) complex were also applied as catalysts at 26 °C for 24–72 h in the reaction under discussion to provide dialkyl arylphosphonates in variable yields (47–96%) using diisopropylethylamine in acetonitrile and KOAc in tetrahydrofuran, respectively.^17,18 The disadvantages of the coupling reactions with arylboronic acids include the need, in most cases, for bidentate P-ligands or N-ligands, variable yields, and often long reaction times. In the Pd(II)/(bidentate) phosphine-catalyzed cases, the involvement of an oxidizing agent (even air) may seem somewhat unusual, as in the P–C coupling of bromoarenes, there was no need for this actor.

In the past few years, we developed a P–C coupling, where it was not necessary to add the usual mono- or bidentate P-ligands. Under MW conditions, the reaction between bromoarenes and >P(O)H reagents (dialkyl phosphites and secondary phosphine oxides) took place if the catalyst precursor, Pd(OAc)₂ was combined with some excess of the P-reagent.¹⁹ The point was that the trivalent tautomeric form (>P–OH) of the >P(O)H species may act as a ligand to Pd(0). Upon applying 10% of the Pd(II) salt, there was a need for 30% extra quantity of the P-reagent. One equivalent of the >P(O)H species to the precursor ensured the Pd(II) → Pd(0) reduction, while the remaining two equivalent quantities served as the P-ligands to Pd(0).²⁰ The detailed mechanism for the “P-ligand-free” Hirao reaction was explored by high-level quantum chemical calculations.^20,21 It was found that the rate-determining step is the reagent insertion into the Pd complex or the Pd–C bond formation that may be promoted by MW assistance. Our procedure meant a green approach, as there was no need to add the usual expensive P-ligands; hence, cost and environmental burden can be saved. Regarding atomic efficiency, starting from arylboronic acids means an advantage over the variation applying bromoarenes, not speaking about the fact that the former protocol is halogen-free. It was a challenge for us to develop a new protocol combining the halogen-free option with our MW-assisted method lacking the use of the usual P-ligands. It was another challenge to justify the need for an oxidizing agent and to evaluate the mechanism.

Results and Discussion

Preparative Results

The coupling of phenylboronic acid with diphenylphosphine oxide was chosen as the basic model of the MW-assisted Pd-catalyzed process. 10 mol % Pd(OAc)₂ was applied as the catalyst precursor at 135 °C using different bases in a quantity of 1.1 equiv and acetonitrile or ethanol as the solvent. The P-reagent was measured in a 1.2 equiv quantity in order to provide the two Ph₂POH ligands. We worked at aerobic conditions (Table 1). The crude reaction mixtures were analyzed by ³¹P NMR and liquid chromatography–mass spectrometry (LC–MS). Performing the reaction in the presence of Cs₂CO₃ in acetonitrile, after a 2.5 h irradiation the conversion was 80% (Table 1, entry 1). The next run carried out in ethanol was complete after 1.5 h (Table 1, entry 2). In this case, 5% of ethyl diphenylphosphinate could be detected as a byproduct. 1,4-Dioxane was also a suitable solvent under similar conditions (Table 1, entry 3). Changing for K₂CO₃, a treatment at 135 °C for 2.5 h in acetonitrile also led to almost quantitative (96%) conversion (Table 1, entry 4). However, the accomplishment in ethanol was more efficient, as required a shorter irradiation time of 1.5 h (Table 1, entry 5). Only 3% of (EtO)Ph₂PO contaminated the product (1a). The use of triethylamine as the base led, after a treatment of 1.5 h, in both solvents to low (11/22%) conversions (Table 1, entries 6 and 7). From the best experiments (marked by entries 2–4), triphenylphosphine oxide (1a) was obtained in 78–81% yields after flash column chromatography. Under an inert atmosphere, the P–C coupling did not take place.

Table 1. Optimization of the Coupling Reaction between Phenylboronic Acid and Diphenylphosphine Oxide.

					product composition (%)a,b
entry	base	solvent	t (h)	conversion (%)a	1a	(EtO)Ph2PO	yield (%) of 1a
1	Cs2CO3	MeCN	2.5c	80	80
2c	Cs2CO3	EtOH	1.5	100	95	5	83
3	Cs2CO3	dioxane	1.5	100	100		79
4	K2CO3	MeCN	2.5d	96	96		78
5	K2CO3	EtOH	1.5	100	97	3	80
6	Et3N	MeCN	1.5	11	11
7	Et3N	EtOH	1.5	22	22

^aOn the basis of relative ³¹P NMR intensities.

^bThe average of two or three parallel experiments.

^cThe coupling was also performed on a larger scale applying 1.0 mmol of PhB(OH)₂ and 1.2 mmol of Ph₂P(O)H. In this case, the yield of 1a was 87%.

^dThe extrapolated reaction time is 3 h.

In general, the couplings were performed using 0.41 mmol of the phenylboronic acid. Carrying out the reaction on a 1.0 mmol scale, the yield of Ph₃PO was 87% (footnote “c” of Table 1/entry 2). As a comparison, 10% Pd(PPh₃)₄ was also tested in the coupling reaction of phenylboronic acid with Ph₂P(O)H at 135 °C for 1.5 h using 1.1 equiv of Cs₂CO₃ in ethanol. In this case, the reaction was not entirely clear-cut, and the yield of Ph₃PO was 65%.

In the next series of experiments, the reaction of phenylboronic acid with different >P(O)H reagents was investigated at 135 °C applying 10 mol % Pd(OAc)₂ as the catalyst precursor. The base/solvent combinations included Cs₂CO₃/EtOH and K₂CO₃/MeCN (Table 2). The coupling with bis(4-methylphenyl)phosphine oxide was somewhat slower than that with Ph₂P(O)H, no matter if it was carried out using Cs₂CO₃ in EtOH or K₂CO₃ in MeCN (Table 2, entries 3 and 4 vs entries 1 and 2). After an irradiation of 2 and 3 h, respectively, the conversion was complete. Beyond the 85/81% proportion of the expected bis(4-methylphenyl)-phenylphosphine oxide (1b), there was 15/19% of tris(4-methylphenyl)phosphine oxide as the byproduct (Table 2, entries 3 and 4). A similar situation was observed, when bis(3,5-dimetylphenyl)phosphine oxide was the reagent; however, in this instance, the coupling became even slower, as the complete conversion required a reaction time of 2.5 and 4 h, respectively (Table 2, entries 5 and 6). Diaryl-phenylphosphine oxide 1c was formed in 88 and 79%, respectively. The corresponding tris(3,5-dimethylphenyl)phosphine oxide was present in the mixture as a minor (12/21%) byproduct. From the best experiments, the diaryl-phenylphosphine oxides 1a–c were isolated in yields of 74–83% after chromatography. Changing for diethyl phosphite, the coupling with phenylboronic acid was slower at 135 °C, as the completion took 4 h (Table 2, entry 7). However, at 150 °C, an irradiation of 0.5 h was enough (Table 2, entry 8). In both cases, the reaction was clear-cut, and diethyl phenylphosphonate (1d) was obtained in 84/82% yield after purification. The combination of K₂CO₃/MeCN was, in this case, less efficient: after an irradiation at 135 °C for 4 h, the conversion was only 63% (Table 2, entry 9). However, at 150 °C/2 h, phosphonate 1d was the only product prepared in 73% yield (Table 2, entry 10). The next >P(O)H reagent, ethyl phenyl-H-phosphinate behaved similarly as (EtO)₂P(O)H, and complete conversion could be attained after 4 h at 135 °C or 0.5 h at 150 °C (Table 2, entries 11 and 12). In the latter instance, 9% of (EtO)₂PhPO also appeared in the crude mixture. Ethyl diphenylphosphinate (1e) was isolated in 82/86% yields.

Table 2. Coupling Reaction between Phenylboronic Acid and Different >P(O)H Reagents.

						product composition (%)a,b
entry	Y1, Y2	base	solvent	t (h)	conversion (%)a	1	Ar3PO	yield (%)
1	Ph	Cs2CO3	EtOH	1.5	100b	95c		83 (1a)
2	Ph	K2CO3	MeCN	2.5	96	96		78 (1a)
3	4-MeC6H4	Cs2CO3	EtOH	2	100	85	15	78 (1b)
4	4-MeC6H4	K2CO3	MeCN	3	100	81	19	72 (1b)
5	3,5-diMeC6H3	Cs2CO3	EtOH	2.5	100	88	12	74 (1c)
6	3,5-diMeC6H3	K2CO3	MeCN	4	100	79	21	56 (1c)
7	EtO	Cs2CO3	EtOH	4	100	100		84 (1d)
8	EtO	Cs2CO3	EtOH	0.5d	100	100		82 (1d)
9	EtO	K2CO3	MeCN	4	63	63
10	EtO	K2CO3	MeCN	2d	100	100		73 (1d)
11	EtO, Ph	Cs2CO3	EtOH	4	100	100		82 (1e)
12	EtO, Ph	Cs2CO3	EtOH	0.5d	100	91e		86 (1e)

^aOn the basis of relative ³¹P NMR intensities.

^bThe average of two or three parallel experiments.

^c5% of (EtO)Ph₂PO as the byproduct.

^dThe temperature was 150 °C.

^e9% of (EtO)₂PhPO as the byproduct.

In the next round, Ph₂P(O)H was reacted with a series of arylboronic acids, in the first approach, under the conditions applied above using Cs₂CO₃ in EtOH (Table 3). The coupling of 4-Me, 2-Me, 3-Me, and even the 4-F-substituted phenylboronic acids took place similarly as that with the unsubstituted PhB(OH)₂. Complete conversions were attained after an irradiation of 1.5 h at 135 °C. The proportion of the expected products (2f–i) was 71–87%, while that of the (EtO)Ph₂PO was 5–13%. Compounds 2f–i were prepared in 67–80% yield (Table 3, entries 2–5). It was surprising that the similar reaction of 4-chlorophenylboronic acid with 1.2 equiv of Ph₂P(O)H at 135 °C/1.5 h afforded 1,4-bis(diphenylphosphinoyl)benzene 3A. The crude mixture contained 49% of bisphosphinoyl compound 3A and 51% of Ph₃PO (Table 3, entry 6). There was no expected 4-chlorophenyl-diphenylphosphine oxide 2j in the mixture. Product 3A was isolated by chromatography in a yield of 23%. To promote the formation of the phosphinoyl-chlorobenzene 2j, the coupling was performed at a lower temperature of 90 °C for 4 h. Sure enough, the mixture comprised 46% of the monophosphinoyl product 2j, 5% of bisphosphinoyl 3A, 11% of (EtO)Ph₂PO, and 38% of Ph₃PO formed probably by dechlorination of 4-chlorophenyl-diphenylphosphine oxide (2j) (Table 3, entry 7). The small quantity of bisphosphinoyl compound 3A among the components referred to the crucial role of temperature on the selectivity toward the mono- and bisphosphinoylated products (2j and 3A). Repeating the previous P–C coupling on conventional heating at 90 °C/4 h, the conversion remained incomplete (77%), and the proportion of species 2j, 3A, and Ph₃PO was 12, 41, and 18%, respectively, suggesting that the competitive dechlorination of 4-chlorophenyl-diphenylphosphine oxide (2j) was suppressed, and hence, more bis(Ph₂P(O)) product (3A) could be formed (Table 3, entry 8). Returning to the result of the experiment marked by Table 3, entry 6, the low yield of 23% of the selective phosphinoylation may be explained by the fact that the 1.2 equiv quantity of Ph₂P(O)H was not enough. Considering that a quantitative bisphosphinoylation would require 2.4 equiv of Ph₂P(O)H, an experiment was carried out using this higher amount of the P-reactant. However, under such conditions, the proportion of bis-product 3A was not increased, and the excess of Ph₂P(O)H was involved in side reactions. In respect of the 3-chlorophenylboronic acid, the outcome of the P–C coupling with Ph₂P(O)H was similar to the reaction of the 4-chlorophenyl reagent. After an irradiation at 135 °C for 1.5 h, only 53% of bisphosphinoyl derivative 3B, 6% of (EtO)Ph₂PO, and 41% of Ph₃PO were present (Table 3, entry 10). The major component (3B) was isolated in a yield of 25%. Repeating the Hirao reaction at 90 °C for 4 h, the monophosphinoyl compound 2k was also present in 35%, beyond the 22% proportion of bis derivative 3B (Table 3, entry 11), and hence, the significant effect of the temperature was confirmed. In the thermal variation carried out, this occasion at 90 °C for 22 h, the proportion of 1,3-bis(diphenylphosphinoyl)benzene (3B) was increased to 44% (Table 3, entry 12). It can be noted that on MW irradiation, the statistically occurring local overheatings²² may cause the more intensive dechlorination of the primarily formed chlorophenyl-diphenylphosphine oxides (2j and 2k).

Table 3. P–C Coupling of Substituted Arylboronic Acids with Diphenylphosphine Oxide.

					product composition (%)a,b
entry	Z	T	t (h)	conversion (%)a	2	3	(EtO)Ph2PO	Ph3PO (1a)	yield (%)
1	H	135	1.5	100b	95 (1a)		5		83 (1a)
2	4-Me (f)	135	1.5	100	81		5	14	73 (2f)
3	2-Me (g)	135	1.5	100	71		13	16	67 (2g)
4	3-Me (h)	135	1.5	100	87		8	5	80 (2h)
5	4-F (i)	135	1.5	100	75		10	15	70 (2i)
6	4-Cl (j)	135	1.5	100		49 (3A)		51	23 (3A)
7	4-Cl (j)	90	4	100	46	5	11	38	(2j)c
8	4-Cl (j)	90d	4	77	12	41 (3A)	6	18
9	4-Cl (j)	135e	1	100		23 (3A)	5	72
10	3-Cl (k)	135	1.5	100		53 (3B)	6	41	25 (3B)
11	3-Cl (k)	90	4	96	35	22 (3B)	11	28	(2k)f
12	3-Cl (k)	90c	22	100	33	44 (3B)	4	19

^aOn the basis of relative ³¹P NMR intensities of the P-components.

^bThe average of two or three parallel experiments.

^c31P NMR (CDCl₃) δ 28.5, δ_P lit.²³ (CDCl₃) 28.2; HRMS (m/z): calcd for C₁₈H₁₅OPCl [M + H]⁺, 313.0549; found, 313.0542.

^dOn conventional heating.

^e2.4 equiv of Ph₂P(O)H was used.

^f31P NMR (CDCl₃) δ 28.1, δ_P lit.²⁴ (CDCl₃) 28.1; HRMS (m/z): calcd for C₁₈H₁₅OPCl [M + H]⁺, 313.0549; found, 313.0538.

Finally, the substituted arylboronic acids were reacted with diethyl phosphite measured in a 1.2 equiv quantity using Cs₂CO₃ as the base and EtOH as the solvent (Table 4). The couplings with 4-MePh-, 2-MePh-, 3-MePh-, and 4-FPh-boronic acids were efficient on irradiation at 150 °C for 30 min. The diethyl arylphosphonates (1d and 4f–i) were isolated in yields of 77–83% (Table 4, entries 1–7). The similar reactions of the 4-ClPh- and 3-ClPh-boronic acids carried out under similar conditions were accompanied by the formation of 19% and 16% of (EtO)₂PhPO (1d), respectively, and the expected products 4j and 4k could be obtained in 66/71% yields. The reductive dechlorination was a side reaction also in this case.

Table 4. Hirao Reaction between Substituted Arylboronic Acids and Diethyl Phosphite.

entry	Z	conversion (%)a	proportion of 4 (%)a,b	yield (%)
1	H	100	95	83 (1d)
2	4-Me	100	100	77 (4f)
3	2-Me	100	100	78 (4g)
4	3-Me	100	100	80 (4h)
5	4-F	100	100	77 (4i)
6	4-Cl	100c	81	66 (4j)
7	3-Cl	100d	84	71 (4k)

^aOn the basis of relative ³¹P NMR intensities.

^bThe average of two or three parallel experiments.

^c19% of (EtO)₂PhPO as the byproduct.

^d16% of (EtO)₂PhPO as the byproduct.

The diaryl-phenylphosphine oxides (1a–c), aryl-diphenylphosphine oxides (2f–i), diethyl arylphosphonates (1d, 4f–k), ethyl diphenylphosphinate (1e), and bisphosphinoyl derivatives 3A and 3B, all together 17 compounds, were prepared by the method developed, and they were fully characterized by ³¹P, ¹³C and ¹H NMR, as well as HRMS. The resulting phosphine oxides and related compounds may be utilized as P-ligands after deoxygenation.

Theoretical Calculations

There are only a few examples in the literature for Hirao reactions starting from arylboronic acids. There is no detailed mechanistic study for this version of the P–C coupling, and only a putative cycle was described.¹³ However, it occurred that an oxidant is needed to promote the reaction.¹³⁻¹⁵ Looking at the overall reaction, the +3 oxidation number of the P atom in the tautomeric form of diphenylphosphine oxide is increased to +5 in the product triphenylphosphine oxide (1a). At the same time, the oxidation numbers of the boron and carbon atoms of the boronic acid remains unchanged. The main process is exothermic (Figure 1). We confirm that during the course of the reaction, Pd²⁺ is reduced to Pd⁰ that is then oxidized back by the oxygen present. The O₂ is reduced from the state 0 to −2 during the transformation.

Figure 1.

Overall transformation and reaction enthalpy (ΔH_R), as well as Gibbs free energy (ΔG_R) for the Hirao reaction of Ph₂P(O)H with phenylboronic acid.

First, we explored a complex equilibrium of Pd(OAc)₂ in the presence of excess of Ph₂P(O)H as the ligand (L), including two-, three-, and tetraligations to afford species 5, 6, and 7, respectively. The tautomeric form Ph₂POH of Ph₂P(O)H is able to organize a strong hydrogen bond net around the Pd²⁺. An inorganic base (e.g., K₂CO₃) may deprotonate one or two Ph₂POH units to provide complexes 8, 9, and 10, and as a consequence, the bonded Ph₂POH pairs are stabilized, forming one (as in 8 or 9) or two (as in 10) quasi bidentate ligands (Figure 2). This spontaneous arrangement around the Pd²⁺ ion may be considered, as if a self-assembling bidentate P-ligand or two bidentate P-ligands were (indicated as Q; blue diamonds) around the central Pd²⁺ion. Formation of the tetraligated Pd²⁺ complex (10) is the most favorable in the series. This quasi bidentate anionic ligands activate the Pd²⁺ center for the coupling reaction.

Figure 2.

Equilibrium system of complexes formed from Pd²⁺ and Ph₂P(O)H.

Then, we studied the catalytic cycle (Figure 3). In the first step, the boronic acid is deprotonated by the base present. Then, a weak π-complex (6) is formed between the Pd²⁺ center of the catalyst complex and the aryl ring of the boronic acid anion (ΔH = −11.6 kJ mol^–1). The π-complex (11) is transformed to the σ-complex (13) via a well-determined TS (12) with a +117.9 kJ mol^–1 enthalpy gap, which can be considered as a moderate barrier at elevated reaction temperature. The resulting σ-complex with an aryl anion (13) is of a high enthalpy content (106.2 kJ mol^–1). The elimination of metaboric acid (HOBO) is favorable, but the entry of an additional Ph₂POH ligand leading to complex 15 with an enthalpy of −7.3 kJ mol^–1 is the real driving force. In the next step, the aryl anion is transferred from the central Pd²⁺ to the P atom of the adjacent ligand via TS 16 with a lower enthalpy content of 77.8 kJ mol^–1 yielding the final tiphenylphosphine oxide (1a). During the reductive elimination step, the Pd²⁺ is converted to Pd⁰. Finally, the Pd⁰ is regenerated to Pd²⁺ by reaction with the O₂ of air. Then, the catalytic cycle may start again. The enthalpy diagram for the P–C coupling under discussion can be seen in Figure 4. The suggested mechanism comprises two steps (involving transition states 12 and 16), which have impact on the overall reaction rate. As the first step leading to transition state 12 exhibits the higher enthalpy barrier, the route via species 12 is the rate-determining step. The overall reaction enthalpy follows a slightly exothermic run until the formation of the triphenylphosphine oxide (1a) that is connected with the elimination of Pd⁰ complex 17. However, the subsequent reoxidation of Pd⁰ complex 17 to Pd²⁺ catalyst 18 with the oxygen of air is rather exothermic, making the “quasi” catalytic process irreversible.

Figure 3.

Formation of the desired triphenylphosphine oxide (1a) via a Pd-catalyzed reaction cycle.

Figure 4.

Enthalpy diagram for the Pd(OAc)₂-catalyzed P–C coupling reaction of phenylboronic acid and diphenylphosphine oxide.

During the P–C coupling of Ph₂P(O)H and arylboronic acids, a significant amount of triphenylphosphine oxide (1a) was also formed beside the expected aryl-diphenylphosphine oxide (2f–k) as discussed above (Table 3). In the case of 4-chlorophenyl- and 3-chlorophenylboronic acid, the dehalogenation by the Pd catalyst may also be a reasonable side reaction; however, for the 4-, 2- and 3-methylphenyl- and 4-fluorophenylboronic acid derivatives, the question arises how the triphenylphosphine oxide (1a) byproduct may be formed. Well, catalyst complex 18 may take up a Ph₂POH ligand to give complex 9 (Figure 5). Migration of the phenyl ring from the Pd²⁺ to the adjacent P atom via transition state 19 leads to key intermediate 20, which then enters into the previously discussed catalytic process, yielding triphenylphosphine oxide (1a) without the involvement of the arylboronic acid. The activation enthalpy for the 9 → 20 transformation is ca 200 kJ mol^–1 that is significantly higher than the activation barrier of the rate-determining step of the main reaction (117.9 kJ mol^–1). For this, the side reaction remains a minor component. The other byproduct, Ph₂P(O)OEt may be formed by the P–C coupling of Ph(OEt)(OH) (22) with Ph₂P(O)H. Species 22 is the result of the interaction of intermediate 21 and ethanol.

Figure 5.

Proposed route for the formation of the triphenylphosphine oxide (1a) and ethyl diphenylphosphine oxide side products.

Conclusions

In summary, the less applied, halogene-free Hirao reaction of arylboronic acids and a series of >P(O)H reagents, such as diarylphosphine oxides, diethyl phosphite, and ethyl phenyl-H-phosphinate, was studied in detail. Another green aspect was that not traditional (cost-meaning and environment-burdening) mono- or bidante P-ligands were used to serve the P-ligand to the Pd(OAc)₂ precursor (10%) but the excess (20%) of the >P(O)H reagent via its >P–OH trivalent tautomer form. MW assistance enhanced the P–C couplings that were optimized for the different substituted cases. Theoretical calculations supported that there is no oxidative addition step, as the primary Pd²⁺/>P–OH···^–O–P< complex remains unchanged during the addition of the aryl anion and the addition of the tautomer form of the P-reagent. In the last reductive elimination step, the central Pd²⁺ ion of the catalyst is reduced to Pd⁰. For this, it is necessary to apply a stoichiometric oxidant, that is, in our case, air. The ligation of Pd²⁺ with two >P(O)H units that form a dimer-like associate enhances the reactivity of the central Pd²⁺ in complexation with the aryl anion. Formation of the typical byproducts, e.g., (EtO)Ph₂PO and Ph₃PO, the latter formed also by dechlorination, was also explained.

Experimental Section

General Information

The reactions were carried out in a CEM Discover Model SP (300 W) focused microwave reactor (CEM Microwave Technology Ltd., Buckingham, U.K.) equipped with a stirrer and a pressure controller using 80–100 W irradiation under isothermal conditions. The reaction mixtures were irradiated in sealed 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 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, in CDCl₃ solution. 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) in high-resolution, positive electrospray mode. The melting points of products 1a, 1b, 1c, 2f, 2g, 2h, 2i, and 3A were determined using a Setaram differential scanning calorimetry 92 device.

General Procedure for the P–C Coupling of Phenylboronic Acid and >P(O)H Reagents (Table 2, Entries 1, 3, 5, 8, and 12)

To a MW glass vessel were added 1 mL of ethanol, 0.038 mmol (0.0085 g) of Pd(OAc)₂, 0.41 mmol (0.050 g) of phenylboronic acid, 0.49 mmol of diarylphosphine oxide [diphenylphosphine oxide: 0.10 g, bis(4-methylphenyl)phosphine oxide: 0.11 g, bis(3,5-dimethylphenyl)phosphine oxide: 0.13 g], 0.49 mmol (0.063 mL) of diethyl phosphite, or 0.49 mmol (0.074 mL) of ethyl phenyl phosphinate, and 0.45 mmol (0.15 g) of cesium carbonate. Then, the vial was closed and irradiated in the MW reactor isothermally at 135–150 °C for 0.5–2.5 h (Table 2, entries 1, 3, 5, 8, and 12). The reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after evaporation of the filtrate was filtered through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluant. The crude mixture was analyzed by ³¹P NMR spectroscopy. Then, if the sample was relevant, it was purified further by column chromatography (silica gel, ethyl acetate–hexane 1:1 as the eluant) to afford products 1a–e.

This procedure was repeated on a larger scale starting from 1.0 mmol (0.12 g) of phenylboronic acid, 1.2 mmol (0.24 g) of diphenylphosphine oxide, 1.1 mmol (0.36 g) of Cs₂CO₃, 0.10 mmol (0.022 g) of Pd(OAc)₂ and 3.5 ml of ethanol. After an irradiation at 135 °C for 1.5 h, the work-up was similar as above to furnish 0.24 g (87%) of Ph₃PO.

Following Compounds Were Thus Prepared

Triphenylphosphine Oxide (1a) (Table 2, Entry 1)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.087 g (83%) obtained as white crystals; mp. 156–157 °C, mp lit.²⁵ 156.6–157.4 °C; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 29.1, δ_P lit.²⁵ (162 MHz, CDCl₃) 29.5; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 132.7 (d, J = 103.8 Hz), 132.2 (d, J = 9.9 Hz,), 132.0 (d, J = 2.8 Hz), 128.6 (d, J = 12.1 Hz), δ_C lit.²⁵ (100 MHz, CDCl₃) 132.8 (d, J = 104.6 Hz), 132.5 (d, J = 9.9 Hz), 131.9 (d, J = 2.2 Hz), 128.4 (d, J = 12.1 Hz); ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.59 (m, 6H), 7.56–7.48 (m, 3H), 7.48–7.38 (m, 6H), δ_H lit.²⁵ (400 MHz, CDCl₃) 7.70–7.64 (m, 6H), 7.56–7.52 (m, 3H), 7.48–7.43 (m, 6H); HRMS (m/z): calcd for C₁₈H₁₆OP [M + H]⁺, 279.0939; found, 279.0941.

Bis(4-methylphenyl)phenylphosphine Oxide (1b) (Table 2, Entry 3)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.090 g (78%) obtained as white crystals; mp. 76 °C, mp lit.¹¹ 78–79 °C; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 27.8, δ_P lit.²⁶ (162 MHz, CDCl₃) 30.5; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 142.4 (d, J = 2.8 Hz), 133.1 (d, J = 104.1 Hz), 132.1 (d, J = 10.3 Hz), 132.1 (d, J = 9.8 Hz), 131.8 (d, J = 2.7 Hz), 129.4 (d, J = 106.6 Hz), 129.3 (d, J = 12.5 Hz), 128.5 (d, J = 12.1 Hz), 21.6 (s), δ_C lit.²⁶ (100 MHz, CDCl₃) 142.6 (d, J = 2.9 Hz), 133.0 (d, J = 102.5 Hz), 132.2 (d, J = 10.2 Hz), 132.0 (d, J = 8.7 Hz), 131.9 (d, J = 3.2 Hz), 129.4 (d, J = 106.9 Hz), 129.4 (d, J = 12.6 Hz), 128.6 (d, J = 11.8 Hz), 21.7; ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.61 (m, 2H), 7.61–7.47 (m, 5H), 7.47–7.37 (m, 2H), 7.32–7.18 (m, 4H), 2.39 (s, 6H); δ_H lit²⁶ (400 MHz, CDCl₃) 7.68–7.62 (m, 2H), 7.53 (dd, J₁ = 11.8 Hz, J₂ = 8.0 Hz, 4H), 7.48 (m, 1H), 7.24 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 4H), 2.38 (s, 6H); HRMS (m/z): calcd for C₂₀H₂₀OP [M + H]⁺, 307.1252; found, 307.1252.

Bis(3,5-dimethylphenyl)phenylphosphine Oxide (1c) (Table 2, Entry 5)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.094 g (74%) obtained as white crystals; mp. 159 °C, mp. lit.²⁶ 158.6–159.2 °C; ³¹P{¹H} NMR (121.5 MHz, CDCl₃): δ 29.6, δ_P lit.²⁶ (162 MHz, CDCl₃) 30.9; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 138.1 (d, J = 12.7 Hz), 133.7 (d, J = 2.8 Hz), 133.1 (d, J = 103.1 Hz), 132.4 (d, J = 105.3 Hz), 132.1 (d, J = 9.9 Hz), 131.7, 129.7 (d, J = 9.8 Hz), 128.4 (d, J = 12.0 Hz), 21.4 (s), δ_C lit.²⁶ (100 MHz, CDCl₃) 138.3 (d, J = 12.2 Hz), 133.9 (d, J = 2.3 Hz), 133.1 (d, J = 102.7 Hz), 132.4 (d, J = 102.6 Hz), 132.3 (d, J = 9.7 Hz), 131.9 (d, J = 2.2 Hz), 129.8 (d, J = 10.0 Hz), 128.6 (d, J = 11.7 Hz), 21.56; ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.62 (m, 2H), 7.55–7.39 (m, 3H), 7.28 (d, J = 12.2 Hz, 4H), 7.15 (s, 2H), 2.31 (s, 12H), δ_H lit.²⁶ (400 MHz, CDCl₃) 7.68–7.63 (m, 2H), 7.55–7.51 (m, 1H), 7.47–7.42 (m, 2H), 7.26 (d, J = 12.4 Hz, 4H), 7.15 (s, 2H), 2.31 (s, 12H); HRMS (m/z): calcd for C₂₂H₂₄OP [M + H]⁺, 335.1565; found, 335.1566.

Diethyl Phenylphosphonate (1d) (Table 2, Entry 8)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.068 g (84%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 18.9, δ_P lit.⁹ (162 MHz, CDCl₃) 18.8; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 132.5 (d, J = 3.0 Hz), 131.9 (d, J = 9.8 Hz), 128.6 (d, J = 15.0 Hz), 128.5 (d, J = 188.0 Hz), 62.2 (d, J = 5.4 Hz), 16.4 (d, J = 6.5 Hz), δ_C lit.⁹ (100 MHz, CDCl₃) 132.3 (d, J = 2.7 Hz), 131.7 (d, J = 9.2 Hz), 128.44 (d, J = 15.2 Hz), 128.41 (d, J = 187.6 Hz), 62.0 (d, J = 5.9 Hz), 16.3 (d, J = 6.5 Hz); ¹H NMR (300 MHz, CDCl₃) δ 7.84–7.71 (m, 2H), 7.56–7.37 (m, 3H), 4.21–3.97 (m, 4H), 1.29 (t, J = 7.1 Hz, 6H), δ_H lit.⁹ (400 MHz, CDCl₃) 7.82 (m, 2H), 7.55 (∼tq, J₁ = 7.5 Hz, J₂ = 1.4 Hz, 1H), 7.47 (m, 2H), 4.12 (m, 4H), 1.32 (td, J₁= 7.0 Hz, J₂ = 0.5 Hz, 6H); HRMS (m/z): calcd for C₁₀H₁₆O₃P [M + H]⁺, 215.0837; found, 215.0835.

Diphenyl Ethylphosphinate (1e) (Table 2, Entry 12)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.080 g (86%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 32.2, δ_P lit.²⁷ (120 MHz, CDCl₃) 30.8; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 132.0 (d, J = 2.8 Hz), 131.7 (d, J = 137.0 Hz), 131.6 (d, J = 10.1 Hz), 128.4 (d, J = 13.1 Hz), 61.1 (d, J = 5.9 Hz), 16.5 (d, J = 6.6 Hz), δ_C lit.²⁷ (75 MHz, CDCl₃) 139.9 (d, J = 11.1 Hz), 133.7 (d, J = 143.4 Hz), 130.9 (d, J = 12.9 Hz), 127.0, 59.0, 16.7; ¹H NMR (300 MHz, CDCl₃) δ 7.88–7.75 (m, 4H), 7.58–7.39 (m, 6H), 4.16–4.01 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), δ_H lit.²⁷ (300 MHz, CDCl₃) 7.70–7.63 (m, 4H), 7.43–7.31 (m, 6H), 4.16–4.09 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H); HRMS (m/z): calcd for C₁₄H₁₆O₂P [M + H]⁺, 247.0888; found, 247.0889.

General Procedure for the P–C Coupling of Arylboronic Acids and Diphenylphosphine Oxide or Diethyl Phosphite (Table 3, Entries 2–6 and 10 and Table 4, Entries 2–7)

To 0.038 mmol (0.0085 g) of Pd(OAc)₂ in 1 mL of ethanol were added 0.41 mmol of the arlylboronic acid [4-, 2-, or 3-methylphenylboronic acid: 0.056 g, 4-fluorophenylboronic acid: 0.057 g, 4- or 3-chlorophenylboronic acid: 0.064 g], 0.49 mmol (0.10 g) of diphenylphosphine oxide or 0.49 mmol (0.063 mL) of diethyl phosphite, and 0.45 mmol (0.15 g) of cesium carbonate. Then, the resulting mixture was irradiated in a closed vial in the MW reactor isothermally at 135 or 150 °C for 1.5 or 0.5 h (Table 3, entries 2–6 and 10 and Table 4). The reaction mixture was diluted with 3 mL of EtOH, filtrated, and the residue obtained after evaporation of the filtrate was filtered through a thin (2–3 cm) layer of silica gel using ethyl acetate as the eluant. The crude mixture obtained was analyzed by ³¹P NMR spectroscopy. Then, if the sample was relevant, it was purified further by column chromatography (silica gel, ethyl acetate–hexane 1:1 as the eluant) to afford products 2f–4k.

Following Compounds Were Thus Prepared

(4-Methylphenyl)diphenylphosphine Oxide (2f) (Table 3, Entry 2)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.081 g (73%) obtained as a white solid; mp 118–119 °C, mp. lit.¹³ 129.5–130.2 °C; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 29.3, δ_P lit.¹³ (162 MHz, CDCl₃) 29.1; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 142.4 (d, J = 2.8 Hz), 132.8 (d, J = 105.9 Hz), 132.1 (d, J = 10.2 Hz), 132.0 (d, J = 9.9 Hz), 131.8 (d, J = 2.7 Hz), 129.2 (d, J = 12.6 Hz), 129.1 (d, J = 106.4 Hz), 128.4 (d, J = 12.1 Hz), 21.6 (s), δ_C lit.¹³ (100 MHz, CDCl₃) 142.5 (d, J = 2.6 Hz), 132.9 (d, J = 104.1 Hz), 132.2 (d, J = 10.2 Hz), 132.1 (d, J = 10.0 Hz), 131.9 (d, J = 2.8 Hz), 129.3 (d, J = 12.5 Hz), 129.2 (d, J = 106.4 Hz), 128.5 (d, J = 11.9 Hz), 21.6; ¹H NMR (500 MHz, CDCl₃) δ 7.80–7.40 (m, 12H), 7.29–7.11 (m, 2H), 2.40 (s, 3H), δ_H lit.¹³ (400 MHz, CDCl₃) 7.67–7.62 (m, 4H), 7.56–7.48 (m, 4H), 7.44–7.40 (m, 4H), 7.26–7.23 (m, 2H), 2.37 (s, 3H); HRMS (m/z): calcd for C₁₉H₁₈OP [M + H]⁺, 293.1095; found, 293.1101.

(2-Methylphenyl)diphenylphosphine Oxide (2g) (Table 3, Entry 3)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.074 g (67%) obtained as white crystals; mp. 120–121 °C, mp. lit.²⁸ 121.5–122.9 °C; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 31.8, δ_P lit.²⁸ (202 MHz, CDCl₃) 31.8; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 143.4 (d, J = 8.0 Hz), 133.5 (d, J = 12.9 Hz), 132.8 (d, J = 103.6 Hz), 132.1 (d, J = 2.6 Hz), 132.0 (d), 131.8 (d, J = 2.7 Hz), 130.8 (d, J = 103.2 Hz), 128.6 (d, J = 12.0 Hz), 125.2 (d, J = 12.8 Hz), 21.7 (d, J = 4.7 Hz), δ_C lit.²⁸ (125 MHz, CDCl₃) 143.2 (d, J = 8.2 Hz), 133.4 (d, J = 12.4 Hz), 132.6 (d, J = 102.6 Hz), 132.0 (d, J = 2.7 Hz), 131.8 (d, J = 10.0 Hz), 131.7 (d, J = 2.7 Hz), 130.7 (d, J = 103.5 Hz), 128.5 (d, J = 12.7 Hz), 125.1 (d, J = 12.7 Hz), 21.6 (d, J = 5.4 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.66 (m, 4H), 7.55 (tq, J₁ = 7.3 Hz, J₂ = 1.6 Hz, 2H), 7.47 (td, J₁ = 7.7 Hz, J₂ = 2.8 Hz, 4H), 7.42 (tt, J₁ = 7.6 Hz, J₂ = 1.6 Hz, 1H), 7.28 (dd, J₁ = 7.6 Hz, J₂ = 4.1 Hz, 1H), 7.13 (td, J₁ = 7.6 Hz, J₂ = 2.9 Hz, 1H), 7.03 (ddd, J₁ = 14.1 Hz, J₂ = 7.8 Hz, J₃ = 1.1 Hz, 1H), 2.45 (s, 3H), δ_H lit.²⁸ (500 MHz, CDCl₃) 7.68–7.62 (m, 4H), 7.57–7.52 (m, 2H), 7.49–7.45 (m, 4H), 7.44–7.39 (m, 1H), 7.30–7.26 (m, 1H), 7.15–7.10 (m, 1H), 7.05–7.00 (m, 1H), 2.45 (s, 3H); HRMS (m/z): calcd for C₁₉H₁₈OP [M + H]⁺, 293.1095; found, 293.1094.

(3-Methylphenyl)diphenylphosphine Oxide (2h) (Table 3, Entry 4)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.089 g (80%) obtained as a white solid; mp. 122–123 °C, mp. lit.²⁶ 123.7–124.2 °C; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 29.3, δ_P lit.²⁹ (162 MHz, CDCl₃) 29.5; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 138.5 (d, J = 12.1 Hz), 132.8 (d, J = 3.0 Hz), 132.7 (d, J = 104.0 Hz), 132.5 (d, J = 9.5 Hz), 132.3 (d, J = 96.7 Hz), 132.1 (d, J = 9.9 Hz), 131.9 (d, J = 2.6 Hz), 129.2 (d, J = 10.2 Hz), 128.5 (d, J = 12.0 Hz), 128.3 (d, J = 12.9 Hz), 21.4 (s), δ_C lit.²⁹ (100 MHz, CDCl₃) 138.4 (d, J = 15.9 Hz), 133.1, 132.8 (d, J = 2.4 Hz), 132.5 (d, J = 9.5 Hz), 132.2 (d, J = 103.4 Hz), 132.0 (d, J = 9.8 Hz), 131.8 (d, J = 2.5 Hz), 129.2 (d, J = 10.2 Hz), 128.5 (d, J = 12.1 Hz), 128.2, 21.5; ¹H NMR (500 MHz, CDCl₃) δ 7.72–7.67 (m, 4H), 7.61–7.55 (m, 3H), 7.50–7.47 (m, 4H), 7.42–7.34 (m, 3H), 2.39 (s, 3H), δ_H lit.²⁹ (400 MHz, CDCl₃) 7.64 (dd, J₁ = 11.6 Hz, J₂ = 7.6 Hz, 4H), 7.56–7.49 (m, 3H), 7.44–7.43 (m, 4H), 7.32 (m, 3H), 2.33 (s, 3H); HRMS (m/z): calcd for C₁₉H₁₈OP [M + H]⁺, 293.1095; found, 293.1097.

(4-Fluorophenyl)diphenylphosphine Oxide (2i) (Table 3, Entry 5)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.079 g (70%) obtained as pale yellow crystals; mp. 134–135 °C, mp.³⁰ 134–135 °C; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 28.5, δ_P lit.²³ (162 MHz, CDCl₃) 28.3; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 165.0 (dd, J₁ = 3.2 Hz, J₂ = 253.6 Hz), 134.5 (dd, J₁ = 11.3 Hz, J₂ = 8.8 Hz), 132.3 (d, J = 105.0 Hz), ∼132.1 (d, J ∼ 3.0 Hz), 132.0 (d, J = 12.2 Hz), 128.53 (d, J = 12.2 Hz), 128.52 (dd, J₁ = 106.5 Hz, J₂ = 3.4 Hz), 115.8 (dd, J₁ = 13.2 Hz, J₂ = 21.4 Hz), δ_C lit.²³ (100 MHz, CDCl₃) 165.0 (dd, J₁ = 254.2 Hz, J₂ = 3.2 Hz), 134.6 (dd, J₁ = 11.3 Hz, J₂ = 8.9 Hz), 132.5 (d, J = 105.2 Hz), 132.1 (d, J = 4.1 Hz), 132.0, 128.7 (dd, J₁ = 106.6 Hz, J₂ = 3.1 Hz), 128.6 (d, J = 12.5 Hz), 115.9 (dd, J₁ = 22.6 Hz, J₂ = 13.3 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.75–7.37 (m, 12H), 7.20–7.06 (m, 2H), δ_H lit.²³ (400 MHz, CDCl₃) 7.67–7.60 (m, 6H), 7.53–7.49 (m, 2H), 7.44–7.41 (m, 4H), 7.11 (t, J = 8.5 Hz, 2H); HRMS (m/z): calcd for C₁₈H₁₅FOP [M + H]⁺, 297.0845; found, 297.0850.

1,4-Phenylenebis(diphenylphosphine oxide) (3A) (Table 3, Entry 6)

In this case, dichloromethane–methanol 97:3 was used as the eluant. Yield: 0.021 g (23%) obtained as white crystals; mp. 300–301 °C, mp. lit.²⁵ >300 °C; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 28.6, δ_P lit.²⁵ (162 MHz, CDCl₃) 30.5; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 137.0 (dd, J₁ = 100.6 Hz, J₂ = 2.7 Hz), 132.3, 132.06 (d, J = 10.1 Hz), 132.06, 131.7 (d, J = 105.2 Hz), 128.7 (d, J₁ = 12.8 Hz), δ_C lit.²⁵ (100 MHz, CDCl₃) 136.9 (d, J = 100.2 Hz), 132.3, 132.0 (d, J = 13.9 Hz), 131.9, 131.0, 128.7 (d, J = 12.2 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.76 (m, 4H), 7.66 (ddd, J₁ = 12.1 Hz, J₂ = 8.4 Hz, J₃ = 1.3 Hz, 8H), 7.57 (tq, J₁ = 7.4 Hz, J₂ = 1.5 Hz, 4H), 7.48 (td, J₁ = 7.8 Hz, J₂ = 2.8 Hz, 8H), δ_H lit.²⁵ (400 MHz, CDCl₃) 7.77–7.74 (m, 4H), 7.69–7.64 (m, 8H), 7.58–7.55 (m, 4H), 7.50–7.46 (m, 8H); HRMS (m/z): calcd for C₃₀H₂₅O₂P₂ [M + H]⁺, 479.1330; found, 479.1320.

1,3-Phenylenebis(diphenylphosphine oxide) (3B) (Table 3, Entry 10)

In this instance, dichloromethane–methanol 97:3 was used as the eluant. Yield: 0.023 g (25%) obtained as colorless oil; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 28.5, δ_P lit.²⁵ (162 MHz, CDCl₃) 30.5; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 135.5 (dd, J₁ = 10.1 Hz, J₂ = 3.1 Hz), 135.4 (t, J = 11.2 Hz), 133.6 (dd, J₁ = 101.8 Hz, J₂ = 10.7 Hz), 132.2 (d, J = 2.3 Hz), 132.0 (d, J = 10.2 Hz), 131.7 (d, J = 105.1 Hz), 129.0 (t, J = 11.3 Hz), 128.6 (d, J = 12.5 Hz), δ_C lit.²⁵ (100 MHz, CDCl₃) 135.4–135.2 (m, 2C), 135.1, 133.5 (dd, J₁ = 101.7 Hz, J₂ = 10.7 Hz), 132.0, 131.8 (d, J = 10.3 Hz), 131.5 (d, J = 104.9 Hz), 128.8 (t, J = 11.2 Hz), 128.4 (d, J = 12.6 Hz), 127.1; ¹H NMR (500 MHz, CDCl₃) δ 7.96 (ddm, J₁ = 12.5 Hz, J₂ = 7.7 Hz, 2H), 7.69 (tt, J₁ = 11.7 Hz, J₂ = 1.5 Hz, 1H), 7.62 (tt, J₁ = 7.7 Hz, J₂ = 2.5 Hz, 1H), 7.58 (dd, J₁ = 12.1 Hz, J₂ = 7.9 Hz, 8H), 7.53 (t, J = 7.4 Hz, 4H), 7.41 (td, J₁ = 7.7 Hz, J₂ = 2.8 Hz, 8H), δ_H lit.²⁵ (400 MHz, CDCl₃) 7.98–7.93 (m, 2H), 7.71 (t, J = 11.7 Hz, 1H), 7.63–7.50 (m, 13H), 7.43–7.38 (m, 8H); HRMS (m/z): calcd for C₃₀H₂₅O₂P₂ [M + H]⁺, 479.1330; found, 479.1323.

Diethyl (4-Methylphenyl)phosphonate (4f) (Table 4, Entry 2)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.067 g (77%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 20.5, δ_P lit.¹⁷ (162 MHz, CDCl₃) 19.5; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 142.8 (d, J = 3.1 Hz), 131.7 (d, J = 10.3 Hz), 129.1 (d, J = 15.4 Hz), 125.0 (d, J = 190.1 Hz), 61.9 (d, J = 5.3 Hz), 21.6 (d, J = 1.15 Hz), 16.2 (d, J = 6.5 Hz), δ_C lit.¹⁷ (100 MHz, CDCl₃) 142.9 (d, J = 3.3 Hz), 131.8 (d, J = 10.4 Hz), 129.3 (d, J = 15.4 Hz), 125.0 (d, J = 190.2 Hz), 61.9 (d, J = 5.3 Hz), 21.6, 16.3 (d, J = 6.3 Hz); ¹H NMR (300 MHz, CDCl₃) δ 7.75–7.63 (m, 2H), 7.25–7.20 (m, 2H), 4.19–3.94 (m, 4H), 2.37 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H), δ_H lit.¹⁷ (400 MHz, CDCl₃) 7.63 (dd, J₁ = 12.9 Hz, J₂ = 7.8 Hz, 2H), 7.24–7.16 (m, 2H), 4.12–3.93 (m, 4H), 2.33 (s, 3H), 1.24 (t, J = 6.9 Hz, 6H); HRMS (m/z): calcd for C₁₁H₁₈O₃P [M + H]⁺, 229.0994 found 229.0996.

Diethyl (2-Methylphenyl)phosphonate (4g) (Table 4, Entry 3)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.067 g (78%) obtained as colorless oil; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 19.5, δ_P lit.¹⁷ (162 MHz, CDCl₃) 19.4; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 141.8 (d, J = 10.1 Hz), 133.9 (d, J = 10.4 Hz), 132.4 (d, J = 2.8 Hz), 131.2 (d, J = 15.0 Hz), 126.8 (d, J = 184.0 Hz), 125.4 (d, J = 14.8 Hz), 61.9 (d, J = 5.5 Hz), 21.2 (d, J = 3.7 Hz), 16.3 (d, J = 6.6 Hz), δ_C lit.¹⁷ (100 MHz, CDCl₃) 141.8 (d, J = 10.4 Hz), 133.9 (d, J = 10.3 Hz), 132.4 (d, J = 2.9 Hz), 131.1 (d, J = 15.5 Hz), 127.0 (d, J = 184.4 Hz), 125.3 (d, J = 14.9 Hz), 61.8 (d, J = 5.6 Hz), 21.2 (d, J = 3.7 Hz), 16.3 (d, J = 6.6 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.96–7.90 (m, 1H), 7.47–7.43 (m, 1H), 7.32–7.25 (m, 2H), 4.24–4.05 (m, 4H), 2.60 (s, 3H), 1.35 (t, J = 7.1 Hz, 6H), δ_H lit.¹⁷ (400 MHz, CDCl₃) 7.95–7.88 (m, 1H), 7.45–7.40 (m, 1H), 7.29–7.23 (m, 2H), 4.20–4.03 (m, 4H), 2.58 (s, 3H), 1.33 (t, J = 7.0 Hz, 6H); HRMS (m/z): calcd for C₁₁H₁₈O₃P [M + H]⁺, 229.0994; found, 229.0993.

Diethyl (3-Methylphenyl)phosphonate (4h) (Table 4, Entry 4)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.069 g (80%) obtained as colorless oil; ³¹P{¹H} NMR (202.4 MHz, CDCl₃) δ 19.5, δ_P lit.¹⁷ (162 MHz, CDCl₃) 19.2; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 138.3 (d, J = 14.9 Hz), 133.2 (d, J = 3.1 Hz), 132.3 (d, J = 10.0 Hz), 128.8 (d, J = 9.6 Hz), 128.4 (d, J = 15.8 Hz), 128.1 (d, J = 187.6 Hz), 62.1 (d, J = 5.4 Hz), 21.3 (s), 16.3 (d, J = 6.5 Hz), δ_C lit.¹⁷ (100 MHz, CDCl₃) 138.2 (d, J = 14.8 Hz), 133.1 (d, J = 3.0 Hz), 132.2 (d, J = 9.7 Hz), 128.7 (d, J = 9.7 Hz), 128.3 (d, J = 15.4 Hz), 128.0 (d, J = 187.0 Hz), 61.9 (d, J = 5.2 Hz), 21.2, 16.3 (d, J = 6.2 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.67–7.57 (m, 2H), 7.38–7.34 (m, 2H), 4.19–4.03 (m, 4H), 2.40 (s, 3H), 1.33 (t, J = 7.1 Hz, 6H), δ_H lit.¹⁷ (400 MHz, CDCl₃) 7.63–7.52 (m, 2H), 7.33–7.27 (m, 2H), 4.16–3.97 (m, 4H), 2.34 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H); HRMS (m/z): calcd for C₁₁H₁₈O₃P [M + H]⁺, 229.0994; found, 229.0992.

Diethyl (4-Fluorophenyl)phosphonate (4i) (Table 4, Entry 5)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.068 g (77%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 18.7, δ_P lit.¹⁷ (162 MHz, CDCl₃) 17.7; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 165.2 (dd, J₁ = 3.9 Hz, J₂ = 253.4 Hz), 134.2 (dd, J₁ = 11.2 Hz, J₂ = 8.9 Hz), 124.4 (dd, J₁ = 192.7 Hz, J₂ = 3.4 Hz), 115.6 (dd, J₁ = 16.3 Hz, J₂ = 21.4 Hz), 62.0 (d, J = 5.4 Hz), 16.2 (d, J = 6.4 Hz), δ_C lit.¹⁷ (100 MHz, CDCl₃) 165.3 (dd, J₁ = 253.1 Hz, J₂ = 4.1 Hz), 134.5 (dd, J₁ = 11.2 Hz, J₂ = 8.8 Hz), 124.4 (d, J = 192.7 Hz), 115.8 (dd, J₁ = 22.1 Hz, J₂ = 16.2 Hz), 62.1 (d, J = 5.4 Hz), 16.3 (d, J = 6.2 Hz); ¹H NMR (300 MHz, CDCl₃) δ 7.81–7.70 (m, 2H), 7.11–7.00 (m, 2H), 4.15–3.93 (m, 4H), 1.32–1.15 (m, 6H), δ_H lit.¹⁷ (400 MHz, CDCl₃) 7.80 (ddd, J₁ = 14.0 Hz, J₂ = 7.4 Hz, J₃ = 6.9 Hz, 2H), 7.17–7.09 (m, 2H), 4.19–4.00 (m, 4H), 1.30 (t, J = 7.2 Hz, 6H); HRMS (m/z): calcd for C₁₀H₁₅FO₃P [M + H]⁺, 233.0743; found, 233.0742.

Diethyl (4-Chlorophenyl)phosphonate (4j) (Table 4, Entry 6)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.062 g (66%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 18.5, δ_P lit.³¹ (162 MHz, CDCl₃) 18.1; ¹³C{¹H} NMR (75.5 MHz, CDCl₃) δ 139.0 (d, J = 4.1 Hz), 133.2 (d, J = 10.7 Hz), 128.9 (d, J = 15.6 Hz), 127.1 (d, J = 190.9 Hz), 62.3 (d, J = 5.5 Hz), 16.4 (d, J = 6.4 Hz), δ_C lit.³¹ (62.5 MHz, CDCl₃) 138.5, 134.5, 129.2, 123.3, 58.0, 16.8; ¹H NMR (300 MHz, CDCl₃) δ 7.81–7.65 (m, 2H), 7.51–7.40 (m, 2H), 4.21–4.00 (m, 4H), 1.32 (t, J = 7.0 Hz, 6H), δ_H lit.³¹ (250 MHz, CDCl₃) 7.69–7.61 (m, 2H), 7.38–7.33 (m, 2H), 4.04–3.95 (m, 4H), 1.22 (t, 6H); HRMS (m/z): calcd for C₁₀H₁₅ClO₃P [M + H]⁺, 249.0447; found, 249.0446.

Diethyl (3-Chlorophenyl)phosphonate (4k) (Table 4, Entry 7)

Eluant: ethyl acetate–hexane 1:1; Yield: 0.067 g (71%) obtained as colorless oil; ³¹P{¹H} NMR (121.5 MHz, CDCl₃) δ 17.4, δ_P lit.³² (202.4 MHz, CDCl₃) 16.7; ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 134.7 (d, J = 20.3 Hz), 132.4 (d, J = 3.0 Hz), 131.6 (d, J = 10.7 Hz), 130.7 (d, J = 187.9 Hz), 129.74 (d, J = 16.3 Hz), 129.69 (d, J = 9.2 Hz), 62.3 (d, J = 5.5 Hz), 16.2 (d, J = 6.4 Hz), δ_C lit.³² (125.7 MHz, CDCl₃) 134.8 (d, J = 20.3 Hz), 132.5 (d, J = 3.0 Hz), 131.6 (d, J = 10.7 Hz), 130.7 (d, J = 188.2 Hz), 130.0 (d, J = 16.2 Hz), 129.8 (d, J = 9.1 Hz), 62.5 (d, J = 5.5 Hz), 16.3 (d, J = 6.4 Hz); ¹H NMR (500 MHz, CDCl₃) δ 7.81–7.59 (m, 2H), 7.51–7.43 (m, 1H), 7.40–7.31 (m, 1H), 4.20–3.96 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H), δ_H lit.³² (500 MHz, CDCl₃) 7.78–7.37 (m, 4H), 4.18–4.02 (m, 4H), 1.31 (t, J = 7.0 Hz, 6H); HRMS (m/z): calcd for C₁₀H₁₅ClO₃P [M + H]⁺, 249.0447; found, 249.0448.

Computational Methods

All computations were carried out with the Gaussian16 program package (G16),³³ using standard convergence criteria for the gradients of the root-mean-square (RMS) force, maximum force, and RMS displacement and maximum displacement vectors (3.0 × 10^–4, 4.5 × 10^–4, 1.2 × 10^–3, and 1.8 × 10^–3). Computations were carried out at the M06-2X level of theory.³⁴ The basis set of 6-31G(d,p) was applied for C, H, O, P, N, and B and SDD/MWB28 for Pd.³⁵ The vibrational frequencies were computed at the same levels of theory, in order to confirm properly all structures as residing at minima on their potential energy hypersurfaces (PESs). Thermodynamic functions U, H, G, and S were computed at 398.15 K. Besides the vacuum calculations, the IEFPCM method was also applied to model the solvent effect, by using the default settings of G16, setting the ε = 24.852 (for ethanol).³⁶ See the Supporting Information for details.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c01269.

• ³¹P, ¹³C, and ¹H NMR spectra and data of the theoretical calculations (PDF)

The authors declare no competing financial interest.