Photostimulated synthesis of 2-(diphenylphosphino)benzoic acid by the S RN 1 reaction

2-(Diphenylphosphino)benzoic acid, isolated as the ester, was obtained by the photostimulated reaction of 2-chlorobenzoate ion with Ph 2 P – ions in good yield in liquid ammonia. The reaction did not occur in the dark; it was inhibited by m -dinitrobenzene and partially inhibited by a radical trap such as TEMPO. The results were consistent with the S RN 1 mechanism. No evidences for aromatic nucleophilic substitution (S N Ar) or benzyne mechanisms were found.


Introduction
Tertiary phosphines constitute the group of ligands most widely used in transition metalcatalyzed reactions, mainly due to their electron-donating capacity and versatile tuning abilities via steric and electronic properties. 1 Accordingly, the development of new synthetic approaches to obtain organophosphines is increasingly recognized as central in the synthesis of new ligands.A variety of methods for the formation of C-P bond have been established, including direct construction via transition metal-catalyzed cross-coupling reactions, 2 or less common radical protocols. 3unctionalized phosphines containing hydrophilic substituent, such as diphenylphosphino benzoic acid (DPPBA) derivatives, represent a versatile family of water-soluble ligands.2c, 4 Moreover, DPPBA has found applications as an important phosphine building block for the design of C2-symmetric Trost ligands, 5 a class of ligands widely applied for asymmetric Pdcatalyzed allylic substitution. 6DPPBA has also been established as a ligand in allylic substitution. 7Additionally, DPPBA has been used as the base for a variety of phosphine-based ligands applied to different metal-catalyzed reactions, 8 as well as a mediator in Staudinger reactions. 9everal procedures to obtain DPPBA derivatives have been reported.One of them is the Pdcatalyzed P-C coupling reaction of ArX with Ph2PH. 10 This process generally requires several hours or days of reaction at high temperatures.Recently, the synthesis of DPPBA by microwave heating using Pd-catalyzed cross-coupling reactions was described. 11However, only 26% yield of the product was achieved.We reported the synthesis of DPPBA by the Pd-catalyzed phosphination with stannane n-Bu3SnPPh2 and 2-iodobenzoic acid to provide the tertiary phosphine oxide in 69% isolated yield. 12DPPBA can also be prepared by the Ni-catalyzed crosscoupling of methyl 2-(trifluoromethyl-sulfonyloxy)benzoate with Ph2PCl. 13Additionally, the synthesis of DPPBA was accomplished by the nucleophilic reaction of 2-fluorobenzoate salt with Ph2PK. 14The DPPBA was also obtained by metal-halogen exchange in 2-bromobenzoate salt, followed by phosphorylation of the resulting 2-lithiated benzoate salt with Ph2PCl. 15ormally, most of the procedures involve several steps, high temperatures, many hours of reaction and generally low overall yields.Thus, a simple, efficient and general method of synthesizing triarylphosphines would be particularly interesting.The SRN1 reaction is an attractive synthetic alternative to obtain triarylphosphines.
The SRN1 reaction is a process in which radicals and radical anions are intermediates, through which an aromatic nucleophilic substitution could be achieved. 16The scope of this process has increased considerably and nowadays it serves as an important synthetic strategy.It is compatible with many substituents, and several nucleophiles, such as carbanions and heteroatom anions react to give new C-C or C-heteroatom bonds in good yields. 16he reactions of Ph2P -ions with methyl and methoxy phenyl halide derivatives, 17 naphthyl and quinolyl halides, 17b and also diarylsulfides, sulfones, and sulfoxides 18 have been reported to afford aryldiphenylphosphines in good yields by the SRN1 mechanism.Although these synthetic strategies are known, so far there has been no instance of the reaction of the phosphorus nucleophiles with an aromatic acid with an appropriate leaving group.In the present study, we report the SRN1 reaction to obtain triarylphosphines with 2-chlorobenzoic acid as starting substrates.
Substrate 1 was proposed to react with Ph2P -ions in excess through a benzyne mechanism to achieve the cine substitution product 3. On the other hand, the reaction of 1 with one equivalent of Ph2P -ions gave the substitution product 2 through a SNAr type of mechanism (Scheme 1).However, mechanistic studies were not conducted.
Here we report our results on the synthesis of 2-(diphenylphosphino)benzoic acid by the photostimulated SRN1 substitution reaction using 1 and Ph2P -ions as starting substrates.Our work focused on the development of a new strategy to synthesize triarylphosphines and explore the mechanism that takes place.

Results and Discussion
The Ph2P -ions were easily prepared in liquid ammonia (-33 ºC) by the reaction of Ph3P with Na metal (2 equiv).The H2N -ions generated in the formation of Ph2P -ions were neutralized with t-BuOH.17c The photostimulated reaction (120 min) of 1 with the Ph2P -ions (1.1 equiv) was quenched with NH4NO3.The liquid ammonia was allowed to evaporate.The residue was treated with EtOH-H2SO4 to form the ester to facilitate product quantification and isolation (Equation 1).
In dark conditions (90 min), the reaction did not proceed and the substrate remained unaltered (entry 5, Table 1).These results excluded an aromatic nucleophilic substitution (SNAr) or benzyne mechanisms.The fact that Ph2P -ions react only under photostimulation with 1 suggest that there was an electron transfer (ET) from Ph2P -ions to 1 under irradiation to initiate the reaction.This is highly probable because Ph2P -ions absorb strongly in the visible region (λ > 350 nm), 16 being the best candidates for absorption in the common reaction conditions used.
A complete inhibition of the reaction was observed when 1 was irradiated in the presence of m-dinitrobenzene (m-DNB), a good electron acceptor 16 (entry 6, Table 1).This could be attributed to electron transfer events that are being inhibited, which would indicate the occurrence of a chain mechanism.The photostimulated reaction of 1 was partially inhibited by 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (entry 7, Table 1), a free radical traps.All these results suggest that this reaction proceeds through the SRN1 mechanism.We propose that 1 receives an electron from Ph2P -ions under irradiation to yield the radical dianion 7 (Scheme 2).Fragmentation of the C-Cl bond of 7 gives the distonic radical anion 8 and Cl -anion.The intermediate 8 reacts with Ph2P -ions to afford the radical dianion 9.An ET from 9 to 1 forms the substitution product 2 and the radical dianion 7, propagating the reaction chain.The reaction of 1 with Ph2P -ions in liquid ammonia to obtain 2, under diferent conditions of temperature, concentration, photostimulation and without adding t-BuOH, was reported to occur by the S N Ar mechanism. 19However, our studies lead us to propose that the reaction occurs by the SRN1 mechanism.To provide further evidence to support our mechanism, we conducted the experiments under the same experimental conditions as those previously reported (Table 2).
Under the same reaction conditions described, 1 was allowed to react with Ph2P -ions in liquid ammonia at -78 ºC under ambient light conditions. 19The residue was treated with EtOH-H2SO4 to achieve the corresponding esters to facilitate the product quantification and isolation.The product 4 was obtained in 46%, together with the reduced product 5 and the unreacted substrate as 6 (compared entry 1 with entry 2, Table 2).The reaction was totally inhibited in the presence of 20 mol % m-DNB and partially inhibited by 20 mol % TEMPO (entries 3 and 4, Table 2).Moreover, the reaction was slower in dark conditions (compared entry 1 with entry 5, Table 2).Thus, this reaction occurs in dark conditions (thermal initiation) but is faster under the photostimulation of ambient light.17a In summary, we found that the reaction was stimulated by light and that in the presence of low amounts of a good electron acceptor or TEMPO, the reaction was considerably inhibited.Accordingly, these results suggest that in these experimental conditions the reaction occurs by the SRN1 mechanism with both thermal and photochemical initiation steps. 20However, with an excess of amide ions, the product 3 is formed by the benzyne mechanism, as reported. 19

Experimental Section
General.Gas chromatographic analyses were performed on a Hewlett Packard 5890 series II with a flame ionization detector and equipped with the following column: HP1 column (0.53 mm x 5 m).Quantification by GC was performed by the internal standard method.Gas Chromatographic-Mass Spectrometer analyses were carried out on a Shimadzu QP-5050 spectrometer equipped with a quadrupole detector and a VF-5 ms column (30 m x 0.25 mm x 0.25 μm). 1 H NMR (400.16MHz), 31 P NMR (162 MHz) and 13 C NMR (100.62 MHz) spectra were recorded on a High Resolution Spectrometer Bruker Advance 400 in CDCl3 as solvent and against internal TMS ( 1 H) and external 85% phosphoric acid ( 31 P).Coupling constants (J) are given in Hz units.Irradiation was conducted in a reactor equipped with two 400-W lamps of metal iodide refrigerated (Philips, Model HPI-T) with water.An Orion 420A pHmeter with Ag/Ag + electrode was used for the potentiometric titration of halide ions in the aqueous phases.PhCO2H, 2-ClC6H4CO2H, Na metal, Ph3P, t-BuOH, NH4NO3, EtOH and H2SO4 were commercially available and used as received.THF was dried over Na metal and benzophenone, and distilled under atmosphere of N2.All solvents were analytical grade and used as received from the supplier.Silica gel (0.063-0.200 mm Macherey-Nagel) was used in column chromatography.5 and 6 were prepared according to the literature procedure. 21hyl 2-(diphenylphosphoryl)benzoate (4) 22 : Representative procedure for photostimulated reactions of 1 with Ph2P -ions in liquid ammonia Ammonia (150 mL), previously dried with Na metal under N2, was condensed into a 250 mL three-necked, round-bottomed flask equipped with a coldfinger condenser charged with ethanol, a nitrogen inlet, and a magnetic stirrer.PPh3 (0.144 g, 0.55 mmol) was then added, and Na metal was introduced in small pieces; addition was continued until the solution kept its dark brown color for at least 15 min.After its color turned red, t-BuOH (0.5 mL, 0.55 mmol) was added to eliminate the H 2 N -anions formed.An orange solution of Ph 2 P -ions was obtained.2-Chlorobenzoic acid was added to the solution to form 1 (0.078 g, 0.50 mmol), and the mixture was irradiated for 120 min with two metal iodide lamps of 400 W refrigerated with water.The reaction was quenched with an excess of NH4NO3 and the ammonia was allowed to evaporate.Water (50 mL) was added to the residue and SO4H2 was afterwards added until the aqueous phase reached pH 1-2.The aqueous phase was extrated with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with H2O (20 mL) and dried over anhydrous MgSO4; the solvent was evaporated under vacuum.The chloride ions in the aqueous solution were determined by potentiometry.The crude products were mixed with EtOH (1.8 mL, 30.8 mmol) and concentrate H2SO4 (0.05 mL, 0.94 mmol) in a 10 mL tube sealed and equipped with a magnetic stirrer.The mixture was heated to 80 °C for 4 days.The excess of EtOH was eliminated on a rotary evaporator and allowed cooling.The residue was dissolved with water (50 mL) and NaHCO3 was then added until reaching pH 8-9.

Conclusions
The experimental results showed the efficient synthesis with good yields of 2-(diphenylphosphino)benzoic acid in ammonia by the SRN1 mechanism.No evidence for aromatic nucleophilic substitution (SNAr) or benzyne mechanisms was found.Considering the availability and simplicity of the starting materials, the short reaction times, as well as the mild conditions of the procedure, we have demonstrated that the SRN1 reaction could be useful to prepare different triarylphosphines in good yields.
As mentioned, DPPBA has found applications as an important building block for a variety of phosphine-based ligands.So we believe that aryl-phosphorus bond formation by the S RN 1 reaction offers important opportunities for the synthesis of DPPBA with a wide range of substituents, for example with electron-donating groups in different positions of the aromatic acid.It should be noted the diference with the SNAr, where aromatic substrates having electronwithdrawing group are accepted.

Supplementary material
See Supplementary material for experimental procedures and full spectroscopic data for all compounds.

Table 1 .
Reactions of 1 with Ph2P -ions by SRN1 mechanism.a a Reactions carried out under N2 in 150 mL of liquid ammonia (-33 ºC), with 1.0 equiv of 1, 1.1 equiv of Ph2P -ions, 1.1 equiv of t-BuOH.Irradiation was conducted in a photochemical reactor equipped with two 400 W lamps refrigerated with water unless otherwise indicated.b Determined potentiometrically.c Yields were determined by GC (internal standard method).d Not quantified.e Reaction carried out under N2 in 150 mL of liquid ammonia, with 1 equiv of 1, 2 equiv of Ph2P - ions, 2 equiv of t-BuOH.

Table 2 .
Reactions of 1 with Ph2P -ions under the experimental conditions reported in ref 19 aReactions carried out under N2 in 10-15 mL of liquid ammonia at -78 ºC, with 1 equiv.(4.44 mmoles) of 1, 1 equiv.(4.44 mmoles) of Ph2P -ions and 2.5 h of stirring before adding 1 and 0.5 h of stirring before adding of THF (6 mL).b Determined potentiometrically.c Yields were determined by GC (internal standard method).d Reported results, see Ref. 19. e 2-Chlorobenzoic acid was added in one portion.