Synthesis Convenient and Scalable Synthesis of Aryldichlorophosphines and Primary Arylphosphines via Perthiophosphonic Anhydrides

: A scalable synthetic route to both primary arylphosphines ArPH2 and aryldichlorophosphines ArPCl2 is reported. The C-P bond formation was performed in a highly regiospecific manner through electrophilic substitution of selected aromatic hydrocarbons (ArH) with phosphorus pentasulfide. The resultant perthiophosphonic anhydrides Ar2P2S4 were then reacted with LiAlH4 to give primary phosphines ArPH2. Subsequent reaction of ArPH2 with phosgene solution gives dichlorophosphines ArPCl2. Each reaction step requires minimum purification and uses commercially available and economical precursors. The scope of the reaction was shown to include alkoxy and phenoxy substituted benzenes as well as naphthalene and fluorene as starting materials.

Dichlorophosphines appear to be ubiquitous within synthetic organophosphorus chemistry, [7][8][9][10][11][12] despite this, the commercial availability of aryldichlorophosphines is limited and so laboratory scale syntheses have to be employed where access to a wider range of these compounds is required. A major challenge to overcome in these syntheses is the need for a highly selective formation of the desired species, which is crucial due to the limited options for post-synthetic purification, generally limited to fractional distillation (for sufficiently volatile species). Other options (in particular chromatography) are generally not accessible due to the very reactive nature of dichlorophosphines towards both oxygen and moisture. P-C bond formation is a crucial step in the synthesis of aryldichlorophosphines. Early examples involved reacting aromatic hydrocarbons or anisol derivatives with PCl3 in the presence of a Lewis acid catalyst such as AlCl3 or SnCl4 (Scheme 2, route (i)). 13,14 Later examples used reaction of PCl3 with respective Grignard (or organolithium) reagent (Scheme 2, route (ii)) and this method is still routinely employed. 15,16 The disadvantage of this synthetic route is that due to the high reactivity of the Grignard (or organolithium) reagent often the products of multiple substitution (Ar2PCl and Ar3P) are formed in significant amounts, impacting the yield of the dichlorophosphine. This synthetic route also suffers from poor functional group tolerance.

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This article is protected by copyright. All rights reserved. To prevent the formation of byproducts due to multiple substitution, a protective group strategy was devised in which PCl3 was replaced with ClP(NR2)2 (Scheme 2, route (iii)). Intermediate aminophosphinyl species ArP(NR2)2 is formed, which is isolated and then reacted with excess HCl gas to form the dichlorophosphine. 4,17 While this synthetic route does prevent multiple substitution from occurring, a new challenge is presented through the use of HCl gas and separation of the dichlorophosphine from the co-formed dialkylammonium chloride.
More recently a systematic investigation of the synthesis of aryl-and heteroaryldichlorophosphines was reported by Karaghiosoff 18 in which organozinc reagents were employed in the place of Grignard or organolithium reagents (Scheme 2, route (iv)). Lower polarity of C-Zn vs. C-Mg and C-Li bonds resulted in more controlled reactivity of organozinc species compare to Grignard reagents and organolithiums. Whilst this route presents improvement over the more conventional routes as it does avoid multiple substitution products and offers good functional group tolerance, it requires observing the right stoichiometry carefully, and distillation (or recrystallisation for solids) of the highly reactive product as a final purification step.
As outlined above the synthesis of dichlorophosphines is not straightforward, with multiple issues presented for each synthetic method. Our recent investigations required a synthesis of a series of

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This article is protected by copyright. All rights reserved. This unique method offers a route to a previously difficult to access dichlorophosphine FcPCl2 in high yield, is easily scalable, uses economical commercially available precursors and does not require complex purification. The P-C bond forming step, in which perthiophosphonic anhydride Fc2P2S4 is formed from ferrocene and P4S10, proceeds fully regioselectively with high yield (>80%). 19 Herein we report the expansion of this synthetic route to make a selection of primary and dichloroaryl phosphines.

Perthiophosphonic anhydrides synthesis
The synthetic route towards primary and dichloroaryl phosphines (Scheme 4) begins with the synthesis of the perthiophosphonic anhydride compounds (1A -1F). These six particular compounds were selected due to the ease at which they can be synthesised, this is achieved by a simple heating of P4S10 with the related hydrocarbon precursor -anisole, phenetole, 2-t-butylanisole, diphenyl ether, fluorene and naphthalene, respectively, at high temperature (150 -190 °C, reaction time 1-5 hours). All of these compounds have previously been reported in the literature [20][21][22] with the exception of fluorene derivative 1F. The arene reactants served also as solvents for the reaction, hence the molar ratio of reactants 1 : 2 to 1 : 2.5 was used (P : ArH). The reactions were performed under a gentle stream of nitrogen and the exhaust gasses were bubbled through aqueous NaOH solution to remove H2S formed as a by-product. The liquid mixtures obtained after heating were left Accepted Manuscript to cool to rt and the formed solid products were filtered off, washed with dichloromethane or diethyl ether and dried in vacuo. 1A -1F form as yellow or white solids in yields in the range of 31-65% (see Table 1). They can be manipulated in air; however, they hydrolyse slowly hence long-term storage requires well-sealed vials.
While other routes exist for the synthesis of perthiophosphonic anhydrides, these are generally more complex and require several steps hence are less suitable to prepare starting materials for the synthetic sequence in this work. 23,24 An important point to make is that the arenes selected in this work contain no functional groups that will provide additional reactivity toward P4S10 such as ketones, esters and alcohols. 25,26 On the other hand, presence of electron donating groups (such as OMe) on the aromatic ring results in improved yields and shorter reaction times. Due to the inherent insolubility of perthiophosphonic anhydrides no NMR data could be collected for 1A -1F. Nevertheless, the follow-on reactivity (see below) indicates the P-C bond formation is fully regiospecific in the reactions of P4S10 with both activated and non-activated arenes used in this study, with no other regioisomers detected by 31

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Reduction to Primary Phosphines
With the desired Ar2P2S4 compounds in hand the next step was to reduce these with LiAlH4 (4 eq. of LiAlH4 per Ar2P2S4 were used) to the corresponding primary phosphines ArPH2 (2A -2F). Both Ar2P2S4 and LiAlH4 were suspended in Et2O, and the two suspensions added together slowly at 0 °C. The resulting suspension was filtered, degassed water was added, followed by a second filtration. In both filtrations, efficient washing of the solid on the filter was essential to achieve good yields. The filtrate and washings were collected, and the volatiles were removed in vacuo to yield the desired primary phosphines. No further purification was performed, the phosphines 2A-2D were obtained in good purity and reasonable yields (33-52%). The naphthalene species 2F was obtained in 8% yield only and small amount of naphthalene (formed in the reduction step rather than carried over from previous step) was present as shown by 1 H NMR. Also, the reduction of 1E led to partial cleavage of the C-P bond as small amounts of fluorene were detected by 1 H NMR alongside the major product 2E. Despite this, both 2E and 2F were of sufficient purity for further synthetic use and were used as obtained in the preparations of respective dichlorophosphines as described below.
Other reducing reagents (NaH and NaBH4) were tested for the reduction of 2A-2F, however no phosphine was produced even at elevated temperatures in ethereal solvents.
Interestingly, of the six primary phosphine compounds synthesised in this work only two have been previously reported in the literature (2A and 2F), 27, 28 demonstrating the ability of this synthetic route to provide access to a wider range of primary phosphines. Despite the lack of steric bulk protection, phosphines 2E and 2F showed remarkable stability in air in both the solid state and in solution with minimal oxidation observed. This enhanced stability to oxidation could be due to the conjugated aromatic system of naphthalene and fluorene, as the additional conjugation has been shown to stabilise primary phosphines against oxidation. 27   The diphosphine impurities presented no issues for the subsequent chlorination step as they were present in very small amounts and were converted to the same end product (ArPCl2) on chlorination.

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Hence no attempt was made to remove these via further purification.

Chlorination to Dichlorophosphines
In

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triphosgene was used as an alternative chlorinating reagent at rt for selected examples of primary phosphines, giving full conversion to respective dichlorophosphines as judged by 31 P{ 1 H} NMR.
Syntheses of 3B, 3C, 3D and 3E have not been reported previously. In addition to multinuclear NMR spectroscopy (as mentioned above) they were characterised also by MS spectroscopy. The spectroscopic data obtained by us for previously reported species (3A and 3F) agreed with the literature (see Experimental section).

Conclusion
A multigram synthesis of a series of primary arylphosphines and aryldichlorophosphines is reported.
All steps use convenient, commercially available and economical reagents. Each step requires minimum purification, which is of importance due to the highly reactive nature of both compound types. The initial step (formation of perthiophosphonic anhydrides) proceeds highly regiospecifically and the nature of subsequent steps means multiple substitution is avoided, hence employing protection and subsequent deprotection strategies is not required. Future work will look to further extend the scope of this reaction to other R2P2S4 compounds.

General Considerations
All manipulations (unless indicated otherwise) were performed under an atmosphere of nitrogen

Synthesis of perthiophosphonic anhydrides 1A-1F
All syntheses in this section were performed under a gentle stream of nitrogen, and the exhaust gasses were bubbled through aqueous NaOH solution to remove H2S formed as a by-product. The subsequent workup was performed in air (in a well ventilated fumehood).
Lawesson's Reagent, (4-MeO-C6H4)2P2S4 (1A) 1A was synthesised according to a previously reported literature procedure. 20     hours. The liquid mixture was then allowed to cool to room temperature, giving a solid clump. DCM

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This article is protected by copyright. All rights reserved. was allowed to cool slowly to room temperature, at which point a yellow solid began to precipitate.

General Procedure for the Synthesis of Primary Phosphines (2A-2F)
The respective perthiophosphonic anhydride 1A-1F was suspended in diethyl ether (150 ml) and cooled to 0°C. A suspension of LiAlH4 (4 eq.) in ether (50 ml) was added in small portions with vigorous stirring. The resulting mixture was stirred for 1 hour at 0°C. The mixture was then filtered to remove the insoluble solids which were washed with ether (2 x 10 ml). The filtrate and washings were collected, cooled to 0°C and degassed water (2 ml) was added cautiously dropwise. The resulting suspension was filtered again to remove the insoluble solids that had formed and the solid on the filter was washed with DCM (2 x 20 ml). The filtrate and washings were collected, and the volatiles were removed in vacuo to yield the desired primary phosphines 2A-2F.

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This article is protected by copyright. All rights reserved. Compound 2A has been reported previously 28 but no characterisation data were provided.

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Values are in agreement with literature data. 27 General Procedure for the Synthesis of Dichlorophosphines (3A-3F) The respective primary phosphine (2A-2F) was dissolved in DCM (150 ml) and cooled to -10°C. A solution of phosgene (20% solution in toluene, 2.1 eq.) was added dropwise over 30 minutes. The resulting solution was allowed to warm to room temperature and stirred for a further 5 hours. The volatiles were removed in vacuo to yield the desired dichlorophosphine 3A-3F.
Safety note: Phosgene and carbon monoxide (evolved in the chlorination reaction) are highly toxic, use of well-ventilated fumehood is essential for this step.