UV-mediated hydrophosphinylation of unactivated alkenes with phosphinates under batch and flow conditions

A UV-mediated hydrophosphinylation of unactivated alkenes with H-phosphinates and hypophosphorous acid under radical free conditions is presented. The reaction affords selectively a large number of structurally diverse organophosphorous compounds in moderate to good yields under mild reaction conditions in the presence of an organic sensitizer as catalyst irradiated by UV-A LEDs. Furthermore, the high yielding hydrophosphinylation in continuous flow is disclosed.


Introduction
Organophosphorus compounds have attracted much attention due to their wide range of applications in materials, catalysis, natural bioactive products and pharmaceuticals. 1 In particular, phosphinates (P(O)(OR)R 1 R 2 , R 1 /R 2 ¼ hydrogen and/or carbon) have been the target of numerous synthetic efforts as they are versatile precursors to organophosphorus compounds and represent a sustainable alternative to the use of phosphorous trichloride. 2 Indeed, phosphinates can be considered as the synthetic equivalents of phosphorous trichloride with several advantages in terms of stability and toxicity. In this regard, the development of efficient and selective methodologies for the preparation and functionalization of phosphinates (P(O)(OR)H 2 ) and H-phosphinates (P(O)(OR)R 1 H) has been extensively studied, mostly by the group of Montchamp. 2,3 Hydrophosphinylation of unactivated alkenes is one of these routes that provide a direct access to functionalized organophosphorous compounds. 4 This atom economical process has been reported to proceed via transition metal catalysis, 5 or radical activation (Scheme 1a and b). 6 Despite the signicant progress in this chemistry, these transformations suffer from some drawbacks like the relatively harsh conditions, narrow substrates scopes and costly catalytic system thus limiting their chemical and pharmaceutical applications. Recently, Lakhdar and co-workers reported a hydrophosphinylation of unactivated alkenes with ethyl and butyl phosphinates under photocatalytic conditions (Scheme 1c), 7 even though diphenyl iodonium triate which acted as sacricial oxidant is not a heavy metal, the use of catalytic quantity is always preferred in term of sustainability and environmental benignity. Alternatively, pioneering work from the group of Dondoni 8 demonstrated that P(O)-centered radical can be generated from H-phosphonates under UV-A irradiation, in the presence of 2,2-dimethoxy-2-phenylacetophenone (DMPA) as photoinitiator, and added to alkene functionalized carbohydrates. However, the reaction requires the use of a large excess of phosphonates (100 eq.). Mathé and coworkers 9 then extended this free radical hydrophosphonylation to activated and unactivated alkenes, similar reaction with hypophosphorous acid and H-phosphinates derivatives 10 have not been studied previously.
In this context, we envisaged that continuous-ow systems in combination with a sensitizer irradiated by UV-A LEDs (l ¼ 365 Scheme 1 Hydrophosphinylation of phosphinates with unactivated alkenes. nm) would result in a signicant enhancement of the reaction. Over the last decade, interest has grown for ow chemistry based on microuidic technology in particular towards large-scale application due to its signicant improvement over traditional batch reactors concerning reduced consumption of chemicals, solvents and time together with enhanced yields, selectivity and control over reaction conditions. An easy scale up is also one of the characteristic of photo-reactions which are conducted in microreactors. In batch reactors, light penetration through the reaction media is limited which restrains the efficiency of photochemical processes. This drawback can be overcome with continuous microow reactors since their small optical lengths improve sample irradiation and also enhance heat and mass transfer. 11 Therefore, in view of the growing demand to develop efficient, mild and sustainable methods to access phosphinates and as a continuation of our interest in photocatalyzed processes, 12 we herein report an original UV-mediated hydrophosphinylation of unactivated alkenes with hypophosphorous acid and less reactive H-phosphinates derivatives under batch and ow conditions.

Hydrophosphinylation of unactivated alkenes with Hphosphinates under batch conditions
Initially, the hydrophosphinylation of relatively challenging Hphosphinate (1a) with octene (2a) in equimolar amounts in the presence of a photoinitiator under UV-A irradiation was selected as a model to investigate the reaction. The use of one equivalent of 4,4 0 -dimethoxybenzophenone (4,4 0 -DMBP) was found to be effective furnishing 3a aer stirring in acetonitrile under an ambient inert atmosphere for 3 h (Table 1, entry 1, 42%). An investigation of solvents showed that the reaction efficiency was further enhanced when performed in DMSO (Table 1, entry 4, 69%) or acetic acid 6b,13 (entry 5, 70%) as previously observed for radical process with H-phosphinates, whereas moderate yields were obtained with ethyl acetate (entry 2, 46%) or DMF (entry 3, 52%). Importantly a very low catalyst loading could promote the reaction yield up to 84% (entries 6 and 7). Moreover, the loading could be further decreased but a prolonged reaction time was required (Table 1, entry 8, 86%). Interestingly, the photoinitiator DMPA (2,2-dimethoxy-2-phenylacetophenone) was not efficient in our case since the phosphorylated product was formed in a moderate yield (Table 1, entry 15, 32%). Furthermore, none of the common photoinitiators (thioxantone, 4methoxyacetophenone, benzophenone) exhibited a better catalytic effect (Table 1, entries 12-14). Control experiments revealed that the photoinitiator, inert conditions and light were essential for this reaction (Table 1, entries 9-11). It is noteworthy that using a 4,4 0 -DMBP derivative functionalized with an ionic liquid moiety 14 (4,4 0 -(2-(1-methylimidazolium)ethoxy) benzophenone dibromide, DIBP) as photosensitizer led to the same conversions as previously observed furnishing an excellent way to simplify the purication procedure by simple washing of the reaction media thus improving the synthetic efficiency by avoiding chromatography (Table 1, entry 16).
The generality of the method was investigated, with the scope of the reaction being explored with respect to the H-phosphinate component, and the results are summarized in Table 2. Various P(O)-H compounds were employed to react with 1-octene 2a giving the corresponding 3a-g with isolated yields ranging from 30 to 76% (Table 2, entries 1-7). As expected, in all of the cases the anti Markovnikov product was observed. The reaction is not limited to H-phosphinate esters as H-phosphinate acid 1b could also deliver the desired product with a good yield (entry 2, 64%) in contrast to H-phosphinate acid 1c whose corresponding phosphinate acid product 3c was difficult to obtain in high purity (entry 3, 30%). However, Hphosphinate including unactivated alkyl and benzyl derivatives reacted successfully regardless of the ester chosen ( Table 2, entries 4-6). When using (hydroxymethyl)-H-phosphinate ester, which was reported to have several application, 15 the branched product 3g was obtained with a signicant yield of 75% (Table 2,  entry 7). To further evaluate the substrate scope, a series of alkenes were tested with H-phosphinate 1a ( Table 2, entries [8][9][10][11][12]. The reaction with allyl benzene gave the corresponding product 3h with 48% of yield ( Table 2, entry 8). Interestingly, 1a reacted with hindered alkene giving 3i with a modest yield of 27% (Table 2, entry 9). Note that halogens like Br and alcohol groups were well tolerated which indicates a potential for further functionalization ( Table 2, entries 10-12).
Although the detailed reaction mechanism is unclear, based on literature precedents 6i,16 all these results could be well explained by a radical chain mechanism as depicted in Scheme 2. Upon irradiation, the excited state of the photoinitiator 17 abstracts a proton from H-phosphinates to form the phosphoryl radical 18 which adds to the terminal carbon of the alkenes. The carbon centered radical can then abstract a proton from Hphosphinate 1 to regenerate the phosphoryl radical.

Hydrophosphinylation of unactivated alkenes with Hphosphinates under ow conditions
With the successful results for the hydrophosphinylation under batch conditions, the reaction was then performed under continuous ow to further improve its efficiency in a shorter amount of time. The continuous ow hydrophosphinylation was performed using a continuous ow microuidic system composed of a high pressure syringe pump delivering the homogeneous reaction mixture at specic ow rates to a commercially available microreactor (Mikroglas Dwell Device® microreactor from Invenios Europe, Langen, Germany) irradiated by HP UV-A lamp. This microreactor is made up of Foturan® glass that is transparent up to 300 nm allowing to work at a wide range of wavelengths (UV-A & visible).
We were delighted to nd that H-phoshinate derivatives (3a, b, k) could be obtained with 4,4 0 -DMBP as photoinitiator within a shorter reaction time than in batch (30 min vs. 5 h), indicating the importance of the short light path length provided by the microreactor, with slightly higher isolated yield, highlighting the potentials of this process (Scheme 3). This results offer the possibility to conduct the reaction on large scale without erosion of the yields.

Hydrophosphinylation of unactivated alkenes with hypophosphorous acid under batch conditions
To further demonstrate the utility of our protocol, we sought to test its potential for the hydrophosphinylation of various A slight modication of the previous batch conditions (see Table 1, ESI †) allowed us to obtain the corresponding Hphosphinates 1 with 31 P NMR yield ranging from 49 to 96%. A 2 : 1 molar ratio of hypophosphorous acid-alkenes was necessary to obtain a high conversion without the formation of the disubstituted by-product. However despite the observed high conversions, isolated yields were modest due to difficult purications. In all of the cases, the reaction was chemoselective where only mono substituted phosphinates were observed. As for H-phosphinate, the reaction proceeded well with terminal (1c-h) and cyclic alkenes (1j). Hindered alkenes delivered the desired compounds like 1i with a moderate yield of 31%, which is still higher than that obtained with H-phosphinate ester. H-Phosphinate acid 1k however was difficult to obtain in high purity. Similar to the rst reaction assessed, the reaction tolerates functional groups such as amines or alcohols (1l-n) but the obtained H-phosphinate acids were not isolated. Although the scope of this reaction seems to be limited, H-phosphinate acids could be easily esteried 19 in situ and therefore the resulting procedure offers signicant synthetic advantages.

General information
All reagents were purchased from commercial suppliers (Strem Chemicals Inc., Sigma-Aldrich or Alfa Aesar) and were used without further purication. Thin-layer chromatography (TLC) was performed on Silica gel 60 F254 plates (Merck) and visualized under UV (254 nm) or by staining with potassium permanganate or phosphomolybdic acid. Column chromatography was performed with 63-200 mesh silica gel. NMR spectra were recorded on a Bruker AVANCE 300 spectrometer at 300 MHz (75 MHz). Chemical shis are reported in parts per million relative to solvent signal and coupling constants are reported in hertz (Hz). High-resolution mass spectra (HRMS) were performed on a Thermo LTQ Orbitrap mass spectrometer using nanoESI ionization. H-Phosphinates derivatives 1 and 4,4 0 -(2-(1methylimidazolium)ethoxy)benzophenone dibromide (DIBP) 14 were prepared according to the reported procedure. The illumination was performed by UV-A LEDs (365 nm, irradiance ¼ 230 mW cm À2 ) Omnicure® AC475 model from Lumen Dynamics (Excelitas Technologies, Waltham, MA, USA). Note that the irradiance was measured at the surface of the reactor using a radiometer.

General procedure A for the hydrophosphinylation with Hphosphinate 1 derivatives under batch conditions
A solution of a selected H-phosphinate 1 (0.3 mmol, 1 equiv.), an alkene 2 (0.3 mmol, 1 equiv.) and DIPB (0.03-0.15 mmol, 10-50 mol%) in degazed DMSO (1.5 mL) was irradiated under 365 nm and N 2 for 16 h. Ethyl acetate (30 mL) was added and the reaction mixture was washed with saturated solution of NaHCO 3 (2 Â 15 mL) and brine (2 Â 15 mL). The organic layer was dried over MgSO 4 , ltered and concentrated under reduce pressure. The residue was then puried by ash chromatography on silica gel if necessary to afford the corresponding organophosphorous compound. General procedure B for the hydrophosphinylation with hypophosphorous acid To a 50% aqueous solution of hypophosphorous acid (79.2 mg, 0.6 mmol, 2 equiv.) in DMSO (3 mL) was added an alkene 2 (0.3 mmol, 1 equiv.), 4,4 0 -DMPA (15.5 mg, 0.06 mmol, 20 mol%). The reaction mixture was irradiated under 365 nm and ambient atmosphere for 16 h. Ethyl acetate (30 mL) was added and the organic layer was washed with brine (3 Â 15 mL). To the organic layer a 0.03 M solution of NaHCO 3 (30 mL, 1 mmol) was added. The aqueous layer was washed with ethyl acetate (2 Â 15 mL), acidied with 1 M HCl (2 mL, 2 mmol), saturated with NaCl and extracted with ethyl acetate (30 mL). The last ethyl acetate layer was dried over Na 2 SO 4 , ltered and concentrated under reduce pressure. The residue was then puried by ash chromatography on silica gel using 9 : 1 : 0.5 DCM-MeOH-AcOH as the eluant to afford the desired pure H-phosphinate acid 1.

Conclusions
In conclusion, we developed an efficient UV-mediated hydrophosphinylation of unactivated alkenes with H-phosphinate under free radical conditions giving a straightforward access to a wide range of phosphorous compounds providing a metal free alternative for the preparation and functionalization of P(O)-H bonds. This reaction can be carried out using an ionic liquid soluble photosensitizer while maintaining good yield. Furthermore, the reaction with hypophosphorous acid is disclosed for the rst time. Finally, a continuous ow hydrophosphinylation was also reported which allowed faster reaction time with high yields, highlighting the potential of our methodology for rapid scale up and in-line synthesis. Taking into account the simplicity of our reaction conditions we believe this procedure will be appealing for further chemical and pharmaceutical applications.

Conflicts of interest
There are no conicts to declare.