Highly efficient and extremely simple protocol for the oxidation α-hydroxyphosphonates to α-ketophosphonates using Dess-Martin periodinane

Dess-Martin periodinane has been demonstrated for the first time to be an efficient reagent in metal – free oxidation of α-hydroxyphosphonates to α-ketophosphonates under ambient conditions. Acquiescent reaction conditions and a simple isolation procedure are the noteworthy features of the developed protocol.


Introduction
In organophosphorus chemistry, phosphonates are interesting complements to phosphates in terms of biological activity. 1 α-Ketophosphonates act as, mimic of phosphoserine in drug development process 2 , as enzyme inhibitors 3 and inhibitors of PTPIB. 4 The α-ketophosphonates constitute as an important class of organophosphonates and are fascinating as well as versatile molecules in organic synthesis. 5Apart from their possible derivatization to hydrazones, 6 oximes 7 as well as imines 8 they can be reduced to corresponding αhydroxyphosphonates, 9,10 and can be used as acylating agents and in the Wittig reaction 11 .They can serve as substrates in stereoselective aldol, 12,13 Mukaiyama 14 and in retro Diels-Alder reaction. 15,16ichaelis-Arbuzov reaction between an acid chloride and trialkylphosphite is a general method for the preparation of α-ketophosphonates. 17,18However, the method is suitable mainly for simple aromatic as well as aliphatic acid chlorides.Alternatively, they can also be prepared by the oxidation of an easily accessible αhydroxyphosphonate.Our interest in the synthesis of α-ketophosphonates stems from an earlier report on the synthesis of α-hydroxyphosphonates from our laboratory. 19In continuation of the same, we planned to undertake the synthesis of α-ketophosphonates by oxidation of α-hydroxyphosphonates.
A literature survey revealed that the oxidation protocols reported to this aim mostly employ either high valent metal oxide (MnO2, 20 CrO3 21 ) or their mineral salts (KMnO4, 22 ZnDC 23 , PCC, 24 PDC 25 and QCC 26 ).However, these protocols are plagued with the necessity of more than a stoichiometric amount of toxic metal salts coupled with the generation of inorganic waste and these facts are the matters of serious concern in the context of environmental compatibility.To circumvent these issues we had developed a conceptually different protocol for the synthesis of α-ketophosphonates by oxidation of corresponding α-trimethylsilyloxy phosphonates under free-radical conditions 27 (Scheme 1A).However, the essentiality of the prior synthesis of α-trimethylsilyloxy phosphonates and reflux conditions remains to be the major limiting factors of this protocol.Consequently, there still remains scope for further innovation towards operational simplicity, milder reaction conditions and shorter reaction times coupled with the avoidance of toxic metal salts in the oxidation of α-hydroxyphosphonates to α-ketophosphonates.With our continued interest in the development of newer synthetic methodologies, we set out to develop a practical method for the oxidation of αhydroxyphosphonates to α-ketophosphonates (Scheme 1B).

Results and Discussion
A great variety of oxidants bear testimony in the literature for the oxidation of alcohols.However, the very high sensitivity of C(O)-P bond in the resultant α-ketophosphonates towards hydrolysis poses limitations in the selection of proper oxidant as well as the reaction conditions.Keeping this particular limitation in mind we planned to develop a metal-free protocol for the synthesis of α-ketophosphonates.
It is well known that, oxone is a stable 2:1:1 ternary composite of KHSO5, K2SO4 and KHSO4 and it's use in various organic transformations is well documented.We have reported earlier the use of oxone in the oxidation of sulfides to sulfoxides as well as sulfones, 28 in the oxidation of hydrazides to diacylhydrazines. 29owever, the use of water being essential in oxone mediated oxidation of alcohols and the same being detrimental in the oxidation of α-hydroxyphosphonates, we focused our search on the reports on the use of water insoluble oxone derivatives in the oxidation of alcohols.It was revealed that two derivatives of oxone viz.1][32][33][34] However, these reagents have not been explored in the oxidation of α-hydroxy phosphonates.Hence, two model reactions were initially performed using diethyl [(4-chlorophenyl) (hydroxy) methyl] phosphonate, 1a, as the substrate.Thus, to a well stirred solution of 1a (1mmol) in dry acetonitrile (5 mL) was added TBAP or BTPP (300 mg).Stirring was continued and the reaction was monitored by TLC.However, both these oxidants failed to furnish desired αketophosphonate, 2a, in acceptable yield at ambient temperature.Heating the same reaction mixture under reflux was also not beneficial in driving the reaction to completion (entry 1, 2, Table 1).During our search on protocols for the oxidation of alcohols under heterogeneous conditions, we came across an interesting report on the use of silver carbonate supported on cetrimide to this effect. 35However, when the model reaction was performed using the reaction conditions reported for the oxidation of alcohols, 35 the catalyst failed to furnish desired α-ketophosphonate, 2a, in acceptable yield (entry 3, Table 1).All these results prompted us to search for other oxidants for this oxidative transformation.
In recent years, the use of hypervalent iodine reagents such as, Dess Martin periodinane, as well as its cheaper precursor, viz.o-iodoxybezoic acid (IBX) have become the reagents of choice in the oxidation of alcohols and in different areas of organic synthesis. 36Until recently, the practical utility of IBX was limited owing to its insolubility in common organic solvents.However, there are now reports on the use of IBX for the oxidation of alcohols in common organic solvents. 37This prompted us to test the efficacy of IBX in the oxidation of α-hydroxyphosphonates.Thus, a well stirred mixture of α-hydroxyphosphonate, 1a, and IBX (1 mmol, each) was allowed to reflux in dry acetonitrile (5 mL) and the reaction was monitored by TLC.No appreciable conversion of α-hydroxyphosphonate, 1a, to ketophosphonate, 2a, was noticed (entry 4, Table 1).The reaction was then repeated using double as well as triple equivalents of IBX in acetonitrile as well as ethyl acetate as the reaction media.Although a noticeable increase in the yield of expected α-ketophosphonate, 2a, was observed, even after prolonged heating the reaction did not go to completion (Entry 5, 6; Table 1).9][40][41][42][43][44][45] Based upon these studies it was planned to explore this reagent-oxidant combination in the oxidation of 1a.Accordingly, a model reaction was carried wherein a mixture of 1a (1mmol), IBX (0.1 mmol) and BTPP (1 mmol) in dry acetonitrile (5 mL) was stirred under reflux conditions.We did not notice any appreciable progress in the reaction (entry 7, Table 1).However, with an increase in the proportion of BTPP from one equivalent to three equivalents, the desired ketophosphonate, 2a, resulted in excellent yield (entry 8, Table 1).At this stage, it is worthy to note that although we were successful in obtaining the desired αketophosphonate, 2a, in excellent yield and in an acceptable time, the main limitations of using IBX -BTPP combination were associated with very high proportion of BTPP, it's high molecular weight, cost and, the reflux conditions.To circumvent these limitations, we planned to test the suitability of another hypervalent oxidant viz.Dess Martin periodinane, DMP, in the oxidation of α-hydroxyphosphonates.We can disclose that simple stirring together at ambient temperature a solution of 1a, and Dess-Marin periodinane (1:1 equiv.) in dry acetonitrile or dichloromethane (5 mL) afforded the desired α-ketophosphonate, 2a, in excellent yield in a very short time (entry 9, Table 1).
With a view to establish the generality of the reaction conditions and to explore the scope of the developed protocol, variety of α-hydroxyphosphonates having electron donating as well as electron withdrawing substituents were shown to undergo smooth oxidation to furnish corresponding αketophosphonates in excellent yield (Table 2).Similarly, the α-hydroxy phosphonates derived from heterocyclic as well as conjugated aldehyde viz.cinnamaldehyde also furnished corresponding αketophosphonate.In general the reactions were fast and no undesirable products were detected.

Conclusions
In summary, we have developed a clean and practically simple protocol for the oxidation of αhydroxyphosphonates to α-ketophosphonates in excellent yields using Dess-Martin periodinane as an efficient oxidizing agent.Ambient reaction conditions, metal-free environment and very short reaction times are the noteworthy features of the developed protocol.

Experimental Section
General.α-Hydroxyphosphonates were prepared by potassium phosphate-catalyzed reaction of respective phosphites with various aldehydes. 19