Bifunctionalized Allenes. Part XIII. A Convenient and Efficient Method for Regioselective Synthesis of Phosphorylated α-Hydroxyallenes with Protected and Unprotected Hydroxy Group

The paper describes a convenient and efficient method for regioselective synthesis of phosphorylated α-hydroxyallenes using an atom economical [2,3]-sigmatropic rearrangement of intermediate propargyl phosphites or phosphinites. These can be readily prepared via reaction of protected alkynols with dimethyl chlorophosphite or chlorodiphenyl phosphine respectively in the presence of a base.


Introduction
The synthesis and application of allene derivatives has had a great influence in preparative organic chemistry during the last three decades. The crucial structural characteristic of allenes is the presence of two π electron clouds separated by a single sp-hybridized carbon atom. Due to that very unique structural and electronic arrangement allenic compounds have an extraordinary reactivity profiles [1][2][3][4][5][6][7][8]. Moreover, functionalized allenes have also attracted growing attention due to their versatility as key building blocks for organic synthesis. The synthetic potential of functionalized allenes has been OPEN ACCESS thoroughly explored in recent years. The research in that area has led to the development of novel methods for the construction of a variety of functionalized heterocyclic and carbocyclic systems [9][10][11][12][13].
Since the reversible interconversion of propargylic phosphites, phosphonites and phosphinites to allenyl phosphonates, phosphinates and phosphine oxides was discovered five decades ago [60,61], it has become one of the most thoroughly investigated and synthetically applied [2,3]-sigmatropic rearrangements. Numerous synthetic applications of the rearrangement have been reported, such as its use in the synthesis of allenic steroids for substrate-induced inactivation of aromatase [72], in the efficient synthesis of (2R)-2-amino-5-phosphonopentanoic acid (AP5) as a powerful and selective N-methyl-D-aspartate (NMDA) antagonist [73], in the preparation of the phosphonate analogues of phosphatidyl derivatives [74,75], and, in the synthesis of new acyclic analogues of nucleotides containing a purine or pyrimidine moiety and an allenic skeleton [76,77].
Our research program on the chemistry of the bifunctionalized allenes requires a convenient method to introduce a phosphorus-containing group such as phosphonate or phosphine oxide group as well as a hydroxyalkyl group in the first position to the allenic system of double bonds. The above-mentioned groups attract more and more researchers' attention as useful functionalities in organic synthesis. The emphasis is particularly on the applications of these groups as temporary transformers of chemical reactivity of the allenic system in the synthesis of eventually heterocyclic compounds.

Synthesis of Phosphorylated α-Hydroxyallenes with Protected Hydroxy Group
The main target in our research, and namely 1,1-bifunctionalized allenes, was achieved as a range of the phosphorylated α-hydroxyallenes 7, 9, 10, and 11 were prepared by applying the following four-step procedure: (i) protection of hydroxy group in the propagylic alcohols 1; (ii) subsequent reaction with Grignard reagent to give the protected alkynols 5; (iii) interaction with dimethyl chlorophosphite or chlorodiphenyl phosphine in the presence of a base; and finally (iv) [2,3]-sigmatropic rearrangement of the protected propargyl phosphites or phosphinites.

Synthesis of Phosphorylated α-Hydroxyallenes with Unprotected Hydroxy Group
Compounds 7 and 9 were stable enough to be handled at ambient temperature. The hydroxy group was deprotected by stirring the ethanol solution of the protected hydroxylalkyl-allenephosphonates 7 and hydroxylalkyl-allenyl phosphine oxides 9 in the presence of 0.1 equiv. PPTS at room temperature for 6 h, according to Scheme 4 and Table 4.    After a conventional work-up, all allenic products 7, 9, 10, and 11 were isolated as stable yellow or orange oils by column chromatography and identified by 1 H-, 13 C-, and 31 P-NMR and IR spectra as well as by elemental analysis.

General Information
All new synthesized compounds were purified by column chromatography and characterized on the basis of NMR, IR, and microanalytical data. NMR spectra were recorded on DRX Bruker Avance-250 ( 1 H at 250.1 MHz, 13 C at 62.9 MHz, 31 P at 101.2 MHz) and Bruker Avance II + 600 (Bruker BioSpinGmbH, Karlsruhe, Germany) ( 1 H at 600.1 MHz, 13 C at 150.9 MHz, 31 P at 242.9 MHz) spectrometers for solutions in CDCl 3 . All 1 H-and 13 C-NMR experiments were measured referring to the signal of internal TMS and 31 P-NMR experiments were measured referring to the signal of external 85% H 3 PO 4 . J values are given in hertz. IR spectra were recorded with an FT-IRAfinity-1 Shimadzu spectrophotometer (Shimadzu, Tokyo, Japan). Elemental analyses were carried out by the Microanalytical Service Laboratory of Faculty of Chemistry and Pharmacy, University of Sofia, Bulgaria, using Vario EL3 CHNS(O) (Elementar Analysensysteme, Hanau, Germany). Column chromatography was performed on Kieselgel F 254 60 (70-230 mesh ASTM, 0.063-0.200 nm, Merck, Darmstadt, Germany). Et 2 O and THF were distilled from Na wire/benzophenone, CH 2 Cl 2 was distilled over CaH 2 , other commercially available chemicals were used without additional purification unless otherwise noted. Reactions were carried out in oven dried glassware under an argon atmosphere and exclusion of moisture. All compounds were checked for purity on TLC plates Kieselgel F 254 60 (Merck). [80][81][82][83] for Synthesis of the Alkynyloxy-tetrahydro-2H-pyrans 2 A solution of alkynols 1 (60.0 mmol) and DHP (7.6 g, 90.0 mmol) [0.152 g/mL] in dry methylene chloride (50 mL) containing PPTS (1.5 g, 6.0 mmol) [0.03 g/mL] is stirred for 4 h at room temperature. Then the reaction was quenched with saturated NaHCO 3 end extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, distillation gives an essentially quantitative yield of the alkynyloxy-tetrahydro-2H-pyrans 2 (95%-99%) which are described in the literature [80][81][82][83].

General Procedure for Synthesis of (Tetrahydro-2H-pyran-2-yloxy)-alkynols 5
Ethylmagnesium bromide [prepared from magnesium (1.2 g, 50.0 mmol) [0.024 g/mL] and ethyl bromide (5.5 g, 50.0 mmol) [0.11 g/mL] in dry THF (50 mL)] is added dropwise under stirring to substituted alkynyloxy-tetrahydro-2H-pyrans 2 (50.0 mmol) and then the mixture is refluxed for 2 h. The solution of the prepared alkynyl magnesium bromides 3 is added dropwise under stirring to the ketones 4 (100.0 mmol). The mixture is refluxed for 24 h and after cooling is hydrolyzed with a saturated aqueous solution of ammonium chloride. The organic layer is separated, washed with water, and dried over over anhydrous sodium sulfate. Solvent and the excess of ketone are removed by distillation. Purification of the residue is achieved by column chromatography (silica gel, Kieselgel Merck 60 F 254 ) with ethyl acetate-hexane (5:1). The pure products 5 had the following properties:     13

Conclusions
In conclusion, a convenient and efficient method for regioselective synthesis of a new family of 1,1-bifunctionalized allenes has been explored. Phosphorylated α-hydroxyallenes prepared were derived from [2,3]-sigmatropic rearrangement of the intermediate propargyl phosphites or phosphinites formed in the reaction of protected alkynols with dimethylchloro phosphite or chlorodiphenyl phosphine in the presence of a base. Further investigations on this potentially important synthetic methodology are currently in progress. At the same time, the synthetic application of the prepared phosphorylated α-hydroxyallenes with protected or unprotected hydroxy group for synthesis of different heterocyclic compounds is now under investigation in our laboratory as a part of our general synthetic strategy for investigation of the scope and limitations of the electrophilic cyclization and cycloisomerization reactions of bifunctionalized allenes. Results of these investigations will be reported in due course.