The McKenna reaction – avoiding side reactions in phosphonate deprotection

The McKenna reaction is a well-known and popular method for the efficient and mild synthesis of organophosphorus acids. Bromotrimethylsilane (BTMS) is the main reagent in this reaction, which transforms dialkyl phosphonate esters into bis(trimethylsilyl)esters, which are then easily converted into the target acids. However, the versatile character of the McKenna reaction is not always used to its full extent, due to formation of side products. Herein, demonstrated by using model examples we have not only analyzed the typical side processes accompanying the McKenna reaction, but also uncovered new ones. Further, we discovered that some commonly recommended precautions did not always circumvent the side reactions. The proposed results and recommendations may facilitate the synthesis of phosphonic acids.


General procedure: 3 Synthesis of phosphonocarboxylate analogues of risedronate
(9a-e) Step I: The reaction was run under inert gas atmosphere (Ar). In a dried round-bottomed flask equipped with a septum the appropriate phosphonoacetate (1 equiv) in 15 mL of dry S4 dichloromethane (0.3 M solution) was placed. The mixture was cooled to −40 °C and TiCl4 (1 equiv) and triethylamine (2.8 equiv) were added slowly, maintaining the temperature constant. After 15 minutes, 3-pyridinealdehyde was added dropwise. The reaction mixture was stirred for 30 min at −40 °C, followed by 24 h at room temperature. Then, 30 mL of water and saturated Na2CO3 were added to adjust pH to around 9 and the mixture was extracted with CHCl3 (5 × 30 mL). The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash column chromatography (DCM/acetone 0-30%).
Step II: In a round-bottomed flask the appropriate vinyl analogue of phosphonocarboxylate (1 equiv) in MeOH (0.1 M solution) was placed. Then, the NiCl2·6H2O (1.2 equiv) was added, the mixture cooled to −40 °C and NaBH4 added in portions until the substrate disappeared as monitored by mass spectrometry. The reaction was quenched by the addition of a saturated aqueous solution of NH4Cl and the mixture extracted with CH2Cl2 (4 × 60 mL) at pH 9 (adjusted with Na2CO3(sat.)). The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash column chromatography (DCM/acetone 0-50%).
Step III: The reaction was run under inert gas atmosphere (Ar). In a dried round-bottomed flask equipped with a septum NaH (1.2 equiv; 60% dispersion in mineral oil) in 10 mL of dry THF

2-Chloro-N-phenethylacetamide (13)
(The procedure is based on a modified method from literature. 5

Synthesis of compounds 15-17
The reactions were run under inert gas atmosphere (Ar). In a dried round-bottomed flask equipped with a septum 4-nitro-N-(prop-2-yn-1-yl)benzamide (10, 0.245 mmol, 1 equiv) was placed and dissolved in dry ACN (50 mg/1.5 mL). Then, triethyl phosphonoacetate (0.245 mmol, 1 equiv) and H2O (0.490 mmol, 2 equiv) were subsequently added, followed by BTMS (2.94 mmol, 12 equiv). The septum was exchanged with a fitted glass stopper and additionally secured with parafilm. After 24 h in a 36 °C sand bath, the solution was evaporated and the mixture was subjected to solvolysis in acetone. After 5 min, the solvent was evaporated, the residue dissolved in CHCl3 and extracted with NaHCO3 (2 × 2,5 mL). The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash column chromatography (CH2Cl2).  Found 284.9874.

3-Bromo-N-phenethylpropanamide (18)
The reaction was run under inert gas atmosphere (Ar). In a dried round-bottomed flask equipped with a septum N-phenethylacrylamide (11, 0.285 mmol, 1 equiv) was placed and dissolved in dry ACN (50 mg/1.5 mL). Then, triethyl phosphonoacetate (0.285 mmol, 1 equiv) and H2O (0.143 mmol, 0.5 equiv) were subsequently added, followed by BTMS (not distilled, 3.42 mmol, 12 equiv). The septum was exchanged with a fitted glass stopper and additionally secured with parafilm. After 24 h in a 36 °C sand bath the solution was evaporated and the mixture was subjected to solvolysis in acetone. After 5 min, the solvent was evaporated, the residue dissolved in CHCl3 and extracted with NaHCO3 (2 × 2.5 mL). The extract was dried (MgSO4) and concentrated to give the crude product, which was purified by flash column chromatography (DCM/acetone 0-10%).
After 24 h in a 36 °C sand bath the solution was evaporated and the mixture was subjected to solvolysis in acetone. After 5 min the solvent was evaporated.

X-ray Crystallography of compound 15
X-ray data of single crystals of the title compound were measured on an APEX II CCD X-ray diffractometer using graphite-monochromated CuKα radiation (λ = 1.54184 Å). Data were collected using the APEX-II software 9 , integrated using SAINT 10 and corrected for absorption using the multi-scan approach (SADABS). 11 Final cell constants were determined from full least squares refinements of all observed reflections. The structures were solved using intrinsic phasing (SHELXT) 12 and refined with full squares refinement on F 2 using the SHELXTL software. 13,14 All hydrogen atoms were added at calculated positions and refined isotropically with a riding model. A thermal ellipsoid plot of the title compound is given in Figure S3. A summary of the experimental crystallographic data is presented in Table S1. The crystallographic data (CCDC 1919198) have been deposited in the Cambridge Crystallographic Data Base. S13 Figure S3: Molecular structure of 15 from X-ray crystallographic analysis. (Thermal ellipsoids are shown at the 50% probability level.)

Note
Since compounds 16 and 17 were isolated as mixture, for the description of NMR data symbols (16 and 17) were used whenever distinction was possible. When two complementary signals overlapped, no distinction was made.

Optimization of oxazole synthesis
In the first approach we generated HBr by the reaction between equimolar amounts of BTMS and water (0.5:0.5 and 3:3) (Table S2, entry 2 and 3). We obtained mixture of products and substrate, achieving higher conversion for the 3:3 molar ratio of reagents.
Next, we excluded BTMS from the reaction and used 33% HBr in AcOH or 40% HBr in H2O, respectively. The application of the HBr solution in AcOH led again to a mixture of products 15-17 and the substrate (Table S2, entries 4-6), while using solely hydrobromic acid (40%) led to recovery of the substrate (Table S2, entry 7).