Aminoalkylphosphinic acids

Chen, S. and Coward, J.K., A general method for the synthesis of N-protected a-aminoalkylphosphinic acids, Tetrahedron Lett., 37, 4335, 1996. 

The [l-(benzhydrylamino)alkyl]phosphinic acid 32 was heated with an excess of 48% HBr (5 times weight) at 100 °C for 1-2 h until two distinct phases separated. (Note the 48% HBr is pretreated by extraction three times with an equal volume of CH2C12 to remove any bromine, which oxidizes the phosphinic acid.) The mixture was concentrated to dryness under reduced pressure and the residue was taken up in H20. The aqueous soln was washed several times with Et20 to remove DpmBr and concentrated to a thick oil. (Note complete removal of the solvent is important at this point otherwise, residual HBr interferes in the next step.) The oily residue of 1-aminoalkylphosphinic acid hydrobromide was dissolved in EtOH (lOmL-g ) and propylene oxide was added dropwise until precipitation began. The mixture was allowed to stand until precipitation was complete, and the solid 33 was collected by filtration, washed successively with EtOH and Et20, and dried. For Alap analogue mp 223-224 °C 31P NMR (D20, 5) 22.2. 

A mixture of the alkylated adducts 39 and 1.5M HC1 (15-20mL-mmol ) was heated to reflux for 2-8h until hydrolysis was complete, as determined by 31P NMR. The mixture was concentrated in vacuo, the residue was dissolved in H20, and the soln was washed with Et20 and reconcentrated in vacuo. The product was finally purified by ion-exchange chromatography or by dissolution in hot EtOH (twice the minimum volume required) followed by cooling to rt and precipitation of the zwitterion by the addition of propylene oxide. The 1-aminoalkylphosphinic acids 33 were isolated as white solids. 

If desired, aminoalkylphosphinic acids may be readily oxidized to the phosphonic acid derivatives.[56,63] In fact, some care needs to be taken to exclude air when working with or storing phosphinic acids to prevent this oxidation. 

Scheme 15 Resolution of Z- and Boc-Protected Aminoalkylphosphinic Acids by Crystallization of...

The first enantioselective synthesis of 1-aminoalkylphosphinic acids (319) based on the addition of phenylphosphinate (320) to chiral imines (321) and standard removal of protecting groups from the adducts (322) has been realized (Scheme 86). 

The ready oxidation of (l-aminoalkyl)phosphonous acids (aminoalkylphosphinic acids) with aqueous bromine, to give (l-aminoalkyl)phosphonic acids, raises still further the potential usefulness of the former. In a useful modification to one synthesis, the reaction between an aldehyde and either (R)- or (5 )-l-phenylethylamine hypophosphite salt yields the A-substituted (l-aminoalkyl)phosphinic acid which is simultaneously oxidized and deprotected when treated with bromine water. ... 

Salicylaldehyde and triethyl phosphite upon heating gave, instead of the expected diphosphonate (20), the rearranged phosphate-phosphonate (21). A new method to obtain 1-aminoalkylphosphinic acids (22) has been published it involves addition of bis(trimethylsilyl) phosphonite to Af-trityl imines, followed by hydrolysis. A similar reaction of bis(trimethylsilyl) phosphonite with 1-pyrroline trimer gave 2-pyrrolidinylphosphinic acid in 90% yield. Bis(trimethylsilyl) phosphonite with carbamoyl chlorides and triethylamine gave fair yields of the carbamoylphosphonites (23). ... 

Scheme 13 Synthesis of a-Aminoalkylphosphinates from Phosphinic Acid 56"59 ...

Intramolecular transesterification of aminoalkylphosphinate (400) and direct intramolecular esterification of the related phosphinic acid (401) provided a simple route to a new 2-oxo-l,4,2-oxazephosphinane (402) (Figure 69). ... 

The procedure by which the first representatives were obtained <78TL44l, 78JOM(i54)l> proved very effective. It starts with the four-membered chain of a 2-aminoalkylphosphine/arsine or 2-aminophenylphosphine/arsine and completes the ring by condensation with a carboxyUc acid derivative. In the former case full unsaturation is reached by thermolysis of the condensation product... 

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