Phospha-Michael reactions

The phospha-Michael reaction has been the last hetero-Michael reaction to be developed under iminium activation. In addition to the selectivity issues that have to be addressed, the identification of a suitable phosphorous nucleophile has been the most difficult task to overcome when developing the reaction because of the high tendency of phosphines toward oxidation in the presence of air. The first example was developed independently by Melchiorre and 

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Terada expanded the phospha-Michael reaction to include diphenyl-phosphites [128]. A novel binaphthol-derived guanidine catalyst promoted the addition in high yields and enantioselectivities (Scheme 73). Functionalizing the external nitrogen with a diphenylmethine moeity enhanced selectivities for a large scope of nitro-olefm derivatives. 

Asymmetric synthesis of P-phosphono-malonates via K0H/Fe203 catalyzed phospha-Michael reaction to Knoevenagel acceptors has been achieved by Enders and Tedeschi [57]. The reaction did not proceed when only KOH was used as a catalyst Fe203 was the best diastereoselective support among the other supports tested, A1203, ZnO, Cu20, Mn02 and MgO. 

Alkyl phosphonates are prepared smoothly by TMG (1) catalysed aldol-type addition of dialkyl phosphites to ketones and imines under mild conditions [28] (Scheme 4.9). Dialkyl phosphites can also serve as good nucleophiles for Michael addition (phospha-Michael Reaction). 

Scheme 3.37 Enantioselective phospha-Michael reactions between diphenylphosphine and a,P-unsaturated aldehydes.

For a leading review on the asymmetric phospha-Michael reaction see D. Enders, A. Saint-Dizier, M.-I. Lannou and A. Lenzen, Eur. J. Org. Chem., 2005, 29. 

Scheme 4.74 The catalytic enantioselective phospha-Michael reactions using cinchona alkaloid-based catalysts.

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

Phospha-Michael reactions are useful to establish a P-C bond. The addition of >P(0)H species (e.g., dialkyl phosphites and secondary phosphine oxides) at the end of electron-poor double bonds may be facilitated by bases, like NaOR, NaOH, or DBU [56]. The addition of P-heterocyclic nucleophiles was also studied. Dibenzo[c.e][l,2]oxa-phosphorine oxide (36) added easily on the double bond of methyl vinyl ketone xmder MW conditions in the absence of any solvent (Scheme 12) [57]. 

The MW-assisted phospha-Michael reaction was then extended to the addition of dialkyl phosphites, a phenyl-H-phosphinate and diphenylphosphine oxide to maleic derivatives, N-substituted maleimide, and maleic acid anhydride giving rise to >P(0)-substituted succinic derivatives (38 and 39) (Scheme 13) [58]. 

SCHEME 13 Phospha-Michael reactions between >P(0)H species and maleic derivatives. 

SCHEME 14 Phospha-Michael reactions with l-phenyl-2-phospholene 1-oxide. 

G. Keglevich, M. Sipos, D. Takacs, K. Ludanyi, Phospha-Michael reactions involving P-heterocyclic nucleophiles. Heteroatom Chem. 19 (2008) 288-292. 

SCHEME 4.64 Potassium carbonate-promoted phospha-Michael reactions [117]. 

SCHEME 4.67 Sodium hydride-promoted phospha-Michael reactions [120, 121],... 

Despite the great interest in chiral phosphines and the success in the phospha-Michael addition to enals, only one example of an organocatalytic phospha-Michael reaction to enones can be found in the Uterature. 

The mechanism and origin of enantioselectivity has been evaluated for a bicyclic guanidine-catalyzed phospha-Michael reaction between diphenyl-phosphine oxide and p-nitrostyrene by DFT calculations (Scheme 32). The catalyst was found to be involved in all three steps of the catalytic cycle proposed. 

An one-pot convenient method for the synthesis of a variety of 2,2 -dicyanoalkylphosphonates (557) by a tandem Knoevenagel-phospha-Michael reaction of triethyl phosphite (556) with aryl/heteroaryl/alkyl aldehydes (554) and malonitrile (555) in an aqueous micellar solution of sodium stearate,using surfactants, such as cetyltrimethylammonium bromide as a eationic mieelle and TritonX-100 as a neutral micelle at their critical micellar eoncentrations (CMC), has been described by Sobhani and Parizi (Scheme 138). ... 

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