Imines phosphorus nucleophile addition

If a nucleophilic addition at a carbonyl or imine carbon occurs, the product is still a phosphinate (from a phosphonous ester) or a phosphine oxide (from a phosphinous ester), but the reaction is commonly referred to as an Abramov or Pudovik reaction. An example of the Pudovik reaction is shown below (equation 16). Addition of the phosphorus nucleophile to the /3-carbon atom of an a, /3-unsaturated substrate (Michael addition) is commonly referred to as a hydrophosphinylation reaction. ... 

As shown in Fig. 8, two possibilities are conceivable for the addition step of the imine to the lanthanoid-phosphite complex Ha. To determine whether structure V or VI seems to be the more reasonable in the addition reaction of a dimethyl phosphite with the C=N double bond of cyclic imines, several hydrophos-phonylation experiments using different types of phosphites were carried out in the presence or absence of the Lewis acid boron trifluoride. As it was shown that a high level of Lewis acid activation of the imine is required independently from the nucleophilicity of the phosphorus nucleophile which was used, a transition state of type VI appeared to exist as the dominant transition state structure. 

The asymmetric addition of phosphorus nucleophiles to imines provides direct access to phosphorus-containing chiral amines. While this chemistry is dominated by the use of phosphites and related compounds, a report by Duan outlines a successful protocol for the asymmetric addition of secondary phosphines to imines (Scheme 4.30) [81]. The reaction was catalyzed by a chiral palladium compound comprised of a palladium(II) center Ugated by a resolved pincer compound. A range of aryl and heteroaryl imines as well as several secondary phosphines were successfully used in this reaction. To aid in the isolation of the phosphines, the authors added elanental sulfur at the end of the P—C bond-fomung reaction. This chenustry provides access to a range of chiral N,P Ugands for metal centers that were previously challenging to prepare and isolate. 

Addition of Phosphorus Nucleophiles to Imines As the Pudovik and the Abramov reactions constitute phosphorus analogs of the aldol reaction, there is also a phosphorus equivalent for the Mannich reaction, namely, the Kabachnik-Fields reaction (see Scheme 47.7). In this process, phosphorus nucleophiles add to imines to produce a-aminophosphonate derivatives, which can be considered amino acid analogs. These compounds by themselves, or when incorporated into short peptides, find applications as enzyme inhibitors or as antibacterial and antifungal agents. However, in only a few instances were optically pure derivatives prepared for biological and pharmaceutical applications. Examples include the synthesis of antibiotic ala-fosfalin 82, penicillopepsin 83, and HIV protease... 

An interesting example of a diastereoselective addition of a phosphorus nucleophile to imines is the reaction used for the preparation of iminosugar phosphonates (Scheme 47.23). In this synthetic protocol, imine 101 reacted with a silylated P(III) derivative with high diastereoselectivity, producing intermediate 102 that upon deprotection was... 

Along with diastereoselective reactions, an enantioselec-tive addition of phosphorus nucleophiles to imines, using chiral catalysts, has also been developed. In some cases, the same catalysts as those for the hydrophosphony-lation of a carbonyl group were used. 

As well as the Bingel reaction and its modifications some more reactions that involve the addition-elimination mechanism have been discovered. 1,2-Methano-[60]fullerenes are obtainable in good yields by reaction with phosphorus- [44] or sulfur-ylides [45,46] or by fluorine-ion-mediated reaction with silylated nucleophiles [47]. The reaction with ylides requires stabilized sulfur or phosphorus ylides (Scheme 3.9). As well as representing a new route to l,2-methano[60]fullerenes, the synthesis of methanofullerenes with a formyl group at the bridgehead-carbon is possible. This formyl-group can be easily transformed into imines with various aromatic amines. 

The most common method for the synthesis of phosphinopeptides is the addition of a nucleophilic, trivalent phosphorus species to a carbon electrophile, including conjugated double bonds, alkylating agents, imines, and carbonyl compounds. By analogy with the phosphite ester additions described above, the nucleophilic form of a phosphinic acid is the trivalent species, generated from the more stable, pentavalent PH derivative by deprotonation or by silylation (cf. Scheme 2). 

With a YbPB catalyst at room temperature, 86% yield and 98% ee were obtained. After extensive optimization of the catalyst, solvent, temperature, pressure, and catalytic loading, 98% yield and 98% ee was achieved using YbPB (5 mol%) at 50°C for 48 h in 1 7 THFitoluene. The active catalyst was isolated its structure is similar to that shown in Scheme 5-46, and a similar mechanism was proposed. Additional spectroscopic studies suggested that complexation of the phosphite to the lanthanide center was a plausible first step, and that the P-C bond is formed by nucleophilic attack of phosphorus on an N-complexed imine [34]. 

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