Phosphorus electrophiles

Diylide 1, by reaction with a phosphorus electrophile, Ph2PCl, lead instantaneously via a nucleophilic substitution and intramolecular prototropy to the formation of functionalized monoylides 10 (Scheme 11). 

Other procedures for the synthesis of P-ketophosphonates based on the use of a phosphorus electrophile have been explored. For example, the reaction of dialkyl chlorophosphates with the dilithium derivatives of a-bromo ketones has been described,but the yields of isolated products remain modest. The Lewis acid-catalyzed reaction of oc-hydroxy ketones with dialkyl chlorophosphites constitutes an efficient synthesis of P-ketophosphonates in high yields (92-96%, Scheme 7.42). This reaction is of special value for the preparation of oc-fully substituted P-keto-phosphonates. ... 

Taillefer et al. have reported a one-pot method for the preparation of a, 3-unsaturated organophosphorus compounds through the reaction of lithium diphenylphosphonium diylides with phosphorus electrophiles and aldehydes. In the first step, treatment of diylides (91) with chlorodiphenylphosphine results in the formation of mono-ylide intermediates (92) and (93). Subsequent addition of aldehyde (94) produces either alkenes (95) or phosphines (96) (Scheme 22). The product obtained is critically dependent upon the nature of the ylide substituents and the aldehyde employed. For example, non-stabilised ylide (91a) reacts with chlorodiphenylphosphine and aromatic, heteroaromatic or enolisable aldehydes (94a-f) producing the corresponding phosphines (96), predominantly as the Z isomer. However, with 4-phenylcyclohexanone the only product obtained from (91a) is the alkene, (4-methylenecyclohex-l-yl)benzene. Non-stabilised ylide (91b) reacts with chlorodiphenylphosphine and benzaldehyde (94a) to give primarily alkene product whereas para-nitrobenzaldehyde (94c) yields only the phosphine product. Semi-stabilised ylide (91c), and stabilised ylide (91d), react... 

The amido proton of the backbone linkage 119-120 and Gln-11 both act to increase phosphorus electrophilicity by coordination with phosphate oxygens ... 

Lys-41, although 3A distant from the TBP, increases phosphorus electrophilicity and stabilizes the phosphorus TBP. 

It is generally claimed that phosphoryl transfer may follow basically two pathways (see O Fig. 5.1). In the dissociative mechanism a trigonal metaphosphate intermediate is formed (Xu and Guo 2008), while the associative mechanism involves a relatively stable, trigonal bipyra-midal intermediate (Lahiri et al. 2003). Note that an intermediate refers to a local energy minimum on the reaction path. However, a third option has to be mentioned, too, this is the classical Sn2 mechanism with a trigonal bipyramidal transition state, referring to a maximum on the reaction path (Bernardi et al. 2002). The preferred pathway is determined by the nature of the phosphorus electrophile, the nucleophile, and the reaction medium (solvent or enzyme active site). Earlier computer simulations indicate that associative and dissociative mechanisms are similarly favored in the aqueous phase (Floridn and Warshel 1998), and also calculations for different enzymes support either dissociative or associative pathways depending on a variety of factors (Klahn et al. 2006) (O Fig. 30-9). 

Reaction of Chiral Organometallic Compounds with Phosphorus Electrophile... 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

The reaction between esterase and phosphorus inhibitor (109) is bimolecular, of the weU-known S 2 type, and represents the attack of a nucleophilic serine hydroxyl with a neighboring imida2ole ring of a histidine residue at the active site, on the electrophilic phosphorus atom, and mimics the normal three-step reaction that takes place between enzyme and substrate (reaction ). 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

These compounds generally exist in carbonyl forms. The oxygen function can be converted into halogen by phosphorus halides. Reactions with electrophiles are quite complex. Thus urazole (511) reacts with diazomethane quickly to yield (512), which is more slowly converted into (513). 1-Phenylurazole gives (514) however, 4-phenylurazole yields (515). Oxadiazolinones of type (516) can be alkylated at both O- and N-atoms. 

Ionic Inflate derivatives of nonmetallic elements such as selenium, sulfur, phosphorus, and iodine form an important class of reagents lor organic chemistry. Highly electrophilic phenylselenyl triflate can be used in the cyclization of 5- and 6-hydroxyalkenes, affording the corresponding tetrahydrofurans and pyrans [132] (equation 68). 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

Alcohol attack generates an unstable intermediate that undergoes nucleophilic attack by CL at carbon. Compare electrostatic potential maps of methanol, thionyl chloride intermediate, and phosphorus trichloride intermediate. What features of these maps are consistent with an electrophilic reactive intermediate ... 

Phospholes and analogs offer a wide variety of coordination modes and reactivity patterns, from the ti E) (E = P, As, Sb, Bi) through ri -dienic to ri -donor function, including numerous and different mixed coordination modes. Electrophilic substitution at the carbon atoms and nucleophilic properties of the phosphorus atom are well documented. In the ri -coordinated species, group V heteroles nearly acquire planarity and features of the ir-delocalized moieties (heterocymantrenes and -ferrocenes). 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

The reactivity of the phosphorus ylide 1 strongly depends on substituents R R. For preparative use R often is a phenyl group. When R or R is an electron-withdrawing group, the negative charge can be delocalized over several centers, and the reactivity at the ylide carbon is reduced. The reactivity of the carbonyl compound towards addition of the ylide increases with the electrophilic character of the C=0 group. R R are often both alkyl, or alkyl and aryl. 

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