1,2-addition reactions phosphonate carbanions

An efficient asymmetric synthesis of P-aminoalkylphosphonates 212 via addition of phosphonate carbanions to enantiopure sulfinimines has been reported (Scheme 25). A range of novel 3-phosphonocyclobutyl amino acids have been prepared via the versatile intermediate 3-oxocyclobutylphosphonate (213) (Scheme 26). Sphingosine-1-phosphonate (215) has been synthesised from the 2-A,3-0-protected 1-0-mesyl derivative 214 of sphingosine via conversion to the bromide and an Arbuzov reaction with trimethyl phosphite.Chain extension of 215 provided a route to homo-sphingosine-1-phosphonate (216). 

The Michael reaction can also be applied to the formation of cyclopropanic systems. Thus, Michael addition of phosphonate carbanions, generated by electrochemical technique or by thal-lium(I) ethoxide in refluxing THF, to a,p-unsaturated nitriles provides a convenient preparation of substituted 2-cyanocyclopropylphosphonates via a tandem Michael addition-cycloalkylation sequence (Scheme 6.25). - - ... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Other examples of functionalization at C-2 via phosphorus ylides and phosphonate carbanions are described in Section 4.12.11. Utilization of 2-non-phosphorus-containing carbanions was also exemplified. Thus, 2-silicon-substituted 1,3-benzodithioles were synthesized via deprotonation of benzo-l,3-dithiole 245 with -BuLi and subsequent treatment of the resulting anion with trimethylsilyl chloride (TMSCl) to give 2-(trimethylsilyl)-benzo-l,3-dithiole 246 (Scheme 29). The second silyl group was introduced by further deprotonation of 246 ( -BuLi) followed by the reaction with an additional equivalent of TMSCl. Tin-substituted benzo-l,3-dithioles were synthesized in a similar way but the deprotonation of the monostannyl derivative was carried out with LDA (Scheme 29) <1996CL171>. 

The 1,4-addition reaction of stabilized allylic carbanions with conjugated enones is normally complicated by the ambident reactivity of the carbanion. Clean 7-selective conjugate addition to cyclic enones, however, has been observed with lithiated allylic sulfoxides, phosphine oxides and phosphonates... 

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

Whether a Michael or a Horner reaction occurs when an a)3-unsaturated ketone is treated with a phosphonate carbanion depends upon the conditions. Chalcone and the ester phosphonate (135) gave the product of a Horner reaction with sodium hydride in diglyme, but Michael addition occurred with sodamide in ether. 

Phosphonate carbanions (97), generated by the addition of various carbanions to vinylphosphonates, provide routes to functionalized alkenes. Thermolysis of the dienes (98) prepared in this way offers a route to 1,4-disubstituted benzenes via electrocyclization of the intermediate trienes (99) (Scheme 17). The reaction of phosphonate carbanion (100) with alkyl or aryl benzenethiosulphonates provides a general synthesis of the useful dialkyl alkyl- and aryl-thiomethyl-phosphonates (101). ... 

When R is a simple alkyl group, addition of the phosphonate carbanion to the carbonyl compound occurs but the intermediate does not undergo elimination. Since the reaction sequence results in the conversion of an aldehyde or ketone to an alkene, as does the Wittig reaction, but works well when electron-withdrawing... 

The intermediate product 162, formed from the nudeophilic addition of 1,2-alle-nic phosphonate or 1,2-allenic phosphine oxide with allylic alcohol, would also undergo a Claisen rearrangement to form 2-oxo-5-alkenyl phosphonate or phosphine oxide 163 [85], The rearrangement is accelerated by the carbanionic nature of the intermediate 162. For the conjugate addition step, the reaction temperature is crucial since the reaction at 0 °C afforded mainly /i,y-unsaturated product whereas a,/8-unsaturated products were formed at 20 °C. 

Milder reaction conditions have been developed for the HWE reaction of phosphonate-stabilized carbanions to increase yields, accommodate sensitive substrates and to minimize undesired side reactions such as double bond migrations, the Cannizzaro reaction, Knoevenagel condensation and Michael addition. For example, a number of different bases have been employed to generate the carbanion. These include sodium hydroxide under phase-transfer conditions, potassium carbonate, barium hydroxide, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene (see Protocol 10).22... 

The better defined participation of carbonyl radical anions is evident [56] in the electrocatalyzed reaction between aromatic carbonyl compounds (or other easily reduced carbonyl compounds) and dialkyl phosphonates (Scheme 18). In similar vein, and also in Scheme 18, radical anions generated from aromatic aldehydes may abstract a proton from an added acidic hydrocarbon such as fluorene (pXa22.6) or indene (pXa20.1), and the resulting carbanion adds to unreduced aldehyde. The chain reaction is propagated by protonation of the addition product by another molecule of hydrocarbon [57]. Reaction is by controlled potential coelectrolysis in THE, at the aldehyde reduction potential, and substantial yields are only obtained with 2,6-dichlorobenzaldehyde. 

Anions of a-silyl phosphonates of type (153) also undergo additions to carbonyl compounds. The corresponding addition products, 3-silyl alkoxides, can react with ketones to yield the product of the Peterson alkenation or the Wittig reaction. In practice only the Peterson product (154) is obtained, indicating that loss of OSiMes is faster than elimination of C PPhs (Scheme 68). 72 If the a-silyl carbanion is adjacent to a chlorine atom (155), an internal displacement reaction follows the initial formation of the -silyl alkoxide, and epoxides (156) are formed (Scheme 69). 74... 

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