Aldehydes Homer-Wadsworth-Emmons reaction

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

Homer-Wadsworth-Emmons reactions of ketones and aldehydes with phosphono-acetate esters, (R20)2P(=0)CH2C02R1, produce E/Z mixtures of a, /Tunsaturated esters. Use of the conventional reagent, sodium hydride, gives some selectivity. The combination of tin(II) triflate and A -cthylpipcndine enhances—and sometimes also reverses—the selectivity in most cases studied.71 Six-membered oxo-coordinated tin intermediates are proposed to control the selectivities observed. A similarly selective synthesis of trisubstituted exocyclic alkenes from cyclic ketones has been reported.72... 

You will learn about the reaction of a-metalated phosphonic acid esters with aldehydes in Section 11.3 in connection with the Homer-Wadsworth-Emmons reaction. This reaction also seems to give a Irans-con figured oxaphosphetane (Figure 4.46). Again, a. vyn-selective /3-elim-ination of a compound with P=0 double bond should occur. One of the elimination products is (EtO)2P(=O)O0. As a second product an alkene is produced that is predominantly or exclusively irans-configured. 

Homer-Wadsworth-Emmons reactions are C=C-forming condensation reactions between the Li, Na, or K salt of a /1-koto- or an a-(alkoxycarbonyl )phosphomc acid dialkyl ester and a carbonyl compound (see Figure 4.46). These reactions furnish a,/3-unsaturated ketones or 0 ,/3-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced /ra/ov-selectively or, in the case of alkenes with trisubstituted C=C double bonds, -selectively. 

Condensations between aldehydes and metalated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Homer-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a pi electron withdrawing group, for example, an alkenyl group, a polyene or a C=N group. The Homer-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C=C double bond /ra/ ,v-selectively. 

Motoyoshiya, J., Kusaura, T., Kokin, K., Yokoya, S. i., Takaguchi, Y., Narita, S., Aoyama, H. The Homer-Wadsworth-Emmons reaction of mixed phosphonoacetates and aromatic aldehydes geometrical selectivity and computational investigation. Tetrahedron 2001,57, 1715-1721. 

The allylsilanes are effective intennediates in the construction of various carbocyclic systems, and the Homer-Wadsworth-Emmons reaction appears to be well suited to prepare this class of compounds. Thus, diethyl 2-(trimethylsilyl)-l-(ethoxycarbonyl)ethylphosphonate reacts with aldehydes 5 ° and ketones under standard Homer-Wadsworth-Emmons reaction... 

The dimethyl 2-(zert-butyldimethylsilyl)-2-oxoethylphosphonate reacts smoothly with a variety of aldehydes under standard Homer-Wadsworth-Emmons reaction conditions (NaH, THF, room temperature) or mud nonbasic conditions (LiCl, DBU, MeCN, room temperature) to give the corresponding tran5 -a,P-unsaturated acylsilanes in excellent yields (54-97%) with high stereoselectivity (Scheme 2.37). However, this reaction is considerably slower under these mild conditions (24 h) compared to standard conditions (90 min). The efforts to extend the reaction to ketones were disappointing. ... 

The readily available diethyl 2-cyano-2-(trimethylsilyl)ethylphosphonate appears to be an attractive reagent for the synthesis of 2-cyano-l,3-butadienes. Their formation combines the Peterson and Homer-Wadsworth-Emmons reactions in a one-pot process. The reaction has been developed with a variety of aldehydes, and the yields are generally high (34-89%, Scheme 2.38). ... 

The electrophilic phosphonylation of chloromethyl phenyl sulfone in the presence of n-BuLi (2 eq) proceeds smoothly at low temperature, probably via the sulfone dianion, to give diethyl 1-lithio-1-chloro-l-(phenylsulfonyl)methylphosphonate. This is treated in situ with aliphatic or aromatic aldehydes and ketones to obtain a-chloro-a,(3-unsaturated ketones by the Homer-Wadsworth-Emmons reaction in good overall yields (76—85%)... 

Dialkyl 1-substituted chloromethylphosphonates, prepared either by electrophilic or nucleophilic chlorination (see Sections 3.1.1.8.2 and 3.1.7.2), readily react with aromatic or heteroaromatic aldehydes in the presence of a base ( -BuLi, NaH, or r-BuOK, Homer-Wadsworth-Emmons reaction), and the resulting chloroalkenes are directly dehydrohalogenated to give the corresponding alkynes in moderate to good overall yields. 10.451 455 yjjg j est suited base for the last step seems to be t-BuOK (Scheme 3.70). °5 5 ... 

The reaction of diethyl 1-lithio-1-chloroalkyIphosphonates, prepared from diethyl 1,1-dichlo-roalkylphosphonates and -BuLi in the presence of LiBr, with aldehydes and aliphatic ketones gives diethyl 1,2-epoxyalkylphosphonates in 61-81% overall yields and not the Homer-Wadsworth-Emmons reaction product." These carbanions also react with CO2 at -100°C to afford diethyl... 

Long-chain phosphonylated aldehydes aie generally prepared to achieve the formation of macro-cycles via an intramolecular Homer-Wadsworth-Emmons reaction. The phosphonate group is frequently incorporated at one extremity of the chain by a carbanionic approach. Thus, displacement of iodide of the alkyl chain containing epoxide by the sodium enolate of diethyl l-(ethoxycarbo-nyl)methylphosphonate at 50°C in DMF leads to diethyl l-(ethoxycarbonyl)-4,5-epoxyalkylphos-phonate in 78% yield (Scheme 4.21). 

An interesting approach to the central eight-membered ring of ceroplastol I is based on an intramo-lecnlar Homer-Wadsworth-Emmons reaction employing a diethyl 7-formylalkylphosphonate. The C-7 aldehyde, protected as a 1,3-dioxolane, is obtained in 20% yield by a Michael addition of an alkenyllithium to 2-(diethoxyphosphinyl)cyclopentenone in THF at -78°C. Hydrolysis of the acetal nsing HjO and TsOH in reflnxing acetone yields 89% of the phosphonylated ketoaldehyde (Scheme, 5.56). ... 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

To date long-chain phosphonylated aldehydes (n > 10) have been prepared exclusively as precursors for the synthesis of 11- to 17-membered macrocycles via intramolecular Homer-Wadsworth-Emmons reactions (Scheme 5.63). This widely used cyclization step provides the best method for preparing macrocycles. 

The Homer-Wadsworth-Emmons reaction is among the most important reactions for effecting a two-carbon chain elongation of a carbonyl functional group - " It can be described as a general synthetic protocol for the conversion of aldehydes and ketones into aji-unsaturated carbonyl compounds and their derivatives " ... 

An added and valuable advantage found in this attractive and mild approach to dialkyl cyanoalkylphosphonates is the possibility of trapping the phosphonate carbanions in situ by reaction with an aldehyde or ketone when the desired product is the olefin resulting from the Homer-Wadsworth-Emmons reaction (Scheme 6.6). 

Electrolysis of diethyl phosphite in MeCN containing tetraethylammonium salts in the presence of chloroacetonitrile and aldehyde gives the corresponding a,P-unsaturated nitriles in satisfactory yields as a mixture of (E)- and (Z)-isomers, indicating that the cyanomethylphosphonate carbanion is generated then reacted during sequential Michaelis-Becker and Homer-Wadsworth-Emmons reactions. ... 

Oxygen and nitrogen nucleophiles add to diethyl l-(ethoxycarbonyl)vinylphosphonate to generate the formation of various fused heterocyclic compounds. Thus, A -carbapcncrns are readily prepared by the Michael addition of A-lithio-4-vinylazetidin-2-one to diethyl l-(ethoxycarbo-nyl)vinylphosphonate followed by ozonolysis of the adduct and subsequent treatment of the generated aldehyde by intramolecular Homer Wadsworth-Emmons reaction (Scheme 8.28). ... 

Ando, K., Convenient preparations of (diphenylphosphono)acetic acid esters and the comparison of the Z-selectivities of their Homer-Wadsworth-Emmons reaction with aldehydes depending on the ester moiety, J. Org. Chem., 64, 8406, 1999. 

Rubottom oxidation reactions have been conducted on enolsilanes derived from a number of different carbonyl derivatives including carboxylic acids and esters.15 For example, the Rubottom oxidation of bis(trimethylsilyl)ketene acetal 30 provided a-hydroxy carboxylic acid 31 in 81% yield. Use of alkyl trimethylsilyl ketene acetal substrates generates a-hydroxy esters, as seen in the conversion of 32 to 33.16 The synthesis of 3-hydroxy-a-ketoesters (e.g., 36) has been accomplished via Rubottom oxidation of enolsilanes such as 35 that are prepared via Homer-Wadsworth-Emmons reactions of aldehydes and ketones with 2-silyloxy phosphonoacetate reagent 34.17 The a-hydroxylation of enolsilanes derived from P-dicarbonyl compounds has also been described, although in some cases direct oxidation of the P-dicarbonyl compound is feasible without enolsilane formation.18... 

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