Enolates hexamethylphosphoric triamide

On the other hand, the predominant formation of the diastereomeric aldols 3 b results from the titanium enolate 1 b of (S )-5,5-dimethyl-4-tert-butyldimethylsilyloxy-3-hexanone. For this purpose, the ketone is first deprotonated with A-(bromomagnesio)-2,2,6,6-tetramethylpiperidine and the magnesium enolate, presumably (E) configurated, formed is thereby treated with hexamethylphosphoric triamide and triisopropyloxytitanium chloride. After sonification, the aldehyde is added to give predominantly aldol adducts 3b the diastereomeric ratio of 3b/2b surpasses 95 5 and the chemical yields range from 85 to 88%53b. 

The final ring coupling reaction is usually an O-alkylation of the sodium enolate with a methyl sulfonate-, bromo-, or chloro-butenolide in acetonitrile or an ether solvent (8.22-24). Use of the methyl sulfonate derivative is least preferred because of its poor stability (9,24). The isolated hydroxymethylene lactone can be allowed to react with the bromobutenolide using potassium carbonate in hexamethylphosphoric triamide (caution a potential carcinogen). 

Caubere et al. [64, 65] also employed enolates as nucleophiles to intercept the intermediates produced from 32a and the mixture of sodium amide and a sodium enolate. Scheme 6.12 illustrates the results obtained by using the enolates of cyclohexanone and cyclopropyl methyl ketone. The former furnished only the ketone 43 in hexamethylphosphoric triamide as solvent, but almost exclusively the cyclobuta-... 

DMSO and /V, A- dime th y I fo nn a in i d c (DMF) are particularly effective in enhancing the reactivity of enolate ions, as Table 1.2 shows. Both of these compounds belong to the polar aprotic class of solvents. Other members of this class that are used as solvents in reactions between carbanions and alkyl halides include N-mcthyI pyrro I i donc (NMP) and hexamethylphosphoric triamide (HMPA). Polar aprotic solvents, as their name implies, are materials which have high dielectric constants but which lack hydroxyl groups or other... 

A striking reversal of the stereoselectivity has been observed when hexamethylphosphoric triamide is added as a cosolvent in kinetic enolate formation7. This effect can be attributed to a disruption of the pericyclic transition-state model1. 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

After selective generation of the syn- or anH -enolate of an amide, it is usually reacted with a haloalkane, often the iodide. Allylic and benzylic bromides also react satisfactorily, and dimethyl and diethyl sulfate have also been used in some cases. A solution of the alkylating agent in an ethereal solvent, usually tetrahydrofuran, is added to the enolate, usually at low temperature. A polar, aprotic cosolvent, such as hexamethylphosphoric triamide, is frequently used as an additive in the alkylation step. The use of this suspected carcinogen is prohibited in some countries, which limits the usefulness of many of the reactions described below. However, similarly effective in many cases are some ureas, such as the commercially available 1,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone (DMPU)12. 

Formation of the enolate from 1-methyl-2-pyrrolidone (a y-lactam) is accomplished by treatment with lithium diethylamide in hexamethylphosphoric triamide/benzene at — 20 °C. Addition of bromomethane or (chloromethyl)benzene then results in good yield of the a-alkylation product15. 

Intramolecular cyclization of 6-(mesyloxymethyl)bicyclo[4.4.0]dcc-l-cn-3-one using lithium diiso-propylamide produced almost exclusively the y-alkylation product tricyclo[5.3.1.01,6]undec-5-en-4-one (17), together with a trace amount of the 2-alkylation product tricyclo[5.3.1 016]undec-5-en-8-one (18).17 Surprisingly, the a-alkylation product 18 was the major product when the cyclization was carried out using potassium tert-butoxide.17 The preference for y-alkylation over a-alkylation can be rationalized by the Hammond postulate which favors y-alkylation due to the less reactant-like transition state when lithium diisopropylamide is used. Alternatively, when potassium /ert-butoxide and 18-crown-6 in hexamethylphosphoric triamide is used, the reactivity of the enolate anion is significantly enhanced. As a result, the transition state becomes reactant-like so that a-alkylation is the predominant process.17... 

HYDROXYLATION OF ENOLATES WITH OXODIPEROXYMOLYBDENUM(PYRIDINE)-(HEXAMETHYLPHOSPHORIC TRIAMIDE), MoOc-Py-HMPA (MoOPH) ... 

Dipolar aprotic solvent. This cyclic urea can serve as a substitute for the carcinogenic hexamethylphosphoric triamide (HMPT) in reactions of highly nucleophilic and basic reagents. It mimics the effect of HMPT in Wittig olefination und in selective generation of various enolates. It forms homogeneous solutions with I IIF even at -78°. ... 

The tendeney towards reaetion at the center with the maximum eleetron density inereases when dipolar non-HBD solvents are employed owing to the laek of speeifie solvation cf. solvents HCON(CH3)2 and CH3SOCH3 in Table 5-22). Thus, in the alkylation of the enolate ions of 1,3-dicarbonyl compounds, the greatest yields of the 0-alkylated isomers are obtained in hexamethylphosphoric triamide, followed by dipolar non-HBD solvents of the amide type [372-375]. 

To summarize, it can be stated that the freer the ambident anion in every respect, the larger the 0/C-alkylation ratio in the case of 1,3-dicarbonyl compounds [365]. Thus, if 0-alkylation products are desired in the alkylation of enolates, dipolar non-HBD and dissociating solvents such as A, A -dimethylformamide, dimethyl sulfoxide, or, especially, hexamethylphosphoric triamide should be used. If C-alkylation is desired, protic solvents like water, fluorinated alcohols, or, in the case of phenols, the parent phenol will be the best choice [365]. 

Enolate Hydroxylation. Treatment of the sodium enolates with the Davis oxaziridine reagent affords the hydroxylated products with the same sense of induction as the alkylation products (eq 23). Although high diastereoselectivity may be achieved with Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH), such reactions proceed in lower yields. 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

Stereoselective trans a-hydroxylation of (5)-dihydro-5-(t-butyldiphenylsiloxymethyl)-2(3/f)-furanone can be realized in good yield by enolization and reaction with the Oxodiperox-ymolybdenum(pyridine)(hexamethylphosphoric triamide) complex (MoOPH) (eq 10). Appropriate manipulation of the resulting trans-hydroxylactone provides 1,3-polyols typified by (18), as well as tetrahydropyran (19) which is a key intermediate in mevinic acid syntheses. ... 

Oxodiperoxymolybdenum-pyridine-hexamethylphosphoric triamide, MoOj CjHsN-HMPA (MoOPH), which is prepared from molybdenum trioxide, M0O3 [531,532], hydroxylates the enolates of ketones and esters in the a position with respect to the carbonyl groups [537, 532, 533] and, in the presence of mercuric acetate, converts acetylenes into a-dicarbonyl compounds [534]. 

Despite the fact that the uncatalyzed reactions are reported to be very rapid at -78 °C, Deiunark has demonstrated that the addition reaction is dramatically accelerated in the presence of a catalytic amounts of Lewis-basic phospho-ramides, such as hexamethylphosphoric triamide (HMPA). This remarkable observation coupled with mechanistic investigations has led to the successful development of chiral phosphoramides 248 to 250 as Lewis-base catalysts for enan-tioselective Mukaiyama aldol addition reactions. Initial investigations documented the superiority of phosphoramide 250 in delivering products of high optical purity for example, the addition reaction of enol trichlorosilane derived from methyl acetate with trimethylacetaldehyde at -78 °C affords the aldol adduct in 62% ee and 78% yield (Eq. 53). 

The formation of ( )-enolates is favored in tetrahydrofuran alone, whereas addition of metalchelating solvents such as hexamethylphosphoric triamide, A,A, /V, Ar-tetranncthylcthylenedi-amine or l,4-dimethyltetrahydro-2(l//)-pyrimidinone reverses the enolate configuration to the (Z)-product. The best seleetivities were obtained with 45% l,3-dimethyltetrahydro-2(l//)-pyrimidinone. In comparison to lithium diisopropylamide in 23% hexamethylphosphoric triamide. slightly bulkier bases, i.e., lithium hexamethyldisilanazide, have proved to be more E selective256. 

Enantioselective reduction of acetylenic ketones is a route frequently used to prepare the starting materials. The synthesis of a dihydrocompactin precursor 10 involves such a reaction sequence via Ireland rearrangement of 8477. Problems arising with considerable C-silylation of the ester enolate in the rearrangement of 8 can be overcome by adding hexamethylphosphoric triamide to the enolate (1.2 mL/mmol), followed by four equivalents of /ert-butylchlorodimethyl-silane in tetrahydrofuran. The product ester 9 is obtained as a 12 1 mixture of diastereomers in 81 % yield ... 

Enolization of macrocyclic enediyne lactones 11 results surprisingly in the formation of (/ . )-silyl ketene acetals 12 or 13 [lithium hexamethyldisilazanide is usually a lithium diisopropyl-amide/hexamethylphosphoric triamide substitute giving rise to the formation of (Z)-silyl ketene acetals] whereas (Z)-12a,b are obtained in the presence of hexamethylphosphoric triamide. 

Lithiation of hexamethylphosphoric triamide with MeLi in ether followed by addition of dimesityl- or mesitylphenylketene yields the stable enols (181 Ar = Ph or mesityl) together with the amides MesCHArCONMeR (R = Me or Et). The structures of... 

The reaction between cyclic ketone enolates and diethyl phosphorochloridite followed by aerial oxidation of the intermediate P(III) esters, yields mixtures of C - and (7-phosphorylated products. The formation of the (1 -oxoalkyl)phosphonic diesters was optimized using diethyl ether as solvent (although better yields were sometimes obtained for reactions in Et20/THF when hexamethylphosphoric triamide was added) when the... 

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