Hexamethylphosphoric triamide, alkylation

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Ar-Alkylations of 5//-dibenz[6,/]azcpines, e.g. 5 > 8 can be readily achieved via their nitranions, which are generated from the NH compounds by standard methodology, e.g. with sodium hydride, or sodamide, in refluxing toluene or xylene.30-J1-bt, 7° 124,1 s2 Occasionally, dioxane,187 or a mixture of tetrahydrofuran and hexamethylphosphoric triamide is used as solvent.137... 

It is very interesting, however, that in alkane potassium diazoate alkylations with Meerwein s reagent (triethyloxonium tetrafluoroborate, Et30+BF4) in CH2C12 suspensions or with alkyl halides in hexamethylphosphoric triamide solutions, azoxy compounds (6.4) are formed, i.e., alkylation takes place at the (3-nitrogen (Moss et al., 1972). 

Cuprous iodide catalyzes the reaction of various alkyl chlorides, bromides, and iodides in hexamethylphosphoric triamide (HMPT), to give the complexed product RaSnXj, which can then be further alkylated with a Grignard reagent, or can be hydrolyzed to the oxide and converted into various other compounds, R2SnY2 (43). This promises to be a useful laboratory method, e.g.,... 

The tetraorganotin compounds, R4Sn, show no tendency to increase their coordination number, owing to their weak, Lewis acidity conferred by the four electron-releasing alkyl groups. It has, however, been claimed (353) that trimethyl(trifluoromethyl)tin forms a 1 1 adduct with hexamethylphosphoric triamide, and that this may be isolated in the solid state. 

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). 

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-Alkylation, -acylation and -sulfonation are also promoted by a polar solvent, such as HMPA (hexamethylphosphoric triamide).This acts to solvate the ions (promoting dissociation), but in a non-polar solvent like diethyl ether or tetrahydrofuran (THF), attack by most carbon electrophiles upon indolylmagnesium bromide proceeds at C-3 (Scheme 7.9). 

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. 

In an analogous manner the enantiomeric unsaturated bicyclic lactam 11 was transformed via conjugate addition of dimethyl 1,3-propanedioate (sodium amide/hexamethylphosphoric triamide) and subsequent alkylation with (bromomethyl)benzene to give the dialkylated product 12 in 20% yield12. 

Tricyclic lactams, such as exo- and c r/n-3a,4,7,7a-tetrahydro-4,7-methano-2-phenyl-1 //-isoin-dolc-1,3(2//)-dione (4), have been transformed into their dianions by treatment with slightly more than two equivalents of lithium diisopropylamide in tetrahydrofuran, sometimes with hexamethylphosphoric triamide as cosolvent. Alkylation with iodomethane or the bifunctional 1,4-dibromobutane leads to dialkylated products2. 

The regio- and stereoselective alkylations of a number of bicyclic racemic dioxopiperazines have been reported3. For example, dioxopiperazine 9 is deprotonated by lithium diisopropyl-amide in tetrahydrofuran at — 78 °C to yield a monoanion. Alkylation with iodomethane in the presence of hexamethylphosphoric triamide gives products 10 and 11 in a 81 19 ratio and 75 % yield based on recovered starting material3. 

A camphor-based 3-acyl-2-oxazolidinone has also been used for diastereoselective alkylations66. The A-acylated auxiliary 18 is prepared in three steps from 7,7-dimethyl-2-oxobicy-clo[2.2.1]heptane-l-carboxylic acid (ketopinic acid, 17)67. Deprotonation by lithium diiso-propylamide in tetrahydrofuran at — 78 °C and subsequent alkylation with activated halides [(bromo- or (iodomethyl)benzene, 3-bromo- or 3-iodopropene] furnished moderate to good yields of alkylation products in high diastereomeric ratios (>97 3 by H NMR). With added hexamethylphosphoric triamide the alkylation yields are increased and bromoalkanes also give satisfactory yields. The diastereomeric ratios are, however, much lower (d.r. 70 30 to 85 15)67. 

The alkylating agent, usually an iodoalkane is added in hexamethylphosphoric triamide. Chlorides or bromides can also be used, preferably in the presence of 10 mol% tetrabutylam-monium iodide5,6. The diastereomeric ratio of the crude alkylation products 2/3 is usually excellent, ranging from 95 5 to 99.5 0.5 (see Table 13 and references 17 and 19). The alkylation products are most conveniently purified by recrystallization which removes the small amount of the minor diastereomer. 

Thus, starting from the (—)-(S )-a-(methoxymethyl)benzeneethanaminc derived imines at low temperatures, (S )-2-methylcycloalkanones are obtained via the -azaenolates, whereas (R)-configurated products are obtained via the thermodynamically more stable Z-azaenolates by refluxing the anion solutions prior to alkylation. However, a high degree of enantiomeric excess is obtained only under thermodynamic conditions, presumably due to different selectives in the alkylation step (see Table 3). Variation of the base (/ert-butyllithium, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidide) and additives (hexamethylphosphoric triamide) did not improve the EjZ ratio (enantiomeric excess) significantly9. 

Chiral enamines prepared from /f-oxo esters and the tcrt-butyl ester of (.V)-valine are lithiated by LDA (—78 °C, toluene or THF, 1 h)18 19. Both enantiomers of the alkylation product are obtained with a high degree of diastercoselectivity starting from one auxiliary when the reaction is performed under the addition of different ligands (see Table 6). Addition of one equivalent of hexamethylphosphoric triamide (1IMPA) causes coordination of the lithium atom and alkylation from the top side18. 

On the other hand, alkylation of 2-chloromethyl-4,5-dihydrooxazolcs furnishes 2-chloro-alkanoic acids in good chemical yields but in low enantiomeric excess. Attempted alkylation of the deep red anion solution at —98 to —40 C resulted in little or no alkylation. Alkylation at 20 °C occurred in 80 -90 % yield, however, the products were nearly racemic. Alkylation in the presence of 2 equivalents of hexamethylphosphoric triamide proceeds at 78 C in 85-94% yield, however, enantiomeric excesses were low in comparison to alkylations of the corresponding 2-alkyl-substituted 4,5-dihydrooxazoles7. 

The best alkylation occurs at low temperature in the presence of 10 12 equivalents of hexamethylphosphoric triamide (HMPA). Without IIMPA, the enantiomeric excesses arc lower and the methylation is slower. Furthermore, the chiral moiety of the mixed sulfate, as well as the Schiff base moiety of the methyl glycinate, determines the outcome of the a-alkylations. 

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... 

Perfluoronaphthalene undergoes multiple fluorine elimination by sulfur nucleophiles under similar conditions.3 Whereas the 2.6-bis(alkylsulfanyl)hexafluoronaphthalenes (alkyl = Me, Et, i-Pr) can be obtained in good yields (< 53%), tetra- and penta-substituted products are accessible in very poor yields. However, moderate yields of hexakis(alkylsulfanyl)-substituted products can be obtained in hexamethylphosphoric triamide, i.e. under conditions suitable for complete replacement of all fluorine atoms.3... 

Significant synthetic advantage has been attained from the already mentioned sequence 8- 9- -11. This sequence, based on the appropriate lithium cuprate 6 and the alkyl halide JT7, was successfully used for the preparation of diastereomeric 11-deoxy-9-prostanoids 1 8. The natural trans-configuration of the prostanoids was obtained by alkylation of the intermediate complex in the presence of hexamethylphosphorous triamide. It seems likely that the observed alteration of stereochemistry is closely con-... 

The solubility of rare earth hydrides in organic solvents is increased by appropriate additives, too. For this purpose the hydrides are reacted with electron-donor ligands such as alkyl benzoates, alkyl propionates, alkyl tolu-ates, dialkylethers, cyclic ethers, alkylated amines, N,N -dimclhylacelamide, AT-methyl-2-pyrrolidone, trialkyl and triaryl phosphines, trialkyl phosphates and triaryl phosphates, trialkyl phosphates, hexamethylphosphoric triamide, dimethyl sulfoxide, etc. Prior to use as a polymerization catalyst the prereacted mixture of the rare earth hydride plus the additive is prereacted with Al-alkyl-based Lewis acids in the temperature range of 60-100 °C for 10 min to 24 h [351,352]. 

RCO , an indifferent nucleophile in prohc solvents, enjoys a large rate enhancement, permitting rapid alkylation with haloalkanes in hexamethylphosphoric triamide [301, 302], When the Williamson ether synthesis is carried out in dimethyl sulfoxide [303], the yields are raised and the reaction time shortened. Displacements on unreactive haloarenes become possible [304] (conversion of bromobenzene to tert-butoxybenzene with tert-C UgO in dimethyl sulfoxide in 86% yield at room temperature). The fluoride ion, a notoriously poor nucleophile or base in protic solvents, reveals its hidden capabilities in dipolar non-HBD solvents and is a powerful nucleophile in substitution reactions on carbon [305],... 

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]. 

In non-HBD, non-dissociating solvents, a corresponding proposal can be made hard counterions (alkali metal cations) should associate preferably with the hard site, and the substrate RX with the soft site in the activated complex composed of RX and the ambident ion pair [366]. With increasing hardness of the counterion (increasing charge density), the fraction of C-alkylation should increase in non-HBD solvents and decrease on solvent insertion into the ion pair. Indeed, the C-ethylation of M (ethyl acetoacetate) in dimethyl sulfoxide or hexamethylphosphoric triamide increases in the order M = R4N < Cs < K < Na < Li [373]. 

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. 

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