Hexamethylphosphoric triamide addition

The Roussel group has described recently a novel method for the synthesis of 2,2-dimethyl-A" -3-keto steroids. Thus addition of potassium t-butoxide to a solution of 19-nortestosterone (25) in tetrahydrofuran containing methyl iodide and hexamethylphosphorous triamide at —70° affords the 2,2-dimethyl compound (26) in good yield.Methylation of A" -3-ketone by the classical conditions, namely addition of methyl iodide to a solution of the steroid and potassium /-butoxide, leads to the 4,4-dimethyl product. 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

This procedure, which involves the addition of an anion derived from a nitrile to an unactivated acetylenic bond under rather mild conditions, is a convenient general method for the synthesis of a-vinyl-nitriles (see Table I). The reaction proceeds smoothly in either dimethyl sulfoxide or hexamethylphosphoric triamide (see p. 103 for warning) as solvent with a tetraalkylam monium salt as catalyst. The products thus prepared are obtained in yields higher2 than those obtained under conventional conditions, which generally require higher temperatures and elevated pressures.3-4... 

The simple hexaalkylditins, RsSnSnRs, do not disproportionate on heating, but, in oxolane (tetrahydrofuran) or acetonitrile in the presence of a base such as a Grignard reagent, or in the more strongly basic solvent hexamethylphosphoric triamide (HMPT), disproportionation readily occurs at room temperature, and, in HMPT, addition occurs to such alkynes as phenylacetylene and diphenylbutadiyne. The disproportionation is considered to proceed by nucleophilic attack upon tin (259, 260), e.g.,... 

Based on the fact that hexamethylphosphoric triamide can greatly enhance the stereoselectivity of the reaction, chiral phosphorous amidites of type 90 have been synthesized and tested for inducing asymmetric conjugate additions, and indeed good results have been obtained. For example, Scheme 8-31 shows that product was obtained with 87% ee.72... 

The amount of molecular sieves 4 A largely influences the product s ee[11]. Usually 100 mg (for the CMHP oxidation) or 1 g (for the TBHP oxidation) of MS 4A for 1 mmol of substrate is enough however, in the case where chemical yield and/or optical yield are not high, use of excess MS 4A often improves them. The addition of achiral ligands such as tributylphosphine oxide, tri-o-tolyl- and tri-/)-tolylphosphine oxides, hexamethylphosphoric triamide, triphenylpho-sphate, lutidine N-oxide, and l,3-dimethyl-2-imidazolidinone were found to be less effective than that of triphenylphosphine oxide in the epoxidation of chalcone. 

Scheme 6.3. Influence of added TMSCI on the diastereo-selectivity of the conjugate addition of dibutylcuprate to enone 17 (TMS = trimethylsilyl, HMPT = hexamethylphosphoric triamide).

Tab. 6.2. HMPT = Results of diastereoselective cuprate additions to enone hexamethylphosphoric triamide). 95 (TMS = trimethylsilyl,...

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. 

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. 

Acceleration of the vinylcyclobutane to cyclohexene rearrangement of vinylcyclobutanols by conversion to the potassium alkoxide was first reported by Wilson and Mao.50 Typically, the [1,3] shift occurs at a satisfactory rate in tetrahydrofuran between room and reflux temperature. Sodium51 or lithium alkoxides52 also rearrange in this temperature range. The reaction rate can be further increased by addition of crown ethers or hexamethylphosphoric triamide.50,53... 

Note 4) are added. After the mixture is stirred for few minutes at 25°C, the resulting clear and colorless solution is cooled to - ,5aC (Notes 5,6). A 2.73 M solution (45.0 mL, 0.123 mol) of ethylmagneslum bromide in ether (Note 7) is added dropwlse with a syringe or cannula over a period of 10 min. The suspension of yellow-orange solid is stirred at -45°C for 2 hr, and 1-octyne (16.0 mL, 0.109 mol Note 4) is added with a syringe or cannula over a period of 2 min. After the solution is stirred at -45°C for 2 hr, it is cooled to -78°C (Note 5) and maintained at this temperature during the successive additions of hexamethylphosphoric triamide (40 mL, 0.229 mol Note 4)... 

They may be synthesized by deprotonation and silylation of carboxylic esters or lactones (Equations Si3.15 and Si3.16). Note that in the example depicted in Equation Si3.15 the E isomer is generated if the reaction is performed in THF, but addition of polar HMPA [hexamethylphosphoric triamide, (Mc N P O] to the reaction mixture gives the Z isomer. 

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]. 

A flask was charged with l,3,5-tris(3, 3, 3 -trifluoropropyl)-l,3,5-hexamethylcyclo-trisiloxane (0.3 mol) that had been melted by heating the solid to 40°C to 50°C and then treated with vinylmethyldichlorosilane (0.3 mol). The mixture was further treated with the dropwise addition of hexamethylphosphoric triamide (0.0015 mol) and the... 

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