Hexamethylphosphoric triamide carcinogenicity

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). 

Method A a,a-Doubly deprotonated nitroalkanes react with aldehydes to give intermediate nitronate alkoxides, which afford yyw-nitroalcohols as major products (18 7-47 3) by kinetic protonation at -100 °C in THF-HMPA. The carcinogenic hexamethylphosphorous triamide (HMPA) can be replaced by the urea derivative (DMPU). 

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. 

CAUTION Hexamethylphosphoric triamide (HMPA) is a substance suspected of carcinogenic potential in man. Appropriate safety precautions and procedures should be adopted when handling this reagent. 

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°. ... 

In contrast, dipolar aprotic solvents possess large relative permittivities (sr > 15), sizeable dipole moments p > 8.3 10 ° Cm = 2.5 D), and average C.f values of 0.3 to 0.5. These solvents do not act as hydrogen-bond donors since their C—H bonds are not sufficiently polarized. However, they are usually good EPD solvents and hence cation sol-vators due to the presence of lone electron pairs. Among the most important dipolar aprotic solvents are acetone, acetonitrile [75], benzonitrile, A,A-dimethylacetamide [76, 77], A,A-dimethylformamide [76-78], dimethylsulfone [79], dimethyl sulfoxide [80-84], hex-amethylphosphoric triamide [85], 1-methylpyrrolidin-2-one [86], nitrobenzene, nitro-methane [87], cyclic carbonates such as propylene carbonate (4-methyl-l,3-dioxol-2-one) [88], sulfolane (tetrahydrothiophene-1,1-dioxide) [89, 90, 90a], 1,1,3,3-tetramethylurea [91, 91a] and tetrasubstituted cyclic ureas such as 3,4,5,6-tetrahydro-l,3-dimethyl-pyr-imidin-2-(l//)-one (dimethyl propylene urea, DMPU) [133]. The latter is a suitable substitute for the carcinogenic hexamethylphosphoric triamide cf. Table A-14) [134]. 

Caution. Hexamethylphosphoric triamide is suspected to be carcinogenic. Inhalation or skin contact should be avoided. 

Caution Hexamethylphosphoric triamide has been identified as a carcinogen. Glove protection is required during the handling in Part B. 

Independent work of Kenner [57], Castro [58], Hmby [59], and Yamada [60] has shown the potential of applying derivatives of trisdimethylaminophos-phonium salts for the activation of carboxylic acids and subsequent preparation of amides and peptides (Fig. 7). The first phosphonium salt-based reagents commercially available were pi-oxo-bis-[tris(dimethylamino)-phos-phonium]-bis-tetrafluoroborate (22) ( Bates reagent ) [61] and benzotria-zol-1 -yl-iV-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (23) (BOB) [62]. Later, Coste et al. [63] described the pyrrolidino derivative of BOP, benzotriazol-1 -yl-7V-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (24) (PyBOP), which does not form carcinogenic hexamethylphosphoric triamide (HMPA) as a by-product [64]. Furthermore, phosphonium salts derived from HOAt, such as (7-azabenzotriazol-l-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (25) (AOP) and (7-azabenzotriazol-l-yloxy)-tris(pyrrolidino)phosphonium hexafluorophosphate (26) (PyAOP), have also been prepared and are generally more efficient than BOP and PyBOP [31,65,66]. 

Caution. Benzene, hexamethylphosphorous triamide, and dichloro-phosphoranetriyltris[dimethylamine] are suspected carcinogens. The reaction should be conducted in a well-ventilated hood, and gloves should be worn at all times. The synthesis must be carried out in the absence of any moisture. Airless Schlenk ware and two-ended filters with side-arm gas inlets for filtration are recommended. Solvents should be dried rigorously. 

The LD50 and carcinogenicity of compounds are measured as well. For known compounds, one can look up the data in manuals, such as Sax s Dangerous Properties of Industial Materials. For new compounds, the tests are done in-house, both the LD50 and the Ames test. There is no hard rule for what is too toxic in the plant, but typically the rule of thumb may be following table I. Solvents that are carcinogens are avoided, e.g., chloroform, carbon tetrachloride, dioxane, benzene and hexamethylphosphoric triamide. ... 

Handling, Storage, and Precautions is very stable, not hygroscopic, and can be stored indefinitely under vacuum. The related bromine derivative is an exceptionally safe azide, that does not detonate by shock, friction, rapid heating, or even flame. When used in combination with carboxylic acids, the potential carcinogenic Hexamethylphosphoric Triamide is a side-product and the reagent must be handled with caution. ... 

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