Chloromethyl chlorosulfate: a new, catalytic method of preparation and reactions with some nucleophiles

Abstract

The reaction of liquid (gamma-) SO3 with CH2Cl2 at room temperature leads to SO3 insertion into the C-Cl bonds, giving the useful chloromethylating agent chloromethyl chlorosulfate (CMCS). The process is very slow but becomes rapid on addition of catalytic quantities of trimethyl borate. The product mixture consists almost entirely of CMCS and the product of further sulfation, methylene bis(chlorosulfate)(MBCS), in a ratio of ca. 2 : 1, but typical yields of CMCS, isolated by distillation, are only 30-35%. The catalysed reaction in the homogeneous liquid phase at -45 degrees C has been followed as a function of time and of reactant concentration by 1H nmr spectroscopy. It is observed that, besides CMCS and MBCS, three additional, transient products (designated A, B and C) are formed. Products A, B and C decompose slowly at -45 degrees C but much more rapidly if the reaction mixture is raised to room temperature, giving additional CMCS and MBCS. From an analysis of the SO3 balance, it is inferred that products A, B and C arise from the reaction of one molecule of CH2Cl2 with respectively two, three and four molecules of SO3; they are suggested to be chloromethyl chloropolysulfates. By measuring initial rates of CMCS formation or total CH2Cl2 consumption, it is shown that the reaction is first order in the catalyst and roughly third order in SO3. A mechanistic scheme is proposed in which SO3 forms equilibrating zwitterionic molecular complexes with CH2Cl2. of 1 : 1, 2 : 1 and higher stoichiometries. The boron-containing catalyst can activate these complexes towards nucleophilic attack at carbon by the negatively charged oxygen of another zwitterion. An analogous mechanism can be written for the conversion of CMCS into MBCS by SO3 in the presence of trimethyl borate. CMCS reacts rapidly with anionic nucleophiles, such as halide or acetate ions (X-), in homogeneous solution of their tetrabutylammonium salts in CD3CN, or in a two-phase system (CDCl3/H2O) using alkali-metal salts in conjunction with a phase-transfer catalyst. In both situations the products (ClCH2X) arise by rapid nucleophilic displacement of the chlorosulfate moiety; this then more slowly liberates chloride ion, which converts further CMCS into CH2Cl2. The reactivity of CMCS has been compared with that of MBCS and methyl chlorosulfate (MCS) in competitive experiments; the reactivity order is MCS > MBCS > CMCS >> CH2Cl2. Evidence is also presented suggesting that, in contrast to the halide nucleophiles, reaction of CMCS with sodium phenoxide in tetrahydrofuran solution leads to nucleophilic displacement of the sulfur-bound chloride.

Development of Efficient Processes for the Preparation of Di-tert-butyl Potassium Phosphate and Di-tert-butyl (Chloromethyl) Phosphate

“…With optimized conditions to prepare DTBPP ( 2 ), we moved onto its reaction with CMCS. At the outset of this work we speculated that two main degradation pathways existed to explain the varying yields reported for the conversion of CMCS to 3 : CMCS hydrolysis (Scheme , pathway B) and dichloromethane (DCM) formation (Scheme , pathway C) …”

Development of a Process for the Preparation of Chloromethyl Chlorosulfate

“…Initially, we examined the known literature procedures ,− to develop a preliminary knowledge of the key challenges in preparing this molecule, which we hoped to leverage in our development of a more scalable process for the preparation of CMCS. However, all the current processes proved unfavorable for large scale use and little useful information was gained from the processes; the reaction conditions were not suitable for our use, and the reactions produced complex mixtures of products requiring extensive purification.…”

“…Binderup and Hansen showed that CMCS could be prepared by refluxing chlorobromomethane and chlorosulfonic acid; however, this procedure again produced CMCS in low yield. More recently, Power et al demonstrated that SO 3 could directly insert into one of the carbon–chlorine bonds of dichloromethane (DCM) when catalyzed by trimethyl borate . This process has significant advantages over the previous procedures; for example, only ambient temperature is required, and the reaction proceeds quickly.…”

Novel synthesis of benzotriazolyl alkyl esters: an unprecedented CH2 insertion

“…This enzymatic hydrolysis generates the dye that has strong affinity to the surface and can be detected by SERRS at very low levels and consequently allow for an enzyme assay with ultra-sensitivity for enzyme turnover monitoring. 4–6 …”

“…The most common synthetic approaches to synthesize BAEs are condensation of the hydroxymethylbenzotriazole and carboxylic acids, 3 and the reaction of the appropriate sodium benzotriazolate with chloromethyl esters. 4 …”