2- imidazole-4-sulfonyl chloride

Azolesulfonic acids frequently exist as zwitterions. The usual derivatives are formed, e.g. pyrazole-3-, -4- and -5-sulfonic acids all give sulfonyl chlorides with PCI5. The sulfonic acid group can be replaced by nucleophiles under more or less vigorous conditions, e.g. by hydroxyl in imidazole-4-sulfonic acids at 170 °C, and by hydroxyl or amino in thiazole-2-sulfonic acids. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

The corresponding AfA -sulfonyldiimidazole, prepared from sulfonyl chloride and imidazole, is of surprisingly low reactivity in every respect. It forms stable crystals of m.p. 141 °C which can be sublimed in vacuum and recrystallized from ethanol without alcoholysis. Even in dilute aqueous hydrochloric acid hydrolysis occurs only very slowly. 

A sulfonyl chloride group rapidly reacts with amines in the pH range of 9-10 to form stable sulfonamide bonds. Under these conditions, it also may react with tyrosine —OH groups, aliphatic alcohols, thiols, and histidine side chains. Conjugates of sulfonyl chlorides with sulf-hydryls and imidazole rings are unstable, while esters formed with alcohols are subject to nucleophilic displacement (Nillson and Mosbach, 1984 Scouten and Van der Tweel, 1984). The only stable derivative with proteins therefore is the sulfonamide, formed by reaction with e-lysine... 

In what was intended as another experimental probe to ascertain whether a concerted or stepwise mechanism was involved in substitution reactions of arenesulfonyl chlorides, Rogne (1975) measured the enthalpies of transfer from propanol to acetonitrile for the transition states, SAH, for the reaction of imidazole with (a) benzoyl chloride and (b) benzenesulfonyl chloride. He found that SAH was considerably more negative for the reaction involving the sulfonyl chloride than for the one involving benzoyl chloride. This means that the transition state for attack of imidazole on benzenesulfonyl chloride is considerably better solvated by acetonitrile relative to its solvation by propanol... 

In addition to moving the sulfonyl chloride earlier in the synthesis, the commercial route also uses an acyl imidazole to form a key amide bond (13.77 — 13.79) instead of an acid chloride (13.67 — 13.70, Scheme 13.12). Carbonyldiimidazole (13.76) is an expensive reagent, but the use of acyl imidazole 13.77 gives many advantages. The yields of the amide-forming reaction are higher, and solvent requirements are greatly simplified. The overall... 

Substituted imidazole-4,5-dicarbohydroxamic acids on Lossen rearrangement form 1-hydroxyxanthines. Thiazole-4,5-dicarbohydroxamic acids in their partial Lossen degradation, however, show little differentiation between the 4- and 5-position and hence mixtures of the [4,5-d] and the [5,4-d] structures (447) and (448) are formed. The isomer distribution appears to be affected by the solvent as well as by the sulfonyl chloride utilized in the reaction (68JHC331). 

Preparative Methods the most convenient preparation of (/ ,/ )-stilbenediamine is described in Organic Syntheses." Condensation of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid (eq 1) produces a spirocyclic 2//-imidazole (mp 105-106 °C). Reduction with Lithium in THF/NH3 followed by an ethanol quench and hydrolysis with aqueous HCl (eq 2) affords the racemic diamine as a pale yellow solid (mp 81-82 °C). Resolution is achieved by multiple recrystallizations of the tartaric acid salts ifom water/ethanol. The sulfonamides are prepared by reaction of the enantiomeri-cally pure diamine with the appropriate anhydride or sulfonyl chloride in CH2CI2 in the presence of Triethylamine and a catalytic amount of 4-Dimethylaminopyridine (eq 3). 

Imidazole sodium salt (10 mmol), dichloromcthane (20 ml) and methane-sulfonyl chloride (10 mmol) are mixed with stirring and cooling in an ice bath under nitrogen. After stirring at 35 C (24 h) (as for 1-benzoylimidazole, see Section 7.1.4) the mixture is pressure filtered and extracted with dichloromethane (3x5 ml) under nitrogen. The solvent is then removed, and the crude product (82%) is recrystallized from toluene, m.p. 85-87°C. 

In acetic acid solution 30% hydrogen peroxide converts 2-imidazolyl methyl sulfides into sulfones" " and sometimes sulfoxides. In tri-fluoracetic acid the sulfoxides are formed preferentially periodate, too, can give the sulfoxides. Oxidation of 4-mercaptoimidazoles under mild conditions gives bis(4-imidazolyl) disulfides which can be cleaved by hydrogen sulfide. With 15% alkaline hydrogen peroxide at 90°C the sulfonic acid is the major product. Imidazole-5-sulfonyl chlorides give sulfonamides... 

This method of imidazolylzinc chloride synthesis has also found application in the synthesis of a sulfonyl chloride to be used in the preparation of some potential factor Xa inhibitors [17]. Thus, following imidazole metalation and quenching with ZnCl2, a chemoselective coupling reaction occurred to provide 16. Treatment with sulfur dioxide provided the sulfinic acid, which upon treatment with thionyl chloride, provided the requisite sulfonyl chloride 17. 

A-Phosphorylated imidazoles and benzimidazoles can be made by direct phosphorylation by halides, esters, amides, amidoesters, isocyanates, and thiocyanates of phosphorus-containing acids, or from reaction of phosphonic or phosphinic imidazolides with a sulfonic acid or anhydride <82CB1636>. Stable charge transfer complexes are produced when a 1 1 or 1 2 ratio of imidazole (or benzimidazole) and sulfur trioxide are refluxed in ether, dioxane, THE, or 1,2-dichloroethane. These complexes are stable on storage in the absence of water and have sharp melting points. Indeed, the benzimidazole SO3 complex must be boiled for five hours in water to decompose it. On fusion, the complexes form the C-sulfonic acids (see Section 3.02.5.3.3) <87CHE1084>. Sulfonyl chlorides readily A-sulfonate imidazoles <94JMC332>. 

The sodium salt of imidazole reacts with acyl chlorides, sulfonyl chlorides or trimethylsilyl chloride in dichloromethane to give the corresponding 1-substituted imidazoles. As for acylation, 4- or 5-sub-stituted imidazoles yield mixtures of products. 

Alternative reagents used to couple nucleosides include mesitylenesulfonyl chloride (161) and 2,4,6-triisopropylbenzenesulfonyl chloride (162). Of the three reagents mentioned so far, DCC is the least reactive. In some cases, the chloride unit of the sulfonyl chloride is not reactive enough and that unit must be replaced with something more reactive. p-Toluenesulfonyl imidazolide (165) and mesitylenesulfonyl imidazolide (165) are used in such cases. These reagents are prepared by reacting either /)-toluenesulfonyl chloride (163) or mesitylenesulfonyl chloride (161) with imidazole (166). 

Consequently, the Na-salt of imidazole can also be reacted with acid chlorides, sulfonyl chlorides, and triaUcylchlorosilanes to give the corresponding 1-substituted imidazoles 8 [379],... 

Imidazole 44 reacts with excess chlorosulfonic acid to give an excellent yield of the 4-sulfonyl chloride 45 (Equation 10) the chlorosulfonation was also achieved by heating the heterocycle 44 with chlorosulfonic acid (1.5 equivalents) in excess thionyl chloride (Equation 10). ... 

The action of chlorosulfonic acid on 2-(4-chlorophenyl)imidazole also gave the 4-sulfonyl chloride with preferential substitution occurring in the imidazole ring rather than in the phenyl nucleus - presumably the orientation is as a result of favourable stereoelectric factors. ... 

In agreement with this argument, 2-(4-nitrophenyl)imidazole was chlorosulfo-nated in the imidazole ring yielding the 4-sulfonyl chloride.The phenyl nucleus is now deactivated by the presence of the electron-withdrawing nitro group, so sulfonation occurs in the imidazole ring. 

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