2- imidazole-4-sulfonyl

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

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. 

PROTECTION FOR IMIDAZOLES, PYRROLES, AND INDOLES A -Sulfonyl Derivatives... 

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. 

Besides short ELPS, longer ELPs have also been conjugated to synthetic polymers. In one approach, Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry was applied. For this purpose, ELPs were functionalized with azides or alkynes via incorporation of azidohomoalanine and homopropargyl glycine, respectively, using residue-specific replacement of methionine in ELP via bacterial expression [133]. More recently, an alternative way to site-selectively introduce azides into ELPs was developed. Here, an aqueous diazotransfer reaction was performed directly onto ELP[V5L2G3-90] using imidazole-1-sulfonyl azide [134]. 

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. 

The imidazolides required for these reactions can be prepared from sulfonyl chlor-ides[1] or sulfonic anhydrides[2] and imidazole, or by treatment of the corresponding sulfonic acid with CDI,[1] ImSOIm,[3] or ImS02Im[3] (see Section 10.1.1). However, for the synthesis of sulfonamides it is more convenient to employ a one-pot reaction starting from the free sulfonic acid, CDI or ImSOIm, and the appropriate amine [1]... 

Similarly, /V-sulfonyl-protected vinylimidazole 597 reacts with PTAD to provide the cycloaddition reaction product 598 which easily undergoes the retro-Diels-Alder reaction upon heating or with acid treatment. The primary product is easily isomerized using a base to the aromatized condensed imidazole 599 (Scheme 95) <1998TL4561>. 

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... 

Hetero-Substituenten in 1-Stellung lassen sich oft hydrolytisch abspalten. Beispiele dafiir sind die 1-Sulfonyl-imidazole (s. o.) und die Phosphorsaure-imidazolide (Bd. XII/2, S. 271). 

Sulfonyl-Gruppen wic z.B. 1-Benzolsulfonyl-1036 oder 1-Dimethylaminosulfonyl-891,1027.1037 (Einfuhrung S. 141 Abspaltung S. 108) werden ebenfalls vereinzelt als Schutzgruppen fur Imidazole eingesetzt. 

Schwefel-Funktionen wie Mercapto, Arylthio oder Alkylthio, sind die bei weitem am haufigsten durch Oxidation umgewandelten Hetero-Atome in der Seitenkette. Als Produkte werden je nach Edukt und Reaktionsbedingungen Diimidazolyl-disulfane, Sulfo-, Chlorsulfo-nyl-, Sulfinyl- bzw. Sulfonyl-imidazole erhalten. 

Azoles containing a free NH group react comparatively readily with acyl halides. yV-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (75) — (76) or type (79)—>(80) or (81). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. 

Treatment of methyl 4,6-0-benzylidene-2-benzyloxycarbonylamino-2-deoxy-3-0-(imidazole-l-sulfonyl)-a-D-glucopyranoside with tetrabutylammonium iodide in refluxing toluene (3 h) gave the corresponding iodo derivative in 90% yield [68] (Scheme 13). When... 

Imidazole-l-sulfonyl esters of a-D-galactopyranoside derivatives are easily transformed to their corresponding 3,6-anhydro derivatives [78] at room temperature in dry DMF, by intramolecular participation of 3-O-methyl substituent (Scheme 16). Formation of... 

Attempted displacement of the 2-O-imidazole-1 -sulfonyl ester of methyl 3,4,6-tri-O-rhethyl 3-D-galactopyranoside with azide ion led to the formation of the corresponding 2,5-arihydro sugar [86], as illustrated in Scheme 17. The predominance of a ring-contraction... 

Evidence for the tetrahedral intermediate includes a Hammett p constant of+2.1 for the deacylation reaction of substituted benzoyl-chymotrypsins and the formation of tetrahedral complexes with many inhibitors, such as boronates, sulfonyl fluorides, peptide aldehydes, and peptidyl trifluoromethyl ketones. In these last the chemical shift of the imidazole proton is 18.9 ppm, indicating a good low-barrier H-bond, and the pJQ of the imidazolium is 12.1, indicating that it is stabilized by 7.3 kcal mol 1 compared to substrate-free chymotrypsin. The imidazole in effect is a much stronger base, facilitating proton removal from the serine. 

A, 1,1,1 -Tetrafluoro-/V- (trifluoromethyl)sulfonyl methanesulfonamide, see lV-Fluorobis(trifluoromethanesulfonyl)imide, 0640b 1.3a, 4,6a-Tetrahydro-lV,lV -dinitroimidazo[4,5-ii]imidazole-2,5-diamine, see Octahydro-2,5-bis(nitroimino)imidazo[4,5-(i]imidazole, 1511... 

Further examples of the functionalization of sulfur compounds with iodine(III)-nitrogen ylides include copper-catalyzed imidations of phenyl benzyl sulfide with [(sulfonylimino)iodo]benzenes possessing imidazole and pyridine rings in the sulfonyl moiety [34], and uncatalyzed tosylimidations of diaminothiocarboxylate inner salts 26 (Scheme 14) with Phi = NTs to give 27 [35]. 

Sulfonylation of free sucrose with 3 equiv. of p-toluenesulfonyl chloride in pyridine affords the l, 6,6 -tri-tritosylated sucrose in moderate yield,151,152 accompanied by the 6,6 -di-substituted as well as penta- and tetra-substituted derivatives. Using the more bulky mesitylenesulfonyl chloride, the T,6,6 -tri-sulfonylated derivative was obtained in 55% yield.152 Direct regioselective 2-p-toluenesulfonylation of sucrose with 7V-(/>-toluenesulfonyl)imidazole has been reported.106... 

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... 

---