Amines sulfonyl chlorides

A -Unsubstituted 1,2,4-diazaphospholes (4) undergo A -alkylation by reaction with alkyl vinyl ether, sulfur ylides, and diazo compounds <95HAC403>. They react with acyl chlorides in a 2 1 molar ratio to give a mixture of the A -acylated diazaphosphole and the diazaphosphole hydrochloride. Preparative A -acyclation is achieved in presence of a tertiary amine. Sulfonyl chlorides and phosphorus trichloride also give A -substitution reactions (Scheme 2) <87TH 422-01 >. 

N -Heterocyclic Sulfanilamides. The parent sulfanilamide is manufactured by the reaction of A/-acetylsulfanilyl chloride with excess concentrated aqueous ammonia, and hydrolysis of the product. Most heterocycHc amines are less reactive, and the condensation with the sulfonyl chloride is usually done in anhydrous media in the presence of an acid-binding agent. Use of anhydrous conditions avoids hydrolytic destmction of the sulfonyl chloride. The solvent and acid-binding functions are commonly filled by pyridine, or by mixtures of pyridine and acetone. Tertiary amines, such as triethylamine, may be substituted for pyridine. The majority of A/ -heterocycHc sulfanilamides are made by simple condensation with A/-acetylsulfanilyl chloride and hydrolysis. 

A variation of this procedure is used for sulfisomidine because of the different character of the amino group in the 4-position of a pyrimidine ring. Two moles of the sulfonyl chloride are condensed with one mole of 4-amino-2,6-dimethy1pyrimidine in the presence of triethylamine. The resulting bis(acetylsulfanilyl) derivative is readily hydrolyzed to the product. The formation of the bis(acetylsulfanilyl) derivative has also been employed for other heterocycHc amines, eg, for synthesis of sulfathiazole and sulfamoxole (44), but the 1 1 reaction is probably preferable. 

A/ -HeterocycHc derivatives can be formed in some cases by a ring closure to give the heterocycle. Sulfadiazine, sulfamethazine, sulfamerazine, and sulfathiazole have been prepared in this fashion, but also by the usual procedure from the sulfonyl chloride and heterocycHc amine. The synthesis of sulfamethazine from sulfaguanidine is an example of the ring closure method. 

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, aHenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphoms oxychloride [10025-87-3] POCl (H)- Because sulfonic acids are generally not converted directiy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphoms pentachlotide [10026-13-8] and phosphoms pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl haUdes (12,13). The conversion may also be accompHshed by continuous electrolysis of thiols or disulfides in the presence of aqueous HCl [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfutic acid [7789-21-17, or by reaction of the sulfonic acid or sulfonate with fluorosulfutic acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl haUde, can be achieved under oxidative halogenation conditions (15). 

Sulfonamides, as a class, are simple to manufacture once the isolation conditions for the moderately stable sulfonyl chloride have been estabUshed. Basically all processes iavolve the addition of the sulfonyl chloride paste to excess ammonia or amine ia aqueous solution. The product can usually be filtered off ia a reasonably pure form with only the hydrolysis product remaining ia the Hquor. 

The sulfonyl chloride group is the cure site for CSM and determines the rate and state of cure along with the compound recipe. It is less stable than the Cl groups and therefore often determines the ceiling temperature for processing. The optimum level of sulfonyl chloride to provide a balance of cured properties and processibiUty is about 2 mol % or 1—1.5 wt % sulfur at 35% Cl. It also undergoes normal acid chloride reactions with amines, alcohols, etc, to make useful derivatives (17). 

V,/V dipheny1ethy1enediamine. The cure mechanism probably involves an amine-catalyzed decomposition of the sulfonyl chloride group or a path of radical anions. The cross-link probably involves the HVA-2. Calcium hydroxide or other SO2 absorbers must be included for development of good mechanical properties. 

The much-used sulfonylation by aromatic sulfonyl chlorides is illustrated by the conversion of quinazolin-4-amine into the sulfonamide (247) using p- nitrobenzenesulfonyl chloride at 60 °C (56JCS3509). 

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 DNMBS derivative, readily prepared from an amine and the sulfonyl chloride, is efficiently (0 = 0.65) cleaved photochemically hv >300 nm, EtOH, NH3 BH3, 77-91% yield). " ... 

Like the trifluoromethylsulfonamides, phenacylsulfonamides are used to prevent dialkylation of primary amines. Phenacylsulfonamides are prepared in 91-94% yield from the sulfonyl chloride and cleaved in 66-77% yield by Zn/AcOH/trace HCl. ... 

Aliphatic sulfonyl chlorides that have a-hydrogen substituents, react with simple tertiary amines, such as trimethylamine, to generate sulfenes or perhaps their amine adducts 446). These species are suggested by the incorporation of one (but not more) deuterium atoms on reaction of sulfonyl chlorides with deuterated alcohols and triethylamine (447-450). A 2 1 adduct of sulfene and trimethylamine with proposed sulfonyl-sulfene structure could be isolated (451). 

This sulfonate, prepared from B0CNHCH2CH2C(CH3)2CH20H and the sulfonyl chloride (Pyr, 100% yield) is cleaved by initial BOC cleavage to release the free amine after pH adjustment to 7-8. Intramolecular displacement occurs to release the sulfonate and a pyrrolidine. ... 

The Bts derivative is formed from the sulfonyl chloride, either using apro-tic conditions for simple amines or by the Schotten-Baumann protocol for amino acids (87-97% yield). The primary drawback of this reagent is that its stability depends on its quality. It can on occasion rapidly and exothermically lose SO2 to give 2-chlorobenzothiazole. ... 

The drugs are available by one of two fairly straightforward routes. Chlorosulfonation of acetanilide gives the corresponding sulfonyl chloride (88) reaction with the appropriate amine gives the intermediate, 89. Hydrolysis in either acid or base leads to the sulfanilamide (90). 

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, IJ5 acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). ... 

Since the ring nitrogen at 3 is now comparable in reactivity to the amine at 4, acylation with one equivalent of 88 gives a mixture of products. The desired product, sulfaisodimidine (109), can be obtained by acylation with an excess of the sulfonyl chloride (140) followed by alkaline hydrolysis. The rate of saponification of the sulfonamide group attached to the ring nitrogen is sufficiently greater to cause it to be lost selectively. 

Inclusion of a para acetyl group requires a somewhat different approach to the preparation of these compounds. Reaction of the diazonium salt from p-aminoacetophenone with sulfur dioxide affords the sulfonyl chloride, 203 this is then converted to the sulfonamide, 204, Elaboration via the carbamate with cyclohexyl-amine affords acetohexamide (205). ... 

The most important group of derivatives for the amino function (Fig. 7-4) is the carbamate group, which can be formed by reactions with acids, acid chlorides or acid anhydrides. A series of chlorides as 2-chloroisovalerylchloride [1], chrysanthe-moylchloride [2] and especially chloride compounds of terpene derivatives (cam-phanic acid chloride [3], camphor-10-sulfonyl chloride [4]) are used. The a-methoxy-a-trifluoromethylphenylacetic acid or the corresponding acid chloride introduced by Mosher in the 1970s are very useful reagents for the derivatization of amines and alcohols [5]. 

Addition, chloroform, to olefins to form 1,1,3 tnchloroalkanes, 46, 106 chlorosulfonyl isocyanate to isobutylene to give 0-isovaleiolactam-N-sulfonyl chloride, 46, SI cyclohexyl amine to silicon tetraiso-cyanate, 46, 69... 

The three steps 32-34 have been suggested77 to be equilibria, and the overall equilibrium must lie far to the left because no adduct 23 is found in the reaction mixture when the reaction of sulfonyl chloride with olefin is carried out in the absence of a tertiary amine. A second possible mechanism involving oxidative addition of the arenesulfonyl halide to form a ruthenium(IV) complex and subsequent reductive elimination of the ruthenium complex hydrochloride, [HRulvCl], was considered to be much less likely. 

The treatment of sulfonyl chlorides with ammonia or amines is the usual way of preparing sulfonamides. Primary amines give N-alkyl sulfonamides, and secondary amines give N,N-dialkyl sulfonamides. The reaction is the basis of the Hinsberg test for distinguishing between primary, secondary, and tertiary amines. N-Alkyl sulfonamides, having an acidic hydrogen, are soluble in alkali, while N,N-dialkyl sulfon-... 

An efficient method has been developed for the conversion of pyrimidine-2-thiol into the sulfonyl chloride 75, which was reacted in situ with amines. A modified method gave the rather more stable (and storable) sulfonyl fluoride 74 <06JOC1081>. 

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