Sulfonylation of amines

Sulfonylation of amines can be a useful way of differentiating (chemically) between primary, secondary, and tertiary amines by what is known as the Hinsberg test. Primary and secondary amines both react with a sulfonyl chloride, but only the sulfonamide from the primary amines has an N—H hydrogen. The sulfonyl group makes this hydrogen relatively acidic and the sulfonamide therefore dissolves readily in sodium hydroxide solutions. The secondary amine does not give a base-soluble amide, whereas the tertiary amine gives no sulfonamide ... 

Types of reaction S-N bond formation Reaction conditions Acetonitrile, room temperature Synthetic strategy Sulfonylation of amines Cataiyst Indium (In) metal... 

Substitutions of Sn2 type are frequently used for carbon-carbon or carbon-heteroatom bond formation. However, little attention has been devoted to the development of such reactions in water. This is likely due to concerns about competitive hydrolysis of the electrophile in water and SN2-type reactions being slower in aqueous conditions than in aprotic polar solvents due to the higher cost of desolvation of nucleophiles. We shall discuss the ring opening of epoxides and aziridines, palladium-catalyzed allylic substitutions, as well as acylations and sulfonylations of amines and alcohols. 

Wheieas the BPO—DMA ledox system works well for curing of unsaturated polyester blends, it is not a very effective system for initiating vinyl monomer polymerizations, and therefore it generally is not used in such appHcations (34). However, combinations of amines (eg, DMA) and acyl sulfonyl peroxides (eg, ACSP) are very effective initiator systems at 0°C for high conversion suspension polymerizations of vinyl chloride (35). BPO has also been used in combination with ferrous ammonium sulfate to initiate emulsion polymerizations of vinyl monomers via a redox reaction (36). 

Instead of amines, sulfonamides have also been used as starting materials, producing the highly reactive sulfonyl isocyanates, which have found apphcations in the manufacture of dmgs for diabetics and as drying agents (qv) (4,9,16). 

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]. 

A-Acido imines (R R"C = N —X=0) like /V-acyl (X = CR) /V-sulfonyl [X = S(R)=0]2-7 or /V-diphenylphosphinoylimines [X = P(C6H5)2]3 are masked inline derivatives of ammonia. Compared to the imines themselves these activated derivatives are better electrophiles showing less tendency to undergo undesired deprotonation rather than addition of organometal-lics1812 The apparent advantages of these compounds have been exploited for asymmetric syntheses of amines, amides, amino acids and /J-lactams1-8 I6. 

Reduction, carboxyl groups, 56,83 Reduction of a,0-unsaturated p-toluene-sulfonyl-hydrazones to alkenes, 59,42 Reductive alkylation, 56,52 Reductive cleavage, 56, 101 Resolution of amines, 55,80, 83 Rexyn 201,55,4 Rhodium(III) oxide, 57, 1 Ring contraction, 56, 107 Ring expansion of cycloalkanones to cycloalkenones, 59, 113... 

Amines can react with sulfonyl chlorides, but the product of the reaction depends upon the type of amine. 

Sulfonylations of anions formed by deprotonation of azinones are not described in previous editions <1984CHEC(2)1, 1996CHEC-II(6)1>. 4,5-Dichloropyridazin-3(2//)-one is sulfonylated at N-2 with several benzenesulfonyl chlorides in the presence of a base <2002JHC203>. Reactions of the resulting compounds with amines yield sulfonamides (see Section 8.01.8.5). 

Formally, the synthetic route outlined in Scheme 6 constitutes the preparation of a new ring system from another. Nucleophilic attack of amine on the sulfonate ester, a particularly good leaving group, leads to monocyclic compound 67. Conversion of the sulfonic acid moiety into a sulfonyl chloride by POCI3 then yields the sulfonyl chloride siVu, which then undergoes nucleophilic attack by the pendant amine resulting in the chiral sultam 68. 

Enantioselective synthesis of /3-amino alcohols by Sml2-mediated cross-pinacol coupling of the planar chiral iV-sulfonyl(ferrocenylidene)amine with ferrocene carboxaldehyde is achieved by facile reduction of the ferrocenyli-dene amine with Sml2, followed by enantioselective addition to the aldehyde (Equation (75)). ... 

The replacement of the reactive 5-chloro by a sulfonamido group in 1,2,4-thiadiazoles affords a convenient synthesis of the 5-sulfonamido heterocycles.92- 3,168-172 173 Thus, 5-halogeno compounds (171), on treatment with p-acetamidobenzenesulfonamide and potassium carbonate in diphenyl ether at 200°, afford the sulfonamido derivatives (170) in 70 % yields. Nitrobenzenesulfonamides do not react. This route is valuable, because the products are obtainable with difficulty by sulfonylation of the parent amine (see Section III,D, 1,A).8-8S-86-87 The superiority of route 171 -> 170 over route 169-y 170, though unusual in the heterocyclic field, recalls similar observations made in the synthesis of sulfonamidotriazines.174... 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

Sulfonamides have usually been prepared on solid supports by sulfonylation of aliphatic or aromatic amines with sulfonyl chlorides or by N-alkylation of other sulfonamides (Figure 8.1). 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

Support-bound secondary amines are more readily sulfonylated than primary amines, as shown by the many examples reported in the literature (Table 8.8 [117— 121]). Typically, the sulfonylation of polystyrene-bound amines is conducted in DCM, but THF [122], DMF [97,123], pyridine [124], or mixtures thereof can sometimes give better results [105]. NMM, DIPEA, and pyridine have mainly been used as bases. 

HINSBERG REACTION. Reaction of primary and secondary amines with sulfonyl halides to give sulfanamides because the products front primary amines are soluble in alkali and those from secondary amines are not. and since tertiary amines do not react, this method is useful for the sepantlion and identification of amines. 

Soon after the application of sulfonylation to sugar derivatives, the action of hydrazine17 on l,2 5,6-di-0-isopropylidene-3-0-tosyl-D-glucose, and of ammonia297 on l,2 3,4-di-0-isopropylidene-6-0-tosyl-D-galactose, was found to proceed similarly. Immediate application of this principle to preparation298 of aminated cellulose derivatives,86299 of possible... 

Predict the products of reactions of amines with ketones and aldehydes, alkyl halides and tosylates, acid chlorides, sulfonyl chlorides, nitrous acid, and oxidizing agents. Propose mechanisms where appropriate. 

This protocol is typical of the sulfonylation of a primary amine. The tritoluene-sulfonylated derivative can also be obtained by an alternative method.3... 

Reaction of 4-oxo l/7-chromene-3-sulfonyl chloride with an excess of 1,3-diaminopropane believed to proceed through acylation/ring-opening sequence. Open-chain intermediate 175 undergoes intramolecular cyclization accompanied by elimination of amine and formic acid to afford 1,2,6-thiadiazocine ring system 176 (Scheme 46 <1994AP819>). 

Phenol derivatives, in which the hydroxyl group has been converted to an ether or an ester, are incapable of coupling under normal conditions. Similarly, acyl derivatives of amines (benzoyl, acetyl, etc.) are unreactive. The sulfonyl derivatives of primary amines, such as p-tolu-enesulfonanilide, are exceptions these compounds are soluble in caustic alkali and behave as phenols toward diazo compounds. 

True 3-imino-2,3-dihydrobenz[d]isothiazole-l,1-dioxides (82) are capable of existence provided they bear an alkyl or aryl substituent in 2-position as in saccharin anils (23). The free imino compound (82a R = Me, R =H) is obtained from isomerization of o-cyano-V-methyl-phenylsulfonamide in the presence of methylamine,256 or more generally preparation of 82 may start from o-cyanophenylsulfonyl chloride together with an excess of amine.3, 256 A straightforward approach uses cyclization of an o-sulfamylbenzamide monosubstituted at each amide function, like o-(iV-phenylsulfamyl)benzanilide (83)257 with phosphorus pentoxide, phosphorus pentachloride, or preferably phosphorus oxychloride.135,257 Similarly, 2-chlorocarbonylbenzene sulfonyl chloride... 

---