Alkyl with sulfonamides

Commercially important arenesulfonyl isocyanates are not directly accessible from the corresponding sulfonamides via phosgenation due to lack of reactivity or by-product formation at elevated temperatures. A convenient method for their preparation consists of the reaction of alkyl isocyanates with sulfonamides to produce mixed ureas which, upon phosgenation, yield a mixture of alkyl and arenesulfonyl isocyanates. The desired product can be obtained by simple distillation (16). Optionally, the oxalyl chloride route has been employed for the synthesis of arenesulfonyl isocyanate (87). 

Amides can also be alkylated with diazo compounds, as in 10-49. Salts of sulfonamides (ArS02NH ) can be used to attack alkyl halides to prepare N-alkyl sulfonamides (ArS02NHR) that can be further alkylated to ArS02NRR. Hydrolysis of the latter is a good method for the preparation of secondary amines. Secondary amines can also be made by crown ether assisted alkylation of F3CCONHR (R = alkyl or aryl) and hydrolysis of the resulting F3CCONRR. ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

Dithioacids have been generated from carbon disulfide with Grignard reagents or alkyl lithium at 0 °C. Subsequent treatment with sulfonamide in situ gives the corresponding both aliphatic as well as aromatic thioamides in 70-90% yields (Scheme 10).31... 

In view of this background, we developed a new chiral auxiliary to allow for the first time the efficient asymmetric a-alkylation of sulfonamides [90]. After testing some amine auxiliaries mainly based on proline, which did not show high diastereoselectivities, we synthesized the 4-biphenyl-substituted 2,2-dimethyl-l,3-dioxan-5-amine 108 as a new auxiliary. The racemate obtained according to Erlenmeyer s phenylserine synthesis was resolved with tartaric acid to give both enantiomers. 

N-Alkylation of sulfonamides 0-94 Alkylation of sulfonamides 0-99 Reaction of halo sulfonamides with boranes... 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

Because many more alcohols than alkyl halides are commercially available, the Mitsu-nobu reaction enables the synthesis of larger and more diverse compound arrays than alkylation with alkyl halides. A -AcyIsuIfonamides are strongly acidic and can be alkylated with diazomethane (Entry 6, Table 8.9) or trimethylsilyldiazomethane [137]. Resin-bound sulfonamides have been N-acylated by treatment with acyl halides, and N-carbamoylated by treatment with isocyanates [138]. 

Table 8.10. N-Alkylation of sulfonamides with support-bound electrophiles.

The reaction of methyl ester of D-alanine 185 with 4-methoxy-2-nitrobenzenesulfonyl chloride 186 in presence of ethyl diisopropylamine gave the sulfonamide 187, which was alkylated with allyl bromide 188 to afford 189 (Scheme 41). Ozonolysis of 189 resulted in the formation of aldehyde 190, and the subsequent reductive cyclization with zinc and AcOH led to the benzothiadiazepine 120 through intramolecular reductive alkylation. Using similar reaction sequence, the 1,2,5-thiadiazepines 191 and 192 were also synthesized <2003JME1811>. 

In addition, sulfonamides bear more acidic, compared to carboxamides, protons that can be selectively A-alkylatcd or V-acylatcd. Thus, alkylation of sulfonamide catenane and rotaxane with Frechet-dendrons of 2nd generation led to the first representatives of the dendrocatenane 15 and dendrorotaxane 16 [46], respectively. These compounds were of especial interest, since they allowed for the first time to study chiral induction of topologically chiral cores on appended dendrons and to compare to the analogous centrochiral dendrimers for which phenomenon of the crypto-optical activity was postulated [47],... 

The silver salt of sulfonamide 53 can be effectively silylated with trialkylchlorosilanes to N-substituted derivatives 54 <1998ZFA147> or alkylated with methyl iodide giving iV-methyl benzenesulfonamide 55 <1995PS91>. Bis(benzenedisulfonamide) silane 17 was obtained from dichlorodimethylsilane (Scheme 3). 

Thiazetidines may be prepared by alkylation of the sodium salts obtained conveniently by thiocarbamoylation of the sulfonamides 191 with isothiocyanates in the presence of sodium hydride in DMF. Alkylation with bromo-chloromethane or dibromomethane yields the substituted 2-imino-l,3-thiazetidines 41 <2002SUL105>. 

To obtain sufficient quantities of benzazepinone 10 for large-scale synthesis of 1, the Yamanouchi process group subsequently turned to the preparation of 10 in a five-step sequence commencing with anthranilic acid 16.33 Acid-mediated esterification of 16 followed by aniline tosylation provided sulfonamide 17, which was subsequently alkylated with 4-chlorobutyronitrile to furnish the jV-(3-cyanopropyl)anthranilate 18. Dieckmann cyclization of 18 with sodium hydride in DMF then established the... 

Weinreb and coworkers [166] achieved the synthesis of the spermidine alkaloid anhydrocannabistivene (277) using alkylation of sulfonamide as a ring closure means. As shown in Scheme 93, the linear precursor 275 was treated with an excess of K2CO3 in refluxing CHjCN to afford the desired lactam 276in 58% yield. 

Table 2 Substrate scope in the alkylation of aldehydes with sulfonamide lb ...

Monohalogenothiazoles, 567 nucleophilic substitution reactions, 322 with amines. 567 with ArSH, 567 with benzamide, 567 with OH", 567 with OR", 567 relative reactivities, 568 with SR", 567 with sulfinic acid salts, 567 with sulfonamide, 567 reactions, with alkyl halides, 574 with n-butyllithium, 573 with Gtignard reagents, 573 reeduction of, with nickel, 573 with zinc, 573... 

Under certain conditions, amides can add directly to alkenes to form V-alkylated amides. Sulfonamides react in a similar manner. 3-Pentenamide was cyclized to 5-methyl-2-pyrrolidinone by treatment with trifluorosulfonic acid. Acyl hydrazine derivatives also cyclized in the presence of hypervalent iodine reagents to... 

Mori et al. have shown that asymmetric alkylation with an allylic tosyl amide followed by a zirconium-promoted cyclization provides an efficient route to mesembrine and mesembrane alkaloids [107]. The best ee was obtained with BINAPO as the ligand. Scheme 28. The product was obtained in 86% ee and following recrystallization the sulfonamide was obtained in 99% ee. 

A few other studies of allylations of N-sulfonyl imines by allylic silanes have been published. Shono et al. found that azetidine derivative 22 can be converted to allyl compound 115 [25b] [Eq. (26)]. The functionalized sulfonamides 116 [Eq. (27)] have all been alkylated with allyl trimethylsilane and Lewis acids [34]. In general, the best yields of 117 were obtained with SnCl4, BF3 etherate, Znl2 and FeCl3 as catalysts. Lower yields were obtained with TiCl4 and Et2AlCl. Similarly, the a-hydroxy and a-methoxy sulfonamides 51 could be alkylated to give... 

A-Alkylation of sulfonamides occurs at room temperature with benzylic, allylic and propargylic alcohols in the presence of Bi(OTf)3 and KPFg." ... 

---