Sulfonamides, alkylation with alcohols

This reaction was initially reported by Fukuyama and co-workers in 1995. It is a two-step conversion of primary amines into secondary amines via ortho-nitrobenzenesulfonation in conjunction with the Mitsunobu Reaction and subsequent removal of the o-nitrobenzenesulfonyl group by thiophenol. Therefore, this reaction is generally known as the Fukuyama amine synthesis. In addition, it is also referred to as the Fukuyama-Mitsunobu A -alkylation," Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama-Mitsunobu Reaction. In this reaction, the o-nitrobenzenesulfonyl-protected amine is alkylated with alcohol in the presence of PPhs and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection occurs in a very mild condition (almost neutral ). The o-nitrobenzenesulfonyl group is simply called the Fukuyama sulfonamide protecting groupThis reaction has become a versatile method... 

Martmez-Asencio A, Ramon DJ, Yus M (2010) A-Alkylation of poor nucleophilic amine and sulfonamide derivatives with alcohols by a hydrogen autotransfer process catalyzed by copper(ll) acetate. Tetrahedron Lett 51(2) 325-327... 

Weak nitrogen nucleophiles, such as amides and sulfonamides, have proven more difficult to alkylate with alcohols. The limited reports of such transformations usually require higher temperatures (>175 °C), which may be due to slow and reversible condensation to form the N-acyl imine intermediate. Watanabe and coworkers disclosed the first amide N-alltylation with primary alcohols at 180 °C. ° Jenner found that RuCls-catalysed amide allqrlation at 210 °C was effective for secondary alcohols as well. Jenner s protocol was also sufficient for the alltylation of secondary amides with primary alcohols to provide tertiary amides at 225 °C. Williams and coworkers reported primary amide N-alltylation under microwave irradiation at 175 °C, reducing the reaction time to two hours. Cu(OAc)2 was also found to be a useful catalyst for primary amide N-alltylation with benzylic alcohols. Primary ureas and carbamates have also been alkylated with alcohols using [Cp IrCl2]2 (Scheme 12.7). 

Sulfonamide iV-alkylation with alcohols is an important transformation due to the abundance of the sulfonamide moiety in drugs. Traditional sulfonamide synthesis involves the reaction of a sulfonyl chloride with a primary or secondary amine. However, these methods require the use of unstable sulfonyl chlorides and generate stoichiometric salt waste. In contrast, the N-alkylation of sulfonamides with alcohols presents a convenient alternative that utilises stable starting materials and produces water as the... 

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. ... 

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]. 

In 2015, Xiao and co-workers reported an iridium complex (14)-catalyzed N-alkylation of amines with alcohols under mild conditions (100 °C) (Scheme 22) [113]. Anilines, heteroarylamines, A -alkyl-A(-arylamines, and sulfonamides could serve as A-nucleophiles. The same method can also be applied to amine-based N-... 

Some water-soluble and water-tolerant iridium catalysts have also been developed in recent years. In 2010, Williams and co-workers found [Cp Irl2] is a water-tolerant catalyst for A -alkylation of primary and secondary amines and sulfonamides in aqueous media [115]. In the same year, Fujita, Yamaguchi and coworkers also reported a water-soluble and air-stable [Cp Ir(NH3)3][I]2-catalyzed multi-alkylation of aqueous ammonia with alcohols (Eq. 25) [116]. The catalyst could be recycled by an easy procedure that still maintains high activity. Moreover, quinolizidines could also be achieved from the reaction of aqueous ammonia and a water soluble triol employing the same method. 

Li and co-workers reported an iridium complex 15-catalyzed iV-alkylation of sulfonamides with alcohols in aqueous media (Eq. 27) [119]. 

Scheme 24 Proposed mechanism for iron-catalyzed alkylation of sulfonamide with alcohol Springer 320 Reprinted from the journal...

Scheme 33 Proposed mechanism for Cu-catalyzed Al-alkylation of sulfonamides with alcohols under air...

In 2012, Xu and co-workers continued to report a Cu-catalyzed aerobic N-alkylation reaction of sulfonamides, anilines and heteroarylamines with alcohols under air (Eq. 61) [192]. The authors evaluated the effects of the additives on the reaction. They not only observed the promoting effect of air, but also found that aldehyde contamination in substrate alcohols could also lead to more efficient reactions either under either air or under nitrogen. Besides, they observed the successful oxidation of alcohol by Cu(ll) under anaerobic conditions (Eq. 62). 

Ramon D, Martinez-Asencio A, Yus M (2011) Palladium(ll) acetate as catalyst for the A-alkylation of aromatic amines, sulfonamides, and related nitrogenated compounds with alcohols by a hydrogen... 

Shi F, Tse MK, Beller M et al (2009) Copper-catalyzed alkylation of sulfonamides with alcohols. Angew Chem Int Ed 48(32) 5912-5915... 

Feng SL, Liu CZ, Xu Q et al (2011) Rhodium-catalyzed aerobic V-alkylation of sulfonamides with alcohols. Chin Chem Lett 22(9) 1021-1024... 

Scheme 12.8 JV-Alkylation of sulfonamides and sulfinamides with alcohols.

Simple palladium(II) salts such as chloride and acetate efficiently catalyse aerobic oxidative A-alkylation of amines and amides with alcohols. This method is suitable for a variety of sulfonamides, amides, aromatic and heteroaromatic amines as well as benzylic and heterobenzylic alcohols with a low loadings of the catalyst (0.5-1 mol%) and the alcohols. A selective carbon-carbon double bond assisted o-C-H olefination is catalysed by palladium(II) acetate. The terminal oxidant is oxygen. Addition of TFA is essential for any meaningful yield. (PdOCOCF3)+ has been proposed as the active catalyst. The observed large difference in the inter- and intra-molecular KIE values implied that the coordination of the C=C bond occurs before C-H palladation in the catalytic cycle consequently, a mechanism involving the initial coordination of allylic C=C bond to (PdOCOCF3)+ followed by selective o-C-H bond metalation has... 

Mg or Ca in MeOH, " baker s yeast, Sm/l2, LiMe2NBH3, and tin complexes prepared from SnCl2 or Sn(SR)2. This reaction, combined with RX —+ RN3 (10-65), is an important way of converting alkyl halides RX to primary amines RNH2 in some cases the two procedures have been combined into one laboratory step. Sulfonyl azides (RSO2N3) have been reduced to sulfonamides (RSO2NH2) by irradiation in isopropyl alcohol and with NaH. ... 

---