Sulfonamides, alkylation arylation

Alkyl aryl telluriums and diaryl telluriums react with anhydrous (V-chloro-/V-sodioarenesulfonamides in refluxing chloroform in the presence of 18-crown-6 to yield diorgano tellurium arenesulfonimides1. When the reactions are carried out with the hydrated sulfonamides in methanol, diorgano tellurium oxides are formed1. 

We are going to do a little more than simply give the reactions that eventually made up the synthesis of dofetilide. We are going to put ourselves in the place of the chemists who invented the synthesis and try to see what led them to the reactions they chose. First, we should inspect the structure of the molecule. There are two sulfonamides, one at each end. We have seen how to make sulfonamides earlier in this chapter when saccharin was being discussed. The usual way is to react the amine with a sulfonyl chloride. In this case we shall need to react methane sulfonyl chloride (MeS02Cl or MsCl) with the aromatic amines. This is a well-known reaction and should work well here. The other functional groups—tertiary amine and alkyl aryl ether—should not interfere so no protection is needed. 

The 3-alkyl-3,4-dihydro-2//-l-thia-2,4-diazine 1,1-dioxide 224 is produced by heating the appropriate aldehyde with 2-aminobenzenesulfonamide in iV-methyl-2-pyrrolidone (NMP) at 100°C <2001BML3103>. 3-Aryl-3,4-dihy-dro-2//-l-thia-2,4-diazine 1,1-dioxides 225 are the products of heating preformed bis(sulfonamides) with aryl aldehydes in dimethyl sulfoxide (DMSO) <20040JC373>. The 3,4-annulated derivative 226 is the result of a reaction between the corresponding 2-aminobenzenesulfonamide and homophthalaldehyde <1996AP51>. 

A number of alkylation products from MeOTf and heterocycles have been advocated as useful intermediates. Thus treatment of 2-substituted thiazoles with MeOTf in acetonitrile, followed by reduction of the salt formed with sodium borohydride/CuO in CH2CI2, leads to aldehydes. l-(Benzenesulfonyl)-3-methylimidazolium and l-(/>-toluenesulfonyl)-3-inethylimidaz-olium triflates have been proposed as efficient reagents for the preparation of aryl sulfonamides and aryl sulfonates. MeOTf alkylates 2,5-oxazoles to give salts which can be reduced by PhSiHs/CsP to give 4-oxazolines, and these provide a route to stabilized azomethine ylides. ... 

Coupling of (R)-IO and (R)-ll to (R)-12 is completed by the well-known Suzuki-Miyaura reaction where Pd(0) complex catalyzes the formation of the C-C bond (Sect. 6.3, Example 6.4). In the next step, the protecting group is eliminated and the C=C bond reduced by achiral Ir(I) complex to trans-(lR,4S)-14. It is important to note the wrong R configuration at the C(l) atom in this and the previous intermediate. Inversion of the configuration in (15,45)-15 is achieved by the Mitunobu reaction with diphenylphosphorylazide (dppa) as the source of nucleophilic azide ions in the presence of DBU. This reaction is the method of choice for the transformation of alcohols in many other functionalities, azides, esters, alkyl-aryl ethers, imides, sulfonamides, etc., and its mechanism is explained in considerable detail [21, 22]. 

Another point for structural diversification is the sulfonamide group. Imai had already shown that a wide variety of groups could be introduced at this position to optimize the reaction. Since a wide variety of sulfonyl chlorides are commercially available, a number of different types of groups could be examined (Scheme 3.34). Testing of a variety of aryl and alkyl groups on the 1,2-cyclohexanediamine backbone demonstrates that the simple methanesulfonamide 122 is clearly superior or equal to many other analogs in the cyclopropanation of cinnamyl alcohol (Table 3.11). Another concern which was directly addressed by this survey was the question of catalyst solubility. 

O-Alkyl-7 und O-Aryl-hydroxylamine8 lassen sich mit Lithiumalanat in die Komponenten spalten bzw. re-duktivumlagern , O-Acyl-10bzw. N-Sulfonyl-hydroxylamine11 imerstenSchritt zum Hydroxylamin und Al-kohol bzw. Sulfonamid reduzieren. 

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. ... 

Trialkylboranes react rapidly and in high yields with a-halo ketones,a-halo esters, a-halo nitriles, and a-halo sulfonyl derivatives (sulfones, sulfonic esters, sulfonamides) in the presence of a base to give, respectively, alkylated ketones, esters, nitriles, and sulfonyl derivatives. Potassium tert-butoxide is often a suitable base, but potassium 2,6-di-tert-butylphenoxide at 0°C in THF gives better results in most cases, possibly because the large bulk of the two tert-buXy groups prevents the base from coordinating with the R3B. The trialkylboranes are prepared by treatment of 3 mol of an alkene with 1 mol of BH3 (15-16). With appropriate boranes, the R group transferred to a-halo ketones, nitriles, and esters can be vinylic, or (for a-halo ketones and esters) aryl. " °... 

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. ... 

Solutions of dinitrogen pentoxide in methylene chloride or chloroform have been used for the V-nitration of the sodium salts of some V-alkylsulfamides. " Sulfonamide substrates with both alkyl and aryl substituents are V-nitrated in excellent yields with this reagent. Aromatic ring nitration occurs when aryl substituents are present. 

A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3//)-ones show depressant activity, while the benzoate esters of substituted 3-(2-hydroxyethyl)-l,2,3-benzotriazin-4(3f0-one are reported to function as coronary dUating agents," as do certain other compounds of this type." 3-(o-Haloaryl)-l,2,3-benzotriazin-4(3i/> ones are claimed to have antisecretory," anoretic, anticonvulsant, and hypoglycemic activity, and a variety of other 3-aryl derivatives are stated to be relaxants, tranquilizers, sedatives, hypnotics, or cramp inhibitors. A number of derivatives of 10, R = H, in which the 3-substituent is a long alkyl chain containing a terminal sulfonamide group have been claimed to act. as antidiabetics. ... 

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. 

Table 8.9. N-Alkylation and N-arylation of support-bound sulfonamides and sulfinamides.

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