Alkyl substituted sulfonamides

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

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. 

The cyclic sulfonamide (377) can be prepared by heating 5-aminopentanesulfonyl chloride. 4-Chloro-2-benzoylbenzenesulfonyl chloride reacts with acetamidine to give the o-benzoyl-N-phenylsulfonylamidine which can be cyclized with base to give the fully unsaturated 1,2-benzothiazepine 1,1-dioxide (378 R = R1 = H). Alkyl-substituted amidines give the 3-imino derivatives (66USP3377357). 

The bifunctional pyrrolidine sulfonamide catalyst, 38, having basic pyrrolidine nitrogen and Bronsted acidic sulfonamide function, mediates the addition of aldehydes to nitrostyrenes in high yield and selectivity (Scheme 2.47) [34]. Alkyl-substituted nitroolefins afford, however, product in low yield and in low selectivity. 

Several synthetic approaches to the l,2-benzothiazin-3-ones have been described. Usually, an ortho-substituted sulfonamide was cyclized to form the thiazine ring. For example, Lombardino and Wiseman14,38 treated /V-methyl-o-toluenesulfonamide (45) with butyllithium the dianion with CO 2 produced o-sulfamoylphenylacetic acid 46 which was cyclodehydrated to 3,4-dihydro-2-alkyl-l,2-benzothiazin-3(2H)-one 1,1-dioxide (47) in good yield (Eq. 10). This same reaction sequence was applied to analogs of 47 such as the 7-methyl, the 7-chloro, and the 2-benzyl derivatives.38... 

Polyamine chain extension, 48-56 by acrylamide 51, 52. 53 by aziridine 48,49 by l-bromo-3-chloropropane, 55 by (2-bromoethyl)phthalimide, 51 by 3-bromopropylphthalimide, 53 by chloroacetonitrilc, 51 by chloroacetyl chloride. 50 by lV-(2-chloroethyl)acetamide, 52 by derivatives of chloroacetic acid. 50 by dichloro(o)-bromoalkyl)boranes. 56 by IV-ethylchloroacetamide, 52 by 3-phthalimidopropyl tosylate, 54 by /V-tosyl-2-bromoethylamine, 49 by 2-(N-tosylamino)ethyl tosylate. 49 by Af-tosylaminoacetyl chloride, 50 Polyamino diols. 59 Polyaza-crown macrocycles. 349-367 alkyl-substituted. 364.365 from bis-sulfonamides, 358-361 from diacid dichlorides, 352-357 from diesters, 352-357 from dihalides, 362-366 from diols, 366 from ditosylates. 362-366 Polyaza-crown macrocycles (miscellaneous), table. 392... 

Series of halo- and alkyl-substituted benzene- and naphthalene-sulfonamides have been obtained by this method. 

Replacement or removal of the sulfonamide group at position 7 yields compounds with little or no diuretic activity. Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic that is 10-fold more active than the unsaturated derivative. Substitution with a lipophilic group at position 3 gives a marked increase in the diuretic potency. Haloalkyl, aralkyl, or thioether substitution increases the lipid solubility of the molecule and yields compounds with a longer duration of action. Alkyl substitution on the 2-N position also decreases the polarity and increases the duration of diuretic action. Although these compounds do have carbonic anhydrase activity, there is no correlation of this activity with their saluretic activity (excretion of sodium and chloride ions). 

Krause has shown that gold(III) salts catalyze the intramolecular emJo-hydroamina-tion of N-protected a-aminoallenes [35]. For example, treatment of the diasteromeri-cally pure a-allenyl sulfonamide 44 with a catalytic amount of AUCI3 in dichlor-omethane at 0 °C for 1 h formed the pyrroline derivative 45 in 95% yield with 96% diastereomeric purity (Scheme 11.6). The protocol tolerated aryl and alkyl substitution of the distal allenyl carbon atom and was also effective for the hydroamination of N-unprotected a-allenylamines although these latter transformations required considerably longer reaction time. In a similar manner, Lee has reported the gold (Ill)-catalyzed ewdo-hydroamination of 4-allenyl-2-azetidinone 46 to form bicydic P-lactams 47 (Eq. (11.25)) [36]. 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above Grignard condensation followed by dehydration gives thiothixine (42). 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

With these solid supports in hand, we turned our attention to a new route to the synthesis of our target molecule 23 (Scheme 8). The tricky reductive amination should be replaced by an N-alkylation. To that end, bromoacetic acid is attached to 24c using DIC and Hiinig s base followed by the nucleophilic substitution with the corresponding benzy-lamine in DMSO/toluene (1 1), which can be easily monitored by the Beilstein test, followed by sulfonamide formation in DCM using N-methylmorpholine as base. For the final cleavage, 2% TFA in DCM is used and the resulting solution is filtered in a saturated NaHCC>3 solution to neutralise the acid before evaporation of the solvent. The crude product was then crystallised from ethyl acetate/heptane to yield the desired product in 27% yield overall and 99A% HPLC purity (see Table 4). 

This reaction is typical for the synthesis of sulfonylureas it is mildly exothermic and proceeds smoothly in a variety of inert aprotic solvents. The product is usually obtained in very high yield, as a fine crystalline precipitate. The sulfonyl isocyanates are readily prepared from the substituted benzene sulfonamides by reaction with phosgene, Fig. 3, in the presence of an alkyl isocyanate, for example, butyl isocyanate in an inert solvent at 120 to 140°C according to the general procedure of H. Ulrich and A. A. R. Sayigh (Ref. 3). 

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. ... 

Numerous methods to prepare individual classes of aliphatic diazo compounds have been extensively developed. The major strategies for their synthesis involve the alkaline cleavage of N-alkyl-N-nitroso-ureas, -carboxamides and -sulfonamides, dehydrogenation of hydrazones, as well as diazo group transfer from sulfonyl and related azides to active methylene compounds, and electrophilic diazoalkane substitution reactions. These synthetic methods have been comprehensively reviewed (15,16). Useful information on the preparation of selected diazo compounds can be found elsewhere (6,17). 

Davis et al. [88] described the asymmetric synthesis of a-substituted primary sulfonamides involving the diastereoselective a-alkylation of N-sulfonylcamphor-imine dianions, while Huart and Ghosez reported an enantioselective synthesis of bicyclic cyclopentenones via a stereoselective 1,4-addition of metallated enan-tiopure sulfonamides to cyclic enones [89]. 

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