Sulfonamides, formation

In terms of cost, the effectiveness of the catalytic cycle in the ring closure makes this process economical in palladium. The first three steps in the reaction sequence -- ring opening of an epoxide by a Grignard reagent, converison of an alcohol to an amine with inversion, and sulfonamide formation from the amine — are all standard synthetic processes. 

Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation the Si-TrisAmine was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining <06MCL3777>. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

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). 

The combinatorial reactions chosen for the novel amines were amide bond formation and sulfonamide formation. The novel carboxylic acids were derivatized to simple amides. For the amine reactions, we chose two simple carboxylic acids (propionic acid and benzoic acid) and two simple sulfonyl chlorides (methyl-sulfonyl chloride and benzenesulfonyl chloride) as the capping groups. Propyl amine and benzylamine were chosen as the capping groups to react with the novel carboxylic acids. Because only one reactant will be variable, these combinatorial libraries were essentially 1 x N libraries, where the one reactant was a simple reactant and the N component is the novel amines or acids. 

The Hinsberg test, which can distinguish primary, secondary, and tertiary amines, is based upon sulfonamide formation. In the Hinsberg test, an amine is reacted with benzene sulfonyl chloride. If a product forms, the amine is either a primary or secondary amine, because tertiary amines do not form stable sulfonamides. If the sulfonamide that forms dissolves in aqueous sodium hydroxide solution, it is a primary amine. If the sulfonamide is insoluble in aqueous sodium hydroxide, it is a secondary amine. The sulfonamide of a primary amine is soluble in an aqueous base because it still possesses an acidic hydrogen on the nitrogen, which can be lost to form a sodium salt. 

Combinatorial sequences that comprise amine acylation can frequently be expanded to sulfonamide formation using sulfonyl chlorides (unspecified sulfochlorides [9, 52] aliphatic and aromatic sulfochlorides [19] aromatic sulfochlorides [80,102]). Sulfonation of aliphatic diamines with protected (3-aminoalkane sulfonyl chlorides was carried out in the presence of polymer-bound 4-dialkylaminopyridine [130] (see also Table 3.11). 

A five-step process was planned to provide a focused array of compounds incorporating three points of diversity arising from sulfonamide formation, A -alkylation, and substituent variation (Scheme 18.21). The route makes use of established reliable reactions such that the entire process was readily antomated using a Zinsser Sophas robotic platform. The first reaction uses apolymer-supported sulfonyl transferreagent, derived from the immobilization... 

Sulfonamide formation is the basis for a chemical test, called the Hinsberg test, that can be used to demonstrate whether an amine is primary, secondary, or tertiary. 

Scheme 1.1 Schreiber s split-pool synthesis of 1,3-dioxanes with high substitutional diversity. Reagents and conditions (1) R SH or R R N (2) (i) ArCH(OMe)2, MejSiCl, HCl, dioxane (ii) PPTS, THF-MeOH (iii) piperidine (iv) Me3SiCl (3) amide, urea, thiourea or sulfonamide formation.

Protection of Nitrogen Formation of Sulfonamides. Unlike the corresponding arenesulfonyl chlorides, benzenesulfonyl bromide has been used much less extensively in organic synthesis. Primary amines and imidazoles (eq 1) have been converted to the corresponding benzenesulfonamides and, with indoles, bromi-nation at C-3 occurs with concomitant sulfonamide formation (eq 2). ... 

Synthetic strategy Direct oxidative conversion of thiols to sulfonyl chlorides, followed by sulfonamide formation... 

It is interesting that sulfonamide formation does not occur. .. allylic strain issues ... 

Sulfonamide Formation. Reaction of mesitylenesulfonyl chloride with amines in the presence of Pyridine or Triethylamine yields the corresponding sulfonamides (eq 1 ), which have been used as intermediates in synthesis. 

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