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In the field of medicinal chemistry, sulfonamide moiety is a common substructure and plays an important role for biological activity.1) For example, Celecoxib, a blockbuster drug, contains a sulfonamide unit. Because of their favorable physicochemical properties, sulfonamides have good affinity with target proteins, which make sulfonamides promising candidates for fragment-based drug design (FBDD).2) Replacement of a subunit in some drugs with structurally similar substituents sometimes improve potency and selectivity. This phenomenon is known as bioisosterism. Owing to their structural similarity and an acidic proton, sulfonamides can be utilized as bioisosteres of carboxylic acids.3)
Figure 1. (a) Typical drugs containing sulfonamide moiety, (b) Sulfonamides as bioisostere of carboxylic acids, (c) Image of fragment-based drug design (FBDD) (Image modified and adapted from Ref. 2)
Generally, primary sulfonamides are synthesized by condensation between sulfonyl chlorides and ammonia. This protocol is reliable and widely used, but there are some limitations when desired sulfonyl chlorides are not available. Sulfoamides are also obtained from thiols by the reaction between ammonia under oxidative conditions. Nevertheless, tert-alkyl groups and electron-rich hetero aromatic compounds are not applicable due to their sensitivity to oxidative conditions.
To solve these problems, Willis et al. reported a new reagent, tBuONSO (Product No. U0150) Commercially available Grignard reagents and organolithium reagents nucleophilically attack the sulfur atom of tBuONSO to give primary sulfonamides.4) This method is widely applicable to a variety of substrates like tertiary amines and hetero aromatic compounds, which are sensitive to oxidative conditions. Bulky alkyl groups such as tert-butyl group are also applicable. In addition, tBuONSO is applicable in complex drug-like structures, so that Celecoxib was successfully synthesized with this method (Scheme 2).
Scheme 1. Strategies for preparing primary sulfonamides
Scheme 2. Selected primary sulfonamides obtained by tBuONSO
Advantages
- Stable and easy-to-handle liquid
- Enables the synthesis of primary sulfonamides from Grignard reagents or organolithium reagents
- Enhances drug discovery study such as fragment-based drug design and parallel library synthesis
N-Mono-Alkylation of Sulfonamides
Sulfonamides undergo N-mono-alkylation by hypervalent iodine compounds (Product No. I0479), Ir(ppy)3 (Product No. T3716), CuTC (Product No. C2312), BPhen (Product No. D0905) and BTMG (Product No. B6052).5) In general, N-mono-alkylation is difficult because of competing the multi alkylation and substrate’s steric bulkiness. Therefore, this protocol is anticipated to be a good synthetic application of sulfonamides and it will provide a library containing diverse fragments useful for drug discovery.
Scheme 3. N-alkylation of sulfonamides
References
- 1) Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere
- 2) (review) The rise of molecular simulations in fragment-based drug design (FBDD): an overview
- 3) (review) Bioisosterism: A Rational Approach in Drug Design
- 4) Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl-O-(tert-butyl)hydroxylamine, t-BuONSO
- 5) Decarboxylative sp3 C-N coupling via dual copper and photoredox catalysis
