The Role of Sulphonamides and N-Sulphonyl Ketimines

Sulphonamides were first used to treat bacterial infections in 1990 by “Gerhard Domagk.” They entered a large class of drug domains with the passage of time, including anti-obesity drugs such as topiramate, which causes changes in gluconeogenesis and lipogenesis, diuretics such as furosemide, which inhibits the luminal Na-K-Cl co-transporter in the thick ascending limb of the loop of Henle, by binding to the chloride transport channel, causing sodium, chloride, and potassium loss in urine, hence lowering the BP.[6] Acetazolamide is a GABA-A receptor-mediated analgesic and anti-neuropathic drug that inhibits HCO3-dependent depolarization. Sulfamethoxazole has an antibacterial action via blocking the enzyme dihydropteroate synthase. To produce molecular variety, sulphonamides are commonly used as transitory and intrinsic guiding groups to C-H functionalization and reuse the fragments for late-stage alterations.

Because sulphonamides are a medical pharmacophore, their utility as a substrate and directing group has been widely anticipated. Sulphonamides are a type of directing group that may easily guide the flow of metal with a lone pair of electrons by coordinating through nitrogen electrons and functionalize the molecule selectively. Sulphonamides have excellent compatibility and tolerance for a variety of functional groups, which is difficult to produce using traditional synthetic methods. Sulphonamides are poor coordinating directing groups, but their importance as a functional group with therapeutic activity has made them trustworthy.

N-sulphonyl ketimines/aldimines, on the other hand, are a powerful bioactive motif with a distinctive structural architecture. Its cyclic form has been widely investigated as a chiral auxiliary and is also used as a ligand in asymmetric synthesis. Src kinase inhibitors, human leukocyte elastase inhibitors, PFT inhibitors, and HCV inhibitors all contain them. Because of their selectivity and capacity to produce C-C and C-N bonds, as well as spiro compounds with diastereo selectivity, sulphonyl ketimines/aldimines are used as directing groups in C-H activations/functionalization. Strong directing groups like amides, pyridines, and amines can easily functionalize the molecule, but removing them from the moiety is difficult. As a result, sulphur hetero atoms including guiding molecules, as well as their congeners such as sulphones, sulphonamides, sulphoxamies, and sulphonyl ketimines/aldimines, are increasingly being used as easily detachable anchors following functionalization.

C-H activation is defined as the cleavage of unreactive C-H bond, followed by C-C or C-X (X=N, O, S) bond formation to give rise to a desired functionalized molecule. OR Catalytic reactions of transition metal complexes with the unreactive C-H bonds of alkanes, arenes or alkyl chains to form a new metal carbon bond which is the most fundamental linkage in organic chemistry.

1.2. Comparison Between Traditional Cross-Coupling and C-H Bond Activation

Traditional Cross-Coupling reaction requires extra procedures for preparing organic halides (or triflates) compounds, and organic boron or metal compounds and pre-functionalization is required whereas C-H activation approach avoids such pre-functionalization, thus making this reactions step more economic, cost effective and eco-friendly system.

Traditional Cross-Coupling

C-H Bond Activation

2. C-C Bond Formation

2.1. Arylation

As it is considered as an essential motif in many bioactive compounds, the creation of bi-aryl moiety through C-H activation flourished in the synthesis of polyarenes, hetero-biaryls, polymers, and complex substrates. The classic approach of biaryl synthesis includes atom-inefficient and time-consuming cross-couplings. Singh and colleagues used a weakly coordinated sulphonamide as a guiding group in a palladium-catalyzed ortho mono-arylation. The reaction between substituted benzene sulphonamides and substituted iodobenzenes was carried out in acetic acid with Pd(OAc)2 as a catalyst and Ag2O as an oxidant to produce the final products.

The mechanism involves the creation of carbometalated (C-M) cyclic complex A via coordination between the Pd catalyst and substrate 1a, which are consecutively oxidatively added to 2 to produce intermediate B, resulting in a change in palladium oxidation state from II to IV. In the presence of Ag2O and AcOH, parallel reductive elimination yields the desired product 3a.

Scheme 1: The regioselective mono-arylation of sulphonamides with proposed mechanism.

Chen and his colleagues[22] used bi-dentate auxiliary amino acids to achieve ortho-directed mono arylation of the substrate 4 with aryl iodide .Bulkier groups, such as gem-dimethyl, increased the activity of the substrate among the various auxiliaries. The reaction was tolerated well by aryl iodide 2 with various substitutions on the para- and meta-positions, but not by ortho owing to steric hindrance. The reaction proceeded smoothly with various electrondonating groups (EDG) and heterocyclic compounds as substrates, but the electron-withdrawing group (EWG) produced good results with AgOAc instead of NaOAc.

Scheme 2. Mono-arylation mediated by bidentate auxiliary linked sulphonamide directing group

Green atom economical method.

The reaction shows good functional group compatibility and proceeds in a highly selective manner at the ortho position of arenes connected to sulphonamide sulphur atoms.

2.1.a. Scope of aryl sulphonamide : Diversification of Celecoxib

Late-stage functionalization: Hui-Xiong Dai et al used a sulphonamide drug candidate to perform late-stage, site-specific diversification.

They then used late-stage site-selective diversification of a sulphonamide drug candidate with many potentially reactive C-H linkages to manufacture novel Celecoxib analogues as possible COX-2 inhibitors.

They used Pd(OAc)2 as a catalyst to establish a series of six categorically different sulfonamide C-H functionalization processes (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation).

Scheme 3. Diversification of Celecoxib

2.2. Alkylation

The rhodium-catalyzed carbenoid functionalization of sulphonamides via C-H activation was described by Xu and colleagues.[24] Natural and complicated compounds can be post-synthesised thanks to the carbenoid functionality. Aryl sulphonamides (a) as a substrate were combined with diazomalonates (b) to produce carbenoid functionalized products in this process.

Phenyl , furyl , thienyl, preferentially gave monoalkylation at ortho and meta position.

Switching of site selectivity of aryl sulphonamides containing strong directing groups (N-heterocyclics) to introduce carbenoid functionalization was documented in recent investigations by the same research group.[25] In the case of sulphonamide, molecules with two directing groups are competing with each other, and catalyst concentration favours the reaction. The reaction demonstrated huge tolerance to additional highly directed groups such as pyridine, pyrrole, thiazole, pyrimidine, and others when using 5 mol percent Rhodium and toluene as a solvent.

Scheme 5. Site selectivity of aryl sulphonamides containing strong directing groups.

2.3. Alkynylation

The scope of ortho-alkynylation of primary sulphonamides with terminal alkynes employing an Ir(III) catalyst was investigated by Li and colleagues.[26] Because both sulphonamides and alkynes act as scaffolding in potential bioactive compounds, they are widely used. Using the highly electrophilic metal-catalyst [IrCp*Cl2]2 and a suitable oxidative system that promotes regioselectivity of various functionalized arenes and tetrasubstituted olefins, C-H was produced. With the help of AgNTf2, NaOAc, and Cs2CO3, desirable products were obtained by substituting phenyl sulphonamides with terminal alkynes in the presence of an iridium catalyst in the presence of AgNTf2, NaOAc, and CS2CO3 .Variations of these conventional conditions failed to produce the idealistic combination’s expected yield. The reactivity of primary sulphonamides was higher than that of N-substituted sulphonamides. Substitutions on the aryl ring with fluoro, chloro, nitro, and cyano groups, on the other hand, were favourably responded.

Chen’s group has successfully demonstrated rhodium-catalyzed direct C-H bond alkynylation of aryl sulphonamides with different activated alkynes to yield alkynylated benzene sulphonamides and alkynylated cyclized benzosultams. TIPS’ versatility as a coupling partner allowed substituents like EDG and EWG to be tolerated, resulting in high yields. With nitro, biphenyl, and ortho-substituted groups, the reaction was shown to be compatible. Alkynylation and intermolecular cyclization of sultams were followed in good yield by coupling partner with TMS/TES of bromo acetylene. C-H activation of substrate by Rh(III) coordination forms cyclometalated complex in the mechanistic pathway.

2.4. Carbonylation

Panda and colleagues synthesised carbonylated sulphonamides and N-sulphonyl ketimines, which are useful as heterocyclic synthons and chiral auxiliaries. Using palladium as a catalyst, ortho-carbonylation with sulphonamide as a directing group and aldehyde as a coupling partner is followed by intramolecular annulation, yielding cyclic ketimines. This approach is gratifying since it avoids the use of strong Grignard and organolithium reagents. With a variety of halogens as substrates, alkyl groups facilitated the reaction in a moderate yield, whereas the nitro group failed to produce the required product. With aryl and aliphatic aldehydes, the reaction went smoothly.

3. The C-N Bond Formation

3.1. SulphonamidationDue to the issue of pre-functionalization and the use of bulky ligands, traditional methods of amidation using cross-coupling reactions like Buchwald-Hartwig and Ullman-Goldberg are limited. As a result, C-H activation is preferred since it simplifies the synthesis process. In the subject of C-H functionalization, various types of amidating agents have been studied. In the world of pharmaceuticals, carbazoles are tricyclic ring structures containing indole as a heterocyclic motif that have remarkable phytochemical features of medicinal value.

Young and his colleagues created these privileged compounds by employing Pd-catalyzed intramolecular oxidative C-H amination of N-tosyl-2-arylanilines to activate C-H activation. To make carbazoles, the current process starts with C-H activation and then forms an intramolecular C-N bond.

Jeganmohan and colleagues looked into the possibilities of amidation of sulphonyl ketimines using less expensive organic azides. The required compounds were obtained by cyclic N-sulphonyl imine directed C-H amidation of sultams with sulphonyl azides in the presence of ruthenium catalyst under favourable conditions.

Loh and colleagues described iridium catalysed C-H amidation, in which N-sulphonyl ketimines and organic azides produced sulphonamidated sultums with good regioselectivity under mild circumstances.