Organophotoredox‐Catalyzed Decarboxylative N‐Alkylation of Sulfonamides

We developed an organophotoredox‐catalyzed reaction for N‐alkylation of sulfonamides with aliphatic carboxylic acid‐derived redox active esters as alkylating reagents. Under mild and transition metal‐free conditions, a series of functionalized N‐alkylated sulfonamides were prepared. This protocol also enabled the functionalization of pharmaceutical drugs bearing a sulfonamide or carboxylic acid moiety. This radical‐mediated process allowed the assembly of three components including sulfonamides, redox active esters, and alkenes to yield complex sulfonamides in a one‐pot manner.

We developed an organophotoredox-catalyzed reaction for Nalkylation of sulfonamides with aliphatic carboxylic acid-derived redox active esters as alkylating reagents. Under mild and transition metal-free conditions, a series of functionalized Nalkylated sulfonamides were prepared. This protocol also enabled the functionalization of pharmaceutical drugs bearing a sulfonamide or carboxylic acid moiety. This radical-mediated process allowed the assembly of three components including sulfonamides, redox active esters, and alkenes to yield complex sulfonamides in a one-pot manner.
CÀ N bond formation is one of the most widely used and essential synthetic tools in modern medicinal chemistry. [1] Sulfonamides in particular are found in a broad range of agrochemicals and pharmaceutical drugs. [2] Transition metalcatalyzed CÀ N coupling between sulfonamides and aryl electrophiles is considered one of the most powerful and robust synthetic methods to yield a diverse range of N-arylated sulfonamides. [3] Recently, C(sp 3 )-rich scaffolds found in natural bioactive compounds were reported to act as three-dimensional fragments controlling both the shape and direction of drug molecules precisely. [4] Since then, there has been great demand for the development of equally robust synthetic methods to construct such 3D molecules. As with N-arylation chemistry, N-alkylation of sulfonamides has traditionally relied on transition metal catalysis ( Figure 1A). For example, transition metal catalyzed intramolecular or intermolecular hydroamination of alkenes, [5] metal nitrenoid-mediated C(sp 3 )-H amination [6] and dehydrative alkylation with alcohols [7] have been reported. Although other approaches have been introduced, such as those using strong acids [8] and electrophilic iodine reagents, [9] the scope of compatible sulfonamides and alkyl groups under these conditions is reasonably limited.
In previous reports, our group developed an organophotoredox-catalyzed reaction for the decarboxylative cross-coupling between heteroatom nucleophiles and aliphatic carboxylic acidderived redox active esters. [10,11] In this reaction, a photoexcitable phenothiazine acted as a radical-polar crossover catalyst, [12] which causes a single electron transfer to a redox active ester, producing the phenothiazine cation radical and the corresponding alkyl radical upon decarboxylation. The alkyl radical is oxidized to the carbocation equivalent by the phenothiazine cation radical. The generated carbocation equivalent reacts with various heteroatom nucleophiles including aliphatic alcohols, amides and thiols. This protocol enabled us to forge unprecedented C(sp 3 )-heteroatom bonds under mild conditions without using transition metal catalysts. We hypothesized that the photochemically-generated carbocation species would couple with sulfonamide nucleophiles to produce N-alkylated sulfonamides, thereby providing a similarly mild set of conditions to generate these important 3D scaffolds.
Herein, we report an alternative protocol for the Nalkylation of sulfonamides through visible-light-mediated organophotoredox catalysis using aliphatic carboxylic acid-derived redox active esters as alkylating reagents ( Figure 1B). This process does not require the use of transition metal catalysts or strong acids, presenting a key advantage over several traditional equivalent methods. A broad array of N-alkylated sulfonamides were prepared with high functional group compatibility.
After our initial screening of nitrogen-based nucleophiles, sulfonamides were found to be amenable to our organophotoredox-catalyzed decarboxylative alkylation. To establish the protocol for N-alkylation of sulfonamides, conditions screening was performed on the representative reaction between ptoluenesulfonamide (1 a) and pivalic acid-derived redox active ester (2 a). Based on our results from similar decarboxylative cross-couplings, we started our screening with catalytic amounts of N-phenyl benzo[b]phenothiazine (PTH1) [13] and lithium tetrafluoroborate, with dichloromethane as the solvent, stirring under blue LED light. The trial reaction proceeded well to furnish the desired N-alkylated product (3 aa) in 83 % isolated yield without the formation of the N,N-dialkylated by-product (Table 1, entry 1).
The structure of photocatalyst was critical to drive the desired reaction (Table 1, entries 2-4). For example, the use of PTH2, bearing a benzo[a]phenothiazine scaffold, resulted in low conversion of substrate (entry 2). [14] The product yield dramatically decreased when a simple phenothiazine-based catalyst (PTH3) was used instead of PTH1 (entry 3). A poor yield was also observed when using N-phenyl benzo[b]phenoxazine (POX1) as a photoredox catalyst (entry 4).
The additive and solvent were also noted to play a significant role in this catalysis. As in our previous report, lithium tetrafluoroborate salt was essential to promote the reaction. At least 10 mol% lithium tetrafluoroborate was required to guarantee high reaction efficiency (Table 1, entries 5-7). The desired product was not obtained with the use of other solvents, such as ethyl acetate, acetone and acetonitrile (entries 8-10). When 2 a was used as a limiting reagent, a comparable yield was noted (entry 11).
With the optimal reaction conditions established, the scope of applicable sulfonamides was examined with tert-butyl redox active ester 2 a (Scheme 1, top). The reactions with o-and mtoluenesulfonamide gave the corresponding N-alkylated products in moderate yields (3 ba and 3 ca). Various halogen substituents were well-tolerated under the optimized reaction conditions (3 da-3 fa). Further to this, neither electron-deficient nor electron-donating groups significantly affected the reaction efficiency (3 ha-3 ja). Aliphatic sulfonamides were also suitable substrates to yield C(sp 3 )-rich sulfonamide scaffolds with this organophotoredox catalysis (3 ka and 3 la). Our protocol also allowed the functionalization of the sulfonamide-containing pharmaceutical drug substrates, zonisamide and celecoxib (3 ma and 3 na).
Next, we evaluated the scope of redox active esters with 1 a as a coupling partner (Scheme 1, bottom). It was possible to synthesize alternative acyclic N-alkyl sulfonamides using our protocol (3 ab). Notably, aliphatic rings of various sizes could be readily installed with moderate efficiencies. (3 ac-3 ae). Redox active esters containing a tetrahydropyranyl group or an adamantyl group participated in the reaction as good alkylating reagents (3 af and 3 ag, respectively). An α-alkoxy derived substituent was well tolerated under these reaction conditions. (3 ah). This alkylation protocol was applicable not only to aromatic sulfonamides but equally to aliphatic sulfonamides (3 li and 3 lg). The reactions with tertiary and secondary benzylic redox active esters also proceeded well to afford the corresponding alkylated products in moderate to high yields (3 aj-3 al). We also demonstrated how our photocatalyzed sulfonamidation transformation could be applied to carboxylic acidcontaining druglike molecules, such as loxoprofen and gemfibrozil (3 am and 3 an). Additionally, two sulfonamide-containing drugs were shown to react with 2 o to furnish the desired alkylated products (3 mo and 3 no). Although the yields were low, these results display the potential application of our reaction to high-throughput organic synthesis of drug-like molecules.
To gain insight into the reaction mechanism, we carried out the stoichiometric reaction of PTH1 and the 1-adamantanecarboxylic acid-derived redox active ester 2 g in the presence of lithium tetrafluoroborate salt (Figure 2A). After blue light irradiation for 6 h, a peak corresponding to the alkylsulfonium intermediate PTH1-2g was detected by direct analysis in real time -high resolution mass spectrometry (DART-HRMS). This result provided evidence towards the presence of the proposed alkylsulfonium intermediate in this organophotoredox-catalyzed reaction. The same trial with 2 a instead of 2 g was unsuccessful, likely due to the instability of the tertiary butyl cation or the corresponding alkylsulfonium species.
The proposed mechanism is outlined in Figure 2B. Based on our previous report, PTH1 and a redox active ester (2) form an [a] The reaction was carried out with 1 a (0.2 mmol), 2 a (0.3 mmol), PTH1-EDA complex (A) which has absorption bands in the visible region.
[10b] Subsequently, photo-induced single electron transfer from PTH1 to 2 occurs to afford the radical cation form (B) of PTH1 and the radical anion form (C) of 2. After a collapse of C with release of carbon dioxide, the corresponding alkyl radical (D) is generated. The recombination of D and B through a radical-radical coupling or single electron transfer affords the alkylsulfonium intermediate (E). Finally, E reacts with a sulfonamide 1 to form the N-alkylated product (3) and regenerate PTH1. Next, we looked into expanding the scope of our photoreaction further by utilizing it in a multi-component coupling (Scheme 2). We took advantage of the characteristic radicalmediated process of our pathway by employing it in a radicalrelay type difunctionalization of an alkene. [15] As in our previous study on organophotoredox-catalyzed alkene difunctionalization, [10b] PTH4 was used as the catalyst. Although the yields were moderate, our photoredox catalysis could assemble sulfonamides, styrenes and redox active esters to form complex benzyl sulfonamides (5 aaf, 5 eaf and 5 abf).
In summary, we applied our organophotoredox catalysis to the N-alkylation of sulfonamides with aliphatic carboxylic acid- [d] EtOAc (0.9 mL, 0.2 M) was used.

Figure 2. Mechanistic Studies
Scheme 2. Three-Component Coupling derived redox active esters as alkylating reagents. Under mild and transition metal-free conditions, functionalized N-alkylated sulfonamides were prepared. This protocol also enabled the functionalization of pharmaceutical drug substrates containing either carboxylic or sulfonamide moieties. Finally, taking advantage of the radical-mediated process employed in our reaction allowed us to assemble three component complex sulfonamides with relative ease.