Deaminative Fluorination of Sulfonamides via Aminocyclopropenium Activation

Abstract

This report discloses a deaminative fluorination of secondary sulfonamides promoted by diaminocyclopropenium activation. The reaction proceeds through isolable sulfonamide–cyclopropenium adducts that undergo selective substitution at sulfur upon treatment with fluoride. This method provides access to sulfonyl fluorides from abundant sulfonamides, enabling the functionalization of bioactive molecules and as well as the mild cleavage of sulfonamide protecting groups.

Graphical Abstract

Sulfonamides (R’SO₂NR₂) appear in numerous biologically active molecules and pharmaceutical compound collections.^1,2 Until recently, they were largely viewed as terminal functional groups, since there were few synthetic methods for their selective functionalization.^3,4 However, over the last decade, SO₂NR₂ groups have increasingly emerged as sites for the late-stage diversification of lead molecules.² Accordingly, numerous researchers have pursued mild and selective approaches to convert the S–N bond into new functionalities.^2,3,4,5

Electrophilic activation is an attractive but underexplored strategy for sulfonamide functionalization.⁴ Here, the −NR₂ is converted into a leaving group, and the resulting R’SO₂⁺ synthon undergoes nucleophilic attack at S to generate functionalized products (Figure 1). Literature reports have demonstrated activation of the −NR₂ group with dimethyoxytetrahydrofuran,^4a tert-butyl nitrite or pyrylium salts^4b,c,d (Figure 1, I), diethylaminosulfur trifluoride^4e (DAST; Figure 1, II), or trichloroisocyanuric acid^4f (TCCA; Figure 1, III). However, these activating reagents have limitations limited with respect to practicality and substrate/nucleophile scope. For instance, TCCA is strongly oxidizing, DAST is moisture and thermally sensitive,⁶ and pyrylium salts are incompatible with some nucleophilic functional groups.^4b,c Additionally, pyrylium activation is inherently limited to 1° sulfonamide substrates.

Figure 1.

Examples of functionalization of sulfonamides via SO₂⁺ synthons

We sought to develop a complementary electrophilic activation of sulfonamides that leverages easy-to-handle cyclopropenium (CP) reagents as activators. Pioneering work by Lambert⁷ and Hu⁸ has shown that cyclopropeniums can activate aliphatic alcohols and carboxylic acids towards deoxyfunctionalization reactions. We hypothesized that an analogous deaminative functionalization of sulfonamides (Figure 1, IV) could be achieved with appropriate selection of CP derivative and nucleophile. We demonstrate herein that the combination of a diaminocyclopropenium salt and KF promotes the conversion of secondary sulfonamides to sulfonyl fluorides under mild conditions, representing the first example of cyclopropenium-mediated deamination. This transformation is applied to the diversification of bioactive sulfonamides as well as to the cleavage of a sulfonamide protecting group.

We initially explored the use of CP derivatives to promote transamination between 4-fluoro-N-phenylbenzenesulfonamide (1) and piperidine (Figure 2). Sulfonamide 1 was combined with a CP derivative and DABCO in a mixture of DCE/MeTHF, and ¹⁹F NMR spectroscopy was used to monitor the formation of adduct A. After 8 h at 80 °C, piperidine was added to release the target sulfonamide 2. Diphenylcyclopropenium CP-I, which was popularized by Lambert for deoxyfunctionalization reactions, afforded <1% of adduct A-I or transamination product 2. In contrast, the more resonance-stabilized diaminocyclopropenium⁹ CP-II gave 50% yield of adduct A-II and 10% of 2 under otherwise identical conditions.¹⁰

Figure 2.

Impact of CP structure on reaction to form A and 2

We next pursued the isolation of intermediate A-II. Treatment of a mixture of 1 and CP-II with NaH led to clean conversion to the chloride salt A-II-Cl. Ion exchange with NH₄PF₆, then afforded hexafluorophosphate salt A-II-PF₆ in 75% yield (Figure 3). This salt is a stable crystalline solid that was stored on the benchtop for >12 months without detectable decomposition. X-ray quality crystals were obtained by vapor diffusion of diethyl ether into an acetonitrile solution of A-II-PF₆. Analysis of the structure reveals that the S(VI)–N bond in A-II-PF₆ (1.672 Å) is 0.04 Å longer than that in 1 (1.632 Å); it is also significantly longer than that in related 2° and 3° sulfonamides (range of 1.617 Å to 1.651 Å; see Figures S1 and S2).^11,12

Figure 3.

Isolation and x-ray structure of intermediate A-II

The reaction of A-II-PF₆ with piperidine/DABCO at 100 °C in MeTHF afforded two major ArSO₂-containing products: 2° sulfonamide 1 (60%) and 3° sulfonamide 2 (16%) (Figure 4, i). Product 2 derives from the desired attack of piperidine at sulfur, while 1 is formed via undesired attack of piperidine on the cyclopropenium carbon to form C (Figure 5). Attempts to optimize the selectivity for and yield of 2 by varying solvent, base, and reaction conditions proved unsuccessful. However, careful analysis of the crude ¹⁹F NMR spectra of many of these reactions revealed traces of a second sulfur-functionalization product – sulfonyl fluoride 3.

Figure 4.

Reaction of A-II-PF₆ with nucleophiles.

Figure 5.

Computed ΔG_298,THF (kcal/mol) for path a (attack at cyclopropenium; ΔG_a) and path b (attack at sulfur; ΔG_b) as a function of nucleophile (Nu)

The observation of 3 (which is believed to derive from DABCO-induced degradation of PF ⁻₆ to F⁻; Figure 4, ii and Figures S3–S5) led us to hypothesize that fluoride nucleophiles might provide higher yields and better selectivity for sulfur functionalization. Indeed, the reaction of A-II-PF₆ with KF/18-crown-6 or KHF₂/18-crown-6 afforded sulfonyl fluoride 3 in 88% and 92% yield, respectively, with >20:1 selectivity over 1. Further optimization revealed that reaction with KF/18-crown-6 in DCE proceeds in 90% yield over just 4 h at 80 °C.¹³

To better understand the observed selectivity, DFT calculations (ωB97X-D/def2-TZVP//B3LYP-D3/6–31G*-SMD (THF)) were performed to compare ΔG for attack at the cyclopropenium carbon (path a, ΔG_a) to attack at sulfur (path b, ΔG_b) as a function of nucleophile. As summarized in Figure 5, the experimental selectivity reflects the thermodynamics of the reactions with piperidine versus fluoride (modeled as KHF₂). For piperidine, ΔΔG (ΔG_b – ΔG_a) is +2.1 kcal/mol, consistent with the observed moderate selectivity for 1 over 2. In contrast, with KHF₂ ΔΔG is −16.6 kcal/mol, consistent with the >20:1 selectivity for 3 over 1. The calculations suggest that byproduct C in pathway a is the primary driver of selectivity. Attack of piperidine at carbon affords a trisaminocyclopropenium product C that is highly stabilized by π-donation from the new nitrogen substituent. This renders pathway a thermodynamically favorable (ΔG = −17.1 kcal/mol). By comparison, the electronegative fluorine is far less stabilizing, thus rendering this pathway thermodynamically uphill (ΔG = +13.5 kcal/mol).

We next pursued the one-pot conversion of secondary sulfonamides to sulfonyl fluorides using 1 as a model system. Combining 1 (1 equiv), CP-II-PF₆ (1 equiv), KF (4 equiv), and 18-crown-6 (1 equiv) in DCE at 80 °C for 16 h afforded 4-fluorobenzenesulfonyl fluoride (2) in 84% yield.¹⁴ These one-pot conditions proved general for electronically and sterically diverse secondary aryl sulfonamides (Figure 6, i). Various functional groups were tolerated, including aryl bromides and iodides (4–6), nitro substituents (10), enolizable ketones (16), pyridines and quinolines (17, 20), and azoles (18, 21, 22). Anilines, including both unsubstituted (7) and N,N-dimethyl substituted (15), also proved compatible. These functional groups are susceptible to side reactions (condensation, electrophilic aromatic substitution) with other activating reagents (e.g., pyrylium salts and TCCA). Secondary alkyl sulfonamides (16, 19) also reacted smoothly under the optimized conditions. Finally, this transformation was effective for derivatives of bioactive scaffolds (N-PMP celecoxib and N-PMP valdecoxib). A one-gram (2.05 mmol) scale-up of the deaminative fluorination was conducted on N-PMP celecoxib, affording 65% isolated yield of 22. Finally, sulfamide (20) reacted to form a sulfamoyl fluoride (R’₂N–SO₂F) product in 35% yield.

Figure 6.

(i, ii) Substrate scope. (iii) Telescoped sulfur-fluoride functionalization. Conditions: ⁱ20, CP-II-PF₆ (1 equiv), KF (4 equiv), and 18-crown-6 (1 equiv) in DCE at 80 °C for 16 h. ⁱⁱRasp-berry ketone (0.8 equiv), IMesHCl (11 mol %), DBU (10 mol %), acetonitrile, 4 Å MS, RT, 24 hr. ⁱⁱⁱ2-methylbenzothiazole (1 equiv), LiHMDS (1 M THF), dimethoxyethane, 0 °C → RT. ^iv1-(6-(Trifluoromethyl)pyridin-2-yl)piperazine (1.05 equiv), Ca(NTf₂)₂ (1.1 equiv), DABCO (2.2 equiv), THF, RT.

Reactions with sulfanilamide drug derivatives (Figure 6, ii), illustrate the complementarity of this transformation to the pyrylium activation approach.^4b.c Sulfabenz, sulfamethoxazole, sulfapyridine, and sulfamethazine afforded 7 in synthetically useful yields (23–75%) via cyclopropenium activation. These are not viable substrates for pyrylium activation because (a) they are 2° sulfonamides (and thus cannot undergo condensation) and (b) they contain a nucleophilic aniline functional group.^4c In contrast, cyclopropenium activation was generally ineffective for 1° sulfonamides. This is exemplified by the reactivity of the parent sulfanilamide, which afforded <1% of 7 under our standard conditions.

The S^VI–F products of these transformations are of potential utility as electrophiles in chemical biology.¹⁵ In addition, they serve as synthetic intermediates for the formation of new S^VI–heteroatom and S^VI–carbon bonds.¹⁶ We next explored telescoping the crude reaction mixture from CP-II-promoted sulfonamide fluorination to various sulfur-fluoride exchange reactions. This sequence afforded products of S^VI–C, S^VI–O, and S^VI–N coupling in good yield over two steps (Figure 6, iii).

Finally, this approach enables the recovery of both the sulfonyl fluoride (vide supra) and amine products of the S^VI–N bond cleavage. The latter are incorporated into a cyclopropena-mine and can be released as the acylated amine upon treatment with acetyl chloride and piperidine (Figure 7). This sequence offers a new approach for cleaving tosylate protecting groups. For example, amino acid 26 was converted to 27 in 45% yield over three telescoped steps.¹⁷

Figure 7.

Cleavage of tosylate protecting groups on 2° amines.ⁱ 26, CP-II-PF₆ (1 equiv), KF (4 equiv), and 18-crown-6 (1 equiv) in DCE at 80 °C for 16 h. ^vacetyl chloride (1 equiv), DABCO (1.2 equiv), piperidine (10 equiv), DCE, 80 °C.

In summary, this Letter describes a method for the deaminative fluorination of secondary sulfonamides via activation with diaminocyclopropenium reagents. The reactions proceed via sulfonamide–cyclopropenium intermediates. With piperidine as a nucleophile, these intermediates undergo competing attack at C and S; however, fluoride nucleophiles result in selective functionalization at S. Various sulfonyl fluorides can be accessed via a 2-step, one-pot procedure and then further diversified via sulfur-fluoride exchange chemistry. Overall, this work expands the synthetic utility of sulfonamides and establishes cyclopropenium activation as a platform for deaminative sulfur(VI) functionalization.

Supplementary Material

The Supporting Information is available free of charge on the ACS Publications website.

Procedure details, DFT calculations, synthesis, isolation, characterization, x-ray crystallographic data, and NMR spectra (PDF)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information