Hypervalent iodine-catalyzed conjugate addition with sulfonamides

A hypervalent iodine-catalyzed conjugate addition with a sulfonamide nucleophile is described here. This reaction utilizes catalytic amounts of iodoarene and oxidant for the generation of the active hypervalent iodine catalyst. Activation of the enone substrate by the hypervalent iodine catalyst enables the nitrogen nucleophile addition that eventually forms a useful  -aminocarbonyl product. This hypervalent iodine-catalyzed Aza-Michael reaction represents an interesting alternative to existing conjugate addition protocols


Introduction
Nitrogen-containing compounds are widely represented in pharmaceuticals, natural products, and agrochemicals. 1 Consequently, a plethora of efforts have been devoted from the synthetic community focusing on accessing nitrogen-containing compounds. 2-43][14][15][16][17][18] However, many of these catalyst systems are air and/or moisture sensitive, rendering their practicality somewhat limited.In addition, the presence of trace toxic metals raises concern in terms of their applications in medicinal synthesis.[21][22] Scheme 1. Background.
4][25] In short, features including ease of access, air and moisture stability, structural diversity, and a broad range of reactivity renders hypervalent iodine reagents highly attractive in catalysis and organic synthesis.Hypervalent iodine catalysis has been extensively applied in a number of reaction settings such as oxidation, spirolactonization, rearrangement processes, alkene difunctionalizations, etc. [26][27][28][29][30][31][32] This mode of catalysis has been restricted to electron-rich olefin structures due to the electrophilic nature of the hypervalent iodine catalyst.4][35] Given these features, we wondered if the practical features of hypervalent iodine catalyst could be suited for the development of an efficient aza-Michael reaction.As part of our research interest in synthetic methods design to access useful nitrogen-containing compounds, [36][37][38][39][40][41][42][43][44] we disclose here a practical hypervalent iodine-catalyzed aza-Michael reaction with simple sulphonamides as the nitrogen nucleophile (Scheme 1c).
Our work started with cyclohexenone 1 and sulfonamide 2 as the model substrates.In terms of the hypervalent iodine catalyst, we adopted the use of iodotoluene as the catalyst precursor and selectfluor as the oxidant since such a protocol is well known in hypervalent iodine catalysis literature. 33,34Our initial solvent choice of dichloromethane (DCM), unfortunately, did not provide any desired product (Table 1, entry 1).Gratifyingly, the reaction provided the desired product in 53% yield when we changed the solvent to acetonitrile (MeCN) (Table 1, entry 2).Following this lead, we screened several catalyst and oxidant loading combinations, however, the reaction yield did not improve drastically and stayed consistent around 50% yield (Table 1, entry 3-5).In cases, the increase of oxidant loading seemed detrimental to the product yield (Table 1, entry 4).During our stoichiometry studies, we realized that a simple increase in the cyclohexenone loading to 2 equivalents afforded the most optimal reaction conditions (Table 1, entry 6).Furthermore, control reactions demonstrated that both the catalyst and the oxidant are essential to a productive reaction.Table 1.Optimization studies a.Standard conditions: 1 (0.4 mmol), 2 (0.2 mmol), iodoarene catalyst (0.02 mmol), oxidant (0.04 mmol), MeCN (0.5 M), r.t., 16 h.Yields were determined by 1 H NMR analysis using 1,3-benzodioxole as the internal standard.Yield in parenthesis was isolated yield.
With the optimized conditions in hand, we quickly evaluated a preliminary scope for this reaction.In this case, a number of sulfonamide substrates readily provided the desired products in good to great yields (Table 2).For instance, both electron-donating and -deficient substituents on the sulfonamides were well tolerated (Table 2, products 4-7).Sulfonamides containing heteroaromactics such as thiophenes and pyrazole, and cross-coupling ready functional group such as bromide were also viable substrates in this reaction (Table 2, products 8-10).In addition, alkyl sulfonamides including methyl, cyclopropyl, and camphor proceeded smoothly to afford the corresponding products (Table 2, products 11-13).In terms of the enone substrates, we demonstrated that cyclopentenone could also generate the desired conjugate addition product, albeit with diminishing efficiency (Table 2, product 14).To probe the utility of this reaction for pharmaceutical synthesis, we were delighted to show that the drug Celebrex could readily participate to afford the desired amination product 15 in 61% yield (Table 2, product 15).These substrates, collectively, indicate that this conjugate addition protocol has the potential to be a widely applicable tool in the syntheses of -aminocarbonyl motifs.Finally, we conducted derivatization studies using the standard product 3.In one case, we demonstrated a simple reduction of 3 with LiAlH4 and AlCl3 in THF to afford the product 16 in 69% yield.In another, we employed MeMgBr for a straightforward methyl addition for the ketone functionalization to observe the formation of product 17 in 62% yield (Scheme 2).Having a reasonable substrate scope in hand and drawing inspiration from existing literatures of hypervalent iodine catalysis and conjugate addition reactions, we tentatively propose the following mechanistic framework for this reaction. 45To initiate the reaction, the iodoarene catalyst precursor is first oxidized to the active hypervalent iodine form A, which is characterized and known from previous reports. 46he active catalyst then activates the ,-unsaturated ketone via the carbonyl oxygen coordination to generate B. Conjugate addition by the sulfonamide nucleophile results in the enolate intermediate C. Following this, proton transfer affords the conjugate addition product.During this step, the active catalyst is regenerated to undergo another cycle (Scheme 3).Scheme 3. Proposed catalytic cycle.

Conclusions
We have developed a useful protocol for the aza-Michael reaction using sulfonamides as the nitrogen nucleophile.This reaction tolerates a fairly extensive scope of sulfonamides including heteroaromatics, and in one case, even a drug molecule Celebrex can readily participate in this reaction.The practicality of this reaction is further testified with open-air conditions.We have also shown that the product can be easily

Experimental Section
General.Commercial reagents and solvents were purchased from Sigma Aldrich, Oakwood Chemicals, Alfa Aesar, Matrix Scientific, Acros Organic and were used as received.Organic solutions were concentrated under reduced pressure on an IKA rotary evaporator using an acetone-dry ice bath.Chromatographic purification of products was accomplished using flash chromatography on 230-400 mesh silica gel.Thin-layer chromatography (TLC) was performed on Analtech 250 mm silica gel HLF UV-250 plates.Visualization of the developed plates was performed by fluorescent quenching and/or potassium permanganate. 1H and 13 C NMR spectra were recorded on a Bruker instrument (600 and 150 MHz) or INOVA 600 (600 and 150 MHz) and are internally referenced to residual protio solvent signals (for CDCl3, 7.27 and 77.0 ppm, respectively).Data for 1 H NMR are reported as follows: chemicals shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, h = heptet, m = multiplet, br = broad), integration, coupling constant (Hz). 13C spectra were reported as chemical shifts in ppm and multiplicity where appropriate.
General Procedure for hypervalent iodine-catalyzed conjugate addition reaction.To an 8 mL vial equipped with a stir bar was added 4-iodotoluene (5 mg, 0.02 mmol), Selectfluor (14 mg, 0.04 mmol) and sulfonamide (0.2 mmol).Then solvent (MeCN, 0.4 mL) was added via a syringe, followed by enone (0.4 mmol).The reaction mixture was then stirred 16 h at room temperature.The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to afford the pure product.

Table 2 .
Substrate scope studies