Hypervalent iodine-mediated formation of S–S, C–S, C–O, and C–N bonds

Abstract Di(4-nitrobenzoyloxy)iodo]benzene (1), a hypervalent iodine compound, is easy to prepare and stable as a solid, and was shown to be a useful functional group transforming agent in this report. Oxidative synthesis of symmetrical disulfides from thiols in the presence of compound 1 alone was performed in 58–100% yields. Furthermore, ESI-MS demonstrated that premixing of 1 and Ph3P yields the corresponding acyloxyphosphonium, which can acylate thiols to produce thioesters in 69–100% yields. With the assistance of a mixture of 1 and Ph3P, hydroxy and amino groups were benzoylated to esters and amides, respectively, also in 9–100% yields. Graphical Abstract

and carbon-carbon bond formations. [7] For example, PIDA mediated the vinylic arylation 7a and PIFA involved tandem Hofmann-type rearrangement. [8] Chemists have demonstrated the utility of hypervalent iodine compounds in the coupling reactions. For example, Lin and Lee developed the PIFA-mediated preparation of acylsulfenic acid alkyl esters and benzoyl alkyl disulfides (Fig. 2a). [9] Without the assistance of the hypervalent iodine reagent, the synthesis of such molecules is difficult or the preparation method is inconvenient. In 2004, [10] Wacharasindhu reported the hypervalent iodine-promoted metal-free S-H activation allowed the construction of S-S, S-N, and S-C bonds (Fig. 2b). In 2008, [11] Zhou described the acylation of alcohols, phenols and amines with PIDA in the presence of I 2 and Ph 3 P to give the corresponding esters or amides (Fig. 2c). Later, [12] Murphy presented the hypervalent iodine-based activation of Ph 3 P enabled the acylation of alcohols (Fig. 2d).
Encouraged by those results, but some limitations are also recognized. In these strategies, acylation is usually limited to acetylation, or in Zhou's acylation requires the addition of I 2 , and his group did not touch C-S bond formation. Herein, we disclose a  hypervalent iodine reagent, compound 1 (X ¼ OCOC 6 H 4 NO 2 , Fig. 2e), as a very useful reagent for the oxidation of thiols to disulfides and for the benzoylation of thiols or alcohols or amines. In addition, molecules modified by benzoylation are known to enhance their biological evaluation, such as the antibacterial agent (1-(2-(benzyloxy)-2oxoethyl)-1H-1,2,3-triazol-4-yl)methyl benzoate analogues [13] and anticancer paclitaxel paclitaxel (Taxol). [14] Although di(4-nitrobenzoyloxy)iodo]benzene (1) is not commercially available, this hypervalent iodide compound can be prepared in multigram form by treating PIDA with 4-nitrobenzoic acid in methanol, the yield is 80-95%. [15] Compound 1 was imagined to be an oxidizing agent for the conversion of DIAD-H 2 (the reduced form of DIAD) to DIAD and be a masked nucleophile (p-nitrobenzoate). Exposure of the chiral alcohol (S)-(-)-ethyl lactate (5d) ([a] D À13.3) to catalytic Mitsunobu conditions (1, DIAD-H 2 and Ph 3 P) gave 6d with an optical rotation of [a] D þ12.0 (Scheme 1). However, acylation of 5d with 4-nitrobenzoic acid under Steglich conditions gave a product with similar optical results ([a] D þ14.2). Also, carbodiimide-mediated esterification is known to preserve the configuration of the stereogenic center. This suggests that 1 failed to catalyze the Mitsunobu reaction as the S N 2 product was not obtained. Only the 1-related acylation was observed.
1 reacted with other substrates such as p-thiocresol (2a) in the presence of Ph 3 P with or without DIAD-H 2 in heated toluene, resulting in the formation of trace amounts of the acylated product 4a and most of the disulfide 3a (Scheme 1). Interestingly, the above reaction was performed in a sealed tube and the disulfide was produced exclusively.
Further studies found that the addition of Ph 3 P had no effect on the oxidation of thiols to disulfides. The results are consistent with the finding of Wacharasindhu's work where PIDA was used as an oxidizing agent. [10] The substrate scope is summarized in Table 1.
Aromatic and aliphatic thiols showed good oxidation reactivity, yielding 73-100% disulfides in the presence of 1 (entries 1-3, 5-7, and 9-11, Table 1). Cyclic and heterocyclic thiols can also be successfully converted to disulfides (entries 4 and 8). Our method for preparing disulfides from hypervalent iodine 1 does not require any metal catalysts, and the by-products (4-nitrobenzoic acid and iodobenzene) are relatively Scheme 1. The study of the chemistry of di(4-nitrobenzoyloxy)iodo]benzene (1). simple. Moreover, this method not only tolerates the existence of different functional groups, but also is applicable to thiol structures with different electronic properties. Furthermore, it is worth noting that thiols are completely consumed and oxidized to disulfides. The proposed method provides an excellent method for the preparation of disulfides, since unreacted thiols are usually difficult to separate from disulfides by silica gel column chromatography.
To clarify the trace formation of thioester 4a when p-thiocresol was mixed with equal equivalents of 1 and Ph 3 P, we also investigated the effect of the stoichiometry of 1 and Ph 3 P in the thiol acylation. The ratio of 1 and Ph 3 P was changed to 1.25:1 and the isolated yield of 4a increased to 6% (entry 1, Table 2). Furthermore, 1 and Ph 3 P were premixed at 60 C for 3 h (entries 2-5), and when Ph 3 P was used in large excess, the proportion of acylated products increased and a single product was achieved (entry 4). The optimal conditions were found to be a premixed mixture of 1.5 equiv of 1 and 2 equiv of Ph 3 P at 80 C for 1 h and 4a was obtained quantitatively (entry 6).
Under the optimized conditions available, various thiols were tried in order to investigate the substrate scope of the reaction. As shown in Table 3, the corresponding products can be obtained from aromatic and aliphatic thiols with 100% conversion. The exception is dodecanethiol (2c), which is slightly less reactive, possibly due to perturbation of its long carbon chain. Although 74% of the thioester 4c was provided, the reaction was incomplete even after heating up to 4 h, with formation of traces of the disulfide 3c (entry 3). Aromatic thiols (2a, 2b, 2f, 2g and 2i) were converted to the corresponding thioesters in good yields of 69-90% under the given conditions (entries 1, 2, 6, 7 and 9). Thioesters 4d and 4e were both produced in excellent yields from aliphatic thiols 2d and 2e (entries 4 and 5). 2-Mercaptothiazoline (2h) can be converted to the corresponding thioester (entry 8). In contrast, 2-mercaptobenzothiazole (2j) was completely consumed without any thioester product (entry 10). Also, the thiol with the strong electron-withdrawing trifluoromethyl group reacted well under acylation conditions, leading to the formation of 4k (76%, entry 11).
Based on the above oxidation and acylation of thiols, as well as previous literature discussions, [9,11] we speculated a possible reaction mechanism (Scheme 2). Nucleophilic attack of the iodine atom of 1 by a thiol affords intermediate i, which is attacked by another thiol to form a symmetrical disulfide (Scheme 2a). Addition of Ph 3 P leads to a different reaction (Scheme 2b). 1 is activated by Ph 3 P to form intermediate ii, an acyloxyphosphonium ion. The acyloxyphosphonium salts are known to acylating agents in peptide synthesis. [16] The derivation of such acyloxyphosphonium from acylated hypervalent iodines (such as 1) and Ph 3 P is convenient and demonstrated in this study. Furthermore, intermediate ii was confirmed by ESI-MS detection. [17] Nucleophilic attack of ii by the thiol produces an acylated product (thioester).
With the chemistry of 1 in the above sulfur-containing compounds, we also established a method for hydroxy acylation. Initially, alcohol reactivity was checked using 1.5 equiv of 1 and 1.5 equiv of Ph 3 P. There were still many starting materials that yielded only 40% of the corresponding product 6a (entry 1, Table 4). According to the previous experiments, Ph 3 P is the initiator of acylation, and it is necessary to increase the ratio of Ph 3 P. The equivalents of 1 and Ph 3 P were adjusted to 1.2 and 1.5, respectively, but the yield of benzoylated product did not improve (entry 2). When 1 equivalent of Cs 2 CO 3 was used as an additive in the reaction, the yield increased to 63% (entry 3). Excess or catalytic amounts of Cs 2 CO 3 were also found to result in lower yields (entries 4 and 5). In addition, other bases were tried (entries 6-10). Although there was no improvement in the conversion, the addition of Et 3 N (1.0 equiv) gave the reaction 76% conversion and the isolated yield of 68% (entry 9).
A number of alcohols were tested under optimized conditions and conversions are given for each case. The aliphatic alcohols 5c-5g achieved 100% conversion in the reaction (entries 3-7, Table 5). Among them, only the tertiary alcohol tert-butanol (5e) had a very low yield of 9% (entry 5). The low isolated yield can be explained by the intrinsic low nucleophilicity of tert-butanol. Although some alcohols had modest conversion problems, in general, primary alcohols were reactive to acylation, yielding 78-100% esters (entries 2 and 6-8), while secondary alcohols yielded the corresponding esters (63-74%, entries 1, 3, 4, 9 and 10).
At the same time, we also studied the acylation of amino compounds. In general, amides are easier to produce by substitution than esters because the amine nitrogen is more nucleophilic than the alcohol oxygen. For the acylation of amines, the stoichiometric effect of 1 and Ph 3 P was investigated using benzylamine as substrate. When 1.5 equivalents of 1 and 1.5 equivalents of Ph 3 P were involved in the reaction, optimized conditions were achieved and the formation of 8a increased to 79% yield (from 68% using 1.2 equivalents of 1). Other primary or secondary amines were also investigated. Tryptamine (7f) has two amidatable amino groups, the primary of which is more reactive (entry 6, Table 6). Also, secondary amines gave the corresponding amides in Scheme 2. Proposed mechanism.   40-71% yields (entries 7-10). Among them, dibutylamine (7g) was a case where an alkyl chain was broken during the reaction process, resulting in the secondary amide 8g' (20%) as a by-product, so the yield of 8g was only 40% (entry 7). Compound 8g' may be generated by the oxidation-derived imine of 8g by HVI. [18] The nitrogen atoms of the secondary amines 7h and 7i are part of the ring and are not cleaved, resulting in relatively good yields (entries 8 and 9). In summary, we demonstrate a metal-free method for the rapid preparation of disulfides, thioesters, esters, and amides with diverse structures. The development of hypervalent iodine reagent chemistry has made the oxidation of thiols highly efficient. For the synthesis of thioesters, esters, and amides, compound 1 was activated by the addition of Ph 3 P to obtain acylated products. We believe that the formation of the key intermediate acyloxyphosphonium (ii) is involved in the acylation reaction, as its occurrence has been confirmed by ESI-MS. The method we developed provides an efficient and metal-free method with the advantages of broad applicability to different structural functional groups and high yields.

General
All solvents and reagents were obtained commercially and used without further purification, unless otherwise noted. NMR spectra ( 1 H at 400 MHz; 13 C at 101 MHz) were recorded on a JEOL-400 MHz spectrometer in deuterium solvents such as CDCl 3 (d ¼ 7.24 in 1 H NMR, d ¼ 77.0 in 13 C NMR) and DMSO-d 6 (d ¼ 2.49 in 1 H NMR, d ¼ 39.5 in 13 C NMR) at ambient temperature. 1 H and 13 C chemical shifts are given in ppm (d) relative to tetramethylsilane (d ¼ 0.00). Mass spectra were obtained on a Bruker Daltonics BioTOF III spectrometer (ESI-MS). FTIR data was obtained on a Bruker/Tensor27 Fourier-transform infrared spectrometer. Flash column chromatography was carried out using Merck Kieselgel Si60 (40-63 lm). Thin-layer chromatography (TLC) plates were visualized by exposure to ultraviolet light at 254 nm and/or immersion in a staining solution (phosphomolybdic acid, ninhydrin, anisaldehyde or potassium permanganate) followed by heating on a hot plate. Concentration refers to rotary evaporation. Column chromatography was performed on silica gel (70-230 mesh ASTM).

Experimental
Di(4-nitrobenzoyloxy)iodo]benzene (1) [15] A mixture of iodobenzene diacetate (6.442 g, 20 mmol) and 4-nitrobenzoic acid (7.682 g, 2.3 equiv) in a round-bottomed flask was added dry MeOH (17 mL) as solvent and heat to 45 C on a rotary evaporator for 30 min. After the reaction was finished the solvent was drained with vacuum distillation. The precipitated white solid was filtered with B€ uchner funnel, washed with dry MeOH three times and dried under reduced pressure to afford the title compound ( Typical procedure a for the preparation of disulfides To a sealed tube (5 mL) was added the hypervalent iodine reagent 1 (134 mg, 1 equiv), toluene (1.25 mL) and p-thiocresol (2a, 31.0 mg, 0.25 mmol). The reaction mixture was stirred at 60 C for 2 h. After the reaction was completed via TLC analysis, the mixture was concentrated under reduced pressure and was purified by column chromatography.

Typical procedure B for the preparation of thioesters
A mixture of the hypervalent iodine reagent 1 (402 mg, 1.5 equiv) and Ph 3 P (262 mg, 2.0 equiv) in toluene (2.5 mL) in a sealed tube (5 mL) was heated at 80 C for 1 h. Then p-thiocresol (2a, 62 mg, 0.5 mmol) was added to the above mixture. The reaction was kept stirring at 80 C for another 0.5 h. After the reaction was completed via TLC analysis, the mixture was concentrated under reduced pressure and was purified by column chromatography.

Typical procedure C for the preparation of esters
To a sealed tube (5 mL) was added the hypervalent iodine reagent 1 (322 mg, 1.2 equiv), Ph 3 P (197 mg, 1.5 equiv) and toluene (2.5 mL). Then 1-phenylethanol (5a, 60 lL, 0.5 mmol) and Et 3 N (70 lL, 1 equiv) were added in sequence. The reaction mixture was stirred at 80 C for 3 h. After the reaction was completed via TLC analysis, the mixture was concentrated under reduced pressure, which was purified by column chromatography.

Typical procedure D for the preparation of amides
To a sealed tube (5 mL) was added the hypervalent iodine reagent 1 (402 mg, 1.5 equiv), Ph 3 P (197 mg, 1.5 equiv) and toluene (2.5 mL). Then benzyl amine (7a, 55 lL, 0.5 mmol) was added. The reaction mixture was stirred at 80 C for 2 h. After the reaction was completed via TLC analysis, EtOAc (10 mL) was added to the mixture. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution (3 mL) for three times. The organic layer was separated, dried over anhydrous MgSO 4 and concentrated under reduced pressure and was purified by column chromatography.

Disclosure statement
No potential conflict of interest was reported by the author(s).