Synthesis of 4-Diarylamino-3-iodo-2(5H)-furanones via the Simultaneous α-Iodination and N β -Arylation by an Efficient Difunctionalizable Transfer Reagent PhI(OAc)2

Abstract During the studies on the intramolecular cyclization of 4-arylamino-2(5H)-furanones via the Pd-catalyzed C-H activation, a kind of difunctionalization reaction caused by the designed oxidant PhI(OAc)2 [(diacetoxyiodo)benzene, DIB] was accidentally discovered. When 1.5 eq. DIB is used as a difunctionalizable transfer reagent in the 40 h reaction at 60°C and CH3CN as solvent, 4-diarylamino-3-iodo-2(5H)-furanones can be obtained with the yields of 57–91% (usually more than 73%). The simultaneous α-iodination and N β -arylation reaction without metal catalyst is efficient and convenient. This novel utilization with a greater atom economy provides a simple and practical conversion route for the synthesis of the potential biological 2(5H)-furanone compounds containing multifunctional groups. GRAPHICAL ABSTRACT

The evaluations on the influences of different DIB dosages show that the yield is obviously elevated with the increase of DIB dosage ( Table 1, entries 1-3) and 1.5 eq. DIB is the most advantageous for the reaction with the greatest yield of 86% (entry 3). With continually increasing DIB dosage, there is a trend of lower yields (entries 4 and 5). Therefore, the suitable DIB dosage should be 1.5 eq. Reaction solvent is another important influencing factor. It can be seen that, among the different solvents (entries 3, 6-11), CH 3 CN is the best (entry 3).
When the reaction temperature is decreased from 60 C to 30 C, the yield can be lowered (entry 12), but when increasing the temperature, the yield does not increase yet (entry 13). Thus, the suitable reaction temperature should be 60 C (entry 3). Similarly, shortening the reaction time is not beneficial to the yield (entry 14), and extending the time cannot further improve the yield yet as anticipated (entries 15 and 16), indicating that the suitable reaction time should be 40 h (entry 3). Therefore, the optimal reaction conditions for this N b -arylation and a-iodination reaction can be summarized as follows: 1.5 eq. PhI(OAc) 2 in CH 3 CN at 60 C for 40 h.

Influences of Different Substrates
Under the optimized conditions, the substrate scopes are examined ( Table 2). Though different substrates 1 can react smoothly with the yields of 57-91% (usually more than 73%), it seems that whether methoxy or benzyloxy, or ethoxy in 5-position of 2(5H)-furanone 1, the change of the yields is not regular. Similarly, whether p-position substituted group of benzene ring in 4-arylamino of the substrates 1 is an electron-withdrawing group or electron-donating group has no obvious effects on the reaction. In other words, different groups can be tolerated in the process.
Of course, with the increase of the number of electron-donating group (e.g., methyl) in 4-arylamino, the yields have a rising trend ( Table 2, entries 2 vs 3, 10 vs  11). Interestingly, if there is p-bromo substituted or m-chloro substituted (especially the latter) benzene ring in 4-arylamino of the substrates 1, the reaction usually has a relatively greater yield than other cases (entries 7, 8, 15, and 16). However, the reasons for these phenomena are not very clear yet; they may be related to the reaction mechanism, which is further discussed in the following.
At the same time, the structures of all new products 2a-2s are demonstrated by their Fourier-transform infrared (FTIR), ultraviolet (UV), NMR spectroscopic, mass spectrometry (MS), and elemental analysis data. Meanwhile, the structures of the products 2a and 2e are also confirmed by the x-ray crystallographic data, and their ORTEP structures are respectively shown in Figs. 1 and 2.

Possible Reaction Mechanism
There is no report on the synthesis of 4-diarylamino-3-iodo-2(5H)-furanones via the difunctionalizable transfer reagent DIB. According to the literature on the   (Continued ) hypervalent organic iodine reagents, [17,18,67] a possible mechanism for the N b -arylated a-iodo reaction in the presence of DIB is proposed (Scheme 3). First, a-iodo iminium salt A would be formed from substrates 1 and PhI(OAc) 2 . However, intermediate A is greatly unstable for the presence of a lactone ring system, which would be deprotonated instantly to give the stabilized a-iodo butenolide B. With the leave of AcOH, intermediate B would be converted to iodine-nitrogen 1,4-dipoles C. [5,6,67,73] Finally, the ipso attack of the negative nitrogen on the phenyl ring, through a five-membered cyclic intermediate D, [67,74] would afford the N b -arylated a-iodo butenolide 2 (Scheme 3).

SYNTHESIS OF 4-DIARYLAMINO-3-IODO-2(5H)-FURANONES
It is obvious that the R 2 substituent on benzene ring in the substrates 1 is not greatly related to the stability of the important intermediate D. Therefore, whether R 2 substituent is electron-withdrawing or electron-donating, it has relatively less effect on the reaction (Table 2). Of course, according to the reaction mechanism, not only the N-arylated substituted furanones but also the N-alkylated substrates are suitable for this system. [67] Meanwhile, this is an intramolecular functional group transfer process indeed, which is confirmed by the comparative experiment. Scheme 4 is purposely designed as an intermolecular reaction, but no corresponding product was obtained or detected.
According to the reaction mechanism and the results in the literature, [5,6,17,18,67,73,74] we can conclude that, as an important difunctionalizable transfer reagent, DIB is also suitable for the simultaneous a-iodination and O b -arylation reaction of b-hydroxyl-a,b-unsaturated carbonyl compounds. Therefore, these investigations provide a simple difunctionalized conversion route with greater atom economy for b-amino(hydroxyl)-a,b-unsaturated carbonyl compounds, including 4-aryl-amino-2(5H)-furanones.
It is noticeable that not only 4-amino-2(5H)-furanones can be a-iodinated in this way, but also the product 4-diarylamino-3-iodo-2(5H)-furanones can be easily dehalogenated. [57] Thus, further combining the different conversion of C sp2 -I in organic synthesis, [59,[75][76][77] the simple and easy difunctionalizable reactions of simultaneous a-iodination and N(O) b -arylation can provide a good platform for more functional interconversions using iodo a,b-unsaturated carbonyl compounds as intermediates. Of course, this result also makes the intramolecular cyclization of 4-arylamino-2(5H)-furanones via the Pd-catalyzed C-H activation more possible, which is in progress in our laboratory.

CONCLUSION
In summary, a series of novel 3-iodo-2(5H)-furanone derivatives containing multibenzene rings are synthesized via the green difunctionalizable transfer reagent PhI(OAc) 2 . This method is very simple, convenient, and mild with greater atom economy. It provides a practical route for the synthesis of some potential bioactive 2(5H)-furanone compounds with multifunctional groups.

EXPERIMENTAL
All melting points were determined on an X-5 digital melting-point apparatus and were uncorrected. Infrared spectra were recorded on a Bruker Vector 33 FT-IR instrument by liquid film method in the absorption range of 4000-450 cm À1 . 1 H and 13 C NMR spectra were obtained in CDCl 3 on a Varian DRX 400-MHz spectrometer, and tetramethylsilane (TMS) was used as an internal standard. The UV absorption peaks were measured by Shimazu UV-2550 ultraviolet absorption detector with dichloromethane as a solvent. Elemental analysis was performed on a Thermo Flashea TM 112 elemental analyzer. The mass spectra (MS) were recorded on Thermo LCQ DECA XP MAX mass spectrometer.
All reagents and solvents were commercially available and used as received. The intermediates 5-alkoxy-4-arylamino-2(5H)-furanones 1 were prepared according to the literature. [57b] Typical Procedure A flame-dried 25-mL round-bottomed flask was charged with 5-alkoxy-4arylamino-2(5H)-furanones 1 (0.2 mmol) in CH 3 CN (5 mL), and PhI(OAc) 2 (1.5 eq.) in CH 3 CN (5 mL) was added dropwise in 25 min. The mixture was stirred at 60 C, and the reaction was monitored by TLC. After the completion of the reaction (about 40 h), the reaction was allowed to cool to room temperature. The reaction mixture was diluted with a saturated aqueous solution of NH 4 Cl (20 mL) and extracted with ethyl acetate (3 Â 20 mL). Then, the organic layer was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The purification of the residue by silica-gel column chromatography yielded the desired compounds 2 in 57-91% isolated yields (

X-Ray Structure Determination of Compounds 2a and 2e
Two suitable x-ray-quality crystals of compound 2a and 2e were respectively grown by slow evaporation of petroleum ether=dichloromethane solvent mixture in the temperature variation of 25 C. Diffraction data of 2a and 2e were collected on a Bruker APEX II Smart CCD diffractometer equipped with graphitemonochromated MoKa radiation (k ¼ 0.71073 Å ) using the x-scan technique. The data were corrected for absorption with the SADABS program. The structures were solved by direct methods using the SHELXS-97 program and all the nonhydrogen atoms were refined anisotropically with the full-matrix leastsquares on F 2 using the SHELX-97 program. [78] Crystallographic data for the structures reported in this article have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. 962686 and 962687. Copies of the data can be obtained free of charge on application to the director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. E-mail: deposit@ccdc.cam.ac.uk.