Convenient Synthesis of Benziodazolone: New Reagents for Direct Esterification of Alcohols and Amidation of Amines

Hypervalent iodine heterocycles represent one of the important classes of hypervalent iodine reagents with many applications in organic synthesis. This paper reports a simple and convenient synthesis of benziodazolones by the reaction of readily available iodobenzamides with m-chloroperoxybenzoic acid in acetonitrile at room temperature. The structure of one of these new iodine heterocycles was confirmed by X-ray analysis. In combination with PPh3 and pyridine, these benziodazolones can smoothly react with alcohols or amines to produce the corresponding esters or amides of 3-chlorobenzoic acid, respectively. It was found that the novel benziodazolone reagent reacts more efficiently than the analogous benziodoxolone reagent in this esterification.


Introduction
Iodine(III)-containing heterocycles represent one of the most important classes of hypervalent iodine reagents [1][2][3][4][5][6][7][8]. Among them, the five-membered iodine-oxygen heterocycles, which are known by the general name of benziodoxolones, have found wide application in organic synthesis [9][10][11][12][13][14]. In particular, benziodoxolone derivatives 1 (Figure 1) have attracted significant interest as atom-transfer reagents and oxidants [5,[10][11][12][13][14]. Recently, benziodoxolone derivatives have been used as effective oxidants for coupling of carboxylic acids with alcohols or amines leading to the corresponding esters or amides, respectively [15][16][17][18][19]. Benziodazolone compounds 2, nitrogen analogs of benziodoxolones, are also known and offer the possibility of fine-tuning the reactivity by modifying the substituent on the nitrogen atom [20][21][22][23]. Thus, a number of reagents of 2 with various nitrogen-containing ligands and functional groups have been developed [24][25][26][27][28]. For example, benziodazolone compounds 2 supported by various ligands are known as atom-transfer reagents and can act as very effective electrophilic reagents for a variety of substrates, including azidation [20], alkynylation [24], and trifluorothiomethylation reagents [25]. Very recently, Zhang and coworkers investigated the synthesis and structural characterization of a stable fluorobenziodazolone compound and demonstrated that the novel reagent can efficiently perform ring-extended fluorination reactions for various three-membered ring compounds [26]. In addition, benziodazolones 3 are also capable of working as oxidants in dehydrogenative coupling reactions between various two-component molecules [27]. To the best of our knowledge, however, this is the first report where benziodazolones serve as the coupling assistant reagents, and their ligands serve as the coupling partners for alcohols and amines. Our group previously reported that bicyclic benziodazolone 4 could be employed as an efficient reagent for oxidatively assisted coupling of carboxylic acids with alcohols or amines in the presence of phosphines [28]. Therefore, in view of the growing interest in cyclic hypervalent iodine reagents, we focused on benzoidazolone 3, whose acyloxy ligand is also a potential coupling partner for alcohols and amines. In the present paper, we report a convenient and one-step procedure for the preparation of various 3-chlorobenzoyloxy-substituted benziodazolone derivatives 5 from the respective benzamides. In combination with PPh 3 and pyridine, these new benziodazolones can smoothly react with alcohols or amines producing the corresponding esters or amides of 3-chlorobenzoic acid, respectively.

Results and Discussion
A novel series of 3-chlorobenzoyloxy-substituted benziodazolone derivatives 5a-j were prepared in one step by the reaction of readily available benzamides 6 with mchloroperoxybenzoic acid (mCPBA) in acetonitrile at room temperature. In this method, by evaporation of the solvent and simply washing with ether, analytically pure benziodazolones 5 were obtained as stable, white solids in moderate to good yields. The structures of the products of 5 were confirmed by NMR spectroscopy, high-resolution mass spectrometry, and single-crystal X-ray crystallography of benziodazolone 5a (Scheme 1 and Figure 2).  Next, we investigated the use of benziodazolone 5a as a reagent for oxidatively assisted cross-coupling of alcohols with specially added carboxylic acids in the presence of a base (4-dimethylaminopyridine, DMAP) and PPh 3 based on the previously reported procedures [15][16][17][18][19]27]. However, in contrast to previously reported reactions, yields of the desired carboxylic esters were low, and the main isolated products were m-chlorobenzoates formed by direct aroylation of alcohols with reagent 5a. Therefore, considering the importance of substituted benzoates in organic chemistry, we focused on the reactions of the 3-chlorobenzoyloxy ligand in benziodazolone 5a with alcohols and amines.
Optimization studies of this new reaction using alcohol 7a as a model substrate have been performed in the absence of solvent with varying bases, phosphines, and ratios of reactants (Table 1). The reaction of 7a in the presence of excessive benziodazolone 5a (2.4 equiv.), Ph 3 P (2.4 equiv.) and DMAP (2.4 equiv.) afforded ester 8a in a 71% yield (entry 1). The further addition of m-chlorobenzoic acid to the reaction mixture did not improve the yield (entry 2). However, lowering the amounts of 5a, DMAP, and Ph 3 P to 1.8 equivalents did not significantly change the yield (entry 3), and when the amounts of 5a, DMAP, and Ph 3 P were lowered to 1.2 equivalents, the yield increased to 84% (entry 4). Whereas, the further reduction of the amount of DMAP (0.6 equiv.) resulted in a significantly reduced yield (entry 5). Then, we tested several other bases (entries [6][7][8][9][10][11], and pyridine showed superior results with yields up to 91% (entry 9). When Bu 3 P was used instead of Ph 3 P, the yield of the product was lower (entry 11). In addition, no product was formed in the absence of a phosphine (entry 12), and a low yield was observed in the absence of a base (entry 13). Next, we investigated the reactivity of the prepared benziodazolones 5 under the similar condition of entry 9 (entries [14][15][16][17][18][19][20][21][22]. Likely due to the decomposition of the reagents during the reaction with 5b, c, e, and j, the reaction did not proceed efficiently, and 7a was detected in the reaction mixture (entries 14, 15, 17, and 22). In contrast, when other benziodazolones 5d, f-i, were employed, the reactions proceeded effectively to give the desired ester compound 8a in moderate to good yields (entries 16, 18-21). Using optimized reaction conditions, we investigated the scope of the esterification reaction of alcohols 7 with benziodazolone 5a (Scheme 2). In general, the reactions of primary and secondary alcohols 7a-h afforded esters 8a-h in moderate to high yields. In the reactions with alcohols 7i-l having unsaturated bonds, the respective ester compounds 8i-k were obtained in low to good yields without any loss of unsaturated bonds, albeit with a low yield of 8l. Meanwhile, the reaction with sterically hindered tert-butanol gave only trace amounts of product 8m. Scheme 2. Esterification of alcohols using reagent 5a; 7-alcohols; 5a-benziodazolone; 8a-m-esters.
Under similar reaction conditions, primary amines 9a-d reacted with reagent 5a to form amides 10a-d in moderate to high yields (Scheme 3). In the case of the reaction with sterically hindered tert-butylamine, the desired amide compound 10d was obtained in 43%. This is likely because of the high nucleophilicity of amines. Scheme 3. Amidation of amines using reagent 5a; 9-amines; 5a-benziodazolone; 10a-d-amides.
In the next study, the reactivity between benziodazolone 5a and benziodoxolone 11, which could be easily synthesized from acetoxybenziodoxolone and 3-chlorobenzoic acid via a ligand exchange procedure, was compared. The condensation reaction of alcohol 7a and the prepared reagent 11 gave the desired ester 8a in only a 21% yield (Scheme 4). This is because 11 was hardly miscible in the mixture. From this result, it was found that the efficiency of benziodazolone 5a was better than that of benziodoxolone 11 in this esterification reaction system. In order to clarify the reaction mechanism of esterification, we carried out several control experiments (Scheme 5). Firstly, when the reaction of alcohol 7a with benziodazolone 5a did not proceed with the ligand exchange reaction, 5a was recovered from the reaction mixture in a quantitative amount (reaction 1). Then, we performed mass spectrometry experiments (see Supplementary Materials for detail). When 5a was treated with pyridine, the peak of the ligand exchange product 12 was not detected, but when 5a was treated with DMAP, the peak of the ligand exchange product 13 was detected. This may be due to DMAP being a stronger nucleophile than pyridine (reactions 2 and 3) [29]. Next, when the reaction of benziodazolone 5a with alcohol 7a and Ph 3 P was attempted, the peaks of Ph 3 PO and the estimated benziodazolone derivative structures such as 14 and 15 could be detected, while unfortunately, the mass peak of the expected ligand exchange intermediate 16 could not be observed directly (reaction 4 and Figure 3). The observed peaks were probably generated by the reaction of intermediate 16 from the ligand exchange reaction between Ph 3 P and 5a with moisture in the air during the mass experiment. Thus, these results may indicate that benziodazolone 5a reacts with Ph 3 P before pyridine or alcohol 7a. Notably, the reaction using benziodazolone 5a in the absence of Ph 3 P has been found to not proceed with the desired esterification at all (Table 1, entry 12).  Based on the results of these blank experiments and considering previously published mechanistic rationalizations [15,17,19], we propose the following mechanistic scheme for the esterification reaction (Scheme 6). The reaction initially involves the ligand exchange between benziodazolone 5a and Ph 3 P via TS1 to generate the zwitterion intermediate 16.
Then the carboxylate anion attacks the phosphorus center to produce intermediate 17.
Next, 17 is converted to the phosphonium salt 18, which then reacts with pyridine and alcohol 7, respectively, to afford N-acyl pyridinium salt 19. Finally, 19 undergoes nucleophilic acyl substitution from the alkoxide of the counterion giving the desired ester 8. Although benziodoxolone requires a base such as DMAP in the ligand exchange with phosphine, it can smoothly proceed without a base in the case of benziodazolone 5a due to the significantly greater trans influence of the benziodazolone ring compared to the benziodoxolone ring [30]. Therefore, pyridine may mainly play a role in accelerating the nucleophilic acyl substitution for the formation of N-acyl pyridinium salts 19. Scheme 6. Proposed mechanism of esterification reaction using reagent 5a; 5a-benziodazolone; 6a-iodobezamide; Ts1-transition state 1; 15-estimated benziodazolone structure; 16,17-intermediates; 18-phosphonium salt; 19-N-acyl pyridinium salt.

General Experimental Remarks
All reactions were performed in open air with a stopper and oven-dried glassware. All commercial reagents were ACS grade and were used without further purification. NMR spectra were recorded on a Varian Inova 500 MHz NMR spectrophotometer ( 1 H NMR and 13 C NMR; Palo Alto, CA, USA) and Bruker 400 MHz NMR spectrophotometer ( 1 H NMR and 13 C NMR; Billerica, MA, USA). Melting points were determined in an open capillary tube with a Mel-temp II melting point apparatus. Infrared spectra were recorded on PerkinElmer Spectrum 1600 series FT-IR spectrometer (Waltham, MA, USA).

General Procedure for Preparation of 3-Chlorobenzoyloxybenziodazolone 5
Iodobenzamide 6 was added at 0 • C to a stirred mixture of m-CPBA in acetonitrile. The reaction was stirred for 12 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure to give solid residue. Then diethyl ether was added to the solid residue to prepare the suspended solution, which was filtered, and dried in a vacuum to give the desired 3-chlorobenzoyloxybenziodazolone 5. Single crystals of product 5a suitable for X-ray crystallographic analysis were obtained by slow crystallization from the acetonitrile solution. X-ray diffraction data for 5a were collected on Rigaku RAPID II Image Plate system using graphite-monochromated CuKα radiation (λ = 1.54187 Å) at 173 K. The structure was solved by Sir 2011 and refined on F 2 using ShelXle. Crystal data for 5a C 17 H 15 ClINO 3 are as follows: monoclinic, space group P2 1 /c, a = 12.6913 (3)

Typical Procedure for Esterification and Amidation Using Benziodazolones
Triphenylphosphine (47 mg, 0.18 mmol), pyridine (14 mg, 0.18 mmol), and alcohol 7 (0.15 mmol) or amine 9 (0.15 mmol) were added to a test tube containing benziodazolones 5 (0.180 mmol). The mixture was then stirred at room temperature for 1 h. After the reaction was completed, dichloromethane (3.0 mL) was used to transfer the reaction mixture to a separatory funnel. Then saturated NaHCO 3 (3.0 mL) was added, and the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by preparative TLC (hexane:ethyl acetate = 3:1) afforded the analytically pure 8 or 10.

Conclusions
In conclusion, we have developed novel benziodazolone compounds readily prepared from iodobenzamides using mCPBA, and the solid structure was confirmed by X-ray crystallography. These new benziodazolones can act as coupling assistant reagents to alcohols and amines, and their ligands can act as a coupling partner to give the corresponding ester and amides in moderate to good yields. In addition, it was found that the newly synthesized benzoiodazolone demonstrated better efficiency than the corresponding benziodoxolone in the esterification reaction.