K2S2O8-Mediated Difunctionalization of C≡C Bonds in Water: A Simple and Efficient Approach to α,α-Dihaloacetophenones from Phenylacetylenes and NaX

Abstract A novel K2S2O8-mediated oxy-1,1-dihalogenation of alkynes with NaX in the presence of water has been developed, affording α,α-dihaloacetophenones in moderate to good yields. The advantages of this reaction are mild reaction conditions, operational simplicity, and use of pure water as reaction medium. A plausible reaction mechanism is proposed on the basis of mechanistic studies. GRAPHICAL ABSTRACT


INTRODUCTION
The transformation of alkynes is an essential functional group interconversion for organic synthesis. [1][2][3][4][5] The resulting compounds from alkyne functionalization take a privileged position in drug discovery, supramolecular chemistry, polymer chemistry, materials science, and biotechnology. [2] Among intensive research in alkyne chemistry, vicinal difunctionalization of alkynes involving the simultaneous installation of two different vicinal chemical bonds exemplifies a class of reactions with significant synthetic potential to rapidly increase molecular complexity. [3] In this regard, oxyhalogenation of alkynes has recently attracted attention because it installs two versatile handles (carbonyl and halide) for further structural elaboration. [4,5]

RESULTS AND DISCUSSION
In our previous studies, phenacyl bromides could be efficiently synthesized via K 2 S 2 O 8 -mediated tandem hydroxybromination and oxidation of styrenes using KBr as a bromine source in the presence of water. [9] We envisioned that a,a-dihaloacetophenones can be generated in a similar fashion if the styrenes are replaced with phenylacetylenes. When phenylacetylene was reacted with KBr in the presence of K 2 S 2 O 8 in H 2 O at 60 C for 12 h, we were delighted to see that our desired product, a,a-dibromoacetophenone, was indeed formed in 85% yield (Table 1, entry 1). The control experiment showed that K 2 S 2 O 8 was necessary for the reaction to proceed (Table 1, entry 2). Among the bromine sources screened, NaBr was found to be most effective (Table 1, entries 3-5). When other persulfate salts, such as Na 2 S 2 O 8 or (NH 4 ) 2 S 2 O 8 , were used in place of K 2 S 2 O 8 , the desired product was obtained in poor yields (Table 1, entries 6 and 7). Changing the solvent to CH 3 OH-H 2 O, CH 3 CN-H 2 O or CH 3 CH 2 OH-H 2 O afforded 62-65% yield of product, whereas the use of organic solvents alone as the solvent gave no product (Table 1, entries 8-13). When the mixed solvent of other solvent-H 2 O was used as the reaction medium, only the desired a,a-dibromoacetophenone was detected by gas chromatography (GC) and the remaining starting material decomposed in those cases, whereas organic solvents afforded trans-1,2-dibromo-1-phenylethene as the major product. Increasing the reaction temperature to 70 C did not benefit the reaction (Table 1, entry 14). The reaction between phenylacetylene and KCl in the presence of K 2 S 2 O 8 in H 2 O at 60 C for 12 h provided the desired a,a-dichloroacetophenone in 45% yield (Table 1, entry 15). After a series of optimizations, the best yield (58%) was achieved when NaCl was used as chlorine source in the presence of K 2 S 2 O 8 (Table 1, entry 16). On the basis of these results, we determined the optimized conditions to be K 2 S 2 O 8 (2.5 equiv), NaX (2.0 equiv), H 2 O, 60 C, and 12 h (for details, see the supplementary The conversion is given in parentheses. d trans-1,2-Dibromo-1-phenylethene was obtained in 42%. . Although phenylacetylene reacted with NaBr or NaCl in the presence of K 2 S 2 O 8 to afford the corresponding a,a-dibromoacetophenone and a,adichloroacetophenone, the reaction of phenylacetylene with KI did not gave the corresponding a,a-diiodoacetophenone under the same reactions; instead it provided (E)-1,2-diiodophenylethene as the main product (see Scheme S1 in the Supporting Information).
With the optimized conditions in hand, we next explored the scope of the reaction between various alkynes and NaBr, and the results are summarized in Scheme 1. Diverse phenylacetylenes bearing both electron-donating groups and electronwithdrawing groups provided the desired a,a-dibromoacetophenones in yields ranging from 61 to 78% (2a-2j). It is worth noting that F (2b), Cl (2c), and Br (2d) substituents on the phenyl ring were well tolerated, which enable potential Scheme 1. Oxy-1,1-dibromination of alkynes with NaBr in the presence of K 2 S 2 O 8 . Conditions: alkynes (0.5 mmol), K 2 S 2 O 8 (2.5 equiv), NaBr (2.0 equiv), H 2 O (1 mL), 60 C, 12 h. Isolated yields. applications in further functionalization. [10] In addition, this reaction was also applicable to internal alkynes, 1-phenyl-1-propyne, and 1-phenyl-1-butyne, as demonstrated by the formation of the desirable products in good yields (2k and 2l). While the results of phenylacetylenes were all favorable, the reaction of aliphatic alkynes did not give the corresponding a,a-dibromoketones; instead they afforded dibromides as the main products. For instance, when 1-heptyne was subjected to the same reaction conditions, trans-1,2-dibromo-1-heptene was obtained in 58% yield (2m).

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J.-Y. WANG, Q. JIANG, AND C.-C. GUO a,a-dichloroketone, and only trace amounts of dichloride product (3j) were detected by NMR (see Fig. S1 in the Supporting Information).
To shed light on the mechanism of the reactions, some information has been gathered. When phenacyl chloride and bromide were introduced into the standard conditions, the desired a,a-dichloroacetophenone and a,a-dibromoacetophenone were not detected by GC [Eq.
(1)]. The reaction of b-bromostyrene under the same conditions afforded only a trace amount of a,a-dibromoacetophenone [Eq. (2)]. These results indicate that phenacyl halide and b-halostyrene seem not to serve as intermediates in the reaction. Also, when the reaction was carried out in the presence of BHT (2,6-di-tert-butyl-4-methyl phenol) [Eq. (3)], which was a traditional radical scavenger, a,a-dibromoacetophenone was obtained in 82% yield, thus demonstrating that a radical pathway might not be involved in the present reaction system. Futhermore, Table 1 showed that the reaction did not proceed at all in the absence of K 2 S 2 O 8 . This result shows that K 2 S 2 O 8 plays a role as the oxidant. In addition, the results that we obtained from Table 1 suggested that carbonyl oxygen of a,a-dihaloacetophenone originates from water, not from the molecular oxygen of air. Finally, the presence of the yellow color during the reaction suggests the formation of bromine. [9] Based on these results and related reports, [4,5] a plausible mechanism for the present process is proposed in Scheme 3. Initially, oxidation of the halide ion by the persulfate ion generates molecular halogen, which is trapped by water to give hypohalous acid (HOX). Next, hypohalous acid converts into dihalo monoxide (X 2 O) [5c,11] and undergoes electrophilic addition onto the phenylacetylene to produce a three-membered cyclic halonium ion intermediate A. The cyclic intermediate undergoes ring opening by the nucleophile (XO À , hydroxy or halide ion) to yield the corresponding substituted products B, C, and D. This also further explained the results of Schemes 1 and 2. When substrates were aliphatic alkynes, halonium ion intermediate undergoes ring opening by halide ion to give vicinal dihalo substituted product, whereas when substrates were phenylacetylenes, halonium ion intermediate undergoes ring opening by XO -(path a) and water (path b) to provide vicinal substituted products B and C. Finally, the intermediates B and C are converted into the corresponding a,a-dihaloacetophenone.

CONCLUSIONS
In conclusion, we have developed a highly attractive and operationally simple oxy-1,1-dihalogenation method to construct a,a-dichloroacetophenones and a,adibromoacetophenones. This method is of great value from the viewpoint of green chemistry and organic synthesis due to use of inexpensive halogen sources, K 2 S 2 O 8 as oxidant, and H 2 O as solvent. Further mechanistic studies and development of relevant reactions are currently under investigation.

EXPERIMENTAL
All reagents and solvent were purchased commercially and used without further purification. Mass spectra were measured on a mass instrument (EI). 1 H NMR spectra were recorded on 400 MHz in CDCl 3 , and 13 C NMR spectra were recorded on 101 MHz in CDCl 3 using Tetramethylsilane (TMS) as internal standard. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet), and coupling constants (J) are reported in hertz. Copies of 1 H NMR and 13 C NMR spectra are provided as Supporting Information. K 2 S 2 O 8 (2.5 equiv.), NaX (2.0 equiv.), phenylacetylene (0.5 mmol), and H 2 O (1 mL) were added to a 25-mL Schlenck tube. The reaction mixture was warmed to 60 C (oil bath) and stirred for 12 h. The reaction was cooled to room temperature, and ethyl actate (5 mL) and water (2 mL) were added. The organic layer was separated, and the aqueous phase was extracted with ethyl actate (10 mL Â 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography to give desired product 2,2-dibromo-1-phenylethanone 2a.  129.72, 130.84, 134.53, 186.00. The spectral data agreed with those in the literature. [5a] FUNDING We are grateful for the financial support from the National Natural Science Foundation of China (21372068, J1210040, J1103312) and the Presidential Scholarship for Doctoral Students, Hunan University.

SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher's website.