A method of mild deoxydichlorination of aldehydes catalyzed by Triphenylphosphine oxide

The catalytic system of triphenylphosphine oxide and phthaloyl dichloride catalysing conversion of aldehydes to 1,1-dichlorides is reported. The reaction proceeds via a P (V) catalysis manifold in which triphenylphosphine oxide turnover is achieved using phthaloyl dichloride as a consumable reagent. The application of the developed method on substrates of different structures was demonstrated. We showed the use of unsaturated compounds, including aromatics with and without electron donating / withdrawing groups, as well as satu-rated aliphatic compounds. The possibility of using the developed method on a gram scale was also demonstrated with the deoxydichlorination reaction of 0.03 mol of benzaldehyde catalyzed by triphenylphosphine oxide as an example. The proposed method may be of interest for the production of different herbicides, insecticides and fungicides for the

In addition, geminal dichlorides are also encountered as structural motifs in polyhalogenated natural products [27,28]. At the same time, one of the main areas of application of such compounds is agriculture. Herbicides, insecticides and fungicides are widely used for plant protection in the modern industry ( Fig. 1) [29][30][31]. Most of the waste from such chemical industries contains various halogen-containing compounds, which are extremely toxic to both humans and the environment.
However, traditional synthetic methods often have low selectivity and low atom economy, resulting in the different products of chemical reactions [49][50][51]. Research in this area is at an early stage in the study of such catalytic reactions, but several efficient protocols for the production of dichlorides from aldehydes catalyzed by a Lewis base have been disclosed to date (Scheme 1). Dr. Denton with colleagues previously reported a method for the catalytic deoxydichlorination of aldehydes [52]. In this method, authors used a catalytic system of triphenylphosphine oxide (7.5-15 mol.%) and Oxalyl chloride. The proposed method works well with different unsaturated compounds, but gives a lower yield of 32% with aliphatic compounds. The proposed method exhibits the same catalytic activity as triphenylphosphine oxide [53]. Later Dr. Shipilovskikh with colleges proposed an alternative method for deoxydichlorination of aldehydes catalyzed by diphenyl sulfoxide, using a catalytic system of diphenyl sulfoxide (10 mol.%) and oxalyl chloride (1.5 equiv). The developed method showed excellent yields with unsaturated aldehydes [54].
In this work, we use the combination of the previously reported catalytic system and optimization of the reaction condition. We found that the catalytic activity of triphenylphosphine oxide can be increased by a factor of 10 compared to previously described methods. In addition, in the proposed method, reducing the catalyst load did not affect the catalytic activity in case of unsaturated aldehydes and in case of aliphatic aldehydes, the reaction yield increased to 10%.

Experimental
Yields are given for isolated products showing one spot on a TLC plate and no impurities detectable in the NMR spectrum. The identity of the products prepared by different methods was checked by comparison of their NMR spectra. The 1 H and 13 C NMR spectra were recorded at 400 MHz for 1 H and 100 MHz for 13 C NMR at the temperature of 303 K; the chemical shifts (δ) were measured in ppm with respect to the solvent (CDCl3, 1 Н: δ = 7.26 ppm, 13  The reaction progress was monitored by GC/MS analysis and thin layer chromatography (TLC) on aluminum backed plates with Merck Kiesel 60 F254 silica gel. The TLC plates were visualized either by UV radiation at a wavelength of 254 nm or stained by exposure to a Dragendorff's reagent or potassium permanganate aqueous solution. All the reactions were carried out using dried and freshly distilled solvent.  [53]. The structures of 1-(Dichloromethyl)benzene 4a, (Dichloromethyl)-4-methylbenzene 4b and 1-Bromo-4-(dichloromethyl)benzene 4c are shown in Fig. 2.

Results and Discussion
The investigation commenced with establishing the best conditions for the deoxydichlorination of aldehydes, employing benzaldehyde 1a as a model substrate (Table 1). First, the catalytic triphenylphosphine oxide was investigated. Then, the effects of the solvent, temperature, and equivalents of phthaloyl dichloride on the conversion in the reaction were studied. Phthaloyl dichloride on its own did not produce (Dichloromethyl)benzene 4a (entry 1). The use of stoichiometric quantities of Ph3PO and 2 equiv of phthaloyl dichloride in DCM resulted in low conversion of 1a into 4a (Scheme 3, Table 1, entry 2). With 10 mol.% Ph3PO and 2 equiv of phthaloyl dichloride, 4a was formed in 16% conversion after 3 h (entry 3), which increased to 40% after changing the solvent to toluene (entry 4). Raising the temperature to 100 °C with 10 mol.% Ph3PO and using 2 equiv of phthaloyl dichloride led to the best results of conversion to 95% (entry 9). We then studied the catalytic activity of Ph3PO at 100 °C for 3 hours and found that using 1 mol.% Ph3PO gives a similar result (95% conversion, entry 11). Finally, we studied the effect of the equivalents of phthaloyl dichloride on the conversion of the reaction and found that the use of phthaloyl dichloride at an equivalent of 100 mol.% gives a similar conversion, 95% (entry 12). However, reducing the equivalents of phthaloyl dichloride to 50 mol.% yields the conversion of 43% (entry 13).

Scheme 3 The reaction for optimization conditions
The substrate scope was investigated next. As shown, the reaction works well with different types of aromatic aldehydes, including donor and acceptor substituents at the fourth position of the ring. The use of cinnamaldehyde under the reaction conditions also showed good results. However, the use of aliphatic aldehydes led to the low catalytic activity, which is consistent with the research described previously.
In addition, we studied the possibility of transferring the developed method from the milligram-scale to the gram-scale of (dichloromethyl)benzene, which shows the possibility of industrial application of the developed methods (Scheme 4). The possibility of using 1 mol.% catalyst based on triphenylphosphine oxide, as well as the complete transition of chlorine into the final product, significantly reduces the amount of waste that is toxic to the environment and humans. Also, the results obtained are superior to those described earlier, which indicates the prospects for further development of this catalytic system.

Conclusions
We developed a highly atom economy protocol for a catalytic deoxydichlorination of aldehydes under modified Appel conditions catalyzed by 1 mol.% of triphenylphosphine oxide. The salient features of the method are: (i) operationally simplicity, (ii) low catalyst loading (1 mol.%), (iii) medium reaction times and (iv) mild conditions and all transfer chlorine from phthaloyl dichloride. Also, we showed applications of the developed method on the gram-scale. Scheme