A method of mild deoxydichlorination of aldehydes catalyzed by Triphenylphosphine oxide Chimica Techno Acta ARTICLE published by Ural Federal University 2022, vol. 9(2), No. 20229202 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.2.02 1 of 7 A method of mild deoxydichlorination of aldehydes catalyzed by Triphenylphosphine oxide D.A. Shipilovskikh ab, M.F. Konkova a, I.P. Nikonov a, M.M. Gladysheva a, S.A. Shipilovskikh ac* a: Perm State University, 614990 Perm, Russia b: Perm National Research Polytechnic University, 614990 Perm, Russia c: ITMO University, 197101 St. Petersburg, Russia * Corresponding authors: s.shipilovskikh@metalab.ifmo.ru This paper belongs to the Regular Issue. © 2022, The Authors. This article is published in open access form under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract The catalytic system of triphenylphosphine oxide and phthaloyl di- chloride catalysing conversion of aldehydes to 1,1-dichlorides is re- ported. The reaction proceeds via a P (V) catalysis manifold in which triphenylphosphine oxide turnover is achieved using phthaloyl di- chloride 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 deoxydi- chlorination reaction of 0.03 mol of benzaldehyde catalyzed by tri- phenylphosphine oxide as an example. The proposed method may be of interest for the production of different herbicides, insecticides and fungicides for the agricultural industry. Keywords aldehydes Lewis base catalysis organocatalysis triphenylphosphine oxide nucleophilic substitution agricultural chemistry Received: 15.02.2022 Revised: 23.03.2022 Accepted: 23.03.2022 Available online: 25.03.2022 1. Introduction The development of methods for nucleophilic substitution (SN) in sp3-hybridized carbon centers is the most signifi- cant and widespread problem of chemical transformations in organic synthesis [1–5]. Nucleophilic substitutions are general chemical transformations, as they allow, for ex- ample, strategic building of C–Cl, C–O, C–N and C–C bonds [6–15]. At the same time, compounds such as geminal dihalides are important intermediates in the chemical syn- thesis of useful natural substances, including active bio- logical compounds. Geminal dihalides, especially dichlo- rides, are an important class of intermediates in organic synthesis. They were used for alkenylation of carbonyl compounds [16, 17], cyclopropanation and epoxidation [18–20], dimerization [21, 22] and other purposes [23–26]. 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 appli- cation of such compounds is agriculture. Herbicides, insec- ticides and fungicides are widely used for plant protection in the modern industry (Fig. 1) [29–31]. Most of the waste from such chemical industries contains various halogen- containing compounds, which are extremely toxic to both humans and the environment. Also, the Dichlorides are an important class of inter- mediates in organic synthesis. They were used for alkenylation of carbonyl compounds [32, 33], cyclopropa- nation and epoxidation [34–36], dimerization [37, 38], etc. [39–42]. In addition, geminal dichlorides are also encoun- tered as structural motifs in polyhalogenated natural products such as Caldariomycin, Danicalipin A and un- decachlorosulfolipids A [43–48]. However, traditional synthetic methods often have low selectivity and low atom economy, resulting in the differ- ent products of chemical reactions [49–51]. Research in this area is at an early stage in the study of such catalytic reactions, but several efficient protocols for the produc- tion 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 cata- lytic deoxydichlorination of aldehydes [52]. In this meth- od, 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. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.2.02 http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0002-8917-2583 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.2.02&domain=pdf&date_stamp=2022-3-25 Chimica Techno Acta 2022, vol. 9(2), No. 20229202 ARTICLE 2 of 7 Fig. 1 The most used herbicides, insecticides and fungicides In 2019, Dr. P. Huy showed new catalytic method transformation of aldehydes into geminal dichlorides us- ing a catalytic system of N-formylpyrrolidine (5–10 mol.%) with phthaloyl dichloride (1.2–1.4 equiv). The proposed method exhibits the same catalytic activity as triphenylphosphine oxide [53]. Later Dr. Shipilovskikh with colleges proposed an alternative method for deoxydi- chlorination 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 tri- phenylphosphine 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 alde- hydes and in case of aliphatic aldehydes, the reaction yield increased to 10%. 2. Experimental Yields are given for isolated products showing one spot on a TLC plate and no impurities detectable in the NMR spec- trum. The identity of the products prepared by different methods was checked by comparison of their NMR spectra. The 1H and 13C NMR spectra were recorded at 400 MHz for 1H and 100 MHz for 13C NMR at the temperature of 303 K; the chemical shifts (δ) were measured in ppm with respect to the solvent (CDCl3, 1Н: δ = 7.26 ppm, 13C: δ = 77.16 ppm; [D6] DMSO, 1Н: δ = 2.50 ppm, 13C: δ = 39.52 ppm). The coupling constants (J) are given in Hertz. The splitting patterns of apparent multiplets associated with an averaged coupling constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), dd (doublet of doublets) and br (broadened). The melting points were determined with a «Stuart SMP 30», the val- ues are uncorrected. Flash chromatography was per- formed on silica gel Macherey Nagel (40–63 µm). Scheme 1 Catalytic deoxydichlorination of aldehydes to 1,1-dichlorides Chimica Techno Acta 2022, vol. 9(2), No. 20229202 ARTICLE 3 of 7 The reaction progress was monitored by GC/MS analy- sis 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 Dragen- dorff’s reagent or potassium permanganate aqueous solu- tion. All the reactions were carried out using dried and freshly distilled solvent. 2.1. General method for synthesis of dichlorides from aldehyde Triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%) and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv) were dissolved in 8 mL of anhydrous toluene in a 25 mL round bottom flask equipped with a magnetic stirring bar. After wards, aldehydes 1a–e (1 mmol, 1 equiv) in 2 mL of anhydrous toluene were slow- ly added to this solution with vigorous stirring at 0 °C, followed by heating up to 100 °C and stirring the mixture for 3 h. The reaction progress was monitored by GC-MS. After the reaction was complete, the solution was filtered and concentrated in vacuum. The crude mixture thus ob- tained was purified by flash chromatography on silica (pe- troleum ether/Et2O – 19/1). For gram-scale example , the mixture was purified by distillation. The general method for synthesis is shown in Scheme 2. Scheme 2 General method for synthesis 2.1.1. (Dichloromethyl)benzene 4а Obtained from 1a (106 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in an- hydrous toluene (10 mL). Colorless oil (142 mg, 88%, for gram-scale 4.05 g, 84%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 6.73 (s, 1H, CH), 7.44–7.46 (m, 3H, HAr), 7.64–7.66 (m, 2H, HAr). 13C NMR (CDCl3, 100 MHz) δ (ppm): 72.2, 126.0, 128.9, 123.0, 140.3 [55]. 2.1.2. 1-(Dichloromethyl)-4-methylbenzene 4b Obtained from 1b (120 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 2 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in anhydrous toluene (10 mL). Colorless oil (159 mg, 91%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 2.42 (s, 3H, CH3), 6.69 (s, 1H, CH), 7.16–7.24 (m, 2H, HAr), 7.44–7.51 (m, 2H, HAr). 13C NMR (CDCl3, 100 MHz) δ (ppm): 21.8, 71.6, 126.0, 129.1, 137.2, 140.7 [56]. 2.1.3. 1-Bromo-4-(dichloromethyl)benzene 4с Obtained from 1с (185 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in an- hydrous toluene (10 mL). Colorless oil (194 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 6.70 (s, 1H, CH), 7.43–7.49 (m, 2H, HAr), 7.49–7.56 (m, 2H, HAr). 13C NMR (CDCl3, 100 MHz) δ (ppm): 72.0, 124.2, 128.1, 131.7, 139.5 [53]. The structures of 1-(Dichloromethyl)benzene 4a, (Di- chloromethyl)-4-methylbenzene 4b and 1-Bromo-4- (dichloromethyl)benzene 4c are shown in Fig. 2. Fig. 2 1-(Dichloromethyl)benzene 4a, (Dichloromethyl)-4- methylbenzene 4b and 1-Bromo-4-(dichloromethyl)benzene 4c 2.1.4. 1-(dichloromethyl)-2-methoxybenzene 4d Obtained from 1d (136 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in an- hydrous toluene (10 mL). Colorless oil (143 mg, 75%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 3.87 (s, 3H, CH3), 6.93–7.17 (m, 1H, CH, 2H, HAr), 7.29–7.32 (0, 1H, HAr), 7.71–7.83 (m, 2H, HAr). 13C NMR (CDCl3, 100 MHz) δ (ppm): 54.1, 64.5, 109.3, 120.1, 127.1, 128.3, 130.0, 152.4 [53]. 2.1.5. (3,3-Dichloroprop-1-en-1-yl)benzene 4e Obtained from 1e (132 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in an- hydrous toluene (10 mL). Colorless oil (153 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 6.33 (d, J = 7.6 Hz, 1H, CH), 6.40 (dd, J = 14.7 and 7.6 Hz, 1H, CH), 6.72 (d, J = 14.7 Hz, 1H, CH), 7.30–7.50 (m, 5H, HAr). 13C NMR (CDCl3, 100 MHz) δ (ppm): 73.5, 127.1, 128.1, 129.0, 129.2, 132.5, 134.7 [53]. 2.1.6. 1,1-dichlorooctane 4f Obtained from 1f (128 mg, 1 mmol), triphenylphosphine oxide (Ph3PO) (3 mg, 0.01 mmol, 0.01 equiv, 1 mol.%), and phthaloyl dichloride (203 mg, 1.00 mmol, 1 equiv), in anhydrous toluene (10 mL). Colorless oil (77 mg, 42%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 0.92 (t, J = 7.2 Hz, 3H, CH3), 1.31 (m, 8H, CH2), 1.55 (m, 2H, CH2), 2.20 (m, 2H, CH2), 5.74 (t, J = 6.2 Hz, 1H, CHCl2). 13C NMR (CDCl3, 100 MHz) δ (ppm): 14.0, 22.9, 26.3, 28.7, 29.6, 32.0, 43.9, 73.7. The structures of 1-(dichloromethyl)-2- methoxybenzene 4d, (3,3-Dichloroprop-1-en-1-yl)benzene 4e and 1,1-dichlorooctane 4f are shown in Fig. 3. Chimica Techno Acta 2022, vol. 9(2), No. 20229202 ARTICLE 4 of 7 Fig. 3 1-(dichloromethyl)-2-methoxybenzene 4d, (3,3-Dichloro- prop-1-en-1-yl)benzene 4e and 1,1-dichlorooctane 4f 3. Results and Discussion The investigation commenced with establishing the best conditions for the deoxydichlorination of aldehydes, em- ploying benzaldehyde 1a as a model substrate (Table 1). First, the catalytic triphenylphosphine oxide was investi- gated. 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, en- try 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). Table 1 Optimization of the reaction conditionsa entry equiv of phthaloyl dichloride mol.% Ph3PO solvent T (°C) t (h) conv. (%)b 1 2 – DCM 40 1 0 2 2 100 DCM 40 1 8 3 2 10 DCM 40 3 16 4 2 10 Tol 40 3 40 5 2 10 MeCN 40 3 10 6 2 10 DCE 40 3 18 7 2 10 THF 40 3 32 8 2 10 Et2O 30 3 6 9 2 10 Tol 100 3 95 10 2 5 Tol 100 3 95 11 2 1 Tol 100 3 95 12 1 1 Tol 100 3 95 13 0.50 1 Tol 100 3 43 aGeneral conditions: 1a (0.01 mmol, 1 mol.%) Ph3PO, dry solvent, slowly addition of aldehydes. The reactions were carried out for 1–3 h before an aliquot (50 μL) was taken, quenched with aqueous solvent (1 mL), and analyzed by GC. bConversion to 4a was calculated from GC. 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 cat- alytic activity, which is consistent with the research de- scribed 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.% cat- alyst based on triphenylphosphine oxide, as well as the complete transition of chlorine into the final product, sig- nificantly 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. Scheme 4 Gram-scale application of deoxydichlorination of ben- zaldehyde catalyzed by triphenylphosphine oxide The proposed mechanism is depicted in Scheme 5. We believe that the catalytic cycle start with a quick formation of the intermediate dichlorotriphenylphosphane (B) upon treatment of triphenylphosphine oxide (A) with phthaloyl dichloride. Next, in catalytic cycle, the intermediate B re- acts with aldehyde 1 via oxygen to form the intermediate C, which then undergoes elimination to furnish geminal dichloride 4 and to regenerate the catalyst A. 4. Conclusions We developed a highly atom economy protocol for a cata- lytic deoxydichlorination of aldehydes under modified Ap- pel conditions catalyzed by 1 mol.% of triphenylphosphine oxide. The salient features of the method are: (i) opera- tionally simplicity, (ii) low catalyst loading (1 mol.%), (iii) medium reaction times and (iv) mild conditions and Chimica Techno Acta 2022, vol. 9(2), No. 20229202 ARTICLE 5 of 7 all transfer chlorine from phthaloyl dichloride. Also, we showed applications of the developed method on the gram-scale. Scheme 5 The proposed mechanism related to cyclic transfor- mation of substances Supplementary materials No supplementary data are available. Funding This study was funded by the Russian Science Foundation grant No. 20–73–00081, https://www.rscf.ru/en. Acknowledgments None. Author contributions Conceptualization: S.A.S. Data curation: M.F.K., I.P.N. Formal Analysis: M.F.K., I.P.N., M.M.G. Funding acquisition: D.A.S., S.A.S. Investigation: D.A.S., M.F.K., I.P.N., M.M.G. Methodology: I.P.N., M.M.G. Project administration: S.A.S. Resources: D.A.S., S.A.S. Software: D.A.S., S.A.S. Supervision: S.A.S. Validation: D.A.S., M.F.K., S.A.S. Visualization: D.A.S., I.P.N., S.A.S. Writing – original draft: D.A.S., S.A.S. Writing – review & editing: D.A.S., S.A.S. Conflict of interest The authors declare no conflict of interest. Additional information Authors’ IDs: Shipilovskikh, Daria A., Scopus ID 57193555475; Shipilovskikh, Sergei A., Scopus ID 34168423100. 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