Use of triphenylphosphine-bromotrichloromethane (PPh3-BrCCl3) in the preparation of acylhydrazines, N- methylamides, anilides and N-arylmaleimides from carboxylic acids

Abstract: In certain countries, many of the reagents used to transform carboxylic acids to acyl halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoryl chloride, thionyl chloride and sulfuryl chloride are difficult to come by. Against this background, the authors developed the reaction system triphenylphosphine (PPh3) – bromotrichloromethane (BrCCl3) to prepare acyl halides in situ. In the following, the use of this reagent combination is joined with the reaction of the in situ prepared acyl halides with nitrogen nucleophiles, specifically with hydrazines, methylamine and anilines. The reaction is also used in an intramolecular variant by the reaction of maleanilic acids to N-arylmaleimides..


Introduction
Although there are a number of ways to transform carboxylic acids to acyl halides, the reagents needed such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoryl chloride, thionyl chloride and sulfuryl chloride are not always available in certain countries. Against this background, the authors developed the reaction system triphenylphosphine (PPh3)bromotrichloromethane (BrCCl3) to prepare acyl halides in situ [1,2]. This reaction system is a variation of the Appel reagent [3], where tetrachloromethane (CCl4) is replaced by the environmentally less hazardous BrCCl3. It was noted that the in situ prepared acyl halides could be reacted with alcohols, and primary and secondary amines to esters and amides, respectively [4]. In the following, the treatment of carboxylic acids is followed by their reaction with hydrazines, methylamine and anilines. Also, further examples [5] will be given to transform maleianilic acids to N-arylmaleimides with the action of PPh3-BrCCl3 in the presence of triethylamine as base.

General remarks
Melting points were measured on a Stuart SMP 10 melting point apparatus and are uncorrected. Infrared spectra were measured with a Thermo/Nicolet Nexus 470 FT-IR ESP spectrometer and a Perkin Elmer Spectrum Two spectrometer. 1 H and 13 C NMR spectra were recorded with a Varian 400 NMR spectrometer (1H at 395.7 MHz, 13 C at 100.5 MHz). The assignments of the carbon signals were aided by DEPT 90 and DEPT 135 experiments (DEPT = Distortionless Enhancement by Polarisation Transfer). The chemical shifts are relative to TMS (solvent CDCl3, unless otherwise noted). Mass spectra were measured with a JMS-01-SG-2 spectrometer, and with an Agilent QTOF 6540 UHD. Column chromatography, where necessary, was performed on recycled silica gel (S, 0.063 mm -0.1 mm, Riedel de Haen and Merck grade 9385).
Cinnamamide (11a). -A solution of triphenylphosphine (1.89 g, 7.21 mmol) and bromotrichloromethane (BrCCl3, 1.56 g. 7.86 mmol) in dry CH3CN (15 mL) is stirred at rt for 30 min., during which in turns dark yellow. Then, cinnamic acid (4a, 965 mg, 6.51 mmol) is added, and the resulting mixture is stirred at 70˚C for 40 min. Thereafter, the solution is cooled to rt, and aq. ammonia (10 mL, ammonium hydroxide, 25 wt%) is added dropwise to the solution. Thereafter, the reaction mixture is heated at 70˚C for 10h. The cooled solution is added to water (50 mL) and the ensuing mixture is extracted with CHCl3 (2 X 30 mL). The combined organic phase is dried over anhydrous MgSO4 and concentrated in vacuo. The residue is subjected to column chromatography over silica gel (CH2Cl2-ether 10:1) to give 11a as a colorless solid (718 mg, 75%); mp. 148˚C (Lit.

Results and Discussion
Previously, it had been established that the reactions of the modified Appel reagent BrCCl3-PPh3 are similar to those of CCl4-PPh3. This includes the dehydration of aldoximes and amides to nitriles (1) and the amidation of carboxylic acids (4). Only the actual Appel reaction itself, ie., the transformation of alkanols to haloalkanes with BrCCl3-PPh3 is more complex, where under certain conditions the transfer of the bromo-substituent vs. the chloro-substituent is not selective (2). In the following, the authors tried to examine whether amidation reactions of carboxylic acids with the less nucleophilic anilines would proceed equally well as with amines. Also, the authors investigated the reactions with hydrazines. Here, the use of ammonium salts such as methylammonium chloride and hydrazinium salts such as hydrazinium sulfate was probed as well as was the reaction of carboxylic acids with aq. ammonia in the presence of BrCCl3-PPh3. Finally, the scope of an intramolecular imidation was looked at to transform maleianilic acids to N-arylmaleimides (5) The reaction of benzoic acids 1, treated with BrCCl3-PPh3, with anilines 2 proceeded straightforward to give the anilides 3 ( Table 1). The anilines were added slowly while the reaction mixture was at reflux. It was noted that the reactions are exothermic. The products were isolated by column chromatographic separation on silica gel. The reactions were also carried out successfully with cinnamic acids 4 ( Table 2) and phenylacetic acids 6 ( Table 3) as substrates.
The release of methylamine in situ, within a reaction mixture of initially carboxylic acid, triphenylphosphine and bromotrichloromethane by equilibration with added triethylamine was seen to work well, providing the corresponding N-methyl amides in acceptable yields ( Table 4).
The reaction of aq. ammonia with the in situ prepared acyl halides proceeded equally well, showing that the amidation of the acyl halides proceeded faster than their hydrolysis (Tables 5 and 6).
For the reaction of the in situ prepared acyl halides, three available hydrazines/hydrazine salts available to us were chosen: 1-methyl-1-phenylhydrazine (12), 2,4-dinitrophenylhydrazine (14), and hydrazinium sulfate. 1-Methyl-1-phenylhydrazine is liquid, so its addition to the in situ prepared acyl halides poses no problem. The 2,4-dinitrophenylhydrazine (14) commercially available to us was dampened with water, most likely to lessen the chance of a detonation of the material. Thus, hydrazine 14 was dried in an oven at 37 °C for 48h before use. Hydrazine itself was released in situ by equilibration of hydrazinium sulfate and triethylamine just as in the case of the use of methylammonium chloride (see above). In all cases, the reaction proceeded reasonably well, delivering acyl hydrazides 13 and 15 (Tables 7 and 8), and in the case of hydrazine itself, 1,2-bis(aroyl)hydrazines 16 were obtained (Table 9).
Finally, our work (5) on using the modified Appel reagent PPh3-BrCCl3 for a ring closure of maleianilic acids to N-maleimides was expanded slightly. While previously we had utilized anilines available to us commercially in these reactions, here, we prepared the anilines through a hydrolysis of the corresponding acetamides 17. The general published procedure (7) works very well and allows for the construction of a substituted acetamide before releasing the substituted aniline by hydrolysis.         Table 10. Reaction of maleianilic acids 20 to N-arylmaleimides 21.

Conclusion
In conclusion, it can be said that acyl halides, prepared in situ by the action of PPh3-BrCCl3 on carboxylic acids can be transformed further in one pot by the reaction with anilines and hydrazines to anilides and hydrazides, respectively. Also, ammonium and hydrazinium salts can be used when trimethylamine is added as base. Furthermore, the reaction of maleianilic acids with PPh3-BrCCl3 provides N-arylmaleimides.