A novel and highly efficient esterification process using triphenylphosphine oxide with oxalyl chloride

Triphenylphosphine oxide (TPPO) and oxalyl chloride ((COCl)2) are used as novel and high-efficiency coupling reagents for the esterification of alcohols with carboxylic acids via the TPPO/(COCl)2 system at room temperature for 1 h. The reaction represents the first TPPO-promoted esterification under mild and neutral conditions with excellent yields. Furthermore, we proposed a plausible mechanism with the help of 31P NMR spectroscopy.


Introduction
As is well known, carboxylic esters are fundamental organic compounds in organic synthesis and have been widely used in chemical and pharmaceutical industries, such as spices, daily chemical industries, foods, medicines, rubbers, coating materials and so on [1]. Owing to the importance of esters, numerous chemical methods have been reported to accomplish this basic transformation [2,3]. Esters are primarily prepared from the condensation of carboxylic acids with alcohols; generally, the most common methods for the preparation of ester proceed via carboxyl group activation and subsequent reaction with a suitable alcohol [4]. Among them, acid halides were recognized as powerful esterifying agents because of their complete conversion and high yields; however, to the best of our knowledge, acid halides always generate highly acidic by-products such as hydrochloric acid, which could result in decomposition of the initial materials; this method has almost no application in the synthesis of a natural product because of greater possibility of reaction with some acidsensitive functional groups [2][3][4]. Moreover, acid chlorides are prone to hydrolysis under basic conditions through the standard ketene intermediate (scheme 1) [4]. Therefore, it is crucial to find a mild coupling system for the further development of chemistry. ignored with reference to the listed advantages compared with the classical Mitsunobu reaction. This neutral method is applicable for natural product synthesis. Moreover, there is great potential in the chemical industry to resolve the waste due to the by-products of TPPO. Fortunately, there is no report describing the utilization of TPPO with (COCl) 2 for the esterification system thus far.

Preparation of esters by using TPPO/(COCl) 2
To a cold solution of TPPO (1.4 g, 5 mmol) in acetonitrile (CH 3 CN, 5 ml), (COCl) 2 (0.55 ml, 6.5 mmol) was added slowly in drops under magnetic stirring. After 10 min, carboxylic acid (1 equiv, 5 mmol) was added and stirred for 10 min. Then, alcohol (1.3 equiv, 6.5 mmol) and Et 3 N (0.67 ml, 5 mmol) were added in sequence. The reaction was carried out under the protection of nitrogen gas, and the reaction temperature was room temperature. Stirring was continued for 1 h. The progress of reaction was followed by thin layer chromatography (TLC). After the reaction, mixture was evaporated in vacuo and the final product was purified by column chromatography with petroleum ether/ethyl acetate (8 : 1) as the eluent. All esters presented in table 3 are previously known and reported compounds. (table 1) TPPO (1.4 g, 5 mmol), CH 3 CN (5 ml), (COCl) 2 (0.55 ml, 6.5 mmol), PhCOOH (0.67 g, 5 mmol), PhCH 2 OH (0.67 ml, 6.5 mmol) and Et 3 N (0.67 ml, 5 mmol) were added as in the previous procedure. The reaction was carried out under different reaction temperatures and times. In the end, the yield was measured by TLC (table 1).

Procedure for recycling TPPO
At the end of the reaction, the mixture was evaporated in vacuo and corresponding esters with TPPO were separated by column chromatography. The residue was purified with an eluent of 8 : 1 petroleum ether/ethyl acetate and then the polarity of the eluent was changed to 2 : 1, and TPPO was obtained. The crude product was evaporated and dried in vacuo. The white solid obtained was the reusable TPPO.

Results and discussion
As mentioned above, in order to optimize the reaction conditions, we firstly chose benzoic acid (1 equiv) and benzyl alcohol (1.3 equiv) as reaction substrates, which were stirred in CH 3 CN for 1 h at room temperature under the protection of nitrogen gas and then was added TPPO (1 equiv)/(COCl) 2 (1.3 equiv); the reaction mixture was neutralized by triethylamine (Et 3 N), and the desired ester, benzyl benzoate, was obtained in a 90% yield (table 1, entry 1). Initially, we tested the influence of reaction time from 1 to 4 h and different organic solvents including CH 3 CN, PhMe, CH 2 Cl 2 and C 2 H 4 Cl 2 at different temperatures to find the most suitable conditions for the reaction; the best results are summarized in table 1.
According to the results obtained in different organic solvents (table 1, entries 4-6), the esterification yields had no obvious difference. As is well known, TPPO has a better solubility in CH 2 Cl 2 or C 2 H 4 Cl 2 than CH 3 CN and PhMe, and during the experimental phenomena, we found that the solid       in CH 3 CN was dissolved rapidly after the addition of (COCl) 2 , and there were no obvious changes in the phenomena in other solvents; hence we chose CH 3 CN as the reaction solvent. Moreover, by monitoring the reaction using TLC, we found that the reactant was consumed within 1 h and that extended reaction time cannot improve product yields appreciably. By contrast, as the reaction progressed, some generated esters were decomposed because of the reversibility of the reaction (table 1, entries 1-3). Generally, temperature is an important factor for various reactions. However, it had no obvious influence in this system as seen in table 1, entries 6-8.
We also examined the effect of different ratios of TPPO/(COCl) 2   As the esterification reaction of benzoic acid to benzyl benzoate gave a 90% yield (table 3, entry 1), we first applied our reaction conditions to the carboxylic acids carrying both electron-donating groups (-OMe and -Me) (table 3, entries 3 and 4) and electron-withdrawing groups (-NO 2 and -Cl) (table 3, entries 2, 5 and 17), and these carboxylic acids gave their corresponding esters in good yields. However, there was a little difference between electron-donating groups and electrophilic groups. The position of substituent groups could affect the esterification yields (table 3, entries 2 and 17); it was easy to find that m-nitrobenzoic acid has lower conversion (90%) compared to p-nitrobenzoic acid (94%). By now, we clearly realized that the double bond had a crucial role in the esterification (table 3, entry 6); it improved the yield (95%). Of course, steric effects via acids were examined. It was evident that the steric hindrance of acids is an influencing factor for the esterification yield (table 3, entries 7, 8 and 16), which reduces the conversion appreciably.
In comparison, aliphatic alcohols had lower reactivity than aromatic alcohols (table 3, entries 1 and 9, 1 and 10). However, as is to be expected, this impact could be ignored when employing electron-deficient carboxylic acids (table 3, entries 6 and 11, entries 2 and 14). Moreover, the aromatic acid was more reactive than the aliphatic acid (table 3, entries 1 and 15) just as we expected. Tertiary alcohols because of their steric hindrance were tested to react with benzoic acid; as we expected, there was little corresponding ester generated (table 3, entry 12); besides, secondary alcohols gave lower yields for the same reason (table 3, entries 6 and 13).
To explore the effect between substrates and corresponding yields accurately, we have provided a summary about the times of reaction for different substrates in table 4. The progress of the reaction was followed by TLC, and the final product was purified by column chromatography.
As shown in table 4, some cases indicated that the reactants were consumed at 1 h, and most substrates proved that increased reaction time will not change yields greatly, with the exception of table 4, entry 7 by TLC. In conclusion, esterification was difficult to be carried out for substrates with bulky chemical constitution.  165.60, 139.53, 135.81, 131.13, 128.76, 128.67, 128.60

Conclusion
In conclusion, we developed a new and efficient method for the synthesis of esters with excellent yields by the TPPO/(COCl) 2 system. In comparison with the previous methods for the esterification between carboxylic acids and alcohols, this system offered several advantages. Firstly, this system reduced the side reactions that occurred during the classical Mitsunobu reaction, improved the atom efficiency and reduced the reaction cost, because the raw material TPPO is an industrial by-product of the production of various chemicals and has the characteristic of being widely available, and at the end of this reaction, TPPO could be recycled and only CO, CO 2 and HCl are wasted. Secondly, the corresponding esters could be generated with excellent yields in mild and neutral conditions, and can be applied to some substrates bearing sensitive groups in contrast to esterification via the formation of acid chloride. Finally, this system has simple experimental operation at the end of the reaction and the reaction liquid was purified by column chromatography directly. Moreover, we also proposed a plausible mechanism according to 31 P NMR spectroscopy. In our laboratory, we will conduct further investigation of the modified reaction system to extend the application of TPPO.