A practical chlorination of tert -butyl esters with PCl 3 generating acid chlorides

Abstract

For the first time, using PCl₃, a range of tert-butyl esters is chlorinated successfully, allowing access of both aromatic acid chlorides and aliphatic acid chlorides in good yields. The method features simple reaction conditions and wide substrate scope. Various tert-butyl esters including aryl esters, alkenyl esters, and alkyl esters were tolerated well in the reaction. A plausible mechanism is proposed.

Keywords

acid chlorides chlorinating reagent chlorination phosphorus trichloride

Introduction

Acid chlorides (RCOCl) are important intermediates in organic synthesis and are widely used in agricultural chemicals, medicines, dye industries, and so on.^1–4 RCOCls are commonly prepared from reactions of the corresponding carboxylic acids or anhydrides with chlorinating reagents such as oxalyl chloride,^5–7 thionyl chloride,^8–10 phosphorus oxychloride,¹¹ phosphorus pentachloride,^12,13 and triphosgene.¹⁴ In addition to the above well-known methods for preparing acid chlorides from carboxylic acids, there are only a few literature reports on the conversion of other functional groups into acid chlorides directly.^15–18 Among them, a few examples of the conversion of tert-butyl esters into the corresponding acid chlorides were demonstrated.^19–22 However, the chlorinating reagent was limited to thionyl chloride and a large excess was required in the reaction. Therefore, the development of practical, green, and simple methods for the conversion of esters into acid chlorides is still desirable.

Phosphorus trichloride (PCl₃) is a cheap and readily available industrial chemical. Although one molecule of PCl₃ may provide three chlorine atoms for chlorination, there are few examples using PCl₃ for chlorination and most of them are limited to the conversion of carboxylic acids into acid chlorides.^23–26 We were interested in the potential of PCl₃ for the conversion of esters into the corresponding acid chlorides. Herein, we report a practical and simple method for the chlorination of tert-butyl esters with PCl₃, allowing access to various acid chlorides. Notably, good yields of the desired products could be obtained even when 0.667 equiv. of PCl₃ were used in gram-scale reactions.

Results and discussion

We started this work with the reaction of tert-butyl benzoate (1a) with PCl₃. As shown in Table 1, an 86% yield of benzoyl chloride was generated at 80 °C under N₂ by mixing 1a and PCl₃ for 3 h (entry 1). Delightfully, a 98% yield of 2a was obtained when the mixture was stirred under air in a 25-mL sealed tube (entry 2). Further screening of the solvent did not improve the reaction efficiency (entries 3–5). Notably, the reaction also proceeded smoothly under solvent-free conditions, albeit with a decreased yield (entry 6). Using 0.667 equiv. of PCl₃, the product was generated in 81% yield (entry 7), indicating that more than two Cl atoms from PCl₃ were utilized for the chlorination. In particular, when the reaction was scaled up to 10 mmol, an 83% yield of product was obtained even when 0.667 equiv. of PCl₃ was used in the reaction (entry 8).

Table 1.

Optimization of the reaction conditions.^a


Entry	Conditions	Solvent	Yield^b
1	N₂	CH₃CN	86%
2	Air	CH₃CN	98%
3	Air	THF	35%
4	Air	Toluene	75%
5	Air	CHCl₃	74%
6	Air	None	89%^c
7	Air	CH₃CN	81%^d
8	Air	CH₃CN	83%^e

Conditions: a mixture of 1a (0.3 mmol) and PCl₃ (0.3 mmol) in solvent (0.6 mL) was stirred at 80 °C for 3 h.

GC yield based on 1a using dodecane as an internal standard.

No solvent.

0.667 equiv. of PCl₃ were used.

10 mmol scale, 0.667 equiv. of PCl₃, CH₃CN (20 mL).

Bold: means the conditions listed in entry 2 is the optimum conditions.

With the optimum conditions identified, we next investigated the generality of this reaction. As shown in Table 2, various tert-butyl esters were efficiently chlorinated by PCl₃. Electron-rich aryl esters such as tert-butyl 4-methylbenzoate, tert-butyl 2,4,6-trimethylbenzoate, and tert-butyl 4-methoxybenzoate were compatible under the present reaction conditions, affording the corresponding acid chlorides (2b–d) in good-to-high yields. Esters with electron-withdrawing groups such as F, Cl, CF₃, and Ac on the benzene ring also reacted smoothly with PCl₃, giving the expected products 2e–h in good yields. A substrate bearing a vinyl group was also applicable in this chlorination reaction, furnishing the desired product 2i in 81% yield. The substrate scope was also extended to tert-butyl 2-naphthoate, and the expected product, 2-naphthoyl chloride (2j), was obtained in 70% yield under similar conditions. Moreover, tert-butyl cinnamate was tolerated well in this system to give product 2k. Another remarkable feature of this reaction is the successful chlorination of alkyl esters. For example, tert-butyl benzylic esters 1l and 1m and simple alkyl tert-butyl esters 1n and 1o reacted with PCl₃ readily to afford the desired products in good-to-excellent yields. However, when methyl, isopropyl, phenyl, and benzyl benzoate were subjected to the reaction, only trace amounts of the desired products were detected by gas chromatography–mass spectrometry (GC-MS).

Table 2.

Reactions of tert-butyl esters with PCl₃.^a

Conditions: 1 (1.3 mmol), PCl₃ (1.3 mmol), CH₃CN (2.0 mL), 80 °C, 3 h. Isolated yields of the product were based on three parallel reactions.

60 °C, 6 h.

100 °C.

To evaluate the difference in reactivity between different tert-butyl esters, the reactions of alkyl and aryl esters bearing different substituents (CF₃, F, H, and MeO) with PCl₃ were conducted. As shown in Scheme 1, only a trace amount of product was detected when electron-deficient tert-butyl 4-(trifluoromethyl)benzoate and PCl₃ were stirred in CH₃CN (0.6 mL) at 80 °C for 15 min. Tert-butyl 4-fluorobenzoate reacted with PCl₃; however, the yield was low (32%) compared to that obtained using tert-butyl benzoate (53% yield). In contrast, compared with tert-butyl benzoate, electron-rich tert-butyl 4-methoxybenzoate gave the product 2d in a higher yield (67%). Furthermore, tert-butyl hexanoate was chlorinated by PCl₃ successfully, furnishing the desired product in 90% yield. Thus, the reactivity of the benzoic esters follows an increasing order of CF₃ < F < H < OMe, that is, an electron-rich ester was more rapidly chlorinated by PCl₃ than an electron-deficient ester. In addition, it appears that alkyl esters have higher reactivity than aryl esters under this system.

Scheme 1.

Reactions of different tert-butyl esters with PCl₃.

To gain some insights into the reaction, two control experiments were performed. HCl (1.5 equiv.) was used instead of PCl₃ in the reaction and an 89% yield of PhCOOH was generated (equation 1). According to the literature,^27,28 an acid can react with PCl₃ to give the corresponding chloride. To confirm the critical role of HCl in the reaction, 2.0 equiv. of pyridine were added, with only a trace amount of product detected (equation 2). These results revealed that the corresponding acid generated from the acidolysis of the ester with HCl was probably the intermediate in the reaction.

Based on the above results and previous literature reports,^19,27,28 we speculated that there are two paths for the reaction. As shown in Scheme 2, one pathway involves the protonation of 1 by HCl generated from the reaction of PCl₃ with H₂O present in air or solvent (path a). The other is the complexation of 1 with PCl₃ followed by elimination of a tert-butyl cation (path b). The intermediates A and B which are produced during these two processes can react with (OH)_nPCl_3 − n (n = 0, 1, 2) or HCl to afford acid chlorides 2.

Scheme 2.

Plausible mechanism.

Conclusion

In summary, the conversion of various tert-butyl esters into acid chlorides was achieved using PCl₃ as the chlorinating reagent, providing a variety of acid chlorides in good-to-excellent yields. Unlike other methods using a large excess of the chlorinating reagent in the reaction, this approach features simple reaction conditions and no more than 1 equiv. of PCl₃ is used.

Experimental

Unless otherwise noted, all reagents were purchased from commercial suppliers and used without purification. All reactions were performed in 25-mL glass Schlenk tubes carried out under an air atmosphere. Visualization on thin layer chromatography (TLC) was achieved using UV light (254 nm). ¹H NMR and ¹³C NMR spectra were measured on a Bruker AV-II 500-MHz NMR spectrometer (¹H: 500 MHz, ¹³C: 125.76 MHz), using CDCl₃ as the solvent with tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in ppm and referenced to residual solvent peaks (CHCl₃ in CDCl₃: 7.26 ppm for ¹H and 77.0 ppm for ¹³C). The coupling constants (J) are given in Hz. GC-MS was conducted on a Shimadzu GCMS-QP2010 plus equipped with an EI ion source. A FULI GC9790II instrument equipped with flame ionization detector (FID) was used to analysis the reaction mixture.

Typical procedure for the reaction of tert-butyl esters with PCl₃ (yield based on three parallel reactions): under air, the esters (1.3 mmol) and PCl₃ (1.3 mmol) were added to a 25-mL dried Schlenk tube, followed by CH₃CN (2.0 mL). The sealed tube was heated at 80 °C for 3 h. After the reaction mixture had been cooled to room temperature, evaporation of the solvent under vacuum and distillation of the residue under reduced pressure gave the analytically pure acid chloride.

Note that the yields listed below are based on three parallel reactions and each reaction was performed on 1.3 mmol scale. The mass of the product is the total mass for three parallel reactions.

Benzoyl chloride (2a): Colorless oil, yield 96% (3.74 mmol, 526 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.15 (d, J = 7.5 Hz, 2H), 7.73–7.70 (m, 1H), 7.56–7.53 (m, 2H); ¹³C NMR (125.76 MHz, CDCl₃): δ 168.5, 135.4, 133.2, 131.5, 129.0. GC-MS (EI, 70 eV): m/z = 140 (M⁺).²⁹

4-Methylbenzoyl chloride (2b): Light yellow oil, yield 78% (3.04 mmol, 470 mg); ¹H NMR (500 MHz, CDCl₃): δ 7.99 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 168.0, 146.9, 131.6, 130.5, 129.7, 21.8. GC-MS (EI, 70 eV): m/z = 154 (M⁺).³⁰

2,4,6-Trimethylbenzoyl chloride (2c): Colorless oil, yield 49% (1.91 mmol, 349 mg); ¹H NMR (500 MHz, CDCl₃): δ 6.92 (s, 2H), 2.42 (s, 6H), 2.34 (s, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 170.7, 140.7, 136.3, 133.0, 128.6, 21.2, 19.4. GC-MS (EI, 70 eV): m/z = 182 (M⁺).³¹

4-Methoxybenzoyl chloride (2d): White solid, yield 76% (2.96 mmol, 506 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.10–8.08 (m, 2H), 6.99–6.97 (m, 2H), 3.92 (s, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 167.2, 165.4, 134.0, 125.4, 114.3, 55.8. GC-MS (EI, 70 eV): m/z = 170 (M⁺).³⁰

4-Fluorobenzoyl chloride (2e): Colorless oil, yield 91% (3.55 mmol, 563 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.19–8.16 (m, 2H), 7.24–7.20 (m, 2H); ¹³C NMR (125.76 MHz, CDCl₃): δ 167.1 (d, J_C-F = 258.9 Hz), 167.1, 134.3 (d, J_C-F = 9.9 Hz), 129.5, 116.3 (d, J_C-F = 22.1 Hz). GC-MS (EI, 70 eV): m/z = 158 (M⁺).³⁰

4-Chlorobenzoyl chloride (2f): Colorless oil, yield 89% (3.47 mmol, 607 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.08–8.06 (m, 2H), 7.51–7.50 (m, 2H); ¹³C NMR (125.76 MHz, CDCl₃): δ 167.4, 142.3, 132.6, 131.6, 129.4. GC-MS (EI, 70 eV): m/z = 175 (M⁺).³⁰

4-(Trifluoromethyl)benzoyl chloride (2g): Colorless oil, yield 88% (3.43 mmol, 716 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.27 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H); ¹³C NMR (125.76 MHz, CDCl₃): δ 167.6, 136.5 (q, J_C-F = 32.7 Hz), 136.2, 131.6, 126.1 (d, J_C-F = 3.8 Hz), 123.2 (q, J_C-F = 272.7 Hz). GC-MS (EI, 70 eV): m/z = 208 (M⁺).³²

4-Acetylbenzoyl chloride (2h): White solid, yield 76% (2.96 mmol, 541 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.15–8.13 (m, 2H), 8.00–7.99 (m, 2H), 2.60 (s, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 197.0, 167.9, 141.8, 136.5, 131.5, 128.6, 27.0. GC-MS (EI, 70 eV): m/z = 182 (M⁺).³⁰

4-Vinylbenzoyl chloride (2i): Light yellow oil, yield 81% (3.16 mmol, 526 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.02–8.01 (m, 2H), 7.47–7.46 (m, 2H), 6.77–6.71 (m, 1H), 5.93 (d, J = 17.5 Hz, 1H), 5.49 (d, J = 11.0 Hz, 1H); ¹³C NMR (125.76 MHz, CDCl₃): δ 167.8, 144.4, 135.4, 131.9, 131.9, 126.6, 118.6. GC-MS (EI, 70 eV): m/z = 166 (M⁺).³³

2-Naphthoyl chloride (2j): White solid, yield 70% (2.73 mmol, 520 mg); ¹H NMR (500 MHz, CDCl₃): δ 8.76 (s, 1H), 8.08–8.02 (m, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.73–7.69 (m, 1H), 7.65–7.62 (m, 1H); ¹³C NMR (125.76 MHz, CDCl₃): δ 168.5, 136.4, 134.8, 132.3, 130.4, 130.1, 129.9, 128.9, 127.9, 127.5, 125.3. GC-MS (EI, 70 eV): m/z = 190 (M⁺).³⁴

Cinnamoyl chloride (2k): White solid, yield 61% (2.38 mmol, 396 mg); ¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, J = 15.5 Hz, 1H), 7.61–7.59 (m, 2H), 7.53–7.45 (m, 3H), 6.68 (d, 16.0 Hz, 1H); ¹³C NMR (125.76 MHz, CDCl₃): δ 166.2, 150.8, 133.0, 132.1, 129.3, 129.1, 122.3. GC-MS (EI, 70 eV): m/z = 166 (M⁺).³⁵

2-(p-Tolyl)acetyl chloride (2l): White oil, yield 65% (2.54 mmol, 427 mg); ¹H NMR (500 MHz, CDCl₃): δ 7.06–7.01 (m, 4H), 3.95 (s, 2H), 2.22 (s, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 172.2, 138.1, 129.8, 129.5, 128.3, 52.8, 21.3. GC-MS (EI, 70 eV): m/z = 168 (M⁺).³⁶

2-Phenylpropanoyl chloride (2m): Light yellow oil, yield 78% (3.04 mmol, 513 mg); ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.42 (m, 2H), 7.40–7.37 (m, 1H), 7.35–7.33 (m, 2H), 4.17 (q, J = 7.0 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 175.7, 137.5, 129.2, 128.3, 128.0, 57.5, 18.8. GC-MS (EI, 70 eV): m/z = 168 (M⁺).³⁷

3-Phenylpropanoyl chloride (2n): Colorless oil, yield 57% (2.23 mmol, 375 mg); ¹H NMR (500 MHz, CDCl₃): δ 7.38–7.35 (m, 2H), 7.31–7.28 (m, 1H), 7.26–7.24 (m, 2H), 3.26 (t, J = 8.0 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H); ¹³C NMR (125.76 MHz, CDCl₃): δ 173.1, 138.7, 128.8, 128.4, 126.9, 48.6, 31.0. GC-MS (EI, 70 eV): m/z = 168 (M⁺).¹⁹

Hexanoyl chloride (2o): Colorless oil, yield 94% (3.67 mmol, 493 mg); ¹H NMR (500 MHz, CDCl₃): δ 2.90 (t, J = 7.5 Hz, 2H), 1.76–1.71 (m, 2H), 1.37–1.34 (m, 4H), 0.94–0.91 (m, 3H); ¹³C NMR (125.76 MHz, CDCl₃): δ 173.9, 47.1, 30.5, 24.8, 22.2, 13.8. GC-MS (EI, 70 eV): m/z = 134 (M⁺).³⁸

Supplemental Material

Supplementary_material – Supplemental material for A practical chlorination of tert-butyl esters with PCl₃ generating acid chlorides

Supplemental material, Supplementary_material for A practical chlorination of tert-butyl esters with PCl₃ generating acid chlorides by Xiaofang Wu, Lei Zhou, Ruoqi Yang, Fengzhe Guo, Zi-Long Tang and Jing Xiao in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: J.X. is grateful for financial support from the National Natural Science Foundation of China (21703061), the Natural Science Foundation of Hunan Province (2017JJ3081), and the Open Project Program of Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education (E21744).

ORCID iD

Jing Xiao

Supplemental material

Supplemental material for this article is available online.

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