Direct α-halogenation of carboxylic acids with N-bromosuccinimide (NBS) or trichloroisocyanuric acid (TCCA) in the presence of catalytic amounts of 4-trifluoromethylbenzoic anhydride and H₂SO₄

Abstract

α-Halogenation of carboxylic acids with N-bromosuccinimide (NBS) or trichloroisocyanuric acid (TCCA) in the presence of catalytic amounts of 4-trifluoromethylbenzoic anhydride and H₂SO₄ in 1,2-dichloroethane was devised. The method does not need prior conversion to acyl chlorides, and the reactions could be applied to a gram-scale synthesis.

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Halogenation of organic substrates such as ketones,¹ aromatics,² double bonds³ and allyl compounds⁴ is a widely employed and significant transformation in synthetic organic chemistry, because the resulting halogenated compounds serve as valuable synthetic intermediates for diverse subsequent conversions.⁵ Among these reactions, α-halogenation of carboxylic acids also represents a particularly important process. However, this transformation is generally more difficult than halogenation of ketones due to the lower reactivity of the carbonyl group in carboxylic acids. Nevertheless, several methods for achieving α-halogenation of carboxylic acids have been developed.^5,6 A traditional example is the Hell–Volhard–Zelinsky (HVZ) reaction, which involves the use of Br₂ in the presence of a catalytic amount of P (red phosphorus) or PCl₃.⁷ While this method is effective, it typically requires long reaction times, high temperature and strict anhydrous conditions. Furthermore, Br₂ is difficult to handle and a large amount of HBr is generated. Alternative approaches which utilize SOCl₂ as a solvent have been devised.⁸ These reactions proceed more rapidly and work-up procedure is quite simple, but they require the in situ conversion of carboxylic acids to acyl chlorides and the hydrolysis of the resulting α-brominated acyl chlorides. This method causes the release of large amounts of toxic gases such as SO₂ and HCl by the decomposition of SOCl₂, raising concerns regarding a safety and environmental point.

α-Chlorination of carboxylic acids is more difficult than α-bromination.⁹ Although several methods have been reported until now, these reactions require longer reaction times than bromination and often cause undesired reactions. Moreover, Cl₂ gas is hazardous and more difficult to handle. An efficient procedure of the halogenation in SOCl₂ using N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or I₂ has been developed.¹⁰ NXS is advantageous due to their ease of handling and relatively mild reactivities. Notably, benzylic positions are not affected in this method. However, this method also needs the conversion of carboxylic acids to the corresponding acyl chlorides and the hydrolysis of the resulting α-halogenated acyl chlorides to regenerate carboxylic acids. Large amounts of toxic SO₂ and HCl gases are released by the decomposition of SOCl₂ during the reactions and work-up. Thus, direct and environmentally benign procedures using easy-to-handle reagents have been desired to develop.

In this paper, we report a direct method for the α-halogenation of carboxylic acids using NBS or trichloroisocyanuric acid (TCCA) in the presence of catalytic amounts of 4-trifluoromethylbenzoic anhydride (8) and H₂SO₄ in 1,2-dichloroethane (DCE).

First, we examined the α-bromination of hexanoic acid (1) using 1.1 mmol of NBS in the presence of catalytic amounts of various additives and TsOH·H₂O in DCE. The results are summarized in Table 1. In the presence of I₂ which is known to catalyse α-halogenation of carboxylic acids,^8a no reaction occurred (entry 2). Similarly, I₂-copper salts¹¹ which are effective additives in the α-iodination of carboxylic acids, failed to promote the reaction (entries 3 and 4). 2-Chloro-1-methylpyridinium iodide (3)¹² and 3,5-bis(trifluoromethyl)phenylboronic acid (4)¹³ which activate carboxylic acids in esterification and amidation, respectively, also showed no activity (entries 5 and 6).

Table 1 α-Bromination of 1 with NBS in the presence of some additives^a

Entry	Additive	NBS (mmol)	Acid	Time (h)	Yield^b (%)
a Reaction conditions: 1 (1.0 mmol), acid, additive, NBS, DCE (0.5 mL), 80 °C. b Determined by ^1H NMR spectroscopy based on 1. c MeCN was used instead of DCE. d CH3(CH2)4COOMe (1.0 mmol) was used instead of 1.
1	None	1.1	TsOH·H2O (10 mol%)	2	0
2	I2	1.1	TsOH·H2O (10 mol%)	2	0
3	CuCl	1.1	TsOH·H2O (10 mol%)	2	0
4	CuCl2	1.1	TsOH·H2O (10 mol%)	2	0
5		1.1	TsOH·H2O (10 mol%)	2	0
6		1.1	TsOH·H2O (10 mol%)	2	0
7		1.1	TsOH·H2O (10 mol%)	2	0
8		1.1	TsOH·H2O (10 mol%)	2	0
9		1.1	TsOH·H2O (10 mol%)	2	0
10		1.1	TsOH·H2O (10 mol%)	2	52
11		1.5	TsOH·H2O (10 mol%)	5	68
12		2.0	TsOH·H2O (10 mol%)	5	92
13		2.2	TsOH·H2O (10 mol%)	4	100
14		1.1	H2SO4 (10 mol%)	1.5	79
15		1.3	H2SO4 (10 mol%)	2.5	91
16		1.4	H2SO4 (10 mol%)	3	100
17		2.8	H2SO4 (10 mol%)	4	100
18		1.4	—	3	0
19		1.4	H2SO4 (5 mol%)	3	73
20^c		1.4	H2SO4 (10 mol%)	3	35
21^d		1.4	H2SO4 (10 mol%)	10	0

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We further explored the reactions using catalytic amounts of benzoic anhydrides 7¹⁴ and 8¹⁵ bearing electron-withdrawing substituents on the benzene ring, anticipating the activation of carbonyl groups in carboxylic acids (entries 9 and 10). Indeed, the use of anhydride 8 afforded the desired product 2 (2 h, 52%) (entry 10). In contrast, anhydride 7 did not produce 2, probably due to steric hindrance caused by the ortho-substituted nitro and methyl groups during the bromination process although bearing a nitro group as an electron-withdrawing substituent (entry 9).¹³ 2.2 equivalents of NBS were required for complete conversion when TsOH·H₂O was used (entry 13).

It would be attributed to the hydrolysis of 8 to the corresponding carboxylic acid. We employed H₂SO₄ which does not possess water of crystallization, so that the reaction proceeded faster to give the product 2 in better yield (79%) within the shorter reaction time (1.5 h) (entry 14). Complete bromination realised with 1.4 equivalents of NBS (entry 16). The use of a large excess amount of NBS (2.8 equivalents) exclusively led to monobromide 2 with no detectable formation of the α,α-dibromo derivative (entry 17). No reaction was observed in the absence of H₂SO₄ (entry 18). When MeCN was used as a solvent, the reaction proceeded more slowly (entry 20). It is noteworthy that the methyl ester of 1 was unreactive under the employed conditions (entry 21).

Next, the α-bromination of various carboxylic acids was carried out using 1.4 equivalents of NBS. As shown in Table 2, most of the corresponding α-bromides except 12 were produced in excellent yields. During the reactions, the formation of a small amount of molecular bromine was observed. Carboxylic acids bearing electron-withdrawing groups such as the bromo substituent as well as α,α-disubstituted ones, required longer reaction times to achieve satisfactory conversions (entries 7–9). Because the bromination of 3-phenylpropanoic acid (18) gave a large amount of dibromide 14 (50%) (entry 5), we conducted the reaction using 1.05 equivalents of NBS. Under the conditions, bromination occurred preferentially at the benzylic position via the radical mechanism (entry 6). In the HVZ procedure of compound 18, it has been reported that a mixture of compounds 12 and 13 yielded.¹⁶

Table 2 α-Bromination of various carboxylic acids with NBS^a

Entry	Time (h)	Product	Yield^b (%)
a Reaction conditions: carboxylic acid (1.0 mmol), H2SO4 (10 mol%), anhydride 8 (10 mol%), NBS (1.4 mmol), DCE (0.5 mL), 80 °C. b Isolated yield. c NBS (1.05 mmol). d Determined by ^1H NMR spectroscopy based on the starting material.
1	5		88 (100)^d
2	3		87 (100)^d
3	3		91 (100)^d
4	5		89 (100)^d
5	4
6^c	1.5	(13)^d	(69)^d	(17)^d
7	10		80 (90)^d
8	9		87 (100)^d
9	10		87 (100)^d

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The chlorination of compound 18 under various conditions was investigated (Table 3). We compared the reactions under normal, solvent-free¹⁷ and highly concentrated¹⁸ conditions (entries 1–6). TCCA exhibited higher reactivity than NCS in every case although it also afforded the benzylic substitution product 20. Under highly concentrated conditions, chlorination proceeded most rapidly (entry 6). The prolonged reaction using TCCA led to almost quantitative conversion (entry 9), whilst the prolonged reaction using NCS did not increase the yield (entry 8). An attempt to accelerate the reaction by the addition of 10 mol% of I₂ under normal conditions resulted in the low yields of 19 and 20 in spite of the accelerating effect of I₂ (entry 10).

Table 3 α-Chlorination of carboxylic acid under various conditions^a

Entry	Reagent	DCE (mL)	19 (%)	20 (%)
a Conditions: 18 (1.0 mmol), H2SO4 (10 mol%), anhydride 8 (10 mol%), reagent (2.4 equiv.), 60 °C, 20 min, 80 °C, 4 h. b Determined by ^1H NMR spectroscopy based on 18. c 60 °C, 20 min, 80 °C, 8 h. d 60 °C, 20 min, 80 °C, 14 h. e I2 (10 mol%) was added.
1	NCS	0.5	12	0
2	TCCA	0.5	10	7
3	NCS	—	8	0
4	TCCA	—	31	30
5	NCS	0.1	19	0
6	TCCA	0.1	32	40
7^c	TCCA	0.1	41	47
8^d	NCS	0.1	17	0
9^d	TCCA	0.1	43	50
10^d^,^e	TCCA	0.5	9	12

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The results for the α-chlorination of various carboxylic acids are summarized in Table 4. Since the chlorination proceeded more slowly than bromination, 2.4 equivalents of chlorinating reagents were employed.^10a Most of the α-chlorinated compounds except 19 and 27 were produced in excellent yields using TCCA under highly concentrated conditions. During the reactions, the formation of a small amount of chlorine was observed, which was detected by DPD (diethyl-p-phenylenediamine) and syringaldazine (3,5-dimethoxy-4-hydroxybenzaldazine) methods. Carboxylic acids bearing electron-withdrawing substituents such as the chloro group as well as α,α-disubstituted ones, required longer reaction times (entries 6–8). The addition of 10 mol% of I₂ increased the yield of 27 probably due to the formation of more active ICl (entry 9).^2f,19 The prolonged reaction did not improve the yield (entry 10). α-Iodination of carboxylic acid 18 using N-iodosuccinimide (NIS) or I₂ was examined at 80 or 130 °C under normal, solvent-free and highly concentrated conditions, but the reactions did not occur (SI, Table S1).

Table 4 α-Chlorination of various carboxylic acids with TCCA^a

Entry	Time (h)	Product	Yield^b (%)
a Reaction conditions: carboxylic acid (1.0 mmol), H2SO4 (10 mol%), anhydride 8 (10 mol%), TCCA (0.8 mmol), DCE (0.1 mL), 80 °C. b Isolated yield. c 60 °C, 20 min, 80 °C, 14 h. d I2 (10 mol%) was added. e 60 °C, 20 min, 80 °C, 24 h. f 60 °C, 20 min, 80 °C, 96 h. g Determined by ^1H NMR spectroscopy based on the starting material.
1	12		87 (96)^g
2	10		92 (100)^g
3^c	14
4	12		83 (93)^g
5	12		93 (l00)^g
6	15		85 (96)^g
7	27		88 (93)^g
8	24
9^d^,^e	24	(44)^g
10^d^,^f	96	(48)^g

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α-Bromination could also be performed under highly concentrated conditions.¹⁸ The results are summarised in Table 5. On the other hand, under solvent-free conditions, the reaction mixture did not form a melt at 80 °C because of the insolubility and high melting point of NBS (175–178 °C). All α-brominated carboxylic acids except 12 were produced in good yields under highly concentrated conditions. Under these conditions, the amount of the solvent could be reduced. When compound 18 was brominated, α-brominated carboxylic acid 12 was formed in a higher yield (53%) compared with the reaction under normal conditions probably due to the increased polarity resulting from the smaller amount of less polar solvent DCE (entry 5). In these cases, carboxylic acids bearing electron-withdrawing groups such as bromo as well as α,α-disubstituted ones, also required longer reaction times (entries 6–8).

Table 5 α-Bromination of various carboxylic acids under highly concentrated conditions^a

Entry	Time (h)	Product	Yield^b (%)
a Reaction conditions: carboxylic acid (1.0 mmol), H2SO4 (10 mol%), anhydride 8 (10 mol%), NBS (1.4 mmol), DCE (0.1 mL), 80 °C. b Isolated yield. c NBS (1.05 mmol). d Determined by ^1H NMR spectroscopy based on the starting material.
1	5		86 (100)^d
2	4		88 (100)^d
3	3		86 (100)^d
4	5		85 (100)^d
5^c	1
6	7		77 (88)^d
7	7		86 (100)^d
8	7		89 (100)^d

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In order to expand the scope of this method, the current procedure was successfully scaled up to 20-fold. Under these conditions, bromides 2 and 17 as well as chlorides 24 and 26 could be isolated in good yields without any difficulty (2: 4.5 h, 90%, 17: 15 h, 90%, 24: 18 h, 94%, 26: 40 h, 86%).

The reaction of 1 under the employed conditions was monitored by ¹H NMR spectroscopy. As shown in Fig. 1, the bromination using NBS was much faster than that using Br₂, indicating that most of the α-bromination was mediated by NBS rather than liberated Br₂.

Fig. 1 Comparative bromination of 1 using NBS and Br₂.

A plausible mechanism for bromination is depicted in Scheme 1.^9c Carboxylic acid A undergoes an equilibrium with the catalyst 8, affording the corresponding mixed anhydride C and compound B.²⁰ In the presence of a catalytic amount of H₂SO₄, mixed anhydride C is transformed to its enol form D, which subsequently undergoes the bromination with NBS to generate E. The intermediate E reacts with A to yield the α-brominated product F along with the regeneration of mixed anhydride C.

Scheme 1 Plausible mechanism for the α-bromination of carboxylic acids.

In order to verify the involvement of an enol intermediate in the catalytic cycle, H/D scrambling experiments were conducted in the presence of CD₃OD. Under the reaction conditions without halogenating agents, 12% deuterium incorporation at the α-position of the produced CD₃ ester of 1 was observed. This is considered to be formed before esterification of 1.

In conclusion, an efficient procedure for the α-halogenation of carboxylic acids was realised using NBS or TCCA in the presence of catalytic amounts of 4-trifluoromethylbenzoic anhydride and H₂SO₄. This method does not require prior conversion of carboxylic acids to the corresponding acyl chlorides, nor the hydrolysis of the resulting α-halogenated acyl chlorides. The process does not release a large amount of toxic gas such as SO₂ or HCl. In addition, NBS and TCCA are convenient and easy to handle, and furthermore, the use of highly toxic and corrosive reagents such as PCl₃ and SOCl₂etc. is avoided.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5ob01483b.

Acknowledgements

We thank CCRF, Institute for Research Promotion, Niigata University for NMR measurements.

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