Efficient Dibromination of Aromatics with Fe(NO₃)₃·9H₂O/FeBr₃

Abstract

A simple, efficient, and environmentally friendly methodology for the dibromination of anisoles using Fe(NO₃)₃·9H₂O/FeBr₃ at room temperature was developed. In general, anisoles bearing electron-donating or weak electron-withdrawing groups gave the dibrominated product in good to excellent yields, while anisoles bearing a strong electron-withdrawing group gave a high yield of the monobromination product. This protocol was also suitable for the bromination of 2- or 4-substituted substrates. Importantly, this protocol was also applicable for gram-scale synthesis. It is hopeful that this methodology will have great use in organic synthesis.

Key words

dibromination - Fe(NO₃)₃·9H₂O - FeBr₃ - anisoles - mild conditions

Brominated aromatic compounds are valuable building blocks in organic chemistry, when considering their important role in transition-metal-mediated cross-coupling reactions[1] and that they are widely employed in medical chemistry[2] and materials science.[3] The development of efficient and mild methods for the bromination of aromatic compounds is an intensively investigated area of great significance. The processes use electrophilic brominating reagents with the bromide ion as the primary brominating source;[4] the bromide ion can also be used with an oxidant.[5] Meanwhile, there are other ways including transition-metal-catalyzed bromination[6] and radical bromination.[7] Traditionally, the most common brominating source was Br₂, which is toxic, dangerous for the environment and the operator, and difficult to handle. Also, NBS (N-bromosuccinimide) is an alternative to a minor extent with respect to Br₂.[8] In recent years, considerable attention has been paid to the development of new route for the construction of halogenated scaffolds and safe and readily available halide sources, such as alkali metal halides (halide = I, Br, Cl), have been reported.[5a] [9] But most reports have focused on the monobrominated of arenes with the dibrominated product generally as the side product under the reaction conditions.[10]

Dihaloarenes are also crucial substrates for the preparation of drug frameworks and are useful synthetic intermediates for some organic materials.[11] There are a few reports on the straight synthesis of dihaloarenes. Neella and co-workers reported the thermoregulated highly regioselective mono- and dihalogenations of phenols and anilines in water employing new Lewis base adducts (LBAs) [DBUBr]⁺Br^– and [DBUI]⁺I^– as green reagents.[12] The Maegawa group developed a novel dihalogenation method using a combination of N-halosuccinimides and PhSTMS or PhSSPh under mild reaction conditions.[13] In 2024, an operationally simple electrochemical protocol for the dibromination of aromatic amines with 1,2-dibromoethane under constant current electrolysis at room temperature in the absence of a metal catalyst or an external oxidant was reported; the reaction was conducted with hexafluoroisopropanol (HFIP)/tetrabutylammonium tetrafluoroborate (TBATFB) a under nitrogen atmosphere.[14] Meanwhile, some other routes for the synthesis of dibrominated products utilized dehydroxymethyl bromination,[15] decarboxyl bromination,[16] and further bromination of monobrominated aromatics.[10b] [d] Recently, we developed a simple, efficient and environmentally friendly methodology for the halogenation of anisoles using Fe(NO₃)₃·9H₂O/KBr or NaI at room temperature for 2 h. We also found that Fe(NO₃)₃·9H₂O combined with bromine salts also successfully afforded 4-bromoanisole, while using Fe(NO₃)₃·9H₂O/FeBr₃ gave a large amount of dibromoaromatic compound as a side product.[17] Herein, we report the direct synthesis of dibromoaromatic compounds in one-step with high yield and high selectivity. It was found that Fe(NO₃)₃·9H₂O/FeBr₃ was efficient for the synthesis of dibromoarenes from anisole under room temperature for 5 h. m-Substituted anisoles were obtained in high to excellent yields, except those containing a strong electron-withdrawing group that produced the monobromoaromatic product. Meanwhile, for the substrates with an o- or p-halogen group were transformed into the corresponding dibromination product in high to excellent yields. In addition, this protocol was readily scaled up to 15-mmol scale without loss its efficiency.

Table 1 The Optimization of Dibromination of Anisole^a

Entry	M-Br	Additive	Solvent	Time (h)	Yield (%) of 1/2
1	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	58/39b
2	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	77/20c
3	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	85/13d
4	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	99/0
5	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	78/16e
6	FeBr3	Fe(NO3)3·9H2O	CH3CN	5	70/25f
7	FeBr3	Ce(NO3)3·6H2O	CH3CN	5	0/8
8	FeBr3	Cu(NO3)2	CH3CN	5	60/21
9	FeBr3	Co(NO3)2	CH3CN	5	39/40
10	FeBr3	FeCl3	CH3CN	5	0/9
11	FeBr3	Fe2(SO4)3	CH3CN	5	0/6
12	KBr	Fe(NO3)3·9H2O	CH3CN	5	0/14g
13	NaBr	Fe(NO3)3·9H2O	CH3CN	5	0/14g
14	LiBr	Fe(NO3)3·9H2O	CH3CN	5	0/20g
15	CuBr2	Fe(NO3)3·9H2O	CH3CN	5	0/95h
16	FeBr3	Fe(NO3)3·9H2O	H2O	5	2/42
17	FeBr3	Fe(NO3)3·9H2O	DMSO	5	3/41
18	FeBr3	Fe(NO3)3·9H2O	DMF	5	3/48
19	FeBr3	Fe(NO3)3·9H2O	NMP	5	3/47
20	FeBr3	Fe(NO3)3·9H2O	hexane	5	24/55
21	FeBr3	Fe(NO3)3·9H2O	CH2Cl2	5	42/37
22	FeBr3	Fe(NO3)3·9H2O	EtOAc	5	15/65
23	FeBr3	Fe(NO3)3·9H2O	MeOH	5	4/54
24	FeBr3	Fe(NO3)3·9H2O	EtOH	5	3/43
25	FeBr3	Fe(NO3)3·9H2O	CH3CN	4	94/2
26	FeBr3	Fe(NO3)3·9H2O	CH3CN	3	86/12
27	FeBr3	Fe(NO3)3·9H2O	CH3CN	6	90/0

^a Conditions: substrate (0.5 mmol), Br source (0.7 mmol), additive (0.125 mmol), CH₃CN (3 mL), r.t., 5 h, unless otherwise stated. GC yield.

^b Br source (0.4 mmol).

^c Br source (0.5 mmol).

^d Br source (0.6 mmol).

^e Additive (0.1 mmol).

^f Additive (0.075 mmol).

^g Br source (2.1 mmol).

^h Br source (1.05 mmol)

At the outset of our investigation, the optimization of dibromination of anisole (0.5 mmol) with Fe(NO₃)₃·9H₂O/FeBr₃ was studied in various ratios in CH₃CN for 5 h at room temperature (Table [1], entries 1–6). To our delight, the ratio of dibromination/monobromination product increased with increasing of amount of FeBr₃, giving the desired product in appreciable conversion. More importantly, 2,4-dibromo-1-methoxybenzene was the only product using Fe(NO₃)₃·9H₂O (0.125 mmol)/FeBr₃ (0.75 mmol), and no 4-dibromo-1-methoxybenzene was observed (Table [1], entry 4). Then, by lowering the amount of Fe(NO₃)₃·9H₂O, the selectivity and yield of desired product did not improved, however, a large amount of the monobrominated product was produced (Table [1], entries 5 and 6). Other types of nitrates (Ce(NO₃)₃·6H₂O, Cu(NO₃)₂, Co(NO₃)₂), Fe sources (FeCl₃, Fe₂(SO₄)₃), and other metal bromides (KBr, NaBr, LiBr, CuBr₂) did not give better results than the combination of Fe(NO₃)₃·9H₂O/FeBr₃ (Table [1], entries 7–15). The reaction was less efficient when conducted in other solvents, including H₂O, NMP, DMSO, MeOH, EtOH, EtOAc, and n-hexane, while in those solvents, the monobrominated product was the main product (Table [1], entries 16–24). For the reaction time, it was shown that the best yield and selectivity was offered at the reaction hold for 5 h (Table [1], entries 4 and 25–27).

With the optimal reaction conditions in hand, next we moved to explore the substrate scope for this dibromination reaction. Gratifyingly, it was obvious that the yield of dibrominated product was not effected by the length of alkyl chain of the alkoxy group (Table [2], entries 1–4). All of the reactions of the electron-donating alkyl phenyl ethers proceeded smoothly to give the corresponding o,m-dibrominated product in excellent yields. Isopropoxybenzene, containing a sterically hindered group also offered the desired product in 98% yield. For the analogues containing a strong electron-donating group gave the dibromination product in excellent yields, except 1,4-dimethoxybenzene, which gave 1,4-dimethoxy-2-nitrobenzene as the main product (Table [2], entries 5–9). Anisoles containing a weak electron-donating group also gave the desired dibromination product but at a different position with respect to the position of methoxy group (Table [2], entries 10–12). For example, 4-methylanisole gave only 2-bromo-1-methoxy-4-methylbenzene as the monobromination product in 90% yield, while 2-methylanisole gave 4-bromo-1-methoxy-2-methylbenzene as the monobromination product in 66% yield together with 1,5-dibromo-2-methoxy-3-methylbenzene as the dibromination product in 19% yield. 3-Methylanisole gave two different dibromination products in 95% yield. Importantly, increasing the reaction time to 7 h for 2-methylanisole gave the dibromination product in 91% yield.

Table 2 Dibromination of Anisole-Type Substrates^a

Entry	Substrate	Product	Yield (%)
1		2,4-dibromo-1-methoxy­benzene	>99/92b
2		2,4-dibromo-1-ethoxy­benzene	>99/91b
3		2,4-dibromo-1-isopropoxybenzene	98/93b
4		2,4-dibromo-1-butoxy­benzene	>99/92b
5		1,2-dibromo-4,5-dimethoxybenzene	92/88b
6		1,5-dibromo-2,4-dimethoxybenzene	99/90b
7		1,4-dimethoxy-2-nitro­benzene	68/50b
		1,4-dibromo-2,5-dimethoxybenzene	32/25b
8		6,7-dibromo-2,3-dihydro­benzo[b][1,4]dioxine	>99/94b
9		5,6-dibromobenzo[d][1,3]dioxole	98/89b
10		4-bromo-1-methoxy-2-methylbenzene­	66/<1c
		1,5-dibromo-2-methoxy-3-methylbenzene	19/91c
11		1,3-dibromo-4-methoxy-2-methylbenzene	78
		1,5-dibromo-2-methoxy-4-methylbenzene	19
12		2-bromo-1-methoxy-4-methylbenzene­	90/86b
13		4-bromo-1,2-dimethyl­benzene	94
14		1-bromo-2,4-dimethyl­benzene	88
15		2-bromo-1,4-dimethyl­benzene	83
16		2,4-dibromo-1,3,5-trimethylbenzene	96/91b
17		–	<1
18		–	<1
19		N-(4-bromophenyl)acetamide	47/19d
		(2,4-dibromophenyl)acetamide	46/52d
20		1,2-dibromo-4-methoxy­benzene	32
		1,2,3-tribromo-4-methoxybenzene	23/39d
		1,2,4-tribromo-5-methoxybenzene	41/61d
21		1-bromo-2-chloro-4-methoxybenzene­	28
		1,5-dibromo-2-chloro-4-methoxybenzene­	52/70d
		1,3-dibromo-2-chloro-4-methoxybenzene­	17/28d
22		2-bromo-5-methoxy­benzaldehyde	97/74d
		2,6-dibromo-3-methoxybenzaldehyde	<1/23d
23		methyl 2-bromo-5-methoxybenzoate	91/37d
		methyl 2,6-dibromo-3-methoxybenzoate­	6/60d
24		1-bromo-4-methoxy-2-(trifluoromethyl)benzene­	98d/93b
25		2-bromo-5-methoxy­benzonitrile	97d/92b
26		–	NR

^a Conditions: substrate (0.5 mmol), Br source (0.7 mmol), additive (0.125 mmol), CH₃CN (3 mL), r.t., 5 h, GC yield.

^b Isolated yield.

^c 60 °C, 7 h.

^d 60 °C, 5 h.

Moreover, we next investigated the scope of the reaction with 2- or 4-substituted substrates; the results are summarized in Table [3]. All reactions of 2- or 4-halogen substituted substrates were conducted under standard conditions and in most cases they were transformed into the monobromination product in high to excellent yields (Table [3], entries 1–5). For 2-iodoanisole and 4-iodoanisole, some halogen exchanged product was obtained to give 2,4-dibromoanisole (Table [3], entries 6 and 7); this is similar to previous results.[18] We also tested other substrates with medium electron-withdrawing groups in the 2-position, the desired products with 4-Br substitution were also obtained in high to excellent yields after a longer reaction time (Table [2], entries 8–10). 2-Chloro- and 2-(trifluoromethyl)benzamides gave p-substituted products in 95% and 71% yield (Table [3], entries 11 and 12).

o-, m-, and p-Xylenes gave high yields of the monobromination product, while mesitylene gave the dibromination product in 96% yield under these conditions (Table [2], entries 13–16). We also tested phenol and aniline under the reaction conditions; the reaction did not take place, which may be attributed complexation of -NH₂ and -OH groups with iron ions (Table [2], entries 17 and 18). It should be noted that benzamide was found to be compatible with this protocol, offering the monobromination product (47%) and the dibromination product (19%) (Table [2], entry 19).

With these results in hand, we utilized 3-substituted anisoles to further explore the substrate scope. 3-disubstituted anisoles containing a weak electron-withdrawing group, like -Cl or -Br, gave the dibromination product in excellent yields at 60 °C for 5 h. 3-Bromoanisole gave 2,3,4-tribromoanisole (39%) and 2,4,5-tribromoanisole (61%), while 3-chloroanisole gave 1,3-dibromo-2-chloro-4-methoxybenzene (28%) and 1,5-dibromo-3-chloro-2-methoxybenzene (70%) (Table [2], entries 20 and 21). For 3-substituted substrates with medium electron-withdrawing group, like -CHO, -COOCH₃, the desired products were obtained in low to moderate yields under the optimized reaction conditions (Table [2], entries 22 and 23). 3-Substituted substrates containing a strong electron-withdrawing group (CF₃, CN) gave sluggish reactions that gave the dibromination product at higher temperatures (Table [2], entries 24 and 25). But unfortunately, the heteroarene 4-methoxypyridine did not react under the standard conditions (Table [2], entry 26).

Table 3 Bromination of 2- or 4-Substituted Substrates^a

Entry	Substrate	Product	Yield (%)
1		4-bromo-2-chloro-1-methoxybenzene­	94/90b
2		2-bromo-4-chloro-1-methoxybenzene­	90/86b
3		2-bromo-4-fluoro-1-methoxybenzene­	88/83b
4		2,4-dibromo-1-methoxybenzene	99
5		2,4-dibromo-1-methoxybenzene	95
6		4-bromo-2-iodo-1-methoxybenzene	65
		2,4-dibromo-1-methoxybenzene	34
7		2-bromo-4-iodo-1-methoxybenzene­	17
		2,4-dibromo-1-methoxybenzene	80
8		5-bromo-2-methoxybenzaldehyde	63/93c
9		1-(5-bromo-2-methoxyphenyl)ethan-1-one	81
10		methyl 5-bromo-2-methoxybenzoate­	71/93d
11		N-(4-bromo-2-chlorophenyl)acetamide	95
12		N-(4-bromo-2-(trifluoromethyl)phenyl)acetamide	71/65b

^a Conditions substrate (0.5 mmol), Br source (0.7 mmol), additive (0.125 mmol), CH₃CN (3 mL), r.t., 5 h, GC yield.

^b Isolated yield.

^c 60 °C, 5 h.

^d 60 °C, 10 h.

Importantly, this dibromination could be easily scaled up to gram level. For anisole and 1,2-dimethoxybenzene (Scheme [1]), the reaction was scaled up to 20 mmol to give the corresponding dibromination products in 92% (4.9 g) and 90% (5.4 g) isolated yields, respectively. This advantage makes this present method more attractive for large-scale production dibromination in organic synthesis.

Scheme 1 Scale-up of the dibromination reaction

Meanwhile, the generally accepted radical scavengers in organic chemistry, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) were added to the reaction with anisole. It was found that the addition of TEMPO and BHT did not prevent the bromination process (Table S1). Although, the dibrominated product was not obtained when TEMPO (1 equiv.) or BHT (0.75 equiv.) was added, the monobromination product was still obtained in 86% and 46% yield, respectively. We also examined the reaction of 4-bromoanisole with TEMPO or BHT under the standard conditions and found that the yield of bromination product decreased with increasing amount of radical scavenger.[19] Hence 5% yield of dibromination product was obtained in the present of 1 equivalent of TEMPO (Table S2), while 23% yield of dibromination product was obtained in the present of 1 equivalent of BHT. In other word, this reaction may not take place through radical pathway and it is possible that it occurs by a typical electrophilic bromination to a large extent.

In conclusion, we have developed a novel dibromination method using a combination of Fe(NO₃)₃·9H₂O and FeBr₃ under mild reaction conditions. This method was shown to be applicable to most of anisoles with strong and weak electron-donating groups and anisoles with weak electron-withdrawing group. For anisoles with middle strong electron-withdrawing group, the reaction requires longer reaction times or higher temperature to achieve an excellent yield. But for the substrate with strong electron-withdrawing group, the main product was the monobromination product. Furthermore, this reaction proceeds under mild conditions and employs solid reagents that are relatively low odor and easy to handle. Further, this approach was scalable to gram level, offering an attractive opportunity for further applications in organic synthesis. Moreover, the elucidation of the reaction mechanism was not clear enough and broadening of the application space to similar reactions are currently underway.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 04 October 2025

Accepted after revision: 09 December 2025

Accepted Manuscript online:
11 December 2025

Article published online:
20 January 2026