Microwave-Assisted Debromination of α-Bromoketones with Triarylstibanes in Water

Abstract

Several α-bromoarylketones were reacted with triarylstibanes under microwave irradiation in water to obtain the corresponding debrominated ketones. Under similar reaction conditions, 1,2-elimination of vic-dibromides in water afforded the corresponding E-olefins. This reaction is the first example of organoantimony compounds utilized for organic transformation in water.

The chemistry of organic and inorganic antimony compounds has attracted significant attention in recent years.^1–3) In particular, trivalent organoantimony(III) compounds (stibanes) have been used for a wide variety of transformations such as alkylation of carbonyl compounds,⁴⁾ Pd-catalyzed cross-coupling reactions,^5–11) photochemical reaction,¹²⁾ catalytic oxidative cyclization,¹³⁾ and asymmetric reactions with optically active compounds.^14–18) Stibane reagents such as triphenylstibane have low toxicity,^19–21) and are therefore promising reagents in organic synthesis. Extensive studies have been carried out on the reductive dehalogenation reactions of α-halocarbonyl compounds using reagents such as active metals, low-valent metals, metal hydrides, and halide salts.^22–25) Among these, organoantimony reagents such as tributylstibane,²⁶⁾ triphenylstibane,²⁶⁾ diphenyl stibane,²⁷⁾ diphenylantimonymagnesium,²⁸⁾ and NaBH₄-SbBr₃ reagent²⁹⁾ are known. Akiba et al. have reported that tributylstibane is an efficient reagent for the debromination of phenacyl bromides.²⁶⁾ However, such aliphatic tertiary stibanes are unstable toward air and moisture. Therefore, their use is limited in routine organic synthesis. In contrast, triarylstibanes are easier to handle, exhibit low toxicity, and are readily available. Unfortunately, debromination of phenacyl bromides using triphenylstibane reportedly requires a long reaction time (6 d) and the substrate scope of this reaction also remains unclear.²⁶⁾ Owing to the environmental benefit and favorable effect of water on chemical transformations, it is desirable, albeit challenging, to perform organic reactions in aqueous media. However, only a limited number of examples of dehalogenation reactions of α-halo carbonyl compounds have been reported in literature with water as the reaction solvent.^30–33) As the microwave irradiation has been successfully applied for performing organic syntheses in aqueous solution,^34–40) we investigated the microwave-assisted debromination of α-bromoketones with triarylstibane reagents in water.

As the starting point for optimization studies, the dehalogenation of phenacyl halides 1a and 2a with triarylstibanes 3a–c was examined in the presence of a proton source based on the reaction solvent used. The results of these reactions and a comparison between conventional heating and microwave irradiation methods (Methods A and B, respectively) are summarized in Table 1. In the case of conventional heating (Method A, entries 1–4), the treatment of phenacyl bromide 1a with triphenylstibane 3a at 100°C in dioxane–H₂O (9 : 1) afforded acetophenone 4a in 79% yield. However, a long reaction time was required (48 h) to obtain the product (entry 4). On the other hand, when the identical reaction was performed under microwave irradiation, the progress of the reaction could be confirmed even after 10 min (entry 5). The reaction between 1a and 3a under microwave irradiation (150 W, maximum temperature. 120°C) in water for 10 min gave 4a in excellent yields (entry 6). The optimum amounts of the triarylstibane reagent, and active substrates, and microwave irradiation condition for this reaction are shown in entries 5–17. When water was used as the solvent, superior results were obtained in comparison with the solvent mixture of dioxane–H₂O by conventional heating (entries 4, 6). This reaction may be considered as a stoichiometric reaction between 1a and 3a because decreasing the amount of 3a reduces the yield of 4a (entries 6–8). The reaction is complete in a short time of 10 min (entries 6, 9, 10). In addition, lowering the reaction temperature and microwave power gave significantly lower yields of 4a (entries 11, 12). It is noteworthy that the reactivity of triarylstibane 3b having the electron-donating methoxy group is higher than that of 3c, which has a chloro group (entries 13, 14). Inferior yields were obtained when phenacyl chloride 2a was used as the substrate (entries 15–17). Thus, under optimum reaction conditions, phenacyl bromide 1a was treated with 1.1 equiv. of the antimony reagent (3a or b) in water under microwave irradiation (150 W, maximum temperature of 120°C) for 10 min (entries 6, 13). The reagent utilized for investigating the scope and limitations of this reaction was the commercially available organoantimony compound triphenylstibane 3a. Meanwhile, it is known that phosphine reagents such as triphenylphosphonium iodide⁴¹⁾ and polymer-supported triphenylphosphine⁴²⁾ can be used for dehalogenation of α-halo carbonyl compounds in acetonitrile or methanol solution. Therefore, we were interested in reactivity of group 15 (pnictogen) reagents and the reaction of 1a using various triarylpnictogen reagents such as Ph₃P 3d, Ph₃As 3e, and Ph₃Bi 3f was also examined under microwave irradiation in water. The debromination product 4a was obtained in good yield (83%) using Ph₃P as the reagent while the yields were 3 and 20% using Ph₃As and Ph₃Bi, respectively (entries 18–20). These results including the case of Ph₃Sb do not follow the periodic table trend of reactivity.

Table 1. Reaction of Phenacyl Halides with Triarylstibanes under Conventional Heating and Microwave (MW) Irradiation

Entry	Methoda)	Substrateb)	Ar3M (eq)	M	Ar	Solvent	Temp (°C)	Time	Yield (%)c)
									4a	Recovery of 1a or 2a	Recovery of Ar3M 3
1d)	A	1a	3a (1.1)	Sb	C6H5	EtOH	80e)	48 h	47	18	10
2	A	1a	3a (1.1)	Sb	C6H5	H2O	100e)	7 h	55	—	10
3	A	1a	3a (1.1)	Sb	C6H5	CH3CN–H2O (9 : 1)	100e)	48 h	57	17	6
4	A	1a	3a (1.1)	Sb	C6H5	Dioxane–H2O (9 : 1)	100e)	48 h	79	6	22
5	B	1a	3a (1.1)	Sb	C6H5	Dioxane–H2O (9 : 1)	120	10 min	58	35	39
6	B	1a	3a (1.1)	Sb	C6H5	H2O	120	10 min	91	2	—
7	B	1a	3a (0.6)	Sb	C6H5	H2O	120	10 min	58	35	37
8	B	1a	3a (0.1)	Sb	C6H5	H2O	120	10 min	10	85	—
9	B	1a	3a (1.1)	Sb	C6H5	H2O	120	15 min	79	5	—
10	B	1a	3a (1.1)	Sb	C6H5	H2O	120	5 min	70	13	27
11	B	1a	3a (1.1)	Sb	C6H5	H2O	100	10 min	75	10	11
12f)	B	1a	3a (1.1)	Sb	C6H5	H2O	120	10 min	61	31	33
13	B	1a	3b (1.1)	Sb	4-MeOC6H5	H2O	120	10 min	92	—	—
14	B	1a	3c (1.1)	Sb	4-ClC6H5	H2O	120	10 min	51	44	45
15	B	2a	3a (1.1)	Sb	C6H5	H2O	120	10 min	14	82	85
16	B	2a	3b (1.1)	Sb	4-MeOC6H5	H2O	120	10 min	32	57	55
17	B	2a	3c (1.1)	Sb	4-ClC6H5	H2O	120	10 min	4	87	89
18	B	1a	3d (1.1)	P	C6H5	H2O	120	10 min	83	—	3
19	B	1a	3e (1.1)	As	C6H5	H2O	120	10 min	3	86	90
20	B	1a	3f (1.1)	Bi	C6H5	H2O	120	10 min	20	72	68

a) Method A is conventional heating in oil bath (entries 1–4). Method B is MW irradiation (150 W) heating (entrise 5–20). b) 1 mmol scale. c) The yields were determined by GLC analysis. d) 2-Ethoxy-1-phenylethanone as by-product (32%). e) Bath temperature. f) MW irradiation at 100 W.

In order to demonstrate the efficiency and generality of this procedure, the reaction of various α-bromoketones 1 was examined in the presence of triphenylstibane 3a under microwave irradiation in water. These results are summarized in Table 2. The reactions of 3a with α-bromoketones 1b–f containing electron-donating or electron-withdrawing groups on the phenyl ring afforded the corresponding products 4b–f in excellent yields (entries 1–5). The reaction of the sterically hindered substrates 1g and h gave the corresponding alkyl aryl ketones 4g and h without any difficulty, (entries 6, 7) and the reaction of α-bromoketones 1i and j having a heterocyclic ring also resulted in the formation of 4i and j without affecting the heterocycle (entries 8, 9). Evidently, the aroyl group of the α-bromoketone substrates is essential for the reaction to take place. It was observed that the yield of the debrominated product 4k was reduced when the coumarin derivative 1k was used (entry 10) and the substrates such as 1-bromo-1-phenylpropan-2-one 1l, and 2-bromomethylnaphthalene 1m did not form any debromination products. These results indicate that the reaction has high substrate specificity and is effective in transforming α-bromoarylketones into their corresponding reduced products.

Table 2. Microwave-Assisted Debromination of α-Bromoketones 1 with Triphenylstibane 3a^a)

a) All reactions were carried out MW irradiation (150 W, max. temp. 120°C, 10 min) using a mixture of 1 (1 mmol), triphenylstibane 3a (1.1 mmol) and H₂O (1 mL). b) Isolated yield.

The mechanism of this reaction may be considered to be similar to that proposed by Akiba et al. for the debromination of phenacyl bromides with antimony reagents.²⁶⁾ A plausible mechanism of the debromination of α-bromoketones using triphenylstibane in water is shown in Chart 1. The nucleophilic attack of antimony on α-bromoketone may result in the formation of the stibonium salt 5 which equilibrates with the enolantimony species 6. This intermediate can then undergo hydrolysis to give the alkyl aryl ketone 4. The reaction of phenacyl bromide (1a: 1 mmol) with benzaldehyde (8: 1 eq) in the presence of triphenylstibane 3a (1.1 eq) and MS 4 Å under microwave irradiation (150 W, maximum temperature 150°C, 10 min) without base and solvent resulted in the formation of the chalcone 9 in 54% yield (Chart 2). This result suggests the generation of intermediates 5 and/or 6 during the studied transformation.

Chart 1. Possible Mechanism

Chart 2. Control Reaction

This reaction was also applied to the 1,2-elimination of the vic-dibromide 10 (diastereomeric ratio based on ¹H-NMR: 10a=>99% de, 10b=96% de) with triphenylstibane 3a under microwave irradiation in water to give only the corresponding debrominated (E)-olefins 9 and 11 in good yields (Chart 3). The mechanism of this reaction is currently under investigation.

Chart 3. Microwave-Assisted 1,2-Elimination

In conclusion, triphenylstibane is a useful reagent for the debromination of α-bromoarylketones and formation of the corresponding alkyl aryl ketones. Furthermore, it can also be used for the 1,2-elimination reaction of vic-dibromides to form the corresponding debrominated E-olefins under microwave irradiation in water. To the best of our knowledge, this work is the first representative example of organoantimony compounds utilized for organic transformation in water.

Acknowledgments

Partial financial support for this work was provided by a research Grant from Institute of Pharmaceutical Life Sciences, Aichi Gakuin University and Hokuriku University.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials (detailed experimental procedure, physical data, and NMR spectra of isolated products).

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