An improved and sustainable approach for the synthesis of α,β-dibromo ketones using ceric ammonium nitrate and ammonium bromide

1 Introduction

The central theme of organic synthesis is carbon-carbon and carbon-heteroatom bond-forming reactions which comprise a major progress in modern synthesis, and this progress in turn results in development of novel methodologies. The application of carbon-centered radicals resulting from redox processes mediated by high-valent metal salts such as Mn (III), Co (III), V (V) and Ce (IV) has emerged as a powerful tool for carbon-carbon bond formation in recent years [1, 2]. The use of Ce (IV) reagents as convenient oxidants for a variety of substrates is well established [3–5]. Recently, C-C [6–9] and C-heteroatom [10–13] bond-forming reactions mediated by ceric ammonium nitrate (CAN) have been the subject of considerable interest [8–13]. One-electron oxidant CAN is one of the most important reagents, which appeals more and more with explored findings, as well as due to its use as Lewis acid catalyst from the group of lanthanide (IV) complexes in organic synthesis [8]. For the generation of radicals, CAN has been found to have the chemically upper hand in many respects to widely employed manganese triacetate [14]. CAN has some auxiliary advantages in terms of low toxicity, cost, solubility in many organic solvents and stability in air.

Organic bromine compounds have traditionally played an important role as intermediates in the production of agrochemicals, pharmaceuticals and dyes and others [15, 16]; some bromine compounds have been used as flame retardant and disinfectant. Bromination [17, 18] is termed as an important organic transformation, and bromination-debromination strategy for the protection-deprotection of double bonds has a substantial role in organic synthesis. Also, dibromoalkanes are important compounds widely used as versatile synthetic intermediates in a considerable number of useful transformations and for the protection-deprotection of unsaturated hydrocarbons [19–23]. The conventional method for bromination involves the use of bromine in chlorinated solvents [24], and unfortunately, a vast number of reported procedures employ highly polluting reaction conditions. In this context, several alternate green brominating agents have been reported to avoid the use of hazardous molecular bromine. Some of the methods worth mentioning are I₂O₅-KBr [25], potassium and ammonium halides [26] as the bromine source, oxybromination of activated aromatic compounds catalyzed by ammonium molybdate [27], environmentally benign electrophilic and radical bromination “in water”: H₂ O₂ -HBr system [28], NH₄Br-oxone [29, 30], solvent-free bromination reactions with sodium bromide and oxone [31], bromination of chalcones using grinding technique [32], action of tetrabutylammonium tribromide on para-substituted chalcones in protic and aprotic media [33], in situ generated bromine under oxidative conditions [34], pyridiniumbromide-perbromide, quaternary ammonium tribromide or tribromide perbromide [35]. Though the search for sustainable protocol has led to tremendous progress in this area, most of the methods suffer from use of acid or organic solvents and are time consuming. Herein we present two approaches for bromination of enones under mild conditions and hence a step forward towards sustainable method development in tune with the current research scenario.

2 Materials and methods

Melting points were recorded by open capillary method on an electrothermal melting point apparatus and are uncorrected. The NMR spectra were recorded in CDCl₃ with tetramethylsilane as an internal standard on Agilent VnmrJ 3.2 Spectroscopy 400/54 ASP, USA; IR spectra were recorded on a FT-IR 3.1 Win-BOMEM, Italy, apparatus. Flash chromatography was performed on thin layer chromatography (TLC) grade silica gel, and analytical TLC was performed on Merck silica gel 60 F254 pre-coated plates. The spots were visualized under UV light or by iodine vapors. Solvents were distilled before use. Ammonium bromide and ceric ammonium nitrate were procured from SD Fine chemicals, Mumbai, India, and in the preparation of chalcones we used benzaldehyde produced by Rankem, New Delhi, acetophenone from Hi-media, Mumbai, and NaOH from SD Fine Chemicals. All other commercial substrates were purchased from standard sources, and most of them were from SD Fine chemicals and were used as such.

3 Results and discussion

CAN in the presence of NH₄Br brings about bromination of enones and chalcones to afford the corresponding dibromide in good to excellent yields (Scheme 1).

Scheme 1:

Reaction of chalcone with different ammonium halides.

As the nature of the solvent is expected to play a crucial role in bromination, the reaction has been studied in different solvents commonly employed for the same. Table 1 displays the different solvents employed and their effect on yield and time. The reaction proceeded in most of the solvents screened, and acetonitrile was found to be the solvent of choice to afford the dibromo compound in 90% yield within 30–35 min at room temperature. Also, the reaction proceeded in appreciable way in DMF/DMSO in terms of conversion and time required for completion. The best results were obtained in grinding method under moist conditions to the tune of 90% yield within 20–25 min.

Further, the applicability of the present conditions with other ammonium halides have been explored, and the results are presented in Table 2. As is obvious from the table, the present reaction conditions did not work with ammonium iodide and fluoride for the respective halogen addition in both the methods studied, while chlorination with ammonium chloride proceeded in moderate yield in acetonitrile, and no reaction was observed in the grinding method.

Table 2

Halogenations of chalcones with CAN using different ammonium halides.^a

Sr. No.	Substrate	Ammonium halide	Product	% Yield
				Stirring with solvent A	Grinding with few drops of water B
1.		NH4F	No reaction	No reaction	No reaction
2.		NH4Cl		52	No reaction
3		NH4Br		91	90
4		NH4I	No reaction	No reaction	No reaction

^aHalogenations of chalcone in CH₃CN with different ammonium halides were carried out under all possible conditions like mild heating and reflux to get good yields in minimum time, and the optimized results are presented here.

Having optimized the reaction conditions for bromination in solvent acetonitrile and by grinding method (Scheme 2), different substituted enones/chalcones were subjected to the reaction conditions, and the results are presented in Table 3. Methyl vinyl ketone and benzylideneacetone (Table 3, entries 1 and 2) required less time for conversion compared to other substituted chalcones. As expected, the reaction proceeded better with chalcones bearing electron-donating substituents as compared to the ones bearing electron-withdrawing groups. Substituents on the aromatic ring exert effect on the conversion and time. It is remarkable that bromination of methoxy-substituted chalcones (Table 3, entries 5 and 14) proceeded well under grinding method, and the same in acetonitrile gave low yield of 20% after 11–12 h of stirring at room temperature.

Table 3

Bromination of different α,β unsaturated ketones with NH₄Br and CAN.^a

Sr. No.	Substrate	Product	% Yieldb		Time		M. P. in °C
			Stirred in solvent	Grinding in mortar and pestle	Stirred in solvent	Grinding in mortar and pestle
1			52	–	1 h	–	–
2			67	65	10 min	15–20 min	-
3			93	91	25–30 min	15–20 min	123–125
4			91	90	35–40 min	15–20 min	156–158
5			94	90	35–40 min	15–20 min	147–149
6			20	75	4 h	15–20 min	146–148
7			83	79	35–40 min	15–20 min	188–190
8			87	82	35–40 min	15–20 min	156–158
9			93	90	35–40 min	15–20 min	171–173
10			91	89	35–40 min	15–20 min	185–186
11			87	82	35–40 min	15–20 min	175–177
12			92	90	35–40 min	15–20 min	155–157
13			87	80	35–40 min	15–20 min	142–144
14			91	88	35–40 min	15–20 min	148–150
15			20	75	4 h	15–20 min	90–92
16			83	80	35–40 min	15–20 min	130–132

^aMethod A: Reaction was performed at room temperature (28–30°C) with two equivalent of CAN in acetonitrile.

Method B: The reaction was carried out by grinding the reactants with mortar and pestle.

^bYields refer to pure isolated products fully characterized by spectral and analytical methods.

Scheme 2:

Synthesis of dibromo chalcone using ammonium bromide and CAN.

Mechanistically, the bromination seems to proceed via addition of bromine radical formed by single-electron transfer to CAN (Figure 1).

Figure 1:

Mechanism for synthesis of dibromo chalcone using ammonium bromide and CAN.

4 Conclusion

As dibromoalkanes are important compounds widely used as versatile synthetic intermediates in a considerable number of useful transformations, their easy access by the present method would find widespread use in organic synthesis. The present work highlights the usefulness of CAN and NH₄Br as ecofriendly and mild reagent and salt, for economical, ecologically favorable bromination protocol with easy workup procedure coupled with short reaction times. The grinding method looks attractive in terms of conversion and reaction time, and the ease of handling cheaper ammonium bromide as a source of bromine makes the strategy an option of choice.