Solvent and catalyst-free bromofunctionalization of olefins using a mechanochemical approach

Bromofunctionalizations of olefins are an important class of chemical transformations. N-Bromoimide reagents are commonly used in these reactions but catalysts and chlorinated solvents are often employed to achieve a reasonable reaction rate. In this report, we present a solvent and catalyst-free bromofunctionalization of olefins using mechanical force.

Bromofunctionalization of olenic substrates represents one of the most useful classes of halogenation reactions. It allows for the simultaneous addition of a bromine atom and another functional group across the alkene C-C double bond. 1 Further modication of the bromine handle can be easily done using conventional methods. These reactions are fundamentally important in industrial chemical synthetic processes where environmental sustainability should be taken into serious consideration. 2 Although molecular bromine is an inexpensive halogen source, using it in halogenation processes has proven problematic due to its corrosive and toxic nature. 3 Oxidative bromination, which involves the in situ generation of bromine via the oxidation of a bromide anion, provides a greener alternative and can avoid the use of stoichiometric amounts of molecular bromine. However, these methods are not suitable for the co-halogenation of olens (e.g. bromocyclization) because dibromination readily occurs as the major side reaction. 4 Thus, milder and more user-friendly halogen sources such as N-bromosuccinimide (NBS) and 1,3-dibromo-5,5dimethylhydantoin (DBDMH) are frequently employed in many bromofunctionalization reactions. 5 Well reported examples include bromocyclization reactions such as bromolactonization [6][7][8][9][10][11][12][13][14][15] and bromoetherication [16][17][18][19] as well as the more challenging intermolecular bromoesterication. [20][21][22][23][24][25][26] Because of the high polarity of the N-bromoimide reagents, polar solvents such as N,N-dimethylformamide and acetonitrile are oen required for good solvation which poses difficulties in the purication process. The use of relatively less polar solvents such as dichloromethane and chloroform are also commonly reported. However, various catalysts (e.g. Lewis bases to activate the electrophilic Br) or additives (e.g. Brønsted bases to deprotonate the pronucleophiles such as carboxylic acids) are oen required to achieve high reactivity. Furthermore, the use of chlorinated solvents in industrial settings is strongly regulated due to its ability to cause ozone depletion as well as its biological carcinogenicity. 27,28 Our previous work in this area include the use of lipophilic indole catalysts as a solid-to-liquid phase bromine shuttle for efficient bromination with N-bromoimide reagents in environmentally benign lipophilic solvent. 29-31 Despite these precedent efforts on establishing greener bromofunctionalization of olens, recycling solvents at a large scale is still highly energy-consuming and is undesirable at industrial sectors. In view of the ever-increasing demand for green chemical protocols, the development of more sustainable bromofunctionalization processes is still highly desired.
Mechanochemistry has re-emerged as a tool in various chemical transformations. 32 This strategy uses mechanical energy to induce various reactions. In many occasions, solvents are not required and the mechanochemically activated reactions can oen result in higher efficiency and selectivity. Herein, we report a comprehensive study on the halo-O-cyclization of olenic substrates using mechanical force under solvent and catalyst-free conditions. The protocol has also been applied to the three-component intermolecular bromoester-ication of olens. Using a Retsch mixer mill we have successfully achieved the solvent, catalyst and additive-free bromolactonization, bromoetherication and intermolecular bromoesterication reactions with N-bromoimide reagents (Scheme 1, eqn (1)-(3)). These reactions proceeded efficiently with near equimolar quantities of all reagents at ambient conditions. The products can be puried by column-free ltration and the bromine carrier byproducts (e.g. succinimide of NBS) can be recovered effectively for recycling.
We began our investigation using the bromolactonization of various 1,1-disubstituted alkenoic acids to produce g-lactones.
Though this type of reaction is well-documented, reported examples oen rely on the use of high boiling point polar or chlorinated solvents in combination with various catalyst systems. 1 A recent example was reported by Tungen and coworkers, where the organoselenium catalyst, named DECAD, was found to catalyze the efficient bromolactonization of various olenic acids (Scheme 2, eqn (1)). 6 However, this protocol requires the use of acetonitrile as solvent, which is not trivial to remove due to its relatively high boiling point and water miscibility. Furthermore, the reaction system is water sensitive and molecular sieves are needed. Another recent report by Kumar and co-workers showcased the use of a C 2symmetric sulde catalyst carrying two dihydroquinine chiral scaffolds in various asymmetric bromolactonization reactions (Scheme 2, eqn (2)). 33 In this example, a solvent blend with chloroform was required to dissolve the various reaction components in order to maintain efficient reactivity.
Using a mixer mill at an oscillation frequency of 20 Hz with solid samples of alkenoic acid 1a and NBS, 14% of lactone 2a was produced in 10 minutes (Table 1, entry 1). When the reaction was conducted in dichloromethane, only 10% of 2a was detected even aer 2 hours (entry 2). No reaction was observed when the solids of 1a and NBS were mixed using a magnetic stirrer bar (entry 3). These results highlight the crucial effect of mechanical force on the bromolactonization. At an oscillation frequency of 30 Hz and with a longer reaction time, gradual improvement in reaction conversion was observed leading to complete reaction aer 2 hours (entries 4-6). Bromolactonization using the more reactive halogen source DBDMH gave near quantitative yields of 2a in a shorter time period (entry 7). NBS is known to readily decompose through light-activated radical pathways, causing faster reaction rates in the solution phase (as indicated by a rapid change from a colorless to a red/brown solution). Since the reaction was carried out in a stainlesssteel milling chamber, the enclosed system is completely shielded from light; thereby minimizing the undesirable NBS radical decomposition.
Alkenoic acids carrying various substituents were examined in order to evaluate the inuence of electronic effects on the reaction efficiency. The relatively electron rich 4-methyl and 4methoxy phenyl alkenoic acids (1b and 1c) afforded lactones 2b and 2c in 98 and 87% yields, respectively. Relatively electron-decient olens are typically less reactive towards electrophilic halogenations; due to a lower availability of the p-electrons for formation of a haliranium intermediate. Nonetheless, 4-chloro, 4-uoro and 4-triuoromethyl phenyl olenic acids readily cyclized to give lactones 2d, 2e, and 2f in 98, 90 and 98% yields, respectively, in one hour. The acylated alkenoic acid 1g was also well tolerated under the mild conditions, yielding lactone 2g in 81% yield. This method was also compatible with the 1,2-disubstituted trans-olenic acid 3, providing 4 in good yield and diastereoselectivity ( Table 2).
In view of the high efficiency, low operational complexity and environmental sustainability of this mechanical force-driven bromocyclization; we then sought to test its compatibility with less reactive substrates. The bromocycloetherications of olenic alcohols 5 were chosen because they are known to be less efficient when compared to the analogous bromolactonization reactions. 17  as the brominating reagent, substrate 5a yielded 58% of the bromoether 6a in only 10 minutes (Table 3, entry 1). The reaction efficiency was far superior to that of the solvated reaction in dichloromethane (entry 2). Increasing the oscillation frequency gave higher yields within the same time period (entry 3) and full conversion was realized aer 1 hour (entries 4-5). Using our optimized conditions, we continued to evaluate the reaction using olenic alcohols of varied electronic properties ( Table 4). The relatively electron-rich p-tolyl olenic alcohol 5b gave near quantitative yield of the product tetrahydrofuran 6b. Good yields were also obtained when the relatively electron-rich and electron-decient olenic alcohols were subjected to the same conditions. 4-Methoxy (5c), 4-chloro (5d), 4-uoro (5e), 4-triuoromethyl (5f) and 3,5-bistriuoromethyl (5g) phenyl substituted olenic alcohols gave products 6c-6g in 76-98% yield.
To further explore the scope of this mechanochemical bromination protocol, the intermolecular bromoesterications of alkenes and carboxylic acids was chosen as our next target. These reactions are intrinsically sluggish when compared to their intramolecular counterparts due to a higher reaction entropy. 34 This low reactivity is oen overcome using either a super-stoichiometric amount of the acid partner or directly as the solvent; resulting in poor atom-economy. For example, in two separate publications by Braddock et al. the tetramethylguanidine (TMG) and iso-amarine were used to catalyze the bromoacetoxylation of styrene (Scheme 3a). 35,36 In these examples, chlorinated solvent and a large excess of acetic acid was required to effectively promote the reaction. More recently Pimenta et al. has reported the use of DABCO as a catalyst in the bromoacetoxylation of various alkenes (Scheme 3b). 22 In this example two equivalents of acetic acid were required when the reaction was conducted in dichloromethane. The authors then chose to use an excess of acetic acid as a replacement for the environmentally hazardous dichloromethane solvent. In view of the undesired conditions required for this type of reaction, we sought to optimize our mechanochemical bromofunctionalization protocol to achieve a more efficient and environmentally sustainable alternative.
In our initial substrate optimization, benzoic acid 7a and styrene 8a were used as the reacting partners with a near Table 2 Substrate scope of bromolactonization a a Reactions were conducted using a Retsch mixer mill (MM 400) in a 10 mL zirconium oxide chamber with alkenoic acid 1 (0.2 mmol) and NBS (0.22 mmol) at ambient temperature. The yields are isolated yields.  equimolar ratio. When NBS was used as the bromine source, the reaction did not proceed (Table 5, entries 1 and 2). Using DBDMH as the bromine source, full conversion was reached aer 10 minutes at an oscillation frequency of 30 Hz (entries 3 and 4). In contrast, very poor yields were obtained when the reaction was conducted neat or under full solvation in dichloromethane (entries 5 and 6, respectively). We also compared the source of mechanical force. It was found that the reaction using a mixer mill is more efficient than that of a planetary mill (entry 7), although the planetary mill is more suitable for scaled up processes.
Next, various benzoic acid derivatives 7 were tested using styrene 8a as the reaction partner. The sterically bulky and relatively electron-rich benzoic acid derivatives 2,4-dimethyl (7b) and 2,4,6-trimethyl benzoic acid (7c) reacted efficiently with styrene 8a to produce bromoesters 9ba and 9ca in 82% and 90% yields, respectively. The relatively electron-decient benzoic acid derivatives carrying 2-bromo (7d) and 2-uoro (7e) substituents also reacted smoothly, giving nearly quantitative yields of bromoesters 9da and 9ea. A moderate decrease in yield of ester 9fa was observed when 4-nitrobenzoic acid 7f was subjected to the same reaction conditions. We believe that the strong electron-withdrawing ability of the nitro substitution may reduce the nucleophilicity for the carboxylate group. The aliphatic acid derivative, 3-phenylpropionic acid 7g was also well-tolerated, yielding bromoester 9ga in 96% yield.
To demonstrate the column-free product isolation and bromine carrier recyclability of this method, a scaled-up ltration/recovery experiment was conducted. When the bromolactonization of 1a was conducted in a reaction chamber of the same size but at 1 mmol scale. At an oscillation frequency of 30 Hz, the reaction reached completion aer 1 hour (Scheme 4A). Pure hexane was used to rinse the contents of the mill chamber into a sintered funnel, where the solid remains of the bromine carrier was removed from the product. This gave a 95% isolated yield of lactone 2a in high purity (see ESI, Section G †). The residue was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. This returned a 98% recovery of the 5,5-dimethylhydantoin which can be recycled for the synthesis of DBDMH. Next, the bromocycloetherication of 5a was scaled up to 1 mmol scale. At an oscillation frequency of 30 Hz, the reaction reached completion aer 3 hours (Scheme 4B). The sample was puried by ltration using an analogous approach as in the bromolactonization example. This protocol gave product 6a in 93% and succinimide in 99% (see ESI, Section G †). A column-free ltration purication of the bromoester product and recovery of 5,5-dimethylhydantoin was also demonstrated. Using cyclohexene 8h and benzoic acid 7a as the reacting partners with DBDMH as the bromine source, complete reaction was achieved aer 3 hours under an oscillation frequency of 30 Hz (Scheme 4C). Extraction of the milling chamber with hexane and ltration over sintered glass, gave the bromoester 9ah in 99% yield together with 95% recovery of 5,5dimethylhydantoin with high purity (see ESI, Section G †).

Conclusions
In summary, with a mechanochemical approach we have successfully achieved high efficiency in various bromofunctionalization reactions of olens using N-haloimides as the bromine source. This method allows for the reactions to proceed under solvent, catalyst and additive-free conditions. Avoiding the need for environmentally hazardous chlorinated solvents commonly employed to provide good solvation of the N-haloimides. Reaction efficiency was also maintained in the absence of any catalyst or additives, allowing the reaction to proceed in a mild manner within a short reaction period. The substrate scope for bromolactonization, bromoetherication and bromoesterication have shown great compatibility with varied steric and electronic substrate properties. With near equimolar amounts of substrates and excellent recyclability of the bromine source, this method offers superior atom economy when compared to existing protocols. Furthermore, hassle-free ltration purication circumvents the need for ash-column Scheme 4 Efficient product isolation and imide recovery.
chromatography. Together with the ease of operation we believe that mechanochemical methods can provide both time and energy saving alternatives to the traditionally solvated reaction protocols of bromofunctionalizations of olens.

Conflicts of interest
There are no conicts to declare.