HBr–DMPU: The First Aprotic Organic Solution of Hydrogen Bromide

Abstract

HBr and DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone) form a room-temperature-stable complex that provides a mild, effective, and selective hydrobrominating reagent toward alkynes, alkenes, and allenes. HBr–DMPU could also replace other halogenating reagents in the halo-Prins reaction, ether cleavage, and deoxybromination reactions.

Alkyl and alkenyl bromides are common substrates in a wide scope of transformations, including nucleophilic substitution reactions,^[1] metallation reactions^[2] and transition metal-catalyzed cross-coupling reactions.^[3] Highly efficient synthetic approaches toward organic halides are in high demand because of their crucial role in synthesis. Electrophilic addition of hydrogen halides to alkenes and alkynes provides a uniformed approach toward branched alkyl and alkenyl halides, and is a model reaction in most textbooks of organic chemistry.^[4] Compared with other approaches, including deoxyhalogenation,^[5] Hunsdiecker reaction,^[6] hydrometallation–electrophilic halogenation,^[7] olefin metathesis^[8] and transition-metal-catalyzed hydrohalogenation,^[9] the electrophilic addition of hydrogen halides is atom economical. However, to succeed in such transformation, handling gaseous hydrogen halides^[10] with special and expensive equipment^[11] is almost always required. While there maybe other methods to achieving hydrobromination of alkynes and alkenes, these usually involve the use less environmentally benign precursors, conditions and low atom economy.^[12] Moreover, HBr addition to alkynes and alkenes in solution also results in uncontrollable radical-chain additions that give the anti-Markovnikov products.^[13] We herein report the first room temperature stable solution of HBr in a neutral aprotic organic solvent, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) that expands the utility of HBr. This complex yielded a mild, effective and selective hydrobrominating reagent toward alkynes, alkenes and allenes. HBr–DMPU could also replace other less atom economical halogenating reagents in the halo-Prins reaction and deoxybromination reactions.

Although several easy-to-handle HBr reagents are available commercially or have been recently made,^[14] none of them are good choices for a more general hydrobromination reactions due to scope limitations. An acetic acid solution of HBr is capable of hydrobrominating unsaturated hydrocarbons, but selectivity between hydrohalogenation and undesired hydroacetoxylation is poor,^[15] because of the weak, but still nucleophilic, acetate anion and the reduced nucleophilicity of halide anions in protic medium.^[16] In addition, the rearrangement of the intermediate carbocation is not uncommon.^[17] Triphenylphosphine hydrobromide is known as an alternative HBr source, but triphenylphosphine tends to further react with formed alkyl bromides to produce phosphonium salts.^[18] Kropp et al.^[19] have highlighted a few applications of HBr with the aforementioned challenges. In this regard, HBr solution in a neutral aprotic medium would be the optimal choice to prevent competitive solvolysis reaction and to achieve high reactivity. However, the excess reactivity of HBr toward ethers and esters excludes ethereal and ester solvents. Inspired by the concept of hydrogen bond basicity (pK_BHX) that was first systematically summarized by Laurence,^[20] we previously succeeded in a new formulation of hydrogen fluoride, HF–DMPU,^[21] which exhibits a higher reactivity than its predecessors^[22] in a wide scope of transformations. We hypothesized that DMPU could effectively form hydrogen bond complexes with HBr. In addition, DMPU is inert toward alkylation reactions, thus it should not compete with HBr. We were pleased to find that by passing HBr gas through DMPU, we obtained a solution of HBr–DMPU in the form of a room temperature-stable liquid (Table 1, entry 3) with a higher mass percentage compared to other HBr solutions.

Table 1.

Comparison of different formulations of hydrogen halide solutions

Entry	Formulation	Mole ratio (HX:solvent)	pKBHX of stabilizer
1	HBr–water, 48 %[a]	0.21	0.65
2	HBr–AcOH, 33 %[a]	0.36	N/A
3	HBr–DMPU, 58 %	2.2	2.79

^[a]Commercially available.

We tested the reactivity of HBr–DMPU in hydrohalogenation reactions. HBr–DMPU showed a high reactivity toward alkyne 1a. Under neat conditions, it completely converted 1a into the hydrobromination product 1b in 83% yield, without the formation of the 6-exo-trig cyclization product (Equation (1)).^[23] Gram-scale reaction gave the same product in 85 % isolated yield (Equation 1). A small amount of gem-dibromide, as a result of a two-fold hydrobromination, was observed after extended reaction times. HBr–DMPU eliminated the use of gaseous HBr,^[10b] the competitive hydroacetoxylation reaction using HBr–HOAc^[15d] and eliminated the use of a catalyst.^[9a,24]

(1)

A wide scope of alkynes reacted smoothly with HBr–DMPU under ambient conditions (Table 2). Homopropargyl ester 1b, amide 1c and imide 1d afforded the corresponding 3-bromo-but-3-enyl ester 2b, amide 2c and imide 2d in 82, 83, and 80 % yields, respectively, without any ester cleavage. Hex-5-ynoic acid 1e and its nitrile 1f also yielded products 2e and 2f in 78 and 89 % respectively. Phenylacetylene, 1h, yielded (1-bromovinyl)benzene and (2-bromovinyl)benzene in a 97:3 ratio with a combined 92 % yield. With internal alkynes, 1-phenyl-propyne 1i yielded a 3:2 mixture of α- and β-bromides 2i with exclusive Z-configuration. The exclusive formation of Z-isomers (trans addition) indicated to us that this transformation follows an Ad3 mechanism^[25] and that the bromide concentration in the reaction medium is not low.^[17] Hydrobromination of decyne 1j provided 2j in a similar yield. 1k and 1l yielded the corresponding hydrobromination product 2k and 2l in regioselective manner, albeit with a lower selectivity for 2k. This is probably due to the diminished steric difference between methyl and bromomethyl moieties.^[25a,26] Diphenylacetylene (1m) yielded the Z-product in a modest 68 %. The unsymmetrical diaryl acetylene (1n) gave a 4.6:1 mixture of regioisomers. The reaction with derivatized amino acid (1o) and estrone (1p) also proceeded in 71 and 95 % yields, respectively, showing the wide applicability of this method.

Table 2.

Hydrobromination of alkynes^[a]

^[a]Reaction conditions: 1 (0.3 mmol), 0.15 mL of HBr–DMPU (58 % w/w), room temperature, yields are isolated. [b] Reaction run at 70 °C.

Alkenes are also suitable substrates for HBr–DMPU hydrobromination (Table 3). Allylbenzenes 3a–3c and tridecene 3e afforded the corresponding Markovnikov hydrobromination products 4a, 4b, 4c, and 4e in excellent yields. The reaction time of 3b should be limited to 1 hour, since prolonged reaction times caused the demethylation of 4b. Styrene 3d was completely hydrobrominated, without the formation of commonly observed polymers.^[27] Homoallyl amide 3f, imide 3g, and ester 3h afforded the corresponding hydrobromination products in good yield and with functional group tolerance. 4f could be directly converted into azetidine 5 upon a treatment with sodium hydride in DMF (Eq. 2). The hydrobromination of internal alkenes was partially successful. β-Methyl styrene 3i and cyclohexene could be hydrobrominated in quantitative yield but several substrates could not be effectively hydrobrominated. For example, hydrobromination of α-methyl styrene 3k could be only partially achieved, even after an extended reaction time or after adding extra loading of HBr–DMPU. Hydrobromination of methyl cinnamate 3l and stilbene 3m was not successful due to their slow conversion, competition with undesired demethylation or easy loss of HBr during purification. [Eq. 2]

Table 3.

Hydrobromination of alkenes^[a]

^[a]Reaction conditions: 3 (0.3 mmol), 0.15 mL of HBr–DMPU (58 % w/w), room temperature, yields are isolated. Numbers in parenthesis are NMR yields using CH₂Br₂ as an internal standard.

(2)

Alkynes are known to be less reactive than alkenes in a wide scope of electrophilic addition reactions,^[28] because of the anticipated highly energetic vinyl cation intermediate.^[25a] However, using HBr–DMPU, alkyne 1b showed a faster conversion than alkene 1m in both, parallel and competition experiments (Scheme 1). This inversed reactivity could be attributed to the high concentration of HBr in the reaction medium, signaling a reaction profile that is different from that in diluted reaction medium.^[29]

Scheme 1.

Reactivity comparison.

HBr–DMPU was shown to be very useful in other bromination reactions. For example, typical halogenating reagents employed in organic synthesis are gaseous hydrogen halides, metal halides (e.g. AlX₃, InX₃, NbX₅, GaX₃, FeX₃, SnX₄), sulfonyl halides, boron halides, phosphorus halides or silicon halides (Scheme 2),^[30] which either require special handling or produce large amounts of side products after the reaction, and each transformation requires a different halogenating reagent. HBr–DMPU, on the other hand, provided a uniform solution to all these transformations. It could substitute niobium and gallium halides in the bromo-Prins reaction (Scheme 2a). It could also convert alkyl alcohols 7 into alkyl bromides 8, thus replacing the corrosive PBr₃ (Scheme 2b).^[31] Hydrobromination of allenenoic ester 9a occurred with the regioselective protonation of the sp2-hybridized α-carbon, producing a β-vinylic cation that was further trapped by bromide to provide a vinyl bromide 9b in 54 % yield (Scheme 2c).^[32] The reduced yield was primarily caused by cleavage of the benzyl group, since formation of benzyl bromide was observed on GC-MS.

Scheme 2.

Other synthetic reactions using HBr–DMPU.

In conclusion, HBr–DMPU is a good alternative to existing of hydrogen bromide solutions. Its advantages lie in the ease of handling, high HBr concentration, high reactivity towards the hydrobromination of alkenes and alkynes without competition reactions caused by rearrangement or solvolysis. It also served as an effective substitution to other bromides in bromination transformations.

Experimental Section

Preparation of HBr–DMPU

HBr–DMPU was prepared by dropping hydrobromic acid to phosphorus pentoxide, passing evolved gas through a phosphorus pentoxide drying tower, and trapping dried HBr gas by DMPU under an argon atmosphere of ambient pressure.

General procedure of hydrobromination of alkenes and alkynes

To an argon-flushed 2-dram vial loaded with 0.3 mmol of alkene or alkyne, 0.15 mL of HBr–DMPU (58 w/w%) was added under stirring at room temperature. GC-MS and TLC monitored reaction progress. Once complete, the reaction mixture was quenched by adding 2 mL of saturated sodium bicarbonate solution and extracted 3 times with 2 mL of ethyl acetate. To the combined extract, 1 gram of silica gel was added, and the solvent was removed under a reduced pressure. The final product was purified by flash column chromatography using ethyl acetate-hexane eluent