1,3-Dibromo-5,5-dimethylhydantoin as a Precatalyst for Activation of Carbonyl Functionality

Activation of carbonyl moiety is one of the most rudimentary approaches in organic synthesis and is crucial for a plethora of industrial-scale condensation reactions. In esterification and aldol condensation, which represent two of the most important reactions, the susceptibility of the carbonyl group to nucleophile attack allows the construction of a variety of useful organic compounds. In this context, there is a constant need for development of and improvement in the methods for addition-elimination reactions via activation of carbonyl functionality. In this paper, an advanced methodology for the direct esterification of carboxylic acids and alcohols, and for aldol condensation of aldehydes using widely available, inexpensive, and metal-free 1,3-dibromo-5,5-dimethylhydantoin under neat reaction conditions is reported. The method is air- and moisture-tolerant, allowing simple synthetic and isolation procedures for both reactions presented in this paper. The reaction pathway for esterification is proposed and a scale-up of certain industrially important derivatives is performed.


A. Bader charge analysis
DFT calculations were performed with the PWscf code from the Quantum ESPRESSO distribution using the generalized gradient approximation (GGA) of Perdew--Burke--Ernzerhof (PBE). Bader charge analysis was performed by generating charge densities with single point self-consistent-field calculations of US-PP optimized structures using the PAW (projectoraugmented-wave) potentials and 1000 Ry kinetic energy cutoff for charge density and then computing the Bader charges using the bader program.
The results of the Bader charge analysis are summarized in Table S1. Bader charges for the carbon and oxygen atoms of the carbonyl group were calculated and the analysis confirmed that the positive charge on the carbonyl carbon atom decreases by changing the substituents on the para-position of the phenyl ring in the following order: NO2 > H > OMe > OH. In the case of p-OH-benzoic acid the carbon atom is not as positively charged as in the case of benzoic acid. It should however be noted that the results refer to gas-phase calculations and the presence of solvent could influence these results. Figure S1. Schematic depiction of the meaning of labels used Table S1. The qO label designated the charge of oxygen of the carbonyl group, while the qC label designates the charge of the carbon of the carbonyl group, of the various investigated carboxylic acids. Table S1. Calculated Bader charges for the carbon (qC) and oxygen (qO) atoms of the carbonyl group in units of elementary charge (schematically depicted in Fig. S1), for investigated substituted benzoic acids.  Dehydrocholic acid methyl ester (33a) [20] The mixture of dehydrocholic acid (0.25 mmol, 101.6 mg), MeOH (0.5 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 5 h. After the completion of the reaction, the mixture was cooled to room temperature and MeOH was evaporated under the reduced pressure. The residue was dissolved in ethyl acetate and first washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water and then with 10 mL of 10% HCl(aq). The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. Cholic acid n-butyl ester (30d) [28] The mixture of cholic acid (0.25 mmol, 102.1 mg), n-butanol (0.5 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and MeOH was evaporated under the reduced pressure. The residue was dissolved in ethyl acetate and washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. Litocholic acid n-butyl ester (32d) [29] The mixture of litocholic acid (0.25 mmol, 94.1 mg), n-BuOH (0.5 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and n-BuOH was evaporated under the reduced pressure. The residue was dissolved in ethyl acetate and washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure.

Dehydrocholic acid n-butyl ester (33d)[30]
The mixture of dehydrocholic acid (0.25 mmol, 101.6 mg), n-BuOH (0.5 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and n-BuOH was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and first washed with the mixture of 1 mL of saturated Na2S2O3(aq), 2 mL of saturated NaHCO3(aq) and 10 mL of distilled water and then with 10 mL of 10% HCl(aq). The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. 3β-O-Acetyl-cholesterol (34k) [36] The mixture of cholesterol (0.25 mmol, 96.6 mg), EtOAc (1 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and additional 10 mL of ethyl acetate was added. The solution was washed with the mixture of 1 mL of saturated Na2S2O3(aq), 2 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. 3β-Acetyloxy-5α-androstan-17-on (34l) [37] The mixture of epi-androsterone (0.5 mmol, 145.2 mg), EtOAc (1 mL) and DBDMH (0.018 mmol, 5.1 mg) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and additional 10 mL of ethyl acetate was added. The solution was washed with the mixture of 1 mL of saturated Na2S2O3(aq), 2 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. .
The mixture of butanal (2.0 mmol, 180.2 μL) and DBDMH (0.14 mmol, 40 mg) was stirred in a 25 mL reactor tube at 80 °C for 45 min. After the completion of the reaction, the mixture was cooled to room temperature and dissolved in 10 mL of EtOAc. The solution was washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. (E)-2-pentylnon-2-enal (37m) [40] The mixture of heptanal (2.0 mmol, 279.6 μL) and DBDMH (0.14 mmol, 40 mg) was stirred in a 25 mL reactor tube at 80 °C for 1.5 h. After the completion of the reaction, the mixture was cooled to room temperature and dissolved in 10 mL of EtOAc. The solution was washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. (E)-2-octyldodec-2-enal (38m) [41] The mixture of decanal (2.0 mmol, 376.6 μL) and DBDMH (0.14 mmol, 40 mg) was stirred in a 25 mL reactor tube at 80 °C for 1.5 h. After the completion of the reaction, the mixture was cooled to room temperature and dissolved in 10 mL of EtOAc. The solution was washed with the mixture of 1 mL of saturated Na2S2O3(aq), 1 mL of saturated NaHCO3(aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under the reduced pressure. D. Scale-up procedure for preparation of methyl benzoate (1a) and isolation of 5,5-dimethylhydantoin The mixture of benzoic acid (30 mmol, 3.66 g), MeOH (15 mL) and 1,3-dibromo-5,5dimethylhydantoin (2.10 mmol, 0.60 g) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed with water (3 x 30 mL). The water layers were combined, concentrated to the volume of 8 mL by rotary evaporation and again extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure to yield 5,5-dimethylhydantoin. The organic layer from the first washing of the crude reaction mixture was washed with the mixture of 20 mL of saturated NaHCO3 (aq), 20 mL of 10% Na2S2O3 (aq) and 100 mL of distilled water. The water layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure to furnish methyl benzoate as colourless oil.
Yield (5,5-dimethylhydantoin) [43]: 227 mg, 85%. E. Scale-up procedure for preparation of methyl citrate (29a) The mixture of citric acid (30 mmol, 5.76 g), MeOH (60 mL) and DBDMH (0.70 mmol, 0.600 g) was stirred in a 25 mL reactor tube at 70 °C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with the mixture of 10 mL of saturated NaHCO3 (aq), 10 mL of saturated Na2S2O3 (aq) and 50 mL of distilled water and the water phase was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried with Na2SO4 and the solvent was evaporated under reduced pressure to furnish methyl citrate as a white solid. Yield: 6.53 g, 93%.
F. Scale-up procedure for preparation of methyl stearate (21a) The mixture of stearic acid (30 mmol, 8.53 g), MeOH (15 mL) and DBDMH (0.70 mmol, 0.600 g) was stirred in a 25 mL reactor tube at 70 °C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with the mixture of 20 mL of saturated NaHCO3 (aq), 20 mL of 10% Na2S2O3 (aq) and 100 mL of distilled water and the water phase was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with distilled water (2 x 20 mL), dried with Na2SO4 and the solvent was evaporated under reduced pressure to furnish methyl stearate as a white solid. Yield: 8.96 g, 100%.
G. Scale-up procedure for preparation of cholic acid methyl ester (30a) The mixture of cholic acid (2.0 mmol, 0.814 g), MeOH (8 mL) and DBDMH (0.14 mmol, 40 mg) was stirred in a 25 mL reactor tube at 70 °C for 5 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with the mixture of 5 mL of saturated NaHCO3 (aq), 5 mL of 10% Na2S2O3 (aq) and 20 mL of distilled water and the water phase was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with distilled water (2 x 20 mL), dried with Na2SO4 and the solvent was evaporated under reduced pressure to furnish cholic acid methyl ester as white solid. Yield: 0.845 g, 100%.