Catalytic α-selective deuteration of styrene

Deuterated Styrene Derivatives

Deuterium-labeled compounds have a wide range of uses in research in different fields. Compared with the C-H bond, the bond strength of the C-D bond is increased, which may cause significant changes in the reactivity of the reactants. In pharmaceutical chemistry research, doping deuterium atoms is a common strategy to modify the absorption, distribution, metabolism and excretion (ADME) characteristics of candidate drugs. Deuterium-labeled compounds can also be used as tracers and analytical standards to help people understand the metabolic mechanism of drugs. In synthetic chemistry research, deuterium-labeled compounds are widely used for the measurement of kinetic isotope effects and the tracking of reaction pathways. Therefore, it is of great significance to develop catalytic methods for direct selective conversion of C-H bond regions to C-D bonds. Selective hydrogen isotope exchange, especially at the benzyl site, heteroatom ortho-sites, and aromatic rings, has made significant progress in recent years. Deuterated substitutions of olefins also have high application value. Although some metal-catalyzed deuterated substitutions of inactive olefins have been reported, deuterated substitutions of styrene derivatives are very rare. In addition to competing reactions of C-H bond activation of aromatic hydrocarbons, how to control the check point selectivity of deuterated substitutions of styrene is also its main challenge. Castarlenas and Oro et al. reported that the Rh-catalyzed method achieved β, β-bis-deuterated substitutions of styrene, but there is no effective method of styrene α-selective deuterated substitutions.

Research Background and Challenges

Recently, the research group of Professor Jeffrey S. Bandar from the Department of Chemistry of Colorado State University in the United States reported a practical catalytic method for the synthesis of α-selective deuterated styrene derivatives. The above process was achieved by the reversible addition of methanol to styrene using KO-t-Bu as the catalyst and DMSO-d6 as the deuterated reagent. The concentration of methanol is crucial to the yield and selectivity. Related work was published in J. Am. Chem. Soc.

Reaction conditions and mechanisms

The authors have reported that the organic superbase P4-t-Bu can be used as a highly active catalyst to realize the anti-Martensitic addition reaction of alcohol to styrene, which is controlled by thermodynamic equilibrium. The mechanism study shows that MeOH is not easy to add in polar solvents. Using the addition of methanol to 4- (trifluoromethyl) styrene (1) as a model reaction, the authors determined that the yield of β-phenylene ether 2 at equilibrium in m-xylene was 21% (Keq = 0.20) and 9% at equilibrium in dimethyl sulfoxide (DMSO) (Keq = 0.07). The author believes that if the reaction is carried out in DMSO-d6 solvent, MeOH undergoes hydrogen/deuterium (H/D) exchange and reversible addition, thereby achieving α-selective deuteration of styrene. The author's preliminary investigation found that P4-t-Bu (10 mol%) can catalyze the α-selective deuteration reaction of 1, with a yield of 88% and a deuteration rate of> 99%. And KO-t-Bu also has similar activity and can be used as the first choice catalyst for further research.

The author proposes that the process of α-deuterated generation proceeds according to the pathway of Figure 3. First, KO-t-Bu captures hydrogen from MeOH and undergoes H/D exchange with DMSO-d6, forming KOMe. Then, MeOD performs nucleophilic addition to styrene to generate partially deuterated phenethyl ether 3. Finally, 3 eliminates MeOH to generate α-deuterated styrene. Excess DMSO-d6 may be the driving force that pushes the equilibrium forward.

Although the mechanism of the reaction is conceptually simple, the alpha-deuteration process must be much faster than other reactions promoted by bases. The C-H bond of weakly acidic aromatic hydrocarbons is easily deuterated in the basic DMSO-d6 solution. In addition, it is necessary to avoid the alkali-catalyzed polymerization of styrene or SNAr side reactions, and to inhibit the direct participation of MeOH in the addition reaction.

Scope of application of substrate

The authors found that although each substrate needs to be adjusted empirically for the optimal reaction temperature and time, the use of 1 or 3 equivalents of MeOH and 10 mol% of KO-t-Bu can be used as general reaction conditions. Electron-deficient as well as neutral styrenes are suitable substrates with moderate to excellent yields, while electron-rich styrenes have insufficient electrophilicity under these conditions, making it difficult to establish an equilibrium. Halogenated styrenes, including ortho-substituted bromide (4), chloride (5), and iodide (6), can also undergo selective α-deuterated generation. The reaction is also compatible with meta-and para-ester (7), amino (8), trifluoromethylthio (9), and diphenyl (10) functional groups. Both the fused aromatic system and the heteroaromatic hydrocarbon-modified styrene contain highly acidic aryl C-H bonds and can also undergo selective α-deuteration, including naphthalene (11 and 12), anthracene (13), pyridine (14 and 15), isoquinoline (16) and quinoline (17) vinyl. β-methylstyrene (18) can undergo alpha-and γ-deuteration by simple deprotonation, and β-methoxystyrene (19) and distyrene derivatives (20) can also undergo selective deuteration.

Reaction Optimization and Strategies

Next, the authors explore the key role of MeOH in promoting selective α-deuteration. Using styrene 14 as a substrate, they tracked the mass balance (14 + 14-α-d) of α-deuterated styrene and styrene in the presence of different amounts of MeOH (0.25, 0.5, and 1.0 equivalents). When 0.25 equivalents of MeOH were used, the deuteration rate was significantly accelerated, but the mass balance was close to 0%. While 1 equivalents of MeOH formed a completely α-deuterated product while maintaining a mass balance of more than 90%. When KO-t-Bu was used as a base and no alcohol was added, the main by-product of the reaction was polystyrene. These studies show that in order to use MeOD to rapidly deuterate benzyl anions and exceed the rate of styrene anionic polymerization, MeOH needs to maintain a certain concentration.

Considering the key role of alcohols in the reaction process, changing the structure of alcohols may overcome competing side reactions. O-halogenated styrene can undergo effective α-deuteration, but the more active 2-chloro-3-vinylpyridine (21) mainly undergoes SNAr reaction, and only 21% of α-deuteration 21 is obtained by adding MeOH. The author believes that nucleophilic alcohols with greater steric resistance can promote α-deuteration. The use of 1-cyclopropanol (22) and 18-crown-6 can achieve 96% of α-deuteration in a yield of 63%. Other challenging substrates can also be improved using this strategy.

Summary

The research group of Professor Jeffrey S. Bandar reported an efficient and high-deuteration method to achieve α-deuteration substitution of styrene compounds. The reagents used in the reaction are cheap and easy to obtain, the method is easy to operate, and has good substrate applicability. This simple and practical method has important application value in chemical and pharmaceutical research.