59th Annual Report on Research 2014

We investigated the use of NHC catalysts to accomplish direct anodic oxidation of the Breslow intermediate, absent redox mediators, and an expanded scope of alcohol coupling partners. Although direct bulk electrolysis of Breslow intermediates were previously unknown,   cyclic voltammetry studies of Breslow intermediates derived from thiazolium precatalysts showed that these intermediates have much lower oxidation potentials than their parent aldehydes (-0.9 V and > 2 V vs SCE, respectively).   

Initial screenings revealed 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and CH₃CN as the optimal base and solvent, respectively. An extensive catalyst screen indicated that thiazolylidines were more effective than their imidazolylidene, triazolylidene, and acyclic diaminocarbene counterparts. In general, good to excellent yields were obtained for a wide variety of aldehyde substrates (Figure 1), including substrates with ortho substitution and electrophilic groups, such as carboxylic acid, cyano, and ester functionalities. A notable limitation within the aldehyde scope is revealed when electron-rich benzaldehydes, such as 4-methoxy- and 4-dimethylaminobenzaldehyde, were employed. The reduced electrophilicity of these substrates results in at best sluggish conversion to the desired products, consistent with other approaches involving NHC-catalyzed oxidations of electron-rich benzaldehydes. Reactivity was restored by moving the electron-donating group out of conjugation with the aldehyde (e.g., 3-methoxybenzaldehyde) providing the desired ester in 87% isolated yield.

Moving away from aromatic aldehydes, it was found that cyclohexanecarboxaldehyde and α,β-unsaturated aldehydes reacted smoothly without evidence of competitive side reactions, such as aldol reactions, Stetter reactions, lactone formation, or conjugate reduction. A broad range of alcohols were also found to participate in the oxidative esterification. Most notably, functionalized and activated alcohols such as benzyl alcohol, allyl alcohol, propargyl alcohol, 4-pentyn-1-ol, and 2-(trimethylsilyl)ethanol proceeded smoothly. However, when s-BuOH and t-BuOH were employed, little to no ester was obtained even at elevated temperatures. 

Expanding upon the scope of NHC-catalyzed anodic oxidation of aldehydes, we demonstrated the direct conversion of aldehydes to thioesters. The switch to thiol coupling partners in place of alcohols was nontrivial, as the corresponding thiolates were found to be readily oxidized by the azolium precatalysts. Specifically, control experiments confirmed the formation of disulfides in the presence of azolium salts and strong bases, and disulfide formation was found to preclude thioester formation.

Figure 1.  NHC-catalyzed anodic oxidation of aldehydes to esters.

Following an extensive base screen, it was found that the base strength and concentration strongly influenced the product distribution. Optimal conditions involved using 50 mol % of 4-dimethylaminopyridine at slightly elevated temperatures. These conditions ultimately furnished access to thioesters derived from a broad scope of aldehyde and thiol precursors, with yields ranging from 56 to 89% (Figure 2). Unactivated and ortho-substituted aldehydes proceeded smoothly, as did cyclohexane carboxaldehyde. Electron-deficient aldehydes, including heteroaromatic 2-pyridinecarboxyaldehyde, provided good to excellent yields. Unfortunately, the use of α,β-unsaturated aldehydes resulted in poor yields presumably due to conjugate addition of the thiol. Thiols including primary thiols, benzyl, 2-chlorobenzyl, and 2-furfuryl thiol each gave good yields of the desired thioesters. Additionally, a secondary thiol, cyclohexanethiol, furnished the desired thioester in 63% yield. 

The undesirable thiolate oxidation by thiazolium-based NHC precursors that was observed during the development of our thioesterifications led us to investigate the reduction potentials of azolium precatalysts. Unwanted oxidation may be avoided in future studies through judicious selection of azolium precatalysts based upon their reduction potentials. We recently reported the reduction potentials of various classes of azolium cations, including a series of electronically varied thiazolium species, and introduced the first report of N-aryl thiazolinium salts.

Figure 2.  Aldehyde and thiol substrate scope for NHC-catalyzed anodic oxidations of aldehydes to thiosesters.

We evaluated the redox properties of multiple azolium salts using cyclic voltammetry. Each cyclic voltammogram (CV) was taken with a sweep rate of 100 mV/s and ferrocene (0.010 M) was added as an internal standard. Irreversible reduction peaks were observed in the CVs of each azolium species. We investigated several commonly used classes of azolium species for direct comparison, and an expanded set of thiazolium salts that demonstrated the extent to which electronic modification of the N-aryl moiety can be used to tune the reduction potential of the thiazolium ring (Figure 3). 

Figure 3. Half-wave reduction potentials of azolium salts (counterions omitted for clarity). Values in parentheses are E_1/2 values (V vs SCE) for the corresponding cation. Mes = 2,4,6-trimethylphenyl, DiPP = 2,6-diisopropylphenyl, PMP = p-methoxyphenyl, DEP = 2,6-diethylphenyl.

Within the series of N-aryl thiazolium salts (5a – j), a noticeable electronic influence was observed upon variation of the N-aryl ring. The incorporation of inductively electron donating groups (5b, 5c, 5d) shifts the E_1/2 ca. 100 mV more negative. In contrast, electron deficient groups (5i and 5j) shifted the E_1/2 ca. 100 mV more positive. Somewhat surprisingly, incorporation of a p-methoxyphenyl group at nitrogen (5g) resulted in little change in E_1/2 in comparison with the N-phenyl analogue (5h). This result may be due to the inability of the 5g system to adopt coplanarity of the N-aryl and thiazolium rings, due in part to the backbone methyl group of the latter. The > 200 mV range of E_1/2 values for this set is nearly as broad as that observed across the span of benzothiazolium, thiazolinium, and thiazolium salts combined. Interestingly, the N-aryl thiazolinium salts were found to be easier to reduce than their unsaturated thiazolium counterparts (5c and 5d). This was surprising to us considering the relative difficulty in reducing the corresponding saturated imidazolinium species 1.

In summary, we have demonstrated the organocatalyzed anodic oxidation of aldehydes at low controlled potentials. This method circumvents the use of stoichiometric exogenous oxidants and high cell potentials, and produces minimal byproducts. Relatively low catalyst loadings were successful for oxidative esterification and thioesterification of aldehydes, with H₂ gas as the only stoichiometric byproduct. In addition, the redox properties of a broad series of azolium salts were systematically investigated via cyclic voltammetry. These electrochemical studies may aid in the development of azolium-based materials, NHC precatalysts, electrosynthesis of NHCs, and correlation of electrochemical properties and other fundamental reactivities.