Quaternary carbon synthesis never worries!
The quaternary ammonium reaction of nitrogen atoms is a polar bonding reaction that originated in the 19th century and is one of the earliest examples of C-N bond formation in organic synthesis. Its simplicity and the wide availability of the required feedstock stand in stark contrast to the way chemists construct quaternary carbon compounds. Similar to quaternary ammonium, a simple and predictable method can be used to form quaternary C, which has been attracting chemists. Pioneering research by Hirobeand and colleagues has shown that iron porphyrins can achieve Drago-Mukaiyama-type olefin hydration. Seminal study by Setone et al. found secondary alkyl iron porphyrins that can be formed upon exposure to [Fe(TPP)Cl] and NaBH4. Fe-H formation and metal hydride hydrogen atom transfer (MHAT) explain branched-chain selective hydrogen metallization reactions. Brault and Neta described the alkyl-Fe3+ (TPP) complex as an intermediate with a single electron density localized on C, which explains its ironporphyrin-like behavior. Shenvi et al. catalyzed the formation of C-C bonds between benzylbromide and alkenes with the same iron complexes and silanes, forming a quaternary center through a bimolecular homosubstitution (SH2) reaction. Baran's group demonstrated the decarboxylated Negishi coupling of iron-catalyzed oxidative active esters (RAEs) and various aryl organometallic reagents. Based on these findings, it is plausible that RAEs may quaternize free radicals through a catalytic cycle in which Fe(II)porphyrins form and trap open-shell intermediates generated by olefins or other RAEs. These two associated catalytic cycles produce Fe(II) under reducing conditions, which may scavenge hydroxy-phthamine, producing primary and/or tertiary radicals. Since the tertiary alkyl complex is unstable above 0 °C, it is preferred to trap the primary radical so that it is intercepted by the tertiary radical in the SH2 reaction. The same tertiary radicals can be formed from olefins and the hydrogenation of iron, which can regenerate iron(II) by MHAT or hydrogen evolution reaction (HER). Unlike many MHAT reactions, this catalytic cycle does not require an exogenous oxidant; RAEs re-oxidize Fe(II) to (III).
Based on these findings, the team of Ryan Shenvi, Phil S. Baran and Yu Kawamata from the Scripps Research Institute in the United States reported a simple combination of catalyst and reducing agent that can convert carboxylic acids and olefins to quaternary carbon through quaternary ammonium of free radical intermediates. The work was published in Science under the title "Carbon quaternization of redox active esters andolefins by decarboxylative coupling". The first authors of the paper are Dr. Xu-cheng Gan (graduated from the Yin Liang group of the Institute of Organic Chemistry), Dr. Zhang Benxiang (graduated from the Li Chaozhong group of the Institute of Organic Chemistry) and Nathan Dao, two of whom are young Chinese scholars who graduated from the Shanghai Institute of Organic Chemistry.
Figure 1. Brief description of the reaction [Establishment of reaction conditions] RAE 5 is used with olefin 7 or RAE 8 to generate product 6. The following conditions are used: Fe(TPP)Cl complex, alkali, reducing agent and 1,2-dichloroethane (DCE)/acetone mixed solvent. The choice of base is crucial, and in this study, CsOAc was the best choice. An increase in yield can be observed after Ar or N2 bubbling of the reaction mixture. If the solvent is not suitable for acetone, it will result in a reduced yield, which may be due to the solvent nature of the catalyst. The use of other iron sources such as Fe(acac)3 also leads to a decrease in conversion rates. As observed in other MHATs, the use of prefabricated silanes can significantly improve conversion rates. For RAE-RAE coupling, the product yield under the above optimized conditions is only 9%. Increasing the iron load to 20% can lead to a significant increase in conversion rates. The yield could be further improved by converting the reducing agent from silane to zinc metal, changing the solvent composition to 7:4 DCE/acetone, and replacing CsOAc with KOAc. The use of weak acid (Et3N•HCl) can activate Zn(0), which increases the yield of product 6 to 61%. The final optimized RAE-RAE coupling conditions do not apply to olefin-RAE coupling, and vice versa. Both conditions used a simple combination of commercially available reagents and the same Fe(TPP)Cl catalyst. Iron-catalyzed decarboxylation coupling does not require O2 for the catalytic cycle (Fe2+ to Fe3+). Iron(II) porphyrins are converted to iron(III) under hypoxic conditions by reacting with RAE or the free radicals it generates. 1H NMR studies showed that Fe (TPP) complexed with n-pentyl CO (NHPI) before forming n-pentyl Fe (TPP). Iron (TPP) can be produced from its corresponding hydrides by hydrogen evolution or olefin MHAT. Thus, Fe(TPP)Cl mimics the polyfunctional groups of precious metals in the functionalization catalysis of inner (coordination) olefins. In the case of RAE-RAE coupling, zinc metal can reduce and break down NHPI esters into C-center radicals. The optimal bases for the above two different conditions are empirically determined and may play different roles. Silanes may require the addition of Lewis base to increase hydrogenation strength and accelerate the hydrogenation rate of the metal during the formation of MHAT with olefins.
Figure 2. Optimization of reaction conditions [substrate applicability of the reaction] With the determination of the quaternary ammonium conditions for olefins and carboxylate radicals, the authors further studied the applicability of the conditions. These conditions have been found to be compatible with a range of functional groups, including carbamates, amides, alkyl halides, epoxides, halogenated aryls, esters, alcohols, nitriles, tertiary amines, ketones, ureas, and electron-rich or electron-deficient heterocycles. It is important to note that alkyl bromide, terminal alkyne, and alkyl borates can remain unchanged during quaternization. Similarly, although aryl iodide and electron-deficient aryl chloride are commonly used for free radical cross-coupling, they are not affected. In the case of olefins, preferential reactivity can be obtained during RAE-RAE coupling, while olefins with poor reactivity are less likely to react during RAE-olefin coupling. Stable radicals from heteroatoms or aryl carboxylic acids can also be conjugated. In the case of RAE-RAE coupling of this substrate, FeOEP can result in a substantial increase in yield. In addition, complex drug molecular structures can be efficiently coupled to obtain quaternary carbon analogues36 to 40. The reactions described above are very simple and practical, use inexpensive reagents, have fast set-up times, and have proven suitable for gram preparation. Under hypoxic conditions, it can be easily scaled up to gram levels without changing the yield.
Figure 3. Reaction Applicability【Simplified Quaternary Carbon Synthesis】There is no doubt that the reaction in this report can significantly simplify the synthesis of quaternary carbon-containing molecules. In previous synthesis, the traditional pathway relied on a wide range of redox operations, functional group conversion and other steps. In contrast, the modularization and Lego-like transformation of molecular structures can be achieved through the commercial building blocks (olefins and acids) through the direct carbon-quaternary ammonization of free radical intermediates, avoiding traditional inefficient strategies. For example, simple alkyne-53 was previously prepared in 8 steps during the synthesis of prostaglandin analogues, only one of which formed a C-C bond, while the key quaternary carbon was introduced in the form of dimethylcyclohexanone-52, the backbone of which was lengthily edited and synthesized. In contrast, conjugation of commercially available olefin 54 to RAE obtained from simple alkyne-containing acids under free radical quaternary ammonium conditions yields 53 in just two steps (48% separation yield). 56 is a component of steroid analogue synthesis and was previously obtained by classical carbonyl chemistry, C-C homology, and various reagents such as Br2, Mg, and OsO4. Using this method, after the free radical quaternization reaction with 58 pairs of olefin 57, the same structure was directly obtained, and then acidified with a separation yield of 45%. 60 contains two quaternary carbon centers, previously obtained by starting with glutaric anhydride 59 and by an 11-step inefficient reaction. Based on this method, diene61 was first cross-coupled with methacrylate by alkene-olefin Fe-catalyzed MHAT (yield 72%), and then radical quaternization reaction was performed with RAE 63 to 62 to obtain the same product 60 with a separation yield of 58%, thus avoiding the use of 9 inefficient steps and toxic reagents. 65 is often used as a substrate in cyclic isomerization studies, which were previously obtained through a 15-step reaction that relies on alkyne hydrogen metallization, Wittig reaction, carbonyl chemistry, and acetyl addition as key C-C bond formation steps. This lengthy step requires the use of a protecting group and a large number of redox operations. A more intuitive "Lego"-style approach is achieved through radical countersynthesis. Thus, the silver-nickel-facilitated decarboxylation of acid 66 with ethylene iodide 67, followed by free radical quaternization of alkyne-containing RAE68, yields 65 in just five steps without any redox operation. Free radical quaternization can also be used to construct backbones in natural products. For example, meperidine-70 has a quaternary carbon at the C-3 position and is a key backbone in madangamine alkaloids. In the previous seven-step synthesis, the construction of the quaternary carbon center still relied on carbonyl chemistry starting with 2-piperidone. Of these seven steps, two form C-C bonds. Starting with commercial acid 71, simple alkylation is carried out, and then free radical quaternization with free alcohols containing RAE70 can be synthesized in three steps. α-Tocopherol analogue 74 is useful for the regulation of microglial activation and requires a 10-step reaction to obtain. In a completely different move from this strategy, commercially available Trolox can efficiently bind to the desired alkyl side chain with RAE72 by free radical quaternization (58% yield), which can be obtained in just three steps74.
Figure 4. To summarize the utility of the reaction, this study proposes a novel method to simplify the synthesis of quaternary carbon frameworks, achieved by utilizing quaternary ammonium of free radical intermediates, using a simple combination of catalysts and reducing agents to convert carboxylic acids and olefins into tetrasubstituted carbon atoms. This method reduces the synthetic burden and makes it easier and scalable to obtain quaternary carbon-containing products from simple chemical feedstocks. Source: Frontiers of Polymer Science