Background and Originality Content
Functionalization of unactivated sp3 C–H bonds of cyclic and linear alkanes to high-value-added chemicals is one of the most important classes of chemical transformations and has high synthetic potential in synthetic chemistry.[1]Unfortunately, the high bond dissociation energy, low selectivity of alkyl sp3 C–H, and over oxidation of products make them inert to various reactions and lead to low yields or poor selectivity.[2] Despite these challenges, activation of unactivated sp3 C−H bonds has been received much attention for the construction of halo-alkanes, alcohols, and ketones[3] which are common groups and subunits found ubiquitously in natural products, pharmaceuticals, agrichemicals, and organic materials.[4]In recent years, various methods have been developed for the chlorination, bromination, and oxidation of the inert C−H bonds involving the use of transition metal-containing or free catalysts/reagents.[5]
With environmental problems becoming increasingly prominent, non-metallic and environmentally friendly synthetic approaches, are more and more needed. Aromatic peracids, ozone, dioxiranes, etc., were used for the halogenation or oxidation of alkyl sp3 C−H bonds.[5f,5j,6] N -chloroamines, sodium nitrite (cat.) were employed for the halogenation of alkyl sp3 C–H bonds.[7]Electron-deficient amide was utilized as the directing group for synthesis of lactones via functionalization of nonactivatedsp3 C−H Bonds.[8]With growing demands of using inexpensive, commercially available reagents, hypervalent iodine (III) has been widely used to trigger various reactions owing to its unique reactivity, low toxicity, and environment friendliness.[9] For example, Maruoka reported the oxidation of alkyl C−H bonds by ortho -nitrophenyl derivative of (diacetoxyiodo)benzene (DIB) in the presence oftert -butyl hydroperoxide (TBHP).[10]Laborious preparation of ortho -nitrophenyl derivative of DIB and using of explosive peroxide render practicability of this method limited. Yeung’s system, which utilizes less moisture-sensitive DIB for the oxidation of C–H bonds, proved to be incompetent for activation alkyl C–H bonds, because of its low activity of iodanyl radical generated from stable DIB.[11] Compared with the other methods (e.g., ligand exchange, thermal decomposition or
Scheme 1 . Functionalization of Alkyl sp3 C–H Bonds
single-electron transfer approach) photolysis can induce the generation of iodanyl radical from hypervalent iodine (III) reagents under milder conditions.[5f] Therefore, based on our previous work on iodine (III),[12] we assumed that if iodanyl radical with the activity high enough to activate inert C−H bond could be generated from DIB under photolysis, then halogenation, and oxidation of the inert C−H bonds would be realized under mild conditions.
Herein, we report a new photo induced approach to generate iodanyl radical using DIB, which can realize the direct chlorination, bromination, and oxidation of unactivated sp3 C−H bond by NaCl, KBr, or water, respectively. Inspired by the pioneering work of Maruoka,[10a,13] our strategy for the functionalization of unactivated sp3 C–H bond with DIB under photolysis is shown in scheme 1. First, an acetoxyl radical1 and an iodanyl radical 2 would be formed from the photolysis of DIB. Then iodanyl radical 2 reacted with unactivated alkane to afford an alkyl radical 3 through hydrogen abstraction. The alkyl radical 3 couples with different coupling reagents to lead the different alkylation products through path A (radical pathway) or path B (ionic pathway: alkyl cation would be generated by single electron transfer (SET) from alkyl radical, which could be captured with various nucleophilic reagents, such as chloride, bromide, or water to afford haloalkanes, alcohols, ketones, respectively.)
Results and Discussion
Based on the design and our previous work of DIB, cyclohexane was used as a model substrate to optimize the chlorination (Table 1). Delightedly, the desired product chlorocyclohexane could be observed in 32% yield, when DIB was used as the oxidant, and NaCl as the chlorine source in DCM under blue light for 3 h (entry 1). Initially, different amount of DIB was studied (entries 2-5), and 3.5 equivalent of DIB was chosen. Encouraged by the positive experimental results and in consideration of the role of water in the expected pathway, we tested the effect of water on the system. Without water, no product was observed, which may be due to the poor solubility of NaCl. However, when more than 0.5 mL of water was added to the reaction, decreasing yields were obtained, mainly due to the insolubility of DIB in water (entries 8-12). The employment of polar solvents failed to improve the efficiency of the reaction (entries 13-15). Next, the influence of reaction time was also tested, and 5h gave the best result, providing halogenation products in 80% yield, while a further prolonged period led to a slightly declined yield (entries 16-21). The screening of chlo-rides revealed that NaCl performed best (entries 22-23).
Replacement of blue light with purple light resulted in a diminished yield (entry 24). Furthermore, in the dark, the desired product4a could not be observed, indicating that irradiation is necessary for the generation of iodanyl radical (entry 25). To our delight, cyclohexyl bromide 4b and cyclohexanol 4c can also be constructed albeit in moderate yields just via changing NaCl with KBr or water. The optimal conditions were shown in entries 26 and 27 (for detailed optimizing process, see the Supporting Information).
With these optimal conditions in hands, different cyclic and linear alkanes were investigated, as listed in Table 2. The chlorination, bromination, and oxidation of cycloalkanes such as cyclopentane and cyclooctane were first tested and both provided the corresponding chlorocycloalkanes, bromocycloalkanes, alcohols, and ketones, in moderate to good yields when NaCl, KBr or H2O was added, respectively (products 5a-5c and 6a-6c ). The activation of inert secondary and tertiary sp3 C–H bond in adamantane also proceeded smoothly. In oxidation reaction, 1-adamantanol was generated in moderate yield, and as for chlorination and bromination reactions, two monohalogenation isomers were generated in good yields (products 7a-7c ). When substrate with primary, secondary and tertiary carbon (such as methyl cyclohexane) was subjected to the standard conditions, highly selective halogenation or oxidation at tertiarycarbon was observed to furnish corresponding haloalkane or alcohol (8a-8c ). For linear alkanes including heptane, octane, the halogenation and oxidation products (9a-9c and10a-10c ) were delivered in moderate to good yields, with unsatisfactory regioselectivities. When substrates with only one kind of carbonyl α sp3 C−H or active benzyl were exposed to the conditions, their
Table 1. Optimization of oxidation and halogenation of cyclohexane by DIBa