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