Thiyl radical promoted iron-catalyzed-selective oxidation of benzylic sp3 C-H bonds with molecular oxygen

Article abstract of DOI:10.1039/c9cc06584a

A ligand-free iron-catalyzed method for the oxygenation of benzylic sp³ C-H bonds by molecular oxygen (1 atm) using a thiyl radical as a cocatalyst has been developed. This transformation provides a facile access to amides, esters and ketones from readily accessible corresponding amines, ethers and alkanes. It features high regioselectivity, mild oxidative conditions and excellent functional group compatibility, providing good opportunities to the site-selective functionalization of complex molecules. Preliminary mechanistic studies suggest that this reaction may not undergo a benzylic cation intermediate pathway and the carbonyl oxygen atom in the products may be derived from molecular oxygen.

Full text of DOI:10.1039/c9cc06584a

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Thiyl radical promoted iron-catalyzed-selective
oxidation of benzylic sp3 C–H bonds with
molecular oxygen†
Cite this: Chem. Commun., 2019,
55, 12699
Received 26th August 2019,
Accepted 19th September 2019
Shasha Geng,‡a Baojian Xiong,‡a Yun Zhang,‡a Juan Zhang,a Yun He *a and
ab
Zhang Feng
*
DOI: 10.1039/c9cc06584a
rsc.li/chemcomm
A
ligand-free iron-catalyzed method for the oxygenation of
Recently, a range of transition-metal catalysts, organocatalysts
benzylic sp3 C–H bonds by molecular oxygen (1 atm) using a thiyl and photoredox catalysis have been employed in the oxidation of
radical as a cocatalyst has been developed. This transformation benzylic C–H bonds.4 Among these methods, iron-based catalysts
provides a facile access to amides, esters and ketones from readily stand out, due to their abundance, low cost and environmental
accessible corresponding amines, ethers and alkanes. It features friendliness.5 However, iron-catalyzed oxidation of amine sp3 C–H
high regioselectivity, mild oxidative conditions and excellent func- bonds has been scarcely reported, and studies using molecular
tional group compatibility, providing good opportunities to the oxygen as the terminal oxidant are yet to be realized.6 In 2015, an
site-selective functionalization of complex molecules. Preliminary iron-catalyzed oxidation of aliphatic amines to amides using
mechanistic studies suggest that this reaction may not undergo a peroxide ester PhCO3tBu was disclosed by the Emmert group,6a
benzylic cation intermediate pathway and the carbonyl oxygen in which a cationic imine intermediate was proposed and water
atom in the products may be derived from molecular oxygen.
was employed as the oxygen atom source. Herein, we report a
ligand-free iron-catalyzed method for the selective oxygenation of
Selective oxidations of benzylic C–H bonds offer significant and benzylic sp3 C–H bonds by molecular oxygen (1 atm) using a thiyl
useful transformations in organic chemistry to convert feed- radical as a cocatalyst.
stock into valuable synthetic building blocks.1 For instance,
As shown in Scheme 1, the sp3 C–H bond dissociation
oxidation of benzylic alkanes to the corresponding alcohols or energies of benzylic alkanes and ethers are closely similar.7 It’s
ketones provides a facile method for the late-stage diversifica- no surprise that both benzylic alkanes and benzylic ethers can
tion of complex biomolecules via oxidation of sp3 C–H bonds.1 be directly oxidized to the corresponding ketones and esters
This transformation has thus attracted much attention and under the same reaction conditions using the above-mentioned
numerous methods have been developed. However, some of protocols.3 Inspired by the work of the MacMillan group,8 we
these reactions involve the use of stoichiometric amounts of envisioned that the high regioselectivity of this oxygenation
additional oxidants or suffer from cost or poor environmental reaction would be achieved if the benzylic carbon-centered
friendliness.2 Moreover, these reactions also have poor chemo- radical could be selectively generated among different sp3
selectivity, which would directly oxidize benzylic amines, C–H bonds by a highly reactive thiyl radical via a hydrogen
alkanes and ethers to the corresponding carbonyl compounds abstraction process (Scheme 1).9
under the same conditions.3 As a result, late-stage site-selective
To test this hypothesis, we initiated our study on the
functionalization of complex molecules bearing different reac- oxygenation of cyclic amines as the desired lactams are impor-
tive sp3 C–H bonds remains challenging.3 It is of great interest tant motifs in organic synthesis. Previous studies of our group10
to develop a highly selective method for the oxidation of demonstrated that the thiol and ferrocene-based catalytic systems
benzylic C–H bonds.
are highly efficient in oxidizing CQC bonds.11 Thus, ferrocene
derivatives were firstly evaluated in the presence of disulfide S1,
and 17–25% yields of the desired product 1aa were obtained
(Table 1, entries 1–4). Fe5 bearing an electron-rich amine can
deliver the desired product in 43% yield (Table 1, entry 5). Other
thiyl radical sources were also screened, and disulfide S1 stood
out (Table 1, entries 6–8). Moreover, a catalytic amount of
inorganic bases was found to improve the efficiency of the
reaction (Table 1, entries 9–12). Sodium phosphate can promote
a Chongqing Key Laboratory of Natural Product Synthesis and Drug Research,
School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331,
P. R. China. E-mail: fengzh@cqu.ac.cn, yun.he@cqu.edu.cn
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc06584a
‡ These authors contributed equally.
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disulfide S1 was used as the catalyst. These results suggest that
both iron catalyst and disulfide play important roles in facilitat-
ing the oxygenation of benzylic C–H bonds.
With the optimized conditions established, we examined the
scope of this iron-catalyzed oxygenation reaction. The results
showed that this reaction could serve as a general protocol
for the diversification of cyclic amines and isochromanones.
The substrate scope for the oxygenation of amines to amides
was examined. As shown in Table 2, tertiary benzylic amines
reacted smoothly under the optimized conditions. Both
electron-rich and electron-poor groups on the N-phenyl ring
could be tolerated. Substrate 5a containing a nitro group, which
always suffers from low efficiency in a single-electron transfer
catalytic system, could also be tolerated. The cyclic amines
bearing different N-protecting groups, such as Ac, Cbz, Alloc,
and Boc, also performed well, furnishing the corresponding
amides in good yields (7aa–11aa, 59–70%). To test the selectivity
of this thiyl radical and iron-based catalytic system, substrates
(12a–14a) containing different reactive C–H bonds were
examined. These substrates showed high selectivity during
the oxidation, and only C–H bonds on the cyclic ring could
be oxygenated. Furthermore, the oxygenation of ethers to esters
Scheme 1 Proposed mechanism for the oxygenation of benzylic amine sp3
C–H bonds via the merging of the thiyl radical process and iron catalysis.
this reaction, providing the corresponding amide 1aa in 66% was also explored. The substrates bearing alkyl substituents in
yield. Encouraged by the results, we further investigated the the alkyl ring furnished the corresponding products in good
oxygenation of isochromans to provide the isochromanones, yields (2bb–3bb, 79–80%). The substituents in the aromatic
which occurs frequently in natural products and biomolecules. ring revealed a slight electronic effect, and the isochromans
To our delight, bis(diphenylphosphino)ferrocene Fe1 can containing a strong electron-donating group performed well
deliver the desired product in 75% yield (Table 1, entry 13). with moderate to good yields (6bb–8bb, 62–75%), which is in
Control experiments revealed the necessity of disulfide (Table 1, sharp contrast to previous reports,6b in which the electron-rich
entry 13 vs. 17). It should be mentioned that less than 10% of the substrates performed with only low efficiency. Substrates
desired product was also observed along with the concomitant bearing an acetoxy or boronate ester group also delivered
formation of other unidentifiable compounds when only the corresponding products in moderate yields, respectively
Table 1 Representative results for the optimization of the iron-catalyzed selective oxygenation of amine 1a and isochroman 1ba
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv.), O2 (1 atm), [Fe] (0.03 mmol, 0.1 equiv.), disulfide (0.03 mmol, 0.1 equiv.),
dioxane (0.5 mL), 80 1C, 15 h. Determined by 1H NMR using mesitylene as an internal standard. The isolated yield is shown in parentheses.
b
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Table 2 Scope of the iron-catalyzed oxygenation of benzylic sp3 C–H bondsa
a
Reaction conditions: oxygenation of amines to amides: amine (0.3 mmol, 1.0 equiv.), O2 (1 atm), (dimethylaminomethyl)ferrocene (0.03 mmol,
0.1 equiv.), disulfide (0.03 mmol, 0.1 equiv.), dioxane (0.5 mL), Na3PO4 (0.03 mmol, 0.1 equiv.), 80 1C, 15 h; oxygenation of ethers to esters: ether
(0.3 mmol, 1.0 equiv.), O2 (1 atm), 1,10-bis(diphenylphosphino)ferrocene (0.03 mmol, 0.1 equiv.), disulfide (0.03 mmol, 0.1 equiv.), dioxane
b
(0.5 mL), 80 1C, 15 h. Reaction conditions: oxygenation of amines to amides: amine (0.2 mmol, 1.0 equiv.), O2 (1 atm), (dimethylaminomethyl)-
ferrocene (0.02 mmol, 0.1 equiv.), dioxane (0.1 mL), t-BuOLi (0.02 mmol, 0.1 equiv.), 80 1C, 15 h; oxygenation of ethers to esters: ether (0.3 mmol,
1.0 equiv.), O2 (1 atm), acetylferrocene (0.03 mmol, 0.1 equiv.), Na2CO3 (0.1 equiv.), dioxane (0.5 mL), 80 1C, 15 h.
(9bb–10bb, 60–70%), paving a way for further diversification of
The high regioselectivity and mildness of this benzylic C–H
isochromanones. In addition, substrates possessing a halide bond oxidation approach was further demonstrated by its
group also exhibited good reactivity, leading to the desired applicability in oxygenation of benzylic alkanes and non-
compounds in good yields (12bb–14bb, 71–80%). Notably, cyclic benzylic ethers. As shown in Scheme 2, substrates 1b,
isochroman 11b containing benzylic ether C–H bonds and 19b, 20b and 21b, bearing one very similar benzylic C–H bond,
allylic C–H bonds also performed smoothly, and importantly, produced the corresponding carbonyl compounds by other
only oxygenation of benzylic ether C–H bonds occurred. In common oxidative protocols due to their strongly oxidative
addition, this transformation could be extended to naphthyl conditions.3a–c Interestingly, we found that this iron/thiyl radical
and hetero-aromatic derivatives, although only moderate yields catalytic system can selectively oxidize the benzylic C–H bonds,
were obtained (15bb–16bb, 45–60%). Since this approach and only cyclic ether 1b could react in the presence of Fe1 and S1,
exhibited high efficiency in oxidizing isochroman derivatives, which is in sharp contrast to previous methods, where the
we turned our attention to the oxidation of phthalans benzylic C–H bonds of ether 19b, alkane 20b and 21b could be
as phthalides are also very important structures in natural oxygenated easily. Encouraged by these results, substrates 15a and
products. Gratifyingly, the corresponding esters were obtained 22b possessing two reactive benzylic C–H bonds provided the
in moderate yields using phthalans 17b and 18b as substrates. desired products in moderate yields. It should be noted that the
To show the scalability of this protocol, gram-scale synthesis acyclic ethers and alkanes (19b, 20b, and 23b, Scheme 2) could
was conducted, and the desired products were obtained in also be converted to their corresponding carbonyl compounds in
acceptable yields (1aa, 35% and 1bb, 30%).
moderate yields when Fe5 or Fe2 was used as a catalyst in the
It should be noted that alternative thiyl radical-free conditions
were also established after extensive studies. Comparison of the
results is shown in parentheses in Table 2. Amines and ethers
showed similar results. Substrates without sensitive functional
groups could perform well, providing the corresponding amides
and esters in good yields (1aa–4aa, 73–82%; 1bb–4bb, 68–92%;
and 13bb–15bb, 70–87%), but low conversion and poor selectivity
would occur with substrates bearing sensitive functional groups,
which were monitored by TLC. These results revealed that the
thiyl radical iron-based catalytic system is superior to thiyl radical-
free catalytic systems. Furthermore, the oxygenation of substrates
13a–14a and 11b exhibited high selectivity, which encouraged
us to further investigate the site-selectivity of these thiyl radical
iron-based catalytic systems.
Scheme 2 Regioselective oxygenation of benzylic sp3 C–H bonds via
iron catalysis.
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