Metal-free oxidative functionalization of C(sp3)-H bond adjacent to oxygen and radical addition to olefins

Article abstract of DOI:10.1021/acs.orglett.5b00088

A DTBP-promoted oxidative functionalization of a C(sp³)-H bond adjacent to oxygen and intermolecular radical addition to olefins without use of any metal catalyst or photoredox catalysis is reported. The reaction has a wide scope of olefin, alcohol, and cycloether substrates, which provides an easy way for direct preparation of α,ω-amino alcohols.

Full text of DOI:10.1021/acs.orglett.5b00088

Letter
pubs.acs.org/OrgLett
Metal-Free Oxidative Functionalization of C(sp3)−H Bond Adjacent to
Oxygen and Radical Addition to Olefins
Wei Zhou, Ping Qian, Jincan Zhao, Hong Fang, Jianlin Han,* and Yi Pan
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing,
210093, China
S
* Supporting Information
ABSTRACT: A DTBP-promoted oxidative functionalization
of a C(sp3)−H bond adjacent to oxygen and intermolecular
radical addition to olefins without use of any metal catalyst or
photoredox catalysis is reported. The reaction has a wide scope
of olefin, alcohol, and cycloether substrates, which provides an
easy way for direct preparation of α,ω-amino alcohols.
irect C−C bond formation via selective C−H bond
addition to simple alkenes under metal-free conditions would
be an ideal pathway for the construction of C(sp3)−C(sp3)
bonds. Very recently, our group explored a metal-free oxidative
C(sp3)−H bond functionalization of alkanes and subsequent
conjugate addition to chromones for preparation of 2-
alkylchromanones.15 To the best of our knowledge, the radical
addition of hydroxyl alkanes to unactivated olefins under metal-
free conditions without the use of photoredox catalysis has never
been reported.16 Herein, we reported a DTBP-promoted
oxidative functionalization of the C(sp3)−H bond adjacent to
oxygen and intermolecular radical addition to olefins under
metal-free conditions, affording the α,ω-amino alcohols as
products (Scheme 1). The resulting α,ω-amino alcohols are
useful organic intermediates and exist in many medicinal and
biological compounds.17
D
functionalization has been an extremely popular research
topic in recent years because it can eliminate synthetic steps,
alleviate waste, and improve limitations for the preparation of
functionalized substrates.1 Compared with C(sp2)−H function-
alization, the functionalization of C(sp3)−H bonds is more
challenging due to the low reactivity of aliphatic C−H bonds and
lack of a coordination site for a metal catalyst.2 Recently, varieties
of approaches have been explored on C(sp3)−H bond
functionalization adjacent to heteroatoms, which generate new
bonds as well as allow introduction of alcohol, ether, amide, or
other functional groups.3 Transition-metal-catalyzed functional-
ization of C(sp3)−H bonds followed by cross-coupling (cross-
dehydrogenative-coupling, CDC) has been well developed by Li
and other groups.4 Further, metal-free cross-dehydrogenative-
coupling reactions of C(sp3)−H bonds have been explored very
recently.5 However, the reaction proceeding via functionaliztion
of C(sp3)−H bonds and radical addition is a more challenging
task and highly appreciated but scarely studied.
Scheme 1. Metal-Free Radical Addition Reaction
The photoredox-catalyzed radical addition reaction, with
environmentally friendly conditions and which can be
considered as a green tool for the synthetic chemist, has attracted
much attention.6 These reactions usually are performed under
visible-light photoredox catalysis with the use of metal catalysts,
generating the radicals by homolytic cleavage of C−X (X = O, N,
S) bonds and radical addition to electron-deficient olefins.7
Recently, many examples have been reported on photoredox-
catalyzed radical addition with α-silyl amines,8 α-bromo
carboxylates,9 amines,10 α-halo amides,11 aryl diazonium
salts,12 alcohols and ethers13 as radical precursors. Very recently,
the Stephenson group explored a visible light-mediated radical
addition of α-bromo carboxylates to 3-methylindole in the
presence of iridium to gain insight into the kinetic behavior of
catalysts.14 However, all these radical addition reactions usually
need light conditions, expensive metal catalysts, and special
starting materials, which lower the synthetic efficiency and atom
economy.
Our initial goal was to optimize the reaction conditions with
N-allylbenzamide 1a and isopropanol as model substrates, which
is shown in Table 1. According to our previous reports on
functionalization of the C(sp3)−H bond,15 the reaction here
between N-allylbenzamide 1a (0.5 mmol) and isopropanol (2.5
mL) was conducted in the presence of 2.0 equiv of TBHP at 120
°C for 5 h. Very surprisingly, the reaction afforded the addition
product 2a, instead of the cross-dehydrogenative-coupling
(CDC) product, with a 66% chemical yield (entry 1, Table 1).
Next, we decided to screen some oxidants to improve the
With our continuous interests in sp3 C−H functionalization,
direct sp3 C−H functionalization and subsequent radical
Received: January 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00088
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Radical Addition of Isopropanol with Substituted
N-Allylbenzamide
a
b
entry
oxidant (equiv)
temp (°C)
t (h)
yield (%)
c
1
TBHP (2.0)
120
120
120
120
120
100
80
5
66
71
57
33
83
40
trace
81
72
20
d
2
TBPA (2.0)
5
e
3
TBPB (2.0)
5
f
4
DCP (2.0)
5
g
5
DTBP (2.0)
5
6
DTBP (2.0)
DTBP (2.0)
DTBP (4.0)
DTBP (1.5)
DTBP (1.0)
DTBP (2.0)
DTBP (2.0)
24
24
5
7
8
120
120
120
120
120
9
24
24
5
10
11
12
h
63
i
5
31
a
Standard conditions: N-allylbenzamide (0.5 mmol), isopropanol 2.5
b
mL, oxidant 2.0 equiv, 120 °C, 5 h, under N2. Isolated yield based on
N-allylbenzamide. TBHP = tert-Butyl hydroperoxide, 5.0−6.0 M in
decane. TBPA = tert-Butyl peroxyacetate. TBPB = tert-Butyl
peroxybenzoate. DCP = Dicumyl peroxide. DTBP = di-tert-Butyl
peroxide. 5.0 mL of isopropanol was used. 0.5 mL of isopropanol
c
d
e
f
g
h
i
was used.
chemical yields. The use of other oxidants, such as TBPA and
TBPB, also provided the expected product with similar yields
(71% and 57% respectively, entries 2 and 3). In the presence of
DCP, the reaction still happened, but gave a dramatically lower
chemical yield (33%, entry 4). DTBP was the best oxidant for this
reaction and resulted in obviously an increased yield (83%, entry
5). The temperature showed a significant effect on the yield.
Running the same reaction at 100 °C (entry 6) resulted in a
dramatically lower yield (40%), and almost no desired product
was obtained when the reaction was performed at 80 °C (entry
7); even the reaction time was prolonged to 24 with almost all the
starting materials remaining. Finally, we would like to mention
here the attempts to use greater (entry 8) and lesser (entries 9
and 10) amounts of the oxidant. Increasing the amount of DTBP
to 4 equiv did not lead to any improvement in chemical yield,
while decreasing the amount to 1.0 equiv resulted in a low
reaction rate and dramatically lower chemistry yields (24 h, 20%
yield, entry 10). The loading amount of isopropanol also showed
an effect on the reaction, and obvious lower yields were found
when 5 or 0.5 mL of isopropanol was used (63% and 31%
respectively, entries 11 and 12).
The above optimization study allowed us to carry out the next
part of this work for the investigation of the substrate scope.
Isopropanol was used as the simple alcohol reactant in the scope
study of various olefins with α-amido groups (Scheme 2). The
process has a broad scope, giving the expected α,ω-amino
alcohols with good yields. One may see that, in a series of olefins
with substituents on the aromatic ring 1a−1m, neither the nature
of the substituent, such as halogen atoms (2c−2h, 2k−2m),
trifluoromethyl (2i), or trifluoromethoxy (2j), nor the position
on the aromatic ring has an apparent effect on the chemical yields
of these radical addition reactions, mainly because they are far
away from the C−C double bond.
a
Standard conditions: olefin 1 (0.5 mmol), isopropanol 2.5 mL, DTBP
2.0 equiv, 120 °C, 5 h, under N2. Isolated yield based on N-
allylbenzamide.
aliphatic amido group also resulted in the product with moderate
yields of 51% (2p). In order to further extend the substrate scope,
a β-amido olefin 1q, was tried in the reaction, which also could
work and afford the desired product with a 42% yield (2q).
Finally, the substrates with substituents on the C−C double
bond were tried, and the results indicate that steric hindrance had
an effect on the radical addition. For example, the reaction with a
terminal substituted olefin did not proceed at all, and no product
was found (2s), while a 2-methyl substituted olefin could work
well affording the product with a good yield of 81% (2r).
As the next goal of this study on radical addition reactions, the
variation in the substrates with the C(sp3)−H bond adjacent to
oxygen was studied to investigate the reactivity and regiose-
lectivity of this system (Scheme 3). As shown in Scheme 3, the
reaction could work with a range of alcohols, including open
chain and cyclo alcohols. It is noticed that the reaction with cyclo
alcohols showed higher efficiency, giving the desired product
with good chemical yields (3g−3i, 66−82%), compared with the
results of open chain alcohols (3a−3f, 25−53%). For the cases of
open chain alcohols, it is noteworthy that the yield becomes poor
if the length of the chain increases, and only a 25% yield was
obtained with hexanol as starting material (3e).
Fortunately, ethers (Scheme 4), such as tetrahydrofuran, 2,2-
dimethyl-1,3-dioxolane, tetrahydropyran, 1,4-dioxane, benzo[d]-
[1,3]dioxole, 2-methyltetrahydrofuran, and 1,3-dioxane, could
also work well in this system resulting in good to excellent yields
(3j−3p, 58−92%). It was noted that the reactions showed almost
no evident regioselectivity, and ratios of 1.8:1 (3o-1:3o-2) and
1:1.2 (3p-1:3p-2) were found.
To understand the mechanism of this reaction, an
intermolecular competing kinetic isotope effect (KIE) experi-
ment was conducted with isoproponal and [D]-isoproponal as
Notably, the substrates with a naphthyl group, instead of a
phenyl group, also reacted smoothly with isoproponal to give the
desired products in slightly lower yields (63% for 2n and 51% for
2o respectively). Interestingly, reactions of an olefin with an
B
DOI: 10.1021/acs.orglett.5b00088
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
radical intermediates during the transformation. Finally, [D]-
isoproponal was used as starting material for this reaction and still
the same product [D]2a was obtained, which indicates that the H
introduced into the product should be from the original N-
allylamide part.
Scheme 3. Radical Addition of Primary and Secondary
Alcohol with N-Allylbenzamide
a
Based on the above results and previous studies,15 we
proposed a mechanism for the current metal-free oxidative
radical addition reaction (Scheme 6). The reaction is initiated by
Scheme 6. Possible Mechanism
a
Standard conditions: N-allylbenzamide 1a (0.5 mmol), isopropanol
2.5 mL, DTBP 2.0 equiv, 120 °C, 5 h, under N2. Isolated yield based
on 1a.
a
Scheme 4. Radical Addition of Ether with N-Allylbenzamide
homolysis of DTBP, affording tert-butoxy radical intermediate A
under heating. Then, cleavage of the C(sp3)−H bond gives the α-
hydroxyisopropyl radical B through oxidation of isopropanol by
intermediate A. A subsequent radical addition of B to olefin 1a
generates intermediate C, which undergoes a 1,3-H shift from the
N−H group to give intermediate D. Then, intermediate D reacts
with t-BuOH, affording the final product 2a and a tert-butoxy
radical intermediate A. The tert-butoxy radical intermediate A
goes into the next radical cycle.
As an integral part of this study, we sought preliminary results
on the chemistry of the radical addition product 2a, which is a
useful chemical transformation. Of particular interest is the
intramolecular cyclization of the compound 2a into the
compound 4, which proceeds through the intramolecular
substitution resulting in the amide bearing a cycloamino group
(Scheme 7). First, 2a was transferred into ester, which underwent
cyclization in the presence of BF3−Et2O with a total 71%
chemical yield.
a
Standard conditions: N-allylbenzamide 1a (0.5 mmol), ether 2.5 mL,
DTBP 2.0 equiv, 120 °C, 5 h, under N2. Isolated yield based on 1a.
bUsing 5 equiv of 1,3-benzodioxole with 2.5 mL of EtOAc as solvent.
starting material. As shown in Scheme 5a, an obvious KIE was
found with the ratio of 5:1 (kH:kD), which was determined by 1H
Scheme 5. Investigation of Mechanism
In summary, we explored an unexpected DTBP-promoted
radical addition reaction of olefins with alcohols and ethers
without use of any metal catalyst and any light initiation. This
reaction involves new C(sp3)−C(sp3) bond formations via
C(sp3)−H bond functionalization and an unexpected radical
Scheme 7. Transformation of 2a
NMR spectroscopy by analyzing the ratio of 2a and [D]2a. This
discloses that cleavage of the C(sp3)−H bond adjacent to oxygen
to form the radical may be involved in the rate-determining steps
of this procedure. In addition, one radical-trapping reagent
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to
the reaction, which was found to completely inhibit the reaction.
The reaction gave almost no desired product, and this supports
C
DOI: 10.1021/acs.orglett.5b00088
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Letter
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yields. This process enriches the content of radical addition
under metal-free conditions.
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ASSOCIATED CONTENT
* Supporting Information
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M. J. Am. Chem. Soc. 2013, 135, 1823.
■
S
Experimental procedures, full spectroscopic data for compounds
2, 3, and 4 and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Nakajima, M.; Lefebvre, Q.; Rueping, M. Chem. Commun. 2014,
50, 3619.
AUTHOR INFORMATION
Corresponding Author
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̈
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725.
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(16) For the metal-free radical addition of alcohol to alkynes to form
C(sp2)−C(sp3), see: Liu, Z. Q.; Sun, L.; Wang, J. G.; Han, J.; Zhao, Y. K.;
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*E-mail: hanjl@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21102071 and
21472082).
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D
DOI: 10.1021/acs.orglett.5b00088
Org. Lett. XXXX, XXX, XXX−XXX