Selective C[sbnd]O bond formation: highly efficient radical dioxygenation of alkenes initiated by catalytic amount of tert-butyl hydroperoxide

Article abstract of DOI:10.1016/j.tet.2016.10.029

A highly selective radical dioxygenation of alkenes using hydroxamic acid and O₂with 5–10 mol % of tert-butyl hydroperoxide as a catalyst was developed. On the basis of this newly developed strategy, a wide range of phenylethanol derivatives with a variety of functional groups can be effectively synthesized.

Full text of DOI:10.1016/j.tet.2016.10.029

Accepted Manuscript
Selective C-O bond formation: highly efficient radical dioxygenation of alkenes
initiated by catalytic amount of tert-butyl hydroperoxide
Xiao-Feng Xia, Su-Li Zhu, Qing-Tao Hu, Chao Chen
PII:
S0040-4020(16)31063-8
10.1016/j.tet.2016.10.029
TET 28170
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 August 2016
Revised Date: 8 October 2016
Accepted Date: 14 October 2016
Please cite this article as: Xia X-F, Zhu S-L, Hu Q-T, Chen C, Selective C-O bond formation: highly
efficient radical dioxygenation of alkenes initiated by catalytic amount of tert-butyl hydroperoxide,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.029.
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Selective C-O bond formation: highly
efficient radical dioxygenation of alkenes
initiated by catalytic amount of tert-butyl
hydroperoxide
Leave this area blank for abstract info.
Xiao-Feng Xia,* Su-Li Zhu, Qing-Tao Hu, Chao Chen
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Selective C-O bond formation: highly efficient radical dioxygenation of alkenes
initiated by catalytic amount of tert-butyl hydroperoxide
Xiao-Feng Xia a , Su-Li Zhua , Qing-Tao Hu a, Chao Chen a
a The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi,
Jiangsu, 214122, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly selective radical dioxygenation of alkenes using hydroxamic acid and O2
with 5-10 mol% of tert-butyl hydroperoxide as a catalyst was developed. On the basis
of this newly developed strategy, a wide range of phenylethanol derivatives with a
variety of functional groups can be effectively synthesized.
Available online
Keywords:
Dioxygenation
Hydroxamic acid
Radical addition
Selective oxidation
1-Phenylethanol
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
dioxygenation of alkenes was achieved by Lei group.6 However,
a metal-free conditions for this transformation have not been
widely studied up to now,7 and thus the search for alternatives
which allows to control the selectivity of the alkene
dioxygenation, particularly involving environmental friendly
pathway, still remains challenging.
Selective oxidation and oxidative functionalization of
organic molecules under mild reaction conditions to
construct various oxygenated compounds would be the most
important strategy and considered to be an essential area of
research in modern organic synthesis.1 Molecular oxygen is
a perfect source to incorporate into organic molecules
because of environmentally safe and abundantly available
in nature.2 A variety of transition-metal catalyzed oxygen
incorporation in organic molecules have been developed,
however, limited reports talk about such activation of
molecular oxygen under metal-free conditions.3 Alkenes are
abundant simple chemical feedstocks and organic
molecules, which have been used widely in organic
synthesis, and methods for their concise, selective oxidative
functionalization are attractive to assemble substituted
alcohols4 and ketones.2c A number of transition-metal-
catalyzed reactions have been developed for the
incorporation of oxygen in alkenes by the activation of
molecular oxygen.2c For instance, in 2010, Jiang group
reported a palladium-catalyzed dihydroxylation of olefins
with oxygen as sole oxidant, but 8 atm of molecular oxygen
was needed, which limited the utility of this reaction.5 In
2015, a copper-/cobalt-catalyzed highly selective radical
———
Scheme 1. Dioxygenation of Alkenes.
Recently,
N-hydroxyphthalimide
(NHPI) and
N-
hydroxybenzotriazole were used as hydroxylamine reagent
via an radical pathway to synthesize α-oxygenated ketones
Corresponding author. Tel./ fax: +86-510-85917763; e-mail: xiaxf@jiangnan.edu.cn

2
Tetrahedron
by the Lei,6 Adimurthy,7a Punniyamurthy,8 Woerpel,9 and
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our group.10 In our previous work, we successfully realized
1-phenylethanol derivatives synthesis using TsOH as
catalyst, 4 equivalent tert-butyl hydroperoxide (TBHP) as
the oxidant. Lei group also discovered the same reaction
using cobalt as the catalyst.6 Considering the importance of
these phenylethanols, the development of metal-free and
acid-free conditions is desirable to avoid the possible
contamination of metals and acid to environment. In 2015,
Zou group reported an air oxidative radical
hydroxysulfurization of styrenes initiated by 0.5 mol % of
TBHP.11 Inspired by this work and in continuation of our
efforts on the difunctionalization of alkenes,12 we envisaged
whether 1-phenylethanol derivatives can be obtained via an
radical addition, when catalysis loading of TBHP was used
under oxygen atmosphere (Scheme 1-b).
4
2.0 equiv. TBHP (5-6 M in DCE
22h
12h
12h
24h
24h
24h
48h
61%
69%
89%
84%
98%
90%
95%
decane)+air
5
2.0 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
6
1.2 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
7
0.4 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
8
0.2 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
2. Results/Discussion
In order to screen the suitable reaction condition according
to our assumptions, first, omission of the catalyst was
carried out, and an 80% yield of product was separated but
for a longer reaction time (22h, Table 1, entry 2).
Decreasing the oxidant loading to 2.0 equivalents, the yield
was decreased to 61% in the air. Interestingly, using 1 atm
oxygen as the co-oxidant, 1.2 equivalents of TBHP can give
an 89% yield (12h). Then, the loading of TBHP was further
decreased to 0.1 equivalents, and a 90% yield of 3a was
detected under 1 atm oxygen conditions (entry 9, 24h). A
95% yield of product was also obtained using 0.05
equivalents of TBHP and 1 atm oxygen as the oxidant but
for about 48 h (entry 10). Only using oxygen as the oxidant,
no target product was observed at room temperature (entry
9
0.1 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
10
0.05 equiv. TBHP (5-6 M in DCE
decane) + 1 atm O2
11
12
13
1 atm O2
1 atm O2
DCE
DCE
48h
48h
24h
N.R.
40% c
N.R.
0.1 equiv. TBHP (5-6 M in DCE
decane) + 1 atm Ar
o
11), and only 40% yield was obtained at 60 C, indicating
the importance of TBHP. In addition, only using 0.1
equivalents of TBHP as the oxidant under argon
atmosphere, no reaction occurred. It was noteworthy that
using 3.0 equivalents of TBHP as oxidant under argon
atmosphere, no product was achieved. These phenomenon
meant the oxygen was very significant for this
transformation (entries 13 and 14).
14
3.0 equiv. TBHP (5-6 M in DCE
decane)+ 1 atm Ar
24h
N.R.
a
Reaction conditions: 1a (2.0 equiv., 0.6 mmol), NHPI (0.3 mmol),
oxidant, and solvent (3.0 mL), at room temperature.
b Isolated yield.
Table 1. Initial studies for the reaction of dioxygenation of
c The reaction was carried out at 60 oC.
alkenes.a
Under the optimized conditions (Table 1, entry 9), the
alkene substrate scope was proved to be quite general with
activated terminal alkenes and disubstituted alkenes
participating in the dioxygenation reaction effectively
(Scheme 2). A wide range of substrates and functional
groups are tolerated including fluoro, chloro, bromo,
methoxy, cyano, tertiary butyl and ester substituents at the
Entry
1
Oxidative Condition
Solvent
Time
76h
Yieldb
80%
different positions of styrenes. Cyclic alkenes such as 1,2-
4.0 equiv. TBHP (5-6 M in CH3CN
decane)+ air
dihydronaphthalene can provide the dioxygenation product
3i in 80% yield. α-Methylstyrene and corresponding
substituents can participate in this transformation in a short
time (3j and 3k). Notably, 1,1-diphenylethylene proved to
be an effective alkene substrate, yielding tertiary alcohol 3n
in 63% yield. Phenyl substituted conjugated diene such as
2
3
4.0 equiv. TBHP (5-6 M in DCE
decane)+air
22h
22h
80%
93%
(1E,3E)-1,4-diphenylbuta-1,3-diene was tolerated to deliver
a isomer 3o (dr=1:1) in a high yield only for 6h. Unactivated
alkenes such as norbornene can also produce the target
product 3q, and only the major isomer was separated, but
3.0 equiv. TBHP (5-6 M in DCE
decane)+air

3
3.0 equivalents of TBHP was needed, and the same for the
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synthesis
of
product
3p
.
In
addition,
N-
hydroxybenzotriazole was also suitable for this
transformation, and the corresponding products 4a-4e were
obtained in good to high yields under optimized conditions
(Scheme 3).
Scheme 4. Ketone synthesis under standard condition.
Gratifyingly, the reaction could be readily scaled up without
loss of its efficiency. When 5 mmol scale was carried out,
1.24g (88%) 3a was obtained implying its potential
synthetic utility (Scheme 5).
OH
O
O
10 mol% TBHP
O
N
+
NOH
1 atm O2
O
DCE (10 mL), 48h
O
3a, 1.24g, 88%
6.0 mmol
5.0 mmol
Scheme 5. Scaled-up Reaction.
To gain insight into the reaction mechanism, the control
experiments were carried out (Scheme 6). First, a mixture of
styrene and 4-vinylbenzonitrile with NHPI was subjected to
the standard conditions in order to elucidate the electronic
preference of the reacting alkenes (eq 1). Under the
competitive conditions, a 3.4:1 ratio of products was
obtained, which means that electron-rich alkenes are
inclined to radical addition. Then, when 2.0 equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added
in the reaction system, no target product was observed, but a
60% yield of TEMPO-captured product
6 was separated,
which meant that a radical addition mechanism may be
involved in this transformation (eq 2). In addition, omission
of styrene under the standard conditions, the NHPI can be
recovered after reacting with 2.0 equivalents of D2O. The
hydrogen atom of OH in NHPI was partly substituted by
deuterium atom (H/D= 7:3), which indicated that NHPI can
be easily activated in this reaction conditions (eq 3). Last,
when 2.0 equivalents of H218O was added to the reaction
systems, no 18O-labeled product 3a was isolated, indicating
the hydroxyl oxygen atom of the alcohols came from O2 (see
supporting information).
Scheme 2. The scope of the activated alkenes. a3.0
equivalents of TBHP was added in the systems.
Scheme
3
.
The reaction of styrenes with
N-
hydroxybenzotriazole.
When (1-bromovinyl)benzene was subjected to the standard
reaction conditions, a ketone product 5a was yielded via
elimination HBr from the intermediate (Scheme 4). In
addition, interestingly, when 1-methyl-4-vinylbenzene was
carried out in
this condition, a mixed product 5b
(
major:minor=3:1)was obtained.

4
Tetrahedron
spectrometry (HRMS) spectra was obtained on a Thermo
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Scientific LTQ Orbitrap XL instrument equipped with an ESI
source; copies of their 1H NMR and 13C NMR spectra are
provided.
4.2 Typical procedure for the synthesis of product 3
To a solution of N-hydroxyphthalimide (2, 0.3 mmol, 48.9
mg) in DCE (3.0 mL) was added styrene (1a, 0.6 mmol), 10%
TBHP (5-6 M in decane). The flask was evacuated and backfilled
with O2 for 3 times. The reaction mixture was then stirred for 24
h at room temperature. After the reaction, the resulting mixture
was quenched with water and extracted twice with EtOAc. The
combined organic extracts were washed with brine, dried over
Na2SO4 and concentrated. Purification of the crude product by
flash column chromatography afforded the product 3a (petroleum
ether/ethyl acetate as eluent (6:1)).
2-(2-hydroxy-2-phenylethoxy)isoindoline-1,3-dione, 3a, 1H
NMR (400 M HZ, CDCl3): 9.57 (s, 1 H, OH), 7.78-7.84 (m, 2 H),
7.75-7.77 (m, 2 H), 7.32-7.41 (m, 5 H), 5.41 (dd, J = 4.0, 4.0 Hz,
1 H), 4.49-4.51 (m, 2 H); 13C NMR (100 MHz, CDCl3): 163.8,
135.8, 134.8, 127.1, 123.8, 85.5, 78.9;
Scheme 6. Control experiments.
On the basis of these results and previous studies,10,11
possible mechanism was proposed in scheme 7. Firstly,
PINO radical initiated by TBHP selectively adds to 1a to
a
form intermediate alkyl radical
captured by intermediate
following by grabing a hydrogen atom from TBHP to form
hydroperoxide III Intermediate III reacts with NHPI to
give radical IV, which then obtains a hydrogen atom to
afford product 3a
I
. The molecular oxygen was
I
to form peroxy radical II
,
.
.
Acknowledgments
We thank the National Science Foundation of China NSF
21402066, the Natural Science Foundation of Jiangsu
Province (BK20140139), and the Fundamental Research
Funds for the Central Universities (JUSRP11419) for
financial support. Financial support from MOE&SAFEA for
the 111 project (B13025) is also gratefully acknowledged.
References and notes
1
2
(a) Wu, W.; Jiang, H. Acc. Chem. Res. 2012
McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015
For reviews on reactions performed with the use of molecular
oxygen as an oxidant, see: (a) Wendlandt, A. E.; Suess A. M.;
,
45, 1736; (b)
48, 1756.
,
Stahl, S. S. Angew. Chem., Int. Ed. 2011
Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012
3381; (c) Xu, J.; Song, Q. Chin. J. Org. Chem. 2016 36, 1151;
,
50, 11062; (b) Shi,
,
41
,
,
(d) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45,
851.
Scheme 7. Proposed mechanism
3
(a) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei,
A. Angew. Chem., Int. Ed. 2013 52, 7156; (b) Lu, Q.; Zhang,
J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc.
2013 135, 11481; (c) Piera, J.; Bäckvall, J.-E. Angew. Chem.,
Int. Ed. 2008 47, 3506; (d) Giglio, B. C.; Schmidt, V. A.;
Alexanian, E. J. J. Am. Chem. Soc. 2011 133, 13320; (e)
Wong, Y.-C.; Hsieh, M.-T.; Amancha, P. K.; Chin, C.-L.;
Liao, C.-F.; Kuo, C.-W.; Shia, K.-S. Org. Lett. 2011 13, 896;
(f) Lin, R.; Chen, F.; Jiao, N. Org. Lett. 2012 14, 4158.
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994 94, 2483.
Wang, A.; Jiang, H. J. Org. Chem. 2010
Lu, Q.; Liu, Z.; Luo, Y.; Zhang, G.; Huang, Z.; Wang, H.;
Liu, C.; Miller, J. T.; Lei, A. Org. Lett. 2015 17, 3402.
(a) Samanta, S.; Donthiri, R. R.; Ravi, C.; Adimurthy, S. J.
Org. Chem. 2016 81, 3457; (b) Liu, C.-R.; Ding, L.-H.; Guo,
,
3. Conclusions
,
In conclusion, we have developed a concise and efficient
selectively radical dioxygenation of styrenes initiated by 5-
,
,
10 mol
%
of tert-butyl hydroperoxide with N-
hydroxyphthalimide or N-hydroxybenzotriazole under
oxygen atmosphere. This strategy is straightforward,
requires no additives, and involves simple manipulations. In
addition, the reaction can be effectively scaled up.
,
,
4
,
5
6
, 75, 2321.
4. Experimental section
,
7
,
4.1 General information
G.; Liu, W.-W. Eur. J. Org. Chem. 2016, 910; (c) Keshari, T.;
Yadav, V.-K.; Srivastava, V.-P.; Yadav, L. D. S. Green
Column chromatography was carried out on silica gel. Unless
1
Chem. 2014
Wang, H.; Liu, Z.; Lei, A. Angew. Chem., Int. Ed. 2013
7156; (e) Wang, H.-M.; Lu, Q.-Q.; Qian, C.-H.; Liu, C.; Liu,
K.; Chen, K.; Lei, A. Angew. Chem., Int. Ed. 2016 55, 1094;
,
16, 3986; (d) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.;
noted H NMR spectra were recorded on 400 MHz in CDCl3 or
CD3COCD3, 13C NMR spectra were recorded on 100 MHz in
CDCl3 or CD3COCD3. IR spectra were recorded on an FT-IR
spectrometer and only major peaks are reported in cm-1. Melting
points were determined on a microscopic apparatus and were
uncorrected. All new products were further characterized by
HRMS (high resolution mass spectra), high resolution mass
,
52
,
,
(f) Liu, K.; Li, D.-P.; Zhou, S.-F.; Pan, X.-Q.; Shoberu, A.;
Zou, J.-P. Tetrahedron 2015, 71, 4031; (g) Lu, Q.; Liu, C.;
Huang, Z.; Ma, Y.; Zhang, J.; Lei, A. Chem. Comun. 2014
,
50, 14101.

5
8
9
Bag, R.; Sar, D.; Punniyamurthy, T. Org. Lett. 2015
2010.
Andia, A. A.; Miner, M. R.; Woerpel, K. A. Org. Lett. 2015
17, 2704.
,
17
,
Wang, H.; Xia, Y.; Gao, H.; Liu, X.; Liang, Y.-M. J. Org.
Chem. 2015, 80, 290.
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,
10 Xia, X.-F.; Zhu, S.-L.; Gu, Z.; Wang, H.; Li, W.; Liu, X.;
Liang, Y.-M. J. Org. Chem. 2015 80, 5572.
11 Zhou, S.-F.; Pan, X.; Zhou, Z.-H.; Shoberu, A.; Zou, J.-P. J.
Org. Chem. 2015 80, 3682.
12 (a) Xia, X.-F.; Zhu, S.-L.; Chen, C.; Wang, H.; Liang, Y.-M.
J. Org. Chem. 2016 81, 1277; (b) Xia, X.-F.; Gu, Z.; Liu, W.;
,
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