1,1,1,3,3,3-Hexafluoroisopropanol as an efficient medium for the room temperature oxidation of styrenes to benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2020.152527

A room temperature N-hydroxyphthalimide-catalyzed oxidation of styrene derivatives to the corresponding aldehydes has been developed. The use of 1,1,1,3,3,3-hexafluoroisopropanol as the solvent was determined as being key for efficient oxidation. The incorporated oxygen atom originates from molecular dioxygen.

Full text of DOI:10.1016/j.tetlet.2020.152527

Journal Pre-proofs
1,1,1,3,3,3-Hexafluoroisopropanol as an Efficient Medium for the Room
Temperature Oxidation of Styrenes to Benzaldehydes
Zhuyong Zhang, Weidong Chen, Junfei Luo
PII:
S0040-4039(20)31020-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152527
TETL 152527
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 July 2020
23 September 2020
29 September 2020
Please cite this article as: Zhang, Z., Chen, W., Luo, J., 1,1,1,3,3,3-Hexafluoroisopropanol as an Efficient
Medium for the Room Temperature Oxidation of Styrenes to Benzaldehydes, Tetrahedron Letters (2020), doi:
https://doi.org/10.1016/j.tetlet.2020.152527
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1,1,1,3,3,3-Hexafluoroisopropanol as an Efficient
Medium for the Room Temperature Oxidation of
Styrenes to Benzaldehydes
Leave this area blank for abstract info.
Zhuyong Zhanga, Weidong Chena and Junfei Luoa,
Cat. NHPI
O
R
R
HFIP, RT, O2
22 examples
up to 83%
R = -H, -Me, -tBu, -OMe, F, Cl, Br, NO2, CF3, OAc, NHAc, CO2H




Mild conditions
Cheap catalyst
Benign Process
High FG tolerance

1
Tetrahedron Letters
journal homepage: www.elsevier.com
1,1,1,3,3,3-Hexafluoroisopropanol as an Efficient Medium for the Room Temperature
Oxidation of Styrenes to Benzaldehydes
Zhuyong Zhanga, Weidong Chena and Junfei Luoa, 
a School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A room temperature N-hydroxyphthalimide-catalyzed oxidation of styrene derivatives to the
corresponding aldehydes has been developed. The use of 1,1,1,3,3,3-hexafluoroisopropanol as
the solvent was determined as being key for efficient oxidation. The incorporated oxygen atom
originates from molecular dioxygen.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
1,1,1,3,3,3-Hexafluoroisopropanol
Mild conditions
Oxidation
Olefins
Aldehydes
———
 Corresponding author: Junfei Luo, e-mail: luojunfei@nbu.edu.cn.

2
Tetrahedron
with a pyridine bisimidazoline ligand.17 Additionally, methods
1. Introduction
for the copper complex catalysed cleavage of olefins were also
reported.18 These examples further emphasized the importance of
aerobic oxidation in this area.
Alkene cleavage is an important transformation in
organic synthesis to obtain carbonyl compounds.1 The
ozonolysis of olefins is often utilised for the generation of
carbonyls, but suffers from safety issues and inconvenient
synthetic operation.2 While methods using other
stoichiometric oxidants, such as KMnO4,3 OsO4,4
chromium(VI) reagents,5 hypervalent iodine,6 and meta-
chloroperoxybenzoic acid7 have been reported, they often
involve large amounts of waste production and over-
oxidation. Thus, increased focus has been placed on the use
of metal catalysts in combination with benign oxidants.8
Most notably, RuCl3-NaIO4 in the mixed solvent system
CCl4-CH3CN-H2O (2:2:3) was discovered by Sharpless and
co-workers,9 and many other elegant methods based on
ruthenium catalysts have also been reported.10 For instance,
Bera and co-workers demonstrated a highly efficient method
for the selective oxidation of olefins to aldehydes catalysed
Organic radicals show similar behaviour to high-valent
metals, and have attracted attention in catalytic aerobic
oxidation.19 In this regard, Jiao and co-workers reported a NHPI-
catalysed scission of olefins to obtain aldehyde products at
elevated temperature.20 This method was generally limited to
disubstituted alkenes; only one example of a mono-substituted
olefin was reported in low yield (26%) in the presence of
stoichiometric acetone oxime. Later on, Jiao and co-workers
reported the 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-
catalysed selective cleavage of olefins in the presence of 1.5
equivalents of TMSN3 under oxygen.21 The aerobic oxidative
cleavage of gem-disubstituted alkenes catalyzed by 2,2-
azobis(isobutyronitrile) (AIBN) was also reported.22 On the basis
of these reports, the development of a methodology for the room
temperature, aerobic organo-catalysed scission of olefins, in
particular for mono-substituted alkenes, would represent a useful
contribution for this area. Herein, we report a NHPI-catalysed
aerobic oxidation of olefins to the corresponding aldehydes. The
use of HFIP (1,1,1,3,3,3-hexafluoroisopropanol) as the solvent is
key to this reaction, allowing the transformation of styrenes to
benzaldehydes in a highly selective and efficient manner.
by
a
NHC−Ru(II) complex.11 Methods based on
photocatalysis, enzymatic conversion, and electrochemistry
have also been reported.12
The development of catalytic methods using abundant and
green molecular oxygen as the terminal oxidant is of upmost
interest as it is inexpensive and, ideally, forms H2O as a benign
side-product.13 However, to the best of our knowledge, methods
for the catalytic aerobic oxidation of olefins to the corresponding
aldehydes are rarely reported. In this regard, the palladium-
catalysed oxidation of olefins to aldehydes under acidic
conditions has been reported under high temperature and oxygen
pressure.14 Metal porphyrin complexes15 have been reported as
suitable catalysts for the scission of olefins but resulted in low
selectivity.
2. Results and Discussion
We first examined the model oxidation of p-tert-butylstyrene
(1a) under the conditions discovered by Jiao and co-workers,20
and found that this mono-substituted styrene resulted in very
poor yield, with only 5% of the benzaldehyde product 2a being
obtained (Entry 1). We then tested different solvents for this
transformation, and it was interesting to find that the fluorinated
solvent HFIP, exhibited superior reactivity for the oxidation of
styrene, with 83% yield of the corresponding aldehyde 2a being
produced without any other additive (Entries 2-8). However, the
non-fluorinated alcohol, propan-2-ol was much less efficient,
leading to only 20% yield of 2a (Entry 9). 2,2,2-Trifluoroethanol
was also tested and 46% yield was obtained (Entry 10). Finally,
the control reactions demonstrated that this conversion did not
proceed without the NHPI catalyst or oxygen (Entries 11 and 12).
Satisfyingly, the oxidation reaction could be carried out at room
temperature without a decrease in the yield (Entry 13). The
reaction showed high selectivity, without any epoxide, radical
coupling products or carboxylic acid being observed.
(A) Traditional methods
Stoichiometric
O
 Stoichiometric waste
 Harsh oxidants
Oxidants
e.g. DDQ, MnO2
Ph
(B) Catalytic oxidation
N
N
N
O
Ph
Br
Br
cacta.t.
Ru
Oxidants
NHC-Ru catalyst
Ph
4-tBu-Ph
(C) : Metal-catalysed aerobic oxidation
Ph
O
S
O
N
FeIII OTf
O
N
cacta.t.
+ H2O
Table 1. Optimization of the reaction conditions.a
N
O
S
O
Ph
O2
4-tBu-Ph
NHPI (X mol %)
O
Ph
tBu
tBu
PyBisulidine Fe catalyst
Solvent (0.1 M)
T (°C), O2, 24 h
(D) This work: NHPI-catalyzed oxidation
1a
2a
O
O
cacta.t.
N
OH
+ H2O
Entry
NHPI
T (°C)
Solvent
DMA
Yield 2a (%)
O2
O
1
2
3
4
5
6
7
8
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
80
80
80
80
80
80
80
80
5
 Commercially available cheap catalyst
 Mild conditions
NHPI catalyst
DCE
1,4-dioxane
THF
20
12
28
15
0
Scheme 1. Representative methods for the oxidation of styrenes
to aldehyde derivatives.
EtOAc
H2O
An iron-N-hydroxyphthalimide system was also proven
competent using an atmospheric pressure of oxygen, although the
oxidation was unselective.16 The selectivity issue was solved by
Xiao and co-workers who used a combination of an iron catalyst
MeCN
HFIP
34
83

3
O
9
10 mol %
10 mol %
-
80
80
80
80
25
Propan-2-ol
TFE
20
46
3
4
78%b
83%b
Me
Me
10
11
12b
13
2c
1c
HFIP
0
O
10 mol %
10 mol %
HFIP
trace
82
2d
1d
HFIP
O
48%
(79%)c
[a] Unless otherwise noted, the reactions were performed using 0.2
mmol of 1a in 1.0 mL of solvent under air for 24 h. Isolated yields.
NHPI = N-hydroxyphthalimide.
5
F
F
2e
2f
1e
O
O
[b] The reaction was performed under N2.
42%
(71%)b,c
6
Cl
Cl
1f
We then turned our attention to probe the scope of the NHPI-
catalysed oxidation of olefins with differently decorated styrenes.
In general, the electron-rich styrenes were more reactive than the
electron-poor substrates in this oxidation process. In detail, the
58%
(81%)b,c
7
Br
Br
1g
1h
1i
2g
O
substrate with
a strong electron-donating methoxy group
8
45%b
56%b
0
O2N
F3C
O2N
F3C
substituted at the para-position was well tolerated, giving 83%
yield (2b). The weak electron-donating methyl substituted
styrene and non-substituted styrene also proceeded efficiently,
although prolonged reaction times were required (2c and 2d). 4-
Halogenated (-F, -Cl, -Br) styrenes, on the other hand, resulted in
relatively low yields under the standard conditions. However, the
oxidation of 4-halogenated styrenes could be significantly
promoted by the addition of cobalt acetate (2e-g). Substrates with
the strong electron-withdrawing nitro and trifluoromethyl groups
were less reactive, affording 45% and 56% yield, respectively
(2h and 2i). In this case, the addition of cobalt acetate did not
improve the yields. Substrates bearing the hydroxyl functionality
were unreactive, and the reaction with amine-substituted
substrates led to decomposition (1j and 1k). However, acyl
protection of the amine/hydroxyl groups resulted in a successful
transformation (2l and 2m). The carboxyl group substituted
styrene 1n reacted sufficiently without requiring protection. m-
Methylstyrene 1j and o-methylstyrene 1k were chosen to test the
effect of the substituent position, with lower reactivity observed
compared to p-methylstyrene, although the yields could be
improved by the addition of cobalt acetate. Di-substituted olefins
were also tested to investigate the reaction scope. Both cis- and
anti-1,2-diphenylethene (1l and 1m) were found to be
compatible, leading to the same product benzaldehyde 2d in 76%
and 78% yield, respectively. 1,1-Disubstituted olefins (1n and
1o) were less reactive in comparison to the mono-substituted and
1,2-disubstituted olefins, giving the corresponding ketones in
moderated yields. Selected hetero-aromatic alkenes were also
investigated. Although 3-vinylpyridine (1u) only afforded 17%
of the desired product 2u, N-methyl-3-vinylindole (1v) gave the
corresponding aldehyde 2v in moderate yield.
2h
2i
O
9
O
10
11
12
13
14
15
16
HO
HO
H2N
1j
2j
O
O
Trace
65%b,c
46%b,c
50%b,c
H2N
AcO
AcHN
HO2C
1k
1l
2k
2l
AcO
O
AcHN
HO2C
1m
2m
O
1n
2n
O
40%
(75%)b,c
1o
1p
2o
2q
O
O
O
45%
(80%)b,c
17
18
19
76%b
78%b
72%b
2d
1q
Table 2. Scope of the oxidation of styrenes.a
2d
1r
NHPI (10 mol %)
O
R
R
HFIP, RT
O
1
2
1s
2s
Entry
1
Substrate
Product
Yield (%)
82%
O
O
20
21
60%b
tBu
tBu
1t
2t
1a
2a
2b
N
N
O
O
17%b,c
2
83%
MeO
MeO
1u
2u
1b

4
Tetrahedron
O
regenerating the PINO radical to complete the catalytic cycle
(Scheme 3). A previous report by Jiao and co-workers was
generally limited to the reaction of di-substituted alkenes, which
are able to better stabilise the radical intermediate (c.f. II and
II’). In our case, we are able to engage less reactive mono-
substituted alkenes. Thus, the superior performance of the
reaction in HFIP may be attributed to a stabilizing affect of HFIP
on the intermediate radical species.25 Based on the results in
Table 1, entries 8-10, the more acidic HFIP could also promote
the generation of PINO from NHPI since the transformation
proceeded easily under acidic conditions.26 Additionally, HFIP
and the benzaldehyde product may form a H-bond adduct,
preventing over-oxidation to the carboxylic acid.27 Detailed
examination of the reaction mechanism is still ongoing in our lab.
22
56%b,c
N
N
Me
Me
1v
2v
[a] Unless otherwise noted, the reactions were performed using 0.2
mmol of 1 in 1.0 mL of HFIP at room temperature for 24 h under 1 atm.
of O2. Isolated yields;
[b] The reactions were performed for 48 h;
[c] 5 mol % of Co(OAc)2 was added.
Control reactions were carried out to help understand the
reaction mechanism. The oxidation did not proceed without the
NHPI catalyst or oxygen (Scheme 2a and b) The addition of
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO)
completely
O
LnCoII
stopped the reaction which suggested that a radical initiation
pathway is possible (Scheme 2c). This also explained why the
substrates containing phenol or aniline moieties significantly
decreased the reactivity. Finally, the formation of 18O labelled
aldehyde 2o’ in the presence of 18O2 indicated that the oxygen
atom originated from molecular dioxygen (Scheme 2d). Finally,
the reaction was compatible with the addition of acid but did not
tolerate the addition of base, suggesting the acidic character of
HFIP is important.
O2
N
OH
O
LnCoIIIOO
or
LnCoIIIOOCoIIILn
LnCoIIIOR
R = OH or H
O
N
OH
O
a)
O
no catalyst
O
N
O
tBu
tBu
HFIP, RT, N2
O
O
1d
1d
2d
, 0
I
PINO ( )
b)
NHPI (10 mol %)
HFIP, RT, N2
HCHO
O
O
tBu
tBu
O
O
O
O
2d
, trace
O
N
O
N
c)
O
O
NHPI (10 mol %)
TEMPO (0.5 equiv)
III
II
R
tBu
d)
tBu
HFIP, RT, O2
O2
PINO
1d
2d
, trace
II'
18O
NHPI (10 mol %)
HFIP, RT, 18O2
Ph
Ph
Scheme 3. Putative reaction mechanism
Ph
2d'
Ph
1o
1d
1d
, 55%
, 82%
, <5%
e)
3. Conclusion
NHPI (10 mol %)
AcOH (2.0 equiv.)
O
We have developed a room temperature NHPI-catalyzed
oxidation of styrenes to benzaldehydes. This method allows
mono-substituted alkenes to be efficiently converted into the
corresponding aldehydes. Aromatic alkenes containing a variety
functional groups such as alkyl, alkoxyl, halogen, nitro, ester,
amide and carboxyl, were all found to be compatible in the
oxidation reactions.
tBu
f)
tBu
tBu
HFIP, RT, O2
2d
2d
NHPI (10 mol %)
Pyridine (2.0 equiv.)
O
tBu
HFIP, RT, O2
Scheme 2 Preliminary mechanism study.
Conflicts of interest
On the basis of the above observations and previous reports,
we suggest the reaction is triggered by the formation of PINO
radical (I) from NHPI.19a,19b,23 In the case of the reaction with
cobalt acetate, the reaction could begin with the oxidation of
Co(II) by molecular oxygen to afford Co(III) complexes, which
promotes the transformation from NHPI to PINO radical,24
consequently enhancing the reactivity in some cases. The PINO
radical reacts with styrene to give carbon radical II, which is
followed by the trapping of molecular oxygen to furnish peroxyl
radical III. The cleavage of III gives the aldehyde product,
possibly through a dioxetane intermediate, while simultaneously
There are no conflicts to declare.
Acknowledgments
We thank the Natural Science Foundation of Zhejiang
Province (No. LQ19B020002), and the Ningbo Municipal
Natural Science Foundation (No. 2019A610027).

5
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Phthalocya. 2006, 10, 942-947.
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Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

6
Tetrahedron
Cat. NHPI
O
R
R
HFIP, RT, O2
22 examples
up to 83%
R = -H, -Me, -tBu, -OMe, F, Cl, Br, NO2, CF3, OAc, NHAc, CO2H




Mild conditions
Cheap catalyst
Benign Process
High FG tolerance
Highlights
 Discovered a NHPI-catalyzed
oxidation of styrenes to
benzaldehyde derivatives.
 Practical convenience and highly
functional group tolerance.
 Mild reaction conditions and
low-cost reagents.