4CzIPN catalyzed photochemical oxidation of benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2021.152878

A green photoredox oxidation of benzylic primary and secondary alcohols to aldehydes and ketones with air as an oxidant was reported. The oxidation shows broad substrate scope and excellent selectivity over benzylic alcohols to the aliphatic alcohols. Further mechanistic studies revealed a quinuclidine mediated HAT process, and blue LEDs promoted 4CzlPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) photoredox cycle were involved in our oxidation.

Full text of DOI:10.1016/j.tetlet.2021.152878

Tetrahedron Letters 67 (2021) 152878
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
4CzIPN catalyzed photochemical oxidation of benzylic alcohols
a
a
b
b
a,
⇑
Heng Zhang , Tianyun Guo , Mingzhong Wu , Xing Huo , Shouchu Tang ,
b,
⇑
a,
⇑
Xiaolei Wang , Jian Liu
a
School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A green photoredox oxidation of benzylic primary and secondary alcohols to aldehydes and ketones with
air as an oxidant was reported. The oxidation shows broad substrate scope and excellent selectivity over
benzylic alcohols to the aliphatic alcohols. Further mechanistic studies revealed a quinuclidine mediated
HAT process, and blue LEDs promoted 4CzlPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) pho-
toredox cycle were involved in our oxidation.
Received 14 December 2020
Revised 21 January 2021
Accepted 24 January 2021
Available online 4 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Photocatalysts
Oxidation
Air
Benzylic alcohols
Introduction
have been made to search for an organic photocatalyst, and several
photocatalysts like EY [9], Flavin [10], Rose Bengal [11], 9-fluo-
Hydroxyl is a ubiquitous functional group in chemistry, and the
synthesis of carbonyl compounds via alcohol oxidation is one of
the most important transformations in both academia and indus-
renone [12], thioxanthenone [13] have emerged in photo enabled
oxidation (Scheme 1C).
Recently, the photoredox-mediated hydrogen atom transfer
(HAT) process shows powerful strength in CAH bond functional-
ization [14]. MacMillan [15] and Wendlandt [16] used quinuclidine
as a HAT mediator, successfully achieved the selective hydrogen
try. However,
unfriendly oxidants, such as MnO
a
stoichiometric amount of environmentally
, TPAP, hypervalent iodine
2
reagents (Scheme 1A) [1], simultaneously, with the release of
harmful wastes such as dimethyl sulfide, are often used in the tra-
ditional oxidation of alcohols. This gives rise to the development of
environment-friendly catalytic methods that are performed by
using transition-metal-free, green, and sustainable processes.
Due to the advantages of green and sustainable characteristics,
photocatalysis-based chemical transformations had attracted
much attention and made tremendous progress over the past
abstraction to the
Inspired by these researches, we envisaged that the easily formed
-hydroxyl carbon radical specie may be trapped by a type of reac-
a-hydroxyl group and further C-modification.
a
tive oxygen species (ROS) to realize the oxidation of the alcohol.
Therefore, here we report a green method to oxidize alcohols into
corresponding carbonyl products via a quinuclidine mediated pho-
tocatalyzed HAT process (Scheme 1D).
2
two decades. Meanwhile, the oxygen (O ) as an ideal oxidant due
to its environment-friendliness, can be irradiated to reactive oxy-
gen species (ROS) by photocatalysis, and this process has been
widely used in chemical oxidation [2]. Based on these findings,
many metal-based photocatalysts (Pt [3], Ti [4], Cu [5], Ru [6], Bi
Results and discussion
To begin with, the reaction of benzyl alcohol 1a with 4CzlPN
and quinuclidine was tested. Irradiation of the sample solution in
MeCN/DMSO with blue LEDs under room temperature and air
atmosphere, the desired benzaldehyde 2a was obtained in 44%
yield (Table 1, Entry 1). Adding a hydrogen bond acceptor tetra-
[
7], Au [8]) have been developed to oxidize alcohols into ketones/
aldehydes (Scheme 1B). Although widely accepted, it suffers from
some limitations due to the economics and toxicity of these metal
catalysts. A more elegant and metal-free strategy is highly
demanded in photocatalyzed oxidation. Therefore, many efforts
butylammonium
p-chlorobenzoate
4
(4-ClOBzBu N)
slightly
decreased the yield (Table 1, Entry 2). Alternation of the reaction
solvents to MeCN (Table 1, Entry 3), DMF (Table 1, Entry 4) did
not improve the yield a lot. Otherwise, a slightly better result could
be obtained in DMSO with a yield of 50% (Table 1, Entry 5).
Meanwhile, in order to facilitate work-up and separation, a mixed
⇑
Corresponding authors.
E-mail addresses: Tangshch@lzu.edu.cn (S. Tang), wangxiaolei@lzu.edu.cn
(
X. Wang), jianliu@lzu.edu.cn (J. Liu).
https://doi.org/10.1016/j.tetlet.2021.152878
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

H. Zhang, T. Guo, M. Wu et al.
Tetrahedron Letters 67 (2021) 152878
time was extended, or performed under an oxygen atmosphere, the
yield was still not significantly improved, we speculated that there
should be a steric hindrance during the HAT process. To broaden
the substrates spectrum, we then investigate the oxidation of 1-
naphthalenemethanol 1j and cyclic benzyl alcohol. To our delight,
the rigid benzyl alcohol analogues with the steric hindrance of
benzylic position did not hamper the reaction (1k-n), and the
desired ketone products were isolated in good yields. Compared
with benzhydryl, a rigid structure was conducive to the reaction.
Subsequently, benzyl alcohols with electron-withdrawing groups
were tested. 4-Bromobenzyl alcohol 1o and 2-chlorobenzyl alcohol
1
p were converted into products with 70% and 86% yields respec-
tively, and the latter showed good reactivity [13]. Other substrates
with an electron withdrawing substitute (1q-t) were found to be
over-oxidized under standard conditions. If we removed Bu
4 2
NH -
PO , meanwhile extended the reaction time, desired aldehydes
4
could be obtained with moderate yields. Though this result was
unexpected, a clear mechanism was still under investigation.
Scheme 1. Oxidation of alcohols to carbonyl compounds.
Furthermore, heteroaromatic alcohol analogue 1u and
a-hydroxy
solvent of MeCN/DMSO was chose in our reaction. Replacing 4-
ClOBzBu N with tetrabutylammonium phosphate (Bu NH PO ),
ester analogue 1v could also be converted to the desired
aldehyde smoothly. What is striking about the results in this table
were 2w and 2x. The excellent selectivity was achieved on the
benzylic position only and the aliphatic alcohols were not
disturbed [17].
4
4
2
4
no significant improvement was observed (Table 1, Entry 6). Fortu-
nately, when 4 Å molecular sieves were added to the system, the
yield increased sharply from 50% to 88% (Table 1, Entry 7), we con-
sidered it improved the reaction efficiency by removing water and
boosting the decomposition of hydrogen peroxide described by
After substrate spectrum evaluation, control experiments were
carried out to investigate the actual rule of the reaction factors and
investigate the reaction mechanism (Table 3). Taking benzyl alco-
hol 1a as substrate, there was no formation of the product in the
absence of light (Table 3, Entry 2), photocatalyst (Table 3, Entry
4), or under Ar atmosphere (Table 3, Entry 3). Otherwise, benzalde-
hyde could be detected without quinuclidine, which indicated the
redox cycle was accelerated by quinuclidine (Table 3, Entry 5).
Then the effect of different quenchers on the reaction was exam-
ined. When butylated hydroxytoluene (BHT) (3 eq) was added into
the mixture of reactants as a radical scavenger, the yield dropped
sharply to 10% (Table 3, Entry 6). Using sodium azide as a singlet
oxygen scavenger, the monitored yield has also dropped dramati-
cally (Table 3, Entry 7). Meanwhile, benzoquinone as a superoxide
radical anion scavenger also inhibited the reaction (Table 3, Entry
2
Cibulka [10b]. Meanwhile, O (balloon) atmosphere also revealed
favorable yield (Table 1, Entry 8), but the air atmosphere was
eligible for reaction convenience in subsequent experiments.
With these optimized conditions in hand, we then explored the
substrate scope (Table 2). Various methoxy substituted benzyl
alcohols (1b-e) were firstly tested under the optimized reaction
conditions and could be oxidized with high yields up to 90%. Inter-
estingly, ortho-substitution in the aromatic ring did not hamper
the reaction process, which displayed distinct results compared
with previous work [13]. The benzyl alcohol substituted with an
amino group (1f, 1g) was then tested which has never been tried
under photocatalyzed oxidation. A time prolong was needed for
4
-(Boc-amino) benzyl alcohol 1f to get the product with 82% yield,
while 2-(Boc-amino) benzyl alcohol 1g bearing steric hindrance
2
8). Furthermore, the addition of CuCl hindered the process of reac-
reacted moderately under standard conditions with the yield of
tion (Table 3, Entry 9). The above results indicated there was a rad-
ical process involving single electron transfer and hydrogen atom
transfer in this photoredox system.
7
5%. When phenyl substituted benzyl alcohol was tested, 4-
biphenylmethanol 1h also showed excellent reactivity. On the con-
trary, benzhydryl 1i had a slightly decreased reactivity, the desired
benzophenone 2i was obtained with a yield of 66%. Even if reaction
To further investigate the reaction mechanism, we carried out
0
the oxidation of deuterium-labelled 1-indanol 1k under standard
Table 1
a
Optimization of the reaction conditions.
Entry
Solventb
Additivesc
Atmosphere
Yieldd (%)
1
2
3
4
5
6
7
8
MeCN/DMSO
MeCN/DMSO
MeCN
DMF
DMSO
MeCN/DMSO
MeCN/DMSO
MeCN/DMSO
w/o
Air
Air
Air
Air
Air
Air
Air
44
31
30
39
50
51
88
95
4-ClOBzBu
4-ClOBzBu
4-ClOBzBu
4-ClOBzBu
4
4
4
4
N
N
N
N
Bu
4
Bu
4
Bu
4
NH
NH
NH
2
2
2
PO
PO
PO
4
4
4
+ MS
+ MS
O
2
a
Reaction condition: benzyl alcohol (0.2 mmol), 4CzlPN (3 mol%), quinuclidine (10 mol%), solvent (1 mL), Air (balloon) or O
2
(balloon), room temperature (rt), under 8 W
blue LEDs irradiation. For the detailed optimization, see Table S1 and Table S2.
b
MeCN/DMSO: MeCN (1 mL) + DMSO (0.1 mL).
c
Bu
4
NH
2 4 4
PO (25 mol%), 4-ClOBzBu N (25 mol%), 200 mg 4 Å Molecular sieves were activated under vacuum at 200 °C for 30 min prior to use.
d
Yield determined by GC using n-dodecane as an internal standard.
2

H. Zhang, T. Guo, M. Wu et al.
Tetrahedron Letters 67 (2021) 152878
Table 2
Table 3
Control experiments for the photochemical oxidation of benzyl alcohol.a
a
Substrate scope for the oxidation of benzylic primary and secondary alcohols.
Entry Controlled
parameter
Notes
Yield
(%)
1
2
3
4
5
6
7
8
Standard conditions
No light
Ar atmosphere
No PC
No quinuclidine
BHT (3 eq)
88
0
0
0
10
10
54
5
Radical scavenger
Singlet oxygen scavenger
NaN
3
(1 eq)
Benzoquinone (1 eq) Superoxide radical anion
scavenger
9
CuCl
2
(1 eq)
Electron scavenger
4
a
Reaction condition: benzyl alcohol (0.2 mmol), 4CzlPN (3 mol%), quinuclidine
10 mol%), Bu NH PO (25 mol%), MS (200 mg), MeCN (1 mL), DMSO (0.1 mL), Air
balloon), room temperature (rt), under 8 W blue LEDs irradiation, yields were
(
(
4
2
4
determined by GC using n-dodecane as an internal standard.
Scheme 2. Kinetic isotope effect (KIE) experiment.
Table 4
aReaction condition: alcohol (0.2 mmol), 4CzlPN (3 mol%), quinuclidine (10 mol%),
Fluorescence quenching experiments.
4 2 4
Bu NH PO (25 mol%), MS (200 mg), MeCN (1 mL), DMSO (0.1 mL), Air (balloon),
room temperature (rt), under 8 W blue LEDs irradiation. All are isolated yields
except 2a and 2p.
b
2
In presence of O (balloon).
c
Prolonged the reaction time to 15 h.
d
4 2 4
Prolonged the reaction time to 20 h, and without Bu NH PO .
H D
conditions (Scheme 2). The K /K value of 1.4 in the kinetic isotope
effect experiment uncovered that CAH bond cleavage was the rate-
determining step. Thereafter, the Stern–Volmer fluorescence
quenching experiments was investigated. The fluorescence inten-
sity of 4CzlPN was quenched dramatically by quinuclidine and O
2
instead of benzyl alcohol (Table 4 and Figs. S2-4), revealed that
the excited 4CzlPN did not interact directly with benzyl alcohol,
but with quinuclidine and oxygen.
diate II. Finally, a protonation and elimination of the intermediate
Based on all the mechanistic study above, we proposed a plau-
sible mechanism in Scheme 3. Irradiation of photocatalyst 4CzlPN
with blue LEDs generated the excited PC* (E1/2 [PC*/PC ] = 1.35 V
2 2
II delivered the final product 2a and H O .
In conclusion, we have developed a green and robust method
for the oxidation of benzylic primary and secondary alcohols with
good functional group tolerance. Notably, our oxidation strategy
has shown advanced benefit for the substrates that bearing a
space-hindered ortho-substitute and good selectivity on the ben-
zylic alcohols over aliphatic alcohols. Detailed mechanistic
research revealed a quinuclidine mediated HAT process and blue
LED promoted photoredox cycle was involved in our oxidation.
This method represents a powerful example of the photoredox
transformation and can be a beneficial supplement to the alcohol
oxidation arsenal.
red
ꢀ
vs SCE) [18], which is sufficient for the oxidation of quinuclidine
ox
1
(
E
1/2 = 1.1 V vs SCE) [14g] to its radical cation. Singlet oxygen O
was also generated through an energy transfer process between
and excited PC* at the same time [2b,19]. Then a HAT process
happened between the benzyl alcohol 1a and quinuclidine
radical cation to yield the -hydroxy radical I. Meanwhile, the
2
O
2
a
ꢀ
ox
ꢀ
reduced form of the photocatalyst PC (E1/2 [PC/PC ] = 1.21 V vs
SCE) [18] reduced O
oxide radical anion O
1
red
1
Åꢀ
2
2
(E1/2 [ O
2
/O ] = 0.65 V vs SCE) [20] to super-
Åꢀ
2
which integrates with I to produce interme-
3

H. Zhang, T. Guo, M. Wu et al.
Tetrahedron Letters 67 (2021) 152878
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