Photoinduced Carbon Tetrabromide Initiated Aerobic Oxidation of Substituted Toluenes to Carboxylic Acids

Article abstract of DOI:10.1055/s-0039-1691534

A mild and metal-free procedure is reported for the aerobic oxidation of substituted toluenes to carboxylic acids by using CBr ₄ as initiator under irradiation from a 400 nm blue light-emitting diode.

Full text of DOI:10.1055/s-0039-1691534

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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–C
letter
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Synlett
K. Zheng et al.
Letter
Photoinduced Carbon Tetrabromide Initiated Aerobic Oxidation
of Substituted Toluenes to Carboxylic Acids
Kun Zheng
Me
COOH
O2 (balloon)
CBr4 (10 mol%)
Xiaoyu Yan
R
R
Guofu Zhang
Xinhuan Yan
Xiaoqing Li*
Xiangsheng Xu *
MeCN, rt,
400 nm LEDs
R = t-Bu, MeO, F, Cl, Br, I,
22 examples
41–96% yield
NO2, CN, CH2Br, COR1
College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
xqli@zjut.edu.cn
future@zjut.edu.cn
Received: 17.10.2019
LiBr or HBr
Accepted after revision: 28.11.2019
Published online: 13.12.2019
hν (400 W)
Me
COOH
DOI: 10.1055/s-0039-1691534; Art ID: st-2019-k0567-l
CBr4–PPh3
R
+ O2 (balloon)
R
fluorescent lamp
Abstract A mild and metal-free procedure is reported for the aerobic
oxidation of substituted toluenes to carboxylic acids by using CBr4 as
initiator under irradiation from a 400 nm blue light-emitting diode.
CBr4
This work
400 nm LED
Key words metal-free synthesis, photooxidation, toluenes, benzoic
acids
Scheme 1 Photoinduced aerobic oxidation of substituted toluenes to
carboxylic acids
Aerobic oxidation of toluene and substituted toluenes is
one of the most important and most fundamental transfor-
mations in organic synthesis, because of the importance
nm light-emitting diode (LED) (Table 1, entries 1 and 2).
Notably, an 8% yield of benzaldehyde was obtained when a
460 nm LED was used. Inspired by these results, we decided
1
and versatility of the corresponding carboxylic acids in the
2
fine-chemical industry. Although this transformation has
Table 1 Optimization of the Reaction Conditionsa
found broad applications, it still suffers from some limita-
tions, such as the use of metal catalysts, the need for harsh
3
Me
COOH
CHO
reaction conditions, and poor selectively. In recent years, a
O2 (balloon)
great deal of research effort has been devoted to the devel-
opment of metal-free procedures for aerobic oxidation of
substituted toluenes to carboxylic acids as alternatives to
CBr4 (10 mol%)
+
MeCN, rt
visible light
1a
2a
3
4
the conventional protocols. Among these, photochemical
reactions provide an alternative to classical reactions under
thermal control, avoiding the need for harsh reaction con-
ditions and improving the selectively (Scheme 1). Itoh and
co-workers developed an aerobic oxidation of substituted
toluenes by UV irradiation in the presence of LiBr or HBr.5
b
Entry Catalyst
Light source
Yield (%) of 2a
Yield (%) of 3
1
CBr
CBr
4
4
fluorescent lamp
460 nm LED
440 nm LED
400 nm LED
400 nm LED
400 nm LED
400 nm LED
trace
trace
38
trace
8
2
3
CBr4
CBr4
26
21
2
They also improved the reaction by employing a CBr –PPh
4
3
4
70
system as bromine source under visible-light irradiation.6
Here, we report a simpler aerobic oxidation of substituted
5c
6e
CBr
–
98 (96)d
–
4
–
toluenes under visible-light irradiation with CBr as an ini-
4
7
CCl
4
–
–
tiator without the assistance of PPh3.
a
We commenced our studies by investigating the aerobic
oxidation of toluene (1a). In our initial attempt, only a trace
amount of benzoic acid was detected under visible-light ir-
radiation by a general-purpose fluorescent lamp or a 460
Reaction conditions: toluene 1a (0.5 mmol), catalyst (10 mol%), MeCN (10
balloon, rt, 24 h.
GC yields with 1,4-dioxaneas internal standard.
mL), 60 W 400 nm LED, O
2
b
c
48 h.
Isolated yield.
No catalyst.
d
e
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2019. Thieme. All rights reserved. Synlett 2019, 30, A–C
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B
Synlett
K. Zheng et al.
Letter
to test LEDs with a shorter wavelength. To our delight, by
using a 440 nm LED, the desired benzoic acid (2a) and
benzaldehyde (3) were formed in yields of 38 and 26%, re-
spectively (entry 3). A further reduction in the wavelength
of the light to 400 nm increased the yield of benzoic acid
The disubstituted methylarenes 1t and 1u also performed
well in this reaction. Perhaps most importantly, this trans-
formation is not limited to substituted toluenes; for exam-
ple, 1-bromo-2-methylnaphthalene readily underwent this
aerobic oxidation to give acid 2v in 53% yield. However,
none of the reactions was scaled to above 0.5 mmol because
of concerns regarding the formation of potentially explo-
sive peroxide and hydroperoxide intermediates.7
The aerobic oxidation of toluene was then monitored
over a period of 48 hours. GC analysis showed that benzal-
dehyde was the main product during the first ten hours, but
this was later consumed to form benzoic acid (Figure 1).
(
2a) to 70% (entry 4). Moreover, prolonging the reaction
time to 48 hours increased the yield to 96% (entry 5). Con-
trol experiments suggested that CBr4 was essential for a
successful aerobic oxidation of toluene (entry 6), as struc-
turally similar CCl gave no reaction (entry 7).
4
With the optimized reaction conditions in hand,7 we
next investigated the scope of the scope (Scheme 2). A di-
verse array of methylarenes with a variety of functional
groups (tert-butyl, methoxy, fluoro, chloro, bromo, iodo, ni-
tro, nitrile, bromomethyl, or acyl) were tolerated in this re-
action. Generally, para-substituted methylarenes, which
gave products 2a–k in yields of 72–96%, were more effec-
tive substrates than their meta- or ortho-substituted ana-
logues, which gave products 2l–q in yields of 41–68%. Nota-
bly, whereas the methyl group of 4-(bromomethyl)toluene
(
1j) was smoothly oxidized, the bromomethyl group was
unaffected by the reaction conditions, possibly due to the
steric effect of the neighboring bromine atom. The terminal
methyl group of a propionyl group was also tolerated to af-
ford the corresponding product 2r in good yield. Further-
more, we found that 4-methylbenzophenone could be oxi-
dized to the acid 2s, but with modest efficiency (63% yield).
Figure 1 Monitoring the aerobic oxidation of toluene
Me
2
CO H
O2 (balloon)
CBr4 (10 mol%)
To gain more insights into the reaction pathway for the
aerobic oxidation, we treated benzaldehyde with O under
R
R
2
MeCN, rt, 60 h
various conditions (Table 2). The reaction of benzaldehyde
under the optimized reaction conditions gave a 97% conver-
sion into 2a, demonstrating its competency as an interme-
diate (Table 2, entry 1). Control experiments revealed that
the reaction efficiency was reduced significantly in the ab-
sence of visible-light irradiation (entries 2 and 3). In con-
trast, the reaction under visible-light irradiation in the ab-
4
00 nm blue LED
1
2
COOH
COOH
COOH
R
R
R
R = Br, 2l, 52%
R = NO2, 2m, 54%
R = CN, 2n, 65%
R = F, 2o, 41%
R = Cl, 2p, 60%
R = Br, 2q, 53%
R = t-Bu, 2b, 72%
R = OMe, 2c, 95%
R = F, 2d, 86%
sence of CBr was moderately successful (entry 4), suggest-
4
ing that the interaction between light and CBr4 might
promote the photoinduced oxidation. Notably, no acyl bro-
mide was detected when the reaction was conducted in the
presence of 4 Å molecular sieves (entry 5), indicating that
R = Cl, 2e, 82%
R = Br, 2f, 80%
R = I, 2g, 82%
COOH
O
R = NO2, 2h, 84%
R = CN, 2i, 72%
R = CH2Br, 2j, 75%
R = Ac, 2k, 92%
COOH
6
acyl bromides might be not involved as intermediates. The
Me
O
2s, 63%
decrease in the yield might be due to the opacity of the
solution caused by the addition of the molecular sieves.
Based on these experiments and on previous results, a
plausible mechanism is proposed in Scheme 3. Under irra-
diation and/or activation by a charge-transfer (CT) complex
of toluene with CBr4,8 homolysis of CBr4 gives a tribro-
momethyl radical and a bromo radical. The reaction of tolu-
ene with the bromo radical gives a benzyl radical (I) and
2r, 79%
COOH
COOH
Br
Br
Br
COOH
OMe
F
2
t, 79%
2u, 79%
2v, 53%
9
Scheme 2 Scope of the reaction. Reagents and conditions: 1 (0.5
mmol), CBr (10 mol%), MeCN (10 mL), 60 W 400 nm LED, O balloon,
rt, 60 h. Isolated yields are reported.
initiates a chain oxidation process. The reaction of the ben-
4
2
zyl radical (I) with dioxygen yields benzyl hydroperoxide
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2019. Thieme. All rights reserved. Synlett 2019, 30, A–C

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K. Zheng et al.
Letter
Table 2 Control Experiments
References and Notes
CHO
COOH
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds: Mechanistic Principles and Synthetic Meth-
odology Including Biochemical Processes; Academic Press: New
York, 1981. (b) Simandi, L. Catalytic Activation of Dioxygen by
Metal Complexes; Kluwer Academic: Boston, 1992. (c) Henry,
P. M. Palladium Catalyzed Oxidation of Hydrocarbons; Reidel:
Dordrecht, 1980.
O2 (balloon)
conditions
3
2a
b
Entry
Catalyst
Light
Yield (%)
(
2) (a) Nguyen, T. T.; Grigorjeva, L.; Daugulis, O. Angew. Chem. Int.
Ed. 2018, 57, 1688. (b) Li, Q.; Meng, L.; Zhou, S.; Deng, X.; Wang,
N.; Ji, Y.; Peng, Y.; Xing, J.; Yao, G. Eur. J. Med. Chem. 2019, 180,
1
2
3
4
CBr
CBr
–
4
400 nm
–
97
4
5
509. (c) Oliveira, C.; Bagetta, D.; Cagide, F.; Teixeira, J.; Amorim,
–
1
R.; Silva, T.; Garrido, J.; Remiao, F.; Uriarte, E.; Oliveira, P. J.;
Alcaro, S.; Ortuso, F.; Borges, F. Eur. J. Med. Chem. 2019, 174, 116.
(d) Zhang, Z.; Hao, K.; Li, H.; Lu, R.; Liu, C.; Zhou, M.; Li, B.; Meng,
Z.; Hu, Q.; Jiang, C. Eur. J. Med. Chem. 2019, 181, 111564.
–
400 nm
400 nm
23
64
5c
CBr
4
a
Reaction conditions: PhCHO (3; 0.5 mmol), CBr
balloon, rt, 48 h.
GC yields with 1,4-dioxane as internal standard.
4
(10 mol%), MeCN (10
mL), 60 W 400 nm LED, O
2
(3) (a) Miki, J.; Osada, Y.; Tachibana, Y.; Shikada, T. Catal. Lett. 1995,
30, 263. (b) Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.;
Ishii, Y. J. Org. Chem. 1997, 62, 6810. (c) Yamazaki, S. Org. Lett.
b
c
4
Å molecular sieves added.
1999, 1, 2129. (d) Rogovin, M.; Neumann, R. J. Mol. Catal. A:
Chem. 1999, 138, 315. (e) Bandyopadhyay, R.; Biswas, S.;
Bhattacharyya, R.; Guha, S.; Mukherjee, A. K. Chem. Commun.
(
II), which is then transformed into benzaldehyde (3).9b Fi-
nally, benzaldehyde (3) is further oxidized to benzoic acid
2) on prolonging the reaction time.
1999, 1627. (f) Das, B. K.; Clark, J. H. Chem. Commun. 2000, 605.
10
(g) Fraga-Dubreuil, J.; Garcia-Verdugo, E.; Hamley, P. A.;
Vaquero, E. M.; Dudd, L. M.; Pearson, I.; Housley, D.;
Partenheimer, W.; Thomas, W. B.; Whiston, K.; Poliakoff, M.
Green Chem. 2007, 9, 1238. (h) Wang, J.-Q.; He, L.-N. New J.
Chem. 2009, 33, 1637. (i) Nakamura, R.; Obora, Y.; Ishii, Y. Adv.
Synth. Catal. 2009, 351, 1677. (j) Cui, L.-Q.; Liu, K.; Zhang, C. Org.
Biomol. Chem. 2011, 9, 2258. (k) Hu, Y.; Zhou, L.; Lu, W. Synthesis
(
blue LED (400 nm)
CBr4
• CBr3
+
Br •
CH3
or
CBr4
CT complex
2017, 49, 4007.
(
4) (a) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama,
T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934. (b) Paul, S.;
Nanda, P.; Gupta, R. Synlett 2004, 531. (c) Lu, T.; Mao, Y.; Yao, K.;
Xu, J.; Lu, M. Catal. Commun. 2012, 27, 124. (d) Liu, G.; Tang, R.;
Wang, Z. Catal. Lett. 2014, 144, 717. (e) Ozen, R. Asian J. Chem.
•
CH3
CH
O
H
2
CHO
2
CO H
O
Br •
HBr
O2
O2
ref. 9
ref. 10
2
014, 26, 941. (f) Heidari, M.; Sedrpoushan, A.; Mohannazadeh,
1
I
II
3
2
F. Org. Process Res. Dev. 2017, 21, 641.
(
5) (a) Itoh, A.; Hirashima, S.-i. Synthesis 2006, 1757. (b) Itoh, A.;
Hashimoto, S.; Kodama, T.; Masaki, Y. Synlett 2005, 2107.
6) Sugai, T.; Itoh, A. Tetrahedron Lett. 2007, 48, 9096.
7) Arylcarboxylic Acids 1a–v; General Procedure
Scheme 3 Plausible mechanism
(
(
In conclusion, we have developed a simple and effective
method for the photoinduced aerobic oxidation of substi-
tuted toluenes to benzoic acids under mild metal-free con-
CAUTION: The reaction is inherently explosive in nature
because significant concentrations of peroxide and hydroperox-
ide intermediates are generated. Appropriate precautions
should be adopted. The reaction should not be scaled up.
A solution of the appropriate substrate 1 (0.5 mmol) and CBr4
ditions. The method uses easily handled CBr as the only
4
initiator and a 400 nm LED as a source of visible light. The
transformation exhibits a broad scope and good functional-
group compatibility.
(0.05 mol) in anhyd MeCN (10 mL) was stirred in a round-
bottom flask fitted with an O balloon, and irradiated externally
2
with a 60 W 400 nm LED at rt. When the reaction was complete
(
TLC), the solvent was evaporated under reduced pressure. The
Funding Information
residue was purified by column chromatography (silica gel).
Benzoic Acid (2a)
This work was supported by the National Key Research and Develop-
ment Program of China (2017YFC0210900).()
White solid; yield: 58.6 mg (96%); mp: 120–121 °C; R = 0.73
f
1
(
50% EtOAc–PE). H NMR (500 MHz, CDCl ):  = 8.34–8.02 (m, 2
3
H), 7.71–7.54 (m, 1 H), 7.48 (t, J = 7.9 Hz, 2 H).
(
(
8) King, J. W.; Quinney, P. R. J. Chromatogr. 1970, 49, 161.
9) (a) Tripathi, S.; Singh, S. N.; Yadav, L. D. S. RSC Adv. 2016, 6,
14547. (b) Sandhiya, L.; Zipse, H. Chem. Eur. J. 2015, 21, 14060.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691534.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
(10) Sankar, M.; Nowicka, E.; Carter, E.; Murphy, D. M.; Knight, D. W.
Bethell D.; Hutchings, G. J. Nat. Commun. 2014, 5, doi:
10.1038/ncomms 4332.
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2019. Thieme. All rights reserved. Synlett 2019, 30, A–C