The cumene/O2 system: A very simple tool for the radical chain oxidation of some functional groups

Article abstract of DOI:10.1039/c7nj01666b

Due to the relative stability of the cumyl radical, cumenes and α-methyl-styrenes are ideally structured to directly harvest the oxidizing reactivity of O₂ and initiate radical chain reactions in catalyst-free conditions. In the absence of additional substrates, these processes can lead to acetophenones. In the presence of substrates, the cumene oxidation process can be intercepted in various chain reactions, affording very simple protocols for functional group oxidation.

Full text of DOI:10.1039/c7nj01666b

NJC
View Article Online
View Journal
LETTER
The cumene/O system: a very simple tool for the
2
radical chain oxidation of some functional
Cite this:DOI: 10.1039/c7nj01666b
groups†‡
Received 14th May 2017,
Accepted 27th June 2017
ab
a
a
A. Malekafzali, K. Malinovska and F. W. Patureau
*
DOI: 10.1039/c7nj01666b
rsc.li/njc
Due to the relative stability of the cumyl radical, cumenes and
a-methyl-styrenes are ideally structured to directly harvest the
2
oxidizing reactivity of O and initiate radical chain reactions in
catalyst-free conditions. In the absence of additional substrates,
these processes can lead to acetophenones. In the presence of
substrates, the cumene oxidation process can be intercepted in
various chain reactions, affording very simple protocols for func-
tional group oxidation.
Phenones are traditionally prepared by ozonolysis (CQC bond
1
cleaving oxidation of styrenes with O
tion of styrenes with O
3
), metal catalysed oxida-
2
2
, such as in the Wacker process, or
simply by oxidation of their alkyl benzene precursors, to name
3
only a few methods. The chemistry of phenones, their prepara-
tion but also their very rich and versatile reactivity has been at
the heart of organic synthesis for well over a century. Recently,
Jianliang Xiao reported a CQC bond cleaving oxidation of
styrenes towards the corresponding phenones while using an
iron(III)-triflate catalyst bearing a tridentate amine ligand, with
4
O
2
as the terminal oxidant (Scheme 1). More recently, Xiao
Wang reported an analogous protocol utilizing an aromatic
disulfide organocatalyst under white LED, also under 1 atm of
5
O
2
. The latter methods afford the corresponding phenones in
good yields at mild temperatures (as low as 25 1C, Scheme 1).
However to what extend exactly does one need a catalyst for this
reaction to occur? While the activation of molecular O can be
2
troublesome in mild reaction conditions without a catalyst,
some early work conducted by Hayashi in 2002 did document
the neat transformation of a-methyl-styrenes into acetophenones
6
with O as the sole reagent.
2
Scheme 1 Oxygenolysis of (a-methyl)-styrenes according to recent
4
5
reports of Xiao (top) Wang (middle), selected examples, in comparison
6
a
to the catalyst-free method of Hayashi (beneath).
FB Chemie, Technische Universi a¨ t Kaiserslautern, Erwin-Schr o¨ dinger Str. 52,
6
7663 Kaiserslautern, Germany. E-mail: patureau@chemie.uni-kl.de;
Web: http://www.chemie.uni-kl.de/patureau
b
Chemistry Department, Tarbiat Modares University, Jalale-Ale-Ahmad Highway,
Beyond Hayashi’s catalyst free method for a-methyl-
styrenes, it seemed clear that based on the known chemistry
1
4117-13116 Tehran, Iran
6
†
‡
All the work presented here was conducted in Kaiserslautern.
of cumyl-hydroperoxide, pure cumene should also be a competent
substrate in this reaction. This assumption is moreover supported
Electronic supplementary information (ESI) available: Experimental procedures
and analytical data. See DOI: 10.1039/c7nj01666b
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017
New J. Chem.

View Article Online
Letter
NJC
by the decades-old decomposition of cumyl-hydroperoxide, which competing C–C bond cleaving pathways. Interestingly, utilizing
7
is known to yield acetophenone. It thus occurred to us that 2-phenyl-butane instead of cumene is more effective at 150 1C
8
cumene, a precursor to a-methyl-styrene, would probably display than cumene, with a yield of acetophenone of 3.20 mmol (entry 2).
a similar reactivity than Hayashi’s oxygenolysis with O , in Notably, C–C bond cleavage occurs with a very large preference on
2
9
completely additive free conditions. We thus conducted an initial the side of the longer alkyl chain, as the acetophenone product
reactivity and mechanistic survey, summarized in Table 1.
largely exceeds the propiophenone product by a ratio of 96 :4
The following reaction conditions were eventually selected: (entry 2). This suggests the intermediacy of the corresponding
4
5
cumene, 14 mmol, is placed in an 85 mL glass reactor, which is styrene as a significant intermediate, similarly to the Xiao, Wang
6
2
then flushed with O for approximatively 1 minute, and then and Hayashi systems, the internal alkene being largely favored
sealed and heated up for 24 h at 190 1C. When cumene is over the external one in the case of an in situ dehydrogenative
submitted to those conditions, one molecule of O produces event. This is confirmed by entry 3, in which neat a-methylstyrene
2
9
approximatively one molecule of acetophenone. The reaction is is also converted to acetophenone (3.25 mmol). We also tried to
still operational at 150 1C but conversion is then lower run the reaction under air at cumene’s boiling point. Only 2.6% of
(1.62 mmol, Table 1, entry 1). By increasing reaction tempera- the cumene converted to acetophenone in those open-flask con-
ture, dehydration of the dimethyl-phenyl-carbinol byproduct ditions. With those initial conditions in hand, we then evaluated
increases also, yielding the corresponding a-methyl styrene the effects of some simple electron donating and withdrawing
which can then re-engage itself in an oxidation event with O
2
substitution patterns (Table 1). We found that strongly withdraw-
4
to produce the desired acetophenone. As opposed to the ing groups (R = Ac, 2j), make the cumenes unreactive, likely by
4
5
Xiao and Wang systems, in which the position of the olefin preventing the first oxidation step: the cumyl H-atom abstraction.
starting material is already defined in the substrate, starting For halides, methoxy, and phenyl functional groups, the tolerance
directly from unsymmetrical alkyl-benzene precursors can offer is generally acceptable. A mechanism is proposed in Scheme 2
10
consisting in a stepwise radical dehydrogenation, producing
a-methyl-styrene which would then be further oxidized with O
2
Table 1 Initial screening overview in 85 mL sealed reactors, with 1 atm of
1
O
2
(3.5 mmol Æ 0.2 mmol), yields in (mmol) determined by H NMR
integration, internal standard: 1,1,2,2-tetrachloroethane
Scheme 2 Possible chain propagation mechanisms taking into account
the observed by-products of Table 1, PATH I through a-methyl-styrene,
6
notably proposed by Hayashi, and PATH II through the cumyl-hydroperoxide
7
route, notably documented by Di Somma.
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017

View Article Online
NJC
Letter
6
in a Hayashi-like mechanism. Alternatively, a classical cumyl- phenols with phenothiazines in excellent yields, a reaction which
8
hydroperoxide route can be considered, as documented notably we previously reported. A similar system also allows the C–S cross
7
by Di Somma, which is also reasonable in view of some of the dehydrogenative coupling between phenols and thiophenols,
12
byproducts observed in Table 1. In any case, 2 mmol of 2,4,6-tri- although with moderate yields (product 8a, 44%). We thus
tert-butylphenol added to the reactor as a radical inhibitor wondered whether the cumene/O system would also be compe-
2
suppresses acetophenone formation (Scheme 2). This result thus tent for simple functional group oxidation. We therefore con-
confirms the radical chain character of this transformation. sidered the oxidation of a series of organic substrates under those
Because cumene is so readily oxidized by O , it may potentially conditions. For example, benzhydrol 9 yields benzophenone
2
be a good solvent to carry out simple functional group oxidation (entry 14, 97% isolated yield). Diphenylmethane 10 also yields
and/or oxidative coupling reactions through radical chain oxida- benzophenone (entry 15, 88%), while xanthene (11) and fluorene
tions. In two recent cross-dehydrogenative coupling methods, the (12) produce xanthone 16 and fluorenone 17 with 93% and 74%
cumene/O2 couple was utilized as an enabling (re-)oxidizing yield respectively. Finally 1,2-diphenylhydrazine (13) yields azo-
strategy (Scheme 3). One method relies on a Ru/Cu catalysed benzene 18 (93%). All were efficiently transformed while simply
1
1
C–H/N–H bond activation system, while the other method is being heated up in cumene under 1 atm of O
2
at 150 1C, without
8
entirely additive-free. The cumene/O
direct and additive-free cross dehydrogenative C–N coupling of the most studied reactions in the literature.
2
system notably enables the any further additive. These trivial oxidation processes are among
13–16
However the vast
majority of these oxidative methods rely on metal additives,
sometimes also on externally added oxidants, which arguably
makes our method an interesting alternative.
In conclusion, the oxidative C–C bond cleaving oxidation
of cumenes or a-methyl-styrenes with O towards the corres-
2
ponding phenones can proceed efficiently without a catalyst.
These typically require significantly higher temperatures how-
1
7
ever than under catalytic conditions. Importantly, the O
2
mediated oxidation of cumene can be intercepted in the frame
of cross dehydrogenative couplings, or the simple oxidation of
diverse functional groups. Clearly, cumene and its congeners
are well suited for the organic activation of O towards oxidative
2
applications.
Acknowledgements
The research of FWP is generously supported by the DFG-funded
transregional collaborative research center SFB/TRR 88 ‘‘Cooperative
effects in homo and heterometallic complexes’’ (http://3MET.de),
DFG funded project PA 2395/2-1, COST Action CA15106 (CHAOS),
and since March 2017: by ERC project 716136: ‘‘2O2ACTIVATION’’.
A. M. also acknowledges a fellowship from the Iranian ministry of
science, research and technology. Mr Alexander Jones is acknowl-
edged for teaching the laboratory techniques to K. M.
Notes and references
1
A selection: (a) R. W. Murray, Acc. Chem. Res., 1968, 1, 313;
(
(
b) R. Criegee, Angew. Chem., Int. Ed. Engl., 1975, 14, 745
Angew. Chem., 1975, 87, 765); (c) R. L. Kuczkowski, Chem.
Soc. Rev., 1992, 21, 79; (d) S. G. Van Ornum, R. M. Champeau
and R. Pariza, Chem. Rev., 2006, 106, 2990.
2
A selection: (a) T. Punniyamurthy, S. Velusamy and J. Iqbal,
Chem. Rev., 2005, 105, 232; (b) C. N. Cornell and M. S.
Sigman, Inorg. Chem., 2007, 46, 1903; (c) J. A. Keith and P. M.
Henry, Angew. Chem., Int. Ed., 2009, 48, 9038; (d) J. J. Dong,
W. R. Browne and B. L. Feringa, Angew. Chem. Int. Ed., 2015,
54, 734.
2
Scheme 3 Cumene/O as a simple oxidizing method, isolated yields.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017
New J. Chem.

View Article Online
Letter
NJC
3
Selected references: (a) K. Suga, K. Ohkubo and S. Fukuzumi,
J. Phys. Chem. A, 2003, 107, 4339; (b) A. Rajagopalan, M. Lara
and W. Kroutil, Adv. Synth. Catal., 2013, 355, 3321;
Sustainable Chem. Eng., 2016, 4, 2333; ( j) S. Yang, L. Peng,
P. Huang, X. Wang, Y. Sun, Ch. Cao and W. Song, Angew.
Chem., Int. Ed., 2016, 55, 4016; (k) A. Al-hunaiti, M. Raisanen
and T. Repo, Chem. Commun., 2016, 52, 2043; (l) C. Miao,
H. Zhao, Q. Zhao, C. Xiaa and W. Sun, Catal. Sci. Technol.,
2016, 6, 1378; (m) Y. Kuwahara, Y. Yoshimuraa and
H. Yamashita, Catal. Sci. Technol., 2016, 6, 442; (n) T. Uematsu,
Y. Miyamoto, Y. Ogasawara, K. Suzuki, K. Yamaguchi and
N. Mizuno, Catal. Sci. Technol., 2016, 6, 222; (o) A. Shaabani,
Z. Hezarkhani and E. Badali, RSC Adv., 2015, 5, 61759;
(p) Y. Chen, X. Feng, X. Huang, Z. Lin, X. Pei, S. Li, J. Li,
S. Wang, R. Li and B. Wang, Chem. Eur. J., 2015, 21, 13894;
(q) R. Chebolu, A. Bahuguna, R. Sharma, V. K. Mishra and
P. C. Ravikumar, Chem. Commun., 2015, 51, 15438; (r) H. Yi,
C. Bian, X. Hu, L. Niu and A. Lei, Chem. Commun., 2015,
51, 14046; (s) O. Mart ´ı nez-Ferrat ´e , G. J. P. Britovsek, C. Claver
and P. W. N. M. van Leeuwen, Inorg. Chim. Acta, 2015, 431, 156;
(t) S. K. Pahari, P. Pal, A. Sinhamahapatra, A. Saha, C. Santra,
S. C. Ghosh, B. Chowdhury and A. B. Panda, RSC Adv., 2015,
5, 45144; (u) S. K. Pahari, P. Pal, D. N. Srivastava, S. Ch.
Ghosh and A. B. Panda, Chem. Commun., 2015, 51, 10322;
(v) G. Urgoitia, R. SanMartin, M. T. Herrero and E. Domınguez,
Chem. Commun., 2015, 51, 4799; (w) B. Muehldorf and R. Wolf,
Chem. Commun., 2015, 51, 8425; (x) F. Napoly, R. Kieffer, L. Jean-
G ´e rard, C. Goux-Henry, M. Draye and B. Andrioletti, Tetrahedron
Lett., 2015, 56, 2517; (y) Y. Wang, Y. Kuang and Y. Wang, Chem.
Commun., 2015, 51, 5852; (z) J.-K. Li, X.-Q. Huang, S. Yang,
H.-W. Ma, Y.-N. Chi and C.-W. Hu, Inorg. Chem., 2015, 54, 1454.
(
c) A. Rubinstein, P. Jimenez-Lozanao, J. J. Carbo, J. M.
Poblet and R. Neumann, J. Am. Chem. Soc., 2014, 136, 10941;
d) J.-P. Wan, Y. Gao and L. Wei, Chem. – Asian J., 2016, 11, 2092.
A. Gonzalez-de-Castro and J. Xiao, J. Am. Chem. Soc., 2015,
37, 8206.
(
4
5
1
(a) Y. Deng, X.-J. Wei, H. Wang, Y. Sun, T. No ¨e l and X. Wang,
Angew. Chem., Int. Ed., 2017, 56, 832, see also; (b) X. Baucherel,
J. Uziel and S. Jug ´e , J. Org. Chem., 2001, 66, 4504.
See also: (a) Y. Hayashi, M. Takeda, Y. Miyamoto and
M. Shoji, Chem. Lett., 2002, 414; (b) R. Lin, F. Chen and
N. Jiao, Org. Lett., 2012, 14, 4158.
A selection: (a) M. S. Kharasch, A. Fono and W. Nudenberg,
J. Org. Chem., 1951, 16, 113; (b) A. Baignee, J. A. Howard,
J. C. Scaiano and L. C. Stewart, J. Am. Chem. Soc., 1983,
6
7
105, 6120; (c) I. Di Somma, R. Andreozzi, M. Canterino and
V. Caprio, AIChE J., 2008, 54, 1579; (d) I. Di Somma,
R. Marotta, R. Andreozzi and V. Caprio, Process Saf. Environ.
Prot., 2013, 91, 262; (e) Y.-S. Duh, Thermochim. Acta, 2016,
637, 102.
8
9
(a) M.-L. Louillat-Habermeyer, R. Jin and F. W. Patureau,
Angew. Chem., Int. Ed., 2015, 54, 4102, see also: (b) Y. Zhao,
B. Huang, C. Yang and W. Xia, Org. Lett., 2016, 18, 3326.
Cumene is a better starting material than neat a-methyl-
styrene. In the latter case, a white precipitate also appears,
presumably oligomeric by-products.
1
1
1
0 A recent review on radical mechanisms: A. Studer and 14 Selected recent methods for the oxidation of hydrazines:
D. P. Curran, Angew. Chem., Int. Ed., 2016, 55, 58.
1 M.-L. Louillat, A. Biafora, F. Legros and F. W. Patureau,
Angew. Chem., Int. Ed., 2014, 53, 3505.
(a) L. Wang, A. Ishida, Y. Hashidoko and M. Hashimoto,
Angew. Chem., Int. Ed., 2017, 56, 870; (b) M. Lin, Z. Wang,
H. Fang, L. Liu, H. Yin, C.-H. Yan and X. Fu, RSC Adv., 2016,
6, 10861; (c) B. Dutta, S. Biswas, V. Sharma, N. O. Savage,
S. P. Alpay and S. L. Suib, Angew. Chem. Int. Ed., 2016,
2 See ESI‡ for details. Other examples, with unfortunately
lower yields.
5
5, 2171; (d) S. Singh, P. Chauhan, M. Ravi, I. Taneja,
Wahajuddinb and P. P. Yadav, RSC Adv., 2015, 5, 61876;
e) S. Donck, E. Gravel, A. Li, P. Prakash, N. Shah, J. Leroy,
H. Li, I. N. N. Namboothiri and E. Doris, Catal. Sci. Technol.,
015, 5, 4542; ( f ) T. Hashimoto, D. Hirose and T. Taniguchia,
(
2
Adv. Synth. Catal., 2015, 357, 3346; (g) K. Monir, M. Ghosh,
S. Mishra, A. Majee and A. Hajra, Eur. J. Org. Chem., 2014, 1096;
(h) S. Okumura, C.-H. Lin, Y. Takeda and S. Minakata, J. Org.
1
3 For the oxidation of 9, 10, 11, and 12, see these selected
recent methods: (a) H. Wang, Z. Wang, H. Huang, J. Tan
Chem., 2013, 78, 12090; (i) W. Gao, Z. He, Y. Qian, J. Zhao and
Y. Huang, Chem. Sci., 2012, 3, 883.
and K. Xu, Org. Lett., 2016, 18, 5680; (b) F. Rusch, J.-C. 15 For other selected related systems, see: (a) M. Mitra,
Schober and M. Brasholz, ChemCatChem, 2016, 8, 2881;
c) A. Alanthadka, E. S. Devi, S. Nagarajan, V. Sridharan,
A. Suvitha and C. U. Maheswari, Eur. J. Org. Chem., 2016,
H. Nimir, S. Demeshko, S. S. Bhat, S. O. Malinkin,
M. Haukka, J. Lloret-Fillol, G. C. Lisensky, F. Meyer, A. A.
Shteinman, W. R. Browne, D. A. Hrovat, M. G. Richmond,
M. Costas and E. Nordlander, Inorg. Chem., 2015, 54, 7152;
(b) C. Jin, L. Zhang and W. Su, Synlett, 2011, 1435; (c) B. Xu,
E. M. Hartigan, G. Feula, Z. Huang, J.-P. Lumb and
B. A. Arndtsen, Angew. Chem., Int. Ed., 2016, 55, 15802.
(
4
2
872; (d) G. Pandey, R. Laha and D. Singh, J. Org. Chem.,
016, 81, 7161; (e) B. Majumdar, T. Bhattacharya and
T. K. Sarma, ChemCatChem, 2016, 8, 1825; ( f ) R. Xie,
G. Fan, L. Yang and F. Li, ChemCatChem, 2016, 8, 363;
(
g) Z. Ma, H. Zhang, Z. Yang, G. Ji, B. Yu, X. Liu and Z. Liu, 16 See also: (a) G. Franz and J. H. Sheldon, Oxidation, in
Green Chem., 2016, 18, 1976; (h) M. Zarghani and
B. Akhlaghinia, RSC Adv., 2016, 6, 38592; (i) S. Verma,
R. B. N. Baig, M. N. Nadagouda and R. S. Varma, ACS
Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH,
Weinheim, 2000; (b) C. Aellig, D. Scholz and I. Hermans,
ChemSusChem, 2012, 5, 1732; (c) I. Hermans, E. S. Spier,
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017

View Article Online
NJC
Letter
7
U. Neuenschwander, N. Turra and A. Baiker, Top. Catal.,
009, 52, 1162.
7 Proper safety precautions should be utilized for these reac-
explosions. The amount of O
2
is calculated utilizing the
2
gas equation PV = ZÁnÁRÁT in which Z, the compressibility
1
factor, is approximated to 1 for O gas at 20 1C and atmo-
2
tions, suitable protective shields, etc. Upscaling in batch
spheric pressure. In those conditions, which prevail when
conditions is not advised. In the acetophenone process
the reactor is filled and closed, 85 mL of O gas represents
2
(
Table 1), utilizing O2 as limiting reagent is designed at
approximatively 3.5 mmol of O , Æ0.2 mmol estimated
2
making the reaction safer for the operator. This approach
has the merit of avoiding cumyl-hydroperoxide isolation, as
it is usually done otherwise, potentially leading to
precision because of small differences in the handmade
glass reactors, small variations of room temperature, and
2
accuracy of the O -flushing technique.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017
New J. Chem.