AIBN initiated functionalization of the benzylic sp3 C[sbnd]H and C[sbnd]C bonds in the presence of dioxygen

Article abstract of DOI:10.1016/j.tetlet.2020.152806

A sp³ C[sbnd]H bond functionalization and C[sbnd]C bond cleavage were realized by AIBN/O₂ catalyst system, providing a series of benzophenones under mild reaction conditions. The mechanistic study shows that a peroxide intermediate is involved in this transformation, and in the case of diphenylmethanes, the sp³ C[sbnd]C bond is cleaved through the peroxide rearrangement, which might provides a new way to cleave relatively strong C[sbnd]C bond and be applied to more general C[sbnd]C bond activation.

Full text of DOI:10.1016/j.tetlet.2020.152806

Tetrahedron Letters 66 (2021) 152806
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AIBN initiated functionalization of the benzylic sp3 CAH and CAC bonds
in the presence of dioxygen
a
a
a
a,
Yingying Hu a, Yu Shao b, Shuwei Zhang a, , Yuan Yuan , Zheng Sun , Yu Yuan , Xiaodong Jia
⇑
⇑
a School of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, China
b School of Information Engineering, Yangzhou University, Huayang West Road 196, Yangzhou, Jiangsu 225127, China
a r t i c l e i n f o
a b s t r a c t
A sp3 CAH bond functionalization and CAC bond cleavage were realized by AIBN/O2 catalyst system, pro-
viding a series of benzophenones under mild reaction conditions. The mechanistic study shows that a
peroxide intermediate is involved in this transformation, and in the case of diphenylmethanes, the sp3
CAC bond is cleaved through the peroxide rearrangement, which might provides a new way to cleave rel-
atively strong CAC bond and be applied to more general CAC bond activation.
Article history:
Received 12 November 2020
Revised 20 December 2020
Accepted 25 December 2020
Available online 12 January 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
AIBN
CAH bond oxidation
CAC bond cleavage
Aerobic oxidation
Benzophenones
Introduction
radical to initiate radical reactions [6]. However, AIBN initiated
sp3 CAH bond functionalization is still rare. It is well-known that
In the past decades, great development has been achieved in the
functionalization of the inert CAH bonds [1–3], in which the reac-
tions mediated by free radical intermediates show a huge advan-
tage in the functionalization of sp3 CAH bond due to the nature
that the saturated CAH bonds are prone to undergo homolytic fis-
sion. Therefore, in recent years, radical CAH bond activation grad-
ually become the mainstream of sp3 CAH activation, and a large
number of elegant transformations have been developed [3,4].
Among them, the aerobic functionalization of sp3 CAH bond is par-
ticularly noticeable, for dioxygen might be one of the mildest and
greenest oxidants. However, its weak oxidizability as well as low
concentration in general solvents limits the application in organic
synthesis, albeit some great progress has been achieved [4m-o, 5]. As
part of our research interests, screen of the catalyst systems that
can promote the participation of oxygen has been a focus in the
study of our group [5]. Although in our previous research, the tri-
arylamine radical cation salts and alkyl nitrites were found to be
a kind of good initiator of the CAH bond oxidation, new catalyst
systems are still highly desirable.
the considerable difference in bond dissociation energies (BDE)
between the starting materials and the products is one of the most
important driving forces of radical reactions. Given the BDE of the
CAH bond in isobutyronitrile is comparable or even lower than
most sp3 CAH bonds, intermolecular hydrogen atom transfer
(HAT) between the 2-cyanoprop-2-yl radical and sp3 CAH bond
containing substrates are generally not efficient (Scheme 1, eq 1)
[7]. For the same reason, most initiators used in sp3 CAH activation
are peroxides (such as TBHP, DTBP), in which the OAH bonds of the
corresponding alcohols are greatly stronger than most sp3 CAH
bonds. At the other hand, in the aerobic conditions, the generated
2-cyanoprop-2-yl radical can smoothly capture dioxygen to form
2-cyano-2-propyloxyl radical species, and this process was widely
utilized to achieve various CAH bond cyanation [8]. So we ques-
tioned whether this 2-cyano-2-propyloxyl radical could initiate
the functionalization of sp3 CAH bond and other inert chemical
bond activation (Scheme 1, eq 2). Herein, we reported an AIBN ini-
tiated aerobic oxidation of the benzylic sp3 CAH bond and cleavage
of sp3 CAC bond.
2,20-Azobis(isobutyronitrile) (AIBN) is popularly used as a radi-
cal initiator in various radical reactions. Through pyrolysis, after
extruding amolecule of N2, it can release the 2-cyanoprop-2-yl
Results and discussion
To test our idea, diphenylmethane 1a was chosen as a model
substrate to explore the suitable conditions for the aerobic CAH
bond oxidation (Table 1). To our delight, in the presence of
⇑
Corresponding authors.
E-mail addresses: 006485@yzu.edu.cn (S. Zhang), jiaxd1975@163.com (X. Jia).
https://doi.org/10.1016/j.tetlet.2020.152806
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Y. Hu, Y. Shao, S. Zhang et al.
Tetrahedron Letters 66 (2021) 152806
monosubstituted substrates were employed to test the influence
of the substituent effect. The results show that halogen atom did
not affect the reaction efficiency, giving the desired products in
moderate to good yields (2b-2d), and even iodine atom can be
smoothly tolerated. When the electron-donating groups were con-
nected on the phenyl ring, the expected products were isolated in
lower yields (2f-2 g). The reason might lie in that in the presence of
electron-rich phenyl ring, the rearrangement of the generated per-
oxide would be accelerated (see Scheme 5). By GC–MS, the corre-
sponding benzoic acids were detected, which suggested that the
rearrangement of the peroxide intermediate occurred. The
Scheme 1. Cleavage of CAH and CAC bonds.
dioxygen, the desired reaction occurred smoothly, and benzophe-
none 2a was isolated in 69% yield (entry 1). Increasing the amount
of AIBN, higher yields were obtained (entries 1–5), and 3 equiva-
lent of AIBN gave the best result, providing 2a in 82% isolated yield
(entry 4). When the reaction temperature was reduced to 60 °C, the
reaction efficiency was lower and a large number of the starting
material remained unchanged (entry 5). Then, a solvent screen
was performed, and the results show that MeCN is still the best
solvent (entries 6–14). It is worth noting that when toluene was
employed as the solvent, benzaldehyde was detected by GC–MS,
which implied that the relatively active benzylic CAH bond might
disturb the desired reaction process. In the examination of the
reaction scope we can see that the substrates with benzylic methyl
groups generally gave lower yields of the expected products (vide
post).
With the best reaction conditions established, the reactions of
various substituted diphenylmethanes were performed under
the standard reaction conditions (Scheme 2). At the outset,
Scheme 2. The aerobic oxidation of diphenylmethanes.
Table 1
Optimization of the oxidation of diphenylmethane.
a
Entry
AIBN (x equiv)
Solvent
T (oC)
Yield (%)
1
2
3
4
5
6
7
8
1.5
2.0
2.5
3.0
4.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-Dioxane
DCE
anisole
THF
CHCl3
toluene
NO2Me
ClPh
75
75
75
75
75
60
75
75
75
75
75
75
75
75
75
69%
71%
72%
82%
81%
51%
30%
61%
22%
9%
45%
28%
55%
48%
15%
9
10
11
12
13
14
15
DMF
a
Isolated yields.
2

Y. Hu, Y. Shao, S. Zhang et al.
Tetrahedron Letters 66 (2021) 152806
Table 2
Optimization of the oxidation of diphenylethane.
a
Entry
Solvent
Time (h)
Additive (mol %)
Yield (%)
b
b
b
c
c
c
1
2
3
4
5
6
7
8
MeCN
ClPh
DCE
72
72
72
72
96
96
96
96
96
96
96
96
72
72
none
none
none
none
20 (44)
10 (34)
15 (22)
,
,
,
b
c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
35 (<10)
,
b
c
CF3CO2H (30)
MeSO2OH (30)
p-TsOH (30)
FeBr2 (30)
FeCl3 (30)
FeCl2 (30)
NiCl2 (30)
NiBr2 (30)
NiBr2 (15)
NiBr2 (15)
20 (36) ,
22 (26) b, c
b,
c
19 (41)
25c
9
10c
10
11
12
13
14
14c
b,
c
c
c
39 (<10)
68 (<10)
49 (<10)
b,
b,
d
88 (<10) b,
a
b
c
Isolated yields;
The yields in the brackets are the yields of 4a;
3 equivalent of AIBN added;
d
4 equivalent of AIBN added.
existence of strong electron-withdrawing CF3 group would desta-
bilize the corresponding radical intermediate, therefore, product
2 h was obtained in reduced yield (2 h). As a comparison, conjugate
electron-withdrawing groups, such as NO2 and CN, could increase
the stability of the radical intermediate, giving the desired ben-
zophenones in higher yields (2i-2j). The substrates with meta-
groups could also be well tolerated in this reaction, providing the
desired products in acceptable yields (2 k-2n). Then, various sub-
stituted diphenylmethanes were evaluated (2o-2y), and again,
conjugate electron-withdrawing groups gave better results (2v-
2w). Benzylnaphthalene 1z was also tolerated in this CAH bond
oxidation, albeit the yield was slightly lower (2z).
With the success of sp3 CAH bond oxidation, we decided to try a
more difficult reaction. Since the peroxide intermediate would be
generated in the reaction, we questioned whether the peroxide
rearrangement could be utilized to promote the cleavage of sp3
CAC bond. With this idea in mind, the reaction of 1,1-dipheny-
lethane 3a was tested under the standard reaction conditions
(Table 2). To our disappointed, benzophenone 2a was isolated in
only 20%, which was disturbed by phenyl benzoate 4a in 44% yield
(entry 1). Then, several solvents were screened (entries 1–4). When
CHCl3 was employed as the solvent, the selectivity was improved,
and only trace amount of phenyl benzoate was detected (entry 4).
Next, a series of Brönsteic acid were added into the reaction solu-
tion, however, the results were not satisfactory (entries 5–7). To
accelerate the peroxide rearrangement, Lewis acids were tested
(entries 8–14) and NiBr2 exhibited good activity, providing the
desired product in 68% yield (entry 12). Further optimization of
the reaction condition showed that 4 equivalent of AIBN with
15 mol % NiBr2 in CHCl3 gave the best result and the desired sp3
CAC bond cleaved product was obtained in 88% yield (entry 14).
Next, the reactions of various representative 1,1-dipheny-
lethanes were conducted under the optimized conditions, and
the results were compiled in Scheme 3. From the results we can
see that no matter electron-donating or electron-withdrawing
groups could be well tolerated in this reaction, generating the
expected products in acceptable yields. It is worth noting that ben-
zylic methyl group still interfere with the reaction, giving the cor-
responding benzophenone 2f in poor yield.
Scheme 3. The aerobic oxidation of diphenylethanes.
AIBN, no reaction occurred (eq 1–2), which supported that AIBN
and dioxygen cannot solely initiate the oxidation of the CAH bond.
Equation 3 shows that the reaction was totally inhibited in the
existence of TEMPO, implying that a radical intermediate might
be involved in this CAH oxidation. Since the mechanism of the oxi-
dation of diphenylmethane is relatively simple, the reaction of 1,1-
diphenylethane was focused on. First, the reaction mixture was
analyzed by HRMS, and a peroxide intermediate (calcd for C18H19
-
NO2 + Na+, 304.1308; found, 304.1299) were detected (eq 4). This
intermediate suggested that the CAC bond is cleaved by the rear-
rangement of the corresponding peroxide. Fortunately, when the
model reaction was quenched before completion, this peroxide
intermediate 5 was isolated in 12% yield, which is suspected to
be generated through the coupling between radical intermediate
D and 2-cyanoprop-2-yl radical A (see Scheme 5). This result might
explain why the transfer of methyl group is preferred rather than
more nucleophilic phenyl group, for the 2-cyanopropan-2-yl group
is bulky and the shift of phenyl group is inhibited by steric
hindrance.
According to the results of control experiments and the litera-
ture precedents [8],
a plausible mechanism was proposed
To illuminate the reaction mechanism, several control experi-
ments were performed (Scheme 4). In the absence of dioxygen or
(Scheme 5). By pyrolysis, 2-cyanoprop-2-yl radical A is generated
and trapped by dioxygen, giving the 2-cyano-2-propyloxyl radical
3

Y. Hu, Y. Shao, S. Zhang et al.
Tetrahedron Letters 66 (2021) 152806
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This work was financially supported by National Natural
Science Foundation of China (NNSFC, No. 21562038) for supporting
our research. The authors also thank Jiangsu Provincial Natural
Science Foundation (BK20161328) for financial support.
Appendix A. Supplementary data
Experimental details, mechanistic study and spectroscopic data
to this article can be found online. Supplementary data to this arti-
cle can be found online at https://doi.org/10.1016/j.tetlet.2020.
152806.
Scheme 4. Control experiments.
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diphenylmethane, elimination of cyanohydrin directly provides
the product 2. If R group is methyl, NiBr2 coordinates with the per-
oxide 5 to accelerate the extrusion of cyanohydrin, and benzophe-
none 2 is yielded after the peroxide rearrangement. In the absence
of NiBr2, the rate of peroxide rearrangement is slow, and an alkoxy
radical E will be generated by homolysis of the peroxide interme-
diate 5. Then, the alkoxy radical undergoes radical rearrangement
to provide a more stable carbon-centered radical F, which is cap-
tured by dioxygen, resulting in the formation of intermediate G.
After the final b-fragmentation of intermediate G, phenyl benzoate
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Conclusion
In summary, a functionalization of sp3 CAH and CAC bonds was
developed by AIBN/O2 catalyst system, synthesizing a series of
benzophenones under mild reaction conditions. In particular, this
reaction provides a new way to cleave relatively strong CAC bond
through the rearrangement of the generated peroxide intermedi-
ate, which are potentially useful for the study of CAC bond activa-
tion. Application of this catalyst system to other reactions together
with the mechanistic studies are still underway in our laboratory.
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