Acetohydrazone: A Transient Directing Group for Arylation of Unactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.6b01170

A straightforward and efficient method has been developed for the synthesis of 2-benzylbenzaldehyde derivatives from 2-methylbenzaldehyde and iodobenzene via a C(sp³)-H activation process. In the course of the activation reaction, acetohydrazon

Full text of DOI:10.1021/acs.orglett.6b01170

Letter
pubs.acs.org/OrgLett
Acetohydrazone: A Transient Directing Group for Arylation of
Unactivated C(sp3)−H Bonds
Fei Ma,† Min Lei,*,‡ and Lihong Hu*,†,‡
†Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, P. R. of China
‡State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, Shanghai 201203, P. R. of China
S
* Supporting Information
ABSTRACT: A straightforward and efficient method has been developed for the synthesis of 2-benzylbenzaldehyde derivatives
from 2-methylbenzaldehyde and iodobenzene via a C(sp3)−H activation process. In the course of the activation reaction,
acetohydrazone is formed between 2-benzylbenzaldehyde and acetohydrazine as a transient directing group. As a new kind of
transient directing group, acetohydrazone exhibits a remarkable directing effect to give corresponding products in good to
excellent yields.
As shown in Figure 1, we tried to introduce acetohydrazone
to the substrate as a transient directing group.13 After
2-Benzylbenzaldehyde derivatives are an important intermedi-
ate which are used widely for the synthesis of fused ring
compounds,1 spiro compounds,2 natural products,3 and
biologically active compounds.4 Due to the importance of
these compounds, a lot of methods for the synthesis of them
have been reported: (i) oxidation of 2-benzylbenzyl alco-
hol;3b,4a,5 (ii) Suzuki cross-coupling reaction;1a,6 (iii) Vilsmeier
reaction;7 (iv) Kumada−Tamao−Corriu reaction;8 (v) C−F9
or C−H10 activation reaction. Although a number of modified
methods under improved conditions have been reported, many
of them suffer from drawbacks such as unsatisfactory yields,
poor substrate tolerance, difficult-to-obtain starting materials,
and the use of stoichiometric and/or relatively expensive
reagents. Therefore, searching for more facile and practical
synthetic routes to 2-benzylbenzaldehyde derivatives is still
highly desirable work.
During the past decades, C−H activation reactions have
become powerful tools in modern organic synthesis.11 In
general, a directing group is required to covalently bind to
substrates and then form a bidentate coordination with a
transition metal to control selectivity and facilitate reactivity in
C−H activation reaction.12 However, these processes have two
significant shortcomings: (i) a directing group must be
introduced to the substrate in advance which dramatically
increased the workload; (ii) the removal of the directing groups
from product always needs harsh reaction conditions. In this
paper, in order to solve the problems mentioned above, a
transient directing group is put forward which includes three
processes: (i) the formation of a transient directing group; (ii)
the C−H activation process; (iii) the removal of the directing
group.
Figure 1. Acetohydrazone as transient directing group.
completion of the C−H activation reaction, the transient
directing group was removed by hydrolysis. To verify our idea,
the reaction of 2-methylbenzaldehyde (1a) and 1-iodo-4-
methoxybenzene (2a) was carried out using Pd(OAc)2 as the
catalyst, AgOAc as the oxidant, and acetohydrazide as the
additive in AcOH. The mixture was stirred at 120 °C for 24 h,
and the desired product 2-(4-methoxybenzyl)benzaldehyde
(3a) was obtained in 64% yield. This result clearly indicated
that introducing acetohydrazone as the transient directing
group was a feasible route. To improve the yield and optimize
the reaction conditions, this model reaction was carried out
under different conditions, and the results are summarized in
Table 1.
Preliminary experiments suggested that the solvents had a
significant impact on the model reaction. Hence, various
solvents, such as toluene, 1,4-dioxane, DMF, DMSO, MeCN,
EtOH, and AcOH, were applied to promote this coupling
reaction. As shown in Table 1, the reaction could not proceed
smoothly to obtain the corresponding product 3a except for
Received: April 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
compounds with different leaving groups, such as Br-, Cl-,
TsO-, and TfO-, as substrates to replace 2a. In these cases, the
results showed that the reaction could not take place, and the
desired 3a was not formed (see Supporting Information).
In order to gauge the scope of the C(sp3)−H activation
arylation process, reaction of various aryl iodides and 2-
methylbenzaldehyde (1a) was carried out under the optimized
conditions (Scheme 1). As shown in Scheme 1, para, meta, and
Table 1. Optimization of the Reaction Conditions
Scheme 1. C(sp3)−H Arylation of Aryl Iodides (2) with 2-
b
entry
solvent
toluene
oxidant
AgOAc
yield (%)
a b
,
Methyl-benzaldehyde (1a)
1
0
0
2
1,4-dioxane
AgOAc
3
DMF
AgOAc
0
4
DMSO
AgOAc
0
5
MeCN
AgOAc
0
6
EtOH
AgOAc
0
7
AcOH
AgOAc
64
81
85
80
80
77
75
59
62
39
45
70
0
8
AcOH−H2O = 2:3
AcOH−H2O = 1:1
AcOH−H2O = 2:1
AcOH−H2O = 4:1
AcOH−H2O = 8:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AcOH−H2O = 1:1
AgOAc
9
AgOAc
10
11
12
13
14
15
16
17
18
19
20
21
AgOAc
AgOAc
AgOAc
Ag2O
Ag2CO3
AgTFA
CuSO4
Cu(OAc)2
Cu(TFA)2·nH2O
PhI(OAc)2
K2S2O8
1,4-BQ
15
0
a
Reaction conditions: 1a (1.2 mmol), 2a (1.0 mmol), Pd(OAc)2 (10
mol %), acetohydrazide (40 mol %), oxidant (2.0 mmol, 2 equiv),
b
solvent (10 mL), 120 °C, 24 h. Isolated yields.
AcOH as solvent (Table 1, entries 1−7). One possible reason
for these results was that acid could promote the reaction of 1a
and acetohydrazide to form acetohydrazone. Furthermore, we
found the hydrolysis of acetohydrazone was incomplete after
the C(sp3)−H activation reaction, which led to only a moderate
yield of 3a (64%). Inspired by this phenomenon, we thought
that adding an appropriate amount of water might promote the
hydrolysis of acetohydrazone to increase the yield of 3a.
Therefore, the model reaction was carried out under similar
conditions in AcOH−H2O as a mixed solvent. The results
presented in Table 1 showed that the yields of 3a were
increased greatly (77−85%) when using AcOH−H2O as
solvent (Table 1, entries 8−12), and AcOH−H2O (v/v, 1:1)
proved to be effective (Table 1, entry 9).
a
Standard conditions: 1a (1.2 mmol), 2 (1.0 mmol), Pd(OAc)2 (10
mol %), acetohydrazide (20 mol %), AgOAc (2.0 mmol, 2 equiv),
AcOH−H2O (10 mL, v/v, 1:1), 110 °C, 24 h. Isolated yields.
b
Then, a series of oxidants, such as Ag-salts, Cu-salts,
PhI(OAc)2, K2S2O8, and 1,4-BQ, were examined for this
model reaction. By a screening of oxidants, AgOAc was found
to be optimal to obtain 3a in 85% isolated yield (Table 1, entry
9). Therefore, AgOAc was chosen as the oxidant for all further
reactions.
In addition, the other factors, such as the Pd-catalyst and the
amount of acetohydrazide and temperature, were also
investigated and these contents are provided in the Supporting
Information. Then, optimal reaction conditions were obtained
by using Pd(OAc)2 (10 mol %), acetohydrazide (20 mol %),
AgOAc (2 equiv), and AcOH−H2O (v/v, 1:1) to afford desired
product 3a in 91% yield. Furthermore, we also carried out the
reaction under the optimal conditions using aromatic
ortho substituted substrates were chosen to examine the effect
of steric hindrance on this reaction. The results clearly indicated
that both para and meta substituted aryl iodides could react
smoothly to obtain the corresponding products 3a−j in good
yields (45−93%). In contrast, ortho substitued aryl iodides
failed to yield desired product 3l−o. These results suggested
that steric hindrance could significantly effect this reaction.
Moreover, a heterocyclic substrate (4-iodopyridine) was
applied for this C(sp3)−H activation arylation reaction, and
the desired product 3k was obtained in 42% yield.
We further investigated the reactions of 1-iodo-4-methox-
ybenzene (2a) with substituted 2-methylbenzaldehydes
(Scheme 2). All of the aryl 2-methylbenzaldehydes were
B
DOI: 10.1021/acs.orglett.6b01170
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
coupled with iodobenzene to afford the products 3a, 3p−s in
good yields (75−93%).
coordination of the acetohydrazone moiety in Int-1 to the
Pd(OAc)2 species occurs to form the chelated cyclometalated
Pd-complex Int-2, followed by formation of Int-3. Then,
oxidation−addition of Int-3 and aryl iodide takes place to form
Int-4, which undergoes reductive elimination to obtain Int-5.
Subsequently, Int-5 is decomposed to Int-6 along with the Pd0
species. Int-6 is hydrolyzed to the desired product 3 and
acetohydrazide. The catalytic cycle is completed by the
AgOAc/AcOH-promoted reoxidation of Pd0 into the starting
Pd(OAc)2 species.
Scheme 2. C(sp3)−H Arylation of 1-Iodo-4-methoxybenzene
ab
,
(2a) with Aldehyde (1)
In conclusion, we have demonstrated a straightforward and
efficient procedure for the synthesis of 2-benzylbenzaldehyde
derivatives from 2-methylbenzaldehyde and iodobenzene via a
C(sp3)−H activation process. In the course of the activation
reaction, acetohydrazone serves as a transient directing group
which has several main advantages: (i) the directing group need
not be introduced to substrate in advance; (ii) bidentate
coordination of the acetohydrazone moiety is an efficient
directing group; (iii) the directing group is easy to remove from
the intermediate to obtain the desired product.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01170.
Experimental procedures and spectral data for all
compound (PDF)
a
Standard conditions: 1 (1.2 mmol), 2a (1.0 mmol), Pd(OAc)2 (10
mol %), acetohydrazide (20 mol %), AgOAc (2.0 mmol, 2 equiv),
AcOH−H2O (10 mL, v/v, 1:1), 110 °C, 24 h. Isolated yields.
b
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mlei@simm.ac.cn.
*E-mail: lhhu@simm.ac.cn.
Notes
On the basis of the experimental results, a possible
mechanism for the C(sp3)−H activation arylation reaction is
presented in Scheme 3. Initially, aldehyde reacts with
acetohydrazide to form acetohydrazone (Int-1), which serves
as a directing group in the next step. Then, bidentate
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 3. Proposed Mechanism
This work was supported by the National Natural Science
Foundation of China (Grants 81273397 and 81561148011),
the Chinese National Science & Technology Major Project
“Key New Drug Creation and Manufacturing Program” (Grant
2013ZX09508104).
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