A dual role for acetohydrazide in Pd-catalyzed controlled C(sp3)-H acetoxylation of aldehydes

Article abstract of DOI:10.1039/d0ra01927e

The palladium catalyzed aldehyde directed acetoxylation of C(sp³)-H bonds was realized by a transient directing group approach for the first time. Crucial to the successful outcome of this reaction is the dual role of acetohydrazide as a directing group for the catalytic C(sp³)-H activation process and as a protecting group for the CHO functional group. The applicable methodology exhibits good functional group tolerance and occurs readily under mild conditions.

Full text of DOI:10.1039/d0ra01927e

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A dual role for acetohydrazide in Pd-catalyzed
controlled C(sp3)–H acetoxylation of aldehydes†
Cite this: RSC Adv., 2020, 10, 12192
*
Juan Chen, Chaolumen Bai, XingWen Tong, Dan Liu and Yong-Sheng Bao
The palladium catalyzed aldehyde directed acetoxylation of C(sp3)–H bonds was realized by a transient
directing group approach for the first time. Crucial to the successful outcome of this reaction is the dual
role of acetohydrazide as a directing group for the catalytic C(sp3)–H activation process and as
a protecting group for the CHO functional group. The applicable methodology exhibits good functional
group tolerance and occurs readily under mild conditions.
Received 29th February 2020
Accepted 12th March 2020
DOI: 10.1039/d0ra01927e
rsc.li/rsc-advances
oxidants and the CHO functional group is not oxidized in the
reaction process. In these processes, the TDG plays a dual role,
Introduction
one role is to act as a directing group of the catalytic cycle,
another is to act as a protecting group of the CHO functional
group. Inspired by this concept, we questioned whether
aldehyde-directed C(sp3)–H oxidation could be achieved using
the TDG approach.
Due to the ubiquitous nature of C–H bonds in organic mole-
cules, selective functionalization of C(sp3)–H bonds emerged as
a powerful tool in step-economical organic synthesis, featuring
applications in pharmaceutical agent construction, bioactive
molecules, and materials.1 Recently, the direct formation of
a C–O bond via C(sp3)–H activation, particularly acetoxylation,
has attracted much attention in organic synthesis2 because
organic molecules bearing acetoxy group(s) are important
structural features in drugs3 and agricultural chemicals.4
Various directing groups, such as oxazoline,2a,5 o-methyl oxime,6
pyridine,6,7 Boc-protected amines,8 Bts-protected amines,9
primary amines,10 quinazolinones11 and bidentate auxiliary
groups,12 have been successfully employed for stoichiometric
chelate-directed acetoxylation of C(sp3)–H bonds (see Scheme
1). Despite this signicant progress, the development of
oxidizable groups, such as aldehydes, for the directed acetox-
ylation of C(sp3)–H bonds is arguably highly desirable. There
are a number of remaining challenges in the selective C(sp3)–H
acetoxylation of aldehydes: (1) the tendency of CHO functional
groups to undergo undesired oxidation; (2) competitive metal
insertions into formyl C–H bonds; and (3) the weak coordi-
nating ability of this group. To date only one example of
aldehyde-directed ortho-hydroxylations of benzaldehydes via
C(sp2)–H activation has been reported.13
Herein, we describe a novel palladium catalyzed TDG
approach for the direct and selective C(sp3)–H acetoxylation of
aldehydes. This developed methodology provides a catalysis
route for C–O bond formation in a straightforward fashion,
which successfully suppresses the undesired oxidation of the
–CHO group and the acetoxylation products could be trans-
formed into various biologically active compounds such as
indeno[1,2-b]quinolines,21
ve-membered
azacyclic
compounds,22 mycophenolic acid which is an important
Very recently, the transient directing group (TDG) approach
has been extended to the palladium-catalyzed ortho-C(sp3)–H
bond arylations of aldehydes by the groups of Yu,14 Hu15,
Chen,16 Bull,17 Ge,18 Wang19 and Wei.20 Notably, all these
processes called for stoichiometric quantities of silver salts as
College of Chemistry and Environmental Science, Inner Mongolia Key Laboratory of
Green Catalysis, Inner Mongolia Normal University, Hohhot, 010022, China. E-mail:
sbbys197812@163.com; Tel: +86-471-4392442
† Electronic supplementary information (ESI) available: Characterization data for
the products, 1H NMR and 13C NMR spectra of the products. See DOI:
10.1039/d0ra01927e
Scheme 1 The development of C(sp3)–H acetoxylation.
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antiparasitic, antineoplastic and antiviral agent,23 an interme-
diate of coleophomone which has antifungal activity and shows
inhibition of human heart chymase,24 varitriol which is associ-
ated with high levels of biological activity toward renal, CNS,
and breast cancer cell lines25 and an s-trans-heterodiene
framework26 (see Scheme 2). Therefore, the methodology of
aldehyde-directed selective acetoxylation of C(sp3)–H bonds can
greatly reduce the steps of the total synthesis of these biologi-
cally active compounds.
Results and discussion
The study commenced with 2-methylbenzaldehyde (1a) as
a model substrate. We initially employed the PhI(OAc)2/
Pd(OAc)2 catalyzed system which has been shown to be
a favourable system for C–H bond acetoxylation27 using glycine
T1 as the TDG (see ESI, Table S1†). Unfortunately, we found that
PhI(OAc)2 as an oxidant and acetate source was totally unreac-
tive (see Table 1, entry 1). Other oxidants and acetate sources
were screened and nally AcOH was chosen to be the external
acetate source and solvent (see ESI, Table S1†). Gratifyingly,
when K2S2O8 was used as the inorganic peroxide-based
oxidant,28 the desired C(sp3)–H acetoxylation product, o-for-
mylbenzyl acetate (2a) was isolated in 35% yield aer reuxing
1a in AcOH (entry 2). Using AcOH as the acetate source, organic
peroxides and H2O2 all can facilitate the acetoxylation reaction
albeit with low yields of 2a (entries 3–5). The results indicated
that the novel C(sp3)–H acetoxylation of aldehydes probably
involved a radical process. Then various TDGs, including amino
acids, hydrazides, aminopyridine and aminoquinoline, were
tested and acetohydrazide T3 gave the best performance (entries
6–12). A control experiment indicated that the transient
Experimental
General procedure for Pd(OAc)2 catalyzed C(sp3)–H
acetoxylation reaction
A mixture of o-methylbenzaldehyde 1a (0.20 mmol), Pd(OAc)2
(4.5 mg, 10 mol%), acetohydrazide (40 mol%), MCM-48 (24 mg,
0.40 mmol), H2O (9 mL, 0.50 mmol) and K2S2O8 (108.2 mg, 0.40
mmol) in AcOH (2.0 mL) was added to a 25 mL oven dried
reaction tube. The reaction mixture was heated and reuxed for
ꢀ
48 h at 110 C. Aer cooling to room temperature, the mixture
was ltered, and the ltrate was evaporated in vacuo. The
residue was puried by ash column chromatography (silica
gel, ethyl acetate/petroleum ether ¼ 1 : 5 to 1 : 10 as an eluent)
to afford the desired product 2a. All the products were also
Table 1 Optimization of the reaction conditionsa
1
conrmed by comparing the H NMR and 13C NMR data with
authentic samples.
Gram-scale synthesis
In a gram-scale reaction, o-methylbenzaldehyde 1a (1 g, 8.33
mmol), Pd(OAc)2 (186.67 mg, 10 mol%), acetohydrazide
(246.67 mg, 40 mol%), MCM-48 (1 g, 16.67 mmol), H2O (375.0
mL, 0.50 mmol) and K2S2O8 (4.50 g, 16.67 mmol) in AcOH (60.0
mL) were added to a 100 mL oven dried round ask. The reac-
ꢀ
tion was carried out at 110 C for 48 h in an oil bath under air
conditions. Aer being cooled to room temperature, the reac-
tion solution was evaporated in vacuo. The residue was puried
by ash column chromatography (silica gel, ethyl acetate/
petroleum ether ¼ 1 : 10 as an eluent) to afford the desired
product 2a (904.8 mg, 61% yield).
Entry
TDG
Oxidant
Yieldb %
1
2
3
4
5
6
7
8
T1
T1
T1
T1
T1
T2
T3
T4
T5
T6
T7
T8
PhI(OAc)2
K2S2O8
H2O2
Cumene hydroperoxide
CH3CO3H
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
NP
35
11
21
15
22
46
NP
9
23
NP
NP
NP
61
73
9
10
11
12
13
14c
15d
K2S2O8
K2S2O8
K2S2O8
K2S2O8
T3
T3
K2S2O8
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol%), TDG
b
c
(40 mol%), and AcOH (2.0 mL), 110 ꢀC, 48 h. Isolated yields. MCM-
48 (0.4 mmol, 24 mg) was added. MCM-48 (0.4 mmol, 24 mg) and
d
H2O (9 mL, 0.5 mmol) were added.
Scheme 2 Application of the acetoxylation product.
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directing group had a vital role in this reaction (entry 13). With experiments were conducted. To our delight, the gram-scale
the aim of overcoming the lipophobicity of the inorganic synthesis of the acetoxylation product 2a was carried out
oxidant, a molecular sieve (MCM-48) was added to the reaction without signicant lost in efficiency under the same reaction
solution and the yield of 2a increased to 61% (entry 14). Adding conditions (see Scheme 3A). As shown in Scheme 3B, propionic
small amounts of water also effectively promotes the reaction acid and butyric acid were all moderate reaction partners with
because the addition of water reduces the concentration of the a minor modication of the standard reaction conditions giving
imine intermediate and prevents decomposition during the the corresponding product propionate 2s and butyrate 2t,
reaction14 (entry 15).
respectively, and no acetoxylation product was observed, which
With the optimal reaction conditions in hand, we explored conrmed that the acetate group of Pd(OAc)2 is not involved in
the scope with respect to the o-methylbenzaldehyde derivatives the reaction process. A radical trapping experiment was carried
(see Table 2). The reaction can tolerate various functional out to judge the possibility of a radical process (Scheme 3C).
groups, including alkyl, alkoxy, halogen (F, Br and Cl), tri- When the model reaction was carried out in the presence of
uoromethyl, and nitro groups. Both electron-withdrawing (2b– TEMPO [(2,2,6,6-tetramethyl-piperidin-1-yl)oxy, 0.4 mmol],
2h) and electron-donating substituents (2i–2r) were tolerated in a radical scavenger, only a trace (<5% yield) of the acetoxylation
the C(sp3)–H acetoxylation reaction, and their reactivities did product was observed, but the captured benzyl radical was not
not exhibit a signicant difference. Substrates with a 3- detected. This result further conrmed that the reaction probably
substituted group (2c, 2h, 2k, 2n) were well-tolerated, thus involves a radical process but it may be irrelevant to the C–H
indicating a high steric tolerance of this system. When there is activation step. When Ac2O was employed as the solvent and
a methyl group at both the ortho-positions of the formyl group, acetate source instead of AcOH, the reaction could not proceed
mono-acetoxylation (2d, 2e) and bis-acetoxylation products (2d0, (Scheme 3D). In view of the fact that Ac2O is a more effective
2e0) were isolated.
acetate source than AcOH under the palladium catalyst,6b,8,12b,12d
To further establish the general utility of this transformation we have reason to believe that AcOH may participate in the
and shed some light on the reaction mechanism, some control radical process while it is harder for Ac2O to generate radicals.
According to the present experimental results and the
commonly accepted mechanism from the literature, a plausible
reaction mechanism is proposed (see Scheme 4). First, o-
methylbenzaldehyde reacts with acetohydrazide to form aceto-
hydrazone I, which serves as a directing group in the next step.
Table 2 Substrate scope of C(sp3)–H acetoxylation of o-methyl-
benzaldehyde derivativesa
Second, bidentate coordination of the acetohydrazone moiety in
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (0.02 mmol),
Scheme 3 (A) Gram scale synthesis of 2a, (B) screening the aliphatic
acid scope, (C) the radical trapping experiment, and (D) screening the
acetohydrazone (0.08 mmol), MCM-48 (0.4 mmol), H2O (0.5 mmol),
AcOH (2.0 mL), 110 ꢀC, 48 h.
acetate source.
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Acknowledgements
This research was nancially supported by the National Science
Foundation of China (21861030), the Program for Young
Talents of Science and Technology in Universities of Inner
Mongolia Autonomous Region (NJYT-17-A22) and Research
Innovation Fund of Inner Mongolia Normal University Grad-
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