Chelation-directed remote: Meta -C-H functionalization of aromatic aldehydes and ketones

Article abstract of DOI:10.1039/c9cc05807a

We disclose herein the development of a versatile 1,2-diol directing template for palladium-catalyzed remote meta-C-H functionalization of aromatic aldehydes and ketones. In situ-generation of acetals and ketals, as well as removal afterwards, makes the C-H bond functionalization process more straightforward and efficient. This also represents the first example of chelation-directed meta-C-H functionalization of aromatic aldehydes and ketones.

Full text of DOI:10.1039/c9cc05807a

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Chelation-directed remote meta-C–H
functionalization of aromatic aldehydes
and ketones†
Cite this: Chem. Commun., 2019,
5, 12408
5
Received 27th July 2019,
Accepted 24th September 2019
Shuguang Xie, Sen Li, Wenqian Ma, Xiaohua Xu* and Zhong Jin
*
DOI: 10.1039/c9cc05807a
rsc.li/chemcomm
We disclose herein the development of a versatile 1,2-diol directing
In light of the extreme significance of aldehyde and ketone groups
template for palladium-catalyzed remote meta-C–H functionaliza- in organic synthesis, an approach to the synthesis of structurally
tion of aromatic aldehydes and ketones. In situ-generation of acetals diverse aromatic aldehyde and ketone derivatives is highly valuable.
and ketals, as well as removal afterwards, makes the C–H bond Considering the electron-withdrawing properties of the carbonyl
functionalization process more straightforward and efficient. This group, we reasoned that the transformation of the carbonyl groups
also represents the first example of chelation-directed meta-C–H of aromatic aldehydes and ketones into the corresponding acetal and
functionalization of aromatic aldehydes and ketones.
ketal groups would improve the low reactivity of these electron-poor
arenes towards palladation, and also interrupt the competing carbonyl
Carbonyl compounds are not only widely distributed in biologi- group-directed ortho-C–H activation. Furthermore, the resulting
cally significant natural products, but are also very important acetals/ketals can serve as a protecting group, preventing transition-
synthetic intermediates in pharmaceuticals, agrochemicals and metal-catalyzed or -mediated oxidation degradation of the carbonyl
organic materials. Nowadays, transition-metal-catalyzed C–H func- group on aromatic aldehydes and ketones. Herein, we report the
tionalization has been emerging as a state-of-the-art strategy for development of a chelation-directed palladium-catalyzed meta-
1
the synthesis of aldehyde and ketone derivatives. By using either a selective C–H functionalization of aromatic aldehydes and ketones
2
3
4
carbonyl group directly or a preinstalled or transient directing enabled using an elaborated nitrile template (Scheme 1d). Addition-
group, ortho-selective C–H functionalization of aromatic aldehydes ally, we demonstrate a streamlined sequential one-pot manipulation
and ketones could be achieved elegantly. However, due to the of the attachment of a directing template, meta-C–H olefination, and
competitive chelation-assisted ortho-C–H activation, functionaliza- removal of the template, highlighting the synthetic application of
tion of remote meta- or para-C–H bonds on aromatic aldehyde and this chelation-directed remote meta-C–H functionalization strategy.
5
ketone derivatives still remains a tremendous challenge. With the
Through recognition of the distance, geometry and electro-
9
assistance of a 5,6,7,8-tetramethylphenanthroline ligand, iridium- nic nature of the directing template, chelation-assisted remote
catalyzed meta-selective C–H borylation of aromatic aldehydes was meta-C–H functionalization on the arenes could be realized via
recently achieved via in situ-generated imines by the Chattopad-
6
hyay group (Scheme 1a). The Ackermann group also depicted that
meta-C–H bonds on aromatic ketimines could be selectively alky-
lated by a s-chelation ortho-cycloruthenation activation pathway
7
(
Scheme 1b). Very recently, the Yu group developed a palladium-
catalyzed pyridine-directed meta-C–H arylation reaction on masked
aromatic aldehydes by using a norbornene derivative as a transient
8
mediator (Scheme 1c). Meanwhile, there have been no reports of
transition-metal-catalyzed chelation-directed meta- or para-C–H
functionalization of aromatic aldehydes and ketones to date.
State Key Laboratory and Institute of Elementoorganic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, P. R. China.
E-mail: xiaohuaxu@nankai.edu.cn, zjin@nankai.edu.cn
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Functionalization of meta-C–H bonds on aromatic aldehydes
c9cc05807a
and ketones. TMP = 3,4,5-trimethoxyphenyl.
1
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a
Table 1 Sequential one-pot meta-C–H olefination of aldehydes
Scheme 2 Directed meta-C–H functionalization via in situ-generated
acetal. Yield, regio-selectivity, and ratio of mono- versus di-products were
1
determined by H NMR of the crude product with CH
standard.
2 2
Br as an internal
the different s-binding linkages. In general, these target C–H
bond substrates were attached to the directing template using a
variety of functional groups, such as ester, amide, (silyl) ether,
1
0
sulfonate, and other groups. Relatively, because the labile
cyclic scaffold of acetals and ketals is not beneficial to the
directing chelation of the template, attachment of a directing
group to the substrates through the formation of an acetal or
a
Isolated yield. Unless indicated, C–H olefination gave a trace amount
of di-products for the duplicate meta-C–H bonds.
1
1
ketal group remains scarce.
Encouraged by our previous studies on remote meta-C–H func-
12
13
tionalization of arene-tethered alcohols and tertiary amines using providing meta-C–H olefination products in good to excellent
a salycilonitrile template, salycilonitrile-derived 1,2-ethanediol tem- yields. Halogen atoms (fluoro, chloro, and bromo) in different
plates T –T were thus engineered to investigate their meta-C–H substituted patterns are completely compatible with the present
1
4
directing potential towards aromatic carbonyl derivatives (Scheme 2). protocol (1c and 1i–k). Regrettably, olefination of benzaldehydes
Of note, these 1,2-diol directing templates can be easily prepared bearing a m-methoxy (1f) or p-methyl group (1g and 1n) gave the
from the substituted salycilonitriles and epichlorohydrin via a two- desired products with poor meta-selectivity. Disubstituted alde-
step sequence in almost quantitative overall yields. Condensation hydes are also compatible substrates for this C–H olefination
1 4
of the directing templates T –T with benzaldehyde in the presence (1m–q). The sterically hindered 2,6-disubstituted aldehydes
of catalytic p-toluenesulfonic acid proceeded smoothly to give the (1p and 1q) can also deliver the meta-functionalized products
corresponding acetals. Gratifyingly, palladium-catalyzed C–H olefina- in satisfactory yields. Template-directed C–H olefination of N-Ts
tion of the acetals thus obtained successfully delivered the desired 5-indole-carbaldehyde afforded a C3-olefinated product as the
C–H functionalized products with exclusive meta-selectivity. The major isomer (1r).
ortho-C–H olefinated products were identified as the major side-
Besides aromatic aldehydes, the compatibility of aromatic
products. It is noteworthy that the reactivity of the template highly ketones in this directed meta-C–H olefination methodology was
correlates with the electronic density on the phenyl group. Compared also investigated (Table 2). To our delight, acetophenones bear-
with the unsubstituted salycilonitrile template T
1
, the template T
4
ing various substituents (2b–i), such as alkyl, alkyoxyl, halo, and
incorporating 4,5-dimethoxyl groups in the phenyl group improved trifluoromethoxyl groups, are all suitable substrates for this C–H
the yields of meta-C–H functionalization greatly from 61% to 89%. olefination reaction. C–H functionalization with different 2,4-
In contrast, pyrimidine-derived template T only provided modest and 3,4-disubstituted acetophenones (2j–m) also proves viable,
5
regioselectivity (meta :ortho = 66 : 34). Most importantly, meta-C–H affording meta-olefinated products in good to excellent yields. In
functionalization of aromatic carbonyl compounds can occur in a addition to acetophenones, benzophenone (2o) is compatible
sequential one-pot manner, and separation of the intermediate with the protocol, albeit with declined meta-selectivity. Unfortu-
acetals is not necessary operationally. p-Toluenesulfonic acid used nately, the C–H olefination reaction of the fused-ring aromatic
as a dehydrative agent in the formation of the acetals can also serve ketones, such as 3,4-dihydro-1-naphthalenone and 2,3-dihydro-
as a catalyst for subsequent hydrolysis of meta-functionalized acetals 1-indenone, did not provide the desired C–H functionalized
to release the aldehyde products, which does not interfere with the products, which is probably attributed to the rigid, difficult
procedure of C–H functionalization.
rotating conformation of the fused-ring ketals.
Having identified the optimal directing template, we surveyed
Moreover, the scope of olefin partners was also surveyed (Table 3).
4
the scope of benzaldehydes subsequently. A variety of aromatic With the assistance of template T , meta-C–H functionalization
aldehydes were therefore subjected to this sequential one-pot of aldehyde and ketone derivatives with a wide range of olefins
meta-olefination reaction (Table 1). Both electron-donating and smoothly afforded the olefination products at the meta position.
-
withdrawing groups on aromatic aldehydes are well tolerated, Acrylates bearing a substituent at the a- or b-position (3c–f) are
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a
Table 2 Sequential one-pot meta-C–H olefination of ketones
Scheme 3 The control and deuteration experiments.
Scheme 4 Up-scale reaction and recovery of the template.
the C–H bond might be involved in the rate-determining step
(Scheme 3b).
The sequential one-pot methodology makes meta-C–H func-
Isolated yield. Unless indicated, C–H olefination gave a trace amount tionalization of aromatic aldehydes and ketones easily scalable
a
of di-products for the duplicate meta-C–H bonds.
(
Scheme 4). Therefore, directed C–H olefination of benzalde-
hyde was run on 4 mmol scale to provide the meta-olefinated
benzaldehyde 1d in a yield of 79%. The template could also be
recovered quantitatively after hydrolysis.
well tolerated in the protocol. Cyclic a,b-unsaturated esters
3g and 3h) were also demonstrated suitable for this sequential
(
In particular, the carbonyl group on meta-C–H function-
alized aldehydes and ketones could be successfully diversified
towards a wide range of functional groups (Scheme 5, also see
the ESI†), further demonstrating the synthetic application of
chelation-directed meta-C–H functionalization.
In conclusion, directed remote meta-C–H olefination of
aromatic aldehydes and ketones was realized. Conversion of
aldehydes and ketones into acetals and ketals not only improves
the reactivity of arenes, but also prevents competing directed
ortho-C–H functionalization. This sequential one-pot methodol-
ogy streamlines the installation of DG and removal afterwards,
making meta-C–H functionalization straightforward and efficient.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21172111
and 21672116).
one-pot olefination reaction.
Generally, two diastereomers (syn and anti) were formed in
all cases of acetals and ketals because of the use of racemic
epichlorohydrin (see the ESI†), and both of them were shown to
be able to afford meta-C–H olefination products, probably
resulting from the twistable five-membered cyclic conforma-
tion of acetals and ketals as well as the flexibility of the
directing group. The control experiment demonstrated that
the presence of the nitrile group in the template is necessary
for directed C–H functionalization (Scheme 3a). Removal of the
nitrile group from T caused C–H olefination to halt completely.
4
Additionally, without the formation of acetal in advance,
direct C–H functionalization also failed to give the desired
products. The kinetic isotope effect for meta-C–H olefination
H D
was determined to be k /k E 2.1, indicating that cleavage of
Table 3 Scope of the olefins
Scheme 5 Diversification of meta-C–H olefinated benzaldehyde.
1
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Conflicts of interest
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