Sequential C-H activation enabled expedient delivery of polyfunctional arenes

Article abstract of DOI:10.1039/d1cc03243g

Modular construction of polyfunctional arenes from abundant feedstocks stands as an unremitting pursue in synthetic chemistry, accelerating the discovery of drugs and materials. Herein, using the multiple C-H activation strategy with versatile imidate esters, the expedient delivery of molecular libraries of densely functionalized sulfur-containing arenes was achieved, which enabled the concise construction of biologically active molecules, such as Bipenamol.

Full text of DOI:10.1039/d1cc03243g

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Sequential C–H activation enabled expedient
delivery of polyfunctional arenes†
Cite this: DOI: 10.1039/d1cc03243g
Wensen Ouyang,
Yang Gao, Yanping Huo,
Xiaoqing Cai, Xiaojian Chen, Jie Wang, Jianhang Rao,
Qian Chen and Xianwei Li
Received 18th June 2021,
Accepted 7th July 2021
*
DOI: 10.1039/d1cc03243g
rsc.li/chemcomm
Modular construction of polyfunctional arenes from abundant
feedstocks stands as an unremitting pursue in synthetic chemistry,
accelerating the discovery of drugs and materials. Herein, using the
multiple C–H activation strategy with versatile imidate esters, the
expedient delivery of molecular libraries of densely functionalized
sulfur-containing arenes was achieved, which enabled the concise
construction of biologically active molecules, such as Bipenamol.
The exploration of the concise construction of synthetically
valuable polyfunctional arenes holds a great synthetic promise
and challenge.1 Towards this end, the catalytic cascade reaction,
using aryl halides or borons, such as the Catellani-type reaction,
has emerged as one reliable strategy for a quick access to
molecular complexiety.2 In this context, sequential multiple
C–H activation that features step-economy and provides a new
retro-synthetic insight would be highly desirable for the direct
introduction of multiple functionalities into molecules.
Scheme 1 Expedient delivery of polyfunctional arenes.
However, formidable challenges remain in the controllable
multiple C–H activation3 (Scheme 1): (1) elusive control of site-
selectivity, which often leads to the formation of difunctionaliza-
tion byproducts; (2) coordinative saturation derived from the pharmaceuticals, and the concise construction of biologically
intrinsic directing group and the first introduced functionality, active molecules, such as Bipenamol.
leading to the deactivation of the catalyst; (3) steric and electronic
This initiative study commenced with selective C–H activation
influence, caused by the first C–H functionalization intermediate. using a synthetic versatile imidate ester 1a5 and switchable C–H
To enhance the overall synthetic practicality, the use of weak sulfenylation6 was observed under Rh(III) catalysis7 using Ag(I) or
coordination would be also beneficial for the second C–H Cu(II) as the key additive, affording nitrile- or imidate ester-
activation process, thus providing an arsenal for the modular substituted thioethers 3a or 4a (see Table S1 in ESI† for details).
construction of molecular libraries of multiple functionalized Notably, the obtained 1,2-thiobenzonitriles8 are key skeletons in
arenes.4 With the above principle in mind, herein, using versa- pharmaceuticals, pesticides and advanced materials, while nitrile-
tile imidate esters as the key directing groups and by the well- directed C–H sulfenylation remains underdeveloped.9 To our
tuning of the catalytic systems, we developed a multiple C–H delight, Rh(III) exhibited an optimal result, and the use of Cu(II)
activation strategy-enabled modular access to poly-substituted salt or Ag(I) switched the selectivity for the generation of the
arenes, enabling the multiple C–H activation of materials and imidate ester- or nitrile-substituted thioether product 3a or 4a
(entries 1 and 2). The metal catalyst candidate investigation
revealed that Ru(II) exhibited slightly lower yield (entry 3);
however, Ir(III), Pd(II) and Ni(II) salts showed no efficiency in
School of Chemical Engineering and Light Industry, Guangdong University of
this transformation (entries 4–6). Control experiments indicated
Technology, Guangzhou, 510006, China. E-mail: xwli@gdut.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1cc03243g that the Rh(III) catalyst was indispensable (entry 7), and AgNTf2
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exhibited better performance than that of AgSbF6 (entries 8 and 9).
HOAc or PivOH performed sluggishly when they were used to
replace sodium acetate (entry 10), while the Cu(II) salt was also
essential for the generation of thioether 3a (entry 12). Notably,
thiol could also act as the sulfenylation reagent, albeit in a
moderate yield (entry 13). 1,2-Dichloroethane was the optimal
solvent, while the use of acetone or tBuOH led to a trace amount
of the desired product (entry 14).
Under the optimal conditions, we explored the synthetic
generality of this tunable C–H sulfenylation (Scheme 6). Great
functional group tolerance was observed; halides including
fluoro (3b), chloro (3c), bromo (3d), trifluoromethyl (3f) and
even iodo (3e), were compatible, holding a great synthetic
potential for the further decoration of thioether products via
cross-couplings. Readily transformable groups, nitro (3g), benzyl
chloride (3i) and methoxyl (3h), were also compatible. Hetero-
cycles and fused rings were compatible in this regioselective C–H
sulfenylation (3j, 3k); notably, the site-selective C6–H sulfenyla-
tion of indole (3l) was obtained. For disulfides reagents, aromatic
and aliphatic disulfides were amenable, in which ester (3m),
methoxyl (3o), fluoro (3p), chloro (3r), bromo (3q) were well
tolerated. Notably, no obvious steric effect was observed, and
2,6-disubstituted disulfides were viable sulfenylation partners (3r,
3s, 3t). Thiophene-(3u), naphthalene-(3v), benzyl-(3w) and pentyl
(3x)-substituted disulfides could afford the desired products in
good yields. The site-selective modification of the L-menthol
derivative was also achieved (3y).
Scheme 2 Site-selective C–H sulfenylation. aConditions: 1a (0.3 mmol),
2a (0.3 mmol), [Cp*RhCl2]2 (2 mol%), AgNTf2 (8 mol%), Cu(OAc)2ꢀH2O
(2.0 equiv.), DCE (1 mL), 100 1C, 12 h. bCu(OAc)2ꢀH2O (1.0 equiv.) and BQ
(0.5 equiv.) were used instead of Cu(OAc)2ꢀH2O (2.0 equiv.). cWith AgOAc
(1.2 equiv.) instead of Cu(OAc)2ꢀH2O.
Intriguingly, the use of Ag(I) salt under Rh(III) catalysis
switched the selectivity, affording thioether products 4. Functional
groups including fluoro (4f), chloro (4d), bromo (4c), ester (4e) and
primary amine (4g) were well compatible. Heterocycle- and
naphthalene-derived imidate esters (4h, 4i) could afford the
desired products with good efficiency. The site-selective modifica-
tion of a pioglitazone analogue (4j) was also achieved (Scheme 2).
The site-specific C–H activation of multiple-functionalized
arenes provide a valuable insight into novel drug discovery,
thus accelerating the new drug discovery.10 Competing coordi-
nation studies (Scheme 3) reveal that the imidate ester showed
directing priority towards ester (3z), ketone (4j) and phenol ester
(3za), while pyrazole overrode imidate ester (4k) in this site-
selective C–H sulfenylation. The regio-selective modification of a
probenecid analogue took place exclusively (3zb) with the C–H
bonds proximal to sulfonamide and ester remained intact. This
procedure also enabled the modification of a biaryl nitrile-type
liquid crystal molecule (3zc), while ibuprofen (3zd) and estrone
(3ze) could be decorated with nitrile and thioether functionalities.
The transformable products could serve as a versatile plat-
form for the construction of functionalized sulfur molecular
libraries (Scheme 3). For instance, the benzo[b]thiophene ske-
leton could be introduced via the cross-coupling of halides to
Scheme 3 Synthetic application. Conditions: (a) 3d (0.1 mmol), Pd(PPh3)4
(5 mol%), 1,4-dioxane (0.1 M), NaHCO3 (aq.), benzo[b]thiophen-2-
ylboronic acid (1.1 equiv.), r.t. to reflux, 1 h; (b) 3a (0.1 mmol), mCPBA
(1.5 equiv.), EtOAc (0.2 M), 0 1C, 12 h; (c) 3w (0.1 mmol), NaOH (1.5 M,
30 equiv.), ethylene glycol (0.04 M), 130 1C, overnight; HCl (2 M, 40 equiv.);
(d) 3a (0.1 mmol), LiAlH4 (4 equiv.), Et2O (0.2 M), 0 1C, 1 h; 4 M NaOH (aq.);
(e) 3t (0.3 mmol), PdCl2(PPh3)2 (2 mol%), KOPiv (2.0 equiv.), DMA, 140 1C, 12 h.
afford 5, a potential liquid crystal molecule. The oxidation of Significantly, bipenamol 10 could be concisely obtained from
the thioether product led to sulfone 6, and the hydrolysis of commercially available thiosalicylic acid via the ortho C–H
nitrile afforded carboxylic acid 7, while benzyl amine 8 was sulfenylation of the imidate ester, followed by a reduction with
obtained through the reduction of nitrile. Functionalized LiAlH4, with a total 72% yield in two steps.
dibenzo[b,d]thiophene 9 could be accessed via a sequential
The switchable C–H sulfenylation stimulated us to investi-
C–H thiolation, followed by intramolecular C–H arylation. gate multiple C–H activation, leading to polyfunctional arenes,
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thioethers, expediting the divergent construction of polyfunctional
arenes (Schemes 4-4).
This sequential C–H activation could also be switched with
Ag(I) or Cu(II) salt as the key additive, affording polyfunctional
arenes 12 or 14 (Scheme 5). Further assessment of substrates
indicated that an array of aryl imidate esters with methyl (12e,
14f), methoxyl (12f), fluoro (12c) and chloro (14c) substituents
could be compatible. Disulfides (12a, 12b) including poly-
substituted (14b), and even steric hindered aryl disulfides
(14a) were viable coupling partners. Olefins (12d) including
halide-substituted styrenes (14d, 14e) were suitable substrates.
Significantly, sequential C3–H olefination and C1–H sulfenylation
of naphthalene were achieved with great site-selectivity, affording
1,2,3-functionalized naphthalene 14g, which is a synthetically
valuable skeleton while difficult to access. The ibuprofen analogue
could also undergo this sequential C–H activation (12g).
The dual cross-dehydrogenative coupling (CDC) strategy
provided an expedient arena for the rapid construction of
molecular complexity.13 We thus conducted further attempts
for the sequential introduction of olefin and heterocycles via
multiple C–H activation. To our delight, with the assistance of
PivOH under Rh(III) catalysis, two C–C bonds were constructed
through sequential aryl C–H/alkenyl C–H bond and aryl
C–H/heteroaryl C–H bond activation, affording multifunctional
arenes 15, in which thiophene and benzothiophene could act
as suitable partners (Scheme 5-5). Notably, biaryl nitriles are
widely used liquid crystal materials, considering the readily
modifiable obtained products, this procedure might find
their further utilization in pharmaceuticals, agrochemicals
Scheme 4 Primary investigation for sequential C–H activation.
which were promising while challenging skeletons. Extensive and materials science.
investigation revealed that with the assistance of MPAA (mono-
N-protected amino acid) under this Rh(III) catalysis using the
imidate, multiple C–H activation was achieved (Scheme 4-1),11
while ketone, ester, N-nitroso anilines or amides performed
sluggishly. For N–Ts amide 1a-6, only oxidative olefination
product 1a-60 was obtained, which exhibited no efficiency
for further C–H sulfenylation (see ESI† for details). Notably,
dehydrogenative olefination enabled by imidates was obtained
under the Rh(III)/MPAA catalysis, affording 13a, followed by a
C–H sulfenylation under Rh(III) catalysis (Scheme 4-2). Control
experiments indicated that the successive addition of imidate
esters 1, disulfides 2, and olefin 3 into this multiple C–H
activation under Rh(III) catalysis led to no desired products
(Scheme 4-3). Moreover, the isolated 4 showed no reactivity
in the subsequent dehydrogenative olefination under Rh(III)
catalysis. It was speculated that this sequential C–H activation
might proceed via an imidate ester-enabled C–H activation to
afford rhodacycle A, which assisted the generation of C–H
sulfenylated product 3b by the addition of electrophilic dis-
ulfide 2. Further interaction of thioether and intrinsic imidate
ester group led to the coordinative saturation of Rh(III),12 and
thus, led to no catalytic reactivity of Rh(III) species B. Finally,
1,2-thiobenzonitriles product 3n was obtained, with the treat-
ment of base to the intermediate 3b or B.
Scheme 5 Sequential multiple C–H activation. Conditions: 1 (0.3 mmol),
The obtained multiple-functionalized arenes could be further
converted to the corresponding ketone- or amide-substituted
11 (0.45 mmol), CPs (0.45 mmol), [Cp*RhCl2]2 (3 mol%), AgNTf2 (10 mol%),
Cu(OAc)2ꢀH2O (2.0 equiv.), DCE (1 mL), 100 1C, 18 h.
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Notes and references
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Scheme 6 Proposed mechanism.
Inspired by the related precedent literature and the experi-
mental observations, a tentative mechanism was proposed
(Scheme 6). First, with the assistance of MPAA,6,14 the C–H
activation of 1a takes place to give rhodacycle species A. A
subsequent oxidative Heck reaction leads to intermediate C or
C0 via second C–H activation, which facilitates further reaction
with sulfide species D generated from disulfide 2, affording key
intermediate E. Finally, the desired multiple C–H activation
products 12 or 14 are obtained via C–S bond formation, and the
re-oxidation of the released Rh(I) species by Ag(I) or Cu(II)
oxidant. With key intermediate C, the dual cross-dehydrogenative
coupling of the imidate ester with arene and terminal olefins can
also proceed with the assistance of PivOH and the oxidant, affording
multiple-functionalized products 15.
Notably, when disulfides 2 were subjected into the reaction
prior to terminal olefins 11, C–H sulfenylation occurred affording
4. However, the coordinative saturation of the imidate and
thioether group to Rh(III) led to the deactivation of the Rh(III)
catalyst, and thus, no second C–H activation proceeded.
In summary, by the judicious choice of versatile imidate
esters as the key directing groups and through well tuning of
the catalytic systems, sequential C–H activation was developed,
leading to polyfunctional arenes. This transformation enabled
the multiple C–H modification of pharmaceuticals and advanced
material analogues, and the concise construction of biologically
active molecules. Further endeavor towards the expedient
delivery of functionalized pharmaceuticals and materials via
sequential C–H activation is underway.
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We are grateful for the financial support by the National
Natural Science Foundation of China (No. 22071034, 21602032)
and the Science and Technology Planning of Guangdong Pro-
vince (No. 2019A050510042).
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Conflicts of interest
There are no conflicts to declare.
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