Design of Bowl-Shaped N-Hydroxyimide Derivatives as New Organoradical Catalysts for Site-Selective C(sp3)?H Bond Functionalization Reactions

Article abstract of DOI:10.1002/anie.202003982

A series of new bowl-shaped N-hydroxyimide derivatives has been designed and used as selective organoradical catalysts. A number of these bowl-shaped N-hydroxyimide derivatives exhibit excellent site-selectivity in the amination of benzylic C(sp³)?H bonds in aromatic hydrocarbon substrates.

Full text of DOI:10.1002/anie.202003982

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Accepted Article
Title: Design of Bowl-ShapedN-Hydroxyimide Derivatives as New
Organoradical Catalysts for Site-Selective C(sp3)-H Bond
Functionalization Reactions
Authors: Terumasa Kato and Keiji Maruoka
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Design of Bowl-Shaped N-Hydroxyimide Derivatives as New Organoradical
Catalysts for Site-Selective C(sp3)-H Bond Functionalization Reactions
Terumasa Kato*[a] and Keiji Maruoka*[a],[b],[c]
Abstract: A series of new bowl-shaped N-hydroxyimide derivatives
has been designed and used as selective organoradical catalysts. A
number of these bowl-shaped N-hydroxyimide derivatives exhibit
excellent site-selectivity in the amination of benzylic C(sp3)-H bonds
in aromatic hydrocarbon substrates.
The functionalization of unactivated C(sp3)-H bonds is one of the
most important chemical transformations in organic chemistry,
as it offers great potential to simplify synthetic sequences and to
add functionality to a wide variety of organic molecules.[1]
Unfortunately, such transformations still remain challenging as
the high energy of the C(sp3)-H bond renders it inert toward
many reagents and catalysts. Previous attempts to transform
such bonds via metal-mediated or -free reactions have often
resulted in poor yield and/or low selectivity, thus reducing the
practical applicability of those methods.[2] N-Hydroxyphthalimide
(NHPI),
a
metal-free N-hydroxyimide derivative,[3] and its
derivatives such as N,N'-dihydroxypyromellitimide (NDHPI),[4] N-
hydroxysaccharin (NHS),[5] and N,N′,N″-trihydroxyisocyanuric
acid (THICA)[6] are well-known organoradical catalysts that can
transform various unactivated C(sp3)-H bonds into the
corresponding C(sp3)-X,[7] C(sp3)-C,[8] C(sp3)-O,[9] and C(sp3)-
N[10] bonds (Scheme 1a). Moreover, several chiral NHPI
derivatives have been reported in enantioselective radical
oxidations (Scheme 1b).[11] However, there are still only few
examples of N-oxy-type organoradical catalysts/reagents for the
site-selective functionalization of unactivated C(sp3)-H bonds
either in the absence or presence of directing groups.[12] Our
contribution to this area is based on endowing N-oxyimide
radical species with a bowl-shaped architecture in order to
discriminate between sterically more and less hindered C(sp3)-H
bonds. Herein, we report our initial results on site-selective
amination reactions of unactivated C(sp3)-H bonds by newly
designing bowl-shaped N-hydroxyimido derivatives with
predictable site-selectivity (Scheme 1c).
Scheme 1. Examples of N-hydroxyimide-derived organoradical catalysts.
The space-filling models of N-hydroxy-3,4-diarylmaleimide
derivatives 1~3a are shown in Scheme 2.[13] The examination of
these models suggests that bowl-shaped organoradical catalyst
of the type 3 might be appropriate for the site-selective
functionalization of hydrocarbons. Accordingly, we prepared
various derivatives of N-hydroxy-3,4-diarylmaleimide 3. As
shown in Table 1, we evaluated these organoradical catalysts
for their efficiency toward the site-selective amination of 1-
cyclohexyl-4-ethylbenzene.
[a]
[b]
[c]
Dr. T. Kato, Prof. Dr. K. Maruoka
School of Chemical Engineering and Light Industry, Guangdong
University of Technology, Guangzhou 510006, China
Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan
Prof. Dr. K. Maruoka
Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo, Kyoto 606-8501, Japan
Fax: (+81) 75-753-9578
Scheme 2. Space-filling models of the N-hydroxymaleimide derivatives 1~3a.
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document
In a control experiment, we treated 1-cyclohexyl-4-ethylbenzene
(7a) with diethyl azodicarboxylate (DEAD) (0.10 mmol) in 1,2-
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dichloroethane (0.15 M) in the presence of NHPI (5 mol%) at 80
ºC for 120 h, which almost quantitatively afforded a mixture of 8a
and 9a in a ratio of 53:47 (entry 1).[14] Replacement of the NHPI
catalyst with N-hydroxy-3,4-diphenylmaleimide (1), N-hydroxy-
slightly lower site-selectivity (entry 8) than 3a. In contrast, the
sterically hindered NHPI derivative 6 showed virtually no site-
selectivity (entry 9). The choice of solvents is also highly
important for the success of the reaction. Polyhalogenated
solvents such as 1,1,2,2-tetrachloroethane and carbon
tetrachloride showed excellent site-selectivity (8:9, 100:0).
However, other solvents such as t-butyl acetate, acetonitrile,
DMSO, chlorobenzene, and heptane were less effective (64:36
to 85:15: cf. Supporting Information), which implies that a
conformational change could occur in the biphenyl moieties
when using these solvents. The results of examining other
factors such as the catalyst loading, the substrate ratios, the
amount of DEAD used, other DEAD derivatives, the
concentration of the reagents, the reaction time, and the reaction
temperature are shown in the Supporting Information.
In marked contrast, the reaction of 1-cyclohexyl-4-
iropropylbenzene substrate 7b, which contains sterically similar
cyclohexyl and isopropyl substituents, with DEAD (0.10 mmol) in
1,2-dichloroethane (0.15 M) in the presence of 3a (5 mol%) at
80 ºC for 120 h afforded a mixture of 8b and 9b in a ratio of
90:10 (entry 11). In order to achieve an even higher site-
selectivity, more sterically hindered N-hydroxyimide derivative
3c was prepared,[15] and applied as a catalyst for the reaction of
7b in 1,1,2,2-tetrachloroethane. Although the reaction
proceeded slowly, it afforded a mixture of 8b and 9b in a 95:5
ratio (entry 12). Finally, the l-menthyl-derived N-hydroxyimide
catalyst 3d exhibited perfect site-selectivity (entry 13).[15]
3,4-di(1-naphthyl)maleimide
(4),
or
N-hydroxy-3,4-di(2-
phenylphenyl)maleimide (2) under otherwise identical conditions
furnished mixtures of 8a and 9a in ratios of 53:47, 48:52, and
51:49, respectively (entries 2-4). In contrast, the use of N-
hydroxy-3,4-di(2-(4-tert-butyl)phenylphenyl)maleimide (5a) and
N-hydroxy-3,4-di(2-(4-phenyl)phenylphenyl)maleimide
(5b)
enhanced the site-selectivity for the sterically less hindered
C(sp3)-H bonds to 68:32 and 72:28, respectively (entries 5 and
6). The best catalytic performance was observed for N-hydroxy-
3,4-bis(2-(3,5-di-tert-butyl)phenylphenyl)maleimide (3a), which
resulted in near perfect site-selectivity (entry 7).[15] N-Hydroxy-
3,4-bis(2-(3,5-diphenyl)phenylphenyl)maleimide (3b) produced a
Table1. Optimization of the reaction conditions for the site-selective amination
of substrate 7.[a]
Table 2. Scope of the site-selective amination of various substrates.[a]
Combined
Ratio (8:9)[b]
Entry
Substrate
Catalyst
Yield [%][b]
1
2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
NHPI
1
>99
>99
>99
>99
>99
72
53 : 47
53 : 47
48 : 52
51 : 49
68 : 32
72 : 28
100 : 0
80 : 20
55 : 45
53 : 47
90 : 10
95 : 5
3
4
4
2
5
5a
5b
3a
3b
6
6
7
84 (53)[c]
8
73
9
>99
>99
76
10
11
12[d]
13[d]
NHPI
3a
3c
3d
22
13
100 : 0
[a] Reaction conditions (unless otherwise noted): diethyl azodicarboxylate
(DEAD, 0.10 mmol), catalyst (5 mol%) in 1,2-dichloroethane (0.15 M) at 80
ºC for 120 h. [b] The yield and ratio were determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as the internal standard. [c]
Use of DEAD (0.50 mmol). [d] In 1,1,2,2-tetrachloroethane (0.15 M).
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selectivity when using the bowl-shaped catalysts 3c and/or 3d.
Even more remote control of the site-selectivity was achieved
when using bowl-shaped catalysts 3c and/or 3d for the reaction
of the ethylbenzene derivatives 18, 20, and 22, with different β,β-
disubstituted alkyl groups at the para-position. The use of
excess substrate (6.0 equiv) for the reaction of 18 and 22
enhanced the yield of 19 and 23, respectively (entries 18 and 26
vs. entries 17 and 25; see also entry 13 vs. entry 12). Substrates
24 and 26, which contain β-(tert-alkyl)ethyl substituents at the
ethylbenzene para-position exhibited high selectivity when using
bowl-shaped catalyst 3d. Notably, even 1-ethyl-4-hexylbenzene
(28) showed some site-selectivity when using 3c. 1-Cyclohexyl-
3-ethylbenzene (30) and 1-cyclohexyl-4-methylbenzene (32)
exhibited excellent to high site-selectivity when using 3a or 3c.
This
phenyltetrahydronaphthalene (34) in the presence of 3d.
As shown in Scheme 3, the synthetic utility of this approach
was demonstrated by the successful site-selective
functionalization of estrone 3-methyl ether (36).
approach
also
works
well
for
1-
Scheme 3. Site-selective amination of estrone 3-methyl ether (36).
The present approach is also applicable to the simultaneous
intermolecular site-selective amination of two different
substrates 38 and 39 (Scheme 4).
[a] Reaction conditions (unless otherwise noted): diethyl azodicarboxylate
(DEAD, 0.10 mmol), catalyst (5 mol%) in 0.15 M of either 1,2-dichloroethane
(DCE: for 3a) or 1,1,2,2-tetrachloroethane (TCE: for 3c and 3d) at 80 ºC for
120 h. [b] 6.0 equiv of the substrate used.
Scheme 4. Intermolecular site-selective amination of 38 and 39.
The origin of the observed high to excellent site-selectivity can
be rationalized by examining the space-filling models of the
sterically hindered N-hydroxy-3,4-diarylmaleimide derivative 3c
during the site-selective hydrogen abstraction of the benzylic
C(sp3)-H bond of 1-cyclohexyl-4-ethylbenzene (7a) (Scheme 5).
With the optimized conditions in hand, we subsequently
examined the scope of the site-selective amination with respect
to a series of unsymmetrically substituted benzene substrates
(Table 2). The reaction of the ethyl- and 3-pentyl-substituted
benzene 10 in the presence of bowl-shaped catalyst 3a
furnished almost exclusively the desired isomer 11.
Ethylbenzene derivatives 12, 14, and 16 with different sec-alkyl
substituents at the para-position afforded high to excellent
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3435; b) C. Zheng, S.-L. You, RSC Adv. 2014, 4, 6173–6214; c) L. Ping,
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Scheme 5. Space-filling models in the site-selective abstraction of the benzylic
hydrogen atom at the ethyl side of 7a with the sterically hindered N-
hydroxymaleimide derivative 3c.
[8]
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In conclusion, we have designed and synthesized a series of
novel bowl-shaped N-hydroxyimide derivatives as organoradical
catalysts for the site-selective amination of benzylic C(sp3)-H
bonds. Further investigations into the applications of bowl-
shaped N-hydroxyimide catalysts of the type 3c and 3d for other
C-H activation and functionalization reactions, as well as the
design of more efficient bowl-shaped N-hydroxyimide catalysts,
are currently in progress in our laboratory.
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Acknowledgements
This work was supported by JSPS KAKENHI grants
JP26220803 and JP17H06450 (Hybrid Catalysis).
Conflicts of interest
The authors declare no conflict of interests.
[13] The geometry of the space-filling models was optimized by the density
functional theory (DFT) calculations at the B3LYP/6-31G++(d,p) level of
theory using the Gaussian 09 software package. M. J. Frisch, et al.,
Gaussianꢀ09, RevisionꢀA.02, Gaussian, Inc., Wallingford CT, 2009.
[14] Y. Amaoka, S. Kamijo, T. Hoshikawa, M. Inoue, J. Org. Chem. 2012, 77,
9959–9969.
Keywords: N-hydroxyimide • site-selectivity • amination • diethyl
azodicarboxylate • radical reactions
[1]
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[15] Catalyst 3 was prepared in 2-step sequence from 1-(benzyloxy)-3,4-
dibromo-1H-pyrrole-2,5-dione: Catalyst 3a: 63% overall yield; catalyst
3c: 29% overall yield; catalyst 3d: 39% overall yield (see also
Supporting Information). The synthetic pathways of arylboronic acids
and their overall yields from the known compounds are described in
Supporting Information.
[2]
.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Terumasa Kato* Keiji Maruoka*
Page No. – Page No.
Design of Bowl-Shaped N-
Hydroxyimide Derivatives as New
Organoradical Catalysts for Site-
Selective C(sp3)-H Bond
A series of new bowl-shaped N-hydroxyimide derivatives has been designed and used
as selective organoradical catalysts. A number of these bowl-shaped N-hydroxyimide
derivatives exhibit high to excellent site-selectivity in the amination of benzylic C(sp3)-H
bonds in aromatic hydrocarbon substrates.
Functionalization Reactions
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