A Direct Approach to Decoration of Bioactive Compounds via C-H Amination Reaction

Article abstract of DOI:10.1021/acs.orglett.9b03717

The development of new methods to achieve the direct synthesis of bioactive organic molecules is always an important topic in organic synthesis. We hereby demonstrate that N-methoxyamide is an excellent amino source in the iridium-catalyzed intermolecular C-H amination reaction. The linkage of two bioactive organic molecules can be well achieved with this new protocol. More than 20 examples of decorated bioactive compounds were reported, which can facilitate the discovery of new bioactive molecules.

Full text of DOI:10.1021/acs.orglett.9b03717

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Direct Approach to Decoration of Bioactive Compounds via C−H
Amination Reaction
Guodong Ju,† Chunchen Yuan,† Dongjie Wang,† Jingyu Zhang,*,‡ and Yingsheng Zhao*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science
Soochow University, Suzhou 215123, P. R. China
‡College of Energy, Soochow Institute for Energy and Materials Innovations, Soochow University, Suzhou 215006, P. R. China
S
* Supporting Information
ABSTRACT: The development of new methods to achieve the direct synthesis of bioactive organic molecules is always an
important topic in organic synthesis. We hereby demonstrate that N-methoxyamide is an excellent amino source in the iridium-
catalyzed intermolecular C−H amination reaction. The linkage of two bioactive organic molecules can be well achieved with
this new protocol. More than 20 examples of decorated bioactive compounds were reported, which can facilitate the discovery
of new bioactive molecules.
ver the past few decades, transition-metal-catalyzed
Ocarbon−hydrogen (C−H) bond activation processes
have emerged as useful methods in the field of chemical
synthesis.1 For example, they can usually shorten the reaction
steps in the synthesis of natural products or useful synthetic
blocks and aid in the late-stage functionalization of organic
compounds with functional groups such as fluorine,2
trifluoromethyl,3 difluoromethyl,4 cyano,5 etc.6 Although
these different types of C−H activation reactions have been
extensively explored, the direct coupling of two bioactive
molecules via C−H activation to generate new bioactive
compounds has limited examples. While the carbon−nitrogen
(C−N) bond is one of the most fundamental links in various
drugs and bioactive molecules, the direct connection between
two bioactive molecules,7 or the installation of a key skeleton
of a bioactive compound onto another drug molecule via the
C−N bond, would surely facilitate new discoveries in
Figure 1. Novel application for C−N bond formation.
pharmaceutical chemistry.8 Representative routes to realize
C−N formation include the transition-metal-catalyzed Ull-
mann reaction and Buchwald−Hartwig coupling.9 However,
the requirement for aryl (pseudo) halides as the prefunction-
alized starting materials to react with amines (amides) limits
their application. In the past two decades, the metal-catalyzed
direct C−H amination reaction has provided an ideal route to
construct the C−N bonds10 and new aminating reagents such
chloramines,11 organic azides,12 and hydroxylamine13 have
been extensively explored. Despite the significant progress in
C−H amination reactions, the C−H amination strategy to link
two different bioactive molecules remains a challenge. Here, we
demonstrate the linkage of two bioactive molecules via the C−
N bond by iridium(III)-catalyzed direct C−H amination
reactions by employing the N-methoxyamides as the effective
aminating reagents (Figure 1b). A wide variety of well-known
drugs, including Adapalene, Ataluren, Vitamin E succinate,
Pregabalin, and Gabapentin, and key intermediates of
Roflumilast, Fluxapyroxad, and Vismodegib, can be introduced
to other bioactive molecules such as 6-arylpurinyl nucleosides,
Celecoxib, Ataluren, and Edaravone, leading to the rapid
construction of new bioactive pharmaceuticals (Figure 1c).
N-Methoxyamides are a class of stable compounds, which
are easily synthesized from carboxylic acid derivatives.
Meanwhile, the carboxyl group is a highly important functional
group that is the key intermediate of bioactive compounds and
well-known drugs. Very recently, our group has demonstrated
the N-methoxyamide can be used as an effective aminating
reagent with a rhodium catalyst.14 Hence, a bioactive
Received: October 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03717
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compound possessing an N-heterocycle and a drug containing
a carboxylic acid moiety directly linked via the C−N bond is
possible (Figure 1a).
bond. All of these aminating reagents derived from drugs can
be directly coupled with 6-arylpurinyl nucleosides leading to
the corresponding products in moderate to good yields (3a−
3k).
To further demonstrate our proposal to link two bioactive
molecules together via the C−N bond through the
intermolecular C−H amination reaction, benzyl-protected
Celecoxib,24 which is used to treat the pain and inflammation
associated with osteoarthritis, rheumatoid arthritis, and
ankylosing spondylitis, was used to couple the aminating
reagents derived from bioactive compounds (Scheme 2). A
With these conditions in mind, we tried to connect two
bioactive molecules of 6-arylpurinyl nucleosides with 2-(1-
((1,3-dioxoisoindolin-2-yl)methyl)cyclohexyl)-N-methoxy-
acetamide (2a) via the direct C−H amination reaction.
Initially, the 6-arylpurinyl nucleoside (1a) was treated with
2a in the presence of [Cp*Ir(III)Cl2]2 (5 mol %) and AgSbF6
(20 mol %) in 1,2-dichloroethane at 140 °C for 18 h under
nitrogen. Amidated product 3a was obtained in 69% yield.
Interestingly, the product 3a can achieve an 85% yield, when
sodium acetate (20 mol %) was used as the additive. The
sodium acetate may act as a proton transfer reagent in
activating the C−H bond.15
Scheme 2. Scope of Aminating Reagents in C−H Amination
a
Reactions
Encouraged by these results, we transformed a variety of
well-known drugs and key intermediates of bioactive
compounds, such as Adapalene,16 Ataluren, Probenecid,17
Vitamin E succinate, Pregabalin, Gabapentin, Undecylenic
acid,18 Stearic acid,19 and key intermediates of Roflumilast20
into the aminating reagents (Scheme 1). As the 6-arylpurinyl
nucleosides usually exhibit potent antimycobacterial,21 anti-
HCV,22 and cytostatic activities,23 a new or improved
biological property might be obtained when the known drugs
were introduced to 6-arylpurinyl nucleosides via the C−N
Scheme 1. Cross-coupling Two Bioactive Molecules via C−
a
H Amination Reactions
a
4 (0.20 mmol), 5 (0.4 mmol), [Cp*IrCl2]2 (5 mol %), AgSbF6 (20
mol %), NaOAc (20 mol %) in solvent (1.5 mL) for 18 h under
nitrogen in a sealed tube. Isolated yields.
variety of bioactive compounds of amino acids including
Carbocratine (5a), Gabapentin (5b), Abufene (5c), and
Aminalon (5d) could be coupled with benzyl-protected
Celecoxib, providing the aminated products in moderat to
good yields. The β-amino acids are a class of highly important
bioactive compounds, which are used as key intermediates for
various drugs, such as Pantothenic acid, Remifentanil,
Balsalazide, etc. The β-amino acids of Carbocratine can be
readily converted to aminating reagents and introduced to
Ataluren in good yields by intermolecular amination (6e).
Edaravone25 is a commercially available intravenous
medication which is used in recovery following a stroke and
to treat amyotrophic lateral sclerosis. However, when
Edaravone was directly treated with aminating reagents from
Probenecid, the desired intermolecular amination product
could not be obtained, but the carboxybenzyl-protected
Edaravone was an effective coupling partner for this trans-
a
4 (0.20 mmol), 5 (0.3 mmol), [Cp*IrCl2]2 (5 mol %), AgSbF6 (20
mol %), NaOAc (20 mol %) in solvent (1.5 mL) for 18 h under
nitrogen in a sealed tube. R2 = Bn. Isolated yields.
b
B
DOI: 10.1021/acs.orglett.9b03717
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation (Scheme 2). For example, the aminating reagents
from Probenecid and Ataluren coupled well with the
carboxybenzyl-protected Edaravone under standard reaction
conditions, yielding the intermolecular aminated products (6g
and 6h) in good yields. The aminating reagents from the key
intermediates of Roflumilast and Fluxapyroxad were all easily
introduced onto carboxybenzyl-protected Edaravone in good
yields (6f and 6i), respectively. Importantly, the gram scale
reaction was easily achieved, yielding the product 6h in 58%
yield (Scheme 3a). We next demonstrated the carboxybenzyl
Scheme 5. Plausible Catalytic Cycle
Scheme 3. Gram Scale Reaction and Further
Transformation
iridium(III)-induced C−H activation. Coordination of the
aminating reagent to I produces complex II. The activated
proton in complex II can be removed under assistance of the
acetate anion, leading to the complex III. The protonic acid
may activate the methoxy group, which would produce an
iridium(V) complex, followed by reductive elimination to give
complex IV, and finally followed by protonation to give the
product 9.
In conclusion, N-methoxyamide was an excellent novel
aminating reagent in the iridium-catalyzed intermolecular
amination reaction. It can provide a unique approach to link
two different bioactive organic molecules via the intermolec-
ular C−N bond formation, which can facilitate the discovery of
new bioactive molecules. We anticipate that the linkage of two
different organic bioactive molecules through the C−H
functionalization strategy will be a new future direction for
C−H activation. The pharmacological activities of the
synthesized novel derivatives are currently underway in our
laboratory.
protecting group could be easily removed, leading to the
coupled bioactive molecule 7 in excellent yields. It is worth
noting that the acetyl groups were easily removed from 3b
under mild conditions, generating the product 3b′ in excellent
yield (Scheme 3b).
The aminating reagent 8 was prepared and further subjected
to the standard reaction conditions. To our delight, the
product 9 was isolated in 63% yield, accompanied with 4-
biphenylmethanol 10 at 60% yield (Scheme 4a). This result
Scheme 4. Preliminary Mechanistic Study
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03717.
Experimental procedures, new compounds character-
ization data, including the NMR spectra (PDF)
indicated that when N-methoxyamide was employed as the
aminating reagent, the side product was methanol. Although
the catalytic amount sodium acetate has a promoting effect for
this transformation, when we increase its amount more than 50
mol %, the yield of 9 dramatically decreased (Scheme 4b).
These results indicate that the reaction is more prone to
proceed under acidic conditions.15
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jyzhang@suda.edu.cn.
*E-mail: yszhao@suda.edu.cn.
ORCID
Yingsheng Zhao: 0000-0002-6142-7839
Notes
Based on these results and previous reports,26 a plausible
catalytic cycle was proposed (Scheme 5). First, a five-
membered iridacycle intermediate I was generated via the
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b03717
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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C−H Amidation of Arenes with N-Methoxyamide as an Amidating
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ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (Nos. 21772139, 21572149), Jiangsu Province
Natural Science Found for Distinguished Young Scholars
(BK20180041), Project of Scientific and Technologic Infra-
structure of Suzhou (SZS201708), and the PAPD Project.
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