Regio-Divergent C—H Alkynylation with Janus Directing Strategy via Ir(III) Catalysis

Article abstract of DOI:10.1002/cjoc.202000204

Directing strategy has been extensively exploited to maintain activity and selectivity for the rapid access to functionalized molecules and pharmaceutical targets. However, ‘one-to-one’ activation model was usually achieved through traditional directing strategy. Herein, we achieved ‘one-to-two’ activation model by slight modification of simple and practical ketoxime and amide functionality. With judicious choice of directing groups, Csp³—H and Csp²—H bond alkynylation reaction, and more significantly, dehydrogenative Csp³—H alkynylation, were realized, enabling the regio-divergent late-stage modifications of pharmaceuticals.

Full text of DOI:10.1002/cjoc.202000204

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Regio-Divergent C-H Alkynylation with Janus Directing Strategy via Ir(III)
Catalysis
Authors: Xianwei Li, Guangxin Liang,* Zhang-Jie Shi*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000204.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000204.
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Regio-Divergent C-H Alkynylation with Janus Directing Strategy via
Ir(III) Catalysis
1,2
3,4,5
Xianwei Li,1,6 Guangxin Liang,* Zhang-Jie Shi*
1State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
2School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
3Department of Chemistry, Fudan University, Shanghai 200433, China
4College of Chemistry and Molecular Engineering, Peking University, Beijing 100871
5State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032 6School of
Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China
KEYWORDS Regio-
-
-stage modifica-
tion of pharmaceuticals.
ABSTRACT: Directing strategy has been extensively exploited to maintain activity and selectivity for the rapid access to functionalized mole-
-to-
we achi
-to-
choice of directing groups, Csp3-H and Csp2-H bond alkynylation reaction, and more significantly, multiple dehydrogenative Csp3-H alkynyl-
ation, were realized, enabling the regio-divergent late-stage modifications of pharmaceuticals.
The exploration of catalytic methodologies that enable the selective
functionalization of aliphatic C-H bonds is of great importance in
synthetic chemistry, which has witnessed great advancements. Di-
recting proximity strategy1 has been widely utilized in transition-
metal catalyzed C-H functionalizations, which has spurred the in-
ventions of various types of directing groups, leading to simultane-
ous acquirement of reactivity and selectivity.
Generally, directing groups were often introduced to achieve the
high efficiency and regioselectivity in C-H fucntioanlization, while
-to-
regioselectivity. While regio-divergent modification of target mole-
cules, which would provide new retrosynthetic logic for the synthe-
sis of complex molecules, remained promising and challenging.
Thus, a strategy that enabled regio-divergent2 modification of two
types of Csp3-H bonds, by judicious development of directing
groups, would greatly enhanced the overall synthetic efficiency.
Along this line, rich reactivity and diverse modifications of bioac-
tive molecules and materials could be well explored, which might
provide new insight into modern organometallic and synthetic
Scheme 1. Janus directing groups in C-H functionalization.
chemistry.
On the other hand, alkynes are widely used across various fields,
To commence our study in Csp3-H alkynylation, we were inspired
by the versatility and applicability of ketoximes and primary am-
ides, which can be easily introduced and readily transformed. We
started our investigation by attempting the Csp3-H alkynylation of
readily available O-methythyl-2-methyl cyclehexone 1a using
(bromoethynyl)triisopropylsilane 3a under
including synthetic organic chemistry, nature products, pharma-
ceutical chemistry and functional materials.3 The diverse and rich
chemistry associated with alkyne compounds have inspired the
discovery various efficient methods toward their expedient deliv-
ery. Although various methodologies for the selective introduction
of alkyne functionality have been developed, direct introduction of
C-C triple bond into molecules through Csp3-H alkynylation re-
mained a formidable challenges.4
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000204
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transition-metal catalysis.6 After extensive exploration of reaction
conditions, we found that with [Cp*IrCl2]2 and AgNTf2 as the cata-
lyst, trace amount of the desired Csp3-H alkynylation product 3a
was observed. To our delight, 3a could be obtained in 75% yield
with 2 equivalent of AgOAc was added as additive, other silver
additives, such as AgNO3 as well as Ag2CO3 gave the desired prod-
uct in relative lower yield (entries 3, 4). Further investigation of
the effect of the additives revealed that Cu(OAc)2, CsOPiv showed
low efficiency (entries 5,6) while PhI(OAc)2, NFSI totally shut
down the reaction (entries 7, 8). 100 oC was optimal for this trans-
formation, since lower yields were observed with 80 or 120 ℃
(entries 9, 10). Lower the amount of AgOAc led to the decreased
yield of the product 3a (entry 11). The combination of AgOAc and
Li2CO3 under [Cp*IrCl2]2 and AgNTf2 catalytic system gave the
optimal result (entry 12). Notably, when AgSbF6 was used instead
of AgNTf2, no desired Csp3-H bond alkynylation product 3a was
obtained, which revealed the significance of the coordinating anion
of the catalyst (entry 13). Control experiments with other metal
catalysts candidates, such as Ru(II) and Pd(II) salts, showed no
efficiency in this transformation (entries 14, 15). The catalyst sys-
tem is critical for this transformation: 1); 2) other common metal
catalyst, such as Pd(OAc)2 and [Ru(p-cymene)Cl2]2 could not
deliver the target molecule 3a. When the solvent DCE was changed
to toluene or 1,4-dioxane (entries 16, 17), the reaction showed very
low catalytic efficiency. Moreover, 2.5 equivalent amount of the
alkynyl bromide is essential for achieving the full conversion of the
ketoxime substrates (entry 18).
With the optimal condition in hand, we then explored the sub-
strate scope with respect to the ketoxime component. As depicted
in Scheme 2, in general, the ketoxime substrates showed great regi-
-
Csp3-H bond alkynylation. I
-H elimi-
nation byproducts were observed, which probably due to the rigidi-
ty of the generated five-membered metalcycle intermediate. Under
-methyl cyclic ketoxime deriva-
tives 1a-1i underwent regioselective Csp3-H bond alkynylations
with good efficiency. The substitution variant of the O-alkyl of the
ketoximes, such as methyl, ethyl and benzyl groups, all gave the
-alkynylation products in good yield (3b, 3c, 3d). Nota-
bly, when the substrates containing potential multi-reactive posi-
tion on Csp2-H and Csp3-H bond, this transformation showed
-methyl Csp3-H
of the ketoxime substrates to give the desired Csp3-H bond alkynyl-
ation products (3b-3i). Furthermore, we also conducted function-
alizations of R-(-)-Carvone derived ketoximes, and Csp3-H al-
kynylation products (3e-3g) were obtained in good efficiency with
the vinyl moiety remained inert. Substrates contained an ester
group 1o could readily undergo Csp3-H bond alkynylation reaction
of the methyl at the quaternary carbon center.
This reaction also showed good selectivity towards the primary
Csp3-H bond. For example, 1k and 1l, which contained 2o -Csp3-
H and 1o δ-Csp3-H, no desired alkynylation product was observed
under the standard reaction conditions. Importantly, since no Ir(0)
species was involved in the catalytic cycle, halogen substituents
could be present. Thus, subsequent elaboration of the products by
standard cross-coupling reactions is possible. Fenchone, the first
antibiotics for the treatment of human diseases, the corresponding
ketoxime could also deliver the desired Csp3-H bond alkynylation
product. Moreover, enone and acetophenone derived ketoximes
1m and 1n, were also suitable in the Csp2-H alkynylation, which
demonstrate the generality of the catalytic system. To further
demonstrate the synthetic application of this transformation, late-
-Santonin by regioselective Csp3-H alkynyla-
Table 1. Optimization of the endo-type Csp3-H alkynylation of
ketoximes.
tion was well achieved (3q). Considering the rich reactivity of al-
kyne functionality, this transformation might provide a valuable
platform for the rapid construction of biologically active molecules
libraries.
Traditional directing groups utilized in directed Csp3-H func-
-to-
d-
ered that ketoxime groups could act as janus directing group in this
catalytic Csp3-H alkynylation. Notably, further exploitation of this
Janus directing group would lead to the rapid construction of com-
plex molecules in a concise manner. Inspired by the above results,
we underwent further attempts for the exo-type7 Csp3-H bond al-
kynylation of the ketoximes. Cyclic ketoximes were selected as the
o
research subject, as the 2o
-Csp3-H in the substrates re-
mained inert in this catalytic system. Initial results depicted in
Scheme 2 revealed that, cyclohexanone derived ketoxime 1t
showed better efficiency than that of cyclopentanone and cyclohep-
tanone (please see the supporting information for details). Then,
we chose 1r as the mode substrate for the further optimization of
this reaction conditions, the results revealed that increase the
amount of catalyst gave better results.
aUnless otherwise indicated, the reactions were performed with substrate 1a
(0.2 mmol), 2a (2.5 equiv), catalyst (2.5 mol %), AgNTf2 or AgSbF6 (15 mol
%), and additive (10 mol %) in solvent (0.5 mL) at the indicated temperature
for 24 h. bDetermined by NMR, yield in the parenthesis is the isolated yield.
cAgOAc (2.0 equiv.), Li2CO3 (1.0 equiv.). d 2a (1.5 equiv.).
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Scheme 2. Regio-divergent Csp3-H and Csp2-H alkynylation of ketoximes via Ir(III) catalysis.
We then further investigated this ketoxime directed exo-type
Csp3-H bond alkynylation, the results are summarized in Scheme 2.
This transformation behaved the following features: 1) this reac-
tion only deliver the mono-functionalized products, when there
were more than one potential reactive site (5a, 5b). 2) in the pres-
ence of methylene Csp3-H, this reaction took place specifically at
the methyl Csp3-H position; even when the substrates contained
benzylic Csp3-H, these positions remained unreacted (5d); 3)
although five or six-membered metalcycles could be generated in
this Ir(III)-catalyzed Csp2-H bond alkynylation (5g), while no
Csp3-H alkynylation took place for -Csp3-H bond (5e). Func-
tional groups such as OTBS (5h), trifluoromethoxyl (5i), fluoro
(5l), chloro (5j, 5k) and methoxyl (5m) could be readily compati-
ble.
On the other hand, primary amides serve as important function-
ality in various biologically active molecules, for instance, phenyla-
cetamides occurred as key skeletons in pharmaceuticals such as
Nepafenac, Atenolol and Darifenacin, however, primary aryla-
cetamides were challenging substrates, probably due to the tau-
tomerization of the distal O-coordinating acetamides.8
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Scheme 3. Regio-divergent Csp2-H alkynylation and multiple dehydrogenative Csp3-H alkynylation via Ir(III) catalysis.
Internal oxidants enabled directing strategy9 has been proven to
exhibit improved levels of reactivity and selectivity in recent catalyt-
Late-stage modification of pharmaceuticals such as Naproxen and
Ketoprofen, using this regioselective Csp2-H alkynylation strategy,
considering the readily transformable alkyne functionality, this
methodology might provide new insight into the rapid construction
of their molecular libraries. Notably, steric hindered silicon-
contained alkynyl bromide could be used in this Csp2-H alkynyla-
tion.12
Intriguingly, when the N-substitution of the amides was changed
to N-Cl amides from the corresponding primary amides, multiple
dehydrogenative Csp3-H alkynylation products 9 were obtained as
the major products, which might be derived from sequential Csp3-
-H elimination and oxidative C-H alkynylation pro-
ic C-
-
Cl amide facilitated C-H activation,10 we found that regio- and
chemoselective modifications of acetamides were realized (Scheme
3): with primary amide as the directing groups, ortho-selective
Csp2-H alkynylation product 8; while with CONHCl as the inter-
nal oxidizing directing group in this C-H alkynylation, multiple
dehydrogenative Csp3-H alkynylation was observed.11 It should be
noted that although significant progress has been made towards
-desaturation of Csp3-H bonds adjacent to un-
saturated C-X bonds, direct catalytic desaturation of primary am-
ides remained to be explored, probably
acidity.
-
cess (8l, 9a). Substituents on the aryl rings of the N-Cl amides,
such as fluoro (9b), chloro (9c), bromo (9d) and methoxyl (9e),
could be compatible in this multiple dehydrogenative Csp3-H al-
kynylation, affording to various functionalized conjugated enynes.
However, relatively lower efficiency was observed with secondary
benzylic Csp3-H bonds (9f, 9g) were used as the substrates in this
transformation.
The detailed mechanism remained to be elusive, while prelimi-
nary observation revealed that this dehydrogenative C-H alkynyla-
tion might proceed via intramolecular dehydrogenation to give the
corresponding primary acrylamides, and followed by enamides
directed Csp2-H alkynylation (please see the Supporting Infor-
As summarized in Scheme 3, for Csp2-H alkynylation of acetam-
ides, a possible six-membered iridacycle intermediate might be
involved. A variety of functionality, such as halides including fluoro
(8b), chloro (8c), bromo (8d), trifluoromethyl (8e), trifluoro-
methoxyl (8f), could be tolerated, and hold great synthetic poten-
tial for the further manipulation in pharmaceuticals and functional
materials. Readily transformable nitro group (8g) could also be
compatible. This Csp2-H alkynylation tool place at less hindered
position with meta-substituted aryl acetamide substrates. C3-H
alkynylation was observed for C2-acetamide naphthalene substrate.
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mation for the discussions). Further mechanistic investigation and
synthetic potential of this dehydrogenative C-H functionalization
are underway.
Inert Csp3-H alkynylation of heterocycles served as an efficient
tool applied in the advanced material science, however, remained a
formidable challenge, mainly due to: 1) the inherent directing ef-
fect of the heteroatom of heterocycles, which might lead to catalyst
poisoning and the competitive Csp2-H bond functionalization of
the heterocycles versus directed Csp3-H bond functionalization; 2)
the competition reactivity of the in situ generated alkyl organome-
tallic intermediate towards readily -H elimination and the desired
Csp3-H bond activation. Significantly, the undesired Glaser cou-
pling required the efficient catalytic systems for the Csp3-H al-
kynylation.
Scheme 5. Late-stage modification of pharmaceuticals via regio-
divergent C-H alkynylation.
We applied this optimal catalytic system to test the reactivity of a
variety of the synthetic valuable nitrogen heterocycles, the results
are summarized in Scheme 4. Alkyl groups such as ethyl and iso-
propyl on pyridine (11a, 11b) underwent directed Csp3-H alkynyl-
ation reaction without the observation of C2-H alkynylation of
pyridine. Glycol masked imine derived dioxazines could also deliv-
er the alkynylation products 11c, 11d, which hold the potential
application in high-grade organic pigment. Pyrazine derivatives,
common used as flavor, spices and pharmaceutical intermediates,
are compatible in this catalytic system (11e, 11f, 11g). Moreover,
indazoles (11h, 11i) and quinolones (11j, 11k), which were wide-
ly used as synthetic and pharmaceutical intermediates, could also
participate in this nitrogen directed Csp3-H bond alkynylation.
In summary, we have developed an efficient and general Csp3-H
and Csp2-H bond alkynylation reaction assisted by Janus ketox-
ime13 or amide groups, which afforded densely functionalized mol-
ecules in a concise fashion. This methodology would provide new
synthetic insight into realizing efficient derivation of simple alco-
hols, ketones and amides. By well-designed directing groups in this
robust Ir(III) catalytic system, exo and endo type directing effect
were smoothly tuned for the regio-selective Csp3-H and Csp2-H
alkynylation, which could be applied for divergent modification of
pharmaceuticals including ibuprofen and celecoxib. This versatile
C-H alkynylation reaction might provide further synthetic insight
into rapid construction of molecular complexity, and multiple de-
saturative-functionalization from bulk chemicals, leading to value-
added products.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental procedures and spectra data for all new compounds
(PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: lianggx@shanghaitech.edu.cn; zjshi@fudan.edu.cn
Notes
Th
Scheme 4. Synthetic versatile of this Ir(III) catalysis towards N-
functionalities in C-H alkynylation.
To further demonstrate the synthetic application of this method-
ology, we selected drug molecular ibuprofen derived amides for the
late-stage functionalization. Regioselective Csp2-H alkynylation of
the primary amide proceed smoothly under Ir(III) catalysis (8p),
in which a six-membered iridacycle intermediate might be involved.
Intriguing, when we performed late-stage modification of ibuprofen
derived N-Cl amide, the dehydrogenative Csp3-H alkynylation
product was obtained in moderated yield (9h). Although further
optimization of this dehydrogenative Csp3-H functionalization was
needed, this transformation might provide new insight into the
late-stage modification of pharmaceuticals with regio-divergent
selectivity.
ACKNOWLEDGMENT
We are grateful for the financial supported by the National Natural
Science Foundation of China (21602032 to X. L; 21971122,
21772097, 21572104 to G. L.), and GDUT Analysis and Test Center
for the HRMS analysis. National Key Research and Development Pro-
gram of China (2017YFD0201404).
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