Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines via a C-H Activation Strategy Using Ethenesulfonyl Fluoride as Ethylene Provider

Article abstract of DOI:10.1021/acs.orglett.9b01364

A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for modification of Sorafenib was also accomplished.

Full text of DOI:10.1021/acs.orglett.9b01364

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines
via a C−H Activation Strategy Using Ethenesulfonyl Fluoride as
Ethylene Provider
Chen Li and Hua-Li Qin*
State Key Laboratory of Silicate Materials for Architectures; and School of Chemistry, Chemical Engineering and Life Science,
Wuhan University of Technology, 205 Luoshi Road, Wuhan, Hubei Province 430070, P.R. China
S
* Supporting Information
ABSTRACT: A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a
class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for
modification of Sorafenib was also accomplished.
yridine moieties are ubiquitously found as key motifs in
Pagrochemicals, natural products, functional materials,
ligands, catalysts, and small molecule therapeutics.1 Substituted
pyridines were ranked the most common heterocycles in
medicinal chemistry and pharmaceutical industry because of
their diverse biological activities.2 Indeed, pyridine motifs are
present in more than 100 FDA approved drugs including those
blockbuster drugs of omeprazole (Prilosec), loratadine
(Claritin), imatinib (Gleevec), and sorafenib (Nexavar), as
illustrated in Figure 1.3
picolinamide as a directing group for C−H bonds function-
alization has been emerging as a new portal to pyridine-
containing molecules.8 In fact, Rh(III)-catalyzed olefination/
annulation of picolinamides has been proven to be a highly
efficient method,9 whereas installing an ethylene moiety onto
pyridine rings still remains untouched.
The ethylene functionality is an abundant feedstock for
organic synthesis;10 therefore, installing an ethylene onto the
pyridine rings will provide a versatile handle for manipulation
of pyridine-containing compounds to access libraries of
pyridine cores for accelerating drug discovery progress.11
Ethenesulfonyl fluoride (ESF)12 is sensitive to nucleophilic
solvents, bases, and nucleophiles. In addition, ESF is very likely
to polymerize upon being heated.
However, most of the C−H bond functionalization requires
bases and/or elevated temperatures, which makes the coupling
reactions of C−H bonds with ESF much more challenging.
Herein, we described a Rh(III)-catalyzed annulative insertion
of ethylene onto picolinamides for accessing to a series of
unique pyridine-containing molecules bearing a terminal olefin
functionality using ESF as a free ethylene provider (Scheme 1).
Initially, we tested the reaction of readily available 2-
picolinamide (1a) and ESF (2) using 5 mol % of [Cp*RhCl2]2
as catalyst and 2 equiv of AgOAc as oxidant in 1,2-
Figure 1. Representative blockbuster drugs containing pyridine
moieties.
Picolinamides (2-pyridinecarboxamide) are a class of very
important pyridine derivatives with unique properties for drug
discovery and ligand development.4 The development of
general, efficient, mild, and reliable methods for the
construction of pyridines and picolinamides has been
considered as a very significant target for the organic chemistry
community.5 However, the electron-deficient property and
strong Lewis basicity have resulted in the relatively low
reactivity of pyridines rings, which has made it difficult to
construct and diversify pyridine-containing molecules, includ-
ing picolinamdes.6 On the other hand, transition-metal-
catalyzed C−H bond functionalization has become a powerful
tool for organic synthesis, medicinal chemistry, and material
sciences in a step and atom-economical manner.7 The use of
Scheme 1. Rh(III)-Catalyzed Annulative Insertion of
Ethylene onto Picolinamides
Received: April 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dichloroethane (DCE) at 130 °C; fortunately, a small amount
of desired product 3a was obtained (Table 1, entry 1). In order
atmosphere, which indicated that oxygen might facilitate the
conversion of 1a (Table 1, entries 8−10).
It is worth noting that the 5 mol % loading Rh catalyst was
essential to ensure the complete transformation of starting
material because a significantly decreased yield of 3a was
obtained when 2 mol % catalyst was used (Table 1, entry 11).
Further control experiments showed that both the Rh catalyst
and copper oxidant were necessary for this transformation
(Table 1, entries 12 and 13). Remarkably, reducing the
reaction time from 24 to 12 h successfully improved the yield
of 3a from 83% to 93%, which may be attributed to the
instability of the terminal olefin to undergo various possible
side reactions at high temperature. (Table 1, entry 14).
Therefore, the conditions of Table 1, entry 14, were chosen as
standard procedure for further examination of substrate scope
and functional group compatibility.
Table 1. Screening Conditions for the Rh(III)-Catalyzed
Reaction of Picolinamide and Ethenesulfonyl Fluoride
a
b
AgSbF6
(Y mol %)
temp
(°C)
yield
entry
oxidant (X equiv)
(3a, %)
1
2
3
AgOAc (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2·H2O
(2.0)
/
/
/
130
130
130
trace
16
33
4
5
6
7
8
Cu(OAc)2·H2O
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
130
120
110
120
120
120
120
120
120
58
With these optimized conditions in hand, we subsequently
explored the substrate scope and limitations of this Rh(III)-
catalyzed annulative insertion of ethylene onto picolinamides
1. As shown in Scheme 2, it was pleasing to find that
(2.0)
Cu(OAc)2·H2O
(2.0)
Cu(OAc)2·H2O
(2.0)
Cu(OAc)2·H2O
(1.5)
Cu(OAc)2·H2O
(2.5)
Cu(OAc)2·H2O
(2.0)
Cu(OAc)2·H2O
(2.0)
Cu(OAc)2·H2O
(2.0)
Cu(OAc)2·H2O
(2.0)
83
63
62
Scheme 2. Scope Examination of Rh(III)-Catalyzed
a
Annulation
80
c
9
75
d
10
80
e
11
55
f
12
trace
13
14
/
AgSbF6 (20)
AgSbF6 (20)
120
120
trace
93
g
Cu(OAc)2·H2O
(2.0)
a
Reaction conditions: mixture of 1a (0.2 mmol), 2 (0.4 mmol, 2
equiv), [Cp*RhCl2]2 (5 mol %), oxidant, and DCE (0.1 M) was
reacted at a corresponding temperature for 24 h under air atmosphere.
b
The yield was determined by HPLC using 3a as the external
standard (tR = 3.79 min, λmax = 251.2 nm, acetonitrile/water = 70:30
c
d
(v/v)). Under argon atmosphere. Under oxygen atmosphere.
e
f
g
Using 2 mol % of [Cp*RhCl2]2. Without [Cp*RhCl2]2. The
reaction was run for 12 h.
to improve the yield of 3a, a series of oxidants was surveyed.
Delightedly, the use of 2 equiv of Cu(OAc)2 or Cu(OAc)2·
H2O furnished the product 3a in 16% and 33% yield,
respectively (Table 1, entries 2 and 3), while other commonly
used oxidants provided the final product 3a in undetectable
level (see the Supporting Information (SI) for details).
Interestingly, the addition of AgSbF6 (20 mol %) as co-
catalyst gave a significant improved yield of 58% (Table 1,
entry 4).
Encouraged by this result, we next turned to exploration of
the influence of solvents, and the results indicated DCE was
the best choice. Decreasing the reaction temperature to 120 °C
afforded a dramatically increased yield of 83% (Table 1, entry
5), while further reducing the temperature to 110 °C led to a
significant decreasing yield of 3a (63%, Table 1, entry 6). The
amount of Cu(OAc)2·H2O loading was also investigated, and 2
equiv Cu(OAc)2·H2O was found to provide the best yield
(Table 1, entries 5, 7, and 8). Performing the reaction under an
oxygen atmosphere or air atmosphere generated slightly higher
yields of 3a compared to that conducted under argon
a
Reaction conditions: mixture of 1 (1.0 mmol, 1 equiv), 2 (2.0 mmol,
2 equiv), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Cu(OAc)2·
H2O (2 equiv), and DCE (0.1 M) was reacted at 120 °C for 12 h
b
c
under air atmosphere. Isolated yields. The reaction was run for 18 h.
d
The reaction was conducted on a 10 mmol scale (1h, 1.78 g).
B
DOI: 10.1021/acs.orglett.9b01364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
picolinamides (1) bearing both electron-donating and
electron-withdrawing groups at different positions of the
pyridine rings afforded their corresponding products 3 in
moderate to high isolated yields (3a−3f, 43−93%). The X-ray
structure of 3c in Scheme 2 clearly showed the formation of
the pyrido pyrrolone skeleton bearing a terminal olefin moiety.
N-substitution of the amides with either alkyl groups (1a−1o)
or aryl groups (1p−1z) were smoothly transformed to their
corresponding products 3a−3o or 3p−3z using this method.
Notably, N-butylquinoline-2-carboxamide (1g), a polycyclic
substrate, was also converted to the corresponding annulative
product 3g with relatively lower yield compared to its
monocyclic counterparts. Remarkably, the efficiency of
annulative insertion ethylene to N-sec-butylpicolinamide (1h)
was not deteriorated when the reaction was performed on a 10
mmol (1.78 g) scale, furnishing the corresponding product 3h
in 75% isolated yield. Much to our delight, benzyl N-
substituted and heterocycle N-substituted picolinamides
afforded the desired products 3m and 3n in good yields,
respectively. The conversion of N-(4-bromophenethyl)-
picolinamide 1o to its annulative product 3o was also
accomplished smoothly in 62% yield, leaving a bromine
atom intact for further transformations. Subsequent examina-
tion of substrate scope was expended to N-aryl-substituted
picolinamides, which revealed that regardless of whether
electron-rich or electron-deficient or the steric hindrance of
substitutions on the aryl rings of amides (1p−1z), the
efficiency of the desired transformation was not obviously
affected. Furthermore, nicotinic acid and isonicotinic acid
derivatives (1aa and 1ab) were examined under the standard
reaction conditions; however, their corresponding products
(3aa and 3ab) were not generated. Interestingly, the use of the
benzamide (1ac) afforded a mixture of products 3ac (29%
yield) and 3ad (35% yield) after reaction with ESF under the
standard reaction conditions without formation of the
corresponding terminal olefins.
was subjected to modification as illustrated in Scheme 4.
Unsurprisingly, the corresponding product (11) was smoothly
obtained under the developed conditions in moderate yield.
Scheme 4. Modification of Sorafenib Using the Developed
Method
A plausible mechanism for the reaction of Rh(III)-catalyzed
annulative insertion of ethylene onto picolinamide 1 was
proposed in Scheme 5. Rhodation of picolinamide 1 with
Scheme 5. Plausible Mechanism
[Cp*RhCl2]2 produced the five-membered rhodacycle inter-
mediate A, which was followed by an olefin insertion to
generate the seven membered ring B. The intermediate B
underwent a β-hydride elimination to provide the ortho-
olefinated intermediate C as an excellent Michael acceptor.
The subsequent intramolecular Michael addition furnished a
five-membered amide D, which went through an oxidative
electron-transfer process to generate the iminium intermediate
E. The hydrolysis of sulfonyl fluoride and the following
elimination of SO3 provided the desired terminal olefin
product 3.
As depicted in Scheme 3, the utility of our products was
demonstrated. The terminal olefin skeleton of compound 3v
Scheme 3. Late-Stage Transformations of Terminal Olefin
Moieties of Products 3
Because the intermediate D was not isolatable from the
reaction, a similar analogue 3ae was synthesized from the
reaction of benzamide (1ae) and ESF for investigating
desufonylation mechanism (Scheme 6). The experimental
results revealed that 3ae was completely transformed to the
corresponding terminal olefin 3af in the presence of pyridine
and copper oxidant, while without the presence of pyridine the
desufonylation did not occur. Because the picolonamide
moiety possesses a pyridine functionality, it was very likely
Scheme 6. Desufonylation Study
was subjected to an oxidation to form the pyridine-fused
phthalimide product 3va in excellent yield using KMnO4 as
oxidant.13 The terminal olefin of 3c was highly functionalized
to an acetal 3ca.14 Interestingly, m-CPBA-mediated oxidation
of annulative product 3f led to the formation of a mixture of
imide 3fa and epoxypropane analogue 3fb in about a 1.1:1.0
ratio.15
To apply this method for modification of complicated
molecules, the FDA-approved drug sorafenib (10), a very
important Raf kinase inhibitor for the treatment of cancer,16
C
DOI: 10.1021/acs.orglett.9b01364
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Letter
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that the picolonamide also served as a special base to promote
the desufonylation of intermediate D to generate terminal
olefin 3.
In summary, we have developed a Rh(III)-catalyzed
annulative method for insertion of ethylene onto picolinamides
providing a portal to a class of unique pyridine-containing
molecules bearing a terminal olefin for manipulations. In
addition, diversifications of the terminal olefin moieties of the
new molecules, such as oxidation and epoxidation, were also
evaluated. The utilization of this method for late-stage
modification of the drug sorafenib was achieved. Further
studies on the bioactivities of the constructed new compounds
are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01364.
General methods, synthetic procedures, and character-
ization (PDF)
Accession Codes
CCDC 1905736 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qinhuali@whut.edu.cn.
ORCID
Hua-Li Qin: 0000-0002-6609-0083
Notes
The authors declare no competing financial interest.
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Z.; Derosa, J.; Engle, K. M. Palladium(II)-Catalyzed Regioselective
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), the Wuhan Applied Funda-
mental Research Plan of Wuhan Science and Technology
Bureau (Grant No. 2017060201010216), the 111 Project (No.
B18038), and Wuhan University of Technology for the
financial support.
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DOI: 10.1021/acs.orglett.9b01364
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