Cobalt(III)-Catalyzed Oxadiazole-Directed C-H Activation for the Synthesis of 1-Aminoisoquinolines

Article abstract of DOI:10.1021/acs.orglett.7b01119

Aromatic heterocycles have been identified as effective directing groups (DGs) in C-H functionalization but can be retained as undesired bulky substituents in the final products. Herein, we report a Co(III)-catalyzed 1-aminoisoquinoline synthesis strategy based on oxadiazole-directed aromatic C-H coupling with alkynes and a subsequent redox-neutral C-N cyclization reaction. This labile N-O bond-based protocol has allowed the toleration of a broad range of functional groups.

Full text of DOI:10.1021/acs.orglett.7b01119

Letter
pubs.acs.org/OrgLett
Cobalt(III)-Catalyzed Oxadiazole-Directed C−H Activation for the
Synthesis of 1‑Aminoisoquinolines
Fan Yang, Jiaojiao Yu, Yun Liu, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: Aromatic heterocycles have been identified as effective directing
groups (DGs) in C−H functionalization but can be retained as undesired bulky
substituents in the final products. Herein, we report a Co(III)-catalyzed 1-
aminoisoquinoline synthesis strategy based on oxadiazole-directed aromatic C−H
coupling with alkynes and a subsequent redox-neutral C−N cyclization reaction.
This labile N−O bond-based protocol has allowed the toleration of a broad range
of functional groups.
ransition-metal-catalyzed directed functionalization of C−
heterocycle products are synthetically challenging. Targeted
synthesis of heterocycles has been primarily achieved by the use
of simple functional groups (e.g., amide,4 imine,5 oxime,6 azo,7
hydrazone,8 nitrosamine,9 amidine,10 carboxylic acid, and their
derivatives11) as DGs. However, in these transformations, DGs
are generally, in part or as a whole, sequestered into the
heterocycles. As such, it is difficult to install synthetically
versatile functional groups as reactive handles for further
structural elaboration.
T
H bonds has emerged as an important synthetic tool in
organic chemistry.1 Many aromatic heterocycles (e.g., pyridine,
pyrimidine, pyrazole, quinolone, triazole) have been identified
as effective directing groups (DGs) for these coupling reactions
(Scheme 1a).2 Attractive synthetic features associated with this
Scheme 1. Synthesis Strategy of the Aromatic Heterocycle
Directing Groups
We have been interested in the exploration of a redox-
neutral, heterocycle DG-based strategy for the achievement of
distinct reactivity patterns that are otherwise impossible to
realize with previously documented methods. Two 1,2,4-
oxadiazol-5(4H)-one-enabled heterocycle synthesis protocols
have been developed as a result of these efforts. By using a
labile N−O bond as the internal oxidant, 1-aminoisoquinolines
and 1-aminopyridines can be synthesized respectively via
Co(III) and Rh(III) catalysis, with CO2 released as the sole
byproduct.12 In the search for a DG with a higher reactivity, we
have turned our attention to the 5-methyl-1,2,4-oxadiazole
(abbreviated herein as oxadiazole) group. The rationale behind
the use of an oxadiazole group is the following: oxadiazole is a
stable aromatic motif that exhibits strong coordination
capability; the labile N−O bond in the oxadiazole motif can
potentially react as an internal oxidant.
Herein, we report the development of a new Co(III)-
catalyzed 1-aminoisoquinoline synthesis strategy based on
oxadiazole-directed aromatic C−H coupling with alkynes and
a subsequent redox-neutral C−N cyclization reaction (Scheme
1c). 1-Aminoisoquinolines are an important class of com-
pounds that display a wide range of biological activities,
including kinase13 and topoisomerase inhibition,14 antibacte-
rial,15 and antiproliferation activity.16 Notably, the utility of
type of DGs include high reactivity, adaptability to a wide-range
of metal catalysts, and a broad coupling partner scope.
However, significant drawbacks also exist, such as requirement
of external oxidants, general retention of unintended bulky
DGs, and not being atom-economic. The heterocycles can be
linked to a heteroatom in the original DG design and,
subsequently, be either removed or transformed into other
functional groups (Scheme 1b) if desired.3 Direct applications
of heterocycle DGs in targeted construction of other useful
Received: April 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
oxadiazole has enabled the achievement of heightened
reactivity, high product yields, and a broad substrate scope.
We commenced our investigations by examining Co(III)-
catalyzed coupling between 5-methyl-3-phenyl-1,2,4-oxadiazole
(1a) and 1,2-bis(4-methoxyphenyl)ethyne (2a) under various
reaction conditions (Table 1). In the presence of CoCp*-
Scheme 2. Substrate Scope of Oxadiazoles
ab
,
Table 1. Optimization of Reaction Conditions
a
Conditions: 1a−1p (0.2 mmol, 1 equiv), 2a (1.2equiv), CoCp*-
(CO)I2 (10 mol %), AgSbF6 (20 mol %), LiOAc (20 mol %), TFE
(0.5 mL) at 90 °C for 12 h, under nitrogen. Isolated yields. 85%
b
c
a
Conditions: 1a (0.2 mmol, 1 equiv), 2a (1.2 equiv), Co(III) catalyst
yield at 1 mmol scale.
(10 mol %), Ag salt (20 mol %), additive (20 mol %), TFE (0.5 mL) at
b
c
90 °C for 12 h under nitrogen. Isolated yields. Blank test without
d
Co(III) catalyst. 130 °C.
interpreted based on the steric effect. A mixture of regioisomers
was observed for 1l and 1m as the substrates. Replacement of
the phenyl ring of 1a with a thiophene ring (1n) and a
naphthalene ring (1o) gave the corresponding products in 74%
and 61% yields, respectively. Furthermore, we carried out a 1
mmol scale reaction between 1a and 2a under standard
condition and an 85% yield is achieved, thus verifying the
potential synthetic utility of our protocol. The alkyne scope was
next examined using 1e as the reacting partner (Scheme 3).
(CO)I2 (10 mol %), AgSbF6 (20 mol %), and LiOAc (20 mol
%), a cyclization product, 3,4-bis(4-methoxyphen-yl)-
isoquinolin-1-amine (3a), can be generated in 75% yield
(entry 12) after reacting at 90 °C in TFE (2,2,2-trifluoro-
ethanol) for 12 h. No reaction between 1a and 2a was observed
under AgSbF6 (20 mol %)/KOAc (20 mol %) conditions
(entry 1). Merely 5% and 7% yields were obtained for 3a with
KOAc (20 mol %) or AgSbF6 (20 mol %) as the exclusive
additive (entries 2 and 3). The acidic condition is inferior for
catalysis as compared to the basic condition. The replacement
of HOAc with LiOAc results in an improved yield (entries 9
and 12). Further investigation revealed 90 °C as the optimum
temperature, and the product yield is very sensitive to the
variation of temperature. Among the examined additives,
LiOAc proved to be the most effective (entries 3−10). The
counterion associated with the silver salt is also critical, and
AgSbF6 gave the best result (entries 10−12). Several Co(III)
complexes were evaluated as the catalyst precursors (entries
12−16), and CoCp*(CO)I2 appeared as the most powerful
one. Other Co(III) complexes, either in the dimer
([CoCp*I2]2, [CoCp*Cl2]2) or cationic ([CoCp*(MeCN)3]-
(SbF6)2, [CoCp*(C6H6)](PF6)2) format, all exhibit lower
catalytic activity.
a b
,
Scheme 3. Substrate Scope of Alkynes
The substrate scope of oxadiazoles was first examined by
reacting with coupling partner 2a (Scheme 2). A wide range of
oxadiazole derivatives are compatible with the protocol. Both
electron-rich (1a−1c) and electron-poor (1d−1h) para-
substituted oxadiazoles can react efficiently. Excellent regiose-
lectivity is observed for the majority of meta-substituted
substrates (1i, 1j, 1k, 1p). The regioselectivity for 1i, 1j, and
1k is, however, opposite to that for 1p, which can be
a
Reactions were carried out on 0.2 mmol scales. Conditions: 1e (0.2
mmol, 1 equiv), 2q−2z (1.2 equiv), CoCp*(CO)I2 (10 mol %),
AgSbF6 (20 mol %), LiOAc (20 mol %), TFE (0.5 mL) at 90 °C for
b
12 h under nitrogen, Isolated yields.
B
DOI: 10.1021/acs.orglett.7b01119
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Organic Letters
Letter
The optimized conditions can accommodate both symmetri-
cally substituted diarylalkynes (2q−2w) and dialkylalkyne (2y)
and unsymmetrically substituted aryl/alkyl alkynes. The 1,2-
di(thiophen-2-yl)ethyne (2x) also reacts in good yield.
Scheme 5. Preliminary Mechanistic Experiments
Intrigued by the efficiency of this Co(III)-catalyzed trans-
formation, experimental mechanistic studies were performed to
determine its reaction pathway. We therefore first conducted
two intermolecular competition experiments. The reaction
favors an electron-rich oxadiazole and electron-poor alkyne (see
the Supporting Infomation (SI)). We next carried out a series
of deuterium-labeling experiments to further investigate the
Co(III)-catalyzed C−H activation and subsequent steps.
Heating 1a or 1e alone under deuterated optimized conditions
(replacement of TFE with TFE-d3) and 1a-d5 alone under
optimized conditions shows significant H/D scrambling
(Scheme 4a). These results support the reversibility of the
Scheme 6. A Plausible Reaction Mechanism
Scheme 4. H/D Exchange Study
C−H metalation step under alkyne-free conditions. Further
deuterium-labeling experiments between 1a or 1e with coupling
partner 2a indicate the absence of H/D scrambling at the ortho
position of the directing group (Scheme 4b), thus supporting
the conclusion that alkyne migratory insertion occurs efficiently
and irreversibly. Analogously, for 1a-d5, deuterium loss is
identified only in the absence of alkyne 2a; in the presence of
2a, no deuterium loss is identified in either 1a-d5 and 3a-d4
(Scheme 4c,4d). Besides, the observed intermolecular KIE
values of 2.4 (kH/kD, for parallel experiments) and 2.2 (for
competition experiment) suggest that the C−H bond cleavage
step is plausibly the rate-determining step (see the SI).
To further probe the details of the reaction pathway, we have
intercepted the acetyl-retained intermediate 5q by utilizing
DCE as the solvent (Scheme 5a). The ring opening of
oxadiazole apparently occurs through the cleavage of the labile
N−O bond and subsequent tautomerization of the acetimidic
acid to the acetamide form. The final product 4q can be
smoothly transformed from 5q under optimized conditions
(Scheme 5b).
generation of [CoCp*]2+ (I) from CoCp*(CO)I2 and AgSbF6
with the simultaneous release of CO and iodide ligands,
coordination of AcO− to give [CoCp*(OAc)]+ (II), further
coordination of 1a to afford Co(III) complex III, turnover-
limiting C−H activation to form a cobaltacycle IV, coordina-
tion of 2a to yield Co(III) complex V, migratory insertion of
alkyne to furnish alkenylcobalt intermediate VI, simultaneous
C−N cyclization and ring opening of oxadiazole to give the
acetyl-retained 5q, regeneration of Co(III) complex I, and
deacetylation of 5q to provide 4q as the final product.
In summary, we have successfully developed herein a
Co(III)-catalyzed oxadiazole-directed C−H activation method
for the synthesis of 1-aminoisoquinolines. Mechanistic studies
support a concerted ring closing (C−N cyclization)/ring
opening (of oxadiazole) process as well as initial formation of
a N-acetyl-retained intermediate and subsequent deacetylation
generation of the final product. The labile N−O bond-based
protocol allows the operation of an internal oxidation
mechanism and toleration of a broad range of functional
groups.
On the basis of the present observations and previous
transition metal chemistry,12 the mechanistic sequence of this
Co(III)-catalyzed process is proposed in Scheme 6: in situ
C
DOI: 10.1021/acs.orglett.7b01119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01119.
■
S
Experimental procedure, characterization of the products
(PDF)
1
Copies of the H and 13C NMR spectra of selected
products (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinz@nju.edu.cn.
ORCID
Jin Zhu: 0000-0003-4681-7895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
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