Synthesis of α-Ketone-isoquinoline Derivatives via Tandem Ruthenium(II)-Catalyzed C-H Activation and Annulation

Article abstract of DOI:10.1021/acs.orglett.8b02759

A new ruthenium(II)-catalyzed tandem C-H activation/cyclization/hydrolysis cascade process of 2H-imidazoles and alkynes for facile and regioselective access to α-ketone-isoquinolines has been successfully developed. 2H-Imidazole as the novel traceless directing group has been well applied in this paper. The protocol features mild reaction conditions and easily accessible starting materials, and α-ketone-isoquinolines could be applied to further construct more complex heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.8b02759

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α‑Ketone-isoquinoline Derivatives via Tandem
Ruthenium(II)-Catalyzed C−H Activation and Annulation
Xiao-Lin Wu and Lin Dong*
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
S
* Supporting Information
ABSTRACT: A new ruthenium(II)-catalyzed tandem C−H activation/
cyclization/hydrolysis cascade process of 2H-imidazoles and alkynes for
facile and regioselective access to α-ketone-isoquinolines has been suc-
cessfully developed. 2H-Imidazole as the novel traceless directing group
has been well applied in this paper. The protocol features mild reaction
conditions and easily accessible starting materials, and α-ketone-isoquinolines
could be applied to further construct more complex heterocyclic compounds.
α-substituted isoquinolines were only limited to amine, ester,
ether, α-alkyl, and aryl groups.8 In addition, 2H-imidazole as
the directing group has not been studied in C−H activation
yet.9 Therefore, there is increased interest in developing
α-ketone isoquinoline derivatives.10 Herein, we report a less
expensive ruthenium(II)-catalyzed cascade reaction to build
novel α-ketone-isoquinoline derivatives via C−H activation/
cyclization/hydrolysis of imide into the carbonyl group cascade
process of 2H-imidazoles and alkynes (Scheme 1, eq 2). It is
worth mentioning that the 2H-imidazoles in this cascade
reaction can act as a traceless directing group.
soquinoline has received much attention due to a wide
1
Irange of biological activities (Figure 1).
Thus, diverse
Figure 1. Pharmaceuticals and natural products bearing isoquinolines.
We commenced our investigations by examining the cascade
cyclization between 2,2,4-trimethyl-5-phenyl-2H-imidazole
(1a) and 1,2-diphenylethyne (2a) under various reaction con-
ditions (Table 1). To our delight, in the presence of [RuCl2-
(p-cymene)]2 (5 mol %) and Cu(OAc)2·H2O (2 equiv), the
cyclization product 3aa can be generated in 40% yield (entry 1)
after reacting at 100 °C in DCE for 12 h. Further introduction
of Cu(OTf)2 (1 equiv) and CF3COOAg (1 equiv) as the
co-oxidant can improve the yield of 3aa (entries 2−7). The
solvent screening showed that the product yield is very sen-
sitive to the variation of solvent, and TFE is a suitable solvent
(entries 8−12). In addition, the addition of acid is beneficial to
the reaction, and 1-AdCOOH proved to be the most effective
additive (entries 13−16). In addition, substitutions of
cyclohexyl and phenyl groups (1b and 1c) at the 2 position
on the 2H-imidazole ring were also tolerated in the tandem
reaction but exhibited slightly less reaction efficiency, probably
due to the steric effect (entries 17 and 18). Furthermore,
the reactions could be carried out on larger scales, and the
yields of 3aa have declined but still in good yields (entries 19
and 20). However, the data implied that the scale of reac-
tions had a crucial effect on the efficiency of this one-pot
reaction.11
synthetic methods have been developed for constructing iso-
quinoline derivatives.2 Furthermore, chemists continued to
devise novel synthetic methodologies based on the principles
of atom- and step-economy.3 In 2003, Jun et al. pioneered
chelation-assisted C−H activation to synthesize isoquinoline.4
Since then, different coupling partners such as imines, amines,
hydrazones, and azides have also been utilized (Scheme 1,
eq 1).5−7
Scheme 1. Construction of α-Substituted Isoquinolines via
Tandem C−H Activation/Annulation
However, despite that synthesis of isoquinolines has
achieved great success via C−H activation, highly function-
alized isoquinoline derivatives have rarely been developed, and
Received: August 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Table 2. Substrate Scope of 2H-Imidazoles
yield of 3aa
b
entry
oxidant/equiv
Cu(OAc)2·H2O/2
Cu(acac)2/2
Cu(OTf)2/2
CF3COOAg/2
AgOAc/2
additive
solvent
(%)
1
2
3
4
5
6
7
8
9
--
--
--
--
--
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TFE
40%
32%
43%
21%
33%
58%
32%
65%
33%
25%
N.R.
48%
70%
77%
65%
62%
51%
32%
69%
51%
Cu(OTf)2/1 + CF3COOAg/1 --
Cu(OTf)2/1 + AgOAc/1 --
Cu(OTf)2/1 + CF3COOAg/1 --
Cu(OTf)2/1 + CF3COOAg/1 --
PhCl
dioxane
MeCN
MeOH
TFE
10 Cu(OTf)2/1 + CF3COOAg/1 --
11 Cu(OTf)2/1 + CF3COOAg/1 --
12 Cu(OTf)2/1+ CF3COOAg/1 --
13 Cu(OTf)2/1 + CF3COOAg/1 PivOH
14 Cu(OTf)2/1 + CF3COOAg/1 1-AdCOOH
TFE
15 Cu(OTf)2/1 + CF3COOAg/1 PhOCH2COOH TFE
16 Cu(OTf)2/1 + CF3COOAg/1 AcOH
TFE
TFE
TFE
TFE
TFE
c
17 Cu(OTf)2/1 + CF3COOAg/1 1-AdCOOH
d
18 Cu(OTf)2/1 + CF3COOAg/1 1-AdCOOH
e
19 Cu(OTf)2/1 + CF3COOAg/1 1-AdCOOH
f
20 Cu(OTf)2/1 + CF3COOAg/1 1-AdCOOH
a
Reaction conditions: 1a (0.05 mmol, 1 equiv), 2a (1.2 equiv),
[RuCl2(p-cymene)]2 (5 mol %), additive (2 equiv), solvent (0.5 mL)
b
c
at 100 °C for 12 h under air. Isolated yield. 1b, R4 = R5
=
d
e
f
cyclohexyl. 1c, R4 = Me, R5 = Ph. 1a (0.3 mmol). 1a (2 mmol).
a
Scheme 2. Substrate Scope of Alkynes
a
Reaction conditions: unless otherwise specified, 1 (0.05 mmol,
1 equiv), 2a (1.2 equiv), [RuCl2(p-cymene)]2 (5 mol %), Cu(OTf)2
(1 equiv), CF3COOAg (1 equiv), 1-AdCOOH (2 equiv), and TFE
b
(0.5 mL) at 100 °C for 6−18 h, under air. Isolated yield.
c
d
1 (0.3 mmol). PivOH (2 equiv).
investigating the reaction between 2,2,4-trimethyl-5-phenyl-
2H-imidazole (1a) and various alkynes (Scheme 2). Various
diphenylethynes with valuable functional groups on the aro-
matic ring, either electron-donating or -withdrawing groups,
could react smoothly with 1a to afford the corresponding
products (3ab−3ae) in moderate to good yields (57%−85%).
The substituent at the ortho-position of the phenyl ring was
tolerated in the reaction system but provided the correspond-
ing product 3af in low yield, which may be influenced by steric
effects. It is noteworthy that dialkyl-substituted alkyne 1g
reacted smoothly affording 3ag in 63% yield. Moreover, single
isomers 3ah and 3fi were isolated by using nonsymmetrical
alkynes as coupling partners. However, terminal alkynes could
not react under the standard reaction conditions.
We next focused our attention to the scope of the 2H-
imidazoles (Table 2). Pleasingly, a variety of 2H-imidazoles
reacted smoothly with 2a. The substituents at the ortho-, meta-,
and para-positions of the phenyl ring were all tolerated in the
cascade reaction, providing corresponding products (3da−3ka)
in good to moderate yields. Furthermore, the reaction of
thiophene-functionalized 2H-imidazole exhibited good efficiency
a
Reaction conditions: unless otherwise specified, 1 (0.05 mmol,
1 equiv), 2 (1.2 equiv), [RuCl2(p-cymene)]2 (5 mol %), Cu(OTf)2
(1 equiv), CF3COOAg (1 equiv), 1-AdCOOH (2 equiv), and TFE
(0.5 mL) at 100 °C for 6−18 h, under air. Isolated yield.
b
c
2 (0.3 mmol). PivOH (2 equiv).
Equipped with a set of optimized conditions (Table 1, entry
14), we explored the scope of the cross-coupling reaction by
B
DOI: 10.1021/acs.orglett.8b02759
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
for coupling with 1a, producing 3la in 69% yield. The
substrates with n-butyl or phenyl groups on the 2H-imidazole
ring also showed good reactivity, delivering various α-ketone-
isoquinolines (3ma and 3na) in moderate yields. Depressingly,
no corresponding aldehyde product 3oa was obtained when
2,2-diethyl-4-phenyl-2H-imidazole (1o) was used.
In order to better illustrate of the α-substituted carbonyl
isoquinolines, further transformations of the units were
conducted in Scheme 3.11 Surprisingly, the versatile 3aa
generate intermediate IV.12a,11 Then, the reduced Ru is
reoxidized to regenerate active species Ru(II) participating in
the next catalytic cycle. Finally, the C−N bond cleavage and
imide hydrolysis process occurs to afford the annulation
product 3aa.
In summary, we have developed a new ruthenium(II)-catalyzed
cascade reaction of 2H-imidazoles with alkynes, which involves
direct C−H activation/cyclization/hydrolysis of imide into
the carbonyl group cascade process by using 2H-imidazole as
a traceless directing group. Furthermore, a broad scope of
α-substituted carbonyl isoquinoline derivatives have been
synthesized which could be applied to the concise synthesis
of related complex molecules. Further studies of synthetic
applications are under investigation in our laboratory.
Scheme 3. Synthetic Applications of the Corresponding
Products
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02759.
Experimental procedures, structural proofs, and NMR
spectra of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dongl@scu.edu.cn.
ORCID
Lin Dong: 0000-0002-8004-821X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the NSFC
(21572138).
■
Scheme 4. Plausible Reaction Mechanism
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Org. Lett. XXXX, XXX, XXX−XXX