Construction of C(sp2)-X (X = Br, Cl) Bonds through a Copper-Catalyzed Atom-Transfer Radical Process: Application for the 1,4-Difunctionalization of Isoquinolinium Salts

Article abstract of DOI:10.1021/acs.orglett.7b03751

A highly efficient Cu-catalyzed 1,4-difunctionalization of isoquinolinium salts was developed with ether and X^- (X = Br, Cl) as the halogen source under mild conditions. This transformation involves the combination of oxidative coupling and copper-catalyzed halogen atom-transfer radical processes. This method not only provides an efficient way to prepare various substituted azaarenes but also achieves the selective construction of C(sp²)-X (X = Br, Cl) bonds from a halogen anion and nucleophilic carbon atom via a free-radical process.

Full text of DOI:10.1021/acs.orglett.7b03751

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of C(sp2)−X (X = Br, Cl) Bonds through a Copper-
Catalyzed Atom-Transfer Radical Process: Application for the 1,4-
Difunctionalization of Isoquinolinium Salts
Qiu Sun, Yuan-Yuan Zhang, Jing Sun, Ying Han, Xiaodong Jia, and Chao-Guo Yan*
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, China
S
* Supporting Information
ABSTRACT: A highly efficient Cu-catalyzed 1,4-difunctionalization of isoquinolinium salts was developed with ether and X− (X
= Br, Cl) as the halogen source under mild conditions. This transformation involves the combination of oxidative coupling and
copper-catalyzed halogen atom-transfer radical processes. This method not only provides an efficient way to prepare various
substituted azaarenes but also achieves the selective construction of C(sp2)−X (X = Br, Cl) bonds from a halogen anion and
nucleophilic carbon atom via a free-radical process.
Scheme 1. Introduction
he direct C−H functionalization of N-heterocycles, such as
Tisoquinolines (including the corresponding isoquinolinium
salts), has emerged as an efficient and robust alternative to
traditional synthetic strategies.1 Due to the low reactivity of the π-
electron-deficient pyridine skeleton, functionalization on the
pyridine ring is a great challenge.2 Although unusual, examples of
free-radical processes have provided the possibility of mono-
functionalization of isoquinolines, such as the Minisci reac-
tion,3−5 C-1 oxidation reaction,6 and C-4 nucleophilic sub-
stitution reaction.7 1,4-Difunctionalization of isoquinolines is a
highatom-andstep-efficientstrategytosimultaneouslyintroduce
two functional groups onto unsaturated aromatic rings; however,
examples remained limited. Recently, Kapur and co-workers
reported the synthesis of 1,4-disubstituted isoquinolines and
dihydroisoquinolines by two steps via a heteroatom-guided
electrophilic palladation reaction.8
On the other hand, alkenyl halides have served as versatile
synthesis precursors in different cross-coupling reactions.9 The
introduction of a carbon−halogen bond at the C-4-position of
isoquinoline derivatives provides an important application
prospect in organic synthesis. Conventionally, the construction
ofcarbon−halogen bonds involvesa substitutionprocess through
polar reactions (Scheme 1, path a and b). The ideal reagents for
this transformation derive from nucleophilic halogen sources,
such as Cl and Br anions, because naturally occurring halogens
exist almost exclusively as halogen anion equivalents. However,
owing to the nucleophilic nature of the C-4 position of
isoquinolinium salts, introduction of halogens by polar reactions
is extremely difficult. Alternatively, free-radical coupling can also
be utilized to construct carbon−halogen bonds (Scheme 1, path
c), albeit the coupling of these two transient radical intermediates
is not efficient. The Cu-catalyzed atom-transfer process is an
efficient method to construct carbon−halogen bonds, in which
free-radical intermediates react withCucomplexes, furnishingthe
desired halogenated products (Scheme 1, path d).10,11 Although
this reaction has a number of advantages, halogenated substrates
are needed to generate the C-centered radical intermediate by the
homolytic cleavage of the carbon−halogen bond. Therefore, we
hypothesized that we could generate a free radical by radical C−H
activation,1k,12 which upon adding to isoquinolinium salts would
afford a radical center on the C-4 position. Therefore, a halogen
anion could be used as a halogen source to construct carbon−
halogen bonds through a Cu-catalyzed atom-transfer reaction.
Received: December 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Theα-oxyalkyl radicaladdition reactiontoheteroaromatics has
attracted much attention,3−5,13 and the addition of an α-oxyalkyl
radical to isoquinolinium salts might be a practical method to
form a C-4 radical by tautomerism from the corresponding cation
radical of an enamine. With particular interest in free-radical-
initiated processes, we envision that the 1,4-difunctionalization of
isoquinolinium salts could be realized by the combination of a
radical addition reaction and atom-transfer radical process.
Herein, we report the free-radical C-1 alkylation and C-4
halogenation of isoquinolinium salts with ethers and a readily
available halogen anion.
Scheme 2. Scope of Isoquinolinium Salts
To test the above hypothesis, we focused the initial studies on
the reaction of 2-benzylisoquinolin-2-ium bromide (1a) and
benzo[d][1,3]dioxole (2a) with 1 equiv of tert-butyl hydro-
peroxide (TBHP) and 5 mol % Cu(acac)2 at 60 °C for 1 h (Table
1, entry 1). The desired C-1 alkylation and C-4 halogenation
a
a
Table 1. Modification of the Typical Reaction Conditions
Reaction conditions: 1 (0.3 mmol), 2a (3 mmol, 10 equiv), 70%
TBHP in water (3 equiv), and Cu(acac)2 (5 mol %) at room
temperature for 10 min; neat, isolated yield.
benzyl moiety, as substrates bearing both electron-donating (3b−
d, 85%−87%) and electron-withdrawing groups (3e−h, 69%−
80%) worked well with good to excellent yields. Importantly, the
diversity of the products was further increased, as this procedure
allows access to 2-(1-menaphthyl) (3i, 69%), (2-menaphthyl)
(3j, 75%), ethoxycarbonyl methyl (3k, 88%), and methoxycar-
bonyl methyl (3l, 87%) derivatives. Additionally, different
substituents on the isoquinolin core structure 1m, 1o, and 1p
also worked well to generate in 84−92% yields. In particular, this
procedure was not limited to bromine salts; isoquinolinium
chlorides 1n, 1q, and 1r could also be served as a reaction partner
in this reaction, affording 3n, 3q, and 3r in 51−83% yields.
The scope of the ether component of this reaction was also
evaluated, and the results are shown in Scheme 3. As anticipated,
5-chloro and 5-bromo substituted benzo[d][1,3]dioxoles reacted
smoothly under the standard conditions to give the correspond-
ing products 4a and 4b in 72% and 71% yields, respectively.
Notably, both 4a and 4b have no other diastereoisomers;
b
entry
catalyst
oxidant
solvent
temp (°C) yield (%)
c
1
2
3
4
5
6
7
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(OAc)2·H2O
Cu2O
TBHP
free
60
60
rt
rt
rt
rt
rt
rt
rt
rt
rt
42
TBHP
TBHP
TBHP
TBHP
DTBP
DCP
free
67
free
86
free
55
free
10
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
−
free
trace
trace
75
free
d
8
d
TBHP
TBHP
TBHP
−
CH2Cl2
DMF
free
9
70
10
11
15
Cu(acac)2
free
0
a
Reaction conditions: 1a (0.3 mmol), 2a (3 mmol, 10 equiv), 70%
TBHP in water (3 equiv), catalyst (5 mol %), 10 min. Isolated yield.
b
c
d
1 equiv of TBHP. 2 mL of solvent.
a
Scheme 3. Scope of Ethers
product 3a was obtained in 42% yield. Further screening results
are listed in Table 1. For example, excess oxidant (3 equiv) was
beneficial to obtain a better yield of 3a (67%, entry 2). The best
result (86%) was obtained upon decreasing the reaction
temperature to rt (entry 3), which was due to inhibition of the
side product isoquinolone.6b Among the tested catalysts,
Cu(acac)2 was superior to Cu(OAc)2·H2O (55%) and Cu2O
(10%) (entries 4−5). Notably, the reaction was quite sensitive to
oxidants, and only trace product was detected when other radical
initiators, such as di-tert-butyl peroxide (DTBP) and dicumyl
peroxide (DCP), were chosen (entries 6−7). In addition,
additional solvents, i.e., CH2Cl2 and dimethylformamide
(DMF), were not beneficial in obtaining satisfactory results
(entries 8−9). Control experiments showed that the catalyst and
oxidant critically affected the reaction efficiency. A very low yield
(15%) was obtained in the absence of oxidant or catalyst (entries
10−11). For more details of the screening experiments, see Table
S1 of the Supporting Information.
a
With the optimized reaction conditions in hand, the scope and
limitation of the isoquinolinium salts were studied, as shown in
Scheme 2. Generally, the reaction efficiency was not sensitive to
the electronic properties of the substituents on the aryl ring of the
Reaction conditions: 1a (0.3 mmol), 2 (3 mmol, 10 equiv), 70%
TBHP in water (0.9 mmol, 3 equiv), and Cu(acac)2 (5 mol %) at
room temperature for 10 min; neat, isolated yield. 0 °C for 1 h. The
reaction time was 1 h.
b
c
B
DOI: 10.1021/acs.orglett.7b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
however, the block of 1,3-benzodioxole with 5-Cl/Br substitution
has no symmetry. 1,3-Dioxolane also reacted with 1a to give 4c in
41% yield with a prolonged reaction time of 1 h. However, the
reaction temperature had to be lowered to 0 °C because of the
higher reactivity and instability of the 1,3-dioxole radical
intermediate. Subsequently, some other ethers, such as
tetrahydrofuran, tetrahydropyran, and 2-methyltetrahydrofuran,
also smoothly underwent the reaction under the optimized
conditions with a prolonged reaction time of 1 h, leading to the
desired products 4d−4f in good yields (61−81%) and diastereo-
selectivities ranging from 1 to 1.5:1. Unfortunately, the reaction
wasnotcompatible withdioxaneand diethylether, as<10%yields
were obtained.
Scheme 5. Plausible Reaction Mechanism
Several control experiments were conducted to gain insight
intothistransformation, andtheresultsarecompiledinScheme4.
Scheme 4. Control Experiments
undergoes a deprotonation process to give the difunctional
product 4a.
To demonstrate the utility of this transformation, an
application toward the preparation of synthetic intermediates
was investigated. Isoquinolines are versatile scaffolds in natural
product synthesis.16 Therefore, developing an easy and efficient
synthetic method for the preparation of 4-functionalized
isoquinolines still remains an attractive goal. To this end, a
Suzuki coupling reaction of 3a with (4-methoxyphenyl)boronic
acid 7 proceeded smoothly to generate the corresponding
product 8 in 82% yield (Scheme 6),17 and the structure of 8 was
Scheme 6. Potential Application of this Method
Initially, under the standard conditions, 3 equiv of 2,2,6,6-
tetramethyl-1-piperidinyloxyl (TEMPO) were added into the
reaction mixture. The reaction was totally inhibited, and no
desired product 4d was detected. The radical adducts 5 and 6d
were determined by HRMS [m/z 228.1963 (calcd for
[C14H25NO2 + H]+, 228.1964)] and E [m/z 455.2868 (calcd
for [C29H37N2O2]+, 455.2850)] (Scheme 3a), which implied that
a radical process was involved in this transformation (for more
control experiments with TEMPO existence, see Supporting
Information.). Next, the bromine source of the reaction was
investigated. As shown in Scheme 3b, NBS was used as the only
bromine source to react with 2-benzylisoquinolin-2-ium
tetrafluoroborate (1a′) and tetrahydrofuran (THF) under the
standard conditions; the desired product 4d was not obtained.
Alternatively, with NaBr, 4d was successfully generated in 65%
yield, which strongly implied the bromide anion was necessary for
this transformation.
unambiguously confirmed by X-ray diffraction (CCDC
1584285). Therefore, the introduction of a bromo substituent
at the 4-position offers a different possibility for the synthesis of 4-
position functionalized isoquinolines.
In conclusion, we developed the efficient and practical Cu-
catalyzed1,4-difunctionalizationofisoquinoliniumsaltsinvolving
the combination of oxidative coupling and halogen atom-transfer
radical processes under fairly mild conditions. This reaction not
only provides an efficient method to prepare various substituted
azaarenes but also achieves the selective construction of C−X (X
= Br, Cl) bonds from a halogen anion and nucleophilic carbon
atom. Additionally, the application of the C−X bond of the
product was studied in a Suzuki cross-coupling reaction. This
method may open a new route for the activation of the C−H
bonds of isoquinolines to design new reactions. Further
investigation of this strategy, focusing on the functionalization
of other azaarene compounds via a free-radical process, is
underway in our laboratory.
Basedontheaboveresultsandpreviouslyreportedreactions,5 a
plausible reaction mechanism was proposed (Scheme 5). First,
the initial Cu-catalyzed homolytic decomposition of TBHP
generates radical intermediates A and B.14 Both of the radical
species then abstract a hydrogen from the 2-position of THF to
give the nucleophilic radical C, which preferentially adds to the C-
1 position of 2-benzylisoquinolin-2-ium bromide, leading to the
electrophilic radial cation D. The resonance structure of
intermediate D is E. Then, Cu complexes mediate an atom-
transfer radical reaction to give F.10a,15 Finally, intermediate F
C
DOI: 10.1021/acs.orglett.7b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03751.
■
S
Experimental procedures, analytical data, and copies of the
1H, 13C NMR and 19F NMR spectra (PDF)
Accession Codes
CCDC 1584285 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cgyan@yzu.edu.cn.
ORCID
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Xiaodong Jia: 0000-0002-0120-8255
Chao-Guo Yan: 0000-0002-2777-9582
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21572196), the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions for financial
support (No. BK 2013016), and the China Postdoctoral Science
Foundation (No. 2017M621831). The Analytical Center of
Yangzhou University is acknowledged for analytical assistance.
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