Synthesis of 4-Iodoisoquinolin-1(2 H)-ones by a Dirhodium(II)-Catalyzed 1,4-Bisfunctionalization of Isoquinolinium Iodide Salts

Article abstract of DOI:10.1021/acs.orglett.8b03614

An efficient Rh₂(II,II)-catalyzed reaction has been developed under mild conditions. This synthetic method proceeds through iodination/oxidation of readily available isoquinolinium iodide salts under aerobic conditions with good to excellent yields. 4-Iodoisoquinolin-1(2H)-ones are important building blocks for biologically and medicinally important compounds. The developed methodology was applied to the gram-scale synthesis of a key intermediate in the synthesis of the CRTH2 antagonist CRA-680.

Full text of DOI:10.1021/acs.orglett.8b03614

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 4‑Iodoisoquinolin-1(2H)‑ones by a Dirhodium(II)-
Catalyzed 1,4-Bisfunctionalization of Isoquinolinium Iodide Salts
Zaixiang Fang, Yi Wang, and Yuanhua Wang*
College of Chemistry, Sichuan University, Chengdu 610064, P.R. China
S
* Supporting Information
ABSTRACT: An efficient Rh2(II,II)-catalyzed reaction has been
developed under mild conditions. This synthetic method proceeds
through iodination/oxidation of readily available isoquinolinium
iodide salts under aerobic conditions with good to excellent yields.
4-Iodoisoquinolin-1(2H)-ones are important building blocks for
biologically and medicinally important compounds. The developed
methodology was applied to the gram-scale synthesis of a key intermediate in the synthesis of the CRTH2 antagonist CRA-680.
soquinolin-1-(2H)-ones are privileged structural motifs that
Scheme 2. Representative Recent Examples of the Direct
Oxidation of Isoquinolinium Salts to Isoquinolin-1-(2H)-
ones
I
are ubiquitous in natural and bioactive compounds, such as
thalifoline, rosettacin, etc. (Scheme 1).1 Owing to their
Scheme 1. Biologically Active Natural Products and Drug
Candidates Containing the Isoquinolin-1-(2H)-one Motif
important biological activities, including as antidepressant,
antiulcer, and antihypertensive agents, the synthesis of
isoquinolin-1(2H)-ones and their amide analogues has
attracted considerable interest, and a number of synthetic
methods have been developed over the past few years.2 Among
the many reported effective synthetic approaches, the direct
oxidation of easily prepared isoquinolinium salts3a,b to
isoquinolin-1-(2H)-ones is a convenient and efficient meth-
od.3c,d The traditional oxidation method requires excess
K3Fe(CN)6 as the oxidant, resulting in a large amount of
harmful K4Fe(CN)6 as waste.4 Other approaches include
copper-, iodine-, or phosphite-catalyzed oxidative functionali-
zations of isoquinolines leading to isoquinolones.5 Recently,
several elegant methods have been reported (Scheme 2). Fu
and co-workers reported a visible-light-mediated radical
catalyst and air as the sole oxidant (Scheme 2b).6 Huang et
al. described a carbene-catalyzed aerobic oxidation of
isoquinolinium salts to isoquinolones (Scheme 2c).7 Notably,
isoquinolin-1(2H)-ones are also frequently used as scaffolds in
medicinal chemistry (Scheme 1).8 For example, lead
compounds containing isoquinolin-1-(2H)-ones are used in
the treatment of asthma and tumors as depicted in Scheme
1.8a,b
Received: November 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In the discovery and development of drugs or drug
candidates, it is highly desirable to develop important synthetic
blocks on which the pharmacophore can be efficiently
constructed. Vinyl iodides are versatile synthons that are
widely used in highly effective metal-catalyzed cross-coupling
reactions because a weaker carbon−iodine bond is more
reactive, facilitating the oxidative addition better than aryl
bromides and aryl chlorides.9
Table 1. Optimization of Conditions for Oxidation and
Iodination of N-Methylisoquinolinium Salts
a
b
entry
solvent
catalyst
yield (%)
Thus, iodine-functionalized isoquinolin-1-(2H)-one deriva-
tives would be ideal building blocks in biomedical research as
they are effective coupling partners. A typical example is the 4-
iodoisoquinolin-1-(2H)-ones, which are used in the synthesis
of a series of CRTH2 antagonists as key synthetic
intermediates (Scheme 1).8a Herein, as part of our continuing
studies of one-electron oxidation reactions catalyzed by
Rh2(II,II) complexes,10 we report an efficient, one-step
formation of 4-iodoisoquinolin-1-(2H)-ones from a readily
available isoquinolinium iodide salt employing Rh2(II,II) and
acetoxybenziodoxolone (IBA-OAc)11 with ambient air as the
oxidant. During our studies on Rh2(II,II)-catalyzed azidation
reactions with azidobenziodoxolone (IBA-N3) reagents,11
small amounts of substituted isoquinolones were detected
when N-alkylisoquinolin salts were used as substrates. This
observation led to the discovery that the Rh2(II,II) complex
combined with IBA-OAc catalyzes the difunctionalization of
isoquinolines12 to form 4-iodoisoquinolin-1-(2H)-ones in one
step. The studies to optimization this reaction began with a
solvent screening using N-methylisoquinolin-2-ium iodide (1a)
as the substrate. Initially, considering the water solubility of
alkylisoquinolin salts, mixed solvents such as methanol
(MeOH)/H2O, DCE/H2O, and dimethyl carbonate
(DMC)/H2O were used, and MeOH/H2O gave better yields
(Table 1, entries 1−4). Further investigations revealed that the
yields of product 2a were greatly improved to 85% when pure
MeOH was applied as the solvent (Table 1, entry 5).
Therefore, other alcohol solvents were also examined, and
the results were inferior to that achieved with MeOH (Table 1,
entries 6 and 7). It is worth mentioning that a large amount of
iodine was observed to stick on the walls of the reaction tube
when hexafluoroisopropanol (HFIP) was used as the solvent.
We reason that the iodine was insoluble in the HFIP and
precipitated on the tube wall, which led to the poor yield of 2a.
This observation suggested that iodine may be generated and
be involved in this reaction system. It was noted the
isoquinolinium bromide salt cannot give the desired product
2a. Next, the screening of the reaction temperature indicated
that 50 °C was optimal (Table 1, entries 8 and 9). Other
hypervalent iodine reagents were also investigated, and 1-
hydroxy-3-oxobenziodoxole (IBA-OH),11 which is structurally
similar to IBA-OAc, resulted in 73% yield of 2a, while
PhI(OAc)2 gave poor results (Table 1, entries 10 and 11).
Decreasing the amount of IBA-OAc to 0.8 mmol lowered the
yield of 2a to 49%, while increasing the amount of IBA-OAc
had little effect on the yield of 2a (Table 1, entries 12 and 13).
For comparison, other Rh2(II,II) complexes were evaluated in
the reaction. By replacing Rh2(esp)2 with common Rh2(OAc)4,
the reaction occurred with only 14% yield of 2a (Table 1, entry
15). The catalytic effect of Rh2(OPiv)4 is similar to that of
Rh2(esp)2 at 1 mol % catalyst loading, which leads to 86% yield
of 2a (Table 1, entry 16). However, when the catalyst loading
was reduced, the efficiency of Rh2(OPiv)4 gradually became
lower than that of Rh2(esp)2. When the loading of Rh2(OPiv)4
was reduced to 0.3 mol %, the yield of the reaction dropped
1
2
3
4
5
6
7
MeOH/H2O (v/v = 3/1)
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
none
Rh2(OAc)4
Rh2(OPiv)4
Rh2(esp)2
Rh2(OPiv)4
Rh2(esp)2
Rh2(OPiv)4
Cu(acac)2
Co(OAc)2
Rh(Cp*)Cl2
52
46
48
26
85
72
trace
61
82
8
DCE/H2O (v/v = 3/1)
DMC/H2O (v/v = 3/1)
THF/H2O (v/v = 3/1)
MeOH
EtOH
HFIP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
c
8
9
d
e
10
11
12
13
14
15
16
17
18
19
20
21
22
f
73
49
82
g
h
complex
14
86
86
82
78
51
49
43
trace
i
i
j
j
MeOH
MeOH
MeOH
MeOH
k
k
23
a
Reactions were performed by using 1a (0.53 mmol), IBA-OAc (1.06
b
mmol), solvent (2 mL), and catalyst (1.0 mol %) at 50 °C. Yield
c
after column chromatography. The reaction temperature was 25 °C.
d
e
The reaction temperature was 40 °C. PhI(OAc)2 (1.06 mmol) was
f
g
used instead. IBA-OH (1.06 mmol) was used instead. IBA-OAc (0.8
h
i
mmol) was used. IBA-OAc (1.33 mmol) was used. 0.5 mol % of
catalyst was used. 0.3 mol % of catalyst was used. 5 mol % of catalyst
was used. esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropanoate
j
k
significantly (Table 1, entry 20). As described in previous
reports, the performance of Rh2(II,II) complexes in the
oxidation reaction was related to its structural stability.
Rh2(esp)2, with its characteristic chelating structure, shows
high stability and resists degradation during reactions.10,13
Other metal catalysts, such as Cu(acac)2 and Co(OAc)2, were
less efficient and gave inferior yields (Table 1, entries 21 and
22). The Rh(III) catalyst only gave a trace amount of desired
compound 2a (Table 1, entry 23). Thus, 0.5 mol % of
Rh2(esp)2 was selected as the optimal catalyst loading.
Next, with the optimized conditions in hand, we extensively
expanded the scope of substrates 1. The various N-
methylisoquinolinium salts bearing different substituents on
the aromatic ring were applied in the reaction (Scheme 3). It
was found that the substrates 1 with electron-donating and
electron-withdrawing groups at the C-6 and C-7 positions all
gave moderate to high yields of desired products 2b−f.
Functionalities including amide, ester, halogen, and aromatic
groups were well tolerated. However, the efficiency of the
reaction was significantly affected by the position of the
substituents on 1. Substrates 1 with electron-withdrawing
substituents gave higher yields than those with electron-
donating groups. For example, with a methyl ester group on
B
DOI: 10.1021/acs.orglett.8b03614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for the Oxidation and Iodine of
N-Methylisoquinolinium Salts
Scheme 4. Substrate Scope for Oxidation and Iodination of
N-Alkylisoquinolinium Salts
a
a
a
Reactions were performed by using 3 (0.8 mmol), IBA-OAc (1.6
mmol), CH3OH (3 mL), and Rh2(esp)2 (0.5 mol %) at 50 °C. Yield
b
after column chromatography. Rh2(esp)2 (1.0 mol %) was used.
a
c
Reactions were performed by using 1 (0.8 mmol), IBA-OAc (1.6
IBA-OAc (3.2 mmol) was used.
mmol), CH3OH (3 mL), and Rh2(esp)2 (0.5 mol %) at 50 °C. Yield
after column chromatography. Rh2(esp)2 (1.0 mol %) was used.
b
hydroxyiodoethane-substituted 3p is used as the substrate, the
o-iodobenzoic acid generated in the reaction from IBA-OAc
undergoes an esterification reaction with the hydroxyl group to
give 4p in 43% yield.
To explore the synthetic practicality of this transformation, a
gram-scale reaction was conducted to prepare 4e, which is a
key intermediate for the synthesis of the CRTH2 antagonist
CRA-680 (Scheme 5).8a The reaction showed good perform-
ance, smoothly giving 85% yield of 4e from 3e.
Next, we conducted a number of experiments to elucidate
the reaction mechanism (Scheme 6). Dioxygen is the co-
oxidant in the reaction, and this was confirmed by the
nitrogen-protected experiment (Scheme 6, eqs 1 and 2). Under
a nitrogen atmosphere, 1a gave a trace amount of product 2a
and was primarily transformed into 4-iodoisoquinoline 5. After
the C-6 position, the yield of product 2f reached 98%, while
acetylamino (NHAc) group substituted 1e gave product 2e in
only 50% yield. Products 2g−o were obtained in good yields
when various halogenated substrates 1g−j as well as aryl
substituted substrates 1k−o were applied. Notably, products
2g−j with halogen substituents are attractive for further
synthetic elaboration. It is worth mentioning that substrates
1p−s with substituents on the C-5 and C-8 positions resulted
in complex reaction mixtures. We reason that steric effects may
have caused the reaction to fail. Next, isoquinoline salts with
different N-substituents were synthesized to extend the scope
of the procedure (Scheme 4). Substrates with linear and
branched aliphatic substituents (3a−f) gave 4a−f in good
yields of 84−94%. Product 4h, in which the N-substituent
contained a chloride, can be further derivatized regardless of
the moderate yield. Substrates 3i−k and 3m−n, which were
highly susceptible to benzylic oxidation under standard
conditions due to the presence of benzyl groups, still gave
desired products 4i−k and 4m−n in satisfactory yields when
the catalyst loading was increased to 1.0 mol %. N-Allyl-
substituted substrate 3l resulted in a complicated mixture at
the end of the reaction, and only a 24% yield of 4l was
obtained after silica gel chromatography. The low yield of 4l
was attributed to the high reactivity of the double bond, which
allowed it to readily form unidentified byproducts. When two
N-substituted isoquinoline derivatives were connected by an
alkyl linker, dimeric 4-iodoisoquinolin-1-(2H)-one (4o) was
obtained successfully. It is interesting to note that when 1-
Scheme 5. Gram-Scale Experiment
C
DOI: 10.1021/acs.orglett.8b03614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Control Experiments
Scheme 7. Proposed Mechanism
dioxygen in air to form peroxide 16. After the methoxy group
leaves and cleavage of the O−O bond, product 2a is obtained
with the help of the iodide accompanying dioxygen and iodine
formation.6
In summary, we have developed a Rh2(II,II)-catalyzed one-
pot reaction starting from readily accessible isoquinoline iodide
salts to efficiently prepare 4-iodoisoquinolones, which are
important building blocks in the synthesis of lead compounds
in drug discovery. Mechanistic investigations revealed that this
methodology proceeds through an iodine substitution with
molecular iodine generated in situ and a radical-mediated
aerobic oxidation. Further mechanistic studies and application
of various hypervalent iodine reagents in other Rh2(II,II)-
catalyzed reaction systems are currently underway.
the addition of the free-radical inhibitors 2,6-di-tert-butyl-4-
methylphenol (BHT) or 4-methoxyphenol (MEHQ) under
the standard reaction conditions, only a trace of 2a was
detected, which indicated a free-radical reaction mechanism is
active (Scheme 6, eq 3). In addition, the reaction still gave 5 as
the main product. As mentioned above, molecular iodine was
generated in the reaction. Therefore, the formation of 5
indicated that the substrate may be more susceptible to
substitution with iodine. Further studies revealed that the
reaction rate of the iodination was faster than that of the
oxidation. If the oxidation occurred first, bifunctional alkene
product 7 was obtained rather than product 2a (Scheme 6, eq
4). 4-Phenyl-substituted substrate 8 readily gave oxidized
isoquinoline product 9 under standard conditions without
interference from the iodide ion (Scheme 6, eq 5), suggesting
the iodination and oxidation are two independent processes
occurring in the reaction system.
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.8b03614.
Additional experimental procedures and spectroscopic
data for all new compounds are supplied (PDF)
On the basis of the results of these experiments and previous
reports of the oxidation of isoquinoline,5−7 a plausible
mechanism is proposed (Scheme 7). IBA-OAc first reacts
with iodide ions of 1a to produce molecular iodine through
redox reactions14 and isoquinolinium cation 10. After that, the
nucleophilic addition of MeOH to 10 generates enamine
intermediate 11. Then, the 11 rapidly reacts with iodine to
form 4-iodo-substituted isoquinolinium 12, which undergoes 1,
4-elimination to form 13.15 The liberation of the bound anion
to generate isoquinolinium cation 10 is key to the reaction
since I2 reacted with isoquinolinium iodide or bromide salt
under reaction conditions cannot give the iodine product 5. At
the same time, Rh2(esp)2 undergoes one-electron oxidation by
IBA-OAc to give Rh2(esp)2OAc.10a Subsequently, the
nucleophilic addition of MeOH to 13 lead to hemiaminal-
type intermediate 14. Rh2(esp)2OAc then abstracts a hydrogen
atom from 14 to form radical 15, which is captured by the
Accession Codes
CCDC 1870347 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: yhwang@scu.edu.cn.
ORCID
Yuanhua Wang: 0000-0003-0514-6976
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b03614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We are grateful for the financial support provided by National
Natural Science Foundation of China (21272162).
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