I2/TBHP mediated multiple C[sbnd]H bonds functionalization of azaarenes with methylarenes to synthesize iodoisoquinolinones via iodination/N-benzylation/amidation sequence

Article abstract of DOI:10.1016/j.tetlet.2019.151328

An oxidative multi-functionalization of azaarenes with benzylic C[sbnd]H bonds of methylarenes via iodination/N-benzylation/amidation cascade, to produce N-benzyl-4-iodoisoquinolin-1(2H)-ones and N-benzyl-3-iodoquinolin-2(1H)-ones is developed. The molecular iodine plays a triple role in activating benzylic sp³ C[sbnd]H bond of methylbenzenes, accelerating the oxidation process and serving as iodination reagent. This reaction utilizes cheap and readily available azaarenes and methylarenes as starting materials and proceeds under metal-free conditions to construct C-I, C[sbnd]N and C[dbnd]O bonds consecutively and afford iodo(iso)quinolinones efficiently.

Full text of DOI:10.1016/j.tetlet.2019.151328

Journal Pre-proofs
I2/TBHP mediated multiple C-H bonds functionalization of azaarenes with
methylarenes to synthesize iodoisoquinolinones via iodination/N-benzylation/
amidation sequence
Wen-Kun Luo, Cong-Ling Xu, Luo Yang
PII:
S0040-4039(19)31115-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151328
TETL 151328
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 September 2019
18 October 2019
24 October 2019
Please cite this article as: Luo, W-K., Xu, C-L., Yang, L., I /TBHP mediated multiple C-H bonds functionalization
2
of azaarenes with methylarenes to synthesize iodoisoquinolinones via iodination/N-benzylation/ amidation
sequence, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151328
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1
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I2/TBHP mediated multiple C-H bonds
functionalization of azaarenes with
methylarenes to synthesize
Leave this area blank for abstract info.
iodoisoquinolinones via iodination/N-
benzylation/amidation sequence
Wen-Kun Luo, Cong-Ling Xu and Luo Yang*
I
I2 (0.45 equiv. )
TBHP (3.5 equiv.)
R
R
H
+
N
20 oC, 6 h
N
1
R'
R'
O
H
3
2


Metal-free sp and dual sp C-H functionalization for C-I, C-N and C=O bonds construction
Effective iodination/N-alkylation/amidation cascade reaction

1
Tetrahedron Letters
journal homepage: www.elsevier.com
I2/TBHP mediated multiple C-H bonds functionalization of azaarenes with
methylarenes to synthesize iodoisoquinolinones via iodination/N-benzylation/
amidation sequence
Wen-Kun Luo, Cong-Ling Xu and Luo Yang*
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan University, Hunan 411105, PR China
E-mail: yangluo@xtu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
An oxidative multi-functionalization of azaarenes with benzylic C-H bonds of methylarenes via
iodination/N-benzylation/amidation cascade, to produce N-benzyl-4-iodoisoquinolin-1(2H)-ones
Received in revised form
Accepted
Available online
and N-benzyl-3-iodoquinolin-2(1H)-ones is developed. The molecular iodine plays a triple role in
3
activating benzylic sp C-H bond of methylbenzenes, accelerating the oxidation process and
serving as iodination reagent. This reaction utilizes cheap and readily available azaarenes and
methylarenes as starting materials and proceeds under metal-free conditions to construct C-I, C-
N and C=O bonds consecutively and afford iodo(iso)quinolinones efficiently.
Keywords:
iodination
2
009 Elsevier Ltd. All rights reserved.
benzylation
amidation
C-H bond functionalization

2
Introduction
The isoquinolin-1(2H)-one as a highly important structural subunit widely exists in plentiful natural
[1]
products and potent pharmaceuticals. The fascinating biological profiles of these compounds have stimulated
researchers to develop various methods for the synthesis of isoquinolin-1(2H)-ones and their structural
[2]
analogues. However, most of these transformations over-relied on the expensive noble metal catalysts and
[
3]
elaborately designed substrates, such as iodocycliaztion of ortho-alkynylbenzamides,
transition-metal
[4]
catalyzed coupling and cyclization of ortho-halogenated benzamides with alkynes or ketones, and directed
[5]
ortho C-H activation and annulation of N-substituted benzamides with alkynes. Over the past years, the
synthesis of N-benzyl isoquinolin-1(2H)-ones and their analogues has attracted considerable interest, and a
number of synthetic methods have been developed. These methods consist of two main categories, which
applied isoquinolinium salts or isoquinolines as starting materials, respectively. From the isoquinolinium salts
to synthesis of N-benzyl isoquinolin-1(2H)-ones (Scheme 1a), the traditional oxidation method reported by
[6a]
Arakawa
amount of harmful K
with Eosin Y as the photo catalyst and air as the sole oxidant. Huang and co-workers described a carbene-
requires excess K
3
Fe(CN)
6
as the oxidant in a strong alkaline atmosphere, resulting in a large
[6b]
4
Fe(CN)
6
as waste. Later on, Fu
reported a visible light-mediated aerobic oxidation
[6c]
[6d]
catalyzed reactions with ambient air as the oxidant and oxygen source. Very recently, Wang
developed a
Rh-catalyzed one-pot reaction starting from isoquinolines iodide salts to prepare 4-iodoisoquinolones with
IBA-OAc as oxidant (Scheme 1a). On the other hand, only two examples reported from the un-functionalized
isoquinolines to synthesis of N-benzyl isoquinolin-1(2H)-ones (Scheme 1b). One of them was developed in
[
6e]
our laboratory
using iodine-catalyzed oxidative functionalization of isoquinolines with methylarenes via
[6f]
N-benzylation/amidation cascade, which was later achieved by Yan
utilizing Cu/DTBP combination
through a similar pathway. Considering the synthetic cost and efficiency, constructing the isoquinolin-1(2H)-
one motif from cheap and readily available starting materials is highly expected.
2
Meanwhile, the catalytic system of I /TBHP is environmentally friendly strategy for various oxidation,
especially for radical-type transformations, due to its metal-free conditions and with tert-butyl alcohol as the
[13]
byproduct (derived from the oxidant used) . Consecutive multiple C-H bonds functionalization for C-C and
C-X bonds formation is also an ideal choice, which is atom-economical and avoids time-consuming
[
7]
[6e]
protection/deprotection manipulation and isolation of intermediates. In our previous work , a catalytic
3
amount of iodine played a crucial role in activating the benzylic sp C-H bond to provide benzylic iodide for
the subsequent transformation. Unexpectedly, while increasing the loading of iodine from 5 to 20 mol%, the
yield of isoquinolin-1(2H)-one dropped and a byproduct was isolated and characterized as 4-iodoisoquinolin-
1
(2H)-one (Scheme 1c), which should be an important structural motif for the synthesis of other 4-
functionalized isoquinolin-1(2H)-one considering various transformations based on aryl iodides, especially
for diversity-oriented synthesis. Thus, we reported herein an efficient iodine/TBHP mediated construction of
4
-iodoisoquinolin-1(2H)-ones with readily available isoquinolines and methylarenes as starting materials via
multiple C-H bonds functionalization.

3
(a) Synthesis of N-benzyl isoquinolin-1(2H)-ones from isoquinolinium salts:
O
Arakawa's Work
ref. 6a
N
Ar
K4Fe(CN)6
KOH
N
N
N
Ar
Ar
Ar
Br-
Br-
Fu's Work
ref. 6b
O
O
N
Ar
Eosin Y, hv
air, Cs CO3
2
Huang's Work
ref. 6c
N
N
Ar
Ar
NHC
Br-
air, DBU
Wang's Work
ref. 6d
O
2
Rh (esp)2
N
Ar
I-
IBA-OAc
I
(b) Synthesis of N-benzyl isoquinolin-1(2H)-ones from isoquinoline:
O
Our previous report
ref. 6e
N
cat. I2
TBHP
N
N
Ar
+
+
H
H
Ar
Ar
O
Yan's Work
ref. 6f
N
CuBr
Ar
Ar
DTBP
(
c) Iodine-mediated iodination/N-benzylation/amidation domino reaction
O
This work
N
0.45 equiv. I2
N
+
H
Ar
oxidant
I
Scheme 1. Various pathways for the construction of N-benzyl (iodo)isoquinolin-1(2H)-ones.
Results and discussion
With our previous studies on oxidative benzylic C-H bond transformation[6e, 8a-b] and above considerations
in mind, a concise optimization was carried out with isoquinoline (1a) and toluene (2a) as the substrates for
the cascade reaction. When tert-butyl hydroperoxide (TBHP, 70% aq.) as the oxidant and 0.5 equiv molecular
iodine was added, the targeted 4-iodoisoquinolinone (3a) was isolated in 46% yield. The subsequent screening
on oxidants revealed that both the di-tert-butyl peroxide (DTBP) and hydro peroxide was ineffective, which
was the same as our previous results (entries 2 and 3). Next, considering the instability of aryl iodide under
oxidative environment, the reaction time, the dosage of TBHP and molecular iodine, and the reaction
temperature were evaluated in detail (entries 4-9), which increased the yield of 4-iodoisoquinolinone gradually
from 51% to 77% (see the SI for the detailed optimization).
Table 1. Optimization for the on the cascade reaction[a]
H
I
I2, [O]
+
N
N
Temp.
O
1a
2a
3a
entry [I] (mol %)
[O] (equiv)
Temp (C) Time yield [%] [b]
1
2
I
I
2
2
(50)
(50)
TBHP (3.5)
DTBP (3.5)
120
120
12 h
12 h
46
< 2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
I
I
I
2
2
2
2
2
2
2
2
2
2
(50)
(50)
(50)
(50)
(50)
(60)
(45)
(45)
(45)
(45)
H
2
O
2
(3.5)
120
120
120
120
120
120
120
110
100
90
12 h
8 h
6 h
3 h
6 h
6 h
6 h
6 h
6 h
6 h
0
TBHP (3.5)
TBHP (3.5)
TBHP (3.5)
TBHP (4.0)
TBHP (4.0)
TBHP (4.0)
TBHP (4.0)
TBHP (4.0)
TBHP (4.0)
47
51
40
61
55
66
70
77
68
1
0
1
2
1
1
[
a]
Conditions: 1a (0.4 mmol), iodine (mol%), oxidant (equiv), toluene (0.8 mL) as solvent, reacted at given temperature and time under
air unless otherwise noted.
[b]
Isolated yields of 3a.

4
With the optimized reaction conditions in hand (Table 1, entry 11), we proceeded to investigate the
generality of this multi-functionalization of isoquinoline with benzylic C-H bonds. The substrate scope for the
methylarene moiety is listed in Table 2. Methylarenes bearing electron-donating or withdrawing substituents
were successfully tolerated during the iodination/N-benzylation/amidation cascade to afford the 4-
iodoisoquinolinones in good yields, such as methyl (2b), methoxy (2c), bromo (2d), chloro (2e), fluoro (2f),
methoxycarbonyl (2m) and cyano (2n) groups at the para-position of arenes. Among them, 1-cyano-4-
methylbenzene (2n) gave a lower yield of 49%, which might be caused by the inefficient C-H iodination of
methyl arenes under the reaction conditions (3n). Gratifyingly, no obvious steric hindrance effect for this
cascade reaction could be found when substituent groups were located at ortho or meta-position of arenes,
such as mesitylene (2g), meta-xylene (2j), ortho-xylene (2k) and ortho-bromotoluene (2l). Additionally,
ethylbenzene (2h), 1,2,3,4-tetrahydronaphthalene (2o) and n-propylbenzene (2i) were also reactive in this
cascade reaction, producing the corresponding 4-iodoisoquinolinones in medium to moderate yields.
Table 2. Influence of alkylarenes on the cascade reaction
H
I
4
5 mol% I2
4
equiv TBHP
+
N
00 oC, 6 h
N
1
R
R
O
1a
2a-2o
3a-3o
I
I
I
Me
OMe
N
N
N
O
I
O
O
I
3a, 77%
3b, 64%
3c, 70%
I
F
Br
Cl
N
N
N
O
I
O
I
O
I
3
d, 64%
3e, 65%
3f, 60%
Me
N
3
N
N
Me
O
O
O
I
g, 63%
3h, 71%
3
i, 68%
I
I
Me
N
Br
N
N
Me
O
I
O
I
O
I
3l, 50%
3j, 67%
3k, 65%
CO2Me
CN
N
N
N
O
O
O
3m, 57%
3n, 49%
3o, 40%
Encouraged by the exciting results obtained from the multi-functionalization of isoquinoline with various
alkylarenes, then we focused our attention on the scope of azaarenes (Table 3). As expected, 6-methyl (1b),
6
-tert-butyl (1c) and 6-bromo (1d) substituted isoquinolines turned out to be suitable substrates for this
transformation. To our delight, besides isoquinolines, the optimized reaction conditions can also be applied to
the iodination/N-benzylation/amidation cascade reaction of quinoline (1e), 6-cholroquinoline (1f), and 6-
bromoquinoline (1g) with toluene (3a), albeit the yields were lower than isoquinoline (1a) accompanied by
unidentified by-products. It’s worth noting that for these three quinoline substrates tested, the iodination
[9]
selectively took place at the C3; in contrast, for all of the isoquinolines, the iodination selectively proceeded
[10]
at the C4. This regio selectivity was in accordance with the report by Sun and Wang et. al, where quinoline
and isoquinoline were transformed into iodinated heteroarenes at C3 and C4, respectively, with 2 equiv. of
molecular iodine and TBHP.
Table 3. Influence of azaarenes on the cascade reaction

5
I
H
45 mol% I2
R
R
I
4
equiv TBHP
+
100 oC, 6 h
N
N
N
O
O
or
1
1
1
1
b-1d
e quinoline
6-chloroquinoline
2a
5b-5d
5e-5g
f
g 6-bromoquinoline
I
I
I
tBu
Br
Me
N
O
N
N
O
O
5b, 75%
5c, 67%
5d, 78%
Br
I
I
Cl
I
N
O
N
5
O
N
O
e, 45% (12h)
5f, 54% (9h)
5g, 56% (9h)
To verify the utility of this multi-functionalization method, we further scaled up this cascade reaction of
isoquinoline (1a) and toluene under the optimized conditions, which provided the target 4-iodoisoquinolinone
(3a) and un-iodinated concomitant (4a) in 62% and 25% yields respectively (Scheme 2).
H
I
H
4
5 mol% I2
equiv TBHP
00 oC, 6 h
4
+
+
N
N
N
1
O
O
1a, 8 mmol
2a, 16 mL
3a, 1.79 g, 62%
4a, 25%
Scheme 2. Gram-scale experiment.
During our previous studies on iodine-catalyzed N-benzylation/amidation cascade to synthesize
isoquinolinone (4a) selectively, the mechanistic experiments supported a pathway including: iodination of the
3
benzylic sp C-H bond to provide benzylic iodide, quaternary ammonium salt formation and nucleophilic
addition of TBHP. The reaction conditions of this iodination/N-benzylation/amidation cascade reaction were
almost the same as the previous one, except increasing the dosage of molecular iodine, so we speculated that
the mechanism of this cascade reaction should be similar to the previous one and the iodination can either take
place after the isoquinolinone formation, or in contrast, the azaarene was iodinated first and then N-
benzylation/amidation took place. To determine which sequence reflects the true reaction pathway, several
control experiments were designed and carried out.
First, the isoquinolinone (4a) instead of isoquinoline (1a) as starting material was subjected into this
iodination/N-benzylation/amidation cascade reaction under the optimized conditions with chlorobenzene as
solvent, which failed to provide targeted iodinated product (3a, Scheme 3a). This result proved that
isoquinolinone (4a) could not be iodinated once it has been formed, so that 4a is not the active intermediate in
this reaction. Then, in the absence of toluene, isoquinoline (1a) was iodinated at C4 in chlorobenzene under
the standard conditions to produce 4-iodoisoquinoline (1p) in 16% yield (Scheme 3b). Later, 4-
iodoisoquinoline (1p) as the substrate successfully took part in this cascade reaction (Scheme 3c), which
demonstrated that the C4-iodinated isoquinoline (1p) could continue the subsequent N-benzylation/amidation
steps to provide isoquinolinone (3a) successfully. There’s another possibility that the C4-iodination was
realized after the N-benzylation step but before the amidation step, so isoquinolinium iodide (6) was prepared
2
from isoquinolines and benzyl iodide, and then subjected into the similar reaction but without adding I (since
the iodide salts was used, Scheme 3d). The results revealed that only 50% (28 vs 31%) of the C4 was iodinated
among the isoquinolinone products, so the N-benzylation/iodination/ amidation sequence was less likely.
Overall, the iodination/N-benzylation/amidation sequence was well-supported by the current mechanistic
experiments. It’s worth noting that in this iodination/N-benzylation/amidation cascade reaction, the molecular
3
iodine not only acts as a catalyst to activate the benzylic sp C-H bond of methylbenzenes, but also serves as
iodination reagent.

6
I
4
5 mol% I2
(a)
4 equiv TBHP
N
N
PhCl, 100 oC, 6 h
O
I
O
4a
3a, trace
4
5 mol% I2
equiv TBHP
PhCl, 100 oC, 6 h
4
(b)
N
N
1a
1p, 16%
I
H
I
4
5 mol% I2
4 equiv TBHP
00 oC, 6 h
+
(c)
N
N
1
O
R
O
1
p
2a
3
a, 64%
1a
+
I
Bn
benzene
reflux
0 mol % I2
3
.5 equiv TBHP
(d)
N
N
PhCl, 120 o
C
-
I
6
4a, R = H, 28%
a, R = I, 31%
3
Scheme 3. Mechanistic investigation on the cascade reaction.
Based on the above mechanistic studies and literature reports, [9] a plausible mechanism for this multi-
functionalization of azaarenes via iodination/ N-benzylation/amidation is proposed in Scheme 4, with the
reaction of isoquinoline (1a) and toluene (2a) shown as an example. First, the initial reaction of TBHP with
t
molecular iodine forms BuOI and HOI, which undergoes a homolytic cleavage to produce an iodine radical
and adds to C4 of isoquinoline (1a) to provide a radical intermediate A. The intermediate A would realize re-
aromatization to yield 4-iodoisoquinoline (1p) either by direct hydrogen abstraction or by oxidation to carbon
[
11]
3
cation and deprotonation pathway. On the other hand, the benzylic sp C-H bond iodination reaction occurs
t
via a homolytic attack involving BuOI or HOI to generate benzyl iodide, which reacts with isoquinoline
readily to generate quaternary ammonium salt intermediate B. Subsequently, the nucleophilic addition of
[12a]
TBHP provides hemiaminal-type peroxide C,
which further undergoes O-O bond cleavage to afford
isoquinolinone product (3a). The molecular iodine as the catalyst can be regenerated by the oxidation of
[12, 13]
hydrogen iodide with TBHP.
tBuOOH
+
I2
tBuO
I
+
HO I
tBuOI or HOI
I
I
tBuO• or OH•
N
N
p
N
tBuO• or OH•
tBuOH or H2O
1a
A
1p
B
tBuOI
I
1
H
tBuO•
I
N
I-
tBuOH
I
I
TBHP
N
N
HI
tBuOH
OOBut
O
C
3a
Scheme 4. Plausible mechanism.
Conclusions
In conclusion, we have developed an efficient oxidative functionalization of azaarenes with benzylic C-H
bonds via iodination/N-benzylation/amidation cascade, to produce N-benzyl-4-iodoisoquinolin-1(2H)-ones
and N-benzyl-3-iodoquinolin-2(1H)-ones. This method utilizes cheap and readily available un-functionalized
azaarenes and methylarenes as starting materials and proceeds under metal-free conditions with moderate
yields, avoiding the usage of expensive noble metal catalysts and generation of halide and metal wastes, thus
is a practical method for the construction of iodo(iso)quinolinones.

7
Experimental Section
A general experimental procedure is described as following: an oven-dried reaction vessel was charged with
isoquinoline (1a, 0.4 mmol, 1 equiv.), iodine (0.18 mmol, 45 mol%), toluene (2a, 0.8 mL), TBHP (1.6 mmol,
4
2
equiv, 70% in H O) under air. The vessel was sealed and heated at 100 °C (oil bath temperature) for 6 h.
Afterwards the resulting mixture was cooled to room temperature, transferred to silica gel column directly and
eluted with petroleum ether and ethyl acetate (10:1) to give N-benzyl-4-iodoisoquinolin-1(2H)-one (3a, 111.2
mg) in 77% yield.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (21772168) and the project
of innovation team of the Ministry of Education (IRT_17R90).
Supplementary data
Supplementary data (experimental procedures, detailed optimization, mechanistic studies, compound
characterization and NMR spectra) associated with this article can be found, in the online version, at
https://doi.org/10.1016/
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I2/TBHP mediated multiple C-H bonds
functionalization of azaarenes with
methylarenes to synthesize
Leave this area blank for abstract info.
iodoisoquinolinones via iodination/N-
benzylation/amidation sequence
Wen-Kun Luo, Cong-Ling Xu and Luo Yang*
I
I2 (0.45 equiv. )
TBHP (3.5 equiv.)
R
R
H
+
N
20 oC, 6 h
N
1
R'
R'
O
H
3
2


Metal-free sp and dual sp C-H functionalization for C-I, C-N and C=O bonds construction
Effective iodination/N-alkylation/amidation cascade reaction

9

1
0
3
2



Metal-free sp and dual sp C-H functionalization for C-I, C-N and C=O bonds construction
Effective iodination/N-alkylation/amidation cascade reaction
3
Iodine plays a triple role in sp C-H bond activation, oxidation and as iodination reagent
Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests: