Copper(II) catalyzed heterobenzylic C(sp3)-H activation: Two efficient halogenation methodologies towards heterobenzyl halides

Article abstract of DOI:10.1016/j.tet.2018.02.058

Two practical and simple synthetic methodologies towards various heterobenzyl halides were developed. A series of 2-halomethylquinolines were readily prepared by the one-pot reaction of 2-methylquinolines with CuX (X = I, Br, Cl) and TBHP in CH₃CN. A large variety of heterobenzyl iodides, including 2-iodomethylquinolines, 2-iodomethylquinoxalines, 2-iodiomethylbenzooxazole, and 2-iodiomethylbenzothiazole, were efficiently synthesized by one-pot reaction of 2-methylheterocycles with iodine in the presence of CuSO₄·5H₂O in CH₃CN.

Full text of DOI:10.1016/j.tet.2018.02.058

Accepted Manuscript
3
Copper(II) catalyzed heterobenzylic C(sp )-H activation: Two efficient halogenation
methodologies towards heterobenzyl halides
Wen Zhu Bi, Chen Qu, Xiao Lan Chen, Sheng Kai Wei, Ling Bo Qu, Shu Yun Liu, Kai
Sun, Yu Fen Zhao
PII:
S0040-4020(18)30218-7
10.1016/j.tet.2018.02.058
TET 29329
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 November 2017
Revised Date: 13 February 2018
Accepted Date: 23 February 2018
Please cite this article as: Bi WZ, Qu C, Chen XL, Wei SK, Qu LB, Liu SY, Sun K, Zhao YF, Copper(II)
3
catalyzed heterobenzylic C(sp )-H activation: Two efficient halogenation methodologies towards
heterobenzyl halides, Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.058.
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ACCEPTED MANUSCRIPT
Copper(II) catalyzed heterobenzylic C(sp3)-H
activation: two efficient halogenation methodologies
towards heterobenzyl halides
Wen Zhu Bi a,c, Chen Qub, Xiao Lan Chen*,a, Sheng Kai Weia, Ling Bo
Qua, Shu Yun Liua, Kai Suna and Yu Fen Zhaoa,c
Affiliation:
a College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, 450052, China.
b Department of Chemical and Biomolecular Engineering, University of
Notre Dame, Notre Dame, Indiana 46556, United States.
c The Key Laboratory for Chemical Biology of Fujian Province, Xiamen
University, Xiamen, 361005, China.
*Corresponding to: Xiao Lan Chen; Tel: +86-371-67767051, Fax:
+86-371-67767051, E-mail address: chenxl@zzu.edu.cn.
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Abstract
Two practical and simple synthetic methodologies towards various
heterobenzyl halides were developed. A series of 2-halomethylquinolines
were readily prepared by the one-pot reaction of 2-methylquinolines with
CuX (X = I, Br, Cl) and TBHP in CH3CN. A large variety of heterobenzyl
iodides, including 2-iodomethylquinolines, 2-iodomethylquinoxalines,
2-iodiomethylbenzooxazole, and 2-iodiomethylbenzothiazole, were
efficiently synthesized by one-pot reaction of 2-methylheterocycles with
iodine in the presence of CuSO4·5H2O in CH3CN.
Keywords: Copper(II) catalyst; 2-halomethylazaarenes; C(sp3)-H
halogenation; one-pot procedure
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1. Introduction
Organic halides are generally applied as crucial synthetic precursors
for organic synthesis. For example, the substitution reactions of organic
halides with various nucleophiles (e.g. cyanide, thiocyanate, azide, amine
etc.) could afford various organic compounds.1 Organic halides are also
indispensable starting reactants in coupling reactions, such as Stille,
Suzuki, Heck, Sonogashira, and Buchwald-Hartwig reactions.2
Meanwhile, organometallic compounds, such as Grignard reagents,
Gilman reagents, are made from organic halides.3 Generally, chloro- or
bromoalkanes can be synthesized by free radical halogenation reaction of
alkanes with chlorine or bromine. In contrast, the direct free radical
iodination of alkanes by iodine is not feasible experimentally because of
its large activation energy of hydrogen atom-abstraction step.4 The
iodination of alkanes is thus especially challenging. As a consequence, in
the past few decades, many efforts have been made for the synthesis of
organoiodides.
Heterocycles are reported in more than 90% of the new synthetic
biologically active compounds.5 Among them, quinolines, oxazoles,
thiazoles and quinoxalines are the most commonly existence skeleton
structure in medicinal and agricultural compounds. Considerable efforts
have been attributed to their synthesis and functionalization over the past
decades.6 It is especially worth mentioning that heterobenzyl halides are
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extremely important synthetic precursors for numerous biologically
important compounds.7 For example, as illustrated in Scheme 1,
heterobenzyl halides, especially 2-halomethylquinolines, have frequently
served as key synthetic building blocks for many clinical drugs,7a-i
luminescence imagings,7j chemosensors,7k-l and numerous other
biologically active heterocyclic compounds.7m Scheme 2 shows four
traditional synthetic methods for some important heterobenzyl halides, in
particular 2-halomethylquinolines. The most traditional method for
2-halomethylquinolines
is
free
radical
halogenation
of
2-methylquinolines with NIS, NBS or NCS, respectively (Scheme 2a).
However, the main drawback is that multi-halogenation is usually
difficult to avoid.7d,7g,8 Scheme 2b shows a multi-step synthetic approach
for some heterobenzyl halides. After oxidation followed by reduction, the
Scheme 1. Various applications of the heterobenzyl halides.
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starting 2-methylazaarenes are initially changed to their corresponding
benzylic alcohols, which then react with SOCl2 or PBr3 to produce the
target heterobenzyl halides.7m,7k,9 Scheme 2c shows a two-step method
reported previously for synthesizing 2-chloromethylquinoline, however,
owing to the formation of equal amount of by-product, the yield is
generally low.7a,10 Scheme 2d shows a widely used cyclization method for
the
synthesis
of
2-chloromethylbenzooxazole
or
2-chloromethylbenzothiazol, however, an additional time-consuming
synthetic procedure is required if one wants to get
2-iodomethylbenzooxazole or 2-iodomethylbenzothiazol.11 Recently,
microwave-assisted
halogenation
for
with
1,2-dicholoethane/1,2-dibromoethane12a
some
heterobenzyl
chlorides/bromides, and PPh3 induced iodination reaction for
2-iodomethylquinolines12b were reported successively, however, some
drawbacks such as harsh or inconvenient reaction conditions, as well as
relative narrow substituent scopes are still waiting to be overcome. Thus,
the development of simple, facile and efficient synthetic methods for
various heterobenzyl halides from readily available reagents is highly
required. Herein, we disclose two practical and simple synthetic
methodologies towards various heterobenzyl halides (Scheme 2e). As
shown in Scheme 2e-I, a series of 2-halomethylquinolines were readily
prepared by the one-pot reaction of 2-methylquinolines with CuX (X = I,
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Br, Cl) and TBHP in CH3CN. Then we developed the second synthetic
methodology as shown in Scheme 2e-II, by which a large variety of
heterobenzyl
iodides,
including
2-iodomethylquinolines,
and
2-iodomethylquinoxalines,
2-iodiomethylbenzooxazole,
2-iodiomethylbenzothiazole, were efficiently synthesized by one-pot
reaction of 2-methylheterocycles direct with iodine in the presence of
CuSO4·5H2O in CH3CN. The remarkable merits of the two synthetic
methodologies include cheap and easily available reactants, high
regioselectivity, a wide scope of products, as well as an efficient one-pot
synthetic procedure.
Scheme 2. Comparison of traditional works with this work.
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2. Results and discussion
We started with establishing the optimal reaction conditions for the first
reaction shown by Scheme 2e-I. The optimal reaction conditions were
screened by using the model reaction of 2-methylquinoline (1a) with CuI
(2a) (Table 1). Initially, the model reaction was carried out in the
presence of various oxidants, such as O2 in air, K2S2O8, TBHP, DTBP or
H2O2. The target compound 3a was obtained in yields of trace, 32%, 43%,
27% and 13%, respectively (entries 1-5). TBHP gave the highest yield of
2-iodomethylquinoline (3a) among all the oxidants tested (entry 3). Then
the amount of TBHP was screened (entries 6-9). It can be seen that a
satisfied yield (81%, entry 8) was obtained as 8 eq. of TBHP was
employed. Following that, a suitable amount of CuI was screened (entries
8, 10-11). The results showed that 1.2 eq. of CuI brought about the best
yield (89%). Subsequently, influences of different solvents on the model
reaction were investigated (entries 10, 12-17). It can be seen that the
reaction did not occur in DMSO and DMF (entries 12-13), however, the
reaction occurred in THF (yield: 59%), p-dioxane (yield: 67%), CH2Cl2
(yield: 57%) and toluene (yield: 17%). Among all the solvents tested,
CH3CN brought the most satisfied yield of 3a (89%, entry 10). The
following investigation on temperature (entries 10, 18-20) and reaction
time (entries 10, 21-24) indicated that the initially used temperature
(70 °C) and reaction time (8 h), as shown by entry 10, were still the best
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choices. Thus, the optimized reaction conditions are: 2-metylquinoline
(0.5 mmol), CuI (1.2 eq.) in the presence of TBHP (8 eq.) at 70 °C for 8 h
(as indicated by entry 10).
Table 1. Optimization of reaction conditionsa
Entry
2a (eq.)
Oxidant (eq.)
Solvent
Temp. (°C)
Time (h) Yield (%)b
1
2
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.2)
CuI (1.4)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
O2 (air)
K2S2O8 (2)
TBHP (2)
DTBP (2)
H2O2 (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
30
50
90
70
70
70
70
8
8
tracec
32
3
8
43
4
8
27
5
8
13
6
TBHP (4)
TBHP (6)
TBHP (8)
TBHP (10)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
8
55
7
8
75
8
8
81
9
8
76
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8
89
8
87
8
n.r.c
n.r.c
59
8
THF
8
p-dioxane
CH2Cl2
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
8
67
8
57
8
17
8
53
8
57
8
87
4
49
6
71
10
12
85
83
aOptimal conditions: 1a (0.5 mmol), 2a (1.0-1.4 eq.), oxidant (2-10 eq.), solvent (2 mL) at
b
c
30-90 °C for 4-12 h. Isolated yields. Detected by TLC. n.r. = no reaction. 70% aqueous
solution of TBHP and 30% aqueous solution of H2O2 were used.
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With the optimal reaction conditions in hand, the other
2-methylquinolines and CuX (X = I, Br, Cl), were then employed to
examine the scope of the reaction (Scheme 3). It can be seen that, under
optimal reaction conditions, various 2-methylquinolines bearing electron
donating group (-CH3, -OCH3, -OCF3) or electron withdrawing groups (-F,
-Cl, -Br, -NO2) reacted well with CuI, giving the corresponding
2-iodiomethylquinoline derivatives 3a-h in good to excellent yields.
Electronic effects were observed in those cases. It can be seen that
2-methylquinolines bearing electron withdrawing groups tended to give
relatively high yields, in which, 2-methylquinoline with the strongest
electron withdrawing nitro group gave the highest yield of 3h. It was
pleased that CuBr and CuCl were well capable of reacting with various
2-methylquinolines,
affording
the
corresponding
2-bromomethylquinolines (3i-m) and 2-cholomethylquinolines (3n-r) in
good to excellent yields.
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Scheme 3. Scope of the halogenation reaction of 2-methylquinolines.
It is especially worth mentioning that after the reaction of
2-methylquinolines and CuI, the organic phase of extraction always
presented a purple color, and the water phase presented a blue color. The
previously reported works6c,13 have already proved that TBHP can oxidize
Cu(I) into Cu(II), and I- into I2. Thus the purple color in organic phase
should be caused by the presence of I2, and the blue color in water phase
indicated the presence of Cu2+. The further starch-iodine test of the
organic phase also gave a positive result. Base on the observations, a
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possible reaction mechanism was thus proposed accordingly as shown in
Scheme 4. Initially, CuI was oxidized by t-BuOOH to produce Cu2+ and I2
(Scheme 4-i). Then the lone pair of electrons on the nitrogen atom in
2-methylquinoline (1) coordinated to Cu2+ to give intermediate 2,13d
which subsequently was deprotonated to yield complex 3. Following that,
I2 started to approach complex 3 in the orientation shown by 4, resulting
in an energetically favorable six-membered ring containing transition
state (4’). After that, a multi-electron rearrangement in the six-membered
ring started to occur, leading to the formation of target
2-iodomethylquinoline (5), together with Cu2+ and I-. Finally, Cu2+
oxidize I- to form I2 and CuI (2Cu2+ + 4I- = 2CuI + I2). Meanwhile, THBP
oxidize CuI to form Cu2+ and I2. The regenerated Cu2+ and I2 were then
reused for another reaction cycle (Scheme 4-ii).
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Scheme 4. Proposed reaction mechanism for the halogenation of
2-methylquinolines.
It was realized that Cu2+ and I2 were in fact real reactants for the
above-mentioned iodination reaction. Thus, we further developed another
methodology towards 2-iodomethylheterocycles using Cu2+ as catalyst
and I2 as the halogen source (Scheme 5).
Scheme 5. A new synthetic method to 2-iodiomethylheterocycles.
We initiated the study by establishing the optimal experimental
conditions using 2-methylquinoline (1a) and I2 as the starting substrates
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as summarized in Table 2. It was pleased to observe that 1a did react with
I2 in the presence of 0.2 eq. of different copper(II) salts, including CuCl2,
CuBr2, Cu(acac)2, CuSO4·5H2O, or Cu(OAc)2·H2O, in CH3CN at 70 °C
for 3 h, giving 4a in different yields (Table 2, entries 1-5). Among those
tested copper(II) salts, CuSO4·5H2O resulted the highest yield of 4a (35%,
entry 4). Following that, the amount of CuSO4·5H2O was investigated
(entries 4 and 6-8). The yield of 4a increased from 35% to 62% as the
amount of CuSO4·5H2O increased from 0.2 eq. to 0.4 eq. (entries 4 and
6-7), and then began to drop a little bit as the amount reached up to 0.5 eq.
(entry 8). The amount of I2 was also surveyed. The yield of 4a increased
from 62% to 83% with the increase of I2 from 0.5 eq. to 0.75 eq. (entries
7 and 9), and then decreased a little bit to 81% as the amount of I2 was
continuously raised (entry 10). Investigation on the influence of various
solvents was subsequently carried out (entries 9 and 11-18). Among all
the solvents tested, including DMF, DMSO, EtOH, p-dioxane, toluene,
THF, CH2Cl2 and DCE, CH3CN still brought about the highest yield
(83%) (entry 9). The influence of temperature on the reaction was further
investigated as shown in entries 9, 19-21. The yield of 4a increased
dramatically from 27% to 83% as the temperature was raised from 30 °C
to 70 °C, and then decreased to 79% as the temperature was continuously
raised to 90 °C (entry 21). Finally, the influence of reaction time on the
model reaction was investigated. The yield increased remarkably from 29%
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to 83% as the reaction time prolonged from 1 h to 3 h (entries 9, 22-23),
and then did not change a lot as the reaction time continuously increased
to 4 and 5 h (entries 24 and 25). Thus, the best yield was obtained by
employing 0.5 mmol 2-methylquinoline, 0.75 eq. of I2, 0.4 eq. of
CuSO4·5H2O and 2 mL CH3CN at 70 °C for 3 h, as indicated by entry 9.
Table 2. Optimization of reaction conditionsa
Entry I2 (eq.)
Catalyst (eq.)
Solvent Temp. (°C) Time (h) Yield (%)b
1
0.5
0.5
CuCl2 (0.2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
30
50
90
70
70
70
70
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
4
5
27
29
30
35
33
53
62
61
83
81
23
27
34
67
17
59
57
79
27
57
79
29
47
81
80
2
CuBr2 (0.2)
3
0.5
Cu(acac)2 (0.2)
4
0.5
CuSO4·5H2O (0.2)
Cu(OAc)2·H2O (0.2)
CuSO4·5H2O (0.3)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.5)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
CuSO4·5H2O (0.4)
5
0.5
6
0.5
7
0.5
8
0.5
9
0.75
1.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
DMSO
EtOH
p-dioxane
toluene
THF
CH2Cl2
DCE
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
aOptimal conditions: 1a (0.5 mmol), I2 (0.5-1.0 eq.), catalyst (0.2-0.5 eq.), solvent (2 mL) at
30-90 °C for 1-5 h. bIsolated yields.
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With the optimal reaction conditions in hand, we then examined the
substrate scope of the iodination reaction (Scheme 6). As it can be seen, a
variety of substituted 2-methylquinoline bearing electron donating groups
(-OCH3, -CH3, -OCF3) or electron withdrawing groups (-F, -Cl, -Br, -NO2,
-CF3) reacted well with iodine, affording the corresponding
2-iodiomethylquinoline 4a-m in good to excellent yields. Moreover,
disubstituted
2-methylquinolines,
including
2,6-dimethyl-4-(phenylsulfonyl)quinoline,
6-methoxy-2-methyl-4-(phenylsulfonyl)quinoline,
and
6-methoxy-2-methyl-4-tosylquinoline, all worked well with the new
synthetic method, affording the corresponding iodination products 4n-p
in moderate to good yields with excellent regioselectivity. To our surprise,
our newly developed methodology even progressed well with many other
important methylazarenes, including 3-methylbenzoquinoline (4q),
1-methylisoquinoline
(4r),
2-methylbenzothiazole
(4s),
2-methylbenzooxazole (4t), 2-methylquinoxaline (4u) as well as
2,3-dimethylquinoxaline (4v), leading to the corresponding products
(4q-v) in moderate to excellent yields.
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Scheme 6. Scope of the iodination reaction of 2-methylheterocycles.
When Br2 was used as reactant in the second method (Scheme 7a),
the disubstituted product, 2-(dibromomethyl)-quinoline (4w), instead of
2-bromomethylquinoline was finally obtained as the major product.
When Cl2 was used as reactant in the second method (Scheme 7b),
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2-cholomethylquinoline (4x) was successfully obtained as the major
product. However, using toxic Cl2 gas is dangerous and inconvenient.
Thus, the first method is still deserved to be kept for synthesis of
2-bromomethylquinolines and 2-cholomethylquinolines.
Scheme 7. Bromination and chlorination of 2-methylquinoline using
method II.
The related reaction mechanism was proposed as shown in Scheme 8.
The reaction cycle shown in Scheme 8 is just same as that shown in
Scheme 4-ii. The additional information given by Scheme 8 is that I-,
resulted from the reaction, was oxidized by Cu2+ to regenerate I2 as well
as CuI. The regenerated I2 could be used for further reaction cycle and the
formation of CuI drove the reaction to completion.
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Scheme 8. Proposed reaction mechanism for the iodination of
2-methylheterocycles.
Additionally, several control experiments were carried out to explore
the related reaction mechanism as shown in Scheme 9. When
4-methylquinoline or 6-methylquinoline were employed to react with I2
in the presence of CuSO4·5H2O in CH3CN, corresponding iodination
compounds were not detected (Scheme 9a-b). These additional control
experiments might well serve as the experimental support for the
proposed mechanism that indicates the essentiality of coordination of
copper(II) to nitrogen.13d When the reaction was carried out under N2
protection (Scheme 9c) or in the presence of the widely used radical
scavenger 2,2,6,6-tetra-methyl-l-piperidinyloxy (TEMPO) (Scheme 9d),
the both reactions proceeded smoothly, which possibly rule out the
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requirement of oxygen and the involvement of radical intermediates.
These additional experiments strongly backed up the above proposed
mechanism.
Scheme 9. Additional studies for mechanism.
3. Conclusions
In conclusion, we developed two practical and simple synthetic
methodologies towards various heterobenzyl halides. A series of
2-halomethylquinolines were readily prepared by the one-pot reaction of
2-methylquinolines with CuX (X = I, Br, Cl) and TBHP in CH3CN. Based
on the success of the first synthetic methodology, we developed the
second synthetic methodology, by which a large variety of heterobenzyl
iodides, including 2-iodomethylquinolines, 2-iodomethylquinoxaline,
2-iodiomethylbenzooxazole and 2-iodiomethylbenzothiazole, were
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efficiently synthesized by one-pot reaction of 2-methylheterocycles direct
with iodine in the presence of CuSO4·5H2O in CH3CN. The remarkable
merits of the synthetic methodologies are cheap and easily available
reactants, high regioselectivity, a wide scope of products, as well as an
efficient one-pot synthetic procedure. The methodologies will
undoubtedly become practical choices for preparation of many kinds of
2-halomethylazaarenes, many of which are indispensable synthetic
precursors of numerous biologically targets.
4. Experimental Section
4.1 Materials and method
All reagents were purchased from Sigma-Aldrich, J&KCHEMICA
or TCI (Shanghai) and used without further purification. TLC was
performed on silica gel plates and preparative chromatograph on columns
1
13
of silica gel (200-300 mesh). H, C NMR spectra were recorded with a
Bruker Avance 400 MHz spectrometer operating at 400.13, 100.61 MHz,
13
respectively, with C NMR spectra being recorded with broad band
proton decoupled. All NMR spectra were recorded in CDCl3 at room
1
13
temperature (20 ± 2 °C). H and C chemical shifts are quoted in parts
per million downfield from TMS. High resolution mass spectra (HR MS)
were obtained with a Waters Micromass Q-Tof Micro instrument using
the ESI technique.
4.2 General procedure for the synthesis of 2-halomethylquinoline
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derivatives (method I).
2-Methylquinoline derivatives (0.5 mmol), cuprous halide (0.75
mmol), TBHP (8.0 eq., 70% aqueous solution) and CH3CN (2 mL) were
stirred at 70 °C for 8 h. Then, the reaction mixture was diluted by water
and extracted with CH2Cl2 (3 × 15 mL). The X2 (X =I, Br, Cl) in organic
phase was quenched by Na2S2O3. The combined organic layers were
washed with saturated NH4Cl aqueous solution and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo. The desired
product was obtained by silica gel chromatography (petroleum ether/ethyl
acetate, v/v = 10/1).
4.3 General procedure for the synthesis of 2-iodiomethylazaarenes
(method II).
2-Methylazaarenes (0.5 mmol), iodine (0.375 mmol, 95.3 mg),
CuSO4·5H2O (0.2 mmol, 50 mg) and CH3CN (2 mL) were stirred at
70 °C for 3 h. Then, the reaction mixture was diluted by water and
extracted with CH2Cl2 (3 × 15 mL). The residue I2 in organic phase was
quenched by Na2S2O3. The combined organic layers were washed with
saturated NH4Cl aqueous solution and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. The desired product
was obtained by silica gel chromatography (petroleum ether/ethyl acetate,
v/v = 10/1).
2-iodiomethylquinoline (method I: 3a, method II: 4a)[12b]. Yellow oil,
21

ACCEPTED MANUSCRIPT
method I: 3a yield: 89%, method II: 4a yield: 83%. 1H NMR (400 MHz,
CDCl3) δ: 4.67 (s, 2H), 7.50-7.55 (m, 2H), 7.71 (m, 1H), 7.78 (d, J = 8.0
13
Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H). C NMR
(101 MHz, CDCl3) δ: 6.9, 121.1, 126.9, 127.1, 127.5, 129.1, 130.0, 137.2,
147.6, 158.4. HRMS Calcd for C10H8IN [M + H]+: m/z 269.9774, Found
269.9781.
2-(iodomethyl)-6-methylquinoline (method I: 3b, method II: 4b)[12b]
.
Yellow oil, method I: 3b yield: 65%, method II: 4b yield: 65%.1H NMR
(400 MHz, CDCl3) δ: 2.52 (s, 3H), 4.67 (s, 2H), 7.48 (d, J = 8.4 Hz, 1H),
13
7.54 (m, 2H, 5), 7.93 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H). C
NMR (101 MHz, CDCl3) δ: 7.0, 21.6, 121.1, 126.4, 127.1, 128.7, 132.3,
136.6, 136.9, 146.1, 157.4. HRMS Calcd for C11H10IN [M + H]+: m/z
283.9931, Found 283.9933.
2-(iodomethyl)-6-methoxyquinoline (method I: 3c, method II: 4c)[12b]
.
Yellow oil, method I: 3c yield: 57%, method II: 4c yield: 62%. 1H NMR
(400 MHz, CDCl3) δ: 3.93 (s, 3H), 4.67 (s, 2H), 7.05 (d, J = 2.4 Hz, 1H),
7.37 (dd, J = 2.8 Hz, J = 9.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.94 (d, J
= 9.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ:
7.1, 55.6, 105.1, 121.4, 122.6, 128.1, 130.5, 136.0, 143.6, 155.7, 158.1.
HRMS Calcd for C11H10INO [M + H]+: m/z 299.9880, Found 299.9883.
2-(iodomethyl)-7-(trifluoromethoxy)quinoline (method I: 3d, method II:
1
4j). Yellow oil, method I: 3d yield: 71%, method II: 4j yield: 83%. H
22

ACCEPTED MANUSCRIPT
NMR (400 MHz, CDCl3) δ: 4.66 (s, 2H), 7.39 (dd, J = 2 Hz, J = 8.8 Hz,
1H), 7.54 (d, J = 8.8 Hz), 7.82 (d, J = 9.2 Hz, 1H), 7.89 (s, 2H), 8.13 (d, J
13
= 8.4 Hz, 1H). C NMR (101 MHz, CDCl3)
δ
: 6.2, 119.0, 119.2, 120.9,
121.6 (JC-F = 34.9 Hz), 125.3, 129.3, 137.0, 148.0, 150.0, 160.0.19F NMR
(376 MHz, CDCl3) δ: -58.2. HRMS Calcd for C11H7F3INO [M + H]+: m/z
353.9597, Found 353.9596.
6-fluoro-2-(iodomethyl)quinoline (method I: 3e, method II: 4e)[12b]
.
Yellow oil, method I: 3e yield: 90%, method II: 4e yield: 85%.1H NMR
(400 MHz, CDCl3) δ: 4.66 (s, 2H), 7.42 (m, 1H), 7.49 (m, 1H), 7.54 (d, J
13
= 8.4 Hz, 1H), 8.05 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H). C NMR (101
MHz, CDCl3) δ: 6.4, 110.7 (JC-F = 21.6 Hz), 120.2 (JC-F = 25.5 Hz), 121.9,
127.7 (JC-F = 10.1 Hz), 131.6 (JC-F = 9.3 Hz), 136.6 (JC-F = 5.2 Hz), 144.6,
19
157.8, 160.6 (JC-F = 247.4 Hz). F NMR (376 MHz, CDCl3) δ: -112.4.
HRMS Calcd for C10H7FIN [M + H]+: m/z 287.9680, Found 287.9681.
6-chloro-2-(iodomethyl)quinoline (method I: 3f, method II: 4f). Yellow
1
oil, method I: 3f yield: 83%, method II: 4f yield: 81%. H NMR (400
MHz, CDCl3) δ: 4.65 (s, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.66 (m, 1H), 7.77
(s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ: 6.4, 122.0, 126.2, 127.6, 130.7, 130.9, 132.6, 136.3,
146.0, 158.8. HRMS Calcd for C10H7ClIN [M + H]+: m/z 303.9384,
Found 303.9391.
6-bromo-2-(iodomethyl)quinoline (method I: 3g, method II: 4g)[12b]
.
23

ACCEPTED MANUSCRIPT
Yellow oil, method I: 3g yield: 87%, method II: 4g yield: 79%. 1H NMR
(400 MHz, CDCl3) δ: 4.65 (s, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.78 (dd, J =
2.4 Hz, J = 9.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H),
13
8.02 (d, J = 8.4 Hz, 1H). C NMR (101 MHz, CDCl3)
δ
: 6.4, 120.7,
122.0, 128.1, 129.6, 130.8, 133.4, 136.2, 146.2, 158.9. HRMS Calcd for
C10H7BrIN [M + H]+: m/z 347.8879, Found 347.8879.
2-(iodomethyl)-6-nitroquinoline (method I: 3h, method II: 4h). Yellow oil,
method I: 3h yield: 91%, method II: 4h yield: 87%. 1H NMR (400 MHz,
CDCl3) δ: 4.69 (s, 2H), 7.68 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H),
8.30 (d, J = 8.8 Hz, 1H), 8.48 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 8.76 (d, J
13
= 2.4 Hz, 1H). C NMR (101 MHz, CDCl3)
δ
: 5.6, 123.0, 123.4, 124.2,
124.4, 125.8, 130.9, 138.8, 149.7, 162.5. HRMS Calcd for C10H7IN2O2
[M + H]+: m/z 314.9625, Found 314.9628.
1
2-(bromomethyl)quinoline (method I: 3i)[12a]. Yellow oil, yield: 76%. H
NMR (400 MHz, CDCl3) δ: 4.73 (s, 2H), 7.55-7.59 (m, 2H), 7.75 (m, 1H),
7.83 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz,
13
1H). C NMR (101 MHz, CDCl3)
δ
: 34.2, 121.2, 127.1, 127.4, 127.6,
129.1, 130.1, 137.5, 147.3, 156.9. HRMS Calcd for C10H8BrN [M + H]+:
m/z 221.9913, Found 221.9915.
2-(bromomethyl)-6-fluoroquinoline (method I: 3j)[7m]. Yellow oil, yield:
77%. 1H NMR (400 MHz, CDCl3) δ: 4.70 (s, 2H), 7.43 (m, 1H), 7.50 (m,
1H), 7.59 (d, J = 8.4 Hz, 1H), 8.07 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H). 13C
24

ACCEPTED MANUSCRIPT
NMR (101 MHz, CDCl3) : 18.5, 110.7 (JC-F = 22.9 Hz), 120.3 (JC-F
δ
=
25.2 Hz), 122.0, 128.0 (JC-F = 11.5 Hz), 131.7 (JC-F = 9.2 Hz), 136.7 (JC-F
19
= 6.9 Hz), 144.5, 156.3, 160.8 (JC-F = 242.5 Hz). F NMR (376 MHz,
CDCl3) δ: -112.0. HRMS Calcd for C10H7BrFN [M + H]+: m/z 239.9819,
Found 239.9821.
2-(bromomethyl)-6-chloroquinoline (method I: 3k)[7m]. Yellow oil, yield:
1
73%. H NMR (400 MHz, CDCl3) δ: 4.70 (s, 2H), 7.60 (d, J = 8.4 Hz,
1H), 7.67 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 8.01
(d, J = 9.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ
: 34.1, 122.1, 126.2, 127.9, 130.89, 130.9, 132.9, 136.4, 145.9, 157.2.
HRMS Calcd for C10H7BrClN [M + H]+: m/z 255.9523, Found 255.9525.
6-bromo-2-(bromomethyl)quinoline (method I: 3l)[7m]. Yellow oil, yield:
1
71%. H NMR (400 MHz, CDCl3) δ: 4.69 (s, 2H), 7.59 (d, J = 8.4 Hz,
1H), 7.80 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.98
(d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ
: 34.1, 121.0, 122.1, 128.4, 129.6, 131.0, 133.5, 136.3, 146.1, 157.4.
HRMS Calcd for C10H7Br2N [M + H]+: m/z 299.9018, Found 299.9016.
2-(bromomethyl)-6-nitroquinoline (method I: 3m)[12a]. Yellow oil, yield:
1
81%. H NMR (400 MHz, CDCl3) δ: 4.73 (s, 2H), 7.74 (d, J = 8.8 Hz,
1H), 8.20 (d, J = 9.2 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.50 (dd, J = 2.0
13
Hz, J = 9.2 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H). C NMR (101 MHz,
CDCl3)
δ
: 33.5, 122.3, 123.1, 123.4, 124.2, 124.3, 126.1, 131.2, 139.0,
25

ACCEPTED MANUSCRIPT
160.8. HRMS Calcd for C10H7BrN2O2 [M + H]+: m/z 266.9764, Found
266.9768.
2-(chloromethyl)quinoline (method I: 3n, method II: 4x)[12a]. Yellow oil,
method I: 3n yield: 67%, method II: 4x yield: 73%. 1H NMR (400 MHz,
CDCl3) δ: 4.68 (s, 2H), 7.51-7.60 (m, 2H), 7.72 (m, 1H), 7.79 (d, J = 8.4
13
Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H). C NMR
(101 MHz, CDCl3) δ: 6.9, 121.1, 126.9, 127.1, 127.5, 129.1, 130.0, 137.2,
147.6, 158.4. HRMS Calcd for C10H8ClN [M + H]+: m/z 178.0418, Found
178.0424.
2-(chloromethyl)-6-fluoroquinoline (method I: 3o)[12a]. Yellow oil, yield:
69%. 1H NMR (400 MHz, CDCl3) δ: 4.83 (s, 2H), 7.45 (m, 1H), 7.51 (m,
1H), 7.63 (d, J = 8.8 Hz, 1H), 8.08 (m, 1H), 8.16 (d, J = 8.4 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ: 47.2, 110.7 (JC-F = 21.7 Hz), 120.3 (JC-F =
25.6 Hz), 121.3, 128.1 (JC-F = 10.0 Hz), 131.7 (JC-F = 8.2 Hz), 136.7 (JC-F
= 4.5 Hz), 144.5, 156.1 (JC-F = 3.0 Hz), 160.7 (JC-F = 247.4 Hz). 19F NMR
(376 MHz, CDCl3) δ: -112.0. HRMS Calcd for C10H7ClFN [M + H]+: m/z
196.0324, Found 196.0327.
6-chloro-2-(chloromethyl)quinoline (method I: 3p)[12a]. Yellow oil, yield:
1
61%. H NMR (400 MHz, CDCl3) δ: 4.82 (s, 2H), 7.63 (d, J = 8.8 Hz,
1H), 7.67 (dd, J = 2.0 Hz, J = 9.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 8.01
(d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ
: 47.1, 121.4, 126.3, 128.0, 130.86, 130.9, 132.8, 136.4, 145.8, 157.1.
26

ACCEPTED MANUSCRIPT
HRMS Calcd for C10H7Cl2N [M + H]+: m/z 212.0028, Found 212.0030.
6-bromo-2-(chloromethyl)quinoline (method I: 3q)[8b]. Yellow oil, yield:
1
64%. H NMR (400 MHz, CDCl3) δ: 4.82 (s, 2H), 7.64 (d, J = 8.4 Hz,
1H), 7.80 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 8.00
(d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ
: 58.5, 120.9, 121.4, 128.5, 129.6, 130.9, 133.5, 136.3, 146.0, 157.2.
HRMS Calcd for C10H7BrClN [M + H]+: m/z 255.9523, Found 255.9525.
2-(chloromethyl)-6-nitroquinoline (method I: 3r)[12a]. Yellow oil, yield:
1
73%. H NMR (400 MHz, CDCl3) δ: 4.87 (s, 2H), 7.80 (d, J = 8.4 Hz,
1H), 8.21 (d, J = 9.2 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 2.4
13
Hz, J = 9.2 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H). C NMR (101 MHz,
CDCl3) δ: 58.5, 122.3, 123.1, 123.4, 124.3, 126.2, 131.1, 139.0, 149.4,
160.6. HRMS Calcd for C10H7ClN2O2 [M + H]+: m/z 223.0269, Found
223.0271.
2-(iodomethyl)-6-(trifluoromethoxy)quinoline (method II: 4d). Yellow oil,
1
yield: 87%. H NMR (400 MHz, CDCl3) δ: 4.67 (s, 2H), 7.59 (m, 3H),
13
8.10 (m, 2H). C NMR (101 MHz, CDCl3)
δ
: 6.3, 117.6, 120.5 (JC-F
=
19
260.1 Hz), 122.1, 124.0, 127.2, 131.4, 137.0, 145.8, 147.2, 159.1. F
NMR (376 MHz, CDCl3) : -58.3. HRMS Calcd for C11H7F3INO [M +
δ
H]+: m/z 353.9597, Found 353.9597.
2-(iodomethyl)-6-(trifluoromethyl)quinoline (method II: 4i). Yellow oil,
yield: 89%. 1H NMR (400 MHz, CDCl3) δ: 4.68 (s, 2H), 7.61 (d, J = 8.8
27

ACCEPTED MANUSCRIPT
Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 8.13-8.20 (m, 2H). C
NMR (101 MHz, CDCl3) : 6.1, 122.3, 123.9 (JC-F = 270.6 Hz), 125.4
13
δ
(JC-F = 4.4 Hz), 125.6 (JC-F = 2.9 Hz), 128.6 (JC-F = 32.7 Hz), 130.3, 137.9,
148.5, 160.9. 19F NMR (376 MHz, CDCl3)
δ
: -62.4. HRMS Calcd for
C11H7F3IN [M + H]+: m/z 337.9648, Found 337.9646.
7-chloro-2-(iodomethyl)quinoline (method II: 4k)[12b]. Yellow oil, yield:
1
73%. H NMR (400 MHz, CDCl3) δ: 4.64 (s, 2H), 7.46-7.51 (m, 2H, 3,
6-H), 7.70 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ: 6.4, 121.3, 125.4, 127.9, 128.2, 128.7, 135.8,
137.0, 147.9, 159.6. HRMS Calcd for C10H7ClIN [M + H]+: m/z
303.9384, Found 303.9388.
7-bromo-2-(iodomethyl)quinoline (method II: 4l). Yellow oil, yield: 77%.
1H NMR (400 MHz, CDCl3) δ: 4.65 (s, 2H), 7.53 (d, J = 8.4 Hz, 1H),
7.61-7.67 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ: 6.3, 121.4, 124.1, 125.6, 128.7, 130.4, 131.5,
132.7, 137.1, 159.6. HRMS Calcd for C10H7BrIN [M + H]+: m/z
347.8879, Found 347.8879.
2-(iodomethyl)-7-nitroquinoline (method II: 4m). Yellow oil, yield: 83%.
1H NMR (400 MHz, CDCl3) δ: 4.70 (s, 2H), 7.69 (d, J = 8.8 Hz, 1H),
7.95 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.32 (dd, J = 9.2 Hz, J
13
= 2.4 Hz, 1H), 8.95 (s, 1H). C NMR (101 MHz, CDCl3)
δ
: 5.5, 120.3,
124.1, 125.4, 129.1, 130.1, 133.2, 137.0, 146.6, 161.2. HRMS Calcd for
28

ACCEPTED MANUSCRIPT
C10H7INO2 [M + H]+: m/z 314.9625, Found 314.9623.
2-(iodomethyl)-6-methyl-4-(phenylsulfonyl)quinoline (method II: 4n).
Yellow oil, yield: 79%. 1H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 4.72
(s, 2H), 7.53-7.64 (m, 4H), 7.98-8.01 (m, 3H), 8.23 (0s, 1H), 8.31 (s, 1H).
13C NMR (101 MHz, CDCl3)
δ: 5.66, 22.3, 121.2, 121.6, 122.9, 127.9,
129.5, 129.9, 133.1, 134.0, 139.5, 140.1, 144.9, 147.6, 157.2. HRMS
Calcd for C17H14INO2S [M + H]+: m/z 423.9863, Found 423.9869.
2-(iodomethyl)-6-methoxy-4-(phenylsulfonyl)quinoline (method II: 4o).
Yellow oil, yield: 57%. 1H NMR (400 MHz, CDCl3) δ: 3.90 (s, 3H), 4.73
(s, 2H), 7.37 (m, 1H), 7.52-7.56 (m, 2H), 7.62 (m, 1H), 7.97-7.99 (m, 3H),
7.78 (d, J = 2.8 Hz, 1H), 8.32 (s, 1H). 13C NMR (101 MHz, CDCl3)
δ: 5.8,
55.7, 102.1, 121.8, 122.6, 123.7, 127.8, 129.5, 131.6, 140.0, 140.1, 143.7,
145.2, 155.3, 159.4. HRMS Calcd for C17H14INO3S [M + H]+: m/z
439.9817, Found 439.9814.
2-(iodomethyl)-6-methoxy-4-tosylquinoline (method II: 4p). Yellow oil,
1
yield: 47%. H NMR (400 MHz, CDCl3) δ: 2.40 (s, 3H), 3.91 (s, 3H),
4.72 (s, 2H), 7.32-7.36 (m, 2H), 7.38 (d, J = 2.8 Hz, 1H), 7.80 (s, 1H),
13
7.87 (d, 2H), 7.98 (d, 1H), 8.30 (s, 1H). C NMR (101 MHz, CDCl3)
δ
:
5.8, 25.8, 55.7, 102.2, 121.6, 122.5, 123.6, 127.9, 130.1, 131.6, 137.1,
144.1, 145.18, 145.23, 155.3, 159.4. HRMS Calcd for C18H16INO3S [M +
H]+: m/z 453.9974, Found 453.9972.
3-(iodomethyl)benzo[f]quinoline (method II: 4q)[12b]. Yellow oil, yield:
29