Transition metal free oxygenation of 8-aminoquinoline amides in water

Article abstract of DOI:10.1039/c8gc00191j

The oxygenation of 8-aminoquinoline amides by benzoyl peroxide at the C5 position in water is developed in the absence of a transition metal catalyst, affording the desired products in moderate to good yields of up to 88%. Mechanism studies reveal that the reaction would involve a radical process.

Full text of DOI:10.1039/c8gc00191j

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Zhou, X. Yao, X.
Weng, K. Wang and H. Xiang, Green Chem., 2018, DOI: 10.1039/C8GC00191J.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Green Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C8GC00191J
Journal Name
COMMUNICATION
Transition Metal Free Oxygenation of 8-Aminoquinoline Amides in
Water
Received 00th January 20xx,
Accepted 00th January 20xx
Xinghui Yao, Xin Weng, Kaixuan Wang, Haifeng Xiang and Xiangge Zhou*
DOI: 10.1039/x0xx00000x
www.rsc.org/
without catalyst is less reported.
Abstract: The oxygenation of 8-aminoquinoline amides by benzoyl
peroxide at the C5 position in water is developed in the absence of
transition metal catalyst, affording the desired products in
moderate to good yields up to 88%. Mechanism studies reveal that
the reaction would involve a radical process.
8-Aminoquinoline is an important scaffold in many
natural products and pharmaceuticals. For example,
primaquine, pamaquine and tafenoquine, which contain 8-
aminoquinoline fragment, have been reported as antimalarial
drugs (Figure 1).1 Accordingly, the derivatization of 8-
aminoquinolines has attracted an increasing number of
attentions, and different functional groups have been
introduced into the scaffold by many methods such as metal
catalysis or multiple steps.2 Recently, with considerable
progress in the C−H funcꢀonalizaꢀon,3 substitutions at the C2,4
C45-6 positions of quinoline has been reported. Meanwhile,
some approaches for direct construction of bonds between
carbons and heteroatoms at the C5 position of quinolines have
also been developed. For example, as shown in Figure 2, Stahl,
Zhang and co-workers reported copper-catalyzed chlorination
in acetic acid.7-8 Copper-catalyzed C5-sulfonylation in toluene,
DCE or dioxane as solvent was also developed by Wei,9 Wu,10
Zeng,11 Liu12 and Chan and co-workers, respectively.13 Kanai
group reported trifluoromethylation of quinolones in DCE.14 Xu
and co-workers reported metal-free amidation reactions with
DME as solvent.15 Wu group realized phosphonation of 8-
aminoquinoline amides in dioxane.16 Although great progress
has been achieved in this field, most of these transformations
were performed in the presence of transition metal catalyst
and in organic solvents, the method of metal free C-5
functionalization of 8-aminoquinoline in water is rare.
Figure 1. Representative 8-aminoquinolines as antimalarial drugs
O
R
S
O
N
O
HN
Cl
R
R
R1
O
P
O
O
N
R2
HN
R
N
NH
O
R
O
O
N
NH
H
N
R
R
O
N
O
NH
N
N(SO2Ar)2
F3C
On the other hand, benzoyl peroxides are usually
regarded as
a low toxic and widely used arylation or
benzoyloxylation reagent in many organic reactions.17-21 The
methodology of benzoyl peroxide as source of benzoyloxyl
group for C(sp2)-H bond activation and C-O bond construction
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University,
Chengdu 610064, China. zhouxiangge@scu.edu.cn; Fax: +86-28-85412904.
Electronic supplementary information (ESI) available: All optimization tables
and copies of crystallographic data. CCDC 1582941. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C8GC00191J
COMMUNICATION
Journal Name
Figure 2. Some examples of C-H functionalization at C5-position of [a] All reactions were carried out with 1a (0.1 mmol), 2a (0.2
8-aminoquinoline
mmol), additive (0.1 mmol) and solvent (1.0 mL) for 18hr. [b]
Isolated yields. [d] DCE 1,2-dichloroethane, TBAI
tetrabutylammonium iodide, TBAB = tetrabutylammonium
bromide, TBAHS = tetrabutylammonium hydrogen sulfate. [e]
0.02 mmol additive for 24hr.
=
=
Furthermore
，
compared with organic solvents, water is a
green and friendly solvent for chemical reactions. And many
successful examples of C-H bond functionalization in water
have been reported.22 In continuation of our work on aqueous
catalysis,23 herein is reported the oxygenation of 8-
aminoquinoline amides in water. This work has the following
advantages: water was used as solvent instead of normally
used harmful organic solvents; the reactions were performed
in the absence of transition metal catalyst, which would be
beneficial to the workup procedure and potential applications;
reaction condition is mild without inert atmosphere.
We commenced our investigations with 8-aminoquinoline
amide 1a and benzoyl peroxide 2a as model substrates in
toluene (1.0 mL) at room temperature without metal catalyst
and additives, which gave only 5% desired product 3a (Table 1,
entry 1). After the examination of various solvents, water was
found to give similar result of 7% yield, while DMF, DMSO, THF
and DCE retarded the reactions (entries 2–6). Meanwhile,
addition of transition metal salts such as Pd(OAc)2, Cu(OAc)2,
FeCl3 and Ni(OAc)2 seemed to be unnecessary, which caused
similar or less yields (entries 7-10). Further experiments
indicated higher temperature would be beneficial to the
reaction, and 20% yield was obtained at 80°C (entries 11-14).
Acidic or basic additives seemed to have few or bad effects on
the results (entries 15-24). At last, different phase transfer
reagents were examined, exhibiting significant effects on the
results. However, when TBAI or TBAB was used, the
corresponding halogenated product was obtained as main
product with only trace of desired product (entries 25-26).
Therefore, TBAHS was selected for this reaction, affording 47%
Yield. Furthermore, after addition of NaHCO3, the yield was
improved to be 82% (entries 27-28), and the amount of
additive could be reduced to be 20 mmol% with similar yield
80% albeit longer reaction time 24hr. Therefore, the optimized
reaction conditions were TBAHS and NaHCO3 was used as
additive in H2O at 80°C.
Table 1. Optimization of the reaction conditions[a]
Entry Solvent Additive
Temp. Yield
[%][b]
[ºC]
1
2
3
4
5
6
7
8
Toluene
DMF
DMSO
THF
DCE
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
25
25
25
25
25
25
25
25
25
25
40
60
80
100
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
5
0
0
0
Under the optimized reaction conditions, different amides
were then tested, and the results were listed in Scheme 1. In
general, both alkyl amides (3a-3e) and aryl amides (3f-3k) gave
Trace
7
0
Pd(OAc)2
Cu(OAc)2
FeCl3
the desired products in moderate to good yields. And Aryl
amides bearing electron-donating groups seemed to be more
beneficial to this reaction. Methoxyl group substituted
substrate gave 3g in the highest yield 88% in Scheme 1. The
molecular structure of 3j was confirmed by single crystal X-ray
diffraction study (Figure 3). Furthermore, 2-methyl or 6-chloro-
8-aminoquinoline amides substrates could also give the
desired products in 73% or 47% yield.
8
9
Trace
0
9
15
20
20
8
20
trace
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29[e]
Ni(OAc)2
K2CO3
NH4OAc
Cs2CO3
Next, a variety of benzoyl peroxides were examined in the
oxygenation of N-(quinolin-8-yl) butyramide (1a). As shown in
Scheme 2, benzoyl peroxides bearing electron-donating groups
exhibited higher activities than those with electron-
withdrawing groups. For example, para-methyl or ethyl
substituted substrates gave 73% and 75% yields of desired
products (3s and 3t), while para-chloro or trifluoromethyl
substituted ones gave 60% and 46% yields, respectively (3p
and 3q). Steric effect was also found in the case of para and
ortho- chloro substituted substrates, which resulted in 60%
and 34% yields (3p and 3n). Besides, heteroarene peroxides
bearing furan or thiophene ring could also be applied in this
reaction, affording the desired products in 56% or 58% yield
CH3COOH
CF3COOH
NaOH
Sodium benzoate
Na2CO3
t-BuOK
CH3COONa
TBAI
TBAB
TBAHS
TBAHS/NaHCO3
TBAHS/NaHCO3
trace
0
18
20
22
20
trace
trace
47
82
80
(
3w,3x).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 5
View Article Online
DOI: 10.1039/C8GC00191J
Journal Name
Scheme 1. Substrate scope of the 8-aminoquinoline amides
COMMUNICATION
Scheme 2. Substrate scope of benzoyl peroxides.
O
O
O
O
R
O
HN
O
R
R
N
NH
O
NH
O
NH
O
TBAHS/NaHCO3
TBAHS/NaHCO3
N
O
N
N
O
O
H2O
O
H2O
80℃, 24hr
O
O
O
80℃ 24hr
O
O
R
R
O
3
O
1a
2
3
1
2a
O
O
O
O
O
O
NH
O
NH
NH
O
HN
O
HN
HN
N
N
N
N
N
N
N
N
N
Cl
O
O
O
O
Cl
O
O
O
3o, 52%
O
O
Cl
O
O
3n, 34%
3p, 60%
3a, 82%
3c, 75%
3b, 79%
O
O
O
O
O
O
HN
HN
HN
NH
NH
NH
N
N
N
N
N
O
O
O
CF3
O
O
O
O
O
O
O
O
O
O
O
O
3r, 65%
3f, 85%
3d, 80%
3e, 69%
3q, 46%
3s, 73%
O
O
O
HN
O
HN
O
O
HN
N
N
NH
NH
NH
CF3
O
R
O
O
N
N
N
O
O
O
3ia,
3ib
3ic
R1=F,
R2=Cl,
R3=Br,
80%
, 81%
, 81%
O
O
O
O
O
O
O
3i
3g, 88%
3h, 79%
O
3u, 77%
O
O
O
O
3t, 75%
3v, 62%
S
HN
O
O
HN
HN
O
O
O
N
N
NH
NH
NH
O
O
O
N
N
N
O
O
O
O
S
O
3l, 73%
O
3j, 65%
O
3k,57%
O
O
O
O
3y, 59%
O
O
3x, 58%
Cl O
3w, 56%
O
O
HN
O
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), additive
(0.02 mmol), H2O (1.0 mL), 24hr. The yields shown here are
isolated yields.
N
3m, 47%
Reaction conditions: 1a (0.1 mmol),
2
(2.0 equiv), additive
(0.02 mmol), H2O (1.0 mL), 24hr. The yields shown here are
isolated yields.
Scheme 3. Explore the reaction pathway
Figure 3. Crystal structure of 3j
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C8GC00191J
COMMUNICATION
In order to explore the possible reaction pathway, free
Journal Name
radical inhibition experiments were then performed as shown
in Scheme 3a. Addition of 0.4 mmol free radical trapping
reagent 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) would
suppress the reaction completely, formation of only trace of
product, indicating radical procedure would be involved in this
reaction. Furthermore, the methyl substituted substrate 1z
was synthesized and reacted with 2a, and no desired product
was obtained, which suggested the hydrogen atom of amide
group would be vital to this radical procedure (Scheme 3b).24
Scheme 5. Reaction conditions: 1a (1.07g, 5 mmol), 2a (3.02g,
2.0 equiv.), additive (1 mmol), H2O (5.0 mL), 24hr.
At last, the possibility of application of this protocol was
explored. As shown in Scheme 6, compound 4, which is a
potential molecule for treating endoplasmic reticulum stress-
caused disease,25 could be synthesized by this protocol without
toxic by-products and harsh conditions in a total yield of 71%.
Scheme 6. Synthesis of 5-methoxyquinolin-8-amine
Conclusions
In summary,
a
transition-metal free C−H bond
oxygenation of 8-aminoquinolines on the C5 position with
various benzoyl peroxides was developed. This synthetic
approach provides a simple and direct route to a wide variety
of C5-position oxygenation compounds. Further investigation
is currently underway in this lab.
Scheme 4. Plausible reaction pathway and optimized geometry
of transition state
Acknowledgements
A
We are grateful to the Natural Science Foundation of
China (grant nos. 21472128, J1310008).
Based on these results and our preliminary computational
studies using DFT methods implemented in Gaussian 09 (see
supporting information), a plausible reaction pathway for the
oxygenation of 8-aminoquinoline amides is outlined in Scheme
Notes and references
4. At first, benzoyloxyl radical
during reaction.17 Then,
aminoquinoline 1a to form amidyl radical intermediate
through transition state , which was found to be endothermic
(ΔΔG298=17.8 kJmol-1). The interatomic distances of Ha-Oa and
Ha-Ob are 1.782Å and 2. 271Å respectively. And intermediate
would be formed in the presence of proton.15 At last, the
desired product could be obtained from the reaction
between and another benzoyloxyl radical.
E
would be formed from BPO
1
a) G. W. Mihaly, S. A. Ward, G. Edwards, D. D. Nicholl, M. L.
Orme, A. M. Breckenridge, Br. J. clin. Pharmac., 1985, 19
E
would be reacted with 8-
,
B
745; b) B. Lell, J. F. Faucher, M. A. Missinou, S. Borrmann, O.
Dangelmaier, J. Horton, The Lancet., 2000, 355, 2041.
J. M. Contelles, E. P. Mayoral, A. Samadi, M. C. Carreiras, E.
Soriano, Chem. Rev., 2009, 109, 2652.
a) T. W. Lyons, M. S. Sanford, Chem. Rev., 2010, 110, 1147; b)
L. Ackermann, Chem. Rev., 2011, 111, 1315; c) K. M. Engle, T.
S. Mei, M. Wasa, J. Q. Yu, Acc. Chem. Res., 2012, 45, 788; d)
X. Chen, K. M. Engle, D.H. Wang, J. Q. Yu, Angew. Chem. Int.
Ed., 2009, 48, 5094; e) Y. W. Wu, Y. Q. Chen, T. Liu, M. D.
Eastgate, J. Q. Yu, J. Am. Chem. Soc., 2016, 138, 14554; f) H.
Wang, M. M. Lorion, L. Ackermann, Angew. Chem. Int. Ed.,
2016, 55,10386.
A
2
3
C
D
C
The scaled-up experiment was also carried out by using
1a and 2a as substrates, and 75% yield could be obtained,
which indicated its potential applications.
4
A. M. Berman, J. C. Lewis, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc., 2008, 130, 14926;
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 5 of 5
View Article Online
DOI: 10.1039/C8GC00191J
Journal Name
COMMUNICATION
5
a) X. Y. Ren, P. Wen, X. K. Shi, Y. L. Wang, J. Li, S. Z. Yang, H.
Yan, G. S. Huang, Org. Lett., 2013, 15, 5194; b) C. W. Zhu, M.
L. Yi, D. H. Wei, X. Chen, Y. J. Wu, X. L. Cui, Org. Lett., 2014,
16, 1840.
6
a) M. Wasa, B. T. Worrell, J. Q. Yu, Angew. Chem. Int. Ed.,
2010, 49, 1275; Angew. Chem., 2010, 122, 1297. b) Q. Chen,
X. M. Jourdin, P. Knochel, J. Am. Chem. Soc., 2013, 135, 4958;
c) S. Yamamoto, Y. Saga, T. Andou, S. Matsunaga, M. Kanaia,
Adv. Synth. Catal., 2014, 356, 401.
7
8
9
A. M. Suess, M. Z. Ertem, C. J. Cramer, S. S. Stahl, J. Am.
Chem. Soc., 2013, 135, 9797.
H. L. Guo, M. M. Chen, P. Jiang, J. Chen, L. X. Pan, M. Wang,
C. S. Xie, Y. H. Zhang, Tetrahedron, 2015, 71, 70.
H. W. Liang, K. Jiang, W. Ding, Y. Yuan, L. Shuai, Y. C. Chen, Y.
Wei, Chem. Commun., 2015, 51, 16928.
10 H. J. Qiao, S. Y. Sun, F. Yang, Y. Zhu, W. G. Zhu, Y. X. Dong, Y.
H. Wu, X. T. Kong, L. Jiang, Y. J. Wu, Org. Lett., 2015, 17,
6086.
11 J. Wei, J. X. Jiang, X. S. Xiao, D. Lin, Y. F. Deng, Z. F. Ke, H. F.
Jiang, W. Zeng, J. Org. Chem., 2016, 81, 946.
12 J. Xu, C. Shen, X. L. Zhu, P. F. Zhang, M. J. Ajitha, K. W. Huang,
Z. F. An, X. G. Liu, Chem. Asian J., 2016, 11, 882.
13 J. M. Li, J. Weng, G. Lu, A. S. C. Chan, Tetrahedron Lett., 2016,
57, 2121.
14 Y. Kuninobu, M. Nishi, M. Kanai, Org. Biomol. Chem., 2016,
14, 8092.
15 D. Ji, X. He, Y. Xu, Z. Xu, Y. Bian, W. Liu, Q. Zhu, Y. Xu, Org.
Lett., 2016, 18, 4478.
16 M. Sun, S. Sun, H. Qiao, F. Yang, Y. Zhu, J. Kang, Y. Wu, Y. Wu,
Org. Chem. Front., 2016, 3, 1646.
17 W. Y. Yu, W. N. Sit, Z. Y. Zhou, A. S. C. Chan, Org. Lett., 2009,
11, 3174.
18 D. K. Li, N. Xu, Y. C. Zhang, L. Wang, Chem. Commun., 2014,
50, 14862.
19 C. Qian, D. Lin, Y. Deng, X. Q. Zhang, H. F. Jiang, G. Miao, X. H.
Tang, W. Zeng, Org. Biomol. Chem., 2014, 12, 5866.
20 M. Sun, Z. Wang, J. X. Wang, P. Y. Guo, X. X. Chen, Y. M. Li,
Org. Biomol. Chem., 2016, 14, 10585.
21 a) H. Gotoh, Y. Hayashi. Chem. Commun., 2009,
Kano, H. Mii; K. Maruoka. J. Am. Chem. Soc., 2009, 131
0, 3083; b) T.
,
3450; c) O. Lifchits, N. Demoulin, B. List. Angew. Chem. Int.
Ed. 2011, 50, 9680; d) O. Lifchits, N. Demoulin, B. List.
Tetrahedron, 2012, 68, 7568; e) Z. Zhou, J. Cheng, J. T. Yu.
Org. Biomol. Chem., 2015,13, 9751. f) T. Kanemitsu, M. Sato,
M. Yoshida, E. Ozasa, M. Miyazaki, Y. Odanaka, K. Nagata, T.
Itoh. Org. Lett., 2016, 18, 5484.
22 a) S. A. Ohnmacht, P. Mamone, A. J. Culshaw, M. F. Greaney,
Chem. Commun., 2008, 0, 1241; b) P. B. Arockiam, C.
Fischmeister, C. Bruneau, P. H. Dixneuf. Angew. Chem. Int.
Ed. 2010, 49, 6629; c) S. A. Ohnmacht, A. J. Culshaw, M. F.
Greaney, Org. Lett., 2010, 12, 224; d) F. H. Xiao, Q. Shuai, F.
Zhao, O. Basle, G. J. Deng, C. J. Li, Org. Lett., 2011, 13, 1614;
e) L. Ackermann, J. Pospech, H. K. Potukuchi, Org. Lett.,
2012, 14, 2146; f) N. P. Ramirez, I. Bosque, J. C. Gonzalez-
Gomez, Org. Lett., 2015, 17, 4550; g) J. T. Hu, T. L. Lan, Y. H.
Sun, H. Chen, J. N. Yao, Y. Rao, Chem. Commun., 2015, 51
14929.
,
23 a) F. Luo, J. Yang, Z. Li, H. Xiang, X. Zhou, Eur. J. Org. Chem.,
2015, 2463; b) F. Luo, Y. Long, Z. Li, X. Zhou, Acta. Chim.
Sinica., 2016, 74, 805; c) Z. Wu, F. Luo, S. Chen, Z. Li, H.
Xiang, X. Zhou, Chem. Commun., 2013, 49,7653; d) Z. Wu, S.
Chen, C. Hu, Z. Li, H. Xiang, X. Zhou, Chem. Cat. Chem., 2013,
5, 2839.
24 J. Xu, C. Shen, X. L. Zhu, P. F. Zhang, M. J. Ajitha, K. W. Huang,
Z. F. An, X. G. Liu. Chem-Asian J., 2016, 11, 882.
25 D. Russell PCT Int. Appl. (2016), WO 2016032569 A1.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins