A metal-free aerobic oxidative bromination of anilines and aryl ketones with 2-methylpyridinium nitrate as a reusable ionic liquid

Article abstract of DOI:10.1177/1747519819895978

An aerobic oxidative bromination of anilines and aryl ketones catalyzed by recyclable 2-methylpyridinium nitrate ionic liquid is achieved in water using hydrobromic acid as the bromine source and molecular oxygen as the oxidant. The catalytic system shows good efficiency and atom economy.

Full text of DOI:10.1177/1747519819895978

895978CHL0010.1177/1747519819895978Journal of Chemical ResearchLi et al.
research-article2019
Research Article
Journal of Chemical Research
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A metal-free aerobic oxidative bromination
of anilines and aryl ketones with
2-methylpyridinium nitrate as a reusable
ionic liquid
https://doi.org/10.1177/1747519819895978
DOI: 10.1177/1747519819895978
journals.sagepub.com/home/chl
Ming-Fang Li1* , Jian Wang2*, Yong-Xin Ke1, Song-Cheng Pan1,
Hong Yin2, Wenting Du2 and Jing-Hua Li1
Abstract
An aerobic oxidative bromination of anilines and aryl ketones catalyzed by recyclable 2-methylpyridinium nitrate ionic
liquid is achieved in water using hydrobromic acid as the bromine source and molecular oxygen as the oxidant. The
catalytic system shows good efficiency and atom economy.
Keywords
aerobic oxidative brominations, anilines, aryl ketones, metal-free reactions
Date received: 21 July 2019; accepted: 28 November 2019
explosion in the case of H2O2 employed as an oxidant,
Introduction
especially at elevated temperatures. Recently, the Wang
Brominated compounds are important intermediates that
group released an oxidative bromination with ionic liquid
have been widely used in the synthesis of pharmaceuti-
(IL) as both solvent and catalyst.14 However, they use
cals, biologically active compounds, agrochemicals, and
stoichiometric IL and corrosive bromine as agent, and
other functional chemicals.1,2 The C–Br bond can be eas-
ily transformed into C–C and C–heteroatom bonds via
1College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, P.R. China
2School of Pharmacy, Hangzhou Medical College, Hangzhou, P.R. China
various classic reactions such as Stille, Suzuki, Heck, and
Sonogashira.3–6 The development of new and “greener”
methods for bromination has consistently been one of the
topics that chemists have focused on. Oxidative bromina-
tion is a promising reaction which can be performed with
a combination of bromide anions and a variety of oxi-
*These authors contributed equally to this work.
Corresponding author:
Jing-Hua Li, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P.R. China.
8,9
10–14
dants,7 among which H2O2 and O2
are the most
environmentally friendly. However, there is a risk of Email: lijh@zjut.edu.cn

2
Journal of Chemical Research 00(0)
Table 1. Aerobic bromination of aniline derivatives catalyzed
only anisole derivatives are successfully brominated. In
our previous report,15 a non-metal catalyzed aerobic oxi-
dative bromination of anisoles and phenols was estab-
lished, which could be carried out smoothly in the presence
of a catalytic amount of 2-methylpyridinium nitrate ionic
liquid (2-MePy·HNO3). (2-Methylpyridinium nitrate is a
white hygroscopic solid that melts while being slightly
heated or exposed to humid air, affording a sticky liquid;
strictly speaking, it is an “IL” but not an “RTIL” (room-
temperature ionic liquid).) We speculated that this system
can also be applied to the aromatic bromination of ani-
lines and α-bromination of ketones.
by 2-MePy·HNO3.a
Entry
1
Substrate 1
Product 2
Time (h)
8
Yield (%)b
85 (83)
NH2
NH2
1a
Br
2a
Results and discussion
NH2
NH2
2
3
8
8
84 (77)
84 (80)
According to the conditions reported in our previous arti-
cle, we started our optimization studies for aniline bromi-
nation with 0.3 equivalents of 2-methylpyridinium nitrate
and hydrobromic acid at 80℃; however, only 55% con-
version was achieved (see Table S1 in Supplemental
Material). The conversion increased when more of the
catalyst was added and 1.1 equivalents of the IL, and a
temperature of 90℃ is needed to obtain the maximum
efficiency. The effect of other solvents (common solvent
such as H2O, CH2Cl2, tetrahydrofuran (THF), methanol,
ethanol, and ethyl acetate (EA)) was subsequently investi-
gated. The results showed that water introduced from hyd-
robromic acid (40% aqueous solution), rather than other
additional solvents, gave the best conversion for the reac-
tion (Table S1 in Supplemental Material). We assume that
the reason for the low conversion in these additional sol-
vents is due to the diluted reactants and lower boiling
point of these solvents.
Subsequently, we expanded the substrate scope with
different substituents on the phenyl ring and nitrogen, and
the results are listed in Table 1. Aniline derivatives with
an electron-donating group (EDG) or an electron-with-
drawing group (EWG) on the phenyl ring could all be
monobrominated in good yields (Table 1). For p-substi-
tuted anilines (Table 1, entries 4–6, 9, and 10), monobro-
mination occurred at the o-position relative to the amino
group. For other anilines, bromination occurred preferen-
tially at the p-position (Table 1, entries 1–3, 7, 8 and 11).
Substitution of a hydrogen atom on nitrogen with a methyl
did not strongly affect the bromination efficiency (Table
1, entry 11). Normally, dibromination of anilines is more
difficult than monobromination because the phenyl ring is
slightly deactivated by the existing bromine atom. It is
interesting to note that when the amount of hydrogen bro-
mide was raised to 2.8 equivalents, the dibrominated
derivative became the major product in good yield (Table
1, entry 12). The stoichiometric use of nitrate does not
limit the sustainability of this system. The catalyst can be
recycled at least four times without a significant decrease
in activity (See Table S2 in Supplemental Material)
Different from anilines, aryl ketones can be transformed
into their corresponding α-brominated derivatives in high
yields with 0.1 equivalents of 2-methylpyridinium nitrate
and 1.1 equivalents of HBr (40% aqueous solution) at 60℃
1b
Br
2b
NH2
NH2
1c
Br
2c
NH2
NH2
Br
4
5
6
8
6
86 (83)
84 (78)
75 (61)
1d
2d
NH2
NH2
Br
1e
2e
NH2
NH2
Br
12
OCH3
OCH3
1f
2f
7c
6
8
8
84 (83)
79 (77)
86 (83)
NH2
Cl
NH2
Cl
1g
Br
2g
NH2
NH2
8
Cl
Cl
Br
1h
2h
9c
NH2
NH2
Br
Cl
Cl
1i
2i
(Continued)

Li et al.
3
Table 1. (Continued)
Table 2. Aerobic α-bromination of aryl ketones catalyzed by
a
2-MePy·HNO3.
Entry
10c
Substrate 1
Product 2
Time (h)
8
Yield (%)b
84 (80)
O
O
HBr, O2
Cat.
R2
R2
Br
NH2
NH2
Br
R1
R1
3
4
NO2
1j
NO2
2j
Entry Substrate 3
Product 4
Time (h) Yield (%)b
NHCH3
NHCH3
11
12
12
84 (80)
84 (77)
O
O
1
2
3
6
6
8
95 (88)
94 (86)
92 (81)
Br
1k
3a
3b
4a
4b
Br
O
O
2k
Br
12c,d
NH2
NH2
Br
O
O
1l
Br
Br
2l
aAerobic oxidative bromination conditions were as follows: substrate
(5mmol), HBr (5.5mmol, 40% aqueous solution), 2-MePy·HNO3
(5.5mmol), 90℃, O2 balloon.
3c
4c
O
O
4
5
10
8
93 (84)
92 (82)
bGas chromatography yield.The figures in parentheses are isolated yields.
cReaction was carried out under reflux conditions.
dHBr (14mmol, 40% aqueous solution) and 2-MePy·HNO3 (5.5mmol)
were used.
Br
Br
Br
3d
4d
O
O
(see Table S3 in Supplemental Material for optimization of
the reaction conditions). There is no significant substituent
effect of the phenyl ring on this α-bromination of aryl
ketones 3 (Table 2).
Br
3e
4e
aAerobic oxidative bromination conditions were as follows: substrate
The proposed mechanism is described as a sequential (5mmol), HBr (5.5mmol, 40% aqueous solution), 2-MePy·HNO3
(0.5mmol), O2 balloon, 60℃.
cascade of double-cycle oxidation–reduction reactions
(Scheme 1). Nitrate anions play a critical catalytic role in
bGas chromatography yield.The figures in parentheses are isolated yields.
“activating” molecular oxygen.16–19 The pyridinum cation
may synergistically enhance the catalytic activity of nitrate.
In our previous report, 2-methylpyridinum shows the best
efficiency as counter ion for nitrate.14
Conclusion
In summary, the 2-MePy·HNO3–catalyzed aerobic oxida-
tive bromination of anilines and ketones has been devel-
oped with hydrobromic acid as the bromine source.Anilines
Scheme 1. Proposed mechanism of the nitrate-catalyzed
and ketones have been converted into their corresponding
bromo-compounds in good yields. Compared with existing
reports of oxidative brominations in ILs,14 only catalytic
amount of non-metal IL is used in our system with broader
substrate scope. The whole procedure avoids the handling
of Br2 and toxic volatile organic solvents, and shows good
efficiency and atom economy.
aerobic oxidative bromination.
Tables 1 and 2. Thin layer chromatography (TLC) and gas
chromatography (GC) were used to monitor the progress of
the reaction.
Purification and identification of the product
For 2a-2l. Ten milliliters of saturated Na2CO3 aqueous
solution was added at the end of the reaction, and the result-
ing mixture was extracted with 20mL EA three times. The
combined organic layer was washed with water and dried
over Na2SO4; the concentrated residue was purified by col-
umn chromatography (silica gel, petroleum ether (PE): EA
from 200:1 to 80:1) to afford product 2.
Experimental
General procedure
A mixture of substrate 1 or 3 (5mmol), HBr (5.5mmol,
40% aqueous solution), and 2-methylpyridinium nitrate
(5.5mmol) was stirred in a reaction flask equipped with a
condenser and an O2 balloon at the temperature given in

4
Journal of Chemical Research 00(0)
For 4a-4e. Ten milliliters of saturated NaHSO3 aqueous ORCID iD
solution was added at the end of the reaction, and the mix-
Ming-Fang Li
https://orcid.org/0000-0001-5696-3074
ture was extracted with 20 mL EA three times. The com-
bined organic layer was then washed with water and dried
over Na2SO4; the concentrated residue was purified by col-
umn chromatography (silica gel, PE: dichloromethane
(DCM) from 50:1 to 30:1) to afford product 4.
Supplemental material
Supplemental material for this article is available online.
References
1. Pingali SRK, Madhav M and Jursic BS. Tetrahedron Lett
2010; 51: 1383–1385.
Characterization of products
2. Saikia I, Borah AJ and Phukan P. Chem Rev 2016; 116:
6837–7042.
2a:4-Bromoaniline. The compound was obtained as brown
solid, yield 0.714g (83%), m.p. 64–66oC. δ H (500MHz,
CDCl3; TMS) 7.26–7.23 (m, 2H), 6.58–6.55 (m, 2H), 3.67
(br, 2H).
3. Li JH, Liang Y and Xie YX. Tetrahedron 2005; 61: 7289–7293.
4. Miyaura N and Suzuki A. Chem Rev 1995; 95: 2457–2483.
5. Ziegler CB and Heck RF. J Org Chem 1978; 43: 2941–2946.
6. Zhang J, Li T and Zhao XH. J Colloid Interface Sci 2016;
463: 13–21.
7. Podgorsek A, Zupan M and Iskra J. Angew Chem Int Ed
2009; 48: 8424–8450.
8. Galloni P, Mancini M and Floris B. Dalton Trans 2013; 42:
11963–11970.
2j: 2-Bromo-4-nitroaniline. The compound was obtained as
brown solid, yield 0.868g (80%), m.p. 100–102°C. δ H
(500MHz, CDCl3; TMS) 8.39 (d, J=2.5Hz, 1H), 8.04 (dd,
J=8.9, 2.5Hz, 1H), 6.75 (d, J=8.9Hz, 1H), 4.84 (s, 2H).
9. Mendoza F, Guerrero RR and Fuentes CH. Tetrahedron Lett
2016; 57: 5644–5648.
10. Wang J, Wang W and Li JH. Green Chem 2010; 12: 2124–
2126.
11. Wang JQ, Wang XL and Niu ZQ. Synth Commun 2015; 46:
165–168.
4e: 2-Bromoindanone. The compound was obtained as yel-
low sticky oil, yield 0.865g (82%). δ H (500MHz, CDCl3;
TMS) 7.85 (d, J=7.5Hz, 1H), 7.67 (t, J=7.5Hz, 1H),
7.47–7.43 (m, 2H), 4.66 (dd, J=7.5, 3.2Hz, 1H), 3.84 (dd,
J=18.1, 7.5Hz, 1H), 3.43 (dd, J=18.1, 3.2Hz, 1H).
12. Huang ZJ, Li FB and Chen BF. ChemSusChem 2013; 6:
1337–1340.
13. Ghorpade AK, Huddar SN and Akamanchi KG. Tetrahedron
Lett 2016; 57: 4918–4921.
14. Ren YL, Wang BY, Tian XZ, et al. Tetrahedron Letters
2015; 56: 6452–645.
Acknowledgements
We are grateful for the support provided by the Zhejiang Provincial
Program for Cultivation of High-Level Innovative Health Talents
(2014).
15. Wang J, Chen SB, Wang SG, et al. Aust J Chem 2015; 68:
513–517.
Declaration of conflicting interests
16. Prebil R, Laali KK and Stavber S. Org Lett 2013; 15: 2108–
2111.
17. Noe M, Perosa A, Selva M, et al. Green Chem 2010; 12:
1654–1660.
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
18. Chiappe C, Leandri E and Tebano M. Green Chem 2006; 8:
742–745.
Funding
The author(s) received no financial support for the research, 19. Earle MJ, Katdare SP and Seddon KR. Org Lett 2004; 6:
authorship, and/or publication of this article.
707–710.