Transition-metal-free synthesis of quinolines from 2-nitrobenzyl alcohol in water

Article abstract of DOI:10.1016/j.tetlet.2015.10.062

A method for the synthesis of quinolines from cheap and readily available 2-nitrobenzyl alcohol without a transition-metal catalyst in water has been developed, providing a convenient method for accessing quinolines. The reaction features an intramolecular redox process, which generates the key intermediate leading to product formation.

Full text of DOI:10.1016/j.tetlet.2015.10.062

Accepted Manuscript
Transition-metal-free Synthesis of Quinolines from 2-Nitrobenzyl Alcohol in
Water
Meijuan Zhu, Chao Wang, Weijun Tang, Jianliang Xiao
PII:
S0040-4039(15)30259-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.062
TETL 46891
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
21 September 2015
14 October 2015
18 October 2015
Please cite this article as: Zhu, M., Wang, C., Tang, W., Xiao, J., Transition-metal-free Synthesis of Quinolines
from 2-Nitrobenzyl Alcohol in Water, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.10.062
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Graphical Abstract
Transition-metal-free Synthesis of
Quinolines from 2-Nitrobenzyl Alcohol in
Water
Meijuan Zhu,a Chao Wang,a,* Weijun Tang,a Jianliang Xiaoa,b

1
Tetrahedron Letters
journal homepage: www.els evier.com
Transition-metal-free Synthesis of Quinolines from 2-Nitrobenzyl Alcohol in Water
Meijuan Zhu,a Chao Wang,a,* Weijun Tang,a Jianliang Xiaoa,b
a Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education and School of Chemistry and Chemical Engineering, Shaanxi Normal
University, Xi’an, 710062, China
b Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K.
Fax: 86-29-81530727; E-mail: c.wang@snnu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
A method for the synthesis of quinolines from cheap and readily available 2-nitrobenzyl alcohol
without a transition-metal catalyst in water has been developed, providing a convenient method
for accessing quinolines. The reaction features an intramolecular redox process, which generates
the key intermediate leading to product formation.
Received in revised form
Accepted
Available online
Keywords:
2015 Elsevier Ltd. All rights reserved
.
quinolines
2-nitrobenzyl alcohol
ketones
aqueous reaction
base
Quinoline scaffold exists widely in natural products and drug
molecules.1 Due to its importance, several name reactions, e.g.
Skraup,2 Doebner Miller,3 Conrad-Limpach,2 Gould-Jacobs,4
Knorr2 and Friedländer synthesis,5 have been developed to access
quinoline compounds.6 In the Friedländer synthesis, 2-
aminobenzaldehyde, which is unstable7 and is generally formed
in-situ by the reduction of 2-nitrobenzaldehyde with
stoichiometric Fe/HCl,8 is used to react with ketones. Recent
development of Friedländer synthesis has allowed the use of
relatively stable 2-aminobenzyl alcohol as a precursor, which
generates 2-aminobenzaldehyde through transition metal or base
catalysed hydrogen transfer to ketone substrates.9 Very recently,
Jiang and co-workers reported the use of stable and easily
available 2-nitrobenzyl alcohol as a precursor via a Ru catalysed
of the quinoline product from them could be easily monitored by
1H NMR with an internal standard.
Table 1 Screening of reaction conditionsa
O
OH
+
NO2
N
Ph
1a
2a
3a
Entry
Base
Solvent
T (oC)
90
Yield(%)b
1
NaOH
Isopropanol
Isopropanol
Isopropanol
Isopropanol
5
2
CH3COONa
K2CO3
90
0
3
90
0
4
N(Et)3
90
0
o
hydrogen transfer strategy to synthesise quinolines at 150 C.10
5
t-BuOK
DBU
Isopropanol 90
10
0
Herein, we disclose our finding that 2-nitrobenzyl alcohol could
react with ketones to form quinolines without any transition
metal catalysts with water as solvent (Scheme 1).
6
Isopropanol
EtOH
90
7
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KOH
90
15
7
[Pd, Ru], or base
OH
O
8
Pentanol
1,4-dioxane
DMF
90
+
R2
NH2
R1
9
90
0
[Ru]
R2
R1
OH
OH
R1
10
11
12
13
14c
15d
16e
17
90
0
+
+
R2
NO2
N
DMSO
H2O
90
0
t-BuOK
OH
O
90
22
35
49
13
54
53
This work
R2
R1
NO2
Water
Transition metal free
H2O
120
120
120
120
120
Stable and readily
available substrates
H2O
Scheme 1. Synthesis of quinolines via metal-catalysed and metal-free
reactions.
H2O
Our initial idea was to use a metal catalyst and an alcohol as
reductant to promote the reaction of 2-nitrobenzyl alcohol with a
ketone to form quinolines. The reaction between 2-nitrobenzyl
alcohol and propiophenone was chosen as a model, as the yield
H2O
H2O

2
Tetrahedron
a
Reaction condition: 2-nitrobenzyl alcohol (0.5 mmol), 2a (1.0 mmol),
of radical scavengers, such as TEMPO and BHT, did not inhibit
base (0.5 mmol), solvent (3 mL), 90 oC, 12 h, under Ar.
b The yields were determined by 1H NMR with 1,3,5-trimethoxylbenzene as
internal standard.
the model reaction (Scheme 3), which suggests that the reaction
may not proceed via radical intermediates. The drop of yields
might stem from the disturbance of the physical mixture of
substrates by the additional reagents, as these compounds all
have small solubility in water. It was reported that nitro groups
could be reduced to amino groups with alcohols in the presence
Table 2 Synthesis of quinolines in watera
c
Reaction performed using 2 equivalents of t-BuOK.
d
The reaction was performed with the addition of 5 mol% of the phase
transfer catalyst tetrabutylammonium chloride.
e The reaction time was 24 h.
Various transition-metal catalysts, including iridicyles
developed in our group,11 was tested for the model substrates
with isopropanol as solvent and NaOH as base at 90 oC for 12 h.
The quinoline product was indeed observed, albeit with low yield
(ca. 5% for all the metal catalysts tested, see Table S1).
Surprisingly, running a background reaction revealed that the
formation of the quinoline product did not require any transition
metal catalysts (Table 1, entry 1). However, the addition of
NaOH (1 equivalent) is essential for the product formation. As
base promoted reduction reactions have been reported,12 the
effect of different bases was then examined (Table 1, entries 1-6).
A strong base, t-BuOK, improved the yield to 10% (Table 1,
entry 5). Various solvents were then screened with t-BuOK as
base (Table 1, entries 7-12), and the results showed that the
desired product was obtained only in alcohols and water, with
water giving the highest yield (Table 1, entry 12). By increasing
the reaction temperature to 120 oC, the yield could be further
improved to 35% in 12 h (Table 1, entry 13). With 2 equivalents
Entry
Ketone
Product
Yield (%)b
1
54
2
3
60
34
4
5
6
46
24
56
o
of t-BuOK at 120 C, the yield of desired product rose to 49%
(Table 1, entry 14). When the amount of propiophenone was
decreased to 1 equivalent, the reaction also took place, but the
yield was lower than that with 2 equivalents (Table 1, entry 15).
Prolonging the reaction time to 24 h led to full conversion of 2-
nitrobenzalcohol, with the quinoline product isolated in 54%
yield (Table 1, entry 16). Analysis of the reaction mixture
revealed that ca. 37% of 2-aminobenzoic acid was formed. As t-
BuOK will react with water to form KOH and t-BuOH, KOH
was tested as a base in water and a similar of 53% was obtained
(Table 1, entry 17).
7
8
59
67
Although the yield of the quinoline product was not high, the
by-product could be easily separated from the desired product via
simple extraction. Therefore we thought it was worth examining
the substrate scope of this protocol. The results are shown in
Table 2. The steric and electronic nature of substituents on the
aromatic ring of aryl ketones affects the activity of the reaction.
Aryl ketones with electron withdrawing para-substituents
generally showed higher activities than ones with electron
donating groups (Table 2, entries 2-9). Thus, over 60% of
isolated yields were obtained for 4-Br and 4-CF3 substituted
substrates (Table 2, entries 8, 9). Substituents at meta-position to
the carbonyl group on the aromatic ring decrease the activity of
the reaction (Table 2, entries 10, 11) and only a trace amount of
product was formed with ortho-substituted substrates. Sulfur
containing substrates were tolerated (Table 2, entries 5 and 12).
These might be difficult for transition metal catalysed reactions
as the sulfur atom might poison the metal catalysts. The protocol
is also viable for the sterically bulky 2-naphthyl acetophenone,
albeit with low yield (Table 2, entry 13). However, the protocol
is not applicable to aliphatic ketones, as only trace yield was
obtained. Aromatic ketones other than methyl ketones also
reacted, but with lower yield than the corresponding methyl
ketones, probably due to their increased steric hindrance (Table 2,
entries 1, 14). The practical usefulness of this method is
demonstrated by a gram scale reaction of 2-nitrobenzyl alcohol
with 4-bromoacetophenone (Scheme 2).
9
69
10
11
51
17
12
65
13
14
30
28
The mechanism of the reaction was next studied. It was
reported that t-BuOK could react with organic molecules to
generate radicals.13 Thus, experiments were carried out to check
the possibility of a radical pathway for the reaction. The addition
a Reaction conditions: 2-nitrobenzyl alcohol (0.5 mmol), ketone (1.0 mmol),
t-BuOK (1.0 mmol), H2O (3 mL), 120 oC, 24 h, under Ar.
b Isolated yield.

3
Scheme 2. Gram scale preparation of quinoline.
Scheme 3. The effect of radical scavengers. Reaction conditions: 2-
nitrobenzyl alcohol (0.5 mmol), radical scavenger (0.5 mmol), 2a (1.0
mmol), t-BuOK (1.0 mmol), H2O (3 mL), 120 oC, 24 h, under Ar.
Scheme 5. Proposed reaction mechanism.
University (IRT_14R33), the 111 project (B14041), Shaanxi
Provincial Natural Science Foundation (2014JQ2048), the
Fundamental Research Funds for the Central Universities
(GK261001316, GK261001329, GK261001095), the Program for
Key Science and Technology Innovative Team of Shaanxi
Province (2012KCT-21 and 2013KCT-17), and the Scientific
Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry.
Scheme 4. Intramolecular vs intermolecular hydrogen transfer.
of bases.12e Thus, we carried out an experiment in the absence of
ketone substrate under standard conditions to see if the key
intermediate 2-aminobenzaldehyde could be isolated. 2-
nitrobenzalcohol was converted to 2-aminobenzoic acid instead
of 2-aminobenzaldehyde in 56% yield with 2 equivalents of t-
BuOK in water at 120 oC for 24 h under Ar atmosphere (Scheme
4). The formation of 2-aminobenzoic acid might result from the
Cannizzaro reaction of 2-aminobenzaldehyde intermediate,
which may be formed by intramolecular hydrogen transfer
mediated by the base (Scheme 5, from 1 to 5). Subjecting 5 to the
standard conditions, no reaction took place, indicating 5 is not an
intermediate for quinoline formation but rather a by-product.
Interestingly, little intermolecular reaction took place between
nitrobenzene and benzyl alcohol under standard conditions for 24
h (Scheme 4), indicating that the reduction process is initiated by
an intramolecular hydrogen transfer process. In the presence of a
ketone substrate, the 2-aminobenzaldehyde intermediate will
undergo an aldol reaction with the ketone substrate under basic
conditions followed by cyclisation to form the quinoline product
(Scheme 5).9d,9k,9m,14
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for Changjiang Scholars and Innovative Research Team in

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