An N-heterocyclic carbene-catalyzed approach to the indirect Friedl?nder quinoline synthesis

Article abstract of DOI:10.1039/c4ra07858f

Quinolines have been obtained through the indirect Friendl?nder annulation starting from 2-aminobenzyl alcohol or derivatives from it and ketones catalyzed by N-heterocyclic carbene, and the synthesis of polysubstituted quinolines through a one-pot, two-step tandem reaction starting from readily available ketones and alcohols via alpha-alkylation and indirect Friedl?nder annulation under air also has been presented.

Full text of DOI:10.1039/c4ra07858f

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Graphical Abstract
Quinolines have been obtained through the indirect Friendländer annulation starting from
2-aminobenzyl alcohol and ketones catalyzed by -heterocyclic carbene.
N

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A N-Heterocyclic Carbene - Catalyzed Approach to
the indirect Friedländer Quinoline Synthesis
Cite this: DOI: 10.1039/x0xx00000x
Yanfang Zhu, Chun Cai*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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quinoline compounds. In 2008, Yus and coꢀworkers 17 reported the tꢀ
Quinolines have been obtained through the indirect
Friendländer annulation starting from 2-aminobenzyl
BuOK (1.0 equiv) catalyzed system with benzophenone (100 mol%)
as hydride scavenger in dioxane at 90 °C under an argon atmosphere
gave the expected 2ꢀphenyl quinoline in an excellent yield (99%). In
alcohol and ketones catalyzed by
N-heterocyclic carbene,
and the synthesis of polysubstituted quinolines through a
one-pot, two-step tandem reaction starting from readily
available ketones and alcohols via alpha-alkylation and
indirect Friedländer annulation under air also has been
presented.
22
the same year, Verpoort and coꢀworkers demonstrated the same
example in dioxane using tꢀBuOK (1.5 equiv) as the catalyst at 80 oC
23
under air with the yield of 94%. And Liang et al. reported this
reaction proceed in toluene with tꢀBuOLi (2.0 equiv) as the catalyst
at 110 °C under an argon atmosphere afforded the yield of 94% after
12 h. However, these approaches often suffer from excess bases,
high temperature, and sometimes need an atmosphere of argon.
Therefore, development of an alternative method for the indirect
Friedländer transformations still remains a challenge.
The quinoline scaffold is one of the ubiquitous structures that exist
1
in pharmaceuticals and biologicals. 2ꢀArylquinoline scaffolds are
of particular importance for the construction of a wide range of
biologically active molecules, such as Pꢀselectin antagonism,
2ꢀ6
In recent years, Nꢀheterocyclic carbenes (NHCs) have received
considerable attention as an important and powerful class of
organocatalysts24ꢀ26 with tremendous applications in a variety of
synthetic transformations and as versatile ligands27ꢀ29 in transition
antimalarial, and antitumor activities.
Because of the diverse
pharmacological value of quinolines, a variety of novel and
expeditious approaches have been reported in recent years.
metal catalysis. However, the reaction catalyzed by NHCs
Conventional routes for the synthesis of quinolines, such as the
Skraup, Doebner–von Miller, Conrad–Limpach, and Pfitzinger
syntheses, suffer from harsh reaction conditions, low
stereoselectivity or consist of multiple steps, resulting in low overall
30ꢀ32
employing other substrates was quite limited,
except aldehydes.
33ꢀ39 Herein, we wish to report the indirect Friedländer synthesis of
quinolines from aminoalcohol and ketone using NHCs in the
presence of a base, without any transitionꢀmetal catalyst. (Scheme
1).
7
yields, limiting their applicability. The Friendländer annulation
starting from unstable 2ꢀaminobenzaldehyde and ketones has proven
to be one of the most simple, straightforward, and widely used ways
to develop quinoline compounds. Despite some acids8ꢀ16 have been
employed for the reaction, these procedures often suffer from the
unstable 2ꢀaminobenzaldehyde17 and the formation of side products
as a result of the selfꢀaldol condensation of the 2ꢀaminoaryl
carbonyls. 18
In order to overcome the drawbacks mentioned before, the
transitionꢀmetal catalyzed the indirect Friedländer annulation has
obtained considerable attention as a useful tool for the synthesis of
quinoline compounds, in which the indirect Friedländer reaction
using 2ꢀaminobenzyl alcohols instead of 2ꢀaminoaryl carbonyls have
emerged as a promising alternative.19ꢀ21 However, this indirect
method gave final products contaminated with traces of transition
metals, which are limited in some industrial applications. Otherwise,
baseꢀmediated indirect Friedländer transformations can also afford
Scheme 1. Synthesis of substituted quinolines from 2ꢀaminobenzyl
alcohol and ketones.
Our investigation began with the reaction of 2ꢀaminobenzyl alcohol
1a with acetophenone 2a catalyzed by precursor A in the presence of
KOH under air at 60 °C. To our delight, the target annulation
product 3a was obtained (Table 1, entry 1). Consequently, a series of
other precursors (Fig.1) were evaluated, wherein precursor B
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displayed the highest catalytic activity (Table 1, entry 2). Optimal
amount of acetophenone 2a was selected to be two equivalents to 1a
(Table 1, entries 2 and 5). The excess ketone may serve as a
hydrogen acceptor, accelerating the oxidation of the alcohol function
to an aldehyde. It was found that the bases drastically affected the
reaction. An excellent yield (90%) of product 3a can be achieved
when KOH was used (Table 1, entry 2), while, using other weaker
bases such as K2CO3, NEt3 and Cs2CO3, no reaction occurred (Table
1, entries 6ꢀ8). In addition, decreased base dosage was found to
afford unsatisfactory yield of 3a (Table 1, entry 9). With the amount
of precursor B decreased to 1 mol%, the yield dropped to 80%
(Table 1, entry 10). Optimization of solvents for the synthesis of 3a
employing the precursor B was also undertaken and it was found that
among toluene, DMF, CH3Cl and dioxane (Table 1, entries 2, 11ꢀ13),
the best solvent in terms of yield was toluene (Table 1, entry 2).
Thus, nonpolar solvents, toluene, chloromethane were proven to be
better effective than polar solvents on the reaction. Notably,
performing the reaction in the absence of precursor B led to a low
yield product 3a (Table 1, entry 14). It should be noted that the
indirect Friedländer synthesis of quinolines from aminoalcohol and
ketones using NHC catalyst could be proceed readily at a lower
temperature and under an atmosphere of air, as compared to those
approaches that only using base as catalysts. 17, 22, 23
11
12
13
14
1:2
1:2
1:2
1:2
KOH(1)
KOH(1)
KOH(1)
KOH(1)
DMF
43
85
38
38
B
B
B
-
CH3Cl
dioxane
toluene
a
Reaction conditions: 1, 2a and precursor (2 mol%) were mixed together in
toluene (2 ml）under air and finally base was added, 60 oC, for 1 h.
b
precursor (1mol%) was used.
Fig. 1 Nꢀheterocyclic carbene precursors used in the reaction
With the optimized reaction conditions in hand, we set out to explore
the substrate scope of this process. In all cases, moderate to excellent
yields could be achieved. Both electronꢀdonating substituents
including methyl and methoxy groups as well as electronꢀ
withdrawing substituents such as bromo and trifluoromethyl groups
on the aromatic ring of acetophenone were well tolerated in this
reaction (Table 2, 3aꢀ3e). The quinolines using other aryl ketones
with longer chains also could be obtained in excellent yields (3f, 3g
in Table 2). In addition, the protocol could be employed also with
aliphatic ketones, with similar excellent results (3hꢀ3l in Table 2). 2ꢀ
Acetylpyridine was well tolerated in this reaction to give 3m in
moderate yield. 2ꢀAminobenzyl alcohols with methyl on the alphaꢀ
position also finished the desired products 3n in good yield. 2ꢀ
Aminobenzyl alcohol with electronꢀdonating and electronꢀ
withdrawing groups on the aromatic ring gave excellent yields of
products (3o, 3p in Table 2).
Table 1. NHCꢀCatalyzed optimization of conditions for the reaction
of 1a with 2aa
Entry
Precursor 1:2a Base
(equiv)
Solvent
Isolated
Yield[%]
1
2
1:2
1:2
1:2
1:2
1:1
1:2
1:2
1:2
1:2
1:2
KOH(1)
KOH(1)
KOH(1)
KOH(1)
KOH(1)
K2CO3(1)
NEt3(1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
84
90
79
82
61
nr
A
B
C
D
B
B
B
B
B
B
Table 2. Synthesis of quinolines from (2ꢀaminophenyl) methanol
and ketonesa
3
4
5
3a 90% yield
3b 95% yield
3c 90% yield
6
7
nr
8
Cs2CO3(1) toluene
KOH(0.5) toluene
nr
3d 83% yield
3e 86% yield
3f 85% yield
9
69
80
10 b
KOH(1)
toluene
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3g 87% yield
3h 85% yield
3i 70% yield
Entry
R1
R2
R5
R6
Quinoline
Isolated
yield
3j 93% yield
3k 84% yield
3l 82% yield
[%]
1
2
H
H
H
H
H
H
Br
H
H
H
85 (46)b
83
7a
7b
7c
7d
7e
7f
H
H
OMe
Br
H
3m 65% yield
3n 62% yield
3o 79% yield
3
4
5
6
7
H
H
65
H
OMe
CF3
H
81
H
H
63
CH3
H
H
68
3p 95% yield
H
H
72
7g
a
a Reaction conditions: 5 (0.6 mmol), 4 (0.5 mmol), precursor A (0.2 mol%), KOH
(0.5 mmol), toluene (1.5 mL), 110 oC, 5 h. This was followed by the addition of 2ꢀ
aminobenzyl alcohol (0.25 mmol), precursor B (2 mol%), KOH (0.25 mmol), 80
Reaction conditions: 2ꢀaminobenzyl alcohol (0.5 mmol), 2 (1.0 mmol),
o
precursor B (2 mol%), KOH (0.5 mmol), toluene (2 mL), 60 C, for 1 h,
under air. Isolated yield based on 2ꢀaminobenzyl alcohol.
b
oC, 4 h; Reaction conditions: 5 (0.6 mmol), 4 (0.5 mmol), precursor A (0.2
mol%), KOH (0.5 mmol), toluene (1.5 mL), 110 oC, 5 h. This was followed by the
addition of 2ꢀaminobenzyl alcohol (0.25 mmol), precursor B (2 mol %), KOH
(0.25 mmol), 60 oC, 4 h.
Encouraged by upon results we then envisioned that the use of
alphaꢀalkylation of ketones with alcohols in conjunction with the
indirect Friedländer synthesis would be suitable for creating more
complicated quinoline compounds. To our delight, this reaction
proceeded very smoothly, afforded the corresponding products in
moderate to excellent yields. When 4a was reacted with 5a in the
presence of 0.2 mol % of precursor A and 1.0 equiv of KOH at
110 °C (bath temp) for 5 h, the desired αꢀalkylated ketone 6a was
formed in 98% yield. For the second step, substrates 6a and 2ꢀ
aminobenzyl alcohol were reacted at 60 °C for 1 h with the precursor
B and 1 equiv of KOH to form the product quinoline 7a in 46 %
yield. When 6a was allowed to react with 2ꢀaminobenzyl alcohol at
80 °C for 4 h, 7a was produced in 85% yield. After establishing ideal
conditions for the oneꢀpot reaction, we investigated the scope of this
twoꢀstep tandem reaction with various ketones and alcohols
catalyzed by NHC. The electronic effect had an obvious influence on
this reaction (Table 3, 7aꢀ7e). Electronꢀrich benzyl ketones and
benzyl alcohols have a relatively higher reactivity, affording the
corresponding products in good yields (Table 3, 7b, 7d). 2ꢀ
Aminobenzyl alcohol with electronꢀwithdrawing groups on the
aromatic ring and methyl on the alphaꢀposition also finished the
desired products in good yields (Table 3, 7f, 7g). It should be noted
that the indirect Friedländer synthesis of quinolines through a oneꢀ
pot, twoꢀstep tandem reaction using NHC catalyst could be proceed
readily at a lower temperature and under an atmosphere of air, as
compared to the approach.21
The proposed mechanism for the reaction is presented in Scheme 2.
The base deprotonates Nꢀheterocyclic carbene salt to generate a free
carbene. The role of NHC may be to assist both proton and hydride
transfer from 1 to 2, forming the intermediate. One equivalent of 2
acts as hydrogen acceptor and is converted to the corresponding
alcohol in the oxidation process of 1. A cross aldol reaction between
the 3 and deprotonated ketone, followed by a cyclization step, leads
to the quinoline.
Table 3. NHCꢀcatalyzed coupling of various alcohols with ketones
and subsequent addition of 2ꢀaminobenzyl alcohol or derivatives
from it to produce quinolines.a
Scheme 2. Proposed reaction mechanism and cyclic intermediate.
J. Name., 2012, 00, 1-3 | 3
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DOI: 10.1039/C4RA07858F
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Chemical Engineering College, Nanjing University of Science &
Technology, 200 Xiaolingwei, Nanjing 210094, P. R. China. Fax: +86-25-
84315030; Tel.: +86-25-84315514; E-mail: c.cai@mail.njust.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
procedures and characterization of new products.
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