Metal-free aerobic one-pot synthesis of substituted/annulated quinolines from alcohols via indirect Friedl?nder annulation

Article abstract of DOI:10.1039/c5ob01422k

Metal-free, operationally simple, and highly efficient one-pot aerobic process for the synthesis of functionalized/annulated quinolines is devised from easily available 2-aminobenzyl alcohol/2-aminobenzophenones and alkyl/aryl alcohols for the first time. The process involves two sequential reactions, namely in situ aerial oxidation of alcohols to the corresponding aldehydes/ketones followed by Friedl?nder annulation.

Full text of DOI:10.1039/c5ob01422k

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DOI: 10.1039/C5OB01422K
Journal Name
COMMUNICATION
Metal-free aerobic one-pot synthesis of substituted/annulated
quinolines from alcohols via indirect Friedländer annulation
Received 00th January 20xx,
Accepted 00th January 20xx
Namrata Anand, Suvajit Koley, B. Janaki Ramulu and Maya Shankar Singh*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Metal-free, operationally simple, and highly efficient one-pot methods are not usually employed in medicinal applications
aerobic process for the synthesis of functionalized/annulated due to the contamination with traces of metals. Martίnez and
15
quinolines is devised from easily available 2-aminobenzyl co-workers
reported potassium tert-butoxide catalyzed
alcohol/2-aminobenzophenones and alkyl/aryl alcohols for the Oppenauer oxidation of 2-aminobenzyl alcohol followed by
first time. The process involves two sequential reactions, namely condensation with ketone to give corresponding quinolines.
Common methods for the oxidation of alcohols are Dess-
Martin, Corey-Kim, Swern and Oppenauer oxidation.
in situ aerial oxidation of alcohols to the corresponding
aldehydes/ketones followed by Friedländer annulation.
16
17
18
19
Moreover, the usual solvents employed result in very tedious
workup procedures. Furthermore, to make this century-old
Friedländer reaction more practical and general, we attempted
to develop a metal-free indirect Friedländer annulation that
uses cheap and readily available alcohols as an electrophilic
partner instead of expensive enolizable carbonyl compounds.
Cascade reactions, which allow multiple transformations
in a one-pot process, were recognized as an environmentally
friendly and atom-economic strategy for building molecules
Quinolines and their derivatives are privileged structural
motifs, which are present in numerous natural products as
well as in pharmaceutical agents. Functionalized quinolines
exhibit
antimalarial,
antibacterial,
anti-inflammatory,
antiasthmatic, antifungal, analgesic and HIV-1 integrase
1
,2
inhibitory properties.
Owing to their broad range of
biological importance, significant efforts have been made for
3
the synthesis of quinoline derivatives. The most prevalent
20
with structural diversity and molecular complexity.
It
strategies for the construction of quinoline ring involve
4a
continues to be an area of intense interest to develop new
protocols to construct valuable molecules from cheap and
readily accessible starting materials by concise steps. Our
interest in exploring the simple and efficient method for the
anilines and carbonyl compounds such as Combes, Conrad–
4
b,c
4d,e
5
6a,b
Limpach,
Gould-Jacobs,
conventional methods, some other named reactions such as
Doebner–von Miller,
Friedländer, Skraup,
6c
7
and Povarov methods. Besides these
21
8a,b
8c
8d,e
synthesis of quinolines led us to consider the use of
inexpensive and easily available alkyl/aryl/benzyl alcohols
towards the synthesis of functionalized quinolines. Herein, we
report a metal-free, highly efficient, environmentally benign,
and extremely simple strategy for the synthesis of
substituted/annulated quinolines (Scheme 1). The tandem
process involves in situ aerial oxidation of both the alcohol
components followed by Friedländer annulation in the
presence of KOH at 80 °C temperature in open atmosphere.
Pfitzinger, Niementowski and Knorr quinoline synthesis
are being frequently utilized. However, most of them suffer
from harsh reaction conditions, unstable and expensive
starting materials, often expensive catalysts, low yields, and
problems associated with the storage of carbonyl reagents.
Besides above methods, several organometal-catalyzed
approaches have recently been developed for the construction
9
of quinoline scaffolds.
Indirect Friedländer approaches using 2-aminobenzylic
alcohols and ketones catalyzed by transition-metal complexes
1
0
11
12
13
derived from ruthenium, palladium, iridium, rhodium,
14
and copper have also been reported. In general, the above
Scheme 1 Synthesis of quinolines 3 via indirect Friedlander annulation.
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COMMUNICATION
Journal Name
In our initial experiment, 2-aminobenzyl alcohol (1a) and 10). Subsequently, we screened organic bases such as Et N and
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3
1
-butanol (2a) were chosen as the model substrates to DBU in place of KOH, which could not eveDnOIt:r1i0g.g1e03r9t/hCe5OreBa01c4ti2o2nK
optimize the reaction conditions. The observations under (Table 1, entries 11 and 12). Control experiments (without any
varying conditions are summarized in Table 1. The reaction of base or in presence of oxidizing agent I ) did not provide a
2
2
-aminobenzyl alcohol (1a, 1 mmol) with 1-butanol (2a, 4 trace of the desired quinoline 3aa (Table 1, entries 13 and 14).
mmol) in presence of KOH (1 mmol) was carried out at 80 °C in Changing the solvent from alcohol to DMF did not offer a
an open flask. The workup of the reaction afforded compound better result (Table 1, entry 15). Thus, the optimum reaction
3
aa in 36% yield, which was characterized as 3-ethyl quinoline condition for the synthesis of quinoline 3aa was achieved by
(Table 1, entry 1). Here, 1-butanol plays dual role of reactant employing 1a (1 mmol), 2a (4 mmol), and KOH (5 mmol) at 80
as well as solvent. Encouraged by this observation, we °C for 6 h in open atmosphere.
performed the above test reaction at room temperature, but
a
Table 2 Scope of substrates for the synthesis of quinolines
3
no trace of 3aa was observed even after 24 h, and 1a
remained completely unreacted (Table 1, entries 2 and 3).
After evaluating the role of temperature, next we performed
the model reaction at 80 °C with higher loading of KOH. To our
pleasure, not only the yield of the desired product 3aa was
increased to 88%, but the time required for the completion of
the reaction was also reduced significantly (Table 1, entries 4
and 5). Further increment in the loading of KOH could not
improve the results (Table 1, entry 6).
Table 1 Optimization of reaction conditions
Entry Base (mmol)
Temp (°C)
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
KOH (1)
KOH (1)
KOH (5)
KOH (3)
KOH (5)
KOH (6)
80
25
25
80
80
80
80
80
80
80
80
80
80
80
80
c
16
24
24
10
6
36
a
-
-
a
72
88
88
6
b
KOH (5)
aq. KOH
24
24
10
8
24
24
8
trace
c
a
-
NaOH (5)
76
64
t
1
0
1
2
3
4
5
K OBu (5)
a
Reaction conditions: 2-Aminobenzyl alcohol 1a or 1b (1 mmol), alcohol
4 mmol), KOH (5 mmol), 80 °C, 5-7 h, open flask.
2
a
1
1
1
1
1
Et
3
N (5)
-
-
-
-
(
a
DBU (5)
None
a
With the optimized reaction conditions in hand, the
generality and scope of the substrates for the direct
construction of quinolines ( ) were examined and are shown in
a
I
2
(5)
24
10
d
KOH (5)
49
3
a
b
d
No reaction. Inert atmosphere. 50 mol% of aq. KOH was used. 1 mmol Tables 2 and 3. The one-pot cascade process serves as a
of each 1a, 2a and 5 mmol of KOH in DMF was heated at 80 °C.
general approach to access various substituted/annulated
quinolines in high yields. The protocol tolerated well with 2-
aminobenzyl alcohol (1a), 2-amino-2,3-dibromobenzyl alcohol
Next, to evaluate the role of aerial oxygen, we performed
the model reaction under inert atmosphere at 80 °C.
Remarkably, the rate of reaction became highly sluggish and
only trace of the desired product 3aa was observed on TLC
plate after 24 h (Table 1, entry 7). The above observation
suggests that air is crucial as hydride scavenger for the
reaction. In an attempt to find a green solvent, we performed
the model reaction in aqueous KOH, but the starting materials
(
1b) with wide range of acyclic (2a
-
d, 2g and 2k-m) and cyclic
in
alcohols (2h ) affording the corresponding quinolines 3
good yields. Noteworthy, both primary and secondary alcohols
undergo in situ aerial oxidation in presence of KOH to give the
corresponding
-
j
aldehydes/ketones
followed
by
cyclocondensation to give the desired quinolines
3
. Moreover,
2
-methoxy ethanol (2d) was also tolerated well under the
optimal reaction conditions to give 3-methoxy quinoline 3ad in
1% yield (Table 2). Accordingly, the reaction of 2-aminobenzyl
remained completely unconsumed even after 24 h of heating
Table 1, entry 8). Use of NaOH and K OBu separately in place
of KOH could not improve the result (Table 1, entries 9 and
t
(
9
alcohol (1a) with 2-butanol (2g) led to the formation of 2,3-
2
| J. Name., 2012, 00, 1-3
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Org aP nl ei ca s &e dB oi o nmo to la ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
dimethyl quinoline (3ag) in 79% yield. Tetrahydronaphthalen-
COMMUNICATION
After successful utilization of benzophenonVeiesw,Arwticele Onnelixnet
-ol (2j) also reacted readily under the optimal conditions to extended our study to 2-aminoacetopheDnOoI:n1e0.1(013f)9./CT5rOeaB0tm14e22nKt
1
furnish the corresponding fused quinoline 3aj in 62% yield. of 1f with 1-butanol (2a) under the standard optimized
After the successful synthesis of 3-substituted, 3,4- reaction conditions provided unexpected 2,4-disubstituted
disubstituted, and annulated quinolines we turned our quinoline (
attention toward the construction of 2-substituted quinolines. ethyl-4-methyl quinoline (
Reaction of 2-aminobenzyl alcohol (1a) with 1-phenyl ethanols above observation limits the scope and generality of the
2k-m) leads to the formation of corresponding quinolines 3ak- protocol to some extent. Here, 2-aminoacetophenone under
4
) in 95% yield, while no trace of the expected 3-
5
) was obtained (Scheme 2). The
(
3
am in good yields (Table 2). The phenyl ring bearing both the reaction conditions undergoes self-condensation to form
2
3a
electron-withdrawing as well as electron-donating group at 2- quinoline
(4), and second component alcohol does not take
position of the quinoline ring are well tolerated with no part in the reaction and simply plays a role of solvent only.
prominent electronic effect on the outcomes of the reaction. Structures of all the synthesized quinolines are confirmed by
1
13
Interestingly, we found that the oxidation of both the alcohols their satisfactory H and C NMR studies and comparison with
1
0b-f,23
1
a
and
2
could be mediated by strong base and air without the the reported ones.
The chemistry is amenable to both
22
use of metal catalyst or ketone as proton scavenger.
small and gram-scale reactions. The reaction of 2-
aminobenzophenone 1c (5 g, 25 mmol) with ethanol 2b (6 mL)
proceeded smoothly to provide 4.63 g of product 3cb (89%),
which is comparable to the small scale experiment (Table 3).
a
Table 3 Scope of 2-aminobenzophenones (1c-e) with alcohols (2)
Scheme 2 Unexpected formation of 2-(2-aminophenyl)-4-methylquinoline 4.
Based on o4ur entire experimental outcomes and
2
literature report, a possible reaction mechanism for the
formation of quinoline
the reaction starts with aerial oxidation of alcohols 1a and
their corresponding hydroperoxides and . Next, the
hydroperoxides and react with KOH to form their
respective alkoxides, and finally to aldehydes and with
elimination of H O . Thus, in situ generated both the aldehydes
3
is outlined in Scheme 3. It seems that
2
to
A
B
A
B
C
D
2
2
C
and
D
under basic conditions endure a dehydrative
. Finally, the intermediate
undergoes intramolecular aldol-type condensation to give
condensation to give intermediate
E
E
the desired quinoline
3. In fact, during the reaction of 2-
aminobenzyl alcohol (1a) and ethanol (2b) under optimized
conditions, we isolated 2-aminobenzaldehyde
validates the proposed pathway of the reaction.
(C), which
a
Reaction conditions: 2-Aminobenzophenone 1c, 1d or 1e (1 mmol), alcohol 2 (4
b
mmol), KOH (5 mmol), 80 °C, 5-10 h. gram-scale yield of 3cb 89%.
To illustrate the broad synthetic utility and generality of
our one-pot cascade protocol, we further treated 2-
aminobenzophenones (1c, 1d and 1e) with various acyclic as
well as cyclic alcohols separately under the optimal reaction
conditions. Both acyclic (2a-g and 2k) and cyclic alcohols (2h
Scheme 3 Possible mechanism for the synthesis of quinoline 3.
To gain more insight into the reaction mechanism, we
treated 2-aminobenzaldehyde with butan-1-al under the
similar reaction conditions, which afforded the desired 3-ethyl
quinoline 3aa in 95% yield, suggesting the intermediacy of
aldehydes during the course of the reaction.
and 2i
affording the corresponding quinolines
Table 3), showing the versatility of this approach.
)
reacted smoothly with 2-aminobenzophenones
3
in 78-95% yields
(
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COMMUNICATION
Journal Name
Carreiras and E. Soriano, Chem. Rev., 2009, 10Vi9ew, A2r6tic5le2Oanlninde
Structurally diverse substituted/annulated quinolines have
been synthesized via one-pot two-component cascade
coupling of 2-aminobenzyl alcohol/2-aminobenzophenones
with alkyl/aryl alcohols in open atmosphere. The reaction
involved the metal-free in situ aerial oxidation of alcohols
followed by Friedländer annulation to furnish the
corresponding quinolines. This method not only provides an
excellent complement to substituted/annulated quinoline
synthesis, but also avoids the use of hazardous reagents and
tedious purification. The merits of this procedure are its
operational simplicity, user-friendly, high yields, ease of
purification, economic viability, and ready availability of the
starting materials. In addition to its simplicity, the protocol
nicely tolerates both acyclic and cyclic alcohols.
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DOI: 10.1039/C5OB01422K
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0/2013), New Delhi and the Council of Scientific and
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Delhi, India. N. A. and S. K. are thankful to UGC, New Delhi and
B. J. R. thanks to CSIR, New Delhi for research fellowship.
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DOI: 10.1039/C5OB01422K
Table of Content
Metal-free one-pot aerobic synthesis of functionalized/annulated
quinolines is devised from viable alcohols via indirect Friedländer
annulation.
This journal is © The Royal Society of Chemistry 20xx
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