Superbase-Mediated Indirect Friedl?nder Reaction: A Transition Metal-Free Oxidative Annulation toward Functionalized Quinolines

Article abstract of DOI:10.1002/ejoc.202000365

A superbase mediated indirect Friedl?nder reaction towards functionalized quinolines has been realized. The reaction was performed with o-aminobenzyl alcohol and ketones having an active methylene moiety in the presence of KOH and in DMSO. The reaction proceeds predominantly via initial formation of an imine intermediate and subsequent oxidation of the benzyl alcohol functionality and condensation to afford substituted quinolines. We could also demonstrate that a minor fraction of the reaction proceeds via a chalcone intermediate. The transition metal-free oxidative annulation was found to be general affording 2-substituted, 2,3-disubstituted/fused or multi-substituted quinolines. The reaction was extended towards the functionalization of natural products and the applicability of the reaction for gram-scale synthesis of quinolines was also demonstrated.

Full text of DOI:10.1002/ejoc.202000365

A Journal of
Accepted Article
Title: Superbase Mediated Indirect Friedländer Reaction: A Transition
Metal-Free Oxidative Annulation toward Functionalized
Quinolines
Authors: Rahul P, Nitha P R, Vishnu K. Omanakuttan, Sheba Ann
Babu, P Sasikumar, Vakayil K. Praveen, Henning Hopf, and
Jubi John
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000365
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10.1002/ejoc.202000365
European Journal of Organic Chemistry
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Superbase Mediated Indirect Friedländer Reaction: A Transition
Metal-Free Oxidative Annulation toward Functionalized
Quinolines
Rahul P.,[a],[b] Nitha P. R.,[a],[b] Vishnu K. Omanakuttan,[a],[b] Sheba Ann Babu,[a],[b] P. Sasikumar,[a]
Vakayil K. Praveen,*[a],[b] Henning Hopf*[c] and Jubi John*[a],[b]
Abstract:
A
superbase mediated indirect Friedländer reaction
modified or indirect Friedländer quinoline synthesis protocols
with dehydrogenative cyclisation of 2-aminobenzyl alcohol with
carbonyl compounds (or alcohols) were developed in the
presence of metal catalysts (Scheme 1).[6] Different complexes
of metals such as Ru,[6b] Rh,[6c] Ir,[6d-f] Cu,[6g] Ni[6h-i] and Re[6j] were
utilized as catalysts in indirect Friedländer quinoline synthesis. In
addition, several heterogeneous catalysts which includes Ru-HT
(ruthenium on hydrotalcite support), Pd/C, Pd(OAc)2/PEG-2000,
Ag-Pd alloy on carbon and a Cu based MOF were also
developed and used for synthesizing substituted quinolines
(Scheme 1).[7]
towards functionalized quinolines has been realized. The reaction
was performed with o-aminobenzyl alcohol and ketones having an
active methylene moiety in the presence of KOH and in DMSO. The
reaction proceeds predominantly via initial formation of an imine
intermediate and subsequent oxidation of the benzyl alcohol
functionality and condensation to afford substituted quinolines. We
could also demonstrate that a minor fraction of the reaction proceeds
via a chalcone intermediate. The transition metal-free oxidative
annulation was found to be general affording 2-substituted, 2,3-
disubstituted/fused or multi-substituted quinolines. The reaction was
extended towards the functionalization of natural products and the
applicability of the reaction for gram scale synthesis of quinolines
was also demonstrated.
Another advancement in the area of indirect Friedländer
quinoline synthesis was the introduction of metal-free
strategies.[8] The first among them was reported in 2008 by
Ramón, Yus and co-workers which combined the Meerwein-
Ponndorf-Verley reaction of 2-aminobenzyl alcohols with
benzophenone and the Friedländer annulation to synthesize
quinoline derivatives.[8a] Recently, an N-heterocyclic carbene-
catalyzed indirect Friedländer quinoline synthesis was reported
by Zhu and Cai.[8b] and an aerobic one-pot synthesis by Singh et
al (Scheme 1).[8c] These reported metal-free methodologies
required additional reagents (benzophenone for the MPV
reaction of 2-aminobenzyl alcohol[8a] or the presence of a
catalyst.[8b] We were interested in developing a transition metal-
free and additional reagent-free methodology for quinoline
synthesis based on the indirect Friedländer reaction.
Introduction
The class of quinoline derivatives pose a continuous challenge
to synthetic chemists in devising straightforward routes for
accessing them.[1] The profound interest invested in this
heterocyclic moiety is due to its wide applicability in
pharmaceuticals,[2] materials[3] and industry.[4] Substituted
quinolines exhibit promising biological activities such as
antimalarial, antibacterial, antiviral, antitumor, analgesic,
anticonvulsant, anti-inflammatory etc.[2] These findings have
resulted in the development of blockbuster drugs (of natural and
synthetic origin) such as quinine, chloroquine, camptothecin,
pitavastatin, bedaquiline, lenvatinib, tipifarnib and saquinavir
which are being heavily used worldwide for the treatment of
different ailments.
Several classical organic reactions exist which utilizes
arylamines as precursors for the synthesis of quinoline and its
derivatives and out of which Friedländer quinoline synthesis can
still be considered as one of the most direct routes for accessing
this important heterocycle.[5] The traditional Friedländer reaction
involves a base promoted condensation of 2-amino-substituted
carbonyl compound (aromatic) and an α-methylene group
containing carbonyl derivative followed by dehydration. Recently,
[a]
Mr. Rahul P., Miss Nitha P. R., Mr. Vishnu K. Omanakuttan, Miss
Sheba Ann Babu, Dr. P. Sasikumar, Dr. Vakayil K. Praveen, Dr. Jubi
John
Chemical Sciences and Technology Division, CSIR-National
Institute for Interdisciplinary Science and Technology (CSIR-NIIST),
Thiruvananthapuram-695019, India. Email: vkpraveen@niist.res.in,
jubijohn@niist.res.in
https://www.niist.res.in/english/scientists/jubi-john/research-
interests.html
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad-201002, India.
Scheme 1. Indirect Friedländer synthesis of quinolines from 2-aminobenzyl
alcohol.
[b]
[c]
Prof. Henning Hopf
Institut für Organische Chemie, Technische Universität
Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany.
Email: h.hopf@tu-bs.de
Superbasic medium (mainly the combination of KOH and
DMSO) have been utilized extensively by Trofimov and others
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10.1002/ejoc.202000365
European Journal of Organic Chemistry
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for effecting different organic transformations such as
chalcogenation, cross-coupling, intramolecular cyclization,
heterocyclic synthesis, styrylation, inter- and intramolecular
hydromaminations etc.[9] Verma and co-workers made use of the
KOH-DMSO system for the synthesis of functionalized
quinolines from o-aminobenzyl alcohol and alkynes.[10] The
reaction proceeded via a [4 + 2] cycloadditions of alkyne with
azadiene (in situ generated from o-aminobenzyl alcohol). An
efficacious methodology for the oxidation of active methylenes
and benzhydrols to corresponding carbonyl compounds
mediated by a base-DMSO system was reported by Ravikumar
et al.[11] Motivated by the above mentioned reports on the use of
superbasic media and owing to our interest in heterocyclic
synthesis,[12] we hypothesized that functionalized quinolines
could be generated from o-aminobenzyl alcohol and α-
methylene group containing carbonyl derivatives via an
oxidation-condensation sequence in the presence of a base-
DMSO system and most importantly in the absence of any
additional reagent or catalyst.
did not affect the reaction yield and in this line the reactions with
2’-methoxy (2d) and 2’-methylacetophenone (2e) afforded the
products 3d and 3e in good yields, whereas the reaction with 2’-
hydroxyacetophenone (2f) furnished the product 3f only in 56%
yield.
Table 1. Optimization studies
Entry
Base
Time
T (oC)
Yield of
3a[a] (%)
1
KOH
7
7
7
7
7
7
7
7
48
7
7
7
80
80
80
80
80
80
80
120
RT
80
80
80
80
48
51
61
-
2
tBuONa
tBuOK
NaOH
K2CO3
KOH
3
4
5
6[b]
7[c]
8[c]
9[c]
10[d]
11[c]
12[e]
83
88
59
23
72
-
KOH
Result and Discussions
KOH
KOH
KOH
-
We commenced our investigations by selecting o-aminobenzyl
alcohol 1a and 4’-methoxy acetophenone 2a as model
substrates. The initial reaction was performed with one
equivalent each of 1a and 2a in the presence of KOH (1.0
equivalent) and DMSO (1.0 mL) at 80 oC for 7 h. As expected, 2-
(4-methoxyphenyl)quinoline 3a was isolated in 80% yield (Table
KOH
86
t
1, entry 1). Different bases other than KOH such as BuONa,
tBuOK, NaOH and K2CO3 were screened for the present indirect
Friedländer quinoline synthesis (Table 1, entries 1-5). From the
tested bases, KOH was found to be the best and the reaction
failed to furnish any product in presence of K2CO3. Increasing
the equivalents of o-aminobenzyl alcohol had a beneficial effect
on the outcome of the reaction. Thus, with 1.2 equivalents of 1a,
the substituted quinoline was isolated in 88% yield (Table 1,
entries 1, 6 and 7). Next, we checked the effect of change in
temperature on the yield of the reaction. It was found that both
Reaction conditions: [a] 1a (1.0 equiv.), 2a (1.0 equiv., 0.6 mmol), base (1.0
equiv.), DMSO (1.0 mL), 80 oC, 7 h. [b] 1a (1.1 equiv.). [c] 1a (1.2 equiv.). [d]
1a (1.2 equiv.), KOH (0.5 equiv.). [e] 1a (1.2 equiv.), argon atmosphere.
The superbase mediated oxidative annulation proceeded
well with di- (2g) and tri-methoxy acetophenones (2h) affording
the products 3g and 3h in excellent yields. The presence of
electron withdrawing groups were found to influence the reaction
outcome
as
the
reactions
with
both
3’-
o
increasing (to 120 C) and decreasing the temperature (to RT)
(trifluoromethyl)acetophenone (2i) and 3-nitroacetophenone (2j)
could only furnish the corresponding 2-substituted quinolines 3i
and 3j in poor yields. Another interesting observation that we
came across was in the reaction with 4’-chloroacetophenone
and o-aminobenzyl alcohol 1a. In contrary with our expectation
of 2-(4-chlorophenyl)quinoline 3k, we obtained a dehalogenated
quinoline derivative. The dehalogenation of aromatic compounds
with a DMSO-base combination was reported earlier which
might be the reason for the present observation.[13] The oxidative
annulation also worked with acetylferrocene affording 2-
ferrocenylquinoline 3l in 45% yield. 2-Naphthylquinole 3m was
synthesized in excellent yield but after 14 h of reaction time. By
starting with 1,3-dicetylbenzene we could synthesize 1,3-di-
quinolylbenzene 3n in 69% yield. Finally, the reactivity of
different acetylheteroarenes toward the present indirect
Friedländer reaction was examined and thus pyridyl (3o), furyl
(3q) and thienyl (3r) substituted quinolines were synthesized in
good yields.
considerably decreased the yield of 3a (Table 1, entries 7-9). A
decrease in the equivalents of KOH (to 0.5 equivalents) was
found to lower the yield of 3a to 72% (Table 1, entry 10) and the
reaction failed to afford any product in the absence of KOH
(Table 1, entry 11). Finally, conducting the reaction under inert
atmosphere didn’t significantly influence the outcome of the
reaction proving that oxygen is not required for the oxidation
step (Table 1, entry 12).
The scope and limitation of the indirect Friedländer quinoline
synthesis was then studied (Table 2) under the optimized
conditions [1 (1.2 equiv.), 2 (1.0 equiv.), KOH (1.0 equiv.),
DMSO (1.0 mL), 80 oC, 7 h]. Both acetophenone 2b and 4’-
methylacetophenone 2c participated in the oxidative annulation
with o-aminobenzyl alcohol 1a affording the corresponding
products 3b and 3c in 75 and 80% respectively. 2-Phenyl
quinoline 3b was also synthesized in gram scale and in good
yield (70%) by starting with 1.0 g of acetophenone 2b. A
substituent on the ortho-position of the aryl ring of acetophenone
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10.1002/ejoc.202000365
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Table 2. Generality of indirect Friedländer reaction toward 2-substituted
Table 3. Generality of indirect Friedländer reaction toward 2,3-
quinolines
disubstituted/fused quinolines
Reaction conditions: 1a (1.2 equiv.), 4 (1.0 equiv., 0.6 mmol), KOH (1.0 equiv.,
0.6 mmol), DMSO (1.0 mL), 80 oC, 7 h. [a] intractable reaction mixture.
Subsequently, we examined the effect of substituents on o-
aminobenzyl alcohols on the outcome of the superbase
mediated quinoline synthesis (Table 4). We commenced with the
reaction of acetophenone 2b with 1-(2-aminophenyl)ethan-1-ol
1b. The reaction was complete in 7 h and from which the 2,4-
disubstituted quinoline 3ad was isolated in 75% yield. 2-
aminobenzhydrol 1c also reacted with ease affording the 2,4-
diphenylquinoline 3ae in good yield.
Reaction conditions: 1a (1.2 equiv.), 2 (1.0 equiv., 0.6 mmol), KOH (1.0 equiv.,
0.6 mmol), DMSO (1.0 mL), 80 oC, 7 h. [a] started with 1.0 g of 2b. [b] 120 oC,
12 h. [c] 14 h.
Next, we turned our attention in synthesizing 2,3-
disubstituted/fused quinolines via the developed superbase
mediated oxidative annulation (Table 3). We commenced our
investigations with o-aminobenzyl alcohol 1a and cyclohexanone
under the optimized conditions and 1,2,3,4-tetrahydroacridine 3r
was isolated in 72% yield. The reaction with 4-
methylcyclohexanone also afforded the corresponding
substituted tetrahydroacridine derivative 3s in 68% yield. Other
cyclic ketones such as cycloheptanone and cyclooctanone
afforded the 2,3-fused quinoline derivatives 3t and 3u in good
yields. The indirect Friedländer reaction was also found to work
well with tetralone 4e and methoxytetralone 4f from which the
respective dihydrobenzo[c]acridine derivatives 3v and 3w were
isolated in excellent yields. We then checked the reactivity of
propiophenone 4g and butyrophenone 4h and these ketones
reacted well under the optimized conditions affording the
corresponding 2,3-disubstitued quinolines 3x and 3y in good
yields. We have also checked the reactivity of acyclic ketones
such as acetone and 2-hexanone but to our dismay, after the
required time an intractable reaction mixture was observed. The
importance of the present oxidative annulation was exemplified
by performing ‘quinolization’ of natural products containing an
enolizable ketone moiety. Thus both menthone (mixture of
isomers) and 5α-cholestan-3-one were treated with o-
aminobenzyl alcohol 1a under our optimized conditions and the
corresponding annulated natural products 3ab and 3ac were
isolated.
Table 4. Generality of indirect Friedländer with substituted o-aminobenzyl
alcohol.
Reaction conditions: 1a (1.2 equiv.), 2 (1.0 equiv., 0.6 mmol), KOH (1.0 equiv.,
0.6 mmol), DMSO (1.0 mL), 80 oC, 7 h.
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Next, we checked the reactivity of 2-amino-3-methylbenzyl
alcohol 1d under the optimized conditions and the respective
quinoline derivative 3af was obtained in 86% yield (Table 4).
The reaction of 1-(2-aminophenyl)-2,2,2-trifluoroethan-1-ol 1e
annulation to furnish 2-substituted quinoline by the elimination of
H2O.
also
proceeded
well
affording
2-phenyl-4-
(trifluoromethyl)quinoline 3ag in 74% yield. Lastly we checked
the reactivity of 2-amino-4-chlorobenzyl alcohol 1f with
acetophenone and as observed earlier (Table 2, compound 3k)
we obtained the dehalogenated product.
In order to prove the mechanism of the superbase mediated
indirect Friedländer quinoline synthesis we carried out several
experiments with substrates 1a and 2b (Scheme 2). The
possibility for a radical mediated reaction was ruled out with the
first reaction (Scheme 2a) where 1a and 2b were allowed to
react under the optimized conditions but in the presence of 1.0
equivalent of BHT from which 2-phenylquinoline 3b was isolated
in 73% yield. It is reported that the classical Friedländer
quinoline synthesis can proceed either via the imine 5 or o-
amino chalcone 6 as intermediates.[5] When 5 was subjected to
the optimized conditions, we were able to isolate the expected
product 3b in 90% yield after an hour (Scheme 2b). On the other
hand, when o-amino chalcone 6 was allowed to react at the
optimized conditions, the reaction took 5 h to furnish 88% of 3b
(Scheme 2c). These results show that the present superbase
Scheme 2. Reactions to support the mechanism of superbase mediated
indirect Friedländer quinoline synthesis.
mediated
quinoline
synthesis
might
be
proceeding
predominantly via the imine intermediate 5 rather than the
chalcone 6 and that imine formation must be happening
preferentially over the oxidation of the benzyl alcohol moiety.
Finally, we were able to detect the formation of Me2S as a by-
product by conducting a GCMS experiment (Scheme 2d).[14]
Conclusion
In conclusion, we have developed a mild, transition metal-free
and general methodology for the synthesis of functionalized
quinolines. In contrast to the reported methods that required
either metal catalysts (homogeneous or heterogeneous) or
additional reagents (hydride scavenger or NHC catalyst) our
strategy required only the combination of KOH in DMSO. In this
superbasic medium, the reaction proceeds predominantly via the
formation of an imine and successive oxidation of 2-aminobenzyl
alcohol to the corresponding aldehyde followed by condensation
with the enamine moiety. We could propose a mechanistic
postulate by isolating the imine intermediate and by subjecting it
to oxidative annulation conditions. We could also show that a
From the results obtained for the experiments depicted
above, we believe that the first step of quinoline synthesis
(predominant pathway) would be the condensation of amino
group of 2-aminobenzylalcohol and acetophenone to yield the
imine 5 (Scheme 3). This will be followed by the oxidation of the
alcohol to the corresponding carbonyl group which proceeds via
a mechanism analogous to the one proposed by Ravikumar et
al.[11a] Initially the base will generate the alkoxide intermediate A
from 5. The adduct B is then formed by the attack of the
alkoxide to the electrophilic sulfur of DMSO. Subsequently
proton transfer occurs from the benzylic carbon to the alkoxide
generating the carbanion C which further undergoes an E1cb
elimination furnishing the corresponding carbonyl compound D.
An intramolecular aldol addition occurs in intermediate D to
furnish the dihydroquinoline E from which water is eliminated to
finally afford the substituted quinoline derivative.[5] The
secondary pathway will commence with the benzylic alcohol
functionality to the o-amino benzaldehyde I by following a similar
mechanism as shown before. The o-amino chalcone 6 is then
formed by the condensation of I with acetophenone. The
minor fraction of the reaction proceeds via
intermediate. This oxidative annulation worked well affording
mono-, di- and poly-substituted quinolines in good yields. In the
a chalcone
case
of
halogen
substituted
quinoline
derivatives,
dehalogenation was observed as reported earlier. It is
noteworthy to mention that we could synthesize substituted
quinoline by this methodology in gram scale thereby proving
the applicability of the reaction. In addition, we also utilized
this superbase mediated oxidative annulation to
functionalize natural products. We are currently focusing on
other superbase mediated reactions of 2-aminobenzyl
alcohol and the results will be published
.
intermediate
6
subsequently undergoes intramolecular
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Scheme 3. Mechanism of superbase mediated indirect Friedländer quinoline synthesis.
7 84−7 79 (m, 2H), 7 7 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.05
(d, J = 8.5 Hz, 1H), 3.89 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ
160.8, 156.9, 148.3, 136.6, 132.3, 129.6, 129.5, 128.9, 127.4, 126.9,
125.9, 118.6, 114.2, 55.4 ppm. HRMS (ESI-Orbitrap) m/z: (M +H)+ calcd
for C16H14NO 236.1070, found 236.1078.
Experimental Section
General
All chemicals were of the best grade commercially available and were
used without further purification. All solvents were purified according to
the standard procedures; dry solvents were obtained according to the
literature methods and stored over molecular sieves. Analytical thin-layer
chromatography was performed on polyester sheets pre-coated with
silica gel containing fluorescent indicator ( 254)
ravity column chromatography was performed using neutral alumina,
and mixtures of ethyl acetate hexanes were used for elution elting
points were determined using a calibrated digital melting point apparatus
( chi 53 melting point apparatus). NMR spectra were recorded with
Bruker Avance-300 (300 MHz for 1H NMR, 75 MHz for 13C{1H} NMR)
and Bruker AMX-500 (500 MHz for 1H NMR, 125 MHz for 13C{1H} NMR)
instruments. All spectra were measured at 300 K, unless otherwise
specified. The chemical shifts δ are given in ppm and referenced to the
external standard TMS or internal solvent standard. 1H NMR coupling
2-phenylquinoline (3b).[6i,14a] Following the general experimental
procedure with o-aminobenzyl alcohol 1a (99 mg, 0.80 mmol),
acetophenone 2b (81 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3b as white solid
(103 mg, 75%). For the gram-scale preparation of 3b, the yield was 70%
(1.19 g). Analytical data of 3b: p: 84−87 °C 1H NMR (500 MHz, CDCl3,
T ) δ 8 2 −8 15 (m, 4H), 7 85 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8 Hz,
1H), 7 73−7 7 (m, 1H), 7 53−7 49 (m, 3H), 7 47−7 44 (m, 1H) ppm
13C{1H} NMR (125 MHz, CDCl3, T ) δ 157 4, 148 3, 139 7, 136 8,
129.8, 129.7, 129.3, 128.9, 127.6, 127.5, 127.2, 126.3, 119.1 ppm.
HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C15H12N 206.0964, found
206.0975.
constants (J) are reported in Hertz (Hz) and multiplicities are indicated as
follows s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
2-(p-tolyl)quinoline (3c).[6i,14a] Following the general experimental
procedure with o-aminobenzyl alcohol 1a (99 mg, 0.80mmol), 4-
methylacetophenone 2c (90mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3c as white solid
(117 mg, 80%). Analytical data of 3c: p: 81−84 °C 1H NMR (500 MHz,
CDCl3, T ) δ 8 17 (t, J = 9 Hz, 2H), 8.07 (d, J = 8 Hz, 2H), 7.84 (d, J =
8.5 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.71 (t, J = 8 Hz, 1H), 7.50 (t, J = 7.5
Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 2.43 (s, 3H) ppm . 13C{1H} NMR (125
MHz, CDCl3) δ 157 4, 148 3, 139 4, 136 9, 136 7, 129 7, 129 6, 127 4,
127.1, 126.1, 118.9, 21.4 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd
for C16H14N 220.1121, found 220.1124.
(doublet of doublets). Mass spectra were performed with
a
ThermoFinnigan MAT95XL, a ThermoFisher Scientific LTQ Orbitrap
Velos, and an Agilent 6890 gas chromatograph with JMS-T100GC
spectrometer or with a ESI/ HRMS at 60,000 resolution using Thermo
Scientific Exactive mass spectrometer with orbitrap analyzer. Gas
chromatographic analysis was performed using GCMS-TQ8030
SHIMADZU.
Experimental procedure for the synthesis of substituted quinoline
derivatives: To a reaction tube equipped with a magnetic stirring bar,
acetophenone 2 (1.0 equiv.), o-aminobenzylalcohol 1 (1.2 equiv.) and
KOH (1 equiv.) and 1 mL of DMSO were added. The resultant reaction
mixture was kept for stirring at 80°C for 7 h. After completion of the
reaction, water was added and the aqueous layer extracted thrice with
ethylacetate. The organic layer was dried over anhydrous Na2SO4 and
the solvent was removed under vacuum. The residue was then purified
by column chromatography (neutral alumina, eluent: mixtures of
ethylacetate/hexanes) to afford the corresponding 2-substituted
quinolines
2-(2-methoxyphenyl)quinoline (3d).[6i,14a] Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 2-methoxyacetophenone 2d (100 mg, 0.67 mmol), KOH (38 mg,
0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h.
The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3d as colorless liquid (129 mg, 82%). Analytical data of 3d: 1H
NMR (500 MHz, CDCl3, T ) δ 8 18−8 13 (m, 2H), 7 89−7 82 (m, 3H),
7.70 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 8 Hz, 1H),
7.13 (t, J = 7.5Hz, 1H), 7.03 (d, J = 8 Hz, 1H), 3.86 (s, 3H) ppm. 13C{1H}
NMR (125 MHz, CDCl3) δ 157 2, 157 2, 148 3, 135 1, 131 5, 13 4,
129.8, 129.6, 129.2, 127.4, 127.1, 126.2, 123.5, 121.3, 111.4, 55.7 ppm.
HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C16H14NO 236.1070, found
236.1072.
2-(4-methoxyphenyl)quinoline (3a).[6i,14a] Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 4-methoxyacetophenone 2a (100 mg, 0.67 mmol), KOH (38 mg,
0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h.
The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3a as white solid (138mg, 88%). Analytical data of 3a: Mp:
125−126 °C 1H NMR (500 MHz, CDCl3, T ): δ 8 18−8 13 (m, 4H),
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2-(o-tolyl)quinoline (3e).[6i,14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol), 2-
methylacetophenone 2e (90 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3e as white solid,
104 mg (71%). Analytical data of 3e: Mp: 69−71°C 1H NMR (500 MHz,
CDCl3, T ) δ 8 21 (d, J = 8 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.86 (d, J
= 8 Hz, 1H), 7.74 (t, J = 8 Hz, 1H), 7.58−7.53 (m, 2H), 7.50 (d, J = 7 Hz,
1H), 7.36−7.33 (m, 3H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ
160.3, 147.9, 140.8, 136.1, 136.0, 130.9, 129.7, 129.6, 128.5, 127.5,
126.8, 126.4, 126.0, 122.4, 20.4 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+
calcd for C16H14N 220.1121, found 220.1124.
product 3i as white solid (84 mg, 46%). Analytical data of 3i: Mp:
51−53 °C 1H NMR (500 MHz, CDCl3, T ) δ 8 47 (s, 1H), 8 36 (d, J =
7.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.90 (d, J =
8.5 Hz, 1H), 7.86 (d, J = 8 5 Hz, 1H), 7 78−7 72 (m, 2H), 7 65 (t, J = 7.5
Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ
155.6, 148.3, 140.4, 137.2, 131.3 (q, j = 32.5 Hz), 130.7, 130.0, 129.8,
129.3, 127.5, 127.4, 126.8, 125.9 (q, j = 3.8 Hz), 124.4 (q, j = 3.8 Hz),
118.6 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C16H11F3N
274.0844, found 274.0851.
2-(3-nitrophenyl)quinoline (3j).[14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 1.2 0.80 mmol), 3-
nitroacetophenone 2j (110.6 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol)
in DMSO (1.0 mL) at 120 °C and subsequent stirring for 12 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexanes) to afford the desired product 3j as white solid
(44 mg, 26%). Analytical data of 3j: 1H NMR (500 MHz, CDCl3, T ) δ
9.06 (s, 1H), 8.57 (d, J = 8 Hz, 1H), 8 33−8 31 (m, 2H), 8 2 (d, J = 8 Hz,
1H), 7.95 (d, J = 8.5Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.79 (t, J = 8 Hz,
1H), 7.72 (t, J = 8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3) δ 148 3, 141 3, 137 4, 137 1, 133 3, 13 2, 129 9, 129 8,
127.6, 127.1, 123.9, 122.5, 118.4 ppm. HRMS (ESI-Orbitrap) m/z:
(M+H)+ calcd for C15H11N2O2 251.0815, found 251.0825.
2-(quinolin-2-yl)phenol (3f).[14c] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol), 2-
hydroxyacetophenone 2f (92 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol)
in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3f as white solid
(83 mg, 56%). Analytical data of 3f: p: 113−115 °C 1H NMR (500 MHz,
CDCl3, T ) δ 15 24 (s, 1H), 8 27 (d, J = 9 Hz, 1H), 8 6−8 3 (m, 2H),
7.95 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.74 (t, J = 8 Hz, 1H),
7 57−7 54 (m, 1H), 7 37 (t, J = 7. 5 Hz, 1H) 7.09 (d, J = 8.5 Hz, 1H), 6.96
(t, J = 7. 5 Hz, 1H) ppm. 13C{1H} N (125 Hz, CDCl3) δ 161 , 158 ,
144.8, 137.6, 130.5, 127.6, 127.5, 126.9, 126.7, 126.6, 119.0, 118.7,
118.7, 117.3 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C15H12NO
222.0913, found 222.0924.
2-Ferrocenylquinoline (3l).[14c] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol),
acetylferrocene 2l (153 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3l as red solid (94
mg, 45%). Analytical data of 3l: p: 135−138 °C.. 1H NMR (500 MHz,
CDCl3, T ) δ 8 4 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8 Hz, 1H), 7.66 (d, J
= 7.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.48– 7.45 (m, 1H), 5.07 (s, 2H),
4.47 (s, 2H), 4.06 (s, 5H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 159 5,
148.3, 135.4, 129.4, 129.0, 127.5, 126.7, 125.4, 119.5, 84.0, 70.4, 69.7,
68.0 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C13H10NS
314.0627, found 314.0621.
2-(2,5-dimethoxyphenyl)quinolone (3g). Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 2,5-dimethoxyacetophenone 2g (121 mg, 0.67 mmol), KOH (38
mg, 0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7
h. The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3g as white solid (138 mg, 78%). Analytical data of 3g: Mp:
141−143 °C 1H NMR (500 MHz, CDCl3, T ) δ 8 16 (t, J = 9.5 Hz, 2H),
7.91 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 5 Hz, 1H), 7 72−7 7 (m, 1H), 7 53 (t,
J = 7.5 Hz, 1H), 7.45 (s, 1H), 6.98 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 156 9, 154 1, 151 6, 148 3, 135 2,
130.4, 129.7, 129.3, 127.4, 127.1, 126.3, 123.4, 116.2, 116.1, 113.3,
56.6, 55.9 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C17H16NO2
266.1176, found 266.1181.
2-(naphthalen-2-yl)quinoline
(3m).[14c]
Following
the
general
experimental procedure with o-aminobenzyl alcohol 1a (99 mg, 0.80
mmol), 2-acetonaphthone 2m (114 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 14 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3m as a pale
yellow solid (135 mg, 79%). Analytical data of 3m: 1H NMR (300 MHz,
CDCl3, T ) δ 8 63 (s, 1H), 8 39 (dd, J1= 8.7 Hz, J2 = 1.8 Hz, 1H), 8.27–
8.23 (m, 2H), 8.04–7.99 (m, 3H), 7.93–7.89 (m, 1H), 7.86–7.83 (m, 1H),
7 79−7 74 (m, 1H) 7 58−7 53 (m, 3H) ppm 13C{1H} NMR (75 MHz,
CDCl3) δ 157 1, 148 3, 136 9, 136 8, 133 8, 133 5, 129 7, 129 7, 128 8,
128.6, 127.7, 127.5, 127.2, 127.1, 126.7, 126.3, 126.3, 125.0, 119.1 ppm.
2-(2,3,4-trimethoxyphenyl)quinoline (3h). Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 2,3,4-trimethoxyacetophenone 2h (141 mg, 0.67 mmol), KOH (38
mg, 0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7
h. The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3h as white solid (172 mg, 87%). Analytical data of 3h: Mp:
1 4−1 6 °C 1H NMR (500 MHz, CDCl3, T ) δ 8 16−8 15 (m, 2H), 7 9
(d, J = 9 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d,
J = 8.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.5Hz, 1H), 3.95 (s,
3H), 3.93 (s, 3H), 3.77 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ
156.6, 154.6, 152.3, 148.3, 142.4, 135.5, 129.6, 129.3, 127.6, 127.4,
127.0, 126.1, 125.8, 122.9, 108.1, 61.5, 61.1, 56.2 ppm. HRMS (ESI-
Orbitrap) m/z: (M+H)+ calcd for C18H18NO3 296.1281, found 296.1287.
1,3-di(quinolin-2-yl)benzene
(3n).[14d]
Following
the
general
experimental procedure with o-aminobenzylalcohol 1a (197 mg, 1.6
mmol), 1,3-diacetylbenzene 2n (109 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3n as white
solid (153 mg, 69%). Analytical data of 3n: Mp: 138-141 °C. 1H NMR
(500 MHz, CDCl3, T ) δ 8 97 (s, 1H), 8 3 –8.27 (m, 4H), 8.23 (d, J =
8.5 Hz, 2H), 8.04 (d, J = 9 Hz, 2H), 7.86 (d, J = 8 Hz, 2H), 7.75 (t, J = 7.5
Hz, 1H), 7.70 (t, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 2H) ppm. 13C{1H} NMR
(125 MHz, CDCl3) δ 157 2, 148 3, 14 3, 136 9, 129 8, 129 8, 129 5,
128.6, 127.5, 127.3, 126.8, 126.4, 119.2 ppm. HRMS (ESI-Orbitrap) m/z:
(M+H)+ calcd for C17H24N2 333.1386, found 333.1395.
2-(3-(trifluoromethyl)phenyl)quinoline (3i).[14b] Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 3-trifluoromethylacetophenone 2i (126 mg, 0.67 mmol), KOH (38
mg, 0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for
7
h. The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexanes) to afford the desired
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000365
European Journal of Organic Chemistry
FULL PAPER
2-(pyridin-2-yl)quinoline (3o).[14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol), 2-
acetylpyridine 2o (81 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3o as white solid
(103 mg, 75%). Analytical data of 3o: p: 98−1 °C 1H NMR (500 MHz,
CDCl3, T ) δ 8 74−8 73 (1H, m), 8 65 (d, J = 8 Hz, 1H), 8.56 (d, J = 8.5
Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.88-7.84 (m,
2H), 7.73 (t, J = 8 Hz, 1H) 7.55 (t, J = 7.5Hz, 1H), 7.35 (t, J = 6 Hz, 1H)
ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 156 4, 156 2, 149 2, 148 , 137 ,
136.8, 129.8, 129.6, 128.3, 127.6, 126.8, 124.1, 121.9, 119.0 ppm.
HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C14H11N2 207.0917, found
207.0922.
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 159 1, 146 7, 135 , 13 6,
128.5, 128.3, 127.2, 126.9, 125.5, 37.8, 33.1, 31.4, 29.1, 21.7 ppm.
HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C14H16N 198.1277, found
198.1286.
7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline (3t).[14c] Following the
general experimental procedure with o-aminobenzylalcohol 1a (99 mg,
0.80 mmol), cycloheptanone 4c (75 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3t as white
solid (84 mg, 64%). Analytical data of 3t: p: 92−94°C 1H NMR (500
MHz, CDCl3, T ) δ 8 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8
Hz, 1H), 7.61 (t, J = 8 Hz, 1H), 7.44 (t, J = 7 5 Hz, 1H), 3 21−3 2 (m, 2H),
2 93−2 92 (m, 2H), 1 89−1 74 (m, 6H) ppm 13C{1H} NMR (125 MHz,
CDCl3) δ 164 7, 146 2, 136 5, 134 6, 128 5, 128 4, 127 4, 126 8, 125 8,
40.1, 35.5, 32.2, 28.9, 27.0 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+
calcd for C14H16N 198.1277, found 198.1270.
2-(furan-2-yl)quinoline (3p).[14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol), 2-
acetylfuran 2p (74 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in DMSO
(1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude product was
purified by neutral alumina column chromatography (10% ethyl acetate in
hexanes) to afford the desired product 3p as white solid (90 mg, 69%).
Analytical data of 3p: p: 87−89 °C 1H NMR (500 MHz, CDCl3, T ) δ
8.17 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H),
7.79 (d, J = 8 Hz, 1H), 7 72−7 69 (m, 1H), 7 63 (s, 1H), 7 5 (t, J = 7.5 Hz,
1H), 7.22 (s, 1H), 6.60 (s, 1H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ
149.0, 144.2, 136.7, 129.9, 129.4, 127.6, 127.2, 126.2, 117.5, 112.2,
110.2 ppm.
6,7,8,9,10,11-hexahydrocycloocta[b]quinoline (3u).[14d] Following the
general experimental procedure with o-aminobenzylalcohol 1a (99 mg,
0.80 mmol), cyclooctanone 4d (85mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3u as
colorless liquid (74 mg, 52%). Analytical data of 3u: 1H NMR (500 MHz,
CDCl3, T ) δ 8 3 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 8 Hz,
1H), 7.62 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 3.17 (t, J = 6.5 Hz,
2H), 2.96 (t, J = 6 Hz, 2H), 1.90 (s, 2H), 1.78 (s, 2H), 1.41 (s, 4H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 163 2, 147 , 135 2, 135 , 128 5,
128.4, 127.6, 126.9, 125.6, 35.3, 32.7, 32.1, 31.0, 26.0, 25.9 ppm. HRMS
(ESI-Orbitrap) m/z: (M+H)+ calcd for C15H18N 212.1434, found 212.1438.
2-(thiophen-2-yl)quinoline (3q).[14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol), 2-
acetylthiophene 2q (85 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3q as white solid
(92 mg, 65%). Analytical data of 3q: p: 131−134 °C 1H NMR (500 MHz,
CDCl3, T ) δ 8 15 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H),
7 82−7 76 (m, 3H), 7 7 (t, J = 7 5 Hz, 1H), 7 51−7 47 (m, 2H), 7 18−7 16
(m, 1H), ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 152 4, 148 1, 136 7,
129.8, 129.3, 128.6, 128.1, 127.5, 126.1, 125.9, 117.7 ppm. HRMS (ESI-
Orbitrap) m/z: (M+H)+ calcd for C13H10NS 212.0528, found 212.0539.
5,6-dihydrobenzo[c]acridine
(3v).[14a]
Following
the
general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80), 1-
tetralone 4e (98 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in DMSO (1.0
mL) at 80°C and subsequent stirring for 7 h. The crude product was
purified by neutral alumina column chromatography (10% ethyl acetate in
hexane) to afford the desired product 3v as white solid (138 mg, 89%).
Analytical data of 3v: Mp: 59-62°C. 1H NMR (500 MHz, CDCl3, T ) δ
8.57 (d, J = 8 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.92 (s, 1H), 7.74 (d, J =
8 Hz, 1H), 7 66−7 63 (m, 1H), 7 48−7 41 (m, 2H), 7 37 (t, J = 7. 5 Hz, 1H),
7.27 (d, J = 7.5 Hz, 1H), 3.13 (t, J = 7 Hz, 2H), 3.01 (t, J = 7 Hz, 2H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 153 4, 147 7, 139 4, 134 7, 133 7,
130.6, 129.7, 129.4, 129.1, 128.7, 128.0, 127.9, 127.4, 126.9, 126.1,
28.9, 28.4 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C17H14N
232.1121, found 232.1129.
1,2,3,4-tetrahydroacridine (3r).[14c] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg, 0.80 mmol),
cyclohexanone 4a (66 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3r as pale yellow
1
solid (88 mg, 72%). Analytical data of 3r: H NMR (300 MHz, CDCl3,
T ) δ 7 99 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H),
7 62−7 56 (m, 1H), 7 44−7 39 (m, 1H), 3 13 (t, J = 6.6 Hz, 2H), 2.94 (t, J
= 6 6 Hz, 2H), 2 2−1 93 (m, 2H), 1 88−1 83 (m, 2H) ppm 13C{1H} NMR
(75 MHz, CDCl3) δ 159 2, 146 3, 135 1, 13 9, 128 5, 128 , 127 1, 126 8,
125.5, 33.4, 29.1, 23.1, 22.8 ppm.
4-methoxy-5,6-dihydrobenzo[c]acridine (3w). Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 5-methoxy-1-tetralone 4f (118 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3o as white
solid (157 mg, 90%). Analytical data of 3o: Mp: 120-123°C. 1H NMR (500
MHz, CDCl3, T ) δ 8 22 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H),
7.92 (s, 1H), 7.74 (d, J = 8 Hz, 1H), 7 65−7 62 (m, 1H), 7 47 (t, J = 7.5 Hz,
1H), 7.38 (t, J = 8.5Hz, 1H), 6.96 (d, J = 8 Hz, 1H), 3.90 (s, 3H), 3.09 (t, J
= 6.5 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 156 3, 153 4, 147 6, 135 9, 133 6, 13 6, 129 5, 128 5, 128 2,
127.9, 127.4, 126.9, 126.1, 118.4, 111.4, 55.7, 28.3, 20.4 ppm. HRMS
(ESI-Orbitrap) m/z:(M+H)+ calcd for C18H16NO 262.1226, found 262.1236.
2-methyl-1,2,3,4-tetrahydroacridine (3s).[14f] Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), 4-methylcyclohexanone 4b (75mg, 0.67 mmol), KOH (38 mg,
0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h.
The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3s as white solid (90 mg, 68%). Analytical data of 3s: Mp:
78−79°C 1H NMR (500 MHz, CDCl3, T ) δ 7 97 (d, J = 8.5 Hz, 1H),
7.74 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.41 (t, J =
7 5 Hz, 1H), 3 23−3 2 (m, 1H), 3 12−3 5 (m, 1H), 3 −2 96 (m, 1H),
2 59−2 53 (m, 1H), 2 6−1 95 (m, 2H), 1 62−1 54 (m, 1H), 1 11 (d, J = 7
3-methyl-2-phenylquinoline
(3x).[14a]
Following
the
general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000365
European Journal of Organic Chemistry
FULL PAPER
mmol), propiophenone 4g (90 mg, 0.67 mmol), KOH (38 mg, 0.67 mg) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3x as colourless
liquid (89 mg, 61%). Analytical data of 3x: 1H NMR (500 MHz, CDCl3,
T ) δ 8 13 (d, J = 8 Hz, 1H), 8.00 (s, 1H), 7.76 (d, J = 8 Hz, 1H),
7 67−7 64 (m, 1H), 7 58 (d, J = 7 Hz, 2H), 7 52−7 47 (m, 3H), 7 44-7.41
(m, 1H), 2.45 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 16 6,
146.6, 140.9, 136.8, 129.3, 129.2, 128.9, 128.8, 128.3, 128.2, 127.6,
126.8, 126.4, 20.7 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for
C16H14N 220.1121, found 220.1134.
21.4, 18.7, 12.0, 11.7 ppm. HRMS (ESI-Orbitrap) m/z: (M+ H)+ calcd for
C17H22N 472.3938, found 472.3962.
4-methyl-2-phenylquinoline
(3ad).[14g]
Following
the
general
experimental procedure with 1-(2-aminophenyl)ethan-1-ol 1b (110 mg,
80 mmol), acetophenone 2b (81 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3ad as a pale
yellow solid (110 mg, 75%). Analytical data of 3ad: 1H NMR (300 MHz,
CDCl3, T ) δ 8 31 – 8.24 (m, 3H), 7.99 (d, J = 8.7 Hz, 1H), 7.80– 7.75
(m, 1H), 7.72 (s, 1H), 7.62 – 7.53 (m, 4H), 2.74 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3) δ 156 8, 147 9, 144 6, 139 6, 13 1, 129 1, 129 ,
128.6, 127.4, 127.0, 125.8, 123.4, 119.5, 18.8 ppm.
3-ethyl-2-phenylquinoline (3y).[14a] Following the general experimental
procedure with o-aminobenzylalcohol 1a (99 mg,0.80 mmol),
butyrophenone 4h (99 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol) in
DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexanes) to afford the desired product 3y as colourless
liquid (90 mg, 58%). Analytical data of 3y: 1H NMR (500 MHz, CDCl3,
T ) δ 8 13 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J = 8 Hz, 1H),
7 68−7 65 (m, 1H), 7 56−7 53 (m, 3H), 7 5 −7 42 (m, 3H), 2 9 (q, J =
7.5 Hz,2H), 1.20 (t, J = 7.5Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3)
δ 16 7, 146 4, 14 9, 135.3, 134.9, 129.3, 128.8, 128.7, 128.3, 128.1,
127.8, 127.0, 126.4, 26.0, 14.7 ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+
calcd for C17H16N 234.1277, found 234.1283.
2,4-diphenylquinoline (3ae).[14g] Following the general experimental
procedure with (2-aminophenyl)(phenyl)methanol 1c (159 mg, 0.80
mmol), acetophenone 2b (81 mg, 0.67 mmol), KOH (38 mg, 0.67 mmol)
in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The crude
product was purified by neutral alumina column chromatography (10%
ethyl acetate in hexane) to afford the desired product 3ae as a pale
yellow solid (135 mg, 72%). Analytical data of 3ae: 1H NMR (300 MHz,
CDCl3, T ) δ 8 27 (d, J = 8.4 Hz, 1H), 8.22 – 8.20 (m, 2H), 7.92 (d, J =
8.7 Hz, 1H), 7.83 (s, 1H), 7.77 – 7.72 (m, 1H), 7.58 – 7.46 (m, 9H) ppm.
13C{1H} NMR (75 MHz, CDCl3) δ 156 9, 149 2, 148.8, 139.6, 138.4, 130.1,
129.6, 129.4, 128.8, 128.6, 128.4, 127.6, 126.3, 125.8, 125.6, 119.4 ppm.
4-isopropyl-1-methyl-1,2,3,4-tetrahydroacridine (3ab). Following the
general experimental procedure with o-aminobenzylalcohol 1a (99 mg,
0.80 mmol), menthone (isomeric mixture) 4i (104 mg, 0.67 mmol), KOH
(38 mg, 0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring
for 7h. The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexanes) to afford the desired
product 3ab as a colourless liquid and as an isomeric mixture (ratio 2:1)
(109 mg, 68%). Analytical data of 3ab: 1H NMR (500 MHz, CDCl3, TMS)
δ 7 99 (d, J = 8.5 Hz,1.5 H), 7.94 (s, 0.53H), 7.85 (s, 1H), 7.72 (t, J = 8.5
Hz, 1.5H), 7.60 (t, J = 7Hz, 1.54H), 7.43 (t, J = 7 Hz, 1 54H), 3 13−3 7
(m, 1.62H), 3.02 – 2 95 (m, 3 17H), 2 6−2 4 (m, 1 2H), 1 94−1 85 (m,
3 3 H), 1 76−1 74 (m, 1 63H), 1 41 (d, J = 6.5 Hz, 1.6H), 1.37 (d, J = 7
Hz, 3.08H), 1.11 (d, J = 6.5 Hz, 3.04H), 1.07 (d, J = 7 Hz, 1.70H), 0.75 (d,
J = 6.5 Hz, 3.00H), 0.67 (d, J = 6.5 Hz, 1.63H) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ 162 , 161 7, 146 7, 146 4, 137 1, 136 8, 134 2, 132 4,
128.7, 128.5, 128.3, 128.2, 127.1, 126.9, 126.8, 125.4, 47.6, 47.0, 33.3,
32.9, 31.4, 31.3, 30.5, 28.6, 23.1, 21.8, 21.2, 21.0, 20.8, 18.7, 17.5, 17.0
ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for C17H22N 240.1747,
found 240.1752.
8-methyl-2-phenylquinoline
(3af).[14a]
Following
the
general
experimental procedure with (2-amino-3-methylphenyl)methanol 1d (110
mg, 0.80 mmol), acetophenone 2b (81 mg, 0.67 mmol), KOH (37.5 mg,
0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h.
The crude product was purified by neutral alumina column
chromatography (10% ethyl acetate in hexane) to afford the desired
product 3af as a pale yellow solid (126 mg, 86%). Analytical data of 3af:
1H NMR (300 MHz, CDCl3, T ) δ 8 29−8 26 (m, 2H), 8 19 (d, J = 8.4
Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.59 – 7.56 (m,
1H), 7 54−7 51 (m, 2H), 7 49−7 45 (m, 1H) 7 44−7 39 (m, 1H), 2 92 (s,
3H) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ 155 5, 147 1, 139 8, 137 7,
137.0, 129.7, 129.2, 128.8, 127.5, 127.1, 126.0, 125.4, 118.2, 17.9 ppm.
2-phenyl-4-(trifluoromethyl)quinoline (3ag). Following the general
experimental procedure with 1-(2-aminophenyl)-2,2,2-trifluoroethan-1-ol
1e (151 mg, 0.80 mmol), acetophenone 2b (81 mg, 0.67 mmol), KOH
(37.5 mg, 0.67 mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring
for 7 h. The crude product was purified by neutral alumina column
chromatography (5% ethyl acetate in hexane) to afford the desired
product 3ag as a white solid, 135 mg (74%). Analytical data of 3ag: 1H
NMR (500 MHz, CDCl3, T ) δ 8 3 (d, J = 8 Hz, 1H), 8 23−8 20 (m, 3H),
8.17 (d, J = 8.5 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 8 Hz, 1H),
7.60-7.52 (m, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 156 7, 149 2,
138.5, 130.7, 130.4, 130.0 129.0, 127.9, 127.5, 123.9 (q, J = 2.5 Hz ),
116.0(q, J = 1.3Hz) ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for
C16H11F3N 274.0838, found 274.0842.
(3aS,3bR,13S,13bS,15aR)-13,15a-dimethyl-1-(6-methylheptan-2-yl)-
2,3,3a,3b,4,5,5a,6,13,13a,13b,14,15,15a-tetradecahydro-1H-
cyclopenta[5,6]naphtho[1,2-b]acridine (3ac). Following the general
experimental procedure with o-aminobenzylalcohol 1a (99 mg, 0.80
mmol), cholestan-3-one 4j (260 mg, 0.67 mmol), KOH (38 mg, 0.67
mmol) in DMSO (1.0 mL) at 80 °C and subsequent stirring for 7 h. The
crude product was purified by neutral alumina column chromatography
(10% ethyl acetate in hexane) to afford the desired product 3ac as white
solid (88 mg, 28%). Analytical data of 3ac: p: 183−186 °C 1H NMR
(500 MHz, CDCl3, T ) δ 7 97 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.70 (d,
J = 8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 3.08 (dd,
J1 = 18 Hz, J2 = 5.0 Hz, 1H), 2.99 (d, J = 16 Hz, 2H), 2.79 (dd, J1 = 18 Hz,
J2 = 13 Hz, 1H), 2.61 (d, J = 16.0 Hz, 1H), 2.06 (d, J = 12 Hz, 1H),
1 88−1 75 (m, 3H), 1 67−1 62 (m, 5H), 1 54−1 47 (m, 2H), 1 4 −1 34 (m,
4H), 1 28−1 21 (m, 2H), 1 15−1 4 (m, 6H), 1 2− 98(m, 2H), 94 (d, J
= 6 Hz, 3H), 0.87 (d, J = 6 Hz, 6H), 0.80 (s, 3H), 0.70 (s, 3H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 158 6, 146 7, 135 7, 13 3, 128 5,
128.3, 127.3, 126.8, 125.4, 56.5, 56.4, 53.6, 43.6, 42.5, 42.3, 40.0, 39.5,
37.5, 36.2, 35.8, 35.6, 35.3, 31.7, 28.8, 28.3, 28.2, 24.3, 23.9, 22.8, 22.6,
(2-((1-phenylethylidene)amino)phenyl)methanol (5). The imine
intermediate was synthesized by treating o-aminobenzylalcohol 1a (200
mg, 1.62 mmol), acetophenone 2b (194 mg, 1.62 mmol) in benzene (5.0
mL) at 100 °C during which water was removed by azeotropic distillation.
After 12 h, the reaction mixture was allowed to cool and the precipitate
formed was filtered and purified by washing with benzene to afford the
desired product 5 as a white solid (218 mg, 60%). Analytical data of 5: 1H
NMR (500 MHz, Acetone-d6, T ) δ 8 22 (d, J = 8.5 Hz, 1H), 8.16 (d, J =
8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8. Hz, 2H), 7.62 (t, J =
7.5. Hz, 1H), 7.41 (t, J = 7.5. Hz, H), 6.97(d, J = 8 Hz, 2H), 3.76 (s, 2H),
1.92 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 161 2, 156 3, 148 3,
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136.7, 131.8 ,129.5, 129.3, 128.7, 127.6, 127.0, 125.9, 118.1, 114.1,
54.8, 29.4 ppm. HRMS (ESI-Orbitrap) m/z: (M+Na)+ calcd for
C15H15NNaO 248.1046, found 248.1055.
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nitrobenzaldehyde, the reaction mixture was quenched with water. The
crude product was filtered and recrystallized from ethanol. To a solution
of the resulting (E)-2-nitrochalcone (1 mmol) in ethanol (15 mL) was
added iron powder (183 mg, 3 mmol), followed by HCl (1.0 N, 1.3 mL.).
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The reaction mixture was vigorously stirred at 80 C. After the complete
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cool at room temperature and then extracted with ethylacetate. The
organic layer was washed with saturated Na2CO3 solution and brine,
dried over Na2SO4, and concentrated to afford the desired product 6 as
yellow solid, 116 mg (52%). Analytical data of 6: 1H NMR (500 MHz,
CDCl3, T , δ 8 4-8.02 (m, 2H), 8.00 (d, J = 15 5 Hz, 1H), 7 6 −7 57
(m, 1H), 7.54-7 48(m, 4H), 7 23−7 2 (m, 1H), 6 81(t, J = 7.5 Hz, 1H),
6.73 (d, J = 8 Hz, 1H), 4.07 (s, 2H) ppm. 13C{1H} NMR (125 MHz, CDCl3)
δ 19 3, 146 2, 140.1, 138.4, 132.8, 131.7, 128.6, 128.5, 128.2, 121.8,
120.3, 119.0, 116.8, ppm. HRMS (ESI-Orbitrap) m/z: (M+H)+ calcd for
C15H14NO 224.1070, found 224.1072.
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Acknowledgements
The authors thank Dr. K. V. Radhakrishnan, Principal Scientist,
CSIR-NIIST for the constructive discussions. RP, NPR and SAB
thanks CSIR and VKO thanks UGC for research fellowship. J.J.
and V.K.P. thanks the Director of CSIR-NIIST for the support
and JJ thanks Alexander von Humboldt Foundation for an
experienced research grant. The authors also thank Mrs.
Saumini Mathew and Mrs. Viji S. of CSIR-NIIST for recording
NMR and mass spectra, respectively.
Keywords: Superbase; Indirect Friedländer Reaction; Quinoline;
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Indirect Friedländer Reaction*
Rahul P., Nitha P. R., Vishnu K.
Omanakuttan, Sheba Ann Babu, P.
Sasikumar, Vakayil K. Praveen, Henning
Hopf, Jubi John
Page No. – Page No.
Text for Table of Contents
Superbase Mediated Indirect
Friedländer Reaction: A Transition
Metal-Free Oxidative Annulation
toward Functionalized Quinolines
A transition metal-free superbase mediated indirect Friedländer reaction was developed for accessing functionalized
quinolines.
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