Metal-Free Synthesis of Alkenylazaarenes and 2-Aminoquinolines through Base-Mediated Aerobic Oxidative Dehydrogenation of Benzyl Alcohols

Article abstract of DOI:10.1002/ejoc.202100420

A metal-free, base-mediated, and atom-efficient oxidative dehydrogenative coupling of substituted phenylmethanols (benzyl alcohols) with methyl azaarenes or phenylacetonitriles to afford substituted alkenylazaarenes or 2-aminoquinolines, respectively is described. CsOH.H₂O was discovered to be the base of choice for obtaining optimal yields of the title compounds, although the reaction could proceed with KOH as well. The protocol that works efficiently in the presence of air is amenable over broad range of substrates.

Full text of DOI:10.1002/ejoc.202100420

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Metal-Free Synthesis of Alkenylazaarenes and 2-
Aminoquinolines through Base-Mediated Aerobic Oxidative
Dehydrogenation of Benzyl Alcohols
Dipak J. Dahatonde,[a] Aritra Ghosh,[a, b] and Sanjay Batra*[a, b]
A
metal-free, base-mediated, and atom-efficient oxidative
base of choice for obtaining optimal yields of the title
compounds, although the reaction could proceed with KOH as
well. The protocol that works efficiently in the presence of air is
amenable over broad range of substrates.
dehydrogenative coupling of substituted phenylmethanols
(benzyl alcohols) with methyl azaarenes or phenylacetonitriles
to afford substituted alkenylazaarenes or 2-aminoquinolines,
respectively is described. CsOH.H2O was discovered to be the
Introduction
The oxidative dehydrogenative coupling of alcohols has
emerged as an attractive option for the synthesis of a variety of
functionalized organic molecules and synthesis of variety of N-
heterocycles.[1] Extrusion of hydrogen and water as the by-
product, atom economy and sustainability due to ready
availability of alcohols from several industrial processes or
renewable resources are the key attributes, which have
contributed to the growth of such transformations. From initial
focus on the use of precious and toxic noble-metal-based
catalysts,[2] currently more acceptable earth-abundant Mn, Fe,
Co, Ni or Cu-based catalysts are effective options for executing
such coupling reactions.[3] During our program to discover
compounds to treat Visceral Leishmaniasis,[4] we became
interested in performing α-olefination of 2-methylquinolines as
analogous compounds were reported to display antileishmanial
activity (Figure 1).[5] Given the significance of aryl-substituted
olefins, bearing N-heteroarene unit in various natural products,
drug molecules and materials,[6] engineering new strategies for
its synthesis has been a topic of continued research.[7] In
particular, there has been a spurt of papers related to
dehydrogenative coupling of alcohols for realizing α-olefina-
tions of N-heteroarenes under a variety of metal-based and
metal-free conditions during the last few years. Appraisal of
these protocols revealed that most of the metal-mediated
reactions were performed under strongly basic conditions
Figure 1. 2-Styrylquinolines as antileishmanial agents against L. donovani.[5a]
(Figure 2). For example, Kempe et al.[8] used 40% KOH whereas
Maji et al.[9] used 1.0 equiv. of KOtBu together with Mn
complexes for carrying out the α-olefinations of N-heteroarenes
with alcohols. Likewise, coupling reactions with Ni, Co and Fe-
based catalysts were also carried out in the presence of KOtBu
(1.0 equiv).[10] Instead, the metal-free dehydrogenative cou-
plings for α-olefinations of azaarenes invariably used the
oxidant with catalytic amount of base.[11] Strategically in such
reactions the alcohol is oxidized to aldehyde or ketone, which is
the reactive intermediate that condenses with the acidic methyl
of azaarenes. Earlier, Wolfson et al. reported high catalytic
activity and full selectivity of alkali metal hydroxides for aerobic
oxidation of phenylmethanols in a nonpolar medium (Fig-
ure 3).[12] Even the synthesis of aldimine via reaction between
[a] D. J. Dahatonde, A. Ghosh, S. Batra
Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute
BS-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar
Pradesh, India
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
http://www.cdri.res.in/1426.aspx?id=1426
[b] A. Ghosh, S. Batra
Academy of Scientific and Innovative Research
CSIR – Human Resource Development Centre, (CSIR-HRDC) Campus,
Sector 19, Kamla Nehru Nagar, Ghaziabad-201002, Uttar Pradesh, India
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100420
Figure 2. Different routes to the synthesis of alkenyl azaarene.[7–10]
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produced best yield of 3ah was heating 1.0 equiv. of 1a with
°
1.2 equiv. of 2h in toluene at 110 C under air.
With the optimized conditions in hand, we tested the scope
of the strategy with different 2-methyl quinolines and arylme-
thanols. In first set of reactions, 2-methyl quinoline 1a was
treated with many arylmethanols (2a–z) under the standardized
conditions. We discovered that yields of products 3 varied
between 45 to 87% for the alcohols to which the methodology
was compatible (Scheme 1). It is worth mentioning that for
most cases the column chromatographic purification was not
required as the removal of solvent and addition of water
furnished the pure solid products. It was found that whereas (2-
chlorophenyl)methanol 2c afforded the product 3ac in 58%
yield, (2-flourophenyl) and (2-iodophenyl)methanols (2d and
2e) failed to yield the products 3ad and 3ae, respectively and
1a was recovered unreacted. The (3-chlophenyl)methanol 2f
was attuned to the protocol to offer the 2-styrylquinoline 3af in
71% yield but the reaction of (3-phenoxyphenyl)methanol 2g
was unsuccessful. Except for the (4-nitrophenyl)methanol (2m),
the reactions with all other (4-substitutedphenyl)methanols
were successful to afford the products 3ah–3al, 3an–3ao in
65–87% yields. The reactions with (di- or tri-substituted phenyl)
methanols (2p–2t) too furnished the corresponding styryl
derivatives 3ap–at in 45–70% yields. For the alcohol 2p,
optimal yield of the product 3ap was achieved by performing
the reaction for 48 h in the presence of 2.0 equiv. of alcohol. It
is highlighted that 3ap is the starting material for preparing
antimalarial natural compound (�)-Galipinine.[16] The reaction of
(1-naphthyl)methanol 2u also smoothly gave the product 3au
in 76% yield. Amongst the heterocyclic methanols investigated
during the study, (thiophene-2-yl)methanol 2v and (pyridine-3-
yl)methanol 2x gave the respective product 3av and 3ax,
whereas alcohols 2w and 2y were found to be unsuited. When
Figure 3. Reactions encompassing aerobic oxidative dehydrogenation reac-
tions of alcohols in the presence of base exclusively.[11–13]
benzylamine and phenylmethanol in the presence of KOH in
toluene under heating in air was reported earlier.[13] Moreover,
there are citations, which describe the synthesis of heterocycles
via oxidation of phenylmethanols in the presence of base
exclusively.[14] However, the literature lacks report on the
synthesis of alkenyl azaarenes via dehydrogenative coupling of
alcohols with methyl azaarenes using base exclusively. There-
fore, we were impelled to investigate α-olefination of 2-meth-
ylquinoline via dehydrogenative coupling of phenyl methanol
in the presence of a base only with the notion that this would
allow a metal-free and sustainable route to 2-alkenyl azaarenes.
Herein, we disclose the results of our investigations toward a
metal-free base-mediated direct olefination of methyl-substi-
tuted azaarenes with aryl methanols. We expanded the scope
of the protocol to the synthesis of substituted 2-aminoquino-
lines via reaction between (2-aminophenyl)methanol and
phenylacetonitriles. Notably during the writing of this work,
Maji et al. disclosed another Mn-based catalyzed C-alkylation of
methyl N-heteroarenes with primary alcohols wherein it was
claimed that trace product was formed in the presence of KOtBu
exclusively.[15]
Results and Discussion
In a pilot reaction in the Schlenk tube fitted with air balloon, 2-
methylquinoline (1a) and (4-methylphenyl)methanol (2h) were
t
°
heated at 120 C in the presence of BuOK (1.0 equiv) in xylenes
for 24 h. We were pleased to discover that the desired 2-
styrylquinoline 3ah was obtained in 30% yield together with
the starting substrate 1a and p-tolualdehyde. Encouraged by
the results, we examined different base including tBuONa,
NaOH, KOH and CsOH.H2O and found CsOH.H2O to be the
superior reagent for this reaction. The reaction in dioxane gave
moderate yield of 3ah but yields were inferior in DMF, DMSO or
MeCN. We found that in most cases, the starting material 1a
was recovered and therefore we screened the reaction with
enhanced amount of 2h and found that 1.2 equiv. was suited
for optimal yield. In addition, the reaction was discovered to
work efficiently when performed in the presence of air together
with the use of freshly distilled toluene (refer to Table S1,
Supporting Information). Thus, the optimized condition that
Scheme 1. Scope of the synthesis of 2-Styrylquinolines.[a] 1a was recovered
from the reaction.[b] 2.0 equiv. of 2a was used.
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checked independently, we found that the transformation of (2-
the reaction of 4-methoxy-2-methylquinoline (1e) with 2a
instead of the expected 4-methoxy-2-styrylquinoline (3ea)
resulted in 4-benzyloxy-2-styrylquinoline (3fa) in 44% yield.
However, reactions of 2a with 2-methyl-8-nitro-quinoline (1g)
or 2-ethylquinoline (1h) were unsuccessful to afford 3ga or
3ha, respectively.
Towards broadening the scope of the strategy, next we
investigated reactions with 2-methylquinoxaline 4, which is
more nucleophilic as compared to /2-methylquinoline. Accord-
ingly, 4 was treated with 2a under the optimized condition and
we were delighted to discover reaction was completed in 6 h to
afford the product 5a in 94% yield (Scheme 3). Subsequently,
pyridyl)methanol 2w to the corresponding pyridine-2-aldehyde
under the influence of base was unsuccessful. Moreover, direct
reaction of pyridine-2-aldehyde with 1a in the presence of
CsOH.H2O to obtain 3aw was unproductive too.
Interestingly, the (4-fluorophenyl)methanol 2z instead of
the expected 3az afforded 3az’ in 35% yield. Perhaps the
fluoro-group of the aldehyde being electrophilic in nature
undergoes nucleophilic aromatic substitution by the alcohol in
the presence of a base.
In the next set of reactions, we investigated the protocol by
reacting differently substituted 2-alkylquinolines with substi-
tuted phenylmethanols 2. The reaction of 6-chloro and 6-
bromo-2-methylquinoline (3b–c) with 2a gave the respective 2-
styryl quinolones 3ba and 3ca in 75–77% yield (Scheme 2). The
STB-8 reagent[6h] i.e. a (E)-2-(2-([1,1’-biphenyl]-4-yl)vinyl)-6-meth-
oxyquinoline (3do) was prepared in 35% yield by reacting 6-
methoxy-2-methylquinoline 1d with [1,1’-biphenyl]-4-ylmetha-
nol (2o) under the optimized conditions. Isolation of aldehyde
in the reaction accounted for lower yield of 3do. Conversely,
reactions of
4 with different arylmethanols (2b–s) were
evaluated and in all cases except for (2-fluorophenyl)methanol
2d and (4-nitrophenyl)methanol 2m, the required products
(5b–c, 5e–l, 5n–5s) were obtained in 64–91% yields. Although
the time required for the reaction varied between 6–15 h, unlike
2-styrylquinolines, here the chromatographic purification was
essential to obtain pure products. We found that (3-phenox-
ypheny)methanol 2g which was inert to 2-methylquinoline
reacted with 4 to afford the corresponding product 5g. For
assessing the scalability, gram scale reaction 2s with 4 was
performed to isolate the product 5s without diminution of yield
though time consumed for completion of reaction was
relatively higher. Notably, reactions of heterocyclic alcohols 2v
and 2x furnished the respective products 5v and 5x in 33%
and 40% yields only and the time consumed for reaction of 2v
was 28 h. Unlike 2-methylquinoline, here the reaction of 4 with
2z gave the styryl product 5z in 44% yield together with the
ether derivative 5z’ in 25% yield.
These results made it apparent that base alone is sufficient
to perform the oxidation of the alcohol to aldehyde under
aerobic conditions, which in turn reacts with methyl of the
azaarenes to afford 2-styrylazaarene. Thus, we considered
investigating the scope further with other methyl-azaarene
systems. In this context, 2,3-dimethylquinoxaline 6a was treated
Scheme 2. Scope of the reaction with different substituted 2-
alkylquinolines.[a]complex reaction mixture was observed.[b] 1h and benzal-
dehyde were recovered and no coupling product was observed even after
prolonged reaction time.
°
with 1.0 equiv. of 2a in toluene under heating at 110 C for
24 h. The reaction resulted in the formation of a mixture of
products from which we could isolate 2-styrylquinoxaline 7aa
in 20% yield together with 2,3-bisstyrylquinoxaline 7a’a in trace
amount (Scheme 4). Nonetheless, increasing the amount of the
Scheme 3. Scope of the protocol with 1,4-quinoxalines. Yields are based on
the substrate 4.[a]Starting material 4 was recovered.
Scheme 4. Scope of the protocol with different 2-methylazarenes.[a]-
Unreacted starting material was recovered.
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2a to 4.0 equiv. produced 7a’a in 72% yield. Subjecting 2-
methylpyrazine 6b to reaction with alcohols 2a, 2h or 2n
afforded the corresponding 2-styrylpyrazines 7ba, 7bh or 7bn
in 73–86% yields. We also investigated the reaction of 2a with
4-methylquinoline 6c, 1-methyliosquinoline 6d, 2-meth-
ylbenzothioazole 6e, and 2-methylbenzoxazole 6f and it was
satisfying to discover that the protocol was amenable for all
substrates though yield of 7ca, 7da, 7ea and 7fa varied. For
6f, we recovered the unreacted starting material together with
benzaldehyde in the reaction mixture.
However, even increasing the amount of alcohol or reaction
time the yields of 7fa did not improve. Conversely, the reaction
of 2a with 1,9-dimethyl-9H-β-carboline 6g under the optimised
conditions was unsuccessful to offer product 7ga.
Successful implementation of the protocol provided the
impetus to study the fate of reaction between (2-aminophenyl)
methanol and phenylacetonitriles under the optimized con-
dition as it may offer 2-aminoquinolines. Although several
strategies for the synthesis of 2-aminoquinolines are known,[17]
to the best of our knowledge metal-free synthesis of 2-
aminoquinolines from (2-aminophenyl)methanol is not re-
ported. Therefore, (2-aminophenyl)methanol 8a was treated
with phenylacetonitrile 9a in the presence of CsOH.H2O in
°
toluene at 110 C and we were pleased to isolate the desired 2-
aminoquinoline 10aa in 56% yield together with amide 11 (see
Table S2, Supporting Information). Assuming that high temper-
ature may induce hydrolysis of phenylacetonitrile by the water
released during the process, we considered optimizing the
reaction for the base and temperature. Interestingly, we
discovered that the reaction was successful in the presence of
CsOH.H2O as well as KOH and unlike for 2-methylquinoline (1),
herein only 1.0 equiv. of either base was required (see
Supporting Information). In addition, the superior yields of
10aa was obtained by use of 1.2 equiv. of phenylacetonitrile.
Thus the conditions which offered the optimal yield of the 3-
phenyl-2-aminoquinoline 10aa were (2-aminophenyl)methanol
(1.0 equiv) and phenylacetonitrile (1.2 equiv) in the presence of
Scheme 5. Scope of the formation of 2-aminopyridine derivatives in the
presence of base only.[a] Starting substrate was recovered,[b] 4.0 equiv. of 9l
was used.
f), all other substrates afforded the products (10ca–10da,
10ga–10ha) in 68–89% yields. The suitability of the method
was also studied with aliphatic nitriles such as butyronitrile 9l
and phenylpropionitrile 9m and it was found that whereas
butyronitrile afforded the product 10al in 40% yield, the
reaction with the latter was unsuccessful. Notably, the reaction
between 8a and 9l was performed with 4.0 equiv. of 9l to
obtain the product.
We extended the study to include the use of secondary
alcohol in the reaction. Accordingly, when (2-aminophenyl)(-
phenyl)methanol 12 was subjected to reaction with 9a in the
presence of CsOH.H2O, we isolated acridin-9(10H)-one 13 as the
major product in 30% yield (Scheme 6). Literature cites the
formation of such product oxidative CÀ H amination of 2-
aminobenzophenone in the presence of KOtBu and DMSO.[18]
However, when the same reaction was performed in the
presence of KOH, we isolated the required 2-amino-3,4,–
diphenylquinoline 14 in 25% yield together with the 2-amino-
benzophenone 15 but with no trace of acridin-9(10H)-one.
Finally, to exemplify the utility of the 2-aminoquinoline
derivatives, in a representative reaction compound 10aa was
treated with acetophenone in the presence of Cu(OAc)2 and ZnI
in dichlorobenzene to produce 2,4-diphenylimidazo[1,2-a]
°
CsOH.H2O (1.0 equiv) or KOH (1.0 equiv) under heating at 90 C
for 24 h.
With the optimized conditions in hand, we investigated the
scope with a variety of (2-aminophenyl)methanol (8a–h) and
arylacetonitriles (9a–l) in the presence of CsOH.H2O and KOH
and the results are presented in Scheme 5. In the first set of
experiments methanol 8a and 8b were treated with several
phenyl acetonitriles (9a–h) and except for the nitro group
bearing phenylacetonitrile 9c, all substrates offered the desired
products 10aa–10ab, 10ad–10ah, 10ba–10bb, 10bd–bh in
68–88% yields. It was observed that reactions performed in the
presence of CsOH.H2O gave relatively better yields of products
than the ones pursued in KOH. Next, we investigated the
protocol by reacting heteroarylacetonitriles (9i–k) with 8a and
8b, which gave the products 10ai, 10bi, 10aj, 10bj, 10ak,
10bk in low yields. Perhaps recovery of the starting material
explained the low yields. Subsequently, the scope of the
reaction was evaluated with different (substituted-2-amino-
phenyl)methanols (8c–h). We observed that except for the
methanols bearing 4-fluoro and 4-nitrophenyl substitution (8e–
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gel (100–200 mesh) or neutral alumina. Analytical grade solvents
for the column chromatography were used as received.
General procedure for the synthesis of alkenylazaarenes (3aa–3az
and 3ba, 3ca, 3do, 3fa, 7aa–7fa) as exemplified for 3ah.
Method A. To a two way 50 mL round-bottom flask equipped with a
stirring bar and condenser (attached with an air balloon on the top)
was added 2-methylquinoline 1a (0.20 g, 1.40 mmol), (4-tolyl)
methanol 2h (0.20 g, 1.68 mmol), and CsOH.H2O (0.21 g,
°
1.39 mmol) in toluene (3 mL) and the mixture was heated at 110 C
Scheme 6. Reaction with secondary alcohol.
under stirring. The reaction was continued for 24 h and on
completion (as monitored by TLC), the solvent was removed
completely under the reduced pressure. The residue thus obtained
was triturated with H2O (10 mL) to furnish 3ah as a yellow solid
product that was filtered and dried in vacuum.
quinolone 16 in 32% yield together with the recovery of
starting material (58%) (Scheme 7).[19]
Method B. For the products where solid was not obtained, the
residue was extracted with H2O (25 mL) and EtOAc (3×20 mL). The
combined organic layers was washed with brine (20 mL), dried over
anhydrous Na2SO4, filtered and evaporated to furnish the crude
product. Purification by silica gel column chromatography using
hexanes/ EtOAc (9:1, v/v) as the eluent, to yield the product.
Conclusion
In summary, we have developed a base-mediated facile,
practical and atom-efficient method for preparing the alkenyl
azaarenes and 2-aminoquinolines utilizing (substitutedaryl)
methanols or substituted (2-aminophenyl)methanols, respec-
tively. The protocol scores over the reported methodologies as
it does not requires the use of a metal catalyst or ligand and is
tenable in the presence of air only. Comparatively, the
CsOH.H2O was found more efficient than KOH, speculatively
due to Cesium effect.[20] This method tolerates wide range
methyl azaarenes and arylmethanols. The protocol was success-
fully extended for the synthesis of 2-aminoquinolines from (2-
aminophenyl)methanol and phenylacetonitriles via aerobic
oxidative cyclocondensation.
General procedure for the synthesis of 2-Styrylquinoxalines (5a–5z)
as exemplified by the synthesis of 5a.
To a round-bottom flask fitted with condenser (having an air
balloon) was added 2-methyl quinoxaline 4 (0.20 g, 1.39 mmol),
phenyl methanol 2a (0.18 g, 1.66 mmol), and CsOH. H2O (0.21 g,
°
1.39 mmol) in toluene (3 mL) was heated at 100 C. The reaction
progress was monitored by TLC. After completion, the solvent was
removed under vacuum and the residue was directly adsorbed on
silica. Purification by column chromatography on silica gel using
hexanes/ EtOAc (9:1, v/v) as eluent afforded the product 5a.
General procedure for the synthesis of 3-Phenylquinolin-2-amines
(10aa–10am, 10ba–10bk, 10ca–10ha, 14) as exemplified for
10aa.
A round-bottom flask equipped with a stirring bar, condenser
(attached with an air balloon on the top) was charged with 2-
(aminophenyl)methanol 8a (0.20 g, 1.62 mmol), phenylacetonitrile
9a (0.23 g, 1.94 mmol), and the base (CsOH.H2O: 0.24 g or KOH:
Experimental Section
General Information- Unless otherwise stated, all reactions were
performed in non-dry glassware under an air atmosphere and were
monitored by analytical thin layer chromatography (TLC). TLC was
performed on pre-coated silica gel plates. After elution, plate was
visualized under UV illumination at 254 nm for UV active materials.
Further visualization was achieved either via Iodine or KMnO4
solution. The melting points were recorded on a hot stage
apparatus and are uncorrected. IR spectra were recorded using a
FTIR spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on 400 or 500 MHz NMR spectrometers with CDCl3 or
DMSO-d6 as solvent, using TMS as an internal standard (chemical
°
0.090 g, 1.62 mmol) in toluene (6 mL) and heated at 90 C for 24 h
under vigorous stirring. On completion, the solvent was removed
from the reaction mixture and the residue was directly adsorbed on
neutral alumina for column chromatography. Purification using
hexanes/ EtOAc (7:3, v/v) as eluent afforded the product 10aa as a
white solid.
Acknowledgements
1
shifts in δ). Peak multiplicities of H-NMR signals were designated
as s (singlet), brs (broad singlet), d (doublet), dd (doublet of
The authors DJD and AG gratefully acknowledge the financial
support from CSIR, New Delhi, in the form of fellowships. The
authors acknowledge the SAIF, CDRI for providing the spectro-
scopic data. This is CDRI Communication no 10233.
doublet),
t (triplet), q (quartet), m (multiplet) etc. Coupling
constants (J) are in Hz. The ESI-MS and HRMS were recorded on
triple quadrupole Mass spectrometer and orbitrap velos pro mass
spectrometer. Column chromatography was performed using silica
Conflict of Interest
The authors declare no conflict of interest.
Scheme 7. Utility of 2-aminoquinoline.
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K. Mackay, R. H. Friend, P. L. Burns, A. B. Holmes, Nature 1990, 347, 539–
541.
Keywords: Alkenyl
azaarene
Nitrogen
·
2-Aminoquinoline
·
Benzylalcohol
·
heterocycles
·
Oxidative
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Manuscript received: April 7, 2021
Revised manuscript received: April 16, 2021
Accepted manuscript online: April 20, 2021
Eur. J. Org. Chem. 2021, 2746–2751
www.eurjoc.org
2751
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