Copper catalyzed oxidative coupling of ortho-vinylanilines with N-tosylhydrazones: Efficient synthesis of polysubstituted quinoline derivatives

Article abstract of DOI:10.1016/j.jcat.2018.04.005

Efficient and general copper catalyzed oxidative cyclization of ortho-vinylaniline has been accomplished employing N-tosylhydrazone as coupling partner. Various substituted quinoline derivatives of biological importance were achieved in good to excellent

Full text of DOI:10.1016/j.jcat.2018.04.005

Journal of Catalysis 363 (2018) 102–108
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Priority Communication
Copper catalyzed oxidative coupling of ortho-vinylanilines
with N-tosylhydrazones: Efficient synthesis of polysubstituted
quinoline derivatives q
⇑
Angula Chandra Shekar Reddy, Pazhamalai Anbarasan
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient and general copper catalyzed oxidative cyclization of ortho-vinylaniline has been accomplished
employing N-tosylhydrazone as coupling partner. Various substituted quinoline derivatives of biological
importance were achieved in good to excellent yield. The important features are the high functional
group tolerates, up-gradation to gram scale synthesis and possible one-pot synthesis of quinoline from
corresponding carboxaldehyde. Synthetic potential of the obtained quinoline derivatives was demon-
strated through CAH bond functionalization reaction. Furthermore, preliminary mechanistic investiga-
tion revealed the possible generation of non-stabilized diazo compound and imine derivative as
potential intermediates as well as copper catalyzed electrocyclic reaction and oxidative aromatization.
Ó 2018 Elsevier Inc. All rights reserved.
Received 20 February 2018
Revised 29 March 2018
Accepted 3 April 2018
Keywords:
Oxidative cyclization
Copper
Tosylhydrazone
Quinoline
Ortho-vinylaniline
Annulation
1. Introduction
diazo compounds and functionalization has been extensively
studied for the construction of various carbocyclic and heterocyclic
Substituted quinolines are prevalent heterocyclic molecule
found in bioactive natural products, pharmaceuticals and func-
tional materials [1–5]. Representative examples of quinoline con-
taining therapeutically important molecules are shown in Fig. 1.
Because of the importance, various methods for the synthesis of
quinoline have been demonstrated in the past years [6,7]. Tradi-
tionally, quinolines are synthesized through condensation of anili-
nes with suitable coupling reagent in the presence of acid or base
promoter, viz. Knorr, Friedländer, Skraup reaction and etc [8–12].
These methods suffer from limited substrates scope and harsh
reaction conditions. Recently, these methods were replaced by
transition metal catalyzed annulation of aniline derivatives
[13–20] and ortho-vinylanilines [21–28] and have proved to be
an efficient strategy for quinoline synthesis. Having said, the
development of practical and general method for the synthesis of
quinolines is in high demand.
compounds. However, construction of quinoline framework
employing N-tosylhydrazone derivatives is rather limited [33,34].
On the other hand, transition metal utilized in most the developed
transformation are precious palladium-based catalyst [35,36] and
only limited methods employs readily available and inexpensive
copper based catalyst [37].
Given the importance of quinoline framework and excellent
reactivity of N-tosylhydrazones as well as our interest in the uti-
lization of ortho-vinylanilines as efficient synthon for the construc-
tion of various heterocycles [38–42], we envisioned the oxidative
cyclization of ortho-vinylanilines with N-tosylhydrazones derived
from carboxaldehydes employing copper catalyst. Successful
development of method would offer new, efficient and general
method for the synthesis of quinoline derivatives. Thus, we herein
disclose the copper catalyzed synthesis of quinoline from ortho-
vinylanilines and N-tosylhydrazones (see Scheme 1).
In the past decades, N-tosylhydrazones have emerged as an effi-
cient coupling partner in the transition metal catalyzed cross
coupling reactions [29–32]. Among the various reactivities of
N-tosylhydrazones, recently, in-situ generation of non-stabilized
2. Results and discussion
To begin with, ortho-vinylaniline 1a and N-tosylhydrazone 2a
were synthesized from corresponding aniline and benzaldehyde
[43], respectively, and utilized as model substrate in the copper
catalyzed oxidative cyclization to quinoline derivative. After the
q
The article belongs to the thematic issue on mechanism of molecular catalysis.
Corresponding author.
E-mail address: anbarasansp@iitm.ac.in (P. Anbarasan).
⇑
https://doi.org/10.1016/j.jcat.2018.04.005
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
103
Fig. 1. Examples of quinoline containing therapeutically important molecules.
Scheme 1. Copper catalyzed oxidative cyclization of ortho-vinylanilines with N-tosylhydrazones.
initial studies, reaction of 1 equivalent of 1a, 2.5 equivalents of 2a
and 3 equivalents of K2CO3 in the presence of 10 mol% of Cu(acac)2
and 20 mol% of PPh3 in mixture of dioxane/water (9:1 ratio) at 120
°C for 8 h under normal air atmosphere afforded the expected 2,4-
diarylquinoline product 3a in 51% yield (Table 1, entry 1). To
improve the oxidative cyclisation, influence of various copper cat-
alysts and ligands were examined. Among the various copper cat-
alyst examined, Cu(acac)2 proved to be best catalyst for the present
oxidative cyclization of 1a with 2a (Table 1, entries 2–7). On the
other hand, phosphine based ligands were found to be superior
compare to nitrogen based ligands (Table 1, entries 8–11). Based
on the ready availability and economic viability of various phos-
phine ligands tested, PPh3 was chosen as best ligand for the further
studies.
Next, solvents such as chloroform, tetrahydrofuran, toluene
and diglyme were screened at 120 °C in presence of Cu(acac)2
and PPh3. Although most of them gave the comparable yield of
3a, diglyme gave the highest yield of 72% in only 5 h reaction time
Table 1
Copper catalyzed oxidative cyclization of ortho-vinylanilines with N-tosylhydrazones: Optimization.a
Entry
Catalyst
Ligand
Solvent
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
Cu(acac)2
Cu(OAc)2ÁH2O
CuBr2
CuO
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
(p-tolyl)3P
(2-furyl)3P
DPPF
Bipy
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
CHCl3
THF
Toluene
Diglyme
Diglyme
Diglyme
Diglyme
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
140
140
51
42
24
18
15
12
31
54
54
52
38
60
37
65
72
CuTc
Cu(CH3CN)4OTf
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
–
9
10
11
12
13
14
15c
16c
17c,d
18c,d
84 (83)d
NR
11
Cu(acac)2
–
a
Reaction conditions: 1a (50 mg, 0.22 mmol, 1 equiv), 2a (160 mg, 0.55 mmol, 2.5 equiv), catalyst (0.02 mmol, 10 mol%), ligand (0.04 mmol, 20 mol%), K2CO3 (92 mg, 0.66
mmol, 3 equiv), solvent (1.5 mL), temp, 8 h.
b
Isolated yield.
5 h.
With 2.5 equivalents of K2CO3. NR = no reaction.
c
d

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A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
(Table 1, entries 12–15). Subsequently, increasing temperature to
140 °C afforded the quinoline 3a in 84% yield. Interestingly, similar
results were observed with 2.5 equivalents of K2CO3 (Table 1, entry
16). It is important to note that in the absence of Cu(acac)2 and
PPh3 either no reaction or low yield of 3a was observed (Table 1,
entries 17–18). This suggested that the presence of Cu(acac)2 and
PPh3 are highly essential for the present oxidative cyclisation and
indeed the reaction is catalyzed by copper catalyst.
Having achieved the optimal reaction conditions for the oxida-
tive cyclization of ortho-vinylanilines with N-tosylhydrazones,
scope and generality of ortho-vinylanilines were investigated.
Various substitutions on the aryl moiety of aniline were tolerated
to afford the corresponding quinolines in good yield (Scheme 2).
For instance, ortho-vinylanilines derived from aniline and
para-substituted (p-methyl, p-tert-butyl and p-phenyl) anilines
gave the products 3b and 3c–3e, respectively, in ꢀ75% yield. Ster-
ically challenging 6-methyl and 3,5-dimethyl ortho-vinylanilines
afforded the corresponding quinolines 3f and 3g, respectively, in
moderate yield. Formation of quinolines 3h and 3i, containing
acetal and free hydroxyl, were achieved in 61 and 50% yield,
respectively. 6-Halo substituted 2,4-diarylquinolines 3j and 3k
were synthesized in good yield from corresponding ortho-
vinylaniline derivatives. Interestingly, electron withdrawing
ethoxycarbonyl-substituted ortho-vinylaniline underwent smooth
reaction to furnish 3l in 65% yield. Reaction of ortho-vinylaniline
derived from
a-naphthylamine also afforded the benzofused
quinoline derivative 3m in 71% under the optimized conditions.
Next, effect of substitution on the alkene was examined. As can
Scheme 2. Scope of ortho-vinylaniline derivatives.

A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
105
be seen in Scheme 2, p-methyl, p-ethyl and p-tert-butylphenyl sub-
stituted alkene-containing ortho-vinylanilines gave the corre-
sponding quinoline derivatives 3n–3p in comparable yield.
Similarly, electron donating methoxy and electron withdrawing
fluoro substituted aryl containing quinolines (3q–3s) were
achieved in 71% and ꢀ77% yield. Most importantly, thiophene
sion of benzaldehyde to quinoline was envisaged. Thus, treatment
of p-methylbenzaldehyde 4 with tosylhydrazine in methanol at
room temperature followed by removal of methanol and reaction
of resultant mixture with Cu(acac)2, PPh3 and K2CO3 in diglyme
at 140 °C afforded the quinoline 3a in 70% (Scheme 4b). To further
widen the scope of one-pot transformation, substituted aldehydes
and ortho-vinylaniline derivatives were subjected under the one-
pot transformation. Interestingly, all of them afforded the corre-
sponding quinolines in good yields.
and alkene at the a-position of ortho-vinylanilines were well toler-
ated under the present conditions to afford the product 3t and 3u
in 76 and 81% yield, respectively.
Subsequently, effect of various substitutions on the N-
tosylhydrazone was studied. N-Tosylhydrazone derived from elec-
tron donating substitution-containing benzaldehyde under the
optimized conditions afforded the expected quinolines 3v–3x in
excellent yield. Similarly, halogenated aryl containing quinoline
derivatives 3y–3aa was achieved in 79, 71 and 71% yield, respec-
tively. Importantly, ortho-methoxy and cyano substitutions were
well tolerated under the present oxidative cyclization conditions
to afford the corresponding quinoline derivatives 3ab–3ac in good
yield. Furthermore, formation of heteroaryl, such as pyridine and
furan, substituted quinolines 3ad and 3ae were obtained in 51
and 68% yield, respectively (see Scheme 3).
After exploring the generality of the oxidative cyclization of
ortho-vinylanilines 1 and N-tosylhydrazone 2, demonstration of
their synthetic utility was deliberate. Gram scale reaction of 1a
with 2a under the optimized conditions afforded the product 3a
in 76% yield, which is comparable to the small-scale reaction and
thus the applicability in the large-scale synthesis could be readily
envisioned (Scheme 4a). Since N-tosylhydrazones 2 were achieved
from corresponding carboxaldehyde, next one-pot direct conver-
Subsequently, quinoline was visualized a good chelating atom
for the palladium catalyzed C-H bond functionalization. Reaction
of 3a with N-bromosuccinimide in the presence of 10 mol% of Pd
(OAc)2 in acetonitrile at 100 °C afforded the CAH bromination pro-
duct 5 in 59% yield (Scheme 4c). Similarly, palladium catalyzed
phenylthiolation of CAH bond of 3a was achieved with N-
(phenylthio)succinimide [44] in 68% yield.
Next, various control experiments were performed to get
insight into the plausible mechanism of the present copper cat-
alyzed oxidative cyclization. To demonstrate the possible forma-
tion of non-stabilized diazo compound, N-tosylhydrazone 2a was
treated with potassium carbonate in diglyme at room temperature
for 1 h followed by addition of 1a, Cu(acac)2 and PPh3 and heating
at 140 °C for 5 h gave the expected quinoline 3a in 58% yield
(Scheme 5a). The lower yield may be due to the possible decompo-
sition of non-stabilized diazo compound in the absence of 1a.
Reaction of possible NAH insertion product 7 in the present cat-
alytic cycle gave only 18% yield of 3a after 24 h, which suggests
that NAH insertion product 7 may not be the potential intermedi-
ate of the copper catalyzed oxidative cyclization (Scheme 5b).
Scheme 3. Scope of N-tosylhydrazone derivatives.

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A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
Scheme 4. Synthetic utility.
Next, to identify the generation of potential intermediate, the reac-
tion of 1a and 2a was performed in the presence of Cu(acac)2 and
PPh3 at 80 °C for 2 h. Interestingly, formation of inseparable mix-
ture of product 3a and imine 8 was observed in 60% yield in 1:5
ratio, along with small amount of benzaldehyde (Scheme 5c).
Treatment of the obtained mixture under copper catalyzed condi-
tions for 3 h gave the quinoline 3a in 69% yield. But, in the absence
of copper catalyst at 140 °C for 5 h afforded the quinoline 3a in
only 37% yield. To further confirm the formation of potential inter-
mediate 8, the imine 9 was synthesized via reaction of correspond-
ing aniline and aldehyde and subjected for the oxidative
cyclization. As expected, better oxidative cyclization of 9 was
observed under copper catalyzed conditions than the thermal
induced process (Scheme 5d). Furthermore, to rule out the involve-
ment of benzaldehyde in the present transformation, reaction was
performed with 1a and p-methylbenzaldehyde 4 under the opti-
mized condition. The reaction led to the formation of 3a in only
10% yield even after treating for 16 h. These studies revealed that
(1) non-stabilized diazo compound is generated from N-
tosylhydrazone on reaction with K2CO3, (2) NAH insertion product
7 might be the dead end of catalytic cycle, (3) potential intermedi-
ate imine 8 is generated from initial nucleophilic addition of

A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
107
Scheme 5. Mechanistic investigation.
ortho-vinylaniline to copper carbene derived from non-stabilized
diazo compound followed by oxidation and (4) final electrocycliza-
tion and oxidation also requires the presence of copper catalyst to
make the overall transformation successful.
hand, regeneration of active copper catalyst A could be achieved
from E through possible redox process [47] in the presence of oxy-
gen that is present in air (see Scheme 6).
Based on the preliminary mechanistic investigation, we postu-
late the plausible mechanism for the developed copper catalyzed
oxidative cyclization of 1 and 2. Reaction of N-tosylhydrazone 2
with K2CO3 would generate non-stabilized diazo compound B,
which on trapping with copper catalyst A would form copper car-
bene complex C. Formation of intermediate D could be envisioned
through the initial co-ordination of ortho-vinylaniline 1 with cop-
per carbene complex C followed by 1,1-migratory insertion into
NAH bond. Subsequent oxidation of D would afford the observed
intermediate F and possible generation of copper catalyst E. Cop-
3. Conclusion
In conclusion, we have successfully demonstrated an efficient
and general copper catalyzed oxidative cyclization of ortho-
vinylaniline with N-tosylhydrazone. The developed reaction toler-
ates various functional groups and allows the synthesis of diverse
quinoline derivatives of importance in good to excellent yield.
Importantly, the method was successfully extended to the gram
scale synthesis and one-pot synthesis of quinoline from corre-
sponding carboxaldehyde. Synthetic potential of the obtained
quinoline derivatives were explored through CAH bond functional-
ization reaction. Furthermore, preliminary mechanistic investiga-
tion revealed the possible generation of non-stabilized diazo
compound and imine derivative as potential intermediates as well
per promoted thermal 6p-electrocyclic reaction of imine F would
furnish the cyclic intermediate G, which on subsequent aromatiza-
tion driven imine-enamine isomerization would give dihydro-
quinoline H. Finally, copper catalyzed oxidation of H would
afford the observed quinoline derivatives 3 [45,46]. On the other

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A.C.S. Reddy, P. Anbarasan / Journal of Catalysis 363 (2018) 102–108
Scheme 6. Plausible mechanism.
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