Ionic liquid - An efficient recyclable system for the synthesis of 2,4-disubstituted quinolines via Meyer-Schuster rearrangement

Article abstract of DOI:10.1055/s-0028-1087340

An improved and eco-friendly method for the synthesis of 2,4-disubstituted quinolines via Meyer-Schuster rearrangement of 2-aminoaryl ketones and phenylacetylenes in the presence of zinc trifluoromethanesulfonate in [hmim]PF₆ has been developed

Full text of DOI:10.1055/s-0028-1087340

LETTER
3001
Ionic Liquid – an Efficient Recyclable System for the Synthesis of
2,4-Disubstituted Quinolines via Meyer–Schuster Rearrangement
S
ynthesis of 2,4-D
u
isubstituted
p
Q
uinoline
s
a
via
M
eyer–
m
S
chuste
r
Rearrangement Sarma, Dipak Prajapati*
Department of Medicinal Chemistry, North East Institute of Science and Technology, Jorhat 785 006, Assam, India
Fax +91(376)2370011; E-mail: dr_dprajapati2003@yahoo.co.uk
Received 4 June 2008
linear optical properties with excellent mechanical prop-
erties.21 Several methods such as Skraup, Doebner–von
Miller, Friedländer and Combe reactions have been devel-
oped for the preparation of quinolines,22 but due to their
importance as substructures in a broad range of natural
and designed products, significant effort continues to be
directed into the development of new quinoline-based
structures23 and new methods for their constructions.24
Amongst methodologies reported for the preparation of
quinolines, Friedländer annulation is the most straightfor-
ward protocol. However, various Brønsted acids em-
ployed in this reaction require harsh reaction conditions
and lead to several side reactions.25 Under thermal or
base-catalysis conditions, 2-aminobenzophenone fails to
react with simple ketones such as cyclohexanone and b-
keto esters26,27 Most of the reported protocols for the syn-
thesis of quinolines suffered from the usage of harmful or-
ganic solvents, high reaction temperature, prolonged
reaction time, low yields, tedious workup procedures, and
the use of stoichiometric and/or relatively expensive re-
agents. Consequently, there is great current interest in as-
sembling quinoline systems from acyclic precursors28 and
an even increasing demand for selective, cheap, eco-
benign, and low-cost protocols for their synthesis.29
Abstract: An improved and eco-friendly method for the synthesis
of 2,4-disubstituted quinolines via Meyer–Schuster rearrangement
of 2-aminoaryl ketones and phenylacetylenes in the presence of zinc
trifluoromethanesulfonate in [hmim]PF6 has been developed.
Key words: ionic liquid, Meyer–Schuster rearrangement, green
solvents, quinolines
In recent years, the application of ionic liquids as alterna-
tive reaction media was frequently reported in the litera-
ture.1–4 It has attracted increasing attention and been
successfully used in a variety of catalytic reactions as en-
vironmentally benign solvents and catalysts due to their
relatively low viscosities, low vapor pressure, and high
thermal and chemical stability.5,6 Their nonvolatile nature
can reduce the emission of toxic organic compounds and
facilitate the separation of products and/or catalysts from
the reaction solvents. They are being used as green sol-
vents for the immobilization of transition-metal-based
catalysts, Lewis acids, and enzymes.7–9 Much attention
has currently been focused on the organic reactions with
ionic liquids as catalysts or solvents, and many organic re-
actions were performed in ionic liquids with high perfor-
mances.10–13 Many reactions such as Friedel–Crafts
reactions,14 arene hydrogenation,15 dimerizations of al-
kenes,16 allylations of aldehydes,17 Heck reactions,18 and
Diels–Alder reactions19 have been reported with good re-
sults, which offered some new clues indicating that use of
ionic liquids as catalysts may not only be possible for
those traditionally important reactions, but also practical
and even highly efficient. To our knowledge, so far there
is no report in the literature on the Meyer–Schuster rear-
rangement mediated by ionic liquids for the synthesis of
2,4-disubsituted quinolines. Herein, we wish to report an
efficient, simple, and recyclable protocol with the en-
hancements in reaction rates for the synthesis of 2,4-di-
substituted quinolines using [hmim]PF6 as recyclable
ionic liquid in the presence of 1 mol% zinc triflate.
To overcome the problems arising from the addition of
stoichiometric amounts of the Brønsted and Lewis acidic
or basic reagents, we report herein an efficient and novel
synthesis of 2,4-disubstituted quinolines using [hmin]PF6
as green solvent in presence of catalytic amount of zinc
triflate via Meyer–Schuster rearrangement. Accordingly,
treatment of 2-amino-5-chloro-2¢-fluorobenzophenone
(1a) with phenylacetylene (2) in [hmim]PF6 and in the
Ar
Ar
[hmim]PF6
Zn(OTf)2
2
O
+
R
Ph
R
NH2
Ph
N
3
1
a Ar = 2-FC6H4, R = 6-Cl
b Ar = Ph, R = H
The quinoline derivatives occur in several natural prod-
ucts and pharmacologically active substances displaying a
broad range of biological activity.20 They are also known
for their formation of conjugated molecules and polymers
that combine enhanced electronic, optoelectronic, or non-
c Ar = Ph, R = 6-Cl
N
N
–
d Ar = Ph, R = 6-NO2
e Ar = Ph, R = 8-NO2
f Ar = 2-ClC6H4, R = 6-Cl
g Ar = 2-FC6H4, R = H
h Ar = Me, R = H
[hmim]PF6
PF6
–
[bmim]BF4
BF4
SYNLETT 2008, No. 19, pp 3001–3005
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087340; Art ID: D20508ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

3002
R. Sarma, D. Prajapati
LETTER
presence of 1 mol% zinc triflate, when heated at 80–90 °C alytic processes, a protocol involving a lower amount of
for about 2.5 hours, resulted the formation of 2-phenyl-4- Zn(OTf)2 would be more appreciable, so we decided to
(2¢-fluorophenyl)-6-chloroquinoline (3a) mp 125 °C in extend the scope of the reaction using only 1 mol% of the
98% yield30 (Scheme 1). Rate enhancement of the reac- catalyst. Various 2-aminoaryl ketones 1b–h were reacted
tion was observed when 5 mol% or 10 mol% of Zn(OTf)2 similarly with phenylacetylene in the presence of 1 mol%
were used but relatively lower yield (75% or 65%) was Zn(OTf)2 in [hmim]PF6, and the corresponding 2,4-disub-
obtained due to decomposition of the starting material. stituted quinolines 3b–h were isolated in excellent yields.
Moreover, use of lesser amount (0.5 mol%) of Zn(OTf)2 The reactions are generally clean and no side products like
led to weaker results (50–60%) in longer reaction time. In dihydroquinoline could be detected in the NMR spectra of
view of the current interest in environmentally benign cat- the crude products.
Table 1 Synthesis of 2,4-Disubstituted Quinolines 3
Entry
1
2-Aminoaryl ketones
Quinolines
Reaction time (h) Yield (%)a
2.5
98 (95)
O
F
Cl
F
Cl
Ph
N
NH2
N
Ph
2
3
2.0
2.5
90 (89)20
95 (93)
Ph
O
Ph
NH2
O
Cl
Cl
NH2
O
N
Ph
4
5
2.0
2.5
94 (90)
90 (88)
O2N
O2N
NH2
Ph
N
O
NH2
NO2
Ph
N
NO2
6
7
8
2.5
2.5
2.5
92 (89)
90 (88)
9020
O
Cl
Cl
Cl
Cl
NH2
F
N
Ph
O
F
NH2
Me
N
Ph
Me
O
NH2
N
Ph
a Yields in parentheses indicate yields in the second run.
Synlett 2008, No. 19, 3001–3005 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,4-Disubstituted Quinolines via Meyer–Schuster Rearrangement
3003
All the products thus obtained were characterized by spec- Table 2 Effects of Various Solvents on Meyer–Schuster Rearrange-
tral analyses (IR, 1H NMR, and MS). To demonstrate the
ment
generality of this reaction, we next studied the scope of
this reaction under the optimized conditions and the re-
sults are summarized in Table 1.
Entry
Product Solvent
Reaction time (h) Yield (%)a
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
MeCN
5
4
6
5
6
3
3
30
15
10
20
15
35
50
98
Under this reaction conditions, we then investigated the
Meyer–Schuster rearrangement using three different ionic
liquids, such as [bmim]PF6, [hmim]PF6, and [bmim]BF4.
Among these, 1-hexyl-3-methylimidazolium hexafluoro
phosphate ([hmim]PF6) was found to give excellent
yields. For instance, 2-amino-5-chloro-2¢-fluoroben-
zophenone with phenylacetylene in ionic liquids
[hmim]PF6, [bmim]PF6, and [bmim]BF4 gave 98%, 50%,
and 35% yields, respectively. The presence of catalytic
amounts of zinc triflate was found to be essential for the
reaction outcome. Indeed in the absence of this catalyst,
the reaction did not yield any fruitful product even after 8
hours of heating. Further increase of reaction time also did
not yield any characterizable product rather decomposi-
tion of starting materials occurred. Interestingly, when
zinc triflate was replaced by 1 mol% InCl3 in the above re-
action, the ionic liquids [hmim]PF6 and [bmim]PF6 both
were found equally effective, and the quinoline deriva-
tives were obtained in comparable yields, but the ionic liq-
uid [bmim]BF4 was very less effective. All reactions
exhibited pronounced rate accelerations, and excellent
yields were obtained for isolated products 3 with
[hmim]PF6. In general, the reaction is very clean, rapid,
efficient, and involves simple workup procedure. Encour-
aged by the results obtained with ionic liquids, we turned
our attention toward the possibility of recycling the ionic
liquids. Since the products 2,4-disubstituted quinolines
were fairly soluble in ionic phase, they could be easily
separated by simple extraction with diethyl ether. The re-
maining ionic liquid was recovered and reused in subse-
quent experiments with gradual decrease in activity. For
example, 5-chloro-2-aminobenzophenone 3c with phenyl-
acetylene gave 95%, 93%, and 80% yields over three cy-
cles. To compare the efficiency of this method, we carried
out the reaction in various organic solvents such as dichlo-
romethane, acetonitrile, DMF, ethanol, and THF (2 mL)
in the presence of catalytic amount of zinc triflate under
similar reaction conditions. The reaction was found to be
slow in organic solvents and afforded less yields of the de-
sired product (Table 2).
EtOH
THF
DMF
CH2Cl2
[bmim]BF4
[bmim]PF6
[hmim]PF6 2.5
a Reaction conditions: 2-aminobenzophenone (1.5 mmol), phenylacetyl
ene (3 mmol), solvent (1 g), Zn(OTf)2 (15 mg), 80–90 °C.
Ar
Ar
HO
[hmim]PF6
Zn(OTf)2
O
+
R
NH2
Ph
Ph
NH2
1
2
3'
Ar
Ar
N
Meyer–Schuster
rearrangement
– H2O
O
Ph
R
Ph
NH2
3
Scheme 2
In conclusion, we have developed the use of ionic liquid
[hmin]PF6 as green and reusable reaction medium, as well
as promoter for the Meyer–Schuster rearrangement of
various substituted 2-aminobenzophenones and phenyl-
acetylene to afford corresponding 2,4-disubstituted
quinolines33 utilizing catalytic amount of zinc triflate in
excellent yields. This method not only provides an excel-
lent complement to substituted quinoline synthesis, but
also avoids the use of hazardous acids or bases and harsh
reaction conditions. The yields obtained by this method
are superior to the corresponding Friedländer synthesis,
which uses o-acylanilines and ketones.34 In addition to its
simplicity and selectivity, this reaction shows the ability
to tolerate a variety functional groups (nitro, chloro, fluo-
ro, and amino) and will constitute a useful alternative to
the commonly utilized procedures.
Use of 1 mol% of zinc triflate in conjunction with
[hmim]PF6 showed rate enhancements and excellent
yields in this Meyer–Schuster rearrangement. As shown
in Table 1, the method appears to be quite general and un-
der these reaction conditions nitro groups, which are sen-
sitive to reductions by metals,31 do survive. Although the
detailed mechanism of the reaction is not clear at this
stage, it seems likely that the reaction is proceeded by ini-
tial alkynylation of the 2-aminoaryl ketone 1 with phenyl-
acetylene (2) to form the propargylic alcohol 3¢, followed
by Meyer–Schuster rearrangement32 to the enone, and cy-
clization (Scheme 2) occurs to give the products.
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for financial support and Director, North East Institute of
Science & Technology (NEIST), Jorhat for his keen interest and
constant encouragement.
Synlett 2008, No. 19, 3001–3005 © Thieme Stuttgart · New York

3004
R. Sarma, D. Prajapati
LETTER
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(30) General Procedure for the Synthesis of 2,4-Disubstituted
Quinoline Derivatives under Thermolytic Conditions
Using Ionic Liquids
A mixture of 2-amino-5-chloro-2¢-fluoro-benzophenone
(1a, 0.25 g, 1 mmol), and phenylacetylene (0.18 g, 1.8
mmol) in 1-hexyl-3-methylimidazolium hexafluoro-
phosphate (1 g) was placed in a round-bottom flask (50 mL)
in the presence of Zn(OTf)2 (15 mg). Two phases were
formed at r.t. The flask was then dipped in a pre-heated oil
bath at 80–90 °C (bath temperature), the mixture becomes
homogeneous, and was stirred for about 2.5 h. After
completion (monitored by TLC), the reaction mixture was
cooled to r.t. and extracted with Et2O (2 × 15 mL). The ether
layer was dried over anhyd Na2SO4 for 10 h and
concentrated in a rotary evaporator to half the volume and
left overnight. The yellow crystals of the products so
obtained was filtered, dried, and recrystallized from CHCl3–
MeOH (1:1) mixture to get the pure product; mp 125 °C in
98% yield. The filtrate containing the Et2O is evaporated to
expel the Et2O completely and ionic liquid is reused directly
for the second run. Similarly other 2-aminoaryl ketones and
phenylacetylene were reacted in the presence of Zn(OTf)2
under thermal heating at 80–90 °C to produce the
corresponding quinoline derivatives in excellent yields. The
results are summarized in the Table 1.
Synlett 2008, No. 19, 3001–3005 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,4-Disubstituted Quinolines via Meyer–Schuster Rearrangement
3005
2-Phenyl-4-(2¢-fluorophenyl)-6-chloroquinoline (3a)
2-Phenyl-4-(2¢-chlorophenyl)-6-chloroquinoline (3f)
Mp 112 °C. IR (KBr): 1615, 1375, 1275, 1165, 1130 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.30 (s, 1 H), 7.42–7.88 (m,
7 H), 8.15 (s, 1 H), 8.16–8.25 (m, 4 H). Anal. Calcd for
C21H13Cl2N: C, 72.21; H, 3.72, N, 4.01. Found: C, 72.14; H,
3.80; N, 4.10. MS: m/z = 349 [M+].
Mp 125 °C. IR (KBr): 1615, 1370, 1280, 1165, 1125 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.15–7.28 (m, 7 H), 7.72 (m,
1 H), 8.02 (m, 1 H), 8.10–8.30 (m, 4 H). Anal. Calcd for
C21H13ClFN: C, 75.68; H, 3.90; N, 4.20. Found: C, 75.70; H,
4.02; N, 4.11. MS: m/z = 333 [M+].
2,4-Diphenylquinoline (3b)
2-Phenyl-4-(2¢-fluorophenyl)quinoline (3g)
Mp 107 °C. IR (KBr): 1610, 1370, 1270, 1160, 1125 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.10–7.23 (m, 9 H), 7.65 (m,
1 H), 7.95 (m, 1 H), 8.10–8.25 (m, 4 H). Anal. Calcd for
C21H15N: C, 89.69; H, 5.34; N, 4.98. Found: C, 89.75; H,
5.42; N, 4.88. MS: m/z = 281 [M+].
Mp 90 °C. IR (KBr): 1615, 1375, 1275, 1160, 1130 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.10–7.23 (m, 7 H), 7.65 (m,
1 H), 8.02 (m, 1 H), 8.15–8.30 (m, 4 H). Anal. Calcd for
C21H14FN: C, 84.28; H, 4.68; N, 4.68. Found: C, 84.38; H,
4.58; N, 4.76. MS: m/z = 299 [M+].
6-Chloro-2,4-diphenylquinoline (3c)
(31) Kalyanam, N.; Rao, G. W. Tetrahedron Lett. 1993, 34, 1647.
(32) Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli,
M. D. J. Org. Chem. 1977, 42, 3403.
(33) For some of the most recent work on quinoline synthesis,
see: (a) Ahmed, N.; Lier, E. V. Tetrahedron Lett. 2007, 48,
13. (b) Arcadi, A.; Bianchi, G.; Inesi, A.; Marinelli, F.;
Rossi, I. Synlett 2007, 1031. (c) Sakai, N.; Annaka, K.;
Konakahara, T. J. Org. Chem. 2006, 71, 3653.
Mp 98 °C. IR (KBr): 1610, 1375, 1270, 1165, 1125 cm–1. 1H
NMR (90 MHz, CDCl3): d = 7.12–7.25 (m, 8 H), 7.65 (m,
1 H), 8.05 (m, 1 H), 8.13–8.28 (m, 4 H). Anal. Calcd for
C21H14ClN: C, 80.00; H, 4.44; N, 4.44. Found: C, 80.09; H,
4.50; N, 4.35. MS: m/z = 315 [M+].
2,4-Diphenyl-6-nitroquinoline (3d)
Mp 264 °C. IR (KBr): 1630, 1375, 1240, 1150, 1040 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.25–7.65 (m, 8 H), 7.83 (m,
1 H), 8.05–8.15 (m, 5 H). Anal. Calcd for C21H14N2O2: C,
77.30; H, 4.29; N, 8.59. Found: C, 77.37; H, 4.20; N, 8.68.
MS: m/z = 326 [M+].
(d) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.;
Thomas, A. W.; Verron, J.; Masciadri, R. Tetrahedron 2007,
63, 2811. (e) Wang, G.-W.; Jia, C. S.; Dong, Y.-W.
Tetrahedron Lett. 2006, 47, 1059. (f) Subhas Bose, D.;
Kumar, R. K. Tetrahedron Lett. 2006, 47, 813. (g) Lee,
B. S.; Lee, J. H.; Chi, D. Y. J. Org. Chem. 2002, 67, 7884.
(h) Jia, C. S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol.
Chem. 2006, 4, 104.
2,4-Diphenyl-8-nitroquinoline (3e)
Mp 264 °C. IR (KBr): 1635, 1375, 1240, 1150, 1035 cm–1.
1H NMR (90 MHz, CDCl3): d = 7.25–7.60 (m, 8 H), 7.75 (m,
1 H), 8.12–8.20 (m, 5 H). Anal. Calcd for C21H14N2O2: C,
77.30; H, 4.29; N, 8.59. Found: C, 77.41; H, 4.35; N, 8.49.
MS: m/z = 326 [M+].
(34) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37; yields of
67% and 55% were reported for 3d and 3h, respectively.
Synlett 2008, No. 19, 3001–3005 © Thieme Stuttgart · New York