A green, solvent-free one-pot synthesis of disubstituted quinolines via A3-coupling using 1 mol% fecl3

Article abstract of DOI:10.3987/COM-15-13391

A simple and green route towards disubstituted quinolines via A³-coupling using 1 mol% FeCl3 is described. Using this approach, the above-mentioned derivatives were synthesized in moderate to good yields (45-95%) under solvent-free, microwave conditions. Preliminary investigations have indicated that a further decrease in catalyst amount is possible with a satisfactory yield still observed.

Full text of DOI:10.3987/COM-15-13391

HETEROCYCLES, Vol. 92, No. 9, 2016
1655
HETEROCYCLES, Vol. 92, No. 9, 2016, pp. 1655 - 1664. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 10th December, 2015, Accepted, 8th July, 2016, Published online, 26th July, 2016
DOI: 10.3987/COM-15-13391
A
GREEN,
SOLVENT-FREE
ONE-POT
SYNTHESIS
OF
3
DISUBSTITUTED QUINOLINES VIA A -COUPLING USING 1 MOL%
FeCl
3
Shivani Naidoo and Vineet Jeena*
School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville,
Pietermaritzburg, 3209, South Africa; E-mail: Jeenav1@ukzn.ac.za
Abstract – A simple and green route towards disubstituted quinolines via
3
A -coupling using 1 mol% FeCl
3
is described. Using this approach, the
above-mentioned derivatives were synthesized in moderate to good yields
45-95%) under solvent-free, microwave conditions. Preliminary investigations
(
have indicated that a further decrease in catalyst amount is possible with a
satisfactory yield still observed.
The advancement of new resourceful procedures that allow for the formation of C–C bonds with high
selectivity, operational simplicity, functional group tolerance and environmentally friendly properties from
1
easily obtainable reagents is an important topic in synthetic organic chemistry. Within this context,
3
2
A -coupling has proven to be an exciting and innovative method for the formation of C–C bonds. The
3
coupling reaction of an aldehyde, amine and alkyne (hence A -coupling) has been shown to be a
convenient process for the formation of propargylamines and this methodology has been well documented
3
3
in the literature. In addition to the well-studied propargylamine synthesis, the A -coupling can also
produce quinolines under the appropriate reaction conditions. (Scheme 1).2
R3
O
conditions
R1
R3
R1
+
R2
+
H
NH2
N
R2
3
Scheme 1. Synthesis of disubstituted quinolines via A -coupling
Quinolines, in particular, have generated considerable interest due to their broad range of biological activity
4
5
against Alzheimer’s disease, neovascular eye diseases and protein kinase, DYRK1A, which is a vital

1656
HETEROCYCLES, Vol. 92, No. 9, 2016
6
intercellular regulator which fuels neurological alterations found in persons with Down syndrome to name
but a few.
3
In 2002, the first synthesis of quinolines via A -coupling was reported using 30 mol% CuCl as a catalyst,
however, in this case, the yields were low (34-48%), due to side products such as the reduced imine and
7
8
9
uncyclized propargylamine. In 2003, Yadav and co-workers and, in 2004, Zhang and co-workers, both
used 30 mol% CuBr doped Montmorillonite K-10 as a catalyst. While both these papers report the synthesis
3
of quinolines in good to excellent yields via A -coupling, they must be judged with caution, as these
reactions were carried out with multimode commercial microwaves (“kitchen” microwave ovens), which
are incompatible with currently employed, temperature and pressure controlled single mode scientific
1
0
reactors. In 2010, Török and co-workers used unmodified Montmorillonite K-10 towards the synthesis of
substituted quinolines and good to excellent yields were obtained, however, a large amount of catalyst was
1
1
3
required (0.50 g). In 2009, FeCl
3
was applied to A -coupled quinoline synthesis due to it’s low cost and
1
2
environmentally friendly properties. This reaction, however, was characterized by good to excellent
1
3
yields (56-95%) in long reaction times (24 h). In an attempt to address these issues, Wang and co-workers
changed the solvent from toluene to dichloroethane and a slight improvement in reaction time (12 h) was
1
4
observed, although the desired products were formed in excellent yields (81-93%). In addition, it has been
argued that in both of the systems above, the FeCl
catalyst loading of 10 mol% was unsatisfactory.15
3
Recently, the scientific community has moved away from the use of metal chlorides, due to the
3
above-mentioned disadvantages, and has directed their research, in A -coupled quinoline synthesis,
1
6
and 5 mol% Fe(OTf)
.17 The use of metal
towards metal triflates such as the use of 5 mol% Cu(OTf)
2
3
triflates produced the disubstituted quinolines in excellent yields, however, these catalysts are expensive
and a tedious, time-consuming catalyst recover and reuse study must be undertaken.17
We believe that metal chlorides are preferable over metal triflates if the above-mentioned challenges can be
overcome. Herein, we propose an advancement of previously reported syntheses through the development
3
of a green, solvent-free method for synthesizing 2,4-disubstituted quinolines via an A -coupled approach,
using just 1 mol% FeCl
3
(Scheme 2). We envisaged that a low catalyst loading coupled with the
inexpensive nature of FeCl
3
will generate a powerful catalytic system and proceeded to test this hypothesis
3
by attempting the synthesis of quinolines via A -coupling.
R3
N
O
1
mol% FeCl3
R1
R3
R1
+
R2
+
H
NH2
R2
3
Scheme 2. Current work to synthesize 2,4-diphenylquinolines via A -coupling

HETEROCYCLES, Vol. 92, No. 9, 2016
1657
Our studies commenced with a test reaction using aniline (1a), benzaldehyde (2a) and phenylacetylene (3a)
under various conditions such as sonication and conventional heating, but the desired product was formed
in disappointing yields (Table 1, entries 1 and 2). We then focused our attention towards microwave-
assisted organic synthesis (MAOS), as these conditions have shown to greatly reduce reaction times and
1
8
improve yields when compared to conventional heating. The use of solvents such as dichloromethane,
water, and toluene under microwave irradiation, was then evaluated (Table 1, entries 3-5) and again
disappointing yields were observed (trace-40%). This prompted us to test the effect of solvent-free
reactions as microwave-assisted organic synthesis is known to benefit under these conditions.19 The
reaction was attempted under open and closed-vessel microwave irradiation as the choice of these
2
0
conditions has a pronounced effect on the reaction yield. Under closed-vessel microwave conditions
Table 1, entry 6) the desired product was formed in a moderate yield (51%). Next, the reaction was
performed under open-vessel conditions, (Table 1, entry 7) and, to our delight; the desired compound was
formed in a 91% isolated yield. To highlight the importance of FeCl , the reaction was attempted in the
(
3
absence of a catalyst and, as expected, no product was detected under these conditions (Table 1, entry 8).
Table 1. Optimization of reaction conditions for the synthesis of 2,4-diphenylquinoline 4a via
3
a
A -coupling
Catalyst
1 mol%)
Entry
Solvent
Conditions
sonication
Temp. (°C)
Time
3 h
Yield (%)b
(
room
temperature
1
2
3
4
5
6
7
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
3
3
3
3
3
–
trace
26
conventional
heating
–
120
35
3 h
dichloromethane
MWc
MW
MW
40 min
40 min
40 min
40 min
40 min
trace
15
water
100
110
120
120
toluene
40
MW
closed-vessel)
–
51
(
MW
open-vessel)
FeCl
3
–
91
(

1658
HETEROCYCLES, Vol. 92, No. 9, 2016
MW
open-vessel)
8
–
–
120
40 min
0
(
a
3
Optimization study for the synthesis of 2,4-diphenylquinoline via A -coupling: aniline (1a) (1 mmol),
b
c
benzaldehyde (2a) (1 mmol) and phenylacetylene (3a) (1 mmol). Isolated yield. MW = Microwave.
With the optimized conditions in hand, we turned our attention to evaluating the scope and limitations of
the devised system. A variety of aldehydes and anilines were used to synthesize various disubstituted
quinolines and the results are summarized in Table 2. Aldehydes bearing a range of functional groups
(Table 2, entries 2-4), displayed good to excellent yields (55-93%) while substituted anilines (Table 2,
entries 5-7), also displayed excellent results (71-90%). To further investigate our procedure, substituted
benzaldehydes, anilines and phenylacetylenes were evaluated (Table 2, entries 8-10) and under these
reaction conditions, the desired quinolines were formed in excellent yields (83-95%). Next, we expanded
our substrate scope to alkyl aldehydes and alkyl alkynes as alkyl substrates are rarely investigated in
3
17
13
A -coupled quinoline synthesis and when they are, the yields are often low, even when scientific
microwave reactors were used.11a In our first study; we investigated the coupling of
cyclohexanecarboxaldehyde, p-anisidine, and phenylacetylene in the presence of 1 mol% FeCl . The
3
reaction mixture was purified by column chromatography and we were delighted to isolate the desired
product 4k (Table 2, entry 11) albeit in a moderate yield of 45%. To further test the robustness of the 1
mol% FeCl system, we sought to test the effect of an alkyl alkyne on the devised system and the reaction of
3
benzaldehyde, aniline and 3-butyn-1-ol was examined (Table 2, entry 12). The reaction mixture was
1
analyzed using H NMR spectroscopy and only starting materials were present with a trace amount of
product detected. The 1 mol% FeCl system was extremely efficient on aryl substrates but the synthesis of
3
alkyl substituted quinolines continues to be a challenge for synthetic organic chemists.21
3
Table 2. Quinoline derivatives synthesized using 1 mol% FeCl
3
via A -coupling
R3
N
R1
R1
O
1
mol% FeCl3
R3
+
+
R2
H
open vessel microwave
R2
NH2
o
irradiation, 120 C, 40 min
1
2
3
4
Entry
R1
H
H
H
H
R2
R3
Ph
Ph
Ph
Ph
Product (%)
4a (91)
1
2
3
4
Ph
4-BrC
6
H
4
4b (80)
4-MeC
6
H
4
4c (93)
2
4-NO C
6
H
4
4d (55)

HETEROCYCLES, Vol. 92, No. 9, 2016
1659
5
6
7
8
9
Cl
Et
Ph
Ph
Ph
Ph
Ph
Ph
4e (90)
4f (71)
4g (71)
4h (86)
4i (95)
OMe
Cl
Ph
4-MeC
6
H
4
Br
4-BrC
6
H
4
4
Ph
1
0
1
2
OMe
OMe
H
4-BrC
6
H
Ph
4j (83)
4k (45)
4j (trace)
1
1
cyclohexyl
Ph
Ph
(CH ) OH
2
2
To complement our studies above, we attempted to further decrease the catalyst amount to 0.5 and 0.1
mol% (Scheme 3, entries 1 and 2), using our optimized test reaction (Table 1, entry 7), however, in these
cases, only trace amounts of the product were observed. The use of microwave chemistry has a number of
advantages such as high yields and short reaction times and the benefits of this approach have been well
1
8
documented in the literature. There are, however, limitations to microwave chemistry such as; scale-up
applicability and consequently, scientific microwave reactors cannot be run for hours on end and these
22
factors must be considered when choosing reaction conditions. Due to the limitations of microwave
chemistry highlighted above, we chose to exploit our earlier observation in which 26% of the desired
quinoline was formed in 3 hours under conventional heating (Table 1, entry 2). The optimized reaction
was repeated in the presence of 0.5 and 0.1 mol% FeCl
catalyst loading was decreased to 0.1 mol%, only trace amounts of the product was observed (Scheme 3,
entry 4). However, when the catalyst loading was decreased to just 0.5 mol% FeCl (Scheme 3, entry 3),
3
under conventional heating for 7 days. When the
3
an excellent isolated yield of 73% was obtained. These results indicate that with sufficient time, the catalyst
loading can be further decreased and still produce the desired compound in a satisfactory yield.
o
1
2
3
4
.) 0.5 mol% FeCl
.) 0.1 mol% FeCl
.) 0.5 mol% FeCl
3
3
, 40 min, 120 C, open-vessel microwave irradiation, trace
o
, 40 min, 120 C, open-vessel microwave irradiation, trace
3
, 7 days, 120 °C, conventional heating, 73%
.) 0.1 mol% FeCl3, 7 days, 120 °C, conventional heating, trace
Scheme 3. Synthesis of 2,4-diphenylquinoline using decreased amounts of FeCl under microwave and
3
conventional heating

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HETEROCYCLES, Vol. 92, No. 9, 2016
In summary, we have developed a convenient and green method towards disubstituted quinolines using an
3
A -coupling approach. A series of 2,4-disubstituted quinolines were synthesized in moderate to good yields,
from a variety of readily available aldehydes, amines, and alkynes, under solvent-free, microwave
conditions using just 1 mol% FeCl
product was still obtained in a satisfactory yield of 73%. The application of very low catalyst loadings
coupled with the inexpensive nature of FeCl make this a very attractive route towards quinolines and will
3
. The catalyst loading was further decreased to 0.5 mol% and the desired
3
be a valuable addition to synthetic organic chemistry. Further studies are underway to expand this catalytic
system to other challenging substrates, using the above-mentioned protocol and will be reported in due
course.
EXPERIMENTAL
All starting reagents were purchased from Sigma-Aldrich and used without further purification. The silica
gel (130–270 mesh) was used for column chromatography. All microwave synthesis was carried out on a
CEM Focused MicrowaveTM which uses an infrared sensor located below the microwave cavity floor to
1
13
measure temperature. The H and C NMR spectra were obtained on a Bruker Avance III 400 or Bruker
Avance III 500 spectrometer operating at 400 MHz or 100 MHz. NMR spectra were referenced against
the residual CDCl
3
present in δ
H
7.26 ppm or the δ 77.0 ppm. The mass spectrometric identification of
C
the products has been carried out using a Perkin Elmer Spectra One. IR spectra were recorded on a Smiths
®
IdentifyIR Spectrometer. All melting points were determined using a Kofler hot-stage melting apparatus
and are uncorrected.
General procedure for the synthesis of quinolines
Aldehyde (1 mmol), amine (1 mmol), alkyne (1 mmol) and FeCl (1 mol%) was added to a cylindrical
3
microwave reaction vessel and irradiated for 40 min at 120 °C. The reaction mixture was cooled to room
temperature, filtered through a short silica plug and the solid residues washed well with EtOAc. The
solvent was removed in vacuo and the product purified by column chromatography to produce the title
compounds.
-1
2
,4-Diphenylquinoline (Table 2, 4a): a yellow solid; mp 110-111 °C; IR (neat, cm ): 2932, 1458, 1276;
1H NMR δ (ppm) 8.30-8.27 (d, J = 8.62, 1H), 8.23-8.20 (m, 2H), 7.93-7.90 (d, J = 8.33, 1H), 7.83 (s, 1H),
1
3
7
.77-7.72 (m, 1H), 7.58-7.46 (m, 9H); C NMR (100 MHz, CDCl ) δ (ppm) 156.9, 149.3, 148.7, 139.6,
3
1
38.4, 130.1, 129.6, 129.4, 129.3, 128.9, 128.6, 128.5, 127.5, 126.4, 125.8, 127.7, 119.3; m/z (%) = 282
29), 281 (M ) (100), 280 (100), 278 (15). Data in agreement with literature.13,23
+
(

HETEROCYCLES, Vol. 92, No. 9, 2016
1661
-
1
2
1
1
1
-(4-Bromophenyl)-4-phenylquinoline (Table 2, 4b): a white solid; mp 113-114 °C; IR (neat, cm ):
1
458, 1276, 1054, 758; H NMR δ (ppm) 8.25 (d, J = 8.52, 1H), 8.10 (d, J = 8.73, 2H), 7.91 (d, J = 8.51,
1
3
H), 7.77-7.53 (m, 10H); C NMR (100 MHz, CDCl
3
) δ (ppm) 155.8, 152.5, 150.2, 148.8, 138.5, 132.4,
30.3, 130.2, 129.6, 129.4, 129.1, 129.0, 127.1, 126.2, 124.5, 124.2, 119.3; m/z (%) = 360 (100), 359
+
24,25
(
M ) (82), 278 (41), 139 (41). Data in agreement with literature.
-1
2
-(4-Methylphenyl)-4-phenylquinoline (Table 2, 4c): a yellow solid; mp 115-116 °C; IR (neat, cm ):
1
2
932, 2932, 1738, 1622, 1458; H NMR δ (ppm) 8.29 (d, J = 8.32, 1H), 8.11 (d, J = 8.32, 2H), 7.91 (d, J
=
8.46, 1H), 7.81 (s, 1H), 7.77-7.72 (m, 1H), 7.58-7.50 (m, 5H), 7.50-7.45 (m, 1H), 7.35 (d, J = 8.21, 2H),
1
3
2
.44 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 157.2, 149.6, 149.0, 139.9, 138.8, 137.0, 130.3, 129.9,
+
1
29.8, 128.9, 128.7, 127.9, 126.5, 126.1, 126.0, 119.6, 21.7; m/z (%) = 295 (M ) (100), 294 (100), 202
(
35). Data in agreement with literature.23,26
-
1
2
2
7
1
3
-(4-Nitrophenyl)-4-phenylquinoline (Table 2, 4d): a yellow solid; mp 155-156 °C; IR (neat, cm ):
1
850, 1738, 1622; H NMR δ (ppm) 8.41-8.36 (m, 4H), 8.28 (d, J = 8.59, 1H), 7.94 (d, J = 8.63, 1H),
1
3
.86 (s, 1H), 7.79 (t, J = 8.14, 1H), 7.58-7.53 (m, 6H); C NMR (100 MHz, CDCl ) δ (ppm) 154.4, 150.4,
3
49.0, 148.8, 145.7, 138.2, 130.6, 130.5, 129.9, 129.1, 128.7, 127.7, 126.6, 126.2, 124.3, 119.4; m/z (%) =
26 (M ) (100), 280 (44), 279 (38), 139 (29). Data in agreement with literature.24,27,15
+
-
1
6
1
7
1
-Chloro-2,4-diphenylquinoline (Table 2, 4e): a yellow solid; mp 129-130 °C; IR (neat, cm ): 2932,
1
738, 1054; H NMR δ (ppm) 8.20-8.18 (m, 3H), 7.87 (d, J = 2.09, 1H), 7.84 (s, 1H), 7.66-7.67 (m, 1H),
1
3
.60-7.48 (m, 8H); C NMR (100 MHz, CDCl
3
) δ (ppm) 157.4, 149.0, 147.4, 139.4, 138.1, 132.6, 132.0,
30.9, 130.0, 129.8, 129.3, 129.2, 129.1, 127.9, 126.9, 124.9, 120.4; m/z (%) = 317 (33), 316 (60), 315
+
23,28
(
M ) (100), 314 (100). Data in agreement with literature.
-
1
1
6
-Ethyl-2,4-diphenylquinoline (Table 2, 4f): a brown oil; IR (neat, cm ): 2964, 1574, 1276, 1255; H
NMR δ (ppm) 8.20 (d, J = 7.40, 2H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (m, 10H), 2.79 (q, J = 7.40, 2H),
13
1
.29 (t, J = 7.52, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 156.4, 149.1, 147.9, 142.9, 140.1, 139.0,
1
31.0, 130.3, 130.0, 129.5, 129.2, 128.9, 128.7, 127.9, 126.1, 123.6, 119.8, 29.5, 15.9; m/z (%) = 309
+
11a
(
M ) (100), 294 (89), 280 (71), 139 (19). Data in agreement with literature.
-1
6
-Methoxy-2,4-diphenylquinoline (Table 2, 4g): a brown oil; IR (neat, cm ): 2932, 1738, 1622, 1054,
1
1
022, 758; H NMR δ (ppm) 8.18-8.17 (m, 3H), 7.78 (s, 1H), 7.58-7.47 (m, 7H), 7.45-7.40 (m, 2H), 7.20
1
3
(
d, J = 2.75, 1H), 3.81 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 158.1, 154.9, 148.1, 145.2, 140.0,
3

1662
HETEROCYCLES, Vol. 92, No. 9, 2016
1
39.1, 131.9, 129.7, 129.3, 129.1, 129.0, 128.7, 127.6, 127.0, 122.1, 119.9, 104.0, 55.7; m/z (%) = 312
20), 311 (M ) (100), 310 (27). Data in agreement with literature.29
+
(
-1
6
-Chloro-2-phenyl-4-p-tolylquinoline (Table 2, 4h): a yellow oil; IR (neat, cm ): 2850, 2432, 1738,
1
1
622, 1244; H NMR δ (ppm) 8.19 (m, 3H), 7.90 (d, 1H, J = 2.19), 7.83 (s, 1H), 7.67 (dd, J = 9.00, 2.38
1
3
Hz, 1H), 7.46 (m, 7H), 2.50 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 157.4, 148.9, 147.5, 139.6,
1
3
39.0, 135.2, 132.5, 132.0, 130.7, 129.9, 129.7, 129.3, 127.9, 127.0, 126.4, 124.9, 120.4, 21.6; m/z (%) =
30 (38), 329 (M ) (100), 328 (52). Data in agreement with literature.11a
+
-
1
6
1
7
1
-Bromo-2-(4-bromophenyl)-4-phenylquinoline (Table 2, 4i): a yellow oil; IR (neat, cm ): 2932, 2850,
1
738, 1628, 1244; H NMR δ (ppm) 8.14-8.08 (d, 3H), 8.04-8.03 (d, 1H), 7.82 (s, 2H), 7.67-7.60 (d, 2H),
1
3
.59-7.52 (m, 5H); C NMR (100 MHz, CDCl
3
) δ (ppm) 156.2, 137.9, 133.7, 132.5, 132.0, 129.8, 129.5,
+
29.3, 128.3, 127.4, 124.7, 121.2, 119.9; m/z (%) = 439 (M ) (100), 358 (29), 278 (41), 139 (64). Data in
agreement with literature.30
2-(4-Bromophenyl)-6-methoxy-4-phenylquinoline (Table 2, 4j): a yellow solid; mp 134-136 °C, IR
-1
1
(
neat, cm ): 2932, 2850, 1738, 1622, 1054, 1022; H NMR δ (ppm) 8.16 (d, J = 9.14, 1H), 8.06 (d, J =
8
1
1
.60, 2H), 7.73 (s, 1H), 7.64 (d, J = 8.48, 2H), 7.56-7.52 (m, 5H), 7.42 (q, J = 6.49, 1H), 7.19 (d, J = 2.68,
1
3
H), 3.81 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 158.5, 153.5, 148.9, 144.8, 138.8, 132.4, 131.6,
29.7, 129.4, 129.2, 128.9, 127.3, 126.8, 124.2, 122.7, 119.6, 104.2, 55.9; m/z (%) = 390 (41), 389 (M+)
(
100), 388 (18). Data in agreement with literature.29
-1
2
-Cyclohexyl-6-methoxy-4-phenylquinoline (Table 2, 4k): a yellow oil; IR (neat, cm ): 2924, 2853,
1
1
618, 1593, 1493, 1473, 1440; H NMR δ (ppm) 8.06 (d, J = 9.13 Hz, 1H), 7.56-7.48 (m, 5H), 7.35 (dd, J
9.1, 2.7 Hz, 1H), 7.22 (s, 1H), 7.16 (d, J = 2.7 Hz, 1H), 3.77 (s, 3H), 2.95 (tt, J = 11.8, 3.1 Hz, 1H),
.07 (d, J = 11.7 Hz, 2H), 1.89 (d, J = 12.8 Hz, 2H), 1.78 (d, J = 12.7 Hz, 1H), 1.65 (ddd, J = 24.80,
=
2
1
13
2.50, 2.60 Hz, 2H), 1.48 (ddd, J = 15.60, 11.20, 3.10 Hz, 2H), 1.38-1.28 (m, 1H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 164.0, 157.5, 147.7, 144.0, 139.0, 130.6, 129.4, 128.6, 128.3, 126.3, 121.4, 120.2, 103.9,
+
5
5.5, 47.2, 33.0, 26.6, 26.1; m/z (%) = 317 (M ) (5), 316 (13), 290 (37), 235 (24). Data in agreement with
literature.16
ACKNOWLEDGEMENTS
We are grateful to the National Research Foundation (NRF) of South Africa for providing a postgraduate
bursary (SN) and to the University of KwaZulu-Natal for financial assistance.

HETEROCYCLES, Vol. 92, No. 9, 2016
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