Synthesis of Novel 5-(N-Substituted-Anilino)-8-Hydroxyquinolines via Hartwig-Buchwald Amination Reaction

Article abstract of DOI:10.1007/s12039-015-0960-5

Three novel 5-(N-substituted-anilino)-8-benzyloxyquinoline derivatives were efficiently synthesized via Hartwig-Buchwald amination reaction. The new 5-(N-substituted-anilino)-8-benzyloxyquinolines were reduced for 1-3 h to give the corresponding 5-(N-substituted-anilino)-8-hydroxyquinolines. Extending the reduction reaction time to 7 h afforded the corresponding 1,2,3,4-tetrahydro-8-hydroxyquinoline derivatives.

Full text of DOI:10.1007/s12039-015-0960-5

c
J. Chem. Sci. Vol. 127, No. 11, November 2015, pp. 1937–1943. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-0960-5
Synthesis of Novel 5-(N-Substituted-Anilino)-8-Hydroxyquinolines via
Hartwig-Buchwald Amination Reaction
WALAA A E OMARa,b,∗ and OSMO E O HORMIa
aDepartment of Chemistry, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland
bDepartment of Science and Mathematics, Faculty of Petroleum and Mining Engineering, Suez University,
Suez 43721, Egypt
e-mail: Walaa.omar@suezuniv.edu.eg
MS received 17 April 2015; revised 1 July 2015; accepted 10 August 2015
Abstract. Three novel 5-(N-substituted-anilino)-8-benzyloxyquinoline derivatives were efficiently synthe-
sized via Hartwig–Buchwald amination reaction. The new 5-(N-substituted-anilino)-8-benzyloxyquinolines
were reduced for 1–3 h to give the corresponding 5-(N-substituted-anilino)-8-hydroxyquinolines. Extending the
reduction reaction time to 7 h afforded the corresponding 1,2,3,4-tetrahydro-8-hydroxyquinoline derivatives.
Keywords. Hartwig–Buchwald amination; electron-rich phosphine ligands; 5-anilino-8-hydroxyquinoline;
1,2,3,4-tetrahydroquinolin-8-ol; catalytic hydrogenation.
1. Introduction
Although palladium catalyzed coupling of quino-
lines with different amines has been reported,1,6,13,31–33
reports concerning coupling between quinoline sub-
strates and secondary anilines are rare.34 Herron et al.10
reported that the metal complexes of 5-diphenylami-
no-8-hydroxyquinoline 4c acted as an efficient mate-
rial in organic electronic devices. They produced the
8-hydroxyquinoline derivative 4c by non-optimized
palladium catalyzed coupling between 5-chloro-8-
hydroxyquinoline and diphenylamine under reflux for
180 h.
On the other hand, 1,2,3,4-tetrahydroquinolines
are important organic synthetic intermediates and
building blocks for alkaloids and biologically active
compounds.35–39 Moreover, they have been used suc-
cessfully as ligands in coupling reactions.40,41 Direct
hydrogenation of quinoline derivatives is the most con-
venient route to synthesize tetrahydroquinoline deriva-
tives. However, the hydrogenation reaction usually
requires applying high hydrogen pressure.42–48
Recently, we reported the synthetic route for 5-ami-
no-8-hydroxyquinolines equipped with alicyclic amines
namely, pyrrolidine, piperidine and morpholine using
optimized palladium catalyzed Hartwig–Buchwald
amination.6 In the present work, three secondary
aniline substrates namely, N-methyaniline, 3-MeO-
N-methylaniline and diphenylamine were coupled
with 5-bromo-8-benzyloxyquinoline 2 in H–B ami-
nation reaction using commercially available ligands,
L1, L2, L3 and L4, to produce the corresponding
5-anilino-8-benzyloxyquinolines. The corresponding
Quinolines functionalized with amino substituents are
particularly important due to their wide applications
especially in medicine and photovoltaics.1–10 Hartwig–
Buchwald amination is an efficient reaction for the
coupling of amines with aryl halides.11–14 The reaction
is preferred over other C–N bond-forming methodolo-
gies because of the milder reaction conditions and the
relatively higher yields.15,16 In addition, the availability
of the starting materials and a wide variety of ligands
provide access to a range of hindered and functional-
ized aryl amines. The choice of the palladium/ligand
combination to be used during the coupling has turned
out to be problematic.6,13,17–21 A suitable catalytic sys-
tem was found to vary according to the steric and elec-
tronic requirements of both the substrate and the amine.
Hence, for the amination reaction to proceed efficiently
towards the formation of the desired coupling product,
the reaction conditions should be optimized. In contin-
ued efforts, many research groups employed different
catalytic systems (Pd/L) for this coupling and many phos-
phine and carbene ligands have rapidly emerged.11,13,19–25
Among the electron rich phosphine ligands, the ster-
ically demanding (2-biphenyl)di-tert-butylphosphine
(Johnphos) L1,6,26 tri-tert-butylphosphine (TTBP)
L2,27,28 di-tert-butylneopentylphosphine (DTBNpP)
L3,6,14,29 and tricyclohexylphosphine L4 were effec-
tively used in H–B amination reactions30 (figure 1).
∗For correspondence
1937

1938
Walaa A E Omar and Osmo E O Hormi
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
P
P
P
P
t-Bu
t-Bu
JohnPhos
L1
TTBP
L2
DTBNpP
L3
PCy3
L4
Figure 1. The commercially available ligands L1, L2, L3 and L4.
5-anilino-8-hydroxyquinolines and 5-anilino-1,2,3,4- 2.2a 5-(N-methylanilino)-8-benzyloxyquinoline (3a):
tetrahydro-8-hydroxyquinolines were prepared via The title compound was prepared by following the gen-
mild, ligand-free catalytic hydrogenation.
eral procedure. Specific amounts of chemicals used:
Compound 2 (200 mg, 0.64 mmol), Pd(AcO)2 (7.15 mg,
0.032 mmol), ligand L3 (19.37 mg, 0.064 mmol),
sodiumtert-butoxide (76.5 mg, 0.80 mmol) and N-
methylaniline (0.086 mL, 0.80 mmol). The reaction
was stirred for 30 min in an oil bath at 110–12◦C.
The crude product was purified by flash chromatogra-
phy using n−hexane/acetone (1/1) giving 3a as pale
yellow crystals (195 mg, 90 C.1H NMR (200 MHz,
CDCl3)δ 3.32 (s, 3H), 5.35 (s, 2H), 6.49 (d, J =
8.067 Hz, 2H), 6.66 (t, J = 7.058 Hz, 1H), 7.11 (t,
J = 8.067 Hz, 2H), 7.33-7.60 (m, 8H), 8.03 (d, J =
8.47 Hz, 1H), 8.89 (d, J = 3.83 Hz, 1H); 13C NMR
(50 MHz, CDCl3)δ 40.33, 70.90, 109.97, 113.229 (2C),
117.33, 121.86, 127.13 (2C), 127.56, 127.93, 128.73
(2C), 129.03 (2C), 132.32, 136.92, 137.55, 141.46,
149.59, 150.12, 153.14. HRMS (M+H)+ calc for C23
H21N2O: 341.1654, found: 341.1661.
2. Experimental
2.1 General
All reactions were carried out under argon atmosphere
except the palladium catalyzed reduction reactions,
which were carried out under hydrogen atmosphere.
Solvents were dried by molecular sieves of proper pore
size. 5-Bromo-8-hydroxyquinoline 1 was purchased
from Tokyo Chemical Industry Co. (TCI). 8-(Benzyl-
oxy)-5-bromoquinoline 2 was synthesized according to
previously published procedures.6,49 Ligands (L1–L4)
have been used in the form of tetrafluoroborate salts
and were purchased from Sigma–Aldrich Chemical Co.
Palladium acetate was purchased from Fluka Chemical
Co. Melting points were determined using a METTLER
TOLEDO DSC821 at a heating rate of 20◦C/min. NMR
analyses (1H and 13C) were performed using Bruker
DPX 200 (200 MHz) spectrometer using DMSO-d6
or CDCl3 solutions referenced internally to Me4Si,
Jvalues are given in Hz. TLC were performed on dry
silica gel plates and developed by using chloroform/
methanol mixture as eluent.
2.2b 5-(3-Methoxy-N-methylanilino)-8-benzyloxyquin-
oline (3b): The title compound was prepared by fol-
lowing the general procedures. Specific amounts of
chemicals used: Compound 2 (200 mg, 0.64 mmol),
Pd(AcO)2 (7.15 mg, 0.032 mmol), ligand L3 (19.37
mg, 0.064 mmol), sodium tert-butoxide (76.5 mg,
0.80 mmol) and 3-methoxy-N-methylaniline (0.10 mL,
0.80 mmol). The reaction was stirred for 5–6 h at
140–15◦C. The crude product was purified by flash
chromatography using n−hexane/acetone (1/1) giv-
2.2 General procedure for the synthesis of 5-anilino-
8-benzyloxyquinoline (3a–c) via Hartwig–Buchwald
amination reaction
In an oven-dried vessel with a magnetic stirring bar, ing 3b as yellow crystals (205 mg, 87 DMSO-d6)δ
toluene was added and bubbled with argon for 10 min. 3.28 (s, 3H), 3.60 (s, 3H), 5.32 (s, 2H), 6.04 (d, J
Compound 2, Pd(OAc)2 (5 mol%), ligand of choice = 5.99 Hz, 2H), 6.25 (d, J = 9.03 Hz, 1H), 6.98 (t,
after optimization (10 mol%), sodium tert-butoxide J = 8.20 Hz, 1H), 7.30-7.59 (m, 8H), 7.98 (d, J =
(1.25 equiv) and aniline derivative (1.25 equiv) were 8.30 Hz, 1H), 8.89 (d, J = 3.23, 1H); 13C NMR (50
added and the reaction mixture was stirred under argon MHz, CDCl3)δ 40.40, 55.06, 70.82, 99.79, 101.97,
at optimized temperature. The reaction mixture was 106.44, 109.88, 121.95, 126.04, 127.21 (2C), 127.51,
then allowed to cool to room temperature, filtered 127.94, 128.70 (2C), 129.72, 132.30, 136.83, 137.25,
through a thin pad of silica gel and the solvent was 141.35, 149.57, 151.48, 153.18, 160.55. HRMS
evaporated under vacuum. The product was purified by (M+H)+ calc for C24H23N2O2: 371.1760, found:
flash chromatography using the proper eluent.
371.1767.

5-Anilino-8-hydroxyquinoline derivatives
1939
(M+H)+ calc for C17H16N2O2: 280.1212, found:
2.2c 5-(N-phenylanilino)-8-benzyloxyquinoline (3c):
The title compound was prepared by following the gen-
eral procedure. Specific amounts of chemicals used:
Compound 2 (100 mg, 0.32 mmol), Pd(AcO)2 (10 mol
L4 (20 mol 0.40 mmol) and diphenylamine (2 equiv.,
107.7 mg, 0.64 mmol). The reaction was stirred for 24 h
at 150◦C. The crude product was purified by flash chro-
matography using n−hexane/acetone (4/1) giving 3c as
bright yellow crystals (105 mg, 82 NMR (200 MHz,
CDCl3)δ 5.46 (s, 2H), 6.89-7.06 (m, 6H), 7.15-7.43
(m, 10H), 7.54 (d, J = 6.81, 2H), 8.22 (dd, J = 8.60 Hz,
J = 1.44 Hz 3.60, 1H), 8.96 (dd, J = 4.30 Hz, J = 1.08
Hz, 1H); 13C NMR (50 MHz, DMSO-d6)δ 70.95, 110.0,
121.53 (4C), 121.73 (2C), 121.92, 127.22 (2C), 127.56,
127.72, 127.94, 128.71(2C), 129.15 (4C), 132.61,
135.77, 136.87, 141.50, 148.22(2C), 149.51, 153.06.
HRMS (M+H)+ calc for C28H23N2O: 403.1810, found:
403.1811.
280.1224.
2.3c 5-(N-phenylanilino)quinolin-8-ol (4c): The title
compound was prepared according to the general proce-
dure. Bright yellow crystals (33.76 mg, 87 C. 1H NMR
(200 MHz, CDCl3)δ 6.90-7.38 (m, 13H), 8.22 (d, J =
8.14 Hz, 1H), 8.79 (d, J = 2.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3)δ110.55, 121.49(4C), 121.71 (3C),
122.08, 126.77, 129.14 (4C), 133.29, 134.26, 138.94,
147.94, 148.26 (2C), 150.80. HRMS (M+H)+ calc for
C21H17N2O: 313.1349, found: 313.1341.
2.4 General procedure for the synthesis of 5-anilino-
1,2,3,4-tetrahydroquinolin-8-ol (5a-c)
In a dry two-necked round bottom flask, 50 mg of 5-
anilino-8-benzyloxyquinoline (3a–c) and 10 mg Pd–C
(10 wt%) were stirred and refluxed in ethanol under
hydrogen atmosphere for 7 h. The reaction mixture was
then filtered through a thin pad of silica gel. The filtrate
was concentrated and allowed to stand at room temper-
ature overnight. The product was filtered and dried in
an oven at 60◦C.
2.3 General procedures for the synthesis of 5-anilino-
8-hydroxyquinoline (4a–c)
In a dry two-necked round bottom flask, 50 mg of 5-
anilino-8-benzyloxyquinoline (3a–c) and 10 mg Pd–C
(10 wt%) were stirred and refluxed in ethanol under
hydrogen atmosphere for 1–3 h. The reaction mixture
was filtered through a thin pad of silica gel. The filtrate
was concentrated and allowed to stand at room tem-
perature overnight. The product appeared as yellowish
precipitate, which was filtered and dried in an oven at
60◦C.
2.4a 5-(N-methylanilino)-1,2,3,4-tetrahydroquinolin-
8-ol (5a): Compound 5a was prepared according to
the general procedure. yellow crystals (33.24 mg, 89
121–12◦C.1H NMR (200 MHz, DMSO-d6)δ 1.67 (m,
2H), 2.32 (t, J = 6.05 Hz, 2H), 3.06 (s, 3H), 3.15 (t,
J = 4.71 Hz, 2H), 4.79 (s, br, NH), 6.12 (d, J = 7.98
Hz, 1H), 6.39-6.57 (m, 4H), 7.05 (t, J = 7.98 Hz,
2H), 9.12 (s, br, OH); 13C NMR (50 MHz, DMSO-
d6)δ21.70, 23.02, 112.18 (2C), 112.40, 114.10, 115.90,
119.17, 129.13 (2C), 135.34, 138.19, 142.13, 149.85.
HRMS (M+H)+ calc for C16H19N2O: 255.1497, found:
255.1501.
2.3a 5-(N-methylanilino)quinolin-8-ol (4a): Compound
4a was prepared according to the general procedure,
(31.6 mg, 86 (200 MHz, DMSO-d6)δ 3.28 (s, 3H), 6.46
(d, J = 7.65 Hz, 2H), 6.61 (t, J = 7.01 Hz, 1H), 7.03-
7.14 (m, 3H), 7.33 (d, J = 8.29 Hz, 1H), 7.45-7.53 (m,
1H), 7.98 (d, J = 7.65 Hz, 1H), 8.85 (d, J = 2.96 Hz,
1H), 9.96 (s, br, OH); 13C NMR (50 MHz, DMSO-
d6)δ40.40, 110.25, 113.23 (2C), 117.28122.06, 126.65,
127.17, 129.02 (2C, 132.83, 136.02, 139.07, 148.10,
150.22, 150.95. HRMS (M+H)+ calc for C16H15N2O:
251.1184, found: 251.1187.
2.4b 5-(3-methoxy-N-methyl-anilino)-1,2,3,4-tetrahy-
droquinolin-8-ol (5b): Compound 5b was prepared
according to the general procedures. (29.17 mg, 76
C.1H NMR (200 MHz, DMSO-d6)δ 1.76 (m, 2H),
2.3b 5-(3-methoxy-N-methyl-anilino)quinolin-8-ol (4b): 2.38 (m, 2H), 3.06 (s, 3H), 3.20 (m, 2H), 3.62 (s, 3H),
The title compound was prepared according to the 5.94-6.02 (m, 2H), 6.16-6.21 (dd, J = 1.88 Hz, J =
general procedure. (30.5 mg, 81 (200 MHz, CDCl3)δ 8.17 Hz, 1H), 6.53 (d, J = 8.48 Hz, 1H), 6.72 (d, J =
3.37 (s, 3H), 3.71 (s, 3H), 6.16 (m, 2H), 6.29 (d, J = 8.48 Hz, 1H), 6.97 (t, J = 8.17 Hz, 1H), 10.03 (s, br,
7.93 Hz, 1H), 7.07 (t, J = 7.21 Hz, 1H), 7.20-7.46 (m, OH); 13C NMR (50 MHz, DMSO-d6)δ20.31, 22.25,
3H), 8.13 (d, J = 7.93 Hz, 1H), 8.83 (s, 1H); 13C NMR 55.12, 98.70, 101.53, 105.66, 113.45, 121.64, 125.73,
(50 MHz, CDCl3)δ40.50, 55.10, 99.76, 101.91, 106.43, 127.49, 130.04, 137.98, 145.91, 150.90, 160.67. HRMS
110.49, 121.10, 126.62, 127.47, 128.32, 129.67, (M+H)+ calc for C17H21N2O2: 285.1603, found:
133.06, 135.77, 138.81, 150.84, 151.51, 160.66. HRMS 285.1613.

1940
Walaa A E Omar and Osmo E O Hormi
5-amino-8-benzyloxyquinoline 2.6 L1, L2 and L3
proved to be efficient ligands in this coupling. The cone
angles of ligands play an important role in determining
the catalyst system activity.6,14,50
2.4c 5-(N-phenylanilino)-1,2,3,4-tetrahydroquinolin-
8-ol(5c): Compound 5c was prepared according to the
general procedure; bright yellow crystals (34.6 mg, 88
20–20◦C.1H NMR (200 MHz, DMSO-d6)δ 1.67 (m,
2H), 2.25 (t, J = 6.78 Hz, 2H), 3.12 (t, J = 5.81 Hz, 2H),
6.19 (d, J = 7.75 Hz, 1H), 6.57 (d, J = 8.72 Hz, 1H),
6.80-6.93 (m, 6H), 7.18 (t, J = 7.75 Hz, 4H), 9.38 (s,
br, OH); 13C NMR (50 MHz, DMSO-d6)δ21.44, 23.56,
112.82, 117.51, 120.53 (4C), 121.14 (2C), 129.44 (4C),
133.85, 136.27, 143.08, 147.47 (3C). HRMS (M+H)+
calc for C21H21N2O: 317.1654, found: 317.1686.
A main side product that was observed during pal-
ladium catalyzed amination reactions was the arene or
the reduction product of 2.6,51 Hartwig et al.51 explained
that the formation of the arene along with the desired
amine during the reaction is due to competitive reduc-
tive elimination of the arylamine and β-hydrogen elim-
ination from the amidoaryl intermediate. Moreover, the
ratio of the amine to arene is controlled by steric and
electronic factors of both the substrate and the ligand.
As the ligands, L1, L2 and L3 succeeded to dif-
ferent extents in the coupling of the secondary satu-
rated amines, piperidine, pyrrolidine and morpholine
with 5-bromo-8-benzyloxyquinolines 2,6 and we inves-
tigated their performance in the coupling of 2 with
secondary aniline derivatives, namely N-methylaniline,
3-methoxy-N-methyl aniline and diphenylamine.
On the basis of our initial studies, the stable palla-
dium acetate (5 mol%) proved to be a good source of
palladium in H–B amination. In order to optimize the
3. Results and Discussion
In this work, we aimed to explore the utility of
commercially available phosphine ligands in Hartwig–
Buchwald palladium catalyzed amination of quinoline
derivative, 5-bromo-8-benzyloxyquinoline 2, with three
secondary anilines (scheme 1). For such a coupling,
sterically demanding phosphine ligands, L1, L2, L3
and L4 have been employed (figure 1).
Previously, we investigated the H–B palladium
catalyzed amination of secondary cyclic amines with
II
I
2
1
3a-c
III
IV
4a-c
5a-c
a, R1 = Me, R2 = H
b, R1 =Me, R2 = OMe
c, R1= Ph, R2 = H
Scheme 1. Reagents and conditions: (I) BnBr, K2CO3, DMF, rt, 1 h; (II)
Pd(OAc)2, Ligand (L1–L4), NaO-t-Bu (1.25 equiv.), aniline (1.25 equiv),
toluene, 110–150◦C, 0.5–24 h; (III): Pd–C (10 wt%), H2, ethanol, reflux, 1–3
h; (IV): Pd–C (10 wt%), H2, ethanol, reflux, 7 h.

5-Anilino-8-hydroxyquinoline derivatives
1941
reaction conditions, initially we used palladium acetate at high temperature as 150◦C. Testing L1 and L2 did
and L1 to couple 2 with N-methylaniline. After 24 h of not lead to any improvement in the reaction. Since
reflux at 110–120◦C, 1H-NMR from the crude reaction the phenyl is planar, diphenylamine can exhibit less
mixture revealed incomplete conversion of the starting steric hindrance than N-methylaniline, hence a less ster-
material to products. In addition, the formation of 8- ically demanding ligand with smaller cone angle is
(benzyloxy)quinoline, which is the reduction product of probably needed to couple 2 with diphenylamine. It
2, was observed noticeably along with the desired ami- has been reported that tricyclohexylphosphine ligand
nation product (table 1, entry 1). In contrast, the uti- L4 was used successfully in the coupling of substi-
lization of L2 instead of L1 (table 1, entry 2) under tuted aryl bromides with substituted anilines giving the
same conditions afforded the amination product in high amination products in quantitative yields.30 Employ-
yield (89%) and complete conversion was observed. ing tricyclohexylphosphine ligand L4 (cone angle =
The debrominated product was formed as a minor side 170◦)50 instead of L3 under same reaction condition at
product (11%). When L3 was employed as the ligand 150◦C was found to form about 70% conversion of the
(table 1, entry 3), similar to L2, complete conversion starting materials to products after 24 h. Raising the
was observed. In addition, the highest yield of 3a was catalyst loading to be 10 mol% of palladium acetate
obtained (93%) while the side reduction product was resulted in a complete conversion giving the desired
reduced noticeably to be 7%. To adjust the reaction time amination product in about 84% in the crude prod-
for the coupling of 2 with N-methylaniline using L3 as ucts mixture along with the undesired reduction product
the ligand, the reaction was repeated and traced with in about 16%. Herron et al.10 reported the production
TLC. Complete conversion was observed after 30 min. of 4c via palladium-catalyzed amination of 5-chloro-8-
Having a defined and efficient catalytic system, the hydroxyquinoline with diphenylamine in refluxed diox-
coupling of 2 with 3-MeO-N-methylaniline has been
examined under the same reaction conditions (L3 and
110–120◦C). Surprisingly, the reaction did not pro-
ane/toluene for 180 h. The long reaction time led to
catalyst deactivation and consequently decreased the
yield. In this work, optimization of the reaction con-
ceed efficiently and only 3% of the starting material ditions and use of 2 as the starting material led to
converted to products. Raising the temperature to 140– the production of 4c effectively and decreased the
150◦C afforded the desired coupling product 3b after reaction time considerably. In general, the decreased
6 h in high yield (89% in the crude reaction mixture). activity of diphenylamine in the coupling may be
Ligand cone angle (θ) of L3 increased with the replace- attributed to the lower nucleophilicity compared to the
ment of tert-butyl group in L2 with neopentyl group N-methylanilines. Table 2 summarizes the optimum
(L2, θ = 194◦ < L3, θ = 198◦).14 The increased cone conditions for the coupling of each aniline substrate
angle of L3 allows better accommodation for the steri- with 2.
cally hindered substrates.30 This can explain the slightly
increased efficiency of L3 compared to L2 during the B amination reaction of 2 with each secondary ani-
coupling of secondary anilines.
line substrate, the products were purified by flash chro-
Encouraged by the successful results we obtained matography using the appropriate eluents.
After exploration of the optimal conditions for H–
using L3 in the coupling, we were interested to inves-
The following step in this work was the depro-
tigate the coupling of 2 with diphenylamine using the tection of compounds 3a–c to obtain the 5-anilino-8-
same ligand. We observed very weak conversion even hydroxyquinoline derivatives 4a–c. The protecting ben-
zyloxy group at 8-position in 2 tolerated the strong
basic medium employed in this amination and could
Table 1. Pd catalyzed amination of 8-(Benzyloxy)-5-
bromoquinoline 2 with N-methylanilinea.
be smoothly removed after the coupling by catalytic
hydrogenation. The deprotection took place using mild
ligand-free palladium-catalyzed hydrogenation. A bal-
loon filled with hydrogen gas fixed on top of condenser
was the hydrogen source in the reaction media. The cat-
alytic hydrogenation happened selectively on the ben-
zyloxy group at 8-position in 1–3 h giving 4a–c in good
to high yields. Prolonged catalytic hydrogenation (6–7
h) under same condition resulted in a subsequent reduc-
tion of the pyridyl ring in the quinoline nucleus afford-
ing the corresponding 5-anilino-1,2,3,4-tetrahydro-8-
hydroxyquinoline derivatives 5a–c smoothly in high
Entry Ligand (θ)b Start (%) Red. Product (%) Prod. 3a (%)
1
2
3
L1 (246◦)
L2 (194◦)
L3 (198◦)
40
0
0
32
11
7
28
89
93
aReaction conditions: 50 mg of 2 , Pd(AcO)2 (5mol%),
Ligand (10 mol%), NaO-t-Bu (1.25 equiv.), amine (1.25
equiv.), Toluene at 110–120◦C under argon atmosphere.
bBetween brackets is the ligand cone angle.14,50
cisolated yield. The percentages were analyzed by 1H NMR
of the crude reaction mixture after reaction time 24 h.

1942
Walaa A E Omar and Osmo E O Hormi
Table 2. Optimum reaction conditions for the coupling of 8-(Benzyloxy)-5-bromoquinoline 2 with secondary aniline
substrates and the yields of compounds 3a-c.a
Aniline derivative
Ligand (θ)b
T (◦C)
Reaction time
Product
Yieldc
N-methylaniline
3-Methoxy-N-methylaniline
Diphenylamine
L3 (198◦)
L3 (198◦)
L4 (170◦)d
110-120
140-150
150
30 min
6 h
24 h
3a
3b
3c
93 (90)
89 (87)
86 (82)
aReaction conditions: 100-200 mg of 2, Pd(AcO)2 (5mol%), Ligand (10 mol%), NaO-t-Bu (1.25 equiv.), toluene under argon
atmosphere.
bBetween brackets is ligand cone angle.14,50
cYields analzed by 1H NMR from crude reaction mixture, number between bracket is the isolated yield after purification by
flash chromatography.
d10 mol% of Pd(AcO)2 was used in this coupling.
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yields. The subsequent hydrogenation of 4a–c to 5a–
c is attributed to the presence of the hydroxyl group
in 4a-c that facilitates the hydrogenation of quinoline
nucleus.52
4. Conclusions
The Hartwig–Buchwald coupling reaction is an
effective key step in the preparation of 5-anilino-8-
benzyloxyquinoline,
5-anilino-8-hydroxyquinoline
and 5-anilino-1,2,3,4-tetrahydro-8-hydroxyquinoline
derivatives. Optimization of the reaction conditions
and choice of a suitable catalyst/ ligand combination
are prerequisites to obtain complete conversion and
product yields. 5-Anilino-8-benzyloxyquinoline could
be reduced smoothly by catalytic hydrogenation afford-
ing the corresponding 8-hydroxyquinoline derivatives.
Once the 5-anilino-8-hydroxyquinolines were formed,
the hydroxyl group facilitated further reduction of
the pyridyl ring in the quinoline nucleus affording
5-anilino-1,2,3,4-tetrahydro-8-hydroxyquinolines.
Generally, all the reactions took place smoothly and
under mild conditions.
15. Fischer C and Koenig B 2011 Beilstein J. Org. Chem. 7
Supplementary Information
59
16. Miyata O, Shirai A, Yoshino S, Takeda Y, Sugiara M
and Naito T 2006 Synlett 6 893
17. Yin J, Zhao M M, Huffman M A and McNamara J M
2002 Org. Lett. 4 3481
1H NMR, 13C NMR spectra and HRMS for all new
products are given in supplementary information, avail-
able at www.ias.ac.in/chemsci.
18. Nadri S, Rafiee E, Jamali S and Joshaghani M 2014
Tetrahedron Lett. 55 4098
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Acknowledgements
The authors thank Mrs. Päivi Joensuu for the HRMS
data.
21. Harris M C, Huang X and Buchwald S L 2002 Org. Lett.
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