Direct oxytosylation of 8-amidoquinolines by koser's reagent: An efficient strategy for 5-substituted 8-amidoquinolines

Article abstract of DOI:10.1055/s-0037-1610212

A metal-free remote oxytosylation of 8-amidoquinolines has been achieved using Koser's reagent to produce 5-tosyloxy-8-amidoquinolines in good yields. This method is compatible with various functional groups present on the aromatic ring.

Full text of DOI:10.1055/s-0037-1610212

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
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Synthesis
Z. Begum et al.
Paper
Direct Oxytosylation of 8-Amidoquinolines by Koser’s Reagent:
An Efficient Strategy for 5-Substituted 8-Amidoquinolines
Zubeda Beguma
G. Bhavania
B. Sridharb
Basireddy V. Subba Reddy*a
OTs
O
O
PhI(OAc)2
Ar
N
H
Ar
N
H
TsOH or TsNHNH2
DCM, 25 °C
N
N
R
R
a
Center for Semiochemicals, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
bvsreddyiict@gmail.com
R = Me, CH2OH
15 examples
0–89% yield
7
b
Laboratory of X-ray Crystallography, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
8
Received: 09.05.2018
sphere. The Koser’s reagent was prepared from p-toluene-
sulfonic acid or p-toluenesulfonyl hydrazide using readily
available (diacetoxyiodo)benzene (Scheme 1).9
Accepted after revision: 20.06.2018
Published online: 07.08.2018
DOI: 10.1055/s-0037-1610212; Art ID: ss-2018-t0022-op
Abstract A metal-free remote oxytosylation of 8-amidoquinolines has
been achieved using Koser’s reagent to produce 5-tosyloxy-8-amido-
quinolines in good yields. This method is compatible with various func-
tional groups present on the aromatic ring.
OH
I(OAc)2
I
TsX (1.2 equiv)
OTs
DCM, 25 °C, 15 min
X = OH, NHNH2
Koser's reagent (2)
Key words Koser’s reagent, C–H activation, 8-amidoquinolines, oxy-
tosylation, hypervalent iodine reagents
Scheme 1 Preparation of Koser’s reagent
Introduction of oxygen functionality on aromatic and
heteroaromatic ring is a challenging task in organic synthe-
sis. Recently, a few strategies have been developed for the
To optimize the reaction conditions, the oxytosylation
of N-(quinolin-8-yl)benzamide (1a) with p-toluenesulfonic
acid or p-toluenesulfonyl hydrazide was attempted in the
1
oxytosylation of aromatic systems through a C–H bond oxi-
dation. In recent years, 8-amidoquinolines have successful-
presence of 20 mol% PhI(OAc) in dichloromethane (Scheme
2).
2
2
ly been employed for the aromatic C–H bond functionaliza-
tion. On the other hand, a remote functionalization of 8-
3
OTs
O
O
amidoquinolines have been reported with diversified re-
agents to generate 5-substituted 8-amidoquinolines
through a C–H activation. In recent years, Koser’s reagent 2
PhI(OAc)2
N
N
H
H
N
TsOH or TsNHNH2
DCM, 25 °C
N
4
1a
3a
has gained importance as a versatile and effective source for
oxytosylation of organic compounds. Recently, Shen et al.
Scheme 2 Oxytosylation of N-(quinolin-8-yl)benzamide (1a)
5
6
reported the iodobenzene-catalyzed synthesis of aryl sul-
fonate esters by the remote functionalization of amino-
quinolines at room temperature using peracetic acid as oxi-
dant. However, there have been no reports on oxytosylation
of 8-amidoquinolines at C-5 position using Koser’s reagent.
Following our interest on C–H functionalization,7 we
herein report an efficient strategy for the synthesis of 5-to-
syloxy-8-amidoquinolines using Koser’s reagent, which is
The product 3a was isolated in low yield (20%) under
these conditions (Table 1, entry 1). Therefore, the above re-
action was carried out using a stoichiometric amount of
PhI(OAc) . Interestingly, the product 3a was obtained in ex-
2
cellent yield under the above conditions (entry 2). However,
no reaction was observed in the absence of PhI(OAc) (entry
2
3). The product 3a was obtained only in 40% yield when the
reaction was performed in acetonitrile (entry 4).
generated in situ from PhI(OAc) and p-toluenesulfonic acid
2
(
p-TSA). The required precursors were prepared from 8-
These initial findings encouraged us to study the scope
of this methodology. This method is compatible with differ-
ent 8-amidoquinolines bearing chloro-, bromo-, fluoro-,
methyl-, and trifluoromethyl substituents on the aromatic
aminoquinoline and the corresponding carboxylic acid us-
ing EDCI and DMAP in CH Cl at 0 °C under nitrogen atmo-
2
2
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Z. Begum et al.
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Table 1 Optimization of Reaction Conditions in the Formation of 3aa
OTs
O
O
N
PhI(OAc)2
N
H
Entry
PhI(OAc)
2
(equiv) p-TSA (equiv) Solvent
Time (h) Yield (%)
R
H
R
N
N
TsOH (2), DCM, 25 °C
1
2
3
0.2
1.05
0
1.2
1.2
1.2
1.2
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
1.0
12
20
86
0
1
3
R1
R1
OTs
NH
OTs
OTs
OTs
6
4
1.0
MeCN
12
40
N
N
N
N
a
Reaction was performed in 1.5 mmol scale at 25 °C.
O
O
NH
O
NH
O
NH
Br
ring of the carboxylic acid moiety (Scheme 3). The substitu-
ent present on the aryl group of 8-amidoquinolines had
shown significant effect on the conversion. The presence of
halide or methyl group on the aryl ring gave the product in
good yield. The reaction was quite successful not only with
aromatic but also with heteroaromatic substrates (3k).
However, the reaction was unsuccessful with amides de-
rived from 8-aminoquinoline and carboxylic acids like 4-ni-
trobenzoic acid and acetic acid (3p and 3q). Similarly, the
amide derived from aniline and benzoic acid also failed to
give the desired product (3r). Furthermore, no desired
product was obtained either with 8-aminoquinoline or
with NBoc, and NCbz derivative of 8-aminoquinoline. All
the products were thoroughly characterized by NMR, IR,
and mass spectrometry. The reaction is highly selective and
no oxytosylation was observed on the aryl ring of the car-
boxylic acid moiety (Scheme 3). This method was success-
fully applied for a gram scale (1.2 g) synthesis of product
3
a, 86%
Cl 3b, 84%
3c, 85%
Me 3d, 86%
OTs
OTs
OTs
OTs
N
N
N
N
O
NH
O
NH
O
NH
O
NH
F
Cl
Br
3
e, 84%
3f, 76%
3g, 80%
OTs
CF3
3h, 70%
OTs
OTs
NH
OTs
NH
N
N
N
N
O
O
O
NH
O
NH
S
3d.
F3C
CF3
F
Finally, the structure of 3a was confirmed unambigu-
ously by a single crystal X-ray structural analysis (Figure
3
i, 72%
3j, 82%
3k, 81%
3l, 75%
OTs
10
1).
OTs
OTs
NH
OTs
OH
N
N
N
N
O
NH
O
O
NH
O
NH
Br
3m, 85%
3n, 89%
3o, 80%
NO2 3p, 0%
OTs
OTs
N
O
NH
O
NH
Me
3q, 0%
Figure 1 ORTEP diagram of 3a
3r, 0%
Scheme 3 Scope of the reaction. Yield refers to pure products after
chromatography.
In addition, a differential deprotection of both tosyl and
amide groups has been achieved by merely changing the re-
action conditions (Scheme 4). Deprotection of the amide
functionality was achieved to give the product 4 using HCl
without affecting the tosyl group. The selective deprotec-
tion of tosyl group was accomplished to produce product 5
using NaOH in methanol (Scheme 4).
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
Z. Begum et al.
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tions), and the coupling constants in Hz. For 13C NMR, CDCl3 (δ =
OTs
NH
OTs
7
7.00) was used as internal standard and spectra were obtained with
1
HCl
reflux, 4 h
complete proton decoupling. DMSO (δ = 2.50) for H NMR and DMSO
(δ = 39.43) for C NMR. Low-resolution MS and HRMS data were ob-
Me
13
N
N
tained using ESI ionization. IR spectra were recorded on an FT-IR
NH2
–1
spectrophotometer (neat) and reported in cm . Melting points were
4
O
3d
measured on micro melting point apparatus. Glass syringes were used
to transfer solvents. Crude products were purified by column chroma-
tography on silica gel of 60–120 or 100–200 mesh. TLC plates were
visualized by exposure to UV light and/or by exposure to I2 vapors
and/or by exposure to methanolic acidic solution of 2-naphthol fol-
lowed by heating (<1 min) on a hot plate ( 250 °C).
NaOH, MeOH
reflux, 2 h
OH
Me
N
N-(Quinolin-8-yl)benzamides 1; General Procedure
NH
To a solution of the respective carboxylic acid (6 mmol), the corre-
sponding 8-aminoquinoline (6 mmol), and DMAP (73 mg, 0.6 mmol)
in anhyd CH Cl (30 mL) was added a solution of EDCI (1.38 g, 7.2
O
5
2
2
Scheme 4 Deferential deprotection of amide and tosyl groups
mmol) in CH Cl (30 mL) through a dropping funnel at 0 °C under N
2
2
2
atmosphere. The mixture was allowed to stir at r.t. for overnight. After
completion, the mixture was diluted with CH Cl (50 mL). The organic
Mechanistically, the reaction proceeds likely through a
2
2
layer was washed with aq 1 N HCl (15 mL), followed by aq NaHCO (15
sequential formation of intermediates A to C from 8-amido-
3
11
mL), brine (25 mL), and dried (NaSO ). The organic solvent was re-
4
quinoline 1a and Koser’s reagent. Finally, the displace-
ment of aryliodonium ion by tosylate anion would give the
desired product 3a (Scheme 5).
moved by evaporation and the residue was purified by column chro-
matography using EtOAc/hexane to afford the desired pure N-(quino-
lin-8-yl)arylamide 1.
N-(Quinolin-8-yl)benzamide (1a)
OH
I
White solid; yield: 188 mg (94%); mp 68–70 °C.
O
I
OTs
IR (neat): 3350, 3053, 1982, 1673, 1530, 1480, 1385, 1264, 1177,
O
OTs
N
–1
1
070, 825, 757, 689 cm .
N
H
N
1
H NMR (400 MHz, CDCl ): δ = 10.40 (br s, 1 H), 8.93 (dd, J = 4.1, 1.4
3
N
– H2O
Hz, 1 H), 8.25 (dd, J = 8.3, 1.4 Hz, 1 H), 8.10 (d, J = 7.2 Hz, 2 H), 8.02 (d,
J = 9.0 Hz, 1 H), 7.51–7.67 (m, 6 H).
1a
(
A)
13
C NMR (CDCl , 100 MHz): δ = 165.3, 148.2, 138.6, 136.3, 135.0,
3
134.5, 131.8, 128.8, 127.9, 127.2, 121.7, 121.6, 116.5.
O
O
HRMS (EI): m/z (M + Na)+ calcd for C16H12N ONa: 271.0842; found:
2
N
I
N
I
271.0868.
OTs
TsO
N
N
(
B)
(
C)
4-Chloro-N-(quinolin-8-yl)benzamide (1b)
Yellow solid; yield: 186 mg (93%); mp 100–102 °C.
O
IR (neat): 3332, 1674, 1530, 1477, 1327, 1261, 1089, 897, 751, 662
–
1
N
H
OTs
cm .
1
–
PhI
H NMR (500 MHz, CDCl ): δ = 10.6 (br s, 1 H), 8.86 (dd, J = 7.6, 1.3 Hz,
3
N
1
H), 8.78 (dd, J = 4.2, 1.6 Hz, 1 H), 8.10 (dd, J = 8.2, 1.6 Hz, 1 H), 7.96
3a
(d, J = 8.5 Hz, 2 H), 7.38–7.56 (m, 5 H).
Scheme 5 A plausible reaction path way
13
C NMR (CDCl , 100 MHz): δ = 164.1, 148.3, 138.6, 138.0, 136.3,
3
134.3, 133.4, 129.0, 128.6, 127.9, 127.3, 121.8, 121.7, 116.5.
In conclusion, we have developed a novel strategy for
the direct oxytosylation of 8-amidoquinolines using Koser’s
reagent. The present strategy provides a rapid access to C-5
substituted 8-amidoquinolines in a single step process un-
der mild conditions. It is totally a metal-free approach.
HRMS (EI): m/z (M + H)+ calcd for C16H12ClN O: 283.0632; found:
2
283.0639.
2-Bromo-N-(quinolin-8-yl)benzamide (1c)
Light brown solid; yield: 178 mg (89%); mp 86–88 °C.
IR (neat): 3334, 2924, 2853, 1673, 1529, 1480. 1420, 1324, 1259,
–1
1065, 896, 792, 653 cm
.
1
1H NMR (500 MHz, CDCl
Hz, 1 H), 8.82 (dd, J = 4.1, 1.5 Hz, 1 H), 8.19 (t, J = 1.8 Hz, 1 H), 8.14 (dd,
J = 8.2, 1.5 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 7.67 (d, J = 7.9 Hz, 1 H),
7.50–7.57 (m, 2 H), 7.42–7.46 (m, 1 H), 7.38 (t, J = 7.9 Hz, 1 H).
H NMR spectra were recorded at 500 MHz, 300 MHz, and 400 MHz,
3
): δ = 10.66 (br s, 1 H), 8.87 (dd, J = 7.4, 1.3
13
1
and C NMR at 125 MHz, 100 MHz, and 75MHz. For H NMR, TMS
was used as an internal standard (δ = 0) and the values are reported as
follows: chemical shift, multiplicity, integration (standard abbrevia-
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Z. Begum et al.
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13
13
C NMR (CDCl , 100 MHz): δ = 163.8, 148.4, 138.6, 137.0, 136.4,
C NMR (CDCl , 100 MHz): δ = 165.4, 148.3, 138.8, 136.4, 134.9,
3
3
1
1
34.8, 134.2, 130.6, 130.3, 127.9, 127.4, 125.6, 123.0, 122.0, 121.7,
16.7.
134.6, 132.7, 132.3, 129.2, 128.7, 128.0, 127.9, 127.89, 127.83, 127.5,
126.8, 123.7, 121.7.
HRMS (EI): m/z (M)+ calcd for C16H11BrN O: 327.0128; found:
HRMS (EI): m/z (M + H)+ calcd for C20H15N O: 299.1178; found:
2
2
327.0150.
299.1181.
4-Methyl-N-(quinolin-8-yl)benzamide (1d)
N-(Quinolin-8-yl)-4-(trifluoromethyl)benzamide (1h)
White solid; yield: 184 mg (92%); mp 136–138 °C.
White solid; yield: 180 mg (90%); mp 92–94 °C.
IR (neat): 3348, 2972, 1674, 1610, 1532, 1418, 1284, 1181, 1117, 944,
IR (neat): 3343, 2929, 1669, 1539, 1480, 1326, 1141, 1065, 1013, 828,
–1
–1
826, 753, 662 cm
.
600 cm
.
1
1
H NMR (500 MHz, CDCl ): δ = 10.66 (br s, 1 H), 8.98 (dd, J = 7.6, 1.2
H NMR (500 MHz, CDCl ): δ = 10.66 (br s, 1 H), 8.84 (d, J = 7.4 Hz, 1
3
3
Hz, 1 H), 8.84 (dd, J = 4.4, 1.6 Hz, 1 H), 8.56 (s, 1 H), 8.09–8.14 (m, 2 H),
H), 8.75 (d, J = 4.1 Hz, 1 H), 8.07 (t, J = 8.8 Hz, 3 H), 7.70 (d, J = 8.0 Hz, 2
7.98–8.01 (m, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.86–7.89 (m, 1 H), 7.49–
H), 7.42–7.52 (m, 2 H), 7.34–7.39 (m, 1 H).
7
.60 (m, 4 H), 7.41–7.44 (m, 1 H).
13
C NMR (CDCl , 125 MHz): δ = 163.7, 148.3, 138.5, 138.2, 136.3,
3
13
C NMR (CDCl , 125 MHz): δ = 165.4, 148.2, 142.3, 138.8, 136.3,
134.0, 133.2 (q, JC,F = 32.6 Hz), 127.8, 127.6, 127.2, 125.7, 125.7, 124.8,
122.6, 122.1, 121.7, 116.6.
HRMS (EI): m/z (M + H)+ calcd for C17H12F N O: 317.0896; found:
3
1
2
34.7, 132.3, 129.4, 128.8, 128.0, 127.4, 127.3, 121.6, 121.5, 116.4,
1.5.
3
2
HRMS (EI): m/z (M + H)+ calcd for C17H15N O: 263.1178; found:
317.0884.
2
263.1184.
N-(Quinolin-8-yl)-3,5-bis(trifluoromethyl)benzamide (1i)
Pale yellow solid; yield: 176 mg (88%); mp 156–158 °C.
3-Chloro-N-(quinolin-8-yl)benzamide (1e)
Yellow solid; yield: 186 mg (93%); mp 80–82 °C.
IR (neat): 3334, 3062, 1677, 1545, 1487, 1376, 1276, 1189, 1119, 896,
761, 695 cm .
–1
IR (neat): 3736, 3355, 3055, 2358, 1670, 1536, 1476, 1383, 1330,
–1
1255, 1176, 904, 787, 762, 727, 678, 648 cm
.
1
H NMR (400 MHz, CDCl ): δ = 10.78 (br s, 1 H), 8.84–8.88 (m, 2 H),
3
1
H NMR (400 MHz, CDCl ): δ = 10.56 (br s, 1 H), 8.82 (dd, J = 7.4, 1.4
8.48 (s, 2 H), 8.19 (dd, J = 8.3, 1.5 Hz, 1 H), 8.08 (s, 1 H), 7.56–7.60 (m,
3
Hz, 1 H), 8.73 (dd, J = 4.2, 1.7 Hz, 1 H), 8.03 (dd, J = 8.1, 1.5 Hz, 1 H),
2 H), 7.47–7.52 (m, 1 H).
7
H).
.98 (t, J = 1.8 Hz, 1 H) , 7.84 (dt, J = 7.8, 1.1 Hz, 1 H), 7.32–7.50 (m, 5
13
C NMR (CDCl , 125 MHz): δ = 162.2, 148.6, 138.6, 137.2, 136.5,
3
133.7, 132.4 (q, JC,F = 33.6 Hz), 127.9, 127.5, 127.3, 125.32, 125.30,
13
C NMR (CDCl , 125 MHz): δ = 163.7, 148.3, 138.6, 136.8, 136.3,
125.2, 122.6, 121.9, 116.9.
3
1
1
34.9, 134.1, 131.8, 130.0, 127.9, 127.7, 127.3, 125.1, 122.0, 121.7,
16.6.
HRMS (EI): m/z (M + H)+ calcd for C18H11F N O: 385.0770; found:
6
2
385.0775
HRMS (EI): m/z (M + H)+ calcd for C16H12ClN O: 283.0633; found:
2
283.0636.
4-Fluoro-N-(quinolin-8-yl)benzamide (1j)
White solid; yield: 182 mg (91%); mp 89–90 °C.
5
-Bromo-2-fluoro-N-(quinolin-8-yl)benzamide (1f)
IR (neat): 3447, 3351, 3061,1666, 1541, 1506, 1485, 1330, 1224, 1165,
Brown solid; yield: 178 mg (89%); mp 280–282 °C.
–1
1012, 822, 757, 649 cm
.
IR (neat): 3327, 3129, 2924, 1638, 1548, 1502, 1276, 1054, 1007, 820,
1
H NMR (500 MHz, CDCl ): δ = 10.66 (br s, 1 H), 8.89 (dd, J = 7.4, 1.3
3
–1
781, 656 cm .
Hz, 1 H), 8.82 (dd, J = 4.1, 1.6 Hz, 1 H), 8.15 (dd, J = 8.2, 1.6 Hz, 1 H),
8.05–8.10 (m, 2 H), 7.50–7.59 (m, 2 H), 7.43–7.46 (m, 1 H), 7.20 (t, J =
1
H NMR (400 MHz, CDCl ): δ = 11.06 (br s, 1 H), 8.89 (dd, J = 7.0, 1.4
3
Hz, 1 H), 8.81 (dd, J = 4.0, 1.3 Hz, 1 H), 8.30 (dd, J = 6.6, 2.5 Hz, 1 H),
8.6 Hz, 2 H).
8
.11 (d, J = 8.1 Hz, 1 H), 7.47–7.49 (m, 3 H), 7.39–7.44 (m, 1 H), 7.07 (t,
13
C NMR (CDCl , 100 MHz): δ = 166.2, 164.2, 163.7, 148.3, 138.7,
3
J = 8.8 Hz, 1 H).
136.4, 134.4, 131.3, 129.7, 129.6, 128.0, 127.4, 121.8, 121.7, 116.5,
13
C NMR (CDCl , 125 MHz): δ = 160.7, 159.9, 158.2, 148.5, 136.2,
115.9, 115.7.
3
1
1
36.1, 134.7, 134.4, 127.9, 127.3, 123.7, 123.6, 122.3, 121.7, 118.3,
18.0, 117.6, 117.3.
HRMS (EI): m/z (M + H)+ calcd for C16H12FN O: 267.0928; found:
2
267.0935.
HRMS (EI): m/z (M + H)+ calcd for C16H11BrFNO: 345.0033; found:
45.0043.
3
N-(Quinolin-8-yl)thiophene-2-carboxamide (1k)
Pale yellow solid; yield: 150 mg (75%); mp 88–90 °C.
N-(Quinolin-8-yl)-2-naphthamide (1g)
IR (neat): 3346, 3073, 2924, 1651, 1533, 1483, 1355, 1267, 1115,
Colorless solid; yield: 176 mg (88%); mp 118–120 °C.
–1
1055, 819, 731, 643 cm
.
IR (neat): 3354, 3046, 1668, 1525, 1482, 1322, 1129, 830, 771, 674
1
H NMR (400 MHz, CDCl ): δ = 10.58 (br s, 1 H), 8.82–8.85 (m, 2 H),
.16 (dd, J = 8.3, 1.7 Hz, 1 H), 7.83 (dd, J = 3.7, 1.1 Hz, 1 H), 7.50–7.59
3
–1
cm
.
8
1
H NMR (500 MHz, CDCl ): δ = 10.66 (br s, 1 H), 8.98 (dd, J = 7.6, 1.2
(m, 3 H), 7.44–7.48 (m, 1 H), 7.16–7.19 (m, 1 H).
3
Hz, 1 H), 8.84 (dd, J = 4.4, 1.6 Hz, 1 H), 8.56 (s, 1 H), 8.09–8.14 (m, 2 H),
13
C NMR (CDCl , 100 MHz): δ = 160.0, 148.3, 140.1, 138.5, 136.3,
3
7.98–8.01 (m, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.86–7.89 (m, 1 H), 7.49–
134.3, 130.9, 128.4, 127.99, 127.90, 127.4, 121.75, 121.71, 116.5.
7.60 (m, 4 H), 7.41–7.44 (m, 1 H).
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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HRMS (EI): m/z (M + H)+ calcd for C14H11N OS: 255.0586; found:
1
H NMR (400 MHz, CDCl ): δ = 10.79 (br s, 1 H), 8.89 (dd, J = 5.9, 2.9
2
3
255.0593.
Hz, 1 H), 8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.36 (d, J = 8.8 Hz, 2 H), 8.20 (d,
J = 8.6 Hz, 3 H), 7.58–7.61 (m, 2 H), 7.48–7.53 (m, 1 H).
1
3
N-(Quinolin-8-yl)-[1,1′-biphenyl]-4-carboxamide (1l)
White solid; yield: 170 mg (85%); mp 139–141 °C.
C NMR (CDCl , 100 MHz): δ = 163.1, 149.7, 148.5, 140.5, 138.6,
3
136.5, 133.9, 128.4, 128.0, 127.4, 124.0, 122.5, 121.9, 116.9.
+
IR (neat): 3359, 3026, 2360, 1664, 1536, 1483, 1386, 1327, 1258,
HRMS (EI): m/z calcd for C16
294.0880.
H
12
N
3
O
3
(M + H) : 294.0873; found:
–1
1177, 1002, 895, 824, 743, 643 cm
.
1
H NMR (500 MHz, CDCl ): δ = 10.77 (br s, 1 H), 8.95 (d, J = 7.6 Hz, 1
3
N-(Quinolin-8-yl)acetamide (1q)
H), 8.84 (d, J = 3.9 Hz, 1 H), 8.14 (d, J = 8.2 Hz, 3 H), 7.74 (d, J = 8.0 Hz,
2
H), 7.64 (d, J = 7.4 Hz, 2 H), 7.36–7.60 (m, 6 H).
Colorless solid; yield: 158 mg (79%); mp 76–78 °C.
1
3
C NMR (CDCl , 100 MHz): δ = 165.1, 148.3, 144.6, 140.0, 138.8,
IR (neat): 3286, 2924, 1665, 1533, 1481, 1422, 1377, 1320, 1257,
1092, 1004, 824, 789, 691 cm .
3
–1
1
1
36.4, 134.6, 133.8, 129.0, 128.1, 128.0, 127.8, 127.5, 127.4, 127.2,
21.7, 116.6.
1
HNMR (500 MHz, CDCl ): δ = 9.78 (br s, 1 H), 8.79 (dd, J = 4.2, 1.7 Hz,
3
HRMS (EI): m/z (M + H)+ calcd for C22H17N O: 325.1335; found:
1 H), 8.76 (dd, J = 7.3, 1.2 Hz, 1 H), 8.14 (dd, J = 8.1, 1.5 Hz, 1 H), 7.41–
2
325.1366.
7.55 (m, 3 H), 2.35 (s, 3 H).
13
C NMR (CDCl , 125 MHz): δ = 168.8, 148.1, 138.2, 136.4, 134.5,
3
3-Bromo-N-(quinolin-8-yl)benzamide (1m)
127.9, 127.4, 121.6, 121.4, 116.4.
Light brown solid; yield: 178 mg (89%); mp 88–90 °C.
HRMS (EI): m/z (M + Na)+ calcd for C11H10N ONa: 209.0685; found:
2
IR (neat): 3421, 3333, 2924, 1673, 1526, 1476, 1419, 1325, 1256,
209.0681.
–1
1062, 901, 828, 733 cm .
1
Oxytosylation; General Procedure
H NMR (500 MHz, CDCl ): δ = 10.65 (br s, 1 H), 8.88 (dd, J = 7.4, 1.5
3
Hz, 1 H), 8.83 (dd, J = 4.2, 1.6 Hz, 1 H), 8.19 (t, J = 1.8 Hz, 1 H), 8.15 (dd,
J = 8.2, 1.5 Hz, 1 H), 7.96 (dt, J = 7.9, 1.0 Hz, 1 H), 7.68 (d, J = 7.9 Hz, 1
H), 7.51–7.59 (m, 2 H), 7.43–7.48 (m, 1 H), 7.39 (t, J = 7.7 Hz, 1 H).
To a solution of PhI(OAc) (509 mg, 1.58 mmol) in CH Cl (10 mL) was
2
2
2
added TsOH·H O (342 mg, 1.8 mmol). The resulting suspension was
2
stirred for 15 min at r.t. and then a solution of 8-amidoquinoline 1b
1
3
(423 mg, 1.5 mmol) in CH Cl (5 mL) was added rapidly. The progress
2 2
C NMR (CDCl , 100 MHz): δ = 163.6, 148.3, 138.5, 136.9, 136.3,
3
of the reaction was monitored by TLC. Upon completion, the mixture
was diluted with H O and extracted with CH Cl and the combined
1
1
34.7, 134.1, 130.6, 130.2, 127.9, 127.3, 125.6, 123.0, 122.0, 121.7,
16.6.
2
2
2
organic extracts were concentrateds under reduced pressure. The
resulting residue was purified by column chromatography using
EtOAc/hexane to afford the pure tosyloxyamide 3b.
HRMS (EI): m/z (M)+ calcd for C16H11BrN O: 327.0128; found:
3
2
27.0129.
N-(2-Methylquinolin-8-yl)benzamide (1n)
8
-Benzamidoquinolin-5-yl 4-Methylbenzenesulfonate (3a)
White solid; yield: 299 mg (92%); mp 88–90 °C.
IR (neat): 3331, 3025, 1668, 1541, 1467, 833, 693 cm–1
White solid; yield: 156 mg (86%); mp 174–176 °C.
.
IR (neat): 3353, 2922, 1673, 1529, 1485, 1369, 1182, 1002, 859, 808,
708, 662, 639 cm
1
–1
H NMR (400 MHz, CDCl ): δ = 2.77 (s, 3 H), 7.34 (d, J = 8.4 Hz, 1 H),
.
3
7
1
.47–7.59 (m, 5 H), 8.04–8.10 (m, 3 H), 8.90 (dd, J = 7.0, 1.9 Hz, 1 H),
0.81 (s, 1 H).
1
H NMR (400 MHz, CDCl ): δ = 10.59 (br s, 1 H), 8.86 (dd, J = 4.1, 1.5
3
Hz, 1 H), 8.79 (d, J = 8.6 Hz, 1 H), 8.41 (dd, J = 8.4, 1.5 Hz, 1 H), 8.05
(dd, J = 8.3, 1.2 Hz, 2 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.52–7.61 (m, 3 H),
7.50 (dd, J = 8.4, 5.1 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.03 (d, J = 8.5 Hz,
1 H), 2.46 (s, 3 H).
13
C NMR (100.6 MHz, CDCl ): δ = 165.3, 157.2, 138.1, 136.5, 135.3,
3
133.9, 131.7, 128.8, 127.2, 126.4, 126.1, 122.4, 121.4, 116.5, 25.4.
HRMS (EI): m/z (M + H)+ calcd for C17H15N O: 263.1184; found:
2
13
263.1169.
C NMR (CDCl , 100 MHz): δ = 165.5, 149.0, 145.8, 139.6, 138.9,
3
134.8, 133.9, 132.0, 131.4, 130.0, 128.9, 128.7, 127.3, 123.0, 122.2,
N-[2-(Hydroxymethyl)quinolin-8-yl]benzamide (1o)
119.9, 115.3, 21.7.
Colorless solid; yield: 290 mg (85%); mp 116–118 °C.
HRMS (EI): m/z (M + H)+ calcd for C23H19N O S: 419.1060; found:
2
4
IR (neat): 3444, 3332, 3049, 2929, 1646, 1542, 1408, 1065, 693 cm–1
.
419.1095.
1
H NMR (400 MHz, CD OD): δ = 4.96 (s, 2 H), 7.56–7.71 (m, 6 H), 8.09
3
8
-(4-Chlorobenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
(
1
d, J = 7.4 Hz, 2 H), 8.34 (d, J = 8.5 Hz, 1 H), 8.80 (d, J = 7.5 Hz, 1 H).
(3b)
3
C NMR (100.6 MHz, CD OD): δ = 166.0, 160.0, 137.8, 136.9, 134.7,
3
White solid; yield: 152 mg (84%); mp 106–108 °C.
1
33.8, 131.8, 128.6, 127.2, 126.9, 126.2, 122.0, 119.4, 116.7, 65.0.
IR (neat): 3346, 2922, 1674, 1531, 1482, 1372, 1181, 1090, 1002, 856,
HRMS (EI): m/z (M + H)+ calcd for C17H15N O : 279.1134; found:
2
2
2
–1
754, 664 cm
.
79.1115.
1
H NMR (500 MHz, CDCl ): δ = 10.60 (br s, 1 H), 8.85 (dd, J = 4.2, 1.2
3
Hz, 1 H), 8.75 (d, J = 8.6 Hz, 1 H), 8.39 (dd, J = 8.5, 1.2 Hz, 1 H), 7.98 (d,
J = 8.3 Hz, 2 H), 7.77 (d, J = 8.2 Hz, 2 H), 7.48–7.52 (m, 3 H), 7.32 (d, J =
4
-Nitro-N-(quinolin-8-yl)benzamide (1p)
Yellow solid; yield: 120 mg (60%); mp 154–156 °C.
8.2 Hz, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 2.45 (s, 3 H).
IR (neat): 3444, 3352, 3102, 2924, 2853, 1677, 1517, 1479, 1340,
–1
1256, 1107, 824, 708 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
Synthesis
Z. Begum et al.
Paper
1
3
C NMR (CDCl , 125 MHz): δ = 164.3, 149.0, 145.9, 139.8, 138.8,
IR (neat): 3449, 3334, 2923, 2853, 1669, 1540, 1468, 1398, 1366,
1260, 1171, 1042, 995, 853, 788, 661 cm .
3
–1
1
1
38.4, 133.6, 133.1, 132.0, 131.5, 130.0, 129.1, 128.7, 123.0, 122.3,
19.9, 115.3, 21.7.
1
H NMR (400 MHz, CDCl ): δ = 10.73 (br s, 1 H), 8.86 (dd, J = 4.1, 1.3
3
HRMS (EI): m/z (M + H)+ calcd for C23H18ClN O S: 453.0670; found:
4
Hz, 1 H) , 8.79 (d, J = 8.5 Hz, 1 H), 8.38 (dd, J = 8.4, 1.3 Hz, 1 H), 8.31
(dd, J = 6.7, 2.5 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.61–7.66 (m, 1 H),
2
4
53.0678.
7
8
.49 (dd, J = 8.5, 4.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.14 (dd, J = 11.0,
.8 Hz, 1 H),7.06 (d, J = 8.5 Hz, 1 H), 2.45 (s, 3 H).
8
-(2-Bromobenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
13
(3c)
C NMR (CDCl , 100 MHz): δ = 160.7, 160.1, 158.2, 149.2, 145.8,
3
White solid; yield: 153 mg (85%); mp 138–140 °C.
140.1, 138.9, 136.59, 136.5, 134.7, 133.8, 132.0, 131.3, 130.0, 128.6,
23.5, 123.3, 122.9, 122.3, 119.8, 118.4, 118.1, 117.7, 116.1, 21.7.
1
IR (neat): 3334, 3070, 2921, 1664, 1531, 1371, 1170, 1047, 1002, 851,
–1
HRMS (EI): m/z (M)+ calcd for C23
799, 668 cm
.
H16BrFN O S: 515.0071; found:
2 4
1
515.0088.
H NMR (500 MHz, CDCl ): δ = 10.56 (br s, 1 H), 8.84 (dd, J = 4.1, 1.6
3
Hz, 1 H), 8.74 (d, J = 8.5 Hz, 1 H), 8.36 (dd, J = 8.3, 1.0 Hz, 1 H), 8.16 (s,
8
-(2-Naphthamido)quinolin-5-yl 4-Methylbenzenesulfonate (3g)
1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 7.9 Hz,
1 H), 7.50 (dd, J = 8.4, 5.1 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.31 (d, J =
8.0 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 1 H), 2.44 (s, 3 H).
White solid; yield: 145 mg (80%); mp 126–128 °C.
IR (neat): 3358, 2922, 1667, 1529, 1488, 1367, 1182, 1048, 1005, 857,
730, 657 cm
13
–1
C NMR (CDCl , 100 MHz): δ = 163.8, 149.1, 145.9, 139.8, 138.8,
.
3
1
1
36.7, 135.0, 133.4, 132.0, 131.3, 130.6, 130.3, 130.0, 128.6, 125.6,
23.1, 122.9, 122.3, 119.8, 115.4, 21.7.
1
H NMR (400 MHz, CDCl ): δ = 10.73 (br s, 1 H), 8.88 (dd, J = 4.1, 1.4
3
Hz, 1 H), 8.84 (d, J = 8.5 Hz, 1 H), 8.55 (s, 1 H), 8.40 (dd, J = 8.5, 1.5 Hz,
1 H), 7.96–8.10 (m, 3 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2
H), 7.56–7.61 (m, 2 H), 7.50 (dd, J = 8.5, 4.1 Hz, 1 H), 7.32 (d, J = 8.1 Hz,
HRMS (EI): m/z (M)+ calcd for C23H17BrN O S: 497.0165; found:
2
4
497.0188.
2
H), 7.06 (d, J = 8.6 Hz, 1 H), 2.46 (s, 3 H).
13
8-(4-Methylbenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
C NMR (CDCl , 125 MHz): δ = 165.5, 149.0, 145.8, 139.6, 138.9,
3
(
3d)
135.0, 133.9, 132.7, 132.09, 132.01, 131.4, 130.0, 129.2, 128.8, 128.7,
128.0, 127.8, 126.9, 123.6, 123.0, 122.2, 119.9, 115.3, 21.7.
White solid; yield: 156 mg (86%); mp 122–124 °C.
HRMS (EI): m/z (M)+ calcd for
469.1235.
C H N O S: 469.1217; found:
27 20 2 4
IR (neat): 3362, 3926, 1671, 1530, 1468, 1370, 1184, 1002, 857, 735,
–1
659, 537 cm
.
1
H NMR (400 MHz, CDCl ): δ = 10.73 (br s, 1 H), 8.85 (dd, J = 4.1, 1.5
3
8
-[4-(Trifluoromethyl)benzamido]quinolin-5-yl 4-Methylben-
Hz, 1 H), 8.78 (d, J = 8.6 Hz, 1 H), 8.39 (dd, J = 8.4, 1.5 Hz, 1 H), 7.94 (d,
J = 8.1 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.49 (dd, J = 8.5, 4.2 Hz, 1 H),
zenesulfonate (3h)
7.33 (t, J = 8.3 Hz, 4 H), 7.02 (d, J = 8.5 Hz, 1 H), 2.46 (s, 6 H).
White solid; yield: 126 mg (70%); mp 132–134 °C.
1
3
C NMR (CDCl , 100 MHz): δ = 165.4, 148.9, 145.8, 142.6, 139.5,
IR (neat): 3355, 1678, 1532, 1487, 1327, 1186, 1065, 1002, 858, 737,
660 cm .
3
–1
1
38.8, 134.0, 132.0, 131.9, 131.3, 130.0, 129.5, 128.7, 127.3, 123.0,
1
22.2, 119.9, 115.1, 21.7, 21.5.
1
H NMR (400 MHz, CDCl ): δ = 10.66 (br s, 1 H), 8.85 (d, J = 3.9 Hz, 1
3
+
HRMS (EI): m/z (M + Na) calcd for C24H20N O SNa: 455.1605; found:
H), 8.76 (d, J = 8.5 Hz, 1 H), 8.40 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 8.0 Hz,
2 H), 7.75–7.83 (m, 4 H), 7.50 (dd, J = 8.4, 4.1 Hz, 1 H), 7.30–7.36 (m, 2
H), 7.05 (d, J = 8.5 Hz, 1 H), 2.46 (s, 3 H).
2
4
455.1620.
13
8-(3-Chlorobenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
C NMR (CDCl , 100 MHz): δ = 164.0, 149.1, 145.9, 140.0, 138.8,
3
(3e)
138.0, 133.6 (q, JC,F = 33.6 Hz), 133.4, 132.0, 131.5, 130.0, 128.6, 127.7,
White solid; yield: 152 mg (84%); mp 146–148 °C.
125.98, 125.94, 123.0, 122.4, 119.9, 115.5, 21.7.
HRMS (EI): m/z (M + H)+ calcd for C24
487.0939.
H F N O S: 487.0934; found:
IR (neat): 3333, 3077, 2920, 2363, 1666, 1531, 1370, 1170, 1002, 851,
18 3 2 4
–1
799, 718, 660 cm
.
1
H NMR (500 MHz, CDCl ): δ = 10.59 (br s, 1 H), 8.86 (dd, J = 4.2, 1.6
3
8
-[3,5-Bis(trifluoromethyl)benzamido]quinolin-5-yl 4-Methyl-
benzenesulfonate (3i)
White solid; yield: 130 mg (72%); mp 132–134 °C.
Hz, 1 H), 8.75 (d, J = 8.5 Hz, 1 H), 8.39 (dd, J = 8.5, 1.6 Hz, 1 H), 8.02 (t,
J = 1.8 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.55 (d,
J = 8.0 Hz, 1 H), 7.45–7.52 (m, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.04 (d, J =
8
.5 Hz, 1 H), 2.46 (s, 3 H).
IR (neat): 3285, 3063, 2927, 1678, 1541, 1366, 1280, 1132, 1047, 852,
13
–1
C NMR (CDCl , 100 MHz): δ = 164.0, 149.1, 145.9, 139.8, 138.8,
796, 684 cm
.
3
1
1
36.5, 135.1, 133.5, 132.1, 132.0, 131.4, 130.1, 130.0, 128.6, 127.7,
25.2, 123.0, 122.3, 119.9, 115.4, 21.7.
1
H NMR (400 MHz, CDCl ): δ = 10.73 (br s, 1 H), 8.86 (dd, J = 4.1, 1.3
3
Hz, 1 H), 8.79 (d, J = 8.5 Hz, 1 H), 8.38 (dd, J = 8.4, 1.3 Hz, 1 H), 8.31
(dd, J = 6.7, 2.5 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.61–7.66 (m, 1 H),
7.49 (dd, J = 8.5, 4.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.5 Hz,
HRMS (EI): m/z (M + H)+ calcd for C23H18ClN O S: 453.0670; found:
2
4
453.0676.
2
H), 7.09 (d, J = 8.5 Hz, 1 H), 2.46 (s, 3 H).
13
8-(2-Bromo-5-fluorobenzamido)quinolin-5-yl 4-Methylbenzene-
C NMR (CDCl , 125 MHz): δ = 162.4, 149.3, 145.9, 140.3, 138.8,
3
sulfonate (3f)
136.9, 132.9, 132.7, 132.4, 132.1, 132.0, 131.6, 130.0, 128.6, 127.5,
125.5, 124.0, 123.1, 122.5, 121.8, 119.8, 115.9, 21.7.
Light brown solid; yield: 138 mg (76%); mp 120–122 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
Synthesis
Z. Begum et al.
Paper
HRMS (EI): m/z (M + Na)+ calcd for C25H17F N O SNa: 555.0808;
found: 555.0846.
IR (neat): 3426, 3334, 3068, 2924, 2661, 2550, 1688, 1531, 1481,
1371, 1306, 1168, 1046, 940, 804, 744 cm .
6
2
4
–1
1
H NMR (400 MHz, CDCl ): δ = 10.58 (br s, 1 H), 8.87 (d, J = 4.0 Hz, 1
3
8
-(4-Fluorobenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
H), 8.74 (d, J = 8.5 Hz, 1 H), 8.40 (d, J = 8.4 Hz, 1 H), 8.18 (s, 1
H), 7.95 (d, J = 7.7 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 7.7 Hz,
1 H), 7.51 (dd, J = 8.4, 4.1 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H) , 7.33 (d, J =
(3j)
White solid; yield: 148 mg (82%); mp 182–184 °C.
8
.0 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 1 H), 2.45 (s, 3 H).
13C NMR (CDCl
, 100.6 MHz): δ = 163.9, 149.1, 145.9, 139.9, 138.8,
136.7, 136.6, 135.0, 133.4, 133.1, 132.0, 131.4, 130.6, 130.4, 130.0,
IR (neat): 3349, 3072, 2923, 1674, 1598, 1532, 1485, 1372, 1328,
–1
1233, 1182, 1000, 854, 736, 662 cm
.
3
1
H NMR (400 MHz, CDCl ): δ = 10.6 (br s, 1 H), 8.86 (dd, J = 4.2, 1.5 Hz,
H), 8.76 (d, J = 8.5 Hz, 1 H), 8.41 (dd, J = 8.5, 1.5 Hz, 1 H), 8.04–8.09
3
128.6, 125.6, 123.1, 123.0, 122.3, 119.8, 115.5, 21.7.
1
+
(m, 2 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.50 (dd, J = 8.4, 5.1 Hz, 1 H), 7.33 (d,
HRMS (EI): m/z (M) calcd for C23
H
17BrN
2
O
4
S: 497.0165; found:
J = 8.0 Hz, 2 H), 7.23 (t, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.6 Hz, 1 H), 2.45 (s,
497.0180.
3
H).
1
3
8-Benzamido-2-methylquinolin-5-yl 4-Methylbenzenesulfonate
3n)
C NMR (CDCl , 125 MHz): δ = 166.1, 164.1, 149.0, 145.8, 139.7,
3
(
1
1
38.8, 133.7, 132.0, 131.5, 131.02, 131.00, 130.0, 129.7, 129.6, 128.7,
23.0, 122.3, 119.9, 116.0, 115.9, 115.3, 21.7.
Colorless solid; yield: 220 mg (89%); mp 184–186 °C.
HRMS (EI): m/z (M + H)+ calcd for C23H18FN O S: 437.0966; found:
IR (neat): 3340, 3055, 2921, 1668, 1531, 1367, 1183, 1024, 819, 631
cm .
2
4
–1
437.0974.
1
H NMR (400 MHz, CDCl ): δ = 2.46 (s, 3 H), 2.76 (s, 3 H), 6.92 (d, J =
3
8
-(Thiophene-2-carboxamido)quinolin-5-yl 4-Methylbenzenesul-
8.5 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 2 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.52–7.63
(m, 3 H), 7.76 (d, J = 8.3 Hz, 2 H), 8.04 (d, J = 6.6 Hz, 2 H), 8.29 (d, J = 8.5
Hz, 1 H), 8.74 (d, J = 8.5 Hz, 1 H), 10.74 (s, 1 H).
fonate (3k)
White solid; yield: 146 mg (81%); mp 130–132 °C.
13C NMR (100.6 MHz, CDCl
134.9, 133.2, 132.08, 132.02, 131.48, 129.98, 128.92, 128.7, 127.2,
123.1, 121.1, 118.8, 115.2, 25.3, 21.8.
): δ = 165.4, 158.2, 145.8, 139.8, 138.4,
IR (neat): 3339, 3072, 2921, 1657, 1534, 1487, 1369, 1191, 1094, 994,
3
–1
848, 720, 668 cm
.
1
H NMR (500 MHz,CDCl ): δ = 10.48 (br s, 1 H), 8.85 (dd, J = 2.8, 1.3
3
HRMS (EI): m/z (M + H)+ calcd for C24
H N O S: 433.1222; found:
Hz, 1 H), 8.68 (d, J = 8.5 Hz, 1 H), 8.38 (d, J = 8.3 Hz, 1 H), 7.81 (dd, J =
21 2 4
2
7
.4, 1.0 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.59 (d, J = 4.8 Hz, 1 H), 7.47–
.51 (m, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.18 (t, J = 4.2 Hz, 1 H), 7.02 (d,
433.1187.
J = 8.5 Hz, 1 H), 2.45 (s, 3 H).
8-Benzamido-2-(hydroxymethyl)quinolin-5-yl 4-Methylbenzene-
sulfonate (3o)
13
C NMR (CDCl , 100 MHz): δ = 160.0, 149.0, 145.8, 139.6, 138.6,
3
1
1
33.6, 132.0, 131.4, 131.2, 130.0, 128.6, 128.3, 127.9, 123.0, 122.2,
19.9, 115.2, 21.7.
Viscous liquid; yield: 192 mg (80%).
IR (neat): 2923, 2853, 1742, 1460, 1376, 720 cm–1
.
HRMS (EI): m/z (M + H)+ calcd for C21H17N O S : 425.0624; found:
2
4
2
1
H NMR (400 MHz, CDCl ): δ = 2.47 (s, 3 H), 5.00 (s, 2 H), 7.00 (d, J =
3
425.0644.
8.6 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.51–7.58 (m, 4 H), 7.77 (d, J = 8.4
Hz, 2 H), 8.00 (d, J = 8.3 Hz, 2 H), 8.43 (d, J = 8.6 Hz, 1 H), 8.80 (d, J = 8.6
Hz, 1 H), 10.39 (s, 1 H).
8-([1,1′-Biphenyl]-4-ylcarboxamido)quinolin-5-yl 4-Methylben-
zenesulfonate (3l)
13
C NMR (100.6 MHz, CDCl ): δ = 165.4, 159.2, 145.9, 134.8, 133.2,
3
White solid; yield: 136 mg (75%); mp 134–136 °C.
132.5, 132.2, 130.0, 129.0, 128.7, 127.3, 127.1, 122.3, 119.8, 119.6,
IR (neat): 3427, 3355, 2922, 2853, 1669, 1530, 1485, 1345, 1183,
116.1, 65.1, 21.8.
–1
1100, 997, 843, 789, 676 cm
.
HRMS (EI): m/z (M + H)+ calcd for C24H21N O S: 449.1171; found:
449.1145.
2
5
1
H NMR (400 MHz, CDCl ): δ = 10.7 (br s, 1 H), 8.88 (dd, J = 4.0, 1.2 Hz,
3
1
H), 8.81 (d, J = 8.5 Hz, 1 H), 8.41 (dd, J = 8.4, 1.3 Hz, 1 H), 8.13 (d, J =
8
.3 Hz, 2 H), 7.78 (d, J = 7.7 Hz, 4 H), 7.66 (d, J = 7.2 Hz, 2 H), 7.46–7.54
Gram-Scale Synthesis of 8-(4-Methylbenzamido)quinolin-5-yl 4-
Methylbenzenesulfonate (3d)
(m, 3 H), 7.39–7.44 (m, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.04 (d, J = 8.5 Hz,
1
H), 2.46 (s, 3 H).
To a solution of PhI(OAc)2 (1.54 g, 4.78 mmol, 1.05 equiv) in CH Cl2
2
13
C NMR (CDCl , 125 MHz): δ = 165.2, 149.0, 145.8, 144.9, 139.9,
(10 mL) was added TsOH·H O (1.04 mg, 5.4 mmol, 1.2 equiv) and the
3
2
1
1
39.6, 138.9, 133.9, 133.4, 132.1, 131.4, 130.0, 129.0, 128.7, 128.1,
27.8, 127.5, 127.2, 123.0, 122.2, 119.9, 115.3, 21.7.
resulting suspension was stirred for 5 min at r.t. Then, a solution of 4-
methyl-N-(quinolin-8-yl)benzamide (1d; 1.2 g, 4.58 mmol, 1 equiv)
HRMS (EI): m/z (M + H)+ calcd for C29H23N O S: 495.1373; found:
in CH Cl (20 mL) was added rapidly to the above suspension. The
2 2
2
4
progress of the reaction was monitored by TLC. Upon completion, the
mixture was diluted with CH Cl (30 mL) and H O (20 mL), and the
495.1375.
2
2
2
aqueous layer was extracted with CH Cl (3 × 20 mL). The combined
2
2
8
-(3-Bromobenzamido)quinolin-5-yl 4-Methylbenzenesulfonate
organic layers were dried (Na SO ). The solvent was removed by evap-
2
4
(3m)
oration and the residue was purified by flash chromatography to give
the product 3d as a white solid; yield: 1.6 g (3.7 mmol, 81%).
Colorless solid; yield: 153 mg (85%); mp 106–108 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
Synthesis
Z. Begum et al.
Paper
Deprotection of the Amide Functionality; 8-Aminoquinolin-5-yl
-Methylbenzenesulfonate (4)
solution of 8-(4-methylbenzamido)quinolin-5-yl 4-methylben-
References
4
(1) (a) Arnold, R.; Nutter, W.; Stepp, W. J. Org. Chem. 1959, 24, 117.
A
(b) Clawson, R. W.; Deavers, R. E.; Akhmedov, N. G.; Soderberg,
zenesulfonate (3d; 500 mg, 1.16 mmol) in aq 2 M HCl (20 mL) was
heated under reflux for 3 h. The progress of the reaction was moni-
tored by TLC. After complete conversion, the mixture was quenched
with aq NaHCO3 and diluted with CH Cl (30 mL). The organic layer
B. C. G. Tetrahedron 2006, 62, 10829. (c) Pan, L.; Wang, L.; Chen,
Q.; He, M. Synth. Commun. 2016, 24, 198.
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C.; Tomkinson, N. C. O. Org. Lett. 2007, 9, 4009.
2
2
was washed with H O (20 mL) and the aqueous layer was extracted
2
(3) (a) Yan, Q.; Chen, Z.; Yu, W.; Yin, H.; Liu, Z.; Zhang, Y. Org. Lett.
with CH Cl (3 × 20 mL). The combined organic layers were dried
2
2
2
2
015, 17, 2482. (b) Ye, X.; Petersen, J. L.; Shi, X. Chem. Commun.
015, 51, 7863. (c) Reddy, V. P.; Qiu, R.; Iwasaki, T.; Kambe, N.
(
Na SO ). Removal of the solvent followed by purification on silica gel
2 4
afforded the product 4 as a brown solid; yield: 90 mg (80%); mp 118–
20 °C.
IR (neat): 3488, 3385, 2923, 1592, 1478, 1357, 1171, 1044, 849, 789,
Org. Biomol. Chem. 2015, 13, 6803. (d) Liu, J.; Zhuang, S.; Gui, Q.;
Chen, X.; Wang, W.; Ten, Z. Chem. Commun. 2015, 51, 6418.
1
(e) Shang, R.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2015, 137,
–
1
6
60 cm .
7660. (f) Whiteoak, C. J.; Planas, O.; Company, A.; Ribas, X. Adv.
1
H NMR (400 MHz, CDCl ): δ = 8.72 (dd, J = 4.1, 1.4 Hz, 1 H), 8.15 (dd,
Synth. Catal. 2016, 358, 1679. (g) Dou, Y.; Xie, Z.; Sun, Z.; Fang,
H.; Shen, C.; Zhang, P. ChemCatChem 2016, 8, 3570. (h) Liang, S.;
Manolikakes, G. Adv. Synth. Catal. 2016, 358, 2371. (i) Chen, H.;
Li, P.; Wang, M.; Wang, L. Org. Lett. 2016, 18, 4794. (j) Arockiam,
P. A.; Guillemard, L.; Delord, J. W. Adv. Synth. Catal. 2017, 359,
3
J = 8.5, 1.5 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.33 (dd, J = 8.5, 4.1 Hz, 1
H), 7.27 (d, J = 7.9 Hz, 2 H), 6.95 (d, J = 8.3 Hz, 1 H), 6.70 (d, J = 8.3 Hz,
1
H), 2.42 (s, 3 H).
13
C NMR (CDCl , 125 MHz): δ = 147.9, 145.4, 143.3, 137.8, 135.3,
3
2571. (k) Li, J. M.; Wang, Y. H.; Yu, Y.; Wu, R. B.; Weng, J.; Lu, G.
132.4, 130.5, 129.7, 128.6, 123.3, 121.8, 120.4, 107.8, 21.7.
ACS Catal. 2017, 7, 2661. (l) Ghosh, T.; Maity, P.; Ranu, B. C. Org.
Lett. 2018, 20, 1011. (m) Mondal, S.; Hajra, A. Org. Biomol. Chem.
MS (ESI): m/z = 314 (M + Na)+.
2
018, 16, 2846.
Deprotection of the Tosyl Group; N-(5-Hydroxyquinolin-8-yl)-4-
methylbenzamide (5)
(
4) (a) Liang, H.; Jiang, K.; Ding, W.; Yuan, Y.; Shuai, L.; Chen, Y.;
Wei, Y. Chem. Commun. 2015, 51, 16928. (b) Xu, J.; Zhu, X.;
Zhou, G.; Ying, B.; Ye, P.; Su, L.; Shen, C.; Zhang, P. Org. Biomol.
Chem. 2016, 14, 3016. (c) Cong, X.; Zeng, X. Org. Lett. 2014, 16,
3716. (d) Liu, X.; Wu, Z.; Luo, X.; He, Y.; Zhou, X.; Fan, Y.; Huang,
G. RSC Adv. 2016, 6, 71485 .
To a stirred solution of 8-(4-methylbenzamido)quinolin-5-yl 4-meth-
ylbenzenesulfonate (3d; 500 mg, 1.16 mmol) in anhyd MeOH (15 mL)
was added NaOH (51 mg, 1.3 mmol) and heated to reflux for 1 h. The
progress of the reaction was monitored by TLC. Upon completion,
MeOH was removed under reduced pressure. The mixture was diluted
with CH Cl (30 mL). The organic layer was washed with H O (20 mL)
(5) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.; Wettach, R.
H. J. Org. Chem. 1982, 47, 2487.
2
2
2
and the aqueous layer was extracted with CH Cl (3 × 20 mL). The
(6) Shen, C.; Yang, M.; Xu, J.; Chen, C.; Zheng, K.; Shen, J.; Zhang, P.
RSC Adv. 2017, 7, 49436.
2
2
combined organic layers were dried (Na SO ) The solvent was re-
2
4
moved by evaporation and the residue was purified by flash chroma-
tography to give the product 5 as a white solid; yield: 100 mg (84%);
mp 214–216 °C.
(7) (a) Reddy, B. V. S.; Reddy, C. R.; Reddy, M. R.; Yarlagadda, S.;
Sridhar, B. Org. Lett. 2015, 17, 3730. (b) Reddy, C. R.; Yarlagadda,
S.; Ramesh, B.; Reddy, M. R.; Sridhar, B.; Reddy, B. V. S. Eur. J.
Org. Chem. 2017, 2332.
IR (neat): 3328, 1644, 1548, 1503, 1283, 1189, 1010, 740, 664 cm–1
.
(
8) (a) Hao, X.; Chen, L.; Ren, B.; Li, L.; Yang, X.; Gong, J.; Niu, J.;
Song, M. Org. Lett. 2014, 16, 1104. (b) Yang, Y.; Shi, L.; Zhou, Y.;
Li, H.; Zhu, W.; Zhu, H. Bioorg. Med. Chem. 2010, 20, 6653.
9) (a) Yusubov, M. S.; Wirth, T. Org. Lett. 2005, 7, 519. (b) Nabana,
T.; Togo, H. J. Org. Chem. 2002, 67, 4362. (c) Abe, S.; Sakuratani,
K.; Togo, H. J. Org. Chem. 2001, 66, 6174. (d) Tuncay, A.;
Dustman, J. A.; Fisher, G.; Tuncay, C. I. Tetrahedron Lett. 1992, 33,
7647.
1
H NMR (500 MHz, CDCl ): δ = 9.19 (br s, 1 H), 9.14 (s, 1 H), 7.67 (d, J =
3
3.0 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 6.67 (d, J = 7.9 Hz, 2 H), 6.33 (dd,
J = 8.2, 4.1 Hz, 1 H), 6.14 (d, J = 7.7 Hz, 2 H), 5.74 (d, J = 8.2 Hz, 1 H),
(
1.20 (s, 3 H).
13
C NMR (CDCl , 125 MHz): δ = 162.4, 147.2, 147.0, 140.1, 137.5,
3
130.3, 129.8, 127.6, 125.1, 124.5, 118.9, 118.0, 115.8, 106.3, 19.4.
HRMS (EI): m/z (M + H)+ calcd for C17H15N O : 279.1128; found:
2
2
(
10) CCDC 1553346 contains supplementary crystallographic data
for the structure 3a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
279.1161.
Acknowledgment
(
11) (a) Basdevant, B.; Legault, C. Y. Org. Lett. 2015, 17, 4918.
(
8
b) Carreras, V.; Sandtorv, A. H.; Stuart, D. R. J. Org. Chem. 2017,
2, 1279.
Z.B. thanks CSIR, New Delhi for the award of a fellowship.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610212. Copies of H and 13C NMR
1
spectra of products are provided.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H