Iron-Catalyzed Regioselective Remote C(sp2)-H Carboxylation of Naphthyl and Quinoline Amides

Article abstract of DOI:10.1021/acs.joc.9b01184

Iron(III)-catalyzed regioselective direct remote C-H carboxylation of naphthyl and quinoline amides was developed using CBr₄ and alcohol. The reaction involves a radical pathway using a coordination activation strategy and single electron transfer process. The use of sustainable iron catalysis, selectivity, and the substrate scope are the important practical features.

Full text of DOI:10.1021/acs.joc.9b01184

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Note
Iron-Catalyzed Regioselective Remote C(sp2)-
H Carboxylation of Naphthyl and Quinoline Amides
Sandeep Kumar, Sourav Pradhan, Subhasish Roy, Pinaki Bhusan De, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01184 • Publication Date (Web): 26 Jul 2019
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Iron-Catalyzed Regioselective Remote C(sp2)-H Carboxylation of Naphthyl and Quinoline
Amides
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Sandeep Kumar, Sourav Pradhan, Subhasish Roy, Pinaki Bhusan De and Tharmalingam
Punniyamurthy*
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Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
O
OR'
H
Sustainable catalyst
Fe (cat.)
R'OH
CBr4
+
Bench stable C1 source
X
X
H
Remote (C4 & C5) carboxylation
X = CH, N
NHCOR
NHCOR
ABSTRACT: Iron(III)-catalyzed regioselective direct remote C-H carboxylation of naphthyl and
quinoline amides has been developed using CBr4 and alcohol. The reaction involves a radical
pathway using a coordination activation strategy and single electron transfer process. The use of
sustainable iron-catalysis, selectivity and the substrate scope are the important practical features.
The selective carboxylation of pervasive CAr−H bonds is one of the most important transformations
for the synthesis of aryl carboxylic acid derivatives, which are classified as the versatile building
blocks in the construction of biologically active molecules, pharmaceuticals and fine chemicals.1
Thus, the gases2 such as CO2, CO and their surrogates3 are considerably studied using metal and
metal-free conditions for this purpose. With the emergence of the directed C-H functionalization,4
efforts are recently made to develop the site-selective C-H carboxylation of arenes. In this realm,
Yu and co-workers reported a Pd-catalyzed ortho-selective carboxylation of aryl carboxylic acids
and anilides using CO as the C1 source (See SI, Scheme S1a).5 Soon after, Iwasawa and co-
workers demonstrated a Rh-catalyzed ortho-selective carboxylation of 2-phenylpyridines
employing CO2 as the C1 source (Scheme S1a).6 Later, Greaney and co-workers demonstrated a
Ru-catalyzed meta-selective carboxylation of 2-phenylpyridines using CBr4 as the C1 source
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(Scheme S1b).7,8 Naphthalenes and quinolines are the important structural scaffolds of functional
materials, pharmaceuticals and agrochemicals (Figure S1).9 Thereby, the functionalization of
neighboring C210 and C811 positions of 1-naphthylamides has been achieved noticeably, while the
remote C4 functionalization is underdeveloped. Recently, the coordination activation strategy12
and single electron transfer (SET) guided remote C-H functionalization has emerged as an
effective synthetic tool for the radical addition reactions.13 The base metal, iron is relatively
abundant, less expensive and omnipresent in enzymes, having the binding ability to N- and O-
based ligands.14 Substantial attention is thus focused on the development of sustainable iron-based
catalytic systems.15 Herein, we report an iron-catalyzed picolinamide (PA) assisted remote C-H
carboxylation of 1-naphthylamides via the coordination activation strategy and SET12 using CBr4
as a masked carboxylate functionality (Scheme S1c). The scope can be expanded for the remote
carboxylation of quinolinamides. The selectivity and substrate scope are the important practical
features.
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At the outset, optimization of the reaction condition was commenced utilizing N-(naphthalen-1-
yl)picolinamide 1a as a model substrate with a series of iron-catalysts, additives and solvents at
varied temperature (Scheme 1, Table S1, see SI). To our delight, the remote C-4 carboxylation
occurred to give the ester 2a in 47% yield, when 1a was stirred with 10 mol % Fe(acac)3 and 3
equiv CBr4 in a 1:1 mixture of methanol and 1,4-dioxane at 90 °C. The yield was increased to 51%
using methanol as a solvent, whereas dimethylacetamide (DMA), CH3CN, (CH2Cl)2,
trifluoroethanol and water gave inferior results. In a set of iron catalysts screened, Fe(acac)3, FeCl3,
FeSO4•7H2O, ferrocene and Fe(NO3)3•9H2O, the former produced superior results. Subsequent
screening using additives led to enhance the yield to 65% with PivOH, whereas 1-Ad-OH and
MesCO2H gave <63% yield. Decreasing the catalyst loading (5 mol %) or CBr4 or temperature
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(60 oC) led to drop in the yield. Control experiment confirmed that no carboxylation was observed
in the absence of the iron-catalyst.
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Scheme 1. Optimization of Reaction Conditions
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9
NHPA
NHPA
CBr4
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Fe-source
additive
solvent, 90oC
COOCH3
H
1a
CH3OH
2a
Next, the scope of the procedure was investigated for the esterification of a series of 1-
naphthylamides (Scheme 2). The substrate 1b having C-8 phenoxy substituent underwent reaction
to give the methyl ester 2b in 67% yield. Recrystallization of 2b in CH3CN yielded single crystal
whose structure was determined using the X-ray analysis (see SI). The reaction of 1c bearing C8
p-tolyoxy functionality produced 2c in 61% yield, whereas the substrates having 3-chloro 1d and
3-trifluoromethyl 1e groups on the C-8 phenoxy ring gave 2d and 2e in 64 and 65% yields,
respectively. In addition, the substrates containing C-8 thiophenyl 1f and phenyl 1g groups
carboxylated to afford the esters 2f and 2g in 55 and 51% yield, respectively. Further, the reaction
of the substrate 1h having C-8 morpholine functionality provided the methyl ester 2h in 49% yield.
The reaction of C8-methoxy substrate 1i gave 2i in 49% yield, whereas 5-ethoxy 1j and 2-
morpholino 1k substrates were incompatible to give the desired esters. Interestingly, the alkyl
carboxylation scope was extended using ethanol and n-propanol as the alkyl source in place of
methanol at 130 oC. For example, the reaction of 1-naphthylamides 1a and 1b having C-8 phenoxy
substituent was carried out as the representative examples, in ethanol to give the ethyl esters 2l and
2m in 47 and 50% yields, respectively, while 1a in n-propanol gave the n-propyl ester 2n in 45%
yield. In contrast, the reaction using isopropanol was unsuccessful, which may be due to the
difficulty in alcoholysis via the nucleophilic substitution of the bulkier secondary alcohol.
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Scheme 2. Substrate Scope of 1-Naphthylamidesa,b
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CBr4
NHPA
NHPA
10 mol % Fe(acac)3
1equiv PivOH
R'OH, 90-130 oC
NHPA
8
9
R
R
H
COOR'
2b-o
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1b-k
NHPA
O
NHPA
X
N
COOCH3
COOCH3
2k
OEt
COOCH3
, n.d.
alcohol scopec
2j
, trace
2b
, X = OPh, 67%
2c,
2d
2e
2f
2g
X = 4-CH3C6H4, 61%
, X = 3-ClC6H4, 64%
, X = 3-CF3C6H4, 65%
, X = SPh, 55%
NHPA
X
, X = Ph, 51%, 30 h
, X = morpholinyl, 49%, 30 h
, X = OCH3, 49%
2h
2i
COOY
2l
, X = H, Y = Et, 47%
2m
, X = OPh, Y = Et, 50%
n
2n
2o
, X = H, Y= Pr, 45%
i
, X = H, Y = Pr, n.d.
aReaction conditions: 1 (0.2 mmol), CBr4 (0.6
mmol), ROH (1.5 mL), PivOH (0.2 mmol),
Fe(acac)3 (10 mol %), 90 °C, 24 h. bIsolated yield.
cReaction temperature 130 oC. n.d. = not detected.
The effect of archetypal chelating groups was investigated (Scheme S2). The substrates with
bi-dentate chelating groups, pyrazine and isoquinoline were carboxylated to produce the methyl
esters 2p and 2q in 57 and 58% yields, respectively, whereas the substrates having benzamide and
N-methyl benzamide failed to produce the esters 2r and 2s, respectively, which suggest that the
bidentate N,N-chelation and relative N-H acidity are crucial for the carboxylation.
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Scheme 3. Substrate Scope of 8-Aminoquinolinamides.a,b
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4
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7
8
9
H3COOC
O
O
10 mol % Fe(acac)3
1 equiv PivOH
N
H
R
+
N
R
CBr4
H
N
N
CH3OH:1,4-dioxane (1:1)
130 oC, 30 h
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3a-n
4a-n
H3COOC
H3COOC
4a
, X = H, 63%
O
O
4b
, X = 2-Br, 63%
4c, = 3-CH ,
CH3
CH3
N
X
66%
N
3
X
H
H
N
4d
, X = 4-F, 61%
N
4e
, X = 4-I, 62%
4h
, 68%
4f
, X = 4-CH3, 64%
4g
, X = 4-CF3, 60%
H3COOC
O
H3COOC
H3COOC
O
N
Ph
NHX
H
N
N
H
X
N
N
X
4m
4n
, X = Me, 61%
, X = Ph, 52%
4k
4l
4i
4j
, X = SO2Ph, n.d.
, X = P(O)Ph2, n.d.
, X= 2-thienyl, 55%
, X = t-butyl, 57%
aReaction conditions: 3a-n (0.2 mmol), CBr4 (0.8 mmol), Fe(acac)3 (10 mol%), PivOH (0.2
mmol), CH3OH:1,4-dioxane (1:1; 1.5 mL), 130 °C, 30 h. bIsolated yield. n.d. = not detected.
The scope of the protocol was extended for the remote C5 carboxylation of analogous 8-
aminoquinolinamides (Scheme 3). The carboxylation occurred at an elevated temperature (130 oC)
in a 1:1 mixture methanol and 1,4-dioxane. For example, the substrate 3a having N-benzoyl
substituent underwent reaction to provide the methyl ester 4a in 63% yield. Similarly, the reaction
of the substrates bearing electron-withdrawing and donating groups in the benzoyl ring can be
accomplished. Thus, the substrate bearing 2-bromo group 3b underwent carboxylation to give 4b
in 63% yield. Similar result was obtained with 3c having 3-methyl group, giving 4c in 66% yield.
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The carboxylation of the substrates having 4-fluoro 3d, 4-iodo 3e, 4-methyl 3f and 4-
trifluoromethyl 3g functional groups could be achieved in 60-64% yields. Likewise, 3h having
3,4-dimethyl substituent underwent carboxylation to give the ester 4h in 68% yield. Further, the
substrate 3i bearing N-2-thiophene carbonyl could be carboxylated to furnish the methyl ester 4i
in 55% yield, whereas 3j having N-pivaloyl substituent afforded the desired ester 4j in 57% yield.
In contrast, N-sulfonyl 3k and N-phosphonyl 3l quinolinamides showed no carboxylation, which
suggest that electronic nature of the amide is crucial for the chelation. While, quinolines bearing
2-methyl 3m and 2-phenyl 3n substituents underwent reaction to deliver the esters 4m and 4n in
61 and 51% yields, respectively.
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Scheme 4. Control Experiments
(a) Deuterium Scrambling Experiment
NHPA
D
NHPA
D
CBr4
standard conditions
CH3OH
H
COOCH3
1a-d
, 87%-D
2a-d
, 64%, 87%-D
(b) Radical Scavenger Experiments
O
CBr4
N
Me
standard conditions
O
O
1a
2a
TEMPO (3 equiv) or
BHT (3 equiv)
CH3OH
trace
5
detected in ESI-MS
found: 216.1592
calcd: 216.1594
To gain insight into the catalytic cycle, the mode of chelation of the substrate was investigated.
The peri-C-D bond in 1a-d was intact, which suggests that no H/D exchange occurs and the remote
C-H functionalization presumably dictated via the coordination activation strategy (Scheme 4a).
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Scheme 5. Plausible Catalytic Cycle
3
4
O
5
6
7
8
RO
Br3C
2 ROH
O
NHPA
Br3C
NHPA
alcoholysis
X
N
H
X
2
9
F
X
N
N
1
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FeLn
H+
O
LH
L = acac, OPiv
O
N
III
X
N
[Fe ]
ROH
III
X
N
[Fe ]
E
HBr
A
FeIII
+ Br-
FeII
Fe
Br
H
CBr3
N
CBr4
H
Br3C
SET
O
+
O
Br3C
N
N
III
X
N
[Fe ]
X
[FeIII]
D
H
B
Br3C
SET
FeII
O
+
FeIII
N
CBr4
II
X
N
[Fe ]
CBr3 + Br-
C
The radical scavenger experiments employing 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
and 2,6-di-tert-butyl-4-methyl-phenol (BHT) yielded a trace amount of 2a (Scheme 4b).7 In
addition, the ESI-MS analysis of the reaction mixture revealed the formation of the TEMPO adduct
5 (See SI), which suggest that the reaction involves a radical pathway. Thus, Fe(acac)3 with PivOH
can give an active Fe(III) species, which can react with the substrate 1 to produce the complex A
(Scheme 5). The CBr3 radical can be generated from CBr4 via SET13 using Fe(II), which is in-situ
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yielded from Fe(III) reduction with alcohol.16 The CBr3 radical can react at the electrophilic carbon
to produce the radical intermediate B, that can convert to C by SET. Disproportionation of C can
give the Fe(III) species D and the imminent Fe(II) species can be oxidized to Fe(III) by CBr4
present excess in the reaction. Deprotonation of D by bromide ion, that can be formed from CBr4
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using Fe(II), can lead to the formation of E. Protodemetalation can furnish F and regenerate the
active Fe(III) catalyst. Alcoholysis16 of F can give the target esters and the proposed catalytic cycle
explains the use of excess CBr4. PivOH may also help to reduce the pH to facilitate the reduction
of Fe(III)16b along with the protodemetalation to realize the product formation.
Scheme 6. Synthetic Applications
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NHPA
OPh
NHPA
[a]
[b]
Reduction
CH2OH
NHPA
Etherification
COOMe
2b
, 73%
6a
, 68%
2a
NH2
NH2
COOMe
[d]
[c]
Hydrolysis
DG removal
COOH
, 75%
COOMe
, 71%
scale-up: 51% (on 2 mmol scale)
6c
6b
Reaction conditions: [a] 2a (0.1 mmol), LiAlH4 (0.1
mmol), THF, 0-60 oC, 16 h, 68%; [b] 2a (0.2 mmol),
PhB(OH)2 (0.4 mmol), Cu(OAc)2 (0.3 mmol),
Cs2CO3 (0.5 mmol), 130 oC, 10 h, air, DMSO (1 mL),
73%; [c] 2a (0.1 mmol), NaOH (0.1 mmol), CH3OH,
o
90 C, 12 h, 71%; [d] 2a (0.1 mmol), NaOH (0.4
mmol), CH3OH, 90 oC, 24 h, 75%.
Finally, the synthetic utility was investigated using 2a as a representative example (Scheme 6).
The scale-up (2 mmol) reaction of 1a was carried out and 2a was obtained in 51% yield. The ester
functional group can selectively be reduced utilizing LiAlH4 to furnish the alcohol 6a in 68% yield.
In addition, the peri-selective etherification can be carried out using a Cu(II)-mediated C-H
functionalization with phenylboronic acid to afford 2b in 73% yield. Further, the amide hydrolysis
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can selectively be performed using NaOH in methanol to afford 6b in 71% yield, while the
hydrolysis of both the amide and ester groups can be carried out using an excess NaOH in methanol
to produce 4-amino-1-naphthoic acid 6c in 75% yield.
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In summary, we have developed an iron(III)-catalyzed direct carboxylation of the remote C-H
bonds of 1-naphthylamine and 8-aminoquinoline derivatives using CBr4 as the C1 source via a
coordination activation strategy and SET process. The use of sustainable iron-catalyst and
selectivity are the important practical features. Synthetic elaborations of the ester have also been
accomplished.
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EXPERIMENTAL SECTION
General Information. Fe(acac)3, ferrocene, FeCl3 and Fe(NO3)3•9H2O of Merck, and CBr4 from
Aldrich were utilized as received. The solvents were purchased from commercial sources and dried
according to standard procedure. Purification of the reaction products was carried out on column
chromatography using Merck silica gel (60-120 mesh). Analytical TLC was performed on Merck
silica gel G/GF 254 plate. NMR spectra were recorded on Bruker 400 MHz and Bruker Avance
III 600 MHz using CDCl3 and DMSO-d6 as solvent and Me4Si as an internal standard. Chemical
shifts (δ) were reported in ppm and spin-spin coupling constants (J) were given in Hz. Melting
points were determined using Buchi B-540 apparatus and are uncorrected. FT-IR spectra were
recorded using Thermo Fisher Scientific spectrometer. Mass spectra were recorded on a Q-TOF
ESI-MS instrument (model HAB 273). Single crystal X-ray data were collected on Agilent single
crystal X-ray diffractometer, equipped with Mo X-ray source (MoK), CCD detector (Eos) and
the structure was solved by direct method using SHELXL-14 (Göttingen, Germany).
General Procedure for the Preparation of Amides. To a stirred solution of amine (1 mmol) and
Et3N (1.2 mmol) in CH2Cl2 (5 mL) at 0 °C was added acid chloride (1 mmol) in CH2Cl2 (5 mL)
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drop wise. The mixture was allowed to warm upto room temperature and the starring was
continued for 10-12 h. The progress of the reaction was monitored by TLC using ethyl acetate and
hexane. After completion, the reaction mixture was diluted with CH2Cl2 (30 mL) and washed with
brine (2 x 5 mL) and water (1 x 5 mL). Drying (Na2SO4) and evaporation of the solvent gave a
residue that was purified on a short pad of silica gel column chromatography using ethyl acetate
and hexane as an eluent. Naphthylamides 1a,11a 1b-e,17 1f,11b 1g,12 1h,11d 1i,19d 1k,11a 1l-m,12 1n-
o,19c and quinolinamides 3a,19a 3b,19c 3c-d11c 3e,15b 3f-g,19a 3h,11d 3i,19a 3j,19c 3k,19c 3l,19b and 3m-
n,19c are reported compounds and analyzed by comparing with the literature data. To show the
purity, 1H NMR spectra are provided.
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General Procedure for the C4 Carboxylation of 1-Naphthylamides. 1-Naphthylamide 1 (0.2
mmol), CBr4 (199 mg, 0.6 mmol), Fe(acac)3 (7 mg, 0.02 mmol), PivOH (20.4 mg, 0.2 mmol) and
alcohol (1.5 mL) were stirred in a sealed tube at 90-130 oC for the appropriate time in an oil bath.
The progress of the reaction was monitored by TLC using n-hexane and ethyl acetate as an eluent.
The reaction mixture was then cooled to room temperature and treated with water (5 mL), and the
mixture was extracted using ethyl acetate (3 × 10 mL). Drying (Na2SO4) and evaporation of the
solvent gave a residue that was purified on silica gel column chromatography using n-hexane and
ethyl acetate as an eluent.
General Procedure for C5 Carboxylation of 8-Aminoquinolinamides. 8-Aminoquinolinamide
3 (0.20 mmol), CBr4 (266 mg, 0.80 mmol), Fe(acac)3 (7 mg, 0.02 mmol), PivOH (20.4 mg, 0.2
mmol), CH3OH (0.75 mL) and 1,4-dioxane (0.75 mL) were stirred in a sealed tube at 130 oC for
the appropriate time in an oil bath. The work up and purification processes were carried out as
described above in general procedure for the carboxylation of 1-naphthylamides. Purification on
silica gel column chromatography using n-hexane and ethyl acetate as an eluent afforded target
esters.
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Scale-up Synthesis of 2a. 1-Naphthylamide 1a (496 mg, 2 mmol), CBr4 (1.99 g, 6 mmol),
Fe(acac)3 (70.6 mg, 0.2 mmol), PivOH (204 mg, 2 mmol) and CH3OH (10 mL) were stirred in a
sealed tube at 90 oC for 24 h in an oil bath. The work-up was followed as reported in the general
procedure. Purification on silica gel column chromatography using n-hexane and ethyl acetate
(92/8) as an eluent afforded 2a in 51% yield (312 mg).
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N-(Naphthalen-1-yl)picolinamide 1a.11a The compound 1a was synthesized according to the
reported procedure in 65% yield (161 mg). 1H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 8.73-8.71
(m, 1H), 8.39 (dd, J = 14.0, 7.6 Hz, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.99-7.87 (m, 2H), 7.71 (d, J =
8.4 Hz, 1H), 7.62-7.50 (m, 4H).
N-(8-Phenoxynaphthalen-1-yl)benzamide 1b.17 The compound 1b was synthesized according to
the reported procedure in 80% yield (272 mg). 1H NMR (600 MHz, CDCl3) δ 13.02 (s, 1H), 9.03-
9.01 (m, 1H), 8.25 (d, J = 6.6 Hz, 2H), 7.85-7.80 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.62-7.54 (m,
2H), 7.42-7.37 (m, 2H), 7.36-7.31 (m, 2H), 7.25-7.20 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 6.98-6.93
(m, 1H).
N-(8-(p-Tolyloxy)naphthalen-1-yl)benzamide 1c.17 The compound 1c was synthesized
according to the reported procedure in 70% yield (262 mg). 1H NMR (400 MHz, CDCl3) δ 13.09
(s, 1H), 9.03-9.01 (m, 1H), 8.26-8.25 (m, 2H), 7.85-7.81 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.59-
7.52 (m, 2H), 7.38-7.28 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.93-6.91 (m,
1H), 2.37 (s, 3H).
N-(8-(3-Chlorophenoxy)naphthalen-1-yl)benzamide 1d.17 The compound 1d was synthesized
according to the reported procedure in 63% yield (236 mg). 1H NMR (400 MHz, CDCl3) δ 12.70
(s, 1H), 8.99-8.97 (m, 1H), 8.37 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.87-7.83 (m, 1H),
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7.67-7.65 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.28-7.27 (m, 2H), 7.12-7.09 (m,
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N-(8-(3-(Trifluoromethyl)phenoxy)naphthalen-1-yl)benzamide 1e.17 The compound 1e was
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synthesized according to the reported procedure in 71% yield (290 mg). H NMR (400 MHz,
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CDCl3) δ 12.64 (s, 1H), 8.98-8.96 (m, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.86-
7.81 (m, 1H), 7.69-7.66 (m, 2H), 7.60-7.56 (m, 2H), 7.45-7.37 (m, 4H), 7.23 (d, J = 8.0 Hz, 1H),
7.02-7.00 (m, 1H).
N-(8-(Phenylthio)naphthalen-1-yl)benzamide 1f.11b The compound 1f was synthesized
according to the reported procedure in 73% yield (259 mg). 1H NMR (600 MHz, CDCl3) δ 12.25
(s, 1H), 8.66 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.97-7.96 (m, 1H), 7.85-
7.80 (m, 3H), 7.60 (t, J = 7.8 Hz, 1H), 7.47-7.45 (m, 2H), 7.01-6.96 (m, 3H), 6.82-6.81 (m, 2H).
N-(8-Phenylnaphthalen-1-yl)benzamide 1g.12 The compound 1g was synthesized according to
the reported procedure in 71% yield (230 mg). 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 8.25
(d, J = 7.2 Hz, 1H), 8.17 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),
7.81 (d, J = 8.0 Hz, 1H), 7.77-7.73 (m, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.41 (d, J
= 7.3 Hz, 2H), 7.33-7.29 (m, 2H), 7.18 (t, J = 8.0 Hz, 2H), 7.00 (t, J = 7.2 Hz, 1H).
N-(8-Morpholinonaphthalen-1-yl)benzamide 1h.11d The compound 1h was synthesized
according to the reported procedure in 80% yield (266 mg). 1H NMR (400 MHz, CDCl3) δ 13.85
(s, 1H), 9.14-9.11 (m, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.96-7.92 (m, 1H),
7.67-7.64 (m, 1H), 7.62-7.60 (m, 1H), 7.54-7.49 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.39-7.37 (m,
1H), 4.27-4.21 (m, 2H), 3.86-3.83 (m, 2H), 3.20 (d, J = 12.0 Hz, 2H), 3.06-3.00 (m, 2H).
N-(8-Methoxynaphthalen-1-yl)picolinamide 1i.19d The compound 1i was synthesized according
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8.99-8.98 (m, 1H), 8.71 (d, J = 4.2 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.94-7.91 (m, 1H), 7.57 (d,
J = 7.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.93 (d, J =
7.8 Hz, 1H), 4.21 (s, 3H).
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N-(5-Ethoxynaphthalen-1-yl)picolinamide 1j. The compound 1j was synthesized according to
the reported procedure in 61% yield (178 mg). 1H NMR (600 MHz, CDCl3) δ 10.73 (s, 1H), 8.70-
8.69 (m, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.94-
7.92 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.54-7.50 (m, 2H), 7.47 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8
Hz, 1H), 4.22 (q, J = 6.0 Hz, 2H), 1.56 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
162.3, 155.4, 150.3, 148.2, 137.8, 132.2, 127.5, 126.59, 126.53, 125.2, 122.6, 119.2, 112.5, 105.0,
64.0, 14.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17N2O2 293.1285; found 293.1285.
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N-(2-Morpholinonaphthalen-1-yl)picolinamide 1k.11a The compound 1k was synthesized
according to the reported procedure in 65% yield (216 mg). 1H NMR (600 MHz, CDCl3) δ 10.30
(s, 1H), 8.74 (d, J = 4.2 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.89 (d, J = 8.4 Hz,
1H), 7.83-7.81 (m, 2H), 7.56-7.54 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.43-7.38 (m, 2H), 3.83-3.81
(m, 4H), 3.02-3.00 (m, 4H).
N-(Naphthalen-1-yl)pyrazine-2-carboxamide 1l.12 The compound 1i was synthesized according
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to the reported procedure in 76% yield (189 mg). H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H),
9.58-9.57 (m, 1H), 8.86-8.84 (m, 1H), 8.68-8.67 (m, 1H), 8.37-8.35 (m, 1H), 8.04-8.02 (m, 1H),
7.92-7.90 (m, 1H), 7.75-7.73 (m, 1H), 7.61-7.52 (m, 3H).
N-(Naphthalen-1-yl)isoquinoline-1-carboxamide 1m.12 The compound 1j was synthesized
according to the reported procedure in 61% yield (181 mg). 1H NMR (400 MHz, CDCl3) δ 11.07
(s, 1H), 9.82-9.79 (m, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.41-8.38 (m, 1H), 8.15 (d, J = 8.4 Hz, 1H),
7.91 (d, J = 7.2 Hz, 3H), 7.77-7.72 (m, 3H), 7.59-7.54 (m, 3H).
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N-(Naphthalen-1-yl)benzamide 1n.19c The compound 1k was synthesized according to the
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reported procedure in 53% yield (131 mg). H NMR (600 MHz, CDCl3) δ 8.22 (s, 1H), 8.06 (s,
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N-Methyl-N-(quinolin-8-yl)benzamide 1o.19c The compound 1o was synthesized according to
the reported procedure in 81% yield (212 mg). 1H NMR (600 MHz, CDCl3) δ 8.98-8.97 (m, 1H),
8.12 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.43-7.41 (m, 1H), 7.38-7.33 (m, 2H), 7.28 (d,
J = 7.2 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 2H), 3.59 (s, 3H).
N-(Quinolin-8-yl)benzamide 3a.19a The compound 3a was synthesized according to the reported
procedure in 65% yield (161 mg). 1H NMR (400 MHz, CDCl3) δ 10.75 (s, 1H), 8.96-8.93 (m, 1H),
8.85-8.84 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.10-8.08 (m, 2H), 7.62-7.53 (m, 5H), 7.49-7.46 (m,
1H).
2-Bromo-N-(quinolin-8-yl)benzamide 3b.19c The compound 3b was synthesized according to the
reported procedure in 63% yield (206 mg). 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.96-8.94
(m, 1H), 8.80-8.78 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.73-7.68 (m, 2H), 7.63-7.56 (m, 2H), 7.48-
7.43 (m, 2H), 7.37-7.33 (m, 1H).
3-Methyl-N-(quinolin-8-yl)benzamide 3c.11c The compound 3c was synthesized according to the
reported procedure in 61% yield (159 mg). 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.95 (d,
J = 7.2 Hz, 1H), 8.78-8.77 (m, 1H), 8.19-8.17 (m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.62-7.54 (m,
2H), 7.47-7.44 (m, 1H), 7.42-7.38 (m, 1H), 7.33 (t, J = 7.2 Hz, 2H), 2.61 (s, 3H).
4-Fluoro-N-(quinolin-8-yl)benzamide 3d.11c The compound 3d was synthesized according to the
reported procedure in 59% yield (157 mg). 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.92-8.90
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(m, 1H), 8.86-8.85 (m, 1H), 8.22-8.19 (m, 1H), 8.12-8.09 (m, 2H), 7.63-7.56 (m, 2H), 7.51-7.48
(m, 1H), 7.25-7.21 (m, 2H).
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4-Iodo-N-(quinolin-8-yl)benzamide 3e.15b The compound 3e was synthesized according to the
reported procedure in 55% yield (205 mg). 1H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 8.91-8.89
(m, 1H), 8.85-8.84 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz,
2H), 7.62-7.56 (m, 2H), 7.50-4.47 (m, 1H).
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4-Methyl-N-(quinolin-8-yl)benzamide 3f.19a The compound 3f was synthesized according to the
reported procedure in 67% yield (175 mg). 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.95-8.92
(m, 1H), 8.86-8.84 (m, 1H), 8.20-8.17 (m, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H),
7.55-7.52 (m, 1H), 7.49-7.46 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H).
N-(Quinolin-8-yl)-4-(trifluoromethyl)benzamide 3g.19a The compound 3g was synthesized
according to the reported procedure in 65% yield (205 mg). 1H NMR (400 MHz, CDCl3) δ 10.79
(s, 1H), 8.93-8.91 (m, 1H), 8.87-8.85 (m, 1H), 8.23-8.18 (m, 3H), 7.82 (d, J = 8.0 Hz, 2H), 7.64-
7.57 (m, 2H), 7.52-7.49 (m, 1H).
3,4-Dimethyl-N-(quinolin-8-yl)benzamide 3h.11d The compound 3h was synthesized according
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8.95-8.93 (m, 1H), 8.86-8.85 (m, 1H), 8.19-8.16 (m, 1H), 7.85 (s, 1H), 7.82-7.80 (m, 1H), 7.59 (t,
J = 8.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.48-7.45 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H), 2.35
(s, 3H).
N-(Quinolin-8-yl)thiophene-2-carboxamide 3i.19a The compound 3i was synthesized according
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8.86-8.83 (m, 2H), 8.19-8.17 (m, 1H), 7.85-7.83 (m, 1H), 7.60-7.52 (m, 3H), 7.49-7.46 (m, 1H),
7.19-7.17 (m, 1H).
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N-(Quinolin-8-yl)pivalamide 3j.19c The compound 3j was synthesized according to the reported
procedure in 67% yield (153 mg). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 1H), 7.88-
7.86 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.55-7.45 (m, 3H), 1.44 (s, 9H).
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N-(Quinolin-8-yl)benzenesulfonamide 3k.19c The compound 3k was synthesized according to
the reported procedure in 73% yield (270 mg). 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.75-
8.74 (m, 1H), 8.09-8.07 (m, 1H), 7.92-7.90 (m, 2H), 7.84-7.82 (m, 1H), 7.46-7.39 (m, 4H), 7.36
(t, J = 8.0 Hz, 2H).
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P,P-Diphenyl-N-(quinolin-8-yl)phosphinic amide 3l.19b The compound 3l was synthesized
according to the reported procedure in 71% yield (244 mg). 1H NMR (400 MHz, CDCl3) δ 8.77-
8.75 (m, 1H), 8.13-8.10 (m, 1H), 8.02 (s, 1H), 7.98-7.92 (m, 4H), 7.57-7.53 (m, 2H), 7.50-7.45
(m, 4H), 7.44-7.37 (m, 2H), 7.33-7.24 (m, 2H).
N-(2-Methylquinolin-8-yl)benzamide 3m.19c The compound 3m was synthesized according to
the reported procedure in 51% yield (133 mg).1H NMR (600 MHz, CDCl3) δ 10.82 (s, 1H), 8.90-
8.89 (m, 1H), 8.09-8.05 (m, 3H), 7.60-7.55 (m, 3H), 7.53-7.49 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H),
2.77 (s, 3H).
N-(2-Phenylquinolin-8-yl)benzamide 3n.19c The compound 3n was synthesized according to the
reported procedure in 43% yield (139 mg). 1H NMR (600 MHz, CDCl3) δ 10.96 (s, 1H), 8.94-8.93
(m, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 2H), 8.12 (d, J = 7.2 Hz, 2H), 7.96 (d, J =
8.4 Hz, 1H), 7.62-7.55 (m, 7H), 7.51 (t, J = 7.2 Hz, 1H);13C{1H} NMR (150 MHz, CDCl3) δ 165.3,
155.2, 139.2, 138.5, 137.4, 135.4, 134.7, 131.9, 129.7, 129.1, 129.0, 127.48, 127.44, 127.3, 127.0,
121.5, 119.4, 116.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H17N2O 325.1335; found
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Methyl 4-(picolinamido)-1-naphthoate 2a. Light yellow solid; yield 65% (40 mg); analytical
TLC on silica gel Rf 0.45 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl acetate 92/8);
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1H), 7.99-7.95 (m, 1H), 7.70-7.65 (m, 2H), 7.57-7.54 (m, 1H), 4.00 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.7, 162.4, 149.8, 148.3, 138.0, 136.9, 132.5, 131.4, 127.9, 127.0, 126.9, 126.6,
125.8, 123.0, 122.7, 120.4, 115.9, 52.2; IR (KBr) 3350, 2952, 1707, 1698, 1534, 1201 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C18H15N2O3 307.1077; found 307.1092.
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Methyl 5-phenoxy-4-(picolinamido)-1-naphthoate 2b. Colorless solid; yield 67% (53 mg);
analytical TLC on silica gel Rf 0.47 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 92/8); mp 142-144 °C; 1H NMR (400 MHz, CDCl3) δ 13.36 (s, 1H), 9.08 (d, J = 8.4 Hz,
1H), 8.82-8.79 (m, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.26-8.20 (m, 2H), 7.85-7.81 (m, 1H), 7.48-7.39
(m, 3H), 7.37-7.33 (m, 1H), 7.24-7.18 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 167.9, 163.2, 156.4, 154.6, 150.2, 147.9, 139.1, 137.5, 134.8, 132.2,
129.9, 127.5, 126.4, 124.4, 122.4, 122.2, 121.8, 120.3, 117.9, 115.1, 114.4, 52.2; IR (KBr) 3375,
2923, 1713, 1689, 1578, 1207 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C24H19N2O4,
399.1339; found 399.1351.
Methyl 4-(picolinamido)-5-(p-tolyloxy)-1-naphthoate 2c. Colorless solid; yield 61% (50 mg);
analytical TLC on silica gel Rf 0.45 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 92/8); mp 154-156 °C; 1H NMR (400 MHz, CDCl3) δ 13.44 (s, 1H), 9.08 (d, J = 8.5 Hz,
1H), 8.77 (d, J = 8.6 Hz, 1H), 8.28-8.24 (m, 3H), 7.87-7.82 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.35
(m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.13-7.10 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 3.99 (s, 3H), 2.37
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 163.2, 155.1, 154.0, 150.3, 148.0, 139.2, 137.5,
134.9, 134.1, 132.2, 130.4, 127.5, 126.4, 122.4, 122.2, 121.5, 120.3, 117.8, 115.0, 113.9, 52.3,
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20.9; IR (KBr) 3276, 2954, 1703, 1689, 1585, 1283 cm-1 ; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C25H21N2O4 413.1496; found 413.1500.
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Methyl 5-(3-chlorophenoxy)-4-(picolinamido)-1-naphthoate 2d. Colorless solid; yield 64% (55
mg); analytical TLC on silica gel Rf 0.46 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 92/8); mp 152-154 °C; 1H NMR (600 MHz, CDCl3) δ 13.08 (s, 1H), 9.07 (d, J = 8.4 Hz,
1H), 8.88-8.86 (m, 1H), 8.34-8.33 (m, 1H), 8.29-8.25 (m, 2H), 7.88-7.85 (m, 1H), 7.52-7.49 (m,
1H), 7.43-7.41 (m, 1H), 7.30-7.27 (m, 2H), 7.15-7.13 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.04-7.02
(m, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 163.1, 157.5, 153.4, 150.1, 147.9,
138.7, 137.6, 135.2, 134.9, 132.3, 130.6, 127.5, 126.6, 124.4, 122.7, 122.6, 122.4, 120.6, 118.1,
117.7, 115.5, 52.3; IR (KBr) 3275, 2950, 1706, 1688, 1579, 1246 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C24H18ClN2O4 433.0950; found 433.0972.
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Methyl 4-(picolinamido)-5-(3-(trifluoromethyl)phenoxy)-1-naphthoate 2e. Colorless solid;
yield 65% (61 mg); analytical TLC on silica gel Rf 0.46 in 10% ethyl acetate/hexane; purification
(n-hexane/ethyl acetate 92/8); mp 164-166 °C; 1H NMR (400 MHz, CDCl3) δ 13.02 (s, 1H), 9.06
(d, J = 8.4 Hz, 1H), 8.91-8.88 (m, 1H), 8.30-8.28 (m, 2H), 8.26-8.24 (m, 1H), 7.88-7.84 (m, 1H),
7.59 (s, 1H), 7.54-7.50 (m, 1H), 7.48-7.44 (m, 1H), 7.42-7.39 (2H), 7.23-7.21 (m, 1H), 7.08-7.06
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(m, 1H), 4.01 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 167.8, 163.1, 157.1, 153.2, 150.1,
147.8, 138.6, 137.7, 135.0, 134.2 (JC-F = 166 Hz), 132.3, 130.5, 127.5, 126.7, 123.0, 122.7 (JC-F
=
25.0 Hz), 120.8 (JC-F = 3.7 Hz), 118.2, 117.2 (JC-F = 3.8 Hz), 115.75, 115.7, 52.3; 19F NMR (377
MHz, CDCl3) δ -62.58; IR (KBr) 3270, 2953, 1711, 1681, 1581, 1241 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C25H18F3N2O4 467.1213; found 467.1228.
Methyl 5-(phenylthio)-4-(picolinamido)-1-naphthoate 2f. Colorless solid; yield 55% (46 mg);
analytical TLC on silica gel Rf 0.45 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 92/8); mp 166-168 °C; H NMR (400 MHz, CDCl3) δ 12.76 (s, 1H), 9.13-9.11 (m, 1H),
8.66-8.64 (m, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.14-8.11 (m, 1H), 7.89-7.84
(m, 2H), 7.59-7.55 (m, 1H), 7.49-7.44 (m, 1H), 6.99-6.97 (m, 3H), 6.79-6.77 (m, 2H), 4.01(s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 162.9, 150.3, 148.1, 138.9, 138.7, 137.7, 137.4, 134.8,
130.9, 128.95, 128.93, 127.2, 126.8, 126.7, 126.5, 125.9, 124.9, 124.7, 122.8, 120.5, 52.5; IR
(KBr) 3453, 2960, 1713, 1686, 1571, 1233 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C24H19N2O3S 415.1111; found 415.1119.
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Methyl 5-phenyl-4-(picolinamido)-1-naphthoate 2g. Colorless solid; yield 51% (39 mg);
analytical TLC on silica gel Rf 0.47 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 92/8); mp 146-150 °C; 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 9.04 (d, J = 8.6, 1H),
8.48 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.17-8.16 (m, 1H), 8.08 (d, J = 7.7 Hz, 1H),
7.79-7.75 (m, 1H), 7.64-7.60 (m, 1H), 7.44-7.40 (m, 3H), 7.34-7.31 (m, 1H), 7.25-7.21 (m, 2H),
7.06-7.03 (m, 1H), 4.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 162.1, 149.5, 147.5,
142.5, 137.9, 137.5, 137.2, 133.8, 131.2, 130.8, 129.4, 128.4, 127.2, 126.7, 126.14, 126.11, 124.5,
124.4, 122.0, 119.5, 52.3; IR (KBr) 3346, 2949, 1713, 1685, 1575, 1276 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C24H19N2O3 383.1390; found 383.1404.
Methyl 5-morpholino-4-(picolinamido)-1-naphthoate 2h. Light yellow solid; yield 49% (38
mg); analytical TLC on silica gel Rf 0.43 in 15% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 85/15); mp 148-150 °C; 1H NMR (400 MHz, CDCl3) δ 14.20 (s, 1H), 9.14 (d, J = 8.5 Hz,
1H), 8.84-8.81 (m, 1H), 8.75-8.73 (m, 1H), 8.39-8.37 (m, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.98-7.93
(m, 1H), 7.58-7.53 (m, 2H), 7.44-7.42 (m, 1H), 4.26-4.20 (m, 2H), 3.98 (s, 3H), 3.86 (d, J = 11.2
Hz, 2H), 3.20 (d, J = 11.6 Hz, 2H), 3.05-2.99 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.2,
163.0, 153.0, 151.1, 149.9, 148.1, 137.8, 135.5, 134.4, 130.2, 128.1, 126.6, 123.5, 121.9, 119.3,
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117.4, 114.3, 65.6, 54.0, 52.4; IR (KBr) 3451, 2954, 1712, 1682, 1520, 1239 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C22H22N3O4 392.1605; found 392.1616.
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Methyl 5-methoxy-4-(picolinamido)-1-naphthoate 2i. Yellow liquid; yield 49% (33 mg);
analytical TLC on silica gel Rf 0.46 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 94/6); 1H NMR (400 MHz, CDCl3) δ 13.55 (s, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.73-8.71 (m,
1H), 8.66-8.63 (m, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.53-
7.49 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 4.23 (s, 3H), 3.97 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3)
δ 168.0, 162.8, 156.4, 150.8, 148.0, 139.6, 137.6, 134.7, 131.9, 127.4, 126.3, 122.7, 122.0, 119.4,
116.6, 114.7, 106.3, 56.3, 52.0; IR (KBr) 3010, 2925, 1709, 1683, 1586, 1536, 1400, 1250 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17N2O4 337.1183; found 337.1186.
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Ethyl 4-(picolinamido)-1-naphthoate 2l. Colorless solid; yield 47% (30 mg); analytical TLC on
silica gel Rf 0.42 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl acetate 92/8); mp 122-
124 °C; 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 9.11-9.09 (m, 1H), 8.74-8.72 (m, 1H), 8.59
(d, J = 8.0 Hz, 1H), 8.38-8.36 (m, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.17-8.15 (m, 1H), 7.99-7.95 (m,
1H), 7.68-7.65 (m, 2H), 7.58-7.54 (m, 1H), δ 4.47 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 162.4, 149.8, 148.3, 138.0, 136.8, 132.5, 131.2, 127.8,
127.0, 126.9, 126.6, 125.9, 123.5, 122.7, 120.4, 116.0, 77.1, 61.1, 14.5; IR (KBr) 3436, 2985,
1705, 1622, 1534, 1286 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17N2O3 321.1234;
found 321.1239.
Ethyl 5-phenoxy-4-(picolinamido)-1-naphthoate 2m. Colorless solid; yield 50% (41 mg);
analytical TLC on silica gel Rf 0.43 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 94/6); mp 118-120 °C; 1H NMR (400 MHz, CDCl3) δ 13.34 (s, 1H), 9.08 (d, J = 8.4 Hz,
1H), 8.81-8.78 (m, 1H), 8.28-8.21 (m, 3H), 7.86-7.82 (m, 1H), 7.48-7.34 (m, 4H), 7.23-7.17 (m,
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3H), 7.02-7.00 (m, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); C{1H} NMR (150
MHz, CDCl3) δ 167.6, 163.2, 156.5, 154.6, 150.2, 147.9, 138.9, 137.5, 134.8, 132.0, 129.9, 127.4,
126.4, 124.4, 122.7, 122.4, 121.8, 120.3, 117.9, 115.1, 114.5, 61.1, 14.5; IR (KBr) 3469, 2925,
1689, 1690, 1580, 1245 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C25H21N2O4 413.1496;
found 413.1510.
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Propyl 5-phenoxy-4-(picolinamido)-1-naphthoate 2n. Colorless solid; yield 45% (30 mg);
analytical TLC on silica gel Rf 0.41 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 92/8); mp 116-118 °C; H NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 9.11-9.09 (m, 1H),
8.73-8.71 (m 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.37-8.35 (m, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.16-8.14
(m, 1H), 7.98-7.94 (m, 1H), 7.67-7.64 (m, 2H), 7.56-7.53 (m, 1H), 4.37 (t, J = 6.7 Hz, 2H), 1.87
(q, J = 7.1 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 162.4,
149.8, 148.3, 138.0, 136.8, 132.5, 131.2, 127.8, 127.0, 126.9, 126.6, 125.9, 123.5, 122.7, 120.4,
116.0, 66.7, 22.3, 10.8; IR (KBr) 3436, 2924, 1746, 1701, 1536, 1236 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C20H19N2O3 335.1390; found 335.1406.
Methyl 4-(pyrazine-2-carboxamido)-1-naphthoate 2p. Colorless solid; yield 57% (35 mg);
analytical TLC on silica gel Rf 0.41 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 92/8); mp 158-162 °C; 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 9.59 (s, 1H), 9.12-9.09
(m, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.71-8.70 (m, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.2 Hz,
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1H), 8.12-8.08 (m, 1H), 7.69-7.67 (m, 2H), 4.01 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
167.6, 161.1, 148.1, 145.0, 144.4, 142.7, 136.2, 132.4, 131.2, 128.0, 127.1, 126.8, 125.8, 123.7,
120.0, 116.6, 52.3; IR (KBr) 3466, 2924, 1712, 1682, 1580, 1289 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C17H14N3O3 308.1030; found 308.1045.
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Methyl 4-(isoquinoline-1-carboxamido)-1-naphthoate 2q. Light yellow solid; yield 58% (41
mg); analytical TLC on silica gel Rf 0.41 in 10% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 92/8); mp 156-158 °C; H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 9.81-9.79 (m, 1H),
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2H), 7.78-7.75 (m, 2H), 7.68-7.65 (m, 2H), 4.01 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
167.8, 163.9, 147.1, 140.1, 137.9, 137.3, 132.5, 131.4, 130.9, 129.3, 127.9, 127.8, 127.6, 127.1,
126.9, 126.5, 126.1, 125.5, 122.9, 120.6, 115.9, 52.2; IR (KBr) 3469, 2924, 1712, 1691, 1581,
1242 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H17N2O3 357.1234; found 357.1249.
Methyl 8-benzamidoquinoline-5-carboxylate 4a. Colorless solid; yield 63% (39 mg); analytical
TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl acetate 96/4);
mp 188-190 °C; 1H NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 9.54 (dd, J = 1.6 Hz, 1H), 8.94 (d, J
= 8.4 Hz, 1H), 8.89-8.87 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.11-8.08 (m, 2H), 7.63-7.54 (m, 4H),
3.99 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 165.8, 148.3, 139.1, 138.5, 135.4, 134.8,
133.1, 132.3, 129.0, 127.5, 127.4, 123.2, 119.9, 114.7, 52.2; IR (KBr) 3442, 2924, 1707, 1687,
1574, 1281 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H15N2O3 307.1077; found
307.1086.
Methyl 8-(2-bromobenzamido)quinoline-5-carboxylate 4b. Colorless solid; yield 63% (49 mg);
analytical TLC on silica gel Rf 0.47 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 95/5); mp 156-158 °C; 1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 9.53-9.50 (m, 1H),
8.94 (d, J = 8.0 Hz, 1H), 8.82-8.80 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.74-7.70 (m, 2H), 7.60-7.57
(dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.48-7.45 (m, 1H), 7.40-7.37 (m, 1H), 4.00 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.8, 166.2, 148.4, 138.7, 138.3, 138.0, 135.3, 133.9, 133.0, 131.9, 129.8,
127.8, 127.4, 123.3, 120.4, 119.8, 115.1, 52.2; IR (KBr) 3297, 2921, 1709, 1676, 1527, 1279 cm-
1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H14BrN2O3 385.0182; found 385.0184.
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Methyl 8-(3-methylbenzamido)quinoline-5-carboxylate 4c. Colorless solid; yield 66% (42 mg);
analytical TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 96/4); mp 146-148 °C; 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 9.53-9.50 (m, 1H),
8.93 (d, J = 8.0 Hz, 1H), 8.80-8.79 (m, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.58 (dd,
J = 8.8 Hz, 4.4 Hz, 1H), 7.44-7.40 (m, 1H), 7.36-7.32 (m, 2H), 3.99 (s, 3H), 2.61 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.4, 166.8, 148.3, 139.2, 138.3, 137.1, 136.2, 135.3, 133.0, 131.6,
130.8, 127.4, 126.2, 123.2, 119.9, 114.6, 52.2, 20.4; IR (KBr) 3339, 2953, 1711, 1686, 1574, 1279
cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17N2O3 321.1234; found 321.1251.
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Methyl 8-(4-fluorobenzamido)quinoline-5-carboxylate 4d. Colorless solid; yield 61% (40 mg);
analytical TLC on silica gel Rf 0.47 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 95/5); mp 167-168 °C; H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 9.55-9.53 (m, 1H),
8.91 (d, J = 8.3 Hz, 1H), 8.89-8.87 (m, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.13-8.10 (m, 2H), 7.62 (dd,
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J = 8.8, 4.2 Hz, 1H), 7.27 (s, 1H), 7.24-7.22 (m, 1H), 3.99 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 166.8, 164.6 (JC-F = 251.5 Hz), 148.4, 138.9, 138.5, 135.5, 133.1, 131.0, 130.0 ((JC-F
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9.0 Hz), 127.4, 123.3, 120.0, 116.2 (JC-F = 21.9 Hz), 116.0, 114.7, 52.3; F NMR (565 MHz,
CDCl3) δ -106.83; IR (KBr) 3341, 2924, 1712, 1679, 1573, 1223 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C18H14FN2O3 325.0983; found 325.1001.
Methyl 8-(4-iodobenzamido)quinoline-5-carboxylate 4e. Colorless solid; yield 62% (54 mg);
analytical TLC on silica gel Rf 0.47 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 95/5); mp 156-158 °C; H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.55-9.53 (m, 1H),
8.91 (d, J = 8.3 Hz, 1H), 8.90-8.88 (m, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.94-7.92 (m, 1H), 7.83-7.80
(m, 2H), 7.62 (dd, J = 8.7, 4.2 Hz, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8,
165.0, 148.4, 138.7, 138.4, 138.3, 135.5, 134.2, 133.0, 129.0, 127.4, 123.3, 114.8, 99.6, 52.2; IR
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(KBr) 3437, 2924, 1712, 1686, 1527, 1280 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for [M+H]+
C18H14IN2O3 433.0044; found 433.0056.
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Methyl 8-(4-methylbenzamido)quinoline-5-carboxylate 4f. Colorless solid; yield 64% (41 mg);
analytical TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 96/4); mp 159-161 °C; H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.55-9.52 (m, 1H),
8.93 (d, J = 8.3 Hz, 1H), 8.89-8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.00-7.98
(m, 2H), 7.61 (dd, J = 8.8 Hz, 4.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 3.99 (s, 3H), 2.46 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 165.8, 148.3, 142.9, 139.2, 138.4, 135.4, 133.2, 132.0,
129.7, 127.6, 127.4, 123.2, 119.6, 114.6, 52.2, 21.7; IR (KBr) 3470, 2952, 1708, 1682, 1527, 1283
cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17N2O3 321.1234; found 321.1240.
Methyl 8-(4-(trifluoromethyl)benzamido)quinoline-5-carboxylate 4g. Colorless solid; yield
60% (45 mg); analytical TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-
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hexane/ethyl acetate 96/4); mp 168-170 °C; H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 9.56-
9.53 (m, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.89-8.88 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.21-8.18 (m,
2H), 7.85-7.82 (m, 2H), 7.63 (dd, J = 8.8 Hz, 4.2 Hz, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.7, 164.4, 148.4 , 138.5, 138.3, 138.0, 135.6, 134.4 (JC-F = 26.6 Hz), 133.8, 133.0,
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128.0, 127.8 (JC-F = 270.9 Hz), 126.1 (JC-F = 3.6 Hz), 123.4, 120.4, 115.0, 52.3; F NMR (565
MHz, CDCl3) δ -62.96; IR (KBr) 3342, 2924, 1712, 1683, 1527, 1283 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C19H14F3N2O3 375.0951; found 375.0978.
Methyl 8-(3,4-dimethylbenzamido)quinoline-5-carboxylate 4h. Colorless solid; yield 68% (46
mg); analytical TLC on silica gel Rf 0.45 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
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acetate 94/6); mp 166-168 °C; H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 9.55-9.52 (m, 1H),
8.93 (d, J = 8.4 Hz, 1H), 8.89-8.88 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.82-7.80 (m,
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1H), 7.60 (dd, J = 8.8 Hz, 4 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 2.39 (s, 3H). 2.36 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 166.0, 148.3, 141.6, 139.3, 138.5, 137.4, 135.4,
133.2, 132.4, 130.2, 128.8, 127.4, 124.8, 123.2, 119.6, 114.6, 52.1, 20.09, 20.06; IR (KBr) 3346,
2948, 1713, 1685, 1576, 1276 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H19N2O3
335.1390; found 335.1396.
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Methyl 8-(thiophene-2-carboxamido)quinoline-5-carboxylate 4i. Colorless solid; yield 55%
(35 mg); analytical TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-
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hexane/ethyl acetate 95/5); mp 158-160 °C; H NMR (400 MHz, CDCl3) δ 10.89 (s, 1H), 9.54-
9.52 (m, 1H), 8.89-8.87 (m, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.87-7.85 (m,
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1H), 7.63-7.59 (m, 2H), 7.21-7.19 (m, 1H), 3.99 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
166.8, 160.3, 148.3, 139.7, 138.8, 138.2, 135.4, 133.1, 131.6, 129.0, 128.1, 127.4, 123.3, 119.8,
114.7, 52.2; IR (KBr) 3332, 2921, 1708, 1673, 1573, 1281 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H13N2O3S 313.0641; found 313.0642.
Methyl 8-pivalamidoquinoline-5-carboxylate 4j. Colorless solid; yield 57% (33 mg); analytical
TLC on silica gel Rf 0.48 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl acetate 95/5);
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mp 158-160 °C; H NMR (400 MHz, CDCl3) δ 10.55 (s, 1H), 9.51-9.48 (m, 1H), 8.83-8.82 (m,
1H), 8.78 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.58-7.55(m, 1H), 3.96 (s, 3H), 1.43 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.7, 166.8, 148.2, 139.2, 138.4, 135.3, 133.1, 127.3,
123.1, 119.4, 114.3, 52.1, 40.6, 27.7; IR (KBr) 3355, 2961, 1705, 1684, 1520, 1281 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H19N2O3 287.1390; found 287.1413.
Methyl 8-benzamido-2-methylquinoline-5-carboxylate 4m. Colorless solid; yield 61% (39 mg);
analytical TLC on silica gel Rf 0.47 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 94/6); mp 189-190 °C; 1H NMR (600 MHz, CDCl3) δ 11.14 (s, 1H), 9.40 (d, J = 8.4 Hz,
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1H), 8.90 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.63-7.60 (m,
1H), 7.57 (t, J = 7.8 Hz, 2H), 7.49 (d, J = 9.6 Hz, 1H), 3.98 (s, 3H), 2.79 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 166.8, 165.5, 157.2, 138.2, 137.8, 135.3, 134.8, 132.1, 131.9, 128.9, 127.3,
125.4, 123.9, 119.6, 114.6, 52.0, 25.1; IR (KBr) 3327, 1703, 1687, 1533, 1400, 1276 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C19H17N2O3 321.1234; found 321.1237.
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Methyl 8-benzamido-2-phenylquinoline-5-carboxylate 4n. Colorless solid; yield 52% (39 mg);
analytical TLC on silica gel Rf 0.47 in 5% ethyl acetate/hexane; purification (n-hexane/ethyl
acetate 94/6); mp 187-188 °C; 1H NMR (600 MHz, CDCl3) δ 11.29 (s, 1H), 9.61 (d, J = 9.0 Hz,
1H), 8.95 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 7.2 Hz, 2H), 8.14 (d, J = 7.2
Hz, 2H), 8.10 (d, J = 9.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.58 (t, J = 7.8 Hz, 4H), 7.55 (d, J = 7.2 Hz,
1H), 4.01 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.9, 165.6, 155.1, 139.0, 138.7, 138.2,
136.4, 135.0, 132.8, 132.4, 130.1, 129.2, 129.1, 127.5, 127.4, 126.3, 120.9, 119.8, 115.0, 77.3,
77.1, 76.9, 52.2; IR (KBr) 3339, 1712, 1676, 1525, 1400, 1261 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C24H19N2O3 383.1390; found 383.1389.
N-(4-(Hydroxymethyl)naphthalen-1-yl)picolinamide 6a. LiAlH4 (3.8 mg, 0.1 mmol) was
suspended in THF (10 mL) and cooled to 0 °C in an ice bath in a 25 mL round bottom flask kept
under nitrogen atmosphere.18a A solution of 2a (30.6 mg, 0.1 mmol) in THF (5 mL) was added
dropwise via syringe at 0 °C. The resultant mixture was stirred at 60 oC for 6 h in an oil bath. The
reaction was then cooled to room temperature and quenched by addition of EtOAc (15 mL). The
organic layer was separated and the solid was extracted with EtOAc (2 x 15 mL). Drying (Na2SO4)
and evaporation of the solvent gave a residue that was purified on silica gel column
chromatography using ethyl acetate and hexane (20/80) as eluent to give 6a. White solid, yield
68% (19 mg), mp 186-188 °C; 1H NMR (600 MHz, CDCl3) δ 10.79 (s, 1H), 8.73-8.71 (m, 1H),
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8.37-8.35 (m, 2H), 8.24-8.22 (m, 1H), 8.15-8.13 (m, 1H), 7.98-7.95 (m, 1H), 7.64-7.53 (m, 4H),
5.15 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 162.4, 150.0, 148.2, 138.0, 133.3, 132.9, 132.1,
126.9, 126.7, 126.6, 126.4, 126.1, 124.9, 122.7, 121.2, 118.1, 63.9; IR (KBr) 3516, 3350, 2920,
1678, 1540, 1288 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15N2O2 279.1128; found
279.1124.
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General Procedure for Copper-Mediated Etherification.17 Compound 2a (0.2 mmol, 61.2 mg),
phenylboronic acid (48.8 mg, 0.4 mmol), Cs2CO3 (0.5 mmol, 163 mg), Cu(OAc)2 (0.3 mmol, 55
mg) and DMSO (1.0 mL) were stirred in a preheated oil bath at 130 °C under air for 10 h in an oil
bath. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as an
eluent. After completion, the reaction mixture was cooled to room temperature, diluted with
EtOAc (45 mL). The mixture was washed with aqueous ammonia (3mL), brine (5 mL) and water
(5 mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica
gel column chromatography using n-hexane and ethyl acetate as an eluent (90/10) to give 2b as
white solid; yield 73% (58 mg,). The characterization data were identical to the reported.
Methyl 4-amino-1-naphthoate 6b. To a stirred solution of NaOH (0.1 mmol, 4 mg) in CH3OH
(1.5 mL), 2a (30.6 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature
for 2 min and heated at 90 °C for 12 h. The progress of the reaction was monitored by TLC using
ethyl acetate and hexane as an eluent. After completion, the reaction mixture was allowed to cool
to room temperature, diluted with EtOAc (20 mL). The solution was washed with 0.5 N HCl (4 ×
5 mL), brine (5 mL) and water (5 mL). Drying (Na2SO4) and evaporation of the solvent gave a
residue that was purified on silica gel column chromatography using n-hexane and ethyl acetate
(90/10). White solid, 71% yield (14 mg); mp 168-170 °C;1H NMR (400 MHz, CDCl3) δ 9.16-9.14
(m, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.81(d, J = 8.4 Hz, 1H), 7.63-7.58 (m, 1H), 7.51-7.47 (m, 1H),
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6.72 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 147.3, 133.3,
132.9, 128.0, 126.9, 125.1, 122.8, 120.8, 116.2, 107.6, 51.7; IR (KBr) 3491, 2960, 2924, 2853,
1681, 1261 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H12NO2 202.0863; found 202.0889.
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4-Amino-1-naphthoic acid 6c. The above described procedure for 6b was followed prolonging
the reaction to 24 h. purification (n-hexane/ethyl acetate 50/50); White solid, 75% yield (14 mg);
mp 174-176 °C, lit18b 176 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.12 (d, J = 8.4 Hz,
1H), 8.15 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.1 Hz, 1H), 7.40 (t, J = 7.6 Hz,
1H), 6.64-6.62 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.4, 150.2, 133.6, 133.4, 127.4,
125.9, 123.6, 122.6, 121.8, 111.8, 105.5; IR (KBr) 3481, 2954, 2924, 2853, 1577, 1244 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for [M+H]+ C11H10NO2 188.0706; found 188.0733.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information having scheme S1, figure S1, table S1, Scheme S2, crystal structure
of 2b and NMR spectra of all the products is available free of charge on the ACS Publications
website at DOI:
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: tpunni@iitg.ac.in
Notes
The author declares no competing financial interest.
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■ ACKNOWLEDGMENTS
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We thank Science and Engineering Research Board (CRG/2018/000406) and Council of Scientific
and Industrial Research (02(0255)/16/EMR-II) for the financial supports. One of us (SK) thanks
Indian Institute of Technology Guwahati for Institute Postdoctoral Fellowship. We are grateful to
Department of Chemistry and Central Instrumentation Facility, Indian Institute of Technology
Guwahati for NMR and mass facilities.
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REFERENCES
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Chem. Soc. 2008, 130, 17676. (b) Gooβen, L. J.; Rodríguez, N.; Gooβen, K. Carboxylic acids
as Substrates in Homogeneous Catalysis. Angew. Chem., Int. Ed. 2008, 47, 3100. (c) Oelke, A.
J.; France, D. J.; Hofmann, T.; Wuitschik, G.; Ley, S. V. Piperazic Acid-Containing Natural
Products: Isolation, Biological Relevance and Total Synthesis. Nat. Prod. Rep. 2011, 28, 1445.
(d) Font, M.; Quibell, J. M.; Perry, G. J. P.; Larrosa, I. The Use of Carboxylic acids as Traceless
Directing Groups for Regioselective C–H Bond Functionalization. Chem. Commun. 2017, 53,
5584. (e) Chen, J.; Song, Y.; Bojadzic, D.; Tamayo-Garcia, A.; Landin, A. M.; Blomberg, B.
B.; Buchwald, P. Small-Molecule Inhibitors of the CD40–CD40L Costimulatory Protein–
Protein Interaction. J. Med. Chem. 2017, 60, 8906.
2. For some examples, see: (a) Fujiwara, Y.; Takaki, K.; Taniguchi, Y. Exploitation of Synthetic
Reactions via C-H Bond Activation by Transition Metal Catalysts. Carboxylation and
Aminomethylation of Alkanes or Arenes. Synlett 1995, 591. (b) Boogaerts, I. I. F.; Nolan, S.
P. Carboxylation of C−H Bonds Using N-Heterocyclic Carbene Gold(I) Complexes. J. Am.
Chem. Soc. 2010, 132, 8858. (c) Yoo, W.-J.; Capdevila, M. G.; Du, X.; Kobayashi, S. Base-
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