Visible Light-Promoted Photocatalytic C-5 Carboxylation of 8-Aminoquinoline Amides and Sulfonamides via a Single Electron Transfer Pathway

Article abstract of DOI:10.1021/acs.joc.9b00942

An efficient photocatalytic method was developed for the remote C5-H bond carboxylation of 8-aminoquinoline amide and sulfonamide derivatives. This methodology uses in situ generated ^?CBr₃ radical as a carboxylation agent with alcohol and is further extended to a variety of arenes and heteroarenes to synthesize the desired carboxylated product in moderate-to-good yields. The reaction proceeding through a single electron transfer pathway was established by a control experiment, and a butylated hydroxytoluene-trapped aryl radical cation intermediate in high-resolution mass spectrometry was identified.

Full text of DOI:10.1021/acs.joc.9b00942

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Article
Visible Light Promoted Photocatalytic C-5 Carboxylation of 8-Amino
Quinoline Amides and Sulfonamides via a Single Electron Transfer Pathway
Chiranjit Sen, Tapan Sahoo, Harshvardhan Singh, Eringathodi Suresh, and Subhash Chandra Ghosh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00942 • Publication Date (Web): 16 Jul 2019
Downloaded from pubs.acs.org on July 16, 2019
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Visible Light Promoted Photocatalytic C-5
Carboxylation of 8-Amino Quinoline Amides and
Sulfonamides via a Single Electron Transfer Pathway
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Chiranjit Sen, Tapan Sahoo, Harshvardhan Singh, a,b Eringathodi Suresh, b,c and Subhash
a,b
a,b
Chandra Ghosh*, a,b
a
Natural Products and Green Chemistry Division,
b
Academy of Scientific and Innovative Research (AcSIR)
c
Analytical and Environmental Science Division and Centralized Instrument Facility
Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI), G.B. Marg,
Bhavnagar-364002, Gujarat, India.
R2
CO Me
2
R2
H
R1
R1
N
N
+
CBr4
Ru(bpy) Cl 6H O
3 2. 2
H
N
H
N
45W CFL light, 24h
7
7 examples
upto 81% yield
K CO , MeOH
2
3
O
O
O
R4
regioselectivity at C-5 site
k /k = 1.04
S
1
R3,
R =
H
D
single electron transfer pathway
ABSTRACT: An efficient photocatalytic method was developed for the remote C5-H bond
carboxylation of 8-amino quinoline amide and sulphonamide derivatives. This methodology
uses in situ generated •CBr radical as carboxylation agent with alcohol and further extended
3
to a variety of arenes and heteroarenes to synthesize the desired carboxylated product in
moderate to good yields. The reaction proceeds through a single electron transfer (SET)
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pathway was established by a control experiment and identifying BHT trapped aryl radical
cation intermediate in HRMS.
INTRODUCTION
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Quinoline and its derivatives are widely considered as a pivotal structural motif of a diverse
1
array of natural products, pharmaceuticals, and functional materials. Several antimalarial
drugs like primaquine, pamaquine, bulaquine, and tafenoquine contain an 8-aminoquinoline
2
scaffold. Commercial drugs like imiquimod, anticancer agents, chloroquine an antimalarial
drug, and levofloxacin an antibiotic, contains an amino group and a carboxylic group in the
3
quinoline moiety. Also, 8-sulfonamidoquinoline scaffolds are widely used for the selective
4
turn-on Zn(II) fluorescent sensors. Moreover, quinoline carboxylates are widely recognized
as a pivotal structural component and play a predominant role as precursors for a variety of
5
biologically active molecules. Therefore, considerable efforts have been made for the
6
functionalization of quinoline derivatives. Among them, remote C-5 functionalization of 8-
7
-
aminoquinoline is one of the challenging and interesting topics for the chemist (Scheme 1).
8
9
10
11
Several reports have been described for halogenation, sulfonylation, nitration, azidation,
12
13
14
15
16
17
acyloxylation, phosphonation, thiolation, thioesterification, amination, alkylation,
difluoroalkylation,18 hydroxylation19 trifluoromethylation20 and selenylation. 21 However,
despite the considerable advances no example for C-5 carboxylation are reported in the
literature. Therefore, the development of highly efficient methods for direct regioselective
carboxylation of quinoline scaffold under the mild and sustainable condition is highly desirable
for organic synthesis. In this context, visible light mediated photocatalysis can run under mild
2
2
conditions and proceed mostly via a radical or radical ion intermediate. The simple and
efficient generation of such reactive intermediates by visible light and applied them in organic
transformations received considerable attention. In this regard, carbon tetra bromide used as a
masked carboxylating reagent, initial incorporation of •CBr radical to the aromatic nuclei,
3
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C-N bond formation
X
C-S/ C-Se/C-P bond formation
X
N
N
NHZ
Reported
NHZ
2
X = SR, SO R, SeR, POR2
X = NO , N , NR
2
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Reported
C-C bond formation
C-Halo bond formation
X
X
H
Reported
Reported
N
N
N
NHZ
NHZ
NHZ
X = CF , CF R, alkyl
X = Cl, Br, I
3
2
This Work
carboxylation
CO R
C-O bond formation
X
Reported
2
N
N
NHZ
NHZ
X = OH, OAc, OSO R
2
Scheme 1: C-5 functionalization of 8-amino quinoline derivatives
2
3
followed by alcoholysis to deliver the desired carboxylate. Mukminov and co-workers first
demonstrated the iron-catalyzed carboxylation of the only benzofuran, at 100-140 C. Greaney
2
4
and co-workers reported the ruthenium (III) chloride catalyzed meta-carboxylation of arenes
containing azine type directing group at 85C, with a moderate yield (44-63%). Very recently
we have also reported the copper‐catalyzed C‐4 carboxylation of 1‐naphthylamide derivatives
2
5
26
in moderate to good yields. Tang and co-workers reported carboxylation of styrene using
cooperative Eosin -Y as photocatalyst and cobalt iodide with CBr and DMSO. Photocatalytic
4
carboxylation of indoles reported by Bandini and co-workers using [Ru(bpy) ](PF ) as the
3
6 2
photocatalyst, iPr NH as a base, in 0.05 M methanol, under irradiation with 7 W blue LED
2
2
7
light. It is noteworthy that, to achieve the regioselectivity, C(3) substitution of indoles are
essential to furnishing desired indole C(2) carboxylate, without any substituents, indole-3-
carboxylate was obtained in moderate yield. As part of our ongoing research on regioselective
2
8
quinoline C-H functionalization, herein, we report the regioselective C-5 carboxylation of 8-
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aminoquinoline derivatives with CBr and methanol and other alcohols using economic
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Ru(bpy) Cl .6H O as a suitable photocatalyst at room temperature under irradiation with
3
2
2
visible light (45 W CFL lamp). This mild and practical methodology broadly applicable for the
carboxylation of a wide range of 8-amino quinoline amide and sulfonamide derivatives in good
yields.
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RESULTS AND DISCUSSION
We began our study by choosing 2,2-dimethyl-N-(quinolin-8- yl)butanamide (1a) as a model
substrate to identify the catalytic system for carboxylation with CBr and methanol as solvent
4
under irradiation with 45W CFL lamp in the presence of a suitable photocatalyst. Initially,
Ru(bpy) (PF ) was chosen as the photocatalyst, in the presence of K CO as a base, as
3
6 2
2
3
expected the reaction goes well, and 67% of desired carboxylated product was isolated (table
, entry 1). Altering the photocatalyst’s counter anion to chloride i.e., more economic
Ru(bpy) Cl .6H O was tested and to our delight improvement in the yield (entry 2, 72%) was
1
3
2
2
observed. Replacement of Ru(II) photocatalyst to the other organo photocatalyst like Eosin-Y,
Rose Bengal and 9-Mesityl-10-methylacridinium perchlorate were unsuccessful (entries 3-5).
Table 1: Screening of reaction conditions[a]
Catalyst
O
O
Base
5W CFL light, 24h
4
N
+
CBr4
O
NH
solvent
N
O
NH
1a, 0.25 mmol
3 equiv
2a
Entry
Photocatalyst
Ru(bpy) (PF )
Base
Solvent
Yield %
1
2
3
4
K CO
2
MeOH
MeOH
MeOH
MeOH
67
3
6 2
3
3
3
3
Ru(bpy) Cl .6H O
K CO
2
72
3
2
2
Eosin-Y
Rose Bengal
K CO
2
NR
NR
K CO
2
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9-Mesityl-10-methylacridinium K CO
Perchlorate
MeOH
NR
2
3
6
7
8
9
1
1
Ru(bpy) Cl .6H O
Na CO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
60
65
35
66
33
24
25
30
3
2
2
2
3
Ru(bpy) Cl .6H O
NaOAc
NaHCO3
K PO
3
2
2
Ru(bpy) Cl .6H O
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Ru(bpy) Cl .6H O
3
2
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4
0
1
Ru(bpy) Cl .6H O
iPr NH
3
2
2
2
Ru(bpy) Cl .6H O
DABCO
3
2
2
12
Ru(bpy) Cl .6H O
Et N
3
2
2
3
1
1
1
3
4
5
Ru(bpy) Cl .6H O
DBU
3
2
2
Ru(bpy) Cl .6H O
K CO
2
30[b]
3
2
2
3
3
NR[c]
Ru(bpy) Cl .6H O
K CO
2
3
2
2
16
1
Ru(bpy) Cl .6H O
MeOH
MeOH
12
18
3
2
2
[d]
7
Ru(bpy) Cl .6H O
K CO
2
3
2
2
3
[
a]
under argon atmosphere, [b] 7 W blue LED; [c] without light, [d] under oxygen atmosphere, NR: no
reaction
Further, we optimized the reaction by varying the base, inorganic bases like Na CO , NaHCO ,
2
3
3
NaOAc and K PO did not improve the yield (entries 6-9), while organic bases such as iPr NH,
3
4
2
DABCO, Et N, DBU showed diminished reactivity (entries 10-13). Subsequently, various mix
3
solvent was screened (SI, Table S2), in methanol acetonitrile (1: 4) mixed solvent similar yield
(
69 %) was achieved. Altering of the light source to 7W blue LED, was ineffective only 30%
of carboxylated was isolated, while, in the absence of light no reaction was observed (entries
4-15).
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Table 2: Substrate scope for 8-amido quinoline moiety
O
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
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0
1
2
3
4
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9
0
O
O
O
O
O
O
N
N
N
N
N
O
NH
O
NH
O
NH
O
NH
O
NH
2a, 72%
2b, 70%
2d, 60%
2e, 71%
2c, 60%
O
O
O
O
O
O
R = H,
2h, 80%
R = Me, 2i, 80%
R = OMe, 2j, 77%
N
N
N
R = F,
R = Cl,
R = Br,
R = I,
2k, 78%
2l, 77%
2m, 74%
2n, 70%
O
NH
O
NH
O
NH
R = CF3, 2o, 63%
2f, 65%
2f
R
2g, 61%
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
NH
O
NH
O
NH
O
NH
N
R
NH2
S
R
MeO
OMe
R = Cl,
R = Br,
R = I,
2p, 70%
2q, 71%
2r, 67%
R = F, 2t, 56%
R = Me,2u, 70%
OMe
2v, 66%
2w, 76%
2x, 70%
R = Me, 2s, 76%
O
O
O
O
O
O
O
O
R
O
I
N
N
N
N
O
NH
NH
R = OMe, 2ab, 75%
R = Me, 2ac, 77%
O
NH
O
NH
R = F,
2ad, 60%
R = Cl, 2ae, 73%
R = Br, 2af, 71%
R = CF3, 2ag, trace
2y, 66%
2z, 75%
2aa, 70%
Unless otherwise mentioned reactions were carried out in a sealed tube in the presence 1 (0.25 mmol),
CBr (0.75 mmol), Ru(bpy) Cl .6H O (2 mol%), K CO (0.5 mmol) and MeOH (2 mL) under visible
4
3
2
2
2
3
light (45 W CFL lamp) for 24h at room temperature.
Then the reaction was carried out in the absence of K CO , afforded12% of the desired product,
2
3
which indicates that the base is essential for this reaction (entry 16). Performing the reaction
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under oxygen atmosphere only 18% of the carboxylated product was obtained (entry 17),
indicates that oxygen restrains the reaction thus inert atmosphere is desired.
With the optimization condition in hand, we next explore the substrate scope for the
carboxylation of various 8-aminoquinoline amides as shown in Table 2. The carboxylation
proceeds well with 8-aminoquinoline alkyl amides (entries 2a-2g) produced the corresponding
carboxylated product in 60-72% yield. Regardless of acyclic (2a-2c), or cyclic (2d-2g), and
even sterically hindered like adamantyl carboxamides (2g, 61%) showed similar reactivity. In
addition, the structure of the 2f was undoubtedly confirmed by the single crystal X-ray analysis
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
4
4
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4
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4
4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
0
1
2
3
4
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7
8
9
0
1
2
3
4
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9
0
(CCDC- 1888178, see SI for details). Moreover, 8- aminoquinoline aromatic amides with
electron donating (2i-2j, 2s, 2u-v), neutral (2h, 80%) or electron withdrawing groups (2k-r, 2t)
at the para, meta, and ortho- position works similarly to give C5-carboxylated product.
Interestingly, NH-Boc protected amine furnished the C5-carboxylated product but with the
deprotection of the Boc group (2w, 76%). Replacement of the aryl with thienyl or naphthyl
amides exerted comparable yields (2x, 2y). Next, the substitution on the quinoline moiety was
explored, substitution with methyl at C-2 and with iodo at C-3 delivered C-5 carboxylation
product in high yields (2z, 75%, 2aa, 70%). Moreover, substitution at the C-6 position,
sterically hindered for C-5 carboxylation, with variety of electron donating (-OMe, 2ab; -Me,
2
ac) and withdrawing functional group (halo) does not have any effect on reactivity and
regioselectivity for carboxylation. While, in the presence of a trifluoromethyl group, a strong
electron withdrawing group inhibits the reaction, an only a trace amount of desired product was
observed (2ag, trace). It was also reported that the presence of strong electron withdrawing
group (like nitro and cyano) in the quinoline moiety inhibits the halogenation8b and
thiocyanation 21b reaction which proceeds through the SET mechanism, thus electron rich
arenes work better in this system. Encouraged by these results for carboxylation of 8-
aminoquinoline alkyl/aryl amides with CBr /MeOH, we turned our attention for the
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carboxylation of other important sulphonamide derivatives, results are summarized in Table 3.
When N-(quinolin-8-yl)toluenesulfonamide was used as a substrate with CBr /MeOH, C5-
4
carboxylated product was obtained in very good yield
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Table 3: Substrate scope for 8-amino quinoline sulfonamides
O
S
O
O
S
O
O
S
O
4
4
a, R = Me, 74%
b, R = H, 75%
N
N
O
O
NH
4c, R = Ph, 62%
O
O
NH
N
4d, R = tBu, 71%
4e, R = Br, 66%
4f, R = F, 77%
O
O
NH
4g, R = CN, 77%
4h, R = CF3, 81%
R
O
4i, 75%
4j, 70%
O
O
O
R
N
O
O
NH
N
S
F
O
O
NH
F
F
F
F
S
R = OMe, 4l, 79%
R = CF , 4m, trace
4k
3
4k, 59%
Reaction conditions: substrate 3 (0.25 mmol), CBr (0.75 mmol), Ru(bpy) Cl .6H O (2 mol%), K CO
3
4
3
2
2
2
(0.5 mmol) and MeOH (2 mL) under visible light (45 W CFL lamp) for 24h at room temp.
(Table 3, 4a, 74%). N-(quinolin-8-yl)benzenesulfonamide also provided similar yields of the
carboxylated product (4b, 74%). Several para-substituted benzenesulfonamides including
electron-donating (4c, 4d), and electron-withdrawing group (4e-4h) were tested and found
compatible for our developed process and delivered carboxylated product in good to excellent
yields (up to 81%). Moreover, the alkyl sulfonamides (4i, 75%) works well under optimal
conditions. In addition, the reaction with naphthalene sulphonamide and pentafluorobenzene
sulphonamides afforded exclusively C5-carboxylated product in good yields (4j, 70% and 4k,
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1
9%) respectively, the structure of 4k was further confirmed by X-ray crystallography (CCDC-
888239). It is important to note that, one of the most efficient membrane-permeable
2
9
fluorescent probes for zinc (II), 6-methoxy-8-p-toluenesulfonamido-quinoline (TSQ, 3l), is
carboxylated with high yield and excellent regioselectivity (4l, 79%), and could be applicable
for further sensing studies. As observed in the quinoline amide case, similarly in the presence
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
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5
5
5
5
5
5
6
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of strong electron withdrawing group (-CF ) in the quinoline moiety, carboxylation completely
3
inhibited (4m). To further demonstrate the potential application of this methodology, we have
performed the carboxylation with different alcohols as demonstrated in Table 4. To our delight,
when ethanol was used as solvent instead of methanol compound 1a and 3h were carboxylated
efficiently and afforded ethyl carboxylate products in similar yields (5a, 61%, and 5b, 65%).
However, when tert-amyl alcohol and tert-butanol were used, lower yields (5c, 25% and 5d,
2
5%) obtained in the carboxylation might be due to the steric factor. In addition, the structure
of the tert-butyl carboxylated product (5d) was confirmed by X-ray crystallography (CCDC-
888179).
Table 4: Substrate scope with different alcohols
1
O
O
O
O
O
O
O
O
N
N
O
N
O
NH
N
O
O
NH
S
O
NH
O
NH
S
5a, 61%
5b, 65%
5c, 25%
5d, 25%
5d
Reaction conditions: Substrate (0.25 mmol) CBr (0.75 mmol), Ru(bpy) Cl .6H O (2 mol%), K CO
3
4
3
2
2
2
(0.5 mmol), alcohol (250 µL), acetonitrile (1.5 mL) under visible light (45 W CFL lamp) for 24h at
room temperature.
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4
4
4
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5
5
5
5
5
5
5
6
Next, we further explored the possibility of extending the reaction to the other arenes and
hetarenes. To our delight, the carboxylation worked well with a variety of aromatic and
heteroaromatic compounds, providing carboxylated products in good yields (Table 5). The
carboxylation proceeds well with β-naphthol (6a, 62%), and several electron donating and
withdrawing group substituted β –naphthol (6b-6i). It is noteworthy that functional groups like
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8
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9
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2
3
4
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9
0
Table 5: Substrate scope with different arenes and hetarenes
CO Me
CO2Me
OH
CO Me
CO2Me
OH
R= Br, 6e, 60%
2
2
OH
R
OH
Br
R
R= CO Me, 6f, 65%
2
R= CHO,6g, 60%
R= CN, 6h, 63%
R= OMe, 6i, 61%
R= Br, 6c, 61%
R= OMe, 6d, 63%
6a, 62%
6b, 66%
CO Me
CO Me
2
N
2
N
N
N
Ph
Ph
N
N
Cl
R
CO Me
CO2Me
CO Me
2
MeO C
2
2
OH
NHBz
R= H, 6l, 70%
R= Cl, 6m, 69%
6n, 71%
6o, 67%
6j, 60%
6k, 61%
CO Me
2
S
N
N
N
Ph
Cl
N
Ph
N
N
N
H
CO Me
2
CO Me
CO Me
2
2
6r, 52%
6s, 78%
6p, 68%
6q
, 70%
Br
Br
R= Me, 6v, 80%
R= OMe, 6w, 65%
R= SPh, 6x, 76%
R= Cl, 6y, 80%
R= I, 6z, 70%
CO Me
CO Me
2
2
R
S
MeO C
X
2
S
X= O, 6t, 70%
X= S, 6u, 65%
6aa, 67%
Reaction conditions: Substrate (0.25 mmol) CBr (0.75 mmol), Ru(bpy) Cl .6H O (2 mol%), K CO
3
4
3
2
2
2
(0.5 mmol), and methanol (2 mL ) under visible light (45 W CFL lamp) for 24h at room temperature.
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hydroxyl, aldehyde, cyano, and bromo are well tolerated in this transformation. When α-
naphthol was used, di carboxylated product was obtained in good yield (6j, 60%). However, 1-
benzamidonaphthalene afforded C4-carboxylated product in good yield (6k, 61%). A series of
other heteroaromatic compounds including imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazole,
indole, benzofuran, benzothiophene and, thiophenes were all compatible with this
transformation and afforded very good yields (6k-6aa, up to 80%). The regioselectivity of the
hetarenes due to the higher reactivity of that position of the corresponding radical cation species
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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4
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5
5
5
5
5
5
6
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6 30
and CBr radical would preferentially react at that position to get the desired product. ,
3
Furthermore, the selective removal of the amide group (2h) with HCl to synthesize
corresponding free amine substrates in excellent yield (2w, 98%), showcased the synthetic
utility of our method.
A series of experiments were carried out under the standard reaction condition with several
designed substrates (8a-h, Figure 1). When, N-methyl-N-(quinolin-8-yl)benzamide (8a), N, N-
dibenzylquinolin-8-amine (8b), N-benzylquinolin-8-amine (8c) and 8-aminoquinolin (8d) were
examined under standard condition, no carboxylation product was obtained. These results
indicate that the presence of secondary amide or sulphonamide is crucial, they help to stabilize
the intermediate radical/ radical cation species and played a key role in the regioselective
carboxylation.
O
Bn
Bn
H N
2
N
N
N
H
N
N
N
Bn
N
8a
8b
8c
8d
Br
O
N
O
N
H
N
N
N
N
Ph
H
8f
8g
8h
8e
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 1: Unreactive substrates
Also, when C-3 amido quinoline (8e) was used no carboxylated product was observed, even
when C-5 position is blocked (8f) no carboxylation takes place in any other position. Moreover,
simple quinoline or isoquinoline are also found unreactive.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
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9
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9
0
1
2
3
4
5
6
7
8
9
0
To gain insight into the reaction mechanism, a series of the experiment were carried out. Upon
addition of the radical scavenger, TEMPO or BHT the reaction was completely inhibited for
both amide (1a) and sulfonamide (3a) substrates (Scheme 2A), we have also identified the BHT
trapped sulfonamide compound in HRMS. These results consistent with the literature report in
the similar system, 8a, 16a, 16c-d indicates that the reaction might undergo through a single electron
transfer (SET) pathway, and generates aryl radical at C5-position quinoline moiety.
Scheme 2: Control experiments for the mechanistic study
A) Radical inhibition studies
Standard conditions
2a
1a
additive
a) TEMPO
b) BHT
no reaction
no reaction
OH
CO Me
2
Standard conditions
TsHN
TsHN
+
N
N
4a
3a
N
additive
a) TEMPO
b) BHT
NHTs
(b) detected by HRMS
not obtained
not obtained
B) kinetic isotope effect (KIE) studies
H/D
O
O
H/D
D/H
O
N
standard conditions
5h
D/H
O
N
+
D/H
N
NH
NH
O
NH
Ph
h/1h-D
50:50)
60%
Ph
4
0%
Ph
1
1h/1h-D
k /k = 1.04
2h/ 2h-D
51: 49)
H
D
(
(49:51)
(
CF3
C) Isolation of ortho ester intermeiate
Ru(bpy) Cl 6H O (2 mol%),
F3C
O
O
3
2.
2
K CO (0.5 mmol)
+
CBr4
0.75 mmol)
2
3
TsHN
O
(
CF CH OH 250 l
CF3
N
3
2
TsHN
, 40%
3a 0.25 mmol
CH3CN 1.5 mL
N
7
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Next, kinetic isotope effect (KIE) for the reaction was determined by the intermolecular
competitive reaction of two isotopomeric substrates (1h and 1h-D, Scheme 2-B), and k /k
H
D
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
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2
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2
3
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7
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9
0
ratio = 1.04 was obtained. Which indicates that C-H bond cleavage is not involved in the rate
determining step.8a,21b Next, we used 2,2,2 trifluoroethanol instead of methanol as alcohol
source, to our surprise we have found the orthoester (Scheme 2C, 7), which indicates that all
three Br in CBr (III) was replaced by an alkoxy group, then converted to the desired ester.
3
Then, the role of light was investigated, the reaction completely stops at dark and restarted once
again when the light was on. Also, oxidation potential was measured for compound 1h and 3a
+
and found 1.30 V and 0.78 V vs Fc /Fc respectively. (see supporting information for details).
On the basis of the above experimental observations and previous literature report 7, 8a, 16a, 16c-d,
21, 22a, 24-26,
a tentative mechanism was proposed in scheme 3 using N-(quinolin-8-
yl)arylsulfonamide (3) as an
Scheme 3: Proposed mechanism
Ru(bpy) 2+
*Ru(bpy)32+
3
X
N
H
N
CBr4
[3]
X
CBr3
N
H
N
(
I)
H
CBr3
CBr3
X
X
N
N
H
N
H
N
(
II)
(
III)
3
MeOH
O
-3HBr
CO Me
2
O
O
X
-MeBr
N
H
X
N
H
-MeOH
N
N
[4]
(
IV)
X = amide or sulfonamide
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
example of this photocatalytic carboxylation. Ru(bpy)32+ upon irradiation with visible light
0
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8
9
0
1
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3
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6
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8
9
0
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9
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
+
undergoes lowest energy triplet excited state *Ru(bpy) . This photo-excited species reduced
3
CBr to generate •CBr radical species and KBr, and catalyst self-oxidized to intermediate
4
3
Ru(bpy)33+ Ru species. Next, a single electron transfer (SET) process occurred between RuIII
III
and the 8-aminoquinoline moiety and provided quinoline radical cation complex (I) 7, 21 and
2
+
regenerates the photocatalyst Ru(bpy) , the whole process proceed via oxidative quenching
3
cycle of photoexcited state *Ru(bpy)32+ species. Next, the tribromomethyl radical may then
react with the aromatic radical cation species (I) at the C-5 position of the quinoline moiety,
produced an aryl cation (II). Rearomatization of the intermediate (II) via deprotonation yielded
8a
(III) and followed by methanolysis provided orthoester (IV), which upon hydrolyzed under
acidic condition and provided the desired ester (4).
CONCLUSION
In summary, we have developed a visible light promoted remote C-5 carboxylation of 8-amino
quinoline amides or sulfonamides via direct C-H functionalization using CBr and methanol or
4
other alcohol. This carboxylation method run under mild conditions (RT, 45W white LED)
with wide substrate scope and well functional group tolerance. The applicability of the method
further showcased by the functionalization of TSQ the most efficient membrane-permeable
fluorescent probes for zinc (II) and selective deprotection of amide group to synthesis 8-
aminoquinoline-5-carboxylate. Control experiments, with trapping of radical intermediate,
reveals that reaction proceeds through a single electron transfer pathway.
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EXPERIMENTAL SECTION
General Information:
All reactions were carried out in oven-dried glassware under standard reaction conditions. All
chemicals were purchased from TCI and catalysts were purchased from Sigma Aldrich and
used without further purifications. All solvents were dried by the standard reported procedures
and stored over activated molecular sieves. Purification of compounds done by flash
chromatography (200-400 mesh silica gel) was used by gradient elution of ethyl acetate (EA)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
and n-hexane mixture. H/ C NMR was recorded on 600/151 MHz NMR spectrometer in
1
9
CDCl unless otherwise mentioned, using TMS as the reference in ppm. F-NMR spectra were
3
recorded at 600 MHz. The following abbreviations were used to describe peak splitting patterns
when appropriate, s = singlet, Broad singlet (br.s), d = doublet, t = triplet, m = multiplet, dd =
doublet of doublet, ddd= doublet of doublet of doublet, td = triplet of doublet, dt = doublet of
triplet, qd = quartet of doublet, m= multiplet, Coupling constants J, were reported in hertz unit
(Hz). Mass spectral data for the new compound were obtained using electro spray ionization
time-of-flight (ESI-TOF) mode on the mass spectrometer.
Experimental procedure for carboxylation reaction:
Procedure: A mixture of 2,2-dimethyl-N-(quinolin-8-yl)butanamide 1a (61 mg, 0.25 mmol, 1
equiv.,), carbon tetrabromide 0.75 mmol (3 equiv., 249 mg ), catalyst Ru(bpy) Cl .6H O 2
3
2
2
mol% (3.8 mg) and K CO 0.5 mmol (2equiv., 69 mg) were taken in a reaction tube under
2
3
nitrogen atmosphere, then 2mL methanol was added over it. The mixture was stirred and
irradiated using a 45W CFL lamp (Havells 45W, 2800 lumen, Cool Daylight 6500K, without
any filter) at a distance of about 5 cm for 24h. After completion of the reaction, the reaction
mixture was poured into H O (10 mL) and extracted with DCM (3×10 mL). The combined
2
organic layer was washed with brine (15 mL) and dried over Na SO . The solvent was removed
2
4
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2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
under reduced pressure, and the crude reaction mixture was purified by flash chromatography
using n-hexane /ethyl acetate (95/5) as an eluent to isolate the desired carboxylated product.
All other C-5 carboxylated products were purified by flash chromatography using n-hexane
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
/
ethyl acetate (5-10%) as an eluent and prepared following this general procedure.
Removal of the directing group:
Methyl 8-benzamidoquinoline-5-carboxylate (2h, 0.25 mmol, 76.5 mg) was taken in a 10 mL
reaction tube with 2mL ethanol as solvent. Conc. HCl (0.5 mL) was slowly added over it at
room temperature. Then, the reaction mixture was refluxed for 12h and reaction progress was
monitored by TLC. Upon completion of the reaction, the solvent was removed under reduced
pressure. 10 mL of saturated NaHCO solution was added for quenching and extracted with
3
DCM (3 x 25 mL). The combined organic layer was washed with brine and dried over
anhydrous Na SO . The solvent was removed under reduced pressure, and the desired product
2
4
was purified (2w, 98%, 43 mg) by flash chromatography using silica gel and EtOAc/n-hexane
10%) as an eluent.
(
Control experiment in the presence of radical inhibitor TEMPO and BHT
A mixture of 2,2-dimethyl-N-(quinolin-8-yl)butanamide 1a 0.25 mmol (1 equiv., 61 mg ),
carbon tetrabromide 0.75 mmol (3 equiv., 249 mg ), catalyst Ru(bpy) Cl .6H O 2 mol% (3.8
3
2
2
mg) , base K CO 0.5 mmol (2equiv., 69 mg) and radical inhibitor TEMPO or BHT were taken
2
3
in a reaction tube under nitrogen atmosphere at room temperature. Then methanol (2mL) was
added and stirred for 24h using a 45W CFL lamp as a light source (Havells 45W, 2800 lumen,
Cool Daylight 6500K) at a distance of about 5 cm. Reaction progress was by monitored by
TLC. No product was obtained even after 24h, and the reaction is completely inhibited by the
radical scavenger.
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Isolation and detection of intermediate:
Procedure: A mixture of 4-methyl-N-(quinolin-8-yl)benzenesulfonamide (3a), (74.5 mg, 0.25
mmol, 1 equiv.,), carbon tetrabromide 0.75 mmol (3 equiv., 249 mg), catalyst
Ru(bpy) Cl .6H O 2 mol% (3.8 mg) and K CO 0.5 mmol (2equiv., 69 mg) were taken in a
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
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3
3
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3
4
4
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4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
2
3
reaction tube under nitrogen atmosphere, then 250µl 2,2,2-trifluoroethanol and 1.5 mL
acetonitrile was added over it. The mixture was stirred and irradiated using a 45W CFL light
source at a distance of about 5 cm for 24h. After completion of the reaction, the reaction
mixture was poured into H O (15 mL) and extracted with DCM (3×20 mL). The combined
2
organic layer was washed with brine (15 mL) and dried over Na SO . The solvent was removed
2
4
under reduced pressure, and the crude reaction mixture was purified by flash chromatography
using n-hexane /ethyl acetate (90/10) as an eluent to isolate the desired ortho ester (7) product.
Physical Properties and Characterization Data of the Synthesized Compounds
Methyl 8-(2,2-dimethylbutanamido)quinoline-5-carboxylate (2a)
1
White solid, mp 98 – 100 C, n-hexane/EtOAc (95/5), 72% (54 mg) H NMR (600 MHz, CDCl
3
) δ 10.53 (s, 1H), 9.51 (d, J = 7.2 Hz, 1H), 8.90 – 8.74 (m, 2H), 8.37 (d,
O
O
J = 8.1 Hz, 1H), 7.58 (dd, J = 8.7, 4.1 Hz, 1H), 3.98 (s, 3H), 1.78 (q, J =
1
3
1
7
.5 Hz, 2H), 1.40 (s, 6H), 0.96 (t, J = 7.5 Hz, 3H). C{ H} NMR (151
N
MHz, CDCl ) δ 177.3, 166.9, 148.3, 139.2, 138.5, 135.3, 133.2, 127.4,
O
NH
3
1
23.1, 119.4, 114.4, 52.2, 44.4, 34.2, 25.2, 9.4. HRMS (ESI): m/z calcd
+
for C H N O Na [M+Na] : 323.1372, found 323.1359.
1
7
20
2
3
Methyl 8-pivalamidoquinoline-5-carboxylate (2b)
White solid, mp 140 – 142 C n-hexane/EtOAc (95/5), 70% (50 mg). H NMR (600 MHz,
1
CDCl ) δ 10.56 (s, 1H), 9.55 – 9.44 (m, 1H), 8.86 – 8.74 (m, 2H), 8.36 (d,
3
O
O
J = 8.4 Hz, 1H), 7.57 (dd, J = 8.7, 4.1 Hz, 1H), 3.97 (s, 3H), 1.44 (s,
1
3
1
9
H). C{ H} NMR (151 MHz, CDCl ) δ 177.8, 166.9, 148.3, 139.2,
3
N
O
NH
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
5
6
1
38.5, 135.3, 133.2, 127.3, 123.1, 119.4, 114.4, 52.2, 40.7, 27.8. HRMS (ESI): m/z calcd for
+
C H N O [M+H] : 287.1396, found 287.1404.
1
6
19
2
3
Methyl 8-(2-ethylhexanamido)quinoline-5-carboxylate (2c)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
semi solid, n-hexane/EtOAc (95/5), 60% (61 mg). H NMR (600 MHz, CDCl ).δ 10.14 (s, 1H),
3
9.51 (dd, J = 8.7, 1.6 Hz, 1H), 8.86 – 8.78 (m, 2H), 8.36 (d, J = 8.3 Hz,
O
O
1
1
H), 7.58 (dd, J = 8.7, 4.1 Hz, 1H), 3.98 (s, 3H), 2.42 (tt, J = 8.9, 5.3 Hz,
H), 1.88 – 1.75 (m, 2H), 1.69 – 1.58 (m, 2H), 1.42 – 1.32 (m, 4H), 1.01
N
O
NH
13
1
(
t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). C{ H} NMR (151 MHz,
CDCl ) δ 175.5, 166.8, 148.2, 139.0, 138.1, 135.3, 133.1, 127.4, 123.1,
3
1
19.5, 114.6, 52.1, 51.2, 32.6, 29.9, 26.3, 22.9, 14.1, 12.2. HRMS (ESI):
m/z calcd for C H N O [M+H]: 329.1865, found 329.1844.
1
9
25
2
3
Methyl 8-(cyclohexanecarboxamido)quinoline-5-carboxylate (2d)
1
White solid, mp 116 – 118 C, n-hexane/EtOAc (95/5), 60% (47 mg). H NMR (600 MHz,
CDCl ).δ 10.19 (s, 1H), 9.51 (d, J = 7.4 Hz, 1H), 8.88 – 8.59 (m, 2H),
3
O
O
8
.36 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.7, 4.1 Hz, 1H), 3.98 (s, 3H), 2.50
tt, J = 11.8, 3.5 Hz, 1H), 2.09 (dd, J = 13.3, 2.1 Hz, 2H), 1.91 – 1.85 (m,
2H), 1.78 – 1.71 (m, 1H), 1.66 – 1.59 (m, 2H), 1.44 – 1.36 (m, 2H), 1.32
(
N
O
NH
13
1
(
m, 1H). C{ H} NMR (151 MHz, CDCl ) δ 175.4, 166.9, 148.2, 139.2,
3
1
35.4, 133.2, 127.4, 123.2, 119.4, 114.6, 52.2, 47.1, 29.8, 25.9, 25.8. HRMS (ESI): m/z calcd
+
for C H N O Na [M+Na] : 335.1372, found 335.1363
1
8
20
2
3
Methyl 8-(cyclopentanecarboxamido)quinoline-5-carboxylate (2e)
1
White solid, mp 118 – 120 C, n-hexane/EtOAc (95/5), 71% (53 mg). H
O
O
NMR (600 MHz, CDCl ).δ 10.15 (s, 1H), 9.49 (dd, J = 8.7, 1.6 Hz, 1H),
3
N
O
NH
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.85 – 8.72 (m, 2H), 8.34 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.7, 4.1 Hz, 1H), 3.97 (s, 3H), 2.98
1
3
1
(p, J = 8.1 Hz, 1H), 2.12 – 1.95 (m, 4H), 1.89 – 1.78 (m, 2H), 1.75 – 1.63 (m, 2H). C{ H}
NMR (151 MHz, CDCl ) δ 175.6, 166.8, 148.1, 139.2, 138.0, 135.3, 133.2, 127.3, 123.1, 119.3,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
14.4, 52.1, 47.6, 30.7, 26.1. HRMS (ESI): m/z calcd for C H N O Na [M+Na] : 321.1215,
1
7
18
2
3
found 321.1210.
Methyl 8-(cyclopropanecarboxamido)quinoline-5-carboxylate (2f)
1
White solid, mp 164 – 166 C, n-hexane/EtOAc (95/5), 65% (44 mg). H NMR (600 MHz,
CDCl ).δ 10.33 (s, 1H), 9.52 (d, J = 9.2 Hz, 1H), 8.84 (d, J = 3.3 Hz, 1H),
3
O
O
8
1
2
1
.74 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.6, 4.0 Hz,
H), 3.98 (s, 3H), 1.95 – 1.69 (m, 1H), 1.29 – 1.08 (m, 2H), 1.05 – 0.89 (m,
N
O
NH
1
3
1
H). C{ H} NMR (151 MHz, CDCl ) δ 172.9, 166.9, 148.2, 139.1, 137.9,
3
35.4, 133.2, 127.4, 123.2, 119.4, 114.5, 52.2, 16.6,. HRMS (ESI): m/z calcd
+
for C H N O [M+H] : 271.1083, found 271.1070.
1
5
15
2
3
Methyl 8-((3r,5r,7r)-adamantane-1-carboxamido)quinoline-5-carboxylate (2g)
1
White solid, mp 196 – 198 C, n-hexane/EtOAc (95/5), 61% (56 mg). H NMR (600 MHz,
CDCl ).δ 10.53 (s, 1H), 9.57 – 9.39 (m, 1H), 8.86 (d, J = 5.1 Hz, 1H),
3
O
O
8
.81 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 9.0, 4.4
Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 2.11 (d, J = 2.7 Hz, 6H), 1.814-1.671
N
1
3
1
O
NH
(m, 6H). C{ H} NMR (151 MHz, CDCl ) δ 177.3, 166.9, 148.3, 139.2,
3
138.5, 135.3, 133.2, 127.4, 123.1, 119.3, 114.5, 52.2, 42.6, 39.4, 36.6,
+
2
8.3. HRMS (ESI): m/z calcd for C H N O [M+H] : 365.1865, found
2
2
25
2
3
3
65.1861.
Methyl 8-benzamidoquinoline-5-carboxylate (2h)
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1
White solid, mp 175 – 177 C, n-hexane/EtOAc (95/5), 80% (61 mg). H NMR (600 MHz,
CDCl ) δ 11.05 (s, 1H), 9.58 – 9.47 (m, 1H), 8.90 (dd, J = 36.3, 5.4 Hz, 2H),
3
O
O
8.42 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 7.4 Hz, 2H), 7.66 – 7.53 (m, 4H), 3.99
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
(
s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 166.8, 165.8, 148.4, 139.1,
3
N
O
NH
1
38.5, 135.4, 134.8, 133.1, 132.4, 129.0, 127.5, 127.4, 123.3, 119.9, 114.7,
+
52.2. HRMS (ESI): m/z calcd for C H N O [M+H] : 307.1083.1603,
1
8
15
2
3
found 307.1078.
Methyl 8-(4-methylbenzamido)quinoline-5-carboxylate (2i)
1
White solid, mp 162 – 164 C, n-hexane/EtOAc (95/5), 80% (64 mg). H NMR (600 MHz,
CDCl ).δ 11.01 (s, 1H), 9.55 – 9.48 (m, 1H), 8.89 (dd, J = 31.7, 5.4 Hz, 2H),
3
O
O
8.40 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 8.6, 4.1 Hz,
13
1
1
H), 7.35 (d, J = 7.9 Hz, 2H), 3.99 (s, 3H), 2.46 (s, 3H). C{ H} NMR (151
N
O
NH
MHz, CDCl ) δ 166.9, 165.7, 148.3, 143.0, 139.2, 138.5, 135.4, 133.2, 132.,
3
129.7, 127.5, 127.4, 123.3, 119.6, 114.6, 52.2, 21.7. HRMS (ESI): m/z calcd
+
for C H N O [M+H] : 321.1239, found 321.1236.
1
9
17
2
3
Methyl 8-(4-methoxybenzamido)quinoline-5-carboxylate (2j)
1
White solid, mp 154 – 156 C, n-hexane/EtOAc (95/5), 77% (65 mg). H NMR (600 MHz,
CDCl ).δ 10.99 (s, 1H), 9.54 (dt, J = 8.7, 1.6 Hz, 1H), 8.92 (dd, J = 8.3,
3
O
O
1.5 Hz, 1H), 8.88 (dt, J = 4.0, 1.5 Hz, 1H), 8.42 (dd, J = 8.3, 1.4 Hz, 1H),
8
7
.07 (dd, J = 8.8, 1.0 Hz, 2H), 7.61 (ddd, J = 8.7, 4.1, 1.5 Hz, 1H), 7.07 –
N
O
NH
1
3
1
.04 (m, 2H), 3.99 (s, 3H), 3.91 (s, 3H). C{ H} NMR (151 MHz, CDCl )
3
δ 166.9, 165.3, 163.0, 148.3, 139.3, 138.5, 135.4, 133.2, 129.5, 127.5,
127.1, 123.3, 119.5, 114.5, 114.3, 55.7, 52.2. HRMS (ESI): m/z calcd for
O
+
C H N O Na [M+Na] : 359.1008, found 359.1016.
1
9
16
2
4
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Methyl 8-(4-fluorobenzamido)quinoline-5-carboxylate (2k).
1
White solid, mp 182 – 184 C, n-hexane/EtOAc (95/5), 78% (63 mg). H NMR (600 MHz,
CDCl ).δ 10.98 (s, 1H), 9.62 – 9.43 (m, 1H), 8.97 – 8.80 (m, 2H), 8.41 (d,
3
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 8.2 Hz, 1H), 8.18 – 8.04 (m, 2H), 7.61 (dd, J = 8.6, 4.0 Hz, 1H), 7.30
13
1
–
1
7.17 (m, 2H), 3.99 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 166.8,
3
N
O
NH
65.4 (d, 1J C-F = 252 Hz), 164.6, 148.4, 138.9, 138.4, 135.5, 133.1, 130.0
(d, 3J C-F = 9 Hz), 127.4, 123.3, 120.0, 116.2 (d, 2J C-F = 22.5 Hz), 114.7,
+
F
52.2. HRMS (ESI): m/z calcd for C H FN O Na [M+Na] : 347.0808,
1
8
13
2
3
found 347.0777
Methyl 8-(4-chlorobenzamido)quinoline-5-carboxylate (2l)
1
White solid, mp 184 – 186 C, n-hexane/EtOAc (95/5), 77% (66 mg). H NMR (600 MHz,
CDCl ).δ 10.98 (s, 1H), 9.52 (d, J = 9.2 Hz, 1H), 8.87 (dd, J = 11.3, 6.4 Hz,
3
O
O
2
4
H), 8.39 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 8.7,
1
3
1
.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 3.99 (s, 3H). C{ H} NMR (151
N
MHz, CDCl ) δ 166.8, 164.6, 148.4, 138.7, 138.7, 138.4, 135.5, 133.1,
O
NH
3
1
33.0, 129.3, 128.9, 127.3, 123.3, 120.0, 114.7, 52.2. HRMS (ESI): m/z
+
calcd for C H ClN O [M+H] : 341.0693, found 341.0684
1
8
14
2
3
Cl
Methyl 8-(4-bromobenzamido)quinoline-5-carboxylate (2m)
White solid, mp 196 – 198 C, n-hexane/EtOAc (95/5), 74% (71 mg). H
1
O
O
NMR (600 MHz, CDCl ).δ 11.02 (s, 1H), 9.54 (d, J = 9.5 Hz, 1H), 8.90 (dd,
3
J = 15.0, 6.5 Hz, 2H), 8.42 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.71
N
O
NH
13
1
(d, J = 8.1 Hz, 2H), 7.63 (dd, J = 8.6, 4.1 Hz, 1H), 4.00 (s, 3H). C{ H} NMR
(
151 MHz, CDCl ) δ 166.8, 164.8, 148.5, 138.8, 138.4, 135.5, 133.7, 133.1,
3
Br
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2
2
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6
1
32.3, 129.1, 127.4, 127.3, 123.4, 120.2, 114.8, 52.3. HRMS (ESI): m/z calcd for
+
C H BrN O [M+H] : 385.0188, found 385.0190.
1
8
14
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
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8
9
0
Methyl 8-(4-iodobenzamido)quinoline-5-carboxylate (2n)
1
White solid, mp 182 – 184 C, n-hexane/EtOAc (95/5), 70% (76 mg). H NMR (600 MHz,
CDCl ).δ 11.01 (s, 1H), 9.58 – 9.47 (m, 1H), 8.93 – 8.83 (m, 2H), 8.42 (d,
3
O
O
J = 8.2 Hz, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.81 (t, J = 4.9 Hz, 2H), 7.62 (dd,
1
3
1
J = 8.6, 4.0 Hz, 1H), 4.00 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
N
O
NH
166.8, 165.0, 148.4, 138.8, 138.4, 138.3, 135.5, 134.2, 133.1, 129.1, 127.4,
1
23.4, 120.2, 114.8, 99.6, 52.3. HRMS (ESI): m/z calcd for C H IN O Na
18 13 2 3
+
[
M+Na] : 454.9869, found 454.9864.
I
Methyl 8-(4-(trifluoromethyl)benzamido)quinoline-5-carboxylate (2o)
1
White solid, mp 177 – 179 C, 63% (59 mg). H NMR (600 MHz, CDCl ).δ 11.07 (s, 1H), 9.53
3
(d, J = 8.6 Hz, 1H), 8.89 (dd, J = 18.8, 6.0 Hz, 2H), 8.41 (d, J = 8.2 Hz, 1H),
O
O
8
1
1
.19 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 8.7, 4.1 Hz,
1
3
1
H), 4.00 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 166.7, 164.4, 148.5,
3
N
O
NH
38.5, 138.3, 138.0, 135.5, 133.9 (q, 2J C-F = 33 Hz), 133.0, 128.0, 127.4,
126.1 (q, 3J C-F = 3 Hz), 123.7 (q, 1J C-F = 272 Hz), 123.3, 120.4, 115.0, 52.3.
+
CF3
HRMS (ESI): m/z calcd for C H F N O [M+H] : 375.0957, found
19
14
3
2
3
3
75.0985 .
Methyl 8-(3-chlorobenzamido)quinoline-5-carboxylate (2p)
1
White solid, mp 161 – 163 C 70% (60 mg). H NMR (600 MHz, CDCl ).δ 10.99 (s, 1H), 9.57
3
– 9.47 (m, 1H), 8.89 (dd, J = 6.6, 4.7 Hz, 2H), 8.41 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 2.1 Hz,
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O
1
H), 7.95 (d, J = 7.9 Hz, 1H), 7.62 (dd, J = 8.6, 4.0 Hz, 1H), 7.58 (d, J = 8.6
1
3
1
Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 4.00 (s, 3H). C{ H} NMR (151 MHz,
N
O
NH
CDCl ) δ 166.8, 164.4, 148.5, 138.7, 138.4, 136.6, 135.5, 135.3, 133.0,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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5
6
0
1
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0
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4
5
6
7
8
9
0
1
32.4, 130.3, 128.0, 127.4, 125.5, 123.4, 120.2, 114.9, 52.3. HRMS (ESI):
Cl
+
m/z calcd for C H ClN O [M+H] : 341.0693, found 341.0689.
1
8
14
2
3
Methyl 8-(3-bromobenzamido)quinoline-5-carboxylate (2q)
1
White solid, mp 121 – 123 C (71%, 68 mg). H NMR (600 MHz, CDCl ).δ 10.99 (s, 1H), 9.57
3
– 9.48 (m, 1H), 8.93 – 8.85 (m, 2H), 8.42 (d, J = 8.7 Hz, 1H), 8.22 (d, J
O
O
=
2.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd,
1
3
1
J = 8.8, 4.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 4.00 (s, 3H). C{ H} NMR
(151 MHz, CDCl ) δ 166.8, 164.3, 148.5, 138.7, 138.4, 136.8, 135.5,
N
O
NH
3
1
35.3, 133.0, 130.9, 130.6, 127.4, 125.9, 123.4, 123.3, 120.6, 114.9, 52.3.
Br
+
HRMS (ESI): m/z calcd for C H BrN O [M+H] : 385.0188, found
1
8
14
2
3
3
85.0190.
Methyl 8-(3-iodobenzamido)quinoline-5-carboxylate (2r)
1
White solid, mp 174 – 176 C, (67%, 72 mg) H NMR (600 MHz, CDCl ). δ 10.94 (s, 1H), 9.60
3
–
9.39 (m, 1H), 8.88 (dd, J = 6.3, 3.7 Hz, 2H), 8.39 (d, J = 8.5 Hz, 2H), 8.01
O
O
(d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.61 (dd, J = 8.9, 4.3 Hz, 1H),
1
3
1
7
.36 – 7.20 (m, 1H), 3.99 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
N
O
NH
166.8, 164.1, 148.5, 141.2, 138.6, 138.4, 136.7, 135.5, 133.0, 130.6, 127.3,
1
26.45, 123.3, 120.2, 114.9, 94.8, 52.3. HRMS (ESI): m/z calcd for
I
+
C H IN O Na [M+Na] : 454.9869, found 454.9859.
1
8
13
2
3
Methyl 8-(3-methylbenzamido)quinoline-5-carboxylate (2s)
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White solid, mp 143 – 145 C, (76%, 61 mg). H NMR (600 MHz, CDCl ).δ 11.02 (s, 1H),
3
9
.58 – 9.46 (m, 1H), 8.92 (dd, J = 31.0, 6.7 Hz, 2H), 8.42 (d, J = 8.1 Hz,
O
O
1H), 7.95 – 7.83 (m, 2H), 7.61 (dd, J = 8.7, 4.1 Hz, 1H), 7.48 – 7.40 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
2
H), 4.00 (s, 3H), 2.49 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 166.9,
3
N
O
NH
166.1, 148.4, 139.2, 139.0, 138.5, 135.4, 134.8, 133.2, 128.9, 128.3, 127.4,
124.5, 123.3, 119.8, 114.8, 52.2, 21.7. HRMS (ESI): m/z calcd for
+
C H N O [M+H] : 321.1239, found 321.1238
1
9
17
2
3
Methyl 8-(2-fluorobenzamido)quinoline-5-carboxylate (2t)
1
White solid, mp 193 – 195 C, (56%, 46 mg ). H NMR (600 MHz, CDCl ). δ 11.46 (s, 1H),
3
9
.51 (dd, J = 8.7, 1.6 Hz, 1H), 8.97 (d, J = 8.3 Hz, 1H), 8.89 (dd, J = 4.1, 1.6
O
O
Hz, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.22 (td, J = 7.8, 1.8 Hz, 1H), 7.68 – 7.51
13
1
(
m, 2H), 7.35 (td, J = 7.8, 1.0 Hz, 1H), 7.26 (m, 1H), 4.00 (s, 3H). C{ H}
N
O
NH
1
NMR (151 MHz, CDCl ) δ 166.9, 162.1, 160.8 (d, J
= 249 Hz), 148.5,
C-F
3
F
139.3, 138.5, 135.25, 134.1 (d, 3J C-F = 10.5 Hz), 133.0, 132.3, 127.4, 125.1,
23.3, 121.8 (d, 2J C-F = 27 Hz), 120.2, 116.6 (d, 2J C-F = 24 Hz), 115.4, 52.2.
1
+
HRMS (ESI): m/z calcd for C H FN O [M+H] : 325.0988, found 325.0989.
1
8
14
2
3
Methyl 8-(2-methylbenzamido)quinoline-5-carboxylate (2u)
1
White solid, mp 153 – 155 C, (70%, 56 mg). H NMR (600 MHz, CDCl ).δ 10.53 (s, 1H),
3
9.59 – 9.46 (m, 1H), 8.94 (d, J = 8.2 Hz, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.42 (d, J = 8.1 Hz,
O
O
1
7
H), 7.70 (d, J = 7.3 Hz, 1H), 7.59 (dd, J = 9.0, 4.3 Hz, 1H), 7.43 (t, J =
1
3
1
.6 Hz, 1H), 7.40 – 7.29 (m, 2H), 4.00 (s, 3H), 2.61 (s, 3H). C{ H} NMR
N
(
151 MHz, CDCl ) δ 168.5, 166.9, 148.3, 139.2, 138.3, 137.1, 136.2,
3
O
NH
135.4, 133.1, 131.7, 130.8, 127.5, 127.4, 126.3, 123.3, 120.0, 114.7, 52.3,
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0.4. HRMS (ESI): m/z calcd for C H N O [M+H] : 321.1239, found 321.1237.
1
9
17
2
3
Methyl 8-(3,4,5-trimethoxybenzamido)quinoline-5-carboxylate (2v)
1
White solid, mp 198 – 200 C, (66%, 65 mg). H NMR (600 MHz, CDCl ).δ 10.96 (s, 1H),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
.55 (d, J = 8.3 Hz, 1H), 8.89 (dd, J = 16.2, 6.2 Hz, 2H), 8.44 (d, J = 8.2
O
O
Hz, 1H), 7.62 (dd, J = 8.7, 4.1 Hz, 1H), 7.31 (s, 2H), 4.00 (s, 9H), 3.95 (s,
N
13
1
3
1
H). C{ H} NMR (151 MHz, CDCl ) δ 166.9, 165.6, 153.6, 148.4,
3
O
NH
39.0, 138.5, 135.5, 133.2, 130.3, 127.5, 123.3, 119.9, 114.7, 105.0, 61.2,
O
O
+
56.6, 52.3. HRMS (ESI): m/z calcd for C H N O [M+H] : 397.1400,
2
1
21
2
6
O
found 397.1384.
Methyl 8-aminoquinoline-5-carboxylate (2w)
1
White solid, mp 170 – 172 C, (76%, 38 mg). H NMR (600 MHz, CDCl ).δ 9.51 (d, J = 7.6
3
Hz, 1H), 8.80 – 8.69 (m, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.6,
O
O
1
3
1
4.0 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.56 (s, 2H), 3.93 (s, 3H). C{ H}
NMR (151 MHz, , CDCl ) δ 167.4, 149.0, 147.2, 135.1, 134.0, 128.7,
3
N
NH2
1
23.2, 113.2, 107.6, 107.5, 51.7. HRMS (ESI): m/z calcd for C H N O
11 11 2 2
+
[M+H] : 203.0821, found 203.0815
Methyl 8-(thiophene-2-carboxamido)quinoline-5-carboxylate (2x)
1
White solid, mp 164 – 166 C, (70%, 55 mg). H NMR (600 MHz, CDCl ).δ 10.90 (s, 1H),
3
9
.62 – 9.45 (m, 1H), 8.93 – 8.76 (m, 2H), 8.41 (d, J = 8.1 Hz, 1H), 7.87 (d,
O
O
J = 3.9 Hz, 1H), 7.69 – 7.58 (m, 2H), 7.24 – 7.16 (m, 1H), 3.99 (s, 3H).
1
3
1
C{ H} NMR (151 MHz, CDCl ) δ 166.9, 160.3, 148.4, 139.8, 138.8,
3
N
O
NH
138.2, 135.5, 133.1, 131.7, 129.1, 128.2, 127.4, 123.3, 119.9, 114.7, 52.2.
S
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HRMS (ESI): m/z calcd for C H N O S [M+H]: 313.0647, found 313.0625.
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6
13
2
3
Methyl 8-(1-naphthamido)quinoline-5-carboxylate (2y)
1
semi solid, (66%, 59 mg). H NMR (600 MHz, CDCl ).δ 10.73 (s, 1H), 9.53 (d, J = 8.8 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H), 9.05 (d, J = 8.3 Hz, 1H), 8.77 (d, J = 3.8 Hz, 1H), 8.53 (d, J = 8.3 Hz,
O
O
1H), 8.47 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.97 – 7.90 (m, 2H),
13
1
7
1
1
.64 – 7.54 (m, 4H), 4.01 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
N
O
NH
68.1, 166.9, 148.4, 139.3, 138.3, 135.4, 134.2, 134.0, 133.1, 131.7, 130.4,
28.6, 127.6, 127.4, 126.8, 125.9, 125.6, 125.0, 123.3, 120.1, 114.9, 52.3.
+
HRMS (ESI): m/z calcd for C H N O [M+H] : 357.1239, found 357.1215.
2
2
17
2
3
Methyl 8-benzamido-2-methylquinoline-5-carboxylate (2z)
1
White solid, mp 198 – 200 C, (75%, 60 mg). H NMR (600 MHz, CDCl ).δ 11.13 (s, 1H),
3
9
1
.39 (d, J = 9.1 Hz, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 8.1 Hz,
H), 8.11 – 8.08 (m, 2H), 7.60 (dq, J = 15.2, 7.6 Hz, 3H), 7.48 (d, J = 8.5
O
O
1
3
1
Hz, 1H), 3.99 (s, 3H), 2.79 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
N
O
NH
1
1
67.0, 165.7, 157.4, 138.4, 138.0, 135.4, 135.0, 132.3, 132.1, 129.1,
27.5, 125.6, 124.1, 119.8, 114.7, 52.2, 25.4. HRMS (ESI): m/z calcd for
+
C H N O [M+H] : 321.1239, found 321.1236.
1
9
17
2
3
Methyl 8-benzamido-3-iodoquinoline-5-carboxylate (2aa)
1
White solid, mp 180 – 182 C, (71%, 77 mg). H NMR (600 MHz, CDCl ).δ 10.79 (s, 1H),
3
1
1
0.00 – 9.90 (m, 1H), 9.03 – 8.88 (m, 2H), 8.39 (td, J = 8.0, 3.5 Hz,
O
O
1
3
1
H), 8.05 (d, J = 7.9 Hz, 2H), 7.65 – 7.53 (m, 3H), 3.99 (s, 3H). C{ H}
I
NMR (151 MHz, CDCl ) δ 166.4, 165.7, 153.8, 143.3, 139.3, 136.6,
N
3
O
NH
1
34.6, 134.0, 132.5, 129.1, 128.8, 127.5, 118.7, 115.2, 93.3, 52.3.
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HRMS (ESI): m/z calcd for C H IN O Na [M+Na] : 454.9869, found 454.9859.
1
8
13
2
3
Methyl 8-benzamido-6-methoxyquinoline-5-carboxylate (2ab)
1
White solid, mp 148 – 150 C, (76%, 64 mg). H NMR (600 MHz, CDCl ).δ 10.94 (s, 1H),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
.95 (s, 1H), 8.73 – 8.69 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.5
O
O
Hz, 2H), 7.60 (dt, J = 26.8, 7.5 Hz, 3H), 7.51 – 7.47 (m, 1H), 4.09 (s, 3H),
O
O
13
1
4
.02 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 167.4, 165.9, 157.1,
3
N
NH
1
46.3, 138.2, 134.7, 133.9, 133.3, 132.4, 129.1, 127.5, 126.8, 123.3,
110.0, 103.8, 57.0, 52.5. HRMS (ESI): m/z calcd for C H N O Na
1
9
16
2
4
+
[
M+Na] : 359.1008, found 359.1016.
Methyl 8-benzamido-6-methylquinoline-5-carboxylate (2ac)
1
White solid, mp 85 – 87 C, (77%, 62 mg). H NMR (600 MHz, CDCl ).δ 10.83 (s, 1H), 8.85
3
(
s, 1H), 8.80 (d, J = 4.6 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5
O
O
Hz, 2H), 7.58 (dt, J = 14.9, 7.1 Hz, 3H), 7.51 (dd, J = 8.6, 4.1 Hz, 1H), 4.03
13
1
(
s, 3H), 2.63 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 168.8, 165.7,
3
N
O
NH
1
1
47.8, 137.9, 137.1, 136.1, 135.0, 134.0, 132.2, 129.0, 127.5, 125.9, 123.1,
+
22.7, 118.9, 52.3, 21.6. HRMS (ESI): m/z calcd for C H N O [M+H] :
19 17
2
3
3
21.1239, found 321.1222
Methyl 8-benzamido-6-fluoroquinoline-5-carboxylate(2ad)
1
White solid, mp 130 – 132 C, (60%, 48.6 mg). H NMR (600 MHz, CDCl ) δ 10.90 (s, 1H),
3
8
1
.81 (d, J = 7.8 Hz, 1H), 8.76 (d, J = 3.0 Hz, 1H), 8.72 (d, J = 12.7 Hz,
O
O
1
3
1
H), 8.01 (d, J = 7.2 Hz, 2H), 7.52 (m, 4H), 3.96 (s, 3H). C{ H} NMR
F
1
(151 MHz, CDCl ) δ 165.8, 165.1, 160.7 (d, J = 257 Hz), 147.7, 135.7,
3
C-F
N
134.8 (d, 3J C-F = 6 Hz) , 134.4, 132.6, 130.3, 129.1, 128.6, 127.6, 123.8,
O
NH
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1
07.8 (d, 2J C-F = 15 Hz), 106.8 (d, 2J C-F = 33 Hz), 52.7. HRMS (ESI): m/z calcd for
+
C H FN O Na [M+Na] : 347.0808, found 347.0783
1
8
13
2
3
Methyl 8-benzamido-6-chloroquinoline-5-carboxylate (2ae)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
White solid, mp 105 – 107 C, (73%, 62 mg). H NMR (600 MHz, CDCl ) δ 10.73 (s, 1H),
3
8.95 (d, J = 1.6 Hz, 1H), 8.79 (d, J = 4.2 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H),
O
O
8
3
.00 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.3 Hz, 4H),
Cl
1
3
1
.99 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 166.6, 165.7, 148.7,
3
N
O
NH
137.0, 136.9, 134.5, 133.7, 132.5, 130.3, 129.1, 128.62, 127.5, 126.2,
+
1
23.5, 117.5, 53.0. HRMS (ESI): m/z calcd for C H ClN O [M+H] :
1
8
14
2
3
3
41.0693, found 341.0677
Methyl 8-benzamido-6-bromoquinoline-5-carboxylate (2af)
1
White solid, mp 120 – 122 C, (71%, 68 mg). H NMR (600 MHz, ) δ 10.78 (s, 1H), 9.19 (s,
1H), 8.88 (d, J = 4.9 Hz, 1H), 8.22 (d, J = 9.5 Hz, 1H), 8.07 (d, J = 7.3 Hz,
O
O
13
1
Br
2H), 7.62 – 7.60 (m, 1H), 7.59 – 7.55 (m, 3H), 4.07 (s, 3H). C{ H} NMR
(151 MHz, ) δ 167.27, 165.66, 148.80, 137.11, 136.77, 134.50, 133.81,
N
O
NH
1
32.50, 130.33, 129.09, 128.63, 127.51, 126.35, 123.45, 120.17, 53.00.
+
For C H BrN O Na [M+Na] : 407.0007, found 407.9985
1
8
13
2
3
Ethyl 8-benzamidoquinoline-5-carboxylate (5a)
1
White solid, mp 86 – 88 C, (32%, 24 mg). H NMR (600 MHz, CDCl ) δ 11.06 (s, 1H), 9.54
3
O
O
(d, J = 9.1 Hz, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 3.3 Hz, 1H), 8.43
d, J = 8.3 Hz, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.64 – 7.53 (m, 4H), 4.46 (q, J
(
N
13
1
= 7.1 Hz, 2H), 1.47 (t, J = 7.3 Hz, 3H). C{ H} NMR (151 MHz, ) δ 166.5,
O
NH
1
65.8, 148.3, 139.0, 138.5, 135.5, 134.9, 133.0, 132.4, 132.0, 129.0, 127.5,
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23.2, 121.8, 120.3, 114.7, 61.2, 14.6. HRMS (ESI): m/z calcd for C H N O [M+H] :
19 17 2 3
21.1161, found 321.1250.
tert-Butyl 8-(2-methylbenzamido)quinoline-5-carboxylate (5d)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
White solid, mp 110 – 112 C, (25%, 23 mg). H NMR (600 MHz, CDCl ) δ 10.50 (s, 1H),
3
9.49 (d, J = 8.4 Hz, 1H), 8.92 (d, J = 8.2 Hz, 1H), 8.78 (d, J = 3.4 Hz, 1H),
O
O
8
1
.33 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.56 (dd, J = 8.7, 4.0 Hz,
H), 7.42 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 11.5, 7.5 Hz, 2H), 2.61 (s, 3H),
N
1
3
1
1.68 (s, 9H). C{ H} NMR (151 MHz, CDCl ) δ 168.5, 165.9, 148.2, 138.6,
3
O
NH
1
1
38.4, 137.0, 136.3, 135.5, 132.7, 131.7, 130.8, 127.5, 127.3, 126.2, 123.0,
22.1, 114.7, 81.7, 28.5, 20.4. HRMS (ESI): m/z calcd for C H N O Na
2
2
22
2
3
+
[M+Na] : 385.1528, found 385.1539.
Product Spectral characterization data of 8-aminoquinolinyl sulphonamides:
Methyl 8-(4-methylphenylsulfonamido)quinoline-5-carboxylate (4a)
The pure compound 4a was isolated by flash chromatography (n-hexane/EtOAc ,90/10) yielded
1
white solid, mp 136 – 138 C, (74%, 66mg). H NMR (600 MHz,
O
O
CDCl ).δ 9.61 (s, 1H), 9.42 – 9.36 (m, 1H), 8.82 – 8.74 (m, 1H), 8.24 (d,
3
J = 8.8 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.54
(dd, J = 8.7, 4.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 3.94 (s, 3H), 2.31 (s,
N
O
S
O
NH
13
1
3
1
H). C{ H} NMR (151 MHz, CDCl ) δ 166.6, 148.7, 144.4, 138.4,
3
37.9, 136.3, 135.3, 132.3, 129.8, 127.5, 127.4, 123.5, 120.0, 112.0, 52.2,
+
21.6. HRMS (ESI): m/z calcd for C H N O SK [M+K] : 395.0468, found 395.0482.
1
8
16
2
4
Methyl 8-(phenylsulfonamido)quinoline-5-carboxylate (4b)
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