One-Pot Reductive Alkylation of 2,4-Dihydroxy Quinolines and Pyridines

Article abstract of DOI:10.1021/acs.joc.1c00496

A one-pot, Hantzsch ester-mediated Knoevenagel condensation-reduction reaction has been developed for alkylation of a wide range of substituted 2,4-quinoline diols and 2,4-pyridine diols with aldehydes. The process is operationally simple to perform, scalable, and provides highly useful C-3 alkylated quinoline and pyridine diols in yields of 58-92%. The alkylation products can be converted to 2,4-dihaloquinoline and pyridine substrates for further functionalization.

Full text of DOI:10.1021/acs.joc.1c00496

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One-Pot Reductive Alkylation of 2,4-Dihydroxy Quinolines and
Pyridines
Pratik R. Chheda,* David A. Kummer, Rachel T. Nishimura, Kelly J. McClure,
and Hariharan Venkatesan
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ABSTRACT: A one-pot, Hantzsch ester-mediated Knoevenagel
condensation−reduction reaction has been developed for alkylation
of a wide range of substituted 2,4-quinoline diols and 2,4-pyridine
diols with aldehydes. The process is operationally simple to
perform, scalable, and provides highly useful C-3 alkylated
quinoline and pyridine diols in yields of 58−92%. The alkylation
products can be converted to 2,4-dihaloquinoline and pyridine
substrates for further functionalization.
using Hantzsch ester as a reducing agent for direct alkylation
of activated methylene-containing scaffolds.13 However, these
reports are limited to aliphatic activated methylene-containing
scaffolds such as Meldrum’s acid, malononitrile, ethyl 2-
INTRODUCTION
■
Functionalized quinolines and pyridines are important
nitrogen-containing heterocycles, forming key structural
units in several active pharmaceuticals,1 natural products,2
and agrochemicals.3 Additionally, highly functionalized quino-
lines and pyridines are also important synthetic and
functional intermediates and serve as useful ligands in metal
catalysis.4 Conventionally, pyridines are synthesized de novo
by either cycloaddition of amines and carbonyl compounds,5
multicomponent reactions,6 or metal-catalyzed cycloaddi-
tions,7 while quinolines are constructed from anilines
following classical annulation reactions (Combes synthesis,
Skraup synthesis, Conard−Limpach synthesis, Gould−Jacobs
reaction, etc.),8 all of which utilize harsh reaction conditions
and have limited potential to introduce diversity.
Alternatively, electron-rich quinolines and pyridines can be
directly functionalized by substitution reactions9 or by
directing-group-mediated metalation-trapping reactions.10 Re-
cently, transition-metal-catalyzed C−H activation reactions
have been developed, but only a few systems selectively
functionalize the C-3 position in quinolines and pyridines.11
Driven by our laboratory’s need to explore substitutional
variation of the C-3-benzyl group on a series of RAR-related
orphan receptor gamma t modulators, we sought to develop
an operationally simple and scalable synthetic method to
functionalize the C-3 position of 6-bromoquinoline (1a).1b
Toward this end, we envisioned a one-pot, reductive
alkylation reaction cascade. Recently, there have been several
reports of single-step reductive alkylation reactions of
activated methylene-containing aliphatic scaffolds. Ramach-
ary’s group developed a series of proline-catalyzed reactions
using diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy-
late (Hantzsch ester) as a reducing agent (Scheme 1).12
Similarly, Wang et al. reported a base-catalyzed approach
cyanoacetate, and 2-(4-nitrophenyl)acetonitrile.13 Alterna-
14
́
tively, methods reported by Borbely et al. and Popowycz
et al.15 utilize triethyl amine formic acid and a two-step
method for C-3 alkylation of 2,4-dihydroxyquinoline to yield
the coupled products, respectively. Herein, we report a
simple, scalable method to construct 3-substituted quinolines
by coupling of 2,6-dihydroxy quinolines and aldehydes
through a condensation−reduction sequence employing the
Hantzsch ester as a mild hydride source. The developed
reaction is robust, operationally simple, scalable, and has a
wide substrate scope with successful C-3 functionalization of
pyridines in addition to quinolines. Optimization of the
reaction parameters is presented followed by exploration of
the aldehyde, quinoline, and pyridine substrate scope.
RESULTS AND DISCUSSION
■
Initial screening of the reaction conditions was performed for
C-3 alkylation of 6-bromoquinoline-2,4-diol (1a) with 4-
methylbenzaldehyde (2a) in the presence of 1 equiv of
Hantzsch ester (3) and included variations of the solvent,
temperature, base, and reaction time (Table 1). The reaction
was optimized to provide high yield of 4a and avoid the
Received: March 1, 2021
https://doi.org/10.1021/acs.joc.1c00496
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© XXXX American Chemical Society
A

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Scheme 1. General Methods for Reductive Alkylation
Table 1. Optimization of Reaction Conditions
b
entry
solvent
base
temperature (°C)
time (h)
4a:5a LCMS A%
yield (%)
1
2
3
4
5
6
7
8
ACN
80
40
100
65
18
18
18
18
18
3
3
3
3
8
3
3
2
18
2
NR
NR
NR
trace of 4a
trace of 4a
2:1
5:1
5:1
13:1
5:1
1:6
1:6
100% 5a
>30:1
>50:1
DCM
water
MeOH
EtOH
DMSO
DMA
NMP
DMF
DMF
DMF
DMF
80
c
c
c
100
100
100
100
80
80
80
80
80
34
74
81
64
69
9
10
11
12
13
14
15
d
TEA
d
K2CO3
e
DMF
pyridine
pyridine
5a-99
86
83
100
a
General reaction conditions: 1a (0.21 mmol), 2a (0.21 mmol), and 3 (0.21 mmol) in 2 mL of solvent at a specific temperature for a specific time.
b
c
d
Ratio of peak area of 4a:5a based on LCMS. Isolated product is a mixture of 4a and 5a. Reaction using 1.2 equiv (0.25 mmol) of the respective
e
base. In the absence of Hantzsch ester.
B
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a b c
, ,
Table 2. Scope of C-3 Alkylation with Aldehydes 2
a
b
General reaction conditions: 1a (2.10 mmol), 2 (2.10 mmol), and 3 (2.10 mmol) in 7 mL of pyridine at 100 °C. Used 2 equiv of aldehyde.
c
Yield over two steps.
formation of undesired Michael adduct 5a. Reactions in
°C gave homogeneous reaction mixtures with complete
consumption of 1a in 3 h but led to the formation of
substantial amounts of undesired bis-addition product 5a
(entries 6−8). The isolation and purification of the products
formed were a challenge due to their low solubility, high
polarity, and similar solubility to the reduced Hantzsch ester
pyridine (HEP) byproduct formed in the reaction. Surpris-
ingly, reactions in dimethylformamide (DMF) had better
acetonitrile, dichloromethane, or water under refluxing
conditions after 18 h did not lead to the formation of any
product, presumably due to the poor solubility of 1a in these
solvents. Reaction in refluxing methanol or ethanol yielded
only trace amounts of product after 18 h with the recovery of
1a. Reaction in higher boiling solvents such as dimethyl
sulfoxide, dimethylacetamide, or N-methyl pyrrolidine at 100
C
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a
Table 3. Scope of C-3 Alkylation with Quinolines and Pyridines
a
General reaction conditions: 6 (2.10 mmol), 2a (2.10 mmol), and 3 (2.10 mmol) in 7 mL of pyridine at 100 °C.
overall reaction profiles with lower amounts of undesired 5a
with increasing temperatures. Addition of either triethyl
amine or potassium carbonate to reactions run in DMF at 80
°C favored the formation of 5a over 4a (entries 12 and 13).
The omission of Hantzsch ester from the reaction was carried
out in DMF and gave complete conversion of 1a to 5a (entry
13). A significant improvement in yield and ease of isolation
was achieved when reactions were run in pyridine. Increasing
the temperature from 80 to 100 °C gave complete
consumption of 1a in 2 h with the almost exclusive
formation of 4a over 5a (entry 15). Although unverified, a
possible explanation for this selectivity is the higher rate of
reduction of the Knoevenagel adduct with Hantzsch ester in
pyridine as compared to that of the Michael addition of the
second molecule of 1a. Additionally, the desired product 4a
crashed out of pyridine upon cooling and the residual
Hantzsch ester and HEP were easily eliminated via trituration
with diethyl ether.
electron-withdrawing substituents such as nitro (4c, 4k, 4n),
methyl ester (4d), trifluoromethyl (4e), nitrile (4g),
carboxylic acid (4f), and bromide (4h, 4m, 4p) or
electron-donating substituents such as methyl (4a, 4q),
methoxy (4i, 4l, 4o), and dimethylamino (4j) at the para-,
meta-, and ortho-positions of the aryl ring furnished the C-3
alkylated quinolines in good yields (62−92%). Reaction of 1a
with sterically hindered 2,6-dimethylbenzaldehyde required
the addition of 2 equiv of the aldehyde and furnished the
product 4r in a 73% yield. Nitrogen-containing hetero-
aromatic aldehydes like pyridine carbaldehydes (4s, 4t, 4u),
pyrazine-2-carbaldehyde (4v), pyridazine-2-carbaldehyde
(4w), and 4-methylimidazole-5-carbaldehyde (4x) were also
well tolerated and furnished the desired products in good
yields (76−89%). In addition, other heteroaromatic aldehydes
like thiophene-2-carbaldehyde (4y) and furan-2-carbaldehyde
(4z) furnished the desired products in 69 and 79% yields,
respectively. Next, we looked at aliphatic and heteroaliphatic
aldehydes such as N-Boc piperidine-4-carbaldehyde (4aa), N-
boc azetidine-3-carbaldehyde (4ab), tetrahydropyran-4-carbal-
dehyde (4ac), cyclohexane-4-carbaldehyde (4ad), cyclo-
With optimized reaction conditions in hand, the aldehyde
(Table 2) and quinoline (or pyridine; Table 3) substrate
scopes were examined. Aromatic aldehydes having either
D
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propane carbaldehyde (4ae), isobutyraldehyde (4ag), and
trifluoropropanal (4af), all of which furnished the desired
products in good yields (59−86%). The yield for reaction
with isobutyraldehyde (4ag) was low because the C-3
alkylated product was sparingly soluble in ethyl ether leading
to loss during purification. Finally, product 4ah was obtained
as the dichloroquinoline adduct after treatment of the crude
reaction mixture with phosphorus oxychloride at 80 °C due
to the challenges with isolation of the intermediate quinoline
diol; the yield was 77% after chromatographic purification
over the two steps.
We investigated substitutions on the quinoline ring and
expanded the scope to commercially available 4-hydroxycou-
marin, 4-hydroxythiocoumarin, and variably substituted 2,4-
dihydroxypyridines, as summarized in Table 3. Quinolines
lacking any substituents (7a) or having electron-donating
substituents like methoxy (7b, 7e), methyl (7c, 7f), and
electron-deficient halogen substituents (7d, 4a) at various
positions furnished C-3 alkylated products in good yields
(58−80%). Reaction of 1,8-naphthyridine-2,4-diol with 2a
furnished the product 7g in an 84% yield. Quinoline having
an appended saturated ring like in tetrahydro-2,4-dihydrox-
yquinoline and 6,7-dihydro-5H-cyclopenta [b]pyridine-2,4-
diol furnished the desired products 7j and 7k in 85 and
86% yields, respectively. In addition, other heteroatom-
containing diols, 4-hydroxycoumarin and 4-hydroxythiocou-
marin, furnished the C-3 alkylated products 7e and 7f in an
81% yield, respectively. This chemistry was also applied to
substituted 2,4-pyridine diols having variable substitutions
(7l, 7m, 7n, 7o, 7p) to give the C-3 alkylated products in
good yields (74−92%). As expected, reaction with either
quinolin-2-ol or quinolin-4-ol did not yield any C-3 alkylated
product. A multigram scale reaction of 1a and 6l with 2a
gave the desired C-3 alkylated products 4a and 7l in 90%
(Table 2) and 84% (Table 3) yields, respectively.
carried out in methanol furnished product 12, albeit in a low
yield (16%).17 Additionally, the reaction of 8c with a
nitrogen nucleophile dimethyl amine gave an easily separable
mixture of C-2 and C-4 monosubstituted products 13 and 14
in 14 and 83% yields, respectively.
The dichlorinated intermediates were further function-
alized, as depicted in Scheme 4. The C-4 chlorine on
quinoline 8b and pyridine 8c was selectively cyanated using
0.5 equiv of zinc cyanide under palladium catalysis to furnish
the C-4 cyanated products 15 and 19 in 88 and 71% yields,
respectively.18 Alternatively, the reaction of 8b with 2 equiv
of zinc cyanide under the same reaction conditions furnished
the bis-cyanated product 16 in a 97% yield.18 Also, the C-2
chloride of quinoline 8b was substituted with azide and
cyclized with N-1 nitrogen to form a tetrazole to furnish
product 18 in an 87% yield. Finally, using a recent literature
report19 for regioselective cross coupling of halogenated
pyridines by variation of reaction solvent, the C-2 vs C-4
chloride of pyridine 8c was selectively coupled with methyl
magnesium bromide to furnish either the C-2 methylated
product 20 or the C-4 methylated product 21 in 83 and 26%
yields, respectively.
CONCLUSIONS
■
In conclusion, we report a robust and scalable one-pot
method for C-3 alkylation of variably substituted 2,4-
dihydroxy quinolines and pyridines with broad substrate
scope. The reaction proceeds under catalyst-free conditions in
as little as 2 h and avoids chromatography by employing a
simple purification by trituration with diethyl ether. We
demonstrate that the resulting C-3 alkylated products can be
easily derivatized to obtain a variety of highly functionalized
and versatile synthetic intermediates.
EXPERIMENTAL SECTION
■
Treatment of C-3 alkylated-2,4-dihydroxy quinolines and
pyridines with POCl3 under refluxing reaction conditions
yielded the corresponding C-3 alkylated-2,4-dichloroquino-
lines and pyridines (Scheme 2).16 2,6-Dichlorinated quino-
General Information. All commercially available reagents
(including diols from series 1 and 6 and aldehydes from series 2)
and solvents were purchased from Sigma-Aldrich and used directly
without further purification unless otherwise noted. In instances
where degassed solvents were used, it was accomplished by bubbling
nitrogen gas through the solution for 30 minutes. Reactions were
monitored either by thin-layer chromatography (carried out on silica
plates, silica gel 60 F254, Merck) and visualized under UV light or by
LCMS on an Agilent 1260 Infinity instrument. Flash chromatog-
raphy was performed using the Telodyne Isco Combiflash Rf
Scheme 2. Chlorination of C-3 Alkylated Diols
instrument using RediSep gold Rf silica columns. H NMR and 13C
1
NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker
1
Avance spectrometer operating at 500 MHz for H NMR and 126
MHz for 13C{1H} NMR at ambient temperature. All peaks are
reported in ppm on a scale downfield from TMS and using the
residual solvent peak in CDCl3 (H δ = 7.26 and C δ = 77.16 ppm)
or DMSO-d6 (H δ = 2.50 and C δ = 39.52 ppm) or TMS (δ = 0.0)
1
as an internal standard. Data for H NMR are reported as follows:
chemical shift (ppm, scale), multiplicity (s =singlet, d = doublet, t =
triplet, q = quartet, m = multiplet and/or multiplet resonances, dd =
double of doublets, dt = double of triplets, bs = broad singlet),
coupling constant (Hz), and integration. Data for 13C NMR are
reported in terms of chemical shift (ppm, scale), multiplicity, and
coupling constant (hertz). All high-resolution mass spectra (HRMS)
were measured on an Agilent Technologies 6200 series mass
spectrometer using electrospray ionization (ESI) time-of-flight
(TOF). Melting points were measured on a Stanford Research
System’s OptiMelt melting point apparatus.
lines and pyridines are highly functionalized, versatile
synthetic intermediates amenable to further derivatization.
Schemes 3 and 4 highlight examples of this chemistry.
The chlorine atom at the C-2 position of 8a was selectively
substituted by either an oxygen (sodium methoxide) or
nitrogen nucleophile (azetidine) to furnish products 9 and 10
in 78 and 85% yields, respectively (Scheme 3). Similarly, the
reaction of dichlorinated pyridine 8c with sodium methoxide
in toluene displaced the C-2 chlorine atom to furnish product
11 in a 91% yield.17 Alternatively, the same transformation
General Experimental Procedure A: Product Precipitates
out of Pyridine Solvent. Methyl 4-((6-Bromo-2,4-dihydroxyqui-
nolin-3-yl)methyl)benzoate (4d). A stirring, heterogeneous mixture
E
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Scheme 3. Functionalization of 2,4-Dichloroquinoline 8a and Pyridine 8c
containing 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv),
methyl 4-formylbenzoate (348 mg, 2.1 mmol, 1 equiv), and diethyl
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (533 mg, 2.1
mmol, 1 equiv) in pyridine (7 mL) was warmed to 100 °C using
a heating block fitted on a stir plate. During warming, the solids
dissolved. After 2 h, the reaction flask was allowed to cool to room
temperature whereupon the solid crashed out of the solution.
Diethyl ether was added and then the heterogeneous mixture was
sonicated. After 5 min, the solids were collected by filtration with
suction and then washed with additional ether. The solids were
transferred to a glass vial and dried in a vacuum oven (<1 mmHg,
75 °C, 2 days) to provide compound 4d as an off-white solid (673
mg, 83%). Mp 322−324 °C; 1H NMR (500 MHz, DMSO-d6) δ
11.52 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H),
7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J
= 8.7 Hz, 1H), 4.00 (s, 2H), 3.82 (s, 3H); 13C{1H} NMR (126
MHz, DMSO-d6) δ 166.7, 163.7, 157.9, 147.1, 137.2, 133.1, 129.5,
129.0, 127.5, 125.6, 117.8, 117.7, 113.3, 111.3, 52.4, 29.3; HRMS
(ESI) m/z: [M + H]+ calcd for C18H15BrNO4 388.0184; found
388.0192.
General Experimental Procedure B: Product Does Not
Precipitate out of Pyridine Solvent. 5-Chloro-3-(4-
methylbenzyl)pyridine-2,4-diol (7m). A stirring, heterogeneous
mixture containing 5-chloropyridine-2,4-diol (303 mg, 2.08 mmol,
1 equiv), 4-methylbenzaldehyde (0.245 mL, 2.1 mmol, 1 equiv), and
diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (528 mg,
2.1 mmol, 1 equiv) in pyridine (7 mL) was warmed to 100 °C using
a heating block fitted on a stir plate. During warming, the solids
dissolved. After 4 h, the reaction flask was allowed to cool to room
temperature whereupon pyridine was removed by rotary evaporation
resulting in a sticky semisolid. Diethyl ether was added to the
residue, and the mixture was sonicated giving a solid. The solids
were collected by filtration and washed with additional diethyl ether.
The solids were transferred to a glass vial and dried in a vacuum
oven (<1 mmHg, 75 °C, 2 days) to provide compound 7m as an
1
off-white solid (468 mg, 90%). Mp 248−250 °C; H NMR (500
MHz, DMSO-d6) δ 10.80 (bs, 2H), 7.46 (s, 1H), 7.09 (d, J = 8.1
Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 3.73 (s, 2H), 2.22 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.1, 158.9, 137.9, 134.9,
132.0, 129.0, 128.6, 112.8, 105.6, 29.0, 21.1; HRMS (ESI) m/z: [M
+
+ H] calcd for C13H13ClNO2 250.0635; found 250.0627.
Experimental Procedures for the Substrates Described in
Table 2. 6-Bromo-3-(4-methylbenzyl)quinoline-2,4-diol (4a).
Synthesized from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1
equiv) and 4-methylbenzaldehyde (250 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure A to provide compound
1
4a as a white solid (596 mg, 83%). Mp 258−260 °C. H NMR (500
MHz, DMSO-d6) δ 11.48 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.61
(dd, J = 8.7, 2.2 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.1
Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 3.88 (s, 2H), 2.22 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 157.2, 138.0, 137.1,
134.8, 132.9, 129.0, 128.6, 125.4, 117.8, 117.6, 113.3, 112.5, 28.6,
21.0; HRMS (ESI) m/z: [M + H]+ calcd for C17H15BrNO2
344.0286; found 344.0291.
6-Bromo-3-benzyl-quinoline-2,4-diol (4b). Synthesized from 6-
bromoquinoline-2,4-diol (501 mg, 2.1 mmol, 1 equiv) and
benzaldehyde (214 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4b as a white solid
1
(521 mg, 75%). Mp 250−252 °C. H NMR (500 MHz, DMSO-d6)
δ 11.50 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 8.7, 2.3 Hz,
1H), 7.30−7.17 (m, 5H), 7.16−7.09 (m, 1H), 3.94 (s, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 157.3, 141.1, 137.1,
133.0, 128.7, 128.5, 126.0, 125.4, 117.7, 117.6, 113.3, 112.3, 29.0;
HRMS (ESI) m/z: [M + H]+ calcd for C16H13BrNO2 330.0129;
found 330.0130.
F
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Scheme 4. Functionalization of 2,4-Dichloroquinoline 8b and Pyridine 8c
6-Bromo-3-(4-nitrobenzyl)quinoline-2,4-diol (4c). Synthesized
from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv) and
4-nitrobenzaldehyde (318 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4c as a white solid
Hz), 123.9, 117.8, 117.7, 113.3, 111.3, 29.1; HRMS (ESI) m/z: [M
+ H]+ calcd for C17H12BrF3NO2 398.0003; found 398.0006.
4-((6-Bromo-2,4-dihydroxyquinolin-3-yl)methyl)benzoic Acid
Pyridine Salt (4f). Synthesized from 6-bromoquinoline-2,4-diol
(502 mg, 2.1 mmol, 1 equiv) and 4-formylbenzoic acid (315 mg,
2.1 mmol, 1 equiv) following General Experimental Procedure A to
provide compound 4f as a white solid (778 mg, 82%). Mp 341−343
1
(686 mg, 88%). Mp 292−294 °C. H NMR (500 MHz, DMSO-d6)
δ 11.52 (s, 1H), 8.29−7.92 (m, 3H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H),
7.56−7.42 (m, 2H), 7.24 (d, J = 8.7 Hz, 1H), 4.05 (s, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 158.5, 149.9, 146.1,
137.3, 133.2, 129.8, 125.7, 123.7, 117.9, 117.7, 113.3, 110.7, 29.4;
HRMS (ESI) m/z: [M + H]+ calcd for C16H12BrN2O4 374.9980;
found 374.9982.
1
°C. H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.63−8.54
(m, 2H), 8.10 (d, J = 2.3 Hz, 1H), 7.86−7.75 (m, 3H), 7.62 (dd, J
= 8.7, 2.2 Hz, 1H), 7.43−7.30 (m, 4H), 7.24 (d, J = 8.7 Hz, 1H),
3.99 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 167.8, 163.7,
157.8, 150.1, 146.5, 137.2, 136.6, 133.1, 129.6, 128.8, 128.7, 125.5,
124.4, 117.7, 117.7, 113.3, 111.5, 29.3; HRMS (ESI) m/z: [M +
H]+ calcd for C17H13BrNO4 374.0026; found 374.0027.
6-Bromo-3-(4-(trifluoromethyl)benzyl)quinoline-2,4-diol (4e).
Synthesized from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1
equiv) and 4-trifluoromethylbenzaldehyde (286 μL, 2.1 mmol, 1
equiv) following General Experimental Procedure A to provide
4-((6-Bromo-2,4-dihydroxyquinolin-3-yl)methyl)benzonitrile
(4g). Synthesized from 6-bromoquinoline-2,4-diol (502 mg, 2.1
mmol, 1 equiv) and 4-cyanobenzaldehyde (275 mg, 2.1 mmol, 1
equiv) following General Experimental Procedure A to provide
1
compound 4e as a white solid (640 mg, 77%). Mp 273−275 °C. H
NMR (500 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.11 (d, J = 2.3 Hz,
1H), 7.63 (dd, J = 8.7, 2.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.45
(d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.7 Hz, 1H), 4.01 (s, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 157.9, 146.2, 137.2,
133.1, 129.4, 126.9 (q, J = 31.5 Hz), 126.0, 125.6, 125.3 (q, J = 3.7
1
compound 4g as a white solid (649 mg, 87%). Mp 312−314 °C. H
NMR (500 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.10 (d, J = 2.3 Hz,
1H), 7.69 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 8.7, 2.2 Hz, 1H), 7.42
G
https://doi.org/10.1021/acs.joc.1c00496
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
(d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.7 Hz, 1H), 4.00 (s, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.6, 158.1, 147.4, 137.3,
133.2, 132.4, 129.7, 125.6, 119.5, 117.8, 117.7, 113.4, 110.9, 108.9,
29.5; HRMS (ESI) m/z: [M + H]+ calcd for C17H12BrN2O2
355.0082; found 355.0084.
(m, 3H), 3.92 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
163.7, 157.9, 144.1, 137.2, 133.1, 131.3, 130.7, 128.9, 127.9, 125.6,
121.8, 117.8, 117.7, 113.3, 111.5, 28.8; HRMS (ESI) m/z: [M +
H]+ calcd for C16H12Br2NO2 407.9235; found 407.9239.
6-Bromo-3-(2-nitrobenzyl)quinoline-2,4-diol (4n). Synthesized
from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1 equiv) and
2-nitrobenzaldehyde (317 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4n as a cream solid
6-Bromo-3-(4-bromobenzyl)quinoline-2,4-diol (4h). Synthesized
from 6-bromoquinoline-2,4-diol (501 mg, 2.1 mmol, 1 equiv) and 4-
bromobenzaldehyde (387 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4h as a cream solid
1
(645 mg, 82%). Mp 277−279 °C. H NMR (500 MHz, DMSO-d6)
1
δ 11.54 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 8.1, 1.4 Hz,
1H), 7.64 (dd, J = 8.7, 2.2 Hz, 1H), 7.58−7.47 (m, 1H), 7.41 (ddd,
J = 8.3, 7.4, 1.4 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 7.7
Hz, 1H), 4.17 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
163.7, 158.7, 150.1, 150.0, 137.4, 135.4, 133.5, 133.3, 130.0, 127.4,
125.6, 124.6, 117.7, 113.4, 109.3, 26.0; HRMS (ESI) m/z: [M +
H]+ calcd for C16H12BrN2O4 374.9980; found 374.9984.
(787 mg, 92%). Mp 263−265 °C. H NMR (500 MHz, DMSO-d6)
δ 11.47 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 8.7, 2.2 Hz,
1H), 7.43−7.36 (m, 2H), 7.25−7.16 (m, 3H), 3.88 (s, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 157.9, 140.7, 137.2,
133.0, 131.3, 131.0, 125.5, 119.0, 117.9, 117.6, 113.3, 111.6, 28.6;
HRMS (ESI) m/z: [M + H]+ calcd for C16H12Br2NO2 407.9235;
found 407.9237.
6-Bromo-3-(2-methoxybenzyl)quinoline-2,4-diol (4o). Synthe-
sized from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1
equiv) and 2-methoxybenzaldehyde (287 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure A to provide compound
4o as a white solid (598 mg, 79%). Mp 281−283 °C. 1H NMR
(500 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H),
7.63 (dd, J = 8.8, 2.3 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.14 (ddd,
J = 8.1, 7.1, 2.1 Hz, 1H), 6.95 (dd, J = 8.2, 1.1 Hz, 1H), 6.80−6.67
(m, 2H), 3.85 (s, 5H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
163.7, 158.0, 157.6, 137.2, 133.0, 128.1, 127.6, 127.1, 125.4, 120.5,
117.7, 117.6, 113.3, 110.6, 110.2, 55.7, 23.4; HRMS (ESI) m/z: [M
+ H]+ calcd for C17H15BrNO3 360.0235; found 360.0221.
6-Bromo-3-(4-methoxybenzyl)quinoline-2,4-diol (4i). Synthe-
sized from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1
equiv) and 4-methoxybenzaldehyde (254 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure A to provide compound
4i as a cream solid (530 mg, 71%). Mp 273−275 °C. 1H NMR
(500 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H),
7.60 (dd, J = 8.8, 2.3 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.20−7.13
(m, 2H), 6.82−6.75 (m, 2H), 3.68 (s, 3H); 13C{1H} NMR (126
MHz, DMSO-d6) δ 163.7, 157.8, 157.0, 137.0, 133.0, 132.9, 129.7,
125.4, 117.8, 117.6, 113.9, 113.3, 112.8, 55.4, 28.1; HRMS (ESI) m/
z: [M + H]+ calcd for C17H15BrNO3 360.0235; found 360.0227.
6-Bromo-3-(4-(dimethylamino)benzyl)quinoline-2,4-diol (4j).
Synthesized from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1
equiv) and 4-(dimethylamino)benzaldehyde (316 mg, 2.1 mmol, 1
equiv) following General Experimental Procedure A to provide
6-Bromo-3-(2-bromobenzyl)quinoline-2,4-diol (4p). Synthesized
from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv) and 2-
bromobenzaldehyde (390 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4p as a white solid
1
compound 4j as a cream solid (541 mg, 69%). Mp 238−240 °C. H
1
(728 mg, 85%). Mp 324−326 °C. H NMR (500 MHz, DMSO-d6)
NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.06 (d, J = 2.3 Hz,
1H), 7.59 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.15−
7.01 (m, 2H), 6.65−6.50 (m, 2H), 2.79 (s, 6H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 163.8, 156.9, 149.3, 137.0, 132.8, 129.2,
128.9, 125.4, 117.9, 117.5, 113.2, 113.2, 113.0, 40.9, 27.9; HRMS
(ESI) m/z: [M + H]+ calcd for C18H18BrN2O2 373.0551; found
373.0546.
δ 11.55 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.7, 2.3 Hz,
1H), 7.61 (dd, J = 7.9, 1.4 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.23−
7.16 (m, 1H), 7.16−7.07 (m, 1H), 6.83 (dd, J = 7.7, 1.7 Hz, 1H),
3.94 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 158.9,
139.4, 137.4, 133.2, 132.6, 128.7, 128.1, 128.0, 125.6, 125.0, 117.8,
117.7, 113.3, 109.4, 30.2; HRMS (ESI) m/z: [M + H]+ calcd for
C16H12Br2NO2 407.9235; found 407.9238.
6-Bromo-3-(3-nitrobenzyl)quinoline-2,4-diol (4k). Synthesized
from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1 equiv) and
3-nitrobenzaldehyde (317 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4k as a yellow
solid (673 mg, 86%). Mp 277−279 °C. 1H NMR (500 MHz,
DMSO-d6) δ 11.55 (s, 1H), 8.12 (d, J = 2.2 Hz, 2H), 8.02 (ddd, J =
8.2, 2.4, 1.0 Hz, 1H), 7.73 (dt, J = 7.8, 1.3 Hz, 1H), 7.63 (dd, J =
8.7, 2.2 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H),
4.05 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 158.1,
148.1, 143.6, 137.3, 135.7, 133.2, 129.9, 125.6, 123.2, 121.2, 117.8,
117.7, 113.4, 111.1, 28.9; HRMS (ESI) m/z: [M + H]+ calcd for
C16H12BrN2O4 374.9980; found 374.9980.
6-Bromo-3-(3-methoxybenzyl)quinoline-2,4-diol (4l). Synthe-
sized from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1
equiv) and 3-methoxybenzaldehyde (184 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure A to provide compound
4l as a cream solid (682 mg, 90%). Mp 221−223 °C. 1H NMR
(500 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H),
7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.13 (t, J =
7.9 Hz, 1H), 6.87−6.78 (m, 2H), 6.74−6.66 (m, 1H), 3.91 (s, 2H),
3.69 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 159.6,
157.2, 142.6, 137.1, 133.0, 129.4, 125.4, 121.0, 117.7, 117.6, 114.8,
113.3, 112.2, 111.2, 55.3, 29.0; HRMS (ESI) m/z: [M + H]+ calcd
for C17H15BrNO3 360.0235; found 360.0235.
6-Bromo-3-(2-methylbenzyl)quinoline-2,4-diol (4q). Synthesized
from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv) and 2-
methylbenzaldehyde (246 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4q as a white solid
1
(578 mg, 81%). Mp 306−308 °C. H NMR (500 MHz, DMSO-d6)
δ 11.52 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.7, 2.2 Hz,
1H), 7.26 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 6.8 Hz, 1H), 7.04 (td, J
= 7.4, 1.5 Hz, 1H), 6.99 (td, J = 7.5, 1.5 Hz, 1H), 6.78 (d, J = 7.3
Hz, 1H), 3.84 (s, 2H), 2.38 (s, 3H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 163.8, 157.9, 138.6, 137.2, 136.5, 133.0, 130.0, 126.8,
126.0, 125.9, 125.4, 117.8, 117.6, 113.3, 110.8, 26.6, 19.9, HRMS
(ESI) m/z: [M + H]+ calcd for C17H15BrNO2 344.0286; found
344.0285.
6-Bromo-3-(2,6-dimethylbenzyl)quinoline-2,4-diol (4r). Synthe-
sized from 6-bromoquinoline-2,4-diol (503 mg, 2.1 mmol, 1 equiv)
and 2,6-dimethylbenzaldehyde (560 mg, 4.2 mmol, 2 equiv)
following General Experimental Procedure B to provide compound
1
4r as a white solid (544 mg, 73%). Mp 303−305 °C. H NMR (500
MHz, DMSO-d6) δ 11.36 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.58
(dd, J = 8.7, 2.2 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.94−6.85 (m,
3H), 3.86 (s, 2H), 2.31 (s, 6H); 13C{1H} NMR (126 MHz, DMSO-
d6) δ 63.5, 157.2, 137.9, 137.3, 137.0, 132.7, 128.2, 125.5, 125.3,
117.6, 117.5, 113.1, 112.2, 25.0, 20.8; HRMS (ESI) m/z: [M + H]+
calcd for C18H17BrNO2 358.0442; found 358.0456.
6-Bromo-3-(3-bromobenzyl)quinoline-2,4-diol (4m). Synthesized
from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv) and 3-
bromobenzaldehyde (387 mg, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 4m as a cream
solid (520 mg, 62%). Mp 268−270 °C. 1H NMR (500 MHz,
DMSO-d6) δ 11.51 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.62 (dd, J =
8.7, 2.3 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.30−7.14
6-Bromo-3-(pyridin-2-ylmethyl)quinoline-2,4-diol (4s). Synthe-
sized from 6-bromoquinoline-2,4-diol (503 mg, 2.1 mmol, 1 equiv)
and picolinaldehyde (200 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 4s as a cream solid
1
(527 mg, 76%). Mp 307−309 °C. H NMR (500 MHz, DMSO-d6)
δ 11.52 (s, 1H), 8.52 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.01 (d, J =
H
https://doi.org/10.1021/acs.joc.1c00496
J. Org. Chem. XXXX, XXX, XXX−XXX

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2.4 Hz, 1H), 7.86−7.74 (m, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H),
7.35 (d, J = 7.5 Hz, 1H), 7.33−7.28 (m, 1H), 7.23 (d, J = 8.7 Hz,
1H), 4.14 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.5,
160.6, 148.2, 138.6, 137.2, 133.2, 125.4, 123.3, 122.4, 117.6, 113.3,
109.5, 32.0; HRMS (ESI) m/z: [M + H]+ calcd for C15H12BrN2O2
331.0082; found 331.0081.
7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.36−7.11 (m, 2H), 6.99−6.76 (m,
2H), 4.10 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.4,
157.4, 143.6, 137.2, 133.1, 126.9, 125.5, 125.1, 123.9, 117.8, 117.7,
113.3, 111.9, 23.7; HRMS (ESI) m/z: [M + H]+ calcd for
C14H11BrNO2S 335.9694; found 335.9696.
6-Bromo-3-(furan-2-ylmethyl)quinoline-2,4-diol (4z). Synthe-
sized from 6-bromoquinoline-2,4-diol (500 mg, 2.1 mmol, 1
equiv) and furan-2-carbaldehyde (202 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
6-Bromo-3-(pyridin-3-ylmethyl)quinoline-2,4-diol (4t). Synthe-
sized from 6-bromoquinoline-2,4-diol (503 mg, 2.1 mmol, 1
equiv) and nicotinaldehyde (196 μL, 2.1 mmol, 1 equiv) following
General Experimental Procedure A to provide compound 4t as a
1
4z as a tan solid (530 mg, 79%). Mp 246−248 °C. H NMR (500
1
white solid (606 mg, 88%). Mp 264−266 °C. H NMR (500 MHz,
MHz, DMSO-d6) δ 11.49 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.62
(dd, J = 8.7, 2.3 Hz, 1H), 7.45 (dd, J = 1.9, 0.9 Hz, 1H), 7.23 (d, J
= 8.7 Hz, 1H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 5.91 (dd, J = 3.2, 1.1
Hz, 1H), 3.93 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
163.4, 158.2, 154.1, 141.3, 137.2, 133.1, 125.6, 117.9, 117.6, 113.3,
110.8, 108.7, 105.5, 22.6; HRMS (ESI) m/z: [M + H]+ calcd for
C14H11BrNO3 319.9922; found 319.9920.
DMSO-d6) δ 11.53 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.35 (dd, J =
4.8, 1.7 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.71−7.50 (m, 2H),
7.30−7.10 (m, 2H), 3.93 (s, 2H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 163.7, 158.6, 150.1, 147.2, 137.3, 137.0, 136.1, 133.0,
125.7, 124.4, 123.7, 118.2, 117.6, 113.2, 111.0, 26.6; HRMS (ESI)
m/z: [M + H]+ calcd for C15H12BrN2O2 331.0082; found 331.0084.
6-Bromo-3-(pyridin-4-ylmethyl)quinoline-2,4-diol (4u). Synthe-
sized from 6-bromoquinoline-2,4-diol (502 mg, 2.1 mmol, 1 equiv)
and isonicotinaldehyde (200 μL, 2.1 mmol, 1 equiv) following
General Experimental Procedure A to provide compound 4u as a
tert-Butyl 4-((6-Bromo-2,4-dihydroxyquinolin-3-yl)methyl)-
piperidine-1-carboxylate (4aa). Synthesized from 6-bromoquino-
line-2,4-diol (502 mg, 2.1 mmol, 1 equiv) and tert-butyl 4-
formylpiperidine-1-carboxylate (450 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
1
white solid (616 mg, 89%). Mp 375−377 °C. H NMR (500 MHz,
1
DMSO-d6) δ 11.53 (s, 1H), 8.46−8.36 (m, 2H), 8.12 (d, J = 2.2
Hz, 1H), 7.63 (dd, J = 8.7, 2.2 Hz, 1H), 7.31−7.18 (m, 3H), 3.94
(s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 158.5,
150.3, 149.6, 137.3, 133.1, 125.6, 124.2, 117.9, 117.7, 113.3, 110.3,
28.7; HRMS (ESI) m/z: [M + H]+ calcd for C15H12BrN2O2
331.0082; found 331.0077.
4aa as a white solid (740 mg, 81%). Mp 164−168 °C. H NMR
(500 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.03 (d, J = 2.3 Hz, 1H),
7.59 (dd, J = 8.7, 2.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.89 (d, J
= 11.4 Hz, 2H), 2.60 (s, 2H), 2.53 (d, J = 7.0 Hz, 2H), 1.78−1.68
(m, 1H), 1.56−1.48 (m, 2H), 1.39 (s, 9H), 1.15−1.05 (m, 2H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.9, 157.2, 154.3, 137.0,
6-Bromo-3-(pyrazin-2-ylmethyl)quinoline-2,4-diol (4v). Synthe-
sized from 6-bromoquinoline-2,4-diol (500 mg, 2.1 mmol, 1 equiv)
and pyridazine-2-carbaldehyde (225 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
132.7, 125.3, 117.7, 117.5, 113.2, 111.2, 78.8, 35.4, 32.0, 29.9, 28.6;
HRMS (ESI) m/z: [M + H]+ calcd for C20H26BrN2O4 [M + H -
100]+ 337.0051; found 337.0559.
tert-Butyl-3-((6-bromo-2,4-dihydroxyquinolin-3 yl)methyl) Aze-
tidine-1-carboxylate (4ab). Synthesized from 6-bromoquinoline-
1
4v as a cream solid (567 mg, 82%). Mp 298−300 °C. H NMR
(500 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H),
8.49 (dd, J = 2.6, 1.5 Hz, 1H), 8.44 (d, J = 2.6 Hz, 1H), 8.07 (d, J
= 2.3 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.25 (d, J = 8.7 Hz,
1H), 4.15 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.6,
158.3, 156.4, 144.7, 144.1, 142.5, 137.3, 133.2, 125.5, 117.7, 117.7,
113.4, 109.5, 29.8; HRMS (ESI) m/z: [M + H]+ calcd for
C14H11BrN3O2 332.0034; found 332.0047.
2,4-diol (502 mg, 2.1 mmol,
1 equiv) and tert-butyl 3-
formylazetidine-1-carboxylate (390 mg, 2.1 mmol, 1 equiv) following
General Experimental Procedure A to provide compound 4ab as a
1
white solid (732 mg, 86%). Mp 254−256 °C. H NMR (500 MHz,
DMSO-d6) δ 11.46 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.60 (dd, J =
8.7, 2.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.82 (s, 2H), 3.61 (s,
2H), 2.85 (d, J = 7.5 Hz, 2H), 2.80−2.73 (m, 1H), 1.36 (s, 9H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.0, 157.8, 156.0, 137.0,
6-Bromo-3-(pyridazin-4-ylmethyl)quinoline-2,4-diol (4w). Syn-
thesized from 6-bromoquinoline-2,4-diol (501 mg, 2.1 mmol, 1
equiv) and pyridazine-4-carbaldehyde (228 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
132.9, 125.4, 117.7, 117.6, 113.3, 110.4, 78.6, 28.6, 28.2, 27.7;
HRMS (ESI) m/z: [M + H]+ calcd for C18H22BrN2O4 [M + H -
100]+ 309.0238; found 309.0230.
1
4w as a brown solid (600 mg, 87%). Mp 325−327 °C. H NMR
6-Bromo-3-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-2,4-
diol (4ac). Synthesized from 6-bromoquinoline-2,4-diol (500 mg,
2.1 mmol, 1 equiv) and tetrahydro-2H-pyran-4-carbaldehyde (238
mg, 2.1 mmol, 1 equiv) following General Experimental Procedure
B to provide compound 4ac as a white solid (604 mg, 86%). Mp
271−273 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H),
8.03 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J
= 8.7 Hz, 1H), 3.99−3.60 (m, 2H), 3.29−3.08 (m, 2H), 2.54 (d, J =
7.2 Hz, 2H), 1.87−1.71 (m, 1H), 1.54−1.39 (m, 2H), 1.39−1.20
(m, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 163.9, 157.1,
136.9, 132.7, 125.3, 117.6, 117.5, 113.2, 111.2, 67.6, 34.5, 33.0, 30.3;
HRMS (ESI) m/z: [M + H]+ calcd for C15H17BrNO3 338.0392;
found 338.0392.
(500 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.14 (dd, J = 2.4, 1.3 Hz,
1H), 9.03 (dd, J = 5.3, 1.3 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.65
(dd, J = 8.7, 2.2 Hz, 1H), 7.42 (dd, J = 5.4, 2.4 Hz, 1H), 7.25 (d, J
= 8.7 Hz, 1H), 3.96 (s, 2H); 13C{1H} NMR (126 MHz, DMSO-d6)
δ 163.5, 158.7, 153.0, 151.5, 141.0, 137.4, 133.4, 126.2, 125.7, 117.8,
117.7, 113.4, 109.2, 26.5; HRMS (ESI) m/z: [M + H]+ calcd for
C14H11BrN3O2 332.0034; found 332.0030.
6-Bromo-3-((4-methyl-1H-imidazol-5-yl)methyl)quinoline-2,4-
diol (4x). Synthesized from 6-bromoquinoline-2,4-diol (500 mg, 2.1
mmol, 1 equiv) and 4-methyl-1H-imidazole-5-carbaldehyde (229
mg, 2.1 mmol, 1 equiv) following General Experimental Procedure
A to provide compound 4x as a cream solid (600 mg, 86%). Mp
310−312 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.35 (s, 1H),
7.95 (d, J = 2.3 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J = 8.7, 2.3 Hz,
1H), 7.19 (d, J = 8.7 Hz, 1H), 3.81 (s, 2H), 2.19 (s, 3H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 163.6, 160.9, 137.0, 133.9, 132.8,
132.5, 125.4, 121.4, 119.4, 117.4, 113.1, 109.7, 20.2, 9.4; HRMS
(ESI) m/z: [M + H]+ calcd for C14H13BrN3O2 334.0191; found
334.0188.
6-Bromo-3-(cyclohexylmethyl)quinoline-2,4-diol (4ad). Synthe-
sized from 6-bromoquinoline-2,4-diol (500 mg, 2.1 mmol, 1 equiv)
and cyclohexanecarbaldehyde (235 mg, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
1
4ad as a cream solid (547 mg, 78%). Mp 267−269 °C. H NMR
(500 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.02 (d, J = 2.2 Hz, 1H),
7.59 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 2.49 (d, J
= 6.8 Hz, 2H), 1.75−1.46 (m, 6H), 1.18−1.08 (m, 3H), 1.06−0.93
(m, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.0, 156.7,
136.9, 132.6, 125.2, 117.6, 117.4, 113.1, 112.1, 37.2, 33.1, 30.8, 26.6,
26.4; HRMS (ESI) m/z: [M + H]+ calcd for C16H19BrNO2
336.0599; found 336.0601.
6-Bromo-3-(thiophen-2-ylmethyl)quinoline-2,4-diol (4y). Syn-
thesized from 6-bromoquinoline-2,4-diol (504 mg, 2.1 mmol, 1
equiv) and thiophene-2-carbaldehyde (198 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure A to provide compound
1
4y as a cream solid (486 mg, 69%). Mp 259−261 °C. H NMR
(500 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H),
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6-Bromo-3-(cyclopropylmethyl)quinoline-2,4-diol (4ae). Synthe-
sized from 6-bromoquinoline-2,4-diol (498 mg, 2.1 mmol, 1 equiv)
and cyclopropane carbaldehyde (158 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
(ESI) m/z: [M + H]+ calcd for C17H16NO2 266.1181; found
266.1178.
6-Methoxy-3-(4-methylbenzyl)quinoline-2,4-diol (7b). Synthe-
sized from 6-methoxyquinoline-2,4-diol (398 mg, 2.1 mmol, 1
equiv) and 4-methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
1
4ae as a cream solid (377 mg, 61%). Mp 244−246 °C. H NMR
(500 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H),
7.58 (dd, J = 8.7, 2.2 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 2.52 (d, J
= 6.8 Hz, 2H), 1.05−0.94 (m, 1H), 0.35−0.25 (m, 2H), 0.25−0.13
(m, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.0, 156.6,
136.9, 132.7, 125.3, 117.8, 117.5, 113.2, 113.0, 27.3, 10.8, 4.5;
HRMS (ESI) m/z: [M + H]+ calcd for C13H13BrNO2 294.0129;
found 294.0126.
1
7b as a tan solid (492 mg, 80%). Mp 223−225 °C. H NMR (500
MHz, DMSO-d6) δ 11.25 (s, 1H), 10.26 (s, 1H), 7.43 (d, J = 2.8
Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.19−7.07 (m, 3H), 7.02 (d, J =
7.7 Hz, 2H), 3.89 (s, 2H), 3.79 (s, 3H), 2.22 (s, 3H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 163.4, 157.7, 154.3, 138.3, 134.7,
132.5, 129.0, 128.6, 119.5, 116.8, 116.2, 111.9, 104.9, 55.9, 28.7,
21.0; HRMS (ESI) m/z: [M + H]+ calcd for C18H18NO3 296.1286;
found 296.1286.
6-Bromo-3-(3,3,3-trifluoropropyl)quinoline-2,4-diol (4af). Syn-
thesized from 6-bromoquinoline-2,4-diol (500 mg, 2.1 mmol, 1
equiv) and 3,3,3-trifluoropropanal (241 μL, 4.2 mmol, 2 equiv)
following General Experimental Procedure B to provide compound
6-Methyl-3-(4-methylbenzyl)quinoline-2,4-diol (7c). Synthesized
from 6-methylquinoline-2,4-diol (365 mg, 2.1 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7c as a white solid
1
4af as a cream solid (524 mg, 72%). Mp 273−275 °C. H NMR
(500 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.73 (s, 1H), 8.10 (d, J =
2.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.24 (d, J = 8.7 Hz,
1H), 2.92−2.72 (m, 2H), 2.46−2.30 (m, 2H); 13C{1H} NMR (126
MHz, DMSO-d6) δ 163.4, 157.3, 137.1, 133.2, 127.8 (q, J = 277.1
Hz), 125.4, 117.7, 117.5, 113.4, 110.1, 31.5 (q, J = 27.1 Hz), 16.8.
HRMS (ESI) m/z: [M + H]+ calcd for C12H10BrF3NO2 335.9847;
found 335.9847.
1
(423 mg, 73%). Mp 264−266 °C. H NMR (500 MHz, DMSO-d6)
δ 11.26 (s, 1H), 7.74 (s, 1H), 7.28 (dd, J = 8.3, 1.9 Hz, 1H), 7.18
(d, J = 8.3 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.7 Hz,
2H), 3.88 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H); 13C{1H} NMR (126
MHz, DMSO-d6) δ 163.8, 157.9, 138.3, 136.0, 134.7, 131.5, 130.3,
128.9, 128.6, 122.7, 115.7, 115.3, 111.4, 28.6, 21.1, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C18H18NO2 280.1337; found
280.1334.
6-Bromo-3-isobutylquinoline-2,4-diol (4ag). Synthesized from 6-
bromoquinoline-2,4-diol (501 mg, 2.1 mmol, 1 equiv) and
isobutyraldehyde (191 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 4ag as a cream
solid (369 mg, 59%). Mp 220−222 °C. 1H NMR (500 MHz,
DMSO-d6) δ 11.39 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.57 (dd, J =
8.7, 2.3 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 2.46 (d, J = 7.3 Hz, 2H),
1.90 (dt, J = 13.6, 6.8 Hz, 1H), 0.86 (d, J = 6.7 Hz, 6H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 164.0, 156.8, 136.9, 132.6, 125.2,
117.7, 117.4, 113.1, 112.5, 32.2, 27.7, 22.7; HRMS (ESI) m/z: [M +
H]+ calcd for C13H15BrNO2 296.0286; found 296.0282.
6-Bromo-2,4-dichloro-3-neopentylquinoline (4ah). 6-Bromo-3-
neopentylquinoline-2,4-diol was synthesized from 6-bromoquinoline-
2,4-diol (500 mg, 2.1 mmol, 1 equiv) and pivalaldehyde (456 μL,
2.1 mmol, 1 equiv) following General Experimental Procedure B to
provide 6-bromo-3-neopentylquinoline-2,4-diol as a cream solid,
which was used for the subsequent reaction without further
purification. To a stirring, heterogeneous suspension 6-bromo-3-
neopentylquinoline-2,4-diol (200 mg, 0.7 mmol, 1 equiv) in
acetonitrile (3 mL) was added phosphorus(V) oxychloride (190
μL, 2.1 mmol, 3.1 equiv) and the reaction was allowed to stir at 80
°C using a heating block fitted on a stir plate for 16 h. Once
complete, the reaction was cooled to room temperature (RT) and
added to 10 mL of water to give a white precipitate. The suspension
was sonicated for 5 min, and the solid was filtered and washed with
additional water to give crude 4ah, which was purified by column
chromatography using ethyl acetate in hexanes to give 4ah as a
cream solid (564 mg, 77% over two steps). Mp: 90−92 °C; 1H
NMR (500 MHz, chloroform-d) δ 8.34 (d, J = 2.1 Hz, 1H), 7.84
(d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.9, 2.1 Hz, 1H), 3.16 (s, 2H),
1.06 (s, 9H); 13C{1H} NMR (126 MHz, chloroform-d) δ 153.1,
144.5, 143.0, 134.0, 130.2, 127.1, 127.0, 122.1, 42.8, 35.5, 30.5;
HRMS (ESI) m/z: [M + H]+ calcd for C14H15BrCl2N 345.9765;
found 345.9739.
6-Iodo-3-(4-methylbenzyl)quinoline-2,4-diol (7d). Synthesized
from 6-iodoquinoline-2,4-diol (598 mg, 2.1 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure A to provide compound 7d as a tan solid
1
(580 mg, 71%). Mp 254−256 °C. H NMR (500 MHz, DMSO-d6)
δ 11.46 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.6, 2.0 Hz,
1H), 7.10 (dd, J = 13.2, 8.2 Hz, 3H), 7.02 (d, J = 7.9 Hz, 2H), 3.87
(s, 2H), 2.22 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
163.7, 156.8, 138.5, 137.9, 137.4, 134.8, 131.3, 129.0, 128.6, 118.1,
117.7, 112.4, 84.5, 28.6, 21.1; HRMS (ESI) m/z: [M + H]+ calcd
for C17H15INO2 392.0147; found 392.0150.
7-Methoxy-3-(4-methylbenzyl)quinoline-2,4-diol (7e). Synthe-
sized from 7-methoxyquinoline-2,4-diol (398 mg, 2.1 mmol, 1
equiv) and 4-methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
1
7e as a white solid (426 mg, 69%). Mp 217−219 °C. H NMR (500
MHz, DMSO-d6) δ 11.21 (s, 1H), 10.19 (s, 1H), 7.83 (d, J = 8.6
Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.78
(d, J = 8.5 Hz, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 2.22 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.3, 161.2, 158.3, 139.7,
138.5, 134.7, 128.9, 128.6, 124.6, 110.1, 109.7, 109.0, 98.3, 55.7,
28.4, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for C18H18NO3
296.1286; found 296.1282.
8-Methyl-3-(4-methylbenzyl)quinoline-2,4-diol (7f). Synthesized
from 8-methylquinoline-2,4-diol (366 mg, 2.1 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7f as a white solid
1
(467 mg, 80%). Mp 295−297 °C. H NMR (500 MHz, DMSO-d6)
δ 10.52 (s, 1H), 10.29 (s, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.31 (d, J
= 7.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H),
7.02 (d, J = 7.8 Hz, 2H), 3.92 (s, 2H), 2.41 (s, 3H), 2.22 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.2, 158.4, 138.2, 136.4,
134.8, 131.7, 129.0, 128.6, 123.6, 121.2, 121.1, 115.9, 111.1, 28.5,
21.1, 17.8; HRMS (ESI) m/z: [M + H]+ calcd for C18H18NO2
280.1337; found 280.1334.
Experimental Procedures for the Substrates Described in
Table 3. 3-(4-Methylbenzyl)quinoline-2,4-diol (7a). Synthesized
from quinoline-2,4-diol (336 mg, 2.1 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7a as a tan solid
3-(4-Methylbenzyl)-1,8-naphthyridine-2,4-diol (7g). Synthesized
from 1,8-naphthyridine-2,4-diol (338 mg, 2.1 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 2.1 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7g as a brown
solid (465 mg, 84%). Mp 291−293 °C. 1H NMR (500 MHz,
DMSO-d6) δ 11.77 (s, 1H), 10.67 (s, 1H), 8.49 (dd, J = 4.7, 1.8
Hz, 1H), 8.31 (dd, J = 8.0, 1.8 Hz, 1H), 7.23 (dd, J = 7.9, 4.7 Hz,
1H), 7.15 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 3.90 (s,
2H), 2.23 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.4,
1
(320 mg, 58%). Mp 227−229 °C. H NMR (500 MHz, DMSO-d6)
δ 11.35 (s, 1H), 10.31 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.49−7.42
(m, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.15 (t, J = 8.0 Hz, 3H), 7.02
(d, J = 7.8 Hz, 2H), 3.89 (s, 2H), 2.22 (s, 3H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 163.9, 158.0, 138.2, 138.0, 134.8, 130.4,
129.0, 128.6, 123.1, 121.4, 115.8, 115.4, 111.5, 28.5, 21.0; HRMS
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157.1, 150.5, 149.1, 137.9, 134.9, 132.1, 129.0, 128.6, 118.0, 112.3,
111.3, 28.5, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for
C16H15N2O2 267.1133; found 267.1127.
105.6, 29.0, 21.1; HRMS (ESI) m/z: [M + H]+ calcd for
C13H13ClNO2 250.0635; found 250.0627.
5-Methyl-3-(4-methylbenzyl)pyridine-2,4-diol (7n). Synthesized
from 5-methylpyridine-2,4-diol (260 mg, 2.0 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 1.2 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7n as a tan solid
4-Hydroxy-3-(4-methylbenzyl)-2H-thiochromen-2-one (7h).
Synthesized from 4-hydroxy-2H-thiochromen-2-one (500 mg, 2.8
mmol, 1 equiv) and 4-methylbenzaldehyde (332 μL, 2.8 mmol, 1
equiv) following General Experimental Procedure B to provide
1
(418 mg, 86%). Mp 252−254 °C. H NMR (500 MHz, DMSO-d6)
1
δ 10.85 (bs, 1H), 9.49 (bs, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.00 (d, J
= 7.8 Hz, 2H), 6.98−6.94 (m, 1H), 3.71 (s, 2H), 2.22 (s, 3H), 1.91
(s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.0, 162.7,
138.7, 134.6, 130.7, 128.8, 128.6, 111.3, 107.6, 28.4, 21.1, 13.7;
HRMS (ESI) m/z: [M + H]+ calcd for C14H16NO2 230.1181; found
230.1176.
compound 7h as a beige solid (639 mg, 81%). Mp 184−186 °C. H
NMR (500 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.24 (dt, J = 8.1, 1.0
Hz, 1H), 7.62−7.55 (m, 2H), 7.50 (ddd, J = 8.4, 5.2, 3.3 Hz, 1H),
7.10 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 3.97 (s, 2H),
2.23 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 183.4, 162.5,
137.2, 135.1, 134.9, 130.7, 129.2, 128.5, 127.0, 126.9, 125.9, 124.6,
117.3, 28.9, 21.0.; HRMS (ESI) m/z: [M + H]+ calcd for
C17H15O2S 283.0793; found 283.0797.
6-Methyl-3-(4-methylbenzyl)pyridine-2,4-diol (7o). Synthesized
from 6-methylpyridine-2,4-diol (261 mg, 2.0 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 1.2 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7o as a cream solid
4-Hydroxy-3-(4-methylbenzyl)-2H-thiochromen-2-one (7i). Syn-
thesized from 4-hydroxy-2H-chromen-2-one (243 mg, 1.5 mmol, 1
equiv) and 4-methylbenzaldehyde (180 μL, 1.5 mmol, 1 equiv)
following General Experimental Procedure B to provide compound
1
(408 mg, 85%). Mp 264−266 °C. H NMR (500 MHz, DMSO-d6)
δ 11.04 (s, 1H), 10.10 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.98 (d, J
= 7.8 Hz, 2H), 5.70 (s, 1H), 3.58 (s, 2H), 2.21 (s, 3H), 2.06 (s,
3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.9, 163.6, 143.1,
139.2, 134.4, 128.8, 128.6, 107.9, 98.3, 28.2, 21.1, 18.8; HRMS
(ESI) m/z: [M + H]+ calcd for C14H16NO2 230.1181; found
230.1172.
1
7i as a yellow solid (324 mg, 81%). H NMR (500 MHz, DMSO-
d6) δ 11.61 (s, 1H), 7.99 (dd, J = 8.4, 1.6 Hz, 1H), 7.66−7.56 (m,
1H), 7.42−7.30 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 7.9
Hz, 2H), 3.85 (s, 2H), 2.23 (s, 3H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 163.26, 160.76, 152.43, 137.15, 135.23, 132.28, 129.20,
128.47, 124.35, 123.79, 116.71, 116.65, 104.97, 29.15, 21.05; HRMS
(ESI) m/z: [M + H]+ calcd for C17H15O3 267.1021; found
267.1024.
Ethyl 4,6-Dihydroxy-5-(4-methylbenzyl)-2-(trifluoromethyl)-
nicotinate (7p). Synthesized from ethyl 4,6-dihydroxy-2-
(trifluoromethyl)nicotinate (302 mg, 1.2 mmol, 1 equiv) and 4-
methylbenzaldehyde (142 μL, 1.2 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7p as a cream solid
3-(4-Methylbenzyl)-5,6,7,8-tetrahydroquinoline-2,4-diol (7j).
Synthesized from 5,6,7,8-tetrahydroquinoline-2,4-diol (344 mg, 2.1
mmol, 1 equiv) and 4-methylbenzaldehyde (245 μL, 2.1 mmol, 1
equiv) following General Experimental Procedure B to provide
1
(328 mg, 74%). Mp 166−168 °C. H NMR (500 MHz, DMSO-d6)
δ 11.84 (s, 1H), 10.93 (s, 1H), 7.15−6.97 (m, 4H), 4.29 (q, J = 7.1
Hz, 2H), 3.88 (s, 2H), 2.23 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 165.2, 163.9, 161.6, 136.6,
135.4, 122.7 (q, J = 274.7 Hz), 113.1, 111.9, 62.1, 28.2, 21.0, 14.2;
HRMS (ESI) m/z: [M + H]+ calcd for C17H17F3NO4 356.1109;
found 356.1115.
1
compound 7j as a brown solid (479 mg, 85%). Mp 267−269 °C. H
NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.30 (s, 1H), 7.09 (d,
J = 8.0 Hz, 2H), 6.99 (d, J = 7.8 Hz, 2H), 3.70 (s, 2H), 2.39 (s,
2H), 2.31 (s, 2H), 2.21 (s, 3H), 1.63 (t, J = 3.3 Hz, 4H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 163.7, 162.4, 140.6, 139.0, 134.5,
128.8, 128.6, 108.8, 106.0, 28.2, 26.5, 22.3, 21.7, 21.6, 21.1; HRMS
(ESI) m/z: [M + H]+ calcd for C17H20NO2 270.1494; found
270.1487.
5-(4-Methylbenzyl)pyrimidine-4,6-diol (7q). Synthesized from
pyrimidine-2,4-diol (233 mg, 2.0 mmol,
1 equiv) and 4-
methylbenzaldehyde (245 μL, 1.2 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7q as a tan solid
3-(4-Methylbenzyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2,4-
diol (7k). Synthesized from 6,7-dihydro-5H-cyclopenta[b]pyridine-
2,4-diol (315 mg, 2.1 mmol, 1 equiv) and 4-methylbenzaldehyde
(245 μL, 2.1 mmol, 1 equiv) following General Experimental
Procedure B to provide compound 7k as a tan solid (456 mg, 86%).
1
(416 mg, 92%). Mp 309−311 °C. H NMR (500 MHz, DMSO-d6)
δ 11.77 (s, 2H), 7.93 (s, 1H), 7.11 (d, J = 7.7 Hz, 2H), 7.01 (d, J =
7.7 Hz, 2H), 3.54 (s, 2H), 2.22 (s, 3H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 164.7, 147.6, 138.4, 134.8, 129.0, 128.6, 102.8, 27.9,
21.1; HRMS (ESI) m/z: [M + H]+ calcd for C12H13N2O2 217.0977;
found 217.0988.
1
Mp 348−350 °C. H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H),
9.64 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H),
3.64 (s, 2H), 2.73−2.55 (m, 4H), 2.21 (s, 3H), 1.95 (p, J = 7.5 Hz,
2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 165.1, 161.2, 147.0,
139.3, 134.4, 128.8, 128.6, 110.0, 108.3, 31.3, 28.6, 28.0, 22.2, 21.1;
HRMS (ESI) m/z: [M + H]+ calcd for C16H18NO2 256.1337; found
256.1330.
Scale-Up Procedure. 3-(4-Methylbenzyl)pyridine-2,4-diol (P-
74). Synthesized from pyridine-2,4-diol (4.5 g, 40.5 mmol, 1 equiv)
and 4-methylbenzaldehyde (4.8 mL, 40.5 mmol, 1 equiv) following
General Experimental Procedure B to provide compound P-74 as a
1
cream solid (7.3 g, 84%). Mp 246−248 °C. H NMR (500 MHz,
DMSO-d6) δ 11.00 (s, 1H), 10.24 (s, 1H), 7.16−7.04 (m, 3H), 6.99
(d, J = 7.9 Hz, 2H), 5.92 (d, J = 7.2 Hz, 1H), 3.61 (s, 2H), 2.21 (s,
3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.5, 163.4, 138.9,
134.5, 133.2, 128.8, 128.7, 111.1, 99.5, 28.3, 21.1; HRMS (ESI) m/
z: [M + H]+ calcd for C13H14NO2 216.1024; found 216.1015.
6-Bromo-3-(4-methylbenzyl)quinoline-2,4-diol (P-75). Synthe-
sized from 6-bromoquinoline-2,4-diol (5.0 g, 20.8 mmol, 1 equiv)
and 4-methylbenzaldehyde (2.5 mL, 20.8 mmol, 1 equiv) following
General Experimental Procedure A to provide compound P-75 as a
3-(4-Methylbenzyl)pyridine-2,4-diol (7l). Synthesized from pyr-
idine-2,4-diol (231 mg, 2.0 mmol, 1 equiv) and 4-methylbenzalde-
hyde (245 μL, 1.2 mmol, 1 equiv) following General Experimental
Procedure B to provide compound 7l as a cream solid (358 mg,
1
80%). Mp 246−248 °C. H NMR (500 MHz, DMSO-d6) δ 11.00
(s, 1H), 10.25 (s, 1H), 7.11 (dd, J = 7.6, 5.8 Hz, 3H), 7.00 (d, J =
7.9 Hz, 2H), 5.93 (d, J = 7.2 Hz, 1H), 3.62 (s, 2H), 2.22 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.5, 163.4, 138.9, 134.5,
133.2, 128.8, 128.7, 111.1, 99.5, 28.3, 21.1; HRMS (ESI) m/z: [M +
H]+ calcd for C13H14NO2 216.1024; found 216.1014.
1
white solid (6.44 g, 90%). Mp 258−260 °C. H NMR (500 MHz,
DMSO-d6) δ 11.48 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.61 (dd, J =
8.7, 2.2 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H),
7.02 (d, J = 7.8 Hz, 2H), 3.88 (s, 2H), 2.22 (s, 3H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 163.7, 157.1, 138.0, 137.1, 134.8, 132.9,
129.0, 128.6, 125.4, 117.7, 117.6, 113.3, 112.6, 28.6, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C17H15BrNO2 344.0286; found
344.0285.
5-Chloro-3-(4-methylbenzyl)pyridine-2,4-diol (7m). Synthesized
from 5-chloropyridine-2,4-diol (303 mg, 2.0 mmol, 1 equiv) and 4-
methylbenzaldehyde (245 μL, 1.2 mmol, 1 equiv) following General
Experimental Procedure B to provide compound 7m as a tan solid
1
(468 mg, 90%). Mp 248−250 °C. H NMR (500 MHz, DMSO-d6)
δ 10.80 (s, 2H), 7.46 (s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.02 (d, J =
7.8 Hz, 2H), 3.73 (s, 2H), 2.22 (s, 3H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 163.1, 158.9, 137.9, 134.9, 132.0, 129.0, 128.6, 112.8,
Procedure for Reaction in Scheme 2. 6-Bromo-2,4-dichloro-
3-(4-methylbenzyl)quinoline (8a). To a stirring, heterogeneous
K
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suspension of 6-bromo-3-(4-methylbenzyl)quinoline-2,4-diol (4a) (2
g, 5.8 mmol, 1 equiv) in acetonitrile (20 mL) was added
phosphorus(V) oxychloride (1.62 mL, 17.4 mmol, 3 equiv) and
the reaction was allowed to stir at 80 °C using a heating block fitted
on a stir plate for 16 h. Once complete, the reaction was cooled to
RT and 20 mL of water was added to give a white precipitate. The
suspension was sonicated for 5 min, and the solid was filtered and
washed with additional water to give 8a as a white solid (1.98 g,
diluted with saturated ammonium chloride solution (15 mL) and
then the aqueous fraction was extracted thrice with ethyl acetate (20
mL). The organic fractions were combined, dried over magnesium
sulfate, concentrated, and purified by column chromatography using
ethyl acetate in hexanes as the mobile phase to give 10 as a white
solid (180 mg, 85%). Mp: 132−134 °C; 1H NMR (500 MHz,
chloroform-d) δ 8.17 (dd, J = 1.8, 0.8 Hz, 1H), 7.66−7.55 (m, 2H),
7.13−7.03 (m, 2H), 6.95 (d, J = 8.0 Hz, 2H), 4.27−4.20 (m, 2H),
4.18−4.10 (m, 4H), 2.30 (s, 3H), 2.25−2.15 (m, 2H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 159.0, 145.8, 142.2, 135.9, 135.1,
133.0, 129.3, 128.5, 127.5, 126.6, 123.5, 121.5, 116.3, 53.2, 33.9,
21.0, 16.6; HRMS (ESI) m/z: [M + H]+ calcd for C20H19BrClN2
401.0420; found 401.0381.
1
89%). Mp 154−156 °C; H NMR (500 MHz, DMSO-d6) δ 8.36 (d,
J = 2.1 Hz, 1H), 8.04 (dd, J = 8.9, 2.2 Hz, 1H), 7.97 (d, J = 8.9 Hz,
1H), 7.13−6.99 (m, 4H), 4.41 (s, 2H), 2.24 (s, 3H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 152.0, 144.9, 142.5, 136.1, 135.0, 134.1,
132.1, 131.1, 129.6, 128.3, 127.0, 126.8, 122.6, 36.5, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C17H13BrCl2N 379.9608; found
379.9614.
4-Chloro-2-methoxy-3-(4-methylbenzyl)pyridine (11). To a
stirring solution of 2,4-dichloro-3-(4-methylbenzyl)pyridine (8c)
(100 mg, 0.4 mmol, 1 equiv) in toluene (2 mL) was added sodium
methoxide (245 mg, 4.5 mmol, 11.4 equiv) and the reaction was
allowed to stir at 100 °C using a heating block fitted on a stir plate
for 16 h. Once complete, the reaction was cooled to RT and
concentrated. To this was added 20 mL of water and extracted twice
with ethyl acetate (10 mL) and concentrated to give a white solid.
The solid was then purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 11 as a white solid
2,4-Dichloro-3-(4-methylbenzyl)quinoline (8b). To a stirring,
heterogeneous suspension of 3-(4-methylbenzyl)quinoline-2,4-diol
(7a) (2 g, 7.5 mmol, 1 equiv) in acetonitrile (17 mL) was added
phosphorus(V) oxychloride (2.1 mL, 22.6 mmol, 3 equiv) and the
reaction was allowed to stir at 80 °C using a heating block fitted on
a stir plate for 16 h. Once complete, the reaction was cooled to RT
and 20 mL of water was added to give a white precipitate. The
suspension was sonicated for 5 min, and the solid was filtered and
washed with additional water to give 8b as a tan solid (2.02 g, 88%).
1
(89 mg, 91%). Mp: 89−91 °C. H NMR (500 MHz, chloroform-d)
1
δ 7.92 (d, J = 5.5 Hz, 1H), 7.18−7.11 (m, 2H), 7.09−7.03 (m, 2H),
6.91 (d, J = 5.5 Hz, 1H), 4.06 (s, 2H), 3.94 (s, 3H), 2.29 (s, 3H);
13C{1H} NMR (126 MHz, chloroform-d) δ 163.2, 144.6, 144.5,
135.9, 135.7, 129.0, 128.4, 122.3, 118.3, 54.1, 31.7, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C14H15ClNO 248.0842; found
248.0839.
Mp 172−174 °C; H NMR (500 MHz, DMSO-d6) δ 8.22 (dd, J =
8.5, 1.3 Hz, 1H), 8.06−8.01 (m, 1H), 7.91 (ddd, J = 8.4, 6.9, 1.4
Hz, 1H), 7.81 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.07 (q, J = 8.2 Hz,
4H), 4.41 (s, 2H), 2.24 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-
d6) δ 151.4, 146.3, 143.5, 136.0, 134.4, 131.9, 130.9, 129.6, 129.3,
128.8, 128.3, 125.6, 124.8, 36.4, 21.0; HRMS (ESI) m/z: [M + H]+
calcd for C17H14Cl2N 302.0503; found 302.0505.
2-Chloro-4-methoxy-3-(4-methylbenzyl)pyridine (12). To a
stirring solution of 2,4-dichloro-3-(4-methylbenzyl)pyridine (P-87)
(50 mg, 0.2 mmol, 1 equiv) in methanol (2 mL) was added sodium
methoxide (123 mg, 2.3 mmol, 11.45 equiv) and the reaction was
allowed to stir at 100 °C using a heating block fitted on a stir plate
for 16 h. Once complete, the reaction was cooled to RT and
concentrated. To this was added 10 mL of water and extracted twice
with ethyl acetate (10 mL) and concentrated to give a white solid.
The solid was then purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 12 as a clear oil (8
2,4-Dichloro-3-(4-methylbenzyl)pyridine (8c). To a stirring,
heterogeneous suspension of 3-(4-methylbenzyl)pyridine-2,4-diol
(7l) (1.5 g, 6.9 mmol, 1 equiv) in acetonitrile (20 mL) was
added phosphorus(V) oxychloride (2.06 mL, 22.1 mmol, 3.17
equiv) and the reaction was allowed to stir at 80 °C using a heating
block fitted on a stir plate for 16 h. Once complete, the reaction was
cooled to RT and 20 mL of water was added to give a white
precipitate. The suspension was sonicated for 5 min, and the solid
was filtered and washed with additional water to give a white solid.
The solid was then purified by column chromatography using
methanol in dichloromethane as the mobile phase to give 8c as a
white solid (1.45 g, 83%). Mp 92−94 °C; 1H NMR (500 MHz,
chloroform-d) δ 8.19 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 5.2 Hz, 1H),
7.10 (d, J = 0.9 Hz, 4H), 4.28 (s, 2H), 2.31 (s, 3H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 153.2, 147.5, 146.3, 136.3, 133.8, 129.2,
128.2, 124.2, 35.7, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for
C13H12Cl2N 252.0347; found 252.0355.
1
mg, 16%.) (The reaction also gave 11−36 mg, 73%.) H NMR (500
MHz, chloroform-d) δ 8.16 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 8.1 Hz,
2H), 7.08−7.01 (m, 2H), 6.74 (d, J = 5.6 Hz, 1H), 4.07 (s, 2H),
3.86 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (126 MHz, chloroform-
d) δ 165.3, 152.4, 148.5, 135.7, 135.7, 129.0, 128.4, 123.9, 105.8,
56.1, 31.8, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for
C14H15ClNO 248.0842; found 248.0839.
2-Chloro-N,N-dimethyl-3-(4-methylbenzyl)pyridin-4-amine (14)
and 4-Chloro-N,N-dimethyl-3-(4-methylbenzyl)pyridin-2-amine
(13). To a vial containing 2,4-dichloro-3-(4-methylbenzyl) pyridine
(8c) (50 mg, 0.2 mmol, 1 equiv) was added dimethyl amine (224
μL, 2.0 mmol, 10 equiv) and the resulting suspension was allowed
to stir at 110 °C using a heating block fitted on a stir plate for 16 h.
Once complete, the reaction was concentrated and purified by
column chromatography using ethyl acetate in hexanes as eluent to
give 14 as a white solid (43 mg, 83%) and 13 as a clear oil (7 mg,
14%).
Procedure for Reaction in Scheme 3. 6-Bromo-4-chloro-2-
methoxy-3-(4-methylbenzyl)quinoline (9). To a stirring solution of
6-bromo-2,4-dichloro-3-(4-methylbenzyl)quinoline (8a) (194 mg,
0.5 mmol, 1 equiv) in toluene (3 mL) was added sodium methoxide
(275 mg, 5.1 mmol, 10 equiv) and the reaction was allowed to stir
at 115 °C using a heating block fitted on a stir plate for 48 h. Once
complete, the reaction was concentrated and purified by column
chromatography using ethyl acetate in hexanes as the mobile phase
1
to give 9 as a white solid (151 mg, 78%). Mp: 121−123 °C; H
1
14: mp 87−89 °C; H NMR (500 MHz, chloroform-d) δ 8.12
NMR (500 MHz, chloroform-d) δ 8.26 (s, 1H), 7.69 (d, J = 1.3 Hz,
2H), 7.17 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 4.25 (s,
2H), 4.07 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 161.4, 144.4, 141.1, 136.2, 135.7, 133.3, 129.4,
129.4, 128.8, 127.1, 125.4, 125.0, 118.6, 54.5, 33.2, 21.4; HRMS
(ESI) m/z: [M + H]+ calcd for C18H16BrClNO 376.0104; found
376.0118.
(d, J = 5.6 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 7.01 (d, J = 8.1 Hz,
2H), 6.80 (d, J = 5.6 Hz, 1H), 4.16 (s, 2H), 2.73 (s, 6H), 2.30 (s,
3H); 13C{1H} NMR (126 MHz, chloroform-d) δ 161.8, 154.5,
147.7, 135.6, 135.5, 129.1, 127.8, 124.9, 112.4, 43.7, 34.7, 21.0;
HRMS (ESI) m/z: [M + H]+ calcd for C15H18ClN2 261.1158;
found 261.1164.
1
13: H NMR (500 MHz, chloroform-d) δ 8.09 (d, J = 5.3 Hz,
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-methylbenzyl)quinoline
(10). To
a
stirring solution of 6-bromo-2,4-dichloro-3-(4-
1H), 7.07 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 6.94 (d, J
= 5.3 Hz, 1H), 4.17 (s, 2H), 2.77 (s, 6H), 2.31 (s, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 164.6, 146.3, 145.8, 135.8, 135.5,
129.1, 127.7, 124.5, 118.6, 42.9, 34.4, 21.0; HRMS (ESI) m/z: [M +
H]+ calcd for C15H18ClN2 261.1158; found 261.1160.
methylbenzyl)quinoline (8a) (200 mg, 0.5 mmol, 1 equiv) in
DMF (1.8 mL) was added azetidine (106 μL, 1.6 mmol, 3 equiv)
and the reaction was allowed to stir at 110 °C using a heating block
fitted on a stir plate for 18 h. Once complete, the reaction was
L
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Procedure for Reactions in Scheme 4. 4-Chloro-3-(4-
methylbenzyl)quinoline-2-carbonitrile (15). To a reaction vial
containing 2,4-dichloro-3-(4-methylbenzyl)quinoline (8b) (100 mg,
0.3 mmol, 1 equiv), zinc cyanide (19 mg, 0.2 mmol, 0.5 equiv), and
tetrakis(triphenylphosphine)palladium (38 mg, 0.03 mmol, 0.1
equiv) was added degassed DMF (1 mL) and the resulting
suspension was allowed to stir at 115 °C using a heating block fitted
on a stir plate for 2 h. Once complete, the reaction was
concentrated and purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 15 as a white solid
(ESI) m/z: [M + H]+ calcd for C17H14ClN4 309.0907; found
309.0909.
4-Chloro-3-(4-methylbenzyl)picolinonitrile (19). To a reaction
vial containing 2,4-dichloro-3-(4-methylbenzyl)pyridine (8c) (50
mg, 0.2 mmol, 1 equiv), zinc cyanide (12 mg, 0.1 mmol, 0.5 equiv),
and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol, 0.1
equiv) was added degassed DMF (1 mL) and the resulting
suspension was allowed to stir at 115 °C using a heating block fitted
on a stir plate for 2 h. Once complete, the reaction was
concentrated and purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 19 as a clear oil (34
1
(85 mg, 88%). Mp: 132−134 °C. H NMR (500 MHz, chloroform-
1
d) δ 8.31−8.26 (m, 1H), 8.18−8.13 (m, 1H), 7.87−7.80 (m, 1H),
7.80−7.74 (m, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.6 Hz,
2H), 4.54 (s, 2H), 2.30 (s, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 147.3, 143.3, 136.7, 135.2, 133.8, 133.7, 131.1,
130.6, 130.3, 129.4, 128.6, 127.5, 124.4, 116.4, 36.2, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C18H14ClN2 293.0845; found
293.0851.
mg, 71%). H NMR (500 MHz, chloroform-d) δ 8.47 (d, J = 5.2
Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 7.10
(d, J = 8.0 Hz, 2H), 4.34 (s, 2H), 2.31 (s, 3H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 149.4, 145.7, 139.9, 136.8, 135.7, 133.2,
129.4, 128.5, 128.1, 116.1, 35.7, 21.0; HRMS (ESI) m/z: [M + H]+
calcd for C14H12ClN2 243.0689; found 243.0693.
4-Chloro-2-methyl-3-(4-methylbenzyl)pyridine (20). To a vial
were added 2,4-dichloro-3-(4-methylbenzyl) pyridine (8c) (50 mg,
0.2 mmol, 1 equiv) and Fe(acac)3 (3 mg, 0.01 mmol, 0.04 equiv).
The vial was sealed with a septum cap, evacuated, purged with
nitrogen, and the mixture was dissolved in THF (2 mL) and NMP
(1 mL). The reaction mixture was then treated dropwise with
methyl magnesium bromide (3 M in ether) (76 μL, 0.2 mmol, 1.1
equiv) at ambient temperature. The reaction was allowed to stir for
2 h. Once complete, the reaction was quenched by adding water (3
mL) and extracted with EtOAc (2 × 10 mL). The organic layers
were combined, washed with water (10 mL), concentrated in vacuo,
and purified by column chromatography using ethyl acetate in
hexanes as the mobile phase to give 20 as a clear oil (38 mg, 83%).
1H NMR (500 MHz, chloroform-d) δ 8.28 (d, J = 5.3 Hz, 1H), 7.22
(d, J = 5.3 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 8.0 Hz,
2H), 4.17 (s, 2H), 2.51 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (126
MHz, chloroform-d) δ 159.7, 147.4, 144.7, 136.0, 134.6, 132.4,
129.3, 127.8, 122.6, 34.7, 23.4, 21.0; HRMS (ESI) m/z: [M + H]+
calcd for C14H15ClN 232.0893; found 232.0890.
2-Chloro-4-methyl-3-(4-methylbenzyl)pyridine (21). To a vial
were added 2,4-dichloro-3-(4-methylbenzyl) pyridine (8c) (50 mg,
0.2 mmol, 1 equiv) and Fe(acac)3 (3 mg, 0.01 mmol, 0.04 equiv).
The vial was sealed with a septum cap, evacuated, purged with
nitrogen, and the mixture was dissolved in THF (3 mL). The
reaction mixture was then treated dropwise with methyl magnesium
bromide (3 M in ether) (76 μL, 0.2 mmol, 1.1 equiv) at ambient
temperature. The reaction was allowed to stir for 2 h. Once
complete, the reaction was quenched by adding water (3 mL) and
extracted with EtOAc (2 × 10 mL). The organic layers were
combined, washed with water (10 mL), concentrated in vacuo, and
purified by column chromatography using ethyl acetate in hexanes
as the mobile phase to give 21 as a clear oil (12 mg, 26%). 1H
NMR (500 MHz, chloroform-d) δ 8.16 (d, J = 4.8 Hz, 1H), 7.06
(dd, J = 12.8, 6.3 Hz, 3H), 6.98 (d, J = 8.1 Hz, 2H), 4.16 (s, 2H),
2.30 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR (126 MHz, chloroform-
d) δ 152.5, 149.6, 147.1, 135.9, 134.6, 133.5, 129.3, 127.9, 124.9,
35.0, 21.0, 20.1; HRMS (ESI) m/z: [M + H]+ calcd for C14H15ClN
232.0893; found 232.0891.
3-(4-Methylbenzyl)quinoline-2,4-dicarbonitrile (16). To a reac-
tion vial containing 2,4-dichloro-3-(4-methylbenzyl)quinoline (8b)
(100 mg, 0.3 mmol, 1 equiv), zinc cyanide (78 mg, 0.7 mmol, 2
equiv), and tetrakis(triphenylphosphine)palladium (38 mg, 0.03
mmol, 0.1 equiv) was added degassed DMF (1 mL) and the
resulting suspension was allowed to stir at 115 °C using a heating
block fitted on a stir plate for 2 h. Once complete, the reaction was
concentrated and purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 16 as a white solid
1
(91 mg, 97%). Mp: 181−183 °C; H NMR (500 MHz, chloroform-
d) δ 8.27−8.19 (m, 2H), 7.95−7.86 (m, 2H), 7.31 (d, J = 8.2 Hz,
2H), 7.13 (d, J = 7.6 Hz, 2H), 4.57 (s, 2H), 2.30 (s, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 146.6, 139.9, 137.3, 134.8, 133.3,
132.3, 131.9, 130.7, 129.7, 128.8, 126.9, 125.0, 119.6, 115.8, 114.1,
37.5, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for C19H14N3
284.1187; found 284.1189.
2,4-Diethyl-3-(4-methylbenzyl)quinoline (17). To a degassed
suspension of 2,4-dichloro-3-(4-methylbenzyl)quinoline (8b) (120
mg, 0.4 mmol, 1 equiv) and dichloro (diphenylphosphinoferrocene)
palladium (29 mg, 0.04 mmol, 0.1 equiv) in anhydrous
tetrahydrofuran (4 mL) was added a 1.1 M diethylzinc solution in
toluene (430 μL, 0.5 mmol, 1.2 equiv) and the resulting suspension
was allowed to stir at 65 °C using a heating block fitted on a stir
plate for 18 h. Once complete, the reaction was concentrated and
purified by column chromatography using ethyl acetate in hexanes
as the mobile phase to give 17 as a clear oil (68 mg, 59%). 1H
NMR (500 MHz, chloroform-d) δ 8.06 (dd, J = 8.4, 1.2 Hz, 1H),
7.99 (dd, J = 8.5, 1.3 Hz, 1H), 7.66−7.60 (m, 1H), 7.52−7.45 (m,
1H), 7.04 (d, J = 7.8 Hz, 2H), 6.90 (d, J = 7.9 Hz, 2H), 4.24 (s,
2H), 3.04 (q, J = 7.6 Hz, 2H), 2.91 (q, J = 7.5 Hz, 2H), 2.29 (s,
3H), 1.30 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.7 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 163.5, 147.9, 147.0, 136.6, 135.7,
129.6, 129.2, 128.3, 128.2, 127.7, 126.1, 125.5, 123.6, 33.5, 29.9,
21.8, 20.9, 14.7, 13.6; HRMS (ESI) m/z: [M + H]+ calcd for
C21H24N 290.1908; found 290.1915.
5-Chloro-4-(4-methylbenzyl)tetrazolo[1,5-a]quinoline (18). To a
suspension of 2,4-dichloro-3-(4-methylbenzyl)quinoline (8b) (100
mg, 0.3 mmol, 1 equiv) and sodium azide (32 mg, 0.5 mmol, 1.5
equiv) in ethanol (2.5 mL) was added trifluoro acetic acid (50 μL,
0.7 mol, 2 equiv) and the resulting solution was heated under reflux
using a heating block fitted on a stir plate for 18 h. Once complete,
the reaction was concentrated, diluted with saturated aqueous
ammonium chloride solution (15 mL), and extracted twice with
ethyl acetate (15 mL). The organic fractions were combined,
concentrated, and purified by column chromatography using ethyl
acetate in hexanes as the mobile phase to give 18 as a white solid
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00496.
Detailed characterization data (1H and 13C{1H} NMR
spectra) for all products (PDF)
1
(89 mg, 87%). Mp: 154−156 °C. H NMR (500 MHz, chloroform-
d) δ 8.66 (dd, J = 8.2, 1.2 Hz, 1H), 8.34 (dd, J = 8.4, 1.2 Hz, 1H),
7.89−7.83 (m, 1H), 7.78−7.72 (m, 1H), 7.43 (d, J = 8.1 Hz, 2H),
7.07 (d, J = 7.9 Hz, 2H), 4.64 (s, 2H), 2.27 (s, 3H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 148.2, 136.7, 135.1, 133.9, 131.3, 129.5,
129.3, 129.0, 128.5, 126.6, 124.7, 122.6, 116.8, 34.5, 21.0; HRMS
AUTHOR INFORMATION
Corresponding Author
■
Pratik R. Chheda − Discovery Chemistry, Janssen Research
and Development, San Diego, California 92121, United
M
https://doi.org/10.1021/acs.joc.1c00496
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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States; orcid.org/0000-0001-5788-3324;
Email: pchheda2@its.jnj.com
Authors
David A. Kummer − Lundbeck La Jolla Research Center,
Inc., San Diego, California 92121, United States
Rachel T. Nishimura − Discovery Chemistry, Janssen
Research and Development, San Diego, California 92121,
United States
Kelly J. McClure − Discovery Chemistry, Janssen Research
and Development, San Diego, California 92121, United
States
Hariharan Venkatesan − Discovery Chemistry, Janssen
Research and Development, San Diego, California 92121,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00496
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Heather McAllister for performing HRMS
experiments.
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