Highly Chemoselective Deoxygenation of N-Heterocyclic N-Oxides Using Hantzsch Esters as Mild Reducing Agents

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Highly Chemoselective Deoxygenation of N‑Heterocyclic N‑Oxides

Using Hantzsch Esters as Mild Reducing Agents

Ju Hyeon An, Kyu Dong Kim, and Jun Hee Lee*

Cite This: J. Org. Chem. 2021, 86, 2876 −2894

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sı Supporting Information

ABSTRACT: Herein, we disclose a highly chemoselective room-temperature deoxygenation method applicable to various

functionalized N-heterocyclic N-oxides via visible light-mediated metallaphotoredox catalysis using Hantzsch esters as the sole

stoichiometric reductant. Despite the feasibility of catalyst-free conditions, most of these deoxygenations can be completed within a

few minutes using only a tiny amount of a catalyst. This technology also allows for multigram-scale reactions even with an extremely

low catalyst loading of 0.01 mol %. The scope of this scalable and operationally convenient protocol encompasses a wide range of

functional groups, such as amides, carbamates, esters, ketones, nitrile groups, nitro groups, and halogens, which provide access to the

corresponding deoxygenated N-heterocycles in good to excellent yields (an average of an 86.8% yield for a total of 45 examples).

INTRODUCTION

the nitrogen atom of hydrazine (H NNH ) because of the

2 2

■

presence of an adjacent nitrogen atom with a lone pair of

Chemoselective strategies represent a powerful synthetic skill

that can be used to gain access to useful scaﬀolds that are

otherwise too diﬃcult to synthesize by other methods.

Considering the importance of the N-oxide moiety of N-

heterocycles as a superb directing group for various site-

selective C−H functionalizations, for example, the develop-

ment of eﬃcient protocols for the chemoselective removal of

the oxygen atom from densely functionalized oxygenated

heterocycles under mild and eco-friendly conditions is highly

desirable in organic synthesis. Conventional procedures used

for such a purpose often require harsh conditions that are not

compatible with functionalized substrates.

Over the past decade, visible light-mediated photoredox

catalysis has emerged as a powerful and practical strategy that

enables various chemoselective transformations under inher-

13

electrons (i.e., α-eﬀect).

1

Given their reactivity as superior electron donors in various

photoredox catalysis reactions as well as their beneﬁcial

properties, such as high stability, ready availability, and low

toxicity, we anticipated that 1,4-dihydropyridine-3,5-dicarbox-

ylate esters [Hantzsch esters (HEHs)] would be a suitable

reductant in the proposed chemoselective deoxygenation of N-

oxide-bearing functional groups that are incompatible with the

previously developed conditions (Scheme 1b). From an

environmental perspective, the use of nontoxic, greener

reductants is also highly desirable. Importantly, we anticipated

that HEHs are capable of fulﬁlling all the requirements

mentioned above as both a sacriﬁcial single-electron donor and

2

3

4

−10

14

hydrogen atom donor.

1

ently mild conditions. We became interested in the

chemoselective deoxygenation of N-heterocyclic N-oxides in

the context of our ongoing program to exploit photoredox

catalysis for the development of new synthetic trans-

RESULTS AND DISCUSSION

■

To test the feasibility of our proposal, we selected quinoline N-

oxide 2a bearing an ester functionality as the model substrate.

Pleasingly, the proposed deoxygenation of 2a in acetonitrile

1

2

formations. In this context, we recently reported the use of

inexpensive, commercially available hydrazine hydrate as the

reductant in the visible light photoredox-catalyzed room-

temperature deoxygenation of a range of N-heterocyclic N-

(

CH CN) turned out to be feasible at ambient temperature

3

using several commercial organo- and metallaphotocatalysts

3f

Received: November 24, 2020

Published: January 12, 2021

oxide derivatives (Scheme 1a). However, we realized that

several versatile functional groups, such as the amides,

carbamates, esters, ketones, halogens at the 2- and 4-positions

of quinolines and pyridines, and nitro groups, are not

compatible with the reaction conditions. These incompatibil-

ities are mainly associated with the increased nucleophilicity of

©

2021 American Chemical Society

https://dx.doi.org/10.1021/acs.joc.0c02805

2

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The Journal of Organic Chemistry

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Scheme 1. Visible Light Photocatalytic Deoxygenation of N-Heterocyclic N-Oxides

a

Table 1. Optimization of Reaction Conditions

entry

catalyst

1 (equiv)

time (min)

yield (%)

1

2

3

4

5

6

7

8

9

1

4

1a (1.2)

1b (1.2)

1c (1.2)

1c (1.5)

1d (1.5)

1c (1.5)

5

360

5

60

5

30

600

300

90

86

71

89

91

95

b

eosinY

4

c

54

53

87

d

e

f

0

1

2

3

90

95

g

4

h

0

89

a

b

Optimization reactions were performed on a 0.20 mmol scale of 2a under the irradiation of blue LEDs. All yields are isolated yields. Under

irradiation of green LEDs. DMF (0.05 M) as the solvent. DMSO (0.05 M) as the solvent. In 0.1 M CH CN. Under irradiation of a 30 W CFL.

3

g

h

In the absence of visible light. In the absence of a photocatalyst.

along with Et-HEH 1a as the photoreductant under two 3 W

formation of the deoxygenated product 3a, which is probably

blue LED irradiation (Table 1, entries 1−3). Having identiﬁed

because of its high solubility in CH CN (entry 5). Another

3

II/I

[

Ru(bpy) ]Cl (4, E

= −1.33 V vs the saturated calomel

appealing feature of 1c is that its pyridine byproduct can be

more easily separated from the deoxygenated products 3 by

simple ﬂash column chromatography in comparison to the

pyridines derived from other HEHs. Furthermore, just

increasing the amount of 1c (1.5 equiv to 2a) gave an

3

2

1/2

15a

electrode (SCE) in CH CN, bpy = 2,2′-bipyridine) as a

3

suitable photocatalyst, we also examined other HEHs, such as

Me-HEH 1b and tert-Bu-HEH 1c (entries 4 and 5). Among

the HEHs tested, 1c showed the best performance for the

2

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a

Scheme 2. Deoxygenation of N-Heterocyclic N-Oxides

a

b

Conditions: 2 (0.20 mmol), 1c (0.30 mmol), and 4 (1.0 mol %) in degassed CH CN (4 mL). All yields are isolated yields. In degassed DMSO

3

(0.3 M).

excellent yield of 3a (95%, entry 6). Either using other polar,

ingly, the visible light-mediated deoxygenation reaction

proceeds, even in the absence of a photocatalyst, albeit at a

much slower rate (entry 13).

aprotic solvents [i.e., dimethylformamide (DMF) and dimethyl

sulfoxide (DMSO)] or increasing the concentration of 2a gave

inferior results (entries 7−9). Conveniently, anhydrous

solvents are unnecessary for these photocatalytic reactions.

Switching the source of visible light from blue light-emitting

diodes (LEDs) to a 30 W compact ﬂuorescent lamp (CFL) led

to a somewhat diminished yield (entry 10). Interestingly, the

use of 4-Me-HEH 1d did not aﬀect the outcome of this

transformation at all, although a much-prolonged reaction time

of 10 h was used (entry 11). A control experiment conﬁrmed

that visible light irradiation is essential for the feasibility of this

new reductive deoxygenation protocol (entry 12). Interest-

Under these optimized conditions (Table 1, entry 6), we

found that a diverse range of synthetically valuable functional

groups, such as ester (2a−2e), amide (2f), carbamate (2g),

ketone (2h), nitro (2i), nitrile (2j), triﬂuoromethyl (2k),

halogens (2l−2q), alkyl(s) (2r−2t), aryl (2u), methoxy (2v),

silyloxy (2w), 1,3-dioxolane (2x), and alkynyl (2y) groups,

were all tolerated, and the desired deoxygenated quinoline

derivatives 3a−3y were isolated in good to excellent yields

(Scheme 2). Noteworthy examples include 2a−2i and 2l−2n,

which are incompatible with our previous reaction conditions

2

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Scheme 3. Control Experiments

because of the competitive side reactions caused by the highly

3f

nucleophilic hydrazine hydrate. For example, the deoxygena-

tions of carboxylic acid derivatives (2a−2g) and halogenated

quinolines at the 2- or 4-position (2l−2n) compete with

nucleophilic acyl and aromatic substitutions by the reductant,

respectively. Furthermore, the deoxygenations of ketone 2h

and nitro derivative 2i are hampered by the occurrence of

undesired side reactions such as hydrazone formation and the

reduction of the nitro group, respectively. We also explored the

possibility of using substrate 2z bearing a quinoxaline motif,

which suﬀers from a severe overreduction by the in situ

generated diimide, presumably because of the weak aromaticity

3f,16

of the heterocycle.

Pleasingly, we found that 2z is well-

tolerated in this transformation. Moreover, reactions of

isoquinoline N-oxides 2aa and 2ab and phthalazine N-oxide

(2ac), as well as dialkylarylamine N-oxides 2ad and 2ae and

alkyldiarylamine N-oxide 2af, provided access to the desired

products in synthetically useful yields. We did not observe any

signiﬁcant amounts of byproducts derived from undesired over

reduction in all the cases. Note that most of these

deoxygenations can be completed in only 5 min (Scheme 2).

To gain more insights into the mechanism of the present

deoxygenation reaction, we performed a series of control

experiments. As mentioned above, we performed the

deoxygenation of 2a with 1c in the absence of a photocatalyst

Figure 1. Proposed mechanism.

E₁_/₂_*II/I = +0.77 V vs SCE in CH CN),

15a

(

we did not

3

observe any measurable luminescence quenching of the same

ox

photoexcited species by HEH 1c (E = +0.95 V vs SCE in

1

/2

(

Table 1, entry 13 and Scheme 3a). Interestingly, the

18h

CH CN) in CH CN in our Stern−Volmer experiment. To

3

deoxygenation reaction did proceed to give the desired

product 3a in an 89% yield, albeit at a very sluggish rate

compared to the standard conditions using 4. This experiment

suggests that the photoexcited HEH itself can trigger the

deoxygenation of 2a (vide infra). In addition, a marginal

our surprise, we have found that the emission intensity of the

excited photocatalyst is readily diminished in the presence of

17

either N-oxides 2a or 2e. However, the oxidation of

heterocyclic N-oxides with the excited state of the Ru

photocatalyst seems unlikely because of their high oxidation

20

kinetic deuterium isotope eﬀect (k /k = 1.3) was observed in

H

D

potential.

Based on these observations and literature precedents,

1

7

14,18

the deoxygenation of 2a (Scheme 3b), implying that the rate

determining-step of the overall process might not be the

hydrogen atom transfer (HAT) process (see Figure 1).

Furthermore, the same deoxygenation process was suﬃciently

suppressed by the radical inhibitor galvinoxyl (2.3 equiv to 1c),

indicating that the reaction might proceed via radical or radical

ion intermediates (Scheme 3c).

we have proposed a mechanism for the present deoxygenation,

as shown in Figure 1. The catalytic cycle would begin with the

photoexcitation of both HEH 1 and a photocatalyst Ru-

(

bpy) Cl (4) by visible light irradiation with blue LEDs,

3 2

aﬀording a highly reducing HEH* (1*) and a long-lived

2

+

18

photoexcited state, *[Ru (bpy) ] , respectively. The acidic

3

21

To obtain a better understanding of the photoredox catalytic

nature of 1 (pK of 1a = 3.50 ± 0.70) could facilitate

a

cycle, we also performed a series of ﬂuorescence quenching

photoinduced proton transfer from 1* to A to achieve

equilibrium with an ion-pair consisting of N-hydroxyquinoli-

nium B and HEH anion C via the hydrogen-bonding

intermediate. As a pivotal step, we propose that the subsequent

1

7

experiments with [Ru(bpy) ]Cl (4). In agreement with

3

2

18d

ox

Ngai’s observation, in which HEH 1a (E₁= +0.887 V vs

/2

1

8d,19

2+

SCE in CH CN)

does not quench *[Ru(bpy)₃]

3

2

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II

reduction of the long-lived excited-state species *Ru by the

anion C via a single-electron transfer (SET) process would

portion of N-oxide 2a (0.200 mmol), 1c (0.300 mmol), and

CH CN (4.0 mL), degassed by bubbling with N for 5−10

min and irradiated with blue LEDs. Surprisingly, we found that

the photocatalytic system is so robust that its activity does not

cease even after 12 times of reuse with all complete

conversions (Scheme 5). The average yield for the catalyst

3

2

•

result in the formation of HEH radical D (HEH ) along with

To close the photo-

catalytic cycle with the regeneration of the photocatalyst

+

18c

the reduced species [Ru(bpy) ] .

3

2

+

I

[

Ru(bpy) ] , the available Ru species should be able to

3

reduce cation B via a SET process to aﬀord N-centered radical

E and a hydroxide ion. E would then abstract an activated

hydrogen atom from radical D to furnish quinolinium ion F

and pyridine G. Indeed, this critical HAT process would be

highly facilitated by the strong aromatic stabilization energy of

G. The subsequent deprotonation of F with the hydroxide ion

would ﬁnally provide access to quinoline H and water as a

byproduct (Figure 1).

Scheme 5. Catalyst Reuse Experiment

In the absence of a photocatalyst, the reductive cleavage of

the N−O bond would also be possible by the direct action of C

toward B via a SET process to aﬀord radicals D and E and a

hydroxide ion. Another feasible mechanistic scenario for the

generation of radical species D and E, along with the

hydroxide, might involve the proton-coupled electron transfer

process of the hydrogen-bonded complex forming between

reuse experiment was 86%, and it means that this catalytic

system provides a turnover number (TON) of more than

1

0,000 (860 × 12). To the best of our knowledge, we have

22

quinoline N-oxide A and the excited state 1*. Either through

an ion-pair or a hydrogen-bonding intermediate, the attractive

interaction between the anionic oxygen atom of an N-oxide

and the hydrogen atom bonded to the nitrogen of HEH 1 was

achieved the highest TON reported among any catalytic

deoxygenation reactions of N-heteroaryl N-oxides.

23

The successful execution of the multigram-scale reactions

and the catalyst reuse experiment led us to evaluate the scope

of this deoxygenation reaction for pyridine N-oxides with a low

catalyst loading of 0.1 mol %. Moreover, we found that the use

of [Ir(ppy) (dtbbpy)]PF (ppy = 2-phenylpyridine, dtbbpy =

1

validated by H NMR experiments. Thus, when we gradually

increased the amount of the quinoline N-oxide 2a relative to

that of tert-Bu-HEH 1c, we observed both the proportional

upﬁeld and downﬁeld shifts of the methyl groups and the N−

2

6

III/II

4

,4′-di-tert-butyl-2,2′-bipyridine) (7) (E

= −1.51 V vs

1

/2

1

17

H on 1c, respectively, in the H NMR spectra.

15b

SCE in CH CN)

possessing a more negative reduction

3

To examine the practicability and scalability of this

photocatalytic deoxygenation protocol, we performed a series

of multigram-scale reactions (Scheme 4). First, the deoxyge-

potential than 4 was essential for the smooth removal of the

3f

oxygen atom from the pyridine N-oxides because their N−O

bond dissociation energy is higher than that of quinoline N-

24

oxides. As demonstrated in Scheme 5, fortunately, our

protocol proved feasible for a broad range of functionalized

pyridine N-oxides 5a−5l, providing access to the correspond-

ing pyridines 6a−6l in good to excellent yields irrespective of

both the nature and position of the functional groups. Several

valuable functional groups containing a carbonyl group, such as

ester (5a), amide (5b), and ketone (5c) groups, embedded in

pyridine N-oxides were also well tolerated under the

heteroleptic catalyst 7. Furthermore, pyridine N-oxides 5d−

Scheme 4. Multigram-Scale Reactions

5

e bearing a chlorine substituent(s) at either the 2- or 2,4-

positions are suitable substrates with an excellent eﬃciency.

Pyridine N-oxides 5f−5k having an aryl substituent are

successful substrates, regardless of the position and steric and

electronic nature of the aryl group, providing the correspond-

ing deoxygenated products 6f−6k in good to excellent yields.

Moreover, the compatibility of this deoxygenation reaction

with a medicinally important motif was demonstrated with 7-

azaindole (6l, 91% yield). Unfortunately, 2,2′-bipyridyl-N,N′-

dioxide (5m) exhibited low reactivity, presumably because of

nation of the N-oxide 2c was completed in 20 min on a

multigram scale (3 g, 13 mmol, a 65-fold scale-up) to aﬀord

quinoline 3c in a 95% yield using the standard conditions (1

mol % 4, S/C = 100, 1.5 equiv 1a). Next, the same scale

deoxygenation of 2c was executed nicely to produce the same

yield (95%), which was achieved using a catalyst loading of 0.1

mol % (S/C = 1,000). Gratifyingly, 3c was obtained in a 96%

yield when we performed a larger scale reaction of 2c (4.6 g, 20

mmol, a 100-fold scale-up) with an extremely low catalyst

loading (1.5 mg of 4) of 0.01 mol % (S/C = 10,000) under

otherwise identical conditions, albeit with a slightly extended

reaction time of 55 min (Scheme 4).

its low solubility in CH CN. Further experimentation revealed

3

that a 4:1 mixture of 2,2,2-triﬂuoroethanol (TFE) and CH CN

3

increases the solubility of 5m and thus signiﬁcantly improves

the catalytic performance with only a slight excess of 1c (2.5

equiv), aﬀording 6k in a high yield (Scheme 6).

Moreover, the robustness of the newly developed homoge-

neous catalytic system was further demonstrated by a catalyst

reuse experiment as follows: upon completion of the

photocatalytic deoxygenation of the standard substrate 2a

During the preparation of this manuscript, Jacob von

Wangelin and co-workers reported a similar ﬁnding as ours

in which the deoxygenation of N-heterocyclic N-oxides is

feasible via visible-light photoexcitation of Et-HEH 1a, even in

(

1

0.200 mmol) in CH CN (4.0 mL, 0.05 M) with tert-Bu-HEH

3

25

c (0.300 mmol) in the presence of 0.1 mol % Ru(bpy) Cl

the absence of a photocatalyst. Although the addition of a

metallaphotocatalyst is necessary for the best performance of

3

2

(4), the resulting mixture was repeatedly treated with another

2

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a

Scheme 6. Deoxygenation of Pyridine N-Oxides

a

Conditions: 5 (1.1 mmol, 1.0 equiv), 1c (1.65 mmol, 1.5 equiv), and 7 (0.1 mol %) in degassed CH CN (22 mL, 0.05 M). All yields are isolated

3

b

c

yields. NMR yield using 1,3,5-trimethoxybenzene as an internal standard. Bis-N-oxide 5m (1.1 mmol, 1.0 equiv), 1c (2.75 mmol, 2.5 equiv), and

(0.1 mol %) in degassed TFE/CH CN (4:1, v/v, 13.8 mL, 0.08 M).

7

3

the present deoxygenation protocol, our results compare

favorably with those reported by them in terms of both the

isolated yields and reaction rate, employing only a tiny amount

reactions, even with an extremely low catalyst loading of 0.01

mol % (S/C = 10,000).

2

6

of the catalyst. Whereas they attained an average of 68% yield

calculated based on the better NMR yields) for a total of 22

EXPERIMENTAL SECTION

■

(

General Information. Experiments involving moisture- and/or

air-sensitive compounds were performed in an oven- or ﬂame-dried

glassware with rubber septa under a positive pressure of nitrogen

using standard Schlenk techniques. Nonaqueous reagents were

transferred by a hypodermic syringe. Heating was accomplished by

a silicon oil bath using a temperature controller. Brine is deﬁned as

saturated aqueous solution of sodium chloride. Organic solutions

were concentrated under reduced pressure at 30 °C (water bath

examples with 16 h as the optimal reaction time, we have

achieved an 87% average yield for a total of 45 amine N-oxides

under the reaction conditions. In general, it takes only a few

minutes to complete our deoxygenation reactions, and the

longest reaction time was 3.5 h for pyridine N-oxide 5i.

Moreover, the deoxygenation of several N-heteroaromatic N-

2

5

oxides, such as 6-methoxyquinoline N-oxide (2v, 20% yield

temperature) using a Buchi rotary evaporator, unless otherwise noted.

̈

Reactions were magnetically stirred and monitored by thin-layer

chromatography (TLC) or gas chromatography (GC). Yields refer to

25

vs 80% yield), isoquinoline N-oxide (2aa, 71% yield₂vs 96%

5

yield), 2,6-dichloropyridine N-oxide (5e, 79% yield₂vs 92%

5

1

yield), 4-phenylpyridine N-oxide (5h, 97% yield vs 96%

chromatographically and spectroscopically ( H NMR) homogeneous

25

yield), 7-azaindole N-oxide (5l, 83% yield vs 91% yield), and

(>95%) materials, unless otherwise stated. For deoxygenation

reactions, the stirred mixture was irradiated with two MR16 3 W

blue LED spotlight lamps (12 V, 452 nm) from a distance of

approximately 3 cm. A fan was employed for maintaining the reaction

temperature at room temperature during the irradiation. The melting

points were measured using a Stuart SMP50 apparatus and are

uncorrected. TLC was performed on E. Merck 60-F254 precoated

plates (0.25 mm), and spots were visualized by UV ﬂuorescence (254

nm) quenching, iodine vapor, and KMnO₄staining. Flash

chromatography was carried out with Merck silica gel 60 (200−400

25

2

,2′-bipyridyl N,N′-dioxide (5m, 53% yield vs 91% yield), is

included in these studies. Hence, they allow a direct

comparison of these two deoxygenation protocols.

CONCLUSIONS

■

In conclusion, we have developed a visible light-mediated

photocatalytic method that allows for the highly chemo-

selective deoxygenation of various N-heterocyclic N-oxides

using only a slight excess of a HEH as a photoreductant

without the need for any additional stoichiometric reagents.

The newly established conditions tolerate a wide range of

valuable functional groups, such as amide, carbamate, ester,

ketone, nitrile, nitro, halogens, triﬂuoromethyl groups, and so

forth, thus achieving access to the desired deoxygenated N-

heterocycles in good to excellent yields (an average of an

27

1

13

mesh) according to the procedure of Still et al. H and C NMR

spectra were recorded with a Bruker AVANCE III Ascend 500 (500

and 126 MHz, respectively) and AVANCE III HD (400 and 101

1

9

MHz, respectively) spectrometers. F NMR spectra were obtained on

a Bruker AVANCE III Ascend 500 spectrometer (471 MHz).

1

Chemical shifts of the H NMR (CDCl : 7.26 ppm, DMSO-d : 2.50

3

6

1

3

ppm, CD CN: 1.94 ppm) and C NMR (CDCl : 77.00 ppm,

3

DMSO-d : 39.50 ppm, CD CN: 118.26 ppm) spectra were referenced

6

3

to residual solvent peaks or tetramethylsilane (0.00 ppm) as an

8

6.8% yield for a total of 45 examples). Finally, this

1

internal standard. H NMR spectra are reported as follows: chemical

operationally convenient protocol can be performed under

ambient conditions, does not require dried solvents or any

special laboratory equipment, and allows for multigram-scale

shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quarter, quin

= quintet, sext = sextet, sept = septet, m = multiplet, br = broad), and

coupling constant (J) in Hz and integration. Infrared (IR) spectra

2

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−

1

+

were recorded on a Bruker AVATAR 370 DTGS spectrometer using

1021, 831, 742 cm ; HRMS (ESI, TOF) m/z: calcd for [M + Na]

(C H D NNaO ), 334.1958; found, 334.1958; mp 165.5−167.4 °C.

thin ﬁlm samples on KBr plates and are reported in terms of

1

7

25

2

4

−

1

frequency of absorption (cm ). Low-resolution mass spectra were

acquired using a HP 6890 GC system coupled with a HP 5973 mass

selective detector with electron impact (EI) mode or an Agilent 1260

inﬁnity LC−MS system coupled with an Agilent 6120 quadrupole

mass spectrometer with electrospray ionization (ESI) mode. High-

resolution mass spectra (HRMS) were obtained from the Organic

Chemistry Research Center (OCRC) at Sogang University (Seoul,

Korea) using a Bruker Compact ESI-TOF mass spectrometer.

Materials. Unless otherwise stated, all reagents and solvents were

purchased at the highest commercial quality from commercial

suppliers (Sigma-Aldrich, TCI, Alpha Aesar, Strem, or Acros) and

used as received without further puriﬁcation. [Ru(bpy) ]Cl ·6H O

Preparation of N-Heterocyclic N-Oxides (2 and 5). N-

Heterocyclic N-oxides were prepared according to the literature

procedures, further puriﬁed by recrystallization from an appropriate

mixture of solvents as indicated, and stored in a desiccator.

Methyl Quinoline-6-carboxylate-N-oxide (2a). Prepared accord-

ing to the literature procedure and further puriﬁed by recrystalliza-

3b

tion from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the

title compound as a white solid. H NMR (500 MHz, CDCl

1

): δ 8.78

3

(d, J = 9.1 Hz, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.57 (dd, J = 6.1, 1.0 Hz,

1H), 8.31 (dd, J = 9.1, 1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.35

(dd, J = 8.5, 6.1 Hz, 1H), 3.99 (s, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 165.7, 143.3, 137.0, 130.9, 130.5, 130.0, 129.8, 126.4,

121.9, 120.4, 52.6; LC−MS (ESI) m/z: calcd for [M + 1]

), 204.1; found, 204.1.

Ethyl Quinoline-6-carboxylate-N-oxide (2b). Prepared according

to the literature procedure and further puriﬁed by recrystallization

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.77 (d, J

9.1 Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.56 (dd, J = 6.0, 1.0 Hz,

1

3

1

3

2

3

+

(

4) is a known compound and was purchased from TCI and used as

received.

Preparation of HEHs (1). HEHs were prepared according to the

(C11H10NO

3

29a

literature procedures, further puriﬁed by recrystallization from an

appropriate mixture of solvents as indicated, and stored in a

1

refrigerator under an N atmosphere.

3

2

=

Diethyl 2,6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

28a

(

1a). Prepared according to the literature procedure and further

1H), 8.31 (dd, J = 9.1, 1.8 Hz, 1H), 7.84−7.78 (m, 1H), 7.35 (dd, J =

8.4, 6.1 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H);

C{ H} NMR (126 MHz, CDCl ): δ 165.2, 143.2, 137.0, 130.8 (two

3

puriﬁed by recrystallization from hot EtOH to aﬀord the title

1

13

1

compound as a light green solid. H NMR (500 MHz, CDCl ): δ 5.24

3

(

=

9

(

s, 1H), 4.16 (q, J = 7.1 Hz, 4H), 3.25 (s, 2H), 2.18 (s, 6H), 1.27 (t, J

carbons), 129.9, 129.8, 126.4, 121.8, 120.3, 61.7, 14.3; LC−MS (ESI)

7.1 Hz, 6H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 168.0, 144.8,

1

+

m/z: calcd for [M + 1] (C H NO ), 218.1; found, 218.1.

3

12 12

3

+

9.5, 59.6, 24.8, 19.1, 14.4; GC−MS (EI, 70 eV) m/z: calcd for [M]

Isopropyl Quinoline-6-carboxylate-N-oxide (2c). A 100 mL

29b

C H NO ), 253.1; found, 253.1.

round-bottomed ﬂask was charged with quinoline-6-carboxylate

(861 mg, 4.00 mmol, 1.00 equiv) and CH Cl (13.3 mL), and the

13

19

4

Dimethyl 2,6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

2

28b

(1b). Prepared according to the literature procedure

and further

resulting mixture was cooled in an ice-water bath. A separate pear-

shaped ﬂask was charged with m-CPBA (77%, 1.34 g, 6.00 mmol, 1.50

equiv) in CH Cl (17 mL), and the resulting m-CPBA solution was

puriﬁed by recrystallization from hot MeOH to aﬀord the title

compound as a light green solid. H NMR (500 MHz, DMSO): δ

8

(

1

2

1

3

1

.32 (s, 1H), 3.58 (s, 6H), 3.13 (s, 2H), 2.11 (s, 6H); C{ H} NMR

added dropwise to the ﬂask containing the pyridine at 0 °C via a

126 MHz, DMSO): δ 167.4, 146.7, 96.9, 50.6, 24.7, 17.8; GC−MS

syringe. The pear-shaped ﬂask was rinsed with CH Cl (1.0 mL × 3),

2

+

(

EI, 70 eV) m/z: calcd for [M] (C H NO ), 225.1; found, 225.1.

and the resulting solution was added via a syringe. After stirring for 10

min, the cold reaction mixture was allowed to slowly warm to room

temperature. After stirring for 4 h at that temperature, the reaction

mixture was poured into water (20 mL). The organic layer was

separated, and the aqueous layer was extracted with CH Cl (15 mL

1

15

4

Di-tert-butyl 2,6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxy-

28b

late (1c). Prepared according to the literature procedure

further puriﬁed by recrystallization from hot MeOH to aﬀord the title

and

1

compound as a light green solid. H NMR (500 MHz, CDCl ): δ 5.09

3

2

s, 1H), 3.16 (s, 2H), 2.13 (s, 6H), 1.47 (s, 18H); ¹³C{ H} NMR

1

(

× 3). The combined organic layer was washed successively with

126 MHz, CDCl ): δ 167.6, 143.7, 100.9, 79.4, 28.4, 25.4, 19.2;

aqueous solution of saturated NaHCO , water, and brine, dried over

3

+

GC−MS (EI, 70 eV) m/z: calcd for [M] (C H NO ), 309.2;

anhydrous Na SO , ﬁltered, and concentrated on a rotary evaporator.

1

7

17

4

2

4

found, 309.3.

Di-tert-butyl 2,4,6-Trimethyl-1,4-dihydropyridine-3,5-dicarboxy-

The residue thus obtained was puriﬁed by ﬂash column chromatog-

raphy (EtOAc/MeOH = 8:1) on silica gel to aﬀord an oﬀ-white solid,

which was further puriﬁed by recrystallization from a hot mixture of

28c

late (1d). Prepared according to the literature procedure

and

further puriﬁed by recrystallization from hot MeOH to aﬀord the title

compound as a white solid. H NMR (500 MHz, CDCl ): δ 5.39 (s,

hexanes and EtOAc (1:1, v/v) to yield the title compound as a white

1

3

solid (604 mg, 65%). H NMR (500 MHz, CDCl ): δ 8.77 (d, J = 9.1

3

1

6

1

H), 3.74 (q, J = 6.5 Hz, 1H), 2.21 (s, 6H), 1.48 (s, 18H), 0.94 (d, J =

Hz, 1H), 8.62−8.55 (m, 2H), 8.31 (dd, J = 9.2, 1.8 Hz, 1H), 7.82 (d, J

.5 Hz, 3H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 167.3, 143.1,

1

3

= 8.4 Hz, 1H), 7.35 (dd, J = 8.5, 6.0 Hz, 1H), 5.31 (sept, J = 6.3 Hz,

1

3

1

06.0, 79.3, 29.2, 28.3, 22.1, 19.4; GC−MS (EI, 70 eV) m/z: calcd for

1H), 1.41 (d, J = 6.3 Hz, 6H); C{ H} NMR (126 MHz, CDCl ): δ

3

+

[

M] (C H NO ), 323.2; found, 323.3.

164.7, 143.2, 137.0, 131.2, 130.7, 129.9 (two carbons), 126.4, 121.8,

120.3, 69.4, 21.9. IR (KBr): 3058, 2980, 1711, 1620, 1573, 1455,

17

4

Di-tert-butyl 4-Deuterio-2,6-dimethyl-1,4-dihydro-4-deuterio-

−

1

pyridine-3,5-dicarboxylate (1c-d ). A 25 mL round-bottomed ﬂask

equipped with a magnetic stir bar was charged with tert-butyl

acetoacetate (2.85 g, 18.0 mmol, 2.00 equiv), d -paraformaldehyde

2

1363, 1284, 1258, 1224, 1178, 1148, 1133, 1111, 1093 cm ; HRMS

+

(ESI, TOF) m/z: calcd for [M + Na] (C H NNaO ), 254.0788;

1

3

13

3

2

found, 254.0788; mp 121.1−125.3 °C.

(288 mg, 9.00 mmol, 1.00 equiv), and ammonium acetate (1.04 g,

tert-Butyl Quinoline-6-carboxylate-N-oxide (2d). Prepared ac-

28b

29b

1

3.5 mmol, 1.50 equiv). The resulting mixture was heated in an oil

cording to the literature procedure

and further puriﬁed by

bath (bath temperature = 45 °C) for 4 h with vigorous stirring. The

mixture was allowed to cool to room temperature and treated with

cold water (10 mL). The resulting yellow solid was collected on a

sintered glass ﬁlter, washed with cold water (50 mL × 3) to remove

the remaining salts, and dissolved in CH Cl (100 mL). The resulting

recrystallization from a hot mixture of hexanes and EtOAc (1:1, v/

v) to aﬀord the title compound as a white solid. H NMR (500 MHz,

1

CDCl ): δ 8.76 (d, J = 9.1 Hz, 1H), 8.56 (d, J = 6.1 Hz, 1H), 8.53 (d,

3

J = 1.8 Hz, 1H), 8.26 (dd, J = 9.1, 1.8 Hz, 1H), 7.81 (d, J = 8.4 Hz,

1

3

1

2

1H), 7.34 (dd, J = 8.5, 6.0 Hz, 1H), 1.64 (s, 9H); C{ H} NMR (126

solution was washed successively with H O (30 mL) and brine (30

MHz, CDCl ): δ 164.3, 143.2, 136.9, 132.3, 130.5, 130.0, 129.9,

2

3

mL), dried over anhydrous Na SO , ﬁltered, and concentrated on a

126.5, 121.6, 120.1, 82.2, 28.1; LC−MS (ESI) m/z: calcd for [M +

2

4

+

rotary evaporator. The crude mixture thus obtained was puriﬁed by

1] (C H NO ), 246.1; found, 246.1.

1

4

16

3

recrystallization from hot MeOH to aﬀord the title compound as a

Methyl Quinoline-3-carboxylate-N-oxide (2e). A 100 mL round-

bottomed ﬂask was charged with methyl quinoline-3-carboxylate

1

29c

white solid (1.20 g, 43%). H NMR (500 MHz, CDCl ): δ 5.12 (s,

3

1

3

1

H), 2.13 (s, 6H), 1.47 (s, 18H); C{ H} NMR (126 MHz, CDCl ):

(748.8 mg, 4.00 mmol, 1.00 equiv) and CH Cl (13.3 mL), and the

3

2

δ 167.6, 143.8, 100.7, 79.4, 28.4, 19.1; IR (KBr): 3325, 3242, 2967,

resulting mixture was cooled in an ice-water bath. A separate pear-

shaped ﬂask was charged with m-CPBA (77%, 1.34 g, 6.00 mmol, 1.50

2082, 1695, 1642, 1487, 1366, 1349, 1302, 1252, 1153, 1133, 1058,

2

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The Journal of Organic Chemistry

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Article

equiv) in CH Cl (17 mL), and the resulting m-CPBA solution was

6-Nitroquinoline-N-oxide (2i). Prepared according to the literature

30a

2

added dropwise to the ﬂask containing the pyridine at 0 °C via a

procedure

and further puriﬁed by recrystallization from a hot

syringe. The pear-shaped ﬂask was rinsed with CH Cl (1.0 mL × 3),

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

2

1

and the resulting solution was added via a syringe. After stirring for 10

min, the cold reaction mixture was allowed to slowly warm to room

temperature. After stirring for 30 min at that temperature, the reaction

mixture was poured into water (20 mL). The organic layer was

separated, and the aqueous layer was extracted with CH Cl (15 mL

as a yellow solid. H NMR (500 MHz, DMSO): δ 9.14 (d, J = 2.5 Hz,

1H), 8.77 (dd, J = 6.1, 1.0 Hz, 1H), 8.69 (d, J = 9.5 Hz, 1H), 8.47

(dd, J = 9.5, 2.5 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.5,

1

3

1

6.1 Hz, 1H); C{ H} NMR (126 MHz, DMSO): δ 146.7, 142.7,

138.0, 129.9, 126.6, 125.4, 124.0, 123.3, 121.4; LC−MS (ESI) m/z:

2

+

×

3). The combined organic layer was washed successively with

calcd for [M + 1] (C H N O ), 191.0; found, 191.1.

9

7

2

3

aqueous solution of saturated NaHCO , water, and brine, dried over

3-Cyanoquinoline-N-oxide (2j). Prepared according to the

3

3b

anhydrous Na SO , ﬁltered, and concentrated on a rotary evaporator.

literature procedure and further puriﬁed by recrystallization from

2

4

The residue thus obtained was puriﬁed by ﬂash column chromatog-

raphy (EtOAc/MeOH = 15:1) on silica gel to aﬀord an oﬀ-white

solid, which was further puriﬁed by recrystallization from a hot

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

1

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.75 (d, J

3

= 8.8 Hz, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.99−7.88 (m, 2H), 7.79 (t,

1

3

1

mixture of EtOAc and hexanes (10:1, v/v) to yield the title compound

J = 7.6 Hz, 1H); C{ H} NMR (101 MHz, CDCl ): δ 143.3, 134.8,

3

1

as a white solid (546 mg, 67%). H NMR (500 MHz, CDCl ): δ 9.02

133.3, 130.5, 129.7, 129.0 (two carbons), 120.0, 114.9, 107.2; LC−

3

+

(

d, J = 1.5 Hz, 1H), 8.75 (dd, J = 8.7, 0.9 Hz, 1H), 8.38 (s, 1H), 7.97

MS (ESI) m/z: calcd for [M + 1] (C H N O), m/z 171.1; found,

1

0

7

2

dd, J = 8.1, 1.6 Hz, 1H), 7.86 (ddd, J = 8.7, 7.0, 1.4 Hz, 1H), 7.71

m/z 171.1.

2-(Triﬂuoromethyl)quinoline-N-oxide (2k). A slightly modiﬁed

1

3

1

ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 3.99 (s, 3H); C{ H} NMR (126

10a,36

MHz, CDCl ): δ 163.8, 143.1, 135.0, 132.5, 129.6, 129.5, 129.1,

1

(

procedure of Ochiai was adopted.

To a stirred solution of 2-

3

+

27.6, 124.4, 120.0, 52.9; LC−MS (ESI) m/z: calcd for [M + 1]

C H NO ), 204.1; found, 204.1.

(triﬂuoromethyl)quinoline (150 mg, 0.761 mmol, 1.00 equiv) in

triﬂuoroacetic acid (2.5 mL) was added 30% hydrogen peroxide (30

μL) via a syringe at room temperature. The reaction mixture was then

stirred in an oil bath (bath temperature = 63 °C) for 3 h. At this

point, the hot mixture was treated with the second portion of

hydrogen peroxide (60 μL). After stirring at the same temperature for

7 h, the third portion of hydrogen peroxide (90 μL) was added. After

heating for 14 h, the reaction mixture was allowed to cool to room

temperature, and volatiles were evaporated. The resulting residue was

treated with water (5 mL), and the mixture was concentrated on a

rotary evaporator. The same procedure was repeated several times.

After dilution with CH Cl (10 mL), the mixture was neutralized with

11

10

3

N,N-Diethyl-3-quinolinecarboxamide-N-oxide (2f). A 25 mL

round-bottomed ﬂask was charged with N,N-diethyl-3-quinolinecar-

29b

boxamide

(114 mg, 0.500 mmol, 1.00 equiv) and CH Cl (1.7

2 2

mL), and the resulting mixture was cooled in an ice-water bath. A

separate pear-shaped ﬂask was charged with m-CPBA (77%, 168 mg,

0

.750 mmol, 0.75 equiv) in CH Cl (1.5 mL), and the resulting m-

2 2

CPBA solution was added dropwise to the ﬂask containing the

pyridine at 0 °C via a syringe. The pear-shaped ﬂask was rinsed with

CH Cl (0.5 mL × 2), and the resulting solution was added via a

2

syringe. After stirring for 10 min, the cold reaction mixture was

allowed to slowly warm to room temperature. After stirring for 30 min

at that temperature, the reaction mixture was poured into water (10

mL). The organic layer was separated, and aqueous layer was

extracted with CH Cl (15 mL × 3). The combined organic layer was

2

solid NaHCO until the evolution of CO ceased (Caution!). The

3

2

mixture was then washed successively with aqueous solution of

saturated NaHCO , water, and brine, dried over anhydrous Na SO ,

3

2

4

2

ﬁltered, and concentrated on a rotary evaporator. The crude mixture

thus obtained was puriﬁed by ﬂash column chromatography

washed successively with aqueous solution of saturated NaHCO₃,

water, and brine, dried over anhydrous Na SO , ﬁltered, and

(hexanes/EtOAc = 3:1) to aﬀord the title compound (115 mg,

2

4

1

concentrated on a rotary evaporator. The residue thus obtained was

puriﬁed by ﬂash column chromatography (EtOAc/MeOH = 9:1) on

71%) as a pinky solid. H NMR (500 MHz, CDCl ): δ 8.76 (d, J = 8.8

3

Hz, 1H), 7.91 (dd, J = 8.1, 1.4 Hz, 1H), 7.81 (ddd, J = 8.7, 6.9, 1.4

1

3

1

silica gel to aﬀord the title compound as yellow dense oil (64.4 mg,

Hz, 1H), 7.78−7.70 (m, 2H), 7.63 (d, J = 8.9 Hz, 1H); C{ H}

2

1

5

3%). H NMR (500 MHz, CDCl ): δ 8.71 (d, J = 8.7 Hz, 1H), 8.51

NMR (126 MHz, CDCl ): δ 142.8, 134.9 (q, J

= 34.2 Hz), 131.2,

3

C−F

1

(

d, J = 1.4 Hz, 1H), 7.87 (dd, J = 8.1, 1.4 Hz, 1H), 7.78 (ddd, J = 8.6,

.9, 1.4 Hz, 1H), 7.71 (s, 1H), 7.66 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H),

131.1, 130.4, 128.3, 124.4, 120.5 (q, J

= 272.5 Hz), 119.9, 118.6

C−F

3

19

6

3

(q, J

= 4.1 Hz); F NMR (471 MHz, CDCl ): δ −67.7; LC−MS

C−F

+

3

.56 (br s, 2H), 3.33 (br s, 2H), 1.25 (br s, 3H), 1.17 (br s, 3H);

(ESI) m/z: calcd for [M + 1] (C H F NO), 214.0; found, 214.1.

10 7 3

13

1

C{ H} NMR (126 MHz, CDCl ): δ 166.2, 141.5, 133.5, 131.1,

4-Chloroquinoline-N-oxide (2l). Prepared according to the

2c

3

130.9, 129.6, 129.4, 128.5, 123.0, 119.7, 43.5, 39.7, 14.3, 12.8; IR

literature procedure and further puriﬁed by recrystallization from

(

1

+

KBr): 3436, 3101, 3059, 2976, 2937, 1626, 1580, 1483, 1437, 1364,

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

−

1

309, 1217, 1140, 1082 cm ; HRMS (ESI, TOF) m/z: calcd for [M

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.75 (dd,

3

+

Na] (C H N NaO ), 267.1104; found, 267.1104.

J = 8.8, 1.2 Hz, 1H), 8.42 (d, J = 6.6 Hz, 1H), 8.20 (dd, J = 8.4, 1.4

Hz, 1H), 7.82 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.74 (ddd, J = 8.3, 6.9,

14

16

2

3

-[Bis(tert-butoxycarbonyl)amino]quinoline-N-oxide (2g). Pre-

29d

13

1

pared according to the literature procedure

and further puriﬁed

1.3 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H); C{ H} NMR (126 MHz,

by recrystallization from a hot mixture of hexanes and EtOAc (1:1, v/

v) to aﬀord the title compound as a white solid. H NMR (500 MHz,

CDCl ): δ 142.2, 135.1, 131.1, 129.8, 129.7, 128.1, 125.2, 121.0,

3

1

+

120.4; LC−MS (ESI) m/z: calcd for [M + 1] (C H ClNO), 180.0;

9

7

CDCl ): δ 8.70 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.84

found, 180.0.

3

(

dd, J = 8.2, 1.6 Hz, 1H), 7.75 (ddd, J = 8.7, 6.9, 1.4 Hz, 1H), 7.64

ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.55 (s, 1H), 1.41 (s, 18H); C{ H}

4,7-Dichloroquinoline-N-oxide (2m). Prepared according to the

literature procedure and further puriﬁed by recrystallization from a

1

3

1

30b

NMR (126 MHz, CDCl ): δ 150.6, 140.5, 136.2, 133.1, 130.5, 129.2

hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

3

1

(

two carbons), 128.3, 124.6, 119.7, 84.1, 27.8; LC−MS (ESI) m/z:

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.77 (d, J

3

+

calcd for [M + 1] (C H N O ), 361.2; found, 361.2.

= 2.1 Hz, 1H), 8.41 (d, J = 6.6 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.68

1

9

25

2

5

1

3

1

3

-Acetylquinoline-N-oxide (2h). Prepared according to the

(dd, J = 9.0, 2.1 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H); C{ H} NMR

3b

literature procedure and further puriﬁed by recrystallization from

(126 MHz, CDCl ): δ 142.4, 138.1, 135.8, 130.8, 129.5, 126.7, 126.5,

3

+

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

121.2, 120.0; LC−MS (ESI) m/z: calcd for [M + 1] (C H Cl NO),

214.0; found, 214.0.

9

6

2

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.98 (d, J

3

=

1.5 Hz, 1H), 8.77−8.71 (m, 1H), 8.24 (s, 1H), 8.00 (dd, J = 8.2, 1.4

2-Chloro-4-methylquinoline-N-oxide (2n). Prepared according to

the literature procedure and further puriﬁed by recrystallization

30c

Hz, 1H), 7.86 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.72 (ddd, J = 8.0, 6.9,

1

3

1

.1 Hz, 1H), 2.69 (s, 3H); C{ H} NMR (126 MHz, CDCl ): δ

94.1, 143.0, 134.0, 132.6, 130.6, 129.8, 129.6, 129.2, 126.2, 120.0,

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

3

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.78 (dd,

3

+

2

6.6; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO ), 188.1;

J = 8.7, 1.3 Hz, 1H), 7.92 (dd, J = 8.3, 1.3 Hz, 1H), 7.76 (ddd, J = 8.6,

7.0, 1.4 Hz, 1H), 7.65 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.29 (s, 1H),

1

10

2

found, 188.1.

2

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J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

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Article

1

2

1

.62 (s, 3H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 141.9, 137.7,

6-Methoxyquinoline-N-oxide (2v). Prepared according to the

30d

3

34.2, 130.6, 128.4, 128.3, 124.8, 122.8, 120.4, 18.1; LC−MS (ESI)

m/z: calcd for [M + 1] (C H ClNO), 194.0; found, 194.1.

literature procedure and further puriﬁed by recrystallization from a

+

1

0

9

hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

1

6

-Fluoroquinoline-N-oxide (2o). Prepared according to the

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.65 (d, J

3

0d

literature procedure and further puriﬁed by recrystallization from

= 9.6 Hz, 1H), 8.39 (dd, J = 6.0, 1.1 Hz, 1H), 7.63 (d, J = 8.5 Hz,

1H), 7.42−7.34 (m, 1H), 7.25−7.22 (m, 1H), 7.10 (d, J = 2.4 Hz,

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.76 (dd,

J = 9.0, 5.2 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 8.5 Hz,

H), 7.53−7.45 (m, 2H), 7.31 (dd, J = 8.5, 6.0 Hz, 1H); C{ H}

NMR (126 MHz, CDCl ): δ 161.8 (d, J

1

13

1

3

1H), 3.94 (s, 3H); C{ H} NMR (101 MHz, CDCl ): δ 159.5,

3

137.3, 133.8, 132.0, 125.0, 122.8, 121.5 (two carbons), 105.8, 55.7;

1

3

1

+

1

LC−MS (ESI) m/z: calcd for [M + 1] (C H NO ), 176.1; found,

1

0

10

2

1

= 251.8 Hz), 138.7,

= 5.8 Hz), 122.9 (d,

C−F

176.1.

3

C−F

3

4

1

35.0, 131.7 (d, J

= 10.0 Hz), 124.9 (d, J

4-(((tert-Butyldimethylsilyl)oxy)methyl)quinoline-N-oxide (2w).

C−F

3

2

29d

J_C₋_F= 9.3 Hz), 122.2, 120.3 (d, J

= 25.5 Hz), 111.5 (d, J

=

Prepared according to the literature procedure and further puriﬁed

C−F

2

2.7 Hz); ¹⁹F NMR (471 MHz, CDCl ): δ −109.4; LC−MS (ESI)

by recrystallization from a hot mixture of hexanes and EtOAc (1:1, v/

3

+

1

m/z: calcd for [M + 1] (C H FNO), 164.1; found, 164.1.

v) to aﬀord the title compound as a white solid. H NMR (400 MHz,

9

7

6

-Bromoquinoline-N-oxide (2p). Prepared according to the

CDCl ): δ 8.81 (d, J = 8.1 Hz, 1H), 8.54 (d, J = 6.2 Hz, 1H), 7.91 (d,

3

1a

literature procedure and further puriﬁed by recrystallization from

J = 8.4 Hz, 1H), 7.77 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H), 7.66 (ddd, J =

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.62 (d, J

9.2 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.82

8.3, 6.8, 1.3 Hz, 1H), 7.45 (d, J = 6.2 Hz, 1H), 5.14 (s, 2H), 0.97 (s,

1

3

1

3

9H), 0.16 (s, 6H); C{ H} NMR (101 MHz, CDCl ): δ 140.7,

3

=

(

6

1

−

37.1, 135.4, 130.1, 128.6, 127.5, 123.3, 120.5, 118.2, 61.5, 25.8, 18.4,

+

dd, J = 9.2, 2.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5,

5.3; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO Si), 290.2;

1

6

24

2

.0 Hz, 1H); ¹³C{ H} NMR (101 MHz, CDCl ): δ 140.4, 135.8,

1

3

found, 290.2.

33.8, 131.6, 130.1, 124.6, 123.3, 122.2, 121.8; LC−MS (ESI) m/z:

calcd for [M + 1] (C H BrNO), 224.0; found, 224.0.

-Iodoquinoline-N-oxide (2q). Prepared according to the literature

procedure and further puriﬁed by recrystallization from a hot

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

as a white solid. H NMR (500 MHz, CDCl ): δ 8.49 (d, J = 6.1 Hz,

H), 8.44 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 7.97 (dd, J =

3

-(1,3-Dioxolan-2-yl)quinoline-N-oxide (2x). Prepared according

+

2c

9

7

to the literature procedure and further puriﬁed by recrystallization

6

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

3b

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.71 (d, J

3

=

8.7 Hz, 1H), 8.63 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.1, 1.3 Hz,

1

3

1H), 7.79 (s, 1H), 7.75 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.64 (ddd, J =

1

9

1

13

1

8

.1, 6.9, 1.2 Hz, 1H), 5.94 (s, 1H), 4.15−4.03 (m, 4H); C{ H}

.1, 1.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 6.0 Hz,

NMR (126 MHz, CDCl ): δ 141.5, 134.2, 132.6, 130.6, 129.7, 129.0,

_H₎_;1 C{ H} NMR (126 MHz, CDCl ): δ 140.9, 139.0, 136.6,

3

1

3

1

28.4, 123.5, 119.8, 101.0, 65.4; LC−MS (ESI) m/z: calcd for [M +

35.8, 132.0, 124.2, 122.0, 121.5, 95.1; LC−MS (ESI) m/z: calcd for

M + 1] (C H INO), 272.0; found, 272.0.

+

] (C H NO ), 218.1; found, 218.1.

+

12 12

3

[

9

7

6

-(Phenylethynyl)quinoline-N-oxide (2y). Prepared according to

3

-Methylquinoline-N-oxide (2r). Prepared according to the

30b

the literature procedure

and further puriﬁed by recrystallization

3

1a

literature procedure and further puriﬁed by recrystallization from

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.67 (d, J

8.4 Hz, 1H), 8.40 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 8.1, 1.4 Hz,

H), 7.66 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.58 (ddd, J = 8.1, 6.9, 1.3

Hz, 1H), 7.50 (s, 1H), 2.43 (s, 3H); C{ H} NMR (101 MHz,

CDCl ): δ 139.7, 137.0, 131.2, 130.2, 129.3, 128.7, 127.4, 125.4,

1

compound as a pale yellow solid. H NMR (500 MHz, CDCl ): δ

1

3

8

1

7

.72 (d, J = 9.0 Hz, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.03 (d, J = 1.7 Hz,

H), 7.84 (dd, J = 9.0, 1.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60−

.53 (m, 2H), 7.41−7.34 (m, 3H), 7.30 (dd, J = 8.5, 6.0 Hz, 1H);

=

1

3

1

13

1

C{ H} NMR (126 MHz, CDCl ): δ 140.8, 135.9, 133.0, 131.7,

3

+

131.0, 130.4, 128.9, 128.5, 125.2, 124.2, 122.4, 121.7, 120.1, 92.2,

1

19.6, 18.7; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO),

1

0

10

+

8

2

7.9; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO), m/z

1

7

12

60.1; found, 160.1.

-Methylquinoline-N-oxide (2s). Prepared according to the

46.1; found, m/z 246.1.

Quinoxaline-N-oxide (2z). Prepared according to the literature

4

3

0d

literature procedure and further puriﬁed by recrystallization from

31a

procedure

and further puriﬁed by recrystallization from a hot

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a brown solid. H NMR (400 MHz, CDCl ): δ 8.80

dd, J = 8.7, 1.3 Hz, 1H), 8.43 (d, J = 6.1 Hz, 1H), 7.96 (dd, J = 8.5,

.4 Hz, 1H), 7.76 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H), 7.66 (ddd, J = 8.2,

.8, 1.4 Hz, 1H), 7.14−7.08 (m, 1H), 2.65 (s, 3H); C{ H} NMR

101 MHz, CDCl ): δ 141.0, 134.9, 134.5, 130.0, 129.8, 128.4, 124.7,

21.4, 120.3, 18.3; LC−MS (ESI) m/z: calcd for [M + 1]

C H NO), 160.1; found, 160.1.

1

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

3

1

as a white solid. H NMR (500 MHz, CDCl ): δ 8.66 (d, J = 3.6 Hz,

3

(

1

6

(

1

H), 8.57 (dd, J = 8.6, 1.5 Hz, 1H), 8.34 (d, J = 3.6 Hz, 1H), 8.12

1

3

1

(dd, J = 8.4, 1.3 Hz, 1H), 7.82 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.74

1

3

1

(

ddd, J = 8.5, 7.0, 1.4 Hz, 1H); C{ H} NMR (126 MHz, CDCl ): δ

3

+

146.0, 145.9, 137.5, 131.7, 130.2, 130.1, 129.2, 118.9; LC−MS (ESI)

+

m/z: calcd for [M + 1] (C H N O), 147.1; found, 147.1.

(

8

7

2

10

Isoquinoline-N-oxide (2aa). Prepared according to the literature

2

,6-Dimethylquinoline-N-oxide (2t). Prepared according to the

31a

3

1b

procedure

and further puriﬁed by recrystallization from a hot

literature procedure and further puriﬁed by recrystallization from a

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.67 (d, J

1

as a pale purple solid. H NMR (400 MHz, CDCl ): δ 8.75 (s, 1H),

3

8

1

(

.12 (dd, J = 7.1, 1.7 Hz, 1H), 7.80−7.73 (m, 1H), 7.73−7.67 (m,

=

(

1

8.7 Hz, 1H), 7.60−7.53 (m, 3H), 7.28 (s, 1H), 2.71 (s, 3H), 2.53

13 1

s, 3H); ¹³C{ H} NMR (101 MHz, CDCl ): δ 144.9, 140.1, 137.7,

1

H), 7.65 (d, J = 7.1 Hz, 1H), 7.63−7.54 (m, 2H); C{ H} NMR

3

101 MHz, CDCl ): δ 136.8, 136.1, 129.5, 129.5, 129.0, 128.8, 126.6,

32.4, 129.3, 126.9, 124.6, 122.9, 119.3, 21.3, 18.6; LC−MS (ESI) m/

z: calcd for [M + 1] (C H NO), 174.1; found, 174.1.

3

+

124.9, 124.2; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO),

146.1; found, 146.1.

1

12

9 8

2

-Phenylquinoline-N-oxide (2u). Prepared according to the

2

c

literature procedure and further puriﬁed by recrystallization from

5-Bromoisoquinoline-N-oxide (2ab). Prepared according to the

31c

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (500 MHz, CD CN): δ 8.69 (d,

J = 8.8 Hz, 1H), 7.98−7.90 (m, 3H), 7.82 (dd, J = 8.7 Hz, 1H), 7.79

ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.67 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H),

.57−7.43 (m, 4H); C{ H} NMR (126 MHz, CD CN): δ 145.6,

43.2, 134.9, 131.5, 130.9, 130.6, 130.4, 129.5, 129.4, 129.2, 126.1,

24.6, 120.6; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO),

22.1; found, 222.1.

literature procedure and further puriﬁed by recrystallization from a

1

hot mixture of hexanes and EtOAc (2:1, v/v) to aﬀord the title

3

1

compound as an orange solid. H NMR (400 MHz, CDCl

): δ 8.73

3

(

(d, J = 1.8 Hz, 1H), 8.20 (dd, J = 7.4, 1.8 Hz, 1H), 8.02 (d, J = 7.3 Hz,

1H), 7.82 (dd, J = 7.5, 1.0 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.45 (t, J

1

3

1

7

1

2

3

1

3

1

= 7.9 Hz, 1H); C{ H} NMR (101 MHz, CDCl ): δ 138.0, 135.8,

3

+

132.5, 130.6, 130.1, 127.8, 124.5, 123.7, 121.8; LC−MS (ESI) m/z:

1

5

12

+

calcd for [M + 1] (C H BrNO), 224.0; found, 224.0.

9

7

2

884

https://dx.doi.org/10.1021/acs.joc.0c02805

J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

+

Phthalazine-N-oxide (2ac). Prepared according to the literature

12.6; LC−MS (ESI) m/z: calcd for [M + 1] (C H N O ), 195.1;

1

0

15

2

31d

procedure

and further puriﬁed by recrystallization from a hot

found, 195.2.

3-Acetylpyridine-N-oxide (5c). Commercially available and used as

received without further puriﬁcation. H NMR (500 MHz, CDCl ): δ

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

1

as a white solid. H NMR (400 MHz, CDCl ): δ 9.07 (s, 1H), 8.58 (s,

3

1

H), 7.92 (dd, J = 8.1, 1.1 Hz, 1H), 7.82 (ddd, J = 8.2, 6.9, 1.2 Hz,

8.69 (t, J = 1.7 Hz, 1H), 8.33 (ddd, J = 6.4, 1.7, 0.9 Hz, 1H), 7.75

(ddd, J = 7.9, 1.5, 0.9 Hz, 1H), 7.38 (dd, J = 8.0, 6.4 Hz, 1H), 2.59 (s,

1

3

1

H), 7.71−7.66 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ

3

1

3

1

52.6, 134.0, 132.8, 129.7, 127.5, 127.1, 123.4, 120.9; LC−MS (ESI)

3H); C{ H} NMR (126 MHz, CDCl

135.7, 126.0, 124.5, 26.7; LC−MS (ESI) m/z: calcd for [M + 1]

(C NO ), 138.1; found, 138.1.

5-Bromo-2-chloropyridine-N-oxide (5d). Prepared according to

3

): δ 193.6, 142.3, 139.4,

+

m/z: calcd for [M + 1] (C H N O), 147.1; found, 147.1.

8

7

2

N,N-Dimethyl-1-naphthalenamine-N-oxide (2ad). Prepared ac-

7

H

8

2

3

e

cording to the literature procedure and further puriﬁed by

recrystallization from a hot mixture of hexanes and EtOAc (1:1, v/

v) to aﬀord the title compound as a white solid. H NMR (500 MHz,

CDCl ): δ 9.04 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.90 (d,

33a

the literature procedure and further puriﬁed by recrystallization

1

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.46 (d, J

3

=

2.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.7, 2.0 Hz,

J = 6.8 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.1 Hz, 1H),

1

3

1

H); C{ H} NMR (126 MHz, CDCl ): δ 141.7, 141.2, 128.5,

126.9, 118.0; LC−MS (ESI) m/z: calcd for [M + 1]

7

.52 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 3.87 (s, 6H);

3

+

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 148.6, 135.5, 130.9, 129.3,

3

(C H BrClNO), 207.9; found, 207.9.

1

26.9, 126.0, 125.4, 125.1, 124.2, 118.0, 62.2; LC−MS (ESI) m/z:

5

4

+

2,6-Dichloropyridine-N-oxide (5e). Prepared according to the

calcd for [M + 1] (C H NO), 188.1; found, 188.1.

1

2

14

33b

3

2a

literature procedure and further puriﬁed by recrystallization from a

N-Phenylpiperidine-N-oxide (2ae).

A slightly modiﬁed proce-

3b

hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

dure of Chang was adopted. A 100 mL round-bottomed ﬂask was

charged with N-phenylpiperidine (484 mg, 3.00 mmol, 1.00 equiv)

and CH Cl (2 mL), and the resulting mixture was cooled in an ice-

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 7.45 (d, J

=

3

1

3

1

8.2 Hz, 2H), 7.12 (t, J = 8.1 Hz, 1H); C{ H} NMR (126 MHz,

2

CDCl ): δ 143.6, 125.0, 124.3; LC−MS (ESI) m/z: calcd for [M +

3

water bath. A separate pear-shaped ﬂask was charged with m-CPBA

77%, 1.01 g, 4.50 mmol, 1.50 equiv) in CH Cl (11 mL), and the

+

1

] (C H Cl NO), 164.0; found, 164.0.

5 4 2

(

2

-Phenylpyridine-N-oxide (5f). Prepared according to the

33c

resulting m-CPBA solution was added dropwise to the ﬂask

containing the amine at 0 °C via a syringe. The pear-shaped ﬂask

was rinsed with CH Cl (1 mL × 2), and the resulting solution was

added via a syringe. After stirring for 10 min, the cold reaction mixture

was allowed to slowly warm to room temperature. After stirring for

literature procedure and further puriﬁed by recrystallization from

a hot mixture of hexanes and EtOAc (2:1, v/v) to aﬀord the title

2

1

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.33 (dd,

3

J = 6.5, 1.3 Hz, 1H), 7.82 (dd, J = 8.0, 1.7 Hz, 2H), 7.53−7.39 (m,

4

1

H), 7.30 (td, J = 7.7, 1.3 Hz, 1H), 7.22 (ddd, J = 7.6, 6.5, 2.2 Hz,

5.5 h at that temperature, the reaction mixture was treated with

1

3

1

H); C{ H} NMR (101 MHz, CDCl ): δ 149.3, 140.5, 132.6,

3

K CO (1.80 g, 13.0 mmol). The resulting mixture was further stirred

2

3

29.6, 129.2, 128.3, 127.4, 125.5, 124.5; LC−MS (ESI) m/z: calcd for

for 4 h and ﬁltered on a pad of Celite, and the ﬁltrate was

concentrated on a rotary evaporator. The residue thus obtained was

puriﬁed by ﬂash column chromatography (CH Cl /CH OH = 10:1)

on silica gel to aﬀord a brown solid, which was further puriﬁed by

recrystallization from a hot mixture of hexanes and EtOAc (1:20, v/v)

to aﬀord the title compound as a white solid (174 mg, 33%). H

NMR (500 MHz, CDCl ): δ 7.98 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.0

Hz, 2H), 7.34 (t, J = 6.7 Hz, 1H), 3.67 (t, J = 11.5 Hz, 2H), 3.21 (d, J

=

+

[M + 1] (C H NO), 172.1; found, 172.1.

1

10

3

-Phenylpyridine-N-oxide (5g). Prepared according to the

2

3

33d

literature procedure and further puriﬁed by recrystallization from

a hot mixture of hexanes and EtOAc (2:1, v/v) to aﬀord the title

1

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.47 (t, J

1

3

=

1.7 Hz, 1H), 8.19 (dt, J = 6.5, 1.3 Hz, 1H), 7.57−7.41 (m, 6H),

3

13

1

7.34 (dd, J = 8.0, 6.4 Hz, 1H); C{ H} NMR (101 MHz, CDCl ): δ

3

1

40.4, 137.7, 137.6, 135.2, 129.4 (two carbons), 126.9, 125.8, 124.5;

9.2 Hz, 2H), 2.63 (q, J = 11.8, 10.8 Hz, 2H), 1.85 (d, J = 11.7 Hz,

+

LC−MS (ESI) m/z: calcd for [M + 1] (C H NO): 172.1; found,

1

3

1

11 10

1

H), 1.65 (d, J = 13.4 Hz, 2H), 1.49−1.37 (m, 1H); C{ H} NMR

172.1.

(126 MHz, CDCl ): δ 155.1, 129.0, 128.7, 120.3, 68.5, 21.8, 21.1;

3

4

-Phenylpyridine-N-oxide (5h). Prepared according to the

+

LC−MS (ESI) m/z: calcd for [M + 1] (C H NO), 178.1; found,

34a

1

16

literature procedure and further puriﬁed by recrystallization from

178.3.

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

N-Methyl-N-phenylaniline-N-oxide (2af). Prepared according to

1

compound as a white solid. H NMR (400 MHz, CDCl ): δ 8.29−

32b

3

the literature procedure

from a hot mixture of hexanes and EtOAc (1:10, v/v) to aﬀord the

title compound as a beige solid. H NMR (500 MHz, CDCl ): δ 7.72

and further puriﬁed by recrystallization

13

1

8

.22 (m, 2H), 7.62−7.55 (m, 2H), 7.54−7.40 (m, 5H); C{ H}

NMR (101 MHz, CDCl ): δ 139.3, 138.9, 136.1, 129.3, 129.2, 126.4,

123.7; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO), 172.1;

3

1

+

3

1

10

(

3

d, J = 8.0 Hz, 4H), 7.37 (t, J = 7.8 Hz, 4H), 7.30 (t, J = 7.3 Hz, 2H),

found, 172.1.

.91 (s, 3H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 155.3, 128.9,

1

3

2-(4-Methoxyphenyl)pyridine-N-oxide (5i). Prepared according to

+

34b

1

28.5, 121.0, 62.0; LC−MS (ESI) m/z: calcd for [M + 1]

the literature procedure

and further puriﬁed by recrystallization

(

C H NO), 200.1; found, 200.1.

13 14

from a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

Methyl Nicotinate-N-oxide (5a). Prepared according to the

1

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.31 (dd,

3

32c

literature procedure and further puriﬁed by recrystallization from

a hot mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title

compound as a white solid. H NMR (500 MHz, CDCl ): δ 8.71 (t, J

=

J = 6.4, 1.2 Hz, 1H), 7.86−7.79 (m, 2H), 7.41 (dd, J = 7.9, 2.1 Hz,

1

H), 7.27 (td, J = 7.7, 1.2 Hz, 1H), 7.17 (ddd, J = 7.5, 6.5, 2.1 Hz,

1

3

1

3

1H), 7.03−6.96 (m, 2H), 3.85 (s, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 160.5, 149.0, 140.5, 130.8, 126.9, 125.5, 124.9, 123.8,

113.7, 55.3; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO ),

202.1; found, 202.1.

1.5 Hz, 1H), 8.28 (ddd, J = 6.5, 1.5, 1.0 Hz, 1H), 7.79 (dt, J = 7.9,

3

1

3

1

+

1.1 Hz, 1H), 7.33 (dd, J = 7.7, 6,7 Hz, 1H), 3.91 (s, 3H); C{ H}

1

2

12

2

NMR (126 MHz, CDCl ): δ 163.1, 142.3, 140.1, 129.8, 126.0, 125.7,

3

+

5

2.9; LC−MS (ESI) m/z: calcd for [M + 1] (C H NO ), 154.0;

2-(2,4,6-Trimethylphenyl)pyridine-N-oxide (5j). A 50 mL round-

7

8

3

37

found, 154.1.

bottomed ﬂask was charged with 2-mesitylpyridine (631 mg, 3.20

3

-(N,N-Diethylcarbamoyl)pyridine-N-oxide (5b). Prepared ac-

mmol, 1.00 equiv) and CH Cl (3.2 mL), and the resulting mixture

2

32d

cording to the literature procedure

recrystallization from a hot mixture of hexanes and EtOAc (1:1, v/

v) to aﬀord the title compound as a white solid. H NMR (500 MHz,

and further puriﬁed by

was cooled in an ice-water bath. A separate pear-shaped ﬂask was

charged with m-CPBA (77%, 1.08 g, 4.80 mmol, 1.50 equiv) in

CH Cl (5.5 mL), and the resulting m-CPBA solution was added

1

2

CDCl ): δ 8.19−8.17 (m, 2H), 7.32−7.27 (m, 1H), 7.24−7.19 (m,

dropwise to the ﬂask containing the pyridine at 0 °C via a syringe.

3

1

H), 3.50 (d, J = 7.6 Hz, 2H), 3.23 (d, J = 7.3 Hz, 2H), 1.20 (t, J = 7.2

The pear-shaped ﬂask was rinsed with CH Cl (1.0 mL × 3), and the

2

1

3

1

Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H); C{ H} NMR (126 MHz,

resulting solution was added via a syringe. After stirring for 10 min,

the cold reaction mixture was allowed to slowly warm to room

CDCl ): δ 165.4, 139.4, 137.1, 136.2, 126.0, 123.3, 43.3, 39.6, 14.2,

3

2

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temperature. After stirring for 2 h at that temperature, the reaction

mixture was poured into water (20 mL). The organic layer was

separated, and the aqueous layer was extracted with CH Cl (15 mL

residue was directly puriﬁed by ﬂash column chromatography on silica

gel (hexanes and EtOAc) to aﬀord the corresponding deoxygenated

N-heterocycle (3).

Methyl Quinoline-6-carboxylate (3a). Prepared using methyl

quinoline-6-carboxylate N-oxide (2a, 40.6 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

2

×

3). The combined organic layer was washed successively with

aqueous solution of saturated NaHCO , water, and brine, dried over

3

anhydrous Na SO , ﬁltered, and concentrated on a rotary evaporator.

2

4

The residue thus obtained was puriﬁed by ﬂash column chromatog-

raphy (EtOAc/MeOH = 10:1) on silica gel to aﬀord an oﬀ-white

solid, which was further puriﬁed by recrystallization from a hot

mixture of hexanes and EtOAc (1:1, v/v) to yield the title compound

1.0 mol %), and CH CN (4.00 mL, 0.05 M). Methyl quinoline-6-

carboxylate (3a) (35.4 mg, 95%) was isolated (hexanes/EtOAc =

3

1.2:1) as a white solid. Spectroscopic data matched with those

2c

1

reported in the literature. H NMR (500 MHz, CDCl ): δ 8.86 (dd,

3

1

as a white solid (336 mg, 49%). H NMR (500 MHz, DMSO): δ 8.36

J = 4.2, 1.8 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 8.8, 2.0

Hz, 1H), 8.08 (dd, J = 8.4, 1.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.30

(

dd, J = 6.5, 1.3 Hz, 1H), 7.45−7.42 (m, 1H), 7.38 (td, J = 7.5, 1.3

1

3

1

Hz, 1H), 7.35 (dd, J = 7.7, 2.4 Hz, 1H), 6.94 (s, 2H), 2.28 (s, 3H),

(dd, J = 8.3, 4.2 Hz, 1H), 3.86 (s, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 166.2, 152.2, 149.7, 137.0, 130.7, 129.5, 128.6, 127.8,

127.1, 121.5, 52.1; GC−MS (EI, 70 eV) m/z: calcd for [M]

NO ), 187.1; found, 187.1.

1

3

.94 (s, 6H); ¹³C{ H} NMR (126 MHz, DMSO): δ 148.3, 139.6,

37.7, 136.1, 130.5, 128.2, 127.7, 125.5, 124.7, 20.6, 19.1; IR (KBr):

069, 2915, 1614, 1475, 1421, 1293, 1240, 1159, 1012, 842, 787, 759

3

+

(C11

H

9

2

−

1

+

cm ; HRMS (ESI, TOF) m/z: calcd for [M + Na] (C H NNaO),

Ethyl Quinoline-6-carboxylate (3b). Prepared using ethyl quino-

line-6-carboxylate N-oxide (2b, 43.4 mg, 0.200 mmol, 1.00 equiv), 1c

(92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %),

14

15

2

36.1051; found, 236.1046; mp 126.2−127.6 °C.

2

,2′-Bipyridyl N-Oxide (5k). Prepared according to the literature

34c

procedure

and further puriﬁed by recrystallization from a hot

and CH CN (4.00 mL, 0.05 M). Ethyl quinoline-6-carboxylate (3b,

3

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

37.8 mg, 94%) was isolated (hexanes/EtOAc = 1.5:1) as pale yellow

oil. Spectroscopic data matched with those reported in the

1

as a white solid. H NMR (500 MHz, DMSO): δ 8.77−8.71 (m, 2H),

3

8a

1

literature.

Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.29 (dd, J = 8.8, 1.9 Hz, 1H), 8.24

dd, J = 8.3, 2.0 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.3,

.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H);

H NMR (500 MHz, CDCl ): δ 8.98 (dd, J = 4.2, 1.8

8

7

1

.40−8.33 (m, 1H), 8.13−8.07 (m, 1H), 7.97−7.90 (m, 1H), 7.51−

3

.42 (m, 3H); ¹³C{ H} NMR (126 MHz, DMSO): δ 149.5, 149.4,

1

(

46.1, 140.4, 136.2, 127.4, 126.1, 125.3, 124.8, 124.3; LC−MS (ESI)

+

4

m/z: calcd for [M + 1] (C H N O), 173.1; found, 173.1.

1

0

9

2

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 166.0, 152.4, 150.0, 137.2,

7

-Azaindole N-Oxide (5l). Prepared according to the literature

3

34d

procedure

and further puriﬁed by recrystallization from a hot

130.8, 129.7, 128.9, 128.4, 127.3, 121.7, 61.3, 14.3; GC−MS (EI, 70

+

mixture of hexanes and EtOAc (1:1, v/v) to aﬀord the title compound

eV) m/z: calcd for [M] (C12H11NO ), 201.1; found, 201.1.

2

1

as a pale pink solid. H NMR (400 MHz, CDCl ): δ 13.7 (br s, 1H),

Isopropyl Quinoline-6-carboxylate (3c). Prepared using isopropyl

quinoline-6-carboxylate N-oxide (2c, 46.3 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

3

8.26 (dd, J = 6.2, 0.9 Hz, 1H), 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.41 (d,

J = 3.4 Hz, 1H), 7.04 (dd, J = 7.9, 6.2 Hz, 1H), 6.52 (d, J = 3.3 Hz,

1

(

H); ¹³C{ H} NMR (101 MHz, CDCl ): δ 138.9, 131.4, 127.5,

1

1.0 mol %), and CH CN (4.00 mL, 0.05 M). Isopropyl quinoline-6-

3

+

25.4, 122.5, 115.4, 102.2; LC−MS (ESI) m/z: calcd for [M + 1]

C H N O), 135.1; found, 135.1.

carboxylate (3c, 42.2 mg, 98%) was isolated (hexanes/EtOAc = 1.5:1)

as pale yellow oil. Spectroscopic data matched with those reported in

7

2

38b

1

2

,2′-Bipyridyl N,N′-Dioxide (5m). Prepared according to the

the literature.

Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 8.8, 1.9 Hz, 1H), 8.22

dd, J = 8.2, 2.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.3,

H NMR (500 MHz, CDCl ): δ 8.95 (dd, J = 4.2, 1.8

3

35

literature procedure and further puriﬁed by recrystallization from

hot water to aﬀord the title compound as a white solid. H NMR (500

1

(

4

.2 Hz, 1H), 5.29 (hept, J = 6.3 Hz, 1H), 1.39 (d, J = 6.3 Hz, 6H);

MHz, D O): δ 8.42−8.37 (m, 2H), 7.77 (ddd, J = 8.4, 7.4, 1.2 Hz,

2

1

3

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 165.5, 152.3, 149.9, 137.2,

2

1

(

H), 7.71−7.64 (m, 4H); C{ H} NMR (126 MHz, D O): δ 141.8,

3

2

+

39.8, 131.5, 128.9, 128.5; LC−MS (ESI) m/z: calcd for [M + 1]

130.7, 129.6, 128.9, 128.8, 127.3, 121.7, 68.8, 21.9; GC−MS (EI, 70

+

C H N O ), m/z 189.1; found, m/z 189.1.

eV) m/z: calcd for [M] (C13H13NO ), 215.1; found, 215.2.

2

10

9

2

General Procedure for the Initial Optimization Studies

tert-Butyl Quinoline-6-carboxylate (3d). Prepared using tert-butyl

quinoline-6-carboxylate N-oxide (2d, 49.1 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

(

Table 1). A 10 mL test tube equipped with a small magnetic stir bar

was charged with methyl quinoline-6-carboxylate N-oxide (2a, 40.6

mg, 0.200 mmol, 1.00 equiv), HEH (1, 0.300 mmol, 1.50 equiv), and

a photocatalyst (2.0 μmol, 1.0 mol %). The ﬂask was ﬁtted with a

1.0 mol %), and CH CN (4.00 mL, 0.05 M). tert-Butyl quinoline-6-

3

carboxylate (3d, 44.2 mg, 96%) was isolated (hexanes/EtOAc = 2:1)

rubber septum and CH CN (4.00 mL, 0.05 M) was added via a

as pale yellow oil. Spectroscopic data matched with those reported in

3

38c

1

syringe under an atmosphere of nitrogen. After degassing by N₂

bubbling at room temperature for 10−15 min, the reaction mixture

was then irradiated at room temperature with two 3 W blue LEDs for

the indicated time (see Table 1). Upon the completion of the reaction

as determined by TLC, the reaction mixture was concentrated on a

rotary evaporator. The resulting residue was directly puriﬁed by ﬂash

column chromatography on silica gel (hexanes/EtOAc = 1.2:1) to

aﬀord methyl quinoline-6-carboxylate (3a) as a white solid.

the literature.

H NMR (500 MHz, CDCl ): δ 8.97 (dd, J = 4.2, 1.8

3

Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.29−8.21 (m, 2H), 8.10 (d, J =

1

3

1

8.8 Hz, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 1.63 (s, 9H); C{ H}

NMR (126 MHz, CDCl ): δ 165.2, 152.2, 149.9, 137.2, 130.5, 129.9,

129.5, 129.0, 127.3, 121.6, 81.5, 28.2; GC−MS (EI, 70 eV) m/z: calcd

3

+

for [M] (C14H15NO ), 229.1; found, 229.1.

2

Methyl Quinoline-3-carboxylate (3e). Prepared using methyl

quinoline-3-carboxylate N-oxide (2e, 40.6 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

General Procedure for the Visible Light-Mediated Deoxy-

genation of N-Heterocyclic N-Oxides Using [Ru(bpy) ]Cl ·

1.0 mol %), and CH CN (4.00 mL, 0.05 M). Methyl quinoline-3-

3

2

3

6

H O (4) as the Photocatalyst (Scheme 2). A 10 mL test tube

carboxylate (3e, 34.1 mg, 91%) was isolated (hexanes/EtOAc = 2.8:1)

2

equipped with a small magnetic stir bar was charged with N-

as pale yellow oil. Spectroscopic data matched with those reported in

29c

1

heterocyclic N-oxide (2, 0.200 mmol, 1.00 equiv), tert-Bu-HEH (1c,

the literature.

H NMR (500 MHz, CDCl ): δ 9.35 (d, J = 2.2 Hz,

3

9

2.8 mg, 0.300 mmol, 1.50 equiv), and tris(2,2′-bipyridyl)-

dichlororuthenium(II) hexahydrate (4, 1.5 mg, 2.0 μmol, 1.0 mol

). The ﬂask was ﬁtted with a rubber septum and CH CN (4.0 mL,

1H), 8.71 (dd, J = 2.3, 0.9 Hz, 1H), 8.06 (dd, J = 8.5, 1.0 Hz, 1H),

7.81 (dd, J = 8.2, 1.4 Hz, 1H), 7.73 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H),

1

3

1

%

7.51 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 3.93 (s, 3H); C{ H} NMR

3

0

.05 M) was added via a syringe under an atmosphere of nitrogen.

(126 MHz, CDCl ): δ 165.6, 149.8, 149.6, 138.5, 131.6, 129.3, 128.9,

3

+

After degassing by N bubbling at room temperature for 10−15 min,

127.2, 126.6, 122.7, 52.2; GC−MS (EI, 70 eV) m/z: calcd for [M]

(C H NO ), 187.1; found, 187.1.

2

the reaction mixture was then irradiated at room temperature with

two 3 W blue LEDs for the indicated time (see Scheme 2). Upon the

completion of the reaction as determined by TLC, the reaction

mixture was concentrated on a rotary evaporator. The resulting

1

9

2

N,N-Diethyl-3-quinolinecarboxamide (3f). Prepared using N,N-

diethyl-3-quinolinecarboxamide N-oxide (2f, 48.9 mg, 0.200 mmol,

1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0

2

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μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M). N,N-Diethyl-3-

34.5 Hz), 147.1, 138.1, 130.8, 130.1, 128.8, 128.6, 127.6, 121.6 (q,

3

1

3

19

quinolinecarboxamide (3f, 41.0 mg, 90%) was isolated (CH Cl /

J_C₋_F= 275.2 Hz), 116.7 (q, J

= 2.3 Hz); F NMR (471 MHz,

2

C−F

+

acetone = 3.5:1) as pale yellow oil. Spectroscopic data matched with

CDCl ): δ −66.5; GC−MS (EI, 70 eV) m/z: calcd for [M]

3

38d

1

those reported in the literature.

H NMR (500 MHz, CDCl ): δ

(C H F N), 197.0; found, 197.1.

3

10

6 3

8

1

2

.93 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 8.4 Hz,

H), 7.84 (dd, J = 8.2, 1.4 Hz, 1H), 7.76 (ddd, J = 8.4, 6.8, 1.5 Hz,

H), 7.59 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 3.61 (br s, 2H), 3.32 (br s,

H), 1.29 (br s, 3H), 1.16 (br s, 3H); ¹³C{ H} NMR (126 MHz,

4-Chloroquinoline (3l). Prepared using 4-chloroquinoline N-oxide

(2l, 35.9 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50

equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05

3

1

M). 4-Chloroquinoline (3l, 26.4 mg, 81%) was isolated (hexanes/

CDCl ): δ 168.7, 148.1, 148.0, 134.0, 130.4, 130.1, 129.4, 128.1,

1

for [M] (C H N O), 228.1; found, 228.1.

EtOAc = 4:1) as a white solid. Spectroscopic data matched with those

3

39b

1

27.3, 127.1, 43.5, 39.6, 14.3, 12.9; GC−MS (EI, 70 eV) m/z: calcd

reported in the literature.

H NMR (500 MHz, CDCl ): δ 8.68 (d,

3

+

14

16

2

J = 4.7 Hz, 1H), 8.09 (dd, J = 8.6, 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.2

Hz, 1H), 7.66 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.51 (ddd, J = 8.3, 6.9,

3

-[Bis(tert-butoxycarbonyl)amino]quinoline (3g). Prepared using

1

3

1

3

0

-[bis(tert-butoxycarbonyl)amino]quinoline N-oxide (2g, 72.1 mg,

.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4

1.3 Hz, 1H), 7.35 (d, J = 4.7 Hz, 1H); C{ H} NMR (126 MHz,

CDCl ): δ 149.6, 148.9, 142.3, 130.1, 129.6, 127.3, 126.2, 123.8,

3

+

(

[

1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M). 3-

Bis(tert-butoxycarbonyl)amino]quinoline (3g, 62.3 mg, 90%) was

121.0; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H ClN), 163.0;

found, 163.1.

3

9

6

isolated (hexanes/EtOAc = 3.5:1) as a pale yellow solid.

4,7-Dichloroquinoline (3m). Prepared using 4,7-dichloroquinoline

N-oxide (2m, 42.8 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

29d

Spectroscopic data matched with those reported in the literature.

1

H NMR (500 MHz, CDCl ): δ 8.69 (d, J = 2.5 Hz, 1H), 8.10 (d, J =

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

3

8

.5 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.2, 1.4 Hz, 1H),

(4.00 mL, 0.05 M). 4,7-Dichloroquinoline (3m, 29.0 mg, 73%) was

7

.71 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.55 (ddd, J = 8.1, 6.8, 1.1 Hz,

H), 1.39 (s, 18H); C{ H} NMR (126 MHz, CDCl ): δ 151.2,

isolated (hexanes/EtOAc = 1:1) as a white solid. Spectroscopic data

1

3

1

39c

1

matched with those reported in the literature.

H NMR (500 MHz,

3

50.4, 146.6, 133.4, 132.7, 129.7, 129.2, 127.8, 127.6, 127.0, 83.5,

CDCl ): δ 8.71 (d, J = 4.7 Hz, 1H), 8.09−8.02 (m, 2H), 7.50 (dd, J =

3

+

13 1

9.0, 2.2 Hz, 1H), 7.40 (d, J = 4.7 Hz, 1H); C{ H} NMR (126 MHz,

1

9

24

2

4

CDCl ): δ 150.8, 149.3, 142.5, 136.3, 128.6, 128.5, 125.4, 124.8,

3

+

3

-Acetylquinoline (3h). Prepared using 3-acetylquinoline N-oxide

121.3; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H Cl N), 197.0;

found, 197.1.

9

5

2

.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL,

.05 M). 3-Acetylquinoline (3h, 30.9 mg, 90%) was isolated

2-Chloro-4-methylquinoline (3n). Prepared using 2-chloro-4-

methylquinoline N-oxide (2n, 38.7 mg, 0.200 mmol, 1.00 equiv),

1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol

3

3b

1

%), and CH CN (4.00 mL, 0.05 M). 2-Chloro-4-methylquinoline

3

CDCl ): δ 9.41 (d, J = 2.3 Hz, 1H), 8.68 (dd, J = 2.3, 0.9 Hz, 1H),

(3n, 29.2 mg, 82%) was isolated (hexanes/Et O = 10:1) as a white

3

2

8

.13 (dd, J = 8.5, 1.0 Hz, 1H), 7.92 (dd, J = 8.1, 1.4 Hz, 1H), 7.82

solid. Spectroscopic data matched with those reported in the

39d

1

(

ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H),

literature.

H NMR (500 MHz, CDCl ): δ 7.99 (dd, J = 8.5, 1.3

3

1

2

1

.72 (s, 3H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 196.6, 149.8,

Hz, 1H), 7.93 (dd, J = 8.3, 1.4 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4

Hz, 1H), 7.55 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.21 (s, 1H), 2.66 (s,

3

49.1, 137.2, 131.9, 129.4, 129.3, 129.2, 127.5, 126.8, 26.7; GC−MS

+

13

1

(

EI, 70 eV) m/z: calcd for [M] (C H NO), 171.1; found, 171.1.

3H); C{ H} NMR (126 MHz, CDCl ): δ 150.5, 147.7, 147.6,

1

9

3

6

-Nitroquinoline (3i). Prepared using 6-nitroquinoline N-oxide (2i,

130.2, 129.1, 126.9, 126.6, 123.8, 122.4, 18.0; GC−MS (EI, 70 eV)

+

3

8.0 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50

m/z: calcd for [M] (C H ClN), 177.0; found, 177.1.

1

0

8

equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05

M). 6-Nitroquinoline (3i, 25.3 mg, 73%) was isolated (hexanes/

6-Fluoroquinoline (3o). Prepared using 6-ﬂuoroquinoline N-oxide

(2o, 32.6 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol,

3

EtOAc = 1:1) as a yellow solid. Spectroscopic data matched with

1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL,

3

39a

1

those reported in the literature.

H NMR (500 MHz, CDCl ): δ

0.05 M). 6-Fluoroquinoline (3o, 23.0 mg, 78%) was isolated

3

9

1

.09 (dd, J = 4.2, 1.8 Hz, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.47 (dd, J =

(hexanes/EtOAc = 2:1) as pale yellow oil. Spectroscopic data

matched with those reported in the literature. H NMR (500 MHz,

3f

1

.3, 2.5 Hz, 1H), 8.36 (dd, J = 8.3, 1.7 Hz, 1H), 8.23 (d, J = 9.2 Hz,

1

3

1

H), 7.58 (dd, J = 8.3, 4.2 Hz, 1H); C{ H} NMR (126 MHz,

CDCl ): δ 8.82 (dd, J = 4.3, 1.7 Hz, 1H), 8.05 (dd, J = 9.3, 5.3 Hz,

3

CDCl ): δ 153.8, 150.2, 145.5, 137.8, 131.4, 127.0, 124.6, 122.9,

1

found, 174.1.

Quinoline-3-carbonitrile (3j). Prepared using quinoline-3-carbon-

itrile N-oxide (2j, 34.0 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg,

1H), 8.01 (dd, J = 8.4, 1.8 Hz, 1H), 7.46−7.38 (m, 1H), 7.37−7.30

3

+

13

1

22.8; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N O ), 174.0;

(m, 2H). C{ H} NMR (126 MHz, CDCl ): δ 160.2 (d, J

=

9

6

2

3

C−F

4

248.3 Hz), 149.5 (d, J

= 2.9 Hz), 145.3, 135.2 (d, J

= 5.4 Hz),

= 10.0 Hz), 121.6, 119.6 (d,

= 21.8 Hz). F NMR (471 MHz,

C−F

3

131.9 (d, J

= 9.2 Hz), 128.7 (d, J

C−F

2

19

J_C₋_F= 25.8 Hz), 110.5 (d, J

CDCl ): δ −112.3. GC−MS (EI, 70 eV) m/z: calcd for [M]

(C H FN), 147.0; found, 147.1.

C−F

+

0

.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and

3

CH CN (4.00 mL, 0.05 M). Quinoline-3-carbonitrile (3j, 28.4 mg,

3

9

6

9

2%) was isolated (hexanes/EtOAc = 3:1) as a white solid.

6-Bromoquinoline (3p). Prepared using 6-bromoquinoline N-oxide

(2p, 44.8 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol,

3f

Spectroscopic data matched with those reported in the literature.

1

H NMR (500 MHz, CDCl ): δ 8.98 (d, J = 2.1 Hz, 1H), 8.49 (d, J =

1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL,

3

2

.0 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.89−7.82 (m, 2H), 7.69−7.62

0.05 M). 6-Bromoquinoline (3p, 36.9 mg, 89%) was isolated

m, 1H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 149.6, 148.6, 141.3,

1

(hexanes/EtOAc = 2:1) as pale yellow oil. Spectroscopic data

(

3

3f

1

32.6, 129.7, 128.3, 128.1, 126.0, 117.0, 106.4; GC−MS (EI, 70 eV)

matched with those reported in the literature. H NMR (500 MHz,

+

m/z: calcd for [M] (C H N ), 154.1; found, 154.1.

CDCl ): δ 8.90 (dd, J = 4.3, 1.8 Hz, 1H), 8.03 (dd, J = 8.3, 1.7 Hz,

1

0

6

2

3

2

-(Triﬂuoromethyl)quinoline (3k). Prepared using 2-

triﬂuoromethyl)quinoline N-oxide (2k, 42.6 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

.0 mol %), and CH CN (4.00 mL, 0.05 M). 2-(Triﬂuoromethyl)-

1H), 7.98−7.93 (m, 2H), 7.75 (dd, J = 9.0, 2.2 Hz, 1H), 7.39 (dd, J =

1

3

1

(

8.3, 4.2 Hz, 1H); C{ H} NMR (126 MHz, CDCl ): δ 150.7, 146.8,

3

134.9, 132.9, 131.2, 129.7, 129.3, 121.8, 120.4; GC−MS (EI, 70 eV)

+

1

m/z: calcd for [M] (C H BrN), 207.0; found, 207.1.

3

9

6

quinoline (3k, 27.7 mg, 70%) was isolated (hexanes/Et O = 15:1) as

6-Iodoquinoline (3q). Prepared using 6-iodoquinoline N-oxide

(2q, 27.1 mg, 0.100 mmol, 1.00 equiv), 1c (46.4 mg, 0.150 mmol,

2

a white solid. Spectroscopic data matched with those reported in the

3f

1

literature. H NMR (500 MHz, CDCl ): δ 8.33 (d, J = 8.5 Hz, 1H),

1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (2.00 mL,

3

8

1

.22 (d, J = 8.3 Hz, 1H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H), 7.81 (ddd, J =

0.05 M). 6-Iodoquinoline (3q, 23.3 mg, 91%) was isolated (hexanes/

.5, 6.9, 1.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.66 (ddd, J = 8.1, 6.8,

EtOAc = 1.8:1) as a white solid. Spectroscopic data matched with

.2 Hz, 1H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 147.9 (q, J

1

2

=

those reported in the literature. H NMR (500 MHz, CDCl ): δ

3f

1

3

C−F

3

2

887

https://dx.doi.org/10.1021/acs.joc.0c02805

J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

8

1

.89 (dd, J = 4.3, 1.8 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.99 (dd, J =

mg, 75%) was isolated (hexanes/EtOAc = 6.5:1) as colorless oil.

3f

1

.5, 1.8 Hz, 1H), 7.91 (dd, J = 8.9, 2.0 Hz, 1H), 7.80 (d, J = 8.9 Hz,

Spectroscopic data matched with those reported in the literature.

H

1

3

1

H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H); C{ H} NMR (126 MHz,

NMR (500 MHz, CDCl ): δ 8.92 (d, J = 4.3 Hz, 1H), 8.13 (dd, J =

3

CDCl ): δ 150.8, 147.1, 138.1, 136.4, 134.7, 131.1, 129.8, 121.6, 92.1;

8.5, 1.5 Hz, 1H), 7.86 (dd, J = 8.5, 1.6 Hz, 1H), 7.71 (ddd, J = 8.3,

6.8, 1.4 Hz, 1H), 7.58 (dt, J = 4.4, 1.3 Hz, 1H), 7.54 (ddd, J = 8.3, 6.8,

1.3 Hz, 1H), 5.23 (d, J = 1.4 Hz, 2H), 0.99 (s, 9H), 0.16 (s, 6H);

3

+

GC−MS (EI, 70 eV) m/z: calcd for [M] (C H IN), 255.0; found,

9

6

254.9.

1

3

1

3

-Methylquinoline (3r). Prepared using 3-methylquinoline N-oxide

C{ H} NMR (126 MHz, CDCl ): δ 150.6, 147.7, 146.6, 130.2,

3

(

2r, 31.8 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50

129.0, 126.3, 125.5, 122.4, 117.7, 61.7, 25.9, 18.4, −5.3; GC−MS (EI,

+

equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05

M). 3-Methylquinoline (3r, 26.0 mg, 91%) was isolated (hexanes/

EtOAc = 4:1) as pale yellow oil. Spectroscopic data matched with

those reported in the literature. H NMR (500 MHz, CDCl ): δ

70 eV) m/z: calcd for [M] (C H NOSi), 273.2; found, 273.1.

3

16 23

3-(1,3-Dioxolan-2-yl)quinoline (3x). Prepared using 3-(1,3-dioxo-

lan-2-yl)quinoline N-oxide (2x, 34.6 mg, 0.200 mmol, 1.00 equiv), 1c

(92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %),

3f

1

3

8

.76 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H), 7.72

and CH CN (4.00 mL, 0.05 M). 3-(1,3-Dioxolan-2-yl)quinoline (3x,

3

(

dd, J = 8.2, 1.4 Hz, 1H), 7.63 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.50

ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 2.50 (s, 3H); C{ H} NMR (126

32.3 mg, 80%) was isolated (hexanes/EtOAc = 1.4:1) as pale yellow

1

3

1

3f

oil. Spectroscopic data matched with those reported in the literature.

1

MHz, CDCl ): δ 152.4, 146.5, 134.6, 130.4, 129.1, 128.4, 128.1,

1

(

H NMR (500 MHz, CDCl ): δ 8.95 (d, J = 2.2 Hz, 1H), 8.13 (d, J =

3

+

27.1, 126.5, 18.7; GC−MS (EI, 70 eV) m/z: calcd for [M]

C H N), 143.1; found, 143.2.

2

.2 Hz, 1H), 8.05 (dd, J = 8.5, 1.0 Hz, 1H), 7.72 (dd, J = 8.1, 1.5 Hz,

10

9

1H), 7.62 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.43 (ddd, J = 8.2, 6.9, 1.2

Hz, 1H), 5.91 (s, 1H), 4.09−3.91 (m, 4H); C{ H} NMR (126

MHz, CDCl ): δ 148.9, 148.2, 133.7, 130.6, 129.6, 129.0, 127.8,

1

3

1

4

-Methylquinoline (3s). Prepared using 4-methylquinoline N-oxide

(

2s, 31.8 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50

3

+

equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05

3

127.1, 126.6, 101.9, 65.2; GC−MS (EI, 70 eV) m/z: calcd for [M]

M). 4-Methylquinoline (3s, 25.6 mg, 90%) was isolated (hexanes/

EtOAc = 4:1) as pale yellow oil. Spectroscopic data matched with

those reported in the literature. H NMR (500 MHz, CDCl ): δ

(C H NO ), 201.1; found, 201.2.

12 11 2

6

-(Phenylethynyl)quinoline (3y). Prepared using 6-

3f

1

3

(phenylethynyl)quinoline N-oxide (2y, 49.1 mg, 0.200 mmol, 1.00

equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol,

8

.72 (d, J = 4.3 Hz, 1H), 8.07 (dd, J = 8.5, 1.3 Hz, 1H), 7.91 (dd, J =

.4, 1.5 Hz, 1H), 7.65 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.49 (ddd, J =

1

.0 mol %), and CH CN (4.00 mL, 0.05 M). 6-(Phenylethynyl)-

3

.3, 6.9, 1.3 Hz, 1H), 7.13 (dd, J = 4.3, 1.1 Hz, 1H), 2.61 (s, 3H);

quinoline (3y, 42.3 mg, 92%) was isolated (hexanes/EtOAc = 1.6:1)

13

1

C{ H} NMR (126 MHz, CDCl ): δ 150.0, 147.8, 144.0, 129.8,

3

as a pale yellow solid. Spectroscopic data matched with those reported

3f

1

28.9, 128.1, 126.1, 123.6, 121.7, 18.4; GC−MS (EI, 70 eV) m/z:

in the literature. H NMR (500 MHz, CDCl ): δ 8.89 (dd, J = 4.2,

3

+

calcd for [M] (C H N), 143.1; found, 143.2.

1.8 Hz, 1H), 8.11−8.04 (m, 2H), 7.99 (d, J = 1.8 Hz, 1H), 7.81 (dd, J

10

9

1

3

1

2

,6-Dimethylquinoline (3t). Prepared using 2,6-dimethylquinoline

= 8.8, 1.9 Hz, 1H), 7.61−7.54 (m, 2H), 7.41−7.32 (m, 4H); C{ H}

N-oxide (2t, 34.6 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

NMR (126 MHz, CDCl ): δ 150.8, 147.6, 135.6, 132.1, 131.6, 131.0,

3

129.5, 128.5, 128.4, 127.9, 122.9, 121.6, 121.5, 90.6, 88.9; GC−MS

+

(

4.00 mL, 0.05 M). 2,6-Dimethylquinoline (3t, 23.9 mg, 76%) was

(EI, 70 eV) m/z: calcd for [M] (C H N), 229.1; found, 229.1.

1

7

11

isolated (hexanes/EtOAc = 2.5:1) as an oﬀ-white solid. Spectroscopic

Quinoxaline (3z). Prepared using quinoxaline N-oxide (2z, 29.2

mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv),

3f

1

data matched with those reported in the literature. H NMR (500

MHz, CDCl ): δ 7.90 (s, 1H), 7.89 (s, 1H), 7.50−7.44 (m, 2H), 7.19

4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M).

3

1

3

1

(

d, J = 8.3 Hz, 1H), 2.69 (s, 3H), 2.48 (s, 3H); C{ H} NMR (126

Quinoxaline (3z, 20.0 mg, 77%) was isolated (hexanes/EtOAc = 4:1)

MHz, CDCl ): δ 157.8, 146.4, 135.4, 135.2, 131.5, 128.2, 126.4,

as pale yellow oil. Spectroscopic data matched with those reported in

3

+

40a

1

(

26.3, 121.8, 25.2, 21.3; GC−MS (EI, 70 eV) m/z: calcd for [M]

C H N), 157.1; found, 157.2.

the literature.

H NMR (500 MHz, CDCl ): δ 8.67 (s, 2H), 7.98−

3

13 1

11

7.91 (m, 2H), 7.64−7.54 (m, 2H); C{ H} NMR (126 MHz,

2

-Phenylquinoline (3u). Prepared using 2-phenylquinoline N-

CDCl ): δ 144.6, 142.7, 129.6, 129.2; GC−MS (EI, 70 eV) m/z:

3

+

oxide (2u, 44.3 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

calcd for [M] (C H N ), 130.1; found, 130.1.

8

6

2

3

Isoquinoline (3aa). Prepared using isoquinoline N-oxide (2aa, 29.0

mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv),

(

4.00 mL, 0.05 M). 2-Phenylquinoline (3u, 32.9 mg, 80%) was

isolated (hexanes/EtOAc = 30:1) as pale yellow oil. Spectroscopic

4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M).

3

3f

1

data matched with those reported in the literature. H NMR (500

Isoquinoline (3aa, 24.8 mg, 96%) was isolated (hexanes/EtOAc =

MHz, CDCl ): δ 8.25 (d, J = 8.6 Hz, 1H), 8.23−8.17 (m, 3H), 7.91

2.1:1) as dark brown oil. Spectroscopic data matched with those

3

3f

1

(d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (ddd, J = 8.4,

reported in the literature. H NMR (500 MHz, CDCl ): δ 9.29 (s,

3

1

3

1

6

.8, 1.5 Hz, 1H), 7.61−7.53 (m, 3H), 7.53−7.46 (m, 1H); C{ H}

1H), 8.55 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H),

1

3

1

NMR (126 MHz, CDCl ): δ 157.3, 148.3, 139.7, 136.7, 129.8, 129.6,

7.71−7.63 (m, 2H), 7.60 (t, J = 7.3 Hz, 1H); C{ H} NMR (126

3

1

29.3, 128.8, 127.6, 127.4, 127.2, 126.2, 119.0; GC−MS (EI, 70 eV)

MHz, CDCl ): δ 152.4, 142.8, 135.7, 130.3, 128.7, 127.6, 127.2,

3

+

m/z: calcd for [M] (C H N), 205.1; found, 205.1.

126.4, 120.5; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N),

129.1; found, 129.1.

1

5

11

9

7

6

-Methoxyquinoline (3v). Prepared using 6-methoxyquinoline N-

oxide (2v, 35.0 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

5-Bromoisoquinoline (3ab). Prepared using 5-bromoisoquinoline

N-oxide (2ab, 44.8 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

3

(

4.00 mL, 0.05 M). 6-Methoxyquinoline (3v, 25.3 mg, 80%) was

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

3

isolated (hexanes/EtOAc = 2:1) as pale yellow oil. Spectroscopic data

(4.00 mL, 0.05 M). 5-Bromoisoquinoline (3ab, 36.2 mg, 87%) was

3f

1

matched with those reported in the literature. H NMR (500 MHz,

CDCl ): δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.02 (dd, J = 8.4, 2.0 Hz,

isolated (hexanes/EtOAc = 3:1) as a brown solid. Spectroscopic data

3f

1

3

matched with those reported in the literature. H NMR (500 MHz,

1

H), 7.99 (d, J = 9.2 Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.32

CDCl ): δ 9.18 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 7.92−7.86 (m, 3H),

3

1

3

1

(dd, J = 8.3, 4.2 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H);

7.40 (t, J = 7.8 Hz, 1H); C{ H} NMR (126 MHz, CDCl ): δ 152.6,

3

13

1

C{ H} NMR (126 MHz, CDCl ): δ 157.7, 147.9, 144.4, 134.7,

144.4, 134.8, 133.8, 129.5, 127.6, 127.3, 121.4, 119.2; GC−MS (EI,

3

+

1

30.8, 129.2, 122.2, 121.3, 105.1, 55.5; GC−MS (EI, 70 eV) m/z:

70 eV) m/z: calcd for [M] (C H BrN), 207.0; found, 206.9.

9

6

+

calcd for [M] (C H NO), 159.1; found, 159.1.

Phthalazine (3ac). Prepared using phthalazine N-oxide (2ac, 29.2

mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv),

10

9

4

-(((tert-Butyldimethylsilyl)oxy)methyl)quinoline (3w). Prepared

using 4-(((tert-butyldimethylsilyl)oxy)methyl)quinoline N-oxide (2w,

8.9 mg, 0.100 mmol, 1.00 equiv), 1c (46.4 mg, 0.150 mmol, 1.50

4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M).

3

2

Phthalazine (3ac, 20.1 mg, 77%) was isolated (EtOAc/acetone = 2:1)

equiv), 4 (0.8 mg, 1.0 μmol, 1.0 mol %), and CH CN (2.00 mL, 0.05

M). 4-(((tert-Butyldimethylsilyl)oxy)methyl)quinoline (3w) (20.5

as pale yellow oil. Spectroscopic data matched with those reported in

3

3f

1

the literature. H NMR (500 MHz, CDCl ): δ 9.53 (s, 2H), 7.99−

3

2

888

https://dx.doi.org/10.1021/acs.joc.0c02805

J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

3

1

7

.94 (m, 2H), 7.94−7.89 (m, 2H); C{ H} NMR (126 MHz,

Experimental Procedure for Scheme 3c (in the Presence of

a Radical Inhibitor). A 10 mL test tube equipped with a small

magnetic stir bar was charged with methyl quinoline-6-carboxylate N-

oxide (2a, 30.4 mg, 0.150 mmol, 1.00 equiv), tert-Bu-HEH (1c, 69.6

mg, 0.225 mmol, 1.50 equiv), galvinoxyl free radical (221 mg, 0.525

mmol, 3.50 equiv), and tris(2,2′-bipyridyl)dichlororuthenium(II)

hexahydrate (4) (1.1 mg, 1.5 μmol, 1.0 mol %). The ﬂask was ﬁtted

CDCl ): δ 151.0, 132.6, 126.5, 126.2; GC−MS (EI, 70 eV) m/z:

calcd for [M] (C H N ), 130.1; found, 130.2.

N,N-Dimethyl-1-naphthalenamine (3ad). Prepared using N,N-

dimethyl-1-naphthalenamine N-oxide (2ad, 37.4 mg, 0.200 mmol,

.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.5 equiv), 4 (1.5 mg, 2.0

μmol, 1.0 mol %), and CH CN (4.00 mL, 0.05 M). N,N-Dimethyl-1-

naphthalenamine (3ad, 25.5 mg, 75%) was isolated (hexanes/EtOAc

2:1) as pale yellow oil. Spectroscopic data matched with those

3

+

8

6

2

1

3

with a rubber septum and CH CN (3.00 mL, 0.05 M) was added via a

3

=

^s^y^rⁱⁿ^g^e^uⁿ^d^e^r^aⁿ^a^t^m^o^s^p^h^e^r^e^o^fⁿⁱ^t^r^o^g^eⁿ^.^A^f^t^e^r^d^e^g^a^s^sⁱⁿ^g^b^y^N2

bubbling at room temperature for 10 min, the reaction mixture was

3f

1

reported in the literature. H NMR (500 MHz, CDCl ): δ 8.31 (dd,

3

then irradiated at room temperature with two 3 W blue LEDs. After

irradiation of the reaction mixture for 6 h, the reaction mixture was

concentrated on a rotary evaporator. The resulting residue was

puriﬁed by ﬂash column chromatography on silica gel (hexanes/

EtOAc = 1.2:1) to aﬀord methyl quinoline-6-carboxylate (3a, 2.2 mg,

J = 8.3, 1.3 Hz, 1H), 7.88 (dd, J = 8.2, 1.4 Hz, 1H), 7.60−7.48 (m,

3

6

1

H), 7.45 (t, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.4, 1.1 Hz, 1H), 2.96 (s,

_H₎_;1 C{ H} NMR (126 MHz, CDCl ): δ 150.8, 134.8, 128.8,

3

1

3

28.3, 125.7, 125.6, 125.1, 124.1, 122.8, 113.9, 45.2; GC−MS (EI, 70

+

eV) m/z: calcd for [M] (C H N), 171.1; found, 171.1.

1

2

13

8

%) as a white solid.

Emission Quenching of [Ru(bpy) ]Cl ·6H O (4). A 50 mL

N-Phenylpiperidine (3ae). Prepared using N-phenylpiperidine N-

oxide (2ae, 35.4 mg, 0.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300

3

2

volumetric ﬂask containing the photocatalyst [Ru(bpy) ]Cl ·6H O

mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %), and CH CN

3

2

3

(4, 7.5 mg, 10 μmol) was ﬁtted with a rubber septum and charged

(4.00 mL, 0.05 M). N-Phenylpiperidine (3ae, 27.3 mg, 85%) was

with CH CN (slightly more than 50 mL) via a syringe. The resulting

isolated (hexanes/CH Cl = 1.5:1) as violet oil. Spectroscopic data

3

2

40b

1

solution was then degassed by sparging with nitrogen until its volume

reached 50 mL. The solutions of tert-Bu-HEH 1c (75 mM) and N-

matched with those reported in the literature.

H NMR (500 MHz,

DMSO): δ 7.19 (t, J = 7.5 Hz, 2H), 6.94−6.89 (m, 2H), 6.74 (s, 1H),

1

3

1

oxides 2a and 2e (50 mM) in CH CN were also prepared similarly.

3

(

.14−3.08 (m, 4H), 1.61 (s, 4H), 1.56−1.48 (m, 2H); C{ H} NMR

3

Stern−Volmer luminescence quenching experiments were performed

using a Varian Cary Eclipse ﬂuorescence spectrophotometer. In each

experimentation, the solution of 4 and varying concentrations of

126 MHz, DMSO): δ 151.6, 128.8, 118.3, 115.7, 49.5, 25.1, 23.8;

GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N), 161.1; found,

61.1.

N-Methyl-N-phenylaniline (3af). Prepared using N-methyl-N-

phenylaniline N-oxide (2af, 39.9 mg, 0.200 mmol, 1.00 equiv), 1c

92.8 mg, 0.300 mmol, 1.50 equiv), 4 (1.5 mg, 2.0 μmol, 1.0 mol %),

+

1

15

1

quencher (1c, 2a, or 2e) were combined in degassed CH CN in 1 cm

3

screw-top quartz cuvettes. For the emission quenching of 4, the

photocatalyst concentration was 200 μM, the solution was excited at

(

4

51 nm, and the emission intensity was observed at 612 nm. Plots

and CH CN (4.00 mL, 0.05 M). N-Methyl-N-phenylaniline (3af, 35.1

3

were constructed according to the Stern−Volmer equation I /I = 1 +

0

mg, 96%) was isolated (hexanes/CH Cl = 11:1) as dark green oil.

2

40c

k τ [Q]. I and I represent the intensities of the emission in the

q

0

Spectroscopic data matched with those reported in the literature.

H NMR (500 MHz, CDCl ): δ 7.31 (t, J = 7.8 Hz, 4H), 7.06 (d, J =

.2 Hz, 4H), 6.99 (t, J = 7.3 Hz, 2H), 3.35 (s, 3H); C{ H} NMR

1

absence and presence of a quencher at 612 nm, respectively.

3

Experimental Procedure for a Multigram-Scale Reaction

Using 1 mol % 4 (Scheme 4). A 500 mL round-bottomed ﬂask

equipped with a magnetic stir bar was charged with isopropyl

quinoline-6-carboxylate N-oxide (2c, 3.00 g, 13.0 mmol, 1.00 equiv),

tert-Bu-HEH (1c, 6.02 g, 19.5 mmol, 1.50 equiv), and tris(2,2′-

bipyridyl)dichlororuthenium(II) hexahydrate (4, 97.1 mg, 0.130

mmol, 1.00 mol %). The ﬂask was ﬁtted with a rubber septum and

1

3

1

8

(

7

126 MHz, CDCl ): δ 149.0, 129.1, 121.3, 120.4, 40.2; GC−MS (EI,

3

+

0 eV) m/z: calcd for [M] (C H N), 183.1; found, 183.1.

13 13

Experimental Procedure for Scheme 3a (in the Absence of

a Photocatalyst). A 10 mL test tube equipped with a small magnetic

stir bar was charged with methyl quinoline-6-carboxylate N-oxide (2a,

4

0

0.6 mg, 0.200 mmol, 1.00 equiv) and tert-Bu-HEH (1c, 92.8 mg,

.300 mmol, 1.50 equiv). The ﬂask was ﬁtted with a rubber septum

CH CN (260 mL, 0.05 M) was added via a syringe under an

3

atmosphere of nitrogen. After degassing by N bubbling at room

2

and CH CN (4.00 mL, 0.05 M) was added via a syringe under an

3

temperature for 20 min, the reaction mixture was then irradiated at

room temperature with blue LEDs for 20 min. Upon the completion

of the reaction as determined by TLC, the reaction mixture was

concentrated on a rotary evaporator. The resulting residue was

directly puriﬁed by ﬂash column chromatography on silica gel

atmosphere of nitrogen. After degassing by N bubbling at room

2

temperature for 10 min, the reaction mixture was then irradiated at

room temperature with two 3 W blue LEDs for 300 min. Upon

completion of the reaction as determined by TLC, the reaction

mixture was concentrated on a rotary evaporator. The resulting

residue was directly puriﬁed by ﬂash column chromatography on silica

gel (hexanes/EtOAc = 1.2:1) to aﬀord methyl quinoline-6-carboxylate

(

hexanes/EtOAc = 1.2:1) to aﬀord isopropyl quinoline-6-carboxylate

3c, 2.65 g, 95%) as reddish oil.

Experimental Procedure for a Multigram-Scale Reaction

(

3a, 33.1 mg, 89%) as a white solid.

Experimental Procedure for Scheme 3b (Kinetic Deuterium

Using 0.1 mol % 4 (Scheme 4). A 500 mL round-bottomed ﬂask

equipped with a magnetic stir bar was charged with isopropyl

quinoline-6-carboxylate N-oxide (2c, 3.00 g, 13.0 mmol, 1.00 equiv),

tert-Bu-HEH (1c, 6.02 g, 19.5 mmol, 1.50 equiv), and tris(2,2′-

bipyridyl)dichlororuthenium(II) hexahydrate (4, 9.7 mg, 0.013 mmol,

Isotope Eﬀect). A 10 mL test tube equipped with a small magnetic

stir bar was charged with methyl quinoline-6-carboxylate N-oxide (2a,

40.6 mg, 0.200 mmol, 1.00 equiv), tert-Bu-HEH (1c, 46.4 mg, 0.150

mmol, 0.750 equiv), tert-Bu-HEH-d (1c-d , 46.7 mg, 0.150 mmol,

2

0.10 mol %). The ﬂask was ﬁtted with a rubber septum and CH CN

3

0

.750 equiv), and tris(2,2′-bipyridyl)dichlororuthenium(II) hexahy-

(

260 mL, 0.05 M) was added via a syringe under an atmosphere of

drate (4, 1.5 mg, 2.0 μmol, 1.0 mol %). The ﬂask was ﬁtted with a

nitrogen. After degassing by N bubbling at room temperature for 20

2

rubber septum and CH CN (4.00 mL, 0.05 M) was added via a

3

min, the reaction mixture was then irradiated at room temperature

with blue LEDs for 15 min. Upon completion of the reaction as

determined by TLC, the reaction mixture was concentrated on a

rotary evaporator. The resulting residue was directly puriﬁed by ﬂash

column chromatography on silica gel (hexanes/EtOAc = 1.2:1) to

aﬀord isopropyl quinoline-6-carboxylate (3c, 2.67 g, 95%) as reddish

oil.

Experimental Procedure for a Multigram-Scale Reaction

Using 0.01 mol % 4 (Scheme 4). A 500 mL round-bottomed ﬂask

equipped with a magnetic stir bar was charged with isopropyl

quinoline-6-carboxylate N-oxide (2c, 4.62 g, 20.0 mmol, 1.00 equiv),

tert-Bu-HEH (1c, 9.28 g, 30.0 mmol, 1.50 equiv), and tris(2,2′-

^s^y^rⁱⁿ^g^e^uⁿ^d^e^r^aⁿ^a^t^m^o^s^p^h^e^r^e^o^fⁿⁱ^t^r^o^g^eⁿ^.^A^f^t^e^r^d^e^g^a^s^sⁱⁿ^g^b^y^N2

bubbling at room temperature for 10 min, the reaction mixture was

then irradiated at room temperature with two 3 W blue LEDs for 5

min. Upon completion of the reaction as determined by TLC, the

reaction mixture was concentrated on a rotary evaporator. The

resulting residue was puriﬁed by ﬂash column chromatography on

silica gel (hexanes/EtOAc = 7:1 → 1.2:1) to aﬀord methyl quinoline-

6-carboxylate (3a, 35.2 mg, 94%) along with a 1:1.3 mixture of ditert-

butyl 2,6-dimethylpyridine-3,5-dicarboxylate (pyridine-1c) and di-tert-

butyl 4-deuterio-2,6-dimethylpyridine-3,5-dicarboxylate (pyridine-1c-

d).

2

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J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

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+

14.2, 12.8; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N O ),

1

0

14

2

0

178.1; found, 178.2.

(

400 mL, 0.05 M) was added via a syringe under an atmosphere of

3-Acetylpyridine (6c). Prepared using 3-acetylpyridine N-oxide

(5c, 151 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

nitrogen. After degassing by N bubbling at room temperature for 30

2

min, the reaction mixture was then irradiated at room temperature

with blue LEDs for 55 min. Upon completion of the reaction as

determined by TLC, the reaction mixture was concentrated on a

rotary evaporator. The resulting residue was directly puriﬁed by ﬂash

column chromatography on silica gel (hexanes/EtOAc = 1.2:1) to

aﬀord isopropyl quinoline-6-carboxylate (3c, 4.15 g, 96%) as reddish

oil.

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05

M). 3-Acetylpyridine (6c, 131 mg, 98%) was isolated (hexanes/

3

EtOAc = 1:1) as yellow oil. Spectroscopic data matched with those

41c

1

reported in the literature.

H NMR (500 MHz, CDCl ): δ 9.15 (d,

3

J = 2.0 Hz, 1H), 8.76 (dd, J = 4.9, 1.7 Hz, 1H), 8.21 (dt, J = 8.0, 2.0

1

3

1

Hz, 1H), 7.40 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 2.62 (s, 3H); C{ H}

NMR (126 MHz, CDCl ): δ 196.6, 153.5, 149.9, 135.4, 132.2, 123.6,

3

+

Experimental Procedure for a Catalyst Reuse Experiment

Scheme 5). A 150 mL round-bottomed ﬂask equipped with a

26.6; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H NO), 121.1;

7

(

found, 121.1.

magnetic stir bar was charged with methyl quinoline-6-carboxylate N-

oxide (2a, 40.6 mg, 0.200 mmol, 1.00 equiv), tert-Bu-HEH (1c, 92.8

mg, 0.300 mmol, 1.50 equiv), and tris(2,2′-bipyridyl)-

dichlororuthenium(II) hexahydrate (4, 0.33 mM stock solution in

5

-Bromo-2-chloropyridine (6d). Prepared using 5-bromo-2-chlor-

opyridine N-oxide (5d) (229 mg, 1.10 mmol, 1.00 equiv), 1c (510

mg, 1.65 mmol, 1.50 equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and

CH CN (22.0 mL, 0.05 M). 5-Bromo-2-chloropyridine (6d, 195 mg,

3

CH CN, 0.60 mL, 0.20 μmol, 0.10 mol %). The ﬂask was ﬁtted with a

3

92%) was isolated (hexanes/Et O = 12:1) as a white solid.

2

41d

rubber septum and CH CN (3.4 mL) was added via a syringe under

3

Spectroscopic data matched with those reported in the literature.

H NMR (500 MHz, CDCl ): δ 8.45 (d, J = 2.6 Hz, 1H), 7.76 (dd, J

8.4, 2.6 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H); C{ H} NMR (126

an atmosphere of nitrogen. After degassing by N bubbling at room

1

2

3

temperature for 10 min, the reaction mixture was then irradiated at

room temperature with two 3 W blue LEDs for 5 min. Upon

completion of the reaction as determined by TLC, the reaction

mixture was repeatedly treated with another portion of 2a (40.6 mg,

13

1

=

MHz, CDCl ): δ 150.7, 150.1, 141.2, 125.6, 119.1; GC−MS (EI, 70

3

+

eV) m/z: calcd for [M] (C H BrClN), 190.9; found, 191.1.

5

3

2

,6-Dichloropyridine (6e). Prepared using 2,6-dichloropyridine N-

0

.200 mmol, 1.00 equiv), 1c (92.8 mg, 0.300 mmol, 1.50 equiv), and

oxide (5e, 180 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol,

CH CN (4.0 mL), degassed by bubbling with N for 5−10 min and

3

2

1

.50 equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL,

3

irradiated with blue LEDs. Upon completion of the ﬁnal 12th run as

determined by TLC, the reaction mixture was concentrated on a

rotary evaporator. The resulting residue was directly puriﬁed by ﬂash

column chromatography on silica gel (hexanes/EtOAc = 1.2:1) to

aﬀord methyl quinoline-6-carboxylate (3a, 388 mg, 86% yield in

average) as a white solid.

0

.05 M). 2,6-Dichloropyridine (6e, 149 mg, 92%) was isolated

(

hexanes/Et O = 15:1) as a white solid. Spectroscopic data matched

2

41e

1

with those reported in the literature.

H NMR (500 MHz,

13

1

DMSO): δ 7.94 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H); C{ H}

NMR (126 MHz, DMSO): δ 149.2, 142.8, 123.6; GC−MS (EI, 70

+

eV) m/z: calcd for [M] (C H Cl N), 147.0; found, 146.9.

5

3

2

General Procedure for the Visible Light-Mediated Deoxy-

2

-Phenylpyridine (6f). Prepared using 2-phenylpyridine N-oxide

genation of N-Heterocyclic N-Oxides Using [Ir(ppy) (dtbbpy)]-

2

(

5f, 188 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

PF (7) as the Photocatalyst (Scheme 6). A 50 mL test tube

6

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05

3

equipped with a small magnetic stir bar was charged with N-

heterocyclic N-oxide (5, 1.10 mmol, 1.00 equiv), tert-Bu-HEH (1c,

M). Unfortunately, the deoxygenated N-heterocycle 6f was copolar

with the pyridine derived from 1c. Hence, an NMR yield (87%) was

estimated using 1,3,5-trimethylbenzene as an internal standard. An

analytical sample was obtained by the careful puriﬁcation of the crude

5

10 mg, 1.65 mmol, 1.50 equiv), and (4,4′-di-tert-butyl-2,2′-

bipyridine)bis[(2-pyridinyl)phenyl]iridium(III) hexaﬂuorophosphate

7, 1.0 mg, 1.1 μmol, 0.1 mol %). The tube was ﬁtted with a rubber

septum and CH CN (22.0 mL, 0.05 M) was added under an

(

mixture via ﬂash column chromatography (hexanes/Et O = 3:1) on

2

3

silica gel. Spectroscopic data matched with those reported in the

atmosphere of nitrogen. After degassing by N bubbling at room

2

3f

1

literature. H NMR (500 MHz, CDCl ): δ 8.74−8.68 (m, 1H),

temperature for 10 min, the reaction mixture was then irradiated at

room temperature with two 3 W blue LEDs for the indicated time

3

8

.06−7.98 (m, 2H), 7.74−7.66 (m, 2H), 7.52−7.45 (m, 2H), 7.45−

13 1

7

.38 (m, 1H), 7.24−7.15 (m, 1H); C{ H} NMR (126 MHz,

(see Scheme 6). Upon completion of the reaction as determined by

CDCl ): δ 157.3, 149.5, 139.3, 136.6, 128.8, 128.6, 126.8, 121.9,

TLC, the reaction mixture was concentrated on a rotary evaporator.

The resulting residue was directly puriﬁed by ﬂash column

chromatography on silica gel to aﬀord the corresponding deoxy-

genated N-heterocycle (6).

3

+

1

20.4; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N), 155.1;

found, 155.2.

11

9

3

-Phenylpyridine (6g). Prepared using 3-phenylpyridine N-oxide

(

5g, 188 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

Methyl Nicotinate (6a). Prepared using methyl nicotinate N-oxide

5a, 168 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05

(

3

M). 3-Phenylpyridine (6g, 170 mg, 99%) was isolated (hexanes/

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05

3

EtOAc = 3.2:1) as a white solid. Spectroscopic data matched with

M). Methyl nicotinate (6a) (149 mg, 98%) was isolated (hexanes/

3f

1

those reported in the literature. H NMR (500 MHz, CDCl ): δ

EtOAc = 2:1) as yellow oil. Spectroscopic data matched with those

3

41a

1

8

7

.82 (d, J = 2.5 Hz, 1H), 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 7.79 (dt, J =

.9, 2.0 Hz, 1H), 7.55−7.47 (m, 2H), 7.45−7.38 (m, 2H), 7.38−7.31

reported in the literature.

H NMR (500 MHz, CDCl ): δ 9.12 (d,

3

J = 2.4 Hz, 1H), 8.68 (dd, J = 4.9, 1.8 Hz, 1H), 8.19 (dt, J = 8.0, 2.0

1

3

1

3

1

(m, 1H), 7.28 (dd, J = 7.9, 4.9 Hz, 1H); C{ H} NMR (126 MHz,

Hz, 1H), 7.30 (dd, J = 8.0, 4.9 Hz, 1H), 3.86 (s, 3H); C{ H} NMR

126 MHz, CDCl ): δ 165.5, 153.2, 150.7, 136.8, 125.8, 123.1, 52.2;

CDCl ): δ 148.2, 148.0, 137.5, 136.3, 134.0, 128.8, 127.8, 126.8,

(

3

+

1

23.3; GC−MS (EI, 70 eV) m/z: calcd for [M] (C H N), 155.1;

found, 155.2.

GC−MS (EI, 70 eV) m/z: calcd for [M] (C H NO ), 137.0; found,

11

9

7

2

1

37.2.

N,N-Diethylnicotinamide (6b). Prepared using N,N-diethylnicoti-

namide N-oxide (5b, 214 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg,

.65 mmol, 1.50 equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and

CH CN (22.0 mL, 0.05 M). N,N-Diethylnicotinamide (6b, 180 mg,

4

-Phenylpyridine (6h). Prepared using 4-phenylpyridine N-oxide

5h, 188 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05

(

1

3

M). 4-Phenylpyridine (6h, 164 mg, 96%) was isolated (hexanes/

3

9

2%) was isolated (EtOAc/MeOH = 9:1) as yellow oil. Spectroscopic

EtOAc = 2.2:1) as a white solid. Spectroscopic data matched with

41b

1

3f

1

data matched with those reported in the literature.

H NMR (500

those reported in the literature. H NMR (500 MHz, CDCl

): δ

3

MHz, CDCl ): δ 8.65−8.56 (m, 2H), 7.68 (dt, J = 7.8, 2.0 Hz, 1H),

8.68−8.63 (m, 2H), 7.66−7.61 (m, 2H), 7.53−7.41 (m, 5H);

3

1

3

1

7

.31 (dd, J = 7.8, 4.9 Hz, 1H), 3.52 (br d, J = 7.5 Hz, 2H), 3.23 (br d,

C{ H} NMR (126 MHz, CDCl ): δ 150.2, 148.3, 138.1, 129.1,

3

1

3

1

+

J = 8.1 Hz, 2H), 1.22 (br s, 3H), 1.10 (br s, 3H); C{ H} NMR (126

129.0, 126.9, 121.6; GC−MS (EI, 70 eV) m/z: calcd for [M]

(C H N), 155.1; found, 155.2.

MHz, CDCl ): δ 168.5, 150.2, 147.1, 134.1, 132.9, 123.3, 43.3, 39.4,

3

11

9

2

890

https://dx.doi.org/10.1021/acs.joc.0c02805

J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

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Article

2

-(4-Methoxy)phenylpyridine (6i). Prepared using 2-(4-methoxy)-

orcid.org/0000-0003-4108-5074; Email: leejunhee@

dongguk.ac.kr

phenylpyridine N-oxide (5i, 221 mg, 1.10 mmol, 1.00 equiv), 1c (510

mg, 1.65 mmol, 1.50 equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and

CH CN (22.0 mL, 0.05 M). 2-(4-Methoxy)phenylpyridine (6i, 176.1

Authors

3

mg, 88%) was isolated (hexanes/Et O = 3.3:1) as a white solid.

2

Ju Hyeon An − Department of Advanced Materials Chemistry,

Dongguk University, Gyeongju 38066, Republic of Korea

Kyu Dong Kim − Department of Advanced Materials

Chemistry, Dongguk University, Gyeongju 38066, Republic

of Korea

3f

1

Spectroscopic data matched with those reported in the literature.

H

NMR (500 MHz, CDCl ): δ 8.65 (ddd, J = 4.9, 1.9, 1.1 Hz, 1H),

3

8

.00−7.92 (m, 2H), 7.72−7.67 (m, 1H), 7.67−7.62 (m, 1H), 7.16

(ddd, J = 7.2, 4.8, 1.4 Hz, 1H), 7.04−6.96 (m, 2H), 3.85 (s, 3H);

13

1

C{ H} NMR (126 MHz, CDCl ): δ 160.4, 157.1, 149.5, 136.6,

3

1

32.0, 128.1, 121.3, 119.7, 114.1, 55.3; GC−MS (EI, 70 eV) m/z:

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02805

+

calcd for [M] (C H NO), 185.1; found, 185.2.

12

11

2

-(2,4,6-Trimethylphenyl)pyridine (6j). Prepared using 2-(2,4,6-

trimethylphenyl)pyridine N-oxide (5j, 234.6 mg, 1.10 mmol, 1.00

equiv), 1c (510 mg, 1.65 mmol, 1.50 equiv), 7 (1.0 mg, 1.1 μmol, 0.1

Notes

The authors declare no competing ﬁnancial interest.

mol %), and CH CN (22.0 mL, 0.05 M). 2-(2,4,6-Trimethylphenyl)-

3

pyridine (6j, 156 mg, 72%) was isolated (hexanes/EtOAc = 8:1) as

ACKNOWLEDGMENTS

pale yellow oil. Spectroscopic data matched with those reported in the

■

37

1

literature. H NMR (500 MHz, CDCl ): δ 8.74−8.69 (m, 1H), 7.73

3

We dedicate this paper to Prof. F. Dean Toste (UC Berkeley)

on the occasion of his 50th birthday. We gratefully acknowl-

edge Professors Sang-gi Lee (Ewha Womans University),

Jaiwook Park, Young Ho Rhee, Seung Hwan Cho (POST-

ECH), and Jeung Gon Kim (Chonbuk National University)

for their generous support and helpful discussions. This

research was supported by the National Research Foundation

(NRF) of the Korea-Basic Science Research Program (nos.

N R F - 2 0 1 7 R 1 D 1 A 1 B 0 3 0 2 9 9 2 6 a n d N R F -

2020R1F1A1076460) and the Dongguk University Research

Fund of 2020.

(

td, J = 7.7, 1.8 Hz, 1H), 7.27−7.19 (m, 2H), 6.93 (s, 2H), 2.32 (s,

H), 2.02 (s, 6H); C{ H} NMR (126 MHz, CDCl ): δ 160.1,

49.6, 137.7, 137.3, 136.1, 135.6, 128.2, 124.6, 121.4, 21.0, 20.0; GC−

MS (EI, 70 eV) m/z: calcd for [M] (C H N), 197.1; found, 197.3.

1

3

1

3

1

3

+

1

4

15

2

,2′-Bipyridyl (6k). Prepared using 2,2′-bipyridyl N-oxide (5k, 189

mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50 equiv), 7

(

1.0 mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05 M). 2,2′-

3

Bipyridine (6k, 160 mg, 98%) was isolated (hexanes/EtOAc = 2:1) as

a white solid. Spectroscopic data matched with those reported in the

3f

1

literature. H NMR (500 MHz, CDCl ): δ 8.66 (d, J = 4.7 Hz, 2H),

3

8

7

1

.37 (d, J = 7.9 Hz, 2H), 7.79 (td, J = 7.7, 1.8 Hz, 2H), 7.28 (ddd, J =

1

3

1

.5, 4.7, 1.2 Hz, 2H); C{ H} NMR (126 MHz, CDCl ): δ 156.1,

3

+

49.1, 136.9, 123.6, 121.0; GC−MS (EI, 70 eV) m/z: calcd for [M]

REFERENCES

(

C H N ), 156.1; found, 156.2.

■

10

8

2

(

1) (a) Trost, B. M. Selectivity: A Key to Synthetic Efficiency.

7

-Azaindole (6l). Prepared using 7-azaindole N-oxide (5l, 148 mg,

Science 1983 , 219 , 245 −250. (b) Shenvi, R. A.; O ’Malley, D. P.;

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1

.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50 equiv), 7 (1.0

mg, 1.1 μmol, 0.1 mol %), and CH CN (22.0 mL, 0.05 M). 7-

3

Azaindole (6l, 119 mg, 91%) was isolated (hexanes/EtOAc = 1.5:1)

as a pale purple solid. Spectroscopic data matched with those reported

3f

1

in the literature. H NMR (500 MHz, CDCl ): δ 12.20 (br s, 1H),

3

8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.01 (dd, J = 7.8, 1.6 Hz, 1H), 7.44 (d,

J = 3.5 Hz, 1H), 7.12 (dd, J = 7.8, 4.8 Hz, 1H), 6.54 (d, J = 3.5 Hz,

1

(

H); ¹³C{ H} NMR (126 MHz, CDCl ): δ 148.8, 142.1, 129.0,

1

3

+

25.4, 120.6, 115.6, 100.5; GC−MS (EI, 70 eV) m/z: calcd for [M]

C H N ), 118.1; found, 118.1.

7

6

2

,2′-Bipyridyl (6k). Prepared using 2,2′-bipyridyl N,N′-dioxide

(

5m, 207 mg, 1.10 mmol, 1.00 equiv), 1c (510 mg, 1.65 mmol, 1.50

equiv), 7 (1.0 mg, 1.1 μmol, 0.1 mol %), and a mixture of

CF CH OH and CH CN (4:1, v/v, 13.75 mL, 0.08 M). 2,2′-

3

2

3

Bipyridine (6k, 156 mg, 91%) was isolated (hexanes/EtOAc = 2:1) as

a white solid. Spectroscopic data matched with those reported in the

3f

1

literature. H NMR (500 MHz, CDCl ): δ 8.66 (d, J = 4.8 Hz, 2H),

3

8

7

1

.38 (d, J = 8.1 Hz, 2H), 7.79 (td, J = 7.7, 1.8 Hz, 2H), 7.28 (ddd, J =

1

3

1

.5, 4.8, 1.2 Hz, 2H); C{ H} NMR (126 MHz, CDCl ): δ 156.1,

3

+

49.1, 136.8, 123.6, 121.0; GC−MS (EI, 70 eV) m/z: calcd for [M]

(3) For selected recent examples, see: (a) Gurram, V.; Akula, H. K.;

Garlapati, R.; Pottabathini, N.; Lakshman, M. K. Mild and General

Access to Diverse 1H-Benzotriazoles via Diboron-Mediated N −OH

Deoxygenation and Palladium- Catalyzed C −C and C −N Bond

Formation. Adv. Synth. Catal. 2015 , 357 , 451 −462. (b) Jeong, J.; Lee,

D.; Chang, S. Copper-Catalyzed Oxygen Atom Transfer of N -Oxides

Leading to a Facile Deoxygenation Procedure Applicable to Both

Heterocyclic and Amine N -Oxides. Chem. Commun. 2015, 51, 7035−

(

C H N ), 156.1; found, 156.2.

10 8 2

ASSOCIATED CONTENT

sı Supporting Information

■

*

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02805.

7

038. (c) Jeong, J.; Suzuki, K.; Hibino, M.; Yamaguchi, K.; Mizuno,

N. Selective Deoxygenation of Pyridine N -Oxides through Photo-

redox Catalysis of a Dilacunary Silicotungstate. ChemistrySelect 2016,

Characterization and spectroscopic data for all com-

pounds and mechanistic studies (PDF)

1

, 5042 −5048. (d) Jeong, J.; Suzuki, K.; Yamaguchi, K.; Mizuno, N.

Visible-Light-Responsive Catalysis of a Zinc-Introduced Lacunary

Disilicoicosatungstate for the Deoxygenation of Pyridine N -Oxides.

New J. Chem. 2017, 41, 13226−13229. (e) Gupta, S.; Sureshbabu, P.;

Singh, A. K.; Sabiah, S.; Kandasamy, J. Deoxygenation of Tertiary

Amine N-Oxides Under Metal Free Condition Using Phenylboronic

AUTHOR INFORMATION

Corresponding Author

Jun Hee Lee − Department of Advanced Materials Chemistry,

Dongguk University, Gyeongju 38066, Republic of Korea;

■

2

891

https://dx.doi.org/10.1021/acs.joc.0c02805

J. Org. Chem. 2021, 86, 2876−2894

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

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(

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Highly Chemoselective Deoxygenation of N-Heterocyclic N-Oxides Using Hantzsch Esters as Mild Reducing Agents

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