Visible-Light-Induced C2 Alkylation of Pyridine N-Oxides

Article abstract of DOI:10.1021/acs.joc.6b02891

A photoredox catalytic method has been developed for the direct C2 alkylation of pyridine N-oxides. This reaction is compatible with a range of synthetically relevant functional groups for providing efficient synthesis of a variety of C2-alkylated pyridine N-oxides under mild conditions. Mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.

Full text of DOI:10.1021/acs.joc.6b02891

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Article
Visible-Light-Induced C2 Alkylation of Pyridine N-oxides
Wen-Man Zhang, Jian-Jun Dai, Jun Xu, and Hua-Jian Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02891 • Publication Date (Web): 19 Jan 2017
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Visible-Light-Induced C2 Alkylation of Pyridine N-oxides
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WenꢀMan Zhang, JianꢀJun Dai,* Jun Xu, and HuaꢀJian Xu*
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School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, China
Eꢀmail: daijj@hfut.edu.cn; hjxu@hfut.edu.cn
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RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A photoredox catalytic method has been developed for the direct C2 alkylation of
pyridine
Nꢀoxides. This reaction is compatible with a range of synthetically relevant functional groups for
providing efficient synthesis of a variety of C2ꢀalkylated pyridine
Nꢀoxides under mild conditions.
Mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.
INTRODUCTION
Pyridine Nꢀoxides and their functionalized derivatives are abundant structural components of
biologically active and medicinally important compounds.1 In recent years, considerable efforts
have been devoted to developing new methods for the functionalization of pyridine Nꢀoxides.2–5
However, examples of the direct C2 alkylation of these pyridine Nꢀoxides are limited thus far.6
Almqvist and Olsson achieved 2ꢀsubstituted pyridine Nꢀoxides through the addition of Grignard
reagents to pyridine Nꢀoxides (Scheme 1a).6a In 2009, Li and Itami reported the
crossꢀdehydrogenativeꢀcoupling (CDC) of pyridine Nꢀoxides and cycloalkanes in the presence of
tꢀBuOOꢀtꢀBu under transitionꢀmetal free conditions.6b However, this transformation faces
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limitations, such as poor regionꢀselectivity and harsh reaction conditions (Scheme 1b). In 2013, Fu
and coꢀworkers described an elegant palladiumꢀcatalysed alkylation of pyridine Nꢀoxides with
nonꢀactivated alkyl bromides (Scheme 1c).6c The most important and notable feature of the work
demonstrated by Li, Itami and Fu is that both approaches involve the generation of an alkyl
radical as the key intermediate. This implies that the generation methods of alkyl radicals in
reactions can significantly influence the outcome.
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Scheme 1. C–H Alkylation of Pyridine N-oxides
Thanks to the pioneering studies of Akita and Koike,7 followed by the work of Molander8 and
Chen,9 photoredox catalysis has emerged as an attractive alternative for the generation of alkyl
radicals from potassium alkyltrifluoroborates via singleꢀelectron transfer (SET) processes.10
Inspired by these impressive advances and as a continuation of our studies on photocatalytic
radical reactions,11 we now report an unprecedented direct C2 alkylation of pyridine Nꢀoxides via
visibleꢀlight photoredox catalysis (Scheme 1d).12 Our new reaction uses a readily available simple
photocatalyst and shows good functionalꢀgroup compatibility, thus enabling efficient synthesis of
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a variety of C2ꢀalkylated pyridine Nꢀoxides (32 examples). Moreover, the usefulness of the new
method has also been demonstrated by the successful synthesis of the drug molecule ciclopirox.
RESULTS AND DISSCUSION
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We initially examined the C2 alkylation reaction of 2ꢀmethylpyridine Nꢀoxide (1a) with
potassium cyclohexyltrifluoroborate (2a) as a model substrate using [Ru(bpy)3](PF6)2 as the
photocatalyst. The desired product (3a) was obtained in 78% yield with [Ru(bpy)3](PF6)2 (2
mol%), 1ꢀacetoxyꢀ1,2ꢀbenziodoxolꢀ3ꢀ(1H)ꢀone (BIOAc) (3.0 equiv), TFA (2.0 equiv) in
CH2Cl2/H2O at room temperature under a nitrogen atmosphere and 36 W blue LEDs
irradiation for 24 h (Table 1, entry 1). Replacing BIOAc with a variety of other hypervalent
iodine(III) oxidants,13 including BIOH and PhIO, as well as with a strong oxidant, K2S2O8,
leads to significantly lower yields (Table 1, entries 2–5). When oxygen (1 atm) was employed
in place of BIOAc, the reaction was completely shut down (Table 1, entry 6). Interestingly,
the effect of TFA as an acidic additive was dramatic, because other acids (e.g., TsOH, TfOH,
HOAc and H3PO4) or basic additives (e.g., Na2CO3 and DBU) only resulted in moderate to
low yields (Table 1, entries 7–13). Use of other solvents such as dioxane, CH3CN, HFIP,
acetone, NMP and toluene can also cause the reaction, but the yields were inferior (Table 1,
entries 14–19). The control reactions did not furnish the desired product in the absence of
[Ru(bpy)3](PF6)2 and/or light, thus confirming the role of photoexcited species derived from
the photocatalyst in the reaction (Table 1, entries 20–22).
Table 1. Standard and control reactions a
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Entry
Variation from the standard conditions
Yield (%)b
1
2
none
78
41
<5
18
trace
0
BIOH instead of BIOAc
PhI(OAc)2 instead of BIOAc
K2S2O8 instead of BIOAc
PhIO instead of BIOAc
O2 (1 atm) instead of BIOAc
no TFA
3
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7
34
50
38
44
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21
<2
33
19
41
47
8
8
TsOH instead of TFA
TfOH instead of TFA
H3PO4 instead of TFA
HOAc instead of TFA
Na2CO3 instead of TFA
DBU instead of TFA
dioxane instead of CH2Cl2
CH3CN instead of CH2Cl2
HFIP instead of CH2Cl2
acetone instead of CH2Cl2
NMP instead of CH2Cl2
toluene instead of CH2Cl2
no light
9
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14
<4
0
no [Ru(bpy)3](PF6)2
no light and no [Ru(bpy)3](PF6)2
0
a Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2 equiv), [Ru(bpy)3](PF6)2 (0.004 mmol, 2 mol%), oxidant (0.6
mmol, 3 equiv), additive (2 equiv), CH2Cl2/H2O (2 mL, v : v = 1 : 1), under a N2 atmosphere, 24 h at room temperature with 2 ×
36 W blue LEDs irradiation, unless otherwise stated. b GC yields with 1,1'ꢀbiphenyl as an internal standard added after the
reaction (averages of two runs).
With an optimized set of reaction conditions, we next investigated the scope of the
photocatalytic C2 alkylation process (Table 2a) and found that a variety of pyridine Nꢀoxides
can be successfully transformed to the desired product in modest to good yields (up to 85%).
The reaction can well tolerate many synthetically important functional groups, including ether
(3j), amide (3i), trifluoromethyl (3o, 3h), and even unprotected aliphatic alcohol (3m).
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Moreover, arene rings carrying fluoro (3k), chloro (3o–p), and orthoꢀmethyl (3d–e)
substituents are compatible with the reaction, thus providing additional handles for further
functionalization at the halogenated and C(sp3)–H positions using crossꢀcoupling techniques.
It is notable that other Nꢀcontaining heterocyclic substrates (3c, 3p–q) could also be used in
the reaction. With regard to the scope of potassium alkyltrifluoroborate (Table 2b), both
acyclic (3r–s, 3x–z, 3aa–ad) and cyclic (3t–w) alkyltrifluoroborates are good substrates. Bocꢀ
and Tsꢀprotected piperidineꢀcontaining compounds (3t–u) could be used in the C2 alkylation
reaction. Moreover, functional groups such as ester (3s, 3aa), alkyne (3s), aryl and alkyl
bromides (3x, 3ac), ether (3x–z), cyano (3y), and ketone (3z) can be tolerated in the
transformation. To further demonstrate the synthetic utility of the current reaction, we
conducted reactions on a 1 mmol scale with 1e, 1o and 1s the corresponding product 3e, 3o
and 3s were isolated in 65%, 69% and 45% yields, respectively.
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Table 2. Substrate Scope a
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R
R
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[Ru(bpy)3](PF6)2 (2 mol%)
+
alkyl-BF3K
(2 equiv)
2
BIOAc (3 equiv), TFA (2 equiv)
CH2Cl2/H2O (1:1), r.t., 24 h
36 W blue LED
N
O
alkyl
N
O
H
1
3
a) Scope of the N-oxides
Me
8
X
R
Me
9
Me
N
Cy
N
O
Cy
N
O
Cy
Me
N
O
Cy
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O
N
O
Cy
3e, 63%
X = C, 3b, 61%
X = N, 3c, 56%
3d, 55%
(1 mmol scale: 65%)
3f, 55%
R = Me, 3g, 84%b
R = CF3, 3h, 58%
R = NHBoc, 3i, 58%
R = OBn, 3j, 85%
F
N
O
Cy
HO
N
Cy
N
O
Cy
O
3k, 50%
3l, 54%
3m, 50%
CF3
Cl
Cl
N
O
Cy
Me
N
O
Cy
Cl
N
O
Cy
N
Cy
3o, 75%
(1 mmol scale: 69%)
O
3n, 62%
b) Scope of the potassium alkyltrifluoroborates
3p, 62%
3q, 69%
O
Me
Me
N
Me
Me
Me
N
Ph Me
Me
N
O
O
3s, 48%c
(1 mmol scale: 45%c)
O
N
O
X
3r, 63%c
X = Ts, 3t, 50%
X = Boc, 3u, 48%
N
O
N
O
Me
N
O
O
3v, 53%
Br
3x, 54%c
3w, 60%
Me
R
O
O
N
Me
N
O
O
Me
Me
O
i-Pr
R = 4-CN, 3y, 53%
R = 3-Bz, 3z, 60%
3aa, 56%
Me
N
Me
Me
N
O
Br
Me
N
O
O
3ab, 38%
3ac, 51%
3ad, 55%
a The reactions were carried out for 24 h on a 0.2 mmol scale, isolated yields based on pyridine Nꢀoxides. For details, please see
the Supporting Information. b 2,6ꢀdisubstitued product was obtained in 55% yield with 4 equiv of 2a. c 3 equiv of potassium
alkyltrifluoroborates, 48 h.
Moreover, the current photocatalytic system can be applied to sequential C–H
arylation/alkylation of pyridine Nꢀoxide, as exemplified by the reaction in Scheme 2. According to
the pioneering investigation by Fagnou and coꢀworkers,2a the palladiumꢀcatalysed C–H arylation
of pyridine Nꢀoxide (4) with bromobenzene was achieved in 78% yield, and subsequent treatment
of the resulting Nꢀoxide (5) under our present standard conditions delivered the final alkylated
product 6 in 64% yield.
Scheme 2. Sequential C(sp2)–H Arylation/Alkylation of Pyridine N-oxide
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Reagents and conditions: (i) Arylation, PhBr, Pd(OAc)2 (10 mol%), P(tBu)3·HBF4 (20 mol%), K2CO3 (2 equiv), toluene, 110 °C;
78%; (ii) Alkylation, CyBF3K, [Ru(bpy)3(PF6)2] (2 mol%), BIOAc (3 equiv), TFA (2 equiv), CH2Cl2/H2O (1:1), r.t., 36 W blue
LED; 64%.
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To demonstrate further the synthetic utility with this newly developed protocol, we examined a
new route for the preparation of ciclopirox (9), a diseaseꢀmodifying antifungal drug that can be
used to treat superficial mycoses such as tinea versicolor and tinea pedis.14 As shown in Scheme 3,
we successfully prepared 9 on a laboratoryꢀscale in three steps with more than 59% overall yield
starting from commercially available 2ꢀmethoxyꢀ4ꢀmethylpyridine (7), compared with the existing
method, which resulted in less than 14% overall yield after five steps.15
Scheme 3. Synthetic Application to the Drug Molecule Ciclopirox
To obtain more insight into the mechanism of this photocatalytic reaction, we conducted
radicalꢀtrapping experiments using 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl (TEMPO) and
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) as radical scavengers. In both cases, no C2ꢀalkylated
product 3a was detected. Meanwhile, the alkyl–TEMPO adduct 10 as well as the alkyl–BHT
adduct 11 could be isolated in 90% and 34% yield, respectively (Scheme 4a). These above
observations suggested that the intermediate of an alkyl radical may be generated in the
photocatalytic reaction. Furthermore, potassium cyclohexyltrifluoroborate (2a) was reacted in the
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presence of both electronꢀrich 4ꢀmethylpyridine Nꢀoxide (1g) and electronꢀdeficient
4ꢀtrifluoromethylpyridine Nꢀoxide (1h) under the standard conditions (Scheme 4b). In this case,
the only product detected using GC analysis of the reaction mixture was 3f, arising from reaction
of the more electronꢀrich pyridine Nꢀoxide, thus indicating that the reaction is compatible with an
SEAr mechanism.1a We also determined the intramolecular (kH/kD = 1.1) and intermolecular (kH/kD
= 1.2) kinetic isotopic effect by 1H NMR analysis (Scheme 4c). These results suggest that the C−H
bond cleavage might not be the rate determining step in the photocatalytic process.16 In addition,
the reaction’s quantum yield Φ was measured to be 3.7 (please see the Supporting Information),
indicating a mechanism involving a chain reaction.17
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Based on the above experiments and previous reports,8, 9 we propose the possible mechanism
depicted in Scheme 4d. Initially, the photocatalyst [Ru(bpy)3]2+ is activated by visibleꢀlight
irradiation to give the reducing excitedꢀstate catalyst *[Ru(bpy)3]2+, which is oxidatively quenched
by BIOAc to provide the oxidized catalyst [Ru(bpy)3]3+ and a radical species A. Then SET from
the alkyltrifluoroborate to [Ru(bpy)3]3+ to form the alkyl radical B and regenerating the
[Ru(bpy)3]2+ catalyst.. Sequentially, addition of this alkyl radical B to pyridine Nꢀoxide C
produces radical cation D, which is reoxidized by radical A, delivering the desired product E and
2ꢀiodobenzoic acid F.
Scheme 4. Mechanism Investigations
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a) Radical trapping experiments
4
5
6
7
TEMPO
(2.5 equiv)
Me
Me
Me
Me
Cy
N
O
As in Table 2
10, 90%
Me
N
O
Cy
Me
N
O
1a
H
CyBF3K
tBu
8
3a, Not found
HO
9
BHT
(2.5 equiv)
Cy
tBu
10
11
12
13
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11, 34%
b) Competition experiment
Me
CF3
Me
CF3
As in Table 2
+
+
CyBF3K
N
O
Cy
N
O
Cy
N
N
O
O
1g
1h
3f, 85%
3g, 0%
c) Kinetic isotope effect (KIE)
Intramolecular KIE
As in Table 2
+
H
N
D
H
N
Cy
D
N
Cy
CyBF3K
O
d1-1b
O
3b
O
d1-3b
24% conversion
KIE = 1.1
Intermolecular KIE
H/D
H/D
H/D
H/D
H/D
Cy
H/D
H/D
H/D
H/D
As in Table 2
CyBF3K
20% conversion
N
O
N
O
3b/d4-3b
KIE = 1.2
1b/d5-1b
d) Proposed mechanisim
*[Ru(bpy)3]2+
O
BIOAc
O
I
OH
O
SET
I
A
F
Photoredox
catalysis
[Ru(bpy)3]2+
[Ru(bpy)3]3+
SET
N
O
H
H
R
C
N
O
N
O
R
RBF3K
R
B
D
E
CONCLUSIONS
In summary, we have reported the first example of a photocatalytic C2 alkylation reaction of
pyridine Nꢀoxides. This reaction affords the desired C2ꢀalkylated pyridine Nꢀoxides under mild
conditions. The present reaction has broad substrate scope, including ester, amide, ether, cyano,
ketone, alkyne, and halides. A series of mechanistic studies is consistent with this C–H alkylation
reaction proceeding through the proposed radical pathway. We are currently investigating of new
transformations of alkyl boron reagents via photoredox catalysis.
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EXPERIMENT SECTION
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General Information
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Chemicals and solvents were used as received. H NMR, 13C NMR, 19F NMR spectra were
recorded on a 600 MHz spectrometer at the ambient temperature, using TMS as an internal
standard (chemical shifts in δ). Data are reported as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt =
doublet of triplet, etc.), coupling constant (Hz), and integration. Gas chromatographic (GC)
analyses were performed on a GC equipped with a flameꢀionization detector and an Rtx@ꢀ65 (30
m × 0.32 mm ID × 0.25 ꢁm df) column using biphenyl as an internal standard, added during
reaction workup. GCꢀMS analyses were performed on a GCꢀMS with an EI mode. High resolution
mass spectra were obtained on a HRMSꢀTOF spectrometer. Analytical thin layer chromatography
(TLC) performed on preꢀcoated silica gel plates. After elution, plate was visualized under UV
illumination at 254 nm for UV active materials. Organic solutions were concentrated under
reduced pressure on a rotary evaporator. Column chromatography was performed on silica gel
(200−300 mesh) by standard techniques eluting with solvents as indicated.
1
General Procedure for the Preparation of Pyridine N-oxides 1c-q
To a stirred solution of pyridine (10 mmol) in CHCl3 (20 mL) was added 70% mꢀCPBA (10 mmol),
portion wise at 0 °C. The mixture was stirred at room temperature for 12 h, at which time complete
consumption of starting material was observed by TLC. The reaction mixture was diluted with CHCl3,
and solid K2CO3 (4.0 equiv) was added. The resulting mixture was stirred for an additional 10 min. The
mixture was washed with water for three times. The organic layer was separated and dried with MgSO4,
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filtered and concentrated. The crude product was purified by flash chromatography to afford the
pyridine Nꢀoxides.18
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Procedure for the Preparation of Alkyltrifluoroborates
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Procedure A (2v–w and 2ac): Alkene (10.0 mmol) in THF (2.0 mL) was added dropwise to a solution
of BH3•THF (20 mL, 20 mmol, 1 M solution in THF) at 0 °C. The mixture was stirred for 2 h at room
temperature and H2O (2.0 mL) was slowly added. After stirring for additional 3 h at room temperature,
the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (30 mL), and washed with
saturated aqueous bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated to approximately 5 mL. Petroleum ether was then added. The
resultant precipitate was washed with petroleum ether and dried under vacuum to afford the
alkylboronic acid as white solid or thick oil. A 100 mL roundꢀbottomed flask equipped with a stir bar
was charged with the alkylboronic acid and MeOH (20 mL). To the flask was added KHF2 (15 mL,
3.91 g, 50 mmol), and the resulting suspension was stirred for 2 h and then concentrated to dryness.
The residue, a white solid, was extracted with hot acetone (3 × 30 mL), and the combined filtered
extracts were concentrated to approximately 5 mL. Ether was added and the resultant precipitate was
collected and dried to afford the potassium trifluoroborate as a white solid.9a
Procedure B (2r, 2t–u, 2x–z, 2aa and 2ad): CuI (190 mg, 1.0 mmol), PPh3 (341 mg, 1.3 mmol),
LiOMe (760 mg, 20 mmol), and bis(pinacolato)diboron (3.8 g, 15.0 mmol) were added to a 100 mL
roundꢀbottomed flask equipped with a stir bar. The vessel was evacuated and filled with nitrogen gas
three times. DMF (40 mL) and the alkyl bromide (10 mmol) were added by syringe under a nitrogen
atmosphere. The resulting reaction mixture was stirred vigorously at 25 ºC for 18 h. The reaction
mixture was diluted with EtOAc and filtered through silica gel. Then the mixture was washed with
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saturated aqueous brine (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered,
concentrated and purified by column chromatography to afford the pinacol ester. To the solution of
alkylboronic acids or esters in methanol was added saturated aqueous KHF2 (5.0 equiv). The resulting
suspension was stirred for 2 h and then concentrated to dryness. The residue, a white solid, was
extracted with hot acetone (3 × 30 mL), and the combined filtered extracts were concentrated to
approximately 5 mL. Diethyl ether was added and the resultant precipitate was collected and dried to
afford the potassium trifluoroborate as a white solid.19
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Procedure
C
(2s): To
a
stirred solution of butꢀ2ꢀynꢀ1ꢀol (0.54 mL, 7.2 mmol),
6ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)hexanoic acid (1.15 g, 4.8 mmol) and DMAP (33.6 mg,
0.276 mmol) in anhydrous DCM (10 mL) was added DCC (1.09 g, 5.2 mmol) separately at room
temperature. After stirring for 12 h, the mixture was filtered and washed with 1 M HCl, saturated
NaHCO3 aqueous and brine, respectively. After dried over Na2SO4, the crude product was concentrated
and purified by flash column chromatography to afford pinacol ester as yellow oil. To the solution of
alkylboronic acids or esters in methanol was added saturated aqueous KHF2 (5.0 equiv). The resulting
suspension was stirred for 2 h and then concentrated to dryness. The residue, a white solid, was
extracted with hot acetone (3 × 30 mL), and the combined filtered extracts were concentrated to
approximately 5 mL. Diethyl ether was added and the resultant precipitate was collected and dried to
afford the potassium trifluoroborate as a white solid.20
General Procedure for Visible-Light-Induced C2 Alkylation of Pyridine N-oxides
Method A: To a 10 mL Schlenk tube was sequentially added alkyltrifluoroborates (0.4 mmol),
[Ru(bpy)3](PF6)2 (3.8 mg, 2 mol%), BIOAc (183.6 mg, 0.6 mmol). The tube was evacuated and
backfilled with N2 for three times. Then, pyridine Nꢀoxides (0.2 mmol), CH2Cl2 (1 mL), H2O (1 mL)
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and TFA (30 ꢁL, 0.4 mmol) were added. The reaction mixture was stirred for 24 h at room temperature
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CH2Cl2, and solid K2CO3 (138.2 mg, 5.0 equiv) was added. The resulting mixture was stirred for
an additional 5 min. The organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 5 mL). Then organic layer was combined, dried over sodium sulfate, filtered,
concentrated and purified by column chromatography (silica gel) yielded the desired product.
Method B: To a 10 mL Schlenk tube was sequentially added alkyltrifluoroborates (0.6 mmol),
[Ru(bpy)3](PF6)2 (3.8 mg, 2 mol%), BIOAc (183.6 mg, 0.6 mmol). The tube was evacuated and
backfilled with N2 for three times. Then pyridine Nꢀoxides (0.2 mmol), CH2Cl2 (1 mL), H2O (1 mL) and
TFA (30 ꢁL, 0.4 mmol) were added. The reaction mixture was stirred for 24 h at room temperature
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with blue LEDs (2 × 36 W) irradiation. Upon completion, the reaction mixture was diluted with
CH2Cl2, and solid K2CO3 (138.2 mg, 5.0 equiv) was added. The resulting mixture was stirred for
an additional 5 min. The organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 5 mL). Then organic layer was combined, dried over sodium sulfate, filtered,
concentrated and purified by column chromatography (silica gel) yielded the desired product.
2-cyclohexyl-6-methylpyridine N-oxide (3a): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 28.3 mg, 74% yield). Compound 3a has been previously reported.21 1H NMR (600
MHz, CDCl3) δ 7.05 (dt, J = 6.6, 5.2 Hz, 3H), 3.56 – 3.45 (m, 1H), 2.46 (s, 3H), 1.99 (d, J = 11.9 Hz,
2H), 1.79 (d, J = 13.0 Hz, 2H), 1.72 (d, J = 13.2 Hz, 1H), 1.45 (ddd, J = 16.2, 11.5, 3.2 Hz, 2H), 1.24 –
1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 156.6, 149.0, 125.0, 123.4, 120.5, 37.5, 33.6, 31.0, 26.4,
18.6. Elemental analysis calcd (%) C12H17NO: C 75.35, H 8.96, N 7.32. Found: C 75.21, H 9.07, N 7.18.
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2-cyclohexylpyridine N-oxide (3b): Following the Method A, the resulting mixture was purified by
flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil (0.2 mmol
scale: 21.6 mg, 61% yield). Compound 3b has been previously reported.6f 1H NMR (600 MHz, CDCl3)
δ 8.32 (d, J = 6.4 Hz, 1H), 7.27 (dt, J = 18.0, 7.6 Hz, 2H), 7.13 (dd, J = 9.3, 4.2 Hz, 1H), 3.54 (t, J =
12.0 Hz, 1H), 2.10 – 2.03 (m, 2H), 1.86 (d, J = 13.3 Hz, 2H), 1.80 (d, J = 13.2 Hz, 1H), 1.52 (q, J =
13.0 Hz, 2H), 1.28 (ddd, J = 13.2, 10.6, 4.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 157.1, 139.9,
126.9, 123.3, 123.0, 37.2, 30.9, 26.4, 26.3.
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2-cyclohexylpyrazine N-oxide (3c): Following the Method A, the resulting mixture was purified by
flash chromatography (PE : EA = 2 : 1 to PE : EA = 1 : 1) to give the desired product as a colorless oil
(0.2 mmol scale: 20.0 mg, 56% yield). Compound 3c has been previously reported.21 1H NMR (600
MHz, CDCl3) δ 8.41 (s, 1H), 8.29 (s, 1H), 8.10 (d, J = 3.8 Hz, 1H), 3.34 (t, J = 12.0 Hz, 1H), 2.04 (d, J
= 12.0 Hz, 2H), 1.87 (d, J = 13.3 Hz, 2H), 1.80 (d, J = 13.2 Hz, 1H), 1.49 (dt, J = 25.9, 8.0 Hz, 2H),
1.33 (dddd, J = 20.0, 13.0, 9.8, 3.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ151.8, 145.7, 144.6, 133.9,
35.7, 30.1, 26.3, 26.1.
6-cyclohexyl-2,3-dimethylpyridine N-oxide (3d): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 22.6 mg, 55% yield). 1H NMR (600 MHz, CDCl3) δ 7.01 (d, J = 8.1 Hz, 1H), 6.97 (d,
J = 8.1 Hz, 1H), 3.51 (t, J = 12.0 Hz, 1H), 2.50 (s, 3H), 2.29 (s, 3H), 2.02 (d, J = 11.8 Hz, 2H), 1.83 (d,
J = 13.4 Hz, 2H), 1.77 (d, J = 13.0 Hz, 1H), 1.49 (dt, J = 16.1, 11.5 Hz, 2H), 1.25 (d, J = 13.6 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 154.2, 148.4, 131.5, 127.2, 119.3, 37.7, 31.2, 26.6, 26.4, 19.5, 14.5.
HRMS (ESI) m/z calcd for C13H20NO [M+H]+: 206.1539; found: 206.1540.
2-cyclohexyl-4,6-dimethylpyridine N-oxide (3e): Following the Method A, the resulting mixture was
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purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
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(0.2 mmol scale: 25.9 mg, 63% yield, 1 mmol scale: 133.5 mg, 65% yield). H NMR (600 MHz,
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CDCl3) δ 6.91 (s, 1H), 6.88 (s, 1H), 3.55 (t, J = 12.0 Hz, 1H), 2.49 (s, 3H), 2.28 (s, 3H), 2.02 (d, J =
12.2 Hz, 2H), 1.83 (d, J = 13.4 Hz, 2H), 1.77 (d, J = 13.1 Hz, 1H), 1.54 – 1.45 (m, 2H), 1.30 – 1.22 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 155.9, 148.3, 140.1, 124.3, 121.5, 37.5, 31.3, 26.5, 26.4, 20.6,
18.6. HRMS (ESI) m/z calcd for C13H20NO [M+H]+: 206.1539; found: 206.1542.
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2-cyclohexyl-5,6,7,8-tetrahydroquinoline N-oxide (3f): Following the Method A, the resulting
mixture was purified by flash chromatography (PE : EA = 1:1 to EA) to give the desired product as a
colorless oil (0.2 mmol scale: 25.5 mg, 55% yield). Compound 3f has been previously reported.21 1H
NMR (600 MHz, CDCl3) δ 6.98 (dd, J = 18.6, 8.1 Hz, 2H), 3.54 (t, J = 12.0 Hz, 1H), 2.95 (t, J = 6.6
Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.03 (d, J = 12.2 Hz, 2H), 1.91 – 1.83 (m, 3H), 1.83 – 1.72 (m, 3H),
1.51 (qd, J = 13.1, 3.1 Hz, 2H), 1.31 – 1.25 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 153.9, 148.6,
132.9, 125.9, 119.2, 37.5, 31.1, 28.6, 26.6, 26.4, 25.3, 22.2, 21.8.
2-cyclohexyl-4-methylpyridine N-oxide (3g): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 32.1 mg, 84% yield). 1H NMR (600 MHz, CDCl3) δ 8.15 (d, J = 6.6 Hz, 1H), 7.01 (s,
1H), 6.90 (d, J = 6.5 Hz, 1H), 3.56 – 3.47 (m, 1H), 2.32 (s, 3H), 2.03 (d, J = 12.3 Hz, 2H), 1.84 (d, J =
13.4 Hz, 2H), 1.78 (d, J = 13.1 Hz, 1H), 1.55 – 1.46 (m, 2H), 1.27 (dd, J = 12.7, 3.3 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 156.1, 139.1, 123.9, 123.7, 37.0, 31.0, 26.4, 26.3, 20.7. HRMS (ESI) m/z calcd
for C12H18NO [M+H]+: 192.1383; found: 192.1383.
2-cyclohexyl-4-(trifluoromethyl)pyridine N-oxide (3h): Following the Method A, the resulting
mixture was purified by flash chromatography (PE : EA = 2 : 1 to PE : EA = 1 : 1) to give the desired
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product as a colorless oil (0.2 mmol scale: 28.4 mg, 58% yield). 1H NMR (600 MHz, CDCl3) δ 8.31 (d,
J = 6.7 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 6.3 Hz, 1H), 3.47 (t, J = 11.7 Hz, 1H), 2.06 (d, J = 11.8 Hz,
2H), 1.85 (dd, J = 26.6, 13.1 Hz, 3H), 1.52 (dd, J = 25.8, 12.8 Hz, 2H), 1.29 (dd, J = 23.4, 11.2 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 157.7, 140.0, 126.5 (q, J = 34.9 Hz), 122.6 (q, J = 273.7 Hz), 119.9 (q,
J = 3.7 Hz), 119.5 (q, J = 3.6 Hz), 37.2, 30.4, 26.1, 26.0. HRMS (ESI) m/z calcd for C12H15F3NO
[M+H]+: 246.1100; found: 246.1102.
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4-((tert-butoxycarbonyl)amino)-2-cyclohexylpyridine N-oxide (3i): Following the Method A, the
resulting mixture was purified by flash chromatography (EA to EA : MeOH = 10 : 1) to give the
desired product as a colorless oil (0.2 mmol scale: 33.9 mg, 58% yield). 1H NMR (600 MHz, CDCl3) δ
8.60 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 3.49 (t, J = 12.0 Hz, 1H), 2.03 (d, J =
11.8 Hz, 2H), 1.79 (dd, J = 41.0, 13.0 Hz, 3H), 1.51 – 1.40 (m, 10H), 1.32 – 1.18 (m, 4H). 13C NMR
(151 MHz, CDCl3) δ 156.9, 152.4, 139.7, 112.2, 111.8, 81.6, 37.5, 31.0, 28.3, 26.4, 26.1. HRMS (ESI)
m/z calcd for C16H25N2O3 [M+H]+: 293.1860; found: 293.1860.
4-(benzyloxy)-2-cyclohexylpyridine N-oxide (3j): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a yellow solid
1
(0.2 mmol scale: 48.2 mg, 85% yield). H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 7.2 Hz, 1H), 7.61 –
7.27 (m, 5H), 6.80 (d, J = 3.2 Hz, 1H), 6.70 (dd, J = 7.1, 3.3 Hz, 1H), 5.07 (s, 2H), 3.51 (t, J = 12.0 Hz,
1H), 2.04 (d, J = 12.2 Hz, 2H), 1.83 (d, J = 13.3 Hz, 2H), 1.78 (d, J = 13.1 Hz, 1H), 1.49 (q, J = 13.0
Hz, 2H), 1.26 – 1.17 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 157.9, 157.5, 140.6, 135.1, 128.9, 128.7,
127.7, 109.9, 109.4, 70.8, 37.5, 31.0, 26.3, 26.2. HRMS (ESI) m/z calcd for C18H22NO2 [M+H]+:
284.1645; found: 284.1645.
2-cyclohexyl-3-fluoropyridine N-oxide (3k): Following the Method A, the resulting mixture was
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purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 19.5 mg, 50% yield). 1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 6.4 Hz, 1H), 7.02 (dt,
J = 13.4, 6.7 Hz, 1H), 6.97 (t, J = 8.7 Hz, 1H), 3.81 (t, J = 11.1 Hz, 1H), 1.79 (dt, J = 28.1, 16.4 Hz,
6H), 1.42 (dd, J = 25.7, 12.7 Hz, 2H), 1.34 – 1.22 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 160.0 (d, J
= 248.9 Hz), 136.5, 121.9 (d, J = 9.5 Hz), 113.9 (d, J = 25.4 Hz), 107.5, 35.8, 28.4, 26.6, 25.9. HRMS
(ESI) m/z calcd for C11H15FNO [M+H]+: 196.1132; found: 196.1132. Elemental analysis calcd (%)
C11H14FNO: C 67.67, H 7.23, N 7.17. Found: C 67.73, H 7.45, N 7.09.
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2-cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridine N-oxide H (3l): Following the Method A, the
resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a colorless oil (0.2 mmol scale: 23.5 mg, 54% yield). 1H NMR (600 MHz, CDCl3) δ 7.06 (d,
J = 7.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 3.52 (t, J = 12.0 Hz, 1H), 3.16 (t, J = 7.6 Hz, 2H), 2.97 (t, J =
7.6 Hz, 2H), 2.15 (p, J = 7.7 Hz, 2H), 2.02 (d, J = 11.9 Hz, 2H), 1.83 (d, J = 13.3 Hz, 2H), 1.77 (d, J =
13.1 Hz, 1H), 1.49 (dtt, J = 13.0, 6.4, 3.2 Hz, 2H), 1.29 – 1.21 (m, 3H). 13C NMR (151 MHz, CDCl3) δ
154.7, 153.0, 138.5, 122.4, 120.9, 36.9, 31.5, 31.4, 30.2, 26.5, 26.4, 22.4. HRMS (ESI) m/z calcd for
C14H20NO [M+H]+: 218.1539; found: 218.1538.
2-cyclohexyl-6-(2-hydroxyethyl)pyridine N-oxide (3m): Following the Method A, the resulting
mixture was purified by flash chromatography (EA : MeOH = 10 : 1) to give the desired product as a
colorless oil (0.2 mmol scale: 22.1 mg, 50% yield). 1H NMR (600 MHz, CDCl3) δ 7.28 – 7.21 (m, 1H),
7.15 (dd, J = 12.8, 7.9 Hz, 2H), 5.64 (s, 1H), 4.06 – 3.95 (m, 2H), 3.51 (t, J = 11.8 Hz, 1H), 3.33 – 3.21
(m, 2H), 2.05 (d, J = 12.3 Hz, 2H), 1.85 (d, J = 12.8 Hz, 2H), 1.79 (d, J = 13.0 Hz, 1H), 1.49 (dd, J =
25.9, 13.0 Hz, 2H), 1.32 – 1.24 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 157.3, 151.6, 127.3, 124.1,
121.6, 63.4, 37.8, 35.4, 31.0, 26.4, 26.3. HRMS (ESI) m/z calcd for C13H20NO2 [M+H]+: 222.1489;
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2-cyclohexyl-6-pentylpyridine N-oxide (3n): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 30.7 mg, 62% yield). 1H NMR (600 MHz, CDCl3) δ 7.14 (d, J = 6.8 Hz, 1H), 7.08 (s,
2H), 3.56 (t, J = 11.1 Hz, 1H), 2.91 (d, J = 6.7 Hz, 2H), 2.05 (d, J = 11.9 Hz, 2H), 1.84 (d, J = 12.9 Hz,
2H), 1.78 (d, J = 13.0 Hz, 1H), 1.75 – 1.67 (m, 2H), 1.50 (d, J = 12.9 Hz, 2H), 1.41 – 1.35 (m, 3H),
1.32 – 1.19 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 156.9, 152.8, 125.1,
122.3, 120.4, 37.7, 31.8, 31.1, 29.8, 26.5, 26.4, 26.1, 22.6, 14.1. HRMS (ESI) m/z calcd for C16H26NO
[M+H]+: 248.2009; found: 248.2012.
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2-chloro-6-cyclohexyl-4-(trifluoromethyl)pyridine N-oxide (3o): Following the Method A, the
resulting mixture was purified by flash chromatography (PE : EA = 5 : 1 to PE : EA = 2 : 1) to give the
desired product as a colorless oil (0.2 mmol scale: 42.0 mg, 75% yield, 1 mmol scale: 193 mg, 69%
yield). 1H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 3.50 – 3.42 (m,
1H), 2.06 (d, J = 12.1 Hz, 2H), 1.87 (d, J = 13.5 Hz, 2H), 1.80 (d, J = 13.1 Hz, 1H), 1.54 – 1.45 (m,
2H), 1.27 (ddd, J = 24.3, 12.1, 8.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 159.5, 143.1, 125.8 (q, J =
35.3 Hz), 122.3 (q, J = 272.4 Hz), 120.7 (q, J = 3.9 Hz), 117.4 (q, J = 3.6 Hz), 38.5, 30.5, 26.2, 26.1.
HRMS (ESI) m/z calcd for C12H14ClF3NO [M+H]+: 280.0711; found: 280.0709.
4,7-dichloro-2-cyclohexylquinoline N-oxide (3p): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 5 : 1) to give the desired product as a colorless oil (0.2
mmol scale: 36.7 mg, 62% yield). 1H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H),
7.50 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 2.85 (tt, J = 12.0, 2.9 Hz, 1H), 2.00 (d, J = 12.8 Hz, 2H), 1.89 (d,
J = 13.1 Hz, 2H), 1.78 (d, J = 13.0 Hz, 1H), 1.59 (qd, J = 12.6, 3.0 Hz, 2H), 1.50 – 1.41 (m, 2H), 1.36 –
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1.27 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 168.2, 149.2, 142.6, 136.3, 128.4, 127.6, 125.4, 123.7,
120.2, 47.4, 32.7, 26.5, 26.1. HRMS (ESI) m/z calcd for C15H16Cl2NO [M+H]+: 296.0603; found:
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6-cyclohexylphenanthridine N-oxide (3q): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 5 : 1) to give the desired product as a yellow solid (0.2
mmol scale: 38.3 mg, 69% yield). 1H NMR (600 MHz, CDCl3) δ 8.65 (d, J = 8.2 Hz, 1H), 8.54 (d, J =
8.1 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.69 (q, J = 6.9 Hz, 2H),
7.60 (t, J = 7.5 Hz, 1H), 3.62 (t, J = 11.2 Hz, 1H), 2.07 (t, J = 12.3 Hz, 2H), 1.97 (dd, J = 19.0, 8.3 Hz,
3H), 1.85 (d, J = 12.6 Hz, 1H), 1.67 – 1.53 (m, 3H), 1.44 (dd, J = 24.9, 11.9 Hz, 1H). 13C NMR (151
MHz, CDCl3) δ 165.4, 133.1, 130.0, 128.5, 127.2, 126.2, 125.7, 124.8, 123.4, 122.7, 121.9, 42.1, 32.4,
27.0, 26.4. HRMS (ESI) m/z calcd for C19H20NO [M+H]+: 278.1539; found: 278.1541.
2-methyl-6-phenethylpyridine N-oxide (3r): Following the Method B, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 26.8 mg, 63% yield). 1H NMR (600 MHz, CDCl3) δ 7.30 – 7.25 (m, 2H), 7.25 – 7.11
(m, 4H), 7.08 – 6.96 (m, 2H), 3.25 (t, J = 7.7 Hz, 2H), 3.11 – 3.03 (m, 2H), 2.57 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 151.6, 149.4, 141.1, 128.6, 128.5, 126.2, 124.9, 124.2, 123.5, 33.3, 32.3, 18.4.
HRMS (ESI) m/z calcd for C14H16NO [M+H]+: 214.1226; found: 214.1225.
2-(6-(but-2-yn-1-yloxy)-6-oxohexyl)-6-methylpyridine N-oxide (3s): Following the Method B, the
resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a colorless oil (0.2 mmol scale: 26.4 mg, 48% yield, 1 mmol scale: 123.9 mg, 45% yield).
1H NMR (600 MHz, CDCl3) δ 7.14 (d, J = 4.6 Hz, 1H), 7.11 (s, 2H), 4.62 (q, J = 2.3 Hz, 2H), 2.93 (s,
2H), 2.53 (s, 3H), 2.35 (t, J = 7.5 Hz, 2H), 1.84 (t, J = 2.4 Hz, 3H), 1.72 (dtd, J = 22.9, 15.3, 7.6 Hz,
4H), 1.45 (dt, J = 15.4, 7.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 173.0, 152.5, 149.5, 125.1, 124.0,
123.0, 83.2, 73.4, 52.7, 34.0, 30.9, 29.0, 26.0, 24.7, 18.4, 3.7. HRMS (ESI) m/z calcd for C16H22NO3
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[M+H]+: 276.1594; found: 276.1594.
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2-methyl-6-(1-tosylpiperidin-4-yl)pyridine N-oxide (3t): Following the Method A, the resulting
mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a
yellow solid (0.2 mmol scale: 34.6 mg, 50% yield). 1H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz,
2H), 7.34 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 4.3 Hz, 2H), 7.09 – 7.05 (m, 1H), 3.94 (d, J = 11.7 Hz, 2H),
3.45 (t, J = 12.1 Hz, 1H), 2.50 (s, 3H), 2.44 (s, 3H), 2.41 (d, J = 11.9 Hz, 2H), 2.11 (d, J = 12.5 Hz, 2H),
1.67 (qd, J = 12.5, 3.8 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 154.1, 149.5, 143.7, 133.0, 129.8,
127.8, 125.4, 124.3, 120.6, 46.7, 35.4, 29.3, 21.6, 18.5. HRMS (ESI) m/z calcd for C18H23SN2O3
[M+H]+: 347.1424; found: 347.1424. Elemental analysis calcd (%) C18H22SN2O3: C 62.40, H 6.40, N
8.09, S 9.25. Found: C 62.27, H 6.55, N 8.13, S 9.21.
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2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-methylpyridine N-oxide (3u): Following the Method A,
the resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a colorless oil (0.2 mmol scale: 28.1 mg, 48% yield). Compound 3u has been previously
reported.21 1H NMR (600 MHz, CDCl3) δ 7.16 (d, J = 4.7 Hz, 2H), 7.11 – 7.02 (m, 1H), 4.25 (dd, J =
56.5, 5.9 Hz, 2H), 3.70 (t, J = 12.1 Hz, 1H), 2.90 (s, 2H), 2.53 (s, 3H), 2.03 (d, J = 10.8 Hz, 2H), 1.46
(s, 9H), 1.24 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 154.9, 154.8, 149.4, 125.4, 124.1, 120.6, 79.6,
43.8, 36.2, 29.8, 28.5, 18.6.
2-cyclopentyl-6-methylpyridine N-oxide (3v): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 18.8 mg, 53% yield). Compound 3v has been previously reported.21 1H NMR (600
MHz, CDCl3) δ 7.15 (d, J = 4.0 Hz, 1H), 7.11 (s, 2H), 3.86 – 3.77 (m, 1H), 2.54 (s, 3H), 2.25 – 2.18 (m,
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2H), 1.89 – 1.67 (m, 4H), 1.61 – 1.52 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 156.4, 149.4, 125.0,
123.6, 120.6, 39.7, 31.2, 25.4, 18.6.
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2-cyclododecyl-6-methylpyridine N-oxide (3w): Following the Method A, the resulting mixture was
purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless oil
(0.2 mmol scale: 33.1 mg, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.13 – 7.09 (m, 3H), 3.56 (ddd, J
= 12.0, 7.4, 2.8 Hz, 1H), 2.52 (s, 3H), 2.04 (d, J = 12.1 Hz, 3H), 1.97 – 1.81 (m, 4H), 1.78 (d, J = 13.1
Hz, 3H), 1.50 (qd, J = 13.0, 9.8 Hz, 4H), 1.41 – 1.15 (m, 8H). 13C NMR (151 MHz, CDCl3) δ 156.9,
149.2, 124.9, 123.5, 120.7, 37.7, 31.2, 26.6, 26.4, 18.6. HRMS (ESI) m/z calcd for C18H30NO [M+H]+:
276.2322; found: 276.2324.
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2-(3-(4-bromophenoxy)propyl)-6-methylpyridine N-oxide (3x): Following the Method B, the
resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a colorless oil (0.2 mmol scale: 34.8 mg, 54% yield). 1H NMR (600 MHz, CDCl3) δ 7.40 –
7.30 (m, 2H), 7.16 (dd, J = 7.4, 2.1 Hz, 1H), 7.14 – 7.06 (m, 2H), 6.78 – 6.72 (m, 2H), 3.99 (t, J = 6.1
Hz, 2H), 3.16 – 3.10 (m, 2H), 2.54 (s, 3H), 2.24 (dd, J = 8.1, 6.8 Hz, 2H). 13C NMR (151 MHz, CDCl3)
δ 158.1, 151.5, 149.5, 132.3, 125.0, 124.3, 123.5, 116.4, 112.9, 67.5, 28.2, 25.9, 18.4. HRMS (ESI)
m/z calcd for C15H17BrNO2 [M+H]+: 322.0437; found: 322.0436.
2-(4-(4-cyanophenoxy)butan-2-yl)-6-methylpyridine N-oxide (3y): Following the Method A, the
resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a colorless oil (0.2 mmol scale: 29.9 mg, 53% yield). 1H NMR (600 MHz, CDCl3) δ 7.53 (d,
J = 8.7 Hz, 2H), 7.16 (s, 3H), 6.85 (d, J = 8.7 Hz, 2H), 4.12 – 4.04 (m, 2H), 3.95 (dd, J = 13.7, 6.8 Hz,
1H), 2.52 (s, 3H), 2.29 (dd, J = 13.7, 6.7 Hz, 1H), 2.08 (dd, J = 13.7, 6.8 Hz, 1H), 1.38 (d, J = 7.0 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 162.2, 155.8, 149. 6, 134.0, 125.3, 124.1, 121.1, 119.3, 115.2,
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103.9, 66.9, 34.0, 30.9, 29.8, 18.6. HRMS (ESI) m/z calcd for C17H19N2O2 [M+H]+: 283.1441; found:
283.1441.
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2-(4-(3-benzoylphenoxy)butan-2-yl)-6-methylpyridine N-oxide (3z): Following the Method A, the
resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired
product as a yellow solid (0.2 mmol scale: 43.4 mg, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.78 (d,
J = 8.6 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.17 (s, 3H),
6.87 (d, J = 8.7 Hz, 2H), 4.16 – 4.07 (m, 2H), 3.97 (dd, J = 13.6, 6.8 Hz, 1H), 2.53 (s, 3H), 2.31 (td, J =
13.3, 6.6 Hz, 1H), 2.12 (td, J = 13.4, 6.6 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 195.6, 162.6, 156.1, 149.6, 138.4, 132.6, 131.9, 130.1, 129.8, 128.2, 125.1, 124.0, 121.2,
114.1, 107.4, 66.7, 34.0, 31.0, 18.6, 14.3. HRMS (ESI) m/z calcd for C23H24NO3 [M+H]+: 362.1751;
found: 362.1750.
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2-(4-((2-(4-isobutylphenyl)propanoyl)oxy)butan-2-yl)-6-methylpyridine N-oxide (3aa): Following
the Method A, the resulting mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to
give the desired product as a yellow solid (0.2 mmol scale: 37.7 mg, 56% yield). 1H NMR (600 MHz,
CDCl3) δ 7.20 – 7.15 (m, 2H), 7.14 – 7.04 (m, 4H), 7.00 (t, J = 7.9 Hz, 1H), 4.14 – 4.08 (m, 1H), 4.07 –
4.00 (m, 1H), 3.78 – 3.69 (m, 1H), 3.66 – 3.60 (m, 1H), 2.51 (s, 3H), 2.43 (d, J = 7.0 Hz, 2H), 2.14 –
2.04 (m, 1H), 1.84 (ddd, J = 19.7, 13.3, 6.7 Hz, 2H), 1.45 (dd, J = 7.1, 2.4 Hz, 3H), 1.24 (dd, J = 17.8,
7.0 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 174.7, 155.7, 149.5, 140.5, 137.8,
129.3, 127.2, 125.2, 124.0, 121.3, 63.2, 45.1, 32.9, 31.1, 30.8, 30.2, 22.4, 18.5, 18.2. HRMS (ESI) m/z
calcd for C23H32NO3 [M+H]+: 370.2377.; found: 370.2377.
2,6-dimethylpyridine N-oxide (3ab): Following the Method B (5.0 equiv BIOAc), the resulting
mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a
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colorless oil (0.2 mmol scale: 9.4 mg, 38% yield). Compound 3ab has been previously reported.18 1
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NMR (600 MHz, CDCl3) δ 7.11 (d, J = 7.8 Hz, 2H), 7.08 – 7.03 (m, 1H), 2.49 (s, 6H). 13C NMR (151
MHz, CDCl3) δ 149.2, 125.3, 124.1, 18.3. Elemental analysis calcd (%) C7H9NO: C 68.27, H 7.37, N
11.37. Found: C 68.18, H 7.66, N 11.32.
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2-(6-bromohexyl)-6-methylpyridine N-oxide (3ac): Following the Method B, the resulting mixture
was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a colorless
oil (0.2 mmol scale: 27.8 mg, 51% yield). 1H NMR (600 MHz, CDCl3) δ 7.21 – 7.07 (m, 3H), 3.41 (t, J
= 6.8 Hz, 2H), 3.01 – 2.90 (m, 2H), 2.54 (s, 3H), 1.88 (dd, J = 14.5, 6.9 Hz, 2H), 1.80 – 1.72 (m, 2H),
1.55 – 1.43 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 152.4, 149.3, 124.9, 124.0, 122.9, 34.0, 32.7, 31.0,
28.7, 28.0, 26.1, 18.5. HRMS (ESI) m/z calcd for C12H19BrNO [M+H]+: 272.0645.; found: 272.0645.
2-(cyclopentylmethyl)-6-methylpyridine N-oxide (3ad): Following the Method B, the resulting
mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give the desired product as a
colorless oil (0.2 mmol scale: 21.0 mg, 55% yield). Compound 3ad has been previously reported.21 1
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NMR (600 MHz, CDCl3) δ 7.21 – 6.95 (m, 3H), 2.93 (d, J = 7.3 Hz, 2H), 2.53 (s, 3H), 2.43 (dt, J =
15.3, 7.7 Hz, 1H), 1.78 (dd, J = 11.6, 7.0 Hz, 2H), 1.72 (s, 1H), 1.66 (dd, J = 14.7, 6.6 Hz, 2H), 1.60 –
1.47 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 152.4, 149.3, 125. 6, 123.9, 123.5, 37.3, 36.5, 32.8, 25.1,
18.5.
Sequential C(sp2)–H Arylation/Alkylation of Pyridine N-oxide
C–H arylation step: To a 10 mL Schlenk tube was sequentially added K2CO3 (276 mg, 2.0 mmol),
PtBu3ꢀHBF4 (43.5 mg, 0.15 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol). The tube was evacuated and
backfilled with N2 for three times. Then pyridine Nꢀoxide (380 mg, 4.0 mmol), bromobenzene (157 mg,
1.0 mmol) and toluene (3.5 mL) were added. The mixture was then heated to 110 ºC overnight. The
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reaction mixture was purified by flash chromatography (PE : EA = 1 : 1 to EA) to give 5 as a white
solid (133.5 mg, 78% yield).
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C–H alkylation step: To a 15 mL Schlenk tube was sequentially added 2ꢀphenylpyridine Nꢀoxide
(133.5 mg, 0.78 mmol), potassium cyclohexyltrifluoroborate (297 mg, 1.56 mmol), [Ru(bpy)3](PF6)2
(14.8 mg, 2 mol%), BIOAc (716 mg, 2.34 mmol). The tube was evacuated and backfilled with N2 for
three times. Then, CH2Cl2 (3 mL), H2O (3 mL) and TFA (117 ꢁL, 1.56 mmol) were added. The reaction
mixture was stirred for 24 h at room temperature with blue LEDs (2 × 36 W) irradiation. The reaction
mixture was purified by flash chromatography (EA to EA : MeOH = 10 : 1) to give 6 as a pale yellow
solid (85.5 mg, 64% yield).
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2-phenylpyridine N-oxide (5): Compound 5 has been previously reported.2a 1H NMR (600 MHz,
CDCl3) δ 8.33 (d, J = 4.8 Hz, 1H), 7.80 (dd, J = 7.2, 1.0 Hz, 2H), 7.51 – 7.36 (m, 4H), 7.29 (ddd, J =
7.8, 5.3, 1.2 Hz, 1H), 7.24 – 7.17 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 149.3, 140.5, 132.6, 129.6,
129.3, 128.3, 127.4, 125.9, 124.6.
2-cyclohexyl-6-phenylpyridine N-oxide (6): Compound 6 has been previously reported.21 1H NMR
(600 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.43 – 7.38 (m, 1H), 7.28 – 7.24
(m, 2H), 7.20 (dd, J = 6.9, 3.0 Hz, 1H), 3.61 – 3.53 (m, 1H), 2.12 (d, J = 12.2 Hz, 2H), 1.86 (d, J =
13.4 Hz, 2H), 1.79 (d, J = 13.1 Hz, 1H), 1.55 – 1.46 (m, 2H), 1.34 – 1.26 (m, 3H). 13C NMR (151 MHz,
CDCl3) δ 157.4, 149.5, 133.8, 129.6, 129.2, 128.1, 125.2, 124.5, 121.8, 37.9, 31.0, 26.6, 26.4.
Synthetic Application to the Drug Molecule Ciclopirox
Step 1: To a stirred solution of 2ꢀmethoxyꢀ4ꢀmethylpyridine (7) (123.2 mg, 1.0 mmol) in CHCl3 (2 mL)
was added 70% mꢀCPBA (172.6 mg, 1.0 mmol), portion wise at 0 °C. The mixture was stirred at room
temperature for 12 h. The reaction mixture was diluted with CHCl3, and solid K2CO3 (552.8 mg, 4
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mmol) was added. The resulting mixture was stirred for an additional 10 min. The crude product was
purified by flash chromatography to give the 2ꢀmethoxyꢀ4ꢀmethylpyridine Nꢀoxide as a colorless oil
(128.0 mg, 92% yield).18
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Step 2: To a 15 mL Schlenk tube was sequentially added potassium cyclohexyltrifluoroborate (349.6
mg, 1.84 mmol), [Ru(bpy)3](PF6)2 (17.5 mg, 2 mol%), BIOAc (844.6 mg, 2.76 mmol). The tube was
evacuated and backfilled with N2 for three times. Then, 2ꢀmethoxyꢀ4ꢀmethylpyridine Nꢀoxide (128.0
mg, 0.92 mmol), CH2Cl2 (3 mL), H2O (3 mL) and TFA (138 ꢁL, 1.84 mmol) were added. The reaction
mixture was stirred for 24 h at room temperature with blue LEDs (2 × 36 W) irradiation. The reaction
mixture was purified by flash chromatography (EA to EA : MeOH = 10 : 1) to give
2ꢀcyclohexylꢀ6ꢀmethoxyꢀ4ꢀmethylpyridine Nꢀoxide (8) as a colorless oil (138.4 mg, 68% yield).
Step 3: The 2ꢀcyclohexylꢀ6ꢀmethoxyꢀ4ꢀmethylpyridine Nꢀoxide (8) (138.4 mg, 0.62 mmol) was
dissolved in AcCl (3.0 mL) and refluxed for 1 h. The solvent was removed under reduced pressure. The
residue was dissolved in MeOH (3.0 mL) and stirred overnight at room temperature. MeOH was
removed under reduced pressure and the residue was washed with Et2O to afford ciclopirox (9) as an
offꢀwhite powder (123.2 mg, 95% yield).22
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2-cyclohexyl-6-methoxy-4-methylpyridine N-oxide (8): H NMR (600 MHz, CDCl3) δ 6.66 (s, 1H),
6.53 (s, 1H), 4.00 (d, J = 8.6 Hz, 3H), 3.54 (t, J = 12.0 Hz, 1H), 2.32 (s, 3H), 2.04 (d, J = 12.4 Hz, 2H),
1.81 (d, J = 13.3 Hz, 2H), 1.76 (d, J = 13.8 Hz, 1H), 1.49 (dd, J = 26.1, 13.0 Hz, 2H), 1.28 – 1.22 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 158.0, 156.8, 138.6, 115.6, 105.6, 57.1, 37.2, 31.0, 26.4, 26.4,
21.3. HRMS (ESI) m/z calcd for C13H20NO2 [M+H]+: 222.1489; found: 222.1489.
6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one (9): 1H NMR (600 MHz, CDCl3) δ 6.39 (s, 1H),
6.01 (d, J = 1.4 Hz, 1H), 3.12 (t, J = 11.9 Hz, 1H), 2.17 (s, 3H), 2.00 (d, J = 10.8 Hz, 2H), 1.82 (d, J =
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13.3 Hz, 2H), 1.75 (d, J = 13.0 Hz, 1H), 1.47 – 1.38 (m, 2H), 1.25 (dddd, J = 16.6, 13.2, 9.9, 3.2 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 158.5, 149.9, 147.1, 112.1, 106.0, 38.0, 31.4, 26.4, 26.2, 21.5.
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Supporting Information.
Optimization data, 1H and 13C NMR spectra and HPLC analyses. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: daijj@hfut.edu.cn; hjxu@hfut.edu.cn
ORCID
JianꢀJun Dai: 0000ꢀ0001ꢀ7918ꢀ0080
HuaꢀJian Xu: 0000ꢀ0002ꢀ0789ꢀ3484
Notes
We declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21402036, 21472033, 21502038 and
21272050) and the China Postdoctoral Science Foundation (2014M551793 and 2015T80645) for
financial support.
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