Reductive C2-Alkylation of Pyridine and Quinoline N-Oxides Using Wittig Reagents

Article abstract of DOI:10.1002/anie.201807159

The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N-oxides using Wittig reagents. A wide range of pyridine and quinoline N-oxides were converted into C2-alkylated pyridines and quinolines with excellent site selectivity and functional-group compatibility. Sequential C?H functionalization reactions of pyridine and quinoline N-oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.

Full text of DOI:10.1002/anie.201807159

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Accepted Article
Title: Reductive C2-Alkylation of Pyridine- and Quinoline-N-Oxides
Using Wittig Reagents
Authors: In Su Kim, Sangil Han, Prashant Chakrasali, Jihye Park,
Hyunjung Oh, Saegun Kim, Kyuneun Kim, Ashok Kumar
Pandey, Sang Hoon Han, and Soo Bong Han
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807159
Angew. Chem. 10.1002/ange.201807159
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10.1002/anie.201807159
Angewandte Chemie International Edition
COMMUNICATION
Reductive C2-Alkylation of Pyridine- and Quinoline-N-Oxides
Using Wittig Reagents
Sangil Han,[a,†] Prashant Chakrasali,[b,c,†] Jihye Park,[a] Hyunjung Oh,[a] Saegun Kim,[a] Kyuneun Kim,[ b,c]
Ashok Kumar Pandey,[a] Sang Hoon Han,[a] Soo Bong Han,*[b,c] and In Su Kim*[a]
Abstract: The ability to alkylate pyridines and quinolines is important
for their further development as pharmaceuticals and agrochemicals,
and for other purposes. Herein we describe the unprecedented
reductive alkylations of pyridine- and quinoline-N-oxides using Wittig
reagents. A wide range of pyridine- and quinoline-N-oxides was
used to provide a variety of C2-alkylated pyridines and quinolines
with excellent site selectivities and functional-group compatibilities.
The sequential C−H functionalizations of pyridine- and quinoline-N-
oxides highlight the utility of the developed method. Detailed labeling
experiments were performed in order to understand the mechanism
of this process.
pyridines.[8]
The Wittig reaction, which is based on the reaction of an
aldehyde or ketone with a phosphonium ylide, is ranked among
the most important reactions for C−C bond formation.[9] In
addition, Wittig reagents have also been used as C-nucleophiles
in Michael additions and other alkylation reactions.[10] Moreover,
phosphonium salts have been applied to organocatalytic
Mannich-type processes to afford aza-Morita–Baylis–Hillman
adducts.[11] However, to the best of our knowledge, there are no
reports on C−H alkylation reactions of (hetero)aromatic
compounds using Wittig reagents. Herein, we describe the
transition-metal-free C−H alkylations of pyridine- and quinoline-
N-oxides using phosphonium salts as alkylating reagents to
furnish C2-alkylated pyridines and quinolines.
The ability to C−H alkylate a pyridine is attractive from the
perspectives of organic and medicinal chemistry because
alkylated pyridines have remarkable therapeutic potentials.[1] In
particular, C2-methylated pyridines and quinolines are
recognized as ubiquitous heterocyclic core units that are found
in a variety of pharmaceuticals and agrochemicals.[2] Over the
past few decades, a range of transition-metal-mediated C−H
alkylation reactions of pyridines have been intensively studied.[3]
In addition, much attention has been directed toward radical-
mediated C−H alkylations of pyridines using metal catalysts,
photocatalysts, and stoichiometric oxidants.[4] However, from a
synthetic point of view, the formation of residual metal impurities
and inseparable regioisomers can pose additional barriers to
industrial and pharmaceutical applications. Therefore, it is highly
desirable to develop mild and selective methods for the
construction of C2-alkylated pyridine derivatives under metal-
free conditions. Pyridine-N-oxides have been used as synthetic
precursors for the formation of C2-functionalized pyridine
derivatives.[5] A variety of synthetic transformations using halo,
cyano, amino, phenoxy, thioalkyl, and phosphoryl groups have
been disclosed. However, regioselective C2-alkylations of
pyridine-N-oxides have rarely been described. For example,
Nicolaou et al. reported the C2-methylations of pyridine-N-
oxides using Tebbe‘s reagent (Scheme 1).[6] Grignard reagents
have also been used to prepare C2-alkylated pyridines through
nucleophilic additions to pyridine-N-oxides followed by
elimination.[7] Very recently, Cho and coworkers demonstrated
site-selective alkylations of pyridine-N-oxides using 1,1-
diborylalkanes as alkylating reagents, to give C2-alkylated
Scheme 1. Metal-free site-selective C−H alkylations of pyridine-N-oxides.
Our study was initiated by examining the coupling of 2,2’-
bipyridine-N-oxide (1a) with methyltriphenylphosphonium
bromide (2a) under alkaline conditions, as summarized in Table
1. We were pleased to observe that 1a coupled with 2a in the
o
presence of KOtBu (2 equiv.) in toluene at 80 C to provide the
deoxygenated 6-methyl-2,2'-bipyridine (3a) in 51% yield (Table 1,
entry 1). However, other bases such as NaOtBu, NaOMe, and
DBU were less effective in this transformation (Table 1, entries
2−4). Interestingly, MTBE (t-butyl methyl ether) as the solvent is
unique in its ability to facilitate the coupling reaction to afford the
C2-methylated pyridine derivative 3a in 66% yield (Table 1,
entries 5−7). In addition, this reaction can be extended to other
methyltriphenyl phosphonium salts, such as MePPh3Cl (2b) and
MePPh3I (2c). Notably, MePPh3I (2c) was found to deliver our
desired product 3a in 73% yield (Table 1, entry 9). Increasing
amount of KOtBu to 3 equiv. provided a comparable yield (74%),
as shown in entry 10. The best result was obtained by treatment
with 2 equiv. of KOtBu in MTBE at 110 oC under an atmosphere
of N2 to afford 3a in 81% yield (Table 1, entry 11).
[a]
Dr. S. Han, Dr. J. Park, H. Oh, S. Kim, Dr. A. K. Pandey, S. H. Han,
Prof. Dr. I. S. Kim
School of Pharmacy, Sungkyunkwan University, Suwon 16419,
Republic of Korea
E-mail: insukim@skku.edu
[b]
[c]
P. Chakrasali, K. Kim, Dr. S. B. Han
Division of Bio & Drug Discovery, Korea Research Institute of
Chemical Technology, Daejeon 34114, Republic of Korea
Department of Medicinal and Pharmaceutical Chemistry, University
of Science and Technology, Daejeon 34113, Republic of Korea
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201807159
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COMMUNICATION
Table 2. Scope of pyridine and quinoline N-oxides.[a]
KOtBu (2 equiv)
MTBE
110 oC, 12 h, N2
R1
Table 1. Selected optimization of reaction conditions.[a]
R1
Me PPh3I
N
O
+
N
Me
2c
3a-3l
1a-1l
Me
N
Me
N
Me
Me
entry
base (equiv.)
MePPh3X
solvent
yield[b]
N
Me
N
KOtBu (2)
NaOtBu (2)
NaOMe (2)
DBU (2)
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
toluene
toluene
toluene
toluene
THF
51
18
36
N.R.
53
49
66
40
73
74
81
N
1
3a, 81%
3b, 88%
3c, 62%
2
Me
3
4
N
N
Me
N
Me
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (3)
KOtBu (2)
5
N
N
Me
6
Et2O
3d,
47%
Cl
3e, 64%[a]
3f, 82%[a]
7
MTBE
MTBE
MTBE
MTBE
MTBE
MeO
Br
8
9
N
Me
N
Me
N
Me
10
11[c]
3g, 61%[a]
3h, 80%[a]
3i, 57%[a]
Cl
N
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), base (quantity noted),
solvent (2 mL) at 80 oC for 12 h under N2 in a pressure tube. [b] Isolated
percent yield by flash column chromatography. [c] This reaction was carried
out at 110 oC. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. MTBE = t-butyl
methyl ether.
N
Me
Me
N
Me
3j, 72%[a]
3k, 79%[a]
3l, 64%[a]
[a] Reaction conditions: 1e−1l (0.2 mmol), 2c (0.6 mmol), KOtBu (3 equiv.),
THF (2 mL), 80 oC, 3 h under N2 in pressure tubes.
With the optimized reaction conditions in hand, the scope of
the reaction was examined with a variety of pyridine- and
quinoline-N-oxides and MePPh3I (2c) (Table 2). To our delight,
2,2’-bipyridine-N-oxide 1b was smoothly coupled with MePPh3I
(2c) to provide the unsymmetrical dipyridyl compound 3b in 88%
yield with complete site-selectivity. Notably, this transformation
can readily be used to prepare unsymmetrical dipyridyl
ligands.[12] In addition, 2-phenyl pyridine-N-oxide (1c) was
favored in this transformation, furnishing the C2-methylated
pyridine 3c in good yield. This reaction was also applicable to
pyrazole-containing pyridine-N-oxide 1d, albeit with relatively
decreased reactivity. Moreover, this reaction is only not limited
to pyridine-N-oxides. Under modified reaction conditions, a
variety of quinoline-N-oxides 1e−1k were converted into C2-
methylated quinoline derivatives 3e−3k in moderate to high
yields. Finally, isoquinoline-N-oxide 1l also underwent C−H
methylation to give 3l in 64% yield. The regioselectivity at the
C1-position was particularly noteworthy, and is possibly
ascribable to the higher electrophilicity of the benzylic iminium
carbon.
Table 3. Scope of alkyl phosphonium salts.[a]
[a] Reaction conditions: condition A: 1b (0.2 mmol), 2f−2h (0.6 mmol, 3 equiv.),
NaOMe (3 equiv.), MTBE (2 mL), 110 oC, 12 h under N2 in pressure tubes.
condition B: 1b (0.2 mmol), 2d, 2e and 2i (0.8 mmol, 4 equiv.), KOtBu (4
equiv.), MTBE (2 mL), 110 oC, 12 h under N2 in pressure tubes.
Inspired by these results, we further investigated the C−H
alkylation reaction of pyridine-N-oxide 1b with a variety of
phosphonium salts 2d−2i under the optimal reaction conditions
(Table 3). Linear alkyl phosphonium salts 2d−2f were smoothly
coupled with 1b to give the C6-alkylated products 4a (78%), 4b
(77%), and 4c (45%), respectively. The current protocol could be
applied to the alkoxymethyl phosphonium salt 2g, which
furnished 4d in 65% yield. Moreover, cyclopropyl and branched-
alkyl phosphonium salts 2h and 2i were also compatible with the
current reaction conditions.[13]
To highlight the utility of this protocol, a series of synthetic
transformations were performed, as shown in Scheme 2. First,
we envisaged the sequential syntheses of unsymmetrical 2,2’-
dipyridyl ligands using our developed protocol. To our delight,
2,2’-bipyridine-N-oxide 1b was readily converted into our desired
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10.1002/anie.201807159
Angewandte Chemie International Edition
COMMUNICATION
product
5b.
Moreover,
the
Ir(III)-catalyzed
C−H
3e was partially deuterated using CD3OD under the standard
reaction conditions (eq. 3). These results suggest that the
intramolecular migration of the C2-deuterium might be
completely excluded in the reaction pathway, and the formation
of a phosphonium ylide as an intermediate might be involved.
functionalization[14] of 1e with tosyl azide provided C8-aminated
quinoline-N-oxide 6a, which was subjected to C−H methylation
conditions to afford the 8-aminoquinoline derivative 6b in 87%
yield. Moreover, scale-up of one-pot reaction involving 7a
resulted in the direct formation of 2-methylquinoline (3e) in 50%
yield.
With the above mechanistic information in mind, a plausible
reaction pathway is outlined in Scheme 4. Initially, the
phosphonium salt (MePPh3I) reacts with KOtBu to form the
phosphonium ylide, which subsequently undergoes an
intermolecular [3+2] annulation reaction to afford intermediate I.
Finally, aromatization by an external base leads to the formation
a) sequential C-H alkylations
Me
Me
N
PPh3Br
(3 equiv.)
Me
Me
NaOMe (3 equiv.)
of
the C2-methylated product 3e.
The eliminated
m-CPBA (1.2 eqiuv.)
N
O
triphenylphosphine oxide was observed by 1H NMR
MTBE, 110 o
12 h, N2
C
CH2Cl2, rt, 12 h
N
N
4e, 64% yield
1b
spectroscopy of the crude reaction product in each cases.
Me
Me
MePPh3I (3 equiv.)
KOtBu (2 equiv.)
Me
N
Me
N
N
MTBE, 110 o
12 h, N2
C
N
O
Me
5b, 50% yield
5a, 74% yield
b) sequential C-H funtionalizations
N3-Ts (1.5 equiv.)
[IrCp*Cl2]2 (2 mol %)
AgNTf2 (10 mol %)
MePPh3I (5 equiv.)
KOtBu (5 equiv.)
Scheme 4. Proposed reaction mechanism.
N
Me
N
THF, 80 o
3 h, N2
C
AcOH (30 mol %)
N
NH
NH
O
DCE, 50 oC, 12 h
O
Ts
6b, 87% yield
Ts
6a, 92% yield
1e
To further confirm whether phosphonium ylides are potential
intermediates in this process or not, we performed the reaction
of 1a with bromoalkylphosphonium salts under the standard
reaction conditions (Scheme 5). To our delight, cyclopropylated and
cyclobutylated pyridine derivatives 8a and 8b were formed. This
observation is rationalized through the initial formation of
phosphonium ylides from the bromoalkylphosphonium salts 2k and
2l that then undergo cyclization to afford cyclopropyl and cyclobutyl
phosphonium salts, which then further react with a base to generate
the corresponding ylide intermediates.
c) large-scale one-pot reaction
i) m-CPBA (1.5 eqiuv.), CH2Cl2, rt, 12 h
N
Me
N
ii) MePPh3I (3 equiv.), KOtBu (3 equiv.)
THF, 80 oC, 7 h
7a
(1.3 g, 10 mmol)
3e, 50% yield
Scheme 2. One-pot and sequential transformations.
11% D
KOtBu, THF
80 oC, 3 h, N2
(1)
(2)
(3)
+
Me PPh3I
N
O
D
N
Me
2c
deuterio-3ea, 57%
deuterio-1e, 98% D
35% D
KOtBu, THF
80 oC, 3 h, N2
+
Me PPh3I
N
O
D
N
Me
2c
CD3OD (3 equiv.)
deuterio-3eb, 53%
deuterio-1e, 98% D
Scheme 5. Alkylation using bromoalkyl phosphonium salts.
5% D
KOtBu, THF
In conclusion, we disclosed the unique reactivities of
phosphonium salts in the C−H alkylations of pyridine- and
quinoline-N-oxides. This protocol provides a facile route to the
formation of C2-alkylated pyridine and quinoline derivatives
under mild reaction conditions. High levels of site selectivity and
functional-group tolerance were observed. In particular, the
scaled-up one-pot reactions and sequential C−H transformations
of pyridine- and quinoline-N-oxides highlight the utility of the
developed method. A number of labeling experiments were
carried out to understand the mechanism of this transformation.
80 oC, 3 h, N2
N
Me
N
3e
Me
CD3OD (3 equiv.)
deuterio-3ec, 98%
Scheme 3. Mechanistic investigation.
To gain mechanistic insight into this process, a series of
labeling experiments were performed (Scheme 3). Treatment of
deuterio-1e with MePPh3I (2c) resulted in 11% deuterium
incorporation on the methyl group of the product, deuterio-3ea
(eq. 1). The reaction of deuterio-1e with 2c in the presence of
CD3OD also resulted in 35% deuterium incorporation on the
methyl group (eq. 2). In addition, the methyl group on compound
Acknowledgements
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[11] Y. Zhang, Y.-K. Liu, T.-R. Kang, Z.-K. Hu, Y.-C. Chen, J. Am. Chem.
Soc. 2008, 130, 2456-2457.
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
(Nos. 2016R1A4A1011189 and 2017R1A2B2004786).
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[13] Wittig reagents such as EtO2CCH2PPh3I, BnPPh3I, CH2=CHCH2PPh3I,
and CF2HPPh3I did not provide the corresponding products under the
current reaction conditions, presumably due to the less nucleophilicity
of delocalized carbanion.
Keywords: Alkylation • Methylation • Pyridine-N-oxide •
Regioselectivity • Wittig reagent
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COMMUNICATION
Entry for the Table of Contents
Key Topic: Alkylation of pyridine-N-oxides
COMMUNICATION
Sangil Han, Prashant Chakrasali, Jihye
Park, Hyunjung Oh, Saegun Kim,
Kyuneun Kim, Ashok Kumar Pandey,
Sang Hoon Han, Soo Bong Han,* and In
Su Kim*
Page No. – Page No.
Text for Table of Contents
Reductive C2-Alkylation of Pyridine-
and Quinoline-N-Oxides Using Wittig
Reagents
Alkylated pyridines & quinolines: The unprecedented reductive alkylation of pyridine-
and quinoline-N-oxides using Wittig reagents is described. A wide range of pyridine- and
quinoline-N-oxides was used to provide a variety of C2-alkylated pyridines and
quinolines with excellent site selectivities and functional-group compatibilities.
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