Organocatalytic functionalization of heteroaromatic N-oxides with C-nucleophiles using in situ generated onium amide bases

Article abstract of DOI:10.1039/c3ob40782a

Organocatalytic functionalization of heteroaromatic N-oxides was investigated using in situ generated onium amide bases, and C-nucleophiles were efficiently introduced by the sequential addition-elimination reaction under metal-free conditions, affording 2-substituted nitrogen heteroaromatics generally in good to high yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40782a

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Organocatalytic functionalization of heteroaromatic
N-oxides with C-nucleophiles using in situ generated
onium amide bases†
Cite this: DOI: 10.1039/c3ob40782a
Received 18th April 2013,
Accepted 28th May 2013
DOI: 10.1039/c3ob40782a
Kiyofumi Inamoto,* Yuta Araki, Shoko Kikkawa, Misato Yonemoto,
Yoshiyuki Tanaka and Yoshinori Kondo*
www.rsc.org/obc
Organocatalytic functionalization of heteroaromatic N-oxides N-oxides have also recently been regarded as an ideal choice of
was investigated using in situ generated onium amide bases, substrates for transition metal-catalyzed C–H functionalization
and C-nucleophiles were efficiently introduced by the sequential processes.7 Fagnou et al. extensively studied the Pd-catalyzed
addition–elimination reaction under metal-free conditions, C–H arylation of azine and azole N-oxides.7a,c The Ni-catalyzed
affording 2-substituted nitrogen heteroaromatics generally in alkyne insertion into the C–H bonds α- to the N-oxide moiety
good to high yields.
has also been reported, providing 2-alkenylpyridine N-oxides
under mild conditions.8 Another important approach for
functionalization of heteroaromatic N-oxides involves tran-
sition metal-free systems.9 The oxidative cross-coupling reac-
tion of heteroaromatic N-oxides and alkanes under the
influence of peroxides has been developed.9a Effective utiliz-
ation of a phosphonium salt as a means of pyridine N-oxide
activation for introducing various nucleophiles at the 2-posi-
tion has also been reported, which provides 2-substituted pyri-
dine derivatives.9b In view of the current strict guidelines
limiting the transition metal levels in pharmaceuticals, the
development of C–C bond-forming reactions without using a
transition metal is considered to be an important subject.
During the course of our studies on organocatalytic transform-
ation of aromatic and heteroaromatic compounds,10 we
recently reported a novel catalytic method for deprotonative
functionalization of heteroaromatic compounds under metal-
free, mild conditions in the presence of onium amide bases
generated in situ from the combination of aminosilanes and
onium fluorides (Fig. 1).11 In connection with our method
involving the organocatalytic functionalization of hetero-
aromatic N-oxides using a phosphazene superbase,12 we investi-
gated a metal-free, transformation process of heteroaromatic
Heteroaromatic N-oxides have attracted wide attention as
useful synthetic intermediates, catalysts and ligands, and
some compounds are known to exhibit important biological
activities.1 One of the important methods for functionalization
of heteroaromatic N-oxides is the process using organometallic
C-nucleophiles.2 Among them, aryl Grignard reagents (ArMgX)
have been employed to efficiently introduce carbon functional-
ities at the α-position of N-oxides.3 Addition of ArMgX to
pyridine N-oxides followed by the treatment of the intermedi-
ary 2,4-dienal oximes with acetic anhydride provides a range of
2-substituted pyridines in good to high yields.3a A method
involving the addition of ArMgX to pyridine N-oxides and the
subsequent treatment with electrophiles has recently been
reported for the synthesis of 2,3-dihydropyridine N-oxides,
which can be further transformed into 2,3-disubstituted piperi-
dines.3b A similar procedure can be utilized for the synthesis
of substituted piperidines in an enantioselective manner with
the aid of a chiral ligand.3f On the other hand, when pyridine
N-oxides are treated with alkyl Grignard reagents (RMgX),
proton abstraction at the α-position occurs. The ortho-magne-
siated intermediates can successfully be trapped with electro-
philes such as aldehydes, ketones and halogens.4 Halogen–
magnesium exchange reaction of 2-halopyridine N-oxides
using RMgX also leads to the formation of magnesiated pyri-
dine N-oxides.5 As for deprotonation, regioselective α-zincation
of N-oxides using TMPZnCl is also achieved.6 Heteroaromatic
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki,
Aoba-ku, Sendai 980-8578, Japan. E-mail: inamoto@m.tohoku.ac.jp,
ykondo@m.tohoku.ac.jp; Fax: +81-22-795-3921; Tel: +81-22-795-6804
†Electronic supplementary information (ESI) available: Experimental procedures
and spectral/analytical data. See DOI: 10.1039/c3ob40782a
Fig. 1 Deprotonative functionalization of heteroaromatics using onium amide
bases.
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Fig. 2 Functionalization of heteroaromatic N-oxides.
N-oxides making use of in situ generated onium amide bases,
the results of which are detailed in this paper (Fig. 2).
We commenced our studies by exploring the addition–elimi-
nation reaction of quinoline N-oxide (1a) with phenylacetylene
(2a) using in situ generated onium amide bases (Table 1).
When 10 mol% of TBAF was used as an onium fluoride in the
presence of dimethylaminotrimethylsilane in toluene, the reac-
tion proceeded at room temperature to give 2-phenylethynyl-
quinoline (3aa) in 27% yield (entry 1). The screening of
solvents revealed that the use of THF and DMF improved the
yields (entries 2 and 3). Increasing the amount of aminosilane
resulted in the formation of 3aa in high yield (entry 4). More-
over, the use of TMAF instead of TBAF gave an excellent result,
affording 3aa in 97% yield (entry 5). Using the optimized reac-
tion conditions, the reaction of 1a with 4-methoxyphenylacety-
lene (2b), 4-bromophenylacetylene (2c) and 3-thienylacetylene
(2d) smoothly proceeded as well to provide the corresponding
2-substituted quinolines 3ab–3ad in good to high yields
(entries 6–8).13
Scheme 1 Reaction of various heteroaromatic N-oxides 1b–e with 2a.
Table 2 Reaction of quinoline N-oxide (1a) with azoles 4a–ca
Entry
X
4
x
R′
Temp.
5
Yield (%)
1
2
3
4
5
6
7
S
S
S
S
S
O
NPh
4a
4a
4a
4a
4a
4b
4c
10
10
10
30
50
50
50
Me
Me
TMS
TMS
TMS
TMS
TMS
rt
5aa
5aa
5aa
5aa
5aa
5ab
5ac
4
18
39
65
92
45
20
120 °C
120 °C
120 °C
120 °C
120 °C
120 °C
Substituted quinoline N-oxides 1b and 1c were also found
to be suitable for the process (Scheme 1). In addition, another
class of substrates such as isoquinoline N-oxide (1d) and
4-phenylpyridine N-oxide (1e) successfully reacted with phenyl-
acetylene (2a) to give the corresponding phenylethynylated
compounds 3da and 3ea in high yields.
a Performed on a 0.30 mmol scale.
We next focused our attention on the reaction of quinoline
N-oxide 1a with benzothiazole 4a (Table 2). The above obtained
optimal reaction conditions, however, turned out to be
ineffective for the process (entry 1). While the use of the ele-
vated temperature such as 120 °C had little effect (entry 2), the
reaction utilizing tristrimethylsilylamine instead of dimethyl-
aminotrimethylsilane provided the improved yield (entry 3).
Furthermore, an increased amount of TMAF led to better
results: the reaction in the presence of 50 mol% of TMAF
gave rise to 5aa in high yield (entry 5). Similarly, benzoxazole
(4b) and 1-phenylbenzimidazole (4c) also participated in the
addition–elimination reaction of 1a, and the corresponding
coupling products 5ab and 5ac were obtained, albeit in rela-
tively low yields (entries 6 and 7).
In the reaction of 1-phenylbenzimidazole (4c), 2,2′-biquino-
line (7) was isolated as a side product. In order to examine
the reaction pathway for the formation of 7, 1a was treated
with TMAF and dimethylaminosilane at room temperature in
the absence of a nucleophile, which provided 2,2′-biquinoline
N-oxide (6) in 40% yield (Scheme 2).14 On the other hand,
the same reaction conducted at 120 °C delivered deoxygenated
2,2-biquinoline (7) in 70% yield. To clarify the difference
of the products, independently prepared 2,2′-biquinoline
Table 1 Reaction of quinoline N-oxide (1a) with acetylenes 2a–da
Entry Ar
2
R4NF
x
Solvent
3
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
2a TBAF
2a TBAF
2a TBAF
2a TBAF
2a TMAF
2.5 Toluene 3aa 27
2.5 THF
2.5 DMF
3aa 41
3aa 49
3aa 89
3aa 97
3ab 80
3ac 50
3ad 82
5
5
5
5
5
DMF
DMF
DMF
DMF
DMF
(4-MeO)C6H4 2b TMAF
(4-Br)C6H4
3-Thienyl
2c TMAF
2d TMAF
a Performed on a 0.30 mmol scale.
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This work was partly supported by a Grant-in-Aid for
Scientific Research (B) (No. 23390002), a Grant-in-Aid for Chal-
lenging Exploratory Research (No. 23659001) and a Grant-in-
Aid for Young Scientists (B) (No. 23790002) from Japan Society
for the Promotion of Science, and a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transform-
ations by Organocatalysis” (No. 23390002) from The Ministry
of Education, Culture, Sports, Science and Technology, Japan.
Notes and references
Scheme 2 Formation of 2,2-biquinoline 7.
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Fig. 3 Plausible reaction pathway.
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elucidated, the functionalization of N-oxide 1 may be proceed-
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