Functionalisation of heteroaromatic N-oxides using organic superbase catalyst

Article abstract of DOI:10.1039/c0ob00740d

Functionalisation of quinoline N-oxide was investigated using phophazene base as a catalyst; alkynylation and heteroarylation at 2-position were successfully achieved via nucleophilic addition-elimination process.

Full text of DOI:10.1039/c0ob00740d

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Functionalisation of heteroaromatic N-oxides using organic superbase
catalyst†
Yuta Araki, Koji Kobayashi, Misato Yonemoto and Yoshinori Kondo*
Received 18th September 2010, Accepted 28th October 2010
DOI: 10.1039/c0ob00740d
Functionalisation of quinoline N-oxide was investigated
using phophazene base as a catalyst; alkynylation and
heteroarylation at 2-position were successfully achieved via
nucleophilic addition–elimination process.
The chemistry of heteroaromatic N-oxides have received much
Fig. 1 Reaction of quinoline N-oxide with nucleophiles in the presence
attention due to their usefulness as synthetic intermediates and
their biological or functional importance.1 Various methodologies
have been developed for introducing carbon functionalities into
adjacent position of N-oxide and the use of organometallic
nucleophiles has been considered to be one of the most important
processes for the selective functionalisation.2 Recently, transition
metal catalyzed coupling reactions have been widely used for the
C–H functionalisation of heteroaromatics, and heteroaromatic
N-oxides have been also successfully transformed at adjacent
position of N-oxide.3 Transition-metal free processes are regarded
to be attractive in medicinal oriented synthesis, and the reac-
tions of organolithium, or organomagnesium nucleophiles with
heteroaromatic N-oxide have also attracted recent significant
attention.4 Organosilicon nucleophiles have been also utilized for
the introduction of allyl or cyano moiety,5 but no example for the
introduction of alkynyl or aryl moiety using alkynylsilanes or aryl-
silanes has been reported. In connection with our recent interest
on the development of phosphazene base catalyzed reactions,6 we
focused our study on the use of alkynylsilane and heteroarylsilane
for functionalising heteroaromatic N-oxides. By extending the
concept, we finally developed a new simple process for introducing
carbon functionality via organocatalytic deprotonative addition
of nucleophile in the presence of phosphazene catalyst and
organosilicon additive (Fig. 1).7
of organic superbase catalyst.
the latter alkynylsilane was found to proceed somewhat slower
(Scheme 1).
Scheme 1 Reaction of quinoline N-oxide with alkynylsilanes.
The reaction of quinoline N-oxide with 2-trimethyl-
silylbenzothiazole was then examined and the reaction proceeded
smoothly under the similar reaction conditions at room tempera-
ture. The use of cyclopentylmethyl ether as a solvent gave the best
result and the desired heterobiaryl (6) was obtained in 77% yield
(Scheme 2).
The addition–elimination reaction of quinoline N-oxide with
trimethylsilylphenylacetylene was first investigated and the re-
action proceeded smoothly in the presence of 10 mol%
P4-tBu in DMF to give 2-phenylethynylquinoline (3) in
87% yield (Scheme 1). As other alkynylsilanes, trimethylsilyl-
4-methoxyphenylacetylene and trimethylsilyl-4-chlorophenyl-
acetylene was also used for the reaction and the reaction with
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki
Aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan. E-mail: ykondo@mail.
pharm.tohoku.ac.jp; Fax: +81-22-795-6804; Tel: +81-22-795-6804
† Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for synthesized compounds. See DOI:
10.1039/c0ob00740d
Scheme 2 Reaction of quinoline N-oxide with 2-TMS-benzothiazole.
Plausible reaction pathway for this catalytic nucleophile intro-
duction using organosilicon compounds is shown in Fig. 2. First,
activation of organosilicon compounds by P4-tBu forms a reactive
78 | Org. Biomol. Chem., 2011, 9, 78–80
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Scheme 3 Reaction of quinoline N-oxide with H-nucleophiles using
TMSP.
Fig. 2 Plausible mechanism for functionalisation of quinoline N-oxide
using silylated nucleophiles.
Table 1 Reaction of quinoline N-oxide with phenylacetylene using P4-
tBu and organosilicon additive
Entry
TMS-R
Solvent
Yield (%)
1
2
3
4
TMS-NEt2
TMS-NEt2
TMS-CCMe
TMS-CCMe
DMF
Toluene
DMF
4
7
81
86
Toluene
Fig. 3 Plausible mechanism for functionalisation of quinoline N-oxide.
carbanion, which attacks the 2-position of quinoline N-oxide. The
oxygen anion was silylatedand P4-tBu or related base deprotonates
2-hydrogen of the adduct to eliminate trimethylsilanoxide to
form 2-functionalised quinoline. The phosphazenium silanoxide
reacts with silicon nucleophile to generate the phosphazenium
carbanion complex which attacks quinoline N-oxide for the
following catalytic cycle.
Our next interest was then focused on the development of a
method for introducing carbon functionality via the deprotonative
addition of nucleophile in the presence of phosphazene catalyst
and organosilicon additive. First, the reaction of quinoline N-
oxide and phenylacetylene was examined using 10 mol% P4-tBu
as a catalyst in the presence of an organosilicon additive. When
trimethylsilyldiethylamine was used as an additive, the reaction
proceeded in poor yields (Table 1, entries 1, 2). On the other hand,
when trimethylsilylpropyne (TMSP) was used as an additive, the
yields were dramatically improved (Table 1, entries 3,4). Effect of
solvent was examined using DMF and toluene, but no significant
difference was observed.
adduct to eliminate trimethylsilanoxide. The phosphazenium
silanoxide reacts with silicon additive reagent in the presence
of nucleophile generates the phosphazenium carbanion complex
again. At this moment the exact reason for the effectiveness of
TMSP on the catalytic activity is not clear, but the stability of
the released anion from a silicon additive is considered to be an
important factor. Further systematic experiments for clarifying
the mechanism are needed.
When quinoline N-oxide was reacted in the absence of elec-
trophile with trimethylsilyldiethylamine, dimerization reaction
occurred to give biquinoline N-oxide (8) in 40% yield (Scheme 4).
This type of dimerization reaction has been reported by the treat-
ment of quinoline N-oxide with organometallic deprotonating
agents.8 In our case, it can be understood that quinoline N-oxide
was deprotonated to produce a carbanion which attacked another
quinoline N-oxide to give the biquinoline N-oxide. This kind of
dimerization was first achieved under organocatalytic reaction
conditions by the present work.
The deprotonative catalytic system was then applied for other
nucleophiles using quinoline N-oxide. Terminal alkynes with
methoxyphenyl and 2-pyridyl moieties were employed for the
reaction and the alkynylation proceeded smoothly (Scheme 3).
Quinoline N-oxide was also reacted with benzothiazole in the
presence of 20 mol% P4-tBu and TMSP using c-pentylmethyl ether
as a solvent and benzothiazolylquinoline (6) was obtained in 60%
yield.
Scheme 4 Dimerization of quinoline N-oxide.
Plausible reaction pathway for this catalytic nucleophile intro-
duction is shown in Fig. 3. First, deprotonation of nucleophile
by P4-tBu forms a reactive phosphazenium carbanion complex,
which attacks the 2-position of quinoline N-oxide. The oxygen
anion was then silylated by the silicon additive reagent and another
reactive phosphazenium anion deprotonates 2-hydrogen of the
In summary, phosphazene base catalyzed reactions are found
to be effective for selective functionalisation of quinoline N-oxide
and silylated and non-silylated nucleophiles were successfully
used for the introduction of carbon functionalities. Further
optimization of reaction conditions and expansion of the scope
of the catalytic reactions are under investigation.
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Acknowledgements
This work was partly supported by the Grant-in Aid for Scientific
Research on Priority Areas “Advanced Molecular Transforma-
tions of Carbon Resources” (No.19020005) and “Synergistic
Effects for Creation of Functional Molecules” (No.20036007)
and the Grants (No.19390002) from the Ministry of Education,
Science, Sports and Culture, Japan.
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