Metal-free deprotonative functionalization of heteroaromatics using organic superbase catalyst

Article abstract of DOI:10.1039/c0cc03106b

Metal-free deprotonative functionalization of heteroaromatic compounds was achieved using an organic superbase catalyst; an organosilicon additive such as trimethylsilylpropyne was employed for activating the catalytic cycle of 1,2-addition to carbonyl compounds.

Full text of DOI:10.1039/c0cc03106b

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Metal-free deprotonative functionalization of heteroaromatics using
organic superbase catalystw
Yutaro Hirono, Koji Kobayashi, Misato Yonemoto and Yoshinori Kondo*
Received 7th August 2010, Accepted 1st September 2010
DOI: 10.1039/c0cc03106b
Metal-free deprotonative functionalization of heteroaromatic
compounds was achieved using an organic superbase catalyst;
an organosilicon additive such as trimethylsilylpropyne was
employed for activating the catalytic cycle of 1,2-addition to
carbonyl compounds.
(Table 1, entry 7) and trimethylsilylphenylacetylene (Table 1,
entry 8) did not show activity for the catalytic reaction. Finally
full conversion was achieved using 1.5 eq. TMSP in toluene
(Table 1, entry 9).
Using the catalytic system, the reactions with other electro-
philes are examined. The reaction using pivalaldehyde as an
electrophile proceeded smoothly to give the 1,2-addition
product (3) (Scheme 1). When chalcone was used as an enone
electrophile, 1,2-adduct (4) was obtained in 43% yield and the
formation of 1,4-adduct was not observed (Scheme 1).
The catalytic system using P4-tBu/TMSP was then applied
for the functionalization of other heteroaromatics (Scheme 2).
Benzoxazole was reacted with benzophenone under the reaction
conditions to give the 1,2-adduct (5) in 93% yield. Ethyl
thiophene-2-carboxylate was reacted with benzophenone and
the reaction proceeded at 5-position to give the 1,2-adduct (6)
in 60% yield. 2-Furancarbonitrile was also reacted with
benzophenone, and the 1,2-addition reaction proceeded at
the 5-position to give the adduct (7) in 45% yield after the
reaction mixture was warmed to 50 1C.
Deuteration of heteroaromatics is important in the study of
deprotonation chemistry for mechanistic investigation and for
the fact that deuterated compounds are used in medicinal
chemistry research.8 Various methods for deuteration of
organic molecules are known, and most of the methodologies
include organometallic reactions. In connection with our current
project on organocatalytic deprotonative functionalization of
heteroaromatic compounds, we investigated the organocatalytic
process for the deuteration of heteroaromatics using the
organic superbase. DMSO-d6 was used as a deuteration
reagent in the presence of catalytic P4-tBu, and the catalytic
deuteration was found to proceed smoothly as shown in
Scheme 3. The deuteration of benzothiazole at 2-position
was conducted using a catalytic amount of P4-tBu in
DMSO-d6 at room temperature and quantitative conversion
was achieved in 1 h. Benzoxazole was also deuterated
quantitatively at the 2-position under the same reaction
conditions for 1 h. The deuterations of ethyl thiophene-2-
carboxylate and 2-furancarbonitrile were found to be relatively
slower; the conversion of the former was 43% and the latter
was 91% after 6 h reaction time at room temperature.
Deprotonation of aromatic C–H has been used for selective
functionalization of aromatic and heteroaromatic compounds.1
Various metallic deprotonating reagents of lithium, magnesium,
zinc, copper and aluminium have been widely used in stoichio-
metric manner for this process.2 Deprotonative functionalization
in the presence of an electrophile (in situ trapping) has been
investigated3 and an organic superbase has been also used as a
deprotonating reagent, but a stoichiometric amount of base is
required.4 Organocatalytic processes5 have been regarded to
be attractive from viewpoints of selectivity, safety and sustain-
ability, and the development of organocatalytic processes for
deprotonative functionalization of aromatics and hetero-
aromatics is considered to be one of highly challenging
subjects in organic synthesis. Here we report a simple metal-
free organocatalytic process using the combination of a
phosphazene base6 and an organosilicon reagent as an additive.
Recently phosphazene bases have been regarded to be unique
and attractive reagents in organic synthesis, and various
phosphazene base catalyzed reactions have been reported.7
Our working hypothesis is shown in Fig. 1, in which the key is
the addition of an organosilicon reagent to activate the
catalytic cycle, and it was found that the choice of organo-
silicon additive is very important.
First, the reaction of benzothiazole (1) with benzophenone
in the presence of catalytic P4-tBu was investigated and
various organosilicon reagents were examined as activating
agents. The use of triethylsilane and phenyltrimethylsilane
showed no positive effect on the catalytic activity (Table 1,
entries
1 and 2). When ethyl trimethylsilylacetate and
N,N-dimethyl trimethylsilylacetamide were used as additives,
the catalytic cycle was promoted to a certain extent (Table 1,
entries 3 and 4), but trimethylsilylacetonitrile showed no
promoting effect (Table 1, entry 5). To our surprise, the use
of alkynylsilanes showed significant promoting effect and the
use of 1-trimethylsilylpropyne (TMSP) gave excellent results
both in DMF and toluene (Table 1, entries 6 and 9). 1-Trimethyl-
silylhexyne was less effective than 1-trimethylsilylpropyne
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
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for synthesized compounds. See DOI:
10.1039/c0cc03106b
Fig.
1
Working hypothesis for P4-tBu catalyzed deprotonative
functionalization.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7623–7624 7623

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Table
presence of an organosilicon additive
1
P4-tBu catalyzed 1,2-addition of benzothiazole in the
Entry
Additive
Solvent
t/h
Yielda (%)
1
2
3
4
5
6
7
8
9c
Et3SiH
Me3SiPh
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
24
24
24
24
24
24
24
48
24
0
0
53
Me3SiCH2COOEt
Me3SiCH2COONEt2
Me3SiCH2CN
Me3SiCCMe (TMSP)
Me3SiCCnBu
59
Trace
92 (84)b
77
Scheme 3 P4-tBu catalyzed deuteration of heteroaromatics.
Me3SiCCPh
Me3SiCCMe (TMSP)
7
96
Functional Molecules’’ (No. 20036007) and the Grants
(No. 19390002) from the Ministry of Education, Science,
Sports and Culture, Japan.
a
b
c
Determined by 1H-NMR analysis. Isolated yield. 1.5 eq. of
additive was used.
Notes and references
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Scheme 1 P4-tBu catalyzed functionalization of benzothiazole.
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Scheme 2 P4-tBu catalyzed functionalization of heteroaromatics.
The present deprotonation methodology using catalytic
P4-tBu will provide a new metal-free tool for selective
functionalization of heteroaromatics. The catalytic process is
conceptually novel and is considered to be the first example of
organocatalytic deprotonative functionalization of aromatic
C–H without generating organometallic aromatic species. It is
expected that the process will have wide applicability for
selective functionalization of heteroaromatics and further
investigations on the scope of the reaction and mechanistic
study are underway.
Acknowledgement: This work was partly supported by
the Grant-in Aid for Scientific Research on Priority Areas
‘‘Advanced Molecular Transformations of Carbon Resources’’
(No. 19020005) and ‘‘Synergistic Effects for Creation of
C. Kroll and F. Bruckner, Chem.–Eur. J., 2009, 15, 10397.
¨
c
7624 Chem. Commun., 2010, 46, 7623–7624
This journal is The Royal Society of Chemistry 2010