Nucleophilic aromatic substitution using Et3SiH/cat. t-Bu-P4 as a system for nucleophile activation

Article abstract of DOI:10.1039/b700140a

A novel type of deprotonative arylation of nucleophiles was conducted using Et₃SiH/cat. t-Bu-P4 and the powerful S_NAr reactions of aryl fluorides were accomplished using alcohols and malonates as nucleophiles. The Royal Society of Ch

Full text of DOI:10.1039/b700140a

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Nucleophilic aromatic substitution using Et3SiH/cat. t-Bu-P4 as a
system for nucleophile activation{
Masahiro Ueno,a Misato Yonemoto,a Masahiro Hashimoto,a Andrew E. H. Wheatley,{b Hiroshi Nakaa and
Yoshinori Kondo*a
Received (in Cambridge, UK) 5th January 2007, Accepted 5th February 2007
First published as an Advance Article on the web 28th February 2007
DOI: 10.1039/b700140a
alcohols using superbase-catalyzed coupling reaction has been a
challenge. However, the generation of hydride from Et3SiH using
catalytic t-Bu-P4 has been demonstrated in the reduction of
ketones.2c Therefore, the combination of Et3SiH and catalytic
t-Bu-P4 is considered to represent an attractive hydride generating
system with which to carry out sequential deprotonation and SNAr
reaction. We started our investigation with the arylation of various
alcohols using 2-fluoronitrobenzene. The reaction of 2-fluoroni-
trobenzene with n-hexanol was carried out in the presence of
Et3SiH and 10 mol% of t-Bu-P4 at 100 uC for 2 h. The arylation
reaction proceeded to give the ether quantitatively (Table 1,
entry 1). The reaction with n-butanol also proceeded smoothly
(Table 1, entry 2). Secondary alcohols, such as 2-phenylethyl-
alcohol and 2-butanol were arylated under the same reaction
conditions togive ethers inexcellent yields (Table 1, entries 3 and4).
Aryl fluorides with weaker electron withdrawing groups were
then examined. 4-Fluorobenzonitrile and 4-fluorobenzotrifluoride
were employed and found to be good substrates. Accordingly,
reaction with n-butanol proceeded under the same conditions to
give the corresponding ethers (Table 1, entries 5 and 6).
A novel type of deprotonative arylation of nucleophiles was
conducted using Et3SiH/cat. t-Bu-P4 and the powerful SNAr
reactions of aryl fluorides were accomplished using alcohols
and malonates as nucleophiles.
The nucleophilic aromatic substitution (SNAr) reaction is one of
the most fundamental transformations in synthetic organic
chemistry.1 Various nucleophiles, such as alcohols, phenols,
amines, and 1,3-dicarbonyl compounds, have been employed for
the reaction. Traditionally, highly reactive bases such as NaH,
t-BuOK etc. have been utilized to deprotonate nucleophiles and so
generate reactive anions. The stoichiometric use of bases has been
regarded as essential for completion of the substitution reaction.
However, catalytic use of strong bases is desirable from the
viewpoint of selectivity, safety and environmental benignity.
Recently we have focused our interest on selective molecular
transformations using organic superbases.2 Here we report
effective SNAr reactions via in situ generation of activated
nucleophiles using triethylsilane (Et3SiH) and catalytic t-Bu-P4
(Fig. 1).
Table 1
Entry
R
R9OH
t/h
Yield (%)
Fig. 1
1
2
3
4
5
6
o-NO2
o-NO2
o-NO2
o-NO2
p-CN
n-Hexanol
n-BuOH
PhMeCHOH
EtMeCHOH
n-BuOH
2
2
2
18
13
13
100
97
92
71
98
58
The t-Bu-P4 base was developed as an extremely strong non-
metallic organic base by Schwesinger et al.3 and various of its
deprotonative transformations have been investigated.4 We
recently reported that t-Bu-P4 base can catalyze the coupling
reaction of aryl fluorides with silyl ethers.2c Moreover, Urgaonkar
and Verkade have also reported a similar reaction using a
proazaphosphatrane base as catalyst.5 The use of silyl ether was
required for these reactions, and direct arylation of unsilylated
p-CF3
n-BuOH
When alcohols were reacted with Et3SiH and catalytic t-Bu-P4
in the absence of aryl fluorides at room temperature, the silylation
of alcohols proceeded smoothly. This result indicates that the
deprotonation of alcohol occurs rapidly in this catalytic system,
and that the in situ formation of silyl ethers may be considered a
very fast process.
aGraduate 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
As shown in Table 2, silylations of various alcohols were
examined.6 The reaction of 8-nonen-1-ol with triethylsilane
proceeded smoothly at room temperature in the presence of cat.
t-Bu-P4 and the corresponding silyl ether was obtained in 98%
yield (Table 2, entry 1). Benzyl alcohol was then reacted with
Et3SiH to give the silyl ether in 95% yield (Table 2, entry 2).
a-Phenylethylalcohol was also reacted with Et3SiH at room
bDepartment Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EH. E-mail: aehw2@cam.ac.uk;
Fax: 44-1223-336362; Tel: 44-1223-763122
{ Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for synthesized compounds. See DOI:
10.1039/b700140a
{ JSPS Fellow 19th January 2006–19th April 2006.
2264 | Chem. Commun., 2007, 2264–2266
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temperature and the silyl ether was obtained in 97% yield (Table 2,
entry 3). Silylation of 4-dodecanol was examined using Et3SiH to
give the corresponding silyl ether in 98% yield (Table 2, entry 4).
The silylation of sterically hindered tertiary alcohols also
proceeded smoothly at room temperature and the silyl ether was
obtained in excellent yields (Table 2, entries 5 and 6). Clearly, this
reaction proceeds under mild conditions without forming stoichio-
metric amounts of ammonium salt, which is the fundamental
drawback associated with the conventional method that uses
R3SiCl and amines.
methylmalonate to give the corresponding arylmalonates in 46
and 66% yield, respectively (Table 3, entries
8 and 9).
Conventionally aryl fluorides with weak electron withdrawing
groups have not been used for SNAr reaction with these
C-nucleophiles, and the present method provides a new and
highly effective SNAr reaction protocol.
Table 3
Table 2
Entry
R
R9
EWG1
EWG2
t/h Yield (%)
1
2
3
4
5
6
7
8
9
2-NO2 Me
2-NO2
2-NO2 n-Hexyl COOEt COOEt 24
COOEt COOEt
COOEt COOEt 22
1
99
56
76
95
89
89
97
46
66
H
Entry
R
t/h
Yield (%)
2-NO2 Allyl
2-NO2 Allyl
2-NO2 Allyl
4-NO2 Me
COOEt COOEt
COOEt CN
2
3
3
2
1
2
3
4
5
6
CH2LCH(CH2)7
PhCH2
PhMeCH
n-Hex(n-Pr)CH
PhMe2C
1
1
2
2
3
6
98
95
97
98
95
87
CN
COOEt COOEt
CN
2-CN
4-CN
Me
Me
COOEt COOEt 24
COOEt COOEt 24
Ph3C
A plausible mechanism for the transformations reported here is
shown in Scheme 2. The combination of Et3SiH and cat. t-Bu-P4
is considered to generate a reactive hydride species, which
deprotonates a nucleophile to form a phosphazenium nucleophile
anion. This anion would be highly nucleophilic and would
promote the SNAr reaction, which gives the product and Et3SiF,
regenerating t-Bu-P4 catalyst.
The diaryl ether structural unit has been found in a number of
biologically important natural products, such as vancomycin, and
many synthetic studies for diaryl ethers have been carried out.7
p-Methoxyphenol was used as a representative phenol substrate
and the SNAr reaction using Et3SiH/cat. t-Bu-P4 was examined.
The reaction of 2-fluoronitrobenzene proceeded at room tempera-
ture to give the diaryl ether in 76% yield (Scheme 1).
Scheme 1
Our interest was next focused on using the Et3SiH/cat. t-Bu-P4
system to effect the SNAr reaction of C-nucleophiles. Introduction
of O-nucleophiles to aromatics has been well investigated for SNAr
reactions, but there are limited numbers of successful examples for
the arylation of carbanions by SNAr reaction.8 Highly activated
aryl fluorides, such as fluoronitroarenes have been the only
successful substrates for the SNAr reactions using malonates as
nucleophiles. To begin with, diethyl methylmalonate was reacted
with 2-fluoronitrobenzene at 80 uC for 1 h, and the arylation was
found to proceed smoothly to give the arylmalonate in 99% yield
(Table 3, entry 1). The reaction with diethyl malonate was found
to be slower and the arylmalonate was obtained in 56% yield after
reacting for 22 h (Table 3, entry 2). Other a-substituted malonates
also reacted with 2-fluoronitrobenzene to give arylmalonates
(Table 3, entries 3 and 4). These 2-nitrophenylmalonates are
expected to be important precursors for the synthesis of oxyindole
derivatives.9 a-Substituted cyanoacetate and a-substituted
malononitrile were also found to be excellent C-nucleophiles,
Scheme 2
In summary, a novel type of deprotonative arylation of
nucleophiles was achieved using Et3SiH/cat. t-Bu-P4. The method
provides a more powerful SNAr reaction when compared to the
conventional method using stoichiometric NaH. Further investiga-
tions on the scope and limitations of this reaction and mechanistic
studies on the catalytic system are underway.
This work was partly supported by the Grant-in Aid for
Scientific Research (No. 16659002, No. 18659001) from the
Ministry of Education, Science, Sports and Culture, Japan and
grants from the Sumitomo Foundation and Yamada Science
Foundation and also by a Visiting Fellowship from The Japan
Society for the Promotion of Science.
Notes and references
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with arylation smoothly (Table 3, entries
5
and 6).
4-Fluoronitrobenzene reacted with methylmalonate to give the
arylmalonate in 97% yield (Table 3, entry 7). The less
reactive 2-fluoro- and 4-fluorobenzonitrile also reacted with
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