Angewandte
Chemie
DOI: 10.1002/anie.201404495
Synthetic Methods
Lithiation of a Silyl Ether: Formation of an ortho-Fries
Hydroxyketone**
Hong-Jay Lo, Chin-Yin Lin, Mei-Chun Tseng, and Rong-Jie Chein*
Dedicated to Professor E. J. Corey on the occasion of his 86th birthday
Abstract: A hydroxy-directed alkylation of an N,N-diethylar-
ylamide using CIPE-assisted a-silyl carbanions (CIPE =
complex-induced proximity effect) has been developed using
a simple reagent combination of LDA (lithium diisopropyl-
amide) and chlorosilane. A study of the mechanism, and the
application of the procedure to an anionic Snieckus–Fries
rearrangement for a highly efficient synthesis of the potent
phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, are
reported.
salicylic acid and a mechanistic study. The transformation
involves: 1) a complex-induced proximity effect (CIPE)[5] in
the deprotonation step, 2) an intramolecular Peterson-type[6]
reaction of the resulting a-silyl carbanion with the amide
group, and 3) fission of the final b-oxygenated silyl inter-
mediate. The scope of this procedure is also investigated in
the anionic Snieckus–Fries rearrangement[7] using a variety of
chlorosilane substrates and its use in the efficient synthesis of
the potent phosphatidylinositol 3-kinase (PI3K) inhibi-
tor LY294002[8] is demonstrated.
T
he expanding use of silicon reagents in organic synthesis
The first step of the procedure involved the treatment of
N,N-diethyl salicylamide (1) with TMSCl (1.2 equiv) in the
presence of LDA (2 equiv) in THF at 08C. Surprisingly, o-
hydroxyacetophenone was isolated in 44% yield, along with
30% of residual starting material after 30 min at room
temperature (Table 1, Entry 1). No silyl ether was observed,
resulting from their low cost, versatile properties, and
application to a wide range of reactions, has greatly increased
the prominence of organosilicon chemistry. In 1967,
Peterson[1] reported the successful metalation, using tBuLi
and N,N,Nꢀ,Nꢀ-tetramethyl-1,2-ethane (TMEDA), of the very
weakly acidic compounds tetramethylsilane and n-butyltri-
methylsilane. The formation of the corresponding silylme-
thyllithium compounds provided the first demonstration of
the enhanced acidity of the a-hydrogen atoms of unactivated
organosilanes. The stabilization of a-silyl carbanions has been
attributed to the (p-s*)p overlap between the antibonding
Table 1: Optimization of reaction conditions.
ꢀ
s* orbital of the C Si bond and the adjacent carbanionic
p orbital (or highly polarized carbon–metal bond).[2] Several
unactivated a-silyl carbanions formed by LDA (lithium
diisopropylamide) and assisted by a strong direct-metalation
group (DMG) have since been sporadically reported[3] and
have limited synthetic applications. Among these a-silyl
carbanions, Snieckus et al.[3d] reported an interesting a-silyl
metalation that converted ortho-silylated benzamides into
ortho-fluorosilylated acetophenones by treatment with LDA.
This finding led us to examine whether the hydroxy group of
a hydroxyarylamide could similarly direct the alkyl arrange-
ment through the metalation of silyl ether.[4] Herein, we
report the general application of hydroxy-directed
nucleophilic acyl alkylations of hydroxyarylamides and
Entry
Base (equiv)
Solvent
t [h] at RT
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
LDA (2)
LDA (3)
LDA (4)
LDA (4)
LiNEt2 (4)
NaH (4)
LHMDS (4)
KHMDS (4)
sec-BuLi (4)
LTMP (4)
THF
THF
THF
Et2O
THF
THF
THF
THF
THF
THF
0.5
0.5
0.5
2
12
12
12
12
0.5
0.5
44
76
85
49
0[b]
0[b]
0[c]
0[c]
0[d]
67
[a] Yield of isolated product. [b] Starting material was recovered.
[c] Minor amount of silyl ether was isolated along with residual starting
material. [d] sec-Butyl acylated product was isolated. Highlighted line
indicates optimum reaction conditions.
[*] Dr. H.-J. Lo, M. Sc. C.-Y. Lin, Dr. M.-C. Tseng, Prof. R.-J. Chein
Institute of Chemistry, Academia Sinica
128 Academia Road Sec. 2
and the use of LDA (4 equiv, pKa 35.7[9]) provided the optimal
yield (85%, Entry 3). Employing lithium 2,2,6,6-tetramethyl-
piperidide (LTMP, pKa 37.3[9]) resulted in a lower yield (67%
yield, Entry 10), whereas the use of other lithium amides with
weaker basicities, such as lithium diethylamide (LiNEt2,
pKa 31.7[9,10]) and lithium hexamethyldisilazide (LHMDS,
pKa 29.5[9]), did not afford the desired reaction products
(Entries 5 and 7). Less-hindered bases, such as sec-butyl-
Nankang Taipei 11529 (Taiwan)
E-mail: rjchein@chem.sinica.edu.tw
Name=rjchein
[**] We thank Academia Sinica and Ministry of Science and Technology
(Taiwan) for financial support and MS lab of the Institute of
Chemistry, Academia Sinica for mass analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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