Unusually stable silyl ketones with bowl-shaped tris(2,6-diphenylbenzyl)silyl group for various nucleophilic attacks and α-deprotonation

Article abstract of DOI:10.1055/s-2002-22722

A newly designed, bowl-shaped tris(2,6-diphenylbenzyl)silyl (TDS) group can be successfully utilized as a highly effective shield of ketone carbonyls for various nucleophilic attacks and α-deprotonation. The high shielding effect of the bowl-shaped TDS mo

Full text of DOI:10.1055/s-2002-22722

LETTER
577
Unusually Stable Silyl Ketones with Bowl-shaped Tris(2,6-diphenylbenzyl)-
silyl Group for Various Nucleophilic Attacks and -Deprotonation
U
nusually sta
b
e
le Silyl
K
e
i
tones ji Shirakawa, Naoki Komatsu, Atsuko Iwasaki, Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax +81(75)7534041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 16 December 2001
nation, respectively (Scheme 2).5 The stability of -TDS
ketone 1b toward excess BuLi (3 equiv) under various re-
action conditions follows: 99% recovery at –40 °C for 6
hours; 83% recovery at –20 °C for 4 hours; 58% recovery
Abstract: A newly designed, bowl-shaped tris(2,6-diphenylben-
zyl)silyl (TDS) group can be successfully utilized as a highly effec-
tive shield of ketone carbonyls for various nucleophilic attacks and
-deprotonation. The high shielding effect of the bowl-shaped TDS
1
moiety toward carbonyl and even -protons is verified by the H at 0 °C for 30 minutes. Other alkyllithiums (MeLi and
NMR study of TDS ketone 1a in CDCl3, and by its X-ray analysis.
The TDS ketone 1b can be cleaved with Bu4NF/BF3 OEt2.
t-BuLi), Grignard reagent (MeMgBr), and base (LDA)
exhibited similar unreactivity as shown in the Table
Key words: ketone, silicon, nucleophilic attack, alkyllithium,
Grignard reagent
(entries 4–8). In marked contrast, however, treatment
of -trimethylsilyl ketone 4 with BuLi (3 equiv) in THF at
–78 °C for 1 hour and subsequent addition of benzalde-
hyde at this temperature gave rise to butylation product 5
Ketone carbonyls are one of the most popular and valu- (30%) and enone 6 (45%) via -deprotonation, aldol inter-
able functional groups in organic synthesis, and are often mediate 7, and its subsequent Peterson elimination. Other
masked as ketals, thioketals, enol silyl ethers, enamines, selected examples with different TDS ketones toward RLi
oximes, substituted hydrazones, cyanohydrins, and Schiff and Grignard nucleophiles are also included in the Table.
bases for further chemoselective transformations of mul- Another TDS ketone 1c exhibited similar unreactivity to-
tifunctional organic molecules.1 However, the shield of ward MeMgBr and RLi nucleophiles at low to room tem-
ketone carbonyls without affecting carbonyl moieties has perature for several hours. Sterically less hindered -TDS
never been developed to a useful level due to the lack of ketone 1a is readily susceptible to nucleophilic attack with
appropriate methodologies. Here, we wish to report a new BuLi to furnish alcohol 2a (R = CH2CH2Ph; n = 1) (entry
carbonyl shielding approach against various nucleophilic 2), and -deprotonation with bulky t-BuLi to furnish an
attack using the bowl-shaped tris(2,6-diphenylbenzyl)si- aldol product 8 upon reaction with benzaldehyde in high
lyl (TDS) group (Scheme 1).2,3
yield (entry 3). A similar tendency is also observed in the
case of -TDS ketones 1d and 1e (entries 12–18).
The high shielding effect of the bowl-shaped TDS moiety
toward ketone carbonyl and even -protons was verified
by 1H NMR spectral study of -TDS ketone 1a in CDCl3,
Ph
(CH2)n
(CH2)n
Si
)
R
C
O
Si(CH2
R
C
O
3
Ph
1a (R = CH2CH2Ph; n = 1)
1b (R = CH(CH2Ph)2; n = 1)
1c (R = CH(CH2CH3)2; n = 1)
1d (R = C(CH3)3; n = 2)
1e (R = Ph; n = 2)
Ph
Ph
Ph
excess BuLi PhCHO
(CH2)n
[TDS]
R
C
O
(3 eq)
(3 eq)
)
+
1b
CH2 Si(CH2
3
Ph
THF
-78~0 °C
-78 °C
(TDS = tris(2,6-diphenylbenzyl)silyl)
O
Ph
1b
Scheme 1
Ph
CH2 Si(CH2
Bu OH
Ph
Ph
PhCH2
CH2Ph
+
)
3
)
3
Ph
CH2 Si(CH2
We examined the blocking ability of the TDS moiety for
ketone carbonyl toward a variety of reactive nucleophiles.
Thus, reaction of -TDS ketone 1b4 in THF with excess
BuLi (3 equiv) at –78 °C for 2 hours, at –40 °C for 1 hour,
and at –20 °C for 1 hour resulted, after quenching with
benzaldehyde acceptor at –78 °C, in recovery of most
(~92%) of the starting -TDS ketone 1b without forma-
tion of 2b or 3 via nucleophilic alkylation and -deproto-
HO
O
Ph
Ph
3
2b
Ph
PhCHO
(3 eq)
excess BuLi
(3 eq)
SiMe3
CH2
Ph
THF
-78 °C, 1 h
-78 °C
O
4
Ph
Ph
Ph
SiMe3
CH3
Ph
Ph
Ph
+
Ph
OLi
Ph
Bu OH
O
30%
45%
O
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0577,0579,ftx,en;Y24901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
6
7
5
Scheme 2

578
S. Shirakawa et al.
LETTER
Table Reactivity of - and -TDS Ketones toward Alkyllithiums, Grignard Reagent or Basea
R1
C
H
C
CH2Ph
R1-M (3 eq)
PhCHO (3 eq)
(CH2)n
(CH2)n
CH2
[TDS]
+
+
Ph
R
C
O
[TDS]
1
CH
R
[TDS]
C
O
THF
-78°C
OH
OH
1
2
8
Entry
Ketone 1
R1-M
Reaction Condition
(°C, h)
% Yield of Products
R
n
1
1
2
8
1
2
CH2CH2Ph
MeMgBr
BuLi
–78, 5; –40, 1
–78, 1
92
86
3
t-BuLi
MeLi
–78, 4
90
4
CH(CH2Ph)2
1
–78, 4; –20, 2; 0, 0.5
0, 3; 25, 1
99
94
92
93
99
99
87
87
91
61
91
47
99
5
MeMgBrb
BuLi
6
–78, 2; –40, 1; –20, 1
–78, 4
7
t-BuLi
LDA
8
–78, 2; 0, 3
9
CH(CH2CH3)2
C(CH3)3
Ph
1
2
2
MeMgBrb
BuLi
–20, 1; 0, 1; 25, 1
–78, 2; –40, 2; –20, 1
–78, 2; –40, 2; –20, 1
–20, 1; 0, 1; 25, 0.5
78, 1
10
11
12
13
14
15
16
17
18
t-BuLi
MeMgBr
BuLi
33
46
99
t-BuLi
MeMgBr
78, 2; –40, 2; –20, 1
–20, 0.5; 0, 2
–78, 4
BuLi
–78, 0.3
t-BuLi
–78, 0.5; –20, 3
99
a Reaction of - and -TDS ketones 1 in THF with alkyllithiums, Grignard reagent or base (3 equiv) was carried out under the indicated reaction
conditions, and subsequently treated with benzaldehyde (3 equiv) at –78 °C for 1 h.
b Use of THF/ether solvents (volume ratio, 1:2).
where the upfield shift of -phenethyl protons in 1a com- propriate molecular pocket around carbonyl protons as
pared to the corresponding -trimethylsilyl ketone and the well as -protons for shielding against nucleophilic attack
parent methyl -phenethyl ketone is clearly observed and -deprotonation. This inference is in accord with the
(Figure 1).
1H NMR data on the upfield shift of ketone protons in -
TDS ketone 1a.
α
β
α'
X-CH2-(O=)C-CH2-CH2-Ph
The TDS protecting group of the -TDS ketone 1b is
readily cleaved to the corresponding ketones 9 by treat-
ment with tetrabutylammonium fluoride/BF3 OEt2 com-
plex in acetonitrile/dichloromethane cosolvent under the
standard conditions (Scheme 3).7
1H NMR Data
aromatic-H
δ 6.93 & 7.18
δ 7.18 & 7.27
δ 7.18 & 7.27
α'-H
δ 0.74
δ 2.21
δ 2.12
α-H
β-H
[TDS]-CH2COCH2CH2Ph
Me3Si-CH2COCH2CH2Ph
CH3COCH2CH2Ph
δ 1.54
δ 2.67
δ 2.74
δ 2.05
δ 2.88
δ 2.88
Ph
Ph
Bu4NF / 2BF3•OEt2
Ph
Figure 1
(3 eq)
)
CH2 Si(CH2
3
CH3
Ph
Ph
CH3CN, CH2Cl2
reflux, 13 h
O
O
Ph
The primary structure of -TDS ketone 1a was deter-
mined by single-crystal X-ray diffraction analysis as
shown in Figure 2,6 which suggests the existence of an ap-
1b
9
95% yield
Scheme 3
Synlett 2002, No. 4, 577–579 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Unusually Stable Silyl Ketones
579
Ph
Si(CH2
Ph
Ph
a
)
)
3
Si(CH2
Ph
3
91%
O
10
b
99%
Ph
CH2 Si(CH2
Ph
CH2 Si(CH2
Ph
Ph
c
)
3
)
3
71%
Ph
O
O
Ph
Ph
1b
1a
Scheme 4 Conditions: (a) cat. Pd(OAc)2 (20 mol%), 30% H2O2,
solvent; (b) t-BuLi, BnBr, THF; (c) t-BuLi, HMPA, BnBr, THF.
(4) Synthesis of -TDS ketones 1a and 1b (Scheme 4):
The starting allylsilane 10 was prepared from
allyltrichlorosilane in a similar manner as described in the
synthesis of tris(2,6-diphenylbenzyl)silane. See ref. 2
(5) Quenching with D2O in place of benzaldehyde acceptor
resulted in 99% recovery of the starting -TDS ketone 1b.
(6) The single-crystal of -TDS ketone 1a was obtained by
recrystallization from benzene/ether solvents. Crystal
structure data for 1a: C67H56OSi 2 C6H6, Mw = 1061.47,
monoclinic, space group P-2/a (#13), a = 20.629 Å,
b = 14.155 Å, c = 22.437 Å, V = 6274.8 Å3, Z = 4,
Figure 2 ORTEP diagram of -TDS ketone 1a
References
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999,
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(2) Iwasaki, A.; Kondo, Y.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 10238.
(3) Reviews: (a) Baukov, Y. I.; Lutsenko, I. F. J. Organometal.
Chem. Rev. A 1970, 6, 355. (b) Weber, W. P. Silicon
Reagents for Organic Synthesis; Springer-Verlag: Berlin,
1983.
D
calcd = 1.111 gcm–3, R1 = 0.121.
(7) (a) Kawahara, S.; Wada, T.; Sekine, M. Tetrahedron Lett.
1996, 37, 509. (b) Gevorgyan, V.; Yamamoto, Y.
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Synlett 2002, No. 4, 577–579 ISSN 0936-5214 © Thieme Stuttgart · New York