A Convenient Protecting Group for Aldehydes

Article abstract of DOI:10.1055/s-2001-18767

Aldehydes were cleanly and chemoselectively protected by treatment with tert-butylchlorodimethylsilane and imidazole. The resulting O-tert-butyldimethylsilylimidazolyl aminals were deblocked under mild conditions by employing 9:1. CH3CN - 49 percent HF.

Full text of DOI:10.1055/s-2001-18767

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LETTER
1925
A Convenient Protecting Group for Aldehydes
A
Convenient
P
o
rotecting Gr
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oup
f
or
A
lde
g
hyde
s
Guo Quan, Jin Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487, USA
Fax +1(205)3489104; E-mail: jcha@bama.ua.edu
Received 24 September 2001
conversion in the presence of any adventitious water in
small-scale reactions, use of 1.5 equivalents of tert-butyl-
chlorodimethylsilane proved to be convenient for this al-
dehyde blocking process.
Abstract: Aldehydes were cleanly and chemoselectively protected
by treatment with tert-butylchlorodimethylsilane and imidazole.
The resulting O-tert-butyldimethylsilylimidazolyl aminals were de-
blocked under mild conditions by employing 9:1 CH3CN–49% HF.
Key words: protecting group, aldehydes, tert-butylchlorodimeth- The TBDMS-imidazole group of 2a was readily de-
ylsilane, imidazole, 49% HF
blocked with 9:1 CH3CN–49% HF at room temperature to
afford nonanal (1a) in 96% yield.7 On the other hand, use
of n-Bu4NF gave a complex mixture. Removal of this TB-
DMS-imidazole blocking group was also effected in 93%
yield by 80% HOAc at 80 °C for 24 hours, whereas depro-
tection was slow with 3:1:1 HOAc–H2O–THF at 80 °C.
Thus, the TBDMS-imidazole blocking group of alde-
hydes exhibited considerable stability under relatively
mild acidic conditions.
During the course of studies on a total synthesis, we re-
cently required chemoselective protection of an aldehyde
in the presence of a ketone. An ideal protecting group
would be generally inert to acid, base, nucleophiles, and
hydrides, yet easily removable under relatively mild con-
ditions. Additionally, simple and facile introduction in
laboratory-scale reactions was necessary. O-protected cy-
anohydrins were commonly utilized for this purpose,1,2
but highly desirable was its variant which would exhibit
greater orthogonality with organometallic and hydride-
transfer reagents. As a chemoselective protecting group of
aldehydes, we report herein the use of O-tert-butyldime-
thylsilylimidazolyl aminals, which can be readily intro-
duced and also removed under mild conditions.
Table
Entry
R
Protection
yield
Deprotection
yield
Our choice of tert-butylchlorodimethylsilane–imidazole
was guided by the well-known generation of silyl enol
ethers from aldehydes and ketones by utilizing a silylating
agent (R3SiCl or R3SiOTf) and a tertiary amine (e.g.,
Et3N, Hünig base, or DBU).3,4 It occurred to us that use of
a less basic, secondary amine could lead to the desired ad-
dition product, instead of the elimination product (i.e., si-
lyl enol ethers). Such an ideal secondary amine could be
found in imidazole because of its known nucleophilicity
and also nucleofugality. Survey of the literature indeed re-
vealed two reports on addition of trimethylsilylimidazole
(and its related azoles) to benzaldehyde at room tempera-
ture.5 Surprisingly, however, no additional reports ap-
peared, let alone use of bulkier silyl derivatives. In this
work, tert-butylchlorodimethylsilane was selected to con-
fer greater stability toward various reagents during subse-
quent transformations. Thus, treatment of nonanal (1a)
with tert-butylchlorodimethylsilane (1.5 equiv) and imi-
dazole (5 equiv) in DMF at room temperature (overnight
to 1 day) gave 2a in 96% yield.6 When 10 equivalents of
imidazole were employed, 2a was obtained in quantitative
yield in 5 hours. With less than 5 equivalents of imidazole,
the formation of 2a took much longer. To ensure complete
1
2
3
4
5
6
a: CH3(CH2)7
b: cyclohexyl
c: tert-butyl
d: CH3C(O)(CH2)5
e: Ph
96%
93%
85%
91%
91%
95%
96%
90%
90%
95%
93%
88%
f: PhCH=CH
As illustrated in the Table, we examined the scope of the
TBDMS-imidazole protecting group of several alde-
hydes, 1a–f. The above-mentioned protection and depro-
tection procedures were readily applied to (unhindered
and hindered) aliphatic, aromatic, and , -unsaturated al-
dehydes. Excellent chemoselectivity was observed for an
aldehyde in the presence of a ketone (entry 4).
The selective formation of 2d allowed straightforward
elaboration of the ketone functionality, as shown in the
Scheme. For example, the ketone group of 2d was treated
with NaBH4, MeMgCl, and 1,2-ethanedithiol to give 3, 4,
and 5 in excellent yields. The aldehyde protecting group
of 4 and 5 was then removed cleanly devoid of side reac-
tions to provide 6 and 7 in good yields. As shown in the
preparation of 7, the three-step conversion of keto-alde-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1925,1926,ftx,en;S07401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1926
L. G. Quan, J. K. Cha
LETTER
Scheme
hyde 1d selectively masked the ketone group to allow
subsequent elaboration of the free aldehyde functionality.
(4) For general reviews on synthetic applications of silyl enol
ethers(enoxysilanes), see: (a) Emde, H.; Domsch, D.; Feger,
H.; Frick, U.; Götz, A.; Hergott, H. H.; Hofmann, K.; Kober,
W.; Krägeloh, K.; Oesterle, T.; Steppan, W.; West, W.;
Simchen, G. Synthesis 1982, 1. (b) Brownbridge, P.
Synthesis 1983, 1. (c) Brownbridge, P. Synthesis 1983, 85.
(5) (a) Tomoya, O.; Masanao, M. Agr. Biol. Chem. 1970, 34,
969; Chem. Abstr. 1970, 73, 45564. (b) Gasparini, J. P.;
Gassend, R.; Maire, J. C.; Elguero, J. J. Organomet. Chem.
1981, 208, 309.
Applications of this aldehyde protecting group in natural
product synthesis will be reported in due course.
Acknowledgement
We are grateful to the National Institutes of Health (GM 35956) for
financial support.
(6) Typical Protection Procedure: To a solution of 1a (142
mg, 1 mmol) in DMF (2 mL) were added at r.t. imidazole
(340 mg, 5 mmol) and TBDMSCl (226 mg, 1.5 mmol). The
resulting mixture was stirred overnight for 1 d, diluted with
ether, washed with water, and the organic layer was dried
over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by column chromatography
afforded 311 mg (96%) of 2a: 1H NMR (360 MHz, CDCl3):
= –0.15 (s, 3 H), 0.05 (s, 3 H), 0.83 (s, 9 H), 0.86 (t, J = 6.5
Hz, 3 H), 1.11–1.34 (m, 12 H), 1.77 (m, 1 H), 1.90 (m, 1 H),
5.45 (t, J = 6.2 Hz, 1 H), 7.00 (br s, 1 H), 7.03 (br s, 1 H),
7.56 (s, 1 H); 13C NMR (90 MHz, CDCl3): = –5.6, –5.4,
14.0, 17.8, 22.5, 24.6, 25.4, 28.9, 29.0, 29.3, 31.7, 39.4, 81.5,
115.8, 129.3, 134.9.
(7) Typical Deprotection Procedure: A solution of 2a (324
mg, 1 mmol) in CH3CN (3.6 mL) was placed in a plastic vial,
and 49% HF (0.4 mL) was added. After the resulting mixture
had been stirred at r.t. overnight, it was diluted with ether,
washed with water, followed by 10% NaHCO3, and brine,
and the organic layer was dried over Na2SO4. Concentration
of the organic layer under reduced pressure gave essentially
pure 136 mg (96%) of 1a.
References
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Chem. Soc. 1959, 81, 5725. (b) Stork, G.; Maldonado, L. J.
Am. Chem. Soc. 1971, 93, 5286. (c) Evans, D. A.; Hoffman,
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(d) Rawal, V. H.; Rao, J. A.; Cava, M. P. Tetrahedron Lett.
1985, 26, 4275. (e) For a review of the carbanions of O-
protected cyanohydrins, see: Albright, J. D. Tetrahedron
1983, 39, 3207.
(2) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
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(3) (a) Emde, H.; Götz, A.; Hofmann, K.; Simchen, G. Liebigs
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ethers in preference to the E-isomers.
Synlett 2001, No. 12, 1925–1926 ISSN 0936-5214 © Thieme Stuttgart · New York