2-Norbornyldimethylsilyl ethers (NDMS): A new protecting group for alcohols and carboxylic acids

Article abstract of DOI:10.1055/s-2002-34898

The use of the readily available 2-norbornyldimethylsilyl group (NDMS) in the protection of alcohols and carboxylic acids is described. Stabilities of the corresponding silyl compounds towards various reagents and deprotection conditions are compared with tert-butyldimethylsilyl-, iso-propyldimethyl and trimethylsilyl groups.

Full text of DOI:10.1055/s-2002-34898

LETTER
1919
2-Norbornyldimethylsilyl Ethers (NDMS): A New Protecting Group for
Alcohols and Carboxylic Acids
2
-Norbornyldimeth
i
ylsilyl
e
Ethers ter K. Heldmann,* Jürgen Stohrer, Rafael Zauner
Consortium für elektrochemische Industrie GmbH, Central Research Company of Wacker-Chemie GmbH, Zielstattstraße 20,
81379 München, Germany
Fax +49(89)74844242; E-mail: dieter.heldmann@wacker.com
Received 6 August 2002
Table 1 Relative Stability of Popular Silyl Protecting Groups3
Abstract: The use of the readily available 2-norbornyldimethylsi-
lyl group (NDMS) in the protection of alcohols and carboxylic acids
is described. Stabilities of the corresponding silyl compounds to-
wards various reagents and deprotection conditions are compared
with tert-butyldimethylsilyl-, iso-propyldimethyl and trimethylsilyl
groups.
-SiMe3
(TMS)
-SiMe2-i-Pr -SiMe2-t-Bu -SiMe2Th
-SiiPr3
(TIPS)
(IPDMS)
(TBDMS)
(TDS)
1
86
20000
50000
700000
Key words: silicon, protecting groups, ethers, esters, hydrosilyla-
tion
group does usually not contribute any atoms to the final
target molecule.
Therefore, low-cost protecting groups like trimethylsilyl
are generally favored, if they can fulfill the needs. The
preparation of bulkier silyl groups like TBDMS, preferred
in the research laboratory owing to their simple NMR
spectra and superior stability, involves an organometallic
(Grignard or lithium chemistry) reaction step, which
makes these reagent much more expensive.4,5 This is why
trimethylsilyl is still by far the most widely used silyl pro-
tecting group for large-scale synthesis despite its inferior
performance compared with TBDMS.
The ideal protecting group for an active-hydrogen moiety
such as an alcohol or a carboxylic acid should attach in
high yield, be stable towards a large number of reaction
conditions and, at the same time, be selectively removable
in the presence of other functional groups containing dif-
ferent protecting groups. While no single silyl group can
fulfill all of these conditions in all cases, the availability
of different silyl groups offers an appropriate answer to
nearly every protection-deprotection challenge.1 The
range of organic groups available on the silicon atom
changes both steric and electronic characteristics of the
protecting group and thereby causes different stabilities of
the silyl compound to a wide variety of reaction and
deprotection conditions. It is this versatility, which allows
the synthetic chemist to select a silyl group that can, for
example, be selectively removed in the presence of anoth-
er silyl or other protecting group. The ease and high-yield
introduction and deprotection contribute significantly to
the popularity and utility of silyl protecting groups.2
In order to find a more easily available silyl protecting re-
agent that retains most of the superior properties of the
TBDMS group, we examined the 2-norbornyldimethylsi-
lyl group (NDMS). 2-Norbornyldimethylchloro silane (3)
can be easily prepared by Pt-catalyzed hydrosilylation of
chlorodimethylsilane (2) with 2-norbornene (1) in high
yields.6 By using [COD]PtCl2 as a catalyst, a 94:6-mixture
of exo/endo-isomers 3a/3b is obtained (Scheme 1).7 This
mixture cannot be separated by distillation and is there-
fore used as it is. Chemical purity is usually >99% (GC).
The product is a colorless liquid with bp 120 °C/10 mbar.
Some of the most popular silyl groups used in organic
synthesis and their relative stability towards acid cata-
lyzed solvolysis are shown below (Table 1).
The NDMS chlorosilane is capable of masking primary,
secondary and tertiary alcohols as well as carboxylic acids
by using standard protocols (imidazole or NEt3 as base,
ambient temperature for primary/secondary alcohols).
For applications in the pharmaceutical industry pricing is
a further important topic, especially because the silyl
Scheme 1 Hydrosilylation of norbornene
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1919,1921,ftx,en;G21802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1920
D. K. Heldmann et al.
LETTER
Scheme 2 Synthesis of NDMS-Triflate (94:6 mixture of exo/endo-isomers).
However, in line with the TBDMS group the introduction monly used in desilylation reactions for secondary alco-
of the more sterically demanding NDMS group requires hols. The progress of the reaction was analyzed using GC
harsher reaction conditions (elevated reaction tempera- techniques and compared to a blank sample. For direct
tures, prolonged reaction times) for the formation of comparison, the corresponding silylethers of IPDMS 6
NDMS silyl ethers of tertiary alcohols, e.g. NDMS-ether and TBDMS 8 were treated in the same way as the NDMS
of tert-butanol requires 8 h/80 °C using imidazole as base. silyl ether 7.
Alternatively, we would like to introduce the NDMS silyl All three silyl ethers withstand organometallic reagents
triflate 5 as very powerful silylating reagent capable of si- (entries 1–3) without any noticeable decomposition.
lylating even tertiary alcohols under mild reaction condi- Strong oxidizing agents like pyridine chlorochromate (en-
tions (2,6 lutidine as base, ambient temperature, 2 h, try 4) cause slow decomposition of IPDMS and NDMS,
aqueous work-up). The NDMS silyl triflate can be simply but show almost no effect on TBDMS. All three protec-
prepared by reacting neat NDMS silyl chloride 3 with tri- tion groups are stable towards alkaline hydrolysis at room
flic acid 4 at 60 °C for 10 h (Scheme 2). The triflate is a temperature. Potassium fluoride in methanol does not
colorless liquid that can be purified by direct distillation cause deprotection at ambient temperature. However, at
(bp 100–105 °C/1 mbar) from the reaction flask in 83% reflux slow deprotection can be seen. The rate of IPDMS-
yield. The transformation from chloride to triflate does deprotection with potassium fluoride is about 2–3 times
not alter the exo/endo-ratio according to GC/NMR.
faster than the NDMS-deprotection. Both secondary alkyl
silyl groups are cleaved rapidly by tetrabutylammonium
fluoride in THF, whereas the deprotection of TBDMS
takes some hours (t1/2 ≈ 0.5 h).
Table 2 T1/2 for Cleavage of the Si-O-Bond in Silyl Ethers
The progress of the acid-catalyzed hydrolysis was fol-
lowed by GC over an appropriate period of time. As an ex-
ample, Figures 1 and 2 show the acid hydrolysis of a
primary and a secondary alcohol protected by TMS,
IPDMS, NDMS, TBDMS. The NDMS-ethers are cleaved
2 to 3 times more slowly than the IPDMS ether under
otherwise identical conditions. Despite its steric bulk, the
secondary alkyl residue does not reach the stability of a
tertiary alkyl group (TBDMS). Therefore, the NDMS-si-
lyl group is always the choice if the protecting group has
to withstand an aqueous work-up, which is often difficult
with the TMS group, and strong resistance to dilute acids
is not needed or even prohibitive.
Reagent
2-Propyl
[IPDMS]
2-Norbornyl tert-Butyl
[NDMS]
stable
stable
stable
2 h
[TBDMS]
2 M BuMgCl in THF
n-BuLi in hexane/THF
LiAlH4 in THF
stable
stable
stable
1 h
stable
stable
stable
PCC in CH2Cl2
stable
0.05 M NaOH in MeOH stable
stable
stable
7 h
stable
KF in MeOH (25 °C)
KF in MeOH (65 °C)
n-Bu4NF in THF
stable
2 h
stable
stable
<< 1min
< 1min
> 30 min
In order to determine suitable deprotection conditions si-
lyl ethers of n-butanol, 2-butanol, cyclohexanol, tert-bu-
tanol and phenol were synthesized.8 Table 2 shows
various reaction and cleavage conditions that are com-
Figure 1 Acid-catalyzed hydrolysis of silyl-protected 1-butanol
Synlett 2002, No. 11, 1919–1921 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2-Norbornyldimethylsilyl Ethers
1921
Scheme 3 Preparation of silyl esters.
major isomer. Purity 93% (GC, sum of exo/endo-isomers). Major
impurity was 1,1,3,3-tetramethyl-1,3-dinorbornyl-disiloxane (5%,
hydrolysis of the product). The product can be used for silylations
without any further purification.
References
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; J. Wiley & Sons: New York,
1999. (b) Kocie ski, P. J. Protecting Groups; Thieme:
Stuttgart, 1994.
(2) Lalonde, M.; Chan, T. H. Synthesis 1985, 817.
(3) van Look, G.; Simchen, G.; Heberle, J. Silylating Agents;
Fluka Chemie AG: Buchs, 1995.
Figure 2 Acid-catalyzed hydrolysis of silyl-protected 2-butanol
(4) (a) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190. (b) Morrison, R. J.; Hall, R. W.; Dover, B. T.;
Kamienski, C. W.; Engel, J. F. Eur. Pat. EP 525 880, 1998;
Chem. Abstr. 1993, 118, 192001. (c) Shirahata, A. Eur. Pat.
405 560, 1998; Chem. Abstr. 1991, 114, 164495.
(d) Winterfeld, J.; Abele, B. C.; Stenzel, O. PCT-WO 2000/
64909, 2000; Chem. Abstr. 2000, 132, 279350.
As an example for further applications a silyl ester 11
from NDMS silyl chloride and heptanoic acid (10) was
also prepared (Scheme 3). The NDMS-ester of the car-
boxylic acid withstands aqueous work-up conditions
without deprotection whereas the corresponding TMS-es-
ter suffers quantitative hydrolysis.
(5) An exemption is the AlCl3-catalyzed hydrosilylation of 2,3-
dimethyl-2-butene with dimethylchlorosilane leading to
thexyldimethylchlorosilane: Oertle, K.; Wetter, H.
Tetrahedron Lett. 1985, 26, 5511.
(6) (a) Eddy, V. J.; Hallgren, J. E. J. Org. Chem. 1987, 52,
1903. (b) Green, M.; Spencer, J. L.; Stone, F. G. A.; Tsipsis,
C. A. J. Chem. Soc., Dalton Trans. 1977, 1519.
(7) Depending on the catalyst batch, ratios of 93:7 up to 95:5
were obtained. Major isomer is 3a(exo) according to citation
6.
In summary, several advantages can be envisioned for the
use of the NDMS silyl group as hydroxy protecting moi-
ety: (1) it is readily available at low cost from bulk chem-
icals, (2) its significantly improved stability compared
with trimethylsilyl, exceeding isopropyldimethylsilyl and
almost reaching tert-butyldimethylsilyl, (3) improved
ease of handling as a liquid compared with the solid tert-
butyldimethylchlorosilane.
(8) All silylethers are exo/endo-mixtures with the same ratio as
the silylating agent used. The isomers can be distinguished
by the different chemical shifts of the methyl groups on the
silyl atom in the1H NMR spectra. However, the more
preferable method of analysis is 29Si NMR spectroscopy
providing only two well-distinguished signals, e.g.
Dimethyl-(2-norbornyl)-phenoxy silane: 1H NMR (300
MHz, CDCl3), major isomer: = 0.12 (2s, 6 H), 0.70 (t, 1 H),
1.10–1.5 (m, 8 H), 2.12–2.30 (m, 2 H), 6.70–6.80, 6.82–
6.90, 7.09–7.20 (Phenyl, 5 H); minor isomer: = 0.20
[Si(CH3)2, 6 H]. 29Si NMR (99 MHz, CDCl3), major isomer:
= +17.6; minor isomer: = + 19.6 ppm. Analysis by GC
providing the same ratio is also possible.
2-Norbornyldimethylsilyl Triflate (5)
Triflic acid (7.50 g, 49.0 mmol) is added dropwise to 2-nor-
bornyldimethylchlorosilane (9.50 g, 49.3 mmol) at ambient temper-
ature. The reaction mixture is stirred at 60 °C for 10 h (Attention:
liberation of gaseous HCl). The reaction mixture is subjected to
fractional distillation providing 5 as a colorless liquid (12.3 g, 83%,
bp 100–105 °C/1 mbar), again as a mixture of exo/endo-isomers
1
(GC, same ratio 94:6 in favor of the exo-isomer). H NMR (300
MHz, CDCl3), major isomer: = 0.45 (2 s, 6 H), 0.93 (t, 1 H), 1.10–
1.40 (m, 4 H), 1.50 (d, 2 H), 1.60 (d, 2 H), 2.35 (s, 2 H); minor iso-
mer: only = 0.52 [s, Si(CH3)2] is sufficiently separated from the
Synlett 2002, No. 11, 1919–1921 ISSN 0936-5214 © Thieme Stuttgart · New York