Di- tert -butylisobutylsilyl, another useful protecting group

Article abstract of DOI:10.1021/ol201640y

The di-tert-butylisobutylsilyl (BIBS) protecting group offers new possibilities for synthetic processes because of its steric bulk, robustness of its derivatives, and other special properties.

Full text of DOI:10.1021/ol201640y

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4120–4123
Di-tert-butylisobutylsilyl, Another Useful
Protecting Group
Huan Liang, Lin Hu, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
corey@chemistry.harvard.edu
Received June 17, 2011
ABSTRACT
The di-tert-butylisobutylsilyl (BIBS) protecting group offers new possibilities for synthetic processes because of its steric bulk, robustness of its
derivatives, and other special properties.
The protection of oxygen-containing functionality by
various tertiary silyl groups has contributed greatly to the
progress of synthetic chemistry over the past four decades,
thanks to the availability of a whole series of silyl halides
and triflates and a range of mild conditions for depro-
tection.1 Although the prototypical trimethylsilyl group2 is
too labile for widespread use, a series of other silyl groups
consisting of triethyl- (TES), isopropyldimethyl- (DMIS),3
tert-butyldimethyl- (TBS),4 triisopropyl- (TIPS),5 tert-
butyldiphenyl- (TBDPS) silyl6 offers a range of robustness
(gradually increasing).7 The very bulky tri-tert-butylsilyl
does not appear to be of comparable utility because it is
difficult to prepare in quantity, very difficult to attach,
even to a hydroxyl group, and resistant to cleavage.8 In
this paper, we discuss a silyl protecting group which is
intermediate between tri-tert-butyl and the more useful
TBS, TIPS, and TBDPS groups, specifically the di-tert-
butylisobutylsilyl group (BIBS).
BIBS triflate (BIBSOTf, 3) was readily prepared from inex-
pensive isobutyltrichlorosilane (1)9 ona20gscale(Scheme1).
Isobutyltrichlorosilane (2) was treated with 2 equiv of tert-
BuLi in heptane at 23 °C. Another equivalent of tert-BuLi in
heptane was added, and the mixture was heated at reflux to
form the BIBSH (2) by hydride transfer. This silane was then
converted to BIBSOTf (3)10 by reaction with 1 equiv of triflic
acid at 23 °C (70% overall yield for two steps).
(1) For reviews, see: (a) Wuts, P. G. M.; Greene, T. W. Greene’s
Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: New
York, 2007. (b) Kocienski, P. Protecting Groups, 3rd ed.; Thieme: Stuttgart,
2005. (c) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(2) (a) Sweeley, C. C.; Bentley, R.; Makita, M.; Wells, W. W. J. Am.
Chem. Soc. 1963, 85, 2497. (b) Corey, E. J.; Snider, B. B. J. Am. Chem.
Soc. 1972, 94, 2549.
(3) Corey, E. J.; Varma, R. K. J. Am. Chem. Soc. 1971, 93, 7319.
(4) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(5) (a) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron
Lett. 1981, 22, 3455. (b) Rucker, C. Chem. Rev. 1995, 95, 1009.
(6) (a) Hannessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
(b) Hannessian, S.; Lavallee, P. Can. J. Chem. 1977, 55, 562.
(7) For triphenylsilyl (TPS), see: (a) Barker, S. A.; Brimacombe, J. S.;
Jarvis, J. A.; Harnden, M. R. J. Chem. Soc. 1963, 3403. For triethylsilyl
(TES), see: (b) Hart, T. W.; Metcalfe, D. A.; Scheinmann, F. J. Chem.
Soc., Chem. Commun. 1979, 156. For di-tert-butylmethylsilyl (DTBMS),
see: (c) Bhide, R. S.; Levison, B. S.; Sharma, R. B.; Ghosh, S.; Salomon,
R. G. Tetrahedron Lett. 1986, 27, 671. For tri(trimethylsilyl)silyl
(TTMSS), see: (d) Brook, M. A.; Gottardo, C.; Balduzzi, S.; Mohamed,
M. Tetrahedron Lett. 1997, 38, 6997. For di-tert-butylcyclohexylsilyl, di-
tert-butylcyclopentyl, di-tert-butyl-sec-butylsilyl, see: (e) Kumarathasan,
R.; Boudjouk, P. Tetrahedron Lett. 1990, 31, 3987.
The BIBS group can be especially useful for protecting
acidic hydroxyl groups, for example, phenols, because
(8) For tri-tert-butylsilyl, see: (a) Dexheimer, E. M.; Spialter, L.
Tetrahedron Lett. 1975, 16, 1771. (b) Weidenbruch, M.; Peter, W.
Angew. Chem., Int. Ed. Engl. 1975, 14, 642. (c) Doyle, M. P.; West,
C. T. J. Am. Chem. Soc. 1975, 97, 3777.
(9) Isobutyltrichlorosilane: $35/100 g from Gelest, Inc.
(10) BIBSOTf is a colorless nonfuming liquid, MW 348.14, density
1.25 g/mL at 23 °C, bp 91À93 °C/2 mmHg.
r
10.1021/ol201640y
Published on Web 07/11/2011
2011 American Chemical Society

Table 1. Rates of Hydrolysis of a Series of 4-Nitrophenyl Silyl
Ethers
Scheme 1. Preparation of BIBSH and BIBSOTf
R3Si
t1/2 (min)a
relative rateb
t-Bu2-i-Bu
t-Bu2-n-Bu
t-Bu2-Me
i-Pr3
1096
189
1.0
5.26
28.7
0.75
0.09
34.6
1316
10526
t-Bu-Me2
a Rates measured spectrophotometrically using 4-nitrophenolate (8)
absorption at 403 nm. b Ea for hydrolysis of the BIBS ether was measured
as 18.4 kcal/mol by rate studies over a range of temperatures.
such BIBS ethers are much more stable than the TBS,
TIPS, or TBDPS counterparts. We found that phenol
BIBS ethers can be obtained in high yields, but that the
rates of formation vary considerably depending on the
acidity of the phenol. For example, 4-nitrophenol can be
converted in 97% yield to the BIBS ether in CH2Cl2/Et3N
at 23 °C in 1 h, but the corresponding reaction with phenol
itself is very slow and requires the use of the potassium salt
in THFatreflux for>12 h. Theorder of silylationreaction
rates for a series of phenols with BIBSOTf was found to be
4-NO2-C6H4 > 4-CO2Me-C6H4 > 4-Br or 4-I-C6H4 >
C6H5. The muchfaster reaction ratewith 4-nitrophenoxide
may be due to the availability of a reaction pathway via
solvent-separated ions rather than contact ion pairs. We
were not able to find evidence of a special electron transfer
pathway using 2-allyl-4-nitrophenol as probe (Scheme 2).
The only reaction product in the silylation reaction with
BIBSOTf was the normal silyl ether 5, and none of the
phenoxy radical trapping product 6 was detected.
the BIBS group also provides steric bulk which can assist in
the direction of aromatic substitution, as shown by the
examples in Scheme 3. The efficient position-selective in-
dium-promoted cationic polycyclization of a phenolic BIBS
ether 11 was recently reported from this laboratory.11
Scheme 3. Examples of Phenolic BIBS Ethers
Scheme 2. Probe for a Phenoxy Radical Pathway
The BIBS ether of 2-bromophenol (13) was obtained in
crystalline form and subjected to single crystal X-ray
diffraction analysis, which yielded the structure shown in
Figure1. Inthisstructure, a gearing effect ofseveral methyl
groups in the BIBS subunit is evident as well as strong
steric shielding not only around the silicon atom but also of
the attached oxygen.
Carboxylic acids are readily transformed into the corre-
sponding BIBS esters simply and cleanly by stirring with
1.5 equiv of Et3N and 1 equiv of BIBSOTf at room
temperature in CH2Cl2 solution for ca. 5 h. BIBS esters
are unusually stable for silyl esters and can be chromato-
graphed on silica gel. In ethereal solution, they are un-
changed by washing with water at pH 3À9. Cleavage of the
BIBS esters to the corresponding carboxylic acids can be
The BIBS ethers of phenolsare readily cleaved tothe free
phenols by treatment with n-Bu4NF in THF. They are
promising as synthetic intermediates because they are
stable to silica gel column chromatography or to rapid
washing with cold water at pH 3À9. They can also be
cleaved in aqueous hydroxide solutions, but they are
considerably more stable than other silyl ethers. We have
measured the rates of hydrolysis of a series of 4-nitrophe-
nol silyl ethers 7 in aqueous THF with the results that are
summarized in Table 1.
The much greater stability of the BIBS ether 7 relative to
the TBS or TIPS ethers provides guidance for applications
in multistep synthesis. Protection of a phenolic oxygen by
(11) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2011, 133, 9724.
Org. Lett., Vol. 13, No. 15, 2011
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Scheme 5. Preparation of BIBS Enol Ethers
Figure 1. X-ray structure of (2-bromophenoxy) di-tert-
butylisobutylsilane.
effected by 1 M LiOH in 1:1 THF/H2O at room tempera-
ture or n-Bu4NF in THF.
The silylation of primary and secondary hydroxyl
groups by BIBSOTf (1.7 equiv) and Et3N (3 equiv) can
be accomplished generally but requires heating to 65 °C in
1,4-dioxane for ca. 48 h using an initial concentration of
the alcohol of 1 M. Some representative examples of such
protection reactions are shown in Scheme 4. Deprotection
occurs upon treatment with n-Bu4NF in THF.
in CH2Cl2 at room temperature.12 A number of examples
are provided in Scheme 6. In contrast, secondary amines
do not react under these conditions. These primary amines
can be protected in the presence of secondary amines using
the BIBSOTf-Et3N reagent;a potentially useful device in
synthesis. Deprotection ofBIBS primary amine derivatives
occurs upon treatment with HF/pyridine reagent in THF
at 23 °C for 30 min.
Scheme 4. BIBS Ethers of Alcohols
Scheme 6. BIBS as a Protecting Group for Primary Amines
We also report that BIBSOTf is useful for the conversion
of a variety of methyl ketones to 1-alkenyl-2-BIBS ethers
(i.e., terminal enol ethers; see 22 f 23) with excellent
selectivity. The optimum conditions for effecting this reaction
involve the successive addition of 1.5 equiv of potassium
hexamethyldisilazane to 1 equiv of ketone in THF solution at
À78 °C, followed by 2 equiv of BIBSOTf and 4 equiv of
Et3N. The vinyl silyl ethers shown in Scheme 5 were prepared
selectively in this way. This method also allowed the selective
synthesis of a group of cyclic vinyl enol BIBS ethers.
Secondary amines can be protected as BIBS carbamates
by the reagent combination BIBSOTf, Et3N, and CO2
(1 atm) at room temperature, as indicated in Scheme 7.13
The deprotection of BIBS carbamates of general formula
R1R2NCO2BIBS occurs in high yield by reaction with n-
Bu4NF in THF at 23 °C for 1 h.
Primary amino groups 29 can be protected as N-mono-
BIBS derivatives 30 by treatment with BIBSOTf and Et3N
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Org. Lett., Vol. 13, No. 15, 2011

Scheme 7. Protection of Secondary Amines by BIBSOTf/CO2
Scheme 8. Chemoselectivity
We also report on a number of other interesting cases of
selectivity that havebeenachieved withthe BIBSOTf-Et3N
reagent at 23 °C in CH2Cl2. The structures of the
monosilylated BIBS derivatives that have been prepared
selectively are shown in Scheme 8. In this collection are
instances of clean discrimination between two nitrogen
functions, two oxygen functions and an amino and a
hydroxyl group. In the case of example 48, only low
selectivity was found when TIPSOTf was used instead of
BIBSOTf.
chemical synthesis. It offers significant opportunities for
the more robust protection of various groups and for
enhanced selectivity.
Acknowledgment. We thank Dr. Gerald L. Larson of
Gelest, Inc. for scaling up the preparation of BIBSOTf and
for making it available commercially. H.L. is the recipient
of NSERC postdoctoral fellowship. L.H. is grateful for a
grant from East China JiaoTong University.
In conclusion, the new reagent BIBSOTf provides many
possibilities for the protection of functional groups in
(12) For other N-silyl protection groups, see: (a) Pratt, J. R.; Massey,
W. D.; Pinkerton, F. H.; Thames, S. F. J. Org. Chem. 1975, 40, 1090.
(b) Smith, A. B.; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957. For other silyl-based nitrogen protecting
groups, see: (c) Overman, L. E.; Okazaki, M. E.; Mishra, P. Tetrahedron
Lett. 1986, 27, 4391. (d) Djuric, S.; Venit, J.; Magnus, P. Tetrahedron
Lett. 1981, 22, 1787.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Lipshutz, B. H.; Papa, P.; Keith, J. M. J. Org. Chem. 1999, 64,
3792.
Org. Lett., Vol. 13, No. 15, 2011
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