tert-Butyldimethylsilyl ethers
TBDMS-OR, TBDMS ether, TBS-OR, TBS ether
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 127-141, 708-711.
Stability
H2O: | pH < 1, 100°C | pH = 1, RT | pH = 4, RT | pH = 9, RT | pH = 12, RT | pH > 12, 100°C |
Bases: | LDA | NEt3, Py | t-BuOK | Others: | DCC | SOCl2 |
Nucleophiles: | RLi | RMgX | RCuLi | Enolates | NH3, RNH2 | NaOCH3 |
Electrophiles: | RCOCl | RCHO | CH3I | Others: | :CCl2 | Bu3SnH |
Reduction: | H2 / Ni | H2 / Rh | Zn / HCl | Na / NH3 | LiAlH4 | NaBH4 |
Oxidation: | KMnO4 | OsO4 | CrO3 / Py | RCOOOH | I2, Br2, Cl2 | MnO2 / CH2Cl2 |
General
Trimethylsilyl ethers are too susceptible to solvolysis for them to have any utility as protecting groups. The tert-butyldimethylsilyloxy group is ca. 104 times more hydrolytically stable and holds more promise for such applications.
When the commercially available tert-butyldimethylsilyl chloride (TBDMS-Cl) was initially used as a silylation agent, it was found by E. J. Corey (J. Am. Chem. Soc. 1972, 94, 6192) to react very slowly and to give unsatisfactory yields with alcohols. Even forcing silylation techniques (excess silyl chloride, dry pyridine, elevated temperatures) were not successful. The use of 2.5 eq. imidazole with 1.2 eq. of TBDMS-Cl and dimethylformamide as solvent proved to be effective, and resulted in the mild conversion of various alcohols to tert-butyldimethylsilyl ethers in high yield.
Corey assumed, that the reaction proceeds via N-tert-butyldimethylsilylimidazole as a very reactive silylating agent:
However, newer research by P. Patschinski and H. Zipse shows, that the reaction is indeed catalyzed by DMF (J. Org. Chem. 2014, 79, 8348).
Another key discovery by E. J. Corey (J. Am. Chem. Soc. 1972, 94, 6192) was the rapid cleavage of the silyl ethers to alcohols by treatment with 2-3 eq. tetra-n-butylammonium fluoride (TBAF) in THF at 25°C.
Nucleophilic attack of the small fluoride anion leads to a pentavalent silicon centre which is permitted due to hybridisation with the vacant d-orbitals of silicon. In addition, the formation of the strong Si-F bond is the driving force for a fast cleavage:
tert-Butyldimethysilyl ethers are stable to aqueous base, but may be converted back to the alcohols under acidic conditions (2:1 acetic acid / water at 25°C).
Protection of Hydroxyl Compounds
Reactions of alcohols with silyl chlorides in the presence of N-methylimidazole
were significantly accelerated by addition of iodine. A general and high
yielding method for efficient silylation of primary, secondary, and tertiary
alcohols was developed.
A. Bartoszewicz, M. Kalek, J. Nilsson, R. Hiresova, J. Stawinski, Synlett, 2008,
37-40.
A commercially available proazaphosphatrane is an efficient and mild
catalyst for the silylation of a wide variety of alcohols and phenols,
including acid-sensitive, base-sensitive, and hindered substrates, using
tert-butyldimethylsilyl chloride (TBDMSCl). The reactions are carried
out in acetonitrile from 24 to 40°C and on rare occasions in DMF from 24 to
80°C. Although representative primary alcohols, secondary alcohols, and
phenols were silylated using the more sterically hindered reagent tert-butyldiphenylsilyl
chloride (TBDPSCl), tertiary alcohols were recovered unchanged.
B. A. D'Sa, D. McLeod, J. G. Verkade, J. Org. Chem., 1997,
62, 5057-5061.
Tris(pentafluorophenyl)borane, B(C6F5)3, is
an effective catalyst for a mild and efficient dehydrogenative silation of
alcohols using a variety of silanes. Only the most bulky silanes (Bn3SiH
and iPr3SiH) were not reactive under these conditions.
Generally, the reactions are clean and high yielding, with dihydrogen as the
only byproduct.
J. M. Blackwell, K. L. Foster, V. H. Beck, W. E. Piers, J. Org. Chem.,
1999,
64, 4887-4892.
R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F. Coelho,
Synthesis, 2005, 2297-2306.
Deprotection
Hf(OTf)4 exhibits exceptionally high potency in desilylations. Since the amounts of
Hf(OTf)4 required for the deprotection of 1°, 2°, 3° alkyl and aryl
tert-butyldimethylsilyl (TBS) ethers range from
0.05 mol% to 3 mol%, a regioselective deprotection can be achieved. A chemoselective cleavage of different silyl ethers or
removal of TBS in the presence of most hydroxyl protecting groups was also
accomplished.
X.-A. Zheng, R. Kong, H.-S. Huang, J.-Y. Wei, J.-Z. Chen, S.-S. Gong, Q. Sin, Synthesis, 2019, 51,
944-952.
Sodium tetrachloroaurate(III) dihydrate as catalyst enables a simple and mild
removal of tert-butyl(dimethyl)silyl (TBS) protecting groups. A selective
deprotection of aliphatic TBS ethers is possible in the presence of aromatic TBS
ethers, aliphatic triisopropylsilyl ethers, aliphatic tert-butyl(diphenyl)silyl
ethers, or sterically hindered aliphatic TBS ethers. Additionally, TBS ethers
can also be transformed into benzyl ethers in one pot.
Q. Zhang, X. Kang, L. Long, L. Zhu, Y. Chai, Synthesis, 2015, 47,
55-64.
TBDMS ethers can be cleaved selectively in the presence of isopropylidine, Bn,
Ac, Bz, THP, and TBDPS groups using tetrabutylammonium tribromide in methanol.
This method is high yielding, fast, clean, safe, and cost-effective.
R. Gopinath, B. K. Patel,
Org. Lett., 2000, 2, 4177-4180.
A 50% aqueous methanolic solution of Oxone selectively cleaves primary
tert-butyldimethylsilyl ethers at room temperature. This method enables
deprotection of TBDMS ethers of primary alcohols in the
presence of TBDMS ethers of secondary and tertiary
alcohols and phenols. The silyl ethers of phenols were deprotected at longer
reaction times.
G. Sabitha, M. Syamala, J. S. Yadav,
Org. Lett., 1999, 1, 1701-1703.
Various tert-butyldimethylsilyl (TBDMS) ethers as well as
tert-butyldiphenylsilyl (TBDPS) ethers can be easily deprotected by
employing a catalytic amount of acetyl chloride in dry MeOH in good yields. This
mild and convenient method tolerates various other protecting groups and does
not lead to acylated or chlorinated byproducts.
A. T. Khan, E. Mondal, Synlett, 2003, 694-698.
Catalytic quantities of fluoride at neutral pH in mixed organic-aqueous
solutions that contain buffer cleaved various silicon-oxygen bonds. These
conditions show tolerance for acid- and base-sensitive groups. A modified
procedure using catalytic fluoride in anhydrous dimethyl sulfoxide-methanol
generates primarily volatile silicon byproducts.
A. M. DiLauro, W. Seo, S. T. Phillips, J. Org. Chem., 2011,
76, 7352-7358.
Various tert-butyldimethylsilyl ethers are easily removed in excellent
yields by treatment with a catalytic amount of N-iodosuccinimide in
methanol. This method allows a selective deprotection of TBDMS ethers of
alcohols in the presence of TBDMS ethers of phenols.
B. Karimi, A. Zamani, D. Zarayee, Tetrahedron Lett., 2004,
45, 9139-9141.
PMA supported on SiO2 is found to be an efficient catalyst for the
chemoselective, mild deprotection of TBDMS ethers. Various labile functional
groups such as isopropylidene acetal, OTBDPS, OTHP, Oallyl, OBn, alkene, alkyne,
OAc, OBz, N-Boc, N-Cbz, N-Fmoc, mesylate, and azide are
tolerated. The supported catalyst and the solvent can be readily recovered and
recycled.
G.D. K. Kumar, S. Baskaran, J. Org. Chem., 2005,
70, 4520-4523.
A chemoselective, efficient and operationally simple desilylation of O-tert-butyldimethylsilyl
ethers was achieved using chlorotrimethylsilane and potassium fluoride dihydrate
in acetonitrile.
Y. Peng, W.-D. Z. Li, Synlett,
2006, 1165-1168.
tert-Butyldimethylsilyl (TBDMS) ethers of primary, secondary, and
tertiary alcohols and phenolic TBDMS ethers are desilylated to their
corresponding alcohols and phenols, respectively, in DMSO, at 80°C, in very good
yield in the presence of P(MeNCH2CH2)3N as
catalyst. Desilylations of tert-butyldiphenylsilyl (TBDPS) ethers were
much less effective.
Z. Yu, J. G. Verkade, J. Org. Chem., 2000,
65, 2065-2068.
A microwave-assisted, chemoselective and efficient method for the cleavage of
silyl ethers is catalyzed by Selectfluor. A wide range of TBDMS-, TIPS-, and
TBDPS-protected alkyl silyl ethers can be chemoselectively cleaved in high yield
in the presence of aryl silyl ethers. In addition, the transetherification and
etherification of benzylic hydroxy groups in alcoholic solvents is observed.
S. T. A. Shah, S. Singh, P. J. Guiry, J. Org. Chem., 2009,
74, 2179-2182.
TBDMS ethers of various phenols have been deprotected at room temperature with
KHF2 in MeOH. Carboxylic esters, labile phenolic acetates and TBDMS
ethers of benzylic alcohols were unaffected under these conditions.
M. K. Lakshman, F. A. Tine, T. A. Khandaker, V. Basava, N. B. Agyemang, M. S. A.
Benavidez, M. Gaši, L. Guerrera, B. Zajc,
Synlett, 2017, 28, 381-385.
An efficient and chemoselective protocol using LiOAc as a bifunctional Lewis
acid-Lewis base catalyst allows the selective deprotection of aryl silyl ethers
in the presence of acetates, epoxides, and aliphatic silyl ethers.
B. Wang, H.-X. Sun, Z.-H. Sun, J. Org. Chem., 2009,
74, 1781-1784.
With either 1.0 or 0.10 equivalent of DBU, smooth desilylation of various
aryl silyl ethers was accomplished selectively in the presence of base-sensitive
groups such esters and alkyl silyl ethers. A direct transformation of aryl silyl
ethers into biaryl ethers was possible through tandem desilylation and SNAr
reaction with activated aryl fluorides.
C.-E. Yeom, H. W. Kim, S. Y. Lee, B. M. Kim, Synlett, 2007,
146-150.
Conversion of TBDMS Ethers to Other Functional Groups
A sequential one-pot synthesis for the oxidation of primary and secondary
tert-butyldimethylsilyl (TBDMS) ethers, using the presence of PhIO or
PhI(OAc)2 and catalytic amounts of metal triflates and TEMPO in THF
or acetonitrile tolerates acid-sensitive protecting groups and leaves tert-butyldiphenylsilyl
ethers and phenolic TBDMS groups untouched.
B. Barnych, J.-M. Vatèle, Synlett, 2011,
2048-2052.
Benzyl alcohols and benzyl TBDMS ethers were efficiently oxidized to the
corresponding carbonyl compounds in high yield with periodic acid catalyzed by
CrO3 at low temperature (-78 °C). The oxidation procedure was highly
functional group tolerant and very selective for the TBDMS group over the TBDPS
group.
S. Zhang, L. Xu, M. L. Trudell, Synthesis, 2005, 1757-1760.
Various silyl ethers were readily and efficiently transformed into the
corresponding alkyl ethers in high yields by the use of aldehydes combined with
triethylsilane in the presence of a catalytic amount of iron(III) chloride.
K. Iwanami, K. Yano, T. Oriyama,
Synthesis, 2005, 2669-2672.
A mild and efficient interconversion from silyl ethers to sulfonates esters
proceeds readily in acetonitrile at room temperature in the presence of p-toluenesulfonyl
fluoride and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7ene (DBU). This
method can be used with trimethysilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl
(TBDMS) ethers.
V. Gembus, F. Marsais, V. Levacher, Synlett, 2008,
1463-1466.
With either 1.0 or 0.10 equivalent of DBU, smooth desilylation of various
aryl silyl ethers was accomplished selectively in the presence of base-sensitive
groups such esters and alkyl silyl ethers. A direct transformation of aryl silyl
ethers into biaryl ethers was possible through tandem desilylation and SNAr
reaction with activated aryl fluorides.
C.-E. Yeom, H. W. Kim, S. Y. Lee, B. M. Kim, Synlett, 2007,
146-150.
TBDMS-Protected Hydroxyl Groups in Multi-step Syntheses
Selective hydrogenation conditions of olefin, benzyl ether and acetylene
functionalities in the presence of TBDMS or TES ether have been developed.
H. Sajiki, T. Ikawa, K. Hattori, K. Hirota, Chem. Commun., 2003,
654-655.
R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F. Coelho,
Synthesis, 2005, 2297-2306.
R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F. Coelho,
Synthesis, 2005, 2297-2306.