A Convenient Method for the Removal of Tetrabutylammonium

Salts from Desilylation Reactions

Luca McDermott, Dominick C. Witkowski, and Neil K. Garg*1

Department of Chemistry and Biochemistry, University of California, Los
Angeles, California 90095, United States

Philipp Spieß, Daniel Kaiser and Nuno Maulide

OTBS OH
i. TBAF, THF, 23 °C

Br ii. DOWEX 50WX8 200–400 mesh Br

CaCO3, MeOH, 23 °C
1 2

Procedure (Note 1)

4-Bromophenol (2). A single-necked (24/40 joint) 250 mL round-bottomed

flask is equipped with a Teflon-coated magnetic stir bar (3.0 x 1.5 cm, football-
shaped). The apparatus is flame-dried under reduced pressure and cooled to
23 °C under an atmosphere of nitrogen. The flask is then equipped with a
rubber septum and then placed under positive pressure of nitrogen using a
nitrogen inlet. To the flask is then added (4-bromophenol)(tert-
butyl)dimethylsilane (1) (4.5 g, 3.8 mL, 16 mmol, 1.0 equiv) (Note 2) via
syringe. Then, dry THF (30 mL) (Note 3) is added at 23 °C to the flask via
syringe and stirring is started (300 rpm). After one min of stirring,
tetrabutylammonium fluoride solution (19 mL, 1.0 M in THF, 19 mmol,
1.2 equiv) (Note 4) is added via syringe dropwise over five min (Figure 1A).
The reaction mixture is then allowed to stir (300 rpm) at 23 °C for 30 min
(Note 5). Then, the rubber septum is removed, and calcium carbonate (8.2 g,
82 mmol, 5.3 equiv) (Note 6) is added in one portion followed by Dowex
50WX8, 200–400 mesh, ion exchange resin (24 g) (Note 7) in two equal
portions using a funnel to assist with the addition. To the reaction mixture is
then added methanol (60 mL) (Figure 1B) (Note 8), the rubber septum is

Org. Synth. 2022, 99, 53-67 53 Published on the Web 05/09/2022

DOI: 10.15227/orgsyn.099.0053 Ó 2022 Organic Syntheses, Inc
replaced, including the nitrogen inlet, and the suspension is stirred for 1 h at
23 °C (900 rpm).

Figure 1. A) Reaction setup after addition of TBAF; B) Reaction setup

after addition of DOWEX ion-exchange resin

The resulting mixture is then filtered through a wetted celite pad (28 g,
wetted with methanol (100 mL)) (Note 9) (7 x 4 cm) in a 150 mL medium
porosity fritted Büchner funnel into a 1 L round-bottomed flask (24/40 joint)
(Figure 2) using methanol (300 mL) as the eluent (Note 10).

Org. Synth. 2022, 99, 53-67 54 DOI: 10.15227/orgsyn.099.0053

 Figure 2. Filtration apparatus

The filtrate is then concentrated by rotary evaporation (30 °C, 150 mmHg
to 15 mmHg) under reduced pressure to yield a biphasic mixture of a
colorless liquid and a yellow liquid.
The 1 L round-bottomed flask is then charged with silica gel (10.0 g)
(Note 11). The crude material and silica gel are suspended in methylene
chloride (60 mL) (Note 12) and concentrated under reduced pressure (30 °C,
375 mmHg to 22 mmHg) until a fine powder results. The product-adsorbed
silica is then added to a column (7 cm OD x 20 cm tall) which is prepared
using silica gel (165 g) that is wetted with pentane (500 mL) (Notes 13 and 14)
(Figure 3A, 3B). The column is then eluted with 19:1 pentane:diethyl ether
(2 L) (Note 15), followed by 9:1 pentane:diethyl ether (1 L), followed by 4:1
pentane:diethyl ether (1 L).

Org. Synth. 2022, 99, 53-67 55 DOI: 10.15227/orgsyn.099.0053

 Figure 3. A) Product adsorbed silica gel; B) Column setup

The product is collected in 55 mL culture tubes, and the desired product

elutes in fractions 35–66 (Note 16). These fractions are pooled and
concentrated under reduced pressure (30 °C, 300 mmHg to 22 mmHg). The
resulting yellow oil is then transferred to an 8-dram vial using diethyl ether
and concentrated under reduced pressure (30 °C, 300 mmHg to 22 mmHg).
Then, the resulting oil is dried under high vacuum at 23 °C for 18 h (Note 17)
to yield a crystalline white solid (2.44 g, 88% yield, 98% purity) (Notes 18, 19,
20, and 21).

Org. Synth. 2022, 99, 53-67 56 DOI: 10.15227/orgsyn.099.0053

 Figure 4. Isolated 4-bromophenol (2)

Notes

1. Prior to performing each reaction, a thorough hazard analysis and risk

assessment should be carried out with regard to each chemical substance
and experimental operation on the scale planned and in the context of the
laboratory where the procedures will be carried out. Guidelines for
carrying out risk assessments and for analyzing the hazards associated
with chemicals can be found in references such as Chapter 4 of “Prudent
Practices in the Laboratory" (The National Academies Press, Washington,
D.C., 2011; the full text can be accessed free of charge at
https://www.nap.edu/catalog/12654/prudent-practices-in-the-
laboratory-handling-and-management-of-chemical. See also
“Identifying and Evaluating Hazards in Research Laboratories”
(American Chemical Society, 2015) which is available via the associated
website “Hazard Assessment in Research Laboratories” at
https://www.acs.org/content/acs/en/about/governance/committees
/chemicalsafety/hazard-assessment.html. In the case of this procedure,
the risk assessment should include (but not necessarily be limited to) an

Org. Synth. 2022, 99, 53-67 57 DOI: 10.15227/orgsyn.099.0053

 evaluation of the potential hazards associated with(4-bromophenol)(tert-
butyl)dimethylsilane, tetrahydrofuran, tetrabutylammonium fluoride
solution, calcium carbonate, Dowex 50WX8, 200–400 mesh, ion exchange
resin, methanol, silica gel, methylene chloride, pentane, diethyl ether,
hexanes, EtOAc, Celite, CDCl3, and 1,3,5 trimethoxybenzene.
2. 4-Bromophenol)(tert-butyl)dimethylsilane (> 97%) was purchased from
Sigma-Aldrich corp. and used as received.
3. Tetrahydrofuran (1.0 M in THF) (> 99.9%) was purchased from Fisher
Scientific and used as received. The submitters passed it through an
activated alumina column before use.
4. Tetrabutylammonium fluoride (1 M solution in THF) was purchased
from Sigma-Aldrich corp. and used as received.
5. The progress of the reaction is monitored via TLC analysis on silica gel
with 9:1 hexanes:EtOAc used as the eluent. Hexanes (>98.5%) and EtOAc
(98.5%) were purchased from Fisher Scientific and used as received. The
plate is visualized using a UV lamp (254 nm).

Figure 5. TLC of the crude reaction mixture after 30 minutes. SM =

starting material (starting material Rf: 0.8), CS = co-spot of starting
material and reaction mixture, RXN = reaction mixture (product Rf: 0.2)

Org. Synth. 2022, 99, 53-67 58 DOI: 10.15227/orgsyn.099.0053

6. Calcium carbonate (> 99%) was purchased from Fisher Scientific and
used as received.
7. DOWEX 50WX8 200–400 mesh ion exchange resin was purchased from
Sigma-Aldrich corp. and used as received.
8. Methanol (> 99.8%) was purchased from Fisher Scientific and used as
received.
9. Celite was purchased from Fisher Scientific and used as received.
10. The reaction flask was rinsed three times with methanol (100 mL) to
achieve a quantitative transfer of the contents of the reaction flask
through the celite pad.
11. SiliaFlask P60 (particle size 0.040–0.063 nm) was purchased from
SiliCycle and used as received.
12. Methylene chloride (> 99.5%) was purchased from Fisher Scientific and
used as received.
13. Pentane (98%) was purchased from Honeywell and used as received. The
submitters used hexanes instead of pentane.
14. To assist with quantitative transfer of product-adsorbed silica onto
column, sand is added to the round-bottomed flask and swirled to
remove the silica from the side of the flask. This sand is then added to the
column after the product-adsorbed silica.
15. Diethyl ether (> 99%) was purchased from Fisher Scientific and used as
received.
16. Fractions containing the product were identified by TLC analysis using
9:1 hexanes:EtOAc as the eluent where 2 has an Rf of 0.20. Fractions 35–
66 contained the desired product, and each fraction is rinsed with Et2O
(2 x 1 mL) to ensure quantitative transfer.

Org. Synth. 2022, 99, 53-67 59 DOI: 10.15227/orgsyn.099.0053

 Figure 6. TLC analysis of column fractions

17. Prior to drying at 23 °C, the submitters submerged the dram vial
containing the oil in a dry ice-acetone bath (–78 °C) and dried under high
vacuum (<1 mmHg) for 1 h. The checkers omitted this step and obtained
the same result.
18. To assist with crystallization, crystals on the side of the vial can be placed
in the oil, either by tilting the vial such that the crystals fall into the oil,
or by scraping them into the oil with a spatula. The submitters observed
significantly delayed crystallization that was assisted by brief additional
cooling (–196 °C liquid nitrogen for ~30 sec) after drying.
19. The product can be characterized as follows: 1H NMR (400 MHz, CDCl3)
δ: 7.32 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 5.21 (s, 1H); 13C NMR
(101 MHz, CDCl3) δ: 154.48, 132.63, 117.33, 113.16.; IR (film): 3334, 1487,
1217, 824 cm-1; HRMS-ESI (m/z) [M-H] calcd for C6H4OBr, 170.9451;
found, 170.9451; mp 61–63 °C; Rf 0.20 (9:1 hexanes:EtOAc).
20. A second run on half scale was performed, affording 1.29 g of 2 (94%
yield, 98% purity). The submitters obtained 2.52 g (93% yield, >97%
purity) and 2.37 g (87% yield, >97% purity) of 2 in two separate full-scale
runs.

Org. Synth. 2022, 99, 53-67 60 DOI: 10.15227/orgsyn.099.0053

21. The purity of 2 was determined by qNMR in all cases, using
1,3,5 trimethoxybenzene (Sigma-Aldrich, >99.9%) as the external
standard.

Working with Hazardous Chemicals

The procedures in Organic Syntheses are intended for use only by persons
with proper training in experimental organic chemistry. All hazardous
materials should be handled using the standard procedures for work with
chemicals described in references such as "Prudent Practices in the
Laboratory" (The National Academies Press, Washington, D.C., 2011; the full
text can be accessed free of charge at
http://www.nap.edu/catalog.php?record_id=12654). All chemical waste
should be disposed of in accordance with local regulations. For general
guidelines for the management of chemical waste, see Chapter 8 of Prudent
Practices.
In some articles in Organic Syntheses, chemical-specific hazards are
highlighted in red “Caution Notes” within a procedure. It is important to
recognize that the absence of a caution note does not imply that no significant
hazards are associated with the chemicals involved in that procedure. Prior
to performing a reaction, a thorough risk assessment should be carried out
that includes a review of the potential hazards associated with each chemical
and experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards
associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published
and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and
its Board of Directors do not warrant or guarantee the safety of individuals
using these procedures and hereby disclaim any liability for any injuries or
damages claimed to have resulted from or related in any way to the
procedures herein.

Discussion

Silicon-based protecting groups are commonplace in synthetic routes

to complex organic molecules.2 Their ability to be introduced under mild

Org. Synth. 2022, 99, 53-67 61 DOI: 10.15227/orgsyn.099.0053

conditions, as well as their stability toward harsh reaction conditions, has
made them a widespread tool in organic synthesis. Small silyl protecting
groups, such as the trimethylsilyl group, can be removed under basic or
acidic conditions, but larger silyl protecting groups are generally removed
under fluoride-mediated conditions. One especially useful reagent for the
removal of silyl protecting groups is tetrabutylammonium fluoride (TBAF).3
The solubility of this reagent in organic solvents, as well as its
chemoselectivity, has contributed to its frequent usage in the removal of silyl
protecting groups. On simple systems, where the products are relatively non-
polar, TBAF is easily removed via an aqueous workup. For more polar
products, however, an aqueous workup can result in loss of material to the
aqueous layer or challenging separations.
An attractive alternative protocol for the removal of residual TBAF
was reported by Kishi and co-workers in 2007.4 In this study, removal of these
byproducts was achieved without an aqueous extraction, and applied in the
total synthesis of Halichondrin B. In particular, it was discovered that the
addition of a 50WX8 ion-exchange resin in combination with a mild base,
such as calcium carbonate, was effective in sequestering cationic byproducts,
such as tetrabutylammonium, from reaction mixtures. The proposed
mechanism for this methodology is delineated in Figure 7. First, the
tetrabutylammonium cation exchanges with a proton on the ion-exchange
resin. This equilibrium process is then driven forward by calcium carbonate,
which reacts with HF to form calcium fluoride, water, and carbon dioxide.
After addition of the ion-exchange resin and calcium carbonate, the reaction
mixture can be filtered to provide the desired product. This convenient and
effective procedure removes undesired TBAF-related byproducts and
obviates the need for aqueous extraction.

SO3H + (n-Bu)4N F
DOWEX Residual TBAF Byproducts easily
50WX8 resin removed by
filtration and
evaporation

CaCO3 CaF2
SO3(n-Bu)4N + HF
CO2 + H2O
Figure 7. Mechanism of TBAF removal by DOWEX 50WX8 resin

Org. Synth. 2022, 99, 53-67 62 DOI: 10.15227/orgsyn.099.0053

 The Kishi group explored the utility of this methodology in the syntheses
of several alcohol products (Figure 8). It was observed that carbohydrates,
such as 3, could be isolated from their respective tert-butyl silyl (TBS)-
protected precursors. Furthermore, diols such as 4 and 5 could also be
isolated from the corresponding silyl alcohols using this methodology.

O OMe OH
HO OH
OH
HO OH
OH
OH
3 4 5
Figure 8. Examples of desilylated alcohol products accessed using the
DOWEX 50WX8 resin method

This strategy was also employed in the total synthesis of complex, highly
polar natural products (Figure 9). For example, penta-ol 6 was accessed in
near quantitative yield and served as a key late-stage intermediate in Kishi’s
total synthesis of halichondrin B.4 The natural product alloviroidin (7) was
also isolated following the removal of five TBS groups in the final step of the
total synthesis,5 and tri-ol intermediate 8 was accessed using this
methodology en route to etnangien.6 Finally, tetra-ol 9 was isolated and
further derivitized en route to zincophorin methyl ester.7 Our group has also
found this methodology to be useful for removing TBAF related byproducts
from polar intermediates during total synthesis campaigns. Overall, the ion-
exchange resin strategy for the removal of TBAF related byproducts has
shown to be a convenient and effective workaround to challenges
encountered in the desilylation of alcohols and purification of the resultant
polar products.

Org. Synth. 2022, 99, 53-67 63 DOI: 10.15227/orgsyn.099.0053

 SO2Me
Me HN HO
H OH
HO O O Me
H H
O O N
HO O O HN
H H H NH
OH Me O Me
O HO O O
OH HN O O Me
Me O O NH
O HO
N NH Me
O
HO
HO HO
6 7
intermediate en route alloviroidin
to halichondrin B

Me Me I
Me Me Me
O OH OH OH OH
MeO2C
O O Me O
Me Me H H
Me Me Me Me
O OH
Me
OH
Me Me Me
OMe OH
8 9
intermediate en route intermediate en route to
to etnangien zincophorin methyl ester
Figure 9. Complex late-stage alcohol intermediates and natural products
accessed using the DOWEX 50WX8 resin method. Alcohols highlighted in
pink were revealed using this method.

Herein, we demonstrate the use of this resin to remove TBAF following

the multi-gram scale deprotection of a TBS-protected phenol. In this
procedure, no aqueous workup was required, and 1H NMR analysis of the
crude material showed complete removal of TBAF. Indeed, the only
impurities that remain after ion-exchange resin workup are derived from the
silyl protecting groups. In some cases, such byproducts can be removed
simply by evaporation under vacuum. However, on this scale, we observed
that column chromatography followed by vacuum evaporation is required to
remove all of the silyl byproducts. Overall reaction time, including both
desilylation and treatment with DOWEX resin, was less than 2 hours, and

Org. Synth. 2022, 99, 53-67 64 DOI: 10.15227/orgsyn.099.0053

near quantitative yield of the desired product was observed. This simple
procedure provides an attractive solution for the purification of highly polar
molecules following removal of silyl protecting groups with TBAF.

References

1. Department of Chemistry and Biochemistry, University of California,

Los Angeles, California 90095, United States. E-mail:
neilgarg@chem.ucla.edu. ORCID 0000-0002-7793-2629. The authors are
grateful to the University of California, Los Angeles. These studies were
also supported by shared instrumentation grants from the NSF
(CHE1048804) and the National Center for Research Resources
(S10RR025631).
2. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons: New Jersey, 2007. pp 165–221.
3. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190–6191.
4. Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723–726.
5. Taylor, C. M.; Kutty, S. K.; Edagwa, B. J. Org. Lett. 2019, 21, 2281–2284.
6. Li, P.; Li, J.; Arkian, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org.
Chem. 2010, 75, 2429–2444.
7. Godin, F.; Mochirian, P.; St-Pierre, G.; Guindon, Y. Tetrahedron 2015, 71,
709–726.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

4-Bromophenol)(tert-butyl)dimethylsilane; (67963-68-2)
Tetrabutylammonium fluoride solution 1.0 M in THF; (429-41-4)
Calcium carbonate; (471-34-1)
DOWEX 50WX8, 200-400 mesh, ion exchange resin; (69011-20-7)

Org. Synth. 2022, 99, 53-67 65 DOI: 10.15227/orgsyn.099.0053

 Luca McDermott was born and raised in San
Francisco, CA. In 2020, he received his B.S. in
Biochemistry from Tufts University where he
carried out research under the direction of
Professor Clay S. Bennett. In 2020 he began
graduate studies at the University of California,
Los Angeles, where he is currently a second-year
graduate student in Professor Neil K. Garg’s
laboratory. His dissertation studies are primarily
focused on total synthesis.

Dominick Witkowski was born in Portsmouth, VA

and raised in Northborough, MA. In 2020, he
received his B.A. in Chemistry from Boston
University where he carried out research under the
direction of Professor John A. Porco, Jr. He then
moved to the University of California, Los Angeles
where he is currently a second-year graduate
student in Professor Neil K. Garg’s laboratory. His
studies primarily focus on developing synthetic
methods utilizing strained cyclic allenes.

Neil Garg is a Distinguished Professor of

Chemistry and the Kenneth N. Trueblood
Endowed Chair at the University of California,
Los Angeles. His laboratory develops novel
synthetic strategies and methodologies to enable
the total synthesis of complex bioactive
molecules.

Org. Synth. 2022, 99, 53-67 66 DOI: 10.15227/orgsyn.099.0053

 Philipp Spieß conducted his B.Sc. and M.Sc.
studies at the University of Munich (LMU
Munich) and finished his M. Sc. degree with a
research stay in the group of Prof. Ruben Martin
(ICIQ, Tarragona), working on nickel catalysis. In
2020, he moved to the University of Vienna to
undertake Ph. D studies in Prof. Nuno Maulide's
laboratory. His studies primarily focus on total
synthesis and on developing new methodologies
in the area of amide activation.

Daniel Kaiser received his Ph.D. at the University

of Vienna in 2018, completing his studies under
the supervision of Prof. Nuno Maulide. After a
postdoctoral stay with Prof. Varinder K.
Aggarwal at the University of Bristol, he returned
to Vienna in 2020 to assume a position as senior
scientist in the Maulide group. His current
research focusses on the chemistry of destabilized
carbocations and related high-energy
intermediates.

Org. Synth. 2022, 99, 53-67 67 DOI: 10.15227/orgsyn.099.0053