Detritylation with ytterbium triflate

Article abstract of DOI:10.1016/S0040-4039(00)00270-7

Ytterbium triflate catalyzes the hydrolysis of tritylamines and trityloxy compounds to the corresponding amines and alcohols under mild conditions in high yields. The reactions are conducted in tetrahydrofuran in the presence of 1 equivalent of water. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00270-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2817–2819
Detritylation with ytterbium triflate
Rong Jian Lu,† Daipei Liu and Roger W. Giese ∗
Department of Pharmaceutical Sciences in Bouvé College, Barnett Institute, and Chemistry Department,
Northeastern University, Boston, MA 02115, USA
Received 8 July 1999; revised 17 January 2000; accepted 3 February 2000
Abstract
Ytterbium triflate catalyzes the hydrolysis of tritylamines and trityloxy compounds to the corresponding amines
and alcohols under mild conditions in high yields. The reactions are conducted in tetrahydrofuran in the presence
of 1 equivalent of water. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: detritylation; ytterbium triflate.
Trityl and related groups have been used extensively for N- and O-protection, where detritylation is
accomplished either with a protonic acid (e.g. HCl, CF3CO2H, CCl3CO2H) or a Lewis acid (e.g. ZnBr2,
diisopropylaluminum chloride).1–11
As part of our work on the synthesis of new electrophoric reagents, we observed that N-trityl-β-{p-
[30,50-bis(trifluoromethyl)benzyloxy]phenyl}ethylamine 1 resisted detritylation under various conditions
ordinarily effective for this purpose, such as 1N HCl in ethanol, as summarized in Table 1. However,
compounds 2–5 underwent facile detritylation under this latter condition. We speculated that the nonpolar
environment around the nitrogen in 1 might explain the aberrant behavior of this compound, since this
might make it resist N-protonation.
Accordingly, we tested compounds 6 and 7, where we considered that the major difference between
them might be that 6, possessing an o-methoxy substituent, would provide a more polar environment
around the N-trityl group. While not confirming our hypothesis (e.g. H-bond and inductive differences
may exist), the compounds did behave as anticipated, with 6 and 7 undergoing 95 and 0% detritylation,
respectively, in ethanolic 1N HCl. Compound 7 also resisted detritylation under some other conditions
known to accomplish this kind of reaction, as summarized in Table 1.
Returning to our goal of detritylating 1, we tested ytterbium triflate as a Lewis acid for this purpose,
motivated by the following three considerations: (1) the reagent is known to be a Lewis acid catalyst;12 (2)
the reagent might bring in a polar environment; and (3) Yb has a relatively small radius in the lanthanide
series.13 Indeed, when we reacted 1 at room temperature with a catalytic amount (0.15 mol equivalent) of
∗
†
Corresponding author. Tel: (617) 373-3227; fax: (617) 373-8720; e-mail: rgiese@lynx.neu.edu (R. W. Giese)
Current address: NCI-Frederick Cancer Research and Development Center, Frederick, MD, USA
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00270-7
tetl 16550

2818
Table 1
Detritylation reactionsa
Yb(OTf)3 in tetrahydrofuran containing 1 equivalent of water, the yield of detritylated product was 89%.
Since the yield dropped to 78% when europium triflate was used instead, the smaller size of ytterbium
might have helped. Also shown in Table 1 is the success of these reagents in detritylating 7, as well as
three O-trityl compounds (8, 9, 12). We also detritylated 2–5 with Yb(OTf)3 in high yields as seen.
It has been reported that ytterbium triflate is stable to water,12 which argues against a mechanism
in which the added water reacts with this reagent to produce trifluoromethanesulfonic acid as the true
catalyst. Consistent with this, there was no hydrolysis of the formylidene acetal, an acid-sensitive group,
in 12. 4-(Triisopropylsiloxy)-N-tritylpiperidine 10 was detritylated (89%) without TIPS loss, and the

2819
N-t-Boc compound 11 was stable. Nevertheless, we observed that 1 underwent 30% detritylation when
treated with triflic acid.
In summary, we have developed a mild and efficient detritylation reaction that is effective both in
general and also when applied to nonpolar compounds resistant to conventional detritylation conditions.14
Acknowledgements
This work was supported by NIH Grant CA 71993 received as a subcontract from the Harvard School
of Public Health. Contribution No. 779 from the Barnett Institute.
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14. The deprotection of compound 1 is representative of our method. To N-trityl-β-{p-[30,50-bis(trifluoromethyl)benzyl-
oxy]phenyl}ethylamine (605 mg, 1 mmol) in 5 ml THF was added 93 mg (0.15 mmol) of ytterbium triflate. After stirring at
rt for 10 min under N2, the mixture was treated with 20 µL H2O and stirred for a further 4 h. Saturated, ice-cold NaHCO3
(15 ml) was added and the combined (3×25 ml) ethyl acetate extracts were washed with brine (3×10 ml) and dried over
Na2SO4. Purification by flash chromatography with ethyl acetate:hexanes:triethyl amine (1:1:0.1) gave 323 mg (89%) of a
white solid. 1H NMR (CDCl3), δ 2.15–2.17 (2H, t, CH2), 2.74–2.78 (2H, m, CH2), 2.92 (2H, b, NH2), 5.13 (2H, s, OCH2),
6.91–7.17 (4H, q, Ar) 7.83–7.90 (3H, q, Ar).