The para-siletanylbenzyl (PSB) ether: A peroxide-cleavable protecting group for alcohols and phenols

Article abstract of DOI:10.1016/j.tetlet.2005.03.110

A novel arylmethyl protecting group that is electronically similar to benzyl (Bn) but that can be cleaved under mild oxidizing conditions in the presence of para-methoxybenzyl (PMB) is described herein. para-Siletanylbenzyl (PSB) ethers are formed in one or two steps from the corresponding alcohols and cleaved in one or two steps with basic peroxide. Alcohols and phenols have been protected in good yields and deprotected cleanly under mild oxidative conditions.

Full text of DOI:10.1016/j.tetlet.2005.03.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3283–3285
The para-siletanylbenzyl (PSB) ether:
a peroxide-cleavable protecting group for alcohols and phenols
Hubert Lam, Sarah E. House and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA
Received 9 March 2005; accepted 16 March 2005
Available online 5 April 2005
Abstract—A novel arylmethyl protecting group that is electronically similar to benzyl (Bn) but that can be cleaved under mild oxi-
dizing conditions in the presence of para-methoxybenzyl (PMB) is described herein. para-Siletanylbenzyl (PSB) ethers are formed in
one or two steps from the corresponding alcohols and cleaved in one or two steps with basic peroxide. Alcohols and phenols have
been protected in good yields and deprotected cleanly under mild oxidative conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
The complexities of natural product synthesis and of the
rapidly developing field of carbohydrate synthesis create
a demand for chemically differentiable protecting groups
(PGs) for vulnerable functionality. Benzyl ethers are
among the most popular alcohol PGs due to their ease
of formation, stability to a wide range of reaction condi-
tions, and mild cleavage protocols. Modified arylmethyl
PGs have been tailored for use in more complex
systems.1
We recently reported that aryl-siletanes (silacyclo-
butanes) react with hydrogen peroxide under mild
conditions to afford phenols.6 The oxidation reaction
(silylarene!phenol) dramatically increases the oxida-
tion potential (electron density) of the arene ring.
Seeking to take advantage of this change, we set out to
develop a new arylmethyl PG for alcohols, the cleavage
of which would be triggered by hydrogen peroxide. Un-
like masked PHB ethers,2 latent PHB ethers offer greater
promise in terms of orthogonality with a range of other
common PGs. For example, revealing the PHB interme-
diate does not involve cleavage of a different protecting
group.
Several arylmethyl PGs are cleaved by initial transfor-
mation into a para-hydroxybenzyl (PHB) ether. Jobron
and Hindsgaul first reported the use of O-protected 4-O-
benzyl PGs for carbohydrate chemistry.2 Removal of
the arene 4-O-PG3 under the appropriate conditions re-
veals the PHB ether, which is then easily hydrolyzed.
Cross-coupling of para-bromobenzyl (PBB) ethers pro-
vides a similar effect: palladium-catalyzed amination of
the PBB group yields a labile para-aminobenzyl ether,4
whereas palladium-catalyzed borylation of PBB fol-
lowed by oxidation afforded a PHB ether in a synthetic
approach to ciguatoxin.5
This letter describes preliminary results on the synthesis
and applications of a siletane-substituted benzyl PG for
alcohols and phenols (Scheme 1). para-Siletanylbenzyl
(PSB) derivatives 1a and b were prepared from commer-
cially available 7 (Scheme 2).
Arylmagnesium bromide 67 couples with siletane 7 to
provide 8 in excellent yield. The silyl ether is then selec-
tively removed in acidic methanol to afford PSB alcohol
1a.6 The fact that the arylsiletane is unaffected by these
conditions is encouraging with respect to the potential
utility of PSB ethers. PSB–OH (1a) then yields PSB–Br
(1b) upon treatment with CBr4 and PPh3.2
These efforts reflect the importance of diverse arylmethyl
PGs and highlight the need for orthogonality and func-
tional group compatibility in the cleavage event.
Keywords: Benzyl; Protecting group; Siletane; Oxidation; Strained
silacycle.
We selected a representative sample of aromatic and ali-
phatic alcohols to serve as test cases for the formation
and cleavage of PSB ethers (Fig. 1).
*
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644
8281; e-mail: gdudley@chem.fsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.110

3284
H. Lam et al. / Tetrahedron Letters 46 (2005) 3283–3285
could not be protected efficiently using the same method
R–OH
(2)
X
PHB–X
(5)
even after prolonged reaction times (entries 7 and 8).
Side products and/or low conversions were observed.
We adopted a two-step protection strategy for such sub-
strates (Scheme 3). The alcohol is first derivatized as a
PBB ether,4 which is then silylated via the corresponding
Grignard reagent. This circumvents the independent
synthesis of 1 and increases the scope of PSB-protected
alcohols. The alternative protocol may be useful for pro-
tection of alcohols prior to introducing sensitive
functionality.
Me
Si
PSB–X
(1)
R
R
O
H2O2, KF
K2CO3
O
Me
Si
HO
PSB–OR
(3)
PHB–OR
(4)
Scheme 1. Overview of protection/deprotection of alcohols using the
para-siletanylbenzyl protecting group.
With PSB ethers in hand, we proceeded to the deprotec-
tion using conditions identified previously in our labora-
tory.6 Tamao-type oxidation of aryl ethers 3a and b
provides the deprotected phenols (2a and b)11 in one
step (Table 2, entries 1 and 2). Intermediate PHB ethers
4a and b presumably undergo solvolysis during the
course of the reaction.12
OTBS
(8)
OTBS
(7)
Cl
(6)
Si
X
Me
i, ii
Me
Si
THF, 60 ˚C
95–99%
Si
1a: X = OH
1b: X = Br
MgBr
Me
In the aliphatic ether cases (3c–e), the labile PHB ethers
(4c–e) were isolated and then cleaved2 using FeCl3
(entries 3–5 and 7) or DDQ (entry 6) to give alcohols
2c–e. Alternatively, Smitrovich and Woerpelꢀs more rig-
orous carbosilane oxidation protocol also affords the
PHB ethers (4c and d, entries 6 and 7).13 Such conditions
are not expected to tolerate pendant silyl ether PGs,14
but they do afford excellent yields after a relatively sim-
ple purification.15 PSB ethers can also be removed by
hydrogenolysis (entry 8). PSB ethers are presumably
similar to benzyl ethers in terms of arene oxidation po-
tential, yet they cleave under mild oxidizing conditions
that are unique among the common arylmethyl PGs.
We illustrate this attractive feature through competition
experiments with para-methoxybenzyl (PMB) ether 10.
Scheme 2. Preparation of 1a and b. Reagents and conditions: (i) HCl,
MeOH, 3 h, 94% (1a); (ii) CBr4, PPh3, 12h, 95% ( 1b).
OP
OP
Ph
OP
OP
OP
Ph
OMe
2a
3a
4a
2b
3b
4b
2c
3c
4c
2d
3d
4d
2e P = H
3e P = PSB
4e P = PHB
Figure 1. Alcohols and PSB ethers described in Tables 1 and 2.
Protection of phenols can be achieved using PSB–OH
(1a) under Mitsunobu conditions (Table 1, entries 1
and 4).8 Attempts to alkylate potassium, cesium, or so-
R
O
Mg, THF;
NaH, DMF
R–OPSB
R–OH
(2c-e)
9
3c: 80%
3d: 81%
3e: 84%
dium salts with 1b were unsuccessful (entries 2and 6).
PBB–Br Br
siletane 7
PBB–OR
Arylmethylation of primary alcohols (i.e., 2c) occurs
smoothly with PSB–Br (1b) using freshly prepared
Ag2O;10 this afforded the corresponding PSB ether in
80–83% yield (entry 5). However, secondary alcohols
Scheme 3. Two-step protection of alcohols (and overall yields).
Table 2. Cleavage of PSB ethers
Table 1. Protection of phenols and alcohols as PSB ethers
R
O
R
X
R–OH (2a-e)
R–OH
PSB–OR
(3a-e)
O
(2a-e)
Me
HO
PHB–OR
(4)
Me
Si
Si
PSB–OR
1a: X = OH
1b: X = Br
(3a-e)
Entry
PSB ether
Conditionsa
PHB ether
Alcohol
Entry PSB–X Alcohol Conditionsa PSB ether (% yield)
(% yield)
(% yield)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
a
b
b
a
b
b
b
b
2a A
2a B
2a C
2b A
2c C
2c B
2d C
2e C
3a (74)
—
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3c
3d
3c
D
—
—
2a (89)
2b (86)
2c (99)
2d (97)
2e (94)
2c (90)
2d (97)
2c (88)
D
3a (70)
3b (96)
3c (80–83)
—
(i) D (ii) FeCl3
(i) D (ii) FeCl3
(i) D (ii) FeCl3
(i) E; (ii) DDQ
(i) E; (ii) FeCl3
F
4c (87)
4d (84)
4e (85)
4c (99)
4d (99)
—
3d (50)
3e (38)
a Conditions. A: PPh3, DEAD, CH2Cl2; B: K2CO3/TBAI, Cs2CO3, or
NaH, DMF; C: Ag2O, CH2Cl2.
a Conditions: D: K2CO3, KFÆ2H2O, 30% aqueous H2O2, THF/MeOH,
50 °C;16 E: TBAF, t-BuOOH, DMF, 70 °C; F: H2, 10% Pd/C.

H. Lam et al. / Tetrahedron Letters 46 (2005) 3283–3285
3285
2005.03.110. Experimental procedures (for the prepara-
tion of compounds 1–4 and 8) and characterization data
for new compounds are published alongside the on-line
version of this letter.
DDQ
3c
9
3c
+
10
+
+
94% recovery
96% yield
(1 : 1 mixture)
CH2Cl2
(PMB oxidized)
H2O2, KF
K2CO3
4c
82% yield
(PSB oxidized)
10
3c
+
10
96% recovery
(1 : 1 mixture)
References and notes
X = H, P = H: 2c
X = H, P = PSB: 3c
X = H, P = PHB: 4c
OP
X = OMe, P = H:
9
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999; (b) Kocienski, P. J. Protecting Groups, 3rd
ed.; Thieme: Stuttgart, 2003.
2. Jobron, L.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121,
5835–5836.
X = OMe, P = PMB: 10
X
Scheme 4. Orthogonality in the oxidative cleavage of para-siletanyl-
benzyl (PSB) and para-methoxybenzyl (PMB) ethers.
3. Acetyl- and SEM-protected PHB ethers were employed.
4. Plante, O.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem.
Soc. 2000, 122, 7148–7149.
5. Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
Murai, A. Synlett 2002, 1835–1838.
6. Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Org. Lett.
2003, 5, 4571–4573.
7. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods,
M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem.
1987, 30, 871–880.
PMB ethers can be removed oxidatively with DDQ in
the presence of Bn ethers;1 the same orthogonality is
seen with PSB ethers (Scheme 4). Alternatively, treating
an equimolar mixture of 3c and 10 with basic peroxide
affects only the PSB ether, leaving the PMB group
intact.
In conclusion, the para-siletanylbenzyl PG has been
shown to protect phenols and primary alcohols cleanly.
Its easy removal under mild oxidative conditions as well
as its orthogonality with the PMB group can be advan-
tageous in multi-step synthesis. Our on-going efforts are
aimed at developing new and improved methods for the
arylmethylation of secondary alcohols in order to
address this limitation in the current protocol.
8. Hughes, D. L. Org. React. 1992, 42, 335–656.
9. (a) One drawback of siletane-based PGs is the reactivity of
siletanes toward (hard) alkali metal nucleophiles Matsum-
oto, K.; Shimazu, H.; Deguchi, M.; Yamaoka, H. J.
Polym. Sci., Part A: Polym. Chem. 1997, 35, 3207–3216;
(b) Knischka, R.; Frey, H.; Rapp, U.; Mayer-Posner, F. J.
Macromol. Rapid Commun. 1998, 19, 455–459; (c) Sheikh,
R. K.; Tharanikkarasu, K.; Imae, I.; Kawakami, Y.
Macromolecules 2001, 34, 4384–4389.
10. (a) Tanabe, M.; Peters, R. H. Organic Syntheses; Wiley
and Sons: New York, 1990; Collect; Vol. VII, pp 386–397;
Acknowledgments
´
(b) Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38,
5945–5948.
We thank the FSU Department of Chemistry and Bio-
chemistry for support of this work, Dr. Joseph Vaughn
for assistance with NMR spectroscopy, the Krafft Lab
for the use of their IR spectrometer, and Dr. Umesh
Goli for assistance with mass spectrometry. H.L.
acknowledges a postdoctoral fellowship from the MDS
Research Foundation, and S.E.H. is the recipient of
the Brautlecht Fellowship for undergraduate research.
11. Note that hydroquinone 2b is stable under these
conditions.
12. The expected solvolysis by-products, PHB–OH, and
PHB–OMe, are observed in these reactions.
13. Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61,
6044–6046.
14. For siletane oxidation in the presence of a TBS ether, see
Ref. 6.
15. A by-product believed to result from oxidation of THF is
observed following the Tamao protocol.
16. The oxidations described in Ref. 6 were conducted at
ambient temperature using KHCO3 as the base. The mild
heating employed in conditions D provides shorter reac-
tion times and, in the case of aryl ethers, promotes in situ
solvolysis of the PHB intermediate (4).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.