Copper(II) bromide as efficient catalyst for silyl- to bisarylmethyl ethers interconversion (transprotection)

Article abstract of DOI:10.1016/j.tetlet.2011.08.148

Primary and secondary silylated alcohols are easily converted to bis(methoxyphenyl)methyl (BMPM) ethers in good yields using CuBr₂ as catalyst in acetonitrile at room temperature. Various other protecting groups are compatible with this mild and convenient process.

Full text of DOI:10.1016/j.tetlet.2011.08.148

Tetrahedron Letters 52 (2011) 5820–5823
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(II) bromide as efficient catalyst for silyl- to bisarylmethyl ethers
interconversion (transprotection)
Simon Specklin a, Florian Gallier a, Rofia Mezaache b, Hassina Harkat b, Yénimégué Albert Dembelé c,
a
a,
Jean-Marc Weibel a, , Aurélien Blanc , Patrick Pale
⇑
⇑
a Laboratoire de Synthèse et Réactivité Organiques, Associé au CNRS, Institut de Chimie de Strasbourg UMR 7177, Université de Strasbourg, 67000 Strasbourg, France
b Laboratoire de Chimie et Chimie de l’Environnement, Département de Chimie, Faculté des Sciences, Université de Batna, Batna 05000, Algeria
c Laboratoire de chimie, FMPOS, Université de Bamako, Mali
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2011
Revised 2 August 2011
Accepted 24 August 2011
Available online 1 September 2011
Primary and secondary silylated alcohols are easily converted to bis(methoxyphenyl)methyl (BMPM)
ethers in good yields using CuBr2 as catalyst in acetonitrile at room temperature. Various other protecting
groups are compatible with this mild and convenient process.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Protecting group
Transprotection
Copper
Silyl
Alcohol
Bis(methoxyphenyl)methyl
Organic synthesis of complex molecular structures is still heav-
ily relying on selective protection and deprotection of functional
groups.1,2 Selectivity and compatibility in these critical steps are
often at the heart of a successful synthesis,2,3 and it is not so rare
in total syntheses that a protecting group has to be changed for an-
other one, more compatible with the next steps of the synthesis.3
This is usually performed by deprotection and reprotection. Trans-
protection, converting one protecting group to another, usually
from a different orthogonal set, in a single step would be a better
choice.2 However, straightforward methods for such transprotec-
tion are surprisingly scarce.2,4
Developing new conditions for the protection and deprotection
of alcohols recently led us to introduce diarylmethyl ethers as pro-
tecting groups using palladium(II) salts5 and more recently cop-
per(II) bromide6 as catalysts (Scheme 1, Eq. 1). During our
investigations, we demonstrated that copper(II) bromide induced
the formation of diarylmethyl cations. We thus wondered if cop-
per(II) could also catalyze the interconversion of silyl ethers to
bis(methoxyphenyl)methyl (BMPM) ethers (Scheme 1, Eq. 2).
Copper(II) salts are cheap, nontoxic, soft and mild Lewis acids,
widely used in organic synthesis.7 Among other things, copper(II)
salts have already been applied in a few protection or deprotection
reactions. Trityl,8 tert-butyldimethysilyl9 ethers and acetals,10 such
as tetrahydropyranyl or ethoxyethyl can be cleaved in the presence
of copper(II) salts (Scheme 2, Eq. 1). So far, only two examples of
transprotection, both to acetate, has been reported with copper(II)
salts (Scheme 2, Eqs. 2 and 3).11 So, the transprotection of silyl to
BMPM ethers would offer a new, mild, and interesting method
for organic synthesis. We now report here our results in this area.
As for our protection and deprotection of alcohols as diaryl-
methyl ethers,6 copper bromide(II) proved to be the most efficient
copper catalyst for the interconversion of silyl ethers to diarylmeth-
yl ethers.12 To examine the importance of the nature of the silyl
group in the outcome of this transformation, hexanol was protected
with silyl groups of various bulkiness and electronic properties and
the corresponding derivatives were submitted to copper(II) bromide
⇑
Corresponding authors. Tel./fax: +33 390 24 15 17.
E-mail addresses: jmweibel@unistra.fr (J.-M. Weibel), ppale@unistra.fr, ppale@
Scheme 1. Palladium and copper-promoted protection/deprotection of alcohols
chimie.u-strasbg.fr (P. Pale).
(Eq. 1) and copper-promoted transprotections of silylethers (Eq. 2).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.148

S. Specklin et al. / Tetrahedron Letters 52 (2011) 5820–5823
5821
Scheme 3. Copper-promoted transprotection of an alcohol compared to its
protection.
Scheme 2. Known copper-promoted deprotections and transprotection of alcohols.
and bis(methoxyphenyl)methanol (BMPM-OH) in acetonitrile at
room temperature (Table 1).
The bis(methoxyphenyl)methyl (BMPM) ether derived from
hexanol was produced in every case investigated, but at different
rates. Monitoring the reaction revealed that TES, TPS, and TBS
ethers exhibited a higher kinetic interconversion at the beginning
of the transformation compared to TIPS and TBDPS ethers, the lat-
ter being by far the slowest to interconvert (entry 5 vs 4 vs 1–3).
The reaction rates were thus mostly dependent on the size of the
substituents at the core Si atom. Interestingly, they approximately
followed the rate order of acid-catalyzed hydrolysis of silyl ethers,
known to be due to increasing substituent size and electronic ef-
Scheme 4. Proposed mechanism for the Cu(II)-catalyzed interconversion of silyl
ethers into BMPM ethers.
2
ion,13 the dimethoxybenzhydryl carbocation could then be trapped
by the oxygen atom of the silyl ether, providing a silyl diarylmethyl
oxonium intermediate (B in Scheme 4) while weakening the Si–O
bond. Hydroxide ion transfer to the silyl atom would then give
the corresponding silanol, generating the transprotected product
while regenerating the copper catalyst.
With such a mechanism, it was tempting to check whether
other protecting groups known for their cation stabilizing proper-
ties would react or not. We thus screened several other groups in
the transprotection from silyl ethers to other alcohol protecting
groups (Table 2). Compared to BMPM-OH, the less cation-stabiliz-
ing diphenylmethanol (DPM-OH) cleanly reacted but at a slower
rate, giving within the same duration the corresponding DPM ether
with a lower yield (entry 2 vs 1). The same trend was observed for
trityl (entries 3 and 4) and benzyl derivatives (entries 5 and 6). Tri-
phenylmethanol (Tr-OH) was able to achieve the transprotection
from silyl to trityl ethers, but very slowly, while the monometh-
oxytrityl analog reacted more rapidly, giving the corresponding
ether in reasonable yield (entry 4 vs 3). The reactivity difference
between di- vs triarylmethyl derivatives could be ascribed to the
bulkiness of the latter, as one could expect with the intermediate
fects around the Si atom.
It is worth noting that in all these transformations, except for
that with a TPBDS group, we did not see the formation of hexanol.
Such observations suggested a direct transprotection and not a
stepwise process, including deprotection and re-protection.
To clarify this mechanistic aspect, 4-benzyloxybutanol was pro-
tected using classical conditions into its TIPS ether. The latter was
submitted to copper dibromide and BMPM-OH. As expected, trans-
protection rapidly occurred in high yield but the concomitant
formation of the deprotected 4-benzyloxybutanol was observed
with a nonnegligible yield (Scheme 3). However, the protection
of 4-benzyloxybutanol in the presence of copper dibromide and
BMPM-OH required
a longer reaction time (at least 2 h vs
40 min). These results also suggest a direct transprotection rather
than a stepwise process, although the latter cannot entirely be
ruled out.
From these results, we can infer the following mechanism
(Scheme 4). As shown earlier,6 copper(II) bromide probably acts
as Lewis acid. Reacting with BMPM-OH, it would provide the dim-
ethoxybenzhydryl carbocation and a hydroxycuprate (A in Scheme
4). In close analogy to reactions promoted by the trityl carbocat-
Table 2
Table 1
Screening of other related protecting groupsa
Screening of silyl groups proned to interconversiona
Entry
PG-OH
Time (h)
Yielda (%)
Entry
Silyl group
Time (h)
Yieldb (%)
1
2
3
4
5
6
BMPM-OH
DPM-OH
Tr-OH
MeOTr-OH
Bn-OH
2
2
22
2
24
12
90
45b
42
1
2
3
4
5
SiEt3
SiPh3
SitBuMe2
SiiPr3
SitBuPh2
2
2
2
2
90
86c
81
56b
c
—
78
PMB-OH
30
18
43d
a
[BMPM-OH] = 1 M, [R-OSiR3] = 0.9 M, [Cu2+] = 0.1 M.
Isolated yield after complete conversion.
Estimated yield; due to contamination by bis(methoxyphenyl)methane.
Hexanol was detected as well as some starting material.
a
b
c
Isolated yields of pure product; the starting material accounted for the mass
balance unless otherwise stated.
b
Degradation also occurred.
No reaction.
c
d

5822
S. Specklin et al. / Tetrahedron Letters 52 (2011) 5820–5823
formation of a silyl arylmethyl oxonium species (cf. Scheme 4). As
expected, the less cation-stabilizing benzyl derivatives compared
to the two preceding series proved less reactive. The simplest ben-
zyl alcohol did not react, while the para-methoxybenzyl analog did,
but again very slowly, inducing a low yield of the transprotected
product (entry 6 vs 5).
With these results in hand, we then determined the scope and
limitation(s) of this copper-catalyzed transprotection from silyl-
to BMPM ethers (Table 3). As expected, primary and secondary
alcohols were easily transprotected whereas tertiary alcohols were
unreactive (entries 1–2 vs 3). The latter result is in agreement with
the proposed mechanism, especially with the strain occurring in
the silyl arylmethyl oxonium intermediate (B in Scheme 4). As sus-
pected on these bases, hindered secondary silylated alcohols
proved sensitive to the bulkiness of the silyl group, and they could
be more or less easily transprotected depending on the silyl group
nature, as shown in the reactions of TBS- and TIPS-isomenthol (en-
try 4 vs 5). It is nevertheless worth noting that during these reac-
tions, the transprotected product was obtained without
isomerization, ruling out other cationic mechanisms. Allylic and
benzylic silylated alcohols readily react, cleanly giving the corre-
sponding BMPM ethers (entries 6 and 7). Particularly noteworthy
in the latter series is the geranyl derivative, which did not rear-
range under such conditions, in agreement with the proposed
mechanism (entry 7). We were also glad to notice that even prop-
argyl silyl ethers gave the transprotected product in a very rapid
and clean reaction, with or without protection of the terminal
acetylenic moiety (entries 8 and 9). In the latter, the selectivity is
noteworthy, since only the O-silyl group reacted and not the C-silyl
group (entry 9). In contrast, silylated phenols led to complex
Table 3
Scope and limitation for BMPM ether transprotectiona
Entry
1
Substrates
Products
Time (h)
2
Yieldb (%)
78
2
3
4
74
e
—
24
—
4
4
10c,d
5
6
4
4
82
84
7
5
77
8
9
1
86
89
1.5
e
10
—
‘‘
4
—
11
12
13
3
2
1
92
100
86
14
24
58
15
16
1.5
12
73
48c,d
17
12
40c,d
a
b
c
[BMPMOH] = 1 M, [ROSiR3] = 0.9 M, CuBr2 10 mol%.
Isolated yields of pure product after complete conversion unless otherwise stated.
The starting material was also recovered.
Estimated yield; due to some contamination by bis(methoxyphenyl)methane.
No transprotection and degradation occurred.
d
e

S. Specklin et al. / Tetrahedron Letters 52 (2011) 5820–5823
5823
reaction mixtures, in which the expected transprotected product
References and notes
can hardly be detected (entry 10).
1. Greene, T. W.; Wuts, P. G. M. Protective groups in Organic Synthesis, 3rd ed.; J.
Wiley & Sons: New York, 1999.
Having surveyed the scope of this transprotection with various
alcohols, we then briefly investigated the orthogonality of this
method with other protecting groups. Benzyl, ester, acetal, and car-
bobenzyloxy (CBz) groups proved compatible with this transpro-
tection procedure (entries 11–15). However, Boc-protecting
groups gave less satisfactory results, surprisingly inducing a very
slow reaction but without BOC deprotection14 (entries 16 and 17).
In summary, we have further expanded the scope of synthetic
applications of copper salts in organic chemistry, demonstrating
that transprotection from silyl to diarylmethyl ethers can be
achieved in good to high yields with CuBr2 as catalyst at room tem-
perature. With very mild conditions, with a wide tolerance to other
protecting groups, this new interconversion of silyl to diarylmethyl
protecting groups will find applications in organic synthesis, espe-
cially in the total synthesis of natural products.
2. Kocienski, P. J. Protecting groups, 3rd ed.; G. Thieme: Stuttgart: New York, 2004.
3. (a) Nicolaou, K. C.; Sorensen, E. Classics in Total Synthesis; Wiley-VCH:
Weinheim, 1996; (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003; (c) Nicolaou, K. C.; Chen, J. S. Classics in Total
Synthesis III; Wiley-VCH: Weinheim, 2011.
4. For selected exemples of transprotection: (a) Rawal, V. H.; Michoud, C.;
Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030–3031; (b) Roos, E. C.; Bernabé,
P.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Boesten, W. H. J. J. Org. Chem.
1995, 60, 1733–1740; (c) Furlán, R. L. E.; Mata, E. G. ARKIVOC 2003, x, 32–40;
through organocatalysis, see: (d) Poisson, T.; Dalla, V.; Papamicael, C.; Dupas,
G.; Marsais, F.; Levacher, V. Synlett 2007, 381–386; through Cu-catalysis,see:
(e) Chandra, K. L.; Saranavan, P.; Singh, V. K. Tetrahedron Lett. 2001, 42, 5309–
5311; through Fe-catalysis, see: (f) Asadolah, K.; Heravi, M. M. Monatsh. Chem.
2007, 138, 867–869; (g) Ganem, B.; Small, V. R. J. Org. Chem. 1974, 39, 3728–
3730; (h) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Nucleosides, Nucleotides &
Nucleic Acids 2005, 24, 819–822; (i) Bourdreux, Y.; Lemétais, A.; Urban, D.;
Beau, J.-M. Chem. Commun. 2011, 47, 2146–2148; through other catalysis, see:
(j) Oriyama, T.; Oda, M.; Gono, J.; Koga, G. Tetrahedron Lett. 1994, 35, 2027–
2030; (k) Norsikian, S.; Holmes, I.; Lagasse, F.; Kagan, H. Tetrahedron Lett. 2002,
43, 5715–5717.
Further works are now in progress to further explore the scope
of this reaction and to apply them in total synthesis.
5. (a) Bikard, Y.; Weibel, J.-M.; Sirlin, C.; Dupuis, L.; Loeffler, J.-P.;Pale, P. Tetrahedron
Lett. 2007, 48, 8895–8899;(b)Bikard, Y.;Mezaache, R.; Weibel, J.-M.;Benkouider,
A.; Sirlin, C.; Pale, P. Tetrahedron 2008, 64, 10224–10232.
6. Mezaache, R.; Dembélé, Y. A.; Bikard, Y.; Weibel, J.-M.; Blanc, A.; Pale, P.
Tetrahedron Lett. 2009, 50, 7322–7326.
Typical procedure for the transprotection of silyl alcohols with
BMPM-OH
7. Modern Organocopper Chemistry; Krause, N., Ed.; Wiley: New-York, 2002.
8. Pathak, A. K.; Pathak, V.; Seitz, L. E.; Tiwari, K. N.; Akhtar, M. S.; Reynolds, R. C.
Tetrahedron Lett. 2001, 42, 7755–7757.
9. (a) Tan, Z. P.; Wang, L.; Wang, J. B. Chin. Chem. Lett. 2000, 11, 753–756; (b)
Bhatt, S.; Nayak, S. K. Tetrahedron Lett. 2006, 47, 8395–8399.
10. Wang, J.; Zhang, C.; Qu, Z.; Hou, Y.; Chen, B.; Wu, P. J. Chem. Research (S) 1999,
294–295; (b) Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K.
Tetrahedron Lett. 1998, 39, 3091–3092.
To a solution of the silylated substrate (0.9 mmol) in dry CH3CN
(1 mL) at room temperature under argon, was added bis(4-
methoxyphenyl)methanol (244 mg, 1 mmol) and copper(II) bro-
mide (22 mg, 0.1 mmol). The reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under vacuum
and then diluted with Et2O (20 mL) and water (20 mL). After parti-
tioning, the aqueous layer was extracted three times with Et2O and
the combined organic layers were dried over Na2SO4. The crude
product was then purified by flash chromatography over silica gel.
11. For Cu-catalyzed transprotection to acetates, see Refs. 4e,f and Bhatt, S.; Nayak,
S. K. Lett. Org. Chem. 2008, 5, 435–443. For
a specific Cu-catalyzed
transprotection and reaction in glycochemistry, see: Français, A.; Urban, D.;
Beau, J.-M. Angew. Chem., Int. Ed. 2007, 46, 8662–8665.
12. Copper sulfate, chloride, acetate and triflate were examined as in Ref. 6.
13. (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1984, 1759–1762;
(b) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1985, 447–450; (c)
Kobayashi, S.; Murakami, M.; Mukaiyama, T. Chem. Lett. 1985, 1535–1538; (d)
Ohshima, M.; Murakami, M.; Mukaiyama, T. Chem. Lett. 1985, 1871–1874.
14. N-Boc derivatives are known to undergo deprotection with active silylation
reagent (see Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 5543–5546
and J. Org. Chem. 1990, 55, 870–876) and the silyl oxonium intermediate (B in
Scheme 4) could have acted as such.
Acknowledgments
The authors thank the CNRS, the French Ministry of Research for
financial support, the CMEP-Tassili exchange program for support
to RM and HH, and the French embassy in Mali for financial sup-
port to Y.A.D.