R. Mezaache et al. / Tetrahedron Letters 50 (2009) 7322–7326
7323
catalyst cost, we envisaged replacing palladium salts or complexes
by copper salts. Indeed, our preliminary investigation revealed that
CuCl2 or CuSO4 was able to protect alcohols as DPM ethers,
although very long reaction times were needed.4 Moreover, CuCl2
associated with water in acetonitrile has been reported for depro-
tection of trityl ethers.9 It was thus clear to us that the scope and
the limitation of the use of copper salts as catalyst for the protec-
tion of alcohols with benzhydrol derivatives and deprotection of
substituted benzhydryl ethers are still underestimated.
We present here a very simple, cheap, and environmentally
friendly procedure for the protection and deprotection of alcohols
as BMPM ethers, offering smooth reaction conditions. Chemoselec-
tivity and orthogonality with other protecting groups are also de-
scribed in this Letter.
tries 6–13). As primary alcohols, secondary alcohols were easily
protected whereas tertiary alcohols gave a messy reaction mixture
(entry 6 vs entry 7 vs entry 8). Interestingly, diols were only pro-
tected as mono BMPM ethers in very high to good yields, probably
depending on the way chelation occurred (entry 9 vs entry 10). The
more sensitive allylic and propargylic alcohols were rewardingly
easily protected in nearly quantitative yields under these condi-
tions (entries 11–13). It is worth noting that propargylic alcohol
and (Z)-but-2-en-1,4-diol could not be protected when using Pd
catalysts due to degradation.4,5 The latter results highlighted the
smoothness and effectiveness of this new procedure.
For total synthesis applications, we also set up conditions with
solvent. Acetonitrile was first selected as a solvent for solubility
reasons and we screened copper salts with 4-benzyloxybutanol
as model alcohol (Table 2) again. Except for copper sulfate, the
same trends as without solvent were observed (Table 2 vs Table 1,
entries 1–6) and the superiority of CuBr2 was again observed (entry
6 vs entries 1–5). Interestingly, the protection also occurred in less
polar and coordinating solvents such as dioxane and THF with sim-
ilar rates and yields (entries 7 and 8 vs entry 6).
With these alternative conditions in hand, we again examined
the scope of this protection, emphasizing the compatibility of this
method with other protecting groups (Table 3).
Isomenthol was selected as a secondary alcohol and its protec-
tion proved to be very fast at room temperature (Table 3, entry 1).
Benzylic and allylic alcohols were also easily protected (entries 2
and 3). As suspected from Cu(II) coordination chemistry10 and its
biological implications,11 phenol could not be protected under
our conditions (entry 5) and even interfered with other protections
(entry 4 vs entry 3).
2. Results
In order to find the best catalyst, various copper salts were
screened in the transformation of bis(para-methoxyphenyl)metha-
nol, the most reactive of the benzhydrol derivatives, in ethanol as a
reagent and a solvent at room temperature (Table 1).
As already observed with DPM,4 copper sulfate was able to cata-
lyze the reaction. This protection occurred with higher yield and at
lower temperature than the Pd(II)-catalyzed reactions4,5 but unfor-
tunately with long reaction time (entry 1). Copper(II) chloride, hy-
drated or not (entries 2 and 3), gave nearly similar results but
within only 4 or 5 h. The nature of the Cu(II) counter-ion thus played
a critical role, probably through modulation of Cu(II) Lewis acidity.
Indeed, Cu(OAc)2 did not catalyze the reaction at all, whereas
Cu(OTf)2 catalyzed well (entry 4 vs entry 5). The latter surprisingly
slowed down the reaction rate again and thus behaved as CuSO4 in
this protection (entry 5 vs entry 1). We were eventually pleased to
find that CuBr2 was very effective, quantitatively leading to the
BMPM ether in only 1.5 h at room temperature (entry 6).
Conventional arylmethyl protecting groups such as benzyl and
p-methoxybenzyl (entries
6 and 7) proved fully compatible,
whereas trityl ether rapidly exchanged with bis(methoxy-
phenyl)methyl group leading to a mixture of mono- and diprotect-
ed BMPM ethers (entry 8).12
Ester and acetal groups were also fully compatible with our pro-
tection conditions as exemplified with 4-acetoxybutanol (entry 9)
Having these reaction conditions in hand, we checked if all clas-
ses of alcohols could be protected by this procedure (Table 1, en-
and the more sophisticated methyl 2,3-O-cyclohexyliden-b-D-ribo-
furanoside (entry 10). It is worth noticing that CuCl2 was described
as an effective catalyst for the deprotection of acetals.13 Our condi-
tions are thus clearly milder. Common N-protecting groups such as
benzyloxycarbonyl and tert-butyloxycarbonyl were also compati-
ble with our conditions (entries 11 and 12).
Since diols were easily protected without a solvent, we exam-
ined the protection of hexane-1,5-diol looking for some selectively
for the primary alcohol vs the secondary one in this molecule (en-
Table 1
Effect of copper salts on BMPM ether formation and solvent-free alcohol protectiona
R
OH
O
Cu(II) cat.
ROH, r.t.
+
R-OH
MeO
OMe
MeO
OMe
Entry
Catalyst
R–OH
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuSO4Á5H2O
CuCl2Á2H2O
CuCl2
Cu(OAc)2ÁH2O
Cu(OTf)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
iPrOH
tBuOH
24
5
4
100
100
99
Table 2
Effect of copper salts on BMPM ether formation (condition with solvent)a
6
n.r.c
99
21
1.5
2
18
2
100
94d
n.d.e,f
93g
98g
OH
O
HO
+
Cu(II) cat.
slv, r.t.
OBn
(CH2–OH)2
HO–(CH2)4–OH
OBn
MeO
OMe
MeO
OMe
10
6
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
11
CuBr2
2
100
OH
HO
1
2
3
4
5
6
7
8
CuSO4Á5H2O
CuCl2Á2H2O
CuCl2
Cu(OAc)2ÁH2O
Cu(OTf)2
CuBr2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
30
7
6
8
24
2
n.r.c
70
12
13
CuBr2
CuBr2
2
2
94
OH
73
n.r.c
59
100
OH
[BMPM-OH] = 1 M, [Cu2+] = 0.1 M.
Isolated yield.
No reaction, starting material recovered.
BMPM–OH poorly soluble.
CuBr2 partially soluble, reaction temperature 30 °C.
Not determined.
Only the monoprotected diol was observed.
a
b
c
d
e
f
90
86
86
CuBr2
CuBr2
2
2
Dioxane
[BMPM–OH] = 1 M, [alcohol] = 0.9 M, and [Cu2+] = 0.1 M.
Isolated yield.
No reaction, starting material recovered.
a
b
c
g