PdCl2, a useful catalyst for protection of alcohols as diphenylmethyl (DPM) ethers

Article abstract of DOI:10.1016/j.tetlet.2007.10.045

Primary, secondary, benzylic and allylic alcohols are efficiently converted to the corresponding diphenylmethyl ethers in the presence of catalytic amounts of PdCl₂.

Full text of DOI:10.1016/j.tetlet.2007.10.045

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8895–8899
PdCl2, a useful catalyst for protection of alcohols as
diphenylmethyl (DPM) ethers
Yann Bikard,a,c Jean-Marc Weibel,a Claude Sirlin,b Luc Dupuis,c
Jean-Philippe Loefflerc and Patrick Palea,*
a
`
´ ´ ´
Laboratoire de synthese et reactivite organique, associe au CNRS, Institut Le Bel, Universite L. Pasteur,
67000 Strasbourg, France
´
b
`
´ ´ ´
Laboratoire de syntheses metallo-induites, associe au CNRS, Institut Le Bel, Universite L. Pasteur,
67000 Strasbourg, France
cLaboratoire de signalisations mole´culaires et neurode´ge´nerescence, U 692, INSERM—Universite´ Louis Pasteur,
11, rue Humann, 67085 Strasbourg, France
Received 10 August 2007; revised 3 October 2007; accepted 10 October 2007
Available online 14 October 2007
Abstract—Primary, secondary, benzylic and allylic alcohols are efficiently converted to the corresponding diphenylmethyl ethers in
the presence of catalytic amounts of PdCl2.
Ó 2007 Elsevier Ltd. All rights reserved.
Total syntheses of complex molecules involve many
steps, most of them being required to control functional
groups and mainly to turn down their reactivity through
modification with protecting groups.1 The criteria
involved in the choice of protecting groups are based on
high yielding protection and deprotection steps and, if
possible, chemoselectivity during those steps but also
on orthogonality1b with other protecting and functional
groups.
alcoholate,3 as for most benzyl-type ethers. A few other
methods can nevertheless be found in the literature.
Halogenodiphenylmethanes have been mentioned as
starting materials toward DPM ethers by treatment with
orthoformates at high temperature.4 Diphenylmethanol
in the presence of Brønsted acid,5 strong Lewis acid,6 or
supported acids,7 and other reagents such as diphenyl-
methylphosphate–trifluoroacetic acid8 and diphenyl-
methyldiazomethane8,9 have also been reported.
Deprotection of DPM ethers is mostly achieved by sim-
ple hydrogenation as for any benzyl-type ethers,10 but
electrolytic reduction,11 acidolysis8a,12 and solvolysis13
have also been reported. As a part of our program to
develop new catalytic reactions using transition metals
(especially Pd, Ag and Au salts),14–16 we were interested
in finding a more simple and environmentally friendly
procedure for the formation of DPM ethers and their
deprotection (Scheme 1).
Usually, alcohols are temporarily converted to silyl and
alkyl ethers, the benzyl and para-methoxybenzyl pro-
tecting groups being the most popular due to their
deprotection conditions being orthogonal to each
other.1,2
We present here new chemoselective conditions for the
protection and deprotection of alcohols as diphenyl-
methyl (DPM) ether, offering an interesting alternative
and an orthogonal complement to the common benzyl-
type ethers.
To look for the best catalyst, we began our investiga-
tions by submitting diphenylmethanol 1 in ethanol in
the presence of various metal salts (10 mol %) at 80 °C
Scarcely used in organic synthesis, the formation of
DPM ethers usually involves the nucleophilic substitu-
tion of chloro- or bromodiphenylmethane by a metal
Ph
Ph
PdCl2
10 mol.%
H
R
+
+
H2O
R-OH
Ph
O
Ph
O
80 ºC
1
with or without solvent
2
*
Corresponding author. Tel./fax: +33 390 24 15 17; e-mail: ppale@
chimie.u-strasbg.fr
Scheme 1. Metal-catalyzed formation of DPM ethers.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.045

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Y. Bikard et al. / Tetrahedron Letters 48 (2007) 8895–8899
Table 1. Effect of transition metal salts on DPM ether formation
catalyst
Ph
Ph
Ph Ph
+
H
Ph
O
Ph
O
Ph
O
Ph
Yield 2aa (%)
EtOH, 80 ºC
1
2a
3
Entry
Catalyst
Time (h)
Recovered 1a (%)
Yield 3a (%)
1
2
3
4
5
6
7
8
9
PdCl2
4.3
16
24
48
5.5
24
5.5
1
1
30
27
100
4
2
3
100
95
2
97
Traces
Traces
0b
0b
0
21
8c
85
0d
0
10
3
Pd/C 10%
Pd(OAc)2
NiCl2
AuCl
NaAuCl4
AuCl3
AgOTf
CuCl
CuCl2
Traces
0
75
76
12
0
5
88
95
24
16
48
10
11
CuSO4Æ5H2O
2
a Yield estimated from NMR analysis.
b Benzophenone and diphenylmethane were observed as major products.
c Benzophenone was also detected.
d Formation of a silver mirror.
(reaction rates are dramatically lower without heating)
(Table 1). Depending on the catalyst, two different
products could be produced and easily isolated, the ex-
pected DPM protected ethanol 2a and an ether resulting
from dimerization of diphenylmethanol, compound 3.
Since the starting reagent 1 and products 2a and 3 were
clearly characterized by the chemical shift of their methyne
proton at, respectively, 5.84, 5.37 and 5.41 ppm in
CDCl3, the reactions were followed by NMR and the
product ratios determined by NMR (Table 1).
Ph
H
Ph
O
1
Ph
PdCl2
R
Cl
HOPdCl
Ph
Ph
O
ROH
Ph
2
Ph
H
H
Ph
O
Ph
H
H
Ph Ph
Ph2CHOH
PdCl2
O
Ph
1
In the presence of PdCl2 (entry 1), diphenylmethanol
was rapidly and completely converted to its ether 2a,
nearly without formation of ether 3 or any other
by-products. Surprisingly, palladium on charcoal,
known to be often contaminated with PdCl2 due to its
preparation, gave a complex mixture mostly containing
the starting materials, benzophenone and diphenyl-
methane, even after prolonged reaction time (entry 2).
Other palladium salts, such as Pd(OAc)2, gave almost
the same results (entry 3). These results indicated that
as expected, coordination of diphenylmethanol occurred
but that the Lewis acid character of the salt could be
balanced by b-elimination (see the mechanism below
and Scheme 2).
3
β-elim.
Ph
Ph
HPdCl
HCl
Ph
H
H
Ph
O
Scheme 2. Proposed mechanism for the PdCl2-catalyzed DPM
protection of alcohols.
ether 3 (entry 7). Silver triflate (entry 8) and copper(I)
chloride (entry 9) were not effective whereas copper(II)
salts (entries 10 and 11) gave good results, copper sulfate
being the best of them although the reaction required
two days to be close to completion.
To favor the Lewis acid pathway, we thus turned our
attention to more acidic salts and to salts of metals less
prone to b-elimination. Located in the same column as
palladium in the Mendeleev periodic table, nickel salts
are more acidic. Disappointedly, nickel chloride did
not promote formation of the ether, starting material
was recovered (entry 4). In contrast, gold salts gave high
conversion (entries 5–7). Among them, AuCl gave ether
2 but in moderate yields together with relatively high
amount of the dimeric ether 3 (entry 5). NaAuCl4 gave
similar results with reasonably low amount of 3 but
the reaction required far longer time and was less clean,
yielding a mixture of side-products (entry 6). The more
acidic AuCl3 gave predominately the undesired dimeric
This metal salt screening clearly showed that PdCl2 is a
very efficient catalyst for the protection of alcohols as
DPM ethers, giving high conversion and almost quanti-
tative yield in a few hours.
To rapidly evaluate the scope and the chemoselectivity
of this novel protection procedure, we submitted repre-
sentative examples of the different classes of alcohols in
the presence of diphenylmethanol and PdCl2, the alco-
hol acting as a reagent and solvent in an environmen-
tally friendly procedure (Table 2). Primary alcohols,
allylic and benzylic alcohols, were efficiently converted
into their DPM ethers in a fast reaction under these con-
ditions (entries 1, 4 and 5). Interestingly, a-unsaturated

Y. Bikard et al. / Tetrahedron Letters 48 (2007) 8895–8899
Table 2. Formation of DPM ethers in alcohol (solvent-free conditions)a
8897
Ph
PdCl2
Ph
10 mol.%
R
H
+
H2O
+
R-OH
Ph
Ph
O
O
80 ºC
1
2
Entry
Alcohola
Time (h)
Yieldb (%)
DPM ether (R)
1
2
3
EtOH
iPrOH
tBuOH
4.3
24
72
97
97
19
2a (Et)
2b (iPr)
2c (tBu)
4
5
6
1.7
2.5
24
88
96
0
2d (CH2CH@CH2)
2e (CH2Ph)
—
OH
Bn–OH
PhOH
HO
OH
7
1.5
Degrad.
—
HO
8
9
1.7
16
Degrad.
95c
—
HO
2f c
HO
OH
((CH2)4OH)
a [DPMOH] = 0.2 M in alcohol or phenol.
b Yield estimated by NMR analysis.
c Only the monoprotected product was obtained.
primary alcohols seem to be more reactive than satu-
rated ones, as revealed by shorter reaction times (entries
4 and 5 vs entry 1). More interestingly, the secondary
alcohol isopropyl alcohol, required much longer reac-
tion time (entry 2) while the tertiary alcohol, tert-buta-
nol, is even less reactive under the same conditions
(entry 3). In a similar way, the less nucleophilic phenol
did not react under these conditions (entry 6). Various
primary diols (entries 7–9) were also examined, expect-
ing monoprotection under these non-stoichiometric con-
ditions. Surprisingly, only the saturated one was
transformed and indeed monoprotected in excellent
yield, while the unsaturated ones led to complex mix-
tures (entry 9 vs entries 7 and 8). This monoprotection,
however, required longer time reaction than other pri-
mary alcohols (entry 9 vs entry 1).
Table 3. Formation of benzyl DPM ethers in the presence of solvents.
[Alcohol] = [DPMOH] = 0.2 M in solvent, 10 mol % PdCl2, 80 °C,
16 h
Ph
PdCl2
Ph
10 mol.%
H
Ph
OH
Ph
Ph
Ph
O
O
solvent
80 ºC
1
2e
Entry
Solvents
Yielda (%)
1
2
3
4
5
6
7
DCE
Benzene
Toluene
Acetonitrile
Ethyl acetate
Dioxane
94
92
91
90
Degradation
Degradation
Degradation
DMF
a Yield estimated by NMR analysis.
This novel DPM protection thus offers useful selectivity,
primary alcohols being more rapidly protected than sec-
ondary alcohols, while tertiary alcohols are scarcely pro-
tected and phenols do not react. To our knowledge, such
chemoselectivity has not yet been reported for benzyl-
type protecting groups.
to messy reactions (entries 5–7). Among the solvents
examined, acetonitrile occupied a peculiar position,
allowing for an efficient reaction while being a polar sol-
vent. The well known ability of acetonitrile to coordi-
nate and stabilize Pd species and especially PdCl2 is
probably responsible for the behavior observed here. It
is worth noting that either non-polar solvents or the
relatively polar acetonitrile can thus be used for this
protection, offering a large range to organic chemists.
Rewardingly, reactions performed in apolar solvents
were very clean and the diphenylmethanol dimer 3 can
still be detected but only in less than 5%.
Although the above-mentioned solvent-free protection
of alcohols is very interesting as an environmentally
friendly transformation (Green Chemistry), these condi-
tions may not be very useful within the context of total
synthesis. In multi-step synthesis, the alcohol is clearly
the limiting species and it cannot be used as a solvent.
We therefore developed stoichiometric conditions.
To do so, we looked for solvents compatible with these
DPM protection conditions. The very reactive benzylic
alcohol was chosen as the substrate and it was converted
to its DPM ether in various solvents (Table 3). As
expected, non-coordinating solvents gave the best results
(entries 1–3) while coordinating and polar solvents led
With these stoichiometric conditions in hands, we exam-
ined the scope of this protection in solution. Various
alcohols were converted to their DPM ethers through
this method. Aliphatic primary alcohols carrying or
not other functional groups were easily protected as
DPM ethers in high isolated yields (81–88%) (Table 4,

8898
Y. Bikard et al. / Tetrahedron Letters 48 (2007) 8895–8899
Table 4. PdCl2 catalyzed formation of DPM ethers (conditions with
(Table 2), also led mostly to the same monoDPM ether
2f (entry 7). More functionalized primary alcohol was
also protected in good yield (entry 8).
solvent)a
Ph
Ph
PdCl2
10 mol.%
R
H
+
R-OH
Ph
Ph
O
O
As shown under the solvent-free conditions (Table 2),
allylic and benzylic alcohols proved to be more reactive,
giving the corresponding DPM ethers in good to excel-
lent yield within a few hours (entries 9–11). However,
decomposition occurred upon protection of p-hydroxy-
methylphenol probably due to the long reaction time.
Increasing the amount of DMP-OH decreased the reac-
tion time and allowed to isolate the monoprotected
derivative in reasonable yield, the phenol moiety being
untouched (entry 12). Indeed, simple phenol gave the
ether in very low yield after 4 days (entry 13). Propargy-
lic alcohols did not react under these conditions as
shown for propynol, which was recovered even after 5
days (entry 14). Secondary alcohols reacted more or less
rapidly depending on their bulkiness. Isopropanol
cleanly afforded its ether in 86% yield, whereas L-men-
thol gave only 65% yield within 2 days (entry 16 vs entry
15). For the latter, the reaction rate was not high enough
to impede the competitive formation of ether 3 but a
slight excess of reagent avoided this problem, and the
menthol DPM ether was isolated in good yields (entry
17). To check the selectivity observed without solvent
(Table 2), we submitted a simple and more elaborated
substrate exhibiting primary as well as secondary alco-
hols (entries 18 and 19). As expected, protection
occurred at the primary alcohol in both cases.
solvent
80 ºC
1
2
Entry
Alcohols
Time (h)
Yieldb (%)
1
4
83
OH
OH
Br
2
48
88
9
BnO
TrO
3
4
24
24
83
87
OH
OH
OH
5
48
87
OH
6
7
48
1
81
73c,d
HO
HO
OH
O
8
48
68
O
OMe
O
9
10
11
12
4
4
4
5
76
73
OH
OH
OH
This screening of alcohols revealed that this DPM pro-
tection is tolerant to other functional groups (entries
2–10, 12, 19), compatible with other protecting groups
(entries 3 and 4, 8, 19) and selective toward primary
alcohols (entries 12, 18 and 19).
94
OH
48d,e,f
HO
The various products observed together with the ex-
pected DPM ether shed some light on the mechanism
of the reaction. The formation of ether 3 resulting from
dimerization of diphenylmethanol suggests the interven-
tion of a benzhydryl carbocation (Scheme 2). The latter
or, as shown by the solvent effect, most probably an inti-
mate ion pair including this cation could react with the
alcohol or with diphenylmethanol to give, respectively,
the protected alcohol 2 or the dimeric ether 3. The benz-
hydryl carbocation would be probably formed after
coordination of alcohol oxygen atom to the mild Lewis
acid PdII. The fact that, under some conditions (see Ta-
ble 1), benzophenone and diphenylmethane were pro-
duced confirmed the intermediate formation of a Pd
complex. Upon coordination of the hydroxyl group,
the b-proton present in primary and secondary alcohols
can be transferred to the palladium. This b-elimination
would produce on the one hand benzophenone and on
the other hand a hydridopalladium species able to re-
duce the carbocation also present in the medium
(Scheme 2).
13
14
PhOH
96
24
4g
0g
OH
15
iPrOH
48
86
OH
16
17
48
24
65
74h
OH
18
19
3
56c,f
46e,f
OH
OH
O
HO
HO
48
AcHN
OBn
a [Alcohol] = [DPMOH] = 0.2 M in dichloroethane unless otherwise
stated, 10 mol % PdCl2, 80 °C.
b Yield of pure product after column chromatography.
c Less than 10% of the diprotected diol was also isolated.
d 4 equiv of DPMOH was used.
e Performed in acetonitrile for solubility reasons.
f Only the primary hydroxyl was protected.
g The starting material was recovered.
h 2 equiv of DPMOH was used.
If correct, this mechanism shows that this DPM protec-
tion is reversible and probably displaced toward ether 2
either by the excess of alcohol in the solvent-free version
and/or by removal of water by heating under both
entries 1–6). Interestingly, the diol, which gave the
monoprotected product under solvent-free conditions

Y. Bikard et al. / Tetrahedron Letters 48 (2007) 8895–8899
8899
Acknowledgments
PdCl2 cat.
BnO
BnO
ODMP
OH
EtOH
5h, 80 ºC
The authors thank the ‘CNRS’ and the French Ministry
of Research for financial support. Y.B thanks the ‘Min-
istere de la Recherche et de la Technologie’ for a doc-
88 %
`
Scheme 3. Deprotection of DPM ether using 10 mol % PdCl2 in
ethanol.
toral fellowship.
References and notes
conditions. Interestingly, such proposal allows us to
think that the conditions used for the protection would
also be effective for the deprotection of DPM ethers. It
also suggests that the deprotection should be selective
for DPM ethers.
1. (a) Greene, T. W.; Wuts, P. G. M. Protective groups in
Organic Synthesis, 3rd ed.; J. Wiley & Sons: New York,
1999; (b) Kocienski, P. J. Protecting Groups, 3rd ed.; G.
Thieme: Stuttgart, New York, 2004.
2. For a recent review, see: Weissman, S. A.; Zewge, D.
Tetrahedron 2005, 61, 7833, and references cited therein.
3. Dobson, D.; Todd, A.; Gilmore, J. Synth. Commun. 1991,
21, 601.
4. Gazizov, M. B.; Ibragimov, S. N.; Khamidullina, O. D.;
Karimova, R. F.; Pudovik, M. A.; Sinyashin, O. G. Russ.
J. Gen. Chem. 2005, 75, 1325.
5. (a) Sugsawa, S.; Fujiwara, K. Org. Synth. Coll. 1963, 4, 72;
(b) Mairanovsky, V. G. Angew. Chem., Int. Ed. Engl. 1976,
15, 281; (c) Parades, R.; Perez, R. Tetrahedron Lett. 1998,
39, 2037.
Rewardingly, this hypothesis was confirmed by the
deprotection of one of the previously synthesized
DPM ethers (Scheme 3). 1,4-Butanediol protected at
one end as a benzyl ether and at the other as a DPM
ether was cleanly and rapidly converted to the monob-
enzylated diol using PdCl2 again as catalyst and ethanol
to displace the DPM ether toward the free alcohol and
the corresponding ethoxydiphenylmethane.
In conclusion, we have developed a novel and simple
method for the synthesis of diphenylmethyl ethers from
alcohols and diphenylmethanol using PdCl2 as a cata-
lyst. This reaction, showing interesting chemoselectivity,
offers an alternative for the protection of alcohols.
Moreover, a selective deprotection has been achieved
under conditions orthogonal to other protecting groups.
Both aspects will thus extend the tool box of organic
chemists. Further works are now underway to expand
the scope of this reaction and better understand its
mechanism.
6. (a) Sharma, G. V. M.; Prasad, T. R.; Mahalingam, A. K.
Tetrahedron Lett. 2001, 42, 759; (b) Namboodiri, V. V.;
Varma, R. S. Tetrahedron Lett. 2002, 43, 4593; (c) Stavber,
S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355.
7. (a) Stanescu, M. A.; Varma, R. S. Tetrahedron Lett. 2002,
43, 7307; (b) Romanelli, G. P.; Ruiz, D. M.; Bideberripe,
H. P.; Autino, J. C.; Baronetti, G. T.; Thomas, H. J.
Arkivoc 2007, i, 1.
8. (a) Kolovos, M.; Froussios, C. Tetrahedron Lett. 1984, 25,
3909; (b) Lapatsanis, L. Tetrahedron Lett. 1978, 19, 3943.
9. Roberts, J. D.; Watanabe, W. J. Am. Chem. Soc. 1950, 72,
4869.
10. Olah, G. A.; Prakash, G. K. S.; Narang, S. C. Synthesis
1978, 825.
11. Mairanovsky, V. G. Angew. Chem., Int. Ed. Engl. 1976,
15, 281.
Typical procedure for the formation of DPM ethers from
alcohols:
12. Froussios, C.; Kolovos, M. Synthesis 1987, 1106.
13. Miyake, H.; Fujimura, M.; Tsumura, T.; Sasaki, M.
Chem. Lett. 2006, 35, 778.
14. Selected references: with Pd (a) Halbes-Letinois, U.; Pale,
P. Palladium-Catalyzed Synthesis of Enynes. In Leading
Edge Organometallic Chemistry Research; Cato, M. A.,
Ed.; Nova: New-York, 2006; p 93, and references cited
therein; (b) Halbes, U.; Vasiliev, A.; Pale, P. Eur. J. Org.
Chem. 2005, 2828; (c) Halbes, U.; Pale, P. J. Organomet.
Chem. 2003, 687, 420.
Solvent-free procedure: Diphenylmethanol (100 mg,
0.54 mmol, 1 equiv) was added to a solution of palla-
dium chloride (10 mg, 0.054 mmol, 0.1 equiv) in alcohol
(2.7 ml, 0.2 M). The reaction mixture was then heated at
80 °C until disappearance of the starting materials (TLC
monitoring). Excess of alcohol was then removed in
vacuum and the crude mixture obtained was purified
by column chromatography when necessary.
15. Selected references: with Ag (a) Halbes-Letinois, U.;
Weibel, J.-M.; Pale, P. Chem. Soc. Rev. 2007, 36, 759;
Solution procedure: To a solution of alcohol (1 equiv)
and diphenylmethanol (200 mg, 1.08 mmol, 1 equiv) in
dichloroethane (5 ml/mmol) was added palladium chlo-
ride (20 mg, 0.108 mmol, 0.1 equiv). The reaction mix-
ture was then heated at 80 °C until disappearance of
the starting materials (TLC monitoring). The solvent
was then removed in vacuum and the crude mixture
obtained was purified by column chromatography.
´
(b) Orsini, A.; Viterisi, A.; Bodlenner, A.; Weibel, J.-M.;
´
Pale, P. A. Tetrahedron Lett. 2005, 46, 2259; (c) Viterisi,
A.; Orsini, A.; Weibel, J.-M.; Pale, P. A. Tetrahedron Lett.
2006, 47, 2779.
16. Selected references: with Au (a) Harkat, H.; Weibel, J.-M.;
Pale, P. Tetrahedron Lett. 2006, 47, 6273; (b) Harkat, H.;
Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2007, 48, 1439.