NiCl2·6H2O/NaBH4 in methanol: A mild and efficient strategy for chemoselective deallylation/debenzylation of aryl ethers

Article abstract of DOI:10.1016/j.tetlet.2013.06.072

Deprotection of allyl/benzyl aryl ethers was achieved chemoselectively. The mild and inexpensive reagent combination of NiCl₂·6H ₂O/NaBH₄ in methanol afforded the products in high yields, within a reaction time of 5-10 min.

Full text of DOI:10.1016/j.tetlet.2013.06.072

Tetrahedron Letters 54 (2013) 4540–4543
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Tetrahedron Letters
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NiCl2Á6H2O/NaBH4 in methanol: a mild and efficient strategy for
chemoselective deallylation/debenzylation of aryl ethers
Mangilal Chouhan a, Kapil Kumar a, Ratnesh Sharma a, Vikas Grover b, Vipin A. Nair a,
⇑
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160062, India
b Central Instrumentation Laboratory, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Deprotection of allyl/benzyl aryl ethers was achieved chemoselectively. The mild and inexpensive
reagent combination of NiCl2Á6H2O/NaBH4 in methanol afforded the products in high yields, within a
reaction time of 5–10 min.
Received 2 May 2013
Revised 12 June 2013
Accepted 15 June 2013
Available online 24 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Nickel chloride hexahydrate
Sodium borohydride
Debenzylation
Deallylation
Chemoselectivity
Selective protection and deprotection of functional groups is an
art and challenge in the synthesis of complex organic molecules. Of
the various kinds of protections available for alcohols/phenols,1,2
ethers are widely preferred owing to their stability towards nucle-
ophiles and bases. A number of reagents are used to cleave primary
alkyl aryl ethers such as BBr3,3 EtSNa/DMF,4 TMSI5 and
BCl3/n-Bu4NI.6 Although simple alkyl groups serve as effective
protecting groups, deprotection requires strongly electrophilic
reagents/conditions. Because of their stability, t-butyl ethers are
cleaved under moderately acidic conditions using either CF3COOH7
or FeCl3 in (CH3CO)2O.8 The allyl group, usually stable under basic
and acidic conditions, is another widely used protecting group for
alcohols and phenols. Methods for regeneration of alcohols from
allylic ethers include DDQ,9 NaBH4/I2,10 Me3SiCl/NaI,11
Scheme 1. Debenzylation of aryl benzyl ether.
Table 1
Effect of metal saltsa
Entry
Metal salts
(equiv)
NaBH4
(equiv)
Time (min)
Yield
(%)
1
2
3
4
5
6
7
8
9
—
1.0
—
30
30
30
30
15
30
30
15
5
—
—
CeCl3Á7H2O/NaI12 or Pd/C/H2.13 Cleavage of allyl groups has been
NiCl2Á6H2O (1.0)
14
reported using PdCl2/CuCl/DMF–H2O/O2
or with DIBAL and
FeCl3 (1.0)
1.0
1.0
1.0
1.0
1.0
2.0
3.0
4.0
20
45
70
46
Trace
85
92
93
catalytic NiCl2(dppp).15 The benzyl group can be used for the
protection of the hydroxy groups when acidic conditions for ether
cleavage are not tolerated. The benzyl protection is removed either
by using Pd/C/H2,16 Pd/C/TES,17 I2/TES,18 NaBrO3/Na2S2O419 or with
Na+ or K+ in NH3.20 Lewis acids21 such as FeCl3 and SnCl4 also afford
alcohols from benzyl ethers. The cleavage of inert aryl ethers using
different Ni salts is also reported.22 Though several methods are
available for the deprotection of ethers, the limitations imposed
by the substrates/reagents/procedures provide sufficient scope
CoCl2Á6H2O (1.0)
NiCl2Á6H2O (1.0)
PdCl2 (1.0)
CuCl (1.0)
NiCl2Á6H2O (1.5)
NiCl2Á6H2O (1.5)
NiCl2Á6H2O (1.5)
10
5
a
Benzyloxybenzene (1.0 equiv), methanol (5 mL).
for the development of newer methods. Based on our interests in
reaction methodology23 we were in search of a suitable strategy
for selective protection–deprotection of polyhydroxy compounds,
⇑
Corresponding author. Tel.: +91 172 229 2045; fax: +91 172 221 4692.
E-mail addresses: vn74nr@yahoo.com, vnair@niper.ac.in (V.A. Nair).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.072

M. Chouhan et al. / Tetrahedron Letters 54 (2013) 4540–4543
4541
Table 2
taking advantage of the variations in reactivity/environment of the
hydroxy groups. Our efforts culminated in a mild and efficient pro-
cedure for the deprotection of aryl benzyl ethers and allyl aryl
ethers using NiCl2Á6H2O and NaBH4 in methanol to afford phenols.
The chemoselectivity is demonstrated by the indolent reagent nat-
ure towards alkyl ethers. The procedure utilizes reagents that does
not require prior preparation and has advantages such as neither
strongly basic nor acidic conditions are required, no precautions
to exclude moisture or air from the reaction, inexpensive reagents
and excellent yields in a short reaction time of 5–10 min.
Effect of solventsa
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
Toluene
MeCN
DMF
THF
Water
EtOH
30
30
30
30
30
30
5
—
—
—
—
20
50
92
MeOH
a
Benzyloxybenzene (1.0 equiv), NiCl2Á6H2O (1.5 equiv), NaBH4 (3.0 equiv).
Table 3
Reactions of allyl/benzyl ethers with NiCl2Á6H2O/NaBH4
a
Entry
Substrate
Product
Yieldb (%)
92
1
2
3
93
90
4
5
6
92
88
89
7
8
90
90
9
10
11
12
90
89
90
90
13
14
15
90
87
93
16
88
(continued on next page)

4542
M. Chouhan et al. / Tetrahedron Letters 54 (2013) 4540–4543
Table 3 (continued)
Entry
Substrate
Product
Yieldb (%)
17
88
18
92
a
Substrate (1.0 equiv), NiCl2Á6H2O (1.5 equiv), NaBH4 (3.0 equiv), methanol (5 mL).
b
Isolated yield.
Figure 1. Plausible reaction mechanism.
Scheme 2. Chemoselectivity of the reaction.
A detailed investigation was performed on benzyloxybenzene
5–10 min. While the scope of this procedure was successfully ver-
ified, the chemoselectivity observed was of greater interest. A dis-
tinct difference in reactivity was demonstrated by the alkyl and
aryl benzyl ethers. The aryl ethers underwent reaction while the
impervious alkyl ethers did not, providing selectivity. A similar fate
was observed for allyl aryl ethers under the same reaction condi-
tion (Table 3, entries 10–18), which gave the corresponding phe-
nols in 5–10 min. The procedure works well for aryl rings
bearing both electron-donating and withdrawing groups and the
position of the substituents on the aryl ring did not significantly
deter the quantitative outcome of the reaction. It is to mention that
the ester and nitrile groups would survive the reaction condition to
witness the conversion of aryl ethers to phenols.
by reacting it with sodium borohydride and different metal salts
in methanol at 0 °C (Scheme 1). Salts of transition metals such as
Fe, Co, Ni, Pd and Cu were evaluated (Table 1). NiCl2Á6H2O provided
maximum yields of phenol in 5 min, while other metal salts gave
inferior yields. An examination of the effect of the solvents on
the outcome of the reaction indicated that non-polar and polar
aprotic solvents did not facilitate the reaction while polar protic
solvents such as water and ethanol showed an improvement
(Table 2). The best result was obtained with methanol. From the
above results we concluded that reacting 1.0 equiv of the benzyl
protected phenols with 1.5 equiv of NiCl2Á6H2O and 3.0 equiv of
NaBH4 in methanol medium at 0 °C would be the ideal condition
for the reaction. The optimized condition was generalized with
various benzyl protected phenols, which afforded the products in
excellent yields (Table 3, entries 1–9) within a reaction time of
A plausible mechanism for the reaction is illustrated in Figure 1.
It is expected that nickel forms a chelated complex with the
p-elec-
trons of the aryl ring, which weakens the aryl-oxygen bond signif-

M. Chouhan et al. / Tetrahedron Letters 54 (2013) 4540–4543
4543
icantly. This facilitates the donation of electrons from the oxygen
Acknowledgment
atom to the electron deficient boron resulting in the attack of hy-
dride on the benzylic/allylic carbon, and consequently the cleavage
of the ether linkage. The high bonding affinity between oxygen and
boron aided by the polar protic medium which stabilizes the par-
tial charges of the transition state could be attributed to the faster
reaction kinetics and chemoselectivity. The evidence for complex-
ation is apparent from the inert nature of the alkyl ethers which
did not cleave even with an excess amount of the reagents (Scheme
Funding from the Department of Science and Technology, Gov-
ernment of India is gratefully acknowledged.
Supplementary data
Supplementary data (experimental procedures, compound data
and scanned spectra (1H NMR, 13C NMR and HRMS)) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.06.072.
2). The lack of
p-electrons does not materialize the necessity for
complex formation with nickel. Thus the availability of the
p
-elec-
trons of the aryl ring for complexation, and the coordination be-
tween oxygen and boron in the transition state assist the
reactions of aryl ethers. The effect of coordination was also discern-
ible from the reactions of benzyl/allyl amines which remained
unreactive (Scheme 2), and hence chemoselective cleavage of the
aryl ether was feasible in their presence. This could be rationalized
by the fact that nitrogen forms a strong chelate complex with nick-
el, and therefore lacks coordination with boron to facilitate a
hydride transfer to the allylic/benzylic carbon. The basic nature
of the amine is also neutralized to a significant extent by the Lewis
acid character of NiCl2. On the contrary, the oxygen of the aryl
ethers is a better centre for coordination with boron. Though the
in situ formation of nickel boride and its role in the reaction may
be speculated, it was convincingly eliminated by an independent
reaction. Addition of NaBH4 to a solution of NiCl2Á6H2O in metha-
nol generates a black precipitate of nickel boride with a vigorous
effervescence. Introducing benzyloxybenzene to this reaction mix-
ture did not afford phenol. This result indicates the possibility of
nickel salt forming a chelated complex with the aryl ethers initially
and thereafter the transfer of hydride occurs to cleave the CAO
bond. To a certain extent, in situ formed nickel hydride can also
be envisioned to be responsible for the deprotection.22a Though a
few possibilities could be speculated for the mechanistic aspects
of this reaction, the exact details need to be convincingly
established.
References and notes
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In summary, a highly efficient and economic strategy for
chemoselective deprotection of aryl ethers was developed. The
benzyl/allyl aryl ethers were selectively cleaved in the presence
of their alkyl counterparts, using an inexpensive reagent combina-
tion of NiCl2Á6H2O/NaBH4 in methanol at 0 °C within a short
reaction time of 5–10 min. A variation in reactivity was observed
with other functional groups. While the alkyl ethers remained
inert, the ester and nitrile groups survive the reaction condition.
The benzyl/allyl protected amines were also unreactive. The avail-
ability of the
p-electrons of the aryl ring for complex formation
with nickel, and the coordination between oxygen and boron have
been reasoned for the observed reactivity and chemoselectivity.