Counterattack mode differential acetylative deprotection of phenylmethyl ethers: Applications to solid phase organic reactions

Article abstract of DOI:10.1021/jo801659g

A counterattack protocol for differential acetylative cleavage of phenylmethyl ether has been developed. The phenylmethyl moiety is liberated as benzyl bromide that is isolated and reused providing advantages in terms of waste minimization/utilization and atom economy. The applicability of this methodology has been extended for solid phase organic reactions with the feasibility of reuse of the solid support.

Full text of DOI:10.1021/jo801659g

phenylmethyl ethers with AcBr (3 equiv)-LiBr (20 mol %)
with high chemo- and regioselectivities.3
Since the utility of a PG is associated with its ease of removal
without affecting other protecting/functional groups, the scope
of the de-O-benzylation was evaluated with various substituted
phenylmethyl ethers (Table 1).
Counterattack Mode Differential Acetylative
Deprotection of Phenylmethyl Ethers:
Applications to Solid Phase Organic Reactions
Asit K. Chakraborti* and Sunay V. Chankeshwara
Substrates bearing electron donating group such as alkyl or
alkoxy reacted readily with excellent yields (entries 2, 12-20;
Table 1). The presence of an electron withdrawing group gave
poor to moderate yields (entries 3-6 and 8-10; Table 1) and
required longer time. However, in all the cases the starting
materials could be recovered and reused/recycled increasing the
overall yield of the products. The presence of a halogen atom,
OR, and COMe adjacent to the benzyloxy group assisted the
de-O-benzylation (compare entry 1 with 17; 5 with 18; 6 with
7; 10 with 11; Table 1). Excellent regioselectivity was obtained
with substrates containing both benzyl and nonbenzyl ether
moieties (entries 16-20, 23, 25, 28, 30, and 31) with exclusive
de-O-benzylation. In the case of benzyl cinnamyl ether (entry
27), selective deprotection at the cinnamyl ether was observed.
For substrates having primary and secondary benzylic ether
moieties (entry 26), de-O-benzylation occurred at the primary
benzyl ether. Methyl ether, methyl ester, and benzyl ester groups
remained unaffected (entries 9, 16-20, 23, and 32; Table 1).
Good conversion took place with AcBr-LiCl, albeit lesser
than that of AcBr-LiBr, but the replacement of LiBr by LiI
and LiF was ineffective. Halides (fluoride/chloride/bromide/
iodide) of other metals, e.g., Na, K, Cs, Rb, Ca, and Mg, were
either ineffective or gave poor conversion. The use of AcCl,
AcOH, and Ac2O in combination with LiBr was also ineffective.
No significant ether cleavage was observed in using AcBr or
LiBr (stoichiometric amount) alone at rt or under reflux for 24 h.
Replacement of DCM by other solvents such as DCE, MeCN,
DMF, and NMP did not offer any significant deprotection at rt
or under reflux. The use of ethereal solvents such as THF and
dioxane was also limited due to their reaction with the reagent
system. The protocol was effective at low temperature (ca. -40
°C) with marginal decrease in conversion suggesting the
feasibility of application for highly reactive substrates under
mild conditions.
The course of the reaction is depicted in Scheme 1 and
accounts for the observed reactivity and selectivity. Electrophilic
activation of AcBr by coordination with LiBr4 followed by
nucleophilic attack by the oxygen atom of the ether and
counterattack by the liberated Br- at the benzylic carbon through
the cyclic structure I leads to the acetylated product and benzyl
bromide.
Since, the efficiency of the reaction should depend upon the
nucleophilic property of the oxygen atom of the benzyl ether,
(i) de-O-benzylation of benzyl ethers of alcohols took place at
faster rates than that of the benzyl ethers of phenols (compare
entries 1-23 with 24-31; Table 1), and (ii) the presence of an
electron withdrawing group makes the deprotection sluggish
(entries 3-6 and 8-10; Table 1). The unusual reactivity of
substrates having halogen atom, OR, and COMe groups adjacent
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in
ReceiVed July 29, 2008
A counterattack protocol for differential acetylative cleavage
of phenylmethyl ether has been developed. The phenylmethyl
moiety is liberated as benzyl bromide that is isolated and
reused providing advantages in terms of waste minimization/
utilization and atom economy. The applicability of this
methodology has been extended for solid phase organic
reactions with the feasibility of reuse of the solid support.
Protecting groups (PGs), albeit often under-appreciated,
constitute key components in drug synthesis amounting to >20%
of all chemical transformations and about two key steps per
drug candidate.1 The overall merit of a synthetic process is
highly influenced by the interplay of physicochemical properties,
ease of introduction, cost-effectiveness, and selective manipula-
tion of PGs. The protection and deprotection of the hydroxyl
group are encountered with 30% and 14% frequency, respec-
tively, in the manufacturing process of drugs.1 In this context,
the phenylmethyl ether formation is the most common practice
for protecting hydroxyl groups.2 We describe herein a conve-
nient and high-yield protocol for acetylative cleavage of
* Corresponding author. Fax: 91 (0)172 2214692. Phone: 91 (0)172 2214683.
(1) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337.
(2) Greene, T. W.; Wuts, P. G. M. Protecting Group in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999.
(3) A few recent reports on de-O-benzylation: (a) Fletcher, S.; Guning, P. T.
Tetrahedron Lett. 2008, 49, 4817. (b) Ploypradith, P.; Cheryklin, P.; Niyomtham,
N.; Bertoni, D. R.; Ruchirawat, S. Org. Lett. 2007, 9, 2637. (c) Lla`cer, E.; Romea,
P.; Urp´ı, F. Tetrahedron Lett. 2006, 47, 5815. (d) Vincent, A.; Prunet, J.
Tetrahedron Lett. 2006, 47, 4075. (e) Huang, W.; Zhang, X.; Liu, H.; Shen, J.;
Jiang, H. Tetrahedron Lett. 2005, 46, 5965. For review see: (f) Weissman, A. A.;
Zewge, D. Tetrahedron 2005, 61, 7833. (g) Chakraborti, A. K.; Sharma, L.;
Nayak, M. K. J. Org. Chem. 2002, 67, 6406. (h) Nayak, M. K.; Chakraborti,
A. K. Tetrahedron Lett. 1997, 38, 8749. (i) Oriyama, T.; Kimura, M.; Oda, M.;
Koga, G. Synlett 1993, 437.
(4) Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem.
2004, 3597.
10.1021/jo801659g CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1367–1370 1367

TABLE 1. AcBr-LiBr-Mediated Acetylative Cleavage of
SCHEME 1. The Role of AcBr-LiBr in Acetylative
Deprotection of Phenylmethyl Ethers
Arylmethyl Ethersa
SCHEME 2. The Chelation Effect of a Neighboring Group
SCHEME 3. Differential Deprotection during
Intermolecular Competition between Phenylmethyl Ethers
with Varying Electronic Environment
to the benzyl ether moiety (entries 7, 11, and 17-20) is due to
the chelation effect (Scheme 2) of these groups in providing
assistance of nucleophilic attack by the oxygen atom of the
benzyl ether on the AcBr (complexed with LiBr) and nestling
the incipiently formed Br- in appropriate orientation/position
for nucleophilic attack at the benzylic carbon of the ether
through the cyclic structure II/III.
The influence of the electronic environment in the substrates
on the reaction time and yield of de-O-benzylations encouraged
us to demonstrate the potentiality of this protocol for selective
deprotection of benzyl ethers during intermolecular competi-
tions. Treatment of equimolar mixtures of (i) 4-methoxyphe-
nylbenzyl ether and 4-nitrophenylbenzyl ether, (ii) 4-methox-
yphenylbenzyl ether and 4-cyanophenyl benzyl ether, and (iii)
4-methoxyphenylbenzyl ether and 4-bromophenylbenzyl ether
for 6, 6, and 12 h afforded selectivities (GCMS) of 98:2, 90:
10, and 70:30, respectively, in favor of acetylative de-O-
benzylation of 4-methoxyphenylbenzyl ether. The reaction of
4-methylphenylbenzyl ether and 2,4,6-trimethylphenyl benzyl
ether resulted in 30:70 selectivity (Scheme 3).
a The substrate (1 mmol), AcBr (3 mmol, 3 equiv), and LiBr (20
mol%) in dry DCM were stirred magnetically at rt (30-35 °C) under
argon. b Yield of O-acetylated derivative of the corresponding
phenol/alcohol. c The figure in parentheses represents the yield on the
basis of recycling of the recovered starting material. d Phenol was
isolated as the product. e Yield of 4-benzyloxyphenyl acetate. f The
corresponding phenol was obtained in 6% yield. g Yield of 2-phenethyl
acetate. h Yield of 1-phenethyl acetate. i Yield of benzyl acetate. j Yield
of O-acetylbenzoin. k Yield of (+)-(1S,2R,5R)-isomenthyl acetate. l Yield
of (-)-(1R,2S,5R)-menthyl acetate. m The starting material remained
unchanged and was recovered.
The chelation effect of an adjacent group in differenting the
rate of de-O-benzylation was utilized for selective deprotection
1368 J. Org. Chem. Vol. 74, No. 3, 2009

SCHEME 4. Chelation Effect of the Neighboring Group for
Differential Deprotection of Phenylmethyl Ethers during
Intermolecular and Intramolecular Competition Studies
SCHEME 6. Cleavage of Phenylmethyl Ether Supported on
Merrifield Resin and Recycling of the Solid Support
benzylation required stoichiometric amounts of F3B·OEt2 and
NaI in Ac2O as solvent.6 The hydrogenolysis protocols3c-e
lacking chemoselectivity and a NO2 group or an olefinic
unsaturation undergo reduction. Under hydrogenolysis condi-
tions, the benzyl moiety is lost as the corresponding hydrocarbon
(e.g., toluene) and lacks atom efficiency.7 Under the present
methodology, the phenylmethyl moiety is liberated as benzyl
bromide that was recovered and reused for phenylmethyl ether
formation. The increasing influence of green chemistry on
chemistry based research organization8 and the tight legislation9
on chemical processes to prevent waste, avoid use of toxic
substances,10 etc. press the need for sustainable development.
The use of cheap, easy to handle, and less toxic LiBr as catalyst
and high yield, devoid of side reaction, are the distinct
advantages offered by this newly developed protocol. The
reusability of the benzyl bromide adds another dimension to
this protocol and provides an approach toward sustainable
development in terms of waste minimization/utilization and atom
economy.7
The scope of this de-O-benzylation protocol was extended
to the solid phase organic reaction (SPOR) (Scheme 6). The
progress of the reaction and loading on the solid phase was
monitored/determined by FTIR.11 In model studies 4-hydroxy
acetophenone and 4-methoxy phenol loaded on Merrifield resin
were subjected to de-O-benzylation to regenerate the corre-
sponding phenols in 98% and 95% yields, respectively. The
recovered resin was the corresponding bromide form (FTIR,
DSC) and was reused for loading of 4-hydroxyacetophenone
and 4-cyanophenol. The loading of the phenolic substrates on
the recovered solid support required shorter times and high-
lighted the advantage of the reuse of the recovered resin.
The applicability for SPOR was further demonstrated by
generating a six-component solid phase library by loading six
different phenols on Merrifield resin and treatment of the solid
phase library with AcBr-LiBr to liberate the parent phenols
and the resin as its bromide form (Scheme 7).
SCHEME 5. Differential Deprotection of Phenylmethyl
Ether during Intramolecular Competition Studies
during intermolecular and intramolecular competiton studies
(Scheme 4). Reactions of equimolar mixtures of (i) 4-methox-
yphenylbenzyl ether and 2-methoxyphenylbenzyl ether and (ii)
4-acetylphenylbenzyl ether and 2-acetylphenylbenzyl ether
afforded selectivities (GCMS) of 30:70 and 2:98, after 6 and
12 h, respectively. The reaction of 2,4-dibenzyloxy acetophe-
none exhibited exclusive selectivity in favor of de-O-benzylation
of the phenylmethyl ether adjacent to the COMe group affording
2-hydroxy-4-benzyloxy acetophenone (I) and 2-acetoxy-4-
benzyloxy acetophenone (II) in 50% and 40% yields, respec-
tively. The acetylated product II was formed as the only product
in 40% yield when the reaction was carried out for 6 h and the
unreacted starting material was recovered. A 60% yield of I
was obtained after 12 h along with 25% of II and 5% of the
diacetyl derivative of the di-de-O-benzylated compound.
Excellent selectivity was achieved in intramolecular competi-
tion between (i) benzyl ether and benzyl ester and (ii) benzyl
ethers of phenol and alcohol (Scheme 5). The reaction of benzyl
4-benzyloxybenzoate underwent cleavage of the benzyl ether
group exclusively in 40% yield. The unreacted starting material
was recovered and reused/recycled to increase the overall yield
to 70%. The use of 6 equiv of AcBr afforded 65% yield. In the
case of 4-benzyloxyphenylmethyl phenylmethyl ether, depro-
tection of the alcoholic benzyl ether group took place exclusively
affording the corresponding acetylated product in excellent yield.
Differential cleavage of arylmethyl ethers has been reported
with use of CrCl2 (3 equiv)/LiI (4 equiv) in moisture containing
EtOAc.5 The recent reports on the use of protic acids for the
deprotection of aromatic ethers3a,b often leading to undesired
ring alkylation and requiring a large excess of thioanisole to
suppress the side reaction, which are not applicable to electron-
rich phenolic ethers that generate complex mixtures of
Friedel-Crafts byproduct, are suitable only for phenolic ethers
with an ortho π-electron-withdrawing group and do not work
with alkyl benzyl ethers. The reported acetylative de-O-
In conclusion, a counterattack mode differential acetylative
deprotection of phenylmethyl ethers has been developed. The
benzyl ether moiety that is liberated as benzyl bromide is reused
and offers an advantage through waste minimization/utilization.9
(6) Brar, A.; Vankar, Y. D. Tetrahedron Lett. 2006, 47, 5207.
(7) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233.
(8) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson,
T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green
Chem. 2008, 10, 31.
(9) (a) Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.; Memoli,
S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000, 72, 1207.
(b) DeSimone, J. M. Science 2002, 297, 799.
(10) Sweet, D. V. Registry of Toxic Effects of Chemical Substances 1985-
86; U.S. Government Printing Office: Washington, D.C., 1988, 4049.
(11) (a) Yamada, A.; Kaun, T. H.; Pandurangi, A. V. U.S. Patent 5683709,
Nov 4, 1997. (b) Gallop, M. A.; Fitch, W. L. Curr. Opin. Chem. Biol. 1997, 1,
94. (c) Yan, B. Curr. Opin. Chem. Biol. 2002, 6, 328.
(5) Falck, J. R.; Barma, D. K.; Baati, R.; Mioskowski, C. Angew. Chem.,
Int. Ed. 2001, 40, 1281.
J. Org. Chem. Vol. 74, No. 3, 2009 1369

SCHEME 7. Six-Component Solid Phase Library Synthesis
and Cleavage of Phenols from Solid Support
evaporation. The residue was subjected to column chromatography
purification (60-120 mesh silica gel 20 g, 5% EtOAc in hexane)
to afford 4-methoxyphenyl acetate and 4-nitrophenyl acetate in 98%
and 2% yields, respectively.
Typical Experimental Procedure for Solid Phase Organic
Reaction: Representative Procedure for Cleavage of Merri-
field Resin-Bound Ether. To the suspension of Merrifield resin
bound 4-hydroxy acetophenone [(0.375 mmol, 150 mg, preswelled
in DCM (2 mL) for 0.5 h)] was added the mixture of LiBr (20 mg,
60 mol %) and AcBr (3.00 mmol, 0.234 mL, 3 equiv) in DCM (4
mL) under argon and the resulting mixture was stirred magnetically
for 24 h at room temperature. The resin was collected by filtration
and the filtrate was washed with 5% aq NaHCO3 (4 mL) and
acidified with 5% HCl solution. The organic layer was dried (anh
Na2SO4) and concentrated under rotary vacuum evaporation to
afford the product (IR, 1H NMR, and MS). The solid support was
washed with NMP (3 × 5 mL), water (3 × 5 mL), MeOH (3 × 5
mL), and acetone (3 × 5 mL), respectively. The recovered resin
was dried under vacuum for 0.5 h and was found to be the bromo
derivative of the Merrifield resin exhibiting characteristic absorption
at 1245-1250 cm-1 in the FTIR (the original Merrifield resin has
characteristic absorption at 1263 cm-1 of the CH2Cl moiety).11a
The resin was reused for further reaction.
Reuse of the Bromo-Derived Merrifield Resin Recovered
after Deprotection. The bromo-derived Merrifield solid support
(0.575 mmol, 250 mg) was swelled for 4 h in dry NMP (2 mL).
Simultaneously, in a separate reaction flask 4-cyanophenol (0.21
g, 3 equiv) and K2CO3 (3.6 equiv) were stirred in NMP under argon
atmosphere for 4 h. The potassium salt was transferred to the
swelled Merrifield support and the mixture was stirred for 24 h.
The mixture was filtered through a sintered glass funnel. The solid
support was washed with NMP (3 × 5 mL), water (3 × 5 mL),
MeOH (3 × 5 mL), and acetone (3 × 5 mL), respectively. The
resin was dried over vacuum for 30 min. The loading was
determined by FTIR and Synthesis Monitoring System (SMS). In
the FTIR, complete disappearance of the absorption at 1245-50
cm-1 and appearance of the nitrile signal at 2223 cm-1 indicated
completion of the reaction.
The applicability of this methodology has been extended for
solid phase organic reactions with the feasibility of reuse of
the solid support.
Experimental Section
Typical Experimental Procedure for the LiBr-AcBr-Cata-
lyzed Cleavage of Aryl Benzyl Ethers: 2-Acetylphenyl Acetate
(Entry 11, Table 1). To a magnetically stirred solution of
2-benzyloxyacetophenone (0.56 g, 2.5 mmol) and AcBr (0.93 g,
7.5 mmol, 3 equiv) in DCM (5 mL) was added LiBr (43 mg, 20
mol %). The reaction mixture was stirred at 30-35 °C for 12 h.
After completion of the reaction (TLC), the reaction mixture was
diluted with water (1 mL) and EtOAc (15 mL). The organic layer
was separated and washed with water (10 mL) and brine solution
(10 mL), dried (anh Na2SO4), and concentrated under rotary vacuum
evaporation. The residue was subjected to column chromatography
purification (60-120 mesh silica gel 20 g, 5% EtOAc in hexane)
to afford 2-acetylphenyl acetate as an oil (0.35 g, 78%), identical
(IR, NMR, and EIMS) with an authentic sample.12
Typical Experimental Procedure for Chemoselective O-
Debenzylation of Benzyl Ethers during Intermolecular Com-
petition Studies (Scheme 3): 1-(Benzyloxy)-4-methoxybenzene
vs 4-Benzyloxynitrobenzene. To a magnetically stirred solution
of 1-(benzyloxy)-4-methoxybenzene (0.53 g, 2.5 mmol), 4-benzy-
loxynitrobenzene (0.57 g, 2.5 mmol), and AcBr (0.93 g, 7.5 mmol,
3 equiv) was added LiBr (43 mg, 20 mol %). The reaction mixture
was stirred at 30-35 °C for 12 h. The reaction mixture was diluted
with water (1 mL) and EtOAc (15 mL). The organic layer was
separated and washed with water (10 mL) and brine solution (10
mL), dried (anh Na2SO4), and concentrated under rotary vacuum
Supporting Information Available: Spectral data of all
compounds and scanned spectra of a few representative known
and all unknown compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Chakraborti, A. K.; Gulhane, R.; Shivani, Synthesis 2003, 111.
JO801659G
1370 J. Org. Chem. Vol. 74, No. 3, 2009