Highly efficient and selective deprotection method for prenyl, geranyl, and phytyl ethers and esters using borontrifluoride-etherate

Article abstract of DOI:10.1080/00397911.2011.589561

An efficient, simple, and practical method has been developed for the deprotection of prenyl, geranyl, and phytyl ethers and esters of aromatic and aliphatic compounds using borontrifluoride-etherate (BF₃· OEt₂) at room temperature in good to excellent yields for the first time. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.589561

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Highly Efficient and Selective
Deprotection Method for Prenyl,
Geranyl, and Phytyl Ethers and Esters
Using Borontrifluoride–Etherate
T. Narender a , K. Venkateswarlu a , G. Madhur a & K. Papi Reddy a
a Medicinal and Process Chemistry Division, Central Drug Research
Institute, Lucknow, India
Accepted author version posted online: 20 Jan 2012.Version of
record first published: 05 Sep 2012.
To cite this article: T. Narender, K. Venkateswarlu, G. Madhur & K. Papi Reddy (2013): Highly
Efficient and Selective Deprotection Method for Prenyl, Geranyl, and Phytyl Ethers and Esters
Using Borontrifluoride–Etherate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:1, 26-33
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Synthetic Communications1, 43: 26–33, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.589561
HIGHLY EFFICIENT AND SELECTIVE DEPROTECTION
METHOD FOR PRENYL, GERANYL, AND PHYTYL
ETHERS AND ESTERS USING
BORONTRIFLUORIDE–ETHERATE
T. Narender, K. Venkateswarlu, G. Madhur, and
K. Papi Reddy
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
GRAPHICAL ABSTRACT
Abstract An efficient, simple, and practical method has been developed for the deprotection
of prenyl, geranyl, and phytyl ethers and esters of aromatic and aliphatic compounds using
borontrifluoride–etherate (BF3 ꢀ OEt2) at room temperature in good to excellent yields for
the first time.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Synthetic Communications1 to view the free supplemental file.
Keywords BF3 ꢀ OEt2; deprotection; geranylether; prenylester; prenylether
INTRODUCTION
The proper introduction and removal of protecting groups are two of the most
important and widely carried out synthetic transformations in preparative organic
chemistry,[1] in particular, in the highly selective construction of complex polyfunc-
tional molecules and in the synthesis of natural products such as alkaloids,
Received March 7, 2011.
Address correspondence to T. Narender, Medicinal and Process Chemistry Division, Central Drug
Research Institute, CSIR, Lucknow 226001, India. E-mail: t_narendra@cdri.res.in
26

DEPROTECTION OF PRENYL ETHERS AND ESTERS
27
macrolides, polyether antibiotics, and prostaglandins. Regularly the problem arises
that a given functional group has to be protected or deprotected selectively under
the mildest conditions and in the presence of functionalities of similar reactivity as
well as in the presence of structures sensitive to acids and bases. Organic chemists
have to some extent responded to these challenges to achieve selectivity in organic
synthesis.
During our drug discovery program on the synthesis of bioactive prenylated
chalcones,[2–6] we observed a facile prenyl group deprotection of acetophenones
under the influence of BF3 ꢀ OEt2. Deprotection attempts were also successful on ger-
anyl and phytylated aromatic ethers using BF3 ꢀ OEt2, which prompted us to carry
out further work on this reagent. Our literature survey revealed that several alkyl
groups (methyl,[7–10] ethyl,[11] t-butyl[12,13]) have been used to protect the phenolic
compounds; however, they need drastic conditions for protection as well as depro-
tection, which also affect other functional groups. Newer protecting groups such
as
methoxymethylchloride
(MOMCl)[14–18]
methoxyethoxymethylchloride
(MEMCl),[19] 2-(trimethylsilyl) ethoxymethylchoride (SEMCl),[20,21] and tetrahydro-
phyranoether (THP ethers)[22,23] have been developed that needs milder conditions.
The prenyl group has also been used for protection of alcohols and phenols;[24–34]
however, the reported reagents in deprotection of the prenyl group lack selectivity
in multifunctional compounds. To our knowledge, so far BF3 ꢀ OEt2 has not been
used for the deprotection of prenylethers. We therefore report the selective deprotec-
tion of prenylethers of aromatic compounds using BF3 ꢀ OEt2 for the first time. In
addition, we also demonstrate the utility of geranyl and phytyl groups as protecting
groups and deprotection by BF3 ꢀ OEt2.
Initially phenolic hydroxyls of few aldehydes (1a–1c) and acetophenones
(1d–1e) were protected using prenylbromide in the presence of K2CO3 in dry acetone
to provide the respective prenylethers (2a–2e). The resultant prenyl ethers were
treated with a stochiometric amount of BF3 ꢀ OEt2 in dry 1,4-dioxane, which cleanly
provided the respective deprenylated (1a–1e) compounds in good to excellent yields
(Scheme 1). It is noteworthy to mention here that the BF3 ꢀ OEt2 did not affect the
O-methyl ether of 1c.
Encouraged by these results, we then focused on increasing the chain length of
the alkenyl group (Scheme 2). O-Geranylated compounds were prepared from
3,4-dimethylphenol (1f) and 2,4-dihydroxyacetophenone (1e) using the same proto-
col as described previously and subjected to degeranylation using BF3 ꢀ OEt2, which
again deprotected the geranyl group to give 1f and 1e in excellent yields.
Scheme 1. Protection of aromatic aldehydes and ketones by prenyl bromide and deprotection by
BF3 ꢀ OEt2. Reagents and conditions: (a) K2CO3, dry acetone, prenyl bromide, rt, 5 h; (b) BF3 ꢀ OEt2,
dry 1,4-dioxane, rt.

28
T. NARENDER ET AL.
Scheme 2. Protection of phenol and polyhydroxyacetophenone by geranyl bromide and deprotection by
BF3 ꢀ OEt2. Reagents and conditions: (a) K2CO3, dry acetone, prenyl bromide, rt, 5 h; (b) BF3 ꢀ Et2O, dry
1,4-dioxane, rt, 3 h.
We further explored BF3 ꢀ OEt2 for deprotection of aromatic and aliphatic
esters (Scheme 3). p-Hydroxybenzoic acid (1g) and p-hydroxyphenylacetic acid
(1h) were prenylated to provide 2h and 2i, which contain ester and ether functional-
ity, and subjected to a reaction with BF3 ꢀ OEt2, which deprotected the both prenyl
groups (ether and ester) of 2h and 2i in good yields. Similar results were obtained
with phytyl ester 2j upon reaction with BF3 ꢀ OEt2 to give 1i.
To demonstrate the application of this methodology in the natural product
chemical transformations, chalcone 1j was protected with prenyl and geranyl groups
to give 2k and 2l respectively and subsequently reacted with BF3 ꢀ OEt2, which pro-
vided the dealkenylated chalcone 1j. Prenyl esters (2m and 2n) of two terpenes such
as 3-oxo-freideline-carboxilic acid (1k) and ursolic acid (1l) were prepared and sub-
jected to deprenylation reaction using BF3 ꢀ OEt2 to give respective acids (Scheme 4)
in excellent yields.
Allyl derivative of p-hydroxyacetophenone (2o), N-prenylated nitroaniline
(2p), and O-butyl derivative of 1g were prepared using allylbromide, prenylbromide,
and n-butylbromide, respectively; however, BF3 ꢀ OEt2 did not deprotect any of these
three compounds (Scheme 5), which clearly indicated the selectivity of BF3 ꢀ OEt2
toward prenyl and geranyl groups. To further study the selectivity toward deprotec-
tion of N-alkenyl and O-alkenyl groups, 2r was prepared from 1n, and deprenylation
Scheme 3. Synthesis of esters by prenyl bromide and phytol and their deprotection by BF3 ꢀ OEt2.
Reagents and conditions: (a) K2CO3, dry acetone, prenyl bromide, rt, 5 h; (b) BF3 ꢀ OEt2, dry 1,4-dioxane,
rt, 18 h; (c) DCC, DMAP, dichloromethane, phytol, rt, 4 h.

DEPROTECTION OF PRENYL ETHERS AND ESTERS
29
Scheme 4. Etherification and esterification of a few natural products by prenyl bromide and geranylbro-
mide and deprotection by BF3 ꢀ OEt2. Reagents and conditions: (a) K2CO3, dry acetone, alkenyl bromide,
rt; (b) BF3 ꢀ Et2O, dry 1,4-dioxane, rt.
reactions led to selective deprotection of ester group only to give N,N-
diprenylbenzoic acid (3a).
The reaction mechanism in the deprotection of prenyl, geranyl, and phytyl
group appears (Fig. 1) to be a depolarization of the C-O bond by BF3 ꢀ OEt2, leading
to breaking of the C-O bond and subsequent removal of allylic hydrogen from
methyl group to give the stable diene. The formation of isoprene (diene) was
confirmed by thin-layer chromatography (TLC) and gas chromatography (GC) with
an authentic sample of isoprene during the deprotection reaction on 2d to 1d. In the
case of O-allylated acetophenone (2o), formation of stable diene is not possible, and
hence failure of deprotection to provide 1d, which supports our proposed reaction
mechanism. Further studies, however, are required to confirm the exact reaction
mechanism.
Scheme 5. Synthesis of O-allylated, N-prenylated and O-alkylated aromatic compounds and attempt to
deprotect O-allyl, N-prenyl, and O-alkyl groups by BF3 ꢀ OEt2. Reagents and conditions: (a) K2CO3,
dry acetone, allyl bromide, rt; (b) K2CO3, dry acetone, n-butyl bromide, rt, 12 h; (c) K2CO3, dry acetone,
prenyl bromide, rt, 5 h, 80%; (d) BF3 ꢀ Et2O, dry 1,4-dioxane, rt.

30
T. NARENDER ET AL.
Figure 1. Possible reaction mechanism in the deprotection of aromatic ethers and esters by BF3 ꢀ OEt2.
In summary we developed highly efficient method for selectively deprotecting
the prenyl, geranyl, and phytyl ethers and esters of aromatic and aliphatic com-
pounds using BF3 ꢀ OEt2 for the first time in good to excellent yields. We also demon-
strated geranyl and phytyl groups as protecting groups and deprotection by
BF3 ꢀ OEt2 for the first time. Our method has several advantages such as easy depro-
tection, simple procedure, good yields, and tolerance to other functional groups such
as aromatic alkyl ethers, alkyl esters, amides, alkyl amines, and alkenylamines. This
method can also be very useful in the synthesis and chemical transformation of
natural products of biological importance.
EXPERIMENTAL
1H NMR and 13C NMR spectra were run on Bruker Advance DPX 200- and
300-MHz spectrometers in CDCl3, and tetramethylsilane (TMS) was used as the
internal standard. Electrospray ionization (ESI)–mass spectra (MS) were recorded
on a Jeol S ꢁ 102 ¼ DA-6000. Silica gel (60–120 mesh) was used as stationary phase
to isolate the compounds.
Representative Procedure for Preparation of Prenylated,
Geranylated Alcohol, Phenols, Esters, and Amines
To a stirred solution of alcohol, phenol or amine (1 equivalent) in dry acetone
and dry K2CO3 was added prenyl or geranyl bromide (1 to 2 equivalent) at room
temperature. The resultant solution was stirred for 5–6 h. The reaction mixture
was then filtered through sintered funnel to remove K2CO3 and the filtrate was eva-
porated under reduced pressure. The crude mixture was purified by silica gel column
chromatography using hexane-ethylacetate (99:1) for 2a, 2b, 2d, 2f, 2m,
hexane-ethylacetate (98:2) for 2e, 2g, 2h, 2i, 2n, 2r, hexane-ethylacetate (97:3)
for 2o, 2p, hexane-ethylacetate (96:4) for 2k, 2 l and hexane-ethylacetate (94:6) for
2c as a mobile phase to afford protected compound.

DEPROTECTION OF PRENYL ETHERS AND ESTERS
31
Representative Procedure for Preparation of Phytylated Esters
The solution of carboxylic acid (1 equivalent) in DCM was added DCC
(1.5 equivalents) and DMAP (catalytic amount). Phytol (1.2 equivalents) was then
added to the reaction mixture. Whole solution was stirred for 4 h. The reaction
mixture was then filtered off the solid part and filtrate was concentrated under
reduced pressure. The crude was purified by column chromatography using
hexane-ethylacetate (98:2) mobile phase to afford the pure ester 2j.
Representative Procedure for the Deprotection of Prenylated,
Geranylated, or Phytylated Ethers and Esters
BF3-OEt2 (1.5 to 2 equivalents) gradually was added to a stirred solution of
prenylated ether or ester (1 equivalent) in 1,4-dioxane at room temperature. The
resultant solution was stirred for 3–6 h. The reaction mixture was then diluted with
ethyl acetate and washed with water three to four times to decompose the BF3-OEt2
complexes. The organic solution obtained after extraction was dried over anhydrous
Na2SO4 and filtered, and the solvent was evaporated under reduced pressure.
The crude mixture was purified by silica gel column chromatography using
hexane–ethylacetate (97:3) for 1k, hexane–ethylacetate (96:4) for 1l, hexane–ethyla-
cetate (95:5) for 1a, 1b, 1d, 1e, 2f, and 1i, hexane–ethylacetate (94:6) for 3a, and
hexane–ethylacetate (90:10) for 1c, 1g, 1h, and 1j as a mobile phase to afford the
deprotected compound.
ACKNOWLEDGMENTS
The authors are thankful to Dr. T. K. Chakraborty, director, CDRI, for
support on the synthesis of bioactive compounds, the SAIF Division of CDRI for
spectral data, and the Department of Science and Technology and the Council of
Scientific and Industrial Research, New Delhi, for financial support. This is CDRI
manuscript no. 8057.
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