Cyclopentyl: A novel protective group for phenols

Article abstract of DOI:10.1080/00397910701471253

We have discovered cyclopentyl as a novel group for the protection of hydroxyl functionality of phenols. The key steps involved are cyclopentylation and decyclopentylation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701471253

Synthetic Communicationsw, 37: 2877–2880, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701471253
Cyclopentyl: A Novel Protective Group
for Phenols
Jitendra M. Gajera, Laxmikant A. Gharat,
and Aniket V. Farande
Drug Discovery Chemistry, Glenmark Research Centre, Navi Mumbai,
India
Abstract: We have discovered cyclopentyl as a novel group for the protection of
hydroxyl functionality of phenols. The key steps involved are cyclopentylation and
decyclopentylation.
Keywords: alkyl aryl ether, phenol, protective group
INTRODUCTION
The selective protection and removal of protecting groups is of critical import-
ance in many synthetic sequences. A protecting group should be easy to
introduce, easy to cleave, and stable during the course of various reaction
conditions. Protection of the hydroxyl functionality of phenols is required to
prepare a number of compounds.[1–5] There are various protecting groups
reported in the literature for the protection of hydroxyl functionality of
phenols such as methyl, methoxymethyl (MOM), methoxyethoxymethyl
(MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), tetrahydropy-
ranyl (THP), ethoxy-ethyl (EE), benzyl (R-OBn), 2-napthylmethyl (NAP),
p-methoxybenzyl (PMB), o-nitrobenzyl, p-nitrobenzyl, 9-phenylxanthyl
(pixyl, px), trityl -CPh3 (Tr), triisopropylsilyl (iPr3Si, TIPS), phenyldimethyl-
silyl, t-butyldimethylsilyl (t-BuMe2Si- or TBDMS), t-butyldiphenylsilyl
(t-BuPh2Si-), and esters such as acetates, trifluoroacetate, pivaloate, and
Received in India January 19, 2007
Address correspondence to Jitendra M. Gajera, Drug Discovery Chemistry,
Glenmark Research Centre, A-607, T. T. C. Industrial Area, MIDC, Mahape, Navi
Mumbai 400 709, India. E-mail: jitendrag@glenmarkpharma.com
2877

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J. M. Gajera, L. A. Gharat, and A. V. Farande
benzoate.[6] A protecting group should be easy to introduce, easy to cleave,
and stable under various reaction conditions.
The new chemical entities required for our drug discovery program were
synthesized by multistep synthetic methods.[7] During the course of this work,
a suitable protecting group was required for some of our phenolic intermediates.
For our purpose, an alkyl/cycloalkyl protecting group was considered to be the
most suitable one. Initially, we used methyl as a protective group, but its removal
at the desired stage required very harsh conditions such as refluxing over a long
period using HBr/acetic acid or BBr3 or AlCl3 or alkyl/aryl thiolate. We also
tried isopropyl as a protective group but it turned out to be less stable under
some of our reaction conditions. The idea of using cyclopentyl as a protective
group came from the observations that some of our cyclopentyloxy aryl inter-
mediates underwent decyclopentylation to some extent under Lewis acid
(using stannous chloride). We confirmed this by trying several Lewis acid con-
ditions for removal and found that 33% HBr in acetic acid or 48% aq. HBr can
cleave this group readily. Although there are some compounds reported in the
literature as having a cyclopentyloxy aryl moiety,[8] but practically there are
no reports on cyclopentyl as a protective group for phenols. We now report
cyclopentyl as a novel protective group for phenols.
We prepared several new chemical entities using cylopentyl as a protec-
tive group. We found that cyclopentyl is stable under various reaction con-
ditions such as bromination, oxidation, and acid chloride preparation. It is
also easily cleavable with commercially available 48% aqueous hydrobromic
acid or 33% hydrobromic acid in acetic acid.
RESULTS AND DISCUSSION
4-(Cyclopentyloxy)-3-methoxy benzaldehyde 3 was prepared by reaction of
vanillin 1 and cyclopentyl bromide 2 in the presence of potassium carbonate
using N,N-dimethyl formamide as solvent with a yield of 95%.
Decyclopentylation of 3 using 48% aqueous HBr in acetic acid resulted in
vanillin 1. Also, decyclopentylation is preferred over demethylation under the
given conditions.
EXPERIMENTAL
Commercial solvents and reagents were used without further purification.
1H NMR spectra were recorded on a Varian 300-MHz spectrometer.
Melting points are uncorrected. Elemental analysis was performed on a
Perkin-Elmer analyzer. Mass spectra were recorded on Thermo Finnigan
LCQ DECA XP MAX (Ion Trap) mass spectrometer using an APCI (atmos-
pheric pressure chemical ionization) source in positive mode at capillary
voltage 3.14 V and capillary temperature 2508C (Scheme 1).

Cyclopentyl
2879
Scheme 1.
4-(Cyclopentyloxy)-3-methoxy Benzaldehyde 3
To a well-stirred solution of vanillin 1 (10 g, 0.0657 mol) and anhydrous
potassium carbonate (18.15 g, 0.1315 mol) in N,N-dimethyl formamide
(70 mL), cyclopentyl bromide 2 (10.78 g, 0.0723 mol) was added and heated
to 808C for 3.0 h. Consumption of starting material was checked by means of
thin-layer chromatography (TLC). The reaction mixture was then cooled to
room temperature and filtered to remove inorganic material. The filtrate was
then concentrated under reduced pressure. The residue obtained was diluted
with 5% aqueous hydrochloric acid solution (100 mL) and extracted with
ethyl acetate (2 ꢀ 30 mL). The combined organic layers were washed with
water and dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure gave 3 as light yellow oil with a yield of 13.8 g (95%). IR
(KBr): 2961, 1682, 1594, 1583, 1424, 1266, 1135, 1032, 980 cm 21 1H
.
NMR (300 MHz, CDCl3): d 1.63–2.03 (8H, m), 3.89 (3H, s), 4.86 (1H,
quint.), 6.96 (1H, d, J ¼ 8.1 Hz,), 7.39 (1H, s), 7.42 (1H, d, J ¼ 8.1 Hz), 9.82
(1H, s). Anal. calcd. for C14H18O2: C, 77.11, H, 8.36. Found: C, 77.16; H,
8.45. MS: 221 [M þ H] þ.
Vanillin 1
A solution of 4-(cyclopentyloxy)-3-methoxy benzaldehyde 3 (10 g, 0.0452 mol)
and 48% aqueous HBr (25 mL) in glacial acetic acid (500 ml) was stirred at
708C for 2 h. The progress of the reaction was monitored by TLC. Finally,
the reaction mixture was concentrated under reduced pressure and diluted
with ice water (100 L). The solid was filtered and washed with ice water
(4 ꢀ 25 mL) and petroleum ether (2 ꢀ 25 mL) and dried to afford vanillin 1
as a light yellow solid with a yield of 4.9 g (71%), mp 79–818C. IR (KBr):
1
3192, 1693, 1604, 1312, 1248, 1193, 1087, 1052, 926, 842, 746 cm21. H
NMR (300 MHz, CDCl3): d 3.96 (1H, s), 6.30 (1H, s), 7.05 (1H, d,
J ¼ 8.4 Hz), 7.41 (2H, brs), 0.82 (1H, s). Anal. calcd. for C8H8O3: C, 63.21,
H, 5.35. Found: C, 63.17; H, 5.29.

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J. M. Gajera, L. A. Gharat, and A. V. Farande
ACKNOWLEDGMENTS
The authors are thankful to the analytical Department for Analytical support.
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