Chemoselective formation of 8,9-epoxy-limonene

Article abstract of DOI:10.1081/SCC-200057232

We present here a synthetic path to produce, exclusively, 8,9-epoxylimonene in 75% overall yields. We developed a three step synthetic route. First, the 1,2-double bond of limonene was protected by the formation of the bromo-methylether by cohalogenation

Full text of DOI:10.1081/SCC-200057232

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Chemoselective Formation of
8,9‐Epoxy‐limonene
Queli A. R. Almeida a & Joel Jones Jr. a
a Síntese Orgânica Ambiental , Instituto de Química,
Universidade Federal do Rio de Janeiro , Rio de
Janeiro, Brazil
Published online: 16 Aug 2006.
To cite this article: Queli A. R. Almeida & Joel Jones Jr. (2005) Chemoselective
Formation of 8,9‐Epoxy‐limonene, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:10, 1285-1290,
DOI: 10.1081/SCC-200057232
To link to this article: http://dx.doi.org/10.1081/SCC-200057232
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Synthetic Communicationsw, 35: 1285–1290, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057232
Chemoselective Formation of
8,9-Epoxy-limonene
Queli A. R. Almeida and Joel Jones Jr.
´
´ ˆ
Sıntese Organica Ambiental, Instituto de Quımica, Universidade Federal
do Rio de Janeiro, Rio de Janeiro, Brazil
Abstract: We present here a synthetic path to produce, exclusively, 8,9-epoxy-
limonene in 75% overall yields. We developed a three step synthetic route. First, the
1,2-double bond of limonene was protected by the formation of the bromo-methyl-
ether by cohalogenation with NBS in MeOH. Then, this product was oxidized by
m-chloro-perbenzoic acid to give the corresponding epoxides. Finally, the 1,2-double
bond was restored by a reaction with NH4Cl/Zn leading to 8,9-epoxy-limonene.
The great advantage of this methodology is that the intermediate purification steps
are not necessary.
Keywords: Epoxy, limonene, terpene
INTRODUCTION
8,9-Epoxy-limonene is an important synthetic intermediate that can be used to
synthesize natural compounds such as uroterpenol,[1] a-bisabolol,[1,2]
anymol,[1,2] and 9-hydroxycineoles.[3]
In the literature, we find different methodologies for 8,9-epoxy-limonene
preparation from limonene, such as oxidations with porphyrins metallic
complexes,[4] titanium complexes,[5] tungsten,[6] ruthenium,[7] hydroperoxide
and peroxides formed in situ,[8] photooxidation,[9] and microbiological
transformations.[10]
Received in the USA January 27, 2005
Address correspondence to Joel Jones Jr., Sıntese Organica Ambiental, Instituto de
´
ˆ
´
Quımica, Universidade Federal do Rio de Janeiro, Av. Brigadeiro Trompowsky s/no.,
´ ´
Predio do Centro de Tecnologia, Bloco A, sala 611, Cidade Universitaria, Rio de
Janeiro, CEP 21.941-590, Brazil. Fax: þ55-21-2562-7133; E-mail: soa@iq.ufrj.br
1285

1286
Q. A. R. Almeida and J. Jones Jr.
Until now, the reaction of limonene with nitriles-H2O2 has been the most
important methodology to prepare 8,9-epoxy-limonene.[11] However, it
produces a 1:1 mixture of 1,2-epoxy-limonene and 8,9-epoxy-limonene.
The isomers are separated by distillation.
A synthetic method to 8,9-epoxy-limonene at gram scale was described
by Carlson in 1971.[11e] This method uses limonene and a mixture of benzoni-
trile and hydrogen peroxide (35%), and produces a mixture of mono- and di-
epoxides (30% being 8,9-epoxy-limonene).
RESULTS
Here we present a specific synthetic route to 8,9-epoxy-limonenes (I) in a 75%
overall yield.
Recently, de Mattos and Sanseverino[12] published the cohalogenation of
.
limonene (II) with I2/Cu(OAc)2 H2O in aqueous dioxane to produce chemo-
and regiospecifically pure iodohydrin.
Based on this result, we developed a three-step synthetic route. First,
the 1,2-double bond of limonene was protected by the formation of the
bromo-methyl-ether (III) by cohalogenation with NBS in MeOH at 08C
(Scheme 1). Then, this product was oxidized by m-chloro-perbenzoic acid
(m-CPBA) to give epoxides (IV). Finally, the 1,2-double bond was restored
Scheme 1.

Chemoselective Formation of 8,9-Epoxy-limonene
1287
by a reaction with NH4Cl/Zn. The great advantage of this methodology is that
the intermediate purification steps are not necessary. In this process,
we employed a 10 g scale of limonene to produce 8.4 g of 1:1 mixture of
(4R,8R)-8,9-epoxy-limonene and (4R,8S)-8,9-epoxy-limonene (I) in 75%
overall yield after purification (Scheme 1).
The analysis of the reaction was performed by high-resolution gaseous
chromatography (HRGC), and the product was characterized by spectroscopic
methods[13] and co-injection with the standard sample.
This synthetic route is a simple and efficient one for preparing a 1:1
mixture of (4R,8R)-8,9-epoxy-limonene and (4R,8S)-8,9-epoxy-limonene in
good yields and in .99% purity without any trace of 1,2-epoxide-limonenes.
EXPERIMENTAL
10 g (73.5 mmol) of limonene, 60 mL of methanol, and 13 g (73.5 mmol) of
N-bromo-succinimide (added slowly) were added to a 250-mL flask in an
ice bath. The solution was stirred for 24 h and filtered, and the solvent was
evaporated to obtain an oil. The oil was dissolved in 15 mL of CH2Cl2, the
solution was cooled in an ice bath, and 13 g of m-chloroperbenzoic acid in
50 mL of CH2Cl2 was added dropwise for 20 min. The reaction was stirred
for 72 h. Then, a solution of an aqueous 20% KI was added, producing a
violet solution. A saturated solution of sodium thiosulfate was added until
the violet color vanished completely. The phases were separated and
the organic phase was washed with an aqueous 20% NaHCO3 solution. The
organic combined extracts were dried over anhydrous Na2SO4 and the
solvent was evaporated. The oil was dissolved in 25 mL of EtOH, and 3 g
of Zn and 3 g of NH4Cl were added. The suspension was stirred vigorously
for 24 h at rt, filtered through celite, and fractionated by chromatography
on a silica column (hexano/ethyl acetate 9:1), producing 8.4 g (55.3 mmol)
of 1:1 mixture of (4R,8R)-8,9-epoxy-limonene and (4R,8S)-8,9-epoxy-
limonene (75% yield and .99% purity by HRGC).
Lit. data:[12] 1H NMR, d: 1.26 (3H, s), 1.64 (3H, bs), 1.75–2.05 (5H, m),
2.57, 2.64 (Abq 1H, J ¼ 5 Hz, 2H), 5.36 (1H, bs); 13C NMR, d: 18.16 (CH3),
23.42 (CH3), 25.05 (CH2), 27.57 (CH2), 30.14 (CH2), 40.21 (CH), 53.33
(CH2), 59.18 (C), 119.92 (CH), 134.12 (C); m/z (rel. int.%) 152 (M þ † 2),
121 (23), 119 (11), 105 (16), 95 (17), 94 (100), 93 (38), 91 (33), 79 (89), 77
(24), 67 (34), 55 (27), 53 (30), 43 (38), 41 (55).
(4R,8R)-8,9-epoxy-limonene and (4R,8S)-8,9-epoxy-limonene (I): 1H
NMR (TMS, CDCl3), d: 1.26 (3H, s), 1.50 (2H, m), 1.64 (3H, bs), 1.75–
2.05 (5H, m), 2.57 (1H, dd, J ¼ 4.5 Hz), 2.64 (1H, dd, J ¼ 4.5 Hz), 5.37
(1H, bs); 13C NMR (TMS, CDCl3), d: 18.51 (CH3), 23.37 (CH3), 24.95
(CH2), 27.51 (CH2), 30.05 (CH2), 40.12 (CH), 53.44 (CH2), 59.47 (C),
120.04 (CH), 134.12 (C); EIMS m/z (rel. int.%) 152 (M þ † 3), 137 (19),
121 (90), 119 (25), 109 (13), 105 (39), 93 (72), 91 (65), 84 (28), 79 (100),

1288
Q. A. R. Almeida and J. Jones Jr.
77 (42), 67 (48), 55 (25), 53 (30), 43 (48), 41 (40), and 39 (44). Lit. data:[11e]
1H NMR, d: 1.20 (3 H, s), 1.3–2.2 (10 H, m), 1.63 (3 H, s), 2.35–2.60 (2 H,
dd), 5.37 (1 H, bs).
ACKNOWLEDGMENT
We thank CNPq and CAPES for financial support, and Claudia Moraes de
Rezende for the mass analyses. We thank Flavia M. da Silva for helpful
discussions.
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