Novel synthetic method for muscone

Article abstract of DOI:10.1080/00397910500212619

Muscone is a precious fragrant compound scarce in nature. Many attempts to synthesize this unique natural product have been carried out. In this work, a novel synthetic method for the preparation of muscone from 3-methyl-15- hydroxypentadecanoate is provided. Benzimidazolium salt was used as tetrahydrofolate coenzyme model at formic acid oxidation level and Grignard reagent as nucleophile to which a one-carbon unit was transferred. The biomimetic synthesis of muscone was successfully accomplished using the addition-hydrolysis reaction of benzimidazolium salt with the Grignard reagent. Copyright Taylor & Francis, Inc.

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Novel Synthetic Method for
Muscone
a
a
a
Yuan Guo , Xin‐Liang Wu , Jian‐Li Li , Ruo‐Qian
a
a
Xu & Zhen Shi
a
Department of Chemistry , Northwest University ,
Xi'an, P.R. China
Published online: 18 Aug 2006.
To cite this article: Yuan Guo , Xin‐Liang Wu , Jian‐Li Li , Ruo‐Qian Xu & Zhen
Shi (2005) Novel Synthetic Method for Muscone, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:19,
2489-2494
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Synthetic Communications , 35: 2489–2494, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500212619
Novel Synthetic Method for Muscone
Yuan Guo, Xin-Liang Wu, Jian-Li Li, Ruo-Qian Xu,
and Zhen Shi
Department of Chemistry, Northwest University, Xi’an, China
Abstract: Muscone is a precious fragrant compound scarce in nature. Many attempts to
synthesize this unique natural product have been carried out. In this work, a novel
synthetic method for the preparation of muscone from 3-methyl-15-hydroxypentade-
canoate is provided. Benzimidazolium salt was used as tetrahydrofolate coenzyme
model at formic acid oxidation level and Grignard reagent as nucleophile to which a
one-carbon unit was transferred. The biomimetic synthesis of muscone was success-
fully accomplished using the addition-hydrolysis reaction of benzimidazolium salt
with the Grignard reagent.
Keywords: Benzimidazolium salt, biomimetic synthesis, Grignard reagent, muscone,
3
-methyl-15-hydroxypentadecanoate
Musk is a precious natural perfume and rare medicinal material. Muscone (3-
methylcyclo-pentadecanone) is the main odorous compound of the musk pod
obtained from the male musk deer Moschus moschiferus, and its structure was
[
1]
determined in 1926. For more than half a century, many people have been
working on the synthesis of muscone to find cheap artificial synthetic routes,
and a lot of patents have been published. The synthesis of muscone has been a
[
2]
popular problem in organic synthesis.
The tetrahydrofolate coenzymes are involved in the biochemical transfer
of a one-carbon fragment at different oxidation levels. When the one-carbon
unit is at the formic and oxidation level, the imidazoline with a five-
[3]
membered ring structure is the active site (Scheme 1). If we use benzimida-
zolium salt as tetrahydrofolate coenzyme model to react with the nucleophilic
Received in Japan April 10, 2005
Address correspondence to Zhen Shi, Department of Chemistry, Northwest Univer-
sity, Xi’an 710069, P.R. China. Fax: þ86-29-88303798; E-mail: yuanorganic@163.com
2
489

2490
Y. Guo et al.
Scheme 1.
reagent, such as a Grignard reagent, the one-carbon unit at the formic acid
oxidation level will be transferred to the nucleophilic reagent and the biomi-
metic synthesis to initiate the one-carbon unit transfer reaction of tetrahydro-
folate coenzyme will be accomplished.
We provide a convenient synthetic method for muscone by the intramo-
lecular addition-hydrolysis reaction of Grignard reagent with quaternary
C 55 N bond of benzimidazolium salt 2, which served as the methyl-substituted
one-carbon unit model of tetrahydrofolate coenzyme. The route of the new
synthetic method is shown in Scheme 2.
It has been reported that compounds with quaternary C 55 N double
[
4]
group react with Grignard reagents.
However, the method for
preparing muscone from Grignard reagents and benzimidazolium salt has
not been reported in literature. Because benzimidazole can be prepared
from 3-methyl-15-hydroxy- pentadecanoate, the method provides an
Scheme 2.

Novel Synthetic Method for Muscone
2491
important route for preparing muscone from hydroxy ester and Grignard
reagents.
In our experiments, the addition reaction of the Grignard reagent with
benzimidazolium salt was carried out. Benzimidazolidine obtained from the
addition reaction could be hydrolyzed directly to give muscone in acidic
solution after the addition reaction was finished, a convenient and simple
synthetic method for muscone.
Benzimidazolium salt 2 can be synthesized via bromination of
benzimidazolium salt 1 with hydrobromic acid. Benzimidazolium salt 1
can be synthesized from iodomethane and benzimidazole obtained from
1
microwave irradiation. Grignard reagent was prepared from magnesium
,2-benzenediamine
and 3-methyl-15-hydroxypentadecanoate under
5]
[
[
6]
and benzimidazolium salt 2 in ethyl ether. These starting materials are
readily available. Muscone was synthesized in two steps from benzimidazo-
lium salt and magnesium.
The yield of muscone was 42%, as described in the experimental section,
which is low. It is believed that the reason the yield was lower is the formation
of some side products, such as the intermolecular product, hydrolysis product,
and decomposition product. Further investigation of this reaction is being
conducted in our laboratory.
The mechanism for the reaction of benzimidazolium salt with nucleophile
[
7]
has been proposed in our earlier article. The preparative reaction described
in this article can be reasonably explained by an intramolecular addition
reaction of Grignard reagent with the polarized C 55 N bond of benzimidazo-
lium salt and the formation of benzimidazolidine, which can be hydrolyzed
in acidic solution to give muscone (Scheme 3).
Scheme 3.

2492
Y. Guo et al.
EXPERIMENTAL
Melting points were taken on a XT-4 micromelting apparatus (Beijing) and are
uncorrected. TLC analysis was carried out on glass plates coated with silica
gel-G, and spots were visualized using an ultraviolet (UV) lamp. Elemental
analyses were performed with a Vario EL-III instrument (Germany)
2
1
infrared (IR) spectra in cm and were recorded on a Brucker EQUIOX-55
1
spectrometer (Germany). Proton magnetic resonance spectra (H NMR)
spectra were recorded at 400 MHz on a Varian INOVA-400 spectrometer
(USA), and chemical shifts were reported relative to internal Me Si.
4
General Procedure for the Preparation of Benzimidazolium Salt 2
Benzimidazolium salt 2 can be synthesized via bromination of benzimidazo-
lium salt 1 with hydrobromic acid. Benzimidazolium salt 1 can be synthesized
from iodomethane and benzimidazole obtained from 1,2-benzenediamine and
[
5]
3
-methyl-15-hydroxypentadecanoate under microwave irradiation.
Methyl-15-hydroxypentadecanoate was prepared from ethyl crotonate and
3-
[8]
1
2-iodododecanol under sonication according to the literature. A solution
of sodium (0.02 mol) in ethanol was treated with 0.02 mol of benzimidazole,
.06 mol of iodomethane, and 25 mL of benzene, and then the mixture was
0
refluxed for 18 h. The solvent was removed and the residue was recrystallized
from water to give the bisbenzimidazolium salt.
General Procedure for Muscone
A 250-mL, three-necked, round-bottomed flask, fitted with a tantalum wire
Hershberg stirrer and a condenser, was arranged for use with a nitrogen atmos-
phere. Benzimidazolium salt (2.8 g, 5 mmol), magnesium (0.4 g, 15 mmol),
and 20 mL of anhydrous ether were placed in the flask. The flask was
warmed in a water bath and a small crystal of iodine was added. After the
reaction initiated, 2.8 g (5 mmol) of benzimidazolium salt and 150 mL of
anhydrous ether were added to the reaction mixture again. The mixture was
stirred at refluxing temperature for 28 h and then a 10% solution of hydro-
chloric acid was added slowly; the resulting mixture was heated at 45–
5
08C for 1 h with stirring. Ether was removed and the residue was extracted
with chloroform (3 ꢀ 30 mL). The combined organic extracts were washed
with 5% sodium bicarbonate and dried over anhydrous magnesium sulfate.
After evaporation of the solvent, the crude product was purified by silica-
gel column chromatography (hexane/EtoAc 20 : 1) to give 0.5 g of muscone
(3) as colorless oil. Yield: 42%, ymax (KBr): 1715 (C 55 O), 2920, 2850, 719.
Anal. C H O calcd.: C, 80.67; H, 12.60. Found: C, 80.16; H, 12.85. H
1
1
6 30
NMR (CDC /TMS), d (ppm): 0.92 (d, J ¼ 6 Hz., 3H, CH ), 1.10–2.00
l3
3
þ
m, 23H, CH , CH), 2.10–2.52 (m, 4H, CH ). MS m/z: 238 (M ).
2 2
(

Novel Synthetic Method for Muscone
ACKNOWLEDGMENTS
2493
This work was supported by the Natural Science Foundation of China
No. 20472067).
(
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