Preparation of 3-methylthiodecanal, a flavour compound

Article abstract of DOI:10.3184/174751915X14476885268579

1-Undecen-4-ol was converted into its benzyl ether in 92% yield by reaction with benzyl chloride in the presence of NaH and was then oxidised with a ruthenium catalysis to give the corresponding aldehyde, which was treated directly with ethylene glycol in the presence of pyridinium p-toluenesulfonate to produce 2-(2′-benzyloxynonyl)-1,3-dioxolane in an overall yield of 87%. This intermediate underwent deprotection of the benzyloxy group and mesylation to give 2-(2′-mesyloxynonyl)-1,3-dioxolane in 90% yield, treatment of which with sodium methyl mercaptide followed by cleavage of the 1,3-dioxolane group afforded 3-methylthiodecanal in 81% yield.

Full text of DOI:10.3184/174751915X14476885268579

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 DECEMBER, 731–733
RESEARCH PAPER 731
Preparation of 3-methylthiodecanal, a flavour compound
Hao Liu,a Feiyan Tao,b Baoguo Sun,a Shaoxiang Yang,a Yongguo Liua and Hongyu Tiana*
aBeijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Key laboratory of Flavour Chemistry, Beijing Technology and Business
University, Beijing 100048, P.R. China
bTechnical Research & Development Center, Chuanyu Branch of China Tobacco Corporation, Chengdu 610031, P.R. China
1-Undecen-4-ol was converted into its benzyl ether in 92% yield by reaction with benzyl chloride in the presence of NaH and was then
oxidised with a ruthenium catalysis to give the corresponding aldehyde, which was treated directly with ethylene glycol in the presence
of pyridinium p-toluenesulfonate to produce 2-(2´-benzyloxynonyl)-1,3-dioxolane in an overall yield of 87%. This intermediate underwent
deprotection of the benzyloxy group and mesylation to give 2-(2´-mesyloxynonyl)-1,3-dioxolane in 90% yield, treatment of which with
sodium methyl mercaptide followed by cleavage of the 1,3-dioxolane group afforded 3-methylthiodecanal in 81% yield.
Keywords: 3-methylthiodecanal, 1-undecen-4-ol, oxidation, preparation, flavour compounds
Results and discussion
Volatile sulfur-containing compounds play an important role in
the aromas of many foods, such as tropical fruits, vegetables of
the Allium species (garlic, onion, chive) and Cruciform families
(Brussels sprouts, broccoli, cabbage, cauliflower), and thermally
processed foods (roasted meat, chicken, seafood, coffee).1
The polyfunctional thiols and their derivatives have attracted
a lot of attention due to their unique odour characteristics in
recent years,2-7 among which many compounds possessing the
tropical, fruity or vegetable odour notes feature a 1,3-oxygen-
sulfur functionality, a so-called ‘olfactophore’.8 More and more
compounds containing this olfactophore have been reported
to occur in nature9-12 and many have been approved as safe
flavour ingredients by the Flavour and Extract Manufacturers’
Association (FEMA).13
Our efficient eight-step synthesis of 3-methylthiodecanal 5
is shown in Scheme 1. 1-Undecen-4-ol 1, prepared by the
Grignard reaction of allylmagnesium chloride with octanal,
was converted to the corresponding benzyl ether 2 in 92% yield
by treatment with benzyl chloride in the presence of NaH to
protect the hydroxyl group from oxidation in subsequent steps.
Although ozonolysis is one of the most common methods
for the oxidative cleavage of the C=C bond, we chose the
Ru-catalysed oxidation reported by Niggemann et al.,27
which was more easily carried out than ozonolysis due to
the inconvenient preparation of ozone gas in the laboratory.
4-Benzyloxy-1-undecene 2 was oxidised by 5 mol % of RuCl3
and 2 equiv. of NaIO4 in acetone/acetonitrile/water to afford
the corresponding aldehyde. However, unexpectedly we found
that the aldehyde was unstable and decomposed on a silica
column during purification or on standing overnight. Therefore,
the crude aldehyde was used in the next step directly. Initially,
the deprotection of the benzyloxy group of the aldehyde was
attempted by hydrogenolysis catalysed by Pd/C in methanol
solution so as to protect the carbonyl group by the concurrent
formation of a dimethyl acetal. Unfortunately, it failed and gave
a complex mixture. It was thus decided that protection of the
carbonyl group of the crude oxidation product should precede
the deprotection of the benzyloxy group. This was carried
out by treatment of the crude oxidation product with ethylene
glycol in the presence of pyridinium p-toluenesulfonate to give
2-(2´-benzyloxynonyl)-1,3-dioxolane 3 in an overall yield of
87% in these two steps.
The homologues of 3-methylthioalkanals, which contain a
1,3-oxygen-sulfur functionality occur widely as volatile aroma
components of various plants,14-17 fruit,18 vegetables,19 and
cooked beef liver20 and seafoods.21 Five of these homologues
have obtained FEMA numbers, including 3-methylthiopropanal
(FEMA No. 2747), 3-methylthiobutanal (FEMA No. 3374),
3-methylthiohexanal (FEMA No. 3877), 3-methylthioheptanal
(FEMA No. 4183), and 3-methylthiodecanal (FEMA No. 4734).
3-Methylthiodecanal is a relatively new flavour compound,
which was added to the GRAS (Generally Recognized as
Safe) list in 2013.22 However, the preparation of this flavour
compound has not been reported so far. The most common
method of their preparation in the literature is by conjugate
addition of methanethiol to a,b-unsaturated aldehydes which
affords the corresponding 3-methylthioalkanals directly,23-26
a
route limited only by the availability of the corresponding a,b-
unsaturated aldehydes. In this work, we investigated a synthetic
route starting from 1-undecen-4-ol which involved the oxidation
of its double bond and transformation of its hydroxyl group to
afford 3-methylthiodecanal. We chose this starting material
in view of its accessibility of 1-undecen-4-ol via a Grignard
reaction.
After the deprotection of the benzyloxy group of 3, by
hydrogenolysis using 10% Pd–C, mesylation produced
2-(2´-mesyloxynonyl)-1,3-dioxolane 4. Both the deprotection
and mesylation went smoothly in an overall yield of 90%. The
final product 3-methylthiodecanal 5 was obtained through
a nucleophilic substitution reaction of 4 with sodium methyl
OH
OBn
R
O
O
OBn
R
(i) RuCl3/NaIO4;
MgCl
NaH/BnCl
R
O
R
H
(ii) HOCH2CH2OH/TsOH
3
1
2
O
SCH3
R
O
OMs
R
(i) H2, Pd/C;
(i) CH3SNa;
(ii) TsOH
= n-C
R
7H15-
H
O
(ii) MsCl/Et3N
5
4
Scheme 1
* Correspondent. E-mail: tianhy@btbu.edu.cn

732 JOURNAL OF CHEMICAL RESEARCH 2015
2-(2´-Benzyloxynonyl)-1,3-dioxolane (3)
mercaptide followed by the cleavage of the 1,3-dioxolane
group. The overall yield of the nucleophilic substitution and
deprotection of the carbonyl group was 81%.
Oxidation of the double bond: 4-Benzyloxy-1-alkene 2 (10.4 g,
40 mmol) was dissolved in acetone (80 mL), acetonitrile (80 mL) and
water (68 mL). A solution of RuCl3 (1 M, 2 mL, 2 mmol, 5 mol %)
and NaIO4 (17.12 g, 80 mmol) was added. After stirring for 20 min,
the mixture was diluted with ethyl acetate (30 mL), filtered, and the
filter cake was washed with ethyl acetate (10 mL × 3). The filtrate was
washed with saturated Na2SO3 solution (80 mL) and saturated NaHCO3
solution (30 mL) sequentially. Phases were separated, and the aqueous
layer was extracted with ethyl acetate (30 mL × 3). The combined
organic layers were washed with brine (80 mL) and dried over Na2SO4,
filtered, and evaporated under reduced pressure. The light brown crude
aldehyde was not purified and was used in the next step directly.
Protection of the carbonyl group: A mixture of the aldehyde
obtained above, ethylene glycol (18.6 g, 0.3 mol), pyridinium
p-toulenesulfonate (2.4 g) and toluene (70 mL) was stirred and
heated under reflux for 3 h. The water formed during the reaction
was removed by a Dean–Stark trap. The cooled reaction mixture was
sequentially washed with saturated aqueous NaHCO3, water, and brine.
The solvent was evaporated. The residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate, 30:1) to give
2-(2´-benzyloxynonyl)-1,3-dioxolane 3 as a colourless oil (10.65 g,
87%). 1H NMR d 0.88 (t, J = 6.9 Hz, 3 H, H-C9´), 1.18–1.48 (m, 10 H,
H-C4´-C8´), 1.48–1.70 (m, 2 H, H-C-3´), 1.79 (ddd, J = 13.8, 6.3, 4.8
Hz, 1 H, H-C1´), 2.00 (ddd, J = 13.8, 7.5, 3.9 Hz, 1 H, H´-C1´), 3.62 (m,
1 H, H-C2´), 3.80–4.02 (m, 4 H, H-C4 and H-C5), 4.53 (m, 2 H, CH2
(benzyl)), 5.00 (dd, J = 6.3, 4.2 Hz, 1 H, H-C2), 7.26–7.40 (m, 5 H,
phenyl); 13C NMR d 14.2 (C-9´), 22.7 (C-8´), 25.1 (C-4´), 29.3 (C-5´),
29.7 (C-6´), 31.8 (C-7´), 34.5 (C3´), 38.8 (C1´), 64.7 (C5), 64.8 (C4),
71.2 (CH2 (benzyl), 75.9 (C2´), 102.5 (C2), 127.4 (C4 (phenyl)), 127.8
(C3 and C5 (phenyl)), 128.3 (C2 and C6 (phenyl)), 138.9 (C1 (phenyl));
HRESIMS, m/z 329.20827 [M + Na+] (calcd. for C19H30NaO3,
329.20872).
The solution of 3-methylthiodecanal (0.1% in propylene
glycol) possessed a typical odour of long white radish soup and a
slight fatty scent. It is well known that the stereoisomers of chiral
flavours usually present different odour properties. Among
these homologues, (R)-3-methylthiobutanal presented a typical
odour of cooked potato, whereas the opposite enantiomer was
odourless. In contrast, the enantiomers of 3-methylthiohexanal
and 3-methylthioheptanal showed no stereospecific differences
in their organoleptic properties.28 However, the odours of the
enantiomers of 3-methylthiodecanal are still unknown. To settle
this issue, we planned to prepare its enantiomers based on the
synthetic route designed for the racemate, but using an optically
active 1-undecen-4-ol as starting material.
In summary, 3-methylthiodecanal was easily prepared from
the corresponding homoallylic alcohol 1-undecen-4-ol by the
Ru-catalysed oxidation of its double bond and nucleophilic
substitution by methylthiolate of its hydroxyl group through
its mesylate. The protection and deprotection steps of the
hydroxyl group and the aldehyde group derived from the
oxidation proceeded smoothly in high yields although they
made this synthetic route a little tedious. Overall, it is worthy of
consideration for the preparation of 3-methylthiodecanal due to
the easy availability of starting material, operational simplicity
and the very good yield of each individual step.
Experimental
Allyl chloride, n-octanal, and sodium periodate were purchased from the
Beijing Bailingwei Science and Technology Company, ruthenium (III)
chloride from Sigma-Aldrich Chemical Co., and the other chemicals
from the Beijing Huaxue Shiji Company. NMR spectra were obtained on
a Bruker AV 300 spectrometer (1H NMR at 300 MHz, 13C NMR at 75
MHz) in CDCl3 using TMS as an internal standard. Chemical shifts (d)
are given in ppm and coupling constants (J) in Hz. The high resolution
mass spectra were obtained on a Bruker Apex IV FTMS.
2-(2´-Mesyloxynonyl)-1,3-dioxolane 4
Cleavage of the benzyloxy group: 10% Pd–C (0.525 g) was added to a
solution of the 1,3-dioxolane 3 (4.6 g, 15 mmol) in methanol (50 mL).
After stirring under an atmosphere of hydrogen for 0.5 h, the reaction
mixture was filtered through a pad of celite and concentrated. The
residue was used directly for the next step without purification.
1H NMR d 0.86 (t, J = 6.9 Hz, 3 H, H-C9´), 1.19–1.59 (m, 12 H,
H-C3´-C8´), 1.76 (m, 1 H, H-C1´), 1.89 (m, 1 H, H´-C1´), 2.92 (d, J =
2.4 Hz, 1 H, -OH), 3.80–4.05 (m, 5 H, H-C4, H-C5 and H-C2´), 5.02
(dd, J = 5.1, 3.9 Hz, 1 H, H-C2).
1-Undecen-4-ol (1): The Grignard reaction of allyl magnesium
chloride with octanal, using a method reported by us previously,29
o
gave 1-undecen-4-ol 1 as a colourless oil (85%), b.p. 63–65 C (1.1
mbar); 1H NMR d 0.88 (t, J = 6.9 Hz, 3 H, H-C11), 1.17–1.52 (m, 12 H,
H-C5-C10), 1.57 (d, J = 3.9 Hz, 1 H, -OH), 2.13 (m, 1 H, H-C3), 2.31
(m, 1 H, H´-C3), 3.63 (m, 1 H, H-C4), 5.12 (m, 2 H, H-C1), 5.83 (m, 1
H, H-C2); 13C NMR d 14.0 (C11), 22.6 (C10), 25.6 (C6), 29.3 (C8), 29.6
(C7), 31.8 (C9), 36.8 (C5), 41.9 (C3), 70.7 (C4), 117.9 (C1), 134.9 (C2).
The NMR data were consistent with the literature data.30
Mesylation of the hydroxyl group: Triethylamine (4.2 mL, 30 mmol)
followed by methanesulfonyl chloride (1.4 mL, 18 mmol) was added
to a solution of the alcohol obtained above in CH2Cl2 (40 mL) at 0 ºC.
The mixture was stirred at 0 ºC for 0.5 h and at room temperature
overnight. Then water was added to the reaction mixture and the
organic layer was separated. The aqueous layer was extracted with
ether. The combined organic extracts were dried over MgSO4 and the
solvent was removed under reduced pressure. The residue was purified
by silica gel column chromatography (petroleum ether/ethyl acetate,
10:1) to give the corresponding mesylate as a colourless oil (3.97 g,
4-Benzyloxy-1-undecene (2): Sodium hydride (60% dispersion,
2.4 g, 60 mmol) in one portion was added to a stirred solution of
1 (8.5 g, 50 mmol) in THF (100 mL) and DMF (10 mL) and the
resultant suspension was refluxed for 0.5 h. Benzyl chloride (8.6
mL, 75 mmol) was then added and the reaction mixture was refluxed
for a further 16 h. On cooling, the reaction mixture was poured into
iced water (100 mL) and extracted with ether (100 mL ×3). The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure to give a yellow
oil, which was purified by column chromatography over silica gel
(petroleum ether/ethyl acetate, 30:1) to yield the benzyl ether as
1
90%). H NMR d 0.87 (t, J = 6.9 Hz, 3 H, H-C9´), 1.18–1.46 (m, 10
H, H-C4´-C8´), 1.70–1.80 (m, 2 H, H-C3´), 1.94 (ddd, J = 14.7, 5.4, 4.5
Hz, 1 H, H-C1´), 2.12 (ddd, J = 14.7, 7.8, 4.2 Hz, 1 H, H´-C1´), 3.02 (s,
3 H, Me(mesyl)), 3.82–4.02 (m, 4 H, H-C4 and H-C5), 4.87 (m, 1 H,
H-C2´), 4.98 (dd, J = 5.4, 4.2 Hz, 1 H, H-C2); 13C NMR d 13.9 (C-9´),
22.4 (C-8´), 24.5 (C-4´), 28.9 (C-5´), 29.1 (C-6´), 31.6 (C-7´), 35.3 (C-
3´), 38.3 (Me-S), 38.6 (C-1´), 64.7 (C-5), 64.8 (C-4), 80.1 (C-2´), 101.2
(C-2); HRESIMS, m/z 317.13959 [M + Na+] (calcd for C13H26NaSO5,
317.13932).
1
a light yellow oil (11.96 g, 92%). H NMR d 0.88 (t, J = 7.2 Hz, 3 H,
H-C11), 1.20–1.62 (m, 12 H, H-C5-C10), 2.33 (m, 2H, H-C3), 3.44
(m, 1 H, H-C4), 4.49 (d, J = 11.7 Hz, 1 H, CH2(benzyl)), 4.57 (d, J =
11.7 Hz, 1 H, CH2(benzyl)), 5.02–5.15 (m, 2 H, H-C1), 5.86 (m, 1 H,
H-C2), 7.26-7.42 (m, 5 H, phenyl); 13C NMR d 14.1 (C11), 22.7 (C10),
25.4 (C6), 29.3 (C8), 29.7 (C7), 31.9 (C9), 33.8 (C5), 38.3 (C3), 70.9
(CH2(benzyl)), 78.6 (C4), 116.8 (C1), 127.4 (C4 (phenyl)), 127.7 (C3
and C5 (phenyl)), 128.3 (C2 and C6 (phenyl)), 135.2 (C2), 139.0 (C1
(phenyl)). The NMR data were consistent with the literature data.31
3-Methylthiodecanal 5
Methanethiol was bubbled into an aqueous solution of 2M NaOH
(20 mL) until it was saturated. To the solution was added DMF (20 mL)
and the mesylate 4 (2.94 g, 10 mmol). The mixture was heated at

JOURNAL OF CHEMICAL RESEARCH 2015 733
80 oC for 2 h. On cooling, ethyl acetate (30 mL) was added to dilute the
reaction mixture. The aqueous layer was separated and extracted with
ethyl acetate (20 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concentrated. The
residue obtained was treated with p-toluenesulfonic acid monohydrate
(0.95 g, 5 mmol) in acetone (60 mL) and water (30 mL). The mixture
was stirred at 50oC for 6 h. On cooling, the mixture was extracted with
Et2O. The extract was washed with saturated aqueous NaHCO3, water,
and brine, and dried over MgSO4. After removal of the solvent, the
residue was purified by silica gel column chromatography (n-hexane/
ether, 10:1) to give 3-methylthiodecanal 5 as a light yellow oil (1.64 g,
6
7
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81%). H NMR d 0.88 (t, J = 6.9 Hz, 3 H, H-C10), 1.20-1.34 (m, 8
H, H-C6-C9), 1.43 (m, 2 H, H-C5), 1.59 (m, 2 H, H-C4), 2.06 (s, 3
H, CH3S-), 2.61–2.69 (m, 2 H, H-C2), 3.04 (quintet, J = 6.9 Hz, 1 H,
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(C-4), 40.3 (C-3), 48.1 (C-2), 200.9 (C-1); HRESIMS, m/z 225.12840
[M + Na+] (calcd for C11H22NaSO, 225.12836).
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Financial support from the National Natural Science
Foundation of China (No. 31271932 and 31571886), the
National Key Technology R&D Program (2011BAD23B01)
and the Importation and Development of High-Caliber Talents
Project of Beijing Municipal Institutions (CIT&TCD20140306)
is gratefully acknowledged.
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Received 19 October 2015; accepted 6 November 2015
Paper 1503665 doi: 10.3184/174751915X14476885268579
Published online: 1 December 2015
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