Synthesis of a new odourant, 2-mercapto-4-heptanol

Article abstract of DOI:10.3184/174751915X14253193792383

2-Mercapto-4-heptanol is a relatively new flavour compound that was recently approved as an ingredient by the Flavour and Extract Manufacturers' Association in 2013. Its synthesis, which we have accomplished in four-steps, involved firstly a Grignard reaction of n-butanal with allylmagnesium chloride to prepare 1-hepten-4-ol. This was epoxidised and then converted to 1,2-epithio-4-heptanol, reduction of which with LiAlH₄ gave the target compound in an overall yield of about 54%.

Full text of DOI:10.3184/174751915X14253193792383

184 RESEARCH PAPER
VOL. 39 MARCH, 184–186
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of a new odourant, 2‑mercapto‑4‑heptanol
Shaoxiang Yanga, Wei Gonga, Baoguo Suna,b, Yongguo Liua and Hongyu Tiana,b*
aBeijing Key laboratory of Flavour Chemistry, Beijing Technology and Business University, Beijing 100048, P.R. China
bBeijing Innovation Centre of Food Nutrition and Human Health, Beijing, P.R. China
2-Mercapto-4-heptanol is a relatively new flavour compound that was recently approved as an ingredient by the Flavour
and Extract Manufacturers’ Association in 2013. Its synthesis, which we have accomplished in four-steps, involved firstly a
Grignard reaction of n-butanal with allylmagnesium chloride to prepare 1-hepten-4-ol. This was epoxidised and then converted
to 1,2-epithio-4-heptanol, reduction of which with LiAlH4 gave the target compound in an overall yield of about 54%.
Keywords: 1‑hepten‑4‑ol, 1,2‑epoxy‑4‑heptanol, 1,2‑epithio‑4‑heptanol, flavour, odourant
1,3‑Oxygen‑sulfur functionality has been described as the
“olfactophore” for the tropical, fruity or vegetable odour
notes.1 More and more flavour compounds containing
this functionality have been found to occur naturally, e.g.
3‑mercapto‑2‑methyl‑1‑pentanol reported in cooked onions,2
3‑mercapto‑1‑hexanol identified in yellow passion fruit and
in wines,3,4 and 3‑mercapto‑1‑heptanol detected in hops and
hopped beer.5,6 Learning from nature is the most efficient
way for flavourists to find new odourants for the creation of
flavouring formulations. It is important to find a feasible
synthetic method after identifying an interesting aromatic
compound, especially when it occurs in nature in only trace
amounts.
2‑Mercapto‑4‑heptanol, which contains a 1,3‑oxygen‑sulfur
functionality, isdescribed as possessing a fruity, tropical, guava,
watercress and vegetal odour.7 It was identified in an extract of
red bell peppers in 2008 by the researchers of Firmenich, one of
the biggest international flavours and fragrances companies.8
Thereafter, the neutral form of 2‑mercapto‑4‑heptanol was
verified by the detection of the corresponding cysteine‑S‑
conjugate via degradation catalysed by a β‑lyase by colleagues
of the aforementioned researchers in 2011.9 It was approved as
a flavour ingredient by the Flavour and Extract Manufacturers’
Association (FEMA) in 2013 to appear in the GRAS (Generally
Recognised as Safe) list 26 with FEMA No. 4733.10
unsaturated ketones or aldehydes. To our knowledge, there
has not been any other preparative methods reported for this
potential flavour compound. Therefore, the aim of this work
was to develop a relatively simple and effective synthetic route
to 2‑mercapto‑4‑heptanol. Owing to the ready availability of
1‑hepten‑4‑ol prepared via the Grignard reaction of n‑butanal
with allylmagnesium chloride, a four‑step synthetic route was
designed starting from 1‑hepten‑4‑ol through epoxidation,
conversion to an episulfide, and reduction (Scheme 1).
Results and discussion
The key intermediate, 1‑hepten‑4‑ol, which was prepared
in 87% yield by the Grignard reaction of n‑butanal
with allylmagnesium chloride, was epoxidised by
m‑chloroperoxybenzoic acid to 1,2‑epoxy‑4‑heptanol in 92%
yield as a mixture of two diastereoisomers with a ratio of 56/44
1
(determined by GC and confirmed by H NMR spectral data).
However, it was a little puzzling that the 13C NMR spectral
data (Table 1) of the product we obtained did not match
exactly those of the literature reference data for (1R,4R)‑1,2‑
epoxy‑4‑heptanol,12 although the 1H NMR spectral data of one
diastereoisomer of our product were very close to those in the
Table 1 13C NMR data (δ) of the major and minor diastereoisomers of
compounds 2, 3 and 4
In order to confirm its occurrence in an extract of red bell
peppers, Naef et al.8 designed a synthetic route in which
ethyl butyrylacetate was used as starting material. Sequential
hydrolysis, aldol condensation with acetaldehyde, then Michael
addition with thioacetic acid and reduction with LiAlH4 gave
2‑mercapto‑4‑heptanol in about 8% overall yield. This method
is similar to that reported by Vermeulen and Collin,11 who used
combinatorial chemistry to synthesise a series of mercapto
esters based on the Michael addition of thioacetic acid to α,β-
Compound 2
Compound 3
Compound 4
Carbon
Major
Minor
Major
Minor
Major
Minor
C-1
C-2
C-3
C-4
C-5
C-6
C-7
50.20
46.39
39.19
69.37
39.52
18.41
49.98
46.94
39.35
68.29
39.48
18.42
31.85
24.91
43.51
70.92
39.32
18.41
13.66
33.07
25.82
43.45
70.84
38.75
18.32
13.68
26.29
32.04
47.50
68.71
39.61
18.39
25.18
32.27
48.02
69.44
39.42
18.21
13.70
13.61
OH
O
OH
MgCl
O
MCPBA
H
2
1
S
C
SH OH
OH
H2N
NH2
S
LiAlH4
3
4
Scheme 1
* Correspondent. E‑mail: tianhy@btbu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 185
H–C‑3), 2.29 (m, 1H, H–C‑3), 3.65 (m, 1H, H–C‑4), 5.14 (m, 2H, H–C‑
1), 5.83 (m, 1H, H–C‑2); 13C NMR δ 13.99 (C-7), 18.78 (C-6), 38.87
(C‑5), 41.89 (C‑3), 70.39 (C‑4), 117.65 (C‑1), 134.98 (C‑2). The NMR
data were consistent with those previously reported.14
reference. The authenticity of the product we obtained was
confirmed by a high resolution mass analysis.
1,2‑Epoxy‑4‑heptanol was converted to 1,2‑epithio‑
4‑heptanol by treatment with thiourea in the presence of
Ti(OPri)4 according to the procedure in our previous work.13
1,2‑Epithio‑4‑heptanol was obtained in 80% yield as a mixture
of two diastereoisomers with a ratio of 56/44, which was also
determined by GC and confirmed by 1H and 13C NMR spectral
data (Table 1). Obviously the conversion was stereospecific and
the ratio of the two diastereoisomers of episulfide was in line
with that of the epoxide.
The target product, 2‑mercapto‑4‑heptanol was produced by
the reduction of 1,2‑epithio‑4‑heptanol with LiAlH4 in 84%
yield as a mixture of two diastereoisomers (3/1) determined by
GC and confirmed by 1H and 13C NMR spectral data (Table 1).
1‑Mercapto‑4‑heptanol, a possible by‑product produced by
different regioselectivity was not formed. It was odd that the
ratio of the two diastereoisomers was changed to 3/1 compared
with that of the episulfide. We could not find any literature
which reported that the reduction of an epoxide or an episulfide
by LiAlH4 could have such an effect on stereoselectivity and
the reason is still unclear. Experiments on the reduction of
episulfide with different reductants are being carried out in our
laboratory to elucidate the effects of the various reductants on
stereoselectivity.
1,2-Epoxy-4-heptanol (2): A solution of m‑CPBA (14.8 g, 70%,
0.06 mol) in CH2Cl2 (80 mL) was added to a solution of 1‑hepten‑
4‑ol 1 (5.7 g, 0.05 mol) in CH2Cl2 (40 mL). The solution was stirred
for 10 h at –25 °C. The mixture was quenched with 10% NaOH
solution and extracted by CH2Cl2. The combined extracts were
washed with saturated Na2SO3 and brine, dried over anhydrous
MgSO4, and concentrated. The residue was distilled under reduced
pressure (3.03 kPa, 65–66 °C) to afford 1,2‑epoxy‑4‑heptanol 2
1
(6.00 g; 92%) as a colourless oil. H NMR δ 0.92 (m, 3H, H–C-
7), 1.23–1.64 (m, 5H, H–C‑3, H–C‑5 and H–C‑6), 1.75–1.88 (m,
1H, H–C‑3), 2.25 (br, 1H, –OH), 2.49 (dd, J=4.8, 2.7 Hz, 0.56H,
H–C‑1, major diastereoisomer), 2.60 (dd, J=4.8, 2.7 Hz, 0.44H,
H–C‑1, minor diastereoisomer), 2.77 (t, J=4.8 Hz, 0.56H, H–C‑1,
major diastereoisomer), 2.82 (t, J=4.8 Hz, 0.44H, H–C‑1, minor
diastereoisomer), 3.07 (m, 0.56H, H–C‑2, major diastereoisomer), 3.14
(m, 0.44H, H–C‑2, minor diastereoisomer), 3.75–3.94 (m, 1H, H–C‑4);
13C NMR: (see Table 1); HRESIMS, m/z 153.08887 [M+Na+] (calcd for
C7H14NaO2, 153.08860).
1,2-Epithio-4-heptanol (3): Ti(OPri)4 (3.8 mL, 0.012 mol) was
added to a suspension of 1,2‑epoxy‑4‑heptanol 2 (1.3 g, 0.01 mol) and
thiourea (0.9 g, 0.012 mol) in dry THF (40 mL) at room temperature
under nitrogen. After the addition, thiourea gradually dissolved and a
clear solution formed. The mixture was stirred for 2 h. The solution
was then diluted with ether (20 mL) and quenched with saturated
aqueous NaHCO3 solution. The resulting mixture was stirred
vigorously for 1 h as a white precipitate separated from solution. The
mixture was filtered through a pad of Celite, and the residue was
washed thoroughly with ether and CH2Cl2. The combined organic
phases were then washed with water and brine and then dried over
anhydrous MgSO4. After solvent removal, the residue was purified
by flash chromatography on silica gel (petroleum/EtOAc, 15:1)
to afford 1,2‑epithio‑4‑heptanol 3 (1.17 g; 80%) as a colourless
In summary, the preparation of 2‑mercapto‑4‑heptanol was
achieved in a good chemical yield starting from 1‑hepten‑4‑ol
via epoxidation, substitution with thiourea, and reduction. This
route could be used for the industrial scale production of this
new odourant.
Experimental
Allyl chloride (98%), Ti(OPri)4, m‑chloroperoxybenzoic acid
(MCPBA, 70%), and LiAlH4 were purchased from Beijing Bailingwei
Science and Technology Company (Beijing, P.R. China). The other
chemicals and reagents were purchased from Beijing Huaxue Shiji
Company (Beijing, P.R. China). NMR spectra were obtained on
a Bruker AV300 MHz NMR (1H NMR at 300 MHz, 13C NMR at
75 MHz) in CDCl3 using TMS as internal standard. Chemical shifts (δ)
are given in ppm and coupling constants (J) in Hz. The high resolution
mass spectra was obtained on a Bruker Apex IV FTMS.
For the GC‑MS Chromatography, an Agilent 6890N‑5973i was
used under the following conditions: capillary column DB‑5MS
(30 m×ꢀ0.25 mm×ꢀ0.25 µm); the oven temperature was programmed
from 40 to 280 °C at a rate of 20 °C min–1; carrier gas, helium; flow
rate, 0.8 mL min–1; electron ionisation, 70 eV; ion source temperature,
230 °C.
1-Hepten-4-ol (1): Magnesium turnings (3.8 g, 0.16 mol) were
covered by dry diethyl ether (40 mL) and stirred vigorously under an
atmosphere of nitrogen. A small crystal of iodine was added, followed
by allyl chloride (1.0 mL, 12 mmol). The mixture was heated to induce
reaction, and further allyl chloride (7.7 g, 0.1 mol) in diethyl ether
(40 mL) was added at such a rate that the solution continued to reflux.
After addition, diethyl ether (40 mL) was added and the mixture
was kept refluxing for 0.5 h. After cooling to room temperature, a
solution of n‑butanal (7.2 g, 0.1 mol) in dry diethyl ether (30 mL)
was added dropwise to the solution of allylmagnesium chloride at
room temperature. The reaction mixture was stirred for another
1 h under reflux. The mixture was then cooled to room temperature
and quenched with saturated NH4Cl aqueous solution. The organic
layer was separated and the aqueous layer was extracted with diethyl
ether. The combined organic layer was washed with brine, dried over
anhydrous MgSO4 and concentrated. The residue was distilled under
vacuum to yield 1‑hepten‑4‑ol 1 as a colourless liquid (yield 9.90 g;
87%); b.p. 24–26 °C (3.03 kPa); 1H NMR δ 0.93 (t, J=6.9 Hz, 3H, H–C‑
7), 1.44 (m, 4H, H–C‑5 and H–C‑6), 1.70 (s, 1H, –OH), 2.15 (m, 1H,
1
oil. H NMR δ 0.93 (m, 3H, H–C-7), 1.28–1.57 (m, 4.44 H, H–C-3,
H–C‑5 and H–C‑6), 1.69 (m, 0.56H, H–C‑3, major diastereoisomer),
1.75 (br, 1H, –OH), 1.91–2.13 (m, 1H, H–C‑3), 2.17 (d, J=5.7 Hz,
0.44H, H–C‑1, minor diastereoisomer), 2.25 (d, J=6.3 Hz, 0.56H,
H–C‑1, major diastereoisomer), 2.53 (d, J=5.7 Hz, 0.44H, H–C‑1,
minor diastereoisomer), 2.59 (d, J=6.3 Hz, 0.56H, H–C‑1, major
diastereoisomer), 2.98 (m, 0.44H, H–C‑2, minor diastereoisomer),
3.09 (m, 0.56H, H–C‑2, major diastereoisomer), 3.73–3.88 (m, 1H,
H–C‑4); 13C NMR: (see Table 1); HRESIMS, m/z 169.06521 [M+Na+]
(calcd for C7H14NaOS, 169.06576).
2-Mercapto-4-heptanol (4): Lithium aluminium hydride (0.4 g,
0.01 mol) was suspended in dry tetrahydrofuran (20 mL) under
nitrogen. 1,2‑Epithio‑4‑heptanol 3 (1.5 g, 0.01 mol) dissolved in
dry tetrahydrofuran (10 mL) was added dropwise at 0 °C. After the
addition, the reaction mixture was heated at reflux for 3 h. Then it
was cooled to 0 °C and quenched by careful addition of distilled water
(15 mL) and 10% sodium hydroxide solution (10 mL). The mixture
was filtered over Na2SO4, and the filtrate cake was washed with
THF thoroughly. The combined organic phases were then dried over
anhydrous MgSO4. After solvent removal, the residue was purified by
flash chromatography on silica gel (petroleum/EtOAc, 10:1) to afford
2‑mercapto‑4‑heptanol 4 (1.24 g; 84%) as a colourless oil of a mixture
of two diastereoisomers (3:1). 1H NMR δ 0.90 (t, 3H, J=6.9 Hz, H–C‑
7), 1.22–1.64 (m, 8 H, H–C‑1, H–C‑5, H–C‑6, and –SH), 1.64–1.85 (m,
2H, H–C‑3), 3.09 (m, 0.25 H, H–C‑2, minor diastereoisomer), 3.19 (m,
0.75 H, H–C‑2, major diastereoisomer), 3.72 (m, 0.25 H, H–C‑4, minor
diastereoisomer), 3.86 (m, 0.75 H, H–C‑4, major diastereoisomer);
13C NMR: (see Table 1); GC/MS (EI) (both isomers identical): m/z
31 (11), 43 (60), 55 (100), 61 (96), 71 (59), 73 (37), 81 (19), 87 (30), 99
(29), 114 (41), 130 (13), 148 (3, M+). The NMR and MS data agreed with
those reported.8

186 JOURNAL OF CHEMICAL RESEARCH 2015
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Financial support from the National Natural Science Foundation
of China (No. 31271932), the National Key Technology
R&D Program (2011BAD23B01) and the Importation and
Development of High‑Calibre Talents Project of Beijing
Municipal Institutions (CIT&TCD20140306) is gratefully
acknowledged.
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Received 2 February 2015; accepted 25 February 2015
Paper 1503180 doi: 10.3184/174751915X14253193792383
Published online: 18 March 2015
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