Preparation of 2-hexyl-4-acetoxytetrahydrofuran

Article abstract of DOI:10.3184/174751912X13353412394690

2-Hexyl-4-acetoxytetrahydrofuran is a flavor compound with a sweet, floral-fruity odour. Two different methods for its preparation were investigated starting from 1-decen-4-ol. 1-Decen-4-ol was transformed to 2-hexyl-4-acetoxytetrahydrofuran through mesylation, dihydroxylation, intramolecular nucleophilic substitution and acetylation in overall 70% yield; alternatively, 1-decen-4-ol was epoxidised to 1,2-epoxy-4-decanol, followed by acetylation and dehydration to produce the desired product in overall 48% yield. The two methods gave the product with poor and opposite diastereoselectivity but both routes have advantages on yield or ease of operation over the literature procedure.

Full text of DOI:10.3184/174751912X13353412394690

JOURNAL OF CHEMICAL RESEARCH 2012
JUNE, 333–335
RESEARCH PAPER 333
Preparation of 2-hexyl-4-acetoxytetrahydrofuran
a,b
b
b
a,b
Yong-guo Liu , Xiu-qin Gong , Hong-yu Tian * and Bao-guo Sun
a
School of Chemistry and ChemicalTechnology, Shannxi University of Science &Technology, Xi’an, Shanxi Provine, 710021, P. R. China
bSchool of Food Chemistry, Beijing Key laboratory of Flavor Chemistry, BeijingTechnology and Business University, Beijing 100048, P. R. China
2
-Hexyl-4-acetoxytetrahydrofuran is a flavor compound with a sweet, floral-fruity odour. Two different methods for
its preparation were investigated starting from 1-decen-4-ol. 1-Decen-4-ol was transformed to 2-hexyl-4-acetoxy-
tetrahydrofuran through mesylation, dihydroxylation, intramolecular nucleophilic substitution and acetylation in
overall 70% yield; alternatively, 1-decen-4-ol was epoxidised to 1,2-epoxy-4-decanol, followed by acetylation and
dehydration to produce the desired product in overall 48% yield. The two methods gave the product with poor and
opposite diastereoselectivity but both routes have advantages on yield or ease of operation over the literature
procedure.
Keywords: 2-hexyl-4-acetoxytetrahydrofuran, 1-decen-4-ol, 2-hexyl-4-hydroxytetrahydrofuran, 2,4-dihydroxydecyl acetate,
flavour
2
-Hexyl-4-acetoxytetrahydrofuran has a sweet, floral-fruity
an unstabilised secondary carbocation. Instead they obtained it
by bromination of 1-decen-4-ol followed by dehydrobromina-
tion of 1,2-dibromodecan-4-ol and replacement of Br atom by
a hydroxyl group (Scheme 2).
1
odour with a peach-apricot like taste. It has a tortuous story as
a flavor compound. It had been in the first GRAS (generally
recognised as safe) list released by the Flavour and Extract
Manufacturers’Association (FEMA) with FEMA No. 2566 in
A homologue of 2-hexyl-4-acetoxytetrahydrofuran, 2-tri-
decyl-4-acetoxytetrahydrofuran was obtained by Kashman
et al. in their research on identifying the compounds isolated
1
965, but lost its GRAS status and had been removed from
2
FEMA GRAS list four in 1970. Dramatically it came back to
7
FEMA GRAS list 25 released in 2011 after being banned for
4
from avocado fruit and seeds by chemical means. 2,4-
3
0 years.
Dihydroxy-16-heptadecenyl acetate and 2,4-dihydroxy-16-
heptadecynyl acetate isolated from avocado fruit and seeds
were hydrogenated to give 2,4-dihydroxyheptadecyl
acetate, which was heated azeotropically under reflux in the
presence of TsOH to produce 2-tridecyl-4-acetoxytetrahydro-
furan (Scheme 3).
We expect that 2-hexyl-4-acetoxytetrahydrofuran will be a
versatile ingredient of various fruity flavouring formulations
due to its powerful sweet fruity odour. As far as we know, only
two publications have mentioned this compound, neither
4
,5
referring to its synthesis. Chirskaya et al. reported the prepara-
tion of 3-hydroxytetrahydrofurans from homoallylic alcohols
Here we present two different methods of preparing 2-hexyl-
4-acetoxytetrahydrofuran from 1-decen-4-ol (Scheme 4). In
one route, 1-decen-4-ol (2) was transformed to 2-hexyl-4-
acetoxytetrahydrofuran (4)through mesylation, dihydroxyl-
ation, intramolecular nucleophilic substitution and acetylation;
in another 1-decen-4-ol (1) was epoxidised to 1,2-epoxy-
4-decanol (5), followed by acetylation and dehydration to
produce the desired product (4).
6
(
Scheme 1) by oxidation with 3-chloroperoxybenzoic acid to
produce epoxides, which were hydrolysed in aqueous HClO
4
6
to give triols. The triols were converted in situ under reflux via
carbocation intermediates to 3-hydroxytetrahydrofurans. This
method was applicable to the preparation of 2,2-disubstituted-
4
2
-hydroxytetrahydrofurans. However, it failed to produce
-hexyl-4-hydroxytetrahydrofuran from 1-decen-4-ol due to
4
Scheme 1 3-Hydroxytetrahydrofurans from homoallylic alcohol oxides in the presence of HClO .
Scheme 2 2-Hexyl-4-hydroxytetrahydrofuran from 1-decen-4-ol by bromination.
Scheme 3 2-Tridecyl-4-acetoxytetrahydrofuran from 2,4-dihydroxy-16-heptadecyl acetate.
*
Correspondent. E-mail: tianhy@btbu.edu.cn

3
34 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 4 2-Hexyl-4-acetoxytetrahydrofuran from 1-decen-4-ol by dihydroxylation.
Results and discussion
-Decen-4-ol was obtained by the reaction of allylmagnesium
chloride with n-heptanal in about 86% yield. According to
Comparing the two processes under investigation, the former
gave the product in higher yield although via more steps, while
the latter was more straightforward. The two methods gave the
diastereomers with poor but opposite diastereoselectivity
1
our original plan, 1-decen-4-ol was oxidised by H O to give
2
2
1
based on H NMR spectra and GC analysis. In contrast, the
a 1,2,4-triol, the primary HO group of which was selectively
transformed to its mesylate, followed by intramolecular
nucleophilic substitution in the presence of K CO in MeOH
method of preparing 2-hexyl-4-hydroxytetrahydrofuran
6
reported by Chirskaya et al., which involved bromination of
2
3
1
-decen-4-ol followed by dehydrobromination of 1,2-dibro-
to give 2-hexyl-4-hydroxytetrahydrofuran (Scheme 5). Dihy-
droxylation of 1-decen-4-ol gave 1,2,4-triol almost quantita-
tively, which reacted with 1.1 equiv. of MsCl in CH Cl at
modecan-4-ol and replacement of Br atom by a hydroxyl
group, had no advantage either on yield or ease of operation. In
summary, 2-hexyl-4-acetoxytetrahydrofuran (4) could be pre-
pared from 1-decen-4-ol (1) in preparative yields either through
a four-step process of mesylation, dihydroxylation, intramo-
lecular nucleophilic substitution and acylation or a three-step
process of epoxidation, acylation and dehydration.
2
2
0
°C. The mesylate was not purified and underwent intramo-
lecular nucleophilic substitution in the presence of 2 equiv.
of K CO in MeOH to produce a complicated mixture. This
2
3
undesirable result might be due to the poor regioselectivity of
the mesylation of the triol.
In our revised route (Scheme 4), 1-decen-4-ol (1) was trans-
formed to mesylate (2) before dihydroxylation of the double
bond. The mesylate (2) was obtained in 93% yield and was
oxidised by H O in the presence of HCOOH, to give a 1,2-
Experimental
Allyl chloride (98%) was purchased from Beijing Bailingwei Science
and Technology Company, and other chemicals were purchased from
Beijing Huaxue Shiji Company. The NMR spectra were obtained on a
Bruker AV300 MHz NMR. The high resolution mass spectrum was
performed on a Bruker Apex IV FTMS.
2
2
diol. After workup, 1,2-diol without purification was converted
to 2-hexyl-4-hydroxytetrahydrofuran (3) in the presence of 2
equiv. K CO in MeOH in 89% yield. 2-Hexyl-4-hydroxytetra-
2
3
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
hydrofuran (3) reacted with acetic anhydride in pyridine to
produce 2-hexyl-4-acetoxytetrahydrofuran (4) in 84% yield.
The ratio of the two diastereomers was 42/58. The overall yield
of this route was about 70% yield based on 1-decen-4-ol.
In the other route, we first tried to prepared 2,4-dihy-
droxydecyl acetate (6) by the reaction of 1,2,4-decanetriol
−1
−1
min ; carrier gas, helium; flow rate, 0.8 mL min ; electron ionisation,
0 eV; ion source temperature, 230 °C.
-Decen-4-ol (1): Magnesium turnings (3.6 g, 0.15 mol) were
7
1
covered by dry diethyl ether (50 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 (8.8 mL, 0.108 mol) in diethyl
ether (30 mL) was added at such a rate that the solution continued to
reflux. Then 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-heptanal (11.4 g, 0.1 mol) in dry diethyl ether (30 mL) was added
dropwise to the obtained solution of allylmagnesium chloride at
ca 30 °C. The reaction mixture was then stirred for another 1 h under
reflux. The mixture was then cooled to room temperature and quenched
with Ac O in pyridine. But it failed and gave a very complex
2
mixture. Then 1,2-epoxy-4-decanol (5) was prepared in 89%
yieldthroughtheepoxidationof1-decen-4-ol(1)withMCPBA.
8
According to the literature procedure, 1,2-epoxy-4-decanol
(
5) reacted with AcOK in AcOH under reflux and was con-
verted to 2,4-dihydroxydecyl acetate (6). This intermediate
was not purified and went into next step directly. 2,4-Dihy-
droxydecyl acetate (6) was heated azeotropically under reflux
in the presence of TsOH to produce 2-hexyl-4-acetoxytetrahy-
drofuran (4) in 54% yield based on 1,2-epoxy-4-decanol. The
ratio of the two diastereomers was 54/46. The overall yield of
this route was about 48% yield based on 1-decen-4-ol.
with saturated aqueous NH Cl 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
4
Scheme 5 2-Hexyl-4-hydroxytetrahydrofuran from 1-decen-4-ol by dihydroxylation.

JOURNAL OF CHEMICAL RESEARCH 2012 335
MgSO and concentrated. The residue was distilled under vacuum to
38.4 (C(3), major diastereomer), 72.5 (C(4)),75.0 (C(2), minor
diastereomer), 75.1 (C(2), major diastereomer), 78.2 (C(5), major
diastereomer), 78.9 (C(5), minor diastereomer), 170.4 (C=O, major
diastereomer), 170.6 (C=O, minor diastereomer), HRESIMS; m/z
4
yield a colourless liquid 1-decen-4-ol 1 (13.4 g, 86% yield): b.p. 74–
9
1
7
6 °C (0.75 mm) [lit. b.p. 65.4–66.0 °C (0.16 mm)]; H NMR (CDCl )
3
δ 0.86 (t, J = 6.6 Hz, 3H, Me(10)), 1.18–1.52 (m, 10H, H-C(5)–H-
C(9)), 1.77 (s, 1H, -OH), 2.11 (m, 1H, H-C(3)), 2.26 (m, 1H, H-C(3)),
+
237.14588 [M+Na ](Calcd for C H NaO , 237.14666).
12
22
3
3
(
.60 (m, 1H, H-C(4)), 5.10 (m, 2H, H-C(1)), 5.80 (m, 1H, H-C(2))
see refs 9,10).
-Mesyloxy-1-decene (2): To the solution of 1 (20 mmol, 3.12 g)
in dry CH Cl was added Et N (6 mL) and mesyl chloride (24 mmol,
1,2-Epoxy-4-decanol (5): A solution of MCPBA (2.95 g, 70%, 12
mmol) in CH Cl (30 mL) was added to a solution of 1-decen-4-ol 1
2
2
1
1
4
(1.56 g, 10 mmol) in CH Cl (20 mL). The reaction mixture was
2 2
2
2
3
stirred at rt for 12 h. Saturated NaHCO aqueous solution was added
3
1
.9 mL) at 0 °C. The reaction mixture was stirred for 6 h at rt. The
to the mixture until pH 8 and the mixture was stirred for about 30 min.
The organic layer was separated and the aqueous layer was extracted
with CH Cl (30 mL × 3). The combined organic layer was washed
reaction mixture was washed with dilutes HCl and the aqueous layer
was extracted with CH Cl . The combined organic layer was washed
2
2
2
2
with brine, dried over MgSO and concentrated under vacuum. The
crude product was purified by flash chromatography (silica gel, hexane-
ethyl acetate (8:1 V/V) was used an eluent) to give 4-mesyloxy-
with brine and dried over MgSO . The solvent was removed by
4
4
distillation and the residue was purified by flash chromatography
(silica gel, petroleum ether/ethyl acetate = 6/1) to afford product
1
1
1
-decene 2 as an oil (4.35 g, 93% yield). H NMR (CDCl ) δ 0.87 (t,
1,2-epoxy-4-decanol (5) (1.53 g, 89% yield). H NMR (CDCl ) δ 0.87
3
3
J = 6.6 Hz, 3H, Me(10)), 1.18–1.48 (m, 8H, H-C(6)–H-C(9)), 1.68
m, 2H, H-C(5)), 2.45 (m, 2H, H-C(3)), 2.99 (s, 3H, Me-S), 4.72 (m,
H, H-C(4)), 5.17 (m, 2H, H-C(1)), 5.78 (m, 1H, H-C(2)).
-Hexyl-4-hydroxytetrahydrofuran (3): To a mixture of 30% H O
(t, J = 6.9 Hz, 3H, Me(10)), 1.20–1.68 (m, 11H, H-C(5)–H-C(9)
and H-C(3)), 1.85 (m, 1H, H-C(3)), 2.15 (br. S, 1H, -OH), 2.50 (dd,
J = 2.7, 4.9 Hz, 0.5H, H-C(1), one diastereomer), 2.61 (dd, J = 2.9,
4.9 Hz, 0.5H, H-C(1), the other diastereomer), 2.78 (dd, J = 4.2,
4.9 Hz, 0.5H, H-C(1), one diastereomer), 2.82 (dd, J = 4.2, 4.9 Hz,
0.5H, H-C(1), the other diastereomer), 3.08 (m, 0.5H, H-C(2), one
diastereomer), 3.16 (m, 0.5H, H-C(2), the other diastereomer), 3.80
(
1
2
2
2
(
(
21 mmol, 2.1 mL) and 88% HCOOH (0.21 mol, 9 mL) was added 2
15 mmol, 3.5 g) during 10-15 min. The reaction mixture was cooled
by ice bath and kept at 40-45 °C during addition. Then the mixture
was stirred for 1 h at 40 °C and stood overnight. The mixture was
concentrated under vacuum and cold 30% NaOH aqueous solution
was added to the residue cautiously to keep the temperature below
(
m, 0.5H, H-C(4), one diastereomer), 3.87 (m, 0.5H, H-C(4), the other
13
diastereomer). C NMR (CDCl ) δ 13.9, 22.5, 25.4 and 25.5, 29.2,
3
3
1.7, 37.3 and 37.6, 39.4 and 39.7, 46.6 and 47.0, 50.2 and 50.5, 69.1
4
5 °C. The aqueous layer was extracted with CH Cl and the organic
2 2
and 70.1. (cf. ref. 6).
layers were washed with brine, dried over MgSO , and concentrated
4
2,4-Dihydroxy decyl acetate (6): To a solution of AcOK (20 mmol,
.96 g) in AcOH (20 mL) was added 1,2-epoxy-4-decanol 5 (4 mmol,
under vacuum. The residue was dissolved in MeOH (30 mL) and
1
K CO (30 mmol, 4.2 g) was added. The mixture was stirred at rt for
2
3
0.688 g). The mixture was stirred for 8 h under reflux and then poured
6
h. The solvent was evaporated under vacuum and the residue was
into brine (40 mL). The solution was extracted with Et O (30 mL × 3).
2
diluted with water, extracted with CH Cl . The organic layers were
2
2
The combined organic layers were washed with brine, dried over
washed with brine, dried over MgSO , and concentrated under
4
MgSO , and concentrated under vacuum to give a crude product
4
vacuum. The crude product was purified by flash chromatography
2,4-dihydroxy decyl acetate 6.
(
2
silica gel, hexane-ethyl acetate (4:1 V/V) was used an eluent) to give
-hexyl-4-hydroxytetrahydrofuran (3): Oil, (2.3 g, 89% yield). H
2
-Hexyl-4-acetoxytetrahydrofuran (4) from 2,4-dihydroxy decyl
1
acetate (6): The obtained crude product 6 was dissolved in benzene
(20 mL) and heated azeotropically under reflux for 6 h in the presence
of TsOH (0.5 mmol, 86 mg). The mixture was washed with 5%
NaHCO aqueous solution and with water, dried over MgSO , and
NMR (CDCl ) δ 0.87 (t, J = 6.9 Hz, 3H, Me(6′)), 1.20–1.74 (m, 11H,
3
H-C(1′)–H-C(5′) and H-C(3)), 2.00 (m, 0.58H, H-C(3), major diaste-
reomer), 2.34 (m, 0.42H, H-C(3), minor diastereomer), 3.66 (overlap-
ping dd, J = 4.2, 9.9 Hz, 0.58H, H-C(5), major diastereomer), 3.68
3
4
concentrated. The residue was subjected to flash chromatography
silica gel, hexane-ethyl acetate (8:1 V/V) was used an eluent) to give
-hexyl-4-acetoxytetrahydrofuran 4 (0.46 g) in 54% yield based on
(
overlapping m, 0.42H, H-C(5), minor diastereomer), 3.78 (m, 0.42H,
(
H-C(2), minor diastereomer), 3.83 (m, 0.42H, H-C(5), minor diaste-
reomer), 4.01 (dd, J = 4.2, 9.9 Hz, 0.58H, H-C(5), major diastereo-
mer), 4.09 (m, 0.58H, H-C(2), major diastereomer), 4.44 (m, 0.42H,
H-C(4), minor diastereomer), 4.50 (m, 0.58H, H-C(4), major diaste-
2
1
the amount of 1,2-epoxy-4-decanol 5. Its H NMR spectrum is very
similar to that of the product derived from 2-hexyl-4-hydroxytetrahy-
drofuran 3 except the ratio of diastereomers.
13
reomer). C NMR (CDCl ) δ 14.0 (C(6′)), 22.5 (C(5′)), 26.1 (C(4′),
3
Financial support from the National Natural Science Founda-
tion of P. R. China (No. 31071610), Beijing Natural
Science Foundation Program and Scientific Research Key
Program of Beijing Municipal Commission of Education
(
KZ201110011015), the National Key Technology R&D Pro-
gram(2011BAD23B01)andPHR(IHLB)(No.PHR201008244
and PHR20090504) is gratefully acknowledged.
(
dimethylamino)pyridine (DMAP, 0.5 mmol, 60 mg) in pyridine
15 mL) was added acetic anhydride (22 mmol, 2.1 mL) at rt. The
Received 1 March 2012; accepted 20 March 2012
Paper 1201188 doi: 10.3184/174751912X13353412394690
Published online: 4 June 2012
(
mixture was stirred overnight and quenched with a saturated aqueous
NaHCO solution. The aqueous layer was extracted with diethyl ether
and the organic layers were washed with brine, dried over MgSO , and
3
4
concentrated under vacuum. The crude product was purified by flash
chromatography (silica gel, hexane-ethyl acetate (8:1 V/V) was used
References
1
G.A. Burdock, Fenaroli’s handbook of flavor ingredients, CRC Press, 5th
edn, Florida, 2005, pp. 821.
an eluent) to give 2-hexyl-4-acetoxytetrahydrofuran (4): Oil,(1.79 g,
1
8
4% yield). H NMR (CDCl ) δ 0.85 (m, 3H, Me(6′)), 1.20–1.76
3
2
G. Reineccius, Source book of flavours, Aspen publishers, Inc., 2nd edn,
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(
m, 11H, H-C(1′)–H-C(5′) and H-C(3)), 2.06 (overlapping m, 3H,
Me-C=O), 2.09 (overlapping m, 0.58H, H-C(3), major diastereomer),
3
4
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2
0
1
0
.41 (m, 0.42H, H-C(3), minor diastereomer), 3.71 (overlapping m,
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0.5 Hz, 0.58H, H-C(5), major diastereomer), 3.79 (overlapping m,
.42H, H-C(2), minor diastereomer), 3.94 (m, 0.42H, H-C(5), minor
5
6
diastereomer), 4.00 (m, 0.58H, H-C(2), major diastereomer), 4.13 (dd,
7
8
9
0
Y. Kashman, I. Néeman and A. Lifshitz, Tetrahedron, 1969, 25, 4617.
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J = 4.8, 10.5 Hz, 0.58H, H-C(5), major diastereomer), 5.25 (m, 1H,
13
H-C(4)). C NMR (CDCl ) δ 13.9 (C(6′)), 20.8 (Me-C=O), 22.4
3
(
C(5′)), 25.9 (C(4′), major diastereomer), 26.0 (C(4′), minor diaste-
reomer), 29.2 (C(3′)), 31.6 (C(2′)), 35.0 (C(1′), major diastereomer),
5.4 (C(1′), minor diastereomer), 38.0 (C(3), minor diastereomer),
1
W.R. Wilson and M.E. Guazzaroni, J. Org. Chem., 1989, 54, 3087.
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