Conversion of (Z)-1,4-dihydroxyalk-2-enes into 2,5-dihydrofurans and of alkane-1,4-diols into tetrahydrofurans via acid-catalysed cyclisation of the monoisoureas formed by their copper(I)-mediated reactions with dicyclohexylcarbodiimide

Article abstract of DOI:10.1039/b203389p

(Z)-1,4-dihydroxyalk-2-enes were converted into 2,5-dihydrofurans and alkane-1,4-diols were converted into tetrahydrofurans via acid-catalysed cyclisation of the monoisoureas. The reaction involved protonation of the carbodiimide by acidic phenol followed by reaction with alkanol. Pd/CaCo₃-quinoline catalyst system was employed in the presence of a little triethylamine to overcome partial hydrogenolysis.

Full text of DOI:10.1039/b203389p

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Conversion of (Z )-1,4-dihydroxyalk-2-enes into 2,5-dihydrofurans
and of alkane-1,4-diols into tetrahydrofurans via acid-catalysed
cyclisation of the monoisoureas formed by their copper(I)-mediated
reactions with dicyclohexylcarbodiimide†
1
Michael G. Duffy and David H. Grayson*
University Chemical Laboratory, Trinity College, Dublin 2, Ireland
Received (in Cambridge, UK) 5th April 2002, Accepted 24th May 2002
First published as an Advance Article on the web 10th June 2002
(Z)-1,4-Dihydroxyalk-2-enes react with dicyclohexylcarbodiimide in the presence of catalytic amounts of copper()
chloride to give O-alkyl monoisoureas which cyclise to give 2-substituted-2,5-dihydrofurans and dicyclohexylurea
when they are treated with trifluoroacetic acid. Alkane-1,4-diols likewise give O-alkyl monoisoureas which cyclise to
yield tetrahydrofurans.
Introduction
2,5-Dihydrofurans 1 are an important class of compounds, the
synthesis of which has received considerable attention. For
In connection with other work,14 we needed reliable access to
example, Heck arylation or vinylation of 2,3-dihydrofurans,1
5-(2Ј,5Ј-dihydro-2Ј-furyl)pentanoic acid 5, and attempted to
make this compound as its methyl ester 6c via cyclodehydration
of the (Z)-diol 7c using each of the methodologies described
by Barry and Evans. In the event, treatment of 7c with either
of their reagent combinations led to unsatisfactory yields
(25–30%) of the dihydrofuran 6c. Accordingly, we sought to
develop a more effective method for this transformation.
ring-closing metathesis reactions of diallyl ethers,2 retro-
Diels–Alder reactions of modified furan–2,5-dihydrofuran
cycloadducts,3 Wittig cyclo-olefination reactions of suitable
β-oxaethylphosphoranes4 and selenyl halide-induced cyclis-
ations of α-allenic alcohols5 have all been utilised for this
purpose.
The dehydrative cyclisation of (Z)-1,4-dihydroxyalk-2-enes 2
to give 2,5-dihydrofurans 1 is, in principle, a simple and attract-
ive synthetic route to these compounds. However, this type of
cyclisation is usually effected under relatively harsh acidic con-
ditions. Thus, treatment with sulfuric acid succeeds for some
cases6 but may also lead to the formation of polymers,7 and it
frequently causes acid-catalysed dehydration of the diols 2 so
that variable amounts of α,β-unsaturated carbonyl compounds
are also produced.8
Results and discussion
It has been reported by Vowinkel15 that phenolic ethers can be
synthesised by reaction of an alkanol with a phenol in the
presence of dicyclohexylcarbodiimide (DCC), and Bach16 has
demonstrated by 18O labelling experiments (Scheme 1) that this
Reaction of (Z)-1,4-dihydroxybut-2-ene 2a with the diaryl-
dialkoxysulfane 3 has been reported9 to give 2,5-dihydrofuran
in 84% yield, but the reagent is expensive. Diethoxytriphenyl-
phosphorane 4 efficiently cyclises the same diol10 but this
reagent must be prepared from explosive diethyl peroxide. The
environmentally toxic butyltrichlorotin reacts with the diol 2a
to give 2,5-dihydrofuran (88%) together with some crotonalde-
hyde.11 Barry and Evans have described12,13 how (Z)-1,4-di-
hydroxybut-2-ene 2a can be cyclised in the presence of either
tert-BuOCl–Ph3P–K2CO3 or Ph3P–CCl4 to give 2,5-dihydro-
furan in >60% yields.
Scheme 1
reaction involves protonation of the carbodiimide by the
relatively acidic phenol followed by reaction with the alkanol to
give an O-alkylisourea 8. This then reacts in situ with phenoxide
ion to give the product ether together with dicyclohexylurea.
These observations led us to consider the use of DCC for the
dehydrative cyclisation of (Z)-1,4-dihydroxyalk-2-enes 2 to give
† Electronic supplementary information (ESI) available. Experimental
data for compounds 14a–f, 15a–f, 7a–f, 22a–g, 21a–e and 2b–e: See
http://www.rsc.org/suppdata/p1/b2/b203389p/
DOI: 10.1039/b203389p
J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563
This journal is © The Royal Society of Chemistry 2002
1555

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We have successfully applied this cyclodehydration method-
ology to a series of methyl (Z)-dihydroxyalk-2-enoates 7a–7f
which yielded the ω-(2Ј,5Ј-dihydro-2Ј-furyl)alkanoic esters 6a–
6f under these conditions. The diols 7a–7f were synthesised
(Scheme 3) via chemoselective reaction of lithiated 3-(tetra-
Scheme 2
2,5-dihydrofurans. We reasoned (Scheme 2) that if a (Z)-
configured unsaturated diol 2 could be converted into a mono-
isourea via reaction with DCC, then treatment of the latter with
an acid should lead to a 2,5-dihydrofuran 1.
Although aliphatic carbodiimides are generally quite inert
towards neutral alcohols, the direct synthesis of O-alkyl-
isoureas from monohydric alcohols and diisopropyl- or
dicyclohexylcarbodiimide has been accomplished by using
copper() salts, especially copper() chloride, as catalysts.17
Reactions of this type have been reviewed,18 and Schmidt et al.
have shown19 that diisopropylcarbodiimide reacts with, e.g.,
butane-1,4-diol in the presence of copper() chloride to yield
the bis-O,OЈ-dialkylisourea 9.
Scheme
3
Reagents: (a) BuLi; (b) MeO2CCH2(CH2)nCH2CHO;
(c) PPTS–MeOH; (d) H2–Pd/BaSO4–quinoline.
hydropyran-2Ј-yloxy)propyne with each of the appropriate
aldehydo-esters 13a–13f to give the hydroxy-esters 14a–14f.
Cleavage of the tetrahydropyranyl ether groups of 14a–14f
using PPTS–MeOH yielded the acetylenic diols 15a–15f which
were then partially hydrogenated over Pd/BaSO4–quinoline to
1
give the (Z)-diols 7a–7f. The H NMR spectra of these diols
exhibited J values for their olefinic protons in the range 5–9 Hz,
confirming the expected (Z)-configurations. The protons of the
methylene groups adjacent to the primary hydroxy functions of
each of the diols 7a–7f (and of other related diols described
below) exhibited obvious diastereotopicity, appearing as AB
systems near δ 4.0 ppm.
We have found that when the copper() chloride used by
Schmidt et al.19 is substituted by the cuprous salt the mono-
isourea 10 is efficiently formed from dicyclohexylcarbodiimide
and butane-1,4-diol, even in the presence of excess carbo-
diimide. A similar result was obtained with hexane-1,6-diol
which afforded the monoisourea 11. Each of these compounds
showed the expected spectroscopic features, including sharp IR
absorptions at ca. 1660 cmϪ1 and, in their 1H NMR spectra, 2H
triplets near δ 4.1 ppm which are assigned to the protons of
their C-1 methylene groups.
One-pot treatment of chloroform solutions of each of the
unsaturated diols 7a–7f with DCC–CuCl, followed by heating
at 40 ЊC in the same solvent with an optimised (13 mol%)
amount of trifluoroacetic acid gave the derived 2,5-dihydro-
furans 6a–6f in acceptable yields after purification by chrom-
atography (Table 1).
Reaction of (Z)-but-2-ene-1,4-diol 2a with dicyclohexyl-
carbodiimide under similar conditions gave the crystalline
monoisourea 12, mp 87 ЊC. When a chloroform solution of
this compound was treated with catalytic amounts of either
methanesulfonic or (better) trifluoroacetic acid it was quanti-
tatively converted (NMR) into a mixture of 2,5-dihydrofuran
and dicyclohexylurea, most of the latter crystallising from the
solvent. Furthermore, this overall transformation could be
accomplished as a one-pot process without isolation of the
intermediate isourea 12 by reaction of the diol 2a with DCC–
CuCl followed by the addition of trifluoroacetic acid.
When the diol 7c was reacted with DCC–CuCl alone and the
intermediate isourea was separated, NMR spectroscopy indi-
cated that this was a 75 : 25 mixture of the primary isourea
16 and the isomeric secondary isourea 17. A competition
experiment where one equivalent of each of 1-phenylethanol,
2-phenylethanol and DCC were reacted together in chloroform
in the presence of copper() chloride afforded a mixture con-
taining 91% of the less hindered primary isourea 18. Similarly,
CuCl-catalysed reaction of one equivalent of each of propan-1-
ol, propan-2-ol and DCC gave a 90 : 10 mixture of the derived
primary 19 and secondary isoureas. Given that the degree of
steric hindrance about the secondary hydroxy function of the
diol 7c is significant compared to that in propan-2-ol, the form-
ation of a 75 : 25 mixture of primary and secondary isoureas
from 7c suggests the possibility that an O–OЈ-transfer reaction
proceeding via the cyclic intermediate 20 cannot be ruled out.
1556
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Table 1 Synthesis of methyl ω-(2,5-dihydro-2-furyl)alkanoates from
1,4-dihydroxyalk-2-enes via acid-catalysed cyclisation of their mono-
isoureas
Table 2 Synthesis of 2-substituted-2,5-dihydrofurans from alk-2-ene-
1,4-diols via acid-catalysed cyclisation of their monoisoureas
1,4-Diol
2,5-Dihydrofuran
Yield (%)
1,4-Diol
2,5-Dihydrofuran
Yield (%)
2b
2c
2d
2e
2f
1b
1c
1d
1e
1f
81
90
89
64
79
86
7a
7b
7c
7d
7e
7f
6a
6b
6c
6d
6e
6f
52
62
57
62
57
56
2g
1g
Table 3 Synthesis of 2-substituted tetrahydrofurans from 1,4-diols via
acid-catalysed cyclisation of their monoisoureas
1,4-Diol
Tetrahydrofuran
Yield (%)
25
26
72
85
33
27
28
39a
30a
a as a mixture of diastereoisomers
we were unable to find suitable conditions for the clean
semi-hydrogenation of the enynediol 21g.
Following the general protocol outlined above, each of the
unsaturated diols 2b–2g was readily cyclised via an intermediate
isourea formed by reaction with dicyclohexylcarbodiimide in
the presence of catalytic copper() chloride to give (Table 2) the
derived 2,5-dihydrofurans 1b–1g. These, and the other 2,5-
dihydrofurans discussed above must be stored under an inert
atmosphere since they undergo rapid oxidation in the presence
of air to give the derived furans together with mixtures of more
highly oxygenated compounds.
The cyclodehydration process described above is equally
applicable to the synthesis of tetrahydrofurans. Thus (Table 3),
1,4-dihydroxy-1-phenylbutane 25 gave 2-phenyltetrahydrofuran
26, and methyl 6,9-dihydroxynonanoate 27 gave methyl 5-(tetra-
hydro-2Ј-furyl)pentanoate 28 in good yield when they were each
treated with DCC–CuCl followed by trifluoroacetic acid.
Cyclisation of the more hindered methyl 6,9-dihydroxydecano-
ate 29 was less satisfactory, and methyl 5-(5Ј-methyltetrahydro-
2Ј-furyl)pentanoate 30 was obtained in only 33% yield.
A further series of protected acetylenic diols 21a–21g was
synthesised in good yields from lithiated 3-(2Ј-tetrahydro-
pyranyloxy)propyne and the relevant aldehydes. Cleavage of
the tetrahydropyranyl ether functions of the product acetals
22a–22g using PPTS–MeOH proceeded normally except in
two instances. Thus, the o-methoxy compound 22f yielded the
methyl ether 23, and the enynol 22g afforded a mixture contain-
ing mainly the methyl ether 24 under these conditions. These
results are presumably due to the intervention of, respectively,
stabilised benzylic or allylic cations. However, for each of
the compounds 22f and 22g reaction proceeded normally in
aqueous tetrahydrofuran to afford the expected products 21f
and 21g in good yield.
Experimental
1H NMR spectra were recorded for solutions in CDCl3 using
Bruker WP 80 (with Me4Si as internal standard), Bruker MSL
300 or Bruker DPX 400 MHz spectrometers. Coupling con-
stants are recorded in Hz. Assignments were verified by
appropriate H–H COSY, C–H COSY and DEPT experiments.
IR spectra were recorded for Nujol mulls (N) or liquid films (L)
between sodium chloride plates using Perkin Elmer 883 or
Paragon 1000 spectrometers. High resolution mass spectra were
obtained using a Kratos instrument. Melting points (uncor-
rected) were measured in unsealed capillary tubes using a Stuart
Scientific SMP2 digital apparatus or an Electrothermal IA9100
apparatus. Thin layer chromatography was carried out using
Merck Kieselgel 60 F254 0.2 mm silica gel plates. Column
chromatography was carried out using Merck Kieselgel 60
(230–400 mesh) silica gel. All solvents were dried and distilled
before use. Ethereal extracts of reaction products were dried
over anhydrous magnesium sulfate. Combustion analyses
were obtained from the Microanalytical Laboratory, University
College, Dublin.
The acetylenic diols 21a–21d were successfully semi-hydrogen-
ated to the (Z)-olefinic diols 2b–2e over Pd/BaSO4 poisoned
with quinoline, but use of this catalyst system with the diols 21f
and 21g led to partial hydrogenolysis of their benzylic second-
ary hydroxy groups. This problem was overcome by employing
the catalyst system Pd/CaCO3–quinoline in the presence of a
little triethylamine when reduction proceeded without detec-
table hydrogenolysis to yield 2f and 2g, respectively. However,
J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563
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N,N-Dicyclohexyl-O-(4Ј-hydroxybutyl)isourea 10
J 6.8, CH2OH) and 3.62 (3H, s, CO2CH3) ppm. This hydroxy-
ester (3.8 g) was added to a stirred solution of pyridinium
chlorochromate (6.2 g) in dichloromethane (40 cm3) and the
resulting suspension was allowed to stir at room temperature
during 1.5 h. Ether (40 cm3) was added and the supernatant
liquid decanted from a black gum. The insoluble residue was
extracted thoroughly with ether, and the combined extract was
filtered, evaporated and distilled to give the aldehydo-ester 13a
as an oil20 (2.0 g), bp 80–84 ЊC (14 mmHg), νmax (L) 2955, 1732,
1646, 1438, 1371, 1200, 1167, 1080 and 1006 cmϪ1; δH (300
MHz) 1.93 (2H, m, 3-CH2), 2.36 (2H, t, J 7.3, CH2CO2), 2.52
(2H, dt, J 7.3 and 1.3, CH2CHO), 3.67 (3H, s, CO2CH3) and
9.75 (1H, t, J 1.3, CHO) ppm.
Butane-1,4-diol (0.45 g), dicyclohexylcarbodiimide (1.03 g) and
copper() chloride (20 mg) were stirred in chloroform (10 cm3)
for 12 h. Hexane (15 cm3) was added, and the solution was
filtered to remove precipitated dicyclohexylurea and then evap-
orated to give the isourea 10 as a viscous oil (1.34 g) which had
νmax (L) 3365 and 1664 cmϪ1; δH (80 MHz) 1.25 (10H, m, CH2
groups), 1.7 (14H, m, CH2 groups), 3.2 (2H, br m, exch. D2O,
NH and OH ), 3.7 (2H, t, J 6.2, CH2OH) and 4.13 (2H, t, J 6.2,
CH OC(᎐NR)NHR) ppm; m/z (CI) 297.2554: calculated for
᎐
2
[C17H32N2O2 ϩ H]ϩ 297.2542 [Found: C 68.72, H 10.93, N
9.32%; C17H32N2O2 requires C 68.92, H 10.81, N 9.46%].
N,N-Dicyclohexyl-O-(6Ј-hydroxyhexyl)isourea 11
Methyl 6-oxohexanoate 13b
Hexane-1,6-diol (0.59 g) was reacted with dicyclohexylcarbodi-
imide (1.03 g) in a similar manner to that described above to
yield the isourea 11 (1.48 g) as an oil which had νmax (L) 3358
and 1667 cmϪ1; δH (80 MHz) 1.25 (9H, m, CH2 groups), 1.47
(7H, m, CH2 groups), 1.72 (14H, m, CH2 groups), 3.2 (2H, br
m, exch. D2O, NH and OH ), 3.71 (2H, dt, J 6.5 and 2.0,
CH2OH) and 4.05 (2H, t, J 6.2, CH2OC) ppm; m/z (CI)
325.2849; calculated for [C19H36N2O2 ϩ H]ϩ 325.2855 [Found: C
70.52, H 11.26, N 8.76%; C19H36N2O2 requires C 70.37, H 11.11,
N 8.64%].
ε-Caprolactone (25.0 g) in methanol (250 cm3) with concen-
trated sulfuric acid (2 cm3) was left at room temperature during
48 h. Methanol (200 cm3) was removed at reduced pressure and
the product was extracted with ether. The extract was washed
with aqueous sodium hydrogen carbonate solution followed by
brine, dried, evaporated and distilled to give methyl 6-hydroxy-
hexanoate (27.95 g; 87%) as an oil, bp 92–95 ЊC (0.5 mmHg);
νmax (L) 3416, and 1738 cmϪ1; δH (80 MHz) 1.8 (4H, m, CH2
groups), 2.33 (2H, m, CH2CO2), 3.25 (1H, br s, exch. D2O,
OH ), 3.55 (2H, m, CH2OH) and 3.65 (3H, s, CO2CH3) ppm.
This ester (5.11 g), in dichloromethane (10 cm3), was added to a
suspension of pyridinium chlorochromate (8.2 g) in dichloro-
methane (70 cm3) and the mixture was stirred at room temper-
ature during 2 h. Ether was added and the supernatant liquid
decanted from a black gum. The insoluble residue was thor-
oughly extracted with ether, and the combined extract was
evaporated and distilled to give methyl 6-oxohexanoate 13b as a
colourless oil21 (3.88 g; 77%), bp 69–71 ЊC (0.5 mmHg); νmax (L)
1739 cmϪ1; δH (80 MHz) 1.8 (4H, m, CH2 groups), 2.45 (4H, m,
CH2CO2 and CH2CHO), 3.7 (3H, s, CO2CH3) and 9.4 (1H,
s, CHO) ppm; m/z (EI) 144.0793: calculated for C7H12O3
144.0787.
N,N-Dicyclohexyl-O-[(2Z )-4Ј-hydroxybut-2-enyl]isourea 12
(Z)-But-2-ene-1,4-diol 2a (0.22 g), dicyclohexylcarbodiimide
(0.54 g) and copper() chloride (20 mg) in chloroform (3 cm3)
and acetone (2 cm3) were stirred together during 12 h. Hexane
(15 cm3) was added and the mixture was filtered and evaporated
to yield a solid which was recrystallised from 2 : 3 ether–hexane
to give the isourea 12 (0.45 g; 87%) as colourless crystals,
mp 87.3–87.7 ЊC, which had νmax (N) 3336, 1633 and 1055 cmϪ1
;
δH (80 MHz) 1.22 (10H, m, CH2 groups), 1.7 (10H, m, CH2
groups), 2.7 (1H, br m, CHNHC–N), 3.4 (1H, br m, CHN᎐C–),
᎐
3.55 (1H, exch. D2O, OH ), 4.25 (2H, d, J 6.8, CH2OH), 4.9
(2H, d, J 9.5, CH2OC), 5.7 (2H, m, olefinic) and 6.8 (1H, br s,
exch. D2O, NH ) ppm; δC (100.6 MHz) 151.9 (C᎐N), 132.8
Methyl 7-oxoheptanoate 13c
᎐
(C᎐C), 125.1 (C᎐C), 60.1 (CH OH), 59.8 (CH OC), 55.3 (CH),
᎐
᎐
2
2
Cycloheptene (7.2 g) was dissolved in a mixture of dichloro-
methane (250 cm3) and methanol (50 cm3) to which was added
anhydrous sodium hydrogen carbonate (2 g). The stirred mix-
ture was cooled to Ϫ78 ЊC and a stream of ozone was intro-
duced. The addition of ozone was stopped once the solution
had turned blue. The mixture was purged with nitrogen until
the blue colour had disappeared, brought to room temperature,
and filtered. Benzene (80 cm3) was added, and the volume was
reduced to approximately 50 cm3 by evaporation at reduced
pressure. After dilution with dichloromethane (225 cm3) the
mixture was cooled to 0 ЊC and triethylamine (16 cm3) and
acetic anhydride (21.25 cm3) were added slowly with stirring.
The solution was allowed to warm up gradually and was left
stirring overnight. It was then washed sequentially with dilute
hydrochloric acid, aqueous sodium hydrogen carbonate and
brine. Evaporation of the solvent followed by short path distil-
lation of the crude product yielded 13c as a colourless oil22
34.3 (CH2), 34.2 (CH2), 34.0 (CH2), 25.6 (CH2) and 24.9 (CH2)
ppm; m/z (CI): 295.2390; calculated for [C17H30N2O2 ϩ H]ϩ
295.2385.
2,5-Dihydrofuran
(Z)-But-2-ene-1,4-diol 2a (88 mg) was dissolved in CDCl3
(3 cm3) to which was added 1,3-dicyclohexylcarbodiimide
(225 mg; 1.1 eq.). Copper() chloride (5 mg) was added and the
mixture was stirred at room temperature under a nitrogen
atmosphere during 12 h. Trifluoroacetic acid (15 mg; 0.13eq.)
was then added, and the mixture was heated to 40 ЊC during 6 h
after which time the mixture was cooled and filtered to remove
1
dicyclohexylurea. H NMR spectroscopy of a sample which
had been diluted with additional CDCl3 revealed that all of the
isourea 12 had been consumed and that the solution contained
only 2,5-dihydrofuran together with traces of dicyclohexylurea.
(14.6 g; 62%), bp 82–85 ЊC (0.5 mmHg); νmax (L) 1736 cmϪ1
;
δH (400 MHz) 1.25 (2H, m, 3-CH2), 1.57 (4H, m, 2- and 4-CH2
groups), 2.24 (2H, t, J 7.5, CH2CO2Me), 2.37 (2H, dt, J 7.3 and
1.7, CH2CHO), 3.59 (3H, s, CO2CH3) and 9.75 (1H, t, J 1.5,
CHO) ppm.
Methyl 5-oxopentanoate 13a
δ-Valerolactone (5 g) was dissolved in methanol (100 cm3) with
concentrated sulfuric acid (2 cm3) and the mixture was refluxed
for 12 h. Methanol (60 cm3) was evaporated under reduced
pressure and the product was extracted with ether. The extract
was washed with aqueous sodium hydrogen carbonate followed
by brine, dried and evaporated to give an oil which was distilled,
bp 90–93 ЊC (0.5 mmHg), to give methyl 5-hydroxypentanoate
Methyl 8-oxooctanoate 13d
Cyclooctene (8.25 g) was ozonized in a manner similar to that
described for cycloheptene above to give methyl 8-oxooctanoate
13d as a colourless oil23 (10.6 g; 82%), bp 94–97 ЊC (0.5 mmHg);
νmax (L) 1738 cmϪ1; δH (400 MHz) 1.42 (8H, m, CH2 groups),
2.39 (4H, m, CH2CHO and CH2CO2), 3.65 (3H, s, CO2CH3)
(4.8 g, 73%) as a colourless oil, νmax (L) 3448 and 1736 cmϪ1
δH (300 MHz) 1.55 (2H, m, CH2), 1.66 (2H, m, CH2), 2.31 (2H,
t, J 7.3, CH2CO2), 2.45 (1H, br s, exch. D2O, OH ), 3.58 (2H, t,
;
1558
J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563

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and 9.68 (1H, t, J 1.5, CHO) ppm; m/z (EI) 172.1104: calculated
for C9H16O3 172.1099.
extract was washed with brine, dried and evaporated to yield
one of the acetylenic diols 15a–15f.
Methyl 9-oxononanoate 13e
(c) Partial hydrogenation of the acetylenic diols 15a–15f;
synthesis of the (Z )-dihydroxyesters 7a–7f. A solution of one of
the acetylenic diols 15a–15f (5 mmol) in methanol (10 cm3) with
quinoline (20 mg) was hydrogenated at 1 atm over Pd/BaSO4
(5%w/w; 20 mg). After absorption of the calculated amount of
hydrogen the reaction mixture was filtered through a pad of
Celite which was then washed with ether. The combined mix-
ture and washings were extracted with ethyl acetate, and the
extract was washed sequentially with dilute HCl, aqueous
sodium hydrogen carbonate and brine. The extract was dried
and evaporated to yield one of the (Z)-olefinic diols 7a–7f.
Methyl oleate (22.4 g) was ozonised at Ϫ78 ЊC in dichloro-
methane (250 cm3) and methanol (50 cm3) containing
anhydrous sodium carbonate (2 g) until the appearance of a
blue colour. Nitrogen was then bubbled through the mixture to
remove excess ozone and the cold bath was removed. The mix-
ture was filtered and cooled to 0 ЊC, triethylamine (16 cm3) was
added, and the mixture was allowed to warm to room temper-
ature. After 6 h, the mixture was washed with dilute HCl
followed by brine. The extract was dried and evaporated to
yield an oil which was fractionally distilled to give nonanal, bp
72–74 ЊC (17 mmHg) followed by the aldehydo-ester 13e
which was obtained as an oil24 (6.0 g; 43%), bp 112–116 ЊC
(0.6 mmHg); νmax (L) 1741 cmϪ1; δH (400 MHz) 1.32 (6H, m,
CH2 groups), 1.65 (4H, m, CH2 groups), 2.36 (4H, m, CH2CHO
and CH2CO2Me), 3.70 (3H, s, CO2CH3) and 9.79 (1H, t, J 1.9,
CHO) ppm; m/z (EI) 186.1249: calculated for C10H18O3
186.1256.
(d) Cyclodehydration of the (Z )-olefinic diols 7a–7f; synthesis
of the dihydrofurans 6a–6f. One of the (Z)-olefinic diols 7a–7f
(1 mmol) was dissolved in chloroform (3 cm3) with 1,3-dicyclo-
hexylcarbodiimide (1.1 eq.). Copper() chloride (5 mg) was
added and the mixture was stirred at room temperature under a
nitrogen atmosphere during 12 h. Trifluoroacetic acid (0.13 eq.)
was then added and the mixture was heated to 40 ЊC during 6 h.
After this time hexane (10 cm3) was added and the mixture was
filtered to remove precipitated dicyclohexylurea. This was
washed thoroughly with ethyl acetate and the washings added
to the filtrate. Solvents were evaporated and the resulting oil
was chromatographed using ethyl acetate–hexane 1 : 5 as eluant
to yield one of the dihydrofuran derivatives 6a–6f.
Methyl 10-oxodecanoate 13f
Methyl undec-10-enoate (15 g) was ozonised in a similar
manner to that described above for methyl oleate. After work-
up the crude product was distilled to yield methyl 10-oxo-
decanoate 13f as a colourless oil25 (9.94 g; 66%), bp 126–130 ЊC
(0.5 mmHg), νmax (L) 1740 cmϪ1; δH (80 MHz) 1.5 (12H, m, CH2
groups), 2.28 (4H, m, CH2CO2Me and CH2CHO), 3.65 (3H, s,
CO2CH3) and 9.80 (1H, t, J 1.5, CHO) ppm; m/z (EI) 200.1407:
calculated for C11H20O3 200.1412.
Methyl 5-hydroxy-8-(tetrahydropyran-2Ј-yloxy)oct-6-ynoate
14a. From 3-(tetrahydropyran-2Ј-yloxy)propyne and methyl
5-oxopentanoate; an oil (2.24 g; 83%).
3-(Tetrahydropyran-2Ј-yloxy)propyne26
Methyl 6-hydroxy-9-(tetrahydropyran-2Ј-yloxy)non-7-ynoate
14b. From 3-(tetrahydropyran-2Ј-yloxy)propyne and methyl
5-oxohexanoate; an oil (2.43 g; 86%).
Phosphorus oxychloride (180 mg) was added to a stirred mix-
ture of freshly distilled propargyl (prop-2-ynyl) alcohol (14 g)
and 2,3-dihydropyran (22.5 g) at 0 ЊC. The ice-bath was then
removed and the reaction mixture was stirred at room temper-
ature for 3 h. The mixture was diluted with ether, washed with
brine, dried and evaporated to yield 3-(tetrahydropyran-2Ј-
yloxy)propyne as a colourless oil (30 g; 80%), bp 39–42 ЊC
(0.5 mmHg), νmax (L) 2122 cmϪ1; δH (80 MHz) 1.55–1.68 (4H,
Methyl 4-hydroxy-1-(tetrahydropyran-2Ј-yloxy)dec-2-ynoate
14c. From 3-(tetrahydropyran-2Ј-yloxy)propyne and methyl
5-oxoheptanoate; an oil (2.72 g; 87%).
Methyl
8-hydroxy-11-(tetrahydropyran-2Ј-yloxy)undec-9-
ynoate 14d. From 3-(tetrahydropyran-2Ј-yloxy)propyne and
methyl 5-oxooctanoate; an oil (2.26 g; 73%).
m, CH2 groups), 1.71–1.89 (2H, m, CH2 group), 2.3 (1H, t,
᎐
J 3.0, C᎐CCH ), 3.53 (1H, m, 6Ј-H ), 3.82 (1H, m, 6Ј-H ), 4.15
᎐
a
b
᎐
(2H, d, J 3.0, OCH –C᎐C) and 4.95 (1H, m, 2Ј-H ) ppm.
᎐
2
Methyl
9-hydroxy-12-(tetrahydropyran-2Ј-yloxy)dodec-10-
ynoate 14e. From 3-(tetrahydropyran-2Ј-yloxy)propyne and
methyl 5-oxononanoate; an oil (1.92 g; 62%).
General procedure for the synthesis of methyl ꢀ-(2Ј,5Ј-dihydro-
2Ј-furyl)alkanoates 6a–6f
(a) Reaction of lithiated 3-(tetrahydropyran-2Ј-yloxy)propyne
with aldehydo-esters 13a–13f; synthesis of the tetrahydropyranyl
ethers 14a–14f. To a solution of 3-(tetrahydro-2Ј-pyranyloxy)-
propyne (10 mmol) in dry THF (20 cm3) at Ϫ78 ЊC was added
n-BuLi (2.6 M in hexanes; 10 mmol) dropwise with stirring
under an atmosphere of nitrogen. After 10 min one of the alde-
hydes 13a–13f (10 mmol) in THF (5 cm3) was added dropwise
during 5 min. The reaction mixture was maintained at Ϫ78 ЊC
for a further 15 min before being allowed to warm gradually to
room temperature. It was then poured on to ice and extracted
with ether. The combined extract was washed with brine, dried
and evaporated to yield one of the tetrahydropyranyl ethers
14a–14f.
Methyl 10-hydroxy-13-(tetrahydropyran-2Ј-yloxy)tridec-11-
ynoate 14f. From 3-(tetrahydropyran-2Ј-yloxy)propyne and
methyl 5-oxodecanoate; an oil (2.19 g; 70%).
Methyl 5,8-dihydroxyoct-6-ynoate 15a. From 14a as an oil
(0.72 g; 71%).
Methyl 6,9-dihydroxynon-7-ynoate 15b. From 14b as an oil
(0.83 g; 83%).
Methyl 7,10-dihydroxydec-8-ynoate 15c. From 14c as an oil
(0.99g; 93%).
Methyl 8,11-dihydroxyundec-9-ynoate 15d. From 14d as an oil
(b) Deprotection of the tetrahydropyranyl ethers 14a–14f; syn-
thesis of the diols 15a–15f. One of the tetrahydropyranyl ethers
14–14f (5 mmol) was dissolved in methanol (70 cm3) containing
pyridinium toluene-p-sulfonate (PPTS)27 (125 mg) and the
resulting solution was stirred at 55 ЊC during 3 h. Ethanol
(∼50 cm3) was removed under reduced pressure and the mixture
was diluted with water and extracted with ethyl acetate. The
(1.04 g; 82%).
Methyl 9,12-dihydroxydodec-10-ynoate 15e. From 14e as an
oil (2.1 g; 87%).
Methyl 10,13-dihydroxytridec-11-ynoate 15f. From 14f as an
oil (0.92 g; 76%).
J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563
1559

View Article Online
Methyl (Z )-5,8-dihydroxyoct-6-enoate 7a. From 15a as an oil
(0.81 g; 86%).
28.7 (CH2), 28.6 (CH2), 24.7 (CH2) and 24.5 (CH2) ppm;
m/z (CI): 227.1652: calculated for [C9H14O3 ϩ H]ϩ 227.1647.
Methyl 9-(2Ј,5Ј-dihydro-2Ј-furyl)nonanoate 6f. From 7f
Methyl (Z )-6,9-dihydroxynon-7-enoate 7b. From 15b as an oil
(0.76 g; 75%).
as an oil (134 mg; 56%), νmax (L) 1740, 1074 and 1020 cmϪ1
;
δH (300 MHz) 1.22 (10H, m, CH2 groups), 1.52 (2H, m, CH2),
1.89 (2H, m, CH2), 2.22 (2H, t, J 7.3, CH2CO2Me), 3.64 (3H, s,
CO2CH3), 4.60 (2H, collapsed ABq with long range couplings,
5Ј-CH2), 4.78 (1H, m, 2Ј-H ), 5.76 (1H, m, 4Ј-H ) and 5.85 (1H,
Methyl (Z )-7,10-dihydroxydec-8-enoate 7c. From 15c as an
oil (0.95 g; 88%).
m, 3Ј-H ) ppm; δC (100.6 MHz) 184.4 (C᎐O), 130.8 and 129.4
Methyl (Z )-8,11-dihydroxyundec-9-enoate 7d. From 15d as
an oil (1.04 g; 91%).
᎐
(–C᎐C–), 85.6 (2Ј-CH), 74.4 (5Ј-CH ), 50.9 (CO CH ), 35.6
᎐
2
2
3
(CH2), 33.6 (CH2), 29.2 (CH2), 28.9 (CH2), 28.7 (CH2), 24.8
(CH2) and 24.5 (CH2) ppm. [Found: C 69.52, H 9.93%;
C14H24O3 requires C 69.96, H 10.07%].
Methyl (Z )-9,12-dihydroxydodec-10-enoate 7e. From 15e as
an oil (0.96 g; 79%).
Reaction of methyl (Z )-7,10-dihydroxydec-8-enoate 7c with
DCC–CuCl
Methyl (Z )-10,13-dihydroxytridec-11-enoate 7f. From 15f as
an oil (1.11 g; 91%).
The (Z)-olefinic diol 7c (1 mmol) was dissolved in CDCl3
(3 cm3) with 1,3-dicyclohexylcarbodiimide (1.1 eq.). Copper()
chloride (5 mg) was added and the mixture was stirred at room
temperature under a nitrogen atmosphere during 12 h. Hexane
(5 cm3) and ether (5 cm3) were then added and the mixture was
filtered and evaporated to give an oil (184 mg) which contained
(NMR) the isourea 16 (75%) [δH for 10-CH2 = 4.81 ppm] and
the isourea 17 (25%) [δH for 7-CH = 5.61 ppm].
Methyl 4-(2Ј,5Ј-dihydro-2Ј-furyl)butanoate 6a. From 7a as a
colourless oil (89 mg; 52%), νmax (L) 1737, 1080 and 1020 cmϪ1
;
δH (300 MHz) 1.58 (2H, m, CH2), 1.68 (2H, m, CH2), 2.34
(2H, t, J 7.3, CH2CO2Me), 3.65 (3H, s, CO2CH3), 4.62 (2H,
collapsed ABq with long range couplings, 5Ј-CH2), 4.84 (1H, m,
2Ј-CH ), 5.76 (1H, m, 4Ј-CH ) and 5.76 (1H, m, 3Ј-CH ) ppm;
δC (75.5 MHz) 173.9 (C᎐O), 129.3 and 126.6 (–C᎐C–), 85.5
᎐
᎐
(2Ј-CH), 78.7 (5Ј-CH2), 51.4 (–CO2CH3), 33.9 (–CH2), 25.6
(–CH2) and 20.5 (CH2) ppm; m/z (EI): 170.0943: calculated for
C9H14O3 170.0943.
Competitive reaction of 1-phenylethanol and 2-phenylethanol
with DCC–CuCl: selective formation of N,N-dicyclohexyl-O-
(2Ј-phenylethyl)isourea
Methyl 5-(2Ј,5Ј-dihydro-2Ј-furyl)pentanoate 6b. From 7b
1-Phenylethanol (0.49 g; 4 mmol) and 2-phenylethanol (0.49 g;
4 mmol) were added to DCC (0.82 g; 4 mmol) in chloroform
(10 cm3) with copper() chloride (30 mg). The reaction mixture
was stirred under a nitrogen atmosphere during 6 h. Hexane
(5 cm3) and ether (5 cm3) were added and the mixture was fil-
tered and evaporated to give an oil (1.54 g) which contained
(NMR) N,N-dicyclohexyl-O-(2Ј-phenylethyl)isourea 18 (91%)
as an oil (115 mg; 62%), νmax (L) 1749, 1082 and 1020 cmϪ1
;
δH (300 MHz) 1.5 (6H, m, CH2 groups), 2.31 (2H, t, J 7.3,
CH2CO2Me), 3.65 (3H, s, CO2CH3), 4.61 (2H, collapsed ABq
with long range coupling, 5Ј-CH2), 4.80 (1H, m, 2Ј-H ), 5.76
(1H, m, 4Ј-H ) and 5.87 (1H, m, 3Ј-H ) ppm; δC (75.5 MHz)
174.2 (C᎐O), 129.6 and 126.5 (–C᎐C–), 85.8 (2Ј-CH), 75.0
᎐
᎐
(5Ј-CH2), 51.5 (CO2CH3), 35.6 (CH2), 34.0 (CH2), 25.0 (CH2)
and 24.8 (CH2) ppm; m/z (EI): 184.1100; calculated for
C10H16O3 184.1099.
[CH O–C᎐N appears at δ 4.24 ppm as 2H, t, J 6.8] and
᎐
2
H
N,N-dicyclohexyl-O-(1Ј-phenylethyl)isourea (9%) [PhCHO–
C᎐N appears at δ 5.95 ppm as 1H, q, J 6.5], together with
᎐
H
unreacted 1-phenylethanol.
Methyl 6-(2Ј,5Ј-dihydro-2Ј-furyl)hexanoate 6c. From 7c as an
oil (0.12 g; 57%), νmax (L) 1740, 1074, 1040 and 1020 cmϪ1
;
Competitive reaction of propan-1-ol and propan-2-ol with
DCC–CuCl
δH (400 MHz) 1.4 (8H, m, CH2 groups), 2.25 (2H, t, J 7.5,
CH2CO2Me), 3.59 (3H, s, CO2CH3), 4.42 (2H, m, 5Ј-CH2), 4.65
(1H, m, 2Ј-CH ), 5.75 (1H, m, 3Ј-CH ) and 5.87 (1H, m, 4Ј-CH )
Propan-1-ol (0.22 g; 3.6 mmol) and propan-2-ol (0.22 g;
3.6 mmol) were reacted under nitrogen with DCC (0.75 g;
3.6 mmol) and copper() chloride (30 mg) in chloroform 10 cm3
during 5 h. Hexane (5 cm3) and ether (5 cm3) were added and
the mixture was filtered and evaporated to yield a viscous oil
(1.1 g) which contained (NMR) N,N-dicyclohexyl-O-(propyl)-
ppm; δC (100.6 MHz) 174.2 (C᎐O), 129.7 and 126.3 (–C᎐C–),
᎐
᎐
85.9 (2Ј-CH), 74.9 (5Ј-CH2), 51.4 (CO2CH3), 35.7 (CH2), 33.9
(CH2), 29.1 (CH2), 24.8 (CH2) and 24.8 (CH2) ppm; m/z (EI):
198.1262: calculated for C11H18O3 198.1256.
Methyl 7-(2Ј,5Ј-dihydro-2Ј-furyl)heptanoate 6d. From 7d as
an oil (131 mg; 62%), νmax (L) 1740, 1072 and 1020 cmϪ1; δH (300
MHz) 1.32 (6H, m, CH2 groups), 1.51 (2H, m, CH2), 1.61 (2H,
m, CH2), 2.29 (2H, t, J 7.4, CH2CO2Me), 3.65 (3H, s, CO2CH3),
4.60 (2H, collapsed ABq with long range couplings, 5Ј-CH2),
4.79 (1H, m, 2Ј-H ), 5.76 (1H, m, 4Ј-H ) and 5.85 (1H, m, 3Ј-H )
isourea 19 (90%) [CH O–C᎐N appears at δH 3.95 ppm as 2H, t,
J 6.6] and N,N-dicyclohexyl-O-(2Ј-methylethyl)isourea (10%)
᎐
2
[Me CHO–C᎐N appears at δ 4.95 ppm as 1H, septet, J 6.6],
᎐
2
H
together with unreacted propan-2-ol.
Synthesis of the acetylenic acetals 22a–22g
ppm; δC (75.5 MHz) 174.2 (C᎐O), 129.7 and 126.2 (–C᎐C–),
᎐
᎐
The general procedure utilised for the synthesis of the tetra-
hydropyranyl ethers 14a–14f described above was employed.
85.9 (2Ј-CH), 74.8 (5Ј-CH2), 51.3 (CO2CH3), 35.8 (CH2), 34.0
(CH2), 29.2 (CH2), 29.0 (CH2), 24.9 (CH2) and 24.8 (CH2)
ppm; m/z (CI): 213.1498 calculated for [C12H20O3 ϩ H]ϩ
213.1491.
4-Hydroxy-1-(tetrahydropyran-2Ј-yloxy)dec-2-yne 22a. From
3-(tetrahydropyran-2Ј-yloxy)propyne and heptanal; an oil (2.24
g; 88%).
Methyl 8-(2Ј,5Ј-dihydro-2Ј-furyl)octanoate 6e. From 7e as an
oil (0.13 g; 57%), νmax (L) 1734, 1076 and 1020 cmϪ1; δH (400
MHz) 1.31–1.75 (12H, m, 6 CH2 groups), 2.35 (2H, t, J 7.5,
CH2CO2Me), 3.65 (3H, s, CO2CH3), 4.52 (2H, collapsed ABq
with long range couplings, 5Ј-CH2), 4.75 (1H, m, 2Ј-H ), 5.74
(1H, m, 4Ј-H ) and 5.86 (1H, m, 3Ј-H ) ppm; δC (100.6 MHz)
4-Hydroxy-1-(tetrahydropyran-2Ј-yloxy)tridec-2-yne
From 3-(tetrahydropyran-2Ј-yloxy)propyne and decanal; an oil
(2.46 g; 83%).
22b.
2-Hydroxy-1-phenyl-5-(tetrahydropyran-2Ј-yloxy)pent-3-yne
22c. From 3-(tetrahydropyran-2Ј-yloxy)propyne and phenyl-
acetaldehyde; an oil (2.36 g; 91%).
173.8 (C᎐O), 129.4 and 125.8 (–C᎐C–), 85.6 (2Ј-CH), 74.5
᎐
᎐
(5Ј-CH2), 50.9 (CO2CH3), 35.5 (CH2), 33.6 (CH2), 29.0 (CH2),
1560 J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563

View Article Online
4-Hydroxy-6-phenyl-1-(tetrahydropyran-2Ј-yloxy)hex-2-yne
22d. From 3-(tetrahydropyran-2Ј-yloxy)propyne and 3-phenyl-
propanal; an oil (2.28 g; 83%).
a 66 : 33 mixture of the dimethoxy compound 24 and the
acetylenic diol 21g.
Hydrogenation of the acetylenic diols 21a–21f
1-Hydroxy-1-phenyl-4-(tetrahydropyran-2Ј-yloxy)but-2-yne
22e. From 3-(tetrahydropyran-2Ј-yloxy)propyne and benzalde-
hyde; an oil (2.33 g; 95%).
The general procedure described above which was utilised for
the synthesis of the (Z)-olefinic diols 7a–7f was employed.
(Z )-1,4-Dihydroxydec-2-ene 2b. From 21a as an oil32
(156 mg; 90%).
1-Hydroxy-1-(2Ј-methoxyphenyl)-4-(tetrahydropyran-2Љ-
yloxy)but-2-yne 22f. From 3-(tetrahydropyran-2Ј-yloxy)-
propyne and 2-methoxybenzaldehyde; an oil (2.5 g; 91%).
(Z )-1,4-Dihydroxytridec-2-ene 2c. From 21b as an oil (0.9 g;
85%).
(E )-3-Hydroxy-1-phenyl-6-(tetrahydropyran-2Ј-yloxy)hex-1-
en-4-yne 22g. From 3-(tetrahydropyran-2Ј-yloxy)propyne and
cinnamaldehyde; an oil (2.1 g; 80%).
(Z )-2,5-Dihydroxy-1-phenylpent-3-ene 2d. From 21c as a
solid33 (0.82 g: 92%), mp 61.8–62.1 ЊC.
Hydrolysis of the acetylenic acetals 22a–22g
(Z )-1,4-Dihydroxy-6-phenylhex-2-ene 2e. From 21d as an oil
(0.84 g; 88%).
The general procedure described above which was utilised for
the synthesis of the acetylenic diols 15a–15f was employed.
(Z )-1,4-Dihydroxy-1-phenylbut-2-ene 2f. The acetylenic diol
21e (5 mmol) was hydrogenated at 1 atm in methanol (10 cm3)
containing quinoline (20 mg) and triethylamine (0.5 mg) with
Pd/CaCO3 (5%w/w; 20 mg) to give the diol 2f as needles (0.44 g;
53%), mp 70.9–71.2 ЊC (lit.31 mp 73–75 ЊC), νmax (N) 3253, 1040,
1,4-Dihydroxydec-2-yne 21a. From 22a as an oil28 (0.64 g;
75%).
1,4-Dihydroxytridec-2-yne 21b. From 22b as an oil (0.85 g;
80%).
1025, 737 and 700 cmϪ1; δH (80 MHz) 1.95 (2H, br s, exch. D2O,
᎐
OH ), 4.30 (2H, collapsed ABq, HOCH C᎐C), 5.55 (1H, m,
᎐
2
2,5-Dihydroxy-1-phenylpent-3-yne 21c. From 22c as an oil29
(0.76g; 86%).
CHOH), 5.79 (2H, m, olefinic) and 7.36 (5H, m, ArH ) ppm.
(Z )-1,4-Dihydroxy-1-(2Ј-methoxyphenyl)but-2-ene 2g. The
acetylenic diol 21f (5 mmol) was hydrogenated as described for
21e above to give a solid (0.15 g; 83%), mp 91.8–92.3 ЊC, νmax
(N) 3249, 1640, 1598, 1038, 699 and 672 cmϪ1; δH (300 MHz)
1,4-Dihydroxy-6-phenylhex-2-yne 21d. From 22d as an oil30
(0.81 g; 85%).
1,4-Dihydroxy-1-phenylbut-2-yne 21e. From 22e as needles
(0.68 g; 84%), mp 82.0–82.3 ЊC (lit.31 mp 83–85 ЊC).
2.14 (2H, br s, exch. D2O, OH ), 3.84 (3H, s, OCH3), 4.18 (1H,
᎐
dd, J 13.6 and 4.8, HOCH C᎐C), 4.36 (1H, dd, J 13.5 and 6.2,
᎐
2a
᎐
HOCH C᎐C), 5.75 (3H, m, CHOH, H-2 and H-3), 6.89 (1H,
᎐
2b
4-Hydroxy-1-methoxy-1-(2Ј-methoxyphenyl)but-2-yne
23.
dd, J 8.2 and 1.0, Ar 3Ј-H ), 6.98 (1H, t, J 7.4, Ar 4Ј-H), 7.27
(1H, dt, J 7.4 and 1.8, Ar 5Ј-H ) and 7.38 (1H, dd, 7.6 and 1.7,
Ar 6Ј-H ) ppm; δC (75 MHz) 156.1 (quaternary), 133.4 (CH),
130.8 (quaternary), 129.7 (CH), 129.6 (CH), 126.7 (CH), 121.0
Obtained from 22f as an oil (0.82 g; 73%), bp 169–172 ЊC
(0.5 mmHg); νmax (L) 3401, 1601, 1590, 1248, 1098 and 765
cmϪ1; δH (80 MHz) 1.8 (1H, br s, exch. D2O, OH ), 3.4 (3H, s,
᎐
OCH ), 3.8 (3H, s, ArOCH ), 4.15 (2H, d, J 2.2, HOCH C᎐C),
᎐
3
3
2
(C᎐C), 110.5 (C᎐C), 65.9 (CH), 58.4 (CH ) and 55.3 (CH )
᎐
᎐
2
3
5.45 (1H, t, J 2.2, CHOCH3), 6.95 (2H, m, ArH ), 7.23 (1H, m,
ArH ) and 7.62 (1H, m, ArH ) ppm; m/z (EI): 206.0934: calcu-
lated for C12H14O3 206.0943. [Found: C 69.56, H 6.88%;
C12H14O3 requires C 69.90, H 6.79%].
ppm. [Found: C 68.00, H 7.35%; C11H14O3 requires C 68.02, H
7.27%].
Cyclisation of the olefinic diols 2b–2g
The general procedure described above for the synthesis of the
2-substituted-2,5-dihydrofurans 6a–6f was employed.
1,4-Dihydroxy-1-(2Ј-methoxyphenyl)but-2-yne 21f. The tetra-
hydropyranyl ether 22f (1.38 g) was dissolved in 50% aqueous
THF (80 cm3) containing pyridinium toluene-p-sulfonate
(0.5 g) and the mixture was stirred at 55 ЊC during 3 h. The
mixture was diluted with water and extracted with ethyl acetate,
and the extract was washed, dried and evaporated to yield
the diol 21f (0.47 g; 49%), mp 115.9–116.4 ЊC, νmax (N) 3256,
1601, 1589, 1048, 1023 and 759 cmϪ1; δH (80 MHz) 1.9 (1H,
2-Hexyl-2,5-dihydrofuran 1b. From 2b as an oil34 (124 mg;
81%), νmax (L) 1077 cmϪ1; δH (300 MHz) 0.87 (3H, t, J 6.8, CH3),
1.2 (8H, m, CH2 groups), 1.52 (2H, m, CH2), 4.62 (2H, m,
5-CH2), 4.81 (1H, m, 2-H ), 5.77 (1H, m, 4-H ) and 5.81 (1H,
m, 3Ј-H ) ppm.
br s, exch. D2O, OH ), 3.06 (1H, br s, exch. D2O, OH ), 3.9 (3H,
2-Nonyl-2,5-dihydrofuran 1c. From 2c as an oil35 (175 mg;
90%), νmax (L) 1071 cmϪ1; δH (300 MHz) 0.87 (3H, t, J 6.7, CH3),
1.25 (12H, m, CH2 groups), 1.6 (2H, m, CH2), 4.63 (2H, m,
5-CH2), 4.8 (1H, m, 2-CH ), 5.77 (1H, m, 4-H ) and 5.86 (1H,
m, 3-H ) ppm.
᎐
s, ArOCH ), 4.28 (2H, d, J 2.0, HOCH C᎐C), 5.78 (1H, s,
᎐
3
2
CHOH), 6.95 (2H, m, ArH ), 7.30 (1H, m, ArH ) and 7.81 (1H,
m, ArH ) ppm; m/z (EI): 192.0779: calculated for C11H12O3
192.0786. [Found: C 68.66, H 6.38%; C11H12O3 requires C 68.75,
H 6.25%].
(E )-3,6-Dihydroxy-1-phenylhex-1-en-4-yne 21g. This was
obtained as an oil (0.7 g; 69%) by hydrolysis of 22g using PPTS
in aqueous THF; νmax (L) 3269, 1620, 1601, 1597, 1078, 1063,
2-Benzyl-2,5-dihydrofuran 1d. From 2d as an oil (142 mg;
89%), νmax (L) 3032, 1071, 746 and 699 cmϪ1; δH (300 MHz) 2.85
(2H, dd, J 13.4 and 6.4, CH2aPh), 2.94 (2H, dd, J 13.4 and 6.1,
–CH2bPh), 4.64 (2H, collapsed ABq with long range couplings,
5-CH2), 5.08 (1H, m, 2-CH ), 5.79 (1H, m, 4-H ), 5.88 (1H, m,
3-H ) and 7.27 (5H, m, ArH ) ppm. [Found: C 82.51, H 7.55%;
C11H12O requires C 82.46, H 7.55%].
1015, 845, 746 and 687 cmϪ1; δH (80 MHz) 1.50 (2H, br s, exch.
᎐
D O, OH ), 4.25 (2H, d, J 2.1, HOCH C᎐C), 5.05 (1H, d, J 5.6,
᎐
2
2
CHOH), 6.24 (1H, dd, J 15.2 and 5.7, 3-H ), 6.68 (1H, d, J 15.2,
2-H ) and 7.34 (5H, m, ArH ) ppm; m/z (EI): 188.0841: calcu-
lated for C12H12O2 188.0837. [Found: C 76.81, H 6.29%;
C12H12O2 requires C 76.59, H 6.38%]. Attempted hydrolysis of
22g using PPTS–methanol led to a mixture containing (NMR)
2-(2Ј-Phenylethyl)-2,5-dihydrofuran 1e. From 2e as an oil
(112 mg; 64%), νmax (L) 1624, 1603, 1077, 748 and 699 cmϪ1
;
J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563
1561

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δH (300 MHz) 1.9 (2H, m, 1Ј-CH2), 2.73 (2H, m, 2Ј-CH2), 4.68
(2H, m, 5-CH2), 4.88 (1H, m, 2-H ), 5.79 (1H, m, 4-H ), 5.91
(1H, m, 3-H ) and 7.23 (5H, m, ArH ) ppm; m/z (EI): 174.1037:
calculated for C12H14O 174.1045. [Found: C 82.66, H 8.28%;
C12H14O requires C 82.76, H 8.05%].
30.8 (CH2), 28.6 (CH2), 28.5 (CH2) and 24.5 (CH2) ppm;
m/z (EI): 186.1261: calculated for C10H18O3 186.1256.
Methyl 6,9-dihydroxydecanoate 29
But-1-yn-3-ol was converted into its tetrahydropyranyl ether,
bp 50–52 ЊC at 0.5 mmHg, as described above for the THP
derivative of propynol. To this (4.4 g), at Ϫ78 ЊC in dry THF
(40 cm3), was added n-BuLi (2.5 M; 11.5 cm3). After 10 min at
Ϫ78 ЊC a solution of methyl 6-oxohexanoate (4.2 g) in THF
(20 cm3) was added dropwise. The mixture was allowed to warm
to room temperature and worked up in the usual way to give
methyl 5-hydroxy-2-(tetrahydropyran-2Ј-yloxy)dec-3-ynoate as
an oil (7.8 g), νmax (L) 3448, 1740 and 1020 cmϪ1; δH (400 MHz)
(major diastereoisomer) 1.54 (3H, d, J 6.6, CH3), 1.69 (6H, m,
CH2 groups), 2.39 (6H, m, CH2 groups), 2.58 (2H, t, J 6.6,
CH2CO2Me), 2.87 (1H, br s, exch. D2O, OH ), 3.67 (3H, s,
OCH3), 3.70 (2H, m, 6Ј-CH2), 4.12 (1H, q, J 6.5, 2-H ), 4.35
(1H, t, J 5.4, 5-H ) and 4.72 (1H, m, 2Ј-H ) ppm. The above
tetrahydropyranyl ether (7.8 g) was treated during 3 h at 50 ЊC
with PPTS (0.25 g) in methanol (200 cm3) after which time the
usual work up afforded methyl 2,5-dihydroxydec-3-ynoate as an
oil (4.7 g), νmax (L) 3418 and 1740 cmϪ1; δH (400 MHz) (major
diastereoisomer) 1.48 (3H, d, J 6.6, CH3), 1.39–1.51 (6H, m,
CH2 groups), 2.34 (2H, t, J 6.5, CH2CO2Me), 2.38 (2H, br s,
exch. D2O, OH groups), 3.70 (3H, s, CO2CH3) and 4.25–4.48
(2H, m, CHOH) ppm. The above acetylenic diol (4.7 g), in
methanol (70 cm3), was hydrogenated at 1 atm over 5% Pd/C
(0.3 g) until hydrogen uptake had ceased. Filtration, followed
by evaporation of solvent gave methyl 6,9-dihydroxydecanoate
29 as an oil (4.6 g), νmax (L) 3392 and 1737 cmϪ1; δH (300 MHz)
(major diastereoisomer) 1.16 (3H, d, J 6.2, CH3), 1.48 (4H, m,
CH2 groups), 2.16 (6H, m, CH2 groups), 2.18 (2H, br s, exch.
D2O, OH groups), 2.29 (2H, t, J 7.4, CH2CO2Me), 3.56 (1H, m,
6-H ), 3.59 (3H, s, CO2CH3) and 3.78 (1H, m, 9-H ) ppm;
2-Phenyl-2,5-dihydrofuran 1f. From 2f as an oil (115 mg;
79%), νmax (L) 1606, 1073, 699 and 648 cmϪ1; δH (300 MHz) 4.78
(1H, ABq with further coupling, 5-Ha), 4.89 (1H, ABq with
further coupling, 5-Hb), 5.80 (1H, m, 2-H ), 5.89 (1H, m, 3-H ),
6.04 (1H, m, 4-H ) and 7.35 (5H, m, ArH ) ppm; m/z (EI):
146.0725: calculated for C10H10O 146.0732. [Found: C 82.34, H
6.68%; C10H10O requires C 82.19, H 6.85%].
2-(2Ј-Methoxyphenyl)-2,5-dihydrofuran 1g. From 2g as an oil
(0.76 g; 86%); νmax (L) 1600, 1589, 1241, 1067, 1048, 1027, 754
and 666 cmϪ1; δH (300 MHz) 3.86 (3H, s, OCH3), 4.79 (1H,
ABq with further coupling, 5-Ha), 4.87 (1H, ABq with further
coupling, 5-Hb), 5.97 (2H, m, 3- and 4-H ), 6.15 (1H, m, 2-H ),
6.87 (1H, d, J 8.1, 3Ј-H ), 6.96 (1H, dt, J 7.5 and 0.9, 4Ј-H ), 7.27
(1H, dt, J 7.5 and 1.8, 5Ј-H ) and 7.36 (1H, dd, J 7.5 and 1.8,
6Ј-H ) ppm. [Found: C 75.04, H 7.07%; C11H12O2 requires C
74.98, H 6.86%].
1,4-Dihydroxy-1-phenylbutane 25
The olefinic diol 2f (0.32 g) was hydrogenated at 1 atm in ethyl
acetate (10 cm3) containing triethylamine (0.5 mg) with Pd/C
(5%w/w; 20 mg) to give, after recrystallisation from chloroform,
a solid, mp 73–74 ЊC, (lit.36 75 ЊC) (167 mg; 51%), which had
νmax (N) 3329, 1606, 769 and 704 cmϪ1; δH (300 MHz) 1.65 (2H,
m, 3-CH2), 1.84 (2H, m, 2-CH2), 2.78 (2H, br s, exch. D2O, OH
groups), 3.64 (2H, m, CH2OH), 4.69 (1H, t, J 7.0, CHOH) and
7.31 (5H, m, ArH ) ppm.
δC (75.5 MHz) (major diastereoisomer) 174.3 (C᎐O), 71.7
᎐
2-Phenyltetrahydrofuran 26
(6-CH), 68.2 (9-CH), 51.4 (CO2CH3), 34.8 (7-CH2), 34.5
(8-CH2), 37.2, 35.2, 25.2, 24.9 (CH2 groups) and 23.6 (CH3)
ppm; m/z (CI): 219.1603: calculated for [C11H22O4 ϩ H]ϩ
219.1596.
The diol 25 (170 mg) was treated with DCC–CuCl and then
with trifluoroacetic acid as described above for the olefinic diols
7a–7f to yield the tetrahydrofuran 26 (106 mg; 72%) as an oil,37
νmax (L) 1604, 1057, 1028, 757 and 700 cmϪ1; δH (300 MHz) 1.8,
2.02 and 2.3 (1H, 2H and 1H, ms, CH2 groups), 3.95 (1H, part
of ABq, Jgem 13.8, 5-CH2a), 4.13 (1H, part of ABq, Jgem 13.8,
5-CH2b), 4.9 (1H, t, J 7.0, 2-H ), 7.25 (1H, m, ArH ) and 7.34
(4H, m, ArH ) ppm.
Methyl 5-(5Ј-methyltetrahydro-2Ј-furyl)pentanoate 30
The diol 29 (1.0 g) and dicyclohexylcarbodiimide (0.97 g),
in chloroform (20 cm3) were stirred with copper() chloride
(25 mg) during 24 h. Trifluoroacetic acid (68 mg) was then
added and the mixture was refluxed for 6 h. The solution was
cooled, diluted with hexane (40 cm3), filtered through Celite
and evaporated to give a crude product which was chromato-
graphed over silica gel to yield a 1.4 : 1 mixture of diastereo-
isomers of methyl 5-(5Ј-methyltetrahydro-2Ј-furyl)pentanoate
30 as an oil (0.38 g; 33%), νmax (L) 1740 cmϪ1; δH (400 MHz) 1.13
(1.75H, d, J 6.2, CH3 {major}), 1.16 (1.25H, d, J 6.2, CH3
{minor}), 1.4 (5H, m, CH2 groups), 1.58 (3H, m, CH2 groups),
2.24 (2H, t, J 7.5, CH2CO2Me), 3.58 (3H, s, CO2CH3) and 3.62–
4.06 (2H, overlapping ms, 2Ј-H and 5-H ) ppm; δC (100.6 MHz)
Methyl 6,9-dihydroxynonanoate 27
Methyl 6,9-dihydroxynon-7-ynoate 15b (1.2 g) was hydrogen-
ated in ethyl acetate (25 cm3) over 5% Pd/C (30 mg) until uptake
of hydrogen had ceased. The usual work up afforded methyl
6,9-dihydroxynonanoate 27 as an oil (1.1 g; 94%), νmax (L) 3247,
1734, 1166 and 1048 cmϪ1; δH (300 MHz) 1.28 (8H, m, CH2
groups), 1.46 (2H, m, CH2 group), 2.15 (2H, br s, exch. D2O,
OH ), 2.29 (2H, t, J 6.4, CH2CO2Me) and 3.62 (3H, m, CH2OH
and CHOH) ppm; δC (75.5 MHz) 174 (C᎐O), 72 (CH), 63.9
᎐
(major diastereoisomer) 174 (C᎐O), 79.1 (5Ј-C), 75.0 (2Ј-C),
᎐
(CH2), 52.4 (CH3), 38.1 (CH2), 34.0 (CH2), 29.4 (CH2), 28.7
(CH2), 25.4 (CH2) and 24.9 (CH2) ppm; m/z (EI): 204.1369:
calculated for C10H20O4 204.1362.
51.3 (CO2CH3), 32.7 (CH2), 31.2 (CH2), 35.7 (CH2), 33.9
(CH2), 25.7 (CH2), 24.9 (CH2) and 21.2 (CH3) ppm; m/z (CI):
201.1491: calculated for [C11H20O3 ϩ H]ϩ 201.1491.
Methyl 5-(tetrahydro-2Ј-furyl)pentanoate 28
Acknowledgements
Methyl 6,9-dihydroxynonanoate 27 (0.2 g) was treated with
DCC–CuCl and then with trifluoroacetic acid as described
above for the saturated diol 25 to yield the tetrahydrofuran 28
as an oil (158 mg; 85%), νmax (L) 1741, 1198, 1169 and 1058
cmϪ1; δH (400 MHz) 1.29 (8H, m, CH2 groups), 1.36–1.49 (2H,
m, CH2 groups), 2.28 (2H, t, J 7.3, CH2CO2Me), 3.64, (3H, s,
CO2CH3), 3.69 (1H, m, part of ABq, 5-CH2a), 3.75 (1H, m, part
We thank Dr John O’Brien for the NMR spectra, and the
V. K. Krieble Fund for financial support (to M. G. D).
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78.7 (CH), 66.8 (CH2), 51.1 (CH3), 35.3 (CH2), 33.7 (CH2),
1562 J. Chem. Soc., Perkin Trans. 1, 2002, 1555–1563

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