Stereoselective synthesis of polysubstituted tetrahydropyrans by radical cyclization of epoxides using a transition-metal radical source

Article abstract of DOI:10.1002/ejoc.200500424

Epoxyalkyl propargyl ethers 3a-f and allyl epoxyalkyl ethers 6a-c smoothly undergo radical cyclization reactions using a titanium(III) species (Cp ₂TiCl) as the radical initiator to form polysubstituted tetrahydropyrans 4a-f and 7a-c in good yi

Full text of DOI:10.1002/ejoc.200500424

FULL PAPER
DOI: 10.1002/ejoc.200500424
Stereoselective Synthesis of Polysubstituted Tetrahydropyrans by Radical
Cyclization of Epoxides using a Transition-Metal Radical Source
Biplab Banerjee[a] and Subhas Chandra Roy*[a]
Keywords: Tetrahydropyrans / Radical cyclization / Epoxides / Transition metals
Epoxyalkyl propargyl ethers 3a–f and allyl epoxyalkyl ethers
6a–c smoothly undergo radical cyclization reactions using a
titanium(III) species (Cp2TiCl) as the radical initiator to form
polysubstituted tetrahydropyrans 4a–f and 7a–c in good
yields and with high diastreoselectivity. The titanium(III) spe-
cies was prepared in situ from commercially available titano-
cene dichloride and Zn dust in THF. On the other hand, the
epoxyalkyl propargyl ethers 3g and 3h furnished the spirocy-
clic ethers 4g and 4h, respectively, on radical cyclization re-
action as the sole products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
reactive intermediates in organic synthesis because of the
mildness of their generation, their high functional group
tolerance, and the useful possibilities for the formation of
C–C bonds. A limitation of the classical free radical chemis-
try lies in the substrate-controlled course of the reaction.
An interesting alternative is represented by reagent-con-
trolled transformations.[7] Epoxides are vastly used as build-
ing blocks for organic synthesis due to their ready availabil-
ity and facile substitution reactions with predictable stereo-
chemistry.[8] Our earlier investigations[9] towards the stereo-
selective radical cyclization of epoxy ethers using
Cp2TiCl[10] as the radical initiator have opened the door to
utilize this methodology for the synthesis of complex natu-
ral products. Herein, in continuation to our earlier work
related to 5-exo-dig and 5-exo-trig radical cyclizations,[9] we
wish to report the 6-exo-dig cyclization of epoxyalkyl pro-
pargyl ethers and the 6-exo-trig cyclization of allyl ep-
oxyalkyl ethers using a titanium(iii) species as the radical
initiator to synthesize tetrahydropyran derivatives in a ste-
reocontrolled manner.
Introduction
Six-membered saturated oxygen heterocycles are struc-
tural features of a variety of biologically important natural
products[1] such as polyether antibiotics, marine toxins,
pheromones, and pharmaceutical agents. The tetrahydropy-
ran ring is part of the backbone of various important
carbohydrates, as well as their oligomers and polymers,
which are the most abundant biological molecules[2] on
earth and play several crucial roles in living organisms.
Considerable efforts have been made toward the synthe-
sis of tetrahydropyran-type compounds,[3] for example by
hetero Diels–Alder reactions, via oxiranyl anions, carbonyl
ylides, by Claisen rearrangements, ring opening of epoxides,
iodocyclizations, olefin metathesis, and many others.[4] Re-
cently, there has been an increasing interest in using the
Prins cyclization[4,5] to generate tetrahydropyran derivatives
in a stereocontrolled manner, with potential applications to
the synthesis of polyether antibiotics and other complex
natural products. The ubiquitous presence of polysubsti-
tuted tetrahydropyrans, associated with the challenge of-
fered by the total synthesis of some of these tetrahydropy-
ran-containing natural products, requires the development
of efficient methodologies to synthesize tetrahydropyran de-
rivatives. Therefore, good and efficient methodologies for
the stereocontrolled synthesis of polysubstituted tetra-
hydropyrans are still needed.
Results and Discussion
Preparation of Epoxides and Propargylation and Allylation
of Epoxy Alcohols
Epoxy alcohols 2 were prepared from the corresponding
homoallyl alcohols 1 (prepared from the corresponding al-
dehyde and allyl bromide using Cp2TiCl in THF)[11a] by
treatment with m-CPBA in CHCl3 (Scheme 1).
The explosive growth in free radical chemistry in recent
years reflects its significance as powerful tool in modern
synthetic chemistry.[6] Radicals are frequently employed as
The epoxides 2a–e were found to be a mixture of two
isomers in a ratio of 1:1. This isomeric ratio was determined
from the H NMR signals for the epoxide methine proton,
e.g., for 2b the particular signals appeared as two multiplets
centered at δ = 3.16 ppm for one isomer and at δ =
3.00 ppm for the other. In case of epoxides 2f and 2h the
[a] Department of Organic Chemistry, Indian Association for the
Cultivation of Science,
1
Jadavpur, Kolkata 700032, India
Fax: +91-33-2473-2805
E-mail: ocscr@mahendra.iacs.res.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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B. Banerjee, S. C. Roy
FULL PAPER
Scheme 1. Preparation of epoxyalkyl ethers.
Scheme 2. Radical cyclization of epoxides.
isomeric ratio was found to be 1.5:1. For epoxide 2g, no
distinguishable signals were found to determine the ratio of
the isomers. It might be a single isomer (only one chiral
carbon atom) or a mixture of two diastereomers as we have
observed for 2h (no shift reagent was used). The ratio of
isomers in 2f was determined from the 1H NMR signals for
the methyl protons, which appeared as two singlets at δ =
1.65 ppm for one isomer and at δ = 1.59 ppm for the other.
Since the isomers in 2a–h could not be separated by usual
chromatographic methods, the mixture of isomers was used
for the next step. Thus, compounds 2a–h, on treatment with
propargyl bromide, and compounds 2a,d,e, on treatment
with allyl bromide in the presence of NaH in THF/DMSO
(10:1), furnished 3a–h and 6a–c as an inseparable mixture
of two isomers in the same ratio as observed for 2a–h. This
Thus, the radical cyclization reaction was applied to a
series of substituted epoxy alkynes and the results are sum-
marized in Table 1. The epoxyalkyl ethers 3a–f, upon radi-
cal cyclization reaction, afforded a mixture of two isomeric
products as indicated in Table 1, whereas 3g and 3h fur-
nished the spiro ethers 4g and 4h, respectively, as the only
isolated product.
The ratio of the two isomers in the cyclized products was
determined from the two distinguishable multiplets in the
1H NMR spectra for 4-H, e.g., for 4a, two multiplets cen-
tered at δ = 2.61 ppm for the major isomer and at δ =
2.73 ppm for the minor isomer. For 4f the ratio of isomers
was determined from the two distinguishable singlets of the
1
methyl protons in the H NMR spectra which appeared at
δ = 1.40 ppm for the major isomer and at δ = 1.54 ppm
for the minor isomer. The major isomer in 4a–e was partly
separated by preparative TLC (15% ethyl acetate in light
petroleum ether), but the minor isomer could not be sepa-
rated in pure form, and was always contaminated with the
major isomer. In analogy to the deuteriolysis experiment
reported by RajanBabu and Nugent,[10] presumably, the
highly reactive vinyl radical 3a2, which is formed initially,
abstracts a hydrogen atom from the THF solvent before it
has a chance to encounter any reducing titanium species
3a3. In the case of 4f, the isomers could not be separated
by usual chromatographic methods, and for 4a,c,g the cor-
responding reduced products 5 were obtained in 16, 15, and
35% yield, respectively.
1
isomeric ratio was determined from the H NMR signals
for the epoxide methine proton, e.g., for 3a, the particular
signals appeared as two multiplets centered at δ = 2.88 ppm
for one isomer and at δ = 3.18 ppm for the other. Since the
isomers could not be separated by usual chromatographic
methods, the crude isomeric mixtures were used for the rad-
ical cyclization reactions.
Radical Cyclization of Epoxy Ethers using Cp2TiCl
For the homolytic cleavage of epoxides, a titanium(iii)
reagent (Cp2TiCl) was used at room temperature. A satis-
factory reagent was prepared[10] by stirring a red THF solu-
tion of Cp2TiCl2 with activated Zn dust [Equation (1)]. Af-
ter 15 min, the solution turned lime-green and the forma-
tion of Cp2TiCl was completed.
The cis orientation of the C-2 and C-4 substituents in the
major isomer of cyclized products 4a1–e1 was established by
NOE analysis (Figure 1) of the major isomer, e.g., 4b1 in
which an enhancement (1.5 %) between the signals of 2-H
to 4-H was observed.
This cis relationship between two substituents at C-2 and
C-4 may also be rationalized by invoking well-known con-
formational effects in the intermediates by using models for
2 Cp2TiCl2 + Zn Ǟ 2 Cp2TiCl + ZnCl2
(1)
In a preliminary experiment, 2.1 mol-equiv. of Cp2TiCl selectivities in radical reactions proposed by Beckwith,[12a]
in THF was added dropwise to a THF solution of ep- Houk[12b] and RajanBabu.[12c] Four transition complexes
oxyalkyl propargyl ether 3a. The initial green color of the are possible of the intermediate radical before cyclization.
titanium(iii) species instantly discharged to red upon expo- Here the transition complexes B and D are of higher energy
sure to the epoxide. Quenching of the mixture with 10% than A or C, where a bulky group (phenyl) is in axial posi-
H2SO4 (15 mL) in H2O afforded the tetrahydropyran deriv- tion (Figure 2). Between complexes A and C, complex A
ative 4a as a mixture of two isomers in 78% yield should have a lower energy compared to C, because both
(Scheme 2).
the phenyl and the CH2OTiIV moieties in A are in equato-
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Polysubstituted Tetrahydropyrans
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Table 1. Radical cyclization of epoxyalkyl propargyl ethers using tion of cis products 4a–e derived from A should occur. In
Cp2TiCl.
the case of 4f, where the benzylic hydrogen atom is replaced
by a methyl group, the selectivity decreases. Since the minor
isomer in 4a–f could not be separated by usual chromato-
graphic methods in pure form, the stereochemistry of the
minor isomer remained uncertain.
Figure 2. Transition complexes of the intermediate radical.
On the other hand, similar radical cyclization reactions
were performed on allyl epoxyalkyl ethers 6a–c and the re-
sults are summarized in Table 2. Although theoretically
four isomers are expected in the radical cyclization reaction,
three isomeric products were actually obtained in each case.
The ratio of the three isomers in the cyclized products was
determined from the three distinguishable doublets of
1
methyl protons in the H NMR spectra, e.g., for 7a, two
doublets at δ = 0.90 and 1.07 ppm for the two major iso-
mers and another doublet at δ = 0.93 ppm for the third
minor isomer. The major two isomers in 7a–c were sepa-
rated by preparative TLC (20% ethyl acetate in light petro-
leum ether), but the third minor isomer could not be iso-
lated in pure form as it was produced in very minute quan-
tity. In the case of 6a and 6c, the corresponding reduced
products 8 were also obtained in 8% and 10% yield, respec-
tively.
Comparing with the mode of epoxy/alkyne cyclizations
(Table 1), it may be concluded that the substituents at C-2
(Ar) and C-4 (CH2OH) in the two major isolated isomers
in the cyclized products 7a–c (Table 2) will be in cis (equato-
rial-equatorial) configuration with respect to each other.
[a] Yields refer to pure isolated products.
The third substituent (Me) at C-5 might be trans, e.g. in
7a1 (equatorial-equatorial, lower energy) or cis, e.g. in 7a2
(equatorial-axial, higher energy) with respect to that at C-4
as shown in Figure 3.
This can also be rationalized by analogy with the work
reported in the literature[10] for the higher chemical shift
values of the carbon signals, in general, for trans-1,2-dialk-
ylcycloalkanes. In our case the isolated major isomer, e.g.,
7a1 showed signals at δ = 31.9 (C-5), 44.5 (C-4) ppm and
Figure 1. NOE analysis of 4b1.
the corresponding signals in the isolated minor isomer, e.g.,
7a2 appeared at δ = 29.2 and 41.1 ppm, respectively. Hence,
rial position whereas in C, one is equatorial and the other it is reasonable to assume that the isolated major isomer
is axial. Thus, the transition complex A lies on the pathway should be 7a1 which possesses all the substituents in the
to the more stable product. Therefore, preferential forma- equatorial orientation and in 7a2 the substituents at C-2
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B. Banerjee, S. C. Roy
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Table 2. Radical cyclization of allyl epoxyalkyl ethers using Cp2TiCl.
[a] Yields refer to pure isolated procucts.
and C-4 are equatorial and at C-5 axial. As the minor iso-
lated isomer 7a2 was a crystalline solid, the stereochemistry
was finally proved by an X-ray crystallographic study of 7a2
(Figure 4).
In the radical cyclization reaction of substituted epoxy
alkynes and epoxy olefins using stoichiometric titanocene
chloride as reducing agent, the real nature of the titani-
um(iii) species[13] in THF solution is the symmetric dimeric
complex I having no free coordination site (known from the
solid phase) and there is even the possibility that the di-
meric structure II in THF solution from the very beginning
is of the half-open type (Figure 5), thereby leaving room for
an easily accessible coordination site. Both the dimeric
Figure 3. Comparison of 13C NMR data for 7a1 and 7a2.
Figure 4. X-ray picture of 7a2.
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Polysubstituted Tetrahydropyrans
FULL PAPER
(0.99 g, 90%) as a viscous liquid as an inseparable mixture of two
complex I and II should exhibit the same reactivity as
Cp2TiCl.
isomers in a ratio of 1:1. IR (neat): ν = 3388 (br), 2920, 1602, 1494,
˜
1
1454, 1056 cm–1. H NMR: δ = 1.81–1.94 (m, 1 H), 1.99–2.12 (m,
1 H), 2.49 (dd, J = 2.7, 4.9 Hz, 0.5 H), 2.59 (dd, J = 2.8, 4.8 Hz,
0.5 H), 2.74 (t app, J = 4.6 Hz, 0.5 H), 2.81 (t app, J = 4.5 Hz, 0.5
H), 2.99–3.01 (m, 0.5 H), 3.15–3.18 (m, 0.5 H), 4.90–4.95 (m, 1 H),
7.26–7.39 (m, 5 H). 13C NMR: δ = 41.9, 42.1, 47.2, 47.6, 50.4, 50.6,
72.0, 72.8, 126.0, 126.2, 127.9, 128.1, 128.8, 128.9, 144.3,
144.6 ppm. C10H12O2 (164.20): calcd. C 73.15, H 7.37; found C
73.10, H 7.33.
Figure 5. Dimeric complexes of Cp2TiCl.
In this titenium(iii)-mediated radical cyclization, reduced
products 5 and 8 probably derived from adventitious water
in the reaction medium, thereby forming a water-solvated
1-(3,4-Dimethoxyphenyl)-2-oxiranylethanol (2b): Compound 2b was
prepared according to the same procedure as described for 2a as a
viscous liquid. IR (neat): ν = 3363 (br), 2922, 2839, 1606, 1593,
˜
Cp2TiCl complex and a hydrogen atom transfer process oc- 1525, 1421, 1263 cm–1. 1H NMR: δ = 1.72–1.92 (m, 1 H), 1.98–
2.17 (m, 1 H), 2.50 (dd, J = 2.5, 4.8 Hz, 0.5 H), 2.60 (dd, J = 2.6,
4.8 Hz, 0.5 H), 2.74 (t app, J = 4.2 Hz, 0.5 H), 2.82 (t app, J =
4.5 Hz, 0.5 H), 2.96–2.99 (m, 0.5 H), 3.15–3.18 (m, 0.5 H), 3.86 (s,
3 H), 3.88 (s, 3 H), 4.84–4.90 (m, 1 H), 6.81–6.98 (m, 3 H) ppm.
13C NMR: δ = 41.9, 42.1, 47.1, 47.5, 50.3, 50.6, 56.2, 56.3, 71.7,
72.7, 109.2, 109.3, 111.4, 111.5, 118.1, 118.4, 137.0, 137.3, 148.7,
148.8, 149.3, 149.4 ppm. C12H16O4 (224.25): calcd. C 64.27, H 7.19;
found C 64.12, H 7.11.
curs from water to a carbon-centered free radical forming
the reduced products.[14] In the absence of water only allylic
alcohols can be expected.[15] Although in this paper a stoi-
chiometric amount of titanium(iii) reagent is used, an alter-
native approach using a catalytic[16] amount of the reagent
with different additives has also been reported in the litera-
ture.
1-(4-Benzyloxy-3-methoxyphenyl)-2-oxiranylethanol (2c): Com-
pound 2c was prepared according to the same procedure as de-
Conclusions
scribed for 2a as a viscous liquid. IR (neat): ν = 3404 (br), 3068,
˜
1658, 1583, 1259 cm–1. 1H NMR: δ = 1.76–2.11 (m, 2 H), 2.47 (dd,
J = 2.7, 4.8 Hz, 0.5 H), 2.56 (dd, J = 2.7, 4.7 Hz, 0.5 H), 2.72 (t
app, J = 4.5 Hz, 0.5 H), 2.80 (t app, J = 4.4 Hz, 0.5 H), 2.95–2.98
(m, 0.5 H), 3.13–3.16 (m, 0.5 H), 3.86 (s, 3 H), 4.81–4.86 (m, 1 H),
5.11(s, 2 H), 6.77–6.94 (m, 3 H), 7.26–7.42 (m, 5 H) ppm. 13C
NMR: δ = 41.4, 41.6, 46.6, 46.8, 49.9, 50.1, 55.8, 56.9, 71.3, 71.7,
102.8, 103.9, 109.2, 109.3, 113.7, 113.8, 117.6, 117.9, 127.0, 127.1,
127.6, 128.3, 128.4, 128.5, 128.7, 128.8, 137.0, 137.2, 147.4, 147.5,
149.6, 149.7 ppm. C18H20O4 (300.34): calcd. C 71.98, H 6.71; found
C 71.95, H 6.70.
In summary, we have demonstrated the stereoselective
synthesis of important polysubstituted tetrahydropyran de-
rivatives by radical cyclization of epoxides using a transi-
tion metal radical source. Synthetically versatile substituted
spiro ethers have also been synthesized according to the
same strategy.
Experimental Section
1-(4-Methoxyphenyl)-2-oxiranylethanol (2d): Compound 2d was
General: The compounds described are all racemates. The homoal-
lyl alcohols 1 were prepared[11a] from the corresponding aldehydes
or ketones and allyl bromide using Cp2TiCl in THF and their spec-
troscopic data were compared to those of authentic samples.[11,17]
1H and 13C NMR spectra were recorded in CDCl3 with 300 and
75 MHz NMR spectrometers (Bruker), respectively, using tet-
ramethylsilane as the internal standard and FT-IR spectra were
recorded with a Shimadzu FT IR-8300. Column chromatography
was performed on silica gel (60–120 mesh) and preparative TLC
was performed using Merck pre-coated silica 60 F 254 plates
(0.2 mm). Diethyl ether and tetrahydrofuran were freshly distilled
from sodium. Dimethyl sulfoxide was freshly distilled from calcium
hydride. Petroleum ether of boiling range 60–80 °C was used for
chromatography. Elemental analyses were performed with an ana-
lytical instrument (Dr. Hans Hosli, 0A1, 468) in our analytical
laboratories.
prepared according to the same procedure as described for 2a. IR
1
(neat): ν = 3400 (br), 2916, 1612, 1514, 1247 cm–1. H NMR: δ =
˜
1.70–2.12 (m, 2 H), 2.45 (dd, J = 2.7, 4.8 Hz, 0.5 H), 2.55 (dd, J =
2.7, 4.8 Hz, 0.5 H), 2.70 (t app, J = 4.2 Hz, 0.5 H), 2.78 (t app, J
= 4.3 Hz, 0.5 H), 2.91–2.95 (m, 0.5 H), 3.10–3.13 (m, 0.5 H), 3.78
(s, 3 H), 4.82–4.86 (m, 1 H), 6.85, 6.87 (2 d, J = 8.5 Hz each, total
2 H), 7.24–7.28 (m, 2 H) ppm. 13C NMR: δ = 41.7, 42.1, 47.2, 47.5,
50.4, 50.6, 55.6, 55.6, 71.7, 72.6, 114.1, 114.2, 127.2, 127.4, 136.3,
136.6, 159.4, 159.5 ppm. C11H14O3 (194.22): calcd. C 68.02, H 7.27;
found C 67.98, H 7.21.
1-(Benzo[1,3]dioxol-5-yl)-2-oxiranylethanol (2e): Compound 2e was
prepared according to the same procedure as described for 2a as a
viscous liquid. IR (neat): ν = 3367 (br), 2902, 1610, 1504, 1487,
˜
1
1444, 1247 cm–1. H NMR: δ = 1.70–1.90 (m, 1 H), 1.95–2.13 (m,
1 H), 2.49 (dd, J = 2.6, 4.8 Hz, 0.5 H), 2.59 (dd, J = 2.6, 4.8 Hz,
0.5 H), 2.74 (t app, J = 4.2 Hz, 0.5 H), 2.82 (t app, J = 4.1 Hz, 0.5
H), 2.95–2.99 (m, 0.5 H), 3.12–3.17 (m, 0.5 H), 4.81–4.87 (m, 1 H),
5.94 (s, 2 H), 6.75–6.88 (m, 3 H) ppm. 13C NMR: δ = 41.2, 41.6,
46.6, 46.9, 49.8, 50.1, 71.4, 72.4, 100.9, 100.9, 106.0, 106.1, 108.0,
108.0, 118.8, 119.1, 137.7, 138.0, 147.7 ppm. C11H12O4 (208.21):
calcd. C 63.45, H 5.81; found C 63.32, H 5.78.
2-Oxiranyl-1-phenylethanol (2a): A mixture of homoallyl alcohol
1a (R1, R2 = Ph, H) (1 g, 6.75 mmol) and m-CPBA (2.8 g, 55%
dispersion, 8 mmol) in CHCl3 (100 mL) was stirred at room tem-
perature for 60 h. After that, the reaction mixture was further
stirred with a saturated Na2SO3 solution (30 mL) for 0.5 h and then
the reaction mixture was transfered to a separating funnel and the
chloroform layer was successively washed with saturated aqueous
NaHCO3 (2×20 mL) and brine (15 mL) and dried (Na2SO4). After
removal of the solvent under reduced pressure, the residue obtained
was purified by column chromatography on silica gel (40% ethyl
acetate in light petroleum ether) to furnish epoxy alcohol 2a[18]
1-Oxiranyl-2-phenylpropan-2-ol (2f): Compound 2f was prepared
according to the same procedure as described for 2a as a viscous
liquid. IR (neat): ν = 3433 (br), 2976, 1602, 1494, 1446, 1134 cm–1.
˜
1H NMR: δ = 1.59 (s, 9/5 H), 1.65 (s, 6/5 H), 1.76 (dd, J = 8.0,
14.5 Hz, 6/5 H), 2.01–2.03 (m, 4/5 H), 2.25 (dd, J = 3.6, 14.4 Hz,
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2/5 H), 2.39 (ddd, J = 2.7, 4.8, 15.5 Hz, 3/5 H), 2.62 (t app, J =
4.6 Hz, 3/5 H), 2.69 (t app, J = 4.6 Hz, 2/5 H), 2.83–2.88 (m, 3/5
50.0, 55.6, 55.9, 56.2, 56.2, 56.3, 56.3, 74.6, 74.7, 78.3, 78.5, 80.1,
80.2, 109.6, 109.8, 111.3, 111.4, 119.6, 120.1, 132.9, 133.4, 149.2,
H), 2.91–2.98 (m, 2/5 H), 7.21–7.49 (m, 5 H) ppm. 13C NMR: δ = 149.3, 149.6, 149.7 ppm. C15H18O4 (262.29): calcd. C 68.69, H 6.91;
29.5, 30.6, 46.0, 46.2, 46.4, 46.8, 49.2, 49.4, 73.9, 74.5, 124.5, 124.6, found C 68.56, H 6.88.
126.6, 126.8, 128.1, 128.2, 147.3, 147.4 ppm. C11H14O2 (178.22):
calcd. C 74.13, H 7.92; found C 74.01, H 7.88.
2-[2-[4-(Benzyloxy)-3-methoxyphenyl]-2-(prop-2-ynyloxy)ethyl]oxir-
ane (3c): Compound 3c was prepared according to the same pro-
cedure as described for 3a as a viscous liquid. IR (neat): ν = 3284,
˜
1-(Oxiranylmethyl)cyclohexanol (2g): Compound 2g was prepared
according to the same procedure as described for 2a as a viscous
2999, 2920, 2871, 1604, 1593, 1514, 1454, 1261, 1139 cm–1. 1H
NMR: δ = 1.57–1.65 (m, 0.5 H), 1.80–1.89 (m, 0.5 H), 2.01–2.11
(m, 1 H), 2.36 (dd, J = 2.3, 5.3 Hz, 0.5H) 2.42–2.44 (m, 10.5H),
2.64 (t app, J = 4.3 Hz, 0.5 H), 2.75 (t app, J = 4.2 Hz, 0.5 H),
2.78–2.84 (m, 0.5 H), 3.08–3.14 (m, 0.5 H), 3.75–3.91 (m, 1 H),
3.84 (s, 3 H), 4.05 (ddd, J = 2.3, 6.2, 15.6 Hz, 1 H), 4.51–4.64 (m,
1 H), 5.09 (s, 2 H), 6.72–6.86 (m, 3 H) 7.21–7.40 (m, 5 H) ppm.
13C NMR: δ = 40.8, 41.8, 47.3, 47.9, 49.8, 50.0, 55.7, 56.0, 56.4,
56.4, 71.4, 71.4, 74.6, 74.7, 78.4, 78.5, 80.1, 80.2, 110.2, 110.3,
114.1, 114.2, 119.5, 120.0, 127.6, 127.7, 128.2, 128.3, 128.9, 128.9,
133.5, 134.0, 137.4, 137.5, 148.4, 148.5, 150.3, 150.4 ppm.
C21H22O4 (338.39): calcd. C 74.54, H 6.54; found C 74.41, H 6.50.
liquid. IR (neat): ν = 3396 (br), 2929, 2856, 1651, 1446, 1257 cm–1.
˜
1H NMR: δ = 1.19–1.61 (m, 10 H), 1.75 (dd, J = 4.4, 14.4 Hz, 2
H), 2.08 (br. s, OH), 2.43 (dd, J = 2.7, 4.9 Hz, 1 H), 2.74 (t app, J
= 4.6 Hz, 1 H), 3.08–3.14 (m, 1 H) ppm. 13C NMR: δ = 21.9, 22.0,
25.5, 37.5, 37.8, 44.4, 46.6, 48.8, 71.3 ppm. C9H16O2 (156.22):
calcd. C 69.19, H 10.32; found C 69.04, H 10.28.
1-(Oxiranylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2h): Com-
pound 2h was prepared according to the same procedure as de-
scribed for 2a as a viscous liquid. IR (neat): ν = 3417 (br), 2937,
˜
1487, 1454, 1257, 1101 cm–1. 1H NMR: δ = 1.76–2.25 (m, 6 H),
2.42 (dd, J = 2.7, 4.9 Hz, 2/5 H), 2.48 (dd, J = 2.5, 5.2 Hz, 3/5 H),
2.70–2.87 (m, 3 H), 2.97–3.02 (m, 3/5 H), 3.12–3.16 (m, 2/5 H),
7.07 (d, J = 7.3 Hz, 1 H), 7.14–7.26 (m, 2 H), 7.51–7.57 (m, 1 H)
ppm. 13C NMR: δ = 19.6, 19.8, 29.4, 29.6, 36.6, 36.8, 44.7, 44.9,
46.4, 46.9, 49.0, 49.2, 72.1, 72.2, 125.8, 126.0, 126.1, 126.3, 127.1,
127.2, 128.8, 128.9, 136.3, 136.6, 141.3, 141.9 ppm. C13H16O2
(204.26): calcd. C 76.44, H 7.90; found C 76.29, H 7.85.
2-[2-(4-Methoxyphenyl)-2-(prop-2-ynyloxy)ethyl]oxirane (3d): Com-
pound 3d was prepared according to the same procedure as de-
scribed for 3a as a viscous liquid. IR (neat): ν = 3286, 2999, 2918,
˜
1
2837, 1612, 1512, 1247, 1174, 1076 cm–1. H NMR: δ = 1.61–1.70
(m, 0.5 H), 1.83–1.92 (m, 0.5 H), 2.06–2.16 (m, 1 H), 2.41 (dd, J =
2.3, 5.5 Hz, 0.5H), 2.45–2.48 (m, 10.5H), 2.68 (t app, J = 4.3 Hz,
0.5 H), 2.78 (t app, J = 4.3 Hz, 0.5 H), 2.83–2.86 (m, 0.5 H), 3.12–
3.16 (m, 0.5 H), 3.71–3.89 (m, 1 H), 3.79 (s, 3 H), 4.08 (ddd, J =
2.3, 5.4, 15.6 Hz, 1 H), 4.60–4.70 (m, 1 H), 6.88, 6.89 (2 d, J =
8.7 Hz each, total 2 H), 7.24, 7.26 (2d, J = 8.7 Hz each, total 2 H)
ppm. 13C NMR: δ = 40.3, 41.2, 46.8, 47.3, 49.3, 49.5, 55.0, 55.1,
55.3, 55.3, 74.1, 74.2, 77.5, 77.6, 79.6, 79.7, 113.9, 114.0, 127.8,
128.1, 131.9, 132.4, 159.3, 159.4 ppm. C14H16O3 (232.27): calcd. C
72.40, H 6.93; found C 72.28, H 6.89.
2-[2-Phenyl-2-(prop-2-ynyloxy)ethyl]oxirane (3a): To a stirred sus-
pension of NaH (0.36 g, 60% dispersion, 9 mmol) in dry THF/
DMSO (10:1) (5 mL) was added dropwise a solution of epoxy
alcohol 2a (1 g, 6 mmol) in dry THF (10 mL) at 0 °C under nitro-
gen. After the evolution of hydrogen had ceased, a solution of pro-
pargyl bromide (0.94 g, 7.8 mmol) in dry THF (10 mL) was added
dropwise at 0 °C over 30 min. The reaction mixture was then stirred
at room temperature for 8 h and carefully quenched with ice/water.
After removal of most of the THF under reduced pressure, the
resulting residue was extracted with diethyl ether (3×30 mL). The
combined ether extracts were washed with saturated brine (25 mL)
and dried (Na2SO4). After removal of the solvent under reduced
pressure, the residue obtained was purified by column chromatog-
raphy on silica gel (10% ethyl acetate in light petroleum ether) to
furnish the epoxy ether 3a (1.1 g, 82%) as a viscous liquid as an
2-[2-(Benzo[1,3]dioxol-5-yl)-2-(prop-2-ynyloxy)ethyl]oxirane
(3e):
Compound 3e was prepared according to the same procedure as
described for 3a as a viscous liquid. IR (neat): ν = 3288, 2995,
˜
1
2898, 1487, 1504, 1442, 1244, 1039 cm–1. H NMR: δ = 1.59–1.67
(m, 0.5 H), 1.81–1.89 (m, 0.5 H), 2.03–2.12 (m, 1 H), 2.41 (dd, J =
2.7, 5.5 Hz, 0.5H), 2.45–2.49 (m, 10.5H), 2.69 (t app, J = 4.3 Hz,
0.5H), 2.78 (t app, J = 4.3 Hz, 0.5H), 2.82–2.88 (m, 0.5 H), 3.10–
3.15 (m, 0.5H), 3.80–3.90 (m, 1 H), 4.09 (ddd, J = 2.2, 5.4, 15.7 Hz,
1 H), 4.57–4.66 (m, 1 H), 5.95 (s, 2 H), 6.74–6.84 (m, 3 H) ppm.
13C NMR: δ = 40.3, 41.2, 46.8, 47.3, 49.2, 49.4, 55.1, 55.3, 74.1,
74.2, 77.7, 77.8, 79.5, 79.6, 100.9, 101.0, 106.6, 106.7, 108.0, 108.1,
120.3, 120.7, 133.8, 134.4, 147.3, 147.4, 147.9, 148.0 ppm.
C14H14O4 (246.25): calcd. C 68.29, H 5.72; found C 68.15, H 5.66.
inseparable mixture of two isomers in a ratio of 1:1. IR (neat): ν =
˜
3286, 3030, 2920, 2858, 1494, 1454, 1350, 1089 cm–1 1H NMR: δ
.
= 1.64–1.73 (m, 0.5 H), 1.86–1.94 (m, 0.5 H), 2.08–2.20 (m, 1 H),
2.44 (dd, J = 2.6, 5.4 Hz, 0.5 H), 2.46–2.49 (m, 10.5 H), 2.69 (t
app, J = 4.5 Hz, 0.5 H), 2.79 (t app, J = 4.5 Hz, 0.5 H), 2.85–2.90
(m, 0.5H), 3.16–3.20 (m, 0.5 H), 3.88 (t app, J = 15.5 Hz, each
peak split into doublet, J = 2.2 Hz, 1 H), 4.13 (ddd, J = 2.3, 6.6,
15.7 Hz, 1 H), 4.67–4.77 (m, 1 H), 7.27–7.43 (m, 5 H) ppm. 13C
NMR: δ = 40.9, 41.8, 47.3, 47.8, 49.8, 49.9, 55.8, 56.1, 74.7, 74.8,
78.5, 78.6, 80.0, 80.1, 127.1, 127.3, 128.5, 128.6, 129.0, 129.1, 140.5,
141.0 ppm. C13H14O2 (202.24): calcd. C 77.21, H 6.97; found C
77.09, H 6.92.
2-[2-Phenyl-2-(prop-2-ynyloxy)propyl]oxirane (3f): Compound 3f
was prepared according to the same procedure as described for 3a
as a viscous liquid. IR (neat): ν = 3288, 3055, 2983, 2920, 1685,
˜
1494, 1446, 1380, 1068 cm–1. 1H NMR: δ = 1.71–1.85 (m, 1 H),
1.71 (s, 6/5 H), 1.73 (s, 9/5 H), 2.01–2.12 (m, 1 H), 2.29–2.37 (m,
7/5 H), 2.39 (dd, J = 2.4, 4.7 Hz, 3/5 H), 2.60–2.70 (m, 1 H), 2.75–
2.79 (m, 2/5 H), 3.12–3.17 (m, 3/5 H), 3.81–3.99 (m, 2 H), 7.25–
7.45 (m, 5 H) ppm. 13C NMR: δ = 23.6, 23.7, 46.7, 46.8, 47.0, 47.0,
49.1, 49.2, 51.6, 51.8, 73.8, 73.8, 80.1, 81.3, 81.3, 80.3, 126.2, 126.6,
127.9, 128.0, 128.8, 128.9, 143.6, 144.4 ppm. C14H16O2 (216.27):
calcd. C 77.75, H 7.45; found C 77.66, H 7.40.
2-[2-(3,4-Dimethoxyphenyl)-2-(prop-2-ynyloxy)ethyl]oxirane
(3b):
Compound 3b was prepared according to the same procedure as
described for 3a as a viscous liquid. IR (neat): ν = 3263, 2999,
˜
1
2937, 2837, 1606, 1593, 1515, 1463, 1263, 1026 cm–1. H NMR: δ
= 1.59–1.70 (m, 0.5 H), 1.87–1.95 (m, 0.5 H), 2.06–2.17 (m, 1 H),
2.41 (dd, J = 2.4, 6.1 Hz, 0.5H), 2.48–2.50 (m, 10.5H), 2.70 (t app, 2-{[1-(Prop-2-ynyloxy)cyclohexyl]methyl}oxirane (3g): Compound
J = 4.3 Hz, 0.5 H), 2.80 (t app, J = 4.4 Hz, 0.5 H), 2.83–2.89 (m, 3g was prepared according to the same procedure as described for
0.5 H), 3.13–3.19 (m, 0.5 H), 3.82–3.93 (m, 1 H), 3.87 (s, 3 H), 3.88 3a as a viscous liquid. IR (neat): ν = 3288, 2933, 2858, 1450,
˜
1
(s, 3 H), 4.11 (ddd, J = 2.3, 6.1, 15.6 Hz, 1 H), 4.59–4.69 (m, 1 H),
1062 cm–1. H NMR: δ = 1.20–1.90 (m, 12 H), 2.37 (dd, J = 2.2,
6.81–6.91 (m, 3 H) ppm. 13C NMR: δ = 40.8, 41.8, 47.2, 47.8, 49.8,
4.6 Hz, 1 H), 2.44 (dd, J = 2.7, 5.0 Hz, 1 H), 2.76 (t app, J =
494
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 489–497

Polysubstituted Tetrahydropyrans
4.7 Hz, 1 H), 3.05–3.11 (m, 1 H), 4.03, 4.10 (ABq, J = 15.2 Hz, H), 6.75–6.85 (m, 3 H) ppm. 13C NMR: δ = 40.9, 41.8, 46.9, 47.4,
FULL PAPER
each peak split into doublet, J = 2.3 Hz, 2 H) ppm. 13C NMR: δ
= 21.7, 21.8, 25.5, 34.6, 34.7, 39.9, 46.8, 48.4, 49.3, 73.1, 76.6,
81.1 ppm. C12H18O2 (194.26): calcd. C 74.20, H 9.33; found C
74.10, H 9.31.
49.4, 49.6, 69.1, 69.3, 78.5, 78.6, 100.9, 101.0, 106.5, 106.7, 108.0,
108.0, 116.7, 116.8, 119.9, 120.4, 134.6, 134.7, 135.3, 135.9, 147.1,
147.2, 147.9, 148.0 ppm. C14H16O4 (248.27): calcd. C 67.73, H 6.50;
found C 67.64, H 6.46.
2-{[1-(Prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}-
oxirane (3h): Compound 3h was prepared according to the same
[(2R,4R)-5-Methylene-2-phenyltetrahydro-2H-pyran-4-yl]methanol
(4a1): A solution of titanocene dichloride (0.65 g, 2.6 mmol) in dry
THF (35 mL) was stirred with activated zinc dust (0.482 g,
procedure as described for 3a as a viscous liquid. IR (neat): ν =
˜
1
3286, 2941, 2868, 1487, 1450, 1058 cm–1. H NMR: δ = 1.74–2.15 7.2 mmol) under argon for 1 h (activated zinc dust was prepared
(m, 6 H), 2.28 (t app, J = 2.2 Hz, 1 H), 2.36 (dd, J = 2.6, 4.9 Hz, by washing 20 g of commercially available zinc dust with 60 mL of
1 H), 2.60–2.77 (m, 3 H), 2.88–2.94 (m, 1 H), 3.75, 3.84 (ABq, J = 4 n HCl and thorough washing with water and finally with dry
15.2 Hz, each peak split into doublet, J = 2.6 Hz, 2 H), 7.02 (d, J
= 6.8 Hz, 1 H), 7.09–7.18 (m, 2 H), 7.41 (d, J = 7.9 Hz, 1 H) ppm. was then transferred through a cannula to a dropping funnel and
13C NMR: δ = 20.4, 29.5, 31.7, 45.6, 46.9, 48.7, 51.2, 73.0, 78.7,
was added dropwise to a magnetically stirred solution of the ep-
81.1, 126.2, 126.7, 127.5, 128.9, 137.3, 138.7 ppm. C16H18O2 oxyalkyl propargyl ether 3a (250 mg, 1.2 mmol) in dry THF
acetone and then drying in vacuo). The resulting green solution
(242.30): calcd. C 79.31, H 7.48; found C 79.20, H 7.44.
(30 mL) at room temperature under argon during 40 min. The reac-
tion mixture was stirred for an additional 1.5 h and decomposed
with 10% H2SO4 (15 mL). Most of the solvent was removed under
reduced pressure, and the residue obtained was extracted with di-
ethyl ether (4×30 mL). The combined ether layers were washed
with saturated NaHCO3 (2×20 mL), brine (20 mL) and then dried
(Na2SO4). Removal of the solvent under reduced pressure afforded
a viscous mass which was chromatographed on silica gel (20% ethyl
acetate in light petroleum ether) to yield the cyclized product 4a
(196 mg, 78%) as a mixture of two isomers in a ratio of 4.6:1 and
the reduced product 5a (40 mg, 16%). The major isomer was sepa-
rated by preparative TLC (15% ethyl acetate in light petroleum
ether) of the cyclized crude product to obtain the major isomer 4a1
2-(2-Allyloxy-2-phenylethyl)oxirane (6a): To a stirred suspension of
NaH (77 mg, 60 % dispersion, 1.92 mmol) in dry THF/DMSO
(10:1) (5 mL) was added dropwise a solution of epoxy alcohol 2a
(210 mg, 1.28 mmol) in dry THF (5 mL) at 0 °C under nitrogen.
After the evolution of hydrogen had ceased, a solution of allyl bro-
mide (232 mg, 1.92 mmol) in dry THF (5 mL) was added dropwise
at 0 °C over 30 min. The reaction mixture was then stirred at room
temperature for 8 h and carefully quenched with ice/water. After
removal of most of the THF under reduced pressure, the resulting
residue was extracted with diethyl ether (3×30 mL). The combined
ether extracts were washed with saturated brine (25 mL) and dried
(Na2SO4). After removal of the solvent under reduced pressure, the
residue obtained was purified by column chromatography on silica
gel (10% ethyl acetate in light petroleum ether) to furnish the epoxy
ether 6a (232 mg, 89%) as a viscous liquid as an inseparable mix-
(139 mg, 55%) as a viscous oil. IR (neat): ν = 3420 (br), 2918, 2848,
˜
1
1652, 1450, 1028 cm–1. H NMR: δ = 1.45–1.57 (m, 1 H), 1.53 (br.
s, OH), 2.14 (ddd, J = 2.1, 4.3, 13.0 Hz, 1 H), 2.61–2.65 (m, 1 H),
3.74 (dd, J = 6.1, 10.6 Hz, 1 H), 3.96 (dd, J = 5.6, 10.5 Hz, 1 H),
4.15, 4.36 (AB q, J = 12.3 Hz, 2 H), 4.57 (dd, J = 2.1, 11.3 Hz, 1
H), 4.89 (s, 1 H), 5.03 (s, 1 H), 7.24–7.37 (m, 5 H) ppm. 13C NMR:
δ = 38.9, 42.7, 64.4, 74.1, 80.1, 108.6, 126.2, 127.9, 128.7, 142.4,
144.7 ppm. C13H16O2 (204.26): calcd. C 76.45, H 7.88; found C
76.31, H 7.85. The minor isomer could not be separated in pure
form and was always contaminated with the major isomer.
ture of two isomers in a ratio of 1:1. IR (neat): ν = 3028, 2918,
˜
1
2860, 1647, 1454, 1091 cm–1. H NMR: δ = 1.63–1.70 (m, 0.5 H),
1.86–1.94 (m, 0.5 H), 2.08–2.18 (m, 1 H), 2.46–2.50 (m, 1 H), 2.71
(t app, J = 4.4 Hz, 0.5 H), 2.81(t app, J = 4.4 Hz, 0.5 H), 2.85–
2.91 (m, 0.5 H), 3.19–3.25 (m, 0.5 H), 3.76–4.00 (m, 2 H), 4.48–
4.60 (m, 1 H), 5.16–5.30 (m, 2 H), 5.85–6.00 (m, 1 H), 7.28–7.38
(m, 5 H) ppm. 13C NMR: δ = 40.7, 41.7, 46.8, 47.4, 49.3, 49.5,
69.2, 69.4, 78.6, 78.7, 116.6, 116.7, 126.2, 126.6, 127.5, 127.7, 128.3,
Compounds 4b–h were prepared according to the same procedure
128.4, 134.5, 134.6, 141.2, 141.7 ppm. C13H16O2 (204.26): calcd. C as described for 4a. The major isomers 4b1–4e1 were separated by
76.44, H 7.90; found C 76.38, H 7.87.
preparative TLC (15% ethyl acetate in light petroleum ether) but
the minor isomer in each case could not be separated in pure form
an was always contaminated with the major isomer.
2-[2-(Allyloxy)-2-(4-methoxyphenyl)ethyl]oxirane (6b): Compound
6b was prepared from 2d according to the same procedure as de-
scribed for 6a as a viscous liquid. IR (neat): ν = 2999, 2837, 1612,
[(2R,4R)-2-(3,4-Dimethoxyphenyl)-5-methylenetetrahydro-2H-py-
˜
1
1512, 1247, 1033 cm–1. H NMR: δ = 1.60–1.70 (m, 0.5 H), 1.84–
ran-4-yl]methanol (4b1): Viscous oil. IR (neat): ν = 3417(br), 2937,
˜
1
1.92 (m, 0.5 H), 2.06–2.16 (m, 1 H), 2.45–2.50 (m, 1 H), 2.70 (t
2837, 1651, 1593, 1517, 1263 cm–1. H NMR: δ = 1.40–1.52 (m, 1
app, J = 4.5 Hz, 0.5 H), 2.80 (t app, J = 4.5 Hz, 0.5 H), 2.84–2.89 H), 1.52 (br. s, OH), 2.05 (ddd, J = 2.0, 4.4, 12.9 Hz, 1 H), 2.51–
(m, 0.5 H), 3.15–3.21 (m, 0.5 H), 3.72–3.97 (m, 2 H), 3.82 (s, 3 H), 2.57 (m, 1 H), 3.69 (dd, J = 6.0, 10.6 Hz 1 H), 3.79 (s, 3 H), 3.82
4.43–4.54 (m, 1 H), 5.15–5.29 (m, 2 H), 5.83–5.98 (m, 1 H), 6.90, (s, 3 H), 3.90 (dd, J = 5.8, 10.7 Hz, 1 H), 4.07, 4.28 (ABq, J =
6.91 (2d, J = 8.6 Hz each, 2 H), 7.23–7.29 (m, 2 H) ppm. 13C NMR:
δ = 40.8, 41.8, 47.0, 47.5, 49.5, 49.7, 55.2, 55.2, 69.1, 69.3, 78.3,
78.4, 113.8, 113.9, 116.6, 116.7, 127.6, 127.9, 133.3, 133.8, 134.7,
134.8, 159.1, 159.2 ppm. C14H18O3 (234.28): calcd. C 71.77, H 7.74;
found C 71.70, H 7.71.
12.3 Hz, 2 H), 4.45 (dd, J = 2.0, 11.3 Hz, 1 H), 4.82 (s, 1 H), 4.96
(s, 1 H), 6.74–6.85 (m, 3 H) ppm. 13C NMR: δ = 38.8, 42.7, 56.2,
56.3, 64.4, 74.1, 79.9, 108.5, 109.5, 111.3, 118.5, 135.1, 144.7, 148.8,
149.3 ppm. C15H20O4 (264.31): calcd. C 68.17, H 7.62; found C
68.09, H 7.58.
5-[1-(Allyloxy)-2-oxiranylethyl]benzo[1,3]dioxole (6c): Compound
6c was prepared from 2e according to the same procedure as de-
{(2R,4R)-2-[4-(Benzyloxy)-3-methoxyphenyl]-5-methylenetetra-
hydro-2H-pyran-4-yl}methanol (4c1): Viscous oil. IR (neat): ν =
˜
1
scribed for 6a as a viscous liquid. IR (neat): ν = 3016, 2887, 1504,
3390 (br), 2848, 1651, 1593, 1463, 1031 cm–1. H NMR: δ = 1.45–
˜
1
1487, 1442, 1217, 1041 cm–1. H NMR: δ = 1.54–1.63 (m, 0.5 H),
1.64 (m, 1 H), 1.56 (br. s, OH), 2.10 (ddd, J = 2.0, 4.3, 12.9 Hz, 1
H), 2.57–2.61 (m, 1 H), 3.75 (dd, J = 6.0, 10.6 Hz, 1 H), 3.89 (s, 3
H), 3.96 (dd, J = 5.6, 10.4 Hz, 1 H), 4.13, 4.34 (ABq, J = 12.3 Hz,
1.79–1.88 (m, 0.5 H), 2.00–2.11 (m, 1 H), 2.43–2.47 (m, 1 H), 2.68
(t app, J = 4.3 Hz, 0.5 H), 2.78 (t app, J = 4.3 Hz, 0.5 H), 2.81–
2.86 (m, 0.5 H), 3.11–3.17 (m, 0.5 H), 3.71–3.96 (m, 2 H), 4.36– 2 H), 4.50 (dd, J = 2.0, 11.3 Hz, 1 H), 4.89 (s, 1 H), 5.02 (s, 1 H),
4.48 (m, 1 H), 5.13–5.27 (m, 2 H), 5.80–5.94 (m, 1 H), 5.94 (s, 2
5.13 (s, 2 H), 6.77–6.94 (m, 3 H), 7.25–7.43 (m, 5 H) ppm. 13C
Eur. J. Org. Chem. 2006, 489–497
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
495

B. Banerjee, S. C. Roy
FULL PAPER
NMR: δ = 38.2, 42.2, 55.9, 63.9, 70.9, 73.6, 79.4, 108.0, 109.6,
prepared by washing 20 g of commercially available zinc dust with
113.8, 118.0, 127.6, 127.7, 128.4, 135.2, 137.1, 144.2, 147.4, 60 mL of 4 n HCl and thorough washing with water and finally
149.6 ppm. C21H24O4 (340.40): calcd. C 74.10, H 7.10; found C
73.99, H 7.07.
with dry acetone and then drying in vacuo). The resulting green
solution was then transferred through a cannula to a dropping fun-
nel and was added dropwise to a magnetically stirred solution of
the allyl epoxyalkyl ether 6a (210 mg, 1.03 mmol) in dry THF
(25 mL) at room temperature under argon during 40 min. The reac-
tion mixture was stirred for an additional 1.5 h and decomposed
with 10% H2SO4 (15 mL). Most of the solvent was removed under
reduced pressure, and the residue obtained was extracted with di-
ethyl ether (4×30 mL). The combined ether layers were washed
with saturated NaHCO3 (2×20 mL), brine (20 mL) and then dried
(Na2SO4). Removal of the solvent under reduced pressure afforded
a viscous mass which was chromatographed on silica gel (30% ethyl
acetate in light petroleum ether) to yield the cyclized product 7a
(176 mg, 83%) as a mixture of three isomers in a ratio of 2.6:1:0.2
and the reduced product 8a (17 mg, 8%). The crude 7a was sub-
jected to preparative TLC (20% ethyl acetate in light petroleum
ether) to furnish 7a1 (105 mg, 49%) as a viscous oil and 7a2 (40 mg,
19%) as a crystalline solid, m.p. 138–140 °C. Spectral data of the
[(2R,4R)-2-(4-Methoxyphenyl)-5-methylenetetrahydro-2H-pyran-4-yl-
]methanol (4d1): Viscous oil. IR (neat): ν = 3417 (br), 2916, 2848,
˜
1612, 1514, 1247, 1031 cm–1. 1H NMR: δ = 1.45–1.58 (m, 1 H),
1.57 (br. s, OH), 2.10 (ddd, J = 2.1, 4.4, 12.0 Hz, 1 H), 2.58–2.63
(m, 1 H), 3.74 (dd, J = 6.0, 10.6 Hz, 1 H), 3.79 (s, 3 H), 3.95 (dd,
J = 5.8, 10.6 Hz, 1 H), 4.13, 4.33 (ABq, J = 12.3 Hz, 2 H), 4.52
(dd, J = 2.1, 11.3 Hz, 1 H), 4.89 (s, 1 H), 5.02 (s, 1 H), 6.86 (d, J
= 8.6 Hz, 2 H), 7.28 (d, J = 9.1 Hz, 2 H) ppm. 13C NMR: δ =
38.2, 42.2, 55.1, 63.9, 73.6, 79.2, 107.9, 113.6, 127.0, 134.1, 144.3,
158.9 ppm. C14H18O3 (234.28): calcd. C 71.78, H 7.73; found C
71.70, H 7.71.
[(2R,4R)-2-(1,3-Benzodioxol-5-yl)-5-methylenetetrahydro-2H-pyran-
4-yl]methanol (4e1): Viscous oil. IR (neat): ν = 3417 (br), 2916,
˜
1
2848, 1504, 1488, 1444, 1251 cm–1. H NMR: δ = 1.42–1.62 (m, 1
H), 1.62 (br. s, OH), 2.09 (ddd, J = 2.1, 4.4, 13.0 Hz, 1 H), 2.56–
2.62 (m, 1 H), 3.74 (dd, J = 6.1, 10.6 Hz, 1 H), 3.95 (dd, J = 5.7,
10.6 Hz, 1 H), 4.12, 4.33 (ABq, J = 12.2 Hz, 2 H), 4.48 (dd, J =
2.0, 11.3 Hz, 1 H), 4.88 (s, 1 H), 5.02 (s, 1 H), 5.93 (s, 2 H), 6.77–
6.87 (m, 3 H) ppm. 13C NMR: δ = 38.3, 42.1, 63.9, 73.6, 79.4,
100.8, 106.5, 108.0, 119.1, 136.0, 144.1, 146.7, 146.8 ppm.
C14H16O4 (248.27): calcd. C 67.74, H 6.49; found C 67.63, H 6.45.
major isomer 7a1: IR (neat): ν = 3390 (br), 3030, 2916, 2873, 1600,
˜
1454, 1085 cm–1. 1H NMR: δ = 0.90 (d, J = 6.4 Hz, 3 H), 1.40–
1.75 (m, 4 H including OH), 1.98–2.03 (m, 1 H), 3.24 (t app, J =
11.0 Hz, 1 H), 3.56 (dd, J = 10.7, 6.2 Hz, 1 H), 3.80 (dd, J = 10.7,
3.2 Hz, 1 H), 4.01 (dd, J = 11.4, 4.4 Hz, 1 H), 4.38 (dd, J = 11.0,
2.2 Hz, 1 H), 7.24–7.37 (m, 5 H) ppm. 13C NMR: δ = 14.1, 31.9,
36.8, 44.5, 64.9, 74.2, 79.7, 125.6, 127.2, 128.2, 142.6 ppm.
C13H18O2 (206.27): calcd. C 75.69, H 8.80; found C 75.61, H 8.77.
[(4R)-2-Methyl-5-methylene-2-phenyltetrahydro-2H-pyran-4-yl]-
methanol (4f): Viscous oil. IR (neat): ν = 3396 (br), 2972, 2925,
˜
Spectral data of the minor isomer 7a2: IR (neat): ν = 3433 (br),
˜
1651, 1494, 1446, 1060 cm–1. 1H NMR: δ = 1.40 (s, 6/3 H), 1.54 (s,
3/3 H), 2.15–2.39 (m, 2 H), 2.71 (dd, J = 3.8, 13.5 Hz, 1 H), 3.52–
3.74 (m, 1 H), 3.86–3.94 (m, 1 H), 3.94 (s, 1 H), 4.16, 4.27 (ABq, J
= 13.2 Hz, 1 H), 4.70 (s, 2/3 H), 4.83 (s, 1/3 H), 4.87 (s, 2/3 H),
4.96 (s, 1/3 H), 7.22–7.46 (m, 5 H) ppm. 13C NMR: δ = 26.7, 33.6,
38.5, 39.1, 39.5, 63.9, 66.1, 68.0, 75.3, 76.9, 106.9, 108.2, 124.3,
124.6, 125.9, 126.5, 126.7, 128.1, 128.2, 128.6, 143.6, 144.7, 145.0,
147.7 ppm. C14H18O2 (218.28): calcd. C 77.04, H 8.30; found C
76.90, H 8.25.
2931, 2848, 1454, 1371, 1099 cm–1. 1H NMR: δ = 1.07 (d, J =
7.1 Hz, 3 H), 1.40–1.73 (m, 3 H including OH), 1.87–1.92 (m, 1
H), 2.09–2.18 (m, 1 H), 3.48–3.61 (m, 2 H), 3.77, 3.96 (ABq, J =
11.3 Hz, each peak split into doublet, J = 2.3 Hz, 2 H), 4.34 (dd,
J = 11.3, 2.5 Hz, 1 H), 7.23–7.38 (m, 5 H) ppm. 13C NMR: δ =
11.1, 29.2, 31.8, 41.1, 65.5, 74.6, 79.9, 125.7, 127.8, 128.4,
142.9 ppm. C13H18O2 (206.27): calcd. C 75.69, H 8.80; found C
75.60, H 8.76. The other third isomer could not be isolated in pure
form as it was produced in minute quantity.
(3-Methylene-1-oxaspiro[5.5]undec-4-yl)methanol (4g): Viscous oil.
[(2R,4R,5S)-2-(4-Methoxyphenyl)-5-methyltetrahydro-2H-pyran-4-
yl]methanol (7b1) and [(2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-
tetrahydro-2H-pyran-4-yl]methanol (7b2): Compounds 7b1 and 7b2
were prepared from 6b in 52% and 21% yield, respectively, as vis-
cous oils according to the same procedure as described for 7a1 and
IR (neat): ν = 3390 (br), 2931, 2856, 1651, 1444, 1062 cm–1. 1H
˜
NMR: δ = 1.13–1.74 (m, 10 H), 1.79 (dd, J = 4.7, 13.0 Hz, 1 H),
1.81 (br. s, OH), 2.03–2.07 (m, 1 H), 2.53–2.59 (m, 1 H), 3.62 (dd,
J = 5.9, 10.4 Hz, 1 H), 3.85 (dd, J = 5.9, 10.4 Hz, 1 H), 3.94, 4.11
(ABq, J = 13.0 Hz, 2 H), 4.77 (s, 1 H), 4.91 (s, 1 H) ppm. 13C
NMR: δ = 21.5, 21.7, 25.9, 26.0, 30.3, 37.6, 39.2, 64.3, 65.9, 72.5,
107.0, 145.6 ppm. C12H20O2 (196.28): calcd. C 73.44, H 10.26;
found C 73.36, H 10.23.
7a2. Spectral data of the major isomer 7b1: IR (neat): ν = 3410 (br),
˜
1
2950, 2837, 1612, 1514, 1247, 1033 cm–1. H NMR: δ = 0.88 (d, J
= 6.1 Hz, 3 H), 1.40–1.72 (m, 4 H including OH), 1.95–1.99 (m, 1
H), 3.22 (t app, J = 11.2 Hz, 1 H), 3.56 (dd, J = 10.6, 5.2 Hz, 1
H), 3.73–3.86 (m, 1 H), 3.79 (s, 3 H), 3.99 (dd, J = 11.4, 4.3 Hz, 1
H), 4.30–4.34 (m, 1 H), 6.86 (d, J = 8.4 Hz, 2 H), 7.28 (d, J =
8.6 Hz, 2 H) ppm. 13C NMR: δ = 14.2, 32.0, 36.7, 44.6, 55.2, 65.1,
74.4, 79.5, 113.6, 127.0, 135.0, 158.9 ppm. C14H20O3 (236.30):
calcd. C 71.16, H 8.53; found C 71.06, H 8.49. Spectral data of the
(5Ј-Methylene-3,3Ј,4,4Ј,5Ј,6Ј-hexahydro-2H-spiro[naphthalene-1,2Ј-
pyran]-4Ј-yl)methanol (4h): Viscous oil. IR (neat): ν = 3400 (br),
˜
1
2933, 2866, 1649, 1488, 1448, 1047 cm–1. H NMR: δ = 1.56 (br. s,
OH), 1.66–1.84 (m, 2 H), 1.90–2.08 (m, 3 H), 2.37–2.45 (m, 1 H),
2.68–2.75 (m, 1 H), 2.77–2.89 (m, 2 H), 3.69 (dd, J = 5.7, 10.6 Hz,
1 H), 3.91 (dd, J = 5.9, 10.6 Hz, 1 H), 4.13, 4.36 (AB q, J =
12.9 Hz, 2 H), 4.89 (s, 1 H), 5.03 (s, 1 H), 7.04 (d, J = 7.2 Hz, 1
H), 7.11–7.20 (m, 2 H), 7.55 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR:
δ = 20.4, 30.0, 30.1, 38.8, 40.8, 64.8, 67.6, 74.9, 108.0, 126.6, 127.3,
127.4, 128.9, 137.0, 141.8, 145.5 ppm. C16H20O2 (244.32): calcd. C
78.66, H 8.24; found C 78.52, H 8.20.
minor isomer 7b2: IR (neat): ν = 3398, 2935, 2875, 1614, 1514,
˜
1
1247, 1035 cm–1. H NMR δ: 1.06 (d, J = 7.0 Hz, 3 H), 1.40–1.81
(m, 3 H including OH), 1.83–1.96 (m, 1 H), 1.99–2.16 (m, 1 H),
3.45–3.69 (m, 2 H), 3.71–3.92 (m, 2 H), 3.79 (s, 3 H), 4.28 (dd, J
= 11.3, 2.2 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 2 H), 7.28 (d, J = 8.4 Hz,
2 H) ppm. 13C NMR: δ = 11.0, 27.0, 31.8, 40.9, 55.1, 65.3, 74.5,
79.5, 113.5, 126.8, 135.1, 158.7 ppm. C14H20O3 (236.30): calcd. C
71.16, H 8.53; found C 71.12, H 8.50. The other third isomer could
not be isolated in pure form as it was produced in minute quantity.
[(2R,4R,5S)-5-Methyl-2-phenyltetrahydro-2H-pyran-4-yl]methanol
(7a1) and [(2R,4R,5R)-5-Methyl-2-phenyltetrahydro-2H-pyran-4-yl]-
methanol (7a2): A solution of titanocene dichloride (0.57 g,
2.24 mmol) in dry THF (28 mL) was stirred with activated zinc
dust (0.4 g, 6.12 mmol) under argon for 1 h (activated zinc dust was
[(2R,4R,5S)-2-(1,3-Benzodioxol-5-yl)-5-methyltetrahydro-2H-pyran-
4-yl]methanol (7c1) and [(2R,4R,5R)-2-(1,3-Benzodioxol-5-yl)-5-
496
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 489–497

Polysubstituted Tetrahydropyrans
FULL PAPER
methyltetrahydro-2H-pyran-4-yl]methanol (7c2): Compounds 7c1
and 7c2 were prepared from 6c in 49% and 20% yield, respectively,
as viscous oils according to the same procedure as described for
fand, E. Brown, G. Dujardin, V. Michelet, J. P. Genet, Tetrahe-
dron Lett. 2003, 44, 2141–2144 and references cited therein.
[2] a) H. R. Horton, L. A. Moran, R. S. Ochs, J. D. Rawn, K. G.
Scrimgeour, Principles of Biochemistry, 2nd ed., Prentice Hall,
Upper Saddle River, NJ, 1996; b) K. C. Nicolaou, E. J. Sor-
ensen, Classics in Total Synthesis, Wiley-VCH, Weinheim,
1996.
7a1 and 7a2. Spectral data of the major isomer 7c1: IR (neat): ν =
˜
3417 (br), 3010, 2954, 2879, 1504, 1488, 1442, 1251, 1039 cm–1. 1H
NMR: δ = 0.88 (d, J = 6.4 Hz, 3 H), 1.37–1.81 (m, 4 H including
OH), 1.93–1.98 (m, 1 H), 3.20 (t app, J = 11.0 Hz, 1 H), 3.55 (dd,
J = 10.6, 6.0 Hz, 1 H), 3.78 (dd, J = 10.7, 3.2 Hz, 1 H), 3.98 (dd,
[3] For a review, see: T. L. B. Boivin, Tetrahedron 1987, 43, 3309–
3362.
J = 11.4, 4.4 Hz, 1 H), 4.28 (dd, J = 10.9, 2.1 Hz, 1 H), 5.92 (s, 2 [4] X.-F. Yang, J. T. Mague, C.-J. J. Li, J. Org. Chem. 2001, 66,
H), 6.74–6.89 (m, 3 H) ppm. 13C NMR: δ = 14.1, 31.8, 36.8, 44.4,
64.9, 74.2, 79.6, 100.7, 106.5, 107.8, 118.9, 136.7, 146.6, 147.4 ppm.
C14H18O4 (250.28): calcd. C 67.18, H 7.25; found C 67.10, H 7.22.
739–747 and references cited therein.
[5] a) J. S. Yadav, B. V. Subba Reddy, G. Mahesh Kumar,
Ch. V. S. R. Murthy, Tetrahedron Lett. 2001, 42, 89–91; b) S.
Marumoto, J. J. Jaber, J. P. Vitale, S. D. Rychnovsky, Org. Lett.
2002, 4, 3919–3922 and references cited therein.
Spectral data of the minor isomer 7c2: IR (neat): ν = 3419 (br),
˜
1
3016, 2881, 1504, 1488, 1442, 1215, 1041 cm–1. H NMR: δ = 1.06
[6] a) B. Giese, Radicals in Organic Synthesis Formation of Car-
bon–Carbon Bonds, Pergamon Press, Oxford, 1986; b) D. P.
Curran, Synthesis 1988, 417–439 and 489–513; c) W. B.
Motherwell, D. Crich, Free Radical Chain Reactions in Organic
Synthesis, Academic Press, New York, 1992; d) J. Fossey, D.
Lefort, J. Sorba, Free Radicals In Organic Chemistry, Wiley,
New York, 1995; e) M. Ramaiah, Tetrahedron 1987, 43, 3541–
3676; f) A. Srikrishna, Curr. Sci. 1987, 56, 392–396.
[7] a) A. Gansäuer, Synlett 1998, 801–809; b) A. Gansäuer, H.
Bluhm, Chem. Rev. 2000, 100, 2771–2788; c) A. Gansäuer, M.
Pierobon, H. Bluhm, Synthesis 2001, 2500–2520.
(d, J = 7.1 Hz, 3 H), 1.38–1.78 (m, 3 H including OH), 1.81–1.98
(m, 1 H), 2.02–2.16 (m, 1 H), 3.46–3.61 (m, 2 H), 3.74, 3.93 (ABq,
J = 11.3 Hz, each peak split into doublet, J = 2.0 Hz, 2 H), 4.25
(dd, J = 11.3, 2.4 Hz, 1 H), 5.93 (s, 2 H), 6.74–6.82 (m, 2 H), 6.88
(s, 1 H) ppm. 13C NMR: δ = 11.0, 29.0, 31.7, 40.9, 65.3, 74.4,
79.6, 100.8, 106.5, 107.8, 119.0, 136.9, 146.6, 147.4 ppm. C14H18O4
(250.28): calcd. C 67.18, H 7.25; found C 67.06, H 7.20. The other
third isomer could not be isolated in pure form as it was produced
in minute quantity.
X-ray Crystallographic Structure Determination of 7a2: A colourless
single crystal was analyzed with a DIPLABO Kappa image plate
diffractometer using the oscillation method at 293 K. Crystal size:
0.25 × 0.25 × 0.30 mm3. Crystal system: monoclinic, space group
P21/c (No. 14) with cell parameters a = 9.7060(8) Å, b = 7.9000(6)
[8] a) A. S. Rao, S. K. Paknikar, J. G. Kirtane, Tetrahedron 1983,
39, 2323–2367; b) J. G. Smith, Synthesis 1984, 629–656.
[9] a) P. K. Mandal, G. Maiti, S. C. Roy, J. Org. Chem. 1998, 63,
2829–2834; b) S. C. Roy, K. K. Rana, C. Guin, J. Org. Chem.
2002, 67, 3242–3248.
[10] T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116,
Å, c = 17.0040(11) Å, β = 119.301(3)o, V = 1137.0(2) Å3, ρcalcd.
=
986–997 and references cited therein.
1.205 gcm–3, Z = 4. 6233 reflections were collected, resulting in
3593 independent and 3568 observed [I Ͼ 2σ(I)] reflections. Ab-
sorption coefficient µ = 0.079 mm-1, no absorption correction, 136
refined parameters. Non-hydrogen atoms were refined anisotropi-
cally and H atoms were added at the calculated positions. R1 =
0.1367, wR2 = 0.4104 for data [I Ͼ 2σ(I)].
[11] a) S. Jana, C. Guin, S. C. Roy, Tetrahedron Lett. 2004, 45,
6575–6577; b) A. Rosales, J. L. Oller-López, J. Justicia, A. Gan-
säuer, J. E. Oltra, J. M. Cuerva, Chem. Commun. 2004, 2628–
2629.
[12] a) A. L. J. Beckwith, Tetrahedron 1981, 37, 3073–3100; b) D. C.
Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959–974; c)
T. V. RajanBabu, Acc. Chem. Res. 1991, 24, 139–145.
[13] R. J. Enemerke, J. Larsen, T. Skrydstrup, K. Daasbjerg, J. Am.
Chem. Soc. 2004, 126, 7853–7864 and references cited therein.
[14] A. F. Barrero, J. E. Oltra, J. M. Cuerva, A. Rosales, J. Org.
Chem. 2002, 67, 2566–2571 and references cited therein.
[15] F. Bermejo, C. Sandoval, J. Org. Chem. 2004, 69, 5275–5280.
[16] a) A. Gansäuer, H. Bluhm, M. Pierobon, J. Am. Chem. Soc.
1998, 120, 12849–12859; b) A. Gansäuer, M. Pierobon, Synlett
2000, 1357–1359; c) A. Gansäuer, B. Rinker, M. Pierobon, S.
Grimme, M. Gerenkamp, C. Muck-Lichtenfeld, Angew. Chem.
Int. Ed. 2003, 42, 3687–3690; d) A. F. Barrero, A. Rosales, J. M.
Cuerva, J. E. Oltra, Org. Lett. 2003, 5, 1935–1938; e) J. Justicia,
A. Rosales, E. Bunuel, J. L. Oller-López, M. Valdivia, A. Hai-
dour, J. E. Oltra, A. F. Barrero, D. J. Cardenas, J. M. Cuerva,
Chem. Eur. J. 2004, 10, 1778–1788; f) S. Fuse, M. Hanochi, T.
Doi, T. Takahashi, Tetrahedron Lett. 2004, 45, 1961–1963.
[17] B. C. Ranu, A. Majee, A. R. Das, Tetrahedron Lett. 1995, 36,
4885–4888.
CCDC-278957 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see also the footnote on the first page of
this article): Copies of 1H and 13C NMR spectra of compounds
2a, 2d, 3a, 3d, 4a1, 4d1, 6a, 7a1 and 7a2.
Acknowledgments
B. B. thanks CSIR, New Delhi, for awarding the Fellowship.
[1] a) B. C. Pressman, Annu. Rev. Biochem. 1976, 45, 501–530; b)
S. S. Bhagwat, P. R. Hamann, W. C. Still, S. Buntiny, F. A.
Fitzpatrick, Nature 1985, 315, 511–513; c) V. N. Kale, D. L. J.
Clive, J. Org. Chem. 1984, 49, 1554–1563; d) J. Gong, E. Bon-
[18] F.-X. Felpin, J. Lebreton, J. Org. Chem. 2002, 67, 9192–9199.
Received: June 10, 2005
Published Online: August 26, 2005
Eur. J. Org. Chem. 2006, 489–497
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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