Unexpected Mild Protection of Alcohols as 2-O-THF and 2-O-THP Ethers Catalysed by Cp2TiCl Reveal an Intriguing Role of the Solvent in the Single-Electron Transfer Reaction

Article abstract of DOI:10.1002/ejoc.201500869

A method for the conversion of primary, secondary and tertiary alcohols into the corresponding THF ethers at room temperature and primary and secondary alcohols into the corresponding THP ethers, has been developed using titanium(III) species generated from a catalytic amount of titanocene dichloride or (4R,5R)-(-)-2,2-dimethyl-α,α,α′,α′-tetra(1-naphthyl)-1,3-dioxolane-4,5-dimethanolatotitanium(IV) dichloride:acetonitrile adduct together with manganese(0) as a reductant and bromoform in THF or THP as the solvent. A radical mechanism is proposed for this transformation revealing an intriguing role of the solvent in the single-electron transfer reactions catalysed by the low valent Ti^III system. A set of primary, secondary and benzylic alcohols have been converted into the corresponding THF and THP ethers and tertiary alcohols into the corresponding THF ethers using a catalytic amount of titanium dichloride in good yields and mild reaction conditions.

Full text of DOI:10.1002/ejoc.201500869

FULL PAPER
DOI: 10.1002/ejoc.201500869
Unexpected Mild Protection of Alcohols as 2-O-THF and 2-O-THP Ethers
Catalysed by Cp2TiCl Reveal an Intriguing Role of the Solvent in the Single-
Electron Transfer Reaction
María Jesús Durán-Peña,[a] José Manuel Botubol-Ares,[a] James R. Hanson,[b]
Rosario Hernández-Galán,[a] and Isidro G. Collado*[a]
Keywords: Homogeneous catalysis / Titanium / Radical reactions / Alcohols / Protecting groups
A method for the conversion of primary, secondary and terti-
yl)-1,3-dioxolane-4,5-dimethanolatotitanium(IV) dichloride:
ary alcohols into the corresponding THF ethers at room tem- acetonitrile adduct together with manganese(0) as a reduct-
perature and primary and secondary alcohols into the corre- ant and bromoform in THF or THP as the solvent. A radical
sponding THP ethers, has been developed using titanium(III)
species generated from a catalytic amount of titanocene di-
chloride or (4R,5R)-(–)-2,2-dimethyl-α,α,αЈ,αЈ-tetra(1-naphth-
mechanism is proposed for this transformation revealing an
intriguing role of the solvent in the single-electron transfer
reactions catalysed by the low valent TiIII system.
preparation of THF and THP ethers, some of these use
expensive or toxic reagents, elevated temperatures and high
Introduction
The protection of a hydroxyl group is a common step catalyst loadings and a lengthy work-up procedure. In some
in organic chemistry. The tetrahydrofuranyl (THF)[1] and instances the methods are incompatible with particular
tetrahydropyranyl (THP)[2] ethers are very important pro- functional groups.[1,2]
tecting groups in multi-step organic syntheses[2g,3] as well as
During research to develop a cyclopropanation of allylic
in peptide, nucleotide, carbohydrate, terpenoid and steroid alcohols by low-valent titanium, we obtained the THF
chemistry.[4] These ethers are stable to a wide range of rea- ether of geraniol [(Ϯ)-1a] instead of a cyclopropyl deriva-
gents including metal hydrides, metal triflates, Grignard tive, when the reaction was carried out in THF with alkyl
and organolithium reagents, ylides, alkylating and acylating halides other than methylene iodide (Scheme 1).[7] This ob-
reagents as well as strongly alkaline conditions.[2a,5]
servation led us to study the unexpected reaction which has
Furthermore they can be hydrolysed to give the parent proved to be a mild, efficient method for the protection of
alcohol under mildly acidic conditions.[5] A THP ether can a wide variety of alcohols mediated by TiIII species. In this
be converted directly to a range of functional groups.[6] Al- paper we report the first tetrahydrofuranylation and tetra-
though a number of methods have been reported for the hydropyranylation of alcohols catalysed by Cp2TiCl in the
Scheme 1. Preparation of compound (Ϯ)-1a.
[a] Departamento de Química Orgánica, University of Cádiz,
Facultad de Ciencias,
presence of an alkyl halide and tetrahydrofuran or tetra-
hydropyran. This method affords the 2-O-tetrahydrofuranyl
ethers of primary, secondary and tertiary allylic and benz-
ylic alcohols under mild conditions and at room tempera-
ture and the 2-O-tetrahydropyranyl ethers of primary and
secondary allylic and benzylic alcohols.
Polígono Río San Pedro s/n, 11510 Puerto Real, Cádiz, Spain
E-mail: isidro.gonzalez@uca.es
www.isidrogcollado.es
[b] Department of Organic Chemistry, University of Sussex,
Brighton, Sussex, BN1 9QJ, United Kingdom
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500869.
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I. G. Collado et al.
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sponding to the presence of TiIII, a solution of the alcohol
together with the alkyl halide (4 equiv.) was added (red col-
our) and the reaction was stirred for 16 h at room tempera-
ture. It is worth noting the progressive colour change ob-
served in the reaction solution, which turn from red to
green again, confirming the involvement of TiIV/TiIII spe-
cies in the reaction mixture.[9c] It was then quenched with
water and the crude product was purified by column
chromatography. In all cases the reaction proceeded in good
yield when CHBr3 was used as the alkyl halide (Table 2).
Results and Discussion
Bis(cyclopentadienyl)titanium(III) chloride, Cp2TiIIICl,
known as Nugent’s reagent,[8] has become a very popular
reagent in radical reactions because of its soft one-electron
reductive character.[9] This complex is tolerated by a variety
of functional groups.[10] We prepared Cp2TiCl in situ by
stirring a red solution of the commercially available
Cp2TiCl2 (0.2 equiv.) with manganese dust (8 equiv.) in dry
and degassed tetrahydrofuran to give a green solution of the
TiIII complex.[11] Our initial experiments involved stirring a
THF solution of geraniol and Cp2TiIIICl with a series of
alkyl halides at room temperature overnight (Table 1). We
observed that the THF ether of the hydroxyl group was
formed in the presence of alkyl di- and tribromides (entries
3–6, Table 1) but not in the presence of monohalides (en-
tries 1–2, Table 1). The best yields were obtained with
CHBr3 and CH3CHBr2 due to the generation of stable ha-
logenated radicals.
Table 2. Tetrahydrofuranylation of alcohols using
amount of Cp2TiCl2.
a catalytic
Table 1. Tetrahydrofuranylation of geraniol (1) using different alkyl
halides.
Entry
Alkyl halide
Yield [%]
1
2
3
4
5
6
CH3CH2Br
CH3(CH2)4I
CH2Br2
(CH3)2CBr2
CHBr3
n.r.[a]
n.r.[a]
6%[b]
29%[b]
81%[b]
73%[b]
CH3CHBr2
[a] n.r.: no reaction. [b] Determined from the GC chromatogram
of the crude mixture.
It has been reported that Mn0 promotes the protection
of alcohols by THF.[1c] Consequently in order to determine
the role of each component under our conditions, we car-
ried out the reaction in the absence of Ti, with Mn dust,
Rieke Mn,[12] Mn activated by HCl[13] (8 equiv.), with only
TiIII and with both reagents in different amounts. The re-
sults showed that both TiIII and manganese(0) were re-
quired and that the reaction was not mediated by manga-
nese alone.
Furthermore the number of equivalents of both the tita-
nium complex and the manganese were crucial to the suc-
cess of the reaction. The THF ethers were not obtained
in the absence of an alkyl bromide. We concluded that the
optimum conditions involved titanocene dichloride (A)
(0.2 equiv.), manganese dust (8 equiv.) and the alkyl halide
(either CHBr3 or CH3CHBr2, 4 equiv.) in THF at room
temperature for 16 h.
In order to examine the generality of the procedure, the
reaction was carried out with a series of alcohols using both
CHBr3 and CH3CHBr2 (Table 2). The TiIII species was ob-
tained by reduction of the TiIV with the manganese(0) un-
[a] Determined from the GC chromatogram of the crude mixture.
[b] CH3CHBr2. [c] CHBr3. [d] 10 mol-% Cp2TiCl2. [e] Mixture of
diasteroisomers.
A chiral center is created in the THF ether. Consequently
der an argon atmosphere in dry THF. After the reaction in order to study the possible enantioselectivity of the reac-
mixture had turned a characteristic green colour corre- tion and to shed some light on its mechanism, we explored
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Unexpected Mild Cp2TiCl-Catalysed Protection of Alcohols
the use of the chiral titanium complex (B) with CHBr3. This the vacant co-ordination sites are occupied by a THF mol-
complex was easily converted into the TiIII form in situ ecule.[15] It was suggested that the half-open structure D
using manganese dust in dry, degassed tetrahydrofuran. Al- (Scheme 2) with an accessible co-ordination site might be
though the reaction did not proceed with any enantioselec- the an active reagent in solution.[15] Furthermore stereo-
tive,[14] the yield of the THF ethers was almost quantitative chemical investigations on the pinacolization of unsaturated
in all the cases that we examined (Table 3).
aldehydes have suggested that pentavalent co-ordination on
a TiIII complex may be possible.[16]
Table 3. Tetrahydrofuranylation of alcohols using
amount of the chiral titanium complex B.
a
catalytic
In the light of this we propose a mechanism (Scheme 2)
in which the THF and the alcohol are both co-ordinated to
the partially opened dimeric titanium species D which be-
haves as a template. The conversion of the alcohols to the
corresponding THF acetals involves a free radical mecha-
nism catalysed by titanocene. The colour changes (red to
green) confirms the involvement of TiIV (cycle 2 in
Scheme 2) and TiIII in the reaction.[9c]
The proposed mechanism involves coupled cycles in
which the TiIII species is regenerated at various stages by
the excess Mn0 and both a molecule of THF and another
of the corresponding alcohol[7,17] are coordinated in the
half-open structure D affording the E structure. In one of
these (cycle 2, Scheme 2), the TiIII species generates the di-
bromomethane radical from CHBr3. Two of these radicals
then play a major role in the primary cycle (cycle 1,
Scheme 2) in which the acetal is formed. One abstracts a
hydrogen atom from the α-position of a co-ordinated THF
to form dibromomethane and the heteroatom stabilized
radical F. The other dibromomethyl radical abstracts a
hydrogen atom from the titanium-alcohol complex.[7,18]
Combination of this oxygen radical with a THF radical af-
fords the THF ether.
In support of this mechanism dibromomethane and (Ϯ)-
2-(1-bromoethyl)tetrahydrofuran were detected in the reac-
tion mixture by mass spectrometry when CHBr3 and
CH3CHBr2 respectively, were used as alkyl halides. The for-
mation of a 2-bromotetrahydrofuran intermediate in the re-
action mechanism, which had been proposed previous-
ly,[1b,1c] could not be detected by mass spectrometry (MS).
Furthermore treatment of Cp2TiCl and CHBr3 with
2,4,6-collidine and TMSCl in THF as potential TiIV regen-
erating agents, did not yield the expected 4-bromobutyl tri-
methylsilyl ether or 4-bromobutanol.[19] Interestingly when
these reagents were used in the cyclopropanation reaction
with CH2I2 (Scheme 1), the corresponding 4-iodobutyl tri-
methylsilyl ether and 4-iodobutanol were obtained but the
THF ether was not detected.
[a] Determined from the GC chromatogram of the crude mixture.
[b] Mixture of diasteroisomers.
A similar mechanism is postulated for the chiral titanium
complex B. Its greater steric rigidity and lower conforma-
Our results have shown that primary, secondary, tertiary, tional mobility may account for the increase in yield.
allylic and benzylic alcohols can be converted into their The protection of hydroxyl groups as their tetra-
THF ethers at room temperature in good to excellent yield hydropyranyl ethers is another commonly used strategy in
by the complex A, and quantitatively by the complex B. synthesis because of their stability in the presence of strong
Our previous report on the titanium(III) mediated cyclo- bases and nucleophiles along with its ability to be converted
propanation[7] showed that this would only proceed when directly in other functional groups.[2,6] Consequently
THF was used as the solvent revealing the important role Cp2TiCl was generated in dry degassed tetrahydropyran
of the solvent in these reactions.
and tested against a number of alcohols using CHBr3 as
It has been reported that the principal TiIII species which the alkyl halide. The results (Table 4) showed that primary
are formed in THF by the reduction of Cp2TiX2 (X = Cl, alcohols were converted into the corresponding THP ethers
Br, I) involve a mixture of Cp2TiX and (Cp2TiX)2, in which in good yield at room temperature (entries 1–7, Table 4) but
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Scheme 2. Proposed mechanism for the formation of THF ethers.
secondary alcohols (entries 8–10, Table 4) were only con-
verted in moderate yield at 60 °C. Tertiary alcohols did not
react (entries 11–12, Table 4). The formation of the THP
ethers may be explained by a similar mechanism to that
which has been proposed for THF ethers (Scheme 2). To
the best of our knowledge, it has not previously been ob-
tained Cp2TiCl in THP. Poorer access of the THP to the
coordination site of the partially opened dimeric structure
might account for the moderate yield and more limited
scope of the tetrahydropyranylation reaction. The use of the
titanium complex B did not improve the yield.
Table 4. Tetrahydropyranylation of alcohols using a catalytic
amount of Cp2TiCl2.
The difference in the reaction rates of the primary and
secondary alcohols suggested a possible chemoselectivity
which was examined with (Ϯ)-hexane-1,2-diol [(Ϯ)-25]
(Scheme 3). Only the primary alcohol was protected in 87%
yield and no secondary THP ether could be detected. Fur-
ther experiments are in progress to improve the yield and
extend the scope of the tetrahydropyranylation reaction.
Scheme 3. Tetrahydropyranylation of hexane-1,2-diol [(Ϯ)-25].
Conclusions
We have managed to develop a new catalytic method for
the protection of hydroxyl groups as their THF or THP
ethers using Cp2TiIIICl or the reduced form of a chiral tita-
nium complex in THF or THP and CHBr3 or CH3CHBr2
with manganese as a reductant. We have obtained the corre-
sponding THF ethers from primary, secondary, tertiary, all-
ylic and benzylic alcohols under mild conditions in good to
excellent yields. The THP ethers from primary, secondary,
allylic and benzylic alcohols were formed in moderate
[a] Determined from the GC chromatogram of the crude mixture.
[b] The reaction was carried out at 60 °C. [c] Mixture of diasteroiso-
mers. [d] n.r.: no reaction.
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Unexpected Mild Cp2TiCl-Catalysed Protection of Alcohols
5.08 (dd, J = 4.8, 1.2 Hz, 1 H), 3.84 (m, 2 H), 3.61 (m, 1 H), 3.34
(m, 1 H), 2.01–1.79 (m, 4 H), 1.55 (q, J = 7.0 Hz, 2 H), 1.31 (m, 4
H), 0.89 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 103.7, 67.3, 66.7, 32.3, 29.4, 28.3, 23.5, 22.4, 14.0 ppm. HRMS
(CI+): calcd. for C9H19O2 [M + H]+ 159.1385, found 159.1384.
yields. This unexpected reaction has revealed an interesting
participation of the solvent (THF and THP) which may
arise from an efficient co-ordination with the dimeric spe-
cies (Cp2TiCl)2.[15] In addition this reaction would imply
that previously proposed dimeric half-open complex may
be the active reagent in solution to bring the alcohol and
the THF/THP together.[15]
(؎)-2-(Pent-4-en-1-yloxy)tetrahydrofuran [(؎)-4a]: Yellow oil. IR
(film): ν
= 2939, 1641, 1442, 1094, 1040, 917 cm–1. 1H NMR
˜
max
(400 MHz, CDCl3): δ = 5.80 (ddt, J = 17.2, 10.2, 6.8 Hz, 1 H), 5.08
(dd, J = 4.4, 1.6 Hz, 1 H), 4.99 (ddd, J = 17.2, 3.4, 1.6 Hz, 1 H),
4.93 (m, 1 H), 3.85 (m, 2 H), 3.64 (dt, J = 9.6, 6.8 Hz, 1 H), 3.36
(dt, J = 9.6, 6.8 Hz, 1 H), 2.08 (q, J = 6.8 Hz, 2 H), 1.99–1.80 (m,
4 H), 1.65 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.3,
114.6, 103.8, 66.8, 66.5, 32.3, 30.4, 28.9, 23.5 ppm. HRMS (ESI+):
calcd. for C9H16O2Na [M + Na]+ 179.1048, found 179.1050.
Experimental Section
General Experimental Methods: Unless otherwise noted, materials
and reagents were obtained from commercial suppliers and were
used without further purification. Tetrahydrofuran was freshly dis-
tilled from Na and strictly deoxygenated for 30 min under argon
prior to use. Air- and moisture-sensitive reactions were performed
under an argon atmosphere. Purification by semipreparative and
analytical HPLC was performed with a Hitachi/Merck l-6270 appa-
ratus equipped with a differential refractometer detector (RI-7490).
A LiChrospher® Si 60 (5 μm) LiChroCart® (250 mmϫ4 mm)
(؎)-(E)-2-(Pent-2-en-1-yloxy)tetrahydrofuran [(؎)-5a]: Colourless
oil. IR (film): ν
= 2964, 2877, 1671, 1459, 1348, 1185, 1122,
˜
max
1087 cm–1. H NMR (500 MHz, CDCl3): δ = 5.66 (m, 1 H), 5.46
(m, 1 H), 5.07 (dd, J = 3.6, 2.0 Hz, 1 H), 4.04 (m, 1 H), 3.80 (m,
3 H), 1.98–1.92 (m, 3 H), 1.86–1.81 (m, 2 H), 1.78–1.70 (m, 1 H),
0.92 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
135.8, 125.0, 102.8, 67.6, 66.6, 32.1, 25.1, 23.3, 13.1 ppm. HRMS
1
column and
a
LiChrospher® Si 60 (10 μm) LiChroCart®
(250 mmϫ10 mm) were used in isolation experiments. Silica gel
(Merck) was used for column chromatography. TLC was performed
on Merck Kiesegel 60 F254, 0.25 mm thick plates. Melting points
were measured with a Reichert-Jung Kofler block and are uncor-
rected. Enantiomeric excesses (ee) were measured with a GC using
a Cyclosil B chiral column. Optical rotations were determined with
a digital polarimeter. Infrared spectra were recorded on a FT-IR
spectrophotometer and reported as wave number (cm–1). 1H and
13C NMR measurements were recorded on Varian Unity 400 MHz
and Agilent 500 MHz spectrometers with SiMe4 as the internal ref-
(ESI+): calcd. for C9H16O2Na [M
179.1042.
+
Na]+ 179.1048, found
(؎)-2-Phenethoxytetrahydrofuran [(؎)-6a]: Colourless oil. IR
(film): ν
= 3021, 2987, 1620, 926 cm–1. 1H NMR (500 MHz,
˜
max
CDCl3): δ = 7.30–7.18 (m, 5 H), 5.12 (dd, J = 4.0, 2.8 Hz, 1 H),
3.89 (dt, J = 9.7, 7.3 Hz, 1 H), 3.83 (t, J = 7.2 Hz, 2 H), 3.61 (dt,
J = 9.7, 7.3 Hz, 1 H), 2.88 (t, J = 7.2 Hz, 2 H), 2.00–1.96 (m, 1 H),
1.93–1.87 (m, 2 H), 1.85–1.76 (m, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 139.0, 128.8 (2 C), 128.2 (2 C), 126.0, 103.7, 67.8, 66.8,
36.3, 32.3, 23.4 ppm. HRMS (CI+): calcd. for C12H17O2 [M + H]+
193.1229, found 193.1226.
erence. Chemical shifts were referenced to CDCl3 (δH = 7.25, δC
=
77.0). NMR assignments were made using a combination of 1D
and 2D techniques. Multiplicities are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet;
quint = quintuplet; sext = sextuplet; m = multiplet, br. = broad.
High-Resolution Mass Spectroscopy (HRMS) were recorded with
a double-focusing magnetic sector mass spectrometer in positive
ion mode or in a QTOF mass spectrometer in positive ion APCI
mode or in positive ion electrospray mode at 20 V cone voltage.
(؎)-2-(Benzyloxy)tetrahydrofuran [(؎)-7a]: Colourless oil. IR
(film): ν
= 2949, 2882, 1038, 1026, 734, 697 cm–1. 1H NMR
˜
max
(500 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 5.22 (dd, J = 4.0,
2.0 Hz, 1 H), 4.72 (d, J = 12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1
H), 3.92 (m, 2 H), 2.08–1.99 (m, 1 H), 1.97–1.91 (m, 2 H), 1.89–
1.79 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.2, 128.2
(2 C), 127.7 (2 C), 127.3, 102.9, 68.6, 66.8, 32.2, 23.3 ppm. HRMS
(CI+): calcd. for C11H13O2 [M – H]+ 177.0916, found 177.0916.
Preparation of Compound 12: This compound was obtained by
means of the procedure described in the literature and its spectro-
scopic data were identical to those described in the literature.[7,20]
General Procedure for the Protection of Alcohols Mediated by TiIII
(؎)-2-[(4-Fluorobenzyl)oxy]tetrahydrofuran [(؎)-8a]: Colourless oil.
1
IR (film): ν
= 2884, 1604, 1510, 1222, 1085, 1037, 825 cm–1. H
˜
max
:
NMR (400 MHz, CDCl3): δ = 7.31–7.28 (m, 2 H), 7.03–6.98 (m, 2
H), 5.19 (t, J = 3.0 Hz, 1 H), 4.66 (d, J = 11.6 Hz, 1 H), 4.42 (d, J
= 11.6 Hz, 1 H), 3.96–3.86 (m, 2 H), 2.05–1.98 (m, 1 H), 1.96–1.91
(m, 2 H), 1.89–1.80 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 162.2 (d, JC,F = 244 Hz), 134.1, 129.6, 129.5, 115.3, 115.0,
103.1, 68.1, 67.0, 32.3, 23.4 ppm. HRMS (ESI+): calcd. for
C11H13O2F [M]+ 196.0900, found 196.0905.
A mixture of complex A or B (0.13 mmol) and Mn dust (279 mg,
5.12 mmol) in strictly deoxygenated THF or THP (25.4 mL) under
an Ar atmosphere was stirred at room temperature for 15 min. The
solution turned green. Then, a solution of the corresponding
alcohol (0.64 mmol) and the corresponding alkyl halide
(2.56 mmol) in strictly deoxygenated THF or THP (2.5 mL) was
added, and the mixture was stirred for 16 h. The reaction was
quenched with distilled water (20 mL), extracted with ethyl acetate
(3ϫ 50 mL), dried with anhydrous Na2SO4, and evaporated under
reduced pressure. The resulting crude product was purified by col-
umn chromatography on silica gel using mixtures of hexanes and
ethyl acetate as eluent to afford the corresponding tetra-
hydrofuranyl or tetrahydropyranyl ethers.
(؎)-(2R*,1ЈR*)-2-(1-Phenylethoxy)tetrahydrofuran
and
(؎)-
(2R*,1ЈS*)-2-(1-Phenylethoxy)tetrahydrofuran [(؎)-9a and (؎)-9b]:
Diasteroisomer (Ϯ)-9a; Colourless oil: tR = 10.9 min, petroleum
ether/ethyl acetate (90:10), flow: 3.0 mL/min. IR (film): ν
=
˜
max
2974, 1450, 1283, 1019, 759, 699 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.35–7.25 (m, 5 H), 4.96 (dd, J = 4.4, 1.2 Hz, 1 H),
4.78 (q, J = 6.8 Hz, 1 H), 3.95 (ddd, J = 16.0, 8.4, 6.0 Hz, 1 H),
3.85 (m, 1 H), 2.09–2.00 (m, 1 H), 1.92–1.78 (m, 3 H),1.42 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.7, 128.4
(2 C), 127.4, 126.5 (2 C), 101.1, 73.4, 66.8, 32.3, 24.4, 23.5 ppm.
HRMS (CI+): calcd. for C12H15O2 [M – H]+ 191.1072, found
(؎)-(E)-2-[(3,7-Dimethylocta-2,6-dien-1-yl)oxy]tetrahydrofuran
[(؎)-1a]: Spectroscopic data of compound (Ϯ)-1a were identical to
those described in the literature.[7]
(؎)-2-(Pentyloxy)tetrahydrofuran [(؎)-3a]: Colourless oil. IR
1
(film): ν
= 2920, 1262 cm–1. H NMR (500 MHz, CDCl3): δ = 191.1068.
˜
max
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I. G. Collado et al.
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Diasteroisomer (؎)-9b: Colourless oil; tR = 13.0 min, petroleum
HRMS (ESI+): calcd. for C13H18O2Na [M + Na]+ 229.1204, found
229.1194.
ether/ethyl acetate (90:10), flow: 3.0 mL/min. IR (film): ν
=
˜
max
2974, 2883, 1451, 1182, 1086, 1016, 986, 758, 698 cm–1. H NMR
(400 MHz, CDCl3): δ = 7.34–7.29 (m, 4 H), 7.24–7.20 (m, 1 H),
5.34 (dd, J = 4.8, 1.2 Hz, 1 H), 4.73 (q, J = 6.4 Hz, 1 H), 3.71 (m,
2 H), 2.05–1.76 (m, 4 H), 1.43 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.9, 128.2 (2 C), 126.9, 125.8 (2 C),
102.0, 73.5, 66.8, 32.5, 23.4, 22.3 ppm. HRMS (CI+): calcd. for
C12H15O2 [M – H]+ 191.1072, found 191.1063.
1
(؎)-(2R*,1R*)-2-[(3,7-Dimethylocta-1,6-dien-3-yl)oxy]tetrahydro-
furan and (؎)-(2R*,1S*)-2-[(3,7-Dimethylocta-1,6-dien-3-yl)oxy]-
tetrahydrofuran [(؎)-14a and (؎)-14b]: Diastereoisomer (Ϯ)-14a;
Yellow oil: tR = 5.4 min, petroleum ether/ethyl acetate (95:5), flow:
1.0 mL/min. IR (film): ν
= 2968, 2927, 1639, 1452, 1412, 1376,
˜
max
1112 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.79 (dd, J = 10.8,
17.2 Hz, 1 H), 5.28 (dd, J = 5.0, 2.0 Hz, 1 H), 5.15–5.06 (m, 3 H),
3.92 (dt, J = 7.6, 6.4 Hz, 1 H), 3.77 (dt, J = 7.6, 6.4 Hz, 1 H), 2.00–
1.93 (m, 4 H), 1.91–1.73 (m, 3 H), 1.66 (s, 3 H), 1.58 (s, 3 H), 1.55–
1.49 (m, 1 H), 1.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 143.4, 131.2, 124.6, 114.2, 99.2, 78.1, 66.7, 41.6, 33.3, 25.7, 23.9,
23.1, 22.4, 17.6 ppm. HRMS (CI+): calcd. for C14H25O2 [M + H]+
225.1855, found 225.1848.
(2R*,2ЈR)-2-(pent-4-en-2-yloxy)tetrahydrofuran and (2S*,2ЈR)-2-
(Pent-4-en-2-yloxy)tetrahydrofuran (10a and 10b): Mixture of di-
asteroisomers. Colourless oil. IR (film): ν
= 3075, 2971, 2930,
˜
max
1035, 916 cm–1. H NMR (400 MHz, CDCl3): δ = 5.83–5.71 (m, 2
H), 5.22–4.98 (m, 4 H), 3.90–3.69 (m, 6 H), 2.30–2.22 (m, 2 H),
2.17–2.09 (m, 2 H), 2.00–1.77 (m, 8 H), 1.14 (d, J = 6.4 Hz, 3 H),
1.09 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
135.4, 135.0, 116.8, 116.4, 103.0, 101.3, 72.5, 71.0, 66.6, 66.5, 41.9,
40.8, 32.5, 32.4, 23.4 (2 C), 21.3, 19.1 ppm. HRMS (ESI+): calcd.
for C9H16O2Na [M + Na]+ 179.1048, found 179.1051.
1
Diasteroisomer (؎)-14b: Yellow oil: tR = 6.5 min, petroleum ether/
ethyl acetate (95:5), flow: 1.0 mL/min. IR (film): νmax = 2968, 2927,
˜
1639, 1452, 1412, 1376, 1112 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.92 (dd, J = 17.6, 10.4 Hz, 1 H), 5.31 (dd, J = 5.0, 1.7 Hz, 1
H), 5.15–5.07 (m, 3 H), 3.93 (m, 1 H), 3.77 (m, 1 H), 2.00–1.93 (m,
4 H), 1.91–1.73 (m, 3 H), 1.67 (s, 3 H), 1.59 (s, 3 H), 1.55–1.49 (m,
1 H), 1.26 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.0,
131.2, 124.7, 113.4, 99.0, 77.8, 66.8, 40.1, 33.5, 25.7, 23.9, 23.2,
22.5, 17.6 ppm. HRMS (CI+): calcd. for C14H25O2 [M + H]+
225.1855, found 225.1853.
(2R*,2ЈR)-(Octan-2-yloxy)tetrahydropyran and (2S*,2ЈR)-(Octan-2-
yloxy)tetrahydrofuran (11a and 11b): Diasteroisomer 11a; Colour-
less oil: tR = 13.7 min, petroleum ether/ethyl acetate (100:0), flow:
3.0 mL/min. [α]2D0 = +3.8 (c = 0.8, MeOH). IR (film): ν
= 2924,
˜
max
2854, 1458, 1034 cm–1. H NMR (400 MHz, CDCl3): δ = 5.20 (d,
J = 4.4, 1.6 Hz, 1 H), 3.89 (dt, J = 7.6, 5.6 Hz, 1 H), 3.82 (dt, J =
7.6, 5.2 Hz, 1 H), 3.63 (sext, J = 6.0 Hz, 1 H), 2.02–1.74 (m, 3 H),
1.48 (m, 1 H), 1.38–1.23 (m, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 0.87
(t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 103.4,
73.7, 66.5, 36.7, 32.5, 31.8, 29.4, 25.6, 23.5, 22.6, 21.7, 14.1 ppm.
HRMS (CI+): calcd. for C12H25O2 [M + H]+ 201.1855, found
201.1848.
1
(؎)-(E)-2-[(3,7-Dimethylocta-2,6-dien-1-yl)oxy]tetrahydropyran
[(؎)-15a]: Spectroscopic data of compound (Ϯ)-15a were identical
to those described in the literature.[21]
(؎)-2-(Pentyloxy)tetrahydropyran [(؎)-16a]: Colourless oil. IR
1
(film): ν
= 2929, 903, 745 cm–1. H NMR (500 MHz, CDCl3): δ
˜
max
= 4.56 (dd, J = 6.5, 5.5 Hz, 1 H), 3.86 (ddd, J = 11.2, 7.6, 3.4 Hz,
1 H), 3.73 (dt, J = 9.6, 6.9 Hz, 1 H), 3.49 (m, 1 H), 3.37 (dt, J =
9.6, 6.9 Hz, 1 H), 1.86–1.79 (m, 1 H), 1.74–1.68 (m, 1 H), 1.62–
1.49 (m, 4 H), 1.35–1.24 (m, 6 H), 0.88 (m, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 98.8, 67.7, 62.3, 30.8, 29.4, 28.4, 25.5, 22.6,
19.7, 14.1 ppm. HRMS (ESI+): calcd. for C10H20O2Na [M + Na]+
195.1361, found 195.1371.
Diasteroisomer 11b: Colourless oil: tR = 14.8 min, petroleum ether/
ethyl acetate (100:0), flow: 3.0 mL/min. IR (film): ν
= 2924,
˜
max
2854, 1458, 1034 cm–1. H NMR (500 MHz, CDCl3): δ = 5.21 (br.
d, J = 4.0 Hz, 1 H), 3.84 (m, 2 H), 3.69 (m, 1 H), 2.03–1.92 (m, 1
H), 1.91–1.76 (m, 3 H), 1.46 (m, 1 H), 1.36–1.24 (m, 9 H), 1.08 (d, J
= 6.0 Hz, 3 H), 0.86 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 100.8, 71.0, 66.6, 37.5, 32.5, 31.9, 29.2, 25.7, 23.5,
22.6, 19.4, 14.0 ppm. HRMS (CI+): calcd. for C12H25O2 [M + H]+
201.1855, found 201.1848.
1
(؎)-2-(Pent-4-en-1-yloxy)tetrahydropyran [(؎)-17a]: Colourless oil.
IR (film): ν
= 2934, 2887, 1671, 1452, 1350, 1185, 1122,
˜
max
1027 cm–1. H NMR (500 MHz, CDCl3): δ = 5.82 (ddt, J = 16.8,
10.0, 6.6 Hz, 1 H), 5.02 (ddd, J = 16.8, 4.0, 1.5 Hz, 1 H), 4.95 (m,
1 H), 4.57 (dd, J = 4.3, 2.8 Hz, 1 H), 3.86 (ddd, J = 11.3, 7.9,
3.3 Hz, 1 H), 3.74 (dt, J = 9.6, 6.6 Hz, 1 H), 3.49 (m, 1 H), 3.39
(dt, J = 9.6, 6.6 Hz, 1 H), 2.13 (m, 2 H), 1.86–1.80 (m, 1 H), 1.74–
1.67 (m, 3 H), 1.60–1.50 (m, 4 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 138.4, 114.6, 98.8, 66.9, 62.3, 30.7, 30.4, 28.9, 25.5,
19.6 ppm. HRMS (ESI+): calcd. for C10H18O2Na [M + Na]+
193.1204, found 193.1205.
1
(2R*)-2-{[(1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl]-
oxy}tetrahydrofuran and (2S*)-2-{[(1R,5R)-2-Methyl-5-(prop-1-en-
2-yl)cyclohex-2-en-1-yl]oxy}tetrahydrofuran (12a and 12b): Mixture
of diasteroisomers. Colourless oil: IR (film): ν
= 2968, 2942,
˜
max
2918, 2884, 1645, 1453, 1084, 1032 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 5.52–5.47 (m, 2 H), 5.28 (dd, J = 3.6, 2.4 Hz, 1 H),
5.26 (dd, J = 4.0, 2.4 Hz, 1 H), 4.70 (br. s, 4 H), 4.25 (m, 1 H),
4.08 (m, 1 H), 3.95–3.82 (m, 4 H), 2.24–2.19 (m, 6 H), 2.06–1.80
(m, 10 H), 1.70 (s, 6 H), 1.67 (s, 6 H), 1.52–1.34 (m, 2 H) ppm. 13
C
(؎)-(E)-2-(Pent-2-en-1-yloxy)tetrahydropyran [(؎)-18a]: Colourless
NMR (100 MHz, CDCl3): δ = 149.1 (2 C), 135.3, 135.2, 124.5,
124.4, 109.0, 108.9, 105.5, 100.5, 77.4, 73.3, 66.8, 66.6, 40.8, 40.6,
36.8, 34.0, 32.55, 32.53, 30.9, 30.8, 23.44, 23.36, 20.4 (2 C), 19.3,
19.2 ppm. HRMS (ESI+): calcd. for C14H22O2Na [M + Na]+
245.1517, found 245.1523.
oil. IR (film): ν
= 2931, 2886, 1671, 1454, 1352, 1208, 1121,
˜
max
1
1024 cm–1. H NMR (400 MHz, CDCl3): δ = 5.75 (m, 1 H), 5.56
(m, 1 H), 4.63 (t, J = 3.6 Hz, 1 H), 4.18 (dd, J = 11.6, 6.0 Hz, 1
H), 3.89 (m, 2 H), 3.49 (m, 1 H), 2.06 (quint, J = 7.2 Hz, 2 H),
1.88–1.79 (m, 1 H), 1.75–1.68 (m, 1 H), 1.62–1.50 (m, 4 H), 0.99
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.2,
125.0, 97.8, 67.9, 62.2, 30.7, 25.5, 25.3, 19.6, 13.3 ppm. HRMS
(ESI+): calcd. for C10H18O2Na [M + Na]+ 193.1204, found
193.1199.
(؎)-2-[(2-Phenylpropan-2-yl)oxy]tetrahydrofuran [(؎)-13a]: Yellow
oil. IR (film): ν
= 2978, 1161, 1068, 1037, 1012, 993, 764,
˜
max
700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.41 (m, 2 H), 7.31
(m, 2 H), 7.21 (m, 1 H), 5.09 (dd, J = 4.4, 2.8 Hz, 1 H), 3.92 (dt,
J = 7.8, 6.8 Hz, 1 H), 3.74 (dt, J = 7.8, 5.6 Hz, 1 H), 2.06–1.96 (m,
1 H), 1.88–1.83 (m, 2 H), 1.80–1.67 (m, 1 H), 1.65 (s, 3 H), 1.49 (s, (؎)-2-Phenethoxytetrahydropyran [(؎)-19a]: Spectroscopic data of
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.3, 128.1 (2 C), compound (Ϯ)-19a were identical to those described in the litera-
126.7, 125.7 (2 C), 99.9, 77.3, 66.8, 33.3, 31.5, 27.4, 23.8 ppm. ture.[2a]
6338
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6333–6340

Unexpected Mild Cp2TiCl-Catalysed Protection of Alcohols
(؎)-2-(Benzyloxy)tetrahydropyran [(؎)-20a]: Spectroscopic data of
compound (Ϯ)-20a were identical to those described in the litera-
ture.[2a]
2.0 Hz, 1 H), 3.94–3.89 (m, 1 H), 3.78–3.74, (m, 1 H), 3.64 (dd, J
= 10.5, 2.0 Hz, 1 H), 3.56–3.52 (m, 1 H), 3.50 (dd, J = 10.5, 8.0 Hz,
1 H), 3.14 (d, J = 2.0 Hz, OH), 1.86–1.81 (m, 1 H), 1.78–1.74 (m,
1 H), 1.61–1.51 (m, 4 H), 1.47–1.30 (m, 6 H), 0.90 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 100.1, 74.1, 70.6,
63.2, 32.7, 30.8, 27.7, 25.2, 22.7, 20.0, 14.0 ppm. HRMS (ESI+):
calcd. for C11H22O3Na [M + Na]+ 225.1461, found 225.1459.
(؎)-2-[(4-Fluorobenzyl)oxy]tetrahydropyran [(؎)-21a]: Colourless
oil. IR (film): ν
= 2929, 2886, 1606, 1510, 1226, 1104, 1025,
˜
max
827 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.31 (m, 2 H),
7.05–6.99 (m, 2 H), 4.74 (d, J = 12.0 Hz, 1 H), 4.68 (t, J = 3.6 Hz,
1 H), 4.46 (d, J = 12.0 Hz, 1 H), 3.90 (ddd, J = 11.6, 8.2, 3.4 Hz,
1 H), 3.54 (m, 1 H), 1.90–1.80 (m, 1 H), 1.77–1.69 (m, 1 H), 1.67–
1.52 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.3 (d,
JC,F = 244 Hz), 134.0, 129.6, 129.5, 115.3, 115.1, 97.7, 68.1, 62.2,
30.5, 25.4, 19.4 ppm. HRMS (ESI+): calcd. for C12H15O2 FNa [M
+ Na]+ 233.0954, found 233.0947.
Diasteroisomer (؎)-25b: Colourless oil; tR = 19 min, petroleum
ether/ethyl acetate (90:10), flow: 3.0 mL/min. [α]2D0 = 4.5 (c = 0.1,
CDCl3). IR (film): ν˜max = 3408, 2931, 2886, 1454, 1221, 1104 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.56 (dd, J = 5.0, 2.0 Hz, 1 H),
3.92–3.86 (m, 1 H), 3.77–3.74, (m, 2 H), 3.53–3.49 (m, 1 H), 3.32
(t, J = 9.5 Hz, 1 H), 2.60 (s, OH), 1.85–1.72 (m, 2 H), 1.59–1.31
(m, 10 H), 0.90 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 100.1, 73.0, 70.6, 63.0, 32.9, 30.7, 27.7, 25.3, 22.7,
19.9, 14.0 ppm. HRMS (ESI+): calcd. for C11H22O3Na [M + Na]+
225.1461, found 225.1465.
(؎)-(2R*,1ЈR*)-2-(1-Phenylethoxy)tetrahydropyran and (؎)-
(2R*,1ЈS*)-2-(1-Phenylethoxy)tetrahydropyran [(؎)-22a and (؎)-
22b]: Spectroscopic data of compound (Ϯ)-22a and (Ϯ)-22b were
identical to those described in the literature.[2a]
(2R*,2ЈR)-2-(Pent-4-en-2-yloxy)tetrahydropyran and (2S*,2ЈR)-2-
(Pent-4-en-2-yloxy)tetrahydropyran (23a and 23b): Diasteroisomer
23a; Colourless oil: tR = 28 min, petroleum ether/ethyl acetate
(90:10), flow: 3.0 mL/min. [α]2D0 = –6.9 (c = 0.1, CDCl3). IR (film):
Acknowledgments
This research was supported by grant from Junta de Andalucia
(P07-FQM-02925) and in part from Ministerio de Economía y
Competitividad (MINECO) (AGL2012-39798-C02-01). Use of
NMR facilities at the Servicio Centralizado de Ciencia y Tecnol-
ogía (SCCYT) of the University of Cádiz is acknowledged.
ν
= 2931, 2886, 1454, 1204, 1121 cm–1. 1H NMR (500 MHz,
˜
max
CDCl3): δ = 5.85 (ddt, J = 17.2, 10.2, 7.1 Hz, 1 H), 5.08 (ddt, J =
17.2, 2.2, 1.5 Hz, 1 H), 5.03 (ddt, J = 10.0, 2.2, 1.5 Hz, 1 H), 4.71
(t, J = 3.5 Hz, 1 H), 3.90 (ddd, J = 11.2, 7.8, 3.4 Hz, 1 H), 3.84
(sext, J = 6.2 Hz, 1 H), 3.48 (m, 1 H), 2.38 (m, 1 H), 2.22 (m, 1
H), 1.85–1.78 (m, 1 H), 1.73–1.68 (m, 1 H), 1.58–1.49 (m, 4 H),
1.11 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
135.4, 116.7, 95.9, 70.9, 62.4, 42.0, 31.2, 25.6, 19.7, 18.8 ppm.
HRMS (ESI+): calcd. for C10H18O2Na [M + Na]+ 193.1204, found
193.1200.
[1] a) D. B. G. Williams, S. B. Simelane, M. Lawton, H. H. Kinfe,
Tetrahedron 2010, 66, 4573–4576; b) B. Das, M. Krishnaiah,
V. S. Reddy, K. Laxminarayana, Helv. Chim. Acta 2007, 90,
2163–2166; c) J. R. Falck, D. R. Li, R. Bejot, C. Mioskowski,
Tetrahedron Lett. 2006, 47, 5111–5113; d) M. Ochiai, T. Sueda,
Tetrahedron Lett. 2004, 45, 3557–3559; e) H. Nagano, T. Kat-
suki, Chem. Lett. 2002, 782–783; f) B. Yu, Y. Hui, Synth. Com-
mun. 1995, 25, 2037–2042; g) J. C. Jung, H. C. Choid, Y. H.
Kim, Tetrahedron Lett. 1993, 34, 3581–3584; h) A. M. Maione,
A. Romeo, Synthesis 1987, 250–251; i) C. G. Kruse, E. K.
Poels, F. L. Jonkers, A. van der Gen, J. Org. Chem. 1978, 43,
3548–3553; j) C. G. Kruse, N. L. J. M. Broekhof, A.
Van der Gen, Tetrahedron Lett. 1976, 17, 1725–1728; k) G. Sos-
novsky, Tetrahedron 1961, 13, 241–246; l) G. Sosnovsky, J. Org.
Chem. 1960, 25, 874.
[2] a) B. Kumar, M. A. Aga, D. Mukherjee, S. S. Chimni, S. C.
Taneja, Tetrahedron Lett. 2009, 50, 6236–6240; b) M. Kotke,
P. R. Schreiner, Synthesis 2007, 779–790; c) A. T. Khan, T. Par-
vin, L. H. Choudhury, Synthesis 2006, 2497–2502; d) G. Bar-
toli, R. Giovannini, A. Giuliani, E. Marcantoni, M. Massac-
cesi, P. Melchiorre, M. Paoletti, L. Sambri, Eur. J. Org. Chem.
2006, 1476–1482; e) K. Nagaiah, B. V. S. Reddy, D. Sreenu,
A. V. Narsaiah, ARKIVOC (Gainesville, FL, U.S.) 2005, 192–
199; f) J. R. Stephens, P. L. Butler, C. H. Clow, M. C. Oswald,
R. C. Smith, R. S. Mohan, Eur. J. Org. Chem. 2003, 3827–3831;
g) B. Karimi, J. Maleki, Tetrahedron Lett. 2002, 43, 5353–5355;
h) N. Rezai, F. A. Meybodi, P. Salehi, Synth. Commun. 2000,
30, 1799; i) B. C. Ranu, M. Saha, J. Org. Chem. 1994, 59, 8269.
[3] a) S. Holer, P. Laszol, Synthesis 1986, 655–657; b) T. Kametani,
K. Kigasawa, M. Hiiragi, K. Wakisaka, O. Kusama, H. Sugi,
K. Kawasaki, Heterocycles 1977, 6, 529–33.
Diasteroisomer 23b: Colourless oil; tR = 29 min, petroleum ether/
ethyl acetate (90:10), flow: 3.0 mL/min. [α]2D0 = –2.8 (c = 0.1,
CDCl ). IR (film): ν
= 2934, 2885, 1462, 1208, 1108 cm–1. 1H
˜
3
max
NMR (500 MHz, CDCl3): δ = 5.78 (ddt, J = 17.5, 10.5, 7.0 Hz, 1
H), 5.06–5.01 (m, 2 H), 4.66 (t, J = 3.0 Hz, 1 H), 3.90 (m, 1 H),
3.81 (sext, J = 6.5 Hz, 1 H), 3.51 (m, 1 H), 2.37 (m, 1 H), 2.18 (m,
1 H), 1.85–1.78 (m, 1 H), 1.73–1.65 (m, 1 H), 1.54–1.48 (m, 4 H),
1.21 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
134.9, 116.9, 98.0, 72.6, 62.8, 40.7, 31.0, 25.5, 21.2, 20.0 ppm.
HRMS (ESI+): calcd. for C10H18O2Na [M + Na]+ 193.1204, found
193.1198.
(2R*,2ЈR)-(Octan-2-yloxy)tetrahydropyran and (2S*,2ЈR)-(Octan-2-
yloxy)tetrahydropyran (24a and 24b): Mixture of diasteroisomers;
colourless oil. IR (film): ν
= 2936, 2897, 1022, 912 cm–1. 1H
˜
max
NMR (500 MHz, CDCl3): δ = 4.70 (t, J = 4.5 Hz, 1 H), 4.62 (m,
1 H), 3.94–3.86 (m, 2 H), 3.75 (sext, J = 6.4 Hz, 1 H), 3.70 (sext,
J = 6.4 Hz, 1 H), 3.48 (m, 2 H), 1.86–1.78 (m, 2 H), 1.73–1.66 (m,
2 H), 1.59–1.49 (m, 10 H), 1.31–1.25 (m, 18 H), 1.20 (d, J = 8.0 Hz,
3 H), 1.09 (d, J = 7.5 Hz, 3 H), 0.87 (t, J = 8.5 Hz, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 98.6, 95.6, 73.9, 71.2, 62.9, 62.4,
37.6, 36.5, 31.8 (2 C), 31.4, 31.2, 29.43, 29.40, 25.8, 25.6, 25.5, 25.4,
22.65, 22.62, 21.6, 20.1, 19.7, 19.1, 14.09, 14.08 ppm. HRMS
(ESI+): calcd. for C13H26O2Na [M + Na]+ 237.1830, found
237.1843.
[4] V. Amarnath, A. D. Broom, Chem. Rev. 1977, 77, 183–217.
[5] J. M. Barks, B. C. Gilbert, A. F. Parsons, B. Upeandran, Tetra-
hedron Lett. 2000, 41, 6249–6252.
[6] a) H. Firouzabadi, N. Iranpoor, H. Hazarkhani, Tetrahedron
Lett. 2002, 43, 7139–7141; b) S. Chandrrasekhar, T. Ramach-
andar, M. V. Reddy, M. Takhi, J. Org. Chem. 2000, 65, 4729–
4738; c) M. M. Heravi, H. A. Oskooie, M. Ghassemzadeh, F. F.
Zameni, Monatsh. Chem. 1999, 130, 1253–1256; d) A. Tanaka,
T. Oritani, Tetrahedron Lett. 1997, 38, 1995–1998; e) T. Sato,
(؎)-(S*)-1-[(S*)-Tetrahydro-2H-pyran-2-yl]oxyhexan-2-ol and (؎)-
(S*)-1-[(R*)-Tetrahydro-2H-pyran-2-yl]oxyhexan-2-ol [(؎)-25a] and
[(؎)-25b]: Diasteroisomer (Ϯ)-25a; Colourless oil; tR = 17 min, pe-
troleum ether/ethyl acetate (90:10), flow: 3.0 mL/min. [α]2D0 = +7.1
(c = 0.1, CDCl ). IR (film): ν
= 3406, 2929, 1454, 1204,
˜
3
max
1121 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.57 (dd, J = 5.0,
Eur. J. Org. Chem. 2015, 6333–6340
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6339

I. G. Collado et al.
FULL PAPER
J. Otera, H. Nozaki, J. Org. Chem. 1990, 55, 4770–4772; f) S.
Kim, W. J. Lee, Synth. Commun. 1986, 16, 659–665.
[7] M. J. Duran-Peña, J. M. Botubol-Ares, J. R. Hanson, R. Her-
nandez-Galan, I. G. Collado, Org. Biomol. Chem. 2015, 13,
6325–6332.
[8] For pioneering reports on the use of this reagent, see: T. V.
RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986–
997, and references cited therein.
[9] a) A. Gansäuer, S. Hildebrandt, A. Michelmann, T. Dahmen,
D. von Laufenberg, C. Kube, G. D. Fianu, R. A. Flowers, An-
gew. Chem. Int. Ed. 2015, 54, 7003–7006; b) A. Gansäuer, C.
Kube, K. Daasbjerg, R. Sure, S. Grimme, G. D. Fianu, D. V.
Sadasivam, R. A. Flowers, J. Am. Chem. Soc. 2014, 136, 1663–
1671; c) H. R. Dieguez, A. Lopez, V. Domingo, J. F. Arteaga,
J. A. Dobado, M. M. Herrador, J. F. Quilez del Moral, A. F.
Barrero, J. Am. Chem. Soc. 2010, 132, 254–259.
[12]
[13]
[14]
[15]
S.-H. Kim, M. V. Hanson, R. D. Rieke, Tetrahedron Lett. 1996,
37, 2197–2200.
S. Yamamura, M. Toda, Y. Hirata, Org. Synth. 1973, 53, 86–
89.
Diasteroisomeric excesses were determined by GC on a chiral-
phase column.
a) A. Gansäuer, A. Barchuk, F. Keller, M. Schmitt, S. Grimme,
M. Gerenkamp, C. Mück-Lichtenfeld, K. Daasbjerg, H. Svith,
J. Am. Chem. Soc. 2007, 129, 1359–1371; b) K. Daasbjerg, H.
Svith, S. Grimme, M. Gerenkamp, C. Mück-Lichtenfeld, A.
Gansäuer, A. Barchuk, F. Keller, Angew. Chem. Int. Ed. 2006,
45, 2041–2044; Angew. Chem. 2006, 118, 2095.
a) M. S. Dunlap, K. M. Nicholas, J. Organomet. Chem. 2001,
630, 125–131; b) Y. Handa, J. Inanaga, Tetrahedron Lett. 1987,
28, 5717–5718.
[16]
[10] a) A. Rosales, I. Rodriguez-Garcia, J. Muñoz-Bascon, E. Rol-
dan-Molina, N. M. Padial, L. P. Morales, M. Garcia-Ocaña,
J. E. Oltra, Eur. J. Org. Chem., DOI: 10.1002/ejoc.201500292;
b) S. P. Morcillo, D. Miguel, A. G. Campaña, L. Álvarez de Ci-
enfuegos, J. Justicia, J. M. Cuerva, Org. Chem. Front. 2014, 1,
15–33, and references included therein; c) A. Gansäuer, J. Jus-
ticia, C.-A. Fan, D. Worgull, F. Piestert, Top. Curr. Chem. 2007,
279, 25–52; d) J. M. Cuerva, J. Justicia, J. L. Oller-Lopez, J. E.
Oltra, Top. Curr. Chem. 2006, 264, 63–91; e) A. Gansäuer, H.
Bluhm, Chem. Rev. 2000, 100, 2771–2788.
[11] a) A. F. Barrero, M. M. Herrador, J. F. Quilez del Moral, P. Ar-
teaga, M. Akssira, F. El Hanbali, J. F. Arteaga, H. R. Dieguez,
E. M. Sanchez, J. Org. Chem. 2007, 72, 2251–2254; b) A. Gan-
säuer, H. Bluhm, M. Pierobon, J. Am. Chem. Soc. 1998, 120,
12849–12859.
[17] R. J. Enemærke, J. Larsen, T. Skrydstrup, K. Daasbjerg, Orga-
nometallics 2004, 23, 1866–1874.
[18] M. Paradas, A. G. Campaña, T. Jiménez, R. Robles, J. E. Oltra,
E. Buñuel, J. Justicia, D. J. Cárdenas, J. M. Cuervas, J. Am.
Chem. Soc. 2010, 132, 12748–12756.
[19] J. Ohshita, A. Iwata, F. Kanetani, A. Kunai, Y. Yamamoto, C.
Matui, J. Org. Chem. 1999, 64, 8024–8026.
[20] R. F. Valeev, N. S. Vostrikov, M. S. Miftakhov, Russ. J. Org.
Chem. 2010, 46, 670–673.
[21] a) K.-H. Teng, Anal. Biochem. 2011, 417, 136–141; b) B.
Chappe, Bull. Chem. Soc. Jpn. 1988, 61, 141–148; c) A. Bong-
ini, Synthesis 1979, 8, 618–620.
Received: July 1, 2015
Published Online: August 20, 2015
6340
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