Radical reduction of epoxides using a titanocene(III)/water system: Synthesis of β-deuterated alcohols and their use as internal standards in food analysis

Article abstract of DOI:10.1002/ejoc.201000487

We describe a comprehensive study into the Cp₂TiCl-mediated reductive epoxide ring opening using either water as a hydrogen source or deuterium oxide as a deuterium source. The remarkable chemical profile of this reaction allows access to alcohols with anti-Markovnikov regiochemistry from different epoxides. The use of D₂O as a deuterium source leads to an efficient synthesis of β-deuterated alcohols, including a deuterated sample of tyrosol, a bioactive compound contained in the leaves of the olive, which was successfully applied as an internal standard in food analysis.

Full text of DOI:10.1002/ejoc.201000487

FULL PAPER
DOI: 10.1002/ejoc.201000487
Radical Reduction of Epoxides Using a Titanocene(III)/Water System:
Synthesis of β-Deuterated Alcohols and Their Use as Internal Standards in
Food Analysis
Tania Jiménez,[a] Araceli G. Campaña,[a] Btissam Bazdi,[a] Miguel Paradas,[a]
David Arráez-Román,[b] Antonio Segura-Carretero,[b] Alberto Fernández-Gutiérrez,[b]
J. Enrique Oltra,[a] Rafael Robles,[a] José Justicia,*[a] and Juan M. Cuerva*[a]
Keywords: Titanium / Water chemistry / Radicals / Reduction / Natural products
We describe a comprehensive study into the Cp2TiCl-medi-
ated reductive epoxide ring opening using either water as a
hydrogen source or deuterium oxide as a deuterium source.
The remarkable chemical profile of this reaction allows ac-
cess to alcohols with anti-Markovnikov regiochemistry from
different epoxides. The use of D2O as a deuterium source
leads to an efficient synthesis of β-deuterated alcohols, in-
cluding a deuterated sample of tyrosol, a bioactive com-
pound contained in the leaves of the olive, which was suc-
cessfully applied as an internal standard in food analysis.
Introduction
In the early 1990s, RajanBabu and Nugent described the
synthesis of alcohols from epoxides mediated by a titani-
um(III) complex (Cp2TiCl) in the presence of 1,4-cyclo-
hexadiene (1,4-CHD), a common hydrogen-atom donor.[1]
This protocol usually yields less-substituted alcohols under
mild reaction conditions (Scheme 1, path a).[1,2] Neverthe-
less, their reported yields ranged from excellent (95%) to
poor (6%), depending upon the substitution pattern of the
starting epoxides, which tended to limit the synthetic viabil-
ity of this procedure. In the reduction reaction of monosub-
stituted epoxides the deoxygenating side reaction generally
becomes the preferred pathway (Scheme 1, path b). An-
other limitation of this transformation is the toxic, expens-
ive, and/or foul-smelling nature of the hydrogen-atom do-
nor used, such as 1,4-CHD, Bu3SnH, or tert-butyl thiol.
Although the reaction was improved by Gansäuer et al.,[2]
its main drawbacks remain.
Scheme 1. Radical epoxide opening mediated by Cp2TiCl.
the real hydrogen-atom donors. This idea is supported by
theoretical calculations,[3] and Newcomb et al. have deter-
mined a rate constant of 1.0ϫ105 –1 s–1 for the reduction
of secondary radicals by titanocene(III)/water mixtures[4a]
that is only one order of magnitude lower than that corre-
sponding to HSnBu3 (k = 1.4ϫ106 –1 s–1).[4b]
The use of water as a safe, inexpensive alternative to con-
ventional hydrogen-atom donors in this transformation en-
tails advantages from both practical and economic points
of view. It is also worth noting that the use of deuterium
oxide, a relatively inexpensive, commercially available deute-
rium source,[5] affords β-deuterated alcohols, which are not
easily obtained by other methods, in a very simple and
straightforward way.[6]
Additionally, the use of water can also overcome the for-
mation of undesired deoxygenated compounds. The forma-
tion of these byproducts is commonly related to the pres-
ence of bimetallic species I in the reaction medium
(Scheme 1), which are derived from a heterocoupling radi-
cal process between carbon-centered radical II and
Cp2TiCl. This process can, therefore, be avoided by lower-
We reported in a recent publication that water, a ubiqui-
tous source of hydrogen atoms, can transfer hydrogen atoms
to carbon-centered radicals in the presence of titano-
cene(III) complexes.[3] To explain this process, we assume
that (aqua)titanocene(III) complexes, generated in situ, are
[a] Department of Organic Chemistry, Faculty of Sciences,
University of Granada,
C. U. Fuentenueva s/n, 18071 Granada, Spain
Fax: +34-958-248437
E-mail: jjusti@ugr.es
jmcuerva@ugr.es
[b] Department of Analytical Chemistry, Faculty of Sciences,
University of Granada,
C. U. Fuentenueva s/n, 18071 Granada, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000487.
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Radical Reduction of Epoxides Using a Titanocene(III)/Water System
ing the concentration of free Cp2TiCl and by increasing the from a deoxygenation reaction.[10] A 75% yield of alcohol
concentration of the hydrogen-atom-transfer (HAT) rea- 3 could be obtained on the other hand under our aqueous
gent. Within this context, we have recently reported that conditions by using an optimized mixture of Cp2TiCl2
titanocene(III) reacts almost quantitatively with water to (2.5 equiv.), Mn dust (8 equiv.), and water (10 equiv.;
form an aqua complex, which consequently decreases the Scheme 3).[11] It is worth noting that under these new condi-
concentration of free Cp2TiCl.[3]
tions alkene 4 was not detected. These results support the
In view of all these precedents we have focused our study idea that our procedure is safer, cheaper, and more efficient
upon the remarkable capacity of titanocene(III)/water mix- than that of RajanBabu and Nugent[1] for this kind of sub-
tures to synthesize alcohols by the reductive radical opening strate and thus overcomes some of their main drawbacks.
of epoxides. We also describe an easy, efficient synthesis of Epoxide 2 can also be deuterated with our protocol by
β-deuterated alcohols by using D2O as a deuterium-atom using deuterium oxide instead of water. Both the yield
source. These deuterated derivatives, which present almost (72%) and incorporation of deuterium (76%) obtained
the same physical and chemical properties as their non-deu- indicate that this process represents an efficient way of pre-
terated analogues, have many potential applications. For ex- paring β-deuterated alcohols.
ample, they are used as internal standards in the analysis
of complex mixtures, which is of great interest to the food
and pharmaceutical industries.[7] They are also used in the
study of mechanisms, kinetics, and metabolic routes in
chemistry and biochemistry.[8] Therefore, the development
of simple and efficient methods to introduce deuterium
atoms into organic molecules is an important goal in or-
ganic synthesis.[8]
Olive leaves have traditionally been used as a folk remedy
for combating fevers and other diseases such as malaria and
thus the characterization, biosynthesis, and biotransforma-
tion of phenolic and other polar compounds from the leaves
Scheme 3. Study of the reductive opening of 2 by using H2O, D2O,
or 1,4-cyclohexadiene (1,4-CHD) as hydrogen-/deuterium-atom
and fruit of the olive tree is of considerable interest nowa-
days in research into natural plant profiles. With this in
mind, we also report on an initial study into the use of a
sources.
With this valuable information in our hands we prepared
β-deuterated alcohol, synthesized according to the method epoxides 5–18 to study the scope of this reduction reaction
described here, as an internal standard in the analysis of by using water as the hydrogen source or deuterium oxide
extracts from olive-tree leaves.
as the deuterium source. We conducted the corresponding
We initially turned our attention to tyrosol (1, Scheme 2), reactions under the optimized conditions described above
a phenolic antioxidant that has been related to lower the (Table 1).[11]
incidence of heart disease and certain cancers.[9] For our
In all cases the yields for the epoxide reductions were
needs we chose high-performance liquid chromatography good to excellent (70–98%) with the only exception of sub-
(HPLC) allied with mass spectrometry (MS) detection, strate 18 (Table 1, Entry 14). Mono- (Table 1, Entries 1, 13,
using electrospray ionization (ESI) as an interface, because and 14), di- (Table 1, Entries 2–8, 10, and 12), and trisubsti-
of its extremely efficient resolution and characterization of tuted epoxides (Table 1, Entries 9 and 11) could be used as
a wide range of polar compounds.
starting materials, showing that our method is not condi-
tioned by the substitution pattern in the starting epoxides.
The only limitation seems to be the susceptibility of the
phenyl-substituted epoxides to cationic opening due to the
pKa value of 6.76 that was determined for the mixture of
Cp2TiCl, water, and MnCl2.[11,13] Thus, 18 gave only a low
yield of corresponding alcohol 32. Another important fea-
ture of this reaction is that less-substituted alcohols are al-
ways obtained (Table 1, Entries 1, 7–14), showing anti-Mar-
kovnikov regiochemistry. Therefore, this method may be
considered as offering a successful alternative to the hydro-
Scheme 2. Chemical structure of tyrosol (1).
Results and Discussion
Initially we chose simple monosubstituted epoxide 2 to boration/oxidation reaction. This is due to the formation of
find the best reaction conditions for this transformation de- the more stable radical in the Ti-mediated epoxide opening
spite the fact that it is considered an unsuitable substrate for in most cases.[14] When asymmetric 1,2-disubstituted epox-
the reduction reaction. In fact, when we reduced epoxide 2 ides were used the same trend was observed. For example,
under the conditions described by RajanBabu and Nug- for substrate 9 (Table 1, Entry 5) we obtained the alcohol
ent[1] using 1,4-CHD as the hydrogen-atom donor, we ob- derived from the reduction of the benzylic position. Never-
tained desired alcohol 3 at a yield of only 16% (Scheme 3). theless, when differences in the stability of both potential
The main product was alkene 4 (70%), which is derived radicals were not significant a mixture of products could be
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Table 1. TiIII-mediated epoxide ring opening in the presence of H2O expected. In these cases, the presence of functional groups
or D2O.
may exert a template effect and direct the homolytic open-
ing to one sole position, yielding only one product (Table 1,
Entry 6).
It is noteworthy that the main product in the reduction
of epoxide 16 was anti-Markovnikov alcohol 30 (Scheme 4)
as a 3:7 mixture of cis/trans stereoisomers.[2e] This alcohol
presents the opposite stereochemistry to those obtained by
hydroboration/oxidation reaction of the corresponding al-
kene.[15] Changes in the reaction conditions did not improve
this remarkable stereochemistry, but the use of a bulkier
titanocene(III) complex [(tBuCp)2TiCl2] did provide an ex-
cellent yield (75%) and stereoselectivity (1:9, cis/trans). This
result opens the possibility of developing new titano-
cene(III) complexes to synthesize alcohols from epoxides,
which not only offers an alternative to the hydroboration/
oxidation reaction but also provides complementary stereo-
chemistry, which is difficult to achieve using other methods.
Scheme 4. Hydroboration/oxidation vs. reductive TiIII epoxide
opening to yield 30.
When the radical generated was vicinal to a four-mem-
bered ring (Table 1, Entries 10 and 11) epoxide opening
products 28 and 29 were obtained, which are derived from
the opening of the four-membered rings and subsequent re-
duction of the stabilized tertiary radicals. This suggests that
under our aqueous conditions the reaction rate for four-
membered ring cleavage in epoxides 14 and 15 is faster than
the corresponding reduction processes. Recently,
Fernández-Mateos et al. were able to determine the rate
constant for the ring opening of a bicyclic cyclobutylcarb-
inyl model that generates a trisubstituted radical. The value,
k = 1.1ϫ107 s–1, corresponds to a fast reaction.[16] The rate
constant for the reduction by a (aqua)titanocene(III) com-
plex of trisubstituted radicals is not available for compari-
son, but previous results reported by Newcomb et al. indi-
cate that the rate constant for the reduction of a disub-
stituted radical by titanocene/water mixtures is
1ϫ105 –1 s–1,[4a] which is smaller than that for the opening
of the bicyclic four-membered ring and which would justify
our results. Interestingly, alcohols 28 and 29 (carvotanacet-
ol) are valuable compounds in the foodstuffs and pharma-
ceutical industries,[17] imparting as they do an intense mint
flavor/odor. Some simple derivatives, such as carvotanacet-
one (33)[18] and phellandral (34),[19] are also natural prod-
[a] Epoxide (1 mmol), Cp2TiCl2 (2.5 mmol), Mn dust (8 mmol),
and water (10 mmol). [b] Epoxide (1 mmol), Cp2TiCl2 (2.5 mmol),
Mn dust (8 mmol), and D2O (10 mmol). [c] Deuterium incorpora-
tion was determined on the basis of the [M – 18]+ peak (see ref.[12]).
[d] A good mass spectrum for the determination of D-incorpora-
tion could not be obtained. [e] A 3:7 mixture of cis/trans stereoiso-
mers.
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Radical Reduction of Epoxides Using a Titanocene(III)/Water System
ucts appreciated by these industries. From alcohols 28 and
29, odorous compounds 33 and 34 (Scheme 5) can be ob-
tained by simple oxidation with PCC.[11]
Scheme 6. Preparation of deuterated tyrosol (1-d1).
It is noteworthy that the reduction reaction can also be
carried out with the use of only substoichiometric amounts
of the titanocene(III) complex. In this case, a titano-
cene(III) regenerating agent is required. Among these, only
the combination of 2,4,6-coll·HCl and Mn dust, developed
by the group of Gansäuer,[2,23] gave satisfactory results
(Table 2). For deuteration experiments, 2,4,6-coll·DCl, pre-
pared from 2,4,6-collidine and DCl/7.6  D2O, was used as
the regenerating agent. The catalytic process seems to take
place with the same trends as the stoichiometric protocol.
The yields in many cases are similar (Table 2, Entries 1, 4
and 6) or even better (Table 2, Entry 7) than those con-
ducted under stoichiometric conditions. The results also
showed that the catalytic version works with mono-
(Table 2, Entries 1 and 2), di- (Table 2, Entries 3–6), and tri-
substituted epoxides (Table 2, Entry 7). The isolation of the
corresponding deuterated alcohols with good-to-high deu-
terium incorporation highlighted once again the fact that
our method constitutes an efficient deuteration procedure
for the synthesis of β-deuterated alcohols, resulting in some
cases in better deuterium incorporation than under
stoichiometric conditions. Although the reasons for this are
not clear, the presence of undetermined quantities of adven-
titious deuterium oxide in 2,4,6-coll·DCl might offer an ex-
planation. Also worth remarking upon is the fact that excel-
lent yields of odorous compounds 28 and 29 were obtained
at gram scale (86 and 89%, respectively, from 1 g of starting
material).[11]
Scheme 5. Preparation of carvotanacetone (33) and phellandral
(34).
To our satisfaction, the results obtained in the reductive
epoxide ring opening mediated by Cp2TiCl using D2O as
the deuterium source were on the whole quite good, with
yields only slightly lower than those obtained using water
as the hydrogen source. The incorporation of deuterium was
excellent in many examples (Table 1, Entries 1, 3, 6, 8, 9,
and 14) despite the relatively high isotopic effects associated
with these reactions. Nevertheless, the reasons for the ob-
served variations in deuterium incorporation are still not
clear. The non-deuterated products are apparently derived
from HAT processes from the solvent (i.e., THF).[20] In fact,
HAT side processes from the solvent (i.e., THF) to second-
ary radicals have been described under very similar reaction
conditions.[21] The efficiency of HAT from the
Cp2TiCl(D2O) complex is also expected to vary for different
substrates, and as a consequence, deuterium incorporation
will also vary as a result of the fact that in HAT reactions
a relationship exists between the activation energy of the
process and the nature of the C–H bond formed.[22] Never-
Table 2. Epoxide ring opening catalyzed by TiIII in the presence of
H2O or D2O.
Entry Substrate
Product
% Yield[a] % Yield[b] (% D inc.)
1
2
5
3
78
56
46
86
60
87
91
60 (65)
61 (80)
40 (85)
61 (96)
48 (78)
60 (53)
54 (62)
theless, steric and polar effects also have to be taken into
account. In any case, these reaction conditions constitute
an excellent procedure for the preparation of various kinds
of β-deuterated alcohols.
2
3
4
5
6
7
19
20
21
26
28
29
6
7
12
14
15
Although the yield of deuterated 32-d1 was not com-
pletely satisfactory, we focused our attention on it. A simple
deacetylation reaction (K2CO3/HOMe, 40%) yielded deu-
terated tyrosol (1-d1)[6b] from commercial acetoxystyrene in
only three steps in an overall yield of 10.5%. As mentioned
above, tyrosol (1) is very important to the food industry,
and so analytical chemists have become interested in its use
in food analysis. We went on to use deuterated tyrosol (1-
d1) in a real analysis of olive-leaf extracts (Scheme 6). The
results expressed in mg analyte/g of dry weight olive-leaves
[a] Epoxide (1 mmol), Cp2TiCl2 (0.2 mmol), Mn dust (8 mmol),
water (10 mmol), and 2,4,6-coll·HCl (2 mmol). [b] Epoxide
(1 mmol), Cp2TiCl2 (0.2 mmol), Mn dust (8 mmol), D2O
(10 mmol), and 2,4,6-coll·DCl (2 mmol).
Conclusions
We have described a comprehensive study of radical re-
was 0.2Ϯ0.05 mg/g of 1 in the leaf extracts.[11] It is the first ductive epoxide ring opening promoted by Cp2TiCl under
time that the concentration of this bioactive compound has mild reaction conditions by using innocuous, inexpensive
been determined in an olive-leaf extract by using a deuter- water or deuterium oxide as the hydrogen or deuterium
ated internal standard.
source. The remarkable chemical profile of this reaction al-
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–78 °C and then for 24 h at room temperature. AcOEt was added,
and the organic layer was washed with a saturated solution of
NH4Cl, dried with anhydrous Na2SO4, and concentrated. Products
11, 12, and 16 were purified by flash chromatography on silica gel
(hexane/EtOAc) and characterized by spectroscopy.
lowed us to access alcohols with anti-Markovnikov regio-
chemistry from epoxides with different substitution pat-
terns, thus improving upon the previously reported meth-
ods. The stereochemistry obtained by using this protocol is
also complementary to that obtained with the hydrobor-
ation/oxidation reaction. Moreover, the use of D2O as the
deuterium source allows efficient synthesis of β-deuterated
alcohols, improving the known procedures for the prepara-
tion of these kinds of compounds. We went on to follow
this procedure for the preparation of a deuterated sample
of tyrosol (1-d1), used as an internal standard in the analysis
of foodstuffs, from olive-leaf extract. We have also de-
scribed an efficient catalytic protocol by using substoichi-
ometric quantities of TiIII to prepare multigrams of the
odorous compounds carvotanacetone (33) and phellandral
(34), thus opening the way for possible industrial applica-
tions of our procedure.
1
Epoxide 12: Colorless oil. H NMR (400 MHz, CDCl3): δ = 2.57
(s, 2 H, CH2O), 1.64–1.46 (m, 4 H, CH2), 1.37–1.25 (m, 8 H, CH2),
0.90 (m, 6 H, CH3) ppm. 13C NMR (100 MHz, CDCl3; DEPT): δ
= 59.7 (C), 52.8 (CH2), 34.1 (CH2), 27.2 (CH2), 23.0 (CH2), 14.2
(CH3) ppm. HRMS (ESI+): calcd. for C10H21O [M + H]+
157.1592; found 157.1587.
General Procedure for TiIII-Mediated Epoxide Ring Opening with
H2O as Hydrogen Source (GP 1): Thoroughly deoxygenated THF
(20 mL) was added to a mixture of Cp2TiCl2 (2.5 mmol) and Mn
dust (8 mmol) under an Ar atmosphere, and the suspension was
stirred at room temperature until it turned lime green (after about
15 min). A solution of epoxide (1 mmol) and H2O (10 mmol) in
THF (1 mL) was added, and the mixture was stirred for 24 h, after
which the reaction was quenched with a saturated solution of
KHSO4 and extracted with EtOAc. The organic layer was washed
with brine, dried with anhydrous Na2SO4, and concentrated. Prod-
ucts 3 and 19–32 were purified by flash chromatography on silica
gel (hexane/EtOAc) and characterized by spectroscopy. Yields are
reported in the text and set out in Table 1.
General Procedure for TiIII-Mediated Epoxide Ring Opening with
D2O as Deuterium Source (GP 2): Thoroughly deoxygenated THF
(20 mL) was added to a mixture of Cp2TiCl2 (2.5 mmol) and Mn
dust (8 mmol) under an Ar atmosphere, and the suspension was
stirred at room temperature until it turned lime green (after about
15 min). A solution of epoxide (1 mmol) and D2O (10 mmol) in
THF (1 mL) was added, and the mixture was stirred for 24 h, after
which the reaction was quenched with a saturated solution of
KHSO4 and extracted with EtOAc. The organic layer was washed
with brine, dried with anhydrous Na2SO4, and concentrated. Deu-
terated products 3-d1 and 19-d1–32-d1 were purified by flash
chromatography on silica gel (hexane/EtOAc) and characterized by
spectroscopy. Yields are reported in the text and set out in Table 1.
Experimental Section
General Details: Solvents and additives were thoroughly deoxy-
genated prior to all reactions with titanocene. Water was purified
with a Milli-Q system. Products were purified by flash chromatog-
1
raphy on Merck silica gel 50. H and 13C NMR spectra were re-
corded with 400 and 500 MHz spectrometers in CDCl3. Data are
reported as follows: chemical shift in ppm, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, and m = multiplet), coupling
constant (Hz), and integration. Peak assignments were made with
the aid of the DEPT method. The stereochemistry of the new
stereogenic centers derived from the inclusion of a deuterium atom
in the structure was not determined.[24] The following known com-
pounds were isolated as pure samples and showed 1H and 13C
NMR spectra matching those of the reported compounds: 5,[25]
7,[26] 8,[27] 9,[28] 11,[28] 13,[10] 16,[10] 18,[29] 21-d1,[26a] 22,[30] 23,[31]
24,[32] 25,[33] 26,[34] 27,[35] 28,[36] 31-d1,[37] 32,[38] 33,[18] 34,[19] and 1-
d1.[6b]
General Procedure for TiIII-Catalyzed Epoxide Ring Opening with
H2O as Hydrogen Source (GP 3): Thoroughly deoxygenated THF
(20 mL) was added to a mixture of Cp2TiCl2 (0.2 mmol) and Mn
dust (8 mmol) under an Ar atmosphere, and the suspension was
stirred at room temperature until it turned lime green (after about
15 min). A solution of epoxide (1 mmol), collidine·HCl (7 mmol),
and H2O (10 mmol) in THF (1 mL) was added, and the mixture
was stirred at room temperature for 24 h, after which the reaction
was quenched with a saturated solution of KHSO4 and extracted
with EtOAc. The organic layer was washed with brine, dried with
anhydrous Na2SO4, and concentrated. Products 3, 19–21, 26, 28,
and 29 were purified by flash chromatography on silica gel (hexane/
EtOAc) and characterized by spectroscopy. Yields are reported in
the text and set out in Table 2.
General Procedure for TiIII-Catalyzed Epoxide ring Opening with
D2O as Deuterium Source (GP 4): Thoroughly deoxygenated THF
(20 mL) was added to a mixture of Cp2TiCl2 (0.2 mmol) and Mn
dust (8 mmol) under an Ar atmosphere, and the suspension was
stirred at room temperature until it turned lime green (after about
15 min). A solution of epoxide (1 mmol), collidine·DCl (7 mmol),
and D2O (10 mmol) in THF (1 mL) was added, and the mixture
was stirred at room temperature for 24 h, after which the reaction
was quenched with a saturated solution of KHSO4 and extracted
with EtOAc. The organic layer was washed with brine, dried with
anhydrous Na2SO4, and concentrated. Deuterated products 3-d1,
General Procedure for the Epoxidation of Alkenes with m-CPBA: A
sample of m-CPBA (2 mmol, 70% purity) was added to a solution
of alkene (1 mmol) in CH2Cl2 (20 mL), and the mixture was stirred
at room temperature until the starting material was consumed
(checked by TLC). CH2Cl2 was then added, and the solution was
washed with 2  NaOH, dried with anhydrous Na2SO4, and con-
centrated. Products 5–10, 13, and 18 were purified by flash
chromatography on silica gel (hexane/EtOAc) and characterized by
spectroscopic techniques.
1
Epoxide 10: Colorless oil. H NMR (400 MHz, CDCl3): δ = 4.31
(dd, J = 12.2, 3.2 Hz, 1 H, CHHOAc), 3.88 (dd, J = 12.2, 6.3 Hz,
1 H, CHHOAc), 2.94–2.89 (m, 1 H, CHO-), 2.80 (td, J = 5.5,
2.0 Hz, 1 H, CHO-), 2.05 (s, 3 H, -OCH3), 2.06 (m, 2 H, CH2),
1.53 (dd, J = 13.2, 7.2 Hz, 2 H, CH2), 1.45–1.34 (m, 2 H, CH2),
1.32–1.17 (m, 8 H, CH2), 0.84 (t, J = 6.7 Hz, 3 H, CH2CH3) ppm.
13C NMR (100 MHz, CDCl3; DEPT): δ = 170.7 (C), 64.8 (CH2),
56.7 (CH), 55.3 (CH), 31.8 (CH2), 31.6 (CH2), 29.3 (CH2), 29.2
(CH2), 25.9 (CH2), 22.7 (CH2), 20.8 (CH3), 14.1 (CH3) ppm.
HRMS (ESI+): calcd. for C12H23O3 [M + H]+ 215.1647; found
215.1638.
General Procedure for the Preparation of Epoxides from Ketones: To
a solution of ketone (1 mmol) and CH2Br2 (2 mmol) in THF
(15 mL) cooled to –78 °C was dropwise added BuLi (2.5  in hex-
ane, 1.1 mmol) for 5 min. The mixture was stirred for 5 min at
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Radical Reduction of Epoxides Using a Titanocene(III)/Water System
19-d1–21-d1, 26-d1, 28-d1, and 29-d1 were purified by flash δ = 65.8 (CH2), 30.6 (CH2), 29.2 (CH2), 23.2 (CH2), 14.2 (CH3)
chromatography on silica gel (hexane/EtOAc) and characterized by
spectroscopic techniques. Yields are reported in the text and set out
in Table 2.
ppm (one carbon signal was not observed). HRMS (ESI+): calcd.
for C10H19D [M – H2O]+ 140.1550; found 140.1560.
Compound 27: Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.04
(d, J = 8.2 Hz, 2 H, aromatic CH), 7.55 (m, 1 H, aromatic CH),
7.42 (t, J = 11.1 Hz, 2 H, aromatic CH), 4.44 (ddd, J = 11.5, 3.0,
1.2 Hz, 2 H, CH2OBz), 3.72 (m, 1 H, CHOH), 1.90–1.79 [m, 1 H,
CH(CH3)2], 1.02 (d, J = 6.8 Hz, 3 H, CHCH3), 0.99 (d, J = 6.8 Hz,
3 H, CHCH3) ppm. 13C NMR (100 MHz, CDCl3; DEPT): δ =
167.0 (C), 133.2 (CH), 130.0 (C), 129.7 (CH), 128.5 (CH), 74.9
(CH), 67.9 (CH2), 31.3 (CH), 18.8 (CH3), 17.9 (CH3) ppm. HRMS
(ESI+): calcd. for C12H17O3 [M + H]+ 209.1178; found 209.1171.
Compound 3-d1: Colorless oil. 1H NMR (400 MHz, CDCl3): δ =
3.62 (d, J = 6.4 Hz, 2 H, CH2OH), 1.60–1.48 (m, 1 H, CHD), 1.35–
1.20 (m, 30 H, CH2), 0.87 (t, J = 6.6 Hz, 3 H, CH2CH3) ppm. 13C
NMR (100 MHz, CDCl3; DEPT): δ = 63.1 (CH2), 32.5 (m, CHD),
32.1 (CH2), 29.9 (CH2), 29.8 (CH2), 29.8 (CH2), 25.7 (CH2), 22.8
(CH2), 14.3 (CH3) ppm. HRMS (ESI+): calcd. for C18H35D [M –
H2O]+ 253.2880; found 253.2906.
1
Compound 19-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
1
Compound 27-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
7.31–7.26 (m, 2 H, aromatic CH), 7.21–7.16 (m, 3 H, aromatic
CH), 3.65 (d, J = 6.3 Hz, 2 H, CH2OH), 2.65 (t, J = 7.3 Hz, 2 H,
PhCH2CH2), 1.73–1.57 (m, 3 H, CH2CH2CHD) ppm. 13C NMR
(100 MHz, CDCl3; DEPT): δ = 142.4 (C), 128.5 (CH), 128.4 (CH),
125.9 (CH), 62.8 (CH2), 32.4 (CH2), 32.0 (m, CHD), 27.6 (CH2)
ppm. HRMS (ESI+): calcd. for C10H13DO [M]+ 151.1107; found
151.1114.
8.04 (d, J = 8.3 Hz, 2 H, aromatic CH), 7.55 (t, J = 7.4 Hz, 1 H,
aromatic CH), 7.43 (t, J = 7.7 Hz, 2 H, aromatic CH), 4.44 (dd, J
= 11.5, 3.0 Hz, 1 H, CHHOBz), 4.29 (dd, J = 11.5, 7.4 Hz, 1 H,
CHHOBz), 3.72 (dd, J = 7.2, 2.8 Hz, 1 H, CHOH), 2.30 (br. s, 1
H, OH), 1.01 (s, 3 H, CHCH3), 0.99 (s, 3 H, CHCH3) ppm. 13C
NMR (100 MHz, CDCl3; DEPT): δ = 167.0 (C), 133.2 (CH), 130.0
(C), 129.7 (CH), 128.5 (CH), 74.8 (CH), 67.9 (CH2), 31.3 (m, CD),
18.7 (CH3), 17.7 (CH3) ppm. HRMS (ESI+): calcd. for C12H13DO2
[M – H2O]+ 191.1057; found 191.1063.
1
Compound 20-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
3.64 (br. s, 1 H, CHOH), 1.74–1.55 (m, 1 H, CHD), 1.54–1.21 (m,
20 H, CH2) ppm. 13C NMR (100 MHz, CDCl3; DEPT): δ = 69.2
(CH), 32.5 (CH2), 32.1 (m, CHD), 24.2 (CH2), 23.8 (CH2), 23.4
(CH2), 23.4 (CH2), 23.3 (CH2), 23.3 (CH2), 23.2 (CH2), 20.9 (CH2),
20.9 (CH2) ppm. HRMS (ESI+): calcd. for C12H23DO [M]+
185.1890; found 185.1888.
1
Compound 28-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
5.66 (br. s, 1 H, CH=C), 3.97 (br. s, 2 H, CH2OH), 2.42–1.90 (m,
3 H, CH2 and CH), 1.80–1.35 (m, 2 H, CH2), 1.30–1.15 (m, 2 H,
CH2), 0.88 (s, 6 H, CH3) ppm. 13C NMR (100 MHz, CDCl3;
DEPT): δ = 137.5 (C), 123.0 (CH), 67.4 (CH2), 40.3 (CH)*, 40.2
(CH), 32.3 (CH), 31.7 (m, CD), 28.7 (CH2)*, 28.7 (CH2), 26.5
(CH2), 26.2 (CH2)*, 26.1 (CH2), 20.0 (CH3)*, 19.9 (CH3), 19.8
(CH3)*, 19.6 (CH3) ppm (asterisks refer to minor isomers). HRMS
(ESI+): calcd. for C10H17DO [M]+ 155.1420; found 155.1422.
1
Compound 22-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
3.90–3.75 (m, 3 H, CH2O), 3.55 (ddd, J = 16.5, 10.0, 5.8 Hz, 2 H,
CH2O), 1.73–1.57 (m, 1 H, CHD), 0.89 [s, 18 H, (CH3)3C], 0.01
(m, 12 H, CH3Si) ppm. 13C NMR (100 MHz, CDCl3; DEPT): δ =
70.9 (CH), 67.3 (CH2), 61.2 (CH2), 35.3 (m, CD), 26.1 (CH3), 26.0
(CH3), 18.5 (C), 18.4 (C), –5.2 (CH3), –5.2 (CH3), –5.3 (CH3), –5.3
(CH3) ppm.
1
Compound 29-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
5.57–5.50 (m, 1 H, CH=C), 3.95 (br. s, 1 H, CHOH), 2.01 (dd, J
= 12.9, 9.0 Hz, 1 H, CHH), 1.85 (d, J = 13.2 Hz, 1 H, CHH), 1.76
(s, 3 H, CH3), 1.73–1.57 (m, 1 H, CH2CHCH2), 1.45 (dd, J = 12.0,
9.6 Hz, 1 H, CHH), 1.33 (ddd, J = 12.9, 3.8, 2.9 Hz, 1 H, CHH),
0.88 (s, 3 H, CH3), 0.86 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3; DEPT): δ = 134.6 (C), 125.8 (CH), 68.8 (CH), 35.5 (CH2),
34.0 (m, CD), 29.1 (CH2), 21.0 (CH3), 19.9 (CH3), 19.5 (CH3) ppm.
HRMS (ESI+): calcd. for C10H17DO [M]+ 155.1420; found
155.1420.
1
Compound 23-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
7.40–7.11 (m, 5 H, aromatic CH), 4.22–3.90 (m, 3 H, CH2OAc and
CHOH), 2.84–2.71 (m, 1 H, PhCHD), 2.09 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, CDCl3; DEPT): δ = 171.3 (C), 137.3 (C),
129.4 (CH), 128.7 (CH), 126.8 (CH), 70.7 (CH), 67.8 (CH2), 39.9
(m, CHD), 20.9 (CH3) ppm. HRMS (ESI+): calcd. for C11H11DO2
[M – H2O]+ 177.0900; found 177.0910.
Compound 30-d1: Mixture of 3:7 cis/trans isomers. Colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 3.61 (s, 2 H, cis isomer, CH2OH),
3.41 (s, 2 H, trans isomer, CH2), 1.84–1.73 (m, 2 H, CH2), 1.61–
1.37 (m, 2 H, CH2), 1.08–0.85 (m, 5 H, CH2 and CH), 0.83 [s, 9
H, trans isomer, (CH3)3C], 0.82 [s, 9 H, cis isomer, (CH3)3C] ppm.
13C NMR (100 MHz, CDCl3; DEPT): δ = 68.8 (CH2, trans isomer),
63.8 (CH2, cis isomer), 48.5 (CH2, cis isomer), 48.4 (CH2, trans
isomer), 40.7 (CH), 40.5 (m, CD), 32.7 (C, cis isomer), 32.6 (C,
trans isomer), 30.1 (CH2, cis isomer), 30.0 (CH2, trans isomer), 27.7
(CH3, trans isomer), 27.6 (CH3, cis isomer), 27.5 (CH2, cis isomer),
26.9 (CH2, trans isomer), 22.2 (CH2) ppm. LRMS (ESI+): m/z (%)
= 153 (3) [M – H2O]+, 138 (5), 114 (22), 96 (81), 82 (32), 67 (35),
57 (100), 55 (46).
1
Compound 24-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
4.11 (dd, J = 11.3, 2.5 Hz, 1 H, CHHOAc), 3.93 (dd, J = 11.3,
7.5 Hz, 1 H, CHHOAc), 3.80 (br. s, 1 H, CHOH), 2.07 (s, 3 H,
OCH3), 1.48–1.38 (m, 1 H, CHD), 1.35–1.18 (m, 12 H, CH2), 0.85
(t, J = 6.4 Hz, 3 H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3;
DEPT): δ = 171.4 (C), 70.0 (CH), 68.9 (CH2), 33.2 (m, CHD), 31.9
(CH2), 29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 25.4 (CH2), 22.7 (CH2),
21.0 (CH3), 14.2 (CH3) ppm. HRMS (ESI+): calcd. for C12H21DO2
[M – H2O]+ 199.1698; found 199.1699.
1
Compound 25-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
3.42 (d, J = 10.5 Hz, 1 H, CHHOH), 3.32 (d, J = 10.5 Hz, 1 H,
CHHOH), 1.26–1.13 (m, 14 H, CH2), 0.86–0.75 (m, 6 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3; DEPT): δ = 68.4 (CH2), 35.5
(m, CD), 33.2 (CH2), 32.0 (CH2), 30.1 (CH2), 29.7 (CH2), 29.5
(CH2), 27.1 (CH2), 22.8 (CH2), 16.6 (CH3), 14.2 (CH3) ppm.
LRMS (ESI+): m/z (%) = 155 (3) [M – H2O]+, 154 (8), 127 (4), 112
(9), 98 (15), 70 (65), 57 (100), 55 (86).
1
Compound 32-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
7.21 (d, J = 8.2 Hz, 2 H, aromatic CH), 7.01 (d, J = 8.2 Hz, 2 H,
aromatic CH), 3.80 (d, J = 6.4 Hz, 2 H, CHDCH2OH), 2.86–2.77
(m, 1 H, CHDCH2OH), 2.28 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3; DEPT): δ = 169.8 (C), 149.3 (C), 136.3 (C),
130.1 (CH), 121.7 (CH), 63.5 (CH2), 38.6 (m, CHD), 21.2 (CH3)
1
Compound 26-d1: Colorless oil. H NMR (400 MHz, CDCl3): δ =
3.51 (s, 2 H, CH2OH), 1.39–1.17 (m, 12 H, CH2), 0.88 (t, J = ppm. HRMS (ESI+): calcd. for C10H11DO3 [M]+ 181.0849; found
7.0 Hz, 6 H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3; DEPT): 181.0852.
Eur. J. Org. Chem. 2010, 4288–4295
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4293

J. Justicia, J. M. Cuerva et al.
FULL PAPER
(98 atom-% D, 5 g, j176), LiAlD4 (98 atom-% D, 5 g, j90.30),
and D2 (99.9 atom-% D, 25 L, j221.50) are considerably more
expensive.
Oxidation of 28 and 29 with PCC: A solution of allylic alcohol
(1 mmol) in CH2Cl2 (20 mL) was treated with a sample of PCC
(2 mmol) for 3 h at room temperature. Et2O (40 mL) was added,
and the mixture was washed with 2  NaOH (2ϫ), 2  HCl (2ϫ)
and then with a saturated solution of NaHCO3. The organic layer
was dried with anhydrous Na2SO4, and the solvent was removed.
The residue was submitted to flash chromatography (hexane/
EtOAc, 9:1) to yield ketone 33[18] (146 mg, 96%) or aldehyde 34[19]
(84 mg, 55%).
[6]
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Synthesis of Deuterated Tyrosol (1-d1): A sample of K2CO3 (82 mg,
0.58 mmol) was added to a solution of alcohol 32-d1 (36 mg,
0.2 mmol) in MeOH (5 mL), and the mixture was stirred for 24 h
at room temperature. AcOEt (20 mL) was added, and the organic
layer was washed with water, dried with anhydrous Na2SO4, and
concentrated. The residue was submitted to flash chromatography
(hexane/EtOAc, 1:1) to give 1-d1[6b] (13 mg, 40%) as a colorless oil.
[7]
[8]
Supporting Information (see footnote on the first page of this arti-
cle): Optimization of reaction conditions, analysis of tyrosol, and
1H and 13C NMR spectra of all described and new compounds.
Acknowledgments
We thank the Spanish Ministry of Science and Innovation (MIC-
INN) for its support with projects CTQ2008-06790, AGL2008-
05108-CO3-03/ALI, and AGL2007-60778/ALI. We also thank the
Regional Government of Andalucía for its support with projects
P06-FQM-01726, P07-FQM3213, and P07-AGR-02619, and for fi-
nancial aid to research group FQM339. T. J. is grateful to MICINN
for her FPU fellowship. D. A.-R. and M. P. thank the Regional
Government of Andalucía for their contracts. J. J. thanks MICINN
and the University of Granada for his “Juan de la Cierva” contract.
We also thank New Developments in Nutraceuticals, Inc. for pro-
viding us with the olive-leaf extracts. Finally, we thank Dr. J. Trout
of the University of Granada Scientific Translation Service for re-
vising our English text.
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Detailed experimental procedures and spectroscopic data for
all products described in this paper can be found in the Experi-
mental Section and Supporting Information.
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4294
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4288–4295

Radical Reduction of Epoxides Using a Titanocene(III)/Water System
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very high and side reactions (deoxygenation reactions) become
important, leading to a consequent decrease in yield. Other
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Received: April 9, 2010
Published Online: June 15, 2010
Eur. J. Org. Chem. 2010, 4288–4295
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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