1,2-Diarylethanols by alternative regioselective reductive ring-opening of 2,3-diaryloxiranes

Article abstract of DOI:10.1002/ejoc.200800992

Non-symmetrical ￡rans-2,3-diaryloxiranes have been regioselectively opened by catalytic hydrogenation over Pd/C, NaBH₄/Pd and [Cp ₂TiCl]/H₂O. Although in the catalytic hydrogenation reactions the epoxides were mainly opened at the β-carbon with respect to the substituted aryl ring in all cases, with the [Cp₂TiCl]/H ₂O system the regioselectivity was affected by the electronic properties of the aryl residues, the epoxides being opened on the carbon bearing the most electron-releasing or the least electron-withdrawing group. With the NaBH₄/Pd system different regioisomers were obtained depending on the substituents. Starting from enantioenriched epoxides, no loss of optical purity was observed in the alcohols formed.

Full text of DOI:10.1002/ejoc.200800992

FULL PAPER
DOI: 10.1002/ejoc.200800992
1,2-Diarylethanols by Alternative Regioselective Reductive Ring-Opening of
2,3-Diaryloxiranes
Nadia Di Blasio,[a] Maria Teresa Lopardo,[a] and Paolo Lupattelli*[a]
Dedicated to Professor Carlo Bonini on the occasion of his 60th birthday
Keywords: Epoxides / Ring-opening reactions / Reduction / Alcohols / Enantioselectivity / Regioselectivity
Non-symmetrical trans-2,3-diaryloxiranes have been re- electron-releasing or the least electron-withdrawing group.
gioselectively opened by catalytic hydrogenation over Pd/C,
NaBH4/Pd and [Cp2TiCl]/H2O. Although in the catalytic hy-
drogenation reactions the epoxides were mainly opened at
the β-carbon with respect to the substituted aryl ring in all
cases, with the [Cp2TiCl]/H2O system the regioselectivity
was affected by the electronic properties of the aryl residues,
the epoxides being opened on the carbon bearing the most
With the NaBH4/Pd system different regioisomers were ob-
tained depending on the substituents. Starting from enanti-
oenriched epoxides, no loss of optical purity was observed in
the alcohols formed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ride has been claimed to be one of the best reagents for
reductive epoxide ring-opening.[8] The intermediate
β-titanoxy radicals were reduced efficiently by different hy-
drogen atom donors and, in the case of alkyl epoxides, high
regioselectivity towards the less substituted alcohol was re-
ported.
During our study on the ring-opening reactions of 2,3-
diaryloxiranes,[9] we found that such epoxides were suitable
starting materials for the synthesis of 1,2-diarylbromohyd-
rins,[10] acetonides,[11] as well as pyridyl, furyl[12] and anilino
alcohols[13] in enantiopure form. These results prompted us
to investigate more deeply the reductive ring-opening of
non-symmetrical substituted 2,3-diaryloxiranes with the
aim of finding a general and efficient method. In this con-
text, such epoxides are challenging substrates in terms of
the regioselectivity of the ring-opening due to the small (if
Introduction
The reductive ring-opening of epoxides to the corre-
sponding alcohols has become a powerful tool in organic
synthesis due to the rapid development of efficient and
practical methods for their preparation in both their race-
mic and enantiopure form. Various hydrides[1] are fre-
quently employed for this purpose and milder systems have
been developed to enhance the chemical yield.[2]
The need for a practical version of this reaction with low
environmental impact has generated interest in hetero-
geneous catalytic systems. In particular, various catalysts
based on Ni, Pd and Pt have been developed to increase
the chemo- and regioselectivity of such reactions, even with
enantiopure epoxides.[3] Different hydrogen sources, such as
HCOONH4,[4] and catalysts, such as the ethylenediamine–
Pd/C complex,[5] have been used to improve selectivity and
to prevent further hydrogenolysis of the alcoholic C–O
bond. Nevertheless, solvolysis with methanol remains a
problem, particularly in the case of benzyl epoxides. Re-
cently, Pd nanoparticles, microencapsulated in polyurea,
have been reported to be very efficient in the reductive ring-
opening of different benzyl and alkyl epoxides.[6] Moreover,
a magnetically separable palladium catalyst has been syn-
thesized and reported to be active and selective for the hy-
drogenolysis of different epoxides.[7] Titanocene(III) chlo-
[a] Department of Chemistry, University of Basilicata,
Via Nazario Sauro 85, 85100 Potenza, Italy
Fax: +39-0971-202223
E-mail: paolo.lupattelli@unibas.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Functionalized diarylethanols from diaryl epoxides.
938
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 938–944

Diarylethanols by Reductive Ring-Opening of Diaryloxiranes
any) difference in reactivity between the benzyl carbon tions were highly regioselective, mostly producing only one
atoms. From a synthetic point of view, they represent useful of the two possible regioisomers[16] in good-to-excellent
starting materials because the corresponding diarylethanols chemical yields. In the case of the two trifluoromethyl deriv-
can be envisaged as chiral auxiliaries or ligands in asymmet- atives 1e and 1f, considerable amounts of diarylethanes
ric synthesis, provided the presence of a coordinating het- were formed on further hydrogenolysis (entries 6–8). This
eroatom on the aryl ring[14] (Figure 1).
side-reaction was suppressed in the case of the 2-trifluoro-
methyl derivative 1e when the reaction was performed in
1% AcOH/AcOEt solution (entry 5). In the case of the
trans-β-methylstyrene epoxide, the yield of the expected 3-
Results and Discussion
Our recent results on the efficient, alternative and re- phenyl-2-propanol was also high (entry 10). The regioselec-
gioselective reduction of trans-2-(2-nitrophenyl)-3-phenyl- tivity of the reductive ring-opening by the H2/Pd system
oxirane with either the H2/Pd or NaBH4/Pd system[13] appeared independent of the electronic properties of the
prompted us to investigate various reductive systems with substituent. In fact, for all oxiranes bearing either an elec-
non-symmetrical ortho- and para-substituted 2,3-diaryl- tron-withdrawing (1a, 1b, 1e and 1f) or an electron-releasing
oxiranes. Thus, (E)-2,3-diaryloxiranes 1 were prepared in group (1c and 1d) on one phenyl ring, the regioisomer 2
good yields in racemic form by the reaction of the dimethyl- was obtained as the major product. Even with the weakly
benzylidenesulfur ylide, generated from the corresponding electron-releasing p-fluoro substituent, the same behaviour
sulfonium salt under phase-transfer conditions, with the ap- was confirmed (entry 9). Such regioselectivity was quite
propriate aryl aldehyde (Scheme 1).[10c,11b]
surprising if we consider the classic mechanism of hydro-
genolysis with benzyl-type radicals as the key intermediates.
In fact, none of the results suggested the preferential forma-
tion of a carbon-centred S-type benzyl radical in which the
term “S” refers to the radical stability being affected by
the electron-releasing and -withdrawing groups in the same
direction.[17] This kind of radical should be the substituted
one in all cases and should give the opposite regioisomer.
Apart from mechanistic hypotheses, the synthetic value of
this reaction is evident, particularly for the preparation of
ortho-substituted alcohols 2a and 2c (Figure 2), which can
be envisaged as ligands in the asymmetric synthesis.
Scheme 1. Synthesis of (E)-2,3-diaryloxirane.
Although catalytic hydrogenation over Pd/C is one of the
most simple and clean reduction procedures, in terms of the
reagents used and subsequent work-up, it is only occasion-
ally described as being efficient with epoxides.[15] Moreover,
no systematic study of 2,3-diaryloxiranes is known to have
been carried out. Thus the epoxides of type 1 were treated
with H2 at 1 atm in the presence of a catalytic amount of
10% Pd/C in the appropriate solvent. The most significant
results are collected in Table 1. As can be seen, all the reac- Figure 2. 2-Pyridyl and 2-methoxyphenyl alcohols 2a and 2c.
Table 1. Catalytic hydrogenation of trans non-symmetrical 2,3-disubstituted oxiranes.
Entry[a]
Epoxide
Ar
R
Solvent
Time [h]
2 [%][b]
3 [%][b]
4 [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
2-pyridyl
4-pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3OH
CH3OH
2
2
12
7
2
3
2
3
3
2
90
90
–
–
–
–
–
–
–
40
40
50
–
2-CH3OC6H4
4-CH3OC6H4
2-CF3C6H4
2-CF3C6H4
4-CF3C6H4
4-CF3C6H4
4-FC6H4
EtOAc/1% AcOH
EtOAc/1% AcOH
EtOAc/1% AcOH
CH3OH
EtOAc/1% AcOH
CH3OH
72[c]
87[c]
70[d]
60
28[c]
13[c]
–
1d
1e
1e
–
–
–
–
1f
60
1f
50
1g
CH3OH
CH3OH
70[d]
–
10
1h[e]
Ph
95
–
[a] All reactions were performed by using Pd/C(10%)/substrate, 20 mg/mmol. The conversions were all higher than 99% and were deter-
1
mined by H NMR analysis of the crude product. [b] Isolated yield except for 2c, 3c, 2d and 3d. [c] The ratio was determined by 1H
NMR analysis of the purified alcoholic mixture. [d] No isolable product was obtained from the rest of the crude. [e] Epoxide 1h was
prepared by oxidation of commercial trans-β-methylstyrene with mCPBA.
Eur. J. Org. Chem. 2009, 938–944
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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939

N. Di Blasio, M. T. Lopardo, P. Lupattelli
FULL PAPER
Titanocene(III) chloride represents a valuable reagent for
the radical-mediated reductive ring-opening of epoxides.[8]
This reaction generally generates the most stable β-titanoxy
radical, which can be reduced by a suitable hydrogen-atom
donor to an alcohol with the opposite regiochemistry to
that expected from the reduction with metal hydrides.[18]
Recently, water was presented as an efficient hydrogen-
atom source in such a reaction, working well also with di-
substituted and sterically congested epoxides.[19] Thus we
decided to explore the synthetic usefulness of such a reac-
tion for the reductive ring-opening of 2,3-diaryloxiranes. Figure 3. Alternative formation of the benzyl β-titanoxy radicals 7
and 8.
We treated epoxides 1 with [Cp2TiCl] (2.2 equiv.) and H2O
(40 equiv.) in THF at room temperature. The results are
summarized in Table 2.
Of the various hydrides that are efficient in the reductive
ring-opening of epoxides, LiAlH4 is the most common[20]
and the milder borohydrides often require the presence of
Table 2. Reductive ring-opening of epoxides
[Cp2TiCl]/H2O.
1 mediated by
a Lewis acid, which activates the epoxide towards nucleo-
[21]
philic attack. Indeed, the NaBH4/ZrCl4
SiO2
and Zn(BH4)2/
[22]
systems are reported to be efficient and, recently,
NaCNBH3 in the presence of ZnI2 was found to effect re-
gioselective ring-opening of benzylic epoxides.[23]
It is known that NaBH4 is capable of reducing palladium
salts to metallic palladium and that the latter catalyses the
slow release of hydrogen from the borohydride. This system
has been used for selective nitro reduction[24] and its behav-
iour was proven to be highly dependent upon the reaction
conditions, fluctuating between a simple source of hydrogen
(like in catalytic hydrogenation) and a more “hydridic” rea-
gent. No example of oxiranyl ring-opening with this system
was known before our recent results with trans-2-(2-ni-
trophenyl)-3-phenyloxirane.[13] This encouraged us to test
the NaBH4/Pd system with the above-mentioned diaryl ep-
oxides, looking for a complementary method with respect
to catalytic hydrogenation and the [Cp2TiCl]/H2O system.
Thus, we first optimized the reaction conditions for the re-
duction of trans-2-(2-nitrophenyl)-3-phenyloxirane (9), ob-
taining the corresponding amino alcohol 10 in high yield
(75%) by modifying the procedure of Neilson et al.[25] (see
the Exptl. Sect.) by adding 10% AcOEt to the solvent mix-
ture to solubilize the substrate (Scheme 2).
Entry[a]
Epoxide
Ar
Time [h]
Yield[b] [%]
2
3
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2-pyridyl
4-pyridyl
2-CH3OC6H4
4-CH3OC6H4
2-CF3C6H4
4-CF3C6H4
4-FC6H4
24
24
2
2
2
2
2
no reaction
no reaction
25
12
86
75
1
75
88
14
25
1
1g
[a] The single-electron transfer reagent [Cp2TiCl] was generated in
situ by stirring commercially available [Cp2TiCl2] with Mn dust in
THF. The conversions were all higher than 99% (except for 1a and
1
1b) and were determined by H NMR analysis of the crude prod-
uct. [b] The ratio was determined by 1H NMR analysis of the puri-
fied alcoholic mixture.
The procedure appeared in general to be efficient (mass
balance generally exceeding 90%) with the exception of the
two pyridyl epoxides 1a and 1b (entries 1 and 2) in which
the Ti complex is likely poisoned by the pyridyl ring. The
reaction also showed considerable regioselectivity in all
cases and was strongly affected by the electronic properties
of the aryl residues. In the oxiranes with Ar bearing an
electron-releasing OCH3 group (entries 3 and 4), the main
reaction product was regioisomer 3, whereas in the presence
of an electron-withdrawing CF3 group, regioisomer 2 was
formed preferentially (entries 5 and 6).
Thus, all epoxides were ring-opened at the carbon atom
bearing the most electron-releasing (or the least electron-
withdrawing) group, which indicates that of the two alterna-
tive benzylic β-titanoxy radicals that can be formed as inter-
mediates, 7 is the most favoured (that is, the most stable)
(Figure 3).
Scheme 2. Reductive ring-opening of the o-nitrophenyl epoxide 9.
Then the epoxides 1 were treated with the NaBH4/Pd
system under the same reaction conditions, apart from the
With these results in hand, we were also interested in use of AcOEt, which was not necessary for the solubiliza-
testing the reductive ring-opening of diaryl epoxides with tion of the substrates. The most significant results are col-
hydrides to observe a possible reverse of the regioselectivity. lected in Table 3.
940
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Eur. J. Org. Chem. 2009, 938–944

Diarylethanols by Reductive Ring-Opening of Diaryloxiranes
Table 3. Reductive ring-opening of the epoxides by the NaBH4/Pd epoxide 1a gave, at low conversions, only alcohol 2a,
system.
whereas 1c afforded an equimolar mixture of the regioiso-
Entry[a]
Epoxide Ar
R
Time
[h]
Yield [%][b]
mers 2c and 3c (Scheme 3). The formation of 2a suggests
that with a lower NaBH4/substrate ratio, a hydrogen species
with properties closer to those of catalytic hydrogenation
was operative.
2
3
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2-pyridyl
4-pyridyl
2-CH3OC6H4 Ph
4-CH3OC6H4 Ph
2-CF3C6H4
4-CF3C6H4
Ph
Ph
Ph
4
4
2
2
2
3
–
–
–
80
75
33[c] 67[c]
15[c,d] 60[c,d]
Ph
Ph
CH3
90
65[d]
–
–
–
90
1h
[a] All the reactions were performed at room temp. with a NaBH4/
substrate ratio of 7.5:1.0 and Pd/C(10%)/substrate, 50 mg/mmol.
The conversions were all higher than 99% and were determined by
1H NMR analysis of the crude product. [b] Isolated yield except
for 2c, 3c, 2d and 3d. [c] The ratio was determined by 1H NMR
analysis of the purified alcoholic mixture. [d] No isolable product
was obtained from the rest of the crude.
As can be seen, the NaBH4/Pd system showed a high
efficiency in the reductive ring-opening in terms of conver- Scheme 3.
sion and regioselectivity. The chemical yields were good in
all cases. trans-β-Methylstyrene epoxide 1h was regioselec-
tively opened at the benzylic carbon atom to afford the cor-
These results suggest that a high NaBH4/substrate ratio
responding alcohol 3h as the only product, which confirms
the higher reactivity of the aryl position with respect to the
alkyl one. In the case of non-symmetrical diaryl epoxides,
the regioselectivity was highly affected by the electronic
properties of the substituents in combination with the
unique characteristics of the reagent. Steric effects, if pres-
ent, were negligible as ortho- and para-substituted sub-
strates gave the same type of regioisomer in similar chemi-
cal yield. For substrates with the strong electron-with-
drawing group CF3 (entries 5 and 6), only the regioisomers
2 were detected in the reaction mixtures, the hydrogen ex-
clusively attacking the β-carbon with respect to the substi-
tuted phenyl ring. These results account for an electron-
deficient acyclic intermediate, which has already been pos-
tulated for the ring-opening reaction with LiBr/Amb. 15
system.[10c] Accordingly, in the case of 1c and 1d, which
possess an electron-releasing group on the phenyl ring, re-
gioisomers 3 (α opening) were the major products observed
(entries 3 and 4). On the other hand, this mechanism can
hardly explain the results for pyridyl epoxides 1a and 1b
(bearing an electron-withdrawing heteroaryl group) for
which only alcohols 3 (α opening) were the only product
formed (entries 1 and 2). These results indicate that, in these
cases, the activated epoxide is more likely the reactive spe-
cies in which the electrophilicity of the two oxiranyl carbon
atoms drives the nucleophilic attack. As the sensitivity of
the system to the reaction conditions is well known, we also
explored the effect of changing different reaction param-
eters, that is, the borohydride/substrate and Pd/substrate ra-
tios. The critical role of Pd was evident by the complete
inertness of epoxides 1 in the presence of NaBH4 alone at
room temp. for 24 h. Although different Pd/substrate ratios
(at a given Pd/substrate ratio) not only favours reductive
ring-opening over side-reactions, but also influences the re-
gioselectivity of the reaction. Under these conditions,
NaBH4 likely produces a more “hydridic” reducing reagent
with properties different to those of H2 in catalytic hydro-
genation reactions. To support this hypothesis and to show
that a mechanism involving an acyclic cationic type inter-
mediate was not operating in the case of 1c, we treated it
with ZnI2/NaCNBH3, which is known to proceed by Lewis
acid activation of the epoxide towards nucleophilic attack.
In this case the main reaction product was 2,2-diarylethanol
12 (together with the expected 3c), likely derived from the
reduction of aldehyde 11, which was initially formed by re-
arrangement of the starting epoxide (Scheme 4).[26]
Scheme 4.
Finally, we tried to apply the most efficient procedures
influenced only the reaction times, different NaBH4/sub- to enantiopure 2-pyridyl epoxide (R,R)-1a and o-meth-
strate ratios gave rise to different reaction mixtures. As an oxyphenyl epoxide (R,R)-1c (Scheme 5) to obtain valuable
example, with a NaBH4/substrate ratio of 2.5:1.0, pyridyl ligands that would be useful in asymmetric synthesis.
Eur. J. Org. Chem. 2009, 938–944
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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941

N. Di Blasio, M. T. Lopardo, P. Lupattelli
FULL PAPER
Different regioisomers were obtained by using the H2/Pd,
[Cp2TiCl]/H2O or NaBH4/Pd/C systems. Application of
these procedures to enantiopure epoxides resulted in no loss
of optical purity in the corresponding products.
Experimental Section
General: 1H and 13C NMR spectra were recorded at 500 and
125 MHz, respectively. Mass spectra were recorded with a Hewlett–
Packard 6890 chromatograph equipped with a HP 5973 mass detec-
tor. Commercially available reagents were used without further pu-
rification. All reactions were monitored by TLC on silica gel coated
plates. Column chromatography was carried out by using 60–
240 mesh silica gel at atmospheric pressure.
Scheme 5. Synthesis of enantiopure (R,R)-1a and (R,R)-1c.
Both epoxides (R,R)-1a and -1c were prepared in good
yields and ee values following the literature procedure[11b,12]
starting from 2-pyridinecarbaldehyde and 2-methoxybenz-
aldehyde, respectively, and 1 equiv. of a sulfur ylide, which
was preformed in situ by deprotonation of the sulfonium
salt 13, derived from Eliel’s oxathiane.
Epoxide (R,R)-1a was also submitted to Pd-catalysed hy-
drogenation and reduction with NaBH4/Pd to afford two
regioisomeric pyridyl alcohols (S)-2a and (S)-3a, respec-
tively, as the main products. Analogously, (R,R)-1c was
treated with the [Cp2TiCl] system, which afforded the corre-
sponding alcohol (S)-3c (Scheme 6). In all cases no loss of
optical purity was observed,[27] proving that no epimeri-
zation occurred during the oxiranyl ring-opening, irrespec-
tive of the method used.
(E)-3-Phenyl-2-(2-pyridyl)oxirane (1a): Oxirane 1a was obtained in
67% yield (247 mg from 200 mg of picolinecarbaldehyde) after
1
chromatographic purification (CHCl3/Et2O, 7:3). The H and 13C
NMR spectra were consistent with literature data.[12]
(2R,3R)-3-Phenyl-2-(2-pyridyl)oxirane [(R,R)-1a]: Oxirane (R,R)-1a
was prepared in 82% yield (302 mg from 200 mg of picolinecarbal-
dehyde) and 99% ee (CHIRALCEL ODH, n-hexane/2-propanol,
90:10, flow rate: 1.0 mLmin–1) according to a literature pro-
cedure.[12]
(E)-3-Phenyl-2-(4-pyridyl)oxirane (1b): Oxirane 1b was obtained in
95% yield (350 mg from 200 mg of picolinecarbaldehyde) after
1
chromatographic purification (CHCl3/Et2O, 7:3). The H and 13C
NMR spectra were consistent with literature data.[28]
(E)-2-(2-Methoxyphenyl)-3-phenyloxirane (1c), (E)-2-(4-Meth-
oxyphenyl)-3-phenyloxirane (1d), (E)-3-Phenyl-2-(4-trifluoromethyl-
phenyl)oxirane (1f), (E)-2-(4-Fluorophenyl)-3-phenyloxirane (1g) and
(E)-1-Phenylpropylene Oxide (1h): Oxiranes 1c,d,f–h were obtained
according to literature procedures.[10c]
(2R,3R)-2-(2-Methoxyphenyl)-3-phenyloxirane [(R,R)-1c]: Oxirane
(R,R)-1c was prepared in 65% yield (216 mg from 200 mg of 2-
methoxybenzaldehyde) and 99% ee (CHIRALCEL OJ, n-hexane/
2-propanol, 99:1, flow rate: 0.5 mLmin–1) according to a literature
procedure.[11b]
(E)-3-Phenyl-2-(2-trifluoromethylphenyl)oxirane (1e): Oxirane 1e
was obtained in 90% yield (273 mg from 200 mg of 2-trifluoroben-
zaldehyde) after chromatographic purification (petroleum ether/
CH2Cl2, 4:1) as a colourless oil. Rf = 0.65. 1H NMR (500 MHz,
3
3
CDCl3): δ = 3.76 (d, J = 2.0 Hz, 1 H), 4.23 (d, J = 2.0 Hz, 1 H),
7.37–7.46 (m, 6 H), 7.62 (AB system, JAB = 7.5 Hz, 2 H), 7.68 (d,
3J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 59.1,
62.6, 124.2 (q, 1JCF = 273 Hz), 125.4, 125.5, 125.6, 127.8, 128.1 (q,
2JCF = 32 Hz), 128.5, 128.6, 132.3, 135.8, 136.3 ppm. MS: m/z (%)
= 264 (100) [M]+, 246 (21), 235 (58), 215 (46), 195 (37), 167 (41),
90 (92), 89 (78). C15H11F3O (264.08): calcd. C 68.18, H 4.20; found
C 68.20, H 4.18.
Scheme 6. Reductive ring-opening of enantiopure (R,R)-1a and
(R,R)-1c.
Beyond mechanistic considerations, the synthetic value
of the three different reductive ring-opening methods is un-
questionable. They represent powerful tools for enantio-
specific access to functionalized chiral 1,2-diarylethanols
from easy-to-make diaryl epoxides.
General Procedure for Pd/C Catalytic Hydrogenation: A mixture
of epoxide (1 mmol), 10% Pd/C (60 mg) in CH3OH (20 mL; or
1%AcOH in AcOEt) was stirred at room temperature under H2
(1 atm.). At the end of the reaction the catalyst was removed by
filtration and the mixture was evaporated under vacuum. The prod-
ucts were isolated by chromatographic purification of the crude
product on silica gel.
Conclusions
General Procedure for Reductive Ring-Opening Mediated by
[Cp2TiCl]/H2O: A mixture of [Cp2TiCl2] (1.1 mmol) and Mn dust
(4 mmol) in THF (25 mL) was stirred at room temp. until the red
We have developed a new regio- and enantioselective ap-
proach to 1,2-diarylethanols from the corresponding parent
2,3-diaryloxiranes by the use of suitable reductive systems. colour turned green (about 5 min) and then a deoxygenated solu-
942 Eur. J. Org. Chem. 2009, 938–944
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Diarylethanols by Reductive Ring-Opening of Diaryloxiranes
tion of the corresponding epoxide (0.5 mmol) and H2O (20 mmol)
in THF (3 mL) was added and the mixture stirred for 6 h. The
reaction was quenched with 5% aqueous NaH2PO4 and extracted
with tBuOMe. The organic layer was washed with brine, dried with
anhydrous Na2SO4 and the solvent evaporated under vacuum. The
products were isolated by chromatographic purification of the
crude product on silica gel.
13C NMR (125 MHz, CDCl3): δ = 45.0, 74.5, 124.9, 125.8, 128.0,
128.6, 143.3, 147.4, 149.5 ppm. MS: m/z (%) = 199 (0.2) [M]+, 181
(7.5), 107 (28), 93 (100). C13H13NO (199.10): calcd. C 78.36, H
6.58, N 7.03; found C 78.52, H 6.48, N 7.12.
1-(2-Methoxyphenyl)-2-phenylethanol (2c) and 2-(2-Methoxy-
phenyl)-1-phenylehanol (3c): Alcohols 2c and 3c were obtained as
mixture in 95% yield (96 mg from 100 mg of 1c) by reduction by
Pd/C catalytic hydrogenation, the [Cp2TiCl]/H2O system or the
NaBH4/Pd system after chromatographic purification (petroleum
General Procedure for Reduction with the NaBH4/Pd/C System: A
mixture of NaBH4 (7.5 equiv.) in H2O (7 mL) was poured into a
suspension of 10% Pd/C (50 mg) in CH3OH (5 mL) under argon
and the mixture was cooled to 0 °C. A solution of epoxide (1 mmol)
in CH3OH (10 mL) was added dropwise. At the end of the reaction
the catalyst was removed by filtration, the methanol evaporated
under vacuum and the resulting mixture extracted with EtOAc. The
organic phase was washed with brine, dried on anhydrous Na2SO4
and the solvents evaporated under vacuum. The products were iso-
lated by chromatographic purification of the crude product on sil-
ica gel.
1
1
ether/Et2O, 3:2) and were analysed by H NMR spectroscopy. H
NMR (500 MHz, CDCl3): 72:28 mixture of 2c and 3c: δ = 2.50 (br.
2
3
s, 1 H), 2.98 (A part of ABX system, JAB = 13.0, JAX = 8.0 Hz,
2
3
1 H, 72%), 3.08 (A part of ABX system, JAB = 14.0, JAX
9.0 Hz, 1 H, 28%), 3.15 (B part of ABX system, JAB = 14.0, JBX
= 4.0 Hz, 1 H, 28%), 3.17 (B part of ABX system, JAB = 13.0,
=
2
3
2
3JBX = 3.0 Hz, 1 H, 72%), 3.84 (s, 3 H, 72%), 3.87 (s, 3 H, 28%),
5.00 (X part of ABX system, 3JAX = 9.0, 3JBX = 4.0 Hz, 1 H, 28%),
5.17 (X part of ABX system, 3JAX = 8.0, 3JBX = 3.0 Hz, 1 H, 72%),
6.90 (m, 2 H, 28%), 6.98 (m, 2 H, 72%), 7.10 (d, 3J = 8.0 Hz, 1
H), 7.22–7.27 (m, 2 H), 7.32–7.39 (m, 2 H), 7.62–7.68 (m, 2
H) ppm. 13C NMR (125 MHz, CDCl3): characteristic signals of 2c:
δ = 44.2, 55.3, 71.5 ppm.
2-Phenyl-1-(2-pyridyl)ethanol (2a): Alcohol 2a was obtained in 90%
yield (91 mg from 100 mg of 1a) by Pd/C catalytic hydrogenation
after chromatographic purification (CHCl3/Et2O = 7:3). The 1H
and 13C NMR spectra were consistent with literature data.[12]
(2S)-2-(2-Methoxyphenyl)-1-phenylethanol [(S)-3c]: Alcohol (S)-3c
was obtained in 72% yield [73 mg from 100 mg of (R,R)-1c] by
reduction with the [Cp2TiCl]/H2O system after chromatographic
purification (petroleum ether/toluene/diethyl ether, 7:2:1) as a
colourless oil (Rf = 0.35) and with 90% ee (CHIRALCEL OJ, n-
hexane/2-propanol, 90:10, flow rate: 1.0 mLmin–1). [α]2D5 = +8.8 (c
1-Phenyl-2-(2-pyridyl)ethanol (3a): Alcohol 3a was obtained in 80%
yield (81 mg from 100 mg of 1a) by reduction with the NaBH4/Pd
system after chromatographic purification (CHCl3/Et2O = 7:3).
The 1H and 13C NMR spectra were consistent with literature
data.[12]
(1S)-2-Phenyl-1-(2-pyridyl)ethanol [(S)-2a]: Alcohol (S)-2a was ob-
tained in 90% yield [91 mg from 100 mg of (R,R)-1a] by Pd/C cata-
lytic hydrogenation after chromatographic purification (CHCl3/
Et2O = 7:3) and with 90% ee (CHIRALCEL ODH, n-hexane/2-
propanol, 80:20, flow rate: 1.0 mLmin–1). The optical rotation and
1H and 13C NMR spectra were consistent with literature data.[12]
1
= 0.25, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 2.50 (br. s, 1
H), 3.08 (A part of ABX system, 2JAB = 14.0, 3JAX = 9.0 Hz, 1 H),
2
3
3.15 (B part of ABX system, JAB = 14.0, JBX = 4.0 Hz, 1 H),
3
3
3.87 (s, 3 H), 5.00 (X part of ABX system, JAX = 9.0, JBX
=
3
4.0 Hz 1 H), 6.90 (m, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.22–7.27
(m, 2 H), 7.32–7.39 (m, 2 H), 7.62–7.68 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 41.2, 55.4, 74.3, 110.4, 120.7, 125.7, 127.2,
128.0, 128.2, 131.5, 144.5, 157.6 ppm. MS: m/z (%) = 228 (2)
[M]+, 122 (100), 107 (35), 91 (22). C15H16O2 (228.12): calcd. C
78.92, H 7.06; found C 78.83, H 7.12.
(2S)-1-Phenyl-2-(2-pyridyl)ethanol [(S)-3a]: Alcohol (S)-3a was ob-
tained in 80% yield [81 mg from 100 mg of (R,R)-1a] by reduction
with the NaBH4/Pd system after chromatographic purification
(CHCl3/Et2O, 7:3) and with 90% ee (CHIRALCEL ODH, n-hex-
ane/2-propanol, 80:20, flow rate 1.0 mLmin–1). The optical rota-
1-(4-Methoxyphenyl)-2-phenylethanol (2d) and 2-(4-Methoxy-
phenyl)-1-phenylethanol (3d): Alcohols 2d and 3d were obtained as
a mixture in 95% yield (96 mg from 100 mg of 1d) by Pd/C catalytic
hydrogenation and reduction with the [Cp2TiCl]/H2O system and
in 75% yield by reduction with the NaBH4/Pd system after chroma-
tographic purification (petroleum ether/Et2O, 3:2). The 1H NMR
spectra were consistent with literature data.[29] 1H NMR (500 MHz,
CDCl3): 87:13 mixture of 2d and 3d: δ = 1.85 (br. s, 1 H), 2.90 (m,
2 H), 3.71 (s, 3 H, 13%), 3.73 (s, 3 H, 87%), 4.78 (m, 1 H), 6.77
1
tion and H and 13C NMR spectra were consistent with literature
data.[12]
2-Phenyl-1-(4-pyridyl)ethanol (2b): Alcohol 2b was obtained in 90%
yield (81 mg from 100 mg of 1b) by Pd/C catalytic hydrogenation
after chromatographic purification (CHCl3/Et2O, 7:3) as a colour-
1
less oil. Rf = 0.15. H NMR (500 MHz, CDCl3): δ = 2.87 (A part
2
3
of ABX system, JAB = 13.5, JAX = 8.5 Hz, 1 H), 2.95 (B part of
2
3
ABX system, JAB = 13.5, JAX = 5.0 Hz, 1 H), 3.11 (br. s, 1 H),
4.81 (X part of ABX system, dd, JAX = 8.5, JBX = 5.0 Hz, 1 H),
7.08 (d, J = 7.5 Hz, 2 H), 7.15–7.18 (m, 3 H), 7.22 (dd, J1 = J2 =
3
3
3
3
(d, J = 7.5 Hz, 2 H, 13%), 6.81 (d, J = 7.5 Hz, 2 H, 87%), 7.03
3
3
3
(d, J = 7.5 Hz, 2 H, 13%), 7.11 (d, J = 7.5 Hz, 2 H, 87%), 7.20
7.5 Hz, 2 H), 8.37 (d, 3J = 5.0 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 45.7, 73.6, 120.9, 126.9, 128.6, 129.5, 137.0, 149.5,
152.9 ppm. MS: m/z (%) = 199 (5) [M]+, 180 (6), 108 (69), 92 (100),
91 (72). C13H13NO (199.10): calcd. C 78.36, H 6.58, N 7.03; found
C 78.39, H 6.61, N 7.10.
(m, 5 H) ppm.
2-Phenyl-1-(2-trifluoromethylphenyl)ethanol (2e): Alcohol 2e was
obtained in 70% yield (71 mg from 100 mg of 1e) by catalytic hy-
drogenation (in 1%AcOH/AcOEt) and in 90% yield by reduction
with the NaBH4/Pd system after chromatographic purification (pe-
troleum ether/Et2O, 3:2) as a colourless oil. Rf = 0.45. 1H NMR
1-Phenyl-2-(4-pyridyl)ethanol (3b): Alcohol 3b was obtained in 75%
yield (76 mg from 100 mg of 1b) by reduction with the NaBH4/Pd
system after chromatographic purification (CHCl3/Et2O, 7:3) as a
colourless oil. Rf = 0.21. 1H NMR (400 MHz, CDCl3): δ = 2.91 (A
2
(500 MHz, CDCl3): δ = 2.84 (A part of ABX system, JAB = 14.0,
3JAX = 10.0 Hz, 1 H), 3.10 (B part of ABX system, JAB = 14.0,
2
3JBX = 2.4 Hz, 1 H), 5.33 (X part of ABX system, JAX = 10.0,
3
2
3
part of ABX system, JAB = 14.0, JAX = 5.0 Hz, 1 H), 2.97 (B
3JBX = 2.5 Hz, 1 H), 7.20–7.30 (m, 5 H), 7.33 (dd, 3J1 = J2
=
2
3
part of ABX system, JAB = 14.0, JBX = 8.0 Hz, 1 H), 4.85 (X
7.5 Hz, 1 H), 7.54 (dd, 3J1
=
3J2 = 7.5 Hz, 1 H), 7.58 (d, 3J =
3
3
3
part of ABX system, JAX = 5.0, JBX = 8.0 Hz 1 H), 7.02 (d, J =
5.5 Hz, 2 H), 7.18–7.28 (m, 5 H), 8.36 (d, J = 5.5 Hz, 2 H) ppm.
7.5 Hz, 1 H), 7.80 (d, 3J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz,
3
1
3
CDCl3): δ = 46.2, 70.7, 124.4 (q, JCF = 251 Hz), 125.4 (q, JCF
=
Eur. J. Org. Chem. 2009, 938–944
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
943

N. Di Blasio, M. T. Lopardo, P. Lupattelli
FULL PAPER
2
45, 2041–2044; c) A. Gansäuer, T. Lauterbach, S. Narayan, An-
gew. Chem. Int. Ed. 2003, 42, 5556–5573.
6.0 Hz), 126.5 (q, JCF = 30 Hz), 126.8, 127.5, 127.6, 128.7, 129.5,
132.3, 138.1, 143.0 ppm. MS: m/z (%) = 266 (2) [M]+, 155 (64), 127
(28), 92 (100). C15H13F3O (266.09): calcd. C 67.66, H 4.92; found
C 67.52, H 5.03.
[9] C. Bonini, P. Lupattelli, ARKIVOC 2008, 4, 150–182.
[10] a) A. Solladié-Cavallo, P. Lupattelli, C. Marsol, T. Isarno, C.
Bonini, L. Caruso, A. Maiorella, Eur. J. Org. Chem. 2002,
1439–1444; b) P. Lupattelli, C. Bonini, L. Caruso, A.
Gambacorta, J. Org. Chem. 2003, 68, 3360–3362; c) A. Sol-
ladié-Cavallo, P. Lupattelli, C. Bonini, J. Org. Chem. 2005, 70,
1605–1611.
[11] a) C. Bonini, L. Chiummiento, M. Funicello, M. T. Lopardo,
P. Lupattelli, A. Laurita, A. Cornia, J. Org. Chem. 2008, 73,
4233–4236; b) A. Solladié-Cavallo, E. Choucair, M. Balaz, P.
Lupattelli, C. Bonini, N. Di Blasio, Eur. J. Org. Chem. 2006,
3007–3011.
[12] A. Solladié-Cavallo, M. Roje, T. Isarno, V. Sunjic, V. Vinkovic,
Eur. J. Org. Chem. 2000, 1077–1080.
[13] A. Solladié-Cavallo, P. Lupattelli, C. Bonini, V. Ostuni, N.
Di Blasio, J. Org. Chem. 2006, 71, 9891–9894.
[14] a) K. Nordström, E. Macedo, C. Moberg, J. Org. Chem. 1997,
62, 1604–1609; b) E. N. Jacobsen, A. Pfaltz, H. Yamamoto,
Comprehensive Asymmetric Catalysis, Springer, Berlin, Heidel-
berg, 1999.
1-Phenyl-2-(2-trifluoromethylphenyl)ethanol (3e): Alcohol 3e was
obtained as a mixture with 2e (2e/3e = 86:14) from 1e by reduction
1
with the [Cp2TiCl]/H2O system and identified by characteristic H
NMR signals. 1H NMR (500 MHz, CDCl3): δ = 3.16 (A part of
2
3
ABX system, JAB = 14.0, JAX = 8.5 Hz, 1 H), 3.26 (B part of
2
3
ABX system, JAB = 14.0, JBX = 3.0 Hz, 1 H), 4.95 (X part of
3
3
ABX system, JAX = 8.5, JBX = 3.0 Hz 1 H) ppm.
2-Phenyl-1-(4-trifluoromethylphenyl)ethanol (2f): Alcohol 2f was
obtained in 60% yield (60 mg from 100 mg of 1f) by catalytic hy-
drogenation (in 1%AcOH/AcOEt) and 65% yield (65 mg from
100 mg of 1f) by reduction with the NaBH4/Pd system after chro-
1
matographic purification (petroleum ether/Et2O, 3:2). The H and
13C NMR spectra were consistent with literature data.[30]
1-(4-Fluorophenyl)-2-phenylethanol (2g): Alcohol 2g was obtained
in 70% yield (71 mg from 100 mg of 1g) by catalytic hydrogenation
after chromatographic purification (petroleum ether/Et2O, 4:1).
The 1H and 13C NMR spectra were consistent with literature
data.[30]
[15] S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogen-
ation for Organic Synthesis, Wiley, New York, chapter 13.1.2,
p. 575, 2001.
[16] The regiochemistries of the products were determined by com-
1
parison of H NMR spectra with known compounds (2a, 2d,
2f, 2g, 3d and 3h) or by MS identification of characteristic frag-
ments of type 5 for regioisomer 2 (2b and 2e) and of type 6 for
regioisomer 3 (3b, 3e and 3f).
3-Phenyl-2-propanol (3h): Alcohol 3h was obtained in 95% yield
(96 mg from 100 mg of 1h) by catalytic hydrogenation and 90%
yield by reduction with the NaBH4/Pd system after chromato-
graphic purification (petroleum ether/Et2O, 4:1). The 1H and 13C
NMR spectra were consistent with literature data.[30]
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures for the synthesis of com-
1
[17] a) Z. Wen, Z. Li, Z. Shang, J.-P. Cheng, J. Org. Chem. 2001,
66, 1466–1472; b) R. I. Walter, J. Am. Chem. Soc. 1966, 88,
1923–1930.
pounds 1a–g and 12. H NMR spectra of compounds 1a–h, 2a–g,
3a–d, 3h and 12. 13C NMR spectra of compounds 1e, 2b, 2e, 3b,
3c and 12.
[18] T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116,
986–997.
[19] J. M. Cuerva, A. G. Campaña, J. Justicia, A. Rosales, J. L.
Oller-Lopez, R. Robles, D. J. Càrdenas, E. Buñuel, J. E. Oltra,
Angew. Chem. Int. Ed. 2006, 45, 5522–5526.
[20] M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed.,
Wiley-Interscience, 2001, chapter 10, p. 529.
[21] Y. R. S. Laxmi, D. S. Iyengar, Synth. Commun. 1997, 27, 1731–
1736.
Acknowledgments
We thank the Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) (Project PRIN 2005) and the University of Basili-
cata for financial support.
[22] B. C. Ranu, A. R. Das, J. Chem. Soc. Perk. Trans. 1 1992, 1881.
[23] L. M. Finkielsztein, J. M. Aguirre, B. Lantaño, E. N. Alesso,
G. Y. Moltrasio Iglesias, Synth. Commun. 2004, 34, 895–901.
[24] W. B. Smith, J. Heterocycl. Chem. 1987, 24, 745–748.
[25] T. Neilson, H. C. S. Wood, A. G. Wylie, J. Chem. Soc. 1962,
371.
[1] T. M. Flaherty, J. Gervay, Tetrahedron Lett. 1996, 37, 961–964.
[2] P. Chochrek, A. Kurek-Tyrlik, K. Michalak, J. Wicha, Tetrahe-
dron Lett. 2006, 47, 6017–6020.
[3] L. M. Schultze, H. H. Chapman, N. J. P. Dubree, R. J. Jones,
K. M. Kent, T. T. Lee, M. S. Louie, M. J. Postich, E. J. Prisbe,
J. C. Rohloff, R. H. Yu, Tetrahedron Lett. 1998, 39, 1853–1856. [26] Epoxide 1c in the presence of ZnI2 at room temp. gave an alde-
[4] P. S. Dragovich, T. J. Prins, R. Zhou, J. Org. Chem. 1995, 60,
4922–4924.
hyde of type 9 quantitatively.
[27] The ee values were measured by HPLC analysis using CHI-
RALCEL ODH as the chiral stationary phase (see Exp. Sect.).
[28] V. K. Aggarwal, E. Alonso, I. Bae, G. Hynd, K. M. Lydon,
M. J. Palmer, M. Patel, M. Porcelloni, J. Richardson, R. A.
Stenson, J. R. Studley, J. Vasse, C. L. Winn, J. Am. Chem. Soc.
2003, 125, 10926–10940.
[5] H. Sajiki, K. Hattori, K. Hirota, Chem. Commun. 1999, 1041–
1042.
[6] S. V. Ley, C. Mitchell, D. Pears, C. Ramarao, J.-Q. Yu, W.
Zhou, Org. Lett. 2003, 5, 4665–4668.
[7] M. S. Kwon, I. S. Park, J. S. Jang, J. S. Lee, J. Park, Org. Lett.
2007, 9, 3417–3419.
[8] 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,
[29] G. V. M. Sharma, K. Laxmi Reddy, P. S. Lakshmi, R. Ravi,
A. C. Kunwar, J. Org. Chem. 2006, 71, 3967–3969.
[30] R. P. Singh, B. Twamley, L. Fabry-Asztalos, D. S. Matteson,
J. M. Shreeve, J. Org. Chem. 2000, 65, 8123–8125.
Received: November 13, 2008
Published Online: January 2, 2009
944
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 938–944