Mixed disproportionation versus radical trapping in titanocene(III)-promoted epoxide openings

Article abstract of DOI:10.1016/j.tet.2009.10.038

The formation of either deoxygenation products or allylic alcohols from epoxides is observed when these substrates are treated with Cp₂TiCl under anhydrous conditions. It seems that processes via trisubstituted radicals give allylic alcohols whereas processes via disubstituted radicals may give deoxygenation products or allylic alcohols depending on the structure of the original epoxide. This method allows a controlled access to these functional groups, providing a useful tool in organic synthesis. A mechanistic discussion for these transformations is reported.

Full text of DOI:10.1016/j.tet.2009.10.038

Tetrahedron 65 (2009) 10837–10841
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Tetrahedron
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Mixed disproportionation versus radical trapping in titanocene(III)-promoted
epoxide openings
*
*
*
´
´
Jose Justicia , Tania Jimenez, Sara P. Morcillo, Juan M. Cuerva , J. Enrique Oltra
Department of Organic Chemistry, Faculty of Sciences, University of Granada, C.U. Fuentenueva s/n, E-18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of either deoxygenation products or allylic alcohols from epoxides is observed when these
substrates are treated with Cp2TiCl under anhydrous conditions. It seems that processes via tri-
substituted radicals give allylic alcohols whereas processes via disubstituted radicals may give de-
oxygenation products or allylic alcohols depending on the structure of the original epoxide. This method
allows a controlled access to these functional groups, providing a useful tool in organic synthesis. A
mechanistic discussion for these transformations is reported.
Received 31 July 2009
Received in revised form
21 September 2009
Accepted 9 October 2009
Available online 15 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
eventually evolves to an alkene, the corresponding deoxygenation
product from the original epoxide.3 Nevertheless, the behaviour of
In recent years Cp2TiCl,1 a mild single-electron-transfer reagent
has become an indispensable tool in organic synthesis.2 It has been
used in many interesting transformations, such as the homolytic ring
opening of epoxides,3 the radical cascade cyclization of epoxy-
polyenes,4 Michael-type coupling between aldehydes and conju-
gated alkenals,5 pinacol coupling reactions,6 H-atom transfer from
water to free radicals,7 alkenes and alkynes,8 divergent C–C bond-
forming reactions with modulation by Ni or Pd,9 metal-catalyzed
trisubstituted titanoxy radicals such as I seems to be more complex
than previously thought. In fact, we have observed that from some
epoxides the main products are allylic alcohols (Scheme 2) instead
R1
O
R2
R3
Barbier-type cyclizations and
a
-prenylation of carbonyl derivatives,10
-haloketones to carbonyl
Cp2TiCl
and the Reformastky-type addition of
a
R1
R2
R3
compounds.11 Interestingly, during the last few years new de-
velopments in titanocene-regenerating agents have led to many
transformations being carried out using only 5–20 mol % of titanium
catalyst.12 Within this context, by using a combination of 2,4,6-col-
lidine and trimethylsilyl chloride, developed in our laboratory, we
have been able to regenerate Cp2TiCl2 from different species such as
titanium alkoxides, carboxylates and hydrides.13
ClCp2TiO
I
Cp2TiCl
TiCp2Cl
R2
H
A
B
R
2 R1
ClCp2Ti
ClCp2TiO
R3
ClCp2TiO
R3
II
Between 1988 and 1994 RajanBabu and Nugent developed their
seminal work on the homolytic opening of epoxides promoted by
Cp2TiCl, which, among other transformations, facilitates epoxide
deoxygenation under mild conditions.3 The mechanism proposed
by RajanBabu and Nugent for this transformation is summarized in
Scheme 1, path A. The reaction begins with the homolytic opening
of the oxirane ring mediated by Cp2TiCl,3 which leads to the most
R2
Cp TiClH
+
2
ClCp2TiO
R3
H+
stable b-titanoxy radical. This radical can be subsequently trapped
by a second Cp2TiCl species to yield a bimetallic intermediate that
R1
R2
R3
R2
R3
HO
* Corresponding authors. Tel.: þ34 958248090; fax: þ34 958248437 (J.J. and
J.M.C.); tel.: þ34 958248091; fax: þ34 958248437 (J.E.O.).
E-mail addresses: jjusti@ugr.es (J. Justicia), jmcuerva@ugr.es (J.M. Cuerva),
joltra@ugr.es (J.E. Oltra).
+"TiO"
Scheme 1. Mechanistic hypothesis for Cp2TiCl opening of epoxides.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.038

10838
J. Justicia et al. / Tetrahedron 65 (2009) 10837–10841
of the expected deoxygenation products.7 Thus, an alternative
mechanism may be involved. On the basis of kinetic experiments
we recently concluded that allylic alcohols cannot derive from
Table 1
Ti(III)-mediated opening of epoxides via tertiary radicalsa
Entry
1
Substrate
Product
Yield
54%
a b
-hydride elimination processes in bimetallic species such as II.7
HO
O
Therefore we considered the possibility of a mixed radical dispro-
portionation process,14 which would fit our experimental results
much more coherently (Scheme 1, path B).7
7
1
7
10
HO
O
Cp2TiCl
2
30%
OAc
OAc
THF
ref. 7
HO
O
tBu
2
tBu
11
71%
OAc
OAc
HO
Cp2TiCl
OH
O
O
THF
ref. 4e
BzO
BzO
3
4
76%b
38%
3
Scheme 2. Allylic alcohols obtained from Cp2TiCl-mediated epoxide opening.
12
Allylic alcohols are interesting building blocks in organic synthe-
sis. Additionally, the enantioselective synthesis of these compounds
might be easily accomplished via this procedure, remembering the
fact that enantioenriched oxirane rings can be successfully prepared
via well established asymmetric epoxidation reactions developed by
Sharpless, Katsuki, Jacobsen, Shi and others.15 In fact, a preliminary
experiment supporting this hypothesis has been recently described
by us.7 Nevertheless, the examples reported in the literature are too
scarce to infer when either the deoxygenation reaction or the for-
mation of allylic alcohols would be favoured. In any case, both re-
actions have synthetic interest and a clarification of the requirements
of these transformationswouldbe highly desirable. In fact, previously
described procedures for the deoxygenation of epoxides normally
require stoichiometric amounts of expensive metals, such as Nb, In or
Sm in their elemental state, and the reactions proceed in heteroge-
neous phase.16 Other metal-based electron-transfer reagents, such as
Cr(II), Nb(III) and reactive SmI2 have been used in homogeneous
conditions but are not often compatible with sensitive functional
groups.16 In addition, only a few versions using substoichiometric
amounts of homogeneous metal complexes for epoxide de-
oxygenation have been described.16a,17
Furthermore, the known methods for the synthesis of allylic al-
cohols from epoxides usually require very basic conditions not com-
patible with the presence of several functional groups.18 In contrast,
Cp2TiCl-mediated transformations take place under mild, neutral
conditions, which are compatible with many functional groups.
Within the context of these precedents, we describe here an in-
depth study of the homolytic opening of epoxides mediated by
Cp2TiCl under anhydrous conditions. Instead of the expected
alkenes, allylic alcohols are obtained from some substrates,
a transformation with few precedents in Ti(III) chemistry.7,19 What
is especially noteworthy is that these reactions can be carried out
using only substoichiometric amounts of the Ti(III) catalyst.
58%c
OBz
OBz
O
OH
13
4
HO
O
O
5
6
7
8
48%d
62%e
87%
5
14
OH
6
15
16
17
OAc
OAc
OAc
OAc
HO
HO
O
7
71%
O
8
OAc
O
OAc
9
62%
BzO
BzO
OH
18
9
a
Reactions were carried out by stirring the corresponding epoxide (1 mmol) with
Cp2TiCl2 (2.5 mmol) and Mn dust at rt in dry THF.
2. Results
b
19% reduction product was observed.
A trace of transesterification compound was observed.
32% reduction product was obtained.
Mixture 1:1 of stereoisomers.
c
Epoxides 1–9 were treated with stoichiometric quantities of
Cp2TiCl in anhydrous THF, that are the conditions described by
RajanBabu and Nugent for epoxide deoxygenation.3 Under these
conditions, however, allylic alcohols 10–18 were obtained (Table 1),
whereas deoxygenation products were not detected.
Results summarized in Table 1 confirm that, under anhydrous
conditions, the Ti(III)-mediated opening of epoxides via tri-
substituted radicals gives the corresponding allylic alcohols as main
d
e
products, with no deoxygenation compounds. This fact cannot be put
downto atitaniumradical trapping processto giveanorganometallic
alkyl-Ti(IV) intermediate, followed by
b-hydride elimination, be-
cause we have previously demonstrated that tertiary radicals are not

J. Justicia et al. / Tetrahedron 65 (2009) 10837–10841
10839
(or only very slowly) trapped by the bulky titanocene(III) species.7
Moreover, it is known that primary and secondary alkyl titanium(IV)
intermediates do not result in -hydride eliminationprocesses under
organometallic intermediate would give rise to an alkene, via b-
titanoxy elimination. It should be noted that styrene oxide (20)
only gave a 6% yield of the corresponding deoxygenation product
(28). This failed reaction could be due to the formation of a very
stabilized benzylic radical, which may go on to generate di-
merization products,22 and thus constitutes the main limitation of
this deoxygenation method.
A more complex behaviour was found with disubstituted ep-
oxides. With cyclic 1,2-disubstituted epoxides (23 and 24) we ob-
served that alkenes or allylic alcohols are obtained (entries 5 and 6),
depending on the size of the ring, which indicates a different
mechanism for each transformation. It is possible that the different
ring strain of the eight-membered and 12-membered rings may be
involved in this phenomenon. In the flexible 12-membered ring23
b
some conditions.20 Our experimental results can be better explained
on the basis of an intermolecular mixed disproportionation process,
which leads to the formation of an allylic alcohol, as set out above in
Scheme 1, path B. This reaction may be considered as being a milder
alternative to previously reported processes for the preparation of
allylic alcohols, providing greater selectivity and avoiding the mix-
tures of oxidation compounds obtained with previously described
reagents.18
With epoxides 3 and 5, products (12 and 14) derived from the
homolytic opening of the four-membered ring were obtained,
showing that the original b-titanoxy radical rearranged to a new
trisubstituted radical before the intermolecular mixed dispropor-
tionation process took place. In these cases, minor quantities of
reduction products were also found. It is worth noting that, under
treatment with the Cp2TiCl2/In couple, epoxides 5 and 6 gave de-
oxygenation products whilst formation of allylic alcohols 14 and 15
was not reported.16e
We also studied the behaviour of mono- and disubstituted ep-
oxides 19–26 using the same reaction conditions as those just de-
scribed (stoichiometric Cp2TiCl, dry THF). The results obtained are
summarized in Table 2.
the b-titanoxy radical formed after the epoxide opening may be
trapped by a second titanocene(III) species, leading to the de-
oxygenation product 32, according to the mechanism proposed by
RajanBabu and Nugent.3 On the other hand, in the relatively
strained eight-membered ring,23 the
b-titanoxy radical can hardly
be trapped by a second Cp2TiCl species and so it undergoes a mixed
disproportionation process leading to allylic alcohol 31 (Scheme 1,
path B). In the case of acyclic 1,2-disubstituted epoxides, de-
oxygenation products are always obtained (entries 7 and 8) fol-
lowing path A of Scheme 1. In the case of entry 7, we started from
a 2:8 mixture of the cis/trans isomers of 25 and obtained a 7:3
mixture of the Z:E isomers of 33. Similar isomerisation processes
were observed by RajanBabu and Nugent,3 who obtained the same
mixture of alkenes (7:3, Z:E) from both cis and trans epoxides.
The Ti(III)-based method, which facilitates the preparation of
either allylic alcohols or alkenes from suitable substrates in a pre-
dictable way, can also be undertaken using substoichiometric
Table 2
Ti(III)-mediated opening of epoxides via secondary radicals
Entry
1
Substrate
Product
Yield
80%
O
Ph
Ph
27
19
O
Ph
2
3
6%
Ph
Table 3
28
Ti-catalyzed opening of epoxides 5, 7, 19, 21, 24 and 26a
20
O
Entry
Substrate
Product
Yield
64%b
15
29
89%
15
21
HO
O
MeO2C
MeO2C
MeO2C
MeO2C
4
5
61%
73%
O
1
30
22
5
14
O
OH
23
31
2
74%
OAc
OAc
HO
Ph
O
O
6
7
60%a
75%b
16
7
O
32
24
25
3
4
65%
94%
Ph
27
MeO2C
MeO2C
MeO2C
MeO2C
19
O
O
33
15
29
15
21
8
49%
O
35%c
56%
O
5
26
34
32
24
a
Volatile product 32 was obtained as a roughly 1:1 mixture of cis/trans isomers.
Mixture 7:3 of Z:E isomers.
b
6
O
Monosubstituted epoxides (19–22) always provided de-
oxygenation compounds, as might be expected.21 This can be
explained if we bear in mind path A shown in Scheme 1, proposed
by RajanBabu and Nugent.3 In this kind of epoxides, where steric
34
26
a
Reactions were carried out by stirring the corresponding epoxide (1 mmol) with
Cp2TiCl2 (0.2 mmol) and Mn dust at rt in dry, THF.
b
hindrance is low, the
b-titanoxy radical can be trapped by a second
36% reduction product was obtained.
Volatile product 32 was obtained as a roughly 1:1 mixture of cis/trans isomers.
c
Cp2TiCl species to give an alkyl-Ti(IV) intermediate. This

10840
J. Justicia et al. / Tetrahedron 65 (2009) 10837–10841
amounts of Cp2TiCl, and a mixture of 2,4,6-collidine and Me3SiCl as
titanocene-regenerating agent.13 Ti-catalyzed opening of epoxides
5, 7, 19, 21, 24 and 26 under these conditions gave products 14, 16,
27, 29, 32 and 34, respectively, in moderate (35% for volatile 32) to
excellent (94% for 29) yields (Table 3).
22.5 (CH2), 21.9 (CH3), 21.3 (CH3),16.8 (CH3),15.4 (CH3); HRMS (FAB)
m/z calcd for C24H32O5Na [MþþNa] 423.2147, found 423.2144.
4.3.2. Compound 25. Mixture 2:8 of Z:E isomers. Colourless oil; 1H
NMR (400 MHz, CDCl3)
d 3.66 (s, 3H), 3.65 (s, 3H), 2.64–2.61 (m,
The results obtained under catalytic conditions have the same
profile as those observed when using stoichiometric proportions of
Cp2TiCl. To our knowledge this is the first metal-catalyzed pro-
cedure for the controlled deoxygenation of epoxides at room
temperature, under mild conditions compatible with many func-
tional groups.
2H), 2.03 (dd, J¼14.3, 4.8 Hz, 1H), 1.90 (dd, J¼14.3, 6.4 Hz, 1H), 1.18
(d, J¼4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT)
d 172.1 (C), 55.6
(CH), 54.2 (CH), 53.0 (CH, Z isomer), 52.6 (CH3), 52.5 (CH3), 51.9 (CH,
Z isomer), 38.5 (CH2), 33.8 (CH2, Z isomer), 20.4 (CH3), 20.2 (CH3, Z
isomer), 17.3 (CH3), 13.1 (CH3, Z isomer); HRMS (ESþ) m/z calcd for
C10H17O5 [MþH]þ 217.1076, found 217.1072.
3. Conclusion
4.4. General procedure for Ti-promoted epoxide openings
We describe a method for the deoxygenation or formation of
allylic alcohols from suitable epoxides mediated/catalyzed by tita-
nocene(III). This method facilitates the access to these versatile
functional groups in a controlled way, providing a useful tool in
organic synthesis. Additionally, our results allow us to propose
a plausible mechanism involving a mixed disproportionation pro-
cess to explain the formation of allylic alcohols instead of de-
oxygenation products from tertiary radicals.
Thoroughly deoxygenated THF (20 mL) was added to a mixture
of commercial 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 ep-
oxide (1 mmol) in THF (1 mL) was then added and the mixture was
stirred for 6–18 h, after which the reaction was quenched with
a saturated solution of KHSO4 and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over anhydrous Na2SO4
and the solvent removed. Products 10–18 and 27–34 were purified
by flash chromatography on silica gel (mixtures of hexane/EtOAc)
and characterized by spectroscopic techniques. Yields obtained are
reported in Tables 1 and 2.
4. Experimental section
4.1. General details
For all reactions with titanocene(III) the solvents and additives
were thoroughly deoxygenated prior to use. The following known
compounds were isolated as pure samples and showed NMR
spectra matching those of the reported compounds: 1,24 2,25 4,26
7,27 8,7 10,28 11,29 12,30 15,31 16,32 17,7 19,33 22,34 26,35 31,36 and 33.37
4.4.1. Compound 13. Colourless oil; 1H NMR (400 MHz, CDCl3)
d 8.05
(d, J¼7.5 Hz, 2H), 7.56 (t, J¼7.5 Hz,1H), 7.46 (t, J¼7.5 Hz, 2H), 5.15 (br s,
1H), 5.03(br s,1H), 4.45–4.23 (m, 3H),1.83 (s, 3H);13C NMR (100 MHz,
CDCl3; DEPT)
d 162.0 (C), 143.8 (C), 133.4 (CH), 130.1 (C), 129.9 (CH),
128.7 (CH),113.1 (CH2), 73.9 (CH), 67.9 (CH2),18.9 (CH3); HRMS (ESþ)
m/z calcd for C12H14O2 [MꢀOH]þ 190.0994, found 190.0974.
4.2. General procedure for the preparation of epoxides
(1 and 2) from ketones
4.4.2. Compound 18. Colourless oil; 1H NMR (300 MHz, CDCl3)
d
8.02 (d, J¼7.5 Hz, 2H), 7.53 (t, J¼7.5 Hz, 1H), 7.43 (t, J¼7.5 Hz, 2H),
A solution of ketone (1 mmol), CH2Br2 (2 mmol) in THF (15 mL)
was cooled to ꢀ78 ꢁC and then BuLi (2.5 M in hexane, 1.1 mmol)
was added dropwise for 5 min. The mixture was stirred for 5 min at
ꢀ78 ꢁC and then for 24 h at rt. AcOEt was then added and the or-
ganic layer was washed with saturated solution of NH4Cl, dried
over anhydrous Na2SO4 and the solvent removed. In this manner
products 1–2 were obtained, subsequently purified by flash chro-
matography on silica gel (mixtures of hexane/EtOAc) and finally
characterized by spectroscopic techniques.
5.07 (br s, 1H), 4.79 (dd, J¼11.1, 4.2 Hz, 1H), 4.66 (br s, 1H), 4.38 (m,
1H), 4.27 (dd, J¼11.4, 4.2 Hz, 1H), 4.20 (dd, J¼11.4, 7.8 Hz, 1H), 2.59
(t, J¼6.9 Hz, 1H), 2.00 (s, 3H), 1.95–1.58 (m, 7H), 1.00 (s, 3H), 0.95 (s,
3H), 0.79 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT)
d 171.3 (C), 166.2
(C), 147.7 (C), 132.9 (CH), 130.9 (C), 129.6 (CH), 128.4 (CH), 110.8
(CH2), 81.1 (CH), 73.3 (CH), 61.4 (CH2), 48.9 (CH), 46.7 (CH), 38.8 (C),
38.0 (C), 36.5 (CH2), 30.1 (CH2), 28.2 (CH3), 24.2 (CH2), 21.1 (CH3),
16.9 (CH3), 14.3 (CH3); HRMS (FAB) m/z calcd for C24H32O5Na
[MþþNa] 423.2147, found 423.2144.
4.3. General procedure for the preparation of epoxides
(4, 7–9, 19, 22 and 24–26) from alkenes
4.5. General procedure for Ti-catalyzed epoxide openings
Thoroughly deoxygenated THF (20 mL) was added to a mixture
of commercial Cp2TiCl2 (0.2 mmol) and Mn dust (8.0 mmol) under
an Ar atmosphere and the suspension was stirred at room tem-
perature until it turned lime green (after about 15 min). A solution
of epoxide (1 mmol) and 2,4,6-collidine (7 mmol) in THF (2 mL),
and Me3SiCl (4 mmol) were then added and the mixture was stirred
for 12–18 h. The reaction was then quenched with a saturated so-
lution of KHSO4 and extracted with EtOAc. The organic layer was
washed with brine, dried over anhydrous Na2SO4 and the solvent
removed. Products 14, 16, 27, 29, 32 and 34 were purified by flash
chromatography on silica gel (mixtures of hexane/EtOAc) and
characterized by spectroscopic techniques. Yields obtained are
reported in Table 3.
A sample of MCPBA (2 mmol, 70% purity) was added to a solu-
tion of epoxide (1 mmol) in CH2Cl2, and the mixture was stirred at
rt until the starting material was consumed (TLC analysis). CH2Cl2
was then added and the solution was washed with 2 N NaOH, dried
over anhydrous Na2SO4 and the solvent removed. In this manner
products 4, 7–9, 19, 22, 24–26 were obtained, purified by flash
chromatography on silica gel (mixtures of hexane/EtOAc) and
characterized by spectroscopic techniques.
4.3.1. Compound 9. Colourless oil; 1H NMR (300 MHz, CDCl3)
d 8.02
(d, J¼7.5 Hz, 2H), 7.53 (t, J¼7.5 Hz, 1H), 7.43 (t, J¼7.5 Hz, 2H), 4.70
(dd, J¼11.1, 4.2 Hz,1H), 4.33 (dd, J¼11.5, 4.5 Hz,1H), 4.03 (dd, J¼11.5,
4.5 Hz, 1H), 3.05 (br s, 1H), 2.08 (s, 3H), 2.05–1.60 (m, 6H), 1.35 (s,
3H),1.08 (s, 3H),1.07–0.93 (m, 2H), 0.93 (s, 3H), 0.89 (s, 3H); 13C NMR
Acknowledgements
(75 MHz, CDCl3; DEPT)
d 171.1 (C), 166.2 (C), 132.9 (CH), 130.9 (C),
129.7 (CH),128.7 (CH), 80.8 (CH), 62.7 (CH2), 60.9 (CH), 57.6 (C), 53.4
(CH), 45.2 (CH), 37.9 (C), 36.8 (CH2), 34.9 (C), 27.7 (CH3), 23.8 (CH2),
We thank the Spanish Ministry of Sciences and Innovation
(MCINN) (project CTQ2008-06790) and the Regional Government

J. Justicia et al. / Tetrahedron 65 (2009) 10837–10841
10841
11. Este´vez, R. E.; Paradas, M.; Milla´n, A.; Jime´nez, T.; Robles, R.; Cuerva, J. M.; Oltra,
J. E. J. Org. Chem. 2008, 73, 1616–1619.
´
of Andalucıa (project P05-FQM-1111 and aids to the group FQM339)
for financial support. T.J. thanks MCINN for her FPU fellowship. J.J.
thanks MCINN and the University of Granada for his ‘Juan de la
Cierva’ contract. We thank our English colleague Dr. J. Trout for
revising our English text.
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References and notes
1. Bis(cyclopentadienyl)titanium(III) chloride can be generated in situ by stirring
commercial Cp2TiCl2 with Zn or Mn dust in THF, where it exists as an equi-
librium mixture of the monomer Cp2TiCl and the dinuclear species [Cp2TiCl]2,
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