Non-Cp titanium alkoxide-based homolytic ring-opening of epoxides by an intramolecular hydrogen abstraction in β-titanoxy radical intermediates

Article abstract of DOI:10.1039/c1cc12969d

A low-valent titanium species derived in situ from Ti(O-i-Pr)₄, Me₃SiCl and Mg powder in tetrahydrofuran reacted with epoxides to selectively provide less hindered alcohols via a homolytic ring-opening of epoxides, in which the intermediate β-titanoxy radical intramolecularly abstracted a hydrogen atom from an alkoxy moiety in the titanium complexes.

Full text of DOI:10.1039/c1cc12969d

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COMMUNICATION
Non-Cp titanium alkoxide-based homolytic ring-opening of epoxides
by an intramolecular hydrogen abstraction in b-titanoxy radical
intermediatesw
Tsuyoshi Kawaji, Noriaki Shohji, Kenji Miyashita and Sentaro Okamoto*
Received 20th May 2011, Accepted 26th May 2011
DOI: 10.1039/c1cc12969d
A low-valent titanium species derived in situ from Ti(O-i-Pr)4,
Me3SiCl and Mg powder in tetrahydrofuran reacted with
epoxides to selectively provide less hindered alcohols via a
homolytic ring-opening of epoxides, in which the intermediate
b-titanoxy radical intramolecularly abstracted a hydrogen atom
from an alkoxy moiety in the titanium complexes.
In our study on low-valent titanium chemistry,8 we found
that the treatment of epoxide 1a with Ti(O-i-Pr)4/Me3SiCl/
Mg9 in tetrahydrofuran (THF) at room temperature provided
ring-opening products 2a and 2a0 (98 : 2) in 76% total yield
(Scheme 1). The results suggested that the reaction might
proceed through single-electron transfer from a low-valent
titanium species to the epoxide, generating b-titanoxy radical
intermediates i and ii.
Reduction of epoxides by single-electron transfer gives less
substituted alcohols and can be used to complement metal
hydride reduction which usually yields more substituted
alcohols.1 Until now, Cp2TiCl (Cp = Z5-cyclopentadienyl)
and its derivatives with a substituted Cp group(s) have been
valuable reagents for homolytic ring opening of epoxides.2,3
However, the procedure using these reagents requires stoichio-
metric amounts of
a hydrogen atom source such as
1,4-cyclohexadiene (CHD), t-BuSH and n-Bu3SnH for the
generated b-titanoxy radical in order to attain successful
reduction of epoxides to the corresponding saturated alcohols.4
Recently, water5 and Rh- or Ir-catalyzed hydrogen atom
6
transfer with H2 have been reported as alternative hydrogen
sources for b-titanoxy radicals. However, other than water,
these reagents are toxic, hazardous, expensive and/or foul
smelling; thus, seriously limiting the application of the reaction
for large-scale preparations.7 Moreover, stereocontrol of hydrogen
abstraction by the radical intermediates from such external
sources has been limited.
Herein, we report the first realization of an epoxide ring-
opening reaction mediated by a non-Cp titanium alkoxide
reagent, which can be generated in situ from Ti(O-i-Pr)4,
Me3SiCl and Mg powder under mild reaction conditions. It
was found that the b-titanoxy radical intermediates intra-
molecularly abstracted a hydrogen atom from an alkoxy
moiety attached to the titanium atom. Thus, this method does
not require an external hydrogen source and enables the
intramolecular control of the stereochemistry of the epoxide
reduction.
Department of Material & Life Chemistry, Kanagawa University,
3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan.
E-mail: okamos10@kanagawa-u.ac.jp; Fax: +81 45 413 9970;
Tel: +81 45 481 5661
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc12969d
Scheme 1 Reactions of epoxides.
c
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Chem. Commun., 2011, 47, 7857–7859 7857

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Formation of secondary radical i was kinetically favored
over primary radical ii because of its relatively higher stability.10
Scheme 1 summarizes the representative results of the
present titanium alkoxide-mediated reduction of epoxides.
1,1-Disubstituted epoxides 1b and 1c reacted smoothly with
the titanium reagent to exclusively provide the corresponding
primary alcohols in good yields. As exemplified by these
results, loss of stereochemical information in the substrates
can be rationalized by the formation of the radical intermediates.
The radical mechanism was also supported by the results of 1d
showing epoxide C–O cleavage followed by ring opening of
cyclobutane to yield cyclohexene derivatives 2d and 2d0 0.
g,g-Disubstituted epoxy alcohol MOM-ether 1e was exclusively
converted to the corresponding 1,2-alcohol derivatives 2e.
Meanwhile, styrene oxide (1f) was deoxygenated to styrene
(3f) in 40% GC yield, probably resulting from the relatively
stable benzyl radical intermediate trapped by a second titanium
species in order to promote TiO elimination.2
(at C-2 of resultant 2g). Meanwhile, using the Ti complex
2D4-4, bearing deuterium atoms at the Ti g-positions, did not
show any deuterium incorporation in the products. These
results indicate that the reaction might involve hydrogen
abstraction from the tertiary carbon centre of the alkoxides
attached to the Ti atom (a pathway through iii). The fact that
the reaction with complex 1D-4 did not necessarily show
complete deuteration of 2g can be explained by assuming
that hydrogen abstraction from the primary alkoxide of the
Ti-complexes, which resulted from reduction of 1g, could also
concomitantly occur because of the slower rate of abstraction
from the relatively hindered 4-tert-butylcyclohexyloxy group.
The radical intermediate in the reaction with Ti(O-i-Pr)4
probably abstracts hydrogen atoms from less hindered O-i-Pr
moieties more readily. Further investigation for clarification of
the detailed mechanism is underway.
These results led us to expect that a rigid b-titanoxy radical
of type iv, which is derived from 2-oxa-bicyclo[n.1.0]alkanes,
could intramolecularly abstract a hydrogen to provide the
corresponding alcohol with anti-stereochemistry (Scheme 2).
Therefore, the reactions of epoxides 1h–j with Ti(O-i-Pr)4/
Me3SiCl/Mg were investigated (Scheme 3). In addition, to
facilitate comparison, the corresponding reactions with a
Cp2TiCl2/Mn/CHD reagent were performed. The results are
summarized in Table 1.
To confirm the hydrogen-atom donor in the present
reduction, we performed the reaction of 1g in THF-d8 and
then quenching it with D2O (eqn (1) in Scheme 2). However,
the resulting alcohols 2g and 2g0 showed no deuterium
incorporation. The results suggested that the reaction may
involve hydrogen abstraction by a b-titanoxy radical from an
alkoxy group in the titanium complex(es), as illustrated in iii.
Indeed, as shown in eqn (2), the reaction using tetra(4-tert-
butylcyclohexyloxy)titanium(IV) (4) instead of Ti(O-i-Pr)4,
yielded a mixture of 2g and 2g0 with the co-production
of 4-tert-butylcyclohexanone (21% isolated yield). The
reaction with Ti complex 1D-4, which is deuterated at the
Ti b-position, gave 2g with 41% deuterium incorporation
As expected, the reaction of epoxides 1h, 1i and 1j with
Ti(O-i-Pr)4/Me3SiCl/Mg provided 2-substituted cycloalkan-1-ol
2h, 2i and 2j, respectively, with good to excellent anti-
stereoselectivities. In contrast, the reaction of 1h–j with the
conventional Cp2TiCl2/Mn/1,4-cyclohexadiene reagent pre-
dominantly produced the corresponding alcohols 2 with opposite
syn-stereoselectivities, possibly resulting from intermolecular
hydrogen abstraction from 1,4-cyclohexadiene by the radical
intermediates on the less hindered face of the sp2 radical
opposite to the titanoxide. These results demonstrate the
utility of the present method as a stereoselective and, in certain
cases, a stereo-complementary process. Using a mixture of
1,2-dimethoxyethane (DME)/dichloromethane (DCM) (1/4, v/v)
instead of THF as a solvent improved the yield and selectivity
for the reaction of the cyclohexene oxide derivative 1i.
Although the reason is unclear, the results indicate the
possibility of further tuning the reaction conditions in order
to improve selectivity.z
It can be postulated that a low-valent titanium species could
be generated from Ti(O-i-Pr)4/Me3SiCl/Mg through the following
reaction pathway: (i) titanium i-propoxide reacts with silyl chloride
to afford a titanium chloride compound(s) and i-PrOSiMe3,
Scheme 2 Study on radical hydrogen abstraction.
7858 Chem. Commun., 2011, 47, 7857–7859
Scheme 3 Reactions of 2-oxa-bicyclo[n.1.0]alkanes.
c
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Table 1 Regio- and setereo-selective reduction of 2-oxa-bicyclo-
[n.1.0]alkanes
This work was supported by Grants-in-Aid for Scientific
Research (22550103) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT).
Isolated
Main product
Reagents (equiv.)
1
anti : syna yieldb (%) 2 (R = TBS)
Notes and references
98 : 2
(87 : 13)d
73e (66)d,e
z The reaction of 1h with use of Ti(O-cyclohexyl)4 instead of
Ti(O-i-Pr)4 was slow and gave a complex mixture.
y For further information on functional group compatibility of this
reagent, see ref. 9.
1h
Ti(O-i-Pr)4/Me3SiCl/
Mg (1.2/1.2/3)c
71 : 29
(79 : 21)d
1i
30e (58)d,e
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7857–7859 7859