Control of Homocoupling Versus Reduction in Titanium(III)-Mediated Radical Opening of Styrene Oxides

Article abstract of DOI:10.1002/ejoc.201901625

We describe the use of titanocene monochloride in the implementation of an experimental procedure that enables control of the homolytic opening of styrene oxides in a chemoselectively controlled manner. This leads either to homocoupling products or to phenethyl alcohol derivatives. The process occurs via the generation of benzyl radicals, which may undergo a) recombination or b) reduction, yielding benzyl-Ti(IV) species upon subsequent addition of H₂O to the corresponding hydroxylated compounds. The main goal of this work is the study of the reactivity pattern of styrene oxides towards the formation of the mentioned products, thereby adding value to this interesting building block.

Full text of DOI:10.1002/ejoc.201901625

DOI: 10.1002/ejoc.201901625
Full Paper
Organic Synthesis
Control of Homocoupling Versus Reduction in Titanium(III)-
Mediated Radical Opening of Styrene Oxides
[a]
[a]
José A. González-Delgado* and Jesús F. Arteaga*
Abstract: We describe the use of titanocene monochloride in dergo a) recombination or b) reduction, yielding benzyl-Ti(IV)
the implementation of an experimental procedure that enables species upon subsequent addition of H O to the corresponding
2
control of the homolytic opening of styrene oxides in a chemo- hydroxylated compounds. The main goal of this work is the
selectively controlled manner. This leads either to homocou- study of the reactivity pattern of styrene oxides towards the
pling products or to phenethyl alcohol derivatives. The process formation of the mentioned products, thereby adding value to
occurs via the generation of benzyl radicals, which may un- this interesting building block.
Introduction
Styrene oxide is a versatile and important building block that
is widely used in organic synthesis (Figure 1). Among its signifi-
cant applications, the Lewis acid-mediated ring-opening and
rearrangement into phenylacetaldehyde should be high-
[
1]
lighted. The latter is a highly valuable chemical in the produc-
tion of flavors and perfumes as it provides access to phenethyl
alcohol. Also of interest is the Cp TiCl-catalyzed radical ring-
2
[
2]
opening (CRRO) of the epoxide, which has been employed as
[
3]
an initiator in the living radical polymerization of styrene. In
addition, opening of the epoxide ring, predominantly through
bimolecular nucleophilic substitution (SN ) mechanisms, has
2
been thoroughly studied in the literature. The scope of the at-
[
4]
tack is modulated by the hardness of the nucleophile. Inter-
estingly, the opening of an epoxy derivative by NaN has been
3
recently applied as key step for obtaining the alkyl moiety (side
[
5]
[6]
[7]
chain) of Taxol®. Further, iodine or Fe(III) ions have been
employed by means of Lewis acid catalysis for the opening of
epoxides.
Figure 1. Use of styrene oxide as building block in organic synthesis. (CRRO =
catalyzed radical ring-opening).
Styrene oxides have been reduced to obtain the correspond-
ing anti-Markovnikov alcohols in a process catalyzed by
[12]
ular couplings of these epoxides with nitriles or vinylsulfones
[13]
or in catalyzed hydrogen-atom transfer reactions (CHAT). The
2,3-diphenyl-1,4-diols are of great importance because of its
use both as chiral auxiliaries and as precursors in the synthe-
[
8]
[
Cp TiH]. Significantly, this year has been reported the cata-
2
lyzed regioselective hydrogenation of epoxides likewise leading
to anti-Markovnikov alcohols by using either Ti/Cr cooperative
[14]
[15]
[16]
sis of chroman,
tives (Figure 1).
5-furanone,
or dibenzopentalene deriva-
[
9]
[10]
catalysis or Fe(BF ) ·6H O/tetraphos catalyst system.
[17]
4
2
2
Preparation of 2,3-diphenyl-1,4-diols by modulated radical
ring-opening reaction of styrene oxides have not been studied
Herein we describe a study that potentially allows expanding
the versatility of styrene oxide derivatives as functional syn-
thons in organic synthesis. This method enables chemoselective
control of either the formation of phenethyl alcohol derivatives
[
11]
thoroughly up to now.
Structures related to the latter skele-
tons have been described as secondary products in intermolec-
or homocoupling products. The employed reagent, Cp TiCl, can
guide the process towards either situation just by using differ-
ent reaction conditions.
2
[
a] CIQSO-Center for Research in Sustainable Chemistry and Department of
Chemistry, University of Huelva,
Campus de El Carmen s/n, E-21071 Huelva, Spain
E-mail: jesus.fernandez@diq.uhu.es
jose.gonzalez@dqcm.uhu.es
https://www.uhu-dq.es/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901625.
Results and Discussion
The starting point of this work was from our previous experi-
[
18]
ence with the use of Cp TiCl in epoxide opening in selective
2
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[
19]
cyclization and homocoupling protocols, or in the reduction ene (3a, 5 % yield) (Table 1, entry 1) were obtained. The use of
[
20]
of activated halogenated derivatives in the presence of Brön- similar experimental conditions, but modifying the molar ratio
sted acids. Based on this precedence, we anticipated that the of Ti(III), led to significantly higher amounts of the undesired
use of excessive quantities of Ti(III) (2.0 equivalents) would give by-product 3a (Table 1, entries 2 and 3). This suggested that a
rise to the trapping of the generated radical (I in Figure 2) and large molar excess of Ti(III) could favor an elimination mecha-
yield an alkyl-Ti(IV) intermediate (II in Figure 2). The formation nism and, consequently, the formation of styrene (3a) together
of II directs the reaction mechanism towards the selective for- with Ti O (Figure 2, grey-colored pathway). To facilitate an effi-
2
mation of phenethyl alcohol (2), which suppresses the homo- cient pathway towards the formation of the alcohol 2a, both
coupling path (Figure 2).
the effect of decreasing the reaction temperature as well as the
An initial experiment was carried out with 1.0 mmol of com- influence of substrate concentration [C] were evaluated
mercially available styrene oxide (1a) and 2.2 mmol of Ti(III) (see (Table 1, entries 4–9).
Experimental Section) at 0 °C. Under these conditions and after
Further, the initially employed experimental procedure was
10 min of stirring, phenethyl alcohol (2a, 23 % yield) and styr- modified; instead of carrying out aqueous workup, water was
Figure 2. Proposed reaction mechanism for the Ti(III)-mediated ring opening of styrene oxides 1, represented by 1a (see text below). A stoichiometric amount
of Ti(III) generates the radical I by means of Ti(III)-mediated epoxide ring-opening. A second mole of Ti(III) leads to the alkyl-Ti(IV) intermediate II, which, on
hydrolysis, yields the phenethyl alcohol 2.
2
Table 1. Reaction of styrene derivatives (1a–1c) with Cp TiCl; representative experiments.
Entry
1[
Substrate
Cp
2
TiCl [mmol]
C[a] [M]
T [° C]
T [min]
Product Yield[b] [%]
Total Yield [%]
2[c]
3[c]
5
d]
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
2.2
3.0
5.0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
0.35
0.35
0.35
0.35
0.35
0.35
0.07
0.035
0.035
0.07
0.035
0.07
0.035
0
0
0
0
–20
–78
0
10
10
15
10
10
60
10
15
20
20
30
25
45
23
20
12
55
51
17
70
77
81
61
58
35
31
28
31
29
60
52
20
76
77
81
67
62
42
31
[d]
2
3
4
5
6
7
8
9
1
1
1
1
11
17
5
1
3
[
d]
6
–
–
6
4
7
–
0
–20
–20
–20
–20
–20
0
1
2
3
[
a] Molar concentration of the substrate in the reaction mixture. [b] Products of a, b, or c types, for each case, according to the starting material used. [c]
Yields correspond to isolated product after purification by column chromatography. [d] Test performed with aqueous treatment during the work-up of the
reaction. All other experiments were conducted in a one-pot procedure by adding H O directly to the reaction mixture.
2
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Table 2. Reaction of styrene derivatives (1a–c) with Cp
2
TiCl; experiments towards selective homocoupling.
C[a]
[M]
T
[° C]
t
Product Yield [%]
[b]
Total Homo-coupling
Yield [%]
Entry
Substrate
Cp
2
TiCl
[c]
[c]
6[c] (α,p)
[mmol]
[min]
4
(α,α′)
5
(α,o)
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1.8
1.8
1.8
0.7
0.2
1.0
1.0
1.0
0.7
0.7
0.7
1.0
1.0
1.0
1.0
0.7
0.2
1.0
1.0
1.0
0.7
1.0
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.07
0.035
0.035
0.07
0.35
0.35
0.35
0.35
0.07
0.035
0.35
0.35
0.035
25
0
–78
0
0
5
27
25
21
28
15
64
54
33
29
28
36
24
32
55
60
45
19
56
14
65
52
18
20
22
22
11
1
20
22
22
11
1
67
69
65
50
17
80
82
81
53
76
84
69
42
55
60
45
19
56
14
79
59
18
10
12
15
45
10
10
15
30
20
30
15
45
2
[
d]
4
[
d]
5
6
7
8
9
0
8
8
–15
–78
–78
–78
–78
–78
–78
0
–78
–78
–78
–78
–78
–78
–78
–78
14
24
16
26
36
36
5
–
–
–
–
14
24
8
22
12
9
5
–
–
–
–
–
–
–
–
–
[
d]
0[
d]
1
[d]
1
1
1
2
1
3
1
4
1
5
5
[d]
1
6
20
120
20
900
10
45
600
[d]
1
7
1
8
–
1
9
–
[
e]
2
0
14
[d]
[e]
2
1
7
–
22
[
[
a] Molar concentration of the substrate in the reaction mixture. [b] Products of a, b, or c types, for each case, according to the starting material used.
c] Yields correspond to isolated product after purification by column chromatography. [d] For the substoichiometric protocol for homocoupling reaction, see
Experimental Section. [e] Determined from impure chromatography fractions, which could not be purified further in our hands. Therefore, these yields are
considered rough estimates, and no definite spectroscopic characterization is provided for compound 5c.
added directly to the mixture once 1a had reacted with the Figure 2). Being aware of the role of excess Ti(III) in the transfor-
previously generated Ti(III). This provides the H atom that is mation of the benzyl radical I into II, the Ti(III) molar ratio was
necessary for the formation of the OH group via in situ protona- lowered with respect to those listed in Table 1. Thus, 1.0 mmol
tion of -OTi(IV) (Figure 2, last step). On the one hand, the yields of 1a was treated with 1.8 mmol of Ti(III) at room temperature.
of 2a were found to improve in the experiments that were per- This first test evidenced a predominant formation of the homo-
formed at 0 and –20 °C (Table 1, entries 4–5). However, at a coupling products (4a–6a, 67 % yield) along with smaller
significantly lower temperature (–78 °C) no such effect was seen amounts of phenethyl alcohol 2a and styrene 3a, in 23 % yield
(
Table 1, entry 6). On the other hand, by varying the molar and 3 % yield, respectively (Table 2, entry 1). Noteworthily, the
substrate concentration (Table 1, entries 7–9), it was found that homocoupling resulted in a mixture of 4a (being a 1:1 mixture
the best experimental conditions for the formation of 2a were of diastereomers), 5a, and 6a in a 3:2:2 ratio (Table 2, entry 1).
those corresponding to entry 9, leading to an 81 % yield of 2a It was observed that a tenfold increase of the concentration
without the observation of by-product 3a. Moreover, the use of helped to shift the selectivity in favor of 4 (see Table 1, entry 9,
other styrene oxide derivatives, such as 1b and 1c, led to the and Table 2, entry 1).
formation of the corresponding alcohols 2b and 2c in moderate
This observation and the distribution of the reaction prod-
to good yields (Table 2, entries 10–13). It is noteworthy that ucts is rationalized in the mechanistic proposal depicted in Fig-
significant amounts of homocoupling products (see below) ure 3. The coordination of the epoxide oxygen atom in 1 with
were not observed for the employed experimental conditions Cp TiCl initiates the ring-opening towards the benzyl radical I,
2
of an excess amount of Ti(III).
which is stabilized by the delocalization of the radical center
Encouraged by successful chemoselectivity control, via ad- (see resonance structures I , I , and I ). Thus, the homocoupling
α
o
p
dressing the fate of intermediate II, we attempted to direct the products 4–6 derive from three different combinations that im-
process towards the formation of homocoupling products (see ply these resonance structures: I + I (α, α′ coupling yields 4),
α
α
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I + I (α, ortho coupling yields 5 via intermediate III), and I + retical 1:1 Ti(III)/substrate reaction stoichiometry. Conducting
α
o
α
Ip (α, para coupling yields 6 via intermediate IV). Products that the experiment for this ratio and at 0 °C led to the observation
derive from direct coupling of only I and/or I were not de- of 80 % yield of the homocoupling products and a strong pref-
o
p
tected. The formation of the vinylic double bond in products 5 erence for product 4a (64 % yield; see Table 2, entry 6). Lower-
and 6 is caused by the elimination of a hydroxy-titanium spe- ing the temperature to –15 or –78 °C and keeping the Ti(III):1a
cies, facilitating the re-aromatization of the system (Figure 3, ratio had no effect on the total yield of the homocoupling prod-
I + I and I + I couplings). Additionally, as shown in Figure 2, ucts, but it changed the ratio of 4a–6a and disfavored the for-
α
o
α
p
intermediate I can be trapped by a second mole of Ti(III), yield- mation of 4a; Table 2, entries 7–8.
ing the intermediate II. This enables the formation of com-
Additional tests were carried out to gain further insights into
pounds 2 and 3, as described above. However, when using less the control of the formation of homocoupling products and the
than 2 mol equivalents of the Ti(III) reagent, this path is not involved regioselectivity (i.e., formation of 4a, 5a or 6a). A series
effective.
of experiments were designed to optimize the substrate con-
centration in relation to the amount of Ti(III). For all conditions,
significant yields of α,ortho (5a) and α,para (6a) coupling prod-
ucts were obtained (Table 2, entries 9–13). This allowed us to
conclude that the best conditions for the selective formation of
4a are those used in entry 6 of Table 2. Regarding optimization
of the other homocoupling products, it can be affirmed that a
decrease of the substrate concentration and operation at –78
°
C led to 5a as the major product (Table 2, entries 11–12). 4-
Chloro-styrene oxide (1b) was tested with the idea to evaluate
the impact of the electronic effect of the aryl substituent. We
speculated that increasing the electronic density of the aro-
matic ring could exert a direct influence, favoring the formation
of the benzyl radicals I and I ; Figure 3. This would significantly
o
p
increase the yield of 5b and 6b homocoupling products. A first
test (Table 2, entry 14) under standard conditions led to a mod-
erate yield of 55 % for 4b in very short reaction time. The prod-
ucts 5b and 6b were not observed. The yield of 4b (1:1 mixture
of diastereomers) was slightly increased by carrying out the re-
action at –78 °C (Table 2, entry 15). Other modifications of the
experimental conditions, such as the substrate concentration,
the amount of reagent, or the reaction time, did not yield the
formation of 5b or 6b (Table 2, entries 16–19). Hence, substrate
1b yields selectively 4b as the only coupling product. Finally,
the behavior of the substrate epoxide 1c was studied. The loca-
tion of the methoxy group in the meta position should stimu-
late the opening of the epoxide ring and the formation of
benzyl radical I. Accordingly, the corresponding homocoupling
product 4c (1:1 mixture of diastereomers) was obtained, but
no product 6c was seen. It must be also mentioned that no
diastereoselectivity was found for 4a–c derivatives in under any
of the conditions tested throughout the study.
Figure 3. Proposed mechanism for Ti(III)-mediated homocoupling of styrene
oxide derivatives. The substrate is symbolized as 1, being represented by
structure 1a.
The obtained results encouraged us to optimize the forma-
tion of homocoupling products (Table 2). Thus, the initial reac-
tion conditions for substrate 1a were repeated, but tempera-
tures were decreased to 0 and –78 °C (Table 2, entries 2–3).
However, the yield of the homocoupling product did not im-
Conclusions
prove significantly; only a slight change in the relative distribu- In summary, we have developed a synthetic method to achieve
tion of products 4a–6a was noted. Then, in accordance with control over the chemoselectivity of the homolytic Ti(III)-medi-
the mechanistic proposal, a further decrease of the Ti(III): sub- ated ring opening of styrene oxides, yielding either 2,3-di-
strate molar ratio was tested. This should disfavor the formation phenyl-1,4-diol derivatives or phenethyl alcohol derivatives. The
of II, shifting the competition between the reaction paths of I proposed mechanism involves the generation of benzyl radicals
towards the homocoupling products. Thus, the reactions were that evolve into homocoupling products or phenethyl alcohol
performed with 0.7 or 0.2 mmol of Cp TiCl at room tempera- derivatives in moderate to good chemical yields. The key factor
2
ture. However, the substoichiometric amounts of reagent led is the variation of the amount of Ti(III) reagent, alongside the
to significantly lower yields of 4a–6a (50 % and 17 % yields, fine-tuning of substrate concentration and reaction tempera-
respectively; Table 2, entries 4–5). Hence, the use of 1.0 mmol ture. The presence or absence of excess Ti(III) modulates the
of Ti(III) was considered as ideal, being consistent with the theo- fate of the benzyl radicals that are either directly involved in
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homocoupling or in the formation of an alkyl-Ti(IV) intermedi- concentrated under reduced pressure. The resulting crude was
taken up in THF (5 mL) and stirred at room temperature. Then, TBAF
ate, being competitive pathways. The herein obtained results
on the reactivity of styrene oxides broaden their scope as pre-
cursors for the synthesis of added-value building blocks.
1
1
.0 M in THF (1.1 mmol) was added, and the solution was stirred for
h and concentrated at reduced pressure. The resulting crude was
purified by column chromatography on silica gel to afford the corre-
sponding products.
2
,3-Diphenylbutane-1,4-diol 4a.[21] (2R,3S)-2,3-Diphenylbut-
Experimental Section
1
ane-1,4-diol: White amorphous solid. H NMR (400 MHz, CD OD):
3
Instrumentation, reagents and solvents: All air- and water-sensitive
reactions were performed in flasks that were flame-dried under a
positive flow of argon and conducted under an atmosphere of ar-
gon. Tetrahydrofuran (THF) was freshly distilled prior to use from
sodium/benzophenone and exhaustively deoxygenated for 30 min
under argon for each of the Cp TiCl /Mn reactions. The reagents
δ = 7.22 (m, 6H), 7.18 (m, 4H), 3.48–3.36 (m, 4H), 2.96 (m, 2H) ppm*;
13
C NMR (100 MHz, CD
(4CAr), 126.3 (2CAr), 64.5 (2CH
OD): δ = 142.0 (2CAr,quat), 128.4 (4CAr), 128.1
OH), 50.7 (2CH) ppm. FABHRMS calcd.
H O Na [M + Na] 265.1199, found 265.1189. (2S,3S)-2,3-
18 2
3
2
+
for C16
Diphenylbutane-1,4-diol: Yellow syrup. H NMR (400 MHz,
CDCl ): δ = 7.16–7.09 (m, 6H), 6.96 (d, 4H), 3.99–3.89 (ddd, 4H), 3.25
1
2
2
3
13
were purchased at the highest commercial quality and used with- (t, 2H), 2.56 (bs, 2H) ppm; C NMR (100 MHz, CDCl
out further purification unless stated otherwise. Silica gel SDS 60
(2CAr,quat), 128.6 (4CAr), 128.1 (4CAr), 126.5 (2CAr), 65.6 (2CH
35–70 μm) was used for flash column chromatography. The reac- (2CH) ppm. FABHRMS calcd. for C16H O Na [M + Na] 265.1199,
18 2
): δ = 140.6
3
OH), 51.0
2
+
(
tions were monitored by thin-layer chromatography (TLC), carried found 265.1193. *Signals for OH protons were not observed.
out with 0.25 mm E. Merck silica gel plates (60F-254), using UV light
2
,3-Bis(4-chlorophenyl)butane-1,4-diol (4b): Diastereoisomer 1:
for visualization and a solution of phosphomolybdic acid in ethanol
as developing agent. NMR studies were performed with a Bruker
1
White amorphous solid. H NMR (400 MHz, CD OD): δ = 7.21 (m,
3
8
H), 3.46–3.36 (m, 4H), 2.98 (t, 2H) ppm*; 13C NMR (100 MHz,
CD OD): δ = 140.6 (2CAr,quat), 132.0 (2CAr,quat), 130.0 (4C ), 128.1
1
13
ARX 400 ( H 400 MHz/ C 100 MHz) spectrometer. Accurate mass
determinations were carried out with an AutoSpec-Q mass spec-
trometer arranged in an EBE geometry (Micromass Instrument,
Manchester, UK) and equipped with a FAB source. The instrument
3
Ar
(4C ), 64.0 (2CH OH), 49.8 (2CH) ppm. CIMS calcd. for C H O Cl
Ar
+
2
16 16
2
2
1
[M] 310.0527, found 310.0514. Diastereoisomer 2: Yellow syrup. H
NMR (400 MHz, CDCl ): δ = 7.12 (d, J = 8.4 Hz, 4H), 6.87 (d, J =
+
3
was operated at 8.0 K V of accelerating voltage, and Cs was used
13
8.4 Hz, 4H), 3.89 (d, 4H), 3.18 (t, 2H), 2.46 (bs, 2H); C NMR (100 MHz,
as the primary ion. The low-resolution mass spectra were obtained
with a quadrupolar mass spectrometer Platform II (Micromass In-
struments, Manchester, UK).
CDCl ): δ = 139.1 (2CAr,quat), 132.4 (2CAr,quat), 129.8 (4C ), 128.4
3
Ar
(
[
4C ), 65.2 (2CH OH), 50.2 (2CH) ppm. CIMS calcd. for C H O Cl
M] 310.0527, found 310.0515. *Signals for OH protons were not
Ar
+
2
16 16
2
2
General Procedure for the Reduction Reaction: Standard proto-
observed.
-Phenyl-2-(2-vinylphenyl)ethanol (5a): Colorless oil. 1H NMR
500 MHz, CDCl ): δ = 7.48 (d, J = 7.3 Hz, 1H), 7.30–7.22 (m, 8H),
col: A mixture of Cp TiCl (2.2 mmol) and Mn dust (8.0 mmol) in
2
2
2
(
thoroughly deoxygenated THF (27 mL) was stirred under an Ar at-
mosphere at room temperature until the red solution turned green.
The corresponding styrene oxide (1.0 mmol) in deoxygenated THF
3
7.01 (dd, J = 14.2, 9 Hz, 1H), 5.57 (dd, J = 14.5, 1 Hz, 1H), 5.28 (dd,
J = 9, 1 Hz, 1H), 4.53 (t, J = 6 Hz, 1H), 4.16 (d, J = 6 Hz, 2H) ppm;
(
(
1.6 mL) was then added at –20 °C. On completion of the reaction
TLC monitoring), THF was removed, and the reaction was
13
C NMR (125 MHz, CDCl ): δ = 141.3 (CAr,quat), 138.4 (CAr,quat), 138.2
3
(
CAr,quat), 134.9 (CHolef), 128.9 (2C ), 128.7 (2C ), 128.2 (C ), 127.3
Ar
Ar
Ar
quenched with 1
N HCl, extracted with tBuOMe, washed with brine,
(
C ), 127.2 (2C ), 126.9 (C ), 117.0 (CH
), 66.2 (CH OH), 49.4
Ar
Ar
Ar
2-Olef
2
dried with anhydrous Na SO , and concentrated under reduced
2
4
+
(CH) ppm. CIMS calcd. for C H O [M + H] 224.1201, found
16 16
pressure. The resulting crude was purified by column chromatogra-
phy on silica gel to afford the corresponding products. The NMR
224.1202.
spectroscopic data are identical to those for commercially available 2-Phenyl-2-(4-vinylphenyl)ethanol (6a): Colorless oil. 1H NMR
compounds.
(500 MHz, CDCl
1
3
3
): δ = 7.31–7.15 (m, 9H), 6.61 (dd, J = 17, 11 Hz,
H), 5.64 (d, J = 17 Hz, 1H), 5.14 (d, J = 11 Hz, 1H), 4.15–4.08 (m,
H) ppm; 13C NMR (125 MHz CDCl ): δ = 141.5 (CAr,quat), 141.3
General Procedures for the Homocoupling Reaction: Representa-
tive procedures: A mixture of Cp TiCl (1.0 mmol) and Mn dust
3
2
2
(CAr,quat), 136.6 (CAr,quat), 136.5 (CHOlef), 129.0 (2C ), 128.7 (2C ),
Ar Ar
(8.0 mmol) in thoroughly deoxygenated THF (2 mL) was stirred un-
1
5
2
28.5 (2C ), 127.1 (C ), 126.8 (2C ), 113.9 (CH
3.6 (CH) ppm. CIMS calcd. for C H O [M] 223.1123, found
23.1121.
), 66.3 (CH OH),
2
Ar
Ar
Ar
2-Olef
+
der an Ar atmosphere at room temperature until the red solution
turned green. The corresponding styrene oxide (1.0 mmol) in de-
oxygenated THF (0.9 mL) was then added at –15 °C. On completion
16 16
of the reaction (TLC monitoring), THF was removed, and the reac- 2,3-Bis(3-methoxyphenyl)butane-1,4-diol (4c): Diastereoisomer
1
tion was quenched with 1
N
HCl, extracted with tBuOMe, washed
1: White amorphous solid. H NMR (CDCl , 500 MHz): δ = 7.30 (t,
3
with brine, dried with anhydrous Na SO , and concentrated under
J = 7.9 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 6.88 (s, 2H), 6.83 (dd, J =
2.2, 8.2 Hz, 2H), 3.83 (s, 6H), 3.59 (dd, J = 7.9, 11.0 Hz, 2H), 3.53 (dd,
2
4
reduced pressure. The resulting crude was purified by column chro-
matography on silica gel to afford the corresponding products. For
substoichiometric reactions, a mixture of Cp TiCl (0.7 mmol) and
J = 2.6, 10.9 Hz, 4H), 3.06 (m, 2H) ppm. 13C NMR (CDCl , 125 MHz):
3
δ = 160.3 (2CAr,quat-OMe) 142.3 (2CAr,quat), 130.0 (2C ), 120.6 (2C ),
2
2
Ar
Ar
Mn dust (8.0 mmol) in thoroughly deoxygenated THF (27 mL) was
stirred at room temperature until the red solution turned green.
Then, a solution of the corresponding styrene oxide (1.0 mmol),
114.3 (2C ), 112.4 (2C ), 65.6 (2CH OH), 55.2 (2OMe), 50.8 (2CH)
Ar Ar 2
+
ppm. FABHRMS calcd. for C H O Na [M + Na] 325.1416, found
1
8 22 4
1
325.1426. Diastereoisomer 2: Yellow syrup. H NMR (600 MHz,
2
,4,6-collidine (7.0 mmol), and TMSCl (4.0 mmol) in deoxygenated
CDCl ): δ = 7.07 (t, J = 7.9 Hz, 2H), 6.64 (dd, J = 8.1, 2.0 Hz, 2H),
3
THF (1.6 mL) was added at –78 °C. The latter two served to regener-
6.60 (d, J = 7.5 Hz, 2H), 6.52 (s, 2H), 3.96 (dd, J = 10.9, 4.4 Hz, 2H),
3.92 (dd, J = 10.8, 4.4 Hz, 2H), 3.67 (s, 6H), 3.22 (m, 2H), 1.89 (bs,
[2g]
ate Cp TiCl and thereby closed the catalytic cycle
. The reaction
HCl, extracted
with tBuOMe, washed with brine, dried with anhydrous Na SO , and
2
2
mixture was stirred for 30 min, quenched with 1
N
2H) ppm; 13C NMR (150 MHz CDCl ): δ = 159.4 (2CAr,quat-OMe), 142.1
3
(2CAr,quat), 129.1 (2C ), 121.0 (2C ), 114.5 (2C ), 112.0 (2C ), 65.4
2
4
Ar
Ar
Ar
Ar
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(
2CH OH), 55.0 (2OMe), 50.8 (2CH) ppm. HRFABMS calcd. for
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Keywords: Benzyl radicals · Homocoupling · Organic
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Received: November 5, 2019
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Organic Synthesis
J. A. González-Delgado,*
J. F. Arteaga* ....................................... 1–7
Control of Homocoupling Versus Re-
duction in Titanium(III)-Mediated
Radical Opening of Styrene Oxides
Titanocene monochloride mediates derivatives. Remarkably this protocol
the homolytic opening of styrene ox- encompasses the diverse reactivity
ides in a chemoselectively controlled pattern of styrene oxides towards the
manner, leading either to homocou- desired products, thereby adding
pling products or to phenethyl alcohol value to this interesting building block.
DOI: 10.1002/ejoc.201901625
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim