Preparation and palladium-mediated cross-coupling of α- benzoyloxyalkylzinc bromides

Article abstract of DOI:10.1016/j.tetlet.2013.05.114

Here we report a two-step preparation protocol of α- benzoyloxyalkylzinc bromides from α-benzoyloxyalkyl selenides, and their application to palladium-catalyzed cross-coupling reactions with aryl and vinyl iodides. The developed method effectively provides a variety of benzoyl-protected benzylic and allylic alcohol derivatives through the formation of C(sp³)-C(sp²) bonds without affecting various polar functional groups.

Full text of DOI:10.1016/j.tetlet.2013.05.114

Tetrahedron Letters 54 (2013) 4189–4192
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation and palladium-mediated cross-coupling
of a-benzoyloxyalkylzinc bromides
⇑
Komei Sakata, Daisuke Urabe, Masayuki Inoue
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report a two-step preparation protocol of
a-benzoyloxyalkylzinc bromides from a-ben-
Received 30 April 2013
Accepted 24 May 2013
Available online 4 June 2013
zoyloxyalkyl selenides, and their application to palladium-catalyzed cross-coupling reactions with aryl
and vinyl iodides. The developed method effectively provides a variety of benzoyl-protected benzylic
and allylic alcohol derivatives through the formation of C(sp3)–C(sp2) bonds without affecting various
polar functional groups.
Keywords:
Cross-coupling
Metalation
Ó 2013 Elsevier Ltd. All rights reserved.
Synthetic methods
Transition metals
Organozinc compounds
CN
n-Bu3SnH
AIBN
The transition metal-mediated cross-coupling reaction between
organozinc compounds and organohalides, known as the Negishi
coupling reaction, has been utilized as a mild and powerful C–C
bond formation.1 Effective formation of not only C(sp2)–C(sp2)
bonds but also C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds has been
achieved over the years.2 Accordingly, Negishi coupling reactions
have been implemented in synthetic routes to many architectur-
ally complex natural products.3
X
OBz
OBz
ref. 7
R
SePh benzene
reflux
R
R
CN
radical
reaction
A
B
1: X = H
: X = OBz
2
I
a
-Oxyalkyl metals are versatile reaction intermediates for the
5
introduction of oxygen-substituted sp3-carbon centers, and their
cross-coupling reactions are especially useful for the construction
of multiple oxygenated carboskeletons of natural products. Conse-
OBz
OBz
OBz
Zn
R
R
Br
R
ZnBr
cross
coupling
quently, transition metal-catalyzed reactions of
and
-oxyborates5 have been developed to connect the
bon centers with C(sp2) or C(sp3) centers of the coupling partners.
On the other hand, -oxyalkylzinc reagents are rarely employed for
a
-oxystannanes4
-oxy car-
3
4
6
a
a
Scheme 1. Plan for preparation and cross-coupling of
a-benzoyloxyalkylzinc
bromides.
a
cross-coupling reactions, and only their Cu-mediated reactions
have been disclosed.6 Here we report a two-step preparation pro-
liver the adduct B via formation of a C(sp3)–C(sp3) bond.7 Due to
the reliability in its preparation and chemical stability in its han-
dling, we planned to use selenide 2 as a precursor to highly reac-
tocol of
a-benzoyloxyalkylzinc bromides from a-benzoyloxyalkyl
selenides, and their application to the Negishi coupling reaction
with aryl and vinyl iodides.
tive
a-benzoyloxyalkyl bromide 3. Specifically, displacement of
Previously, we developed the intermolecular radical reaction of
the phenylselenyl group of 2 with a Br atom would generate bro-
a-acyloxyalkyl selenide 2, which was prepared by the seleno-Pum-
mide 3.8 Next, zincation of 3 would lead to
a-benzoyloxyalkylzinc
merer reaction of alkyl selenide 1 (Scheme 1). The radical species
A, generated from 2, efficiently added to C@C double bonds to de-
bromide 4,9 which would couple with aryl or vinyl iodide 5 by the
action of a palladium catalyst to afford 6 through C(sp3)–C(sp2)
bond formation. Importantly, product 6 has a characteristic struc-
ture that is not accessible by the radical-based methodology. In
addition, this reaction sequence would expand the potential utility
⇑
Corresponding author. Tel.: +81 3 5841 1354; fax: +81 3 5841 0568.
E-mail address: inoue@mol.f.u-tokyo.ac.jp (M. Inoue).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.114

4190
K. Sakata et al. / Tetrahedron Letters 54 (2013) 4189–4192
Table 1
Syntheses of
Table 2
Coupling reactions of various
a
-benzoyloxyalkyl bromides 3a
a
-benzoyloxyalkyl bromides 3 with aryl iodide 5aa
1. m-CPBA
PhSeBr, CH2Cl2
-45 to 0 °C
OBz
Pd(OAc)2 (5 mol%)
R
I
CH2Cl2, -78 °C
OBz
OBz
Br
3
OBz
X
+
R
SePh
SPhos (10 mol%)
R
SePh
2
R
R
2. Bz2O, BzONa
toluene,100 °C
CO2Me
CO2Me
1
3
5a
6
: X = Br (2 equiv)
PCy2
OMe
4: X = ZnBr
MeO
α-benzoyloxyalkyl selenide 2
α-benzoyloxyalkyl bromide 3
Li, naphthalene, ZnBr2
TMSBr, THF/DMI
entry
1
and yield
and yield
OBz
OBz
entry
1
α-benzoyloxyalkyl bromide 3
product 6 and yield
Ph
Ph
SePh
Br
OBz
2a: 88%
3a: 86%
OBz
Ph
OBz
OBz
Ph
2b
TBDPSO
TBDPSO
Br
SePh
Br
CO2Me
3a
6a: 79%
OBz
2b: 81%
3b: 64%
OBz
OBz
OBz
TBDPSO
AcO
AcO
AcO
3
4
SePh
Br
2
3
TBDPSO
Br
2c: 55%
3c: 90%
CO2Me
3b
OBz
OBz
6b: 55%
OBz
EtO2C
SePh
EtO2C
Br
OBz
2d: 46%
OBz
SePh
3d: 86%
OBz
Br
AcO
Br
CO2Me
3c
5
6
6c: 78%
2e: 86%
3e: 75%
OBz
OBz
OBz
OBz
EtO2C
4
5
6
EtO2C
Br
SePh
Br
CO2Me
3d
3e
2f: 88%
3f: 74%
6d: 93%
OBz
OBz
Br
a
Conditions for bromination: 2, PhSeBr (1.5 equiv), CH2Cl2 (0.1 M).
Conditions for bromination: 2b, PhSeBr (1.0 equiv), NaHCO3 (1.0 equiv), CH2Cl2
b
CO2Me
6e: 92%
OBz
(0.1 M), 0 °C.
OBz
Br
of
transition metal catalyzed reactions.
First, the structurally distinct -benzoyloxyalkyl selenides 2a–f
a-acyloxyalkyl selenide 2 as a stable synthetic intermediate for
CO2Me
3f
6f: 98%
a
were synthesized from the corresponding selenides 1a–f (Table 1),
demonstrating the high applicability of the seleno-Pummerer reac-
tion.7,10 The selenoxides, which were produced by m-CPBA oxida-
tion of selenides 1a–f at À78 °C, were heated to 100 °C in toluene
with Bz2O and BzONa, leading to the rearranged products 2a–f. Ex-
change of the phenyl selenide with the bromide was realized by
the action of PhSeBr.11 When 2a was treated with PhSeBr at
a
Reagents and conditions: 3 (2.0 equiv), Li (8.0 equiv), naphthalene (8.0 equiv),
ZnBr2 (4.0 equiv), TMSBr (0.1 equiv), THF/DMI = 1/1 (0.1–0.2 M), rt; 5a (1.0 equiv),
Pd(OAc)2 (5 mol %), SPhos (10 mol %), rt.
Ac (entry 3), and ethoxycarbonyl (entry 4) groups. The alkylzinc
compounds 4e and 4f with branched carboskeletons were also
coupled with 5a to provide 6e and 6f, respectively (entries 5 and
6).
The broad scope of the cross-coupling was demonstrated using
aromatic iodides 5b–k having various functional groups on the
benzene rings (Table 3). Aryl iodides bearing electron-withdrawing
groups at the para-position efficiently functioned as the coupling
À45 °C in CH2Cl2,
a-benzoyloxyalkyl bromide 3a was smoothly
formed (entry 1). The acid-labile TBDPS protective group was re-
tained during the conversion of 2b into 3b (entry 2), although
the addition of NaHCO3 as an acid scavenger was necessary. The
acetyl and ethoxycarbonyl groups of 2c and 2d were compatible
with the bromination conditions, affording 3c and 3d, respectively
(entries 3 and 4). Furthermore, more sterically congested 2e and 2f
bearing cycloalkane moieties were transformed to 3e and 3f,
respectively, under the same conditions (entries 5 and 6).
partners of a-benzoyloxyalkylzinc bromide 4a to provide products
6g–k (entries 1–5). The yields of nitrile 6j (entry 4) and aldehyde
6k (entry 5) were modest, but were increased when Pd(dba)2
(10 mol %) and TFP (20 mol %)16,17 were used as the catalyst in-
stead of Pd(OAc)2/SPhos. The intact aldehyde moiety of the coupled
product 6k highlighted the high chemoselectivity of the present C–
C bond formation. While the electron-donating para-methoxy
group caused b-elimination of the benzoate group of 6l after the
coupling to afford 7 (entry 6), the meta-methoxy group induced
no elimination, and the adduct 6m was obtained (entry 7). In con-
trast to the high-yielding transformations of methyl para-iodoben-
zoate 5a (79%, entry 1, Table 2) and methyl meta-iodobenzoate 5i
(85%, entry 8), the yield of methyl ortho-iodobenzoate 5j was lower
(27%, entry 9), suggesting that the methoxycarbonyl group
adjacent to the reacting carbon negatively affected the coupling
Having established the procedure for syntheses of
a-ben-
zoyloxyalkyl bromides 3a–f, we explored their zincation and sub-
sequent Negishi coupling reactions with aryl iodide 5a (Table 2).
After screening the reagents and conditions, Rieke’s protocol12
was adopted for zincation in a 1:1 mixed solvent of THF and 1,3-di-
methyl-2-imidazolidinone (DMI),13,14 and Pd(OAc)/SPhos15 was
applied as the catalyst for the cross-coupling. Namely, organozinc
species 4a was first generated from 2 equiv of 3a in THF/DMI at
room temperature, and then coupled with 1 equiv of aryl iodide
5a in the presence of Pd(OAc)2 (5 mol %) and SPhos (10 mol %) to
afford the adduct 6a (entry 1). This coupling procedure enabled
to the production of 6b–d without affecting the TBDPS (entry 2),

K. Sakata et al. / Tetrahedron Letters 54 (2013) 4189–4192
4191
Table 3
Coupling reactions of
Table 4
Coupling reactions between
a
-benzoyloxyalkyl bromide 3a with various aryl iodides 5a
a
-benzoyloxyalkyl bromide 3 and vinyl iodides 5a
Pd(OAc)2 (5 mol%)
SPhos (10 mol%)
OBz
OBz
OBz
Ar
I
Pd(dba)2 (15-30 mol%)
OBz
X
5
Ar-I
+
Ph
Ph
+
R
X
TFP (30-60 mol%)
R
3a
4a
6
: X = Br (2 equiv)
: X = ZnBr
3
4
5
6
: X = Br (2 equiv)
: X = ZnBr
PCy2
O
MeO
OMe
Li, naphthalene,ZnBr2
TMSBr, THF/DMI
P
O
Li, naphthalene, ZnBr2
TMSBr, THF/DMI
O
entry
Ar-I 5
products 6 and yield
entry
1a
3
vinyl iodide 5
product 6 and yield
OBz
I
OBz
Ph
I
CO2Me
5l
Ph
3a
CO2Me
R
5b: R = COMe
5c: R = CONH2
5d: R = NO2
6q: 54%
OBz
R
1
2
3
4
6g: 95%
6h: 81%
I
Ph
Ph
2a
3b
3a
3a
6i: 77%
6j: 72% (90%) b
6k: 31% (70%) b
O
5m
O
6r: 50%
OBz
5e: R = CN
5
6
5f: R = CHO
5g: R = OMe
I
6l: 0%
Ph
O
5n
O
6s: 55%
OMe
7: 37%
OBz
I
OBz
I
Ph
4b
5b
3e
3f
O
5n
O
6t: 53%
R
R
7c
8
5h: R = OMe
5i: R = CO2Me
6m: 42%
6n: 85%
OBz
I
OBz
O
5n
I
O
Ph
6u: 50%
9
MeO2C
MeO2C
6o: 27%
OBz
5j
a
Reagents and conditions: 3 (2.0 equiv), Li (8.0 equiv), naphthalene (8.0 equiv),
ZnBr2 (4.0 equiv), TMSBr (0.1 equiv), THF/DMI = 1/1 (0.1–0.2 M), rt; 5 (1.0 equiv),
Pd(dba)2 (15 mol %), TFP (30 mol %), rt.
I
Ph
b
10
Reagents and conditions: 3 (2.0 equiv), Li (8.0 equiv), naphthalene (8.0 equiv),
N
N
ZnBr2 (4.0 equiv), THF/DMI = 1/1 (0.1–0.2 M), rt; 5n (1.0 equiv), Pd(dba)2 (30 mol %)
and TFP (60 mol %), rt.
Ts
Ts
5k
6p: 58%
a
Reagents and conditions: 3a (2.0 equiv), Li (8.0 equiv), naphthalene (8.0 equiv),
ZnBr2 (4.0 equiv), TMSBr (0.1 equiv), THF/DMI = 1/1 (0.1–0.2 M), rt; 5 (1.0 equiv),
Pd(OAc)2 (5 mol %), SPhos (10 mol %), rt.
Yield in parentheses was obtained, when Pd(dba)2 (10 mol %) and TFP (20 mol %)
cally stable
generality of the
a
-benzoyloxyalkyl selenides, and demonstrated the
b
a-acyloxyzinc reagents as reactive intermediates
were used instead of Pd(OAc)2 and SPhos.
c
for palladium-mediated cross-coupling reactions. The present zin-
cation and coupling reactions both proceeded at room temperature
under mild conditions, and effectively provided benzylic and allylic
alcohol derivatives through formation of C(sp3)–C(sp2) bonds with-
out affecting a wide range of potentially reactive electrophilic func-
tional groups.
The reaction was performed at 0 °C.
efficiency. Finally, indole derivative 5k was coupled with 4a to pro-
vide 6p (entry 10).
The versatility of the a-benzoyloxyalkylzinc bromides was fur-
ther proven by their successful cross-coupling reactions with vinyl
iodides (Table 4). For these reactions, the Pd(dba)2/TFP catalyst
system was found to be consistently superior to the Pd(OAc)2/
SPhos system. Pd(dba)2/TFP indeed promoted the reaction between
(E)-methyl 3-iodoacrylate 5l and zinc bromide 4a to produce the
adduct 6q (entry 1). Cyclic vinyl iodides 5m and 5n also partici-
pated in the reaction with 4a, giving rise to 6r and 6s, respectively
(entries 2 and 3). When organozinc compounds bearing the cyclo-
alkanes (4e and 4f) and the cyclic vinyl iodide 5n were employed,
the cross-coupling reaction delivered 6t and 6u, respectively, with
the two carbocycles (entries 4 and 5).
Acknowledgments
This research was financially supported by the Funding Pro-
gram for Next Generation World-Leading Researchers (JSPS) to
M.I. and a Grant-in-Aid for Young Scientists (B) (JSPS) to D.U.
Supplementary data
Supplementary data (experimental protocol and characteriza-
tion data of all newly synthesized compounds) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.05.114.
In summary, we have developed a two-step protocol for the
preparation of
a-benzoyloxyalkylzinc bromides from the chemi-

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K. Sakata et al. / Tetrahedron Letters 54 (2013) 4189–4192
Knochel, P., Jones, P., Eds.; Oxford: New York, 1999; p 179; (d) Knochel, P.;
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