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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),