Table 2. Stereoselective Reformatsky reaction of α-bromoesters 1
with aldehydes
Table 3. Stereoselective Pd-catalyzed coupling of α-bromoester 1a
with iodobenzene
Entry
Catalyst, Ligand
[Pd(PPh3)4]
Pd(OAc)2, 2 PPh3
Pd/equiv Temp./°C Yielda/% drb (3a/4a)
1
2
3
4
5
6
7
8
9
0.05
0.05
0.05
0.05
0.05
0.05
0.05
66
66
66
66
rt
66
66
66
66
66
66
66
66
66
rt-50
38
34
35
80
35
57
39
76
82
48
61
68
3
77/23
83/17
83/17
78/22
71/29
78/22
87/13
36/64
42/58
74/26
70/30
83/17
nd
Entry Substrate R1 R2
R3
Ph
Product Yielda/%
drb
Pd(OAc)2, dppf
1
1a
Ph
H
2d
92
56/44
Pd(OAc)2, 2 P(o-Tol)3
Pd(OAc)2, 2 P(o-Tol)3
Pd(OAc)2, 2 JohnPhos
Pd(OAc)2, (R)-BINAP
[Pd2(dba)3], 2 P(o-Tol)3 0.05
[Pd2(dba)3], 4 P(o-Tol)3 0.05
MeO
MeO
2
1a
2e
96
62/38
3
4
1a
1b
n-Hept
Ph
2f
2g
74
90
60/40
®
-(CH2)4-
MeO
MeO
5
6
1b
2h
94
57
®
®
10 [Pd2(dba)3], 4 JohnPhos 0.05
11 [Pd2(dba)3], 4 X-Phos
12 [Pd2(dba)3], 4 S-Phos
13 Pd-PEPPSI-IPr
14 [PdP(t-Bu)3Br]2
15 [PdP(t-Bu)3Br]2
0.05
0.05
0.05
0.05
0.05
1b
n-Hept
2i
b
1
aIsolated. Ratio was determined by H NMR.
91
64
94/6
94/6
ketones to give trans-adducts 2a, 2b, and 2c, respectively, in
good yield with excellent trans-selectivity (trans-add/cis-add =
>99/1) (Table 1, Entries 1, 2, and 4). (ii) A similar reaction of
2,3-cis-disubstituted cyclic substrate 1b with cyclopentanone
also gave the corresponding trans-adduct with excellent trans-
selectivity (trans-add/cis-add = >99/1) (Table 1, Entry 4). (iii)
Increase in the stereocongestion between the ketone and the
substituted cyclopropane prevented the reaction from occurring
(Entries 3, 5, and 6). (iv) Reactions of 1b with aldehydes also
proceeded to provide good to high yields with excellent trans-
selectivities (trans-add/cis-add = >99/1) at the α-position and
moderate diastereoselectivities10 [2 (re-face-adduct)/3 (si-face-
adduct) = 56/44-62/38] at the β-position (Table 2, Entries 1-
3). Products 2d and 2e are important intermediates for the highly
diastereoselective synthesis of dihydronaphthalene-lignan de-
livatives.3e,3f
These successful results led us to investigate the Pd-
catalyzed coupling of the cyclopropyl-Zn-enolate, generated
from α-bromo-β-phenylcyclopropanecarboxylates, with phenyl
iodides. Optimizations of reaction conditions are summarized in
Table 3. Treatment of the Zn-enolate, generated from 1a, with
iodobenzene at 66 °C in THF in the presence of [Pd(PPh3)4]
afforded diphenylcyclopropanecarboxylic esters 3a and 4a in
38% yield (Entry 1). In the cases of Pd(OAc)2 with phosphine
ligands, such as PPh3, dppf, BINAP, JohnPhos adversely
affected the coupling. Use of a tri(o-tolyl)phosphine ligand7a
increased the yield of the coupling (Entry 4). The same reaction
at room temperature resulted in decreased yield (Entry 5). In the
case of [Pd2(dba)2] rather than Pd(OAc)2, a tri(o-tolyl)phosphine
ligand also promoted the desired reaction to provide good to
high yields (Entries 8 and 9). Use of four equivalents of the
ligand increased the yield slightly. Buchwald ligands,11 such as
Johnphos, X-Phos, and S-Phos are also effective in promoting
the coupling in moderate to good yields (48-68%) with good
trans-selectivities (70/30-83/17). In the presence of PEPPSI-
IPr, small amounts of esters 3a and 4a were obtained (Entry 13).
Notably, the coupling reaction using [PdP(t-Bu)3Br]27a promoted
the reaction in high yield with high trans-selectivity (Entry 14).
The same reaction at rt-50 °C gave 3a and 4a in 64% yield
(Entry 15). Thus, the use of [PdP(t-Bu)3Br]2 at 66 °C in THF
b
1
aIsolated. Ratio was determined by H NMR.
(method A) is the most efficient condition for this coupling
(Entry 14). Other conditions involving Pd(OAc)2 with two
equivalents of P(o-Tol)3 (method B) and [Pd2(dba)3] with four
equivalents of P(o-Tol)3 (method C) are also considered to
be practical conditions (Entries 4 and 9) even though the
diastereomer ratios (dr) are moderate.
Next, we investigate the coupling reaction of cyclopropyl-
Zn-enolate with several kinds of aryl or allyl iodide under the
identified optimized conditions. The reaction of 1a with p-anisyl
iodide in the presence of [PdP(t-Bu)3Br]2 (method A) proceeded
to give diarylcyclopropane 3b as the major product in high yield
with high trans-selectivity (Table 4, Entry 2). In the case of
methyl p-iodobenzoate, the reaction proceeded to afford 3c as
the major product with minor diastereomer 4c in moderate yield
(Entry 4). Use of Pd(OAc)2 with 2 equiv of P(o-Tol)3 (method
B) reversed the stereoselectivity (Entries 3 and 5). Under
condition B, the coupling of 1a with o-substituted phenyl iodide
took place with high trans-selectivity (Entries 6 and 7). Under
condition A, the same reaction of styryl iodide increased the
yield of the coupling with high trans-selectivity (Entry 8). In the
case of cis-disubstituted analog 1b instead of 1a, the coupling
proceeded in 38-66% yields with excellent trans-selectivities
(>99/1) (Entries 9-16). Regardless of the method (A, B, or C),
yields and stereoselectivities (>99/1) were similar for reactions
of 1b (Entries 9-11). The electron-withdrawing group on the
benzene ring decreased the yield of the coupling (Entry 13).
This result is consistent with the reaction of 1a (Entries 4 and 5).
In the references and Supporting Information,12 we considered
the stereoselectivity based on the plausible transition state in the
Pd-catalyzed coupling reaction of cyclopropyl-Zn-enolate with
aryl iodide.
In conclusion, we achieved a few highly stereoselective
syntheses of cyclopropane derivatives by using the Reformatsky
reaction and Pd-catalyzed arylation of 1-(methoxycarbonyl)cy-
clopropylzinc bromide. The present methods are new avenues
for the stereoselective synthesis of highly substituted cyclo-
propylcarbonyl compounds.
© 2015 The Chemical Society of Japan | 819
Sakuma, Daichi
