Highly efficient substitution of allylic picolinates with copper reagents derived from aryl-, alkenyl-, furyl-, and thienyl-lithiums

Article abstract of DOI:10.1016/j.tet.2009.11.052

Substitution of optically active allylic picolinate, cis R¹-CH(OC(O)(2-Py))CH{double bond, long}CHR² (R¹=(CH₂)₂Ph, R²=CH₂OTBS), with phenylcopper reagents derived from salt free

Full text of DOI:10.1016/j.tet.2009.11.052

Tetrahedron 66 (2010) 676–684
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Tetrahedron
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Highly efficient substitution of allylic picolinates with copper reagents derived
from aryl-, alkenyl-, furyl-, and thienyl-lithiums
*
Yohei Kiyotsuka, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Substitution of optically active allylic picolinate, cis R1-CH(OC(O)(2-Py))CH]CHR2 (R1¼(CH2)2Ph,
R2¼CH2OTBS), with phenylcopper reagents derived from salt free PhLi (2 equiv) and CuBr$Me2S (2 and
1 equiv, respectively) was highly promoted by MgBr2 (3 equiv), producing anti SN20 product regio- and
stereoselectively. This reagent system was proven to be general with several picolinates (R1, R2: Ph(CH2)2,
PMBO(CH2)3, Me, TBSOCH2, PMBOCH2, c-Hex). Furthermore, aryl copper reagents prepared from ArLi,
which was in turn prepared by Li–halogen exchange, was proven to be compatible with the substitution
in the presence of larger quantity of MgBr2 than that of LiX coproduced by the exchange. Substitution
was not interfered with the steric hindrance on aryl coppers (Ar: 2-MeOC6H4, 2,6-(MOMO)2-4-MeC6H2,
2,6-Me2C6H3, etc.). Similarly, stereodefined cis and trans alkenyl, furyl, and thienyl reagents gave the
corresponding anti SN20 products efficiently.
Article history:
Received 8 September 2009
Received in revised form 11 November 2009
Accepted 12 November 2009
Available online 15 November 2009
Keywords:
Allylic substitution
Picolinates
Copper reagents
Aryl lithiums
MgBr2
Ó 2009 Elsevier Ltd. All rights reserved.
Regioselectivity
Stereoselectivity
1. Introduction
report a full account of the study, focusing on synthetic advantage
of the lithium strategy (Scheme 1).
Allylic substitution of secondary allylic alcohol derivatives with
organocopper reagents is a potentially useful tool to create chiral
carbon center by C–C bond formation.1 Although copper reagents
prefer anti SN20 pathway,2 regio- and stereoselectivities are gener-
ally dependent on the potency of a leaving group, nucleophilicity of
copper reagent, and electronic/steric factors of reagents and the
allylic moiety. To attain high selectivity, several excellent leaving
groups such as o-(Ph2P)C6H4CO2,3 o-(Ph2P]O)C6H4CO2,4 C6F5CO2,5
(RO)2P(O)O6 have been developed. Unfortunately, the potency of
these groups was insufficient for aryl and alkenyl copper reagents
that are less nucleophilic than alkyl reagents. Recently, we have
introduced the picolinoxy leaving group, which showed high re-
activity toward aryl and alkenyl copper reagents derived from
Grignard reagents.7 We then turned our attention to organo-
lithium-based copper reagents with expectation of that the scope
of copper reagents for the allylic substitution would be expanded
with the various preparations of RLi such as halogen–lithium ex-
change, ortho lithiation, and direct lithiation. Preliminary study
along this line was published as a communication.8 Herein, we
R3Li
CuBr•Me2S
" R3-Cu "
N
O
R2
R2
O
+
R3
R1
R1
MgBr2
2
1
anti SN2' product
R3: Ph, Ar,
hetero-Ar,
cis and trans alkenyls,
alkyl
Scheme 1. Allylic substitution of picolinates.
Although the (S) chirality is drawn for 1, a (R) isomer is used in some cases.
2. Results and discussion
Salt free PhLi9 (2 equiv per picolinate) was mixed with different
quantities of CuBr$Me2S (2, 1, and 0.5 equiv) at 0 ꢀC for 20–30 min
to prepare three phenylcopper reagents formulated as PhCu,
Ph2CuLi, and Ph2CuLiþ2 PhLi, which are defined herein as Ph/Cu
(2:2, 2:1, and 2:0.5) reagents, respectively. However, the major
course of reaction with rac-1a (R1¼(CH2)2Ph, R2¼CH2OTBS) in THF
at 0 ꢀC for 1 h was attack to the carbonyl carbon to produce alcohol
rac-4a in considerable yields (Table 1, entries 1, 3, and 7).
* Corresponding author. Tel./fax: þ81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.052

Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
677
Table 1
Preliminary study using rac-1aa
Ph-M + CuBr·Me2S
Ph
Ph
OH
OC(O)(2-Py)
R2
(MgBr2)
R2
+
;
" Ph-Cu "
;
R1
R2
R1
R2
R1
R1
THF, 1 h, 0 °C
rac-2a
rac-4a
rac-1a
rac-3a
Ph-M: PhLi, PhZnBr·LiBr, Ph2Zn·2LiBr
R1: (CH2)2Ph, R2: CH2OTBS
Entry
Ph-Mb (equiv)
CuBr$Me2S (equiv)
MgBr2 (equiv)
Ratioc of rac-2a:-3a:-4a:-1a
Yieldd,e (%)
1
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
PhLi (2)
2
2
1
1
1
1
0.5
0.5
0.5
0.5
1.5
1.5
0
3
0
2
3
4
0
3
0
3
0
6
9:0:69:22
100:0:0:0
11:0:47:42
84:0:15:1
100:0:0:0
98:0:2:0
48:0:44:8
98:2:0:0
17:0:47:36
94:0:6:0
nd
97
nd
nd
94
92
nd
95
nd
nd
nd
89
2f
3
4
5f
6
7
8f
9
PhZnBr$LiBrg (2)
PhZnBr$LiBrg (2)
Ph2Zn$2LiBri (3)
Ph2Zn$2LiBri (3)
10
11h
12
31:0:46:23
100:0:0:0
a
Reactions were carried out at 0 ꢀC unless otherwise noted.
Salt free PhLi was used.
b
c
d
e
f
Determined by 1H NMR spectroscopy of the crude products.
Isolated combined yields of rac-2a and -3a.
nd: not determined.
Reaction at ꢁ60 to ꢁ50 ꢀC afforded essentially the same result.
Prepared from PhLi (2 equiv per rac-1a) and ZnBr2 (3 equiv).
Cited from Ref. 7.
g
h
i
Prepared from PhLi (6 equiv per rac-1a) and ZnBr2 (3 equiv).
PhLi (2 equiv)
CuBr•Me2S (1 equiv)
MgBr2 (3 equiv)
Fortunately, MgBr2 (3 equiv) added to the reaction mixture was
found to promote the allylic substitution to be completed within
1 h, furnishing rac-2a (trans olefin, JCH]CH¼15 Hz) with almost
complete regioselectivity in high yields (entries 2, 5, and 8).10
Regioisomer rac-3a, prepared independently (see Table 3, entry 1),
was produced in a trace yields (0–2%). Reactions at ꢁ60 to ꢁ50 ꢀC
with these reagents gave comparable results to those at 0 ꢀC
(footnote f in entries 2, 5, and 8). In these entries formation of cis
isomers 5 and 6 was not detected by 1H NMR spectroscopy.11 To
optimize quantity of MgBr2, less or more than 3 equiv of MgBr2 were
added to a solution of the Ph/Cu (2:1) reagent. With 2 equivof MgBr2,
production of rac-2a was appreciably improved, but was in an in-
sufficient level (entry 4 vs entry 3), whereas 4 equiv of MgBr2 pro-
moted almost complete production of rac-2a (entry 6). These results
led us to state that the larger equivalent of MgBr2 than Liþ is neces-
sary to attain high reactivity and regioselectivity (requirement 1).12
It is likely that the picolinoxy group is activated by MgBr2
through coordination to the carbonyl oxygen and the pyridyl
nitrogen.
Ph OC(O)(2-Py)
OTBS
rac-2a
+
5
THF, 1 h, 0 °C
(86 : 14)
7
Scheme 2. Substitution of trans picolinate 7.
Zinc reagents derived from PhLi and ZnBr2 were examined next
as sources of the Ph/Cu reagent. Two (2) equiv of PhZnBr$LiBr was
mixed with CuBr$Me2S (0.5 equiv) at 0 ꢀC for 30 min to prepare the
Ph/Cu(2:0.5) reagent, which was subjected to reactionwith rac-1a at
0 ꢀC for 1 h in the absence and presence of MgBr2 (3 equiv). As
expected, high efficiency was provided with MgBr2 (entry 10 vs
entry 9). A similar result was observed with a copper reagent derived
from Ph2Zn$2LiBr and CuBr$Me2S (entry 12 vs entry 11). These re-
sults would be useful in a case that zinc reagent is available easily.13
The three copper reagent systems used in entries 2, 5, and 8 of
Table 1 were applied to (S)-1a13 (95–98% ee), which afforded(R)-2ain
high yields. The R configuration was determined by comparison of
the retention time on a chiral HPLC with an authentic sample of the
known configuration,7 thus confirming the anti SN20 pathway of the
reaction. Excellent CT (98%), defined as percentage (%) of enantio-
meric excess (ee) of product over picolinate, was attained with the
Ph/Cu (2:2 and 2:1) reagents and little dependent on reaction tem-
peratures (entries 1–4). On the other hand, Ph/Cu (2:0.5) gave
somewhat low CT of 71% (entry 5), which was not fully improved at
ꢁ60 ꢀC (entry 6). Thus, 2–1 equiv of CuBr$Me2S toward RLi (2 equiv)
was established to realize high CT (requirement 2). Additionally, the
use of 2–1 equiv of CuBr$Me2S is operational advantage in that pre-
cise measurement of CuBr$Me2S for preparation of copper reagent
and control of temperatures in a narrow range are not necessary.
To obtain more information about the low CTobserved in entries
5 and 6, LiBr (2 equiv) was added to the Ph copper reagent derived
from PhMgBr (2 equiv) and CuBr$Me2S (0.5 equiv). Indeed, LiBr
lowered the original CT (98%) to 82% (Scheme 3), thus proving the
OTBS
Ph
Ph
Ph
OTBS
Ph
5
6
The above conditions were applied to trans picolinate 7 to
examine the importance of the cis geometry of the picolinate
(Scheme 2). The reaction completed within 1 h at 0 ꢀC with excel-
lent regioselectivity (>95%). However, a mixture of rac-2a and the
cis isomer 5 was obtained in a 86:14 ratio, indicating importance of
the cis geometry for the high selectivity. Interestingly, this selec-
tivity is different from that obtained with PhMgBr/CuBr$Me2S in
a 2:1 ratio, which produced regioisomers rac-2a and rac-3a (trans
isomer of 5) in a 60:40 ratio.7

678
Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
negative effect of LiBr co-generated in the preparation of the Ph/Cu
reagent from PhLi and CuBr$Me2S.
effective (entry 3). Substitution of (S)-1d at the established tem-
perature (0 ꢀC) gave 2d with a slightly low ee of 94% ee (entry 4),
which was improved to 97% by conducting the reaction at ꢁ60 ꢀC
(see result in a parenthesis). These results coupled with that
obtained with (S)-1a (Table 2) imply that the substitution is
marginally interfered with the sizes of a methylene and an
alkoxymethyl substituents on the allylic moiety. A larger c-hexyl
group attached to the olefin carbon did not interfere with the
efficiency as well (entry 5).
PhMgBr (2 equiv)
CuBr•Me2S (0.5 equiv)
(R)-2a
(S)-1a
–60 ~ –40 °C, 1 h
" LiBr (2 equiv) "
without LiBr 98% CT, 83% yield
with LiBr 82% CT, 76% yield
Bulky copper reagents were examined next. First, a lithium re-
agent prepared from anisole by ortho lithiation16 with n-BuLi was
converted to the corresponding copper reagent of the 2:1 type
according to requirement 2. This reagent underwent substitution
smoothly with (S)-1a to produce 2f in 85% yield with comparable
CT to that obtained with the Ph/Cu reagent (entry 6). In a similar
manner, the lithium anion produced by ortho lithiation of 1,3-
(MOMO)2-5-MeC6H3 was converted to copper reagent, which
furnished 2g in 97% yield without any loss in CT (entry 7). Next,
2,6-dimethylphenylcopper reagent was prepared by Li–Br ex-
change of 1-Br-2,6-Me2C6H3 with t-BuLi followed by reaction with
CuBr$Me2S. Substitution of (S)-1a with this copper reagent pro-
ceeded well in the presence of 5 equiv of MgBr2 according to
requirement 1, delivering 2h with 97% CT in 88% yield (entry 8).
Another bulky reagent that possesses a latent CO2R group also
furnished product 2i highly efficiently (entry 9). We think these
examples are surely enough to demonstrate the high potency of the
picolinate strategy.
Scheme 3. Influence of LiBr on CT.
The requirements 1 (MgBr2>LiBr) and 2 (Ph/Cu¼1–2:1) estab-
lished above for the copper reagents derived from salt free PhLi
should be applicable to organolithiums prepared by the methods
such as direct lithiation and ortho lithiation. Successful examples of
this statement are presented in the latter paragraphs.
Next, PhLi prepared in situ by Li–halogen exchange was in-
vestigated. First, 4 equiv of t-BuLi were added to 2 equiv of PhBr at
0 ꢀC in Et2O. After 30 min, PhLi (2 equiv) coproduced with LiBr
(2 equiv), Me2C]CH2 (2 equiv), and t-BuH (2 equiv) was mixed
with CuBr$Me2S (1 equiv) to produce the Ph/Cu (2:1) reagent and
LiBr (totally 4 equiv). According to requirement 1 substitution of (S)-
1a with this Ph/Cu reagent was carried out with 5 equiv of MgBr2 to
furnish (R)-2a with excellent product selectivity and reactivity
(Table 2, entry 8). The Ph/Cu prepared from PhI and t-BuLi gave
a similar result (entry 10). In contrast, use of n-BuLi (2 equiv) for
lithiation of PhX (X¼Br, I; 2 equiv) afforded unidentified products
(entries 7 and 9).
The p-F-C6H4 copper reagent bearing the electron-withdrawing
group afforded compound 2j with a slightly low CT of 95% in 92%
Table 2
Allylic substitution of (S)-1aa with Ph copper reagents derived from PhLi
Ph
OC(O)(2-Py)
CH2OTBS
PhLi / CuBr•Me2S / MgBr2
THF, 1 h
Ph(CH2)2
CH2OTBS
Ph(CH2)2
(S)-1a
(R)-2a
Product (R)-2ab
Entry
Source of PhLi (equiv)
CuBr$Me2S (equiv)
MgBr2 (equiv)
Temp (ꢀC)
CTc,d (%)
Yield (%)
1
2
3
4
5
6
7
8
9
Salt free PhLie (2)
Salt free PhLie (2)
Salt free PhLie (2)
Salt free PhLie (2)
Salt free PhLie (2)
Salt free PhLie (2)
PhBr (2)þn-BuLi (2)
PhBr (2)þt-BuLi (4)
PhI (2)þn-BuLi (2)
PhI (2)þt-BuLi (4)
2
2
1
1
0.5
0.5
1
1
1
3
3
3
3
3
3
3
5
3
5
0
98
98
98
98
71
84
d
97
92
92
92
92
90
0f
93
0f
90
ꢁ60 to ꢁ50
0
ꢁ60 to ꢁ50
0
ꢁ60 to ꢁ50
0
0
0
0
98
d
10
1
98
a
95–98% ee.
b
c
d
e
f
The absolute configuration was determined by chiral HPLC analysis.
Chirality transfer (CT) defined by (% ee of (R)-2a/% ee of (S)-1a)ꢂ100.
Determined by chiral HPLC analysis.
Obtained from a company.
Unidentified compounds were produced.
To examine the potency of the present allylic substitution, the
yield (entry 10). However, the CT was improved easily by con-
ducting the reaction at ꢁ20 ꢀC (see the result in a parenthesis).
Copper reagents derived from furan and thiophene by direct
lithiation are marginally reactive toward conjugate addition to
enones.17,18 Due to the low reactivity, the latter is used as a dummy
ligand in the Lipshutz reagent (Fig. 1).18 In contrast, these copper
reagents showed sufficient reactivity in the present substitution to
furnish 2k and 2l in good yields with high CT (entries 11 and 12).
Usually, direct insertion of Mg to cis R-CH]CH-Br suffers from
isomerization of the double bond to such extend that depends on
the size of a substituent (R) on the olefinic carbon.19 In cases of
R¼n-C6H13 and Me, for example, 15% and 3% isomerizations have
Ph/Cu (2:1 and 1:1) reagents were applied to several picolinates
bearing different substituents. These picolinates were prepared
according to the recent papers,7,14 in which asymmetric hydrogen
transfer reaction of acetylenic ketones with (S,S)-chiral Ru cata-
lyst15 was used to synthesize 94–99% ee of (S)-1a, -d, and -1e.
Substitution of (S)-1b, the regioisomer of (S)-1a, with the Ph/
Cu (2:1) reagent at 0 ꢀC for 1 h in the presence of MgBr2 (3 equiv)
produced the regioisomer of 2a (i.e., 2b) with excellent efficiency,
which is similar to that of 2a (Table 3, entry 1; cf. Table 2, entry
3). Picolinate (R)-1c showed similar reactivity toward the Ph/Cu
(2:1) reagent (entry 2). The other Ph/Cu (1:1) reagent was also

Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
679
Table 3
Allylic substitution of optically active picolinates with copper reagentsa
b,c
Entry
Allylic picolinate
(% ee)
RLi (equiv)
Method giving RLi
CuBr/Me2S
(equiv)
MgBr2
(equiv)
anti SN20 product
Structure
CT (%)
99
Yield (%)
Ph
Ph Ph
OTBS
OTBS
1
PhLi (2)
d
1
3
3
87
(2-Py)COO
2b
2c
(S)-1b (99% ee)
OPMB
(2-Py)COO
OPMB
Ph
2
PhLi (2)
d
1
98
84
(R)-1c (99% ee)
3
4
(R)-1c (99% ee)
PhLi (2)
PhLi (2)
d
d
2
1
3
3
2c
98
87
(2-Py)COO
Ph
94 (97)
82 (92)d
Ph
Ph
2d
(S)-1d (94% ee)
(2-Py)COO
c-Hex
c-Hex
PMBO
PMBO
5
6
PhLi (2)
d
1
1
3
3
98
99
94
85
Ph
2e
(S)-1e (99% ee)
TBSO
OTBS
(2-Py)COO
Ph
Li
ortho Lithiation
using n-BuLi
(2)
Ph
R
OMe
OMe
2f, R =
(S)-1a (95% ee)
MOMO
MOMO
OMOM
ortho Lithiation
using n-BuLi
2g, R =
7
8
(S)-1a (98% ee)
(S)-1a (97% ee)
Li
1
1
3
5
>99
97
88
(2)
MOMO
Li–Br exchangee
97
Li
(2)
2h, R =
O
ortho Lithiation
using n-BuLi
2i, R =
9
(S)-1a (97% ee)
(S)-1a (98% ee)
(S)-1a (95% ee)
1
1
1
3
5
3
>99
98
N
N
(2)
O
Li
2j, R =
2k, R =
10
11
Li–Br exchangee
95 (97)
92 (92)d
F
Li
(2)
F
O
S
Direct lithiation
using n-BuLi
99
86
(2)
Li
O
S
Direct lithiation
using n-BuLi
2l, R =
12
(S)-1a (97% ee)
1
3
99
83
(2)
Li
(continued on next page)

680
Table 3 (continued)
Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
Entry
Allylic picolinate
(% ee)
RLi (equiv)
Method giving RLi
CuBr/Me2S
(equiv)
MgBr2
(equiv)
anti SN20 product b,c
Structure
CT (%)
98
Yield (%)
75
C5H11
C5H11
(3)
(3)
13
14
(S)-1a (98% ee)
Li–I exchangee
Li–I exchangee
1.5
1.5
7
7
2m, R =
Li
(S)-1a (95% ee)
(S)-1a (95% ee)
99
98
82
93
2n, R =
2o, R =
Li
Li
(2)
15
Li–I exchangee
1
5
C5H11
C5H11
a
Reactions were carried out at 0 ꢀC for 1 h unless otherwise noted.
b
c
Regioselectivities for all of the reactions were >97% by 1H NMR spectroscopy.
The absolute configurations of 2b and 2d were determined by comparison of the retention times on a chiral HPLC with authentic samples of the known configuration.
Those of other products were determined by analogy of 2a, 2b, and 2d.
d
e
At ꢁ60 ꢀC (entry 4); ꢁ20 ꢀC (entry 10).
Corresponding halide (3 or 2 equiv) and t-BuLi (6 or 4 equiv).
4. Experimental
2–
2 Li+
Cu(CN)R
4.1. General
S
Infrared (IR) spectra are reported in wave numbers (cmꢁ1). The
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured
Figure 1. Lipshutz reagent for conjugate addition to enones.
been observed, respectively.19b,c In contrast, Li–halogen exchange
of cis R-CH]CH-X (X¼Br, I) with t-BuLi proceeds with retention of
the cis geometry. This method was coupled with the present sub-
stitution to deliver n-C5H11- and c-C6H11-substituted cis olefin
moieties to the allylic position of (S)-1a in good yields and with
high CT (entries 13 and 14). Substitution with trans 1-heptenyl
copper reagent afforded 2o efficiently (entry 15).
We then applied the present protocol to alkyllithium. As shown
in Scheme 4, n-Bu2CuLi$LiBr underwent substitution even in the
absence of MgBr2, furnishing the anti SN20 products 2p and 2q from
(S)-1a and (R)-1c, respectively. High reactivity of the Bu reagent is
probably attributable to the nucleophilicity of the Bu anion, that is,
stronger than that of aryl and alkenyl anions.
in CDCl3 using SiMe4 (
d
¼0 ppm) and the center line of CDCl3 triplet
(d¼77.1 ppm) as internal standards, respectively. Signal patterns are
indicated as br s, broad singlet; s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet. Coupling constants (J) are given in hertz (Hz).
In some cases chemical shifts of carbons accompany plus (for C and
CH2) and minus (for CH and CH3) signs of APT experiments (At-
tached Proton Test). After the reactions, organic extracts were
concentrated by using a rotary evaporator and residues were pu-
rified by chromatography on silica gel (Merck, silica gel 60; Kanto,
spherical silica gel 60 N).
4.2. Allylic substitution
The reactions of (S)-1a with Ph coppers prepared by various
ways are described below (Section 4.2.1) as the general methods.
n-BuLi (2 equiv)
CuBr·Me2S (1 equiv)
OTBS
TBSO
(2-Py)COO
Ph
Ph
n-Bu
THF, –20 °C, 1 h
4.2.1. (R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2,6-diphenyl-3-hexene
((R)-2a). Table 2, entry 1: to an ice-cold suspension of CuBr$Me2S
(39.5 mg, 0.192 mmol) in THF (1.6 mL) were added PhLi (0.180 mL,
1.08 M in cyclohexane/Et2O, 0.194 mmol) and MgBr2 (1.40 mL,
0.20 M in THF, 0.280 mmol). After 30 min at 0 ꢀC, a solution of (S)-
1a (39.5 mg, 0.0960 mmol, 98% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h, and
diluted with hexane and saturated NH4Cl with vigorous stirring.
The layers were separated and the aqueous layer was extracted
with hexane twice. The combined extracts were washed with brine,
dried over MgSO4, and concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to afford
(R)-2a (34.0 mg, 97%, 96% ee, 98% CT). The 1H NMR spectrum and
retention time of (R)-2a on chiral HPLC were identical with those
reported.7
Table 2, entry 3: to an ice-cold suspension of CuBr$Me2S
(22.0 mg, 0.107 mmol) in THF (1.4 mL) were added PhLi (0.200 mL,
1.08 M in cyclohexane/Et2O, 0.216 mmol) and MgBr2 (1.60 mL,
0.20 M in THF, 0.320 mmol). After 30 min at 0 ꢀC, a solution of (S)-
1a (44.1 mg, 0.107 mmol, 98% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to afford
(R)-2a (36.2 mg, 92%, 96% ee, 98% CT by chiral HPLC analysis).
Table 2, entry 8: to an ice-cold solution of PhBr (0.022 mL,
0.209 mmol) in Et2O (1 mL) was added t-BuLi (0.250 mL, 1.57 M in
pentane, 0.393 mmol) slowly. After 30 min at 0 ꢀC, a solution of
(S)-1a
(95% ee)
2p
95% CT, 90% yield
n-BuLi (2 equiv)
CuBr·Me2S (1 equiv)
OPMB
PMBO
(2-Py)COO
n-Bu
THF, –15 °C, 1 h
(R)-1c
(98% ee)
2q
98% CT, 82% yield
Scheme 4. Reaction with the n-BuLi/CuBr$Me2S reagent.
3. Conclusions
Substitution of allylic picolinates with aryl, alkenyl, and heter-
oaryl coppers derived from the organolithiums and CuBr$Me2S was
studied. We found that addition of MgBr2 substantially enhanced
the substitution, giving anti SN20 products highly selectively in good
yields. Furthermore, we elucidated the following requirements for
high efficiency: (1) quantity of MgBr2 should be more than that of
Liþ (requirement 1); (2) 1–2 equiv of CuBr$Me2S should be used
toward 2 equiv of RLi (requirement 2). With these requirements, not
only sterically bulky reagents but also electronically less nucleo-
philic reagents furnished anti SN20 products efficiently as summa-
rized in Tables 2 and 3. In addition, cis alkenyl copper reagents
underwent substitution with retention of the cis geometry.

Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
681
MgBr2 (2.40 mL, 0.20 M in THF, 0.480 mmol) and CuBr$Me2S
(19.9 mg, 0.0968 mmol) were added to the solution. The resulting
mixture was stirred at 0 ꢀC for 30 min, and a solution of (S)-1a
(39.8 mg, 0.0967 mmol, 95% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h, to
afford (R)-2a (33.0 mg, 93%, 93% ee, 98% CT by chiral HPLC
analysis).
Table 2, entry 10: to an ice-cold solution of PhI (0.024 mL,
0.214 mmol) in Et2O (1 mL) was added t-BuLi (0.250 mL, 1.57 M in
pentane, 0.393 mmol) slowly. After 30 min at 0 ꢀC, a solution of
MgBr2 (2.40 mL, 0.20 M in THF, 0.480 mmol) and CuBr$Me2S
(19.7 mg, 0.0958 mmol) were added to the solution. The resulting
mixture was stirred at 0 ꢀC for 30 min, and a solution of (S)-1a
(39.5 mg, 0.0960 mmol, 95% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to
afford (R)-2a (31.8 mg, 90%, 93% ee, 98% CT by chiral HPLC
analysis).
enantiomeric information (97% ee, 98% CT) was determined by
chiral HPLC analysis: Chiralcel OD-H; hexane/i-PrOH¼98/2, 0.2 mL/
min, rt; tR (min)¼41.9 (R), 47.9 (S).
4.2.6. (R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(2-methoxyphenyl)-6-
phenylhex-3-ene (2f). Table 3, entry 6: to an ice-cold solution of
anisole (0.025 mL, 0.23 mmol) in THF (1.4 mL) was added n-BuLi
(0.13 mL, 1.60 M in hexane, 0.208 mmol) slowly. After 30 min at
0 ꢀC, a solution of MgBr2 (1.60 mL, 0.20 M in THF, 0.32 mmol) and
CuBr$Me2S (21.2 mg, 0.103 mmol) were added to the solution. The
resulting mixture was stirred at 0 ꢀC for 30 min, and a solution of
(S)-1a (42.4 mg, 0.103 mmol, 95% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to afford
2f (34.6 mg, 85%, 94% ee, 99% CT). The 1H NMR spectrum of 2f was
identical with that reported.7
4.2.7. (R,E)-2-[(2,6-Bis(methoxymethoxy)-4-methyl)phenyl]-1-
[(tert-butyldimethylsilyl)oxy]-6-phenylhex-3-ene
(2g). Table
3,
4.2.2. (S,E)-1-[(tert-Butyldimethylsilyl)oxy]-4,6-diphenylhex-2-ene
(2b). Table 3, entry 1: to an ice-cold suspension of CuBr$Me2S
(19.5 mg, 0.0949 mmol) in THF (1.6 mL) were added PhLi
(0.180 mL, 1.08 M in cyclohexane/Et2O, 0.194 mmol) and MgBr2
(1.40 mL, 0.20 M in THF, 0.280 mmol). After 30 min at 0 ꢀC, a so-
lution of (S)-1b (39.0 mg, 0.0947 mmol, 99% ee) in THF (1 mL) was
added to it dropwise. The resulting mixture was stirred at 0 ꢀC for
1 h to afford 2b (30.1 mg, 87%, 98% ee, 99% CT). The 1H NMR
spectrum and retention time of 2b were identical with those
reported.7
entry 7: to an ice-cold solution of 1,3-bis(methoxymethoxy)-5-
methylbenzene (43.9 mg, 0.207 mmol) in THF (1.6 mL) was added
n-BuLi (0.120 mL, 1.60 M in hexane, 0.192 mmol) slowly. After
30 min at 0 ꢀC, a solution of MgBr2 (1.40 mL, 0.20 M in THF,
0.280 mmol) and CuBr$Me2S (19.3 mg, 0.0939 mmol) were added
to the solution. The resulting mixture was stirred at 0 ꢀC for
30 min, and a solution of (S)-1a (38.7 mg, 0.0940 mmol, 98% ee) in
THF (1 mL) was added to it dropwise. The resulting mixture was
stirred at 0 ꢀC for 1 h to afford a mixture of 2g and (2,6-(MOMO)2-
4-MeC6H2)2 in a 84:16 ratio by 1H NMR analysis (54.1 mg in total,
97% yield of 2g): 1H NMR (300 MHz, CDCl3)
d
ꢁ0.08 (s, 3H), ꢁ0.07
4.2.3. (S,E)-5-((4-Methoxybenzyl)oxy)-4-phenylhex-2-ene
(2c). Table 3, entry 2: to an ice-cold suspension of CuBr$Me2S
(23.6 mg, 0.115 mmol) in THF (1.3 mL) were added PhLi (0.210 mL,
1.08 M in cyclohexane/Et2O, 0.227 mmol) and MgBr2 (1.70 mL,
0.20 M in THF, 0.340 mmol). After 30 min at 0 ꢀC, a solution of (R)-
1c (37.4 mg, 0.115 mmol, 99% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to afford
2c (27.1 mg, 84%, 97% ee, 98% CT). The 1H NMR spectrum of 2c was
identical with that reported.7
(s, 3H), 0.78 (s, 9H), 2.21 (s, 3H), 2.15–2.28 (m, 2H), 2.57 (t, J¼8 Hz,
1H), 3.39 (s, 6H), 3.72 (dd, J¼10, 6 Hz, 1H), 3.96 (dd, J¼10, 9 Hz,
1H), 4.08 (ddd, J¼9, 7, 6 Hz, 1H), 5.06 (s, 4H), 5.46 (dt, J¼15, 7 Hz,
1H), 5.86 (dd, J¼15, 8 Hz, 1H), 6.52 (s, 2H), 7.03–7.12 (m, 3H), 7.13–
7.22 (m, 2H); 13C NMR (75 MHz, CDCl3)
36.1, 42.5, 56.2, 65.3, 94.6, 109.2, 117.2, 125.7, 128.3, 128.5, 130.6,
130.7, 137.7, 142.4, 156.0.
d
ꢁ5.1, 18.5, 21.8, 26.0, 34.8,
Transformation of 2g to alcohol for determination of the
structure: to a solution of the above mixture of 2g and (2,6-
(MOMO)2-4-MeC6H2)2 in THF (1 mL) was added Bu4NF (0.14 mL,
1.0 M in THF, 0.14 mmol). The reaction was carried out at rt
overnight to furnish the corresponding alcohol (34.1 mg, 94% from
4.2.4. (R,E)-1,5-Diphenylhex-3-ene (2d). Table 3, entry 4: to an ice-
cold suspension of CuBr$Me2S (16.8 mg, 0.0817 mmol) in THF
(1.6 mL) were added PhLi (0.15 mL, 1.08 M in cyclohexane/Et2O,
0.162 mmol) and MgBr2 (1.30 mL, 0.20 M in THF, 0.260 mmol). After
30 min at 0 ꢀC, a solution of (S)-1d (23.0 mg, 0.0817 mmol, 94% ee)
in THF (1 mL) was added to it dropwise at ꢁ60 ꢀC. The resulting
mixture was stirred at ꢁ60 ꢀC for 1 h to afford 2d (17.8 mg, 92%, 91%
ee, 97% CT). The 1H and 13C NMR spectra of 2d and its retention time
were identical with that reported.7
;
(S)-1a): IR (neat) 3430, 1610, 1583, 1046 cmꢁ1 1H NMR (300 MHz,
CDCl3)
d
1.53 (br s, 1H), 2.29 (s, 3H), 2.32 (ddd, J¼8, 7, 7 Hz, 2H),
2.63 (dt, J¼14, 8 Hz, 1H), 2.71 (dt, J¼14, 7 Hz, 1H), 3.46 (s, 6H),
3.70–3.81 (m, 1H), 3.85–3.95 (m, 1H), 4.18 (dt, J¼8, 8 Hz, 1H), 5.14
(s, 4H), 5.62 (dt, J¼15, 7 Hz, 1H), 5.87 (dd, J¼15, 8 Hz, 1H), 6.61 (s,
2H), 7.11–7.20 (m, 3H), 7.22–7.28 (m, 2H); 13C NMR (75 MHz,
CDCl3)
d
21.8 (ꢁ), 34.6 (þ), 35.9 (þ), 42.8 (ꢁ), 56.2 (ꢁ), 64.5 (þ),
94.5 (þ), 109.3 (ꢁ), 116.1 (þ), 125.9 (ꢁ), 128.3 (ꢁ), 128.5 (ꢁ), 129.9
(ꢁ), 132.2 (ꢁ), 138.3 (þ), 142.0 (þ), 155.9 (þ); HRMS (FAB) calcd for
C23H30O5Na [(MþNa)þ] 409.1991, found 409.1988. The enantio-
meric information (98% ee, >99% CT) was determined by chiral
HPLC analysis: Chiralcel AD-H; hexane/i-PrOH¼98/2, 0.3 mL/min,
rt; tR (min)¼108.2 (S), 112.5 (R).
4.2.5. (R,E)-1-Cyclohexyl-6-((4-methoxybenzyl)oxy)-1-phenylhex-2-
ene (2e). Table 3, entry 5: to an ice-cold suspension of CuBr$Me2S
(18.3 mg, 0.0890 mmol) in THF (1.5 mL) were added PhLi (0.170 mL,
1.08 M in cyclohexane/Et2O, 0.184 mmol) and MgBr2 (1.40 mL,
0.20 M in THF, 0.280 mmol). After 30 min at 0 ꢀC, a solution of (S)-
1e (37.8 mg, 0.0892 mmol, 99% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to afford
4.2.8. (R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(2,6-dimethylphenyl)-
6-phenylhex-3-ene (2h). Table 3, entry 8: to an ice-cold solution of
2-bromo-1,3-dimethylbenzene (0.026 mL, 0.195 mmol) in Et2O
(1 mL) was added t-BuLi (0.280 mL, 1.57 M in pentane, 0.361 mmol)
slowly. After 30 min at 0 ꢀC, a solution of MgBr2 (2.30 mL, 0.20 M in
THF, 0.460 mmol) and CuBr$Me2S (18.8 mg, 0.0914 mmol) were
added to the solution. The resulting mixture was stirred at 0 ꢀC for
30 min, and a solution of (S)-1a (37.6 mg, 0.0913 mmol, 97% ee) in
THF (1 mL) was added to it dropwise. The resulting mixture was
stirred at 0 ꢀC for 1 h to afford 2h (31.7 mg, 88%): IR (neat) 1255,
2e (31.9 mg, 94%): IR (neat) 1612, 1513, 1248 cmꢁ1
;
1H NMR
(300 MHz, CDCl3) 0.70–0.96 (m, 2H), 1.04–1.28 (m, 3H), 1.32–1.90
d
(m, 8H), 2.07 (dt, J¼7, 7 Hz, 2H), 2.86 (dd, J¼9, 9 Hz, 1H), 3.40 (t,
J¼7 Hz, 2H), 3.80 (s, 3H), 4.39 (s, 2H), 5.38 (dt, J¼15, 7 Hz, 1H), 5.57
(dd, J¼15, 9 Hz, 1H), 6.87 (d, J¼9 Hz, 2H), 7.06–7.30 (m, 7H); 13C
NMR (75 MHz, CDCl3)
d
26.47 (þ), 26.49 (þ), 26.6 (þ), 29.2 (þ), 29.6
(þ), 31.4 (þ), 31.5 (þ), 42.6 (ꢁ), 55.3 (ꢁ), 56.4 (ꢁ), 69.5 (þ), 72.6 (þ),
113.8 (ꢁ), 125.8 (ꢁ), 127.9 (ꢁ), 128.3 (ꢁ), 129.3 (ꢁ), 130.2 (ꢁ), 130.8
(þ), 133.3 (ꢁ), 145.0 (þ), 159.2 (þ); HRMS (FAB) calcd for
C26H34O2Na [(MþNa)þ] 401.2457, found 401.2447. The
1099, 836 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
ꢁ0.06 (s, 3H), ꢁ0.02

682
Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
(s, 3H), 0.84 (s, 9H), 2.25–2.38 (m, 8H), 2.65 (t, J¼8 Hz, 2H), 3.72–
3.84 (m, 1H), 3.96–4.07 (m, 2H), 5.39 (dt, J¼16, 7 Hz, 1H), 5.81 (dm,
J¼16 Hz, 1H), 6.93–7.04 (m, 3H), 7.11–7.19 (m, 3H), 7.21–7.28 (m,
(dd, J¼10, 7 Hz, 1H), 3.74 (dd, J¼10, 7 Hz, 1H), 5.51 (dt, J¼16, 6 Hz,
1H), 5.61 (dd, J¼16, 7 Hz, 1H), 6.95 (ddt, J¼9, 9, 2 Hz, 2H), 7.07–7.21
(m, 5H), 7.22–7.30 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.4 (ꢁ),
2H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.3 (ꢁ), 18.3 (þ), 21.8 (ꢁ), 26.0
18.3 (þ), 25.9 (ꢁ), 34.7 (þ), 35.9 (þ), 50.5 (ꢁ), 67.5 (þ), 114.9 (d,
J¼21 Hz) (ꢁ), 125.8 (ꢁ), 128.3 (ꢁ), 128.6 (ꢁ), 129.7 (d, J¼7 Hz) (ꢁ),
131.0 (ꢁ), 131.3 (ꢁ), 138.3 (d, J¼3 Hz) (þ), 142.0 (þ), 161.6 (d,
J¼242 Hz) (þ); HRMS (FABþ) calcd for C24H33FOSiNa [(MþNa)]þ
407.2194, found 407.2182. The enantiomeric information (94% ee,
97% CT) was determined by chiral HPLC analysis of the corre-
sponding alcohol: Chiralcel OD-H; hexane/i-PrOH¼98/2, 0.5 mL/
min, rt; tR (min)¼64.3 (R), 75.2 (S).
(ꢁ), 34.9 (þ), 36.0 (þ), 46.4 (–), 65.2 (þ), 125.8 (ꢁ), 126.2 (ꢁ), 128.3
(ꢁ), 128.5 (ꢁ), 130.0 (ꢁ), 130.3 (ꢁ), 138.8 (þ), 142.2 (þ); HRMS (FAB)
calcd for C26H38OSiNa [(MþNa)þ] 417.2590, found 417.2592. The
enantiomeric information (94% ee, 97% CT) was determined by
chiral HPLC analysis of the corresponding alcohol: Chiralcel OD-H;
hexane/i-PrOH¼98/2, 0.4 mL/min, rt; tR (min)¼50.1 (S), 71.9 (R).
4.2.9. (R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-[2-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)phenyl]-6-phenylhex-3-ene (2i). Table 3, entry
9: to an ice-cold solution of 4,4-dimethyl-2-phenyl-2-oxazoline
(0.035 mL, 0.205 mmol) in THF (1.6 mL) was added n-BuLi (0.12 mL,
1.60 M in hexane, 0.192 mmol) slowly. After 30 min at 0 ꢀC, a solu-
tion of MgBr2 (1.40 mL, 0.20 M in THF, 0.280 mmol) and CuBr$Me2S
(19.1 mg, 0.0929 mmol) were added to the solution. The resulting
mixture was stirred at 0 ꢀC for 30 min, and a solution of (S)-1a
(38.3 mg, 0.0930 mmol, 97% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to afford
a mixture of 2i and Ar2 in a 82:18 ratio by 1H NMR analysis (48.8 mg
4.2.11. (S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(furan-2-yl)-6-phe-
nylhex-3-ene (2k). Table 3, entry 11: to an ice-cold solution of
furan (0.015 mL, 0.206 mmol) in THF (1.6 mL) was added n-BuLi
(0.120 mL, 1.60 M in hexane, 0.192 mmol) slowly. After 30 min at
0 ꢀC, a solution of MgBr2 (1.40 mL, 0.20 M in THF, 0.280 mmol)
and CuBr$Me2S (19.2 mg, 0.0934 mmol) were added to the solu-
tion. The resulting mixture was stirred at 0 ꢀC for 30 min, and
a solution of (S)-1a (38.4 mg, 0.0933 mmol, 95% ee) in THF (1 mL)
was added to it dropwise. The resulting mixture was stirred at
0 ꢀC for 1 h to afford 2k (28.5 mg, 86%): IR (neat) 1471, 1255, 1105,
in total, 98% yield of 2i): IR (neat) 1645, 1102, 1038, 837 cmꢁ1 1H
ꢁ0.06 (s, 3H), ꢁ0.04 (s, 3H), 0.84 (s, 9H),
;
837 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.01 (s, 6H), 0.88 (s, 9H),
NMR (300 MHz, CDCl3)
d
2.32–2.44 (m, 2H), 2.70 (t, J¼8 Hz, 2H), 3.44 (ddd, J¼7, 7, 7 Hz, 1H),
3.75 (dd, J¼10, 7 Hz, 1H), 3.86 (dd, J¼10, 7 Hz, 1H), 5.53–5.68 (m,
2H), 6.03 (dd, J¼3, 1 Hz, 1H), 6.31 (dd, J¼3, 2 Hz, 1H), 7.17–7.23 (m,
3H), 7.26–7.33 (m, 2H), 7.34 (dd, J¼2, 1 Hz, 1H); 13C NMR (75 MHz,
1.38 (s, 6H), 2.39 (ddd, J¼8, 7, 7 Hz, 2H), 2.67 (dd, J¼8, 7 Hz, 2H),
3.75 (dd, J¼10, 7 Hz, 1H), 3.81 (dd, J¼10, 6 Hz, 1H), 4.06 (s, 3H), 4.40
(ddd, J¼7, 7, 6 Hz, 1H), 5.56 (dt, J¼16, 7 Hz, 1H), 5.70 (dd, J¼16, 7 Hz,
1H), 7.13–7.29 (m, 7H), 7.34 (ddd, J¼8, 8, 1 Hz, 1H), 7.66 (dd, J¼8,
CDCl3)
d
ꢁ5.39 (ꢁ), ꢁ5.36 (ꢁ), 18.4 (þ), 25.9 (ꢁ), 34.6 (þ), 35.8
1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.3 (ꢁ), 18.3 (þ), 26.0 (ꢁ),
(þ), 45.5 (ꢁ), 65.5 (þ), 105.8 (ꢁ), 110.1 (ꢁ), 125.8 (ꢁ), 128.3 (ꢁ),
128.4 (ꢁ), 128.5 (–), 132.3 (ꢁ), 141.1 (ꢁ), 142.0 (þ), 155.7 (þ);
HRMS (FAB) calcd for C22H32O2SiNa [(MþNa)þ] 379.2069, found
379.2071. The enantiomeric information (94% ee, 99% CT) was
determined by chiral HPLC analysis of the corresponding alcohol:
Chiralcel OB-H; hexane/i-PrOH¼98/2, 0.2 mL/min, 40 ꢀC; tR
(min)¼93.5 (S), 110.0 (R).
28.4 (ꢁ), 34.8 (þ), 36.0 (þ), 46.3 (ꢁ), 67.1 (þ), 67.9 (þ), 78.9 (þ),
125.7 (ꢁ), 125.9 (ꢁ), 128.2 (þ), 128.3 (ꢁ), 128.6 (ꢁ), 128.7 (ꢁ), 130.0
(ꢁ), 130.2 (ꢁ), 131.1 (ꢁ), 131.4 (ꢁ), 142.2 (þ), 142.4 (þ), 162.9 (þ);
HRMS (FAB) calcd for C29H41NO2SiNa [(MþNa)þ] 486.2804, found
486.2799.
Transformation of 2i to alcohol for determination of the struc-
ture: to a solution of the above mixture of 2i and Ar2 in THF (1 mL)
was added Bu4NF (0.14 mL, 1.0 M in THF, 0.14 mmol). The reaction
was carried out at rt overnight to furnish the corresponding alcohol
4.2.12. (S,E)-1-[(tert-Butyldimethylsilyl)oxy]-6-phenyl-2-(thiophen-
2-yl)hex-3-ene (2l). Table 3, entry 12: to an ice-cold solution of
thiophene (0.016 mL, 0.200 mmol) in THF (1.6 mL) was added n-
BuLi (0.12 mL, 1.60 M in hexane, 0.192 mmol) slowly. After 30 min
at 0 ꢀC, a solution of MgBr2 (1.40 mL, 0.20 M in THF, 0.280 mmol)
and CuBr$Me2S (18.9 mg, 0.0919 mmol) were added to the solution.
The resulting mixture was stirred at 0 ꢀC for 30 min, and a solution
of (S)-1a (37.8 mg, 0.0918 mmol, 97% ee) in THF (1 mL) was added
to it dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to
(30.6 mg, 94% from (S)-1a): IR (neat) 3292, 1739, 1642, 1046 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d 1.38 (s, 3H), 1.41 (s, 3H), 2.31–2.44 (m,
2H), 2.67 (dt, J¼14, 8 Hz, 1H), 2.72 (dt, J¼14, 8 Hz, 1H), 3.61 (dd,
J¼10, 10 Hz, 1H), 4.07 (dd, J¼10, 5 Hz, 1H), 4.10 (d, J¼8 Hz, 1H), 4.14
(d, J¼8 Hz, 1H), 4.48 (ddd, J¼10, 10, 5 Hz, 1H), 5.43 (br s, 1H), 5.48–
5.62 (m, 2H), 7.14–7.32 (m, 7H), 7.40 (ddd, J¼8, 8, 1 Hz, 1H), 7.67
(dm, J¼8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
28.2 (ꢁ), 28.8 (ꢁ),
34.7 (þ), 35.8 (þ), 45.1 (ꢁ), 68.1 (þ), 68.5 (þ), 79.2 (þ), 125.9 (ꢁ),
126.1 (ꢁ), 127.6 (þ), 128.2 (ꢁ), 128.4 (ꢁ), 128.6 (ꢁ), 129.1 (ꢁ), 130.9
(ꢁ), 131.1 (ꢁ), 131.2 (ꢁ), 141.8 (þ), 143.8 (þ), 163.0 (þ); HRMS (EI)
calcd for C23H27NO2 [Mþ] 349.2042, found 349.2046. The enan-
tiomeric information (97% ee, >99% CT) was determined by chiral
HPLC analysis: Chiralcel OD-H; hexane/i-PrOH¼97/3, 0.5 mL/min,
rt; tR (min)¼33.7 (R), 41.3 (S).
afford 2l (28.5 mg, 83%): IR (neat) 1255, 1107, 837 cmꢁ1
;
1H NMR
(300 MHz, CDCl3) 0.06 (s, 6H), 0.93 (s, 9H), 2.37–2.48 (m, 2H), 2.75
d
(dd, J¼9, 7 Hz, 2H), 3.70–3.86 (m, 3H), 5.60–5.74 (m, 2H), 6.85 (dt,
J¼4, 1 Hz, 1H), 6.99 (dd, J¼5, 4 Hz, 1H), 7.21 (dd, J¼5, 1 Hz,1H), 7.22–
7.27 (m, 3H), 7.29–7.37 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.3
(ꢁ), 18.4 (þ), 26.0 (ꢁ), 34.5 (þ), 35.9 (þ), 46.8 (ꢁ), 67.8 (þ), 123.5
(ꢁ), 124.1 (ꢁ), 125.9 (ꢁ), 126.4 (ꢁ), 128.4 (ꢁ), 128.6 (ꢁ), 130.8 (ꢁ),
131.9 (ꢁ), 142.0 (þ), 145.7 (þ); HRMS (FAB) calcd for C22H32OSSiNa
[(MþNa)þ] 395.1841, found 395.1842. The enantiomeric in-
formation (96% ee, 99% CT) was determined by chiral HPLC analysis
of the corresponding alcohol: Chiralcel OB-H; hexane/i-PrOH¼97/
3, 0.3 mL/min, rt; tR (min)¼62.1 (R), 64.9 (S).
4.2.10. (R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(4-fluorophenyl)-6-
phenylhex-3-ene (2j). Table 3, entry 10: to an ice-cold solution of
1-bromo-4-fluorobenzene (0.020 mL, 0.182 mmol) in Et2O (1 mL)
was added t-BuLi (0.220 mL, 1.57 M in pentane, 0.345 mmol)
slowly. After 30 min at 0 ꢀC, a solution of MgBr2 (2.20 mL, 0.20 M
in THF, 0.440 mmol) and CuBr$Me2S (17.8 mg, 0.0866 mmol) were
added to the solution. The resulting mixture was stirred at 0 ꢀC for
4.2.13. (S,10E,3Z)-1-[(tert-Butyldimethylsilyl)oxy]-2-(40-phenyl-10-
butenyl)non-3-ene (2m). Table 3, entry 13: to an ice-cold solution
of (Z)-1-iodo-1-heptene (58.1 mg, 0.259 mmol) in Et2O (1 mL)
was added t-BuLi (0.320 mL, 1.57 M in pentane, 0.502 mmol)
slowly. After 30 min at 0 ꢀC, a solution of MgBr2 (2.90 mL, 0.20 M
in THF, 0.580 mmol) and CuBr$Me2S (25.8 mg, 0.125 mmol) were
added to the solution. The resulting mixture was stirred at 0 ꢀC
for 30 min, and a solution of (S)-1a (34.4 mg, 0.0836 mmol, 98%
30 min, cooled to ꢁ20 ꢀC.
A solution of (S)-1a (39.8 mg,
0.0967 mmol, 97% ee) in THF (1 mL) was added to it dropwise. The
resulting mixture was stirred at ꢁ20 ꢀC for 1 h to afford 2j
(30.6 mg, 92%): IR (neat) 1509, 1099, 836 cmꢁ1; 1H NMR (300 MHz,
CDCl3)
d
ꢁ0.07 (s, 3H), ꢁ0.06 (s, 3H), 0.83 (s, 9H), 2.34 (ddd, J¼8, 6,
6 Hz, 2H), 2.68 (dd, J¼8, 6 Hz, 2H), 3.40 (ddd, J¼7, 7, 7 Hz, 1H), 3.68

Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
683
ee) in THF (1 mL) was added to it dropwise. The resulting mix-
4.2.16. (S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-butyl-6-phenylhex-2-
ene (2p). To a suspension of CuBr$Me2S (18.8 mg, 0.116 mmol) in
THF (2 mL) was added n-BuLi (0.12 mL, 1.55 M in hexane,
0.186 mmol) slowly at ꢁ20 ꢀC. The resulting mixture was stirred at
ꢁ20 ꢀC for 30 min, and a solution of (S)-1a (37.6 mg, 0.0913 mmol,
95% ee) in THF (1 mL) was added to it dropwise. The mixture was
allowed to warm to ꢁ20 ꢀC for 1 h to afford 2p (28.6 mg, 90%, 90%
ee, 95% CT). The 1H NMR spectrum of 2p was identical with that
reported.7
ture was stirred at 0 ꢀC for 1 h to afford 2m (24.1 mg, 75%): IR
(neat) 1255, 1103, 836 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.03 (s,
6H), 0.85–0.94 (m, 3H), 0.89 (s, 9H), 1.23–1.38 (m, 6H), 2.03 (dt,
J¼8, 6 Hz, 2H), 2.31 (dt, J¼7, 8 Hz, 2H), 2.66 (t, J¼8 Hz, 2H), 3.16
(ddt, J¼9, 7, 7 Hz, 1H), 3.47 (d, J¼7 Hz, 2H), 5.20 (dd, J¼11, 9 Hz,
1H), 5.39 (dd, J¼16, 7 Hz, 1H), 5.39–5.57 (m, 2H), 7.14–7.23 (m,
3H), 7.24–7.32 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.2 (ꢁ), 14.2
(ꢁ), 18.5 (þ), 22.7 (þ), 26.0 (ꢁ), 27.7 (þ), 29.5 (þ), 31.7 (þ), 34.8
(þ), 36.1 (þ), 43.7 (ꢁ), 67.0 (þ), 125.8 (ꢁ), 128.3 (ꢁ), 128.5 (ꢁ),
129.3 (ꢁ), 130.2 (ꢁ), 130.9 (ꢁ), 131.4 (ꢁ), 142.2 (þ); HRMS (FAB)
calcd for C25H42OSiNa [(MþNa)þ] 409.2903, found 409.2899. The
enantiomeric information (96% ee, 98% CT) was determined by
chiral HPLC analysis of the corresponding alcohol: Chiralcel AD-
H; hexane/i-PrOH¼99/1, 0.2 mL/min, 40 ꢀC; tR (min)¼69.2 (R),
76.2 (S).
4.2.17. (R,E)-1-[(2-Butylpent-3-enyloxy)methyl]-4-methoxybenzene
(2q). To a suspension of CuBr$Me2S (22.4 mg, 0.109 mmol) in THF
(2 mL) was added n-BuLi (0.13 mL, 1.66 M in hexane, 0.216 mmol)
slowly at ꢁ15 ꢀC. The resulting mixture was stirred at ꢁ15 ꢀC for
30 min, and a solution of (R)-1c (35.4 mg, 0.109 mmol, 98% ee) in
THF (1 mL) was added to it dropwise. The mixture was allowed to
warm to 0 ꢀC for 1 h to afford 2q (23.5 mg, 82%): IR (neat) 1612,
4.2.14. (R,1Z,4E)-3-[(tert-Butyldimethylsilyl)oxymethyl]-1-cyclo-
1513, 1248, 1092, 1038 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.87 (t,
hexyl-7-phenylhepta-1,4-diene (2n). Table 3, entry 14: to an ice-
J¼7 Hz, 3H), 1.11–1.36 (m, 5H), 1.40–1.52 (m, 1H), 1.67 (dd, J¼6, 1 Hz,
3H), 2.20–2.32 (m, 1H), 3.30 (d, J¼9 Hz, 2H), 3.80 (s, 3H), 4.43 (s,
2H), 5.23 (ddq, J¼16, 8, 1 Hz, 1H), 5.47 (dq, J¼16, 6 Hz, 1H), 6.87 (d,
cold
solution
of
(Z)-(2-iodovinyl)cyclohexane
(61.7 mg,
0.261 mmol) in Et2O (1 mL) was added t-BuLi (0.32 mL, 1.57 M in
pentane, 0.502 mmol) slowly. After 30 min at 0 ꢀC, a solution of
MgBr2 (3.00 mL, 0.20 M in THF, 0.600 mmol) and CuBr$Me2S
(26.0 mg, 0.126 mmol) were added to the solution. The resulting
mixture was stirred at 0 ꢀC for 30 min, and a solution of (S)-1a
(34.7 mg, 0.0843 mmol, 95% ee) in THF (1 mL) was added to it
dropwise. The resulting mixture was stirred at 0 ꢀC for 1 h to
J¼8 Hz, 2H), 7.25 (d, J¼8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 14.2
(ꢁ), 18.2 (ꢁ), 22.9 (þ), 29.3 (þ), 31.5 (þ), 43.0 (ꢁ), 55.3 (ꢁ), 72.6 (þ),
74.1 (þ), 113.8 (ꢁ), 125.9 (ꢁ), 129.2 (ꢁ), 130.9 (þ), 133.1 (ꢁ), 159.1
(þ); HRMS (FAB) calcd for C17H26O2 [Mþ] 262.1933, found 262.1939.
The enantiomeric information (96% ee, 98% CT) was determined by
chiral HPLC: Chiralcel OB-H; hexane/i-PrOH¼98/2, 0.2 mL/min,
40 ꢀC; tR (min)¼61.8 (R), 72.9 (S).
afford 2n (27.5 mg, 82%): IR (neat) 1255, 1105, 837, 775, 698 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.04 (s, 6H), 0.89 (s, 9H), 0.96–1.35
(m, 6H), 1.53–1.76 (m, 4H), 2.18–2.36 (m, 3H), 2.66 (dd, J¼8, 6 Hz,
2H), 3.18 (ddt, J¼10, 6, 7 Hz, 1H), 3.47 (d, J¼7 Hz, 2H), 5.09 (dd,
J¼11, 10 Hz, 1H), 5.30 (dd, J¼11, 10 Hz, 1H), 5.40 (dd, J¼16, 6 Hz,
1H), 5.52 (dd, J¼16, 7 Hz, 1H), 7.13–7.21 (m, 3H), 7.23–7.30 (m,
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan. The authors thank Ms. M. Ishikawa of Center for Advanced
Materials Analysis, Technical Department, Tokyo Institute of Tech-
nology, for HRMS analysis.
2H); 13C NMR (75 MHz, CDCl3)
d
ꢁ5.2 (ꢁ), ꢁ5.1 (ꢁ), 18.5 (þ),
25.99 (þ), 26.04 (þ), 26.07 (ꢁ), 26.13 (þ), 33.3 (þ), 33.6 (þ), 34.8
(þ), 36.1 (þ), 36.8 (ꢁ), 43.9 (ꢁ), 67.2 (þ), 125.8 (ꢁ), 127.5 (ꢁ),
128.3 (ꢁ), 128.5 (ꢁ), 130.1 (ꢁ), 131.2 (ꢁ), 137.3 (ꢁ), 142.2 (þ);
HRMS (FAB) calcd for C26H42OSiNa [(MþNa)þ] 421.2903, found
421.2902. The enantiomeric information (94% ee, 99% CT) was
determined by chiral HPLC analysis of the corresponding alcohol:
Chiralcel OD-H; hexane/i-PrOH¼98/2, 0.2 mL/min, 40 ꢀC; tR
(min)¼52.5 (R), 55.5 (S).
References and notes
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butenyl)non-3-ene (2o). Table 3, entry 15: to an ice-cold solution of
(E)-1-iodo-1-heptene (49.8 mg, 0.222 mmol) in Et2O (1 mL) was
added t-BuLi (0.260 mL, 1.57 M in pentane, 0.404 mmol) slowly.
After 30 min at 0 ꢀC, a solution of MgBr2 (2.50 mL, 0.20 M in THF,
0.500 mmol) and CuBr$Me2S (20.8 mg, 0.101 mmol) were added to
the solution. The resulting mixture was stirred at 0 ꢀC for 30 min,
and a solution of (S)-1a (41.6 mg, 0.101 mmol, 95% ee) in THF (1 mL)
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for 1 h to afford 2o (36.4 mg, 93%): IR (neat) 1255, 1104, 836 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.03 (s, 6H), 0.85–0.94 (m, 3H), 0.89
(s, 9H), 1.23–1.41 (m, 6H), 1.99 (dt, J¼7, 7 Hz, 2H), 2.32 (dt, J¼8, 6 Hz,
2H), 2.68 (t, J¼8 Hz, 2H), 2.81 (ddt, J¼7, 7, 7 Hz, 1H), 3.49 (d, J¼7 Hz,
2H), 5.32 (dd, J¼16, 7 Hz, 1H), 5.32–5.43 (m, 1H), 5.43 (dd, J¼16,
7 Hz, 1H), 5.51 (dt, J¼16, 6 Hz, 1H), 7.14–7.22 (m, 3H), 7.24–7.32 (m,
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d
ꢁ5.2 (ꢁ), 14.2 (ꢁ), 18.5 (þ), 22.6
(þ), 26.0 (ꢁ), 29.2 (þ), 31.5 (þ), 32.8 (þ), 34.8 (þ), 36.1 (þ), 48.5 (ꢁ),
67.0 (þ), 125.8 (ꢁ), 128.3 (ꢁ), 128.6 (ꢁ), 130.0 (ꢁ), 130.6 (ꢁ), 131.1
(ꢁ), 131.9 (ꢁ), 142.2 (þ); HRMS (FAB) calcd for C25H42OSiNa
[(MþNa)þ] 409.2903, found 409.2897. The enantiomeric in-
formation (93% ee, 98% CT) was determined by chiral HPLC analysis
of the corresponding alcohol: Chiralcel OD-H; hexane/i-PrOH¼98/
2, 0.2 mL/min, 40 ꢀC; tR (min)¼51.2 (R), 57.8 (S).

684
Y. Kiyotsuka, Y. Kobayashi / Tetrahedron 66 (2010) 676–684
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Ph
L
i, L = (2-Py)CO2
ii, L = (EtO)2P(O)O iv, L = MsO
iii, L = C6F5CO2
CH2OTBS
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10. Attempted reaction with PhLi (2 equiv) and MgBr2 (3 equiv) produced a mix-
ture of rac-4a and -1a in a 21:79 ratio.
11. The cis isomers were synthesized by the method of Ref. 7.
12. We also examined reaction of several allylic esters i–iii with the Ph reagent
derived from PhLi (2 equiv), CuBr$Me2S (1 equiv), and MgBr2 (3 equiv) un-
der the optimized conditions mentioned in entry 5 of Table 1. No reaction
took place with the isonicotinate i, which possesses the nitrogen atom at
the 4 position, while pentafluorobenzoate iii gave 4% of rac-2a. In contrast,
phosphate ii showed slightly lower reactivity than picolinate rac-1a, af-
fording a mixture of rac-2a and ii in a 90:10 ratio by 1H NMR spectroscopy.
Preparation of mesylate iv was unsuccessful due to decomposition during
the purification.