Stereospecific cross-coupling between alkenylboronates and alkyl halides catalyzed by iron-bisphosphine complexes

Article abstract of DOI:10.1021/jo202151f

A stereospecific and high-yielding cross-coupling reaction between alkenylboron reagents and alkyl halides is described. The reaction has been achieved by using well-defined iron-bisphosphine complexes such as 1b FeCl ₂(3,5-t-Bu₂-SciOPP), which was recently developed by the authors' group. Various nonactivated alkyl bromides and chlorides possessing a base/nucleophile-sensitive functional group can participate in the cross-coupling, demonstrating its utility for stereoselective synthesis of functional molecules bearing a carbon-carbon double bond.

Full text of DOI:10.1021/jo202151f

Note
pubs.acs.org/joc
Stereospecific Cross-Coupling between Alkenylboronates and Alkyl
Halides Catalyzed by Iron−Bisphosphine Complexes
Toru Hashimoto,†,‡ Takuji Hatakeyama,‡ and Masaharu Nakamura*,‡
‡
†Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, and International Research Center for
Elements Science, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
S
* Supporting Information
ABSTRACT: A stereospecific and high-yielding cross-cou-
pling reaction between alkenylboron reagents and alkyl halides
is described. The reaction has been achieved by using well-
defined iron−bisphosphine complexes such as 1b FeCl2(3,5-t-
Bu2-SciOPP), which was recently developed by the authors′
group. Various nonactivated alkyl bromides and chlorides
possessing a base/nucleophile-sensitive functional group can
participate in the cross-coupling, demonstrating its utility for
stereoselective synthesis of functional molecules bearing a
carbon−carbon double bond.
tereoselective synthesis of olefins is of great importance in
organic chemistry; therefore, there has been continual
examined the activation of alkenylboron reagent 2 by using
alkyllithium reagents (Scheme 1).15 As expected from our
S
effort to develop more efficient synthetic methods for over one
hundred years.1 The metal-catalyzed cross-coupling reaction
has emerged as a powerful tool for carbon−carbon bond
formation, and hence, various alkenylation reactions based on
coupling technology were studied and applied in a number of
synthetic studies.2 Among them, considerable effort has
recently been devoted to develop an efficient coupling between
alkenylmetal reagents and alkyl halides. Fu developed a series of
palladium- and nickel-catalyzed alkenylation reactions of
primary and secondary alkyl halides with alkenyltin,3 zinc,4
zirconium,5 and boron reagents.6 Oshima found that cobalt
catalysts were effective for the alkenylation of primary and
secondary alkyl halides with 1-(trimethylsilyl)-
ethenylmagnesium bromide.7 Iron-catalyzed cross-coupling8
has also been applied to the alkenylation of alkyl halides with
organomagnesium or zinc reagents: Cossy and Cahiez
independently reported the alkenylation of alkyl halides with
alkenylmagnesium reagents using FeCl3/TMEDA9 and Fe-
(acac)3/TMEDA/HMTA10 catalyst systems. We also devel-
oped the iron-catalyzed coupling reaction of alkyl halides with
alkenylzinc reagents using the FeCl3/TMEDA catalyst system,
adding an example of a highly stereoselective alkenylation
reaction.11 Despite the apparent advantage of iron catalyst in
the cross-coupling of alkyl halides12,13 and availability of
stereochemically pure alkenyl boron compounds, there have
been no examples of stereospecific alkenylation of nonactivated
alkyl halides with organoboron reagents.14 Herein, we report an
efficient iron-catalyzed Suzuki−Miyaura coupling reaction
between E- and Z-alkenylboronic acid pinacol esters 2 and
alkyl halides, which proceeds in a stereospecific manner under
mild conditions.
Scheme 1. Cross-Coupling of Alkyl Halides with
Alkenylboron Reagents in the Presence of Iron−
Bisphosphine Complexes 1
previous arylation-type coupling reactions, the resulting lithium
alkenylborates 3 were found to be effectively coupled with alkyl
halides in the presence of a catalytic amount of MgBr2 and
divalent iron−bisphosphine complexes 1 [FeCl2(SciOPPs)].16
Table 1 summarizes the results of the screening of
alkenylborates 3aa−3ac, prepared from the corresponding
alkenylboron reagent 2a using an alkyl lithium or magnesium
reagent (see the Experimental Section for the confirmation of
their formations), in the coupling reaction with chlorocyclo-
heptane 5. As shown in entries 1 and 2, the reaction using t-
BuLi resulted in a slightly better yield (69%) of the coupling
product 4a than that using BuLi (66%), as well as the formation
of byproducts (8% cycloheptene and 2% cycloheptane). At an
Since our initial screening of inorganic bases to activate
alkenylboron reagents did not yield any coupling products, we
Received: October 28, 2011
Published: December 8, 2011
© 2011 American Chemical Society
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Note
a
Table 1. Catalyst and Additive Screening of the Cross-Coupling between Alkenylborate 3aa−3ac and Chlorocycloheptane 5
c
GC yield (%)
b
d
c
entry
Fe cat.
R′-M
BuLi
alkenyl borate
X
yield of 4a(%)
C7H12
C7H14
RSM 5(%)
1
2
3
la
la
la
lb
lb
lb
3aa
3ab
3ab
3ab
3ab
3ac
20
20
20
20
0
66
69
55
83
0
8
7
2
2
3
2
0
5
0
15
21
27
5
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuMgCl
t-BuLi
10
5
e
4
5
6
7
0
97
56
92
0
4
12
0
FeCl2(dppbz)2
3ab
20
0
a
b
c
Reactions were carried out on a 0.4−0.5 mmol scale. NMR yield. Yields of cycloheptene and cycloheptane and recovery of chlorocycloheptane
d
e
were determined by GC analysis using undecane as an internal standard. Recovery of chlorocycloheptane. The reaction was carried out at 40 °C
for 24 h.
elevated temperature (40 °C), the reaction took place in a less
selective manner, resulting in a lower yield of 4a (entry 3). Iron
catalyst 1b was found to be more effective than 1a to give 4a in
83% yield (entry 4). In the absence of MgBr2, the coupling
reaction did not take place and chlorocycloheptane 5 was
recovered quantitatively (entry 5).15,17 We currently assume
that MgBr2 accelerates transmetalation between borate and the
iron catalyst.15 The use of t-BuMgCl instead of alkyllithium
gave sluggish results, probably owing to instability of the
magnesium alkenylborate (entry 6). Interestingly, the parent
iron complex FeCl2(dppbz)2 (R = H in Scheme 1), which is an
efficient catalyst for iron-catalyzed Negishi coupling,18 did not
show any catalytic activity (entry 7). The peripheral steric
demand19 of 1a and 1b is crucial for the present coupling
reaction. It should be noted that the double bond geometry was
completely retained in all cases.
Table 2 illustrates the scope of the stereospecific coupling
reaction in the presence of iron complexes 1. As shown in
entries 1−10, a variety of primary and secondary alkyl bromides
participate in the reaction. E- and Z-Alkenylboron reagents
possessing a silyl ether moiety were coupled with bromocyclo-
heptane at −20 °C to give the corresponding coupling products
in 98% and 93% yield, respectively, without any loss of
geometrical purity. While the reactions with α-substituted
alkenylboron reagents required an elevated temperature (40
°C) and gave the coupling product in modest yield, the
trisubstituted olefin was obtained also in a highly stereoselective
manner (entry 4). We assume that α-substitution impedes the
transmetalation between alkenylboron reagents and iron
complexes 1 and the same tendency was found in the reaction
with 1-styrylboron reagent (entry 8). As shown in entries 5−10,
the coupling reaction is chemoselective: the acetoxy, benzoyl,
carbamate, ethoxycarbonyl, cyano, and cyclopropyl groups
remained untouched under the reaction conditions. Based on
the high functional group compatibility and quantitative
formation of lithium borates, the intermediacy of alkenyllithium
or magnesium reagents is unlikely. Although no reactions of
nonactivated primary alkyl chlorides took place, benzyl and allyl
chlorides could participate in the stereospecific coupling
reaction. The reaction of methyl 4-(chloromethyl)benzoate
took place at −20 °C to give the coupling product in 44% yield
along with the dimer of the benzoate (20% yield) and the
alkane (<5% yield) (entry 11). Cinnamyl chloride was also
coupled with the alkenylboron reagent to give α-attack product
4l rather than γ-attack product 4m (entry 12).20
We carried out the reaction of N-allyl-N-(2-bromoethyl)-4-
methylbenzenesulfonamide with 3ab under standard reaction
conditions to determine if the radical-mediated cyclization/
coupling reaction21 takes place (Scheme 2). The expected
product 4n was obtained in 56% yield along with byproducts
(3-methyl and 3-methylene pyrrolidine derivatives in 25% and
3% yield, respectively, and N-allyl-N-ethyl-4-methylbenzene-
sulfonamide in 10% yield), suggesting the intermediacy of an
alkyl radical intermediate, as we reported for related
reactions.11,13a,h,i,15,17a,18b Although the details regarding the
reaction mechanism are unclear and need further investigations,
it is assumed that the retention of the alkene geometry during
radical-mediated cross-coupling is a result of stereospecific
transmetalation from boron to iron and stereospecific
substitution of the alkenyl ligand on the iron center by the
alkyl radical intermediate, which results in the formation of a
monohalogenated iron(II) intermediate and the corresponding
cross-coupling product.22
In summary, a stereospecific cross-coupling between various
alkenylboron reagents and alkyl halides has been achieved for
the first time by using structurally well-defined iron−
bisphosphine complexes. The present alkenylation method
possesses the following synthetically attractive features: it is
stereospecific, high yielding, functional group tolerant, and rare
metal free, and has a broad scope for application to alkyl
halides.
EXPERIMENTAL SECTION
■
General. All the reactions dealing with air- or moisture-sensitive
compounds were carried out in a dry reaction vessel under a positive
pressure of argon or nitrogen. Air- and moisture-sensitive liquids and
solutions were transferred via a syringe or a stainless steel cannula.
Proton nuclear magnetic resonance (1H NMR), carbon nuclear
magnetic resonance (13C NMR) and boron nuclear magnetic
resonance (11B NMR) spectra were reported on a NMR spectrometer
(392, 98.5, and 96.3 MHz, respectively). Proton, carbon, and boron
chemical shift values are reported in parts per million (ppm, δ scale)
downfield from Me4Si, Me4Si, and BF3·OEt2, respectively, and are
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Note
Table 2. Cross-Coupling of Alkyl Halides with Alkenylboron
Reagents
Scheme 2. Cross-Coupling via Alkyl Radicals
a b
,
film thickness). NMR yield was determined for a crude product by 1H
NMR analyses by using 1,1,2,2-tetrachloroethane or pyrazine as an
internal standard. GC yield was determined upon calibration by using
undecane as an internal standard. Purity of isolated compounds was
determined by GC analysis and/or 1H NMR analysis. High-resolution
mass spectra (HRMS) were obtained using the electron impact (EI)
method. Iron catalysts 1a and 1b were prepared as described in the
literature.15
Preparation of Lithium Alkenylborate 3ab from 2-[(1E)-5-
tert-Butyldimethylsilyloxypent-1-en-1-yl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane 2a and tert-Butyllithium. To a THF
solution (2.0 mL) of 2-[(1E)-5-tert-butyldimethylsilyloxypent-1-en-1-
yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2a (0.196 g, 0.60 mmol)
was added t-BuLi (0.38 mL, 1.59 M in pentane, 0.60 mmol) at −78
°C. The reaction mixture was stirred at the same temperature for 30
min, and then at 0 °C for 30 min. The solvent was removed in vacuo at
0 °C. Quantitative formation of borate was determined by 1H and 13
C
NMR spectra of the residual solid in THF-d8 (> 97% conversion). 1H
NMR (THF-d8, 392 MHz) δ 0.03 (s, 6H), 0.64 (s, 9H), 0.89 (s, 9H),
1.05 (s, 6H), 1.08 (s, 6H), 1.55 (tt, J = 6.7 and 7.2 Hz, 2H), 1.99 (dt, J
= 6.7 and 7.2 Hz, 2H), 3.61 (t, J = 6.7 Hz, 2H), 5.42 (dt, J = 6.7 and
17.2 Hz, 1H), 5.71 (d, J = 17.2 Hz, 1H); 13C NMR (THF-d8, 98.5
MHz) δ −5.1 (2C), 19.0, 26.4 (3C), 28.2 (2C), 28.5 (2C), 30.6 (3C),
33.9, 34.5, 64.1, 78.1 (2C), 130.7; 11B NMR (THF-d8, 96.3 MHz) δ
5.65 (brs). The 13C NMR signals of the carbons α to the boron were
not observed because of the nuclear quadrupole resonance.
Representative Procedure for the Iron-Catalyzed Reaction
Shown in Table 1. To a THF solution (2.0 mL) of 2a (0.75 mmol)
was added organometallic reagents (0.70 mmol) at −78 °C. The
reaction mixture was stirred at the same temperature for 30 min, and
then at 0 °C for 30 min. The solvent was removed in vacuo at 0 °C. To
the residual borate were added THF (1.2 mL), undecane (0.25 mmol),
chlorocycloheptane (0.50 mmol), MgBr2 (0.10 mmol, 20 mol %), and
an iron catalyst (25 μmol, 5.0 mol %) at −78 °C. The coupling
reaction was carried out at −20 °C for 24 h. After cooling to ambient
temperature, aqueous NH4Cl (saturated, 2.0 mL) was added. The
aqueous layer was extracted five times with Et2O. The combined
organic extracts were filtered with a pad of Florisil. The yield of 4a was
determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal
standard. The yields of cycloheptane and cycloheptene, and the
recovery of chlorocycloheptane were determined by GC analysis of the
crude product using undecane as an internal standard.
Procedure A; A Representative Procedure for the Iron-
Catalyzed Reaction Shown in Table 2. Synthesis of (E)-tert-
butyl[(5-cycloheptylpent-4-en-1-yl)oxy]dimethylsilane (4a). To a
THF solution (2.0 mL) of 2a (0.196 g, 0.60 mmol) was added t-
BuLi (0.35 mL, 1.59 M in pentane, 0.56 mmol) at −78 °C. The
reaction mixture was stirred at the same temperature for 30 min, and
then at 0 °C for 30 min. The solvent was removed in vacuo at 0 °C. To
the residual borate were added THF (1.2 mL), undecane (38.0 mg,
0.24 mmol), bromocycloheptane (71.2 mg, 0.40 mmol), MgBr2 (0.80
mL, 0.10 M in THF, 80 μmol), and iron complex 1a (0.40 mL, 50.0
mM in THF, 20 μmol, 5.0 mol %) at −78 °C. The coupling reaction
was carried out at −20 °C for 24 h. After cooling to ambient
a
Reactions were carried out at −20 to 0 °C for 24 h on a 0.4−1.5
mmol scale. Lithium alkenylborates were prepared from corresponding
alkenylboron reagents using t-BuLi unless otherwise noted.
b
c
Alkenylboron reagents employed were geometrically pure. 10
d
e
mmol scale. BuLi was used instead of t-BuLi. Reaction was carried
out at 40 °C for 24 h. trans/cis = 57/43. Using 20 mol % 1a.
f
g
referenced to Me4Si (δ 0.0), CDCl3 (δ 77.0), BF3·OEt2 (δ 0.0),
respectively. IR spectra were recorded on an ATR-FTIR spectrometer.
Characteristic IR absorptions are reported in cm−1. Gas chromato-
graphic (GC) analysis was performed on a GC system equipped with
FID detector and capillary column (30 m × 0.25 mm i.d., 0.25 mm
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Note
temperature, aqueous NH4Cl (saturated, 2.0 mL) was added. The
aqueous layer was extracted five times with Et2O. The combined
organic extracts were filtered with a pad of Florisil. The title
compound (0.117 g, 98% yield, > 99% pure on GC analysis) was
obtained as a colorless oil after silica gel column chromatography
(hexane/AcOEt = 50/1). Rf = 0.69 (hexane/AcOEt = 10/1); IR (neat)
2926, 2855, 1461, 1388, 1361, 1256, 1099, 1106, 966, 939, 833, 773,
662; 1H NMR (CDCl3, 392 MHz) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.24−
1.33 (m, 2H), 1.39−1.74 (m, 12H), 2.00 (dt, J = 7.2 and 6.3 Hz, 2H),
2.05−2.12 (m, 1H), 3.60 (t, J = 6.3 Hz, 2H), 5.31 (dt, J = 15.4 and 6.3
Hz, 1H), 5.41 (dd, J = 7.2 and 15.4 Hz, 1H); 13C NMR (CDCl3, 98.5
MHz) δ −5.3 (2C), 18.4, 26.0 (3C), 26.2 (2C), 28.4 (2C), 28.8, 32.8,
35.0 (2C), 42.8, 62.6, 126.3, 137.7; HRMS (EI) m/z [M − t-Bu]+
calcd for C14H27OSi 239.1831; found 239.1828.
50/1). Rf = 0.48 (hexane/AcOEt = 4/1); mixture of cis and trans
isomers: IR (neat) 3025, 2929, 2859, 1730, 1599, 1492, 1448, 1368,
1
1233, 1157, 1123, 1090, 1027, 965, 899, 842, 745, 693; H NMR
(CDCl3, 392 MHz) δ 1.25−1.48 (m, 4H), 1.56−1.69 (m, 2H), 1.89−
1.92 (m, 2H), 2.04 (s, 3H), [2.07 (s, 3H)], 2.13−2.16 (m, 1H), [2.23
(br, 1H)], 4.70 (m, 1H), [5.00 (m, 1H)], 6.13 (dd, J = 6.1 and 15.9
Hz, 1H), [6.21 (dd, J = 6.7 and 15.9 Hz, 1H)], 6.37 (d, J = 15.9 Hz,
1H), [6.39 (d, J = 15.9 Hz, 1H)], 7.17−7.21 (m, 1H), 7.26−7.37 (m,
4H); 13C NMR (CDCl3, 98.5 MHz) δ 21.4, 29.2 (2C) [27.3, 2C], 31.3
(2C) [30.7, 2C], 40.1 [39.5], 72.9 [69.6], 126.0 (2C) [126.0, 2C],
127.0 [126.0], 128.2 [128.0], 128.5 (2C) [128.5, 2C], 134.9 [135.4],
137.6 [137.7], 170.6; HRMS (EI) m/z [M]+ calcd for C16H20O2
244.1463; found 244.1455. The values in parentheses refer to the
minor (cis) isomer.
Synthesis of (Z)-tert-Butyl[(5-cycloheptylpent-4-en-1-yl)oxy]-
dimethylsilane (4b). The reaction was carried out according to
Procedure A on a 0.40 mmol scale by using bromocycloheptane (71.6
mg, 0.40 mmol), 2-[(1Z)-5-tert-butyldimethylsilyloxypent-1-en-1-yl]-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.196 g, 0.60 mmol), t-BuLi
(0.35 mL, 1.59 M in pentane, 0.56 mmol), MgBr2 (0.80 mL, 0.10 M in
THF, 80 μmol), and iron complex 1a (0.40 mL, 50.0 mM in THF, 20
μmol, 5.0 mol %). Conditions: −20 °C, 24 h. The title compound
(0.112 g, 93% yield, > 99% pure on GC analysis) was obtained as a
colorless oil after silica gel column chromatography (hexane/AcOEt =
50/1). Rf = 0.66 (hexane/AcOEt = 10/1); IR (neat) 2926, 2855, 1471,
1461, 1388, 1361, 1254, 1100, 1006, 988, 939, 833, 773, 728, 679, 662;
1H NMR (CDCl3, 392 MHz) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.23−1.32
(m, 2H), 1.42−1.66 (m, 12H), 2.08 (dt, J = 7.2 and 7.6 Hz, 2H),
2.40−2.49 (m, 1H), 3.61 (t, J = 6.3 Hz, 2H), 5.19 (dt, J = 7.2 and 10.5
Hz, 1H), 5.31 (dd, J = 9.9 and 10.5 Hz, 1H); 13C NMR (CDCl3, 98.5
MHz) δ −5.3 (2C), 18.3, 23.6, 26.0 (3C), 26.4 (2C), 28.4 (2C), 33.1,
35.3 (2C), 37.8, 62.7, 125.9, 137.4; HRMS (EI) m/z [M − t-Bu]+
calcd for C14H27OSi 239.1831.; found 239.1832.
Synthesis of (E)-(2-Cycloheptylethenyl)benzene (4c). The reaction
was carried out according to Procedure A on a 0.51 mmol scale by
using bromocycloheptane (89.5 mg, 0.51 mmol), (E)-4,4,5,5-
tetramethyl-2-(2-phenylethenyl)-1,3,2-dioxaborolane (0.173 g, 0.75
mmol), t-BuLi (0.42 mL, 1.65 M in pentane, 0.70 mmol), MgBr2
(1.00 mL, 0.10 M in THF, 0.10 mmol), and iron complex 1a (0.50
mL, 50.0 mM in THF, 25 μmol, 5.0 mol %). Conditions: −20 °C, 24
h. The title compound (96.8 mg, 96% yield, 99% pure on GC analysis)
was obtained as a colorless oil after silica gel column chromatography
(100% hexane). 1H and 13C NMR spectra have been attached.
Analytical data for the title compound have been reported.11
Synthesis of (E)-Oct-4-en-4-ylcycloheptane (4d). The reaction was
carried out according to Procedure A on a 0.40 mmol scale by using
bromocycloheptane (71.1 mg, 0.40 mmol), (Z)-4,4,5,5-tetramethyl-2-
(oct-4-en-4-yl)-1,3,2-dioxaborolane (0.191 g, 0.80 mmol), BuLi (0.48
mL, 1.59 M in hexane, 0.76 mmol), MgBr2 (0.80 mL, 0.10 M in THF,
80.0 μmol), and iron complex 1a (0.400 mL, 50.0 mM in THF, 20
μmol, 5.0 mol %). Conditions: 40 °C, 24 h. The title compound (48.6
mg, 58% yield, > 99% pure on GC analysis) was obtained as a colorless
oil after silica gel column chromatography (100% hexane). Rf = 0.68
(100% hexane); IR (neat) 2956, 2922, 2858, 1458, 1376, 1260, 1068,
892, 805, 741; 1H NMR (CDCl3, 392 MHz) δ 0.88 (t, J = 7.2 Hz, 3H),
0.90 (t, J = 7.2 Hz, 3H), 1.25−1.40 (m, 8H), 1.48−1.62 (m, 4H),
1.67−1.71 (m, 4H), 1.92−1.97 (m, 5H), 5.08 (t, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 98.5 MHz) δ 13.9, 14.5, 22.7, 23.4, 27.2 (2C), 27.9
(2C), 29.8, 32.6, 35.1 (2C), 47.3, 122.5, 146.6; HRMS (EI) m/z [M]+
calcd for C15H28 208.2191; found 208.2185.
Synthesis of (E)-6-Methyl-1,8-diphenyloct-7-en-1-one (4f). The
reaction was carried out according to Procedure A on a 0.40 mmol
scale by using 6-bromo-1-phenylheptan-1-one (0.107 g, 0.40 mmol),
(E)-4,4,5,5-tetramethyl-2-(2-phenylethenyl)-1,3,2-dioxaborolane
(0.276 g, 1.2 mmol), t-BuLi (0.73 mL, 1.59 M in pentane, 1.16 mmol),
MgBr2 (0.80 mL, 0.10 M in THF, 80.0 μmol), and iron complex 1a
(1.60 mL, 50.0 mM in THF, 80 μmol, 20.0 mol %). Conditions: −20
°C, 24 h. The title compound (97.3 mg, 83% yield, > 98% pure on GC
analysis) was obtained as a colorless oil after purification by GPC
(eluent: CHCl3). Rf = 0.47 (hexane/AcOEt = 4/1); IR (neat) 3059,
3024, 2929, 2865, 1739, 1683, 1597, 1579, 1492, 1448, 1409, 1365,
1279, 1217, 1179, 1072, 1001, 966, 912, 848, 746, 690, 657; 1H NMR
(CDCl3, 392 MHz) δ 1.08 (d, J = 6.7 Hz, 3H), 1.38−1.46 (m, 4H),
1.70−1.79 (m, 2H), 2.31 (m, 1H), 2.96 (t, J = 7.2 Hz, 2H), 6.08 (dd, J
= 8.0 and 15.7 Hz, 1H), 6.34 (d, J = 15.7 Hz, 1H), 7.17−7.21 (m, 1H),
7.26−7.36 (m, 4H), 7.43−7.47 (m, 2H), 7.52−7.57 (m, 1H), 7.93−
7.96 (m, 2H); 13C NMR (CDCl3, 98.5 MHz) δ 20.7, 24.4, 27.2, 36.9,
37.2, 38.6, 126.0 (2C), 126.8, 128.0 (2C), 128.2, 128.4 (2C), 128.5
(2C), 132.9, 136.7, 137.0, 137.8, 200.5; HRMS (EI) m/z [M]+ calcd
for C21H24O 292.1827; found 292.1828.
Synthesis of 1-Benzyloxycarbonyl-4-[(1E)-2-cyclopropylvinyl]-
piperidine (4g). The reaction was carried out according to Procedure
A on a 0.42 mmol scale by using 4-bromo-N-(benzyloxycarbonyl)-
piperidine (0.125 g, 0.42 mmol), (E)-2-(2-cyclopropylethenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (0.116 g, 0.60 mmol), t-BuLi (0.35
mL, 1.59 M in pentane, 0.56 mmol), MgBr2 (0.80 mL, 0.10 M in THF,
80 μmol), and iron complex 1a (0.40 mL, 50.0 mM in THF, 20 μmol,
5.0 mol %). Conditions: 0 °C, 24 h. The title compound (0.102 g, 85%
yield, > 99% pure on GC analysis) was obtained as a white solid after
silica gel column chromatography (hexane/AcOEt = 50/1 to 20/1). Rf
= 0.42 (hexane/AcOEt = 4/1); IR (neat) 3006, 2932, 2852, 1694,
1498, 1468, 1427, 1363, 1289, 1275, 1246, 1217, 1171, 1118, 1071,
1016, 962, 910, 865, 811, 763, 731, 696; 1H NMR (CDCl3, 392 MHz)
δ 0.29−0.33 (m, 2H), 0.64−0.69 (m, 2H), 1.21−1.34 (m, 3H), 1.64−
1.67 (m, 2H), 2.02−2.11 (m, 1H), 2.77−2.83 (m, 2H), 4.15 (br, 2H),
4.95 (dd, J = 8.5 and 15.2 Hz, 1H), 5.12 (s, 2H), 5.44 (dd, J = 6.7 and
15.2 Hz, 1H), 7.30−7.32 (m, 1H), 7.35−7.36 (m, 4H); 13C NMR
(CDCl3, 98.5 MHz) δ 6.5 (2C), 13.6, 32.0, 38.6 (2C), 44.0 (2C), 66.9,
127.8 (2C), 127.9, 128.4 (2C), 131.8, 132.8, 137.0, 155.3; HRMS (EI)
m/z [M]+ calcd for C18H23NO2 285.1729; found 285.1724.
Synthesis of 1-Benzyloxycarbonyl-4-(1-phenylvinyl)piperidine
(4h). The reaction was carried out according to Procedure A on a
0.40 mmol scale by using 4-bromo-N-(benzyloxycarbonyl)piperidine
(0.120 g, 0.40 mmol), 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-
dioxaborolane (0.184 g, 0.80 mmol), BuLi (0.48 mL, 1.59 M in
hexane, 0.76 mmol), MgBr2 (0.80 mL, 0.10 M in THF, 80 μmol), and
iron complex 1a (0.80 mL, 50.0 mM in THF, 40 μmol, 10.0 mol %).
Conditions: 40 °C, 24 h. The title compound (99.1 mg, 77% yield, >
99% pure on GC analysis) was obtained as a white solid after silica gel
column chromatography (hexane/AcOEt = 50/1 to 20/1). Rf = 0.38
(hexane/AcOEt = 4/1); IR (neat) 3032, 2939, 2855, 1693, 1626,
1495, 1468, 1427, 1381, 1363, 1318, 1275, 1253, 1217, 1125, 1074,
1027, 943, 900, 865, 776, 763, 732, 696; 1H NMR (CDCl3, 392 MHz)
δ 1.34−1.44 (br, 2H), 1.78−1.81 (br, 2H), 2.59 (tt, J = 3.6 and 11.2
Hz, 1H), 2.83 (br, 2H), 4.26 (br, 2H), 5.00 (s, 1H), 5.13 (s, 2H), 5.18
(s, 1H), 7.27−7.36 (m, 10H); 13C NMR (CDCl3, 98.5 MHz) δ 31.4,
Synthesis of (E)-4-(2-Phenylethenyl)cyclohexyl Acetate (4e). The
reaction was carried out according to Procedure A on a 0.40 mmol
scale by using trans-4-bromocyclohexyl acetate (88.6 mg, 0.40 mmol),
(E)-4,4,5,5-tetramethyl-2-(2-phenylethenyl)-1,3,2-dioxaborolane
(0.140 g, 0.61 mmol), t-BuLi (0.34 mL, 1.65 M in pentane, 0.56
mmol), MgBr2 (0.80 mL, 0.10 M in THF, 80.0 μmol), and iron
complex 1a (0.40 mL, 50.0 mM in THF, 20 μmol, 5.0 mol %).
Conditions: −20 °C, 24 h. The title compounds (85.7 mg, 88% yield,
> 99% pure on GC analysis, cis:trans = 43/57) was obtained as a
colorless oil after silica gel column chromatography (hexane/AcOEt =
1171
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Note
40.7 (2C), 44.5 (2C), 67.0, 111.4, 126.6 (2C), 127.3, 127.8 (2C),
127.9, 128.3 (2C), 128.5 (2C), 136.9, 142.0, 152.8, 155.2; HRMS (EI)
m/z [M]+ calcd for C21H23NO2 321.1729; found 321.1741.
hexane).1H and 13C NMR spectra have been attached. Analytical data
for the title compounds have been reported.23
Synthesis of (E)-3-{6-[(tert-Butyldimethylsilyl)oxy]hex-2-en-1-yl}-
1-tosylpyrrolidine (4n). The reaction was carried out according to
Procedure A on a 0.40 mmol scale by using N-allyl-N-(2-bromoethyl)-
4-methylbenzenesulfonamide (0.127 g, 0.40 mmol), 2a (0.261 g, 0.80
mmol), t-BuLi (0.48 mL, 1.59 M in pentane, 0.76 mmol), MgBr2 (0.80
mL, 0.10 M in THF, 80 μmol), and iron complex 1b (1.60 mL, 50.0
mM in THF, 80 μmol, 20.0 mol %). Conditions: 0 °C, 24 h. The title
compound (97.2 mg, 56% yield, 98% pure on GC analysis) was
obtained as a white oil after silica gel column chromatography
(hexane/AcOEt = 15/1). Rf = 0.38 (hexane/AcOEt = 4/1); IR (neat)
2928, 2856, 1598, 1471, 1388, 1344, 1305, 1289, 1253, 1160, 1036,
1016, 969, 939, 834, 815, 774, 708, 661; 1H NMR (CDCl3, 392 MHz)
δ 0.04 (s, 6H), 0.89 (s, 9H), 1.36−1.46 (m, 1H), 1.50−1.57 (m, 2H),
1.85−1.93 (m, 3H), 1.97−2.10 (m, 3H), 2.43 (s, 3H), 2.82 (dd, J = 8.1
and 9.7 Hz, 1H), 3.19 (dt, J = 9.9 and 7.6 Hz, 1H), 3.29−3.34 (m,
1H), 3.37 (dd, J = 7.2 and 9.7 Hz, 1H), 3.58 (t, J = 6.3 Hz, 2H), 5.26
(dt, J = 15.1 and 6.3 Hz, 1H), 5.36 (dt, J = 15.1 and 6.7 Hz, 1H), 7.32
(d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 98.5
MHz) δ −5.3 (2C), 18.3, 21.5, 25.9(3C), 28.7, 30.9, 32.5, 36.0, 38.7,
47.5, 52.7, 62.5, 127.4, 127.5 (2C), 129.6 (2C), 132.1, 134.0, 143.2;
HRMS (EI) m/z [M − t-Bu]+ calcd for C19H30NO3SSi 380.1716;
found 380.1710.
Large-Scale Procedure for the Cross-Coupling Reaction of
Bromocycloheptane and 4,4,5,5-Tetramethyl-2-phenyl-1,3,2-
dioxaborolane. To a THF solution (50 mL) of (E)-4,4,5,5-
tetramethyl-2-(2-phenylethenyl)-1,3,2-dioxaborolane (3.46 g, 15.0
mmol) was added t-BuLi (8.80 mL, 1.59 M in pentane, 14.0 mmol)
at −78 °C. The reaction mixture was stirred at the same temperature
for 30 min, and then at 0 °C for 30 min. The solvent was removed in
vacuo at 0 °C. To the residual borate were added THF (50 mL),
bromocycloheptane (1.78 g, 10.1 mmol), MgBr2 (368.2 mg, 2.0
mmol), and iron complex 1a (575.3 mg, 0.50 mmol, 5.0 mol %) at
−78 °C. The coupling reaction was carried out at −20 °C for 24 h.
After cooling to ambient temperature, aqueous NH4Cl (saturated, 10.0
mL) was added. The aqueous layer was extracted five times with
hexane. The combined organic extracts were filtered with a pad of
Florisil. (E)-(2-cycloheptylethenyl)benzene (4c) (1.79 g, 88% yield, >
99% pure on GC analysis) was obtained as a colorless oil after silica gel
column chromatography (100% hexane).
Synthesis of (E)-Ethyl 12-[(tert-Butyldimethylsilyl)oxy]dodec-8-
enoate (4i). The reaction was carried out according to Procedure A on
a 0.40 mmol scale by using ethyl 7-bromo-heptanoate (95.1 mg, 0.40
mmol), 2a (0.261 g, 0.80 mmol), t-BuLi (0.48 mL, 1.59 M in pentane,
0.76 mmol), MgBr2 (0.80 mL, 0.10 M in THF, 80 μmol), and iron
complex 1b (0.40 mL, 50.0 mM in THF, 20 μmol, 5.0 mol %).
Conditions: 0 °C, 24 h. The title compound (0.105 g, 73% yield, >
99% pure on GC analysis) was obtained as a colorless oil after silica gel
column chromatography (hexane/AcOEt = 50/1). Rf = 0.61 (hexane/
AcOEt = 4/1); IR (neat) 2929, 2856, 1737, 1463, 1371, 1252, 1179,
1
1099, 1034, 1006, 967, 939, 834, 774, 726, 662; H NMR (392 MHz,
CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.23−1.27 (m, 3H), 1.29−1.38
(m, 6H), 1.53−1.66 (m, 4H), 1.94−2.05 (m, 4H), 2.28 (t, J = 7.2 Hz,
2H), 3.60 (t, J = 6.3 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 5.39 (m, 2H);
13C NMR (98.5 MHz, CDCl3) δ −5.3 (2C), 14.2, 18.3, 24.9, 26.0
(3C), 28.7, 28.8, 29.0, 29.4, 32.5, 32.7, 34.4, 60.1, 62.6, 129.8, 130.6,
173.9; HRMS (EI) m/z [M − t-Bu]+ calcd for C16H31O3Si 299.2042;
found 299.2032.
Synthesis of (Z)-12-[(tert-Butyldimethylsilyl)oxy]dodec-8-eneni-
trile (4j). The reaction was carried out according to Procedure A on
a 0.41 mmol scale by using 7-bromoheptanenitrile (77.3 mg, 0.41
mmol), 2-[(1Z)-5-tert-butyldimethylsilyloxypent-1-en-1-yl]-4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolane (0.261 g, 0.80 mmol), t-BuLi (0.48 mL,
1.59 M in pentane, 0.76 mmol), MgBr2 (0.80 mL, 0.10 M in THF, 80
μmol), and iron complex 1b (0.40 mL, 50.0 mM in THF, 20 μmol, 5.0
mol %). Conditions: 0 °C, 24 h. The title compound (0.104 g, 83%
yield, > 99% pure on GC analysis) was obtained as a colorless oil after
silica gel column chromatography (hexane/AcOEt = 25/1). Rf = 0.50
(hexane/AcOEt = 4/1); IR (neat) 2928, 2857, 1734, 1463, 1387,
1361, 1254, 1096, 1006, 966, 939, 834, 774, 715, 661; 1H NMR
(CDCl3, 392 MHz) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.32−1.38 (m, 4H),
1.43−1.47 (m, 2H), 1.56 (tt, J = 6.3 and 8.1 Hz, 2H), 1.66 (tt, J = 7.1
and 7.2 Hz, 2H), 2.01−2.10 (m, 4H), 2.33 (t, J = 6.7 Hz, 2H), 3.61 (t,
J = 6.3 Hz, 2H), 5.34 (dt, J = 10.8 and 5.8 Hz, 1H), 5.39 (dt, J = 10.8
and 5.8 Hz, 1H); 13C NMR (CDCl3, 99.5 MHz) δ −5.3 (2C), 17.1,
18.3, 23.5, 25.4, 25.9 (3C), 27.0, 28.4, 28.6, 29.3, 32.9, 62.6, 119.8,
129.6, 129.8; HRMS (EI) m/z [M − t-Bu]+ calcd for C14H26NOSi
252.1784; found 252.1781.
Synthesis of (Z)-Methyl 4-(non-2-en-1-yl)benzoate (4k). The
reaction was carried out according to Procedure A on a 0.40 mmol
scale by using methyl 4-(chloromethyl)benzoate (74.7 mg, 0.40
mmol), (Z)-4,4,5,5-tetramethyl-2-(oct-1-en-1-yl)-1,3,2-dioxaborolane
(0.191 g, 0.80 mmol), t-BuLi (0.48 mL, 1.60 M in pentane, 0.76
mmol), MgBr2 (0.80 mL, 0.10 M in THF, 80.0 μmol), and iron
complex 1b (0.40 mL, 50.0 mM in THF, 20 μmol, 5.0 mol %).
Conditions: −20 °C, 24 h. The title compound (45.9 mg, 44% yield, >
98% pure on GC analysis) was obtained as a colorless oil after
purification by GPC (eluent: CHCl3). Rf = 0.58 (hexane/AcOEt = 4/
1); IR (neat) 2954, 2925, 2854, 1722, 1610, 1575, 1508, 1435, 1378,
1309, 1275, 1191, 1107, 1020, 969, 918, 853, 836, 807, 756, 725, 699;
1H NMR (CDCl3, 392 MHz) δ 0.87−0.90 (m, 3H), 1.22−1.41 (m,
8H), 2.14 (dt, J = 6.7 and 7.2 Hz, 2H), 3.45 (d, J = 5.8 Hz, 2H), 3.90
(s, 3H), 5.49−5.59 (m, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.95 (d, J = 7.6
Hz, 2H); 13C NMR (CDCl3, 98.5 MHz) δ 14.1, 22.6, 27.3, 29.0, 29.6,
31.7, 33.5, 51.2, 126.8, 127.8, 128.3 (2C), 129.7 (2C), 131.9, 146.8,
167.1; HRMS (EI) m/z [M]+ calcd for C17H24O2 260.1776; found
260.1770.
Synthesis of (1E,4E)-1,5-Diphenylpenta-1,4-diene (4l) and (E)-
Penta-1,4-diene-1,3-diyldibenzene (4m). The reaction was carried
out according to Procedure A on a 1.51 mmol scale by using cinnamyl
chloride (0.230 g, 1.51 mmol), (E)-4,4,5,5-tetramethyl-2-(2-phenyl-
ethenyl)-1,3,2-dioxaborolane (0.518 g, 2.25 mmol), t-BuLi (1.32 mL,
1.59 M in pentane, 2.10 mmol), MgBr2 (3.00 mL, 0.10 M in THF,
0.30 mol), and iron complex 1b (1.50 mL, 50.0 mM in THF, 75 μmol,
5.0 mol %). Conditions: 0 °C, 24 h. The title compounds (0.290 g,
87% yield, > 99% pure on GC analysis, 4l/4m = 89/11) were obtained
as a white solid after silica gel column chromatography (100%
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR for all new compounds and 11B NMR for
3ab. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*masaharu@scl.kyoto-u.ac.jp
■
ACKNOWLEDGMENTS
■
This research was supported by a grant from the Japan Society
for the Promotion of Science (JSPS) through the “Funding
Program for Next Generation World-Leading Researchers
(NEXT Program),” initiated by the Council for Science and
Technology Policy (CRTP). Financial support from the
Noguchi Institute is gratefully acknowledged. T. Hashimoto is
grateful for a Research Fellowship for Young Scientists from
JSPS (213169).
REFERENCES
■
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Note
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1173
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