C2-Symmetric tetrafluorobenzobarrelenes as highly efficient ligands for the iridium-catalyzed asymmetric annulation of 1,3-dienes with 2-formylphenylboron reagents

Article abstract of DOI:10.1016/j.tetasy.2008.07.014

New C₂-symmetric chiral diene ligands bearing a tetrafluorobenzobarrelene framework were prepared via a [4+2] cycloaddition of 1,4-bis((methoxymethoxy)methyl)benzene with tetrafluorobenzyne. The diene ligands realized the iridium-catalyzed enantioselective [3+2] annulation of 1,3-dienes with 2-formylphenylboron reagents giving 1-indanol derivatives in high yields and with high enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2008.07.014

Tetrahedron: Asymmetry 19 (2008) 1778–1783
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Tetrahedron: Asymmetry
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C2-Symmetric tetrafluorobenzobarrelenes as highly efficient ligands
for the iridium-catalyzed asymmetric annulation of 1,3-dienes with
2-formylphenylboron reagents
*
*
Takahiro Nishimura , Yuichi Yasuhara, Makoto Nagaosa, Tamio Hayashi
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2008
Accepted 6 July 2008
New C2-symmetric chiral diene ligands bearing a tetrafluorobenzobarrelene framework were prepared
via a [4+2] cycloaddition of 1,4-bis((methoxymethoxy)methyl)benzene with tetrafluorobenzyne. The
diene ligands realized the iridium-catalyzed enantioselective [3+2] annulation of 1,3-dienes with 2-form-
ylphenylboron reagents giving 1-indanol derivatives in high yields and with high enantioselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
F
1. Introduction
F
F
F
F
F
X = OCH2OCH3 2a
OH 2b
Recent findings of the distinctive features of chiral diene ligands
for transition metal-catalyzed asymmetric reactions have ex-
panded the possibility of ligand design for late transition met-
als.1–5 The chiral dienes represented by those based on the
bicyclo[2.2.2]octadiene framework2,3 have frequently displayed
higher activities and enantioselectivities than chiral phosphine li-
gands in catalytic asymmetric reactions. However, their successful
use has been limited to rhodium-catalyzed reactions except for
Carreira’s kinetic resolution in an iridium-catalyzed allylic substi-
tution.2a On the other hand, we have recently reported a [3+2]
annulation, which is catalyzed by an iridium complex coordinated
with a diene, [IrCl(cod)]2 (cod = 1,5-cyclooctadiene), where the
more electron-rich double bond of 1,3-diene participates in the
reaction while the terminal carbon of the reactive double bond
forms a bond with the carbonyl carbon of 2-formylphenylboronic
acid giving indanol derivatives (Scheme 1).6 Attempts to use chiral
bicyclo[2.2.2]octadiene ligands in place of cod for asymmetric syn-
thesis with the iridium-catalyzed annulation were disappointing,
with the reactions only giving a low yield of the annulation product
due to their low coordination ability to iridium (vide infra).
Ph 2c
F
F
Ph
OSiPh3 2d
Ph
X
X
Bn-bod* 3
1
(tfb)
2
Scheme 2.
Tetrafluorobenzobicyclo[2.2.2]octatriene
(tetrafluorobenzo-
barrelene; tfb) 1 (Scheme 2) and its derivatives are known to
possess high coordination abilities toward rhodium(I) and
iridium(I) due to their electron-deficient character.7 They can be
prepared in one step by the formal [4+2] cycloaddition of aromatic
compounds with tetrafluorobenzyne generated from penta-
fluorophenyllithium or -magnesium.8 Recently, the high perfor-
mance of tfb 1 as a ligand has been disclosed by Masuda, where
a cationic rhodium complex coordinated with 1 proved to be an
efficient catalyst for polymerization of phenylacetylene.9 Herein,
we report the development of C2-symmetric disubstituted tetra-
fluorobenzo[2.2.2]octatrienes 2 and their successful application
to the iridium-catalyzed asymmetric annulation.
R5
R5
OH
R2
[Ir(OH)(cod)]2
(5 mol % Ir)
2. Results and discussion
R1
+
O
R4
R2
R4
Et3N (2.5 equiv)
toluene
R3
B(OH)2
R3
The C2-symmetric tfb dienes were prepared via a straightfor-
ward pathway (Scheme 3). The [4+2] cycloaddition of 1,4-
bis((methoxymethoxy)methyl)benzene 4 with tetrafluorobenzyne
generated according to a known procedure,8b,c gave the 2,5-disub-
stituted tfb dl-2a. Its resolution by the use of a chiral stationary
phase column (Chiralcel OD-H) gave both enantiomers (R,R)-2a
and (S,S)-2a, whose absolute configurations were assigned by
R1
Scheme 1. Iridium-catalyzed [3+2] annulation.
* Corresponding authors.
E-mail addresses: tnishi@kuchem.kyoto-u.ac.jp (T. Nishimura), thayashi@
kuchem-u.ac.jp (T. Hayashi).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.014

T. Nishimura et al. / Tetrahedron: Asymmetry 19 (2008) 1778–1783
1779
activity is attributed to the dissociation of the Bn-bodꢀ ligand from
iridium. Thus, the generation of free Bn-bodꢀ ligand (78% based on
[IrCl(Bn-bodꢀ)]) was observed in the reaction of 5a with 2-form-
ylphenylboronic acid in the presence of [IrCl(Bn-bodꢀ)]2 (5 mol %
of Ir) at 80 °C for 0.5 h. The yield of 6a was much higher (50%) with
the chiral tfb ligand 2c, because the Ir/2c complex retains its cata-
lytic activity for a longer time (entries 5 and 6). The tetra-
fluorobenzo-framework is responsible for the high efficiency of
tfb ligand 2c in the present iridium-catalyzed reaction, which is
demonstrated by the results obtained above with Bn-bodꢀ 3 and
tfb 2c, with both of the dienes being substituted with benzyl
groups on the olefinic double bonds. The use of triphenylsilyl-
oxymethyl-substituted tfb ligand 2d improved the yield of 6a up
to 61% (entry 7). The enantioselectivity of the (1S,3S)-6a isomer
is high, ranging between 92% and 94% ee with the chiral tfb ligands
2a–d. The absolute configuration of 6a was determined to be
(1S,3S) by X-ray analysis of the N-tosylcarbamate 7 derived from
6a, whose Flack parameter is ꢁ0.04(5) with this configuration
(Scheme 4, Fig. 1).10
F
F
X
F
pentafluorobenzene
BuLi
resolution by
chiral HPLC
(R,R)-2a
+
F
hexane
Chiralcel OD-H
(S,S)-2a
0 ºC—rt, 12 h
X
X
X
dl-2a
12%
4: X = OCH2OCH3
F
F
F
F
F
F
(a)
F
F
CH3OCH2O
HO
OCH2OCH3
OH
(R,R)-2a
(R,R)-2b
(b), (c)
(d)
F
F
F
F
F
F
F
F
O
Ph
Ph3SiO
Ph
OSiPh3
(R,R)-2c
(R,R)-2d
OH
O
NHTs
+
TsNCO
Scheme 3. Reagents and conditions: (a) concd HCl, MeOH, 60 °C (90% yield);
(b) NBS, PPh3, CH2Cl2, 0 °C; (c) PhMgBr, THF, rt (48% yield in two steps); (d) Ph3SiCl,
imidazole, DMF, rt (86% yield).
pyridine
rt, 12 h
6a
7: 71%
consideration of the stereochemical reaction pathway in the rho-
dium-catalyzed asymmetric 1,4-addition of phenylboronic acid to
2-cyclohexen-1-one. Thus, the diene, which gave (R)-3-phenylcy-
clohexanone (97% ee), was decided to be an (R,R)-isomer. Removal
of the methoxymethyl protecting group in (R,R)-2a gave diol (R,R)-
2b (X = OH), which led to (R,R)-2c (X = Ph) and (R,R)-2d
(X = OSiPh3).
Scheme 4.
The results obtained for the reaction of isoprene (5a) with
2-formylphenylboronic acid (2 equiv) in the presence of iridium
catalysts (5 mol % of Ir) coordinated with chiral tfb ligands 2 are
summarized in Table 1, which also contain those obtained with
one of the chiral bicyclo[2.2.2]octadiene ligands (Bn-bodꢀ 3)3 for
comparison. The Ir/Bn-bodꢀ catalyst lost its catalytic activity within
0.5 h resulting in a very low yield (5%) of indanol 6a even after a
prolonged reaction time (entries 1 and 2). The loss of catalytic
Table 1
Iridium-catalyzed asymmetric [3+2] annulation of 2-formylphenylboronic acid with
isoprene 5aa
OH
[IrCl(coe)2]2 (5 mol % Ir)
CHO
chiral diene (10 mol %)
+
Et3N (2.5 equiv)
B(OH)2
toluene
(1 : 2)
5a
60 °C, 12 h
6a
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
(R,R)-Bn-bodꢀ
(R,R)-Bn-bodꢀ
(R,R)-2a
(R,R)-2b
(R,R)-2c
3
3
0.5
12
12
12
0.5
12
5d
—
—
5d
38
44
9d
50
61
94 (1S,3S)
93 (1S,3S)
—
92 (1S,3S)
94 (1S,3S)
Figure 1. ORTEP illustration of 7 with thermal ellipsoids drawn at 50% probability
level. Crystal data for 7: 20H21NO4S, Mw = 371.45, space group C2 (#5), a =
C
29.145(7) Å, b = 9.783(2) Å, c = 17.526(4) Å, V = 4232.2(17) Å3, Z = 8, Dcalcd = 1.166 g/
(R,R)-2c
(R,R)-2d
cm3, T = 123 K, R = 0.0394 (I > 2.00
Flack parameter = ꢁ0.04(5).
r(I)), Rw = 0.1137 (I > 2.00r(I)), GOF = 1.115,
12
a
Reaction conditions; isoprene 5a (0.30 mmol), 2-formylphenylboronic acid
diene ligand (10 mol %), Et3N
(0.60 mmol), [IrCl(coe)2]2 (5 mol % of Ir),
a
(0.75 mmol) in toluene (0.9 mL) at 60 °C for 12 h.
An equilibrium experiment between diene ligands and their
iridium complexes using tfb 2c and Bn-bod 3 proved the much
b
Isolated yield.
c
Determined by HPLC analysis with a chiral stationary phase column: Chiralcel
higher coordination ability of the tfb ligand over the bod ligand
OD-H.
11
d
Determined by 1H NMR.
(Scheme 5). Thus, ½IrClðcoeÞ2ꢂ2
(coe = cyclooctene), (R,R)-2c

1780
T. Nishimura et al. / Tetrahedron: Asymmetry 19 (2008) 1778–1783
rate in place of 2-formylphenylboronic acid (entry 1). The 1,3-
(R,R)-2c
[IrCl((R,R)-2c)]2
97%
3%
(2 equiv to Ir)
dienes 5b–e substituted with an alkyl group at the 1- or 2-position
underwent the [3+2] annulation at the more electron-rich double
bond to give the corresponding 1-indanols 6 in high yields (73–
87%) (entries 2–5). The enantioselectivity was high (92–95% ee)
for both 1- and 2-substituted dienes (entries 1–5).
[IrCl(coe)2]2
+
+
+
+
C6D6
(R,R)-3
[IrCl((R,R)-3)]2
50 °C, 6.5 h
(2 equiv to Ir)
(R,R)-2c
[IrCl((R,R)-2c)]2
97%
3%
(1.5 equiv to Ir)
[IrCl((R,R)-3)]2
+
+
C6D6
50 °C, 5 h
(R,R)-3
[IrCl((R,R)-3)]2
(0.5 equiv to Ir)
3. Conclusion
Scheme 5. Coordination experiments.
In conclusion, we have developed C2-symmetric dienes having a
tetrafluorobenzobarrelene (tfb) framework as a new type of chiral
diene ligand. These chiral dienes realized the iridium-catalyzed
enantioselective [3+2] annulation of 1,3-dienes with 2-form-
ylphenylboron reagents.
(2 equiv to Ir), and (R,R)-3 (2 equiv to Ir) were dissolved in C6D6,
and the solution was kept at 50 °C. After 6.5 h, the solution reached
an equilibration state where the iridium complex consisted of 97%
of [IrCl((R,R)-2c)]2 and 3% of [IrCl((R,R)-3)]2. The equilibrium of the
same composition was also observed in the reaction (50 °C, 5 h)
starting with [IrCl((R,R)-3)]2, (R,R)-2c (1.5 equiv to Ir), and (R,R)-3
(0.5 equiv to Ir). It follows that the tfb diene 2c coordinates to
the iridium chloro-bridge dimer much more strongly (>50 times)
than the bod diene.
4. Experimental
4.1. General
All anaerobic and moisture-sensitive manipulations were car-
ried out with standard Schlenk techniques under predried nitrogen
or glove box techniques under argon. NMR spectra were recorded
on a JEOL JNM LA-500 spectrometer (500 MHz for 1H, 125 MHz
for 13C). Chemical shifts are reported in d ppm referenced to an
internal SiMe4 standard or the residual peaks of dichlorometh-
ane-d2 (CDHCl2, d 5.30) and benzene-d6 (d 7.16) for 1H NMR, and
chloroform-d (d 77.16), dichloromethane-d2 (d 53.52), and ben-
zene-d6 (d 128.06) for 13C NMR: the following abbreviations are
used; s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br:
broad. Elemental analyses were performed at the Micro analytical
center, Kyoto University. High-resolution mass spectra were ob-
tained with a Bruker micrOTOF spectrometer. Optical rotations
were measured on a JASCO DIP-370 polarimeter or JASCO P-2200
polarimeter. Preparative recycling gel permeation chromatography
was performed with JAI LC-908 equipped with JAIGEL-1H and ꢁ2H
using chloroform as an eluent.
Table 2 summarizes the results obtained for the reaction of sev-
eral 1,3-dienes with potassium trifluoro(2-formylphenyl)borate,12
which was carried out in the presence of iridium/(R,R)-2d as a cat-
alyst (5 mol % of Ir) in toluene/H2O at 60 °C for 12 h. In the reaction
of isoprene 5a, the chemical yield of the [3+2] annulation product
6a was increased from 61% to 82% by the use of the potassium bo-
Table 2
Iridium-catalyzed asymmetric [3+2] annulation of potassium trifluoro(2-formylphe-
nyl)borate with 1,3-dienesa
OH
[IrCl(coe)2]2 (5 mol % Ir)
CHO
BF3K
R2
(R,R)-2d (10 mol %)
R2
+
R1
Et3N (2.5 equiv)
toluene/H2O (4/1)
60 °C, 12 h
5
(1 : 2)
R1
6
Entry
1
Diene
Product
Yieldb
(%)
eec
(%)
4.2. Materials
OH
82
73
83
83
87
95
94
93
92
92
Benzene and hexane were distilled over benzophenone ketyl.
CH2Cl2 and DMF were distilled from CaH2. Methanol was distilled
over magnesium turnings. THF and toluene were purified by pass-
ing through a neutral alumina column under nitrogen atmosphere.
Isoprene was purchased from Wako Chemicals and distilled prior
to use. Triethylamine was purchased from Wako Chemicals and
distilled over KOH prior to use. ½IrClðcoeÞ2ꢂ211 potassium (2-formyl-
phenyl)trifluoroborate,13 1,3-dienes 5b,14 5c,15 5d,16 and 5e17 were
prepared according to the reported procedures. All other chemicals
were purchased from commercial suppliers and used as received.
5a
6a
OH
2
3
4
Ph
5b
6b
Ph
OH
OH
OH
C6H13
C6H13
5c
6c
4.3. Preparation of 1,4-bis[(methoxymethoxy)methyl]benzene
4
OSiMe2 tBu
OSiMe2 tBu
6d
5d
To a solution of 1,4-benzenedimethanol (13.8 g, 100 mmol) and
diisopropylethylamine (68 mL, 0.40 mol) in CH2Cl2 (100 mL) was
added chloromethyl methyl ether (30 mL, 0.40 mol) at ꢁ20 °C,
and the solution was allowed to warm up to room temperature
and stirred for 24 h. The mixture was quenched with satd aq
NaHCO3 and extracted with Et2O. The combined organic layer was
washed with brine, dried over Na2SO4, and filtered. Evaporation of
the solvent followed by a flash column chromatography on silica
gel with hexane/ethyl acetate (7:1) gave compound 4 (21.5 g, 95%
yield). 1H NMR (CDCl3) d 3.41 (s, 6H), 4.59 (s, 4H), 4.70 (s, 4H),
7.35 (s, 4H); 13C NMR (CDCl3) d 55.5, 69.0, 95.8, 128.1, 137.5. HRMS
(ESI) calcd for C12H18NaO4 (M+Na)+ 249.1097, found 249.1097.
CO2Me
5
5e
CO2Me
6e
a
Reaction conditions; 1,3-dienes 5 (0.30 mmol), potassium trifluoro(2-formyl-
phenyl)borate (0.60 mmol), [IrCl(coe)2]2 (5 mol % of Ir), (R,R)-2d (10 mol %), Et3N
(0.75 mmol) in toluene (0.9 mL) at 60 °C for 12 h.
b
Isolated yield.
c
Determined by HPLC analysis with a chiral stationary phase column: Chiralcel
OD-H.

T. Nishimura et al. / Tetrahedron: Asymmetry 19 (2008) 1778–1783
1781
4.4. Preparation of 2,5-bis[(methoxymethoxy)methyl]-7,8-
tetrafluorobenzobicyclo[2.2.2]octatriene 2a
phy on silica gel with hexane gave (R,R)-2c (74 mg, 53% yield) as a
white solid. 1H NMR (CDCl3) d 3.52 (d, J = 16.4 Hz, 2H), 3.55 (d,
J = 16.4 Hz, 2H), 4.80 (d, J = 5.9 Hz, 2H), 6.25–6.31 (m, 2H), 7.02 (d,
J = 7.8 Hz, 4H), 7.16–7.31 (m, 6H); 13C NMR (CDCl3) d 39.7, 45.3,
126.6, 128.6, 129.1, 130.4–130.7 (m), 132.8, 136.0–138.5 (m),
137.7, 140.3–142.6 (m), 153.6. Anal. Calcd for C26H18F4: C, 76.84;
To a solution of 4 (6.8 g, 30 mmol) and pentafluorobenzene
(2.5 g, 15 mmol) in hexane (15 mL) was added n-BuLi (1.6 M in
hexane, 10 mL, 16 mmol) at 0 °C. After completion of the addition,
the solution was allowed to warm up to room temperature and
stirred for 12 h. The resulting mixture was quenched with H2O, fil-
tered through a Celite pad, and extracted with Et2O. The combined
organic layer was washed with brine, dried over MgSO4, and fil-
tered. Evaporation of the solvent followed by flash column chro-
matography on silica gel with hexane/ethyl acetate (9:1) and gel
permeation chromatography gave dl-2a (648 mg, 12% yield) as a
colorless oil. Resolution was carried out by use of a chiral station-
ary phase column [Chiralcel OD-H (2.0 cm I.D. ꢃ 25 cm), hexane/2-
propanol = 98:2, t1 = 14 min for (R,R)-2a, t2 = 18 min for (S,S)-2a] to
give both enantiomers (R,R)-2a and (S,S)-2a. An injection of 40 mg
of dl-2a in hexane (2 mL) without the recycling operation gave
(R,R)-2a and (S,S)-2a, quantitatively. (R,R)-2a: 1H NMR (CDCl3) d
3.36 (s, 6H), 4.17 (dd, J = 12.8, 1.5 Hz, 2H), 4.19 (dd, J = 12.8,
1.5 Hz, 2H), 4.52 (d, J = 6.5 Hz, 2H), 4.55 (d, J = 6.5 Hz, 2H), 5.14
(ddt, J = 5.9, 1.6, 0.9 Hz, 2H), 6.69 (dq, J = 5.9, 1.6 Hz, 2H); 13C
NMR (CDCl3) d 43.1, 55.5, 66.5, 95.5, 129.7–130.1 (m), 135.1,
136.2–138.7 (m), 140.7–143.0 (m), 151.1. Anal. Calcd for
H, 4.46. Found: C, 76.72; H, 4.36. ½a D20
¼ þ28:4 (c 1.00, CHCl3).
ꢂ
4.7. Preparation of (1R,4R)-2,5-bis[(triphenylsiloxy)methyl]-
7,8-tetrafluorobenzobicyclo[2.2.2]octatriene (R,R)-2d
To a mixture of (R,R)-2b (146 mg, 0.51 mmol), Ph3SiCl (601 mg,
2.0 mmol), and imidazole (347 mg, 5.1 mmol) was added DMF
(2.0 mL) at 0 °C, and the solution was allowed to warm up to room
temperature and stirred for 24 h. The mixture was quenched with
H2O and extracted with Et2O. The combined organic layer was
washed with brine, dried over MgSO4, and filtered. Evaporation
of the solvent followed by a flash column chromatography on silica
gel with hexane/EtOAc (80:1) and gel permeation chromatography
gave (R,R)-2d (350 mg, 86% yield) as a white solid. 1H NMR (CDCl3)
d 4.39 (dd, J = 13.7, 1.7 Hz, 2H), 4.44 (dd, J = 13.7, 1.7 Hz, 2H), 4.98
(d, J = 6.0 Hz, 2H), 6.41 (dq, J = 6.0, 1.7 Hz, 2H), 7.30–7.37 (m, 12H),
7.38–7.44 (m, 6H), 7.52–7.58 (m, 12H); 13C NMR (CDCl3) d 42.4,
63.7, 128.0, 130.0–130.4 (m), 130.3, 132.8, 133.8, 135.5, 136.0–
138.6 (m), 140.4–142.9 (m), 153.3. Anal. Calcd for C50H38F4O2Si2:
C
½
18H18F4O4: C, 57.76; H, 4.85. Found: C, 57.60; H, 4.83.
a 2D0
ꢂ
¼ ꢁ8:2 (c 0.97, CHCl3). (S,S)-2a: ½a D20
ꢂ
¼ þ8:2 (c 0.98, CHCl3).
C, 74.79; H, 4.77. Found: C, 74.99; H, 4.78. ½a D20
¼ þ11:1 (c 1.04,
ꢂ
CHCl3).
4.5. Preparation of (1R,4R)-2,5-bis(hydroxymethyl)-7,8-
tetrafluorobenzobicyclo[2.2.2]octatriene (R,R)-2b
4.8. General procedure for preparation of iridium–chiral diene
complexes
To a solution of (R,R)-2a (212 mg, 0.57 mmol) in methanol
(4 mL) was added conc. HCl aq (4 drops). After heating at 60 °C
for 4 h, the mixture was quenched with H2O and extracted with
Et2O. The organic layer was washed with satd aq NaHCO3, brine,
dried over MgSO4, and filtered. Evaporation of the solvent followed
by a flash column chromatography on silica gel with hexane/ethyl
acetate (1:1) gave (R,R)-2b (145 mg, 90% yield) as a white solid. 1H
NMR (CDCl3) d 1.50 (br s, 2H), 4.23–4.35 (br m, 4H), 5.13–5.17 (m,
2H), 6.65 (dq, J = 6.0, 1.8 Hz, 2H); 13C NMR (CDCl3) d 42.8, 62.8,
129.8–130.2 (m), 133.3, 136.3–138.7 (m), 140.8–143.0 (m), 154.2.
Anal. Calcd for C14H10F4O2: C, 58.75; H, 3.52. Found: C, 58.67; H,
[IrCl(coe)2]2 (22.4 mg, 0.05 mmol Ir) and a chiral diene (0.050
mmol) were dissolved in benzene (2.0 mL), and the mixture was
heated at 60 °C for 12 h. After being cooled to room temperature,
the reaction mixture was concentrated under reduced pressure to
give a quantitative yield of the iridium–chiral diene complex.
4.8.1. [IrCl((R,R)-Bn-bodꢀ)]2
1H NMR (CD2Cl2) d 0.17–0.30 (m, 4H), 0.38–0.51 (m, 4H), 2.65
(d, J = 13.8 Hz, 4H), 3.26 (d, J = 13.8 Hz, 4H), 3.37 (dd, J = 6.1,
1.2 Hz, 4H), 3.99–4.06 (m, 4H), 7.17–7.23 (m, 4H), 7.23–7.29 (m,
8H), 7.29–7.34 (m, 8H); 13C NMR (CD2Cl2) d 29.1, 36.1, 43.2, 47.0,
53.8, 126.4, 128.4, 129.0, 138.9. HRMS (ESI) calcd for C44H44Cl3Ir2
(M+Cl)ꢁ 1063.1745, found 1063.1796.
3.60. ½a 2D0
¼ ꢁ17:2 (c 1.02, CHCl3).
ꢂ
4.6. Preparation of (1R,4R)-2,5-dibenzyl-7,8-tetrafluoro-
benzobicyclo[2.2.2]octatriene (R,R)-2c
4.8.2. [IrCl((R,R)-2c)]2
To a solution of (R,R)-2b (116 mg, 0.40 mmol) in CH2Cl2 (10 mL)
were added successively PPh3 (233 mg, 0.89 mmol) and NBS
(158 mg, 0.89 mmol) at 0 °C. After stirring for 30 min, the mixture
was quenched with H2O and extracted with Et2O. The combined or-
ganic layer was washed with brine, dried over MgSO4, and filtered.
Evaporation of the solvent followed by a flash column chromatogra-
phy on silica gel with hexane/ethyl acetate (8:1) gave (1R,4R)-2,5-
bis(bromomethyl)-7,8-tetrafluorobenzobicyclo[2.2.2]octatriene
(R,R)-2b0 (160 mg, 96% yield) as a white solid. 1H NMR (CDCl3) d 4.13
(dd, J = 10.5, 1.0 Hz, 2H), 4.16 (dd, J = 10.5, 1.0 Hz, 2H), 5.13–5.17 (m,
2H), 6.71–6.76 (m, 2H); 13C NMR (CDCl3) d 31.8, 44.9, 128.7–129.1
(m), 136.0, 136.7–139.1 (m), 140.9–143.0 (m), 149.8. Anal. Calcd
for C14H8Br2F4: C, 40.81; H, 1.96. Found: C, 41.08; H, 1.97.
1H NMR (CD2Cl2) d 2.75 (d, J = 13.9 Hz, 4H), 3.34 (d, J = 5.7 Hz,
4H), 3.36 (d, J = 13.9 Hz, 4H), 5.34 (d, J = 5.7 Hz, 4H), 7.01–7.08
(m, 8H), 7.09–7.15 (m, 12H); 13C NMR (CD2Cl2) d 34.3, 41.9, 45.7,
52.9, 126.7, 128.3–128.7 (m), 128.5, 129.1, 136.2 137.2–138.6
(m), 139.0–140.6 (m). HRMS (ESI) calcd for
C52H36Cl3F8Ir2
(M+Cl)ꢁ 1303.0993, found 1303.0974.
4.8.3. [IrCl((R,R)-2d)]2
1H NMR (CD2Cl2) d 2.49 (dd, J = 5.8, 0.9 Hz, 4H), 3.37 (d,
J = 11.4 Hz, 4H), 4.18 (d, J = 11.4 Hz, 4H), 5.26 (d, J = 5.8 Hz, 4H),
7.27–7.34 (m, 24H), 7.36–7.47 (m, 36H); 13C NMR (CD2Cl2) d
35.4, 43.8, 51.2, 64.2, 128.0, 129.0–129.4 (m), 130.4, 133.6, 135.2,
137.8–139.4 (m), 139.7–141.6 (m). HRMS (ESI) calcd for
½
a 2D0
ꢂ
¼ ꢁ31:1 (c 0.99, CHCl3). To a solution of (R,R)-2b0 (143 mg,
C
100H76Cl2F8Ir2NaO4Si4 (M+Na)+ 2083.3212, found 2083.3207.
0.35 mmol) in THF (6.0 mL) was added PhMgBr (2.0 M in THF,
0.38 mL, 0.77 mmol) at 0 °C, and the solution was allowed to warm
up to room temperature and stirred for 12 h. The resulting mixture
was quenched with H2O and extracted with Et2O. The combined or-
ganic layer was washed with brine, dried over MgSO4, and filtered.
Evaporation of the solvent followed by a flash column chromatogra-
4.9. Procedure for coordination experiments of chiral diene
ligands Bn-tfbꢀ (2c) and Bn-bodꢀ (3)
In an NMR sample tube, [IrCl(coe)2]2 (4.5 mg, 0.010 mmol of Ir),
(R,R)-Bn-tfbꢀ (2c) (8.1 mg, 0.020 mmol), and (R,R)-Bn-bodꢀ (3)

1782
T. Nishimura et al. / Tetrahedron: Asymmetry 19 (2008) 1778–1783
(5.7 mg, 0.020 mmol) were placed under N2, and C6D6 (0.6 mL) was
added at room temperature. Then, the mixture was heated at 50 °C
for 6.5 h. After cooling to room temperature, 1H NMR was mea-
sured to show the complete conversion of [IrCl(coe)2]2 with the
formation of 97% of [IrCl((R,R)-2c)]2 and 3% of [IrCl((R,R)-3)]2. An-
other equilibrium experiment was carried out in C6D6 at 50 °C
for 5 h starting with [IrCl((R,R)-3)]2 (5.1 mg, 0.010 mmol of Ir),
(R,R)-2c (6.1 mg, 0.015 mmol), and (R,R)-3 (1.4 mg, 0.05 mmol).
J = 7.4 Hz, 1H), 7.25–7.29 (m, 2H), 7.29–7.36 (m, 1H); 13C NMR
(CDCl3) d 46.6, 47.3, 53.6, 74.5, 112.9, 124.50, 124.52, 126.4,
127.8, 127.8, 128.5, 130.5, 137.8, 145.3, 146.4, 146.9. HRMS (ESI)
calcd for C18H18O1Na1 (M+Na)+ 273.1250, found 273.1244.
4.11.2. (1S,2R,3R)-2-Hexyl-3-vinyl-2,3-dihydro-1H-inden-1-ol
6c [CAS: 944382-94-9 for the racemic compound 6c]
White solid. The ee was measured by HPLC (Chiralcel OD-H col-
umn ꢃ 2,
hexane/2-propanol = 98:2,
0.3 mL/min,
254 nm,
4.10. Procedure for iridium-catalyzed asymmetric annulation
of isoprene with 2-formylphenylboronic acid
t1 = 42.9 min (minor), t2 = 53.6 min (major)). ½a D20
ꢂ
¼ þ80:0 (c 0.89,
CHCl3) for 93% ee. 1H NMR (CDCl3) d 0.90 (t, J = 6.8 Hz, 3H), 1.25–
1.43 (m, 6H), 1.45–1.61 (m, 2H), 1.61–1.79 (m, 2H), 1.87 (dd,
J = 8.2, 1.8 Hz, 1H), 1.91–1.99 (m, 1H), 3.27 (dd, J = 8.9, 8.8 Hz,
1H), 4.84 (t, J = 7.8 Hz, 1H), 5.18 (dd, J = 9.7, 1.9 Hz, 1H), 5.21
(ddd, J = 17.1, 1.9, 0.9 Hz, 1H), 5.79 (ddd, J = 17.1, 9.7, 8.9 Hz, 1H),
7.09–7.16 (m, 1H), 7.23–7.31 (m, 2H), 7.36–7.43 (m, 1H); 13C
NMR (CDCl3) d 14.2, 22.8, 27.9, 29.9, 31.9, 32.4, 53.4, 57.6, 80.7,
116.6, 123.8, 124.5, 127.4, 128.3, 140.5, 143.8, 144.6.
[IrCl(coe)2]2 (6.7 mg, 0.015 mmol of Ir) and a chiral diene
(0.030 mmol) were dissolved in benzene (2.0 mL), and the mixture
was heated at 60 °C for 1 h. After being cooled to room tempera-
ture, the reaction mixture was concentrated under reduced
pressure. To the residue were added successively 2-form-
ylphenylboronic acid (90.0 mg, 0.60 mmol), toluene (0.90 mL), tri-
ethylamine (105 mL, 0.75 mmol), and isoprene (20.4 mg,
0.30 mmol), and the mixture was heated at 60 °C for 12 h. The mix-
ture was quenched with H2O and extracted with Et2O. The com-
bined organic layer was dried over MgSO4, filtered, and
concentrated on a rotary evaporator. The residue was purified by
a flash column chromatography on silica gel with hexane/EtOAc
(10:1) as an eluent to give (1S,3S)-3-methyl-3-vinyl-2,3-dihydro-
1H-inden-1-ol 6a [CAS: 944382-93-8 for the racemic compound
6a]. The absolute configuration of 6a was determined by X-ray
crystallographic analysis of the corresponding N-tosylcarbamate
of 6a (vide infra). The ee was measured by HPLC (Chiralcel OD-H
column, hexane/2-propanol = 98:2, 0.8 mL/min, 254 nm, t1 = 16.6
4.11.3. (1S,2R,3R)-2-[2-(tert-Butyldimethylsiloxy)ethyl]-3-
vinyl-2,3-dihydro-1H-inden-1-ol 6d
White solid. The ee was measured by HPLC (Chiralcel OD-H col-
umn ꢃ 2,
hexane/2-propanol = 150:1,
0.3 mL/min,
224 nm,
t1 = 43.3 min (minor), t2 = 45.6 min (major)). ½a D20
ꢂ
¼ þ39:9 (c 0.97,
CHCl3) for 92% ee. 1H NMR (CDCl3) d 0.13 (s, 3H), 0.14 (s, 3H),
0.95 (s, 9H), 1.69–1.79 (m, 1H), 1.90–2.01 (m, 2H), 3.20 (t,
J = 9.3 Hz, 1H), 3.76 (ddd, J = 10.7, 10.6, 2.6 Hz, 1H), 3.99 (dt,
J = 10.7, 4.0 Hz, 1H), 4.53 (d, J = 2.6 Hz, 1H), 4.87 (dd, J = 7.9,
2.6 Hz, 1H), 5.20 (dd, J = 16.7, 1.9 Hz, 1H), 5.21 (dd, J = 10.2,
1.9 Hz, 1H), 5.74 (ddd, J = 16.7, 10.2, 9.3 Hz, 1H), 7.09 (d,
J = 7.3 Hz, 1H), 7.19–7.30 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H); 13C
NMR (CDCl3) d ꢁ5.3, ꢁ5.1, 18.5, 26.1, 34.6, 53.6, 57.9, 64.0, 79.7,
117.5, 123.7, 123.9, 127.4, 127.7, 139.5, 143.0, 144.4. HRMS (ESI)
calcd for C19H30O2Si1Na1 (M+Na)+ 341.1907, found 341.1905.
min (major), t2 = 21.7 min (minor)). ½a D20
¼ þ30:3 (c 1.06, CHCl3)
ꢂ
for 95% ee. 1H NMR (CDCl3) d 1.34 (s, 3H), 1.80 (br d, J = 8.2 Hz,
1H), 2.09 (dd, J = 13.3, 5.0 Hz, 1H), 2.36 (dd, J = 13.3, 6.6 Hz, 1H),
4.97 (dd, J = 17.3, 1.2 Hz, 1H), 5.03 (dd, J = 10.7, 1.2 Hz, 1H), 5.20–
5.26 (m, 1H), 6.14 (dd, J = 17.3, 10.7 Hz, 1H), 7.13–7.17 (m, 1H),
7.26–7.34 (m, 2H), 7.40–7.45 (m, 1H); 13C NMR (CDCl3) d 26.2,
48.7, 50.7, 74.8, 111.9, 123.8, 124.6, 127.5, 128.7, 144.2, 147.5,
149.1.
4.11.4. Methyl 2-[(1S,2R,3R)-1-hydroxy-3-vinyl-2,3-dihydro-1H-
inden-2-yl]acetate 6e
Colorless oil. The ee was measured by HPLC (Chiralcel OD-H col-
umn, hexane/2-propanol = 95:5, 0.4 mL/min, 254 nm, t1 = 14.2 min
4.11. General procedure for iridium-catalyzed asymmetric
annulation of 1,3-dienes with potassium 2-formylphenyl-
trifluoroborate
(minor), t2 = 15.9 min (major)). ½a D20
¼ þ94:4 (c 1.05, CHCl3) for
ꢂ
92% ee. 1H NMR (CDCl3) d 2.30 (dddd, J = 10.1, 9.4, 7.7, 4.2 Hz,
1H), 2.63 (dd, J = 16.4, 10.1 Hz, 1H), 2.84 (dd, J = 16.4, 4.2 Hz, 1H),
3.26 (dd, J = 9.4, 9.1 Hz, 1H), 3.73 (s, 3H), 3.81 (d, J = 3.8 Hz,
1H), 4.99 (dd, J = 7.7, 3.8 Hz, 1H), 5.22 (ddd, J = 16.6, 1.7, 0.7 Hz,
1H), 5.23 (ddd, J = 10.3, 1.7, 0.5 Hz, 1H), 5.75 (ddd, J = 16.6, 10.3,
9.1 Hz, 1H), 7.10 (d, J =7.3 Hz, 1H), 7.22–7.32 (m, 2H), 7.43 (d,
J = 7.1 Hz, 1H); 13C NMR (CDCl3) d 36.2, 52.1, 53.0, 53.2, 79.8,
118.0, 123.9, 124.1, 127.7, 128.2, 138.8, 142.3, 143.9, 174.9. HRMS
(ESI) calcd for C14H16O3Na1 (M+Na)+ 255.0992, found 255.0993.
[IrCl(coe)2]2 (6.7 mg, 0.015 mmol Ir) and (R,R)-2d (24.1 mg,
0.030 mmol) were dissolved in benzene (2.0 mL), and the mixture
was heated at 60 °C for 1 h. After being cooled to room tempera-
ture, the reaction mixture was concentrated under reduced
pressure. To the residue were added successively potassium
2-formylphenyltrifluoroborate (127 mg, 0.60 mmol), toluene
(0.90 mL), H2O (0.23 mL), triethylamine (105 mL, 0.75 mmol), and
a 1,3-diene (0.30 mmol), and the mixture was heated at 60 °C for
12 h. The mixture was quenched with H2O and extracted with
Et2O. The combined organic layer was dried over MgSO4, filtered,
and concentrated on a rotary evaporator. The residue was purified
by a flash column chromatography on silica gel with hexane/EtOAc
as an eluent.
4.12. Transformation of 6a into (1S,3S)-3-methyl-3-vinyl-2,3-
dihydro-1H-inden-1-yl tosylcarbamate 7
To a solution of 6a (39.7 mg, 0.23 mmol) in pyridine (3 mL) was
added p-toluenesulfonyl isocyanate (0.30 mL, 2.0 mmol), and the
mixture was stirred at room temperature for 12 h. The mixture
was quenched with H2O and extracted with CH2Cl2. The combined
organic layer was dried over MgSO4 and filtered. Evaporation of the
solvent followed by a flash column chromatography on silica gel
with hexane/EtOAc (3:1) gave compound 7 (60.3 mg, 71% yield,
>99% ee) as a white solid. Colorless crystals of 7 suitable for X-
ray crystallographic analysis were obtained by recrystallization
from 1,4-dioxane/hexane. The crystal structure has been deposited
at the Cambridge Crystallographic Data Centre (deposition num-
ber: CCDC 680000). This analysis determined compound 6a to be
a (1S,3S)-enantiomer. The ee was measured by HPLC (Chiralcel
4.11.1. (1S,3S)-3-Benzyl-3-vinyl-2,3-dihydro-1H-inden-1-ol 6b
Pale yellow oil. The ee was measured by HPLC (Chiralcel OD-H
column, hexane/2-propanol = 98:2, 0.4 mL/min, 254 nm, t1 = 21.4
min (major), t2 = 24.3 min (minor)). ½a D20
¼ þ56:9 (c 0.84, CHCl3)
ꢂ
for 94% ee. 1H NMR (CDCl3) d 1.73 (br s, 1H), 1.96 (dd, J = 13.3,
5.8 Hz, 1H), 2.57 (dd, J = 13.3, 7.0 Hz, 1H), 2.93 (d, J = 13.3 Hz,
1H), 2.94 (d, J = 13.3 Hz, 1H), 4.42–4.55 (m, 1H), 5.01 (dd, J = 17.4,
0.8 Hz, 1H), 5.11 (dd, J = 10.7, 0.8 Hz, 1H), 6.25 (dd, J = 17.4,
10.7 Hz, 1H), 6.78–6.85 (m, 2H), 7.09–7.17 (m, 3H), 7.19 (d,

T. Nishimura et al. / Tetrahedron: Asymmetry 19 (2008) 1778–1783
1783
Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54; (e) Shintani, R.;
Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem., Int. Ed. 2007, 46, 7277.
4. For selected examples of chiral diene ligands for asymmetric reactions, see: (a)
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125,
11508; (b) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7,
307; (c) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T. Tetrahedron: Asymmetry
2005, 16, 1673; (d) Kina, A.; Ueyama, K.; Hayashi, T. Org. Lett. 2005, 7, 5889; (e)
Noël, T.; Vandyck, K.; Van der Eycken, J. Tetrahedron 2007, 63, 12961; (f) Wang,
Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336; (g)
Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. Adv. Synth. Catal.
2007, 349, 2331; (h) Läng, F.; Breher, F.; Stein, D.; Grützmacher, H.
Organometallics 2005, 24, 2997.
5. For examples of the reactions using chiral dienes, see: (a) Takahashi, A.; Aso,
M.; Tanaka, M.; Suemune, H. Tetrahedron 2000, 56, 1999; (b) Grundl, M. A.;
Kennedy-Smith, J. J.; Trauner, D. Organometallics 2005, 24, 2831.
6. Nishimura, T.; Yasuhara, Y.; Hayashi, T. J. Am. Chem. Soc. 2007, 129,
7506.
OD-H column, hexane/2-propanol/Et2NH = 9:1:0.1, 0.4 mL/min,
254 nm,
t1 = 18.0 min
(major),
t2 = 34.0 min
(minor)).
½
a 2D0
ꢂ
¼ ꢁ17:2 (c 0.55, CHCl3) for >99% ee. 1H NMR (CDCl3) d 1.33
(s, 3H), 2.12 (dd, J = 14.1, 4.0 Hz, 1H), 2.34 (dd, J = 14.1, 6.9 Hz,
1H), 2.44 (s, 3H), 4.97 (dd, J = 17.2, 0.9 Hz, 1H), 4.99 (dd, J = 10.6,
0.9 Hz, 1H), 5.98 (dd, J = 17.2, 10.6 Hz, 1H), 6.11 (dd, J = 6.9,
4.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.18–7.24 (m, 1H), 7.24–7.30
(m, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.30–7.36 (m, 1H), 7.46–7.56 (br
s, 1H), 7.87 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3) d 21.8, 26.2, 46.7,
48.9, 79.9, 111.7, 123.9, 125.8, 127.5, 128.6, 129.7, 129.9, 135.6,
138.7, 145.1, 145.9, 150.5, 150.6. HRMS (ESI) calcd for
C
20H21N1Na1O4S1 (M+Na)+ 394.1083, found 394.1086.
7. For an review, see: (a) Esteruelas, M. A.; Oro, L. A. Coord. Chem. Rev. 1999, 193–
195, 557; For selected early examples of the synthesis of iridium–
tetrafluorobenzobarrelene complexes, see: (b) Uson, R.; Oro, L. A.; Carmona,
D.; Esteruelas, M. A.; Foces-Foces, C.; Cano, F. H.; Garcia-Blanco, S. J. Organomet.
Chem. 1983, 254, 249; (c) Uson, R.; Oro, L. A.; Carmona, D.; Esteruelas, M. A.
Inorganica. Chim. Acta 1983, 73, 275; (d) Uson, R.; Oro, L. A.; Carmona, D.;
Esteruelas, M. A. J. Organomet. Chem. 1984, 263, 109; (e) Uson, R.; Oro, L. A.;
Carmona, D.; Esteruelas, M. A.; Foces-Foces, C.; Cano, F. H.; Garcia-Blanco, S.;
Vazquez de Miguel, A. J. Organomet. Chem. 1984, 273, 111.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research from the MEXT, Japan. Y.Y. thanks a research fellowship
of the Japan Society for the Promotion of Science for Young
Scientists.
8. (a) Brewer, J. P. N.; Heaney, H. Tetrahedron Lett. 1965, 4709; (b) Brewer, J. P. N.;
Eckhard, I. F.; Heaney, H.; Marples, B. A. J. Chem. Soc. (C) 1968, 664; (c)
Callander, D. D.; Coe, P. L.; Tatlow, J. C.; Uff, A. J. Tetrahedron 1969, 25, 25.
9. (a) Saeed, I.; Shiotsuki, M.; Masuda, T. Macromolecules 2006, 39, 8567; (b)
Saeed, I.; Shiotsuki, M.; Masuda, T. Macromolecules 2006, 39, 8977.
10. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
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