Preparation of C2-symmetric bicyclo[2.2.2]octa-2,5-diene ligands and their use for rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids

Article abstract of DOI:10.1021/jo047831y

(Chemical Equation Presented) C₂-Symmetric bicyclo[2.2.2]octa-2, 5-dienes containing benzyl, phenyl, and substituted phenyl groups at 2 and 5 positions were prepared enantiomerically pure by way of bicyclo[2.2.2]octane-2, 5-dione as a key intermediate. These chiral diene ligands were successfully applied to rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones. High enantioselectivity (up to 99% ee) as well as high catalytic activity was observed in the addition to both cyclic and linear substrates.

Full text of DOI:10.1021/jo047831y

Preparation of C2-Symmetric Bicyclo[2.2.2]octa-2,5-diene Ligands
and Their Use for Rhodium-Catalyzed Asymmetric 1,4-Addition of
Arylboronic Acids
Yusuke Otomaru, Kazuhiro Okamoto, Ryo Shintani, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received December 9, 2004
C2-Symmetric bicyclo[2.2.2]octa-2,5-dienes containing benzyl, phenyl, and substituted phenyl groups
at 2 and 5 positions were prepared enantiomerically pure by way of bicyclo[2.2.2]octane-2,5-dione
as a key intermediate. These chiral diene ligands were successfully applied to rhodium-catalyzed
asymmetric 1,4-addition of arylboronic acids to R,â-unsaturated ketones. High enantioselectivity
(up to 99% ee) as well as high catalytic activity was observed in the addition to both cyclic and
linear substrates.
Introduction
1,4-addition.5 The bicyclo[2.2.1]heptadiene skeleton, on
which our chiral diene Bn-nbd* is based, was found to
have a drawback in that the dienes substituted with aryl
groups at 2 and 5 positions are not stable enough to be
handled in the air under light. Very recently, we re-
ported6 (1R,4R)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene
(Ph-bod*) and its dibenzyl-substituted analogue (Bn-
bod*) as a new family of C2-symmetric chiral diene
ligands and their application to two types of rhodium-
catalyzed asymmetric addition of arylboron reagents: one
is asymmetric arylation of N-tosylarylimines giving dia-
rylmethylamines6 and the other is asymmetric arylative
cyclization of alkynals.7 Here we wish to report a full
description of the preparation of enantiomerically pure
2,5-disubstituted bicyclo[2.2.2]octa-2,5-dienes (R-bod*)
and their use for the rhodium-catalyzed asymmetric 1,4-
addition of arylboronic acids to R,â-unsaturated ketones.8
Successful use of chiral dienes as a new type of chiral
ligand is one of the most significant developments in the
research field of asymmetric catalysis. They have been
demonstrated to be highly effective for some of the
asymmetric reactions catalyzed by late transition metal
complexes.1 In 2003, we prepared, as a first example of
the chiral diene ligand, (1R,4R)-2,5-dibenzylbicyclo[2.2.1]-
hepta-2,5-diene (Bn-nbd*)2 using palladium-catalyzed
asymmetric hydrosilylation of norbornadiene as a key
step. This C2-symmetric diene ligand showed high enan-
tioselectivity in rhodium-catalyzed asymmetric addition
of organoboronic acids to R,â-unsaturated ketones2 and
fumaric and maleic compounds.3 Next year Carreira
reported C1-symmetric bicyclo[2.2.2]octadienes and their
successful use for iridium-catalyzed kinetic resolution of
allyl carbonates4 and the rhodium-catalyzed asymmetric
* To whom correspondence should be addressed. Phone: 81-75-753-
3983. Fax: 81-75-753-3988.
(5) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett.
2004, 6, 3873.
(6) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
(7) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 54.
(8) For reviews: (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003,
103, 2829. (b) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169. (c)
Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem.,
Int. Ed. 2001, 40, 3284. (d) Hayashi, T. Synlett 2001, 879.
(1) For a short review: Glorius, F. Angew. Chem., Int. Ed. 2004,
43, 3364.
(2) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508.
(3) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett.
2004, 6, 3425.
(4) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
10.1021/jo047831y CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/24/2005
J. Org. Chem. 2005, 70, 2503-2508
2503

Otomaru et al.
SCHEME 1a
(-)-1, whose enantiomeric purity was determined to be
97.5% ee by an HPLC analysis with a chiral stationary
phase column. Its recrystallization from ethanol provided
the enantiomerically pure (>99% ee) diketone (R,R)-1.
The absolute configuration (R,R) was assigned by com-
parison of its optical rotation with the literature value.12
Ditriflate formation followed by palladium-catalyzed
cross-coupling of (R,R)-ditriflate 2 with PhCH2MgBr and
PhMgBr gave (1R,4R)-(+)-2,5-dibenzylbicyclo[2.2.2]octa-
2,5-diene ((R,R)-Bn-bod* (3a)) and (1R,4R)-(-)-2,5-
diphenylbicyclo[2.2.2]octa-2,5-diene ((R,R)-Ph-bod* (3b)),
respectively. It is remarkable that bicyclo[2.2.2]octadiene
ditriflate 2 can be isolated as a stable compound and can
be used for the subsequent cross-coupling reaction while
its norbornadiene analogue, bicyclo[2.2.2]heptadiene
ditriflate, readily undergoes decomposition during the
workup.2
Some of the chiral dienes 3 were found to be optically
resolved by use of a chiral stationary phase column
(Chiralcel OJ) of a preparative size (route B). Both
enantiomers of 3a and 3b were obtained in an enantio-
merically pure form. The enantiomers of C2-symmetric
chiral dienes substituted with 2-methylphenyl (3c) and
3,5-dimethylphenyl (3d) groups were also separated
efficiently by the chiral HPLC technique. Route C shows
the preparation route by way of optical resolution of
ditriflate 2. This route is particularly useful for the diaryl-
substituted dienes whose enantiomers are not separable
using the chiral HPLC columns. Enantiomerically pure
(R,R)-dienes containing 4-methoxyphenyl (3e) and 4-tri-
fluoromethylphenyl (3f) were obtained through this route.
Considering that the optical resolution of diketone 1 by
recrystallization of the diastereomeric dihydrazone shown
in route A is not very efficient, route B or C is more
practically useful than route A.
Treatment of (S,S)-Ph-bod* (3b) with [RhCl(C2H4)2]2
in CH2Cl2 at room temperature for 30 min gave diene-
rhodium complex [RhCl((S,S)-Ph-bod* (3b))]2, whose X-
ray crystal structure is shown in Figure 1. The steric
difference between a bulky phenyl group and a small
hydrogen on the ligand is effectively dissecting the space
in a C2-fashion, thereby creating a very good chiral
environment around the rhodium.
a Reagents and conditions: (a) R*NHNH2, cat. NaOAc, cat.
AcOH, EtOH, reflux. (b) resolution by recrystallization from
MeOH. (c) 20% H2SO4, reflux. (d) Recrystallization from EtOH;
(e) (i) LDA, THF; (ii) Tf2NPy-2. (f) RMgBr, PdCl2(dppf) (1 mol %),
Et2O, reflux. (g) Resolution by HPLC with Chiralcel OJ (hexane/
2-propanol).
Results and Discussion
The synthetic routes to the C2-symmetric chiral dienes,
2,5-disubstituted bicyclo[2.2.2]octa-2,5-dienes, are shown
in Scheme 1. The key compound in this reaction scheme
is racemic bicyclo[2.2.2]octane-2,5-dione (dl-1), which was
readily obtained by Diels-Alder cycloaddition of 2-ac-
etoxypropenenitrile with a trimethylsilyl enol ether
derived from 2-cyclohexenone according to the reported
procedures.9 The diketone 1 was treated with excess
lithium diisopropylamide (LDA) and N-(2-pyridyl)-
triflimide to give 70% yield of di(alkenyl triflate) 2, which
was subjected to the cross-coupling with the Grignard
reagents (RMgBr) catalyzed by PdCl2(dppf)10 leading to
the corresponding 2,5-disubstituted bicyclo[2.2.2]octa-
2,5-dienes 3 in high yields.
The enantiomerically pure dienes 3 were obtained
through optical resolution of either diketone 1 (route A),
dienes 3 themselves (route B), or ditriflate 2 (route C).
In route A, racemic diketone dl-1 was converted into a
diastereomeric mixture of dihydrazones by condensation
with (R)-5-(1-phenylethyl)semioxamazide11 and fractional
recrystallization of the dihydrazone from methanol gave
one of the diastereomeric isomers with high selectivity.
Acidic hydrolysis of this dihydrazone gave diketone (R,R)-
The C2-symmetric bicyclo[2.2.2]octa-2,5-dienes 3 con-
taining substituents at 2 and 5 positions were examined
as chiral ligands for the rhodium-catalyzed asymmetric
1,4-addition of arylboronic acids 5 to R,â-unsaturated
ketones 4 (Scheme 2).8,13-15 As a general procedure, to a
solution containing an arylboronic acid 5 (0.60 mmol) and
(12) Some other methods for the optical resolution of diketone 1 have
been reported: (a) Hill, R. K.; Morton, G. H.; Peterson, J. R.; Walsh,
J. A.; Paquette, L. A. J. Org. Chem. 1985, 50, 5528. (b) Naemura, K.;
Takahashi, N.; Tanaka, S.; Ida, H. J. Chem. Soc., Perkin Trans. 1 1992,
2337. (c) Kinoshita, T.; Haga, K.; Ikai, K.; Takeuchi, K.; Okamoto, K.
Tetrahedron Lett. 1990, 31, 4057. (d) Almqvist, F.; Ekman, N.; Frejd,
T. J. Org. Chem. 1996, 61, 3794 and references therein.
(13) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T. Tetrahedron Lett. 1998, 39, 8479. (c) Takaya, Y.; Senda,
T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asym-
metry 1999, 10, 4047. (d) Takaya, Y.; Ogasawara, M.; Hayashi, T.
Tetrahedron Lett. 1999, 40, 6957. (e) Hayashi, T.; Senda, T.; Takaya,
Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591. (f) Hayashi,
T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716. (g)
Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
(14) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
(9) Werstiuk, N. H.; Yeroushalmi, S.; Guan-Lin, H. Can. J. Chem.
1992, 70, 974.
(10) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
(11) Optical resolution of ketones using (R)-5-(1-phenylethyl)semi-
oxamazide has been reported: Leonard, N. J.; Boyer, J. H. J. Org.
Chem. 1950, 15, 42.
2504 J. Org. Chem., Vol. 70, No. 7, 2005

C2-Symmetric Bicyclo[2.2.2]octa-2,5-diene Ligands
TABLE 1. Asymmetric 1,4-Addition of Phenylboronic
Acid (5m) to Enones 4a and 4d Catalyzed by
[RhCl(C2H4)2]2/Dienes (3)a
[yield (%)]b % eec (config)
entry
ligand
6am
6dm
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
[97] 95 (R)
[97] 96 (R)
[97] 83 (R)
[99] 81 (R)
[99] 95 (R)
[96] 94 (R)
[97] 94 (R)
[95] 85 (R)
[89] 78 (R)
[88] 87 (R)
[91] 78 (R)
[90] 92 (R)
a The reaction was carried out with enone 4a or 4d (0.30 mmol),
phenylboronic acid (5m, 0.60 mmol), [RhCl(C2H4)2]2 (3 mol % Rh),
diene (3, diene/Rh ) 1.1/1.0), and 1.5 M aq KOH (0.10 mL) in
dioxane (1.0 mL) at 30 °C for 1 h. b Isolated yield after silica gel
chromatography. c Determined by HPLC analysis with a chiral
stationary phase column (Chiralcel OD-H: hexane/2-propanol )
98/2).
FIGURE 1. ORTEP illustration of [RhCl((S,S)-Ph-bod* (3b))]2
with thermal ellipsoids drawn at the 50% probability level
(shown as a monomer for clarity). The ORTEP for the whole
dimeric molecule is shown in the Supporting Information.
SCHEME 2
which were chosen as a typical cyclic enone and a typical
acyclic enone, respectively. The addition to 2-cyclo-
hexenone (4a) proceeded smoothly at 30 °C with all of
the diene ligands to give high yields (>96%) of 3-phenyl-
cyclohexanone (6am) whose absolute configuration is R.
Highest enantioselectivity (96% ee) was observed with
Ph-bod* (3b). Bn-bod* (3a) and diaryl-dienes containing
para substituents 3e and 3f also exhibited high en-
antioselectivities (94-95% ee) while diaryl-dienes sub-
stituted at ortho or meta positions 3c and 3d were less
enantioselective ligands. For the acyclic enone 4d, Bn-
bod* (3a) was more enantioselective than diaryl-substi-
tuted dienes including Ph-bod* (3b), giving 6dm of 94%
ee. Of the diaryl-substituted dienes, that substituted
with 4-trifluoromethylphenyl groups (3f) was better than
the others. It is important that the 1,4-addition was
completed at 30 °C within 1 h. It follows that the catalytic
activity of the diene-rhodium complexes is higher than
that of rhodium complexes coordinated with chiral phos-
phorus ligands, typically binap.14
The dienes Bn-bod* (3a) and Ph-bod* (3b), which
showed the highest enantioselectivity in the asymmetric
1,4-addition to linear enone 4d and cyclic enone 4a,
respectively, were examined for their ability in the
addition to some other linear and cyclic enones and a
cyclic R,â-unsaturated ester. The results are summarized
in Table 2, which also contains the data reported using
Bn-nbd* (7)2 for comparison. In general, the results
obtained with Bn-bod* (3a) are almost the same as those
obtained with Bn-nbd* (7), indicating that the chiral
environments constructed around the rhodium center by
two benzyl groups on the diene ligands are almost the
same irrespective of their diene backbone, bicyclo[2.2.2]-
octadiene (bod) or bicyclo[2.2.1]heptadiene (nbd). Both of
these dibenzyl-substituted dienes 3a and 7 showed high
enantioselectivity for linear enones 4d and 4e (entries 4
and 5), while their enantioselectivity for cyclic enones was
not particularly high. The superiority of Ph-bod* (3b) to
the dibenzyl-substituted dienes was observed for all the
cyclic enones and cyclic enoate examined (entries 1-3
and 6). In particular, cyclopentenone (4b) gave the
phenylation product 6bm with 99% enantioselectivity.
The enantioselectivity was kept high for several types
of arylboronic acids in the 1,4-addition to cyclopentenone
(4b) and 3-nonen-2-one (4e) catalyzed by rhodium com-
plexes coordinated with Ph-bod* (3b) and Bn-bod* (3a),
a chiral diene-rhodium catalyst16 (3 mol %) generated
from [RhCl(C2H4)2]2 and a chiral diene ligand (R,R)-3 in
dioxane (1.0 mL) was added enone 4 (0.30 mmol) and 1.5
M aqueous KOH (0.1 mL), and the mixture was stirred
at 30 °C for 1 h. The 1,4-addition product 6 was isolated
by silica gel chromatography after the filtration through
a pad of silica gel. Table 1 summarizes the results
obtained for the addition of phenylboronic acid (5m) to
2-cyclohexenone (4a) and 5-methyl-3-hexene-2-one (4d),
(15) (a) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem.
2000, 65, 5951. (b) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66,
8944. (c) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921.
(d) Kuriyama, M.; Nagai, K.; Yamada, K.-i.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932. (e) Reetz, M. T.;
Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083. (f) Amengual, R.;
Michelet, V.; Geneˆt, J.-P. Synlett 2002, 1791. (g) Pucheault, M.; Darses,
S.; Geneˆt, J.-P. Tetrahedron Lett. 2002, 43, 6155. (h) Pucheault, M.;
Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2002, 3552. (i) Itooka, R.;
Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000. (j) Boiteau, J.-
G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681,
1385. (k) Shi, Q.; Xu, L.; Li, X.; Jia, X.; Wang, R.; Au-Yeung, T. T.-L.;
Chan, A. S. C.; Hayashi, T.; Cao, R.; Hong, M. Tetrahedron Lett. 2003,
44, 6505. (l) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett 2003, 1040.
(m) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003,
68, 9481. (n) Ma, Y.; Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B.
Angew. Chem., Int. Ed. 2003, 42, 5871.
(16) We presume the formation of [Rh(OH)(3)]2 as an active catalyst.
J. Org. Chem, Vol. 70, No. 7, 2005 2505

Otomaru et al.
TABLE 2. Asymmetric 1,4-Addition of Phenylboronic
Acid (5m) to Enones 4 Catalyzed by [RhCl(C2H4)2]2/
(R,R)-dienes (3a, 3b, and 7)a
SCHEME 4
[yield (%)]b % eec (config)
product
entry
6
Bn-bod* (3a) Ph-bod* (3b) Bn-nbd* (7)
1
6am
6bm
6cm
6dm
6em
6fm
[97] 95 (R)
[94] 86 (R)
[91] 91 (R)
[97] 94 (R)
[94] 98 (S)
[79] 65 (R)
[97] 96 (R)
[97] 99 (R)
[95] 92 (R)
[95] 85 (R)
[90] 83 (S)
[75] 95 (R)
[94] 96 (R)d
[88] 88 (R)d
[81] 90 (R)d
[81] 97 (R)d
[84] 95 (S)
[44] 89 (R)
2e
3e
4f
5
6f
a The reaction was carried out with enone 4a-f (0.30 mmol),
phenylboronic acid (5m, 0.60 mmol), [RhCl(C2H4)2]2 (3 mol % Rh),
diene (3a, 3b, and 7, diene/Rh ) 1.1/1.0), and 1.5 M aq KOH (0.10
mL) in dioxane (1.0 mL) at 30 °C for 1 h. b Isolated yield after
silica gel chromatography. c Determined by HPLC analysis with
chiral stationary phase columns: Chiralcel OD-H for 6am, 6cm,
6dm, and 6em; OB-H for 6bm; OG for 6fm. d Reported in ref 2.
e At 50 °C. f For 3 h.
Conclusions
SCHEME 3a
We described the preparation of enantiomerically pure
C2-symmetric bicyclo[2.2.2]octa-2,5-dienes which bear
benzyl, phenyl, and substituted phenyl groups at 2 and
5 positions. These chiral diene ligands showed high
enantioselectivity (up to 99% ee) in the rhodium-
catalyzed asymmetric 1,4-addition of arylboronic acids
to R,â-unsaturated ketones. We are currently applying
these chiral diene ligands to a variety of catalytic
asymmetric reactions, especially to those where the chiral
diene ligands are more suitable than other types of
ligands in catalytic activity. The rhodium-catalyzed ad-
dition reactions to fumaric/maleic compounds,3 N-sul-
fonylimines,6 and alkynals7 are some of the examples.
Experimental Section
Preparation of 2,5-Disubstituted Bicyclo[2.2.2]octa-
2,5-dienes 3. The enantiomerically pure dienes were obtained
by optical resolution of racemic compounds, diketone 1 (route
A), diene 3 (route B), or ditriflate 2 (route C).
a The reaction was carried out for 3 h.
(A) Resolution of Racemic Bicyclo[2.2.2]octane-2,5-
dione (1). To a mixture of bicyclo[2.2.2]octane-2,5-dione (dl-
1) (7.43 g, 53.8 mmol) and (R)-5-(1-phenylethyl)semioxam-
azide11 (22.3 g, 107.6 mmol) in 250 mL of ethanol was added
a small amount of sodium acetate and acetic acid, and the
mixture was heated to reflux for 3 h. After it was cooled to
room temperature, the precipitates formed were collected on
a filter and washed with ethanol. The solid product was
recrystallized three times from methanol to give 3.34 g (12%
yield) of the dihydrazone. For hydrolysis of the hydrazone, a
suspension of the dihydrazone in 100 mL of 20% sulfuric acid
was heated to reflux for 4 h. The reaction mixture was
extracted with CH2Cl2 four times. The combined organic layers
were washed with 0.2 N NaOH twice and then dried over
magnesium sulfate. Removal of the solvent gave the crude
diketone 1, which is 97.5% ee by HPLC analysis with chiral
stationary phase column, Chiralcel OJ (hexane/2-PrOH ) 1/1).
The crude diketone was purified by recrystallization from
ethanol to give 335 mg (4.5% yield) of (1R,4R)-bicyclo[2.2.2]-
octane-2,5-dione ((R,R)-1) as a white solid which is >99% ee
by HPLC analysis. [R]20D -55 (c 1.22, CHCl3) (lit.12d [R]20D +50
(c 0.55, CHCl3) for (S,S)-1).
respectively (Scheme 3). The addition of arylboronic acids
substituted with methoxy (5n) or trifluoromethyl group
(5o) at the para position and methyl group at the ortho
position (5p) all gave the corresponding 1,4-addition
products with over 95% enantioselectivity for both 4b and
4e.
The rhodium complex coordinated with the chiral
bicyclo[2.2.2]octa-2,5-dienes 3 of (R,R) absolute configu-
ration constructs an effective C2-symmetric environment
with the benzyl or aryl substituents located at upper left
and lower right positions (Scheme 4). At the addition of
a phenylrhodium species to enones in the catalytic cycle,17
the olefinic double bond of enones coordinates to the
rhodium in a manner avoiding the steric repulsions
between the substituent on the diene ligand and a
carbonyl moiety of the enones. The alkyl substituent at
the â-position is not a decisive factor on controlling the
enantioface of olefin coordination. Thus, both cyclic
enones and linear enones undergo the phenylrhodation
from their Rre-face giving the 1,4-arylation products of
the observed absolute configuration.
(1R,4R)-2,5-Bis(trifluoromethanesulfonyloxy)bicyclo-
[2.2.2]octa-2,5-diene ((R,R)-2). Lithium diisopropylamide
(LDA) was generated by dropwise addition of a 1.59 M solution
of n-BuLi (692 µL, 1.10 mmol) in hexane to a -78 °C solution
of diisopropylamine (154 µL, 1.10 mmol) in 0.50 mL of THF.
This solution was stirred for an additional 20 min before a
solution of (1R,4R)-bicyclo[2.2.2]octane-2,5-dione ((R,R)-1) (50.0
(17) We have established the catalytic cycle of the rhodium-catalyzed
1,4-addition reactions: see ref 14.
2506 J. Org. Chem., Vol. 70, No. 7, 2005

C2-Symmetric Bicyclo[2.2.2]octa-2,5-diene Ligands
mg, 0.362 mmol) in 1.0 mL of THF was slowly added at -78
°C. The resulting mixture was stirred at -78 °C for an
additional 1 h, before a solution of N-(2-pyridyl)triflimide (394
mg, 1.10 mmol) in 1.0 mL of THF was slowly added at -78
°C. This mixture was warmed to room temperature while being
stirred for 2 days. Ice water was added to quench the reaction
and the organic solvent was removed in vacuo. The aqueous
layer was extracted with Et2O three times. The combined
organic layers were washed with 10% NaOH and then dried
over magnesium sulfate. Removal of the solvent gave the crude
product, which was purified by chromatography on silica gel
column (hexane/diethyl ether ) 10/1) to give 102 mg (70%
yield) of (1R,4R)-2,5-bis(trifluoromethanesulfonyloxy)bicyclo-
[2.2.2]octa-2,5-diene ((R,R)-2) as a colorless oil. 1H NMR
(CDCl3) δ 1.56-1.64 (m, 2H), 1.82-1.90 (m, 2H), 3.69-3.73
(m, 2H), 6.16 (dd, J ) 7.2 and 2.9 Hz, 2H). 13C{1H} NMR
(CDCl3) δ 24.7, 40.2, 118.6 (q, JC-F ) 320 Hz), 119.4, 155.1.
Anal. Calcd for C10H8F6O6S2: C, 29.86; H, 2.00. Found: C,
29.99; H, 2.13.
hexane/2-propanol ) 90/10, flow ) 10 mL/min, wavelength )
1
254 nm. H NMR (CDCl3) δ 1.52-1.64 (m, 4H), 2.30 (s, 6H),
3.83 (dd, J ) 6.2 and 1.9 Hz, 2H), 6.34 (dd, J ) 6.2 and 1.9
Hz, 2H), 7.11-7.20 (m, 8H). 13C{1H} NMR (CDCl3) δ 20.7, 25.5,
43.0, 125.6, 126.7, 128.1, 130.2, 131.1, 135.6, 140.3, 148.4.
Anal. Calcd for C22H22: C, 92.26; H, 7.74. Found: C, 92.40; H,
7.81. [R]20 +178 (c 0.65, CHCl3).
D
(1R,4R)-2,5-Bis(3,5-dimethylphenyl)bicyclo[2.2.2]octa-
2,5-diene ((R,R)-3,5-Me2C6H3-bod* (3d)). Similarly, the
reaction of dl-2 (402 mg, 1.0 mmol) with 3,5-dimethylphenyl-
magnesium bromide (5.31 mL, 1.13 M, 6.0 mmol) and PdCl2-
(dppf) (7.3 mg, 10 µmol) in Et2O gave 257 mg (82% yield) of
racemic 2,5-bis(3,5-dimethylphenyl)bicyclo[2.2.2]octa-2,5-diene
(dl-3d) as a white solid. Enantiomerically pure diene (R,R)-
3d was obtained by separation of the racemic diene on
Chiralcel OJ column with hexane/2-propanol ) 90/10, flow )
10 mL/min, wavelength ) 254 nm. 1H NMR (CDCl3) δ 1.53 (s,
4H), 2.31 (s, 12H), 4.18 (d, J ) 6.3 Hz, 2H), 6.58 (dd, J ) 6.3
and 1.7 Hz, 2H), 6.86 (s, 2H), 7.05 (s, 4H). 13C{1H} NMR
(CDCl3) δ 21.4, 25.8, 40.2, 122.7, 128.4, 128.9, 137.9, 138.3,
146.9. Anal. Calcd for C24H26: C, 91.67; H, 8.33. Found: C,
(1R,4R)-2,5-Dibenzylbicyclo[2.2.2]octa-2,5-diene ((R,R)-
Bn-bod* (3a)). To a mixture of (1R,4R)-2,5-bis(trifluoro-
methanesulfonyloxy)bicyclo[2.2.2]octa-2,5-diene ((R,R)-2) (78.9
mg, 0.20 mmol) and PdCl2(dppf) (1.4 mg, 2.0 µmol) in 1.5 mL
of Et2O was added benzylmagnesium bromide (3.33 mL, 0.36
M, 1.2 mmol) in Et2O at room temperature, and the reaction
mixture was heated to reflux for 24 h. After being cooled to
room temperature, the reaction mixture was quenched with
water and extracted with Et2O. The combined organic layers
were dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by preparative TLC
(silica gel, hexane/ethyl acetate ) 10/1) and GPC to give 33.8
mg (59% yield) of (1R,4R)-2,5-dibenzylbicyclo[2.2.2]octa-2,5-
diene ((R,R)-3a) as a white solid. 1H NMR (CDCl3) δ 1.07-
1.15 (m, 2H), 1.18-1.26 (m, 2H), 3.22-3.28 (m, 2H), 3.43 (s,
4H), 5.82 (dd, J ) 6.1 and 1.2 Hz, 2H), 7.12 (d, J ) 7.6 Hz,
4H), 7.17 (t, J ) 7.6 Hz, 2H), 7.26 (t, J ) 7.6 Hz, 4H). 13C{1H}
NMR (CDCl3) δ 26.1, 40.1, 41.1, 125.9, 128.15, 128.24, 129.0,
139.7, 147.2. Anal. Calcd for C22H22: C, 92.26; H, 7.74.
91.39; H, 8.42. [R]20 -13 (c 0.66, CHCl3).
D
(C) Resolution of Racemic 2,5-Bis(trifluoromethane-
sulfonyloxy)bicyclo[2.2.2]octa-2,5-diene (2). Racemic 2,5-
bis(trifluoromethanesulfonyloxy)bicyclo[2.2.2]octa-2,5-diene (dl-
2) was prepared in the same manner as described above.
Enantiomerically pure ditriflate (R,R)-2 was obtained by
separation of the racemic ditriflate on Chiralcel OJ column
with hexane/2-propanol ) 98/2, flow ) 5 mL/min, wavelength
) 210 nm.
(1R,4R)-2,5-Di(4-methoxyphenyl)bicyclo[2.2.2]octa-2,5-
diene ((R,R)-4-MeOC6H4-bod* (3e)). Grignard cross-coupling
of (R,R)-2 (121 mg, 0.30 mmol) with 4-methoxyphenylmagne-
sium bromide (2.0 mL, 1.2 mmol) and PdCl2(dppf) (2.2 mg, 3.0
µmol) in Et2O for 6 h, followed by aqueous workup and GPC
purification, gave 60.9 mg (64% yield) of (1R,4R)-2,5-di(4-
methoxyphenyl)bicyclo[2.2.2]octa-2,5-diene ((R,R)-3e) as a white
1
solid. H NMR (CDCl3) δ 1.53 (s, 4H), 3.80 (s, 6H), 4.15 (d, J
Found: C, 92.17; H, 7.85. [R]20 +86 (c 0.71, CHCl3).
D
) 6.4 Hz, 2H), 6.51 (dd, J ) 6.4 and 2.1 Hz, 2H), 6.87 (d, J )
8.9 Hz, 4H), 7.37 (d, J ) 8.9 Hz, 4H). 13C{1H} NMR (CDCl3) δ
25.9, 40.0, 55.4, 113.9, 125.9, 127.1, 131.0, 146.5, 158.7. Anal.
Calcd for C22H22O2: C, 82.99; H, 6.96. Found: C, 82.73; H,
(1R,4R)-2,5-Diphenylbicyclo[2.2.2]octa-2,5-diene ((R,R)-
Ph-bod* (3b)). Grignard cross-coupling of (R,R)-2 (78.9 mg,
0.20 mmol) with phenylmagnesium bromide (1.0 mL, 1.2 M,
1.2 mmol) and PdCl2(dppf) (1.4 mg, 2.0 µmol) in Et2O was
carried out at reflux for 8 h in a manner similar to the
preparation of (R,R)-3a. The crude product was purified by
preparative TLC (silica gel, hexane/benzene ) 10/1) to give
39.5 mg (78% yield) of (1R,4R)-2,5-diphenylbicyclo[2.2.2]octa-
7.08. [R]20 -5.0 (c 0.55, CHCl3).
D
(1R,4R)-2,5-Bis(4-trifluoromethylphenyl)bicyclo[2.2.2]-
octa-2,5-diene ((R,R)-4-CF3C6H4-bod* (3f)). Grignard cross-
coupling of (R,R)-2 (121 mg, 0.30 mmol) with 4-trifluorome-
thylphenylmagnesium bromide (2.0 mL, 1.2 mmol) and
PdCl2(dppf) (2.2 mg, 3.0 µmol) in Et2O for 6 h, followed by
aqueous workup and purification by preparative TLC (silica
gel, hexane/benzene ) 20/1), gave 82.9 mg (70% yield) of
(1R,4R)-2,5-bis(4-trifluoromethylphenyl)bicyclo[2.2.2]octa-2,5-
1
2,5-diene ((R,R)-3b) as a white solid. H NMR (CDCl3) δ 1.56
(s, 4H), 4.23 (d, J ) 6.3 Hz, 2H), 6.63 (dd, J ) 6.3 and 2.0 Hz,
2H), 7.22 (t, J ) 7.5 Hz, 2H), 7.32 (t, J ) 7.5 Hz, 4H), 7.44 (d,
J ) 7.5 Hz, 4H). 13C{1H} NMR (CDCl3) δ 25.8, 40.0, 124.7,
126.8, 128.5, 129.1, 138.2, 146.8. Anal. Calcd for C20H18: C,
1
diene ((R,R)-3f) as a white solid. H NMR (CDCl3) δ 1.58, (s,
92.98; H, 7.02. Found: C, 93.03; H, 7.14. [R]20 -30 (c 0.72,
D
4H), 4.26 (d, J ) 6.4 Hz, 2H), 6.75 (dd, J ) 6.4 and 2.0 Hz,
2H), 7.52 (d, J ) 8.3 Hz, 4H), 7.58 (d, J ) 8.3 Hz, 4H). 13C-
{1H} NMR (CDCl3) δ 25.5, 40.1, 124.3 (q, J ) 271 Hz), 125.0,
125.5 (q, J ) 3.8 Hz), 129.0 (q, J ) 32 Hz), 131.4, 141.4, 145.8.
Anal. Calcd for C22H16F6: C, 67.01; H, 4.09. Found: C, 67.08;
CHCl3).
(B) Resolution of Racemic 2,5-Disubstituted Bicyclo-
[2.2.2]octa-2,5-dienes. Racemic 2,5-bis(trifluoromethane-
sulfonyloxy)bicyclo[2.2.2]octa-2,5-diene (dl-2) and dienes dl-
3a and dl-3b were prepared in a same manner as described
above. Enantiomerically pure samples of dienes 3a and 3b
were obtained by separation of the racemic dienes on Chiralcel
OJ column with hexane/2-propanol ) 200/1, flow ) 5 mL/min,
wavelength ) 254 nm, and hexane/2-propanol ) 98/2, flow )
8 mL/min, wavelength ) 254 nm, respectively.
(1R,4R)-2,5-Di(2-methylphenyl)bicyclo[2.2.2]octa-2,5-
diene ((R,R)-2-MeC6H4-bod* (3c)). In a manner similar to
the preparation of (R,R)-3a, cross-coupling of dl-2 (402 mg,
1.0 mmol) with 2-methylphenylmagnesium bromide (6.5 mL,
0.93 M, 6.0 mmol) and PdCl2(dppf) (7.3 mg, 10 µmol) in Et2O
for 24 h gave 207 mg (72% yield) of racemic 2,5-di(2-
methylphenyl)bicyclo[2.2.2]octa-2,5-diene (dl-3c) as a colorless
oil. Enantiomerically pure diene (R,R)-3c was obtained by
separation of the racemic diene on Chiralcel OJ column with
H, 4.18. [R]20 -12 (c 0.84, CHCl3).
D
Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl-
boronic Acids to Enones. The reaction conditions and
results are summarized in Tables 1 and 2, and Scheme 3. A
typical experimental procedure (entry 2 in Table 1) is shown
below: A solution of [RhCl(C2H4)2]2 (1.8 mg, 9.0 µmol Rh),
(1R,4R)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene ((R,R)-3b) (2.6
mg, 9.9 µmol), and phenylboronic acid (5m) (73.2 mg, 0.60
mmol) in 1 mL of dioxane was stirred at room temperature
for 5 min. To this mixture was added 2-cyclohexenone (4a)
(28.8 mg, 0.30 mmol) and aqueous KOH (0.1 mL, 1.5 M, 0.15
mmol). After being stirred at 30 °C for 1 h, the mixture was
passed through a short silica gel column (eluent: diethyl
ether). Evaporation of the solvent followed by preparative TLC
(silica gel, hexane/ethyl acetate ) 3/1) gave 50.8 mg (97% yield)
J. Org. Chem, Vol. 70, No. 7, 2005 2507

Otomaru et al.
of (R)-6am, which is 96% ee. The products 6 obtained by the
rhodium-catalyzed asymmetric 1,4-addition were fully char-
acterized by comparison of their spectral and analytical data
with those reported in the literature: ref 13a for 6am, 6bm,
6cm, 6dm, and 6em. ref 13c for 6fm, and ref 13d for 6bn and
6bo.
Cell constants and an orientation matrix for data collection
corresponded to a primitive monoclinic cell with dimensions
a ) 13.45(1) Å, b ) 19.80(1) Å, c ) 18.97(1) Å, R ) 90°, â )
93.82(3)°, γ ) 90°, V ) 5039.6(6) Å3. For Z ) 6 and fw ) 793.44,
and the calculated density is 1.57 g/cm. Based on the system-
atic absences of 0k0 (k ( 2n), packing considerations, a
statistical analysis of intensity distribution, and the successful
solution and refinement of the structure, the space group was
determined to be P21 (no. 4).
The data were collected at a temperature of -150 ( 1 °C to
a maximum 2θ value of 55.0°. A total of 74 oscillation images
were collected. A sweep of data was done using ω scans from
130.0° to 190.0° in 3.0° steps, at ø ) 45.0° and φ ) 0.0°. The
exposure rate was 90.0 s/deg. A second sweep was performed
using ω scans from 0.0° to 162.0° in 3.0° steps, at ø ) 45.0°
and φ ) 180.0°. The exposure rate was 90.0 s/deg. The crystal-
to-detector distance was 127.40 mm. Readout was performed
in the 0.100 mm pixel mode.
3-(2-Methylphenyl)cyclopentanone (6bp): The ee was
determined on a Chiralcel OD-H column with hexane/2-
propanol ) 98/2, flow ) 0.3 mL/min. 1H NMR (CDCl3) δ 1.97-
2.06 (m, 1H), 2.25-2.42 (m, 3H), 2.38 (s, 3H), 2.44-2.51 (m,
1H), 2.63 (dd, J ) 18.3 and 7.5 Hz, 1H), 3.57-3.65 (m, 1H),
7.13-7.23 (m, 4H). 13C{1H} NMR (CDCl3) δ 19.6, 30.0, 38.3,
38.5, 45.3, 124.7, 126.4, 126.5, 130.6, 135.9, 141.0, 218.6. Anal.
Calcd for C12H14O: C, 82.72; H, 8.10. Found: C, 82.43; H, 8.29.
[R]20 +59 (c 1.00, CHCl3) for the R isomer of 96% ee.
D
4-(4-Methoxyphenyl)nonan-2-one (6en): The ee was
determined on a Chiralcel OJ-H column with hexane/2-
propanol ) 100/1, flow ) 0.5 mL/min. 1H NMR (CDCl3) δ 0.82
(t, J ) 7.0 Hz, 3H), 1.08-1.27 (m, 6H), 1.47-1.62 (m, 2H),
2.00 (s, 3H), 2.65 (dd, J ) 15.9 and 7.1 Hz, 1H), 2.68 (dd, J )
15.9 and 7.3 Hz, 1H), 3.05 (dtd, J ) 9.5, 7.3 and 5.4 Hz, 1H),
3.78 (s, 3H), 6.82 (d, J ) 8.8 Hz, 2H), 7.08 (d, J ) 8.8 Hz, 2H).
13C{1H} NMR (CDCl3) δ 14.0, 22.5, 27.0, 30.6, 31.7, 36.6, 40.6,
51.2, 55.2, 113.8, 128.3, 136.6, 158.0, 208.2. Anal. Calcd for
Of the 48 571 reflections that were collected, 11 826 were
unique (Rint ) 0.021); equivalent reflections were merged. The
linear absorption coefficient, µ, for Mo KR radiation is 11.7
cm-1. The data were corrected for Lorentz and polarization
effects.
C16H24O2: C, 77.38; H, 9.74. Found: C, 77.64; H, 9.91. [R]20
+18 (c 1.02, CHCl3) for the S isomer of 95% ee.
D
The structure was solved by direct methods and expanded
using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using
the riding model. The final cycle of full-matrix least-squares
refinement on F was based on 10 449 observed reflections (I
> 3.00σ(I)) and 1298 variable parameters and converged
(largest parameter shift was 0.00 times its esd) with un-
weighted and weighted agreement factors of R ) ∑||Fo| - |Fc||/
4-(4-Trifluoromethylphenyl)nonan-2-one (6eo): The ee
was determined on a Chiralcel AS column with hexane/2-
propanol ) 500/1, flow ) 0.3 mL/min. 1H NMR (CDCl3) δ 0.83
(t, J ) 6.9 Hz, 3H), 1.03-1.30 (m, 6H), 1.50-1.67 (m, 2H),
2.04 (s, 3H), 2.73 (d, J ) 7.1 Hz, 2H), 3.20 (broad quint, J )
7.3 Hz, 1H), 7.29 (d, J ) 8.0 Hz, 2H), 7.54 (d, J ) 8.0 Hz, 2H).
13C{1H} NMR (CDCl3) δ 14.0, 22.4, 27.0, 30.6, 31.7, 36.2, 40.9,
50.5, 124.3 (q, J ) 271 Hz), 125.4 (q, J ) 3.8 Hz), 127.9, 128.6
(q, J ) 32 Hz), 149.0 (q, J ) 1.5 Hz), 207.1. Anal. Calcd for
2
∑|Fo| ) 0.029, Rw ) [∑w(|Fo| - |Fc|)2/∑wFo ]1/2 ) 0.043.
The standard deviation of an observation of unit weight was
2.12. Unit weights were used. Plots of ∑w(|Fo| - |Fc|)2 versus
|Fo|, reflection order in data collection, sin θ/λ, and various
classes of indices showed no unusual trends. The maximum
and minimum peaks on the final difference Fourier map
corresponded to 5.30 and -3.18 e-/Å3, respectively.
C16H21OF3: C, 67.12; H, 7.39. Found: C, 67.04; H, 7.41. [R]20
D
+8.5 (c 0.93, CHCl3) for the S isomer of 97% ee.
4-(2-Methylphenyl)nonan-2-one (6ep): The ee was de-
termined on a Chiralcel OJ-H column with hexane/2-propanol
1
) 100/1, flow ) 0.3 mL/min. H NMR (CDCl3) δ 0.82 (t, J )
All calculations were performed using the CrystalStructure
crystallographic software package and Tables S1-S12 in the
Supporting Information provide the full crystallographic data
for the X-ray structure.
6.9 Hz, 3H), 1.06-1.27 (m, 6H), 1.50-1.63 (m, 2H), 2.01 (s,
3H), 2.36 (s, 3H), 2.68 (dd, J ) 12.3 and 7.0 Hz, 1H), 2.72 (dd,
J ) 12.3 and 7.3 Hz, 1H), 3.44 (broad quint, J ) 7.3 Hz, 1H),
7.05-7.18 (m, 4H). 13C{1H} NMR (CDCl3) δ 14.0, 19.8, 22.5,
26.9, 30.6, 31.9, 35.7, 36.5, 50.6, 125.5, 125.8, 126.2, 130.4,
136.0, 143.1, 208.1. Anal. Calcd for C16H24O: C, 82.70; H,
Acknowledgment. This work has been supported
in part by a Grant-in-Aid for Scientific Research, the
Ministry of Education, Culture, Sports, Science and
Technology, Japan (21 COE on Kyoto University Alli-
ance for Chemistry).
10.41. Found: C, 82.56; H, 10.51. [R]20 +17 (c 0.96, CHCl3)
D
for the S isomer of 98% ee.
X-ray Crystal Structure of [RhCl((S,S)-3b)]2. A red
dichloromethane solution of [RhCl((S,S)-3b)]2 was prepared.
Crystals suitable for X-ray structural analysis were obtained
by layering with hexane at room temperature. A red prism of
dimensions 0.50 × 0.40 × 0.30 mm3 was mounted on a glass
fiber. All measurements were made on a Rigaku RAXIS
RAPID imaging plate area detector with graphite monochro-
mated Mo KR radiation. Indexing was performed from 3°
oscillations that were exposed for 30 s. The crystal-to-detector
distance was 127.40 mm.
Supporting Information Available: Tables of complete
X-ray crystallographic data for [RhCl((S,S)-3b)]2 and the
corresponding CIF file. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO047831Y
2508 J. Org. Chem., Vol. 70, No. 7, 2005