Expanding the C2-symmetric bicyclo[2.2.1]hepta-2,5-diene ligand family: Concise synthesis and catalytic activity in rhodium-catalyzed asymmetric addition

Article abstract of DOI:10.1021/jo061385s

New C₂-symmetric bicyclo[2.2.1]hepta-2,5-dienes bearing methyl and phenyl substituents at the 2 and 5 positions were prepared enantiomerically pure through a two-step sequence starting from the readily available bicyclo[2.2.1]hepta-2,5-dione. Due to the instability or volatility of these dienes, their isolation was achieved through the formation of the corresponding stable [RhCl(diene)]₂ complexes. These chiral rhodium complexes displayed high activity and enantioselectivity (up to 99% ee) in the rhodium-catalyzed 1,4-addition and 1,2-addition of phenylboronic acid to cyclic enones and N-sulfonylimines, respectively.

Full text of DOI:10.1021/jo061385s

Expanding the C2-Symmetric
tuted [2.2.1] and [2.2.2] bicyclic olefins have emerged as
privileged structures, forming stable rhodium complexes and
displaying consistently high levels of enantiocontrol and activity.
Chiral 2,5-disubstituted bicyclo[2.2.1]heptadienes (nbd*) are
ideal scaffolds as they can be efficiently generated through the
palladium-catalyzed asymmetric hydrosilylation of norborna-
Bicyclo[2.2.1]hepta-2,5-diene Ligand Family:
Concise Synthesis and Catalytic Activity in
Rhodium-Catalyzed Asymmetric Addition
Guillaume Berthon-Gelloz and Tamio Hayashi*
Department of Chemistry, Graduate School of Science,
6
diene. However, attempts to expand the nbd* substitution
pattern to aromatic groups were foiled by the instability of the
resulting 2,5-arylbicyclo[2.2.1]heptadienes (Ar-nbd*).2a These
downfalls with the nbd* backbone led us to investigate the
structurally similar 2,5-disubstituted bicyclo[2.2.2]octadiene
Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
ReceiVed July 4, 2006
(
bod*) ligands of which we have recently reported the
2
e
preparation. The major drawbacks from the synthesis of the
chiral bod* ligands are the low yielding resolution of the key
intermediate, bicyclo[2.2.2]octa-2,5-dione, or the need to sepa-
rate the racemic ligand by chiral HPLC in the final step.
Prompted by the spectacular results obtained with the 2,5-
diphenylbicyclo[2.2.2]octadiene (Ph-bod*) ligand and the very
similar levels of enantiocontrol between Bn-nbd* and Bn-bod*,
we set out to reinvestigate the synthesis of 2,5-disubstituted
bicyclo[2.2.1]heptadienes. We present herein a highly efficient
two-step synthesis of the chiral methyl, benzyl, and phenyl
disubstituted bicyclo[2.2.1]heptadienes, from the easily acces-
sible chiral bicyclo[2.2.2]hepta-2,5-dione. This novel route
allows a rapid access to previously unattainable Me and Ph
substituted bicyclo[2.2.1]hepta-2,5-dienes. The catalytic activity
of the [RhCl(nbd*)]2 complexes in the 1,4-addition of phenyl-
boronic acid to cyclic enones and the 1,2-addition to N-
sulfonylimines is presented.
2
New C -symmetric bicyclo[2.2.1]hepta-2,5-dienes bearing
methyl and phenyl substituents at the 2 and 5 positions were
prepared enantiomerically pure through a two-step sequence
starting from the readily available bicyclo[2.2.1]hepta-2,5-
dione. Due to the instability or volatility of these dienes,
their isolation was achieved through the formation of the
7
,8
2
corresponding stable [RhCl(diene)] complexes. These chiral
rhodium complexes displayed high activity and enantiose-
lectivity (up to 99% ee) in the rhodium-catalyzed 1,4-addition
and 1,2-addition of phenylboronic acid to cyclic enones and
N-sulfonylimines, respectively.
Our previously disclosed synthetic route for Bn-nbd* involved
the circuitous mono acetal protection of chiral diketone (R,R)-
1
2
. This route was chosen because the corresponding bistriflate
proved difficult to isolate. Very recently, Van der Eycken et
7
The recent introduction of chiral diene ligands is a major
landmark in the field of asymmetric catalysis. Chiral diene
al. reported the synthesis of the racemic bistriflate 2 directly
from the corresponding racemic diketone 1, where the combina-
tion of a mild triflating agent (PhNTf2), KHMDS, and low
reaction temperature proved instrumental for the isolation of
1
ligands have displayed higher activity and enantioselectivities
than chiral diphosphine ligands in a number of rhodium- and
iridium-catalyzed reactions.2 Of the several of chiral diene
-4
9
bistriflate 2 in good yield. We were able to further refine these
2
3-5
backbones explored by our group and others,
2,5-disubsti-
reaction conditions to obtain chiral bistriflate (R,R)-2 reproduc-
ibly in over 85% isolated yield on a 10 mmol scale. Thus, a
clean conversion of diketone (R,R)-1 was obtained by slow
addition of a toluene solution of KHMDS onto a mixture of
(
1) For a concise review see: Glorius, F. Angew. Chem., Int. Ed. 2004,
3, 3364.
2) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, H. J. Am. Chem.
4
(
1
0
(R,R)-1 and 2-PyNTf2 in THF (Scheme 1). Bistriflate 2 was
Soc. 2003, 125, 11508. (b) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi,
T. Org. Lett. 2004, 6, 3425. (c) Tokunaga, N.; Otomaru, Y.; Okamoto, K.;
Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
d) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005,
, 307. (e) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org.
Chem. 2005, 70, 2503. (f) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T.
Tetrahedron Asymmetry 2005, 16, 1673. (g) Hayashi, T.; Tokunaga, N.;
Okamoto, K.; Shintani, R. Chem. Lett. 2005, 34, 1480. (h) Shintani, R.;
Kimura, T.; Hayashi, T. Chem. Commun. 2005, 3213. (i) Shintani, R.;
Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757. (j) Shintani, R.;
Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc.
unstable and prone to rapid decomposition (formation of a black
tar) if traces of acid were present, but this could be avoided by
storing 2 over a small amount of anhydrous K2CO3.
(
7
11
With convenient access to bistriflate (R,R)-2, we set forth to
find optimal cross-coupling conditions with Grignard reagents.
From literature precedents, we selected NiCl2(dppe), PdCl2-
12
13
14
15
(dppf), Co(acac)3, and Fe(acac)3 as potential catalysts for
2
005, 127, 54. (k) Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T.
(5) Grundl, M. A.; Kennedy-Smith, J. J.; Trauner, D. Organometallics
2005, 24, 2831.
(6) Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.
The asymmetric hydrosilylation produces a chiral disilylnorbornane of
>99% ee, which is converted into norbornanedione (1) by way of
norbornanediol.
Angew. Chem., Int. Ed. 2005, 44, 3909. (l) Kina, A.; Ueyama, K.; Hayashi,
T. Org. Lett. 2005, 7, 5889. (m) Chen, F.-X.; Kina, A.; Hayashi, T. Org.
Lett. 2006, 8, 341. (n) Nishimura, T.; Yasuhara, Y.; Hayashi, T. Org. Lett.
2
2
006, 8, 979. (o) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc.
006, 128, 5628.
(
3) (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
(7) Smith, B. T.; Wendt, J. A.; Aub e´ , J. Org. Lett. 2002, 4, 2577.
(8) Berkessel, A.; Schr o¨ der, M.; Sklorz, C. A.; Tabanella, S.; Vogl, N.;
Lex, J.; Neud o¨ rfl, J. M. J. Org. Chem. 2004, 69, 3050.
(9) Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt,
L.; Van der Eycken, J. Org. Lett. 2006, 8, 363.
Soc. 2004, 126, 1628. (b) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira,
E. M. Org. Lett. 2004, 6, 3873. (c) Paquin, J.-F.; Defieber, C.; Stephenson,
C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850. (d) Paquin,
J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005,
7
, 3821.
(10) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(11) When stored over K2CO3, bistriflate (R,R)-2 showed no sign of
decomposition at R.T. for several weeks.
(4) L a¨ ng, F.; Breher, F.; Stein, D.; Gr u¨ tzmacher, H. Organometallics
2
005, 24, 2997.
1
0.1021/jo061385s CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/10/2006
J. Org. Chem. 2006, 71, 8957-8960
8957

SCHEME 1. Optimized Synthesis of Bistriflate (R,R)-2
TABLE 2. Iron-Catalyzed Cross-Coupling and
Rhodium-Complexation Sequencea
TABLE 1. Screening of Catalyst Systems for the Grignard
entry
RMgX
product
yield (%)b
a
Cross-Coupling of Bistriflate (R,R)-2 with BnMgCl
1
2
3
BnMgClc
[RhCl((R,R)-Bn-nbd*)]
[RhCl((R,R)-Me-nbd*)]
[RhCl((R,R)-Ph-nbd*)]
2
(5a)
(5b)
(5c)
80
50
55
d
MeMgBr
2
PhMgBre
2
a
Reagent and conditions: (a) (R,R)-2 (1 equiv), RMgX (4 equiv),
Fe(acac)3 (5 mol %), THF/NMP (N-methylpyrrolidinone, 20/1, 0.1 M), 0
b
°
C, 5 min; (b) [RhCl(C2H4)2]2 (0.5 equiv), toluene, 25 °C, 2 h. Isolated
t (h)b
3a/4c
yield (%)d
yield over 2 steps. 2 M in THF. d 1 M in Et2O. e 3 M in Et2O.
c
entry
cat. (mol %)
NiCl (dppe), 1
T (°C)
1
2
3
4
a
2
40
40
0
1
1
0.25
0.25
0.7
0.6
0.6
13
44
45
28
98
PdCl (dppf), 1
Co(acac)
Fe(acac)
2
e
3
, 5
, 5
of the cross-coupling with PhMgBr, the reaction yielded the
desired (R,R)-Ph-nbd* (3c) along with a significant amount of
biphenyl due to the homocoupling of the Grignard reagent.
Although GC/MS analysis of the crude reaction mixture was
very clean, all attempts to obtain a pure sample of (R,R)-Ph-
nbd* (3c) were frustrated by its decomposition in solution and
its contamination by biphenyl. To circumvent the problem
associated with the isolation of (R,R)-Me-nbd* (3b) and (R,R)-
Ph-nbd* (3c), the crude dienes were reacted directly with 0.5
equivalents of [RhCl(C2H4)2]2 in toluene (Table 2). This led to
the formation of the corresponding [RhCl(nbd*)]2 (5a-c)
complexes which could be isolated in analytically pure form
by chromatography on silica gel.
e
3
0
To a mixture of bistriflate (R,R)-2 (0.25 mmol, 1 equiv) and catalyst
in THF (2.5 mL, 0.1 M) was added BnMgCl (1.0 mmol, 1 M in Et2O, 4
equiv) at 0 °C, and the mixture was stirred at the indicated temperature.
Time for complete conversion of (R,R)-2 (GC/MS). Ratio of products
determined by H NMR. Yield calculated from the mixture of (R,R)-3a
b
c
1
d
e
and 4. NMP (1 equiv relative to BnMgCl) used as cosolvent. dppe: 1,2-
bis(diphenylphosphino)ethane; dppf: 1,1′-bis(diphenylphosphino)ferrocene;
NMP: N-methylpyrrolidinone.
the Grignard cross-coupling. As a model reaction, we chose
the reaction of bistriflate (R,R)-2 with four equivalents BnMgCl,
which yields the stable and isolable (R,R)-Bn-nbd* diene. The
results are depicted in Table 1.
To assess whether the Ph-nbd* decomposes when subjected
to light or acid or both, a fresh sample of Ph-nbd* in C6D6 was
shielded from light while another sample was stored over K2-
CO3. Two control samples were prepared; one was left in C6D6
under ambient conditions while the other was kept at -30 °C.
The decomposition rates of the Ph-nbd* samples were monitored
The palladium- and nickel-catalyzed cross-coupling reactions
Table 1, entries 1 and 2) displayed very similar product profiles
(
and proceeded swiftly to lead to complete conversion of the
starting bistriflate (R,R)-2 in less than 1 h (GC/MS analysis).
These reactions were hampered by a significant amount of
1
by H NMR. The decomposition of the Ph-nbd* C6D6 solutions
homocoupling product, 1,2-diphenylethane (4), which consumed
-
3
-1
the excess BnMgCl employed.16 Use of a larger excess of
displayed roughly zero-order kinetics, 5.7 × 10
h
(t1/2 ≈
-
3
-1
7
5 h) and 6.6 × 10
h
(t1/2 ≈ 62 h) for the sample stored
BnMgCl (6 equiv) leads to a higher yield of diene (R,R)-3a,
1
7
over K2CO3 and the sample shielded from light, respectively.
The control sample under ambient conditions decomposed only
but the product is contaminated with several equivalents a 4.
Gratifyingly, the iron-catalyzed reaction provided an almost
quantitative yield of (R,R)-3a in less than 5 min with the end
product being contaminated with only a minute amount of 4 (7
mol %) (Table 1, entry 4).
-
3
-1
slightly faster (8.0 × 10 h , t1/2 ≈ 54 h), although complete
decomposition of Ph-nbd* in CDCl3 occurred in less than 24
h. The sample at -30 °C showed only a small amount of
decomposition after 5 days. The origin of the instability of the
Ph-nbd* is presumably due to the presence of a styrene moiety
in a strained bicyclic[2.2.1] core, and this effectively lowers
π* of the alkene rendering it highly reactive and prone to radical
and acid-catalyzed decomposition. Although it leads to inherent
instability of the ligand, this property is key for increasing the
stability of the corresponding [RhCl(Ph-nbd*)]2 complex.
The rhodium dimer [RhCl(Ph-nbd*)]2 (5c) proved to be
remarkably stable and showed no sign of decomposition when
its toluene solution was exposed to air for several weeks.
Moreover, the melting point of 5c was over 300 °C (in an air
atmosphere) and the complex remained stable at this elevated
temperature. This is in contrast with the [RhCl(Bn-nbd*)]2
complex which slowly decomposed at its melting point (163-
With efficient cross-coupling conditions in hand, we next
turned our attention to the synthesis of Me-nbd* and Ph-nbd*
ligands. Bistriflate (R,R)-2 reacted smoothly with MeMgBr to
yield (R,R)-2,5-dimethylbicyclo[2.2.1]heptadiene ((R,R)-Me-
nbd*, 3b) as a volatile compound which rendered its isolation
18
in an analytically pure form exceedingly difficult. In the case
(
12) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
9
4, 4374. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun.
1
972, 144.
(13) (a) Hayashi, T.; Konishi, M.; Kumada, M. Tetrahedron Lett. 1979,
2
1, 1871. (b) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
(
(
14) Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159.
15) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487.
(
b) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199. (c) Scheiper, B.;
Bonnekessel, M.; Krause, H.; F u¨ rstner, A. J. Org. Chem. 2004, 69, 3943.
16) In the GC/MS analysis of the reaction mixture, a significant amount
1
65 °C). The X-ray crystal structure of [RhCl((R,R)-Ph-nbd*)]2
5c) is depicted in Figure 1. Analysis of the key structural
parameters of 5c reveals a very close resemblance with the
(
(
of monocoupled product in which the triflate function has been reduced is
observed.
2e,f
parent [RhCl((S,S)-Ph-bod*)]2 dimer. Hence, the Rh-Cl bond
distance 2.4001(6) (vs 2.405(3) Å for [RhCl(Ph-bod*)]2), the
alkene bond distance (C(1)-C(2)) 1.407(3) Å (vs. 1.42(1) Å
for [RhCl(Ph-bod*)]2), and the bite angle (C(2)-Rh(1)-C(4))
67.64(9)° (vs. 67.8(3)° for [RhCl(Ph-bod*)]2) are in close
(17) The separation of 4 from 3a is difficult due to the low polarity of
these compounds (Rf > 0.6 in pentane). Thus, minimizing the amount of 4
is necessary for obtaining Bn-nbd* with acceptable purity.
(18) The low molecular weight, 120 g/mol, and its branched structure
contribute to making (R,R)-Me-nbd* a highly volatile compound.
8
958 J. Org. Chem., Vol. 71, No. 23, 2006

TABLE 4. Asymmetric 1,2-Addition of Phenylboronic Acid to
N-Sulfonylimine Catalyzed by [RhCl(nbd*)]2 (5a-c)a
entry
9
[RhCl(nbd*)]
[RhCl(Me-nbd*)]
2
yield (%)b
% eec
89
1
2
3
4
5
9a
9a
9a
9b
9b
9b
2
(5b)
96 (10a)
98 (10a)
96 (10a)
93 (10b)
88 (10b)
92 (10b)
d
[RhCl(Bn-nbd*)]
2
(5a)
(5c)
(5b)
(5a)
(5c)
92
[RhCl(Ph-nbd*)]
[RhCl(Me-nbd*)]
2
99
82
81
2
e
[RhCl(Bn-nbd*)]
[RhCl(Ph-nbd*)]
2
6
2
98
a
The reaction was carried out with 9 (0.10 mmol, 1 equiv), 7 (0.12 mmol,
3
.6 equiv B), [RhCl((nbd*)]2 (5) (3 mol % Rh), and 3.1 M aq KOH (0.02
b
mmol, 6.5 µL, 0.2 equiv) in 1,4-dioxane 0.4 mL) at 60 °C for 6 h. Isolated
yield after silica gel chromatography. c Determined by HPLC analysis with
d
a chiral stationary phase column (Chiracel OD-H). Reported in ref 2c.
2
FIGURE 1. ORTEP illustration of [RhCl((R,R)-Ph-nbd*)] (5c) with
thermal ellipsoids at the 50% probability level (shown as a monomer
for clarity). Selected bond distances (Å) and angles (°): Rh(1)-Cl(2),
e
Reported in ref 2d.
2
1
.4001(6); Rh(1)-C(1), 2.080(2); Rh(1)-C(2), 2.127(2); C(1)-C(2),
.407(3); C(4)-C(5), 1.414(3); C(2)-Rh(1)-C(5), 81.94(8); C(1)-
bulk of the substituents on the nbd* ligand (Table 3, entries 2
and 3) leads to incremental but marginal increase in enantiose-
lectivity. The 1,4-addition to 2-cyclopentenone (6b), a much
more demanding substrate, proved more telling of the difference
of steric effects between (R,R)-Me-nbd* (85% ee) and (R,R)-
Ph-nbd* (96% ee) (Table 3, entries 4 and 5); the latter is close
to the enantioselectivity previously reported with the (R,R)-Ph-
Rh(1)-C(4), 81.19(9); C(2)-Rh(1)-C(4), 67.64(9); C(1)-C(2)-C(4)-
C(5), 1.1(2); C(1)-C(2)-C(14)-C(19), -179.7(2); C(4)-C(5)-C(8)-
C(9), 166.4(2).
TABLE 3. Asymmetric 1,4-Addition of Phenylboronic Acid to
Cyclic Enones Catalyzed by [RhCl(nbd*)]2 (5a-c) Complexesa
2
e
bod* ligand (99% ee).
To gain further insight into the reaction scope offered by the
Me-nbd* and Ph-nbd* ligands, we investigated the rhodium-
catalyzed 1,2-addition of phenylboronic acid to N-sulfonyl-
imines. This reaction is much more sensitive to the size of the
substituents on the diene and on the backbone-type.2 Both
the 1,2-addition to N-tosyl and N-nosyl imines was investigated,
the latter being more synthetically useful though more chal-
lenging.
c,d
yield (%)b
% eec
entry
6
[RhCl(nbd*)]
[RhCl(Me-nbd*)]
2
1
2
3
4
5
6a
6a
6a
6b
6b
2
(5b)
90 (8a)
87 (8a)
89 (8a)
86 (8b)
92 (8b)
95
96
97
85
96
[RhCl(Bn-nbd*)]
2
(5a)
(5c)
(5b)
(5c)
[RhCl(Ph-nbd*)]
[RhCl(Me-nbd*)]
2
2
[RhCl(Ph-nbd*)]
2
The enantioselectivities observed with (R,R)-Me-nbd* and
(R,R)-Bn-nbd* were quite similar for both imines 9a and 9b
(Table 4, entries 1 vs 2 and 4 vs 5). It is remarkable that the
a
The reaction was carried out with 6 (0.5 mmol, 1 equiv), 7 (0.2 mmol,
.2 equiv B), [RhCl((nbd*)]2 (5) (3 mol % Rh), and 1.5 M aq KOH (0.25
1
mmol, 0.17 mL, 0.5 equiv) in 1,4-dioxane (1.7 mL) at 25 °C for 1 h.
(R,R)-Ph-nbd* ligand showed high enantiocontrol in the phe-
b
Isolated yield after silica gel chromatography. c Determined by HPLC
nylation of the imines 9a and 9b (Table 4, entries 3 and 6).
Particularly, the enantioselectivity of 98% ee observed for
N-nosyl imine 9b is striking because the closely related (R,R)-
Ph-bod* ligand only gave 89% ee under the same reactions
analysis with a chiral stationary phase column (Chiracel OD-H for 8a and
Chiracel OB-H for 8b).
agreement. The elongated alkene bond in 5c reveals predominant
back-bonding of the rhodium center onto the alkene. The small
dihedral angle between the double bond and the plane of the
phenyl group (-179.7(2)° and 166.4(2)° for C(1)-C(2)-
C(14)-C(19) and C(4)-C(5)-C(8)-C(9), respectively) indicates
conjugation of the π system; this effect further reinforces the
back-bonding through delocalization and probably accounts for
the higher stability of [RhCl(Ph-nbd*)]2 (5c) over [RhCl(Bn-
nbd*)]2 (5a). The similarities between the solid-state structures
of [RhCl(Ph-nbd*)]2 (5c) and [RhCl(Ph-bod*)]2 is somewhat
2
d
conditions. Thus, subtle steric and electronic differences in
these ligands that are not revealed by comparison of structural
features in the X-ray analysis bring about a significant effect
on the enantioselection process.
In summary, two new rhodium complexes bearing chiral
methyl and phenyl 2,5-disubstituted bicyclo[2.2.1]heptadiene
ligands were synthesized and fully characterized. The synthesis
is highly efficient, and the corresponding rhodium complexes
([RhCl(nbd*)]2) can be isolated in 42-68% yield over three
surprising when one considers the large difference in stability
between the free Ph-nbd* and Ph-bod* dienes.19
steps starting from the readily available (R,R)-2,5-norbornanedi-
one. These new rhodium complexes displayed high levels of
activity and enantioselectivities in the 1,4-addition and 1,2-
addition of phenylboronic acid to cyclic enones and to aryl
N-sulfonyl imines, respectively. The [RhCl(Ph-nbd*)]2 complex
performs exceptionally well in both reactions and leads to
enantioselectivities that are similar or better than the parent
[RhCl(Ph-bod*)]2 complex.
The catalytic activity of these new complexes in the 1,4-
addition of phenylboronic acid to cyclic enones was evaluated
Table 3). The high level of enantiocontrol achieved by [RhCl-
(
(
(R,R)-Me-nbd*)]2 (5b), 95% ee, (Table 3, entry 1) is truly
impressive, given the small size of the Me-nbd* ligand with a
molecular weight of only 120 g/mol and only two methyl groups
effecting the enantiocontrol of the reaction. The increase of steric
J. Org. Chem, Vol. 71, No. 23, 2006 8959

Experimental Section
Preparation of [RhCl((R,R)-Me-nbd*)]
run on 0.50 mmol of (R,R)-2 using a MeMgCl (3 M in Et
solution. Hexane was substituted for pentane. The residual solvent
was carefully evaporated on a rotary evaporator to yield crude (R,R)-
2
(5b). The reaction was
O)
2
Preparation of Bistriflate (R,R)-2. To a solution diketone (R,R)-
(1.24 g, 10 mmol, 1 equiv) and 2-PyNTf
18
10
2
(8.60 g, 24 mmol,
2
.4 equiv) in dry THF (30 mL, 0.30 M) at -78 °C was slowly
1
Me-nbd* (3b). H NMR (CDCl
3
): δ 1.76 (d, J ) 1.8 Hz, 6H),
added KHMDS (44 mL, 0.50 M in toluene, 23 mmol, 2.3 equiv)
affording a clear, light-red solution. Stirring was further continued
for 1 h at -78 °C at which point the reaction turned light brown
1
2
7
.87 (t, J ) 1.7 Hz, 2H), 3.02 (m, 2H), 6.06 (dd (app. t), J ) 1.9,
.0 Hz, 2H) ppm; 13C{ H} NMR (CDCl
1.7 (CH ), 132.5 (CH), 154.9 (C) ppm. Complex 5b was isolated
Cl , 60/
): δ 1.22 (s, 2H),
.73 (d, J ) 11.0 Hz, 6H), 3.47 (d, J ) 1.9 Hz, 2H), 3.55 (d, J )
1
3 3
): 16.9 (CH ), 54.9 (CH),
2
3
and turbid. The reaction was quenched with a sat. NaHCO solution
as an orange solid after flash chromatography (hexane/CH
2
2
at this temperature. After warming to room temperature, the layers
were separated and the aqueous layer was extracted twice with
hexane. The combined organic layers were sequentially washed with
1
4
1
1
0), 65 mg (0.13 mmol, 50%). H NMR (CDCl
3
.5 Hz, 2H) ppm; 13C{ H} NMR (CDCl
1
): 20.3 (d, JC-Rh ) 2 Hz,
), 46.9 (d, JC-Rh ) 10.9 Hz, CH), 55.6 (d, JC-Rh ) 3.6 Hz,
), 58.6 (d, JC-Rh ) 7.8 Hz, CH), 66.5 (d, JC-Rh ) 11.3 Hz, C)
3
5
% NaOH solution (until the aqueous layer remained colorless),
CH
CH
3
water, and brine. The organic layer was dried over K CO . The
2
3
2
crude product was purified by flash chromatography over silica
gel (hexane/ethyl acetate 95/5) affording 3.30 g (8.5 mmol, 85%)
of bistriflate (R,R)-2 as a colorless oil. To avoid decomposition,
D
ppm; [R] 25 -285 (c 0.6, CHCl
for C18 Rh : C, 41.81, H, 4.68; found C, 42.08, H, 4.55.
Preparation of [RhCl((R,R)-Ph-nbd*)] (5c). The reaction was
run on 0.50 mmol of (R,R)-2 using a solution of PhMgBr (2.5 M
3
); mp 137-139 °C; anal. calcd
H24Cl
2
2
the product was stored over K
2
CO
reported in ref 9. H NMR (CDCl
.51 (m, 2H), 6.49 (dd (app. t), J ) 2.4, 2.4 Hz, 2H) ppm; C-
3
. Racemic bistriflate 2 has been
): δ 2.60 (t, J ) 1.8 Hz, 2H),
2
1
3
1
13
2 3
in Et O) to yield crude Ph-nbd* (3c). H NMR (CDCl ): δ 2.31 (t,
3
{
1
J ) 1.4 Hz, 2H), 4.10 (t, J ) 2.0 Hz, 2H), 7.06 (dd (app. t), J )
2.2, 2.1 Hz, 2H), 7.49-7.46 (m, 6H), 7.63-7.65 (m, 4H) ppm;
H} NMR (CDCl
3
): 50.3 (CH), 73.1 (CH ), 118.5 (q, JC-F ) 321
2
D
Hz, CF ), 123.7 (CH), 168.2 (C) ppm; [R] 25 +24 (c 0.35, CHCl ).
3
3
13
1
3 2
C{ H} NMR (CDCl ): 52.3 (CH), 69.7 (CH ), 124.9 (CH), 127.3
Procedure for the Catalyst Screening for Cross-Coupling of
Bistriflate (R,R)-2 with Benzylmagnesium Chloride (Table 1).
To a solution of bistriflate (R,R)-2 (97 mg, 0.25 mmol, 1 equiv),
NMP (120 µL, Table 1, entries 3 and 4), and a catalyst (amount
indicated in Table 1) in THF (2.5 mL, 0.1 M) at 0 °C was added
the BnMgCl (1 mL, 1 mmol, 1.0 M in Et
nitrogen. The reaction was stirred for the indicated time and
temperature before being quenched by sat. NH Cl at 0 °C. The
aqueous layer was extracted three times with hexane. The combined
organic extracts were washed three times with water followed by
4
a wash with brine and dried over MgSO . The crude product was
passed through a plug of silica gel, eluted with hexane, and
concentrated in vacuo. The crude product, consisting of (R,R)-Bn-
(
5
CH), 128.5 (CH), 134.6 (CH), 141.3 (C), 156.9 (C) ppm. Complex
c was isolated as a bright-red crystalline solid after flash
chromatography (hexane/CH Cl , 60/40), 105 mg (0.14 mmol,
): δ 1.28 (s, 2H), 3.67 (d, J ) 2.4 Hz,
H), 4.21 (dd, J ) 1.4, 1.7 Hz, 2H), 7.36-7.37 (m, 6H), 7.50-
2
2
1
5
2
7
5%). H NMR (CDCl
3
2
O, 4 equiv) under
.53 (m, 4H) ppm; 13C{ H} NMR (CDCl
), 57.9 (d, JC-Rh ) 6.8 Hz,
CH), 65.1 (d, JC-Rh ) 10.9 Hz, C), 127.2 (CH), 127.8 (CH), 128.2
1
3
): 41.3 (d, JC-Rh ) 10.8
Hz, CH), 52.9 (d, JC-Rh ) 2.6 Hz, CH
2
4
D
(
CH), 138.5 (C) ppm; [R] 25 -52 (c 1.05, CHCl
anal. calcd for C38 Rh ‚H O: C, 58.26, H, 4.37; found C,
8.63, H, 4.24.
Genral Procedure for the Asymmetric 1,4-Addtion of Phe-
nylboronic Acid to Cyclic Enones (6). To a solution of [RhCl-
nbd*)] (5) (3 mol % Rh) and phenylboroxine (7, 62 mg, 0.20
3
); mp > 300 °C;
H
32Cl
2
2
2
5
1
nbd* (3b) and 1,2-diphenylethane (4), was analyzed by H NMR
and compared to the spectral data previously reported in ref 2a.
(
2
mmol, 1.2 equiv of boron) in 1.7 mL of 1,4-dioxane was added
the cyclic enone 6 (0.50 mmol, 1 equiv) and KOH aq. (1.5 M,
A Typical Procedure for the Preparation of [RhCl(nbd*)]
Complexes. Preparation of [RhCl((R,R)-Bn-nbd*)] (5a) (Table
, entry 1). A solution of BnMgCl (2 mL, 2 mmol, 1.0 M in Et O,
equiv) was added dropwise to a solution of bistriflate (R,R)-2
, (8.8 mg, 5 mol %), and NMP
250 µL) in THF (5 mL, 0.1 M) at 0 °C under nitrogen. The initial
2
2
0
.17 mL, 0.25 mmol, 0.5 equiv). The solution was stirred at 25 °C
for 1 h. The resulting mixture was passed through a short silica
gel pad and eluted with Et O. Evaporation of the solvent followed
2
2
4
2
(194 mg. 0.50 mmol), Fe(acac)
3
by chromatography over silica gel (hexane/ethyl acetate ) 95/5)
gave (R)-3-phenylcycloalkanone 8 as a colorless oil. Compounds
a-b were fully characterized by comparison of the spectral and
analytical data with those reported in the literature.
General Procedure for the Asymmetric 1,2-Addition of
Phenylboronic Acid to N-Sulfonyl Imines. To a solution of [RhCl-
(
clear, orange solution became pale yellow before turning dark brown
toward the end of the addition. The reaction mixture was further
stirred for 5 min at that temperature before being quenched by sat.
8
20
NH
The combined organic extracts were washed three times with water
followed by a wash with brine and dried over K CO . The crude
4
Cl. The aqueous layer was extracted three times with hexane.
(
nbd*)]
and imine 9 (0.10 mmol, 1 equiv) in 1,4-dioxane (0.4 mL) was
O: 1 equiv to boron)
2
5 (3 mol % Rh), phenylboroxine 7 (0.12 mmol, 1.2 equiv),
2
3
product was passed through a plug of silica gel and eluted with
hexane. Crude (R,R)-Bn-nbd* (3a) was characterized by comparison
of the spectral and analytical data with those reported in the
added KOH aq. (6.5 µL, 3.1 M, 0.2 equiv, H
2
at room temperature. The resulting homogeneous solution was
literature.2 The crude product was dissolved in toluene (5 mL, 0.1
a
stirred for 6 h at 60 °C. The mixture was passed through a short
silica gel pad and eluted with Et
followed by chromatography over silica gel (hexane/ethyl acetate
4/1) gave the arylated product 10. Compounds 10a and 10b were
2
O. Evaporation of the solvent
2 4 2 2
M), and [RhCl(C H ) ] (97 mg, 0.25 mmol, 1 equiv) was added.
The mixture was stirred under nitrogen for 2 h and the solvents
were removed in vacuo. The product was purified by flash
chromatography over silica gel (hexane/CH
mg (0.20 mmol, 80%) of complex 5a as a light-yellow crystalline
)
fully characterized by comparison of their spectral and analytical
2 2
Cl , 1/1) to yield a 164
data with those reported in the literature.2
c,d
1
solid. H NMR (CDCl
H), 3.51 (s, 4H), 3.76 (d, J ) 14.4 Hz, 4H), 3.80 (s, 4H), 7.26 (d,
J ) 7.0 Hz, 4H), 7.34 (t, J ) 7.5 Hz, 8H), 7.26 (d, J ) 7.5 Hz,
3
): δ 0.77 (s, 4H), 3.08 (d, J ) 14.4 Hz,
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan (21 COE on
Kyoto University Alliance for Chemistry). G.B.-G. gratefully
acknowledges the Japanese Society for the Promotion of Science
for the award of a short-term fellowship.
4
1
8
H). 13C{ H} NMR (CDCl
Hz, CH), 53.3 (d, JC-Rh ) 3.0 Hz, CH
CH), 70.1 (d, JC-Rh ) 11.4 Hz, C), 126.4 (CH), 128.5 (CH), 129.1
CH), 138.7 (C) ppm; [R] 25 +56 (c 0.60, CHCl
65 °C (dec).
3
): 40.6 (CH ), 47.7 (d, JC-Rh ) 10.8
), 60.1 (d, JC-Rh ) 7.1 Hz,
2
2
D
(
1
3
); mp ) 163-
Supporting Information Available: Experimental details for
the acquisition and structure refinement for rhodium complex (R,R)-
5
c, the corresponding CIF file, and spectroscopic data for all new
(
19) Ph-bod* can be easily handled and stored indefinitely at room
compounds are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
temperature.
(20) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
JO061385S
8
960 J. Org. Chem., Vol. 71, No. 23, 2006