of azabenzonorbornadiene 3a with arylboronic acids was
inconsistent, giving quantitative reaction with phenylboronic
acid but a complex mixture of products with 4-chloro-
phenylboronic acid. Attempts to improve the yield of these
reactions were not fruitful: changes in ligand, solvent, and
protocol for addition of reagents led to no significant
improvement in yield.6
as a solvent, the reaction requires an inorganic base and water
for good activity.15
Using Tol-BINAP as our standard ligand, we next
investigated the effects of different solvents on reactivity and
enantioselectivity (Table 1). No obvious trend was observed;
Few examples of the addition of heteroaryl species to
activated alkenes have been reported,7 and the development
of such reactions would be especially interesting and valuable
for medicinal chemistry purposes. For this reason we
broadened our studies by investigating the boronic acid
addition reaction with different metals. Palladium was an
obvious choice, because we have previously reported asym-
metric ring-opening reactions with dialkylzinc nucleophiles
and Pd(II) catalysts8 and because Pd(II) species are known
intermediates in the Suzuki cross-coupling reaction and
undergo transmetalation with organoborons.9
Satisfyingly, we immediately observed the desired re-
action10 of 1a with phenylboronic acid and Pd[(R)-Tol-
BINAP]Cl2 catalyst, using our standard conditions previously
used with rhodium catalysts.5a Complete conversion was
observed, and the product 2aa11 was obtained with 67% ee,
as a single diastereomer (cis) as observed previously with
rhodium.12 No reaction was observed with either nickel or
platinum catalysts.13 Among the wide variety of ligands
screened in this model reaction, Tol-BINAP showed the best
combination of reactivity and enantioselectivity.14 Surpris-
ingly, poor enantioselectivities are observed with the ferro-
cene-based ligands, which give excellent enantioselectivities
in the analogous rhodium-catalyzed reaction.5a With THF
Table 1. Solvent Studiesa
entry nucleophile
solvent
ee (%)b conversion (%)b
1
2
3
4
5
6
7
8
9
A
A
B
B
B
B
B
B
B
B
B
toluene
80
68
67
72
75
83
77
100
95
38
87
32
DCEc
THF
CH3CN
EtOAc
acetone
DMF
i-PrOH
MeOH
MeOH (-20°C)
8:2 MeOH/H2O
0
65
70
86
65
50
100 (after 1 h)
100
100
10
11
a Protocol: Pd(CH3CN)2Cl2 (2.2 mg, 0.05 equiv) and ligand (0.055 equiv)
were added to a 1 dram vial containing a stir bar. The vial was sealed with
a 14 mm septum and flushed with N2 before solvent (0.5 mL) was added.
The resulting solution/suspension was stirred for ∼40 min before a solution
of oxabicycle 1 (25 mg, 1 equiv) and PhB(OH)2 (26 mg, 1.2 equiv) was
added by syringe from a sealed vial with solvent (0.5 mL total). Finally, an
aqueous solution of Cs2CO3 (5 M in H2O, 35 µL, 1 equiv) was added. b As
measured by chiral HPLC (see Supporting Information for details). c 1,2-
Dichloroethane.
(6) Deuterium labeling studies and characterizations of the oligomeric
products demonstrate that rhodium catalysts can promote C-H activation
reactions from carbometalated intermediates, leading to undesired products.
These results will be presented in a forthcoming full paper.
of reactions with furan- and thiophene-3-boron species yielded one example
from the literature: the rhodium-catalyzed conjugate addition of thiophene-
3-tetrafluoroborate to cyclohexenone: Batey, R. A.; Thadani, A. N.; Smil,
D. V. Org. Lett. 1999, 1, 1683.
(8) (a) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2000,
122, 1804. (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org Lett. 2000, 2,
1971. (c) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001,
123, 6834.
(9) For reviews of the Suzuki reaction, see: (a) Suzuki, A.; Miyaura, N.
Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999,
576, 147. (c) Danishefsky, S. J.; Chemler, S. R.; Trauner, D. Angew. Chem.,
Int. Ed. Eng. 2001, 40, 4544. (d) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633.
(10) It should be noted that during the preparation of this manuscript,
the Pd(II)-catalyzed conjugate addition of organoboronic acids was reported
by Miyaura and co-workers: Miyaura, N.; Nishikata, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2003, 42, 2768.
(11) For other ring-opening syntheses of compound 2aa, see refs 5 and
21 and also: (a) Fiaud, J.-C.; Moinet, C. Tetrahedron Lett. 1995, 36, 2051.
(b) Kosugi, M.; Fugami, K.; Hagiwara, S.; Oda, H. Synlett 1998, 477. (c)
Nakamura, M.; Nakamura, E.; Matsuo, K.; Inoue, T. Org. Lett. 2003, 5,
1373.
(12) Generally, addition of carbon-centered nucleophiles gives cis ring-
opened products; however, Cu(I)-catalyzed ring-openings of 1a have recently
been reported giving predominantly trans products: (a) Feringa, B. L.;
Pineschi, M.; Bertozzi, F.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.
Org. Lett. 2002, 4, 2703. (b) Carretero, J. C.; Arraya´s, R. G.; Cabrera, S.
Org. Lett. 2003, 5, 1333.
however, reaction in methanol was found to be much faster
than any of the other solvents, giving complete reaction in
less than 1 h (entry 9).16 The high reactivity in methanol
allowed us to bring the temperature down to -20 °C, which
gave improved ee (86%) and complete conversion using 5
mol % catalyst (entry 10).17
Since our objective with the switch in metal from rhodium
to palladium was to increase the scope of the ring-opening
reactions (nucleophiles and alkene substrates), we also
examined the ring-opening of the less-reactive azabicyclic
alkene 3a with furan-3-boronic acid. An initial screening of
achiral ligands18 indicated drastic differences in reactivity.
Among the ligands studied, only DPPP (1,3-bisdiphenyl-
phosphinopropane) gave excellent results.19 Monophosphines
(15) Cs2CO3 and CsF gave enantioselectivity and reactivity superior to
that of NaOAc, NEt3, and KOH.
(16) Use of methanol with Rh(I) catalysts leads to exclusive ring-opening
with methanol as a nucleophile; no such products are observed with Pd(II)
catalysts.
(17) This optimized result is slightly lower than that observed with the
Rh(I)/PPF-P(t-Bu)2 system (ref 5a).
(18) Low enantioselectivites (<30%) have been observed in a preliminary
screening of chiral ligands in the ring opening of 3a with phenylboronic
acid.
(13) Ni(DPPP)Cl2 and Pt[(R)-BINAP]Cl2 both failed to catalyze any
reaction of 1a under the optimized conditions given in Table 2 (5 mol %
catalyst).
(14) See Supporting Information for complete details.
(19) See Supporting Information for full details.
3696
Org. Lett., Vol. 5, No. 20, 2003