of some functional groups. Hence, a method to efficiently
prepare functionalized meta-substituted arenes would be
synthetically useful since many physiologically active com-
pounds contain this structural moiety.10
Scheme 3. Proposed Mechanism
We optimized the reaction conditions by varying the
alkylboronic acid, solvent, equivalents of alkyl halide, base,
and norbornene, as well as the effect of different additives
and the method of boronic acid addition.11 Scheme 2
Scheme 2. Optimized Conditions
illustrates our optimized conditions employing slow addition
of isopropylboronic acid,12 resulting in trisubstituted arene
4a in 89% yield.13
The proposed mechanism for this transformation is based
on that described by Catellani (Scheme 3).14 The first step
involves oxidative addition of the iodoarene with Pd(0),
followed by carbopalladation onto norbornene forming 6.
Subsequent C-H activation and elimination of HI by the
base forms palladacycle 7.
(5) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 40, 1045-
1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127-8134. (c) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org.
Chem. 2002, 67, 3972-3974. Pache, S.; Lautens, M. Org. Lett. 2003, 5,
4827-4830.
A second oxidative addition of the alkyl halide to
palladium is proposed to form Pd(IV) species 8. Reductive
elimination of intermediate 8 leads to the ortho-alkylated
arene 9. This sequence can be reiterated in the second ortho
position leading to 10. Decarbopalladation with concomitant
expulsion of norbornene gives intermediate 11, which can
then undergo a palladium-catalyzed C-H bond formation
to regenerate Pd(0) and complete the catalytic cycle. We
supposed the final C-H bond formation occurs via trans-
metalation of 11 with the alkylboronic acid giving 12,
followed by a â-hydride elimination to generate palladium
hydride 13 and a reductive elimination to the meta-substituted
arene 4.
Control experiments to elucidate the mechanism indicated
that reduced product was also formed in the absence of
alkylboronic acid, though in much lower yield. This suggests
a second pathway may also be occurring (Scheme 4, eq 1).
Using deuterated iodoethane, we observed only deuterated
product, implying that the alkyl halide was acting as an
alternative hydride source (Scheme 4, eq 2).15 The detailed
reaction pathway for C-H bond formation using alkyl
halides as a hydride source is still under investigation. This
reduction of iodoarenes appears to be a general reaction that
is not limited to our norbornene-containing conditions
(Scheme 4, eq 3).
(6) (a) For Suzuki coupling: Catellani, M.; Motti, E.; Minari, M. Chem.
Commun. 2000, 157-158. (b) For Sonogashira coupling: Motti, E.; Rossetti,
M.; Bocelli, G.; Catellani, M. J. Organomet. Chem. 2004, 689, 3741-
3749.
(7) Product 2 was identified by 1H NMR but not isolated due to the
difficult separation. Catellani reported NaO2CH gave the reduced product
2 (ref 4) but the only examples were with iodobenzene and unfunctionalized
alkyl halides.
(8) (a) Shen, Y.; Liu, H.; Chen, Y. J. Org. Chem. 1990, 55, 3961-
3962. (b) Shen, Y.; Liu, H.; Wu, M.; Du, W.; Chen, Y.; Li, N. J. Org.
Chem. 1991, 56, 7160-7162.
(9) (a) Tamao, K. J. Organomet. Chem. 2002, 653, 23-26. (b) Reddy,
G. S.; Tam, W. Organometallics 1984, 4, 632-634.
(10) (a) Stuerzebecher, J.; Vieweg, H.; Wikstroem, P. WO 9208709,
1992. (b) Stuerzebecher, J.; Prasa, D.; Hauptmann, J.; Vieweg, H.;
Wikstro¨m, P. J. Med. Chem. 1997, 40, 3091-3099. (c) Ornstein, P. L.;
Bleisch, T. J.; Arnold, M. B.; Kennedy, J. H.; Wright, R. A.; Johnson, B.
G.; Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp, D. D.; Herin,
M. J. Med. Chem. 1998, 41, 358-378.
(11) Optimization was carried out using HPLC yields.
(12) In a one-pot version the yield of compound 4a is 78%.
(13) General procedure for the multicomponent reaction: Pd(OAc)2
(4.5 mg, 0.02 mmol, 0.1 equiv), PPh3 (10.5 mg, 0.04 mmol, 0.2 equiv),
and molecular sieves (powder, 4 Å, 50 mg) were dissolved in absolute
acetonitrile (0.5 mL) under nitrogen and stirred for 15 min. The iodoarene
(0.2 mmol, 1 equiv), Cs2CO3 (325 mg, 1.0 mmol, 5 equiv), norbornene
(113 mg, 1.2 mmol, 6 equiv), alkyl halide (2.0 mmol, 10 equiv), 0.1 mL of
DMPU, and 0.5 mL of acetonitrile were added and the mixture was heated
to reflux. Isopropylboronic acid (26.4 mg, 0.3 mmol, 1.5 equiv) dissolved
in 1.0 mL of acetonitrile was then added at a rate of 0.08 mL/h via syringe
pump. After 20 h, the mixture was cooled to room temperature, diluted
with pentane, hydrolyzed with H2O, and extracted with pentane or ether.
After drying with MgSO4 the crude product was purified by chromatography
(silica, hexane/EtOAc).
(15) Experiments with deuterated solvents (CD3CN), other solvents
(DME), and without additives (MS and DMPU) using C2H5I always gave
the nondeuterated product in similar yields thereby excluding other hydride
sources (additives or solvent).
(14) Proposed mechanism is based on mechanistic studies published by
Catellani, Pregosin, and co-workers (see refs 3b and 3c).
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Org. Lett., Vol. 7, No. 18, 2005