I. Fernꢃndez, D. Solꢀ, and M. A. Sierra
sition structures (TSs) show
only one negative eigenvalue in
their diagonalized force con-
stant matrices, and their associ-
ated eigenvectors were con-
firmed to correspond to the
motion along the reaction coor-
dinate under consideration
using the intrinsic reaction co-
[25]
ordinate (IRC) method.
The
Wiberg bond indices Bi and
atomic charges were computed
[26]
by using the NBO
method.
The solvents effects were taken
into account by using the
[27]
PCM.
Single-point calcula-
tions (PCM-B3LYP/def2-SVP)
on the gas-phase optimized ge-
ometries were performed to es-
timate the change in the Gibbs
energies in the presence of
THF or toluene as the solvent.
Scheme 10. Computed reaction profile for the transformation of 12-ester into 15-ester-I and 3M. The numbers
ꢀ
1
close to the arrows indicate the PCM-corrected free energies (DG298 in kcalmol ) using toluene (plain values)
or THF (values in parenthesis) as the solvent. The bond lengths are given in ꢅ. All the data have been com-
puted at the PCM-B3LYP/def2-SVP level.
General methods: All the commercial-
ly available reagents were used with-
out further purification. b-Amino-
ketone 10 and alcohol 11 are known
[
3d]
1
13
compounds.
H and C NMR spec-
by a-arylation or nucleophilic substitution pathways, respec-
tively, depending on the presence or absence of phenol in
the reaction media. In contrast, the corresponding ketone
reactant gives rise to a mixture of the nucleophilic addition
alcohol product and the a-arylation indole product, even in
the presence of phenol. Although the product ratio depends
on the base used and can be tuned using bidentate phos-
phines, as illustrated by the complete conversion and oppo-
site chemoselectivity provided by both the BINAP and xant-
phos ligands. The outcome of all these processes is nicely ex-
plained by the formation of a common four-membered pal-
ladacycle intermediate from which the competitive nucleo-
philic attack and a-arylation reactions occur. Finally, the
effect of phenol in the process favors the formation of enol
complexes, which are stabilized by an intramolecular hydro-
gen bond between the hydroxy group of the enol moiety
and the oxygen atom of the phenoxy ligand, thus making
tra were recorded in CDCl
3
with Me Si (TMS) as the internal standard.
4
The chemical shifts are reported in ppm d downfield from TMS. Yields
were obtained by gas chromatography with N,N-dimethylaniline as an in-
ternal standard, which was added to the crude reaction mixture in an
amount equal to the quantitative yield. TLC analysis was carried out on
SiO
2
, and the spots were located with UV light.
0
Representative procedure for the Pd -catalyzed a-arylation of ketone 10
with KOtBu as the base (Table 2, entry 6): Phenol (57 mg, 0.60 mmol),
KOtBu (0.30 mmol, 0.3 mL, 1m in tert-butyl alcohol), [Pd
2 3
ACHTUNGTNERGUN( dba) ] (9 mg,
0
.01 mmol), and xantphos (11.5 mg, 0.02 mmol) were added to a solution
of ketone 10 (75 mg, 0.198 mmol) in THF (10 mL) under argon. The solu-
tion was heated at 758C for 48 h. The reaction mixture was cooled at
room temperature, was diluted with CH
aqueous NaHCO and 1m aqueous NaOH. The organic layer was dried
and concentrated. The residue was purified by flash chromatography on
SiO (CH Cl /MeOH, 99.5:0.5) to give indole 20 (39.5 mg, 80%) as
pale-yellow solid. M.p. 1058C (recrystallized from isopropanol);
H NMR (300 MHz): d=2.52 (s, 3H), 5.35 (s, 2H), 7.15 (m, 2H), 7.24–
2 2
Cl , and washed with saturated
3
2
2
2
a
1
1
3
7.38 (m, 6H), 7.75 (s, 1H), 8.40 ppm (dm, J=7.8 Hz, 1H); C NMR
75.4 MHz): d=27.6 (CH ), 50.7 (CH ), 110.1 (CH), 117.5 (C), 122.6
(2CH), 123.4 (CH), 126.4 (C), 126.9 (2CH), 128.2 (CH), 129.0 (2CH),
34.9 (CH), 135.7 (C), 137.0 (C), 193.0 ppm (C); elemental analysis (%)
(
3
2
[28]
the a-arylation process much easier.
1
calcd for C17
N 5.52.
H15NO: C 81.90, H 6.06, N 5.62; found: C 81.78, H 6.33,
Experimental Section
Computational details: All the calculations reported herein
[21]
were obtained with the GAUSSIAN09 suite of programs.
Electron correlation was partially taken into account by
using the hybrid functional usually denoted as B3LYP and
Acknowledgements
[22]
Support for this study by MEC (Spain) (grants CTQ2010–20714-C02–01/
BQU, CSD2007–0006 (Programa Consolider-Ingenio 2010), and
CTQ2009–07175) and by CAM (P2009/PPQ1634-AVANCAT) is grateful-
ly acknowledged. Dr. I. Fernꢃndez is a Ramꢆn y Cajal fellow.
using the double-z quality plus polarization def2-SVP basis
[
23]
set for all the atoms (this basis sets include effective core
potentials (ECPs) for palladium and iodine atoms). The re-
actants and products were characterized by frequency calcu-
[24]
lations and have positive definite Hessian matrices. Tran-
&
8
&
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!