Organic Letters
Letter
Scheme 4. Further Transformations of 3ba, 3bf, and 3bi
Figure 1. Solid state structure of compound 3ah. Ellipsoids are
represented at 50% probability. H atoms are shown as spheres of
a
Scheme 3. Substrate Scope and Limitations
intramolecular Claisen condensation, and this feature was
investigated. Treating 7bf with NaOMe in methanol led to the
formation of aromatized fluorenone 8 in 71% yield, following
elimination of H2O. While this demonstrates the applicability
of these products as enolates, valuable stereochemical
information is lost here. To explore other possibilities, we
subjected 3bi, with two acetal functionalities, to acidic
conditions, envisaging that both groups could be deprotected
in one step (Scheme 4, route B). A subsequent acid catalyzed
aldol reaction could then result in a cyclized product. We were
delighted to see that the use of p-TsOH in wet acetonitrile led
to the formation of tricyclic compound 9. Remarkably, this
product, which contains four stereogenic centers, forms with
complete diastereoselectivity. This reaction demonstrates that
our method can be utilized to build up significant molecular
complexity from a flat achiral starting material, benzoic acid.
In order to explain the high regioselectivity and facial
selectivity of the transformation, we have performed a
quantum chemical study, relying on Density Functional
Theory (DFT) calculations. Our calculations, which were
done with Gaussian16,13 were mostly performed at the B3LYP-
D3/def2-TZVP//def2-SVPD level of theory. The Solvent
Model Density (SMD) method was used to include implicit
consideration of acetonitrile solvation effects.14 More details of
the calculations are given in the Supporting Information. The
B3LYP-D3 functional has a reported mean average deviation
from CCSD(T)/CSB results of 1.6 and 2.3 kcal/mol for
barrier heights and reaction energies, respectively, in a
selection of Pd-catalyzed reactions.15 The method has also
previously been used to model Heck reactions.16
The formation of 3aa, without phosphine ligands, was
chosen as a model system for our calculations (Table 1, entry
5). Because the experimental reaction was performed with a
silver additive in a polar solvent, a fast halide abstraction from
palladium was assumed. In other words, all structures were
modeled using acetate and acetonitrile ligands.
An extensive screening of migratory insertion transition
states and their conformational space was conducted (see SI).
Transition state structures (TS1−TS8) for the eight possible
arylations are shown in Figure 2. For each possibility, the
complexes are depicted in their lowest energy ligand
conformations. The lowest energy pathway, TS1 (see SI,
Figure S86), leads to C−C bond formation in the C-4 position,
a
Performed in a Carousel 12 Plus Reaction Station from Radleys,
using a metal heating block. NMR yields (isolated yields in
parentheses). Products formed with complete diastereoselectivity,
with the exception of 3db, formed as a 1:1 mixture of diastereomers.
We subsequently explored further synthetic transformations
of products 3. Cleavage of the acetal in 3ba and 3bf, using
CF3COOH, afforded ketones 7ba and 7bf in high yields
(Scheme 4, route A). Compound 7bf, containing a ketone and
a proximal ester group, could potentially undergo an
C
Org. Lett. XXXX, XXX, XXX−XXX