Published on Web 11/22/2007
Organocatalytic Vinyl and Friedel-Crafts Alkylations with Trifluoroborate
Salts
Sandra Lee and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544, and DiVision of Chemistry,
California Institute of Technology, Pasadena, California 91125
Received September 6, 2007; E-mail: dmacmill@princeton.edu
Over the last 8 years, our laboratory has developed the concept
of iminium catalysis, a mode of LUMO-lowering activation that
has enabled the invention of a large number of enantioselective
organocatalytic transformations including Diels-Alder cycloaddi-
tions, Friedel-Crafts alkylations, Mukaiyama-Michael additions,
hydrogenations, and heteroconjugate additions.1 Central to the utility
of this technology has been the discovery that a wide variety of
π-rich aromatics, such as indoles, pyrroles, furans, and aniline rings,
readily participate in iminium-catalyzed 1,4-addition with enals, a
Friedel-Crafts mechanism that ensures highly rigid regiocontrol
with respect to ring functionalization (e.g., indole selective for
3-position, pyrrole 2-position, etc.).2
Design Plan. The seminal work of Petasis5 has established that
boronic acids can be utilized as a robust π-activation group that
enables aryl and vinyl moieties to readily undergo 1,2-iminium
addition as part of a powerful three-component coupling protocol
(eq 1, TS-1).6 With this mechanism in mind, we hypothesized that
an iminium catalysis platform might be susceptible to boronate
conjugate addition, wherein an amine component would now
function as a chiral catalyst in lieu of a coupling partner (eq 2).
However, direct analogy to the Petasis reaction would require the
use of γ-oxy-substituted enals to ensure activation of the boronic
acid via formation of a tethered boronate nucleophile (TS-2), a
structural restriction that would greatly limit the scope of the
electrophile. To address this issue, we proposed the use of
preformed borate complexes, such as Vedejs-Molander BF3K
salts,7 to enable intermolecular 1,4-addition without the need for
pre-association to an alkoxy group (TS-3), a simple modification
that we hoped would allow π-neutral or π-deficient nucleophiles
to enantioselectively couple with a broad range of enals.
To our delight, exposure of crotonaldehyde to potassium styryl-
trifluoroborate in the presence of imidazolidinone catalyst 1‚HCl
and hydrofluoric acid8 did indeed provide the desired γ,δ-
unsaturated aldehyde product with enantioinduction and good levels
of reaction efficiency (Table 1, entry 1, 94% yield, 56% ee). Further
evaluation revealed that the tryptophan-derived imidazolidinone
catalyst 2‚HCl exhibited optimal conversion and enantiocontrol in
solvents such as 1,2-dimethoxyethane (DME) or toluene (entries 5
and 6, 87% ee). The superior levels of induction and efficiency
exhibited by catalyst 2‚HCl in DME prompted us to select these
conditions for further exploration.
The scope of the organo(trifluoro)borate nucleophile was next
examined (Table 2). Styryltrifluoroborate salts, with varied substitu-
tion on the aromatic ring, were successful reaction partners (entries
1-3, 70-96% yield, 87-95% ee). Extension of this protocol to
electron-deficient heteroaromatics9 that are traditionally inert to
iminium catalysis reveals that 2-formyl furans, benzofurans, and
N-Boc-indoles become excellent π-nucleophiles upon incorporation
of a BF3K moiety (entries 4-7, 79-94% yield, 91-97% ee).
Perhaps, most important, these salts can indeed provide nontradi-
tional regiocontrol as part of a Friedel-Crafts pathway. As revealed
in entry 7, site-specific alkylation of an electron-deficient indole
at the 2-position was accomplished without any loss in enantiose-
lectivity (79% yield, 91% ee).10 We anticipate that the discovery
that BF3K salts can direct the regioselectivity of aromatic alkylations
will likely find broad application throughout the larger realm of
electrophilic aromatic substitution chemistry.
A diverse and representative scope of R,â-unsaturated aldehydes
is well tolerated in this process (Table 3), inclusive of both alkyl
(entries 1 and 2, 90-97% yield, 93-97% ee) and aryl substituents
(entry 5, 69% yield, 92% ee). Additionally, significant electronic
variation of the olefin substituent from a methyl ester group to a
protected alcohol has little effect on enantiocontrol (entries 3 and
4, g88% ee).
Recently, we hypothesized that the inherent value of iminium
catalysis might be greatly expanded via the identification of a
traceless activation group that would (i) allow π-neutral or
π-deficient substrates to function as suitable nucleophiles for
iminium catalysis, while (ii) enabling site-specific alkylation of
aromatic nucleophiles outside of the constraints of Friedel-Crafts
regioselectivity. Herein we report the first use of vinyl and
heteroaryl trifluoroborate salts as viable substrates for amine-
catalyzed conjugate additions. While BF3K salts are routinely
employed in transition metal catalysis,3 to our knowledge, this is
the first use of this activation group for organic catalysis or Friedel-
Crafts alkylations.4
9
15438
J. AM. CHEM. SOC. 2007, 129, 15438-15439
10.1021/ja0767480 CCC: $37.00 © 2007 American Chemical Society