Tetrahedron Letters
An organocascade approach to a,a-chlorofluoroalcohols
Montgomery D. Hayes a, Melanie Rodríguez-Alvarado b, Stacey E. Brenner-Moyer a,
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a Department of Chemistry, Brooklyn College, 2900 Bedford Avenue, Brooklyn, NY 11210, USA
b Department of Chemistry, Rutgers University—Newark, 73 Warren Street, Newark, NJ 07102, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorinated, tetrasubstituted, carbon stereocenters are challenging to install enantioselectively.
gem-Chlorofluoro compounds contain a fluorinated, tetrasubstituted stereocenter, and are an entrée into
other such compounds. We report herein the first catalytic, enantioselective method to prepare
gem-chlorofluoro compounds from unfunctionalized aldehydes. This one-pot method precludes the
Received 15 May 2015
Accepted 29 May 2015
Available online 6 June 2015
isolation of volatile and/or reactive
a
-haloaldehyde intermediates.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Fluorine
Organocatalysis
Synthetic method
The introduction of fluorinated stereocenters has garnered
much attention recently, owing to the increasing prevalence of flu-
orine-containing chiral drugs.1 Fluorinated, tetrasubstituted, stereo-
centers, as exist in the compounds in Figure 1, can be a particularly
challenging motif to access. Installation of this motif via asymmet-
ric carbon–fluorine bond-forming reactions often requires the use
of enantiopure starting materials or stoichiometric chiral fluorinat-
ing reagents, as in the synthesis of influenza antiviral 1 and
thalidomide analog 2, respectively.2,3 More often, however, stereo-
centers of this type are introduced in racemic form, necessitating a
resolution of the resulting enantio- or diastereomeric mixture, as
occurred in the Hoffmann-La Roche synthesis of 3.4
Chiral gem-chlorofluoro compounds (i.e., 8, Scheme 1) also pos-
sess a fluorinated, tetrasubstituted, stereocenter. They may also be
considered lynchpin intermediates, as SN2 displacement of
chlorine can potentially provide access to an array of compounds
containing other fluorinated stereocenters.5d
Within the past decade, several catalytic asymmetric methods
to produce enantiopure gem-chlorofluoro compounds have
emerged. The majority of these methods are limited to b-dicar-
bonyl substrates.5 Methods applicable to substrates other than b-
dicarbonyl compounds require that either the carbon–fluorine or
carbon–chlorine bond be in tact prior to the enantiodetermining
step.6
medicinal compounds.7 Building on these studies, we envisioned
that a cascade reaction combining successive enamine-catalyzed
a-halogenation reactions would be an effective means of generat-
ing enantiopure gem-chlorofluoro compounds in one-pot starting
from simple aldehyde substrates (Scheme 1). The advantages of
this strategy are that it does not necessitate prior installation of
one of the carbon–halogen bonds and it avoids isolation of volatile,
reactive, aldehyde intermediates.
At the outset, we were well aware that the merging of two cat-
alytic reactions into a cascade reaction poses non-trivial challenges
(vide infra). With this realization already in mind, the starting
point for the development of the cascade reaction was to assess
the compatibility of the two catalytic reactions, and the goal was
to develop the most operationally simple process possible. Thus,
both orders of successive halogenations were initially consid-
ered,8,9 as was the possibility of using a single catalyst/solvent
system for the entire transformation.10 Development of a cascade
reaction in which the chlorination reaction was first, followed by
the fluorination reaction, ultimately proved more fruitful.
Toward this end, starting with the reaction conditions reported
for the enamine-catalyzed
a-fluorination of a
-chloroaldehydes,6a
we examined the fluorination reaction in the presence of succin-
imide and pentachlorophenol, the byproducts of chlorination
using the electrophilic chlorine sources N-chlorosuccinimide (NCS)
and 2,2,3,4,5,6-hexachlorocyclohexanone,8a respectively (Table 1).
Whereas fluorination was hampered by the presence of
pentachlorophenol (18% conversion), it was unaffected by the
presence of succinimide (entries 2 and 3). This result dictated the
choice of NCS as the chlorine source, which, in turn, influenced the
choice of catalyst for the chlorination step.
We have previously investigated organocascade reactions as
efficient methods to produce fluorinated substructures of
⇑
Corresponding author at present address: Department of Chemistry, Rutgers
University—Newark, 73 Warren Street, Newark, NJ 07102, USA. Tel.: +1 973 353
5457; fax: +1 973 353 1264.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.