Visible Light Photoredox Cross-Coupling of Acyl Chlorides with Potassium Alkoxymethyltrifluoroborates: Synthesis of α-Alkoxyketones

Article abstract of DOI:10.1021/acs.orglett.5b03705

A visible-light, single-electron-transfer (SET), photoredox cross-coupling for the synthesis of α-alkoxyketones has been developed. In this method, various aliphatic and aromatic acyl chlorides were successfully coupled with structurally diverse potassium

Full text of DOI:10.1021/acs.orglett.5b03705

Letter
pubs.acs.org/OrgLett
Visible Light Photoredox Cross-Coupling of Acyl Chlorides with
Potassium Alkoxymethyltrifluoroborates: Synthesis of
α‑Alkoxyketones
Javad Amani, Esmat Sodagar, and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A visible-light, single-electron-transfer (SET), photo-
redox cross-coupling for the synthesis of α-alkoxyketones has been
developed. In this method, various aliphatic and aromatic acyl
chlorides were successfully coupled with structurally diverse
potassium alkoxymethyltrifluoroborates, producing the corresponding α-alkoxyketones with high yields. In this operationally
simple and mild cross-coupling protocol, the desired ketones are obtained in one step from bench stable starting materials by a
bond connection that is unique to both alkylboron chemistry and photoredox/Ni catalysis.
mong the many virtues of organoboron reagents is their
Because of their enhanced reactivity, acyl halides represent
Atolerance of sensitive functional groups, which can be used virtually the only class of electrophiles that can react with
organoboron “ate” complexes in intermolecular reactions.5
to advantage for late-stage incorporation of functional groups
Despite their relatively high reactivity as electrophiles, acyl
chlorides have been used relatively sparingly in reactions with
alkylboron compounds. One of the inherent drawbacks of the
methods applied to date is the necessity to handle air-sensitive
trialkylboranes, from which the requisite “ate” complexes are
generated. Additionally, only one of the three alkyl groups on
boron is transferred. The latter issue can be resolved by
employing alkyl-9-BBN reagents from which appropriate “ate”
complexes can be generated, but air sensitivity remains an issue,
and with the 9-BBN derivatives one is additionally restricted in
terms of functional group incorporation and accessibility to
diverse substructures.
within highly elaborated substructures. In counterbalance to
this is the decidedly nonpolar nature of the carbon−boron
bond, which attenuates the nucleophilic reactivity of alkylboron
reagents toward nearly all electrophiles. As a consequence of
this limited reactivity, an effective means to activate alkylboron
reagents in a highly selective manner is of utmost importance
and value in order to take full advantage of their desirable
physical and chemical properties.
We, and others, have recently unveiled novel reactivity
patterns of alkyltrifluoroborates based on single electron
transfer (SET) oxidation, generating radicals that can take
part in a variety of diverse transformations.1 As an important
extension of this, we introduced a novel concept for dual
catalytic cross-coupling in which the effective transmetalation
occurs via an SET pathway, exploiting the production of
radicals generated upon oxidation of the boron reagents.2
Visible light photoredox catalysis based on simultaneous
activation and engagement of the reactive partners with two
distinct catalysts through low-barrier, open-shell processes has
emerged as a valuable paradigm for the design of single
electron-transfer pathways.3 Under the dual catalysis paradigm,
the synergistic roles of an Ir photoredox catalyst and a Ni
catalyst enable broad application in the cross-coupling of
diverse potassium alkyltrifluoroborates with aryl and heteroaryl
bromides under remarkably mild conditions (i.e., weak base,
room temperature).2a,4
Boronic acids and boronate esters resolve both of these
particular issues associated with trialkylboron “ate” complexes,
but not without some added burdens of their own. Knochel
developed a transmetalative protocol that was quite effective as
a route to ketones,6 but this protocol required the use of 6
equiv of flammable dialkylzinc reagents and 2 equiv of CuCN
to effect the acylation. Beyond this, there appear to be only two
reports of transition-metal-catalyzed cross-coupling between
alkylboronic acids and carboxylic acid chlorides. In the first, a
single example (phenethylboronic acid) was reported of a Pd-
catalyzed process that was carried out at 70 °C with no yield or
detailed procedure.7 The second was restricted to cyclopropyl-
2
boronic acids (possessing significant Csp -bond character),
which also involved a Pd-catalyzed procedure requiring 2
equiv of acid chloride and 2 equiv of Ag2O in toluene at 80 °C.8
To broaden the range of electrophiles to which the
photoredox/Ni dual catalytic cross-coupling could be applied,
the reaction of acyl chlorides with potassium α-alkoxymethyl-
In an effort to expand the scope of this paradigm for cross-
coupling, attention was turned toward its application to halide
electrophiles outside of the aryl/heteroaryl manifold. The goal
was to provide access to useful substructures in an approach
that was underrepresented in terms of previous alkylboron
chemistry. Acyl chlorides were targeted as the first of such
electrophiles.
Received: December 30, 2015
© XXXX American Chemical Society
A
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Letter
trifluoroborates was chosen as a test case (eq 1). The synthesis
of α-alkoxyketones has attracted much attention. These
structures serve as versatile and valuable building blocks in
the construction of various natural products, as well as being of
some importance in food chemistry, where they have been
identified as flavor components in a wide variety of foods.9
Although there are many techniques available for the
synthesis of α-alkoxyketones,10 often these methods are limited
and demonstrate a lack of generality because of their harsh
conditions. Also in currently available protocols, α-alkoxyke-
tones are generally obtained by multistep syntheses in low
overall yields. Thus, a complementary, operationally simple,
mild, and high yield synthesis route would enjoy a privileged
role in accessing these structures.
Table 1. Scope of Potassium Alkoxymethyltrifluoroborates
in Cross-Coupling with Hydrocinnamoyl Chloride
Scheme 1 shows the mechanism for Ir-photoredox/Ni dual
catalysis that we proposed would lead to the desired
transformation. The mechanistic scheme is adapted from our
studies on cross-coupling of alkyltrifluoroborates with aryl and
heteroaryl halides.11
Scheme 1. Proposed Mechanism for the Photoredox Cross-
Coupling of Acyl Chlorides with Potassium
Alkoxymethyltrifluoroborates
To validate the visible-light photoredox cross-coupling of
acyl chlorides with potassium alkoxymethyltrifluoroborates,
hydrocinnamoyl chloride and potassium benzyloxymethyl-
trifluoroborate were chosen as model coupling partners in the
presence of Ir[dF(CF3)ppy]2(bpy)PF6, [dF(CF3)ppy = 2-(2,4-
difluorophenyl)-5-(trifluoromethyl)pyridine, bpy = 2,2′-bipyr-
idine] I as a photocatalyst. An extensive screening of various
reaction parameters (e.g., solvent, Ni catalyst, ligand, and
additive) was carried out by means of microscale high-
throughput experimentation (HTE) to determine suitable
conditions for cross-coupling.12 As a result of the initial
screens, the treatment of hydrocinnamoyl chloride with
potassium benzyloxymethyltrifluoroborate in the presence of
3 mol % of I, 6 mol % of NiCl2·dme, 6 mol % of 4-tert-butyl-2-
(2-pyridyl)oxazoline L1, and 1 equiv of lutidine in THF at
room temperature produced the desired α-alkoxyketone in
good yield (see Supporting Information, Table S1, entry 1, 74%
yield). Further investigations revealed that changing the base
from lutidine to Cs2CO3 provided a significant improvement in
yield (Table S1, entry 2, 83%). Also, a decrease of catalyst
loading to 2 mol % of I, 4 mol % of NiCl2·dme, and 4 mol % of
L1 did not affect the yield of the reaction considerably and is
a
Reaction completed on 5.9 mmol scale with 1 mol % Ir photocatalyst
b
and 2 mol % NiCl2·dme/L1. Determined by SFC using L1 under the
optimized conditions. Determined by SFC using 4 mol % L2 as a
ligand at −25 °C. er = enantiomeric ratio.
c
economically and environmentally beneficial (entry 5). Lower
concentrations (0.05 M) increase the yield of the reaction,
while higher molarities (0.2 M) result in diminished yields
(Table S1, entries 6 and 7, respectively). Finally, control
experiments were carried out to confirm the essential roles of
the photocatalyst, Ni catalyst, and additives (Table S1, entries
3−5).
B
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Table 2. Scope of Potassium Alkoxymethyltrifluoroborates
Table 3. Scope of Acyl Chlorides in the Cross-Coupling
in Cross-Coupling with Benzoyl Chloride
These conditions were used to explore the scope of the
2
3
alkoxymethyltrifluoroborate component in this Csp −Csp cross-
coupling protocol in reactions with hydrocinnamoyl chloride
(Table 1). All types of alkoxymethyltrifluoroborates utilized,
containing primary, secondary, and tertiary alkoxy groups
(entries 1−8, 9, and 10, respectively), were successfully coupled
to give the corresponding products in moderate to very good
yields. To demonstrate the scalable nature of this coupling, a
reaction on 5.9 mmol scale to generate 1a was performed. In
this reaction, using reduced loadings of the catalysts (1 mol %
of I and 2 mol % of Ni/L1), the desired product was obtained
in 75% yield (entry 1, Table 1). In contrast to traditional cross-
couplings, in this proposed SET mechanism radical inter-
mediates are produced from alkoxymethyltrifluoroborate
precursors. Therefore, the stereochemical outcome of the
reaction is presumably determined by the rate of reductive
elimination from diastereomeric complexes X (Scheme 1),
where the ligands on Ni are enantioenriched.10 Consequently,
use of an appropriate chiral ligand would enable the
stereoconvergent synthesis of enantioenriched α-alkoxyketones
from racemic organotrifluoroborate starting materials via
prochiral radical intermediates. Using hydrocinnamoyl chloride
and racemic potassium 3-benzyloxy-3-trifluoroboratopropyl-
benzene as a model reaction, a screen of various chiral ligands
under the developed conditions was conducted. Use of 2,2′-
isopropylidenebis[(4R)-4-benzyl-2-oxazoline, L2] as a ligand
afforded the desired ketone 1k in 91% yield with an
enantiomeric ratio (er) of 81:19 (entry 11, Table 1).
Next, attention was turned to exploring the scope of the acyl
chloride component. Interestingly, as revealed in Table 3, we
found that a broad range of acyl chlorides readily participate in
this cross-coupling reaction. Cyclopropane- and cyclobutane-
carbonyl chlorides were well tolerated, generating the
corresponding α-alkoxyketones in 93% and 80% yields,
respectively (entries 1 and 2). An acyl chloride bearing a
bulky group, 1-adamantanecarbonyl chloride, provided the
desired cross-coupled product with an excellent yield (entry 3,
85%). Additionally, the reaction with 4-morpholinecarbonyl
chloride produced 2-(benzyloxy)-1-morpholinoethanone as an
α-alkoxyamide in 77% yield (entry 10).
In conclusion, a visible light photoredox cross-coupling of
acyl chlorides with potassium alkoxymethyltrifluoroborates has
been developed to access a variety of α-alkoxyketones with high
yields. This mild and operationally simple method is functional
group tolerant and produces the desired ketones in one step
from bench stable starting materials. The protocol described
herein not only represents an expansion of the photoredox/Ni
dual catalytic paradigm into new electrophile space but also
constitutes one of the few methods to couple alkylboron
reagents with acyl chlorides. Because of the scope of the
reaction, this cross-coupling protocol provides an efficient
means to synthesize complex α-alkoxyketones. Further develop-
To demonstrate the efficiency of this protocol for the
coupling of aromatic acyl chlorides, benzoyl chloride was
reacted with different alkoxymethyltrifluoroborates under the
optimal conditions (Table 2). All of the alkoxymethyltrifluoro-
borates utilized were successfully coupled, affording the desired
products in yields up to 91%. These results serve to highlight
the complementary nature of this novel method for the
synthesis of both aliphatic and aromatic α-alkoxyketones.
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03705.
Experimental procedures, HTE data, compound charac-
terization data, and NMR spectra for all compounds
(PDF)
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(12) (a) For more details about the screening through microscale
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2013, 46, 71.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gmolandr@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM
113878). Frontier Scientific is thanked for the donation of
boron compounds used in this investigation. Johnson-Matthey
is acknowledged for the donation of IrCl3 used for the synthesis
of the photocatalyst. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
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