Direct β-functionalization of cyclic ketones with aryl ketones via the merger of photoredox and organocatalysis

Article abstract of DOI:10.1021/ja410478a

The direct β-coupling of cyclic ketones with aryl ketones has been achieved via the synergistic combination of photoredox catalysis and organocatalysis. Diaryl oxymethyl or aryl-alkyl oxymethyl radicals, transiently generated via single-electron reduction

Full text of DOI:10.1021/ja410478a

Communication
pubs.acs.org/JACS
Direct β‑Functionalization of Cyclic Ketones with Aryl Ketones via the
Merger of Photoredox and Organocatalysis
Filip R. Petronijevic,† Manuel Nappi,† and David W. C. MacMillan*
́
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: The direct β-coupling of cyclic ketones with
aryl ketones has been achieved via the synergistic
combination of photoredox catalysis and organocatalysis.
Diaryl oxymethyl or aryl−alkyl oxymethyl radicals,
transiently generated via single-electron reduction of
ketone precursors, readily merge with β-enaminyl radical
species, generated by photon-induced enamine oxidation,
to produce γ-hydroxyketone adducts. Experimental
evidence indicates that two discrete reaction pathways
can be operable in this process depending upon the nature
of the ketyl radical precursor and the photocatalyst.
he direct β-functionalization of saturated ketones and
Taldehydes is an important yet elusive goal in organic
chemistry.1 While carbonyl groups are readily amenable to ipso-
and α-carbon substitution with a range of nucleophiles and
electrophiles respectively,2,3 activation at the β-methylene
position poses a significant synthetic challenge. With a few
notable exceptions,1,4 carbonyl β-functionalization has tradition-
are accessed via carbene catalysis,9,10 nucleophilic addition of
ally been restricted to the conjugate addition of soft nucleophiles
acetal-protected Grignard reagents,11 or stoichiometric metal-
into α,β-unsaturated carbonyl systems. As such, the development
of a general catalytic platform5 for the direct β-functionalization
of saturated ketones or aldehydes would represent a conceptual
and practical advance for the field. In this context, our lab has
recently introduced an unprecedented 5πe−carbonyl activation
mode that capitalizes on the synergistic merger of photoredox
catalysis and amine organocatalysis to accomplish the direct β-
arylation of saturated aldehydes and ketones (eq 1).1a This
strategy relies on the coupling of two catalytically generated
radical species: a β-enaminyl radical formed via oxidation and
deprotonation of a ketone-derived enamine and a radical anion
generated by photocatalytic reduction of an aryl nitrile.6 Here, we
further advance this activation concept to describe the first β-
functionalization of saturated cyclic ketones with aryl ketones to
deliver γ-hydroxyketone motifs, a protocol that formally
represents a homoenolate aldol reaction using simple carbonyl
substrates, a household light source, and two commercial
catalysts (eq 2).
activated homoenolate equivalents.12−16
Drawing from the mechanistic insights gained in the course of
our β-arylation program,1a we envisioned a direct β-coupling of
saturated ketones with aryl−alkyl and diaryl ketone precursors.
Specifically, we postulated that a transiently formed nucleophilic
β-enaminyl 5πe− species (1) would be intercepted by a ketyl
radical (2) to directly form a γ-hydroxyketone adduct (eq 2).17
Notably, both radical species would be generated in catalytic
quantities through the operation of two concurrent activation
pathways: a photoredox cycle (en route to 2) and an
organocatalytic cycle (en route to 1).
The specific mechanistic details of our proposed synergistic
merger of visible-light-mediated photoredox catalysis and
organocatalysis18,19 are outlined in Scheme 1. Irradiation of
tris(2-phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] (8) with
visible light produces a long-lived (1.9 μs) photoexcited state,20
*Ir(ppy)3 (9), which can be readily oxidized or reduced by an
appropriate substrate quencher. While *Ir(ppy)3 (9) is a strong
Among the most fundamental carbonyl α-functionalization
reactions in organic chemistry is the aldol coupling of
nucleophilic enolates with electrophilic ketones or aldehydes to
deliver valuable β-hydroxycarbonyl motifs.7 Although the aldol
reaction has been widely exploited for the α-functionalization of
carbonyl substrates for over 140 years,8 analogous “homo-aldol”
transformations that allow for the direct β-functionalization of
carbonyls remain elusive. Typically, homoaldol-type synthons
21
red
+
reductant (E1/2 [Ir(ppy)3 /*Ir(ppy)3] = −1.73 V vs SCE),
its capacity for single electron transfer (SET) with diarylketones
such as benzophenone would be endergonic (E1/2red = −1.83 V vs
SCE).22 However, in an acidic medium, the standard reduction
Received: October 15, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja410478a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Proposed Mechanism for the β-Ketone Coupling
Table 1. Initial Studies towards the β-Coupling of Ketones
a
1
Yield determined by H NMR using 1,3-benzodioxole as an internal
b
c
standard. Reaction performed in the absence of catalyst 3. Reaction
performed in the absence of light. CFL = compact fluorescent light.
potential of the ketone is elevated and therefore it is easier to
reduce, rendering this step experimentally feasible.23 As such,
electron transfer (ET) between an aryl ketone and excited state 9
would provide the oxidized IrIV(ppy)3 (10) system along with
the corresponding ketyl radical 2. Concurrent with this
photoredox cycle, we envisioned a second organocatalytic
cycle, commencing with condensation of amine catalyst 3 with
the ketone coupling partner (i.e., cyclohexanone) to generate an
electron-rich enamine 4. The facile oxidation of this intermediate
fluorescent light, the γ-alkyloxy adduct was formed in 67%
yield (entry 3). The desired product was accompanied by
significant amounts (12%) of benzophenone dimer, which we
assume arises from the combination of two molecules of ketyl
radical 2. Notably, further improvements in reaction efficiency
were achieved through addition of 1 equiv of LiAsF6,28 which
suppresses formation of this undesired diol, presumably via the
production of a lithium alkoxide ketyl radical that is inert to
dimerization (entry 9, 81% yield). The critical roles of the
photocatalyst, organocatalyst, and light were demonstrated
through control experiments, wherein no desired product was
detected in the absence of any of these components (entries 10−
12).
Having identified optimal conditions for this photocatalytic,
direct β-ketone−ketone coupling reaction, we aimed to define
the scope of the enaminyl radical precursor. As shown in Table 2,
a series of differentially substituted cyclohexanone-derived
substrates were readily coupled with benzophenone. It is of
note that incorporation of both alkyl and aryl substituents at
positions 3 and 4 of the cyclohexanone ring is well-tolerated
(entries 2−5, 43−79% yield). As expected, the presence of
groups at the ring 4-position induces higher levels of
diastereoselectivity than substituents at the cyclohexanone 3-
position (cf. entries 4 and 5). Interestingly, while cyclopentanone
served as a suitable substrate for this reaction (entry 6, 65%
yield), 7-membered ketones gave low yields of the desired β-
alkyloxy product (10−20% yield; see Supporting Information).
We next sought to establish the scope of the ketyl radical
substrate in this β-carbonyl functionalization reaction. As shown
in Table 3, a range of substituted benzophenones can serve as
by IrIV(ppy)3 (E1/2 [Ir(ppy)3 /Ir(ppy)3] = +0.77 V vs SCE;
E1/2red 4 = +0.38 V vs SCE)24 serves to reduce the photocatalyst
to its ground state, thereby completing the photocatalytic cycle.
Formation of the desired enaminyl radical cation 5 would then
induce an increase in the acidity of the allylic C−H bond,
facilitating deprotonation at the β-position.1a The transiently
formed 5πe− species 1 should then readily couple with ketyl
radical 2 to form the γ-hydroxyketone enamine 6. Finally,
enamine hydrolysis would serve to release the β-union product 7
and regenerate 3, completing the organocatalytic cycle. With
respect to achieving chemoselective reduction of benzophenone
in the presence of cyclohexanone, it was expected that the
significantly lower standard reduction potential of cyclo-
red
+
hexanone (E1/2 = −2.79 V vs SCE)25 would render this
red
substrate thermodynamically indisposed toward reduction.
We first explored the proposed direct β-carbonyl coupling
reaction in the context of cyclohexanone and benzophenone
(Table 1). Examination of a range of photocatalysts, amines,
bases, and solvents (entries 1−6) revealed the combination of
Ir(ppy)3 (8) and 1,4-diazabicyclo[2.2.2]octane (DABCO) as the
base to be most effective. For example, when a DMPU solution26
containing the ketone substrates, Ir(ppy)3 (8), DABCO, and
azepane organocatalyst (3)27 was irradiated with 26 W
B
dx.doi.org/10.1021/ja410478a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 2. Scope of the Ketone-Enaminyl Radical Precursor
Table 3. Scope of the Ketyl Radical Coupling Precursor
a
Reaction typically performed with 20 mol % of amine catalyst 3, 20
mol % of AcOH, 1 equiv of LiAsF6, 2 equiv of DABCO, 2 equiv of
b
c
water. Reaction performed with 10 equiv of water. Diastereose-
1
lectivity determined by H NMR analysis.
viable coupling partners using our optimized conditions (entries
1−3, 56−81% yield) to furnish γ-hydroxyketone products with
high levels of efficiency. Notably, a slightly diminished yield was
obtained with 4-methoxybenzophenone (entry 2, 56% yield),
likely due to the electron-donating group on the aromatic ring,
which lowers the standard reduction potential of the ketone.
At this stage we turned our attention to aryl−alkyl ketone
reaction partners, a more challenging substrate class given that
ketyl radical formation would be thermodynamically disfavored
with respect to the analogous benzophenone system. Indeed,
initial efforts to achieve this photocatalytic β-heterocoupling
reaction using acetophenone met with little success using our
previously optimized conditions. We recognized that the excited
state of the photocatalyst (9) is not sufficiently reducing to
a
Diastereoselectivity, where relevant, was determined by 1H NMR
b
analysis to be 1−1.2:1. Reaction conditions as performed in Table 2.
of electron-withdrawing groups onto the carbonyl alkyl
substituent (entries 11 and 12, 54−62% yield).
To further probe the mechanistic course of this transformation
and the specific utility of each photocatalyst as a function of ketyl
radical subclass, we performed a series of Stern−Volmer
quenching studies. As expected, these experiments revealed
that benzophenone quenches the excited state of Ir(ppy)3 (9)
(Figure 1), lending support to our initial hypothesis in Scheme 1.
However, similar experiments performed with acetophenone (or
acetophenone in the presence of acetic acid)30 and Ir(p-MeO-
ppy)3 revealed that no excited state quenching was observed with
red
induce ketyl radical formation from acetophenone via ET (E1/2
= −2.14 V vs SCE),20 a reduction potential that is considerably
lower than that of benzophenone. Fortunately, we identified
Ir(p-MeO-ppy)3 as an effective photocatalyst for the reduction of
aryl−alkyl ketones, and indeed, this system enabled a large
increase in the ketyl-radical partner scope (Table 3, entries 4−
12). We initially speculated that incorporation of electron-
donating substituents on the photocatalyst aryl ligand would
enhance the reduction potential of the IrL3 excited state, thereby
allowing ketyl radical formation to become facile with aryl−alkyl
ketones.29 However, subsequent studies suggest that the use of
Ir(p-MeO-ppy)3 leads to a change in the order of ET events with
enamine oxidation becoming the primary interaction for the IrL3
excited state (vide infra). Using the Ir(p-MeO-ppy)3 catalyst,
both electron-deficient (entries 5 and 7, 65% yield) and electron-
rich (entries 8 and 9, 73−79% yield) acetophenone derivatives
readily coupled with cyclohexanone to generate γ-hydroxyketone
adducts. Moreover, heteroaryl−methyl ketones were also
suitable reaction partners in this transformation (entries 6 and
10, 56−69% yield). Although higher alkyl homologues of
acetophenone failed to participate in this β-functionalization
protocol, reaction efficiency was recovered via the introduction
Figure 1. Ir(ppy)3 emission quenching with benzophenone and
enamine 4.
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data are provided. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
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113, 5322.
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AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
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Author Contributions
†F.R.P. and M.N. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Financial support was provided by the NIGMS (R01
GM103558-01) and kind gifts from Merck, Amgen, and AbbVie.
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