Direct β-alkylation of aldehydes via photoredox organocatalysis

Article abstract of DOI:10.1021/ja502639e

Direct β-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon-induced enamine oxidation provides an activated β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C-H functionalization protocol can be achieved both inter-and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable.

Full text of DOI:10.1021/ja502639e

Communication
pubs.acs.org/JACS
Direct β‑Alkylation of Aldehydes via Photoredox Organocatalysis
Jack A. Terrett, Michael D. Clift, and David W. C. MacMillan*
Merck Center for Catalysis, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
catalytically generated radical speciesa β-enaminyl radical
ABSTRACT: Direct β-alkylation of saturated aldehydes
has been accomplished by synergistically combining
photoredox catalysis and organocatalysis. Photon-induced
enamine oxidation provides an activated β-enaminyl
radical intermediate, which readily combines with a wide
range of Michael acceptors to produce β-alkyl aldehydes in
a highly efficient manner. Furthermore, this redox-neutral,
atom-economical C−H functionalization protocol can be
achieved both inter- and intramolecularly. Mechanistic
studies by various spectroscopic methods suggest that a
reductive quenching pathway is operable.
formed via oxidation and β-deprotonation of an enamine, and a
radical anion generated by photocatalytic reduction of a
cyanoarenethat couple to form β-aryl carbonyl products.
Furthermore, we recently demonstrated the generality of this
activation platform via direct β-aldol reaction of ketones with
transiently generated aryl ketyl radicals to form γ-hydroxyketone
adducts.1i Here we translate this generic activation mode to
direct β-alkylation of saturated aldehydes with Michael acceptors.
This formal “homo-Michael” transformation delivers β-alkyl
aldehydes by a combination of photoredox and amine catalysis
(eq 2), further emphasizing the utility of this novel 5πe− carbonyl
activation mode for a broad range of previously unknown
transformations.
Within the discipline of organic chemistry, the Michael
reaction is among the most prevalent and commonly employed
strategies to couple electrophilic olefins with enolates or
enamines to deliver α-carbonyl alkylated products.5 While 1,4-
conjugate addition of α-carbonyl nucleophiles is a well-
established transformation,5,6 an analogous “homo-Michael”
reaction, in which the β-position of a fully saturated carbonyl
species functions as the nucleophile, is essentially unknown.1g
Indeed, current methods for installing alkyl groups at the β-
position of carbonyls typically require the use of unsaturated
carbonyl substrates and stoichiometric organometallic reagents,
such as organocuprates.7 Based on the insight gained over the
course of our β-arylation program,1f we hypothesized that a
transiently generated 5πe− β-enaminyl radical intermediate
(formed via an enamine oxidation/deprotonation sequence)
could be intercepted by a Michael acceptor, prior to a terminal
reduction step.8 Most importantly, this organocatalytic, redox-
neutral, and atom-economical approach would provide direct
access to a diverse range of β-alkyl aldehydes via a single chemical
transformation, requiring no substrate preactivation or use of
stoichiometric transition metals.
irect β-functionalization of saturated carbonyls has recently
D
become an important goal within the field of new reaction
invention.1 While chemical methods that induce bond
formations at the ipso- and α-positions of CO moieties have
long been established within organic synthesis,2,3 it is remarkable
that the β-functionalization of esters, ketones, aldehydes, and
amides has been effectively limited to the addition of soft
nucleophiles to α,β-unsaturated systems. Recently, our labo-
ratory introduced a unique 5πe− carbonyl activation mode
utilizing the synergistic merger of organocatalysis and photo-
redox catalysis4 to accomplish the direct β-arylation of saturated
ketones and aldehydes (eq 1).1f This strategy employs two
Based on our previous work in organocatalysis and visible
light-promoted photoredox catalysis,9 we propose the β-Michael
mechanism outlined in Scheme 1. Initial excitation of hetero-
leptic Ir(III) photocatalyst IrIII(dmppy)2(dtbbpy)PF6 (dmppy =
2-(4-methylphenyl)-4-methylpyridine, dtbbpy = 4,4′-di-tert-
butyl-2,2′-bipyridine) (1) by visible light produces the photo-
excited *IrIII state 2, which can act as both a strong oxidant
IV/ III
(E*1/I2II/II = +0.55 V vs SCE in MeCN) and reductant (E
* =
1/2
−0.87 V vs SCE) in a single-electron transfer (SET) event with
an appropriate substrate quencher.10 Concurrent condensation
of a secondary amine catalyst 4 onto an aldehyde forms the
enamine intermediate 5. Based on the analysis of standard
Received: March 14, 2014
Published: April 22, 2014
© 2014 American Chemical Society
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Communication
Scheme 1. Proposed Mechanism of the β-Alkylation Reaction
Table 1. Initial Studies toward the β-Alkylation Reaction
a
light
source
yield
entry
photocatalyst
Ir(ppy)3
organocatalyst
(%)
1
2
3
4
5
6
7
8
i-Bu2NH
i-Bu2NH
i-Bu2NH
i-Bu2NH
pyrrolidine
i-Pr2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
none
26 W CFL
26 W CFL
26 W CFL
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
none
7
50
52
64
6
Ru(bpy)3Cl2
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(dtbppy)2(dtbbpy)PF6
Ir(dmppy)2(dtbbpy)PF6
Ir(dmppy)2(dtbbpy)PF6
Ir(dmppy)2(dtbbpy)PF6
none
77
80
56
84
0
b
9
c
10
reduction potentials, we hypothesized that *IrIII 2 should readily
oxidize the catalytically generated electron-rich enamine 511 to
form the respective radical cation 6 and the reduced Ir(II)
photocatalyst 3. Given the substantial increase in acidity of the β-
C−H following enamine oxidation, we presumed that deproto-
nation of the β-methylene of the radical cation 6 would be facile,
forming nucleophilic β-enaminyl radical intermediate 7 (5πe−-
activated intermediate).1f This transiently generated 5πe− system
could be rapidly intercepted by an electrophilic Michael acceptor,
forging the desired C−C bond while producing the α-acyl radical
11
12
13
0
blue LEDs
blue LEDs
0
Ir(dmppy)2(dtbbpy)PF6
0
a
Yield determined by 1H NMR analysis using methyl benzoate as
internal standard. Reactions performed with 2.0 equiv of octanal and
1.0 equiv of DABCO. Reaction complete after 12 h. Reaction
performed in the absence of DABCO. CFL = compact fluorescent
light.
b
c
electrophile (entry 5), a problem that is commonly confronted
in prototypical Michael reactions with organocatalysts.13 In
contrast, increasing the steric bulk on the secondary amine
catalyst by installing α-branched alkyl groups adjacent to the
nitrogen position provided superior efficiency (entries 6 and 7).
Indeed, the use of the modified photocatalyst Ir(dmppy)2-
(dtbbpy)PF6 with dicyclohexylamine was found to be optimal,
providing the β-alkylated product in 84% yield (entry 9). Last,
control experiments revealed the requirement for base, light,
photocatalyst, and organocatalyst in this new β-alkylation
protocol (entries 10−13).
With the optimal β-alkylation conditions in hand, we sought to
determine the generality of this direct β-Michael addition. As
shown in Table 2, we identified a broad range of electrophilic
olefin acceptors as effective alkylation partners for this protocol.
Notably, aryl substitution at the α-position of acrylate olefins
proved highly effective for both benzyl and methyl ester systems
(entries 1 and 2, 83% and 79% yield), presumably due to
formation of a benzylic radical in the key C−C bond-forming
step (radical 8, Scheme 1). Sterically demanding arenes are
readily accommodated on the acrylate coupling partner (entry 3,
77% yield). Electron-rich and electron-deficient arenes on the
olefin are also tolerated (entries 4 and 5, 69% and 79% yield),
including a series of halogen-substituted phenyl rings (entries 5−
7, 69−79% yield). Importantly, unsubstituted acrylates, vinyl
sulfones, acryloyl oxazolidinones, and acrylonitriles are also
competent electrophiles in this direct β-alkylation reaction
(entries 8−12, 50−80% yield). Interestingly, highly electrophilic
adduct 8. Reducing this 3πe− species 8 (E = −0.59 to −0.73 V
red
1/2
vs SCE)12 with the available IrII species 3 (E
= −1.52 V vs
III/II
1/2
SCE)10 would then return the photocatalyst to its ground state 1,
completing the photoredox catalytic cycle. Finally, protonating
the enolate along with enamine hydrolysis (thereby completing
the organocatalytic cycle by regenerating amine 4) would then
deliver the β-alkylated product 9.
We initiated our examination of the proposed β-alkylation
protocol using benzyl 2-phenyl acrylate as the electrophilic
coupling partner and octanal as the saturated carbonyl
component. To our delight, we observed the desired β-alkylation
product (albeit in a modest 7% yield) using Ir(ppy)3 as
photocatalyst and diisobutylamine as the amine organocatalyst
(Table 1, entry 1). From an early stage we identified that the use
of 1,4-diazabicyclo[2.2.2]octane (DABCO) as an organic base
and DME as solvent was essential for the desired bond formation
to be realized. Early comparisons of photocatalysts revealed
noticeable improvements in efficiency when switching to more
oxidizing photocatalysts, such as Ru(bpy)3Cl2 and Ir(ppy)2-
(dtbbpy)PF6 (cf. entries 1−3). Tuning the light source to the
maximum absorption wavelength of the photocatalyst (λmax
=
450 nm)10 via the use of blue LEDs resulted in further
improvements in efficiency (entry 4). At this point, we next
examined the influence of the organocatalyst in this β-alkylation
protocol. As might be expected, employing a more nucleophilic
amine catalyst dramatically diminished reaction yields due to a
competing 1,4-heteroconjugate addition with the acrylate
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a
a
Table 2. Scope of the Michael Acceptor Coupling Partner
Table 3. Scope of the Aldehyde in the β-Alkylation Reaction
a
a
Isolated yields, see SI for experimental details. Diastereomeric ratios
Isolated yields, see SI for experimental details. Diastereomeric ratios
b
(dr) 1−1.3:1, determined by 1H NMR analysis. Reaction time = 24 h.
b
c
1
1−2:1, determined by H NMR analysis. Reaction time = 24 h. 5.0
c
d
d
e
5.0 equiv of DABCO and 3.0 equiv of octanal for 30 h. 5.0 equiv of
equiv of butanal. 3.0 equiv of aldehyde. HOAc used instead of TFA.
f
g
DABCO, 5.0 equiv of octanal, 40 mol% Cy2NH, and HOAc instead of
TFA. 3.0 equiv of octanal.
Reaction time = 36 h. 10 equiv of propionaldehyde.
e
A series of Stern−Volmer fluorescence quenching experi-
ments were performed in an effort to provide evidence for the
mechanistic proposal outlined in Scheme 1. Indeed, we have
determined that the emission intensity of *IrIII(dmppy)2-
(dtbbpy)PF6 is dramatically diminished in the presence of the
operating enamine (formed in situ from dicyclohexylamine and
octanal), thereby indicating that enamine oxidation is likely the
first step in the photoredox cycle.15 Comparatively, there is no
fluorescence quenching when the amine catalyst, aldehyde
donor, or benzyl 2-phenyl acrylate acceptor is exposed separately
to the photoexcited *IrIII species. In addition, electron
paramagnetic resonance (EPR) spectroscopy has revealed the
existence of an organic radical (giso = 1.9858) following excitation
of the photocatalyst in the presence of enamine; this signal is
absent if either aldehyde or amine is removed.15 It is important to
consider that an alternative catalysis mechanism might involve
single-electron reduction of the Michael acceptor prior to
coupling with the β-enaminyl radical (a radical−radical
combination that would be consistent with our previous β-
Michael acceptors such as alkylidene malonates do not
participate in this β-coupling reaction. Remarkably, these
reaction partners form aldehyde α-alkylation products exclu-
sively, a regiochemical outcome that is not observed for other
Michael acceptors shown in Table 2 (e.g., acrylates, vinyl
sulfones, and acrylonitriles).14
We next focused our attention on the scope of the aldehydic
coupling partner, as exemplified in Table 3. Aliphatic aldehydes
function broadly, regardless of the inherent steric bulk positioned
around the reactive β-C site (entries 1 and 2, 79% and 72% yield).
Importantly, a variety of functional groups are tolerated on the
alkanal system, including ethers, esters, alkynes, and alkenes
(entries 3−6, 66−83% yield). Perhaps most notably, quaternary
C centers can be formed in a facile manner utilizing this new
transformation, with rapid alkylation of β-sites that are found
within cyclic (tetrahydropyran and piperidine) and acyclic (gem-
dimethyl) systems (entries 7−10, 72−78% yield). β-Amino
aldehydes are competent substrates for formation of stereogenic
amines with good levels of reaction efficiency (entry 11, 66%
yield). Intriguingly, propionaldehyde undergoes β-alkylation at
the terminal methyl site using these photoredox conditions
(entry 12, 59% yield), indicating that primary β-enaminyl radicals
can be generated in this protocol.
arylation and β-aldol studies). However, this pathway would
red
depend on a facile reduction of benzyl 2-phenyl acrylate (E
=
1/2
−1.97 V vs SCE),10 which is thermodynamically unfavorable for
either the *IrIII or IrII oxidation state of photocatalyst 1. Indeed,
EPR studies indicate that no organic radical is generated with
benzyl 2-phenyl acrylate in the presence of either photocatalyst 1
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Journal of the American Chemical Society
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a
Scheme 2. Intramolecular β-Alkylation Cyclization Reaction
ACKNOWLEDGMENTS
Financial support was provided by NIHGMS (R01 01
GM093213-01) and gifts from Merck and Amgen.
■
REFERENCES
■
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likely involved in the catalytic cycle.15 As such, we conclude that
addition of a 5πe− β-enaminyl radical (such as 7) to the ground
state of the Michael acceptor coupling partner (as shown in
Scheme 1) is the operating C−C bond-forming step.17
Last, to further explore the utility of this new β-alkylation
reaction, we have investigated intramolecular variants as a
mechanism to rapidly access ring systems of various formats. As
shown in Scheme 2, both 6-exo and 5-exo cyclizations are
accomplished with useful efficiencies and diastereocontrol (47−
54% yield, 4−9:1 dr). This provides further evidence that the
critical key step does not involve radical−radical coupling, given
the low probability of generating two radicals simultaneously on
the same molecule.
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In summary, through the synergistic combination of organo-
catalysis and photoredox catalysis, we have accomplished the first
direct β-alkylation of fully saturated aldehydes with Michael
acceptors. We have further demonstrated the utility of a 5πe− β-
enaminyl activation platform as a general approach to direct β-
functionalization of carbonyls. Importantly, this C−H bond
activation method is entirely redox-neutral and atom-econom-
ical, and it requires no preactivation of either coupling partner.
Mechanistic studies have provided spectroscopic evidence
supporting a reductive quenching pathway, in which C−C
bond formation occurs by β-enaminyl radical addition into a
ground-state Michael acceptor. Efforts toward expanding the
scope of the carbonyl coupling partner as well as developing an
asymmetric variant are currently underway and will be reported
in due course.
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(14) At this stage we have found Michael acceptors bearing β-
substitution to be less competent in the described intermolecular β-
alkylation protocol.
(15) See SI for fluorescence quenching and EPR data.
(16) Flamigni, L.; Barbieri, A.; Sabatini, C.; Ventura, B.; Barigelletti, F.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) When coupling partners that undergo facile single-electron
reduction, such as vinyl ketones, are employed, no desired β-alkylated
product is formed, and only dimerization of the coupling partner is
observed. This suggests against a radical−radical coupling event in the
key C−C bond-forming step of this protocol.
AUTHOR INFORMATION
■
Corresponding Author
dmacmill@princeton.edu
Notes
The authors declare no competing financial interest.
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