Direct Aldehyde Csp2?H Functionalization through Visible-Light-Mediated Photoredox Catalysis

Article abstract of DOI:10.1002/chem.201704224

The development of methods for carbon–carbon bond formation under benign conditions is an ongoing challenge for synthetic chemists. In recent years there has been considerable interest in using selective C?H activation as a direct route for generating rea

Full text of DOI:10.1002/chem.201704224

DOI: 10.1002/chem.201704224
Communication
&
Organophotocatalysis
Direct Aldehyde Csp2ÀH Functionalization through Visible-Light-
Mediated Photoredox Catalysis
Minh Duy Vu, Mrinmoy Das, and Xue-Wei Liu*[a]
more favorable in organic synthesis. Consequently, it is of
Abstract: The development of methods for carbon–
great interest to selectively activate Csp2ÀH of aldehydes for
carbon bond formation under benign conditions is an on-
useful organic transformations, especially under benign condi-
going challenge for synthetic chemists. In recent years
tions. Initial success in CÀH activation of aldehydes, mostly fol-
there has been considerable interest in using selective CÀ
lowing radical pathways, has been presented by several
H activation as a direct route for generating reactive inter-
groups. The first example using thiol as the polarity reversal
mediates. Herein, the use of visible-light-mediated dual
catalyst (PRC) was demonstrated by Harris and Waters in
photoredox organocatalysis as
a mild and effective
1952.[6] Since then, other types of PRC were utilized such as N-
hydroxyphthalimide[7] and peroxides (sources of electrophilic
O radicals)[8] for more efficient abstraction of the aldehyde hy-
drogen atom. However, a common drawback is that the radical
initiation step usually takes place at elevated temperature or
with excessive usage of reagents. From 2007, Fagnoni, Albini,
and co-workers successfully utilized tetrabutylammonium dec-
atungstate (TBADT) for the activation under UV irradiation at
room temperature.[9] Nevertheless, the scope of reaction was
limited to only linear aldehydes because significant decarbony-
lation was observed in the case of branched aldehydes. More
recently, auto-oxidation of aldehydes was also applied as a
simple method of Csp2ÀH activation by Caddick and co-workers
in 2010.[10] Despite the convenience of the catalyst-free pro-
cess, the reaction actually occurs at a very slow rate and is
prone to the formation of several over-oxidation side-products
owing to prolonged heating conditions in some cases. The
most recent method was presented by Maruoka et al. using
hypervalent iodine as the initiator via a radical chain mecha-
nism.[11]
method for Csp2ÀH activation of aldehydes is reported, re-
sulting in the generation of acyl radicals. These nucleo-
philic acyl radical species can undergo either addition to
electrophilic alkenes or nickel-catalyzed cross-coupling re-
actions to provide a quick access to broad range of un-
symmetrical ketones, which are abundantly found in
many organic building blocks.
Acyl radicals have long been employed in organic synthesis as
useful transient synthetic intermediates.[1] Their nucleophilic
nature has mostly been demonstrated in Michael addition-type
reactions for the synthesis of 1,4-dioxo compounds.[2] The gen-
eration of this radical, however, has been a great challenge.
Early examples utilized CÀX bond homo-cleavage, where X can
be a good leaving group.[3] The method generally requires
high loading of toxic organotin initiator compounds, together
with harsh heating conditions, which usually leads to undesira-
ble decarbonylation pathways. More elegant approaches make
use of direct CÀO bond cleavage from carboxylic acids or CÀC
bond cleavage from pyruvic acid derivatives under visible-light
photoredox conditions.[4] The atom economy as well as sub-
strate availability limits the synthetic application of these
methods, despite mild reaction conditions. The acyl radical, on
the other hands, could also be prepared in situ by alkyl radical
addition to CO.[5] However, highly pressurized CO is required to
ensure a good conversion rate, and so special equipment is
necessary.
Visible-light-mediated photoredox transformation of organic
compounds has been attracting significant interest in recent
years. MacMillan and co-workers pioneered the use of coopera-
tive catalytic systems employing an organocatalyst (hydrogen
atom transfer; HAT catalyst) and a photoredox catalyst (elec-
tron transfer catalyst) for selective CÀH activation of several or-
ganic compounds (Scheme 1b). The methods incorporated the
PRC concept for CÀH activation and photoinduced electron
transfer (PET) for catalyst activation as well as regeneration.
Hence, a series of novel CÀC bond formation was successfully
performed under ambient conditions. Thiols were firstly
chosen as the HAT catalyst for the dual catalytic cycle.[12] Subse-
quently, selective functionalization of challenging unactivated
Csp3ÀH centers was accomplished by Glorius[13] using benzoyl
radical as the HAT catalyst, along with Knowles[14] and Rovis[15]
with proton-coupled electron transfer concepts to form amidyl
radicals as the HAT catalysts. Most recently, quinuclidine was
also harnessed as the new powerful HAT catalyst that is able to
abstract hydrogen from strong Csp3ÀH bonds owing to the
Overall, toward the viewpoint of sustainable chemistry in
recent decades, direct selective CÀH functionalization becomes
[a] M. D. Vu, M. Das, Prof. X.-W. Liu
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: xuewei@ntu.edu.sg
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under
https://doi.org/10.1002/chem.201704224.
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Table 1. Selected results for the optimization of reaction conditions.[a]
Entry
Catalyst
Co-catalyst Solvent Yield [%][b]
1
2
3
4
5
6
7
8
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C2
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C3
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
49
–
–
–
–
–
–
–
–
–
60
–
–
–
[Ru(bpy)3][PF6]2
[Ir(ppy)2(dtbbpy)]PF6
C1
C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
9
MeOH
DCM
10
11[c]
12[d]
13[e]
14
15
MeCN
MeCN
MeCN
MeCN
MeCN
[Ir(dFCF3ppy)2(dtbbpy)]PF6
[Ir(dFCF3ppy)2(dtbbpy)]PF6 C1
C1
–
–
–
[a] Reactions were carried out under inert atmosphere (Ar or N2) using
3 equiv aldehyde. [b] Yield of isolated product. [c] Using 5 equiv alde-
hyde. [d] Reaction under open air. [e] Reaction in dark. C1 = Quinuclidine.
C2 = 1-Octanethiol. C3 = tert-Butylthiol. C4 = Ethyl 2-mercaptopropio-
nate.
Scheme 1. Acyl radical formation and CÀH activation strategy through pho-
toredox catalysis.
high bonding energy of NÀH bonds (100 kcalmolÀ1) of the qui-
nuclidinium radical intermediate.[16]
adduct (3aa). To evaluate the ability of quinuclidine as the HAT
catalyst, several experiments using different co-catalysts were
carried out. Although aliphatic thiols were reported as promis-
ing PRC, facilitating Csp2ÀH activation of aldehydes, our results
show that they are not compatible with the catalytic cycle (En-
tries 2–4). A range of photoredox catalysts was also tested.
Among other Ru and Ir complexes, [Ir[dF(CF3)ppy]2(dtbbpy)]PF6
(dF = 3,5-diFluoro; ppy = 2-phenylpyridine; dtbbpy = 4,4’-di-
tert-butyl-2,2’-bipyridine) was the best candidate. The result
agrees with the electrochemical potential measurement of the
Drawing on this inspiration, our group proposes a strategy
for aldehyde Csp2ÀH activation that provides direct access to
the acyl radical that can subsequently be employed in useful
transformations (Figure 1). We anticipate that the Csp2ÀH bond
in aldehyde is significantly weak (86–87 kcalmolÀ1)[1] and could
undergo hydrogen atom abstraction by quinuclidinium cation-
ic radicals.
Our initial trials utilized benzaldehyde and 2-cyclohexeneone
as the model substrates for optimization studies (Table 1). To
our delight, the reaction gave moderate yields of the desired
catalyst (Er1e=d2 =1.21 V) and supports the hypothesis that reduc-
ox
tive quenching first occurs to oxidize quinuclidine (E
=
1=2
1.10 V) to the HAT-active form. Our efforts to further optimize
the reaction condition by varying the solvent was unsuccessful.
Entries 7–10 show that acetonitrile (MeCN) is the solvent of
choice, whereas protic- and more-polar solvents such as
MeOH, DMSO, and DMF are not suitable for the reaction. Con-
trol experiments reinforce the necessity of both the catalysts
as well as visible-light irradiation (entries 13–15). Auto-oxida-
tion of the aldehyde was eliminated (entry 12) since the reac-
tion open to air yielded mainly carboxylic acids from the alde-
hyde.
The poor reactivity of benzaldehyde is probably attributed
to weak nucleophilicity of the phenacyl radical. Reaction yield
increased when large excess of the aldehyde used (entry 11).
Therefore, we proceed to evaluate the scope of the reaction
using optimized condition as stated on various aldehyde and
Michael acceptors (Table 2). Aromatic aldehydes generally give
low-to-moderate yields (3ab and 3 fb). Aliphatic aldehydes in-
Figure 1. Proposed aldehyde activation pathway employed in electron-defi-
cient olefin addition. LED= light emitting diode. SET= single electron trans-
fer. HAT= hydrogen atom transfer
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Table 2. Substrate scope evaluation for hydroacylation of electron-deficient alkenes.[a]
[a] Unless otherwise indicated, reactions were carried out in inert atmosphere (Ar or N2) under irradiation of 34 W blue LED for 12–16 h at RT (308C).
5 Equiv aldehyde was used. Yields refer to isolated products. Gram-scale reactions were performed using 0.1 mol% photoredox catalyst and 1 mol% HAT
catalyst for 48 h.
cluding both linear and branched chains react smoothly under
Table 3. Initial substrate scope evaluation for cross-coupling of aldehydes
with aryl bromides.[a]
the optimized conditions (3db, 3eb, and 3mb). Interestingly,
selective Csp2ÀH activation was achieved in the presence of
weaker benzylic Csp3ÀH bonds (3kb and 3lb).
In the case of branched aldehydes, to our delight, there was
only trace amount of decarbonylated product observed (GC-
MS). Our method hence shows its superiority over reported
procedures using high energy activating sources (UV and
heat). Gram-scale reactions also performed well over a pro-
longed reaction time with the minimal usage of both catalysts
(ca. 0.1 mol% [Ir] and 1.0 mol% quinuclidine; 3eb). The syn-
thetic utility of the protocol has also been demonstrated by
the successful transformation of a variety of olefin acceptors.
Almost quantitative yields was obtained in the case of alpha-
beta unsaturated ketones with di-substituted (3bh) or cyclic
structures (3ba). Other electron-withdrawing groups such as
sulphone (3bf) and cyanide are also well tolerated, although
the conversion was rather low for acrolein addition (3bi). To
our surprise, cyclohexanecarboxyl radical was unable to open
cyclopropane ring (3be); the starting material was fully recov-
ered in this case.
[a] Unless otherwise indicated, all reactions were carried out under inert
atmosphere (N2) using freeze-pump-thaw techniques. Fans were used to
cool the reaction vials (308C).
with organohalides at ambient temperature. Prior work on
direct coupling of aldehydes has been rather underexplored.
Chang et al. presented a bimetallic system for the direct cou-
pling in 2005, nonetheless, a directing group on the aldehyde
is necessary.[18] Seminal work performed by Xiao and co-work-
ers utilized modified Heck coupling conditions under elevated
temperatures.[19] Most recent progress was illustrated by Satya-
narayana, using equimolar silver salts and peroxide.[20]
The application of this CÀH activation strategy can be ex-
tended to cooperative catalysis with Ni-catalyzed cross-cou-
pling of acyl radicals with organohalides. After initial screening,
we have found 1 mol% Ir[dF(CF3)ppy]2(dtbbpy)PF6, 1 mol%
NiCl2·DME
(DME=1,2-dimethoxyethane)
together
with
1.2 mol% dtbbpy ligand, and 1.2 equiv quinuclidine base in
DMSO (0.05–0.10m) over 24 h to be the optimized conditions.
The scope of our cross-coupling was evaluated on electron-de-
ficient aryl bromides with various aliphatic aldehydes (Table 3).
The initial yields were low-to-moderate, owing to unwanted re-
duction of aryl bromide substrate. The phenomenon was simi-
larly observed by MacMillan through the hypothesized proto-
dehalogenation pathway.[17] Although our preliminary results
still need further optimization, we are glad to present, to our
knowledge, the first example of direct coupling of aldehydes
In conclusion, a mild and selective aldehyde Csp2ÀH activa-
tion method was developed on the basis of cooperative
organo-photoredox chemistry. The acyl radical formed under
benign conditions could then undergo either addition to elec-
tron-deficient olefins, or coupling with aryl bromides, enabling
facile access to a series of non-symmetrical ketones. Further
optimization for direct aldehyde cross-coupling as well as syn-
thetic applications of the protocol are underway.
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Experimental Section
General Procedure: An oven-dried 8 mL vial was charged with
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%), quinuclidine (10 mol%) and
alkene (1 equiv; added only if solid at RT). The mixture was subse-
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Acknowledgements
The authors gratefully acknowledge the National Research
Foundation (NRF2016NRF-NSFC002-005) and the Ministry of
Education (MOE 2013-T3-1-002), Singapore for financial sup-
port of this research.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: aldehydes
reactions · photocatalysis · synergistic catalysis
·
CÀH activation
· cross-coupling
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Manuscript received: September 8, 2017
Version of record online: && &&, 0000
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Communication
COMMUNICATION
Mood lighting: Visible-light-mediated
dual photoredox organocatalysis as a
mild and effective method for Csp2ÀH
activation of aldehydes is reported. The
resulting nucleophilic acyl radical spe-
cies can undergo either addition to
electrophilic alkenes or nickel-catalyzed
cross-coupling reactions to provide a
quick access to a broad range of unsym-
metrical ketones, commonly found in
many organic building blocks.
&
Organophotocatalysis
M. D. Vu, M. Das, X.-W. Liu*
&& – &&
Direct Aldehyde Csp2ÀH
Functionalization through Visible-
Light-Mediated Photoredox Catalysis
Chem. Eur. J. 2017, 23, 1 – 5
www.chemeurj.org
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ