Reductive Cross-Coupling of Aldehydes and Imines Mediated by Visible Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03394

Under photoredox catalysis conditions, the conventional electrophilic reactivity of ketimines is inverted to generate nucleophilic species. As a result, chemoselective cross-electrophile couplings between aldehydes and ketimines are achieved via umpolung

Full text of DOI:10.1021/acs.orglett.8b03394

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reductive Cross-Coupling of Aldehydes and Imines Mediated by
Visible Light Photoredox Catalysis
Rui Wang,† Mengyue Ma,† Xu Gong,† Xinyuan Fan,*,† and Patrick J. Walsh*,†,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816, P. R. China
‡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: Under photoredox catalysis conditions, the conventional
electrophilic reactivity of ketimines is inverted to generate nucleophilic
species. As a result, chemoselective cross-electrophile couplings between
aldehydes and ketimines are achieved via umpolung reactivity of ketimines
to furnish amino alcohols (44 examples with good to excellent yields). To
illustrate the utility of the amino alcohol products, 1,2-dihydroindol-3-
one-based fluorophores are easily synthesized using the coupling products.
Finally, a plausible reaction pathway is discussed.
Scheme 1. Reactivity of Imines under Various Conditions
mines are commonly used as electrophiles in coupling with
Inucleophilic partners to construct bioactive nitrogen-
containing compounds. Coupling of imines with electrophiles
(e.g., carbonyls), however, is challenging because it requires
reactivity inversion of the imine.1 It has been shown that the
CN double bond of imines reacts with metals and metalloids
(e.g., niobium, tantalum, ytterbium, titanium, lanthanum, tin,
silicon, and magnesium, among others) to generate metal-
laziridines or carbon−metal bonds, which are nucleophilic at
carbon (Scheme 1, eq 1).2 These species react with aldehydes
to afford amino alcohols. Addition of cyanides into the CN
double bond of imines is another method to invert the imine
reactivity. The nitrile moiety facilitates the generation of a
carbanionic species (Scheme 1, eq 2) that readily reacts with
aldimines to ultimately generate diimines.3 A recent strategy
involves conversion of the N-diarylmethyl imines into 2-
azaallyl anions by base-promoted deprotonation4 or decarbox-
ylation (Scheme 1, eq 3).5 These 2-azaallyl anion intermediates
are nucleophilic and have inspired many useful imine
transformations.5a,b,6
Over the past decade photoredox catalysis has emerged as a
powerful tool to initiate the radical reactivity of CX double
bonds (X = NR or O).7 For instance, imines accept an electron
during the photoredox catalytic cycle, generating reactive
radical anion intermediates exhibiting C-centered radical
reactivity. Such species undergo homocoupling to yield
ethylene diamine derivatives (Scheme 1, eq 4).8 Similarly,
homocoupling of carbonyls via radical pathways has been
demonstrated in the synthesis of pinacol coupling products
(Scheme 1, eq 5).8a,b Reports on nucleophilic reactivity of
imines mediated by photoredox catalysis, however, are scarce.9
Our team10 and Polyzos’group7n recently disclosed that α,α-
diarylketimines can be reduced to the corresponding amines
under photocatalytic conditions with sacrificial amines.7o In
our work, water acted as the proton source (or D2O, Scheme 1,
eq 6), supporting the proposed carbanionic nature of the
intermediate.10 This photocatalytic umpolung imine reactivity
was subsequently used by Yu and co-workers.11
Received: October 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03394
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Letter
These unusual results inspired us to explore the nucleophilic
reactivity of these intermediates toward other electrophiles.12
Compared to the reduction reaction, which generates C−H
bonds (Scheme 1, eq 6), the formation of C−C bonds is more
attractive for the introduction of complexity and the
construction of functional molecules. Efficient cross-electro-
phile coupling reactions between imines and aldehydes by
photoredox catalysis, however, are still challenging. This is
likely due to the prevailing radical coupling mechanisms,
necessitating the generation of two different types of radical
intermediates under the same conditions and their highly
chemoselective coupling. Herein, we report a novel and
efficient cross-electrophile coupling of ketimines with
aldehydes mediated by photoredox catalysis using visible
light (Scheme 1, eq 7).
[Ru(bpy)3](PF6)2 (Ru-1), and [Ru(bpz)3](PF6)2 (Ru-2) were
examined, but led to decreased AY or no observed product.
Sacrificial amines were next examined. Interestingly, all the
amines tested were effective reductants and promoted the
cross-electrophile coupling reaction (TMA, TEA, DIPEA, and
TMEDA, 80−89% AY), with Cy2NMe being optimal (95%
AY).
Encouraged by the excellent reactivity under the optimized
conditions, we next aimed to explore the scope of the cross-
electrophile coupling reaction (Scheme 3). The isolated yield
Scheme 3. Cross-Electrophile Couplings between
Benzaldehyde and Ketimines
We initiated our study with cross-electrophile coupling
between benzophenone imine (1a, 1.0 equiv) and benzalde-
hyde (2a, 1.2 equiv) in acetonitrile, with Cy2NMe as the
sacrificial electron donor and [Ir(4′-F-ppy)2bpy]PF6 (Ir-1) as
the photoredox catalyst (Scheme 2). To our delight, under
Scheme 2. Examination of Photoredox Catalysts and
Sacrificial Electron Donors for the Cross-Electrophile
Coupling Reaction
from coupling 1a with benzaldehyde was 94% (3aa). Replacing
the benzylic aryl of the ketimine 1a with differentially
substituted aryls did not significantly affect the reactivity
(3ab−3ai, 79−93% yields). Ketimines with heterocyclic
substituents, N-(2-pyridylmethyl), N-(3-pyridylmethyl), N-(2-
thiophenylmethyl), and N-(2-furanylmethyl)ketimines, reacted
smoothly with benzaldehyde to afford the corresponding
products (3aj−3am, 81−88% yields). The 4,4′-dichlorobenzo-
phenone ketimine was also tested, giving the desired product
3an in 83% yield. The current photoredox catalyzed reaction
conditions were effective with cross-electrophile coupling
reactions between benzaldehyde and N-phenyl ketimine or
its halogen-substituted analogues (3ao−3ar, 72−90%). Heter-
ocyclic N-(3-pyridyl)ketimine was coupled with benzaldehyde
in 76% yield (3as). Reaction of N-n-butyl ketimine afforded
the product in 90% yield (3at), and the N-allyl ketimine
provided the product in 82% yield (3au). 4-Methyl and 4-
methoxy benzophenone ketimines coupled with 2a smoothly
(3av, 68%; 3aw, 64%). Reactions with 2-thiophenyl ketimines
yielded the desired products in good yields (3ax, 71%; 3ay,
blue LED light irradiation, the desired β-amino alcohol
product 3aa was obtained in 25% assay yield [AY, determined
by 1H NMR, see Supporting Information (SI) for details].
Interestingly, modification of the bipyridine ligand of the
iridium catalyst with tert-butyl groups at the 4,4′-positions
dramatically improved the AY (93%, Ir-2). Further introduc-
tion of fluorine atoms (Ir-3) or trifluoromethyl groups (Ir-4)
into the catalyst, however, decreased the AY to 82% and 42%,
respectively. We next tested [Ir(ppy)2(4,4′-tBu-bpy)]PF6 (Ir-
5), which contains no fluorine but maintains the tert-butyl
groups on the bipyridine ligand. Excellent AY (95%) was
obtained with catalyst Ir-5. The commonly used photoredox
catalysts fac-Ir(ppy)3 (Ir-6) and its analogues (Ir-7 and Ir-8),
B
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Letter
82%). The alkyl ketimine derived from 2-naphthylmethyl
ketone reacted with benzaldehyde to give the coupling product
3az in 69% yield. Throughout these studies, the use of
unsymmetrical benzophenone imines resulted in formation of
diastereomers (∼1:1 dr).
Scheme 5. Transformations of Representative Products
The aldehyde scope was examined next (Scheme 4).
Halogen substituted benzaldehydes coupled with ketimine 1a
Scheme 4. Cross-Electrophile Couplings between Aldehydes
and Ketimines
thiol−ene click reaction,16 was obtained in 52% yield. It is
noteworthy that the product structure can be easily fine-tuned
using our cross-electrophile coupling method, making it
possible to adjust the fluorophore spectra, as well as to anchor
different functional groups for diverse applications.
To rationalize the observed reactivity, we postulate that the
catalyst is irradiated by visible light to its excited state [Ir]3+*,
which is reduced by Cy2NMe to generate [Ir]2+ and the amine
radical cation, [Cy2NMe]+•. Ketimine 1 is activated by the
amine radical cation, [Cy2NMe]+•, to form a 2-center-3-
electron interaction.8a,17 This complex is then reduced by one
electron from [Ir]2+ and forms the radical anion intermediate
A/B.18 Due to the high reactivity of the N-centered radical, B
is quickly quenched by HAT from [Cy2NMe]+ to give the
intermediate carbanion C and the iminium ion. Carbanion C
attacks the aldehyde via nucleophilic addition, ultimately
affording the β-amino alcohol product (Scheme 6A). The
Scheme 6. Plausible Reaction Pathway
smoothly in good yields (3ba−3ga, 63−87% yields).
Benzaldehydes with electron-withdrawing 4-CF3 or electron-
donating 2-methyl, 4-methyl, or 4-tert-butyl groups reacted
with imines 1 effectively, affording the desired products in high
yields (3ha−3ka, 77−95% yields). Alkyl aldehydes, such as n-
propanal and cyclohexanal, were also readily coupled with
imine 1a under the optimal conditions (3la, 80%; 3ma, 64%).
Heterocyclic substrates 2-furanyl aldehyde and 2-thiophenyl
aldehyde furnished the desired products in high yields (3la,
79%; 3ma, 85%). The coupling between 2-thiophenyl ketimine
1y with n-propanal, 2-furanyl aldehyde, or 2-thiophenyl
aldehyde afforded the corresponding products (3ly, 75%;
3ny, 79%; 3oy, 71%). To our delight, n-propanal also coupled
with the 2-naphthylmethyl ketimine under the optimal
conditions to give the desired product (3zy, 77% yield).
We next set out to demonstrate the utility of the products
prepared above. One-step conversion of 3ar into benzomor-
pholines, which are core structures of potentially bioactive
compounds,13 was achieved in 70% yield via a O-arylation
reaction (Scheme 5, eq 8). A second application of our
products was realized by conversion to fluorescent organic
molecules, which play important roles in biological studies
(biomolecule labeling, living system imaging, activity probing,
etc.).14 Cyclization of 3ea by Buchwald−Hartwig amination,
followed by Dess-Martin periodinane (DMP) oxidation,
yielded 1,2-dihydroindol-3-one type fluorophores (Scheme 5,
eq 9).15 Fluorophore 6a was synthesized in 60% overall yield.
Its vinyl-functionalized analogue 6b, which is capable of
labeling biomolecules-containing free thiol groups via the
postulated ketimine activation pathway is based on the
umpolung reactivity of diarylketimines under photoredox
catalysis observed by us10 and Polyzos7n and under electro-
chemical conditions by Reed.18a Indeed, our previous
computational calculation on the spin density of the radical
anion intermediate supported that B is more favorable than A
since the nitrogen atom carries more radical character than the
carbon atom (see SI).18b However, a radical coupling
mechanism involving both aldehyde and ketimine reductions
is also possible based on the previously reported pinacol
C
DOI: 10.1021/acs.orglett.8b03394
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, reductive coupling of imines with aldehydes by
stoichiometric metal complexes is a synthetically valuable
transformation. To avoid the use of highly reactive metal-based
reagents, and circumvent generation of copious waste
products, we have demonstrated the photoredox catalyzed
cross-electrophile coupling of ketimines and aldehydes. Such
reactions generally proceed via radical−radical coupling
mechanisms. In contrast, we have demonstrated cross-electro-
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pathway with photoredox catalysis. The advantages of the
nucleophilic addition are exemplified with the cross-electro-
phile couplings between ketimines and aldehydes, which are
difficult to achieve via radical−radical coupling pathways due
to challenges associated with the generation of two different
radical species and their chemoselective coupling. We have also
demonstrated that the amino alcohol products prepared herein
are easily converted into biological fluorescent probes or
biologically active compounds by palladium catalyzed coupling
reactions. Other transformations exploiting the novel umpo-
lung reactivity of imines are currently underway in our group.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03394.
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Procedures, characterization data, and spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xinyuanfan@pku.edu.cn (X.F.).
*E-mail: pwalsh@sas.upenn.edu (P.J.W.).
ORCID
Xinyuan Fan: 0000-0002-3099-8495
Patrick J. Walsh: 0000-0001-8392-4150
Notes
(7) (a) Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.;
Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 17735. (b) Hager, D.;
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Chem. Soc. 2015, 137, 8404. (e) Fava, E.; Millet, A.; Nakajima, M.;
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2016, 52, 14434. (g) Kizu, T.; Uraguchi, D.; Ooi, T. J. Org. Chem.
2016, 81, 6953. (h) Qi, L.; Chen, Y. Angew. Chem., Int. Ed. 2016, 55,
13312. (i) Fava, E.; Nakajima, M.; Nguyen, A. L.; Rueping, M. J. Org.
Chem. 2016, 81, 6959. (j) Li, W.; Duan, Y.; Zhang, M.; Cheng, J.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
X.F. thanks the Young Scientists Fund of the National Natural
Science Foundation of China (21708020) and the Natural
Science Foundation of Jiangsu Provence (BK20170969) for
financial support. P.J.W. is grateful to the NSF (CHE-
1464744) for support.
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