Visible-Light-Promoted Intramolecular α-Allylation of Aldehydes in the Absence of Sacrificial Hydrogen Acceptors

Article abstract of DOI:10.1021/acs.orglett.0c02742

We report herein an unprecedented protocol for radical cyclization of aldehydes with pendant alkenes via synergistic photoredox, cobaloxime, and amine catalysis. The transformation was achieved in the absence of external oxidants, providing a variety of 5-, 6-, and 7-membered ring products with alkene transposition in satisfactory yields. The reaction exhibits wide functional group compatibility and occurs under mild conditions with extrusion of H2.

Full text of DOI:10.1021/acs.orglett.0c02742

pubs.acs.org/OrgLett
Letter
Visible-Light-Promoted Intramolecular α‑Allylation of Aldehydes in
the Absence of Sacrificial Hydrogen Acceptors
Jia-Li Liu,# Jia-Lin Tu,# and Feng Liu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02742
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ABSTRACT: We report herein an unprecedented protocol for
radical cyclization of aldehydes with pendant alkenes via synergistic
photoredox, cobaloxime, and amine catalysis. The transformation
was achieved in the absence of external oxidants, providing a
variety of 5-, 6-, and 7-membered ring products with alkene
transposition in satisfactory yields. The reaction exhibits wide
functional group compatibility and occurs under mild conditions
with extrusion of H2.
Scheme 1. Cobalt-Catalyzed Radical−Olefin Coupling for
C−C bond Formation
he formation of C−C bonds via radical reactions is
T
acknowledged as a powerful strategy in organic synthesis.
Transition metals are capable of mediating the generation of
carbon-centered radicals and, most importantly, providing high
levels of control over regio- and stereoselectivity of the radical
reactions through a catalytic process.1,2 In particular, the Heck-
type reaction3 via cobalt-catalyzed radical-olefin coupling was
recognized as a valuable approach for synthesis of function-
alized alkene derivatives, which are achieved by an addition/
elimination sequence of organocobalt intermediates.4−7 Of
these reports, Oshima reported an intermolecular Heck-type
reaction of alkyl halides with styrenes in the presence of
superstoichiometric Me3SiCH2MgCl via cobalt−phosphine
catalysis (Scheme 1a).4 Furthermore, Carreira et al. described
the cobaloxime-catalyzed intramolecular Heck-type coupling of
alkyl iodides with olefins upon visible-light irradiation (Scheme
1a).5 Carboxylic acids and alkanes, as abundant and
inexpensive feedstocks, have been also employed as efficient
alkyl radical precursors for cobalt-catalyzed olefination8 and
Heck-type reactions (Scheme 1b).6 Note that powerful
photoredox catalysts are essential for the radical decarbox-
ylation, and external oxidant is not required in these examples.
Despite the aforementioned efforts, the use of other alkyl
radical precursors to develop new cobalt-catalyzed radical-
olefin reactions to meet various synthetic demands is still of
great interest. Electron-rich enamine derived from carbonyl
compound could be liable to lose an electron to produce
enaminyl radical species via photoredox catalysis.9 Thus, we
envisioned that this electrophilic radical would undergo
addition to an alkene to generate a C−C bond and a new
alkyl radical, followed by β-H elimination to give a new double
bond through cobaloxime catalysis.
functionalization of carbonyl compounds via the catalytic
generation of reactive electron-rich enamine nucleophiles.11−14
MacMillan et al. described that stoichiometric oxidation of a
transiently formed enamine could proceed smoothly to provide
Received: August 16, 2020
The α-functionalization of carbonyl compounds is a
fundamental and well-established synthetic strategy for
creating new C−C bonds.10 The amine-catalyzed process
could enable the development of valuable methods for α-
https://dx.doi.org/10.1021/acs.orglett.0c02742
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
an enaminyl radical intermediate, which can be readily
intercepted by a variety of prefunctionalized/activated olefins,
thus giving the α-allyl products via an additional oxidation
process.15−17 However, these methods require (1) at least 2
equiv of external oxidant and (2) the need for pregenerated
olefin partners (for example, allyl silanes, silyl ketene, or
acetals).9 Herein, we report an intramolecular α-allylation of
aldehydes with pendant alkenes for synthesis of various
hetero/carbocyclic ring systems via the synergistic merging
of a cobaloxime catalyst, a photoredox catalyst, and an amine
catalyst in the absence of external oxidant (Scheme 1c).
Intramolecular α-allylation of aldehyde 1a upon visible light
irradiation (22 W blue LEDs) was chosen as a model reaction.
After evaluation of a variety of organic solvents, photocatalysts,
Co catalysts, and amine catalysts (Table 1 and Tables S1−S3),
we were pleased to find that, with 2.5 mol % of
[Ir(ppy)2(dtbbpy)]PF6, 5 mol % of Co(dmgH)2(4-CN-
Py)Cl, and 20 mol % of morpholine as the triple catalyst
system and DMSO (0.1 M) as the solvent, the catalytic
reaction readily offered the cyclization trans-product 2a in 80%
yield at rt (Table 1, entry 10). The control experiments
revealed that the photoredox catalyst, Co catalyst, amine
catalyst, and visible light were all essential for the success of the
reaction (Table 1, entries 14−17).
Having established optimal conditions for the visible-light-
promoted reaction, the substrate scope and limitation were
then investigated. As shown in Scheme 2, the method exhibited
quite general scope with respect to structural diversity of the
linkers and the pendant alkenes. As might be expected, this
radical transformation achieved high stereocontrol at the two
carbon centers involved in the cyclization. Note that the radical
cyclization might be reversible.9 The substrates with various
aromatic substitutions installed on the double bonds proved to
be suitable for the reaction, affording the functionalized
piperidines 2c−k and 2s−t in good yields. Other aldehyde
derivatives that possess a broad array of pendant 1,2,2-
trisubstituted or 1,2-disubstituted alkenes were also well
accommodated by this catalytic reaction, furnishing the desired
products in satisfactory yields (2l−r and 2u). In the example of
2q, the reaction proceeded smoothly to achieve good E/Z
selectivity. We further explored the 5-exo, 6-endo, 7-exo, and 7-
endo cyclization (3a−e). This protocol would allow access to
the 5-, 6-, and 7-membered cyclic ring systems, although the 7-
exo cyclization is not effective. To demonstrate the synthetic
utility of the method, a gram-scale reaction (1.01 g of 1j) was
conducted. The reaction still proceeded very well, providing
the desired product 2j in 70% yield.
a
Table 1. Optimization of Reaction Conditions
b
yield
entry solvent
photocatalyst
Co catalyst
(%)
1
DMSO [Ir(ppy)2(dtbbpy)]
PF6
Co(dmgH)(dmgH2)
Cl2
71
We further examined intermolecular radical-olefin coupling
through the triple catalytic system. The reaction of aldehyde 4
and α-methylstyrene, as might be expected, gave the desired α-
allyl aldehyde 5 in 36% yield though the aldol-type product
was also isolated in 34% yield (Scheme 3, eq 1). On the other
hand, we found that the reaction of 3-phenylpropanal (7), in
the absence of olefin coupling partner, furnished cinnamalde-
hyde (8) as the direct dehydrogenative product (Scheme 3, eq
2). These results demonstrated that the competitive aldol
reaction and direct dehydrogenative mode for α,β-unsaturated
aldehyde formation could influence the outcome of this triple
catalytic reaction.
2
DMF
[Ir(ppy)2(dtbbpy)]
PF6
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)(dmgH2)
Cl2
41
<5
23
<5
7
3
MeCN [Ir(ppy)2(dtbbpy)]
PF6
4
PhCl
DCE
THF
[Ir(ppy)2(dtbbpy)]
PF6
[Ir(ppy)2(dtbbpy)]
PF6
[Ir(ppy)2(dtbbpy)]
PF6
5
6
Co(dmgH)(dmgH2)
Cl2
7
DMSO Ir(ppy)3
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)(dmgH2)
Cl2
Co(dmgH)2(4-CN-
Py)Cl
Co(dmgH)2(4-OMe-
Py)Cl
Co(dmgH)2(4-CF3-
Py)Cl
10
25
<5
80
27
72
34
<5
0
8
DMSO Ru(bpy)3(PF6)2
On the basis of our observations and previous reports,6−8
a
−
9
DMSO Acr+-Mes ClO4
proposed mechanism is outlined in Scheme 4. The process
begins with the condensation of morpholine catalyst and an
aldehyde to give an enamine intermediate, followed by a single-
electron oxidation to provide the critical enaminyl radical
cation species A. Subsequently, this electrophilic radical readily
undergoes cyclization to form an alkyl radical B. The reduced
photosensitizer IrII complex can be oxidized by the CoIII
catalyst to accomplish the photoredox catalytic cycle, as well
as the generation of a CoII complex. Next, the alkyl radical B
could be captured by the CoII complex to generate an
organocobalt(III) complex C. The subsequent β-H elimination
process occurs to furnish the olefin product 2 and a CoIII−H
intermediate while also liberating the amine catalyst through
hydrolysis. Finally, protonation of the CoIII−H complex leads
to completion of the cobalt catalytic cycle and H2 extrusion.
In summary, we have developed a visible-light-mediated
cyclization approach for synthesis of formyl-substituted
heterocycles and carbocycles with alkene transposition. With
the merger of cobalt catalysis, photoredox catalysis, and amine
10
11
12
13
14
15
16
17
DMSO [Ir(ppy)2(dtbbpy)]
PF6
DMSO [Ir(ppy)2(dtbbpy)]
PF6
DMSO [Ir(ppy)2(dtbbpy)]
PF6
DMSO [Ir(ppy)2(dtbbpy)]
PF6
CoCl2·6H2O
c
DMSO [Ir(ppy)2(dtbbpy)]
PF6
DMSO
Co(dmgH)2(4-CN-
Py)Cl
Co(dmgH)2(4-CN-
Py)Cl
DMSO [Ir(ppy)2(dtbbpy)]
PF6
DMSO [Ir(ppy)2(dtbbpy)]
PF6
0
d
Co(dmgH)2(4-CN-
Py)Cl
0
a
1a (0.20 mmol), photocatalyst (2.5 mol %), Co catalyst (5 mol %),
morpholine (20 mol %), and solvent (2 mL), rt, blue LEDs (22 W),
b
c
d
24 h. Isolated yield (%). In the dark. Without amine catalyst.
B
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Scheme 2. Substrate Scope of Aldehydes with Pendant
Alkenes
Scheme 3. Further Experiments
a b
,
Scheme 4. Proposed Mechanism
catalysis, the radical reaction proceeds well under mild,
external-oxidant-free conditions and exhibits wide functional-
group compatibility. Notably, this multicatalytic method could
be applicable to 5-exo, 6-exo, 6-endo, and 7-endo cyclization.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02742.
Experimental details, characterizations, and copies of 1H
and 13C NMR spectra for all compounds (PDF)
Accession Codes
CCDC 2023542 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Feng Liu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China; orcid.org/0000-0003-
2669-5448; Email: fliu2@suda.edu.cn
Authors
a
Reaction conditions: 1 (0.20 mmol), [Ir(ppy)2(dtbbpy)]PF6 (2.5
Jia-Li Liu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China
mol %), Co(dmgH)2(4-CN-Py)Cl (5 mol %), morpholine (20 mol
b
%), and DMSO (2 mL), rt, blue LEDs (22 W), 24 h. Isolated yield.
1
Diastereoselectivity ratio (d.r.) and E/Z ratio determined by the H
c
NMR spectra. 1j (1.01 g, 2.4 mmol).
C
https://dx.doi.org/10.1021/acs.orglett.0c02742
Org. Lett. XXXX, XXX, XXX−XXX

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pubs.acs.org/OrgLett
Letter
(7) (a) Zhang, G.; Zhang, L.; Yi, H.; Luo, Y.; Qi, X.; Tung, C.-H.;
Wu, L.-Z.; Lei, A. Visible-Light Induced Oxidant-Free Oxidative
Cross-Coupling for Constructing Allylic Sulfones from Olefins and
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(c) Tu, J.-L.; Liu, J.-L.; Tang, W.; Su, M.; Liu, F. Radical Aza-
Cyclization of α-Imino-oxy Acids for Synthesis of Alkene-Containing
N-Heterocycles via Dual Cobaloxime and Photoredox catalysis. Org.
Lett. 2020, 22, 1222.
Jia-Lin Tu − Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02742
Author Contributions
#J.-L.L. and J.-L.T. contributed equally to this work.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of the
Jiangsu Higher Education Institutions of China (Grant No.
18KJA350001) and the Priority Academic Program Develop-
ment of the Jiangsu Higher Education Institutes (PAPD) is
acknowledged. We are grateful to Prof. Lin He from Lanzhou
Institute of Chemical Physics (LICP) for training on and use
of a GC for H2 detection.
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