Visible-Light-Mediated Umpolung Reactivity of Imines: Ketimine Reductions with Cy2NMe and Water

Article abstract of DOI:10.1021/acs.orglett.8b00778

A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D₂O as an inexpensive deuterium source (≥95% D ratio). The mechanism of this unusual transformation is probed.

Full text of DOI:10.1021/acs.orglett.8b00778

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Umpolung Reactivity of Imines: Ketimine
Reductions with Cy2NMe and Water
Rui Wang,† Mengyue Ma,† Xu Gong,† Grace B. Panetti,‡ 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, People’s Republic of 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: A novel carbanionic reactivity of imines mediated by
photoredox catalysis is demonstrated. The umpolung imine reactivity is
exemplified by proton abstraction from water as a key step in the reduction
of benzophenone ketimines to amines (up to 98% yield). Deuterium is
introduced into amines efficiently using D2O as an inexpensive deuterium
source (≥95% D ratio). The mechanism of this unusual transformation is
probed.
ver the past decade, photoredox catalysis has emerged as
a powerful tool to conduct radical transformations
sulfones, leading to homoallylic amine derivatives (Scheme 1,
eq 3).5
O
initiated by light energy.1 Under photoredox catalysis, imines
are reduced via single electron transfer (SET) processes to
generate highly reactive radical anion intermediates. Elegant
studies by the MacMillan and Molander groups have shown
that the imine radical anions undergo radical coupling reactions
with other alkyl radical intermediates to afford α-alkylated
amines (Scheme 1, eq 1).2 With aminomethyl radical species,
While imines have traditionally been used as electrophiles in
organic transformations, these recent photoredox studies shed
light on the potential reactivity of imines via C-centered
radicals. Although the reactivity can be envisioned to occur
through a carbon-based radical (Scheme 1, eqs 1−3), another
resonance form can be drawn with the radical on nitrogen, and
the anion on carbon, as illustrated in resonance form B
(Scheme 1, eq 4). Indeed, a previous report on electrochemical
reductions of imines has indicated that the radical anion
intermediates were stabilized by resonance A/B in some cases.6
Although B might be anticipated to exhibit umpolung reactivity,
such behavior has not been previously reported to our
knowledge. Herein, we disclose the umpolung reactions7 of
ketimines under photocatalytic conditions, as demonstrated by
their reduction8 in the presence of amines and water.
Scheme 1. Visible-Light-Mediated Imine Transformations
We have recently been interested in the umpolung9 and
radical reactivity10 of the azaallyl species derived from aldimines
and ketimines. The importance of amine derivatives in
medicinal chemistry inspired us to explore the reactivity of
imines under photoredox conditions. Unfortunately, our initial
experiments with the N-benzyl imine of benzaldehyde and a
variety of photoredox catalysts and sacrificial amines failed to
yield the desired reduction product 2, probably because of the
high energy of the carbanion-based resonance form B.6
We next turned our attention to ketimines derived from
benzophenone to better stabilize the carbanionic resonance
form B. Thus, with ketimine 1a, 10 equiv of water, and 2 equiv
of triethylamine as the sacrificial electron donor, reaction
mixtures were subjected to irradiation with a blue light-emitted
diode (LED) at room temperature in the presence of various
the radical coupling reactions with the imine radical anion
intermediates afforded ethylenediamine derivatives, as shown
by the Ooi and Rueping groups.3 Rueping, Sudo, and their co-
workers independently demonstrated the dimerization of these
radical anion intermediates (Scheme 1, eq 2).4 The teams of
Chen and Dixon discovered imine radical anions add to allylic
Received: March 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
photocatalysts (5 mol %). To our delight, the reduction
product 2a was generated in 41% assay yield (AY, determined
by HPLC) with the common photoredox catalyst [Ru(bpy)3]-
Cl2 (Ru-1) (Table 1, entry 1). Similar results were observed
87% AY) (Table 1, entry 9) or bulky tBu substituents on the
bipyridine ligand (Ir-6, 75% AY) (Table 1, entry 10). These
results suggest that catalysts with more electron-rich ligands
might exhibit greater activity. Therefore, we next examined
catalysts with fewer fluorines, while maintaining the tBu
substituents on the ligands. We were pleased to find that
excellent results were obtained with catalysts Ir-7, Ir-8, and Ir-9
(≥94% AY) (Table 1, entries 11−13).
Table 1. Optimization of Umpolung Reduction of Ketimine
a
1a Mediated by Visible Light
Sacrificial electron donors were screened next. Among the
five amines tested [TEA, NMe3, TMEDA, EtN(iPr)2 and
Cy2NMe], all gave excellent results (≥94% AY) (Table 1,
entries 13−17). It is noteworthy that quantitative yield was
observed with Cy2NMe after 40 min (Table 1, entry 17). With
the optimized catalyst and electron donor in hand, we next
focused on decreasing the catalyst loading. Although longer
reaction times were needed at lower loadings of Ir-9 (Table 1,
entries 18−20), excellent yields were maintained with catalyst
loadings as low as 0.1 mol % (98% isolated yield) (Table 1,
entry 20).
Encouraged by the efficiency of this catalytic reduction of
imines, we next aimed to explore the scope. The results are
summarized in Scheme 2. Substrates with benzyl groups
bearing ortho-, meta-, or para-chloro substituents worked
smoothly under the standard conditions (2b−2d) (82−93%).
Other halogens, e.g., 4-F (2e) (98%) or 4-Br (2f) (97%), also
gave very high yields. The substrate bearing a 4-CF3-substituted
b
entry
PC (5 mol %)
Ru-1
amine
TEA
yield (%)
1
2
41
40
Ru-2
TEA
3
Ru-3
TEA
N.D.
N.D.
N.D.
N.D.
N.D.
73
4
Ru-4
TEA
5
Ir-1
TEA
6
Ir-2
TEA
Scheme 2. Visible-Light-Mediated Umpolung
7
Ir-3
TEA
a
Transformation of Ketimines
8
Ir-4
TEA
9
Ir-5
TEA
87
10
11
12
13
14
15
16
Ir-6
TEA
75
Ir-7
TEA
95
Ir-8
TEA
94
Ir-9
TEA
95
Ir-9
TMA
TMEDA
DIPEA
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
94
Ir-9
96
Ir-9
97
c
17
Ir-9 (5 mol %)
Ir-9 (1 mol %)
Ir-9 (0.5 mol %)
Ir-9 (0.1 mol %)
99
d
18
99
e
19
99
f
20
99 (98)
a
Reactions conducted with 1a (0.1 mmol), H2O (1 mmol), catalyst
(0.1−5 mol %) and amine (0.2 mmol) in 1 mL MeCN at room
b
temperature under 20 W blue LED irradiation. Yields determined by
HPLC using mesitylene as internal standard. N.D. = not detected.
c
d
Catalyst loading = 5 mol %, reaction time = 40 min. Catalyst loading
e
= 1 mol %, reaction time = 100 min. Catalyst loading = 0.5 mol %,
reaction time = 4 h. Catalyst loading = 0.1 mol %, reaction time = 12
f
h, isolated yield: 98%.
when using [Ru(bpy)3](PF6)2, indicating that the anion of the
catalyst does not affect its reactivity (Table 1, entry 2).
However, the other ruthenium catalysts [Ru(bpz)3]Cl2 and
[Ru(bpz)3](PF6)2 were not effective in this transformation
(Table 1, entries 3 and 4). Catalyst fac-Ir(ppy)3 (Ir-1) and its
derivatives (Ir-2 and Ir-3) were also tested, but they did not
exhibit activity (Table 1, entries 5−7). However, when the
catalyst [Ir(2′,4′-F2-5-CF3-ppy)2(bpy)]PF6 (Ir-4) was used,
73% AY was obtained, suggesting higher activity of [Ir-
(ppy)2(bpy)]PF6 type catalysts (Table 1, entry 8). Slightly
improved AY was obtained when using related iridium catalysts
with either fewer fluorines on the phenyl-pyridine ligand (Ir-5,
a
Reaction was conducted with 1 (0.1 mmol), H2O (1 mmol), catalyst
(0.1 mol %) and Cy2NMe (0.2 mmol) in 1 mL MeCN at room
temperature under 20 W blue LED irradiation. Isolated yield.
B
DOI: 10.1021/acs.orglett.8b00778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzyl exhibited slightly decreased reactivity (2g) (84%). The
reductions were efficient when substrates with electron-
donating groups, such as 4-Me, 4-t-Bu or 4-OMe, were
employed, which provided the amine products in 90−94%
yields (2h−2j).
Another possible pathway to afford 2 entails a carbon-based
radical of either A or protonated A from a PCET process
(proton-coupled electron transfer),11 which abstracts a hydro-
gen atom from [Cy2NMe]+ • or Cy2NMe. To differentiate these
pathways from carbanion-based deprotonation of water, we
performed the reaction using D2O under the same conditions
Heterocycles are important in medicinal chemistry. With this
in mind, we examined substrates with heteroatom-substituted
benzyl groups. The 2- and 3-pyridyl derivatives afforded
products in 65% and 73% yields (2k and 2l, respectively).
Substrates bearing 2-thiophenyl and 2-furanyl groups furnished
products 2m and 2n in ≥97% yield. The N-phenyl imine
provided the reduction product 2o in 84% yield. The reaction
remained efficient when electron-withdrawing 2-F (2p) (94%)
or electron-donating 4-OMe substituents (2q) (93%) were
introduced into the N-aryl group. A heterocyclic substrate
bearing a N-(3-pyrridyl) imine was reduced in 86% yield (2r).
N-Alkyl imines were examined next. N-Methyl and n-butyl
imines afforded the products 2s and 2t in 95% and 92% yields,
respectively. Reaction with N-allyl imine led to 2u in excellent
yield (95%), indicating selectivity for reduction of the NC
bond over the CC bond. The use of benzophenone
derivatives with halogen 2-F, 2-Cl, or 4-Cl, or electron-donating
4-Me or 4-OMe groups did not affect the reactivity (83−96%)
(2v−2z). The 9-fluorenyl imine was also tested, affording the
amine product 2aa in 87% yield. Finally, when reduction of the
2-thiophenyl substrate was performed under the standard
conditions, the desired product 2ab was obtained in 84% yield.
It is noteworthy that the radical coupling adducts between
ketimines and Cy2NMe were not detected with these
substrates, indicating a different mechanism for the current
transformation, compared to previously reported radical
processes.3,4
We postulate that the catalytic cycle for ketimine reduction
starts with catalyst excitation by visible-light irradiation to give
[Ir]3+*, which then abstracts one electron from Cy2NMe to
produce [Ir]2+ and the amine radical cation. Subsequent single
electron transfer from [Ir]2+ to the ketimine regenerates [Ir]3+
and reduces imine 1 to the radical anion, which is stabilized by
resonance forms A3c,4a,5a and B.6 Since the N-radical in
resonance form B is highly reactive, it would be quickly
quenched by the Cy2NMe radical cation to give iminium
intermediate C. Subsequent deprotonation of H2O by the
ketiminyl anion forms a C−H bond, affording the final reduced
product 2 (see Scheme 3).
1
and monitored the reaction using H NMR spectroscopy in
MeCN-d3. Integration of the resulting reaction mixture
indicated 93% deuterium incorporation at the benzylic C−H
in the product, clearly showing that water supplies the proton
in the C−H bond-forming step (Scheme 4, eq 1).
Scheme 4. Probing the Reaction Pathway
To further examine the role of water, we performed the
reaction in the absence of added water in MeCN-d3 and
followed the reaction by 1H NMR spectroscopy (Scheme 4, eq
1
2). After 12 h of reaction, H NMR indicated a complex
mixture with 22% of starting material 1a, 44% of reduced
product 2a and 34% of unidentified side products, indicating
that water is essential for the completion of the umpolung
reduction. When the reaction was performed in the absence of
catalyst12 or Cy2NMe or was conducted in darkness, no
reduction product was observed, indicating each component is
essential for the reaction (see Scheme S1 in the Supporting
Information).
Conventionally, the introduction of a deuterium atom into
an imine requires expensive deuterated reducing agents, e.g.,
NaBD4. Our method offers an efficient way to make α-
deuterated amines using D2O, which is arguably the most ideal
deuterium source, because of its safety and low cost. Therefore,
several representative substrates were chosen to react with D2O
under the standard conditions. Excellent deuterium ratios were
obtained in all cases (≥95% D, 74−97% yield) (2k−2ab in
Scheme 5). The advantage of using D2O instead of other
expensive deuterated reducing agents was further exemplified
with large-scale reactions. Reaction of 1 mmol of 1o with D2O
was performed, furnishing the deuterated amine 2o(D) in 93%
yield with 97% D incorporation. The reaction scale was further
extended to 2 g of 1t (8.5 mmol), affording the α-deuterated
product 2t(D) in 95% yield and 98% D ratio.
Scheme 3. Postulated Reaction Pathway
In summary, photoredox catalysis has engendered new
transformations of imines, mainly via exploiting the carbon-
based radical reactivity of the radical anion intermediate A.
Herein, we advance a novel polarity-inverted reactivity of imine
radical anions. At this early stage of our work, we proposed that
the observed reactivity via the carbanionic resonance structure
B is favored, because of stabilization of the negative charge by
delocalization over the two aryl groups. Based on this reactivity,
we have developed an extremely efficient catalytic system for a
visible-light-mediated umpolung reduction of imines. Excellent
yields with a broad range of ketimine substrates have been
obtained. Our method is safer and more environmentally
friendly by harvesting light energy, compared to the traditional
C
DOI: 10.1021/acs.orglett.8b00778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 5. Synthesis of α-Deuterated Amines using D2O
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Reactions conducted with 1 (0.1 mmol), D2O (1 mmol), catalyst (0.1
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temperature under 20 W blue LED irradiation. Isolated yield. Large-
scale reactions were performed at 1 mmol scale for 2o and 8.5 mmol
scale for 2t.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00778.
■
S
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.).
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Xinyuan Fan: 0000-0002-3099-8495
Patrick J. Walsh: 0000-0001-8392-4150
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.J.W. is grateful to the NSF (No. CHE-1464744) for support.
X.F. thanks the Young Scientists Fund of the National Natural
Science Foundation of China (No. 21708020) and the Natural
Science Foundation of Jiangsu Provence (No. BK20170969)
for financial support.
D
DOI: 10.1021/acs.orglett.8b00778
Org. Lett. XXXX, XXX, XXX−XXX