Electroselective and Controlled Reduction of Cyclic Imides to Hydroxylactams and Lactams

Article abstract of DOI:10.1021/acs.orglett.1c00430

An efficient and practical electrochemical method for selective reduction of cyclic imides has been developed using a simple undivided cell with carbon electrodes at room temperature. The reaction provides a useful strategy for the rapid synthesis of hydroxylactams and lactams in a controllable manner, which is tuned by electric current and reaction time, and exhibits broad substrate scope and high functional group tolerance even to reduction-sensitive moieties. Initial mechanistic studies suggest that the approach heavily relies on the utilization of amines (e.g., i-Pr2NH), which are able to generate α-aminoalkyl radicals. This protocol provides an efficient route for the cleavage of C-O bonds under mild conditions with high chemoselectivity.

Full text of DOI:10.1021/acs.orglett.1c00430

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Letter
Electroselective and Controlled Reduction of Cyclic Imides to
Hydroxylactams and Lactams
Ya Bai, Lingling Shi, Lianyou Zheng, Shulin Ning, Xin Che, Zhuoqi Zhang, and Jinbao Xiang*
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ABSTRACT: An efficient and practical electrochemical method for selective reduction of cyclic imides has been developed using a
simple undivided cell with carbon electrodes at room temperature. The reaction provides a useful strategy for the rapid synthesis of
hydroxylactams and lactams in a controllable manner, which is tuned by electric current and reaction time, and exhibits broad
substrate scope and high functional group tolerance even to reduction-sensitive moieties. Initial mechanistic studies suggest that the
approach heavily relies on the utilization of amines (e.g., i-Pr2NH), which are able to generate α-aminoalkyl radicals. This protocol
provides an efficient route for the cleavage of C−O bonds under mild conditions with high chemoselectivity.
ydroxylactams and lactams are important structural
motifs of a variety of bioactive compounds in medicinal
While numerous methods exist to generate hydroxylac-
tams10 and lactams,11 the selective monoreduction of readily
available imides represents the most straightforward and
efficient route to both classes of compounds.12 Over the past
several decades, considerable efforts have been devoted to the
development of convenient reductive approaches to access
hydroxylactams and lactams (Scheme 1). Conventional
chemical reduction of imides for the synthesis of hydrox-
ylactams and lactams generally rely on hydride reagents,13−15
metal reductants,16 or transition-metal catalysts.17,18 For
example, the application of common hydride reagent NaBH4
yields hydroxylactams, but the reduction product was always
accompanied by over-reduction byproducts.13 Use of another
typical hydride reagent polymethylhydrosiloxane (PMHS)
leads to N-alkyl hydroxylactams or N-alkyl lactams.14,15
Metal reductant zinc can be used for the reduction of
phthalimides to the corresponding lactams under acidic
conditions.16 The application of ruthenium catalysts is an
important methodology for the selective reduction of imides at
hydrogen pressures.17,18 So far, few imides have been explored
for the synthesis of hydroxylactams or lactams on the
utilization of photoredox catalysis.19 In 2003, Griesbeck’s
H
chemistry.1 For example, chlorthalidone is a prescription drug
used to treat high blood pressure (Figure 1).2 Azaspirene,
Figure 1. Important biologically active compounds involving the
hydroxylactam and lactam motif.
isolated from fungus of Neosartorya sp., is an angiogenesis
inhibitor.3 7-Hydroxystaurosporine is a protein kinase inhibitor
with potential as an anticancer agent.4 Staurosporine, isolated
from Streptomyces sp. in 1977, is a cell permeable alkaloid
exhibiting anticancer activity.5 Hericenone B, isolated from the
fruiting body of Hericium erinaceum, has a strong antiplatelet
activity.6 EM-12, an analogue of thalidomide, showed potential
antiangiogenic activity.7 Lenalidomide is a medication used to
treat multiple myeloma and myelodysplastic syndromes.8
Indoprofen is a nonsteroidal anti-inflammatory drug
(NSAID).9
Received: February 4, 2021
Published: March 8, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00430
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2298−2302
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a
Scheme 1. Reduction Strategies of Cyclic Imides to
Hydroxylactams and Lactams
Table 1. Optimization of the Reaction Conditions
b
entry
variation from standard conditions
yield (%)
1
2
3
none
graphite as cathode
94
44
50
90
73
71
23
9
MeOH instead of EtOH
CH2Cl2 instead of EtOH
morpholine instead of i-Pr2NH
i-Pr2NEt instead of i-Pr2NH
pyridine instead of i-Pr2NH
no i-Pr2NH
c
4
5
6
7
8
9
no electric current
25 mA instead of 20 mA
0
d
10
86(3a, R2 = H)
a
Standard conditions: graphite anode, RVC cathode, 1a (0.4 mmol),
i-Pr2NH (2.4 mmol), n-Bu4NBF4 (0.6 mmol), EtOH (6 mL),
undivided cell, constant current = 20 mA, room temperature, 2 h.
b
c
Isolated yield. 3 Å molecular sieves (300 mg) were added.
d
Graphite anode, RVC cathode, 1a (0.4 mmol), i-Pr2NH (2.4
mmol), n-Bu4NBF4 (0.6 mmol), EtOH (6 mL), undivided cell,
constant current = 25 mA, room temperature, 3 h.
or using another base such as morpholine (entry 5), i-Pr2NEt
(entry 6), or pyridine (entry 7).29 i-Pr2NH and electrical
current are necessary for this reaction on the basis of control
experiments (entries 8 and 9). Furthermore, adjusting the
current to 25 mA and prolonging the reaction time to 3 h
resulted in 86% lactam 3a (entry 10), indicated that the
chemoselectivity of the electroreduction can be readily
controlled by changing the current and reaction time.
group reported the photoreduction of N-methylphthalimide
for the synthesis of corresponding hydroxylactam and lactam,
but poor chemoselectivity was observed.19d The electrosyn-
thesis of hydroxylactams and lactams from phthalimides has
been reported by several groups.20−27 However, all cases
employ a divided cell system to afford reduced products, and
toxic Pb/Hg cathode was required for the synthesis of lactams
(R2 = H).26,27 Consequently, despite these promising
advances, it still remains a significant challenge to develop a
general and efficient protocol that allows for highly selective
monoreduction of imides to afford diverse hydroxylactams and
lactams with broad substrate scope under mild reaction
conditions.
As part of our continuing effort in developing new
electrochemical methods,28 herein we report a new practical
electrosynthetic approach to the highly selective and controlled
reduction of imides using a simple undivided cell with
inexpensive carbon electrodes.
We first identified the optimal reaction conditions for the
electrochemical reduction of N-phenylphthalimide 1a, which
involved constant-current electrolysis using a reticulated
vitreous carbon (RVC) cathode and graphite anode in an
undivided cell containing i-Pr2NH, n-Bu4NBF4, and EtOH at
room temperature for 2 h (Table 1) (see Supporting
Information for an extensive sampling). Under these mild
conditions, the desired hydroxylactam 2a was isolated in 94%
yield (entry 1). In comparison, reduced yields were obtained
when the reaction conditions were modified in one of the
following manners: changing the cathode to graphite (entry 2),
changing the solvent to MeOH (entry 3) or CH2Cl2 (entry 4),
Having optimized the reaction conditions, we next examined
the scope of the electroreduction reaction by testing a series of
imides (Table 2). To our satisfaction, high reactivity and
selectivity were observed with aromatic and aliphatic
substrates. A variety of functional groups, including alkoxy
(OEt), alkyl (Me), halogen (F), and ester (CO2Et)
substituents in the N-phenyl ring, were tolerated in the
reaction system (2a−e, 3a−e). Moreover, it is important that a
range of reduction-sensitive N-alkyl functional groups,
including alkenes, alkynes, epoxides, halides, esters, and
ketones were all well compatible with our electrochemical
conditions (2f−p, 3f−p). Furthermore, it is interesting to note
that tuning the electron density of the benzene ring had a
significant effect on the regioselectivity. Two isomers were
obtained for electron-donating groups (2q and 2r, 3q and 3r),
while a single product was obtained for electron-withdrawing
groups (2s, 3s). As expected, only the product 2t or 3t was
obtained when azaphthalimide 1t was used. Finally, the desired
product can also be obtained from nonconjugated imide by
slightly changing the reaction conditions, albeit in lower yield
(2u, 3u). Notably, we did not observe further reduction
toward the corresponding isoindolines in any of the cases.
These results indicated that the electroreduction reaction
exhibits high selectivity toward the functional group.
To further evaluate the practicality of our electrochemical
method, we performed the reaction on a 6 mmol scale
(Scheme 2). By prolonging the reaction time to 24 and 30 h
under the corresponding conditions, the products 2a and 3a
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a c
,
b c
,
Table 2. Synthesis of Hydroxylactams 2 and Lactams 3
Scheme 2. Gram-Scale Experiments
(see Supporting Information for details), suggesting that a
radical process should be involved in the electroreduction
reaction (Scheme 3A,B).
Scheme 3. Radical-Trapping Experiments
To further elucidate the mechanism of this reaction,
deuterium-labeling experiments using C2H5OD instead of
EtOH were conducted for the reduction of imide 1a under the
corresponding standard conditions, [D]-2a (90% D incorpo-
ration) and [D]-3a (83% D incorporation) were isolated in
90% and 86% yield, respectively (Scheme 4A,B). It is
noteworthy that 90% yield of 2a was obtained when the
aprotic solvent CH2Cl2 was used instead of EtOH performed
in standard conditions (entry 4, Table 1). Furthermore, with
CH2Cl2 as the solvent, no product 2a was detected when i-
Pr2NH was changed to pyridine or 2,2,6,6-tetramethylpiper-
idine (TEMP) (See Supporting Information), and 68% yield of
2a was isolated when i-Pr2NH was changed to i-Pr2NEt
(Scheme 4C). The results showed that only those reagents
able to generate an α-aminoalkyl radical promoted the desired
reactivity. To further validate the role of i-Pr2NH, the model
experiment was performed using i-Pr2ND instead of i-Pr2NH
and CH2Cl2 as the solvent; [D]-2a (47% D incorporation) and
[D]-3a (41% D incorporation) were obtained in 36% and 54%
yield, respectively (Scheme 4D).
a
Standard conditions (except where designated): graphite anode,
RVC cathode, 1 (0.4 mmol), i-Pr2NH (2.4 mmol), n-Bu4NBF4 (0.6
mmol), EtOH (6 mL), undivided cell, constant current = 20 mA,
b
room temperature. Standard conditions (except where designated):
graphite anode, RVC cathode, 1 (0.4 mmol), i-Pr2NH (2.4 mmol), n-
Based on the observations above and literature report-
s,19a,22,30 a possible mechanism for the electroreduction
reaction was proposed using 1a as model substrate (Scheme
5). As a start, diisopropylamine undergoes fast proton
exchange with EtOH and loses proton and electron at the
anode to generate the α-aminoalkyl radical 4, which exists in
equilibrium with alkylaminyl radical 5. Meanwhile, 1a obtains a
proton and an electron at the cathode producing the radical
intermediate 7, followed by direct C−H abstraction from
radical 4 or 5 to furnish product 2a and N-isopropyl-2-
propanimine 6. Subsequently, compound 2a undergoes
Bu4NBF4 (0.6 mmol), EtOH (6 mL), undivided cell, constant current
c
d
= 25 mA, room temperature. Isolated yield. Constant current = 25
e
f
g
mA. i-Pr2NH (0.8 mmol). Constant current = 30 mA. DMSO
h
I
instead of EtOH, 45 °C. i-Pr2NH (3.2 mmol). CF3CH2OH (TFE)
instead of EtOH; i-Pr2NEt instead of i-Pr2NH.
were obtained in 87% and 82% yield, respectively, which
demonstrated the synthetic utility of this methodology.
Radical-trapping experiments indicated that the desired
product 2a or 3a was completely suppressed when radical
scavenger TEMPO was added under the standard conditions
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Scheme 4. Control Experiments
Detailed synthesis procedures and compound character-
ization (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Jinbao Xiang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China; orcid.org/0000-0002-2628-3075;
Email: jbxiang@jlu.edu.cn
Authors
Ya Bai − The Center for Combinatorial Chemistry and Drug
Discovery of Jilin University, The School of Pharmaceutical
Sciences, Jilin University, Changchun, Jilin 130021, P. R.
China
Lingling Shi − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Lianyou Zheng − The Center for Combinatorial Chemistry
and Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Shulin Ning − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Scheme 5. Proposed Reaction Mechanism
Xin Che − The Center for Combinatorial Chemistry and Drug
Discovery of Jilin University, The School of Pharmaceutical
Sciences, Jilin University, Changchun, Jilin 130021, P. R.
China
Zhuoqi Zhang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00430
protonation and loses a molecule of H2O to form the iminium
ion 8, which obtains an electron at the cathode producing the
radical 9. Finally, intermediate 9 extracts a hydrogen atom
from radical 4 or 5 to yield the corresponding product 3a and
6.
In summary, we have successfully developed an efficient and
practical electrochemical method for selective and controlled
reduction of cyclic imides at room temperature. This reaction
utilizes a simple undivided cell with carbon electrodes to
synthesize hydroxylactams and lactams with broad substrate
scope and highly reducible functional group compatibility.
Initial mechanistic studies reveal that the utilization of amines
that are able to generate α-aminoalkyl radicals is crucial for
promoting the desired reduction reaction. As a green synthetic
method, this approach offers an appealing alternative to
conventional routes and provides an efficient tool for the
cleavage of C−O bonds under mild conditions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Sci-Tech Development
Project of Jilin Province in China (No. 20200801039GH), the
“Chunhui Plan” Cooperative Research Project of Ministry of
Education of China, the Foundation of Jilin Educational
Committee (No. JJKH20211225KJ), and the Outstanding
Young Teacher Training Program of Jilin University.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
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