Electrochemical Difunctionalization of Alkenes by a Four-Component Reaction Cascade Mumm Rearrangement: Rapid Access to Functionalized Imides

Article abstract of DOI:10.1002/anie.201913332

An electrochemical four-component reaction cascade Mumm rearrangement was developed. It is a rare example of in situ generation of O-acyl isoamides for 1,3-(O→N) acyl transfer. Inexpensive, commercially available arylethylenes, aryl or heterocyclic acids, acetonitrile, and alcohols were used as substrates. A wide range of aryl acids and alcohols were tolerated and provided imides in satisfactory yields. Subsequent hydrolysis of imides could be utilized to synthesize valuable amides and β-amino alcohol derivatives.

Full text of DOI:10.1002/anie.201913332

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Accepted Article
Title: Electrochemical Difunctionalization of Alkenes via Four-
component Reactions Cascade Mumm Rearrangement: Rapid
Access to Functionalized Imides
Authors: Peipei Sun, Xiaofeng Zhang, Ting Cui, Xin Zhao, and Ping Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913332
Angew. Chem. 10.1002/ange.201913332
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Electrochemical Difunctionalization of Alkenes via Four-
component Reactions Cascade Mumm Rearrangement: Rapid
Access to Functionalized Imides
Xiaofeng Zhang, Ting Cui, Xin Zhao, Ping Liu,* and Peipei Sun*
In memory of Professor Yong-Min Zhang
Abstract: An electrochemical four-component reaction cascade
Mumm rearrangement was developed, representing a rare example
of in situ generation of O-acyl isoamides for 1,3-(ON) acyl transfer.
Inexpensive, commercially available arylethylenes, aryl or
heterocyclic acids, acetonitrile, and alcohols were used as
substrates. A wide range of aryl acids and alcohols were found to be
tolerated and provided imides in satisfactory yields. Subsequent
hydrolysis of imides could be utilized to synthesize valuable amides
and β-amino alcohol derivatives.
a substrate produces a radical, and the subsequent addition to
an alkene generates a new radical, which undergoes further
anodic oxidation to form a cation, and finally combines with other
nucleophiles (path c),[8a-f] or alkene itself is directly converted to
radical cation by anodic oxidation (path d)[8g-h]. The indirect
electrolysis using redox catalysts lowers the potential of
substrates (path e) or alkenes (path f) and enables the stepwise
addtion of radicals or nucleophiles to alkene moiety.[9]
Multicomponent reactions (MCRs) combine three or more
reactants in a single chemical step and incorporate substantial
portions of all the components into the same products.[1] During
the past decades, this strategy has been successfully used for
natural products synthesis and drug discovery.[2] One-pot
multicomponent reactions are synthetically attractive because
they enable access to diverse and complex molecules with
several distinctive features, such as step efficiency, atom
economy, operational simplicity and environmental friendliness,
etc.[3] In general, multicomponent processes are initiated by
addition of highly reactive reagents (e.g. isocyanides in Ugi or
Passerini reactions) or capture of active intermediates generated
in situ.[4] As one type of active intermediates, radical can also be
involved in multicomponent reactions.[5]
Alkenes are one of common and versatile radical acceptors,
and recent years have witnessed the considerable progress in
the field of radical alkenes difunctionalization.[6] These three-
component processes are mainly initiated by oxidation of a
reagent, followed by intermolecular radical addition to C=C
double bond to generate a new radical, which then undergoes
potential alternative pathways: (a) radical cross-coupling
(Scheme 1, path a), or (b) oxidation to generate a carbocation,
and the sequential addition of an external nucleophile (path
b).[6c] Electrochemistry has currently emerged as an important
approach in olefin difunctionalization due to the high
chemoselectivity and relatively mild conditions, which allows
reactions to be conducted in the absence of oxidizing agents.[7]
Electrochemical difunctionalization of alkenes is proposed to
occur via direct or indirect electrolysis. The direct electrolysis of
Scheme 1. Difunctionalization of alkenes involving radical or radical cation
Imides
pharmaceuticals[11] and exhibit diverse biological properties,
such as anticancer,[12] antifungal[13] and antibacterial activities[14]
extensively
exist
in
natural
products,[10]
.
In view of their wide applications, great efforts have been
devoted to develop efficient methods for the synthesis of imides.
Conventionally, approaches were established by the N-acylation
of amides with acyl halides, aldehydes, esters, thioesters,
methylarenes, or potassium acyltrifluoroborates.[15] Other
methods, including the direct oxidation of N-alkyl acetamides or
cyclic amines, can also be used for the construction of imides.[16]
The abovementioned methods, however, possess one even
several drawbacks, involving requirement of strong bases,
dangerous oxidants, expensive transition-metal catalysts or
complicated substrates.
[*]
X. Zhang, T. Cui, X. Zhao, Dr. P. Liu, Prof. Dr. P. Sun
School of Chemistry and Materials Science, Jiangsu Provincial Key
Laboratory of Material Cycle Processes and Pollution Control,
Jiangsu Collaborative Innovation Center of Biomedical Functional
Materials, Nanjing Normal University, Nanjing 210023 (P. R. China)
E-mail: sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/
The classical Ugi four-component reactions involve
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interaction of a carbonyl compound, an amine, an isonitrile and a
carboxylic acid to produce an α-acylaminoamide (Figure 1-A).[4a]
The reaction of imine intermediates with isonitriles and
carboxylic acids can generate O-acyl isoamide intermediates.
The final step is a 1,4-(ON) acyl transfer of O-acyl isoamides
to give α-acylamino amides. Similarly, 1,3-(ON) acyl transfer
(Mumm rearrangement) of O-acyl isoamides was utilized to
synthesize imides in several very early reports, but required
preparation of unstable precursor imidoyl chlorides.[17] Synthesis
of imides using in situ generated O-acyl isoamides from readily
available substrates under mild conditions is environmentally
desirable. As a part of our continuous studies on design of
radical MCRs,[18] herein, we demonstrate the feasibility of
electrochemical 4CR of alkenes, aryl acids, acetonitrile and
alcohols cascade Mumm rearrangement to construct
functionalized imides (Figure 1-B).
transformation was much less efficient using other supporting
electrolyte such as Bu4NBF4 or LiClO4 (entries 6–7). Changing
n
the ratio of CH3CN and CH3OH revealed the optimal conditions
employed a 4:1 ratio of CH3CN to CH3OH (entries 1, 8–9).
Further improvements were realized through decreasing the
current density to 5 mA and 6 mA with the same amount of
electricity, providing 3aa in 83% and 81% yields, respectively
(entries 10–11). However, increasing the current density was
unfavorable for the formation of 3aa (entry 12). Finally, the
reaction was completely abolished in the absence of electric
current (entry 13).
Table 1. Optimization of reaction conditions.[a]
Entry
Anode/
Cathode
Pt(+)/Pt(-)
CH3CN (x mL)/
CH3OH (y ml)
8/2
Current/
Time
8 mA/6.25 h
Yield
(%)[b]
80
1
2[c]
Pt(+)/Pt(-)
C(+)/Pt(-)
Pt(+)/C(-)
Pt(+)/Ni(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
Pt(+)/Pt(-)
8/2
8/2
8/2
8/2
8/2
8/2
5/5
9/1
8/2
8/2
8/2
8/2
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
8 mA/6.25 h
5 mA/10 h
6 mA/8.33 h
10 mA/5 h
79
40
45
75
31
34
72
78
83
81
56
0
3
4
5
6[d]
7[e]
8
9
10
11
12
13
0/10 h
[a] Reaction conditions: platinum plate anode (10 mm × 10 mm), platinum
plate cathode (10 mm × 10 mm), 1a (0.6 mmol), 2a (0.9 mmol), nBu4NPF6
(0.05 M), CH3CN/CH3OH (10 mL), under air, r.t., 6 h, undivided cell. [b]
Isolated yields based on 1a. [c] Under Ar. [d] nBu4NBF4 instead of nBu4NPF6.
[e] LiClO4 instead of nBu4NPF6.
With the optimized reaction condition in hand, we firstly
explored the generality of the electrochemical 4CR by the
variation of aryl acids (Scheme 2). Aryl acids bearing electron-
Figure 1. 4CRs via acyl transfer to generate α-acylamino amides or imides
t
donating groups (Me, Et, Bu) and halogen substituents (F, Cl,
Br) could provide the imide products (3ab–3af, 3ah–3al) in good
yields (70–85%), regardless of these substituents at the ortho-,
meta- or para-position of the benzene ring. Strongly electron-
donating methoxy group was less efficient and gave the desired
product 3ag in moderate yield (46%). To our delight, electron-
deficient aromatic acids with nitro, cyano and trifluoromethyl
groups were also suitable for this transformation, and gave the
corresponding products in moderate to excellent yields (3am–
3ap). The structure of the imide 3ao was characterized by X-ray
crystallography (CCDC number 1942912). The aryl acid bearing
two substituents such as 2,5-dimethylbenzoic acid was good
reaction partner and furnished the desired product 3aq in 76%
yield. Notably, 4-biphenylcarboxylic acid, 2-naphthoic acid and
unsaturated heterocyclic acids (2t, 2u) were suitable for this
electrochemical reaction as well, and comparable yields were
obtained under the optimal reaction conditions (3ar–3au). It was
Initially, we selected styrene (1a) and benzoic acid (2a) as
the model substrates and performed the reaction in acetonitrile
and methanol (Table 1). The electrolysis was conducted under 8
mA constant current in an undivided cell equipped with a
platinum plate anode and cathode containing electrolyte
nBu4NPF6 under air. Gratifyingly, the electrochemical 4CR
indeed occurred and an imide product N-acetyl-N-(2-methoxy-1-
phenylethyl)benzamide (3aa) was obtained in 80% yield (entry
1). Encouraged by this result, more investigations about the
reaction conditions were conducted. A similar yield (79%) was
obtained when the reaction was performed under Ar atmosphere
(entry 2). Changing the platinum plate anode or cathode to
graphite plate led to lower yields (entries 3–4). The replacement
of platinum plate cathode with other metal material such as Ni
electrode also showed inferior results (entries 5). Supporting
electrolyte had obvious influence on the reaction efficiency. The
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noteworthy that alkeny and alkynyl of the aryl acids (2v, 2w)
were well tolerated, either (3av, 80%; 3aw, 83%). We also
anticipated that the present protocol might be applicable to the
late-stage functionalization of pharmaceutical molecules and
natural products. For instance, probenecid, which was primarily
used in treating gout and hyperuricemia,[19] provided the
expected product 3ax in 80% yield. The menthol derivative 2y
delivered the desired product 3ay in good yield (75%). It should
be noted that the use of aliphatic carboxylic acids as the starting
materials under the same conditions did not give the desired
imides.
and furnished the desired products 3da–3ka in satisfactory
yields (63–80%). It should be noted that arylethylenes containing
halogen groups at ortho-position also work well, regardless of
the steric hindrance (3fa and 3ia). Unfortunately, other electron-
deficient or electron-rich arylethylenes, and alkylalkenes were
not suitable for this electrochemical difunctionalization reaction.
Due to the limitation of the olefins, we attempted to do more in-
depth research. Electron-deficient olefins, such as 4-
cyanostyrene, showed no distinct oxidation potential in the range
of 0–2.5 V. Electron-rich olefins such as 1,1-diphenylethylene
more easily formed the dimethoxylation product under the
standard condition (see the Supporting Information).[8h] Bromo
substituted triarylamines were frequently used as electron
mediators.[20] Indeed, we found that the yields of 3ba and 3ca
were improved to 52% and 50% respectively when tris(4-
bromophenyl)amine (10 mol%) was added.
Scheme 3. Reaction scope of arylethylenes 1. [a] Tris(4-bromophenyl)amine
(10 mol%) was added.
Additionally, we further explored the generality and scope of
the alcohols. As shown in Scheme 4, primary alcohols such as
ethanol, n-propanol, isobutanol as well as secondary alcohol
such as isopropanol and tertiary alcohol such as tertiary butanol
could tolerate the reaction and furnished the desired products
4aa–4ae in good yields (50–76%). Unfortunately, no desired
reaction occurred when benzyl alcohol was used as the
substrate.
Scheme 2. Reaction scope of aryl acids 2.
Subsequently, the scope of arylethylenes was examined by
using 4-cyanobenzoic acid (2o) as the reaction partner (Scheme
3). It should be pointed out that electronic effects of substituents
of arylethylenes had significant influence on their reaction
efficiency. Arylethylenes substituted with moderately electron-
donating groups, such as 4-methylstyrene and 4-tert-
butylstyrene, delivered the products 3ba and 3ca in 36% and
25%, respectively. Low yields could be attributed to the
formation of complicated byproducts. Gratifyingly, a series of
arylethylenes possessing halogen groups (F, Cl, Br) at different
position of the benzene ring participated smoothly in the reaction
Scheme 4. Reaction scope of alcohols.
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Scheme 6. Isotope labeling reactions.
To evaluate the practicality and scalability of the
electrochemical 4CR, we performed the reaction on a 6 mmol
scale (Scheme 5, eq 1). By increasing the current density to 10
mA and prolonging the reaction time to 48 h, the product 3ao
was obtained in 76% yield (4.56 mmol), which demonstrated the
synthetic utility of this methodology. The imide 3ao could easily
be transformed to corresponding amide 5aa (90%) by treatment
with NaOH aq. at room temperature (eq 2, left). Interestingly, the
product 3ao could be hydrolyzed completely in the presence of
concentrated hydriodic acid, and DL-phenylglycinol (5ab) was
obtained in 76% yield (eq 2, right).
Based on the control experiments, the cyclic voltammetry
studies and relative literature reports, we proposed a possible
mechanism for the electrochemical 4CR as follows: Initially, the
anodic oxidation of styrene (1a) through single-electron-transfer
produced a radical cation A (Scheme 7).[8g-h, 21] The nucleophilic
addition of cation A with CH3O- generated from cathodic
reduction of methanol resulted in the formation of carbon-
centered radical B, followed by the anodic oxidation to deliver
another carbocation C. The intermolecular trapping of cation C
with acetonitrile led to carbocation D, which could smoothly
combine with PhCOO- generated from the cathodic reduction of
PhCOOH. Finally, due to its structural instability,[17] the
intermediate E would soon undergo Mumm rearrangement to
furnish the desired product 3aa.
Scheme 5. Gram-scale synthesis and product transformations.
In order to probe the reaction mechanism, several
deuterium-labeling experiments were designed and conducted
(Scheme 6). Two parallel reactions, one with CH3OH and
CD3OD (2 mL, 1:1) and the other with CH3CN and CD3CN (8 mL,
1:1), were respectively conducted under standard conditions (eq
3 and 4). The relative ratio of the product 3ao and d3-
3ao(CD3OD) or d3-3ao(CD3CN) was 1:1, indicating that the
introduction of methoxy group and acetonitrile in this
electrochemical 4CR may not be the rate-determining step (see
the Supporting Information). The 18O-labeled experiment
suggested that an oxygen atom of the imide [18O]-3ak came
from the O18-labeled 4-chlorobenzoic acid [18O]-2k (eq 5). This
result indicated that a rearrangement was likely involved in this
electrochemical reaction. Cyclic voltammetry studies indicated
that styrene had the lowest oxidation potential (1.60 V vs SCE)
than methanol and benzoic acid (both with no distinct oxidation
peak) in the range of 0–2.5 V, revealing that the initial step of the
electrochemical 4CR may be the oxidation of styrene (see the
Supporting Information).
Scheme 7. Proposed mechanism for the electrochemical 4CR.
In summary, we have developed an electrochemical four-
component reaction for the synthesis of imides from
arylethylenes, aryl or heterocyclic acids, acetonitrile and
alcohols. The electrochemical 4CR can perform on a gram scale
and the products can be easily converted to amide and β-amino
alcohol. This organic electrosynthesis enables generation of
unstable O-acyl isoamides precursor for Mumm rearrangement
from very common substrates, which is difficult for previous
methods. The protocol features low cost, oxidant- and catalyst-
free conditions, and good scalability. Our developed
transformation provides a modular approach for the synthesis of
imides, and relative electrochemical MCRs are ongoing in our
laboratory.
Acknowledgements
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Xiaofeng Zhang, Ting Cui, Xin Zhao,
Ping Liu,* and Peipei Sun*
Page No. – Page No.
Electrochemical Difunctionalization
of Alkenes via Four-component
Reactions Cascade Mumm
Rearrangement: Rapid Access to
Functionalized Imides
A four-component reaction based on arylethylenes, aryl acids, acetonitrile, and alcohols has been designed that enables the
difunctionalization of alkenes and the formation of imides under electrochemical conditions. Mechanistic studies support a 1,3-(ON)
acyl transfer of O-acyl isoamides via Mumm rearrangement.
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