Catalyst-free, direct electrochemical synthesis of annulated medium-sized lactams through C-C bond cleavage

Article abstract of DOI:10.1039/c9gc03901e

A catalyst-free, direct electrochemical synthesis of synthetically challenging medium-sized lactams through C-C bond cleavage has been developed. In contrast to previous typical amidyl radical cyclization, this electrosynthetic approach enabled step-economical ring expansion through a unique remote amidyl migration under mild, metal- and external-oxidant-free conditions in a simple undivided cell. The strategy features unparalleled broad substrate scope with all ring sizes of (hetero)aryl-fused 8-11-membered rings and hetero atom-tethered rings, high yields, and good functional group tolerance. Our experimental and computational findings provided strong support for a SET-based reaction manifold.

Full text of DOI:10.1039/c9gc03901e

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Catalyst-free, direct electrochemical synthesis of
annulated medium-sized lactams through C–C
bond cleavage†
Cite this: DOI: 10.1039/c9gc03901e
Received 12th November 2019,
Accepted 6th December 2019
Zhongnan Xu,‡a Zhixing Huang,‡a Yueheng Li,a Rositha Kuniyil,b Chao Zhang,a
a
Lutz Ackermann *b and Zhixiong Ruan
*
DOI: 10.1039/c9gc03901e
rsc.li/greenchem
A catalyst-free, direct electrochemical synthesis of synthetically challenging, to develop catalyst- and reagent-free radical cycli-
challenging medium-sized lactams through C–C bond cleavage zations in a green and sustainable manner.
has been developed. In contrast to previous typical amidyl radical
In the meantime, organic electrochemistry,10 employing
cyclization, this electrosynthetic approach enabled step-economi- protons and electrons as redox reagents, has been established as
cal ring expansion through a unique remote amidyl migration an eco-friendly, atom-economic and increasingly powerful green
under mild, metal- and external-oxidant-free conditions in
a
tool11 for molecular synthesis.12 In this context, amidyl radical
simple undivided cell. The strategy features unparalleled broad generated by electro-oxidation of the amide N–H bond via direct
substrate scope with all ring sizes of (hetero)aryl-fused 8–11-mem- or indirect electrolysis was applied by the groups of Moeller,13
bered rings and hetero atom-tethered rings, high yields, and good Waldvogel,14 Zeng15 and Xu12n–s in various C–N bond-forming
functional group tolerance. Our experimental and computational cyclization reactions to construct N-containing heterocycles
findings provided strong support for
a
SET-based reaction (Scheme 1b). Despite these major advances, the reported electro-
chemical methods involving amidyl radicals are limited to
manifold.
produce 5 or 6-membered rings through typical amidyl radical
Medium-sized lactams (8–11-membered rings)1 are important
structural motifs as they are featured in numerous natural pro-
ducts and bioactive molecules, such as inter alia decursivine,
rhazinilam, balasubramide, and dibenzepin.2 These scaffolds
can generally be accessed by only a few limited methods,
mostly by intramolecular carbonylation,3 ring-closing meta-
thesis (RCM),4 Claisen-type rearrangement5 and among
others.6 More recently, Liu and coworkers reported a photo-
catalytic synthesis of medium-sized lactams by employing
ruthenium based redox catalyst and equivalent acetoxybenzio-
doxole (BI-OAc) as oxidant (Scheme 1a).7 However, these intra-
molecular cyclization reactions have thus far largely been
limited to high-dilution solvent, transition-metal catalysts or
stoichiometric chemical oxidants,8 which badly violate the
green chemistry postulates.9 Thus, it is highly desirable, yet
cyclizations, the electrochemical oxidative C–N bond formation
to afford 8–11-membered lactams has proven to be elusive.
With our continuing efforts in developing efficient electro-
chemical syntheses of heterocycles,12g,l,16 we herein report a
aKey Laboratory of Molecular Target & Clinical Pharmacology and the State Key
Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth
Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, P.R. China.
E-mail: zruan@gzhmu.edu.cn
bInstitut für Organische und Biomolekulare Chemie, Georg-August-Universität
Göttingen, Tammannstraße 2, 37077 Göttingen, Germany.
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
†Electronic supplementary information (ESI) available. CCDC 1948620. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9gc03901e
‡These authors contributed equally to this work.
Scheme 1 Electrochemical synthesis of lactams by C–C cleavage.
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first electrochemical synthesis of medium-sized lactams via a nol solvent also produced the desired 1a in moderate yield
rare amidyl radical migration by C–C bond cleavage (entries 7–10). The choice of electrode material proved critical
(Scheme 1c). Notable features of our general strategy include because a dramatically reduced product yield was obtained
(1) exceedingly mild and environmental-friendly reaction con- when using a Pt anode (entry 11).
ditions in a transition metal-17 and chemical oxidant-free18
With the optimized electrooxidation in hand, we explored
fashion, and (2) an unparalleled broad substrate scope high- the viable substrate scope first testing the effect exerted by sub-
lighting all ring sizes of (hetero)aryl-fused medium-sized rings stituents on the arene of the aniline moiety (Scheme 2). The
and hetero atom-tethered rings with high functional group electrolysis reaction exhibited excellent compatibility with a
tolerance. In contrast to previous typical amidyl radical cycliza- variety of electron-withdrawing and electron-donating groups
tion, this electrosynthetic approach set the stage for atom- and at either the meta- or para-position20 of the aniline to afford
step-economical ring expansion through a unique remote desired products (2a–2g). Thereafter, we investigated the effect
amidyl (hetero)aryl migration from carbon to nitrogen.
of substituents on the aryl ring of the tetrahydronaphthalene
At the outset of our studies, we probed a variety of different motif. Thus, the robust nature of the electrooxidative ring-
electrolysis conditions employing an undivided cell equipped expansion transformation was reflected by fully tolerating a
with a graphite anode and a platinum cathode towards the wealth of valuable functionalities, including sensitive chloro,
envisioned C–N bond formation of substrate 1a, which is bromo and fluoro groups, which could serve as a handle for
readily prepared from commercially available 1-tetralone in a future late-stage modifications. Subsequently, we explored the
single step (Table 1, and Tables S1 in the ESI†).19 The optimal scope with respect to viable annulated ring size scaffolds. To
results were obtained when substrate 1a was directly electro- our delight, the strategy for the direct electrochemical syn-
lyzed at a constant current in a mixed electrolyte solution of thesis of medium-sized lactams hence provided 8- to 11-mem-
n-Bu4NBF4 in MeCN/H2O (9 : 1) at room temperature under bered medium-sized lactams 2–5 in good yields.
atmospheric conditions without additional catalysts or bases.
Furthermore, encouraged by these exciting results, we next
Under these conditions, the desired 9-membered lactam 2a investigated the compatibility with various substituted ketones
was isolated in 98% yield (Table 1, entry 1). The structure of 2a in the electrochemical ring-expansion approach (Scheme 3). A
was unambiguously confirmed by single-crystal X-ray diffrac- wealth of alkyl and aryl substituents on the different position
tion studies. The electrolyte and current were both found to be of rings, including methyl (6, 7), 2-fluorophenyl (8) and 3,4-
essential for the reaction to achieve the optimal yield (entries 2 dichlorophenyl (9), were found to be fully tolerated by the opti-
and 3). Thus, among a variety of electrolytes, Et4NBF4 and mized electrooxidation. The practical utility of our approach
n-Bu4NPF6 showed good efficacy (entries 4 and 5), while was further illustrated by successfully performing the desired
Et4NClO4 displayed poor performance (entry 6). Further
control experiments verified the essential role of H2O as the
proton source, since performing the electrolysis in the metha-
Table 1 Optimization of reaction conditionsa
Entry
Deviation from standard conditions
Yieldb [%]
1
2
None
No n-Bu4NBF4
98
0
3
4
5
6
7
8
9
10
11
No current
0
Et4NBF4 instead of n-Bu4NBF4
n-Bu4NPF6 instead of n-Bu4NBF4
Et4NClO4 instead of n-Bu4NBF4
No H2O
MeOH instead of MeCN/H2O (9 : 1)
MeCN/H2O (3 : 1) instead of MeCN/H2O (9 : 1)
MeCN/H2O (1 : 1) instead of MeCN/H2O (9 : 1)
Pt as anode
81
96
48
Trace
51
90
84
20
a Reaction conditions: Undivided cell, graphite anode, Pt cathode, 1a
(0.2 mmol), n-Bu4NBF4 (0.2 mmol), MeCN/H2O (9 : 1, 5.0 mL), constant
current = 8.0 mA, 2.3 h (3.4 F mol−1), 23 °C, under air. b Yields of iso-
lated product.
Scheme 2 Scope of medium-sized annulated lactams fused with aryl
rings. a 4.5 h. b 3.0 h.
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Scheme 4 Gram-scale synthesis and product transformations.
Reaction conditions: (a) Allyl bromide, NaH, THF, 0 °C → rt, 50%. (b) Allyl
bromide, LDA, THF, −78 °C → rt, 56%. (c) Allylmagnesium chloride, THF,
rt, 62%.
In light of the outstanding versatility of the electrocatalytic
ring-expansion methodology we became intrigued by delineat-
ing its mode of action. To this end, the possible involvement
of an amidyl radical was strongly supported by the formation
of oxyamination products 23 and 24 from corresponding
amides 21 and 22, with TEMPO as radical terminator, respect-
ively, bearing an anilide moiety the same with that in sub-
strates 1a and 1e, under the otherwise optimized conditions
except that temperature was changed to 50 °C (Scheme 5a).
According to the reported radical hydroamination mediated by
amidyl radical,13,21 the reaction was likely via a pathway invol-
ving 5-exo-trig intramolecular cyclization followed by TEMPO
addition.21a The formation of amidyl radical was further sup-
ported by intermolecular competition experiments between
electronically discriminated substrates 1, revealing electron-
rich substrates being inherently more reactive (Scheme 5b),
which is in good agreement with previous findings reported in
the literature.21d
Scheme 3 Scope of medium-sized lactams with substituted rings or
fused with (hetero)aryl rings. a 6.7 h. b 3.0 h. c 50 °C, 4.5 h.
expansion with substrates bearing additional fused arenes
within the backbones of the expanding rings, to effectively
deliver 8-membered lactam 10 and 10-membered lactam 11 in
excellent yields, respectively. Gratifyingly, the 2-pyridine-con-
taining substrate was smoothly transformed to the pyridine-
annulated medium-sized lactam 12 in 84% yield under
the optimized conditions. In addition, other azacycle-
possessing substrates also survived our electrooxidative reac-
tion conditions with extended time to give the desired lactams
13–15, albeit in somewhat lower yields. It is particularly
noteworthy that the substrate 16 featuring oxygen-tethered
ring was well accepted by the robust metal-free electrooxida-
tion regime to generate the corresponding product 17 at 50 °C.
These observations mirror the unique potential for
applications in the assembly of diversity decorated medium-
sized scaffolds.
Likewise, cyclic voltammetric analysis revealed key mechan-
istic insights into the electrochemical transformation
(Fig. 1).22 The voltammogram disclosed that anodic oxidation
of the substrate 1a, generating amidyl radical species A,
occurred at a potential of ca. 2.2 V (vs. Ag/AgCl), followed by an
The outstanding potential of our ring-expansion approach
was further demonstrated by its easy scalability and versatile
transformations of the generated medium-sized β-keto lactams
(Scheme 4). For instance, we electrolyzed 2.8 g (8 mmol) of
alcohol 1a to deliver the corresponding 9-membered product
2a in 85% yield, without appreciable loss in efficacy.
Furthermore, products 18–20 featuring an allyl tag on
varied site positions, could be obtained by the nucleophilic
substitution of lactam 2a with allyl bromide and nucleophilic
addition to ketone with an allyl Grignard reagent in 50–62%
yields. Besides, other common and useful manipulations,
such as Suzuki–Miyaura coupling of aryl bromide with an aryl
boronic acid, of our prepared medium-sized lactams were also
readily amenable.19
Scheme 5 Summary of key mechanistic findings.
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Scheme 6 A plausible mechanistic pathway.
Fig. 1 Cyclic voltammograms of 0.1 M n-Bu4NBF4 in acetonitrile (blank,
black line), substrate 1a (blue line) and product 2a (red line). Reference
electrode: Ag/AgCl in 3 M KCl in H2O. Scan rate = 200 mV s−1
.
Based on our mechanistic studies, a plausible mechanism
is proposed using 1a as a model substrate (Scheme 6). The
reaction is first initiated by the anodic oxidation of the amidyl
N–H bond in 1a, leading to the generation of an amidyl radical
intermediate A, which could then readily undergo intra-
molecular cyclization with the aryl ring to form a new C–N
bond in delocalized radical B, followed by selective C–C bond
cleavage to furnish the neutral ketyl radical C. Finally, single-
electron oxidation of this ketyl radical C followed by the loss of
a proton would afford the medium-sized lactam 2a. However,
due to the two close oxidative waves of 1a in cyclic voltammo-
gram, the cationic pathway cannot be excluded.23
irreversible oxidation of the intermediate C, affording the
desired product 2a at a potential of ca. 2.3 V, well below the
oxidation potential of the medium-sized lactam 2 (ca. 2.5 V vs.
Ag/AgCl), protecting the product from oxidative decomposition
partly.12d
The possible reaction mechanism was next examined by
computational density functional theory (DFT) calculations
(Fig. 2). The first pathway commences with a cyclization via a
5-membered ring transition state, followed by a favorable
β-scission step. Cyclisation via 6-membered ring transition
state was also considered, but is energetically unfavorable. The
second rationale initiates with a hydrogen atom transfer from
the hydroxyl group to the amidyl radical, followed by β-scission
(see Fig. S4†).19 However, the first pathway was found to be
energetically favorable.
Conclusions
In summary, we have reported on the first electrochemical
ring-expansion protocol for the direct synthesis of a variety of
synthetically challenging medium-sized lactams by means of
C–C bond cleavage. The strategy provides expedient access to a
diverse range of 8–11-membered (hetero)arene-annulated
lactams with ample scope, high yield, and broad functional
group tolerance. Thus, exceedingly mild electrolysis of amide
substrates under catalyst- and external-oxidant-free conditions
occurred efficiently in an undivided cell. Detailed mechanistic
studies revealed a remote radical migration pathway via a SET-
type fashion.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Support by the National Natural Science Foundation of China
(21901052), the Guangdong Province Universities and Colleges
Pearl River Scholar Funded Scheme (2019), the Guangzhou
Education Bureau University Scientific Research Project
(201831845), the Guangzhou Science and Technology Project
(201707010008) and the DFG (Gottfried-Wilhelm-Leibniz prize
to L. A.) is most gratefully acknowledged.
Fig. 2 Computed relative Gibbs free energy profile for the cyclization
and β-scission elementary steps in kcal mol−1 starting from intermediate
A at the B3LYP-D3(BJ)/6-311++G(d,p) + SMD(Acetonitrile)//B3LYP-D3
(BJ)/6-31+G(d) level of theory. The cyclization via both 5-membered
ring transition state (black) and 6-membered ring transition state (red)
were analysed. Non-relevant hydrogen atoms were omitted for clarity.
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