Electrocatalytic generation of amidyl radicals for olefin hydroamidation: Use of solvent effects to enable anilide oxidation

Article abstract of DOI:10.1002/anie.201510418

Oxidative generation of synthetically important amidyl radicals from N-H amides is an appealing and yet challenging task. Previous methods require a stoichiometric amount of a strong oxidant and/or a costly noble-metal catalyst. We report herein the first electrocatalytic method that employs ferrocene (Fc), a cheap organometallic reagent, as the redox catalyst to produce amidyl radicals from N-aryl amides. Based on this radical-generating method, an efficient intramolecular olefin hydroamidation reaction has been developed. Easy access to N-arylamidyl radicals: The first electrocatalytic method for the generation of amidyl radicals from anilides has been developed using ferrocene (Cp₂Fe) as a highly reactive, yet chemoselective redox catalyst. Based on this radical-generating method, a highly chemo- and diastereoselective olefin hydroamidation reaction has been developed.

Full text of DOI:10.1002/anie.201510418

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International Edition: DOI: 10.1002/anie.201510418
German Edition: DOI: 10.1002/ange.201510418
Organic Electrochemistry Very Important Paper
Electrocatalytic Generation of Amidyl Radicals for Olefin
Hydroamidation: Use of Solvent Effects to Enable Anilide Oxidation
Lin Zhu+, Peng Xiong+, Zhong-Yi Mao, Yong-Heng Wang, Xiaomei Yan, Xin Lu, and Hai-
Chao Xu*
Abstract: Oxidative generation of synthetically important
preparation, Knowles disclosed an efficient photoredox olefin
hydroamidation reaction catalyzed by an Ir complex (Sche-
me 1).[2h] Despite these advances, a common disadvantage of
À
amidyl radicals from N H amides is an appealing and yet
challenging task. Previous methods require a stoichiometric
amount of a strong oxidant and/or a costly noble-metal
catalyst. We report herein the first electrocatalytic method
that employs ferrocene (Fc), a cheap organometallic reagent, as
the redox catalyst to produce amidyl radicals from N-aryl
amides. Based on this radical-generating method, an efficient
intramolecular olefin hydroamidation reaction has been devel-
oped.
À
the abovementioned N H activation approaches consists in
their requirement for a stoichiometric chemical oxidant[4]
and/or expensive noble-metal reagent.[5] To address these
limitations, we report herein the first electrocatalytic method
for the generation of amidyl radicals from N-aryl amides
using the inexpensive ferrocene (Fc or Cp2Fe)[6] as a highly
reactive and yet chemoselective redox catalyst. With this
method, we have developed an intramolecular olefin hydro-
amidation reaction that tolerates a host of sensitive functional
groups (Scheme 1).[7]
N
itrogen-centered radicals are versatile intermediates for
the construction of nitrogen-containing compounds. Unfortu-
nately, their use in synthesis is limited because of the difficulty
associated with their preparation.[1] Recently, the oxidative
À
Electro-oxidation of the amide N H bond can be
accomplished either through direct electrolysis or indirectly
with the help of an electron-relaying redox catalyst.[8,9] An
example of the direct electrolysis method was reported by
Moeller as an environmentally friendly approach to generate
nitrogen radicals.[10] In comparison, indirect electrolysis can
usually avoid electrode passivation, eliminate kinetic inhib-
ition, and achieve better selectivity.[8b] In this regard, we have
recently developed the first electrochemical aminooxygena-
tion of unactivated alkenes, in which 2,2,6,6-tetramethylpi-
peridine-N-oxyl radical (TEMPO) was used as both a medi-
ator to generate amidyl radicals and an oxygen-atom donor
for the carbon radical generated from the cyclization.[9h]
While the excellent reactivity of TEMPO towards carbon
radicals is beneficial for their oxygenation, it precludes their
participation in other types of bond-forming reactions. Hence,
we embarked on the quest for a non-interfering redox catalyst
in the hope of expanding the application scope of the
electrochemically generated amidyl radicals.
À
activation of the N H bond has emerged as an appealing, yet
challenging method for the generation of amidyl radicals.[2]
One of the pioneering methods in this field was developed by
Nicolaou[2a] using readily available N-aryl amide substrates
and 2-iodoxybenzoic acid (IBX) as oxidant to achieve facile
hydroamidation[3] of a wide range of functionalized olefins
À
(Scheme 1). Subsequently, catalytic activation of the N H
bond to generate nitrogen radicals was applied by the groups
of Chiba,[2c] Zheng,[2d] Li,[2e] Xiao,[2f] and Knowles[2g] in various
À
C N bond-forming reactions. While this manuscript was in
Allylic carbamate 1a, which bears an electron-deficient
N-aryl group that makes it difficult to be oxidized, was chosen
as the model substrate and studied for its redox properties in
cyclic voltammetry experiments along with Fc. The electrode
potential of 1a (Ep/2 =+ 0.83 V vs. saturated calomel elec-
trode; SCE) in basic MeOH solution[11] was much higher than
that of Fc (Ep/2 =+ 0.37 V vs. SCE). Consequently, the
cathodic curve of Fc remained unaffected by the addition of
1a (Figure 1, left), suggesting the absence of electron transfer
between 1a and Fc+. In contrast, the adoption of a mixed
solvent of THF/MeOH (5:1) lowered the electrode potential
of 1a and simultaneously increased that of Fc so that their Ep/2
were much closer, differing by only 60 mV (1a: Ep/2 =+
0.61 V;[11] Fc: Ep/2 =+ 0.55 V, vs. SCE), which enabled effi-
cient electron transfer as evidenced by the disappearance of
the back-scan curve (Figure 1, right). These results suggested
Scheme 1. Intramolecular olefin hydroamidation using amidyl radicals.
[*] L. Zhu,[+] P. Xiong,[+] Z.-Y. Mao, Y.-H. Wang, Prof. Dr. X. Yan,
Prof. Dr. X. Lu, Prof. Dr. H.-C. Xu
Collaborative Innovation Center of Chemistry for Energy Material
Key Laboratory of Chemical Biology of Fujian Province
Department of Chemistry, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Homepage: http://chem.xmu.edu.cn/kydw_ktz/hcxu/index.htm
[+] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201510418.
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Screening a panel of functionally diverse carbamates,
ureas, and amides revealed a broad substrate scope for the
electrocatalytic hydroamidation reaction (Table 2; for addi-
tional scope, see Table S1 in the Supporting Information).
First, the N-aryl group could accommodate a wide variety of
substituents with different electronic and/or steric properties
(entries 1–9).[14] Second, the substitution pattern and config-
=
uration of the alkene C C bond did not have a negative
Table 2: Substrate Scope.[a]
Entry
Substrate
Product
Electricity Yield [%],[b]
[F molÀ1 dr[c]
]
Figure 1. Cyclic voltammograms in 0.1m nBu4NBF4/MeOH (left) or
5:1 THF/MeOH (right). a and a’: Fc (3 mm). b and b’: Fc (3 mm), 1a
(7.5 mm). c and c’: Fc (3 mm), 1a (7.5 mm), NaOMe (7.5 mm).
the possibility of oxidizing anilides using electrochemically
generated Fc+ in a non-polar solvent.[12,13]
As a proof of concept, a pilot electrocatalytic hydro-
amidation reaction of 1a was carried out in an undivided cell
with 10 mol% Fc using a mixed solvent of THF/MeOH (5:1)
under reflux conditions (Table 1). To our delight, the product
Table 1: Optimization of electrolysis conditions for hydroamidation.[a]
Entry Electrolysis conditions
Electricity Yield [%][c]
[FmolÀ1
]
1
2
THF/MeOH (5:1), Fc (10 mol%)
THF/MeOH (5:1), Fc (5 mol%), 1,4-
CHD (5 equiv), Na2CO3 (1 equiv) “stan-
dard conditions”
3.4
3.5
80
90
3
4
5
6
7
entry 2 but THF/MeOH (1:1)
entry 2 but reaction at RT
entry 2 but no THF, or Fc, or electricity 2.5
entry 2 but in air
entry 2 but using 1.0 g of 1a
2.5
2.5
66
7(72)
NR
92
4.4
4.0
71
[a] Carbon anode, Pt cathode, constant current=5 mA, 1a (0.3 mmol),
solvent (9 mL), nBu4NBF4 (0.9 mmol), reflux, argon. [b] Determined by
1H NMR analysis of the crude reaction mixture. [c] Isolated yield.
Recovered starting material in parenthesis. NR=no reaction.
2a was isolated in 80% yield (entry 1). Subsequent reaction
optimization improved the yield to 90% by adopting a reac-
tion system that consisted of 5 mol% Fc, 1 equiv of Na2CO3
and 5 equiv of 1,4-cyclohexadiene (1,4-CHD) in an electro-
lyte of nBu4BF4 in THF/MeOH (5:1) (entry 2). The formation
of 2a was supressed by lowering the concentration of THF
(entry 3) or performing the reaction at RT (entry 4), and
could be completely abolished by withholding Fc or THF, or
by not supplying electricity (entry 5). It should be emphasized
that the reaction could be conducted under atmospheric
conditions (entry 6) or on gram scale (entry 7).
[a] C anode, Pt cathode, 5 mA, 1 (0.3 mmol), Fc (0.015 mmol), 1,4-CHD
(1.5 mmol), nBu4NBF4 (0.9 mmol), Na2CO3 (0.3 mmol), THF (7.5 mL),
MeOH (1.5 mL), reflux, 3–9 h. [b] Isolated yield. [c] Determined by
1H NMR analysis of the crude reaction mixture. dr=diastereomeric ratio.
TBS=tert-butyldimethylsilyl. PMP=4-methoxyphenyl.
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impact on the cyclization efficiency. As a result, substrates
bearing mono- (entry 10), di- (entries 11–20), and trisubsti-
tuted olefins (21–22) with an acyclic or cyclic structure are
well-tolerated. Branched allylic carbamates (entries 13–15)
and ureas (entries 16–17) cyclized to give the desired products
in excellent diastereoselectivity except the allylic carbamate
with a trans-alkene (entry 18).[15]
CHD afforded indoline 16 following an oxidative termination
[Eq. (2)].
The radical nature of the hydroamidation reaction was
investigated by electrolyzing substrate 17 bearing a cyclo-
propyl group as the radical clock (Scheme 4, top). The
The electrocatalytic hydroamidation detailed in this study
offers two key advantages. On the one hand, the process
exhibits excellent compatibility with various functionalities
including base/acid-labile groups, such as chiral esters
(entry 20) and Boc-protected amino esters (21; Boc = tert-
butyloxycarbonyl), and oxidation-sensitive groups, such as
free alcohols (entry 13), sulfonamides (entry 14), and N-aryl
carbamates (Scheme 2). On the other hand, the current
Scheme 2. Chemoselectivity of the electrocatalytic hydroamidation
reaction.
method simultaneously afforded broad reactivity with ani-
lides and outstanding chemoselectivity. For example, while
the carbamate groups of 3 and 5 are all oxidation-active, the
electrocatalytic reaction was observed only on the relatively
electron-rich PMP-substituted carbamate moiety (Scheme 2).
The synthetic utility of the hydroamidation reaction was
further demonstrated. The synthesis of the androgen receptor
modulator 10 was previously achieved through a 7-step route
that started with aldehyde 7 (Scheme 3).[16] In comparison,
Scheme 4. Mechanistic studies and rationale.
formation of the ring-opening product provides compelling
evidence for a radical-type mechanism.
Based on the results elucidated in this and our earlier
study,[9h] a plausible mechanism is proposed using 1d as
a model substrate (Scheme 4, bottom). Application of electric
current first causes the anodic oxidation of Fc to Fc+ and
cathodic reduction of MeOH to H2 and MeOÀ. The latter
deprotonates 1d to give its conjugate base I. Instead of being
reduced at the cathode, the ferric catalyst Fc+ rapidly oxidizes
I via single-electron-transfer to furnish the key amidyl radical
intermediate II and to regenerate Fc. This electron transfer
step is facilitated in less polar media because of reduced
solvation of the ionic species. The electrochemically gener-
ated MeOÀ is thought to be critical for the reaction as no
electron transfer was detected when no base was added (cf.
Figure 1) or when Na2CO3 was used as the base (Figure S1).
The final prodcut 2d is formed by cyclization of amidyl radical
II onto the tethered olefin, followed by H-atom abstraction of
Scheme 3. Synthesis of androgen receptor modulator 10.
our method, which involved a key hydroamidation step to
form the cyclic urea moiety, was able to complete the
synthesis in 4 steps from aldehyde 8. Moreover, the electro-
chemically generated nitrogen radical intermediate can
trigger tandem cyclizations to construct polycyclic N-hetero-
cycles.[17] For example, diene substrate 11 and 13 reacted
smoothly to afford the tricyclic products 12 and 14, respec-
tively, as a single diastereomer [Eq. (1)]. Interestingly,
cyclization of 15 in the absence of the H-atom donor 1,4-
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In conclusion, we have developed an unprecedented
electrocatalytic method in which an assortment of function-
alized, olefin-bearing amidyl radicals can be efficiently
prepared through the use of Fc as the redox catalyst and
subjected to intramolecular hydroamidation to synthesize
valuable lactams and cyclic carbamates and ureas. The success
of this transformation relies on the use of a non-polar solvent
to lower the oxidation potential of anilides relative to that of
Fc, which facilitate the electron transfer between the sub-
strate and Fc+. Efforts are underway in our laboratory to
extend the application of this method to other aminative
functionalization reactions.
[9] For recent advances in electroorganic synthesis, see: a) R.
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[11] The oxidation potential of the sodium salt of 1a was reported
(see Figure S2 for details). The neutral form of 1a was oxidized
at a potential greater than 1.5 V versus SCE.
[12] For the elegant application of solvent effect in achieving redox
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Acknowledgements
Financial support of this research from XMU, NSFC (grant
number 21402164), the “Thousand Youth Talents Plan” and
Fundamental Research Funds for the Central Universities.
Keywords: amidyl radicals · electrochemistry · ferrocene ·
hydroamidation · redox catalysts
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2226–2229
Angew. Chem. 2016, 128, 2266–2269
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Received: November 10, 2015
Published online: January 6, 2016
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