Electrochemical Aziridination by Alkene Activation Using a Sulfamate as the Nitrogen Source

Article abstract of DOI:10.1002/anie.201801106

The first direct aziridination of triaryl-substituted alkenes was achieved by means of an electrochemical process that could extend to multisubstituted styrenes. Specifically, hexafluoroisopropanol sulfamate was used as a nucleophilic nitrogen source. Mechanistic experiments suggest that this electrochemical process proceeds by stepwise formation of two C?N bonds through reactions between cationic carbon species and the sulfamate.

Full text of DOI:10.1002/anie.201801106

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Accepted Article
Title: Electrochemical Aziridination via Alkene Activation with a
Sulfamate as Nitrogen Source
Authors: Jin Li, Wenhao Huang, Jingzhi Chen, Lingfeng He, Xu Cheng,
and Guigen Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801106
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10.1002/anie.201801106
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Electrochemical Aziridination via Alkene Activation with a
Sulfamate as Nitrogen Source
Jin Li,[a] Wenhao Huang,[a] Jingzhi Chen,[a] Lingfeng He,[a] Xu Cheng,*[a][b][c] Guigen Li[a]
We dedicate this work to Professor Benjamin List on the occasion of his fiftieth birthday
Abstract: The first direct aziridination of triaryl-substituted alkenes
with various nitrogen sources by the groups of Yoshida,[13]
was achieved by means of an electrochemical process that could
Waldovogel,[14] Zeng and Little,[15] Andrieu and Devillers,[16]
Baran,[17] and Xu.[18] In addition, novel strategies for
electrochemical C(sp3)–H amination were recently reported by
Yoshida,[19] Huang,[20] Stahl,[21] and Lei.[22] The transformations of
ketones to amine were also demonstrated with broad scope.[23]
Of particular interest to us were recent reports of
functionalization of alkenes under electrochemical conditions.[24]
In light of these previous reports, we envisioned that an
electrocatalytic aziridination protocol could be used to realize
direct aziridination of triaryl-substituted alkenes (Scheme 1b). In
such a protocol, the first step would be not opening of the double
bond of the alkene but rather electron transfer from the
conjugated molecule to the anode, leading to a carbocation
radical.[25] The following stepwise formations of C-N bonds using
nucleophilic nitrogen source would furnish aziridine products.
extend
to
multisubstituted
styrenes.
Specifically,
nucleophilic
hexafluoroisopropanol sulfamate was used as
a
nitrogen source. Mechanistic experiments suggest that this
electrochemical process proceeds via stepwise formation of two C–
N bonds by means of reactions between cationic carbon species and
the sulfamate.
Aziridines are reactive nitrogen building blocks that can
undergo a variety of useful transformations for pharmaceuticals[1]
and the fabrication of functional materials.[2] The importance of
aziridines is reflected in the extensive effort devoted to their
synthesis and in the variety of strategies developed for that
purpose.[3] One such strategy is the direct aziridination of
alkenes, which affords efficient access to this functionality.
Nitrenes are frequently employed as reactive aziridination
species, and they can be generated from azide or amine
derivatives in the presence of a terminal oxidant such as
Pb(OAc)4.[4] In addition, hypervalent iodine[5] and other
reagents[6] have been introduced as efficient reagents for
producing nitrene intermediates from various amine derivatives.[7]
In 2002, Yudin and co-workers reported the first example of
electrochemical aziridination with a nitrene species derived from
N-aminophthalimide(Scheme 1a),[8] and Zeng and Little recently
demonstrated the first electrocatalytic aziridination of alkenes via
a nitrogen radical pathway mediated by n-BuN4I (Scheme 1a).[9]
Despite tremendous advances, triaryl-substituted alkenes
remain outside the substrate scope of direct aziridination
reactions, for two reasons. First, formation of the aziridine ring
eliminates the effects of conjugation of the aryl groups. Second,
the three aryl groups hinder the approach of the nitrogen source.
Recently, the renaissance[10] in the use of electrochemistry in
organic synthesis[11] has demonstrated the advantages of
electrochemistry for numerous challenging reactions.[12] In
particular, electrocatalytic protocols have been extensively
employed to introduce nitro groups into molecules chemo- and
regioselectively. For example, the challenging task of
constructing aromatic C(sp2)–N bonds has been accomplished
Scheme 1. Pathways for Direct Aziridination of Alkenes
To evaluate the feasibility of such a protocol, we subjected 1a
to constant-potential electrolysis with graphite felt as electrodes
in the presence of sulfamate 2a in acetonitrile in an undivided
cell at a potential of 5 V with LiClO4 as the electrolyte. The
desired aziridine product (3a) was achieved in 57% yield with
K3PO4 as base (Table 1, entry 1). By changing the base to 2,6-
lutidine, 3a was isolated in 87% yield with a 44% current
efficiency (entry 2). The reactions of other reagents, such as
acetamide 2b and toshyl amide 2c, failed to give nitrogen
adducts (entries 3 and 4). No reaction occurred in the absence
of a base or in the absence of electricity (entries 5 and 6). Metal
catalysts applied in the aziridination of alkenes via nitrene
pathway were evaluated with 1a and 2a as starting material.
CuI[26] did not give any aziridination product. By using 5 mol %
Rh2(OAc)4,[27] only trace of 3a was detected on GC-MS.
[a]
Institute of Chemistry and Biomedical Sciences, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, National Demonstration Center for
Experimental Chemistry Education, Nanjing University, Nanjing,
210023, China
E-mail: chengxu@nju.edu.cn
[b]
[c]
State Key Laboratory Cultivation Base for TCM Quality and Efficacy,
Nanjing University of Chinese Medicine, Nanjing, China
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, China
With the optimized conditions in hand (Table 1, entry 2), we
subjected a series of triaryl-substituted alkenes to the protocol
(Table 2). We began by testing substrates with one or more
halogen-substituted aryl groups. Aziridines 3b-3f bearing one F,
Cl or Br atom were achieved in good to excellent yields. Di- and
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201801106
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trihalogen-substituted substrates gave rise to corresponding
aziridine derivatives 3g–3j in moderate to good yields.
Subsequently, triphenylethylenes bearing different groups (2k–
2o, respectively) were converted to desired products 3k–3o in
good yields. Ester groups were tolerated; products 3p–3r were
generated in 71–85% yields. Diphenyl-naphthalenyl-substituted
aziridine 3s could also be synthesized, in 76% yield, at a
working potential of 6 V.
Table 1. Optimization of Conditions for Electrochemical Aziridination of
Triphenylethylenea
yield(%)b
57
Because the steric congestion due to the three aryl groups
was not a factor in this electrochemical process, we explored the
entry
1
Nitrogen source
base
reactions of alkenes
4 substituted with alkyl groups as
K3PO4
substrates (Table 3). 32%-73% yields of compounds 5a–5e
were obtained from the corresponding substrates with para-
substitutions on phenyl rings. Whereas when an o-methoxy
group was present, the yield of 5f was moderate. We also
evaluated substrates bearing a p-alkoxyphenyl group and a
second substituent on the phenyl ring and were able to obtain
aziridination derivatives 5g–5l in yields ranging from 44% to 61%
with 5 V or higher operating potentials (5j-5l). The methylthio
group in substrate 4m was compatible and target product 5m
was isolated in 62% yield. Aziridines 5n with a naphthalenyl and
5o with a benzothiophenyl group were generated in 44% and 47%
yields, respectively. A spiro compound 5p was prepared in 42%
87
2
2a
2,6-lutidine
(4.5 F/mol, 44%)c
3
4
AcNH2 2b
2,6-lutidine
2,6-lutidine
-
-
TsNH2 2c
5
2a
2a
2a
2a
nr
6d
7e
8f
2,6-lutidine
nr
nr
trace
yield from 4p containing
a
cyclohexylidene moiety.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), base (0.6 mmol), LiClO4 (0.1
Tetrasubstituted alkene 4q gave the corresponding aziridine
product 5q in 74% yield. Aziridination of (Z)-alkene 4r afforded a
48% yield of 5r with a 3:2 trans/cis ratio.
b
mmol), CH3CN (5 mL), graphite felt electrodes, 5 V, rt, argon, 5 h. Isolated yields
c
d
are provided. nr, no reaction. charge consumption and Faradaic efficiency No
electricity. e 1a (0.2 mmol), 2a (0.3 mmol), CuI (10 mol %), PhIO (0.3 mmol), 4 Å MS,
CH3CN, rt, 18 h. f 1a (0.2 mmol), 2a (0.2 mmol), Rh2(OAc)4 (5 mol %), PhI(OAc)2 (0.3
mmol), MgO (1.0 mmol), CH2Cl2, 40 oC, 8 h.
Table 3. Electrochemical Aziridination of Multisubstituted Styrenes 4a
Table 2. Electrochemical Aziridination of Triaryl ethylenes a
a
Reaction conditions: 4 (0.2 mmol), 2a (0.3 mmol), 2,6-lutidine (0.6 mmol),
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), 2,6-lutidine (0.6 mmol), LiClO4
LiClO4 (0.1 mmol), CH3CN (5 mL), argon, graphite felt electrodes, 5 V, rt.
Isolated yields are provided.
(0.1 mmol), CH3CN (5 mL), argon, graphite felt electrodes, 5 V, rt. Isolated yields are
reported.
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a) Cyclic voltammertry experiment of reactants
aziridine product 7a. Cationic species generated from stilbenes
6b, 6c and 6d could also be trapped by reaction with MeCN. On
the basis of the above-described results, we propose the
reaction pathway illustrated in Scheme 2c. First, the alkene
undergoes anodic oxidation to form carbocation radical A.
Addition of the sulfamate nucleophile and deprotonation by
lutidine produce neutral radical species B, which is oxidized on
the anode to carbocation C. Finally, ring closure furnishes the
aziridine product. Lutidine is regenerated at the cathode by
releasing hydrogen. In addition, LiClO4 activated 2,6-lutidine or
CH3CN can also participate in discharging process at cathode. [28]
A gram scale reaction was carried out simply by increasing
the size of the graphite felt electrodes using the standard
conditions employed in Table 2, and aziridine 3a was obtained in
82% yield (Scheme 3). Visible-light-induced ring-opening of 3a
with methanol as a nucleophile gave compound 8 in 77% yield.
In addition, 3a could be readily hydrolyzed with NaOH to free
aziridine 9 in 89% yield. Reaction of 9 with HF–pyridine complex
afforded amine 10, which bears a fluorine atom. Amine 11 could
be obtained in 65% yield by hydrogenation of 9. The free
aziridine could be re-protected with acetic anhydride, giving 12
as the only product.
0.0
lutidine + LiClO4
-2.0x10-4
2a + lutidine + LiClO4
-4.0x10-4
-6.0x10-4
1a + lutidine + LiClO4
-8.0x10-4
1a + 2a + lutidine + LiClO4
(Table 1, entry 2)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Potential (V)
Scheme 3. Gram Scale Synthesis and Derivations of 3a
In summary, we have developed
a
protocol for
electrochemical synthesis of aziridines with a sulfamate as the
nitrogen source. The protocol was compatible with triaryl-
substituted alkenes and multisubstituted styrenes as substrates.
We propose a reaction pathway that involves a carbocation
intermediate and proceeds via two stepwise electron transfers
and formation of two C–N bonds by nucleophilic attack by the
sulfamate nitrogen. Enabled by electrochemistry, this protocol
represents the first example of aziridination of triaryl-substituted
alkenes.
Scheme 2. Mechanistic Investigation and Plausible Reaction Pathway
To validate the involvement of cationic carbon species, we
carried out cyclic voltammetry experiments on the reaction
mixture (Table 1, entry 2), as well as on various combinations of
the reactants (Scheme 2a). These experiments revealed that
electron transfer to the anode occurred at +2.0 V (vs SCE),
which is nearly identical to the oxidation potential of 1a in the
reaction mixture. This observation supports our assumption that
the reaction began with activation of the alkene via electron
transfer to generate a carbon cation radical. Next, to verify the
formation of a second carbon cationic intermediate leading to
aziridine, we subjected several stilbenes, which are less bulky
than alkenes 1 and 4, to the electrochemical reaction conditions
(Scheme 2b). We found that the carbocation generated from 6a
could be trapped by the CH3CN solvent to afford five-membered-
ring compound 7a as the major product. Separate reactions of
(E)- and (Z)-Stilbene gave similar yields of the same trans-
Acknowledgements
This work was supported by the National Science Foundation
of China (nos. 21572099 and 21332005), by the Natural Science
Foundation of Jiangsu Province (no. BK20151379), and by the
Open Project of State Key Laboratory Cultivation Base for TCM
Quality and Efficacy, Nanjing University of Chinese Medicine (no.
TCMQ & E 201702).
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An electrochemical aziridination of
triaryl ethylene was achieved via
alkene activation pathway with
sulfamate as nitrogen source. Two
stepwise electron transfers were keys
to the construction C-N bonds from
congested and conjugation-stabilized
alkenes. With this approach, tri and
tertrasubstituted styrenes were also
converted two corresponding
Jin Li, Wenhao Huang, Jingzhi Chen,
Lingfeng He, Xu Cheng,* Guigen Li
Page No. – Page No.
Electrochemical Aziridination via
Alkene Activation with a Sulfamate as
Nitrogen Source
azirindines.
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