Electrochemical Regioselective Phosphorylation of Nitrogen-Containing Heterocycles and Related Derivatives

Article abstract of DOI:10.1002/adsc.202000997

The site-selective functionalization of biologically important nitrogen-containing heterocycles and related derivatives remains a challenging and important task. We report herein on the direct regiodivergent N1/C2 phosphorylation of free indole derivatives. Cyclic voltammograms and EPR data indicate that by utilizing different electrolyte-mediated anodic oxidation to generate different active indole species, a diverse collection of N1 and C2 phosphorylation products could be obtained in moderate to high yields under exogenous-oxidant-free and metal-catalyst-free electrochemical conditions. In addition, N?P coupling was also found to be compatible with various alkylamines. (Figure presented.).

Full text of DOI:10.1002/adsc.202000997

Title: Electrochemical Regioselective Phosphorylation of Nitrogen-
Containing Heterocycles and Related Derivatives
Authors: Yong Deng, Shiqi You, Mengyao Ruan, Ying Wang, ZuXing
Chen, GuiChun Yang, and Meng Gao
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000997
Link to VoR: https://doi.org/10.1002/adsc.202000997

10.1002/adsc.202000997
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Electrochemical Regioselective Phosphorylation of Nitrogen-Containing Heterocycles and Related
DerivativesYong Deng,a Shiqi You,a Mengyao Ruan, a Ying Wang, a Zuxing Chen, a
Guichun Yang, a* and Meng Gaoa*
a
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecule & School of
Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, P. R. of China. E-mail:
yangguichun@hubu.edu.cn; drmenggao@163.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
and other positions on free indoles have been
reported,[6] but reaction-condition-controlled selective
N1 and C2 functionalization of free indoles remains
relatively unexplored. As a result, the straightforward
and simple routes for the N-H/C-H region-switchable
functionalization of free indoles continues to be a
highly attractive challenge.
Abstract. The site-selective functionalization of
biologically important nitrogen-containing heterocycles
and related derivatives remains a challenging and
important task. We report herein on the direct
regiodivergent N1/C2 phosphorylation of free indole
derivatives. Cyclic voltammograms and EPR data indicate
that by utilizing different electrolyte-mediated anodic
oxidation to generate different active indole species, a
diverse collection of N1 and C2 phosphorylation products
could be obtained in moderate to high yields under
exogenous-oxidant-free
and
metal-catalyst-free
electrochemical conditions. In addition, N-P coupling was
also found to be compatible with various alkylamines.
Keywords: Electrochemical Oxidation; Free Indoles;
Regioselectivity; N1/C2 Phosphorylation
Indoles and their partially saturated derivatives
represent an important class of N-containing
heterocycles and are basic constituents of numerous
natural products, biologically active alkaloids and
agrochemicals.[1] The indole ring is present in 24
currently marketed pharmaceutical products, making it
the fourth most prevalent heteroaromatic ring.[2] This
key heterocyclic core is also widely used in both
organic synthesis and in material science.[3] Due to
their characteristic properties, the functionalization of
indoles has attracted considerable interest and direct
C−H/N-H activation has become one of the most
powerful strategies for the functionalization of
indoles.[4] Numerous processes have been developed
for modifying the indole structure, among which the
N1, C2 and C3 positions have proven to be the main
reactive sites.[5] Regarding reaction selectivity, the
most feasible approaches involve blocking a specific
position or the use of auxiliary groups. Although
significant progress has been made, the selectivity and
efficiencies of these strategies still leave room for
improvement due to the similar reactivity of N-H/C-H
bonds. Only a few examples of systems that allow a
reaction-condition-dependent switch between C2, C3,
Scheme 1. Electrochemical Oxidative Regioselective
Phosphorylation of Free Indoles.
Electrochemical oxidation is recognized as an
efficient and environmentally benign synthetic
strategy and has attracted significant interest.[7]
Processes have also been developed for the
functionalization of indoles aided by electrochemical
oxidation (Scheme 1).[8] Electrosynthesis could be
used to achieve electron transfer between the
electrodes and substrates or catalysts, thus avoiding
the use of excess exogenous oxidants and thus, the
generation of waste products. It is well known that
supporting electrolytes are necessary for increasing the
conductivity of organic systems in electrosynthesis,
but their potential application in mediating the
divergent activity of substrates has not been fully
1
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10.1002/adsc.202000997
Advanced Synthesis & Catalysis
developed.[9] We hypothesized that the use of different
electrolytes would lead to the production of different
types of intermediates in the electrochemical oxidation
of indoles (Scheme 1).
Scheme 1, since the reactive sites of the free indole
could be tuned by the use of different electrolytes, the
desired N-H/C-H functionalization would be expected
to occur with a high degree of selectivity.
Based on the above results, triethyl phosphite was
then added to capture the intermediates. To our delight,
the indole N1 and C2 phosphorylation product 3a and
4a were indeed obtained. Both N1 and C2
phosphoindoles represent an important class of
organophosphorus compounds, which are found not
only in various biologically active compounds, but
also have widespread applications in the fields of
material science and organic synthesis as ligands.[10]
Jin and Liu [8a] recently reported on the electrochemical
oxidative dehydrogenative phosphorylation of N-
heterocycles with P(O)-H compounds, which
significantly simplified the N-P coupling process
(Scheme 1). However, an equivalent amount of base
was required in their reaction and diethyl phosphite
was tolerated, but afforded the corresponding product
in poor yield. Therefore, this novel electrochemical
oxidative cross-coupling reaction for the synthesis of
phosphorus-containing indoles prompted us to
investigate this issue further.
0.00050
KI
0.00045
KI+Indole
nBu4NClO4
0.00040
0.00035
0.00030
0.00025
0.00020
0.00015
0.00010
0.00005
0.00000
-0.00005
nBu4NClO4+Indole
Indole
-0.250.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 3.25
Potential / V(vs Ag/AgCl)
Experiment
Simulation
Our investigation commenced with 1H-indole (1a)
and triethyl phosphite (2a) as starting materials with
CH3CN as the solvent. As shown in Table 1, by
employing a two-electrode system with a carbon rod
as an anode, a platinum plate as a cathode, and KI as
the electrolyte, the desired N1 phosphoindole 3a was
produced in 92% yield with a 5 mA constant current in
an undivided cell (Table 1, entry 1). The use of nBu4NI
resulted in a reactivity that was similar to KI (entry 2)
while KBr was less effective than KI (entry 3). As was
expected, the desired high regioselective C2
phosphoindole 4a could be obtained by using
nBu4NClO4 instead of KI (entry 4). Regarding the
3460
3480
3500
3520
3540
Field(G)
Figure 1. a) Cyclic voltammograms of different electrolytes
and free indole. b) EPR spectrum of the reaction mixture
containing KI and free indole in CH3CN at room
temperature under electric conditions with DMPO as a free
radical scavenger.
n
choice of supporting electrolyte, both Bu4NBF4 and
With this in mind, we investigated the redox
properties of free indoles in cyclic voltammetry in
different electrolytes. Using nBu4NClO4 as the
electrolyte (Figure 1a), the cyclic voltammograms
showed irreversible oxidation waves for free indole
due to the electron-rich nature of the indole ring. This
result indicates that free indole could be oxidized by
the anode with the generation of a radical-cation
intermediate. However, when nBu4NClO4 was
replaced with KI, no oxidation peak was observed for
free indole, and iodide potassium exhibited a dual
oxidation peak at 0.07V and 0.46V versus Ag/Ag+,
respectively. At the same time, EPR spectroscopy
were also performed in an attempt to detect a radical
intermediate with the addition of the free radical spin-
trapping agent 5, 5-dimethyl-1-pyrroline N-oxide
(DMPO) (Figure 1b). An EPR signal corresponding to
an N-centered radical species was observed in the
standard reaction and this was confirmed by computer
simulation. These results indicate that free indole
could also be oxidized to generate an N-centered
radical intermediate, which was different from the
typically produced radical-cation intermediate. The N-
centered radical arose from the reversible homolytic
cleavage of an N-iodo intermediate. As shown in
n
NaBF4 were less effective than Bu4NClO4 (entry 5
and 6). No desired product was obtained without
electric current (entry 7). We also examined the
reaction under various other conditions, including
different electrolytes, solvent, and the amount of
triethyl phosphite (2a). In the case of some conditions
that resulted in low yields, the C3 phosphorylation
product was also observed (see SI for full details
regarding the optimization of the reaction conditions).
2
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10.1002/adsc.202000997
Advanced Synthesis & Catalysis
Table 1. Impact of reaction parameters on the direct
oxidative cross-coupling.
b)
Yield [%]
Entrya)
electrolyte
P(OEt)3
(3a or 4a)
3.0
equiv.
3.0
equiv.
3.0
equiv.
4.0
equiv.
4.0
equiv.
4.0
equiv.
3.0
1
2
KI
nBu4NI
KBr
92
n.d.
n.d.
n.d.
75
75
10
3
4
nBu4NClO4
nBu4NBF4
NaBF4
KI
n.d.
n.d.
n.d.
n.d.
5
30
6
58
7 c)
n.d.
equiv.
a) Reaction conditions (3a): undivided cell, carbon rod anode,
Pt cathode, 1a (0.3 mmol), 2a (0.9 mmol), KI (0.2 mmol),
MeCN (5 mL), air, rt, 5 mA, 6 h. Reaction conditions (4a):
Undivided cell, carbon rod anode, Pt cathode, 1a (0.3 mmol),
2a (1.2 mmol), nBu4NClO4 (0.1 mmol), MeCN (10 mL), air,
rt, 5 mA, 4 h. b) Isolated yields. n.d. = not detected. c) without
electric current.
Scheme 2. Substrate scope for the electrochemical oxidative
N1 phosphorylation of indoles. Reaction conditions:
undivided cell, carbon rod anode, Pt cathode, 1 (0.3 mmol),
2 (0.9 mmol), KI (0.2 mmol), MeCN (5 mL), air, rt, 5 mA,
a)
6 h. Yield of isolated products. KI (0.3 mmol), 10mA, 8h.
It is noteworthy that various alkylamines, such as
N,4-dimethylbenzenesulfonamide,
N-methyl-1-
phenylmethanamine, and dibenzylamine could also be
employed to easily give the desired products (Scheme
3, 3w-3ab). The reaction was not successful for
primary amines, e.g. phenylamine and butylamine. In
With the optimized conditions in hand, various
substituted indoles and N-containing heterocycles 1
were reacted with trialkyl phosphite (Scheme 2). To
our delight, the reaction could be readily extended to a
variety of substituted indoles, and even methyl,
methoxy, nitryl, halogen, cyano or carboxyl
substituted indoles provided N1 phosphorylation
products in moderate to good yields (Scheme 2, 3a-3k).
The structure of the product 3c was also unequivocally
established by an X-ray single-crystal analysis.[11]
Additionally, despite the bulky steric hindrance or the
presence of a long alkyl chain, P(OiPr)3 and P(OnBu)3
could both be used in the reaction, with the N1
phosphorylation products being produced in good
yields (Scheme 2, 3l-3n). It should also be noted that
other N-containing heterocycles, such as 1H-
pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, 1H-
indazole, 9H-carbazole, and indoline were also found
to be suitable reaction partners in this reaction
(Scheme 2, 3p-3u). However, no product was detected
when diphenylphosphine oxide was used as a substrate.
a
gram-scale reaction using the established
electrochemical strategy, the reaction proceeded
smoothly with 3a being obtained in 84% yield (for
more details, see the SI).
Scheme 3. Substrate scope for the electrochemical oxidative
N-H phosphorylation. Reaction conditions: undivided cell,
carbon rod anode, Pt cathode, 1 (0.3 mmol), 2a (0.9 mmol),
KI (0.3 mmol), MeCN (5 mL), air, rt, 5 mA, 6 h. Yield of
isolated products.
3
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10.1002/adsc.202000997
Advanced Synthesis & Catalysis
Scheme 5. Mechanistic experiments
In summary, we reported on the regiodivergent N-
H/C-H functionalization of free indoles via the use of
different electrolytes; in addition, N-P coupling was
also found to be compatible with various alkylamines.
Under exogenous-oxidant-free and metal-catalyst-free
electrochemical oxidation conditions, a diverse
collection of valuable N1 and C2 phosphorylation
products were obtained in moderate to high yields, by
electrochemical anodic oxidation using different
electrolytes to generate different active indole species.
From the synthetic point of view, this protocol
represents a green and simple strategy to produce
phosphorus-containing indole derivatives from basic
starting materials.
Scheme 4. Substrate scope for the electrochemical oxidative
C2 phosphorylation of indoles. Reaction conditions:
undivided cell, carbon rod anode, Pt cathode, 1 (0.3 mmol),
2 (1.2 mmol), nBu4NClO4 (0.1 mmol), MeCN (10 mL), air,
rt, 5 mA, 4 h. Yield of isolated products.
To gain preliminary mechanistic information
concerning this transformation, some mechanistic
experiments were performed. No product was detected
when HPO(OEt)2 was used as a substrate (Scheme 5a),
which indicates that HPO(OEt)2 is not the reaction
intermediate. In addition, when the diethyl
phosphorochloridate 6 was used as the substrate
instead of 2a to react with 1a under the standard
conditions, the corresponding product was not
produced (Scheme 5b). This indicates that the diethyl
phosphosphinyl iodide might not be the active species
in this transformation.
Scheme 6 shows our proposed mechanism for this
electrochemical transformation, based on the above
results and previous studies.[12] For the N1
phosphorylation, 1H-indole 1a reacts with the in-situ
generated hypervalent iodine species to give
intermediate 8. The reversible homolytic cleavage of
the N-iodo intermediate 8 gives an iodine radical and
the nitrogen-centered radical 7 which was detected in
the above EPR spectra. The nitrogen-centered radical
7 is then captured by 2a to afford the intermediate 9;
finally, the ensuing dealkylation of 9 forms the N1
phosphorylation product 3a. At the same time, protons
were reduced at the cathode with the formation of H2.
With respect to C2 phosphorylation, 1a is first
oxidized at the anode to form the radical cation
intermediate 10, which then is captured by P(OEt)3 2a
and delivers the adduct 11, and 11 then undergoes
further anodic oxidation, dehydrogenation and ensuing
dealkylation resulting in the formation of the C2
phosphorylation product 4a.
Scheme 6. Proposed mechanism.
Experimental Section
General Procedures for Preparation of the
Phosphorylation Products 3a and 4a: For 3a: In an oven-
dried three-necked flask (25 mL) equipped with a stirring
bar, the indole 1a (35.1 mg, 0.3 mmol), P(OEt)3 (155.1 uL，
0.9 mmol), KI (33.2 mg, 0.2 mmol) were combined and
added. Under the atmosphere of air, CH3CN (5 mL) was
injected respectively into the tubes via syringes. The flask
was equipped with carbon rod (ϕ 6 mm, about 10 mm
immersion depth in solution) as the anode and a platinum
plate (15 mm×15 mm×0.3 mm) as the cathode. The reaction
4
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10.1002/adsc.202000997
Advanced Synthesis & Catalysis
mixture was stirred and electrolyzed at a constant current of
5 mA at room temperature for 6 h. After completion of the
reaction, as indicated by TLC and GC-MS, the pure product
(yield: 92%, 69.82 mg) was obtained by flash column
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate= 10:1). For 4a: Indole 1a (35.1 mg, 0.3 mmol),
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n
P(OEt)3 (206.8 uL, 1.2 mmol), Bu4NClO4 (34.2 mg, 0.1
mmol) were combined and added. Under the atmosphere of
air, CH3CN (10 mL) was injected respectively into the tubes
via syringes. The flask was equipped with graphite rod (ϕ 6
mm, about 10 mm immersion depth in solution) as the anode
and platinum plate (15 mm×15 mm×0.3 mm) as the cathode.
The reaction mixture was stirred and electrolyzed at a
constant current of 5 mA at room temperature for 4 h. After
completion of the reaction, as indicated by TLC and GC-
MS, the pure product (yield: 75%, 56.93 mg) was obtained
by flash column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate= 5:1). The spectroscopic data
of the products 3a and 4a are presented below. All of the
known compounds gave satisfactory spectroscopic values
and are analogue to spectroscopic data reported in the
literature. All the known compounds had satisfactory
spectroscopic features which were analogous to
spectroscopic data reported in the literature. 3a:1H NMR
(400 MHz, Chloroform-d) δ 7.75 (d, J = 8.2 Hz, 1H), 7.59
(d, J = 7.8 Hz, 1H), 7.44 (dd, J = 3.2, 1.6 Hz, 1H), 7.29-7.24
(m, 1H), 7.23-7.16 (m, 1H), 6.63 (q, J = 3.1 Hz, 1H), 4.23-
4.13 (m, 2H), 4.06-3.95 (m, 2H), 1.27-1.23 (m, 6H). 13C
NMR (101 MHz, Chloroform-d) δ 136.61 (d, J = 4.8 Hz),
130.82 (d, J = 10.2 Hz), 128.47 (d, J = 7.0 Hz), 123.28,
121.91, 120.78, 113.29, 107.08 (d, J = 8.5 Hz), 63.65 (d, J
= 4.9 Hz), 15.69 (d, J = 6.8 Hz). 31P NMR (162 MHz,
CDCl3) δ−3.07. HRMS (ESI) cald. for (M+H)+C12H17NO3P:
254.0941; found, 254.0943. 4a:1H NMR (400 MHz,
Chloroform-d) δ 10.53 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53
(d, J = 8.3 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.5
Hz, 1H), 7.05 (dd, J = 4.1, 1.6 Hz, 1H), 4.22-4.11 (m, 4H),
1.34 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, Chloroform-
d) δ 138.42 (d, J = 12.9 Hz), 127.34 (d, J = 15.5 Hz), 123.53
(d, J = 220.18 Hz), 124.33, 121.64, 120.36, 112.30, 111.49
(d, J = 17.0 Hz), 62.79 (d, J = 5.0 Hz), 16.19 (d, J = 6.7 Hz).
31P NMR (162 MHz, CDCl3) δ 10.95. HRMS (ESI) calcd.
for (M+H)+C12H16NO3P: 254.0941; found 254.0947.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21702081) and Jiangxi Provincial
Education Department Foundation (No. GJJ160325).
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Advanced Synthesis & Catalysis
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10.1002/adsc.202000997
Advanced Synthesis & Catalysis
COMMUNICATION
Electrochemical Regioselective Phosphorylation of
Nitrogen-Containing Heterocycles and Related
Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Yong Deng, Shiqi You, Mengyao Ruan, Ying
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