Phosphoric Acid Mediated Light-Induced Minisci C?H Alkylation of N-Heteroarenes

Article abstract of DOI:10.1002/ejoc.202001538

Herein, we report an environmentally-friendly light-induced Minisci alkylation of N-heteroarenes with a broad substrate scope using diphenyl phosphate as catalyst under metal- and photocatalyst-free conditions. The radical precursor redox-active esters (R

Full text of DOI:10.1002/ejoc.202001538

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doi.org/10.1002/ejoc.202001538
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Phosphoric Acid Mediated Light-Induced Minisci CÀ H
Alkylation of N-Heteroarenes
Songyang Jin+,[a] Xinxin Geng+,[a] Yujun Li,[a] and Ke Zheng*[a]
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Herein, we report an environmentally-friendly light-induced
Minisci alkylation of N-heteroarenes with a broad substrate
scope using diphenyl phosphate as catalyst under metal- and
photocatalyst-free conditions. The radical precursor redox-
active esters (RAEs) were introduced as alkylating reagents for
the functionalization of N-heteroarene derivatives including
pyridine, quinoline, and isoquinoline. Mechanistic studies
suggested that diphenyl phosphate played a key role via
hydrogen bonding in the catalytic cycle.
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The functionalization of N-heteroarenes has always been a
transformation of great interest in organic chemistry due to
their omnipresence in varieties of pharmaceuticals and bio-
Scheme 1. Methods for Minisci reaction.
logically active molecules.[1–2] As a versatile method for the
derivation of N-heteroarenes, the Minisci reaction, which has
been developed since 1970s, has matured into a powerful
strategy for CÀ H functionalization of diverse N-heteroarenes.[3–4]
The primal methods were implemented using Ag salts and
stoichiometric
light-induced Minisci reactions in 2017 by Glorius group.[15] Over
recent years, carboxylic acids and the redox-active esters (RAEs,
derived from carboxylic acids) serving as alkylating agents were
applied in light-induced Minisci reactions by several
groups,[16–18] as well as in asymmetric fashion.[18g–h] Our continu-
ing pursuit of the discovery of new methods under photo-
catalyst-free conditions has led us to explore a new photo-
chemical protocol for Minisci alkylation to construct the
functionalized N-heteroarenes. Herein, we report an environ-
mentally-friendly light-induced Minisci-type reactions of N-
heteroarenes with good functional group tolerance under mild
conditions (metal- and photocatalyst-free, at room temper-
ature). A series of functionalized N-heteroarenes were synthe-
sized in high yields by employing redox-active esters (RAEs) as
radical precursors.
We began our optimization by choosing lepidine (1a) and
pivalic acid-derived RAE (2a) as the model substrates in the
presence of 20 mol% diphenyl phosphate (PA) under the
irradiation of 10 W 395 nm LEDs (Table 1). To our delight, this
transformation could proceed smoothly in 1,4-dioxane to give
the desired product in excellent yield (92% yield, entry 1). Other
solvents such as DCM and THF led to lower yields (entries 2–3).
A brief survey of catalyst loading showed that 20 mol%
diphenyl phosphate could give the best outcome, lower yields
were obtained under higher or lower catalyst loading (en-
tries 4–5). Meanwhile, reducing the equivalents of RAE gave a
slightly decreased yield (entry 6). A series of control experi-
ments indicated that the diphenyl phosphate and purple light
were crucial to facilitate this transformation (entries 7–9).
With optimized reaction conditions in hand, the generality
of this strategy was investigated. Several commercially available
amounts of persulfates as oxidants and an excess amount of
alkyl carboxylic acids as radical precursors (Scheme 1a).[5] Over
the past decade, photo-redox organocatalysis has undergone a
dramatic development and shown its broad application in
organic synthesis.[6–8] As an efficient and environmentally
friendly method to produce carbon radicals, the photochemistry
was also applied in Minisci-type reactions,[9] where a diverse set
of radical precursors such as peroxides,[10] alkyl halides,[11] boric
acids or salts,[12] alcohols[13] and ethers,[14] etc. has been utilized
in light-induced Minisci-type reactions (Scheme 1b). Despite
significant advances that have been made in this field, the
existing methods usually require stoichiometric or excess
amount of strong acids or oxidants, or with limited substrate
scope, using expensive catalysts, and so on. Thus, the develop-
ment of efficient, environmentally-friendly, and facile approach
for Minisci CÀ H alkylation of N-heteroarenes is still highly
desired.
As one of the most diverse organic compounds, the
carboxylic acids were employed as radical precursors in the
[a] S. Jin,+ X. Geng,+ Y. Li, Prof. K. Zheng
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
E-mail: kzheng@scu.edu.cn
http://chem.scu.edu.cn/hxen/info/1003/1461.htm
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001538
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Table 1. Optimization of reaction conditions.[a]
functional groups were also tolerable, finishing the target
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products with better outcomes comparing to the secondary
alkyl radicals (3i–3l). It was noted that this method could be
applied to late-stage functionalization of the bioactive mole-
cules. The RAE derived from fenofibrate acid, which was used as
antihyperlipidemic drug, was well-tolerable to this protocol,
affording the desired product in excellent yield (3l, 91% yield).
Unfortunately, the primary alkyl radicals were not suitable
coupling partners in this reaction.
Entry
Deviation from standard conditions
Yield [%][b]
Next, a series of N-heteroarenes with various functional
groups were subjected to this protocol. To our delight, the
substrate scope could be expanded to the pyridine rings. As
depicted in Scheme 3, the methyl nicotinate (3m, 84% yield)
and its analogs with methyl- and amino-groups could proceed
smoothly to give corresponding products in moderate to good
yields (3n, 82% yield; 3o, 65% yield). The hexyl nicotinate
could also conveniently convert to the product in high yield
(3p, 76%). For the scope of quinolines, isoquinoline reacted
successfully to furnish 3q in 44% yield. The quinolines with
diverse substituents at the C6-position were next investigated.
The quinolines with halides (3r-s), methyl (3t), and electron-
withdrawing group (3u) were well tolerated, giving the
corresponding products in good yields with high regioselectiv-
ities (alkylation occurred at C2-position exclusively). Similarly, 3-
methyl quinoline was used successfully to deliver the mono-
substituted product (3v, 57% yield). In addition, quinoxyfen,
which is used as bactericide, was amenable to this protocol, the
product 3w was obtained in 54% yield.
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none
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DCM as solvent
THF as solvent
10 mol% PA
30 mol% PA
1.1 equiv. 2a
no phosphoric acid
no light
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0
460 nm LEDs
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), PA (0.02 mmol),
395 nm LEDs (10 W), nitrogen atmosphere, rt=room temperature. [b]
Isolated yields.
secondary and tertiary aliphatic acids-derived RAEs were
subjected to the reaction as alkyl radical precursors. As shown
in Scheme 2, a range of cyclic-alkylated products was obtained
in moderate to high yields when the RAEs with four-, five-, six-,
seven-membered ring were used as radical precursors (3b–e),
where the six-membered ring gave the best result among these
analogs (3d, 78% yield). Furthermore, a bridged-ring substitu-
ent also underwent smooth radical coupling to produce the
corresponding product in high yield (3f). The amino acid- and
phenoxyacetic acid-derived RAEs were also compatible, yielding
the desired coupling products in high efficiencies (3g, 67%
yield and 3h, 75% yield). Various tertiary alkyl radicals with
To gain insights into the mechanism, several control experi-
ments were performed. As depicted in Scheme 4, when 2
equivalents of radical scavenger 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) was added into the standard reaction, the
transformation was suppressed completely, which indicated
that a radical process was involved in this reaction (Scheme 4a).
Unlike the traditional light-induced Minisci-type reaction, there
Scheme 2. Substrate scope for the RAEs. [a] Reaction conditions: 1a
(0.2 mmol), 2 (0.4 mmol), PA (0.04 mmol, 20 mol%), 1,4-dioxane (2.0 mL),
10 W LEDs (395 nm), rt, N2. [b] Isolated yields.
Scheme 3. Substrate scope for the N-heteroarenes. [a] Reaction conditions: 1
(0.2 mmol), 2a (0.4 mmol), PA (0.04 mmol, 20 mol%), 1,4-dioxane (2.0 mL),
10 W LEDs (395 nm), rt, N2. [b] Isolated yields.
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Scheme 4. Control experiments.
Scheme 5. Proposed mechanism.
was no photocatalyst serving as oxidant or reductant to
produce radicals in this protocol. We envisioned that the N-
heteroarene 1a might coordinate with the diphenyl phosphate
via hydrogen bonding to form a photosensitive intermediate,
which could absorb light to trigger this transformation. To
gather direct evidence for this conjecture, several control
experiments were conducted. As shown in Scheme 4b and
Scheme 4c, no desired products were obtained when N-oxide
1aa or 2-methylquinoline 2ab (H atom on C2-position was
replaced by methyl group) were used as substrates, which
indicated that the diphenyl phosphate was coordinated with
substrate 1a via double hydrogen bonding. Moreover, when 1a
was subjected to the standard conditions without 2a, the self-
step). Additionally, the traditional radical propagation started
from the addition of alkyl radical IV to the substrate 1a was
also considered as an alternative pathway to produce the
desired product 3a (more detail see SI, Figure S4).
In conclusion, we have developed a light-induced Minisci
alkylated reaction under metal- and photocatalyst-free con-
ditions. A series of functionalized N-heteroarenes were synthe-
sized by employing redox-active esters (RAEs), derived from the
commercially-available carboxylic acids, as radical precursors.
Mechanism studies suggested that a key photosensitive inter-
mediate was formed by the coordination of diphenyl phosphate
and N-heteroarene via hydrogen bondings and the trans-
formation undergo radical pathway. Further application of this
strategy in asymmetric Minisci reaction is underway.
coupling product was observed via
a radical pathway
(Scheme 4d), indicating the aromatic radicals could arise
directly from the irradiation of the mixture of 1a and PA.[19]
Moreover, the UVÀ Vis spectroscopic measurements were
performed on various combinations of 1a, 2a, and catalyst PA. Acknowledgements
The results showed an obvious redshift of absorption onset
when the substrate 1a was mixed with PA, tailing into the
wavelength range of 400 nm (in SI, Figure S2). These results
indicated that a photosensitive intermediate might formed
from 1a and PA in our system.
Based on the above mechanistic results, a proposed
mechanism was depicted in Scheme 5. First, a photosensitive
intermediate I is generated by the coordination of PA and 1a
via double hydrogen bonding, which was irradiated with visible
We thank the National Natural Science Foundation of China (Nos.
21602142), and Sichuan University for financial support. We thank
the Xiaoming Feng laboratory (SCU) for access to equipment. We
also thank the comprehensive training platform of the Specialized
Laboratory in the College of Chemistry at Sichuan University for
compound testing.
light to form the excited state II. The excited state II, which acts Conflict of Interest
as a strong reducing reagent, transfers an electron to the redox-
active esters 2a, leading to the corresponding alkyl radical IV
along with the aromatic radical III.[19] We considered that, as the
most favorable pathway, the radical-radical coupling was
occurred to deliver the final product 3a and regenerate the PA
in the presence of the resultant base (produced from the SET
The authors declare no conflict of interest.
Keywords: Alkylation · Heterocycles · Lewis acids · Light-
induced · Radicals
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Manuscript received: November 25, 2020
Revised manuscript received: January 5, 2021
Accepted manuscript online: January 14, 2021
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