Photocatalytic Cyclization/Defluorination Domino Sequence to Access 3-Fluoro-1,5-dihydro-2 H-pyrrol-2-one Scaffold

Article abstract of DOI:10.1021/acs.orglett.1c01477

We herein report an unprecedented photoinduced cyclization/defluorination domino process of N-allylbromodifluoroacetamide with cyclic secondary amines. Consequently, a wide array of valuable 3-fluoro-1,5-dihydro-2H-pyrrol-2-ones were facilely prepared from readily available starting materials under mild conditions. Preliminary mechanistic investigations suggest that a radical chain propagation and amine-promoted defluorination pathway are presumably involved in this transformation.

Full text of DOI:10.1021/acs.orglett.1c01477

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Letter
Photocatalytic Cyclization/Defluorination Domino Sequence to
Access 3‑Fluoro-1,5-dihydro‑2H‑pyrrol-2-one Scaffold
Zhi-Peng Ye, Yuan-Zhuo Hu, Jian-Ping Guan, Kai Chen, Fang Liu, Jie Gao, Jun-An Xiao,
Hao-Yue Xiang,* Xiao-Qing Chen, and Hua Yang*
Cite This: Org. Lett. 2021, 23, 4754−4758
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ABSTRACT: We herein report an unprecedented photoinduced cyclization/defluorination domino process of N-allylbromodi-
fluoroacetamide with cyclic secondary amines. Consequently, a wide array of valuable 3-fluoro-1,5-dihydro-2H-pyrrol-2-ones were
facilely prepared from readily available starting materials under mild conditions. Preliminary mechanistic investigations suggest that a
radical chain propagation and amine-promoted defluorination pathway are presumably involved in this transformation.
1,5-Dihydro-2H-pyrrol-2-ones, an important class of unsatu-
rated conjugated derivatives of γ-lactams, are ubiquitously
present in numerous bioactive natural products1 and
pharmaceuticals,2 as 1,5-dihydro-2H-pyrrol-2-one derivatives
show a range of pharmacological activities such as anticancer,2c
HIV-1 antiviral,2d and antitumoral properties2e and FPR1
antagonist behavior2i (Scheme 1a). Undoubtedly, extensive
attention has been garnered for the facile construction of 1,5-
dihydro-2H-pyrrol-2-ones. On the contrary, it is widely
accepted that the physicochemical and bioactive properties
of compounds can be intrinsically modulated by introducing a
fluorine atom, and thus fluorinated compounds are pervasive
within a wide range of pharmaceuticals, agrochemicals, and
materials.3 Following this line, fluorinated 1,5-dihydro-2H-
pyrrol-2-ones, especially 3-fluoro-1,5-dihydro-2H-pyrrol-2-one,
have been surprisingly underestimated (Scheme 1b).4,5 To our
surprise, the ring-closing metathesis is almost the exclusive
pathway to assemble this type of ring system, which might
tremendously hurdle the comprehensive examination of the
bioactivities of this class of scaffold. Consequently, it can be
conceived that a new synthetic pathway and reaction mode for
the synthesis of 3-fluoro-1,5-dihydro-2H-pyrrol-2-one is rather
demanding but still appealing.
Scheme 1. Current Status for 3-Fluoro-1,5-dihydro-2H-
pyrrol-2-ones and Their Synthetic Profiles
Recently, N-allylbromodifluoroacetamides have emerged as
powerful building blocks for the rapid construction of
fluorinated heterocyclic scaffolds.6 To date, a library of 3,3-
difluoro-γ-difluoro-γ-lactams has been assembled from N-
allylbromodifluoroacetamides through a 5-exo-trig cyclization
process. In 2020, our group developed a visible-light-induced,
catalyst-free radical cross-coupling cyclization of N-allylbro-
Received: April 29, 2021
Published: June 1, 2021
https://doi.org/10.1021/acs.orglett.1c01477
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4754−4758
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modifluoroacetamides with diselenides or disulfides, facilely
affording a wide range of sulfo- or seleno-engineered lactams
(Scheme 1c). In this process, a trace amount of 3,3-difluoro-4-
methylenepyrrolidin-2-one 5a was serendipitously observed.
This observation intrigued us to further examine the
hypothesis that employing a nucleophile to trigger the
following SN2′-type defluorination leads to the construction
of new type of fluorinated framework. As part of our continued
interest in the photoredox catalysis and fluorinated hetero-
cycles,7 we herein report the first example of a unique
cyclization/defluorination domino pathway of N-allylbromodi-
fluoroacetamides to assemble a wide array of valuable 3-fluoro-
1,5-dihydro-2H-pyrrol-2-one, wherein aza-heterocycles were
effectively merged into the scaffold (Scheme 1c).
2). Encouraged by these results, we further optimized the
reaction parameters. Solvent screening demonstrated that
DMSO was identified to be the optimal choice (Table 1,
entries 2−5). Subsequently, a series of photocatalysts were
evaluated, and fac-Ir(ppy)3 gave superior results in promoting
this transformation (Table 1, entries 6−8). Other additives
such as KI, NSI, and NaBr (Table 1, entries 9−11) and other
bases (Table 1, entries 12−14) resulted in inferior reaction
efficiency. Obviously, the base played a significant role in this
reaction, which could probably promote the defluorination
process and consume HF produced during the reaction process
(Table 1, entry 15). Finally, the amount of additive was
investigated (Table 1, entries 16−18), and 3 equiv of NaI gave
the best yield of 3a. Control experiments revealed that both a
photocatalyst and light were essential for this transformation
(Table 1, entries 19 and 20).
We started our investigation by using N-allyl-2-bromo-2,2-
difluoro-N-phenylacetamide (1a) and morpholine (2a) as
model substrates (Table 1). Unfortunately, when the reaction
Having established the reaction conditions, we next shifted
our attention to explore the substrate scope of this photo-
catalytic transformation (Scheme 2). Initially, two pharma-
ceutically important aza-heterocycles, morpholine (2a) and
a
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope Investigation
b
entry
PC
solvent
base
yield (%)
c
1
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ru(bpy)3
Rose Bengal
Ir(ppy)2(dtbpy)
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
DMSO
DMSO
THF
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K3PO4
n.d.
58
2
3
4
5
6
7
8
trace
trace
trace
trace
trace
13
MeCN
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
d
9
50
e
10
11
12
13
14
15
16
17
18
19
trace
n.d.
52
trace
31
trace
63
73
f
TMEDA
CH3COONa
g
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
h
i
58
n.r.
n.r.
hj
,
20
fac-Ir(ppy)3
a
Unless otherwise noted, the reaction was carried out on a 0.2 mmol
scale in solvent (2 mL) with a molar ratio of 1a/2a = 1:4; base (2
equiv), NaI (1 equiv), photocatalyst (2.5 mol %), irradiating with 30
W blue LEDs, Ar, rt, 2 h; n.d. = not detected; n.r. = no reaction.
b
c
d
e
Isolated yields. Without NaI. KI (1 equiv) instead of NaI. NIS (1
f
g
equiv) instead of NaI. NaBr (1 equiv) instead of NaI. 2 equiv of
NaI. 3 equiv of NaI. 4 equiv of NaI. In the dark.
h
i
j
was carried out under the routine photocatalytic conditions
(Table 1, entry 1), the desirable product was not detected.
Instead, 3,3-difluoro-4-methyl-1-phenylpyrrolidin-2-one (for
details, see the Supporting Information) was isolated as the
major product, which was formed through a 5-exo-trig
cyclization of 1a followed by a direct HAT process. To
address this problem, we subsequently attempted to add 1
equiv of NaI to immediately capture the methyl radical
intermediate, thus circumventing the following HAT process.
To our delight, in the presence of NaI, an aminated product 3a
with defluorination was furnished in 53% yield (Table 1, entry
a
Standard conditions: 1 (0.2 mmol), 2 (0.8 mmol, 4 equiv), K2HPO4
(0.4 mmol, 2 equiv), DMSO (2 mL), fac-Ir(ppy)3 (2.5 mol %), and
NaI (0.6 mmol, 3 equiv) were irradiated with 30 W blue LEDs, Ar, rt,
2 h; isolated yield. Performed on 2 mmol of 1o.
b
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tert-butyl piperazine-1-carboxylate (2b),8 were employed as the
coupling partners to verify the viability and limitation of N-
allylbromodifluoroacetamides 1. As shown in Scheme 2, both
amines 2a and 2b were amenable to this protocol, and they
reacted with diverse N-phenyl and N-benzyl substrates 1 to
give the desired products 3a−3al in moderate to good
chemical yields, although relatively lower yields were obtained
for morpholine 2a. The electronegativity and position of the
substituent on the phenyl or benzyl moiety of substrates 1 had
a significant impact on the chemical yield, but there was no
clear pattern. Subsequently, other heterocycles were also
evaluated, and it was noteworthy that 2,6-dimethylmorpholine
(2c) with severe steric hindrance was also suitable for this
photocatalytic transformation, furnishing the corresponding
product 3am in a satisfactory yield (67%). Moreover, N-
acetyl-, N-Cbz-, and N-ethoxycarbonyl-substituted piperazine
could deliver the desired products 3an−3ap in 39−67% yield
as well. Gratifyingly, another important amine, 4-carbethox-
ypiperidine, was also able to serve as an effective coupling
partner to react with N-allyl-2-bromo-2,2-difluoro-N-phenyl-
acetamide, albeit with a low yield (23%). However, N-alkyl- or
N-heterocyclic-substituted bromodifluoroacetamide was un-
able to proceed in the transformation. Presumably because of
their steric hindrance, internal alkenes have been tested in the
standard reaction, but no desired products were isolated. N-
(But-3-en-1-yl)-N-(dibromofluoromethyl)benzamide has been
synthesized and subjected to the standard conditions, but no
six-membered product was obtained. We also tested several
cyclic amines, including 1-methylpiperazine and piperidine,
and linear amines, but no desired amino product was detected.
Presumably, these unsuccessful amines preferred to serve as
hydrogen atom donors to undergo a HAT process rather than
as nucleophiles to proceed in SN2 nucleophilic substitution to
give the desired products. Other type of nucleophiles
(including aniline, alcohols, TMSN3, and thiophenol) have
been evaluated, but no desired products were isolated under
the current conditions. Pleasingly, a scale-up reaction of 3o was
performed, affording the desired product smoothly in a similar
yield. Further transformation of the as-prepared product 3a has
also been performed, which unfortunately only rendered a
fairly complex reaction under the current reaction conditions
(Scheme 2, bottom).
To gain mechanistic insights into this process, several
control experiments were implemented (Scheme 3; see the
Supporting Information for details). The radical inhibition
experiments were performed by adding butylated hydroxyto-
luene (BHT) under the standard reaction conditions. The
formation of 3a was completely suppressed but with a 48%
yield of BHT adduct 4a, suggesting that a radical pathway was
involved in the transformation (Scheme 3a). It is worth noting
that the transformation for 3a was impeded by adding 1 equiv
of 1-methylpiperazine, and only 3,3-difluoro-4-methyl-1-
phenylpyrrolidin-2-one (5a) was obtained (Scheme 3b).
These results essentially verify our hypothesis that there was
a competitive HAT process involved in this photocatalytic
procedure. The Stern−Volmer studies revealed that both 1a
and 2a could quench the photoexcited fac-Ir(ppy)3. (For
details, see the Supporting Information.) On/off and off/on
experiments on the reaction of 1a and 2a demonstrated that
the corresponding product 3a could be produced upon
constant irradiation and in the dark, suggesting that a radical
chain propagation pathway might be involved. (For details, see
the Supporting Information.) Moreover, a quantum yield of Φ
Scheme 3. Control Experiments and Proposed Mechanism
= 27.7 (for details, see the Supporting Information) was in
agreement with the results of the on/off experiments.
Interestingly, the bromo-substituted cyclic intermediate 6a
could directly deliver the desired product 3a even without
light, indicating that the final amination/defluorination step is
not a photocatalytic process. However, the reaction efficiency
for the conversation of 6a to 3a dramatically decreased in the
absence of NaI, illustrating that NaI was able to effectively
inhibit the HAT process and promote the desired trans-
formation (Scheme 3c). Moreover, piperidine also reacted with
6a to afford the corresponding product 3ar (Scheme 3c). On
the contrary, 3,3-difluoro-4-methylenepyrrolidin-2-one 7 was
submitted to the standard conditions with morpholine, and 3a
was obtained in 64% yield, implying that this intermediate was
possibly involved in the process.
On the basis of the previously described experimental
observation, the possible reaction mechanism is thus proposed
(Scheme 3, bottom). Upon irradiation by visible light,
photocatalyst Ir3+ was sensitized to excited *Ir3+, which
underwent an oxidative quenching by N-allylbromodifluor-
oacetamide 1 to generate the radical intermediate A and the
corresponding Ir4+. A single-electron transfer between the
iodine ion and Ir4+ would complete the catalytic cycle,
regenerating the photocatalyst and giving an iodine radical.
Subsequently, a rapid 5-exo-trig radical cyclization of A formed
the cyclic radical species B. Once the intermediate B was
captured by hydrogen atom, the byproduct was predominantly
formed. Alternatively, radical−radical cross-coupling with an
iodine radical or the direct abstraction of a bromine atom from
substrate 1 resulted in the intermediate 6. Finally, the
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intermediate 6 underwent a nucleophilic substitution and the
subsequent elimination of HF promoted by the base to deliver
the intermediate B. Otherwise, the intermediate 6 underwent
an elimination process to generate intermediate 7,5,9 which
would proceed in a SN2′-type reaction to ultimately give the
product 3.
Xiao-Qing Chen − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-8768-8965
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01477
In conclusion, we have developed a visible-light-promoted
cyclization/defluorination reaction of N-allylbromodifluoroa-
cetamides to facilely assemble a 3-fluoro-1,5-dihydro-2H-
pyrrol-2-one scaffold under mild conditions. Meanwhile, a
series of biologically valuable heterocycles were engineered
into this privileged scaffold, which would offer more options
for further biological investigation. This work would inspire a
broader exploitation of new synthetic protocols for fluorinated
heterocycles.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (22078370, 21776318,
22078369, 81703365, 22003077), Basic Science Center
Project for National Natural Science Foundation of China
(no. 72088101, the Theory and Application of Resource and
Environment Management in the Digital Economy Era),
Natural Science Foundation of Hunan Province (2018JJ3868,
2020JJ4682), the Fundamental Research Funds for Central
South University (2020zzts401), and Central South University.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01477.
REFERENCES
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Experimental details and characterization data for new
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CCDC 2070010 contains the supplementary crystallographic
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AUTHOR INFORMATION
■
Corresponding Authors
Hua Yang − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China;
orcid.org/0000-0002-5518-5255; Email: hyangchem@
csu.edu.cn
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Hao-Yue Xiang − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-7404-4247;
Email: xianghaoyue@csu.edu.cn
Authors
Zhi-Peng Ye − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Yuan-Zhuo Hu − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Jian-Ping Guan − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Kai Chen − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Fang Liu − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Jie Gao − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Jun-An Xiao − College of Chemistry and Materials Science,
Nanning Normal University, Nanning 530001, P. R. China
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