Photocatalytic reductive radical-radical coupling of: N, N ′-cyclicazomethine imines with difluorobromo derivatives

Article abstract of DOI:10.1039/c8cc09385g

A visible-light-induced difluoroalkylation of N,N′-cyclicazomethine imine was successfully realized through a novel photoredox radical-radical cross-coupling reaction. This developed protocol exhibits high functional group tolerance and affords a variety

Full text of DOI:10.1039/c8cc09385g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Photocatalytic reductive radical-radical coupling of N, N'-
cyclicazomethine imines with difluorobromo derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Peng-Ju Xia,a,§ Zhi-Peng Ye,a,§ Dan Song,a Ji-Wei Ren,a Han-Wen Wu,a Jun-An Xiao,c Hao-Yue
Xiang,*,a Xiao-Qing Chen,*,a, b Hua Yang*,a, b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A visible-light-induced difluoroalkylation of N,N'-cyclicazomethine imine high electrophilicity of the iminium moiety, nucleophilic
was successfully realized through a novel photoredox radical-radical cross- additions of N,N'-cyclicazomethine imines,10 including
coupling reaction. This developed protocol exhibits high functional group arylation,10a cyanation10b and trifluoromethylation,10c have
tolerance and affords a variety of difluorinated 3-pyrazolidinone scaffolds. been employed to functionalize the dinitrogen heterocycle
Extensive mechanistic investigations have been undertaken, well revealing (Scheme 1). Considering the limited available transformations
the involvement of a reductive radical-radical coupling pathway.
for this valuable synthon and the needs for broad biological
studies, one would expect to deeply exploit its new reaction
modes and fully appreciate its synthetic potentials, especially in
the booming visible-light photoredox transformations. Herein,
we report our efforts on the exploration in the photochemical
performance of N,N'-cyclicazomethine imines under visible
light.
N,N'-cyclicazomethine imines (3-oxopyrazolidin-1-ium-2-ides)
were firstly reported by Dorn and Otto in 1968.1 Their synthetic
utilities have always attracted considerable interest as they can
serve as vital synthons in straightforward and effective entries
to pyrazolones and the related dinitrogen-fused heterocyclic
derivatives.2 The significant dinitrogen-fused analogues were
proven to exhibit a range of biological activities,3 such as
inhibition of COX-2,4 anti-alzheimer,5 and insecticidal activity6.
The versatile reactivities of N,N'-cyclicazomethine imines have
been consistently pursued, allowing the facile construction of
diversified dinitrogen-fused heterocyclic systems. Prominently,
Scheme 1. Reaction Profiles of N, N'-cyclicazomethine Imines
reaction profiles of N, N'-cyclic azomethine imines
nucleophilic
addition
[3+n]
dimerization
O
annulation
O
O
R1
N
N
previous work
N
N
NH
N
N
owing to their inherent dipolar feature,
a range of
R1
N
O
dipolarophiles including olefins,7a alkynes,7b enones,7c
isocyanides,7d and allenes7e were amenable to [3+n] annulation
with N,N'-cyclicazomethine imines to assemble a wide range of
R1
R1 Nu
O
N
N
visible-light photocatalysis
O
O
R1
radical-radical
coupling
this work
NH
dinitrogen heterocycles (Scheme 1). Interestingly,
a
versatile
synthon
N
N
PC
N
RF
dimerization of N,N'-cyclicazomethine imine under irradiation
of UV-light was observed by Geissler in 1983, leading to form 1,
5-diazabicycle (Scheme 1).8 Thereafter, Dorn also observed that
N,N'-cyclicazomethine imines could yield small amount of
centrosymmetric dimers via a concerted [π4s+π4s]-pathway
under photochemical conditions (Scheme 1).9 In contrast to the
well-established cyclization pathways, direct functionalizations
of N,N'-cyclicazomethine imines afforded alternative modes for
enriching the library of dinitrogen-fused heterocycles. Given the
R1
R1
RF
photochemical
property
new fluorinated
heterocycle scaffold
new reaction mode
Recently, developing new and efficient methods for the
synthesis of fluorinated molecules, especially
difluoromethylene group (CF2),11 has received great attention
because of the unique properties of difluoromethylene group.12
In particular, among various fluorinating reagents, it was found
that BrCF2X regents could effectively generate CF2 radicals via
diverse single electron transfer pathways.13 Intrigued by the
photochemical properties of N,N'-cyclicazomethine imines and
driven by our continued interest in the fluorination of
heterocycles, we developed a novel protocol for achieving the
difluoroalkylation of N,N'-cyclicazomethine imines through a
visible-light photocatalytic reductive radical-radical coupling
aCollege of Chemistry and Chemical Engineering, Central South University, Changsha
410083, P. R. China E-mail: hyangchem@csu.edu.cn, xianghaoyue@csu.edu.cn,
xqchen@csu.edu.cn.
bKey Laboratory of Hunan Province for Water Environment and Agriculture Product
Safety, Central South University, Changsha 410083, P. R. China
cCollege of Chemistry and Materials Science, Guangxi Teachers Education University,
Nanning 530001, Guangxi, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for products. See
DOI: 10.1039/x0xx00000x
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Chem. Commun., 2018, 00, | 1
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these considerations in mind,
a
model reactiVoienw Aortifcle ONn,Nlin'e-
process (Scheme 1), which would offer new platform for
exploring the versatile reactivities of these valuable synthons.
DOI: 10.1039/C8CC09385G
cyclicazomethine imine 1a and BrCF2CO2Et 2a was designed and
employed to optimize the reaction conditions at room temperature
under irradiation with a 30 W blue LEDs lamp in the presence of
Ir(ppy)3 (Table 1). First, various solvents were screened (Table 1,
entries 1-4). The starting material 1a was consumed completely in 2
hours and 3a was obtained in 17% yield when DMSO was used as the
solvent. However, other solvents did not give better results even in
the prolonged reaction time. It was rationalized that the addition of
a base is essential for this reaction since the by-product HBr should
be effectively neutralized to accelerate the reaction (Table 1, entry
5). Accordingly, other bases were then screened (Table 1, entries 6–
10). Gratifyingly, when Cs2CO3 was used, the reaction yield was
remarkably improved to a synthetically useful yield (74%). However,
other sacrificial electron donor including 1, 4-dihydropyridine (HEH)
and 3-mercaptopropionic acid (3-MPA) were unable to afford the
corresponding product. The yield of 3a was reduced to some extent
no matter with the reduction or increase in the amount of reducing
agent (Table 1, entries 13 & 14). The chemical yield further increased
to 88%, when the amount of DMSO was cut to half (entry 15). It can
be concluded that the photocatalyst and visible-light are all crucial
for this protocol (Table 1, entries 16-17). Notably, the chemical yield
of 3a was drastically reduced in the absence of H2O (Table 1, entry
18), indicating the importance of water in this transformation.
Finally, the structure of 3a was confirmed by X-ray crystallographic
analysis.15
Table 1. Optimization of Reaction Conditionsa
O
photocat (2.0 mol %)
red (1.5 equiv.)
additive (1.5 equiv.)
O
HN
Ph
N
BrCF2COOEt
N
N
solvent
rt, 2 h
30 W blue LED
CF2COOEt
Ph
1a
CCDC 1858543
3a
2a
Reducing
agent
Entry
Photocat
Solvent
Additive
Yield (%)
1
2
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
-
MeCN
CH2Cl2
DMF
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
HEH
Et3N
Et3N
NR
NR
Trace
17
3
Et3N
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Et3N
5
-
NR
30
6
DMAP
TMEDA
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7a
8
63
54
9
74
10
11
12
13b
14c
15d
16
17e
18f
NR
Trace
NR
27
With the optimized reaction conditions in hand, a series of
diversely substituted azomethine imines 1 were investigated for
extending the substrate scope (Table 2). Satisfyingly, as for o-
substituted and m-substituted (bearing electron-withdrawing and
electron-donating groups) phenyl azomethine imines, moderate to
excellent chemical yields (48%-99%) were generally acquired (3b–3i).
Similarly, for p-substituted phenyl azomethine imine, moderate
chemical yields (55%-73%) were consistently obtained (3j–3o). When
using o, m-disubstituted and m, p-disubstituted phenyl azomethine
imines as substrates, the corresponding product 3p and 3q were
easily obtained in good chemical yield respectively (85% and
94%).The azomethine imines containing 2-naphthyl and (E)-styryl
groups were also amenable to this protocol, albeit with slightly
reduce yields (3r and 3s). Moreover, heterocyclic analogues 3t and
3u were also successfully accomplished in synthetically useful yields
(3t and 3u). Noticeably, the more steric 5-phenyl-substituted
azomethine imine was also applicable to this protocol, affording the
expected adduct 3v in 70% yield. Significantly, the complex substrate
containing a biologically relevant unit (diacetone-D-glucose) was also
evaluated and the desired product 3w was secured in 87% yield.
Additionally, another biologically and synthetically interesting unit –
isatin was successfully incorporated to deliver the corresponding
product 3x (46%) by merely modifying the base to K2HPO4 in a
prolonged reaction duration (Scheme 2). The structures of 3v and 3x
were also confirmed by X-ray crystallographic analysis.15
3-MPA
-
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
Asc-H
53
88
NR
NR
29
Ir(ppy)3
Ir(ppy)3
aUnless otherwise noted, the reaction was carried out in 0.2 mmol scale in solvent
(2 mL) at rt with a molar ratio of 1a/2a = 1:3. b 0.5 equiv. of ascorbic acid was used.
c2.5 equiv. of ascorbic acid was used. dCarried out in 1 mL of DMSO. eWithout LED.
fCarried out in dry DMSO.
Initially, the reduction potential of N,N'-cyclicazomethine imine 1a
was examined by cyclic voltammetry, which would be crucial for the
studies on their photochemical behaviours. It was found that a
Ep/2
reduction wave was recorded at -1.68 V vs. Ag/AgCl (
= -1.61 V
red
vs. SCE. in MeCN, see ESI for details). Subsequently, we realized that
the strongly reducing photocatalyst Ir(ppy)3 (Ered = -1.73 V vs. SCE. in
MeCN)14 could serve as an electron donor to reduce N,N'-
cyclicazomethine imine 1a directly from its excited state, which was
further confirmed by the Stern−Volmer plot measurements (see ESI
Table 2. Substrate Scope of N, N'-Cyclicazomethine Iminesa
for details). As
a result, the corresponding radical of N,N'-
cyclicazomethine imine 1a could be efficiently generated, which
could undergo a well-designed racial-radical coupling process. With
2 | Chem. Commun., 2018, 00,
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Ir(ppy)3 (2.0 mol %)
Asc-H (1.5 equiv)
Cs2CO3 (1.5 equiv)
O
O
benzoxazole units are widely present in many bioactivVeiecwoAmrtipcloeuOnndlinse,
DOI: 10.1039/C8CC09385G
these results are of particular significance for drug discovery.
N
HN
BrCF2COOEt
N
N
DMSO
rt, 2 h
30 W blue LED
2a
Unfortunately, non-conjugated substrates, such as N, N'-azomethine
imines derived from phenylacetaldehyde and cyclohexanone, were
unable to give the desired products. It is probably due to the higher
reduction potentials of these non-conjugated substrates referred to
those conjugated ones.
R1
CF2COOEt
R1
3
1
substitution pattern
O
O
HN
HN
3b,
3c,
3d,
3e,
X
80% yield
X
= Br
OMe
Me
OH
= F
Cl
3f,
3g,
N
48% yield
62% yield
69% yield
74% yield
N
99% yield
74% yield
59% yield
CF2COOEt
OMe 3h,
Me
3i,
CF2COOEt
X
Table 3. Substrate Scope of Bromodifluoro Derivativesa
X
O
O
Ir(ppy)3 (2.0 mol %)
O
O
HN
HN
O
Asc-H (1.5 equiv)
N
N
X
= F
Cl
Br
Me
Et
3j,
3k,
3l,
3m,
3n,
3o,
64% yield
55% yield
73% yield
73% yield
59% yield
59% yield
Cs2CO3 (1.5 equiv)
HN
N
CF2COOEt
N
CF2COOEt
BrCF2
HN
N
N
DMSO
rt, 2 h
30 W blue LED
Cl
CF2COOEt
F
Ph
Ph
CF2
Cl
3p,
Br
OH
X
1a
2
%
4
85 yield
3q,
94% yield
varied functional group
O
O
O
O
O
=
t-Bu
4a,
4b,
4c,
40% yield
87% yield
99% yield
4f,
4g,
4h,
86% yield
74% yield
99% yield
N
N
H
HN
N
HN
HN
N
N
O
O
O
Bn
CF2COOEt
CF2COOEt
CF2COOEt
N
N
H
N
3s,
%
3t,
69% yield
44 yield
3r,
43% yield
O
biologically relevant motif
N
H
CO2Me
N
O
O
O
HN
O
O
O
HN
NH
N
O
Ph
N
N
4d,
4e,
Cy
Ph
81% yield
90% yield
4i,
4j,
56% yield
93% yield
N
H
O
N
N
CF2COOEt
CF2COOEt
Ph
CF2COOEt
O
O
S
O
O
O
3v,
%
70 yield
3w,
%
87 yield
3u,
O
64% yield
N
CCDC 1858544
H
NBoc
aUnless otherwise noted, the reaction was carried out with a molar ratio of 1a/2 = 1:3 in
0.2 mmol scale in DMSO (1 mL) at rt for 2 h.
R
4l,
R
34% yield
4m, 28% yield
= 4-Me
4-Bu
4-Cl
4-Br
5-Me
5-Cl
N
4n,
4o,
4p,
4q,
37% yield
32% yield
48% yield
53% yield
O
4k,
R
73% yield
= H
Scheme 2. Reaction of Isatin-incorporated N,N’-cyclic Azomethinea
aUnless otherwise noted, the reaction was carried out with a molar ratio of 1a/2
O
O
= 1:3 in 0.2 mmol scale in DMSO (1 mL) at rt for 2 h.
N
HN
Ir(ppy)3 (2.0 mol %)
K2HPO4 (1.5 equiv.)
N
N
CF2COOEt
O
BrCF2COOEt
O
DMSO (2mL)
rt, 12 h
30 W blue LED
a
Figure 1. Mechanistic Studies
N
N
H
H
3x
46% yield
CCDC 1877660
O
a)
b)
BrCF2COOEt
TEMPO/BHT
HO
NH
N
F F
aUnless otherwise noted, the reaction was carried out with a molar ratio of 1a/2
OEt
N
1a
3a
O
= 1:3 in 0.2 mmol scale in DMSO (1 mL) at rt for 12 h.
standard
conditions
O
I
II
Not observed
Detected by HRMS
Detected by HRMS
Subsequently, to further demonstrate the generality of this
protocol, a range of bromodifluoroamides and 2-(bromodifluor-
omethyl)benzoxazoles were also investigated and the results are
summarized in Table 3. Firstly, various N-substituted bromodifluor-
oacetamides were subjected to the reaction to afford the correspo-
nding products (4a-4e) in moderate to excellent chemical yields
(40%-99%). Obviously, the steric effect of tert-butyl group has a
severe impact on the chemical yield. Otherwise, both cyclic and
acyclic N, N-dialkylamides were suitable as coupling partners, giving
the corresponding products (4f-4j) in varied yields (56%-99%). It can
be observed that six-membered amides usually afforded relatively
lowered yields. For 2-(bromodifluoromethyl)benzoxazole substrates,
the presence of substituents evidently undermined the yields (4l-4q,
28%-53%) while unsubstituted substrate 2k afford the desired
product in good yield (73%). Given the fact that amide and
F
N
O
F
Br
F
F
O
N
O
standard conditions
F
1a
without
N
F
2k
5
, 36% yield
To gain mechanistic insights into the reaction, several control
experiments were carried out. The radical inhibition
experiments were conducted by adding 2,2,6,6-tetramethyl-1-
piperdinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol
(BHT) under the standard reaction conditions, and the reactions
were significantly inhibited along with the formation of the
radical adducts I and II respectively (detected by HRMS) (Figure
1, a). Additionally, in the absence of 1a, the dimerization
product 5 from 2-(bromodifluoromethyl)benzoxazole 2k was
isolated (Figure 1, b). These results indicate that a free-radical
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Chem. Commun., 2018, 00, | 3
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pathway might be involved in this photocatalytic
transformation. To ensure whether this reaction is governed by
Author Contributions
View Article Online
§P.-J. X. and Z.-P. Y. contributed equally to tDhOisI:w1o0r.1k0.39/C8CC09385G
Notes
a
radical chain propagation process or a visible-light
photocatalytic one, light/dark experiments were also
investigated. Predictably, the product formation was observed
The authors declare no competing financial interest.
only during the periods with constant irradiation, suggesting ACKNOWLEDGMENT
that a chain propagation-type mechanism was unlikely involved
We gratefully acknowledge the financial support from the
(see ESI for details). Further Stern−Volmer plot measurements
showed a significant quenching of the excited Ir(ppy)3 by N,N'-
cyclicazomethine imines in DMSO (see ESI for details).
Obviously, the electron transfer process could also be promoted
by ascorbic acid. However, it is worth mentioning that a
complementary quenching cycle by ascorbic acid or chain
propagation process could not be completely ruled out by the
current experimental results.
Based on the above-mentioned results and the redox
potentials of the involved species, a possible mechanism for this
reaction is proposed in Scheme 3. Firstly, Ir(ppy)3 was excited by
visible light to generate the reductant *Ir(ppy)3 (Ered = -1.82 V vs
Ag/AgCl in DMSO), which rapidly reduced N,N'-
cyclicazomethine imines 1a' (Ered = -1.76 V vs Ag/AgCl in DMSO)
via single-electron transfer (SET) to generate radical anion B and
Ir(IV). And thermodynamically, N,N'-cyclicazomethine imine 1a
with a lower reduction potential than BrCF2CO2Et was then
preferentially reduced by *Ir(ppy)3 via a single-electron transfer.
Subsequently, ascorbic acid (Eox = +0.32 V vs Ag/AgCl in DMSO)
was oxidized by Ir(IV) (Eox = +0.68 V vs Ag/AgCl in DMSO) to
complete the photocatalytic cycle (see ESI for details). The
National Natural Science Foundation of China (21576296,
21676302, 21776318, and 81703365), Natural Science
Foundation of Hunan Province (2017JJ3401), and Central South
University.
Notes and references
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resulting ascorbyl radical tended to proceed
a
disproportionation reaction to generate dehydroascorbic acid
(DAsc) and ascorbate (Asc-) simultaneously. Synchronously,
ascorbate further reduced BrCF2CO2Et to deliver difluoroalkyl
radical A.16 Finally, the sequential radical-radical coupling and
protonation facilely gave the final product 3a.
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Ir3+
Asc
O
O
photocatalytic
*Ir3+
SET
cycle
N
N
DAsc
N
base
N
Ir4+
Ph
1a
SET
Ph
1a'
O
O
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Chem. Commun. 1981, 930.
2a
radical-radical
coupling
NH
N
N
O
N
B
then
H
CF2CHOOEt
A
Ph
OEt
Ph
13 (a) P. Xu, W. Li, J. Xie, C. Zhu, Acc. Chem. Res. 2018, 51, 484;
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F
F
3a
In summary, we successfully developed a visible-light photoredox
catalyzed radical-radical cross-coupling reaction between N, N'-
cyclicazomethine imines and BrCF2X, furnishing difluorinated 3-
pyrazolidinone scaffolds in good to excellent yields under mild
conditions. Moreover, the wide tolerance of functional groups and
high synthetic efficiency of the developed protocol would enable its
practical applications in drug discovery. Furthermore, this work
uncovered the hidden potentials of N, N'-cyclicazomethine imines in
visible-light photocatalytic transformations, which would inspire the
broad exploitation of synthetic utilizations.
4 | Chem. Commun., 2018, 00,
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DOI: 10.1039/C8CC09385G
O
O
HN
N
N
Photocatalysis
X
Br
N
X
R
F F
R
F F
> 40 examples
up to 99% yield
R
X = COOEt, CONR'2
= Ar, Py, Furyl
heteroaryl
A variety of difluorinated 3-pyrazolidinone scaffolds were prepared through a novel
photoredox radical-radical cross-coupling reaction of N,N'-cyclicazomethine imines.