Photocatalytic radical cyclization of α-halo hydrazones with β-ketocarbonyls: Facile access to substituted dihydropyrazoles

Article abstract of DOI:10.1039/c7cc01470h

A mild and efficient method for the photocatalytic radical cyclization of α-halo hydrazones with β-ketocarbonyls has been described. This strategy provides a potential protocol for the construction of functionalized 4,5-dihydropyrazoles in moderate to high yields.

Full text of DOI:10.1039/c7cc01470h

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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Photocatalytic radical cyclization of α-halo hydrazones with β-
ketocarbonyls: Facile access to substituted dihydropyrazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Jing-miao Yu, Guo-Ping Lu, Chun Cai*
DOI: 10.1039/x0xx00000x
www.rsc.org/
R2
Ts
A mild and efficient method for the photocatalytic radical
cyclization of α-halo hydrazones with β-ketocarbonyls has
been described. This strategy provides a potential protocol
for the construction of functionalized 4, 5-dihydropyrazoles in
moderate to high yields.
NH
NH
N
N
R1
X
X = Br, Cl
R1
base
photocatalysis
Ts
R2
N
N
R2
N
5
R CHN
2
Cu
R
7
N
(a)
N
(b)
N
or
R8
Dihydropyrazoles, and the corresponding unsaturated
R1
R6
S
R1
R1
analogues, pyrazoles, represent
a class of privileged
heterocycles that occur in biologically active natural products
and pharmaceuticals such as anti-amoebic, hypotensive,
analgesic, anti-bacterial, anti-cancer, anti-depressant and
photocatalysis
base
R2
NH
1
(c) this work
O
O
N
nonsteroidal anti-inflammatory agents . As a consequence, a
Br
R3
R4
R1
plethora of synthetic approaches toward this structures have
2
received considerable attention in modern organic synthesis .
Scheme 1. Reaction design
α-halogeno hydrazones, as powerful and versatile synthons,
which can generate electron-deficient dienes (1,2-diaza-1,3-
dienes) in situ in the presence of base, could react with either
strategy demonstrated that visible-light photocatalysis has
tremendous potential for direct transformation of N-H bonds
into N-centered radicals , frequently without strong
11
3
4
a sulfur ylide or a diazo compound , accessing 4,5-
dihydropyrazoles(scheme 1a). These reactions, however, are
often plagued by the need of excess base and high reactive
stoichiometric oxidants under mild conditions compared to
1
2
conventional methods . Soon after, the xiao group developed
photoredox-catalyzed tandem radical
a
4
5
6
partners such as diazo compounds , olefins and 1,3-dipolars , trifluoromethylation/cyclization of β,γ-unsaturated hydrazones
otherwise α-halogeno hydrazones will undergo the and oximes to construct CF
3
-containing dihydropyrazoles and
isoxazolines . Recently, Wu reported visible light photoredox-
catalyzed radical addition of alkyl radicals to
monosubstituted hydrazones followed by intramolecular
1
3
7
homocyclodimerization in the presence of excess base .
a
From the viewpoints of green and sustainable chemistry,
visible light photoredox catalysis has been extensively applied
to the development of a wide range of new carbon−carbon
1
4
8
cyclization, affording the 1,3,5-trisubstituted pyrazoles .
Inspired by the previous work, herein, we report a new
photocatalytic radical cyclization of α-halo hydrazones with
β-ketocarbonyls for selective synthesis of functionalized 4, 5-
dihydropyrazoles (scheme 1c).
9
bond and carbon-heteroatom bond formations, because of its
1
0
low cost, easy availability, and environmental friendliness .
For instance, in 2014, the Xiao group reported the first visible-
light photocatalytic intramolecular addition of N-centered
9
a
hydrazonyl radical to terminal alkenes for direct assembly of
the dihydropyrazole architectures(scheme 1b). This elegant
At the outset of our investigation, α-bromo-N-benzoyl
hydrazone 1a was employed as the model substrate to react
with ethyl acetoacetate 2a to afford the desired product ethyl
5
-acetyl-1-benzoyl-3-phenyl-4,5-dihydro-1H-pyrazole-5-
carboxylate 3aa We initially investigated the use of
Ru (bpy) Cl (tris(bipyridine)ruthenium(II) chloride) as visible-
light catalysts, K HPO as base, irradiated with a blue LED lamp
.
2
3
2
2
4
in MeCN at room temperature for 24h (Table 1, entry 1) and
were disappointed to observe 3aa in quite a low yield(12%)
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a
a, b
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of 1, 3-dicarbonyl compounds
b
Entry
Photocatalyst
Base
HPO
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
Yield (%)
c
1
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
Cl
3
Cl
3
Cl
3
Cl
2
2
2
2
K
2
4
12
50
2
3
4
NaOH
tBuOK
c
88(78)
Cs
2
CO
CO
3
3
65
7
d
5
eosin Y
Cs
2
6
7
8
9
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
-
3
3
3
3
3
3
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
-
CHCl
3
80
56
58
22
5
DMSO
MeOH
2 2
CH Cl
1
0
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
e
1
1
0
f
12
tBuOK
tBuOK
tBuOK
tBuOK
0
g
h
1
1
3
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
Cl
3
Cl
3
Cl
2
2
2
0
4
62
67
i,j
1
5
a
Reaction conditions: 1a (0.2 mmol), 2a (0.25 mmol), photocatalyst (2 mol%),
base (0.3 mmol), solvents (2.0 mL), 5W blue LEDs, air, 24h, at room temperature.
b
c
d
e
Determined by GC. Isolated yield. Using 23W white LEDs as the light source.
f
g
h
Without base. Without photocatalyst. Without visible light irradiation.
i
j
3 2
Performed with 1 mol % of Ru(bpy) Cl . The reaction was conducted in Ar. 48h.
together with a large amount of ethyl 2-benzoyl-3-methyl-6-
phenyl-1,2-dihydropyridazine-4-carboxylate. To our
gratification, the use of stronger base NaOH led to a sharp
enhancement of the yield of 3aa to 44% (Table 1, entry 2).
Further investigations revealed that the use of tBuOK gave a
a
Reaction conditions: a--bromo-hydrazone 1a (0.2 mmol), 1,3-dicarbonyl
superior performance and afforded 3aa in 88% yield (78% compounds 2 (0.25 mmol), Ru(bpy) Cl (2 mol%), tBuOK (1.5 equiv) and MeCN (2
3
2
isolated yield) (Table 1, entry 3), while altering the base from mL), irradiation with blue LEDs under air atmosphere at room temperature for 24
b
c
h.
Isolated yield.
Ethyl 1-benzoyl-3-phenyl-4,5-dihydro-1H-pyrazole-5-
tBuOK to CsCO
65%) (Table 1, entry 4). In addition, organic dye such as eosin
Y was evaluated as an alternative to transition metal
3
led to a slightly lower yield of 3aa relatively
d
carboxylate 3ae’ was isolated in 15% yield. Cs
2
3
CO (1.5 equiv.) instead of tBuOK.
(
e
determined by GC-MS
1
5
complexes in photoredox catalysts, the yield of 3aa was
entry 14). It took more time for full conversion when the
reaction was conducted under an argon atmosphere (Table 1,
entry 15).
dramatically reduced (Table 1, entry 5), presumably by the
0a, 16
1
unfavorable redox potential
of the photocatalyst relative
to that of substrate 1a. A brief survey of reaction media
showed that chloroform showed a behavior similar to
acetonitrile (Table 1, entries 6). Other solvents such as DMSO,
methanol, dichloromethane and dioxane either gave inferior
results or completely impeded the reaction (Table 1, entries 7-
With the optimized reaction conditions in hand, we explored
the scope of 1, 3-dicarbonyl compounds 2, with α-bromo-N-
benzoyl hydrazone 1a as a reaction partner. Acetoacetates
bearing either methyl, ethyl, sterically bulky tert-butyl or
benzyl ester group were compatible with this reaction, leading
to the desired cycloadducts in satisfying yields (53-80%) (Table
10). Overall, acetonitrile remained the best solvent for the
photocatalytic cyclization. It was found that base was essential
to the reaction because no reaction occured without base
Table 1, entry 11). Control experiments showed that no
expected product was detected in the absence of
photocatalyst or light irradiation, thus indicating that the
reaction may be proceeding via a photocatalytic process (Table
2
,
3aa
benzoylacetate 2g were well-tolerated, whereas ethyl
trifluoroacetoacetate 2e only generated the
detrifluoroacetylated product 3ae’ in 15% yield (Table 2, 3ae
-ad). Note that ethyl butyrylacetate 2f and ethyl
-
ag). In a similar manner, we were pleased to find that not only
β-ketone esters but also 1,3-diketones 2h,j,k and β-ketone
amide 2l could be exposed to the reaction conditions
delivering the targeted products, showing comparable or
1, entries 12, 13). These experiments demonstrated that light,
Ru (bpy) Cl and tBuOK are all essential for the reaction.
2
3
2
Attempts to decrease the amount of photocatalyst let to a
reduction in yield (Table 1,
reduced yields. (Table 2, 3ah-aj). In the cases of
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a, b
Table 3. Scope of α-bromo-hydrazones
electron- deficient α-bromo-hydrazones 1d-g, i-k underwent a
rapid decompositon and resulted in lower yields using CsCO
as base. After a series of trials, moderate to good yields (52-
7%) of the corresponding products 3da-ga, ia-ka were
3
8
3
obtained by switching the solvent to CHCl (Table 3, 3da-ga, ia-
ka).
Substrates bearing fluoro at different positions of the
aromatic ring could reacted with 2a to give the products in 68-
8
7% yields (Table 3, 3da, ja and ka). Moreover, naphthal- and
tert-butyl-substituted substrates were also transformed into
the desired products 3la and 3ma in 88% and 84% yields (Table
2
3la and 3ma). Changing the R substituent to either p-tolyl,
3,
pyridine or methyl group had little effect on the reaction
efficiency under the standard reaction conditions (Table 3,
3na-pa). In contrast, no reaction of 2a with N-Ts α-bromo-
hydrazone 1q occurred, because of the decomposition of N-Ts
α-bromo-hydrazone under the standard reaction conditions,
affording
the
1-methyl-4-(styrylsulfonyl)benzene
as
17
byproduct .
To gain insight into the mechanism, control experiments
were carried out. Firstly, addition of radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) led to an obvious
inhibition of the reaction, suggesting the reaction may
undergo a radical mechanism. Moreover, it was found that
ethyl 2-benzoyl-3-methyl-6-phenyl-1,2-dihydropyridazine-4-
carboxylate is obtained as the major product when the base is
used alone.
a
Reaction conditions: a-bromo-hydrazones 1 (0.2 mmol), ethyl acetoacetate 2a
0.25 mmol), Ru(bpy) Cl (2 mol%), tBuOK (1.5 equiv) and MeCN (2 mL),
irradiation with blue LEDs under air atmosphere at room temperature for 24 h.
Scheme 2. A proposed mechanism
(
3
2
b
c
d
Isolated yield. Cs
2
CO
3
(1.5 equiv.) instead of tBuOK. CHCl
3
instead of MeCN.
On the basis of the preliminary results and previous
9
b, 18
literatures
, a plausible mechanism is proposed in Scheme
3
1,3-diketones, CsCO showed better results compared to
2. Firsty, nucleophilic replacement of α-bromo-hydrazone 1a
tBuOK(Table 2, 3ai). Diethyl malonate 2n was also
examined,however, only a trace amount of 3an was detected
by GC-MS (Table 2, 3al).
with ethyl acetoacetate 2a takes place under basic conditions.
Further deprotonation of the α-bromo-hydrazone 1a affords
the anionic intermediate
A using tBuOK as a strong enough
Next, the substrate generality with respect to the α-bromo-
base. Reductive quench of the excited state of the
2
+
hydrazones
1 was investigated. Under the standard reaction
photocatalyst (*[Ru(bpy) ] ) by the anionic intermediate
A
via
a single electron transfer (SET) process to form the N-centered
radical intermediate . Catalyst turnover may be accomplished
3
conditions, both electron-donating and -withdrawing groups
on the aromatic ring of the α-bromo-hydrazones show a
tendency to deacetylation, giving predominantly the
B
by the reduction of adventitious oxygen including trace
amounts of oxygen gas in the solvent, together with the
2 3
deacetylated products. Fortunately, we discovered that Cs CO
-
generation of the superoxide radical anion (O ) and the
.
was a viable base for the cyclization of electron-rich α-bromo-
hydrazones with ethyl acetoacetate, furnished the desired
products in 78−89% yield (Table 3, 3ba, ca and ha). However,
2
2
ground state of the photocatalyst ([Ru(bpy) ] ). The resultant
+
3
N-radical intermediate
B
undergoes a radical intramolecular
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addition to enolate. Subsequently, this superoxide radical
anion may abstract a hydrogen atom from the radical
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1
Conclusions
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1
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, 1844.
In summary, we have developed a new photocatalytic
method for cyclization of α-halo hydrazones with
β-ketocarbonyls. This method provides straightforward access
to the corresponding highly functionalized 4, 5-
dihydropyrazole derivatives in generally good yields under
mild conditions and features a broad substrate scope, wide
group tolerance and chemoselectivity. This novel, facile and
effecient photocatalytic strategy underline the great potential
for the synthesis of nitrogen-containing molecule.
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We gratefully acknowledge the Natural Science Foundation
of China (21402093) and Jiangsu (BK20140776), Chinese
Postdoctoral Science Foundation (2016T90465, 2015M571761)
and Priority Academic Program Development of Jiangsu Higher
Education Institutions for financial support.
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