Copper-catalyzed aerobic cascade cycloamination and acyloxylation: A direct approach to 4-acyloxy-1H-pyrazoles

Article abstract of DOI:10.1039/c5ob00409h

A novel direct transformation of hydrazones to acyloxylated pyrazoles by copper-catalyzed regioselective olefinic C(sp²)-H bond cycloamination and acyloxylation was performed under mild conditions, which combines the formation of the pyrazole skeleton and installation of an acyloxyl group in a single step, using facile carboxylic acids as the acyloxylation reagents.

Full text of DOI:10.1039/c5ob00409h

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DOI: 10.1039/C5OB00409H
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Copper‐Catalyzed Aerobic Cascade Cycloamination
and Acyloxylation: A Direct Approach to 4‐Acyloxy‐
1H‐pyrazoles
Cite this: DOI: 10.1039/x0xx00000x
Zhengwei Ding,a Qitao Tan,a Mingchun Gaoa and Bin Xu*,a,b,c
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/x0xx00000x
www.rsc.org
diazoacetates18a or hydrazines,18b,18c and the 1,3-dipolar
A novel direct transformation of hydrazones to acyloxylated
pyrazoles by copper-catalyzed regioselective olefinic C(sp2)–H
bond cycloamination and acyloxylation was developed under
mild conditions, which combines the formation of the
pyrazole skeleton and installation of an acyloxyl group in a
single step, using facile carboxylic acids as the acyloxylation
reagents.
cycloaddition of diazo compounds or other N=N bond containing
dipoles with alkynes19 or alkenes.20 In particular, 4-acyloxy-
pyrazole nucleus is exemplified as a unique structure in many
potentially biologically active compounds,21 which are generally
prepared by direct acylation of the corresponding 4-hydroxy-
pyrazoles, however multi-steps are required for the synthesis of
the latter in turn.22 For example, 4-acyloxy-1
H-pyrazoles have
been synthesized in three steps from 1,3-diketones by sequential
halogenation, substitution and condensation reaction with
hydrazine.23 While these methods allow the construction of 4-
acyloxypyrazoles, development of a novel and more efficient
synthetic methodology to this valuable structural unit is highly
desirable.
Transition-metal-catalyzed regioselective C–O bond formation
via C–H functionalization of arenes has been developed as an
efficient approach for the acyloxylation and hydroxylation of
C(sp2)–H bonds.1-3 In contrast to ortho C–H bond oxidation of
benzene rings, the regioselectivity of C–O bond formation of
heterocycles is mainly controlled by their inherent reactivity and,
consequently, no ortho-directing groups are necessary. However,
there are only a few reports on direct acyloxylation of
heterocycles in which the scope of substrates is mainly limited to
electron-rich pyrroles and indoles,4 and most of these
transformations have been restricted to acetoxylation employing
PhI(OAc)2 as a terminal oxidant under the catalysis of Pd(OAc)2
(Scheme 1).4 Furthermore, carboxylic acids are seldom applied in
these reactions as the coupling source probably due to their rapid
formation of complex with metals.2a,2g,5 In this event, an
alternative efficient approach to acyloxyl heterocycles would be
to combine the heterocyclic ring construction and acyloxylation
in one step and ideally, employing simple carboxylic acids as the
acyloxylation reagents under the catalysis of non-noble metals,
which would be particularly attractive in terms of synthetic
efficiency (Scheme 1).
Previous work:
"OAc"
ortho-Directing C-O formation
H
OAc
Het
Het
Acetoxylation of heterocycles
"OAc" = PhI(OAc)2, Ac2O, HOAc, M(OAc)n
This work:
P(O)(OEt)2
H
N
R2
OC(O)R
NH
N H
H
N
selective annulative
acyloxylation
H
+ RCO2H
R2
R1
Het
[Cu], O2
R1 Het
H
Scheme 1 Acyloxylation through C–H bond functionalization.
Pyrazole derivatives represent a major class of nitrogen-
containing heterocycles with a wide range of biological and
pharmacological activities6 including analgesic,7 antibacterial,8
antidepressant,9 anti-inflammatory,10 antiviral,11 anticancer,12 and
antihypertensive properties.13 They have appeared as the core
structures in a large variety of commercial leading drugs and
pesticides, such as Celebrex,14 Cyenopyrafen,15 and
Fenpyroximate,16 as well as utilized as useful ligands for some
cross-coupling reactions.17 Generally, classical approaches to
substituted pyrazoles involved the condensation reaction between
1,3-dicarbonyl compounds or their equivalents with
In the context of our research program aimed at efficient
construction of heterocycles through C–H amination reaction,24
herein, we report a novel direct transformation of hydrazones to
acyloxylated pyrazoles by copper-catalyzed regioselective
olefinic C(sp2)–H bond cycloamination and acyloxylation,
whereby in sequence the C–N/C–O bonds are formed followed
by one N–P bond cleavage of unique
N-diethoxy-phosphoryl
hydrazones under mild conditions (Scheme 1). To our knowledge,
the given approach represents the first transformation of
hydrazones to 4-acyloxy-1H-pyrazoles which combines the
formation of the pyrazole skeleton and installation of an acyloxyl
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group in a single step, using facile carboxylic acids as the P(O)(OEt)2 was replaced by P(O)(Oi-Pr)2 or P(O)(OMe)2, the
acyloxylation reagents. yield of 3aa was reduced to 44% and 36%, respectively (entries
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We started our study by exploring the reaction of diethyl (2- 18–19). No product was observed when leaving groups such as
DOI: 10.1039/C5OB00409H
((E
)-1,3-diphenylallylidene)hydrazinyl)phosphonate (1a) in the Ts or Ac were used instead (entries 20–21), indicating the vital
presence of CuCl2 (10 mol%) and AcOH (1.2 equiv) in DMSO role of P(O)(OR)2 for such a transformation. Finally, copper salt
under oxygen atmosphere. However, no acetoxylated product 3aa proved to be indispensable as no desired product was detected in
was obtained in the absence of a base (entry 1, Table 1). the absence of copper salt (entry 22).
Intriguingly, the addition of Na2CO3 to the reaction led to the
isolation of 3aa25 in 52% yield together with the direct cyclized extended the reaction to a range of readily available phosphoryl
byproduct 3,5-diphenyl-1 -pyrazole (
) in 23% yield (entry 1).26 hydrazones as shown in Table 2. Substrates bearing both
An extensive screening of the bases (entries 3–4), the amounts of electron-donating and electron-withdrawing groups proceeded
AcOH and base (entries 5–6), and solvents (entries 7–10) efficiently to give the desired products (3ba 3ga) selectively
With the optimized reaction conditions in hand, we then
H
4
–
revealed that the use of K2CO3 as a base in DMSO with 1.2 with moderate to good yields. This protocol was not limited to
equivalents of acetic acid turned out to be the best choice and simple benzene-containing hydrazones, substrates bearing a
resulted in the desired product 3aa in a 63% yield (entry 3). naphthyl group also gave the desired products (3ha and 3ia
)
Furthermore, it was observed that the existence of water played a smoothly. Pyrazoles containing different heterocycles (3ja and
subtle role for this transformation, and the isolated yield could 3ka) were also obtained in moderate yields. Gratifyingly, product
improve to 69% in a mixed solvent of DMSO and H2O (
v
/
v
=
containing a double bond (3la), which could be reserved for
30:1) with the yield of byproduct suppressed to 15% (entry 11). further functionalization, was also prepared by this method and
4
Lowering or elevating the reaction temperature led to lower the C=C double bond remained intact during the reactions.
yields (entries 12–13). Slightly decreased yield was obtained Furthermore, the reactions show very good selectivity as no
when the reaction was conducted under air atmosphere (entry 14), indazoles were observed significantly in all cases which could be
while no apparent product could be detected under nitrogen formed through the aromatic C(sp2)–H bond functionalization
atmosphere (entry 15), which suggested that molecular oxygen other than the olefinic C(sp2)–H amination. However, try to
was crucial to this reaction. Switching of CuCl2 to other copper expand the aryl substitution to aliphatic substituents failed, no
sources afforded similar results (entries 16–17). Next, the effect designed acetoxylated products obtained. Notablely, the absolute
of leaving group in the substrate
1
was investigated. When
spectroscopic analysis for products is convoluted, due to their
dynamic tautomeric forms that NH-pyrazoles can adopt.
Table 1 Optimization of the Reaction Conditions.a
Table 2 Hydrazone scope in the synthesis of pyrazoles. a,b
NH
NH
NH
N
N
N
Entry
R
Cu salt
Base
Solvent
Yieldb [%]
MeO
Cl
OAc
OAc
OAc
1
2
3
4
5
6
7
8
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(Oi-Pr)2
P(O)(OMe)2
Ts
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene
CH3CN
DCE
ND
3ca
4 h, 67%
3aa
5 h, 69%
3ba
6 h, 70%
Na2CO3
K2CO3
Et3N
52 (23)
63 (20)
ND
Br
NH
N
NH
NH
N
N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
56c
58d (21)
45 (14)
ND
OAc
OAc
3ea
OAc
MeO
Br
3fa
8 h, 61%
3da
4 h, 60%
5 h, 66%
9
ND
ND
10
11
12
13
14
15
16
17
18
19
20
21
22
NH
N
NH
N
NH
N
DMSO/H2O 69 (15)
DMSO/H2O 47e
DMSO/H2O 54f (26)
DMSO/H2O 57g
DMSO/H2O NDh
DMSO/H2O 66i
DMSO/H2O 63
Br
OAc
OAc
OAc
Br
3ga
4 h, 47%
3ha
3ia
4 h, 65%
4 h, 63%
NH
N
Cu(OAc)2 K2CO3
NH
N
NH
N
CuCl
CuCl2
CuCl2
CuCl2
CuCl2
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO/H2O 44j (21)
DMSO/H2O 36 (33)
DMSO/H2O ND
DMSO/H2O ND
DMSO/H2O ND
O
OAc
OAc
OAc
N
3la
8 h, 47%
3ja
6 h, 55%
3ka
6 h, 52%
Ac
P(O)(OEt)2
a Reaction conditions: 1a–1l (0.3 mmol), 2a (0.36 mmol), CuCl2 (10 mol %),
K2CO3 (0.36 mmol) in DMSO/H2O (1.5 mL, v/v = 30:1), O2, 50 oC. b Isolated
yield.
a
Reaction conditions: 1a (0.3 mmol), AcOH (0.36 mmol), copper catalyst
(10 mol%), base (0.36 mmol) in solvent (1.5 mL), 50 oC, O2, 6 h. Ac =
Acetyl, Ts = 4-Toluenesulfonyl, ND = Not detected. DMSO/H2O refers to a
b
mixed solvent with DMSO/H2O = 30:1 (v/v). Isolated yield. The value in
In order to further explore the generality and scope of this
method, various carboxylic acids were investigated, and the results
are summarized in Table 3. Both acyclic and cyclic aliphatic
carboxylic acids could all give corresponding pyrazoles expectedly
(3ab–3ad) with good yields under the optimized conditions, even for
parentheses is the isolated yield of byproduct 3,5-diphenyl-1H-pyrazole (4). c
d
AcOH (0.3 mmol), K2CO3 (0.3 mmol). AcOH (0.45 mmol), K2CO3 (0.45
mmol). At 40 C. At 60 C. Under air. Under N2. Reacted for 28 h.
Reacted for 16 h.
e
o
f
o
g
h
i
j
2 | Org. Biomol. Chem., 2015, 00, 1‐4
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a substrate with highly sterically hindered substitution (3ac). ((E)-1,3-diphenylallylidene)hydrazinyl) phosphornate (1a’), was
Substrate with N-acetyl proline could also be employed in this employed under the standard conditions. To our delight,
a
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transformation to give the desired product 3ae in 60% yield. In phosphonate-containing intermediate 5 could be isolated in 41%
DOI: 10.1039/C5OB00409H
addition, benzoic acid and its derivatives also worked well and yield along with 13% yield of 3aa after reacted for 4 h. Treatment of
afforded the corresponding products in moderate yields, regardless 5 under the standard condition in the absence of copper salt further
of their different electronic and steric properties (3af–3ai). To our afforded the desired 4-acyloxy-1H-pyrazole 3aa in 86% yield (Eq. 2),
delight, this approach also permitted the tolerance of heterocyclic which strongly indicated that 5 might be the key intermediate for this
and alkenyl carboxylic acids and afforded the desired products transformation and the copper salt is not necessary during this step.
smoothly (3aj and 3ak).
Although a detailed reaction pathway remains to be clarified, a
tentative mechanism for this cascade reaction was proposed on the
basis of above investigations (Scheme 3). The reaction initially
proceeded via a one-electron transfer and deprotonation process
from substrate 1a in the presence of CuCl2 to give a radical species
A. The generated radical intermediate A was subsequently trapped
by the intramolecular C=C double bond to produce corresponding
alkyl radical B through the formation of C–N bond.27 Radical B
would react with molecular oxygen to afford a superoxo radical C,
which would deliver Cu(II) alkoxide D by the Fenton-type
fragmentation.28 β-Elimination of D will generate intermediate E
which could be isomerized to the isolable intermediate 5 (R = i-Pr).
Treatment of intermediate 5 with acetic acid gave F and acyl
phosphate G due to the strong affinity between oxygen and
phosphine atoms, which finally afforded the desired pyrazole
product 3aa.29 On the other hand, the formation of the direct
cyclization byproduct 4 will undergo through an intramolecular ionic
pathway in the presence of a base.30,31
Table 3 Carboxylic acid scope in the synthesis of pyrazoles.a,b
a
Reaction Conditions: 1a (0.3 mmol), 2b–2k (0.36 mmol), CuCl2 (10 mol %),
K2CO3 (0.36 mmol) in DMSO/H2O (1.5 mL, v/v = 30:1), O2, 50 oC. Yields shown
are of the isolated products. b Isolated yield.
To gain insight into the reaction mechanism, several control
reactions were performed under the optimized reaction conditions, as
shown in Scheme 2. We firstly conducted the reaction by adding 1.0
equivalent of a radical scavenger 2,2,6,6-tetramethyl-piperidine-1-
oxy (TEMPO) to the reaction of 1a (Eq. 1). To our surprise, the
targeted product 3aa was obtained in only 9% yield and the direct
cyclization byproduct 4 could be isolated in 67% yield, which
implied that the formation of acyloxylated product 3aa mainly
involved a radical process and the competitive byproduct 4 preferred
to form in a non-radical pathway. Try to convert 4 to 3aa and its
deacylated product F (Scheme 3) under optimized conditions failed,
indicating the formation of 3aa and 4 through independent pathways.
In order to isolate the possible key intermediates, a less active
substrate analogue of 1a with isopropyl substitution, diisopropyl-(2-
Scheme 3 Proposed mechanism (ligands are omitted for clarity).
In summary, we have developed a novel protocol for the
copper-catalyzed regioselective synthesis of multisubstituted 4-
acyloxy-1H-pyrazoles in a single step from hydrazones and
carboxylic acids under mild conditions. Highly selective olefinic
C(sp2)–H functionalization was realized through N–P bond
cleavage of unique
N-diethoxy-phosphoryl hydrazones. The
characteristics of wide substrate scope, good functionality
tolerance and synthesis modularity will provide the described
reaction a broad utility in organic synthesis. Currently, we are
engaged in further insight into the mechanism, reaction scope,
and the synthetic applications for other bioactive compounds.
We thank the National Natural Science Foundation of China
(No. 21272149, 21302123), and Innovation Program of Shanghai
Scheme 2 Mechanistic studies. Conditions A: CuCl2 (10 mol%), HOAc (1.2
equiv), K2CO3 (1.2 equiv), in DMSO/H2O (v/v = 30:1), O2, 50 oC.
This journal is © The Royal Society of Chemistry 2015
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