Cu-Catalyzed Aminoacyloxylation of Unactivated Alkenes of Unsaturated Hydrazones with Manifold Carboxylic Acids toward Ester-Functionalized Pyrazolines

Article abstract of DOI:10.1021/acs.orglett.8b01507

A copper-catalyzed aminoacyloxylation of unactivated alkenes of unsaturated hydrazones is achieved by using various commercially available carboxylic acids as the acyloxylating reagents and di-tert-butyl peroxide (DTBP) as the oxidant. By using this metho

Full text of DOI:10.1021/acs.orglett.8b01507

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed Aminoacyloxylation of Unactivated Alkenes of
Unsaturated Hydrazones with Manifold Carboxylic Acids toward
Ester-Functionalized Pyrazolines
Rui-Hua Liu, Zi-Qing Wang, Bang-Yi Wei, Jian-Wu Zhang, Bo Zhou, and Bing Han*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, 730000, PR China
S
* Supporting Information
ABSTRACT: A copper-catalyzed aminoacyloxylation of unactivated
alkenes of unsaturated hydrazones is achieved by using various
commercially available carboxylic acids as the acyloxylating reagents
and di-tert-butyl peroxide (DTBP) as the oxidant. By using this
method, a sequence of structurally diversiform acyloxyl-substituted
pyrazolines are efficiently synthesized. Significantly, many carboxyl-
containing drugs and bioactive molecules with unprotected functional
groups are compatible in this reaction.
the acyloxylating reagents and oxidants3a (Scheme 1c).
he vicinal aminoacyloxylation of unactivated alkenes is of
Tgreat significance for the preparation of β-acyloxyl amines Although great achievements have been made in this field,
these reactions usually require prefunctionalized carboxylates or
a massive surplus of carboxylic acids as the acyloxylating
reagents.2,3 Thus, it is highly desirable to expand the more
efficient aminoacyloxylation of alkenes by using manifold
carboxylic acids, especially the valuable carboxyl-containing
natural products, drugs, and bioactive molecules, as the
acyloxylating reagents.
Carboxylic acids are cheap, easily available substances and are
widely applied in synthetic chemistry.4 A great many carboxyl-
containing drugs and bioactive molecules are essential for
human health and the development of pharmaceutical science.5
The esterification of carboxyl-containing drugs is a very
important tool to ameliorate pharmaceutical absorption,
improve pharmaceutical effect, and enhance pharmaceutical
stability for a longer half-life.6 For example, pivampicillin,6d−f as
a prodrug, is derived from the esterification of the high-efficiency
antibiotic ampicillin,6g,h which greatly increases the bioavail-
ability and prolongs its effects.6d−f In this context, the use of
various readily accessible carboxylic acids and carboxyl-
containing drugs as the acyloxylating reagents would be of
great significance for organic synthesis and pharmaceutical
chemistry.5c,6a
which not only consist of pharmaceuticals but also serve as
useful synthetic intermediates in organic transformations.1
Therefore, chemists have made great efforts to develop various
efficient synthetic tactics for enriching aminoacyloxylation of
alkenes.2,3 For example, Sorensen developed an elegant
palladium-catalyzed aminoacyloxylation of alkenes by using a
stoichiometric amount of PhI(OAc)2 as the acetoxylating
reagent as well as the oxidant2d (Scheme 1a). Zhang reported
a novel palladium-catalyzed aerobic aminoacyloxylation strategy
by employing large excess carboxylic acids as the acyloxylating
reagents2g (Scheme 1b). Chemler described a fascinating
copper-promoted aminoacyloxylation of allenes utilizing a
stoichiometric amount of preprepared cupric carboxylates as
Scheme 1. Strategies for Aminoacyloxylation of Alkenes
Pyrazoline derivatives are essential heterocyclic compounds
and have been extensively applied in pharmaceutical chemistry
and bioorganic chemistry.7 Therefore, the efficient construction
of pyrazoline scaffolds has always drawn attention from chemists
and pharmacists. In recent years, we and other groups have
developed a hydrazonyl radical-participating cyclization tactic
for the preparation of pyrazoline derivatives.8 However, the
aminoacyloxylation of unsaturated hydrazones with carboxylic
Received: May 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acids toward acyloxyl-substituted pyrazolines has not been
realized yet. Herein, we present a practical and efficient
approach for the synthesis of structurally useful acyloxyl-
featured pyrazolines through Cu-catalyzed aminoacyloxylation
of unsaturated hydrazones with carboxylic acids under the
oxidation conditions of di-tert-butyl peroxide (DTBP). Notably,
besides simple aliphatic and aromatic acids, many carboxyl-
containing drugs and bioactive molecules with unprotected
functional groups are all good candidates in this protocol.
Consequently, this reaction not only supplies an effective
strategy for the preparation of structurally diversiform acyloxyl-
featured pyrazolines but also provides a feasible way to realize
the esterification of valuable carboxyl-containing drugs and
bioactive molecules by incorporating useful nitrogen-containing
heterocycles.5c,6a
With the optimized conditions in hand (Table 1, entry 15),
various carboxylic acids were first tested in the reaction. As
depicted in Scheme 2, both aromatic and aliphatic carboxylic
a b
,
Scheme 2. Scope of Carboxylic Acids
We initiated the aminoacyloxylation of alkenes by using
unsaturated ketohydrazone 1a and benzoic acid 2a as the model
substrates under the conditions of DTBP and CuI in acetontrile
at 80 °C for 6 h. The anticipated aminoacyloxylation product
(3a) was isolated in 15% yield (Table 1, entry 1). After the
a
Table 1. Optimization of the Reaction Conditions
b
entry
copper salt
solvent
oxidant
ligand
yield (%)
1
2
3
4
5
6
7
8
CuI
CuCl
CuCl2
Cu(OAc)2
CuSO4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe
EA
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
15
25
5
71
8
62
65
34
65
45
69
20
25
78
82
a
Conditions: 1a (0.30 mmol), carboxylic acids 2 (0.36 mmol),
Cu(OAc)2 (0.06 mmol) and DTBP (0.45 mmol), MeCN, Ar, 80 °C,
b
c
6 h. Isolated yields. 1a (3.0 mmol) was used, and the corresponding
aminoacyloxylation product 3t was isolated in 1.413 g (86%).
DMF
9
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
acids were compatible with this protocol, giving the desired
aminoacyloxylation products in moderate to excellent yields.
Substituted benzoic acids with a series of electronic properties
participated very well in the reaction, as demonstrated in cases
3a−g. Satisfyingly, heterocyclic carboxylic acid such as furoic
acid was also suitable for this conversion, affording the
corresponding product 3h in 63% yield. It is worth noting that
both linear and cyclic aliphatic carboxylic acids were all
amenable in this transformation, providing the aminoacylox-
ylation products 3i−m in good yields. In addition, carboxylic
acids with additional olefin groups were also good partners in the
reaction, as proven by the formation of 3n and 3o in good yields.
To manifest the breadth and scope of this agreement, some
important carboxyl-containing drugs and bioactive molecules
were also employed as the acyloxylating reagents. For instance,
mefenamic acid,9a ibuprofen,9b,c and naproxen,9d which have
been widely applied to treat pain, fever, and inflammation as
nonsteroidal anti-inflammatory drugs,9 were transformed
smoothly in the reaction, delivering the aminoacyloxylation
products 3p−r in good yields. When acetylsalicylic acid, a well-
known drug to treat inflammation, ischemic strokes, blood clots,
and colorectal cancer,10 participated in the reaction, the
corresponding product 3s was also obtained in 58% yield.
When indole-3-acetic acid,11 which served as plant hormone of
the auxin class, was applied to this reaction, the anticipated
product 3u was formed in moderate yield, indicating that an
unprotected indole skeleton was well tolerated in the protocol.
10
11
12
13
14
15
DTBP
DTBP
DTBP
DTBP
phen
bpy
c
d
a
Conditions: 1a (0.30 mmol), 2a (0.36 mmol), copper (0.03 mmol),
oxidant (0.45 mmol), ligand (0.03 mmol, 0.1 equiv), solvent (2 mL),
b
c
Ar, 80 °C, 6 h. Isolated yield based on 1a. Cu(OAc)2 (0.045 mmol)
was used. Cu(OAc)2 (0.06 mmol) was used. TBHP = tert-butyl
hydroperoxide, DCP = dicumyl peroxide, EA = ethyl acetate, DMF =
dimethylformamide, bpy = bipyridine, phen = phenanthroline.
d
screening of a variety of copper salts (Table 1, entries 2−5),
Cu(OAc)2 was found to be the most efficient catalyst for this
transformation, and the yield of 3a was improved to 71% (Table
1, entry 4). No better yield was afforded when the reaction was
carried out under the conditions of other solvents and oxidants
(Table 1, entries 6−11). In addition, the addition of ligands,
such as phenanthroline and bipyridine, was destructive for the
aminoacyloxylation process (Table 1, entries 12 and 13).
Moreover, the amount of Cu(OAc)2 was also evaluated to
enhance the yield of 3a (Table 1, entries 14 and 15), and the
result indicated that the yield can be increased to 82% when 0.2
equiv of Cu(OAc)2 was used.
B
DOI: 10.1021/acs.orglett.8b01507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notably, there was no difficulty when the reaction was carried
out on a gram-scale, as demonstrated in the case of 3t, in which
gout suppressant probenecid12 was involved, indicating the
practicability of this tactic.
Scheme 4. Control Experiments
To further explore the applicability of this approach,
multifarious unsaturated ketohydrazones were then examined
(Scheme 3). Both aryl and heterocycle substituted unsaturated
a b
,
Scheme 3. Scope of Unsaturated Ketohydrazones
essential for this reaction. When a stoichiometric amount of
Cu(OAc)2 was used as the oxidant, the reaction produced the
aminoacyloxylation products 3a and 3i in 30% and 58% yields,
respectively (Scheme 4c). This result disclosed that a ligand
exchange process occurred between carboxylic acids and
Cu(OAc)2.
Based on our previous work on the radical cyclization
reactions of unsaturated hydrazones8 and oximes13 and the
results of control experiments in this work, a copper-catalyzed
hydrazonyl radical-promoted aminoacyloxylation process is
proposed in Scheme 5. First, CuII grabs an electron from
Scheme 5. Proposed Mechanism
a
Conditions: hydrazones 1 (0.30 mmol), 2a (0.36 mmol), Cu(OAc)2
(0.06 mmol), and DTBP (0.45 mmol), MeCN, Ar, 80 °C, 6 h.
hydrazone 1 via a single-electron transfer (SET) process to
produce the hydrazonyl radical A and CuI species,8,13d,e and the
latter is oxidized by DTBP to regenerate CuII species. A possible
alternative process for the generation of the hydrazonyl radical A
is that a hydrogen-atom transfer process occurs between
hydrazones 1 and tertiary butoxy radical which is derived from
the decomposition of DTBP under the catalysis of copper salt.8c
The hydrazonyl radical A subsequently experiences the N atom
5-exo-trig cyclization to form the intermediate B. The reaction of
the intermediate B with the copper species C, which is derived
from ligand exchange between CuII species and carboxylic acids,
produces the intermediate D. Finally, the intermediate D
undergoes reductive elimination to yield the aminoacyloxylation
product 3 and CuI species.13d,14
In conclusion, we have developed a facile and practical
method for the aminoacyloxylation of unactivated alkenes by
applying unsaturated ketohydrazones and carboxylic acids as the
easily available substrates and DTBP as the oxidant under
copper catalysis. By utilizing the approach, a variety of
structurally useful acyloxyl-featured pyrazolines are efficiently
synthesized. This reaction not only presents a new strategy for
the introduction of carboxylic acids into important heterocycles
but also features a broad scope of substrates and a good
functional group compatibility. Further studies on the
application of carboxylic acids as the acyloxylating reagents are
underway in our laboratory.
b
Isolated yields.
hydrazones were feasible in this transformation, affording the
anticipated aminoacyloxylation products 3v−ad in good to
excellent yields. Alkyl-substituted unsaturated hydrazones were
also compatible in this protocol to yield 3ae and 3af in moderate
yields. N-Phenyl hydrazones bearing substituents such as p-
MeO, p-Me, p-Cl, p-CF3, and p-NO2 were all smoothly
converted to the desired products 3ag−ak. When N-benzyl
and N-cyclohexyl substituted ketohydrazones were subjected to
react with 2a, the reaction produced 3al and 3am in 42% and
67% yields, respectively. However, N-acetyl substituted
ketohydrazone was inert in the reaction, and the desired
product 3an was not observed. Notably, γ,δ-unsaturated
hydrazone was also a good partner in this approach, yielding
the acyloxyl-fabricated tetrahydropyridazine 3ao in 80% yield.
To probe the mechanism of this reaction, control experiments
have been conducted as depicted in Scheme 4. When the
reaction was carried out under the copper-free conditions, no
reaction took place (Scheme 4a). To ensure the effective
formation of the tertiary butoxy radical from the decomposition
of DTBP under the copper-free conditions, the reaction
temperature was improved to 100 °C (Scheme 4b).8c However,
no aminoacyloxylation product was obtained, but the hydro-
amination product 4 was formed in 2% yield, along with 92% of
1a recovered. These results indicated that Cu(OAc)2 was
C
DOI: 10.1021/acs.orglett.8b01507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(e) Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem. Soc. 2014, 136,
16439−16443.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01507.
■
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Detailed experimental procedures and spectral data for all
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hanb@lzu.edu.cn
ORCID
Bo Zhou: 0000-0002-8713-5906
Bing Han: 0000-0003-0507-9742
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21422205, 21272106 and 21632001), the Fundamental
Research Funds for the Central Universities (Nos. lzujbky-2016-
ct02 and lzujbky-2016-ct08), Program for the Changjiang
Scholars and Innovative Research Team in University (IRT-
15R28), and the “111” Project for financial support.
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D
DOI: 10.1021/acs.orglett.8b01507
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