Efficient synthesis of 1,5-disubstituted carbohydrazones using K 2CO3 as a carbonyl donor

Article abstract of DOI:10.1021/ol500732c

A novel reaction that generates 1,5-disubstituted carbohydrazones via the carbonylation of tosylhydrazones has been developed. For the first time, the inexpensive, readily available, environmentally friendly, and nongaseous potassium carbonate is used as

Full text of DOI:10.1021/ol500732c

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of 1,5-Disubstituted Carbohydrazones Using
K2CO3 As a Carbonyl Donor
Jun Wen, Chu-Ting Yang, Tao Jiang, Sheng Hu, Tong-Zai Yang, and Xiao-Lin Wang*
Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang 621900, Sichuan Province, China
S
* Supporting Information
ABSTRACT: A novel reaction that generates 1,5-disubsti-
tuted carbohydrazones via the carbonylation of tosylhydra-
zones has been developed. For the first time, the inexpensive,
readily available, environmentally friendly, and nongaseous
potassium carbonate is used as the carbonyl donor for the
transformation. The reaction system exhibited tolerance with
various functional groups and affords the desired products in good to excellent yields. This reaction is expected to be a powerful
tool for the synthesis of carbohydrazone compounds.
a
reylene-containing compounds have often been explored
in the development of pharmaceuticals, agricultural
Table 1. Optimization of Reaction Conditions
U
pesticides, gasoline antioxidants, and corrosion inhibitors.1
Carbohydrazones, in particular, exhibit diverse utility, including
as antibacterial2 and anticonvulsant3 agents, highly efficient
chemosensors,4 and valuable synthetic intermediates.5
additive
(mol %)
carbonyl
donor
temp
(°C)
yield of 3a
b
A number of methodologies for the synthesis of ureylene-
containing compounds (carbohydrazones, ureas) have been
reported. However, these strategies mainly employ phosgene
entry
solvent
(%)
1
−
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KHCO3
K2CO3
K2CO3
K2CO3
60
60
60
60
60
60
60
60
60
60
60
60
80
40
60
NR
82
45
92
83
45
11
2
2a (150)
2a (50)
2a (100)
2b (100)
2c (100)
2a (100)
2a (100)
2a (100)
2a (100)
2a (100)
2a (100)
2a (100)
2a (100)
2a (100)
8
and triphosgene,6 CO,7 and CO2 as sources of the carbonyl
3
moiety, despite their associated significant drawbacks. Phosgene
is corrosive, CO is an explosive gas, and both of them are highly
toxic. CO2 is often used in large excess under high pressure,
thus complicating the process. Recently, alternative carbonyl
group donors have been developed, such as organic
carbonates,9 isocyanate,10 formamides,11 and carbonylimidazo-
lium salts.12 Nevertheless, some of these reagents originate
from phosgene or require costly multistep syntheses. Therefore,
it remains an important challenge to develop an inexpensive,
readily available, and environmentally benign carbonyl donor.
Herein, we report the novel phosphite-mediated synthesis of
1,5-disubstituted carbohydrazones by the carbonylation of
different tosylhydrazones using potassium carbonate as the
carbonyl donor. These facile reactions were carried out in the
absence of transition metals, and a wide variety of substituted
carbohydrazones were obtained in good to excellent yields.
Interestingly, potassium carbonate, one of the most common
inorganic bases, was used as the carbonyl donor for the first
time; the reagent is inexpensive, ecologically friendly, abundant,
nonflammable, and nongaseous.
4
5
6
7
d
8
dioxane
EtOH
0
d
9
0
d
10
11
12
13
14
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
0
trace
trace
31
78
c
15
93
a
Reaction conditions: 1a (0.5 mmol), K2CO3 (0.75 mmol), solvent (2
mL), 10 h, 60 °C, in air. Isolated yield. 99.995% K2CO3 was used.
The phosphorohydrazone 7 was obtained as the product.
b
c
d
probed additive stoichiometry on a small scale (entries 2−4)
and found that 1.0 equiv of 2a was optimal for the reaction,
affording a 92% yield of product (entry 4). The use of other
dialkyl phosphites as additives resulted in lower yields (entries 5
and 6); increasing alkyl group bulkiness decreased the product
yield, indicating that the reaction may sensitive to steric effects
from the dialkyl phosphites. A solvent evaluation revealed that
DMSO was nearly the only suitable solvent for the reaction
For the initial optimization of the reaction conditions, the
carbonylation of tosylhydrazone 1a was selected as a model
reaction system. The results are listed in Table 1. The first
attempted reactions, using K2CO3 as the carbonyl donor and
dimethyl sulfoxide (DMSO) as the solvent (Table 1, entry 1),
afforded no carbonylation product. Addition of phosphite 2a to
the reaction system led to the desired product 1,5-dibenzyl
carbohydrazone (3a) in 82% yield (Table 1, entry 2). We
Received: March 10, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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Letter
(entries 7−10). The use of other carbonates as the carbonyl
donor, such as Na2CO3 and KHCO3 (entries 11, 12), provided
only trace amounts of the desired products. The optimal
reaction temperature was 60 °C (entries 4, 13, and 14); at
higher temperatures, larger quantities of byproducts were
formed. To exclude the possibility that trace impurities were
affecting the reaction, we performed a control experiment using
ultrapure K2CO3 (99.995%) as the carbonyl donor. We were
pleased that nearly the same yield was obtained (entry 15).
The substrate scope was subsequently investigated under the
optimized conditions. First, various benzaldehyde tosylhydra-
zone derivatives 1 were prepared and used for the carbon-
ylation reaction; the results are summarized in Scheme 1.
Scheme 2. Carbonylation Reactions of Other
Tosylhydrazone Compounds
a
Scheme 1. Carbonylation Reactions of Various
a
Benzaldehyde Tosylhydrazone Derivatives
a
Reaction conditions: 4 (0.5 mmol), K2CO3 (0.75 mmol), 2a (0.5
mmol), DMSO (2 mL), 10 h, 60 °C, in air. Isolated yields.
When acetophenone tosylhydrazone was used as the substrate
under the optimized conditions, the product 5a was obtained in
poor yield (29%), indicating that the reaction was sensitive to
steric effects at the α-position. Nonbenzaldehyde tosylhydra-
zones such as cinnamaldehyde and ferrocenecarboxaldehyde
tosylhydrazones gave the desired products 5b and 5c in 74 and
86% yields, respectively. Several tosylhydrazone compounds
based on heteroarenes were also successfully applied in the
reaction (5d−5j), giving the desired products in moderate to
excellent yields. These compounds provide a number of
potential applications in coordination chemistry.
Because tosylhydrazones are readily prepared by mixing tosyl
hydrazide with aldehydes, we investigated the one-pot carbon-
ylation reactions of aldehydes, tosyl hydrazide, and K2CO3. All
the reactants were added simultaneously, without the isolation
of the intermediate tosylhydrazone or an increase in the
reaction time. The carbonylation products were obtained in
similar yields (Scheme 3). It is noteworthy that this reaction
can be carried out on gram scale. For instance, upon
combination of 10 mmol of the starting materials, product 3a
was obtained in 90% yield.
It is known that carbohydrazone compounds have strong
intermolecular hydrogen bonds, and they are an important class
of components for the self-assembly of supramolecular
structures.13 Slow evaporation of a colorless solution of 3a in
MeOH led to the formation of colorless needle crystals. Single
crystal X-ray analysis shows that each unit cell contains two
slightly different molecules conformations of 3a (Figure 1).14
Two molecules of 3a of the same configuration (green in
Figure 1) doubly interact by hydrogen bonding, and another
molecule of 3a (purple in Figure 1) is inserted into the gap.
A sample of 3a at 0.5 wt % in CHCl3 afforded a colorless
solution. When ultrasound was applied to this solution for 1
min (at 0.40 W/cm2 and 40 kHz), a white, immobile gel was
produced (Figure 2a). The morphology of the resulting
a
Reaction conditions: 1 (0.5 mmol), K2CO3 (0.75 mmol), 2a (0.5
mmol), DMSO (2 mL), 10 h, 60 °C, in air. Isolated yields.
Halogen-substituted substrates worked well, leaving halogen
substituents untouched (3b−3e). ortho-Chlorophenyl tosylhy-
drazone also gave an excellent yield of the desired product 3e,
indicating that steric hindrance on the phenyl ring did not affect
the results. Substrates with electron-donating substituents on
the phenyl ring, such as alkyl, methoxyl, and dimethylamino
groups, were also tested, affording the corresponding carbon-
ylation products in excellent yields (3f−3i). The reaction also
tolerated various functional groups such as nitro, cyano, and
hydroxyl moieties; these substrates gave the desired products in
good to excellent yields (3j−3l). Naphthaldehyde tosylhydra-
zone derivatives also underwent smooth transformation to give
good product yields (3m, 3n).
Next, we investigated the carbonylation reactions of other
tosylhydrazone compounds. Scheme 2 summarizes the results.
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Organic Letters
Letter
a
utilized 13C NMR to examine the isolated product and clearly
observed the incorporation of the 13C−carbonyl. This
confirmed that K2CO3 served as the carbonyl source for this
reaction. The reaction did not proceed in the absence of
phosphite; the tosylhydrazones coupled with phosphite to form
phosphorohydrazones.15 Therefore, a possible mechanism for
this reaction was expected to start with the coupling of the
tosylhydrazone with phosphite to form the phosphorohydra-
zone 7 (Scheme 4). Thereafter, the carbonate ion is trapped by
Scheme 3. One-Pot Carbonylation Reactions
Scheme 4. Proposed Mechanism for the Reaction
a
Reaction conditions: 6 (0.5 mmol), TsNHNH2 (0.60 mmol), K2CO3
(0.75 mmol), 2a (0.5 mmol), DMSO (2 mL), 10 h, 60 °C, in air,
b
Isolated yields. Carried out on 10 mmol scale.
7. Its C−O bonds are activated by phosphate.16 Subsequently,
the C−O bonds are cleaved in the acyl transfer process.17 After
two nucleophilic additions followed by an elimination process,
the final product 3a is obtained. To support this mechanistic
proposal, phosphorohydrazone 7 was used as the substrate
under the optimized conditions, and product 3a was obtained
in 80% yield (eq 2). This result was in agreement with the
participation of a phosphorohydrazone as proposed in Scheme
4. Further studies to extend this chemistry and completely
understand the transformation are underway.
Figure 1. X-ray structure of 3a (distances of hydrogen bond in Å).
In summary, we have reported a new carbonylation reaction
of tosylhydrazones for the synthesis of 1,5-disubstituted
carbohydrazones using K2CO3 as the carbonyl donor. The
reaction system tolerates various functional groups and affords
the desired products in good to excellent yields. To the best of
our knowledge, this is the first example of a carbonylation
reaction using K2CO3 as the carbonyl donor. Compared with
other carbonylation agents, K2CO3 is inexpensive, readily
available, ecologically friendly, and nongaseous. The developed
reaction is expected to be a powerful tool for the synthesis of
carbohydrazone compounds, which may have potential
applications in supramolecular chemistry.
Figure 2. (a) Ultrasound induced gelation of 3a. (b) SEM image of
the xerogel obtained from the gel of 3a in CHCl3. (c) Powder X-ray
diffraction patterns of the single crystal and gel (red line) of 3a.
organogel was investigated by scanning electron microscopy
(SEM), which shows the formation of entangled fibers with
diameters of hundreds of nanometers (Figure 2b). The powder
X-ray analysis of the xerogel prepared by air-drying the gel of 3a
in CHCl3 was conducted and compared with the powder X-ray
diffraction pattern of the crystals (Figure 2c), revealing an
amorphous structure. Sonication probably causes the reorgan-
ization of the molecular assemblies, leading to the much longer
entangled fibers, as shown in Figure 2b, that immobilize the
solvent.
ASSOCIATED CONTENT
* Supporting Information
X-ray crystallographic file in CIF format for compound 3a,
experimental details, and spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xlwang@caep.cn.
Notes
To ensure that the carbonyl donor was K2CO3 rather than an
impurity, we investigated the reaction using K2CO3−13C as the
carbonyl donor under the optimized conditions (eq 1). We
The authors declare no competing financial interest.
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Letter
ACKNOWLEDGMENTS
■
This work was financially supported by China Postdoctoral
Science Foundation Grant (No. 2012M521716), the Science
and Technology Development Foundation of China Academy
of Engineering Physics (Grant 2011A0301003), and Training
Program of the Major Research Plan of the National Natural
Science Foundation of China (No. 91026022).
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