N,N-Dicarboxymethyl hydrazine: An old but neglected reagent for chemoselective derivatization of carbonyl compounds

Article abstract of DOI:10.1039/c6ob00189k

N,N-Dicarboxymethyl hydrazine (DCMH) was found to be a chemoselective derivatization reagent of carbonyl compounds and its potential applications in organic synthesis was investigated for the first time. DCMH could be employed as a chemoselective protective reagent of aldehydes and gave the parent aldehydes in satisfactory yields. In proof-of-concept systems, DCMH could play the role of a scavenger to remove aldehydes in the presence of ketones. It was also used as a tagging reagent in the selective isolation of aldehyde from the complex mixture.

Full text of DOI:10.1039/c6ob00189k

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especially aldehydes, are easily attacked by nucleophilic
reagents or oxidizing reagents. The conventional method of
overcoming these problems is to form derivatives of carbonyl
group, so the sensitive substrate can be protected
temporarily.3
Received 00th January 20xx,
Accepted 00th January 20xx
A
number of reagents have been employed in the
derivatization of carbonyl compounds. The formation of
hydrazones play an important role in the protection of the
sensitive carbonyl compounds, as well as used for their
purification, characterization and isolation.4 Hydrazines and
hydrazides, such as N,N-dimethylhydrazine (DMH)5 and
Girard’s reagents6 (Scheme 1), are commonly used for these
purposes. For example, N,N-dimethylhydrazine could be used
as protective reagent of carbonyl compounds and provided
parent aldehydes in high yield and purity after be treated with
CeCl3·7H2O-SiO2.7 Teitelbaum has reported the use of Girard’s
reagent T to isolate carbonyl compounds from mixtures with
higher yields avoiding acidic conditions.8
DOI: 10.1039/x0xx00000x
www.rsc.org/
N,N-dicarboxymethyl hydrazine: an old
but neglected reagent for
chemoselective derivatization of
carbonyl compounds
Maomin Zhen and Yanqing Peng*
Despite of the successful application in organic synthesis,
however, they still have some inherent drawbacks. The acute
toxicity and inhalation danger of N,N-dimethylhydrazine used
in conventional organic reactions make these process unsafe.
Girard’s reagents are hygroscopic and deteriorative easily
when was exposed in the air. These reagents react smoothly
with both aldehydes and ketones; on the other hand, this
means relatively poor chemoselectivity between aldehydes
and ketones. Therefore, it is necessary to develop novel
derivatization reagent of carbonyl compounds with improved
safety, stability and chemical selectivity for the protection,
purification and isolation of carbonyl compounds.
The N,N-dicarboxymethyl hydrazine (DCMH) was found to be
a
chemoselective derivatization reagent of carbonyl compounds and its
potential applications in organic synthesis was investigated for the first time.
DCMH could be employed as a chemoselective protective reagent of
aldehydes and gave parent aldehydes in satisfactory yields. In proof-of-
concept systems, DCMH could play the role of scavenger to remove
aldehydes in the presence of ketones. It was also used as tagging reagent in
the selective isolation of aldehyde from complex mixture.
Introduction
As an important category of the organic compounds, N,N-dicarboxymethyl hydrazine (DCMH) is a noteless organic
aldehydes and ketones have been widely applied in many compound although it has been prepared one hundred years
organic transformations and are key precursors of a variety of ago.9 DCMH was previously employed as a complexant to
valuable fine chemicals including fragrances, vitamins and separate the lanthanons from rare earth mixtures.10 However,
drugs.1 Meanwhile, the derivatization of carbonyl compounds its potential use in organic synthesis has not been explored.
is a general task during the identification, protection and
isolation procedures.2 For instance, carbonyl compounds,
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, Shanghai 200237, P. R. China.
E-mail: yqpeng@ecust.edu.cn; Fax: +86-21-64252603
Electronic Supplementary Information (ESI) available: characterization of all the
prepared compounds, copies of 1H NMR and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
Scheme 1
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During our medicinal research on new enzyme inhibitors, we 1.3%.
Journal Name
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need to introduce a hydrophilic tag to water-insoluble As expected, the reaction rates of both D4O-cI:h1l0o.r1o03b9e/nCz6aOlBd0e0h1y8d9eK
substrates containing carbonyl groups. We found the and 4-chloroacetophenone with DCMH were enhanced at
candidate tagging agent N,N-dicarboxymethyl hydrazine has higher temperature (120 °C) using DMSO as a solvent. After 8
some interesting behavior in treating with different aldehydes hours, the conversion of 4-chloroacetophenone reached to
and ketones. In this paper, we wish to report our work on the 23.1%. In comparison, the reaction of 4-chlorobenzaldehyde
chemoselective interaction between DCMH and carbonyl was also promoted and the ramp of conversion curve (nearly
compounds and its potential application in organic synthesis.
100% about 0.5 h) can be seen in Figure 1B. In other words,
the reaction between DCMH and ketones could still be carried
out successfully at higher temperature in prolonged reaction
time (>24 h). For example, the reaction between 4-
chloroacetophenone and DCMH (Table 1, Entry 12) afford
desired hydrazone in acceptable isolated yield (58%) after 24 h.
These results demonstrated that DCMH has prominent
chemoselectivity between aldehydes and ketones. Moreover,
the chemoselectivity could be regulated by control of the
reaction conditions.
Another potential application of DCMH is to introduce a
hydrophilic tag onto aldehydes selectively in the presence of
ketones. A colorimetric test was designed using Michler's
ketone and 2-hydroxy-5-phenylazo salicylaldehyde as
chromogenic substrates. Initially, Michler's ketone (purple)
and 2-hydroxy-5-phenylazo salicylaldehyde (orange) were
dissolved in the organic phase (lower layer) and DCMH
Results and Discussions
Initially, we attempt to prepare hydrazones of DCMH with
different aldehydes and ketones. To our surprise, however,
aliphatic cyclic ketones (e.g. cyclohexanone) and aromatic
ketones (e.g. acetophenone) are difficult to react with DCMH.
Only trace of expected hydrazones was detected while most of
ketones kept unchanged. In contrast, DCMH reacted with
aldehydes smoothly in satisfactory yields under the same
conditions.
The reaction was further investigated in detail with 4-
chlorobenzaldehyde and 4-chloroacetophenone as model
substrates. A mixture of 4-chlorobenzaldehyde (1 mmol) and
4-chloroacetophenone (1 mmol) were treated with DCMH (2
mmol) in different solvents at different temperatures. The
reactions were monitored by HPLC. As shown in Figure 1A,
when the reaction was performed at 25 °C in methanol, 4-
chlorobenzaldehyde was completely consumed after 3 hours,
while the conversion of 4-chloroacetophenone was less than
distributed in the aqueous layer (Figure 2, A). After the mixture
was stirred for 4 h at room temperature, 2-hydroxy-5-
phenylazo salicylaldehyde was transferred into the aqueous
layer by forming a water-soluble derivative, while unchanged
Michler's ketone was still in the organic layer (Figure 2, B). This
process was identifiable intuitively through color changes of
two phases.
The origin of chemoselectivity was speculated during this
research work. It might be attributed to the (1) zwitterion
between amino group and carboxyl group, and/or (2) electron-
withdrawing induced effect of two carboxyl groups. By using
bis-sodium salt of DCMH, however, the chemoselectivity still
remained. Hence the zwitterion is not the critical factor.
Figure
tagging
2
.
Colorimetric demonstration of chemoselective
Figure 1. Kinetic study on the chemoselectivity of DCMH
between aldehydes and ketones
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Table 1. Protection and deprotection of carbonyl compounds
Substrates
Entry
Protectiona
Deprotectionc
R1
R2
Yield (%)d
Time (h)
Yield (%)d
88
Time (h)
1
2
H
Ph
85
88
78
81
84
82
80
89
91
85
76
58
3
2
4
3
H
4-ClC6H4
2-O2NC6H4
3-HOC6H4
2,4-(Cl)2C6H3
4-MeC6H4
4-MeOC6H4
2-Thienyl
2-Pyridyl
PhCH=CH
CH3(CH2)2
4-ClC6H4
89
3
H
4
78
6
4
H
4
83
5
5
H
3
86
3.5
5
6
H
3
81
7
H
3
84
5
8
H
2.5
2
82
4
9
H
88
3
10
11
12b
H
2
80
6
H
4
75
5
CH3
24
70
9
a Reagents and conditions: aldehydes (2 mmol), DCMH (2.4 mmol), EtOH, room temperature.
b Reagents and conditions: 4-chloroacetophenone (2 mmol), DCMH (2.4 mmol), DMSO, 120 °C.
c Reagents and conditions: substrates (1 mmol), Cu(NO3)2·6H2O (1.2 mmol), CH2Cl2–H2O (1:1), room temperature.
d Isolated yields.
Application of DCMH as a novel and chemoselective protective
reagent of aldehydes
application, DMH has its own drawbacks and limitations.
During our investigation, the potential of DCMH (an analogue
of DMH) as protective reagent was evaluated at the first time.
As shown in Table 1, a serial of aromatic aldehydes, aliphatic
aldehydes and unsaturated aldehyde can be protected by
DCMH under mild conditions. The reaction performed
smoothly without catalyst (approx. 2-4 h) to give
corresponding hydrazones in good yields. In general,
substituted aldehydes bearing both electron-withdrawing and
electron-donating groups on the aromatic ring gave good
yields of hydrazones. Aliphatic aldehydes, heterocyclic
The introduction and removal of protecting groups is one of
the most important and widely carried out synthetic
transformations in preparative organic chemistry.11 As acetals
13
15
(thioacetals),12 oximes and 1,1-diacetates,14 hydrazones
are often employed for the protection of carbonyl groups. In
the family of hydrazine derivatives, N,N-dimethylhydrazine
(DMH) are widely used as protective reagent of carbonyl
compounds in multi-step synthesis, and provided parent
aldehydes through deprotection. Despite the broader scope of
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Table 2 Screening of deprotection reagents
DMH are less polar hydrophobic compounds; however, their
hydrazone derivatives with DCMH are often much polar and
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DOI: 10.1039/C6OB00189K
Reagenta
Time (h)
Yield (%)b
hydrophilic. Hence, after derivation, hydrazone derivatives of
DCMH could be separated readily from less polar organic
compounds by extraction (or other) processes. (3) Safer
handling. DMH is a volatile and highly toxic chemical which
should be handled with care. Inhalation and skin contact with
DMH must be strictly avoided. On the contrary, DCMH is a
non-volatile and relatively low toxic compound.
FeCl3
5
4
8
7
81
88
70
65
Cu(NO3)2·6H2O
oxalic acid
TMSCl-NaI
a
Reagents and conditions: benzylidenehydrazinodiacetic acid
(2 mmol), deprotection reagent (2.4 mmol), CH2Cl2–H2O, room
Application of DCMH as a scavenger to remove excess aldehyde in
the presence of ketone
temperature.
b Isolated yields.
In most of organic synthetic reactions, an excess of certain
reagent is intentionally employed to accelerate the reaction or
to obtain higher yield of desired products. Over the past
decades, solution-phase high throughput synthesis has
emerged as a powerful tool for the rapid generation of
chemical libraries, especially in drug-like lead discovery and
optimization tool in drug screening.22 Solution-phase synthesis
allows for diverse and homogeneous reaction conditions, and
products are readily analyzed and identified, but the rapid
purification or isolation of products from a reaction mixture is
difficult. To overcome this drawback, several purification
protocols have also been developed to simplify the time-
consuming purification procedures often associated with
solution-phase reactions. The most widely employed method
among them is the use of polymer-supported scavenger
reagents.23 Most of commercially available scavengers are
reticulated polymers and the major drawbacks of these
supported scavengers are the high cost and the large amount
generally required to clean up the reaction product. To
address these issues, many innovative purification approaches
have been disclosed. Some fluorous-phase24 scavengers and
PEG supported scavenger reagents25 have been designed to
avoid these limitations.
As a quaternary ammonium type hydrazide, Girard’s reagent T
has been used in scavenging excess acid chlorides to obtain
water-soluble byproducts, which could be removed from the
desired products by extraction with water.26 However, this
reagent could not be employed to remove aldehydes in the
presence of ketones due to its poor chemoselectivity between
aldehydes and ketones. In comparison, DCMH is a stable,
nonhygroscopic (non-deliquescent) white powder which has
excellent chemoselectivity. In this paper, therefore, the
application of DCMH for replacement of Girard’s reagent as a
water-soluble and selective scavenger was then investigated in
two proof-of-concept reactions.
aldehydes and unsaturated aldehyde all reacted well with
good yields. It has been discussed in the kinetic study on the
chemoselectivity of DCMH that 4-chloroacetophenone can also
give desired hydrazone in acceptable isolated yield (58%) after
24 h (Table 1, Entry 12).
The cleavage of N,N-dimethylhydrazones to afford carbonyl
compounds has been studied extensively.16 The classical
method is hydrolysis of N,N-dimethylhydrazones under strong
acidic condition, but this is not appropriate for acid sensitive
aldehydes.17 Hence, various alternative reagents were
developed for this purpose. In the present work, several
representative reagents, including cheap and nontoxic Lewis
20
acids (Fe 18 and Cu 19 salts), a mild Brønsted acid (oxalic acid
)
and a mixed reagents system (TMSCl-NaI 21), were chosen for
the screening of deprotection reagent by using
benzylidenehydrazinodiacetic acid (hydrazone of DCMH with
benzaldehyde) as a substrate. The comparative study shown
that cupric salts was the optimal deprotection reagents in
terms of reaction time, yield, mild condition and simple
operation. Copper(II) chloride and copper(II) nitrate shown
similar activities so the copper(II) nitrate was used in
subsequent experiments (Table 2). The deprotection reactions
were carried out in dichloromethane-water biphase system.
Reaction occurred in aqueous solution of copper (II) nitrate,
and the parent aldehydes thus formed was extracted in to
organic phase. With optimal cleavage reagent in hand, the
deprotection of various hydrazones was tested subsequently.
As shown in Table 1, high yields of carbonyl compounds were
obtained after deprotection. No byproducts and possible
impurities were detected in dichloromethane phase.
In comparison with N,N-dimethyl hydrazine, DCMH has several
prominent superiorities when that is being used in organic
synthesis. (1) Excellent chemoselectivity. The present work has
demonstrated the chemoselectivity of DCMH in the presence
of aldehydes and ketones. This provides an opportunity to
derive aldehydes selectively in the presence of ketones. So
DCMH could be employed as a chemoselective protective
reagent. In a mixture containing both aldehydes and ketones,
the aldehydes would be protected specifically. In the case of a
compound with multiple carbonyl groups, the aldehyde
carbonyl would be protected while ketone carbonyl remained
unchanged. (2) Easier isolation. Most of aldehydes (especially
aromatic ones) as well as their hydrazone derivatives with
Firstly, Mannich reaction among benzaldehyde, acetophenone
and aniline was selected as a model reaction to test the ability
of DCMH as a scavenger in selective removal of benzaldehyde
2
in the presence of the β-amino ketone product 1 (Figure 3A).
Acetophenone (2 mmol) and aniline (2mmol) in ethanol were
treated with an excess of benzaldehyde (2.4 mmol, 1.2 equiv.)
in the presence of a catalytic amount of sulfamic acid (0.1
equiv.). On completion (6 h, room temperature, monitored by
HPLC), DCMH (0.4 equiv.) was added and stirred for an
additional 3 h to react with excess aldehyde. Aqueous sodium
4 | J. Name., 2012, 00, 1-3
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Figure 3 (A) Isolation of β-amino ketone by selected removal of Figure 4 (A) Isolation of α, β-unsaturated ketone by selected
excess benzaldehyde (B) HPLC tracing derivatization of aldehyde (B) HPLC tracing
bicarbonate was then added to the mixture under stirring. The degradation experienced by polymer-supported scavengers
product was extracted with dichloromethane while the water under vigorous stirring.
soluble hydrazine
3 stayed in the aqueous phase. The organic Application of DCMH in the isolation of aldehydes from natural
layers were dried over anhydrous magnesium sulfate and plant products
evaporated to yield the desired product in 91% yield. The
The isolation of specific kinds of natural products is important
resulting β-amino ketone was free from the starting aldehyde
to the scientific community because many of natural products
have medicinal activities and often be evaluated for finding
new biologically active scaffolds and drug candidates.
Unfortunately, these isolation procedures are difficult
endeavours. In general, these isolation procedures relies upon
extraction and/or chromatographic separation techniques
which are dependent upon the physicochemical properties of
the compounds rather than the difference in chemical
reactivity. Recently, Carlson group has reported a functional
group targeted method for chemoselective enrichment and
isolation of natural products with certain functional groups
from complex mixtures based on controllably reversible
covalent enrichment tags.27 In this paper, we wish to describe
our research work on the practicability of using DCMH as a
tagging reagent for the isolation of natural aldehyde from a
complex mixture.
Carbonyl compounds are common constituents of natural
plant products in which they usually mixed with esters,
hydrocarbons and steroids.28 Star anise (Illicium verum Hook. f.)
is not only used as a flavoring ingredient in foods but also used
in aromatherapy and pharmaceutical industries. Dozens of
chemical constituents have been identified from star anise
(Illicium verum Hook. f.), but the major components are trans-
and possible impurities as determined by 1H NMR.
Figure 3B illustrates a typical HPLC tracing observed in this
study. The peak at 8.1 min retention time is due to unreacted
aldehyde
Mannich base
derivatization of unreacted aldehyde as indicated by the
formation of hydrazone (peak at 20.1 min). After be
2
, while the peak at 14.8 min is due to the desired
1
. In this case, treating with DCMH led to
3
extracted with dichloromethane and aqueous sodium
bicarbonate, hydrazone could be removed completely and
essentially pure Mannich base was obtained in high yield.
Another model reaction of choice was the aldol condensation
between 3-acetyl coumarin and benzaldehyde to afford α, β-
unsaturated ketone
1 (Figure 4A). The reaction and scavenging
processes were monitored by HPLC as shown in Figure 4.
DCMH could also be used as an efficient and selective
scavenger just as in Mannich reaction. After the derivatization
and extraction work-up, desired product 3-(3-phenyl-acryloyl)-
chromen-2-one
1 could be obtained in 95% yield with high
purity (98%) as confirmed by 1H NMR. The process was
monitored by HPLC as illustrated in Figure 4B.
In principle, DCMH might be considered to be a suitable
scavenger for other type of reactions which need to purify
ketone type product in the presence of excess aldehyde by
derivatization. It is also worth mentioning that the DCMH
reagent does not suffer from the extensive mechanical
anethole
1, anisole 2, α-pinene 3, fenchone, and anisaldehyde
4
; although there is great difference in the ratio of constituents
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and tagging reagent as have been demonstrated in this paper.
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In some cases, DCMH might be empDloOyIe: 1d0.1a0s39a/Cn6OeBf0fi0c1ie89nKt
alternative reagent of N,N-dimethylhydrazine and Girard’s
reagents in organic synthesis and isolation processes.
Experimental
General remarks
All reagents and solvents were purchased from commercial
1
suppliers and used without further purification. H NMR (400
Hz) and 13C NMR (100 Hz) spectra were recorded on Bruker
AM-400 spectrometer using TMS as an internal standard.
Melting points were measured on BUCHI Melting Point B-450.
Mass spectra were recorded on a Shimadzu QP 1100 EX mass
spectrometer with 70eV ionization potential. IR spectra were
recorded with a Thermo Nicolet 6700 IR spectrophotometer
using KBr pellets. Elemental analyses were carried out with a
Thermo Flash 2000 CHNS/O analyzer. HPLC analysis was
performed on a Hewlett-Packard 1100 instrument.
Synthesis of DCMH
Chloroacetic acid (950 mg, 10 mmol) in water (10 mL) was
neutralized with sodium carbonate (530 mg, 5 mmol) followed
by the addition of hydrazine hydrate (310 mg, 5 mmol). Next, a
second portion of sodium carbonate (530 mg, 5 mmol) was
gradually added at room temperature. On completion, the
temperature was elevated to 70 °C and the solution was
stirred until the gas generation stopped. After cooling, the
solution was acidified to pH 3–4 by hydrochloric acid and the
crude DCMH was then precipitated. Recrystallization from
water gave 614 mg (83% yield) of pure DCMH as white powder.
M.p. 168–169 °C, lit.9 166–167 °C.
Figure 5 (A) Isolation of anisaldehyde through a capture-and-
release strategy (B) HPLC tracing
which largely depend on internal and external factors such as
genetic structures, geographic locations, even storage time.29
To demonstrate the potential of DCMH for chemoselective
enrichment of natural aldehyde, 15 g of crushed Star anise was
extracted by methanol (20 mL) for 12 h. The major
components in obtained extract were identified as trans-
anethole, anisole, α-pinene and anisaldehyde by GC-MS. The
mixture was concentrated to approximately 5 mL and then
treated with excess of DCMH (222 mg, 1.5 mmol). As shown in
the HPLC tracing in Figure 5B, anisaldehyde was tagged
completely within 3 h. Following capture, the hydrazone
General procedure for the protection of aldehydes with DCMH
To a stirred solution of aldehyde (2 mmol) in ethanol (4 mL)
was added DCMH (360 mg, 2.4 mmol). The mixture was stirred
at room temperature and monitored by TLC. Upon completion,
the solution was concentrated while the crude product was
obtained by filtration (washed with ice water). The pure
product was obtained by recrystallization from ethanol.
General procedure for the deprotection with Cu(NO3)2·6H2O
To a stirred solution of Cu(NO3)2·6H2O (338 mg, 1.2 mmol) in
water (2 mL) was added the hydrazone derivatives (1 mmol)
and dichloromethane (2 mL). The mixture is stirred for several
hours (monitored by TLC) at room temperature. Upon
completion, the solution was diluted with 10 mL of aqueous
sodium bicarbonate (100 mg, 1.2 mmol). The organic layer was
separated and the aqueous solution was further extracted
derivative
5 was separated from lipophilic compounds by
extraction. Anisaldehyde (114 mg) could be recovered by
cleavage of the hydrophilic tag with stoichiometric copper (II)
nitrate after liquid-liquid extraction. The product was checked
by HPLC followed by 1H NMR and was essentially pure (99%).
with
dichloromethane
(2×5
mL).
The
combined
dichloromethane solution was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure
to give the pure aldehydes.
Purification of 1,3-diphenyl-3-(phenylamino)propan-1-one with
DCMH
Conclusions
In conclusion, N,N-dicarboxymethyl hydrazine is a water-
soluble, non-volatile, non-hygroscopic and stable reagent with
excellent chemoselectivity between aldehydes and ketones.
DCMH can be used as chemoselective derivatization reagent of
carbonyl compounds such as protective reagent, scavenger
To a stirred solution of benzaldehyde (250 mg, 2.4 mmol) in
ethanol (4 mL) was added acetophenone (240 mg, 2 mmol),
aniline (190 mg, 2 mmol) and sulfamic acid (20 mg, 0.2 mmol)
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4
S. Bala, G. Uppal, A. Kajal, S. Kamboj and V. SVhieawrmArtaic,leInOtn.linJe.
Pharm. Sci. Rev. Res., 2013, 18, 65.
at room temperature. The reaction completed after 6 h as
monitored by TLC. 120 mg of DCMH (0.8 mmol) was then
added and the mixture was stirred for an additional 3 h. The
mixture was diluted with 10 mL of aqueous sodium
bicarbonate (100 mg, 1.2 mmol) and the organic layer was
separated. Aqueous layer was extracted with dichloromethane
(3×5 mL) subsquently. The combined organic solution was
dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give 547 mg of pure 1,3-diphenyl-3-
(phenylamino)propan-1-one (91% yield). M.p. 168–169 °C, lit.30
168–170 °C.
5
6
7
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Purification of 3-(3-phenyl-acryloyl)-chromen-2-one with DCMH
A stirred solution of benzaldehyde (250 mg, 2.4 mmol), 3-
acetyl coumarin (380 mg, 2 mmol) and piperidine (17 mg, 0.2
mmol) in ethanol (4 mL) was refluxed for 5 h. On completion of
the reaction (monitored by TLC), DCMH (120 mg, 0.8 mmol)
was added followed by stirring for further 3 h. The mixture was
then diluted with 10 mL of aqueous sodium bicarbonate (100
mg, 1.2 mmol) while the organic layer was separated. Aqueous
layer was extracted with dichloromethane (3×5 mL). The
combined organic solution was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure
to give the essentially pure 3-(3-phenyl-acryloyl)-chromen-2-
one (525 mg, 95% yield). M.p. 141–142 °C, lit.31 142–143 °C.
Isolation of anisaldehyde from the extract of Star anise with
DCMH
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Crushed Star anise (15 g) was extracted with refluxed
methanol (20 mL) for 12 h. After filtration, the solution
containing trans-anethole, anisaldehyde, anisole and α-pinene
(identified by GC-MS) was concentrated to 5 mL, and then
treated with excess of DCMH (222 mg, 1.5 mmol). The mixture
was stirred for 3 h at room temperature, diluted with 10 mL of
aqueous sodium bicarbonate (168 mg, 2 mmol) and extracted
with dichloromethane (3×5 mL) to remove hydrophobic
components. The aqueous layer was added Cu(NO3)2·6H2O
(422 mg, 1.5 mmol) and stirred for an additional 5 h. The
reaction mixture thus formed was extracted with
dichloromethane (3×5 mL). The combined organic solution was
dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the pure anisaldehyde (114
mg).
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Acknowledgements
Financial support for this work from the National Key
Technology R&D Program (2011BAE06B05) is gratefully
acknowledged.
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