Efficient Method for Aromatic-Aldehyde Oxidation by Cleavage of Their Hydrazones Catalysed by Trimethylsilanolate

Article abstract of DOI:10.1002/ejoc.201601238

The reactions of hydrazones, derived from various aromatic aldehydes bound to Rink resin and hydrazines, with trimethylsilanolate have been studied. In this process, the aldehydes were oxidized to the corresponding carboxylic acids. The reaction was also tested with success in solution, with various aromatic aldehydes easily being oxidized in one pot via hydrazone formation and trimethylsilanolate treatment. A mechanism for the hydrazone cleavage is proposed. The reaction may be used as an alternative method for aldehyde oxidation with the selectivity complementary to that of currently used reactions.

Full text of DOI:10.1002/ejoc.201601238

A Journal of
Accepted Article
Title: Efficient Method of Aromatic Aldehydes Oxidation via Cleavage of their Hydra-
zones Catalyzed by Trimethylsilanolate
Authors: Kristyna Burglova; Sergei Okorochenkov; Milos Budesinsky; Jan Hlavac
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601238
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European Journal of Organic Chemistry
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Efficient Method of Aromatic Aldehydes Oxidation via Cleavage
of their Hydrazones Catalyzed by Trimethylsilanolate
Kristyna Burglova,[a]# Sergei Okorochenkov,[b]# Milos Budesinsky,[c] and Jan Hlavac*[a]
double bonds, which can be oxidized by oxone to epoxides,20 or
Abstract: Hydrazones derived from various aromatic aldehydes
thioethers, which can be transformed to sulfoxides or sulfones.
The oxidation of aldehydes by periodic acid requires a small
amount of pyridinium chlorochromate21 as the metal co-oxidizer,
and this reaction is not selective to primary alcohols, which also
undergo oxidation.
bound to Rink resin and hydrazines were studied under treatment
with trimethylsilanolate. In this process, oxidation of aldehydes to
corresponding carboxylic acids occurred. The reaction was tested
with success also in solution, where various aromatic aldehydes
were easily oxidized via one-pot hydrazone formation and
Oxidation using sodium perborate22 has been reported for the
oxidation of aldehydes to carboxylic acids as well as for the
oxidation of iodoarenes to (diacetoxyiodo)arenes, azines to their
N-oxides and sulfur heterocycles to their corresponding S,S-
dioxides,22, 23 which limits the selectivity to the presence of these
functionalities.
trimethylsilanolate treatment.
A
reaction mechanism for the
hydrazone cleavage is proposed. The reaction can be used as the
alternative method for aldehydes oxidation with the selectivity
complementary to currently used reactions.
An indirect approach for aldehyde oxidation involves their
transformation to hydrazones with subsequent oxidation by tert-
butyl hydroperoxide in the presence of silica-supported
seleneamide.24 However, this procedure is technically
complicated and not specific for some hydrazones where a
mixture of nitrile and carboxylic acid is formed.
Oxidation of hydrazones attached to a solid support has been
previously reported25 using hydrogen peroxide in the presence
of 10% trifluoroacetic acid (TFA) to afford carboxylic acid directly
cleaved from the solid support in yields of 22-40% after
purification. Beside the previously mentioned complications
caused by the presence of peroxides, no further transformation
to the resulting carboxylic acid on the solid support is possible
because of simultaneous cleavage.
Introduction
Oxidation of aldehydes to carboxylic acids belongs to the widely
used synthetic methods. Although number of procedures was
developed, each of them suffers from a limitation preventing
them from their application to concrete substrate.
The direct transformation of aldehydes to carboxylic acids
typically involves metallic oxidizers such as traditional silver(I)
and copper(II) ions or potassium permanganate.1-3 These
oxidations can cause difficulties due to complexation of the
substrate, precipitation of silver in the reaction mixture or trace
amounts of toxic ions remaining in the final substrate.
Aldehyde oxidation using hydrogen peroxide has been
extensively studied as a method in which the presence of a
metal catalyst (e.g. complicated complexes of tungsten4 or
The aforementioned limitations of the currently employed
oxidizers indicate the need for the development of new
procedures with mild conditions for oxidizing aldehydes to
carboxylic acids with better or complementary selectivity and for
enriching the arsenal of synthetic organic chemistry.
molybdenum5)
or
strong
non-selective
oxidizer
(i.e.
benzeneseleninic acid6) is necessary. Recently reported
7
8
additives (e.g. V2O5 or VO(acac)2 ) suffer from poor selectivity
(e.g. oxidation of thioethers to corresponding sulfoxides9-11). In
the presence of the methyltrioxorhenium catalyst,12 this oxidation
is performed in an ionic liquid. Although non-metallic oxidation
with hydrogen peroxide has been previously described,13 the
presence of hydrogen peroxide typically limits the utility of the
reaction for substrates bearing a thiol group that can be oxidized
to a disulfide14, 15 or an electron-deficient double bond, which can
undergo epoxidation.16
Results and Discussion
In our previous study,26 we described the utility of solid-
supported hydrazones as novel traceless linkers for solid-
phase chemistry. The system was composed of a BAL linker
bound directly to the aminomethylene resin, and various
aromatic compounds were released from the support after
cleavage of the C-N single bond by trimethylsilanolate
(TMSOK) (see Scheme 1).
The non-metallic oxidation of aldehydes with oxone, as
described by Baumstark et al.,17 Webb and Ruszkay18 and
Travis et al.,19 suffers from poor selectivity in the presence of
[a]
[b]
Institute of Molecular and Translation Medicine, Faculty of Medicine
Palacký University
Hněvotínská 5, 779 00 Olomouc, Czech Republic
Department of Organic Chemistry, Faculty of Science
Palacký University
17. Listopadu 12, 771 46 Olomouc, Czech Republic
*jan.hlavac@upol.cz; www.orgchem.upol.cz
Institute of Organic Chemistry and Biochemistry AS CR
Flemingovo nám. 2, 166 10 Praha 6, Czech Republic
Scheme 1. Principle of hydrazone traceless linker for solid-
supported synthesis.
[c]
#These authors contributed equally
The mechanism of cleavage was not elucidated, and the
transformation of the hydrazone imino group was not
clarified. To investigate the hydrazone transformation, we
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201601238
FULL PAPER
prepared hydrazones 3a-f derived from variously substituted
analogue 3g does not convert to carboxylic acid at all (see
Scheme 3).
benzaldehydes
1a-f
bound
to
Rink
resin
and
phenylhydrazine 2 (Scheme 2). Cleavage with TMSOK
releases benzene26 and the following cleavage of the
remaining part of substrate from Rink linker by TFA should
release the rest of molecule after TMSOK treatment
(Scheme 2).
Scheme 3. Comparison of reaction of N-(un)substituted hydrazones.
Table 1. Hydrazone cleavage on Rink resin with corresponding yields.
Substitution
Purity of 3 (%)
Conversion of 3 (%)[a]
Yield of 4 (%)[b]
a
b
c
d
e
f
95
99
99
98
96
90
100
58
[d]
[d]
[c]
[c]
100
47
100
46
[d]
[d]
[a]Hydrazone purity and conversion were determined by
LC/MS analysis with PDA detection. [b]Yield was determined
after cleavage and HPLC purification via 1H NMR using
isopropanol as an internal standard. [c]Hydrazone remains
unaffected. [d]Reaction affords a complicated mixture.
Substitution
a
R
To better elucidate the scope and limitations of the reaction
and study the reaction mechanism, we verified the reactivity
of the hydrazones under solution-phase conditions, where
aldehydes with various electronic properties are easily
accessible. The studied aldehydes are summarized in
Scheme 4.
b
c
d
e
f
Scheme 2. General reaction of aldehyde oxidation on solid
support.
We found out, that the hydrazones 3a, 3d and 3e were
oxidized to corresponding carboxylic acids 4a, 4d and 4e
according to Scheme 2 with moderate yields (see Table 1).
Hydrazones 3b and 3c derived from benzaldehyde
immobilized through lower number of atoms than their
analogues 3a, 3d, 3e did not react or afforded complicated
mixture. Hydrazone 3f with strong electron donation did not
react as well. From these experiments we can deduce, that
the hydrazones are possible to easily oxidize to carboxylic
acids on solid support, but the reaction is limited by type of
benzaldehyde substitution and its distance from the surface.
The reaction is also limited to only N-unsubstituted
hydrazones. Contrary to hydrazone 3a, N-methylated
Scheme 4. One-pot oxidation of aldehydes to carboxylic
acids in solution.
The hydrazones 6a-j were formed by reaction with
phenylhydrazine in THF solution. The identity and purity of
the hydrazones were confirmed by LC/MS and immediately,
without isolation, subjected to cleavage with TMSOK
(Scheme 4). The reactivity of various hydrazones was
characterized by yields determined by 1H NMR related to
pure hydrazones. The results are summarized in Table 2.
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European Journal of Organic Chemistry
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Table 2. One-pot transformation of aldehydes to
carboxylates.
Substitution
Purity of 6[a]
Yield of 7[b] (%)
a
b
c
d
e
f
99
96
94
80
96
63
95
63
95
97
83
63
57
43
60
48
81
95
87
82
g
h
i
Figure 1. Conversion of the hydrazone 6j during the
treatment with TMSOK in DMSO (A) under N2 atmosphere;
(B) opened to atmosphere without bubbling; (C) with
bubbling of air.
j
[a]Purity was determined by LC/MS analysis with PDA
detection. [b]Yield was determined via 1H NMR using
isopropanol as an internal standard and is related to the
reaction of pure hydrazone 6(R).
Then, we performed the oxidation of hydrazone 6j in THF in
presence of different bases, namely KOH and MeONa. The
treatment with KOH during 2 hours gave approximately 7%
of carboxylate 7j whereas reaction with MeONa remained
hydrazone 6j almost unaffected. After 12 hours treatment of
6j with KOH or MeONa respectively, the formation of
carboxylate 7j was accompanied with number of impurities.
Thus, for selective conversion of hydrazone to carboxylate,
presence of TMSOK and air oxygen are mandatory.
The results obtained indicate that the oxidation of aldehydes via
hydrazones formation is simple one-pot method affording the
carboxylates from acceptable to excellent yields. The yields
were lower in the cases of electron-withdrawing aldehydes,
whereas p-hydroxybenzoate 7h was formed almost quantitavely.
Good reactivity of substrate 5e can be explained by formation of
carboxylate under the reaction conditions. The reactivity of
aliphatic
aldehydes
(acetaldehyde,
propionaldehyde,
Finally, we monitored the conversion of hydrazone 6j in time
with use of LC/MS (Figure 2). After 5 minutes we have
already observed formation of the first intermediate I1, which
is quantitavely formed after 15 min.
cyclohexylcarbaldehyde and isobutyraldehyde) was not proved.
The mainly decomposition was observed in each case.
Mechanism studies: For the purpose of mechanism study, we
prepared derivative 6j as the model hydrazone and compared its
reactivity under the inert atmosphere, standard presence of air
and under bubbling the reaction mixture with air. We changed
solvent from THF to DMSO to avoid complications with THF
evaporation during bubbling and to exclude presence of
peroxides in solvent. We found out, that the presence of air is
necessary for successful oxidation to carboxylate 7j and
moreover the bubbling of air accelerates the reaction (Figure 1).
From these results it is evident, that the rate of hydrazone
conversion to carboxylate depends on amount of oxygen
dissolved in reaction mixture.
Figure 2. Study of hydrazone 6j conversion. Formation of
intermediates I1 and I2.
HRMS data of this intermediate gave molecular formula
1
C36H38N4O9. H and 13C NMR spectra have shown two sets
of signals in aliphatic and aromatic parts corresponding to
non-symmetrical dimer. According to advanced 1D and 2D
NMR experiments the structure of I1 was determined (Figure
3).
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European Journal of Organic Chemistry
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FULL PAPER
structure is deduced from the LC/HRMS data. According to
higher polarity of I2 in comparison to I1 and molar weight
580.2130 g/mol corresponding to molecular formula
C30H32N2O10, we suggest the structure to be diacylated
hydrazine (Figure 3).
Based on the above-mentioned observation, we propose a
plausible mechanism for the reaction.
The first step (Scheme 5) involves formation of peroxide B,
what is process already described in literature.27 Peroxide B
then decomposes to compound C possibly via radical
cleavage and recombination. In the next step anion D formed
by deprotonation of starting hydrazine A attacks compound
C giving anion E, which is finally stabilized by protonation to
form the intermediate I1.
Figure 3. Proposed structures of first and second
intermediates.
The connection of dimeric parts and structure of nitrogen
containing fragments was established mainly from NOE
contacts and J(N,H) coupling constants detected in 2D-N,H-
HMBC spectra as illustrated in Figure 4.
Scheme 5. Proposed mechanism for formation of
intermediate I1.
Intermediate I1 can undergo the same oxidation as hydrazine
A
with oxygen affording peroxide
F
(Scheme 6).
Intermediate F decomposes via releasing the hydroxyl
radical and radical G to form intermediate I2. Radical G is
finally stabilized to hydrocarbon in recombination with some
radical donor like e.g. TMSOH. The released OH∙ radicals
are able to recombine themselves giving hydrogen
peroxide28 able to attack formed intermediate I2.
Figure 4. Selected observed proton NOE contacts and
detected coupling constants J(N,H) used in the structure
determination of first intermediate I1. Proton and nitrogen
chemical shifts of participating atoms are shown.
Similar intermediate was observed when hydrazones 6a and
6i were monitored in the reaction with use of LC/MS. In both
these cases, intermediates with masses corresponding to
dimeric structures were observed. Formation of dimeric
intermediate during the reaction explains why hydrazones 6a
and 6i can be oxidized only in solution whereas the
immobilized analogues 3c and 3b did not undergo the
oxidation. The reason of non-reactivity of these immobilized
derivatives on solid support can be short distance between
two molecules to be able to cross-link and form the dimer.
When the reaction continues, the second intermediate, I2 is
formed by transformation of I1. This was observed not only
during the treatment of starting hydrazone 6j (see Figure 2
reaction after 30 min), but also when intermediate I1 was
separately treated with TMSOK. Unfortunately, I2 is not
stable enough to be isolated and fully characterized, thus the
Scheme 6. Proposed mechanism of intermediate I1
conversion to I2.
The mechanism of I2 conversion (Scheme 7) is supported by
very similar one described for luminol oxidation.29
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European Journal of Organic Chemistry
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FULL PAPER
gradient (from 95 to 40 % of acetonitrile) over the course of 2.5 min
and then maintains this concentration for 1.5 min. The column was
re-equilibrated at 10% B for 1 min. Method 3, mobile phase
consisted of (A) 0.01 M ammonium acetate in water and (B)
acetonitrile, with linearly programmed gradient (from 0 to 50 % of
acetonitrile) over the course of 3 min, then from 50% to 20% over
the course of 1.5 min, and then from 20 to 0% in 0.5 min. The
column was re-equilibrated at 100% A for 1 min. The APCI
ionization operated at a discharge current of 5 µA, vaporizer
temperature of 350 °C and capillary temperature of 200 °C. Purity of
compounds was determined as ratio of appropriate peak area to
sum of areas of all peaks of the mixture. Areas were determined by
integration of the peaks from PDA detector response. Purification
was performed using semipreparative HPLC with a Waters 1500
series HPLC equipped with an Autosampler 2707, a Binary HPLC
pump 1525, a Waters Photodiode Array Detector 2998 and a
Waters Fraction Collector III with a YMC C18 reverse phase
column, 20 × 100 mm, with 5 µm particles. The mobile phase
consisted of acetonitrile and a 10 mM aqueous ammonium acetate
gradient over 6 min. Flow rate was 15 ml/min. NMR spectra were
measured in DMSO-d6 using Jeol ECX-500 (500 MHz)
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm), and coupling constants (J) are reported in Hertz (Hz). HRMS
analysis was performed using an Orbitrap Elite high-resolution
mass spectrometer (Thermo Fischer Scientific, MA, USA) operating
at positive full scan mode (120 000 FWMH) in the range of 200–900
m/z. The settings for electrospray ionization were as follows: oven
temperature of 300 °C, sheath gas of 8 arb. units and source
voltage of 1.5 kV. The acquired data were internally calibrated with
diisooctyl phthalate as a contaminant in methanol (m/z 391.2843).
Samples were diluted to a final concentration of 20 µmol/l with 0.1%
formic acid in water and methanol (50:50, v/v). The samples were
injected by direct infusion into the mass spectrometer.
Hydroperoxide ion formed during I2 formation can attack
carbonyl group of I2 giving intermediate H, which undergoes
cyclization to J. Deprotonation of J leads to formation of
dianion K and its decomposition to diazene L and two
carboxylate anions 7j. Diazene L is finally spontaneously
decomposed to hydrocarbon according to previously
published mechanism.30
Scheme 7. Decomposition of intermediate I2 to final
carboxylate.
Conclusions
We studied the cleavage of hydrazones derived from aromatic
aldehydes and phenylhydrazine using trimethylsilanolate. The
treatment with TMSOK in presence of air oxygen transforms the
imine group of hydrazone to a carboxylic acid. The reaction
properly works for aromatic aldehydes, while aliphatic ones are
decomposed. The yields of the reaction vary from moderate to
very good, and the formation of volatile benzene simplifies
product isolation. The reaction proceeds well especially in
solution while for polymer supported substrates the reactivity is
limited. The oxidation method is complementary to existing
methods of oxidation, which suffer from various drawbacks.
Although trimethylsilanolate cannot be used in the presence of
hydrolyzable groups such as esters, our new method overcomes
difficulties associated with e.g. metal oxidation or side effects
due to peroxide use and additional complications that have been
previously reported for alternative procedures. In conclusion,
the described method enables easy, one-pot oxidation of
aromatic aldehydes to carboxylic acids via simple formation of
phenylhydrazone.
Analysis of compounds immobilized on solid support.
Analytical sample of resin (~5 mg) was treated with 50% TFA in
dichloromethane (DCM) for 30 min at room temperature, the
cleavage cocktail was evaporated by a stream of nitrogen, and
cleaved compound extracted into 1 mL of MeOH and analyzed on
LC/MS.
General procedure for preparation of Resins 1a-d and 1f.
Rink resin (0.6 mmol/g, 100-200 mesh, 250 mg) was stirred for 20 min in
50% piperidine in DCM, washed with DMF (5×4 mL) and DCM (3×4 mL)
(duration of washing 2 min). Subsequently, solution of carboxylic group
containing aldehyde (1.5 mmol), DIC (1.5 mmol, 234 µL) and HOBt (1.5
mmol, 230 mg) in DMF (3 mL) was added. Slurry was stirred 16 h at
room temperature. Then, resin was washed with DMF (5×4 mL), DCM
(3×4 mL) and methanol (3×4 mL) and dried under nitrogen.
General Procedure for Hydrazone Synthesis on Rink Resin – resins
3a-f
Resin 1a-f (250 mg) was swelled in DMF. Subsequently, solution of
phenylhydrazine 2 (1.5 mmol) in mixture of DMF and DMSO (3 mL, 1:1
v/v) was added to the resin. Slurry was shaken for 3 h at room
temperature. Then, resin was washed with DMF (5×4 mL) and DCM (3×4
mL).
Experimental Section
General Experimental Methods. LC/MS analyses were performed
using UHPLC/MS with an UHPLC chromatograph Acquity with PDA
detector and a single quadrupole mass spectrometer (Waters) with
an X-Select C18 column at 30 °C and a flow rate of 600 µl/min. The
following methods were used for compound analysis: Method 1,
mobile phase consisted of (A) 0.01 M ammonium acetate in water
and (B) acetonitrile, with linearly programmed gradient (from 95 to
40 % of acetonitrile) over the course of 2.5 min and then maintains
this concentration for 1.5 min. The column was re-equilibrated at
10% B for 1 min. Method 2, mobile phase consisted of (A) 0.01 M
formic acid in water and (B) acetonitrile, with linearly programmed
General Procedure for Hydrazone Cleavage from Rink Resin
derivatives 4a, 4d, 4e.
–
The resin with immobilized hydrazone 3a, 3d, 3e (250 mg) was swelled in
DCM. Solution of TMSOK (1.5 mmol, 192 mg) in THF (3 mL) was added.
Slurry was stirred for 1 h at room temperature. Then, resin was washed
with DMF (5×4 mL) and DCM (3×4 mL) and the formed acid was cleaved
by TFA cleavage cocktail to give desired compound 4. The cleavage
cocktail was evaporated and the residue was purified with HPLC. The
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European Journal of Organic Chemistry
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FULL PAPER
formed product was quantified by 1H NMR using isopropanol as an
internal standard.
General Procedure for Preparation of Hydrazones in Solution and
the Subsequent Oxidation by TMSOK –derivatives 7a-j.
Aldehyde 5a-j (0.5 mmol) was dissolved in THF (4 mL) and
phenylhydrazine (0.5 mmol) was added. The solution was stirred for 30
minutes at room temperature. The purity of formed hydrazone 6a-j in the
reaction mixture was checked by LC/MS without its isolation (See SI).
Then, TMSOK (2 mmol) was added and the mixture was stirred 16 h at
room temperature. The solvent was evaporated and the residue
dissolved in D2O to quantify the yield of derivative 7a-j in crude mixture
by 1H NMR with isopropanol as an inner standard. See LC/MS data in SI.
Resin 1e
1H, COOH), 10.14 (s, 1H, NH), 8.10 (s, 1H, N=CH), 7.75 (d, J = 8.5 Hz,
1H, ArH), 7.18 (m, 2H, 2xArH), 6.99 (m, 2H, 2xArH), 6.69 (m, 1H, ArH),
6.59 (d, J = 2.3 Hz, 1H, ArH), 6.57 (dd, J1 = 8.5, J2 = 2.3 Hz, 1H, ArH),
4.02 (t, J = 6.5 Hz, 2H), 3.83 (s, 3H, OCH3), 2.40 (t, J = 7.0 Hz, 2H), 1.95
(m, 2H). 13C NMR (150.9 MHz, DMSO-d6, ppm) δ: 174.3, 160.1, 157.8,
145.8, 132.6, 129.2, 125.7, 118.3, 116.9, 111.9, 106.8, 98.9, 66.9, 55.8,
30.3 24.42. HRMS (ESI) calcd for [M+H]+ C18H21N2O4 329.1496; found:
329.1495.
7i. The compound was isolated by HPLC as white powder in the yield
40%. HPLC separation: acetonitrile gradient 5% to 10% in CH3COONH4
buffer, detection at 240 nm, tR = 3.60 min. LC/MS analysis: MS (ESI)
exact mass calcd. for C10H10O5[M-H]-: 209.05; found: 209.03, tR = 1.06
1
min, purity: 98% (method 2). H NMR (500 MHz, DMSO-d6, ppm) δ:7.92
i. Rink resin (0.6 mmol/g, 100-200 mesh, 250 mg) was stirred for 20 min
in 50% piperidine in DCM, washed with DMF (5×4 mL) and DCM (3×4
mL) (duration of washing 2 min). Subsequently, solution of L-4-(Fmoc-
amino)butyric acid (1.5 mmol, 488 mg), N,N′-Diisopropylcarbodiimide
(DIC) (1.5 mmol, 234 µL) and HOBt (1.5 mmol, 230 mg) in DMF (3 mL)
was added. Slurry was stirred 16 h at room temperature. Then, resin was
washed with DMF (5×4 mL) and DCM (3×4 mL). Yellow color. LC/MS
analysis: MS (ESI) exact mass calcd. for C19H20N2O3 [M+H]+: 325.15;
found: 325.09, tR = 2.71 min, purity: 98% (method 1).
– 7.84 (m, 2H), 7.04 – 6.97 (m, 2H), 4.23 (t, J = 6.0 Hz, 2H), 2.71 (t, J =
6.0 Hz, 2H). 13C NMR (125 MHz, DMSO-d6, ppm) δ: 172.2, 167.1, 162.0,
131.4, 123.2, 114.3, 64.0, 34.0. HRMS (ESI) calcd for [M-H]-
C10H10O5 209.0444; found: 209.0441.
7j. The compound was isolated by HPLC as white powder in the yield
42%. HPLC separation: isocratic elution 5% acetonitrile in CH3COONH4
buffer, detection at 250 and 284 nm, tR = 2.85 min. LC/MS analysis: MS
(ESI) exact mass calcd. for C12H14O6 [M-H]-: 253.08; found: 253.14, tR
=
2.53 min, purity: 98% (method 2). 1H NMR (600 MHz, DMSO-d6, ppm) δ:
12.15 (br, 2H), 7.68 (d, J = 8.7 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 6.55 (dd,
J1 = 8.7, J2 = 2.3 Hz, 1H), 4.05 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 2.39 (t, J
= 7.3 Hz, 2H), 1.95 (m, 2H). 13C NMR (150.9 MHz, DMSO-d6, ppm) δ:
174.3, 166.6, 163.1, 160.8, 133.5, 112.8, 105.7, 99.5, 67.1, 55.9, 30.2,
24.3. HRMS (ESI) calcd for [M+H]+ C12H15O6 255.0863; found: 255.0864.
Intermediate I1. To hydrazone 6j (500 mg, 1.51 mmol) dissolved in
DMSO (10 ml) was added TMSOK (1300 mg, 10.1 mmol). Solution was
stirred at room temperature opened to atmosphere. Aliquots (20 uL) were
taken during the reaction time, immediately quenched with 980 uL of 1%
AcOH in methanol and analyzed by LC-MS. According to LC-MS data,
hydrazone conversion to Intermediate 1 was completed in 70 min.
Reaction was quenched with acetic acid (577 uL, 10.1 mmol), and
poured to ethyl acetate (70 mL), extracted with water (3×50 mL) and
brine (3×50 mL). Organic phase was dried by magnesium sulfate, filtered,
and solvent was removed in vacuo. Desired compound was purified by
flash column chromatography using mixture dichloromethane:isopropanol
12:1 to 10:1 as eluent. Yellowish powder. Yield 170 mg (36%). LC/MS
analysis: MS (ESI) calcd. for C36H38N4O9 [M-H]-: 669.72; found: 669.70,
tR = 2.00 min, purity: 100% (method 1). 1H NMR (600 MHz, DMSO-d6,
ppm) δ: 11.69 (br, 2H, 2xCOOH), 9.99 (s, 1H, NH), 9.90 (s, 1H, NH),
8.03 (d, J = 8.8 Hz, 1H, ArH), 7.66 (d, J = 8.6 Hz, 1H, ArH), 7.22 (m, 2H,
2xArH), 7.14 (m, 2H, 2xArH), 7.00 (m, 2H, 2xArH), 6.82 (m, 1H, ArH),
6.80 (d, J = 2.3 Hz, 1H, ArH), 6.76 (m, 1H, ArH), 6.74 (dd, J1 = 8.8, J2 =
2.3 Hz, 1H, ArH), 6.71 (m, 2H, 2xArH), 6.62 (dd, J1 = 8.6, J2 = 2.3 Hz, 1H,
ArH), 6.48 (d, J = 2.3 Hz, 1H, ArH), 4.11 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H,
OCH3), 3.99 (t, J = 6.4 Hz, 2H), 3.67 (s, 3H, OCH3), 2.40 (t, J = 7.2 Hz,
2H), 2.37 (t, J = 7.2 Hz, 2H), 1.97 (m, 2H), 1.92 (m, 2H). 13C NMR (150.9
MHz, DMSO-d6, ppm) δ: 174.30; 174.26; 165.73; 163.66; 160.63;
159.55; 157.32; 144.86; 144.53; 136.09; 133.52; 132.21; 129.45(2xC);
128.76(2xC); 120.94; 119.42; 115.16; 114.37(2xC); 112.26(2xC); 111.5,
107.3, 106.8, 99.6, 99.2, 67.4, 67.0, 56.9, 56.3, 30.3, 30.2, 24.4, 24.2.
HRMS (ESI) calcd for [M+H]+ C36H38N4O9 671.2708; found 671.2712.
ii. Resin obtained in step (i) was stirred for 20 min in 50% piperidine in
DCM, washed with DMF (5×4 mL) and DCM (3×4 mL) (duration of
washing 2 min). Subsequently, solution of 4-formylbenzoic acid (1.5
mmol, 225 mg), DIC (1.5 mmol, 234 µL) and HOBt (1.5 mmol, 230 mg) in
DMF (3 mL) was added. Slurry was stirred 16 h at room temperature.
Then, resin was washed with DMF (5×4 mL), DCM (3×4 mL) and
methanol (3×4 mL) and dried under nitrogen. LC/MS analysis: MS (ESI)
exact mass calcd. for C12H14N2O3 [M+H]+: 235.10; found: 235.11, tR
1.13 min, purity: 86% (method 1).
=
4a. HPLC separation: acetonitrile gradient 5% to 15% in CH3COONH4
buffer, detection at 250 and 284 nm, tR = 3.50 min. Yield: 22 mg (58%).
LC/MS analysis: MS (ESI) exact mass calcd. for C12H15NO5: [M-H]-:
253.10; found: 253.00, tR = 2.52 min, purity: 98% (method 3). 1H NMR
(500 MHz, DMSO-d6, ppm) δ: 7.56 (d, 1H, J = 8.59 Hz), 7.34 (s, 1H),
6.77 (s, 1H), 6.50 (d, 1H, J = 2.29 Hz), 6.44 (dd, 1H, J1 = 8.59 Hz, J2 =
2.29 Hz), 3.97 (t, 2H, J = 6.87 Hz), 3.74 (s, 3H), 2.22 (t, 2H, J = 7.45 Hz),
1.91 (p, 2H, J = 6.87 Hz). 13C NMR (125 MHz, DMSO-d6, ppm) δ: 173.7,
169.8, 160.9, 159.3, 132.2, 118.9, 104.9, 99.2, 67.0, 55.6, 31.3, 24.6.
HRMS (ESI) calcd for [M+H]+ C12H16NO5 254.1028; found: 254.1023.
4d. White powder. HPLC separation: acetonitrile gradient 5% to 15% in
CH3COONH4 buffer, detection at 250 nm, tR = 4.50 min. Yield: 16 mg
(47%). LC/MS analysis: MS (ESI) exact mass calcd. for C11H13NO4 [M-
H]-: 222.08; found: 221.94, tR = 2.46 min (method 2), purity: 98%. 1H
NMR (500 MHz, DMSO-d6, ppm) δ: 7.92 – 7.83 (m, 2H), 7.31 (s, 1H),
7.03 – 6.95 (m, 2H), 6.77 (s, 1H), 4.03 (t, J = 6.5 Hz, 2H), 2.22 (t, J = 7.4
Hz, 2H), 1.93 (dt, J1 = 12.7 Hz, J2 = 6.2 Hz, 2H). 13C NMR (125 MHz,
DMSO-d6, ppm) δ: 173.6, 167.1, 162.1, 131.3, 123.1, 114.2, 67.3, 31.2,
24.5. HRMS (ESI) calcd for [M-H]- C11H13NO4 671.2708; found 671.2712.
4e. White powder. HPLC separation: isocratic elution 5% acetonitrile in
CH3COONH4 buffer, detection at 243 nm, tR = 3.10 min. Yield: 17 mg
(46%). LC/MS analysis: MS (ESI) exact mass calcd. for C12H14N2O4 [M-
H]-: 249.09; found: 249.11, tR = 2.33 min, purity: 98% (method 3). 1H
NMR (500 MHz, DMSO-d6, ppm) δ: 8.54 (t, J = 5.5 Hz, 1H), 7.92 (d, J =
8.3 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 6.71 (s, 1H), 3.22 (dd,
J1 = 12.7, J2 = 6.8 Hz, 2H), 2.08 (t, J = 7.5 Hz, 2H), 1.71 (p, J = 7.3 Hz,
2H). 13C NMR (125 MHz, DMSO-d6, ppm) δ: 174.1, 168.0, 165.9, 137.6,
136.7, 128.9, 126.8, 40.0, 32.7, 25.1. HRMS (ESI) calcd for [M+H]+
C12H14N2O4 251.1026; found 251.1027.
Acknowledgements
This research project was supported by the Ministry of
Education, Youth and Sport of the Czech Republic (project
IGA_PrF_2016_020) and by the European Social Fund
(CZ.1.07/2.3.00/20.0009). The infrastructure of this project
6j. Yellow powder. Purification by flash column chromatography on silica
gel with dichloromethane-isopropylalcohol (12:10) as the eluent. Yield:
170 mg (36%). LC/MS analysis: MS (ESI) exact mass calcd. for
C18H20N2O4 [M-H]-: 327.14; found: 327.11, tR = 2.05 min (method 3),
purity: 99%. (method 1). 1H NMR (600 MHz, DMSO-d6, ppm) δ: 12.20 (br,
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European Journal of Organic Chemistry
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(Institute of Molecular and Translation Medicine) was supported
by the National Program of Sustainability (project LO1304).
Keywords: Aldehyde • Oxidation • Trimethylsilanolate • Solid-
phase Synthesis
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European Journal of Organic Chemistry
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Aromatic aldehydes oxidation
Kristyna Burglova,Sergei Okorochenkov,
Milos Budesinsky and Jan Hlavac*
Page No. – Page No.
Efficient Method of Aromatic
Aldehydes Oxidation via Cleavage of
their Hydrazones Catalyzed by
Trimethylsilanolate
Aromatic aldehydes can be efficiently oxidized to corresponding carboxylic acids.
The protocol involves two reaction steps in one pot. Firstly, an aldehyde is
transformed to hydrazone by reaction with phenylhydrazine, which is subsequently
treated with trimethylsilanolate yielding carboxylic acid. The oxidation can be
performed both in solution and on solid support.
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European Journal of Organic Chemistry
10.1002/ejoc.201601238
FULL PAPER
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601238
FULL PAPER
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601238
FULL PAPER
This article is protected by copyright. All rights reserved