New (green) methodology for efficient hydrazine cleavage

Article abstract of DOI:10.1039/c6ob00737f

An efficient method for removal of the hydrazine group from (hetero)aromatic substrates has been developed. It can be realized both on a solid support and in solution by synthesis employing a low concentration solution of trimethylsilanolate in tetrahydrofuran or N,N-dimethylformamide. For water-soluble substrates, the reaction can be performed in water, highlighting the eco-friendly attributes of this methodology.

Full text of DOI:10.1039/c6ob00737f

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New (green) methodology for efficient hydrazine
cleavage†
Cite this: DOI: 10.1039/c6ob00737f
Lenka Kubovičová,a Kristýna Bürglováb and Jan Hlaváč*a
An efficient method for removal of the hydrazine group from (hetero)aromatic substrates has been deve-
loped. It can be realized both on a solid support and in solution by synthesis employing a low concen-
tration solution of trimethylsilanolate in tetrahydrofuran or N,N-dimethylformamide. For water-soluble
substrates, the reaction can be performed in water, highlighting the eco-friendly attributes of this
methodology.
Received 7th April 2016,
Accepted 26th April 2016
DOI: 10.1039/c6ob00737f
www.rsc.org/obc
Hydrazine chemistry is a part of important areas in organic
The other oxidative dehydrazination reaction free of metal
synthesis.1 Monosubstituted hydrazines are frequently used ions described by Wobus et al.10 is based on dehydrogenation
intermediates in many synthetic applications, including reac- of the hydrazino group to form diazene, followed by spon-
tions with carbonyl compounds to produce hydrazones,2 taneous loss of nitrogen. This reaction is limited to π-deficient
preparation of indoles by Fisher Indol synthesis,3 synthesis of (hetero)aromatic systems such as derivatives of pyridazine.
aminopyrroles4 and many others.2,5 Although hydrazine syn- Finally hydrazines able to undergo tautomery can be cleaved
thesis is well described,6 including the chiral species,7–9 only via Wolff–Kishner reduction in strong alkaline solutions. The
few methodologies have been reported for dehydrazination reaction is limited to heteroaromatic systems able to form
reactions, which can be advantageously used for indirect hydrazones.18
removal of halogens,10 removal of hydrazine as a protective
All of these above-mentioned reactions either require oxi-
group in synthetic pathways10 or labelling of compounds with dizing agents causing potential side reactions or implement-
deuterium.11
ing toxicity or they are limited to electron-poor substrates.
To the best of our knowledge, the published dehydrazina-
Herein, we report a very fast and efficient methodology for
tion protocols are mostly based on facile oxidation of hydra- dehydrazination of (hetero)aromatic substrates occurring
zines. The oxidizing agents are typically metallic oxides, very under mild conditions. This protocol can be applied in solu-
often silver oxide12 or HgO,13 which cause complications due tion as well as in solid phase organic synthesis (SPOS), which
to the toxicity of the traces of mercury ions remaining in the is not limited only to a laboratory scale but can also be applied
synthesized product or the precipitation of metallic silver as in commercial drug production.19
well as its salts derived from the treated compounds. Dehydra-
During our study on the saponification reaction of immobi-
zination by aqueous copper sulphate was also described.14,15 lized ester 1a using potassium trimethylsilanolate (TMSOK) in
In this reaction, the principles of green chemistry are THF, we observed not only hydrolysis of the methyl ester group
respected, employing a catalytic amount of copper sulphate in but also removal of the hydrazine moiety as well (Scheme 1).
water11 or employing microwave irradiation on supported
Realizing the potential application of this result, we
copper sulphate.16 The disadvantage of this method is the decided to study this unusual hydrazine cleavage in detail. For
possible complexation of a substrate by copper ions. this purpose, we prepared a series of immobilized aromatic
A reaction with nitric oxide in the presence of oxygen in and heteroaromatic hydrazines. Their synthesis employed
tetrahydrofuran (THF) belongs to the methods that avoid the either immobilization of commercially available hydrazines or
use of metal ions for removal of hydrazine, but this reaction their direct preparation on a solid support by nucleophilic sub-
results in the subsequent formation of azides as co-products.17 stitution from the corresponding fluoro derivatives (for details
aDepartment of Organic Chemistry, Faculty of Science, Palacký University,
771 46 Olomouc, Czech Republic
bInstitute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry,
Hněvotínská 5, 779 00 Olomouc, Czech Republic. E-mail: hlavac@orgchem.upol.cz
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, NMR spectra. See DOI: 10.1039/c6ob00737f
Scheme 1 Dehydrazination reaction under saponification conditions.
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see the ESI†). Widely used aminomethylene polystyrene with a
Rink linker was used as the solid support. For better monitor-
ing of the products by LC/MS, a dipeptide linker (β-Ala-Phe)
was introduced before the arylhydrazine moiety.
Table 2 Optimization of the reaction conditions for derivative 1i using
different bases in THF
Entry
Base
t (h)
c (mmol)
Conversiona (%)
1
2
3
4
5
6
7
8
NaOH
NaOH
LiOH
LiOH
t-BuONa
t-BuONa
MeONa
MeONa
DBU
0.5
1.5
0.5
1.5
0.5
1.5
0.5
1.5
0.5
1.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
500.0
500.0
500.0
500.0
500.0
500.0
500.0
500.0
500.0
500.0
200.0
100.0
50.0
27
70
34
62
27
70
9
62
36
82
74
69
76
57
100
100
88
38
The hydrazine derivatives selected to be studied in the reac-
tion were monosubstituted arylhydrazines and arylhydrazines
protected by using Fmoc, mesyl (Ms) and acetyl groups.
The reaction was carried out in THF, where TMSOK was dis-
solved at a concentration of 0.2 mol l−1. The reaction time was
optimized to 30 min at room temperature (RT).
The results of the complete four step synthesis of derivative
2 are summarized in Table 1. The products were isolated by
HPLC purification directly after the reaction, and yields were
calculated compared to the initial loading of the resin. The
methylester group of compounds 1a, 1c and 1d were hydro-
lysed and isolated as carboxylic acid 2a.
9
10
11
12
13
14
15
16
17
18
DBU
TMSOK
TMSOK
TMSOK
TMSOK
TMSOK
TMSOK
TMSOK
TMSOK
25.0
12.5
6.2
3.1
These results clearly demonstrate that the monosubstituted
(hetero)aromatic hydrazines easily undergo hydrazine cleavage
under treatment with TMSOK.
1.6
a Conversion was determined by HPLC with PDA detection.
Obviously, once the (hetero)aromatic hydrazine is pro-
tected, the dehydrazination does not work properly. No conver-
sion during the treatment with TMSOK was observed in the
case of Fmoc protected derivatives 1b, 1f and partially 1j,
where also the products of decomposition were observed.
Although dehydrazination was observed in the case of mesyl-
protected hydrazines 1c and 1k, the yields were low because of
the formation of a number of side products. In the case of
compound 1g no study of the cleavage was performed because
it was possible to prepare the starting material only with very
low purity. Surprisingly, when the hydrazine is substituted
with an acetyl group, the removal of this moiety proceeds with
good conversion as is shown in the case of derivatives 1h and
1l. The low reactivity of Fmocylated hydrazines can be advanta-
geously used for selective protection of the hydrazine group
against trimethylsilanolate treatment. If hydrazine removal is
intended, no protection is necessary. However, if we want to
preserve the hydrazine, e.g., during ester hydrolysis mediated
by using TMSOK, we can avoid the cleavage by facile Fmoc
protection.
We were also interested in knowing whether TMSOK is the
specific base responsible for the cleavage or if it could be
replaced by another base. We therefore selected one model
compound 1i and extended the study to a wider range of
bases, replacing TMSOK with sodium hydroxide (NaOH),
lithium hydroxide (LiOH), sodium tert-butoxide (t-BuONa),
sodium methoxide (MeONa) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (Table 2). At the same time, the influence of the
TMSOK concentration on reactivity was studied as well. The
reactions were monitored by LC/MS.
The results indicate that hydrazine can be cleaved from the
aromatic compound by treatment with different bases.
However, in many cases the remaining starting material
decreases the conversion. The best results, requiring the short-
est reaction times as well as providing the highest product
purities, are achieved using TMSOK.
Table 1 Synthesis of derivatives 2 via dehydrazination of compounds 1
1
R1
R2
2
Yield of 2 a (%)
It is worth highlighting the TMSOK concentration necessary
for successful performance of the reaction. The reaction still
proceeds satisfactorily with a concentration as low as 3 mM
(Fig. 1).
1a
1b
1c
1d
1e
1f
1g
1h
1i
-H
-Fmoc
-Ms
-COMe
-H
-Fmoc
-Ms
-COMe
-H
-Fmoc
-Ms
2a
2a
2a
2a
2e
2e
2e
2e
2i
20b
c
16b
19b
53
c
As solid-phase synthesis is not always applicable in organic
synthesis, we examined the possibility of hydrazine cleavage in
solution as well. Twelve simple (hetero)aromatic hydrazines
were chosen as model substrates, including both electron-
donating as well as electron-withdrawing substituents
(Table 3) in various positions of the aromatic ring, and they
were treated with 0.15 M solution of TMSOK in N,N-dimethyl-
formamide-d7 (d7-DMF). d7-DMF was chosen due to its better
solubilization of the selected substrates and a possibility of
d
54
58
c
1j
1k
1l
2i
2i
2i
17
57
-COMe
a Overall yield determined by 1H NMR spectroscopy after HPLC purifi-
cation and calculated to initial loading of the resin. b Product was iso-
lated as a carboxylic acid. c Product was not observed. d Reaction was
not studied because the preparation of 1g proceeded with very low
purity.
1
direct yield determination using H NMR by comparison with
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Table 4 Hydrazine cleavage in solution with the corresponding yields
in water
Fig. 1 Optimization of the TMSOK concentration for reaction of 1i.
*Conversion was determined by HPLC with PDA detection.
Table 3 Hydrazine cleavage in solution with the corresponding yields
in d7-DMF
Entry Compound 5 Yield of 6 a (%) Yield of 6 at 70 °C, 48 h a (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
3k
99
64
77
81
71
90
98
40
49
—
—
—
—
—
—
—
89
45
a Yield determined by 1H NMR spectroscopy.
Compound 3
Yield of 4 a (%)
Yield of 4 at 70 °C, 48 h a (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
95
35
SM
89
81
55
85
90
—
—
70
51
—
—
—
—
—
—
50
97
substrates 5a–h and hydrazine 3k and examined their reactivity
under the treatment of 0.15 M solution of TMSOK in water
(Table 4). For most substrates the dehydrazination works quan-
titatively within 48 hours in all cases with excellent yields. For
two substrates the temperature had to be increased to achieve
higher yields (Table 4).
Finally we tried to suggest a mechanism for hydrazine
group removal (Scheme 2).
3j
3k
3l
69
Insoluble
42
The reaction of unprotected arylhydrazine AH starts prob-
ably by dissociation of an acidic NH proton. The possibility of
conjugation in the system CH is the stimulation for oxidation
of intermediate BH with air. The air oxidation assistance was
proved by performing the experiment under an inert atmo-
sphere, where no reaction was observed. Decomposition of
diazene CH to hydrocarbon E via anion D is included in other
published mechanisms.11 A similar process can be expected
for acetylated hydrazine AAc, probably when the amide NH
proton is removed first. The analogous acetyl diazene CAc
formed by air oxidation can be then hydrolyzed by trimethyl-
silanolate to give intermediate D again, which is further stabil-
ized by a proton to the final hydrocarbon E. The bulky Fmoc
and strong electronegative mesyl group analogues of hydrazine
AAc are probably more resistant to proton removal and/or oxi-
dation because of steric hindrance and/or the increased elec-
tron withdrawing effect. The suggested mechanism is probably
involved also in cleavage of a hydrazone linker published
recently.22
a Yield determined by 1H NMR spectroscopy.
the residual solvent signal.20 The concentration of TMSOK was
optimized, and the best results were obtained when the con-
centration of TMSOK was 0.15 M. For four derivatives the
general reaction conditions afforded lower yield, therefore the
temperature was increased to 70 °C (Table 4).
The dehydrazination works very well for phenylhydrazine
and substrates with electron-donating groups. Lower yields
must be expected for substrates bearing electron-withdrawing
groups. The good conversion is exemplified by the change in
the NMR spectra as shown in Fig. 2 for derivative 3b (for other
crude NMR spectra see the ESI†).
Although THF and DMF are acceptable solvents from their
toxicity point of view,21 water is still the first choice for “green
chemistry”. We therefore selected another eight water-soluble
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Moreover, such a simple methodology works in solution as
well as on a solid support, and thus it is easily applicable in
industrial production of active pharmaceutical ingredients via
both methodologies, where SPOS is also established for com-
mercial production on a kilogram scale in addition to tra-
ditional solution-phase synthesis.18
Hydrazine removal can be avoided by using a suitable pro-
tecting group, and thus the removal of a hydrazine group can
be directed.
Acknowledgements
This research project was supported by the Ministry of Edu-
cation, Youth and Sports of the Czech Republic (project
IGA_PrF_2016_020) and by the European Social Fund (CZ.1.07/
2.3.00/30.0060 and CZ.1.07/2.3.00/20.0009). The infrastructure
of this project (Institute of Molecular and Translation Medi-
cine) was supported by the National Program of Sustainability
(project LO1304).
Notes and references
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Fig. 2 1H NMR spectra of starting tolylhydrazine 3b (upper spectrum)
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In conclusion, we introduced a new methodology for hydra-
zine cleavage from aromatic substrates. The reaction is wide in
scope and usually occurs at RT in acceptable reaction times.
The reaction requires only low concentrations of TMSOK in
THF or DMF frequently used in chemical research as well as
production. Significantly, for water-soluble substrates, the reac-
tion can be successfully performed even in water, which fully
respects “green chemistry” principles.
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