Solid-supported hydrazone of 4-(4′-Formyl-3′-methoxyphenoxy)butyric acid as a new traceless linker for solid-phase synthesis

Article abstract of DOI:10.1021/ol5034223

The use of a hydrazine derived from a backbone amide linker as a new hydrazone-based traceless linker for solid-phase organic synthesis is described. The stability of the linker was tested under various conditions, including treatment with acids, bases, and borohydrides. Final compounds can be released by selective cleavage using trimethylsilanolate. To demonstrate the versatility of the linker, the synthesis of a model compound under various reaction conditions was performed with good results.

Full text of DOI:10.1021/ol5034223

Letter
pubs.acs.org/OrgLett
Solid-Supported Hydrazone of 4‑(4′-Formyl-3′-
methoxyphenoxy)butyric Acid As a New Traceless Linker for
Solid‑Phase Synthesis
Sergei Okorochenkov,† Kristyna Burglova,‡ Igor Popa,‡ and Jan Hlavac*,†,‡
†Department of Organic Chemistry, Faculty of Science, Palacky University, 771 46 Olomouc, Czech Republic
́
‡Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnev
Olomouc, Czech Republic
̌
otínska
́
5, 779 00
́
S
* Supporting Information
ABSTRACT: The use of a hydrazine derived from a backbone amide linker as a new hydrazone-based traceless linker for solid-
phase organic synthesis is described. The stability of the linker was tested under various conditions, including treatment with
acids, bases, and borohydrides. Final compounds can be released by selective cleavage using trimethylsilanolate. To demonstrate
the versatility of the linker, the synthesis of a model compound under various reaction conditions was performed with good
results.
olid-phase organic synthesis (SPOS) has become an
important tool for the synthesis of chemical libraries over
hydrazones exist depending on the desired product. Reduction
with borohydride leads to alkane products, whereas basic
conditions afford alkenes. Thus, the use of this linker is
limited to reactions with borohydrides and alcoholates.
Several other traceless linkers, such as thioether,23
selenium,24−26 phosphorus,27and tin28 linkers, exist. However,
the use of these linkers is limited for reasons similar to those
described above.
Thus, SPOS still lacks easily accessible, traceless linkers with
sufficient resistance toward different reaction conditions with
the potential for straightforward cleavage at reaction sequence
completion.
In this report, we describe a new hydrazone linker that
exhibits high stability under both acidic and basic conditions,
even at high temperatures. Moreover, the presence of
borohydride in the reaction mixture does not affect the
structure of the linker. In addition, this linker can be easily
and specifically cleaved with the use of trimethylsilanolate.
Additionally, model reactions were performed to demon-
strate the versatility and potential applications of this
hydrazone system as a C−H traceless linker for SPOS.
Hydrazones were formed from their corresponding hydra-
zines, which had been easily prepared via already published
methods (see the Supporting Information) and used as crude
materials and a commercially available, commonly used
backbone amide linker (BAL, 4-(4′-formyl-3′-methoxy-
phenoxy)butyric acid)29,30 that was directly bound to the
common aminomethylene Merrifield resin. The model
S
the past 20 years.1−4
Numerous linkers that connect a solid support to a
compound of interest have been developed during this
period.5−10 To achieve this connection, a binding function
must be present between the individual moieties. After the
desired chemical modifications have been made, the final
compound is cleaved from the solid support and bears either
the original unaffected or a modified functional group,
depending on the binding and cleavage type. To obtain the
substrates, in which no trace of immobilization remains in the
cleaved molecule, so-called traceless linkers11−13 must be used.
Thus, the purpose for a traceless linker is the formation of a
C−H group at the linking site.13
The general problems associated with current linkers are
their limited versatility under different reaction conditions and
the simplicity of “binding to” and/or subsequently “cleaving
from” the polymer.
Acid-sensitive silyl and germanium linkers are among the
earliest developed and most useful traceless linkers.14−16
Highly resistant sulfone linkers represent another group of
traceless linkers.17−20 The drawbacks of these linkers are poor
availability and high cost of cleavage reagents (cuprate,
organomalybdenum or organopalladium agents). Moreover,
the final compounds may form metal ion complexes.
Azide linkers have become very popular in solid-phase
chemistry.21 In this case, alkynes are immobilized through
copper-catalyzed cycloaddition. The triazole that forms can be
cleaved under acidic conditions.
Hydrazone linkers belong to a very important group of
Received: September 11, 2014
Published: December 23, 2014
traceless linkers.22,12 Several possible cleavage conditions for
© 2014 American Chemical Society
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DOI: 10.1021/ol5034223
Org. Lett. 2015, 17, 180−183

Organic Letters
Letter
hydrazones synthesized via this condensation reaction are
depicted in Scheme 1. Cleavage of the final compounds can
be achieved after treatment with trimethylsilanolate in
tetrahydrofuran (THF) with the addition of methanol.
ion, which originated from the imine group, as presented in
the upper part of Scheme 2.
Scheme 2. Proposed Mechanisms for Hydrazone Cleavage
Scheme 1. Synthesis of Model Hydrazones on Solid
Supports
This mechanism was attempted to be proven by the
synthesis of the BAL linker with a deuterated aldehyde group
via modification of the previously published procedure,32
which was converted to deuterated hydrazone 3d-d.
Unfortunately, only nondeuterated hydrocarbon 4d was
detected via liquid chromatography−mass spectrometry
(LC/MS) after cleavage.
The other possibility of a reaction mechanism is transfer of
electrons from the C−N bond to a carbon of the aromatic
system. The resulting anion can be stabilized by a proton
from the present methanol, as presented in the lower part of
Scheme 2.
To provide evidence of this mechanism, we subjected
unsubstituted phenylhydrazone 3f (Ar = phenyl) to the
reaction in the presence of deuterated methanol. The
phenylhydrazone was chosen to avoid any exchange of an
acidic proton present in the studied aromatic part and to
compare the chemical shift of deuterated benzene in NMR
spectra with already published data.33
The synthetic procedure using our new linker was
completed via solvent evaporation and direct high-perform-
ance liquid chromatography (HPLC) purification. This
method was verified for all model compounds (4a−4e), as
the hydrazones were cleaved directly after their formation and
subsequently purified. The yields were calculated relative to
initial aminomethylene resin loading directly in a crude
mixture according to a calibration curve made with
appropriate standards. The results are summarized in Table 1.
Although the cleaved compound yield does not increase
after 0.5 h in some cases (4a, 4d), longer reaction times are
required to maximize the yields for hydrazones 4b, 4c, and 4e
(see Table 1).
Although the resin for reaction was prepared very carefully
to avoid the presence of any exchangeable proton outside the
molecule, and thus the only NH protons can cause a decrease
in isotopic yield, only nondeuterated benzene 4f was detected
1
by H as well as 13C NMR.
Despite the fact that the mechanism remains obscure, the
cleavage time was optimized for individual structures, and the
stability of the resin under various conditions was evaluated.
To determine the stability of the hydrazone linker under
various conditions, the resin was treated with different
reagents, including trifluoroacetic acid (TFA), organic bases,
and hydroxide and borohydride solutions. The stability of the
experimental control was obtained by comparing the HPLC/
photodiode array (PDA) response of cleaved compound 4
before and after treatment of resin 3, recalculated with respect
to 10 mg of resin. The change in the PDA response and the
maximum change of purity achieved within the cleaved
compounds 4 are summarized in Table 2.
Table 1. Cleavage Conditions and Yields of Synthesized
Compounds
cleavage time applied to
yield of compd 4 after
a
substitution
resin 3 (h)
cleavage (%)
a
0.5
3
46
51
47
42
37
b
c
3
d
e
0.5
3
a
Yields were determined from each compound concentration in their
respective cleavage cocktail.
The conditions summarized in Table 2 are optimized for
the time when loading remained unaffected. The maximum
reaction time was 16 h. Stability over a longer time period is
therefore possible; however, this reaction was not verified.
Treatment with potassium hydroxide and sodium borohydride
at elevated temperatures for longer reaction times caused a
noticeable degradation of the polymer support.
The reaction mechanism is difficult to explain. The ability
of trimethylsilanolate to react relatively smoothly with
multiple C−N bonds, demonstrated through reaction with
nitriles to form amides,31 can serve as the reaction starting
point. Reductive C−N bond cleavage between hydrazine and
an aromatic ring can be supported by transfer of the hydride
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DOI: 10.1021/ol5034223
Org. Lett. 2015, 17, 180−183

Organic Letters
Letter
a
Table 2. BAL-Hydrazone Linker Stability
b
c
conditions
maximum change in PDA response after treatment
maximum change of purity
50% TFA, rt, 3 h
4%
7%
7%
7%
4%
4%
5%
5%
4%
6%
7%
7%
5%
5%
5%
5%
AcOH (0.5 M), DMF, rt, 16 h
DIEA (0.5 M), DMF, 60 °C, 16 h
DBU (0.5 M), DMF, 60 °C, 16 h
Pyridine, 60 °C, 16 h
KOH, 10% (w/w), 50 °C, THF/water/MeOH (4:1:1), 3 h
NaBH4 (0.5 M), THF, rt, 3 h
NaBH4 (0.5 M), MeOH/THF (1:5), 50 °C, 30 min
a
b
For detailed data see Supporting Information. The change in PDA response was defined as the change in the HPLC/PDA peak area of each
cleaved compound dissolved in 1 mL of solvent after treatment relative to that of the compound before treatment. Peak areas were recalculated with
c
respect to 10 mg of resin. The maximum value belongs to the worst compound. The change in purity is determined as the change before and after
treatment according to HPLC analysis. The maximum value belongs to the worst compound.
To exemplify the utility of the linker, we performed the
model synthesis of compound 10, an intermediate in the
synthesis of analogues derived from Delavirdine,34 a reverse
transcriptase inhibitor used in the treatment of HIV (Scheme
3). This intermediate can be subsequently transformed to the
Scheme 4. Model Synthesis Using the Proposed Linker
Scheme 3. Structure of Delavirdine35 and Example of
Published Analogue34
target Delavirdine analogue by a series of reactions including
nucleophilic substitution of chlorine at 2-chloro-3-nitro-
pyridine followed by reduction of a nitro group and reductive
amination with acetone, which are standardly used in solid-
phase synthesis.
The synthetic sequence to afford derivative 11 as the
cleaved product from the resin 10 (Scheme 4) included
standard amide formation (providing compounds 6 and 8),
saponification under basic conditions (compound 7),
reduction with a sodium borohydride/methanol system
(compound 9), and acidic cleavage of the Boc protecting
group (compound 10). The synthesis was successfully
performed with an overall yield of 15.4% relative to the
initial loading of the aminomethylene resin after HPLC
purification.
This result confirms that the novel hydrazone linker is
stable under various reaction conditions, including heating in
relatively harsh media, and is applicable in the synthesis of
biologically active compounds via the combination of solid-
phase synthesis and combinatorial chemistry.
In summary, we tested hydrazones derived from a
commonly used BAL linker that were directly bound to an
aminomethylene resin as novel hydrazone linkers for SPOS.
We examined the stabilities of selected systems under various
conditions, including heating in TFA, exposure to 20% KOH,
and treatment with borohydrides. The hydrazones exhibited
good stability under all of these conditions and can be
subsequently cleaved with similar yields and purities. There-
fore, the proposed linker is suitable for the synthesis of
organic compounds under a wide range of reaction
conditions; the synthesized compounds can then be selectively
cleaved by treatment with trimethylsilanolate and subse-
quently purified. The utility of this novel linker was
demonstrated through the synthesis of a model compound
in a reaction sequence that included the aforementioned
conditions. The cleaved compound yields are acceptable for
high-throughput synthesis, which is used to obtain com-
pounds rapidly and in sufficient amounts for screening
regardless of yield. Elucidating the cleavage mechanism of
this novel linker is the focus of future studies in this area.
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Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization, H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
■
Corresponding Author
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Commun. 1998, 18, 1947.
*E-mail: hlavac@orgchem.upol.cz.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research project was supported by the Ministry of
Education, Youth and Sport of the Czech Republic (Projects
TE01020028 and IGA_PrF_2014030) and by the European
Social Fund (CZ.1.07/2.3.00/30.0060, CZ.1.07/2.3.00/
30.0041, and CZ.1.07/2.3.00/20.0009). The infrastructure of
this project (Institute of Molecular and Translation Medicine)
was supported by the National Program of Sustainability
(Project LO1304).
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