4-Chloro-2-fluoro-5-nitrobenzoic acid as a possible building block for solid-phase synthesis of various heterocyclic scaffolds

Article abstract of DOI:10.1021/co300109h

4-Chloro-2-fluoro-5-nitrobenzoic acid is a commercially available multireactive building block that can serve as a starting material in heterocyclic oriented synthesis (HOS) leading to various condensed nitrogenous cycles. This work describes its ability for the preparation of substituted nitrogenous heterocycles having 5-7-membered cycles via polymer-supported o-phenylendiamines. Immobilization of this compound on Rink resin followed by further chlorine substitution, reduction of a nitro group and appropriate cyclization afforded benzimidazoles, benzotriazoles, quinoxalinones, benzodiazepinediones and succinimides. The method developed is suitable for the synthesis of diverse libraries including the mentioned types of heterocycles, which have significant importance in current drug discovery. In this paper, we also report limitation of these method and unsuccessful attempt to prepare an 8-membered benzodiazocine cycle.

Full text of DOI:10.1021/co300109h

Research Article
pubs.acs.org/acscombsci
4‑Chloro-2-Fluoro-5-Nitrobenzoic Acid as a Possible Building Block
for Solid-phase Synthesis of Various Heterocyclic Scaffolds
Sona Krupkova, Petr Funk, Miroslav Soural, and Jan Hlavac*
̌
̌
́
́
̌
Institute of Molecular and Translational Medicine, Department of Organic Chemistry, Faculty of Science, Palacky University,
17 Listopadu 12, 771 46 Olomouc, Czech Republic
S
* Supporting Information
ABSTRACT: 4-Chloro-2-fluoro-5-nitrobenzoic acid is a com-
mercially available multireactive building block that can serve
as a starting material in heterocyclic oriented synthesis (HOS)
leading to various condensed nitrogenous cycles. This work
describes its ability for the preparation of substituted nitro-
genous heterocycles having 5−7-membered cycles via polymer-supported o-phenylendiamines. Immobilization of this compound on
Rink resin followed by further chlorine substitution, reduction of a nitro group and appropriate cyclization afforded benzimidazoles,
benzotriazoles, quinoxalinones, benzodiazepinediones and succinimides. The method developed is suitable for the synthesis of
diverse libraries including the mentioned types of heterocycles, which have significant importance in current drug discovery. In this
paper, we also report limitation of these method and unsuccessful attempt to prepare an 8-membered benzodiazocine cycle.
KEYWORDS: solid-phase synthesis, condensed heterocycles, benzimidazoles, benzotriazoles, quinoxalinones, benzodiazepinediones,
succinimides
benzenecarboxamide derivatives as gonadotropin-releasing hor-
mone receptor antagonists is described in a recent patent.1 The
acid was then used in the synthesis of heterocyclic peptides
employed in the treatment of hepatitis C virus infection2 or
indazolone sulfonamides as 11β-hydroxysteroid dehydrogenase
inhibitors.3 Another application of this component is reported
in work from Feit and Nielson describing the preparation of
benzoic acid derivatives useful as diuretics or saluretics.4 Finally,
the component was used by our team for the preparation of
hydroxyquinolinones,5 which is till now the only described
solid-phase synthetic method utilizing this building block.
Condensed nitrogenous heterocycles represent a large group
of compounds that have been taking an important position in
pharmaceutical chemistry for many years. The significant bio-
logical and pharmacological properties of such molecules have
led to these derivatives being the focus of many investiga-
tions. The benzimidazole,6 benzotriazole,7 quinoxaline,8 benzo-
diazepine9, and benzodiazocine10 scaffolds that were selected
as target structures in this work are already widely known to
have interesting biological properties in drugs currently in the
market.
INTRODUCTION
■
4-Chloro-2-fluoro-5-nitrobenzoic acid is a commercially avail-
able building block that allows large numbers of possible
chemical modifications leading to various heterocyclic struc-
tures. The advantage of this compound is that the heterocyclic
scaffold can be in principle formed on two sides of the mole-
cule, on the “nitro-chloro side” or “carboxy-fluoro side” (struc-
ture a in Figure 1), via suitable modification of the appropriate
Figure 1. Potential of 4-chloro-2-fluoro-5-nitrobenzoic acid as suitable
building block for synthesis of various heterocyclic systems.
As described above, the condensed heterocycles are still attrac-
tive compounds in medicinal chemistry research and that is why,
we have decided to explore the applicability of 4-chloro-2-fluoro-
5-nitrobenzoic acid for the diversity oriented solid-phase
synthesis of compounds that contain various substituted above-
mentioned heterocyclic scaffolds. The combination of solid-phase
synthesis and diversity oriented synthesis offers a very effective
groups. Simultaneous (or subsequent) modification of both
sides of the molecule can also afford tricyclic bisheterocycles in
which two heterocyclic scaffolds are situated at opposite sides
of the central benzene ring (structure b in Figure 1). Lastly,
there is the possibility to prepare uncondensed heterocycles on
the central benzene ring (structure c in Figure 1) and combine
this possibility with formation of the condensed system (struc-
ture d in Figure 1).
Received: September 12, 2012
Revised: November 15, 2012
Published: November 19, 2012
Despite this fact, the application of this acid in chemical
synthesis has so far been rare. Its use for the preparation of
© 2012 American Chemical Society
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way to get sufficient numbers of compounds of various scaf-
folds and substitutions in relatively short time for biological
screening.
Three primary amines (giving substituents R1) and two
alkylbromides (giving substituents R2) were used in random
combination to verify the synthetic accessibility of the target
heterocycles with various substitutions of their scaffold. The
combination of the building blocks used is depicted in Figure 2.
Our initial attention was focused on the reduction of nitro-
anilines 1. We have already attempted to reduce the nitro to an
amino group in our previous work5 and reported this reaction as
unsuccessful. However, later optimization gave promising results
when the concentration of tin(II) chloride solution was increased
from 1.5 to 2.5 M and the resin was carefully prewashed several
times with degassed DMF. Although the reduction took place
under the improved conditions, the resulting o-phenylendiamines
were accompanied with an unknown side product (10−30%,
LC-UV traces). Further optimization of the tin(II) chloride method
using the base (1,8-diazabicycloundec-7-ene (DBU) instead of
N,N-diisopropylethylamine (DIEA)) eliminated the formation of the
side product and all o-phenylendiamine derivatives were obtained in
an excellent purity (over 90%, LC-UV traces). The reactivity of the
diamine intermediates 2 was subsequently studied to form the target
heterocycles 3−7 (Scheme 3).
RESULTS AND DISCUSSION
As key-intermediates, o-phenylendiamines 2 were prepared accord-
ing to Scheme 1 by the reduction of the appropriate nitroanthra-
■
a
Scheme 1. Preparation of o-Phenylendiamine Precursors
a
Ssubstituents R1 and R2 are defined in Figure 2. Reagents and
conditions: (i) SnCl2·2H2O, DBU, DMF, rt, 1 day.
nilates 1 immobilized on Rink amide resin. Preparation of inter-
mediates 1 is described in our previous paper (Scheme 2).5
a
Scheme 2. Synthesis of Intermediates 1
a
Reagents and conditions: (i) 4-chloro-2-fluoro-5-nitrobenzoic acid, DMSO, DIEA, 50 °C, overnight; (ii) amine, DMSO, 120 °C, overnight;
(iii) 2-bromoacetophenone, TEA, DMF, rt, overnight or benzylbromide, DIEA, DMF, rt, overnight
Figure 2. Substituents R1 and R2 used for synthesis of starting nitroanilines.
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Scheme 3. Intended Use of Immobilized o-Phenylendiamine 2{R1,R2} for the Preparation of Various Nitrogenous Heterocycles
a
Scheme 4. Preparation of Benzimidazoles 3{R1,R2,R3}
Benzimidazoles. Solid-phase synthesis of benzimidazoles
has become the object of many investigations. The majority of syn-
thetic methods start from the polymer supported o-phenylendiamine
originating from attachment of 4-fluoro-3-nitrobenzoic acid or
dinitrobenzoic acid to a resin via the carboxylic acid group.11−13
In another method the diamine precursor is attached to the resin
via one of the amino groups.14−16 A different strategy involves
the reaction of phenylendiamines with polymer-bound aldehydes
or esters.17,18 All these approaches have been summarized in a
review by Kamal.19 In our work, we applied simple cyclization
of immobilized intermediates 2 with aldehydes to afford sub-
stituted benzimidazoles 3. Different aldehydes were tested
for this reaction (Figure 3) and their different reactivity was
observed.
a
Reagents and conditions: (i) aldehyde, DMF, rt, overnight or DCM,
reflux, overnight; (ii) TFA/DCM, rt, 1 h.
overnight reflux (Scheme 4). This solvent was then used for
preparative synthesis of all three model compounds 3{1,1,2},
3{2,2,3}, and 3{3,3,1}
Apart from aldehydes, other components such as imidoesters
or esters of benzoic acid were tested, but none of these reagents
yielded the required benzimidazoles.
Benzotriazoles. Since the benzotriazole moiety performs
in organic synthesis as an auxiliary agent in a number of molec-
ular transformations, its application in solid-phase combinato-
rial chemistry contributes to diverse heterocyclic scaffolds.20
Katritzky et al. reported a method based on the reaction of
polymer-supported o-phenylendiamine with isoamyl nitrite.21
Another article describes the preparation of benzotriazoles from
the resin-bound triazene precursors.22,23 We tried to introduce
the nitrogen atom to molecule 2 by means of Katritzky method
with isoamyl nitrite, but the reaction afforded product 4 only as
part of a mixture with other unidentified compounds.
Optimization of the reaction conditions based on the varia-
tion of solvents (DMF and NMP) used, the temperature (reac-
tion was carried out at ambient temperature or at 5 °C) and the
reaction time did not increase the purity of the products. Sub-
sequently we decided to use sodium nitrite as a source of the
nitrosyl cation (Scheme 5).
Figure 3. Aldehydes used for the cyclization to benzimidazoles
3{R1,R2,1−3}.
Whereas p-nitrobenzaldehyde and acetaldehyde easily
yielded benzimidazoles 3{1,1,2} and 3{2,2,3} in DMF after
overnight reaction (Scheme 4), the use of unsubstituted benzal-
dehyde was more complicated. The conversion took place very
slowly and afforded the required product with limited purity
(about 50%, LC-UV traces). We tried to accelerate the reaction
using acidic or basic catalysis or 2,3-dichloro-5,6-dicyanoben-
zoquinone (DDQ) as a oxidative agent, but each attempt
resulted in the undefined mixture of products. Surprisingly, the
reaction was significantly improved by the replacement of sol-
vent and benzimidazole 3{3,3,1} was achieved in DCM after
Although in this case a long reaction time was needed (four
days), model benzotriazoles 4{2,2} and 4{3,3} were obtained in
a high purity (about 90%, LC-UV traces). In the case of the free
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a
Scheme 5. Preparation of Benzotriazoles 4{R1,R2}
Figure 4. Structures of the aimed quinoxaline 5{R1,R2,R3}.
a
Reagents and conditions: (i) NaNO2, AcOH, DMF, rt, 4 days;
(ii) TFA/DCM, rt, 1h.
2, and 3 (Figure 5) to afford model quinoxalinones 5{1,1,2},
5{2,2,3}, and 5{3,3,1}.
carboxylic acid derivative 2{1,1} reaction did not yield the
expected product (according to LC-MS). Thus, target benzo-
triazole 4{1,1} was achieved using the corresponding benzyl
ester 2{1,2} which was hydrolyzed after formation of a triazole
ring (Scheme 6).
Quinoxalinones. Quinoxaline derivatives have attracted the
attention of many researchers and the literature offers many
synthetic pathways carried out on polymer support and provid-
ing various derivatives containing the quinoxaline scaffold. In
our study we tested several methods leading to structures
5{R1,R2,R3}(Figure 4).
Concurrently, we attempted to prepare the target molecule
via convenient HOBt activated acylation followed by the
condensation of amino and carbonyl groups. We supposed the
avoidance of the undesirable decarboxylation and formation of
a benzimidazole, but a benzimidazole side product was detected
as well (Scheme 7). The third listed method involved a modi-
fication of the reaction sequence consisting in the acylation of
nitroaniline 1 and subsequent nitro group reduction followed
by cyclization (Scheme 8). The reaction of compound 1{1,2}
with phenylglyoxilic acid 1 was used as model reaction.
Despite strong deactivation of the amino group caused by the
adjacent nitro group in product 1{1,2} we achieved the desired
amide intermediate 10{1,2,1} by heating of the resin-bound
nitroaniline with acylchloride. Subsequent reduction with tin(II)
chloride resulted in final quinoxaline 5{1,2,1} of high purity
(95%, LC-UV traces). Unfortunately, this method is not universal
for any type of ketocarboxylic acids. In case of acids 2 and 3
(Figure 5) when the formation of their less reactive lactone or
anhydride respectively is probably formed initially, the acylation
step failed and only starting material was recovered.
It follows that two of the listed methods, the direct acylation
and acylation of nitroanilines, provided quinoxalinones in suffi-
cient purity, but the latter was applicable only with significant
limitation concerning the acids used.
Benzodiazepinediones. Although a number of benzodia-
zepine substructures have been prepared on a polymer-support,26
a solid-phase synthesis leading to 1,5-benzodiazepine-2,4-diones
has not been reported so far.
In our case, malonic acid derivatives were applied to close the
7-membered ring via double acylation of the diamine precur-
sors 2. We anticipated the simultaneous formation of both
amides but the reaction with HOBt-activated acids yielded only
acyclic amide 11 with a free carboxylic group (according to LC-
MS analysis) and ring closure had to be completed via intramole-
cular cyclization in next additional step (Scheme 9).
In the case of malonic acid the regioselectivity of the first-
step acylation was not determined as both potential structural
isomers 11 afford the same product 6. However, we suppose a
preferential acylation of the primary amino group which is in
accordance with detailed NMR analysis that has been done
with analogical intermediate 14{2,2,1} (Scheme 11). LC-MS
analysis revealed that the intermediates 11 were contaminated
In solid-phase chemistry immobilized o-fluoro-nitrobenzene
derivatives are involved in most of the strategies reported. For
example Purandare24 prepared quinoxalinone derivatives with a
method based on the reaction of the resin-bound diamine,
originating from the reaction of fluoro-nitro derivatives, with
carbonyl compounds. Vagner and co-workers acquired quin-
oxalinone derivatives with a method based on the substitution
of o-fluoronitrobenzene with polymer-bound amino acid esters.
Subsequent reduction of the resulting o-nitroanilines yielded
dihydroquinoxalinones, which after cleavage from the resin,
were air-oxidized to quinoxalinones.25
We decided to investigate the application of α-ketocarboxylic
acids to obtain quinoxalinone heterocycles. To close the
quinoxalinone ring we tested three methods involving a direct
acylation, hydroxybenzotriazole (HOBt) activated acylation and
an acylation of the nitroanilines 1 with acyl chloride. First we tried
a direct acylation of immobilized phenylendiamines 2 with phenyl-
glyoxylic acid. Beside the expected quinoxalinone 5, we obtained
benzimidazole derivative 3 as a side product (Scheme 7).
After thorough investigation of the reaction, we observed
that the cyclization to quinoxalinone 5 was highly accelerated
by acidic catalysis and thus the formation of undesirable benz-
imidazole 3 was detected only in low purity (about 20%, LC-UV
traces). The choice of the solvent was another factor influencing
the outcome of the reaction. Various solvents and reaction tem-
peratures were combined and tested to achieve the model quin-
oxalinone 5{2,2,1} in as high purity as possible. The best results
were obtained at 80 °C in toluene or at reflux in tetrahydrofuran
under acetic acid catalysis (Table 1).
These conditions were applied to preparative reaction of
diamines 2{1,1}, 2{2,2}, and 2{3,3} with ketocarboxylic acids 1,
a
Scheme 6. Synthesis of Benzotriazole 4{1,1}
a
Reagents and conditions: (i) NaNO2, AcOH, DMF, rt, 4 days; (ii) potassium trimethylsilanolate, THF, rt, overnight; (iii) TFA/DCM, rt, 1 h.
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a
Scheme 7. Synthesis of Quinoxalinones via an Acylation of o-Phenylendiamines 2{R1,R2} with Phenylglyoxylic Acid
a
Reagents and conditions: (i) phenylglyoxylic acid, various solvents (Table 1), rt, overnight or 80 °C (reflux for THF), 2 h or phenylglyoxylic acid,
HOBt, DIC, DMF/DCM, rt or 5 °C, overnight; (ii) TFA/DCM, rt, 1 h.
Table 1. Solvents Tested for the Preparation of
Scheme 9. Two-Step Preparation of Benzodiazepinediones
a
Quinoxalinones 5 (Ratio of Products 5{2,2,1} to 3{2,2,1}
6{R1,R2,R3}
a
According to LC-UV Traces
DMF MeCN NMP dioxane THF DCM toluene
a
a
rt
1:1
1:1
3:2
2:1
nt
1:4
nt
5:1
2:3
1:1
1:2
b
a
cat. AcOH, 80 °C
10:1
nt
10:1
a
b
nt = not tested. Reflux for THF.
Figure 5. α-Ketocarboxylic acids used for the synthesis of
quinoxalinones 5{R1,R2,1−3}.
a
Reagents and conditions: (i) malonic acid, HOBt, DIC, DMF/DCM,
rt, overnight; (ii) HOBt, DIC, THF, 50 °C, 2 h; (iii) TFA/DCM, rt, 1 h.
with a side product which was identified as a result of cross-
coupling reaction leading to compound 13 (5−30%, LC-UV
traces, Figure 6). The structure was verified in case of derivative
13{3,3,4}.
Another noteworthy fact was that the outcome of the first-
step acylation reaction was highly dependent on type of the
malonic acid used (Figure 7).
Whereas disubstituted malonic acids 4, 5, and 6 provided the
corresponding intermediates 11, preparation of an unsubstituted
derivative 11{3,3,1} was unsuccessful due to a decarboxylation of
the acid during the reaction. Reaction with monosubstituted
malonic acids resulted in a mixture of desired carboxy derivative
11{R1,R2,1−3} and the product of a decarboxylation leading to
12 (Scheme 10).
We tried to suppress the decarboxylation by decreasing the
reaction temperature or with use of anhydride formed in situ
with use of N,N-diisopropylcarbodiimide (DIC). However, the
starting diamine 2 did not react under such reaction conditions. As
another alternative the esterification of the malonic acid was done
to avoid the undesired elimination of the carboxylic group. How-
ever, after the reaction with the ester of malonic acid only the
starting diamines 2 were detected. The harsher reaction conditions
Figure 6. Structure of side products 13{3,3,4}.
achieved by heating in DMSO or DMF yielded a complex mixture.
Thus, the applicability of this method is reduced to synthesize only
disubstituted derivatives and thus model compounds 11{3,3,4},
11{1,1,5}, and 11{2,2,6} were prepared.
Neither cyclization step proceeded smoothly. Closing the
cycle under mild reaction conditions identical to the first-step
acylation provided final heterocycles 6 only with low con-
version and significantly contaminated with byproducts. Finally
the model benzodiazepindiones 6{3,3,4}, 6{1,1,5}, and 6{2,2,6}
a
Scheme 8. Formation of Quinoxalinone 5{1,2,1} via Acylation of Nitroaniline 1{1,2}
a
Reagents and conditions: (i) phenylglyoxylic acid chloride, DIEA, dichloroethane (DCE), reflux, overnight; (ii) SnCl2·2H2O, DBU, DMF, rt,
overnight; (iii) TFA/DCM, rt, 1 h.
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were obtained via HOBt acylation in THF at 50 °C. Other
methods such as acidic (AcOH) or basic (DIEA) catalysis or
the use of alternative activating agents (such as BOP) did not
increase the purity.
Figure 7. Malonic acids used for the study of preparation of benzo-
diazepines 6{R1,R2,1−6}.
Figure 8. Dicarboxylic acids used for preparation of succinimide,
maleimide, and phtalimide 8{R1,R2,1−3}.
a
Scheme 10. Acylation of Compounds 11{R1,R2,R3} with Unsubstituted and Monosubstituted Malonic Acid
a
Reagents and conditions: (i) malonic acid, HOBt, DIC, DMF/DCM, rt, overnight; (ii) TFA/DCM, rt, 1 h.
a
Scheme 11. Unsuccessful Synthesis of Benzodiazocinedione Derivatives 7{R1,R2,R3}
a
Reagents and conditions: (i) dicarboxylic acid, HOBt, DIC, DMF/DCM, rt, overnight; (ii) HOBt, DIC, DMF/DCM, rt, overnight; (iii) TFA/DCM,
rt, 1h.
a
Scheme 12. Preparation of Bromo Derivative 8{3,3,2}
a
Reagents and conditions: (i) 2,3-dibromomaleinic acid, HOBt, DIC, DMF/DCM, rt, overnight; (ii) HOBt, DIC, DMF/DCM, rt, overnight;
(iii) 2,3-dibromomaleic acid, DIC, DMF/DCM, rt, overnight, then the process was repeated; (iv) TFA/DCM, rt, 1 h.
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Attempt to Prepare Benzodiazocinediones. After the
successful formation of 7-membered ring, we tried to extend the
methodology for the preparation of 8-membered rings. Despite
various published approaches leading to condensed nitrogenous
Table 2. Summary of the Prepared Compounds
a
b
*
Purity of a crude product (LC-UV traces). Yield of a product after purification (HPLC chromatography). In the case of derivatives 6{1,1,5} and
8{1,1,3}, acylation of an amino group with TFA was observed during the cleavage from the polymer-support using TFA/DCM.
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8-membered ring derivatives27−30 the solid-phase method for the
preparation of such compounds have not been described.
The double acylation with dicarboxylic acids (Scheme 11)
was carried out in two steps as in the case of benzodiazepines 6.
Surprisingly the second-step acylation took place very smoothly
(according to LC-MS analysis) in comparison to the cyclization
of intermediates 11. However, 2D NMR analysis experiments
revealed formation of 5-membered cycle 8 instead of the target 8-
membered cycle 7 (Scheme 11). Preparation of bromoderivative
14{3,3,2} with use of HOBt activation yielded an unidentified
mixture of compounds. In this case the cyclization was performed
by one step acylation with the acid anhydride formed in situ with
use of DIC (Scheme 12).
Three dicarboxylic acids of aliphatic and aromatic structure
(Figure 8) were used at this step. The formation of succinimide,
maleimide and phtalimide was verified on three model compounds
8{1,1,3}, 8{2,2,1}, and 8{3,3,2}.
Although considerable limitations were revealed and in some
cases moderate yields were obtained, the set of novel heterocyclic
derivatives was prepared (Table 2).
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, analytical data, and NMR spectra are
available. These information are available free of charge via the
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AUTHOR INFORMATION
Corresponding Author
*Phone: +420585634405. Fax: +420585634465. E-mail: hlavac@
orgchem.upol.cz.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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The authors are grateful to the Ministry of Education, Youth
and Sport of the Czech Republic, for the project CZ.1.07/
2.3.00/20.0009 supported by the European Social Fund. The
infrastructural part of this project (Institute of Molecular and
Translational Medicine) was supported by the Operational
Program Research and Development for Innovations (Project
CZ.1.05/2.1.00/01.0030).
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