Solid-phase synthesis of 4,7,8-trisubstituted 1,2,3,4-tetrahydro-benzo[e] [1,4]diazepin-5-ones

Article abstract of DOI:10.1021/co300121d

Solid-phase synthesis of 1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones with use of polystyrene resin is described. The starting material was polymer supported 1,2-diaminoethane and as a key synthon, 4-chloro-2-fluoro-5- nitrobenzoic acid was used. The synthetic approach allows the preparation of derivatives with variable substitution at positions 4 and 8. Additionally, a skeletal diversity was increased when the nitro group was reduced and some benzene fused heterocycles were prepared. An expansion of a diazepinone to a benzodiazocinone scaffold was also successful although some limitations in a diversity of target derivatives were observed.

Full text of DOI:10.1021/co300121d

Research Article
pubs.acs.org/acscombsci
Solid-Phase Synthesis of 4,7,8-Trisubstituted 1,2,3,4-Tetrahydro-
benzo[e][1,4]diazepin-5-ones
Barbora Lemrova and Miroslav Soural*
́
Department of Organic Chemistry, Institute of Molecular and Translational Medicine, Faculty of Science, Palacky University,
771 46 Olomouc, Czech Republic
S
* Supporting Information
ABSTRACT: Solid-phase synthesis of 1,2,3,4-tetrahydro-
benzo[e][1,4]diazepin-5-ones with use of polystyrene resin
is described. The starting material was polymer supported
1,2-diaminoethane and as a key synthon, 4-chloro-2-fluoro-
5-nitrobenzoic acid was used. The synthetic approach allows
the preparation of derivatives with variable substitution at positions 4 and 8. Additionally, a skeletal diversity was increased when the
nitro group was reduced and some benzene fused heterocycles were prepared. An expansion of a diazepinone to a benzodiazocinone
scaffold was also successful although some limitations in a diversity of target derivatives were observed.
KEYWORDS: benzodiazepinones, benzodiazocinones, thiazines, thiazepines, bisheterocycles, solid-phase synthesis
Eaton reagent9 and subsequent ring expansion by Schmidt
INTRODUCTION
■
reaction.10 Solid-phase synthesis of some 1,2,3,4-tetrahydro-
Use of polyfunctional building blocks (i.e., more than three
benzo[e][1,4]diazepin-5-ones has been published once with use
different functional groups) in combination with solid-phase
of bromoacetal resin and Leuckart-Wallach reaction.11
synthesis concepts enables quick access to a number of various
Concerning biological activity of the discussed compounds,
organic substances, particularly when diversity oriented syn-
the amount of relevant information is limited. Some derivatives
thesis is applied. In our ongoing research, we have been focused
substituted with alkyl at N4 position were tested as psycho-
on use of 4-chloro-2-fluoro-5-nitrobenzoic acid for the prepa-
tropic agents but such activity was not detected.12 On the other
ration of various heterocyclic scaffolds. Although the substance
hand, interesting biological properties were observed at some
is commercially available and represents an excellent starting
bisheterocyclic derivatives (imidazobenzodiazepinones II and
material for number of chemical transformations, its use in
diazepinoindol-1-ones III) that act as inhibitors of poly(ADP
organic synthesis has been very rare so far. Our current effort
ribosa)polymerase (PARP-1),13,14 an enzyme responsible for
aims to prepare benzene fused heterocycles (BFHs) that com-
apoptosis and DNA reparation. Research in this area is quite
prise two different heterocyclic scaffolds in various combinations
intensive and number of dedicated articles and patents appeared
located at opposite sides of a central benzene ring (Scheme 1).
recently. Except this, an imidazobenzodiazepinone scaffold can be
Quite recently, we published two articles dedicated to the men-
found in a structure of Flumazenil (Anexate) IV, a clinically used
tioned area. In our initial work, 4-chloro-2-fluoro-5-nitrobenzoic
antidote for central nervous system (CNS) benzodiazepines
intoxication.
This article describes a novel approach for the preparation of
1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones I with use of
acid was used for the “right side” heterocycle formation and
3-hydroxypyridin-4(1H)-one scaffold was introduced.1 The
second contribution was focused on the “left side” heterocycle
formation and methodology for the preparation of various
high throughput organic synthesis (HTOS) approach appli-
nitrogen-containing scaffolds was developed (Figure 1).2
cable for the future use of the developed methodology for com-
binatorial synthesis of BFHs depicted in a Scheme 1.
In this contribution, we focused on an expansion of the right
side heterocycles group to increase the number of scaffolds
available for future synthesis of BFHs library. We aimed at the
1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one derivatives I
RESULTS AND DISCUSSION
■
Our initial strategy for the preparation of target compounds was
based on immobilization of ethanolamine to a polystyrene resin
equipped with an acid labile backbone amide linker (BAL). The
polymer supported ethanolamine 1 was subsequently arylated
with 4-chloro-2-fluoro-5-nitrobenzoic and intermediate 2 was
obtained. In a next step, the terminal hydroxy group was reacted
(Figure 1). The preparation of such diazepinones has been
described several times with use of solution-phase synthesis.
For instance, a regioselective reduction of 1,2,3,4-tetrahydro-
5H-1,4-benzodiazepin-2,5-dione with use of LiAlH4 was pub-
lished.3 Alternatively, a benzodiazepine scaffold was synthesized
by a cyclization approach from anthranilamide derivatives,4,5
2-nitrobenzoylchloride,6 or 2-chloro-3-nitrobenzoic acid7 as the
starting material. Also an interesting synthetic pathway start-
ing from o-nitroanilin and acrylonitrile was described8 taking
advantage of the cyclization to a 6-membered scaffold with use of
Received: September 29, 2012
Revised: October 26, 2012
Published: November 2, 2012
© 2012 American Chemical Society
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Scheme 1. Applicability of 4-Chloro-2-fluoro-5-nitrobenzoic Acid in BFHs Synthesis and Heterocyclic Scaffolds Reported
Previously
synthesis and its subsequent immobilization to a polystyrene
resin-BAL system (Scheme 3). The 2-nitrobenzenesulfonyl
(2-Nos) protected, polymer supported diamine 5a was then
arylated with 4-chloro-2-fluoro-5-nitrobenzoic acid to obtain
intermediate 6a. Advantageously, the 2-Nos group enabled an
alkylation of the nitrogen atom to incorporate various ligands
R1 (see Figure 2) to a position 4 of the target diazepinones.
Two alternative methods were tested: (i) alkylation with alkyl-
halides and (ii) alkylation with alcohols under Mitsunobu
protocol. Reaction with ethyl iodide in a presence of a tertiary
base such as triethylamine (TEA) or diisopropylethylamine
(EDIPA) led to alkylation of N−H group but also partial
esterification of a carboxylic group was observed. When 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) was used instead, the
esterification was quantitative and only double-alkylated inter-
mediate 7a{1} was detected. The same reaction conditions (i.e.,
0.5 M solution of alkylhalide in DMF, 16 h) were successfully
tested for benzylbromide. The Mitsunobu reaction was tested
for various alcohols (see Figure 2) and in each case the double
alkylated intermediates 7a{3−7} in an excellent purity were
obtained. From a combinatorial point of view, the modification
based on Mitsunobu alkylation represents much more favorable
alternative with respect to number of commercially available
alcohols.
Figure 1. Target general structure I and already reported biologically
active analogous derivatives II−IV.
with methansulfonylchloride to obtain the reactive ester 3
that should enable replacement of the hydroxy group with
primary amines resulting in N4 substitution of the target scaffold
(Scheme 2). Unfortunately, a presence of a base (pyridine) caused
an activation of a carboxylic group and azlactone 4 was detected as
a side product (about 40%, LC-MS traces). We tried to protect
the carboxylate with help of methylester formation, but the
intermediate 2 exhibited an unexpected resistance toward
various methods (Mitsunobu reaction with methanol, esterifica-
tion with methyl iodide, or diazomethane) and only up to 10%
of a desired methylester was detected in each case. Alternatively,
we also tried to use the methylester of 4-chloro-2-fluoro-
5-nitrobenzoic acid for immobilization on resin 1 (Scheme 2,
step ii), but we did not obtain the sufficiently pure product due
to a side reaction caused by the amide formation (30−40%,
HPLC-UV traces).
In the next step the Nos protective group had to be removed.
Such a cleavage is typically performed with 0.6 M solution of
mercaptoethanol and 0.2 M DBU in DMF for 5 min.15 In our
case, the Nos group was not cleaved under such conditions and
additionally a partial substitution of the chlorine atom with
An alternative strategy consisted in a preparation of N-(2-amino-
ethyl)-2-nitrobenzenesulfonamide with use of solution-phase
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a
Scheme 2. Unsuccessful Strategy for the Preparation of Target Compounds
a
Reagents and conditions: (i) ethanolamine, 10% AcOH in N,N-dimethylformamide (DMF), overnight then NaBH(OAc)3, 5% AcOH in DMF, 4 h;
(ii) 4-chloro-2-fluoro-5-nitrobenzoic acid methylester, diisopropylethylamine (EDIPA), dimethylsulfoxide (DMSO), 50 °C, overnight; (iii) 4-chloro-
2-fluoro-5-nitrobenzoic acid, diisopropylethylamine (EDIPA), dimethylsulfoxide (DMSO), 50 °C, overnight (iv) methyl iodide, DBU,
DMF, overnight or diazomethane, ether, overnight or methanol, PPh3, diisopropylazodicarboxylate (DIAD), anhydrous THF, rt, overnight;
(v) methansulfonylchloride, pyridine, 1 h.
a
Scheme 3. Successful Strategy for the Preparation of Target Compounds (see Figure 2 for R1)
a
Reagents and conditions: (i) N-(2-aminoethyl)-2-nitrobenzenesulfonamide or N-(3-amino-propyl)-2-nitrobenzenesulfonamide, 10% AcOH
in DMF, overnight, then NaBH(OAc)3, 5% AcOH in DMF, 4 h; (ii) 4-chloro-2-fluoro-5-nitrobenzoic acid, EDIPA, DMSO, 50 °C, overnight;
(iii) ethyl iodide or benzylbromide, DBU, DMF, rt, overnight or alcohol, DIAD, PPh3, anhydrous THF, rt, overnight; (iv) mercaptoalcohol, DBU,
DMF, rt, overnight, then (only for 8d) EDIPA, DMSO, 80 °C, overnight; (v) 50% TFA in DCM, rt, 1 h.
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mercaptoethanol was observed. When the reaction time was
prolonged to 16 h and the concentration of DBU was increased
to 0.6 M, only diazepinone derivatives 9a{1−7} were detected
indicating the cyclization to a seven membered ring took
place spontaneously after the cleavage of a protective group.
To prove the cyclization step took place on-resin (also the
cyclization in solution during a cleavage step was possible) we
made the test with Fmoc-OSu: when the resin 8a was treated
with Fmoc-OSu solution the appearance of Fmoc-derived
compounds have not been detected. The same course of
Table 2. List of Prepared [1,4]Thiazines 13a and
[1,4]Thiazepines 13b
a
Purity of crude product after entire reaction sequence; integrated
b
HPLC-UV traces. Overall yields after preparative HPLC purification.
Scheme 5. Synthesis of 8-N-Substituted 1,2,3,4-Tetrahydro-
Figure 2. Building blocks successfully used for the preparation inter-
mediates 7a{R1}.
a
benzo[e][1,4]diazepin-5-ones (for R2,3, See Figure 3)
Table 1. List of Prepared Diazepinones 9
a
a
Purity of crude product after entire reaction sequence; integrated
Reagents and conditions: (i) Amine, DMSO, 150 °C, 200 W, 5 min.; (ii)
b
HPLC-UV traces. Overall yields after preparative HPLC purification.
mercaptoethanol, DBU, DMF, rt, overnight; (iii) 50% TFA in DCM, rt, 1 h.
a
Scheme 4. Preparation of [1,4]Thiazine and [1,4]Thiazepine Containing Bisheterocycles (for R1 see Table 2)
a
Reagents and conditions: (i) MsCl, pyridine, rt, 30 min.; (ii) SnCl2·2H2O, EDIPA, DMF, overnight; (iii) EDIPA, DMSO, 80 °C, 16 h; (iv) 50%
TFA in DCM, rt, 1 h.
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Figure 3. List of successfully tested amines.
reaction was observed when mercaptoethanol was replaced
with mercaptopropanol and mercaptobutanol, respectively. The
appropriate diazepinones were obtained in very good, crude
purity (see Table 1).
Table 3. List of Prepared 8-N-(Di)substituted Diazepinones 16
a
b
compound
crude purity
yield
16{1}
16{2}
16{3}
16{4}
16{5}
16{6}
16{7}
76%
60%
78%
65%
84%
85%
80%
61%
52%
60%
61%
68%
80%
75%
The smooth nucleophilic substitution of intermediates 7
with mercaptoalcohols is quite surprising as we know from our
previous results that harsh conditions are needed for similar
reaction with primary and secondary amines including
strong nucleophiles (piperidine, pyrrolidine).1,2 On the other
hand, the formation of diazepinones 8 can be advantegously
employed for the preparation of thiazine and thiazepine scaf-
fold containing bisheterocycles which demonstrates a very first
application of 4-chloro-2-fluoro-5-nitrobenzoic acid in a
synthesis of BFHs depicted in a Scheme 1. For this purpose,
resins 8a{1}, 8a{2}, 8b{1}, 8b{2}, 8c{1}, and 8c{2} were
reacted with methansulfonyl chloride in pyridine followed by
the reduction of the nitro group with tin(II) chloride dihydrate.
After reduction we observed only about 10% of a tricyclic target
products 12a{1}, 12a{2}, 12b{1}, and 12b{2}, for a quan-
titative cyclization the appropriate resins 11a and 11b had to be
treated with 0.2 M EDIPA in DMSO at 80 °C for 16 h.
Thiazine and thiazepine rings were successfully formed giving
the target compounds in an excellent crude purity (78−93%,
LC-MS traces). In contrast, the preparation of eight membered
ring, [1,4]thiazocane, was unsuccessful. Although the mesyla-
tion gave an appropriate intermediates 11c{1} and 11c{2}
and also their reduction proceeded well, the final ring closure
did not take place even under harsh conditions (including a
microwave heating).
a
Purity of crude product after entire reaction sequence; integrated
b
HPLC-UV traces. Overall yields after preparative HPLC purification.
As the synthesis of benzodiazepinones 9a−c from the poly-
mer supported 1,2-diaminoethane proved to be simple and quite
versatile, we were also interested in use of a similar approach for
the preparation of analogous benzodiazocines 9d (Scheme 3,
m = 2). For this purpose, we prepared N-(3-amino-propyl)-
2-nitro-benzenesulfonamide and immobilized such protected
diamine to a polystyrene resin-BAL system to obtain appro-
priate intermediate 5b.16 Following the previously developed
procedures the cyclization of N-unsubstituted derivative 8d
(R1 = H) was successfully performed. In contrast to a pre-
paration of derivatives 8a−c the reaction did not take place
simultaneously after the cleavage of a Nos group but high tem-
perature was necessary for completion. When the preparation
of N-substituted intermediates 8d was tested (R1 = ethyl or
benzyl), the cyclization did not take place even under harsh
conditions (including microwave heating to 150 °C) which indi-
cates the synthesis of a benzodiazocine derivatives 8d is limited
only to N4-unsubstituted derivatives in this case.
In conclusion we have developed an efficient method for solid-
phase synthesis of diverse 1,2,3,4-tetrahydro-benzo [e][1,4]diazepin-
5-ones from commercially available synthons (alcohols, amines).
Twenty model compounds were prepared and fully characterized,
the target substances were isolated in very good, crude purity and
yields. Except applicability of the developed method for simple
preparation of diverse 4,7,8-substituted benzodiazepinones the
approach can be applied for combinatorial synthesis of libraries
of BFHs (Scheme 1) with use of 4-chloro-2-fluoro-5-nitrobenzoic
acid and previously described procedures.2
To increase a diversity of diazepinones 9a−c{R1} we also
tested a substitution of the chlorine atom at intermediate 7a{1}
with set of primary and secondary amines (Scheme 5). For
similar reaction we have previously developed a procedure con-
sisting in heating with amine solution in DMSO to 120 °C.2 In
our case, the reaction had to be very carefully optimized due to
relatively low reactivity of the starting material toward nucle-
ophilic substitution at position 4 and simultaneous sensitivity of
ester toward nucleophilic adition resulting in amide formation.
We tested different reaction temperatures and solvents (such as
DMSO, N-methylpyrrolidone NMP, diethylene glycole diethyl
ether), but the products were contaminated by the correspond-
ing amides in each case in spite of the substitution being carried
out at lower temperature 80 °C (conventional heating). In con-
trast, use of 10% of amine in DMSO under microwave heating
(200 W, 150 °C, 5 min) surprisingly provided the target deri-
vates 14{1−7} without presence of the amide side products.
This method was found to be suitable for both primary and
secondary amines. Last step was the cyclization to derivatives
15{1−7} according to previously discussed procedure. The
final compounds 15{5}, 15{6}, and 15{7} prepared from pri-
mary amines demonstrate applicability of the reaction sequence
for the preparation of BFHs that contain the “left side” hetero-
cyclic scaffolds of a type depicted in Scheme 1. Synthesis of
such heterocycles was described in our previous paper2 and it is
based on the reduction to o-phenylenediamines and subsequent
cyclocondenzation reactions with appropriate reagents.
ASSOCIATED CONTENT
* Supporting Information
■
S
Supporting Information contains details of experimental
synthetic and analytical procedures and spectroscopic data for
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +420 585634418. Fax: +420 585634465. E-mail:
soural@orgchem.upol.cz.
■
Funding
The authors are grateful to project CZ.1.07/2.3.00/20.0009
coming from European Social Fund and from Palacky University
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(internal Grant No. PrF_2012_023). The infrastructural part of
this project (Institute of Molecular and Translational Medicine)
was supported from the Operational Program Research and
Development for Innovations (project CZ.1.05/2.1.00/01.0030).
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Notes
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resins for solid-phase biotinylation of carboxylic acids. Tetrahedron
Lett. 2011, 52, 5782−5788.
The authors declare no competing financial interest.
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