Polymer-supported stereoselective synthesis of benzimidazolinopiperazinones

Article abstract of DOI:10.1021/jo300836c

We describe the efficient synthesis of 4,7,8,10-tetrasubstituted-(((4S, 10aS)-3-oxo-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)alkyl) amides on solid phase via tandem N-acyliminium ion cyclization-nucleophilic addition reactions. The sy

Full text of DOI:10.1021/jo300836c

Article
pubs.acs.org/joc
Polymer-Supported Stereoselective Synthesis of
Benzimidazolinopiperazinones
Nadezda Cankarova† and Viktor Krchnak*,†,‡
̌
̌
̌
́
̌
́
†Department of Organic Chemistry, Institute of Molecular and Translational Medicine, Faculty of Science, Palacky University, 17.
́
Listopadu 12, 771 46 Olomouc, Czech Republic
‡Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, Indiana
46556, United States
S
* Supporting Information
ABSTRACT: We describe the efficient synthesis of 4,7,8,10-
tetrasubstituted-(((4S,10aS)-3-oxo-3,4,10,10a-tetrahydro-
benzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)alkyl)amides on
solid phase via tandem N-acyliminium ion cyclization−
nucleophilic addition reactions. The synthesis proceeded
with complete stereocontrol of a newly formed stereogenic
center, provided crude material of high purity, and used
commercially available building blocks under mild reaction conditions.
benzimidazole scaffold,4−9 whereas the second utilizes piper-
INTRODUCTION
■
azin-2-one as the starting material.10 The latter synthetic
approach involved a four-component Ugi−Smiles reaction,
which was followed by an acid-catalyzed cyclization, an
intramolecular reductive cyclization, and an oxidation.10
Other related derivatives, such as deazaanalogues of
compound II, 1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-
3(5H)-ones III (Figure 1), are reportedly anxiolytic,11−13
antiviral,14 and antimicrobial15 agents. 3,4,4a,5-Tetrahydro-
benzo[4,5]imidazo[1,2-a]pyridin-1(2H)-ones linked by benzi-
midazoles have also been documented.16 The aromatic part of
1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-3(4H)-ones II,
benzimidazoles, were synthesized several times, in solution17−21
and on solid phase.22−25 Benzimidazole derivatives can serve as
angiotensin II receptor antagonists,26 as inhibitors of trypsin-
like serine protease (factor Xa),27 and as antibacterial agents.28
The synthesis of benzimidazolines and their closely related
compounds, 2-oxo/thioderivatives and spiro-benzimidazolines,
has also been described.16,29−34
Roughley,1 Walters,2 and co-workers reported intriguing papers
devoted to the impact of hybridization of carbon atoms on the
biological and physicochemical properties of compounds. They
emphasized that the incorporation of a greater proportion of
chiral compounds with higher degrees of unsaturation could
improve clinical outcomes, a conclusion that was drawn from
Lovering’s study.3 Lovering introduced a fractional sp3-
character (Fsp3) as a ratio of the number of sp3-hybridized
carbon atoms and total carbon count. It is reported that
marketed drugs tend to have a higher Fsp3 than discovery
compounds do.1,2 On the other hand, Roughley,1 and co-
workers documented that between one-quarter and one-half of
carbon atoms are sp3-hybridized, although it seems that most of
the recently prepared compounds by medicinal chemists are
“flat”. To contribute to syntheses of chiral compounds with
higher degrees of unsaturation, we developed efficient synthesis
of 4,7,8,10-tetrasubstituted-(((4S,10aS)-3-oxo-3,4,10,10a-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)alkyl)-
amides.
On the other hand, 1,2,10,10a-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrazin-3(4H)-ones I can be considered not only as
benzimidazolines fused with piperazin-2-one cycle but also as
hexahydroimidazo[1,2-a]pyrazin-6(5H)-ones IV (Figure 1)
fused with benzene ring. The synthesis of hexahydroimidazo-
[1,2-a]pyrazin-6(5H)-ones IV and their closely related
compounds has been reported many times, in solution35−38
and on solid phase.39 Analogous compounds have also been
used for the preparation of aza-ligands40 or azacyclododecane
derivatives.41 Derivatives of imidazolopyrazine IV have
intriguing biological properties; they can be used for the
The synthesis of 1,2,10,10a-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrazin-3(4H)-ones I (termed “benzimidazolinopiper-
azinones” hereafter, Figure 1) has not been described, although
the preparation of 1,2-dihydrobenzo[4,5]imidazo[1,2-a]-
pyrazin-3(4H)-ones II (Figure 1) has already been reported.
Two main routes lead to those compounds; the first starts from
Received: April 25, 2012
Published: June 7, 2012
Figure 1. Heterocyclic cores.
© 2012 American Chemical Society
5687
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
a
Scheme 1. Stereoselective Synthesis of Benzimidazolinopiperazinones 10 on Solid Phase
a
Reagents and conditions: (i) 50% piperidine in DMF, rt, 15 min; (ii) bromoacetic acid (2 equiv), DIC (1 equiv), DCM, 5 min, then DIEA (1
equiv), rt, 16 h; (iii) aminoacetaldehyde dimethyl acetal, DIEA, DMF, rt, 2 h; (iv) Fmoc-amino acid (1 equiv), HOBt (1 equiv), DIC (1 equiv),
DCM/DMF (1:1), rt, 16 h; (v) 4-nitrobenzenesulfonyl chloride, lutidine, DCM, rt, 4 h; (vi) glycolaldehyde dimethyl acetal, PPh3, DIAD, anhydrous
THF, 0−50 °C, 16 h, repetition; (vii) 2-mercaptoethanol, DBU, DMF, rt, 5 min; (viii) o-fluoronitrobenzene, DIEA, DMSO, 50 °C, 16 h or 4,5-
disubstituted o-fluoronitrobenzenes, DIEA, DMSO, rt, 16 h; (ix) for R4 = piperidin-1-yl: piperidine, DMSO, 50 °C, 16 h; (x) SnCl2·2H2O, DIEA,
DMF, rt, 16 h; (xi) Ac2O, rt, 16 h or carboxylic acid (2 equiv), DIC (1 equiv), DCM/DMF (1:1), rt, 16 h or 4-nitrobenzenesulfonyl chloride,
lutidine, DCM, rt, 16 h; (xii) 50% TFA in DCM, rt, 90 min.
treatment of anorexia,38 cancer,39 and fibrotic disorders,42 and
can also serve as integrin-mediated cell adhesion inhibitors.36
The stereoselective synthesis of different bicyclic nitrogenous
heterocycles utilizing iminium salts has been described several
times. Iminium salts have been used, for example, for the
preparation of quinolizidines,43 pyrrolo[2,1-a]isoquinolines,44
octahydropyrazino[1,2-a]pyrimidin-6-ones,45 bicyclic deriva-
tives containing lactone,46 and 6,6-fused bicyclic scaffold-
containing compounds derived from tripeptides,47 among
others. The chemistry of iminium ions and its application to
the synthesis of diverse heterocycles has been published in
excellent reviews.48−51
Although benzimidazolines fused with other heterocycles
have been subject of synthesis research, no attention has been
paid to benzimidazolines fused with piperazin-2-one. Herein we
report their solid-phase synthesis from acyclic intermediates via
N-acyliminium ion cyclization−nucleophilic addition. The acid-
mediated unmasking of the aldehyde was followed by
spontaneous formation of the cyclic N-acyliminiums. The
mechanism of the acid hydrolysis of acetals in anhydrous
conditions has been reported.52 The nitrogen derived from the
amino acid was substituted with o-fluoronitrobenzenes, and the
nitro group was subsequently reduced to the amino group to
serve as an internal nucleophile for the creation of the fused
ring upon acid-mediated cleavage from solid support.
Herein reported compounds do not suffer from the above-
mentioned shortcomings, such as “flatness” etc. We developed
the synthesis of benzimidazolinopiperazinones characterized by
the presence of two chiral carbons and three sp3-hybridized
carbon atoms on the skeleton, compounds that have potential
biological and therapeutic value. The biological activities will be
reported in due time.
RESULTS AND DISCUSSION
■
Our research aimed to design a general route to benzimida-
zolinopiperazinones with the following criteria in mind: (i)
nonplanar scaffold (sp3 hybridization), (ii) stereoselectivity,
(iii) transformations providing high purity of crude target
compounds, (iv) diverse scaffolds, and (v) commercially
available building blocks.
The synthesis was carried out on Rink amide resin using four
different starting carboxylic acids: bromoacetic acid, Fmoc-β-
Ala-OH, Fmoc-γ-Abu-OH, and Fmoc-4-aminomethylbenzoic
5688
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
Figure 2. Building blocks used for the synthesis of benzimidazolinopiperazinones 10.
acid. Bromoacetic acid was immobilized via symmetric
anhydride in the presence of an N,N′-disopropylethylamine
(DIEA) (Scheme 1, Route I). The bromine was subsequently
substituted with aminoacetaldehyde dimethyl acetal to afford
polymer-supported 2-((2,2-dimethoxyethyl)amino)acetyl bro-
mide 2. The secondary amines were further acylated with
different Fmoc-amino acids to yield polymer-supported amides
3.
(DBU) in DMF for 5 min to remove the 4-Nos-protecting
group. Acylation with different Fmoc-amino acids afforded N-
acylated intermediates 3 (Scheme 1). Three different Fmoc-
amino acids, namely, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, and
Fmoc-Ser(tBu)-OH, were used for acylation, and all of them
afforded expected products. The Fmoc-protecting group was
then cleaved, and the resin-bound primary amines were treated
with three different unsubstituted/4,5-disubstituted o-fluoroni-
trobenzenes to yield intermediates 7. While the substitution of
an amino group with activated o-fluoronitrobenzenes, such as 1-
fluoro-2-nitro-4-(trifluoromethyl)benzene and 1,2-dichloro-4-
fluoro-5-nitrobenzene, proceeded at room temperature, the
reaction with unsubstituted o-fluoronitrobenzene required
elevated temperature (∼50 °C). To further increase the
diversity of the final benzimidazolinopiperazinones, the chlorine
in para position with regard to the nitro group was substituted
with piperidine. All building blocks used in this synthesis are
shown in Figure 2.
Subsequent reduction of the nitro group was carried out with
tin(II) chloride dihydrate in the presence of a base (DIEA) to
afford intermediates 8. Acylation with either Ac2O or carboxylic
acid activated via symmetric anhydride (Fmoc-Gly-OH, 4-
methoxybenzoic acid, 4-bromobenzoic acid) was used for the
final derivatization of the amino group. Reaction with 4-Nos-Cl
afforded appropriate sulfonamides. It was critical for the aniline
nitrogen to be functionalized; otherwise 3,4-dihydro-1H-
quinoxalin-2-one 11 (Scheme 2) was formed as a result of
cyclative cleavage.53 We detected 3,4-dihydro-1H-quinoxalin-2-
ones 11 by LC−MS during routine analysis of intermediates 8.
The target benzimidazolinopiperazinones 10 were obtained
by cleavage of resin-bound intermediates 9 from the resin in
50% trifluoroacetic acid (TFA) in DCM for 90 min. The
substitution patterns of prepared benzimidazolinopiperazinones
10 are described in Table 1. The purity of final crude
compounds was exceptionally high, in the range of 71−99%,
and the total yields were respectable considering a 9- to 13-step
synthesis.
Alternatively, these intermediates can also be obtained using
Route II. The advantage of the Route II over Route I is the
possibility of extending the scope of the target compounds to a
more diverse scaffold. The acylation of Rink resin with various
Fmoc-amino acids was carried out via activation with
diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole
(HOBt) to afford intermediates 4 (Scheme 1, Route II). After
removal of the Fmoc-protecting group in 50% piperidine in
dimethylformamide (DMF) for 15 min, the resin-bound
primary amines were activated with 4-nitrobenzenesulfonyl
chloride (4-Nos-Cl) in dichloromethane (DCM) in the
presence of lutidine to yield appropriate sulfonamides 5. The
subsequent Mitsunobu alkylation with glycolaldehyde dimethyl
acetal afforded N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfona-
mides 6. The Mitsunobu alkylation proceeded without any
impurities, but the conversion did not exceed 90%. As a result
we examined different solvents, namely, anhydrous tetrahy-
drofuran (THF), anhydrous DMF, and anhydrous DCM, as
well as different phosphines (triphenylphosphine or tributyl-
phosphine), and repeated the reaction two times (3 × 16 h).
However, none of these reaction conditions afforded complete
conversion. Finally, 0.1 M solution of the alcohol, 0.1 M PPh3,
and 0.1 M diisopropyl azodicarboxylate (DIAD) in double
volume of anhydrous THF (e.g., we used 20 mL of solution for
1 g of resin) at 50 °C for 16 h and repetition of the Mitsunobu
reaction one time provided satisfactory N-alkylation. Interest-
ingly, the Mitsunobu reaction with glycolaldehyde diethyl acetal
failed to yield N-alkylated product.
The resin-bound sulfonamides 6 were treated with 2-
mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene
5689
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
stereogenic center. Our results are in concord with stereo-
selective synthesis of related bicyclic derivatives tetrahydro-1H-
pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-diones; the absolute
configuration was confirmed by X-ray crystallography.54 In
conlusion, we have confirmed that (S)-configuration on an
amino acid of the acyclic precursor induced the (S)-
configuration on a newly formed stereogenic center (carbon
10a).
Scheme 2. Formation of 3,4-Dihydro-1H-quinoxalin-2-ones
11
a
It is worth noting that the occurrence of two rotamers
depending on the substitution patterns (bulkiness as well as
electronic properties) was observed in NMR spectra. In
general, a bulky R1 substituent increased the amount of the
second rotamer. A similar effect was caused by the electronic
properties of an R4 substituent when the chlorine was replaced
by piperidine. The presence of two rotamers was apparent
mainly at singlet corresponding to the methyl derived from the
acetyl (see the Experimental Section). Herein we reported the
NMR spectra of the major rotamers. 1H NMR spectra of target
compounds acylated with 4-substituted benzoic acids showed
very broad unresolved peaks for both methylene protons at
ambient temperature; therefore, the spectra of derivative
10(1,1,2,4) was measured at elevated temperature (50 °C).
To conclude, we described an efficient solid-phase synthesis
of benzimidazolinopiperazinones via N-acyliminium ion cycli-
zation−nucleophilic addition under mild reaction conditions
using commercially available building blocks. Target com-
pounds with four diversity positions were prepared with full
stereocontrol of the newly formed stereogenic center.
a
Reagents and conditions: (i) 50% TFA in DCM, rt, 30 min.
Importantly, the benzimidazolinopiperazinones 10 are stable
and are not air-oxidized in comparison with the N(10)-
unsubstituted derivatives, benzimidazolinopiperazinones 14
(Scheme 3). To intentionally prepare benzimidazolopiperazi-
nones 15, intermediates 8 were treated with Fmoc-Cl in the
presence of DIEA in DCM for 30 min and yielded intermediate
12. The Fmoc-group served as temporary derivatization of the
primary aniline nitrogen to prevent formation of 3,4-dihydro-
1H-quinoxalin-2-ones 11. Following unmasking of the aldehyde
by 2% TFA in DCM for 16 h, cleavage of the Fmoc-group with
50% piperidine in DMF afforded polymer-supported benzimi-
dazolinopiperazinones 14. Finally, the target benzimidazolopi-
perazinone 15 was obtained after cleavage of the intermediate
14 from the resin with 50% TFA in DCM for 30 min followed
by air oxidation.
The synthesis of benzimidazolinopiperazinones 10 pro-
ceeded with full stereocontrol; the formation of one
EXPERIMENTAL SECTION
■
1
diastereoisomer was confirmed by H and 13C NMR analyses.
Cleavage of Fmoc-Protecting Group and Acylation with
Bromoacetic Acid (Resin 1). Rink resin (100−200 mesh, 0.68
mmol/g, 1 g) was swollen in DCM, washed 3× with DMF, and treated
with 50% piperidine in DMF for 15 min. After washing 3× with DMF
and 3× with DCM, a solution of bromoacetic acid (5 mmol, 700 mg)
in 10 mL of DCM was made in a syringe, and DIC (2.5 mmol, 386
μL) was added. After 5 min, DIU was filtered and DIEA (2.5 mmol,
436 μL) was added to the solution. That solution was added to the
The presence of a proton attached to the carbon 10a indicated
the formation of a fused ring system. The crucial proton
resonated as doublet of doublets at a chemical shift in the range
of 5.6−6.3 ppm (depending on the distribution of electrons).
The J constants were 7−9 Hz and 3−4 Hz, which
unequivocally indicated the configuration of a newly formed
Table 1. Synthesized Derivatives of Benzimidazolinopiperazinones 10
a
b
cmpd
R1
R2
−CH3
−CH3
−CH3
−CH3
−CH3
−CH3
−CH3
−(CH2)4NH2
−(CH2)4NH2
−CH3
−CH2OH
−CH3
R3
R4
R5
purity [%]
MS [M + H]+
yield [%]
10(1,1,1,1)
10(1,1,2,1)
10(1,1,2,2)
10(1,1,2,3)
10(1,1,2,4)
10(1,1,2,5)
10(1,1,4,1)
10(1,2,3,1)
10(2,2,1,1)
10(3,1,3,1)
10(3,3,3,1)
10(4,1,3,1)
10(4,3,3,1)
10(4,3,4,1)
−CH2−
−CH2−
−CH2−
−CH2−
−CH2−
−CH2−
−CH2−
−CH2−
−(CH2)2−
−(CH2)3−
−(CH2)3−
−p-CH2Ph−
−p-CH2Ph−
−p-CH2Ph−
−H
−H
−H
−H
−H
−H
−H
CH3-CO−
CH3-CO−
89
87
95
76
85
71
74
99
94
90
92
82
94
93
303
371
428
463
511
514
420
428
374
399
415
447
463
512
39
36
66
57
63
63
34
19
13
23
36
13
21
30
−CF3
−CF3
−CF3
−CF3
−CF3
−Cl
−Cl
−H
−Cl
−Cl
CH3-CONH-CH2-CO−
−p-CH3OPh-CO−
−p-BrPh-CO−
−p-NO2Ph-SO2−
CH3-CO−
piperidin-1-yl
−Cl
−H
−Cl
−Cl
−Cl
−Cl
CH3-CO−
CH3-CO−
CH3-CO−
CH3-CO−
CH3-CO−
CH3-CO−
CH3-CO−
−Cl
−Cl
−Cl
−CH2OH
−CH2OH
piperidin-1-yl
a
b
Purity of the crude product before purification. Total yield after purification of target compounds prepared in a 9- to 13-step synthesis.
5690
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
a
Scheme 3. Preparation of Benzimidazolopiperazinones 15
a
Reagents and conditions: (i) FmocCl, DIEA, DCM, rt, 30 min; (ii) 2% TFA in DCM, rt, 16 h; (iii) 50% piperidine in DMF, rt, 15 min; (iv) 50%
TFA in DCM, rt, 30 min; (v) 50% TFA in DCM, rt, 16 h.
syringe with the Rink resin and shaken at rt for 16 h and then washed
5× with DCM.
in 10 mL of DCM/DMF (1:1) at rt for 16 h, and were washed 3× with
DMF and 3× with DCM.
Reaction with Aminoacetaldehyde Dimethyl Acetal (Resin
2). Resin 1 (1 g) was swollen in DCM and washed 3× with DMF. A
solution of aminoacetaldehyde dimethyl acetal (10 mmol, 1.09 mL)
and DIEA (10 mmol, 1.74 mL) in 10 mL of DMF was added to the
resin slurry and shaken at rt for 2 h. The resin was washed 3× with
DMF and 3× with DCM.
Acylation with Fmoc-Amino Acids (Resins 3). Resin 2 (1 g)
was swollen in DCM, and a 0.3 M solution of Fmoc-amino acids (3
mmol), HOBt (3 mmol, 460 mg), and DIC (3 mmol, 464 μL) in 10
mL of DCM/DMF (1:1) was added. The resins were shaken at rt for
16 h and washed 3× with DMF and 3× with DCM.
Cleavage of Fmoc-Protecting Group and Reaction with
Unsubstituted or 4,5-Disubstituted o-Fluoronitrobenzenes
(Resins 7). Resins 3 (0.25 g) were swollen in DCM, washed 3×
with DMF, and treated with 50% piperidine in DMF for 15 min. After
washing 3× with DMF and 5× with DMSO, a solution of a 1 M
unsusbtituted or 4,5-disubstituted o-fluoronitrobenzenes (2.5 mmol,
330 μL) and 1 M DIEA (2.5 mmol, 435 μL) in 2.5 mL of dimethyl
sulfoxide (DMSO) was added to the resin, and the resin slurry was
shaken at 50 °C (for unsubstituted o-fluoronitrobenzene) or rt (for
4,5-disubstituted o-fluoronitrobenzenes) for 16 h. The resins were
washed 3× with DMSO and 3× with DCM.
Acylation with Fmoc-Amino Acids (Resins 4). Rink resin
(100−200 mesh, 0.68 mmol/g, 1 g) was swollen in DCM, washed 3×
with DMF, and treated with 50% piperidine in DMF for 15 min. After
washing 3× with DMF and 3× with DCM, a 0.3 M solution of Fmoc-
amino acids (3 mmol), HOBt (3 mmol, 460 mg), and DIC (3 mmol,
464 μL) in 10 mL of DCM/DMF (1:1) was added. The resins were
shaken at rt for 16 h and washed 3× with DMF and 3× with DCM.
Cleavage of Fmoc-Protecting Group and Reaction with 4-
Nos-Cl (Resins 5). Resins 4 (1 g) were washed 3× with DCM and 3×
with DMF and treated with 50% piperidine in DMF for 15 min. After
washing 3× with DMF and 3× with DCM, a solution of 4-Nos-Cl (3
mmol, 663 mg) and lutidine (3.3 mmol, 382 μL) in 10 mL of DCM
was added to the resin, and the resin slurry was shaken at rt for 4 h.
The resin was washed 3× with DCM.
Mitsunobu Alkylation with Glycolaldehyde Dimethyl Acetal
(Resins 6). Resins 5 (1 g) in 20 mL plastic reaction vessel were
washed 3× with anhydrous THF, and a solution of a 0.1 M
glycolaldehyde dimethyl acetal (2 mmol, 202 μL), PPh3 (2 mmol, 525
mg), and 10 mL of anhydrous THF was added to the reaction vessel.
A 10 mL plastic reaction vessel was charged with 0.1 M DIAD (2
mmol, 404 μL) in 10 mL of anhydrous THF. This syringe was
connected to the plastic reaction vessel containing the resin 5.
Connected syringes were left in a freezer for 30 min, and the DIAD
solution was drawn into the syringe with a resin. The resin slurry was
shaken at rt for 10 min and then transferred to a vial and shaken at 50
°C for 16 h. The resin was washed 3× with anhydrous THF and 3×
with DCM. The reaction was repeated for quantitative alkylation.
Cleavage of Nos-Protecting Group and Acylation with
Fmoc-Amino Acids (Resins 3). Resins 6 (1 g) were swollen in
DCM and washed 3× with DMF. A solution of 0.6 M 2-
mercaptoethanol (6 mmol, 420 μL) and 0.2 M DBU (2 mmol, 300
μL) in 10 mL of DMF was added, and resin slurries were shaken for 5
min. The resins were washed 3× with DMF and 3× with DCM. The
resins were subsequently treated with a 0.3 M solution of Fmoc-amino
acids (3 mmol), HOBt (3 mmol, 460 mg), and DIC (3 mmol, 464 μL)
Substitution of Chlorine with Piperidine (Resins 7). Resins 3
(0.25 g) (after substitution with 1,2-dichloro-4-fluoro-5-nitrobenzene)
were swollen in DCM and washed 3× with DMSO, a 0.5 M solution
of piperidine (1.5 mmol, 150 μL) in 3 mL of DMSO was added, and
the resin slurries were shaken at 50 °C for 16 h. The resins were
washed 3× with DMSO and 3× with DCM.
Reduction of the Nitro Group with Tin(II) Chloride
Dihydrate (Resins 8). Resins 7 (0.25 g) were swollen in DCM,
washed 3× with DMF (saturated with N2), and a solution of tin(II)
chloride dihydrate (2.5 mmol, 564 mg) and DIEA (2.5 mmol, 433 μL)
in 2.5 mL of DMF (saturated with N2) was added to the resin. The
resin slurries were shaken at rt for 16 h. The resins were thoroughly
washed 3× with DMF and 3× with DCM.
Acylation with Acetic Anhydride (Resins 9). Resins 8 (0.25 g)
were swollen in DCM, acetic anhydride was added to the resins, and
the resins were shaken at rt for 16 h. The resins were washed 3× with
DCM.
Acylation with Carboxylic Acids (Resins 9). Resins 8 (0.25 g)
were swollen in DCM, and a solution of carboxylic acid (1 mmol) and
DIC (0.5 mmol, 77 μL) in 2.5 mL of DCM/DMF (1:1) was added.
The resins were shaken at rt for 16 h. The resins were washed 3× with
DMF and 3× with DCM.
Sulfonylation with 4-Nos-Cl (Resin 9). Resin 8 (0.25 g) was
washed 3× with DCM. A 0.5 M solution of 4-Nos-Cl (1.25 mmol, 276
mg) and 0.5 M lutidine (1.25 mmol, 145 μL) in 2.5 mL of DCM was
added to the resin, and the reaction slurry was shaken at rt for 16 h.
The resin was washed 5× with DCM.
Reaction with FmocCl (Resin 12). Resin 8 (0.25 g) was swollen
in DCM, and a 0.5 M solution of FmocCl (1.25 mmol, 325 mg) and
0.5 M DIEA (1.25 mmol, 218 μL) in 2.5 mL of DCM was added. The
resin was shaken at rt for 30 min. The resin was washed 3× with
DCM.
Cyclization on Resin (Resin 13). Resin 12 (0.25 g) was swollen
in DCM, and a solution of 2% TFA in 2.5 mL of DCM was added.
5691
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
The resin was shaken at rt for 16 h. The resin was washed 3× with
DCM.
Cleavage of Fmoc-Protecting Group (Resin 14). Resin 13
(0.25 g) was swollen in DCM, washed 3× with DMF, and treated with
50% piperidine in DMF for 15 min. The resin was washed 3× with
DMF and 3× with DCM.
Cleavage, Cyclization (10), Cleavage (15), and Isolation.
Resins 9 and 14 (0.25 g) were treated with 50% TFA in DCM at rt for
90 min. TFA solution was collected, resin was washed 3× with 50%
TFA in DCM, and combined extracts were evaporated by a stream of
nitrogen. The oily residue was dissolved in 1 mL of DMSO and diluted
with 9 mL of 10 mM aqueous ammonium acetate. Depending on the
type of compound, a solution or opalescent solution, occasionally with
precipitation, was formed.
H), 6.44−6.26 (m, 1 H), 4.40 (q, J = 6.9 Hz, 1 H), 4.14 (dd, J = 4.3,
16.6 Hz, 1 H), 4.06−3.99 (m, 2 H), 3.89 (d, J = 16.7 Hz, 1 H), 3.79−
3.62 (m, 2 H), 1.90 (s, 3 H), 1.46 (d, J = 7.0 Hz, 3 H); 13C NMR (151
MHz, DMSO-d6) δ ppm 169.9, 169.6, 168.0, 166.9, 143.8, 131.0, 124.8
(q, J = 270 Hz), 123.9, 123.0 (m), 117.8 (q J = 32.5 Hz), 111.3 (m),
105.6, 70.5, 52.4, 49.9, 41.6, 22.2, 17.9; HRMS (TOF) m/z calcd for
C18H21F3N5O4 [M + H]+ 428.1546, found 428.1540.
A fritted 10 mL syringe was charged with 2 g octadecyl-
functionalized silica gel, and the plug was covered with another
porous disk. Sorbent was wetted with 5 mL of MeCN and washed with
5 mL of 10 mM aqueous ammonium acetate. The solution of the
target compound was passed through the column and was washed with
5 mL of 10 mM aqueous ammonium acetate, and the target
compound was eluted with 5−10 mL of MeCN. The MeCN was
evaporated, and the products were purified by semipreparative reverse
HPLC. All products were isolated by freeze-drying as amorphous
2-((4S,10aS)-10-(4-Methoxybenzoyl)-4-methyl-3-oxo-8-(trifluoro-
methyl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-
1
solids and characterized by LC−MS, HRMS, and H and 13C NMR.
Analytical Data of Individual Compounds. 2-((4S,10aS)-10-
Acetyl-4-methyl-3-oxo-3,4,10,10a-tetrahydrobenzo[4,5]imidazo-
2(1H)-yl)acetamide 10(1,1,2,3). Yield 19.8 mg of amorphous solid
1
(57%): ESI-MS m/z = 463, [M + H]+; H NMR (600 MHz, DMSO-
d6) δ ppm 7.59 (d, J = 8.5 Hz, 2 H), 7.40 (br. s., 1 H), 7.24 (d, J = 8.2
Hz, 1 H), 7.09 (br. s., 1 H), 7.07 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.2
Hz, 1 H), 6.19 (dd, J = 3.8, 8.8 Hz, 1 H), 4.43 (q, J = 7.0 Hz, 1 H),
3.93 (d, J = 16.7 Hz, 1 H), 3.83 (s, 3 H), 3.78 (d, J = 16.7 Hz, 1 H),
3.71 (dd, J = 8.8, 12.0 Hz, 1 H), 1.45 (d, J = 7.0 Hz, 3 H); 13C NMR
(151 MHz, DMSO-d6) δ ppm 169.3, 168.0, 167.0, 161.4, 144.0, 130.9,
129.2, 126.9, 122.5, 124.7 (q, J = 270 Hz), 117.5 (q, J = 32.5 Hz),
114.2, 110.3, 105.7, 71.8, 55.5, 52.3, 50.1, 49.8, 16.9; HRMS (TOF)
m/z calcd for C22H22F3N4O4 [M + H]+ 463.1588, found 463.1570.
2-((4S,10aS)-10-(4-Bromobenzoyl)-4-methyl-3-oxo-8-(trifluoro-
methyl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-
[1,2-a]pyrazin-2(1H)-yl)acetamide 10(1,1,1,1). Yield 9.1 mg of
1
amorphous solid (39%): ESI-MS m/z = 303, [M + H]+; H NMR
(600 MHz, DMSO-d6) δ ppm 7.69 (d, J = 7.3 Hz, 1 H), 7.44 (br. s., 1
H), 7.10 (br. s., 1 H), 6.92 (t, J = 7.5 Hz, 1 H), 6.70−6.62 (m, 2 H),
6.03 (dd, J = 4.7, 7.0 Hz, 1 H), 4.24−4.17 (m, 1 H), 3.98 (d, J = 16.7
Hz, 1 H), 3.91 (d, J = 16.7 Hz, 1 H), 3.63−3.59 (m, 2 H), 2.22 (s, 3
H), 1.45 (d, J = 7.0 Hz, 3 H); 13C NMR (151 MHz, DMSO-d6) δ ppm
169.7, 168.7, 166.9, 141.4, 130.7, 124.7, 118.3, 115.3, 106.8, 71.5, 52.9,
49.7, 49.4, 23.0, 18.2; HRMS (TOF) m/z calcd for C15H19N4O3 [M +
H]+ 303.1457, found 303.1452.
2-((4S,10aS)-10-Acetyl-4-methyl-3-oxo-8-(trifluoromethyl)-
3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-
2(1H)-yl)acetamide 10(1,1,2,4). Yield 24.4 mg of amorphous solid
1
(63%): ESI-MS m/z = 511, [M + H]+; H NMR (600 MHz, DMSO-
d6) δ ppm 7.75 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.29 (br.
s., 1 H), 7.26 (d, J = 8.5 Hz, 1 H), 6.94 (br. s., 1 H), 6.82 (d, J = 8.2
Hz, 1 H), 6.17−6.11 (m, 1 H), 4.41 (q, J = 6.9 Hz, 1 H), 3.92 (d, J =
16.7 Hz, 1 H), 3.80 (d, J = 16.7 Hz, 1 H), 3.74 (td, J = 1.5, 10.1 Hz, 1
H), 3.47 (br. s., 1 H), 1.46 (d, J = 7.0 Hz, 3 H); 13C NMR (151 MHz,
DMSO-d6) δ ppm 169.0, 167.7, 166.0, 143.9, 133.9, 131.8, 130.4,
128.9, 124.3, 124.0 (q, J = 270 Hz), 123.5, 117.5 (q, J = 32.5 Hz),
110.4 (m), 105.6, 71.6, 52.2, 49.9, 49.6, 16.8; HRMS (TOF) m/z calcd
for C21H19BrF3N4O3 [M + H]+ 511.0563, found 511.0587.
acetamide 10(1,1,2,1). Yield 16.3 mg of amorphous solid (36%): ESI-
1
MS m/z = 371, [M + H]+; H NMR (600 MHz, DMSO-d6) δ ppm
7.91 (s, 1 H), 7.46 (br. s., 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.13 (br. s., 1
H), 6.79 (d, J = 8.2 Hz, 1 H), 6.21 (dd, J = 8.4, 3.7 Hz, 1 H), 4.38 (q, J
= 7.0 Hz, 1 H), 4.03 (d, J = 16.7 Hz, 1 H), 3.88 (d, J = 16.7 Hz, 1 H),
3.62−3.73 (m, 2 H), 2.24 (s, 3 H), 1.45 (d, J = 7.0 Hz, 3 H); 13C
NMR (151 MHz, DMSO-d6) δ ppm 169.7, 168.1, 167.7, 144.1, 131.2,
124.9 (q, J = 270 Hz), 122.7, 117.8 (q, J = 32.5 Hz), 111.2, 105.4, 71.6,
52.4, 50.1, 49.9, 23.0, 17.8; HRMS (TOF) m/z calcd for
C16H18F3N4O3 [M + H]+ 371.1331, found 371.1326.
2-((4S,10aS)-10-(2-Acetamidoacetyl)-4-methyl-3-oxo-8-(trifluoro-
methyl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-
2(1H)-yl)acetamide 10(1,1,2,2). Yield 20.9 mg of amorphous solid
(66%): ESI-MS m/z = 428, [M + H]+; 1H NMR (600 MHz, DMSO-
d6) δ ppm 8.34 (t, J = 5.7 Hz, 1 H), 7.90 (br. s., 1 H), 7.47 (br. s., 1
H), 7.30 (d, J = 8.2 Hz, 1 H), 7.15 (br. s., 1 H), 6.82 (d, J = 8.5 Hz, 1
2-((4S,10aS)-4-Methyl-10-((4-nitrophenyl)sulfonyl)-3-oxo-8-(tri-
fluoromethyl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrazin-2(1H)-yl)acetamide 10(1,1,2,5). Yield 24.5 mg of amorphous
1
solid (63%): ESI-MS m/z = 514, [M + H]+; H NMR (600 MHz,
DMSO-d6) δ ppm 8.35 (d, J = 9.1 Hz, 2 H), 8.02 (d, J = 9.1 Hz, 2 H),
7.48 (d, J = 1.8 Hz, 1 H), 7.45 (br. s., 1 H), 7.37 (dd, J = 1.2, 8.2 Hz, 1
H), 7.14 (s, 1 H), 6.73 (d, J = 8.2 Hz, 1 H), 6.17 (dd, J = 4.1, 9.4 Hz, 1
H), 4.24 (q, J = 7.0 Hz, 1 H), 4.01 (d, J = 16.4 Hz, 1 H), 3.82 (d, J =
5692
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
butan-1-aminium Acetate 10(2,2,1,1). Yield 7.0 mg of amorphous
1
solid (13%): APCI-MS m/z = 374, [M + H]+; H NMR (600 MHz,
DMSO-d6) δ ppm 7.70 (d, J = 7.9 Hz, 1 H), 7.38 (br. s., 1 H), 6.89 (t,
J = 7.6 Hz, 1 H), 6.86 (br. s., 1 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.60−
6.65 (m, 1 H), 5.89 (dd, J = 8.5, 3.8 Hz, 1 H), 4.07 (dd, J = 7.5, 4.0 Hz,
2 H), 3.66 (dd, J = 11.9, 3.7 Hz, 2 H), 3.53 (dd, J = 12.0, 8.8 Hz, 2 H),
3.47 (t, J = 6.9 Hz, 2 H), 2.58−2.65 (m, 2 H), 2.36 (br. s., 1 H), 2.27−
2.32 (m, 1 H), 2.25 (s, 2 H), 1.88 (td, J = 9.0, 4.7 Hz, 1 H), 1.78 (s, 3
H), 1.46 (d, J = 5.0 Hz, 2 H), 1.34−1.40 (m, 1 H); 13C NMR (151
MHz, DMSO-d6) δ ppm 173.2, 172.5, 167.3, 166.9, 141.5, 130.4,
124.7, 118.1, 115.4, 106.5, 71.4, 56.9, 48.6, 44.2, 40.1, 33.1, 32.0, 30.5,
23.1, 22.9, 22.5; HRMS (TOF) m/z calcd for C19H28N5O3 [M + H]+
374.2187, found 374.2212.
16.7 Hz, 1 H), 3.76 (dd, J = 9.4, 12.0 Hz, 1 H), 3.48 (dd, J = 4.1, 11.7
Hz, 1 H), 1.16 (d, 3 H); 13C NMR (151 MHz, DMSO-d6) δ ppm
169.5, 167.8, 150.8, 144.9, 140.5, 129.0, 128.5, 125.5 (m), 124.7, 124.5
(q, J = 270 Hz), 118.5 (q, J = 32.5 Hz), 113.3 (m), 107.1, 72.2, 52.1,
50.7, 50.1, 17.6; HRMS (TOF) m/z calcd for C20H19F3N5O6S [M +
H]+ 514.1003, found 514.0983.
4-((4S,10aS)-10-Acetyl-7,8-dichloro-4-methyl-3-oxo-3,4,10,10a-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)butanamide
2-((4S,10aS)-10-Acetyl-8-chloro-4-methyl-3-oxo-7-(piperidin-1-
yl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-
10(3,1,3,1). Yield 12.0 mg of amorphous solid (23%): APCI-MS m/z
1
= 399, [M + H]+; H NMR (600 MHz, DMSO-d6) δ ppm 7.76 (s, 1
H), 7.24 (br. s., 1 H), 6.92 (s, 1 H), 6.73 (br. s., 1 H), 6.10 (dd, J = 7.5,
3.1 Hz, 1 H), 4.29 (q, J = 7.0 Hz, 1 H), 3.61−3.67 (m, 1 H), 3.54−
3.61 (m, 1 H), 3.38−3.41 (m, 1 H), 3.22−3.29 (m, 1 H), 2.27 (s, 3 H),
1.96−2.04 (m, 2 H), 1.59−1.74 (m, 2 H), 1.42 (d, J = 7.0 Hz, 3 H);
13C NMR (151 MHz, DMSO-d6) δ ppm 173.8, 167.6, 167.5, 141.3,
130.9, 126.2, 118.4, 115.8, 107.2, 71.6, 52.5, 48.3, 46.5, 32.3, 22.9, 22.6,
17.9; HRMS (TOF) m/z calcd for C17H21Cl2N4O3 [M + H]+
399.0985, found 399.0956.
yl)acetamide 10(1,1,4,1). Yield 11.3 mg of amorphous solid (34%):
1
APCI-MS m/z = 420, [M + H]+; H NMR (600 MHz, DMSO-d6) δ
ppm 7.65 (s, 1 H), 7.45 (br. s., 1 H), 7.11 (br. s., 1 H), 6.50 (s, 1 H),
6.05 (dd, J = 7.3, 4.4 Hz, 1 H), 4.31 (q, J = 6.8 Hz, 1 H), 4.00 (d, J =
16.7 Hz, 1 H), 3.87 (d, J = 16.7 Hz, 1 H), 3.59−3.64 (m, 2 H), 2.79−
2.92 (m, 4 H), 2.20 (s, 3 H), 1.62 (dt, J = 11.1, 5.5 Hz, 4 H), 1.46−
1.54 (m, 2 H), 1.44 (d, J = 6.7 Hz, 3 H); 13C NMR (151 MHz,
DMSO-d6) δ ppm 169.7, 168.6, 166.7, 147.3, 141.0, 126.2, 116.5,
115.4, 99.8, 71.5, 52.6, 52.5, 49.8, 49.5, 25.9, 23.8, 22.7, 18.3; HRMS
(TOF) m/z calcd for C20H26ClN5NaO3 [M + Na]+ 442.1616, found
442.1618.
4-((4S,10aS)-10-Acetyl-7,8-dichloro-4-(hydroxymethyl)-3-oxo-
3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-
4-((4S,10aS)-10-Acetyl-2-(2-amino-2-oxoethyl)-7,8-dichloro-3-
oxo-1,2,3,4,10,10a-hexahydrobenzo[4,5]imidazo[1,2-a]pyrazin-4-
butanamide 10(3,3,3,1). Yield 20.0 mg of amorphous solid (36%):
1
APCI-MS m/z = 415, [M + H]+; H NMR (600 MHz, DMSO-d6) δ
ppm 7.76 (s, 1 H), 7.23 (br. s., 1 H), 6.89 (s, 1 H), 6.73 (br. s., 1 H),
6.07 (dd, J = 8.7, 4.0 Hz, 1 H), 5.06 (br. s., 1 H), 4.24 (dd, J = 4.5, 3.4
Hz, 1 H), 3.88 (dd, J = 10.4, 4.5 Hz, 1 H), 3.75 (dd, J = 10.3, 2.1 Hz, 1
H), 3.54−3.64 (m, 1 H), 3.46 (dt, J = 13.5, 7.0 Hz, 1 H), 3.29−3.39
(m, 1 H), 3.21 (dt, J = 13.4, 6.8 Hz, 1 H), 2.26 (s, 3 H), 1.98−2.06 (m,
2 H), 1.58−1.73 (m, 2 H); 13C NMR (151 MHz, DMSO-d6) δ ppm
173.8, 167.4, 165.1, 141.6, 130.5, 126.2, 117.9, 115.9, 107.1, 72.5, 62.9,
59.0, 48.1, 46.6, 32.3, 22.8, 22.6; HRMS (TOF) m/z calcd for
C17H21Cl2N4O4 [M + H]+ 415.0934, found 415.0930.
yl)butan-1-aminium acetate 10(1,2,3,1). Yield 6.6 mg of amorphous
1
solid (19%): APCI-MS m/z = 428, [M + H]+; H NMR (600 MHz,
DMSO-d6) δ ppm 7.77 (s, 1 H), 7.45 (br. s., 1 H), 7.11 (br. s., 1 H),
6.93 (s, 1 H), 6.11 (dd, J = 8.1, 4.0 Hz, 1 H), 4.28 (dd, J = 7.9, 4.1 Hz,
1 H), 4.02 (d, J = 16.7 Hz, 1 H), 3.81 (d, J = 16.7 Hz, 1 H), 3.60−3.70
(m, 2 H), 2.60 (t, J = 5.9 Hz, 2 H), 2.24 (s, 3 H), 1.83−1.93 (m, 2 H),
1.40−1.50 (m, 4 H), 1.28−1.37 (m, 2 H); 13C NMR (151 MHz,
DMSO-d6) δ ppm 173.5, 169.5, 167.7, 167.4, 141.9, 130.8, 126.2,
118.3, 115.8, 107.3, 71.8, 56.8, 49.8, 49.7, 40.1, 31.7, 30.6, 23.1, 22.9,
22.3; HRMS (TOF) m/z calcd for C18H24Cl2N5O3 [M + H]+
428.1251, found 428.1243.
4-(((4S,10aS)-10-Acetyl-7,8-dichloro-4-methyl-3-oxo-3,4,10,10a-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)methyl)-
4-((4S,10aS)-10-Acetyl-2-(3-amino-3-oxopropyl)-3-oxo-
1,2,3,4,10,10a-hexahydrobenzo[4,5]imidazo[1,2-a]pyrazin-4-yl)-
benzamide 10(4,1,3,1). Yield 8.0 mg of amorphous solid (13%):
1
APCI-MS m/z = 447, [M + H]+; H NMR (600 MHz, DMSO-d6) δ
ppm 7.93 (br. s., 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 7.73 (s, 1 H), 7.34
(br. s., 1 H), 7.29 (d, J = 7.6 Hz, 2 H), 6.96 (s, 1 H), 6.17 (dd, J = 7.3,
3.2 Hz, 1 H), 4.73 (d, J = 15.3 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 3.68
5693
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
(dd, J = 12.2, 2.8 Hz, 1 H), 3.52−3.58 (m, 1 H), 2.17 (s, 3 H), 1.47 (d,
J = 6.7 Hz, 3 H); 13C NMR (151 MHz, DMSO-d6) δ ppm 168.1,
167.5, 167.5, 141.2, 140.0, 133.3, 130.9, 127.7, 127.3, 126.2, 118.7,
115.8, 107.5, 71.6, 52.7, 49.8, 48.7, 22.9, 17.6; HRMS (TOF) m/z
calcd for C21H21Cl2N4O3 [M + H]+ 447.0985, found 447.0978.
4-(((4S,10aS)-10-Acetyl-7,8-dichloro-4-(hydroxymethyl)-3-oxo-
3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra associated with this article. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: vkrchnak@nd.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Department of Chemistry
and Biochemistry, University of Notre Dame, by the Projects
P207/12/0473 from GACR and CZ.1.07/2.3.00/20.0009 from
the European Social Fund. The infrastructural part of this
project (Institute of Molecular and Translational Medicine)
was supported by the Operational Programme Research and
Development for Innovations (Project CZ.1.05/2.1.00/
01.0030). We gratefully appreciate the use of the NMR facility
at the University of Notre Dame.
methyl)benzamide 10(4,3,3,1). Yield 13.7 mg of amorphous solid
(21%): APCI-MS m/z = 463, [M + H]+; 1H NMR (600 MHz,
DMSO-d6) δ ppm 7.93 (br. s., 1 H), 7.81 (d, J = 8.5 Hz, 2 H), 7.72 (s,
1 H), 7.28−7.39 (m, 3 H), 6.92 (s, 1 H), 6.14 (dd, J = 8.8, 3.2 Hz, 1
H), 5.13−5.20 (m, 1 H), 4.76 (d, J = 15.3 Hz, 1 H), 4.49 (d, J = 15.3
Hz, 1 H), 4.41 (t, J = 3.7 Hz, 1 H), 3.98 (dd, J = 10.0, 4.4 Hz, 1 H),
3.76−3.83 (m, 1 H), 3.63 (dd, J = 12.0, 2.9 Hz, 1 H), 3.49−3.56 (m, 1
H), 2.16 (s, 3 H); 13C NMR (151 MHz, DMSO-d6) δ ppm 167.5,
167.3, 165.7, 141.5, 139.9, 133.2, 130.5, 127.7, 127.3, 126.2, 118.0,
115.9, 107.2, 72.6, 63.0, 59.0, 50.0, 48.5, 22.8; HRMS (TOF) m/z
calcd for C21H21Cl2N4O4 [M + H]+ 463.0934, found 463.0923.
4-(((4S,10aS)-10-Acetyl-8-chloro-4-(hydroxymethyl)-3-oxo-7-(pi-
peridin-1-yl)-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]-
REFERENCES
■
(1) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54 (10),
3451−3479.
(2) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. J. Med.
Chem. 2011, 54 (19), 6405−6416.
(3) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52 (21),
6752−6756.
(4) Topuzyan, V. O.; Kazandzhyan, M. M.; Tamazyan, R. A.;
Aivazyan, A. G. Russ. J. Org. Chem. 2009, 45 (2), 215−217.
(5) Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron 2010, 66 (42),
8231−8237.
(6) Konopski, L.; Serafinowa, B. Cyclic imides of benzimidazole
derivatives. PL 109420, 1976.
pyrazin-2(1H)-yl)methyl)benzamide 10(4,3,4,1). Yield 21.4 mg of
1
amorphous solid (30%): APCI-MS m/z = 512, [M + H]+; H NMR
(7) Serafin, B.; Konopski, L. Pol. J. Chem. 1978, 52 (1), 51−62.
(8) El-Ablack, F. Z. E-J. Chem. 2011, 8 (2), 748−752.
(9) Meng, T.; Zhang, Y.; Li, M.; Wang, X.; Shen, J. J. Comb. Chem.
2010, 12 (2), 222−224.
(10) El Kaim, L.; Grimaud, L.; Purumandla, S. R. J. Org. Chem. 2011,
76 (11), 4728−4733.
(11) Jordan, A. D.; Vaidya, A. H.; Rosenthal, D. I.; Dubinsky, B.;
Kordik, C. P.; Sanfilippo, P. J.; Wu, W. N.; Reitz, A. B. Bioorg. Med.
Chem. Lett. 2002, 12 (17), 2381−2386.
(12) Maryanoff, B. E.; Ho, W.; McComsey, D. F.; Reitz, A. B.; Grous,
P. P.; Nortey, S. O.; Shank, R. P.; Dubinsky, B.; Taylor, R. J., Jr.;
Gardocki, J. F. J. Med. Chem. 1995, 38, 16−20.
(13) Ohta, S.; Naita, Y.; Yuasa, T.; Hatakeyama, S.; Kobayashi, M.;
Kaibe, K.; Kawasaki, I.; Yamashita, M. Chem. Pharm. Bull. 1991, 39,
2787.
(600 MHz, DMSO-d6) δ ppm 7.89−7.97 (m, 1 H), 7.81 (d, J = 7.9 Hz,
2 H), 7.61 (s, 1 H), 7.25−7.36 (m, 3 H), 6.52−6.59 (m, 1 H), 6.06
(dd, J = 9.0, 3.7 Hz, 1 H), 5.13−5.18 (m, 1 H), 4.71 (d, J = 15.6 Hz, 1
H), 4.52 (d, J = 15.3 Hz, 1 H), 4.35−4.43 (m, 1 H), 3.97−4.09 (m, 1
H), 3.77 (d, J = 4.1 Hz, 1 H), 3.59 (dd, J = 12.2, 3.7 Hz, 1 H), 3.41−
3.49 (m, 1 H), 2.78−2.91 (m, 4 H), 2.12 (s, 3 H), 1.58−1.66 (m, 4 H),
1.48−1.52 (m, 2 H); 13C NMR (151 MHz, DMSO-d6) δ ppm 167.6,
166.9, 166.3, 147.3, 141.0, 139.9, 133.3, 127.7, 127.3, 125.6, 116.7,
115.0, 99.8, 72.3, 63.4, 58.9, 52.5, 49.9, 48.1, 25.9, 23.8, 22.6; HRMS
(TOF) m/z calcd for C26H31ClN5O4 [M + H]+ 512.2059, found
512.2053.
(S)-2-(4-Methyl-3-oxo-8-(trifluoromethyl)-3,4-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrazin-2(1H)-yl)acetamide 15(1,1,2). Yield 4.6 mg of
(14) Chiba, T.; Shigeta, S.; Numazaki, Y. Biol. Pharm. Bull. 1995, 18
(8), 1081−1083.
(15) Badawey, E. S. A. M.; Gohar, Y. M. Farmaco 1992, 47 (4), 489−
496.
(16) Thummanagoti, S.; Yellol, G. S.; Sun, C.-M. Tetrahedron Lett.
2011, 52, 2818−2822.
1
amorphous solid (14%): ESI-MS m/z = 327, [M + H]+; H NMR
(17) Kim, Y.; Kumar, M. R.; Park, N.; Heo, Y.; Lee, S. J. Org. Chem.
2011, 76 (23), 9577−9583.
(600 MHz, DMSO-d6) δ ppm 8.00 (s, 1 H), 7.92 (d, J = 8.5 Hz, 1 H),
7.60 (dd, J = 8.5, 1.2 Hz, 1 H), 7.57 (br. s., 1 H), 7.18 (br. s., 1 H),
5.34 (q, J = 6.9 Hz, 1 H), 5.03 (d, J = 16.4 Hz, 1 H), 4.80 (d, J = 16.7
Hz, 1 H), 4.14 (d, J = 16.7 Hz, 1 H), 4.04 (d, J = 16.7 Hz, 1 H), 1.63
(d, J = 7.0 Hz, 3 H); 13C NMR (151 MHz, DMSO-d6) δ ppm 169.3,
166.6, 147.9, 142.8, 135.1, 124.1, 123.3 (m), 118.8 (m), 116.1 (m),
111.8, 52.6, 49.0, 46.0, 18.9 HRMS (TOF) m/z calcd for
C14H14F3N4O2 [M + H]+ 327.1062, found 327.1063.
(18) Adharvana, C. M.; Shobha, D.; Sasaki, T. Tetrahedron Lett. 2011,
52 (43), 5575−5580.
(19) Raghavendra, G. M.; Ramesha, A. B.; Revanna, C. N.; Nandeesh,
K. N.; Mantelingu, K.; Rangappa, K. S. Tetrahedron Lett. 2011, 52
(43), 5571−5574.
(20) Moorthy, J. N.; Neogi, I. Tetrahedron Lett. 2011, 52 (30), 3868−
3871.
5694
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695

The Journal of Organic Chemistry
Article
(21) Siddappa, C.; Kambappa, V.; Siddegowda, A. K. C.; Rangappa,
(54) Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.;
Kahn, M. J. Am. Chem. Soc. 1999, 121 (51), 12204−12205.
K. S. Tetrahedron Lett. 2010, 51 (50), 6493−6497.
(22) Krchn
1627−1630.
(23) Smith, J. M.; Krchn
7633−7636.
̌ ́ ́
ak, V.; Smith, J.; Vagner, J. Tetrahedron Lett. 2001, 42,
̌ ́
ak, V. Tetrahedron Lett. 1999, 40 (43),
(24) Lim, H.-J.; Myung, D.; Lee, I. Y. C.; Jung, M. H. J. Comb. Chem.
2008, 10, 501−503.
(25) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Rao, M.
V. Mini-Rev. Med. Chem. 2006, 6, 71−89.
(26) Ries, U. J.; Mihm, G.; Narr, B.; Hasselbach, K. M.; Wittneben,
H.; Entzeroth, M.; van Meel, J. C.; Wienen, W.; Hauel, N. H. J. Med.
Chem. 1993, 36 (25), 4040−4051.
(27) Zhao, Z.; Arnaiz, D. O.; Griedel, B.; Sakata, S.; Dallas, J. L.;
Whitlow, M.; Trinh, L.; Post, J.; Liang, A.; Morrissey, M. M.; Shaw, K.
J. Bioorg. Med. Chem. Lett. 2000, 10 (9), 963−966.
(28) Ansari, K.; Lal, C. J. Chem. Sci. 2009, 121 (6), 1017−1025.
(29) Sriramurthy, V.; Kwon, O. Org. Lett. 2010, 12 (5), 1084−1087.
(30) Kuethe, J. T.; Varon, J.; Childers, K. G. Tetrahedron 2007, 63
(46), 11489−11502.
(31) Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo, H.;
Venkataraman, K.; Olah, G. A. Org. Lett. 2006, 9 (2), 179−182.
(32) Khurana, J. M.; Kukreja, G.; Bansal, G. J. Chem. Soc., Perkin
Trans. 1 2002, No. 22, 2520−2524.
(33) Mohanazadeh, F.; Nami, N.; Hosseini, S. S. Chin. J. Chem. 2011,
29 (5), 1055−1058.
(34) Rivera, A.; Maldonado, M.; Casas, J. L.; Duse
Acta Crystallogr. 2011, E67, o990.
̌
k, M.; Fejfarova,
́
K.
(35) Vojkovsky, T.; Weichsel, A.; Pat
(10), 3162−3163.
́
ek, M. J. Org. Chem. 1998, 63
́
(36) Stasiak, M.; Kahn, M. Preparation of imidazolopyrazinediones as
integrin-mediated cell adhesion inhibitors. WO 01/16135, 2001.
(37) Argese, M.; Brocchetta, M.; Manfredi, G.; Rebasti, F.; Ripa, G. A
process for the preparation of decahydro-2a,4a,6a,8a-tetraaza-
cyclopent[fg]acenaphthylene and functionalized derivatives. WO
2001079207, 2001.
(38) Flohr, S.; Stengelin, S.; Gossel, M.; Klabunde, T. Preparation of
hexahydropyrazino(1,2-a)pyrimidin-4,7-diones for the treatment of
anorexia. WO 2004/072076, 2004.
(39) Kahn, M. a-Helical peptide mimetics, their preparation and
methods of their use for treating cancer stem cells. WO 2007/056593,
2007.
(40) Delepine, A.-S.; Tripier, R.; Bernard, H.; Le Bris, N.; Handel, H.
Tetrahedron Lett. 2009, 50 (21), 2521−2524.
(41) Argese, M.; Brocchetta, M.; De Miranda, M.; Paoli, P.; Perego,
F.; Rossi, P. Tetrahedron 2006, 62 (29), 6855−6861.
(42) Kahn, M. a-Helical peptide mimetics, their preparation and
methods of their use for treating fibrotic disorders. WO 2007056513,
2007.
(43) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009, 65
(16), 3222−3231.
́
(44) Gonzalez-Temprano, I.; Osante, I.; Lete, E.; Tomayor, N. J. Org.
Chem. 2004, 69 (11), 3875−3885.
(45) Min, B. J.; Gu, X.; Yamamoto, T.; Petrov, R. R.; Qu, H.; Lee, Y.
S.; Hruby, V. J. Tetrahedron Lett. 2008, 49 (14), 2316−2319.
(46) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002,
67 (8), 2424−2428.
(47) Kohn, W. D.; Zhang, L. Tetrahedron Lett. 2001, 42 (27), 4453−
4457.
(48) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104 (5),
2311−2352.
(49) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56 (24),
3817−3856.
(50) Yazici, A.; Pyne, S. G. Synthesis 2009, 3, 339−368.
(51) Yazici, A.; Pyne, S. G. Synthesis 2009, 4, 513−541.
(52) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Org. Chem.
2008, 74 (1), 58−63.
(53) Neagoie, C.; Krchn
DOI: 10.1021/co300023b.
̌ ́
ak, V. ACS Comb. Sci. 2012, 13,
5695
dx.doi.org/10.1021/jo300836c | J. Org. Chem. 2012, 77, 5687−5695