L-Proline and related chiral heterocyclic amino acids as scaffolds for the synthesis of functionalized 2-amino-1,3-selenazole-5-carboxylates

Article abstract of DOI:10.1007/s10593-018-2291-1

[Figure not available: see fulltext.] A series of methyl 2-amino-1,3-selenazole-5-carboxylates possessing a chiral pyrrolidin-2-yl, piperidin-2-yl, or piperidin-3-yl substituent at the C-4 atom of the heteroaromatic ring was designed and synthesized. In the first stage of the synthesis, the carboxylic acid functional group of the L-proline or related chiral heterocyclic amino acid was converted to the corresponding β-keto ester, which was then α-brominated with N-bromosuccinimide. The subsequent reaction of the α-brominated β-keto ester with selenourea afforded the target methyl 2-amino-1,3-selenazole-5-carboxylate. The structures of the novel heterocyclic compounds were confirmed by ¹H, ¹³C, and ⁷⁷Se NMR spectroscopy and HRMS.

Full text of DOI:10.1007/s10593-018-2291-1

DOI 10.1007/s10593-018-2291-1
Chemistry of Heterocyclic Compounds 2018, 54(4), 469–473
L-Proline and related chiral heterocyclic amino acids
as scaffolds for the synthesis of functionalized
2-amino-1,3-selenazole-5-carboxylates
1
,2
1
1
1
Vida Malinauskienė , Aistė Kveselytė , Karolina Dzedulionytė , Aurimas Bieliauskas ,
1
3
1,2
Saulius Burinskas , Frank A. Sløk , Algirdas Šačkus *
1
Institute of Synthetic Chemistry, Kaunas University of Technology,
5
9 K. Baršausko St., Kaunas LT-51423, Lithuania; e-mail: algirdas.sackus@ktu.lt
2
3
Department of Organic Chemistry, Kaunas University of Technology,
9 Radvilenų Pl., Kaunas LT-50254, Lithuania; e-mail: vidulei@gmail.com
Vipergen ApS,
3A Gammel Kongevej, Copenhagen V DK-1610, Denmark; e-mail: fas@vipergen.com
1
2
Published in Khimiya Geterotsiklicheskikh Soedinenii,
018, 54(4), 469–473
Submitted January 15, 2018
Accepted February 13, 2018
2
A series of methyl 2-amino-1,3-selenazole-5-carboxylates possessing a chiral pyrrolidin-2-yl, piperidin-2-yl, or piperidin-3-yl substituent
at the C-4 atom of the heteroaromatic ring was designed and synthesized. In the first stage of the synthesis, the carboxylic acid functional
group of the L-proline or related chiral heterocyclic amino acid was converted to the corresponding β-keto ester, which was then
α-brominated with N-bromosuccinimide. The subsequent reaction of the α-brominated β-keto ester with selenourea afforded the target
1
13
77
methyl 2-amino-1,3-selenazole-5-carboxylate. The structures of the novel heterocyclic compounds were confirmed by H, C, and Se
NMR spectroscopy and HRMS.
Keywords: 2-amino-1,3-selenazole, N-bromosuccinimide, heterocyclic amino acids, β-keto esters, L-proline.
(
S)-Pyrrolidine-2-carboxylic acid (L-proline) is an
mation of only the L-proline carboxylic group, the
synthesis provides pyrrolidin-2-yl-substituted heterocycles.
Recent examples of applications of this strategy include the
important scaffold for the preparation of various functio-
1
nalized heterocycles. When both the amino and carboxylic
8
functional groups of this amino acid are employed in the
construction of a molecular skeleton, the formation of a
chiral condensed heterocyclic system can be achieved. For
example, this synthetic strategy has been applied for the
preparation of pyrrolidin-2-yl-substituted chiral thiazole,
9
10
11
selenazole, coumarin, and phenanthridine derivatives.
In the present work, L-proline and related heterocyclic
amino acids were used in the preparation of novel methyl
2-amino-1,3-selenazole-5-carboxylate derivatives possessing
a chiral N-Boc-protected cycloamino substituent at the
heteroaromatic ring.
2
preparation of chiral pyrrolizidine, pyrrolo[1,2-c][1,3]-
3
4
oxazole, pyrrolo[2,1-c][1,4]benzodiazepine, and benzo[f]-
5
pyrrolo[1,2-a][1,4]diazepine derivatives. Three-component
reactions involving L-proline, isatin, and olefinic dipolaro-
philes, such as chalcones, aroylacrylic acids, or acryl-
amides, gave spiro-fused heterocyclic compounds,
Functionalized 1,3-selenazole moieties are present in
many pharmacologically active substances. Notable examples
12
include potent antiviral agent named selenazofurin and
6
13
including spiro[indole-3,3'-pyrrolizines]. The mechanism
histamine
2
H -receptor agonist named amselamine.
of this reaction involves the decarboxylation of the
intermediate proline coupling adduct with isatin, leading to
the formation of an azomethine ylide, which further
Recently, a series of novel 1,3-selenazole-containing
1,3,4-thiadiazole derivatives have been prepared, and their
anticancer activity have been evaluated.14
In the past few decades, various methods for the
construction of 1,3-selenazole ring systems have been
developed. Most of them are based on the reactions of
undergoes a facile intermolecular 1,3-dipolar cycloaddition
7
reaction with
a
dipolarophile. However, when the
construction of a heterocyclic core is based on a transfor-
0
009-3122/18/54(4)-0469©2018 Springer Science+Business Media, LLC
469

Chemistry of Heterocyclic Compounds 2018, 54(4), 469–473
Scheme 1
α-halocarbonyl compounds with selenium-containing
reagents. 2-Unsubstituted 1,3-selenazoles can be obtained
by the cyclization of α-bromoacetaldehyde or α-bromo-
tives of the aforementioned heterocyclic system have been
identified as potent kinase inhibitors.22
To prepare intermediate β-keto esters 2c–f, as in the case
of β-keto esters 2a,b, we applied the Meldrum's acid
method. After isolation from their respective reaction
mixtures, β-keto esters 2c–f were identified by LCMS and
NMR spectroscopy and immediately treated with NBS in
acetonitrile to afford brominated compounds 3c–f. The
reactions of compounds 3c–f with selenourea afforded the
target 4-(piperidinyl)-substituted 1,3-selenazole-5-carb-
oxylates 4c–f.
1
4
acetophenones with selenoformamide. The reactions of
α-bromo ketones with seleno amides afforded 2-alkyl-,
2
-arylmethyl-, and 2-aryl-substituted 1,3-selenazoles,15,16
while treatment of α-bromo ketones with selenourea gave
17
2
-amino-1,3-selenazoles. Finally, 2-amino-1,3-selenazole-
5
-carboxylates have been prepared by the reaction of
1
8
selenourea with an α-brominated β-keto ester.
The synthetic strategy toward novel 1,3-selenazole
derivatives is outlined in Scheme 1. In case of L-proline the
synthetic sequence began with the preparation of β-keto
ester 2a from N-Boc-L-proline (1a). Greck et al. obtained
To evaluate chemical properties of the synthesized
2-amino-1,3-selenazole-5-carboxylates, we treated com-
pound 4f with acetyl chloride in the presence of Et N and
3
2b
19
the desired ester 2a in Masamune reaction treating
pyrrolidine-2-carboxylic acid with carbonyldiimidazole and
magnesium salt of methylmalonate. However, it has
recently been shown that N-Boc-piperidine-3-carboxylic
acid, which is structurally similar to N-Boc-L-proline (1a),
can be easily converted to the corresponding β-keto ester
by methanolysis of its adduct with Meldrum's acid.20
obtained N-acetylated compound 5 in 78% yield (Scheme 2).
Scheme 2
Treatment of N-Boc-L-proline (1a) with Meldrum's acid
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
in the presence of DMAP, followed by heating of the
intermediate isolated from the reaction mixture in
methanol, afforded β-keto ester 2a. The bromination of
1
The H NMR spectra of compounds 4a–f revealed
characteristic resonance for the Boc-group protons, namely,
a singlet in the 1.15–1.45 ppm region, while the signal of
21
compound 2a was carried out with NBS in acetonitrile.
The reaction afforded desired brominated compound 3a as
a viscous yellow oil which was immediately taken to the
next step. The reaction of compound 3a with selenourea
was performed in MeOH at room temperature. A standard
workup of the reaction mixture and purification of the
product by column chromatography on silica gel afforded
the target product, methyl 2-amino-4-[(2S)-1-(tert-butoxy-
carbonyl)pyrrolidin-2-yl]-1,3-selenazole-5-carboxylate (4a),
in 20% yield (from N-Boc-L-proline (1a)). The (R)-isomer
the protons of the CO Me group appeared as a singlet at
2
3.68–3.76 ppm. The 13C NMR spectra of compounds 4a–f
exhibited signals for the three carbon atoms of the
1,3-selenazole ring in the regions of 111.1–114.6 ppm for
C-5 atom, 165.0–167.2 ppm for C-4 atom, and 172.5–
173.8 ppm for C-2 atom. The 77Se NMR spectra of 4a–f
contained a singlet in the 572.9–579.3 ppm region. The
observed 77Se chemical shifts are consistent with data
reported in the literature for 1,3-selenazoles possessing
similar structures.23
4
b was obtained in 21% yield by an analogous synthetic
protocol starting from N-Boc-D-proline (1b).
The synthesized 1,3-selenazole derivatives 4a–f and 5
exhibited optical activity. The corresponding (R)- and
(S)-enantiomers rotated the plane of plane-polarized light
in equal amounts, but in opposite directions. The specific
Encouraged by these results, we further investigated the
synthesis of this type of 1,3-selenazole derivative employing
N-Boc-protected (S)- and (R)-piperidine-2- and -3-carboxylic
acids 1c–f as starting materials. Recently, racemic
piperidine-2- and piperidine-3-carboxylic acids have been
used to incorporate piperidine ring into the pyrazolo[1,5-a]-
pyrimidine system as a substituent. The required inter-
mediate β-keto esters in such case have been obtained
using the coupling of piperidine-2- and 3-carboxylic acids
with the magnesium salt of monomethyl malonate. Deriva-
optical rotation was dependent on a type of solvent
applied.24 For example, specific rotation [α]
20
for the
D
solution of compound 5 in methanol was +5.9°, while the
corresponding rotation value for the solution in CH
+106.6°.
2
Cl was
2
Thus, a series of new N,O-protected chiral heterocyclic
amino acids that contain 1,3-selenazole structural unit and
4
70

Chemistry of Heterocyclic Compounds 2018, 54(4), 469–473
can be considered as constrained synthetic analogs of
-aminobutyric acid or 5-aminovaleric acid was designed
and synthesized. These chiral amino acids can potentially
be used as scaffolds for the synthesis of more complex
molecules with biological activity or be used as building
blocks for the development of DNA-encoded chemical
libraries.
temperature for 3 h. Then the solvent was removed under
4
reduced pressure and the crude product was purified by
column chromatography on silica gel (hexane–EtOAc,
gradient from 4:1 to 2:1).
Methyl 2-amino-4-[(2S)-1-(tert-butoxycarbonyl)-
pyrrolidin-2-yl]-1,3-selenazole-5-carboxylate (4a). Yield
150 mg (20%), white powder, mp 225°C (decomp.),
2
0
R
f
0.21 (hexane–EtOAc, 2:1), [α]
D
+4.0 (c 0.5, MeOH).
IR spectrum, ν, cm : 1424 (C–O), 1480 (C=N), 1653
Experimental
–1
1
IR spectra were recorded on a Bruker Vertex 70v FTIR
(C=O), 3194 and 3366 (NH
(J, Hz): 1.15 (9H, s, C(CH
pyrrolidine); 1.90 (1H, dt, J = 16.5, J = 5.4, 4-CH
pyrrolidine); 2.21–2.36 (1H, m, 3-CH
3.54 (2H, m, 5-CH pyrrolidine); 3.69 (3H, s, OCH
(1H, t, J = 7.1, 2-CH pyrrolidine); 7.46 (2H, s, NH
2
). H NMR spectrum, δ, ppm
1
13
spectrometer in thin film. H and C NMR spectra (400
and 101 MHz, respectively) and DEPT-135, COSY,
3
)
3
); 1.69–1.85 (2H, m, 3,4-CH
2
2
1
13
1
13
H– C gs-HSQC, and H– C gs-HMBC experiments were
2
pyrrolidine); 3.38–
); 5.44
).
C NMR spectrum, δ, ppm: 24.2 (C-4 pyrrolidine); 28.1
(C(CH ); 32.9 (C-3 pyrrolidine); 47.2 (C-5 pyrrolidine);
51.7 (OCH ); 56.3 (C-2 pyrrolidine); 79.5 (C(CH ); 111.1
); 165.9
recorded on a Bruker Avance III 400 instrument in CDCl
solutions at 25°C, using TMS as internal standard.
3
2
3
2
77
13
Se NMR spectra were obtained on a Bruker Avance III 400
instrument (76 MHz, absolute referencing via frequency
ratio) in CDCl with a direct detection using broad band
)
3 3
3
)
3 3
3
observe (BBO) probe. HRMS were recorded on a
micrOTOF-Q III Bruker spectrometer in electrospray
ionization mode. Melting points were determined on a Melt-
Temp Capillary Melting point Apparatus and are uncor-
rected. Specific optical rotation data were obtained on a
UniPol L SCHMIDT+HAENSCH polarimeter using standard
Method 3 (concentration of compound was included in
calculations automatically). Samples were dissolved in
(C-5 selenazole); 154.8 (NCO); 164.0 (COOCH
3
77
(C-4 selenazole); 173.8 (C-2 selenazole). Se NMR
+
spectrum, δ, ppm: 573.6. Found, m/z: 376.0771 [M+H] .
C
14
H
22
N
3
O Se. Calculated, m/z: 376.0771.
4
Methyl 2-amino-4-[(2R)-1-(tert-butoxycarbonyl)-
pyrrolidin-2-yl]-1,3-selenazole-5-carboxylate (4b). Yield
158 mg (21%), white powder, mp 225°C (decomp.),
2
0
R
f
0.21 (hexane–EtOAc, 2:1), [α]
D
–4.0 (c 0.5, MeOH).
–1
MeOH or CH
Cl
2 2
, stored at room temperature for 1 h, and
IR spectrum, ν, cm : 1424 (C–O), 1480 (C=N), 1653
1
placed in 20-cm tube for the measurement. The purification
of the reaction mixtures was performed using flash
chromatography on a glass column with silica gel (high-
purity grade, Merck grade 9385, pore size 60 Å, particle size
(C=O), 3194 and 3366 (NH
(J, Hz): 1.15 (9H, s, C(CH
pyrrolidine); 1.90 (1H, dt, J = 16.5, J = 5.4, 4-CH
pyrrolidine); 2.21–2.36 (1H, m, 3-CH
3.54 (2H, m, 5-CH pyrrolidine); 3.69 (3H, s, OCH
(1H, t, J = 7.1, 2-CH pyrrolidine); 7.46 (2H, s, NH
2
). H NMR spectrum, δ, ppm
3
)
3
); 1.69–1.85 (2H, m, 3,4-CH
2
2
2
pyrrolidine); 3.38–
); 5.44
).
C NMR spectrum, δ, ppm: 24.2 (C-4 pyrrolidine); 28.1
(C(CH ); 32.9 (C-3 pyrrolidine); 47.2 (C-5 pyrrolidine);
51.7 (OCH ); 56.3 (C-2 pyrrolidine); 79.5 (C(CH ); 111.1
); 165.9
2
30–400 mesh). For TLC, Merck precoated TLC plates
2
3
(
Silica gel 60 F254) were employed. The reagents and solvents
2
13
were purchased from commercial suppliers and used
without further purification unless otherwise indicated.
Synthesis of selenazoles 4a–f (General method). EDC
)
3 3
3
)
3 3
(
575 mg, 3 mmol) was added in portions over 15 min to a
(C-5 selenazole); 154.8 (NCO); 164.0 (COOCH
3
77
solution of enantiopure amino acid 1a–f (2.5 mmol),
(C-4 selenazole); 173.8 (C-2 selenazole). Se NMR
+
Meldrum's acid (433 mg, 3 mmol), and DMAP (458 mg,
3
spectrum, δ, ppm: 572.9. Found, m/z: 376.0771 [M+H] .
.75 mmol) in dry CH
Cl
2 2
(10 ml), and the resulting
C
14
H
22
N
3
O Se. Calculated, m/z: 376.0770.
4
mixture was stirred at room temperature overnight. The
reaction mixture was diluted with CH Cl (40 ml), washed
with 10% KHSO aqueous solution (5 × 25 ml) and brine
1 × 50 ml). Organic layer was separated, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure
to give yellowish oil. The crude product was dissolved in
MeOH (15 ml) and heated at reflux overnight. The reaction
mixture was concentrated under reduced pressure and
purified by column chromatography on silica gel (hexane–
EtOAc, gradient from 4:1 to 2:1) to give β-keto ester 2a–f
in 85–90% yield. A solution of β-keto ester 2a–f (2 mmol)
and NBS (427 mg, 2.4 mmol) in MeCN (10 ml) was stirred
at room temperature. After 2 h, the solvent was removed
under reduced pressure, the resulting residue dissolved in
Methyl 2-amino-4-[(2S)-1-(tert-butoxycarbonyl)-
piperidin-2-yl]-1,3-selenazole-5-carboxylate (4c). Yield
195 mg (25%), white powder, mp 183–184°C, R 0.58
–5.1 (c 0.51, MeOH).
IR spectrum, ν, cm : 1392 (C–O), 1489 (C=N), 1669
2
2
4
f
20
(
(hexane–EtOAc, 2:1), [α]
D
–1
2
4
1
(C=O), 3313 and 3398 (NH
(J, Hz): 1.22 (9H, s, C(CH
piperidine); 1.61–1.73 (1H, m, 5-CH
1.91 (2H, m, 3-CH piperidine); 3.38 (1H, dd, J = 16.3,
J = 8.2, 6-CH piperidine); 3.68 (3H, s, OCH ); 3.74–3.85
(1H, m, 6-CH piperidine); 5.61 (1H, dt, J = 11.5, J = 5.4,
2-CH piperidine); 6.61 (2H, s, NH
δ, ppm: 19.2 (C-4 piperidine); 24.1 (C-5 piperidine); 28.4
(C(CH ); 29.2 (C-3 piperidine); 40.9 (C-6 piperidine);
51.8 (OCH ); 52.4 (C-2 piperidine); 79.7 (C(CH ); 111.6
); 167.2
2
). H NMR spectrum, δ, ppm
); 1.41–1.56 (3H, m, 4,5-CH
piperidine); 1.75–
3
)
3
2
2
2
2
3
2
13
2
). C NMR spectrum,
3 3
)
CH
2
Cl
2
(10 ml) and filtered through silica gel, the filter
3
3 3
)
3
cake was washed with CH
2
Cl
2
(100 ml). The filtrate was
(C-5 selenazole); 156.6 (NCO); 163.8 (COOCH
7
7
concentrated under reduced pressure. The resulting residue
was dissolved in MeOH (20 ml), selenourea (246 mg,
(C-4 selenazole); 172.9 (C-2 selenazole). Se NMR
+
spectrum, δ, ppm: 574.1. Found, m/z: 390.0927 [M+H] .
2
mmol) was added, and the mixture was stirred at room
C H
15 24
N
3
4
O Se. Calculated, m/z: 390.0927.
4
71

Chemistry of Heterocyclic Compounds 2018, 54(4), 469–473
Methyl 2-amino-4-[(2R)-1-(tert-butoxycarbonyl)-
piperidin-2-yl]-1,3-selenazole-5-carboxylate (4d). Yield
in CH
room temperature. After 3 h, the reaction mixture was
diluted with CH Cl (45 ml), washed with 5% NaHCO
aqueous solution (2 × 50 ml) and brine (1 × 50 ml).
Organic layer was separated, dried over anhydrous Na SO
filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (hexane–EtOAc, 4:1). Yield 168 mg (78%), white
2
Cl
2
(5 ml), and the resulting mixture was stirred at
1
32 mg (17%), white powder, mp 183–184°C, R
f
0.58
2
2
3
2
0
(
hexane–EtOAc, 2:1), [α]
D
+5.1 (c 0.46, MeOH).
IR spectrum, ν, cm : 1392 (C–O), 1489 (C=N), 1669
–
1
2
4
,
1
(
(
C=O), 3313 and 3398 (NH
2
). H NMR spectrum, δ, ppm
); 1.41–1.56 (3H, m, 4,5-CH
piperidine); 1.75–
piperidine); 3.38 (1H, dd, J = 16.3, J = 8.2,
piperidine); 3.68 (3H, s, OCH ); 3.74–3.85 (1H, m,
piperidine); 5.61 (1H, dt, J = 11.5, J = 5.4, 2-CH
J, Hz): 1.22 (9H, s, C(CH
3
)
3
2
piperidine); 1.61–1.73 (1H, m, 5-CH
2
1
6
6
.91 (2H, m, 3-CH
2
powder, mp 169.0–169.5°C, R
f
0.55 (hexane–EtOAc, 2:1),
20
20
-CH
-CH
2
3
[α]
D
+5.9 (c 0.5, MeOH), [α]
D
+106.6 (c 0.49, CH
2
Cl ).
2
–
1
2
IR spectrum, ν, cm : 1432 (C–O), 1513 (C=N), 1653
1
3
1
piperidine); 6.61 (2H, s, NH
2
). C NMR spectrum, δ, ppm:
);
);
); 111.6 (C-5
); 167.2 (C-4
(C=O), 1695 (C=O), 3159 (NH). H NMR spectrum,
1
2
5
9.2 (C-4 piperidine); 24.1 (C-5 piperidine); 28.4 (C(CH
9.2 (C-3 piperidine); 40.9 (C-6 piperidine); 51.8 (OCH
2.4 (C-2 piperidine); 79.7 (C(CH
3
)
3
3
δ, ppm (J, Hz): 1.50 (9H, s, C(CH
3
)
3
); 1.41–1.70 (3H, m,
piperidine);
); 2.83 (1H, td, J = 12.4, J = 3.0, 6-CH
piperidine); 3.10 (1H, t, J = 12.1, 2-CH piperidine); 3.56–
3.69 (1H, m, 3-CH piperidine); 3.78 (3H, s, OCH ); 4.07–
4.13 (1H, m, 6-CH piperidine); 4.45 (1H, d, J = 12.1,
2-CH piperidine); 11.28 (1H, s, NH). C NMR spectrum,
δ, ppm: 23.2 (COCH ); 26.1 (C-5 piperidine); 28.7
(C(CH ); 31.2 (C-4 piperidine); 38.1 (C-3 piperidine);
45.6 (C-6 piperidine); 47.8 (C-2 piperidine); 51.9 (OCH );
80.0 (C(CH ); 118.9 (C-5 selenazole); 155.8 (NCO);
162.0 (NHCO); 163.3 (COOCH ); 164.8 (C-4 selenazole);
4,5-CH
2
piperidine); 1.82–1.95 (1H, m, 4-CH
2
3
)
3
2.28 (3H, s, COCH
3
2
selenazole); 156.6 (NCO); 163.8 (COOCH
3
2
7
7
selenazole); 172.9 (C-2 selenazole). Se NMR spectrum,
3
+
δ, ppm: 574.6. Found, m/z: 390.0927 [M+H] . C15
H
24
N
3
O
4
Se.
2
13
Calculated, m/z: 390.0927.
2
Methyl 2-amino-4-[(3S)-1-(tert-butoxycarbonyl)-
piperidin-3-yl]-1,3-selenazole-5-carboxylate (4e). Yield
3
)
3 3
3
27 mg (42%), white powder, mp 197–198°C, R
f
0.51
–5.6 (c 0.53, MeOH). IR spectrum,
ν, cm : 1430 (C–O), 1500 (C=N), 1657 (C=O), 3141 and
3
2
0
(
hexane–EtOAc, 2:1), [α]
D
)
3 3
–1
3
1
77
3
304 (NH
s, C(CH
.99 (1H, m, 4-CH
2
). H NMR spectrum, δ, ppm (J, Hz): 1.45 (9H,
); 1.52–1.73 (3H, m, 4,5-CH piperidine); 1.86–
piperidine); 2.61–2.78 (1H, m, 6-CH
piperidine); 3.58–
.71 (1H, m, 3-CH piperidine); 3.76 (3H, s, OCH ); 3.98–
.28 (2H, m, 2,6-CH piperidine); 6.06 (2H, s, NH ).
C NMR spectrum, δ, ppm: 25.4 (C-5 piperidine); 28.6
C(CH ); 30.4 (C-4 piperidine); 38.2 (C-3 piperidine);
4.7 (C-6 piperidine); 48.6 (C-2 piperidine); 51.9 (OCH );
9.6 (C(CH ); 114.6 (C-5 selenazole); 155.1 (NCO);
64.1 (COOCH ); 165.0 (C-4 selenazole); 172.5 (C-2
169.6 (C-2 selenazole). Se NMR spectrum, δ, ppm:
+
3
)
3
2
673.7. Found, m/z: 432.1032 [M+H] . C17
Calculated, m/z: 432.1032.
H
26
N
3
O Se.
5
1
2
2
piperidine); 2.83–3.06 (1H, m, 2-CH
2
3
4
3
This work has been accomplished with financial support
provided by Vipergen ApS company (Copenhagen, Denmark).
2
2
1
3
References
(
)
3 3
4
7
1
3
1. (a) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825.
(
b) Calaza, M. I.; Cativiela, C. In Amino Acids, Peptides and
3 3
)
Proteins in Organic Chemistry; Hughes, A. B., Ed.; Wiley-
VCH: Weinheim, 2010, vol. 3, p. 83. (c) Singh, P.; Samanta, K.;
Das, S. K.; Panda, G. Org. Biomol. Chem. 2014, 12, 6297.
(a) Guerreiro, P.; Ratovelomanana-Vidal, V.; Genêt, J.-P.
Chirality 2000, 12, 408. (b) Greck, C.; Thomassigny, C.;
Le Bouc, G. ARKIVOC 2012, (viii), 231. (c) Kothapalli, Y.;
Puthukanoori, R. K.; Alapati, S. R. Tetrahedron Lett. 2012,
53, 1891.
3
7
7
selenazole). Se NMR spectrum, δ, ppm: 575.8. Found, m/z:
+
3
90.0927 [M+H] . C15
Methyl 2-amino-4-[(3R)-1-(tert-butoxycarbonyl)-
piperidin-3-yl]-1,3-selenazole-5-carboxylate (4f). Yield
33 mg (30%), white powder, mp 197–198°C, R 0.51
+5.6 (c 0.52, MeOH). IR spectrum,
ν, cm : 1430 (C–O), 1500 (C=N), 1657 (C=O), 3141 and
H N
24 3
O
4
Se. Calculated, m/z: 390.0927.
2
.
2
f
2
0
(
hexane–EtOAc, 2:1), [α]
D
–1
3. Dockerty, P.; Edens, J. G.; Tol, M. B.; Angeles, D. M.;
Domenech, A.; Liu, Y.; Hirsch, A. K. H.; Veening, J.-W.;
Scheffers, D.-J.; Witte, M. D. Org. Biomol. Chem. 2017, 15,
1
3
304 (NH
s, C(CH
.99 (1H, m, 4-CH
2
). H NMR spectrum, δ, ppm (J, Hz): 1.45 (9H,
); 1.52–1.73 (3H, m, 4,5-CH piperidine); 1.86–
piperidine); 2.61–2.78 (1H, m, 6-CH
piperidine); 3.58–
.71 (1H, m, 3-CH piperidine); 3.76 (3H, s, OCH ); 3.98–
.28 (2H, m, 2,6-CH piperidine); 6.06 (2H, s, NH ).
C NMR spectrum, δ, ppm: 25.4 (C-5 piperidine); 28.6
C(CH ); 30.4 (C-4 piperidine); 38.2 (C-3 piperidine);
4.7 (C-6 piperidine); 48.6 (C-2 piperidine); 51.9 (OCH );
9.6 (C(CH ); 114.6 (C-5 selenazole); 155.1 (NCO);
64.1 (COOCH ); 165.0 (C-4 selenazole); 172.5 (C-2
3
)
3
2
8
94.
Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Ma, D. Tetrahedron
010, 66, 5714.
Wang, H.; Jiang, Y.; Gao, K.; Ma, D. Tetrahedron 2009, 65,
956.
1
2
2
4.
5.
6.
piperidine); 2.83–3.06 (1H, m, 2-CH
2
2
3
4
3
2
2
8
1
3
(a) Sapnakurami, M.; Narayana, B.; Samshuddin, S.;
Sarojini, B. K. Molbank 2013, 2013, M802. (b) Prasad, T. A. A.;
Vithiya, B. S. M.; Ignacimuthu, S. Pharma Chem. 2011, 3,
(
)
3 3
4
7
1
3
2
93. (c) Ziarani, G. M.; Moradi, R.; Lashgari, N. ARKIVOC
3 3
)
2
016, (i), 1.
3
7
7
7. Pavlovskaya, T. L.; Yaremenko, F. G.; Lipson, V. V.;
Shishkina, S. V.; Shishkin, O. V.; Musatov, V. I.; Karpenko,
A. S. Beilstein J. Org. Chem. 2014, 10, 117.
selenazole). Se NMR spectrum, δ, ppm: 579.3. Found, m/z:
+
3
90.0927 [M+H] . C15
H N
24 3
O Se. Calculated, m/z: 390.0927.
4
Methyl 2-acetylamino-4-[(3R)-1-(tert-butoxycarbonyl)-
piperidin-3-yl]-1,3-selenazole-5-carboxylate (5). Acetyl
chloride (79 mg, 1 mmol) was added to a solution of selen-
8
.
Dai, C.; Li, D.; Popovici-Muller, J.; Zhao, L.;
Girijavallabhan, V. M.; Rosner, K. E.; Lavey, B. J.; Rizvi, R.;
Shankar, B. B.; Wong, M. K.; Guo, Z.; Orth, P.;
Strickland, C. O.; Sun, J.; Niu, X.; Chen, S.; Kozlowski, J. A.;
azole 4f (195 mg, 0.5 mmol) and Et N (51 mg, 0.5 mmol)
3
4
72

Chemistry of Heterocyclic Compounds 2018, 54(4), 469–473
Lundell, D. J.; Piwinski, J. J.; Shih, N.-Y.; Siddiqui, M. A.
18. (a) Kuarm, B. S.; Madhav, J. V.; Rajitha, B. Lett. Org. Chem.
2011, 8, 549. (b) Kanapickaitė, V.; Martynaitis, V.; Šačkus, A.
ARKIVOC 2009, (xi), 268. (c) Narender, M.; Reddy, M. S.;
Kumar, V. P.; Srinivas, B.; Sridhar, R.; Nageswar, Y. V. D.;
Rao, K. R. Synthesis 2007, 3469.
Bioorg. Med. Chem. Lett. 2011, 21, 3172.
Lalithamba, H. S.; Narendra, N.; Naik, S. A.; Sureshbabu, V. V.
ARKIVOC 2010, (xi), 77.
9
.
1
0. Bandyopadhyay, A.; Gopi, H. N. Org. Biomol. Chem. 2011,
9
, 8089.
19. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem.,
Int. Ed. 1979, 18, 72.
1
1
1. Jin, Y.; Jiang, M.; Wang, H.; Fu, H. Sci. Rep. 2016, 6, 20068.
2. (a) Wray, S. K.; Smith, R. H. A.; Gilbert, B. E.; Knight, V.
Antimicrob. Agents Chemother. 1986, 29, 67. (b) Smee, D. F.;
Huffman, J. H.; Hall, L. L.; Huggins, J. W.; Sidwell, R. W.
Antimicrob. Agents Chemother. 1990, 1, 211.
20. Fischmann, T. O.; Le, H. V.; Madison, V. S.; Mannarino, A. F.;
Mayhood, T. W.; Reichert, P.; Smith, C.; Chan, T.-Y. US
Patent 8440443 B1.
21. (a) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.;
Urbano, A. J. Org. Chem. 1995, 60, 5328. (b) Bričkutė, D.;
Sløk, F. A.; Rømming, C.; Šačkus, A. J. Chem. Soc., Perkin
Trans. 1 2002, 652. (c) Pravst, I.; Zupan, M.; Stavber, S.
Green Chem. 2006, 8, 1001.
22. (a) Dwyer, M. P.; Paruch, K.; Labroli, M.; Alvarez, C.;
Keertikar, K. M.; Poker, C.; Rossman, R.; Fischmann, T. O.;
Duca, J. S.; Madison, V.; Parry, D.; Davis, N.; Seghezzi, W.;
Wiswell, D.; Guzi, T. J. Bioorg. Med. Chem. Lett. 2011, 21,
467. (b) Labroli, M.; Paruch, K.; Dwyer, M. P.; Alvarez, C.;
Keertikar, K.; Poker, C.; Rossman, R.; Duca, J. S.;
Fischmann, T. O.; Madison, V.; Parry, D.; Davis, N.;
Seghezzi, W.; Wiswell, D.; Guzi, T. J. Bioorg. Med. Chem.
Lett. 2011, 21, 471.
1
1
1
3. van der Goot, H.; Eriks, J. C.; Leurs, R.; Timmerman, H.
Bioorg. Med. Chem. Lett. 1994, 4, 1913.
4. Below, H.; Pfeiffer, W.-D.; Geisler, K.; Saghyan, A. S.;
Fischer, C.; Langer, P. J. Heterocycl. Chem. 2014, 52, 592.
5. Zhao, H.-C.; Shi, Y.-P.; Liu, Y.-M.; Li, C.-W.; Xuan, L-N.;
Wang, P.; Zhang, K.; Chen, B.-Q. Bioorg. Med. Chem. Lett.
2
013, 23, 6577.
1
6. (a) Geisler, K.; Pfeiffer, W.-D.; Künzler, A.; Below, H.;
Bulka, E.; Langer, P. Synthesis 2004, 875. (b) Geisler, K.;
Künzler, A.; Below, H.; Bulka, E.; Pfeiffer, W.-D.; Langer, P.
Synthesis 2004, 97.
1
7. (a) Maradolla, M.; Chandramouli, G. V. P. Phosphorus,
Sulfur Silicon Relat. Elem. 2011, 186, 1650. (b) Narender, M.;
Reddy, M. S.; Kumar, V. P.; Reddy, V. P.; Nageswar, Y. V. D.;
Rao, K. R. J. Org. Chem. 2007, 72, 1849. (c) Facchinetti, V.;
Avellar, M. M.; Nery, A. C. S.; Gomes, C. R. B.;
Vasconcelos, T. R. A.; de Souza, M. V. N. Synthesis 2016, 437.
23. Nam, K. N.; Koketsu, M.; Lee, E. H. Eur. J. Pharmacol.
2008, 589, 53.
24. Fischer, A. T.; Compton, R. N.; Pagni, R. M. J. Phys. Chem. A
2006, 110, 7067.
4
73