Efficient Synthesis of Nicotinic Acid Based Pseudopeptides Bearing an Amidoxime Function

Article abstract of DOI:10.1055/s-0034-1379917

The synthesis of nicotinic acid based amino acid units bearing an amidoxime function on the pyridine ring has been developed. The starting 2-cyanonicotinic acid was efficiently coupled with methyl esters of l-α-amino acids to afford intermediate 2-cyanopyridin-3-yl-containing pseudopeptides together with the tautomeric methyl esters of (2S)-2-(7-imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)alkanoic acids. Regioselective pyrrolidine ring opening of these esters occurred upon hydroxylamine hydrochloride treatment, giving rise to the open-chain pyridin-3-yl 2-amidoxime pseudopeptides bearing the same structure as amidoximes obtained by direct hydroxyamination of the corresponding cyano esters.

Full text of DOI:10.1055/s-0034-1379917

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2285–2293
paper
2285
O. V. Ovdiichuk et al.
Paper
Synthesis
Efficient Synthesis of Nicotinic Acid Based Pseudopeptides
Bearing an Amidoxime Function
O
R
Olga V. Ovdiichuka,b
Olga V. Hordiyenko*a
Volodymyr V. Medviedievc
Oleg V. Shishkinc,d
S
O
R
S
NH
N
CO2Me
NH
N
CO2Me
N
OH
O
N
Axelle Arraultb
NH2
OH
N
NH2OH.HCl
6 examples
O
and/or
a Taras Shevchenko National University of Kyiv, Chemistry
Department, 64/13 Volodymyrs’ka str., Kyiv 01601, Ukraine
ov_hordiyenko@univ.kiev.ua
b Laboratoire de Chimie Physique Macromoléculaire, ENSIC,
Université de Lorraine, 1 rue Grandville, BP 20451, 54001
Nancy, France
c SSI Institute for Single Crystals, National Academy of Science
of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
d Department of Inorganic Chemistry, V. N. Karazin Kharkiv
National University, 4 Svobody sq., Kharkiv 61122, Ukraine
N
O
Et3N, MeOH, r.t.
67–79%
R
R
N
S
N
CO2Me
N
CO2Me
OH
N
NH
N
Received: 02.02.2015
Accepted after revision: 27.03.2015
Published online: 19.05.2015
Amidoximes have been shown to possess a wide range
of biological activities, and they are important intermedi-
ates in organic synthesis.7 They are also useful as versatile
building blocks for the synthesis of pharmaceutically im-
portant 1,2,4-oxadiazoles and oxadiazole-derived peptido-
mimetics.8–10
In our attempts to develop a new variety of arginine
peptidomimetics with an amidinoheteroaroyl motif in a
peptide chain, we have elaborated the synthesis of nicotinic
acid based amino acid units bearing an amidoxime function
on the pyridine ring as precursors of the corresponding
amidine-containing pseudopeptides.
We envisioned that the coupling of 2-cyanonicotinic
acid (4) with methyl esters of L-α-amino acids with further
conversion of the cyano residue into an amidoxime group
might be employed as a basic strategy for the synthesis of
the target pyridine-based pseudopeptides.
DOI: 10.1055/s-0034-1379917; Art ID: ss-2015-z0069-op
Abstract The synthesis of nicotinic acid based amino acid units bear-
ing an amidoxime function on the pyridine ring has been developed.
The starting 2-cyanonicotinic acid was efficiently coupled with methyl
esters of L-α-amino acids to afford intermediate 2-cyanopyridin-3-yl-
containing pseudopeptides together with the tautomeric methyl esters
of (2S)-2-(7-imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)al-
kanoic acids. Regioselective pyrrolidine ring opening of these esters oc-
curred upon hydroxylamine hydrochloride treatment, giving rise to the
open-chain pyridin-3-yl 2-amidoxime pseudopeptides bearing the
same structure as amidoximes obtained by direct hydroxyamination of
the corresponding cyano esters.
Key words amino acids, coupling, ring opening, amidoximes, pyri-
dines, pseudopeptides, prodrugs
The amidine moiety is known to effectively replace the
guanidine group of arginine that is used in the synthesis of
arginine mimetics for the treatment of blood-coagulation
disorders.1 Other substrates containing basic groups, such
as guanidines and amidinohydrazones, are also known as
thrombin inhibitors. To enhance their oral bioavailability,
the prodrug principle was developed.2,3 Certain amidoxim-
es have been demonstrated to be reduced in vitro and in
vivo to the amidines,4,5 and this approach has been success-
fully applied to the oral thrombin inhibitor Ximelagatran,
an amidoxime prodrug.6
Preparation of the starting acid 4 was perfomed accord-
ing to a known literature procedure;11,12a,b the synthetic
route is depicted in Scheme 1. Thus, commercially available
quinolinic anhydride (1) was first quickly hydrolyzed with
aqueous ammonia (28%), similar to the method developed
for phthalamic acid,11 to give 2-carbamoylnicotinic acid (2).
Then, ester 3 was obtained by treatment of acid 2 with
methyl chloroformate, which was followed by hydrolysis
with sodium hydroxide (1 M) to give the corresponding 2-
cyanonicotinic acid (4) in 28% overall yield.12a,b
O
CO2Me
CN
CO2H
CN
CO2H
iii
ii
79%
i
56%
O
64%
N
N
N
N
CONH2
O
1
2
3
4
Scheme 1 Reagents and conditions: (i) NH4OH (28%), 70 °C, 10 min; (ii) methyl chloroformate, Et3N, CH2Cl2, 0 °C, 8 h; (iii) 1 M NaOH, MeOH, r.t., 8 h.
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Synthesis
The amination reaction in a series of α-cyanopyridine-
carboxylic acids has been studied previously,12b,c and it was
shown that conversion of the methyl or ethyl ester of 2-cya-
nonicotinic acid (4) into the corresponding cyano amide
was unsuccessful, and produced only cyclic 7-imino-6,7-di-
hydro-5H-pyrrolo[3,4-b]pyridin-5-one upon reaction with
ammonia. Similar bicyclic imines were obtained by treat-
ment of cyano esters with primary amines.12c
O
R
EDCI, HOBt, Et3N
OH
+
ClH3N
R
COOMe
CH2Cl2, r.t.
60–80%
N
CN
4
O
O
R
NH
COOMe
N
+
To investigate the scope of this novel method, the cou-
pling of 2-cyanonicotinic acid (4) with several commercial-
ly available methyl esters of L-α-amino acids (such as Gly,
Ala, Val, Leu, Phe, Pro and Trp) was examined (Scheme 2).
As activating agent, N-ethyl-N′-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDCI) in the presence of
1-hydroxybenzotriazole (HOBt) and triethylamine was
used.13 1H NMR analysis of the reaction products confirmed
that, in most cases, the formation of open-chain methyl es-
ters of (2S)-N-(2-cyanopyridin-3-yl)carbonyl-substituted
amino acids 5 was followed by further intramolecular cy-
clization giving a pyrrolidine ring and production of the
tautomeric methyl esters of (2S)-2-(7-imino-5-oxo-5,7-di-
hydro-6H-pyrrolo[3,4-b]pyridin-6-yl)alkanoic acids 6.
When the valine, alanine and leucine methyl esters
were used, the formation of both products 5 and 6 (a,b,d) in
different ratios, with an increasing amount of the cyclic
form 6, was observed while in the case of glycine, phenyl-
alanine and tryptophan, the individual cyclic esters 6c,e,f
were exclusively isolated. The total yield of the amino acid
derivatives 5 and 6 was 60–80% after purification by col-
umn chromatography (Table 1).
COOMe
N
N
CN
NH
5a,b,d
6a–f
Scheme 2 Synthesis of the methyl esters of (2S)-N-(2-cyanopyridin-3-
yl)carbonyl-substituted amino acids 5a,b,d and (2S)-2-(7-imino-5-oxo-
5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)alkanoic acids 6a–f
We also succeeded in separation of the open 5 and cy-
clic 6 forms of the valine, alanine and leucine derivatives by
flash column chromatography, and in identification of the
1
individual components by means of LC/MS, and H NMR,
13C NMR and IR spectroscopy. The assignment of the syn-
thesized compounds to the open-chain or closed structure
was possible on the basis of comparative analysis of their 1H
NMR spectra (Table 1) and X-ray crystallography data.
The only product formed from the reaction of methyl
glycinate with acid 4 was analyzed by single-crystal X-ray
diffraction. It was shown that this product has the cyclic
structure 6c (Figure 1).
Table 1 Yield and 1H NMR Data for Compounds 5a,b,d and 6a–f
δ, ppm (J, Hz)
Ester
R
H2Ar, d (J = 4.8 Hz)
H3Ar, dd (J, Hz)
H4Ar, d (J, Hz)
NH
6.97
Yielda (%)
5a
6a
5b
6b
6c
5d
6d
6e
8.81
8.87
8.79
8.86
8.87
8.78
8.81
8.81
7.62 (9.0, 4.8)
7.58 (9.0, 4.8)
7.61 (8.1, 4.8)
7.57 (8.1, 4.8)
7.58 (7.8, 4.8)
7.61 (8.1, 4.8)
7.54 (m)
8.18 (9.0)
8.15 (9.0)
8.15 (8.1)
8.14 (8.1)
8.17 (7.8)
8.15 (8.1)
8.09 (6.6)
8.06 (7.8)
37
34
15
58
58
9
i-Pr (Val)
9.33
7.15b
9.34
9.33
7.06c
9.37
9.29
Me (Ala)
H (Gly)
i-Bu (Leu)
Bn (Phe)
76
76
7.51 (7.8, 4.8)
6f
8.69
7.36 (7.8, 4.8)
7.91 (7.8)
9.33
83
N
H
(Trp)
a Isolated yield.
b (d, J = 5.7 Hz).
c (d, J = 6.9 Hz).
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Synthesis
Me
O
Me
O
O
O
NH
O
O
N
N
NH
N
H
N
NH
N
6f'
Figure 2 Structures of 6f′ and 6f
6f
Under the LC/MS analysis conditions (gradient elution
of H2O + 0.1% formic acid and MeCN + 0.1% formic acid),
Figure 1 Molecular structure of compound 6c according to results of
the X-ray diffraction study, with the atom numbering used in the crys-
tallographic analysis; thermal ellipsoids are shown at 50% probability
level
each of the individual samples 5a,b,d and 6a–c,e,f (accord-
1
ing to H and 13C NMR spectra) yielded two peaks, in vari-
able ratios, which corresponded to the same molecular ion
(Table 2). It was found that these major and minor peaks
appear as a result of reversible intramolecular cycliza-
tion/recyclization of compounds 5 and 6 during analysis.
For each compound, the major peak value was around 70–
100% and the minor peak was less than 30%.
In the 1H NMR spectrum of this cyclic glycine derivative
6c, the NH proton resonance appeared at δ = 9.33 ppm. The
individual phenylalanine 6e and tryptophan 6f derivatives
also displayed NH signals in the same region (Table 1). Thus,
the NH proton peaks at δ = 6.97–7.15 ppm should corre-
spond to derivatives 5 with an open chain. Correspondingly,
the open 5 or closed 6 structures in other cases were as-
Table 2 LC/MS Data for Esters 5a,b,d and 6a–c,e,fa
1
signed based on the NH proton chemical shifts in their H
Ester
[М + 1]
Major peak (%)
Minor peak (%)
NMR spectra.
5a
6a
5b
6b
6c
5d
6e
6f
262
262
234
234
220
276
310
349
78–100
87–98
68–96
74–100
78–94
73
0–22
2–13
4–32
0–26
6–22
27
As follows from the X-ray crystallography data, com-
pound 6c adopts the E configuration at the C=N bond and
syn orientation of the NH proton to the aromatic ring, for
steric reasons. The substituent at the N2 atom is almost pla-
nar and has orthogonal orientation with respect to the
rings (the C6–N2–C8–C9 and N2–C8–C9–O3 torsion angles
are 91.93(16)° and 3.24(19)°, respectively; atom numbering
as used in the crystallographic analysis). The structures of
other compounds in this series were assigned by analogy
with 6c.
In the isolated pyrrolopyridines 6a–f the amino acid
residue is attached to the endocyclic nitrogen atom, and not
to the exocyclic imine nitrogen atom as was assumed for
the structure of the major products in the similar reaction
of ester 3 with ethyl or benzyl amine.12c Two products were
also isolated when ester 3 was reacted with benzylhydra-
zine, and their structures were assigned as isomeric pyrrol-
opyridines possessing a benzylamino substituent at either
the imino or the pyrrole nitrogen atom.12d Along with tryp-
tophan derivative 6f, a very small amount of crystals of the
unexpected substance 6f′ was isolated from the reaction
mixture (Figure 2); the crystal structure of 6f′ was reported
previously.14 In contrast to the major cyclic product 6f, this
unexpected material has an open structure that is regioiso-
meric to the nonisolated open form of 6f. Even though the
starting acid 4 was obtained as an individual compound of
100% purity (according to LC/MS data), the presence of the
isomeric ester 6f′ could result from an undetected 3-cy-
anopicolinic acid impurity in the 2-cyanonicotinic acid (4).
87
13
80–88
12–20
a The values were determined on the basis of three LC/MS analyses for each
of the compounds 5a,b and 6a–c,f, and one LC/MS analysis each for 5d
and 6e.
The proline derivative 5g was prepared similarly from
acid 4 in 87% yield. Unlike other amino acids, in the case of
L-proline the formation of only the open-chain product,
methyl (2S)-1-[(2-cyanopyridin-3-yl)carbonyl]pyrrolidine-
2-carboxylate (5g), was possible (Scheme 3).
Most amide bonds in peptides exist almost exclusively
in the trans configuration. The cis form is energetically un-
favorable, largely due to steric hindrance. The cyclic struc-
ture of proline lowers the steric hindrance, making both the
cis and trans forms nearly equally energetically stable.15
Due to this fact, two sets of signals were observed in the 1H
1
NMR spectrum of proline derivative 5g. From the H NMR,
13C NMR and NOESY spectra of 5g, it was possible to esti-
mate the approximate ratio of the rotamers. Cross-peaks
corresponding to the spatial interaction between the pro-
ton at the C4 position of the pyridine ring and the protons
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Synthesis
O
O
H
H
5
O
N
N
H
OMe
MeO
H-L-Pro-OMe
4
OH
CN
O
O
+
EDCI, HOBt
Et3N, CH2Cl2, r.t.
87%
N
N
CN
N
CN
4
trans-5g
77:23
cis-5g
Scheme 3 Synthesis of methyl (2S)-1-[(2-cyanopyridin-3-yl)carbonyl]pyrrolidine-2-carboxylate (5g)
at the C5 position of the pyrrolidine residue indicated that
the major product (ca. 77%) was the trans-isomer; accord-
ingly, the minor product (ca. 23%) was the cis-isomer.
The open-chain methyl esters of (2S)-N-(2-cyanopyri-
din-3-yl)carbonyl-substituted amino acids 5a,b,d,g exhibit-
ed a characteristic cyano group IR absorption band at
around 2237 cm–1. The band intensity was weak, similar to
the almost undetectable absorption of the reference com-
pound, 2-cyanonicotinic acid (4).12b
The next step in the synthesis of amidine prodrugs con-
sisted of transformation of the cyano group into an amidox-
ime function. Methyl esters of (2S)-N-[2-(N′-hydroxycarba-
mimidoyl)pyridin-3-yl]carbonyl-substituted amino acids 7
were obtained as individual products in 67–79% yield from
the corresponding methyl esters 5a,b,d and/or 6a,b,d–f by
treatment with hydroxylamine hydrochloride in methanol
(Table 3).16
The corresponding proline analogue 7g was synthesized
similarly from the cyano derivative 5g in 70% yield (see
Scheme 4). The cyano transformation reaction proceeded
upon stirring the mixture at room temperature overnight,
and the crude products were purified by flash column chro-
matography. For these amidoximes the LC/MS analytical
data showed a high purity of 98% (7e) and 100% (7a,d,g) in
some cases, while for others (7b,f) about 4% and 13% of im-
purities were detected that are assumed to be a result of
substance degradation under the LC/MS analysis conditions
(gradient elution of H2O + 0.1% formic acid and MeCN + 0.1%
formic acid).
A predominance of the trans form for the proline-con-
1
taining amidoxime 7g was observed. The H and 13C NMR
spectra displayed two sets of resonance signals, indicating a
trans/cis isomeric ratio of about 68:32 (Scheme 4).
Both open-chain 5 and the corresponding cyclic 6 ami-
no acid derivatives gave the same open-chain amidoximes
7 as the sole product. No cyclic amidoximes 7′, the forma-
tion of which could be expected according to a previously
reported condensation of the benzene analogue 3-imino-1-
oxoisoindoline with hydroxylamine that led to 3-(hydroxy-
imino)-1-oxoisoindoline (8),17 were found (see Table 3). The
formation of pseudopeptides 7 from esters of type 6 pro-
ceeds via pyrrolidine ring opening by hydroxylamine to af-
ford the same open-chain amidoximes as those obtained
from the corresponding cyano esters 5.
Table 3 Synthesis of the Methyl Esters of (2S)-N-[2-(N′-Hydroxycarb-
amimidoyl)pyridin-3-yl]carbonyl-Substituted Amino Acids 7a,b,d–f
O
R
O
R
NH
N
COOMe
NH
COOMe
N
OH
N
CN
NH2
.
NH2OH HCl
5a,b,d
7a,b,d–f
Et3N, MeOH, r.t.
67–79%
O
O
R
R
N
N
O
COOMe
N
COOMe
N
NH
NMR and X-ray diffraction analysis of the representative
pseudopeptide 7e (Figure 3) confirmed that it consisted of
only one open-chain structural isomer of nicotinic acid.
Thus, the reaction of ester 6e with hydroxylamine proceed-
ed with unexpected selective ring opening at the C–N bond
closest to the imino group moiety. The same regiochemis-
try has been generalized for all other products 7a,b,d,f
formed from this reaction.
N
OH
NH
N
6a,b,d–f
7'
8
OH
5, 6
5a, 6a
R
7
Isolated yield (%)
i-Pr
Me
i-Bu
Bn
7a
79
68
70
77
5b, 6b
5d, 6d
6e
7b
7d
7e
1
The H NMR spectrum of the phenylalanine derivative
7e revealed a chemical shift of δ = 5.49 ppm for the NH2
protons. The other amidoximes 7a,b,d,f and proline deriva-
tive 7g also gave amino group protons with a signal in the
same region, at δ = 5.46–5.50 ppm.
6f
7f
67
N
H
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Synthesis
O
O
O
N
N
N
OMe
MeO
OMe
O
.
O
N
NH2OH HCl
O
N
+
Et3N, MeOH, r.t.
70%
N
CN
N
OH
N
OH
NH2
NH2
5g trans/cis
7g trans/cis = 68:32
Scheme 4 Synthesis of methyl (2S)-1-{[2-(N′-hydroxycarbamimidoyl)pyridin-3-yl]carbonyl}pyrrolidine-2-carboxylate (7g)
Melting points were measured on a Buchi M-560 melting point appa-
ratus. Elemental analyses (C, H, N) were conducted using a Vario Mi-
cro Cube analyzer. LC/MS spectra were recorded using a system that
consisted of a high-performance liquid chromatograph (Agilent 1100
Series) equipped with a diode-matrix and mass-selective detector
(Agilent LC/MSD SL). Parameters for LC/MS analyses: Zorbax SB-C18
column (1.8 μm), 4.6 × 15 mm; gradient elution of solvent A = H2O +
0.1% formic acid and solvent B = MeCN + 0.1% formic acid; eluent
flow: 1 mL/min; volume of injected sample: 1 μL; UV detectors oper-
ating at 215, 254 and 265 nm; ionization method: chemical ioniza-
tion under atmospheric pressure (APCI); ionization mode: simultane-
ous scanning of positive and negative ions in the mass range m/z 80–
1000. IR spectra were recorded with a Perkin–Elmer Spectrum BX
FTIR spectrometer. NMR spectra were measured with Bruker Avance
(300 MHz for 1H, 75 MHz for 13C) and Varian Mercury 400 (400 MHz
for 1H, 100 MHz for 13С) spectrometers with tetramethylsilane as
standard. Preparative column chromatography was carried out with
silica gel 60 (40–63 μm).
Figure 3 Molecular structure of compound 7e according to results of
the X-ray diffraction study, with the atom numbering used in the crys-
tallographic analysis; thermal ellipsoids are shown at 50% probability
level
2-Сarbamoylnicotinic Acid (2)11
Acid 2 was prepared from quinolinic anhydride (1) and aqueous am-
monia according to a literature procedure.11 A suspension of anhy-
dride 1 (7.45 g, 50 mmol) in 28% NH4OH (37 mL) was stirred at 70 °C
for 10 min, whereupon the reactant had dissolved. After the mixture
was cooled to 0 °C, a precipitation was performed by adding 12 M НСl
(dropwise) while cooling. The precipitate was collected by filtration
and dried.
In summary, we have found that 2-cyanonicotinic acid
reacts with methyl esters of different L-α-amino acids to af-
ford methyl esters of (2S)-N-(2-cyanopyridin-3-yl)carbon-
yl-substituted amino acids with an open structure. These
esters undergo further intramolecular pyrrolidine ring
closure leading to the tautomeric methyl esters of (2S)-2-
(7-imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-
yl)alkanoic acids. Reaction of the latter with hydroxylamine
hydrochloride resulted in pyrrolidine ring opening to afford
open-chain amidoximes bearing the same structure as
amidoximes obtained by direct hydroxyamination of the
corresponding cyano esters.
White solid; yield: 4.65 g (56%); mp 176 °C (Lit.12b 175 °C).
1Н NMR (300 MHz, DMSO-d6, 25 °C): δ = 13.26 (s, 1 H, COOH), 8.67
(dd, J = 4.8, 1.4 Hz, 1 H, HAr), 8.04 (dd, J = 7.8, 1.3 Hz, 2 H, 2 × HAr),
7.72–7.44 (m, 2 H, NH2).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 168.1, 167.1, 150.4, 149.6, 136.7,
129.2, 125.2.
Methyl 2-Cyanonicotinate (3)12a,b
To a stirred suspension of 2-carbamoylnicotinic acid (2; 7.47 g, 45
mmol) in CH2Cl2 (50 mL) at 0 °С were added Et3N (13.08 mL, 94
mmol) and methyl chloroformate (7.65 mL, 99 mmol). After the reac-
tion mixture was stirred at r.t. for 8 h, it was diluted with CHCl3 (50
mL) and washed with H2O, dried over MgSO4 and concentrated in vac-
uo. The product was washed with hexane and dried.
This readily available variety of nicotinic acid based
pseudopeptides with an amidoxime function on the pyri-
dine ring might be considered as intermediates towards the
synthesis of the corresponding amidines as arginine pepti-
domimetics and/or as potential amidine prodrugs. Further
studies of similar amidoximes are ongoing in our laborato-
ries.
Pale-yellow solid; yield: 5.76 g (79%); mp 80–83 °C (Lit.12b 89 °C).
IR (KBr): 3090, 2959, 2241, 1726, 1578, 1287 cm–1
.
1Н NMR (300 MHz, DMSO-d6, 25 °C): δ = 8.94 (d, J = 4.8 Hz, 1 H, HAr),
8.48 (d, J = 8.1 Hz, 1 H, HAr), 7.88 (dd, J = 8.1, 4.8 Hz, 1 H, HAr), 3.95 (s, 3
H, OCH3).
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13С NMR (75 MHz, DMSO-d6, 25 °C): δ = 163.0, 153.9, 138.8, 132.4,
13С NMR (75 MHz, CDCl3, 25 °C): δ = 170.3, 166.2, 160.2, 154.9, 150.1,
129.4, 127.5, 116.2, 53.1.
132.2, 127.2, 125.3, 58.7, 52.9, 28.8, 21.8, 20.1.
LC/MS: m/z = 262 [M + H]+.
2-Cyanonicotinic Acid (4)12b
Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C,
59.57; H, 5.80; N, 16.04.
A mixture of ester 3 (3.16 g, 19.5 mmol), MeOH (60 mL) and 1 M
NaOH (22 mL) was stirred at r.t. for 8 h, and then concentrated in vac-
uo. The residue was diluted with H2O (20 mL) and CH2Cl2 (50 mL), and
then the solution was acidified with 1 М НСl under cooling. The re-
sulting precipitate was collected, washed with H2O and hexane, and
dried in vacuo.
Pale-yellow solid; yield: 1.84 g (64%); mp 186 °C [Lit.12b 214 °C, 185 °C
(sublimation)].
1Н NMR (300 MHz, DMSO-d6, 25 °C): δ = 14.25 (s, 1 H, COOH), 8.92
(dd, J = 4.8, 1.5 Hz, 1 H, HAr), 8.47 (dd, J = 8.1, 1.5 Hz, 1 H, HAr), 7.86
(dd, J = 8.1, 4.8 Hz, 1 H, HAr).
Methyl(2S)-2-{[(2-Cyanopyridin-3-yl)carbonyl]amino}propanoate
(5b)
Purification by flash column chromatography (EtOAc–CH2Cl2, 1:1)
gave 5b as a white solid; yield: 0.177 g (15%); mp 135–137 °С.
IR (KBr): 3273, 3080, 2997, 2941, 2237 (CN), 1739, 1648, 1581, 1548,
1226 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.79 (d, J = 4.8 Hz, 1 H, HAr), 8.15
(d, J = 8.1 Hz, 1 H, HAr), 7.61 (dd, J = 8.1, 4.8 Hz, 1 H, HAr), 7.15 (d, J = 5.7
Hz, 1 H, NH), 4.80 (m, 1 H, CHNH), 3.78 (s, 3 H, OCH3), 1.56 (d, J = 7.2
Hz, 3 H, CH3).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 173.4, 163.6, 153.0, 137.4,
135.53, 132.0, 127.3, 116.5, 53.4, 49.7, 18.7.
13С NMR (100 MHz, DMSO-d6 + CCl4, 1:1, 25 °C): δ = 164.2, 153.5,
139.1, 133.1, 130.9, 127.2, 116.4.
Anal. Calcd for C7H4N2O2: C, 56.76; H, 2.72; N, 18.91. Found: C, 56.74;
H, 2.73; N, 18.88.
LC/MS: m/z = 234 [M + H]+.
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.48; H, 4.76; N, 17.95.
Compounds 5a,b,d,g and 6a–f;13 General Procedure
To a solution of 2-cyanonicotinic acid (4; 740 mg, 5 mmol) in CH2Cl2
(30 mL) were added Et3N (1.39 mL, 10 mmol), the corresponding
methyl ester of an amino acid hydrochloride (5 mmol) and HOBt
(0.675 g, 5 mmol). The mixture was stirred at 0 °С and EDCI (0.967 g,
5.05 mmol) was added. Then, the mixture was stirred at r.t. overnight.
The mixture was diluted with CH2Cl2 (50 mL); then, the solution was
washed with 0.1 M HCl (3 × 15 mL) and brine (20 mL), dried over
MgSO4 and concentrated in vacuo.
Methyl (2S)-2-[(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]propanoate (6b)
Purification by flash column chromatography (EtOAc–CH2Cl2, 1:1)
gave 6b as a white solid; yield: 0.671 g (58%); mp 90 °С.
IR (KBr): 3294, 3238, 1743, 1731, 1665, 1403, 1410, 1258 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.34 (br s, 1 H, NH), 8.86 (d,
J = 4.8 Hz, 1 H, HAr), 8.14 (d, J = 8.1 Hz, 1 H, HAr), 7.57 (dd, J = 8.1, 4.8
Hz, 1 H, HAr), 5.24 (q, J = 7.2 Hz, 1 H, CH), 3.73 (s, 3 H, OCH3), 1.74 (d,
J = 7.2 Hz, 3 H, CH3).
Methyl (2S)-2-{[(2-Cyanopyridin-3-yl)carbonyl]amino}-3-methyl-
butanoate (5a)
Purification by flash column chromatography (EtOAc–petroleum
ether, 1:1) gave 5a as a white solid; yield: 0.488 g (37%); mp 142–
143 °С.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 171.1, 165.9, 159.6, 154.8, 150.4,
132.1, 127.1, 125.5, 53.3, 48.6, 15.7.
LC/MS: m/z = 234 [M + H]+.
IR (KBr): 3270, 3081, 2972, 2238 (CN), 1730, 1645, 1549, 1205 cm–1
.
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.45; H, 4.77; N, 17.96.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.81 (d, J = 4.8 Hz, 1 H, HAr), 8.18
(d, J = 9.0 Hz, 1 H, HAr), 7.62 (dd, J = 9.0, 4.8 Hz, 1 H, HAr), 6.97 (br m, 1
H, NH), 4.79 (m, 1 H, CHNH), 3.78 (s, 3 H, OCH3), 2.39–2.28 (m, 1 H,
CH(CH3)2), 1.07 (d, J = 6.0 Hz, 3 H, CH3), 1.03 (d, J = 6.0 Hz, 3 H, CH3).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 172.5, 164.0, 153.1, 137.9, 135.8,
131.6, 127.4, 116.7, 58.9, 53.2, 32.2, 19.7, 18.5.
Methyl [(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyri-
din-6-yl]acetate (6c)
Acetate 6c was obtained as a white solid of analytical purity without
further purification; yield: 0.63 g (58%); mp 160 °С.
LC/MS: m/z = 262 [M + H]+.
IR (KBr): 3198, 3057, 2937, 1736, 1669, 1593, 1440, 1281, 1267, 1248
сm–1
.
Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C,
59.55; H, 5.81; N, 16.12.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.33 (s, 1 H, NH), 8.87 (dd,
J = 4.8, 1.5 Hz, 1 H, HAr), 8.17 (dd, J = 7.8, 1.5 Hz, 1 H, HAr), 7.58 (dd,
J = 7.8, 4.8 Hz, 1 H, HAr), 4.66 (s, 2 H, CH2), 3.77 (s, 3 H, OCH3).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 168.5, 166.0, 159.8, 154.8, 150.4,
132.1, 127.0, 125.6, 53.1, 40.0.
Methyl (2S)-2-[(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-3-methylbutanoate (6a)
Purification by flash column chromatography (EtOAc–petroleum
ether, 1:1) gave 6a as a white solid; yield: 0.438 g (34%); mp 141 °С.
LC/MS: m/z = 220 [M + H]+.
IR (KBr): 3271, 2968, 1734, 1668, 1406, 1212, 1096 cm–1
.
Anal. Calcd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.57;
H, 4.15; N, 19.10.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.33 (br s, 1 H, NH), 8.87 (d,
J = 4.8 Hz, 1 H, HAr), 8.15 (d, J = 9.0 Hz, 1 H, HAr), 7.58 (dd, J = 9.0, 4.8
Hz, 1 H, HAr), 4.80 (d, J = 9.0 Hz, 1 H, CHN), 3.68 (s, 3 H, OCH3), 2.92–
2.80 (m, 1 H, CH(CH3)2), 1.20 (d, J = 6.0 Hz, 3 H, CH3), 0.88 (d, J = 6.0
Hz, 3 H, CH3).
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Synthesis
Methyl (2S)-2-{[(2-Cyanopyridin-3-yl)carbonyl]amino}-4-methyl-
pentanoate (5d)
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.33 (s, 1 H, NH), 8.69 (d, J = 4.8
Hz, 1 H, HAr), 8.29 (s, 1 H, NHAr), 7.91 (d, J = 7.8 Hz, 1 H, HAr), 7.58 (d,
J = 7.5 Hz, 1 H, HAr), 7.36 (dd, J = 7.8, 4.8 Hz, 1 H, HAr), 7.18 (d, J = 7.8
Hz, 1 H, HAr), 7.09–6.98 (m, 3 H, 3 × HAr), 5.58 (dd, J = 10.2, 4.8 Hz, 1 H,
CH), 3.95–3.72 (m, 2 H, CH2), 3.77 (s, 3 H, OCH3).
Purification by flash column chromatography (EtOAc–petroleum
ether, 1:1) gave 5d as a white solid; yield: 0.117 g (9%); mp 117–
118 °С.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 170.6, 166.1, 159.8, 154.5, 149.8,
136.6, 131.8, 127.8, 126.9, 125.0, 123.3, 122.4, 119.8, 119.0, 111.7,
111.6, 53.6, 53.3, 25.1.
IR (KBr): 3280, 3080, 2956, 2871, 2237 (CN), 1740, 1666, 1645, 1584,
1545, 1407, 1205 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.78 (d, J = 4.8 Hz, 1 H, HAr), 8.15
(d, J = 8.1 Hz, 1 H, HAr), 7.61 (dd, J = 8.1, 4.8 Hz, 1 H, HAr), 7.06 (d, J = 6.9
Hz, 1 H, NH), 4.87–4.79 (m, 1 H, CHNH), 3.76 (s, 3 H, OCH3), 1.85–1.66
(m, 3 H, CH + CH2), 0.99–0.95 (2 × d, 6 H, (CH3)2).
LC/MS: m/z = 349 [M + H]+.
Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C,
65.29, H, 4.64; N, 16.02.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 173.5, 163.9, 153.0, 137.5,
135.49, 131.8, 127.3, 116.5, 53.2, 52.4, 42.0, 25.5, 23.4, 22.5.
Methyl (2S)-1-[(2-Cyanopyridin-3-yl)carbonyl]pyrrolidine-2-car-
boxylate (5g)
LC/MS: m/z = 276 [M + H]+.
Purification by flash column chromatography (EtOAc–CH2Cl2, 1:1)
gave 5g as a pale-yellow oil; yield: 1.127 g (87%).
Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C,
60.89; H, 6.23; N, 15.22.
IR (KBr): 2952, 2237 (CN), 1736, 1634, 1428, 1407, 1175 cm–1
.
Methyl (2S)-2-[(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-4-methylpentanoate (6d)
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.74 and 8.70 (2 × d, J = 4.5 Hz, 1
H, HAr), 7.90 and 7.79 (2 × d, J = 7.8 Hz, 1 H, HAr), 7.62–7.51 (m, 1 H,
HAr), 4.71 and 4.28 (2 × m, 1 H, CH), 3.77 and 3.55 (2 × s, 3 H, OCH3),
3.51–3.38 (m, 2 H, CH2N), 2.42–2.31 (m, 1 H, CHH), 2.21–1.77 (m, 3 H,
CHHCH2).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 172.4, 165.2, 164.8, 152.1, 151.9,
138.2, 137.9, 136.4, 136.2, 131.3, 127.4, 127.2, 116.0, 61.4, 59.7, 53.3,
53.1, 49.6, 47.5, 31.8, 29.9, 25.5, 23.3.
Purification by flash column chromatography (EtOAc–petroleum
ether, 1:1) gave 6d as a light-yellow oil; yield: 1.046 g (76%).
IR (KBr): 3276, 2956, 1734, 1665, 1593, 1405, 1257, 1209 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.37 (br s, 1 H, NH), 8.81 (s, 1 H,
HAr), 8.09 (d, J = 6.6 Hz, 1 H, HAr), 7.54 (m, 1 H, HAr), 5.23–5.16 (m, 1 H,
CHN), 3.64 (s, 3 H, OCH3), 2.44–2.36 (m, 1 H, CHH), 1.95–1.90 (m, 1 H,
CHH), 1.44 (m, 1 H, CH(CH3)2), 0.90 and 0.85 (2 × d, J = 5.7 Hz, 6 H,
(CH3)2).
LC/MS: m/z = 260 [M + H]+.
Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C,
59.98; H, 5.07; N, 16.15.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 171.0, 166.1, 159.8, 154.7, 150.1,
132.0, 127.0, 125.3, 53.0, 51.6, 37.7, 25.6, 23.7, 21.7.
LC/MS: m/z = 276 [M + H]+.
Compounds 7a,b,d–g;16 General Procedure
To a solution of the methyl ester of a (2S)-N-(2-cyanopyridin-3-
yl)carbonyl-substituted amino acid 5 and/or the methyl ester of a
(2S)-2-(7-imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)alk-
anoic acid 6 (2 mmol) in MeOH (15 mL) was added Et3N (0.56 mL, 4
mmol) followed by hydroxylamine hydrochloride (0.278 g, 4 mmol),
and the reaction mixture was stirred at r.t. overnight. The mixture
was then concentrated to dryness. The residue was dissolved in EtOAc
(100 mL) and the solution was washed with H2O (20 mL). The organic
layer was dried with MgSO4 and the solvent was removed in vacuo.
The residue was purified by column chromatography.
Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C,
60.85; H, 6.24; N, 15.21.
Methyl (2S)-2-[(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-3-phenylpropanoate (6e)
Purification by flash column chromatography (EtOAc–petroleum
ether, 7:3) gave 6e as a light-yellow solid; yield: 1.174 g (76%); mp
72–73 °С.
IR (KBr): 3275, 3252, 3201, 3062, 3030, 2955, 2923, 2853, 1741, 1731,
1666, 1408, 1256 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 9.29 (s, 1 H, NH), 8.81 (d, J = 4.8
Hz, 1 H, HAr), 8.06 (d, J = 7.8 Hz, 1 H, HAr), 7.51 (dd, J = 7.8, 4.8 Hz, 1 H,
HAr), 7.20–7.14 (m, 5 H, 5 × HAr), 5.47 (dd, J = 10.8, 5.4 Hz, 1 H, CH),
3.78 (s, 3 H, OCH3), 3.72–3.59 (m, 2 H, CH2).
Methyl (2S)-2-({[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}amino)-3-methylbutanoate (7a)
Purification by flash column chromatography (CH2Cl2–EtOH, 95:5)
gave 7a as a white solid; yield: 0.465 g (79%); mp 120–121 °С.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 170.2, 166.0, 159.7, 154.7, 149.9,
IR (KBr): 3297, 1739, 1646, 1534, 1198, 1149 cm–1
.
137.6, 132.0, 129.5, 129.0, 127.3, 127.0, 125.1, 54.2, 53.4, 35.1.
LC/MS: m/z = 310 [M + H]+.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.57 (d, J = 4.8 Hz, 1 H, HAr), 7.92
(d, J = 7.8 Hz, 1 H, HAr), 7.50 (d, J = 8.1 Hz, 1 H, NH), 7.33 (dd, J = 7.8,
4.8 Hz, 1 H, HAr), 5.46 (s, 2 H, NH2), 4.62 (dd, J = 8.1, 5.1 Hz, 1 H,
CHNH), 3.69 (s, 3 H, OCH3), 2.22–2.12 (m, 1 H, CH), 0.94 (d, J = 6.9 Hz,
3 H, CH3), 0.91 (d, J = 6.9 Hz, 3 H, CH3).
Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58. Found: C,
65.81; H, 4.91; N, 13.53.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 172.9, 168.3, 151.4, 150.1, 147.2,
138.4, 131.9, 124.5, 58.8, 52.8, 31.9, 19.4, 18.7.
LC/MS: m/z = 295 [M + H]+.
Methyl (2S)-2-[(7E)-7-Imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-3-(1H-indol-3-yl)propanoate (6f)
Purification by flash column chromatography (CH2Cl2–MeCN, 8:2)
gave 6f as a yellow solid; yield: 1.436 g (83%); mp 119–121 °С.
IR (KBr): 3396, 3266, 3067, 1732, 1664, 1429, 1407, 1260 cm–1
Anal. Calcd for C13H18N4O4: C, 53.05; H, 6.16; N, 19.04. Found: C,
52.92; H, 6.18; N, 18.98.
.
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Synthesis
Methyl (2S)-2-({[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}amino)propanoate (7b)
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.90 (s, 1 H, NH), 8.46 (d, J = 4.8
Hz, 1 H, HAr), 7.72 (dd, J = 4.8, 1.2 Hz, 1 H, HAr), 7.50 (d, J = 7.5 Hz, 1 H,
NH), 7.33–7.24 and 7.18–7.02 (2 × m, 6 H, 6 × HAr), 5.49 (s, 2 H, NH2),
5.07 (dd, J = 12.9, 6.0 Hz, 1 H, CH), 3.62 (s, 3 H, OCH3), 3.32 (m, 2 H,
CH2).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 173.1, 168.6, 151.5, 150.1, 147.0,
137.9, 136.8, 131.7, 128.1, 124.5, 122.4, 119.9, 119.0, 112.1, 109.9,
54.1, 53.1, 28.0.
Purification by flash column chromatography (CH2Cl2–EtOH, 91:9)
gave 7b as a white solid; yield: 0.362 g (68%); mp 74–75 °С.
IR (KBr): 3470, 3322, 3067, 2918, 2849, 1739, 1731, 1641, 1582, 1565,
1547, 1538, 1454, 1216 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.60 (d, J = 4.5 Hz, 1 H, HAr), 7.92
(d, J = 7.8 Hz, 1 H, HAr), 7.46 (d, J = 7.2 Hz, 1 H, NH), 7.36 (dd, J = 7.8,
4.8 Hz, 1 H, HAr), 5.47 (s, 2 H, NH2), 4.75 (m, 1 H, CH), 3.75 (s, 3 H,
OCH3), 1.48 (d, J = 7.2 Hz, 3 H, CH3).
LC/MS: m/z = 382 [M + H]+.
Anal. Calcd for C19H19N5O4: C, 59.84; H, 5.02; N, 18.36. Found: C,
59.65; H, 5.04; N, 18.29.
13С NMR (75 MHz, CDCl3, 25 °C): δ = 174.1, 168.3, 151.2, 150.0, 147.3,
137.9, 131.7, 124.3, 53.0, 49.3, 18.2.
Methyl (2S)-1-{[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}pyrrolidine-2-carboxylate (7g)
LC/MS: m/z = 267 [M + H]+.
Anal. Calcd for C11H14N4O4: C, 49.62; H, 5.30; N, 21.04. Found: C,
49.48; H, 5.32; N, 20.96.
Ester 7g was obtained as a white solid of analytical purity without
further purification; yield: 0.409 g (70%); mp 135–136 °С.
IR (KBr): 3521, 3159, 3117, 3080, 2886, 2867, 2835, 1732, 1651, 1608,
Methyl (2S)-2-({[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}amino)-4-methylpentanoate (7d)
1537, 1471, 1433, 1368, 1199, 1177 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.57 (m, 1 H, HAr), 8.08 (br s, 1 H,
OH), 7.69 and 7.61 (2 × dd, J = 7.8, 1.5 Hz, 1 H, HAr), 7.39–7.26 (m, 1 H,
HAr), 5.50 (br s, 2 H, NH2), 4.74 and 4.11 (2 × dd, J = 8.6, 4.3 Hz, J = 6.1,
2.7 Hz, 1 H, CH), 3.79 and 3.48 (2 × s, 3 H, OCH3), 3.75 (m) and 3.25 (t,
J = 6.5 Hz, 2 H, CH2), 2.38–2.20 and 1.96–1.86 (2 × m, 4 H, CH2CH2).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 173.6, 173.3, 169.5, 169.2, 150.6,
150.3, 149.2, 145.7, 145.2, 137.2, 136.5, 131.5, 131.1, 124.4, 124.0,
61.2, 59.3, 52.9, 52.7, 48.9, 47.4, 31.5, 30.3, 25.2, 23.8.
Purification by flash column chromatography (CH2Cl2–EtOH, 9:1)
gave 7d as a white solid; yield: 0.431 g (70%); mp 114–115 °С.
IR (KBr): 3479, 3377, 3236, 3076, 2955, 1746, 1638, 1581, 1547, 1248
cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.62 (d, J = 4.8 Hz, 1 H, HAr), 7.95
(d, J = 7.8 Hz, 1 H, HAr), 7.41–7.35 (m, 2 H, NH + HAr), 5.46 (br s, 2 H,
NH2), 4.84–4.76 (m, 1 H, CH), 3.76 (s, 3 H, OCH3), 1.78–1.64 (m, 3 H,
CH2 + CH), 0.98 (d, J = 6.3 Hz, 3 H, CH3), 0.96 (d, J = 6.3 Hz, 3 H, CH3).
13С NMR (75 MHz, CDCl3, 25 °C): δ = 174.1, 168.3, 151.4, 150.1, 147.0,
138.4, 131.9, 124.5, 53.0, 52.2, 42.1, 25.5, 23.4, 22.7.
LC/MS: m/z = 293 [M + H]+.
Anal. Calcd for C13H16N4O4: C, 53.42; H, 5.52; N, 19.17. Found: C,
53.25; H, 5.54; N, 19.10.
LC/MS: m/z = 309 [M + H]+.
Anal. Calcd for C14H20N4O4: C, 54.54; H, 6.54; N, 18.17. Found: C,
54.36; H, 6.55; N, 18.10.
X-ray Diffraction Study of Compounds 6c and 7e
The structures were solved by direct methods using the SHELXTL
package.18 Positions of the hydrogen atoms were located from elec-
tron-density difference maps and refined by ‘riding’ model with
Uiso = nUeq of the carrier atom (n = 1.5 for methyl groups, n = 1.2 for
other hydrogen atoms). Full-matrix least-squares refinement of the
structures against F2 in anisotropic approximation for non-hydrogen
atoms using 3209 (6c) and 4673 (7e) reflections was converged to
wR2 = 0.133 (R1 = 0.047 for 2332 reflections with F > 4σ(F), S = 1.03)
for structure 6c and wR2 = 0.096 (R1 = 0.035 for 4279 reflections with
F > 4σ(F), S = 1.02) for structure 7e. The final atomic coordinates and
crystallographic data for molecules 6c and 7e have been deposited
with the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail: depos-
it@ccdc.cam.ac.uk] and are available on request quoting the deposi-
tion numbers CCDC 991411 for 6c and CCDC 991412 for 7e.
Methyl (2S)-2-({[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}amino)-3-phenylpropanoate (7e)
Ester 7e was obtained as a white solid of analytical purity without
further purification; yield: 0.527 g (77%); mp 172 °С.
IR (KBr): 3359, 3201, 3020, 2886, 1723, 1672, 1644, 1586, 1575, 1537,
1276, 934 cm–1
.
1Н NMR (300 MHz, CDCl3, 25 °C): δ = 8.60 (d, J = 4.8 Hz, 1 H, HAr), 7.88
(d, J = 7.8 Hz, 1 H, HAr), 7.63 (d, J = 7.5 Hz, 1 H, NH), 7.37–7.19 (m, 6 H,
6 × HAr), 5.49 (br s, 2 H, NH2), 5.11 (dd, J = 13.5, 6.0 Hz, 1 H, CH), 3.72
(s, 3 H, OCH3), 3.24–3.21 (m, 2 H, CH2).
13С NMR (100 MHz, DMSO-d6 + CCl4, 1:1, 25 °C): δ = 171.9, 167.5,
149.9, 148.7, 147.4, 137.4, 136.8, 131.7, 129.5, 128.4, 126.6, 123.3,
54.2, 51.9, 37.5.
Compound 6c (C10H9N3O3): monoclinic crystals; at 293 K,
a = 5.0866(4) Å, b = 9.0455(7) Å, c = 21.760(1) Å, β = 92.030(7)°,
V = 1000.6(1) Å3, Mr = 219.20, Z = 4, space group P21/n, Dcalc = 1.455
g/cm3, μ(Mo Kα) = 0.111 mm–1, F(000) = 456. Intensities of 10110 re-
flections (3209 independent, Rint = 0.022) were measured on an Xcal-
ibur-3 diffractometer (graphite monochromated Mo Kα radiation,
CCD detector, ω-scanning, 2Θmax = 64°).
LC/MS: m/z = 343 [M + H]+.
Anal. Calcd for C17H18N4O4: C, 59.64; H, 5.30; N, 16.37. Found: C,
59.51; H, 5.32; N, 16.31.
Methyl (2S)-2-({[2-(N′-Hydroxycarbamimidoyl)pyridin-3-yl]car-
bonyl}amino)-3-(1H-indol-3-yl)propanoate (7f)
Compound 7e (C17H18N4O4): monoclinic crystals; at 293 K,
a = 8.5563(3) Å, b = 10.2899(3) Å, c = 10.1182(3) Å, β = 104.315(3)°,
V = 863.19(5) Å3, Mr = 342.35, Z = 2, space group P21, Dcalc = 1.317
g/cm3, μ(Mo Kα) = 0.096 mm–1, F(000) = 360. Intensities of 9410 re-
Purification by flash column chromatography (CH2Cl2–MeOH, 94:6)
gave 7f as a white solid; yield: 0.507 g (67%); mp 129–130 °С.
IR (KBr): 3331, 3043, 1730, 1641, 1582, 1214 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2285–2293

2293
O. V. Ovdiichuk et al.
Paper
Synthesis
flections (4673 independent, Rint = 0.013) were measured on an Xcal-
ibur-3 diffractometer (graphite monochromated Mo Kα radiation,
CCD detector, ω-scanning, 2Θmax = 64°).
(5) Peterlin-Mašič, L.; Cesar, J.; Zega, A. Curr. Pharm. Des. 2006, 12,
73.
(6) Clement, B.; Lopian, K. Drug Metab. Dispos. 2003, 31, 645.
(7) Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.;
Varella, E. A.; Nicolaides, D. N. Curr. Pharm. Des. 2008, 14, 1001.
(8) (a) Jakopin, Z.; Dolenc, M. S. Curr. Org. Chem. 2008, 12, 850.
(b) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337.
(9) Kumar, D.; Patel, G.; Chavers, A. K.; Chang, K.-H.; Shah, K. Eur. J.
Med. Chem. 2011, 46, 3085.
Acknowledgment
The authors thank Campus France for financial support of this work.
(10) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csöregh, I.;
Hesselink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112.
(11) Chapman, E.; Stephan, H. J. Chem. Soc. 1925, 127, 1791.
(12) (a) Sauers, C. K.; Cotter, R. J. J. Org. Chem. 1961, 26, 6.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379917.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2285–2293