Synthesis of imidazo[4,5-b]pyridines with a chiral substituent at the nitrogen atom and their conversion to piperazine derivatives

Article abstract of DOI:10.1007/s10593-012-1056-5

Imidazopyridine and benzimidazole derivatives have been prepared with chiral substituents at the nitrogen atom and have been converted to the corresponding condensed structures fused with a piperazine ring. A method has been developed for the synthesis of novel class of compounds - 6,7,8,9-tetra-hydropyrido[3',2':4,5]imidazo[1,2-a]pyrazine derivatives.

Full text of DOI:10.1007/s10593-012-1056-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
SYNTHESIS OF IMIDAZO[4,5-b]PYRIDINES WITH A
CHIRAL SUBSTITUENT AT THE NITROGEN ATOM AND
THEIR CONVERSION TO PIPERAZINE DERIVATIVES
K. V. Bukhryakov1, A. V. Kurkin1*, and M. A. Yurovskaya1
Imidazopyridine and benzimidazole derivatives have been prepared with chiral substituents at the
nitrogen atom and have been converted to the corresponding condensed structures fused with a piperazine
ring. A method has been developed for the synthesis of novel class of compounds – 6,7,8,9-tetra-
hydropyrido[3',2':4,5]imidazo[1,2-a]pyrazine derivatives.
Keywords: tert-butyl imidazo[4,5-b]pyridine-2-carboxylate, 2-chloro-3-nitropyridine, chiral substituent
at a nitrogen atom, nucleophilic substitution, optically active amino acid esters.
Interest in imidazopyridines is due to their biological activity, the most important aspects of which have
been summarized in a review [1]. Based on this data and with the current trend to use non-racemic medications
in mind, we have developed a method for the synthesis of imidazo[4,5-b]pyridines with a chiral substituent on
the nitrogen atom [2].
Benzimidazoles fused to a piperazine ring are also of special interest, since they possess antiviral [3]
and analgesic [4] properties. It is known that in some cases the exchange of a benzene ring for pyridine
markedly increases biological activity due to the high affinity of the latter towards the benzodiazepine receptor
[5]. The aim of our work was to develop a method for the preparation of a novel class of compounds, namely
the 9-substituted 6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrazine derivatives 1.
N
N
N
NH
R
1
A synthetic route based on the use of L-alanine was initially proposed by us for the preparation of the
target compounds.
The imidazopyridines 6a-c were synthesized using our previously developed procedure for optically
active imidazo[4,5-b]pyridine-2-carboxylates using the enantiomerically pure L-phenylalanine tert-butyl
_______
*To whom correspondence should be addressed, e-mail: kurkin@direction.chem.msu.ru.
1M. V. Lomonosov State University, 1, Build. 3 Leninskie Gory, Moscow 119991, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 831-843, May, 2012. Original
article submitted December 7, 2011.
0009-3122/12/4805-0773©2012 Springer Science+Business Media, Inc.
773

NO2
NH
NH2
NH
NO2
Cl
NH2
H2
Pd/C
N
O
N
N
Bu
-t
R
Et3N
MeCN
Et2O
O
O
O
2a–c
Bu
-t
Bu
-t
R
R
O
O
3a–c
4a–c
O
H
N
OEt
N
N
Cl
O
OEt
(R = Me)
PhMe, 
–H2O
O
O
O
OEt
O
N
N
NH
O
R
R
Bu-t
O
Bu
-t
6a–c
O
5a–c
H
H
N
N
N
N
N
N
Ph
Ph
PhCH2NH2
HCOOH
O
O
N
O
O
N
2-PrOH
50°C
2 days
, 2 days
Me
Me
O
OH
7a
Bu
-t
8a
LiAlH4
N
N
N
N
O
N
N
BH3·THF
H2
Pd/C
N
N
N
N
N
NH
Ph
Ph
Me
Me
Me
O
9a
11a
10a
a R = Me, b R = i-Bu, c R = Bn
ester [2] as the chirality source. It was shown that the selectivity of cyclization of compounds of type 5 with a
phenylalanine residue (forming imidazopyridines or pyridopyrazines) was markedly governed by the solvent
used in the reaction. None the less the cyclization of compound 5a (with an alanine fragment) in toluene
occurred non-selectively. In addition to the imidazopyridine 6a target product, we also separated the minor
pyridopyrazine 12a in the ratio 5:4. Hence we can conclude that both the solvent and the substituent at the
nitrogen atom affect the cyclization route.
H
O
N
PhMe, 
N
N
O
O
5a
6a
+
–H2O
Me
O
12a
6a : 12a = 5 : 4
Bu-t
Ammonolysis of imidazopyridine 6a was brought about with a 3-fold excess of benzylamine by
refluxing in 2-propanol. An attempt to separate acid 8a after hydrolysis of the tert-butyl ester 7a proved
unsuccessful since an intramolecular cyclization occurs under the reaction conditions to give the racemic
compound 9a. The reasons for the loss of chirality in the derivative 9a are considered later. The structure of
compound 9a was confirmed by X-ray structural analysis data (Fig. 1).
774

Reduction of compound 9a with LiAlH4 gave a complex mixture of unidentified reaction products.
When reduced with the BH3·THF complex, however, it was possible to detect an ion mass peak corresponding
to the derivative 10a, but all our attempts to prepare piperazine 10a in a pure state were unsuccessful. We also
attempted to remove the benzyl group from the unpurified compound 10a by hydrogenolysis in the presence of
palladium, but, to our surprise, the mixture contained neither the expected reaction product 11a nor the starting
piperazine 10a.
The target piperazine 11a could only be obtained after exchange of the benzyl group for
2,4-dimethoxybenzyl, the removal of which is generally achieved under milder conditions [6].
Fig. 1. Molecular structure of compound 9a with 50% probability atomic thermal vibration ellipsoids.
The imides 15a-c were prepared from the imidazopyridines 6a-c by the same scheme we used for the
synthesis of compound 9a. Reduction of compound 15a with the BH3·THF complex and treatment with
trifluoroacetic acid without separation of piperazine 16a gave the target 6,7,8,9-tetrahydropyrido[3',2':4,5]-
imidazo[1,2-a]pyrazine 11a, which was isolated as the dihydrobromide after treatment with 20% HBr.
Analysis of the enantiomeric purity of compound 11a by HPLC with a chiral stationary phase showed
total loss of the enantiomeric purity. It has been found that racemization is observed in two stages, viz. the
preparation of amide 13a and its cyclization to the derivative 15a.
OMe
H
N
H
N
MeO
H2N
N
N
N
N
Ar
Ar
HCOOH
O
O
N
O
O
6a–c
N
50°C
2 days
Me3Al, CH2Cl2
room temp., 1 day
R
R
O
OH
Bu
-t
14a–c
13a–c
N
N
N
O
BH3·THF
TFA
N
N
11a
N
N
N
(R = Me)
Ar
Ar
R
15a–c
Me
O
16a
a–c Ar = 2,4-(MeO)2C6H3; a R = Me, b R = i-Bu, c R = Bn
We have attempted to preserve the optical activity in the course of synthetic transformations in order to
obtain final imidazo[4,5-b]pyridines with high enantiomeric purity. With this aim, we tried to carry out a first
775

stage preparation of the pure acid 14a which can be transformed to the amide 15a using mild reagents, which
are employed in peptide synthesis and do not lead to racemization [6]. We have used all of the known methods
for the removal of tert-butyl protection in the ester 13a, but, unfortunately, none of those gave a positive result.
Moreover, the acid 14a proved to be extremely unstable to protonic media. All of the reactions led to its
decarboxylation.
We succeeded in preparing the amide 13a in high enantiomeric purity (ee 98%) by treating compound
6a with 2,4-dimethoxybenzylamine hydrochloride in CH2Cl2 at room temperature in the presence of trimethyl
aluminum [7]. Although the maximum conversion was as low as 40%, racemization was not observed
(according to HPLC with a chiral stationary phase).
The following step in the work was an attempt to exclude racemization in the stage of cyclizing
compounds 13a-c to the amides 15a-c. We have proposed that the presence of the basic pyridine nitrogen atom
can promote racemization due to speeding up of the enolization process in the piperazine fragment. In order to
prove this hypothesis, we have synthesized the benzene analog 13d from the tert-butyl phenylalanine ester 2c
and o-fluoronitrobenzene.
NH2
NO2
NO2
H2–Pd/C
EtOH
F
Et3N, MeCN
, 5 days
NH
NH
2c
O
O
Bu
-t
Bu
-t
Ph
O
Ph
O
4d
3d
O
H
OEt
O
PhMe

Cl
O
I2
O
OEt
H
H
N
OEt
N
N
N
N
N
O
Ar
ArCH2NH2
O
O
O
O
N
O
O
Me3Al, CH2Cl2
room temp., 1 day
O
6d
O
13d
Ph
Ph
Bu-t
Bu
-t
Ph
O
Bu
-t
12d
H
N
N
N
O
N
N
Ar
HCOOH
O
O
N
50°C
2 days
Ar
O
OH
14d
Ph
Ph
15d
Ar = 2,4-(MeO)2C6H3
It should be noted that use of chloroethyl oxalate in the third stage of the synthesis and subsequent
refluxing of the acylation product in toluene does not lead to formation of the benzimidazole 6d (as occurs in
the synthesis of an imidazopyridine) but forms exclusively the quinoxalinedione 12d. In order to prepare
compound 6d, we have used the alternative procedure of treating amine 4d with ethyl glyoxalate in the presence
of iodine (which is needed as oxidant).
Unfortunately, the cyclic amide 15d also failed to show optical activity, and analysis of its enantiomeric
purity allowed us to establish that a racemic compound had been obtained in the course of the synthetic reaction.
776

We then attempted to change the route to a synthesis of the cyclic amide 15a. The acid 17, which was
obtained through hydrolysis of the tert-butyl ester 6a, was dissolved in CH2Cl2 and condensed with
2,4-dimethoxybenzylamine. The process was activated by benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (PyBOP) in the presence of diisopropylethylamine (DIPEA), and the reaction mixture was
then stirred at room temperature for 12 h.
OEt
N
N
OEt
N
N
O
O
N
ArCH2NH2
HCOOH
room temp.
3 days
O
O
N
6a
15a
+
PyBOP, DIPEA
CH2Cl2
room temp., 12 h
Me
Me
HN
18
OH
17
Ar
Ar = 2,4-(MeO)2C6H3
The mixture obtained contained uncyclized amide 18 and cyclic amide 15a, and these were separated in
the pure state and characterized. It was found that the amide 18 was optically active (+17.3º, ee 31%) but the
cyclic diamide 15a was found to be optically inactive (ee 5%).
It is likely that the loss in optical activity is a result of the keto-enol tautomerism in the substrates 15a-d.
N
N
N
N
N
N
O
O
O
X
N
X
X
N
N
Ar
Ar
Ar
R
R
R
O
OH
O
X = CН, N; R = Me, i-Bu, Bn; Ar = Ph, 2,4-(MeO)2C6H3
Hence we have obtained imidazopyridine and benzimidazole derivatives with chiral substituent at the
nitrogen atom and carried out their transformations to the corresponding derivatives fused with a piperazine
ring. Unfortunately, it was not possible to prepare final products with a high enantiomeric purity, but a method
has been developed for synthesis of a previously unknown class of substituted 6,7,8,9-tetrahydro-
pyrido[3',2':4,5]imidazo[1,2-a]pyrazines.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker DPX instrument (400 MHz) using TMS as internal standard
and the solvents D2O (compound 11a), DMSO-d6 (compound 12d), or CDCl3 (remaining compounds). 13C
NMR spectra were recorded on a Bruker AMX-400 instrument (100 MHz) with DMSO-d6 (compounds 11a,
12d) or CDCl3 (remaining compounds) as solvent. Chromato-mass spectrometric studies of the reaction mixture
and separated compounds were performed using a Shimadzu Analytical SCL10Avp liquid chromatograph and
PE SCIEX API 150 mass spectrometer (electrospray, positive ionization). The enantiomeric purity was
measured by HPLC on a Waters Breeze 2 HPLC chromatograph using a Chiralpak AD-H chiral sorbent
(5 micron, column 4.6250 mm, hexane–2-propanol (85:15) as eluent, 1.0 ml/min flow, 20ºC, and with UV
detection at 360 nm). Monitoring of the reaction course and the purity of the compounds obtained was carried
out by using TLC on Sorbfil plates (silica gel CTX-1VE grade) in the system hexane–ethyl acetate (10:1;
777

compound 7a – in CH2Cl2) or by liquid chromatography with the mass spectrometric detector (compounds 9a,
15a-c). Commercial 2-chloro-3-nitropyridine was used from the Aldrich company, and the tert-butyl amino acid
esters were obtained by method [8].
N-(3-Nitropyridin-2-yl)-L-amino Acid Esters 3a-c (General Method). 2-Chloro-3-nitropyridine (11.10 g,
0.07 mol) was added to a solution of the corresponding amino acid ester (0.07 mol) in MeCN (100 ml),
followed by Et3N (14.85 g, 0.147 mol). The product was refluxed for 2 h (TLC monitoring). The solvent was
evaporated, and the residue was treated with water (100 ml) and extracted with EtOAc (350 ml). The extract
was dried over Na2SO4 and evaporated. The residue was chromatographed on a silica gel column using the
system hexane–EtOAc (10:1).
N-(3-Nitropyridin-2-yl)-L-alanine tert-Butyl Ester (3a). Yield 90%. Yellow crystals, mp 63-65ºC;
20
1
[]D +80.2º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 1.49 (9H, s, C(СH3)3); 1.56 (3H, d, J = 7.3,
CHCH3); 4.76-4.79 (1H, m, CHCH3); 6.69 (1H, dd, J = 8.4, J = 4.6, H-5); 8.38 (1H, dd, J = 4.4, J = 1.8, Н-6);
13
8.43 (1H, dd, J = 8.2, J = 1.8, Н-4); 8.49 (1H, d, J = 5.3, NН). C NMR spectrum, , ppm: 18.3 (CH3); 27.9
(C(CH3)3); 50.6 (CHCH3); 81.8 (C(CH3)3); 112.3 (C-5); 135.1 (C-3); 144.6 (C-4); 151.5 (C-2); 155.2 (C-6);
172.2 (C=O). Found, %: C 54.04; H 6.32; N 15.89. C12H17N3O4. Calculated, %: C 53.92; H 6.41; N 15.72.
N-(3-Nitropyridin-2-yl)-L-leucine tert-Butyl Ester (3b). Yield 80%. Yellow crystals; mp 55-57ºC;
[]D20 +23.8º (c 1.01, CHCl3). 1H NMR spectrum, , ppm (J, Hz): 0.98 (3H, d, J = 6.2) and 1.03 (3H, d, J = 6.2,
CH(СН3)2); 1.47 (9H, s, C(СН3)3); 1.76-1.78 (3H, m, СН2CHМе2); 4.76-4.82 (1H, m, CHCH2); 6.69 (1H, dd,
J = 8.2, J = 4.4, H-5); 8.34 (1H, d, J = 6.4, NН); 8.38 (1H, dd, J = 4.9, J = 1.8, Н-6); 8.43 (1H, dd, J = 8.4,
J = 1.8, Н-4). 13C NMR spectrum, , ppm: 22.1 (CH(CH3)2); 22.9 (CH(CH3)2); 25.1 (CH(CH3)2); 28.0
(C(CH3)3); 41.3 (CH2); 53.4 (CHCH2); 81.5 (C(CH3)3); 112.3 (C-5); 128.3 (C-3); 135.1 (C-4); 151.9 (C-2);
155.2 (C-6); 172.2 (C=O). Found, %: C 58.39; H 7.45; N 13.55. C15H23N3O4. Calculated, %: С 58.24; Н 7.49;
N 13.58.
N-(3-Nitropyridin-2-yl)-L-phenylalanine tert-Butyl Ester (3c). Yield 70%. Yellow crystals; mp
137-139ºC; []D20 -112.6º (c 0.76, CHCl3). 1H NMR spectrum, , ppm (J, Hz): 1.41 (9H, s, C(СН3)3); 3.22-3.25
(2H, m, СН2Ph); 5.02-5.04 (1H, m, CHCH2); 6.71-6.75 (1H, m, NH); 7.26-7.29 (5H, m, H Ph); 8.37 (1H, d,
J = 4.5, Н-5); 8.41 (1H, d, J = 8.3, Н-6); 8.46-8.49 (1H, m, Н-4). 13C NMR spectrum, , ppm: 27.9 (C(CH3)3);
38.1 (CH2); 56.0 (CHCH2); 82.0 (C(CH3)3); 108.7 (C-6); 112.4 (C-4'); 127.0 (C-3); 128.5 (C-3',5'); 129.4
(C-2',6'); 135.4 (C-1'); 137.1 (C-4); 155.1 (C-6); 158.0 (C-2); 175.7 (C=O). Found, %: С 63.11; Н 6.12;
N 12.21. С18H21N3O4. Calculated, %: С 62.96; Н 6.16; N 12.24
N-(2-Nitrophenyl)-L-phenylalanine tert-Butyl Ester (3d). L-Phenylalanine t-butyl ester
hydrochloride (5.2 g, 0.020 mol) was added to a solution of 2-fluoronitrobenzene (2.6 g, 0.018 mol) in MeCN
(30 ml), followed by Et3N (3.9 g, 0.038 mol). The product was refluxed for 5 days (TLC monitoring),
evaporated, EtOAc (50 ml) and water (50 ml) added, and the organic layer was separated and dried over
Na2SO4. The product was evaporated, and the residue was chromatographed on a silica gel column using the
20
system hexane–EtOAc (10:1). Yield 4.7 g (74%). Yellow crystals; mp 101-103ºC; []D -117.6º (c 1.00,
1
CHCl3). H NMR spectrum, , ppm (J, Hz): 1.40 (9H, s, C(СН3)3); 3.16-3.29 (2H, m, CH2Ph); 4.35-4.41 (1H,
m, CHCH2); 6.67-6.73 (2H, m, H Ar); 7.24-7.43 (6H, m, H Ph, H Ar); 8.18 (1H, d, J = 8.9, H Ar); 8.19 (1H, d,
13
J = 7.5, NH). C NMR spectrum, , ppm: 27.9 (C(CH3)3); 38.6 (CH2); 57.9 (CHCH2); 82.6 (C(CH3)3); 113.9
(C-4); 116.1 (C-6); 127.0 (C-4'); 127.3 (C-3); 128.7 (C-3',5'); 129.4 (C-2',6'); 135.8 (C-2); 136.0 (C-5); 144.0
(C-1'); 149.8 (C-1); 170.4 (C=O). Found, %: C 66.61; H 6.41; N 8.19. C19H22N2O4. Calculated, %: C 66.65;
H 6.48; N 8.18.
Synthesis of Compounds 6a-c and 12a (General Method). Pd/C (10%) was added to a solution of
compound 3a-c (17.2 mmol) in ether (50 ml) and argon was passed through, followed by hydrogen.
Hydrogenation was carried out in the hydrogen atmosphere at room temperature (TLC monitoring), and the
reaction mixture was then filtered. Et3N (3.2 ml, 22.4 mmol) was added to the filtrate containing the diamino
compound 4a-c. The product was cooled to 0ºC, and ethyl oxalyl chloride (2.3 ml, 20.6 mmol) was added
dropwise. A white precipitate of triethylamine hydrochloride was formed. The mixture was stirred for 1 h at
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room temperature. The precipitate was filtered off, the filtrate washed with water (250 ml), and the organic
layer was dried over Na2SO4 and evaporated. Compound 5a-c was obtained as a yellow, oily liquid which
without further purification was refluxed for 10 h in toluene (100 ml) and evaporated. The residue containing
the products 6a-c and 12a was chromatographed in the corresponding system (see further).
Ethyl 3-[(S)-2-tert-Butoxy-1-methyl-2-oxoethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylate (6a).
The material was chromatographed on a silica gel column using CH2Cl2 to give compound 6a as a light-yellow
20
1
oil. Yield 52%. []D +16.3º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 1.34 (9H, s, C(СН3)3); 1.46
(3H, t, J = 7.1, СН2CH3); 1.86 (3H, d, J = 7.3, CHСH3); 4.48-4.50 (2H, m, СH2CH3); 6.06 (1H, q, J = 7.3,
CHCH3); 7.29 (1H, dd, J = 8.2, J = 4.4, Н-6); 8.16 (1H, dd, J = 8.2, J = 1.1, Н-5); 8.48 (1H, dd, J = 4.4, J = 1.1,
Н-7). 13C NMR spectrum, , ppm: 14.0 (CH2CH3); 17.0 (CHCH3); 27.9 (C(CH3)3); 53.6 (CHCH3); 62.6
(CH2CH3); 82.4 (C(CH3)3); 120.0 (C-6); 129.8 (C-7); 133.7 (C-7a); 141.5 (C-3a); 146.9 (C-5); 147.4 (COOEt);
159.7 (C-2); 168.6 (COOBu-t). Found, %: C 60.05; H 6.52; N 13.03. C16H21N3O4. Calculated, %: С 60.18;
H 6.63; N 13.16.
tert-Butyl (S)-2-(2,3-Dioxo-1,4-dihydropyrido[2,3-b]pyrazin-4-yl)propionate (12a). After separation
of compound 6a, chromatography was continued with ethyl acetate to give compound 12a as gray crystals.
Yield 40%; mp 97-99ºC. []D20 -7.3º (c 1.09, CHCl3). 1H NMR spectrum, , ppm (J, Hz): 1.40 (9H, s, C(СН3)3);
1.70 (3H, d, J = 7.3, CHCH3); 5.97 (1H, q, J = 7.1, CHCH3); 7.19 (1H, dd, J = 7.8, J = 4.7, H-7); 7.76 (1H, d,
J = 7.9, H-8); 8.24 (1Н, d, J = 4.6, H-6). 13C NMR spectrum, , ppm: 14.4 (CHCH3); 27.8 (C(CH3)3); 51.7; 81.9
(C(CH3)3; 119.9 (C-8); 120.9 (C-8a); 124.5 (C-7); 137.8 (C-4a); 142.9 (C-6); 155.3 (С-3); 160.4 (С-2); 168.6
(COOBu-t). Found, %: C 57.68; H 5.82; N 14.48. C14H17N3O4. Calculated, %: C 57.72; H 5.88; N 14.42.
Ethyl 3-[(S)-1-(tert-Butoxycarbonyl)-3-methylbutyl]-3H-imidazo[4,5-b]pyridine-2-carboxylate (6b).
The compound was chromatographed on a silica gel column using CH2Cl2 to give compound 6b as a
20
1
light-yellow oil. Yield 50%. []D +9.5º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 0.78 (3H, d,
J = 6.6, CHСН3); 0.95 (3H, d, J = 6.6, CHCH3); 1.25-1.28 (1H, m, CH(CH3)2); 1.33 (9H, s, C(СН3)3); 1.45 (3H,
t, J = 7.3, СН2CH3); 2.25-2.28 (1H, m, CHСН2); 2.43-2.45 (1H, m, CHСH2); 4.47-4.49 (2H, m, СH2CH3); 6.06
(1H, dd, J = 10.2, J = 4.4, CHCH2); 7.29 (1H, dd, J = 8.2, J = 4.7, Н-6); 8.17 (1H, dd, J = 8.2, J = 1.3, Н-5);
8.49 (1H, dd, J = 4.6, J = 1.3, Н-7). 13C NMR spectrum, , ppm: 13.8 (CH2CH3); 21.3 (CH(CH3)2); 22.6
CH(CH3)2); 24.9 (CH(CH3)2); 27.4 (C(CH3)3); 39.4 (CHCH2); 56.3 (CHCH2); 62.2 (CH2CH3); 81.9 (C(CH3)3);
119.5 (C-6); 129.3 (C-7); 133.2 (C-7a); 141.4 (C-3a); 146.5 (C-5); 147.6 (COOEt); 159.3 (C-2); 168.3
(COOBu-t). Found, %: C 63.08; H 7.45; N 11.54. C19H27N3O4. Calculated, %: C 63.14; H 7.53; N 11.63.
Ethyl 3-[(S)-1-Benzyl-2-tert-butoxy-2-oxoethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylate (6c). The
substance was chromatographed on a silica gel column using CH2Cl2 to give compound 6c as a light-yellow oil.
20
1
Yield 55%. []D -44.3º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 1.39-1.43 (12H, m, C(СН3)3,
СН2CH3); 3.71-3.74 (2H, m, СН2Ph); 4.39-4.42 (2H, m, СH2CH3); 6.36 (1Н, dd, J = 10.4, J = 5.5, NCHCO);
6.85 (2H, dd, J = 6.6, J = 2.7, H Ar); 7.00-7.05 (3H, m, H Ar); 7.25 (1Н, dd, J = 8.2, J = 4.6, Н-6); 8.10 (1Н, dd,
13
J = 8.2, J = 1.5, H-5); 8.43 (1Н, dd, J = 4.6, J = 1.3, H-7). C NMR spectrum, , ppm: 14.2 (CH2CH3); 27.9
(C(CH3)3); 36.7 (CH2Ph); 59.3 (CHCH2); 62.6 (CH2CH3); 82.8 (C(CH3)3); 119.9 (C-6); 126.6 (C-7); 128.2
(C-4'); 128.9 (C-3',5'); 129.6 (C-2',6'); 133.4 (C-7a); 136.9 (C-1'); 141.5 (C-5); 146.8 (C-3a); 147.6 (COOEt);
159.7 (C-2); 167.9 (COOBu-t). Found, %: С 66.86; Н 6.40; N 10.67. C22H25N3O4. Calculated, %: C 66.82;
H 6.37; N 10.63.
Ethyl 1-[(S)-1-Benzyl-2-tert-butoxy-2-oxoethyl]-1H-benzimidazole-2-carboxylate (6d). Pd/C (10%)
was added to a solution of compound 3d (5.0 g, 0.015 mol) in ethanol (50 ml), and argon was passed through,
followed by hydrogen. Hydrogenation was carried out in the hydrogen atmosphere at room temperature. After
reduction of the nitro group, the product was filtered and the mother liquor was treated with a solution of
glyoxalic aldehyde ester (3.0 g, 0.015 mol) (50% solution in toluene) and iodine (3.7 g, 0.015 mol). The solution
obtained was stirred at room temperature for 12 h. The solution was evaporated, and the residue was
chromatographed on a silica gel column using the system hexane–EtOAc (10:1), to give compound 6d (4.7 g,
20
1
82%) as a light-yellow oil. []D -42.7º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 1.36 (3H, t,
779

J = 7.3, СH2СН3); 1.40 (9H, s, C(СН3)3); 3.45 (2H, q, J = 7.3, СH2CH3); 3.67-3.72 (2H, m, CH2Ph); 6.31-6.34
(1H, m, CHCH2); 6.75-6.82 (2H, m, H Ar); 7.03-7.11 (3H, m, H Ar); 7.29-7.41 (3H, m, H Ar); 7.85-7.91 (1H,
13
m, H Ar). C NMR spectrum, , ppm: 14.3 (CH2CH3); 27.8 (C(CH3)3); 36.8 (CHCH2); 60.7 (CHCH2); 62.3
(CH2CH3); 83.1 (C(CH3)3); 111.8 (C-7); 122.2 (C-4); 123.6 (C-6); 125.3 (C-5); 126.9 (C-4'); 128.5 (C-3',5');
128.8 (C-2',6'); 136.5 (C-1'); 140.7 (C-7a); 141.6 (C-3a); 160.0 (COOEt); 161.1 (C-2); 167.8 (COOBu-t).
Found, %: C 69.95; H 6.59; N 7.04. C23H26N2O4. Calculated, %: C 70.03; H 6.64; N 7.10.
tert-Butyl (S)-(2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl)-3-phenylpropionate (12d). The residue,
after evaporation of toluene, was chromatographed on a silica gel column using EtOAc. Yield 82%. White
20
1
crystals; mp 180-182ºC. []D -41.3º (c 1.00, CHCl3). H NMR spectrum, , ppm (J, Hz): 1.35 (9H, s,
C(СН3)3); 3.30-3.51 (2H, m, CH2Ph); 5.70-5.73 (1H, m, CHCH2); 7.04-7.17 (9H, m, H Ar); 12.09 (1H, s, NH).
13C NMR spectrum, , ppm: 27.5 (C(CH3)3); 33.3 (CHCH2); 58.1 (CHCH2); 81.5 (C(CH3)3); 114.9 (C-5); 115.8
(C-7); 123.0 (C-8); 123.7 (C-6); 125.1 (C-4'); 126.4 (C-4a); 128.0 (C-3',5'); 129.0 (C-2',6'); 136.8 (C-8a); 136.9
(C-1'); 153.0 (C-2); 154.8 (C-3); 167.5 (COOBu-t). Found, %: C 68.75; H 5.97; N 7.57. C21H22N2O4.
Calculated, %: C 68.84; H 6.05; N 7.65.
tert-Butyl (S)-2-[2-(Benzylamino)carbonyl-3H-imidazo[4,5-b]pyridin-3-yl]propionate (7a). Benzyl-
amine (0.9 g, 8.4 mmol) was added to a solution of compound 6a (0.9 g, 2.8 mmol) in 2-PrOH (10 ml) and
refluxed for 48 h. The solvent was evaporated, and the residue was chromatographed using CH2Cl2. Yield 84%.
White crystals; mp 107-109ºC. 1H NMR spectrum, , ppm (J, Hz): 1.38 (9H, s, C(СН3)3); 1.96 (3H, d, J = 7.1,
CHCH3); 4.47-4.50 (2H, m, CH2); 6.30 (1H, q, J = 7.1, CHCH3); 7.29-7.42 (6H, m, H Ph, H-6); 8.04-8.07 (2H,
13
m, H-7, NH); 8.49 (1H, d, J = 4.6, H-5). C NMR spectrum, , ppm: 17.0 (CHCH3); 27.7 (C(CH3)3); 43.5
(NHCH2); 53.8 (CHCH3); 82.1 (C(CH3)3); 119.7 (C-6); 127.7 (C-7); 127.9 (C-4'); 128.5 (C-3',5'); 128.8
(C-2',6'); 128.9 (C-7a); 133.3 (C-1'); 137.5 (C-5); 144.1 (C-3a); 146.1 (CONH); 159.0 (C-2); 168.8 (COOBu-t).
Found, %: C 66.12; H 6.21; N 14.65. C21H24N4O3. Calculated, %: C 66.30; H 6.36; N 14.73.
Synthesis of Compounds 13a-d (General Method). Argon was passed through a suspension of 2,4-di-
methoxybenzylamine hydrochloride (1.28 g, 6.3 mmol) in CH2Cl2 (30 ml) and cooled to 0ºC. The reaction was
carried out in an argon atmosphere. A solution of trimethyl aluminum (9.5 ml, 18.9 mmol) (a 2 mol/l solution in
hexane) was added dropwise. The solution formed was stirred for 30 min at room temperature and the
corresponding ester 6a-d (6.3 mmol) in CH2Cl2 (10 ml) was added dropwise. The obtained orange solution was
stirred at room temperature for 1 day. The reaction mixture was poured into a weakly acid aqueos solution (5%
HCl), and the organic layer was separated, washed with water, and dried over Na2SO4. Solvent was evaporated,
and the residue was chromatographed on a silica gel column using the system hexane–EtOAc (10:1).
tert-Butyl (S)-2-[2-(2,4-Dimethoxybenzylaminocarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]propio-
nate (13a). Yield 41%. Light-yellow oil. []D20 +8.8º (c 1.10, CHCl3). 1H NMR spectrum, , ppm (J, Hz): 1.34
(9H, s, C(СН3)3); 1.93 (3H, d, J = 7.2, CHCH3); 3.81 (3H, s, 2'-OCH3); 3.88 (3H, s, 4'-OCH3); 4.55-4.58 (2H,
m, CH2); 6.30 (1H, q, J = 7.2, CHCH3); 6.47-6.49 (2H, m, H Ar); 7.28-7.30 (2H, m, H Ar, H-6); 8.07-8.09 (2H,
m, H-7, NH); 8.46 (1H, dd, J = 4.6, J = 1.5, H-5). 13C NMR spectrum, , ppm: 17.0 (CHCH3); 27.8 (C(CH3)3);
38.8 (CH2); 53.7 (CHCH3); 55.4 (2-CH3O, 4-CH3O); 82.0 (C(CH3)3); 98.6 (C-3'); 100.0 (C-5'); 103.9 (C-1');
118.1 (C-6); 119.5 (C-7); 123.0 (C-7a); 128.4 (C-6'); 130.6 (C-5); 133.3 (C-3a); 145.8 (CONH); 158.7 (C-4');
160.4 (C-2); 160.7 (C-2'); 168.8 (COOBu-t). Found, %: C 62.62; H 6.35; N 12.66. C23H28N4O5. Calculated, %:
C 62.71; H 6.41; N 12.72.
tert-Butyl (S)-2-[2-(2,4-Dimethoxybenzylaminocarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]-4-methyl-
20
1
pentanoate (13b). Yield 43%. Light-yellow oil. []D +5.5º (c 1.03, CHCl3). H NMR spectrum, , ppm (J,
Hz): 0.82 (3H, d, J = 6.4, CHСH3); 1.01 (3H, d, J = 6.4, CHСН3); 1.00-1.04 (10H, m, C(СН3)3, CH(CH3)2);
2.28-2.35 (1H, m) and 2.55-2.63 (1H, m, СH2CH); 3.81 (3H, s, 2'-OCH3); 3.88 (3H, s, 4'-OCH3); 4.57-4.59 (2H,
m, CH2); 6.27-6.30 (1H, m, CHCH2); 6.42-6.50 (2H, m, H Ar); 7.23-7.31 (2H, m, H Ar, H-6); 8.02-8.11 (2H, m,
H-5,7); 8.45-8.48 (1H, m, NH). 13C NMR spectrum, , ppm: 21.4 (CH(CH3)2); 22.7 (CH(CH3)2); 25.0
(CH(CH3)2); 27.4 (C(CH3)3); 38.3 (CH2Ph); 39.3 (CHCH2); 55.0 (2',4'-OCH3); 56.4 (CHCH2); 81.5 (C(CH3)3);
98.2 (C-3'); 103.6 (C-5'); 117.8 (C-1'); 118.9 (C-6); 127.9 (C-7); 130.1 (C-7a); 132.7 (C-6'); 144.35 (C-4); 145.3
780

(C-3a); 148.1 (CONH); 158.2 (C-4'); 158.3 (C-2); 160.3 (C-4'); 168.6 (COOBu-t). Found, %: C 64.61; H 7.04;
N 11.56. C26H34N4O5. Calculated, %: C 64.71; H 7.10; N 11.61.
tert-Butyl (S)-2-[2-(2,4-Dimethoxybenzylaminocarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]-3-phenyl-
propionate (13c). Yield 39%. Light-yellow oil. []D20 -40.7º (c 1.10, CHCl3). 1H NMR spectrum, , ppm (J, Hz):
1.38 (9H, s, C(СН3)3); 3.75-3.84 (5H, m, CH2Ar, 2'-OCH3); 3.86 (3H, s, 4'-OCH3); 4.51-4.52 (2H, m, CH2Ar);
6.44-6.50 (2H, m, CHCH2, H Ar); 6.57-6.69 (1H, m, H Ar); 6.87-7.01 (5H, m, H Ph); 7.18-7.25 (2H, m, H Ar,
H-6); 7.84-7.91 (1H, m, H-7); 7.95 (1H, d, J = 8.1, H-5); 8.39 (1H, d, J = 4.6, NH). 13C NMR spectrum, , ppm:
27.4 (C(CH3)3); 36.2 (CHCH2); 38.1 (CH2Ph); 54.9 (2',4'-OCH3); 58.4 (CHCH2); 81.8 (C(CH3)3); 98.1 (C-3');
103.5 (C-5'); 117.6 (C-1'); 118.8 (C-6); 125.8 (C-7); 127.5 (C-3'',5''); 127.7 (C-4''); 128.5 (C-2'',6''); 130.0
(C-5'); 132.4 (C-7a); 136.8 (C-5); 143.9 (C-1''); 145.1 (C-7a); 147.6 (CONH); 158.1 (C-4'); 158.2 (C-2); 160.2
(C-2'); 167.6 (COOBu-t). Found, %: C 67.33; H 6.18; N 10.77. C29H32N4O5. Calculated, %: C 67.43; H 6.24;
N 10.85.
tert-Butyl (S)-2-[2-(2,4-Dimethoxybenzylaminocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropio-
nate (13d). Yield 23%. Light-yellow oil. []D20 -30.1º (c 0.99, CHCl3). 1H NMR spectrum, , ppm (J, Hz): 1.40
(9H, s, C(CH3)3); 3.46-3.56 (1H, m) and 3.67-3.74 (1H, m, CH2Ar); 3.81 (3H, s, 2'-OCH3); 3.85 (3H, s,
4'-OCH3); 4.45-4.50 (2H, m, CH2Ar); 6.43-6.50 (2H, m, H Ar, CHCH2); 6.79-6.84 (3H, m, H Ar); 6.94-7.05
(3H, m, H Ar); 7.15-7.21 (1H, m, H Ar); 7.28-7.32 (3H, m, H Ar); 7.68-7.85 (1H, m, H Ar); 7.86-7.93 (1H, m,
NH). 13C NMR spectrum, , ppm: 27.4 (C(CH3)3); 36.5 (CHCH2); 38.1 (CH2Ar); 55.0 (2',4'-OCH3); 59.9
(NCH); 82.3 (C(CH3)3); 98.1 (C-3'); 103.6 (C-5'); 111.7 (C-7); 117.9 (C-1'); 120.3 (C-4); 122.9 (C-6); 123.9
(C-5); 126.2 (C-4''); 127.8 (C-3'',5''); 128.5 (C-2'',6''); 130.0 (C-6'); 134.9 (C-7a); 136.3 (C-1"); 140.6 (C-3a);
143.1 (CONH); 158.2 (C-4'); 158.7 (C-2); 160.3 (C-2'); 167.7 (COOBu-t). Found, %: C 69.79; H 6.39; N 8.07.
C30H33N3O5. Calculated, %: C 69.88; H 6.45; N 8.15.
Synthesis of Compounds 9a, 15a-d (General Method). The corresponding amide 7a or 13a-d
(1.8 mmol) was dissolved in formic acid (10 ml) and stirred for 48 h at 50ºC. Solvent was evaporated, and the
residue was chromatographed using CH2Cl2.
7-Benzyl-9-methyl-7H,9H-pyrido[3',2':4,5]imidazo[1,2-a]pyrazine-6,8-dione (9a). Yield 47%; mp
179-181ºC. 1H NMR spectrum, , ppm (J, Hz): 2.04 (3H, d, J = 6.9, CH3); 5.24-5.28 (2H, m, CH2); 5.55 (1H, q,
J = 7.0, CHCH3); 7.31-7.34 (3H, m, H Ph); 7.43 (1H, dd, J = 8.3, J = 4.6, H-3); 7.50-7.54 (2H, m, H Ph); 8.30
(1H, d, J = 8.3, H-4); 8.60 (1H, d, J = 4.5, H-2). 13C NMR spectrum, , ppm: 20.7 (CHCH3); 43.8 (CH2); 54.2
(CHCH3); 120.8 (C-3); 128.1 (C-4); 128.7 (C-4'); 129.3 (C-3',5'); 130.7 (C-2',6'); 133.0 (C-4a); 136.1 (C-1');
137.8 (C-2); 148.0 (C-10a); 152.5 (C-6); 169.2 (C-5a); 173.0 (C-8). Found, %: C 66.41; H 4.61; N 18.29.
C17H14N4O2. Calculated, %: C 66.66; H 4.61; N 18.29.
7-(2,4-Dimethoxybenzyl-9-methyl-7H,9H-pyrido[3',2':4,5]imidazo[1,2-a]pyrazine-6,8-dione (15a).
Yield 53%. White crystals; mp 174-176ºC. 1H NMR spectrum, , ppm (J, Hz): 2.02 (3H, d, J = 7.1, CH3); 3.78
(3H, s, 2-OCH3); 3.81 (3H, s, 4-OCH3); 5.10-5.13 (1H, m) and 5.31-5.33 (1H, m, CH2Ar); 5.52 (1H, q, J = 7.0,
CHCH3); 6.41-6.43 (2H, m, H Ar); 7.20 (1H, d, J = 8.8, H Ar); 7.42 (1H, dd, J = 8.2, J = 4.6, H-3); 8.28 (1H,
dd, J = 8.2, J = 1.2, H-4); 8.59 (1H, dd, J = 4.6, J = 1.2, H-2). 13C NMR spectrum, , ppm: 20.7 (CHCH3); 39.6
(CH2Ar); 54.2 (CHCH3); 55.4 (2'-OCH3); 55.5 (4'-OCH3); 98.6 (C-3'); 104.1 (C-5'); 115.9 (C-3); 118.6 (C-1');
120.7 (C-4); 130.5 (C-4a); 130.6 (C-6'); 136.1 (C-2); 145.8 (C-10a); 147.8 (C-6); 155.3 (C-5a); 158.5 (C-4');
160.6 (C-2'); 169.0 (C-8). Found, %: C 62.10; H 5.02; N 15.31. C19H18N4O4. Calculated, %: C 62.29; H 4.95;
N 15.29.
7-(2,4-Dimethoxybenzyl)-9-isobutyl-7H,9H-pyrido[3',2':4,5]imidazo[1,2-a]pyrazine-6,8-dione
(15b).
1
Yield 73%. White crystals; mp 147-149ºC. H NMR spectrum, , ppm (J, Hz): 0.70 (3H, d, J = 6.4) and 0.91
(3H, d, J = 6.4, CH(CH3)2); 0.80-0.90 (1H, m, CH(CH3)2); 2.15-2.24 (1H, m) and 2.29-2.37 (1H, m, CHСH2);
3.78 (3H, s, 2'-OCH3); 3.79 (3H, s, 4'-OCH3); 5.21 (2H, dd, J = 21.2, J = 12.2, CH2Ar); 5.52 (1H, dd, J = 7.4,
J = 4.8, CHCH2); 6.40-6.44 (2H, m, H Ar); 7.20-7.23 (1H, m, H Ar); 7.41 (1H, dd, J = 8.1, J = 4.8, H-3); 8.28
(1H, dd, J = 8.1, J = 1.3, H-4); 8.58 (1H, dd, J = 4.8, J = 1.3, H-2). 13C NMR spectrum, , ppm: 22.3
(CH(CH3)2); 22.7 (CH(CH3)2); 24.3 (CH(CH3)2); 39.5 (CHCH2); 43.0 (CH2Ar); 55.4 (2'-OCH3); 55.5
781

(4'-OCH3); 57.2 (CHCH2); 98.4 (C-3'); 103.9 (C-5'); 115.9 (C-3); 120.6 (C-1'); 130.5 (C-4); 130.8 (C-4a); 135.9
(C-6'); 138.7 (C-2); 145.8 (C-10a); 147.8 (C-6); 155.5 (C-5a); 158.5 (C-4'); 160.6 (C-2'); 168.4 (C-8). Found,
%: C 64.61; H 5.87; N 13.64. C22H24N4O4. Calculated, %: C 64.69; H 5.92; N 13.72.
9-Benzyl-7-(2,4-dimethoxybenzyl)-7H,9H-pyrido[3',2':4,5]imidazo[1,2-a]pyrazine-6,8-dione (15c).
Yield 59%. White crystals; mp 164-165ºC. 1H NMR spectrum, , ppm (J, Hz): 3.62-3.69 (1H, m) and 4.02-4.08
(1H, m, CHCH2); 3.77 (3H, s, 2'-OCH3); 3.79 (3H, s, 4'-OCH3); 5.01 (2H, s, CH2Ar); 5.82 (1H, dd, J = 4.8,
J = 3.2, CHCH2); 6.31-6.42 (4H, m, H Ar); 6.89-7.00 (3H, m, H Ar); 7.09-7.15 (1H, m, H Ar); 7.48 (1H, dd,
13
J = 8.3, J = 4.3, H-3); 8.31 (1H, d, J = 8.3, H-4); 8.68 (1H, d, J = 4.3, H-2). C NMR spectrum, , ppm: 38.6
(CHCH2); 39.1 (CH2Ar); 55.4 (2'-OCH3); 55.5 (4'-OCH3); 58.9 (CHCH2); 98.4 (C-3'); 104.0 (C-5'); 115.7 (C-3);
120.8 (C-1'); 127.9 (C-4); 128.8 (C-4''); 128.9 (C-3'',5''); 130.3 (C-4a); 130.8 (C-2'',6''); 132.9 (C-6'); 135.9
(C-1''); 139.0 (C-2); 145.8 (C-10a); 147.9 (C-6); 154.8 (C-5a); 158.4 (C-4'); 160.5 (C-2'); 168.0 (C-8). Found,
%: C 67.79; H 5.09; N 12.58. C25H22N4O4. Calculated, %: 67.86; H 5.01; N 12.66.
4-Benzyl-2-(2,4-dimethoxybenzyl)-2H,4H-pyrazino[1,2-a]benzimidazole-1,3-dione (15d). Yield
68%. White crystals; mp 213-215ºC. 1H NMR spectrum, , ppm (J, Hz): 3.54-3.67 (2H, m, CHCH2); 3.77 (3H,
s, 2'-OCH3); 3.79 (3H, s, 4'-OCH3); 4.92-5.04 (2H, m, CH2Ar); 5.61-5.65 (1H, м, CHCH2); 6.33–6.43 (4H, m,
H Ar); 6.89-6.93 (1H, m, H Ar); 6.99-7.05 (2H, m, H Ar); 7.13-7.21 (1H, m, H Ar); 7.46-7.56 (3H, m, H Ar);
8.01-8.06 (1H, m, H Ar). 13C NMR spectrum, , ppm: 38.9 (CHCH2); 39.6 (CH2Ar); 55.4 (2'-OCH3); 55.5
(4'-OCH3); 59.5 (CHCH2); 98.4 (C-3'); 104.0 (C-5'); 111.0 (C-6); 123.0 (C-9); 124.8 (C-1'); 126.4 (C-7); 128.2
(C-8); 128.7 (C-4''); 128.8 (C-3'',5''); 128.9 (C-2'',6''); 130.1 (C-5a); 132.4 (C-6'); 132.9 (C-1''); 138.6 (C-9a);
140.3 (C-1); 143.7 (C-10a); 158.3 (C-4'); 160.4 (C-2'); 168.0 (C-3). Found, %: C 70.71; H 5.20; N 9.43.
C26H23N3O4. Calculated, %: C 70.74; H 5.25; N 9.52.
9-Methyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrazine Dihydrobromide (11a). The
BH3·THF complex (1 mol/l in THF, 5 ml) was added dropwise to a suspension of compound 15a (0.10 g,
0.3 mmol) in THF (10 ml) cooled in an ice bath under a stream of argon. Cooling was removed and the product
was stirred for 10 h at room temperature. The solution obtained was treated with MeOH (5 ml) and evaporated.
The residue was treated with trifluoroacetic acid (10 ml) and stirred for 10 h. The violet solution was
evaporated, 20% aqueous HBr solution (20 ml) was added, and it was washed with ethyl acetate (220 ml). The
aqueous layer was separated and evaporated to dryness, and the residue was washed with acetonitrile. The
precipitate was filtered off, washed with ether, and dried over Na2SO4 to give compound 11a (0.06 g, 57%) as a
1
cream colored powder. Mp 235ºC (sublimes). H NMR spectrum, , ppm (J, Hz): 1.77 (3H, d, J = 6.6, CH3);
3.81-3.83 (1H, m) and 3.96-3.98 (1H, m, CHCH2); 4.96-4.99 (2H, m, CH2NH); 5.18-5.20 (1H, m, CHCH3);
7.59 (1H, dd, J = 8.2, J = 4.9, H-3); 8.24 (1H, d, J = 8.2, H-4); 8.52 (1H, d, J = 4.8, H-2). 13C NMR spectrum, ,
ppm: 17.9 (CH3); 41.9 (CH2NH); 45.9 (CHCH2); 47.2 (CHCH2); 119.8 (C-3); 127.0 (C-4); 133.2 (C-4a); 144.5
(C-2); 146.2 (C-10a); 146.7 (C-5a). Found, %: C 34.11; H 4.12; N 15.90. C10H14N4Br2. Calculated, %: C 34.31;
H 4.03; N 16.01.
Ethyl 3-(S)-2-[(2,4-Dimethoxybenzylamino)-1-methyl-2-oxoethyl]-3H-imidazo[4,5-b]pyridine-2-carb-
oxylate (18). A solution of compound 6a (0.50 g, 1.6 mmol) in formic acid (10 ml) was stirred for 3 days at
room temperature. The solution obtained was evaporated and dissolved in CH2Cl2 (10 ml).
Diisopropylethylamine (1.03 g, 8.0 mmol), 2,4-dimethoxybenzylamine (0.34 g, 1.7 mmol), and PyBOP (0.99 g,
1.9 mmol) were added. The obtained suspension was stirred for 12 h, water (20 ml) was added, and the organic
layer was separated and dried over Na2SO4. Solvent was evaporated and the residue was chromatographed on a
silica gel column using the system hexane–EtOAc (1:1). Initially, compound 15a (0.29 g, 50%) was eluted
20
1
followed by compound 18 (0.04 g, 6%). White crystals; mp 61-63ºC. []D +17.3º (c 1.00, CHCl3). H NMR
spectrum, , ppm (J, Hz): 1.43 (3H, t, J = 7.4, CH2CH3); 1.90 (3H, d, J = 7.3, CHCH3); 3.57 (3H, s, 2'-OCH3);
3.77 (3H, s, 4'-OCH3); 4.22-4.29 (1H, m, CH2Ar); 4.35-4.44 (3H, m, CH2CH3, CH2Ar); 6.15 (1H, dd, J = 14.5,
J = 7.5, CHCH3); 6.31-6.42 (3H, m, H Ar); 7.33 (1H, dd, J = 8.3, J = 4.8, H-6); 8.18 (1H, dd, J = 8.3, J = 1.3,
782

TABLE 1. Basic Bond Lengths (l) in the Compound 9a Structure
Bond
l, Å
Bond
l, Å
Bond
l, Å
N(1)–C(2)
1.447(3)
1.360(2)
1.385(3)
0.980(2)
1.518(3)
1.515(3)
0.960(2)
0.961(2)
0.960(2)
1.217(3)
1.381(3)
1.397(3)
1.472(3)
1.218(2)
C(5)–C(6)
1.466(3)
1.320(3)
1.376(3)
1.404(3)
1.392(3)
0.929(2)
1.352(3)
0.929(2)
1.396(3)
0.929(2)
1.335(3)
1.322(2)
0.970(2)
0.970(2)
C(14)–C(15)
C(15)–C(16)
C(15)–C(20)
C(16–H(16)
C(16)–C(17)
C(17)–H(17)
C(17)–C(18)
C(18)–H(18)
C(18)–C(19)
C(19)–H(19)
C(19)–C(20)
C(20)–H(20)
1.510(3)
1.365(3)
1.355(3)
0.930(2)
1.397(3)
0.930(2)
1.358(3)
0.929(3)
1.342(3)
0.929(2)
1.385(4)
0.931(2)
N(1)–C(6)
C(6)–N(7)
N(1)–C(13)
C(2)–H(2)
N(7)–C(8)
C(8)–C(9)
C(2)–C(21)
C(2)–C(3)
C(8)–C(13)
C(9)–H(9)
C(21)–H(21A)
C(21)–H(21A)
C(21)–H(21C)
C(3)–O(3)
C(9)–C(10)
C(10)–H(10)
C(10)–C(11)
C(11)–H(11)
C(11)–N(12)
N(12)–C(13)
C(14)–H(14A)
C(14)–H(14B)
C(3)–N(4)
N(4)–C(5)
N(4)–C(14)
C(5)–O(5)
TABLE 2. Valence Angles () in the Compound 9a Structure
Angle
,deg.
Angle
, deg.
C(2)–N(1)–C(6)
125.7(2)
128.7(2)
105.3(1)
108.4(2)
111.8(2)
111.4(2)
108.3(2)
108.3(2)
108.5(2)
109.5(2)
109.5(2)
109.6(2)
109.5(2)
109.4(2)
109.3(2)
118.6(2)
120.7(2)
120.6(2)
123.8(2)
119.4(2)
116.8(2)
121.5(2)
116.4(2)
122.0(2)
120.2(2)
N(1)–C(6)–N(7)
114.8(2)
125.0(2)
103.3(2)
131.5(2)
111.2(2)
117.3(2)
122.1(2)
115.9(2)
122.0(2)
119.2(2)
121.6(2)
119.2(2)
117.7(2)
124.4(2)
117.9(2)
112.6(2)
105.4(2)
126.4(2)
128.1(2)
109.1(2)
109.1(2)
112.6(2)
107.8(2)
109.1(2)
C(2)–N(1)–C(13)
C(6)–N(1)–C(13)
N(1)–C(2)–H(2)
N(1)–C(2)–C(21)
N(1)–C(2)–C(3)
C(5)–C(6)–N(7)
C(6)–N(7)–C(8)
N(7)–C(8)–C(9)
N(7)–C(8)–C(13)
C(9)–C(8)–C(13)
C(8)–C(9)–H(9)
H(2)–C(2)–C(21)
H(2)–C(2)–C(3)
C(8)–C(9)–C(10)
H(9)–C(9)–C(10)
C(9)–C(10)–H(10)
C(9)–C(10)–C(11)
H(10)–C(10)–C(11)
C(10)–C(11)–H(11)
C(10)–C(11)–N(12)
H(11)–C(11)–N(12)
C(11)–N(12)–C(13)
N(1)–C(13)–C(8)
N(1)–C(13)–N(12)
C(8)–C(13)–N(12)
N(4)–C(14)–H(14A)
N(4)–C(14)–H(14B)
N(4)–C(14)–C(15)
H(14A)–C(14)–H(14B)
H(14A)–C(14)–C(15)
C(21)–C(2)–C(3)
C(2)–C(21)–H(21A)
C(2)–C(21)–H(21B)
C(2)–C(21)–H(21C)
H(21A)–C(21)–H(21B)
H(21A)–C(21)–H(21C)
H(21B)–C(21)–H(21C)
C(2)–C(3)–O(3)
C(2)–C(3)–N(4)
O(3)–C(3)–N(4)
C(3)–N(4)–C(5)
C(3)–N(4)–C(14)
C(5)–N(4)–C(14)
N(4)–C(5)–O(5)
N(4)–C(5)–C(6)
O(5)–C(5)–C(6)
N(1)–C(6)–C(5)
13
H-7); 8.47 (1H, dd, J = 4.8, J = 1.3, H-5). C NMR spectrum, , ppm: 13.7 (CH2CH3); 16.2 (CHCH3); 39.2
(CH2Ar); 54.5 (2'-OCH3); 54.6 (4'-OCH3); 55.0 (CHCH3); 62.4 (CH2CH3); 98.1 (C-3'); 103.5 (C-5'); 118.0
(C-1'); 119.7 (C-6); 129.5 (C-7); 130.0 (C-6'); 133.5 (C-7a); 141.4 (C-5); 146.7 (C-3a); 147.0 (COOEt); 158.0
(C-4'); 159.0 (C-2); 160.0 (C-2'); 168.2 (CONH). Found, %: C 61.08; H 5.79; N 13.53. C21H24N4O5. Calculated,
%: C 61.16; H 5.87; N 13.58.
783

X-ray Structural Analysis of Compound 9a. Monoclinic crystals of 7-benzyl-9-methyl-7H,9H-pyri-
do[3',2':4,5]imidazo[1,2-a]pyrazine-6,8-dione (9a) were obtained by crystallization from EtOAc. Parameters
were: a = 30.4142(15), b = 4.9443(3), c = 19.8461(12) Å,  = 90.00,  = 102.848(10),  = 90.00º, V = 2909.68
Å3, M = 306.33, Z = 8, space group C 2/c, R factor 3.27%. The X-ray structural data is given in Tables 1 and 2
and has been placed in the Cambridge Crystallographic Data Center as deposit CCDC 853690.
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F. A. Carey and R. J. Sundberg in: Advanced Organic Chemistry. Part B. Reactions and Synthesis, 4th
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