Reaction of ethyl acetoacetate with formaldehyde and primary amines

Article abstract of DOI:10.1134/S1070428013060079

The condensation of ethyl acetoacetate with formaldehyde and primary amines in methanol at 65 C (Mannich reaction) gave up to 92% of hexahydropyrimidine derivatives containing ester and acetyl groups. Analogous reaction with aminopyridines stopped at the stage of formation of linear condensation products.

Full text of DOI:10.1134/S1070428013060079

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 6, pp. 843–848. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © D.R. Latypova, A.G. Badamshin, A.N. Lobov, V.A. Dokichev, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49,
No. 6, pp. 860–865.
Reaction of Ethyl Acetoacetate with Formaldehyde
and Primary Amines
D. R. Latypova, A. G. Badamshin, A. N. Lobov, and V. A. Dokichev
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: dokichev@anrb.ru
Received September 15, 2012
Abstract—The condensation of ethyl acetoacetate with formaldehyde and primary amines in methanol at 65°C
(Mannich reaction) gave up to 92% of hexahydropyrimidine derivatives containing ester and acetyl groups.
Analogous reaction with aminopyridines stopped at the stage of formation of linear condensation products.
DOI: 10.1134/S1070428013060079
Hexahydropyrimidine derivatives are biologically
active compounds exhibiting antitumor [1–4], anti-
platelet [5], antibacterial [3, 6], and antiarrhythmic
activity [7]. Hexahydropyrimidine fragment is a struc-
tural unit of alkaloids verbamethine and verbametrine
[8]. Extensive studies are carried out on the synthesis
of new hexahydropyrimidine derivatives. They are
generally prepared by reaction of 1,3-diamines with
aldehydes or ketones [9–11] or by condensation of CH
acids with formaldehyde and primary amines [12–15].
Especially attractive is one-pot synthesis implying
multi-component condensation without isolation of
intermediate compounds. In the preceding communica-
tion [16] we described an efficient one-step procedure
for the synthesis of hexahydropyrimidines via three-
component condensation of ethyl acetoacetate with
formaldehyde and natural amino acid ester hydro-
chlorides in an AcONa/AcOH buffer at pH 4.
condensation with ethyl acetoacetate and formalde-
hyde. Ethyl 5-acetylhexahydropyrimidine-5-carbox-
ylate derivatives may be used as intermediate products
in the synthesis of α,α-disubstituted β-amino- and
β-hydroxybutyric acids [17].
As primary amines we used methylamine (IIa),
propylamine (IIb), isopropylamine (IIc), butylamine
(IId), benzylamine (IIe), 2-aminoethanol (IIf), pyri-
din-4-amine (IIg), and 3,5-dibromopyridin-2-amine
(IIh). The reactions were carried out at 65°C (reaction
time 5 h), the molar ratio I–CH2O–II being 1:15:4.
Ethyl acetoacetate (I) reacted with formaldehyde (as
a 32.3% aqueous solution) and methylamine (as
a 25.2% aqueous solution) in boiling methanol to pro-
duce in 5 h 5% of ethyl 5-acetyl-1,3-dimethylhexa-
hydropyrimidine-5-carboxylate (IIIa) and 59% of
ethyl 1,3-dimethylhexahydropyrimidine-5-carboxylate
(IVa) (Scheme 1). When AcONa–AcOH buffer was
used [16], the overall yield of IIIa and IVa decreased
to 30%.
In the present communication we report on the
synthesis of a larger number of hexahydropyrimidines;
we also examined how the initial amine structure
affects the yield and composition of products of their
The structure of the amine component essentially
affects the reaction direction. The condensation of
Scheme 1.
O
COOEt
COOEt
Me
R
O
O
MeOH
+
CH2O
+
RNH2
+
Me
OEt
N
N
R
N
N
R
R
I
IIa–IIf
IIIa, IIIb, IIId–IIIf
IVa–IVd, IVf
R = Me (a), Pr (b), i-Pr (c), Bu (d), PhCH2 (e), HO(CH2)2 (f).
843

LATYPOVA et al.
844
Scheme 2.
O
O
COOEt
Me
Me
CH2OH
NH2
N
HN
N
Me
COOEt
O
O
NH HN
+
CH2O
+
+
+
Me
OEt
N
N
N
N
I
IIg
V, 45%
VI, 9%
VII, 7%
H
N
H
N
Br
Br
N
N
O
O
+
CH2O +
Me
OEt
N
NH2
Br
Br
Br
Br
I
IIh
VIII, 77%
propylamine (IIb), butylamine (IId), and 2-amino-
ethanol (IIf) with formaldehyde and ester I at a ratio of
4:15:1 in methanol gave mixtures of the correspond-
ing ethyl 5-acetyl-1,3-dialkylhexahydropyrimidine-5-
carboxylates IIIb, IIId, and IIIf and ethyl 1,3-dialkyl-
hexahydropyrimidine-5-carboxylates IVb, IVd, and
IVf, the latter prevailing; the overall yield ranged from
36 to 72%. By contrast, in the reactions of ethyl aceto-
acetate (I) with formaldehyde and isopropylamine
(IIc), benzylamine (IIe), pyridin-4-amine (IIg), and
3,5-dibromopyridin-2-amine (IIh), only one hexahy-
dropyrimidine III or IV was formed, or the reaction
stopped at the stage of formation of linear condensa-
tion products. From ester I, CH2O, and isopropylamine
(IIc) we synthesized ethyl 1,3-diisopropylhexahydro-
pyrimidine-5-carboxylate IVc in 77% yield. Com-
pound IVc was synthesized previously (yield 42%)
together with ethyl N-isopropyl-3-aminopropanoate by
reaction of ethyl hydrogen malonate with 1,3,5-triiso-
propylhexahydro-1,3,5-triazine [18]; however, no any
proof for the assumed structure was given in [18].
Under similar conditions, aminopyridines IIg and
IIh reacted with ethyl acetoacetate and formaldehyde,
yielding linear condensation products VII and VIII,
respectively (Scheme 2). The reaction of I with 32.3%
aqueous formaldehyde and pyridin-4-amine (IIg) in
boiling methanol gave a mixture of [methyl(pyridin-4-
yl)amino]methanol (V), ethyl 2-acetyl-3-(pyridin-4-yl-
amino)propanoate (VI), and ethyl 3-oxo-2,2′-bis[(pyr-
idin-4-ylamino)methyl]butanoate (VII) in 45, 9, and
7% yield, respectively. N,N′-Bis(3,5-dibromopyridin-
2-yl)methanediamine (VIII) was isolated as colorless
crystals in 77% yield in the reaction of I with formal-
dehyde and 3,5-dibromopyridin-2-amine.
The structure of all newly synthesized compounds
was confirmed by 1H and 13C NMR spectroscopy using
two-dimensional COSY, NOESY, HSQC, and HMBC
techniques for signal assignment and elucidation of the
hexahydropyrimidine structure. The heteroring in com-
pounds IV is most likely to adopt a chair-like con-
formation with equatorial orientation of the ester
group. Signals from the axial protons on C4 and C6
3
appeared as triplets at δ ~2.30 ppm (2J ≈ 11.0, J ≈
Benzylamine (IIe) reacted with ester I and formal-
dehyde to give ethyl 5-acetyl-1,3-dibenzylhexahydro-
pyrimidine-5-carboxylate (IIIe) as the only product
(yield 92%). Compound IIe was synthesized previ-
ously in a lower yield (63%) [19] by FeCl3-catalyzed
Mannich reaction.
11.0 Hz), indicating trans-diaxial interaction with 5-H
which resonated as a triplet of triplets at δ 2.75–
2.90 ppm (3J ≈ 11.0, 4.2 Hz).
To conclude, we have developed a one-pot proce-
dure for the synthesis of hexahydropyrimidine deriva-
tives by reaction of ethyl acetoacetate with formalde-
hyde and primary amines. The yields and composition
of the products depend on the initial amine nature.
Presumably, compounds IV are formed via elimina-
tion of the acetyl group according to the retro-aldol
reaction pattern in the course of generation of the
hexahydropyrimidine structure. After heating an equi-
molar mixture of ethyl 5-acetyl-1,3-dibenzylhexahy-
dropyrimidine-5-carboxylate (IIIe) and isopropyl-
amine (IIc) for 5 h at 65°C, even traces of ethyl 1,3-di-
benzylhexahydropyrimidine-5-carboxylate were not
detected in the reaction mixture [20].
EXPERIMENTAL
The NMR spectra were recorded at 298 K on
1
Bruker AM-300 (300.13 MHz for H and 75.47 MHz
for 13C) and Bruker Avance-III 500 (500.13 MHz for
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

REACTION OF ETHYL ACETOACETATE WITH FORMALDEHYDE
845
1H, 125.47 MHz for 13C, and 50.58 MHz for 15N)
Ethyl 5-acetyl-1,3-dimethylhexahydropyrimi-
dine-5-carboxylate (IIIa) and ethyl 1,3-dimethyl-
hexahydropyrimidine-5-carboxylate (IVa) were ob-
tained from 0.95 g (7.6 mmol) of ester I in 21 ml of
MeOH, 9.7 ml (114 mmol) of 32% aqueous formalde-
hyde, and 3.68 g (30 mmol) of 25.2% aqueous methyl-
amine.
spectrometers using a 5-mm PABBO Z-gradient probe.
1
The 13C and H chemical shifts are given relative to
tetramethylsilane as internal reference; the 15N chem-
ical shifts were determined from the F1-projection of
1
the H–15N HMBC spectra and are given relative to
ammonia. Digital resolution was improved by zero
padding and multiplication of the Fourier image by the
exponential function [lb = 0.1 (1H), 1 Hz (13C)]. The
13C NMR spectra with decoupling from protons were
recorded using the following parameters: spectral win-
dow 29.8 kHz, number of points 64 K, pulse duration
(30°) 3.2 μs, relaxation delay 2 s, number of scans
512–2048; gsCOSY: matrix size 4 K per 512 experi-
ments, spectral window 5.0 kHz, sine bell-shaped
weight function for F1 and F2 projections (ssb 2);
gsHSQC: relaxation delay optimized for JCH = 145 and
JNH = 80 Hz, matrix size 2 K per 256 experiments;
gsHMBC: small coupling constant evolution delay
Compound IIIa was isolated using petroleum
ether–ethyl acetate (7:3) as eluent. Yield 0.06 g (5%),
light yellow oily substance. IR spectrum (film), ν,
1
cm–1: 2791, 1740, 1712, 1350, 1200. H NMR spec-
trum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.13 t (3H,
Me, 3J = 7.1), 2.15 s (6H, MeN), 2.20 s (3H, MeC=O),
2.45–2.60 m (2H, CH2N), 2.60–2.75 m (1H, 2-H),
2.82–3.11 m (3H, CH2N, 5-H), 4.13 q (2H, OCH2, 3J =
7.1). 13C NMR spectrum (75 MHz, CDCl3), δC, ppm:
13.61 (Me), 26.30 (MeC=O), 42.51 (MeN), 56.92
(NCH2), 56.52 (C), 61.25 (OCH2), 78.40 (C2), 168.65
(C=O, ester), 202.96 (C=O). Found: m/z 228.1462
[M]+. C11H20N2O3. Calculated: M 228.1468.
1
1
71.4 ms for H–13C and 142.8 ms for H–15N, matrix
size 2 K per 256 experiments; NOESY: matrix size 2 K
per 256 experiments, spectral window 5.0 kHz, mixing
time 0.5 s. The mass spectra were obtained on
a Thermo Finnigan MAT 95 XP high-resolution mass
spectrometer (electron impact, 70 eV, ion source
temperature 250°C, direct inlet probe temperature 50–
270°C, heating rate 10 deg/min). The IR spectra were
measured on a Shimadzu IR Prestige-21 instrument.
The melting points were determined on a Boetius
melting point apparatus. TLC analyses were carried
out using Silufol plates (Merck) and Sorbfil PTSKh-
AF-A plates (IMID Ltd.); eluent chloroform–methanol
(9:1) or petroleum ether–ethyl acetate (7:3). Silica gel
(70–230 mesh, Macherey-Nagel) was used for column
chromatography (gradient elution with chloroform–
methanol, 0 to 10% of the latter or petroleum ether–
ethyl acetate, 0 to 2% of the latter).
Compound IVa was isolated using petroleum ether–
ethyl acetate (7:3) as eluent. Yield 0.65 g (59%), light
yellow oily substance. IR spectrum (film), ν, cm–1:
1
2791, 1730, 1180. H NMR spectrum (300 MHz,
3
CDCl3), δ, ppm (J, Hz): 1.15 t (3H, Me, J = 7.1),
2.15 d (2H, 4-Hax, 6-Hax, 2J = 11.3), 2.22 s (6H, MeN),
2.55 d (1H, 2-Hax, 2J = 9.4), 2.85 m (1H, CH), 2.98 d.d
2
3
(2H, 4-Heq, 6-Heq, J = 11.3, J = 3.7), 3.40 d (1H,
2-Heq, 2J = 9.4), 4.03 q (2H, OCH2, 3J = 7.1). 13C NMR
spectrum (75 MHz, CDCl3), δC, ppm: 13.95 (Me),
38.15 (CH), 42.04 (NMe), 54.71 (CH2N), 60.37
(OCH2), 77.42 (C2), 171.91 (C=O). Found: m/z
186.1348 [M]+. C9H18N2O2. Calculated: M 186.1363.
Ethyl 5-acetyl-1,3-dipropylhexahydropyrimi-
dine-5-carboxylate (IIIb) and ethyl 1,3-dipropyl-
hexahydropyrimidine-5-carboxylate (IVb) were
synthesized from 0.5 g (4 mmol) of ester I in 27 ml of
MeOH, 0.9 g (15 mmol) of propylamine, and 5.8 ml
(68 mmol) of 32.3% aqueous formaldehyde.
Reaction of ethyl acetoacetate (I) with formalde-
hyde and primary amines IIa–IIh (general proce-
dure). Ethyl acetoacetate, 1 mmol, was dissolved in
methanol, 4 mmol of amine IIa–IIh and 15 mmol of
formaldehyde (as a 32.3% aqueous solution) were
added under stirring, and the mixture was heated for
5 h under reflux. The solvent was distilled off under
reduced pressure, 20 ml of methylene chloride was
added to the residue, the mixture was washed with
water (3×10 ml) and dried over anhydrous sodium
sulfate, the solvent was removed under reduced pres-
sure, and the residue was subjected to column chroma-
tography on silica gel.
Compound IIIb was isolated using petroleum ether
as eluent. Yield 0.29 g (27%), light yellow oily sub-
stance. IR spectrum (film), ν, cm–1: 2966, 1730, 1714,
1
1369, 1207, 731. H NMR spectrum (500 MHz,
3
CDCl3), δ, ppm (J, Hz): 0.97 t (6H, Me, J = 7.1),
3
1.32 t (3H, OCH2Me, J = 7.1), 1.71–1.82 m (4H,
NCH2CH23), 2.33 s (3H, MeC=O), 3.71 t (4H,
2
NCH2CH2, J = 6.8), 3.79 br.d (2H, 4-Hax, 6-Hax, J =
2
13.5), 3.86 br.d (2H, 4-Heq, 6-Heq, J = 13.5), 4.19–
2
4.26 m (2H, 2-H), 4.29 q (2H, OCH2, J = 7.1).
13C NMR spectrum (125 MHz, CDCl3), δC, ppm: 10.62
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

LATYPOVA et al.
846
1
(Me), 13.96 (OCH2Me), 20.66 (NCH2CH2), 26.35
(MeC=O), 45.64 (C4, C6), 56.32 (C5), 56.57 (1-CH2,
3-CH2), 62.00 (C2), 63.74 (OCH2), 166.60 (C=O,
ester), 197.98 (C=O). Found: m/z 284.2086 [M]+.
C15H28N2O3. Calculated: M 284.2094.
1201. H NMR spectrum (500 MHz, CDCl3), δ, ppm
(J, Hz): 0.76–0.99 m (6H, CH2Me), 1.17–1.36 m (7H,
CH2CH2Me, OCH2Me), 1.40–1.58 m (4H, NCH2CH2),
2.30 s (3H, MeC=O), 2.39–3.23 m (4H, 4-H, 6-H),
3.48–3.55 m (2H, 2-H), 3.49–3.71 m (4H, NCH2CH2),
4.15 q (2H, OCH2, J = 7.1). 13C NMR spectrum
2
Compound IVb was isolated using petroleum
ether–ethyl acetate (50 :1) as eluent. Yield 0.41 g
(45%), light yellow oily substance. IR spectrum (film),
(125 MHz, CDCl3), δC, ppm: 13.59 and 13.90
(CH2Me, OCH2Me), 20.53 (CH2Me), 26.70
[C(O)Me], 28.81 (CH2CH2Me), 55.00 (C4, C6), 55.58
(CH2CH2N), 57.52 (C5), 61.48 (OCH2), 76.34 (C2),
169.22 (C=O, ester), 203.77 (C=O). Found: m/z
312.2520 [M]+. C17H32N2O3. Calculated: M 312.2529.
1
ν, cm–1: 1730, 1207. H NMR spectrum (500 MHz,
3
CDCl3), δ, ppm (J, Hz): 0.88 t (6H, Me, J = 7.3),
3
1.23 t (3H, OCH2Me, J = 7.1), 1.50 m (4H,
NCH2CH2), 2.30 d.d (2H, 4-Hax, 6-Hax, 2J = 3J = 10.5),
2
2.35 m (4H, NCH2CH2), 2.72 d (1H, 2-Hax, J = 9.5),
Compound IVd was isolated using petroleum
ether–ethyl acetate (50 :1) as eluent. Yield 0.46 g
(44%), light yellow oily substance. IR spectrum (film),
3
2.88 t.t (1H, 5-H, J = 10.5, 4.2), 3.11 d.d (2H, 4-Heq,
6-Heq, 2J = 10.5, 3J = 4.2), 3.60 d (1H, 2-Heq, 2J = 9.5),
3
4.11 q (2H, OCH2, J = 7.1). 13C NMR spectrum
ν, cm–1: 1730 (C=O), 1199 (C–O). H NMR spectrum
1
(125 MHz, CDCl3), δC, ppm: 11.82 (Me), 14.19
(OCH2Me), 20.12 (NCH2CH2), 37.95 (C5), 53.39
(CH2N), 56.49 (NCH2), 60.67 (OCH2), 74.60 (C2),
172. 40 (C=O). Found: m/z 242. 1980 [M]+.
C13H26N2O2. Calculated: M 242.1989.
(500 MHz, CDCl3), δ, ppm (J, Hz): 0.89 t (6H, Me,
3
3J = 7.3), 1.23 t (3H, OCH2Me, J = 7.1), 1.32 m (4H,
NCH2CH2CH2), 1.46 m (4H, NCH2CH2), 2.29 t (2H,
2
3
4-Hax, 6-Hax, J = 10.5, J = 10.5), 2.38 m (4H,
2
NCH2CH2), 2.70 d (1H, 2-Hax, J = 9.5), 2.86 t.t (1H,
3
2
5-H, J = 10.5, 4.2), 3.11 d.d (2H, 4-Heq, 6-Heq, J =
10.5, 3J = 4.2), 3.59 d (1H, 2-Heq, 2J = 9.5), 4.11 q (2H,
Ethyl 1,3-diisopropylhexahydropyrimidine-
5-carboxylate (IVc) was synthesized from 0.5 g
(4 mmol) of ester I in 27 ml of MeOH, 0.94 g
(16 mmol) of isopropylamine, and 5.1 ml (60 mmol) of
32.3% aqueous formaldehyde; the product was
purified by column chromatography using chloroform–
methanol (9:1) as eluent. Yield 0.88 g (77%), light
OCH2, J = 7.1). 13C NMR spectrum (125 MHz,
3
CDCl3), δC, ppm: 13.25 (CH2Me), 13.70 (OCH2Me),
19.04 (NCH2CH2CH2), 29.05 (NCH2CH2), 34.74 (C5),
43.24 (NCH2CH2), 54.46 (C4, C6), 61.91 (OCH2),
76.45 (C2), 168.83 (C=O). Found: m/z 270.2312 [M]+.
C15H30N2O2. Calculated: M 270.2302.
1
yellow oily substance. H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 1.06 d and 1.08 d (6H each,
Ethyl 5-acetyl-1,3-dibenzylhexahydropyrimi-
dine-5-carboxylate (IIIe) was synthesized from 0.5 g
(4 mmol) of ester I in 27 ml of MeOH, 1.7 g
(16 mmol) of benzylamine, and 5.1 ml (60 mmol) of
32.3% aqueous formaldehyde. The product was puri-
fied by column chromatography using chloroform as
eluent. Yield 1.35 g (92%), light yellow oily liquid. IR
spectrum (film), ν, cm–1: 3600–3200, 2827, 2941,
1732, 1712, 1454, 1359, 1199, 1168, 1028, 752.
1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz):
3
3
Me, J = 6.6), 1.27 t (3H, CH2Me, J = 7.1), 2.37 t
2
3
(2H, 4-Hax, 6-Hax, J = 11.0, J = 11.0), 2.80–2.87 m
2
(2H, CHMe2, 5-H), 2.93 br.d (1H, 2-Hax, J = 9.1),
3.14–3.17 m (2H, 4-Heq, 6-Heq), 3.74 br.d (1H, 2-Heq,
2J = 9.1), 4.14 q (2H, OCH2, 3J = 7.1). 13C NMR spec-
trum (125 MHz, CDCl3), δC, ppm: 14.23 (CH2Me),
18.65 and 19.45 (CHMe2), 39.92 (C5), 49.42 (CH2N),
52.17 (CHMe2), 60.47 (OCH2), 69.63 (C2), 173.03
(C=O). 15N NMR spectrum (50 MHz, CDCl3):
δN 52.83 ppm. Found: m/z 241.1918 [M – H]+.
C13H25N2O2. Calculated: M 241.1911.
3
1.23 t (3H, Me, J = 6), 2.23 s (3H, MeC=O), 2.84 d
2
2
(2H, 4-Hax, 6-Hax, J = 12), 3.02 d (1H, 2-Hax, J = 9),
2
Ethyl 5-acetyl-1,3-dibutylhexahydropyrimidine-
5-carboxylate (IIId) and ethyl 1,3-dibutylhexahy-
dropyrimidine-5-carboxylate (IVd) were obtained
from 0.5 g (4 mmol) of ester I in 27 ml of methanol,
0.9 g (15 mmol) of butylamine, and 5.8 ml (68 mmol)
of 32.3% aqueous formaldehyde.
3.20 d (2H, 4-Heq, 6-Heq, J = 12), 3.36 d (1H, 2-Heq,
2J = 9), 3.57 s and 3.70 s (2H each, CH2Ph), 4.18 q
(2H, OCH2, 3J = 6), 7.24–7.38 m (10H, Ph). 13C NMR
spectrum (75 MHz, CDCl3), δC, ppm: 13.75
(OCH2Me), 26.59 (MeC=O), 56.85 and 59.58 (C4, C5,
C6), 61.36 (OCH2), 73.57 (C2); 126.82, 127.00, 128.03,
128.69, 128.80 (Co, Cm, Cp); 137.37 and 138.27 (Ci),
169.21 (C=O, ester), 203.57 (C=O). Found: m/z
380.2109 [M]+. C23H28N2O3. Calculated: M 380.2094.
Compound IIId was isolated using petroleum ether
as eluent. Yield 0.21 g (18%), light yellow oily sub-
stance. IR spectrum (film), ν, cm–1: 1730, 1712, 1371,
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REACTION OF ETHYL ACETOACETATE WITH FORMALDEHYDE
847
(300 MHz, CDCl3), δ, ppm (J, Hz): 3.28 s (3H, Me),
4.62 d (2H, CH2OH, J = 6.8), 5.82 br.s (1H, OH),
Ethyl 5-acetyl-1,3-bis(2-hydroxyethyl)hexahy-
dropyrimidine-5-carboxylate (IIIf) and ethyl
1,3-bis(2-hydroxyethyl)hexahydropyrimidine-5-car-
boxylate (IVf) were synthesized from 1 g (8 mmol) of
ester I in 35 ml of MeOH, 1.85 g (30 mmol) of
2-aminoethanol, and 9.8 ml (114 mmol) of 32.3%
aqueous formaldehyde.
3
6.60–6.62 m (2H, 2-H, 6-H), 8.20–8.22 m (2H, 3-H,
13
5-H). C NMR spectrum (75 MHz, CDCl3), δC, ppm:
54.34 (Me), 75.06 (CH2OH), 108.48 (C2, C6), 149.46
(C3, C5), 152.65 (C4). Found: m/z 138.0796 [M]+.
C7H10N2O. Calculated: M 138.0802.
Compounds VI and VII were isolated using chloro-
form–methanol (95:5) as eluent. Yield 0.06 g (16%),
mixture VI/VII at a ratio of 4:5 [determined from the
Compound IIIf was isolated using chloroform–
methanol (10:1) as eluent. Yield 0.33 g (15%), yellow
oily substance. IR spectrum (film), ν, cm–1: 3600–
3100, 1728, 1367, 1184. 1H NMR spectrum (500 MHz,
1
intensity ratio of the OCH2 signals in the H NMR
1
3
spectrum, δ 4.06 (m) and 4.16 ppm (q)]. H NMR
CDCl3), δ, ppm (J, Hz): 1.16 t (3H, Me, J = 7.1),
spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.06–
1.16 m and 1.18–1.32 m (3H each, OCH2Me), 2.18 s
and 2.56 s (3H each, MeC=O), 3.33–3.36 m (6H,
CH2NH), 3.96–4.11 m (1H, CHCO2), 4.06 m (2H,
OCH2), 4.16 q (2H, OCH2, 3J = 6), 5.87 br.s (3H, NH),
6.35–6.41 m (2H, 3-H, 5-H), 6.55–6.63 m (4H, 3-H,
5-H), 8.08–8.29 m (6H, 2-H, 6-H). 13C NMR spectrum
(75 MHz, CDCl3), δC, ppm: VI: 13.84 (CH2Me), 28.41
(MeC=O), 43.65 (CH2NH), 54.52 (CHCO2), 62.42
(OCH2), 107.62 (C2, C6), 149.83 (C3, C5), 153.28 (C4),
174.06 (C=O, ester), 204.67 (C=O); VII: 14.11
(CH2Me), 28.39 (MeC=O), 46.22 (CH2NH), 52.88
(CCO2), 61.35 (OCH2), 108.64 (C2, C6), 149.90 (C3,
C5), 152.52 (C4), 170.22 (C=O, ester), 204.51 (C=O).
Found for VI: m/z 236.1002 [M]+. C12H16N2O3. Cal-
culated: M 236.1007. Found for VII: m/z 342.1973
[M]+. C18H22N4O3. Calculated: M 342.1981.
2.15 s (3H, MeC=O), 2.40–2.47 m (6H, NCH2CH2,
4-Hax, 6-Hax), 2.90 br.s (2H, 4-Heq, 6-Heq), 3.05 m (1H,
2-Hax), 3.14 m (1H, 2-Heq), 3.47–3.56 m (4H,
CH2OH), 4.10 q (2H, OCH2, 3J = 7.1). 13C NMR spec-
trum (125 MHz, CDCl3), δC, ppm: 13.65 (Me), 26.22
(MeC=O), 54.76 (C4, C6), 55.77 (NCH2CH2), 58.10
(CH2OH), 59.87 (C5), 61.74 (OCH2), 75.14 (C2),
15
169.06 (C=O, ester), 202.76 (C=O). N NMR spec-
trum (50 MHz, CDCl3): δN 37.57 ppm. Found:
m/z 287.1598 [M – H]+. C13H23N2O5. Calculated:
M 287.1601.
Compound IVf was isolated using chloroform–
methanol (9:1) as eluent. Yield 0.40 g (21%), yellow
oily substance. IR spectrum (film), ν, cm–1: 3600–
1
3100, 1731, 1180. H NMR spectrum (500 MHz,
3
CDCl3), δ, ppm (J, Hz): 1.14 t (3H, Me, J = 7.1),
2.15 s (3H, MeC=O), 2.49–2.54 m (6H, NCH2CH2,
4-Hax, 6-Hax), 2.75 m (1H, 5-H), 2.92–3.01 m (3H,
2-Hax, 4-Heq, 6-Heq), 3.45–3.57 m (5H, 2-Heq, CH2OH),
N,N′-Bis(3,5-dibromopyridin-2-yl)methanedi-
amine (VIII) was synthesized from 0.5 g (4 mmol) of
ester I in 27 ml of MeOH, 4.06 g (16 mmol) of 3,5-di-
bromopyridin-2-amine, and 5.1 ml (60 mmol) of
32.3% aqueous formaldehyde. The product was isolat-
ed by column chromatography using chloroform as
eluent. Yield 3.08 g (77%), colorless crystals, mp 196–
198°C (decomp.). IR spectrum (mineral oil), ν, cm–1:
3421, 1579, 1311, 1224, 1093, 889. 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 5.10 t (2H, CH2),
3
4.03 q (2H, OCH2, J = 7.1). 13C NMR spectrum
(125 MHz, CDCl3), δC, ppm: 13.88 (Me), 38.49 (C5),
52.95 (C4, C6), 55.93 (CH2CH2N), 58.48 (CH2OH),
60.44 (OCH2), 74.34 (C2), 172.00 (C=O). 15N NMR
spectrum (50 MHz, CDCl3): δN 38.21 ppm. Found:
m/z 245.1462 [M – H]+. C11H21N2O4. Calculated:
M 245.1496.
4
4
[Methyl(pyridin-4-yl)amino]methanol (V), ethyl
2-acetyl-3-(pyridin-4-ylamino)propanoate (VI), and
ethyl 3-oxo-2,2-bis[(pyridin-4-ylamino)methyl]-
butanoate (VII) were synthesized from 0.17 g
(1.3 mmol) of ester I in 9 ml of MeOH, 0.5 g
(5.3 mmol) of pyridin-4-amine, and 1.7 ml (20 mmol)
of 32.3% aqueous formaldehyde.
7.14 d (2H, 4-H, J = 2.1), 8.13 d (2H, 2-H, 6-H, J =
2.2). 13C NMR spectrum (75 MHz, CDCl3), δC, ppm:
49.12 (HNCH2NH), 106.11 and 106.98 (C3, C5),
141.70 (C4), 147.03 and 152.91 (C2, C6). Found, %:
C 25.75; H 1.55; Br 61.86; N 10.84. C11H8Br4N4.
Calculated, %: C 25.61; H 1.56; Br 61.96; N 10.86.
This study was performed under financial support
by the Presidium of the Russian Academy of Sciences,
Basic Research Program “Development of Methods for
the Preparation of Chemical Substances and Design of
New Materials” in the framework of the guideline
Compound V was isolated using chloroform–
methanol (9:1) as eluent. Yield 0.17 g (45%), yellow
oily substance. IR spectrum (film), ν, cm–1: 3250–
3000, 2930, 2818, 1601, 1518 (Py). 1H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

LATYPOVA et al.
848
12. The Chemistry of the Nitro and Nitroso Groups,
Feuer, H., Ed., New York: Interscience, 1970, vol. 2.
Translated under the title Khimiya nitro- i nitrozogrupp,
Moscow: Mir, 1973, vol. 2, p. 95.
“Development of Methodology of Organic Synthesis
and Design of Compounds with Valuable Applied
Properties.”
13. Novikov, S.S., Shvekhgeimer, G.A., Sevost’yano-
va, V.V., and Shlyapochnikov, V.A., Khimiya alifati-
cheskikh i alitsiklicheskikh nirosoedinenii (Chemistry of
Aliphatic and Alicyclic Nitro Compounds), Moscow:
Khimiya, 1974.
14. Shakirov, R.R., Vlasova, L.I., Shishkin, D.V., Yarmu-
khamedov, N.N., Baibulatova, N.Z., Semes’ko, D.G.,
Dokichev, V.A., and Tomilov, Yu.V., Izv. Akad. Nauk,
Ser. Khim., 2005, p. 1687.
15. Shakirov, R.R., Dokichev, T.V., Biglova, R.Z., Vlaso-
va, N.M., Baibulatova, N.Z., and Talipov, R.F., Khim.
Geterotsikl. Soedin., 2008, p. 53.
16. Badamshin, A.G., Baibylatova, N.Z., and Doki-
chev, V.A., Kinetics, Catalysis and Mechanism of
Chemical Reactions. From Pure to Applied Science,
Hauppauge, NY: Nova Science, 2011, vol. 1, p. 249.
REFERENCES
1. Billman, J.H. and Meisenheimer, J.L., J. Med. Chem.,
1964, vol. 7, p. 115.
2. Billman, J.H. and Meisenheimer, J.L., J. Med. Chem.,
1965, vol. 8, p. 540.
3. Groszkowski, S., Korzycka, L., and Bilasiewicz, W.,
Pol. J. Pharmacol. Pharm., 1973, vol. 25, p. 573.
4. Siddiqui, A.Q., Merson-Davies, L., and Cullis, P.M.,
J. Chem. Sos., Perkin Trans. 1, 1999, p. 3243.
5. Gravier, D., Dupin, J.-P., Casadebaig, F., Hou, G.,
Boisseau, M., and Bernard, H., Eur. J. Med. Chem.,
1989, vol. 24, p. 531.
6. Horvath, D., J. Med. Chem., 1997, vol. 40, p. 2412.
7. Shakirov, R.R., Yarmukhamedov, N.N., Vlasova, L.I.,
Baibulatova, N.Z., Khisamutdinova, R.Yu., Gabdrakh-
manova, S.F., Karachurina, L.T., and Baschenko, N.Zh.,
Khim.-Farm. Zh., 2006, vol. 40, no. 1, p. 29.
8. Drandarov, K., Guggusbtrg, A., and Hesse, M., Helv.
Chim. Acta, 1999, vol. 82, p. 229.
17. Cardillo, G. and Tomasini, C., Chem. Soc. Rev., 1996,
vol. 25, p. 117.
18. Fukawa, H., Terao, Y., Achiwa, K., and Sekiya, M.,
Chem. Pharm. Bull., 1983, vol. 31, p. 94.
19. Mukhopadhyay, C., Rana, S., and Butcher, R.J., Tetra-
hedron Lett., 2011, vol. 52, p. 4153.
9. Evans, R.F., Aust. J. Chem., 1967, vol. 20, p. 1643.
10. Katritzky, A.R., Singh, S.K., and He, H.-Y., J. Org.
Chem., 2002, vol. 67, p. 3115.
11. Bisceglia, J.A., Diaz, J.E., Torres, R.A., and
20. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 1.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1982, vol. 2, p. 632.
Orelli, L.R., Tetrahedron Lett., 2011, vol. 52, p. 5238.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013