Chemistry of nitroenamines. part 2. synthesis of saturated pyrrolo-pyrimidines and -pyrazines

Article abstract of DOI:10.3987/COM-11-12246

New saturated pyrrolo-pyrimidines and pyrrolo-pyrazines were synthesized from 2-nitromethylene-pyrrolidine. Additionally, some simple aminomethylated derivatives of Mannich type were prepared. The nitro compounds were reduced into diastereomeric amines, w

Full text of DOI:10.3987/COM-11-12246

HETEROCYCLES, Vol. 83, No. 9, 2011
2001
HETEROCYCLES, Vol. 83, No. 9, 2011, pp. 2001 - 2010. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd May, 2011, Accepted, 30th June, 2011, Published online, 13th July, 2011
DOI: 10.3987/COM-11-12246
CHEMISTRY OF NITROENAMINES. PART 2. SYNTHESIS OF
SATURATED PYRROLO-PYRIMIDINES AND -PYRAZINES
Pál Scheiber,* Gábor Tóth,a Mihály V. Pilipecz, Tamás R. Varga, and Péter
Nemes
Department of Chemistry, School of Veterinary Medicine, Szent István University,
H-1400 Budapest, P. O. Box 2, Hungary; e-mail: scheiber.pal@aotk.szie.hu
aDepartment of Inorganic and Analytical Chemistry, Budapest University of
Technology and Economics, H-1111 Budapest, Szt. Gellért tér 4, Hungary
Abstract – New saturated pyrrolo-pyrimidines and pyrrolo-pyrazines were
synthesized from 2-nitromethylene-pyrrolidine. Additionally, some simple
aminomethylated derivatives of Mannich type were prepared. The nitro
compounds were reduced into diastereomeric amines, which were separated and
characterized structurally.
INTRODUCTION
Due to their push pull electronic structure the nitroenamines1 can readily undergo chemical
transformations providing a wide spectrum of various heterocycles. Thus in our preceding papers we have
described the preparation of divers pyrrolizines2 and indolizidines3 starting from
2-nitromethylene-pyrrolidine (1). Enaminoesters, e.g. pyrrolidin-2-ylidene-acetic acid ethyl ester7 were
also subjected to similar Mannich reactions, providing ester derivatives in moderate yields.
Although the thoroughly studied saxitoxin,4 an extremely toxic substance of marine organisms
incorporates a pyrrolo-pyrimidine part in its tricyclic structure, simple pyrrolo-pyrimidines are less
investigated. Based on the enhanced reactivity of the nitroenamines, in this paper we report the synthesis
of some saturated pyrrolo-pyrimidines, along with some new pyrrolo-pyrazines, occurring as subunits in
the molecules of some natural products, e.g. batzelladines5 and naseseazines.6
HO
HO
H
H
N
N
O
H
N
N
H
O
H2N
NH
N
H
O
R
N
H
N
R'
N
H
R"
O
NH2
saxitoxin
batzelladines
naseseazines

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HETEROCYCLES, Vol. 83, No. 9, 2011
RESULTS AND DISCUSSION
Using the nitroenamine 1 as a C-H acid reactant several Mannich reactions were accomplished (Scheme
1). The reactions with various secondary amines in ethanol at room temperature led to formation of
aminomethylated products in good yields (Table 1). Instead of formaldehyde and dimethylamine the
Eschenmoser salt was also applied successfully.
2
3
4
1NH
NH
CH2O, HNR1R2
R1
N
NO2
R2
NO2
1
2 - 8
Scheme 1. Mannich reaction of the nitroenamine 1
As previously noted2 the high chemical shift (9 ppm) of the NH proton may indicate the Z arrangement
of the double bond in 1. We confirmed this configuration by NOE experiments showing interaction
between the olefinic =CH and 4-CH2 protons. In compounds 2-8 the NH chemical shifts appeared also at
9 ppm proving the unchanged configuration.
Table 1. Mannich products obtained from the nitroenamine 1 with secondary amines
Product
Amine
yield
mp, oC
Compound No
R1, R2
dimethylamine
N-methyl-benzylamine
sarcosine
2
3
4
Me, Me
93
71
90
165
110
Me, CH2C6H5
Me, CH2CO2H
171 (dec)
morpholine
piperidine
5
6
71
92
152
O
150-51
2-methylpiperidine
ethyl isonipecotate
7
8
93
44
96
Me
110-112
CO Et
2
Catalytic reduction of 2 gave the mixture of diastereomeric diamines 9 and 10 in comparable amounts.
Noteworthy, that reductive removal of the dimethylamino group proceeded simultaneously. For the sake
of clarity only the enantiomers (5R,5aR) and (5R,5aS) are shown in Scheme 2. In case of the nitroalkenes
3-8 no such removal of the amine component was observed. Upon treatment with diethyl oxalate at 60 oC

HETEROCYCLES, Vol. 83, No. 9, 2011
2003
the mixture of diamines 9 and 10 gave the pyrrolo-piperazine derivatives 11 and 12 (Scheme 2).
Recrystallization led to a nearly pure substance containing the isomers 11 and 12 in a ratio ca. 97:3,
respectively.
NH
N
O
O
H
Me
H
Me
H
NH2
H
N
H
11
NH
9
(CO2Et)2
H2/Pd or Ni
Me2N
NO2
N
O
NH
2
H
H
H
H
Me
N
H
12
O
Me
NH2
10
Scheme 2. Reduction of the Mannich product 2 and its subsequent cyclization
The stereochemistry of 11 and 12 was established by comprehensive one- and two-dimensional NMR
methods using widely accepted strategies.8 The results are displayed in Figure 1.
O
O
159.0
O
N
H
H
O
5
N
5
H
H
155.7
Me
44.8
45.2
H
N
8a
15.8
51.2
H
H
8a
29.1
27.6
H
N
H
1
1
62.1
8
58.3
8
46.8
H
Me
H
H
H
H
H
H
16.8
23.1
22.6
H
H
O
O
3.40m
1.53
H
H
H
O
O
N
0 Hz
H
Me
1.04
N
3.47dq
H
N
3.40m
H
H
8.66d
4.5 Hz
8.44s
H
H
N
3.57
H
Me
1.11
1.97
H
H
H
H
H
H
10 Hz
10.5 Hz
4.5 Hz
4.08ddd
2.06
5.7 Hz
H
H
1.78
3.52td
6 Hz
11
12
Figure 1. Stereochemistry of 11 (H-1,H-8a trans) and 12 (H-1,H-8a cis). Bold numbers above denote the
13C chemical shifts, 1H data are down. The arrows refer to the characteristic 3J (H,H) coupling constants.
3
Based on the significantly different J (H-1,H-8a) coupling constants 11 and 12 were identified
unambiguously. The value of 10.5 Hz in 11 proves the antiperiplanar arrangement of H-1 and H-8a atoms,
whereas the value of 4.5 Hz in 12 supports their gauche position.
The Mannich reactions of the nitroenamine 1 with primary amines gave the pyrrolo-pyrimidines 13-20 in
good yields (Scheme 3, Table 2).

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HETEROCYCLES, Vol. 83, No. 9, 2011
NH
N
2 CH2O, RNH2
1
2 N
4
3
NO2
O2N
R
1
13 - 20
Scheme 3. Mannich reaction of 1 with primary amines
Table 2. Mannich products obtained from the nitroenamine 1 with primary amines
Product
Primary amine
yield, % mp, oC
Compound No
R
methylamine
13
14
15
16
17
18
19
-Me
66
95
93
57
81
71
81
152
89
isopropylamine
tert-butylamine
cyclopropylamine
colamine
-CHMe2
-CMe3
137
-CH(CH2)2
-(CH2)2OH
-CH2CH2OMe
-CH2C6H5
125-26
90
2-methoxy-ethylamine
benzylamine
78-79
123-24
3,4-dimethoxy--phenyl-
ethylamine
20
-CH2CH2C6H3(3,4-OMe)2
83
169-71
Reduction of 19 with Raney-Ni led to a mixture of diastereomers 21 and 22, with equatorial and axial
C(4)-NH2 group, respectively, that was subjected column chromatography affording the pure isomers in a
ratio 83:17 (Scheme 4).
N
N
+
H
H
N
N
H2N
H2N
21 (83%)
22 (17%)
N
H2/Ni
H2/Pd
N
O2N
H2/Pd
19
N
H
N
+
H
NH
NH
24
H2N
H2N
23
Scheme 4. Reduction of 19

HETEROCYCLES, Vol. 83, No. 9, 2011
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1
The NMR signal assignments and the C(4) and C(4a) configurations were determined by H,13C, DEPT,
1
1
1
1H,1H-COSY, H,13C-HSQC, H,1H-NOESY and selective H-NOESY experiments in CDCl3. The
conformation and the characteristic NMR correlations are depicted in Figure 2.
NOE
2.75d
H
1.73
2.31
H
H
H
H
H
73.1
3.06
H
H
21.2
50.0
3.86dd
H
H
6.3 Hz
1
1.82
4a
H
H
1.86
H
H
8
N
N
69.8
1.76t H
H
2.03
H
H
2
N
CH2
59.4
11 Hz
CH2
Ph
Ph
27.9
N
60.8
1.61
H
H
3.60/3.52
9 Hz
11 Hz
H
8.2 Hz
H
4
H2N
H2N
3.00
50.1
1.4 Hz
4.3 Hz
H
H
2.74ddd
a)
b)
1
3
Figure 2. Stereochemistry of the trans diastereomer 21. a) H data. Arrows refer to the characteristic J
1
(H,H) coupling constants (Hz); arrows marked with NOE show the sterically close H atoms observed
upon selective irradiation of H-7 at  2.31; b) 13C chemical shifts.
The H-4 signal at  2.74 ppm appeared with a ddd multiplicity. The measured J (H-4,H-4a) = 9.0 Hz and
J (H-4,H-3) = 11.0 Hz coupling constants are in accordance with their antiperiplanar arrangements,
whereas the value of J (H-4,H-3) = 4.3 Hz supports their gauche relation.
Hydrogenation of 19 with Pd/C catalyst led to formation of a mixture containing 23 predominantly and 24
in negligible amount. These diastereomers were not separated, the structure of 23 was proven by
debenzylation of 21.
In conclusion we have demonstrated the synthetic usefulness of the nitroenamine 2 in preparation of
various Mannich compounds. These primary products were reduced enabling us to prepare new
pyrrolo-pyrazines and pyrrolo-pyrimidines.
EXPERIMENTAL
General. Commercially available (Aldrich, Alfa Aesar) reagents were used. Prior the use the solvents
were redistilled. The reaction mixtures and the purity of the products were checked by analytical TLC
performed on precoated Merck aluminum sheets (DC-Alufolien Kieselgel 60 F254). The spots were
visualized by iodine vapor or Dragendorff reagent. Melting points were determined on a Büchi 20SchmP
apparatus and are uncorrected. HRMS were determined with a Waters LCT Premier XE instrument. IR

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HETEROCYCLES, Vol. 83, No. 9, 2011
spectra were obtained with a Perkin-Elmer 1600 FT/IR instrument (KBr pellet or liquid film). NMR
spectra were recorded at ambient temperature on a Varian UNITY spectrometer (300 MHz for 1H-spectra,
13
75 MHz for C spectra) and compounds 1, 11, 12, 19 and 21 on a Bruker Avance spectrometer (500
MHz and 125 MHz, resp.). Chemical shifts, given on the δ scale, were referenced to the solvent (CDCl3:
13
δC = 77.0 and δH = 7.27; DMSO-d6: δC = 39.5 and δH = 2.50, resp.). In the 1D measurements (1H, C,
DEPT-135), 64K data points were used for the FID. The pulse programs [gs-COSY, gs-HSQC, gs-HMBC,
1D NOESY (mixing time = 350 ms), 2D NOESY (mixing time = 400 ms)] were taken from the Bruker
software library.
2-Nitromethylenepyrrolidine (1). The mixture of 2-methoxypyrroline (135.1 g, 1.36 mol) and
nitromethane (166.1 g, 2.72 mol) was heated under reflux for 20 h. The red solution was concentrated to
give a dark viscous residue which was purified by column chromatography using silica (100 g) and
EtOAc - CH2Cl2 (1:1) eluent mixture. Evaporation furnished an orange solid, 90.2 g (51.8%); an
analytical sample was obtained by recrystallization from ethyl acetate. Pale yellow crystals; mp 109-110
o
1
oC (lit.,9 108 C). IR (KBr) max 3261 (NH), 1611, 1359 (NO2) cm-1; H NMR (CDCl3)  2.14 (2H, m),
13
2.72 (2H, t, J = 7.8 Hz), 3.73 (2H, t, J = 7.2 Hz), 6.63 (s, 1H), 9.20 (br, 1H); C NMR (CDCl3)  21.3,
31.3, 48.4, 106.7, 162.8.
General procedure for the preparation of compounds 2-8
A mixture of 128 mg (1.0 mmol) of 1, 150 mg (5 mmol) of paraformaldehyde and 1.0 mmol of a
secondary amine in 6 mL EtOH was stirred at room temperature for 5 h. The crystalline product was
either filtered off, or the reaction mixture was concentrated and the residue was crystallized. The products
were purified by recrystallization using common alcohols. Yields and melting points are given in Table 1.
Dimethyl-(2-nitro-2-pyrrolidin-2-ylideneethyl)amine (2). Using dimethylamine hydrochloride
o
(Scheme 1) 2.HCl was isolated. Mp 165 C. The free base 2 was obtained by treatment with aqueous
solution of potassium carbonate and subsequent extraction with dichloromethane. IR (KBr) max 3295
1
(NH), 1604, 1338 (NO2) cm-1; H-NMR (CDCl3)  2.07 (2H, m), 2.13 (6H, s), 2.88 (2H, t, J = 7.8 Hz),
3.27 (2H, s), 3.68 (2H, t, J = 7.2 Hz), 9.8 (1H, bs); 13C-NMR (CDCl3)  21.3, 32.1, 44.8, 48.6, 56.0, 115.8,
165.0; HRMS: calculated for C8H15N3O2 [MH]+ 186.1243, found 186.1242.
2.HI was obtained in reaction of 1 with equimolar amount of dimethyl methylene ammonium iodide
(Eschenmoser salt) in EtOH at 20 oC for 4 h. White powderlike product (80%), recryst. from 95% EtOH,
mp 200 oC.
Benzylmethyl-(2-nitro-2-pyrrolidin-2-ylideneethyl)amine (3). Pale yellow plates. IR (KBr) max 3304
1
(NH), 1606, 1350 (NO2) cm-1; H-NMR (CDCl3)  2.13 (2H, m), 2.18 (3H, s), 2.88 (2H, t, J = 7.8 Hz),
3.50 (2H, s), 3.50 (2H, s), 3.52 (2H, s), 3.73 (2H, t, J = 7.3 Hz), 7.10-7.30 (5H, m), 9.80 (1H, bs);

HETEROCYCLES, Vol. 83, No. 9, 2011
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13C-NMR (CDCl3)  21.5, 32.0, 42.0, 48,7, 54.3, 61.8, 116.2, 126.9, 128.1, 128.9, 139.4, 165.4; HRMS:
calculated for C14H19N3O2 [MH]+ 262.1556, found 262.1556.
[Methyl-(2-nitro-2-pyrrolidin-2-ylideneethyl)amino]acetic acid (4). White solid. IR (KBr) max 3264
(NH), 1630 (COOH), 1593, 1371 (NO2) cm-1; 1H-NMR (D2O)  2.04 (2H, m), 2.77 (3H, s), 2.91 (2H, t, J
13
= 7.7 Hz), 3.59 (2H, s), 3.71 (2H, t, J = 7.4 Hz). 4.19 (2H, s); C-NMR (D2O)  23.3, 37.0, 44.0, 52.2,
53.4, 58.7, 60.6, 112.0, 171.3, 173.0; HRMS: calculated for C9H15N3O4 [MH]+ 230.1141, found
211.1155.
4-(2-Nitro-2-pyrrolidin-2-ylideneethyl)morpholine (5). Pale yellow crystals. IR (KBr) max 3321, 3280
1
(NH), 1611, 1345 (NO2) cm-1; H-NMR (CDCl3)  2.16 (2H, m), 2.38-2.45 (4H, m), 2.97 (2H, t, J = 7.9
13
Hz), 3.44 (2H, s), 3.58-3.65 (4H, m), 3.76 (2H, t, J = 7.3 Hz), 9.82 (1H, bs); C-NMR (CDCl3)  21.4,
32.2, 48.7, 53.0, 55.5, 67.0, 115.1, 165.1; HRMS: calculated for C10H17N3O3 [MH]+ 228.1348, found
228.1346.
1-(2-Nitro-2-pyrrolidin-2-ylideneethyl)piperidine (6). Yellowish white crystals. IR (KBr) max 3304
1
(NH), 1604, 1352 (NO2) cm-1; H-NMR (CDCl3)  1.30-1.60 (6H, m), 2.15 (2H, m), 2.30-2.46 (4H, m),
13
2.99 (2H, t, J = 7.9 Hz), 3.41 (2H, s), 3.76 (2H, t, J = 7.2 Hz), 9.80 (1H, bs); C-NMR (CDCl3)  21.5,
24.4, 26.1, 32.1, 48.7, 54.0, 55.8, 116.1, 165.3; HRMS: calculated for C11H19N3O2 [MH]+ 226.1556,
found 226.1549.
2-Methyl-1-(2-nitro-2-pyrrolidin-2-ylideneethyl)piperidine (7). Yellowish white crystals. IR (KBr)

max 3230 (NH), 1607, 1351 (NO2) cm-1; 1H-NMR (CDCl3)  1.05 (3H, d, J = 6.3 Hz), 1.10-1.60 (6H, m),
1,85-2.30 (4H, m), 2.50 - 3.35 (4H, m), 3.65-3.82 (3H, m), 9.91 (1H, bs); 13C-NMR (CDCl3)  18.3, 21.3,
23.5, 25.9, 32.1, 34.4, 48.6, 50.8, 51.1, 56.6, 116.1, 165.4; HRMS: calculated for C12H21N3O2 [MH]+
240.1712, found 240.1701.
1-(2-Nitro-2-pyrrolidin-2-ylideneethyl)piperidine-4-carboxylic acid ethyl ester (8). Yellowish white
crystals. IR (KBr) max 3334 (NH), 1720 (C=O), 1616, 1352 (NO2) cm-1; 1H-NMR (CDCl3)  1.23 (3H, t,
J = 7.1 Hz), 1.55-2.33 (9H, m), 2.72-2.83 (2H, m), 2.98 (2H, t, J = 7.9 Hz), 3.44 (2H, s), 3.76 (2H, t, J =
13
7.3 Hz), 4.09 (2H, q, J = 7.1 Hz), 9.85 (1H, bs); C-NMR (CDCl3)  14.2, 21.4, 28.4, 32.1, 41.2, 48.7,
52.4, 55.3, 60.2, 115.7, 165.4, 175.3; HRMS: calculated for C14H23N3O4 [MH]+ 298.1767, found
298.1762.
1-Pyrrolidin-2-yl-ethylamines (9 and 10). 2 (0.37 g, 2.0 mmol) in 20 mL EtOH was hydrogenated at 25
oC under 0.8 MPa in presence of Pd/C catalyst for 3 h, followed by filtration and evaporation to yield a
colourless oil (0.16 g, 70 %) as a mixture of 9 and 10. These diastereomers were not separated. IR (liquid
film) max 3366 br (NH) cm-1; 1H-NMR (CDCl3)  1.03 and 1.08 (dublets, J = 6.0 Hz, 3H), 1.25-1.90 (4H,
m), 2.40-3.00 (7H, m); 13C-NMR (CDCl3) two series of signals:  20.7, 26.0, 28.3, 46.4, 51.4, 65.7; and 

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20.9, 25.4, 26.8, 46.6, 50.2, 64.9.
Trans- and cis-1-Methyl-1-hexahydropyrrolo1,2-a]pyrazine-3,4-dione (11 and 12). To a mixture of 9
and 10 (540 mg, 3.43 mmol) diethyl oxalate (502 mg, 3.43 mmol) was added. The reaction mixture was
o
stirred at 60 C for 3 h, and the white solid formed upon cooling was separated (230 mg, 40.0%).
Recrystallization from isopropyl alcohol gave the trans diastereomer 11 containing about 3% of 12
(estimated by NMR signal intensities). IR (KBr) max 3430, 3200 (NH), 1689, 1678 (amide-I) cm-1; NMR
data, Figure 1.
General procedure for the preparation of 13-20.
The solution of 1 (1.0 mmol), a primary amine (1.0 mmol) and 0.18 g of 35% formaline (2.0 mmol) in 5
o
mL MeOH was stirred at 25 C for 4-6 h. After a complete reaction monitored by TLC, the solvent was
evaporated in vacuo, and the residue was crystallized and/or recrystallized. Yields and melting points are
given in Table 2.
2-Methyl-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (13). Pale yellow crystals. IR (KBr)

max 1573, 1374 (NO2) cm-1; 1H NMR (CDCl3)  2.12 (2H, m), 2.44 (3H, s), 3.48 (2H, t, J = 7.5 Hz), 3.56
13
(2H, t, J = 7.3 Hz), 3.78 (2H, s), 4.02 (2H, s); C NMR (CDCl3)  20.3, 34.1, 41.4, 50.3, 52.4, 67.2,
113.7, 159.5; HRMS: calculated for C8H14N3O2 [MH]+ 184.1086, found 184.1091.
2-Isopropyl-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (14). Pale yellow crystals. IR
(KBr) max 1575, 1349 (NO2) cm-1; 1H NMR (CDCl3):  1.12 (6H, d, J = 6.5 Hz), 2.10 (2H, m), 2.89 (1H,
13
h, J = 6.5 Hz), 3.43 (2H, t, J = 7.7 Hz), 3.56 (2H, t, J = 7.4 Hz), 3.86 (2H, s), 4.10 (2H, s); C NMR
(CDCl3)  20.3 (overlapped C-7 and CH3 signals), 34.2, 45.3, 51.2, 52.1, 63.0, 115.0, 160.6; HRMS:
calculated for C10H18N3O2 [MH]+ 212.1399, found 212.1399.
2-tert-Butyl-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (15). Pale yellow crystals. IR
1
(KBr) max 1588, 1363 (NO2) cm-1; H NMR (CDCl3)  1.18 (9H, s), 2.11 (2H, m), 3.43 (2H, t, J = 7.8
Hz), 3.58 (2H, t, J = 7.4 Hz), 3.85 (2H, s), 4.07 (2H, s); 13C NMR (CDCl3)  20.3, 26.9, 34.2, 43.0, 52.2,
54.1, 60.8, 116.1, 160.6; HRMS: calculated for C11H20N3O2 [MH]+ 226.1556, found 226.1559.
2-Cyclopropyl-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (16). Pale yellow crystals. IR
1
(KBr) max 1575, 1365 (NO2) cm-1; H NMR (CDCl3):  0.5-0.6 (4H, m), 2.00 (1H, m), 2.13 (2H, m),
13
3.49 (2H, t, J = 7.8 Hz), 3.58 (2H, t, J = 7.4 Hz), 3.94 (2H, s), 4.15 (2H, s); C NMR (CDCl3)  20.3,
34.1, 41.4, 50.3, 52.4, 67.2, 113.7, 159.5; HRMS: calculated for C10H16N3O2 [MH]+ 210.1243, found
210.1249.
2-(4-Nitro-3,5,6,7-tetrahydropyrrolo1,2-c]pyrimidin-2-yl)ethanol (17). Pale yellow crystals. IR (KBr)

max 3384 (OH), 1577, 1367 (NO2) cm-1; 1H NMR (CDCl3)  2.09 (2H, m), 2.59 (1H, bs), 2.66 (2H, t, J =

HETEROCYCLES, Vol. 83, No. 9, 2011
2009
5.1 Hz), 3.44 (2H, t, J = 7.8 Hz), 3.55 (2H, t, J = 7.2 Hz), 3.67 (2H, t, J = 5.1 Hz), 3.84 (2H, s), 4.15 (2H,
13
s); C NMR (CDCl3)  20.1, 34.3, 48.1, 52.4, 55.0, 59.4, 66.2, 113.5, 160.3; HRMS: calculated for
C9H15N3O3 [MH]+ 214.1192, found 214.1187.
2-(2-Methoxy-ethyl)-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (18). Pale yellow crystals.
1
IR (KBr) max 1576, 1351 (NO2) cm-1; H NMR (CDCl3)  2.09 (2H, m), 2.70 (2H, t, J = 5.1 Hz), 3.34
(3H, s), 3.43 (2H, t, J = 7.8 Hz), 3.52 (2H, t, J = 5.1 Hz), 3.55 (2H, t, partly overlapped, J = 7.2 Hz), 3.86
13
(2H, s), 4.17 (2H, s); C NMR (CDCl3)  20.2, 34.2, 48.9, 52.3, 52.7, 58.9, 66.0, 71.0, 113.6, 160.1;
HRMS: calculated for C10H17N3O3 [MH]+ 228.1358, found 228.1347.
2-Benzyl-4-nitro-1,2,3,5,6,7-hexahydropyrrolo1,2-c]pyrimidine (19). Pale yellow crystals. IR (KBr)

max 1579, 1371 (NO2) cm-1; 1H NMR (CDCl3)  2.10 (2H, m), 3.46 (2H, t, J = 7.5 Hz), 3.47 (2H, t, J =
7.5 Hz), 3.69 (2H, s), 3.93 (2H, s), 4.04 (2H, s), 7.25 - 7.35 (m, 5H); 13C NMR (CDCl3)  20.3, 34.2, 48.7,
52.2, 57.6, 64.5, 113.9, 127.7, 128.5, 128.8, 137.1, 160.1; HRMS: calculated for C14H18N3O2 [MH]+
260.1399, found 260.1406.
2-2-(3,4-dimethoxyphenyl)ethyl-4-nitro-1,2,3,5,6,7-hexahydro-pyrrolo1,2-c]pyrimidine (20). Pale
yellow crystals. IR (KBr) max 1577, 1365 (NO2) cm-1; 1H NMR (CDCl3)  2.09 (2H, m), 2.69-2.83 (4H,
m), 3.42-3.52 (4H, m), 3.84 (3H, s), 3.86 (3H, s), 3.96 (2H, s), 4.09 (2H, s), 6.69-6.81 (3H, m); 13C NMR
(CDCl3)  20.2, 34.2, 34.4, 48.0, 52.3, 55.1, 55.9, 66.3, 111.4, 112.0, 113.8, 120.5, 132.0, 147.6, 149,0,
160.0; HRMS: calculated for C17H24N3O4 [MH]+ 334.1767, found 334.1763.
2-Benzyloctahydropyrrolo1,2-c]pyrimidin-4-ylamine (21 and 22). The solution of 19 (1.30 g, 5.0
mmol) in EtOH (30 mL) was hydrogenated with Raney-Ni catalyst (1.1 g) under pressure (initial pressure
0.9 MPa) at 23 oC for 6 h. After removal of the catalyst the solvent was evaporated to yield a pale yellow
oily residue (1.15 g, practically complete conversion). The crude product (1.10 g) was chromatographed
using an eluent mixture (EtOAc - CH2Cl2 - isopropylamine, 40/10/3) to produce the diastereomer 21 (595
o
mg), white crystals, mp 63-64 C, IR (KBr) max 3344, 3249, 3167 (NH), 1609, 1495 (C=C) cm-1; NMR
data of 21: s. Figure 2. and diastereomer 22 (74 mg), as a pale yellow oil. IR (liquid film) max 3400 br
1
(NH2) cm-1; H-NMR (CDCl3)  1.60-2.20 (9H, m), 2.37-2.44 (1H, m), 3.30-3.50 (3H, m), 3.47 (2H, s),
3.86 (1H, d), 7.20-7.40 (5H, m) 13C NMR (CDCl3)  21.0, 24.9, 46.9, 50.6, 59.6, 59.7, 66.8, 75.5, 126.9,
128.1, 128.7, 138.1.
Octahydropyrrolo1,2-c]pyrimidin-4-ylamine (23 and 24). The solution of the nitro compound 19 (2.20
g, 8.5 mmol in 20 mL EtOH) was hydrogenated in presence of 10% Pd/C (1.45 g) at 0.8 MPa and 20 oC.
As the hydrogen consumption ceased (about 3 h), the catalyst and the solvent was removed to yield a
colorless oil (1.0 g, 83%), predominantly the diastereomer 23.
The solution of 21 (190 mg) in EtOH (15 mL) was hydrogenated in presence of 10% Pd/C catalyst (120

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HETEROCYCLES, Vol. 83, No. 9, 2011
mg) at 0.8 MPa and 23 oC. As the hydrogen absorption ceased, the catalyst and the solvent were removed
1
to furnish 23 as a colorless oil (115 mg, in quantitative yield). H-NMR (CDCl3)  1.35-1.7 (4H, m),
1.90-2.45 (8H, m), 2.85-2.95 (2H, m), 3.82 (1H, d); 13C NMR (CDCl3)  20.2, 28.2, 49.8, 52.7, 53.4, 66.8,
70.4; HRMS: calculated for C7H16N3 [MH]+ 142.1344, found 142.1336.
13C NMR signals of the minor component 24 (CDCl3)  22.7, 23.2, 40.2, 46.3, 52.9, 57.1, 68.3.
ACKNOWLEDGEMENTS
The PhD scholarship from Szent István University to M. V. P. is gratefully acknowledged. The authors’s
thanks are due to Dr. L. Balázs for the HRMS measurements.
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