Unexpected tandem condensation of 2-furonitriles with diethylenetriamine

Full text of DOI:10.1007/s10593-010-0512-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
LETTERS TO THE EDITOR
UNEXPECTED TANDEM
CONDENSATION OF 2-FURONITRILES
WITH DIETHYLENETRIAMINE
V. I. Terenin1*, M. V. Galkin1, E. V. Kabanova1, and A. S. Ivanov1
Keywords: imidazo[2,1-c]pyrrolo[1,2-a]pyrazine, condensation reaction.
Pyrrolo[1,2-a]pyrazines have a broad spectrum of biological activity [1, 2]. The method widely used for
synthesis of 1,6-dialkyl-substituted pyrrolo[1,2-a]pyrazines is based on the reaction of substituted 2-acylfurans
with ethylenediamine [3].
We proposed that exchange of the starting 2-acylfurans and ethylenediamine for the corresponding
2-furonitriles and diethylenetriamine respectively permit the preparation of more complex structures. Reaction
of 2-furonitriles with ethylenediamine, however, gave only the 2-(2-furyl)-4,5-dihydro-1H-imidazoles 2a,b.
NH2CH2CH2NH2
N
R
R
O
O
N

N
1a,b
H
2 a (72%), b (75%)
1, 2 a R = H, b R = Me
The exchange of ethylenediamine for diethylenetriamine unexpectedly led to the preparation of tricyclic
structures via refluxing a mixture of the 2-furonitrile (1a) or 5-methyl-2-furonitrile (1b) with diethylenetriamine
for 10 h to give the corresponding 2,3,5,6-tetrahydroimidazo[2,1-c]pyrrolo[1,2-a]pyrazine (3a) or its 8-methyl
analog 3b in 32 and 35% yields respectively.
(NH2CH2CH2)2NH
R
N
N
1a,b

N
1, 3 a R = H, b R = Me
3 a (32%), b (35%)
_______
* To whom correspondence should be addressed, e-mail: vter@org.chem.msu.ru.
1M. V. Lomonosov State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 445-447, March, 2010. Original
article submitted January 21, 2010.
0009-3122/10/4603-0351©2010 Springer Science+Business Media, Inc.
351

We propose the following tandem mechanism for formation of compounds 3a,b. Initial attack of a
terminal nitrogen atom of the diethylenetriamine at atom C(5) of the furan ring leads to formation of the open
intermediate A, subsequent dehydration and ring closing of a pyrrole ring giving the intermediate B which then
forms a pyrazine and finally an imidazole ring.
H
N
N
N
N
N
HO
H
N
O
N
NH2
N
N
– H2O
H
– NH3
B
HN
.
.
N
H2N
NH2
NH2
A
1H and 13C NMR spectra were recorded on a Bruker Avance-400 spectrometer (400 and 100 MHz
respectively) using CDCl3 at temperatures of 23 and 25ºC and with TMS as internal standard. Mass spectra were
taken on a Kratos MS-90 instrument with an ionization energy of 70 eV.
2-(2-Furyl)-4,5-dihydro-1H-imidazole (2a). Ethylenediamine (5 ml, 0.112 mol) was added to 2-furo-
nitrile (4.7 ml, 0.048 mol). The reaction mixture was heated for 4 h, cooled to room temperature, the precipitated
solid filtered off, and the mother liquor evaporated in vacuo. The precipitates were combined, washed with
petroleum ether (40-70 ml), and dried in air. Yield 4.76 g (72%); mp 180ºC (ethylenediamine). The
spectroscopic data agreed with that reported in [4].
2-(5-Methyl-2-furyl)-4,5-dihydro-1H-imidazole (2b) was prepared similarly to compound 2a. Yield
1
6 g (75%); mp 132ºC. H NMR spectrum, , ppm (J, Hz): 2.30 (3H, s, 5-CH3); 3.69 (4H, s, H-4',5'); 4.75 (1H,
br. s, NH); 6.02 (1H, m, H-4); 6.76 (1H, d, J3,4 = 3.1, H-3). 13C NMR spectrum, , ppm: 13.64 (5-CH3); 50.01
(C-4',5'); 107.82 (C-4); 112.57 (C-3); 144.03 (C-5); 154.12 (C-2); 156.75 (C-6). Mass spectrum, m/z (Irel, %):
150 [M]+ (70.89), 149 (34.40), 121 (100), 107 (21.89), 106 (36.45), 94 (6.38), 78 (22.42), 66 (65.07), 51
(76.30), 43 (69.43). Found, %: C 64.11; H 6.90; N 18.48. C8H10N2O. Calculated, %: C 63.98; H 6.71; N 18.65.
2,3,5,6-Tetrahydroimidazo[2,1-c]pyrrolo[1,2-a]pyrazine (3a). Diethylenetriamine (21.6 ml, 0.2 mol)
was added to 2-furonitrile (1a), (9.38 g, 0.1 mol). The reaction mixture was heated for 10 h, poured into ice,
water was added, neutralized with Na2CO3 to weakly alkaline reaction, and extracted with benzene. The benzene
extracts were dried over CaCl2 and solvent was evaporated in vacuo. The residue was distilled in vacuo. Yield
7.8 g (32%); bp 200ºC (15 mm Hg), mp 65ºC. 1H NMR spectrum, , ppm (J, Hz): 3.28 (2H, t, J3,4 = 8.8, 2H-3);
3.33 (2H, t, J5,6 = 5.7, 2H-5); 3.81 (2H, t, J2,3 = 8.8, 2H-2); 4.17 (2H, t, J6,5 = 5.7, 2H-6); 6.20 (1H, dd, J9,10 = 3.8,
13
J9,8 = 2.5, H-9); 6.71 (1H, dd, J8,9 = 2.5, J8,10 = 1.3, H-8); 6.84 (1H, dd, J10,9 = 3.8, J10,8 = 1.3, H-10). C NMR
spectrum, , ppm: 44.29 (C-6); 46.03 (C-5); 51.85 (C-3); 53.26 (C-2); 109.88 (C-9); 110.01 (C-10); 121.65
(C-8); 122.31 (C-11); 159.38 (C-12). Mass spectrum, m/z (Irel, %): 161 [M]+ (69.54), 160 (78.10), 133 (22.48),
119 (8.97), 106 (35.47), 92 (15.53), 79 (21.94), 78 (24.77), 65 (21.44); 42 (100). Elemental analysis is given for
the hydrate of compound 3a. Found, %: C 57.65; H 7.25; N 22.37. C9H11N3·1.5H2O. Calculated, % C 57.43;
H 7.45, N 22.32.
8-Methyl-2,3,5,6-tetrahydroimidazo[2,1-c]pyrrolo[1,2-a]pyrazine (3b) was prepared similarly to
compound 3a from 5-methyl-2-furonitrile (1b). Yield 1.85 g (35%); bp 207ºC (7 mm Hg), mp 105ºC. 1H NMR
spectrum, , ppm (J, Hz): 2.26 (3H, s, CH3); 3.25 (2H, t, J3,2 = 8.7, 2H-3); 3.31 (2H, t, J5,6 = 5.2, 2H-5); 3.79
(2H, t, J2,3 = 8.7, 2H-2); 4.00 (2H, t, J6,5 = 5.2, 2H-6); 5.94 (1H, d, J10,9 = 3.8, H-10); 6.74 (1H, d, J9,10 = 3.8,
H-9). 13C NMR spectrum, , ppm: 11.82 (CH3); 41.40 (C-6); 46.08 (C-5); 51.91 (C-3); 53.34 (C-2); 108.59
(C-9); 109.39 (C-10); 120.87 (C-8); 130.66 (C-10a); 157.67 (C-4a). Mass spectrum, m/z (Irel, %): 175 [M]+
(37.24), 174 (54.78), 147 (19.45), 133 (24.51), 121 (37.30), 106 (20.12), 92 (12.40), 78 (18.17), 56 (100), 42
(55.18). Found, %: C 63.81; H 6.62; N 18.71. C10H13N3. Calculated, %: C 63.98; H 6.71; N 18.65.
352

REFERENCES
1.
2.
3.
4.
S. B. Seredenin, T. A. Voronina, A. Beshimov, V. P. Peresada, and A. M. Likhosherstov, Rus. Pat.
2099055. Chem. Abstr., 128, 290245 (1998).
A. P. Skoldinov, A. M. Likhosherstov, and V. P. Peresada, UK Pat. 2025936. Chem. Abstr., 93, 186406
(1980).
A. M. Likhosherstov, V. P. Peresada, V. G. Vinokurov, and A. P. Skoldinov, Zh. Org. Khim., 22, 2610
(1986).
M. Anastassiadou, S. Danoun, L. Crane, G. Baziard-Mouysset, M. Payard, D. H. Caignard,
M. C. Rettori, and P. Renard, Bioorg. Med. Chem., 9, 585 (2001).
353