Synthesis of alkyl hexahydropyrazino-[1,2-c]pyrimidine-9-carboxylates

Article abstract of DOI:10.1007/s10593-011-0865-2

Cyclocondensation of 3-alkoxycarbonylmethylidenepiperazin-2-ones with α-chlorobenzyl isocyanates gave alkyl 8-aryl-1,6-dioxo-1,3,4,6,7,8- hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates. The use of 1-aryl-2,2,2-trifluoroethyl isocyanates in an analogous cyclization gave 6-aryl-1,8-dioxo-6-trifluoromethyl-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c] pyrimidine-9-carboxylates.

Full text of DOI:10.1007/s10593-011-0865-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
SYNTHESIS OF ALKYL HEXAHYDROPYRAZINO-
[1,2-c]PYRIMIDINE-9-CARBOXYLATES
M. V. Vovk1*, O. V. Kushnir2, N. V. Mel'nichenko1, and I. F. Tsymbal1
Cyclocondensation of 3-alkoxycarbonylmethylidenepiperazin-2-ones with -chlorobenzyl isocyanates
gave alkyl 8-aryl-1,6-dioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates. The
use of 1-aryl-2,2,2-trifluoroethyl isocyanates in an analogous cyclization gave 6-aryl-1,8-dioxo-
6-trifluoromethyl-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates.
Keywords: 3-alkoxycarbonylmethylidenepiperazin-2-ones, 1-aryl-2,2,2-trifluoroethyl isocyanates,
-chlorobenzyl isocyanates, pyrazino[1,2-c]pyrimidine-9-carboxylates, cyclocondensation.
The pyrazino[1,2-c]pyrimidine heterocyclic system is characterized by pronounced pharmacological
properties. In particular, 7-ethyl-2-methyloctahydro-6H-pyrazino[1,2-c]pyrimidin-6-one is the active component
of the known antifilarial compound centperazine [1, 2]. In addition, there are found amongst substituted
octahydropyrazino[1,2-c]pyrimidines compounds with high analgesic, anti-inflammatory, and anti-anorexic
properties [3]. Recently, a series [4] of 1,6,8-trioxoperhydropyrazinopyrimidines has been proposed as novel,
highly functionalized starting materials for peptidomimetics. It should be noted that the methods reported in the
literature [1, 2, 5-7] for preparing pyrazino[1,2-c]pyrimidines are labor intensive and multistage and generally
lead to the target materials in poor yields.
Ar
N
C O
Cl
O
O
Ar
N
O
R
Cl
N
R
NH
R
Cl
N
NH
2a–e
NH
HN
– HCl
HN
HN
Ar
C(O)OR1
Ar
C(O)OR1
C(O)OR1
O
O
O
1a–d
A
4a–j
1a, 4а–e R = H, R1 = Me; 1b, 4f–h R = H, R1 = Et; 1c, 4i R = R1 = Me; 1d, 4j R = Me, R1 = Et; 2a, 4a,i Ar = Ph;
2b, 4b,f Ar = 2-FC6H4; 2c, 4c,g,j Ar = 3-BrC6H4; 2d, 4d Ar = 4-NO2C6H4; 2e, 4e,h Ar = 3,4-Cl2C6H3
_______
*To whom correspondence should be addressed, e-mail: mvovk@i.com.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
2Yu. Fedkovich Chernivtsi National University, 2 Kotsyubinsky St., Chernivtsi 58012; Ukraine, e-mail:
oleg_kushn@ukr.net.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1205-1211, August, 2011.
Original article submitted April 12, 2011.
0009-3122/11/4708-0989©2011 Springer Science+Business Media, Inc.
989

TABLE 1. Characteristics of Compounds 4a-j, 5a-d
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
[M+H]+
mp, oС
Yield, %
С
H
N
4a
C15H15N3O4
59.44
59.80
5.16
5.02
14.09
13.95
302
320
381
347
370
334
395
384
316
409
388
384
384
402
290–292
268–270
263–265
280–282
288–290
263–265
273–275
260–262
> 300
72
80
78
73
70
71
65
63
65
69
56
39
45
62
4b
4c
4d
4e
4f
C15H14FN3O4
C15H14BrN3O4
C15H14N4O6
56.21
56.43
4.48
4.42
12.94
13.16
47.72
47.39
3.58
3.71
11.26
11.05
52.29
52.03
3.96
4.07
16.30
16.18
C15H13Cl2N3O4
C16H16 FN3O4
C16H16BrN3O4
C16H15Cl2N3O4
C16H17N3O4
48.91
48.67
3.67
3.54
11.52
11.35
57.84
57.66
4.78
4.84
12.77
12.61
4g
4h
4i
48.51
48.75
3.96
4.09
10.86
10.66
50.31
50.02
4.05
3.94
11.11
10.94
61.17
60.94
5.36
5.43
13.09
13.33
4j
C17H18BrN3O4
С16H13F4N3O4
С17H16F3N3O4
С17H16F3N3O4
С17H15F4N3O4
49.81
50.02
4.53
4.44
10.16
10.29
282–284
> 300
5a
5b
5c
5d
49.38
49.62
3.54
3.38
11.01
10.85
53.09
53.27
4.35
4.21
10.83
10.96
280–282
285–287
288–290
53.48
53.27
4.14
4.21
11.05
10.96
50.61
50.88
3.64
3.77
10.61
10.47
With the aim of developing an efficient method for the synthesis of polyfunctional pyrazino[1,2-c]-
pyrimidines as key starting materials in a rational search for bioactive compounds, we have proposed a
convenient method for preparing novel pyrazino[1,2-c]pyrimidine-9-carboxylic acid derivatives. This route is
based on the previously tested [8-10] principle of forming the pyrimidine ring via condensation of [–C=C–N–]
binucleophiles and [–C–N=C–] bielectrophiles using the scheme given above. Initially for this task, we selected
the preparatively available [11-13] 3-alkoxycarbonylmethylidenepiperazin-2-ones 1a-d as the first and the
-chloroalkyl isocyanates 2a-e, 3a-c as the second.
It was found that refluxing the methylidene-substituted piperazin-2-ones 1a-d with the -chlorobenzyl
isocyanates 2a-e in dichloromethane is accompanied by formation of good yields of the alkyl 8-aryl-1,6-dioxo-
1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates 4a-j (Table 1). It is most likely that this
reaction occurs by initial addition of the nucleophilic carbon atom of the exocyclic alkoxycarbonyl- methylidene
group of compounds 1a-d to the C=N bond of the N-chloroformylimino form [14] of the isocyanates 2a-e via a
diazadiene mechanism [15] to yield the intermediates A (which then cyclize to the target compounds 4a-j).
When studying the reaction of piperazin-2-ones 1a,b with the 1-aryl-2,2,2-trifluoroethyl isocyanates
3a-c we obtained a qualitatively different result. Hence refluxing the reagents in toluene gave the 6-aryl-
1,8-dioxo-6-trifluoromethyl-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylic acid esters 5a-d.
With the previously revealed [6] dependence of the reaction of isocyanates of type 3a-c and N-substituted
990

TABLE 2. 1H NMR Spectra of Compounds 4a-j, 5a-d*
Com
pound
Chemical shifts, , ppm (J, Hz)
4a
4b
4c
4d
4e
4f
3.36-3.48 (3Н, m, СН2, СН); 3.50 (3Н, s, СН3); 3.76-3.83 (1Н, m, СН);
5.07 (1H, d, J = 2.1, H-8); 7.24-7.35 (5Н, m, H Ar); 7.82 (1Н, d, J = 2.1, H-7);
8.49 (1Н, s, Н-2)
3.34-3.44 (3Н, m, СН2, СН); 3.47 (3Н, s, СН3); 3.78-3.84 (1Н, m, СН);
5.33 (1H, d, J = 2.2, H-8); 7.08-7.32 (4Н, m, H Ar); 7.76 (1Н, d, J = 2.2, H-7);
8.49 (1Н, s, H-2)
3.32-3.44 (3Н, m, СН2, СН); 3.50 (3Н, s, СН3); 3.75-3.81 (1Н, m, СН);
5.11 (1H, d, J = 2.1, H-8); 7.22-7.48 (4Н, m, H Ar); 7.90 (1Н, d, J = 2.1, H-7);
8.54 (1Н, s, H-2)
3.36-3.47 (3Н, m, СН2, СН); 3.49 (3Н, s, СН3); 3.79-3.86 (1Н, m, СН);
5.25 (1H, d, J = 2.2, H-8); 7.54 (2Н, d, J = 9.0, H Ar); 8.09 (1Н, d, J = 2.2, H-7);
8.20 (2Н, d, J = 9.0, H Ar); 8.55 (1Н, s, H-2)
3.34-3.49 (3Н, m, СН2, СН); 3.50 (3Н, s, СН3); 3.76-3.82 (1Н, m, СН);
5.12 (1H, d, J = 2.1, H-8); 7.24-7.28 (1Н, m, H Ar); 7.45 (1Н, d, J = 2.4, H Ar);
7.55 (1Н, d, J = 7.6, H Ar); 7.91 (1Н, d, J = 2.1, H-7); 8.54 (1Н, s, H-2)
0.99 (3Н, t, J = 7.0, СН3); 3.33-3.48 (3Н, m) and 3.81-3.97 (3Н, m, 3СН2);
5.36 (1Н, d, J = 2.0, Н-8); 7.21-7.37 (4Н, m, H Ar); 7.83 (1Н, d, J = 2.0, H-7);
8.54 (1H, s, H-2)
4g
4h
4i
1.05 (3Н, t, J = 7.5, СН3); 3.26-3.32 (3Н, m, СН2, СН); 3.76-3.96 (3Н, m, СН2О, СН);
5.09 (1H, d, J = 2.1, H-8); 7.28-7.47 (4Н, m, H Ar); 7.86 (1Н, d, J = 2.1, H-7);
8.51 (1Н, s, H-2)
1.02 (3Н, t, J = 7.0, СН3); 3.37-3.47 (3Н, m, СН2, СН); 3.75-3.98 (3Н, m, СН2О, СН);
5.19 (1H, d, J = 2.1, H-8); 7.30 (1Н, d, J = 8.0, H Ar); 7.52 (1Н, s, H Ar);
7.64 (1Н, d, J = 8.0, H Ar); 7.95 (1Н, d, J = 2.1, H-7); 8.57 (1Н, s, H-2)
1.11-1.18 (3Н, m, СН3); 2.78-2.98 (1Н, m, СН); 3.57 and 3.60 (3Н, two s, СН3О);
3.62-3.85 (2Н, m, СН2); 5.07 and 5.12 (1H, two d, J = 2.0, H-8);
7.24-7.37 (5Н, m, H Ar); 7.82 and 7.86 (1Н, two d, J = 2.0, H-7); 8.55 (1Н, s, H-2)
4j
1.02-1.08 (3Н, m, СН3); 1.16-1.19 (3Н, m, СН3); 2.86-3.01 (1Н, m) and
3.59-3.92 (4Н, m, СН, СН2, СН2О); 5.05 and 5.11 (1H, two d, J = 2.0, H-8);
7.28-7.45 (4Н, m, H Ar); 7.87 and 7.90 (1Н, two d, J = 2.0, H-7); 8.56 (1Н, s, H-2)
5a
5b
2.86-3.34 (4Н, m, СН2); 3.59 (3Н, s, СН3О); 7.34-4.41 (2Н, m, H Ar);
7.70-7.75 (2Н, m, H Ar); 8.80 (1H, s, NH); 8.99 (1H, s, NH)
2.37 (3Н, s, СН3); 2.84-3.28 (4Н, m, СН2); 3.60 (3Н, s, СН3О);
7.30 (2Н, d, J = 7.2, H Ar); 7.52 (2Н, d, J = 7.2, H Ar); 8.70 (1H, s, NH);
8.83 (1H, s, NH)
5c
1.24 (3Н, t, J = 6.5, СН3); 2.84-3.32 (4Н, m, СН2); 4.08 (2Н, q, J = 6.5, СН2О);
7.36-7.42 (2Н, m, H Ar); 7.64-7.70 (3Н, m, H Ar); 8.72 (1H, s, NH); 8.90 (1H, s, NH)
5d
1.25 (3Н, t, J = 6.5, СН3); 2.88-3.35 (4Н, m, СН2); 4.10 (2Н, q, J = 6.5, СН2О);
7.29-7.35 (2Н, m, H Ar); 7.71-7.74 (2Н, m, H Ar); 8.70 (1H, s, NH); 8.90 (1H, s, NH)
_______
*
19F NMR spectra, , ppm: 5а -111.49 (1F, s, 4-FC6H4), -75.49 (3F, s,
CF3); 5b -74.50 (3F, s, CF3); 5c -74.99 (3F, s, CF3); 5d -111.07 (1F, s,
4-FC6H4), -75.02 (3F, s, CF3).
aminocrotonates in mind, it can be reliably proposed that, in this case, a C-carbamoylation occurs of the
enamine fragment of compounds 1a,b to form the intermediate N-alkylidenecarbamoyl structured products B
which tend to cyclize to the products 5a-d at increased temperature. Such a scheme is confirmed by the
observation of lowered yields of compounds 5b (Ar = 4-MeC6H4) and 5c (Ar = Ph) due to the decreased
electrophilicity of the azomethine bond in the intermediates B resulting from the effect of the indicated donor
aryl substituents.
991

CF3
Cl
CF3
N
Ar
CF3
NH
Ar
NH
Ar
N C O
R
R
N
3a–c
1a,b
HN
HN
– HCl
O
O
C(O)OR1
O
C(O)OR1
5a–d
O
B
5a,b R = H, R1 = Me; 5c,d R = H, R1 = Et; 3a, 5c Ar = Ph; 3b, 5a,d Ar = 4-FC6H4; 3c, 5b Ar = 4-MeC6H4
The composition and structure of the synthesized compounds was confirmed from elemental analysis,
13
chromato-mass spectra, and from their IR, 1H NMR, and C NMR spectra. For compounds 4a-j, the formation
1
of a partially hydrogenated pyrimidine ring is indicated by the presence in the H NMR spectra of doublets for
the H-7 and H-8 protons in the ranges 7.82-8.09 and 5.07-5.33 ppm with spin-spin coupling 2.0-2.2 Hz and by
the C-8 atom signals in the 13C NMR spectra at 50-56 ppm (Table 2).
In turn, the 1H NMR spectra of compounds 4i,j, with the two asymmetric carbon centers at the C-3 and
C-8 atoms, show doubling of the signals for virtually all of the substituents pointing to their existence as an
approximately equal amount of two diastereomers.
The solid state IR spectra (KBr tablets) of compounds 4a-j show three sets of bands in the C=O group
absorption region for the C(O)OR1, NHC(O), and NC (O)NH groups (Table 3). The two latter bands overlap
strongly with one another and the lower-frequency band appears as a shoulder on the higher. The NH group
absorption region is characterized by two sets of bands. In dichloromethane solution, the lower-frequency band
for the C=O group absorption is lost but the medium- and higher-frequency bands remain unchanged. In the NH
group absorption region, the NH bands characteristic for the solid state disappear and a new band at 3410-3415
cm-1 appears. It is thus very likely that the solid state of the studied compounds exist as associates involving both
NHC(O) groups. The carbamoyl group of the pyrazine ring is bound in an associate to the carbamoyl group of
another molecule and the ureido NHC(O) fragment of the pyrimidine ring with the ureido group of another
molecule.
TABLE 3. IR Spectra of Compounds 4a-j, 5a-d
ν, cm–1
C(O)OR1
N–H
Compound
NHC(O)
NHC(O)
KBr
KBr
CH2Cl2
4a
4b
4c
4d
4e
4f
1677
1677
1685
1677
1675
1679
1686
1677
1680
1685
1645
1640
1645
1640
1689
1689
1695
1687
1687
1690
1693
1688
1690
1695
1680
1670
1675
1675
1725
1729
1730
1722
1725
1726
1730
1723
1725
1728
1720
1720
1720
1725
3080, 3210
3079, 3205
3085, 3210
3080, 3210
3070, 3200
3080, 3210
3085, 3210
3080, 3215
3080, 3210
3080, 3210
3130, 3220
3115, 3220
3120, 3230
3125, 3220
3410
3412
3414
3412
3415
3412
3414
3415
3410
3412
4g
4h
4i
4j
5a
5b
5c
5d
992

993

The formation of the 1,8-dioxopyrazino[1,2-c]pyrimidine-9-carboxylic acid derivatives 5a-d agrees with
19F NMR spectroscopic data in which the presence of CF3 group fluorine atoms indicates its position in an
aminal N–C(CF3)Ar–NH fragment [16, 17]. The 13C NMR spectroscopic signals for the C-6 atom appears as a
quartet indicating its tetracoordinate character [18].
Hence regioselective cyclocondensations of 3-alkoxycarbonylmethylidenepiperazin-2-ones with chloro-
benzyl isocyanates appears to be a convenient method for the synthesis of the structurally related 1,6-dioxo- and
1,8-dioxopyrazino[1,2-c]pyrimidine-9-carboxylates and these are promising subjects for further chemical
biological investigation.
EXPERIMENTAL
1
IR spectra were recorded on a UR-20 instrument as KBr tablets and in dichloromethane. H and 13C
NMR spectra were recorded on a Bruker Avance DRX-500 spectrometer (500 and 125 MHz respectively) for
solutions in DMSO-d6 with TMS as internal standard. 19F NMR spectra were taken on a Varian Gemini-2000
spectrometer (188 MHz) using DMSO-d6 with CCl3F as internal standard. Chromato-mass spectra were obtained
on an Agilent 1100 series instrument. Zorbax SB-C18 column, 1.8 µ, 4.6×15 mm. Ionization method:
atmospheric pressure chemical ionization.
3-Alkoxycarbonylmethylidenepiperazin-2-ones 1a-d were synthesized by method [11]. The α-chloro-
benzyl isocyanates 2a-e and 1-aryl-1-chloro-2,2,2-trifluoroethyl isocyanates 3a-c were obtained by methods [9]
and [19] respectively.
Alkyl 8-Aryl-1,6-dioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates (4a-j).
The isocyanate 2 (2.0 mmol) in dichloromethane (5 ml) was added to a solution of the corresponding piperazine
1 (2.0 mmol) in dichloromethane (20 ml) and refluxed for 1.5 h. The reaction mixture was cooled and the
precipitated product was filtered off, dried, and crystallized from ethanol.
Alkyl
6-Aryl-1,8-dioxo-6-trifluoromethyl-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-
9-carboxylates 5a-d. The corresponding isocyanate 3 (2.0 mmol) in toluene (5 ml) was added to a solution of
the corresponding piperazine 1 (2.0 mmol) in toluene (15 ml) and refluxed for 9 h. The reaction mixture was
cooled and the precipitate was filtered off, dried, and crystallized from ethanol.
REFERENCES
1.
2.
3.
D. P. Sahu, Indian J. Chem., 37B, 1149 (1998).
S. Sengupta, D. P. Sahu, and S. K. Chatterjee, Liebigs Ann. Chem., 437 (1993).
B. Anders, K. Konrad, K. Bengt, A. Sigvard, A. Lisbeth, and S. E. H. Hernestam, Ger. Pat. Appl.
19772837089; Chem. Abstr., 90, 204134 (1979).
4.
5.
S. Herrero, A. Salgado, M. T. Garcia-Lopes, and R. Herrant, Tetrahedron Lett., 43, 4899 (2002).
N. Anand, R. K. Chatterjee, R. N. Iyer, R. Sakena, and A. B. Sen, US Pat. Appl. 19713560503; Chem.
Abstr., 74, 141845 (1979).
6.
N. Anand, R. Sakena, R. K. Chatterjee, R. N. Iyer, and A. B. Sen, Brit. Pat. Appl. 19721284582; Chem.
Abstr., 77, 152226 (1972).
7.
8.
S. Sharma, R. Bindra, R. N. Iyer, and N. Anand, J. Med. Chem., 18, 913 (1975).
M. V. Vovk and V. A. Sukach, Zh. Org. Khim., 41, 1261 (2005).
9.
V. A. Sukach, A. V. Bol’but, A. D. Sinitsa, and M. V. Vovk, Synlett, 375 (2006).
M. V. Vovk, O. V. Kushnir, V. A. Sukach, and I. F. Tsymbal, Zh. Org. Khim. 46, 716 (2010).
V. Y. Iwanami, Bull. Chem. Soc. Jpn., 44, 1311 (1971).
10.
11.
12.
J. Toman, J. Klichar, and V. Machacek, Collect. Czech. Chem. Commun., 43, 2179 (1978).
994

13.
14.
15.
16.
M.-J. Fan, G.-Q. Li, and Y.-M. Liang, Tetrahedron, 62, 6782 (2006).
V. I. Gorbatenko and L. I. Samarai, Synthesis, 85 (1980)
L. Ambroise, D. Desmaele, and J. d'Angelo, Tetrahedron Lett., 35, 9705 (1994).
M. V. Vovk and V. V. Pirozhenko, Khim. Geterotsikl. Soedin., 96 (1994). [Chem. Heterocycl. Comp.,
30, 85 (1994)].
17.
18.
19.
M. V. Vovk, P. S. Lebed', V. A. Sukach, and M. Yu. Kornilov, Zh. Org. Khim. , 39, 1852 (2003).
O. V. Kushnir, V. A. Sukach, and M. V. Vovk, Zh. Org. Khim., 45, 768 (2009).
V. N. Fetyukhin, A. S. Koretskii, V. I. Gorbatenko, and L. I. Samarai, Zh. Org. Khim., 13, 271 (1977).
995