Application of the Recyclization Products of 5-Alkyl(aryl)amino-2-(3- phthalimidopropyl)-1,3-oxazole-4-carbonitriles to the Synthesis of Condensed Tricyclic Nitrogenous Structures

Article abstract of DOI:10.1007/s10593-013-1216-2

N-Alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides were obtained by the interaction of 5-alkyl(aryl)amino-2-(3-phthalimidopropyl)-1,3- oxazole-4-carbonitriles with hydrazine hydrate and have been used for the synthesis of substituted 3H,4H,6H,7H,8H-pyrrolo[2,1-h]purin-4-ones, their thione analogs, and also 1,2,3,6,7,8-hexahydro-4H-pyrrolo[2′,1′:2,3] imidazo[4,5-d]-[1,3,2]diazaphosphinine derivatives.

Full text of DOI:10.1007/s10593-013-1216-2

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
APPLICATION OF THE RECYCLIZATION PRODUCTS
OF 5-ALKYL(ARYL)AMINO-2-(3-PHTHALIMIDOPROPYL)-
1,3-OXAZOLE-4-CARBONITRILES TO THE SYNTHESIS OF
CONDENSED TRICYCLIC NITROGENOUS STRUCTURES
S. A. Chumachenko1, O. V. Shablykin1, and V. S. Brovarets1*
N-Alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides were obtained by the
interaction of 5-alkyl(aryl)amino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitriles with hydrazine
hydrate and have been used for the synthesis of substituted 3H,4H,6H,7H,8H-pyrrolo[2,1-h]purin-
4-ones, their thione analogs, and also 1,2,3,6,7,8-hexahydro-4H-pyrrolo[2',1':2,3]imidazo[4,5-d]-
[1,3,2]diazaphosphinine derivatives.
Keywords: N-alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides, 3-alkyl-
2-mercapto-1,2,3,6,7,8-hexahydro-4H-pyrrolo[2',1':2,3]imidazo[4,5-d][1,3,2]diazaphosphinine-4-thione
2-sulfides, 3-alkyl(aryl)-3H,4H,6H,7H,8H-pyrrolo[2,1-h]purin-4-ones, 3-aryl-3H,4H,6H,7H,8H-pyrrolo-
[2,1-h]purine-4-thiones, recyclization.
It was shown previously in [1] that 5-morpholino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitrile
(2) obtained by oxazole cyclization of 2-(4-phthalimidobutanoylamino)-3,3-dichloroacrylonitrile (1) is subject
to recyclization under the action of hydrazine hydrate with the formation of 2-(morpholin-4-ylcarbonyl)-
6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-amine (3). It was interesting to investigate whether similar behavior
would be observed with carbonitriles 4a-d containing primary amine fragments at the position 5 of the oxazole
ring, the recyclization products of which in the future might be used for constructing tricyclic structures. With
this aim, we synthesized oxazoles 4a-d with residues of benzylamine, phenylethylamine, aniline, and 4-methyl
phenylamine. It turned out that hydrazinolysis of them (refluxing in ethanol with hydrazine hydrate) as in the
case of compound 2, also led to recyclization products, the novel N-alkyl(aryl)-3-amino-5H,6H,7H-
pyrrolo[1,2-a]imidazole-2-carboxamides 5a-d.
The composition and structure of compounds 5a-d were confirmed by results of elemental analysis,
chromato-mass spectrometry, as well as IR and NMR spectral data (Tables 1-3). In the 1H NMR spectra of these
substances, in comparison with the initial compounds 4a-d, signals of the methylene groups in the
_______
*To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02660, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1956-1962, December, 2012.
Original article submitted July 31, 2012.
1832
0009-3122/13/4812-1832©2013 Springer Science+Business Media New York

O
CN
N
N
N2H4·H2O
N
N
PhtN
N
( )3
N
O
O
O
NH2
2
Morpholine
CN
3
O
O
CN
RNH2
N2H4·H2O
N
PhtN
Cl
NHR
( )3
N
H
1
PhtN
N
NHR
( )3
O
Cl
NH2
4a–d
5a–d
4, 5 a R = Bn, b R = Ph(CH2)2, c R = Ph, d R = 4-MeC6H4
propylene fragment were shifted downfield, while the NH group signals of the aminoalkyl and aminoaryl
residues were shifted upfield (Table 2). The presence of a primary amino group in the structure of products 5a-d
was confirmed by the occurrence of a broadened singlet at 5.68-5.96 ppm in the region characteristic for such
groups.
On comparing the IR spectra of compounds 5a-d and 4a-d the disappearance of nitrile absorption bands
at 2000-2300 cm-1 was also observed, as was the appearance of intense absorption bands at 3000-3500 cm-1,
assigned to the stretching vibrations of the primary amino group. Similar spectral changes were observed on
recyclization of 5-morpholino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitrile (2) into 2-(morpholin-4-yl-
carbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-amine (3) [1], the structure of which was reliably
confirmed by correlation methods of NMR spectroscopy.
The presence of three labile hydrogen atoms of the amino groups in the structure of compounds 5a-d
raises the possibility of their subsequent use in cyclization reactions. Attempts to synthesize pyrrolo[2,1-h]-
purin-4-ones 7a-d on interacting products 5a-d with an excess of triethyl orthoformate were not successful. The
use of the even more reactive condensing agent (dimethylformamide dimethyl acetal) led to amidines 6a-d,
refluxing of which in anhydrous acetic acid gave pyrrolo[2,1-h]purin-4-ones 7a-d in 54-65% yield. A similar
approach to the synthesis of condensed purin-4-one derivatives was reported previously in [2].
O
O
N
N
Me2NCH(OMe)2
AcOH, 
NHR
R
5a–d
N
N
N
N
6a–d
N
NMe2
7a–d
6, 7 a R = Bn, b R = Ph(CH2)2, c R = Ph, d R = 4-MeC6H4
We have also studied the interaction of aminoimidazoles 5a-d with phosphorus pentasulfide. It was
found that on refluxing the reactants in pyridine in a molar ratio of 1:2, the diazaphosphinines 8a,b were formed
in the case of compounds 5a,b containing an aliphatic amide residue, while in the case of compounds 5c,d with
an aromatic amide residue the reactions stopped at the stage of thioamides 10a,b. The obtained 3-alkyl-2-
mercapto-1,2,3,6,7,8-hexahydro-4H-pyrrolo[2',1':2,3]imidazo[4,5-d][1,3,2]diazaphosphinine-4-thione 2-sulfides
8a,b were converted by the action of methyl iodide into the corresponding dimethyl derivatives 9a,b.
Methylation of products 8a,b was effected regioselectively at the two sulfur atoms but not at the nitrogen atom
of the diazaphosphinine fragment, as indicated by the absence of 1H NMR signal splitting of one of the methyl
groups. In addition, such a direction of alkylation was previously observed in similar compounds [3].
1833

TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp*, °С
Yield, %
C
Н
N
P
S
C21H16N4O3
C22H18N4O3
C14H16N4O
C15H18N4O
C13H14N4O
C14H16N4O
C17H21N5O
C18H23N5O
C16H19N5O
C17H21N5O
C15H14N4O
C16H16N4O
C14H12N4O
C15H14N4O
C14H15N4PS3
C15H17N4PS3
C16H19N4PS3
C17H21N4PS3
C13H14N4S
C14H16N4S
C14H12N4S
C15H14N4S
67.91
67.73
68.22
68.38
65.78
65.61
66.76
66.65
64.32
64.45
65.70
65.61
65.62
65.57
66.25
66.44
64.42
64.63
65.41
65.57
67.49
67.65
68.59
68.55
66.78
66.66
67.60
67.65
45.78
45.89
47.19
47.35
4.45
4.33
4.83
4.70
6.27
6.29
6.67
6.71
5.70
5.82
6.19
6.29
6.63
6.80
6.92
7.12
6.53
6.44
6.70
6.80
5.18
5.30
5.62
5.75
4.71
4.79
5.43
5.30
4.22
4.13
4.59
4.50
15.17
15.05
14.37
14.50
21.69
21.86
20.60
20.72
23.26
23.12
21.95
21.86
22.53
22.49
21.40
21.52
23.70
23.55
22.59
22.49
21.12
21.04
20.17
19.99
22.35
22.21
20.93
21.04
15.39
15.29
14.65
14.72
—
—
181-183
170-172
129-131
66-68
78
69
67
53
75
47
51
50
55
75
60
54
62
65
73
72
62
52
55
52
73
68
4c
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4d
5a
—
5b
5c
—
188-190
(decomp.)
242-244
(decomp)
113-115
Oil
—
5d
6a
—
—
6b
6c
—
125-127
172-174
—
6d
7a
—
217-219
(decomp.)
178-180
—
7b
7c
—
222-224
(decomp.)
202-204
(decomp.)
—
7d
8a
8.61
8.45
8.27
8.14
7.97
7.85
7.57
7.58
—
—
—
—
26.13
26.25 (decomp.)
25.40
25.28 (decomp.)
24.47
24.38
23.71
23.54
12.63
12.41 (decomp.)
11.63
11.77
12.17
11.95 (decomp.)
11.47
11.36 (decomp.)
220-222
214-216
8b
9a
48.60
48.71
50.13
49.98
60.25
60.44
61.81
61.74
62.80
62.66
63.98
63.81
4.69
4.85
5.03
5.18
5.65
5.46
5.77
5.92
4.37
4.51
4.87
5.00
14.37
14.20
13.85
13.71
21.67
21.69
20.68
20.57
20.70
20.88
19.88
19.84
147-149
162-164
218-220
9b
10a
10b
11a
11b
159-161
250-252
290-292
_______
*Solvents for recrystallization: EtOH (compounds 4c,d, 8a,b), EtOH–H2O, 1:1
(compounds 5a-d, 9a,b, 10a,b), acetone (compounds 7a-d, 11a,b).
S
SMe
N
N
N
P2S5, Py
(from 5a,b)
MeI, NaHCO3
HC(OEt)3
Alk
Alk
SMe
N
N
N
P
S
SH
P
S
N
N
5a–d
H
8a,b
9a,b
S
S
P2S5, Py
(from 5c,d)
N
N
NHAr
Ar
N
N
N
N
NH2
11a,b
10a,b
8, 9 a Alk = Bn, b Alk = Ph(CH2)2; 10, 11 a Ar = Ph, b Ar = 4-MeC6H4
1834

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2.01-2.06 (2H, m, CH2); 2.77 (2H, t, J = 6.6, CH2); 3.70 (2H, t, J = 5.8, NCH2);
7.04-7.33 (5H, m, H Ph); 7.80-7.94 (4H, m, H Ar); 10.23 (1H, s, NH)
4c
4d
5a
5b
1.94-2.09 (2H, m, CH2); 2.26 (3H, s, CH3); 2.75 (2H, t, J = 6.8, CH2); 3.70 (2H, t, J = 6.3, NCH2);
7.01-7.21 (4H, m, H Ar);7.75-7.94 (4H, m, H Ar); 10.13 (1H, s, NH)
2.41-2.48 (2H, m, CH2); 2.60 (2H, t, J = 7.2, CH2); 3.74 (2H, t, J = 6.8, NCH2);
4.35 (2H, d, J = 6.0, CH2); 5.70 (2H, s, NH2); 7.15-7.42 (5H, m, H Ph); 7.75 (1H, t, J = 5.6, NH)
2.42-2.49 (2H, m, CH2); 2.51-2.60 (2H, m, CH2); 2.77 (2H, t, J = 7.0, CH2);
3.32-3.41 (2H, m, CH2); 3.73 (2H, t, J = 6.4, CONHCH2); 5.68 (2H, s, NH2);
7.21-7.29 (6H, m, H Ph, NH)
2.50-2.55 (2H, m, CH2); 2.65 (2H, t, J = 7.2, CH2); 3.77 (2H, t, J = 7.0, NCH2);
5.96 (2H, br. s, NH2); 6.92-6.98 (1H, m, H Ph); 7.19-7.27 (2H, m, H Ph);
7.68-7.79 (2H, m, H Ph); 9.12 (1H, br. s, NH)
5c
2.24 (3H, s, CH3); 2.43-2.51 (2H, m, CH2); 2.65 (2H, t, J = 7.0, CH2);
3.76 (2H, t, J = 6.8, NCH2); 5.94 (2H, br. s, NH2); 7.05 (2H, d, J = 6.8, H Ar);
7.65 (2H, d, J = 7.0, H Ar); 9.04 (1H, br. s, NH)
5d
2.41-2.52 (2H, m, CH2); 2.67 (2H, t, J = 7.5, CH2); 2.91 (3H, s, CH3);
3.01 (3H, s, CH3); 3.76 (2H, t, J = 6.8, CH2); 4.39 (2H, d, J = 6.0, NCH2Ph);
7.21-7.32 (5H, m, H Ph); 8.06 (1H, t, J = 6.0, NH); 8.74 (1H, s, N=CH)
6a
6b
2.42-2.51 (2H, m, CH2); 2.65 (2H, t, J = 6.5, CH2); 2.80 (2H, t, J = 7.0, CH2);
2.90 (3H, s, CH3); 3.00 (3H, s, CH3); 3.37-3.44 (2H, m, CH2);
3.78 (2H, t, J = 6.5, CONHCH2); 7.22-7.34 (5H, m, H Ph); 7.59 (1H, t, J = 6.0, NH);
8.71 (1H, s, N=CH)
2.51-2.54 (2H, m, CH2); 2.72 (2H, t, J = 6.6, CH2); 2.98 (3H, s, CH3); 3.06 (3H, s, CH3);
3.82 (2H, t, J = 6.1, NCH2); 6.97-7.01 (1H, m, H Ph); 7.26-7.29 (2H, m, H Ph);
7.72-7.74 (2H, m, H Ph); 8.62 (1H, s, CH); 9.54 (1H, s, NH)
6c
2.24 (3H, s, ArCH3); 2.52-2.57 (2H, m, CH2); 2.71 (2H, t, J = 7.2, CH2); 2.96 (3H, s, NCH3);
6d
3.05 (3H, s, NCH3); 3.80 (2H, t, J = 7.2, NCH2); 7.07 (2H, d, J = 8.4, H Ar);
7.61 (2H, d, J = 8.0, H Ar); 8.61 (1H, s, N=CH); 9.46 (1H, s, NH)
2.52-2.61 (2H, m, CH2); 2.88 (2H, t, J = 7.0, CH2); 4.07 (2H, t, J = 6.3, NCH2);
5.23 (2H, s, CH2Ph); 7.27-7.34 (5H, m, H Ph); 8.49 (1H, s, H-2)
7a
7b
2.59-2.62 (2H, m, CH2); 2.90 (2H, t, J = 7.6, CH2); 2.99 (2H, t, J = 7.0, CH2);
4.05 (2H, t, J = 7.3, CH2); 4.24 (2H, t, J = 7.0, CH2); 7.19-7.31 (5H, m, H Ph);
8.05 (1H, s, H-2)
2.63-2.67 (2H, m, CH2); 2.92 (2H, t, J = 7.3, CH2); 4.12 (2H, t, J = 7.0, NCH2);
7.46-7.58 (5H, m, H Ph); 8.26 (1H, s, H-2)
7c
7d
8a
8b
2.40 (3H, s, CH3); 2.63-2.67 (2H, m, CH2); 2.92 (2H, t, J = 7.5, CH2);
4.11 (2H, t, J = 7.0, NCH2); 7.31-7.40 (4H, m, H Ar); 8.22 (1H, s, H-2)
2.55-2.63 (2H, m, CH2); 3.01 (2H, t, J = 7.0, CH2); 4.06 (2H, t, J = 6.6, NCH2);
5.43 (2H, d, J = 10.4, CH2Ph); 7.13-7.48 (5H, m, H Ph); 10.56 (1H, br. s, NH)*
2.60-2.65 (2H, m, CH2); 3.05 (2H, t, J = 7.5, CH2); 3.09-3.13 (2H, m, CH2);
4.06 (2H, t, J = 7.0, NCH2); 4.37-4.43 (2H, m, NCH2CH2Ph); 7.22-7.45 (5H, m, H Ph);
10.52 (1H, br. s, NH)*
2.10 (3H, d, J = 16.0, CH3); 2.49-2.55 (2H, m, CH2); 2.75 (2H, t, J = 7.0, CH2);
2.86 (3H, s, CH3); 3.76 (2H, t, J = 6.0, NCH2); 5.10-5.42 (2H, m, CH2Ph);
7.25-7.34 (5H, m, H Ph)
9a
9b
2.10 (3H, d, J = 16.0, CH3); 2.50-2.55 (2H, m, CH2); 2.75 (2H, t, J = 7.8, CH2);
3.03 (3H, s, CH3); 3.10-3.31 (2H, m, CH2); 3.74-3.79 (2H, m, CH2);
4.05-4.21 (2H, m, CH2); 7.24-7.37 (5H, m, H Ph)
2.51-2.57 (2H, m, CH2); 2.70 (2H, t, J = 7.5, CH2); 3.82 (2H, t, J = 6.8, NCH2);
7.11-7.37 (3H, m, H Ph); 7.39 (2H, br. s, NH2); 7.77-7.85 (2H, m, H Ph); 10.28 (1H, s, NH)
10a
10b
2.28 (3H, s, CH3); 2.51-2.58 (2H, m, CH2); 2.67 (2H, t, J = 7.6, CH2);
3.79 (2H, t, J = 6.8, NCH2); 7.12 (2H, d, J = 7.9, H Ar); 7.32 (2H, br. s, NH2);
7.65 (2H, d, J = 7.8, H Ar); 10.20 (1H, s, NH)
2.61-2.68 (2H, m, CH2); 2.96 (2H, t, J = 6.8, CH2); 4.15 (2H, t, J = 6.5, NCH2);
7.43-7.57 (5H, m, H Ph); 8.55 (1H, s, H-2)
11a
11b
2.39 (3H, s, CH3); 2.62-2.67 (2H, m, CH2); 2.95 (2H, t, J = 7.0, CH2);
3.79 (2H, t, J = 6.4, NCH2); 7.25-7.36 (4H, m, H Ar); 8.51 (1H, s, H-2)
_______
*The signal of the SH proton was not observed as a result of deuterium exchange.
1835

TABLE 3. IR and Mass Spectra of the Synthesized Compounds
Com-
pound
Mass spectrum, m/z
IR spectrum, ν, cm-1*
[M+H]+
1672*2, 1713 sh (C=O), 2220 (CN), 3146–3323 (NH)
1670*2, 1719 sh (C=O), 2223 (CN), 3129–3367 (NH)
1621 (C=O), 3027–3408 (NH, NH2)
1614 (C=O), 3134–3492 (NH, NH2)
1634 (C=O), 3171–3433 (NH, NH2)
1637 (C=O), 3162–3412 (NH, NH2)
1648 (C=O), 3367–3435 (NH)
1653 (C=O), 3355–3410 (NH)
1655 (C=O), 3365–3420 (NH)
1659 (C=O), 3147–3368 (NH)
1677 sh (C=O)
373
387
257
271
243
257
312
326
298
312
267
281
253
267
367
381
395
409
259
273
269
283
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
1681 sh (C=O)
7b
7c
1697 sh (C=O)
1703 sh (C=O)
7d
8a
1598, 3026–3221 (NH, SH)
1602, 3060–3265 (NH, SH)
1578, 1617
8b
9a
1575, 1613
9b
10a
10b
11a
11b
1594, 3132–3360 (NH, NH2)
1597, 3162–3350 (NH, NH2)
1587
1584
_______
* High intensity bands in the ranges 1500-1700, 2100-2300, and 3000-3600 cm-1
are indicated.
*2 Band caused by 5-amino-1,3-oxazole fragment [4].
Pyrrolo[2,1-h]purine-4-thiones 11a,b, thioxo analogs of compounds 7c,d, were synthesized from
thioamides 10a,b. It should be mentioned that in condensation with triethyl orthoformate, thioamides 10a,b
proved to be more reactive than amides 5c,d, and after refluxing for 3 h gave the corresponding thioxopurines
11a,b in yields of 73 and 68%, respectively.
A method has therefore been developed for the synthesis of new representatives of pyrrolo[2,1-h]purin-
4-ones, pyrrolo[2,1-h]purine-4-thiones, and pyrrolo[2',1':2,3]imidazo[4,5-d][1,3,2]diazaphosphinine-4-thiones,
using N-alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides that were obtained by recycli-
zation of 5-alkyl(aryl)amino-2-(3-aminopropyl)-1,3-oxazole-4-carbonitriles.
EXPERIMENTAL
1
13
31
The IR spectra were recorded on a Vertex 70 spectrometer in KBr pellets. The H, C, and P NMR
spectra were recorded on a Bruker Avance DRX-500 instrument (at working frequencies of 500, 125, and 202
MHz respectively) in DMSO-d6 solution. Chemical shifts are given relative to TMS (internal standard for 1H and
13C nuclei) or 85% H3PO4 (external standard for 31P nuclei). The mass spectra were recorded on a chromato-mass
spectrometer of the Agilent 1100 Series, fitted with a diode matrix and an Agilent LC\MSD SL mass selective
detector; column was Zorbax SB-C18, 4.6×15 mm, 1.8 μm (PN 821975-932); solvents A – MeCN–H2O (95:5),
0.1% trifluoroacetic acid, and B – 0.1% aqueous trifluoroacetic acid; eluent flow rate 3 ml/min; injection volume
1 μl; UV detectors, 215, 254, 285 nm; ionization method CI at atmospheric pressure, scanning range m/z 80-1000.
Elemental analysis was carried out in the analytical laboratory of the Institute of Bioorganic Chemistry and
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Petrochemistry, National Academy of Sciences of Ukraine. Melting points were determined on a Fisher-Johns
instrument.
2-(4-Phthalimidobutyrylamino)-3,3-dichloroacrylonitrile (1) and 5-alkylamino-2-(3-phthalimido-
propyl)-1,3-oxazole-4-carbonitriles 4a,b were obtained by the procedure of [1].
5-Arylamino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitriles 4c,d (General Method). The
corresponding aromatic amine (80 mmol) was added to compound 1 (7.04 g, 20 mmol) in DMF (20 ml). The
mixture was maintained at 20-25°C for a week, water (80 ml) was added, the solid was filtered off, washed with
water, and purified by recrystallization. 13C NMR spectrum of compound 4c, δ, ppm: 24.8 (NCH2CH2CH2);
25.2 (NCH2CH2CH2); 37.2 (NCH2CH2CH2); 88.4 (C-4 oxazole); 114.8 (CN); 118.8; 123.3; 123.4; 129.7; 132.1;
134.8; 139.1; 155.3; 157.0; 168.5 (C=O). 13C NMR spectrum of compound 4d, δ, ppm: 20.8 (CH3); 24.8
(NCH2CH2CH2); 25.2 (NCH2CH2CH2); 37.2 (NCH2CH2CH2); 87.4 (C-4 oxazole); 114.9 (CN); 119.3; 123.4;
130.1; 132.1; 132.6; 134.8; 136.4; 154.8; 157.4; 168.5 (C=O).
N-Alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides 5a-d (General Method).
Hydrazine hydrate (0.25 ml, 5.2 mmol) was added to a suspension of oxazole 4a-d (5 mmol) in EtOH (20 ml).
The mixture was refluxed for 6 h, cooled, and EtOH evaporated in vacuum. The residue was suspended in 4%
aqueous HCl solution (14 ml), the solid was filtered off, and 25% aqueous NaOH solution was added to the
filtrate to pH ~10. The solution was extracted with CH2Cl2 (5×5 ml), dried over Na2SO4, the solvent was
removed in vacuum, the residue was dissolved in CH2Cl2 and washed with 5% aqueous NaOH solution. The
solvent was removed in vacuum, the residue was washed with hexane, and purified by recrystallization.
13C NMR spectrum of compound 5a, δ, ppm: 22.5 (NCH2CH2CH2); 26.5 NCH2CH2CH2; 41.8 (CONHCH2);
42.2 (NCH2CH2CH2); 115.9 (C-NH2); 126.6; 127.8; 128.8; 141.3; 141.4; 145.6; 165.1 (CO). 13C NMR spectrum
of compound 5d, δ, ppm: 20.9 (CH3); 22.5 (NCH2CH2CH2); 26.5 (NCH2CH2CH2); 42.3 (NCH2CH2CH2); 115.7
(C-NH2); 119.4; 129.3; 131.2; 137.7; 142.5; 145.9; 163.3 (CO).
N-Alkyl(aryl)-3-[(dimethylamino)methylidene]amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carbox-
amides 6a-d (General Method). A solution of compound 5a-d (2 mmol) in dimethylformamide dimethyl acetal
(15 ml) was refluxed for 4 h, and the solvent removed in vacuum. The solid was filtered off, washed with
hexane, and compounds 6a-d were used for subsequent syntheses without additional purification. 13C NMR
spectrum of compound 6d, δ, ppm: 20.9 (CH3); 23.2 (NCH2CH2CH2); 26.2 (NCH2CH2CH2); 34.0 (2×NCH3);
42.8 (NCH2CH2CH2); 119.5; 122.0; 129.4; 131.6; 137.5; 143.7; 147.7; 158.1; 162.3 (CO).
3-Alkyl(aryl)-3H,4H,6H,7H,8H-pyrrolo[2,1-h]purin-4-ones 7a-d (General Method). A solution of
amidine 6a-d (2 mmol) in anhydrous AcOH (15 ml) was refluxed for 24 h. The solvent was removed in
vacuum, the residue was washed with water, and purified by recrystallization. 13C NMR spectrum of compound
7a, δ, ppm: 23.4 (NCH2CH2CH2); 26.4 (NCH2CH2CH2); 42.8 (NCH2CH2CH2); 48.9 (CH2Ph); 127.9; 128.0;
128.2; 129.0; 137.9; 146.5; 147.8; 156.2; 158.3 (CO).
3-Alkyl-2-mercapto-1,2,3,6,7,8-hexahydro-4H-pyrrolo[2',1':2,3]imidazo[4,5-d][1,3,2]diazaphosphi-
nine-4-thione 2-Sulfides 8a,b (General Method). P2S5 (0.88 g, 4 mmol) was added to a suspension of
compound 5a,b (2 mmol) in pyridine (5 ml). The reaction mixture was refluxed for 2 h, cooled, 10% HCl
solution (30 ml) was added, the precipitated solid was filtered off, washed with water, and purified by
31
31
recrystallization. P NMR spectrum of compound 8a, δ, ppm: 88.2. P NMR spectrum of compound 8b, δ,
ppm: 85.8. 13C NMR spectrum of compound 8b, δ, ppm: 23.7 (NCH2CH2CH2); 25.9 (NCH2CH2CH2); 34.7;
46.5; 48.7; 126.7; 128.8; 129.0; 132.3; 140.0; 149.5; 152.3; 178.3 (CS).
3-Alkyl-2,4-bis(methylthio)-3,6,7,8-tetrahydro-2H-pyrrolo[2',1':2,3]-imidazo[4,5-d][1,3,2]diazaphosphi-
nine 2-Sulfides 9a,b (General Method). NaHCO3 (0.84, 10 mmol) was added to a suspension of compound
8a,b (2 mmol) in a 1:3 mixture of H2O–EtOH (15 ml), and then MeI (0.85 g, 6 mmol) was added dropwise with
stirring. The reaction mixture was stirred at 20-25°C for 48 h, the resulting solid was filtered off, washed with
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31
water, and purified by recrystallization. P NMR spectrum of compound 9a, δ, ppm: 81.0. P NMR spectrum
of compound 9b, δ, ppm: 78.64. 13C NMR spectrum of compound 9b, δ, ppm: 15.9; 19.7; 23.5 (NCH2CH2CH2);
25.9 (NCH2CH2CH2); 37.0; 41.3; 49.2; 127.3; 129.0; 129.3; 138.4; 153.8; 154.1; 156.6; 160.2.
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N-Alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-thiocarboxamides 10a,b (General
Method). P2S5 (0.88 g, 4 mmol) was added to a suspension of compound 5c,d (2 mmol) in pyridine (5 ml). The
reaction mixture was refluxed for 2 h, cooled, and water (30 ml) added. The precipitated solid was filtered off,
washed with water, and purified by recrystallization.
3-Aryl-3H,4H,6H,7H,8H-pyrrolo[2,1-h]purine-4-thiones 11a,b (General Method). A suspension of
imidazole 10a,b (2 mmol) in triethyl orthoformate (15 ml) was refluxed for 4 h, the precipitated solid was
filtered off, washed with hexane, and purified by recrystallization. 13C NMR spectrum of compound 11a, δ,
ppm: 23.7 (NCH2CH2CH2); 26.3 (NCH2CH2CH2); 43.0 (NCH2CH2CH2); 128.8; 129.5; 129.7; 140.6; 141.0;
141.7; 147.5; 161.4; 177.5 (CS).
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