Synthesis of 3-amino-1-benzyl-4-benzenesulfonyl-2-carbonitrilo-1H-pyrrole and preparation of related pyrrolo[3,2-d]pyrimidines

Article abstract of DOI:10.1134/S1070363212020235

A method for the synthesis of a new 4-phenylsulfonyl-substituted 3-aminopyrrole was developed and related pyrrolo[3,2-d]pyrimidine derivatives were synthesized. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070363212020235

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 2, pp. 317–322. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © R.N. Solomyannyi, S.R. Slivchuk, A.N. Vasilenko, E.B. Rusanov, V.S. Brovarets, 2012, published in Zhurnal Obshchei Khimii, 2012,
Vol. 82, No. 2, pp. 322–327.
Synthesis of 3-Amino-1-benzyl-4-benzenesulfonyl-2-carbonitrilo-
1H-pyrrole and Preparation
of Related Pyrrolo[3,2-d]pyrimidines
R. N. Solomyannyia, S. R. Slivchuka, A. N. Vasilenkoa, E. B. Rusanovb, and V. S. Brovaretsa
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received November 11, 2010
Abstract—A method for the synthesis of a new 4-phenylsulfonyl-substituted 3-aminopyrrole was developed
and related pyrrolo[3,2-d]pyrimidine derivatives were synthesized.
DOI: 10.1134/S1070363212020235
The 3-aminopirrole derivatives are known to
possess antibacterial, anticonvulsant, antiphlogistic,
analgesic and antipyretic activity [1–4]. Therefore, the
synthesis of new biologically active 3-aminopyrrole
derivatives is a relevant task. In our work we
succeeded to synthesize a new compound of this class
which contains a phenylsulfonyl group in position 4 of
the pyrrole fragment that is important for the creation
of drugs with antiviral activity [5] belonging to this
class of compounds. As the starting reagent we used
enaminonitrile I (Scheme 1) that had been synthesized
previously [6]. In its reaction with chloroacetonitrile in
the presence of K2CO3, obviously, the alkylation
product II is initially formed. The latter was not
isolated in individual state, as the reaction proceeds
with intramolecular cyclization involving the nitrile
and active methylene groups and leading to the
formation of tetrasubstituted pyrazole III in 43% yield
(Table 1) [7–9]. Structure of III was proved reliably by
the complex spectral study (Table 2).
Since compound III contains a nitrile and a primary
amine groups at the neighboring carbon atoms of the
ring, we used it for fusion of a pyrimidine fragment.
Like in other studies [10, 11], we used dimethy-
lformamide dimethylacetal as a one-carbon com-
Table 1. Yields, melting points, and elemental analysis data of compounds III, IV, and VII
Found, %
Calculated, %
Yield,
%
mp, °С
Comp. no.
Formula
(solvent)
N
S
N
S
43
75
60
81
93
97
92
85
169–171 (EtOH)
185–187 (C6H6)
12.57
9.42
C18H15N3O2S
C21H20N4O2S
C22H20N4O2S
C24H24N4O3S
C24H20N4O3S
C26H22N4O2S
C27H24N4O2S
C25H20N4O2S
12.45
14.27
13.85
12.49
12.60
12.33
11.96
12.72
9.50
III
14.32
13.94
12.61
12.68
12.45
12.03
12.84
8.20
7.86
7.13
7.18
7.01
6.77
7.25
8.17
7.93
7.15
7.21
7.05
6.84
7.28
IV
176–178 (C6H6)
VIIа
VIIb
VIIc
VIId
VIIe
VIIf
180–182 (C6H6)
218–220 (C6H5CH3)
219–221 (C6H5CH3)
203–205 (C6H5CH3)
188–190 (C6H5CH3)
317

318
SOLOMYANNYI et al.
Scheme 1.
Ph
O
Ph
Ph
O
O
O
O
S
S
S
NH2
CN
N
N
C
C
N
II
ClCH2CN, K2CO3
Δ
O
N
N
H
Ph
CN
Ph
Ph
I
III
(MeO)2CHNMe2
Δ
Ph
Ph
O
O
S
N
S
N
H2NR
NMe2
O
O
NHR
_Me2NH
N
CN
N
CN
Ph
Ph
Va_Vf
IV
Δ
Δ
Ph
Ph
O
O
O
S
S
N
N
O
N
N
N
N
R
NH
VIa_VIf
NHR
VIIa_VIIf
(c), PhCH2 (d), PhCH2CH2 (e), Ph (f).
Ph
R: H2C
Ph
CH CH2 (a),
(b),
CH2
CH2
O
O
Table 2. Spectral data of synthesized compounds
Comp. no. IR spectrum, ν, cm–1
1H NMR spectra (DMSO-d6) δ, ppm
2207 (C≡N), 3357, 5.10 s (2H, CH2), 5.69 s (2H, NH2), 7.21–7.35 m (5H, С6H5), 7.61 m (3H, С6H3), 7.85 s (1H, С5H), 7.95
III
3444 (NH2)
d (2H, С6H2)
2199 (C≡N)
2.90 s (3H, СH3), 2.99 s (3H, СH3), 5.23 s (2H, CH2), 7.23–7.62 m (8H, С6H5, С6H3), 7.71 s (1H, С5–H),
IV
7.92 d (2H, С6H2), 7.97 s (1H, СH)
3442 (NH)
4.05 m (2H, CH2), 4.90 d, 4.92 d (2H, NCH2), 5.78m (3H, СH2, СH), 6.89 t (1H, NH), 7.08–7.35 m (5H,
С6H5), 7.64 m (3H, СH3), 8.12 d (2H, С6H2), 8.29 s (1H, С6–H), 8.41 s (1H, С2–H)
VIIа
3414 (NH)
3444 (NH)
1.26–1.57 m (4H, 2CH2), 3.42–3.90 m (5H, 2СH2, СH), 5.75 s (2H, CH2), 6.57 br..m. (1H, NH), 7.10–
7.40 m (5H, С6H5), 7.60 m (3H, С6H3), 8.10 d (2H, С6H2), 8.38 s (1H, С6–H), 8.40 s (1H, С2–H)
VIIb
VIIc
4.64 d (2H, CH2), 5.77 s (2H, CH2), 5.63 m (1H, СH), 7.11–7.60 m (10H, С6H5, С6H3, СH, NH), 8.11 d
(2H, С6H2), 8.32 s (1H, С6–H), 8.44 s (1H, С2–H)
3444 (NH)
3465 (NH)
4.64 d (2H, CH2), 5.83 s (2H, CH2), 7.16–7.60 m (14H, 2С6H5, С6H3, NH), 8.12 d (2H, С6H2), 8.25 s
(1H, С6–H), 8.45 s (1H, С2–H)
VIId
VIIe
2.74 t (2H, CH2), 3.66 m (2H, CH2), 5.72 s (2H, CH2), 6.83 m (1H, NH), 7.07–7.34 m (10H, 2С6H5), 7.64
m, 8.12 d (5H, С6H5), 8.33 s (1H, С6–H), 8.37 s (1H, С2–H)
3463 (NH)
5.92 s (2H, CH2), 7.08–7.40 m (10H, 2С6H5), 7.63 m, 8.19 d (5H, С6H5), 8.35 s (1H, NH), 8.40 s (1H,
С6–H), 8.61 s (1H, С2–H)
VIIf
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 2 2012

SYNTHESIS OF 3-AMINO-1-BENZYL-4-BENZENESULFONYL-2-CARBONITRILO-...
319
Scheme 2.
Ph
O
O
S
N
H2NR
NMe2
IV
VIIa_VIIf
_Me2NH
NH
N
NHR
VIIIa_VIIIf
Ph
ponent. The condensation of the latter with substituted
3-aminopyrrole III afforded amidines IV in a good
yield (75%). The III → IV transformation was well
formed which are converted into the corresponding
pyrrolo[3,2-d]pyrimidines VII by the process of the
Dimroth rearrangement [10, 11]. We do not exclude
that the formation of compounds VII may also occur
by an alternative way (Scheme 2). The key stage in
this process is adding amine to the nitrile group
followed by VIII → VII cyclization [12]. The choice
between these two directions is difficult, as we failed
to isolate any intermediate.
1
confirmed by the data of IR and H NMR spectra.
Thus, the IR spectra of compounds IV do not contain
intense signals at ν 3357 cm–1 and ν 3444 cm–1
characteristic of the primary amino group. The absence
of the primary amino group follows also from the data
1
of H NMR spectroscopy: the signal at δ 5.69 ppm
disappears, while two singlet signals appear of methyl
groups at δ 2.90 ppm and δ 2.99 ppm.
For an unambiguous proof of the structure of final
compounds VII we used two-dimensional NMR
spectroscopy (COSY, NOESY, HMQC, HMBC), as
well as XRD analysis of compound VIId. Such dual
proof of the structure was carried out in order to avoid
in future application for the pyrrolo[3,2-d]pyrimidine
system of the X-ray diffraction method which was not
always possible to be employed. We completely
assigned all 1H and 13C NMR signals of com-
pound VIId (Fig. 1) and found the correlations listed in
Table 3.
The pyrimidine cyclization was carried out in
boiling toluene under the action of an excess of the
corresponding amine and a catalytic amount of
TsOH·H2O. The first stage of the process probably
includes transamination to the corresponding inter-
mediate amidine V (Scheme 1), which under the
reaction conditions undergoes intramolecular cycliza-
tion involving the nitrile and amino groups. As a result
the intermediate imino compounds VI are apparently
Fig. 1. The main correlations (indicated by arrows) and the assignment of signals (ppm) in 1H and 13C NMR spectra of compound
VIId.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 2 2012

320
SOLOMYANNYI et al.
Table 3. Correlations in compound VIIda revealed using the COSY, NOESY, HMQC, and HMBC spectra
1Н, δ, ppm
NOESY
13С, δ, ppm
HMBC
1Н, δ, ppm
7.63 (C4dH)
COSY
7.60
HMQC
133.48
129.60
127.22
152.66
7.60
7.63, 8.13
7.60
127.22 (C2d, C6d)
7.60 (C3dH, C5dH)
8.13 (C2dH, C6dH)
8.26 (C2H)
7.63, 8.13
7.60
143.29 (C1d), 129.60 (C3d, C5d)
133.48 (C4d), 127.22 (C2d, C6d)
145.01 (C7a), 150.16 (C4)
−
−
8.45 (C6H)
−
7.08, 5.84
7.28, 4.64
137.07
127.22
115.82 (C7), 145.01 (C7a), 150.16 (C4), 52.75 (CH2)
126.90 (C4b), 127.22 (C2b, C6b)
6.95 (C2bH, C6bH)
7.28
7.28 (C3bH, C5bH)
7.28 (C4bH)
6.95
−
6.95
−
128.50
126.90
126.90
129.25
128.40
139.74 (C1b), 128.50 (C3b, C5b)
127.22 (C2c, C6c)
7.08 (C2cH, C6cH)
7.32 (C3cH, C5cH)
7.32 (C4cH)
7.32
7.08
−
7.32
7.08
−
128.40 (C4c), 126.90 (C2c, C6c)
137.42 (C1c), 129.25 (C2c, C6c)
126.90 (C2c, C6c)
5.84 (CH2)
−
7.27, 8.45
6.95
52.75
43.64
115.50 (C4a), 137.42 (C1c), 137.07 (C6)
139.74 (C1b), 150.16 (C4)
4.64 (NHCH2)
7.27
a For the assignment of the signals in compound VIId, see Fig. 1.
The data obtained suggest that a sufficiently
characteristic criterion of the formation of the pyrrolo-
[3,2-d]pyrimidine system is the disappearance of the
13C signal of CN at ~114 ppm in the spectrum of
compound IV and a downfield shift of the CCN 13C
signal corresponding to compound VIId from
~90 ppm to ~115 ppm. Note a fairly strong downfield
CN bonds in the nitrogen heterocycles, while the
length of the second bond is typical for a standard
single C–N (average 1.45 Å). The reason for such non-
equivalence is the conjugation of the lone pair of the
N4 nitrogen atom with the aromatic system of the
heterocycle as indicates also the spatial orientation of
the NH group (the dihedral angle formed between the
plane of H1NC2C7 atoms and the N1N3C1C6 mean-
square plane is only 7°.
1
shift of the H signal of the H6 atom to 8.45 ppm
instead of the expected ~7.5 ppm and of the 13C signal
of C6 to 137.07 ppm instead of ~128 ppm, obviously
due to the magnetic anisotropy of the SO2 group.
Thus, starting with enaminonitrile I we succeeded
to prepare a new 3-aminopyrrole III, which proved to
be a convenient reagent for the synthesis of cyclic
pyrrolo[3,2-d] pyrimidines VIIa–VIIf. This approach
allows us to introduce regioselectively an alkylamino
or arylamino group in position 4, as well as aryl-
sulfonyl group in position 7 of the pyrrolo[3,2-d]pyri-
midine system, which provides a possibility of the syn-
thesis of a large number of compounds for the develop-
ment of new biologically active substances [13–18].
The X-ray diffraction analysis of compound VIId
indicates that the distribution of bond lengths and
angles in the central bicyclic fragment N1–N3C1–C6 is
common for such delocalized systems (Fig. 2). The
bicyclic fragment is almost planar, the average
deviation of atoms from the mean-square plane is
0.014 Å.
Phenyl groups C8–C13, C15, C20 and C21–C26 are
turned relative to the central heterocyclic system by
99°, 101°, and 84°, respectively. The bonds C2N4
1.344(3) and C7N4 1.457(3) Å are not equivalent. The
length of the first is in the typical range of delocalized
EXPERIMENTAL
IR spectra of compounds were recorded on a
Vertex 70 spectrophotometer from tablets with KBr.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 2 2012

SYNTHESIS OF 3-AMINO-1-BENZYL-4-BENZENESULFONYL-2-CARBONITRILO-...
321
by thevdirect method and refined by the full-matrix
least-squares method in anisotropic approximation
using the SHELXS97 and SHELXL97 software
packages [19, 20]. The correction for extinction was
introduced using the SADABS program by the
multiscan method (the minimum to maximum
correction ratio Tmin/Tmax = 0.646871). The hydrogen
atoms were found in differential electron density
syntheses and were refined isotropically. In the
refinement 4737 reflections were used with I > 2σ(I),
{386 refined parameters, number of reflections per
parameter 12.3, a weight scheme was used, ω =
1/[σ2(F02) + (0.0523P)2 + 0.2209P], where P = (F02 +
2Fc2)/3, the ratio of maximum (average) shift to the
error in the final cycle was 0.028(0.005)}. The final
divergence factors R1(F) = 0.0473, wR2(F2) = 0.1010
for the reflections with I > 2σ(I), R1(F) = 0.0894, wR2
(F2) = 0.1202, GOF = 0.999 over all independent
reflections. Residual electron density from the
difference Fourier series after the final refinement
cycle was 0.20 and –0.28 e Å–3.
Fig. 2. The general view of the molecule VIId and the main
bond lengths and angles: N1C1 1.315(3), N1C4 1.359(3), N2C1
1.339(3), N2C2 1.338(3), C2C3 1.405(3), C3C4 1.387(3),
N3C3 1.398(2), N3C6 1.361(3), C5C6 1.368(3), C4C5 1.424(3),
N4C2 1.344(3), N4C7 1.457(3) Å; N1C1N2 129.8(2)°,
C1N2C2 118.0(2)°, N2C2C3 118.08(19)°, C2C3C4 117.96(18)°,
C3C4N1 124.22(19)°, C1N1C4 111.8(2)°, C3C4C5 107.51(18)°,
C6C5C4 106.57(19)°, C4C3N3 107.67(18)°, N3C3C2
134.33(19)°, N4C2C3 125.49(19)°, C6N3C3 107.97(17)°,
N2C2N4 116.4(2)°.
A complete set of X-ray data for compound VIId is
deposited in the Cambridge Crystallographic Database
(CCDC 797022).
3-Amino-1-benzyl-4-benzenesulfonyl-2-carbo-
nitrilo-1H-pyrrole (III). To a suspension of 0.02 mol
of K2CO3 in 30 ml of acetonitrile was added 0.01 mol
of 2-benzenesulfonyl-3-benzylaminoacrylonitrile (I)
and 0.02 mol of chloroacetonitrile. The mixture was
refluxed at stirring for 8 h, then cooled, and 100 ml of
water was added. The precipitate formed was filtered
off, washed with water, and compound III was isolated
and purified by recrystallization.
1H NMR spectra were obtained on a Varian VXR-300
1
NMR spectrometer, heteronuclear H–13C correlation
spectra, on a Mercury-400 spectrometer (400 and 100
MHz respectively) from solutions in DMSO-d6, with
TMS as internal reference. Melting points were
measured on a Fisher–Johns instrument.
N'-(1-Benzyl-4-benzenesulfonyl-2-carbonitrilo-
1H-pyrrol-3-yl)-N,N-dimethylformamidine (IV). To
a solution of 0.01 mol of compound III in 25 ml of
DMF was added 0.02 mol of dimethylformamide
dimethylacetal, and the mixture was stirred for 4 h at
100°C. The solvent was removed in a vacuum and
compound IV was isolated and purified by crystal-
lization.
The X-ray diffraction study of a single crystal of
compound VIId with linear dimensions of 0.14×
0.26×0.38 mm was performed at 173K on a Bruker
Smart Apex II diffractometer (λMoKα radiation,
graphite monochromator, θmax 26.55°, spherical seg-
ment range –10 ≤ h ≤ 10, –27 ≤ k ≤ 28, –14 ≤ l ≤ 14).
In total, 15021 reflections were collected, of which
4737 were independent (the averaging R-factor
0.0486). The crystals of compound VIId, C26H22·
N4O2S, M = 454.54, are monoclinic, space group P2/c,
a = 8.5497(5), b = 22.8987(13), c = 11.7020(7) Å, β =
95.432(2)°, V = 2280.7(2) Å3, Z = 4, dc = 1.324, μ =
0.173 mm–1, F(000) = 952. The structure was solved
4-[N-alkyl(aryl)amino]-5-benzyl-7-benzenesul-
fonyl-5H-pyrrolo[3,2-d]-pyrimidines (VIIa–VIIf). A
mixture of 0.001 mol of the compound IV, 0.002 mol
of corresponding amine and 0.005 g of p-toluene-
sulfonic acid in 5 ml of toluene was refluxed at stirring
for 8 h. The mixture was then cooled, the solvent was
removed in a vacuum and a compound VIIa–VIIf was
isolated and purified by crystallization.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 2 2012

322
SOLOMYANNYI et al.
12. Foucourt, A., Dubouilh-Benard, C., Chosson, E.,
REFERENCES
Corbiere, C., Buquet, C., Ianneli, M., Leblond, B.,
Marsais, F., and Besson, Th., Tetrahedron, 2010,
vol. 16, p. 4495.
1. Tarzia, G., Panzone, G., Leali, M., Burdisso, M.,
Schiatti, P., and Selva, D., Farmako, 1984, vol. 39,
p. 538.
13. Smalley, T.L., Peot, A.J., Boucheron, J.A., and
Dickerson, S., Bioorg. Med. Chem. Lett., 2006, vol. 16,
no. 8, p. 2091.
2. Tarzia, G. and Panzone, G., USA Patent no. 4 140 696,
1988.
14. Esteban-Gamboa, A., Balzarini, J., Esnouf, R.,
Clerca, E., Camarasa, M.J., and Perez-Perez, M.J.,
J. Med. Chem., 2000, vol. 43, no. 5, p. 971.
3. Unverfenth, K., Engel, J., Hoefgen, N., Rostock, A., and
Guenther, R., J. Med. Chem., 1998, vol. 41, no. 1, p. 63.
4. Mezentseva, M.V., Nesterova, I.N., Nikolaeva, I.S.,
Golovanova, E.G., Baklanova, O.V., and Filitis, L.N.,
Khim. Farm. Zh., 1991, vol. 25, no. 6, p. 21.
15. Juan, B.V., Ferrer, J.G., Prieto Soto, J.M., and Novero-
la, A.V., USA Patent no. 232838, 2003.
16. Carotti, A., Stefanachi, A., Ravina, E., Sotelo, E.,
Loza, M.I., Cadavid, M.I., Centeno, N.B., and Nicolotti, O.,
Eur. J. Med. Chem., 2004, vol. 39, no. 10, p. 879.
5. Stephens, E., Felder, M., Sowell, J., and Andrei, G.,
Bioorg. Med. Chem., 2001, vol. 9, no. 5, p. 1123.
6. Slivchuk, S.R., Brovarets, V.S., and Drach, B.S., Dop.
NAN Ukraїni, 2006, no. 3, p. 146.
7. Abdel-Ghany, H., El-Sayed, A.M., and El-Shafei, A.K.,
Synth. Commun., 1995, vol. 25, no. 8, p. 1119.
17. Hiroyuki, N., Hidenori, K., and Hitoshi, H., WO Patent
no. 068163, 2006.
18. Stefanachi, A., Nicolotti, O., Leonetti, F., Cellamare, S.,
Campagna, F., Loza, M.I., Brea, J.M., Mazza, F.,
Gavuzzo, E., and Carotti, A., Bioorg. Med. Chem.,
2008, vol. 16, no. 22, p. 9780.
8. Salaheldin, A.M., Z. Naturforsch. B, 2008, vol. 63,
p. 564.
9. Solomyannyi, R.N., Slivchuk, S.R., and Brovarets, V.S.,
Zh. Obshch. Khim., 2010, vol. 80, no. 11, p. 1795.
10. Kadushkin, A.V., Sokolova, A.S., Solov’eva, N.P., and
Granik, V.T., Khim. Farm. Zh., 1994, vol. 11, p. 15.
11. Kadushkin, A.V., Nesterova, I.N., Golovko, T.V.,
Nikolaeva, I.S., Pushkina, T.V., Fomina, A.N.,
Sokolova, A.S., Chernov, V.A., and Granik, V.G.,
Khim. Farm. Zh., 1990, vol. 24, no. 12, p. 18.
19. Sheldric, G.M., SHELX97. Program for the Solution of
Crystal Structure, University of Gottingen, Germany,
1997.
20. Sheldric, G.M., SHELX97. Program for the Refinement
of Crystal Structure, University of Gottingen, Gottingen
Germany, 1997.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 2 2012