Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine: a new ring system through Dimroth rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.06.104

Derivatives of the new ring system pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine were synthesized from the corresponding angular isomers, through a Dimroth rearrangement, in quantitative yields. Preliminary computational studies demonstrated that this class of compounds could be a good candidate as DNA intercalating agents.

Full text of DOI:10.1016/j.tetlet.2008.06.104

Tetrahedron Letters 49 (2008) 5125–5128
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine: a new ring system
through Dimroth rearrangement
a
a
b
b
Antonino Lauria a, , Ilenia Abbate , Chiara Patella , Noemi Gambino , Arturo Silvestri ,
*
Giampaolo Barone b, Anna Maria Almerico a
a Dipartimento Farmacochimico, Tossicologico e Biologico Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy
b Dipartimento di Chimica Inorganica e Analitica ‘S. Cannizzaro’, Università di Palermo, Viale delle Scienze, Parco d’Orleans II, 90128 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives of the new ring system pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine were synthesized
from the corresponding angular isomers, through a Dimroth rearrangement, in quantitative yields. Pre-
liminary computational studies demonstrated that this class of compounds could be a good candidate
as DNA intercalating agents.
Received 20 May 2008
Revised 18 June 2008
Accepted 23 June 2008
Available online 27 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Flat heterocyclic structures are fundamental moieties in anti-
cancer compounds acting as DNA intercalating agents.1 In fact,
they play a determinant role in the p–p stacking interactions with
O
e
O
d
N
NH
N1
N
4
5
a
a
4
5
the DNA base pairs. Consequently, the modulation of their elec-
tronic and steric features by the presence of opportune substitu-
ents or heteroatoms, could improve this capability. With the aim
to extend the synthetic pathways to new planar heterocyclic ring
systems we focused our studies on the pyrazolo[3,4-d][1,2,3]tri-
azolo[1,5-a]pyrimidine core structure 1 (Fig. 1), isomer of the
angular pyrazolo[4,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2, known
in literature.2
3
N
3
N1
N
N
N
N
N
H
N
2
1
Figure 1. Designed heterocyclic ring systems.
All the above systems can be related to DNA-interactive drugs
such as acridines, anthracyclines, and actinomycins. The principal
driving forces for the intercalation into DNA are stacking,
charge-transfer, as well as hydrogen bonding and electrostatic
interactions.3
A H
O
R1
B (CH2)3COOH
4N
C (CH2)3NnBu2
D (CH2)3CONHCH2COOEt
E (CH2)3COOEt
F (CH2)3CONH(CH2)2Im
R2
R1:
N
N
N
N
G (CH2)3CONHCH(CO2Me)CH2Im
H (CH2)2(CH2CONH)2CH(CO2Me)CH2Im
Recently, we have also reported on the synthesis4 of other sys-
tems incorporating a triazolopyrimidine moiety, the indolo[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidine core structure 3 (Fig. 2), again
related to the abovementioned DNA intercalators. The functionali-
zation by chain shape in 4 position (3, R1 = B–H, R2 = Ph) has shown
to give a remarkable anti-tumor activity in micromolar scale.5
We hypothesize that in a similar fashion to the pyrrolotriazolo-
pyrimidine series,6,7 the Dimroth rearrangement (DR), in basic con-
ditions, could be applied to the angular isomer 4 in hopes of
preparing polyheterocyclic ring 5 (Scheme 1).
3
R2: Ph, CN, CONH2, COOEt, COOMe
Figure 2. Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives with anti-tumor
activity.
X
X
N
NH
N
N
R
N
N
It is clear that a crucial role in this approach is played by the
starting angular isomer 4, for two principal reasons. First, the reac-
tion reported in literature for its preparation2 is not of general
R
N
N
N
N
H
N
N
R1
R1
4
5
R=Ph, CN, CONH2; R1=Ph, Me; X=NH, O
* Corresponding author.
Scheme 1. Synthetic route to pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine core
E-mail address: lauria@unipa.it (A. Lauria).
structure.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.104

5126
A. Lauria et al. / Tetrahedron Letters 49 (2008) 5125–5128
HN
HN
H2N
N
NH
R
N
N
N
R
N
N
N
N
R
N
N
N
N
N
H
N
N
N
N
R1
R1
R1
6'
6
7
R=Ph, Me, CONH2; R1=Ph, Me
Scheme 2. Prototropic shift influences in the Dimroth rearrangement.
derivatives 10. The intermediate resulting from the cycloaddition
reaction could be the 3-(triazol-1-yl)pyrazole of type 11, which
bears an amino group susceptible to further reactions. In fact inter-
mediate 11, in the presence of a vicinal carboxylate function, fur-
ther cyclizes to provide the pyrimidine ring.
The azidopyrazole (8, R1 = CO2Et) was prepared, in good yields,
from the corresponding 2-amino derivative by diazotization with
sodium nitrite in acetic acid and addition in situ of sodium azide
to the intermediate diazonium salt.10 The pyrazole 8 was added
at room temperature to the sodium salts of acetonitriles in ethanol,
under the same experimental conditions successfully used previ-
ously.4,6–8
In this case after 24 h at room temperature the TLC analysis
showed mainly unreacted starting compounds. However, when
the reaction was carried out under reflux the appearance of the
new compounds was observed (TLC monitoring). Therefore, it
seems that in this case the bond-forming efficiency depends on
the first reaction step, consisting in the 1,3-dipolar cycloaddition
to form the triazole moiety (Scheme 3). Probably this is due to a
more electron withdrawing character of the pyrazole ring respect
to the pyrrole one. In this context, it is worth mentioning that
the HOMO–LUMO energy gap, calculated by the DFT B3LYP11
method with the 6-31G(d,p)12 basis set, by the GAUSSIAN 03 program
package,13 resulted to be 462.1 and 414.8 kJ/mol, for the optimized
geometries of azidopyrazole and azidopyrrole, respectively. On the
other hand, the energy of the azidopyrazole HOMO resulted to be
85.3 kJ/mol lower than that of azidopyrrole. Therefore, these re-
sults support the hypothesis that the interaction of the LUMO of
the dipolarophile 10 with the HOMO of 8 should be less favored
compared to that with the HOMO of the analogous pyrrole deriva-
tive. The new compounds 9, derivatives of the ring system pyraz-
olo[4,3-e][1,2,3]triazolo[1,5-a]pyrimidine, were generally isolated
in high yields (70–90%).10 Their structures were confirmed by spec-
troscopic data; in particular by the presence in the IR spectra of the
typical absorption bands (at 3435–2926 and 1661–1644 cmꢀ1) due
COOEt
NR1
CN
R
R2
+
EtO-Na+
EtOH
N
N
N
N
N
10a-c
N
N
R
N
N
N
8
R2=COOEt
a R=Ph; R1=H
b R=CN; R1=H
c R=CONH2; R1=H
O
COOEt
NHR1
NR1
R
N
N
N
N
N
N
N
R
N
N
N
11
9a-c
Scheme 3. Routes to pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine ring systems.
application, since it only allowed to isolate one derivative 4
(X = NH, R = R1 = Ph) due to the other derivatives’ instability during
the work-up. Second, the DR applied onto the imino derivative 6
does not take place, due to the rapid prototropic shift to the more
stable amino isomer 60 (Scheme 2).
In fact the opening of pyrimidine ring and the following DR to
get 7, could allow only in the lactam form 6 and not in the amidine
one 60.
Our experience on 1,3-cycloaddition reactions4,6–8 led us to use
the carboxyethyl derivative (8, R2 = CO2Et) instead of the carbo-
nitrile one (8, R2 = CN). In fact, routes to ring systems 9 can be
provided by domino reactions9 between acetonitriles 10 and azid-
opyrazole 8 under basic conditions (Scheme 3).
Thus, the pyrazole derivative 8 through the azido moiety can act
as a 1,3-dipolar compound in cycloaddition reactions with dipol-
arophiles such as the anions obtained from the methylene active
O
EtO
EtO
O
O
NR1
R
NHR1
NR1
R
R
N
N
N
N
N
N
N
N
N
N
N
N
N
N
HN
9a-c
11
DMSO
H2O
Δ
O
EtO
O
N
N
N
N
HN
N
a R=Ph; R1=H
b R=CN; R1=H
c R=CONH2; R1=H
N
N
R
R
N
N
N
N
R1
R1
12a-c
13
Scheme 4. Dimroth rearrangement mechanism.

A. Lauria et al. / Tetrahedron Letters 49 (2008) 5125–5128
5127
Table 1
DNA fragment docking results (GSCORE)
Entry
R1
A
B
C
D
E
F
G
H
9a
9b
9c
12a
12b
12c
3 (R2 = Ph)
ꢀ5.84
ꢀ6.01
ꢀ7.21
ꢀ5.62
ꢀ5.56
ꢀ5.82
ꢀ5.56
ꢀ5.76
ꢀ6.10
ꢀ7.03
ꢀ5.34
ꢀ5.74
ꢀ5.55
ꢀ6.19
ꢀ7.50
ꢀ7.14
ꢀ9.34
ꢀ6.69
ꢀ6.78
ꢀ6.41
ꢀ7.47
ꢀ6.22
ꢀ6.12
ꢀ8.33
ꢀ5.72
ꢀ5.75
ꢀ5.17
ꢀ6.18
ꢀ5.69
ꢀ5.91
ꢀ7.81
ꢀ5.22
ꢀ5.39
ꢀ5.44
ꢀ6.06
ꢀ7.80
ꢀ7.71
ꢀ8.48
ꢀ7.77
ꢀ7.05
ꢀ7.53
ꢀ8.19
ꢀ6.94
ꢀ7.29
ꢀ7.61
ꢀ7.47
ꢀ6.95
ꢀ6.81
ꢀ7.37
ꢀ7.54
ꢀ7.02
ꢀ6.96
ꢀ6.53
ꢀ6.50
ꢀ6.48
ꢀ7.16
Mean
ꢀ5.95
ꢀ5.96
ꢀ7.33
ꢀ6.21
ꢀ5.93
ꢀ7.79
ꢀ7.21
ꢀ6.88
A: H; B: (CH2)3COOH; C: (CH2)3NnBu2; D: (CH2)3CONHCH2COOEt; E: (CH2)3COOEt; F: (CH2)3CONH(CH2)2Im; G: (CH2)3CONHCH(CO2Me)CH2Im; H: (CH2)2(CH2CONH)2-
CH(CO2Me)CH2Im.
to the presence of a cyclic-amide structure. Moreover, in the 13C
NMR the diagnostic signal of the amide carbonyl moiety was found
in the range 154.8–155.1 ppm.
Thus, as already demonstrated in the case of pyrrolo[3,4-e]-
[1,2,3]triazolo[1,5-a]pyrimidine derivatives which rearranged to
pyrrolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine,7 compounds 9 were
heated under reflux in aqueous DMSO to give pyrazolo[3,4-d]-
[1,2,3]triazolo[1,5-a]pyrimidines 12 in nearly quantitative yields
(Scheme 4).10
At first glance, by analyzing the docking scores reported in
Table 1, it emerged that the new derivatives 9 and 12, when unsub-
stituted (R1 = A), show a DNA binding affinity comparable to 3A.
Moreover, considering the same side chain substituents introduced
in the indolotriazolopirimidine series (R1 = B–H),5 even in this case
again their presence drastically improves the binding affinity if
compared with the unsubstituted derivatives. The docking scores
were found in the range from ꢀ5.17 to ꢀ9.34 and more negative
than the value obtained by us17 for Actinomycin D (GSCORE =
ꢀ4.5). It is note to worth that the same trend observed in case of
indolotriazolopirimidines 3-substituted5 was observed. All docked
ligands revealed a common binding mode with the chromophore
intercalated between the DNA GC base pairs, whereas the side
chain lies along the minor groove (Fig. 3).
Therefore, the pyrazolotriazolopyrimidine derivatives 9 and 12
could be capable of forming stable complexes with DNA. Consider-
ing that the biological activity of Actinomycin D is related to a very
slow dissociation rate of the complex with DNA, the docking
results predict these compounds to be good candidates as anti-
tumor drugs.
This conversion reaction can be envisaged as a ring-opening
ring-closure of the pyrimidine ring in the presence of water.4 The
participation of water in this rearrangement came from the obser-
vation that the reaction does not occur in dry solvents and is in
agreement with a well-acknowledged literature report on the DR
in pyrimidine series.14 The spectroscopic evidence for the rear-
ranged structure, as observed in pyrrole series,6,7 are a general
increase in the IR frequencies for the amide carbonyl and the
downfield shifts (both 1H and 13C) of the methyl moiety signal.
For a preliminary evaluation of the ability of the designed pyr-
azolotriazolopyrimidines 9 and 12 to interact with DNA, we per-
15
formed docking calculations by using the GLIDE software. GLIDE
In conclusion, in this work we have generalized the synthetic
route to the pyrazolo[4,3-e][1,2,3]triazolo[1,5-a]pyrimidine ring
system, previously successfully achieved only in one case. More-
over, by applying the DR it is possible to suitably synthetize
derivatives of the new ring system pyrazolo[3,4-d][1,2,3]tri-
output consists of a score named GSCORE, where a more negative
value indicates a higher binding affinity. The aim of the computa-
tional studies was also to analyze the effect of the chain shape
functionalization on the DNA binding affinity, as already observed
in indolotriazolopyrimidine series.5
azolo[1,5-a]pyrimidine,
a
promising candidate as DNA
The Protein Data Bank16 was searched for DNA fragments bound
with intercalators and the structure 1DSC (an octamer complexed
with Actinomycin D) was selected. The original ligand was re-
moved and the DNA sequence was utilized for the docking
experiments.
intercalating compounds.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.104.
References and notes
1. Snyder, R. D. Mutat. Res. 2007, 623, 72–82.
2. Khan, M. A.; Freitas, A. C. C. J. Heterocycl. Chem. 1980, 17, 1603–1604.
3. Wakelin, L. P. G.; Waring, M. J. In Comprehensive Medicinal Chemistry; Sammes,
P. G., Ed.; Pergamon Press: Oxford, 1990; Vol. 2, pp 703–724.
4. Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.; Cirrincione, G.;
Dattolo, G.; Almerico, A. M. Tetrahedron Lett. 2006, 47, 2187–2190.
5. Lauria, A.; Patella, C.; Dattolo, G.; Almerico, A. M. J. Med. Chem. 2008, 51, 2037–
2046.
6. Lauria, A.; Diana, P.; Barraja, P.; Almerico, A. M.; Cirrincione, G.; Dattolo, G. J.
Heterocycl. Chem. 2000, 37, 747–750.
7. Lauria, A.; Diana, P.; Barraja, P.; Montalbano, A.; Cirrincione, G.; Dattolo, G.;
Almerico, A. M. Tetrahedron 2002, 58, 9723–9727.
8. Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.; Cirrincione, G.;
Dattolo, G.; Almerico, A. M. Heterocycles 2003, 60, 2669–2675.
9. Tietze, L. F. Chem. Rev. 1996, 115–136.
10. Experimental: Melting points (uncorrected) were taken on a Buchi–Tottoli
capillary apparatus; IR spectra were determined in bromoform with a Jasco FT/
IR 5300 spectrophotometer; 1H and 13C NMR spectra were measured at 200
Figure 3. Docking mode of derivative 9bG into DNA fragment.

5128
A. Lauria et al. / Tetrahedron Letters 49 (2008) 5125–5128
and 50.3 MHz, respectively, in (CD3)2SO solution, using a Bruker AC-E series
pyrazolo[4,3-e][1,2,3]triazolo[1,5-a]pyrimidine-3-carboxamide (9c). From
8
200 MHz spectrometer (TMS as internal reference). Column chromatography
was performed with a Biotage FLASH40i chromatography module (prepacked
cartridge system). Ethyl 5-azido-1-methyl-1H-pyrazole-4-carboxylate (8,
and 2-cyanoacetamide (10c), a yellow solid (yield 70%) was obtained: mp
>300 °C; IR: 3435–3070 (NH), 1654 (CO) cmꢀ1 1H NMR d: 3.92 (3H, s, CH3),
;
4.90 (2H, br s, NH2), 7.84 (1H, s, H-6); 13C NMR d: 33.5 (q), 96.6 (s), 104.1 (s),
133.5 (d), 150.1 (s), 151.3 (s), 154.9 (s), 168.2 (s). Anal. Calcd for C8H7N7O2: C,
41.21; H, 3.03; N, 42.05. Found: C, 41.29; H, 3.15; N, 42.19. HRMS: (M+) calcd
for C8H7N7O2 233.0661; found 233.0679.
R = COOEt). To
a
solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-
carboxylate (1.7 g, 10 mmol) in acetic acid (20 mL) and water (4 mL), sodium
nitrite (1.38 g, 20 mmol) in water (4 mL) was added at 0 °C, under vigorous
stirring. After 50 min sodium azide (2.60 g, 40 mmol) was added in portions
and the reactants were stirred for a further 3 h at room temperature. The
mixture, poured into water/ice, was neutralized with NaHCO3 and then it was
extracted with ethyl acetate. The organic layers were combined, dried over
sodium sulfate, and evaporated to dryness. The residue was purified by column
chromatography using dichloromethane/ethyl acetate 95:5 as eluant to give
derivative give 8 as a yellow oil: 1.17 g, yield 60%; IR: 2120 (N3), 1693 (CO)
General method for the preparation of 3-substituted 5-methyl-4,5-dihydro-
8H-pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine (12a,c). A solution of 9 was
heated under reflux in dimethylsulfoxide (99.8%, 10 mL) for 1 h. The cooled
reaction mixture was then poured onto crushed ice and the solid was filtered
off, air dried to give derivatives 12. 5-Methyl-3-phenyl-4,5-dihydro-8H-
pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidin-8-one (12a). From 9a (0.5 g,
1.88 mmol) as a light yellow solid (yield 98%): mp 210 °C; IR: 3370–2965
cmꢀ1
;
1H NMR d: 1.25 (3H, t, J = 6.4 Hz, CH3), 3.69 (3H, s, CH3), 4.31 (2H, q,
(NH), 1698 (CO) cmꢀ1 1H NMR d: 3.82 (3H, s, CH3), 7.12 (1H, t, J = 6.0 Hz, p-Ph),
;
J = 6.4 Hz, CH2), 7.77 (1H, s, H-3); 13C NMR d: 14.4 (q), 35.4 (q), 60.3 (t), 104.7
(s), 139.1 (s), 140.8 (d), 162.4 (s). Anal. Calcd for C7H9N5O2: C, 43.08; H, 4.65; N,
35.88. Found: C, 43.19; H, 4.59; N, 36.08. HRMS: (M+) calcd for C7H9N5O2
195.0756; found 195.0772.
7.31 (2H, dd, J = 6.1 and 6.4 Hz, m-Ph), 7.92 (1H, s, H-7), 8.31 (2H, d, J = 6.4 Hz,
o-Ph); 13C NMR d: 36.5 (q), 99.9 (s), 123.9 (d), 125.0 (d), 126.9 (s), 128.7 (d),
132.6 (d), 135.2 (s), 139.2 (s), 151.4 (s), 156.2 (s). Anal. Calcd for C13H10N6O: C,
58.64; H, 3.79; N, 31.56. Found: C, 58.71; H, 3.75; N, 31.59. HRMS: (M+) calcd
for C13H10N6O 266.0916; found 266.0928. 5-Methyl-8-oxo-5,8-dihydro-4H-
pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine-3-carbonitrile (12b). From 9b
(0.5 g, 2.32 mmol) as a light yellow solid (yield 95%): mp 214 °C; IR: 3389–
General method for the preparation of 3-substituted 8-methyl-4H-
pyrazolo[4,3-e][1,2,3]triazolo[1,5-a]pyrimidines (9a–c). To
a solution of
1.0 mM sodium ethoxide in ethanol (3.9 mL) substituted acetonitriles
(3.9 mmol) in absolute ethanol (10 mL) were added at room temperature.
After being stirred for 15 min a solution of azido derivative 8 (3.6 mmol) in
absolute ethanol (10 mL) was added and the mixture was stirred for a further
8 h under reflux. Evaporation of the solvent under reduced pressure gave a
solid which was purified by column chromatography using dichloromethane/
ethyl acetate 95:5 as eluant. 8-Methyl-3-phenyl-4H-pyrazolo[4,3-e][1,2,3]-
triazolo[1,5-a]pyrimidin-5(8H)-one (9a). From 8 and 2-phenylacetamide (10a),
a yellow solid (yield 90%) was obtained: mp >300 °C; IR: 3356–2926 (NH),
3076 (NH), 2234 (CN), 1671 (CO) cmꢀ1 1H NMR d: 3.91 (3H, s, CH3), 8.09 (1H, s,
;
H-7); 13C NMR d: 36.1 (q), 98.5 (s), 102.9 (s), 115.6 (s), 135.2 (d), 150.2 (s),
151.8 (s), 156.1 (s). Anal. Calcd for C8H5N7O: C, 44.66; H, 2.34; N, 45.57. Found:
C, 44.77; H, 2.39; N, 45.65. HRMS: (M+) calcd for C8H5N7O 215.0556; found
215.0541.
5-Methyl-8-oxo-5,8-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine-
3-carboxamide (12c). From 9c (0.5 g, 2.15 mmol) white solid (yield 95%): mp
203 °C; IR: 3411–3076 (NH), 1668 (CO) cmꢀ1 1H NMR d: 3.95 (3H, s, CH3), 4.70
;
1644 (CO) cmꢀ1
;
1H NMR d: 3.71 (3H, s, CH3), 7.00 (1H, t, J = 6.0 Hz, p-Ph), 7.27
(2H, br s, NH2), 7.91 (1H, s, H-7); 13C NMR d: 35.9 (q), 97.5 (s), 103.9 (s), 134.3
(d), 152.7 (s), 152.9 (s), 155.8 (s), 168.4 (s). Anal. Calcd for C8H7N7O2: C, 41.21;
H, 3.03; N, 42.05. Found: C, 41.38; H, 3.12; N, 42.39. HRMS: (M+) calcd for
C8H7N7O2 233.0661; found 233.0652.
(2H, dd, J = 6.0 and 6.5 Hz, m-Ph), 7.81 (1H, s, H-6), 8.40 (2H, d, J = 6.5 Hz, o-Ph);
13C NMR d:33.5 (q), 97.9 (s), 123.8 (d), 125.0 (d), 126.8 (s), 128.6 (d), 133.9 (d),
134.1 (s), 144.8 (s), 152.5 (s), 155.1 (s). Anal. Calcd for C13H10N6O: C, 58.64; H,
3.79; N, 31.56. Found: C, 58.67; H, 3.71; N, 31.68. HRMS: (M+) calcd for
11. Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
C
13H10N6O 266.0916; found 266.0925. 8-Methyl-5-oxo-5,8-dihydro-4H-
pyrazolo[4,3-e][1,2,3]triazolo-[1,5-a]pyrimidine-3-carbonitrile (9b). From
and malononitrile (10b), brown solid (yield 85%) was obtained: mp
1H NMR d: 3.80
12. Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222; Francl, M. M.;
Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Gordon, M. S.; De Frees, D. J.; Pople, J. A.
J. Chem. Phys. 1982, 77, 3654.
13. Frisch, M. J. et al. GAUSSIAN 03—Revision D.02, Gaussian: Wallingford, CT, 2005.
14. Perrin, D. D.; Pitman, I. H. J. Chem. Soc. 1965, 7071–7082.
15. Schrödinger. GLIDE 4.5, LLC: New York, NY, 2007.
8
a
>300 °C; IR: 3424–3050 (NH), 2232 (CN), 1661 (CO) cmꢀ1
;
(3H, s, CH3), 7.98 (1H, s, H-6); 13C NMR d: 33.8 (q), 98.6 (s), 102.4 (s), 115.6 (s),
134.4 (d), 150.4 (s), 151.9 (s), 154.8 (s). Anal. Calcd for C8H5N7O: C, 44.66; H,
2.34; N, 45.57. Found: C, 44.73; H, 2.31; N, 45.69. HRMS: (M+) calcd for
C8H5N7O 215.0556; found 215.0544. 8-Methyl-5-oxo-5,8-dihydro-4H-
16. Web address: http://www.pdb.org.
17. Supplementary data: docking results output in SD mol format.