Heterocyclization of 6-hydroxyimino-6,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines into 1,2,4-triazolo[1,5-a]pyrimido[5,4-b]- and -[5,6-b]indoles

Article abstract of DOI:10.1070/MC2006v016n05ABEH002361

6-Hydroxyimino-6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines are converted into isomeric 1,2,4-triazolo[1,5-a]pyrimido[5,4-b]-and -[5,6-b]indoles in polyphosphoric acid or under exposure to para-nitrobenzoyl chloride in pyridine.

Full text of DOI:10.1070/MC2006v016n05ABEH002361

Mendeleev
Communications
Mendeleev Commun., 2006, 16(5), 280–282
Heterocyclization of 6-hydroxyimino-6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines
into 1,2,4-triazolo[1,5-a]pyrimido[5,4-b]- and -[5,6-b]indoles
Victoria V. Lipson,*a Sergey M. Desenkob and Oleg V. Shishkinb
a V. Ya. Danilevsky Institute of Endocrine Pathology Problems, 61002 Kharkov, Ukraine. E-mail: lipson@ukr.net
b STC ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, 61001 Kharkov, Ukraine.
E-mail: desenko@isc.kharkov.com
DOI: 10.1070/MC2006v016n05ABEH002361
6-Hydroxyimino-6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines are converted into isomeric 1,2,4-triazolo[1,5-a]pyrimido[5,4-b]-
and -[5,6-b]indoles in polyphosphoric acid or under exposure to para-nitrobenzoyl chloride in pyridine.
Azaheterocyclic hydroxyimino derivatives undergo O-benzoyla-
tion1 under acylation by para-nitrobenzoyl chloride in pyridine
and polyphosphoric acid (PPA), as a result of Beckmann rear-
rangement, form, as a rule, amides.2–4 The aim of this study is
to elucidate the structure of products obtained through the
interaction of 5,7-disubstituted 6-hydroxyimino-6,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidines 2a–c with para-nitrobenzoyl
chloride and PPA.
same products were separated under the heating of initial sub-
stances 2a–c in PPA,§ which allowed us to make a conclusion
that the para-nitrobenzoyl fragment was absent in their structure.
The presumption on the possible formation of Beckmann
rearrangement products was rejected on the basis of the elemental
†
2a: yield 72%, mp 244 °C (decomp.). 1H NMR (300 MHz, [2H6]DMSO)
d: 13.16 (s, 1H), 7.90 (s, 1H), 7.28–7.17 (m, 5H), 6.56 (s, 1H), 2.53 (s,
3H). IR (KBr, n/cm–1): 3168–2640, 1588. Found (%): C, 60.02; H, 4.58;
N, 29.08. Calc. for C12H11N5O (%): C, 59.75; H, 4.56; N, 29.05.
Crystal data for 2a: C12H11N5O, orthorhombic, space group Pbca,
a = 10.399(2), b = 10.345(2) and c = 22.060(4) Å, V = 2373.2(8) Å3,
dcalc = 1.350 g cm–3, Z = 8, m(MoKα) = 0.093 mm–1. Data were measured
on an Enraf-Nonius CAD-4 diffractometer (T = 293 K, graphite-mono-
chromated MoKα radiation, q/2q scan, 2qmax = 60°). The structure was
solved by direct method using the SHELXTL PLUS program package.
Refinement against F2 in an anisotropic approximation (isotropic for the
hydrogen atoms) by a full matrix least-squares method for 2698 reflec-
tions was carried out to wR2 = 0.143 [207 parameters, R1 = 0.054 for
1563 reflections with F > 4s(F), S = 1.04].
Oximes 2a–c were obtained by the nitrosation of 4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidines 1a–c with sodium nitrite in
glacial acetic acid.5 The physico-chemical characteristics of
compound 2b were identical to those reported earlier.5 The
structures of substances 2a,c were established by spectroscopic
methods and, for oxime 2a, by X-ray diffraction analysis.†
The dihydropyrimidine ring adopts a sofa conformation
similar to the 5,7-diphenyl derivative.6 The deviation of the C(5)
atom from the mean plane of remaining atoms coplanar in the
limits of 0.01 Å of the ring is 0.22 Å. The methyl and oxyimino
groups are turned slightly from each other [the C–C–C–N
torsion angle is 8.3(3)°]. The hydroxy group of oxime has an
anti-configuration with respect to the same bond [the C–C=N–O
torsion angle is 179.4(2)°]. The phenyl substituent adopts a
pseudoequatorial orientation [the C–N–C–C torsion angle is
106.2(2)°].7 In the crystal phase, molecules of 2a form planar
networks, which are perpendicular to the crystallographic direction
(001), due to intermolecular hydrogen bonds O(1)–H(1O)···N(2)'
(0.5 – x, –0.5 + y, z) (H···N 1.81 Å, O–H···N 171.2°), C(1)–
H(1)···N(4)' (1.5 – x, 0.5 + y, z) (H···N 2.51 Å, C–H···N 148°).
Compounds 3a–c, 4b,c were obtained under the acylation of
oximes 2a–c by para-nitrobenzoyl chloride in pyridine.‡ The
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference number 299598. For details, see ‘Notice to Authors’,
Mendeleev Commun., Issue 1, 2006.
2c: yield 56%, mp 200 °C (decomp.). 1H NMR (300 MHz, [2H6]DMSO)
d: 13.52 (s, 1H), 7.66 (s, 1H), 7.93–7.20 (m, 9H), 6.86 (s, 1H). IR (KBr,
n/cm–1): 3100–2500, 1544. Found (%): C, 60.36; H, 3.53; N, 20.72; Cl,
10.49. Calc. for C17H12N5ClO (%): C, 60.44; H, 3.56; N, 20.74; Cl, 10.52.
280 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(5), 280–282
C6H4R1
C6H4R1
C(10)
C(9)
C(11)
C(12)
7
1
NOH
NaNO2/AcOH
N
N
N
N
6
2
5
N
N
R
N
N
4
R
C(8)
N(2)
3
H
C(7)
C(5)
1a–c
O2N
2a–c
O(1)
N(1)
C(1)
C6H4R1
N
O
O
, Py
Cl
N(5)
C(4)
N
N
C(3)
O
N(3)
C(2)
N(4)
2a–c
N
N
R
NO2
C(6)
R1
8
9
Figure 1 Molecular structure of 2a. Non-hydrogen atoms are displayed
as thermal ellipsoids with 30% probability. Selected bond lengths and
angles: C(2)–N(4) 1.377(3) Å, C(3)–C(4) 1.470(3) Å, C(4)–N(5) 1.291(2) Å,
N(5)–O(1) 1.371(2) Å, C(4)–N(5)–O(1) 112.5(2)°.
7
10
C6H4R1
9
10
1
NH
1
NH
6
N
N
N
N
PPA
8
+
2a–c
identical, but these substances differed in melting points. All of
these results testify to the isomeric structure of compounds 3b,c
and 4b,c.
2
2
5
7
N
N
R
N
N
4
3
3
4
5
6
3a–c
4b,c
The 1H NMR spectra of compound 3a contain a methyl group
singlet, a broad singlet due to the NH proton at d 11.99 ppm,
which disappears after exchange for deuterium, and a signal of
the C(2)H proton (d 8.61 ppm) is displaced to the weak field
in comparison with the last one in the spectra of compound
2a (d 7.90 ppm). Additionally, resonance of the CH proton of
the pyrimidine ring is absent in the spectra of 3a, but the most
characteristic is the split of aromatic nucleus signals. These
protons are exhibited by a doublet and two multiplets with
integral intensities for 1, 2 and 1 proton, respectively. On the
basis of these data, compound 3a was characterised as 5-methyl-
[1,2,4]triazolo[1,5-a]pyrimido[5,6-b]indole.
Ar
O
NH
R
N
N
a R = Me, R1 = H
b R = Ph, R1 = H
N
N
c R = Ph, R1 = 3-Cl
analysis and mass-spectrometric data, which testified that the
molecular mass in compounds 3a–c, 4b,c reduced by 18 units
in comparison with initial oximes 2a–c. Note that the spectra of
3b, 4b and 3c, 4c are identical. At the first stage of fragmenta-
tion, these compounds lose HCN from the indole fragment. The
elemental analysis data for products 3b, 4b and 3c, 4c were also
The 1H NMR spectra of 3b,c and 4b,c have differences in the
field of aromatic and NH proton resonances. Signals of aryl
protons in compounds 3b,c appeared in a broader range of d
than in the spectra of isomers 4b,c, which testifies to a more
planar structure of these substances. We connect this with the
triazole ring influence on the proton resonance of the C6H4R1
fragment. The difference in the anisotropic influence of the
C6H4R1 substituent appears in the upfield shift of the NH proton
in the spectra of isomer 4 in comparison with 3. This substituent in
compounds 4b,c is located outside the heterocyclic scaffold due
to the triazole ring influence and has a shielding effect on the NH
group. In isomers 3b,c, the phenyl ring is located in the triazolo-
pyrimidine plane and has a disshielding effect on the NH proton.
Aromatic proton signal analysis in the spectra of 3c allows
us to determine the location of the R1 substituent in the indole
fragment. The proton resonance of this unit appears as a singlet,
with an integral intensity for 1H, and as a multiplet for 2H,
which complies with the para-position of the chloride atom
toward the NH group. The experimental data allow us to charac-
terise compounds 3 and 4 as 5-phenyl[1,2,4]triazolo[1,5-a]-
pyrimido[5,6-b]- and 10-phenyl[1,2,4]triazolo[1,5-a]pyrimido-
[5,4-b]indole, respectively.
‡
A mixture of oxime 2a (0.002 mol, 0.48 g) and para-nitrobenzoyl
chloride (0.0025 mol, 0.46 g) in 3 ml of dry pyridine was refluxed for
2 h. After cooling, a solution of HCl (1:1) was added to the reaction mix-
ture, the precipitate was filtered off and crystallised from propan-2-ol. At
first, 0.44 g of para-nitrobenzoic acid (mp 239–241 °C, lit.,9 mp 241 °C)
was obtained, then 0.12 g of 3a, 27% yield, was filtered. Compounds
3b,c, 4b,c were synthesised in a similar way with yields of 17, 20, 12
and 14%, respectively.
§
Oxime 2a (0.002 mol, 0.48 g) in 2 ml of polyphosphoric acid was
boiled for 1 h. After cooling, the reaction mixture was neutralised, the
precipitate of compound 3a was filtered off and crystallised from
propan-2-ol, yield 39%. Compounds 3b,c, 4b,c were synthesised in a
similar manner with yields of 21, 23, 17 and 20%, respectively.
3a: mp 325 °C (decomp.). 1H NMR (300 MHz, [2H6]DMSO) d: 11.99
(s, 1H), 8.61 (s, 1H), 8.38 (d, 1H), 7.76 (m, 2H), 7.43 (m, 1H), 3.06 (s,
3H). IR (KBr, n/cm–1): 3068, 1628, 1560, 1492, 1384, 1348. EI MS, m/z
(%): 223 (M+, 100), 196 (10), 181 (25), 169 (20), 155 (30), 143 (15), 129
(45), 103 (40), 77 (35). Found (%): C, 64.59; H, 4.06; N, 31.41. Calc. for
C12H9N5 (%): C, 64.57; H, 4.04; N, 31.39.
1
3b: mp 330 °C (decomp.). H NMR (300 MHz, [2H6]DMSO) d: 12.29
(s, 1H), 8.79 (s, 1H), 8.46 (d, 1H), 8.19–8.14 (m, 2H), 7.79–7.66 (m,
5H), 7.48–7.41 (m, 1H). IR (KBr, n/cm–1): 3244, 1628, 1604, 1556, 1480,
1364. EI MS, m/z (%): 285 (M+, 100), 258 (20), 129 (12), 103 (28), 77
(25). Found (%): C, 71.57; H, 3.87; N, 24.54. Calc. for C17H11N5 (%):
C, 71.58; H, 3.86; N, 24.56.
3c: mp > 340 °C (decomp.). 1H NMR (300 MHz, [2H6]DMSO) d: 12.39
(s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.14 (m, 2H), 7.83–7.50 (m, 5H).
IR (KBr, n/cm–1): 3212, 1636, 1604, 1548, 1484, 1452, 1376. EI MS, m/z
(%): 319 (M+, 100), 292 (14), 215 (10), 164 (17), 137 (21). Found (%):
C, 63.83; H, 3.12; N, 21.88; Cl, 11.08. Calc. for C17H10N5Cl (%): C,
63.85; H, 3.13; N, 21.91; Cl, 11.11.
C6H4R1
NOH
C6H4R1
NHOH
H+
N
N
N
N
R
N
R
4b: mp 276 °C (decomp.). 1H NMR (300 MHz, [2H6]DMSO) d: 11.62 (s,
1H), 8.80 (s, 1H), 8.51 (m, 1H), 8.01 (m, 2H), 7.79–7.62 (m, 6H). IR (KBr,
n/cm–1): 3312, 1632, 1604, 1560, 1476, 1346. EI MS, m/z (%): 285 (M+,
100), 258 (24), 129 (18), 103 (21), 77 (29). Found (%): C, 71.55; H, 3.88;
N, 24.57. Calc. for C17H11N51(%): C, 71.58; H, 3.86; N, 24.56.
4c: mp 315 °C (decomp.). H NMR (300 MHz, [2H6]DMSO) d: 10.66
(s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.56–7.52 (m, 3H), 7.50–7.35 (m, 5H).
IR (KBr, n/cm–1): 3296, 1630, 1604, 1562, 1478, 1354. EI MS, m/z (%):
319 (M+, 100), 292 (17), 215 (14), 164 (15), 137 (27). Found (%): C,
63.84; H, 3.11; N, 21.93; Cl, 11.13. Calc. for C17H10N5Cl (%): C, 63.85;
H, 3.13; N, 21.91; Cl, 11.11.
R1
C6H4R1
N
H
OH2
NH
H+
– H2O
3 + 4
N
R
N
Mendeleev Commun. 2006 281

Mendeleev Commun., 2006, 16(5), 280–282
4 Y. Tamura and Y. Kita, Jap. Pat., 7659873, C07D, 1977 (Chem. Abstr.,
Thus, 6-hydroxyimino-5-methyl-7-phenyl-6,7-dihydro-1,2,4-
1977, 86, 72460).
triazolo[1,5-a]pyrimidine undergoes dehydration into 5-methyl-
[1,2,4]triazolo[1,5-a]pyrimido[5,6-b]indole on heating with para-
nitrobenzoyl chloride in pyridine or PPA. However, 5,7-diaryl-
substituted oximes give mixtures of isomeric 5-aryl[1,2,4]tri-
azolo[1,5-a]pyrimido[5,6-b]- and 10-phenyl[1,2,4]triazolo[1,5-a]-
pyrimido[5,4-b]indoles under the same conditions. The identity
of the products obtained with the participation of different reagents
testifies to the fact that para-nitrobenzoyl chloride appears in
this case as a source of the acidic medium in which, probably, a
nitrenium cation forms.8 As a result of the successful intra-
molecular electrophilic attack by this cation of the aryl rings,
the isomeric triazolopyrimidoindoles are formed.
5 S. M. Desenko, V. D. Orlov and V. V. Lipson, Khim. Geterotsikl. Soedin.,
1990, 1638 [Chem. Heterocycl. Compd. (Engl. Transl.), 1990, 26, 1362].
6 O. V. Shishkin, S. V. Lindeman, Yu. T. Struchkov, S. M. Desenko,
V. V. Lipson and V. D. Orlov, Kristallografiya, 1993, 38, 275 (Russ.
Crystallography, 1993, 38, 280).
7 Yu. V. Zefirov and P. M. Zorky, Usp. Khim., 1989, 58, 713 (Russ. Chem.
Rev., 1989, 58, 421).
8 J. C. Fishbein and R. A. McClelland, J. Am. Chem. Soc., 1987, 109,
2824.
9 CRC Handbook of Chemistry and Physics, ed. D. R. Lide, CRC Press,
London, 1994, pp. 3–75.
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Received: 23rd March 2006; Com. 06/2706
282 Mendeleev Commun. 2006