Formylation of 4,7-dihydro-1,2,4-triazolo[1,5-a ]pyrimidines using vilsmeier-haack conditions

Article abstract of DOI:10.1002/jhet.875

Formylation of 5-methyl-7-phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidine 1a using Vilsmeier-Haack conditions yields 5-methyl-7-phenyl-4,7- dihydro-1,2,4-triazolo[1,5-a]pyrimidin-6-ylcarbaldehyde 3a. 5,7-Diaryl-4,7- dihydro-1,2,4-triazolo[1,5-a]pyrimidines 1b,c in this reaction apart from formylation undergo recyclization into 5-aryl-1,2,4-triazolo[1,5-a]pyrimidin-6- ylmethane derivatives 4b,c, 5b,c, and 6. The structure of the synthesized compounds was determined on the basis of NMR, IR, and MS spectroscopic data and confirmed by the X-ray analysis of the 6-(ethoxy-phenyl-methyl)-5-phenyl-[1,2,4] triazolo[1,5-a]pyrimidine 6, 5-phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[1,5-a] pyrimidine 11, and 7-phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[4,3-a]pyrimidine 12.

Full text of DOI:10.1002/jhet.875

September 2012
Formylation of 4,7-Dihydro-1,2,4-triazolo[1,5-a]pyrimidines
Using Vilsmeier–Haack Conditions
1019
a
a
Victoria V. Lipson,a,b Nataliya V. Svetlichnaya, Victoria V. Borodina,
Maria G. Shirobokova,a Sergey M. Desenko,c Vladimir I. Musatov,c
Svetlana V. Shishkina,c Oleg V. Shishkin,c and Roman I. Zubatyukc
*
aAntidiabetic Drug Laboratory of Medicinal Chemistry Department, State Institution, “V.Ya.
Danilevsky Institute for Endocrine Pathology Problems” of Academy of Medical Sciences of
Ukraine, Kharkov 61002, Ukraine
bDepartment of Chemistry, V.N. Karazin Kharkov National University, Kharkov 61077, Ukraine
cDivision of Functional Materials Chemistry, State Scientific Institution, “Institute for Single Crystals”
of National Academy of Sciences of Ukraine, Kharkov 61001, Ukraine
*
E-mail: lipson@ukr.net
Received December 9, 2010
DOI 10.1002/jhet.875
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
Formylation of 5-methyl-7-phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine 1a using Vilsmeier–
Haack conditions yields 5-methyl-7-phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidin-6-ylcarbaldehyde
3a. 5,7-Diaryl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines 1b,c in this reaction apart from formylation
undergo recyclization into 5-aryl-1,2,4-triazolo[1,5-a]pyrimidin-6-ylmethane derivatives 4b,c, 5b,c, and
6. The structure of the synthesized compounds was determined on the basis of NMR, IR, and MS
spectroscopic data and confirmed by the X-ray analysis of the 6-(ethoxy-phenyl-methyl)-5-phenyl-
[1,2,4]triazolo[1,5-a]pyrimidine 6, 5-phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine 11, and
7-phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[4,3-a]pyrimidine 12.
J. Heterocyclic Chem., 49, 1019 (2012).
INTRODUCTION
presence of sodium ethoxide [7, 8]. The carbon atom C-6
also became the place of electrophilic attack in the oxi-
dation reaction by air oxygen in basic medium or under
nitrosation by sodium nitrite in glacial acetic acid
[5,6,9]. We used some of the obtained products as start-
ing materials in the synthesis of novel heterocyclic sys-
tems [7–9]. Therefore, the functionalization of partially
reduced pyrimidine ring opens wide opportunities for
the synthesis of novel compounds on the basic of a
dihydro-1,2,4-triazolo[1,5-a]pyrimidine scaffold.
Dihydro-1,2,4-triazolo[1,5-a]pyrimidines are of inter-
est not only as drug-like molecules and objects for phar-
macological trials, for example, as analogs of the well
known inotropic and antiplatelet agent trapidil [1–4] or
vasodilator bumepidil [1], but also as a convenient
model structures for the research in the area of the syn-
thetic chemistry of partially hydrogenated heterocycles.
Investigations of their chemical properties, molecular
structure, and imine–enamine tautomeric equilibrium
have been reported in previous years [1,5–9].
Aryl-substituted 4,7-dihydro-1,2,4-triazolo[1,5-a]pyri-
midines 1, which contain an enamine substructure —
NH—C(R1)¼CH—, represent ambident nucleophiles.
The nitrogen atom N-4 is their hard, and the carbon
atom C-6 is their soft center. In our previous investiga-
tion [5], we found that alkylation selectively took place
at the N-4 atom but not at the C-6 atom, when soft elec-
trophiles like CH3I or hard electrophiles like Me2SO4
were used. The opposite results were obtained when the
alkylation of compound 1a or 1b was performed using
carbonyl 1,3-bielectrophilic agents such as 1,3-diary-
lpropen-1-ones or Mannich base hydrochlorides in the
In this study, we aimed to examine the direction of
the electrophilic attack in dihydropyrimidine ring of
aryl-substituted 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimi-
dines 1a–c in Vilsmeier–Haack reaction.
RESULTS AND DISCUSSION
It was found that 5-methyl-7-phenyl-4,7-dihydro-1,2,4-
triazolo[1,5-a]pyrimidine 1a undergoes reaction with
small excess of POCl3 in DMF for a 3 h period under
condition of steam bath and afforded 6-carbaldehyde 3a
(Scheme 1) with high yield (see “Experimental” sec-
tion). The reaction product was easily isolated from ice
© 2012 HeteroCorporation

1020
V. V. Lipson, N. V. Svetlichnaya, V. V. Borodina, M. G. Shirobokova, S. M. Desenko,
V. I. Musatov, S. V. Shishkina, O. V. Shishkin, and R. I. Zubatyuk
Vol 49
Scheme 1. 1–5: a, R=Me; b, R=Ph; c, R=C6H4-4Cl; 5: R1=Me; 6: R=Ph, R1=Et.
water and purified by crystallization from methanol.
However, in the case of formylation 5,7-diaryl deriva-
tives 1b,c in the above-mentioned reaction conditions, we
had obtained complicated mixture of products from
which compounds 3b,c, 4b,c, and 5b,c or 6 were crystal-
lized. Yields of 6-carbaldehydes 3b,c were low. In the
reaction mixture, we also identified alcohols 4b,c and
alkoxy compounds 5b,c or 6. Compounds 5b,c were
formed in the case of decomposition of the reaction mix-
ture by H2O/MeOH and compound 6 obtained when
H2O/EtOH were used for this purpose. However, in H2O/
i-PrOH medium, formation of alkoxy derivatives was not
observed. In these conditions, only 6-carbaldehydes 3b,c
and alcohols 4b,c were detected. Products of the nitrogen
atom N-4 formylation 7 have not been fixed in any case.
It should be noted that formation of 3b, 4b, and 8–10
compounds mixture also observed in the case utilization
solutions of amines in 2-propanole for the decomposition
of intermediate 2b (Scheme 2). Piperidine, 4-methoxy-
phenylamine, and benzylamine were used as amine com-
ponents in these reactions. The compounds 3b, 4b, and
8–10 were separated by crystallization from 2-propanole.
In our opinion, key role in the formation of alcohols
4b,c, alkoxy 5b,c, 6, and amino-substituted derivatives
8–10 belongs to the intermediates 2. We found that 6-carbal-
dehydes 3a–c did not afford compounds 5 and 6 in acidic
methanol or ethanol solution under long lasting refluxing.
Hydroxy 4b,c, alkoxy 5b,c, 6, and amino derivatives
8–10 probably formed in reaction mixture as a result of
intramolecular rearrangement that accompanied decom-
position of the intermediate products 2 under the action of
H2O and/or alcohol (amine). Under these conditions dihy-
dropyrimidine ring opened and further cyclization took
place with participation of the carbonyl electrophilic center
and accompanied by heteroaromatization.
To prove this reaction mechanism, we have performed
the formylation of 5,7-diphenyl-7-methyl-4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidine 1d by POCl3–DMF mix-
ture. In this case, the CH3 group played the role of the
“marker.” As a result (Scheme 3), we have obtained
two isomers 11 and 12. In this experiment, 6-carbalde-
hyde, alkoxy derivatives, or alcohols have not been
obtained.
The structures of compounds 3a–c, 4b,c, 5b,c, and 6
were confirmed by 1H-, 13C-NMR, IR, mass-spectroscopic
data, and elemental analyses (see “Experimental” section).
In mass spectra of the aldehydes 3a–c obtained by EI
method, peaks corresponding to the molecular ions are
not the most intensive. At the first stage of fragmentation,
these compounds lose CO. Intense peaks (100%) appear
at m/z [M+–C6H5] fragments. In the IR spectra of com-
pounds 3a–c, broad absorption band for associated imino
group at 3416–2384 cm–1 and sharp absorption band for
stretching vibration of carbonyl group at 1652–1632 cm–1
Scheme 2. 8: R2+R3=-C5H10; 9: R2=C6H4-4-OCH3, R3=H; 10: R2=CH2-C6H5, R3=H.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Formylation of 4,7-Dihydro-1,2,4-triazolo[1,5-a]Pyrimidines
Using Vilsmeier–Haack Conditions
1021
Scheme 3
are most characteristic. The high resolution 1H-NMR
spectrum of the aldehyde 3a shows signals suggesting the
presence in their structure aryl ring and CH3 group, the
NH group (broad singlet at d 11.18, which disappears after
exchange for deuterium), the formyl proton (at d 9.71) and
two methine protons H-2 and H-7 (at d 7.67 and d 6.20
ppm), respectively. The spectra of the aldehydes 3b,c differ
from above-mentioned one only by the presence signals for
two aryl rings and absence of CH3 group signal. The
presence in the formyl derivatives 3a–c spectra singlets
of the NH and H-7 protons confirms that the electrophilic
substitution took place at C-6 reaction center and dihydro-
system of the pyrimidine ring in aldehydes 5a–c preserves.
The mass spectra of compounds 4b,c contain low-
intensity (10%) molecular ion peaks [M+] with
m/z 302 and 338/336, respectively. Intense peaks
appear with m/z 272 (100) for compound 4b and m/z
308/306 (32/100) for compound 4c. These radical ions
are generated by successive elimination of the CH2O
fragment from the starting molecules. In mass spectra of
the alkoxy derivatives 5b,c, 6 peaks corresponding to
the molecular ions are also low intensive (13%). At the first
stage of fragmentation these compounds lose alkyl group.
In the IR spectra of alcohols 4b,c broad absorption of
associated OH-group with maximum at 3192 and 3188
cm–1 correspondingly is noted. The IR spectra of alkoxy
compounds 5b,c and 6 unfortunately are low informative,
they contain levy of the bands, which are peculiar to
condensed heterocyclic systems with a few —C¼N—
besides of multiplets of aromatic protons, singlets of H-2
and H-7 protons, contained signals of —CH—O-Alk
fragment. The resonance of H-7 proton shifted downfield
by 3 ppm compared with H-7 signals in the spectra of the
aldehydes 3a–c.
The structures of 8–10 also were proved by spectral
methods. The mass spectrum of the piperidine derivative
8 contains molecular ion peak [M+] with m/z 369 (11) and
ion radical peaks 368 (44, M+–H), 292 (43, M+–C6H5),
285 (66, M+–NC5H10), 207 (100, M+–NC5H10–C6H5).
1
In the H-NMR, spectrum of the compound 8 observed
singlets of three methine protons and multiplets of phenyl
and piperidyl fragments. The spectrum of amine derivative
9 was analogous to such of alcohols 4 and exhibited the
resonance of NH and CH group as doublet correspondingly
at d 6.20 and d 5.63 ppm with J 7.5 Hz. After exchange
with deuterium doublet of the NH group disappeared and
CH signal converted into singlet. In the spectrum of
benzyl-substituted compound 10, resonance of NH group
was absented owing to proton exchange, but signal of the
CH fragment connected with this imino group exhibited
doublet at d 4.97 ppm with J 3.8 Hz.
The products 11 and 12 have the same element content
and molecular weight, but have different melting points
and spectral IR, NMR characteristics. In mass spectra, both
of the compounds 11 and 12 have low intensive molecular
ions’ peaks [M+] with m/z 298. Intense peaks (100%)
appear at m/z 221 [M+–C6H5] fragments.
In IR spectra of 11 and 12, absorption of carbonyl and
associated imino groups were absented. Their 1H-NMR
spectra differed by the chemical shifts of the methine
protons. Finally, the structures of compound 6 and isomeric
triazolo[1,5-a]—11 and—[3,4-a]pyrimidines 12 were estab-
lished by an X-ray crystal structure analysis. Figures 1–3
show a perspective view of these molecules.
1
bonds [10]. The H-NMR spectra of alcohols 4b,c exhibit
multiplets of aromatic protons, singlets of H-2 and H-7
protons, and two doublets of the —CH—OH fragment in
the downfield at d 5.93 (CH) and d 6.26 (OH) ppm with
J 4.8–4.6 Hz. The signal from OH group was identified
by deuterium exchange. The resonance of NH proton in
these spectra and in the spectra of alkoxy derivatives 5b,
c, 6 was absented. Spectra of the compounds 5b,c and 6
The molecular structures of the compound 6, 11, and 12
are very similar. The presence of two vicinal substituents in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1022
V. V. Lipson, N. V. Svetlichnaya, V. V. Borodina, M. G. Shirobokova, S. M. Desenko,
V. I. Musatov, S. V. Shishkina, O. V. Shishkin, and R. I. Zubatyuk
Vol 49
Figure 2. The molecular structure of the compound 11.
torsion angles are 101.9 (1)ꢀ and 103.9 (1)ꢀ, respec-
tively). The ethoxy group has almost sp-conformation
with respect to the C(3)—C(4) bond (the C(3)—C(4)—
C(12)—O(1) torsion angle is –19.5 (1)ꢀ) which is stabi-
lized additionally by the H(3)…O(1) attractive interac-
tion (2.28 Å) which cannot be considered as hydrogen
bond because of too sharp C—H…O angle (99ꢀ). The
ethyl group has ap-conformation relatively the C(4)—C(12)
bond and the C(19)—C(20) bond is antiperiplanar to the
C(12)—O(1) bond (the C(19)—O(1)—C(12)—C(4) and
C(12)—O(1)—C(19)—C(20) torsion angles are –167.1
(1)ꢀ and –169.9 (1)ꢀ, respectively).
Significant disturbance of the conjugation between tria-
zolopyrimidine fragment and p-systems of the substituents
is observed in the molecules 11 and 12 (the C(3)—C(4)—
C(12)—C(19) and C(4)—C(12)—C(13)—C(18) torsion
angles are –54.0 (4)ꢀ 11 50.8 (4)ꢀ 12 and –27.6 (4)ꢀ 11
–26.8 (4)ꢀ 12, respectively).
Figure 1. The molecular structure of the compound 6.
pyrimidine ring leads to appearance of some steric strain.
The repulsion between substituents is slightly weaker in
the molecule 6, where the C(12) atom is sp3-hybridized
as compared with molecules 11 and 12, where the C(12)
atom has sp2-hybridization. Steric strain manifests itself
in appearance of a number of shortened intramolecular
contacts namely the H(7)…H(12) 2.25 Å (the van der
Waals radii sum [11] is 2.34 Å), H(12)…C(7) 2.61 Å
(2.87 Å), H(18)…C(7) 2.84 Å (2.87 Å), C(12)…C(7) 3.22
Å (3.42 Å), and C(18)…C(6) 3.37 Å (3.42 Å) for the mol-
ecule 6, and the C(12)…C(7) 3.11 Å 11, 3.10 Å 12, C(13)
…C(6) 3.19 Å 11, 3.16 Å 12, C(13)…C(7) 3.35 11, 3.21
Å 12, C(18)…C(5) 3.33 Å 11, 3.34 Å 12, C(18)…C(6)
3.40 Å 11, 3.32 Å 12 (the van der Waals radii is 3.42 Å),
C(12)…H(7) 2.79 Å 11, 2.77 Å 12, H(18)…C(4) 2.65 Å
11, 2.66 Å 12, H(19a)…C(14) 2.71 Å 11, 2.70 Å 12, H
(19b)…C(3) 2.78 Å 11, 2.82 Å 12, H(14)…C(19) 2.72 Å
11 and 12, H(3)…C(19) 2.81 Å 11, and 12 (the van der
Waals radii is 2.87 Å), H(19a)…H(14) 2.30 Å 11, 2.27 Å
12 for the molecules 11 and 12. The repulsion between vic-
inal substituents leads also to the elongation of the C(4)—C
(5) (1.436 (1) Å 6, 1.446 (3) Å 11, 1.433 (3) Å 12) and C
(4)—C(12) (1.520 (1) Å 6, 1.493 (3) Å 11, 1.492 (3) Å
12) as compared with their mean values [12] 1.387 Å and
1.478 Å, respectively, and to the twisting of the C(4)—C
(5) bond in the molecules 6 and 12 (the C(12)—C(4)—C
(5)—C(6) torsion angle is –6.5 (1)ꢀ for 6 and –6.0 (4)ꢀ for
12). The phenyl substituent at the C(5) atom is noncoplanar
to the bicycle plane (the N(1)—C(5)—C(6)—C(11) torsion
angle is –49.3 (1)ꢀ 6, –46.9 (3)ꢀ 11, –50.8 (4)ꢀ 12).
CONCLUSION
Thus, 4,7-dihydro-5,7-diphenyl-1,2,4-triazolo[1,5-a]pyri-
midines using Vilsmeier–Haack conditions not only formed
The phenyl ring of the substituent at the C(4) atom in the
molecule 6 is almost orthogonal to the pyrimidine ring, and
it is turned relatively the C(4)—C(12) bond (the C(3)—
C(4)—C(12)—C(13) and C(4)—C(12)—C(13)—C(14)
Figure 3. The molecular structure of the compound 12.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Formylation of 4,7-Dihydro-1,2,4-triazolo[1,5-a]Pyrimidines
Using Vilsmeier–Haack Conditions
1023
MHz, DMSO-d6): d 11.5 (br s, 1H, NH), 9.06 (s, 1H, CH),
7.75 (s, 1H, CH), 6.35 (s, 1H, CH), 7.3–7.6 (m, 10H, phenyl);
MS: m/z (relative intensity, %): 302 (62), 274 (26), 247 (24), 232
(34), 225 (100), 207 (34), 189 (17), 129 (13), 77 (32); Anal.
Calcd. for C18H14N4O: C, 71.51; H, 4.67; N 18.53; Found: C,
71.54; H, 4.70; N 18.55.
6-carbaldehydes, but rearranged to alkoxy, hydroxyl
derivatives and/or vinyl-[1,2,4]triazolo[1,5-a]- or -[4,3-a]
pyrimidines.
EXPERIMENTAL
5-(4-Chlorophenyl)-7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-
a]pyrimidin-6-carbaldehyde (3c). This compound was obtained
in yield 31% as white crystals (methanol), mp 275–278ꢀC; IR
(KBr): 3404–2500 (NH, H-bond), 1652 (CO) cm–1; 1H-NMR
(300 MHz, DMSO-d6): d 11.5 (br s, 1H, NH), 9.06 (s, 1H,
CH), 7.74 (s, 1H, CH), 6.35 (s, 1H, CH), 7.7–7.6 (d.d, 4H,
J 8.2 Hz, Ar-H), 7.3 (m, 5H, phenyl); MS: m/z (relative
intensity, %): 338/336 (9/27), 310/308 (7/20), 282/280
(8/24), 268/266 (9/27), 261/259 (32/100), 243/241 (10/33),
233/231 (14/45), 189 (16); Anal. Calcd. for C18H13ClN4O:
C, 64.20; H, 3.89; N 16.64; Found: C, 64.22; H, 3.93;
N 16.67.
All melting points were measured using Koeffler melting point
apparatus and are uncorrected. IR spectra were taken on a
Specord M-82 spectrometer in KBr pellet. 1H-, 13C-NMR spectra
were recorded at Varian Mercury VX200 at 200 MHz (50 MHz
for 13C) and Bruker AM300 spectrometer at 300 MHz in
DMSO-d6, using TMS as an internal standard (chemical shifts
in parts per million). Mass spectra were taken on a Varian
1200L DIP; ionization mode: EI; electron energy 70 eV.
Elemental analyses were determined using a Perkin-Elmer 2400
instrument.
Starting dihydro-1,2,4-triazolo[1,5-a]pyrimidines 1a–d were
obtained by known methods [5,13]. All other chemicals are
commercially available.
Phenyl(5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methanol
(4b).
This compound was obtained in yield 21% as white
crystals (methanol), mp 211–213ꢀC; IR (KBr): 3192, 1624,
1504, 1492 cm–1; 1H-NMR (300 MHz, DMSO-d6): d 9.23
(s, 1H, CH), 8.67 (s, 1H, CH), 7.0–7.4 (m, 10H, phenyl), 6.27
(d, 1H, J 4.6 Hz, OH), 5.93 (d, 1H, J 4.6 Hz, CH); 13C-NMR
(50 MHz, DMSO-d6): d 69.43, 126.57, 126.93 (C-6), 127.03
(p-C-Ar), 127.68, 127.76, 128.14, 128.90 (p-C-Ar), 134.96
(C-7), 137.43, 142.29, 153.31 (C-3a), 156.19 (C-2), 163.52
(C-5); MS: m/z (relative intensity, %): 302 (54), 274 (11), 225
(11), 171 (12), 128 (10), 105 (30), 77 (100); Anal. Calcd. for
C18H14N4O: C, 71.51; H, 4.67; N 18.53; Found: C, 71.54; H,
4.68; N 18.55.
General procedure for the formylation of the 4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidines (3a–d).
For the preparation
of the compound 3a, a mixture of dihydrotriazolo[1,5-a]pyrimidine
1a (0.86 g, 3 mmol), POCl3 (0.32 mL, 3.5 mmol), and 3 mL DMF
was heated at the steam bath for 3 h. Then, reaction mixture
was stirred in ice water, neutralized by solution of the NaOH to
pH 6 and amorphous precipitate of the carbaldehyde 3a removed
by filtration, purified by recrystallization from a MeOH. In the case
of formylation compounds 3b,c at the analogous conditions
obtained amorphous precipitate refluxed in MeOH (10 mL) for
5 min and filtered insoluble compounds 3b,c. Then after cooling of
solution, crystals of the compounds 4b,c and 5b,c were formed
and separated consequently. Ethoxy derivative 6 was obtained
from EtOH. Compounds 11 and 12 were synthesized from
dihydrotriazolo[1,5-a]pyrimidine 3d by the same procedure and
were crystallized from 2-propanol.
[5-(4-Chlorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-
phenyl-methanol (4c).
yield 19% as white crystals (methanol), mp 212–215ꢀC; IR
(KBr): 3188, 1624, 1520, 1492 cm–1 1H-NMR (300 MHz,
This compound was obtained in
;
DMSO-d6): d 9.22 (s, 1H, CH), 8.68 (s, 1H, CH), 7.0–7.5
(m, 9H, Ar-H), 6.26 (d, 1H, J 4.8 Hz, OH), 5.93 (d, 1H, J
4.8 Hz, CH); MS: m/z (relative intensity, %): 338/336 (6/18),
308/306 (32/100), 281/279 (29/89), 243/241 (8/24), 231/229
(10/30), 225/223 (11/32), 216/214 (12/36), 189 (13); Anal.
Calcd. for C18H13ClN4O: C, 64.20; H, 3.89; N 16.64; Found:
C, 64.21; H, 3.88; N 16.65.
General procedure for the preparation amino derivatives
(8–10).
For the preparation of the compounds 8–10 the
dihydrotriazolo[1,5-a]pyrimidine 1b was formylated by above-
mentioned method and obtained amorphous precipitate refluxed
in 2-propanol (7 mL) with 3 mmol of the appropriate amine for
5 min and filtered insoluble compound 3b. Then, after cooling
of solution, crystals of the compounds 4b and 8 (or 9, 10) were
formed and separated consequently.
6-(Methoxy(phenyl)methyl)-5-phenyl-[1,2,4]triazolo[1,5-
a]pyrimidine (5b).
This compound was obtained in yield
35% as white crystals (methanol), mp 144–146ꢀC; IR (KBr):
1
5-Methyl-7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-
3092, 2940, 2828, 1624, 1520, 1492, 1296 cm–1. H-NMR (300
6-carbaldehyde (3a).
This compound was obtained in yield
MHz, DMSO-d6): d 9.20 (s, 1H, CH), 8.68 (s, 1H, CH), 6.9–7.5
(m, 10H, phenyl), 5.53 (s, 1H, CH), 3.27 (s, 3H, OMe); MS: m/z
(relative intensity, %): 316 (28), 301 (10), 284 (34), 207 (10),
180 (12), 130 (15), 121 (37), 115 (19), 105 (27), 77 (100); Anal.
Calcd. for C19H16N4O: C, 72.14; H, 5.10; N 17.71; Found: C,
72.12; H, 5.12; N 17.73.
5-(4-Chlorophenyl)-6-(methoxy-phenyl-methyl)-[1,2,4]triazolo
[1,5-a]pyrimidine (5c). This compound was obtained in yield
42% as white crystals (methanol), mp 179–182ꢀC; (KBr): 3088,
2940, 2832, 1624, 1596, 1520, 1488, 1308 cm–1. 1H-NMR
(300 MHz, DMSO-d6): d 9.21 (s, 1H, CH), 8.69 (s, 1H, CH),
7.1–7.5 (m, 9H, Ar-H), 5.53 (s, 1H, CH), 3.36 (s, 3H, OMe);
MS: m/z (relative intensity, %): 352/350 (8/25), 337/335 (12/36),
243/241 (31/100), 230/228 (12/34), 216/214 (11/33), 205 (14);
Anal. Calcd. for C19H15ClN4O: C, 65.05; H, 4.31; N 15.97;
Found: C, 65.07; H, 4.34; N 16.01.
83% as white needles (methanol), mp 292–295ꢀC; IR (KBr):
3316–2660 (NH, H-bond), 1648 (CO) cm–1; 1H-NMR: (300
MHz, DMSO-d6): d 11.2 (br s, 1H, NH), 9.71 (s, 1H, CH), 7.67
(s, 1H, CH), 6.20 (s, 1H, CH), 7.2–7.3 (m, 5H, phenyl), 2.45
(s, 3H, Me); 13C-NMR (50 MHz, DMSO-d6): d 56.12, 79.01,
127.00, 126.48 (C-6), 127.48, 127.67, 127.79, 127.89, 128.79
(p-C-Ar), 134.66 (C-7), 137.33, 142.21, 153.32 (C-3a), 156.15
(C-2), 163.84 (C-5); MS: m/z (relative intensity, %): 240 (88),
223 (14), 211 (33), 195 (25), 184 (18), 170 (26), 163 (100),
134 (14), 77 (25); Anal. Calcd. for C13H12N4O: C, 64.99; H,
5.03; N 23.32; Found: C, 65.01; H, 5.06; N 23.34.
4,7-Dihydro-5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidin-6-
carbaldehyde (3b).
30% as white crystals (methanol), mp >300ꢀC; IR (KBr):
3416–2736 (NH, H-bond), 1646 (CO) cm–1 1H-NMR (300
This compound was obtained in yield
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1024
V. V. Lipson, N. V. Svetlichnaya, V. V. Borodina, M. G. Shirobokova, S. M. Desenko,
V. I. Musatov, S. V. Shishkina, O. V. Shishkin, and R. I. Zubatyuk
Vol 49
Table 1
6-(Ethoxy-phenyl-methyl)-5-phenyl-[1,2,4]triazolo[1,5-a]
pyrimidine (6). This compound was obtained in yield 38%
The crystallographic data and experimental parameters for compounds
as white crystals (ethanol), mp 125–127ꢀC. IR (KBr): 2972,
6, 11, and 12.
2924, 1620, 1520, 1492, 1300 cm–1 1H-NMR (300 MHz,
.
Parameter
6
11
12
DMSO-d6): d 9.12 (s, 1H, CH), 8.67 (s, 1H, CH), 7.1–7.5
(m, 10H, phenyl), 5.65 (s, 1H, CH), 3.40 (q, 2H, CH2), 1.09
(t, 3H, Me); MS: m/z (relative intensity, %): 330 (13), 301
(100), 284 (10), 257 (12), 223 (30), 207 (73), 181 (12), 171
(11); Anal. Calcd. for C20H18N4O: C, 72.71; H, 5.49; N
16.96; Found: C, 72.74; H, 5.52; N 17.71.
Formula
Unit cell dimensions
A (Å)
C
20H18N4O
C19H14N4
C19H14N4
9.0403 (5)
9.9674 (7)
11.1218 (8)
107.936 (6)
107.401 (6)
104.184 (6)
844.7 (1)
293
9.823 (2)
19.861 (5)
8.274 (2)
90
106.61 (2)
90
6.994 (2)
28.25 (1)
8.283 (2)
90
112.04 (2)
90
b (Å)
C (Å)
α (ꢀ)
5-Phenyl-6-(phenyl-piperidin-1-yl-methyl)-[1,2,4]triazolo
β (ꢀ)
[1,5-a]pyrimidine (8).
yield 64% as yellow crystals (2-propanol), mp 183–186ꢀC;
IR (KBr): 2964, 2936, 2860, 2804, 1616, 1516, 1492 cm–1
This compound was obtained in
γ (ꢀ)
V (Å3)
1546.8 (6)
193
1516.6 (8)
193
.
1H-NMR (300 MHz, DMSO-d6): d 9.50 (s, 1H, CH), 8.75
(s, 1H, CH), 7.0–7.6 (m, 10H, phenyl), 4.72 (s, 1H, CH),
2.43–1.55 (m, 10H, (CH2)5); MS: m/z (relative intensity,
%): 369 (11), 368 (44), 292 (43), 285 (66), 207 (100), 180
(29), 174 (53), 153 (13), 140 (24), 115 (14), 91 (12), 77
(45); Anal. Calcd. for C23H23N5: C, 74.77; H, 6.27; N
18.95; Found: C, 74.79; H, 6.30; N 18.98.
T (K)
F(0 0 0)
Crystal system
Space group
Z
348
Triclinic
P1
624
624
Monoclinic Monoclinic
P21/c
4
0.079
1.281
50
P21/c
4
0.081
1.307
50
2
μ (mm–1
)
0.083
1.299
60
9904
Dcalc (g cm–3
2Θmax (grad)
Measured
reflections
Independent
reflections
Rint
)
(4-Methoxy-phenyl)-[phenyl-(5-phenyl-[1,2,4]triazolo[1,5-a]
2896
3121
pyrimidin-6-yl)-methyl]-amine (9).
This compound was
4902
2695
2674
obtained in yield 60% as yellow crystals (2-propanol), mp
95–97ꢀC; IR (KBr): 3252, 3060, 3048, 2972, 1624, 1508 cm–1;
1H-NMR (300 MHz, DMSO-d6): d 9.02 (s, 1H, CH), 8.70
(s, 1H, CH), 7.2–7.3 (m, 5H, phenyl), 7.5–7.5 (m, 5H,
phenyl), 6.5–6.7 (dd, 4H, J 7.8 Hz, Ar-H), 6.20 (d, 1H, J
7.5 Hz, NH), 5.63 (d, 1H, 7.5 Hz, CH), 3.6 (s, 3H, OMe);
13C-NMR (50 MHz, DMSO-d6): d 56.79, 55.09, 114.11,
114.52, 125.00 (C-6), 127.08 (p-C-Ar), 127.37, 127.83, 127.86,
128.09, 129.00 (p-C-Ar), 135.48 (C-7), 137.20, 140.48, 140.52,
153.29 (C-3a), 156.17 (C-2), 164.47 (C-5); MS: m/z (relative
intensity, %): 407 (40), 285 (27), 256 (15), 216 (15), 207
(100), 122 (26); Anal. Calcd. for C25H21N5O: C, 73.69; H,
5.19; N 17.19; Found: C, 73.72; H, 5.21; N 17.22.
0.014
2820
0.039
1320
0.040
1291
Reflections with F
> 4σ(F)
R1
wR2
0.036
0.085
0.049
0.123
0.055
0.103
S
0.833
0.911
0.979
CCDC
779,096
779,097
779,098
yellow crystals (2-propanol), mp 220–221ꢀC; IR (KBr): 3116,
1
3052, 1624, 1516, 1492 cm–1; H-NMR (300 MHz, DMSO-d6):
Benzyl-[phenyl-(5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl-)
methyl]-amine (10). This compound was obtained in yield 24%
as yellow crystals, mp 98ꢀC; IR (KBr): 3268, 3060, 1620,
1516, 1488 cm–1; 1H-NMR (300 MHz, DMSO-d6): d 9.48
(s, 1H, CH), 8.68 (s, 1H, CH), 7.0–7.5 (m, 15H, phenyl),
4.97 (d, 1H, J 3.6 Hz, CH), 3.62 (d, 2H, J 4.0 Hz, CH2);
MS: m/z (relative intensity, %): 391 (14), 390 (12), 314
(44), 312 (26), 300 (100), 285 (56), 207 (97), 202 (16), 196
(51), 189 (13), 180 (30), 153 (11), 104 (11), 91 (46); Anal.
Calcd. for C25H21N5: C, 76.70; H, 5.41; N 17.89; Found: C,
76.73; H, 5.43; N 17.91.
d 9.28 (s, 1H, CH), 9.04 (s, 1H, CH), 7.15–7.60 (m, 10H,
phenyl), 5.65 (s, 1H, CH), 5.90 (s, 1H, CH); MS: m/z (relative
intensity, %): 298 (21), 297 (29), 271 (12), 270 (17), 227 (18),
221 (100), 215 (24), 202 (15), 189 (12), 179 (31), 152 (16);
Anal. Calcd. for C19H14N4: C, 76.49; H, 4.73; N 18.78; Found:
C, 76.53; H, 4.76; N 18.82.
The X-ray diffraction study.
X-ray diffraction studies
were performed using an automatic “Xcalibur 3” diffractometer
(CCD detector, ω-scans) for the compound 6 and on the
“Siemens P3/PC” diffractometer (point detector, Θ/2Θ-scan) for
11 and 12 with graphite monochromated MoKα radiation. The
structures were solved by direct method using SHELXTL package
[14]. Crystallographic data and parameters of experiments are
listed in Table 1.
The positions of the hydrogen atoms were located from
electron density difference maps and refined by “riding”
model with Uiso = nUeq of the carrier atom (n = 1.5 for
methyl groups and n = 1.2 for other hydrogen atoms) for
structures 11 and 12. Hydrogen atoms in the structure 6
were refined in isotropic approximation. All nonhydrogen
atoms were refined using anisotropic approximation. The final
atomic coordinates and crystallographic data have been depos-
ited with the Cambridge Crystallographic Data Centre, 12
Union Road, CB2 1EZ, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk).
5-Phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine
(11).
This compound was obtained in yield 42% as light
yellow crystals (2-propanol), mp 160–162ꢀC; IR (KBr): 3048,
1620, 1516, 1488 cm–1; 1H-NMR (300 MHz, DMSO-d6): d
9.46 (s, 1H, CH), 8.76 (s, 1H, CH), 7.13–7.62 (m, 10H,
phenyl), 5.95 (s, 1H, CH), 5.71 (s, 1H, CH); 13C-NMR (50
MHz, DMSO-d6): d 118.87, 126.21, 123.80 (C-6), 127.41
(p-C-Ar), 127.30, 127.64, 128.29, 128.94 (p-C-Ar), 136.48
(C-7), 137.50, 138.43, 143.01, 153.89 (C-3a), 156.12 (C-2),
162.41 (C-5); MS: m/z (relative intensity, %): 298 (17), 297 (26),
271 (10), 270 (14), 227 (14), 221 (100), 215 (19), 202 (17), 189
(14), 179 (28), 152 (14); Anal. Calcd. for C19H14N4: C, 76.49; H,
4.73; N 18.78; Found: C, 76.52; H, 4.74; N 18.80.
7-Phenyl-6-(1-phenyl-vinyl)-[1,2,4]triazolo[4,3-a]pyrimidine
(12).
This compound was obtained in yield 37% as light
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Formylation of 4,7-Dihydro-1,2,4-triazolo[1,5-a]Pyrimidines
Using Vilsmeier–Haack Conditions
1025
[8] (a) Lipson, V. V.; Desenko, S. M.; Ignatenko, I. V.;
Shishkin, O. V.; Shishkina, S. V. Izv Akad Nauk Ser Khim 2006,
55, 335; (b) Lipson, V. V.; Desenko, S. M.; Ignatenko, I. V.; Shishkin,
O. V.; Shishkina, S. V. Russ Chem Bull Int Ed 2006, 55, 345.
[9] Lipson, V. V.; Desenko, S. M.; Shishkin, O. V. Medeleev
Commun 2006, 16, 280.
[10] Bellamy L. J. The Infrared Spectra of Complex Molecules;
Chapman & Hall: London, 1980; Vol. 2, 299 p.
[11] (a) Zefirov, Yu. V. Kristallografiya 1997, 42, 936; (b) Zefirov,
Yu. V. Crystallogr Rep 1997, 42, 865.
[12] Burgi, H.-B.; Dunitz, J. D. Structure Correlation; VCH:
Weinheim, 1994; Vol. b2, p 741.
[13] (a) Orlov, V. D.; Desenko, S. M.; Potekhin, K. A.;
Struchkov, Yu. T. Khim Geterotsikl Soedin 1988, 24, 229; (b) Orlov,
V. D.; Desenko, S. M.; Potekhin, K. A.; Struchkov, Yu. T. Chem
Heterocycl Compd (Engl Transl) 1988, 24, 192.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet