Direct (het)arylation of [1,2,4]triazolo[1,5-a]pyrimidines: Both eliminative and oxidative pathways

Article abstract of DOI:10.1016/j.tet.2017.07.042

(Hetero)arylation of [1,2,4]triazolo[1,5-a]pyrimidine through the direct nucleophilic C[sbnd]H functionalization of the C-7 and C-5 positions has been implemented. The regioselective addition of a (het)aryl magnesium bromide to C-7 of 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine, followed by eliminative aromatization of the intermediate σ^H-adducts, has afforded 7-(hetero)aryl-substituted [1,2,4]triazolo[1,5-a]pyrimidines (the S_N^H reaction, proceeding according to the “addition-elimination” scheme). A second treatment with a Grignard reagent has resulted in the C-5 σ^H-adducts, which have been oxidized while being N-magnesium salts into [1,2,4]triazolo[1,5-a]pyrimidines, bearing various combinations of (hetero)aromatic substituents at C-5 and C-7 (the S_N^H process, realizing via the “addition-oxidation” scheme). As a result of optical and electrochemical studies, the obtained compounds have proved to be promising luminescent dyes and push-pull systems.

Full text of DOI:10.1016/j.tet.2017.07.042

Accepted Manuscript
Direct (het)arylation of [1,2,4]triazolo[1,5-a]pyrimidines: Both eliminative and oxidative
pathways
Nikolay A. Rasputin, Nadezhda S. Demina, Roman A. Irgashev, Gennady L. Rusinov,
Oleg N. Chupakhin, Valery N. Charushin
PII:
S0040-4020(17)30784-6
10.1016/j.tet.2017.07.042
TET 28874
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 May 2017
Revised Date: 14 July 2017
Accepted Date: 24 July 2017
Please cite this article as: Rasputin NA, Demina NS, Irgashev RA, Rusinov GL, Chupakhin ON,
Charushin VN, Direct (het)arylation of [1,2,4]triazolo[1,5-a]pyrimidines: Both eliminative and oxidative
pathways, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.042.
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ACCEPTED MANUSCRIPT
Direct (het)arylation of [1,2,4]triazolo[1,5-a]pyrimidines: both eliminative and
oxidative pathways
Rasputin N.A., Demina N.S., Irgashev R.A., Rusinov G.L., Chupakhin O.N., and Charushin V.N.

ACCEPTED MANUSCRIPT
Direct (het)arylation of [1,2,4]triazolo[1,5-a]pyrimidines: both
eliminative and oxidative pathways
Nikolay A. Rasputin,a,* Nadezhda S. Demina,b Roman A. Irgashev,a,b
Gennady L. Rusinov,a,b Oleg N. Chupakhin,a,b and Valery N. Charushina,b
a
Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S. Kovalevskaya Str., 22,
Ekaterinburg, 620990, Russia;
b
Ural Federal University named after the First President of Russia B. N. Yeltsin, Mira St., 19, Ekaterinburg,
620002, Russia
*Corresponding author. Tel./fax: +7 343 369 30 58. E-mail address: nar@ios.uran.ru
Abstract
(Hetero)arylation of [1,2,4]triazolo[1,5-a]pyrimidine through the direct nucleophilic C–H
functionalization of the C-7 and C-5 positions has been implemented. The regioselective addition
of a (het)aryl magnesium bromide to C-7 of 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine, followed
by eliminative aromatization of the intermediate σH-adducts, has afforded 7-(hetero)aryl-
substituted [1,2,4]triazolo[1,5-a]-pyrimidines (the ꢀꢁꢂ reaction, proceeding according to the
“addition-elimination” scheme). A second treatment with a Grignard reagent has resulted in the
C-5 σH-adducts, which have been oxidized while being N-magnesium salts into
[1,2,4]triazolo[1,5-a]pyrimidines, bearing various combinations of (hetero)aromatic substituents
at C-5 and C-7 (the ꢀꢁꢂ process, realizing via the “addition-oxidation” scheme). As a result of
optical and electrochemical studies, the obtained compounds have proved to be promising
luminescent dyes and push-pull systems.
Keywords
[1,2,4]Triazolo[1,5-a]pyrimidine, (het)aryl magnesium bromide, direct (het)arylation,
Nucleophilic aromatic substitution of hydrogen (ꢀꢁꢂ)
1

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1. Introduction
[1,2,4]Triazolo[1,5-a]pyrimidines (TAPs) (Figure 1) have gained great attention from organic
chemists worldwide in recent years due to a wide range of applications, e.g., biological1 or even
mechanochromic2 ones. At the same time, the pyrimidine ring, having a highly π-deficient
character, is involved in many π-conjugated push-pull structures,3 which form the basis for new
materials for optical and optoelectronic applications. Pyrimidine-based push-pull molecules have
been used as OLED basic components,4 sensors,5 liquid crystals6 and dyes for organic solar
cells.7 In this context, azolo-annulated pyrimidines, including the TAP ring system, can also be
regarded as promising subunits for the design of novel push-pull structures.
Figure 1. [1,2,4]Triazolo[1,5-a]pyrimidine (TAP) structure
Generally, functional TAP derivatives are obtained either through annulation of a
[1,2,4]triazole fragment to a pyrimidine ring, or by condensation of 3-amino-[1,2,4]triazoles
with a variety of 1,3-dielectrophilic reagents, e.g., 1,3-dicarbonyl compounds and vinyl
ketones.8 The most common approach to 5,7-disubstituted-TAP synthesis is the reaction of 3-
amino-[1,2,4]triazoles with chalcones,9 however, this approach has a number of
shortcomings: long reaction times up to three weeks at ambient temperature, or harsh
reaction conditions, such as 120 °C for 24 hours, and a large percentage of various by-
products.10
On the other hand, substituted TAPs can be synthesized through structural modification of
the TAP core. Due to the electron-deficient character of TAP compounds, one main approach to
modify their structures is based on the nucleophilic displacement of halogen (Cl, Br or I) atoms
at the C-5 or C-7 position with N- , C- and O-nucleophiles.11 However, there are only a few
examples of the direct C-H functionalization of TAP.12 To the best of our knowledge, no
reports on the C-H functionalization of TAPs via nucleophilic aromatic substitution of
hydrogen (ꢀꢁꢂ),13 with the use of organomagnesium compounds as nucleophilic species are
available in the literature. In this paper we wish to present a fast and simple way for
(hetero)arylation of TAPs at the C-7 and C-5 positions using Grignard reagents.
2

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2. Results and discussion
2.1 Synthesis
Taking into account the profound tendency of azaaromatic triazolopyrimidines to undergo
nucleophilic additions, we have suggested using Grignard reagents for the direct
functionalization of TAPs. The reaction of the parent TAP 1 with phenylmagnesium bromide
proceeded smoothly in THF, but resulted in the formation of two isomeric adducts at both the C-
7 and C-5 positions in the ratio 1.5:1, respectively, according to 1H NMR spectroscopy and GC-
MS data (Scheme 1).
Scheme 1. Unselective addition of phenylmagnesium bromide to TAP 1.
We have failed to achieve the regioselectivity of phenylmagnesium bromide addition under
various reaction conditions. Therefore, we have chosen 6-bromo-[1,2,4]triazolo[1,5-
a]pyrimidine 4 (6-bromo-TAP) for further research, assuming that the C-6 bromine will increase
the electrophilicity of the C-7 position. The increase is indirectly indicated by chemical shifts of
1
H-7 in H NMR spectra of TAP (9.43 ppm)14 and 6-bromo-TAP (9.91 ppm).15 In addition, this
bromo-compound can easily be obtained by the direct bromination of TAP 1.16
Indeed, 6-bromo-TAP 4 has reacted with Grignard reagents selectively at the C-7 position giving
13
σH-adducts 5a-d (Scheme 2), as evidenced by 1H, C NMR spectroscopy and X-ray diffraction
analysis (Figure 2). However, the observed regioselectivity was only reached at – 78 °C.
Scheme 2. Selective addition of Grignard reagents at C-7 of TAP 4 followed by aromatization of the C-7
adducts.
3

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Figure 2. ORTEP diagram for the X-ray structure of 5c.
Thermal ellipsoids of 50% probability are shown.
The σH-adducts 5a-d transformed into aromatic compounds 6a-d on treatment with triethylamine
(TEA) (Scheme 2). A plausible mechanism involves hydrogen transfer from the N-4 position to
C-6 by the imino-enamine tautomerism followed by 1,2-elemination of HBr (Scheme 3). Yields
of compounds 5 and 6 are shown in Table 1.
Scheme 3. A possible mechanism for aromatization of σH-adducts 5 by action of TEA.
Table 1. Yields of σH-adducts 5 and ꢀꢁꢂ product 6 (Scheme 2).
R1
phenyl
Entry
5a
5b
5c
5d
Yield (%)
Entry
6a
6b
6c
6d
Yield (%)
89
74
81
87
71
82
85
77
4-methoxyphenyl
2-thienyl
4-(N,N-DMAP)a
a 4-(N,N-DMAP) is 4-(N,N-dimethylaminophenyl)
Compounds 6a-d are susceptible to attack by a second Grignard reagent. The addition of
organomagnesium nucleophiles to C-5 has afforded the σH-adducts, which have a tendency to
undergo partial oxidation during the work-up and isolation procedure under air conditions. The
reaction has resulted in the formation of a mixture of intermediate 4,5-dihydro-5,7-disubstituted-
TAPs and aromatic products 8.
We have suggested that the intermediate σH-adducts aromatize by the action of atmosphere
oxygen in the form of the N-magnesium salts. To substantiate this assumption, we have carried
4

ACCEPTED MANUSCRIPT
out experiments on the oxidation of N-magnesium salts with pure oxygen, and this hypothesis
has proved to be correct (Scheme 4). The reaction appears to involve the formation of
intermediate complexes of N-magnesium salts of dihydro-TAP with oxygen, which transform
easily into aromatic compounds 8 (Scheme 5). The oxidation with pure oxygen has enabled us to
obtain compounds 8 without any traces of dihydro-TAPs as impurities. Yields are shown in
Table 2.
Scheme 4. One pot (het)arylation of TAP at the C-5 position using Grignard reagents.
Scheme 5. A possible mechanism for oxidation of N-magnesium salts of σH-adducts with pure oxygen.
Table 2.Yields of compounds resulting from the second nucleophilic addition of a Grignard reagent followed by
aromatization with pure oxygen (Scheme 4).
R1
phenyl
phenyl
phenyl
R2
phenyl
4-methoxyphenyl
2-thienyl
4-(N,N-DMAP)
phenyl
4-methoxyphenyl
2-thienyl
4-(N,N-DMAP)
phenyl
4-methoxyphenyl
2-thienyl
Entry
8aa
8ab
8ac
8ad
8ba
8bb
8bc
8bd
8ca
8cb
8cc
Yield (%)
86
64
53
70
65
67
41
51
64
phenyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
2-thienyl
2-thienyl
2-thienyl
85
73
2-thienyl
4-(N,N-DMAP)
phenyl
4-(N,N-DMAP)
2-thienyl
8cd
8da
8db
8dc
8dd
60
58
49
46
4-(N,N-DMAP)
4-(N,N-DMAP)
4-(N,N-DMAP)
4-(N,N-DMAP)
4-(N,N-DMAP)
40
We have also used a similar approach to obtain pure 4,5-dihydro-TAP compounds 7. The
suggested method has involved neutralization of the N-magnesium salts through treatment of the
reaction mixture with an aqueous solution of NH4Cl under an inert atmosphere (IA) (Scheme 6).
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By using this procedure, we have succeeded in obtaining intermediates 7aa, 7ac, 7ad, 7ca, 7cc,
7cd (Figure 3). The electron-donating character of the substituent R1 plays a crucial role in
stability of the σH-adducts 7. Thus, we have been able to obtain and isolate only 7bc in the series
of 4,5-dihydro compounds, bearing such electron-donating substituents as 4-methoxyphenyl and
4-(N,N-dimethylaminophenyl groups at C-7.
Scheme 6. Consecutive C-H Functionalization of TAP at C-5 by using Grignard reagents.
We have attempted to aromatize 4,5-dihydro derivatives 7 by using various oxidizing agents.
However, the use of Pb(OAc)4, AgNO3, or KMnO4 has resulted in rather complicated reaction
mixtures, so we have failed to isolate any product. Neither K3[Fe(CN)6], chloranil, nor DDQ
reacted successfully with 7, giving only starting materials. Treatment of 7 with perhydrol has
given a significant amount of 6-hydroxylated products 8 according to GC-MS analysis. There are
some literature examples of similar oxidations of adducts by the action of Br2 or NBS, but this
approach can not be applied in the case of 4-(N,N-dimethylaminophenyl) derivatives.17
Compound 7cd
6

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Compound 8cd
Figure 3. The X-ray structure of 4,5-dihydro derivative 7cd and its aromatic form 8cd. Thermal ellipsoids of 50%
probability are shown.
Finally, we have achieved good results in obtaining compounds 8 by using the hypervalent
iodine compound - phenyliodonium diacetate (PIDA) (Scheme 6). In addition, the mixtures of
dihydro-TAPs and aromatic compounds mentioned above have been treated with PIDA to afford
pure aromatic compounds 8. Yields are presented in Table 3. The oxidation procedure with
PIDA can be regarded as an alternative synthetic route for the preparation of the target products
8.
Table 3.Yields of adducts derived from the second addition of Grignard reagent followed by PIDA aromatization
(Scheme 6).
R1
R2
Entry Yield (%) Entry Yield (%)
phenyl
phenyl
phenyl
phenyl
phenyl
4-methoxyphenyl 7ab
2-thienyl
4-(N,N-DMAP)
7aa
71
-
75
55
-
-
62
-
46
-
90
67
-
8aa 79
8aba 56
7ac
7ad
7ba
8ac
46
8ad 61
8baa 58
8bba 59
8bc 43
8bda 47
4-methoxyphenyl phenyl
4-methoxyphenyl 4-methoxyphenyl 7bb
4-methoxyphenyl 2-thienyl
4-methoxyphenyl 4-(N,N-DMAP)
2-thienyl
2-thienyl
2-thienyl
2-thienyl
4-(N,N-DMAP) phenyl
4-(N,N-DMAP) 4-methoxyphenyl 7db
4-(N,N-DMAP) 2-thienyl
4-(N,N-DMAP) 4-(N,N-DMAP)
a Yields are based on compounds 6.
7bc
7bd
7ca
phenyl
4-methoxyphenyl 7cb
2-thienyl
4-(N,N-DMAP)
8ca
8cba 78
8cc
32
56
7cc
7cd
7da
8cd 51
8daa 48
8dba 32
8dca 35
8dda 33
-
-
-
7dc
7dd
2.2 Optical and electrochemical studies
7

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The UV-visible absorption and photoluminescence spectra of compounds 8 have been recorded
at ambient temperature in acetonitrile solution (2 × 10ꢃꢄmol ∙ Lꢃꢅ), and the obtained results are
summarized in Table 4 (also see Supplementary Data). Spectra of derivatives 8aa, 8bb, 8cc and
8dd are depicted in Figure 4.
Compounds 8aa-dd exhibit a very strong light absorption in violet and near UV regions of the
spectrum. Compound 8aa shows the most short-wave absorption band and fluorescence
maximum in the visible spectral region (the blue light), but its relative fluorescence quantum
yield is only 17%. The presence of the 4-methoxyphenyl substitutes in 8bb provides the
bathochromic shift of the absorption band, as well as the tiny bathofluoric shift of fluorescence
due to the donor-acceptor interaction of the methoxy-group with the TAP ring system, the
quantum yield also increases up to 52%. On the other hand, substantial bathochromic and
bathofluoric effects are observed in the presence of the most electron-donating 4-(N,N-
dimethylaminophenyl) substituent (8dd), however, the quantum yield is enhanced
insignificantly, as comparing with 8bb. The spectrum maxima of 2-thienyl-substituted
compounds 8cc are shifted bathochromically and bathofluorically relative to 8aa, but their shifts
are smaller than for 8dd (Figure 3). The quantum yield of 8cc is at the level of 8dd.
Having studied compounds bearing various combinations of substituents, we have revealed some
interesting optical effects. The compound 8cd has the lowest quantum yield (2%), the largest
Stokes shift and shows the greatest bathochromic and bathofluoric shifts. On the contrary,
compound 8ba has the highest quantum yield (55%), but one of the lowest Stokes shifts, small
bathochromic and insignificant bathofluoric shifts. This pattern has possibly been observed
because of an increase in the probability of nonradiating transitions.
The luminescence of compounds varies from blue (8aa, 8ab, 8ac, 8ba, 8bb, 8bc, 8ca, 8cb, 8cc)
to green (8bd, 8da, 8dc, 8dd) and orange (8ad, 8cd). Compounds 8aa, 8bb, 8ca may be good
UV dyes with extinction coefficient ε > 30000, and compounds 8cd and 8da-dd may be used as
dyes in the visible part of spectra.
8

ACCEPTED MANUSCRIPT
(a)
(b)
Figure 4. UV-visible absorption (a) and emission (b) spectra of some 5,7-disubstituted TAPs in acetonitrile after
normalization. Intensity of emission spectra is based on relative quantum yields.
Cyclic voltammetry (CV) measurements of compounds 8aa-dd have been performed to study
the electrochemical properties of compounds 8aa-dd. All CV experiments were carried out in
anhydrous acetonitrile at a concentration of (1 × 10ꢃꢆmol ∙ Lꢃꢅ) for the examined substances
and tetrabutylammonium perchlorate (0.1 M) as the supporting electrolyte under an argon
atmosphere. Reduction potentials have been out of the scan range in the current CV experiments.
Compounds 8 containing only phenyl-, thienyl- and 4-methoxyphenyl- substitutes show two
oxidation waves, while derivatives bearing a 4-(N,N-dimethylaminophenyl)- groups have more
ꢈꢊꢋꢌꢍ
complicated curves and the least onset potentials (ꢇ
) of the first oxidation peaks. The
ꢈꢉ
ꢈꢊꢋꢌꢍ
HOMO energy levels (ꢇꢎꢏꢐꢏ) of these TAPs have been estimated from ꢇ
of the first
ꢈꢉ
ꢈꢊꢋꢌꢍ
ꢕ
ꢖꢗ
ꢒ ꢇꢅ/ꢔ Fc/Fc ꢘ 5.1ꢙ. We have
oxidation peaks by the empirical equation: ꢇꢎꢏꢐꢏ ꢑ ꢒꢓꢇ
ꢈꢉ
used a ꢘ5.10 eV value in the Fermi scale for the formal potential of the Fc/Fc ꢖ redox couple
instead of ꢘ4.8 eV in accordance with a recent discussion of Bazan et al.18 The LUMO energy
levels (ꢇꢚꢛꢐꢏ ) of these compounds have been calculated from their HOMO energy levels
9

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(ꢇꢎꢏꢐꢏ) and the optical band gaps (ꢇꢈꢝꢍ) using equation: ꢇꢚꢛꢐꢏ ꢑ ꢇꢎꢏꢐꢏ ꢘ ꢇꢈꢝꢍ. The obtained
ꢜ
ꢜ
electrochemical data as well as the HOMO/LUMO energy levels are listed in Table 4.
For more information about the optical and electrochemical studies, see Supplementary Data.
Table 4. The optical and electrochemical properties of TAP-cored compounds 8.
ꢞꢟꢦꢧꢤ ꢕꢣꢥꢗ Φb(%) ε (ꢨ ∙ ꢩꢪꢃꢫ ∙ ꢪꢟꢬꢃꢫ
ꢗ
abs
em
a(nm)
λ
a(nm)
max
EHOMO (eV)
ELUMO (eV)
ꢟꢡꢢꢣꢤ
ꢟꢠ
Compound
λ
max
ꢞ
ꢕꢥꢗ
8aa
8ab
8ac
8ad
8ba
8bb
8bc
8bd
8ca
8cb
8cc
8cd
8da
8db
8dc
8dd
312
324
331
389
321
332
338
387
339
345
349
400
394
390
399
393
401
435
422
582
404
421
410
556
397
450
429
602
518
499
534
535
1.55
1.35
1.40
0.56
0.71
1.29
1.32
0.51
1.38
1.25
1.38
0.49
0.53
0.49
0.53
0.44
-6.55
-6.35
-6.40
-5.56
-5.71
-6.29
-6.32
-5.51
-6.38
-6.25
-6.38
-5.49
-5.53
-5.49
-5.53
-5.44
-3.17
-3.35
-3.37
-3.00
-2.63
-3.15
-3.32
-2.94
-3.32
-3.28
-3.51
-3.07
-2.96
-2.95
-3.05
-2.92
3.38
3.00
3.03
2.56
3.08
3.14
3.00
2.57
3.06
2.97
2.87
2.42
2.57
2.54
2.48
2.52
17
39
18
3
55
52
28
15
21
37
29
2
19646
23328
21665
23355
19137
34700
29729
25600
26903
29855
29731
20683
26863
29230
25147
44436
33
52
23
28
3. Conclusion
In conclusion, we have developed an elegant method for the direct (het)arylation of TAPs via the
nucleophilic aromatic substitution of hydrogen (ꢀꢁꢂ) using Grignard reagents as nucleophiles. A
variety of 7-(het)aryl- and 5,7-di(het)aryl-substituted TAPs have been prepared in two or three
steps from readily available 6-bromo-TAP. The first addition of (het)arylmagnesium bromide to
this bicyclic system followed by aromatization provided 7-substituted derivatives in 71-85 %
yields. The second addition of a Grignard reagent with successive oxidation of the obtained σH-
adducts in the form of the N-magnesium salts by pure oxygen has afforded 5,7-disubstituted-
TAP derivatives in 41-86 % yields via the one pot procedure. Physicochemical measurements
have been performed for the obtained series of 5,7-di(het)aryl-substituted TAPs to estimate their
optical and redox properties. Some derivatives have appeared to be good dyes in the UV or
visible regions.
The described approach allows access to a wide range of novel TAPs, thus designing new useful
compounds for material science applications.
4. Experimental
All reagents and solvents were purchased from commercial sources and dried by using standard
procedures before use. [1,2,4]Triazolo[1,5-a]pyrimidine 1, 6-bromo[1,2,4]triazolo[1,5-
a]pyrimidine and phenyliodinium diacetate were prepared according to the earlier reported
procedures.19 Melting points were determined on Boetius combined heating stages and are
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1
uncorrected. Elemental analysis was carried on a Eurovector EA 3000 automated analyzer. H
and 13C NMR spectra were recorded on AVANCE-400 and AVANCE-500 instruments in
DMSO-d6 or CDCl3 with TMS as an internal standard. The GC-MS analysis of all samples was
carried out using an Agilent GC 7890A MS 5975C Inert XL EI/CI GC-MS spectrometer with a
quadrupole mass-spectrometric detector with electron ionization (70 eV), and scan over the total
ionic current in the range m/z 20÷1000 and a quartz capillary column HP-5MS (30 m×0.25 mm,
film thickness 0.25 mm). Column chromatography was carried out using Alfa Aesar silica gel
0.040–0.063 mm (230–400 mesh), eluting with ethyl acetate – hexane (1:1) or ethyl acetate
containing 0.5% of triethylamine. The progress of the reactions and the purity of compounds
were checked by TLC on Sorbfil plates (Russia), in which the spots were visualized with UV
light (λ 254 or 365 nm). X-ray diffraction analysis was performed on an automated X-ray
diffractometer “Xcalibur E” on standard procedure.
Optical spectra were obtained using a Shimadzu UV-2600 double-beam UV-Vis
spectrophotometer, a Varian Cary Eclipse fluorescence spectrophotometer and a Hêllma QS-101
high precision quartz cell in acetonitrile solution. Solutions of compounds with 4-(N,N-
dimethylaminophenyl) substituents were made with the addition of Me4NOH base. Bi-quinine
sulfate was used as the standard for relative quantum yield measuring.20 Cyclic voltammetry was
carried out on a Metrohm Autolab PGSTAT128N potentiostat with a standard three-electrode
configuration. Typically, a three electrode cell equipped with a platinum working electrode, a
Ag/AgNO3 (0.01M) reference electrode, and a glass carbon rod counter electrode was employed.
The measurements were done in anhydrous acetonitrile with tetrabutylammonium perchlorate
(0.1 M) as the supporting electrolyte under an argon atmosphere at a scan rate of 100 mV/s. The
potential of the Ag/AgNO3 reference electrode was calibrated using the ferrocene/ferrocenium
redox couple (Fc/Fc ꢖ).
1.
General procedure for the synthesis of 6-bromo-7-substituted-4,7-dihydro-
[1,2,4]triazolo[1,5-a]pyrimidines.
Magnesium powder (36 mg, 1.5 mmol) was immersed in abs. THF (10 ml) under argon or
nitrogen, and the appropriate bromo(het)arene (1.5 mmol) was added. The reaction mixture was
stirred at room temperature until formation of a clear solution, cooled to – 78 °C and charged
with 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (4) (200 mg, 1 mmol). After 1 hour the bath
temperature was elevated to 50 °C. Two hours later the flask was cooled, and cold water (3 ml)
and ammonium chloride (107 mg, 2 mmol) were added to the reaction mixture. After that, the
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solvent was distilled off in vacuo, the precipitate was filtered off, washed with cold water and
ethyl acetate, dried and recrystallized from isopropanol or acetonitrile to give compounds 5a-d.
1.1
6-Bromo-7-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (5a).
Yield: 246 mg (89 %); white solid; m.p. 161-163 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.16 (d,
J = 4.9 Hz, 1H, NH), 7.57 (s, 1H, N=CH-N), 7.42 – 7.30 (m, 3H, Ph), 7.28 – 7.22 (m, 2H, Ph),
6.97 (dd, J = 5.0, 0.8 Hz, 1H, HN-CH=C), 6.14 (d, J = 0.8 Hz, 1H, CH-N). 13C NMR (126 MHz,
DMSO-d6) δ 149.9, 147.4, 139.2, 128.6, 128.5, 127.6, 125.8, 92.3, 64.9; Anal. Calcd for
C11H9BrN4 (277.13): C, 47.68; H, 3.27; N, 20.22 Found: C, 47.79; H, 3.34; N, 20.19
1.2
6-Bromo-7-(4-methoxyphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (5b).
Yield: 227 mg (74 %); white solid; m.p. 160-162 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s,
1H, NH), 7.56 (s, 1H, N=CH-N), 7.21 – 7.14 (m, 2H, CH=C-CH), 6.95 (s, 1H, HN-CH=C), 6.94
– 6.89 (m, 2H, CH-C(OMe)=CH), 6.08 (s, 1H, CH-N), 3.74 (s, 3H, OMe). 13C NMR (126 MHz,
DMSO-d6) δ 159.4, 149.7, 147.3, 131.3, 128.8, 125.6, 113.9, 92.6, 64.4, 55.1; Anal. Calcd for
C12H11BrN4O (307.15): C, 46.93; H, 3.61; N, 18.24 Found: C, 46.97; H, 3.59; N, 18.19
1.3
6-Bromo-7-(2-thienyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (5c).
1
Yield: 229 mg (81 %); light brown solid; m.p. 156-157 °C; H NMR (500 MHz, DMSO-d6) δ
10.26 (s, 1H, NH), 7.62 (s, 1H, N=CH-N), 7.54 (d, J = 5.2 Hz, 1H, CH=CH-S), 7.20 (d, J = 3.6
Hz, 1H, C=CH-CH), 7.03 – 6.96 (m, 2H, CH=CH-S, HN-CH=C ), 6.52 (s, 1H, CH-N). 13C NMR
(126 MHz, DMSO-d6) δ 149.9, 146.9, 142.9, 127.8, 127.2, 126.7, 125.9, 91.7, 60.1; Anal. Calcd
for C9H7BrN4S (283.15): C, 38.18; H, 2.49; N, 19.79 Found: C, 38.25; H, 2.41; N, 19.71
1.4
6-Bromo-7-(4-(N,N-dimethylaminophenyl))-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine
(5d).
1
Yield: 278 mg (87 %); light yellow solid; m.p. 166-167 °C; H NMR (500 MHz, DMSO-d6) δ
10.06 (s, 1H, NH), 7.54 (s, 1H, N=CH-N), 7.05 (d, J = 8.1 Hz, 2H, CH=C-CH), 6.92 (d, J = 4.4
Hz, 1H, HN-CH=C), 6.67 (d, J = 8.3 Hz, 2H, CH-C(NMe2)=CH), 5.97 (s, 1H, CH-N), 2.88 (s,
13
6H, NMe2). C NMR (126 MHz, DMSO-d6) δ 150.4, 149.6, 147.2, 128.3, 126.5, 125.4, 112.0,
93.2, 64.6, 39.6; Anal. Calcd for C13H14BrN5 (320.19): C, 48.77; H, 4.41; N, 21.87 Found: C,
48.82; H, 4.46; N, 21.80
2.
General procedure for the synthesis of 7-substituted [1,2,4]triazolo[1,5-a]pyrimidines.
12

ACCEPTED MANUSCRIPT
The relevant 6-bromo-7-substituted 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine 5a-d (1 mmol)
and triethylamine (TEA) (0.216 ml, 1.5 mmol) were immersed in acetonitrile and refluxed until
the initial substance completely disappeared (the reaction progress was monitored by TLC).
The reaction mixture was diluted with water, cooled, then the precipitate was filtered off, washed
with water, dried and recrystallized from isopropanol to afford the desired products 6a-d.
2.1
7-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (6a).
Yield: 139 mg (71 %); white solid; m.p. 140-141 °C (lit. 146 °C);21 1H NMR (500 MHz, DMSO-
d6) δ 8.96 (d, J = 4.6 Hz, 1H, N=CH-CH), 8.74 (s, 1H, N=CH-N), 8.24 – 8.17 (m, 2H, Ph), 7.71
13
– 7.61 (m, 4H, Ph, N=CH-CH). C NMR (126 MHz, DMSO-d6) δ 155.7, 155.5, 155.0, 147.3,
131.7, 129.6, 129.5, 128.7, 109.7; Anal. Calcd for C11H8N4 (196.21): C, 67.34; H, 4.11; N, 28.55
Found: C, 67.41; H, 4.16; N, 28.46
2.2
7-(4-Methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (6b).
Yield: 185 mg (82 %); white solid; m.p. 194-195 °C (lit. 197-198 °C);21 1H NMR (500 MHz,
DMSO-d6) δ 8.90 (d, J = 4.7 Hz, 1H, N=CH-CH), 8.73 (s, 1H, N=CH-N), 8.32 – 8.25 (m, 2H,
CH=C-CH), 7.61 (d, J = 4.7 Hz, 1H, N=CH-CH), 7.24 – 7.17 (m, 2H, CH-C(OMe)=CH), 3.89
(s, 3H, OMe). 13C NMR (126 MHz, DMSO-d6) δ 162.0, 155.9, 155.4, 154.7, 147.0, 131.5, 121.5,
114.2, 108.6, 55.6; Anal. Calcd for C12H10N4O (226.24): C, 63.71; H, 4.46; N, 24.76 Found: C,
63.65; H, 4.43; N, 24.82
2.3
7-(2-Thienyl)-[1,2,4]triazolo[1,5-a]pyrimidine (6c).
Yield: 172 mg (85 %); off-white solid; m.p. 179-180 °C (lit. 209-211 °C);22 1H NMR (500 MHz,
DMSO-d6) δ 8.90 (d, J = 4.9 Hz, 1H, N=CH-CH), 8.84 (s, 1H, N=CH-N), 8.59 (dd, J = 3.9, 1.2
Hz, 1H, C=CH-CH), 8.21 (dd, J = 5.0, 1.2 Hz, 1H, CH=CH-S), 8.00 (d, J = 4.9 Hz, 1H, N=CH-
CH), 7.44 (dd, J = 5.0, 3.9 Hz, 1H, CH=CH-S). 13C NMR (126 MHz, DMSO-d6) δ 155.5, 155.4,
154.3, 141.1, 135.5, 133.1, 129.7, 128.3, 106.0; Anal. Calcd for C9H6N4S (202.23): C, 53.45; H,
2.99; N, 27.70 Found: C, 53.53; H, 3.05; N, 27.63
2.4
7-(4-(N,N-dimethylaminophenyl))-[1,2,4]triazolo[1,5-a]pyrimidine (6d).
Yield: 184 mg (77 %); yellow solid; m.p. 209-211 °C (lit. 198-200 °C);23 1H NMR (500 MHz,
DMSO-d6) δ 8.78 (d, J = 4.9 Hz, 1H, N=CH-CH), 8.69 (s, 1H, N=CH-N), 8.35 – 8.28 (m, 2H,
CH=C-CH), 7.57 (d, J = 4.9 Hz, 1H, N=CH-CH), 6.91 – 6.88 (m, 2H, CH-C(NMe2)=CH), 3.07
(s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 156.1, 155.2, 154.1, 152.3, 147.4, 131.0,
13

ACCEPTED MANUSCRIPT
115.1, 111.2, 106.7, 39.6; Anal. Calcd for C13H13N5 (239.28): C, 65.25; H, 5.48; N, 29.27 Found:
C, 65.33; H, 5.45; N, 29.24
3.
General procedure for the synthesis of 5,7-disubstituted 4,5-dihydro[1,2,4]triazolo[1,5-
a]pyrimidines.
Grignard reagent solution was prepared from magnesium powder (36 mg, 1.5 mmol) and the
appropriate bromo(het)arene (1.5 mmol) in THF (10 ml). It was cooled to – 78 °C and the
corresponding 7-substituted-TAP 6 (1 mmol) was added. After 1 hour the bath temperature was
elevated to 50 °C, and the reaction mixture was stirred for an additional 2 hours. When the
reaction was completed, the flask was cooled, and the reaction mixture was charged with cold
water (2-3 ml) and ammonium chloride (107 mg, 2 mmol) under an inert atmosphere. Next the
THF was distilled off in vacuo, the residue was filtered off, washed with cold water, dried and
recrystallized from acetonitrile.
3.1
5,7-Diphenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (7aa).
1
Yield: 195 mg (71 %); white crystals; m.p. 177-178 °C; H NMR (500 MHz, DMSO-d6) δ 8.18
(t, J = 2.0 Hz, 1H, NH), 7.66 – 7.58 (m, 2H, Ph), 7.53 (s, 1H, N=CH-N), 7.45 – 7.35 (m, 7H,
Ph), 7.36 – 7.27 (m, 1H, Ph), 5.52 (dd, J = 5.0, 1.7 Hz, 1H, NH-CH-CH), 5.46 (dd, J = 5.0, 2.0
Hz, 1H, NH-CH-CH). 13C NMR (126 MHz, DMSO-d6) δ 153.4, 149.3, 143.6, 134.4, 131.8,
129.0, 128.7, 128.3, 128.0, 127.7, 126.2, 107.8, 54.1. Anal. Calcd for C17H14N4 (274.33): C,
74.43; H, 5.14; N, 20.42 Found: C, 74.23; H, 5.16; N, 20.63
3.2
7-Phenyl-5-(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a] pyrimidine (7ac).
Yield: 210 mg (75 %); pale brown crystalls; m.p. 169-170 °C; 1H NMR (500 MHz, DMSO-d6) δ
8.36 (t, J = 2.0 Hz, 1H, NH), 7.66 – 7.59 (m, 2H, Ph), 7.55 (s, 1H, N=CH-N), 7.47 (dd, J = 5.0,
1.3 Hz, 1H, CH=CH-S), 7.46 – 7.40 (m, 3H, Ph), 7.08 (dt, J = 3.4, 0.9 Hz, 1H, C=CH-CH), 7.02
(dd, J = 5.0, 3.5 Hz, 1H, CH=CH-S), 5.71 (dd, J = 5.3, 2.1 Hz, 1H, NH-CH-CH), 5.60 (dd, J =
13
5.2, 1.7 Hz, 1H, NH-CH-CH). C NMR (126 MHz, DMSO-d6) δ 152.9, 149.4, 147.7, 134.8,
131.7, 129.2, 128.4, 128.1, 127.1, 125.8, 124.3, 107.2, 49.4. Anal. Calcd for C15H12N4S
(280.35): C, 64.26; H, 4.31; N, 19.99; S, 11.44 Found: C, 64.20; H, 4.35; N, 20.03; S, 11.20
3.3
7-Phenyl-5-(4-(N,N-dimethylaminophenyl))-4,5-dihydro-[1,2,4]triazolo[1,5-a]
pyrimidine (7ad).
14

ACCEPTED MANUSCRIPT
Yield: 96 mg (55 %); lustrous yellow solid; m.p. 180-182 °C; 1H NMR (400 MHz, DMSO-d6) δ
8.00 (d, J = 2.0 Hz, 1H, NH), 7.61 (ddd, J = 6.9, 3.9, 2.1 Hz, 2H, Ph), 7.50 (s, 1H, N=CH-N),
7.42 (dt, J = 4.4, 1.2 Hz, 3H, Ph), 7.19 – 7.12 (m, 2H, CH=C-CH), 6.76 – 6.68 (m, 2H, CH-
C(NMe2)=CH), 5.44 (dd, J = 5.0, 1.7 Hz, 1H, NH-CH-CH), 5.30 (dd, J = 4.9, 1.8 Hz, 1H, NH-
CH-CH), 2.87 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 160.7, 156.0, 155.4, 152.3,
146.6, 131.3, 130.2, 129.7, 129.1, 128.5, 122.7, 111.6, 105.6, 39.2; Anal. Calcd for C19H19N5
(317.40): C, 71.90; H, 6.03; N, 22.07 Found: C, 71.83; H, 5.97; N, 22.15
3.4
7-(4-Methoxyphenyl)-5-(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (7bc).
1
Yield: 191 mg (62 %); light brown solid; m.p. 147-148 °C; H NMR (400 MHz, DMSO-d6) δ
8.31 (t, J = 2.0 Hz, 1H, NH), 7.62 – 7.51 (m, 2H, CH=C-CH), 7.54 (s, 1H, N=CH-N), 7.46 (dd, J
= 5.0, 1.3 Hz, 1H, CH=CH-S), 7.10 – 7.03 (m, 1H, C=CH-CH), 7.05 – 6.95 (m, 3H, CH-
C(OMe)=CH, CH=CH-S), 5.67 (dd, J = 5.2, 2.1 Hz, 1H, NH-CH-CH), 5.51 (dd, J = 5.2, 1.7 Hz,
13
1H, NH-CH-CH), 3.80 (s, 3H, OMe). C NMR (126 MHz, DMSO-d6) δ 159.9, 152.9, 149.3,
147.9, 134.5, 129.8, 127.1, 125.7, 124.3, 124.0, 113.5, 105.9, 55.2, 49.3; Anal. Calcd for
C16H14N4OS (310.38): C, 61.92; H, 4.55; N, 18.05 Found: C, 61.86; H, 4.57; N, 18.12
3.5
7-(2-Thienyl)-5-phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a] pyrimidine (7ca).
Yield: 129 mg (46 %); light brown crystalls; m.p. 176-178 °C; 1H NMR (500 MHz, DMSO-d6) δ
8.26 (t, J = 2.0 Hz, 1H, NH), 7.73 (dd, J = 3.8, 1.2 Hz, 1H, C=CH-CH), 7.64 (dd, J = 5.1, 1.2 Hz,
1H, CH=CH-S), 7.62 (s, 1H, N=CH-N), 7.43 – 7.34 (m, 4H, Ph), 7.33 – 7.27 (m, 1H, Ph), 7.11
(dd, J = 5.1, 3.7 Hz, 1H, CH=CH-S), 5.76 (dd, J = 5.2, 1.7 Hz, 1H, NH-CH-CH), 5.48 (dd, J =
13
5.1, 2.0 Hz, 1H, NH-CH-CH). C NMR (126 MHz, DMSO-d6) δ 153.3, 149.4, 143.5, 132.5,
128.8, 128.5, 128.0, 127.9, 127.8, 127.2, 126.1, 105.6, 54.2. Anal. Calcd for C15H12N4S
(280.35): C, 64.26; H, 4.31; N, 19.99; S, 11.44 Found: C, 64.19; H, 4.37; N, 20.04; S, 11.17
3.6
5,7-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (7cc).
Yield: 257 mg (90 %); off-white solid; m.p. 204-206 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.44
(s, 1H, NH), 7.75 (d, J = 3.7 Hz, 1H, C=CH-CH), 7.67 (d, J = 5.1 Hz, 1H, CH=CH-S), 7.63 (s,
1H, N=CH-N), 7.47 (d, J = 5.0 Hz, 1H, CH=CH-S), 7.13 (t, J = 4.4 Hz, 1H, CH=CH-S), 7.06 (d,
J = 3.5 Hz, 1H, C=CH-CH), 7.01 (t, J = 4.4 Hz, 1H, CH=CH-S), 5.83 (d, J = 5.3 Hz, 1H, NH-
CH-CH), 5.73 (d, J = 5.5 Hz, 1H, NH-CH-CH). 13C NMR (126 MHz, DMSO-d6) δ 152.8, 149.5,
147.5, 132.3, 129.0, 128.3, 128.2, 127.3, 127.1, 125.8, 124.3, 105.0, 49.5; Anal. Calcd for
C13H10N4S2 (286.37): C, 54.52; H, 3.52; N, 19.56 Found: C, 54.44; H, 3.48; N, 19.60
15

ACCEPTED MANUSCRIPT
3.7
7-(2-Thienyl)-5-(4-(N,N-dimethylaminophenyl))-4,5-dihydro-[1,2,4]triazolo[1,5-
a]pyrimi-dine (7cd).
Yield: 216 mg (67 %); dark yellow crystals; m.p. 170-172 °C; 1H NMR (500 MHz, DMSO-d6) δ
8.09 (s, 1H, NH), 7.72 (dd, J = 3.7, 1.2 Hz, 1H, C=CH-CH), 7.63 (dd, J = 5.1, 1.2 Hz, 1H,
CH=CH-S), 7.58 (s, 1H, N=CH-N), 7.16 – 7.08 (m, 3H, CH=C-CH, CH=CH-S), 6.75 – 6.68 (m,
2H, CH-C(NMe2)=CH), 5.68 (dd, J = 5.1, 1.7 Hz, 1H, NH-CH-CH), 5.31 (dd, J = 5.1, 1.8 Hz,
13
1H, NH-CH-CH), 2.86 (s, 6H, NMe2). C NMR (126 MHz, DMSO-d6) δ 153.3, 150.2, 149.3,
132.8, 131.0, 128.1, 127.8, 127.7, 127.2, 127.0, 112.5, 106.1, 53.7, 40.1; Anal. Calcd for
C17H17N5S (323.42): C, 63.13; H, 5.30; N, 21.65 Found: C, 63.18; H, 5.27; N, 21.61
4.
General procedure for the synthesis of 5,7-disubstituted [1,2,4]triazolo[1,5-a]pyrimidines.
General procedure A. Grignard reagent solution was prepared from magnesium powder (36 mg,
1.5 mmol) and the appropriate bromo(het)arene (1.5 mmol) in THF (10 ml). It was cooled to –
78 °C and the corresponding 7-substituted-TAP 6 (1 mmol) was added. After 1 hour the bath
temperature was elevated to 50 °C, and the reaction mixture was stirred for another 2 hours.
Then the oxygen atmosphere was created and kept for 2 hours. When the reaction was
completed, the flask was cooled, and the reaction mixture was charged with cold water (2-3 ml)
and ammonium chloride (107 mg, 2 mmol). The THF was then distilled off in vacuo, the residue
was filtered off, washed with cold water and hexane, dried and recrystallized from isopropanol,
acetonitrile or ethyl acetate – hexane (1:1) to afford the desired products 8aa-dd.
General procedure B. The 5,7-substituted 4,5-dihydro-TAP (7aa-dd) (1 mmol) and
phenyliodinium diacetate (PIDA) (0.320 g, 1 mmol) were immersed in acetonitrile and gently
stirred at room temperature for 6 hours until the starting material had disappeared (the reaction
progress was checked by TLC). Then the residue was purified by flash column chromatography
eluting with either ethyl acetate, or ethyl acetate – hexane (1:1) or ethyl acetate containing 0.5%
of trimethylamine and after that recrystallized from isopropanol, acetonitrile or ethyl acetate –
hexane (1:1) to afford the desired products 8aa-dd.
4.1
5,7-Diphenyl-[1,2,4]triazolo[1,5-a]pyrimidine (8aa).
Recrystallized from isopropanol. Yield: A. 234 mg (86 %) B. 215 mg (79%); off-white solid;
m.p. 165-166 °C (lit. 151-152 °C);24 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H, N=C-CH),
8.46 – 8.37 (m, 2H, Ph), 8.34 – 8.26 (m, 2H, Ph), 8.17 (s, 1H, N=CH-N), 7.74 – 7.56 (m, 6H,
Ph). 13C NMR (126 MHz, DMSO-d6) δ 160.6, 156.0, 155.8, 147.5, 136.1, 131.6, 131.3, 129.9,
16

ACCEPTED MANUSCRIPT
129.8, 129.0, 128.5, 127.8, 106.8; Anal. Calcd for C17H12N4 (272.31): C, 74.98; H, 4.44; N,
20.58 Found: C, 75.02; H, 4.40; N, 20.61
4.2
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from ethyl acetate.
Yield: A. 193 mg (64 %), B. 169 mg (56 %); pale yellow solid; m.p. 173-175 °C (lit. 166 °C)
25 1H NMR
7-Phenyl-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8ab).
;
(500 MHz, DMSO-d6) δ 8.66 (s, 1H, N=C-CH), 8.43 – 8.36 (m, 2H, CH=C-CH), 8.31 – 8.24 (m, 2H,
Ph), 8.10 (s, 1H, N=CH-N), 7.77 – 7.55 (m, 3H, Ph), 7.18 – 7.11 (m, 2H, CH-C(OMe)=CH), 3.88 (s,
3H, OMe). 13C NMR (126 MHz, DMSO-d6) δ 162.0, 155.8, 147.2, 131.5, 130.0, 129.8, 129.6, 128.5,
114.4, 106.2, 55.5; Anal. Calcd for C18H14N4O (302
4.63; N, 18.59
.34): C, 71.51; H, 4.67; N, 18.53 Found: C, 71.56; H,
4.3
7-Phenyl-5-(2-thienyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8ac).
Purified by flash column chromatography eluting with ethyl acetate – hexane (1:1),
recrystallized from ethyl acetate – hexane (1:1). Yield: A. 147 mg (53 %), B. 128 mg (46 %);
1
off-white solid; m.p. 115-120 °C; H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H, N=C-CH),
8.13 – 8.05 (m, 2H, Ph), 7.88 (dd, J = 3.7, 1.2 Hz, 1H, C=CH-CH), 7.68 – 7.58 (m, 4H, Ph,
13
CH=CH-S), 7.50 (s, 1H, N=CH-N), 7.19 (dd, J = 5.0, 3.8 Hz, 1H, CH=CH-S). C NMR (126
MHz, Chloroform-d) δ 156.5, 156.1, 147.9, 142.1, 131.8, 131.6, 130.0, 129.2, 128.9, 128.8,
128.5, 105.5, 77.2; Anal. Calcd for C15H10N4S (278.33): C, 64.73; H, 3.62; N, 20.13 Found: C,
64.69; H, 3.66; N, 20.17
4.4
7-Phenyl-5-(4-(N,N-dimethylaminophenyl))-[1,2,4]triazolo[1,5-a]pyrimidine (8ad).22
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from
acetonitrile. Yield: A. 220 mg (70 %), B. 192 mg (61 %); lustrous dark yellow crystals; m.p.
1
213-214 °C; H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H, N=C-CH), 8.31 – 8.26 (m, 2H,
CH=C-CH), 8.25 – 8.21 (m, 2H, Ph), 7.98 (s, 1H, N=CH-N), 7.70 – 7.60 (m, 3H, Ph), 6.89 – 6.81
(m, 2H, CH-C(NMe2)=CH), 3.05 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 160.6,
155.8, 154.8, 152.0, 146.3, 130.9, 129.3, 128.9, 128.1, 122.8, 111.3, 105.3, 95.5, 39.6; Anal.
Calcd for C19H17N5 (315.38): C, 72.36; H, 5.43; N, 22.21 Found: C, 72.45; H, 5.41; N, 22.18
4.5
7-(4-Methoxyphenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (8ba).26
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from
isopropanol. Yield:A. 196 mg (65 %), B. 175 mg (58 %); white solid; m.p. 174-175 °C; 1H NMR
17

ACCEPTED MANUSCRIPT
(500 MHz, DMSO-d6) δ 8.71 (s, 1H, N=C-CH), 8.44 – 8.35 (m, 4H, Ph, CH=C-CH), 8.12 (s, 1H,
N=CH-N), 7.61 (tt, J = 3.3, 2.1 Hz, 3H, Ph), 7.24 – 7.17 (m, 2H, CH-C(OMe)=CH), 3.90 (s, 3H,
OMe). 13C NMR (126 MHz, DMSO-d6) δ 161.9, 160.4, 155.95, 155.93, 147.2, 136.3, 131.7,
131.2, 128.9, 127.8, 121.8, 114.0, 105.7, 55.6; Anal. Calcd for C18H14N4O (302,34): C, 71.51; H,
4.67; N, 18.53 Found: C, 71.48; H, 4.71; N, 18.51
4.6
5,7-Di(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8bb).
Purified by flash column chromatography eluting with ethyl acetate and recrystallized from
1
isopropanol. Yield: A. 222 mg (67 %), 196 mg (59 %); pale yellow solid; m.p. 183-184°C; H
NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H, N=C-CH), 8.41 – 8.31 (m, 4H, CH=C-CH, CH=C-
CH), 8.03 (s, 1H, N=CH-N), 7.23 – 7.16 (m, 2H, CH-C(OMe)=CH), 7.16 – 7.09 (m, 2H, CH-
C(OMe)=CH), 3.90 (s, 3H, OMe), 3.87 (s, 3H, OMe).13C NMR (126 MHz, DMSO-d6) δ 161.9,
161.8, 160.0, 156.0, 155.7, 146.9, 131.7, 129.5, 128.6, 121.9, 114.3, 114.0, 105.1, 55.5, 55.4;
Anal. Calcd for C19H16N4O2 (332.36): C, 68.66; H, 4.85; N, 16.86 Found: C, 68.67; H, 4.90; N,
16.88
4.7
7-(4-Methoxyphenyl)-5-(2-thienyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8bc).
Purified by flash column chromatography eluting with ethyl acetate – hexane (1:1),
recrystallized from ethyl acetate – hexane (1:1). Yield: A. 126 mg (41 %), B. 132 mg (43 %);
1
beige solid; m.p. 154-155 °C; H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H, N=C-CH), 8.37 –
8.29 (m, 3H, CH=C-CH, C=CH-CH), 8.10 (s, 1H, N=CH-N), 7.92 (dd, J = 5.0, 1.1 Hz, 1H,
CH=CH-S), 7.30 (dd, J = 5.0, 3.7 Hz, 1H, CH=CH-S), 7.24 – 7.17 (m, 2H, CH-C(OMe)=CH),
13
3.90 (s, 3H, OMe). C NMR (126 MHz, DMSO-d6) δ 161.9, 155.9, 155.7, 155.6, 147.0, 142.2,
132.2, 131.7, 130.5, 129.0, 121.7, 114.0, 104.5, 55.6; Anal. Calcd for C16H12N4OS (308.36): C,
62.32; H, 3.92; N, 18.17 Found: C, 62.40; H, 3.95; N, 18.21
4.8
7-(4-Methoxyphenyl)-5-(4-(N,N-dimethylaminophenyl))-[1,2,4]triazolo[1,5-a] pyrimidine
(8bd).
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from a
minimal amount of isopropanol. Yield: A. 176 mg (51 %), B. 162 mg (47 %); bright yellow
1
solid; m.p. 174-175 °C; H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H, N=C-CH), 8.30 (d, J =
8.4 Hz, 2H, CH=C-CH), 8.23 (d, J = 8.5 Hz, 2H, CH=C-CH), 7.89 (s, 1H, N=CH-N), 7.17 (d, J
= 8.4 Hz, 2H, CH-C(OMe)=CH), 6.80 (d, J = 8.6 Hz, 2H, CH-C(NMe2)=CH), 3.89 (s, 3H,
OMe), 3.03 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 161.6, 160.5, 156.1, 155.3, 152.2,
18

ACCEPTED MANUSCRIPT
146.2, 131.5, 129.0, 122.8, 122.1, 113.9, 111.5, 104.4, 55.5, 39.6; Anal. Calcd for C20H19N5O
(345.41): C, 69.55; H, 5.54; N, 20.28 Found: C, 69.61; H, 5.52; N, 20.31
4.9
7-(2-Thienyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (8ca).
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from
isopropanol. Yield: A. 178 mg (64 %), B. 156 mg (56 %); off-white solid; m.p. 180-183 °C; 1H
NMR (500 MHz, DMSO-d6) δ 8.84 – 8.79 (m, 2H, N=C-CH, C=CH-CH), 8.51 (s, 1H, N=CH-
N), 8.42 (dd, J = 6.7, 3.0 Hz, 2H, Ph), 8.22 (dd, J = 5.0, 1.1 Hz, 1H, CH=CH-S), 7.62 (dd, J =
4.9, 1.9 Hz, 3H, Ph), 7.46 (dd, J = 5.0, 3.9 Hz, 1H, CH=CH-S). 13C NMR (126 MHz, DMSO-d6)
δ 160.1, 155.9, 141.3, 136.3, 135.6, 133.3, 131.2, 130.0, 128.9, 128.1, 127.8, 102.9; Anal. Calcd
for C15H10N4S (278.33): C, 64.73; H, 3.62; N, 20.13 Found: C, 64.66; H, 3.58; N, 20.20
4.10 7-(2-Thienyl)-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8cb).
Recrystallized from isopropanol. Yield: A. 262 mg (85 %), B. 240 mg (78 %); light yellow
1
solid; m.p. 182-183°C; H NMR (500 MHz, DMSO-d6) δ 8.81 – 8.74 (m, 2H, N=C-CH,
CH=CH-S), 8.44 (s, 1H, N=CH-N), 8.42 – 8.36 (m, 2H, CH=C-CH), 8.20 (dd, J = 5.0, 1.2 Hz,
1H, C=CH-CH), 7.46 (dd, J = 5.0, 3.9 Hz, 1H, CH=CH-S), 7.19 – 7.12 (m, 2H, CH-
C(OMe)=CH), 3.89 (s, 3H, OMe). 13C NMR (126 MHz, DMSO-d6) δ 161.9, 159.8, 155.7, 155.6,
141.0, 135.3, 133.1, 130.1, 129.5, 128.5, 128.1, 114.3, 102.2, 55.4; Anal. Calcd for C16H12N4OS
(308.36): C, 62.32; H, 3.92; N, 18.17 Found: C, 62.38; H, 3.93; N, 18.11
4.11 5,7-Di(2-thienyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8cc).
Purified by flash column chromatography eluting with ethyl acetate, recrystallized from
isopropanol. Yield: A. 207 mg (73%), B. 91 mg (32 %); brown solid; m.p. 186-188 °C; 1H NMR
(500 MHz, DMSO-d6) δ 8.75 (s, 1H, N=C-CH), 8.74 (dd, J = 3.9, 1.2 Hz, 1H, C=CH-CH), 8.47
(s, 1H, N=CH-N), 8.39 (dd, J = 3.8, 1.1 Hz, 1H, C=CH-CH), 8.21 (dd, J = 5.0, 1.1 Hz, 1H,
CH=CH-S), 7.92 (dd, J = 5.1, 1.0 Hz, 1H, CH=CH-S), 7.46 (dd, J = 5.0, 3.9 Hz, 1H, CH=CH-S),
13
7.33 (dd, J = 5.0, 3.8 Hz, 1H, CH=CH-S). C NMR (126 MHz, DMSO-d6) δ 155.64, 155.61,
155.2, 142.2, 141.1, 135.6, 133.2, 132.2, 130.3, 129.8, 128.9, 128.1, 101.7; Anal. Calcd for
C13H8N4S2 (284.36): C, 54.91; H, 2.84; N, 19.70 Found: C, 54.94; H, 2.79; N, 19.72
4.12 7-(2-Thienyl)-5-(4-(N,N-dimethylaminophenyl))-[1,2,4]triazolo[1,5-a]pyrimidine (8cd).
Purified by flash column chromatography eluting with ethyl acetate containing 0.5 % of
trimethylamine, recrystallized from ethyl acetate, then from isopropanol. Yield: A. 193 mg (60
19

ACCEPTED MANUSCRIPT
%), B. 164 mg (51 %); lustrous brown solid; m.p. 189-191 °C; 1H NMR (400 MHz, DMSO-d6) δ
8.75 (dd, J = 4.0, 1.2 Hz, 1H, C=CH-CH), 8.68 (s, 1H, N=C-CH), 8.34 (s, 1H, N=CH-N), 8.33 –
8.27 (m, 2H, CH=C-CH), 8.17 (dd, J = 5.0, 1.2 Hz, 1H, CH=CH-S), 7.44 (dd, J = 5.1, 3.9 Hz,
1H, CH=CH-S), 6.86 (d, J = 9.0 Hz, 2H, CH-C(NMe2)=CH), 3.06 (s, 6H, NMe2). 13C NMR (126
MHz, DMSO-d6) δ 160.3, 155.7, 155.3, 152.3, 140.5, 134.8, 132.7, 130.3, 129.1, 128.0, 122.8,
111.5, 101.6, 39.1; Anal. Calcd for C17H15N5S (321.40): C, 63.53; H, 4.70; N, 21.79 Found: C,
63.57; H, 4.67; N, 21.82
4.13 7-(4-(N,N-dimethylaminophenyl))-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (8da).
Purified by flash column chromatography eluting with ethyl acetate containing 0.5 % of
trimethylamine, recrystallized from isopropanol. Yield: A. 183 mg (58 %), B. 151 mg (48%);
bright yellow solid; m.p. 177-179 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H, N=C-CH),
8.43 – 8.34 (m, 4H, Ph, CH=C-CH), 8.02 (s, 1H, N=CH-N), 7.59 (dd, J = 5.0, 1.9 Hz, 3H, Ph),
6.90 – 6.83 (m, 2H, CH-C(NMe2)=CH), 3.06 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ
159.9, 155.7, 152.3, 147.5, 136.6, 131.2, 130.9, 128.9, 127.7, 115.5, 111.1, 103.7; Anal. Calcd
for C19H17N5 (315.38): C, 72.36; H, 5.43; N, 22.21 Found: C, 72.42; H, 5.46; N, 22.27
4.14 7-(4-(N,N-dimethylaminophenyl))-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine
(8db).
Purified by flash column chromatography eluting with ethyl acetate containing 0.5 % of
trimethylamine, recrystallized from acetonitrile. Yield: A. 169 mg (49 %), B. 110 mg (32%);
yellow solid; m.p. 190-193 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H, N=C-CH), 8.41 –
8.33 (m, 4H, CH=C-CH, CH=C-CH), 7.98 (s, 1H, N=CH-N), 7.16 – 7.09 (m, 2H, CH-
C(OMe)=CH), 6.92 – 6.85 (m, 2H, CH-C(NMe2)=CH), 3.87 (s, 3H, OMe), 3.07 (s, 6H, NMe2).
13C NMR (126 MHz, DMSO-d6) δ 161.7, 159.6, 156.2, 155.5, 152.2, 147.3, 131.2, 129.4, 128.9,
115.7, 114.3, 111.1, 103.2, 55.4, 39.6; Anal. Calcd for C20H19N5O (345.41): C, 69.55; H, 5.54;
N, 20.28 Found: C, 69.59; H, 5.50; N, 20.33
4.15 7-(4-(N,N-dimethylaminophenyl))-5-(2-thienyl)-[1,2,4]triazolo[1,5-a]pyrimidine (8dc).
Purified by flash column chromatography eluting with ethyl acetate containing 0.5 % of
trimethylamine, recrystallized from isopropanol. Yield: A. 148 mg (46 %), B. 112 mg (35 %);
1
dark yellow solid; m.p. 205-206 °C; H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H, N=C-CH),
8.39 – 8.34 (m, 2H, CH=C-CH), 8.32 (dd, J = 3.8, 1.1 Hz, 1H, C=CH-CH), 8.03 (s, 1H, N=CH-
N), 7.89 (dd, J = 5.0, 1.1 Hz, 1H, CH=CH-S), 7.29 (dd, J = 5.0, 3.8 Hz, 1H, CH=CH-S), 6.92 –
20

ACCEPTED MANUSCRIPT
6.84 (m, 2H, CH-C(NMe2)=CH), 3.07 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 155.9,
155.5, 155.4, 152.3, 147.4, 142.5, 131.7, 131.2, 129.9, 128.8, 115.4, 111.1, 102.5, 39.2; Anal.
Calcd for C17H15N5S (321.40): C, 63.53; H, 4.70; N, 21.79 Found: C, 63.57; H, 4.73; N, 21.85
4.16 5,7-Di(4-(N,N-dimethylaminophenyl))-[1,2,4]triazolo[1,5-a]pyrimidine (8dd).
Purified by flash column chromatography eluting with ethyl acetate containing 0.5 % of
trimethylamine, recrystallized from isopropanol. Yield: A. 143 mg (40 %), B. 118 mg (33 %);
1
dark yellow solid; m.p. 219-221 °C; H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H, N=C-CH),
8.36 – 8.29 (m, 2H, CH=C-CH), 8.28 – 8.21 (m, 2H, CH=C-CH), 7.87 (s, 1H, N=CH-N), 6.92 –
6.87 (m, 2H, CH-C(NMe2)=CH), 6.86 – 6.80 (m, 2H, CH-C(NMe2)=CH), 3.06 (s, 6H, NMe2),
3.04 (s, 6H, NMe2). 13C NMR (126 MHz, DMSO-d6) δ 160.1, 156.4, 155.2, 152.13, 152.11,
146.8, 131.0, 128.9, 123.12, 116.1, 111.6, 111.1, 102.6, 39.6, 39.3; Anal. Calcd for C21H22N6
(358.45): C, 70.37; H, 6.19; N, 23.45 Found: C, 70.35; H, 6.22; N, 23.49
Acknowledgements
This work was supported by the Russian Science Foundation (Project No. 16-13-10435).
Supporting Information
Supplementary data associated with this article can be found, in the online version, at
13
Copies of C and 1H NMR spectra for all new compounds; absorption, excitation and emission
spectra for 8 compounds; data of UV-visible and electrochemical studies.
X-ray crystallographic data for 5c (CCDC: 1516469)
X-ray crystallographic data for 7cd (CCDC: 1510810)
X-ray crystallographic data for 8cd (CCDC: 1510811)
21

ACCEPTED MANUSCRIPT
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