Synthetic procedure to pyrido[2,1-f][1,2,4]triazinium salt and related compounds

Article abstract of DOI:10.1016/j.tet.2018.11.070

N-aminopyridyl ketone salts were reacted with formamide to yield heteroaromatic pyrido[2,1-f][1,2,4]triazinium salts. Upon storage of these products in the presence of water, formation of covalent hydrates have been observed. Reaction of the same starting compound with urethane yielded 3-chloropyrido[2,1-f][1,2,4]triazinium salt which readily reacted with secondary amines to afford 3-amino derivatives. An analogous ring closure reaction of 2-formylaminomethyl- and formaminobenzylpyridine allowed the synthesis of the partially reduced 3,4-dihydropyrido[2,1-f][1,2,4]triazinium compounds. The cyclization procedure was also applied for the synthesis of the related pyrimido[2,1-f][1,2,4]triazinium salt.

Full text of DOI:10.1016/j.tet.2018.11.070

Accepted Manuscript
Synthetic procedure to pyrido[2,1-f][1,2,4]triazinium salt and related compounds
Sándor Bátori, Dorottya Csányi, Daniella Takács, Orsolya Egyed, Zsuzsanna Riedl,
György Hajós
PII:
S0040-4020(18)31460-1
https://doi.org/10.1016/j.tet.2018.11.070
TET 29981
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2018
Revised Date: 22 November 2018
Accepted Date: 30 November 2018
Please cite this article as: Bátori Sá, Csányi D, Takács D, Egyed O, Riedl Z, Hajós Gyö, Synthetic
procedure to pyrido[2,1-f][1,2,4]triazinium salt and related compounds, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2018.11.070.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthetic procedure to heteroaromatic
pyrido[2,1-f][1,2,4]triazinium salt and
related compounds
Leave this area blank for abstract info.
Sándor Bátori, Dorottya Csányi, Daniella Takács, Orsolya Egyed, Zsuzsanna Riedl, and György Hajós
Institute of Organic Chemistry and NMR Research Laboratory of Instrumentation Centre, Research Centre for
Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Magyar tudósok körútja 2.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthetic procedure to pyrido[2,1-f][1,2,4]triazinium salt and related compounds
Sándor Bátoria§, Dorottya Csányia, Daniella Takácsa, Orsolya Egyedb, Zsuzsanna Riedla, and György
Hajósa*
aInstitute of Organic Chemistry and bNMR Research Laboratory of Instrumentation Centre, Research Centre for Natural Sciences, Hungarian Academy of
Sciences, H-1117 Budapest, Magyar tudósok körútja 2.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N-aminopyridyl ketone salts were reacted with formamide to yield heteroaromatic
pyrido[2,1-f][1,2,4]triazinium salts. Upon storage of these products in the presence of
water, formation of covalent hydrates have been observed. Reaction of the same
starting compound with urethane yielded 3-chloropyrido[2,1-f][1,2,4]triazinium salt
which readily reacted with secondary amines to afford 3-amino derivatives. An
Available online
analogous
ring
closure
reaction
of
2-formylaminomethyl-
and
Keywords:
ring closure
zwitterion
heteroaromatic
fused triazinium salt
covalent hydrate
formaminobenzylpyridine allowed the synthesis of the partially reduced 3,4-
dihydropyrido[2,1-f][1,2,4]triazinium compounds. The cyclization procedure was also
applied for the synthesis of the related pyrimido[2,1-f][1,2,4]triazinium salt.
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Out of these four cations, interestingly, synthesis of only
pyrido[1,2-b][1,2,4]triazinium ring system3,4,5 as well as its
isoquinoline-fused analogues6,7 has been described in details.
Large number of fused [1,2,4]triazines have been published in
the literature and, also, extensive reviews1,2 appeared. Among
these compounds, however, relatively few data are available on
ring systems with positively charged bridge head nitrogen atom.
Four structural variations of such heteroaromatic cation can exist
as shown by Fig 1.
Figure 1. The possible heteroaromatic cations of
pyrido[1,2,4]triazinium bicycle with bridge-head nitrogen
atom
Figure 2. Transformation of zwitterions a and b to
methoxy substituted pyrido[2,1-f][1,2,4]triazinium salts c and
* Corresponding author. Institute of Organic Chemistry,
Research Center for Natural Sciences, Hungarian Academy of
Sciences. H-1117 Budapest Budapest, Magyar tudósok körútja 2.
d.
E-Mail address: hajos.gyorgy@ttk.mta.hu
On formation of the second ring system: pyrido[2,1-
f][1,2,4]triazinium cation two pieces of literature information are
available: (i) preliminary notes on its synthesis have been
published without any experimental detail8,9; (ii) zwitterions a
§Present address: H-1214 Budapest, Rákóczi F. út 268/A
1

2
and b (Figure 2) have been synthesized and treated with trimethyl
N-amination of acylketimine 6c-e with O-tosyl
ACCEPTED MANUSCRIPT
oxonium
fluoroborate
to
yield
1-methoxy-3-
hydroxylamine (TSH) gave the final product triazinium salt (4c-
e) in one manipulation step. This reaction proceeded obviously
phenylpyrido[1,2,4]triazinium fluoroborate c and 3-methoxy-1-
phenylpyrido[1,2,4]triazinium fluoroborate d, respectively10.
via formation of the N-amino intermediate
spontaneously underwent ring closure to 4.
7
which
While more detailed descriptions on the tricyclic analogues of
this ring system in patent literature have been disclosed11 due to
some valuable biological effects of these derivatives, no
preparative procedure has yet been reported on the synthesis of
the basic bicyclic heteroaromatic pyrido[2,1-f][1,2,4]triazinium
salt.
Herewith we report on the detailed synthetic route to
pyrido[2,1-f][1,2,4]triazinium salts and describe the first structure
elucidation of these compounds. We also describe the synthesis
of the partially reduced 3,4-dihydro derivatives as well as
application of this procedure for preparation of an analogous
pyrimido[2,1-f][1,2,4]triazinium salt.
Figure 3. Transformation of aromatic pyrido[2,1-f][1,2,4]-
triazinium salts (4a) to covalent hydrates (4aa). The change of
the chemical shift of C4 convincingly supports the fact of the
water addition.
2. Results and discussion
For the synthesis of the target ring system, two pathways have
been elaborated. Common starting compound of these routes was
2-cyanopyridine (1) which was reacted with a Grignard reagent.
Acidic work up of the reaction mixture afforded 2-benzoyl or 2-
p-chlorobenzoylpyridine12 (2a,b, Scheme 1). When this
compound was reacted with O-tosyl hydroxylamine (TSH)13, the
N-amino salt (3a,b) was obtained in acceptable yield (75% and
85%, respectively). Reaction of 3a,b with the appropriate amide
and phosphorus oxychloride resulted in the ring closure to the
pyrido[2,1-f][1,2,4]triazinium salts 4a,b.
When the DMSO solution of 4a was allowed to stand at room
temperature, its NMR spectrum underwent a gradual change: the
intensity of the originally observed pattern of chemical shifts
decreased and, in 3 days, a new set of signals with higher
intensity appeared. As a result of this change, the ratio of the new
and original component was found to be 5:1, approximately.
By comparison of this observation with results earlier found
with the benzologue fused isoquinolinium salt8 we had to assume
that a covalent hydration with participation of traces of water is
taking place in case of 4a as shown in Figure 3. Thus, while the
isolated 4a exists initially in the aromatic form, reaction of this
compound with water results in formation of the “hydrate salt”
4aa. Covalent hydration of various monocyclic and fused
[1,2,4]triazines was earlier known and is well documented in the
literature14,15
.
A full assignment of the two NMR spectra of these two
structures has been carried out. This revealed that the structural
change of the “aromatic salt” (4a) to “hydrate salt” (4aa) is
convincingly supported by the change of the NMR spectra:
carbon shift of C-4 appears in the aromatic species at δ 169.2,
whereas this shift is to be found at essentially higher field in the
hydrate salt (δ 76.3) because of the sp3 hybrid state of this carbon
atom. Similarly, an upfield change of the H-8 shift in the
aromatic compound (δ 9.92) to δ 8.95 in the spectrum of the
hydrate is in agreement with the decreased aromaticity of the
hydrate salt. Our efforts to isolate 4aa in pure crystalline form
unfortunately failed.
Scheme 1
Another synthetic possibility is work up of the reaction
mixture obtained from transformation of 2-cyanopyridine (1) and
Grignard reagent in the presence of ammonium chloride. In this
case extraction with organic solvent led to isolation of ketimine
5. This intermediate proved to be a pale yellow oil, it was not
purified and was transformed immediately to acylimino
derivatives (6c-e) by treatment with the appropriate acid chloride.
2

3
formamide/phosphorus oxychloride. Upon addition of
ACCEPTED MANUSCRIPT
perchloric acid, 4-(4-chlorophenyl)-6,8-dimethylpyrimido[2,1-
f][1,2,4]triazinium perchlorate 17 as a new ring system was
obtained in modest yield.
Scheme 2
A different substitution pattern of the ring closed triazinium
salt was achieved by reaction of N-amino ketone salt 3a with
urethane in the presence of phosphorus oxychloride. By this
It is important to emphasize that, in this reaction, hydrogen
cyanide is evolving as side product. This can be, however,
avoided by an alternative experimental method by using titanium
tetrachloride instead of phosphorus oxychloride as shown in the
experimental part (see Method D).
transformation,
2-chloropyrido[2,1-f][1,2,4]triazinium
perchlorate (8) was obtained in good yield. The chlorine atom in
position 2 readily underwent nucleophilic substitution with
secondary amines. Thus, 2-morpholino (9a) and 2-diethylamino
substituted salts (9b) were obtained with morpholine and
diethylamine, respectively.
3. Conclusion
In this study, a full experimental description has been reported
for the synthesis of the heteroaromatic pyrido[2,1-
f][1,2,4]triazinium salts which was earlier disclosed only in
preliminary publications. In the presence of water, formation of
covalent hydrates has been observed. Similar ring closure
reaction to 3,4-dihydropyrido[2,1-f][1,2,4]triazinium compounds
has also been elaborated. The ring closure procedure was also
An analogous ring closure reaction to that described above can
also be carried out starting from the commercially available 2-
aminomethyl- (10a) and 2-aminobenzylpyridine (10b) as starting
compounds. This procedure allows the synthesis of the 3,4-
dihydropyrido[2,1-f][1,2,4]triazinium salts. Thus, formylation of
10 with ethyl formate affords the formylaminomethyl16 (11a) and
2-formylaminobenzylpyridine (11b) which compounds upon
treatment with TSH give rise to formation of the expected 3,4-
applied for the synthesis of
a
related pyrimido[2,1-
f][1,2,4]triazinium salt.
dihydropyrido[2,1-f][1,2,4]triazinium perchlorates 13a,b.
A
plausible intermediate of this last step is formation of the N-
amino salt 12. In case of 11a an alternative cyclization route has
also been carried out: N-amination and simultaneous
deformylation with perchloric acid yielded the N-amino salt 14
which upon treatment with triethyl orthoformate gave the same
ring closed 13a.
4. Experimental section
Melting points were determined on a Büchi apparatus and are
uncorrected. The ID spectra were recorded on a Thermo Nicolet
Avatar 320 FT-IR spectrometer. NMR experiments were carried
out on Varian INOVA-300 spectrometer equipped with a 5 mm
inverse detection z-gradient probe and on 500 MHz Varian NMR
SYSTEM spectrometers. Measurements were performed at
+30°C in CDCl3 and DMSO-d6. 1H and 13C chemical shifts are
expressed in parts per million (δ) referenced to TMS or residual
solvent signals. The elemental analysis has been carried out with
the Elementar Vario EL III apparatus (at the Analytical
Laboratory for Organic Chemistry, Institute of Organic
Chemistry, Research Centre for Natural Sciences, Hungarian
Academy of Sciences, Magyar tudósok körútja 2, H-1117
Budapest, Hungary). Reactions were monitored with Merck
silica gel 60 F254 TLC plates (0.25 mm thickness). All chemicals
and solvents were used as supplied.
4.1. Ring Closure to Pyrido[2,1-f][1,2,4]triazinium salts
(4a-e)
Scheme 3
Method A: In a well ventilating hood POCl3 (6.7 g, 4 mL, 44
o
mmol) was dropped below 100 C into the stirred solution of 1-
The
ring
closure
methodology
to
pyrido[2,1-
amino-2-aroylpyridinium tosylate (3a,b, 1 mmol) in formamide
(10 mL) (Caution: HCN was liberated during the process!) and
stirring was continued for 30 min. The reaction mixture was
poured onto crushed ice, mixed with 70% HClO4 (2 mL) and
extracted with nitromethane (3 x 10 mL). The organic extract was
concentrated and the residue was recrystallized from a suitable
solvent to give the product.
f][1,2,4]triazinium salts 4 was also successfully applied for the
synthesis of the corresponding pyrimido[2,1-f][1,2,4]triazinium
salt (Scheme 4).
Method B: A mixture of 3a (0.3 g, 1 mmol) with acetamide
(0.6 g, 10 mmol) or benzamide (1.2 g, 10 mmol) in
o
polyphosphoric acid (5 g) was stirred at 170 C for 3 h. The
reaction mixture was poured on ice-water, mixed with 70%
HClO4 (1 mL) and the precipitate was filtered off, washed with
water and CCl4 to give the product.
Method C: Into a solution of the appropriate N-acylketimine
(6c-e, 10 mmol) in CH2Cl2 (5 mL) was dropped a freshly
prepared solution of TSH (1.87 g, 10 mmol) in CH2Cl2 (30 mL)
at room temperature. After being stirred for 1 h, the solvent was
Scheme 4
Thus, pyrimidyl keton 1517 was N-aminated to give the N-
amino
salt
16
which
was
then
treated
with
3

4
evaporated, the residue was mixed with POCl3 and refluxed for
10 min. The excess of the POCl3 was evaporated in vacuo, the
residue was poured into ice-water containing 70% HClO4 (2 mL)
and the precipitate was filtered off, washed with water to give the
product.
(KBr): 3100, 3060, 1590, 1550, 1495, 1440, 1395, 1100 cm-1;
ACCEPTED MANUSCRIPT
δH (500 MHz, DMSO-d6): 7.72-7.89 (6H, m), 8.07 (2H, m), 8.59
(2H, m), 8.70 (1H, m), 8.87 (2H, m), 9.94 (2H, d, J 5.2 Hz); δC
(125 MHz, DMSO-d6): 128.7, 129.3 (2C), 129.8 (2C), 130.0
(2C), 131.1 (2C), 131.6, 132.3, 133.4, 133.5, 134.3, 134.4, 142.1,
144.0, 160.0, 169.5. Starting from 3a and using Method C, 1.49 g
(39%) of white crystals were prepared, mp 265-267 oC.
4-Phenylpyrido[2,1-f][1,2,4]triazinium perchlorate (4a)
This compound was prepared by Method A to give 0.28 g
(90%) of crystals, mp 259-260 C (nitromethane-diethyl ether);
2-t-Butyl-4-phenylpyrido[2,1-f][1,2,4]triazinium perchlorate
(4e)
o
[Found: C, 50.64; H, 2.97; N, 13.62; Cl, 11.52. C13H10ClN3O4
requires C, 50.74; H, 3.28; N, 13.66; Cl, 11.52%]; IR (KBr):
3050, 1600, 1564, 1510, 1460, 1410, 1100 cm-1; UV (EtOH): 297
(4.13), 228 (4.20), shoulder: 350, 325 nm; δH (500 MHz, DMSO-
d6): 7.77 (2H, m, H3’ + H5’), 7.84 (1H, m, H4’), 7.95 (2H, m,
H2’ + H6’), 8.71 (1H, ddd, J 7.7, 6.5, 2.1 Hz, H7), 8.86 (1H, dd,
J 8.3, 2.1 Hz, H5), 8.91 (1H, ddd, J 8.3, 7.7, 1.0 Hz, H6), 9.92
(1H, dd, J 6.5, 1.0 Hz, H8), 9.95 (1H, s, H2); δC (125 MHz,
DMSO-d6): 128.3 (C5), 129.2 (C3’ + C5’), 130.5 (C2’ + C6’),
130.9 (C7), 132.7 (C1’), 132.8 (C4’), 135 .3 (C4a), 141.6 (C8),
144.3 (C6), 154.2 (C2), 169.2 (C4).
This compound was prepared by Method C; 1.49 g (41%), mp
251-253 C; [Found: C, 56.35; H, 5.20; N, 11.22. C17H18ClN3O4
o
requires C, 56.12; H, 4.99; N, 11.55%]; IR (KBr): 3090, 3050,
2970, 1575, 1560, 1480, 1440, 1090, 690 cm-1; δH (500 MHz,
DMSO-d6): 1.53 (s, 9H), 7.74 (2H, m), 7.80 (1H, m), 7.94 (2H,
m), 8.61 ((1H, t, J 7.9 Hz), 8.78-8.84 (2H, m), 9.80 (1H, d, J 5.0
Hz); δC (125 MHz, DMSO-d6): 28.4 (3C), 110.0, 128.3, 129.7
(2C), 131.0 (2C), 131.1, 133.1, 133.5, 133.8, 142.0, 144.1, 168.6,
172.4.
Phenyl-2-pyridyl (N-acyl)ketimine (6c-e).
Hydrate salt formation in solution: identification of 4-
Hydroxy-4-phenyl-3,4-dihydropyrido[2,1-f][1,2,4]triazinium
perchlorate (4aa)
General method: A solution of the appropriate acid chloride
(0.11 mol) in dry toluene (30 mL) was dropped into a stirred
solution of 5 (20 g, 0.11 mol) and triethylamine (11.1 g, 15.3 mL,
0.11 mol) in dry toluene (70 mL) at 0 C. The reaction mixture
was stirred for 1 h, filtered and the solvent was evaporated. The
residue was recrystallized to give the product.
o
δH (500 MHz, DMSO-d6): 7.48 (1H, m, H4’), 7.49 (2H, m,
H3’ + H5’), 7.55 (1H, dd, J 8.2, 1.2 Hz, H5), 7.66 (2H, m, H2’ +
H6’), 8.00 (1H, ddd, J 7.8, 6.7, 1.2 Hz, H7), 8.20 (1H, d, J 5.1
Hz, H2), 8.29 (1H, ddd, J 8.2, 7.8, 1.4 Hz, H6), 8.52 (1H s,,br,
OH), 8.95 (1H, dd, J 6.7, 1.4 Hz, H8), 10.65 (1H, d, J 5.1 Hz,
NH); δC (125 MHz, DMSO-d6): 76.3 (C4), 126.8 (C5), 127.0
(C2’ + C6’), 127.2 (C7), 128.6 (C3’ + C5’), 129.5 (C4’), 139.6
(C8), 141.9 (C1’), 142.8 (C6), 144.3 (C4a), 146.4 (C2).
Phenyl-2-pyridyl (N-acetyl)ketimine (6c)
This compound was prepared by the general procedure using
acetyl chloride as reagent to give 14.9 g (66.5%) of white
o
crystals, mp 83-85 C (diethyl ether); [Found: C, 75.24; H, 5.53;
N, 12.60. C14H12N2O requires C, 74.98; H, 5.39; N, 12.49%]; IR
(KBr): 3010, 2880, 1670, 1640, 1580, 1500, 1440 cm-1; δH (300
MHz, CDCl3) 2.12 (3H, s, CH3-N-acetyl), 7.51-7.55 (3H, m, H-
phenyl), 7.70-7.85 (4H, m H-4, H-5-pyridyl, H-phenyl), 7.93
(1H, dd, J 6.5, 2.0 Hz, H3-pyridyl), 8.69 (1H, dd, J 6.8, 1.7 Hz,
H6-pyridyl).
4-(4-Chlorophenyl)pyrido[2,1-f][1,2,4]triazinium perchlorate
(4b).
This compound was prepared using Method A to give 0.21 g
(62%) of white crystals, mp 254-255 oC (acetonitrile); [Found: C,
45.82; H, 2.71; N, 12.58. C13H9Cl2N3O4 requires C, 45.64; H,
2.65; N, 12.78%]; IR (KBr): 3020, 1610, 1590, 1500, 1430,
1400, 1100 cm-1; δH (500 MHz, DMSO-d6): 7.84 (2H, m), 7.95
(2H, m,), 8.70-8.74 (1H, m), 8.86-8.92 (1H, m), 8.91 (1H, ddd, J
8.3, 7.7, 1.0 Hz, H6), 9.92 (1H, dd, J 6.5, 1.0 Hz, H8), 9.95 (s,
1H, H2); δC (125 MHz, DMSO-d6): 128.8, 129.9 (2C), 131.5,
132.0, 132.8 (2C), 135.7, 138.5, 142.1, 144.8, 149.0, 168.4.
Phenyl-2-pyridyl (N-benzoyl)ketimine (6d)
This compound was prepared by the general procedure using
benzoyl chloride as reagent to give 25.7 g (90%) of white
crystals, mp 104-106 oC (diethyl ether / CH2Cl2 = 2 : 1) );
[Found: C, 79.92; H, 5.10; N, 9.67. C19H14N2O requires C, 79.90;
H, 4.93; N, 9.78C%]; IR (KBr): 3050, 3000, 1655, 1625, 1600,
1570, 1440, 690 cm-1; δH (300 MHz, CDCl3) 7.51-7.55 (3H, m,
H-phenyl), 7.60-7.85 (7H, m, H-phenyl, H-benzoyl), 7.74-7.79
(2H, m H-4, H-5-pyridyl), 7.90 (1H, dd, J 6.5, 2.0 Hz, H3-
pyridyl), 8.73 (1H, dd, J 6.9, 1.6 Hz, H6-pyridyl).
2-Methyl-4-phenylpyrido[2,1-f][1,2,4]triazinium perchlorate
(4c)
This compound was prepared using Method B to give 0.1 g
(31%), mp 269-271 oC (nitromethane-ethanol, white plates);
[Found: C, 52.51; H, 3.94; N, 12.88. C14H12ClN3O4 requires C,
52.27; H, 3.76; N, 13.06%]; IR (KBr): 3050, 2930, 1570, 1510,
1460, 1405, 1100 cm-1; UV (EtOH): 296 (4.09), 232 (4.23),
shoulder: 350, 325 nm; δH (500 MHz, DMSO-d6): 2.96 (3H, s,
CH3), 7.75 (1H, m), 7.83 (2H, m), 7.92 (2H, m), 8.64 (1H, t, J 7.8
Hz), 8.79-8.85 (2H, m,), 9.81 (1H, d, J 5.2 Hz, H8); δC (125
MHz, DMSO-d6): 23.4, 128.0, 129.2 (2C), 130.4 (2C), 130.8,
132.6, 132.7, 133.4, 141.0, 143.5, 164.3, 168.4. Starting from 3a
and using Method C, 1.26 g (39%) of product was prepared, mp
269-271 oC. The compound was identical with that obtained
earlier.
Phenyl-2-pyridyl (N-pivaloyl)ketimine (6e)
This compound was prepared by the general procedure using
pivaloyl chloride as reagent to give 23.1 g (79%) of white
o
crystals, mp 85-87 C (petroleum ether) ); [Found: C, 76.91; H,
6.98; N, 10.44. C17H18N2O requires C, 76.66; H, 6.81; N, 10.52
%];. IR (KBr): 3070, 3050, 2910, 1660, 1625, 1570, 1470, 1440,
690 cm-1; δH (300 MHz, CDCl3) 1.25 (9H, s, CH3-N-tBu), 7.49-
7.52 (3H, m, H-phenyl), 7.75-7.83 (4H, m H-4, H-5-pyridyl, H-
phenyl), 7.98 (1H, dd, J 6.8, 1.9 Hz, H3-pyridyl), 8.70 (1H, dd, J
7.0, 1.8 Hz, H6-pyridyl).
2,4-Diphenylpyrido[2,1-f][1,2,4]triazinium perchlorate (4d)
2-Chloro-4-phenylpyrido[2,1-f][1,2,4]triazinium perchlorate
(8)
Prepared using Method B; 0.16 g (41%), mp 265-267 oC
(acetonitrile-water, white plates); [Found: C, 59.18; H, 3.87; N,
10.70. C19H14ClN3O4 requires C, 59.46; H, 3.68; N, 10.95%; IR
A suspension of 3a (0.37 g, 1 mmol) and urethane (0.18, 2
mmol) in POCl3 (5 mL) was refluxed for 1 h. The excess of
4

5
POCl3 was evaporated in vacuo, the residue was mixed with
acetic acid (3 mL) and 70% HClO4 (0.1 mL) and diethyl ether (3
mL). The precipitate was filtered off, washed with diethyl ether
stirred at room temperature for 30 min. Then it was extracted
ACCEPTED MANUSCRIPT
with dichloromethane (3 x 2mL). The organic phase was dried
over Na2SO4, filtered and evaporated to yield the product as
yellow oil (1.117 g, quant.); IR(KBr): 3279, 2856, 1671, 1495,
699, cm-1; δH (300 MHz, CDCl3): 6.23 (1H, d, J 7.2 Hz, H1),
7.18-7.35 (7H, m, H3′, H5’, H2′′, H3′′, H4′′, H5′′, H6′′), 7.60-
7.66 (1H, m, H4’), 7.80 (1H, br. s, NH), 8.32 (1H, s, H-C=O),
8.56 (1H, d, J 4.8 Hz, H6’); δC (75 MHz, CDCl3): 56.0 (C-1),
122.6 (C-4′′), 122.8 (C-5′), 127.3 (C-2′′, C-6′′), 127.6 (C-3′),
128.7 (C-3′′, C-5′′), 137.0 (C-4′), 141.4 (C-1′′), 148.8 (C-6′′),
158.2 (C-2′), 160.2 (C=O). HRMS (ES) for C13H12N2O [M+H]+:
calcd 212.2474, found 212.2463.
o
to give 0.3 g (88%) of beige crystals, mp 274-277 C;[Found: C,
45.93; H, 2.45; N, 11.98. C13H9Cl2N3O4 requires C, 45.64; H,
2.65; N, 12.28%]; IR (KBr): 3080, 1605, 1600, 1550, 1500,
1450, 1100 cm-1; δH (500 MHz, DMSO-d6): 7.79 (2H, m, H3’ +
H5’); 7.89 (1H, m, H4’); 7.96 (2H, m, H2’ + H6’); 8.76 (1H, td, J
6.5, 3.2 Hz, H7); 8.94 (2H, m, H5 + H6); 9.95 (1H, d, J 6.5 Hz,
H8); δC (125 MHz, DMSO-d6): 129.0 (C5), 129.4 (C3’ + C5’),
130.1 (C7), 130.9 (C2’ + C6’), 131.7 (C1’), 131.8 (C4’), 133.7
(C4a), 141.5 (C8), 144.8 (C6), 159.3 (C2), 171.6 (C4).
3,4-Dihydropyrido[2,1-f][1,2,4]triazinium perchlorate (13a)
2-Morpholino-4-phenylpyrido[2,1-f][1,2,4]triazinium
perchlorate (9a)
To the solution of 1-amino-2-(ammoniomethyl)pyridin-1-ium
perchlorate and tosylate (14, 2.00 g, 5 mmol) and acetonitrile (2.5
mL), triethyl ortoformate (0.69 mL, 0.5 g, 3.3 mmol) was added
and refluxed under magnetic stirring for 3 h. After completion of
the reaction (monitored by TLC), the mixture was evaporated in
order to reduce its volume to 3 mL. HClO4 (70%, 0.5 mL) and
hot ethyl acetate (15 mL) was added to the solution, then cooled
to give colorless crystals. The product was collected by filtration
(1.0 g, 85%, mp 194-199 °C; [Found: C, 35.69; H, 3.60; N,
18.20. C7H8ClN3O4 requires C, 35.99; H, 3.45; N, 17.99%]; IR
(KBr): 3338, 3043, 1640, 1334, 1087 cm-1; δH (300 MHz,
DMSO-d6): 4.87 (2H, s, C(4)H2), 7.75-7.78 (2H, m, H2, H5),
7.87 (1H, m, H7), 8.30-8.36 (1H, dt, J 7.8, 1.2 Hz, H6), 8.67 (1H,
d, J 6.3 Hz, H8), 8.83 (1H, br. s, NH); δC (75 MHz, DMSO-d6):
37.9 (C4), 126.3 (C5), 126.8 (C7), 140.1 (C4a), 140.5 (C8),
143.1 (C6), 150.4 (C2).
A mixture of 8 (0.34 g, 1 mmol) and morpholine (0.17 g, 2
mmol) in acetonitrile (5 mL) was refluxed for 1 h. The reaction
mixture was cooled down to rt, and ethyl acetate (3 mL) was
added. The precipitate was filtered off, washed with diethyl ether
o
to give 0.30 g (76%) of yellow crystals, mp 176 C.;[Found: C,
51.72; H, 4.40; N, 14.32. C17H17ClN4O5 requires C, 51.98; H,
4.36; N, 14.26%]; δH (500 MHz, DMSO-d6) : 3.80 (4H, t, J 4.6
Hz, N-CH2), 3.96 (4H, br. s, O-CH2), 7.72 (2H, m, H3’ + H5’),
7.78, (1H, m, H4’), 7.88 ( 2H, m, H2’ + H6’), 8.34 (1H, ddd, J
7.2, 6.4, 1.7 Hz, H7), 8.37 (1H, ddd, J 8.2, 7.2, 1.3 Hz, H6), 8.45
(1H, dd, J 8.2, 1.7 Hz, H5), 9.32 (1H, dd, J 6.4, 1.3 Hz, H8); δC
(125 MHz, DMSO-d6): 44.2 (N-CH2), 66.0 (O-CH2), 127.9 (C5),
129.0 (C3’ + C5’), 130.1 (C2’ + C6’), 130.5 (C7), 131.3 (C4a),
132.4 (C4’), 132.9 (C1’), 137.9 (C8), 138.8 (C6), 156.7 (C2),
168.0 (C4).
4-Phenyl-3,4-dihydropyrido[2,1-f][1,2,4]triazinium
perchlorate (13b)
2-Diethylamino-4-phenylpyrido[2,1-f][1,2,4]triazinium
perchlorate (9b)
To the solution of N-(phenyl(pyridin-2-yl)methyl)formamide
(11b, 0.25 g, 1.1 mmol) in dichloromethane (2 mL) was cooled
down to 0 °C solution of TSH (0.21 g) in dichloromethane (6
mL) was added under magnetic stirring at 0 °C for 30 min. The
reaction mixture was allowed to warm up to rt and maintained at
this temperature for 3 h. HClO4 (70%, 1 mL) was added to the
mixture, stirred for further 3 h. After completion of the reaction
(2 d, without magnetic stirring), the precipitated product was
filtered off as white crystals (0.33 g, 79%, mp 116-120 °C; IR
(KBr): 3387, 1633, 1490, 1085, 625 cm-1; δH (300 MHz, DMSO -
d6): 6.28 (1H, br. s, H4), 7.39-7.46 (5H, m, H2′, H3′, H4′, H5′,
H6’), 7.73 (1H, d, J 7.8 Hz, H5), 7.89 (1H, m, H7), 8.01 (1H, d, J
4.8 Hz, H2), 8.29 (1H, m, H6), 8.78 (1H, d, J 6.6 Hz, H8), 9.70
(1H, br. s, NH); δC (75 MHz, DMSO-d6): 51.1 (C4), 127.1 (C7),
127.2 (C5), 127.3 (C2′, C6′), 129.5 (C3′, C4′, C5′), 140.7 (C8),
140.9 (C4a), 141.9 (C1′), 143.5 (C6), 149.2 (C2).
A mixture of 8 (0.34 g, 1 mmol) and diethylamine (0.15 g, 2
mmol) in acetonitrile (5 mL) was refluxed for 1 h. The reaction
mixture was cooled down to rt, and ethyl acetate (3 mL) was
added. The precipitate was filtered off, washed with diethyl ether
o
to give 0.28 g (74%) of yellow crystals, mp 164-165 C.;[Found:
C, 53.78; H, 5,01; N, 14.81. C17H19ClN4O4 requires C, 53.90; H,
5.06; N, 14.79%]; δH (500 MHz, DMSO-d6) (ppm): 1.25 (3H, t, J
6.4 Hz, N-CH2-CH3), 1.32 (3H, t, J 6.4 Hz, N-CH2-CH3), 3.75
(2H, q, J 6.4 Hz, N-CH2-CH3), 3.82 (2H, q, J 6.4Hz, N-CH2-
CH3), 7.71 (2H, m, H3’ + H5’), 7.78 (1H, m, H4’), 7.86 (2H, m,
H2’ + H6’), 8.29 (1H, ddd, J 7.3, 5.9, 1.6 Hz, H7), 8.31 (1H, ddd,
J 8.2, 7.3, 1.2 Hz, H6), 8.39 (1H, dd, J 8.2, 1.6 Hz, H5), 9.29
(1H, dd, J 5.9, 1.2 Hz, H8); δC (125 MHz, DMSO-d6): 11.8 +
13.4 (N-CH2-CH3), 42.4 (N-CH2-CH3), 127.7 (C5), 129.0 (C3’ +
C5’), 129.9 (C2’ + C6’), 130.2 (C7), 131.2 (C4a), 132.1 (C4’),
133.2 (C1’), 137.1 (C8), 138.6 (C6), 156.4 (C2), 167.6 (C4).
1-Amino-2-(ammoniomethyl)pyridinium tosylate perchlorate
(14)
The mixture of N-(pyridin-2-ylmethyl)formamide (11a, 1.40
g, 10.28 mmol) and dichloromethane (10 mL) was cooled down
at 0 °C in a round-bottomed flask, then the solution of TSH (0.73
g) in dichloromethane (30 mL) was added under magnetic stirring
at 0 °C for 30 min. The reaction mixture was allowed to warm up
to rt and maintained at this temperature for 3 h. HClO4 (70%, 1
mL) was added to the mixture, stirred for further 3 h. After
completion of the reaction (2 d, without magnetic stirring), the
mixture was concentrated under reduced pressure. The residue
was diluted with acetonitrile (20 mL) and water (1 mL) and
heated. Hot ethyl acetate (10 mL) was added dropwise to the
solution, then it was cooled down, whereupon a solid product
N-(Pyridin-2-ylmethyl)formamide (11a)
A solution of pyridin-2-ylmethanamine (10a, 10.8 g, 10.3
mmol) and ethyl formate was heated under reflux with magnetic
stirring for 1.5 h. After completion of the reaction, the resulting
mixture was evaporated to give the final product 14 as yellow oil,
13.5 g (quant.)14.
N-(phenyl(pyridin-2-yl)methyl)formamide (11b)
To phenyl(pyridin-2-yl)methanamine hydrochloride (10b,
1.167 g, 5.28 mmol) an aqueous solution of sodium hydroxide
(0.217 g, 5.42 mmol in 2 mL) was added, and the mixture was
5

6
deposited. The product was collected by filtration as colorless
ACCEPTED MANUSCRIPT
crystals (2.76 g, 68%, mp 192-195 °C); [Found: C, 39.12; H,
4.74; N, 10.37. C13H18ClN3O7S requires C, 39.45; H, 4.58; N,
10.62%]; IR (KBr): 3307, 2930, 1505, 1209, 1084 cm-1; δH (300
MHz, DMSO-d6): 2.28 (3H, s, CH3), 4.53 (2H, m, CH2), 7.12
(2H, m, H3′, H5′), 7.45 (2H, m, H2′, H6′), 8.04-8.08 (7H, m, H3,
H5, NH2, +NH3), 8.47 (1H, m, H4), 8.95 (1H, d, J 6.0 Hz, H6); δC
(75 MHz, DMSO-d6): 20.8 (CH3), 38.2 (CH2), 125.4 (C2′, C6′),
127.8 (C3, C5), 128.2 (C3′, C5′), 137.9 (C4′), 141.8 (C6), 142.4
(C4), 145.1 (C1′), 146.6 (C2).
Dedication
This paper is cordially dedicated to Professor Leon Ghosez for
acknowledgment of his long lasting successful and high level
activity at Tetrahedron.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/
1-Amino-2-(4-chlorobenzoyl)-4,6-dimethylpyrimidinium
tosylate (16)
A freshly prepared solution of TSH (1.14 g, 6.1 mmol) in
dichloromethane (50 mL) was added to a stirred solution of (4-
chlorophenyl)(4,6-dimethylpyrimidin-2-yl)methanone (15)15 (1.5
g, 6.1 mmol) in dichloromethane (20 mL) at 0 °C. The reaction
mixture was stirred for 30 min, then it was allowed to warm up to
rt. After completion of the rection (3 h), diethyl ether was added
to the solution, the precipitated crystals were filtered off and
recrystallized from acetonitrile to give the product as white-
yellow crystals (1.27 g, 48%, mp 174-176 °C); [Found: C, 55.10;
H, 4.41; N, 9.35; S, 7.67. C20H20ClN3O4S requires C, 55.36; H,
4.65; N, 9.68; S, 7.38%]; IR (KBr): 3218, 3100, 1689, 1221,
1010 cm-1; δH (300 MHz, DMSO-d6): 2.29 (1H, s, CH3 (TsO)),
2.74 (3H, s, 4-CH3), 2.85 (3H, s, 6-CH3), 7.11 (2H, m, H-3'', H-
5''), 7.23 (1H. br. s, NH2), 7.46 (2H, m, H-2'', H-6''), 7.68 (2H, m,
H-3', H-5'), 7.99 (2H, m, H-2', H-6'), 8.28 (1H, br. s, H-5); δC (75
MHz, DMSO-d6): 18.5 (CH3-(TsO)), 20.8 (6-CH3), 24.4 (4-CH3),
124.9 (C-5), 125.5 (C-2'', C-6''), 128.0 (C-3'', C-5''), 129.6 (C-3',
C-5'), 131.5 (C-4'), 137.7 (C-2', C-6'), 137.7 (C-4''), 140.9 (C-1'),
145.5 (C-1''), 156.9 (C-2), 166.4 (C-4, C-6), 174.4 (C=O).
References and notes
1. Neunhoeffer H. “1,2,4-Triazines and their Benzo Derivatives” in
Comprehensive Heterocyclic Chemistry II in; Katritzky, A. R.,
Rees Ch. W. and Scriven E. F. V ed.; Elsevier, 1996; pp 507-573.
2. Prokhorov, A. N. P., Kozhevnikov, D. M.: Triazines, Tetrazines
and Fused Ring Polyaza Systems” in Progress in Heterocyclic
Chemistry, Elsevier: Amsterdam 2011, pp 403-425.
3. Baranova N. V, Sheinkman A. K, Kost A. K. Khim. Geterocycl.
Chem. 1970: 1148.
4. Baranova N. V, Sheinkman A. K, Kost A. K. Khim. Geterocycl.
Chem. 1973:1266.
5. Hajós Gy, Riedl Zs, Gács-Baitz E, Messmer A. Tetrahedron 1992;
48: 8459.
6. Valenciano J, Sanchez-Pavon E, Cuadro A. M, Alvarez-Builla J,
Vaquero, J. Eur. J. Org. Chem. 2007; 15:2423.
7. Szökő E, Kalász H, Kerecsen L, Magyar K. Polish J.
Pharmacology and Pharmacy 1987; 39:177.
8. Hajós Gy, Messmer A, Bátori S, Riedl Zs. Bull. Soc. Chim. Belg.,
1992; 101:597.
9. Messmer, A. Bátori, S. Hajós, Gy. Benkó, P. Pallos, L. Petőcz, L.
A new class of antidepressants: differently fused benzologues of
L. pyrido[2,1-f]-as-triazinium salts. In "Trends in Medicinal
Chemistry" 88, van der Goot H., Domány G., Pallos, L.
Timmerman, H. Ed. Elsevier: Amsterdam 1989; pp 453-466.
10. Bátori S, Juhász-Riedl Zs, Sándor P, Messmer A. J. Heterocyclic
Chem. 1986; 23:375.
4-(4-Chlorophenyl)-6,8-dimethylpyrimido[2,1-
f][1,2,4]triazinium perchlorate (17)
Method A: POCl3 (15 mL) was dropped into a stirred solution
o
of 7 (5 g, 11.5 mmol) in formamide (25 mL) at 80 C (Caution:
HCN was liberated throughout the process!). Stirring was
continued at 80 oC for 1 h and poured on ice-water. The solution
was mixed with 70% HClO4 (0.5 mL) and extracted with
nitromethane (3 x 15 mL). Charcoal was added to the organic
extract and it was dried over MgSO4, filtered and the solvent was
evaporated. The residue was recrystallized from acetonitrile-ethyl
acetate to give pale yellow crystals (0.7 g, 16%, mp 172-174 °C;
[Found: C, 45.52; H, 3.54; N, 14.88. C14H12Cl2N4O4 requires C,
45.30; H, 3.26; N, 15.09% ]; IR (KBr, cm-1): 3420, 3073, 1630,
1478, 1095; δH (300 MHz, CD3CN): 2.97 (3H, s, 6-CH3), 3.07
(3H, s, 8-CH3), 7.69 (2H, m, H3', H5'), 8.34 (1H, s, H7), 8.44
(2H, m, H2', H6'), 9.67 (1H, s, H2); δH (75 MHz, CD3CN): 19.4
(8-CH3), 26.0 (6-CH3), 127.7 (C7), 130.0 (C3', C5'), 131.7 (C4'),
134.2 (C2), 134.9 (C2', C6'), 141.3 (C1'), 160.0 (C6, C8), 167.5
(C4a), 176.2 (C4).
11. a, Messmer A., Bátori, S. Hajós, Gy., Benkó, P., Furdyga, É.,
Petőcz, L., Grasser, I., Szirtné Kiszely, E., Hung. Pat. 190504,
Chem. Abstr. 1985; 103: 37503. b, Messmer, A. Bátori, S., Hajós,
Gy., Benkó, P., Pallos, L., Petőcz, L., Grasser, I., Szirt, E., Belg.
Pat. BE 900,599; Chem. Abstr. 1985; 103:37502
12. Yang H, Huo N, Yang P, Pei H, Lv H, Zhang X. Org. Lett. 2015;
17: 4144.
13. Glover E. E, Rowbottom K. T, J. Chem. Soc. Perkin Trans. 1
1976: 368.
14. Paudler W W, Chen T-K, J Heterocyclic Chem. 1970; 7:769.
15. Albert A. Adv. Heterocyclic Chem, 1976; 20:117.
16. Brahmachari G, Laskar S, Tetrahedron Lett. 2010; 51: 2319.
17. Bátori S, Messmer A, J. Heterocyclic Chem. 1994; 31: 1041
Method D: TiCl4 (3.8 g, 2.2 mL, 20 mmol) was dropped into
dioxane (10 mL) under stirring at 25 ±10 oC. N-
aminopyrimidinium salt 16 (5 mmol) was added to the yellow
suspension and it was heated up to 95 oC. Formamide (3 mL) was
added to the reaction mixture and it was refluxed for 30 min.
Water (30 mL) and 70% HClO4 (5 mL) were added to the cooled
reaction mixture and the resulting solution was extracted with
nitromethane (3 x 30 mL). The combined organic extract was
evaporated to dryness, the residue was recrystallized from a
mixture of acetonitrile-ethyl acetate to give pale yellow crystals
(0.96 g (52%).
The compound was identical with that obtained by method A.
6